8	31700844	In conjunctival melanoma, nuclear localization and activation of beta-catenin appear to be limited, suggesting that inhibition of ARF6, responsible for beta-catenin activation, in subsets of skin melanoma may not represent a treatment option for this tumor.	('tumor', 'Disease', (251, 256))	('inhibition', 'Var', (116, 126))	('ARF6', 'Gene', (130, 134))	('beta-catenin', 'Gene', '1499', (65, 77))	('localization', 'biological_process', 'GO:0051179', ('34', '46'))	('beta-catenin', 'Gene', (152, 164))	('conjunctival melanoma', 'Disease', (3, 24))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (3, 24))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (3, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('beta-catenin', 'Gene', '1499', (152, 164))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('ARF6', 'Gene', '382', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('skin melanoma', 'Disease', 'MESH:D008545', (191, 204))	('skin melanoma', 'Disease', (191, 204))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('beta-catenin', 'Gene', (65, 77))
16	31700844	Recent evidence suggests that cutaneous melanomas and CM have similar molecular features, notably similar mutations in driver genes such as BRAF, NRAS, and NF1.	('NF1', 'Gene', (156, 159))	('cutaneous melanomas', 'Disease', (30, 49))	('NRAS', 'Gene', '4893', (146, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('NF1', 'Gene', '4763', (156, 159))	('CM', 'Phenotype', 'HP:0007716', (54, 56))	('BRAF', 'Gene', '673', (140, 144))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BRAF', 'Gene', (140, 144))	('mutations', 'Var', (106, 115))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('CM', 'Disease', 'MESH:D003229', (54, 56))	('NRAS', 'Gene', (146, 150))
20	31700844	In the canonical Wnt pathway, the presence of specific Wnt ligands, notably Wnt1 and Wnt3a, leads to cytoplasmic accumulation of beta-catenin through preservation from proteasomal degradation.	('proteasomal degradation', 'MPA', (168, 191))	('Wnt1', 'Gene', '7471', (76, 80))	('Wnt3a', 'Gene', (85, 90))	('degradation', 'biological_process', 'GO:0009056', ('180', '191'))	('beta-catenin', 'Gene', '1499', (129, 141))	('beta-catenin', 'Gene', (129, 141))	('canonical Wnt pathway', 'Pathway', (7, 28))	('Wnt3a', 'Gene', '89780', (85, 90))	('Wnt1', 'Gene', (76, 80))	('presence', 'Var', (34, 42))
31	31700844	These data suggest that inhibition of ARF6 may be a way to inhibit the Wnt/beta-catenin pathway in melanoma.	('beta-catenin', 'Gene', '1499', (75, 87))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('inhibition', 'Var', (24, 34))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('ARF6', 'Gene', (38, 42))	('beta-catenin', 'Gene', (75, 87))	('melanoma', 'Disease', (99, 107))	('inhibit', 'NegReg', (59, 66))	('ARF6', 'Gene', '382', (38, 42))
45	31700844	Four CM cell lines were used: T1527A, which has been established at our institution with BRAFG466E and HRASQ61R mutations; CM2005.1 and CRMM1, both with BRAFV600E mutations; and CRMM2 with an NRASQ61L mutation.	('CM', 'Disease', 'MESH:D003229', (123, 125))	('BRAF', 'Gene', (153, 157))	('T1527A', 'Mutation', 'c.1527T>A', (30, 36))	('BRAFV600E', 'Mutation', 'rs113488022', (153, 162))	('CM', 'Phenotype', 'HP:0007716', (5, 7))	('HRASQ61R', 'Gene', (103, 111))	('mutations', 'Var', (112, 121))	('BRAF', 'Gene', '673', (89, 93))	('NRAS', 'Gene', (192, 196))	('CM', 'Phenotype', 'HP:0007716', (123, 125))	('BRAF', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (192, 196))	('BRAF', 'Gene', '673', (153, 157))	('CM', 'Disease', 'MESH:D003229', (5, 7))
77	31700844	The Wnt pathway is not only involved in embryological development but also in the pathogenesis of various tumors, notably in colon adenocarcinoma, where deleterious APC mutations lead to beta-catenin activation.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('mutations', 'Var', (169, 178))	('colon adenocarcinoma', 'Disease', (125, 145))	('APC', 'Gene', (165, 168))	('tumors', 'Disease', (106, 112))	('beta-catenin', 'Gene', (187, 199))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (125, 145))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('beta-catenin', 'Gene', '1499', (187, 199))	('APC', 'Gene', '324', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('APC', 'cellular_component', 'GO:0005680', ('165', '168'))	('activation', 'PosReg', (200, 210))
118	29963229	Low frequency variants conferring moderate risk of melanoma were identified in two genes, MC1R and MITF, which play a key role in melanocyte biology and pigment synthesis regulation.	('regulation', 'biological_process', 'GO:0065007', ('171', '181'))	('pigment synthesis', 'biological_process', 'GO:0046148', ('153', '170'))	('variants', 'Var', (14, 22))	('MITF', 'Gene', (99, 103))	('MITF', 'Gene', '4286', (99, 103))	('MC1R', 'Gene', '4157', (90, 94))	('MC1R', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('pig', 'Species', '9823', (153, 156))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
119	29963229	Recently, genome-wide association studies have highlighted common genetic variants associated with melanoma risk, at loci containing genes involved in pigmentation and naevus count (e.g.	('pigmentation', 'Disease', 'MESH:D010859', (151, 163))	('pigmentation', 'Disease', (151, 163))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('naevus', 'Phenotype', 'HP:0003764', (168, 174))	('associated', 'Reg', (83, 93))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('variants', 'Var', (74, 82))	('pigmentation', 'biological_process', 'GO:0043473', ('151', '163'))
131	29963229	This allele carries a coding variation equivalent to the Sombre mutation in the mouse (Leu102Pro in pigs, corresponding to Leu98Pro in mice).	('Leu98Pro', 'SUBSTITUTION', 'None', (123, 131))	('Leu102Pro', 'Var', (87, 96))	('mouse', 'Species', '10090', (80, 85))	('mice', 'Species', '10090', (135, 139))	('Leu102Pro', 'SUBSTITUTION', 'None', (87, 96))	('pigs', 'Species', '9823', (100, 104))	('Leu98Pro', 'Var', (123, 131))
132	29963229	We therefore hypothesized that this variant, if leading to a constitutive MC1R receptor as seen with the Sombre mutant, could influence melanoma penetrance and worsen the phenotype of animals carrying the MC1R*2 allele.	('MC1R', 'Gene', '4157', (74, 78))	('worsen', 'NegReg', (160, 166))	('variant', 'Var', (36, 43))	('phenotype', 'CPA', (171, 180))	('influence', 'Reg', (126, 135))	('MC1R', 'Gene', '4157', (205, 209))	('MC1R', 'Gene', (205, 209))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('MC1R', 'Gene', (74, 78))	('constitutive', 'MPA', (61, 73))
146	29963229	The third SSC5 region extended over 2 Mb (between 55 and 57 Mb), with the best SNP located within the PLEKHA5 (Pleckstrin Homology Domain Containing A5) gene (DRGA0005864, p-value = 1.99 x 10-5), recently described as a mediator of distant melanoma metastasis in the brain.	('melanoma metastasis', 'Disease', (240, 259))	('DRGA0005864', 'Var', (159, 170))	('PLEKHA5', 'Gene', (102, 109))	('melanoma metastasis', 'Disease', 'MESH:D009362', (240, 259))	('PLEKHA5', 'Gene', '54477', (102, 109))	('Pleckstrin Homology Domain Containing A5', 'Gene', (111, 151))	('Pleckstrin Homology Domain Containing A5', 'Gene', '54477', (111, 151))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))
158	29963229	In the first region (SSC7: 16354696-16407894bp), the top SNP ASGA0031451 is located between ID4 (Inhibitor of DNA Binding 4, HLH Protein) and MBOAT1 (Membrane Bound O-Acyltransferase Domain Containing 1) and reached a p-value of 1.37 x 10-5.	('ASGA0031451', 'Var', (61, 72))	('Membrane Bound O-Acyltransferase Domain Containing 1', 'Gene', '154141', (150, 202))	('ID4', 'Gene', (92, 95))	('MBOAT1', 'Gene', '154141', (142, 148))	('ID4', 'Gene', '3400', (92, 95))	('Inhibitor of DNA Binding 4', 'Gene', '3400', (97, 123))	('DNA', 'cellular_component', 'GO:0005574', ('110', '113'))	('MBOAT1', 'Gene', (142, 148))	('DNA Binding', 'molecular_function', 'GO:0003677', ('110', '121'))	('Inhibitor of DNA Binding 4', 'Gene', (97, 123))
160	29963229	DST codes for the dystonin protein, involved in keratinocyte integrity and mutated in a specific subtype of Epidermolysis Bullosa simplex.	('dystonin', 'Gene', (18, 26))	('Epidermolysis Bullosa simplex', 'Disease', (108, 137))	('DST', 'Gene', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('mutated', 'Var', (75, 82))	('dystonin', 'Gene', '667', (18, 26))
168	29963229	The most significant marker was found on SSC8 (ALGA0114256, p = 1.09 x 10-9), and comparative genomics indicates that it is located in a sequence predicted to be the first intron of the HERC3 gene.	('HERC3', 'Gene', (186, 191))	('HERC3', 'Gene', '8916', (186, 191))	('ALGA0114256', 'Var', (47, 58))
176	29963229	Another cross-species comparison between human and porcine genomes indicated that the SNP MARC0004732 on SSC13 (133415925) can be annotated as a non-synonymous coding variant of the ETV5 (ERM-related molecule) gene.	('ETV5', 'Gene', (182, 186))	('SSC1', 'Gene', (105, 109))	('human', 'Species', '9606', (41, 46))	('SSC1', 'Gene', '366', (105, 109))	('MARC0004732', 'Var', (90, 101))
177	29963229	This polymorphism corresponds to a Tyr271Cys modification, and is predicted as a deleterious variant in humans (rs770229110).	('rs770229110', 'Mutation', 'rs770229110', (112, 123))	('Tyr271Cys', 'Var', (35, 44))	('rs770229110', 'Var', (112, 123))	('Tyr271Cys', 'SUBSTITUTION', 'None', (35, 44))	('humans', 'Species', '9606', (104, 110))
183	29963229	For example, KRAS (KRAS Proto-Oncogene, GTPase) is also located in the SSC5 interval containing PLEKHA5 and is an appealing candidate for melanoma development since RAS proteins frequently undergo somatic or even germline mutations in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('RAS proteins', 'Protein', (165, 177))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('undergo', 'Reg', (189, 196))	('PLEKHA5', 'Gene', (96, 103))	('melanoma', 'Disease', (235, 243))	('germline mutations', 'Var', (213, 231))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('PLEKHA5', 'Gene', '54477', (96, 103))
190	29963229	Out of 20 orthologues of human melanoma-associated loci, 12 contained SNPs with p-values < 10-2 in the MeLiM model, and 6 of them had SNPs reaching a p-value < 10-3: CDKAL1 on SSC7, FTO on SSC6, PLA2G6 on SSC5, TMEM38B-RAD23B on SSC1 and SLC45A2 and TERT on SSC16.	('SLC45A2', 'Gene', (238, 245))	('CDKAL1', 'Var', (166, 172))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('TMEM38B', 'Gene', '55151', (211, 218))	('TMEM38B', 'Gene', (211, 218))	('PLA2G6', 'Gene', '8398', (195, 201))	('SSC1', 'Gene', '366', (258, 262))	('RAD23B', 'Gene', '5887', (219, 225))	('RAD', 'biological_process', 'GO:1990116', ('219', '222'))	('human', 'Species', '9606', (25, 30))	('RAD23B', 'Gene', (219, 225))	('SSC1', 'Gene', (258, 262))	('FTO', 'Gene', '79068', (182, 185))	('FTO', 'Gene', (182, 185))	('PLA2G6', 'Gene', (195, 201))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('SLC45A2', 'Gene', '51151', (238, 245))	('SSC1', 'Gene', '366', (229, 233))	('SSC1', 'Gene', (229, 233))
216	29963229	Also, melanoma ulceration is considered as one of the predictors of poor prognosis in patients, hence more precise molecular characterization would be beneficial, notably by focusing on germline variants influencing melanoma ulceration.	('melanoma ulceration', 'Disease', (216, 235))	('melanoma ulceration', 'Disease', 'MESH:D014456', (216, 235))	('variants', 'Var', (195, 203))	('melanoma ulceration', 'Disease', (6, 25))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma ulceration', 'Disease', 'MESH:D014456', (6, 25))	('patients', 'Species', '9606', (86, 94))
225	29963229	Also, in colorectal cancer cells, CBY1 knockdown has been shown to promote mesenchymal to epithelial transition.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('colorectal cancer', 'Disease', (9, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('knockdown', 'Var', (39, 48))	('promote', 'PosReg', (67, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('mesenchymal to epithelial transition', 'biological_process', 'GO:0060231', ('75', '111'))	('CBY1', 'Gene', '25776', (34, 38))	('mesenchymal to epithelial transition', 'CPA', (75, 111))	('CBY1', 'Gene', (34, 38))
231	29963229	Indeed, an appealing genetic model in the MeLiM pig would be a dual action of germline variants on melanoma occurrence and regression, since all animals affected regress completely and spontaneously without intervention.	('variants', 'Var', (87, 95))	('pig', 'Species', '9823', (48, 51))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
243	29963229	Indeed, DICER knocked-down tumors had a slower growth than controls, due to a more immunogenic phenotype of cells.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('more', 'PosReg', (78, 82))	('slower', 'NegReg', (40, 46))	('growth', 'MPA', (47, 53))	('DICER', 'Gene', '23405', (8, 13))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('knocked-down', 'Var', (14, 26))	('DICER', 'Gene', (8, 13))
246	29963229	To finish with, one of the essential characteristics of a tumor is a facilitated proliferation, most familial melanomas being mutated in CDKN2A or CDK4 thus enhancing cell divisions.	('cell divisions', 'CPA', (167, 181))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('tumor', 'Disease', (58, 63))	('enhancing', 'PosReg', (157, 166))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('CDK', 'molecular_function', 'GO:0004693', ('147', '150'))	('familial melanomas', 'Disease', (101, 119))	('familial melanomas', 'Disease', 'OMIM:155600', (101, 119))	('CDKN2A', 'Gene', (137, 143))	('CDKN2A', 'Gene', '1029', (137, 143))	('CDK4', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('CDK4', 'Gene', '1019', (147, 151))	('mutated', 'Var', (126, 133))
292	29963229	BC Backcross GWAS Genome-Wide Association Study HSA Homo sapiens chromosome LD Linkage Desequilibrium MAF Minimum Allele Frequency MeLiM Melanoblastoma-bearing Libechov Minipig QTL quantitative trait locus SLA Swine Leucocyte Antigen system SNP Single Nucleotide Polymorphism SSC Sus scrofa chromosome	('Homo sapiens', 'Species', '9606', (52, 64))	('HSA', 'Gene', (48, 51))	('Swine', 'Species', '9823', (210, 215))	('Melanoblastoma', 'Disease', (137, 151))	('Single Nucleotide Polymorphism', 'Var', (245, 275))	('Sus scrofa', 'Species', '9823', (280, 290))	('pig', 'Species', '9823', (173, 176))	('Melanoblastoma', 'Disease', 'None', (137, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('291', '301'))	('HSA', 'Gene', '213', (48, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
300	32468052	We have expanded on our observations by including data relating to mutations and copy number alterations at pan-cancer level.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('copy number alterations', 'Var', (81, 104))
302	32468052	Based on increasing data, older age and male sex predispose to severe COVID-19, whilst a number of underlying diseases/conditions are also directly related with significantly higher risk for adverse clinical outcomes from COVID-19.	('severe', 'Var', (63, 69))	('COVID-19', 'Disease', (70, 78))	('COVID-19', 'Disease', 'MESH:C000657245', (222, 230))	('COVID-19', 'Disease', (222, 230))	('COVID-19', 'Disease', 'MESH:C000657245', (70, 78))
322	32468052	Furthermore, using the cBioportal pan-cancer panel, the region and the types of mutations were identified which these two genes have in all the examined cancer types (Figs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (38, 44))
323	32468052	Most of the CTSL mutations are lying on the peptidase region and are mostly found in CESC, ESCA, Mature B-cell Neoplasms, Melanoma and COAD (Fig.	('ESCA', 'Disease', (91, 95))	('B-cell Neoplasms', 'Disease', 'MESH:D016393', (104, 120))	('Melanoma', 'Disease', 'MESH:D008545', (122, 130))	('Melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('found', 'Reg', (76, 81))	('COAD', 'Disease', 'MESH:D029424', (135, 139))	('CTSL', 'Gene', '1514', (12, 16))	('Melanoma', 'Disease', (122, 130))	('B-cell Neoplasms', 'Disease', (104, 120))	('CTSL', 'Gene', (12, 16))	('Neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('CESC', 'Disease', (85, 89))	('COAD', 'Disease', (135, 139))	('mutations', 'Var', (17, 26))
324	32468052	Of note, in most of the cancers the majority of the patients had deletions and partly some gains and amplifications (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gains', 'PosReg', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('deletions', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('patients', 'Species', '9606', (52, 60))
325	32468052	TMPRSS2 mutations were lying across the whole gene region and mostly consist of gene fusions (TMPRSS2-ERG) in prostate adenocarcinoma (Fig.	('TMPRSS2', 'Gene', '7113', (94, 101))	('prostate adenocarcinoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (110, 133))	('TMPRSS2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('TMPRSS2', 'Gene', (94, 101))	('consist', 'Reg', (69, 76))	('TMPRSS2', 'Gene', '7113', (0, 7))
328	32468052	Of note, neither of the two proteins were differentially regulated in LUAD; a comorbidity of severe COVID-19 contrary to ACE-2.	('ACE-2', 'Gene', '59272', (121, 126))	('LUAD', 'Disease', (70, 74))	('severe', 'Var', (93, 99))	('ACE-2', 'Gene', (121, 126))	('COVID-19', 'Disease', 'MESH:C000657245', (100, 108))	('COVID-19', 'Disease', (100, 108))
333	32468052	In our analysis we also demonstrate that the pancreas is riddled with deep deletions for TMPRSS2 where ACE-2 is co-expressed.	('ACE-2', 'Gene', '59272', (103, 108))	('deletions', 'Var', (75, 84))	('TMPRSS2', 'Gene', (89, 96))	('TMPRSS2', 'Gene', '7113', (89, 96))	('ACE-2', 'Gene', (103, 108))
346	30431060	The results demonstrated that CDCA8 was overexpressed in cutaneous melanoma tissues and cells lines compared with normal tissues, and high expression of CDCA8 was significantly associated with poorer prognosis in patients with cutaneous melanoma.	('si', 'Chemical', 'MESH:D012825', (145, 147))	('patients', 'Species', '9606', (213, 221))	('CDCA8', 'Gene', (153, 158))	('poorer', 'NegReg', (193, 199))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('CDCA8', 'Gene', '55143', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('cutaneous melanoma', 'Disease', (227, 245))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (227, 245))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (227, 245))	('high expression', 'Var', (134, 149))	('cutaneous melanoma tissues', 'Disease', (57, 83))	('overexpressed', 'PosReg', (40, 53))	('cutaneous melanoma tissues', 'Disease', 'MESH:C562393', (57, 83))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('CDCA8', 'Gene', '55143', (153, 158))	('associated', 'Reg', (177, 187))	('CDCA8', 'Gene', (30, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))
347	30431060	In in vitro experiments, CDCA8 knockdown inhibited A375 and MV3 cell proliferation, migration and invasion.	('CDCA8', 'Gene', (25, 30))	('A375', 'CellLine', 'CVCL:0132', (51, 55))	('invasion', 'CPA', (98, 106))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('CDCA8', 'Gene', '55143', (25, 30))	('inhibited', 'NegReg', (41, 50))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('knockdown', 'Var', (31, 40))
348	30431060	In addition, CDCA8 knockdown reduced the phosphorylation levels of ROCK1 and myosin light chain, two downstream effector proteins of the ROCK pathway.	('myosin light chain', 'Gene', (77, 95))	('CDCA8', 'Gene', '55143', (13, 18))	('phosphorylation', 'biological_process', 'GO:0016310', ('41', '56'))	('ROCK1', 'Gene', '6093', (67, 72))	('ROCK1', 'Gene', (67, 72))	('knockdown', 'Var', (19, 28))	('myosin light chain', 'Gene', '23209', (77, 95))	('reduced', 'NegReg', (29, 36))	('phosphorylation levels', 'MPA', (41, 63))	('CDCA8', 'Gene', (13, 18))
413	30431060	The overall survival time of patients with high CDCA8 expression was significantly shorter, suggesting that CDCA8 expression might be a prognostic marker in cutaneous melanoma patients.	('expression', 'MPA', (54, 64))	('cutaneous melanoma', 'Disease', (157, 175))	('patients', 'Species', '9606', (29, 37))	('patients', 'Species', '9606', (176, 184))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('high', 'Var', (43, 47))	('CDCA8', 'Gene', '55143', (48, 53))	('CDCA8', 'Gene', (108, 113))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('shorter', 'NegReg', (83, 90))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('CDCA8', 'Gene', '55143', (108, 113))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('CDCA8', 'Gene', (48, 53))
426	30431060	Firstly, cell proliferation activity was examined following CDCA8 knockdown in A375 and MV3 cells using CCK-8 and colony formation assays.	('cell proliferation', 'biological_process', 'GO:0008283', ('9', '27'))	('A375', 'CellLine', 'CVCL:0132', (79, 83))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('CDCA8', 'Gene', (60, 65))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('knockdown', 'Var', (66, 75))	('CDCA8', 'Gene', '55143', (60, 65))
429	30431060	The present results demonstrated that knockdown of CDCA8 suppressed the proliferation of cutaneous melanoma cells.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('CDCA8', 'Gene', (51, 56))	('CDCA8', 'Gene', '55143', (51, 56))	('suppressed', 'NegReg', (57, 67))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('knockdown', 'Var', (38, 47))	('cutaneous melanoma', 'Disease', (89, 107))
430	30431060	Next, wound healing was performed to examine the migration speed of A375 and MV3 cells following CDCA8 knockdown.	('wound healing', 'biological_process', 'GO:0042060', ('6', '19'))	('CDCA8', 'Gene', (97, 102))	('CDCA8', 'Gene', '55143', (97, 102))	('A375', 'CellLine', 'CVCL:0132', (68, 72))	('knockdown', 'Var', (103, 112))
433	30431060	These findings indicated that CDCA8 knockdown inhibited migration and invasion in cutaneous melanoma cells.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('CDCA8', 'Gene', '55143', (30, 35))	('knockdown', 'Var', (36, 45))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('CDCA8', 'Gene', (30, 35))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('inhibited', 'NegReg', (46, 55))
435	30431060	The western blot results demonstrated that CDCA8 knockdown in A375 and MV3 cells reduced the expression levels of ROCK1 and the phosphorylation levels of MLC, two downstream effector proteins of the ROCK pathway (Fig.	('ROCK1', 'Gene', (114, 119))	('knockdown', 'Var', (49, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('A375', 'CellLine', 'CVCL:0132', (62, 66))	('expression levels', 'MPA', (93, 110))	('MLC', 'Gene', (154, 157))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('MLC', 'Gene', '23209', (154, 157))	('CDCA8', 'Gene', (43, 48))	('reduced', 'NegReg', (81, 88))	('ROCK1', 'Gene', '6093', (114, 119))	('CDCA8', 'Gene', '55143', (43, 48))
439	30431060	Based on ONCOMINE and GEO data, CDCA8 expression levels were demonstrated to be overexpressed in cutaneous melanoma tissues compared with normal tissues, and high CDCA8 expression was associated with poor prognosis in cutaneous melanoma patients.	('CDCA8', 'Gene', (163, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (97, 115))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (97, 115))	('expression', 'MPA', (169, 179))	('CDCA8', 'Gene', '55143', (32, 37))	('patients', 'Species', '9606', (237, 245))	('expression levels', 'MPA', (38, 55))	('high', 'Var', (158, 162))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('ONCOMINE', 'Chemical', '-', (9, 17))	('cutaneous melanoma tissues', 'Disease', (97, 123))	('CDCA8', 'Gene', (32, 37))	('overexpressed', 'PosReg', (80, 93))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('cutaneous melanoma', 'Disease', (218, 236))	('CDCA8', 'Gene', '55143', (163, 168))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 236))	('cutaneous melanoma tissues', 'Disease', 'MESH:C562393', (97, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (218, 236))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('si', 'Chemical', 'MESH:D012825', (44, 46))
441	30431060	Notably, CDCA8 knockdown inhibited cell proliferation, migration and invasion in both cutaneous melanoma cell lines.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('cutaneous melanoma', 'Disease', (86, 104))	('knockdown', 'Var', (15, 24))	('migration', 'CPA', (55, 64))	('CDCA8', 'Gene', (9, 14))	('CDCA8', 'Gene', '55143', (9, 14))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('cell proliferation', 'CPA', (35, 53))	('invasion', 'CPA', (69, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('inhibited', 'NegReg', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
445	30431060	In addition, proliferation of human embryonic stem cells (hESCs) was also reduced by CDCA8 knockdown.	('human', 'Species', '9606', (30, 35))	('CDCA8', 'Gene', '55143', (85, 90))	('proliferation', 'CPA', (13, 26))	('knockdown', 'Var', (91, 100))	('reduced', 'NegReg', (74, 81))	('CDCA8', 'Gene', (85, 90))
446	30431060	These studies are consistent with the present findings that CDCA8 knockdown inhibited the A375 and MV3 cell proliferation, migration and invasion.	('invasion', 'CPA', (137, 145))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('A375', 'CellLine', 'CVCL:0132', (90, 94))	('CDCA8', 'Gene', (60, 65))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('inhibited', 'NegReg', (76, 85))	('knockdown', 'Var', (66, 75))	('CDCA8', 'Gene', '55143', (60, 65))	('si', 'Chemical', 'MESH:D012825', (141, 143))
447	30431060	Furthermore, the present analysis revealed that the expression of CDCA8 was significantly associated with lymph node metastasis.	('CDCA8', 'Gene', (66, 71))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('CDCA8', 'Gene', '55143', (66, 71))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('associated', 'Reg', (90, 100))	('lymph node metastasis', 'CPA', (106, 127))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('expression', 'Var', (52, 62))	('si', 'Chemical', 'MESH:D012825', (124, 126))
452	30431060	In the present study, CDCA8 knockdown inhibited ROCK signaling in cutaneous melanoma cells.	('cutaneous melanoma', 'Disease', (66, 84))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('inhibited', 'NegReg', (38, 47))	('CDCA8', 'Gene', (22, 27))	('ROCK signaling', 'MPA', (48, 62))	('knockdown', 'Var', (28, 37))	('CDCA8', 'Gene', '55143', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
460	30431060	The present results suggested that CDCA8 knockdown reduced the expression levels of ROCK1 and phosphorylated MLC in A375 and MV3 cells.	('ROCK1', 'Gene', '6093', (84, 89))	('expression levels', 'MPA', (63, 80))	('ROCK1', 'Gene', (84, 89))	('reduced', 'NegReg', (51, 58))	('CDCA8', 'Gene', (35, 40))	('MLC', 'Gene', (109, 112))	('MLC', 'Gene', '23209', (109, 112))	('CDCA8', 'Gene', '55143', (35, 40))	('A375', 'CellLine', 'CVCL:0132', (116, 120))	('knockdown', 'Var', (41, 50))	('si', 'Chemical', 'MESH:D012825', (69, 71))
461	30431060	Taken together, these findings suggest that CDCA8 knockdown inhibited cutaneous melanoma cell proliferation and invasion potentially via the ROCK signaling pathway.	('si', 'Chemical', 'MESH:D012825', (146, 148))	('cutaneous melanoma', 'Disease', (70, 88))	('ROCK', 'Pathway', (141, 145))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 88))	('invasion', 'CPA', (112, 120))	('knockdown', 'Var', (50, 59))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('inhibited', 'NegReg', (60, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('89', '107'))	('CDCA8', 'Gene', (44, 49))	('signaling pathway', 'biological_process', 'GO:0007165', ('146', '163'))	('CDCA8', 'Gene', '55143', (44, 49))
467	30431060	Further studies to investigate the cell apoptosis following CDCA8 knockdown are necessary.	('si', 'Chemical', 'MESH:D012825', (46, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('CDCA8', 'Gene', (60, 65))	('knockdown', 'Var', (66, 75))	('CDCA8', 'Gene', '55143', (60, 65))
475	33564267	Dual-luciferase reporter assay was utilized to explore the target relationship among HOXA11-AS, miR-152-3p and ITGA9.	('HOXA11-AS', 'Gene', (85, 94))	('miR-152-3p', 'Chemical', '-', (96, 106))	('ITGA9', 'Gene', '3680', (111, 116))	('ITGA9', 'Gene', (111, 116))	('miR-152-3p', 'Var', (96, 106))
477	33564267	HOXA11-AS and ITGA9 were up-regulated while miR-152-3p was down-regulated in melanoma.	('up-regulated', 'PosReg', (25, 37))	('HOXA11-AS', 'Gene', (0, 9))	('ITGA9', 'Gene', '3680', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('down-regulated', 'NegReg', (59, 73))	('ITGA9', 'Gene', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('miR-152-3p', 'Var', (44, 54))	('miR-152-3p', 'Chemical', '-', (44, 54))
478	33564267	Knockdown of HOXA11-AS refrained cell proliferation, metastasis and epithelial-mesenchymal transition (EMT) but induced apoptosis in melanoma cells.	('HOXA11-AS', 'Var', (13, 22))	('epithelial-mesenchymal transition', 'CPA', (68, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('induced', 'Reg', (112, 119))	('apoptosis', 'CPA', (120, 129))	('metastasis', 'CPA', (53, 63))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('melanoma', 'Disease', (133, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('120', '129'))	('apoptosis', 'biological_process', 'GO:0006915', ('120', '129'))	('EMT', 'biological_process', 'GO:0001837', ('103', '106'))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('68', '101'))	('cell proliferation', 'CPA', (33, 51))	('refrained', 'NegReg', (23, 32))
484	33564267	HOXA11-AS could promote melanoma development and be used as a promising biomarker in the diagnosis and treatment for cutaneous melanoma.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('cutaneous melanoma', 'Disease', (117, 135))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('HOXA11-AS', 'Var', (0, 9))	('melanoma', 'Disease', (24, 32))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('promote', 'PosReg', (16, 23))
500	33564267	But the function of miR-152-3p in melanoma is unclear.	('miR-152-3p', 'Chemical', '-', (20, 30))	('miR-152-3p', 'Var', (20, 30))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
540	33564267	The sequences of wild-type (WT) and mutant-type (MUT) HOXA11-AS were cloned into the pGL3 vector (Promega, Madison, WI, USA) and the positive plasmids were named as HOXA11-AS WT and HOXA11-AS MUT.	('si', 'Chemical', 'MESH:D012825', (135, 137))	('pGL3', 'Gene', '6391', (85, 89))	('pGL', 'molecular_function', 'GO:0004598', ('85', '88'))	('mutant-type', 'Var', (36, 47))	('pGL3', 'Gene', (85, 89))	('HOXA11-AS', 'Gene', (54, 63))
550	33564267	The linear relationship among HOXA11-AS, miR-152-3p and ITGA9 in melanoma tissues was analyzed by Spearman correlation coefficient.	('miR-152-3p', 'Var', (41, 51))	('miR-152-3p', 'Chemical', '-', (41, 51))	('ITGA9', 'Gene', '3680', (56, 61))	('ITGA9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
554	33564267	In comparison to normal tissues, the expression of HOXA11-AS was overtly increased in melanoma tissues (Figure 1A).	('increased', 'PosReg', (73, 82))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('HOXA11-AS', 'Var', (51, 60))	('melanoma', 'Disease', (86, 94))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('expression', 'MPA', (37, 47))
555	33564267	There was a lower 5-year overall survival of melanoma patients with high expression of HOXA11-AS by contrast to those patients with low expression of HOXA11-AS (Figure 1B).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('patients', 'Species', '9606', (54, 62))	('high expression', 'Var', (68, 83))	('patients', 'Species', '9606', (118, 126))	('HOXA11-AS', 'Protein', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('overall survival', 'MPA', (25, 41))	('lower', 'NegReg', (12, 17))
556	33564267	Also, HOXA11-AS was markedly up-regulated in melanoma cell lines A875 and M14 compared to normal melanocytes HEMa-LP (Figure 1C).	('HOXA11-AS', 'Var', (6, 15))	('up-regulated', 'PosReg', (29, 41))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
557	33564267	On the contrary, miR-152-3p expression was notably decreased in melanoma tissues (Figure 1D) than that in normal tissues.	('miR-152-3p', 'Chemical', '-', (17, 27))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('decreased', 'NegReg', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('miR-152-3p', 'Var', (17, 27))
558	33564267	It was also inverse that overall survival was noticeably declined in patients with low miR-152-3p level (Figure 1E).	('declined', 'NegReg', (57, 65))	('miR-152-3p', 'Chemical', '-', (87, 97))	('miR-152-3p level', 'Var', (87, 103))	('patients', 'Species', '9606', (69, 77))	('low', 'NegReg', (83, 86))	('overall survival', 'CPA', (25, 41))
561	33564267	The dysregulation of HOXA11-AS and miR-152-3p demonstrated that they might play crucial roles in melanoma.	('miR-152-3p', 'Var', (35, 45))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('roles', 'Reg', (88, 93))	('melanoma', 'Disease', (97, 105))	('dysregulation', 'Var', (4, 17))	('play', 'Reg', (75, 79))	('miR-152-3p', 'Chemical', '-', (35, 45))	('HOXA11-AS', 'Protein', (21, 30))
562	33564267	To investigate the role of HOXA11-AS in melanoma, A875 and M14 cells were transfected with si-HOXA11-AS or si-NC.	('si', 'Chemical', 'MESH:D012825', (91, 93))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('si-NC', 'Var', (107, 112))	('si-HOXA11-AS', 'Var', (91, 103))	('si-HOXA11-AS', 'Chemical', '-', (91, 103))	('si', 'Chemical', 'MESH:D012825', (107, 109))
563	33564267	The qRT-PCR indicated that HOXA11-AS expression was distinctly decreased in si-HOXA11-AS group compared with si-NC group in A875 and M14 cells (Figure 2A and B).	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('decreased', 'NegReg', (63, 72))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('si-HOXA11-AS', 'Var', (76, 88))	('si-HOXA11-AS', 'Chemical', '-', (76, 88))	('HOXA11-AS expression', 'MPA', (27, 47))
564	33564267	Then, MTT assay revealed that cell proliferation was strikingly declined in A875 and M14 cells transfected with si-HOXA11-AS (Figure 2C and D).	('cell proliferation', 'CPA', (30, 48))	('si-HOXA11-AS', 'Chemical', '-', (112, 124))	('declined', 'NegReg', (64, 72))	('MTT', 'Chemical', 'MESH:C070243', (6, 9))	('si-HOXA11-AS', 'Var', (112, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
565	33564267	Flow cytometry manifested that the apoptotic rate was increased after transfection with si-HOXA11-AS in A875 cells (Figure 2E) and M14 cells (Figure 2F).	('si-HOXA11-AS', 'Chemical', '-', (88, 100))	('si-HOXA11-AS', 'Var', (88, 100))	('apoptotic rate', 'CPA', (35, 49))	('increased', 'PosReg', (54, 63))
567	33564267	As shown in Figure 2G and H, the numbers of migrated and invaded cells were significantly fewer in si-HOXA11-AS group than these in si-NC group.	('si-HOXA11-AS', 'Chemical', '-', (99, 111))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('fewer', 'NegReg', (90, 95))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('si-HOXA11-AS', 'Var', (99, 111))
568	33564267	The level of E-cadherin (anti-EMT marker) was signally enhanced but N-cadherin and Vimentin (pro-EMT markers) were reduced (Figure 2I and J) in A875 and M14 cells transfected with si-HOXA11-AS, implying the EMT process was blocked after downregulation of HOXA11-AS.	('EMT', 'biological_process', 'GO:0001837', ('30', '33'))	('reduced', 'NegReg', (115, 122))	('EMT', 'biological_process', 'GO:0001837', ('207', '210'))	('E-cadherin', 'Gene', (13, 23))	('si-HOXA11-AS', 'Var', (180, 192))	('E-cadherin', 'Gene', '999', (13, 23))	('Vimentin', 'cellular_component', 'GO:0045099', ('83', '91'))	('N-cadherin', 'Gene', (68, 78))	('enhanced', 'PosReg', (55, 63))	('N-cadherin', 'Gene', '1000', (68, 78))	('si', 'Chemical', 'MESH:D012825', (180, 182))	('cadherin', 'molecular_function', 'GO:0008014', ('15', '23'))	('Vimentin', 'Gene', '7431', (83, 91))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('Vimentin', 'cellular_component', 'GO:0045098', ('83', '91'))	('Vimentin', 'Gene', (83, 91))	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('si-HOXA11-AS', 'Chemical', '-', (180, 192))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
569	33564267	Thus, knockdown of HOXA11-AS generated the inhibitory effects on cellular proliferation, metastasis, EMT and the stimulative effect on apoptosis.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('EMT', 'CPA', (101, 104))	('knockdown', 'Var', (6, 15))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('EMT', 'biological_process', 'GO:0001837', ('101', '104'))	('inhibitory effects', 'NegReg', (43, 61))	('metastasis', 'CPA', (89, 99))	('HOXA11-AS', 'Gene', (19, 28))	('cellular proliferation', 'CPA', (65, 87))
570	33564267	As shown in Figure 3A, HOXA11-AS WT contained the binding sites with miR-152-3p.	('miR-152-3p', 'Var', (69, 79))	('miR-152-3p', 'Chemical', '-', (69, 79))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('binding', 'Interaction', (50, 57))
571	33564267	Dual-luciferase reporter assay presented that miR-152-3p prominently decreased the luciferase activity of HOXA11-AS WT group, contrasted to the HOXA11-AS MUT group in both A875 and M14 cells (Figure 3B and C).	('luciferase activity', 'molecular_function', 'GO:0047077', ('83', '102'))	('decreased', 'NegReg', (69, 78))	('miR-152-3p', 'Var', (46, 56))	('luciferase activity', 'molecular_function', 'GO:0045289', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('83', '102'))	('activity', 'MPA', (94, 102))	('luciferase activity', 'molecular_function', 'GO:0050248', ('83', '102'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('83', '102'))	('miR-152-3p', 'Chemical', '-', (46, 56))	('luciferase', 'Enzyme', (83, 93))
572	33564267	Additionally, miR-152-3p expression was obviously elevated by knockdown of HOXA11-AS and lessened by overexpression of HOXA11-AS in A875 and M14 cells (Figure 3D and E).	('miR-152-3p', 'Gene', (14, 24))	('HOXA11-AS', 'Gene', (75, 84))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('elevated', 'PosReg', (50, 58))	('miR-152-3p', 'Chemical', '-', (14, 24))	('lessened', 'NegReg', (89, 97))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('knockdown', 'Var', (62, 71))
574	33564267	To explore the regulatory mechanism of HOXA11-AS in melanoma, A875 and M14 cells were transfected with miR-152-3p, miR-152-3p+HOXA11-AS or the relative controls.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('miR-152-3p', 'Chemical', '-', (103, 113))	('miR-152-3p', 'Chemical', '-', (115, 125))	('miR-152-3p', 'Var', (103, 113))	('miR-152-3p+HOXA11-AS', 'Var', (115, 135))
576	33564267	Cell proliferation was inhibited by transfection of miR-152-3p, whereas overexpression of HOXA11-AS alleviated this inhibitory effect (Figure 4C and D).	('miR-152-3p', 'Var', (52, 62))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('inhibited', 'NegReg', (23, 32))	('miR-152-3p', 'Chemical', '-', (52, 62))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('transfection', 'Var', (36, 48))	('Cell proliferation', 'CPA', (0, 18))
577	33564267	Flow cytometry exhibited that miR-152-3p clearly increased the apoptotic rate in A875 and M14 cells, but the promoted effect was partly prevented by HOXA11-AS up-regulation (Figure 4E and F).	('increased', 'PosReg', (49, 58))	('up-regulation', 'PosReg', (159, 172))	('apoptotic rate', 'CPA', (63, 77))	('regulation', 'biological_process', 'GO:0065007', ('162', '172'))	('miR-152-3p', 'Var', (30, 40))	('miR-152-3p', 'Chemical', '-', (30, 40))
579	33564267	Moreover, the E-cadherin upregulation and N-cadherin/Vimentin downregulation caused by miR-152-3p were partially relieved by HOXA11-AS in A875 cells (Figure 4I) and M14 cells (Figure 4J).	('cadherin', 'molecular_function', 'GO:0008014', ('44', '52'))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('miR-152-3p', 'Var', (87, 97))	('Vimentin', 'cellular_component', 'GO:0045099', ('53', '61'))	('N-cadherin', 'Gene', (42, 52))	('miR-152-3p', 'Chemical', '-', (87, 97))	('Vimentin', 'Gene', (53, 61))	('downregulation', 'NegReg', (62, 76))	('N-cadherin', 'Gene', '1000', (42, 52))	('Vimentin', 'cellular_component', 'GO:0045098', ('53', '61'))	('E-cadherin', 'Gene', (14, 24))	('Vimentin', 'Gene', '7431', (53, 61))	('upregulation', 'PosReg', (25, 37))
581	33564267	Meanwhile, the rescued experiment was performed to notarize whether the function of HOXA11-AS knockdown was attributed to miR-152-3p up-regulation.	('miR-152-3p', 'Chemical', '-', (122, 132))	('regulation', 'biological_process', 'GO:0065007', ('136', '146'))	('miR-152-3p', 'Var', (122, 132))	('up-regulation', 'PosReg', (133, 146))	('HOXA11-AS', 'Gene', (84, 93))
582	33564267	After the qRT-PCR analysis, miR-152-3p inhibition was showed to weaken the increase of miR-152-3p level caused by si-HOXA11-AS in A875 and M14 cells (Supplemental Figure 1A and B).	('si', 'Chemical', 'MESH:D012825', (114, 116))	('si-HOXA11-AS', 'Var', (114, 126))	('weaken', 'NegReg', (64, 70))	('miR-152-3p', 'Chemical', '-', (28, 38))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si-HOXA11-AS', 'Chemical', '-', (114, 126))	('miR-152-3p', 'Chemical', '-', (87, 97))	('increase', 'PosReg', (75, 83))	('miR-152-3p level', 'MPA', (87, 103))
583	33564267	The si-HOXA11-AS-induced repression of cell proliferation (Supplemental Figure 1C and D) and the promotion of cell apoptosis (Supplemental Figure 1E and F) were countervailed following the down-regulation of miR-152-3p.	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))	('promotion', 'PosReg', (97, 106))	('si-HOXA11-AS-induced', 'Var', (4, 24))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('si-HOXA11-AS', 'Chemical', '-', (4, 16))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('apoptosis', 'biological_process', 'GO:0097194', ('115', '124'))	('apoptosis', 'biological_process', 'GO:0006915', ('115', '124'))	('miR-152-3p', 'Chemical', '-', (208, 218))	('repression', 'NegReg', (25, 35))	('cell proliferation', 'CPA', (39, 57))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('cell apoptosis', 'CPA', (110, 124))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('down-regulation', 'NegReg', (189, 204))
584	33564267	Similarly, miR-152-3p inhibitor returned the inhibitory regulation of si-HOXA11-AS on cell migration (Supplemental Figure 1G), invasion (Supplemental Figure 1H) and EMT process (Supplemental Figure 1I and J).	('si', 'Chemical', 'MESH:D012825', (131, 133))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('inhibitory regulation', 'MPA', (45, 66))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('miR-152-3p', 'Chemical', '-', (11, 21))	('invasion', 'CPA', (127, 135))	('EMT process', 'CPA', (165, 176))	('cell migration', 'CPA', (86, 100))	('si-HOXA11-AS', 'Gene', (70, 82))	('si-HOXA11-AS', 'Chemical', '-', (70, 82))	('miR-152-3p', 'Var', (11, 21))	('EMT', 'biological_process', 'GO:0001837', ('165', '168'))	('cell migration', 'biological_process', 'GO:0016477', ('86', '100'))
585	33564267	This revert of anti-miR-152-3p to si-HOXA11-AS suggested that the knockdown of HOXA11-AS retarded the development of melanoma via promoting miR-152-3p.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('miR-152-3p', 'Chemical', '-', (20, 30))	('si-HOXA11-AS', 'Chemical', '-', (34, 46))	('development of', 'CPA', (102, 116))	('HOXA11-AS', 'Var', (79, 88))	('promoting', 'PosReg', (130, 139))	('retarded', 'NegReg', (89, 97))	('miR-152-3p', 'MPA', (140, 150))	('knockdown', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('miR-152-3p', 'Chemical', '-', (140, 150))	('melanoma', 'Disease', (117, 125))
586	33564267	Through the prediction of TargetScan, we found that the 3'-UTR of wild-type ITGA9 contained the binding sites of miR-152-3p (Figure 5A).	('miR-152-3p', 'Chemical', '-', (113, 123))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('binding', 'Interaction', (96, 103))	('ITGA9', 'Gene', '3680', (76, 81))	('miR-152-3p', 'Var', (113, 123))	('ITGA9', 'Gene', (76, 81))	('si', 'Chemical', 'MESH:D012825', (104, 106))
587	33564267	The results of dual-luciferase reporter assay showed that the luciferase activity of ITGA9 3'UTR WT group was significantly declined by miR-152-3p, while this phenomenon was not found in ITGA9 3'UTR MUT group (Figure 5B and C).	('miR-152-3p', 'Chemical', '-', (136, 146))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('luciferase activity', 'molecular_function', 'GO:0047077', ('62', '81'))	('activity', 'MPA', (73, 81))	('ITGA9', 'Gene', (85, 90))	('luciferase activity', 'molecular_function', 'GO:0045289', ('62', '81'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('62', '81'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('62', '81'))	('ITGA9', 'Gene', '3680', (187, 192))	('miR-152-3p', 'Var', (136, 146))	('luciferase activity', 'molecular_function', 'GO:0050397', ('62', '81'))	('declined', 'NegReg', (124, 132))	('luciferase', 'Enzyme', (62, 72))	('ITGA9', 'Gene', '3680', (85, 90))	('ITGA9', 'Gene', (187, 192))
590	33564267	The relation between the levels of miR-152-3p and ITGA9 was notably negative (R2=0.711, P< 0.0001) (Figure 5G).	('miR-152-3p', 'Var', (35, 45))	('ITGA9', 'Gene', (50, 55))	('negative', 'NegReg', (68, 76))	('miR-152-3p', 'Chemical', '-', (35, 45))	('ITGA9', 'Gene', '3680', (50, 55))
592	33564267	Furthermore, the mRNA expression of ITGA9 was observably inhibited by miR-152-3p and increased by anti-miR-152-3p transfection (Figure 5J).	('si', 'Chemical', 'MESH:D012825', (28, 30))	('miR-152-3p', 'Var', (70, 80))	('ITGA9', 'Gene', (36, 41))	('inhibited', 'NegReg', (57, 66))	('miR-152-3p', 'Chemical', '-', (103, 113))	('miR-152-3p', 'Chemical', '-', (70, 80))	('anti-miR-152-3p transfection', 'Var', (98, 126))	('mRNA expression', 'MPA', (17, 32))	('increased', 'PosReg', (85, 94))	('ITGA9', 'Gene', '3680', (36, 41))
594	33564267	All above data unraveled that miR-152-3p targeted ITGA9.	('targeted', 'Reg', (41, 49))	('ITGA9', 'Gene', (50, 55))	('miR-152-3p', 'Var', (30, 40))	('ITGA9', 'Gene', '3680', (50, 55))	('miR-152-3p', 'Chemical', '-', (30, 40))
596	33564267	Compared to the si-ITGA9 group, the mRNA and protein levels of ITGA9 were remarkably up-regulated by anti-miR-152-3p in A875 cells (Figure 6A and B) and M14 cells (Figure 6C and D).	('ITGA9', 'Gene', '3680', (63, 68))	('miR-152-3p', 'Chemical', '-', (106, 116))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('ITGA9', 'Gene', (63, 68))	('anti-miR-152-3p', 'Var', (101, 116))	('ITGA9', 'Gene', '3680', (19, 24))	('ITGA9', 'Gene', (19, 24))	('up-regulated', 'PosReg', (85, 97))
599	33564267	Transwell assay indicated that si-ITGA9 visibly decreased cell migration and invasion, but anti-miR-152-3p averted the suppression in part (Figure 6I and J).	('ITGA9', 'Gene', '3680', (34, 39))	('cell migration', 'CPA', (58, 72))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('ITGA9', 'Gene', (34, 39))	('invasion', 'CPA', (77, 85))	('decreased', 'NegReg', (48, 57))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('miR-152-3p', 'Chemical', '-', (96, 106))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('anti-miR-152-3p', 'Var', (91, 106))	('si', 'Chemical', 'MESH:D012825', (31, 33))
600	33564267	In addition, the si-ITGA9-induced accelerative effect on E-cadherin and prohibitive effects on N-cadherin/Vimentin were abated by anti-miR-152-3p in A875 and M14 cells (Figure 6K and L).	('ITGA9', 'Gene', '3680', (20, 25))	('N-cadherin', 'Gene', (95, 105))	('Vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('Vimentin', 'Gene', '7431', (106, 114))	('N-cadherin', 'Gene', '1000', (95, 105))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('E-cadherin', 'Gene', (57, 67))	('ITGA9', 'Gene', (20, 25))	('E-cadherin', 'Gene', '999', (57, 67))	('Vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('miR-152-3p', 'Chemical', '-', (135, 145))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('anti-miR-152-3p', 'Var', (130, 145))	('Vimentin', 'Gene', (106, 114))	('abated', 'NegReg', (120, 126))	('accelerative effect', 'PosReg', (34, 53))
601	33564267	Taken together, miR-152-3p inhibition promoted the progression of melanoma via motivating the expression of ITGA9.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('motivating', 'Reg', (79, 89))	('miR-152-3p', 'Var', (16, 26))	('inhibition', 'Var', (27, 37))	('ITGA9', 'Gene', '3680', (108, 113))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('promoted', 'PosReg', (38, 46))	('progression', 'CPA', (51, 62))	('expression', 'MPA', (94, 104))	('ITGA9', 'Gene', (108, 113))	('miR-152-3p', 'Chemical', '-', (16, 26))	('si', 'Chemical', 'MESH:D012825', (100, 102))
603	33564267	Moreover, qRT-PCR revealed that the mRNA level of ITGA9 was inhibited by HOXA11-AS knockdown but anti-miR-152-3p reverted the inhibitory effect on ITGA9 (Figure 7B).	('miR-152-3p', 'Chemical', '-', (102, 112))	('ITGA9', 'Gene', (50, 55))	('ITGA9', 'Gene', '3680', (147, 152))	('knockdown', 'Var', (83, 92))	('inhibited', 'NegReg', (60, 69))	('ITGA9', 'Gene', (147, 152))	('anti-miR-152-3p', 'Var', (97, 112))	('ITGA9', 'Gene', '3680', (50, 55))	('mRNA level', 'MPA', (36, 46))
604	33564267	Also, Western blot demonstrated that the repression of miR-152-3p conspicuously ameliorated the si-HOXA11-AS-induced ITGA9 protein downregulation in both A875 and M14 cells (Figure 7C and D).	('miR-152-3p', 'Var', (55, 65))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('ITGA9', 'Gene', '3680', (117, 122))	('si-HOXA11-AS', 'Chemical', '-', (96, 108))	('miR-152-3p', 'Chemical', '-', (55, 65))	('ITGA9', 'Gene', (117, 122))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('downregulation', 'NegReg', (131, 145))	('ameliorated', 'PosReg', (80, 91))	('si', 'Chemical', 'MESH:D012825', (96, 98))
605	33564267	These results suggested that HOXA11-AS knockdown inhibited the level of ITGA9 by promoting miR-152-3p.	('level', 'MPA', (63, 68))	('knockdown', 'Var', (39, 48))	('ITGA9', 'Gene', '3680', (72, 77))	('miR-152-3p', 'MPA', (91, 101))	('ITGA9', 'Gene', (72, 77))	('promoting', 'PosReg', (81, 90))	('miR-152-3p', 'Chemical', '-', (91, 101))	('inhibited', 'NegReg', (49, 58))
606	33564267	To further explore the impact of HOXA11-AS in vivo, A875 cells stably expressed sh-NC or sh-HOXA11-AS were subcutaneously injected into the back flank of nude mice to establish the xenograft model of melanoma.	('sh-HOXA11-AS', 'Var', (89, 101))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('sh-HOXA11-AS', 'Chemical', '-', (89, 101))	('melanoma', 'Disease', (200, 208))	('sh-NC', 'Gene', (80, 85))	('nude mice', 'Species', '10090', (154, 163))
607	33564267	As Figure 8A revealed, the tumor volume of sh-HOXA11-AS group was smaller than that of sh-NC group between 1 and 4 weeks.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('sh-HOXA11-AS', 'Chemical', '-', (43, 55))	('tumor', 'Disease', (27, 32))	('smaller', 'NegReg', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('sh-HOXA11-AS', 'Var', (43, 55))
608	33564267	After 4 weeks, tumor weight was lower in sh-HOXA11-AS group by contrast to sh-NC group (Figure 8B).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('sh-HOXA11-AS', 'Var', (41, 53))	('sh-HOXA11-AS', 'Chemical', '-', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('lower', 'NegReg', (32, 37))
610	33564267	The level of miR-152-3p was up-regulated (Figure 8D), while ITGA9 mRNA and protein levels were decreased (Figure 8E and F) in the sh-HOXA11-AS group.	('decreased', 'NegReg', (95, 104))	('miR-152-3p', 'Chemical', '-', (13, 23))	('up-regulated', 'PosReg', (28, 40))	('sh-HOXA11-AS', 'Chemical', '-', (130, 142))	('level', 'MPA', (4, 9))	('ITGA9', 'Gene', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('miR-152-3p', 'Var', (13, 23))	('ITGA9', 'Gene', '3680', (60, 65))
611	33564267	Additionally, E-cadherin protein expression was enhanced while N-cadherin and Vimentin protein levels were reduced after knockdown of HOXA11-AS in vivo (Figure 8G).	('knockdown', 'Var', (121, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('16', '24'))	('E-cadherin', 'Gene', '999', (14, 24))	('HOXA11-AS', 'Gene', (134, 143))	('Vimentin', 'cellular_component', 'GO:0045098', ('78', '86'))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('reduced', 'NegReg', (107, 114))	('enhanced', 'PosReg', (48, 56))	('Vimentin', 'cellular_component', 'GO:0045099', ('78', '86'))	('N-cadherin', 'Gene', (63, 73))	('Vimentin', 'Gene', (78, 86))	('N-cadherin', 'Gene', '1000', (63, 73))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('E-cadherin', 'Gene', (14, 24))	('cadherin', 'molecular_function', 'GO:0008014', ('65', '73'))	('Vimentin', 'Gene', '7431', (78, 86))
612	33564267	The down-regulation of PCNA and cyclinD1 (pro-proliferation proteins) in sh-HOXA11-AS group suggested that silencing HOXA11-AS inhibited the proliferation of melanoma in vivo (Figure 8H).	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('silencing', 'Var', (107, 116))	('PCNA', 'Gene', (23, 27))	('cyclinD1', 'Gene', (32, 40))	('inhibited', 'NegReg', (127, 136))	('HOXA11-AS', 'Gene', (117, 126))	('proliferation', 'CPA', (141, 154))	('cyclinD1', 'Gene', '595', (32, 40))	('sh-HOXA11-AS', 'Chemical', '-', (73, 85))	('PCNA', 'Gene', '5111', (23, 27))	('si', 'Chemical', 'MESH:D012825', (107, 109))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('PCNA', 'molecular_function', 'GO:0003892', ('23', '27'))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('down-regulation', 'NegReg', (4, 19))	('melanoma', 'Disease', (158, 166))
613	33564267	The repression of Bcl-2 (anti-apoptosis marker) and the upregulation of Bax (pro-apoptosis marker) implied that apoptosis was triggered by knockdown of HOXA11-AS in vivo (Figure 8I).	('si', 'Chemical', 'MESH:D012825', (87, 89))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('Bcl-2', 'Gene', (18, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('upregulation', 'PosReg', (56, 68))	('apoptosis', 'CPA', (112, 121))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('knockdown', 'Var', (139, 148))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('Bax', 'Gene', '581', (72, 75))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('25', '39'))	('repression', 'NegReg', (4, 14))	('pro-apoptosis', 'biological_process', 'GO:0043065', ('77', '90'))	('Bcl-2', 'Gene', '596', (18, 23))	('Bax', 'Gene', (72, 75))
614	33564267	At least in part, HOXA11-AS affected the melanoma progression in vivo by modulating miR-152-3p and ITGA9 expression.	('miR-152-3p', 'Protein', (84, 94))	('miR-152-3p', 'Chemical', '-', (84, 94))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('HOXA11-AS', 'Var', (18, 27))	('ITGA9', 'Gene', (99, 104))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('affected', 'Reg', (28, 36))	('modulating', 'Reg', (73, 83))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('expression', 'MPA', (105, 115))	('ITGA9', 'Gene', '3680', (99, 104))
618	33564267	HOXA11-AS might be a satisfactory candidate biomarker of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('HOXA11-AS', 'Var', (0, 9))	('melanoma', 'Disease', (57, 65))
620	33564267	In recent years, Li et al clarified that interfering with the expression of HOXA11-AS inhibited cell proliferation, metastasis and EMT but stimulated apoptosis in breast cancer cells.	('interfering', 'Var', (41, 52))	('apoptosis', 'CPA', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('stimulated', 'PosReg', (139, 149))	('cell proliferation', 'CPA', (96, 114))	('HOXA11-AS', 'Gene', (76, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('metastasis', 'CPA', (116, 126))	('EMT', 'CPA', (131, 134))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('EMT', 'biological_process', 'GO:0001837', ('131', '134'))	('breast cancer', 'Disease', (163, 176))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('inhibited', 'NegReg', (86, 95))
621	33564267	Qu et al found that HOXA11-AS knockdown prominently repressed cell growth and metastasis of laryngeal squamous cell carcinoma.	('repressed', 'NegReg', (52, 61))	('squamous cell carcinoma', 'Disease', (102, 125))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('knockdown', 'Var', (30, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('metastasis', 'CPA', (78, 88))	('cell growth', 'CPA', (62, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
622	33564267	The silence of HOXA11-AS was also showed to reduce proliferation and metastasis but expedite apoptosis of glioma cells.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('silence', 'Var', (4, 11))	('reduce', 'NegReg', (44, 50))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('proliferation', 'CPA', (51, 64))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('glioma', 'Disease', (106, 112))	('HOXA11-AS', 'Gene', (15, 24))	('apoptosis', 'CPA', (93, 102))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('expedite', 'PosReg', (84, 92))
623	33564267	Lu et al unraveled that HOXA11-AS knockdown reduced proliferation and invasion abilities, but induced apoptosis of uveal melanoma (UM) cells.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('proliferation', 'CPA', (52, 65))	('uveal melanoma', 'Disease', (115, 129))	('uveal melanoma', 'Disease', 'MESH:C536494', (115, 129))	('uveal melanoma', 'Phenotype', 'HP:0007716', (115, 129))	('invasion abilities', 'CPA', (70, 88))	('apoptosis', 'CPA', (102, 111))	('UM', 'Phenotype', 'HP:0007716', (131, 133))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('reduced', 'NegReg', (44, 51))	('knockdown', 'Var', (34, 43))	('induced', 'Reg', (94, 101))	('si', 'Chemical', 'MESH:D012825', (108, 110))
626	33564267	Further experiments indicated that proliferation, metastasis (migration and invasion) and EMT of melanoma cells were all repressed but apoptosis was facilitated after HOXA11-AS was knocked down, suggesting that HOXA11-AS played as an oncogenic role in cutaneous melanoma.	('apoptosis', 'CPA', (135, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('135', '144'))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('EMT', 'biological_process', 'GO:0001837', ('90', '93'))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))	('si', 'Chemical', 'MESH:D012825', (80, 82))	('melanoma', 'Disease', (262, 270))	('cutaneous melanoma', 'Disease', (252, 270))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (252, 270))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (252, 270))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('facilitated', 'PosReg', (149, 160))	('HOXA11-AS', 'Gene', (167, 176))	('knocked down', 'Var', (181, 193))	('apoptosis', 'biological_process', 'GO:0097194', ('135', '144'))
627	33564267	MiRNAs are generally considered as tumor suppressors to regulate tumor progression, including miR-152-3p.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-152-3p', 'Var', (94, 104))	('miR-152-3p', 'Chemical', '-', (94, 104))	('tumor', 'Disease', (35, 40))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
628	33564267	For instance, Sun et al illuminated that miR-152-3p overexpression inhibited invasion while motivated cell apoptosis in glioma.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('miR-152-3p', 'Var', (41, 51))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('inhibited', 'NegReg', (67, 76))	('miR-152-3p', 'Chemical', '-', (41, 51))	('invasion', 'CPA', (77, 85))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('glioma', 'Disease', (120, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))	('overexpression', 'PosReg', (52, 66))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
629	33564267	Also, miR-152-3p was down-regulated in prostate cancer and attenuated the abilities of cell proliferation and invasion.	('cell proliferation', 'biological_process', 'GO:0008283', ('87', '105'))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('miR-152-3p', 'Chemical', '-', (6, 16))	('prostate cancer', 'Disease', (39, 54))	('attenuated', 'NegReg', (59, 69))	('down-regulated', 'NegReg', (21, 35))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('miR-152-3p', 'Var', (6, 16))
630	33564267	Consistent with these studies, we found that miR-152-3p expression was overtly declined in melanoma.	('miR-152-3p', 'Var', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('miR-152-3p', 'Chemical', '-', (45, 55))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('declined', 'NegReg', (79, 87))	('si', 'Chemical', 'MESH:D012825', (62, 64))
631	33564267	The upregulation of miR-152-3p inhibited cell proliferation, metastasis and EMT but aggravated apoptosis in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('miR-152-3p', 'Chemical', '-', (20, 30))	('EMT', 'CPA', (76, 79))	('aggravated', 'PosReg', (84, 94))	('cell proliferation', 'CPA', (41, 59))	('apoptosis', 'CPA', (95, 104))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('95', '104'))	('apoptosis', 'biological_process', 'GO:0006915', ('95', '104'))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('EMT', 'biological_process', 'GO:0001837', ('76', '79'))	('metastasis', 'CPA', (61, 71))	('miR-152-3p', 'Var', (20, 30))	('inhibited', 'NegReg', (31, 40))	('upregulation', 'PosReg', (4, 16))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('melanoma', 'Disease', (108, 116))
633	33564267	Cui et al discovered that HOXA11-AS promoted the glioma oncogenesis by targeting miR-140-5p as a miRNA sponge, and Zhan et al declared that HOXA11-AS modulated cellular processes of hepatocellular carcinoma via sponging miR-214-3p.	('miR', 'Gene', (220, 223))	('oncogenesis', 'biological_process', 'GO:0007048', ('56', '67'))	('cellular processes', 'CPA', (160, 178))	('miR-140', 'Gene', (81, 88))	('miR', 'Gene', '220972', (81, 84))	('hepatocellular carcinoma', 'Disease', (182, 206))	('miR-140', 'Gene', '406932', (81, 88))	('3p', 'Chemical', '-', (228, 230))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('miR', 'Gene', '220972', (97, 100))	('promoted', 'PosReg', (36, 44))	('glioma', 'Disease', (49, 55))	('HOXA11-AS', 'Var', (140, 149))	('miR', 'Gene', (81, 84))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('modulated', 'Reg', (150, 159))	('miR', 'Gene', (97, 100))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))	('miR', 'Gene', '220972', (220, 223))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (182, 206))
634	33564267	HOXA11-AS was also reported to expedite the retinoblastoma progression through down-regulating miR-506-3p.	('down-regulating', 'NegReg', (79, 94))	('miR', 'Gene', '220972', (95, 98))	('retinoblastoma', 'Phenotype', 'HP:0009919', (44, 58))	('miR', 'Gene', (95, 98))	('3p', 'Chemical', '-', (103, 105))	('expedite', 'PosReg', (31, 39))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('retinoblastoma', 'Disease', 'MESH:D012175', (44, 58))	('retinoblastoma', 'Disease', (44, 58))	('HOXA11-AS', 'Var', (0, 9))
635	33564267	Herein, we found a sponge effect of HOXA11-AS on miR-152-3p.	('miR-152-3p', 'Var', (49, 59))	('sponge effect', 'MPA', (19, 32))	('miR-152-3p', 'Chemical', '-', (49, 59))
636	33564267	In addition, HOXA11-AS regulated the cellular processes of melanoma partly by acting as a sponge of miR-152-3p.	('HOXA11-AS', 'Var', (13, 22))	('regulated', 'Reg', (23, 32))	('miR-152-3p', 'Chemical', '-', (100, 110))	('cellular processes', 'CPA', (37, 55))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
638	33564267	TargetScan software was used for seeking the target gene of miR-152-3p and the analysis revealed that 3'-UTR of ITGA9 contained the binding sites of miR-152-3p.	('miR-152-3p', 'Chemical', '-', (60, 70))	('miR-152-3p', 'Var', (149, 159))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('binding', 'molecular_function', 'GO:0005488', ('132', '139'))	('miR-152-3p', 'Chemical', '-', (149, 159))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('binding', 'Interaction', (132, 139))	('ITGA9', 'Gene', '3680', (112, 117))	('ITGA9', 'Gene', (112, 117))
639	33564267	Subsequent assays proved that ITGA9 was a downstream target of miR-152-3p.	('miR-152-3p', 'Var', (63, 73))	('ITGA9', 'Gene', (30, 35))	('miR-152-3p', 'Chemical', '-', (63, 73))	('ITGA9', 'Gene', '3680', (30, 35))
640	33564267	Furthermore, the tumor inhibitor role of miR-152-3p in melanoma was partially achieved by targeting ITGA9.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('miR-152-3p', 'Var', (41, 51))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('tumor', 'Disease', (17, 22))	('miR-152-3p', 'Chemical', '-', (41, 51))	('ITGA9', 'Gene', '3680', (100, 105))	('ITGA9', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
642	33564267	Yang et al asserted that HOXA11-AS increased cell viability and invasion ability in renal cancer through regulating miR-146b-5p/matrix metallopeptidase 16 (MMP16) axis.	('renal cancer', 'Disease', 'MESH:D007680', (84, 96))	('HOXA11-AS', 'Var', (25, 34))	('increased', 'PosReg', (35, 44))	('regulating', 'Reg', (105, 115))	('MMP16', 'Gene', '4325', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell viability', 'CPA', (45, 59))	('miR-146b-5p/matrix metallopeptidase 16', 'Gene', (116, 154))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('renal cancer', 'Disease', (84, 96))	('MMP16', 'Gene', (156, 161))	('MMP', 'molecular_function', 'GO:0004235', ('156', '159'))	('renal cancer', 'Phenotype', 'HP:0009726', (84, 96))	('miR-146b-5p/matrix metallopeptidase 16', 'Gene', '4325', (116, 154))	('invasion ability', 'CPA', (64, 80))
643	33564267	Wang et al claimed that HOXA11-AS promoted liver cancer progression via modulating miR-15a-3p/signal transducer and activator of transcription 3 (STAT3) axis.	('HOXA11-AS', 'Var', (24, 33))	('signal transducer and activator of transcription 3', 'Gene', '6774', (94, 144))	('liver cancer', 'Disease', (43, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (43, 55))	('STAT3', 'Gene', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('modulating', 'Reg', (72, 82))	('promoted', 'PosReg', (34, 42))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('3p', 'Chemical', '-', (91, 93))	('STAT3', 'Gene', '6774', (146, 151))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('liver cancer', 'Disease', 'MESH:D006528', (43, 55))
648	33564267	Zhang et al reported that repression of HOXA11-AS refrained the tumorigenesis of non-small cell lung cancer in vivo, and Li et al purported that overexpression of HOXA11-AS stimulated tumor growth of oral squamous cell carcinoma by decreasing miR-518a-3p expression and promoting PDK1 expression in vivo.	('stimulated', 'PosReg', (173, 183))	('miR', 'Gene', '220972', (243, 246))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (81, 107))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 228))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('si', 'Chemical', 'MESH:D012825', (238, 240))	('oral squamous cell carcinoma', 'Disease', (200, 228))	('miR', 'Gene', (243, 246))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('tumor', 'Disease', (184, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('3p', 'Chemical', '-', (252, 254))	('non-small cell lung cancer', 'Disease', (81, 107))	('PDK1', 'Gene', (280, 284))	('si', 'Chemical', 'MESH:D012825', (261, 263))	('decreasing', 'NegReg', (232, 242))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('PDK1', 'molecular_function', 'GO:0004740', ('280', '284'))	('si', 'Chemical', 'MESH:D012825', (291, 293))	('HOXA11-AS', 'Var', (163, 172))	('expression', 'MPA', (285, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('promoting', 'PosReg', (270, 279))	('PDK1', 'Gene', '5163', (280, 284))
652	33564267	HOXA11-AS might be a useful biomarker for the therapy of cutaneous melanoma, which needs further confirmation through clinical exploration.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('cutaneous melanoma', 'Disease', (57, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 75))	('HOXA11-AS', 'Var', (0, 9))
653	31575544	Targeting of copper-trafficking chaperones causes gene-specific systemic pathology in Drosophila melanogaster: prospective expansion of mutational landscapes that regulate tumor resistance to cisplatin Copper, a transition metal, is an essential component for normal growth and development.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('Copper', 'Chemical', 'MESH:D003300', (202, 208))	('mutational', 'Var', (136, 146))	('Drosophila melanogaster', 'Species', '7227', (86, 109))	('copper', 'Chemical', 'MESH:D003300', (13, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (192, 201))
656	31575544	Furthermore, we show that Atox1 or CCS gene silencing in either neuronal or whole-body tissues can critically affect the viability and climbing capacity of transgenic flies, while their double-genetic targeting suggests a rather synergistic mode of action of the cognate protein products.	('CCS', 'molecular_function', 'GO:0052728', ('35', '38'))	('CCS', 'molecular_function', 'GO:0052727', ('35', '38'))	('viability', 'Gene', (121, 130))	('protein', 'cellular_component', 'GO:0003675', ('271', '278'))	('viability', 'Gene', '31009', (121, 130))	('affect', 'Reg', (110, 116))	('climbing capacity', 'CPA', (135, 152))	('Atox1', 'Gene', (26, 31))	('CCS', 'Gene', (35, 38))	('CCS', 'molecular_function', 'GO:0034019', ('35', '38'))	('gene silencing', 'biological_process', 'GO:0016458', ('39', '53'))	('gene', 'Var', (39, 43))
675	31575544	Because of its great importance as a co-factor for numerous enzymes, absence of copper or deviation from its normal distribution pattern can cause severe developmental abnormalities and baneful diseases.	('deviation', 'Var', (90, 99))	('severe developmental abnormalities', 'Phenotype', 'HP:0011344', (147, 181))	('copper', 'Protein', (80, 86))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (154, 181))	('copper', 'Chemical', 'MESH:D003300', (80, 86))	('developmental abnormalities and baneful diseases', 'Disease', 'MESH:D006130', (154, 202))	('absence', 'NegReg', (69, 76))	('cause', 'Reg', (141, 146))
678	31575544	Menkes, an X-linked disorder, is caused by mutations in the ATP7A gene, which is required for copper export from the intestinal cells.	('caused by', 'Reg', (33, 42))	('copper', 'Chemical', 'MESH:D003300', (94, 100))	('X-linked disorder', 'Disease', (11, 28))	('X-linked disorder', 'Disease', 'MESH:D040181', (11, 28))	('mutations', 'Var', (43, 52))	('copper export', 'biological_process', 'GO:0060003', ('94', '107'))	('ATP7A', 'Gene', (60, 65))	('ATP7A', 'Gene', '538', (60, 65))	('Menkes', 'Disease', (0, 6))
680	31575544	On the other hand, Wilson's autosomal disorder is caused by mutations in the ATP7B gene, which plays an important role in the biliary copper efflux from the hepatocytes.	('efflux', 'biological_process', 'GO:0140115', ('141', '147'))	('efflux', 'biological_process', 'GO:0140352', ('141', '147'))	('caused by', 'Reg', (50, 59))	('ATP7B', 'Gene', '540', (77, 82))	("Wilson's autosomal disorder", 'Disease', 'MESH:D006527', (19, 46))	('biliary copper efflux from', 'MPA', (126, 152))	("Wilson's autosomal disorder", 'Disease', (19, 46))	('ATP7B', 'Gene', (77, 82))	('copper', 'Chemical', 'MESH:D003300', (134, 140))	('mutations', 'Var', (60, 69))
682	31575544	Besides ATP7A and ATP7B, other genes with aberrant or lack of expression, and/or activity, may detrimentally harm copper homeostasis, and induce tissue pathologies.	('copper homeostasis', 'biological_process', 'GO:0006878', ('114', '132'))	('copper homeostasis', 'MPA', (114, 132))	('copper', 'Chemical', 'MESH:D003300', (114, 120))	('aberrant', 'Var', (42, 50))	('induce', 'Reg', (138, 144))	('ATP7A', 'Gene', (8, 13))	('ATP7B', 'Gene', '540', (18, 23))	('ATP7A', 'Gene', '538', (8, 13))	('copper homeostasis', 'biological_process', 'GO:0055070', ('114', '132'))	('activity', 'MPA', (81, 89))	('lack', 'NegReg', (54, 58))	('ATP7B', 'Gene', (18, 23))	('tissue pathologies', 'CPA', (145, 163))
686	31575544	In several cases, this has proved to be related to aberrant expression levels of copper transporters.	('copper', 'Chemical', 'MESH:D003300', (81, 87))	('aberrant', 'Var', (51, 59))	('expression levels', 'MPA', (60, 77))	('related', 'Reg', (40, 47))
689	31575544	Moreover, oncogenic deregulation of the copper transporters ATP7A and ATP7B also appears to be critically implicated in the control of cisplatin export from the cell, as their overexpression causes reduced drug accumulation in the cancer cell and tumor resistance to the drug.	('ATP7B', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Disease', (247, 252))	('cancer', 'Disease', (231, 237))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('copper', 'Chemical', 'MESH:D003300', (40, 46))	('ATP7A', 'Gene', (60, 65))	('ATP7B', 'Gene', '540', (70, 75))	('ATP7A', 'Gene', '538', (60, 65))	('reduced', 'NegReg', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('drug accumulation', 'MPA', (206, 223))	('overexpression', 'PosReg', (176, 190))	('deregulation', 'Var', (20, 32))
711	31575544	Remarkably, Atox1 gene suppression significantly increases mortality of female (elav.L>Atox1_RNAi), compared to control (elav.L-GAL4/+) flies, whereas the Atox1-targeted males show notably elevated viability (Fig.	('RNAi', 'biological_process', 'GO:0016246', ('93', '97'))	('Atox1', 'Gene', (12, 17))	('viability', 'Gene', '31009', (198, 207))	('gene', 'Var', (18, 22))	('increases', 'PosReg', (49, 58))	('viability', 'Gene', (198, 207))	('suppression', 'NegReg', (23, 34))	('mortality', 'CPA', (59, 68))	('elevated', 'PosReg', (189, 197))
722	31575544	Control (Act5C-GAL4/+) flies were exposed to either DMSO (group of reference) or DC_AC50 (80 muM) for 20 days and then allowed to survive in the absence of the inhibitor.	('muM', 'Gene', '33903', (93, 96))	('Act5C', 'Gene', '31521', (9, 14))	('DC_AC50', 'Var', (81, 88))	('muM', 'Gene', (93, 96))	('DMSO', 'Chemical', 'MESH:D004121', (52, 56))	('Act5C', 'Gene', (9, 14))
723	31575544	7B) the double-gene (Atox1 and CCS)-targeting-induced Drosophila enhanced mortality (Fig.	('Drosophila enhanced', 'Disease', (54, 73))	('CCS', 'molecular_function', 'GO:0052727', ('31', '34'))	('Drosophila enhanced', 'Disease', 'MESH:C564835', (54, 73))	('CCS', 'molecular_function', 'GO:0052728', ('31', '34'))	('mortality', 'CPA', (74, 83))	('CCS', 'molecular_function', 'GO:0034019', ('31', '34'))	('double-gene', 'Var', (8, 19))
727	31575544	Loss-of-function mutations in these genes can modify tumor-cell response to the drug.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (17, 26))
730	31575544	Alterations in Atox1 and/or CCS gene expression may decisively deregulate cisplatin's trafficking routes and interactions with target molecules (i.e.	('interactions', 'Interaction', (109, 121))	('CCS gene', 'Gene', (28, 36))	('trafficking routes', 'MPA', (86, 104))	('Atox1', 'Gene', (15, 20))	('gene expression', 'biological_process', 'GO:0010467', ('32', '47'))	('cisplatin', 'MPA', (74, 83))	('Alterations', 'Var', (0, 11))	('CCS', 'molecular_function', 'GO:0034019', ('28', '31'))	('deregulate', 'Reg', (63, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('CCS', 'molecular_function', 'GO:0052728', ('28', '31'))	('CCS', 'molecular_function', 'GO:0052727', ('28', '31'))
733	31575544	Our results reveal that cisplatin causes a significant elevation of mortality rates in control (Act5C-GAL4/+) flies (Fig.	('Act5C', 'Gene', '31521', (96, 101))	('cisplatin', 'Var', (24, 33))	('mortality', 'CPA', (68, 77))	('Act5C', 'Gene', (96, 101))	('elevation', 'PosReg', (55, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
740	31575544	Nevertheless, a role of CCS activity in functionally compensating for the lack of Atox1 cannot be excluded, thus indicating the Atox1 effective involvement in cisplatin metabolism.	('CCS', 'molecular_function', 'GO:0034019', ('24', '27'))	('Atox1', 'Var', (128, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('CCS', 'molecular_function', 'GO:0052727', ('24', '27'))	('involvement', 'Reg', (144, 155))	('CCS', 'molecular_function', 'GO:0052728', ('24', '27'))	('metabolism', 'biological_process', 'GO:0008152', ('169', '179'))	('cisplatin', 'MPA', (159, 168))
744	31575544	It seems that neither the Atox1 nor CCS gene are often mutated in any of the cancers examined, with the highest mutation frequency for CCS and Atox1 observed in uterine corpus endometrial carcinoma (UCEC) (1.5%) and liver hepatocellular carcinoma (LIHC) (0.27%) malignancies, respectively (Fig.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('CCS', 'molecular_function', 'GO:0052728', ('135', '138'))	('CCS', 'molecular_function', 'GO:0034019', ('36', '39'))	('CCS', 'Gene', (135, 138))	('liver hepatocellular carcinoma', 'Disease', (216, 246))	('malignancies', 'Disease', 'MESH:D009369', (262, 274))	('endometrial carcinoma', 'Disease', (176, 197))	('malignancies', 'Disease', (262, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('CCS', 'molecular_function', 'GO:0052728', ('36', '39'))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('mutation', 'Var', (112, 120))	('cancers', 'Disease', (77, 84))	('CCS', 'molecular_function', 'GO:0052727', ('135', '138'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (176, 197))	('Atox1', 'Gene', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (216, 246))	('CCS', 'molecular_function', 'GO:0034019', ('135', '138'))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (176, 197))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (222, 246))	('CCS', 'molecular_function', 'GO:0052727', ('36', '39'))
750	31575544	Providing that Atox1 and CCS copper chaperones are essentially engaged in trafficking of cisplatin and in its targeting to specific molecules, their cognate gene mutations, deletions or downregulations may render tumor cells refractory to cisplatin-based therapy.	('tumor', 'Disease', (213, 218))	('mutations', 'Var', (162, 171))	('CCS', 'molecular_function', 'GO:0052727', ('25', '28'))	('CCS', 'molecular_function', 'GO:0052728', ('25', '28'))	('copper', 'Chemical', 'MESH:D003300', (29, 35))	('downregulations', 'NegReg', (186, 201))	('cisplatin', 'Chemical', 'MESH:D002945', (239, 248))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('CCS', 'molecular_function', 'GO:0034019', ('25', '28'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('deletions', 'Var', (173, 182))
760	31575544	Hence, if certain enzymes require copper to control neuropeptide production, or other nervous system-related mechanisms, Atox1-depletion must significantly impair fly kinetic capacity and lifespan in a neuropeptide deficiency-dependent manner.	('neuropeptide deficiency-dependent', 'Disease', 'MESH:D000437', (202, 235))	('copper', 'Chemical', 'MESH:D003300', (34, 40))	('lifespan', 'CPA', (188, 196))	('neuropeptide deficiency-dependent', 'Disease', (202, 235))	('fly kinetic capacity', 'CPA', (163, 183))	('impair', 'NegReg', (156, 162))	('Atox1-depletion', 'Var', (121, 136))
762	31575544	Remarkably, silencing of the CCS gene, specifically in neuronal cells, causes dramatic reduction of kinetic activity (mobility) for both Drosophila sexes during aging (Fig.	('CCS', 'molecular_function', 'GO:0034019', ('29', '32'))	('Drosophila sexes', 'Disease', (137, 153))	('CCS', 'molecular_function', 'GO:0052727', ('29', '32'))	('silencing', 'Var', (12, 21))	('aging', 'biological_process', 'GO:0007568', ('161', '166'))	('Drosophila sexes', 'Disease', 'MESH:D012735', (137, 153))	('kinetic activity', 'MPA', (100, 116))	('CCS', 'molecular_function', 'GO:0052728', ('29', '32'))	('CCS', 'Gene', (29, 32))	('reduction', 'NegReg', (87, 96))
776	31575544	Hence, in Drosophila, absence of Atox1 may cause methylation-mediated reprogramming of gene expression and/or CCND1-dependent cell-cycle arrest, ultimately inducing tissue dysfunction, kinetic impairment and longevity compromise.	('gene expression', 'biological_process', 'GO:0010467', ('87', '102'))	('cause', 'Reg', (43, 48))	('Atox1', 'Gene', (33, 38))	('methyl', 'Chemical', 'MESH:C031105', (49, 55))	('methylation-mediated', 'MPA', (49, 69))	('absence', 'Var', (22, 29))	('tissue', 'CPA', (165, 171))	('inducing', 'Reg', (156, 164))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('126', '143'))	('cell-cycle arrest', 'CPA', (126, 143))	('kinetic impairment', 'Disease', 'MESH:D020240', (185, 203))	('longevity compromise', 'CPA', (208, 228))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('kinetic impairment', 'Disease', (185, 203))	('CCND1-dependent', 'Gene', (110, 125))
798	31575544	The tissue-specific drivers used were: w[*]; P{w[+mC]=GAL4-ninaE.GMR}12 (BL: 1104), W[1118] P{w[+mW.hs]=GawB}Bx[MS1096] (BL: 8860), w[*]; P{w[+mC]=GAL4-elav.L}3 (BL: 8760) and y[1] w[*]; P{w[+mC]=Act5C-GAL4}25FO1/CyO, y[+] (BL: 4414), all obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) (Indianapolis, USA).	('CyO', 'Gene', (213, 216))	('ninaE', 'Gene', '42367', (59, 64))	('Act5C', 'Gene', '31521', (196, 201))	('y[+]', 'Chemical', 'MESH:C072473', (218, 222))	('NIH P40OD018537', 'Chemical', 'MESH:C042687', (294, 309))	('W[1118] P', 'Chemical', 'MESH:C519305', (84, 93))	('Bloomington Drosophila Stock Center', 'Disease', (257, 292))	('CyO', 'Gene', '34350', (213, 216))	('Act5C', 'Gene', (196, 201))	('P40', 'cellular_component', 'GO:0043514', ('298', '301'))	('BL: 8760', 'Var', (162, 170))	('P40', 'cellular_component', 'GO:0070743', ('298', '301'))	('Bloomington Drosophila Stock Center', 'Disease', 'MESH:D008224', (257, 292))	('ninaE', 'Gene', (59, 64))
809	31575544	Flies were allowed to survive and grow on fly food containing 80 muM of DC_AC50 for 20 days and were subjected to a survival assay as previously described.	('muM', 'Gene', (65, 68))	('DC_AC50', 'Var', (72, 79))	('muM', 'Gene', '33903', (65, 68))
818	33824393	The entire specification, delamination, migration, and differentiation process is highly regulated and abnormalities during this craniofacial development cause birth defects.	('abnormalities', 'Var', (103, 116))	('delamination', 'biological_process', 'GO:0060232', ('26', '38'))	('cause', 'Reg', (154, 159))	('th', 'Chemical', 'MESH:D013910', (124, 126))	('th', 'Chemical', 'MESH:D013910', (163, 165))	('rat', 'Species', '10116', (43, 46))	('craniofacial development', 'biological_process', 'GO:1904888', ('129', '153'))	('birth defects', 'Disease', 'MESH:D000014', (160, 173))	('birth defects', 'Disease', (160, 173))
821	33824393	hReg-CNCC allows us to annotate genetic variants of human facial GWAS and disease traits with associated cis-regulatory modules, transcription factors, and target genes.	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('hReg', 'Gene', '5967', (0, 4))	('human', 'Species', '9606', (52, 57))	('hReg', 'Gene', (0, 4))	('th', 'Chemical', 'MESH:D013910', (91, 93))	('variants', 'Var', (40, 48))	('facial GWAS', 'Disease', (58, 69))
822	33824393	For example, we reveal the distal and combinatorial regulation of multiple SNPs to core TF ALX1 and associations to facial distances and cranial rare disease.	('associations', 'Interaction', (100, 112))	('ALX1', 'Gene', '8092', (91, 95))	('TF', 'Gene', '2152', (88, 90))	('ALX1', 'Gene', (91, 95))	('facial distances', 'Disease', (116, 132))	('SNPs', 'Var', (75, 79))	('core', 'cellular_component', 'GO:0019013', ('83', '87'))	('cranial rare disease', 'Disease', 'MESH:D035583', (137, 157))	('th', 'Chemical', 'MESH:D013910', (23, 25))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('cranial rare disease', 'Disease', (137, 157))
824	33824393	hReg-CNCC provides a valuable resource to interpret genetic variants as early as gastrulation during embryonic development.	('variants', 'Var', (60, 68))	('gastrulation', 'biological_process', 'GO:0007369', ('81', '93'))	('hReg', 'Gene', '5967', (0, 4))	('hReg', 'Gene', (0, 4))
827	33824393	It may be useful in interpreting genetic variants involved in embryonic development by linking the cis-regulatory sequences in this network with GWAS SNPs, disease risk loci, and evolutionarily-conserved regions of the genome.	('variants', 'Var', (41, 49))	('th', 'Chemical', 'MESH:D013910', (142, 144))	('GWAS SNPs', 'Disease', (145, 154))	('th', 'Chemical', 'MESH:D013910', (215, 217))	('GWAS SNPs', 'Disease', 'None', (145, 154))	('th', 'Chemical', 'MESH:D013910', (95, 97))	('th', 'Chemical', 'MESH:D013910', (127, 129))
829	33824393	These genetic variants are enriched in enhancers preferentially active in cranial neural crest cells (CNCC) and embryonic craniofacial tissue.	('embryonic craniofacial', 'Disease', (112, 134))	('variants', 'Var', (14, 22))	('embryonic craniofacial', 'Disease', 'MESH:D019465', (112, 134))
831	33824393	Thus, a synthesis of the population genetics and developmental biology holds great promise to understand how differences in DNA sequence alter gene regulation in a specific cellular context and determine differences in their phenotypes.	('synthesis', 'biological_process', 'GO:0009058', ('8', '17'))	('th', 'Chemical', 'MESH:D013910', (21, 23))	('gene regulation', 'MPA', (143, 158))	('th', 'Chemical', 'MESH:D013910', (11, 13))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('regulation', 'biological_process', 'GO:0065007', ('148', '158'))	('alter', 'Reg', (137, 142))	('differences', 'Var', (109, 120))	('DNA sequence', 'Gene', (124, 136))	('determine', 'Reg', (194, 203))	('th', 'Chemical', 'MESH:D013910', (219, 221))
838	33824393	used neural-specific enhancer to isolate pure neural crest subpopulation and knocked down the neural plate border genes and early neural crest specifier genes to construct a gene regulatory network of neural crest.	('neural plate border genes', 'Gene', (94, 119))	('pure', 'molecular_function', 'GO:0034023', ('41', '45'))	('th', 'Chemical', 'MESH:D013910', (90, 92))	('knocked', 'Var', (77, 84))
840	33824393	Most importantly, they ignored the important role of cis-regulatory elements (REs), in which genetic variants located and altered regulation.	('th', 'Chemical', 'MESH:D013910', (31, 33))	('th', 'Chemical', 'MESH:D013910', (18, 20))	('regulation', 'MPA', (130, 140))	('variants', 'Var', (101, 109))	('regulation', 'biological_process', 'GO:0065007', ('130', '140'))	('altered', 'Reg', (122, 129))
841	33824393	For a better understanding of how genetic variants affect human craniofacial traits and diseases, a genome-wide regulatory network with non-coding REs for the human neural crest is in pressing need.	('human', 'Species', '9606', (58, 63))	('affect', 'Reg', (51, 57))	('variants', 'Var', (42, 50))	('th', 'Chemical', 'MESH:D013910', (155, 157))	('human', 'Species', '9606', (159, 164))	('th', 'Chemical', 'MESH:D013910', (133, 135))
960	33824393	The genetic variants in the CRMs of hReg-CNCC, including their functional REs, TGs, and bound TFs, should be useful in the annotation of SNPs identified by GWAS of human facial variation traits.	('TGs', 'biological_process', 'GO:0006342', ('79', '82'))	('hReg', 'Gene', (36, 40))	('th', 'Chemical', 'MESH:D013910', (24, 26))	('human', 'Species', '9606', (164, 169))	('variants', 'Var', (12, 20))	('th', 'Chemical', 'MESH:D013910', (57, 59))	('TF', 'Gene', '2152', (94, 96))	('hReg', 'Gene', '5967', (36, 40))	('th', 'Chemical', 'MESH:D013910', (119, 121))
971	33824393	With the global enrichment signal, we next scanned every facial shape-associated SNPs with P-value in TF-CRM-TG triplet of hReg-CNCC (no SNPs with P-value  were overlapped with hReg-CNCC).	('hReg', 'Gene', '5967', (177, 181))	('hReg', 'Gene', '5967', (123, 127))	('hReg', 'Gene', (177, 181))	('hReg', 'Gene', (123, 127))	('P-value', 'Var', (91, 98))	('TF', 'Gene', '2152', (102, 104))	('th', 'Chemical', 'MESH:D013910', (2, 4))	('th', 'Chemical', 'MESH:D013910', (88, 90))	('th', 'Chemical', 'MESH:D013910', (5, 7))	('th', 'Chemical', 'MESH:D013910', (174, 176))	('th', 'Chemical', 'MESH:D013910', (144, 146))
978	33824393	Literature evidence supported that mis-regulation of these TFs was involved with a facial abnormality.	('involved', 'Reg', (67, 75))	('facial abnormality', 'Phenotype', 'HP:0000271', (83, 101))	('facial abnormality', 'Disease', 'MESH:D005148', (83, 101))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('mis-regulation', 'Var', (35, 49))	('th', 'Chemical', 'MESH:D013910', (53, 55))	('rat', 'Species', '10116', (4, 7))	('TF', 'Gene', '2152', (59, 61))	('th', 'Chemical', 'MESH:D013910', (30, 32))	('th', 'Chemical', 'MESH:D013910', (78, 80))	('facial abnormality', 'Disease', (83, 101))
984	33824393	There were also many SNPs and downstream TGs, such as RUVBL1, which was also associated with the nose and mouth.	('RUVBL1', 'Gene', '8607', (54, 60))	('th', 'Chemical', 'MESH:D013910', (90, 92))	('nose', 'Disease', (97, 101))	('th', 'Chemical', 'MESH:D013910', (93, 95))	('RUVBL1', 'Gene', (54, 60))	('SNPs', 'Var', (21, 25))	('TGs', 'biological_process', 'GO:0006342', ('41', '44'))	('th', 'Chemical', 'MESH:D013910', (109, 111))	('associated', 'Reg', (77, 87))
992	33824393	There were two SNPs (rs12810608, rs11609649) associated with ALX1.	('ALX1', 'Gene', (61, 65))	('rs12810608', 'Var', (21, 31))	('th', 'Chemical', 'MESH:D013910', (58, 60))	('associated', 'Reg', (45, 55))	('rs11609649', 'Var', (33, 43))	('rs11609649', 'Mutation', 'rs11609649', (33, 43))	('ALX1', 'Gene', '8092', (61, 65))	('rs12810608', 'Mutation', 'rs12810608', (21, 31))
993	33824393	SNP rs12810608 (P-value 3.30e-07) was located in ALX1's promoter and SNP rs11609649 (P-value 1.55e-06) was located in a distal regulatory region (97K upstream).	('ALX1', 'Gene', '8092', (49, 53))	('ALX1', 'Gene', (49, 53))	('rs11609649', 'Var', (73, 83))	('rs11609649', 'Mutation', 'rs11609649', (73, 83))	('rs12810608', 'Mutation', 'rs12810608', (4, 14))
1001	33824393	On the distal RE, when allele at rs11609649 was changed to the effective allele, there were a gain of motif "PH0082.1_Irx2/Jaspar" and a loss of motif FOXM1_1/encode.	('th', 'Chemical', 'MESH:D013910', (3, 5))	('FOXM1', 'Gene', '2305', (151, 156))	('th', 'Chemical', 'MESH:D013910', (59, 61))	('Irx2', 'Gene', '153572', (118, 122))	('gain', 'PosReg', (94, 98))	('loss', 'NegReg', (137, 141))	('rs11609649', 'Var', (33, 43))	('rs11609649', 'Mutation', 'rs11609649', (33, 43))	('Irx2', 'Gene', (118, 122))	('th', 'Chemical', 'MESH:D013910', (81, 83))	('FOXM1', 'Gene', (151, 156))
1007	33824393	For example, rs16985457 was located in chr19:54693360-54695240 and chr19:54693360-54695240 was predicted to regulate CNOT3, PRPF31, and LENG1 (Fig.	('CNOT3', 'Gene', '4849', (117, 122))	('LENG1', 'Gene', '79165', (136, 141))	('chr19:54693360-54695240', 'STRUCTURAL_ABNORMALITY', 'None', (39, 62))	('rs16985457', 'Mutation', 'rs16985457', (13, 23))	('PRPF31', 'Gene', '26121', (124, 130))	('PRPF31', 'Gene', (124, 130))	('regulate', 'Reg', (108, 116))	('rs16985457', 'Var', (13, 23))	('chr19:54693360-54695240', 'STRUCTURAL_ABNORMALITY', 'None', (67, 90))	('CNOT3', 'Gene', (117, 122))	('LENG1', 'Gene', (136, 141))	('chr19:54693360-54695240', 'Var', (67, 90))
1009	33824393	For example, rs12810608 was located in chr12:85673460-85674718, which regulates ALX1, and this SNP was associated with three face distances: "EnR-Prn", "EnL-Prn", and "EnR-AlL" (Fig.	('chr12:85673460-85674718', 'STRUCTURAL_ABNORMALITY', 'None', (39, 62))	('th', 'Chemical', 'MESH:D013910', (116, 118))	('rs12810608', 'Var', (13, 23))	('th', 'Chemical', 'MESH:D013910', (90, 92))	('EnL', 'Gene', '4298', (153, 156))	('ALX1', 'Gene', '8092', (80, 84))	('ALX1', 'Gene', (80, 84))	('rs12810608', 'Mutation', 'rs12810608', (13, 23))	('EnL', 'Gene', (153, 156))	('th', 'Chemical', 'MESH:D013910', (119, 121))
1011	33824393	For instance, rs11719548 and rs11711710 were simultaneously located in chr3:12872024-127872868 and chr3:12872024-127872868 regulated RUVBL1 (Fig.	('RUVBL1', 'Gene', '8607', (133, 139))	('rs11719548', 'Var', (14, 24))	('rs11719548', 'Mutation', 'rs11719548', (14, 24))	('rs11711710', 'Var', (29, 39))	('regulated', 'Reg', (123, 132))	('RUVBL1', 'Gene', (133, 139))	('chr3:12872024-127872868', 'STRUCTURAL_ABNORMALITY', 'None', (71, 94))	('chr3:12872024-127872868', 'Var', (71, 94))	('rs11711710', 'Mutation', 'rs11711710', (29, 39))	('chr3:12872024-127872868', 'STRUCTURAL_ABNORMALITY', 'None', (99, 122))
1012	33824393	In summary, hReg-CNCC can improve the enrichment of facial shape-associated SNPs in CNCC and used the TFs, REs, and TGs to help explain how genetic variants get involved in regulation, such as ALX1.	('hReg', 'Gene', (12, 16))	('involved', 'Reg', (161, 169))	('enrichment', 'MPA', (38, 48))	('TGs', 'biological_process', 'GO:0006342', ('116', '119'))	('th', 'Chemical', 'MESH:D013910', (34, 36))	('TF', 'Gene', '2152', (102, 104))	('variants', 'Var', (148, 156))	('ALX1', 'Gene', '8092', (193, 197))	('ALX1', 'Gene', (193, 197))	('th', 'Chemical', 'MESH:D013910', (98, 100))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))	('improve', 'PosReg', (26, 33))	('hReg', 'Gene', '5967', (12, 16))
1019	33824393	For instance, one significant SNP rs758468472 was reported to be associated with "Tooth agenesis" (GWAS with 340,498 participants and 9 risk variants) in GWAS catalog.	('rs758468472', 'Var', (34, 45))	('th', 'Chemical', 'MESH:D013910', (106, 108))	('Tooth agenesis', 'Phenotype', 'HP:0009804', (82, 96))	('Tooth agenesis', 'Disease', 'MESH:D000848', (82, 96))	('rs758468472', 'Mutation', 'rs758468472', (34, 45))	('Tooth agenesis', 'Disease', (82, 96))	('associated', 'Reg', (65, 75))	('participants', 'Species', '9606', (117, 129))	('th', 'Chemical', 'MESH:D013910', (85, 87))	('th', 'Chemical', 'MESH:D013910', (78, 80))
1021	33824393	One of the significant SNPs of "Monobrow" (GWAS with 69,000 participants and 61 significant loci) rs11609649 was located in chr12:85576368-85576871, whose TG was ALX1 and binding TFs were ALX cluster, TFAP2B/A, POU3F3, PRRX2, and NR2F1 (Fig.	('participants', 'Species', '9606', (60, 72))	('TF', 'Gene', '2152', (179, 181))	('th', 'Chemical', 'MESH:D013910', (50, 52))	('ALX', 'Gene', '84941', (162, 165))	('TF', 'Gene', '2152', (201, 203))	('Monobrow', 'Phenotype', 'HP:0000664', (32, 40))	('POU3F3', 'Gene', '5455', (211, 217))	('ALX', 'Gene', (188, 191))	('ALX1', 'Gene', (162, 166))	('binding', 'molecular_function', 'GO:0005488', ('169', '176'))	('rs11609649', 'Var', (98, 108))	('rs11609649', 'Mutation', 'rs11609649', (98, 108))	('th', 'Chemical', 'MESH:D013910', (7, 9))	('NR2F1', 'Gene', '7025', (230, 235))	('ALX1', 'Gene', '8092', (162, 166))	('POU3F3', 'Gene', (211, 217))	('NR2F1', 'Gene', (230, 235))	('PRRX2', 'Gene', '51450', (219, 224))	('TFAP2B/A', 'Gene', '7021', (201, 209))	('ALX', 'Gene', (162, 165))	('ALX', 'Gene', '84941', (188, 191))	('PRRX2', 'Gene', (219, 224))	('chr12:85576368-85576871', 'STRUCTURAL_ABNORMALITY', 'None', (124, 147))	('TFAP2B/A', 'Gene', (201, 209))
1022	33824393	Interestingly, rs11609649 and ALX1 were also detected in annotating GWAS of face distances and their related phenotypes were frontonasal distances (Fig.	('detected', 'Reg', (45, 53))	('ALX1', 'Gene', '8092', (30, 34))	('frontonasal', 'Disease', (125, 136))	('ALX1', 'Gene', (30, 34))	('rs11609649', 'Var', (15, 25))	('rs11609649', 'Mutation', 'rs11609649', (15, 25))	('th', 'Chemical', 'MESH:D013910', (95, 97))
1025	33824393	Putting all the evidence together, SNP rs11609649 was located in a distal RE (97K upstream, chr12:85576368-85576871) and regulated ALX1.	('chr12:85576368-85576871', 'STRUCTURAL_ABNORMALITY', 'None', (92, 115))	('SNP rs11609649', 'Var', (35, 49))	('th', 'Chemical', 'MESH:D013910', (12, 14))	('th', 'Chemical', 'MESH:D013910', (29, 31))	('ALX1', 'Gene', '8092', (131, 135))	('ALX1', 'Gene', (131, 135))	('rs11609649', 'Mutation', 'rs11609649', (39, 49))	('regulated', 'Reg', (121, 130))
1026	33824393	This regulation may be influenced by SNP rs11609649 on the motif binding of IRF3 and FOXM1 (Fig.	('rs11609649', 'Var', (41, 51))	('rs11609649', 'Mutation', 'rs11609649', (41, 51))	('th', 'Chemical', 'MESH:D013910', (55, 57))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('IRF3', 'Gene', (76, 80))	('IRF3', 'Gene', '3661', (76, 80))	('influenced', 'Reg', (23, 33))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('FOXM1', 'Gene', (85, 90))	('FOXM1', 'Gene', '2305', (85, 90))	('SNP', 'Var', (37, 40))	('motif binding', 'Interaction', (59, 72))
1038	33824393	These TFs binding was probably affected by two SNPs, rs62466263 and rs73134905, and finally exerted influence on face width and led to milder face characteristics.	('rs62466263', 'Var', (53, 63))	('rs73134905', 'Var', (68, 78))	('face characteristics', 'Phenotype', 'HP:0001999', (142, 162))	('exerted', 'Reg', (92, 99))	('led to', 'Reg', (128, 134))	('binding', 'Interaction', (10, 17))	('rs73134905', 'Mutation', 'rs73134905', (68, 78))	('affected', 'Reg', (31, 39))	('face', 'MPA', (113, 117))	('rs62466263', 'Mutation', 'rs62466263', (53, 63))	('th', 'Chemical', 'MESH:D013910', (121, 123))	('face width', 'Phenotype', 'HP:0000283', (113, 123))	('TF', 'Gene', '2152', (6, 8))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('influence', 'Reg', (100, 109))	('milder face characteristics', 'MPA', (135, 162))
1058	33824393	For example, chr7:134379901-134380671 was predicted to regulate CALD1.	('CALD1', 'Gene', (64, 69))	('chr7:134379901-134380671', 'Var', (13, 37))	('chr7:134379901-134380671', 'STRUCTURAL_ABNORMALITY', 'None', (13, 37))	('CALD1', 'Gene', '800', (64, 69))	('regulate', 'Reg', (55, 63))
1074	33824393	hReg-CNCC provided a valuable resource to interpret genetic variant as early as gastrulation during embryonic development.	('gastrulation', 'biological_process', 'GO:0007369', ('80', '92'))	('hReg', 'Gene', '5967', (0, 4))	('hReg', 'Gene', (0, 4))	('genetic variant', 'Var', (52, 67))
1075	33824393	Importantly the architecture that upstream, core, and downstream TFs were associated with functions of neural plate border, specification, and migration were explored in hReg-CNCC and biological insights were derived on how this architecture was associated with genetic variants of human facial GWAS, disease traits, and DNA sequence differences in evolution.	('hReg', 'Gene', (170, 174))	('rat', 'Species', '10116', (146, 149))	('th', 'Chemical', 'MESH:D013910', (87, 89))	('human', 'Species', '9606', (282, 287))	('th', 'Chemical', 'MESH:D013910', (224, 226))	('DNA', 'cellular_component', 'GO:0005574', ('321', '324'))	('th', 'Chemical', 'MESH:D013910', (259, 261))	('th', 'Chemical', 'MESH:D013910', (12, 14))	('th', 'Chemical', 'MESH:D013910', (29, 31))	('core', 'cellular_component', 'GO:0019013', ('44', '48'))	('facial GWAS', 'Disease', (288, 299))	('variants', 'Var', (270, 278))	('associated', 'Reg', (246, 256))	('TF', 'Gene', '2152', (65, 67))	('hReg', 'Gene', '5967', (170, 174))
1078	33824393	The traditional method to annotate GWAS variant is to use FUMA or GREAT to establish the association with genes located within 500 kb of the SNPs.	('th', 'Chemical', 'MESH:D013910', (103, 105))	('th', 'Chemical', 'MESH:D013910', (18, 20))	('variant', 'Var', (40, 47))	('th', 'Chemical', 'MESH:D013910', (85, 87))	('th', 'Chemical', 'MESH:D013910', (122, 124))	('th', 'Chemical', 'MESH:D013910', (137, 139))	('association', 'Interaction', (89, 100))
1085	33824393	We show consensus optimization outperforms the naive integrative methods and can fully utilize the information in biological replicates.	('optimization', 'Var', (18, 30))	('outperforms', 'PosReg', (31, 42))	('th', 'Chemical', 'MESH:D013910', (67, 69))	('rat', 'Species', '10116', (58, 61))	('th', 'Chemical', 'MESH:D013910', (43, 45))	('th', 'Chemical', 'MESH:D013910', (95, 97))
1150	33824393	Then the subnetwork of hReg-CNCC associated with a set of SNPs  was obtained as:For RE , we checked all TF-CRM-TG triplets and retained the triplet if its CRM was intersected with this RE.	('th', 'Chemical', 'MESH:D013910', (180, 182))	('hReg', 'Gene', (23, 27))	('triplets', 'Var', (114, 122))	('th', 'Chemical', 'MESH:D013910', (177, 179))	('th', 'Chemical', 'MESH:D013910', (46, 48))	('TF', 'Gene', '2152', (104, 106))	('th', 'Chemical', 'MESH:D013910', (136, 138))	('th', 'Chemical', 'MESH:D013910', (5, 7))	('hReg', 'Gene', '5967', (23, 27))
1194	32426049	Predicting STAT1 as a prognostic marker in patients with solid cancer Aberrant activities of signal transducer and activator of transcription 1 (STAT1) have been implicated in cancer development.	('implicated', 'Reg', (162, 172))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('STAT1', 'Gene', (11, 16))	('patients', 'Species', '9606', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('STAT1', 'Gene', (145, 150))	('STAT1', 'Gene', '6772', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('signal transducer and activator of transcription 1', 'Gene', '6772', (93, 143))	('STAT1', 'Gene', '6772', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Aberrant activities', 'Var', (70, 89))	('cancer', 'Disease', (63, 69))
1199	32426049	Pooled data showed that overexpressed STAT1 favored long overall survival (OS) (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) and disease-specific survival (DSS) (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000).	('disease-specific survival', 'CPA', (129, 154))	('STAT1', 'Gene', (38, 43))	('DSS', 'Chemical', '-', (156, 159))	('favored', 'PosReg', (44, 51))	('overexpressed', 'Var', (24, 37))
1220	32426049	Patients with STAT1 or phospho-STAT1 at a high expression level have a worse outcome compared with patients with STAT1 at a low expression level.	('phospho-STAT1 at', 'Var', (23, 39))	('STAT1', 'Var', (14, 19))	('patients', 'Species', '9606', (99, 107))	('Patients', 'Species', '9606', (0, 8))
1242	32426049	Our analysis revealed that highly expressed STAT1 was a positive predictor for OS among cancer patients (HR = 0.604, 95% CI = 0.431-0.846, p = 0.003) (Figure 3).	('highly expressed', 'Var', (27, 43))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('STAT1', 'Gene', (44, 49))
1246	32426049	The pooled results indicated a positive correlation between highly expressed STAT1 and longer DSS (HR = 0.650, 95% CI = 0.512-0.825, p = 0.000) (Figure 4B).	('highly expressed', 'Var', (60, 76))	('DSS', 'Chemical', '-', (94, 97))	('longer DSS', 'Disease', (87, 97))	('STAT1', 'Gene', (77, 82))
1247	32426049	The first subgroup analyses by region revealed that the pooled HRs were 0.630 (95% CI = 0.337-1.178, p = 0.148) for Asian patients (five studies) and 0.666 (95% CI = 0.431-0.846, p = 0.000) for Non-Asian patients (six studies).	('patients', 'Species', '9606', (204, 212))	('0.666', 'Var', (150, 155))	('0.630', 'Var', (72, 77))	('patients', 'Species', '9606', (122, 130))	('Asian', 'Disease', (116, 121))
1248	32426049	The fourth subgroup analyses by cancer types displayed that highly expressed STAT1 was associated with favorable OS of patients with high-grade serous ovarian cancer (HR = 0.683, 95% CI = 0.497-0.938, p = 0.019) (2 studies), oral squamous cell carcinoma (HR = 0.486, 95% CI = 0.241-0.980, p = 0.044) (two studies), and another five cancers (pooled HR = 0.542, 95% CI = 0.361-0.813, p = 0.003), but not in lung cancer (HR = 1.223, 95% CI = 0.996-1.501, p = 0.055) (two studies).	('oral squamous cell carcinoma', 'Disease', (225, 253))	('lung cancer', 'Disease', (405, 416))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('serous ovarian cancer', 'Disease', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (405, 416))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (405, 416))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('cancer', 'Disease', (332, 338))	('cancers', 'Disease', (332, 339))	('STAT1', 'Gene', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (144, 165))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Disease', (410, 416))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('highly expressed', 'Var', (60, 76))
1265	32426049	The outcomes after analyses indicate that expression of STAT1 is associated with survival of patients based on their cancer type.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STAT1', 'Gene', (56, 61))	('associated with', 'Reg', (65, 80))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('expression', 'Var', (42, 52))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (93, 101))
1271	32426049	The tumor-suppressive role of STAT1 is driven by findings that the reconstitution of STAT1 in STAT1-deficient murine fibrosarcoma cells significantly suppressed tumorigenicity and metastasis in nude mice.	('STAT1-deficient', 'Gene', (94, 109))	('tumor', 'Disease', (4, 9))	('fibrosarcoma', 'Disease', 'MESH:D005354', (117, 129))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (117, 129))	('nude mice', 'Species', '10090', (194, 203))	('suppressed', 'NegReg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('reconstitution', 'Var', (67, 81))	('STAT1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('fibrosarcoma', 'Disease', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (161, 166))	('murine', 'Species', '10090', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
1272	32426049	The high expression of STAT1 is reported to have a good prognosis compared with the low or negative expression of STAT1 in some cancer patients.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (4, 8))	('STAT1', 'Gene', (23, 28))	('cancer', 'Disease', (128, 134))
1273	32426049	However, on the other hand, two studies have identified high STAT1 mRNA levels associated with poor prognosis, tumor progression, and worse survival in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('associated', 'Reg', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('tumor', 'Disease', (111, 116))	('STAT1 mRNA levels', 'MPA', (61, 78))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high', 'Var', (56, 60))
1276	32426049	The survival analysis of TCGA data revealed that highly expressed STAT1 was associated with longer OS in ovarian cancer, rectum adenocarcinoma, sarcoma, and skin cutaneous melanoma.	('sarcoma', 'Disease', (144, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('highly expressed', 'Var', (49, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('skin cutaneous melanoma', 'Disease', (157, 180))	('STAT1', 'Gene', (66, 71))	('longer OS in ovarian cancer', 'Disease', (92, 119))	('rectum adenocarcinoma', 'Disease', (121, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('associated', 'Reg', (76, 86))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (121, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('sarcoma', 'Disease', 'MESH:D012509', (144, 151))	('longer OS in ovarian cancer', 'Disease', 'MESH:C567932', (92, 119))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 180))
1286	32426049	For instance, STAT1 can arrest the cell cycle in response to IFNgamma through direct interaction with cyclin D1 and CDK4 proteins.	('arrest', 'Disease', (24, 30))	('CDK', 'molecular_function', 'GO:0004693', ('116', '119'))	('cell cycle', 'CPA', (35, 45))	('IFNgamma', 'Gene', '3458', (61, 69))	('IFNgamma', 'Gene', (61, 69))	('CDK4', 'Gene', (116, 120))	('cyclin D1', 'Gene', '595', (102, 111))	('CDK4', 'Gene', '1019', (116, 120))	('cyclin D1', 'Gene', (102, 111))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('interaction', 'Interaction', (85, 96))	('STAT1', 'Var', (14, 19))	('cyclin', 'molecular_function', 'GO:0016538', ('102', '108'))	('cell cycle', 'biological_process', 'GO:0007049', ('35', '45'))
1292	32426049	Full-length STAT1alpha isoform has traditionally been considered as the physiologically active form of STAT1 after phosphorylation at Tyr701 and Ser727 residues, and the truncated STAT1beta isoform is considered as a physiological inhibitor of STAT1.	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('Ser727', 'Var', (145, 151))	('Ser727', 'Chemical', '-', (145, 151))	('Tyr701', 'Chemical', '-', (134, 140))	('Ser', 'cellular_component', 'GO:0005790', ('145', '148'))	('Tyr701', 'Var', (134, 140))
1293	32426049	The expression and activation ratio of STAT1alpha and STAT1beta in different cancer types may impact cancer progression and promote a 'switch' from tumor cell proliferation to a death phenotype.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('STAT1beta', 'Var', (54, 63))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (77, 83))	('tumor', 'Disease', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('death', 'Disease', 'MESH:D003643', (178, 183))	('death', 'Disease', (178, 183))	("'switch'", 'PosReg', (134, 142))	('STAT1alpha', 'Gene', (39, 49))	('promote', 'PosReg', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('impact', 'Reg', (94, 100))
1295	32426049	Interestingly, another study shows that STAT1beta protects STAT1alpha from degradation and enhances STAT1 function in esophageal squamous cell carcinoma.	('STAT1alpha', 'Protein', (59, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('STAT1 function', 'MPA', (100, 114))	('enhances', 'PosReg', (91, 99))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('STAT1beta', 'Var', (40, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('degradation', 'MPA', (75, 86))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
1371	30066226	An abnormal baseline NLR is associated with adverse outcomes in advanced and high-risk melanoma, but has not been investigated for Stages I-III melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('abnormal', 'Var', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('associated', 'Reg', (28, 38))	('NLR', 'MPA', (21, 24))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('I-III melanoma', 'Disease', 'MESH:D008545', (138, 152))	('I-III melanoma', 'Disease', (138, 152))
1388	30066226	Similarly, an adjusted baseline PLR lower than 100 was significantly associated with worse overall survival (HR 1.8; 95% CI 1.7 to 1.8) and melanoma-specific survival (HR 1.9; 95% CI 1.7 to 2.2; Table 2), meaning that patients with a low baseline PLR were at approximately twice the risk of death from melanoma during a 10-year period.	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('death', 'Disease', 'MESH:D003643', (291, 296))	('death', 'Disease', (291, 296))	('lower', 'Var', (36, 41))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('patients', 'Species', '9606', (218, 226))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('overall survival', 'CPA', (91, 107))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('worse', 'NegReg', (85, 90))
1389	30066226	The patients with a low NLR and PLR were at three times the risk of death during a 10-year period (HR 3.0; 95% CI 2.4 to 3.7; Fig.	('death', 'Disease', 'MESH:D003643', (68, 73))	('death', 'Disease', (68, 73))	('low', 'Var', (20, 23))	('patients', 'Species', '9606', (4, 12))
1403	30066226	Our findings concur with the evolving hypothesis that host immunity is implicated in the survival of patients with melanoma, whereby a pro-inflammatory state may suppress or eradicate metastasis, explaining our observed better survival of those with a high NLR (i.e., a host inflammatory response).	('patients', 'Species', '9606', (101, 109))	('metastasis', 'CPA', (184, 194))	('high', 'Var', (252, 256))	('melanoma', 'Disease', (115, 123))	('suppress', 'NegReg', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('eradicate', 'NegReg', (174, 183))	('better', 'PosReg', (220, 226))	('inflammatory response', 'biological_process', 'GO:0006954', ('275', '296'))
1405	30066226	However, their study considered patients with pT2b or worse tumors and those presenting with nodal metastases.	('pT2b', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('nodal metastases', 'Disease', (93, 109))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('nodal metastases', 'Disease', 'MESH:D009362', (93, 109))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
1484	30577835	The study that concluded this gene set observed the aberration in NSCLC with oncogenic form of KRAS and inactivated PTEN, in which condition resulted in shorter survival.	('KRAS', 'Gene', '3845', (95, 99))	('NSCLC', 'Disease', (66, 71))	('aberration', 'Var', (52, 62))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('shorter', 'NegReg', (153, 160))	('KRAS', 'Gene', (95, 99))	('PTEN', 'Gene', (116, 120))	('survival', 'MPA', (161, 169))
1522	29081790	Melanoma is among the most immunogenic cancers, with an important mutational load, probably explaining a high rate of partial tumor regression.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('immunogenic cancers', 'Disease', 'MESH:D009369', (27, 46))	('Melanoma', 'Disease', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('immunogenic cancers', 'Disease', (27, 46))	('mutational', 'Var', (66, 76))	('tumor', 'Disease', (126, 131))
1527	29081790	However, genetic susceptibility has been shown to be another factor promoting melanoma development, in around 10% of patients.	('genetic susceptibility', 'Var', (9, 31))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('patients', 'Species', '9606', (117, 125))	('promoting', 'PosReg', (68, 77))
1531	29081790	Loss-of-function mutations thus discard the inhibitory role of the two CDKN2A products, namely p16INK4A and p14ARF on cell cycle progression, leading to enhanced proliferation.	('Loss-of-function', 'NegReg', (0, 16))	('CDKN2A', 'Gene', (71, 77))	('proliferation', 'CPA', (162, 175))	('discard', 'NegReg', (32, 39))	('cell cycle', 'biological_process', 'GO:0007049', ('118', '128'))	('cell cycle progression', 'CPA', (118, 140))	('p16INK4A', 'Var', (95, 103))	('p14ARF', 'Gene', (108, 114))	('enhanced', 'PosReg', (153, 161))	('mutations', 'Var', (17, 26))	('p14ARF', 'Gene', '396553', (108, 114))
1532	29081790	The CDK4 R24C activating mutation is also highly penetrant, although it concerns only a few families worldwide: this non-synonymous substitution changes an amino acid essential for binding of CDK4 to p16INK4A, leading to an increased proliferation.	('proliferation', 'CPA', (234, 247))	('CDK', 'molecular_function', 'GO:0004693', ('192', '195'))	('binding', 'molecular_function', 'GO:0005488', ('181', '188'))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))	('binding', 'Interaction', (181, 188))	('R24C', 'Mutation', 'rs11547328', (9, 13))	('activating', 'PosReg', (14, 24))	('changes', 'Reg', (145, 152))	('CDK4', 'Gene', (4, 8))	('R24C', 'Var', (9, 13))	('increased', 'PosReg', (224, 233))
1535	29081790	For example, a series of polymorphisms, named RHC variants for Red Hair Color variants, are carried by individuals with light skin, blue eyes and red hair, poor tanning ability and sensitivity to sunburn.	('blue eyes', 'Phenotype', 'HP:0000635', (132, 141))	('red hair', 'Phenotype', 'HP:0002297', (146, 154))	('light skin', 'Phenotype', 'HP:0001010', (120, 130))	('Red Hair Color', 'Disease', (63, 77))	('sensitivity to sunburn', 'Phenotype', 'HP:0000992', (181, 203))	('variants', 'Var', (50, 58))	('Red Hair', 'Phenotype', 'HP:0002297', (63, 71))	('variants', 'Var', (78, 86))	('blue eyes and red hair', 'Disease', 'MESH:C567139', (132, 154))
1538	29081790	In two recent studies focusing on somatic mutations in melanoma, the authors reported a more important mutational burden in tumors of patients carriers of 1 or 2 RHC alleles compared to non-RHC patients.	('mutational', 'Var', (103, 113))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('patients', 'Species', '9606', (194, 202))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('RHC', 'Gene', (162, 165))	('patients', 'Species', '9606', (134, 142))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('alleles', 'Var', (166, 173))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
1539	29081790	Since 2011, the MITF gene (Microphtalmia-Associated Transcription Factor) is considered as a medium-risk gene, since two studies involving linkage analysis followed by sequencing, showed the functional impact of the E318K rare mutation on melanoma and renal cell carcinoma risks.	('E318K', 'Mutation', 'rs149617956', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('renal cell carcinoma', 'Disease', (252, 272))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (252, 272))	('E318K', 'Var', (216, 221))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('Microphtalmia-Associated Transcription Factor', 'Gene', (27, 72))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (252, 272))	('Microphtalmia-Associated Transcription Factor', 'Gene', '414902', (27, 72))
1540	29081790	More recently, demonstrated that human melanocytes carrying the MITF E318K mutation could no longer undergo BRAFV 600E-induced senescence, thus promoting melanoma development., mutations in TERT promoter were shown to modify melanoma risk in familial melanoma.	('senescence', 'biological_process', 'GO:0010149', ('127', '137'))	('modify', 'Reg', (218, 224))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (225, 233))	('mutations', 'Var', (177, 186))	('E318K', 'Mutation', 'rs149617956', (69, 74))	('familial melanoma', 'Disease', (242, 259))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('human', 'Species', '9606', (33, 38))	('melanoma', 'Disease', (154, 162))	('familial melanoma', 'Disease', 'OMIM:155600', (242, 259))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('BRAFV 600E', 'Mutation', 'rs113488022', (108, 118))	('melanoma', 'Disease', (251, 259))	('TERT promoter', 'Gene', (190, 203))
1547	29081790	Since the discovery of predisposing variants in TERT promoter, research on melanoma genetics has focused on germline mutations in genes coding for components of the telomere maintenance complex.	('telomere', 'cellular_component', 'GO:0005696', ('165', '173'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('165', '185'))	('telomere', 'cellular_component', 'GO:0000781', ('165', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('TERT promoter', 'Gene', (48, 61))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('variants', 'Var', (36, 44))
1548	29081790	Mutations in POT1, and in ACD and TERF2IP have been associated with melanoma increased risk in around 1% of predisposed families.	('TERF2IP', 'Gene', '100521624', (34, 41))	('ACD', 'Disease', (26, 29))	('ACD', 'Disease', 'MESH:C535474', (26, 29))	('associated', 'Reg', (52, 62))	('POT1', 'Gene', '100192443', (13, 17))	('POT1', 'Gene', (13, 17))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('Mutations', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('TERF2IP', 'Gene', (34, 41))
1557	29081790	For example, used transposon mutagenesis in a BRAFV 600E mouse model to determine a set of genes cooperating with the BRAF mutation to drive melanoma progression.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('BRAFV 600E', 'Mutation', 'rs113488022', (46, 56))	('mutation', 'Var', (123, 131))	('BRAF', 'Gene', (118, 122))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('mutagenesis', 'biological_process', 'GO:0006280', ('29', '40'))	('drive', 'PosReg', (135, 140))	('mouse', 'Species', '10090', (57, 62))
1568	29081790	However, as in rodents, melanoma development is induced by genetic manipulation of oncogenes or ENU-induced mutagenesis, which is a major limitation to study genetic predisposition.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('mutagenesis', 'Var', (108, 119))	('mutagenesis', 'biological_process', 'GO:0006280', ('108', '119'))	('genetic manipulation', 'Var', (59, 79))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('induced', 'Reg', (48, 55))
1570	29081790	Melanoma development has been attributed to a mutation in the intron 6 of STX17, leading to an activation of the ERK pathway.	('STX17', 'Gene', (74, 79))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('STX17', 'Gene', '100157063', (74, 79))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('mutation in', 'Var', (46, 57))	('Melanoma', 'Disease', (0, 8))	('activation', 'PosReg', (95, 105))	('ERK pathway', 'Pathway', (113, 124))	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))
1602	29081790	The fact that at least two of the three models (Sinclair and MeLiM) come from the Hormel swine farm would indicate shared genetic variants, potentially including the melanoma predisposing variants.	('variants', 'Var', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('swine', 'Species', '9823', (89, 94))
1604	29081790	This observation is explained by the absence of melanocytes in the skin of white pigs, due to a complex mutation of the KIT gene.	('KIT', 'molecular_function', 'GO:0005020', ('120', '123'))	('pigs', 'Species', '9823', (81, 85))	('mutation', 'Var', (104, 112))	('KIT', 'Gene', (120, 123))
1605	29081790	Therefore, melanoma predisposing variants could not have an effect on a white animal that does not possess the cell of origin of the tumor.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('variants', 'Var', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
1632	29081790	However, one cannot rule out the possibility that the Duroc pigs used previously harbored small tumors that underwent regression, or that without exhibiting lesions, they still carry predisposing variants that can be transmitted to the progeny.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('pigs', 'Species', '9823', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('variants', 'Var', (196, 204))	('small tumors', 'Disease', (90, 102))	('small tumors', 'Disease', 'MESH:D058405', (90, 102))
1643	29081790	However, subsequent studies showed no association between variants in the gene and melanoma phenotypes.	('variants', 'Var', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
1646	29081790	A microsatellite located close to MC1R was linked to melanoma, even when the analysis was corrected for coat color, proving that pigmentation variation was not the only effect.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('MC1R', 'Gene', (34, 38))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('pigmentation', 'biological_process', 'GO:0043473', ('129', '141'))	('microsatellite', 'Var', (2, 16))	('linked', 'Reg', (43, 49))	('pigmentation', 'Disease', 'MESH:D010859', (129, 141))	('pigmentation', 'Disease', (129, 141))
1649	29081790	The MC1R ED1 allele, associated with melanoma in MeLiM pigs, carries a Leu102Pro polymorphism.	('Leu102Pro', 'SUBSTITUTION', 'None', (71, 80))	('associated', 'Reg', (21, 31))	('MC1R ED1', 'Gene', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('Leu102Pro', 'Var', (71, 80))	('pigs', 'Species', '9823', (55, 59))
1653	29081790	Interestingly, Tibetan pigs also carry the MC1R allele ED1, but no skin lesion has been described in this breed to our knowledge.	('MC1R', 'Gene', (43, 47))	('pigs', 'Species', '9823', (23, 27))	('ED1', 'Var', (55, 58))
1654	29081790	This confirms that MC1R is not sufficient to promote melanoma development but contributes to an increased penetrance.	('increased', 'PosReg', (96, 105))	('penetrance', 'MPA', (106, 116))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('MC1R', 'Var', (19, 23))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))
1659	29081790	An association of a SNP in the exon 19 was shown, once again with the Duroc allele promoting melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('promoting', 'PosReg', (83, 92))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('SNP in', 'Var', (20, 26))
1660	29081790	An association between SLA microsatellites and melanoma was also observed.	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('SLA', 'Gene', (23, 26))	('microsatellites', 'Var', (27, 42))
1670	29081790	Genome modifications should be limited since (i) regression systematically occurs, and thus may indicate that tumors do not escape immune surveillance using favorable mutations in specific genes (ii) the environmental UV-signature that is classically encountered in the genome of human cutaneous melanomas should be absent.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (286, 305))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (286, 305))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (286, 304))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mutations', 'Var', (167, 176))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('cutaneous melanomas', 'Disease', (286, 305))	('melanomas', 'Phenotype', 'HP:0002861', (296, 305))	('human', 'Species', '9606', (280, 285))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
1678	29081790	Also, the identification of somatic mutations in MeLiM that are similar to recurrent variation in human melanoma could pave the way to pharmacogenomics studies.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('MeLiM', 'Gene', (49, 54))	('mutations', 'Var', (36, 45))	('human', 'Species', '9606', (98, 103))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
1682	29081790	First, genome modification could help validating a potential causal mutation for melanoma development.	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('genome modification', 'Var', (7, 26))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
1686	29081790	Among the 115 samples analyzed by the TCGA consortium to establish the genomic classification of cutaneous melanoma, 65% were found with an activating mutation in TERT promoter, and 7% with a focal amplification of TERT locus.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mutation', 'Var', (151, 159))	('cutaneous melanoma', 'Disease', (97, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (97, 115))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (97, 115))	('TERT promoter', 'Gene', (163, 176))	('activating', 'PosReg', (140, 150))
1705	29081790	Among the possible oncogenic mechanisms, HERV-K could participate to cell transformation by insertional mutagenesis, through its rec and np9 oncogenic proteins, or even by modulating the immune response.	('immune response', 'CPA', (187, 202))	('rec', 'MPA', (129, 132))	('insertional mutagenesis', 'Var', (92, 115))	('HERV-K', 'Species', '45617', (41, 47))	('np9', 'Protein', (137, 140))	('cell transformation', 'CPA', (69, 88))	('modulating', 'Reg', (172, 182))	('participate', 'Reg', (54, 65))	('immune response', 'biological_process', 'GO:0006955', ('187', '202'))	('mutagenesis', 'biological_process', 'GO:0006280', ('104', '115'))	('HERV-K', 'Protein', (41, 47))
1830	33329726	This happened for GSE14520(U133B), GSE6919(U95B and C), and GSE 6344(U133B).	('GSE', 'Gene', '317782', (18, 21))	('GSE', 'Gene', (18, 21))	('GSE6919', 'Chemical', '-', (35, 42))	('B', 'Chemical', 'MESH:D001895', (73, 74))	('B', 'Chemical', 'MESH:D001895', (46, 47))	('GSE', 'Gene', (60, 63))	('GSE', 'Gene', '317782', (60, 63))	('U133B', 'Var', (27, 32))	('U133B', 'Var', (69, 74))	('GSE', 'Gene', '317782', (35, 38))	('GSE', 'Gene', (35, 38))	('B', 'Chemical', 'MESH:D001895', (31, 32))
1889	33329726	In this sense, the 33 overexpressed genes used as input for the network construction were related to GOs deeply associated to all cancers, like a positive induction of cell cycle, deregulation of DNA repair, proteolysis, and kinase-related signaling pathways (Figure 2C and Supplementary Figure 1, Supplementary Table 16) (Hanahan and Weinberg,; Pickup et al.,; Sanchez-Vega et al.,).	('DNA repair', 'biological_process', 'GO:0006281', ('196', '206'))	('proteolysis', 'biological_process', 'GO:0006508', ('208', '219'))	('kinase-related signaling pathways', 'Pathway', (225, 258))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cell cycle', 'biological_process', 'GO:0007049', ('168', '178'))	('cell cycle', 'CPA', (168, 178))	('to', 'Gene', '6999', (98, 100))	('cancers', 'Disease', (130, 137))	('proteolysis', 'CPA', (208, 219))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('signaling', 'biological_process', 'GO:0023052', ('240', '249'))	('deregulation', 'Var', (180, 192))	('to', 'Gene', '6999', (123, 125))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('DNA repair', 'Protein', (196, 206))
1953	33329726	BRCA patients with high expression of CTHRC1 had shorter lifespans (HR = 1.7) however.	('CTHRC1', 'Gene', (38, 44))	('pan', 'Gene', '51816', (62, 65))	('patients', 'Species', '9606', (5, 13))	('BRCA', 'Gene', (0, 4))	('high expression', 'Var', (19, 34))	('shorter', 'NegReg', (49, 56))	('CTHRC1', 'Gene', '115908', (38, 44))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('pan', 'Gene', (62, 65))	('BRCA', 'Gene', '672', (0, 4))
1989	33383577	This, as well as the presence of a UV light-induced mutational signature, are clear signs of the role of sunlight in CJM tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutational', 'Var', (52, 62))	('tumor', 'Disease', (121, 126))	('CJM', 'Disease', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
1992	33383577	Transfected conjunctival melanoma cells overexpressing mutant ACSS3 showed higher proliferative activity, supporting the direct involvement of this gene in the tumorigenesis of CJM.	('ACSS3', 'Gene', (62, 67))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (12, 33))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (12, 33))	('higher', 'PosReg', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mutant', 'Var', (55, 61))	('men', 'Species', '9606', (135, 138))	('proliferative activity', 'CPA', (82, 104))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('tumor', 'Disease', (160, 165))	('conjunctival melanoma', 'Disease', (12, 33))	('ACSS3', 'Gene', '79611', (62, 67))
1996	33383577	More precisely, in tumor DNA we detected signs of damage caused by UV light, as well as mutations in the genes BRAF, NF1 and NRAS/HRAS, previously described to be involved in cutaneous melanoma.	('NRAS', 'Gene', (125, 129))	('damage', 'MPA', (50, 56))	('HRAS', 'Gene', (130, 134))	('NF1', 'Gene', '4763', (117, 120))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('NRAS', 'Gene', '4893', (125, 129))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('HRAS', 'Gene', '3265', (130, 134))	('tumor', 'Disease', (19, 24))	('cutaneous melanoma', 'Disease', (175, 193))	('BRAF', 'Gene', '673', (111, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('NF1', 'Gene', (117, 120))	('BRAF', 'Gene', (111, 115))
1998	33383577	In addition, we identified frequent somatic mutations in ACSS3, a gene not yet associated with either conjunctival or cutaneous melanoma, which represents a potential key player in oncogenesis of conjunctival melanoma.	('conjunctival melanoma', 'Disease', (196, 217))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (196, 217))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (196, 217))	('ACSS3', 'Gene', '79611', (57, 62))	('cutaneous melanoma', 'Disease', (118, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('ACSS3', 'Gene', (57, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('mutations', 'Var', (44, 53))	('oncogenesis', 'biological_process', 'GO:0007048', ('181', '192'))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('conjunctival', 'Disease', (102, 114))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
2006	33383577	Previous genetic work on CJM only scored mutations within a panel of known genes that are frequently mutated in melanomas, or copy number variations (CNVs) detected by FISH, MLPA, array-CGH or SNP-array analysis.	('mutations', 'Var', (41, 50))	('melanomas', 'Disease', (112, 121))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('copy number variations', 'Var', (126, 148))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))
2007	33383577	These studies have reported frequent mutations in known CM genes such as BRAF, RAS sequences (NRAS, KRAS, HRAS), NF1, TERT, and KIT, as well as patterns of CNVs resembling that of cutaneous and mucosal melanomas.	('KRAS', 'Gene', (100, 104))	('KIT', 'molecular_function', 'GO:0005020', ('128', '131'))	('TERT', 'Gene', (118, 122))	('TERT', 'Gene', '7015', (118, 122))	('BRAF', 'Gene', (73, 77))	('mucosal melanomas', 'Disease', 'MESH:D008545', (194, 211))	('NRAS', 'Gene', '4893', (94, 98))	('HRAS', 'Gene', '3265', (106, 110))	('mucosal melanomas', 'Disease', (194, 211))	('HRAS', 'Gene', (106, 110))	('KIT', 'Gene', (128, 131))	('CM genes', 'Gene', (56, 64))	('mutations', 'Var', (37, 46))	('NF1', 'Gene', '4763', (113, 116))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('NRAS', 'Gene', (94, 98))	('KRAS', 'Gene', '3845', (100, 104))	('RAS sequences', 'Gene', (79, 92))	('NF1', 'Gene', (113, 116))	('BRAF', 'Gene', '673', (73, 77))	('KIT', 'Gene', '3815', (128, 131))
2009	33383577	In this study, we unbiasedly assessed the landscape of genomic alterations in conjunctival melanoma by characterizing somatic single nucleotide variants (SNVs) and somatic copy number variations (CNVs) through Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS).	('conjunctival melanoma', 'Disease', (78, 99))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (78, 99))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (78, 99))	('WGS', 'Disease', 'None', (267, 270))	('WGS', 'Disease', (267, 270))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('single nucleotide variants', 'Var', (126, 152))	('copy number variations', 'Var', (172, 194))
2018	33383577	WGS or WES analysis identified on average 1,447 somatic SNVs (range 216-4,067) and 87 (range 49-139) small insertions or deletions (indel; all somatic SNVs and small insertions/deletions are available in S2 Table).	('WGS', 'Disease', 'None', (0, 3))	('deletions', 'Var', (121, 130))	('WGS', 'Disease', (0, 3))
2023	33383577	Consistently with the presumed role of UV light in CJM tumorigenesis, in 86% of the samples C>T changes accounted for more than 70% of the total mutational load (Fig 1A).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mutational load', 'Var', (145, 160))	('tumor', 'Disease', (55, 60))	('C>T changes', 'Var', (92, 103))
2024	33383577	Interestingly, the three individuals with the lowest contributions of the C>T changes were samples whose tumors had a tarsal localization and therefore were less exposed to UV light.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('localization', 'biological_process', 'GO:0051179', ('125', '137'))	('changes', 'Var', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
2025	33383577	We next extracted the mutational signatures present in the data by observing the patterns of somatic mutations and by comparing them with the 30 validated signatures of mutational processes in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('human', 'Species', '9606', (193, 198))
2039	33383577	Inactivating mutations in NF1 (Fig 3, S3A Fig, S2 Table) were found in 7/14 samples, always present in a mutually-exclusive pattern with respect to mutations in BRAF.	('NF1', 'Gene', (26, 29))	('Inactivating mutations', 'Var', (0, 22))	('BRAF', 'Gene', (161, 165))	('NF1', 'Gene', '4763', (26, 29))	('BRAF', 'Gene', '673', (161, 165))
2040	33383577	Four samples carried missense mutations in BRAF.	('missense mutations', 'Var', (21, 39))	('BRAF', 'Gene', (43, 47))	('BRAF', 'Gene', '673', (43, 47))
2041	33383577	In three out of these four samples we found the canonical p.V600E missense alteration, and in one sample a p.G466E mutation, also already-reported in various human cancers (S3B Fig).	('p.G466E', 'Mutation', 'rs121913351', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('human', 'Species', '9606', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('p.V600E', 'Mutation', 'rs113488022', (58, 65))	('p.V600E', 'Var', (58, 65))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('p.G466E', 'Var', (107, 114))
2042	33383577	Mutations in genes from the RAS family were identified in three samples (1 in NRAS and 2 in HRAS), in a mutually-exclusive fashion with respect to the hotspot p.V600E in BRAF.	('p.V600E', 'Var', (159, 166))	('BRAF', 'Gene', (170, 174))	('NRAS and 2', 'Gene', '4893', (78, 88))	('RAS', 'Gene', (28, 31))	('HRAS', 'Gene', '3265', (92, 96))	('p.V600E', 'Mutation', 'rs113488022', (159, 166))	('identified', 'Reg', (44, 54))	('HRAS', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (170, 174))
2043	33383577	These tumors carried known hotspot mutations: p.Q61R and p.G13D in HRAS and p.Q61L in NRAS (S3C and S3D Fig).	('NRAS', 'Gene', (86, 90))	('p.Q61R', 'Var', (46, 52))	('p.Q61L', 'Var', (76, 82))	('NRAS', 'Gene', '4893', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('p.G13D', 'Mutation', 'rs112445441', (57, 63))	('HRAS', 'Gene', '3265', (67, 71))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('p.G13D', 'Var', (57, 63))	('HRAS', 'Gene', (67, 71))	('p.Q61R', 'Mutation', 'rs121913233', (46, 52))	('p.Q61L', 'Mutation', 'rs11554290', (76, 82))
2044	33383577	Mutations in hTERT and its promoter were identified in 9/14 tumors, essentially within the same hotspots identified previously in other tumor types (S4 Table).	('hTERT', 'Gene', (13, 18))	('identified', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('hTERT', 'Gene', '7015', (13, 18))	('tumor', 'Disease', (136, 141))	('tumors', 'Disease', (60, 66))
2045	33383577	In addition, we identified missense or loss of function mutations in less-common cutaneous melanoma drivers, such as TP53, NOTCH3, and KIT (Fig 3).	('KIT', 'Gene', '3815', (135, 138))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('NOTCH3', 'Gene', (123, 129))	('missense', 'Var', (27, 35))	('TP53', 'Gene', '7157', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('TP53', 'Gene', (117, 121))	('KIT', 'Gene', (135, 138))	('NOTCH3', 'Gene', '4854', (123, 129))	('cutaneous melanoma', 'Disease', (81, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))	('loss of function', 'NegReg', (39, 55))
2054	33383577	The BRAF mutation is the canonical p.V600E missense change and therefore an already-known driver mutation, confirming the robustness of this method.	('p.V600E', 'Mutation', 'rs113488022', (35, 42))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('p.V600E', 'Var', (35, 42))
2055	33383577	The mutation in USH2A resulted to be a sequence artifact and therefore was discarded from our analysis.	('USH2A', 'Gene', (16, 21))	('USH2A', 'Gene', '7399', (16, 21))	('mutation', 'Var', (4, 12))
2056	33383577	The mutation in ACSS3 is a missense (NM_024560: c.1594C>T/p.P532S), present in a very conserved position and situated 7 amino acids away from an ATP-binding site (S5 Fig), and this alteration creates a site predicted to be phosphorylated by NetPhos.	('c.1594C>T', 'SUBSTITUTION', 'None', (48, 57))	('ACSS3', 'Gene', '79611', (16, 21))	('c.1594C>T', 'Var', (48, 57))	('ACSS3', 'Gene', (16, 21))	('ATP-binding', 'molecular_function', 'GO:0005524', ('145', '156'))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('p.P532S', 'Mutation', 'rs1247209581', (58, 65))
2057	33383577	We searched for the presence of p.P532S in public databases of cancer patients and cancer cell lines, and we identified this particular mutation in two cell lines from neuroblastoma and from cutaneous melanoma (Broad Institute Cancer Cell Lines Encyclopedia v18-07-2018 and COSMIC v90-05-09-2019), as well as 12 additional patients with either cutaneous melanoma (8/12), skin cancer (non-melanoma) (1/12) or cutaneous squamous cell carcinoma (3/12) (cBioPortal v3.1.3).	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (408, 441))	('cancer', 'Disease', (376, 382))	('skin cancer', 'Phenotype', 'HP:0008069', (371, 382))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (227, 233))	('cutaneous melanoma', 'Disease', (191, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (191, 209))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (191, 209))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('neuroblastoma', 'Disease', (168, 181))	('patients', 'Species', '9606', (323, 331))	('patients', 'Species', '9606', (70, 78))	('neuroblastoma', 'Phenotype', 'HP:0003006', (168, 181))	('non-melanoma', 'Disease', (384, 396))	('skin cancer', 'Disease', 'MESH:D012878', (371, 382))	('neuroblastoma', 'Disease', 'MESH:D009447', (168, 181))	('Cancer', 'Disease', 'MESH:D009369', (227, 233))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (418, 441))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (388, 396))	('cancer', 'Disease', (63, 69))	('melanoma', 'Phenotype', 'HP:0002861', (354, 362))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (408, 441))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('non-melanoma', 'Disease', 'MESH:D008545', (384, 396))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (432, 441))	('p.P532S', 'Mutation', 'rs1247209581', (32, 39))	('p.P532S', 'Var', (32, 39))	('skin cancer', 'Disease', (371, 382))	('cutaneous melanoma', 'Disease', (344, 362))	('cutaneous squamous cell carcinoma', 'Disease', (408, 441))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (344, 362))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (344, 362))	('Cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (83, 89))
2058	33383577	Furthermore, 4 additional somatic mutations in ACSS3 were detected in our cohort of patients (S5 Fig).	('ACSS3', 'Gene', (47, 52))	('mutations', 'Var', (34, 43))	('ACSS3', 'Gene', '79611', (47, 52))	('patients', 'Species', '9606', (84, 92))
2067	33383577	Furthermore, silencing of ACSS2 in mouse models of liver cancer leads to dramatic reduction of tumor growth.	('liver cancer', 'Phenotype', 'HP:0002896', (51, 63))	('tumor', 'Disease', (95, 100))	('reduction', 'NegReg', (82, 91))	('liver cancer', 'Disease', 'MESH:D006528', (51, 63))	('ACSS2', 'Gene', (26, 31))	('mouse', 'Species', '10090', (35, 40))	('liver cancer', 'Disease', (51, 63))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('silencing', 'Var', (13, 22))
2069	33383577	All these data indicate that ACSS3 may represent an interesting candidate for tumorigenesis of CJM and that p.P532S could act as an activating driver mutation.	('ACSS3', 'Gene', '79611', (29, 34))	('p.P532S', 'Var', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('ACSS3', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('CJM', 'Disease', (95, 98))	('p.P532S', 'Mutation', 'rs1247209581', (108, 115))
2070	33383577	To investigate its oncogenic impact we transfected the conjunctival recurrent malignant melanoma-1 CRMM-1 cell line (Research Resource Identifier, RRID: CVCL_M593), negative for mutations in ACSS3, with plasmids expressing either cDNA from the wild-type ACSS3 gene (pCMV-ACSS3-wt) or cDNA containing the p.P532S variant (pCMV-ACSS3-mut) under the transcriptional control of the human cytomegalovirus pCMV promoter.	('ACSS3', 'Gene', (271, 276))	('melanoma-1 CRMM-1', 'Disease', 'MESH:D008545', (88, 105))	('human cytomegalovirus', 'Species', '10359', (378, 399))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('ACSS3', 'Gene', '79611', (326, 331))	('ACSS3', 'Gene', (191, 196))	('ACSS3', 'Gene', '79611', (191, 196))	('ACSS3', 'Gene', (326, 331))	('transcriptional control', 'biological_process', 'GO:0006355', ('347', '370'))	('p.P532S', 'Mutation', 'rs1247209581', (304, 311))	('p.P532S', 'Var', (304, 311))	('melanoma-1 CRMM-1', 'Disease', (88, 105))	('ACSS3', 'Gene', '79611', (254, 259))	('malignant melanoma', 'Phenotype', 'HP:0002861', (78, 96))	('ACSS3', 'Gene', (254, 259))	('ACSS3', 'Gene', '79611', (271, 276))
2072	33383577	This was not simply due to increased ACSS3 mRNA expression from the mutant plasmid vs. the wt plasmid, as we could ascertain by plasmid-specific Q-PCR (ACSS3 expression from pCMV-ACSS3-mut vs. pCMV-ACSS3-wt = 89 +- 14 vs. 79 +- 5 arbitrary units, respectively, p-value = 0.39, by t-test), indicating indeed that the effect was consequent to the presence of the p.P532S mutation.	('ACSS3', 'Gene', (152, 157))	('ACSS3', 'Gene', '79611', (152, 157))	('ACSS3', 'Gene', (37, 42))	('ACSS3', 'Gene', '79611', (198, 203))	('p.P532S', 'Mutation', 'rs1247209581', (361, 368))	('p.P532S', 'Var', (361, 368))	('ACSS3', 'Gene', '79611', (37, 42))	('ACSS3', 'Gene', (198, 203))	('ACSS3', 'Gene', '79611', (179, 184))	('ACSS3', 'Gene', (179, 184))	('mutant', 'Var', (68, 74))
2086	33383577	Our analysis showed that genes in the RTK-RAS pathway were altered in all patients (14/14), by SNV or indel, and that all tested samples also showed an alteration by a CNV concordant with the gene expression level of that same gene (either an amplification/gain and significantly higher gene expression or shallow/deep deletion and significantly lower gene expression; see Methods for more details).	('gene expression', 'MPA', (352, 367))	('altered', 'Reg', (59, 66))	('gene expression', 'MPA', (287, 302))	('lower', 'NegReg', (346, 351))	('gene expression', 'biological_process', 'GO:0010467', ('192', '207'))	('higher', 'PosReg', (280, 286))	('shallow/deep deletion', 'Var', (306, 327))	('patients', 'Species', '9606', (74, 82))	('amplification/gain', 'PosReg', (243, 261))	('gene expression', 'biological_process', 'GO:0010467', ('287', '302'))	('RTK-RAS pathway', 'Pathway', (38, 53))	('gene expression', 'biological_process', 'GO:0010467', ('352', '367'))	('indel', 'Var', (102, 107))	('SNV', 'Var', (95, 98))
2093	33383577	They carry significantly lower numbers of C>T changes, but also somatic SNVs overall, and are characterized by a different composition of mutational signatures compared to tumors localized on the light-exposed bulbar conjunctiva.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('C>T changes', 'Var', (42, 53))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', (172, 178))	('lower', 'NegReg', (25, 30))
2097	33383577	In particular, the missense variant p.P532S in this gene was discovered in 3/14 of CJM patients in our cohort and in additional twelve patients and two cell lines in public databases, representing a potential hot-spot mutation.	('patients', 'Species', '9606', (135, 143))	('p.P532S', 'Mutation', 'rs1247209581', (36, 43))	('p.P532S', 'Var', (36, 43))	('CJM', 'Disease', (83, 86))	('patients', 'Species', '9606', (87, 95))
2098	33383577	Furthermore, we showed that overexpression of the mutated (p.P532S) ACSS3 gene leads to higher proliferative activity in the CRMM-1 cells, in line with the hypothesis of oncogenicity of this gene in CJM.	('higher', 'PosReg', (88, 94))	('p.P532S', 'Var', (59, 66))	('proliferative activity', 'CPA', (95, 117))	('ACSS3', 'Gene', '79611', (68, 73))	('overexpression', 'PosReg', (28, 42))	('CRMM-1', 'CellLine', 'CVCL:M593', (125, 131))	('ACSS3', 'Gene', (68, 73))	('p.P532S', 'Mutation', 'rs1247209581', (59, 66))
2101	33383577	For instance, CM patients with a high mutational load respond well to T-cell immunotherapy and patients with desmoplastic melanoma with NF1 mutations, that are also prevalent in CJM, benefit from treatment with immune checkpoint inhibitors.	('patients', 'Species', '9606', (95, 103))	('desmoplastic melanoma', 'Disease', (109, 130))	('benefit', 'PosReg', (183, 190))	('men', 'Species', '9606', (201, 204))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (109, 130))	('patients', 'Species', '9606', (17, 25))	('NF1', 'Gene', (136, 139))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mutations', 'Var', (140, 149))	('NF1', 'Gene', '4763', (136, 139))
2119	33383577	More specifically, a gene was considered as "deleted" if its expression in individuals with deep or shallow deletions was significantly lower compared to the rest of the patients and a gene was considered as "amplified" if its expression in individuals with gains and amplifications was significantly higher compared to the rest of the patients.	('patients', 'Species', '9606', (170, 178))	('lower', 'NegReg', (136, 141))	('shallow deletions', 'Var', (100, 117))	('patients', 'Species', '9606', (336, 344))	('deep', 'Var', (92, 96))	('expression', 'MPA', (61, 71))
2121	33383577	Gateway donor plasmids pDONR221 encoding the synthesized cDNA of human ACSS3 (NM_024560), and the ACSS3 missense mutation NM_024560: c.1594C>T/p.P532S were used as a templates in a Gateway recombination reaction (Gateway LR Clonase cat.	('human', 'Species', '9606', (65, 70))	('cat', 'molecular_function', 'GO:0004096', ('232', '235'))	('ACSS3', 'Gene', '79611', (98, 103))	('ACSS3', 'Gene', '79611', (71, 76))	('ACSS3', 'Gene', (98, 103))	('c.1594C>T', 'SUBSTITUTION', 'None', (133, 142))	('ACSS3', 'Gene', (71, 76))	('c.1594C>T', 'Var', (133, 142))	('p.P532S', 'Mutation', 'rs1247209581', (143, 150))	('NM_024560', 'Var', (122, 131))
2139	33383577	Samples were transferred into a 96 wells plate, and absorbance [A570 nm:A690 nm] was measured with an absorbance plate reader (Hidex Sense).	('sur', 'Gene', (88, 91))	('sur', 'Gene', '6833', (88, 91))	('A690 nm]', 'Var', (72, 80))
2261	29625055	In the LGG marker paper, analysis of OS showed that patients diagnosed with an IDH1 and IDH2 (two very similar genes, hereafter referred to collectively as IDH) mutation with or without 1p/19q codeletion had substantially longer OS than did patients who had wild-type IDH, proving that IDH-1p/19q status represents a more robust survival predictor than LGG histologic subtype.	('IDH-1p', 'Gene', (286, 292))	('IDH', 'Gene', (88, 91))	('IDH1', 'Gene', (79, 83))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (88, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (79, 83))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (156, 159))	('OS', 'Chemical', '-', (229, 231))	('OS', 'Chemical', '-', (37, 39))	('IDH', 'Gene', '3417', (286, 289))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (222, 228))	('IDH2', 'Gene', (88, 92))	('IDH-1p', 'Gene', '3417', (286, 292))	('IDH2', 'Gene', '3418', (88, 92))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (156, 159))
2435	33194692	The abnormal competitive endogenous RNA network promotes the development of tumors and becomes biomarkers for the prognosis of various tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('abnormal', 'Var', (4, 12))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('promotes', 'PosReg', (48, 56))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
2453	33194692	At the same time, a variety of other non-coding RNAs (ncRNAs), such as circular RNA (circRNA), long non-coding RNA (lncRNA), and pseudogenes,etc.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))	('ncRNA', 'Gene', (54, 59))	('ncRNA', 'Gene', (117, 122))	('ncRNA', 'Gene', '220202', (54, 59))	('long non-coding', 'Var', (95, 110))	('ncRNA', 'Gene', '220202', (117, 122))
2486	33194692	Therefore, it is preliminarily determined that 1401 mRNAs (WGCNA-mRNAs) in the brown, blue, and red modules are related to melanoma prognosis.	('related', 'Reg', (112, 119))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('1401 mRNAs', 'Var', (47, 57))
2487	33194692	GO and KEGG analysis of 1401 WGCNA-mRNAs showed that they were mainly enriched in biological processes such as translation initiation (GO:0006413), endoplasmic reticulum localization (GO:0072599, GO:0070972), interferon gamma response (GO:0034341), extracellular matrix composition (GO:0043062, GO:0030198) (Figure 2A and Table 2), and participate in signal pathways such as ribosomes (hsa03010), antigen presentation (hsa04612), phagosomes (hsa04145), cell adhesion molecules (hsa04514), etc., which were closely related to gene translation, immune response and cell positioning (Figure 2B and Table 3).	('translation', 'biological_process', 'GO:0006412', ('530', '541'))	('interferon gamma', 'Gene', (209, 225))	('translation initiation', 'biological_process', 'GO:0006413', ('111', '133'))	('immune response', 'biological_process', 'GO:0006955', ('543', '558'))	('antigen presentation', 'biological_process', 'GO:0019882', ('397', '417'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('148', '169'))	('endoplasmic reticulum localization', 'biological_process', 'GO:0051643', ('148', '182'))	('GO:0030198', 'Var', (295, 305))	('participate', 'Reg', (336, 347))	('GO:0070972', 'Var', (196, 206))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('249', '269'))	('interferon gamma', 'Gene', '3458', (209, 225))	('interferon gamma', 'molecular_function', 'GO:0005133', ('209', '225'))	('cell adhesion', 'biological_process', 'GO:0007155', ('453', '466'))
2505	33194692	The results of TCGA data (Figure 6A) showed that patients with high expression of PRADC1 (P = 0.003), RCC1 (P = 0.004), and FKBP4 (P = 0.053) had low survival rates, and patients with low expression of GBP1 had low survival rates (P = 0.007).	('low', 'NegReg', (146, 149))	('patients', 'Species', '9606', (170, 178))	('RCC1', 'molecular_function', 'GO:0005087', ('102', '106'))	('FKBP4', 'Gene', (124, 129))	('FKBP4', 'Gene', '2288', (124, 129))	('high expression', 'Var', (63, 78))	('FKBP', 'molecular_function', 'GO:0030051', ('124', '128'))	('RCC1', 'Gene', (102, 106))	('survival rates', 'CPA', (150, 164))	('patients', 'Species', '9606', (49, 57))	('PRADC1', 'Gene', '84279', (82, 88))	('PRADC1', 'Gene', (82, 88))
2528	33194692	Abnormal TIME also promotes immune escape, drug resistance and metastasis of melanoma.	('promotes', 'PosReg', (19, 27))	('metastasis', 'CPA', (63, 73))	('Abnormal TIME', 'Var', (0, 13))	('drug resistance', 'biological_process', 'GO:0009315', ('43', '58'))	('drug resistance', 'biological_process', 'GO:0042493', ('43', '58'))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('drug resistance', 'CPA', (43, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('immune escape', 'CPA', (28, 41))
2548	33194692	FKBP51 protein can mediate the inhibition of FK506 on antigen presentation process, and at the same time, its expression is increased in a variety of immune related diseases such as rheumatoid arthritis.	('inhibition', 'NegReg', (31, 41))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (182, 202))	('protein', 'cellular_component', 'GO:0003675', ('7', '14'))	('FK506', 'Chemical', 'MESH:D016559', (45, 50))	('antigen presentation', 'biological_process', 'GO:0019882', ('54', '74'))	('increased', 'PosReg', (124, 133))	('arthritis', 'Phenotype', 'HP:0001369', (193, 202))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (182, 202))	('expression', 'MPA', (110, 120))	('FKBP', 'molecular_function', 'GO:0030051', ('0', '4'))	('FK506', 'Var', (45, 50))	('rheumatoid arthritis', 'Disease', (182, 202))	('antigen presentation process', 'MPA', (54, 82))	('FKBP51', 'Gene', (0, 6))	('protein', 'Protein', (7, 14))
2549	33194692	These reports all support our discovery that the high expression of FKBP4 predicts poor melanoma prognosis, and that FKBP4 is a hub member of TIME-related ceRNA network.	('expression', 'MPA', (54, 64))	('FKBP4', 'Gene', (68, 73))	('FKBP4', 'Gene', '2288', (68, 73))	('FKBP4', 'Gene', '2288', (117, 122))	('FKBP', 'molecular_function', 'GO:0030051', ('117', '121'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('FKBP4', 'Gene', (117, 122))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('hub', 'Gene', '1993', (128, 131))	('poor', 'CPA', (83, 87))	('high', 'Var', (49, 53))	('FKBP', 'molecular_function', 'GO:0030051', ('68', '72'))	('hub', 'Gene', (128, 131))
2578	33194692	First of all, although the role of most RNAs in ceRNA network in melanoma or other tumors has been verified by multiple studies, we still found that miR-137 and some lncRNAs showed no significant statistical difference in survival analysis, which means that the amount of data obtained from the public database is still limited, and may limit the accuracy of analysis to some extent.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('ncRNA', 'Gene', (167, 172))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('ncRNA', 'Gene', '220202', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('miR-137', 'Var', (149, 156))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
2594	33483342	BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively.	('patients', 'Species', '9606', (58, 66))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
2599	33483342	In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('NRAS', 'Gene', '4893', (219, 223))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('NRAS', 'Gene', (76, 80))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (214, 218))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('BRAF', 'Gene', (214, 218))	('melanoma', 'Disease', (197, 205))	('NRAS', 'Gene', '4893', (76, 80))	('V600E', 'SUBSTITUTION', 'None', (136, 141))	('NRAS', 'Gene', (219, 223))	('V600E', 'Var', (136, 141))	('BRAF', 'Gene', '673', (131, 135))
2600	33483342	In our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI.	('melanoma tumor', 'Disease', (23, 37))	('PFS', 'Disease', (103, 106))	('melanoma tumor', 'Disease', 'MESH:D008545', (23, 37))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('melanoma', 'Disease', (143, 151))	('anti-PD1', 'Var', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('patients', 'Species', '9606', (118, 126))	('PFS', 'Disease', 'None', (103, 106))
2605	33483342	Comprehensive genomic analyses of melanoma indicate that cutaneous melanomas can also be divided into four molecular subtypes according to the presence or absence of mutations in oncogenic driver genes: BRAF, NRAS and NF1.	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('mutations', 'Var', (166, 175))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('NF1', 'Gene', (218, 221))	('melanoma', 'Disease', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 76))	('NF1', 'Gene', '4763', (218, 221))	('BRAF', 'Gene', '673', (203, 207))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('NRAS', 'Gene', (209, 213))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (57, 76))	('BRAF', 'Gene', (203, 207))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('cutaneous melanomas', 'Disease', (57, 76))	('NRAS', 'Gene', '4893', (209, 213))
2606	33483342	BRAF V600E/K mutations are almost always mutually exclusive with NRAS mutations in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('NRAS', 'Gene', '4893', (65, 69))	('V600E', 'Var', (5, 10))	('melanoma', 'Disease', (83, 91))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600E', 'SUBSTITUTION', 'None', (5, 10))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('NRAS', 'Gene', (65, 69))
2607	33483342	Patients with BRAF V600E/K mutant cutaneous melanoma are typically younger than average, whereas patients with NF1 mutations are typically older than average.	('NF1', 'Gene', (111, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (34, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('NF1', 'Gene', '4763', (111, 114))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('V600E', 'Var', (19, 24))	('BRAF', 'Gene', '673', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('V600E', 'SUBSTITUTION', 'None', (19, 24))	('BRAF', 'Gene', (14, 18))	('cutaneous melanoma', 'Disease', (34, 52))	('patients', 'Species', '9606', (97, 105))
2608	33483342	The majority of BRAF, NRAS or NF1 mutant cutaneous melanomas are associated with ultraviolet (UV) light-induced DNA damage genomic profiles.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (41, 60))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (41, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (41, 59))	('NF1', 'Gene', (30, 33))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('NF1', 'Gene', '4763', (30, 33))	('NRAS', 'Gene', (22, 26))	('associated', 'Reg', (65, 75))	('cutaneous melanomas', 'Disease', (41, 60))	('NRAS', 'Gene', '4893', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('mutant', 'Var', (34, 40))
2609	33483342	BRAF mutant melanomas are typically associated with intermittent sun exposure, whereas NRAS or NF1 mutant melanomas are associated with chronic sun exposure.	('NRAS', 'Gene', '4893', (87, 91))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Disease', (106, 115))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('NF1', 'Gene', (95, 98))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('NF1', 'Gene', '4763', (95, 98))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('mutant', 'Var', (5, 11))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('associated', 'Reg', (36, 46))	('melanomas', 'Disease', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('NRAS', 'Gene', (87, 91))
2614	33483342	Acral and mucosal melanomas have a lower burden of point mutations relative to cutaneous melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (79, 98))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (79, 98))	('cutaneous melanomas', 'Disease', (79, 98))	('mucosal melanomas', 'Disease', (10, 27))	('point mutations', 'Var', (51, 66))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('lower', 'NegReg', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('Acral and', 'Disease', (0, 9))
2615	33483342	Acral melanomas have a higher incidence of copy number variations, including multiple genomic amplifications.	('Acral melanomas', 'Disease', (0, 15))	('copy number variations', 'Var', (43, 65))	('Acral melanomas', 'Disease', 'MESH:D008545', (0, 15))	('Acral melanomas', 'Phenotype', 'HP:0012060', (0, 15))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))
2616	33483342	Genomic structural variations are more common in mucosal melanoma subtypes.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('common', 'Reg', (39, 45))	('mucosal melanoma', 'Disease', (49, 65))	('mucosal melanoma', 'Disease', 'MESH:D008545', (49, 65))	('Genomic structural variations', 'Var', (0, 29))
2619	33483342	Some data suggest that the distribution of driver mutations in MUPs is similar to the distribution of driver genes in cutaneous melanomas that are associated with intermittent sun exposure, wherein BRAF V600 mutations predominate.	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('BRAF', 'Gene', '673', (198, 202))	('mutations', 'Var', (50, 59))	('BRAF', 'Gene', (198, 202))	('MUPs', 'Gene', (63, 67))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (118, 137))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (118, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('cutaneous melanomas', 'Disease', (118, 137))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
2625	33483342	While not statistically significant, patients who received ipilimumab+nivolumab in Checkmate-067 had longer median OS (not reached, more than 60 months) than patients who received nivolumab alone (36.9 months).	('longer', 'PosReg', (101, 107))	('ipilimumab', 'Chemical', 'MESH:D000074324', (59, 69))	('nivolumab', 'Chemical', 'MESH:D000077594', (70, 79))	('patients', 'Species', '9606', (37, 45))	('nivolumab', 'Chemical', 'MESH:D000077594', (180, 189))	('patients', 'Species', '9606', (158, 166))	('ipilimumab+nivolumab', 'Var', (59, 79))	('median OS', 'MPA', (108, 117))
2627	33483342	Given the increased toxicity associated with combination immunotherapy, it is of great interest to clinicians to be able to identify those patients who could derive sufficient prolonged benefit from anti-PD1 monotherapy, and be spared the increased toxic side effects of combination immunotherapy.	('toxicity', 'Disease', 'MESH:D064420', (20, 28))	('toxicity', 'Disease', (20, 28))	('anti-PD1', 'Var', (199, 207))	('patients', 'Species', '9606', (139, 147))
2629	33483342	For example, the 5-year survival advantage of ipilimumab +nivolumab over nivolumab was more pronounced in BRAF mutant melanoma (60% vs 46%) than it was in BRAF wild-type melanoma (35% vs 32%).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('BRAF', 'Gene', (155, 159))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('mutant', 'Var', (111, 117))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BRAF', 'Gene', '673', (106, 110))	('nivolumab', 'Chemical', 'MESH:D000077594', (58, 67))	('BRAF', 'Gene', (106, 110))	('ipilimumab', 'Chemical', 'MESH:D000074324', (46, 56))	('nivolumab', 'Chemical', 'MESH:D000077594', (73, 82))	('BRAF', 'Gene', '673', (155, 159))
2631	33483342	To date, there are no available published data from Checkmate-067 on the long-term outcomes of patients with NRAS mutations or other primary tumor types such as acral or unknown primary melanoma.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (95, 103))	('mutations', 'Var', (114, 123))	('NRAS', 'Gene', (109, 113))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('tumor', 'Disease', (141, 146))	('NRAS', 'Gene', '4893', (109, 113))
2633	33483342	We performed a single-center retrospective analysis of patients with advanced melanoma who received anti-PD1 immunotherapy at Princess Margaret Cancer Center, University Health Network (PM-UHN) between 2012 and 2019.	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer', 'Disease', (144, 150))	('Cancer', 'Disease', 'MESH:D009369', (144, 150))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('anti-PD1', 'Var', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('patients', 'Species', '9606', (55, 63))
2634	33483342	The PM-UHN Tumor Immunotherapy Program (TIP) and melanoma referral databases were used to identify patients with melanoma who had received anti-PD1-based ICI (either alone or in combination with anti-CTLA4) as palliative treatment for advanced disease.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('Tumor', 'Phenotype', 'HP:0002664', (11, 16))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('anti-PD1-based', 'Var', (139, 153))	('melanoma', 'Disease', (113, 121))	('patients', 'Species', '9606', (99, 107))	('CTLA4', 'Gene', '1493', (200, 205))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('CTLA4', 'Gene', (200, 205))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
2638	33483342	Patients who received anti-PD1 ICI in combination with any non-anti-CTLA4 investigational therapy were also excluded (figure 1).	('Patients', 'Species', '9606', (0, 8))	('anti-PD1', 'Var', (22, 30))	('CTLA4', 'Gene', '1493', (68, 73))	('CTLA4', 'Gene', (68, 73))
2645	33483342	Between 2012 and 2019 at PM-UHN, advanced melanomas were initially assessed for the presence or absence of a BRAF V600E/K mutations using a PCR-based assay.	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('melanomas', 'Disease', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('V600E', 'Var', (114, 119))	('V600E', 'SUBSTITUTION', 'None', (114, 119))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('melanomas', 'Disease', 'MESH:D008545', (42, 51))
2646	33483342	If no BRAF V600E/K mutation was identified, subsequent testing for additional mutations was performed.	('BRAF', 'Gene', (6, 10))	('BRAF', 'Gene', '673', (6, 10))	('V600E', 'Var', (11, 16))	('V600E', 'SUBSTITUTION', 'None', (11, 16))
2649	33483342	In 2015, BRAF wild-type melanomas were assessed for NRAS mutations by next-generation sequencing (NGS).	('NRAS', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('BRAF', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (52, 56))	('melanomas', 'Disease', (24, 33))	('mutations', 'Var', (57, 66))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('BRAF', 'Gene', '673', (9, 13))
2653	33483342	We reviewed a total of 739 medical records and identified 230 individual patients who received anti-PD1+-anti-CTLA4 ICI and had molecular testing for BRAF and NRAS mutations.	('NRAS', 'Gene', (159, 163))	('patients', 'Species', '9606', (73, 81))	('BRAF', 'Gene', (150, 154))	('NRAS', 'Gene', '4893', (159, 163))	('CTLA4', 'Gene', '1493', (110, 115))	('BRAF', 'Gene', '673', (150, 154))	('CTLA4', 'Gene', (110, 115))	('mutations', 'Var', (164, 173))
2657	33483342	The most common genomic subtype was BRAF/NRAS wild type, followed by BRAF V600E/K mutant and NRAS mutant (figure 2B).	('NRAS', 'Gene', '4893', (41, 45))	('BRAF', 'Gene', (36, 40))	('common', 'Reg', (9, 15))	('NRAS', 'Gene', '4893', (93, 97))	('NRAS', 'Gene', (41, 45))	('V600E', 'Var', (74, 79))	('V600E', 'SUBSTITUTION', 'None', (74, 79))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', '673', (36, 40))	('BRAF', 'Gene', (69, 73))	('NRAS', 'Gene', (93, 97))
2658	33483342	As expected, there were significant differences in the frequency of BRAF and NRAS mutations according to primary tumor type (table 1, figure 2).	('tumor', 'Disease', (113, 118))	('BRAF', 'Gene', '673', (68, 72))	('NRAS', 'Gene', (77, 81))	('BRAF', 'Gene', (68, 72))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', '4893', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
2659	33483342	BRAF V600E/K mutations were most common in cutaneous melanomas (42%) and were absent in mucosal melanomas.	('mucosal melanomas', 'Disease', (88, 105))	('cutaneous melanomas', 'Disease', (43, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('mucosal melanomas', 'Disease', 'MESH:D008545', (88, 105))	('common', 'Reg', (33, 39))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('V600E', 'SUBSTITUTION', 'None', (5, 10))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (43, 62))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (43, 62))
2660	33483342	NRAS mutations were most common in unknown primary melanomas (50%) and least common in mucosal melanomas (24%).	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('common', 'Reg', (25, 31))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('melanomas', 'Disease', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mutations', 'Var', (5, 14))	('mucosal melanomas', 'Disease', (87, 104))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('NRAS', 'Gene', '4893', (0, 4))	('mucosal melanomas', 'Disease', 'MESH:D008545', (87, 104))
2661	33483342	BRAF/NRAS wild-type melanomas were most common among mucosal melanoma (76%) and least common among unknown primary melanomas (26%) (figure 2C).	('mucosal melanoma', 'Disease', 'MESH:D008545', (53, 69))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('NRAS', 'Gene', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanomas', 'Disease', (20, 29))	('NRAS', 'Gene', '4893', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', '673', (0, 4))	('wild-type', 'Var', (10, 19))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('melanomas', 'Disease', (115, 124))	('common', 'Reg', (40, 46))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('mucosal melanoma', 'Disease', (53, 69))
2664	33483342	There were no significant differences in the age or gender distribution of patients according to primary tumor type, nor were there are differences in the number of metastatic site, the NLR, or in whether patients were receiving anti-PD1 ICI as a first or later line systemic therapy.	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('anti-PD1', 'Var', (229, 237))
2679	33483342	In multivariable analyses of cutaneous melanomas, adjusting for the number of involved metastatic sites, LDH level, NLR, and the presence of BRAF or NRAS mutations, combination ICI was significantly associated with longer OS compared with anti-PD1 monotherapy (HR 0.57, 95% CI 0.33 to 0.96, p=0.035 (online supplemental table S2).	('BRAF', 'Gene', (141, 145))	('NRAS', 'Gene', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('NRAS', 'Gene', '4893', (149, 153))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (29, 48))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (29, 48))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('mutations', 'Var', (154, 163))	('cutaneous melanomas', 'Disease', (29, 48))	('longer OS', 'CPA', (215, 224))	('BRAF', 'Gene', '673', (141, 145))
2680	33483342	In multivariable analyses of the entire cohort, there was a non-significant trend toward shorter cPFS among patients who had either a BRAF V600E/K or NRAS mutation (HR 1.40, 95% CI 0.99 to 1.96, p=0.056) and OS (HR 1.46, 95% CI 1.00 to 2.13, p=0.052) compared with those who were BRAF/NRAS wild type (table 2).	('BRAF', 'Gene', '673', (280, 284))	('patients', 'Species', '9606', (108, 116))	('NRAS', 'Gene', '4893', (285, 289))	('BRAF', 'Gene', (280, 284))	('BRAF', 'Gene', '673', (134, 138))	('V600E', 'Var', (139, 144))	('BRAF', 'Gene', (134, 138))	('PFS', 'Disease', 'None', (98, 101))	('NRAS', 'Gene', (150, 154))	('PFS', 'Disease', (98, 101))	('V600E', 'SUBSTITUTION', 'None', (139, 144))	('NRAS', 'Gene', '4893', (150, 154))	('shorter', 'NegReg', (89, 96))	('NRAS', 'Gene', (285, 289))
2681	33483342	In multivariable analyses of survival outcomes of patients with cutaneous melanoma (n=183), the presence of either a BRAF or NRAS mutation was significantly associated with shorter cPFS (HR 1.63, 95% CI 1.07 to 2.49, p=0.022) and OS (HR 1.65, 95% CI 1.02 to 2.69, p=0.043) (online supplemental table S2).	('presence', 'Var', (96, 104))	('NRAS', 'Gene', (125, 129))	('patients', 'Species', '9606', (50, 58))	('NRAS', 'Gene', '4893', (125, 129))	('mutation', 'Var', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('shorter', 'NegReg', (173, 180))	('PFS', 'Disease', 'None', (182, 185))	('BRAF', 'Gene', '673', (117, 121))	('cutaneous melanoma', 'Disease', (64, 82))	('PFS', 'Disease', (182, 185))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 82))	('BRAF', 'Gene', (117, 121))
2682	33483342	Patients with NRAS mutant melanoma (n=69) experienced significantly longer cPFS when treated with anti-PD1+anti-CTLA4 ICI (median cPFS not reached) versus anti-PD1 (median cPFS=7.0 months) (figure 5A).	('CTLA4', 'Gene', (112, 117))	('PFS', 'Disease', 'None', (131, 134))	('PFS', 'Disease', 'None', (173, 176))	('PFS', 'Disease', 'None', (76, 79))	('longer', 'PosReg', (68, 74))	('NRAS', 'Gene', '4893', (14, 18))	('PFS', 'Disease', (131, 134))	('PFS', 'Disease', (173, 176))	('PFS', 'Disease', (76, 79))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('mutant', 'Var', (19, 25))	('melanoma', 'Disease', (26, 34))	('CTLA4', 'Gene', '1493', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('NRAS', 'Gene', (14, 18))
2684	33483342	In multivariable analyses of NRAS mutant melanoma, treatment with anti-PD1 +anti-CTLA4 ICI was associated with significantly improved cPFS (HR 0.34, 95% CI 0.16 to 0.71, p=0.004) and OS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003) (online supplemental table S3).	('CTLA4', 'Gene', (81, 86))	('PFS', 'Disease', 'None', (135, 138))	('NRAS', 'Gene', (29, 33))	('PFS', 'Disease', (135, 138))	('NRAS', 'Gene', '4893', (29, 33))	('improved', 'PosReg', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('CTLA4', 'Gene', '1493', (81, 86))	('mutant', 'Var', (34, 40))
2685	33483342	Clinical variables that were independently associated with poor cPFS and OS in NRAS mutant melanoma included >3 metastatic sites and elevated LDH.	('LDH', 'MPA', (142, 145))	('NRAS', 'Gene', '4893', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('elevated', 'PosReg', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('mutant', 'Var', (84, 90))	('PFS', 'Disease', 'None', (65, 68))	('NRAS', 'Gene', (79, 83))	('PFS', 'Disease', (65, 68))
2687	33483342	In BRAF V600E/K mutant melanoma (n=86), there was a significant trend toward longer OS and non-significant trend toward longer cPFS with combination immunotherapy versus anti-PD1 alone (figure 5C, D).	('PFS', 'Disease', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('V600E', 'SUBSTITUTION', 'None', (8, 13))	('melanoma', 'Disease', (23, 31))	('V600E', 'Var', (8, 13))	('BRAF', 'Gene', '673', (3, 7))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('BRAF', 'Gene', (3, 7))	('PFS', 'Disease', 'None', (128, 131))
2688	33483342	In multivariable analyses of survival outcomes among patients with BRAF V600E/K mutant melanoma, anti-PD1+anti-CTLA4 ICI was associated with longer OS (HR 0.47, 95% CI 0.24 to 0.90, p=0.024), as was >3 metastatic sites and NLR >5.	('melanoma', 'Disease', (87, 95))	('BRAF', 'Gene', '673', (67, 71))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('patients', 'Species', '9606', (53, 61))	('V600E', 'Var', (72, 77))	('BRAF', 'Gene', (67, 71))	('V600E', 'SUBSTITUTION', 'None', (72, 77))	('CTLA4', 'Gene', '1493', (111, 116))	('CTLA4', 'Gene', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
2689	33483342	Anti-PD1 regimen type was not significantly associated with cPFS in a multivariable model of BRAF V600E/K mutant melanoma (online supplemental table S4).	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('PFS', 'Disease', 'None', (61, 64))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('PFS', 'Disease', (61, 64))	('V600E', 'Var', (98, 103))	('V600E', 'SUBSTITUTION', 'None', (98, 103))
2694	33483342	A subset of patients with BRAF wild-type melanoma were also assessed for the presence of a KIT mutation.	('patients', 'Species', '9606', (12, 20))	('KIT', 'Gene', '3815', (91, 94))	('BRAF', 'Gene', '673', (26, 30))	('KIT', 'Gene', (91, 94))	('BRAF', 'Gene', (26, 30))	('KIT', 'molecular_function', 'GO:0005020', ('91', '94'))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('mutation', 'Var', (95, 103))
2699	33483342	These tumor types are rare, and the reported numbers of patients with acral or mucosal melanoma that were treated with anti-PD1 ICI were small; our data provide further validation of these observations.	('patients', 'Species', '9606', (56, 64))	('anti-PD1', 'Var', (119, 127))	('mucosal melanoma', 'Disease', (79, 95))	('mucosal melanoma', 'Disease', 'MESH:D008545', (79, 95))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('acral', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
2700	33483342	The unique genomic make-up of acral and mucosal melanomas, as described above, may explain their relative insensitivity to anti-PD1 ICI compared with cutaneous melanomas.	('cutaneous melanomas', 'Disease', (150, 169))	('anti-PD1', 'Var', (123, 131))	('mucosal melanomas', 'Disease', (40, 57))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('mucosal melanomas', 'Disease', 'MESH:D008545', (40, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (150, 169))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (150, 169))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
2701	33483342	We observed a clear overall survival benefit with combination ICI in mucosal and unknown primary melanoma, but there was no survival benefit for combination ICI in acral melanoma.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('acral melanoma', 'Disease', 'MESH:D008545', (164, 178))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('mucosal', 'Disease', (69, 76))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('acral melanoma', 'Phenotype', 'HP:0012060', (164, 178))	('combination', 'Var', (50, 61))	('acral melanoma', 'Disease', (164, 178))
2705	33483342	KIT mutations, while more common in acral melanoma than other subtypes, are still only present in a minority of these tumors.	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('acral melanoma', 'Phenotype', 'HP:0012060', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('common', 'Reg', (26, 32))	('acral melanoma', 'Disease', (36, 50))	('KIT', 'Gene', '3815', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('KIT', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('acral melanoma', 'Disease', 'MESH:D008545', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
2709	33483342	This may represent a promising treatment option for acral melanoma, and there are a number of ongoing clinical trials actively investigating this strategy (NCT03955354, NCT03991975).	('NCT03991975', 'Var', (169, 180))	('acral melanoma', 'Disease', 'MESH:D008545', (52, 66))	('NCT03955354', 'Var', (156, 167))	('acral melanoma', 'Disease', (52, 66))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('acral melanoma', 'Phenotype', 'HP:0012060', (52, 66))
2711	33483342	We found that combination ICI was associated with improved OS over anti-PD1 monotherapy in multivariable analyses of BRAF V600E/K mutant and in NRAS mutant melanoma, but not in BRAF/NRAS wild-type melanoma.	('NRAS', 'Gene', '4893', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('NRAS', 'Gene', '4893', (182, 186))	('melanoma', 'Disease', (156, 164))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Disease', (197, 205))	('mutant', 'Var', (149, 155))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('NRAS', 'Gene', (182, 186))	('improved', 'PosReg', (50, 58))	('NRAS', 'Gene', (144, 148))	('V600E', 'SUBSTITUTION', 'None', (122, 127))	('BRAF', 'Gene', '673', (117, 121))	('V600E', 'Var', (122, 127))	('BRAF', 'Gene', (117, 121))
2712	33483342	Our retrospective analysis provides real-world data supporting the results of the BRAF mutation subset analyses of the Checkmate-067 study, and validates the use of anti-CTLA4+anti-PD1 combination as the preferred ICI regimen for BRAF V600E/K mutant melanoma.	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('CTLA4', 'Gene', '1493', (170, 175))	('BRAF', 'Gene', '673', (230, 234))	('melanoma', 'Disease', (250, 258))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('V600E', 'Var', (235, 240))	('CTLA4', 'Gene', (170, 175))	('BRAF', 'Gene', (230, 234))	('V600E', 'SUBSTITUTION', 'None', (235, 240))
2713	33483342	Previous retrospective studies have examined the relationship between NRAS mutations and ICI outcomes in melanoma, but have not established a relationship between NRAS and poor survival.	('NRAS', 'Gene', (70, 74))	('NRAS', 'Gene', (163, 167))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('ICI outcomes', 'MPA', (89, 101))	('melanoma', 'Disease', (105, 113))	('NRAS', 'Gene', '4893', (70, 74))	('NRAS', 'Gene', '4893', (163, 167))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('mutations', 'Var', (75, 84))
2714	33483342	However, these studies were limited because they include a very small number of NRAS mutant patients who received anti-PD1 ICI or analyzed only those patients who had already progressed on anti-PD1 ICI.	('NRAS', 'Gene', (80, 84))	('patients', 'Species', '9606', (92, 100))	('NRAS', 'Gene', '4893', (80, 84))	('patients', 'Species', '9606', (150, 158))	('anti-PD1', 'Var', (114, 122))	('mutant', 'Var', (85, 91))
2715	33483342	To our knowledge, the observation that NRAS mutations status can function as a predictive marker for anti-PD1 ICI outcomes is a novel finding.	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', '4893', (39, 43))	('NRAS', 'Gene', (39, 43))
2717	33483342	NRAS mutations are mutually exclusive with BRAF V600E/K mutations.	('V600E', 'Var', (48, 53))	('BRAF', 'Gene', '673', (43, 47))	('V600E', 'SUBSTITUTION', 'None', (48, 53))	('BRAF', 'Gene', (43, 47))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
2719	33483342	However, NRAS mutations are generally associated with poor prognosis.	('NRAS', 'Gene', '4893', (9, 13))	('NRAS', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
2720	33483342	The impact of an activating NRAS mutation on the immune composition of the melanoma tumor microenvironment is not well described.	('NRAS', 'Gene', '4893', (28, 32))	('melanoma tumor', 'Disease', (75, 89))	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('activating', 'PosReg', (17, 27))	('melanoma tumor', 'Disease', 'MESH:D008545', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('NRAS', 'Gene', (28, 32))
2721	33483342	Activating BRAF mutations are well known to orchestrate an immune-suppressed tumor microenvironment via various mechanisms, including downregulation of MHC class 1 molecules on the surface of tumor cells, enhanced production of chemokines, which recruit myeloid-derived suppressor cells (MDSCs), and increased expression of vascular endothelial growth factor (VEGF), which promotes myeloid cell maturation.	('downregulation', 'NegReg', (134, 148))	('increased', 'PosReg', (300, 309))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased expression of vascular endothelial growth factor', 'Phenotype', 'HP:0031052', (300, 358))	('vascular endothelial growth factor', 'Gene', '7422', (324, 358))	('production', 'MPA', (214, 224))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('324', '358'))	('VEGF', 'Gene', '7422', (360, 364))	('mutations', 'Var', (16, 25))	('vascular endothelial growth factor', 'Gene', (324, 358))	('expression', 'MPA', (310, 320))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('enhanced', 'PosReg', (205, 213))	('VEGF', 'Gene', (360, 364))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cell maturation', 'biological_process', 'GO:0048469', ('390', '405'))	('tumor', 'Disease', (192, 197))	('MHC class', 'Gene', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('myeloid cell maturation', 'CPA', (382, 405))	('promotes', 'PosReg', (373, 381))	('BRAF', 'Gene', '673', (11, 15))	('tumor', 'Disease', (77, 82))	('BRAF', 'Gene', (11, 15))
2722	33483342	Inhibition of the BRAF V600E/K oncogene in melanoma with BRAF and/or MEK inhibitors also leads to an increase in tumor-infiltrating lymphocytes and other molecular alterations that facilitate immune activation within the tumor immune microenvironment.	('BRAF', 'Gene', '673', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('BRAF', 'Gene', (57, 61))	('MEK', 'Gene', '5609', (69, 72))	('V600E', 'Var', (23, 28))	('MEK', 'Gene', (69, 72))	('increase', 'PosReg', (101, 109))	('immune activation', 'CPA', (192, 209))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('V600E', 'SUBSTITUTION', 'None', (23, 28))	('tumor', 'Disease', (113, 118))	('molecular alterations', 'CPA', (154, 175))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('facilitate', 'PosReg', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('BRAF', 'Gene', '673', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BRAF', 'Gene', (18, 22))
2723	33483342	Therefore, it is conceivable that NRAS mutations, via activation of the downstream MAPK pathway could function similarly to BRAF mutations in this respect.	('downstream MAPK pathway', 'Pathway', (72, 95))	('BRAF', 'Gene', '673', (124, 128))	('mutations', 'Var', (39, 48))	('activation', 'PosReg', (54, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('NRAS', 'Gene', (34, 38))	('BRAF', 'Gene', (124, 128))	('NRAS', 'Gene', '4893', (34, 38))
2724	33483342	Indeed, it has been reported that activating KRAS mutations has been shown to facilitate immune suppression via metabolic reprogramming, which leads to increased glycolysis and MDSC recruitment in triple negative breast cancer and colon cancer.	('MDSC recruitment', 'MPA', (177, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('colon cancer', 'Phenotype', 'HP:0003003', (231, 243))	('metabolic reprogramming', 'CPA', (112, 135))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', (213, 226))	('glycolysis', 'MPA', (162, 172))	('colon cancer', 'Disease', 'MESH:D015179', (231, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('increased', 'PosReg', (152, 161))	('immune suppression', 'CPA', (89, 107))	('KRAS', 'Gene', '3845', (45, 49))	('activating', 'PosReg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('mutations', 'Var', (50, 59))	('colon cancer', 'Disease', (231, 243))	('glycolysis', 'biological_process', 'GO:0006096', ('162', '172'))	('KRAS', 'Gene', (45, 49))	('facilitate', 'PosReg', (78, 88))
2727	33483342	Cutaneous melanomas that lack BRAF V600E/K or NRAS mutations belong to either the NF1 mutant or triple wild-type genomic subgroups.	('Cutaneous melanomas', 'Disease', 'MESH:C562393', (0, 19))	('NRAS', 'Gene', (46, 50))	('V600E', 'Var', (35, 40))	('NF1', 'Gene', (82, 85))	('NRAS', 'Gene', '4893', (46, 50))	('BRAF', 'Gene', (30, 34))	('V600E', 'SUBSTITUTION', 'None', (35, 40))	('NF1', 'Gene', '4763', (82, 85))	('Cutaneous melanomas', 'Disease', (0, 19))	('BRAF', 'Gene', '673', (30, 34))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('Cutaneous melanomas', 'Phenotype', 'HP:0012056', (0, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))
2728	33483342	NF1 mutant melanoma in particular have a high tumor mutation burden (TMB), resulting in a high number of neoantigens, which can be readily detected by T-cells.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('mutant', 'Var', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('TMB', 'Chemical', '-', (69, 72))	('neoantigens', 'MPA', (105, 116))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
2729	33483342	Indeed, high TMB has been associated with increased responsiveness to anti-PD1 monotherapy.	('responsiveness to', 'MPA', (52, 69))	('high', 'Var', (8, 12))	('TMB', 'MPA', (13, 16))	('TMB', 'Chemical', '-', (13, 16))
2730	33483342	We did not assess NF1 mutation status or TMB in our cohort, but we hypothesize that NF1 mutations and/or high TMB would be overrepresented in our cohort of n=55 BRAF/NRAS wild-type cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanomas', 'Phenotype', 'HP:0002861', (191, 200))	('mutations', 'Var', (88, 97))	('NRAS', 'Gene', '4893', (166, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (181, 199))	('NF1', 'Gene', '4763', (84, 87))	('TMB', 'MPA', (110, 113))	('NRAS', 'Gene', (166, 170))	('TMB', 'Chemical', '-', (41, 44))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (181, 200))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (181, 200))	('NF1', 'Gene', (84, 87))	('NF1', 'Gene', '4763', (18, 21))	('overrepresented', 'PosReg', (123, 138))	('cutaneous melanomas', 'Disease', (181, 200))	('TMB', 'Chemical', '-', (110, 113))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('NF1', 'Gene', (18, 21))
2739	32546168	We enrolled in this study a total of 152 patients from TCGA-SKCM (The Cancer Genome Atlas Skin Cutaneous Melanoma project) with complete information in recurrence-related survival time, baseline variables (clinicopathologic variables, mutation status of BRAF and NRAS genes), gene expression data, and whole slide image (WSI) features.	('mutation', 'Var', (235, 243))	('Atlas Skin Cutaneous Melanoma', 'Disease', (84, 113))	('gene expression', 'biological_process', 'GO:0010467', ('276', '291'))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NRAS', 'Gene', (263, 267))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('Cancer', 'Disease', (70, 76))	('NRAS', 'Gene', '4893', (263, 267))	('Atlas Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (84, 113))	('patients', 'Species', '9606', (41, 49))	('BRAF', 'Gene', '673', (254, 258))	('Melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('BRAF', 'Gene', (254, 258))
2816	17565341	Immune cells such as T lymphocytes and DCs have also been reported to secrete various isoforms of TGFbeta, and the presence of this cytokine promotes an immunosuppressive phenotype in both of these cell types (Chen and Wahl, 2003; Ghiringhelli et al, 2005).	('TGFbeta', 'Gene', (98, 105))	('presence', 'Var', (115, 123))	('TGFbeta', 'Gene', '7040', (98, 105))	('promotes', 'PosReg', (141, 149))	('immunosuppressive phenotype', 'MPA', (153, 180))
2835	17565341	We tested the following target genes: the cytokines TGFbeta1, TGFbeta2 and IL-10 (Taqman primer probes codes: Hs00171257, Hs00234244 and Hs00174086, respectively), the enzyme IDO (Hs00158032), two membrane-bound molecules, ILT3 and ILT4 and FOXp3, a nuclear transcription factor (Hs00429000, Hs00275975 and Hs00203958).	('IL-10', 'molecular_function', 'GO:0005141', ('75', '80'))	('ILT4', 'Gene', (232, 236))	('ILT3', 'Gene', (223, 227))	('ILT3', 'Gene', '11006', (223, 227))	('IDO', 'molecular_function', 'GO:0033754', ('175', '178'))	('membrane', 'cellular_component', 'GO:0016020', ('197', '205'))	('TGFbeta1', 'Gene', '7040', (52, 60))	('Hs00234244', 'Var', (122, 132))	('Hs00174086', 'Var', (137, 147))	('Hs00275975', 'Var', (292, 302))	('IDO', 'Gene', (175, 178))	('ILT4', 'Gene', '10288', (232, 236))	('IDO', 'molecular_function', 'GO:0047719', ('175', '178'))	('TGFbeta1', 'Gene', (52, 60))	('Hs00171257', 'Var', (110, 120))	('Hs00158032', 'Var', (180, 190))	('FOXp3', 'Gene', '50943', (241, 246))	('tested', 'Reg', (3, 9))	('Hs00429000', 'Var', (280, 290))	('IL-10', 'Gene', '3586', (75, 80))	('TGFbeta2', 'Gene', (62, 70))	('IL-10', 'Gene', (75, 80))	('IDO', 'Gene', '3620', (175, 178))	('transcription factor', 'molecular_function', 'GO:0000981', ('258', '278'))	('transcription', 'biological_process', 'GO:0006351', ('258', '271'))	('FOXp3', 'Gene', (241, 246))
2838	17565341	Separately, comparisons within two groups of matched samples were performed, namely three complete matched samples, including primary melanoma, negative and positive SLN and seven negative SLN vs positive SLN matched pairs.	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('primary melanoma', 'Disease', 'MESH:D008545', (126, 142))	('positive SLN', 'Var', (157, 169))	('primary melanoma', 'Disease', (126, 142))
2860	17565341	As with ILT3 and FOXp3, expression of both IL-10 and IDO increased with melanoma progression from skin into the lymph nodes, the peak occurring in positive SLN (Figure 1E and F).	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('IDO', 'Gene', '3620', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('expression', 'MPA', (24, 34))	('IDO', 'Gene', (53, 56))	('IL-10', 'Gene', (43, 48))	('ILT3', 'Gene', '11006', (8, 12))	('FOXp3', 'Gene', '50943', (17, 22))	('IDO', 'molecular_function', 'GO:0033754', ('53', '56'))	('IL-10', 'molecular_function', 'GO:0005141', ('43', '48'))	('FOXp3', 'Gene', (17, 22))	('increased', 'PosReg', (57, 66))	('positive SLN', 'Var', (147, 159))	('ILT3', 'Gene', (8, 12))	('IL-10', 'Gene', '3586', (43, 48))	('IDO', 'molecular_function', 'GO:0047719', ('53', '56'))
2902	17565341	Our finding supports the hypothesis that the presence of TGFbeta2 is correlated with melanoma progression (Reed et al, 1994).	('correlated', 'Reg', (69, 79))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('TGFbeta2', 'Gene', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('presence', 'Var', (45, 53))
2937	33091721	Genomic mutations in the v-raf murine sarcoma oncogene homolog B (BRAF), neuroblastoma RAS viral oncogene homolog (NRAS), and neurofibromin 1 (NF1) are involved in melanomagenesis as they alter the mitogen-activated protein kinase (MAPK) pathway.	('neuroblastoma', 'Phenotype', 'HP:0003006', (73, 86))	('neurofibromin 1', 'Gene', '18015', (126, 141))	('NF1', 'Gene', (143, 146))	('neuroblastoma', 'Disease', 'MESH:D009447', (73, 86))	('involved', 'Reg', (152, 160))	('sarcoma', 'Disease', 'MESH:D012509', (38, 45))	('murine', 'Species', '10090', (31, 37))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('NF1', 'Gene', '18015', (143, 146))	('sarcoma', 'Disease', (38, 45))	('neurofibromin 1', 'Gene', (126, 141))	('mutations', 'Var', (8, 17))	('protein', 'cellular_component', 'GO:0003675', ('216', '223'))	('MAPK', 'molecular_function', 'GO:0004707', ('232', '236'))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))	('alter', 'Reg', (188, 193))	('BRAF', 'Gene', (66, 70))	('neuroblastoma', 'Disease', (73, 86))
2940	33091721	Other pathways which are altered in cutaneous melanoma that include increased telomere maintenance, histone modification, methylation, and the alteration of cell cycle and inhibition of apoptosis with mutations in TP53 and cyclin-dependent kinase inhibitor 2A (CDKN2A).	('histone modification', 'MPA', (100, 120))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (223, 259))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('78', '98'))	('TP53', 'Gene', '7157', (214, 218))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (223, 259))	('telomere', 'cellular_component', 'GO:0000781', ('78', '86'))	('increased', 'PosReg', (68, 77))	('apoptosis', 'CPA', (186, 195))	('inhibition', 'NegReg', (172, 182))	('telomere', 'cellular_component', 'GO:0005696', ('78', '86'))	('methylation', 'MPA', (122, 133))	('telomere', 'MPA', (78, 86))	('histone modification', 'biological_process', 'GO:0016570', ('100', '120'))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('CDKN2A', 'Gene', (261, 267))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('223', '256'))	('mutations', 'Var', (201, 210))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('172', '195'))	('cell cycle', 'CPA', (157, 167))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('240', '256'))	('TP53', 'Gene', (214, 218))	('alteration', 'Reg', (143, 153))	('CDKN2A', 'Gene', '1029', (261, 267))
2942	33091721	Currently, the most studied and frequent genetic cause of melanoma is ascribed to BRAFV600E, which is present in 50% of melanomas and responsible for an increased proliferation and the metabolic reprogramming of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanomas', 'Disease', (120, 129))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('increased', 'PosReg', (153, 162))	('proliferation', 'CPA', (163, 176))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (120, 128))	('BRAFV600E', 'Var', (82, 91))	('melanoma', 'Disease', (212, 220))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('metabolic reprogramming', 'CPA', (185, 208))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
2958	33091721	The mutagenic properties of UVR drive the initiation of melanoma are illustrated in Fig.	('mutagenic', 'Var', (4, 13))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('UVR', 'Gene', (28, 31))
2967	33091721	In addition, pheomelanin pigment may induces oxidative stress, lipid damage, and consequent melanoma induction in murine model with BRAFV600E mutation and melanocortin 1 receptor (MC1R) inactivation in melanocytes (to mimic red skin phenotype).	('induces', 'Reg', (37, 44))	('pheomelanin', 'Gene', (13, 24))	('oxidative stress', 'MPA', (45, 61))	('murine', 'Species', '10090', (114, 120))	('lipid damage', 'Disease', 'MESH:D052439', (63, 75))	('pheomelanin', 'Gene', '114618', (13, 24))	('melanocortin 1 receptor', 'Gene', (155, 178))	('BRAFV600E', 'Mutation', 'rs113488022', (132, 141))	('BRAFV600E mutation', 'Var', (132, 150))	('melanocortin 1 receptor', 'Gene', '17199', (155, 178))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('MC1R', 'Gene', '17199', (180, 184))	('MC1R', 'Gene', (180, 184))	('oxidative stress', 'Phenotype', 'HP:0025464', (45, 61))	('inactivation', 'Var', (186, 198))	('lipid damage', 'Disease', (63, 75))
2968	33091721	Indeed, when crossed with an albino allele which ablates the biosynthesis of pheomelanin, it was protective for melanoma initiation.	('pheomelanin', 'Gene', '114618', (77, 88))	('biosynthesis', 'biological_process', 'GO:0009058', ('61', '73'))	('melanoma initiation', 'Disease', 'MESH:D008545', (112, 131))	('ablates', 'Var', (49, 56))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma initiation', 'Disease', (112, 131))	('pheomelanin', 'Gene', (77, 88))
2992	33091721	By comparing BRAFV600E vs BRAFV600E/PTEN-/- mouse melanoma models, Bagati and colleagues elegantly showed that Klf9 deficiency does not affect primary tumor growth but it does promote melanoma metastasis.	('BRAFV600E', 'Var', (13, 22))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('BRAFV600E/PTEN-/-', 'Var', (26, 43))	('promote', 'PosReg', (176, 183))	('deficiency', 'Var', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Klf9', 'Gene', (111, 115))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('melanoma metastasis', 'Disease', 'MESH:D009362', (184, 203))	('mouse', 'Species', '10090', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('tumor', 'Disease', (151, 156))	('melanoma metastasis', 'Disease', (184, 203))	('BRAFV600E', 'Mutation', 'rs113488022', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
3001	33091721	Melanomas with activation of the mutated BRAF have suppressed levels of MITF and PGC1alpha and decreased oxidative metabolism.	('decreased', 'NegReg', (95, 104))	('oxidative metabolism', 'MPA', (105, 125))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('105', '125'))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('PGC1alpha', 'Protein', (81, 90))	('Melanomas', 'Disease', (0, 9))	('levels of MITF', 'MPA', (62, 76))	('mutated', 'Var', (33, 40))	('suppressed', 'NegReg', (51, 61))	('BRAF', 'Gene', (41, 45))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))
3012	33091721	The role of "oxygen sensor" PHD2 in protection from melanoma initiation by regulation of HIF1alpha and HIF2alpha subunits was shown on recently generated mouse model Tyr:CreER; PHD2lox/lox;BRAFV600E possessing melanocyte-specific BRAFV600E and PHD2 loss.	('HIF2alpha', 'Gene', (103, 112))	('mouse', 'Species', '10090', (154, 159))	('ER', 'Gene', '2069', (173, 175))	('melanoma initiation', 'Disease', (52, 71))	('BRAFV600E', 'Var', (189, 198))	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('BRAFV600E', 'Mutation', 'rs113488022', (189, 198))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('HIF1alpha', 'Gene', (89, 98))	('lox', 'Gene', (185, 188))	('lox', 'Gene', (181, 184))	('HIF2alpha', 'Gene', '13819', (103, 112))	('lox', 'Gene', '16948', (185, 188))	('lox', 'Gene', '16948', (181, 184))	('melanoma initiation', 'Disease', 'MESH:D008545', (52, 71))	('BRAFV600E', 'Var', (230, 239))	('BRAFV600E', 'Mutation', 'rs113488022', (230, 239))	('HIF1alpha', 'Gene', '15251', (89, 98))
3013	33091721	Deletion of PHD2 in combination with expression of BRAFV600E in melanocytes were enough to trigger melanoma initiation, and the development of melanoma and lymph node metastasis in mouse models.	('PHD2', 'Gene', (12, 16))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('PHD', 'molecular_function', 'GO:0050175', ('12', '15'))	('melanoma initiation', 'Disease', 'MESH:D008545', (99, 118))	('trigger', 'PosReg', (91, 98))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', (99, 107))	('development', 'CPA', (128, 139))	('melanoma initiation', 'Disease', (99, 118))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('mouse', 'Species', '10090', (181, 186))	('Deletion', 'Var', (0, 8))
3015	33091721	Authors also reported recent studies that PHD2 can directly inactivate AKT protein, part of PI3K signaling pathway, by the hydroxylation of two proline residues.	('PHD2', 'Var', (42, 46))	('PHD', 'molecular_function', 'GO:0050175', ('42', '45'))	('AKT', 'Gene', '207', (71, 74))	('PI3K signaling', 'biological_process', 'GO:0014065', ('92', '106'))	('signaling pathway', 'biological_process', 'GO:0007165', ('97', '114'))	('inactivate', 'NegReg', (60, 70))	('proline', 'Chemical', 'MESH:D011392', (144, 151))	('hydroxylation of two proline residues', 'MPA', (123, 160))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('AKT', 'Gene', (71, 74))	('PI3K signaling pathway', 'Pathway', (92, 114))
3023	33091721	Inhibition of TMXs lead to an increase of mitochondrial ROS promoting oxidation and inhibition of redox sensitive-dephosphatase calcineurin, which is responsible for activation of NFAT1 and melanoma proliferation and migration.	('calcineurin', 'molecular_function', 'GO:0004722', ('128', '139'))	('mitochondrial', 'MPA', (42, 55))	('activation', 'PosReg', (166, 176))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('inhibition', 'NegReg', (84, 94))	('NFAT1', 'Gene', '4773', (180, 185))	('calcineurin', 'molecular_function', 'GO:0004723', ('128', '139'))	('redox', 'MPA', (98, 103))	('oxidation', 'MPA', (70, 79))	('melanoma proliferation', 'Disease', (190, 212))	('melanoma proliferation', 'Disease', 'MESH:D008545', (190, 212))	('NFAT1', 'Gene', (180, 185))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (30, 38))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('promoting', 'PosReg', (60, 69))	('TMXs', 'Gene', (14, 18))	('migration', 'CPA', (217, 226))
3034	33091721	Cells with overexpressed HO-1 had increased proliferation rate, improved resistance to H2O2-induced oxidative stress and angiogenic activity compared to controls.	('H2O2', 'Chemical', 'MESH:D006861', (87, 91))	('overexpressed', 'Var', (11, 24))	('increased', 'PosReg', (34, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('resistance to H2O2-induced oxidative stress', 'MPA', (73, 116))	('proliferation rate', 'CPA', (44, 62))	('angiogenic activity', 'CPA', (121, 140))	('improved', 'PosReg', (64, 72))	('HO-1', 'Gene', (25, 29))
3051	33091721	The supplementation of CoQ10 slowed down the ageing of the skin by protecting it from UV-induced ROS.	('CoQ10', 'Chemical', 'MESH:C024989', (23, 28))	('CoQ10', 'Gene', (23, 28))	('ageing', 'CPA', (45, 51))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('ageing', 'biological_process', 'GO:0007568', ('45', '51'))	('supplementation', 'Var', (4, 19))	('slowed down', 'NegReg', (29, 40))	('protecting', 'NegReg', (67, 77))
3052	33091721	Deficiency of CoQ10 was observed in numerous diseases.	('CoQ10', 'Gene', (14, 19))	('observed', 'Reg', (24, 32))	('CoQ10', 'Chemical', 'MESH:C024989', (14, 19))	('Deficiency', 'Var', (0, 10))
3056	33091721	In addition, it was observed that the patients with metastasis had lower CoQ10 levels than the metastasis-free patients.	('metastasis', 'Var', (52, 62))	('CoQ10 levels', 'MPA', (73, 85))	('patients', 'Species', '9606', (38, 46))	('CoQ10', 'Chemical', 'MESH:C024989', (73, 78))	('lower', 'NegReg', (67, 72))	('patients', 'Species', '9606', (111, 119))
3074	33091721	TMX1/3 depletion altered both mitochondrial organization and metabolism as well as inducing oxidative stress leading to a suppression of melanoma growth.	('altered', 'Reg', (17, 24))	('oxidative stress', 'Phenotype', 'HP:0025464', (92, 108))	('metabolism', 'biological_process', 'GO:0008152', ('61', '71'))	('melanoma growth', 'Disease', (137, 152))	('TMX1/3', 'Gene', '81542;54495', (0, 6))	('inducing', 'Reg', (83, 91))	('mitochondrial organization', 'MPA', (30, 56))	('melanoma growth', 'Disease', 'MESH:D008545', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('oxidative stress', 'MPA', (92, 108))	('depletion', 'Var', (7, 16))	('metabolism', 'MPA', (61, 71))	('TMX1/3', 'Gene', (0, 6))	('suppression', 'NegReg', (122, 133))
3085	33091721	The role of G6PD in cooperation with NADPH oxidase 4 (NOX4) for the support of redox homeostasis has been related to melanoma cells in vitro, indeed targeting both enzymes suppressed cell proliferation.	('G6PD', 'Gene', (12, 16))	('targeting', 'Var', (149, 158))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('NADPH oxidase', 'molecular_function', 'GO:0016174', ('37', '50'))	('NOX4', 'Gene', '50507', (54, 58))	('suppressed', 'NegReg', (172, 182))	('NADPH oxidase', 'molecular_function', 'GO:0008753', ('37', '50'))	('cell proliferation', 'biological_process', 'GO:0008283', ('183', '201'))	('homeostasis', 'biological_process', 'GO:0042592', ('85', '96'))	('cell proliferation', 'CPA', (183, 201))	('melanoma', 'Disease', (117, 125))	('NADPH oxidase 4', 'Gene', '50507', (37, 52))	('G6PD', 'Gene', '2539', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('NOX4', 'Gene', (54, 58))	('NADPH oxidase 4', 'Gene', (37, 52))
3092	33091721	Melanoma cell invasion and metastasis levels were positively correlated with high PKM2 activity as well as the glycolytic capability.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('PKM2', 'Gene', '5315', (82, 86))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('glycolytic capability', 'MPA', (111, 132))	('high', 'Var', (77, 81))	('activity', 'MPA', (87, 95))	('Melanoma', 'Disease', (0, 8))	('metastasis levels', 'MPA', (27, 44))	('PKM2', 'Gene', (82, 86))
3093	33091721	In addition, knockdown of PKM2 markedly attenuated the malignant phenotypes of melanoma cells including cell proliferation, invasion and metastasis in vitro and in vivo, suggesting that PKM2 is a potential therapeutic target in melanoma.	('PKM2', 'Gene', '5315', (26, 30))	('cell proliferation', 'CPA', (104, 122))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('knockdown', 'Var', (13, 22))	('PKM2', 'Gene', (186, 190))	('cell proliferation', 'biological_process', 'GO:0008283', ('104', '122'))	('PKM2', 'Gene', '5315', (186, 190))	('attenuated', 'NegReg', (40, 50))	('melanoma', 'Disease', (79, 87))	('PKM2', 'Gene', (26, 30))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
3100	33091721	Indeed, using PDX and mouse melanoma models, Tasdogan and colleagues showed that the inhibition of MCT1, while not altering primary tumor formation, does lead to a depletion of circulating melanoma cells and a decrease of metastasis.	('melanoma', 'Disease', (28, 36))	('MCT1', 'Gene', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inhibition', 'Var', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('decrease', 'NegReg', (210, 218))	('MCT', 'biological_process', 'GO:0120197', ('99', '102'))	('metastasis', 'CPA', (222, 232))	('tumor', 'Disease', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('mouse', 'Species', '10090', (22, 27))	('melanoma', 'Disease', (189, 197))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
3108	33091721	PHGDH silencing in melanoma cell lines with increased PHGDH copy number leads to the signficant growth inhibition.	('PHGDH', 'Gene', (54, 59))	('copy number', 'Var', (60, 71))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('PHGDH', 'Gene', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('silencing', 'NegReg', (6, 15))	('increased', 'PosReg', (44, 53))	('growth inhibition', 'CPA', (96, 113))
3109	33091721	It was shown that upregulated level of PHGDH is important for tumor initiation and promotion in melanoma mouse model TyrCreER: BRAFV600E; PHGDHtetO in cooperation with BRAFV600E mutation.	('BRAFV600E', 'Mutation', 'rs113488022', (168, 177))	('BRAFV600E', 'Var', (127, 136))	('BRAFV600E', 'Mutation', 'rs113488022', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mouse', 'Species', '10090', (105, 110))	('ER', 'Gene', '2069', (123, 125))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
3110	33091721	Accordingly, increased dietary serine and overexpressed PHGDH promoted tumor growth in mice.	('overexpressed', 'Var', (42, 55))	('mice', 'Species', '10090', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('serine', 'Chemical', 'MESH:D012694', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PHGDH', 'Protein', (56, 61))	('promoted', 'PosReg', (62, 70))	('tumor', 'Disease', (71, 76))	('increased', 'PosReg', (13, 22))
3116	33091721	Folate pathway inhibition by methotrexate, or by knockdown of its key enzymes, inhibited distant metastasis without affecting the growth of primary tumors in the same mice.	('knockdown', 'Var', (49, 58))	('inhibition', 'NegReg', (15, 25))	('primary tumors', 'Disease', (140, 154))	('Folate', 'Chemical', 'MESH:D005492', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('primary tumors', 'Disease', 'MESH:D001932', (140, 154))	('methotrexate', 'Chemical', 'MESH:D008727', (29, 41))	('Folate pathway', 'Pathway', (0, 14))	('distant metastasis', 'CPA', (89, 107))	('inhibited', 'NegReg', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mice', 'Species', '10090', (167, 171))
3117	33091721	Inhibition of 1-CM is already used as a therapeutic strategy in cancer and combined with other agents could prove useful in combating melanoma.	('1-CM', 'Protein', (14, 18))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
3120	33091721	Depletion of Sirt3 resulted in senescence induction, while its overexpression lead to the proliferation of melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('proliferation', 'CPA', (90, 103))	('lead to', 'Reg', (78, 85))	('Sirt3', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('senescence', 'biological_process', 'GO:0010149', ('31', '41'))	('senescence induction', 'MPA', (31, 51))	('overexpression', 'PosReg', (63, 77))
3121	33091721	In a xenograft mouse model, lack of Sirt3 inhibited tumor growth and improved overall survival rate.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('overall survival rate', 'CPA', (78, 99))	('improved', 'PosReg', (69, 77))	('tumor', 'Disease', (52, 57))	('Sirt3', 'Gene', (36, 41))	('inhibited', 'NegReg', (42, 51))	('mouse', 'Species', '10090', (15, 20))	('lack', 'Var', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
3122	33091721	It was also found that mutant p53 induces the expression of Sirt3, and subsequent MnSOD enzymatic activity.	('Sirt3', 'Enzyme', (60, 65))	('induces', 'PosReg', (34, 41))	('MnSOD', 'Gene', '6648', (82, 87))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('MnSOD', 'Gene', (82, 87))	('expression', 'MPA', (46, 56))	('mutant', 'Var', (23, 29))
3124	33091721	Almost 50% of melanoma patients harbor a driver for a mutation found in the BRAF gene, therefore BRAF studies provide for a target-based therapy to control this disease.	('melanoma', 'Disease', (14, 22))	('mutation', 'Var', (54, 62))	('BRAF', 'Gene', (76, 80))	('patients', 'Species', '9606', (23, 31))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
3128	33091721	FDA-approved BRAF and MEK inhibitors have enhanced the prognosis of patients with BRAF mutations, but this combination also lacked reliability and strength.	('prognosis', 'CPA', (55, 64))	('enhanced', 'PosReg', (42, 50))	('BRAF', 'Gene', (82, 86))	('patients', 'Species', '9606', (68, 76))	('MEK', 'Gene', '5609', (22, 25))	('MEK', 'Gene', (22, 25))	('mutations', 'Var', (87, 96))
3131	33091721	BRAFV600E mutation is associated with high levels of aerobic glycolysis genes and suppresses OXPHOS in melanoma cells.	('high levels', 'MPA', (38, 49))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('aerobic glycolysis genes', 'MPA', (53, 77))	('glycolysis', 'biological_process', 'GO:0006096', ('61', '71'))	('suppresses', 'NegReg', (82, 92))	('OXPHOS', 'MPA', (93, 99))	('OXPHOS', 'biological_process', 'GO:0002082', ('93', '99'))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('associated', 'Reg', (22, 32))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('BRAFV600E', 'Var', (0, 9))	('melanoma', 'Disease', (103, 111))
3133	33091721	While BRAF and also NRAS mutations have been shown to upregulate Nrf2, the main antioxidant regulator, the BRAFV600E mutation by itself upregulated transcription factor Klf9, which sensitizes cells to oxidative stress.	('upregulated', 'PosReg', (136, 147))	('mutations', 'Var', (25, 34))	('Nrf2', 'Gene', '4780', (65, 69))	('BRAFV600E', 'Mutation', 'rs113488022', (107, 116))	('upregulate', 'PosReg', (54, 64))	('transcription factor', 'molecular_function', 'GO:0000981', ('148', '168'))	('transcription', 'MPA', (148, 161))	('Nrf2', 'Gene', (65, 69))	('BRAFV600E', 'Gene', (107, 116))	('NRAS', 'Gene', (20, 24))	('oxidative stress', 'Phenotype', 'HP:0025464', (201, 217))	('transcription', 'biological_process', 'GO:0006351', ('148', '161'))
3135	33091721	Therefore, the role of BRAF and also NRAS mutations alone or in combination in the metabolic switch of melanoma needs to be further investigated.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('NRAS', 'Gene', (37, 41))	('BRAF', 'Gene', (23, 27))	('mutations', 'Var', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
3143	33091721	As a matter of fact, inhibition of mitochondrial respiration sensitized JARID1Bhigh slow-cycling melanoma cells to therapy.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('respiration', 'biological_process', 'GO:0007585', ('49', '60'))	('JARID1B', 'Gene', '10765', (72, 79))	('inhibition', 'Var', (21, 31))	('JARID1B', 'Gene', (72, 79))	('mitochondrial respiration', 'MPA', (35, 60))	('respiration', 'biological_process', 'GO:0045333', ('49', '60'))	('sensitized', 'Reg', (61, 71))
3155	33091721	Drug resistance to BRAFi induces metabolic switching from aerobic glycolysis to mitochondrial respiration and consequently increased ROS levels.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('increased', 'PosReg', (123, 132))	('metabolic switching', 'MPA', (33, 52))	('respiration', 'biological_process', 'GO:0045333', ('94', '105'))	('Drug resistance', 'biological_process', 'GO:0042493', ('0', '15'))	('induces', 'Reg', (25, 32))	('Drug resistance', 'Var', (0, 15))	('Drug resistance', 'biological_process', 'GO:0009315', ('0', '15'))	('mitochondrial respiration', 'MPA', (80, 105))	('increased ROS level', 'Phenotype', 'HP:0025464', (123, 142))	('aerobic glycolysis', 'MPA', (58, 76))	('glycolysis', 'biological_process', 'GO:0006096', ('66', '76'))	('respiration', 'biological_process', 'GO:0007585', ('94', '105'))	('ROS levels', 'MPA', (133, 143))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))
3156	33091721	Indeed, BRAFV600E melanoma cells that have developed resistance to inhibitors also display increased OXPHOS, increased dependency on mitochondria for survival, increased ROS production and associated switch from glucose to glutamine metabolism.	('OXPHOS', 'biological_process', 'GO:0002082', ('101', '107'))	('BRAFV600E', 'Mutation', 'rs113488022', (8, 17))	('increased ROS production', 'Phenotype', 'HP:0025464', (160, 184))	('OXPHOS', 'MPA', (101, 107))	('glucose', 'Chemical', 'MESH:D005947', (212, 219))	('increased', 'PosReg', (109, 118))	('dependency on mitochondria for survival', 'MPA', (119, 158))	('switch', 'Reg', (200, 206))	('ROS production', 'MPA', (170, 184))	('increased', 'PosReg', (91, 100))	('glutamine', 'Chemical', 'MESH:D005973', (223, 232))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('increased', 'PosReg', (160, 169))	('BRAFV600E', 'Var', (8, 17))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('223', '243'))	('glucose to glutamine metabolism', 'MPA', (212, 243))	('mitochondria', 'cellular_component', 'GO:0005739', ('133', '145'))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
3185	33091721	New evidence demonstrates that BRAF and MEK inhibitors induce an increase in ROS in melanoma cells.	('increase', 'PosReg', (65, 73))	('MEK', 'Gene', '5609', (40, 43))	('inhibitors', 'Var', (44, 54))	('ROS', 'MPA', (77, 80))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('MEK', 'Gene', (40, 43))	('BRAF', 'Gene', (31, 35))
3195	24369020	Of those 31, 15 CL II/III patients (6th edition T1a) were reclassified as T1b based on the presence of mitoses while 16 CL IV patients (6th edition T1b) were categorized as T1a based on the absence of mitoses.	('T1a', 'Gene', '10630', (173, 176))	('CL II/III', 'Disease', (16, 25))	('T1a', 'Gene', (173, 176))	('mitoses', 'Var', (103, 110))	('T1a', 'Gene', '10630', (48, 51))	('T1a', 'Gene', (48, 51))
3211	24369020	Overall, the incidence of SLN metastasis for thin melanomas is typically low; however, there is a subset of thin melanomas that demonstrates at least a 5% risk for microscopic nodal disease.	('thin melanomas', 'Var', (108, 122))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('SLN metastasis', 'Disease', (26, 40))	('microscopic nodal disease', 'Disease', (164, 189))	('SLN metastasis', 'Disease', 'MESH:D009362', (26, 40))
3224	24369020	Mitotic rate is determined by the number of mitoses per millimeter squared (mm2) in the invasive melanoma component and all sections on the slides should be examined to evaluate for mitoses or "hot spot."	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('mitoses', 'Var', (182, 189))	('invasive melanoma component', 'Disease', 'MESH:D008545', (88, 115))	('invasive melanoma component', 'Disease', (88, 115))
3225	24369020	Another study reported a progressive increase in rates of positive SLNB for invasive melanomas depending on BT: 0.51 to 0.75 mm (3.8%), 0.76 to 0.90 mm (5.3%), and 0.91 to 1.00 mm (10.3%).	('invasive melanomas', 'Disease', 'MESH:D008545', (76, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('0.51', 'Var', (112, 116))	('invasive melanomas', 'Disease', (76, 94))	('0.76', 'Var', (136, 140))
3240	30800067	A direct relationship between COX-2 expression and cancer incidence has already been shown in various tumor types, as well as increased tumorigenesis after genetic manipulation of COX-2.	('COX-2', 'Gene', (180, 185))	('genetic manipulation', 'Var', (156, 176))	('COX-2', 'Gene', '19225', (180, 185))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Disease', (51, 57))	('COX-2', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('COX-2', 'Gene', '19225', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('increased', 'PosReg', (126, 135))	('tumor', 'Disease', (136, 141))
3253	30800067	Following the manifacturer's instructions, a "PBS buffer 10x" was prepared (NaH2PO4.H2O 1.28 g, Na2HPO4.12H2O 5.97 g, NaCl 43.88 g in 500 mL H2O) and stocked at 4 C. Immediately before the experiments, the "PBS buffer 10x" was diluted in distilled water (1:10), to obtain the assay buffer (AB); pH was adjusted to 7.4.	('PBS', 'Chemical', 'MESH:D007854', (207, 210))	('NaH2PO4', 'Chemical', 'MESH:C018279', (76, 83))	('to 7', 'Species', '1214577', (311, 315))	('H2O', 'Chemical', 'MESH:D014867', (106, 109))	('NaH2PO4.H2O', 'Var', (76, 87))	('12H2O', 'Chemical', '-', (104, 109))	('H2O', 'Chemical', 'MESH:D014867', (141, 144))	('water', 'Chemical', 'MESH:D014867', (248, 253))	('Na2HPO4', 'Chemical', 'MESH:C018279', (96, 103))	('PBS', 'Chemical', 'MESH:D007854', (46, 49))	('NaCl', 'Chemical', 'MESH:D012965', (118, 122))	('H2O', 'Chemical', 'MESH:D014867', (84, 87))	('Na2HPO4.12H2O', 'Var', (96, 109))
3311	30800067	60-61 C ESI-MS: 183.1[M + H]+1H-NMR (DMSO-d6): delta d 10.42 (bs, 1H, OH), 7.76 (d, J = 5.0 Hz, 2H), 6.84 (d, J = 5.0 Hz, 2H), 2.96 (q, J = 4.5 Hz, 2H, CH2), 1.23 (t, J = 4.5 Hz, 3H, CH3) 13C-NMR (DMSO-d6): delta 189.68, 163.03, 129.68, 128.27, 115.97, 22.98, 15.38.	('CH3', 'CellLine', 'CVCL:Z390', (183, 186))	('129.68', 'Var', (229, 235))	('delta 189.68', 'Var', (207, 219))	('1H', 'Chemical', '-', (66, 68))	('128.27', 'Var', (237, 243))	('DMSO-d6', 'Chemical', '-', (197, 204))	('DMSO-d6', 'Chemical', '-', (37, 44))	('1H', 'Chemical', '-', (29, 31))	('CH2', 'CellLine', 'CVCL:Z390', (152, 155))	('13C', 'Chemical', '-', (188, 191))
3327	30800067	In particular, cell proliferation 72 h following incubation with naproxen-HBTA (10-30-100 muM) was reduced by 14, 20, and 43%, respectively (P < 0.001) for A375 and by 11.5, 18, and 54%, respectively (P < 0.001) for B16F10 (Table 1).	('B16F10', 'CellLine', 'CVCL:0159', (216, 222))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('A375', 'Var', (156, 160))	('A375', 'CellLine', 'CVCL:0132', (156, 160))	('cell proliferation', 'CPA', (15, 33))	('reduced', 'NegReg', (99, 106))	('naproxen-HBTA', 'Chemical', '-', (65, 78))
3355	30800067	Over 50% of melanomas carrying activating V600E mutations in BRAF (BRAFV600E), an oncogene known to be critical for melanoma proliferation and survival.	('BRAF', 'Gene', '109880', (67, 71))	('V600E', 'Var', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('BRAF', 'Gene', '109880', (61, 65))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('BRAF', 'Gene', (67, 71))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (61, 65))	('activating', 'PosReg', (31, 41))	('BRAFV600E', 'Gene', '109880', (67, 76))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('melanoma proliferation', 'Disease', (116, 138))	('melanoma proliferation', 'Disease', 'MESH:D008545', (116, 138))	('melanomas', 'Disease', (12, 21))	('BRAFV600E', 'Gene', (67, 76))
3388	30800067	We found that CXCL1 plasma levels of tumor-bearing mice treated with naproxen-HBTA were significantly lower as compared to control mice suggesting a potential effect of this new molecule on the production of chemokines involved in the metastasis spreading of malignant melanoma.	('lower', 'NegReg', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mice', 'Species', '10090', (51, 55))	('CXCL1', 'Gene', '14825', (14, 19))	('naproxen-HBTA', 'Var', (69, 82))	('malignant melanoma', 'Phenotype', 'HP:0002861', (259, 277))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('CXCL1', 'Gene', (14, 19))	('naproxen-HBTA', 'Chemical', '-', (69, 82))	('mice', 'Species', '10090', (131, 135))	('malignant melanoma', 'Disease', 'MESH:D008545', (259, 277))	('malignant melanoma', 'Disease', (259, 277))
3400	24831578	Aberrant activation of Wnt/beta-catenin pathway is implicated in various cancers including melanoma.	('cancers', 'Disease', (73, 80))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (27, 39))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('beta-catenin', 'Gene', (27, 39))	('implicated', 'Reg', (51, 61))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
3402	24831578	Similar to breast cancer, beta-catenin-activating mutations are rare in melanomas, and since beta-catenin signaling is implicated in melanoma, we examined the relationship between beta-catenin levels/activity and expression of beta-catenin transcriptional targets Rad6 and microphthalmia-associated transcription factor-M (Mitf-M) in melanoma cell models, and expression of Rad6, beta-catenin, and Melan-A in nevi and cutaneous melanoma tissue specimens.	('transcription factor', 'molecular_function', 'GO:0000981', ('299', '319'))	('Rad', 'biological_process', 'GO:1990116', ('264', '267'))	('Rad6', 'Gene', '852822', (264, 268))	('beta-catenin', 'Gene', (26, 38))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('beta-catenin', 'Gene', '1499', (26, 38))	('melanoma', 'Disease', (72, 80))	('Rad6', 'Gene', '852822', (374, 378))	('Rad6', 'Gene', (264, 268))	('microphthalmia-associated transcription factor', 'Gene', '4286', (273, 319))	('melanoma', 'Phenotype', 'HP:0002861', (428, 436))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', (428, 436))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('beta-catenin', 'Gene', (380, 392))	('nevi', 'Phenotype', 'HP:0003764', (409, 413))	('cutaneous melanoma', 'Disease', (418, 436))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (418, 436))	('Rad6', 'Gene', (374, 378))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('melanoma', 'Disease', 'MESH:D008545', (334, 342))	('beta-catenin', 'Gene', (93, 105))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (418, 436))	('beta-catenin', 'Gene', '1499', (380, 392))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('microphthalmia', 'Phenotype', 'HP:0000568', (273, 287))	('beta-catenin', 'Gene', (180, 192))	('beta-catenin', 'Gene', '1499', (93, 105))	('melanomas', 'Disease', (72, 81))	('beta-catenin', 'Gene', '1499', (180, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))	('Melan-A', 'Gene', '2315', (398, 405))	('Rad', 'biological_process', 'GO:1990116', ('374', '377'))	('microphthalmia-associated transcription factor', 'Gene', (273, 319))	('transcription', 'biological_process', 'GO:0006351', ('299', '312'))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('beta-catenin', 'Gene', (227, 239))	('mutations', 'Var', (50, 59))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('beta-catenin', 'Gene', '1499', (227, 239))	('melanoma', 'Disease', 'MESH:D008545', (428, 436))	('breast cancer', 'Disease', (11, 24))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('Melan-A', 'Gene', (398, 405))	('Mitf-M', 'Gene', (323, 329))	('melanoma', 'Phenotype', 'HP:0002861', (334, 342))	('melanoma', 'Disease', (334, 342))
3405	24831578	Double-immunofluorescence staining of Rad6 and Melan-A in melanoma tissue microarray showed that histological diagnosis of melanoma is significantly associated with Rad6/Melan-A dual positivity in the melanoma group compared to the nevi group (P = .0029).	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('Rad', 'biological_process', 'GO:1990116', ('38', '41'))	('Melan-A', 'Gene', '2315', (47, 54))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('associated', 'Reg', (149, 159))	('Melan-A', 'Gene', (47, 54))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Rad6', 'Gene', '852822', (165, 169))	('Rad6', 'Gene', '852822', (38, 42))	('Melan-A', 'Gene', '2315', (170, 177))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('dual positivity', 'Var', (178, 193))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma', 'Disease', (201, 209))	('Rad6', 'Gene', (165, 169))	('Rad6', 'Gene', (38, 42))	('Melan-A', 'Gene', (170, 177))	('nevi', 'Phenotype', 'HP:0003764', (232, 236))	('Rad', 'biological_process', 'GO:1990116', ('165', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
3416	24831578	However, overexpression of certain Wnt ligands, loss of Wnt inhibitory factors, or mutations in key components of the multiprotein beta-catenin degradation complex contribute to accumulation of beta-catenin and activation of the canonical Wnt signaling pathway.	('mutations', 'Var', (83, 92))	('overexpression', 'PosReg', (9, 23))	('beta-catenin', 'Gene', (131, 143))	('activation', 'PosReg', (211, 221))	('beta-catenin', 'Gene', (194, 206))	('canonical Wnt signaling pathway', 'biological_process', 'GO:0060070', ('229', '260'))	('beta-catenin degradation complex', 'cellular_component', 'GO:0030877', ('131', '163'))	('canonical Wnt signaling pathway', 'Pathway', (229, 260))	('beta-catenin', 'Gene', '1499', (131, 143))	('degradation', 'biological_process', 'GO:0009056', ('144', '155'))	('beta-catenin', 'Gene', '1499', (194, 206))	('accumulation', 'PosReg', (178, 190))
3417	24831578	Aberrant accumulation of beta-catenin in the cytoplasm/nucleus is correlated with poor prognosis for several cancer types.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('beta-catenin', 'Gene', '1499', (25, 37))	('cancer', 'Disease', (109, 115))	('cytoplasm', 'cellular_component', 'GO:0005737', ('45', '54'))	('accumulation', 'PosReg', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('beta-catenin', 'Gene', (25, 37))	('nucleus', 'cellular_component', 'GO:0005634', ('55', '62'))
3420	24831578	Mitf, a basic/helix-loop-helix/leucine-zipper transcription factor was first identified in mouse, mutation of which results in loss of pigmentation.	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('mutation', 'Var', (98, 106))	('mouse', 'Species', '10090', (91, 96))	('loss of pigmentation', 'Disease', 'MESH:D010859', (127, 147))	('pigmentation', 'biological_process', 'GO:0043473', ('135', '147'))	('transcription factor', 'molecular_function', 'GO:0000981', ('46', '66'))	('loss of pigmentation', 'Disease', (127, 147))
3426	24831578	As in breast cancer, beta-catenin activating mutations are rare in melanomas, and since beta-catenin signaling is implicated in melanoma development and progression, we examined the relationship between Rad6, Mitf, and beta-catenin levels/activity in melanoma cell models, and expression of Rad6 in nevi and cutaneous melanomas.	('Rad6', 'Gene', (203, 207))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('beta-catenin', 'Gene', (88, 100))	('Rad', 'biological_process', 'GO:1990116', ('203', '206'))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('implicated', 'Reg', (114, 124))	('melanomas', 'Disease', (67, 76))	('beta-catenin', 'Gene', '1499', (88, 100))	('nevi', 'Phenotype', 'HP:0003764', (299, 303))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('melanomas', 'Disease', 'MESH:D008545', (318, 327))	('breast cancer', 'Disease', (6, 19))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('Rad', 'biological_process', 'GO:1990116', ('291', '294'))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('beta-catenin', 'Gene', (21, 33))	('melanoma', 'Disease', (251, 259))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (308, 327))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (308, 327))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (308, 326))	('melanomas', 'Disease', (318, 327))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('beta-catenin', 'Gene', '1499', (21, 33))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('melanoma development', 'Disease', (128, 148))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('beta-catenin', 'Gene', (219, 231))	('cutaneous melanomas', 'Disease', (308, 327))	('mutations', 'Var', (45, 54))	('Rad6', 'Gene', '852822', (291, 295))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('melanoma development', 'Disease', 'MESH:D008545', (128, 148))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('beta-catenin', 'Gene', '1499', (219, 231))	('Rad6', 'Gene', '852822', (203, 207))	('melanomas', 'Phenotype', 'HP:0002861', (318, 327))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('Rad6', 'Gene', (291, 295))	('melanoma', 'Disease', (128, 136))
3458	24831578	We have previously reported that Rad6 overexpression induces polyubiquitin modifications of beta-catenin that render it insensitive to 26S proteasomal degradation and confer increased transcriptional activity .	('polyubiquitin', 'biological_process', 'GO:0000209', ('61', '74'))	('degradation', 'biological_process', 'GO:0009056', ('151', '162'))	('Rad', 'biological_process', 'GO:1990116', ('33', '36'))	('induces', 'Reg', (53, 60))	('increased', 'PosReg', (174, 183))	('insensitive to 26S proteasomal degradation', 'MPA', (120, 162))	('polyubiquitin', 'molecular_function', 'GO:0005552', ('61', '74'))	('transcriptional activity', 'MPA', (184, 208))	('beta-catenin', 'Gene', (92, 104))	('Rad6', 'Gene', '852822', (33, 37))	('Rad6', 'Gene', (33, 37))	('beta-catenin', 'Gene', '1499', (92, 104))	('polyubiquitin modifications', 'MPA', (61, 88))	('overexpression', 'Var', (38, 52))
3464	24831578	We next performed TOP/FOP Flash reporter assays to determine whether the increased levels of high molecular weight or modified forms of beta-catenin protein in melanoma cell lines translate into higher beta-catenin transcriptional activity.	('beta-catenin', 'Gene', (202, 214))	('beta-catenin', 'Gene', '1499', (136, 148))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('FOP', 'Gene', (22, 25))	('beta-catenin', 'Gene', '1499', (202, 214))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('higher', 'PosReg', (195, 201))	('FOP', 'Gene', '11116', (22, 25))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('modified', 'Var', (118, 126))	('beta-catenin', 'Gene', (136, 148))
3466	24831578	These data suggest that melanoma lines expressing high molecular weight beta-catenin have transcriptionally active beta-catenin.	('beta-catenin', 'Gene', (72, 84))	('beta-catenin', 'Gene', (115, 127))	('beta-catenin', 'Gene', '1499', (72, 84))	('melanoma lines', 'Disease', 'MESH:D008545', (24, 38))	('beta-catenin', 'Gene', '1499', (115, 127))	('transcriptionally active', 'MPA', (90, 114))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('high molecular weight', 'Var', (50, 71))	('melanoma lines', 'Disease', (24, 38))
3501	24831578	Similar analysis of Rad6 and beta-catenin showed an inverse relationship between Rad6 and beta-catenin in the normal areas of SSMM samples with strong beta-catenin staining and negligible Rad6 (Figure 5B, panels a-a"), whereas both Rad6 and beta-catenin staining were detected in the adjacent tumor areas (Figure 5B, panels b-b").	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('beta-catenin', 'Gene', (241, 253))	('Rad6', 'Gene', (20, 24))	('beta-catenin', 'Gene', (90, 102))	('beta-catenin', 'Gene', '1499', (241, 253))	('beta-catenin', 'Gene', '1499', (90, 102))	('beta-catenin', 'Gene', (151, 163))	('Rad6', 'Gene', '852822', (232, 236))	('Rad6', 'Gene', '852822', (81, 85))	('beta-catenin', 'Gene', '1499', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('Rad6', 'Gene', (232, 236))	('Rad6', 'Gene', (81, 85))	('Rad6', 'Gene', '852822', (188, 192))	('negligible', 'Var', (177, 187))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (29, 41))	('Rad6', 'Gene', (188, 192))	('Rad6', 'Gene', '852822', (20, 24))	('tumor', 'Disease', (293, 298))
3527	24831578	The postreplication repair pathway enables completion of DNA replication blocked by damaging DNA lesions via error-free and error-prone bypass mechanisms, and the ubiquitin conjugating activity of Rad6 is critical to this process.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('163', '172'))	('Rad', 'biological_process', 'GO:1990116', ('197', '200'))	('DNA replication', 'biological_process', 'GO:0006260', ('57', '72'))	('damaging', 'Var', (84, 92))	('error-free', 'Disease', 'MESH:D000072662', (109, 119))	('error-free', 'Disease', (109, 119))	('postreplication repair', 'biological_process', 'GO:0006301', ('4', '26'))	('DNA', 'Gene', (93, 96))	('Rad6', 'Gene', (197, 201))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('Rad6', 'Gene', '852822', (197, 201))
3647	28928360	Tumor-associated B-cells induce tumor heterogeneity and therapy resistance In melanoma, therapies with inhibitors to oncogenic BRAFV600E are highly effective but responses are often short-lived due to the emergence of drug-resistant tumor subpopulations.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRAFV600E', 'Mutation', 'rs113488022', (127, 136))	('tumor', 'Disease', (233, 238))	('BRAFV600E', 'Gene', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('inhibitors', 'Var', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))
3664	28928360	The frequency of TAB cells can be associated with improved prognosis in primary melanoma, but has also been associated with increased metastasis and shorter overall survival (OS).	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('increased', 'PosReg', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('overall survival', 'MPA', (157, 173))	('improved', 'PosReg', (50, 58))	('metastasis', 'CPA', (134, 144))	('shorter', 'NegReg', (149, 156))	('frequency', 'Var', (4, 13))
3665	28928360	In murine melanoma models, the presence/level/activity of TAB cells correlates with increased angiogenesis and inflammation, which is associated with STAT3 signaling in tumors and inflammatory cytokine production.	('angiogenesis', 'CPA', (94, 106))	('angiogenesis', 'biological_process', 'GO:0001525', ('94', '106'))	('inflammation', 'biological_process', 'GO:0006954', ('111', '123'))	('cytokine production', 'biological_process', 'GO:0001816', ('193', '212'))	('inflammation', 'Disease', 'MESH:D007249', (111, 123))	('inflammation', 'Disease', (111, 123))	('presence/level/activity', 'Var', (31, 54))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TAB', 'Gene', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('increased', 'PosReg', (84, 93))	('murine', 'Species', '10090', (3, 9))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('tumors', 'Disease', (169, 175))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
3703	28928360	Consistently, neutralization of IGF-1 in TAB-tumor cell co-cultures led to inhibition of FGFR-3 induction (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('IGF-1', 'Gene', '3479', (32, 37))	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('IGF-1', 'Gene', (32, 37))	('TAB-tumor', 'Disease', 'MESH:D009369', (41, 50))	('inhibition', 'NegReg', (75, 85))	('induction', 'MPA', (96, 105))	('TAB-tumor', 'Disease', (41, 50))	('FGFR-3', 'Gene', (89, 95))	('neutralization', 'Var', (14, 28))
3706	28928360	Also, neutralization of FGF-2 in co-cultures showed inhibition of IGF-1 induction (Fig.	('IGF-1', 'Gene', '3479', (66, 71))	('FGF-2', 'Gene', (24, 29))	('FGF-2', 'Gene', '2247', (24, 29))	('induction', 'MPA', (72, 81))	('neutralization', 'Var', (6, 20))	('IGF-1', 'Gene', (66, 71))	('inhibition', 'NegReg', (52, 62))
3726	28928360	Consistently, neutralization of IGF-1 in TAB and tumor cells co-culture rescued the sensitivity of melanoma cells to BRAFi and MEKi (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('IGF-1', 'Gene', '3479', (32, 37))	('IGF-1', 'Gene', (32, 37))	('MEK', 'Gene', (127, 130))	('MEK', 'Gene', '5609', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('rescued', 'PosReg', (72, 79))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('sensitivity', 'MPA', (84, 95))	('neutralization', 'Var', (14, 28))
3727	28928360	We then asked whether tumor cells treated with the BRAFi PLX4720 can induce IGF-1 in B cells as did untreated melanoma cells (Fig.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('induce', 'Reg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('BRAFi PLX4720', 'Var', (51, 64))	('IGF-1', 'Gene', '3479', (76, 81))	('IGF-1', 'Gene', (76, 81))
3746	28928360	Expression array data showed a subgroup of tumor samples clustered by high CD20/CD19 expression enriched for post-treatment samples resistant to various therapies (Supplementary Fig.	('CD19', 'Gene', (80, 84))	('CD20', 'Gene', (75, 79))	('CD20', 'Gene', '931', (75, 79))	('CD19', 'Gene', '930', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('high', 'Var', (70, 74))	('tumor', 'Disease', (43, 48))
3770	28928360	2a, b) confirm the co-expression of IGF-1 with B-cell genes in melanoma biopsies and higher IGF-1 level to be associated with an enhanced frequency of TAB cells (Fig.	('co-expression', 'Var', (19, 32))	('enhanced', 'PosReg', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('IGF-1', 'Gene', '3479', (92, 97))	('IGF-1', 'Gene', (92, 97))	('IGF-1', 'Gene', '3479', (36, 41))	('IGF-1', 'Gene', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('TAB', 'Disease', (151, 154))
3788	28928360	The effect of TAB cells on melanoma heterogeneity and therapy resistance could be reversed by IGF-1 neutralization or FGFR-3 knockdown.	('IGF-1', 'Gene', '3479', (94, 99))	('IGF-1', 'Gene', (94, 99))	('knockdown', 'Var', (125, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGFR-3', 'Gene', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('neutralization', 'Var', (100, 114))
3789	28928360	Activation of FGFR-3 has been shown to reactivate Ras/MAPK signaling conferring resistance to BRAFi and combinations of pan-FGFR/-BRAF inhibitors have shown therapeutic benefits in mouse model.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('resistance to BRAFi', 'MPA', (80, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('FGFR-3', 'Gene', (14, 20))	('MAPK signaling', 'biological_process', 'GO:0000165', ('54', '68'))	('reactivate Ras/MAPK signaling', 'MPA', (39, 68))	('combinations', 'Var', (104, 116))	('Activation', 'Var', (0, 10))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('mouse', 'Species', '10090', (181, 186))
3809	28928360	All cell lines were tested for mycoplasma and short tandem repeat profile (DNA identity) before being used for any experiments.	('short tandem repeat profile', 'Var', (46, 73))	('mycoplasma', 'Disease', (31, 41))	('mycoplasma', 'Disease', 'MESH:D009175', (31, 41))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('tested', 'Reg', (20, 26))
3831	28928360	Illumina or Affymetrix chip data (GSE50509 and GSE8401) were normalized, background-corrected, and summarized using the R package "lumi" or "affy".	('GSE8401', 'Var', (47, 54))	('GSE50509', 'Var', (34, 42))	('GSE8401', 'Chemical', '-', (47, 54))
3853	28928360	Lentiviral particles from 5 individual clones from shRNA Target Sets NM_000142 targeting FGFR-3 and NM_021950 targeting MS4A1 (CD20) were used to infect melanoma cell lines.	('FGFR', 'molecular_function', 'GO:0005007', ('89', '93'))	('CD20', 'Gene', (127, 131))	('CD20', 'Gene', '931', (127, 131))	('MS4A1', 'Gene', '931', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('MS4A1', 'Gene', (120, 125))	('infect melanoma', 'Disease', (146, 161))	('NM_021950', 'Var', (100, 109))	('infect melanoma', 'Disease', 'MESH:D008545', (146, 161))	('NM_000142', 'Var', (69, 78))	('FGFR-3', 'Gene', (89, 95))
3867	28928360	Illumina or Affymetrix chip data are available under accession number GSE50509 and GSE8401.	('GSE8401', 'Chemical', '-', (83, 90))	('GSE50509', 'Var', (70, 78))	('GSE8401', 'Var', (83, 90))
3878	30103475	Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored.	('CRC-SC-associated', 'Disease', (146, 163))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('dysregulated', 'Var', (49, 61))	('malignancies', 'Disease', (75, 87))
3882	30103475	We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins.	('SOD', 'Gene', (107, 110))	('hsa-miR-324-5p', 'Var', (52, 66))	('c-Myc', 'Gene', (202, 207))	('BAX', 'Gene', (271, 274))	('BAX', 'Gene', '581', (271, 274))	('up-regulation', 'PosReg', (239, 252))	('SOD', 'Gene', '6647;6648;6649', (174, 177))	('SOD2', 'molecular_function', 'GO:0004784', ('174', '178'))	('c-Myc', 'Gene', '4609', (202, 207))	('expression', 'MPA', (112, 122))	('vimentin', 'cellular_component', 'GO:0045098', ('192', '200'))	('BcL-xL2', 'Protein', (213, 220))	('cadherin', 'molecular_function', 'GO:0008014', ('258', '266'))	('SOD', 'Gene', (174, 177))	('down-regulation', 'NegReg', (155, 170))	('E-cadherin', 'Gene', (256, 266))	('E-cadherin', 'Gene', '999', (256, 266))	('SOD2', 'molecular_function', 'GO:0004784', ('107', '111'))	('SOD', 'Gene', '6647;6648;6649', (107, 110))	('down-regulation of SOD2', 'biological_process', 'GO:1901670', ('155', '178'))	('4-AAQB', 'Chemical', 'MESH:C555021', (20, 26))	('vimentin', 'cellular_component', 'GO:0045099', ('192', '200'))	('N-cadherin', 'Gene', (180, 190))	('regulation', 'biological_process', 'GO:0065007', ('242', '252'))	('vimentin', 'Protein', (192, 200))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('N-cadherin', 'Gene', '1000', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('reduced', 'NegReg', (99, 106))
3883	30103475	Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('hsa-miR-324-5p', 'Var', (23, 37))	('expression', 'MPA', (9, 19))	('suppressed', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Enhanced', 'PosReg', (0, 8))
3885	30103475	Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.	('CRC', 'Disease', (107, 110))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('4-AAQB', 'Var', (73, 79))	('anti-CSC', 'MPA', (52, 60))	('patients', 'Species', '9606', (171, 179))	('FOLFOX', 'Chemical', '-', (97, 103))	('CRC', 'Disease', (167, 170))	('4-AAQB', 'Chemical', 'MESH:C555021', (73, 79))
3890	30103475	In an earlier work by our team, we demonstrated that 4-acetylantroquinonol B (4-AAQB), a mycelial isolate of Antrodia camphorata, a common Taiwanese camphor tree mushroom with a broad range of documented bioactivities, effectively disrupts essential oncogenic signaling pathways such as the Lgr5/Wnt/beta-catenin, JAK-STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, inhibits the acquisition of the CRC-stem cell (SC) phenotype, down-regulates the expression and/or activities of stemness-associated genes including ALDH1, attenuates tumor aggression, and accentuates chemosensitivity in CRC cells.	('Antrodia camphorata', 'Species', '196114', (109, 128))	('chemosensitivity in CRC cells', 'CPA', (592, 621))	('oncogenic signaling pathways', 'Pathway', (250, 278))	('4-acetylantroquinonol B', 'Chemical', 'MESH:C555021', (53, 76))	('camphor tree', 'Species', '13429', (149, 161))	('mushroom', 'Species', '5341', (162, 170))	('acquisition', 'CPA', (404, 415))	('aggression', 'Phenotype', 'HP:0000718', (564, 574))	('expression', 'MPA', (472, 482))	('activities', 'MPA', (490, 500))	('ALDH', 'molecular_function', 'GO:0004030', ('540', '544'))	('accentuates', 'PosReg', (580, 591))	('ALDH1', 'Gene', (540, 545))	('4-acetylantroquinonol', 'Var', (53, 74))	('signaling', 'biological_process', 'GO:0023052', ('371', '380'))	('attenuates tumor aggression', 'Disease', 'MESH:C538265', (547, 574))	('transmembrane', 'cellular_component', 'GO:0016021', ('332', '345'))	('4-AAQB', 'Chemical', 'MESH:C555021', (78, 84))	('attenuates tumor aggression', 'Disease', (547, 574))	('inhibits', 'NegReg', (391, 399))	('JAK', 'molecular_function', 'GO:0004713', ('314', '317'))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('tumor', 'Phenotype', 'HP:0002664', (558, 563))	('down-regulates', 'NegReg', (453, 467))	('Lgr5/Wnt/beta-catenin', 'Pathway', (291, 312))	('aggression', 'biological_process', 'GO:0002118', ('564', '574'))	('disrupts', 'NegReg', (231, 239))	('transmembrane', 'cellular_component', 'GO:0044214', ('332', '345'))
3897	30103475	Despite documented association between mutations in the SOD2 gene and several pathologies, including sporadic motor neuron disease, idiopathic dilated cardiomyopathy (IDC), premature aging (progeria), and cancer, the role of SOD2 in cancer cells, such as in CRC cells, is not fully understood.	('sporadic motor neuron disease', 'Disease', (101, 130))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('premature aging', 'Disease', (173, 188))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (143, 165))	('SOD', 'Gene', (225, 228))	('SOD', 'Gene', '6647;6648;6649', (56, 59))	('SOD2', 'molecular_function', 'GO:0004784', ('56', '60'))	('mutations', 'Var', (39, 48))	('aging', 'biological_process', 'GO:0007568', ('183', '188'))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (205, 211))	('SOD', 'Gene', (56, 59))	('idiopathic dilated cardiomyopathy', 'Disease', 'MESH:C536277', (132, 165))	('SOD2', 'molecular_function', 'GO:0004784', ('225', '229'))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('association', 'Interaction', (19, 30))	('SOD', 'Gene', '6647;6648;6649', (225, 228))	('cancer', 'Disease', (233, 239))	('idiopathic dilated cardiomyopathy', 'Disease', (132, 165))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (151, 165))
3900	30103475	Deregulation of epigenetic factors and patterns, such as aberrant DNA methylation, histone tail modification, and non-coding RNA (ncRNA) regulation, are implicated in loss of cell identity and contribute to several human pathologies, including cancer.	('DNA', 'Protein', (66, 69))	('contribute', 'Reg', (193, 203))	('epigenetic', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('regulation', 'biological_process', 'GO:0065007', ('137', '147'))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('loss', 'NegReg', (167, 171))	('histone', 'Protein', (83, 90))	('cell identity', 'CPA', (175, 188))	('human', 'Species', '9606', (215, 220))	('cancer', 'Disease', (244, 250))	('aberrant', 'Var', (57, 65))
3901	30103475	There is documented correlation or association between down-regulated miRNA expression, and tumor initiation or metastatic disease progression, however, there is a dearth of information regarding SOD2-regulated miRNA(s) in CRC, and regarding how the epigenetic modulation of SOD2 contributes to the CSC-like and metastatic phenotype of CRC cells.	('SOD', 'Gene', (196, 199))	('SOD', 'Gene', (275, 278))	('CSC-like', 'Disease', (299, 307))	('SOD', 'Gene', '6647;6648;6649', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('epigenetic modulation', 'Var', (250, 271))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('SOD2', 'molecular_function', 'GO:0004784', ('196', '200'))	('down-regulated', 'NegReg', (55, 69))	('CRC', 'Disease', (336, 339))	('SOD', 'Gene', '6647;6648;6649', (196, 199))	('SOD2', 'molecular_function', 'GO:0004784', ('275', '279'))	('contributes', 'Reg', (280, 291))	('tumor initiation', 'Disease', (92, 108))
3904	30103475	Consequently, herein, we provide evidence that hsa-miR-324 interacts with SOD2, and that the aberrant expression of SOD2 enhances the oncogenicity and cancer stem cell-like phenotype of CRC cells and the therapeutic effect of 4-AAQB in these cells is mediated by inducing re-expression of SOD2-suppressed hsa-miR-324.	('4-AAQB', 'Chemical', 'MESH:C555021', (226, 232))	('SOD', 'Gene', (289, 292))	('SOD', 'Gene', (74, 77))	('enhances', 'PosReg', (121, 129))	('SOD2', 'molecular_function', 'GO:0004784', ('116', '120'))	('hsa-miR-324', 'Gene', '442898', (47, 58))	('cancer', 'Disease', (151, 157))	('oncogenicity', 'CPA', (134, 146))	('hsa-miR-324', 'Gene', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('hsa-miR-324', 'Gene', '442898', (305, 316))	('SOD', 'Gene', '6647;6648;6649', (116, 119))	('SOD2', 'molecular_function', 'GO:0004784', ('289', '293'))	('aberrant expression', 'Var', (93, 112))	('SOD2', 'molecular_function', 'GO:0004784', ('74', '78'))	('hsa-miR-324', 'Gene', (305, 316))	('SOD', 'Gene', '6647;6648;6649', (289, 292))	('SOD', 'Gene', '6647;6648;6649', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('SOD', 'Gene', (116, 119))
3926	30103475	Taken together, those findings do indicate that aberrant expression of SOD2 correlates with disease progression, and the SOD2-induced down-regulation of hsa-miR-324 facilitates poor prognosis, while suggesting the molecular targetability of SOD2 and potential therapeutic utility of hsa-miR-324-5p in advanced stage and metastatic CRC patients.	('SOD', 'Gene', (241, 244))	('facilitates', 'PosReg', (165, 176))	('SOD', 'Gene', '6647;6648;6649', (71, 74))	('down-regulation', 'NegReg', (134, 149))	('poor prognosis', 'CPA', (177, 191))	('expression', 'MPA', (57, 67))	('SOD', 'Gene', (121, 124))	('metastatic CRC', 'Disease', (320, 334))	('hsa-miR-324', 'Gene', '442898', (283, 294))	('aberrant', 'Var', (48, 56))	('hsa-miR-324', 'Gene', (283, 294))	('SOD', 'Gene', (71, 74))	('SOD2', 'molecular_function', 'GO:0004784', ('121', '125'))	('SOD2', 'molecular_function', 'GO:0004784', ('241', '245'))	('SOD', 'Gene', '6647;6648;6649', (241, 244))	('hsa-miR-324', 'Gene', '442898', (153, 164))	('SOD2', 'molecular_function', 'GO:0004784', ('71', '75'))	('hsa-miR-324', 'Gene', (153, 164))	('regulation', 'biological_process', 'GO:0065007', ('139', '149'))	('patients', 'Species', '9606', (335, 343))	('SOD', 'Gene', '6647;6648;6649', (121, 124))
3929	30103475	More importantly, considering the clinical relevance of CSC targeting in effective anticancer therapies, we demonstrated that exposure to 2.5 muM, 5 muM, 7.5 muM, or 10 muM 4-AAQB reduced the proportion of DLD-1 SP cells by 4.2% (p < 0.01), 7.4% (p < 0.001), 8.4% (p < 0.001), or 8.9% (p < 0.001), compared to 6.4% by 100 muM verapamil, which specifically inhibits the Hoechst dye-extruding potential of the ATP-binding cassette (ABC) membrane transporter.	('muM', 'Gene', (322, 325))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', (169, 172))	('inhibits', 'NegReg', (356, 364))	('muM', 'Gene', '56925', (158, 161))	('cancer', 'Disease', (87, 93))	('membrane', 'cellular_component', 'GO:0016020', ('435', '443'))	('muM', 'Gene', (158, 161))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', '56925', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('muM', 'Gene', (149, 152))	('4-AAQB', 'Chemical', 'MESH:C555021', (173, 179))	('muM', 'Gene', (142, 145))	('SP', 'Chemical', '-', (212, 214))	('4-AAQB', 'Var', (173, 179))	('reduced', 'NegReg', (180, 187))	('ATP-binding', 'molecular_function', 'GO:0005524', ('408', '419'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('muM', 'Gene', '56925', (322, 325))	('verapamil', 'Chemical', 'MESH:D014700', (326, 335))
3930	30103475	For the HCT116 SP cells treated with 2.5 muM, 5 muM, 7.5 muM, or 10 muM 4-AAQB, we observed 3.1% (p < 0.001), 3.6% (p < 0.001), 4.1% (p < 0.001), or 4.4% (p < 0.001) reduction, respectively, in comparison with 1.8% by 100 muM verapamil (Figure 4C).	('muM', 'Gene', (222, 225))	('4-AAQB', 'Var', (72, 78))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (57, 60))	('muM', 'Gene', (41, 44))	('muM', 'Gene', (68, 71))	('muM', 'Gene', '56925', (48, 51))	('4-AAQB', 'Chemical', 'MESH:C555021', (72, 78))	('muM', 'Gene', (48, 51))	('muM', 'Gene', '56925', (222, 225))	('SP', 'Chemical', '-', (15, 17))	('HCT116', 'CellLine', 'CVCL:0291', (8, 14))	('muM', 'Gene', '56925', (68, 71))	('muM', 'Gene', '56925', (57, 60))	('verapamil', 'Chemical', 'MESH:D014700', (226, 235))
3931	30103475	Additionally, we observed a marked reduction in the SP cell number (Figure 4D), as well as significant cell death and dysmorphism in cultured DLD-1 or HCT116 SP cells exposed to 10 muM 4-AAQB compared to the untreated control group; interestingly, 4-AAQB exhibited no significant inhibitory effect on the viability and/or proliferation of the non-tumor colon cell line, CRL-1831 (Figure 4E).	('tumor colon', 'Disease', 'MESH:D015179', (347, 358))	('dysmorphism', 'Disease', 'None', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('CRL', 'Gene', (370, 373))	('4-AAQB', 'Chemical', 'MESH:C555021', (185, 191))	('SP cell number', 'CPA', (52, 66))	('4-AAQB', 'Chemical', 'MESH:C555021', (248, 254))	('cell death', 'biological_process', 'GO:0008219', ('103', '113'))	('tumor colon', 'Phenotype', 'HP:0100273', (347, 358))	('proliferation', 'CPA', (322, 335))	('SP', 'Chemical', '-', (158, 160))	('reduction', 'NegReg', (35, 44))	('tumor colon', 'Disease', (347, 358))	('4-AAQB', 'Var', (248, 254))	('HCT116', 'CellLine', 'CVCL:0291', (151, 157))	('CRL', 'Gene', '133396', (370, 373))	('SP', 'Chemical', '-', (52, 54))	('muM', 'Gene', '56925', (181, 184))	('muM', 'Gene', (181, 184))	('dysmorphism', 'Disease', (118, 129))
3932	30103475	This data indicates that 4-AAQB inhibits the viability and/or proliferation of human colorectal carcinoma wide-type and side-population cells, as well as corroborating the findings of our previously published work.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (85, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('human', 'Species', '9606', (79, 84))	('4-AAQB', 'Chemical', 'MESH:C555021', (25, 31))	('proliferation', 'CPA', (62, 75))	('viability', 'CPA', (45, 54))	('colorectal carcinoma', 'Disease', (85, 105))	('inhibits', 'NegReg', (32, 40))	('4-AAQB', 'Var', (25, 31))
3933	30103475	Investigating the molecular mechanism underlying the observed inhibitory effect of 4-AAQB in the SOD2-rich CRC SP cells, which serve as in vitro CRC-SC models, the results of our Western blot analyses demonstrate that exposure to 5-10 muM 4-AAQB significantly down-regulates the expression level of SOD2, N-cadherin, vimentin, c-Myc, and Bcl-xL proteins, while up-regulating the expression of E-cadherin and Bax in the DLD-1 or HCT116 SP cells (Figure 5A,B).	('muM', 'Gene', (235, 238))	('Bax', 'Gene', '581', (408, 411))	('up-regulating', 'PosReg', (361, 374))	('4-AAQB', 'Chemical', 'MESH:C555021', (83, 89))	('Bcl-xL', 'Gene', '598', (338, 344))	('c-Myc', 'Gene', (327, 332))	('vimentin', 'cellular_component', 'GO:0045099', ('317', '325'))	('N-cadherin', 'Gene', (305, 315))	('down-regulates', 'NegReg', (260, 274))	('c-Myc', 'Gene', '4609', (327, 332))	('E-cadherin', 'Gene', (393, 403))	('E-cadherin', 'Gene', '999', (393, 403))	('SOD', 'Gene', '6647;6648;6649', (97, 100))	('cadherin', 'molecular_function', 'GO:0008014', ('307', '315'))	('SOD2', 'molecular_function', 'GO:0004784', ('299', '303'))	('SOD', 'Gene', (97, 100))	('N-cadherin', 'Gene', '1000', (305, 315))	('vimentin', 'MPA', (317, 325))	('HCT116', 'CellLine', 'CVCL:0291', (428, 434))	('SOD', 'Gene', '6647;6648;6649', (299, 302))	('4-AAQB', 'Chemical', 'MESH:C555021', (239, 245))	('SOD2', 'molecular_function', 'GO:0004784', ('97', '101'))	('SP', 'Chemical', '-', (111, 113))	('4-AAQB', 'Var', (239, 245))	('SP', 'Chemical', '-', (435, 437))	('expression', 'MPA', (379, 389))	('vimentin', 'cellular_component', 'GO:0045098', ('317', '325'))	('SOD', 'Gene', (299, 302))	('Bax', 'Gene', (408, 411))	('muM', 'Gene', '56925', (235, 238))	('Bcl-xL', 'Gene', (338, 344))	('expression level', 'MPA', (279, 295))	('cadherin', 'molecular_function', 'GO:0008014', ('395', '403'))
3937	30103475	Furthermore, using the RT-PCR, we demonstrated that DLD-1 SP cells treated with 10 muM 4-AAQB exhibited significantly suppressed SOD2 mRNA expression, and conversely up-regulated hsa-miR-324-5p expression.	('SP', 'Chemical', '-', (58, 60))	('4-AAQB', 'Var', (87, 93))	('muM', 'Gene', '56925', (83, 86))	('up-regulated', 'PosReg', (166, 178))	('SOD', 'Gene', '6647;6648;6649', (129, 132))	('SOD2', 'molecular_function', 'GO:0004784', ('129', '133'))	('hsa-miR-324-5p expression', 'MPA', (179, 204))	('4-AAQB', 'Chemical', 'MESH:C555021', (87, 93))	('muM', 'Gene', (83, 86))	('SOD', 'Gene', (129, 132))	('suppressed', 'NegReg', (118, 128))
3938	30103475	These data suggest that the anticancer effect of 4-AAQB, akin to SOD2-silencing, is mediated by hsa-miR-324 and it is associated with EMT- and cell-death-related molecular changes in the colorectal cancer SP cells, at both the transcript and protein levels.	('colorectal cancer', 'Disease', (187, 204))	('hsa-miR-324', 'Gene', (96, 107))	('hsa-miR-324', 'Gene', '442898', (96, 107))	('SOD', 'Gene', (65, 68))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (32, 38))	('4-AAQB', 'Chemical', 'MESH:C555021', (49, 55))	('cell-death', 'biological_process', 'GO:0008219', ('143', '153'))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('4-AAQB', 'Var', (49, 55))	('EMT', 'biological_process', 'GO:0001837', ('134', '137'))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('SP', 'Chemical', '-', (205, 207))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('SOD2', 'molecular_function', 'GO:0004784', ('65', '69'))	('SOD', 'Gene', '6647;6648;6649', (65, 68))
3939	30103475	Having established that 4-AAQB effectively elicits the up-regulation of hsa-miR-324 while down-regulating SOD2 expression, we further investigated the effect of 4-AAQB treatment on the motility and oncogenicity of CRC-SCs using the sorted DLD-1 or HCT116 SP cells.	('down-regulating', 'NegReg', (90, 105))	('4-AAQB', 'Chemical', 'MESH:C555021', (24, 30))	('4-AAQB', 'Chemical', 'MESH:C555021', (161, 167))	('hsa-miR-324', 'Gene', '442898', (72, 83))	('SP', 'Chemical', '-', (255, 257))	('up-regulation', 'PosReg', (55, 68))	('hsa-miR-324', 'Gene', (72, 83))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))	('SCs', 'molecular_function', 'GO:0004776', ('218', '221'))	('expression', 'MPA', (111, 121))	('SOD', 'Gene', '6647;6648;6649', (106, 109))	('4-AAQB', 'Var', (24, 30))	('HCT116', 'CellLine', 'CVCL:0291', (248, 254))	('SOD2', 'molecular_function', 'GO:0004784', ('106', '110'))	('investigated', 'Reg', (134, 146))	('SOD', 'Gene', (106, 109))
3940	30103475	We demonstrated that compared to the observed migration by the untreated cells, exposure to 5-10 muM 4-AAQB significantly attenuates the ability of the SP cells to migrate in a dose-dependent manner over a 24 h time-course (Figure 6A).	('muM', 'Gene', '56925', (97, 100))	('4-AAQB', 'Var', (101, 107))	('SP', 'Chemical', '-', (152, 154))	('4-AAQB', 'Chemical', 'MESH:C555021', (101, 107))	('muM', 'Gene', (97, 100))	('attenuates', 'NegReg', (122, 132))
3941	30103475	At the 24 h time-point, the DLD-1 SP cells treated with 5-10 muM 4-AAQB had lost ~20-29% migratory potential, while the HCT116 SP cells recorded a 41-59% lag in migration, in comparison to observed migration by their untreated counterparts (Figure 6B).	('SP', 'Chemical', '-', (127, 129))	('lost', 'NegReg', (76, 80))	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('muM', 'Gene', (61, 64))	('muM', 'Gene', '56925', (61, 64))	('migratory potential', 'CPA', (89, 108))	('4-AAQB', 'Chemical', 'MESH:C555021', (65, 71))	('migration', 'CPA', (161, 170))	('SP', 'Chemical', '-', (34, 36))	('4-AAQB', 'Var', (65, 71))
3943	30103475	Moreover, we observed that there was a significantly attenuated capacity to form colonies in the 4-AAQB-treated SP cells, in comparison to the untreated SP cells (Figure 6E,F).	('SP', 'Chemical', '-', (153, 155))	('attenuated', 'NegReg', (53, 63))	('4-AAQB', 'Chemical', 'MESH:C555021', (97, 103))	('4-AAQB-treated', 'Var', (97, 111))	('SP', 'Chemical', '-', (112, 114))
3944	30103475	These results indicate that 4-AAQB effectively inhibits the SOD2-mediated motility, invasiveness, and the clonogenicity of CRC-SC cells.	('4-AAQB', 'Chemical', 'MESH:C555021', (28, 34))	('SOD', 'Gene', '6647;6648;6649', (60, 63))	('SOD2', 'molecular_function', 'GO:0004784', ('60', '64'))	('invasiveness', 'CPA', (84, 96))	('clonogenicity of CRC-SC cells', 'CPA', (106, 135))	('SOD', 'Gene', (60, 63))	('4-AAQB', 'Var', (28, 34))	('inhibits', 'NegReg', (47, 55))
3947	30103475	We demonstrated that 4-AAQB significantly inhibited the self-renewal capacity of the DLD-1 (5 muM: 69% inhibition, p < 0.01; 10 muM: 90% inhibition, p < 0.01) or HCT116 (5 muM: 61% inhibition, p < 0.05; 10 muM: 80% inhibition, p < 0.01) primary colonospheres (Figure 7B).	('muM', 'Gene', '56925', (172, 175))	('self-renewal capacity', 'CPA', (56, 77))	('muM', 'Gene', '56925', (206, 209))	('muM', 'Gene', (206, 209))	('muM', 'Gene', '56925', (94, 97))	('muM', 'Gene', '56925', (128, 131))	('4-AAQB', 'Chemical', 'MESH:C555021', (21, 27))	('muM', 'Gene', (172, 175))	('inhibited', 'NegReg', (42, 51))	('HCT116', 'Gene', (162, 168))	('muM', 'Gene', (94, 97))	('muM', 'Gene', (128, 131))	('4-AAQB', 'Var', (21, 27))	('HCT116', 'CellLine', 'CVCL:0291', (162, 168))
3949	30103475	These data indicate that 4-AAQB efficaciously suppresses the CSC-like phenotype, including the proliferation and self-renewal of CRC cells, in vitro.	('4-AAQB', 'Chemical', 'MESH:C555021', (25, 31))	('suppresses', 'NegReg', (46, 56))	('self-renewal of CRC cells', 'CPA', (113, 138))	('CSC-like', 'Disease', (61, 69))	('4-AAQB', 'Var', (25, 31))
3952	30103475	Macro-anatomically, the average weights of the tumors that were resected from the 4-AAQB- and combination-treated mice were significantly lesser than that of the FOLFOX- treated or untreated control mice (4-AAQB vs. control: 334.3  +-  79.4 mg vs. 3674.1  +-  593.1  mg, p  <  0.001; Combination vs. control: 282.6  +-  46.8 mg vs. 3674.1  +-  593.1 mg, p  <  0.001; FOLFOX vs. control: 459.3  +-  57.9 mg vs. 3674.1  +-  593.1 mg, p  <  0.01) (Figure 8A,B), indicating that the xenograft tumor growth was significantly inhibited by 4-AAQB alone or in combination with FOLFOX, compared with the FOLFOX- treated or untreated group.	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('inhibited', 'NegReg', (520, 529))	('tumors', 'Disease', (47, 53))	('4-AAQB', 'Chemical', 'MESH:C555021', (82, 88))	('FOLFOX', 'Chemical', '-', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('4-AAQB', 'Chemical', 'MESH:C555021', (533, 539))	('FOLFOX', 'Chemical', '-', (367, 373))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('4-AAQB', 'Var', (533, 539))	('FOLFOX', 'Chemical', '-', (595, 601))	('mice', 'Species', '10090', (114, 118))	('4-AAQB', 'Chemical', 'MESH:C555021', (205, 211))	('tumor', 'Disease', (47, 52))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (489, 494))	('FOLFOX', 'Chemical', '-', (569, 575))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
3957	30103475	Those results indicate that 4-AAQB is non-toxic to non-cancerous tissues (also see Supplementary Figure S2), and that alone or in synergism with FOLFOX, 4-AAQB significantly inhibits CRC xenograft tumor growth in vivo.	('cancerous', 'Disease', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('4-AAQB', 'Chemical', 'MESH:C555021', (28, 34))	('4-AAQB', 'Var', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('FOLFOX', 'Chemical', '-', (145, 151))	('4-AAQB', 'Chemical', 'MESH:C555021', (153, 159))	('cancerous', 'Disease', 'MESH:D009369', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('inhibits', 'NegReg', (174, 182))
3958	30103475	In our previous work on the role of 4-AAQB in CRC, we provided evidence that 4-AAQB exhibits potent antiproliferative and anti-CSC therapeutic effects in CRC.	('antiproliferative', 'CPA', (100, 117))	('CRC', 'Disease', (154, 157))	('4-AAQB', 'Var', (77, 83))	('4-AAQB', 'Chemical', 'MESH:C555021', (36, 42))	('anti-CSC therapeutic effects', 'CPA', (122, 150))	('4-AAQB', 'Chemical', 'MESH:C555021', (77, 83))
3959	30103475	We showed that 4-AAQB effectively reverses or attenuates the resistance of cancer cells to 5-FU or FOLFOX anticancer therapy, thus, enhancing chemosensitivity both in vitro and in vivo.	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('reverses', 'NegReg', (34, 42))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('chemosensitivity', 'CPA', (142, 158))	('4-AAQB', 'Chemical', 'MESH:C555021', (15, 21))	('4-AAQB', 'Var', (15, 21))	('cancer', 'Disease', (75, 81))	('resistance', 'MPA', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('attenuates', 'NegReg', (46, 56))	('FOLFOX', 'Chemical', '-', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('enhancing', 'PosReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
3964	30103475	This negative epigenetic modulation of SOD2 was shown to be associated with the converse enrichment of hsa-miR-324 and through the interaction of the 3'-UTR of SOD2 mRNA to the 5'-UTR of hsa-miR-324 (Figure 1 and Figure 2).	('epigenetic modulation', 'Var', (14, 35))	('SOD2', 'molecular_function', 'GO:0004784', ('39', '43'))	('hsa-miR-324', 'Gene', '442898', (103, 114))	('hsa-miR-324', 'Gene', '442898', (187, 198))	('SOD', 'Gene', '6647;6648;6649', (160, 163))	('SOD', 'Gene', '6647;6648;6649', (39, 42))	('hsa-miR-324', 'Gene', (103, 114))	('hsa-miR-324', 'Gene', (187, 198))	('SOD', 'Gene', (160, 163))	('interaction', 'Interaction', (131, 142))	('SOD', 'Gene', (39, 42))	('negative', 'NegReg', (5, 13))	('SOD2', 'molecular_function', 'GO:0004784', ('160', '164'))
3967	30103475	Consistent with the latter, in this study we demonstrated the oncogenic role of the aberrant expression of SOD2 in CRC, as evidenced by its ability to facilitate metastatic disease progression through the repression of hsa-miR-324 (Figure 3).	('hsa-miR-324', 'Gene', (219, 230))	('facilitate', 'PosReg', (151, 161))	('SOD', 'Gene', (107, 110))	('CRC', 'Disease', (115, 118))	('metastatic disease progression', 'CPA', (162, 192))	('SOD2', 'molecular_function', 'GO:0004784', ('107', '111'))	('hsa-miR-324', 'Gene', '442898', (219, 230))	('SOD', 'Gene', '6647;6648;6649', (107, 110))	('aberrant', 'Var', (84, 92))
3968	30103475	In addition, we also showed that 4-AAQB inhibits the viability and/or proliferation of human CRC SP cells in a hsa-miR-324-mediated manner, with associated attenuation of the SOD2-facilitated EMT and enhanced cell-death in the SP cells (Figure 4 and Figure 5; Supplementary Figure S1).	('cell-death', 'biological_process', 'GO:0008219', ('209', '219'))	('SOD', 'Gene', '6647;6648;6649', (175, 178))	('cell-death', 'CPA', (209, 219))	('enhanced', 'PosReg', (200, 208))	('4-AAQB', 'Chemical', 'MESH:C555021', (33, 39))	('hsa-miR-324', 'Gene', '442898', (111, 122))	('attenuation', 'NegReg', (156, 167))	('4-AAQB', 'Var', (33, 39))	('human', 'Species', '9606', (87, 92))	('proliferation', 'CPA', (70, 83))	('hsa-miR-324', 'Gene', (111, 122))	('SP', 'Chemical', '-', (97, 99))	('SOD', 'Gene', (175, 178))	('viability', 'CPA', (53, 62))	('EMT', 'CPA', (192, 195))	('EMT', 'biological_process', 'GO:0001837', ('192', '195'))	('SOD2', 'molecular_function', 'GO:0004784', ('175', '179'))	('SP', 'Chemical', '-', (227, 229))	('inhibits', 'NegReg', (40, 48))
3972	30103475	The targeting and killing of these CSC-like SP cells by 4-AAQB is posited as a rational and efficacious therapeutic approach, as it eliminates the quiescent, slowly-dividing, and characteristically therapy-resistant tumor-initiating (and maintaining-) cells, alongside the sensitive rapidly-dividing non-SP cells.	('tumor', 'Disease', (216, 221))	('slowly-dividing', 'CPA', (158, 173))	('4-AAQB', 'Chemical', 'MESH:C555021', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('SP', 'Chemical', '-', (304, 306))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('SP', 'Chemical', '-', (44, 46))	('eliminates', 'NegReg', (132, 142))	('4-AAQB', 'Var', (56, 62))	('quiescent', 'MPA', (147, 156))
3973	30103475	Consistent with this, we provided evidence that 4-AAQB, in a dose-dependent manner, effectively targets the primary colonospheres and subsequent generations of colonospheres, recapitulating the pharmacological inhibition of CRC-SC-related self-renewal or propagation, with associated attenuation of the expression of critical pluripotency transcription factors (Figure 7).	('self-renewal', 'CPA', (239, 251))	('attenuation', 'NegReg', (284, 295))	('4-AAQB', 'Chemical', 'MESH:C555021', (48, 54))	('transcription', 'biological_process', 'GO:0006351', ('339', '352'))	('pluripotency', 'Disease', (326, 338))	('expression', 'MPA', (303, 313))	('4-AAQB', 'Var', (48, 54))	('pluripotency', 'Disease', 'None', (326, 338))	('propagation', 'CPA', (255, 266))
3974	30103475	Understanding that self-renewal, a vital property of the CSC-like SP cells, is associated with the facilitation and maintenance of the proliferative capacity of cancerous cells, makes the clinical implication of our data apparent, as it highlights the putative ability of 4-AAQB to negatively modulate oncogenic self-renewal signaling, thus enhancing the sensitivity of malignant cells to chemotherapeutics, altering their survival strategies, limiting tumorigenesis and/or oncogenicity, and apparently impeding disease recurrence.	('SP', 'Chemical', '-', (66, 68))	('cancerous', 'Disease', 'MESH:D009369', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (453, 458))	('4-AAQB', 'Chemical', 'MESH:C555021', (272, 278))	('negatively', 'NegReg', (282, 292))	('disease recurrence', 'CPA', (512, 530))	('impeding', 'NegReg', (503, 511))	('survival strategies', 'CPA', (423, 442))	('enhancing', 'PosReg', (341, 350))	('oncogenic self-renewal', 'MPA', (302, 324))	('4-AAQB', 'Var', (272, 278))	('altering', 'Reg', (408, 416))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('signaling', 'biological_process', 'GO:0023052', ('325', '334'))	('cancerous', 'Disease', (161, 170))	('limiting', 'NegReg', (444, 452))	('oncogenicity', 'CPA', (474, 486))	('tumor', 'Disease', (453, 458))	('tumor', 'Disease', 'MESH:D009369', (453, 458))	('modulate', 'Reg', (293, 301))	('sensitivity', 'MPA', (355, 366))
3975	30103475	From in vivo validation of our in vitro findings, we confirmed that 4-AAQB alone or in synergism with FOLFOX reduces the tumorigenicity of CRC cells by suppressing SOD and up-regulating hsa-miR-324 expression, in vivo (Figure 8).	('suppressing', 'NegReg', (152, 163))	('reduces', 'NegReg', (109, 116))	('4-AAQB', 'Chemical', 'MESH:C555021', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('hsa-miR-324', 'Gene', '442898', (186, 197))	('tumor', 'Disease', (121, 126))	('SOD', 'Gene', '6647;6648;6649', (164, 167))	('4-AAQB', 'Var', (68, 74))	('hsa-miR-324', 'Gene', (186, 197))	('expression', 'MPA', (198, 208))	('up-regulating', 'PosReg', (172, 185))	('FOLFOX', 'Chemical', '-', (102, 108))	('SOD', 'Gene', (164, 167))	('SOD', 'molecular_function', 'GO:0004784', ('164', '167'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
3978	30103475	In the light of this, we showed in addition that 4-AAQB enhances the sensitivity of CRC cells to the standard of care FOLFOX, and significantly potentiates the anticancer effect of FOLFOX in the murine CRC xenograft models (Figure 8; Supplementary Figure S2).	('4-AAQB', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('4-AAQB', 'Chemical', 'MESH:C555021', (49, 55))	('FOLFOX', 'Chemical', '-', (181, 187))	('sensitivity', 'MPA', (69, 80))	('murine', 'Species', '10090', (195, 201))	('FOLFOX', 'Chemical', '-', (118, 124))	('potentiates', 'PosReg', (144, 155))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('enhances', 'PosReg', (56, 64))
3981	30103475	This present study provides evidence that 4-AAQB alone or by synergistically interacting with FOLFOX, exhibits an enhanced ability to kill CRC cells, inducing marked apoptosis via an epigenetically modulated pathway.	('inducing', 'Reg', (150, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('166', '175'))	('4-AAQB', 'Chemical', 'MESH:C555021', (42, 48))	('FOLFOX', 'Chemical', '-', (94, 100))	('apoptosis', 'biological_process', 'GO:0006915', ('166', '175'))	('enhanced', 'PosReg', (114, 122))	('4-AAQB', 'Var', (42, 48))	('apoptosis', 'CPA', (166, 175))	('epigenetically modulated pathway', 'Pathway', (183, 215))
3987	30103475	We propose that SOD2-enrichment in the CRC cells accentuates mitochondrial biogenesis, activates the intracellular anti-oxidative machinery, alleviates oxidative stress, and enhances the maintenance of the CSC-like phenotype, as well as acquisition of resistance to chemotherapeutic agents, by functional suppression of hsa-miR-324-5p expression and/or activity; however, exposure to 4-AAQB induces the re-expression of hsa-miR-324-5p, attenuates SOD2 expression, and sensitizes the CSC-like SP cells in CRC to FOLFOX therapy.	('SOD', 'Gene', '6647;6648;6649', (16, 19))	('SOD2', 'molecular_function', 'GO:0004784', ('16', '20'))	('SOD2', 'molecular_function', 'GO:0004784', ('447', '451'))	('4-AAQB', 'Var', (384, 390))	('hsa-miR-324-5p', 'Protein', (420, 434))	('FOLFOX', 'Chemical', '-', (511, 517))	('mitochondrial biogenesis', 'MPA', (61, 85))	('SOD', 'Gene', (447, 450))	('enhances', 'PosReg', (174, 182))	('SOD', 'Gene', (16, 19))	('accentuates', 'PosReg', (49, 60))	('expression', 'MPA', (452, 462))	('re-expression', 'MPA', (403, 416))	('intracellular anti-oxidative machinery', 'MPA', (101, 139))	('sensitizes', 'Reg', (468, 478))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('oxidative stress', 'MPA', (152, 168))	('SP', 'Chemical', '-', (492, 494))	('activates', 'PosReg', (87, 96))	('attenuates', 'NegReg', (436, 446))	('oxidative stress', 'Phenotype', 'HP:0025464', (152, 168))	('alleviates', 'NegReg', (141, 151))	('SOD', 'Gene', '6647;6648;6649', (447, 450))	('4-AAQB', 'Chemical', 'MESH:C555021', (384, 390))
3988	30103475	Thus, we propound a novel perspective on the putative roles of 4-AAQB as a hsa-miR-324-mediated CSC-targeting small molecule inhibitor of SOD2 in CRC, in vitro and in vivo.	('4-AAQB', 'Var', (63, 69))	('SOD', 'Gene', (138, 141))	('4-AAQB', 'Chemical', 'MESH:C555021', (63, 69))	('hsa-miR-324', 'Gene', '442898', (75, 86))	('SOD2', 'molecular_function', 'GO:0004784', ('138', '142'))	('hsa-miR-324', 'Gene', (75, 86))	('SOD', 'Gene', '6647;6648;6649', (138, 141))
4007	30103475	Blots were blocked for 1 h with 5% skimmed milk in Tris Buffered Saline with Tween 20 (TBST), incubated overnight at 4  C with specific primary antibodies against SOD2 (1:1000), E-cadherin (1:2000), N-cadherin (1:2000), vimentin (1:1000), c-Myc (1:1000), BAX (1:1000), BCL-xL (1:1000), and beta-actin (1:500).	('BAX', 'Gene', '581', (255, 258))	('BAX', 'Gene', (255, 258))	('c-Myc', 'Gene', (239, 244))	('Tween 20', 'Chemical', 'MESH:D011136', (77, 85))	('c-Myc', 'Gene', '4609', (239, 244))	('beta-actin', 'Gene', (290, 300))	('BCL-xL', 'Gene', '598', (269, 275))	('vimentin', 'cellular_component', 'GO:0045098', ('220', '228'))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('vimentin', 'Protein', (220, 228))	('SOD', 'Gene', '6647;6648;6649', (163, 166))	('1:2000', 'Var', (211, 217))	('N-cadherin', 'Gene', (199, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('180', '188'))	('BCL-xL', 'Gene', (269, 275))	('N-cadherin', 'Gene', '1000', (199, 209))	('TBST', 'Chemical', '-', (87, 91))	('SOD2', 'molecular_function', 'GO:0004784', ('163', '167'))	('SOD', 'Gene', (163, 166))	('beta-actin', 'Gene', '728378', (290, 300))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('vimentin', 'cellular_component', 'GO:0045099', ('220', '228'))	('Tris Buffered Saline', 'Chemical', '-', (51, 71))	('1:2000', 'Var', (190, 196))
4040	30103475	In conclusion, this present study demonstrates that 4-AAQB inhibits the aberrant expression of SOD2 through the re-expression of hsa-miR-324-5p, the negative modulation of pluripotency transcription factors, the augmentation of the BAX/BCL-xL ratios, and the reprogramming of malignant colorectal cancer cells from the aggressive mesenchymal phenotype to a relatively benign epithelial phenotype, subsequently enhancing the sensitivity of the cancer cells to conventional chemotherapy and facilitating better prognosis, as depicted in our Schematic abstract.	('augmentation', 'PosReg', (212, 224))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('SOD', 'Gene', '6647;6648;6649', (95, 98))	('BAX', 'Gene', '581', (232, 235))	('negative', 'NegReg', (149, 157))	('sensitivity', 'MPA', (424, 435))	('aberrant', 'MPA', (72, 80))	('expression', 'MPA', (81, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (286, 303))	('pluripotency', 'Disease', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('SOD', 'Gene', (95, 98))	('cancer', 'Disease', (443, 449))	('hsa-miR-324-5p', 'Gene', (129, 143))	('colorectal cancer', 'Disease', (286, 303))	('BCL-xL', 'Gene', '598', (236, 242))	('enhancing', 'PosReg', (410, 419))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('SOD2', 'molecular_function', 'GO:0004784', ('95', '99'))	('inhibits', 'NegReg', (59, 67))	('pluripotency', 'Disease', 'None', (172, 184))	('BCL-xL', 'Gene', (236, 242))	('cancer', 'Disease', (297, 303))	('4-AAQB', 'Chemical', 'MESH:C555021', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (443, 449))	('reprogramming', 'CPA', (259, 272))	('colorectal cancer', 'Phenotype', 'HP:0003003', (286, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('BAX', 'Gene', (232, 235))	('4-AAQB', 'Var', (52, 58))
4151	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))	('Aberrant', 'Var', (0, 8))	('CDKN2A', 'Gene', '1029', (9, 15))	('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))
4152	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))
4175	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))
4183	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))
4184	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))
4189	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))
4193	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))
4194	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))
4195	21876842	The most prevalent KIT mutations are L576P (exon 11), K642E (exon 13), V559A (exon 11), and D816H (exon 17).	('V559A', 'Var', (71, 76))	('K642E', 'Var', (54, 59))	('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'))
4196	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))
4200	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))
4201	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))	('NRAS', 'Gene', (29, 33))	('GTP hydrolysis locking the', 'MPA', (180, 206))	('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))
4202	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))
4205	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))
4206	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))
4207	21876842	With approximately 70% of cases harboring such a mutation, BRAF is the most commonly mutated protooncogene in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (110, 128))	('mutation', 'Var', (49, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('harboring', 'Reg', (32, 41))
4208	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', '673', (123, 127))	('BRAF', 'Gene', (123, 127))	('dysplastic melanocytic', 'Disease', (57, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (68, 84))	('mutation', 'Var', (111, 119))
4209	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))
4210	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))
4211	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'))	('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))	('mutated', 'Var', (6, 13))	('induces', 'Reg', (19, 26))	('uncontrolled proliferation', 'MPA', (27, 53))
4214	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))
4218	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))
4223	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))
4235	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))
4242	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', (71, 75))	('Mutation', 'Var', (0, 8))	('hydrolysis of GTP', 'MPA', (43, 60))	('prevents', 'NegReg', (30, 38))	('GNAQ', 'Gene', '2776', (12, 16))	('GTP', 'Chemical', 'MESH:D006160', (91, 94))	('GNAQ', 'Gene', '2776', (71, 75))
4246	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))
4247	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))	('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))	('CDKN2A', 'Gene', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('familial cutaneous melanoma', 'Disease', (190, 217))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Disease', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('CDKN2A', 'Gene', '1029', (59, 65))
4251	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))
4255	27833586	Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways.	('Akt', 'Gene', '207', (160, 163))	('NRAS', 'Gene', '4893', (89, 93))	('tumor', 'Disease', (28, 33))	('overactivation', 'PosReg', (120, 134))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('ERK', 'Gene', (147, 150))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('Melanoma', 'Disease', (0, 8))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('NRAS', 'Gene', (89, 93))	('mutations', 'Var', (64, 73))	('ERK', 'Gene', '2048', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Akt', 'Gene', (160, 163))
4256	27833586	The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade.	('BRAF', 'Gene', (76, 80))	('mutated', 'Var', (68, 75))	('BRAF', 'Gene', '673', (76, 80))
4264	27833586	In vitro studies demonstrate that ERbeta ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERbeta activation might impair melanoma development through the inhibition of the PI3K/Akt pathway.	('melanoma cells', 'Disease', (78, 92))	('rat', 'Species', '10116', (24, 27))	('mutation', 'Var', (131, 139))	('Akt', 'Gene', (244, 247))	('inhibition', 'NegReg', (221, 231))	('impair', 'NegReg', (181, 187))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('Akt', 'Gene', '207', (244, 247))	('melanoma', 'Disease', (188, 196))	('proliferation', 'CPA', (61, 74))	('BRAF', 'Gene', '673', (125, 129))	('BRAF', 'Gene', (125, 129))	('NRAS', 'Gene', '4893', (107, 111))	('melanoma cells', 'Disease', 'MESH:D008545', (78, 92))	('rat', 'Species', '10116', (68, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('239', '243'))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('men', 'Species', '9606', (204, 207))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('inhibit', 'NegReg', (49, 56))	('NRAS', 'Gene', (107, 111))
4265	27833586	These data suggest that ERbeta agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas.	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('rat', 'Species', '10116', (88, 91))	('mutant', 'Var', (142, 148))	('NRAS', 'Gene', (137, 141))	('men', 'Species', '9606', (81, 84))	('melanomas', 'Disease', (149, 158))	('NRAS', 'Gene', '4893', (137, 141))
4277	27833586	Family history increases the personal risk of melanoma by three to eight times; this risk increases with the number of affected family members.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Disease', (46, 54))	('Family history', 'Var', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))
4282	27833586	Mutations in genes involved in the processes of melanoma development and progression are very frequently found in melanoma patients.	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('found', 'Reg', (105, 110))	('patients', 'Species', '9606', (123, 131))	('Mutations', 'Var', (0, 9))	('men', 'Species', '9606', (64, 67))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Disease', (114, 122))
4283	27833586	Melanoma is now recognized as a very heterogeneous tumor; however, the majority of patients harbor driver oncogenic mutations at the level of genes encoding for proteins involved in the growth factor receptors signaling pathways (MAPK/ERK and PI3K/Akt).	('Akt', 'Gene', '207', (248, 251))	('Akt', 'Gene', (248, 251))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('230', '234'))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('Melanoma', 'Disease', (0, 8))	('tumor', 'Disease', (51, 56))	('ERK', 'molecular_function', 'GO:0004707', ('235', '238'))	('ERK', 'Gene', (235, 238))	('ERK', 'Gene', '2048', (235, 238))	('PI3K', 'molecular_function', 'GO:0016303', ('243', '247'))	('mutations', 'Var', (116, 125))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
4285	27833586	BRAF is mutated in approximately 50% of melanomas; 80-90% of these activating mutations involve a single substitution of valine in position 600 with glutamic acid (V600E).	('melanomas', 'Disease', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('valine in position 600 with glutamic acid', 'Mutation', 'rs113488022', (121, 162))	('mutations', 'Var', (78, 87))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Mutation', 'rs113488022', (164, 169))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('activating', 'PosReg', (67, 77))	('BRAF', 'Gene', (0, 4))
4286	27833586	Additional, more rare, BRAF mutations include V600K (valine substituted with lysine) and V600D (valine substituted with aspartic acid).	('V600D', 'Mutation', 'rs121913377', (89, 94))	('V600K', 'Var', (46, 51))	('BRAF', 'Gene', '673', (23, 27))	('valine', 'Chemical', 'MESH:D014633', (53, 59))	('BRAF', 'Gene', (23, 27))	('aspartic acid', 'Chemical', 'MESH:D001224', (120, 133))	('lysine', 'Chemical', 'MESH:D008239', (77, 83))	('V600K', 'Mutation', 'rs121913227', (46, 51))	('V600D', 'Var', (89, 94))	('valine', 'Chemical', 'MESH:D014633', (96, 102))
4287	27833586	BRAF mutations mimic phosphorylation on the regulatory domain of the protein; this leads to an enhanced kinase activity of the protein and activation of its downstream targets MEK and ERK.	('kinase activity', 'MPA', (104, 119))	('ERK', 'Gene', '2048', (184, 187))	('activation', 'PosReg', (139, 149))	('ERK', 'molecular_function', 'GO:0004707', ('184', '187'))	('ERK', 'Gene', (184, 187))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('BRAF', 'Gene', '673', (0, 4))	('kinase activity', 'molecular_function', 'GO:0016301', ('104', '119'))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('MEK', 'Gene', (176, 179))	('BRAF', 'Gene', (0, 4))	('enhanced', 'PosReg', (95, 103))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('MEK', 'Gene', '5609', (176, 179))
4290	27833586	Mutations causing the constitutive activation of this small G protein lead to the hyperactivation of its two downstream pathways, the MAPK/ERK and PI3K pathways, involved in the control of both the proliferative and metastatic behavior of tumor cells.	('MAPK', 'molecular_function', 'GO:0004707', ('134', '138'))	('PI3K pathways', 'Pathway', (147, 160))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('rat', 'Species', '10116', (205, 208))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('ERK', 'Gene', (139, 142))	('ERK', 'Gene', '2048', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('small G protein', 'Protein', (54, 69))	('Mutations', 'Var', (0, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('tumor', 'Disease', (239, 244))	('hyperactivation', 'PosReg', (82, 97))	('activation', 'PosReg', (35, 45))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
4291	27833586	NRAS is the most frequently (about 20-30% of tumors) mutated isoform of the RAS family members in melanoma; very recently, an increase in NRAS mutant allele percentage during melanoma progression has been reported.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutant', 'Var', (143, 149))	('NRAS', 'Gene', '4893', (138, 142))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))	('increase', 'PosReg', (126, 134))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (138, 142))
4294	27833586	The KIT receptor is mutated in approximately 15% of mucosal, acral, and chronic sun-damaged melanomas.	('melanomas', 'Disease', (92, 101))	('sun-damaged', 'Phenotype', 'HP:0000992', (80, 91))	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('acral', 'Disease', (61, 66))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('melanomas', 'Disease', 'MESH:D008545', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('mutated', 'Var', (20, 27))
4295	27833586	The presence of KIT mutations is particularly interesting because they usually are mutually exclusive with NRAS and BRAF mutations and because of the availability of specific KIT kinase inhibitors in the clinic.	('BRAF', 'Gene', '673', (116, 120))	('KIT', 'molecular_function', 'GO:0005020', ('16', '19'))	('NRAS', 'Gene', '4893', (107, 111))	('KIT', 'Gene', (16, 19))	('BRAF', 'Gene', (116, 120))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))	('mutations', 'Var', (20, 29))	('NRAS', 'Gene', (107, 111))
4297	27833586	Mutations as well as deletions of PTEN are found in approximately 30% of melanoma cell lines and are frequently associated with mutations in BRAF.	('melanoma', 'Disease', (73, 81))	('BRAF', 'Gene', (141, 145))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutations', 'Var', (128, 137))	('deletions', 'Var', (21, 30))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (34, 38))	('associated', 'Reg', (112, 122))	('BRAF', 'Gene', '673', (141, 145))	('PTEN', 'Gene', '5728', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
4302	27833586	In the general population, the prevalence of CDKN2A mutations in primary melanomas is only 1.2%; however, germ-line mutations in this locus were reported in approximately 20-57% of families with at least three cases of melanomas.	('mutations', 'Var', (52, 61))	('CDKN2A', 'Gene', '1029', (45, 51))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanomas', 'Disease', (219, 228))	('melanomas', 'Disease', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('CDKN2A', 'Gene', (45, 51))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas', 'Disease', 'MESH:D008545', (219, 228))	('melanomas', 'Phenotype', 'HP:0002861', (219, 228))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))
4304	27833586	Alterations of DNA methylation, histone modifications, and modified expression of microRNAs are well-established epigenetic mechanisms of cell neoplastic transformation.	('modified', 'Reg', (59, 67))	('methylation', 'Var', (19, 30))	('expression', 'MPA', (68, 78))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('DNA', 'Protein', (15, 18))	('histone', 'MPA', (32, 39))	('microRNAs', 'Gene', (82, 91))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('rat', 'Species', '10116', (4, 7))
4305	27833586	Melanoma cells present aberrant DNA methylation patterns with DNA hypermethylation at the level of CpG islands in the promoter of tumor suppressor genes (leading to their inactivation) and global DNA hypomethylation (contributing to genomic instability).	('global DNA hypomethylation', 'Var', (189, 215))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('196', '215'))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('Melanoma', 'Disease', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('62', '82'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('inactivation', 'MPA', (171, 183))	('tumor', 'Disease', (130, 135))	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))
4316	27833586	Thus, therapies were developed to specifically target ("targeted therapies") melanomas harboring either the BRAF or the NRAS mutation.	('melanomas', 'Disease', (77, 86))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('NRAS', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('BRAF', 'Gene', '673', (108, 112))	('NRAS', 'Gene', '4893', (120, 124))	('BRAF', 'Gene', (108, 112))	('mutation', 'Var', (125, 133))
4317	27833586	Vemurafenib, the first targeted drug for melanoma, is a selective BRAF V600E inhibitor, approved by the FDA in August 2011.	('V600E', 'Mutation', 'rs113488022', (71, 76))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('BRAF', 'Gene', (66, 70))
4320	27833586	Dabrafenib is a reversible ATP-competitive inhibitor of V600E- and V600K-mutant BRAF that was approved in 2013; however, the median progression-free survival in melanoma patients treated with dabrafenib was found to be shorter than that reported with vemurafenib.	('patients', 'Species', '9606', (170, 178))	('BRAF', 'Gene', (80, 84))	('vemurafenib', 'Chemical', 'MESH:D000077484', (251, 262))	('shorter', 'NegReg', (219, 226))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('progression-free survival', 'CPA', (132, 157))	('V600K-mutant', 'Var', (67, 79))	('V600E-', 'Var', (56, 62))	('dabrafenib', 'Chemical', 'MESH:C561627', (192, 202))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('melanoma', 'Disease', (161, 169))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('V600K', 'Mutation', 'rs121913227', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('BRAF', 'Gene', '673', (80, 84))
4324	27833586	As mentioned above, NRAS is mutated in 20-30% of melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('mutated', 'Var', (28, 35))	('NRAS', 'Gene', '4893', (20, 24))	('NRAS', 'Gene', (20, 24))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('men', 'Species', '9606', (3, 6))
4349	27833586	Melanoma neoplasms are thicker during pregnancy than those diagnosed outside of pregnancy, and this is in line with the observation that diethylstilbestrol enhances melanomagenesis in mouse B16 melanoma cells.	('Melanoma neoplasms', 'Disease', 'MESH:D008545', (0, 18))	('enhances', 'PosReg', (156, 164))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma neoplasms', 'Disease', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('melanoma cells', 'Disease', 'MESH:D008545', (194, 208))	('melanoma cells', 'Disease', (194, 208))	('B16', 'CellLine', 'CVCL:N540', (190, 193))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('neoplasms', 'Phenotype', 'HP:0002664', (9, 18))	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (137, 155))	('mouse', 'Species', '10090', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('diethylstilbestrol', 'Var', (137, 155))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
4381	27833586	Increasing evidence supports a relationship between the perturbation of estrogen signaling and cancer initiation, promotion, and progression.	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('estrogen', 'Protein', (72, 80))	('cancer initiation', 'Disease', 'MESH:D009369', (95, 112))	('cancer initiation', 'Disease', (95, 112))	('promotion', 'CPA', (114, 123))	('perturbation', 'Var', (56, 68))
4398	27833586	Finally, a polymorphism at the AluI restriction site was identified in a high proportion of melanoma, suggesting that the polymorphism of this receptor could be related to a higher susceptibility to the development of this tumor.	('polymorphism', 'Var', (122, 134))	('men', 'Species', '9606', (210, 213))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('related', 'Reg', (161, 168))
4399	27833586	In line with these clinical observations, we recently demonstrated that ERbeta, but not ERalpha, is the ER expressed in human melanoma cell lines, harboring different genetic mutations (A375, BLM, WM115, and WM1552).	('WM115', 'Var', (197, 202))	('human', 'Species', '9606', (120, 125))	('ERalpha', 'Gene', '2099', (88, 95))	('ER', 'Gene', '2099', (88, 90))	('ER', 'Gene', '2099', (72, 74))	('ER', 'Gene', '2099', (104, 106))	('A375', 'CellLine', 'CVCL:0132', (186, 190))	('rat', 'Species', '10116', (61, 64))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('WM1552', 'Var', (208, 214))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('BLM', 'Var', (192, 195))	('melanoma', 'Disease', (126, 134))	('A375', 'Var', (186, 190))	('ERalpha', 'Gene', (88, 95))
4409	27833586	As discussed, some of the proteins involved in these signaling cascades are mutated in the majority of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('mutated', 'Var', (76, 83))	('proteins', 'Protein', (26, 34))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
4412	27833586	Sarti and coworkers reported that 17beta-estradiol exerts a significant inhibitory activity on the proliferation of the human SK-Mel 23 melanoma cell line, expressing ERbeta, but not ERalpha (referred to as "type II estrogen binding site" by these authors).	('human', 'Species', '9606', (120, 125))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (34, 50))	('ERbeta', 'Var', (167, 173))	('inhibitory', 'NegReg', (72, 82))	('ERalpha', 'Gene', '2099', (183, 190))	('ERalpha', 'Gene', (183, 190))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('rat', 'Species', '10116', (106, 109))	('melanoma', 'Disease', (136, 144))	('proliferation', 'CPA', (99, 112))
4415	27833586	The ER antagonist tamoxifen was first shown to induce cell death in human malignant melanoma cells, possibly through inactivation of the IGF-I receptor.	('cell death', 'CPA', (54, 64))	('malignant melanoma', 'Disease', 'MESH:D008545', (74, 92))	('ER', 'Gene', '2099', (4, 6))	('human', 'Species', '9606', (68, 73))	('malignant melanoma', 'Disease', (74, 92))	('melanoma cells', 'Disease', 'MESH:D008545', (84, 98))	('melanoma cells', 'Disease', (84, 98))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('inactivation', 'Var', (117, 129))	('IGF-I receptor', 'Gene', '3480', (137, 151))	('tamoxifen', 'Chemical', 'MESH:D013629', (18, 27))	('IGF-I receptor', 'Gene', (137, 151))	('cell death', 'biological_process', 'GO:0008219', ('54', '64'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
4427	27833586	Surprisingly, in our paper, we could also show that ERbeta agonists were ineffective in reducing the proliferation of A375 and WM1552 (V600E BRAF-mutant) melanoma cells, expressing the ER isoform.	('BRAF', 'Gene', (141, 145))	('V600E', 'Mutation', 'rs113488022', (135, 140))	('rat', 'Species', '10116', (108, 111))	('ER', 'Gene', '2099', (185, 187))	('ER', 'Gene', '2099', (52, 54))	('V600E', 'Var', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('A375', 'CellLine', 'CVCL:0132', (118, 122))	('melanoma cells', 'Disease', 'MESH:D008545', (154, 168))	('melanoma cells', 'Disease', (154, 168))	('BRAF', 'Gene', '673', (141, 145))
4428	27833586	Actually, as mentioned above, NRAS and BRAF mutations are the most frequent oncogenic mutations found in melanoma.	('BRAF', 'Gene', '673', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('BRAF', 'Gene', (39, 43))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', (30, 34))	('NRAS', 'Gene', '4893', (30, 34))	('men', 'Species', '9606', (13, 16))
4429	27833586	NRAS mutations have been reported to be associated with increased activation of the two main downstream pathways: PI3K/Akt and MEK/ERK.	('ERK', 'molecular_function', 'GO:0004707', ('131', '134'))	('MEK', 'Gene', (127, 130))	('ERK', 'Gene', '2048', (131, 134))	('MEK', 'Gene', '5609', (127, 130))	('Akt', 'Gene', '207', (119, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('114', '118'))	('ERK', 'Gene', (131, 134))	('mutations', 'Var', (5, 14))	('Akt', 'Gene', (119, 122))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('activation', 'PosReg', (66, 76))
4430	27833586	On the other hand, in melanoma cells harboring BRAF mutations, only the MEK/ERK signaling cascade was shown to be overactivated.	('mutations', 'Var', (52, 61))	('ERK', 'Gene', '2048', (76, 79))	('overactivated', 'PosReg', (114, 127))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('ERK', 'Gene', (76, 79))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('melanoma cells', 'Disease', 'MESH:D008545', (22, 36))	('melanoma cells', 'Disease', (22, 36))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('MEK', 'Gene', (72, 75))	('MEK', 'Gene', '5609', (72, 75))	('signaling cascade', 'biological_process', 'GO:0007165', ('80', '97'))
4434	27833586	Based on these observations, it seems possible to conclude that ERbeta activation might significantly reduce the growth of cutaneous melanoma cells harboring the NRAS mutation, possibly through the inhibition of the PI3K/Akt signaling pathway (Figure 2).	('cutaneous melanoma', 'Disease', (123, 141))	('Akt', 'Gene', '207', (221, 224))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 141))	('Akt signaling', 'biological_process', 'GO:0043491', ('221', '234'))	('PI3K', 'molecular_function', 'GO:0016303', ('216', '220'))	('growth', 'MPA', (113, 119))	('reduce', 'NegReg', (102, 108))	('mutation', 'Var', (167, 175))	('Akt', 'Gene', (221, 224))	('NRAS', 'Gene', '4893', (162, 166))	('ERbeta', 'Protein', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('225', '242'))	('melanoma cells', 'Disease', 'MESH:D008545', (133, 147))	('melanoma cells', 'Disease', (133, 147))	('NRAS', 'Gene', (162, 166))
4436	27833586	These data suggest that, in melanoma patients harboring the NRAS mutation, ERbeta might represent an effective molecular target for personalized therapeutic interventions.	('melanoma', 'Disease', (28, 36))	('patients', 'Species', '9606', (37, 45))	('mole', 'Phenotype', 'HP:0003764', (111, 115))	('NRAS', 'Gene', (60, 64))	('NRAS', 'Gene', '4893', (60, 64))	('mutation', 'Var', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
4713	24841846	The observed sensitivity increased with melanoma thickness, from 73 2% for Tis to 100% for T2b-T4.	('sensitivity', 'MPA', (13, 24))	('increased', 'PosReg', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma thickness', 'Disease', 'MESH:D008545', (40, 58))	('melanoma thickness', 'Disease', (40, 58))	('T2b-T4', 'Var', (91, 97))
4743	32380816	However, recently, immunomodulatory therapies for mutations in melanocytic lesions have been used effectively to treat the increasing number of patients developing this type of melanoma, thus improving the prognosis of patients with oral mucosal melanoma.	('melanocytic lesions', 'Gene', (63, 82))	('oral mucosal melanoma', 'Disease', (233, 254))	('mutations', 'Var', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Disease', (246, 254))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('patients', 'Species', '9606', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (246, 254))	('patients', 'Species', '9606', (219, 227))	('improving', 'PosReg', (192, 201))	('oral mucosal melanoma', 'Disease', 'MESH:D008545', (233, 254))
4799	32380816	Among cancer immunotherapy agents, immune checkpoint inhibitors that modulate programmed cell death-1 and its ligand have been demonstrated to be effective for treating progressive cutaneous melanoma, although further study is needed to determine their efficacy for oral mucosal melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (181, 199))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('programmed cell death', 'biological_process', 'GO:0012501', ('78', '99'))	('programmed cell death-1', 'Gene', (78, 101))	('oral mucosal melanoma', 'Disease', 'MESH:D008545', (266, 287))	('oral mucosal melanoma', 'Disease', (266, 287))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (181, 199))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('ligand', 'molecular_function', 'GO:0005488', ('110', '116'))	('cutaneous melanoma', 'Disease', (181, 199))	('cancer', 'Disease', (6, 12))	('modulate', 'Var', (69, 77))
4800	32380816	In the current case, pathologically confirmed pT4aN0M0, only postoperative radiotherapy was performed according to the National Comprehensive Cancer Network guidelines.	('pT4aN0M0', 'Var', (46, 54))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))	('Cancer', 'Disease', (142, 148))
4809	30268436	A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-beta Superfamily We present an integromic analysis of gene alterations that modulate transforming growth factor beta (TGF-beta)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA).	('cancer', 'Disease', (287, 293))	('TGF-beta', 'Gene', '7040', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('modulate', 'Reg', (178, 186))	('transforming growth factor beta', 'Gene', (187, 218))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('tumor', 'Disease', (263, 268))	('Signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('TGF-beta', 'Gene', (98, 106))	('alterations', 'Var', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('187', '218'))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('transforming growth factor beta', 'Gene', '7040', (187, 218))	('TGF-beta', 'Gene', '7040', (220, 228))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('TGF-beta', 'Gene', (220, 228))
4810	30268436	Focusing on genes that encode mediators and regulators of TGF-beta signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TGF-beta', 'Gene', (58, 66))	('mutation', 'Var', (120, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (216, 240))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('gastrointestinal cancers', 'Disease', (216, 240))	('frequencies', 'Reg', (201, 212))	('TGF-beta', 'Gene', '7040', (58, 66))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))
4812	30268436	Alterations in the TGF-beta superfamily correlated positively with expression of metastasis-associated genes and with decreased survival.	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (19, 27))	('metastasis-associated genes', 'Gene', (81, 108))	('decreased', 'NegReg', (118, 127))	('survival', 'CPA', (128, 136))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (19, 27))
4813	30268436	Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-beta signaling in each cancer type.	('miR', 'Gene', (105, 108))	('transcriptional', 'MPA', (125, 140))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('TGF-beta', 'Gene', '7040', (153, 161))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('deletion', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('DNA methylation', 'biological_process', 'GO:0006306', ('84', '99'))	('TGF-beta', 'Gene', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (59, 72))	('cancer', 'Disease', (180, 186))	('miR', 'Gene', '220972', (105, 108))
4829	30268436	We analyzed multiple data types: somatic copy number variation (CNV), point mutation, DNA methylation, mRNA expression (from mRNA-seq), miRNA expression (from miRNA-seq), and, for correlative analyses, protein expression (from reverse-phase protein arrays; RPPA).	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('miR', 'Gene', '220972', (136, 139))	('DNA methylation', 'biological_process', 'GO:0006306', ('86', '101'))	('miR', 'Gene', (136, 139))	('point mutation', 'Var', (70, 84))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('mRNA expression', 'MPA', (103, 118))
4835	30268436	Using the cBioPortal definitions, genomic alterations were classified as gene amplifications, gains (low-level amplifications), deep deletions (equivalent to homozygous deletions for non-aneuploidy cases), shallow deletions (heterozygous loss), truncating mutations, inframe mutations, or missense mutations.	('non-aneuploidy', 'Disease', (183, 197))	('truncating', 'Disease', (245, 255))	('gains', 'Disease', (94, 99))	('inframe mutations', 'Var', (267, 284))	('deep', 'Disease', (128, 132))	('missense mutations', 'Var', (289, 307))	('shallow', 'Disease', (206, 213))	('non-aneuploidy', 'Disease', 'MESH:D000782', (183, 197))
4837	30268436	Although alteration frequencies were low, 39% of the tumors contained an alteration in at least one of the 43 genes.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alteration', 'Var', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
4841	30268436	When excluding those six, cumulative mutation frequency (23%) in the TGF-beta core pathways was significantly higher than expected for a randomly selected set of 37 genes (Figure S1C, S1D).	('TGF-beta', 'Gene', (69, 77))	('mutation frequency', 'Var', (37, 55))	('core', 'cellular_component', 'GO:0019013', ('78', '82'))	('TGF-beta', 'Gene', '7040', (69, 77))	('higher', 'PosReg', (110, 116))
4845	30268436	The frequency and type of genomic alteration varied widely across tumor types (Figure 2A and S2A), from no alterations in testicular germline tumors (TGCT) to all three types of alterations (mutation, deletion, and amplification) in urothelial bladder cancers (BLCA).	('deletion', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor', 'Disease', (66, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (215, 228))	('urothelial bladder cancers', 'Disease', (233, 259))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BLCA', 'Phenotype', 'HP:0009725', (261, 265))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
4846	30268436	There were genomic alterations of TGF-beta pathway genes in more than 50% of samples in 12 tumor types (Figure 2A, Tables S2-S4).	('TGF-beta', 'Gene', (34, 42))	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '7040', (34, 42))	('tumor', 'Disease', (91, 96))
4848	30268436	Without adjusting for background alteration burden, among the 39% of TCGA cases that carried TGF-beta pathway gene alterations, SKCM (70%), COAD (65%), and ESCA (65%) had the highest percentages of alterations; THCA (4%), KICH (6%), and TGCT (9%) had the lowest (Table S3).	('TGF-beta', 'Gene', '7040', (93, 101))	('COAD', 'Disease', (140, 144))	('TGF-beta', 'Gene', (93, 101))	('alterations', 'Reg', (198, 209))	('alterations', 'Var', (115, 126))	('KICH', 'Disease', 'None', (222, 226))	('ESCA', 'Phenotype', 'HP:0011459', (156, 160))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('KICH', 'Disease', (222, 226))
4849	30268436	We observed non-silent SMAD4 mutations in 24% and SMAD4 deletions in 13% of pancreatic adenocarcinoma (PAAD) samples (Figure 2A, 2C; Table S4).	('SMAD4', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (29, 38))	('SMAD4', 'Gene', (50, 55))	('pancreatic adenocarcinoma', 'Disease', (76, 101))	('deletions', 'Var', (56, 65))	('PAAD', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (76, 101))	('SMAD4', 'Gene', '4089', (23, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (76, 101))	('SMAD4', 'Gene', '4089', (50, 55))
4850	30268436	Because SMAD4 is the Co-Smad required for transducing the Smad signal to downstream effectors, loss of SMAD4 in PAAD by mutation or deletion suggests a tumor-suppressive role for TGF-beta signaling in PAAD, which is consistent with other reports.	('TGF-beta', 'Gene', (179, 187))	('deletion', 'Var', (132, 140))	('SMAD4', 'Gene', (8, 13))	('a tumor', 'Disease', 'MESH:D009369', (150, 157))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', '4089', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (120, 128))	('a tumor', 'Disease', (150, 157))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (179, 187))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('loss', 'NegReg', (95, 99))	('SMAD4', 'Gene', (103, 108))	('PAAD', 'Disease', (201, 205))	('PAAD', 'Phenotype', 'HP:0006725', (201, 205))
4854	30268436	Diffuse large B-cell lymphoma (DLBC) had a high frequency of deletions spanning different levels of the pathway:: ligands (TGFB2, INHBB, GDF1), receptors or receptor-associated proteins (BMPR1A, ACVR1, ACVR1C, ACV2A, ACVR2B, TGFBRAP1), and Smads (SMAD9):, indicative of a tumor-suppressive role for TGF-beta signaling in these early-stage DLBC cases in the TCGA cohort.	('deletions', 'Var', (61, 70))	('TGF-beta', 'Gene', (299, 307))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (14, 29))	('TGFB2', 'Gene', '7042', (123, 128))	('ACVR1C', 'Gene', (202, 208))	('ACVR1C', 'Gene', '130399', (202, 208))	('INHBB', 'Gene', (130, 135))	('BMPR1A', 'Gene', '657', (187, 193))	('ACV', 'Gene', (195, 198))	('ACV', 'Gene', (210, 213))	('ACV', 'Gene', (202, 205))	('ACVR1', 'Gene', (195, 200))	('a tumor', 'Disease', 'MESH:D009369', (270, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (14, 29))	('signaling', 'biological_process', 'GO:0023052', ('308', '317'))	('TGFB2', 'Gene', (123, 128))	('TGFBRAP1', 'Gene', '9392', (225, 233))	('ACV', 'Gene', '83729', (202, 205))	('ACV', 'Gene', '83729', (195, 198))	('GDF1', 'Gene', (137, 141))	('ACVR2B', 'Gene', '93', (217, 223))	('ACV', 'Gene', '83729', (210, 213))	('ACVR1', 'Gene', '90', (202, 207))	('INHBB', 'Gene', '3625', (130, 135))	('B-cell lymphoma', 'Disease', (14, 29))	('early-stage DLBC', 'Disease', (327, 343))	('ACV', 'Gene', (217, 220))	('a tumor', 'Disease', (270, 277))	('BMPR1A', 'Gene', (187, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('ACVR1', 'Gene', (202, 207))	('ACVR1', 'Gene', '90', (195, 200))	('SMAD9', 'Gene', (247, 252))	('GDF1', 'Gene', '2657', (137, 141))	('TGF-beta', 'Gene', '7040', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ACV', 'Gene', '83729', (217, 220))	('ACVR2B', 'Gene', (217, 223))	('SMAD9', 'Gene', '4093', (247, 252))	('TGFBRAP1', 'Gene', (225, 233))
4860	30268436	PAAD had deletions associated with 14 TGF-beta core genes, suggesting synergistic effects from ligands (BMP family), receptors (BMPR, TGFBR), and SMAD4.	('TGFBR', 'Gene', '7046;7048;7049', (134, 139))	('TGF-beta', 'Gene', (38, 46))	('BMP', 'Gene', (128, 131))	('BMP', 'Gene', (104, 107))	('TGFBR', 'Gene', (134, 139))	('SMAD4', 'Gene', '4089', (146, 151))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('core', 'cellular_component', 'GO:0019013', ('47', '51'))	('TGF-beta', 'Gene', '7040', (38, 46))	('deletions', 'Var', (9, 18))	('BMP', 'Gene', '649', (104, 107))	('SMAD4', 'Gene', (146, 151))	('BMP', 'Gene', '649', (128, 131))
4861	30268436	Colorectal cancers (COAD and READ) were marked by SMAD4 and SMAD3 deletions.	('SMAD3', 'Gene', (60, 65))	('COAD', 'Disease', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancers', 'Disease', (0, 18))	('SMAD4', 'Gene', (50, 55))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('COAD', 'Disease', 'MESH:D029424', (20, 24))	('deletions', 'Var', (66, 75))	('SMAD3', 'Gene', '4088', (60, 65))	('SMAD4', 'Gene', '4089', (50, 55))
4862	30268436	Deletions in genomic regions covering all ACVR genes except ACVR2B were identified as significant in DLBC.	('significant', 'Reg', (86, 97))	('ACV', 'Gene', '83729', (42, 45))	('ACVR2B', 'Gene', (60, 66))	('DLBC', 'Disease', (101, 105))	('ACV', 'Gene', (42, 45))	('ACV', 'Gene', '83729', (60, 63))	('ACVR2B', 'Gene', '93', (60, 66))	('ACV', 'Gene', (60, 63))	('Deletions', 'Var', (0, 9))
4863	30268436	To understand how gene alterations affect transcriptional output of the pathways, we analyzed the mRNA expression of 50 downstream targets of Smad signaling with defined roles as tumor promoters or tumor suppressors (Table S1).	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('alterations', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (198, 203))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('tumor', 'Disease', (179, 184))
4864	30268436	Surprisingly, the directionality of target-gene change was consistent for all mutations, even for mutations in the inhibitors SMAD6/7.	('SMAD6/7', 'Gene', '4091;4092', (126, 133))	('mutations', 'Var', (78, 87))	('SMAD6/7', 'Gene', (126, 133))
4865	30268436	An explanation is that mutations in pathway activators, like TGFB1/2/3 and TGFBR1/2/3, may result in gain of function, whereas mutations in the inhibitors SMAD6 and SMAD7 may result in loss of inhibitory function.	('TGFBR1/2/3', 'Gene', (75, 85))	('TGFBR1/2/3', 'Gene', '7046;7048;7049', (75, 85))	('TGFB1/2/3', 'Gene', (61, 70))	('SMAD7', 'Gene', (165, 170))	('SMAD6', 'Gene', (155, 160))	('mutations', 'Var', (23, 32))	('SMAD7', 'Gene', '4092', (165, 170))	('SMAD6', 'Gene', '4091', (155, 160))	('TGFB1/2/3', 'Gene', '7040;7042;7043', (61, 70))	('gain of function', 'PosReg', (101, 117))	('inhibitory function', 'MPA', (193, 212))
4867	30268436	Similarly, SMAD3 was generally co-amplified with SMAD6; both are in proximal cytogenetic bands, 15q22.33 and 15q22.31, respectively.	('SMAD3', 'Gene', '4088', (11, 16))	('SMAD3', 'Gene', (11, 16))	('SMAD6', 'Gene', '4091', (49, 54))	('15q22.33', 'Var', (96, 104))	('SMAD6', 'Gene', (49, 54))	('15q22.31', 'Var', (109, 117))
4868	30268436	In support of that hypothesis, both the amplification and deletion profiles (rows in Figure 2H-I) of those gene pairs were similar, and, consequently, SMAD2 and SMAD7 are co-clustered, whereas SMAD3 and SMAD6 clustered close to each other.	('SMAD7', 'Gene', (161, 166))	('SMAD7', 'Gene', '4092', (161, 166))	('SMAD2', 'Gene', (151, 156))	('SMAD2', 'Gene', '4087', (151, 156))	('SMAD6', 'Gene', '4091', (203, 208))	('deletion', 'Var', (58, 66))	('SMAD6', 'Gene', (203, 208))	('SMAD3', 'Gene', '4088', (193, 198))	('SMAD3', 'Gene', (193, 198))
4869	30268436	The effect of TGF-beta pathway amplification events on target gene mRNA expression was similar to that of mutations (Figure 2H), suggesting that most mutations in TGF-beta pathway activators are gain of function.	('TGF-beta', 'Gene', '7040', (163, 171))	('TGF-beta', 'Gene', (14, 22))	('gain of function', 'PosReg', (195, 211))	('TGF-beta', 'Gene', (163, 171))	('mutations', 'Var', (150, 159))	('TGF-beta', 'Gene', '7040', (14, 22))
4870	30268436	HMGA2 was overexpressed in samples with either mutations or amplifications in the TGF-beta pathway genes, with the exception of tumors with amplifications in TGFB2, TGFBR2, ACVR2B, SMAD4, SMAD5, or SMAD6.	('TGFBR2', 'Gene', (165, 171))	('SMAD6', 'Gene', (198, 203))	('ACVR2B', 'Gene', '93', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', '7040', (82, 90))	('SMAD4', 'Gene', (181, 186))	('tumors', 'Disease', (128, 134))	('overexpressed', 'PosReg', (10, 23))	('HMGA2', 'Gene', '8091', (0, 5))	('SMAD5', 'Gene', (188, 193))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('TGF-beta', 'Gene', (82, 90))	('ACVR2B', 'Gene', (173, 179))	('SMAD6', 'Gene', '4091', (198, 203))	('SMAD4', 'Gene', '4089', (181, 186))	('amplifications', 'Var', (140, 154))	('TGFB2', 'Gene', '7042', (158, 163))	('TGFBR2', 'Gene', '7048', (165, 171))	('SMAD5', 'Gene', '4090', (188, 193))	('amplifications', 'Var', (60, 74))	('TGFB2', 'Gene', (158, 163))	('HMGA2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
4875	30268436	SMAD5 amplification was associated with increased CDH2 expression; 36 other amplifications were associated with decreased CDH2 expression.	('CDH2', 'Gene', (50, 54))	('CDH2', 'Gene', '1000', (50, 54))	('SMAD5', 'Gene', (0, 5))	('expression', 'MPA', (127, 137))	('CDH2', 'Gene', (122, 126))	('expression', 'MPA', (55, 65))	('CDH2', 'Gene', '1000', (122, 126))	('SMAD5', 'Gene', '4090', (0, 5))	('increased', 'PosReg', (40, 49))	('amplification', 'Var', (6, 19))	('decreased', 'NegReg', (112, 121))
4877	30268436	Another exception was reduced HMGA2 expression in samples with amplifications of SMAD4 or TGFBR2, whereas HMGA2 expression increased in samples with mutations in SMAD4 or TGFBR2 (Figure 2G).	('increased', 'PosReg', (123, 132))	('mutations', 'Var', (149, 158))	('HMGA2', 'Gene', '8091', (30, 35))	('TGFBR2', 'Gene', (90, 96))	('HMGA2', 'Gene', '8091', (106, 111))	('TGFBR2', 'Gene', '7048', (171, 177))	('SMAD4', 'Gene', '4089', (162, 167))	('SMAD4', 'Gene', (81, 86))	('HMGA2', 'Gene', (30, 35))	('HMGA2', 'Gene', (106, 111))	('amplifications', 'Var', (63, 77))	('reduced', 'NegReg', (22, 29))	('TGFBR2', 'Gene', (171, 177))	('TGFBR2', 'Gene', '7048', (90, 96))	('SMAD4', 'Gene', (162, 167))	('expression', 'MPA', (36, 46))	('SMAD4', 'Gene', '4089', (81, 86))	('expression', 'MPA', (112, 122))
4879	30268436	The analysis identified 6genes with hotspot mutations, representing all levels of the TGF-beta pathway (Figure 3A-E).	('TGF-beta', 'Gene', '7040', (86, 94))	('TGF-beta', 'Gene', (86, 94))	('mutations', 'Var', (44, 53))
4881	30268436	Hotspot mutations of BMP5 occurred in 13 cases across 7 cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (8, 17))	('occurred', 'Reg', (26, 34))	('BMP5', 'Gene', (21, 25))	('BMP5', 'Gene', '653', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Hotspot', 'PosReg', (0, 7))
4882	30268436	BMP5 is synthesized as a proprotein, and an R321 stop-codon mutation (4 cases) (Figure 3A) results in loss of the functional, secreted ligand.	('R321 stop-codon', 'Var', (44, 59))	('ligand', 'molecular_function', 'GO:0005488', ('135', '141'))	('BMP5', 'Gene', (0, 4))	('loss', 'NegReg', (102, 106))	('BMP5', 'Gene', '653', (0, 4))
4883	30268436	Frameshift mutations in ACVR2A at the K437 hotspot generate the variants K437Efs*19 (7 cases in 2 cancers) and K437Rfs*5 (69 cases in 5 cancers), resulting in premature stop codons and deletion of two C-terminal helices of the 4-helix bundle (Figure 3A, 3D), which likely disrupt ACV signaling (; Yosef et al., 2017).	('ACV', 'Gene', '83729', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('signaling', 'biological_process', 'GO:0023052', ('284', '293'))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (98, 105))	('K437Efs*19', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('K437Efs', 'Mutation', 'p.K437,FSE', (73, 80))	('ACV', 'Gene', (280, 283))	('disrupt', 'NegReg', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('ACV', 'Gene', '83729', (280, 283))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('K437Rfs*5', 'Var', (111, 120))	('stop codons', 'MPA', (169, 180))	('ACVR2A', 'Gene', '92', (24, 30))	('ACV', 'Gene', (24, 27))	('deletion', 'Var', (185, 193))	('ACVR2A', 'Gene', (24, 30))	('K437Rfs', 'Mutation', 'p.K437,FSR', (111, 118))	('Frameshift mutations', 'Var', (0, 20))
4884	30268436	Type I receptors ACVR1B and ACVR1C have similar C-terminal frameshift mutation hotspots at R485 (6 cases) and R441 (5 cases), respectively (Figure S3).	('ACVR1B', 'Gene', '91', (17, 23))	('ACVR1B', 'Gene', (17, 23))	('R441', 'Var', (110, 114))	('ACVR1C', 'Gene', (28, 34))	('ACVR1C', 'Gene', '130399', (28, 34))	('R485', 'Var', (91, 95))
4885	30268436	TGFBR2 R553 to C or H mutations and BMPR2 N583 frameshift might disrupt interaction with other receptor subunits or binding proteins.	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('BMPR2', 'Gene', '659', (36, 41))	('binding', 'Interaction', (116, 123))	('N583 frameshift', 'Var', (42, 57))	('interaction', 'Interaction', (72, 83))	('TGFBR2', 'Gene', (0, 6))	('R553 to C or H mutations', 'Var', (7, 31))	('frameshift', 'Var', (47, 57))	('TGFBR2', 'Gene', '7048', (0, 6))	('disrupt', 'NegReg', (64, 71))	('BMPR2', 'Gene', (36, 41))
4886	30268436	Hotspots in SMAD4 at R361 and D537 (two conserved sites in R-Smads) normally stabilize homo- or heterotrimer oligomerization (Figure 3C).	('SMAD4', 'Gene', (12, 17))	('stabilize', 'Reg', (77, 86))	('D537', 'Var', (30, 34))	('homo- or heterotrimer oligomerization', 'MPA', (87, 124))	('SMAD4', 'Gene', '4089', (12, 17))
4887	30268436	Those mutations could have widespread effects, because SMAD4 is a binding partner for all Smad-dependent transcriptional regulation.	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('SMAD4', 'Gene', '4089', (55, 60))	('mutations', 'Var', (6, 15))	('SMAD4', 'Gene', (55, 60))
4888	30268436	Mutation at either R361 or D537 in SMAD4 correlates with metastasis and decreased survival in colon cancer.	('survival', 'CPA', (82, 90))	('colon cancer', 'Disease', (94, 106))	('decreased', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SMAD4', 'Gene', '4089', (35, 40))	('D537', 'Var', (27, 31))	('metastasis', 'CPA', (57, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SMAD4', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
4889	30268436	SMAD2 exhibited 13 truncating mutations at S464 (Figure 3A).	('SMAD2', 'Gene', (0, 5))	('SMAD2', 'Gene', '4087', (0, 5))	('S464', 'Var', (43, 47))
4891	30268436	S464 is necessary for proper positioning of SMAD2 for phosphorylation at S465 and S467, both of which mediate interaction of SMAD2 with SMAD4 and dissociation of SMAD2 from TGFBR1 and the adaptor SARA (encoded by ZFYVE9).	('SARA', 'Gene', '9372', (196, 200))	('interaction', 'Interaction', (110, 121))	('SMAD2', 'Gene', (162, 167))	('SMAD4', 'Gene', '4089', (136, 141))	('SMAD2', 'Gene', (44, 49))	('dissociation', 'MPA', (146, 158))	('TGFBR1', 'Gene', '7046', (173, 179))	('mediate', 'Reg', (102, 109))	('TGFBR1', 'Gene', (173, 179))	('S467', 'Var', (82, 86))	('SARA', 'Gene', (196, 200))	('ZFYVE9', 'Gene', '9372', (213, 219))	('SMAD2', 'Gene', '4087', (125, 130))	('ZFYVE9', 'Gene', (213, 219))	('SMAD4', 'Gene', (136, 141))	('SMAD2', 'Gene', '4087', (162, 167))	('SMAD2', 'Gene', (125, 130))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('SMAD2', 'Gene', '4087', (44, 49))
4892	30268436	Hence, S464 mutations may prevent dissociation of SMAD2 from the receptor-adaptor complex, blocking the downstream signal (Figure 3E).	('SMAD2', 'Gene', (50, 55))	('S464 mutations', 'Var', (7, 21))	('downstream signal', 'MPA', (104, 121))	('blocking', 'NegReg', (91, 99))	('SMAD2', 'Gene', '4087', (50, 55))	('dissociation', 'MPA', (34, 46))	('prevent', 'NegReg', (26, 33))
4893	30268436	Of 176 mutations at hotspot sites across 6 genes, 115 (65%) were in cancers of the GI system (Figure S3): 60 in ESCA, 51 in COAD, 3 in PAAD, and 1 in LIHC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers of the GI system', 'Phenotype', 'HP:0007378', (68, 92))	('PAAD', 'Phenotype', 'HP:0006725', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('COAD', 'Disease', (124, 128))	('cancers of the GI system', 'Disease', 'MESH:D009369', (68, 92))	('cancers of the GI system', 'Disease', (68, 92))	('LIHC', 'Disease', (150, 154))	('ESCA', 'Phenotype', 'HP:0011459', (112, 116))	('LIHC', 'Disease', 'None', (150, 154))	('ESCA', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('mutations', 'Var', (7, 16))
4896	30268436	To determine if GI cancers possess a unique signature of altered TGF-beta pathway activity, we compared changes in the expression of 50 downstream genes related to mutations at hotspot sites (Figure 3B).	('TGF-beta', 'Gene', (65, 73))	('expression', 'MPA', (119, 129))	('GI cancers', 'Disease', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('activity', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (164, 173))	('TGF-beta', 'Gene', '7040', (65, 73))
4898	30268436	Notably, CDH2 exhibited an overall reduction in expression except in the context of the BMP5 hotspot mutation.	('CDH2', 'Gene', (9, 13))	('CDH2', 'Gene', '1000', (9, 13))	('BMP5', 'Gene', (88, 92))	('expression', 'MPA', (48, 58))	('BMP5', 'Gene', '653', (88, 92))	('mutation', 'Var', (101, 109))	('reduction', 'NegReg', (35, 44))
4902	30268436	Guided by the enrichment of hotspot mutations in GI cancers, we tested for enrichment of TGF-beta pathway point mutations in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (49, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('tested', 'Reg', (64, 70))	('point mutations', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGF-beta', 'Gene', '7040', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('GI cancers', 'Disease', (49, 59))	('GI cancers', 'Disease', (125, 135))	('TGF-beta', 'Gene', (89, 97))
4903	30268436	Non-silent mutations were significantly more common in GI cancers (596 of 1,511) than in the non-GI cancers (1,606 of 7,614).	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('common', 'Reg', (45, 51))	('non-GI cancers', 'Disease', 'MESH:D009369', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (55, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('GI cancers', 'Disease', 'MESH:D009369', (97, 107))	('Non-silent mutations', 'Var', (0, 20))	('GI cancers', 'Disease', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-GI cancers', 'Disease', (93, 107))
4904	30268436	Deep deletions and amplifications were also significantly enriched in GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Deep deletions', 'Var', (0, 14))	('GI cancers', 'Disease', (70, 80))	('amplifications', 'Var', (19, 33))
4905	30268436	COAD, READ, and STAD had recurrent aberrations in genes at each level of the pathway (ligands, receptors, and SMADs) and all axes (TGFBR, BMPR, ACVR), whereas PAAD had frequent mutations in only SMAD4 and TGFBR2 (Figure S4A).	('TGFBR', 'Gene', (205, 210))	('COAD', 'Disease', (0, 4))	('SMAD4', 'Gene', '4089', (195, 200))	('aberrations', 'Var', (35, 46))	('TGFBR2', 'Gene', '7048', (205, 211))	('ACV', 'Gene', (144, 147))	('mutations', 'Var', (177, 186))	('BMP', 'Gene', (138, 141))	('TGFBR', 'Gene', '7046;7048;7049', (131, 136))	('TGFBR2', 'Gene', (205, 211))	('SMAD4', 'Gene', (195, 200))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('TGFBR', 'Gene', '7046;7048;7049', (205, 210))	('PAAD', 'Phenotype', 'HP:0006725', (159, 163))	('BMP', 'Gene', '649', (138, 141))	('ACV', 'Gene', '83729', (144, 147))	('TGFBR', 'Gene', (131, 136))
4906	30268436	To compare the TGF-beta pathway transcriptional signatures in GI vs. other cancers, we calculated the target gene expression signatures associated with TGF-beta pathway mutations in both groups (Figure 4A-B).	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('TGF-beta', 'Gene', '7040', (152, 160))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('TGF-beta', 'Gene', '7040', (15, 23))	('cancers', 'Disease', (75, 82))	('TGF-beta', 'Gene', (15, 23))	('TGF-beta', 'Gene', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
4908	30268436	Whereas IL6 mRNA was increased in most non-GI cancers with TGF-beta pathway mutations, IL6 upregulation was significantly greater in GI cancers than non-GI cancers (Figure S4B), and within GI cancers IL6 expression was greater in samples with alterations in the TGF-beta pathway genes than those without alterations in the TGF-beta pathway genes.	('non-GI cancers', 'Disease', (39, 53))	('GI cancers', 'Disease', 'MESH:D009369', (189, 199))	('GI cancers than non-GI cancers', 'Disease', 'MESH:D009369', (133, 163))	('non-GI cancers', 'Disease', 'MESH:D009369', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('IL6', 'molecular_function', 'GO:0005138', ('87', '90'))	('TGF-beta', 'Gene', (323, 331))	('GI cancers', 'Disease', 'MESH:D009369', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('IL6', 'Gene', '3569', (8, 11))	('alterations', 'Var', (243, 254))	('IL6', 'Gene', '3569', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (59, 67))	('increased', 'PosReg', (21, 30))	('non-GI cancers', 'Disease', 'MESH:D009369', (149, 163))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('IL6', 'Gene', '3569', (87, 90))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('IL6', 'Gene', (8, 11))	('TGF-beta', 'Gene', '7040', (262, 270))	('IL6', 'Gene', (200, 203))	('GI cancers than non-GI cancers', 'Disease', (133, 163))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IL6', 'Gene', (87, 90))	('expression', 'MPA', (204, 214))	('GI cancers', 'Disease', (189, 199))	('IL6', 'molecular_function', 'GO:0005138', ('200', '203'))	('greater', 'PosReg', (122, 129))	('TGF-beta', 'Gene', '7040', (323, 331))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (76, 85))	('TGF-beta', 'Gene', (262, 270))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GI cancers', 'Disease', 'MESH:D009369', (133, 143))	('IL6', 'molecular_function', 'GO:0005138', ('8', '11'))	('GI cancer', 'Phenotype', 'HP:0007378', (189, 198))	('TGF-beta', 'Gene', '7040', (59, 67))
4909	30268436	Notably, in non-GI cancers associated with GDF1 mutations, IL6 mRNA expression was markedly decreased, suggesting that GDF1 may play different roles in GI and non-GI cancers.	('non-GI cancers', 'Disease', 'MESH:D009369', (159, 173))	('non-GI cancers', 'Disease', (159, 173))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('IL6', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (48, 57))	('GI cancer', 'Phenotype', 'HP:0007378', (163, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('GDF1', 'Gene', (43, 47))	('non-GI cancers', 'Disease', (12, 26))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('decreased', 'NegReg', (92, 101))	('GDF1', 'Gene', '2657', (43, 47))	('GDF1', 'Gene', (119, 123))	('IL6', 'molecular_function', 'GO:0005138', ('59', '62'))	('IL6', 'Gene', '3569', (59, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GDF1', 'Gene', '2657', (119, 123))
4911	30268436	In GI cancers, most TGF-beta pathway gene mutations were associated with increased FOS expression; exceptions were TGFBRAP1, SMAD7, SMAD5, GDF1, BMP5, and ACVRL1.	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('TGF-beta', 'Gene', (20, 28))	('ACVRL1', 'Gene', (155, 161))	('SMAD7', 'Gene', '4092', (125, 130))	('BMP5', 'Gene', (145, 149))	('BMP5', 'Gene', '653', (145, 149))	('TGFBRAP1', 'Gene', '9392', (115, 123))	('SMAD5', 'Gene', (132, 137))	('GDF1', 'Gene', (139, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (73, 82))	('ACVRL1', 'Gene', '94', (155, 161))	('GDF1', 'Gene', '2657', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SMAD5', 'Gene', '4090', (132, 137))	('FOS', 'Gene', (83, 86))	('SMAD7', 'Gene', (125, 130))	('GI cancers', 'Disease', (3, 13))	('TGF-beta', 'Gene', '7040', (20, 28))	('FOS', 'Gene', '2353', (83, 86))	('TGFBRAP1', 'Gene', (115, 123))	('mutations', 'Var', (42, 51))
4912	30268436	In non-GI cancers, only mutations in TGFBR2 were associated with increased FOS expression; all other TGF-beta pathway gene mutations were associated with decreased FOS expression.	('decreased', 'NegReg', (154, 163))	('increased', 'PosReg', (65, 74))	('FOS', 'Gene', (164, 167))	('TGF-beta', 'Gene', '7040', (101, 109))	('TGFBR2', 'Gene', '7048', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FOS', 'Gene', '2353', (164, 167))	('TGF-beta', 'Gene', (101, 109))	('non-GI cancers', 'Disease', (3, 17))	('FOS', 'Gene', (75, 78))	('TGFBR2', 'Gene', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('mutations', 'Var', (24, 33))	('non-GI cancers', 'Disease', 'MESH:D009369', (3, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (7, 16))	('FOS', 'Gene', '2353', (75, 78))
4913	30268436	To compare the transcriptional output resulting from mutations in GI and non-GI cancers, we calculated differences in expression of the 50 target genes associated with mutations in the 43 genes (Figure 4C).	('non-GI cancers', 'Disease', 'MESH:D009369', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('differences', 'Reg', (103, 114))	('expression', 'MPA', (118, 128))	('non-GI cancers', 'Disease', (73, 87))	('mutations', 'Var', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
4914	30268436	The analysis revealed a shift toward repression of transcriptional output in GI cancers with the most significant shifts occurring with mutations in ACVR2B, INHBA, SMAD3, or GDF2.	('GDF2', 'Gene', (174, 178))	('repression', 'NegReg', (37, 47))	('GI cancers', 'Disease', (77, 87))	('SMAD3', 'Gene', '4088', (164, 169))	('INHBA', 'Gene', '3624', (157, 162))	('ACVR2B', 'Gene', '93', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transcriptional output', 'MPA', (51, 73))	('SMAD3', 'Gene', (164, 169))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('INHBA', 'Gene', (157, 162))	('mutations', 'Var', (136, 145))	('GI cancers', 'Disease', 'MESH:D009369', (77, 87))	('ACVR2B', 'Gene', (149, 155))	('GDF2', 'Gene', '2658', (174, 178))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
4915	30268436	In GI cancers, mutations in GDF1 were associated with significantly increased target gene transcription.	('GDF1', 'Gene', '2657', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (15, 24))	('GDF1', 'Gene', (28, 32))	('target gene transcription', 'MPA', (78, 103))	('GI cancers', 'Disease', (3, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (68, 77))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))
4916	30268436	Mutations in any of the 43 genes were associated with reduced mRNA expression in GI cancers compared with non-GI cancers for most target genes with the largest reductions found for HMGA2 and TERT.	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('GI cancers', 'Disease', (81, 91))	('HMGA2', 'Gene', '8091', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('non-GI cancers', 'Disease', 'MESH:D009369', (106, 120))	('non-GI cancers', 'Disease', (106, 120))	('GI cancers', 'Disease', 'MESH:D009369', (81, 91))	('mRNA expression', 'MPA', (62, 77))	('HMGA2', 'Gene', (181, 186))	('Mutations', 'Var', (0, 9))	('reduced', 'NegReg', (54, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
4917	30268436	Compared to non-GI cancers, GI cancers had fewer genes with increased expression resulting from pathway mutations.	('non-GI cancers', 'Disease', (12, 26))	('mutations', 'Var', (104, 113))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('expression', 'MPA', (70, 80))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GI cancer', 'Phenotype', 'HP:0007378', (28, 37))	('increased', 'PosReg', (60, 69))
4918	30268436	In GI cancers, mutations in any of the 43 genes were associated with a significantly increased expression of FOS, IL6, ZEB2, and ZEB1 compared to expression changes of the same genes resulting from pathway mutations in non-GI cancers.	('IL6', 'molecular_function', 'GO:0005138', ('114', '117'))	('ZEB1', 'Gene', '6935', (129, 133))	('IL6', 'Gene', (114, 117))	('increased', 'PosReg', (85, 94))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('mutations', 'Var', (15, 24))	('non-GI cancers', 'Disease', (219, 233))	('non-GI cancers', 'Disease', 'MESH:D009369', (219, 233))	('FOS', 'Gene', (109, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('GI cancers', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'MPA', (95, 105))	('FOS', 'Gene', '2353', (109, 112))	('ZEB1', 'Gene', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ZEB2', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('IL6', 'Gene', '3569', (114, 117))	('GI cancers', 'Disease', (3, 13))	('ZEB2', 'Gene', '9839', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
4919	30268436	Finally, we probed for associations between transcriptional output and TGF-beta pathway gene alterations for all cancers and the GI and non-GI subsets (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (93, 104))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('probed', 'Reg', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('TGF-beta', 'Gene', '7040', (71, 79))	('TGF-beta', 'Gene', (71, 79))
4922	30268436	To explore TGF-beta signaling pathway variation across the 33 cancers in the PanCancer cohort, we computed a "pathway activity score" based on mRNA expression of the 43 genes.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variation', 'Var', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('signaling pathway', 'biological_process', 'GO:0007165', ('20', '37'))
4944	30268436	We attribute this observation to co-occurring amplifications or deletions of SMAD7 and SMAD2 and co-occurring amplifications of SMAD6 and SMAD3 (Figure 1B).	('amplifications', 'Var', (46, 60))	('SMAD7', 'Gene', (77, 82))	('SMAD6', 'Gene', (128, 133))	('SMAD2', 'Gene', '4087', (87, 92))	('SMAD3', 'Gene', '4088', (138, 143))	('deletions', 'Var', (64, 73))	('SMAD7', 'Gene', '4092', (77, 82))	('SMAD2', 'Gene', (87, 92))	('SMAD3', 'Gene', (138, 143))	('SMAD6', 'Gene', '4091', (128, 133))
4951	30268436	We analyzed the combined impact of TGF-beta target gene expression and the 43 core gene alterations on patient survival across the PanCancer cohort.	('TGF-beta', 'Gene', (35, 43))	('gene expression', 'biological_process', 'GO:0010467', ('51', '66'))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (88, 99))	('core', 'cellular_component', 'GO:0019013', ('78', '82'))	('patient', 'Species', '9606', (103, 110))	('TGF-beta', 'Gene', '7040', (35, 43))
4952	30268436	We compared the survival of patients with 3 different cancer profiles: those with high expression of HMGA2 and alterations in any one of the 43 TGF-beta pathway genes (Figure 6C, High HMGA2/TGF-beta mutant), those with high HMGA2 expression and no alterations in any of the 43 genes (Figure 6C, High HMGA2/TGF-beta wild-type), and those with low expression of HMGA2 without considering alterations in TGF-beta pathway genes (Figure 6C, Low HMGA2 expression).	('TGF-beta', 'Gene', '7040', (306, 314))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('HMGA2', 'Gene', '8091', (360, 365))	('high', 'PosReg', (82, 86))	('HMGA2', 'Gene', '8091', (184, 189))	('HMGA2', 'Gene', '8091', (440, 445))	('HMGA2', 'Gene', (300, 305))	('TGF-beta', 'Gene', (401, 409))	('mutant', 'Var', (199, 205))	('HMGA2', 'Gene', (101, 106))	('TGF-beta', 'Gene', (306, 314))	('HMGA2', 'Gene', '8091', (224, 229))	('TGF-beta', 'Gene', '7040', (144, 152))	('patients', 'Species', '9606', (28, 36))	('TGF-beta', 'Gene', '7040', (190, 198))	('cancer', 'Disease', (54, 60))	('HMGA2', 'Gene', (360, 365))	('HMGA2', 'Gene', '8091', (300, 305))	('HMGA2', 'Gene', '8091', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGF-beta', 'Gene', (144, 152))	('HMGA2', 'Gene', (184, 189))	('HMGA2', 'Gene', (440, 445))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (190, 198))	('TGF-beta', 'Gene', '7040', (401, 409))	('HMGA2', 'Gene', (224, 229))
4956	30268436	We saw the opposite for cancers with downregulated CDH2; the worst outcome was associated with low CDH2 expression and mutations in 43 genes (Figure S6B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'NegReg', (95, 98))	('CDH2', 'Gene', (99, 103))	('CDH2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('expression', 'MPA', (104, 114))	('CDH2', 'Gene', '1000', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('mutations', 'Var', (119, 128))	('CDH2', 'Gene', '1000', (51, 55))	('cancers', 'Disease', (24, 31))
4957	30268436	Thus, the expression profile of specific target genes and alterations in the TGF-beta superfamily genes cooperated to increase tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('increase', 'PosReg', (118, 126))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('TGF-beta', 'Gene', '7040', (77, 85))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('TGF-beta', 'Gene', (77, 85))	('alterations', 'Var', (58, 69))
4959	30268436	Because of the association of collagen overexpression and alterations in TGF-beta pathway genes with poor survival, we hypothesize that altered signaling through the TGF-beta superfamily pathways remodels the extracellular matrix to drive metastasis in multiple cancer contexts.	('cancer', 'Disease', (262, 268))	('overexpression', 'PosReg', (39, 53))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', '7040', (166, 174))	('TGF-beta', 'Gene', (73, 81))	('remodels', 'Reg', (196, 204))	('collagen', 'molecular_function', 'GO:0005202', ('30', '38'))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('209', '229'))	('drive', 'PosReg', (233, 238))	('TGF-beta', 'Gene', (166, 174))	('metastasis', 'CPA', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('alterations', 'Var', (58, 69))
4961	30268436	In the GI cohort, only ZEB2 combined with TGF-beta pathway gene alteration yielded a significant difference, with low ZEB2 expression corresponding to a survival benefit.	('ZEB2', 'Gene', '9839', (23, 27))	('ZEB2', 'Gene', (118, 122))	('TGF-beta', 'Gene', (42, 50))	('expression', 'MPA', (123, 133))	('ZEB2', 'Gene', (23, 27))	('alteration', 'Var', (64, 74))	('benefit', 'PosReg', (162, 169))	('low', 'NegReg', (114, 117))	('TGF-beta', 'Gene', '7040', (42, 50))	('ZEB2', 'Gene', '9839', (118, 122))
4962	30268436	In non-GI patients, high expression of the TGF-beta pathway target genes IL6, HMGA2, ZEB2, and FOS was associated with reduced survival particularly when combined with TGF-beta pathway mutations.	('TGF-beta', 'Gene', '7040', (43, 51))	('HMGA2', 'Gene', (78, 83))	('IL6', 'Gene', '3569', (73, 76))	('FOS', 'Gene', (95, 98))	('FOS', 'Gene', '2353', (95, 98))	('expression', 'MPA', (25, 35))	('ZEB2', 'Gene', (85, 89))	('TGF-beta', 'Gene', (43, 51))	('IL6', 'Gene', (73, 76))	('survival', 'MPA', (127, 135))	('reduced', 'NegReg', (119, 126))	('TGF-beta', 'Gene', '7040', (168, 176))	('IL6', 'molecular_function', 'GO:0005138', ('73', '76'))	('HMGA2', 'Gene', '8091', (78, 83))	('ZEB2', 'Gene', '9839', (85, 89))	('patients', 'Species', '9606', (10, 18))	('TGF-beta', 'Gene', (168, 176))	('high', 'PosReg', (20, 24))	('mutations', 'Var', (185, 194))
4963	30268436	Thus, although TGF-beta pathway mutations may not occur as commonly in non-GI cancers, they may be important contributors to mortality.	('non-GI cancers', 'Disease', (71, 85))	('non-GI cancers', 'Disease', 'MESH:D009369', (71, 85))	('contributors', 'Reg', (109, 121))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('mutations', 'Var', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
4981	30268436	We also identified BMPR2 and TGFBR2 as genes with hotspot sites of mutations that were common in STAD and COAD.	('COAD', 'Disease', (106, 110))	('STAD', 'Disease', (97, 101))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('mutations', 'Var', (67, 76))	('TGFBR2', 'Gene', (29, 35))	('BMPR2', 'Gene', (19, 24))	('BMPR2', 'Gene', '659', (19, 24))	('TGFBR2', 'Gene', '7048', (29, 35))
4982	30268436	The cancers with high frequencies of hotspot mutations in those two genes did not have high expression of miRNA 92a-3p, suggesting that there is little selective pressure for both mutation and downregulation by that miRNA.	('downregulation', 'NegReg', (193, 207))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
4983	30268436	To examine the contribution of mutations, amplifications, deletions, DNA methylation and miRNAs to the pathway activity score across tumor types, we computed Pearson's correlations between the pathway activity score and (i) levels of DNA methylation or miRNA expression and (ii) percentages of mutations or CNVs in each tumor type and plotted the results in order of increasing pathway activity score (Figure 7F).	('miR', 'Gene', '220972', (253, 256))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('miR', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CNVs', 'Var', (307, 311))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (133, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('234', '249'))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('DNA', 'cellular_component', 'GO:0005574', ('234', '237'))	('mutations', 'Var', (294, 303))
4986	30268436	Amplifications positively correlated with activity score and played a dominant role in UCS, SARC, ESCA, CHOL, and OV.	('activity score', 'MPA', (42, 56))	('CHOL', 'CellLine', 'None', (104, 108))	('CHOL', 'Disease', (104, 108))	('Amplifications', 'Var', (0, 14))	('correlated', 'Reg', (26, 36))	('UCS', 'Disease', (87, 90))	('OV', 'Phenotype', 'HP:0100615', (114, 116))	('ESCA', 'Phenotype', 'HP:0011459', (98, 102))	('SARC', 'Disease', (92, 96))	('ESCA', 'Disease', (98, 102))
4990	30268436	Some of the key findings of the study were that (i) 39% of the cancers carried TGF-beta pathway gene alterations; (ii) the genomic alterations appeared to affect expression of metastatic and EMT genes; (iii) six hotspot mutations were identified in six genes; (iv) the pathway was most frequently aberrant in GI cancers, which exhibited 115 of the 176 hotspot mutations identified; (iv) high expression of downstream target genes coupled with mutations in the TGF-beta pathway genes was associated with poor outcome, suggesting a net tumor-promoting role of the superfamily across the PanCancer cohort; (v) apparent gene silencing by DNA methylation and deletion of TGF-beta pathway genes were observed most frequently in DLBC, whereas miRNA silencing was seen most often in LAML.	('gene silencing', 'NegReg', (616, 630))	('gene silencing', 'biological_process', 'GO:0016458', ('616', '630'))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('GI cancers', 'Disease', (309, 319))	('tumor', 'Disease', (534, 539))	('miR', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('DLBC', 'Disease', (722, 726))	('DNA methylation', 'biological_process', 'GO:0006306', ('634', '649'))	('TGF-beta', 'Gene', '7040', (666, 674))	('TGF-beta', 'Gene', '7040', (460, 468))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('DNA', 'cellular_component', 'GO:0005574', ('634', '637'))	('GI cancers', 'Disease', 'MESH:D009369', (309, 319))	('TGF-beta', 'Gene', '7040', (79, 87))	('cancers', 'Disease', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (638, 649))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('TGF-beta', 'Gene', (666, 674))	('TGF-beta', 'Gene', (79, 87))	('TGF-beta', 'Gene', (460, 468))	('GI cancer', 'Phenotype', 'HP:0007378', (309, 318))	('deletion', 'Var', (654, 662))	('EMT', 'biological_process', 'GO:0001837', ('191', '194'))	('DNA methylation', 'Var', (634, 649))	('miR', 'Gene', '220972', (736, 739))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
4992	30268436	Although 39% of the cancers had genomic alterations in at least one of the TGF-beta pathway genes, GI cancers were particularly enriched for them.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('genomic alterations', 'Var', (32, 51))	('TGF-beta', 'Gene', '7040', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TGF-beta', 'Gene', (75, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('cancers', 'Disease', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
4993	30268436	GI cancers were most influenced by recurrent hotspot mutations in 6 genes, SMAD4, SMAD2, BMPR2, BMP5, TGFBR2, and ACVR2A.	('BMP5', 'Gene', (96, 100))	('SMAD2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('BMP5', 'Gene', '653', (96, 100))	('BMPR2', 'Gene', (89, 94))	('GI cancers', 'Disease', (0, 10))	('SMAD4', 'Gene', (75, 80))	('TGFBR2', 'Gene', '7048', (102, 108))	('mutations', 'Var', (53, 62))	('hotspot', 'PosReg', (45, 52))	('ACVR2A', 'Gene', '92', (114, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('influenced', 'Reg', (21, 31))	('GI cancers', 'Disease', 'MESH:D009369', (0, 10))	('BMPR2', 'Gene', '659', (89, 94))	('ACVR2A', 'Gene', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('SMAD4', 'Gene', '4089', (75, 80))	('SMAD2', 'Gene', '4087', (82, 87))	('TGFBR2', 'Gene', (102, 108))
4994	30268436	The hotspot mutations in BMP5 and TGFBR2 had not been identified previously, and their function in GI cancer should be explored.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancer', 'Disease', (99, 108))	('mutations', 'Var', (12, 21))	('TGFBR2', 'Gene', '7048', (34, 40))	('GI cancer', 'Disease', 'MESH:D009369', (99, 108))	('BMP5', 'Gene', (25, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('TGFBR2', 'Gene', (34, 40))	('BMP5', 'Gene', '653', (25, 29))
5014	30268436	We selected the list of core TGF-beta superfamily genes used in the paper by searching for the keyword "TGF-beta" in 4 databases: (i) BIOCARTA_TGFB_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/BIOCARTA_TGFB_PATHWAY), (ii) KEGG_TGF_BETA_SIGNALING_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/KEGG_TGF_BETA_SIGNALING_PATHWAY), (iii) GO_0007179 full gene set from BioMart, and (iv) subset of GO_0007179 (filtered by "experimental evidence") from AmiGo.	('core', 'cellular_component', 'GO:0019013', ('24', '28'))	('SIGNALING_PATHWAY', 'biological_process', 'GO:0007165', ('261', '278'))	('AmiGo', 'Gene', '57463', (497, 502))	('TGF-beta', 'Gene', (104, 112))	('AmiGo', 'Gene', (497, 502))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('SIGNALING_PATHWAY', 'biological_process', 'GO:0007165', ('357', '374'))	('TGF-beta', 'Gene', '7040', (104, 112))	('GO_0007179', 'Var', (385, 395))
5015	30268436	(ii) We then performed extensive literature searches and kept only those genes that satisfied any of the following conditions: (a) the gene had previously been implicated in cancer, or (b) the gene was involved in direct binding to and regulation of Smad function, or (c) the gene was phenotypically associated with the TGF-beta superfamily, where mutations or deletions of the gene had resulted in phenotypes similar to those from loss of function of the TGF-beta superfamily pathways.	('TGF-beta', 'Gene', '7040', (320, 328))	('binding', 'molecular_function', 'GO:0005488', ('221', '228'))	('TGF-beta', 'Gene', (456, 464))	('mutations', 'Var', (348, 357))	('implicated', 'Reg', (160, 170))	('TGF-beta', 'Gene', (320, 328))	('involved', 'Reg', (202, 210))	('associated', 'Reg', (300, 310))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resulted', 'Reg', (387, 395))	('binding', 'Interaction', (221, 228))	('deletions', 'Var', (361, 370))	('TGF-beta', 'Gene', '7040', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('regulation', 'biological_process', 'GO:0065007', ('236', '246'))
5032	30268436	Copy-number alterations (CNA) were assessed as deviations in the tumor sample from the paired normal tissue sample, so they only reflected somatic changes.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Copy-number alterations', 'Var', (0, 23))
5040	30268436	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('false', 'biological_process', 'GO:0071878', ('157', '162'))	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('false', 'biological_process', 'GO:0071877', ('157', '162'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
5043	30268436	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient- matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('cga', 'Gene', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('deletion', 'Var', (237, 245))	('rearrangement', 'Var', (262, 275))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('mutation calling', 'Var', (199, 215))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('small insertion', 'Var', (217, 232))
5046	30268436	Each oncoprint visualizes and quantifies the somatic mutation and copy number events in 9,125 patients with 33 cancer types for each gene family in the pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (66, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
5047	30268436	The hotspot mutations are extracted from MC3 MAF file first programmatically for any hotspot site with more than nine counts and validated through a systematic mining in the cBioPortal.	('MC3', 'Gene', '4159', (41, 44))	('mutations', 'Var', (12, 21))	('MAF', 'Gene', '4094', (45, 48))	('MAF', 'Gene', (45, 48))	('MC3', 'Gene', (41, 44))
5048	30268436	For ACVR2A and SMAD4 hotspot mutations are mapped onto the respective protein structures (pdb IDs: 4ASX for ACVR2A and 1DD1 for SMAD4) using the UCSF chimera software.	('SMAD4', 'Gene', (15, 20))	('ACVR2A', 'Gene', (108, 114))	('ACVR2A and 1DD1', 'Gene', '92', (108, 123))	('SMAD4', 'Gene', (128, 133))	('ACVR2A', 'Gene', '92', (4, 10))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('mutations', 'Var', (29, 38))	('ACVR2A', 'Gene', '92', (108, 114))	('SMAD4', 'Gene', '4089', (15, 20))	('SMAD4', 'Gene', '4089', (128, 133))	('ACVR2A', 'Gene', (4, 10))
5058	30268436	Tumor types for which few tumors have been profiled and that have infrequently occurring copy number alterations, GISTIC may fail to identify rare but important somatic events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number alterations', 'Var', (89, 112))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
5059	30268436	As more copy number profiles become available through large-scale tumor sequencing efforts, the ability to detect these rare but significant events will increase.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number', 'Var', (8, 19))
5061	30268436	The genomic alteration frequencies for copy number gains or losses and mutations are extracted from the cBioPortal and programmatically form the MC3 MAF file.	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('MAF', 'Gene', '4094', (149, 152))	('losses', 'NegReg', (60, 66))	('mutations', 'Var', (71, 80))	('MAF', 'Gene', (149, 152))	('copy number gains', 'Var', (39, 56))
5063	30268436	The samples with alterations in each core gene and wild type for all TGF-beta pathway genes are extracted from the MC3 MAF file.	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('TGF-beta', 'Gene', (69, 77))	('core', 'cellular_component', 'GO:0019013', ('37', '41'))	('MC3', 'Gene', '4159', (115, 118))	('MC3', 'Gene', (115, 118))	('TGF-beta', 'Gene', '7040', (69, 77))	('alterations', 'Var', (17, 28))
5064	30268436	The median fold change of transcriptional changes are calculated as the ratio of expression of downstream genes among all core pathway gene mutated, amplified and deleted samples to expression levels in TGF-beta pathway wild type samples.	('TGF-beta', 'Gene', (203, 211))	('core', 'cellular_component', 'GO:0019013', ('122', '126'))	('deleted', 'Var', (163, 170))	('TGF-beta', 'Gene', '7040', (203, 211))	('expression', 'MPA', (81, 91))	('mutated', 'Var', (140, 147))
5068	30268436	The enrichment of genomic TGF-beta pathway genomic alterations in the GI cancers was statistically assessed using a one tailed Fisher's exact test, where the null hypothesis was the odds ratio of alterations in GI vs other cancers was not greater than 1.	('cancers', 'Disease', (223, 230))	('cancers', 'Disease', (73, 80))	('alterations', 'Var', (51, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('TGF-beta', 'Gene', '7040', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('TGF-beta', 'Gene', (26, 34))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
5069	30268436	The transcriptional outcome of GI cancers with TGF-beta pathway disruptions were quantified using the same method and downstream target gene list as we did in the analysis of transcriptional output from all cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GI cancer', 'Phenotype', 'HP:0007378', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('GI cancers', 'Disease', 'MESH:D009369', (31, 41))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('disruptions', 'Var', (64, 75))	('TGF-beta', 'Gene', '7040', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TGF-beta', 'Gene', (47, 55))	('cancers', 'Disease', (34, 41))	('GI cancers', 'Disease', (31, 41))
5093	30268436	We particularly focused on mRNA expression distribution of HMGA2, MMP9, collagens (COL1A1, COL1A2, COL3A1), TERT, FOXP3, CDH2 as the expression of these genes varied significantly between TGF-beta pathway mutated vs. wild type samples.	('mutated', 'Var', (205, 212))	('COL1A2', 'Gene', '1278', (91, 97))	('TERT', 'Gene', (108, 112))	('varied', 'Reg', (159, 165))	('TERT', 'Gene', '7015', (108, 112))	('CDH2', 'Gene', (121, 125))	('MMP9', 'molecular_function', 'GO:0004229', ('66', '70'))	('FOXP3', 'Gene', (114, 119))	('HMGA2', 'Gene', (59, 64))	('COL1A2', 'Gene', (91, 97))	('COL1A1', 'Gene', '1277', (83, 89))	('CDH2', 'Gene', '1000', (121, 125))	('COL3A1', 'Gene', '1281', (99, 105))	('TGF-beta', 'Gene', '7040', (188, 196))	('FOXP3', 'Gene', '50943', (114, 119))	('COL1A1', 'Gene', (83, 89))	('expression', 'MPA', (133, 143))	('MMP9', 'Gene', (66, 70))	('HMGA2', 'Gene', '8091', (59, 64))	('MMP9', 'Gene', '4318', (66, 70))	('TGF-beta', 'Gene', (188, 196))	('COL3A1', 'Gene', (99, 105))
5095	30268436	The resulting thresholds divided the cohorts into three groups as TGF-beta expression, TGF-beta mutant/high target expression, TGF-beta wt/high target expression and low target gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('177', '192'))	('TGF-beta', 'Gene', (87, 95))	('TGF-beta', 'Gene', (66, 74))	('TGF-beta', 'Gene', '7040', (127, 135))	('mutant/high', 'Var', (96, 107))	('TGF-beta', 'Gene', '7040', (87, 95))	('TGF-beta', 'Gene', (127, 135))	('TGF-beta', 'Gene', '7040', (66, 74))
5096	30268436	We merged the TGF-beta mutant/low target expression and TGF-beta wt/low expression cohorts as discriminating between these sets do not inform on the combined effect of TGF-beta mutations and target expression.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (56, 64))	('TGF-beta', 'Gene', (14, 22))	('mutant/low', 'Var', (23, 33))	('mutant/low', 'NegReg', (23, 33))	('TGF-beta', 'Gene', (56, 64))	('TGF-beta', 'Gene', '7040', (14, 22))	('TGF-beta', 'Gene', '7040', (168, 176))
5112	30459941	Mucosal melanomas may harbor activating KIT mutations and other potentially targetable mutations, and therefore targeted treatments may be an option for selected patients.	('patients', 'Species', '9606', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('KIT', 'Gene', (40, 43))	('KIT', 'molecular_function', 'GO:0005020', ('40', '43'))	('mutations', 'Var', (44, 53))	('activating', 'PosReg', (29, 39))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
5155	30459941	A targetable driver mutation in codon V600 of the BRAF gene, which encodes the B-raf protein (a member of the Raf kinase family of growth signal protein transduction kinases), occurs in approximately 50% of cutaneous melanomas.	('BRAF', 'Gene', (50, 54))	('mutation in', 'Var', (20, 31))	('raf', 'Gene', '22882', (81, 84))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('Raf', 'Gene', '22882', (110, 113))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (207, 226))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('cutaneous melanomas', 'Disease', (207, 226))	('occurs', 'Reg', (176, 182))	('raf', 'Gene', (81, 84))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (207, 226))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (207, 225))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('Raf', 'Gene', (110, 113))	('BRAF', 'Gene', '673', (50, 54))	('melanomas', 'Phenotype', 'HP:0002861', (217, 226))	('transduction', 'biological_process', 'GO:0009293', ('153', '165'))
5159	30459941	In addition, a higher proportion of mutations observed in the BRAF gene in mucosal melanoma affects regions of the BRAF gene other than codon 600, or are nonactivating mutations and therefore are not predicted to respond to targeted BRAF inhibition.	('BRAF', 'Gene', '673', (115, 119))	('mucosal melanoma', 'Disease', (75, 91))	('mucosal melanoma', 'Disease', 'MESH:D008545', (75, 91))	('BRAF', 'Gene', (115, 119))	('affects', 'Reg', (92, 99))	('mutations', 'Var', (36, 45))	('BRAF', 'Gene', (233, 237))	('BRAF', 'Gene', '673', (233, 237))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
5160	30459941	Despite the low incidence of targetable V600 mutations in mucosal melanoma, it is essential that BRAF mutation testing is carried out in all cases of mucosal melanoma due to the existence of an effective and licensed treatment option for a very small subset of patients (see Targeted treatment).	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mucosal melanoma', 'Disease', (58, 74))	('V600 mutations', 'Var', (40, 54))	('mucosal melanoma', 'Disease', 'MESH:D008545', (58, 74))	('mucosal melanoma', 'Disease', (150, 166))	('patients', 'Species', '9606', (261, 269))	('BRAF', 'Gene', '673', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('BRAF', 'Gene', (97, 101))	('mucosal melanoma', 'Disease', 'MESH:D008545', (150, 166))
5161	30459941	Mutations in KIT, which encodes a transmembrane receptor tyrosine kinase, can be identified in 7-17% of all patients with mucosal melanoma but may occur as frequently as one in three patients with vulvovaginal melanoma.	('mucosal melanoma', 'Disease', (122, 138))	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (197, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('mucosal melanoma', 'Disease', 'MESH:D008545', (122, 138))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('vulvovaginal melanoma', 'Disease', (197, 218))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (197, 218))	('patients', 'Species', '9606', (108, 116))	('KIT', 'Gene', (13, 16))	('identified', 'Reg', (81, 91))	('transmembrane', 'cellular_component', 'GO:0044214', ('34', '47'))	('transmembrane', 'cellular_component', 'GO:0016021', ('34', '47'))	('patients', 'Species', '9606', (183, 191))
5162	30459941	The specific mutation identified can predict tumor response to targeted inhibition and KIT is already an established therapeutic target in other cancers, for example, gastrointestinal stromal tumors (GIST).	('cancers', 'Disease', (145, 152))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (167, 198))	('tumor', 'Disease', (192, 197))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (167, 198))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('mutation', 'Var', (13, 21))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastrointestinal stromal tumors', 'Disease', (167, 198))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('predict', 'Reg', (37, 44))	('GIST', 'Phenotype', 'HP:0100723', (200, 204))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
5163	30459941	Identification of a potentially targetable activating mutation in KIT in a patient with melanoma may facilitate entry into relevant clinical trials or permit consideration of palliative treatment with a KIT inhibitor, such as imatinib, in the metastatic setting (see Targeted treatment).	('KIT', 'Gene', (66, 69))	('mutation', 'Var', (54, 62))	('KIT', 'molecular_function', 'GO:0005020', ('203', '206'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('facilitate', 'PosReg', (101, 111))	('KIT', 'molecular_function', 'GO:0005020', ('66', '69'))	('activating', 'PosReg', (43, 53))	('imatinib', 'Chemical', 'MESH:D000068877', (226, 234))	('patient', 'Species', '9606', (75, 82))
5165	30459941	Unfortunately, errors in the KIT gene in mucosal melanoma are heterogeneous, dispersed across multiple exons, and included mutations and amplifications.	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('mucosal melanoma', 'Disease', (41, 57))	('mucosal melanoma', 'Disease', 'MESH:D008545', (41, 57))	('KIT', 'Gene', (29, 32))	('errors', 'Var', (15, 21))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
5166	30459941	The majority of melanomas contain potentially actionable genetic mutations and this offers scope for broadening targeted treatment in the future.	('genetic mutations', 'Var', (57, 74))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('melanomas', 'Disease', 'MESH:D008545', (16, 25))	('melanomas', 'Disease', (16, 25))
5167	30459941	Molecular analysis for mutations in other genes known to be mutated in melanoma is recommended if a patient with mucosal melanoma is being considered for a clinical trial.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('mucosal melanoma', 'Disease', 'MESH:D008545', (113, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('patient', 'Species', '9606', (100, 107))	('mutations', 'Var', (23, 32))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('mucosal melanoma', 'Disease', (113, 129))
5204	30459941	Alternatively it has been hypothesized that response to immunotherapy correlates with the number of mutations in a tumor and therefore the antigen load.	('mutations', 'Var', (100, 109))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))
5210	30459941	They did, however, find that their samples had nearly four-times as many structural variants as seen in cutaneous melanoma, such as chromosomal aberrations and copy number alterations.	('chromosomal aberrations', 'Disease', 'MESH:D002869', (132, 155))	('cutaneous melanoma', 'Disease', (104, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (132, 155))	('copy number alterations', 'Var', (160, 183))	('chromosomal aberrations', 'Disease', (132, 155))
5212	30459941	One Chinese study of pathological analysis of 82 cases of oral mucosal melanoma found that the presence of TILs was associated with a lower risk of distant metastases.	('lower', 'NegReg', (134, 139))	('metastases', 'Disease', (156, 166))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('presence', 'Var', (95, 103))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (58, 79))	('oral mucosal melanoma', 'Disease', (58, 79))
5219	30459941	Nearly half of cutaneous melanomas harbor activating BRAF mutations and therefore can be treated with BRAF kinase inhibitors such as dabrafenib (150 mg twice daily), often in combination with an MEK inhibitor, such as trametinib (2 mg once daily).	('cutaneous melanomas', 'Disease', (15, 34))	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', '673', (53, 57))	('MEK', 'Gene', (195, 198))	('BRAF', 'Gene', '673', (102, 106))	('MEK', 'Gene', '5609', (195, 198))	('activating', 'PosReg', (42, 52))	('BRAF', 'Gene', (53, 57))	('dabrafenib', 'Chemical', 'MESH:C561627', (133, 143))	('BRAF', 'Gene', (102, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (15, 34))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (15, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))	('trametinib', 'Chemical', 'MESH:C560077', (218, 228))
5222	30459941	Mucosal melanomas rarely have mutations in BRAF and therefore this is not usually an option for these patients.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('BRAF', 'Gene', '673', (43, 47))	('patients', 'Species', '9606', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('BRAF', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
5223	30459941	However, all mucosal melanoma patients should be tested for BRAF mutations and if an activating BRAF mutation is found in a patient with mucosal melanoma, then the combination of a BRAF and an MEK inhibitor should be considered.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mucosal melanoma', 'Disease', 'MESH:D008545', (137, 153))	('mucosal melanoma', 'Disease', (137, 153))	('BRAF', 'Gene', (181, 185))	('patients', 'Species', '9606', (30, 38))	('BRAF', 'Gene', '673', (181, 185))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('MEK', 'Gene', '5609', (193, 196))	('activating', 'PosReg', (85, 95))	('patient', 'Species', '9606', (30, 37))	('mucosal melanoma', 'Disease', 'MESH:D008545', (13, 29))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('patient', 'Species', '9606', (124, 131))	('MEK', 'Gene', (193, 196))	('mucosal melanoma', 'Disease', (13, 29))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('mutation', 'Var', (101, 109))	('mutations', 'Var', (65, 74))
5224	30459941	Mucosal melanomas do sometimes have activating mutations in KIT and therefore tyrosine kinase inhibitors, such as imatinib and dasatinib, targeting the aberrant protein gene product have been trialed with some positive results.	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('imatinib', 'Chemical', 'MESH:D000068877', (114, 122))	('dasatinib', 'Chemical', 'MESH:D000069439', (127, 136))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('mutations', 'Var', (47, 56))	('KIT', 'Gene', (60, 63))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))	('activating', 'MPA', (36, 46))
5225	30459941	While KIT testing is not currently routinely available in all centers across the UK, mutation analysis is advised in mucosal melanoma, as a small minority of patients will have targetable mutations and may potentially benefit from treatment, ideally within the context of a clinical trial.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('benefit', 'Reg', (218, 225))	('mucosal melanoma', 'Disease', (117, 133))	('mucosal melanoma', 'Disease', 'MESH:D008545', (117, 133))	('KIT', 'molecular_function', 'GO:0005020', ('6', '9'))	('mutations', 'Var', (188, 197))	('patients', 'Species', '9606', (158, 166))
5226	30459941	A Phase II trial of imatinib in 24 patients with either KIT-mutated or KIT-amplified tumors in mucosal, acral or chronically sun-damaged melanoma found that it was effective in patients with KIT-mutated tumors, but not in those where the gene was amplified only.	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('patients', 'Species', '9606', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('imatinib', 'Chemical', 'MESH:D000068877', (20, 28))	('tumors', 'Disease', (85, 91))	('sun-damaged', 'Phenotype', 'HP:0000992', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('KIT-amplified', 'Gene', (71, 84))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('KIT-mutated', 'Var', (191, 202))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))
5227	30459941	Of 13 patients with KIT mutations, seven (54%) had a partial response.	('mutations', 'Var', (24, 33))	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('KIT', 'Gene', (20, 23))	('patients', 'Species', '9606', (6, 14))
5230	30459941	Another trial of imatinib in the same melanoma subtypes in patients with KIT mutations or amplifications treated 25 patients.	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma subtypes', 'Disease', (38, 55))	('patients', 'Species', '9606', (116, 124))	('melanoma subtypes', 'Disease', 'MESH:D008545', (38, 55))	('amplifications', 'Var', (90, 104))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (59, 67))	('KIT', 'molecular_function', 'GO:0005020', ('73', '76'))	('imatinib', 'Chemical', 'MESH:D000068877', (17, 25))
5234	30459941	A trial of dasatinib, intended specifically to target mutations in exon 11, as first-line treatment in mucosal melanomas with KIT mutations gave disappointing results, with response rates of 18.2% and no difference in outcomes between patients with exon 11 KIT mutation than with alternative mutations.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('KIT', 'molecular_function', 'GO:0005020', ('257', '260'))	('patients', 'Species', '9606', (235, 243))	('mutations', 'Var', (54, 63))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('mucosal melanomas', 'Disease', (103, 120))	('mutations', 'Var', (130, 139))	('dasatinib', 'Chemical', 'MESH:D000069439', (11, 20))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('mucosal melanomas', 'Disease', 'MESH:D008545', (103, 120))	('KIT', 'Gene', (257, 260))	('exon 11', 'Var', (249, 256))
5235	30459941	The authors concluded that imatinib should remain the first-choice treatment option for patients with a KIT mutation.	('KIT', 'Gene', (104, 107))	('patients', 'Species', '9606', (88, 96))	('mutation', 'Var', (108, 116))	('imatinib', 'Chemical', 'MESH:D000068877', (27, 35))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))
5236	30459941	In a Phase II trial, patients with all types of melanomas with KIT mutations or amplifications, who had progressed on previous KIT inhibitor therapy, were given second-line nilotinib.	('KIT', 'molecular_function', 'GO:0005020', ('127', '130'))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanomas', 'Disease', (48, 57))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (21, 29))	('nilotinib', 'Chemical', 'MESH:C498826', (173, 182))	('amplifications', 'Var', (80, 94))	('KIT', 'Gene', (63, 66))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
5238	30459941	Unfortunately, targeted treatment for KIT-mutated mucosal melanoma does not offer the clinical reliability observed with BRAF-targeted therapy in cutaneous melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (50, 66))	('BRAF', 'Gene', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('KIT', 'molecular_function', 'GO:0005020', ('38', '41'))	('KIT-mutated', 'Var', (38, 49))	('cutaneous melanoma', 'Disease', (146, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 164))	('mucosal melanoma', 'Disease', (50, 66))	('BRAF', 'Gene', '673', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
5239	30459941	Within the context of clinical trials, activating mutations or amplifications in exons 11 and 13 of the KIT gene have most frequently been associated with durable clinical benefit from KIT inhibitors while other patients have derived no clinical benefit.	('KIT', 'Gene', (104, 107))	('KIT', 'molecular_function', 'GO:0005020', ('185', '188'))	('benefit', 'PosReg', (172, 179))	('KIT inhibitors', 'MPA', (185, 199))	('patients', 'Species', '9606', (212, 220))	('activating mutations', 'Var', (39, 59))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('amplifications in exons', 'Var', (63, 86))
5241	30459941	there was a co-existing NRAS mutation at the start of treatment and all of these patients progressed on imatinib.	('NRAS', 'Gene', '4893', (24, 28))	('mutation', 'Var', (29, 37))	('imatinib', 'Chemical', 'MESH:D000068877', (104, 112))	('patients', 'Species', '9606', (81, 89))	('NRAS', 'Gene', (24, 28))	('progressed', 'PosReg', (90, 100))
5243	30459941	noted that all six responses to KIT inhibition occurred in tumors with L576P or K642E mutations.	('L576P', 'Var', (71, 76))	('inhibition', 'NegReg', (36, 46))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('L576P', 'Mutation', 'rs121913513', (71, 76))	('K642E', 'Var', (80, 85))	('K642E', 'Mutation', 'rs121913512', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
5244	30459941	There were also patients in this study with the V654A and D820Y mutations, known to confer resistance to imatinib in GIST, and these patients both progressed on imatinib.	('D820Y', 'Var', (58, 63))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (133, 141))	('D820Y', 'Mutation', 'rs1057519710', (58, 63))	('imatinib', 'Chemical', 'MESH:D000068877', (105, 113))	('progressed', 'PosReg', (147, 157))	('GIST', 'Phenotype', 'HP:0100723', (117, 121))	('imatinib', 'Chemical', 'MESH:D000068877', (161, 169))	('V654A', 'Var', (48, 53))	('V654A', 'Mutation', 'rs121913523', (48, 53))
5246	30459941	NRAS mutations have been found in 15-20% of melanomas, and this is fairly consistent across all melanoma subtypes, including mucosal.	('melanomas', 'Disease', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma subtypes', 'Disease', (96, 113))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('melanoma subtypes', 'Disease', 'MESH:D008545', (96, 113))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('found', 'Reg', (25, 30))	('NRAS', 'Gene', '4893', (0, 4))
5247	30459941	NRAS mutations are associated with a poor prognosis and are a potential cause of BRAF inhibitor resistance when BRAF is mutated as well.	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', (81, 85))	('cause', 'Reg', (72, 77))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
5249	30459941	MEK inhibitors, which affect the MAPK pathway, may be effective in patients with NRAS mutations and trials combining these with other agents are also ongoing.	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (67, 75))	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('NRAS', 'Gene', (81, 85))	('MAPK pathway', 'Pathway', (33, 45))	('NRAS', 'Gene', '4893', (81, 85))
5270	30459941	Nivolumab was associated with a significant improvement in 1-year recurrence-free survival of 70.5%, compared with 60.8% with ipilimumab.	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('improvement', 'PosReg', (44, 55))	('ipilimumab', 'Chemical', 'MESH:D000074324', (126, 136))	('Nivolumab', 'Var', (0, 9))	('recurrence-free survival', 'CPA', (66, 90))
5277	30459941	Patients who have undergone resection of a GIST tumor harboring a mutation in the KIT gene may be offered imatinib in the adjuvant setting and this does significantly reduce recurrence rates.	('GIST', 'Phenotype', 'HP:0100723', (43, 47))	('GIST tumor', 'Disease', 'MESH:D046152', (43, 53))	('reduce', 'NegReg', (167, 173))	('imatinib', 'Chemical', 'MESH:D000068877', (106, 114))	('Patients', 'Species', '9606', (0, 8))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('mutation', 'Var', (66, 74))	('KIT', 'Gene', (82, 85))	('recurrence rates', 'MPA', (174, 190))	('GIST tumor', 'Disease', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
5278	30459941	Given similar mutations can be identified in up to a third of patients with mucosal melanoma, adjuvant use of KIT inhibitors may offer potential for modifying the course of the disease.	('mutations', 'Var', (14, 23))	('modifying', 'Reg', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('mucosal melanoma', 'Disease', (76, 92))	('patients', 'Species', '9606', (62, 70))	('mucosal melanoma', 'Disease', 'MESH:D008545', (76, 92))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))
5281	30459941	2017 saw the publication of a randomized, double-blind, placebo-controlled trial of adjuvant dabrafenib 150 mg twice daily with trametinib 2 mg once daily in 870 patients with resected stage III cutaneous melanoma possessing a BRAF V600E or V600K mutation.	('V600K', 'Var', (241, 246))	('patients', 'Species', '9606', (162, 170))	('dabrafenib', 'Chemical', 'MESH:C561627', (93, 103))	('V600E', 'Mutation', 'rs113488022', (232, 237))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('V600K', 'Mutation', 'rs121913227', (241, 246))	('V600E', 'Var', (232, 237))	('trametinib', 'Chemical', 'MESH:C560077', (128, 138))	('BRAF', 'Gene', '673', (227, 231))	('cutaneous melanoma', 'Disease', (195, 213))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (195, 213))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (195, 213))	('BRAF', 'Gene', (227, 231))
5283	30459941	Extrapolation of these results to the very small minority of patients with mucosal melanoma harboring the same activating mutations offers future potential for modifying the course of their disease, a possibility of critical clinical significance given their greater risk of death from metastatic disease.	('mucosal melanoma', 'Disease', (75, 91))	('mucosal melanoma', 'Disease', 'MESH:D008545', (75, 91))	('modifying', 'Reg', (160, 169))	('patients', 'Species', '9606', (61, 69))	('mutations', 'Var', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
5318	26334521	Various host factors that may increase the risk of uveal melanoma include Caucasian race, light skin and eye color, and propensity to sunburn.	('light skin', 'Phenotype', 'HP:0001010', (90, 100))	('uveal melanoma', 'Disease', (51, 65))	('Caucasian race', 'Var', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
5389	26334521	The differential diagnosis of T1 hyperintense lesions includes haemorrhage in primary nasal lesions such as haemangioma and juvenile angiofibroma, proteinaceous secretions in mucoceles, fat-containing lesions and haemorrhagic metastases.	('T1 hyperintense lesions', 'Var', (30, 53))	('haemorrhage', 'Disease', (63, 74))	('haemangioma and juvenile angiofibroma', 'Disease', 'MESH:D018322', (108, 145))	('haemorrhage', 'Disease', 'MESH:D006470', (63, 74))	('haemorrhagic metastases', 'Disease', 'MESH:D006470', (213, 236))	('haemorrhagic metastases', 'Disease', (213, 236))
5404	26334521	8b); however, amelanotic melanomas, which comprise approximately 10 to 29 % of anorectal melanomas, are hypointense on T1- and hyperintense on T2-weighted sequences.	('T2-weighted', 'MPA', (143, 154))	('hypointense', 'Var', (104, 115))	('amelanotic melanomas', 'Disease', (14, 34))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('T1-', 'MPA', (119, 122))	('amelanotic melanomas', 'Disease', 'MESH:D018328', (14, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('anorectal melanomas', 'Disease', (79, 98))	('anorectal melanomas', 'Disease', 'MESH:D008545', (79, 98))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
5433	26334521	BRAF mutations are seen in about 10 % of mucosal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('mucosal melanomas', 'Disease', (41, 58))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
5437	26334521	The US Food and Drug Administration (FDA) has approved drugs for BRAF mutant melanoma including the BRAF inhibitors vemurafenib (August 2011) and dabrafenib (May 2013) as well as the MEK inhibitor trametinib (May 2013).	('trametinib', 'Chemical', 'MESH:C560077', (197, 207))	('vemurafenib', 'Chemical', 'MESH:D000077484', (116, 127))	('dabrafenib', 'Chemical', 'MESH:C561627', (146, 156))	('mutant', 'Var', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('BRAF', 'Gene', '673', (100, 104))	('MEK', 'Gene', (183, 186))	('BRAF', 'Gene', '673', (65, 69))	('MEK', 'Gene', '5609', (183, 186))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('BRAF', 'Gene', (100, 104))	('BRAF', 'Gene', (65, 69))
5439	26334521	Mutations in BRAF, KIT and NRAS are rarely seen in uveal melanoma; however more than 80 percent of uveal melanomas have mutations in GNAQ or GNA11.	('GNAQ', 'Gene', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('uveal melanomas', 'Disease', 'MESH:C536494', (99, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('mutations', 'Var', (120, 129))	('GNA11', 'Gene', (141, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('uveal melanoma', 'Disease', (51, 65))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('NRAS', 'Gene', '4893', (27, 31))	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanomas', 'Disease', (99, 114))	('uveal melanomas', 'Phenotype', 'HP:0007716', (99, 114))	('GNA11', 'Gene', '2767', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('NRAS', 'Gene', (27, 31))	('GNAQ', 'Gene', '2776', (133, 137))
5440	26334521	The GNAQ and GNA11 mutations lead to the activation of the downstream MAPK pathway, which may be a potential target for therapeutic intervention.	('GNAQ', 'Gene', '2776', (4, 8))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('mutations', 'Var', (19, 28))	('GNA11', 'Gene', (13, 18))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', '2767', (13, 18))	('activation', 'PosReg', (41, 51))	('downstream MAPK pathway', 'Pathway', (59, 82))
5442	26334521	Mucosal melanomas have an increased prevalence of c-KIT mutations, seen in about 20-25 % cases.	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('c-KIT', 'Gene', '3815', (50, 55))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('c-KIT', 'Gene', (50, 55))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
5443	26334521	Imatinib is a small molecule inhibitor of KIT that inhibits proliferation and induces apoptosis in melanoma cells harbouring KIT mutations, associated with significant clinical response in these patients.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('induces', 'Reg', (78, 85))	('KIT', 'Gene', (125, 128))	('inhibits', 'NegReg', (51, 59))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('mutations', 'Var', (129, 138))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('patients', 'Species', '9606', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('proliferation', 'CPA', (60, 73))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('apoptosis', 'CPA', (86, 95))
5447	26334521	CTLA-4 is a key downregulator of the immune system and blockade of CTLA-4 potentiates the T cell-mediated anti-tumour immune response.	('CTLA-4', 'Gene', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('immune response', 'biological_process', 'GO:0006955', ('118', '133'))	('potentiates', 'PosReg', (74, 85))	('CTLA-4', 'Gene', (67, 73))	('CTLA-4', 'Gene', '1493', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('blockade', 'Var', (55, 63))	('tumour', 'Disease', (111, 117))	('CTLA-4', 'Gene', '1493', (67, 73))
5448	26334521	Inhibition of CTLA-4 by ipilimumab can lead to unique immune-related adverse events (irAEs) such as a rash, colitis, hepatitis, hypophysitis, thyroiditis and pancreatitis.	('lead to', 'Reg', (39, 46))	('rash', 'Disease', 'MESH:D005076', (102, 106))	('CTLA-4', 'Gene', (14, 20))	('hypophysitis', 'Disease', 'MESH:D000072659', (128, 140))	('thyroiditis', 'Disease', (142, 153))	('colitis', 'Phenotype', 'HP:0002583', (108, 115))	('pancreatitis', 'Phenotype', 'HP:0001733', (158, 170))	('ipilimumab', 'Chemical', 'MESH:D000074324', (24, 34))	('pancreatitis', 'Disease', 'MESH:D010195', (158, 170))	('thyroiditis', 'Disease', 'MESH:D013959', (142, 153))	('immune-related adverse events', 'Disease', (54, 83))	('hepatitis', 'Phenotype', 'HP:0012115', (117, 126))	('pancreatitis', 'Disease', (158, 170))	('colitis', 'Disease', (108, 115))	('rash', 'Phenotype', 'HP:0000988', (102, 106))	('Inhibition', 'Var', (0, 10))	('hepatitis', 'Disease', 'MESH:D056486', (117, 126))	('hypophysitis', 'Disease', (128, 140))	('thyroiditis', 'Phenotype', 'HP:0100646', (142, 153))	('colitis', 'Disease', 'MESH:D003092', (108, 115))	('hepatitis', 'Disease', (117, 126))	('rash', 'Disease', (102, 106))	('CTLA-4', 'Gene', '1493', (14, 20))
5461	30066763	SLN biopsy should be considered in all patients with Breslow thickness greater than or equal to 1mm, as well as for those with thickness less than 1mm, but greater than 0.75mm, in the presence of the following adverse factors: Positive deep margins; Lymphatic invasion; Age < 40 years; Significant vertical growth phase; High mitotic index; Clark level IV or greater.	('Lymphatic invasion', 'CPA', (250, 268))	('greater than', 'Var', (71, 83))	('patients', 'Species', '9606', (39, 47))
5498	30066763	In the MSLT-I study, overall survival of patients with false-negative SLN was similar to that of the watchful waiting group that developed lymph node metastasis but was significantly lower than in patients with positive SLN.	('false', 'biological_process', 'GO:0071877', ('55', '60'))	('patients', 'Species', '9606', (197, 205))	('false-negative', 'Var', (55, 69))	('patients', 'Species', '9606', (41, 49))	('false', 'biological_process', 'GO:0071878', ('55', '60'))	('lower', 'NegReg', (183, 188))
5506	30066763	To mitigate the FP rate, four accessory criteria can be used in the analysis of the SLN: Existence of IHC-positive cells inside the lymph node: melanocytic cells in the nodal parenchyma are known to be malignant, while subcapsular or trabecular melanocytic cells are considered benign; Cytologic characteristics, especially those related to the cell nucleus, such as nuclear pleomorphism, hyperchromasia, and enlargement, among others; Absence or presence of evidence of proliferation, such as mitotic figures; Positivity for HMB45 marker, which is less sensitive but highly specific for melanoma.	('melanoma', 'Disease', (588, 596))	('melanoma', 'Disease', 'MESH:D008545', (588, 596))	('hyperchromasia', 'Disease', 'None', (389, 403))	('Positivity', 'Var', (511, 521))	('cell nucleus', 'cellular_component', 'GO:0005634', ('345', '357'))	('HMB45', 'Gene', (526, 531))	('hyperchromasia', 'Disease', (389, 403))	('melanoma', 'Phenotype', 'HP:0002861', (588, 596))
5586	33339193	However, these mechanisms are error-prone processes that can potentially lead to the formation of mutations resulting in melanoma formation.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('mutations', 'Var', (98, 107))	('lead to', 'Reg', (73, 80))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))
5588	33339193	Invasive melanoma contains a larger number of UV-related mutations compared to those found in benign nevi.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('nevi', 'Phenotype', 'HP:0003764', (101, 105))	('UV-related', 'Disease', (46, 56))	('mutations', 'Var', (57, 66))	('Invasive melanoma', 'Disease', (0, 17))	('Invasive melanoma', 'Disease', 'MESH:D008545', (0, 17))
5589	33339193	In addition, inherited conditions such as xeroderma pigmentosum (XP), congenital melanocytic nevi, familial atypical multiple moles and melanoma (FAMMM) syndrome, and BRCA2 mutation all provide evidence for a genetic predisposition to the development of melanoma.	('xeroderma pigmentosum', 'Disease', (42, 63))	('moles', 'Phenotype', 'HP:0003764', (126, 131))	('BRCA2', 'Gene', (167, 172))	('multiple moles', 'Phenotype', 'HP:0001054', (117, 131))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (70, 97))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('melanoma', 'Disease', (136, 144))	('melanoma', 'Disease', (254, 262))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (81, 97))	('congenital melanocytic nevi', 'Disease', (70, 97))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('men', 'Species', '9606', (246, 249))	('familial atypical multiple moles', 'Disease', (99, 131))	('BRCA2', 'Gene', '675', (167, 172))	('men', 'Species', '9606', (55, 58))	('mole', 'Phenotype', 'HP:0003764', (126, 130))	('melanoma (FAMMM) syndrome', 'Disease', 'OMIM:155600', (136, 161))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (42, 63))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('atypical multiple moles', 'Phenotype', 'HP:0001062', (108, 131))	('mutation', 'Var', (173, 181))
5592	33339193	One study found that melanomas located in areas of minimal sun exposure commonly displayed mutations in BRAF or NRAS, while melanomas in chronically sun exposed areas are most commonly associated with mutations in TP53, evidencing that melanoma is a heterogeneous disease stemming from genetic risk factors and accumulated environmental exposures.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanomas', 'Disease', 'MESH:D008545', (124, 133))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('melanomas', 'Disease', (124, 133))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('NRAS', 'Gene', (112, 116))	('TP53', 'Gene', '7157', (214, 218))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('displayed', 'Reg', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('BRAF', 'Gene', (104, 108))	('melanoma', 'Disease', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('men', 'Species', '9606', (330, 333))	('mutations', 'Var', (201, 210))	('associated', 'Reg', (185, 195))	('mutations', 'Var', (91, 100))	('BRAF', 'Gene', '673', (104, 108))	('TP53', 'Gene', (214, 218))	('NRAS', 'Gene', '4893', (112, 116))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
5593	33339193	Recently, the thought of a simple linear progression from nevus to melanoma in situ does not appear to occur; rather, it is the result of an accumulation of multiple different mutations.	('mutations', 'Var', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('result of', 'Reg', (128, 137))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('nevus', 'Phenotype', 'HP:0003764', (58, 63))
5594	33339193	It has been found that melanoma associated mutations can be either somatic or due to environmental factors that are acquired over time.	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('mutations', 'Var', (43, 52))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('men', 'Species', '9606', (92, 95))
5597	33339193	In the work by Bastian, he suggests that there is an inciting oncogenic event that is often a gain of function mutation involving one of the following: NRAS, HRAS, BRAF, KIT, GNAQ, GNA11, ALK, ROS1, RET, and NTRK1.	('ALK', 'Gene', (188, 191))	('HRAS', 'Gene', (158, 162))	('GNA11', 'Gene', (181, 186))	('ROS1', 'Gene', '6098', (193, 197))	('RET', 'Gene', '5979', (199, 202))	('NTRK1', 'Gene', '4914', (208, 213))	('NRAS', 'Gene', (152, 156))	('KIT', 'Gene', (170, 173))	('NTRK1', 'Gene', (208, 213))	('BRAF', 'Gene', '673', (164, 168))	('GNA11', 'Gene', '2767', (181, 186))	('RET', 'Gene', (199, 202))	('ROS1', 'Gene', (193, 197))	('BRAF', 'Gene', (164, 168))	('mutation', 'Var', (111, 119))	('GNAQ', 'Gene', '2776', (175, 179))	('KIT', 'Gene', '3815', (170, 173))	('GNAQ', 'Gene', (175, 179))	('NRAS', 'Gene', '4893', (152, 156))	('HRAS', 'Gene', '3265', (158, 162))	('ALK', 'Gene', '238', (188, 191))	('KIT', 'molecular_function', 'GO:0005020', ('170', '173'))	('gain of function', 'PosReg', (94, 110))
5598	33339193	Given that 30% of cutaneous melanoma arise near a nevus, often with the BRAFV600E mutation, the initial oncogenic mutation is helpful in separating different lesions such as congenital nevi, pigmented lesions on chronic sun damaged (CSD) skin, non-CSD skin pigmented lesions, spitz tumors, and blue nevi.	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('nevus', 'Phenotype', 'HP:0003764', (50, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('congenital nevi', 'Disease', (174, 189))	('nevi', 'Phenotype', 'HP:0003764', (299, 303))	('sun damage', 'Phenotype', 'HP:0000992', (220, 230))	('mutation', 'Var', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('BRAFV600E', 'Gene', (72, 81))	('sun damaged', 'Phenotype', 'HP:0000992', (220, 231))	('CSD skin pigmented lesions', 'Disease', 'MESH:C562576', (248, 274))	('pigmented lesions', 'Disease', (191, 208))	('pigmented lesions', 'Disease', 'MESH:D010859', (257, 274))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('CSD skin pigmented lesions', 'Disease', (248, 274))	('nevi', 'Phenotype', 'HP:0003764', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('pigmented lesions', 'Disease', 'MESH:D010859', (191, 208))	('blue nevi', 'Phenotype', 'HP:0100814', (294, 303))
5603	33339193	Non-CSD melanomas are often associated with BRAFV600E mutations that are found in common nevi as well, while CSD melanomas are often seen to have NF1, NRAS, or BRAFnonV600E mutations.	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('CSD melanomas', 'Disease', 'MESH:C562576', (109, 122))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('CSD melanomas', 'Disease', 'MESH:C562576', (4, 17))	('CSD melanomas', 'Disease', (109, 122))	('mutations', 'Var', (54, 63))	('Non-CSD melanomas', 'Disease', (0, 17))	('NRAS', 'Gene', (151, 155))	('Non-CSD melanomas', 'Disease', 'MESH:C562576', (0, 17))	('BRAF', 'Gene', '673', (44, 48))	('NF1', 'Gene', '4763', (146, 149))	('associated', 'Reg', (28, 38))	('BRAF', 'Gene', (44, 48))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))	('NF1', 'Gene', (146, 149))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('NRAS', 'Gene', '4893', (151, 155))
5605	33339193	The characteristic histologic pagetoid growth pattern is associated with non-CSD melanoma with BRAFV600E mutations.	('non-CSD melanoma', 'Disease', (73, 89))	('BRAFV600E', 'Gene', (95, 104))	('growth pattern', 'biological_process', 'GO:0040007', ('39', '53'))	('non-CSD melanoma', 'Disease', 'MESH:C562576', (73, 89))	('growth pattern', 'biological_process', 'GO:0007150', ('39', '53'))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('mutations', 'Var', (105, 114))	('BRAFV600E', 'Mutation', 'rs113488022', (95, 104))	('associated', 'Reg', (57, 67))
5607	33339193	Ultimately, loss of function in CDKN2A or SWI/SNF primes lesions to become invasive, with mutations in PTEN and TP53 promoting complete invasion.	('PTEN', 'Gene', (103, 107))	('PTEN', 'Gene', '5728', (103, 107))	('mutations', 'Var', (90, 99))	('promoting', 'PosReg', (117, 126))	('CDKN2A', 'Gene', (32, 38))	('SWI/SNF', 'Gene', (42, 49))	('invasion', 'CPA', (136, 144))	('CDKN2A', 'Gene', '1029', (32, 38))	('loss of function', 'NegReg', (12, 28))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
5608	33339193	As found in the study by Colebatch et al., a simple linear progression from nevus to invasive melanoma does not appear to occur, but instead, different branches of mutations occur later in the progression of melanoma with a resultant heterogeneity of neoplasms.	('invasive melanoma', 'Disease', 'MESH:D008545', (85, 102))	('nevus', 'Phenotype', 'HP:0003764', (76, 81))	('neoplasms', 'Disease', 'MESH:D009369', (251, 260))	('neoplasms', 'Disease', (251, 260))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Disease', (208, 216))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('invasive melanoma', 'Disease', (85, 102))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('neoplasms', 'Phenotype', 'HP:0002664', (251, 260))	('mutations', 'Var', (164, 173))
5690	33339193	Other studied immunomarkers include pHH3 and p16.	('p16', 'Gene', '1029', (45, 48))	('p16', 'Gene', (45, 48))	('pHH3', 'Var', (36, 40))
5699	33339193	They showed that miRNA-200c, miRNA-205, and miRNA-23b were downregulated in melanoma, while miR-146a and miR-155 were upregulated.	('miRNA-205', 'Var', (29, 38))	('melanoma', 'Disease', (76, 84))	('miR-146a', 'Gene', (92, 100))	('miR-155', 'Gene', (105, 112))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('miRNA-200c', 'Var', (17, 27))	('downregulated', 'NegReg', (59, 72))	('miR-155', 'Gene', '406947', (105, 112))	('miR-146a', 'Gene', '406938', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('upregulated', 'PosReg', (118, 129))	('miRNA-23b', 'Gene', '407011', (44, 53))	('miRNA-23b', 'Gene', (44, 53))
5708	33339193	This is especially pertinent in patients with conditions that predispose to the development of melanoma such as mutations in PTEN (Cowden syndrome), TP53 (Li Fraumeni syndrome), and multiple XP genes (xeroderma pigmentosum).	('patients', 'Species', '9606', (32, 40))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (201, 222))	('PTEN', 'Gene', (125, 129))	('men', 'Species', '9606', (87, 90))	('PTEN', 'Gene', '5728', (125, 129))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('TP53', 'Gene', '7157', (149, 153))	('xeroderma pigmentosum', 'Disease', (201, 222))	('melanoma', 'Disease', (95, 103))	('men', 'Species', '9606', (162, 165))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('mutations', 'Var', (112, 121))	('TP53', 'Gene', (149, 153))	('men', 'Species', '9606', (214, 217))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (155, 175))	('Li Fraumeni syndrome', 'Disease', (155, 175))
5724	29244840	Results showed that high PVT1 expression group had a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis) compared with the low PVT1 expression group.	('PVT1', 'Gene', (277, 281))	('PVT1', 'Gene', (25, 29))	('epithelioid cell dominant disease', 'Disease', (74, 107))	('PVT1', 'Gene', '5820', (277, 281))	('high', 'Var', (20, 24))	('spindle', 'cellular_component', 'GO:0005819', ('152', '159'))	('PVT1', 'Gene', '5820', (25, 29))	('extrascleral extension', 'CPA', (201, 223))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (74, 107))
5727	29244840	By performing univariate and multivariate analysis, we found that high PVT1 expression was an independent predictor of poor OS in patients with uveal melanoma (HR: 12.015, 95%CI: 1.854-77.876, p = 0.009).	('PVT1', 'Gene', (71, 75))	('OS', 'Chemical', '-', (124, 126))	('PVT1', 'Gene', '5820', (71, 75))	('patients', 'Species', '9606', (130, 138))	('expression', 'MPA', (76, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('high', 'Var', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('uveal melanoma', 'Disease', (144, 158))	('poor OS', 'Disease', (119, 126))
5730	29244840	Some recent studies found that dysregulated lncRNAs are involved in the pathological development of uveal melanoma.	('dysregulated', 'Var', (31, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('lncRNAs', 'Protein', (44, 51))	('uveal melanoma', 'Disease', (100, 114))	('involved', 'Reg', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
5731	29244840	For example, hypermethylated in cancer 1 (HIC1) can induce uveal melanoma progression by activating lncRNA-numb.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('uveal melanoma', 'Disease', (59, 73))	('activating', 'PosReg', (89, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('cancer', 'Disease', (32, 38))	('numb', 'Gene', '8650', (107, 111))	('hypermethylated', 'Var', (13, 28))	('numb', 'Gene', (107, 111))	('induce', 'PosReg', (52, 58))	('HIC1', 'Gene', '3090', (42, 46))	('HIC1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))
5735	29244840	In gastric cancer, high PVT1 expression is an independent prognostic marker for poor overall survival (OS) and disease-free survival (DFS).	('high', 'Var', (19, 23))	('OS', 'Chemical', '-', (103, 105))	('poor', 'NegReg', (80, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PVT1', 'Gene', (24, 28))	('gastric cancer', 'Disease', (3, 17))	('PVT1', 'Gene', '5820', (24, 28))	('disease-free survival', 'CPA', (111, 132))	('overall', 'MPA', (85, 92))	('expression', 'MPA', (29, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
5736	29244840	PVT1 overexpression promotes melanoma cells proliferation, cell cycle progression, and migration.	('migration', 'CPA', (87, 96))	('cell cycle progression', 'CPA', (59, 81))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('cell cycle', 'biological_process', 'GO:0007049', ('59', '69'))	('promotes', 'PosReg', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('PVT1', 'Gene', (0, 4))	('PVT1', 'Gene', '5820', (0, 4))	('overexpression', 'Var', (5, 19))
5750	29244840	Compared with the low PVT1 expression group, the high PVT1 expression was associated with older age (66.80 +- 11.55 vs. 56.50 +- 14.36, p = 0.0007), a higher proportion of epithelioid cell dominant disease (22/40 vs. 12/40, p = 0.024), more cases of distant metastasis (4/28 vs. 0/27, p = 0.043) and extrascleral extension (6/37 vs. 1/38, p = 0.043) and a higher death rate (20/40 vs. 3/40, p<0.0001) (Table 1).	('PVT1', 'Gene', (22, 26))	('epithelioid cell dominant disease', 'Disease', (172, 205))	('death', 'Disease', 'MESH:D003643', (363, 368))	('death', 'Disease', (363, 368))	('PVT1', 'Gene', '5820', (54, 58))	('distant metastasis', 'CPA', (250, 268))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (172, 205))	('extrascleral extension', 'CPA', (300, 322))	('PVT1', 'Gene', '5820', (22, 26))	('high', 'Var', (49, 53))	('PVT1', 'Gene', (54, 58))
5753	29244840	Among the 80 cases of primary uveal melanoma, 14 cases (17.5%) had PVT1 high-amplification (+2) and 47 cases (58.8%) had amplification (+1) (Fig 1A).	('amplification', 'Var', (121, 134))	('PVT1', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('PVT1', 'Gene', '5820', (67, 71))	('primary uveal melanoma', 'Disease', (22, 44))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (22, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('high-amplification', 'PosReg', (72, 90))
5754	29244840	The amplification was associated with significantly higher expression of PVT1 RNA (Fig 1B).	('PVT1', 'Gene', (73, 77))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('expression', 'MPA', (59, 69))	('amplification', 'Var', (4, 17))	('higher', 'PosReg', (52, 58))	('PVT1', 'Gene', '5820', (73, 77))
5758	29244840	By generating Kaplan-Meier curves of OS, we found that high PVT1 expression was associated with significantly shorter OS (p<0.0001) (Fig 2A).	('PVT1', 'Gene', '5820', (60, 64))	('shorter', 'NegReg', (110, 117))	('OS', 'Chemical', '-', (118, 120))	('OS', 'Chemical', '-', (37, 39))	('expression', 'MPA', (65, 75))	('high', 'Var', (55, 59))	('PVT1', 'Gene', (60, 64))
5760	29244840	In univariate analysis, we found that epithelioid cell dominant uveal melanoma, extrascleral extension, high PVT1 expression and low PVT1 DNA methylation were associated with unfavorable OS (Table 2).	('extrascleral', 'Disease', (80, 92))	('low', 'NegReg', (129, 132))	('PVT1', 'Gene', '5820', (109, 113))	('PVT1', 'Gene', (133, 137))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('DNA methylation', 'biological_process', 'GO:0006306', ('138', '153'))	('epithelioid cell dominant uveal melanoma', 'Disease', 'MESH:C536494', (38, 78))	('OS', 'Chemical', '-', (187, 189))	('unfavorable OS', 'Disease', (175, 189))	('high', 'Var', (104, 108))	('epithelioid cell dominant uveal melanoma', 'Disease', (38, 78))	('PVT1', 'Gene', '5820', (133, 137))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('expression', 'MPA', (114, 124))	('PVT1', 'Gene', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
5761	29244840	Multivariate analysis showed that older age (>60) (HR: 2.599, 95%CI: 1.049-6.437, p = 0.039), epithelioid cell dominant uveal melanoma (HR: 4.385, 95%CI: 1.514-12.703, p = 0.006) and high PVT1 expression (HR: 12.015, 95%CI: 1.854-77.876, p = 0.009) were independent predictors for poor OS (Table 2).	('poor OS', 'Disease', (281, 288))	('PVT1', 'Gene', (188, 192))	('OS', 'Chemical', '-', (286, 288))	('PVT1', 'Gene', '5820', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('high', 'Var', (183, 187))	('epithelioid cell dominant uveal melanoma', 'Disease', 'MESH:C536494', (94, 134))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('expression', 'MPA', (193, 203))	('epithelioid cell dominant uveal melanoma', 'Disease', (94, 134))
5765	29244840	21 cases even had PVT1 heterozygous loss (Fig 3A).	('PVT1', 'Gene', (18, 22))	('heterozygous loss', 'Var', (23, 40))	('PVT1', 'Gene', '5820', (18, 22))
5767	29244840	In comparison, heterozygous loss did not necessarily result in PVT1 decrease (Fig 3B).	('PVT1', 'Gene', (63, 67))	('heterozygous', 'Var', (15, 27))	('decrease', 'NegReg', (68, 76))	('PVT1', 'Gene', '5820', (63, 67))
5768	29244840	DNA methylation was weakly and negatively correlated with PVT1 expression in skin melanoma (Pearson's r = -0.352, Spearman's r = -0.480) (Fig 3C).	('skin melanoma', 'Disease', (77, 90))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('negatively', 'NegReg', (31, 41))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('expression', 'MPA', (63, 73))	('methylation', 'Var', (4, 15))	('PVT1', 'Gene', (58, 62))	('correlated', 'Reg', (42, 52))	('skin melanoma', 'Disease', 'MESH:D008545', (77, 90))	('PVT1', 'Gene', '5820', (58, 62))
5772	29244840	The high PVT1 expression group had a higher ratio of primary tumor (67/230) compared with the low PVT1 expression group (35/229) (p = 0.0004) (Table 3).	('PVT1', 'Gene', (98, 102))	('PVT1', 'Gene', '5820', (9, 13))	('PVT1', 'Gene', '5820', (98, 102))	('high', 'Var', (4, 8))	('primary tumor', 'Disease', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('primary tumor', 'Disease', 'MESH:D009369', (53, 66))	('PVT1', 'Gene', (9, 13))
5781	29244840	In this study, we found that high PVT1 expression was associated with a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis), suggesting that high PVT1 expression may confer some malignant phenotypes to uveal melanoma.	('high', 'Var', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (358, 366))	('PVT1', 'Gene', '5820', (296, 300))	('expression', 'Var', (39, 49))	('PVT1', 'Gene', (34, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (352, 366))	('uveal melanoma', 'Disease', (352, 366))	('extrascleral extension', 'CPA', (220, 242))	('uveal melanoma', 'Disease', 'MESH:C536494', (352, 366))	('epithelioid cell dominant disease', 'Disease', 'MESH:D012509', (93, 126))	('PVT1', 'Gene', (296, 300))	('spindle', 'cellular_component', 'GO:0005819', ('171', '178'))	('PVT1', 'Gene', '5820', (34, 38))	('epithelioid cell dominant disease', 'Disease', (93, 126))
5783	29244840	The mechanisms of PVT1 dysregulation in these cancers are quite complex and far from being fully understood.	('dysregulation', 'Var', (23, 36))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('PVT1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PVT1', 'Gene', '5820', (18, 22))
5787	29244840	These findings indicate that dysregulated PVT1 may be caused by both genetic and epigenetic alterations.	('caused by', 'Reg', (54, 63))	('PVT1', 'Gene', (42, 46))	('epigenetic alterations', 'Var', (81, 103))	('dysregulated', 'Var', (29, 41))	('PVT1', 'Gene', '5820', (42, 46))
5789	29244840	In addition, the amplification was associated with significantly higher PVT1 RNA expression.	('PVT1', 'Gene', '5820', (72, 76))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('PVT1', 'Gene', (72, 76))	('amplification', 'Var', (17, 30))	('higher', 'PosReg', (65, 71))
5790	29244840	These findings supported our hypothesis that genetic amplification is a mechanism of aberrant PVT1 expression in uveal melanoma.	('expression', 'MPA', (99, 109))	('PVT1', 'Gene', '5820', (94, 98))	('aberrant', 'Var', (85, 93))	('PVT1', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (113, 127))	('uveal melanoma', 'Disease', 'MESH:C536494', (113, 127))	('uveal melanoma', 'Disease', (113, 127))	('genetic amplification', 'Var', (45, 66))
5792	29244840	In addition, we also observed different levels of copy number alterations and methylation status between uveal melanoma and skin cutaneous melanoma, which indicate that PVT1 dysregulation might be cancer-specific.	('PVT1', 'Gene', '5820', (169, 173))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('numb', 'Gene', '8650', (55, 59))	('numb', 'Gene', (55, 59))	('dysregulation', 'Var', (174, 187))	('cancer', 'Disease', (197, 203))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('skin cutaneous melanoma', 'Disease', (124, 147))	('PVT1', 'Gene', (169, 173))	('methylation status', 'Var', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))
5802	29244840	Inhibition of melanogenesis might enhance the efficacy of radiotherapy and chemotherapy in advanced melanomas.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('enhance', 'PosReg', (34, 41))	('melanomas', 'Disease', (100, 109))	('chemotherapy', 'CPA', (75, 87))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanogenesis', 'Gene', (14, 27))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('radiotherapy', 'CPA', (58, 70))
5805	29244840	Aberrant PVT1 expression is associated with malignant behaviors of uveal melanoma and might independently predict poor OS.	('Aberrant', 'Var', (0, 8))	('PVT1', 'Gene', '5820', (9, 13))	('malignant behaviors of uveal melanoma', 'Disease', (44, 81))	('associated with', 'Reg', (28, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('expression', 'MPA', (14, 24))	('poor OS', 'Disease', (114, 121))	('malignant behaviors of uveal melanoma', 'Disease', 'MESH:C536494', (44, 81))	('OS', 'Chemical', '-', (119, 121))	('predict', 'Reg', (106, 113))	('PVT1', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
5828	27110415	The case patient was of protooncogene braf mutation wild type and went on to receive four cycles of the immunotherapy, ipilimumab in early 2014, which were tolerated well.	('braf', 'Gene', (38, 42))	('mutation', 'Var', (43, 51))	('braf', 'Gene', '673', (38, 42))	('patient', 'Species', '9606', (9, 16))	('ipilimumab', 'Chemical', 'MESH:D000074324', (119, 129))
5843	27110415	Factors predictive of metastasis from uveal melanoma include tumour thickness and genetic aberrations.	('uveal melanoma', 'Disease', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('metastasis', 'CPA', (22, 32))	('tumour thickness', 'Disease', (61, 77))	('tumour thickness', 'Disease', 'MESH:D009369', (61, 77))	('genetic aberrations', 'Var', (82, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
5844	27110415	found for each millimeter increase in tumour thickness that there was a resultant increased risk of metastasis of 1.06.	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour thickness', 'Disease', (38, 54))	('millimeter', 'Var', (15, 25))	('tumour thickness', 'Disease', 'MESH:D009369', (38, 54))	('metastasis', 'CPA', (100, 110))
5846	27110415	Uveal melanomas also differ from cutaneous lesions in their expression of genetic abnormalities, in particular, anomalies of chromosomes 1, 3, 6, and 8.	('genetic abnormalities', 'Disease', (74, 95))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('anomalies', 'Var', (112, 121))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('genetic abnormalities', 'Disease', 'MESH:D030342', (74, 95))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
5849	27110415	A further difference between uveal melanoma and cutaneous melanoma is that the latter frequently carries oncogenic driver mutations in the proteins Raf and Ras, which results in constitutively activated mitogen associated protein kinase (MAPK) pathway signalling and leads to tumorigenesis, cellular proliferation, and dissemination.	('cutaneous melanoma', 'Disease', (48, 66))	('tumorigenesis', 'CPA', (276, 289))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('dissemination', 'CPA', (319, 332))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('Raf', 'Gene', '22882', (148, 151))	('cellular proliferation', 'CPA', (291, 313))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('activated', 'PosReg', (193, 202))	('leads to', 'Reg', (267, 275))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('Raf', 'Gene', (148, 151))	('Ras', 'Gene', (156, 159))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('signalling', 'biological_process', 'GO:0023052', ('252', '262'))	('mutations', 'Var', (122, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('238', '242'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
5851	27110415	Other genetic oncogenic drivers include GNAQ, GNA11, BAP1 mutations, and PTEN (phosphatase and tensin homolog) loss.	('mutations', 'Var', (58, 67))	('PTEN', 'Gene', (73, 77))	('GNAQ', 'Gene', (40, 44))	('loss', 'NegReg', (111, 115))	('PTEN', 'Gene', '5728', (73, 77))	('GNA11', 'Gene', '2767', (46, 51))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('79', '109'))	('GNAQ', 'Gene', '2776', (40, 44))	('BAP1', 'Gene', '8314', (53, 57))	('phosphatase', 'molecular_function', 'GO:0016791', ('79', '90'))	('GNA11', 'Gene', (46, 51))	('BAP1', 'Gene', (53, 57))
5852	27110415	Whether these mutations actually correlate with overall patient outcome is unconfirmed.	('patient', 'Species', '9606', (56, 63))	('correlate', 'Reg', (33, 42))	('mutations', 'Var', (14, 23))
5872	31116161	Isoform-5 expression in metastases showed a significant, positive correlation with survival and tumors over-expressing isoform-5 had significantly decreased growth in a xenograft model.	('over-expressing', 'PosReg', (103, 118))	('growth in a xenograft model', 'CPA', (157, 184))	('metastases', 'Disease', 'MESH:D009362', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('decreased', 'NegReg', (147, 156))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('isoform-5', 'Var', (119, 128))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('decreased growth', 'Phenotype', 'HP:0001510', (147, 163))	('metastases', 'Disease', (24, 34))
5897	31116161	Proteins were separated by SDS-PAGE, transferred to polyvinylidene difluoride filters and probed with the following antibodies: phosphorylated (P)-AKT (S473, 4060S; Cell Signaling), AKT (no.	('S473', 'Var', (152, 156))	('AKT', 'Gene', '207', (182, 185))	('AKT', 'Gene', '207', (147, 150))	('SDS', 'Chemical', 'MESH:D012967', (27, 30))	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (52, 77))	('Signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('AKT', 'Gene', (182, 185))	('AKT', 'Gene', (147, 150))
5898	31116161	9272; Cell Signaling), Actin (sc-1616; Santa Cruz), P-ERK (9101S; Cell Signaling), ERK (4695P; Cell Signaling), and anti-rabbit IgG (7074S; Cell Signaling).	('P-ERK', 'Gene', (52, 57))	('ERK', 'Gene', (83, 86))	('ERK', 'Gene', '5594', (54, 57))	('ERK', 'molecular_function', 'GO:0004707', ('83', '86'))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('Signaling', 'biological_process', 'GO:0023052', ('145', '154'))	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('Signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('Signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('ERK', 'Gene', (54, 57))	('Actin', 'Gene', '100342017', (23, 28))	('ERK', 'Gene', '5594', (83, 86))	('P-ERK', 'Gene', '9451', (52, 57))	('rabbit', 'Species', '9986', (121, 127))	('anti-rabbit', 'Var', (116, 127))	('Actin', 'Gene', (23, 28))
5921	31116161	In a soft agar-based assay, the melanoma cell line over-expressing isoform 5 showed the greatest ability for anchorage-independent growth, while isoform 4 over-expression led to a significant decrease in this growth when compared to the empty vector cell line (p<0.05).	('decrease', 'NegReg', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('agar', 'Chemical', 'MESH:D000362', (10, 14))	('over-expression', 'PosReg', (155, 170))	('isoform', 'Var', (67, 74))	('anchorage-independent growth', 'MPA', (109, 137))
5933	31116161	BRAF inhibitor therapies, including vemurafenib and dabrafenib, are indicated for melanoma patients with activating BRAF V600 E/K mutations, which are often mutually exclusive to oncogenic NRAS mutations.	('patients', 'Species', '9606', (91, 99))	('BRAF', 'Gene', '673', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('BRAF', 'Gene', (116, 120))	('V600 E/K mutations', 'Var', (121, 139))	('melanoma', 'Disease', (82, 90))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('V600 E/K', 'Mutation', 'rs113488022', (121, 129))	('vemurafenib', 'Chemical', 'MESH:D000077484', (36, 47))	('BRAF', 'Gene', (0, 4))	('dabrafenib', 'Chemical', 'MESH:C561627', (52, 62))	('activating', 'PosReg', (105, 115))
5934	31116161	Therefore, we determined the proportion of melanoma tumors with high vs. low mRNA expression of each of the NRAS isoforms in BRAF mutant vs. wild type and NRAS mutant vs. wild-type tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('melanoma tumors', 'Disease', 'MESH:D008545', (43, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mRNA expression', 'MPA', (77, 92))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('mutant', 'Var', (160, 166))	('BRAF', 'Gene', '673', (125, 129))	('melanoma tumors', 'Disease', (43, 58))	('low', 'NegReg', (73, 76))	('mutant', 'Var', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('BRAF', 'Gene', (125, 129))
5935	31116161	mRNA expression levels of isoforms 2 and 3 (top vs. bottom quartile) demonstrated significant differences in the proportion of BRAF mutant vs. wild-type (wt) tumors (Fisher's exact test, p= 0.0486, p= 0.0310, respectively), where the top quartile of both isoforms was lower in BRAF-mutant tumors and higher in BRAF-wt tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('BRAF', 'Gene', '673', (127, 131))	('mRNA expression levels', 'MPA', (0, 22))	('BRAF', 'Gene', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('tumors', 'Disease', 'MESH:D009369', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('BRAF', 'Gene', (310, 314))	('tumors', 'Disease', (158, 164))	('BRAF', 'Gene', '673', (310, 314))	('BRAF', 'Gene', '673', (277, 281))	('BRAF', 'Gene', (277, 281))	('BRAF-wt tumors', 'Disease', 'MESH:D009369', (310, 324))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('BRAF-wt tumors', 'Disease', (310, 324))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumors', 'Phenotype', 'HP:0002664', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('mutant', 'Var', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('lower', 'NegReg', (268, 273))	('tumors', 'Disease', (289, 295))	('tumors', 'Disease', (318, 324))
5937	31116161	Thus, isoforms 2 and 3 were lower in the presence of the BRAF mutation whereas isoforms 1, 2, and 3 were higher in the presence of the NRAS mutation.	('isoforms', 'MPA', (79, 87))	('BRAF', 'Gene', '673', (57, 61))	('higher', 'PosReg', (105, 111))	('lower', 'NegReg', (28, 33))	('isoforms 2', 'MPA', (6, 16))	('BRAF', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))
5942	31116161	Only isoform 5 showed a significant correlation with survival, as high levels of isoform 5 in melanoma metastases were associated with enhanced survival in these patients.	('patients', 'Species', '9606', (162, 170))	('survival', 'CPA', (144, 152))	('high levels', 'Var', (66, 77))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma metastases', 'Disease', (94, 113))	('enhanced', 'PosReg', (135, 143))	('melanoma metastases', 'Disease', 'MESH:D009362', (94, 113))
5955	31116161	The proportion of melanoma tumors with high mRNA expression of isoforms 1, 2 and 3 were significantly increased in NRAS-mutant melanoma tumors identified via TCGA database as compared to wild-type tumors.	('tumors', 'Disease', (136, 142))	('mRNA expression', 'MPA', (44, 59))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('melanoma tumors', 'Disease', 'MESH:D008545', (18, 33))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('NRAS-mutant', 'Gene', (115, 126))	('NRAS-mutant', 'Var', (115, 126))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('melanoma tumors', 'Disease', (18, 33))	('melanoma tumors', 'Disease', 'MESH:D008545', (127, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('melanoma tumors', 'Disease', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Disease', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('increased', 'PosReg', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
5981	32811814	Our previous study has characterized alterations in the composition of the SEC23A secretome upon Sec23a silencing in M14 human melanoma cells and identified S100A8 on the list of the significantly decreased secreted proteins.	('silencing', 'Var', (104, 113))	('composition', 'MPA', (56, 67))	('Sec23a', 'Gene', (97, 103))	('human', 'Species', '9606', (121, 126))	('SEC23A', 'Gene', (75, 81))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('alterations', 'Reg', (37, 48))	('melanoma', 'Disease', (127, 135))	('SEC23A', 'Gene', '10484', (75, 81))
5989	32811814	Specifically, S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy in extravasated tumor cells.	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('SEC23A', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('autocrine', 'CPA', (80, 89))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('S100A8', 'Var', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SEC23A', 'Gene', '10484', (36, 42))	('metastatic colonization', 'CPA', (52, 75))	('tumor', 'Disease', (130, 135))	('inhibits', 'NegReg', (43, 51))
5994	32811814	Baf-A1 (S1413) and Rapamycin (S1039) were purchased from Selleck.	('Baf', 'Gene', '8815', (0, 3))	('S1039', 'Var', (30, 35))	('Baf', 'Gene', (0, 3))	('S1413', 'Var', (8, 13))	('Rapamycin', 'Chemical', 'MESH:D020123', (19, 28))
6001	32811814	The primary antibody of LC3B (ab192890, 1:1000) and P62 (ab207305, 1:2000) were purchased from Abcam.	('ab207305', 'Var', (57, 65))	('ab192890', 'Var', (30, 38))	('LC3B', 'Gene', (24, 28))	('P62', 'Gene', (52, 55))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('P62', 'Gene', '23636', (52, 55))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('LC3B', 'Gene', '81631', (24, 28))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))
6002	32811814	The primary antibody of ATG5 (10181-2-AP, 1:1000), BCL2 (12789-1-AP, 1:500), BECLIN1 (11306-1-AP, 1:500) and TUBULIN (10068-1-AP, 1:2000) were purchased from Proteintech.	('BCL2', 'Gene', '596', (51, 55))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('ATG5', 'Gene', '9474', (24, 28))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('11306-1-AP', 'Var', (86, 96))	('BCL2', 'Gene', (51, 55))	('12789-1-AP', 'Var', (57, 67))	('AP, 1', 'cellular_component', 'GO:0005907', ('94', '99'))	('AP, 1', 'cellular_component', 'GO:0005907', ('65', '70'))	('ATG5', 'Gene', (24, 28))	('AP, 1', 'cellular_component', 'GO:0005907', ('38', '43'))	('BECLIN1', 'Gene', '8678', (77, 84))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('BECLIN1', 'Gene', (77, 84))	('10068-1-AP', 'Var', (118, 128))	('BCL2', 'molecular_function', 'GO:0015283', ('51', '55'))	('AP, 1', 'cellular_component', 'GO:0005907', ('126', '131'))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('10181-2-AP', 'Var', (30, 40))
6006	32811814	Cells were plated in 6-well plates and allowed to reach 50-70% confluence at the time of Ad-mCherry-GFP-LC3B transfection.	('LC3B', 'Gene', (104, 108))	('transfection', 'Var', (109, 121))	('LC3B', 'Gene', '81631', (104, 108))
6027	32811814	The colonization capacity in vitro of tumor cells with altered Sec23a expression was evaluated via soft agar colony formation assay.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Sec23a', 'Gene', (63, 69))	('altered', 'Var', (55, 62))	('colonization capacity', 'CPA', (4, 25))	('agar', 'Chemical', 'MESH:D000362', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('formation', 'biological_process', 'GO:0009058', ('116', '125'))
6028	32811814	The results showed that colony formation in vitro was enhanced in OL-shSec23a cells while inhibited in POL-Sec23a-OE cells (Fig.	('OL-shSec23a', 'Var', (66, 77))	('OL', 'Chemical', '-', (104, 106))	('colony formation in vitro', 'CPA', (24, 49))	('formation', 'biological_process', 'GO:0009058', ('31', '40'))	('inhibited', 'NegReg', (90, 99))	('enhanced', 'PosReg', (54, 62))	('OL', 'Chemical', '-', (66, 68))
6030	32811814	Mice injected with OL-shSec23a cells suffered with significantly enhanced lung metastatic tumor burden in comparison with that injected with OL-N.C. cells.	('OL', 'Chemical', '-', (19, 21))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('enhanced', 'PosReg', (65, 73))	('OL-shSec23a cells', 'Var', (19, 36))	('Mice', 'Species', '10090', (0, 4))	('OL', 'Chemical', '-', (141, 143))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
6031	32811814	In contrast, in mice injected with POL-Sec23a-OE cells, lung metastatic tumor burden was significantly attenuated in comparison with that injected with POL-vector cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('attenuated', 'NegReg', (103, 113))	('OL', 'Chemical', '-', (153, 155))	('tumor', 'Disease', (72, 77))	('OL', 'Chemical', '-', (36, 38))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mice', 'Species', '10090', (16, 20))	('POL-Sec23a-OE cells', 'Var', (35, 54))
6033	32811814	In addition, compared with parental M14 cells, OL cells with higher Sec23a expression possessed enhanced basal level of autophagy and whereas in POL cells with lower Sec23a expression than M14 cells, basal autophagy level was suppressed (Fig.	('autophagy', 'biological_process', 'GO:0016236', ('206', '215'))	('OL', 'Chemical', '-', (146, 148))	('autophagy', 'biological_process', 'GO:0006914', ('120', '129'))	('autophagy', 'biological_process', 'GO:0016236', ('120', '129'))	('enhanced', 'PosReg', (96, 104))	('autophagy', 'biological_process', 'GO:0006914', ('206', '215'))	('expression', 'Var', (75, 85))	('suppressed', 'NegReg', (226, 236))	('OL', 'Chemical', '-', (47, 49))	('basal level', 'MPA', (105, 116))	('basal autophagy level', 'CPA', (200, 221))	('Sec23a', 'Gene', (68, 74))
6037	32811814	Given the data showing that Sec23a inhibited metastatic colonization and activated autophagy in melanoma cells, we next evaluated whether anti-metastatic colonization effect of Sec23a is dependent on autophagy using M14 derivative OL and POL cells.	('autophagy', 'CPA', (83, 92))	('Sec23a', 'Gene', (177, 183))	('autophagy', 'biological_process', 'GO:0006914', ('83', '92'))	('OL', 'Chemical', '-', (231, 233))	('autophagy', 'biological_process', 'GO:0016236', ('200', '209'))	('OL', 'Chemical', '-', (239, 241))	('autophagy', 'biological_process', 'GO:0016236', ('83', '92'))	('Sec23a', 'Var', (28, 34))	('metastatic colonization', 'CPA', (45, 68))	('inhibited', 'NegReg', (35, 44))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('autophagy', 'biological_process', 'GO:0006914', ('200', '209'))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('anti-metastatic colonization', 'CPA', (138, 166))	('activated', 'PosReg', (73, 82))	('melanoma', 'Disease', (96, 104))
6052	32811814	S100A8 has been reported to promote autophagy either through the cross-talk between mitochondria and lysosomes via ROS, or through the formation of BECLIN1-PI3KC3 complex.	('formation', 'biological_process', 'GO:0009058', ('135', '144'))	('BECLIN1', 'Gene', '8678', (148, 155))	('S100A8', 'Var', (0, 6))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('cross-talk', 'Interaction', (65, 75))	('BECLIN1', 'Gene', (148, 155))	('promote', 'PosReg', (28, 35))	('ROS', 'Chemical', '-', (115, 118))	('mitochondria', 'cellular_component', 'GO:0005739', ('84', '96'))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('ROS', 'Protein', (115, 118))	('autophagy', 'CPA', (36, 45))
6053	32811814	We first examined whether BECLIN1 expression could be altered by S100A8 interference, anti-S100A8/A9 antibody, and recombinant S100A8/A9 protein dimer.	('S100A8/A9', 'Gene', '6279;28899', (127, 136))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('expression', 'MPA', (34, 44))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('S100A8', 'Var', (65, 71))	('S100A8/A9', 'Gene', (91, 100))	('BECLIN1', 'Gene', '8678', (26, 33))	('S100A8/A9', 'Gene', (127, 136))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('altered', 'Reg', (54, 61))	('BECLIN1', 'Gene', (26, 33))	('S100A8/A9', 'Gene', '6279;28899', (91, 100))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))
6055	32811814	This observation suggests that S100A8 may also augment the formation of autophagy initiation complex BECLIN1-PI3KC by increasing BECLIN1 expression.	('increasing', 'PosReg', (118, 128))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('expression', 'MPA', (137, 147))	('autophagy', 'CPA', (72, 81))	('formation', 'MPA', (59, 68))	('autophagy', 'biological_process', 'GO:0006914', ('72', '81'))	('S100A8', 'Var', (31, 37))	('BECLIN1', 'Gene', '8678', (101, 108))	('BECLIN1', 'Gene', (101, 108))	('BECLIN1', 'Gene', '8678', (129, 136))	('autophagy initiation complex', 'cellular_component', 'GO:1990316', ('72', '100'))	('BECLIN1', 'Gene', (129, 136))	('autophagy', 'biological_process', 'GO:0016236', ('72', '81'))	('augment', 'PosReg', (47, 54))
6066	32811814	Kaplan-Meier plots analysis revealed that SKCM patients with high Sec23a or Atg5 expression levels had significantly better overall survivals in comparison with patients with low Sec23a or Atg5 expression level (Fig.	('Sec23a', 'Gene', (66, 72))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (161, 169))	('Atg5', 'Gene', (76, 80))
6086	32811814	Prior to this study, S100A8 has been reported to promote autophagy in cancer cells through the cross-talk between mitochondria and lysosomes via ROS, or through the activation of the autophagy initiation complex BECN1-PI3KC3.	('cross-talk', 'Interaction', (95, 105))	('S100A8', 'Var', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('autophagy', 'biological_process', 'GO:0016236', ('183', '192'))	('autophagy', 'biological_process', 'GO:0016236', ('57', '66'))	('ROS', 'Chemical', '-', (145, 148))	('BECN1', 'Gene', (212, 217))	('autophagy', 'biological_process', 'GO:0006914', ('183', '192'))	('ROS', 'Protein', (145, 148))	('autophagy', 'biological_process', 'GO:0006914', ('57', '66'))	('mitochondria', 'cellular_component', 'GO:0005739', ('114', '126'))	('promote', 'PosReg', (49, 56))	('autophagy', 'CPA', (57, 66))	('BECN1', 'Gene', '8678', (212, 217))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('activation', 'PosReg', (165, 175))	('autophagy initiation complex', 'cellular_component', 'GO:1990316', ('183', '211'))
6092	32811814	At the mechanistic level of the pro-autophagy activity of S1008A, although we have shown the effect of S100A8 on BECLIN1 expression, the nature of their interaction is not direct.	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('S100A8', 'Var', (103, 109))	('expression', 'MPA', (121, 131))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('S1008A', 'Var', (58, 64))	('BECLIN1', 'Gene', '8678', (113, 120))	('BECLIN1', 'Gene', (113, 120))	('S1008A', 'Mutation', 'p.S1008A', (58, 64))
6248	24281039	Mutated or aberrant expressed molecules including CDK4, MUM-1, beta-catinin.	('MUM-1', 'Gene', '84939', (56, 61))	('beta-catinin', 'Chemical', '-', (63, 75))	('CDK4', 'Gene', (50, 54))	('CDK4', 'Gene', '1019', (50, 54))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('MUM-1', 'Gene', (56, 61))	('aberrant expressed', 'Var', (11, 29))	('beta-catinin', 'Protein', (63, 75))	('Mutated', 'Var', (0, 7))
6308	24281039	Such recurrences could be due to the lack of presentation of all tumor cell clones in the initial vaccination, or due to subsequent mutations.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))
6313	24281039	They have also reported that patients who expressed DHSR to their irradiated melanoma cells had better survival than those who did not.	('patients', 'Species', '9606', (29, 37))	('melanoma cell', 'Disease', 'MESH:D008545', (77, 90))	('DHSR', 'Var', (52, 56))	('better', 'PosReg', (96, 102))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('survival', 'CPA', (103, 111))	('melanoma cell', 'Disease', (77, 90))
6315	24281039	Mutation or aberrant expression levels of certain kinases can lead to the development and progression of cancer.	('development', 'CPA', (74, 85))	('expression levels', 'MPA', (21, 38))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Mutation', 'Var', (0, 8))	('lead to', 'Reg', (62, 69))	('men', 'Species', '9606', (81, 84))	('progression', 'CPA', (90, 101))	('aberrant', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
6387	32903763	CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors.	('Tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Amplification', 'Var', (6, 19))	('Contributes', 'Reg', (20, 31))	('CCND1', 'Gene', '595', (152, 157))	('Tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CCND1', 'Gene', '595', (0, 5))	('CCND1', 'Gene', (152, 157))	('Immunosuppression', 'MPA', (35, 52))	('Tumors', 'Disease', (134, 140))	('CCND1', 'Gene', (0, 5))	('solid tumors', 'Disease', (225, 237))	('Cyclin D1', 'Gene', '595', (141, 150))	('Cyclin D1', 'Gene', (141, 150))	('Tumors', 'Disease', 'MESH:D009369', (134, 140))	('amplification', 'Var', (159, 172))	('solid tumors', 'Disease', 'MESH:D009369', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Cyclin', 'molecular_function', 'GO:0016538', ('141', '147'))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
6388	32903763	The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown.	('amplification', 'Var', (36, 49))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))
6389	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
6391	32903763	Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs.	('amplification', 'Var', (75, 88))	('CCND1', 'Gene', (69, 74))	('CCND1', 'Gene', '595', (69, 74))
6392	32903763	A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('amplification', 'Var', (8, 21))	('shorter', 'NegReg', (70, 77))	('CCND1', 'Gene', (2, 7))	('overall survival', 'MPA', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CCND1', 'Gene', '595', (2, 7))
6394	32903763	The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-beta signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors.	('hypoxia', 'Disease', (345, 352))	('PI3K', 'molecular_function', 'GO:0016303', ('270', '274'))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('KRAS', 'Gene', '3845', (227, 231))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (178, 215))	('AKT', 'Gene', (276, 279))	('solid tumors', 'Disease', 'MESH:D009369', (366, 378))	('tumors', 'Phenotype', 'HP:0002664', (372, 378))	('p53', 'Gene', (328, 331))	('hypoxia', 'Disease', 'MESH:D000860', (345, 352))	('phosphoinositide 3-kinase', 'Gene', (243, 268))	('KRAS', 'Gene', (227, 231))	('CCND1', 'Gene', '595', (48, 53))	('correlates', 'Reg', (68, 78))	('mTOR', 'Gene', (311, 315))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('CCND1', 'Gene', (48, 53))	('mammalian target of rapamycin', 'Gene', '2475', (280, 309))	('epithelial-mesenchymal transition', 'CPA', (143, 176))	('AKT', 'Gene', '207', (276, 279))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('143', '176'))	('mTOR', 'Gene', '2475', (311, 315))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('mammalian target of rapamycin', 'Gene', (280, 309))	('signaling', 'biological_process', 'GO:0023052', ('317', '326'))	('amplification', 'Var', (54, 67))	('solid tumors', 'Disease', (366, 378))	('p53', 'Gene', '7157', (328, 331))	('phosphoinositide 3-kinase', 'Gene', '5295', (243, 268))	('signaling', 'biological_process', 'GO:0023052', ('353', '362'))
6395	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.	('amplification', 'Var', (35, 48))	('hinders', 'NegReg', (146, 153))	('CCND1', 'Gene', (29, 34))	('ICIs', 'CPA', (222, 226))	('malignancy hallmarks', 'Disease', (117, 137))	('malignancy hallmarks', 'Disease', 'MESH:D009369', (117, 137))	('CCND1', 'Gene', '595', (29, 34))
6402	32903763	Recently, several studies revealed that CCND1 amplification associates with a negative response to ICIs.	('negative', 'NegReg', (78, 86))	('response to ICIs', 'MPA', (87, 103))	('amplification', 'Var', (46, 59))	('CCND1', 'Gene', (40, 45))	('CCND1', 'Gene', '595', (40, 45))
6407	32903763	We hypothesized that CCND1 amplification may be associated with poor clinical benefits of ICI therapy through suppressing the antitumor immunity in TME.	('tumor', 'Disease', (130, 135))	('CCND1', 'Gene', '595', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('suppressing', 'NegReg', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CCND1', 'Gene', (21, 26))	('amplification', 'Var', (27, 40))
6408	32903763	We mainly focused on the predictive function of CCND1 amplification in the TME in the aspect of genome and transcriptome.	('CCND1', 'Gene', (48, 53))	('amplification', 'Var', (54, 67))	('CCND1', 'Gene', '595', (48, 53))
6410	32903763	Importantly, we aimed to explore whether CCND1 amplification correlates with a poor response to ICIs in solid tumors, for which the potential mechanism may be correlated with events within the TME.	('CCND1', 'Gene', '595', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('amplification', 'Var', (47, 60))	('CCND1', 'Gene', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
6418	32903763	Survival information and RSEM-normalized gene-level data from cancers with CCND1 amplification frequency ranked first to 10th were further downloaded.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification frequency', 'Var', (81, 104))	('CCND1', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('CCND1', 'Gene', '595', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
6420	32903763	Patients with CCND1 amplification or neutral phenotypes were further analyzed.	('amplification', 'Var', (20, 33))	('Patients', 'Species', '9606', (0, 8))	('CCND1', 'Gene', (14, 19))	('CCND1', 'Gene', '595', (14, 19))
6424	32903763	Survival information from cancers with CCND1 amplification frequency ranked first to 10th was further downloaded.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('CCND1', 'Gene', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('amplification frequency', 'Var', (45, 68))	('CCND1', 'Gene', '595', (39, 44))
6427	32903763	To explore the association between CCND1 amplification and the clinical outcomes of ICIs, we included CNA and clinical data from four clinical cohorts treated with ICIs.	('amplification', 'Var', (41, 54))	('CCND1', 'Gene', (35, 40))	('CCND1', 'Gene', '595', (35, 40))
6435	32903763	Based on the hallmark gene sets, Gene Set Enrichment Analysis (GSEA) software version 3.0 (Broad Institute) was used to identify the different regulated pathways between the CCND1 amplification and neutral groups in the TCGA pan-cancer cohort ( NES  > 1, NOM P-value <0.10, FDR q-value <0.25).	('GSEA', 'Chemical', '-', (63, 67))	('amplification', 'Var', (180, 193))	('CCND1', 'Gene', '595', (174, 179))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CCND1', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
6441	32903763	Gene expression analysis from the TCGA database showed that CCND1 amplification was significantly related to the upregulation of mRNA expression of CCND1 across the top nine cancer types (TCGA pan-cancer: cancers with CCND1 amplification frequency ranked first to 10th; CHOL was excluded because of the limited number of samples) (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('CCND1', 'Gene', (218, 223))	('CCND1', 'Gene', (60, 65))	('CHOL', 'Disease', (270, 274))	('mRNA expression', 'MPA', (129, 144))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('amplification', 'Var', (66, 79))	('cancers', 'Disease', (205, 212))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (197, 203))	('CCND1', 'Gene', '595', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('CCND1', 'Gene', (148, 153))	('upregulation', 'PosReg', (113, 125))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CHOL', 'Disease', 'None', (270, 274))	('CCND1', 'Gene', '595', (218, 223))	('CCND1', 'Gene', '595', (60, 65))
6442	32903763	Next, we examined the association of CCND1 amplification with clinical outcome for pan-cancer in the TCGA and MSKCC databases.	('cancer', 'Disease', (87, 93))	('CCND1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CCND1', 'Gene', '595', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
6443	32903763	Kaplan-Meier survival analysis showed that CCND1 amplification was not associated with median OS for pan-cancer in the TCGA database.	('amplification', 'Var', (49, 62))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CCND1', 'Gene', (43, 48))	('median OS', 'Disease', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CCND1', 'Gene', '595', (43, 48))
6444	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,838.0 and 2,133.0 days, respectively [P = 0.1305, HR 1.13 (95% CI 0.96-1.32); Figure 1C].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
6447	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,079.0 and 2,002.0 days, respectively [P = 0.0125, HR 1.51 (95% CI 1.07-2.11); Figure S1A].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
6448	32903763	For melanoma in the MSKCC database, the median OS for the CCND1 amplification and CCND1 neutral groups was 13.5 months and not reached [P = 0.0139, HR 2.56 (95% CI 0.79-8.29); Figure S1B].	('CCND1', 'Gene', '595', (58, 63))	('CCND1', 'Gene', (82, 87))	('amplification', 'Var', (64, 77))	('CCND1', 'Gene', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('CCND1', 'Gene', '595', (82, 87))	('melanoma', 'Disease', (4, 12))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
6454	32903763	Based on the impact of CCND1 amplification as a negative prognostic factor for efficacy of ICIs in melanoma, we further investigated its role in patients with a solid tumor.	('patients', 'Species', '9606', (145, 153))	('amplification', 'Var', (29, 42))	('CCND1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('negative', 'NegReg', (48, 56))	('CCND1', 'Gene', '595', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Disease', (167, 172))
6455	32903763	To validate CCND1 amplification as a clinical factor associated with poor prognosis in patients with solid tumors treated with ICIs, we performed three analyses.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CCND1', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CCND1', 'Gene', '595', (12, 17))	('solid tumors', 'Disease', (101, 113))	('amplification', 'Var', (18, 31))	('patients', 'Species', '9606', (87, 95))
6457	32903763	Fifty-two patients with CCND1 amplification were identified comprising of 14 melanomas, 11 head and neck carcinomas (HNCs), 11 bladder carcinomas, eight non-small-cell lung carcinomas, five breast carcinomas, three esophagogastric carcinomas, and one glioma (Table S3).	('melanomas', 'Disease', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('amplification', 'Var', (30, 43))	('carcinomas', 'Disease', 'MESH:D009369', (105, 115))	('lung carcinomas', 'Disease', 'MESH:D008175', (168, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Disease', (173, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (197, 207))	('lung carcinomas', 'Disease', (168, 183))	('carcinomas', 'Disease', 'MESH:D009369', (135, 145))	('CCND1', 'Gene', '595', (24, 29))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('neck carcinomas', 'Disease', 'MESH:D006258', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (91, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('HNCs', 'Phenotype', 'HP:0012288', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('carcinomas', 'Disease', 'MESH:D009369', (231, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('breast carcinomas', 'Disease', 'MESH:D001943', (190, 207))	('CCND1', 'Gene', (24, 29))	('breast carcinomas', 'Disease', (190, 207))	('neck carcinomas', 'Disease', (100, 115))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (127, 144))	('carcinomas', 'Disease', 'MESH:D009369', (173, 183))	('esophagogastric', 'Disease', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Disease', 'MESH:D009369', (197, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('neck', 'cellular_component', 'GO:0044326', ('100', '104'))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (127, 145))	('patients', 'Species', '9606', (10, 18))	('carcinomas', 'Disease', (105, 115))	('breast carcinomas', 'Phenotype', 'HP:0003002', (190, 207))	('bladder carcinomas', 'Disease', 'MESH:D001749', (127, 145))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (157, 183))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('carcinomas', 'Disease', (135, 145))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (153, 183))	('carcinomas', 'Disease', (231, 241))	('glioma', 'Disease', (251, 257))	('bladder carcinomas', 'Disease', (127, 145))
6458	32903763	Across the entire cohort, CCND1 amplification was associated with a decreased OS.	('CCND1', 'Gene', (26, 31))	('decreased', 'NegReg', (68, 77))	('amplification', 'Var', (32, 45))	('CCND1', 'Gene', '595', (26, 31))
6459	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 11.0 and 18.0 months, respectively [P = 0.0024, HR 1.63 (95% CI 1.09-2.43); Figure 2B].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
6460	32903763	We performed a stratified analysis with the melanoma (n = 231) and bladder carcinoma patients (n = 111) and observed a similar association between CCND1 amplification with a shorter OS.	('CCND1', 'Gene', '595', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('amplification', 'Var', (153, 166))	('melanoma', 'Disease', (44, 52))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder carcinoma', 'Disease', 'MESH:D001749', (67, 84))	('CCND1', 'Gene', (147, 152))	('bladder carcinoma', 'Disease', (67, 84))
6461	32903763	In melanoma (n = 231), the median OS for the CCND1 amplification and CCND1 neutral groups was 22.0 and 42.0 months [P = 0.0029, HR 2.48 (95% CI 0.99-6.23); Figure S1D].	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (69, 74))	('CCND1', 'Gene', '595', (45, 50))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('CCND1', 'Gene', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('amplification', 'Var', (51, 64))
6462	32903763	In bladder carcinoma (n = 111), the median OS for the CCND1 amplification and CCND1 neutral groups was 8.0 and 16.0 months, respectively [P = 0.0244, HR 2.17 (95% CI 0.83-5.66); Figure S1E].	('bladder carcinoma', 'Phenotype', 'HP:0002862', (3, 20))	('amplification', 'Var', (60, 73))	('bladder carcinoma', 'Disease', (3, 20))	('bladder carcinoma', 'Disease', 'MESH:D001749', (3, 20))	('CCND1', 'Gene', (78, 83))	('CCND1', 'Gene', (54, 59))	('CCND1', 'Gene', '595', (78, 83))	('CCND1', 'Gene', '595', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
6463	32903763	Recent studies have shown that a high level of TMB associates with improved survival in patients receiving ICIs across a wide variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TMB', 'Chemical', '-', (47, 50))	('high', 'Var', (33, 37))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('TMB', 'MPA', (47, 50))	('improved', 'PosReg', (67, 75))
6466	32903763	The median TMB for the CCND1 amplification and CCND1 neutral groups was 6.79 vs. 5.90 (P = 0.46; Figure S2).	('amplification', 'Var', (29, 42))	('TMB', 'Chemical', '-', (11, 14))	('CCND1', 'Gene', (23, 28))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (23, 28))	('CCND1', 'Gene', '595', (47, 52))	('TMB', 'MPA', (11, 14))
6469	32903763	Of note, according to a study by Robert M. Samstein et al., in patients treated with ICIs, there is a significant association between a high level of TMB and a better OS.	('high', 'Var', (136, 140))	('better', 'Disease', (160, 166))	('TMB', 'MPA', (150, 153))	('patients', 'Species', '9606', (63, 71))	('TMB', 'Chemical', '-', (150, 153))
6470	32903763	But in our stratified analysis, in spite of a high level of TMB, patients with CCND1 amplification have a significantly decreased median OS [10.0 vs. 41.0 months, HR 2.82 (95% CI 1.11-7.20), P = 0.0003; Figure 2D].	('decreased', 'NegReg', (120, 129))	('CCND1', 'Gene', '595', (79, 84))	('median OS', 'MPA', (130, 139))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))	('TMB', 'Chemical', '-', (60, 63))
6471	32903763	Finally, a multivariable analysis using Cox proportional-hazards regression demonstrated that CCND1 amplification was significantly associated with a shorter median OS [HR 1.60 (95% CI 1.16-2.21), P = 0.0040], with adjustment for TMB, cancer type, age, drug class of ICI, and the year of ICI start (Table S4).	('amplification', 'Var', (100, 113))	('TMB', 'Chemical', '-', (230, 233))	('CCND1', 'Gene', (94, 99))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('median OS [', 'MPA', (158, 169))	('CCND1', 'Gene', '595', (94, 99))	('shorter', 'NegReg', (150, 157))
6473	32903763	reported 319 patients with CCND1 amplification and 46 cases received ICIs.	('CCND1', 'Gene', (27, 32))	('amplification', 'Var', (33, 46))	('CCND1', 'Gene', '595', (27, 32))	('patients', 'Species', '9606', (13, 21))
6484	32903763	For example, the median values of B cells (-0.1870 vs. -0.1691, P < 0.001), T cells (-0.2160 vs. -0.1935, P = 0.0090), CD8+ T cells (0.0914 vs. 0.1009, P < 0.001), and DC cells (-0.1810 vs. -0.1465, P = 0.0170) were significantly attenuated in the CCND1 amplification group in breast cancer, while Th2 cells (0.05419 vs. 0.0148, P < 0.001) and MDSCs (0.0051 vs. -0.0198, P = 0.0094) appear upregulated (Figure S4).	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('-0.1870', 'Var', (43, 50))	('CCND1', 'Gene', '595', (248, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('CD8', 'Gene', (119, 122))	('breast cancer', 'Disease', (277, 290))	('attenuated', 'NegReg', (230, 240))	('CD8', 'Gene', '925', (119, 122))	('0.0051 vs. -0.0198', 'Var', (351, 369))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('0.05419', 'Var', (309, 316))	('CCND1', 'Gene', (248, 253))	('upregulated', 'PosReg', (390, 401))	('-0.2160', 'Var', (85, 92))
6485	32903763	The signature of immune cell subsets in HNSCC showed a dramatic decrease in median values of cytotoxic cells (-0.1418 vs. -0.0970, P = 0.0030), T cells (-0.2357 vs. -0.2056, P = 0.0010), CD8+ T cells (0.0730 vs. 0.0761, P = 0.1310), DC cells (-0.2267 vs. -0.1796, P < 0.001), and B cells (-0.1676 vs. -0.1373, P < 0.001), while MDSCs (0.0250 vs. -0.0058, P < 0.001) (Figure S4).	('decrease', 'NegReg', (64, 72))	('-0.1418', 'Var', (110, 117))	('B cells', 'CPA', (280, 287))	('-0.2357', 'Var', (153, 160))	('-0.1676', 'Var', (289, 296))	('DC cells', 'CPA', (233, 241))	('CD8', 'Gene', (187, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('CD8', 'Gene', '925', (187, 190))	('T cells', 'CPA', (144, 151))	('0.0730 vs. 0.0761', 'Var', (201, 218))
6486	32903763	To investigate signaling pathways activated for CCND1 amplification tumors, we performed GSEA comparing the CCND1 amplification group and the CCND1 neutral group in the TCGA pan-cancer cohort.	('CCND1', 'Gene', (142, 147))	('amplification', 'Var', (114, 127))	('tumors', 'Disease', (68, 74))	('CCND1', 'Gene', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('CCND1', 'Gene', '595', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CCND1', 'Gene', '595', (142, 147))	('GSEA', 'Chemical', '-', (89, 93))	('CCND1', 'Gene', '595', (108, 113))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CCND1', 'Gene', (48, 53))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
6493	32903763	Another study showed that cyclin D1 (encoded by CCND1) may play a key role in the maintenance of VEGFs, and antisense to cyclin D1 could be useful for targeting both cancer cells and blood vessels in tumors.	('cyclin D1', 'Gene', (121, 130))	('antisense', 'Var', (108, 117))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cyclin', 'molecular_function', 'GO:0016538', ('121', '127'))	('CCND1', 'Gene', '595', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cyclin', 'molecular_function', 'GO:0016538', ('26', '32'))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cyclin D1', 'Gene', '595', (26, 35))	('tumors', 'Disease', (200, 206))	('cyclin D1', 'Gene', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cyclin D1', 'Gene', '595', (121, 130))	('CCND1', 'Gene', (48, 53))
6496	32903763	We found that CCND1 amplification can hinder not only the natural host immune response but also the efficacy of ICIs.	('CCND1', 'Gene', '595', (14, 19))	('immune response', 'biological_process', 'GO:0006955', ('71', '86'))	('hinder', 'NegReg', (38, 44))	('ICIs', 'CPA', (112, 116))	('amplification', 'Var', (20, 33))	('CCND1', 'Gene', (14, 19))
6497	32903763	A CCND1 amplification may potentially identify a patient population that will not benefit from ICIs irrespective of TMB status.	('TMB', 'Chemical', '-', (116, 119))	('amplification', 'Var', (8, 21))	('CCND1', 'Gene', (2, 7))	('patient', 'Species', '9606', (49, 56))	('CCND1', 'Gene', '595', (2, 7))
6499	32903763	To our knowledge, our results are the first to reveal that a CCND1 amplification may significantly correlate with tumorigenesis and attenuation of various types of effector immune cells in the TME, including cytotoxic cells, T cells, CD8+ T cells, DC cells, and B cells, and upregulation of Treg cells and MDSCs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('upregulation', 'PosReg', (275, 287))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('amplification', 'Var', (67, 80))	('Treg cells', 'CPA', (291, 301))	('CCND1', 'Gene', (61, 66))	('CD8', 'Gene', (234, 237))	('tumor', 'Disease', (114, 119))	('CD8', 'Gene', '925', (234, 237))	('CCND1', 'Gene', '595', (61, 66))	('attenuation', 'NegReg', (132, 143))
6502	32903763	In our analysis of the TCGA pan-cancer cohort, CCND1 amplification showed a statistically significant correlation with high mRNA expression of TGFB1.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('amplification', 'Var', (53, 66))	('CCND1', 'Gene', (47, 52))	('TGFB1', 'Gene', (143, 148))	('high mRNA expression', 'MPA', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCND1', 'Gene', '595', (47, 52))	('TGFB1', 'Gene', '7040', (143, 148))
6503	32903763	More importantly, further study showed significant upregulation of mRNA expression of VEGFA, another known factor inducing tumor immune escape and immunotherapy resistance, associated with the CCND1 amplification phenotype.	('upregulation', 'PosReg', (51, 63))	('tumor', 'Disease', (123, 128))	('VEGFA', 'Gene', (86, 91))	('amplification phenotype', 'Var', (199, 222))	('CCND1', 'Gene', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('VEGFA', 'Gene', '7422', (86, 91))	('CCND1', 'Gene', '595', (193, 198))	('mRNA expression', 'MPA', (67, 82))
6504	32903763	From the survival analysis in TCGA and MSKCC public databases, we found no significant correlation between CCND1 amplification with prognosis in the pan-cancer group.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('CCND1', 'Gene', '595', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('amplification', 'Var', (113, 126))	('CCND1', 'Gene', (107, 112))
6509	32903763	Meanwhile, the analysis of the transcriptome showed that the amplification of CCND1 was strongly correlated with higher expression level of mRNA.	('expression level of mRNA', 'MPA', (120, 144))	('CCND1', 'Gene', (78, 83))	('higher', 'PosReg', (113, 119))	('amplification', 'Var', (61, 74))	('CCND1', 'Gene', '595', (78, 83))
6510	32903763	Thirdly, according to our investigation, activations of a variety of oncogenes and deactivations of tumor suppressor genes were observed along with the amplification of CCND1 in different cancer types.	('amplification', 'Var', (152, 165))	('deactivations', 'MPA', (83, 96))	('activations', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CCND1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('tumor', 'Disease', (100, 105))	('CCND1', 'Gene', '595', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('cancer', 'Disease', (188, 194))	('oncogenes', 'Gene', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
6512	32903763	Nevertheless, the CCND1 amplification is a potential predictive biomarker for the use of ICIs in patients with solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CCND1', 'Gene', '595', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('amplification', 'Var', (24, 37))	('CCND1', 'Gene', (18, 23))	('solid tumors', 'Disease', (111, 123))	('patients', 'Species', '9606', (97, 105))
6513	32903763	In the melanoma pooled cohort, the median OS was shorter in the CCND1 amplification subgroup.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('shorter', 'NegReg', (49, 56))	('median OS', 'MPA', (35, 44))	('CCND1', 'Gene', (64, 69))	('CCND1', 'Gene', '595', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('amplification', 'Var', (70, 83))
6514	32903763	The survival analysis in the MSKCC-IO cohort further verified the negative impact of CCND1 amplification on the efficacy of ICIs.	('ICIs', 'CPA', (124, 128))	('CCND1', 'Gene', '595', (85, 90))	('amplification', 'Var', (91, 104))	('CCND1', 'Gene', (85, 90))	('negative', 'NegReg', (66, 74))
6515	32903763	Strikingly, by comparing CCND1 amplification with TMB in patients with solid tumors from the MSKCC-IO cohort, we found that the association between CCND1 amplification and a worse clinical outcome was more distinct in TMB-high patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CCND1', 'Gene', (25, 30))	('CCND1', 'Gene', (148, 153))	('solid tumors', 'Disease', (71, 83))	('patients', 'Species', '9606', (57, 65))	('CCND1', 'Gene', '595', (25, 30))	('CCND1', 'Gene', '595', (148, 153))	('patients', 'Species', '9606', (227, 235))	('amplification', 'Var', (154, 167))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TMB', 'Chemical', '-', (50, 53))	('TMB', 'Chemical', '-', (218, 221))	('TMB-high', 'Disease', (218, 226))
6516	32903763	This indicates that ICIs may not be useful, and even harmful, to patients with CCND1 amplification.	('CCND1', 'Gene', '595', (79, 84))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))
6517	32903763	First, various types of effector immune cell exclusion and immunosuppression in the TME were found in tumors with CCND1 amplification.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('CCND1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CCND1', 'Gene', '595', (114, 119))	('amplification', 'Var', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
6518	32903763	Second, CCND1 amplification results in high mRNA expression of TGFB1, VEGFA, and HIF1A; these molecules have direct or indirect negative effects on components of the immune system.	('TGFB1', 'Gene', '7040', (63, 68))	('VEGFA', 'Gene', (70, 75))	('HIF1A', 'Gene', (81, 86))	('CCND1', 'Gene', (8, 13))	('HIF1A', 'Gene', '3091', (81, 86))	('TGFB1', 'Gene', (63, 68))	('mRNA expression', 'MPA', (44, 59))	('negative', 'NegReg', (128, 136))	('VEGFA', 'Gene', '7422', (70, 75))	('CCND1', 'Gene', '595', (8, 13))	('amplification', 'Var', (14, 27))
6519	32903763	Finally, some oncogene pathways are activated in CCND1 amplification tumor that may lead to acceleration of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('amplification', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCND1', 'Gene', '595', (49, 54))	('tumor', 'Disease', (69, 74))	('oncogene pathways', 'Pathway', (14, 31))	('activated', 'PosReg', (36, 45))	('tumor', 'Disease', (108, 113))	('acceleration', 'PosReg', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCND1', 'Gene', (49, 54))
6520	32903763	Recently, a study reported on five patients experiencing hyper-progression who had NGS performed on pretreatment tumor tissue, and it confirmed CNAs in MDM2/MDM4, epidermal growth factor receptor (EGFR), and several genes located on 11q13 associated with hyper-progression.	('associated', 'Reg', (239, 249))	('tumor', 'Disease', (113, 118))	('MDM4', 'Gene', (157, 161))	('MDM4', 'Gene', '4194', (157, 161))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('epidermal growth factor receptor', 'Gene', (163, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('EGFR', 'Gene', '1956', (197, 201))	('patients', 'Species', '9606', (35, 43))	('CNAs', 'Var', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('163', '186'))	('MDM2', 'Gene', '4193', (152, 156))	('EGFR', 'Gene', (197, 201))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('MDM2', 'Gene', (152, 156))
6522	32903763	Considering the immunosuppression in the TME and overexpression of various oncogenes caused by CCND1 amplification, patients with such features should avoid ICI monotherapy.	('patients', 'Species', '9606', (116, 124))	('CCND1', 'Gene', (95, 100))	('amplification', 'Var', (101, 114))	('CCND1', 'Gene', '595', (95, 100))
6525	32903763	The small number of CCND1 amplification tumors and the rarity of the event suggest that further additional data are warranted.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('amplification', 'Var', (26, 39))	('CCND1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('CCND1', 'Gene', '595', (20, 25))
6526	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
6529	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in the TME and multiple malignancy hallmark; it may be a common mechanism of resistance to ICIs.	('malignancy hallmark', 'Disease', (121, 140))	('amplification', 'Var', (35, 48))	('malignancy hallmark', 'Disease', 'MESH:D009369', (121, 140))	('CCND1', 'Gene', (29, 34))	('related', 'Reg', (68, 75))	('CCND1', 'Gene', '595', (29, 34))
6576	32021081	Under the above, it is important to note that although progression of UM cannot be excluded in those patients with normal serum MIA levels, abnormal levels of MIA may indicate a probable presence of metastatic disease.	('MIA', 'Gene', (128, 131))	('patients', 'Species', '9606', (101, 109))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('MIA', 'Gene', '8190', (128, 131))	('MIA', 'Gene', '8190', (159, 162))	('UM', 'Disease', 'MESH:C536494', (70, 72))	('metastatic disease', 'Disease', (199, 217))	('indicate', 'Reg', (167, 175))	('MIA', 'Gene', (159, 162))	('abnormal', 'Var', (140, 148))
6663	32021081	Although a positive correlation was found between the presence of CTCs and the probability of metastasis at 5 years, there was no correlation between the positivity of CTCs and clinical risk factors, such as tumor size, histology, or treatment method.	('metastasis', 'CPA', (94, 104))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('presence', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('clinical', 'Species', '191496', (177, 185))	('tumor', 'Disease', (208, 213))
6688	32021081	Therefore, expression of certain miRNAs (let-7b, miR-199a, miR-199a, miR-143, miR-193b, and miR-652) was associated with chromosome 3 status, gene expression profile classes, and prognosis.	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('expression', 'MPA', (11, 21))	('miR-652', 'Gene', (92, 99))	('let-7b', 'Gene', '406884', (41, 47))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('miR-193b', 'Gene', '574455', (78, 86))	('miR-143', 'Gene', '406935', (69, 76))	('miR-193b', 'Gene', (78, 86))	('miR-199a', 'Var', (59, 67))	('let-7b', 'Gene', (41, 47))	('miR-199a', 'Var', (49, 57))	('miR-143', 'Gene', (69, 76))	('miR-652', 'Gene', '724022', (92, 99))	('associated', 'Reg', (105, 115))
6697	32021081	Plasma levels of miR-20a, 125b, 146a, 155, 181a, and 223 were all higher in the patients at the time of diagnosis compared with that of controls.	('patients', 'Species', '9606', (80, 88))	('miR-20a', 'Gene', (17, 24))	('146a', 'Var', (32, 36))	('155', 'Var', (38, 41))	('miR-20a', 'Gene', '406982', (17, 24))	('higher', 'PosReg', (66, 72))	('Plasma levels', 'MPA', (0, 13))
6705	32021081	More than 80% of the UMs present with mutations in the proto-oncogenes GNAQ and GNA11.	('UM', 'Disease', 'MESH:C536494', (21, 23))	('GNA11', 'Gene', '2767', (80, 85))	('present', 'Reg', (25, 32))	('GNAQ', 'Gene', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('mutations', 'Var', (38, 47))	('GNAQ', 'Gene', '2776', (71, 75))	('GNA11', 'Gene', (80, 85))
6706	32021081	For that reason, PCR techniques for ctDNA of UM patients include screening for GNAQ c.626A>T, GNAQ c.626A>C, and GNA11 c.626A>T.	('UM', 'Disease', 'MESH:C536494', (45, 47))	('GNAQ', 'Gene', '2776', (79, 83))	('c.626A>C', 'Mutation', 'rs121913492', (99, 107))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('GNAQ', 'Gene', '2776', (94, 98))	('c.626A>T', 'Var', (84, 92))	('GNAQ', 'Gene', (79, 83))	('c.626A>T', 'Mutation', 'rs121913492', (84, 92))	('c.626A>C', 'Var', (99, 107))	('c.626A>T', 'Mutation', 'rs121913492', (119, 127))	('patients', 'Species', '9606', (48, 56))	('GNAQ', 'Gene', (94, 98))	('UM', 'Phenotype', 'HP:0007716', (45, 47))
6709	32021081	In patients with detectable mutations, ctDNA is detected more frequently than CTCs and therefore appears to have a higher prognostic value.	('patients', 'Species', '9606', (3, 11))	('ctDNA', 'Disease', (39, 44))	('mutations', 'Var', (28, 37))
6719	32021081	Detection of the gene mutation in ctDNA could also be very useful for prognostic classification of UMs as it is in other types of cancer.	('mutation', 'Var', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('UM', 'Disease', 'MESH:C536494', (99, 101))	('cancer', 'Disease', (130, 136))	('UM', 'Phenotype', 'HP:0007716', (99, 101))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ctDNA', 'Gene', (34, 39))
6745	29988983	The patient with MUP harbored a v-Raf murine sarcoma viral oncogene homolog (BRAF) V600E mutation and was assigned to the group of cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('sarcoma viral', 'Disease', 'MESH:D001102', (45, 58))	('V600E', 'Var', (83, 88))	('v-Raf', 'Gene', (32, 37))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (131, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (131, 150))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('patient', 'Species', '9606', (4, 11))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('BRAF', 'Gene', (77, 81))	('v-Raf', 'Gene', '110157', (32, 37))	('sarcoma viral', 'Disease', (45, 58))	('cutaneous melanomas', 'Disease', (131, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('murine', 'Species', '10090', (38, 44))
6746	29988983	In 17% (N = 4) of the patients with cutaneous melanoma, prior treatment was recorded and consisted of targeted therapy with BRAF and MEK inhibitors (33% of BRAF mutant patients; N = 4).	('MEK', 'Gene', (133, 136))	('mutant', 'Var', (161, 167))	('MEK', 'Gene', '5609', (133, 136))	('BRAF', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('patients', 'Species', '9606', (22, 30))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('patients', 'Species', '9606', (168, 176))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))
6771	29988983	Vitiligo as treatment-related AE is typically observed in melanoma patients treated with anti-PD-1 antibodies and indicated positive response to therapy in 4 of our patients (Figure 1, Patient 2, 9, 25, 30).	('anti-PD-1', 'Var', (89, 98))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Vitiligo', 'Phenotype', 'HP:0001045', (0, 8))	('patients', 'Species', '9606', (67, 75))	('Vitiligo', 'Gene', (0, 8))	('Vitiligo', 'Gene', '246319', (0, 8))	('patients', 'Species', '9606', (165, 173))	('Patient', 'Species', '9606', (185, 192))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
6788	31568700	Meanwhile, the high level of MIR155HG was associated with poorer OS in glioblastoma multiforme (GBM), kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and uveal melanoma (UVM).	('glioblastoma multiforme', 'Disease', (71, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (71, 94))	('GBM', 'Disease', (96, 99))	('GBM', 'Disease', 'MESH:D005909', (96, 99))	('glioma', 'Disease', (162, 168))	('KIRC', 'Disease', (137, 141))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (102, 135))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('UVM', 'Disease', 'MESH:C536494', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('KIRC', 'Disease', 'MESH:D002292', (137, 141))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('UVM', 'Disease', (196, 199))	('kidney renal clear cell carcinoma', 'Disease', (102, 135))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('MIR155HG', 'Var', (29, 37))
6789	31568700	(b) The expression of MIR155HG was significantly correlated with infiltrating levels of immune cells and immune molecules, especially with immune checkpoint molecules such as programmed cell death protein 1 (PD-1), PD-1 ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) in most kinds of cancers.	('CTLA4', 'Gene', (287, 292))	('MIR155HG', 'Var', (22, 30))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (242, 285))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (242, 285))	('PD-L1', 'Gene', (230, 235))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('PD-L1', 'Gene', '29126', (230, 235))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('PD-1', 'Gene', (215, 219))	('PD-1', 'Gene', '5133', (215, 219))	('PD-1', 'Gene', (208, 212))	('correlated', 'Reg', (49, 59))	('PD-1', 'Gene', '5133', (208, 212))	('PD-1 ligand 1', 'Gene', (215, 228))	('programmed cell death protein 1', 'Gene', (175, 206))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('infiltrating levels of immune cells', 'MPA', (65, 100))	('CTLA4', 'Gene', '1493', (287, 292))	('programmed cell death', 'biological_process', 'GO:0012501', ('175', '196'))	('PD-1 ligand 1', 'Gene', '29126', (215, 228))	('programmed cell death protein 1', 'Gene', '5133', (175, 206))	('ligand', 'molecular_function', 'GO:0005488', ('220', '226'))
6790	31568700	(c) Detection of clinical CHOL and liver hepatocellular carcinoma tissues confirmed that there was a strong positive correlation between MIR155HG expression and the levels of CTLA4 and PD-L1.	('CTLA4', 'Gene', '1493', (175, 180))	('MIR155HG', 'Var', (137, 145))	('CHOL', 'Disease', (26, 30))	('CTLA4', 'Gene', (175, 180))	('clinical', 'Species', '191496', (17, 25))	('CHOL', 'Disease', 'MESH:D018281', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('liver hepatocellular carcinoma', 'Disease', (35, 65))	('PD-L1', 'Gene', (185, 190))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (35, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (41, 65))	('PD-L1', 'Gene', '29126', (185, 190))
6800	31568700	At the same time, MIR155HG is also thought to be involved in the human immune response.	('involved', 'Reg', (49, 57))	('human', 'Species', '9606', (65, 70))	('MIR155HG', 'Var', (18, 26))	('immune response', 'biological_process', 'GO:0006955', ('71', '86'))
6802	31568700	We also analyzed the association of MIR155HG with tumor-infiltrating immune cells and immune molecules in tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (50, 55))	('MIR155HG', 'Var', (36, 44))	('tumor', 'Disease', (106, 111))
6803	31568700	The results indicated that the expression of MIR155HG in these tumors is closely related to the immunological checkpoint molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('CTLA4', 'Gene', (144, 149))	('LAG3', 'Gene', (151, 155))	('MIR155HG', 'Var', (45, 53))	('tumors', 'Disease', (63, 69))	('PD-L1', 'Gene', (137, 142))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('LAG3', 'Gene', '3902', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TIM3', 'Gene', (161, 165))	('PD-1', 'Gene', (131, 135))	('PD-L1', 'Gene', '29126', (137, 142))	('TIM3', 'Gene', '84868', (161, 165))	('PD-1', 'Gene', '5133', (131, 135))	('CTLA4', 'Gene', '1493', (144, 149))
6805	31568700	Therefore, we believe that MIR155HG can be used as a predictor for assessing the prognosis of cancer patients and the effectiveness of immunotherapy with checkpoint blockade.	('patients', 'Species', '9606', (101, 109))	('MIR155HG', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
6807	31568700	The gene pattern was used to analyze the correlation of MIR155HG with immune cell infiltration in various tumors, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('MIR155HG', 'Var', (56, 64))
6809	31568700	The gene expression profiling interactive analysis (GEPIA) database integrates tens of thousands of tumor and non-tumor samples from TCGA and GTEx gene expression data to analyze gene expression, differential gene expression, survival, correlation, and co-expression of genes online.21 We analyzed the expression of MIR155HG in various tumors and corresponding normal tissues by GEPIA quick start tab.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('gene expression', 'biological_process', 'GO:0010467', ('179', '194'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumors', 'Disease', (336, 342))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Disease', (114, 119))	('gene expression', 'biological_process', 'GO:0010467', ('147', '162'))	('MIR155HG', 'Var', (316, 324))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('gene expression', 'biological_process', 'GO:0010467', ('209', '224'))
6814	31568700	The TIMER online database was used to analyze the differential expression of MIR155HG in 17 types of tumors and adjacent tissues in TCGA, and the differential expression was evaluated by Wilcoxon test.	('MIR155HG', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
6815	31568700	The results showed that, compared to the paracancerous control, MIR155HG was highly expressed in breast invasive carcinoma, HNSC, KIRC, kidney renal papillary cell carcinoma, LUAD, stomach adenocarcinoma and uterine corpus endometrial carcinoma, lower expression in kidney chromophobe (KICH), rectum adenocarcinoma (P < .05) (Figure 1A).	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (97, 122))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('stomach adenocarcinoma', 'Disease', (181, 203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (136, 173))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (143, 173))	('KIRC', 'Disease', (130, 134))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (97, 122))	('kidney chromophobe', 'Disease', (266, 284))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (293, 314))	('LUAD', 'Disease', (175, 179))	('MIR155HG', 'Var', (64, 72))	('KIRC', 'Disease', 'MESH:D002292', (130, 134))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (181, 203))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('kidney renal papillary cell carcinoma', 'Disease', (136, 173))	('expression', 'MPA', (252, 262))	('cancer', 'Disease', (45, 51))	('lower', 'NegReg', (246, 251))	('LUAD', 'Disease', 'MESH:C538231', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('breast invasive carcinoma', 'Disease', (97, 122))	('rectum adenocarcinoma', 'Disease', (293, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))
6816	31568700	The GEPIA database analyzes the expression of MIR155HG in various tumors and matched normal tissues (match TCGA normal and GTEx data), and the results showed that MIR155HG was higher than the matched normal tissue in the lymphoid neoplasm DLBC lymphoma, GBM, KIRC, acute myeloid leukemia, thymoma (cutoff criteria:  log2fold change  > 1.0 and P < .05) (Figure 1B).	('KIRC', 'Disease', (259, 263))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (265, 287))	('lymphoma', 'Disease', (244, 252))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('lymphoma', 'Disease', 'MESH:D008223', (244, 252))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (265, 287))	('thymoma', 'Disease', (289, 296))	('MIR155HG', 'Var', (163, 171))	('thymoma', 'Phenotype', 'HP:0100522', (289, 296))	('KIRC', 'Disease', 'MESH:D002292', (259, 263))	('GBM', 'Disease', (254, 257))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (221, 238))	('GBM', 'Disease', 'MESH:D005909', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (244, 252))	('higher', 'PosReg', (176, 182))	('MIR155HG', 'Var', (46, 54))	('acute myeloid leukemia', 'Disease', (265, 287))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('neoplasm', 'Phenotype', 'HP:0002664', (230, 238))	('leukemia', 'Phenotype', 'HP:0001909', (279, 287))	('tumors', 'Disease', (66, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (271, 287))	('thymoma', 'Disease', 'MESH:D013945', (289, 296))
6817	31568700	We used GEPIA to analyze the relation of MIR155HG and clinical features in 33 kinds of tumors and found that MIR155HG was correlated with OS, DFS, and staging in multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('MIR155HG', 'Var', (109, 117))	('multiple tumors', 'Disease', (162, 177))	('DFS', 'Disease', (142, 145))	('clinical', 'Species', '191496', (54, 62))	('correlated', 'Reg', (122, 132))	('tumors', 'Disease', (87, 93))	('multiple tumors', 'Disease', 'MESH:D009369', (162, 177))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
6818	31568700	The MIR155HG higher expression has better OS and DFS in CHOL and prophase SKCM.	('SKCM', 'Disease', 'MESH:C562393', (74, 78))	('prophase', 'biological_process', 'GO:0051324', ('65', '73'))	('SKCM', 'Disease', (74, 78))	('DFS', 'MPA', (49, 52))	('MIR155HG higher expression', 'Var', (4, 30))	('better', 'PosReg', (35, 41))	('CHOL', 'Disease', (56, 60))	('CHOL', 'Disease', 'MESH:D018281', (56, 60))
6819	31568700	In LUAD and early stage of HNSC, patients with high levels of MIR155HG have better OS than patients with low expression of MIR155HG.	('LUAD', 'Disease', (3, 7))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (33, 41))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('MIR155HG', 'Var', (62, 70))	('better', 'PosReg', (76, 82))
6820	31568700	While high levels of MIR155HG was associated with poor OS in GBM, KIRC, LGG, and UVM, and poor DFS in LGG early stage and UVM MIR155HG was closely related to tumor stage in KICH, KIRC, LUAD, SKCM, Thyroid carcinoma (THCA) (Figure 2; Table S2).	('SKCM', 'Disease', (191, 195))	('GBM', 'Disease', 'MESH:D005909', (61, 64))	('KIRC', 'Disease', (179, 183))	('UVM', 'Disease', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('THCA', 'Disease', 'MESH:D013964', (216, 220))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (197, 214))	('UVM', 'Disease', (122, 125))	('LUAD', 'Disease', (185, 189))	('KIRC', 'Disease', 'MESH:D002292', (179, 183))	('related', 'Reg', (147, 154))	('THCA', 'Disease', (216, 220))	('SKCM', 'Disease', 'MESH:C562393', (191, 195))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (185, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Disease', (158, 163))	('MIR155HG', 'Var', (21, 29))	('UVM', 'Disease', 'MESH:C536494', (81, 84))	('MIR155HG', 'Var', (126, 134))	('Thyroid carcinoma', 'Disease', (197, 214))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('UVM', 'Disease', 'MESH:C536494', (122, 125))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (197, 214))	('GBM', 'Disease', (61, 64))
6821	31568700	According to the correlation between MIR155HG and OS or DFS in eight types of tumors (CHOL, HNSC, GBM, KIRC, LGG, LUAD, SKCM, UVM), the gene pathway enrichment and functional enrichment were further analyzed.	('CHOL', 'Disease', 'MESH:D018281', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SKCM', 'Disease', (120, 124))	('GBM', 'Disease', (98, 101))	('GBM', 'Disease', 'MESH:D005909', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('LUAD', 'Disease', (114, 118))	('LGG', 'Disease', (109, 112))	('UVM', 'Disease', 'MESH:C536494', (126, 129))	('tumors', 'Disease', (78, 84))	('SKCM', 'Disease', 'MESH:C562393', (120, 124))	('KIRC', 'Disease', (103, 107))	('CHOL', 'Disease', (86, 90))	('LUAD', 'Disease', 'MESH:C538231', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('UVM', 'Disease', (126, 129))	('HNSC', 'Disease', (92, 96))	('KIRC', 'Disease', 'MESH:D002292', (103, 107))	('MIR155HG', 'Var', (37, 45))
6822	31568700	The top 80 mRNAs co-expressed with MIR155HG in various tumors were obtained by GEPIA's similar genes model.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MIR155HG', 'Var', (35, 43))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))
6826	31568700	To investigate the correlation between MIR155HG and tumor immune cells, we used the TIMER to analyze the correlation of MIR155HG with tumor purity, lymphocytes, macrophages, neutrophils, DCs, NK cells, Treg cells, mast cells, Th1, Th2, Th17, Tfh cells, MDSC in the above eight tumors.	('Th1', 'Gene', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Th1', 'Gene', '51497', (236, 239))	('tumor', 'Disease', (52, 57))	('MIR155HG', 'Var', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('Th1', 'Gene', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Th1', 'Gene', '51497', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', (277, 282))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (134, 139))	('tumors', 'Disease', (277, 283))
6827	31568700	The results showed that the expression of MIR155HG in CHOL, HNSC, KIRC, LGG, LUAD, and SKCM was significantly correlated with tumor purity and the infiltration level of immune cells such as B lymphocytes, CD8+ T cells, CD4+ T cells and DCs.	('CHOL', 'Disease', (54, 58))	('SKCM', 'Disease', (87, 91))	('LUAD', 'Disease', (77, 81))	('CHOL', 'Disease', 'MESH:D018281', (54, 58))	('correlated', 'Reg', (110, 120))	('infiltration level', 'MPA', (147, 165))	('MIR155HG', 'Var', (42, 50))	('SKCM', 'Disease', 'MESH:C562393', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('KIRC', 'Disease', 'MESH:D002292', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KIRC', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (77, 81))	('tumor', 'Disease', (126, 131))
6829	31568700	MIR155 host gene was highly correlated with NK cells, Treg cells, macrophages, Th1, Tfh cells and M-MDSC in CHOL, HNSC, KIRC, LUAD, and SKCM, and have a certain correlation with MDSC in GBM MIR155HG was related to the infiltration of macrophages, Th1 and DMSC in a certain degree in LGG, and has moderate correlated with Treg cells, Th1 and Tfh cells in UVM (Table S3).	('LUAD', 'Disease', 'MESH:C538231', (126, 130))	('Th1', 'Gene', (79, 82))	('Th1', 'Gene', '51497', (333, 336))	('SKCM', 'Disease', (136, 140))	('GBM', 'Disease', (186, 189))	('Th1', 'Gene', '51497', (79, 82))	('GBM', 'Disease', 'MESH:D005909', (186, 189))	('MIR155', 'Gene', (0, 6))	('UVM', 'Disease', 'MESH:C536494', (354, 357))	('SKCM', 'Disease', 'MESH:C562393', (136, 140))	('KIRC', 'Disease', (120, 124))	('CHOL', 'Disease', (108, 112))	('MIR155HG', 'Var', (190, 198))	('Th1', 'Gene', (247, 250))	('LUAD', 'Disease', (126, 130))	('KIRC', 'Disease', 'MESH:D002292', (120, 124))	('UVM', 'Disease', (354, 357))	('Th1', 'Gene', '51497', (247, 250))	('CHOL', 'Disease', 'MESH:D018281', (108, 112))	('Th1', 'Gene', (333, 336))
6831	31568700	To evaluate the efficacy of MIR155HG in predicting cancer patient response to checkpoint inhibitor, we used the TIMER database to analyze the relevance of MIR155HG and the currently available blocking molecules with superior therapeutic effects PD-1, PD-L1, CTLA4, LAG3, TIM3.	('LAG3', 'Gene', '3902', (265, 269))	('TIM3', 'Gene', '84868', (271, 275))	('PD-L1', 'Gene', '29126', (251, 256))	('CTLA4', 'Gene', '1493', (258, 263))	('PD-1', 'Gene', '5133', (245, 249))	('patient', 'Species', '9606', (58, 65))	('CTLA4', 'Gene', (258, 263))	('MIR155HG', 'Var', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('LAG3', 'Gene', (265, 269))	('PD-L1', 'Gene', (251, 256))	('PD-1', 'Gene', (245, 249))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('TIM3', 'Gene', (271, 275))
6832	31568700	A significant strong positive correlation (cor > 0.5) was found between MIR155HG with PD-1 (PDCD1), PD-L1 (CD274), CTLA4, LAG3, and TIM3 (HAVCR2) molecules in LUAD and SKCM, and with a median or higher correlation in CHOL and UVM patients (cor > 0.3), a significant correlation in HNSC, LGG (P < .0001).	('TIM3', 'Gene', (132, 136))	('UVM', 'Disease', (226, 229))	('HAVCR2', 'Gene', '84868', (138, 144))	('TIM3', 'Gene', '84868', (132, 136))	('CD274', 'Gene', '29126', (107, 112))	('CHOL', 'Disease', (217, 221))	('SKCM', 'Disease', (168, 172))	('HNSC', 'Disease', (281, 285))	('LGG', 'Disease', (287, 290))	('PDCD1', 'Gene', '5133', (92, 97))	('PDCD1', 'Gene', (92, 97))	('CTLA4', 'Gene', '1493', (115, 120))	('LAG3', 'Gene', '3902', (122, 126))	('CHOL', 'Disease', 'MESH:D018281', (217, 221))	('CD274', 'Gene', (107, 112))	('HAVCR2', 'Gene', (138, 144))	('SKCM', 'Disease', 'MESH:C562393', (168, 172))	('LAG3', 'Gene', (122, 126))	('LUAD', 'Disease', (159, 163))	('MIR155HG', 'Var', (72, 80))	('CTLA4', 'Gene', (115, 120))	('UVM', 'Disease', 'MESH:C536494', (226, 229))	('PD-L1', 'Gene', (100, 105))	('PD-L1', 'Gene', '29126', (100, 105))	('patients', 'Species', '9606', (230, 238))	('LUAD', 'Disease', 'MESH:C538231', (159, 163))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))
6834	31568700	The relationship between MIR155HG and immunity was relatively close in the eight types of prognostic-related tumor mentioned above, and what is the relationship with other types of tumors that unrelated to prognosis?	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('MIR155HG', 'Var', (25, 33))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (109, 114))
6836	31568700	The results showed that MIR155HG was significantly negative associated with tumor purity, positive correlated with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('negative', 'NegReg', (51, 59))	('tumor', 'Disease', (76, 81))	('MIR155HG', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
6837	31568700	In LIHC, MIR155HG has a high correlation with immunological checkpoint molecules PD-1, CTLA4, LAG3, and TIM3 (cor > 0.5), and also has a significant correlation with PD-L1.	('LAG3', 'Gene', (94, 98))	('LIHC', 'Disease', 'MESH:D006528', (3, 7))	('PD-L1', 'Gene', '29126', (166, 171))	('TIM3', 'Gene', (104, 108))	('PD-1', 'Gene', (81, 85))	('TIM3', 'Gene', '84868', (104, 108))	('CTLA4', 'Gene', '1493', (87, 92))	('PD-1', 'Gene', '5133', (81, 85))	('CTLA4', 'Gene', (87, 92))	('correlation', 'Interaction', (149, 160))	('LAG3', 'Gene', '3902', (94, 98))	('MIR155HG', 'Var', (9, 17))	('PD-L1', 'Gene', (166, 171))	('correlation', 'Interaction', (29, 40))	('LIHC', 'Disease', (3, 7))
6839	31568700	We also analyzed the relationship between MIR155HG and immune in other tumors, and found that MIR155HG is closely related to immune cells and molecules in most kind of tumors (Figures S2 and S3).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('MIR155HG', 'Var', (94, 102))	('related', 'Reg', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
6840	31568700	Since the great value of MIR155HG predicting the immune checkpoint molecular expression level in tumor, we selected the prognostic-related tumor type CHOL and the prognostic-unrelated tumor type LIHC to detect the correlation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CHOL', 'Disease', (150, 154))	('MIR155HG', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('immune checkpoint molecular expression level', 'MPA', (49, 93))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (184, 189))	('CHOL', 'Disease', 'MESH:D018281', (150, 154))	('LIHC', 'Disease', (195, 199))	('LIHC', 'Disease', 'MESH:D006528', (195, 199))
6841	31568700	The relationship of MIR155HG and the immunological checkpoint molecules PD-L1 and CTLA4 were verified by qRT-PCR.	('PD-L1', 'Gene', '29126', (72, 77))	('MIR155HG', 'Var', (20, 28))	('CTLA4', 'Gene', '1493', (82, 87))	('PD-L1', 'Gene', (72, 77))	('CTLA4', 'Gene', (82, 87))
6842	31568700	The results showed that MIR155HG showed a striking positive correlation with both PD-L1 and CTLA4 in CHOL and LIHC (Figure 7).	('CTLA4', 'Gene', (92, 97))	('LIHC', 'Disease', 'MESH:D006528', (110, 114))	('PD-L1', 'Gene', (82, 87))	('MIR155HG', 'Var', (24, 32))	('PD-L1', 'Gene', '29126', (82, 87))	('positive', 'PosReg', (51, 59))	('LIHC', 'Disease', (110, 114))	('CHOL', 'Disease', (101, 105))	('CTLA4', 'Gene', '1493', (92, 97))	('CHOL', 'Disease', 'MESH:D018281', (101, 105))	('correlation', 'Interaction', (60, 71))
6843	31568700	In this report, we analyzed the expression of MIR155HG in various cancers and paracancer or normal tissues, and analyzed the relationship between MIR155HG expression and OS, DFS and staging, consistent with Wu's finding that MIR155HG was associated with poor tumor prognosis in glioma.10 As reported, the expression of MIR155HG was significantly higher in cancer than paracancer in KIRC,26 and MIR155HG was associated with poor OS.27 GO and KEGG analysis in these types of tumors showed that mRNAs co-expressed with MIR155HG were mostly enriched in immune-related functions and immune-related pathways, which indicated that MIR155HG may be related to immunity.	('tumors', 'Disease', 'MESH:D009369', (473, 479))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (473, 478))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('immune-related functions', 'CPA', (549, 573))	('cancer', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (473, 478))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('glioma', 'Disease', (278, 284))	('enriched', 'Reg', (537, 545))	('KIRC', 'Disease', (382, 386))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('tumors', 'Phenotype', 'HP:0002664', (473, 479))	('cancer', 'Disease', (372, 378))	('glioma', 'Disease', 'MESH:D005910', (278, 284))	('immune-related pathways', 'Pathway', (578, 601))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MIR155HG', 'Var', (516, 524))	('tumor', 'Phenotype', 'HP:0002664', (473, 478))	('KIRC', 'Disease', 'MESH:D002292', (382, 386))	('tumors', 'Disease', (473, 479))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('glioma', 'Phenotype', 'HP:0009733', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('cancer', 'Disease', (66, 72))
6846	31568700	In this study, we examined the association of MIR155HG with immune cells attempting to reveal the immune status in cancer patients by understanding the expression of MIR155HG.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('patients', 'Species', '9606', (122, 130))	('MIR155HG', 'Var', (166, 174))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
6847	31568700	The results showed that MIR155HG was significantly negatively correlated with tumor purity and significantly positively correlated with B cells, CD8+ T cells, CD4+ T cells, and DCs in most kinds of cancers.	('positively correlated', 'Reg', (109, 130))	('negatively', 'NegReg', (51, 61))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Disease', (198, 205))	('MIR155HG', 'Var', (24, 32))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (78, 83))
6848	31568700	Moreover, to fully demonstrate the relationship between MIR155HG and immunity, we also analyzed the association of MIR155HG with immunosuppressive molecules and immunostimulatory molecules in the above described cancer types.	('association', 'Interaction', (100, 111))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('MIR155HG', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
6852	31568700	We found that MIR155HG was significantly associated with immunological checkpoint blocking molecules PD-1, PD-L1, CTLA4, LAG3, and TIM3 in many tumors, and some of those types of tumor have better reactivity against immunological checkpoint blockade.	('tumors', 'Disease', (144, 150))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('reactivity', 'MPA', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TIM3', 'Gene', (131, 135))	('TIM3', 'Gene', '84868', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LAG3', 'Gene', '3902', (121, 125))	('tumor', 'Disease', (144, 149))	('CTLA4', 'Gene', '1493', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('LAG3', 'Gene', (121, 125))	('PD-L1', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Gene', '29126', (107, 112))	('MIR155HG', 'Var', (14, 22))	('PD-1', 'Gene', (101, 105))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CTLA4', 'Gene', (114, 119))	('tumor', 'Disease', (179, 184))
6856	31568700	They found that the expression of LAYN was associated with increased levels of immune permeation of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in colon and gastric cancer.41 Compared with the results of Pan et al, MIR155HG has a wider range of tumor applicability and was more closely related to immune cells and immune molecules.	('LAYN', 'Gene', '143903', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('MIR155HG', 'Var', (233, 241))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', (263, 268))	('LAYN', 'Gene', (34, 38))	('colon and gastric cancer', 'Disease', 'MESH:D013274', (165, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))
6857	31568700	The previous research reported that MIR155HG participate the regulator of innate immunity17 and macrophage polarization,16 and associated with acute rejection, T-cell-mediated acute rejection and graft loss.42 MIR-155 regulates the expression of many immune-specific transcripts, such as regulate polarization of macrophages, DCs maturation, T-cell differentiation, controls B cell proliferation and antibody production.43, 44 Consider that MIR155 is derived from MIR155HG and that MIR155HG play a critical role by interaction with MIR155,9, 10 we speculated that MIR155HG may affect the immune process through its interaction with MIR155 or other mechanisms.	('affect', 'Reg', (577, 583))	('graft loss', 'Disease', 'MESH:D055589', (196, 206))	('B cell proliferation', 'biological_process', 'GO:0042100', ('375', '395'))	('interaction', 'Interaction', (615, 626))	('antibody', 'cellular_component', 'GO:0019815', ('400', '408'))	('graft loss', 'Disease', (196, 206))	('macrophage polarization', 'biological_process', 'GO:0042116', ('96', '119'))	('antibody', 'cellular_component', 'GO:0019814', ('400', '408'))	('MIR-155', 'Gene', '406947', (210, 217))	('MIR155HG', 'Var', (564, 572))	('innate immunity', 'biological_process', 'GO:0045087', ('74', '89'))	('antibody', 'molecular_function', 'GO:0003823', ('400', '408'))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('342', '364'))	('MIR-155', 'Gene', (210, 217))	('antibody production', 'biological_process', 'GO:0002377', ('400', '419'))	('immune process', 'CPA', (588, 602))	('antibody', 'cellular_component', 'GO:0042571', ('400', '408'))
6858	31568700	To preliminarily verify the relationship between MIR155HG and immune infiltration in an individual patient, we verified the correlation between MIR155HG and immune checkpoint molecules PD-L1 and CTLA4 by realtime quantitative reverse transcription polymerase chain reaction (qRT-PCR) in frozen tissue specimens of patients with CHOL and LIHC.	('patient', 'Species', '9606', (99, 106))	('CTLA4', 'Gene', '1493', (195, 200))	('LIHC', 'Disease', (337, 341))	('patients', 'Species', '9606', (314, 322))	('LIHC', 'Disease', 'MESH:D006528', (337, 341))	('CTLA4', 'Gene', (195, 200))	('CHOL', 'Disease', (328, 332))	('MIR155HG', 'Var', (144, 152))	('CHOL', 'Disease', 'MESH:D018281', (328, 332))	('PD-L1', 'Gene', (185, 190))	('reverse transcription', 'biological_process', 'GO:0001171', ('226', '247'))	('patient', 'Species', '9606', (314, 321))	('PD-L1', 'Gene', '29126', (185, 190))
6859	31568700	There was a significant positive correlation between the expression of MIR155HG and PD-L1, CTLA4 in clinical specimens.	('expression', 'MPA', (57, 67))	('clinical', 'Species', '191496', (100, 108))	('PD-L1', 'Gene', (84, 89))	('MIR155HG', 'Var', (71, 79))	('PD-L1', 'Gene', '29126', (84, 89))	('CTLA4', 'Gene', '1493', (91, 96))	('CTLA4', 'Gene', (91, 96))
6861	31568700	In conclusion, the above results indicate that MIR155HG expression might help to predict the prognosis and understanding immune status in cancer.	('MIR155HG', 'Var', (47, 55))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('help', 'Reg', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
6862	31568700	In this study, we found that MIR155HG can be used as a biomarker of prognosis in CHOL, GBM, HNSC, KIRC, LGG, LUAD, SKCM, and UVM through bioinformatics analysis.	('UVM', 'Disease', 'MESH:C536494', (125, 128))	('SKCM', 'Disease', (115, 119))	('GBM', 'Disease', (87, 90))	('KIRC', 'Disease', (98, 102))	('CHOL', 'Disease', (81, 85))	('KIRC', 'Disease', 'MESH:D002292', (98, 102))	('CHOL', 'Disease', 'MESH:D018281', (81, 85))	('UVM', 'Disease', (125, 128))	('LUAD', 'Disease', 'MESH:C538231', (109, 113))	('GBM', 'Disease', 'MESH:D005909', (87, 90))	('HNSC', 'Disease', (92, 96))	('SKCM', 'Disease', 'MESH:C562393', (115, 119))	('LUAD', 'Disease', (109, 113))	('MIR155HG', 'Var', (29, 37))
6863	31568700	And the expression level of MIR155HG has a certain correlation with immune molecules in various types of tumors, especially in HNSC, LUAD, KIRC, SKCM, and LIHC, which are suitable for predicting the curative effect of immune checkpoint blockade therapy.	('tumors', 'Disease', (105, 111))	('correlation', 'Reg', (51, 62))	('KIRC', 'Disease', (139, 143))	('LIHC', 'Disease', (155, 159))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('SKCM', 'Disease', (145, 149))	('LIHC', 'Disease', 'MESH:D006528', (155, 159))	('MIR155HG', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('expression', 'MPA', (8, 18))	('SKCM', 'Disease', 'MESH:C562393', (145, 149))	('HNSC', 'Disease', (127, 131))	('LUAD', 'Disease', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('LUAD', 'Disease', 'MESH:C538231', (133, 137))	('KIRC', 'Disease', 'MESH:D002292', (139, 143))
6931	23133758	In addition, S-100 is common in neural tissue including neural tumours, chondrocytes, lipocytes, and dendritic cells which also can impede diagnosis.	('impede', 'NegReg', (132, 138))	('S-100', 'Var', (13, 18))	('neural tumours', 'Disease', 'MESH:C565640', (56, 70))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('neural tumours', 'Disease', (56, 70))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))
6934	23133758	However, frequent allelic loss at the neurofibromatosis type 1 (NF1) gene locus and high prevalence of basic fibroblast growth factor (bFGF) in cell nuclei offers potential of genetic assays and possible targeted gene therapy in the future.	('basic fibroblast growth factor', 'Gene', '2247', (103, 133))	('neurofibromatosis type 1', 'Gene', '4763', (38, 62))	('allelic loss', 'Var', (18, 30))	('NF1', 'Gene', (64, 67))	('neurofibromatosis type 1', 'Gene', (38, 62))	('basic fibroblast growth factor', 'Gene', (103, 133))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (38, 55))	('NF1', 'Gene', '4763', (64, 67))	('bFGF', 'Gene', '2247', (135, 139))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('109', '133'))	('bFGF', 'Gene', (135, 139))
6941	23133758	Poor prognosis in DNM and NM is associated with age, male gender, and head and neck locations of primary lesions, high Breslow thickness, close (<1 cm) or positive surgical margins.	('DNM', 'Gene', (18, 21))	('neck', 'cellular_component', 'GO:0044326', ('79', '83'))	('DNM', 'Gene', '1759', (18, 21))	('high', 'Var', (114, 118))
6970	29643229	Combination of anti-PD1 and anti-CSF1 receptor (CSF1R) antibodies induced the regression of BRAFV600E-driven, transplant mouse melanomas, a result that was dependent on the effective elimination of TAMs.	('anti-PD1', 'Var', (15, 23))	('CSF1', 'molecular_function', 'GO:0005011', ('48', '52'))	('Combination', 'Interaction', (0, 11))	('melanomas', 'Disease', (127, 136))	('mouse', 'Species', '10090', (121, 126))	('CSF1', 'molecular_function', 'GO:0005011', ('33', '37'))	('BRAFV600E', 'Mutation', 'rs113488022', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('CSF1R', 'Gene', (48, 53))	('TAMs', 'Chemical', '-', (198, 202))	('BRAFV600E-driven', 'Gene', (92, 108))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanomas', 'Disease', 'MESH:D008545', (127, 136))	('regression', 'CPA', (78, 88))	('anti-PD1', 'Gene', (15, 23))
6971	29643229	Collectively, these data implicate CSF1 induction as a CD8+ T cell-dependent adaptive resistance mechanism and show that simultaneous CSF1R targeting may be beneficial in melanomas refractory to immune checkpoint blockade and, possibly, other T cell-based therapies.	('melanomas', 'Disease', (171, 180))	('CSF1', 'molecular_function', 'GO:0005011', ('134', '138'))	('targeting', 'Var', (140, 149))	('CSF1R', 'Gene', (134, 139))	('CSF1', 'molecular_function', 'GO:0005011', ('35', '39'))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('CD8', 'Gene', (55, 58))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('CD8', 'Gene', '925', (55, 58))	('beneficial', 'PosReg', (157, 167))
6983	29643229	For example, expression of CSF1 is associated with poor prognosis in tumors of the reproductive system, such as ovarian, uterine, breast, and prostate cancers.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ovarian', 'Disease', 'MESH:D010051', (112, 119))	('uterine', 'Disease', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast', 'Disease', (130, 136))	('prostate cancers', 'Disease', 'MESH:D011471', (142, 158))	('associated', 'Reg', (35, 45))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'Var', (13, 23))	('CSF1', 'molecular_function', 'GO:0005011', ('27', '31'))	('tumors', 'Disease', (69, 75))	('CSF1', 'Gene', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('prostate cancers', 'Phenotype', 'HP:0012125', (142, 158))	('ovarian', 'Disease', (112, 119))	('prostate cancers', 'Disease', (142, 158))
6984	29643229	Accordingly, preclinical studies have shown that CSF1R blockade may delay tumor growth in some mouse cancer models through the elimination or repolarization of TAMs.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('CSF1', 'molecular_function', 'GO:0005011', ('49', '53'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Disease', (101, 107))	('delay', 'NegReg', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('repolarization', 'MPA', (142, 156))	('TAMs', 'Protein', (160, 164))	('mouse', 'Species', '10090', (95, 100))	('TAMs', 'Chemical', '-', (160, 164))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('blockade', 'Var', (55, 63))	('CSF1R', 'Gene', (49, 54))
6996	29643229	Our results support the notion that concomitant blockade of the CSF1/CSF1R pathway may improve intratumoral CD8+ T cell function and melanoma treatment with immune checkpoint inhibitors, such as PD1- or PDL1-blocking antibodies.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('blockade', 'Var', (48, 56))	('CSF1', 'molecular_function', 'GO:0005011', ('64', '68'))	('CD8', 'Gene', (108, 111))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('CSF1', 'molecular_function', 'GO:0005011', ('69', '73'))	('improve', 'PosReg', (87, 94))	('CSF1/CSF1R', 'Gene', (64, 74))	('CD8', 'Gene', '925', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
7008	29643229	Tumor regions with high density of tumor-infiltrating CD8+ T cells were also enriched in CSF1+ cells and CSF1R+ or CD163+ TAMs, whereas tumor regions with scant CD8+ T cell infiltrates displayed poor TAM infiltration (fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD163', 'Gene', '9332', (115, 120))	('CSF1', 'molecular_function', 'GO:0005011', ('89', '93'))	('CD8', 'Gene', '925', (54, 57))	('CD8', 'Gene', (161, 164))	('CSF1R+', 'Var', (105, 111))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', (136, 141))	('CD163', 'Gene', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CSF1', 'molecular_function', 'GO:0005011', ('105', '109'))	('TAM', 'Chemical', '-', (122, 125))	('CD8', 'Gene', (54, 57))	('TAMs', 'Chemical', '-', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TAM', 'Chemical', '-', (200, 203))	('CD8', 'Gene', '925', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
7022	29643229	Two of the four CTL-melanoma cocultures were autologous (T1185B and T1015A), whereas the other two (Me275 and Me290) were matched for HLA-A2.	('T1185B', 'Var', (57, 63))	('Me290', 'Chemical', '-', (110, 115))	('T1015A', 'Var', (68, 74))	('T1015A', 'Mutation', 'c.1015T>A', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('Me275', 'Chemical', '-', (100, 105))	('T1185B', 'SUBSTITUTION', 'None', (57, 63))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
7056	29643229	We used ovalbumin (OVA)-expressing SM1 cells (SM1-OVA), a mutant BRAFV600E-driven mouse melanoma cell line that secretes high amounts of CSF1 (fig.	('mutant', 'Var', (58, 64))	('mouse', 'Species', '10090', (82, 87))	('BRAFV600E', 'Mutation', 'rs113488022', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('CSF1', 'molecular_function', 'GO:0005011', ('137', '141'))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('ovalbumin', 'Gene', '282665', (8, 17))	('ovalbumin', 'Gene', (8, 17))	('OVA', 'Gene', (19, 22))	('OVA', 'Gene', (50, 53))	('OVA', 'Gene', '282665', (19, 22))	('OVA', 'Gene', '282665', (50, 53))
7061	29643229	Flow cytometric analysis of the tumors showed a significant reduction of MRC1+ (M2-like) TAMs after anti-CSF1R treatment (Fig.	('TAMs', 'Chemical', '-', (89, 93))	('CSF1', 'molecular_function', 'GO:0005011', ('105', '109'))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('reduction', 'NegReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('anti-CSF1R', 'Var', (100, 110))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
7062	29643229	6D) and a significant increase of both CD4+ and CD8+ T cells in the spleens of mice treated with anti-PD1 or combined anti-PD1 and anti-CSF1R antibodies (Fig.	('CD4+', 'CPA', (39, 43))	('mice', 'Species', '10090', (79, 83))	('CD8', 'Gene', (48, 51))	('increase', 'PosReg', (22, 30))	('anti-PD1', 'Var', (118, 126))	('anti-PD1', 'Var', (97, 105))	('CD8', 'Gene', '925', (48, 51))	('anti-CSF1R', 'Var', (131, 141))	('CSF1', 'molecular_function', 'GO:0005011', ('136', '140'))
7065	29643229	We then used another transplant melanoma model, Yummer1.7, which does not express the highly immunogenic OVA protein but has been subject to subsequent rounds of ultraviolet irradiation to induce de novo mutations that better recapitulate the high mutational load of human melanoma.	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('mutations', 'Var', (204, 213))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('OVA', 'Gene', (105, 108))	('human', 'Species', '9606', (267, 272))	('OVA', 'Gene', '282665', (105, 108))
7068	29643229	Remarkably, the combination of anti-CSF1R and anti-PD1 antibodies fully eradicated most of the tumors and greatly extended mouse survival after therapy, indicating strongly additive therapeutic effects of the two antibodies.	('combination', 'Interaction', (16, 27))	('mouse survival', 'CPA', (123, 137))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('extended', 'PosReg', (114, 122))	('mouse', 'Species', '10090', (123, 128))	('eradicated', 'NegReg', (72, 82))	('CSF1', 'molecular_function', 'GO:0005011', ('36', '40'))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('anti-PD1', 'Gene', (46, 54))	('tumors', 'Disease', (95, 101))	('anti-CSF1R', 'Var', (31, 41))
7069	29643229	Finally, we generated a transgenic melanoma model, called iBIP2 (see Supplementary Materials and Methods), which is driven by tamoxifen- and doxycycline-inducible Cdkn2a and Pten deletion and BRAFV600 expression in skin melanocytes.	('Cdkn2a', 'Gene', (163, 169))	('transgenic melanoma', 'Disease', (24, 43))	('transgenic melanoma', 'Disease', 'MESH:D008545', (24, 43))	('iBIP2', 'Chemical', '-', (58, 63))	('tamoxifen', 'Chemical', 'MESH:D013629', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('Pten', 'Gene', (174, 178))	('deletion', 'Var', (179, 187))	('Pten', 'Gene', '19211', (174, 178))	('Cdkn2a', 'Gene', '12578', (163, 169))	('doxycycline', 'Chemical', 'MESH:D004318', (141, 152))	('BRAFV600', 'Gene', (192, 200))
7075	29643229	Myeloid cells encompassing F4/80+ TAMs, Ly6C+ monocytes/monocytic myeloid-derived suppressor cells (mo-MDSCs), and Ly6G+ neutrophils/granulocytic MDSCs (gr-MDSCs) were all more abundant in iBIP2 compared to SM1-OVA tumors.	('OVA tumors', 'Phenotype', 'HP:0100615', (211, 221))	('TAMs', 'Chemical', '-', (34, 38))	('Ly6G+', 'Var', (115, 120))	('SM1-OVA tumors', 'Disease', 'MESH:D012554', (207, 221))	('iBIP2', 'Chemical', '-', (189, 194))	('iBIP2', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('SM1-OVA tumors', 'Disease', (207, 221))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
7077	29643229	7E) showed greatly enhanced expression of Ccl2, Il4, and Cxcl12 in iBIP2 compared to both SM1-OVA and Yummer1.7 tumors.	('Il4', 'Gene', (48, 51))	('iBIP2', 'Chemical', '-', (67, 72))	('Ccl', 'molecular_function', 'GO:0044101', ('42', '45'))	('Il4', 'molecular_function', 'GO:0005136', ('48', '51'))	('Il4', 'Gene', '3565', (48, 51))	('expression', 'MPA', (28, 38))	('OVA', 'Gene', (94, 97))	('OVA', 'Gene', '282665', (94, 97))	('Ccl2', 'Gene', '6347', (42, 46))	('iBIP2', 'Var', (67, 72))	('Ccl2', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cxcl12', 'Gene', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Cxcl12', 'Gene', '6387', (57, 63))	('tumors', 'Disease', (112, 118))	('enhanced', 'PosReg', (19, 27))
7101	29643229	Notably, 2G2 is a potent TAM-depleting agent, as shown previously in both transplant and transgenic cancer models.	('2G2', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transgenic', 'Species', '10090', (89, 99))	('TAM', 'Chemical', '-', (25, 28))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
7106	29643229	In another study, melanoma-bearing mice were treated with a BRAF inhibitor (PLX4720), a CSF1R inhibitor (PLX3397), and anti-PD1 or anti-PDL1 antibodies.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('PLX4720', 'Var', (76, 83))	('anti-PD1', 'Var', (119, 127))	('CSF1', 'molecular_function', 'GO:0005011', ('88', '92'))	('anti-PDL1', 'Protein', (131, 140))	('PLX3397', 'Chemical', 'MESH:C000600259', (105, 112))	('mice', 'Species', '10090', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
7108	29643229	Conversely, PLX3397 inhibits several kinases, including CSF1R [IC50 (median inhibitory concentration), 0.02 muM], cKIT (IC50, 0.01 muM), and FLT3 (IC50, 0.16 muM), so it may have broader effects than CSF1R antibodies on the immune tumor microenvironment.	('FLT3', 'Gene', '2322', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('FLT3', 'Gene', (141, 145))	('inhibits', 'NegReg', (20, 28))	('PLX3397', 'Chemical', 'MESH:C000600259', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('PLX3397', 'Var', (12, 19))	('CSF1', 'molecular_function', 'GO:0005011', ('56', '60'))	('CSF1', 'molecular_function', 'GO:0005011', ('200', '204'))	('tumor', 'Disease', (231, 236))	('kinases', 'Enzyme', (37, 44))	('CSF1R', 'Gene', (56, 61))
7110	29643229	PLX3397 also suppresses extramedullary hematopoiesis by inhibiting the expansion of splenic myeloid precursors, granulocytes, monocytes, and macrophages, as shown in mice.	('hematopoiesis', 'biological_process', 'GO:0030097', ('39', '52'))	('hematopoiesis', 'Disease', 'MESH:C536227', (39, 52))	('suppresses', 'NegReg', (13, 23))	('inhibiting', 'NegReg', (56, 66))	('expansion', 'CPA', (71, 80))	('mice', 'Species', '10090', (166, 170))	('hematopoiesis', 'Disease', (39, 52))	('PLX3397', 'Chemical', 'MESH:C000600259', (0, 7))	('extramedullary hematopoiesis', 'Phenotype', 'HP:0001978', (24, 52))	('PLX3397', 'Var', (0, 7))
7111	29643229	Different modes of CSF1R inhibition, for example, by monoclonal antibodies versus kinase inhibitors with a broader spectrum of molecular targets, may induce tumor responses that vary with the cancer type and patient population.	('tumor', 'Disease', (157, 162))	('patient', 'Species', '9606', (208, 215))	('monoclonal', 'Var', (53, 63))	('CSF1R', 'Gene', (19, 24))	('CSF1', 'molecular_function', 'GO:0005011', ('19', '23'))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('inhibition', 'NegReg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('induce', 'Reg', (150, 156))
7123	29643229	Several clinical trials involve patients enrolled for combination therapies of CSF1R kinase inhibitors (PLX3397, ARRY-382, and BLZ945) and anti-PD1 or anti-PDL1 antibodies (NCT02777710, NCT02452424, NCT02880371, and NCT02829723).	('PLX3397', 'Chemical', 'MESH:C000600259', (104, 111))	('NCT02880371', 'Var', (199, 210))	('patients', 'Species', '9606', (32, 40))	('anti-PDL1', 'Protein', (151, 160))	('NCT02829723', 'Var', (216, 227))	('NCT02452424', 'Var', (186, 197))	('CSF1', 'molecular_function', 'GO:0005011', ('79', '83'))	('anti-PD1', 'Protein', (139, 147))	('CSF1R', 'Gene', (79, 84))	('NCT02777710', 'Var', (173, 184))
7124	29643229	In further trials, patients with solid tumors are being treated with anti-CSF1R antibodies (RG7155, FPA008, and AMG820) in combination with PD1, PDL1, or CTLA4 blockade (NCT02323191, NCT02526017, NCT02713529, and NCT02718911).	('CTLA4', 'Gene', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (19, 27))	('NCT02526017', 'Var', (183, 194))	('solid tumors', 'Disease', 'MESH:D009369', (33, 45))	('CSF1', 'molecular_function', 'GO:0005011', ('74', '78'))	('NCT02718911', 'Var', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('NCT02323191', 'Var', (170, 181))	('CTLA4', 'Gene', '1493', (154, 159))	('NCT02713529', 'Var', (196, 207))	('solid tumors', 'Disease', (33, 45))
7154	29740153	Several ecological studies have suggested, albeit with some uncertainty, that solar UV exposure maybe a potential risk factor of prostate cancer, where studies from regions of low ambient UV showed a reduced risk of developing prostate cancer, while those from regions of high ambient UV showed an increased risk.	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('low', 'Var', (176, 179))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('prostate cancer', 'Disease', (129, 144))	('reduced', 'NegReg', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('prostate cancer', 'Disease', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))
7184	29740153	The reduced risk for those with regional or metastatic CM spread or with increasing Breslow thickness of melanoma is potentially likely due to a lower likelihood of offering prostate cancer testing and/or higher competing causes of death in this group.	('Breslow thickness', 'Var', (84, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (174, 189))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('prostate cancer', 'Disease', (174, 189))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CM', 'Phenotype', 'HP:0012056', (55, 57))	('lower', 'NegReg', (145, 150))	('regional', 'CPA', (32, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (174, 189))
7185	29740153	The reduced risk for those with regional or metastatic CM spread or with increasing Breslow thickness of melanoma, is potentially likely due to a lower likelihood of offering prostate cancer testing, as current guidelines do not recommend screening for prostate cancer in men with a life expectancy of less than 15 years.	('men', 'Species', '9606', (272, 275))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('prostate cancer', 'Disease', (253, 268))	('melanoma', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('prostate cancer', 'Disease', (175, 190))	('CM', 'Phenotype', 'HP:0012056', (55, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (253, 268))	('regional', 'CPA', (32, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (253, 268))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('men', 'Species', '9606', (234, 237))	('Breslow', 'Var', (84, 91))
7207	29740153	The effectiveness of androgen ablation in the treatment for prostate cancer and potential in treatment for melanoma, confirm the importance of androgens for these diseases.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('men', 'Species', '9606', (51, 54))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ablation', 'Var', (30, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('men', 'Species', '9606', (98, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
7209	29740153	The current findings suggest that CM diagnosis increased the risk of developing subsequent prostate cancer.	('CM', 'Phenotype', 'HP:0012056', (34, 36))	('CM diagnosis', 'Var', (34, 46))	('prostate cancer', 'Disease', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (91, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))
7217	29740153	Data items obtained from the NSWCR were categorised as follows: age at diagnosis of CM (<60, 60-64, 65-69, 70-74,75-79, 80+) years; year of PC diagnosis (1972-1979, 1980-1989, 1990-1999, 2000-2008); follow-up period since melanoma diagnosis (0, 1-4, 5-9, 10-14, 15+) years; spread of disease at presentation (localised, regional, distant metastasis and unknown); country of birth (Australia, Overseas); Breslow thickness was categorised according to the 7th edition AJCC Melanoma Staging System guidelines (0.01-1.00 mm, 1.01-2.00 mm, 2.01-4.00 mm, >4.00 mm, missing/unknown).	('PC', 'Phenotype', 'HP:0012125', (140, 142))	('Melanoma', 'Disease', 'MESH:D008545', (471, 479))	('Melanoma', 'Phenotype', 'HP:0002861', (471, 479))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('Melanoma', 'Disease', (471, 479))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('CM', 'Phenotype', 'HP:0012056', (84, 86))	('0.01-1.00', 'Var', (507, 516))
7253	27822007	A total of 7,516 patients with a primary diagnosis of UM were identified to form the final study cohort, using the SEER International Classification of Disease for Oncology (ICD-O-3) codes C69.3 (choroid) and C69.4 (ciliary body and iris).	('C69.3', 'Var', (189, 194))	('C69.4', 'Var', (209, 214))	('patients', 'Species', '9606', (17, 25))	('Oncology', 'Phenotype', 'HP:0002664', (164, 172))	('UM', 'Phenotype', 'HP:0007716', (54, 56))
7297	27822007	Similarly, the COM study demonstrated improved survival rates for iodine-125 brachytherapy compared to enucleation for medium sized melanomas, with comparable 5-year all-cause mortality (19% vs 18%) and 5-year tumor-related mortality (11% vs 9%).	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('improved', 'PosReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('iodine-125 brachytherapy', 'Var', (66, 90))	('tumor', 'Disease', (210, 215))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('survival', 'MPA', (47, 55))	('enucleation', 'biological_process', 'GO:0090601', ('103', '114'))	('melanomas', 'Disease', (132, 141))	('iodine-125', 'Chemical', 'MESH:C000614960', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
7308	27822007	In addition, targeted therapies such as histone deacetylase inhibitors and ipilimumab, as well as genetic counseling to identify BAP1 mutations for patients at high risk for developing UM, are currently under investigation.	('patients', 'Species', '9606', (148, 156))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('BAP1', 'Gene', '8314', (129, 133))	('ipilimumab', 'Chemical', 'MESH:D000074324', (75, 85))	('mutations', 'Var', (134, 143))	('BAP1', 'Gene', (129, 133))
7322	31666118	pTuneos is able to predict the MHC presentation and T cell recognition ability of the candidate neoantigens, and the actual immunogenicity of single-nucleotide variant (SNV)-based neopeptides considering their natural processing and presentation, surpassing the existing tools with a comprehensive and quantitative benchmark of their neoantigen prioritization performance and running time.	('T cell recognition', 'MPA', (52, 70))	('MHC presentation', 'MPA', (31, 47))	('cell recognition', 'biological_process', 'GO:0008037', ('54', '70'))	('single-nucleotide variant', 'Var', (142, 167))	('N', 'Chemical', 'MESH:D009584', (170, 171))
7330	31666118	In general, the prediction of neoantigens based on next-generation sequencing (NGS) data comprises three steps: (1) obtain a list of genomic somatic mutations from whole-exome sequence data and convert it into mutation-containing "neopeptides" of appropriate lengths, (2) predict the binding affinity between the peptides and patient-specific HLA alleles, and (3) evaluate the immunogenicity of the predicted peptides.	('binding', 'molecular_function', 'GO:0005488', ('282', '289'))	('patient', 'Species', '9606', (326, 333))	('mutations', 'Var', (149, 158))	('predict', 'Reg', (272, 279))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('binding affinity', 'Interaction', (284, 300))
7348	31666118	All the mutations were annotated with Ensembl Variant Effect Predictor (VEP) to identify non-synonymous mutations, including SNVs and indels.	('SNVs', 'Var', (125, 129))	('indels', 'Var', (134, 140))	('N', 'Chemical', 'MESH:D009584', (126, 127))
7351	31666118	Both mutant peptide binding affinity and normal peptide binding affinity were predicted between peptides and the (up to 6) patient-specific HLA alleles using NetMHCpan version 4.0 in the binding affinity (BA) model.	('binding', 'molecular_function', 'GO:0005488', ('187', '194'))	('patient', 'Species', '9606', (123, 130))	('binding', 'Interaction', (20, 27))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('peptide binding', 'molecular_function', 'GO:0042277', ('12', '27'))	('mutant', 'Var', (5, 11))	('peptide binding', 'molecular_function', 'GO:0042277', ('48', '63'))
7357	31666118	Next, we constructed three eXtreme Gradient Boosting (XGBoost) algorithm-based machine-learning models to predict the probability of peptides recognized by T cells corresponding to 9-mer, 10-mer, and 11-mer peptides, respectively (Additional file 1: Figure S1.	('to 9', 'Species', '1214577', (178, 182))	('9-mer', 'Var', (181, 186))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('10-mer', 'Var', (188, 194))
7358	31666118	A 10-fold cross-validation reaches an area under the curve (AUC) score of 0.68, 0.77, and 0.77 corresponding to 9-mer, 10-mer, and 11-mer peptides (Additional file 1: Figure S1.	('10-mer', 'Var', (119, 125))	('0.77', 'Var', (90, 94))	('to 9', 'Species', '1214577', (109, 113))
7365	31666118	In the other two studies, some neopeptides resulted from genomic frameshift indels and their corresponding normal peptides were missing or partially missing, and therefore, we identified the most similar peptide by aligning the neopeptide to the reference human proteome with the BLOSUM62 amino acid similarity matrix.	('resulted from', 'Reg', (43, 56))	('human', 'Species', '9606', (256, 261))	('frameshift indels', 'Var', (65, 82))
7385	31666118	Further datasets of immunotherapy-treated patients included a cohort with stage IV NSCLC treated with pembrolizumab (cohort Rizvi) and two cohorts with advanced melanoma treated with anti-CTLA4 immunotherapies (cohort Snyder and cohort Van Allen).	('CTLA4', 'Gene', '1493', (188, 193))	('NSCLC', 'Disease', (83, 88))	('CTLA4', 'Gene', (188, 193))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('pembrolizumab', 'Var', (102, 115))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('patients', 'Species', '9606', (42, 50))
7396	31666118	Second, for SNVs, the nucleotide change is translated into the corresponding amino acid change, which is then applied to the proteome reference, and nucleotide insertion and deletion changes are applied directly to the cDNA reference and translated into a 21-mer peptide containing variant sites.	('amino', 'MPA', (77, 82))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('N', 'Chemical', 'MESH:D009584', (221, 222))	('deletion', 'Var', (174, 182))
7398	31666118	Peptide-MHC binding affinities for both mutant and normal peptides are then determined by NetMHCpan version 4.0.	('mutant', 'Var', (40, 46))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('binding', 'Interaction', (12, 19))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))
7408	31666118	In the original study, the neopeptides OR8B3_T109I (identified from sample MEL_38) and MRPS5_P59L (identified from sample MEL_218) were not processed and presented from endogenously expressed proteins.	('MRPS5_P59L', 'Gene', (87, 97))	('OR8B3_T109I', 'Var', (39, 50))	('P59L', 'Mutation', 'p.P59L', (93, 97))	('T109I', 'Mutation', 'p.T109I', (45, 50))
7411	31666118	In this study, we benchmark the runtime efficiency of pTuneos with existing in silico neoantigen identification tools starting with the list of variants identified by Mutect2 and the expression profile identified by Kallisto from three melanoma patients (phs001005.v1.p1) (Fig.	('variants', 'Var', (144, 152))	('Mutect2', 'Gene', (167, 174))	('patients', 'Species', '9606', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))
7427	31666118	Nevertheless, high neoantigen burden (> median) exhibited improved overall survival in both univariate and multivariate analyses, and the high overall neoantigen immunogenicity score (> median) was associated with overall survival in univariate analysis, while well-established markers including cytolytic activity and MHC II expression were not significantly associated with overall survival (Fig.	('improved', 'PosReg', (58, 66))	('overall survival', 'MPA', (67, 83))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('high', 'Var', (14, 18))	('associated', 'Reg', (198, 208))
7441	31666118	In the cohort Rizvi, the neopeptide ASNASSAAK derived from HERC1 (p.P3278S) mutation in patient CA9903 was revealed to elicit T cell response using multimer assays.	('patient', 'Species', '9606', (88, 95))	('p.P3278S', 'Mutation', 'p.P3278S', (66, 74))	('HERC1', 'Gene', '8925', (59, 64))	('elicit', 'Reg', (119, 125))	('HERC1', 'Gene', (59, 64))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('p.P3278S', 'Var', (66, 74))	('T cell response', 'MPA', (126, 141))
7443	31666118	The first neopeptide TESPEEQHI results from FAM3C (p.K193E) mutation in patient CR9306.	('p.K193E', 'Var', (51, 58))	('CR9306', 'CellLine', 'CVCL:S509', (80, 86))	('FAM3C', 'Gene', (44, 49))	('p.K193E', 'Mutation', 'p.K193E', (51, 58))	('patient', 'Species', '9606', (72, 79))	('FAM3C', 'Gene', '10447', (44, 49))
7445	31666118	The second neopeptide GLEREGFTF results from CSMD1 (p.G3446E) mutation in patient CR0095.	('patient', 'Species', '9606', (74, 81))	('CSMD1', 'Gene', (45, 50))	('p.G3446E', 'Var', (52, 60))	('p.G3446E', 'Mutation', 'p.G3446E', (52, 60))	('results from', 'Reg', (32, 44))	('CSMD1', 'Gene', '64478', (45, 50))
7447	31666118	We found that the predicted MHC class I binding affinity %rank between GLEREGFTF and MHC-I alleles (A0201, A3101, B3502, B3906, C0401, C0702) was all greater than 2 predicted by NetMHCpan 4.0, which means that it could not be presented by MHC-I molecules and it was filtered by pTuneos in the epitope identification step.	('C0702', 'Chemical', 'MESH:C039502', (135, 140))	('B3906', 'Chemical', 'MESH:D001895', (121, 126))	('A3101', 'Var', (107, 112))	('B3906', 'Var', (121, 126))	('B3502', 'Var', (114, 119))	('MHC-I', 'Gene', (85, 90))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('C0702', 'Var', (135, 140))	('A0201', 'Var', (100, 105))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('C0401', 'Chemical', 'MESH:C082341', (128, 133))	('C0401', 'Var', (128, 133))	('binding', 'Interaction', (40, 47))
7455	31666118	It is anticipated that MSI correlated with neoantigen burden and overall neoantigen immunogenicity in STAD as MSI status contributes to the generation of gene mutation and leads to production of more potential neoantigens, while cytolytic activity, which reflects the activity of immune infiltrate T cells, did not exhibit this correlation.	('MSI', 'Var', (110, 113))	('gene mutation', 'MPA', (154, 167))	('more', 'PosReg', (195, 199))	('production', 'MPA', (181, 191))	('neoantigens', 'MPA', (210, 221))	('STAD', 'Disease', 'MESH:D013274', (102, 106))	('STAD', 'Disease', (102, 106))
7458	31666118	However, with the development of tumor and the accumulation of resistance mutation such as p53, ALOX, and IDO1, these mutations would suppress the immune infiltrate, leading to a low CYT or even showing no correlation between neoantigens burden and CYT.	('immune', 'CPA', (147, 153))	('IDO', 'molecular_function', 'GO:0033754', ('106', '109'))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('IDO', 'molecular_function', 'GO:0047719', ('106', '109'))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IDO1', 'Gene', '3620', (106, 110))	('p53', 'Gene', (91, 94))	('low', 'NegReg', (179, 182))	('p53', 'Gene', '7157', (91, 94))	('CYT', 'MPA', (183, 186))	('tumor', 'Disease', (33, 38))	('suppress', 'NegReg', (134, 142))	('IDO1', 'Gene', (106, 110))
7495	22207316	For example, the mutated BRAF, which is detected in up to 62% of cutaneous melanoma and represents a novel target molecule, is rarely found in ocular melanoma.	('ocular melanoma', 'Disease', 'MESH:D008545', (143, 158))	('cutaneous melanoma', 'Disease', (65, 83))	('ocular melanoma', 'Phenotype', 'HP:0007716', (143, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', '673', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('BRAF', 'Gene', (25, 29))	('mutated', 'Var', (17, 24))	('ocular melanoma', 'Disease', (143, 158))
7517	22207316	Melanoma cell lines were established in vitro from surgically resectable tumor lesions from both cutaneous (#1061, 1067, 2710, 4478D, 49318, 0342, 25368 and 7 mel) and ocular (#2130, 4330, 4022, 1141, 37165, 48409 and 15765) melanoma patients.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('49318', 'Var', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('2710', 'Var', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Melanoma', 'Disease', (0, 8))	('#2130', 'Var', (176, 181))	('4478D', 'Var', (127, 132))	('melanoma', 'Disease', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('#1061', 'Var', (108, 113))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (234, 242))
7527	22207316	The monoclonal antibodies (mAbs) used were directed against the following antigens: anti-CD3, anti-CD4, anti-CD25 and anti-CD163 (Novocastra), anti-CD8 (DB Biotech), anti-FOXP3 (CNIO Madrid), anti-GATA3 (Becton-Dickinson; BD Biosciences, San Jose, CA, USA) and anti-T-Bet (Santa Cruz Biotechnology, Inc.).	('CD8', 'Gene', '925', (148, 151))	('CD25', 'Gene', (109, 113))	('FOXP3', 'Gene', '50943', (171, 176))	('CD163', 'Gene', '9332', (123, 128))	('CD25', 'Gene', '3559', (109, 113))	('GATA3', 'Gene', (197, 202))	('CD163', 'Gene', (123, 128))	('anti-CD3', 'Var', (84, 92))	('CD8', 'Gene', (148, 151))	('CD4', 'Gene', (99, 102))	('GATA3', 'Gene', '2625', (197, 202))	('FOXP3', 'Gene', (171, 176))	('CD4', 'Gene', '920', (99, 102))
7541	22207316	The specificity of T-cell recognition was determined by the inhibition of the IFN-gamma release after pre-incubation of target cells with the W6/32 (anti-HLA class I) or L243 (anti-HLA class II DR molecules) mAbs (ATCC).	('inhibition', 'NegReg', (60, 70))	('L243', 'Var', (170, 174))	('IFN-gamma', 'Gene', '3458', (78, 87))	('IFN-gamma', 'Gene', (78, 87))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('cell recognition', 'biological_process', 'GO:0008037', ('21', '37'))
7564	22207316	2, T lymphocytes maintained in culture with IL-2 and IL-15 released the highest amount of IFN-gamma (n. 337 spots/5,000 cells) after the incubation with the autologous tumor cells (#2710 mel) (Fig.	('IL-2', 'molecular_function', 'GO:0005134', ('44', '48'))	('tumor', 'Disease', (168, 173))	('IL-15', 'Gene', '3600', (53, 58))	('IFN-gamma', 'Gene', '3458', (90, 99))	('IFN-gamma', 'Gene', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('IL-15', 'molecular_function', 'GO:0016170', ('53', '58'))	('#2710 mel', 'Var', (181, 190))	('IL-2', 'Gene', '3558', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('IL-2', 'Gene', (44, 48))	('IL-15', 'Gene', (53, 58))
7566	22207316	Specific inhibition of IFN-gamma release was observed after pre-incubation of the autologous tumor cells with the anti-HLA class I mAb (W6/32), not with the anti-HLA class II (L243) mAb (Fig.	('inhibition', 'NegReg', (9, 19))	('anti-HLA', 'Var', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('IFN-gamma', 'Gene', '3458', (23, 32))	('IFN-gamma', 'Gene', (23, 32))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
7576	22207316	Independent MLTC cultures were set up from PBMCs isolated from 6 metastatic cutaneous melanoma patients (#2710, 4478D, JOFR-IA, DAJU, 0342 and 7).	('MLTC', 'Chemical', '-', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('patients', 'Species', '9606', (95, 103))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('#2710', 'Var', (105, 110))
7581	22207316	These T lymphocytes exhibit specific recognition of the autologous tumor lines (285 spots/5,000 cells for #2710 Fig.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('285', 'Var', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
7582	22207316	Instead, low inhibition (26% for #2710) of IFN-gamma release was found in the presence of the anti-MHC class II (L243) mAb (Fig.	('IFN-gamma', 'Gene', '3458', (43, 52))	('IFN-gamma', 'Gene', (43, 52))	('MHC', 'Gene', (99, 102))	('L243', 'Var', (113, 117))	('MHC', 'Gene', '3107', (99, 102))
7597	22207316	We could also isolate CD4+ T cells specifically directed against the autologous tumor (#15765) as shown by the inhibition of IFN-gamma release by L243 mAb in MLTC1 (Figure 1S Panel B of supplementary results).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IFN-gamma', 'Gene', '3458', (125, 134))	('IFN-gamma', 'Gene', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('L243 mAb', 'Var', (146, 154))	('tumor', 'Disease', (80, 85))	('MLTC', 'Chemical', '-', (158, 162))	('CD4', 'Gene', (22, 25))	('MLTC1', 'Gene', (158, 163))	('CD4', 'Gene', '920', (22, 25))	('inhibition', 'NegReg', (111, 121))
7606	22207316	These T-cell cultures expressed, though to a variable extent (20-40% of positive cells), some co-stimulatory receptors such as CD28, NKG2D, OX40 (CD134), 4-1BB (CD137), while CD27 was found positive only in 3/6 patients (4478D, JOFR-IA and DAJU; representative data are shown in Fig.	('JOFR-IA', 'Disease', (228, 235))	('OX40', 'Gene', '7293', (140, 144))	('4-1BB', 'Gene', (154, 159))	('patients', 'Species', '9606', (211, 219))	('OX40', 'Gene', (140, 144))	('CD28', 'Gene', (127, 131))	('CD27', 'Gene', '939', (175, 179))	('CD27', 'Gene', (175, 179))	('NKG2D', 'Gene', '22914', (133, 138))	('CD28', 'Gene', '940', (127, 131))	('CD137', 'Gene', (161, 166))	('4-1BB', 'Gene', '3604', (154, 159))	('CD134', 'Gene', (146, 151))	('4478D', 'Var', (221, 226))	('CD137', 'Gene', '3604', (161, 166))	('CD134', 'Gene', '7293', (146, 151))	('NKG2D', 'Gene', (133, 138))
7615	22207316	Initially, we isolated TILs from 5 metastatic cutaneous melanoma (3 subcutaneous lesions #4478D, 9476, 25368 and 2 lymph node lesions #3681 and 4931, respectively) and from 4 ocular melanoma (3 primary #3470, 1141, 4022 and one metastatic #15765) patients.	('ocular melanoma', 'Disease', 'MESH:D008545', (175, 190))	('ocular melanoma', 'Disease', (175, 190))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('ocular melanoma', 'Phenotype', 'HP:0007716', (175, 190))	('subcutaneous lesions', 'Phenotype', 'HP:0001482', (68, 88))	('patients', 'Species', '9606', (247, 255))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('9476', 'Var', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))
7616	22207316	6 (cutaneous melanoma patients # 3681, 4931, 9476 and 25368, panels A, B and C and primary ocular melanoma patients #3470, 1141 and 4022, panels D, E and F).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('4931', 'Var', (39, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('ocular melanoma', 'Phenotype', 'HP:0007716', (91, 106))	('cutaneous melanoma', 'Disease', (3, 21))	('patients', 'Species', '9606', (22, 30))	('9476', 'Var', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('ocular melanoma', 'Disease', (91, 106))	('ocular melanoma', 'Disease', 'MESH:D008545', (91, 106))	('patients', 'Species', '9606', (107, 115))	('#3470', 'Var', (116, 121))
7622	22207316	All T cells expressed homogeneously CD45RO (data not shown) and high levels of CD28 (40-94% of positive cells; Panels B and E), while CD27 was detected only in TILs from two cutaneous melanoma patients (#25368 and #9476, 39 and 46% of CD8+ T cells, respectively; panel B) and in CD8+ lymphocytes from one ocular melanoma patient (# 3470, 24% of CD8+ T cells; panel E).	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('CD8', 'Gene', (235, 238))	('cutaneous melanoma', 'Disease', (174, 192))	('CD8', 'Gene', (345, 348))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))	('ocular melanoma', 'Phenotype', 'HP:0007716', (305, 320))	('#25368', 'Var', (203, 209))	('CD8', 'Gene', (279, 282))	('CD28', 'Gene', (79, 83))	('ocular melanoma', 'Disease', 'MESH:D008545', (305, 320))	('patients', 'Species', '9606', (193, 201))	('CD8', 'Gene', '925', (235, 238))	('CD27', 'Gene', (134, 138))	('CD28', 'Gene', '940', (79, 83))	('CD8', 'Gene', '925', (345, 348))	('patient', 'Species', '9606', (321, 328))	('#9476', 'Var', (214, 219))	('CD45', 'Gene', (36, 40))	('CD27', 'Gene', '939', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('ocular melanoma', 'Disease', (305, 320))	('CD8', 'Gene', '925', (279, 282))	('CD45', 'Gene', '5788', (36, 40))	('patient', 'Species', '9606', (193, 200))
7626	22207316	CD134 was homogeneously associated with both CD4+ and CD8+ T cells from TILs of #9476 and #1141 cutaneous and ocular melanoma patients, respectively (Fig.	('#1141', 'Var', (90, 95))	('CD8', 'Gene', '925', (54, 57))	('CD134', 'Gene', (0, 5))	('associated', 'Reg', (24, 34))	('CD4', 'Gene', (45, 48))	('CD4', 'Gene', '920', (45, 48))	('ocular melanoma', 'Disease', 'MESH:D008545', (110, 125))	('ocular melanoma', 'Disease', (110, 125))	('CD134', 'Gene', '7293', (0, 5))	('patients', 'Species', '9606', (126, 134))	('ocular melanoma', 'Phenotype', 'HP:0007716', (110, 125))	('cutaneous', 'Disease', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('CD8', 'Gene', (54, 57))
7631	22207316	Notably, an immune infiltrate was detected also by IHC analysis in 10 primary ocular melanoma lesions (representative results of patients #50306324 and 50316250 are shown in the Fig.	('ocular melanoma', 'Phenotype', 'HP:0007716', (78, 93))	('patients', 'Species', '9606', (129, 137))	('ocular melanoma lesions', 'Disease', (78, 101))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('50316250', 'Var', (152, 160))	('ocular melanoma lesions', 'Disease', 'MESH:D008545', (78, 101))
7641	22207316	High levels of IFN-gamma release (355 and 334 spots/5,000 cells for patients #4478D and #15765, respectively) were observed following incubation of TILs from both patients with the autologous tumor cell lines.	('tumor', 'Disease', (192, 197))	('patients', 'Species', '9606', (163, 171))	('#15765', 'Var', (88, 94))	('patients', 'Species', '9606', (68, 76))	('IFN-gamma', 'Gene', '3458', (15, 24))	('IFN-gamma', 'Gene', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
7642	22207316	Moreover, the tumor recognition was HLA-restricted as the cytokine secretion was inhibited (65 and 58% for patients #4478D and #15765, respectively) by the incubation of tumor cells with the anti-HLA-class I (W6/32) mAb, but not by the anti-HLA class II mAb (L243).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', (14, 19))	('cytokine secretion', 'biological_process', 'GO:0050663', ('58', '76'))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cytokine secretion', 'MPA', (58, 76))	('tumor', 'Disease', (170, 175))	('anti-HLA-class', 'Var', (191, 205))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('#15765', 'Var', (127, 133))	('patients', 'Species', '9606', (107, 115))
7647	22207316	8 indicate that efficient expansion (68-148 x 106 T cells) of TILs (#15765 and #4478D) and MLTCs (#4478D, #2710 and #0342) could be achieved with an increase value of 240-592 times (Fig.	('#4478D', 'Var', (98, 104))	('#0342', 'Var', (116, 121))	('#4478D', 'Var', (79, 85))	('MLTCs', 'Chemical', '-', (91, 96))	('#2710', 'Var', (106, 111))	('#15765', 'Var', (68, 74))
7650	22207316	The specific anti-tumor reactivity by MLTC-derived T lymphocytes expanded in vitro in large scale with the use of the REP protocol was obtained for all of the 7 cutaneous or ocular melanoma patients (# 7, 2710, 0342, 4478D, DAJU-1A, JOFR and 15765).	('ocular melanoma', 'Disease', (174, 189))	('obtained', 'Reg', (135, 143))	('REP', 'molecular_function', 'GO:0017137', ('118', '121'))	('tumor', 'Disease', (18, 23))	('patients', 'Species', '9606', (190, 198))	('ocular melanoma', 'Phenotype', 'HP:0007716', (174, 189))	('4478D', 'Var', (217, 222))	('MLTC', 'Chemical', '-', (38, 42))	('# 7', 'Var', (200, 203))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('ocular melanoma', 'Disease', 'MESH:D008545', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
7678	22207316	However, higher levels of co-stimulatory molecules were found in MLTC lymphocytes, suggesting that efficient anti-tumor activity and persistence in vivo can be associated with MLTCs rather than with TILs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MLTCs', 'Chemical', '-', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('MLTC', 'Chemical', '-', (65, 69))	('persistence', 'CPA', (133, 144))	('MLTC', 'Chemical', '-', (176, 180))	('MLTCs', 'Var', (176, 181))
7726	32205655	In a landmark study by Leach et al, blockage of CTLA-4 was demonstrated to cause tumor rejection, as well as future immunologic memory.	('cause', 'Reg', (75, 80))	('CTLA-4', 'Gene', (48, 54))	('blockage', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CTLA-4', 'Gene', '1493', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('memory', 'biological_process', 'GO:0007613', ('128', '134'))	('tumor', 'Disease', (81, 86))
7735	32205655	In 2014, the FDA approved nivolumab based on a study in which patients with metastatic melanoma without BRAF mutations were treated with either nivolumab or dacarbazine, with results showing that nivolumab resulted in superior overall survival and progression-free survival.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('overall survival', 'CPA', (227, 243))	('nivolumab', 'Chemical', 'MESH:D000077594', (26, 35))	('superior', 'PosReg', (218, 226))	('progression-free survival', 'CPA', (248, 273))	('dacarbazine', 'Chemical', 'MESH:D003606', (157, 168))	('nivolumab', 'Chemical', 'MESH:D000077594', (144, 153))	('BRAF', 'Gene', '673', (104, 108))	('nivolumab', 'Chemical', 'MESH:D000077594', (196, 205))	('mutations', 'Var', (109, 118))	('BRAF', 'Gene', (104, 108))	('patients', 'Species', '9606', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
7754	32205655	In addition, cutaneous and conjunctival melanomas share several significant mutational similarities including high expression of BRAF, NRAS, numerous copy number variations, and heat shock protein 90 expressions while having low rates of GNA11, p16, and KIT.	('GNA11', 'Gene', (238, 243))	('NRAS', 'Gene', '4893', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('KIT', 'Gene', '3815', (254, 257))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('KIT', 'molecular_function', 'GO:0005020', ('254', '257'))	('shock', 'Phenotype', 'HP:0031273', (183, 188))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (27, 49))	('high', 'PosReg', (110, 114))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (27, 48))	('NRAS', 'Gene', (135, 139))	('GNA11', 'Gene', '2767', (238, 243))	('conjunctival melanomas', 'Disease', (27, 49))	('p16', 'Gene', (245, 248))	('KIT', 'Gene', (254, 257))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('p16', 'Gene', '1029', (245, 248))	('expression', 'MPA', (115, 125))	('copy number variations', 'Var', (150, 172))	('cutaneous', 'Disease', (13, 22))
7755	32205655	In contrast, conjunctival melanoma differs from uveal melanoma, which instead has higher GNAQ/GNA11 mutations.	('mutations', 'Var', (100, 109))	('GNA11', 'Gene', '2767', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (48, 62))	('conjunctival melanoma', 'Disease', (13, 34))	('uveal melanoma', 'Disease', (48, 62))	('GNAQ', 'Gene', '2776', (89, 93))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (13, 34))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (13, 34))	('higher', 'PosReg', (82, 88))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('GNAQ', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('GNA11', 'Gene', (94, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (48, 62))
7818	22745734	In addition, ALCAM-null mice on a mixed C57BL/6-129 background exhibit retinal dysplasias, including disrupted organization of the outer nuclear layer photoreceptor neurons and invagination of the adjacent retinal pigment epithelium (RPE) and choroid (choriocapillaris); these dysplasias are greatly reduced on a congenic C57BL/6 background, however (data not shown).	('organization', 'CPA', (111, 123))	('retinal dysplasias', 'Disease', (71, 89))	('retinal dysplasias', 'Disease', 'MESH:D015792', (71, 89))	('mice', 'Species', '10090', (24, 28))	('dysplasias', 'Disease', (277, 287))	('choriocapillaris', 'Disease', 'MESH:D008268', (252, 268))	('C57BL/6-129', 'Var', (40, 51))	('invagination', 'CPA', (177, 189))	('choriocapillaris', 'Disease', (252, 268))	('dysplasias', 'Disease', (79, 89))	('retinal dysplasias', 'Phenotype', 'HP:0007973', (71, 89))	('ALCAM-null', 'Gene', (13, 23))	('dysplasias', 'Disease', 'MESH:D004476', (277, 287))	('dysplasias', 'Disease', 'MESH:D004476', (79, 89))
7819	22745734	This previously undocumented expression, as well as the fact that choroidal melanocytes were found within ectopic retinal folds suggests that in the absence of ALCAM, the structure and/or function of melanocytes in the uvea, which includes the choroid, iris, and ciliary body, might be disrupted.	('ALCAM', 'Gene', (160, 165))	('structure', 'CPA', (171, 180))	('uvea', 'Disease', 'MESH:C536494', (219, 223))	('uvea', 'Disease', (219, 223))	('choroidal melanocytes', 'Phenotype', 'HP:0012054', (66, 87))	('retinal folds', 'Phenotype', 'HP:0008052', (114, 127))	('disrupted', 'NegReg', (286, 295))	('absence', 'Var', (149, 156))	('function', 'CPA', (188, 196))
7823	22745734	Unfortunately, these data are necessarily correlative in nature; therefore, an understanding of the contribution of ALCAM to cancer progression and, indeed, normal cell motility and adhesion, has been hampered by a lack of studies aimed at directly manipulating ALCAM levels within particular cell lines and determining the outcome of this manipulation.	('manipulating', 'Var', (249, 261))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cell motility', 'biological_process', 'GO:0048870', ('164', '177'))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
7828	22745734	Silencing of ALCAM using targeted shRNAs in MUM-2B results in both impaired cell motility and reduced invasive capacity in an in vitro assay, consistent with an observed reduction in matrix metalloproteinase activation.	('reduction', 'NegReg', (170, 179))	('impaired cell motility', 'Disease', (67, 89))	('MUM-2', 'Gene', '58485', (44, 49))	('ALCAM', 'Gene', (13, 18))	('reduced', 'NegReg', (94, 101))	('impaired cell motility', 'Disease', 'MESH:D015835', (67, 89))	('MUM-2', 'Gene', (44, 49))	('invasive capacity in an', 'CPA', (102, 125))	('cell motility', 'biological_process', 'GO:0048870', ('76', '89'))	('Silencing', 'Var', (0, 9))
7832	22745734	Conversely, silencing of ALCAM expression in MUM-2B disrupts the formation of adherens junctions.	('formation of adherens junctions', 'CPA', (65, 96))	('silencing', 'Var', (12, 21))	('ALCAM', 'Gene', (25, 30))	('disrupts', 'NegReg', (52, 60))	('MUM-2', 'Gene', '58485', (45, 50))	('formation', 'biological_process', 'GO:0009058', ('65', '74'))	('MUM-2', 'Gene', (45, 50))
7889	22745734	Subsequent analysis of short tandem repeats in the genomic DNA of these uveal melanoma lines indicates that MUM-2B and MUM-2C are, in fact, unlikely to have derived from the same metastasis.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('MUM-2', 'Gene', (108, 113))	('short tandem repeats', 'Var', (23, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('MUM-2', 'Gene', '58485', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MUM-2', 'Gene', '58485', (108, 113))	('MUM-2', 'Gene', (119, 124))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
7890	22745734	Folberg and colleagues (2008) additionally present evidence that OCM-1A and MUM-2C share the same origin, as do MUM-2B, M619, and C918; our data below are consistent with this.	('MUM-2', 'Gene', (76, 81))	('MUM-2', 'Gene', (112, 117))	('OCM-1', 'Species', '83984', (65, 70))	('M619', 'Var', (120, 124))	('C918', 'Var', (130, 134))	('MUM-2', 'Gene', '58485', (76, 81))	('MUM-2', 'Gene', '58485', (112, 117))
7896	22745734	Gap closure analysis of the remaining cell lines revealed that M619 and C918 were fast-moving like MUM-2B, while OCM-1A was slow-moving like MUM-2C.	('MUM-2', 'Gene', (141, 146))	('MUM-2', 'Gene', '58485', (99, 104))	('OCM-1', 'Species', '83984', (113, 118))	('C918', 'Var', (72, 76))	('fast-moving', 'MPA', (82, 93))	('MUM-2', 'Gene', (99, 104))	('MUM-2', 'Gene', '58485', (141, 146))	('M619', 'Var', (63, 67))
7897	22745734	MUM-2B, C918, and M619 all moved at speeds 2-3 fold greater than OCM-1A and MUM-2C (Fig.	('MUM-2', 'Gene', (76, 81))	('MUM-2', 'Gene', '58485', (0, 5))	('greater', 'PosReg', (52, 59))	('OCM-1', 'Species', '83984', (65, 70))	('MUM-2', 'Gene', (0, 5))	('C918', 'Var', (8, 12))	('MUM-2', 'Gene', '58485', (76, 81))	('M619', 'Var', (18, 22))
7898	22745734	ALCAM protein expression was undetectable in OCM-1A and MUM-2C; in contrast, it was similarly high in MUM-2B, C918, and M619 (Fig.	('high', 'PosReg', (94, 98))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('C918', 'Var', (110, 114))	('undetectable', 'NegReg', (29, 41))	('MUM-2', 'Gene', '58485', (102, 107))	('M619', 'Var', (120, 124))	('MUM-2', 'Gene', (102, 107))	('MUM-2', 'Gene', '58485', (56, 61))	('OCM-1', 'Species', '83984', (45, 50))	('ALCAM protein', 'Protein', (0, 13))	('MUM-2', 'Gene', (56, 61))
7905	22745734	To determine whether ALCAM regulates uveal melanoma cell behavior, we began by knocking down ALCAM levels in MUM-2B cells, which normally express high levels of ALCAM.	('MUM-2', 'Gene', '58485', (109, 114))	('knocking', 'Var', (79, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (37, 51))	('ALCAM', 'Gene', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (37, 51))	('MUM-2', 'Gene', (109, 114))	('uveal melanoma', 'Disease', (37, 51))
7911	22745734	Silencing ALCAM results in a significant reduction in motility: sh5 cells exhibit a closure rate nearly 50% lower than that of parental MUM-2B or non-silenced sh6 cells (Fig.	('ALCAM', 'Gene', (10, 15))	('MUM-2', 'Gene', '58485', (136, 141))	('MUM-2', 'Gene', (136, 141))	('closure rate', 'CPA', (84, 96))	('lower', 'NegReg', (108, 113))	('motility', 'CPA', (54, 62))	('Silencing', 'Var', (0, 9))	('reduction', 'NegReg', (41, 50))
7913	22745734	We next sought to determine how silencing ALCAM impacts invasive capacity of MUM-2B uveal melanoma cells.	('impacts', 'Reg', (48, 55))	('MUM-2B uveal melanoma', 'Disease', 'MESH:C536494', (77, 98))	('invasive capacity', 'CPA', (56, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('ALCAM', 'Gene', (42, 47))	('silencing', 'Var', (32, 41))	('MUM-2B uveal melanoma', 'Disease', (77, 98))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
7934	22745734	4) MMP-2 activity was not increased in 2C-ALC compared to parental MUM-2C (Fig.	('MUM-2', 'Gene', '58485', (67, 72))	('2C-ALC', 'Var', (39, 45))	('MMP-2', 'Gene', (3, 8))	('MUM-2', 'Gene', (67, 72))	('activity', 'MPA', (9, 17))	('MMP-2', 'molecular_function', 'GO:0004228', ('3', '8'))	('MMP-2', 'Gene', '4313', (3, 8))
7950	22745734	Neither silencing of ALCAM in sh5 nor its re-expression in sh5rxd appeared to affect levels of ss-catenin or N-cadherin expression (Fig.	('levels of ss-catenin', 'MPA', (85, 105))	('silencing', 'Var', (8, 17))	('ALCAM', 'Gene', (21, 26))	('ss-catenin', 'Chemical', '-', (95, 105))	('affect', 'Reg', (78, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('111', '119'))	('N-cadherin expression', 'MPA', (109, 130))
7959	22745734	Together with our analysis of sh5 silenced cells, these data suggest that ALCAM expression is both necessary and sufficient to promote the recruitment of N-cadherin and ss-catenin to form adherens junctions in uveal melanoma cells.	('cadherin', 'molecular_function', 'GO:0008014', ('156', '164'))	('ss-catenin', 'Chemical', '-', (169, 179))	('uveal melanoma', 'Disease', (210, 224))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('N-cadherin', 'Protein', (154, 164))	('promote', 'PosReg', (127, 134))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('recruitment', 'MPA', (139, 150))	('ss-catenin', 'Protein', (169, 179))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('ALCAM', 'Gene', (74, 79))	('expression', 'Var', (80, 90))
7967	22745734	It appeared that the disruption of homophilic ALCAM contacts thus resulted in increased metastatic potential in cutaneous melanoma cell lines; this was, however, in contrast to previous expression data that predicted ALCAM would promote invasion and metastasis.	('promote', 'PosReg', (229, 236))	('metastatic potential', 'CPA', (88, 108))	('disruption', 'Var', (21, 31))	('cutaneous melanoma', 'Disease', (112, 130))	('increased', 'PosReg', (78, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
7974	22745734	We further find that silencing of ALCAM in the invasive MUM-2B line results in decreased motility, invasiveness, and MMP-2 activation.	('motility', 'CPA', (89, 97))	('decreased', 'NegReg', (79, 88))	('MMP-2', 'molecular_function', 'GO:0004228', ('117', '122'))	('MMP-2', 'Gene', (117, 122))	('ALCAM', 'Gene', (34, 39))	('invasiveness', 'CPA', (99, 111))	('MUM-2', 'Gene', '58485', (56, 61))	('activation', 'PosReg', (123, 133))	('MMP-2', 'Gene', '4313', (117, 122))	('silencing', 'Var', (21, 30))	('MUM-2', 'Gene', (56, 61))
7981	22745734	Thus, changes in the expression and localization of cell adhesion molecules can influence tumor progression by both modulating the adhesion status of a cell and by altering cell signaling.	('adhesion status', 'MPA', (131, 146))	('altering', 'Reg', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell adhesion molecules', 'Protein', (52, 75))	('tumor', 'Disease', (90, 95))	('expression', 'MPA', (21, 31))	('signaling', 'biological_process', 'GO:0023052', ('178', '187'))	('changes', 'Var', (6, 13))	('cell adhesion', 'biological_process', 'GO:0007155', ('52', '65'))	('localization of cell', 'biological_process', 'GO:0051674', ('36', '56'))	('localization', 'MPA', (36, 48))	('cell signaling', 'MPA', (173, 187))	('influence', 'Reg', (80, 89))	('modulating', 'Reg', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
7998	22745734	The reduction in invasiveness we observe appears at odds with the finding that amino-truncated ALCAM expression served to disrupt ALCAM junctions and to reduce MMP-2 activation, but actually increased the invasive capacity of BLM cutaneous melanoma cells  .	('reduce', 'NegReg', (153, 159))	('MMP-2', 'Gene', (160, 165))	('amino-truncated', 'Var', (79, 94))	('ALCAM', 'Gene', (95, 100))	('MMP-2', 'Gene', '4313', (160, 165))	('increased', 'PosReg', (191, 200))	('invasiveness', 'MPA', (17, 29))	('ALCAM junctions', 'MPA', (130, 145))	('disrupt', 'Reg', (122, 129))	('MMP-2', 'molecular_function', 'GO:0004228', ('160', '165'))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('cutaneous melanoma', 'Disease', (230, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (230, 248))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (230, 248))
7999	22745734	An attractive hypothesis that could account for the increased invasiveness caused by a dominant-negative ALCAM versus our own results in which silencing ALCAM results in decreased invasiveness, centers around the cadherin status of the cell lines used in each study.	('invasiveness', 'MPA', (62, 74))	('ALCAM', 'Gene', (105, 110))	('increased', 'PosReg', (52, 61))	('cadherin', 'molecular_function', 'GO:0008014', ('213', '221'))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (213, 221))	('decreased invasiveness', 'Disease', (170, 192))	('ALCAM', 'Gene', (153, 158))	('cadherin', 'Gene', (213, 221))	('decreased invasiveness', 'Disease', 'MESH:D009362', (170, 192))	('silencing', 'Var', (143, 152))
8005	22745734	It will also be important to determine the specificity of the interaction between ALCAM and cadherins: can silencing of ALCAM remove a variety of classical cadherins from adherens junctions in different cell types?	('adherens junctions', 'MPA', (171, 189))	('silencing', 'Var', (107, 116))	('cadherin', 'Gene', (156, 164))	('ALCAM', 'Gene', (120, 125))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (92, 100))	('remove', 'NegReg', (126, 132))	('cadherin', 'Gene', (92, 100))	('cadherin', 'Gene', '999;442858;1000;12558;1003', (156, 164))
8007	33907692	TNFR2: Role in Cancer Immunology and Immunotherapy Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/programmed death-ligand 1), represent a turning point in the cancer immunotherapy.	('ligand', 'molecular_function', 'GO:0005488', ('202', '208'))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('TNFR2', 'Gene', (0, 5))	('Cancer', 'Disease', 'MESH:D009369', (15, 21))	('death', 'Disease', (177, 182))	('anti-CTLA-4', 'Var', (98, 109))	('cancer', 'Disease', (246, 252))	('PD-L1', 'Gene', '29126', (159, 164))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('death', 'Disease', 'MESH:D003643', (177, 182))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('123', '141'))	('death', 'Disease', 'MESH:D003643', (196, 201))	('TNFR2', 'Gene', '7133', (0, 5))	('death', 'Disease', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('PD-L1', 'Gene', (159, 164))	('Cancer', 'Disease', (15, 21))
8009	33907692	CD4+Foxp3+ regulatory T cells (Tregs) represent a major cellular mechanism in cancer immune evasion.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('immune evasion', 'biological_process', 'GO:0051842', ('85', '99'))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('CD4+Foxp3+', 'Var', (0, 10))	('Tregs', 'Chemical', '-', (31, 36))	('immune evasion', 'biological_process', 'GO:0042783', ('85', '99'))
8022	33907692	Indeed, it was reported that the treatment with anti-TNF antibody is effective in the control of irAEs in patients.	('irAEs', 'Disease', (97, 102))	('antibody', 'cellular_component', 'GO:0042571', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019815', ('57', '65'))	('antibody', 'cellular_component', 'GO:0019814', ('57', '65'))	('patients', 'Species', '9606', (106, 114))	('antibody', 'molecular_function', 'GO:0003823', ('57', '65'))	('anti-TNF', 'Var', (48, 56))
8049	33907692	Recently, we have reported that inhibition of two-pore channels with tetrandrine or siRNAs increases the number of CD4+Foxp3+ Tregs in an mTNF-TNFR2-dependent manner in mice.	('siRNAs', 'Gene', (84, 90))	('mTNF', 'Gene', '21926', (138, 142))	('inhibition', 'Var', (32, 42))	('two-pore', 'Protein', (46, 54))	('pore', 'cellular_component', 'GO:0046930', ('50', '54'))	('Tregs', 'Chemical', '-', (126, 131))	('tetrandrine', 'Chemical', 'MESH:C009438', (69, 80))	('mice', 'Species', '10090', (169, 173))	('mTNF', 'Gene', (138, 142))	('CD4+Foxp3+', 'Var', (115, 125))	('increases', 'PosReg', (91, 100))
8057	33907692	Previously, it was shown that activation of TNFR2 in human CD4+ and CD8+ T cells results in the proliferative expansion through the IKK/NF-kappaB pathway, including the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and these pathways of TNFR2 signaling are likely applicable to Tregs.	('IKK', 'Gene', '1147;12675', (132, 135))	('phosphatidylinositol 3-kinase', 'Gene', (183, 212))	('CD8', 'Gene', (68, 71))	('protein kinase B', 'Gene', '2185', (220, 236))	('protein', 'cellular_component', 'GO:0003675', ('220', '227'))	('protein kinase B', 'Gene', (220, 236))	('AKT', 'Gene', '207', (238, 241))	('TNFR2', 'Gene', (44, 49))	('PI3K', 'molecular_function', 'GO:0016303', ('214', '218'))	('activation', 'PosReg', (169, 179))	('phosphatidylinositol 3-kinase', 'Gene', '5294', (183, 212))	('IKK', 'Gene', (132, 135))	('IKK', 'molecular_function', 'GO:0008384', ('132', '135'))	('CD8', 'Gene', '925', (68, 71))	('human', 'Species', '9606', (53, 58))	('activation', 'Var', (30, 40))	('AKT', 'Gene', (238, 241))	('signaling', 'biological_process', 'GO:0023052', ('272', '281'))	('proliferative expansion', 'CPA', (96, 119))	('Tregs', 'Chemical', '-', (307, 312))
8059	33907692	Moreover, a recent study indicates that the stimulatory effect of TNF on Tregs is partially through an epigenetic mechanism that demethylates the foxp3 gene.	('foxp3', 'Gene', '50943', (146, 151))	('demethylates', 'Var', (129, 141))	('foxp3', 'Gene', (146, 151))	('Tregs', 'Chemical', '-', (73, 78))
8060	33907692	Ex vivo activation of Treg cells by the stimulation with anti-CD3/CD28 represses the mTOR pathway and disfavors glycolysis, which contrasts with conventional T (Tconvs) cells.	('activation', 'PosReg', (8, 18))	('glycolysis', 'MPA', (112, 122))	('Treg', 'Chemical', '-', (22, 26))	('glycolysis', 'biological_process', 'GO:0006096', ('112', '122'))	('anti-CD3/CD28', 'Var', (57, 70))	('mTOR', 'Gene', '2475', (85, 89))	('represses', 'NegReg', (71, 80))	('mTOR', 'Gene', (85, 89))	('disfavors', 'NegReg', (102, 111))
8064	33907692	Glycolytic tTreg cells produce lactate from glucose and participate in the complete glycolytic pathway upon TNFR2 co-stimulation, while the net lactate secretion remains unaltered.	('participate', 'Reg', (56, 67))	('Treg', 'Chemical', '-', (12, 16))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('co-stimulation', 'Var', (114, 128))	('lactate', 'Chemical', 'MESH:D019344', (144, 151))	('TNFR2', 'Gene', (108, 113))	('glycolytic pathway', 'Pathway', (84, 102))	('lactate from glucose', 'MPA', (31, 51))	('lactate', 'Chemical', 'MESH:D019344', (31, 38))	('lactate secretion', 'biological_process', 'GO:0046722', ('144', '161'))
8069	33907692	A recent study shows that the exogenous TNF boosts the differentiation and function of iTreg via TNFR2 signaling.	('boosts', 'PosReg', (44, 50))	('function', 'MPA', (75, 83))	('Treg', 'Chemical', '-', (88, 92))	('differentiation', 'CPA', (55, 70))	('iTreg', 'Protein', (87, 92))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('TNF', 'Gene', (40, 43))	('exogenous', 'Var', (30, 39))
8071	33907692	In comparison, TNFR1 deficiency leads to the reduction of the differentiation of inflammatory T cells such as Th1 (T Helper Type 1) and Th17 (T Helper Type 17) cells, while the iTregs function remains intact.	('differentiation', 'CPA', (62, 77))	('TNFR1', 'Gene', '7132', (15, 20))	('deficiency', 'Var', (21, 31))	('Tregs', 'Chemical', '-', (178, 183))	('TNFR1', 'Gene', (15, 20))	('reduction', 'NegReg', (45, 54))
8094	33907692	A recent study shows that the proportion of TNFR2+ cells was markedly higher in CD4+ T cells than CD19+ B cells or CD8+ T cells in the tumor-draining lymph nodes derived from breast cancer patients.	('CD8', 'Gene', '925', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('CD4+ T cells', 'Var', (80, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('breast cancer', 'Disease', (175, 188))	('tumor', 'Disease', (135, 140))	('higher', 'PosReg', (70, 76))	('patients', 'Species', '9606', (189, 197))	('CD8', 'Gene', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
8110	33907692	Future studies may need to focus on those types of human cancers with high TNFR2 gene expression.	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('high', 'Var', (70, 74))	('TNFR2', 'Gene', (75, 80))
8113	33907692	Further, Ki-67 expression is up-regulated by overexpression of TNFR2 in SW1116 cells and inhibited by TNFR2 silence in HT29 cells.	('silence', 'Var', (108, 115))	('TNFR2', 'Gene', (63, 68))	('inhibited', 'NegReg', (89, 98))	('Ki-67', 'Gene', (9, 14))	('up-regulated', 'PosReg', (29, 41))	('expression', 'MPA', (15, 25))	('HT29 cells', 'CellLine', 'CVCL:0320', (119, 129))	('overexpression', 'PosReg', (45, 59))	('SW1116', 'CellLine', 'CVCL:0544', (72, 78))
8115	33907692	It was reported that allelic polymorphisms of TNFR2 (196 M/R (methionine/arginine)-TNFR2 variation) are associated with the development of breast carcinoma: 196 M allelic variant is associated with late-onset of breast cancer in post-menopausal patients, while 196R-TNFR2 in patients with breast carcinoma is associated with increased overall disease-free survival as compared with those absences of 196R allele.	('breast carcinoma', 'Disease', 'MESH:D001943', (139, 155))	('patients', 'Species', '9606', (245, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('associated', 'Reg', (104, 114))	('patients', 'Species', '9606', (275, 283))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('breast carcinoma', 'Phenotype', 'HP:0003002', (289, 305))	('breast cancer', 'Disease', (212, 225))	('196 M/R', 'Var', (53, 60))	('breast carcinoma', 'Phenotype', 'HP:0003002', (139, 155))	('breast carcinoma', 'Disease', (289, 305))	('arginine', 'Chemical', 'MESH:D001120', (73, 81))	('breast carcinoma', 'Disease', (139, 155))	('associated with', 'Reg', (182, 197))	('TNFR2', 'Gene', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast carcinoma', 'Disease', 'MESH:D001943', (289, 305))	('196 M/R', 'SUBSTITUTION', 'None', (53, 60))	('methionine', 'Chemical', 'MESH:D008715', (62, 72))	('increased', 'PosReg', (325, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
8116	33907692	Furthermore, a recent study found that the loss of one TNFR2 allele enhances the incidence of breast cancer in MMTV (mouse mammary tumor virus)-Wnt1 mouse model and results in a more aggressive phenotype and metastasis by activating the canonical NF-kappaB signaling pathway and autocrine production of TNF.	('Wnt1', 'Gene', (144, 148))	('more', 'PosReg', (178, 182))	('canonical NF-kappaB signaling pathway', 'Pathway', (237, 274))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('activating', 'PosReg', (222, 232))	('mouse', 'Species', '10090', (117, 122))	('mouse', 'Species', '10090', (149, 154))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('aggressive phenotype', 'CPA', (183, 203))	('mouse mammary tumor virus', 'Species', '11757', (117, 142))	('loss', 'Var', (43, 47))	('Wnt1', 'Gene', '7471', (144, 148))	('MMTV', 'Species', '11757', (111, 115))	('metastasis', 'CPA', (208, 218))	('enhances', 'PosReg', (68, 76))	('TNFR2', 'Gene', (55, 60))	('autocrine production', 'MPA', (279, 299))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('signaling pathway', 'biological_process', 'GO:0007165', ('257', '274'))	('results in', 'Reg', (165, 175))
8121	33907692	In tumor-bearing TNFR2-/-mice, the development of MDSCs is impaired, and this contributes to the growth inhibition of tumor in mice deficient in TNFR2.	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('development of MDSCs', 'CPA', (35, 55))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TNFR2-/-mice', 'Gene', (17, 29))	('TNFR2', 'Gene', (145, 150))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('impaired', 'NegReg', (59, 67))	('deficient', 'Var', (132, 141))	('growth', 'MPA', (97, 103))
8123	33907692	Deficiency of TNFR2 in MDSCs fails to accumulate in pre-metastatic lesions and results in the down-regulation of arginase-1 expression and reduces liver metastasis of lung cancer in mice.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('TNFR2', 'Gene', (14, 19))	('mice', 'Species', '10090', (182, 186))	('pre', 'molecular_function', 'GO:0003904', ('52', '55'))	('arginase-1', 'Gene', (113, 123))	('liver metastasis of lung cancer', 'Disease', 'MESH:D008175', (147, 178))	('liver metastasis of lung cancer', 'Disease', (147, 178))	('arginase-1', 'Gene', '11846', (113, 123))	('expression', 'MPA', (124, 134))	('reduces', 'NegReg', (139, 146))	('regulation', 'biological_process', 'GO:0065007', ('99', '109'))	('down-regulation', 'NegReg', (94, 109))	('Deficiency', 'Var', (0, 10))
8124	33907692	In mouse 4T1 breast cancer model, the immunosuppressive function and accumulation of MDSCs in TME as well as up-regulation of arginase-1 expression by MDSCs are dependent on TNFR2, through the activation of NF-kappaB and phosphorylation of p38.	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('193', '216'))	('p38', 'Protein', (240, 243))	('phosphorylation', 'biological_process', 'GO:0016310', ('221', '236'))	('expression', 'MPA', (137, 147))	('activation', 'PosReg', (193, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('4T1', 'CellLine', 'CVCL:0125', (9, 12))	('phosphorylation', 'MPA', (221, 236))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('MDSCs', 'Var', (151, 156))	('arginase-1', 'Gene', (126, 136))	('breast cancer', 'Disease', (13, 26))	('up-regulation', 'PosReg', (109, 122))	('regulation', 'biological_process', 'GO:0065007', ('112', '122'))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mouse', 'Species', '10090', (3, 8))	('TNFR2', 'Gene', (174, 179))	('arginase-1', 'Gene', '11846', (126, 136))	('NF-kappaB', 'Protein', (207, 216))
8126	33907692	For example, several in vivo and in vitro studies have shown that MSCs are attributable to the immunosuppressive environment in TME by inhibiting the activation and maturation of DCs, reducing the killing ability of natural killer (NK) cells, promoting Tregs expansion, and suppressing functions of Teff cells.	('Tregs', 'Chemical', '-', (253, 258))	('DCs', 'Protein', (179, 182))	('suppressing', 'NegReg', (274, 285))	('functions', 'CPA', (286, 295))	('inhibiting', 'NegReg', (135, 145))	('promoting', 'PosReg', (243, 252))	('Teff', 'Chemical', '-', (299, 303))	('killing ability', 'CPA', (197, 212))	('MSCs', 'molecular_function', 'GO:0043854', ('66', '70'))	('MSCs', 'Var', (66, 70))	('reducing', 'NegReg', (184, 192))	('Tregs expansion', 'CPA', (253, 268))	('activation', 'MPA', (150, 160))
8132	33907692	It has been reported that TNF could increase the expression of pro-angiogenic mediators such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and IL-8 expression by ECs.	('IL-8', 'molecular_function', 'GO:0005153', ('175', '179'))	('VEGF', 'Gene', (132, 136))	('IL-8', 'Gene', '3576', (175, 179))	('increase', 'PosReg', (36, 44))	('expression', 'MPA', (180, 190))	('expression', 'MPA', (49, 59))	('VEGF', 'Gene', '7422', (132, 136))	('vascular endothelial growth factor', 'Gene', (96, 130))	('TNF', 'Var', (26, 29))	('IL-8', 'Gene', (175, 179))	('vascular endothelial growth factor', 'Gene', '7422', (96, 130))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('96', '130'))	('basic fibroblast growth factor', 'MPA', (139, 169))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('145', '169'))
8133	33907692	Blockade of TNFR2 with anti-TNFR2 monoclonal antibodies (mAbs) leads to the polarization of EPCs towards pro-inflammatory and immunogenic phenotype via TNF-TNFR1 pathway.	('EPCs', 'Disease', (92, 96))	('EPCs', 'cellular_component', 'GO:0140268', ('92', '96'))	('Blockade', 'Var', (0, 8))	('TNFR1', 'Gene', '7132', (156, 161))	('polarization', 'MPA', (76, 88))	('anti-TNFR2', 'Gene', (23, 33))	('TNFR2', 'Gene', (12, 17))	('TNFR1', 'Gene', (156, 161))
8144	33907692	It was shown that splenic IL-10-producing CD19+CD21+ Bregs promote the development of papilloma and growth of cancer in skin carcinogenesis induced by 7, 12-dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA).	('development', 'CPA', (71, 82))	('cancer', 'Disease', (110, 116))	('papilloma', 'Phenotype', 'HP:0012740', (86, 95))	('papilloma', 'Disease', (86, 95))	('12-O-tetradecanoylphorbol-13-acetate', 'Chemical', 'MESH:D013755', (191, 227))	('skin carcinogenesis', 'Disease', (120, 139))	('papilloma', 'Disease', 'MESH:D010212', (86, 95))	('DMBA', 'Chemical', '-', (181, 185))	('7, 12-dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (151, 179))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('promote', 'PosReg', (59, 66))	('CD19+CD21+', 'Var', (42, 52))	('TPA', 'molecular_function', 'GO:0031299', ('229', '232'))	('IL-10', 'molecular_function', 'GO:0005141', ('26', '31'))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (120, 139))	('TPA', 'Chemical', 'MESH:D013755', (229, 232))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer in skin', 'Phenotype', 'HP:0008069', (110, 124))
8162	33907692	Interestingly, TNF blockade can inhibit the AICD and consequently increase CD8+ tumor-infiltrating lymphocytes (TILs) and decrease PD-L1 and TIM-3 expression.	('AICD', 'CPA', (44, 48))	('inhibit', 'NegReg', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'MPA', (147, 157))	('decrease PD', 'Phenotype', 'HP:0032198', (122, 133))	('TIM-3', 'Gene', '84868', (141, 146))	('blockade', 'Var', (19, 27))	('TIM-3', 'Gene', (141, 146))	('AICD', 'biological_process', 'GO:0071948', ('44', '48'))	('CD8', 'Gene', '925', (75, 78))	('decrease', 'NegReg', (122, 130))	('tumor', 'Disease', (80, 85))	('TNF', 'Gene', (15, 18))	('AICD', 'biological_process', 'GO:0006924', ('44', '48'))	('AICD', 'biological_process', 'GO:0071888', ('44', '48'))	('PD-L1', 'Gene', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('increase', 'PosReg', (66, 74))	('PD-L1', 'Gene', '29126', (131, 136))	('CD8', 'Gene', (75, 78))
8165	33907692	The observed benefit of anti-TNF antibodies on the efficacy of ICIs in treating tumors may be at least partially attributable to the blockade of TNFR2 and this possibility should be experimentally addressed in future studies.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('anti-TNF', 'Gene', (24, 32))	('TNFR2', 'Gene', (145, 150))	('anti-TNF', 'Protein', (24, 32))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('blockade', 'NegReg', (133, 141))	('antibodies', 'Var', (33, 43))	('benefit', 'PosReg', (13, 20))
8175	33907692	Moreover, antagonistic antibodies can also reduce TNFR2+CD26- cells and TNFR2+ Treg cells, and expand the Teff cells in Sezary syndrome patients to corrected Treg/Teff ratios in the tumor microenvironment.	('Teff', 'Chemical', '-', (163, 167))	('reduce', 'NegReg', (43, 49))	('expand', 'PosReg', (95, 101))	('tumor', 'Disease', (182, 187))	('antibodies', 'Var', (23, 33))	('Teff', 'Chemical', '-', (106, 110))	('Treg', 'Chemical', '-', (158, 162))	('patients', 'Species', '9606', (136, 144))	('TNFR2+CD26-', 'MPA', (50, 61))	('Treg', 'Chemical', '-', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('Sezary syndrome', 'Disease', (120, 135))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
8176	33907692	Recently, this team also designed several new variants of human TNFR2-specific antagonistic antibody to achieve high TME specificity by killing TNFR2-expressing tumor cells and Tregs.	('antibody', 'cellular_component', 'GO:0042571', ('92', '100'))	('antibody', 'cellular_component', 'GO:0019815', ('92', '100'))	('human', 'Species', '9606', (58, 63))	('Tregs', 'Chemical', '-', (177, 182))	('killing', 'NegReg', (136, 143))	('antibody', 'cellular_component', 'GO:0019814', ('92', '100'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('TNFR2-expressing', 'Gene', (144, 160))	('variants', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('antibody', 'molecular_function', 'GO:0003823', ('92', '100'))	('tumor', 'Disease', (161, 166))
8177	33907692	The optimized version of anti-TNFR2 with IgG2 isoforms stabilize hinge region (disulfide double mutations at C232S and C233S) and the wide separation of antibody arms have demonstrated better TME specificity.	('disulfide', 'Chemical', 'MESH:D004220', (79, 88))	('stabilize', 'PosReg', (55, 64))	('antibody', 'cellular_component', 'GO:0042571', ('153', '161'))	('C232S', 'Mutation', 'p.C232S', (109, 114))	('C233S', 'Var', (119, 124))	('antibody', 'cellular_component', 'GO:0019815', ('153', '161'))	('IgG2', 'cellular_component', 'GO:0071735', ('41', '45'))	('C232S', 'Var', (109, 114))	('C233S', 'Mutation', 'p.C233S', (119, 124))	('antibody', 'cellular_component', 'GO:0019814', ('153', '161'))	('antibody', 'molecular_function', 'GO:0003823', ('153', '161'))
8178	33907692	The TNFR2 antagonistic killing activity is more potent in the cancer cell line with high TNFR2 expression than the cancer cell line with low TNFR2 expression.	('cancer', 'Disease', (115, 121))	('TNFR2', 'Gene', (89, 94))	('high', 'Var', (84, 88))	('TNFR2', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('potent', 'PosReg', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
8179	33907692	Furthermore, the combination treatment with murine-directed anti-TNFR2 antibody (TY101) and anti-PD-1 has a greater rate of tumor regression and elimination over single treatment with either anti-TNFR2 or anti-PD-1.	('antibody', 'cellular_component', 'GO:0019815', ('71', '79'))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('antibody', 'cellular_component', 'GO:0019814', ('71', '79'))	('murine', 'Species', '10090', (44, 50))	('tumor', 'Disease', (124, 129))	('greater', 'PosReg', (108, 115))	('TY101', 'Chemical', '-', (81, 86))	('antibody', 'molecular_function', 'GO:0003823', ('71', '79'))	('elimination', 'CPA', (145, 156))	('anti-PD-1', 'Var', (92, 101))	('antibody', 'cellular_component', 'GO:0042571', ('71', '79'))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
8180	33907692	Even anti-TNFR2 antibody alone possesses a better anti-tumor effect than anti-PD-1 alone in the murine model of CT26 and MC38.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('CT26', 'CellLine', 'CVCL:7254', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))	('anti-TNFR2', 'Var', (5, 15))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))	('murine', 'Species', '10090', (96, 102))
8182	33907692	We found that TNFR2 blocking antibody M861 combined with a sub-optimal dose of CpG oligodeoxynucleotide (CpG ODN) can synergistically inhibit the growth of subcutaneously transplanted mouse CT26 colon tumor by eliminating TNFR2+ Treg cells and increasing tumor-infiltrating IFNgamma+CD8+ CTLs.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('antibody', 'cellular_component', 'GO:0019815', ('29', '37'))	('inhibit', 'NegReg', (134, 141))	('eliminating', 'NegReg', (210, 221))	('antibody', 'cellular_component', 'GO:0019814', ('29', '37'))	('increasing', 'PosReg', (244, 254))	('tumor', 'Disease', (201, 206))	('growth', 'MPA', (146, 152))	('Treg', 'Chemical', '-', (229, 233))	('tumor', 'Disease', (255, 260))	('CD8', 'Gene', '925', (283, 286))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('TNFR2+ Treg cells', 'CPA', (222, 239))	('M861', 'Var', (38, 42))	('antibody', 'molecular_function', 'GO:0003823', ('29', '37'))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('CT26', 'CellLine', 'CVCL:7254', (190, 194))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (83, 103))	('colon tumor', 'Phenotype', 'HP:0100273', (195, 206))	('colon tumor', 'Disease', (195, 206))	('antibody', 'cellular_component', 'GO:0042571', ('29', '37'))	('colon tumor', 'Disease', 'MESH:D003110', (195, 206))	('TNFR2', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mouse', 'Species', '10090', (184, 189))	('CD8', 'Gene', (283, 286))
8183	33907692	Moreover, the combination treatment with anti-TNFR2 blocking antibody and anti-CD25 antibody also results in an enhanced inhibition of tumor growth in mouse 4T1 breast cancer model.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('anti-CD25', 'Var', (74, 83))	('tumor growth', 'Disease', 'MESH:D006130', (135, 147))	('antibody', 'molecular_function', 'GO:0003823', ('84', '92'))	('combination', 'Interaction', (14, 25))	('antibody', 'cellular_component', 'GO:0042571', ('84', '92'))	('antibody', 'cellular_component', 'GO:0019814', ('61', '69'))	('enhanced', 'PosReg', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mouse', 'Species', '10090', (151, 156))	('antibody', 'molecular_function', 'GO:0003823', ('61', '69'))	('antibody', 'cellular_component', 'GO:0019815', ('84', '92'))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('antibody', 'cellular_component', 'GO:0042571', ('61', '69'))	('tumor growth', 'Disease', (135, 147))	('inhibition', 'NegReg', (121, 131))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('antibody', 'cellular_component', 'GO:0019814', ('84', '92'))	('breast cancer', 'Disease', (161, 174))	('4T1', 'CellLine', 'CVCL:0125', (157, 160))	('antibody', 'cellular_component', 'GO:0019815', ('61', '69'))	('anti-TNFR2', 'Gene', (41, 51))
8184	33907692	"TNFR2 agonist" has been repeatedly shown to enhance the ex vivo proliferative expansion of Tregs, maintain the stability of the Treg cell phenotype, and preserve their suppressive function.	('proliferative expansion', 'CPA', (65, 88))	('Tregs', 'Chemical', '-', (92, 97))	('Treg', 'Chemical', '-', (92, 96))	('enhance', 'PosReg', (45, 52))	('agonist', 'Var', (7, 14))	('maintain', 'PosReg', (99, 107))	('Treg', 'Chemical', '-', (129, 133))	('stability', 'CPA', (112, 121))	('TNFR2', 'Gene', (1, 6))	('suppressive function', 'CPA', (169, 189))	('Tregs', 'CPA', (92, 97))
8190	33907692	It is reported that after the treatment with MM-401, the number of Treg cells in human ovarian cancer ascites is reduced.	('ovarian cancer ascites', 'Disease', (87, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('Treg', 'Chemical', '-', (67, 71))	('MM-401', 'Chemical', 'MESH:C587684', (45, 51))	('ascites', 'Phenotype', 'HP:0001541', (102, 109))	('ovarian cancer ascites', 'Disease', 'MESH:D001201', (87, 109))	('MM-401', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('reduced', 'NegReg', (113, 120))	('human', 'Species', '9606', (81, 86))
8191	33907692	As TNFR2 agonists appear to have both anti-tumor and anti-inflammatory effects, future studies can reconcile these seemingly opposite effects.	('TNFR2', 'Gene', (3, 8))	('agonists', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
8192	33907692	Recent pre-clinical studies indicate that targeting TNFR2 with either antagonistic or agonistic antibodies results in tumor inhibition by mobilizing anti-tumor immune responses, eliminating Treg activity, or stimulating the activation of CD8+ CTLs, respectively.	('Treg', 'Chemical', '-', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Treg activity', 'CPA', (190, 203))	('stimulating', 'Reg', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('eliminating', 'NegReg', (178, 189))	('pre', 'molecular_function', 'GO:0003904', ('7', '10'))	('TNFR2', 'Gene', (52, 57))	('activation', 'CPA', (224, 234))	('mobilizing', 'PosReg', (138, 148))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('targeting', 'Var', (42, 51))	('CD8', 'Gene', (238, 241))	('CD8', 'Gene', '925', (238, 241))	('tumor', 'Disease', (154, 159))
8204	33907692	This is mainly based on the fact that only 30~40% of peripheral Tregs are TNFR2-expressing cells in normal mice, while the majority of mouse tumor-infiltrating Tregs are TNFR2hi cells; thus, it is reasonable to assume that inactivation or even depletion of TNFR2-expressing Tregs would not compromise the peripheral tolerance to self-antigen.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('peripheral tolerance to self-antigen', 'CPA', (305, 341))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Tregs', 'Chemical', '-', (160, 165))	('depletion', 'NegReg', (244, 253))	('Tregs', 'Chemical', '-', (274, 279))	('inactivation', 'Var', (223, 235))	('tumor', 'Disease', (141, 146))	('mouse', 'Species', '10090', (135, 140))	('Tregs', 'Chemical', '-', (64, 69))	('mice', 'Species', '10090', (107, 111))
8277	33108391	Additionally, N-Methyl-D-aspartic acid (KEGG ID: C12269) and Fructose 1,6-bisphosphate (KEGG ID: C00354) had significantly higher abundances in primary melanoma vs. EM in positive ion mode and negative ion mode, respectively (S3 Fig).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('EM', 'Chemical', '-', (165, 167))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('abundances', 'MPA', (130, 140))	('higher', 'PosReg', (123, 129))	('KEGG', 'Var', (88, 92))	('KEGG', 'Chemical', '-', (40, 44))	('KEGG', 'Chemical', '-', (88, 92))	('N-Methyl-D-aspartic acid', 'Chemical', 'MESH:D016202', (14, 38))	('Fructose 1,6-bisphosphate', 'Chemical', 'MESH:C029063', (61, 86))	('N-Methyl-D-aspartic acid', 'MPA', (14, 38))
8321	33108391	Loss of FFAR2 has been shown to promote colon cancer and leukemia in murine models, and expression levels are relatively diminished among TCGA melanoma tissues vs. several other cancers according to the Human Protein Atlas.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('diminished', 'NegReg', (121, 131))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('promote', 'PosReg', (32, 39))	('leukemia', 'Disease', 'MESH:D007938', (57, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('leukemia', 'Disease', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('murine', 'Species', '10090', (69, 75))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('FFAR2', 'Gene', (8, 13))	('Human', 'Species', '9606', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('Loss', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('colon cancer', 'Disease', (40, 52))	('cancers', 'Disease', (178, 185))	('expression levels', 'MPA', (88, 105))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))
8322	33108391	Loss of FFAR2 (or obstruction of ligand binding) may be a significant marker of melanoma progression, and is already being examined as a therapeutic target for metabolic and inflammatory diseases.	('FFAR2', 'Gene', (8, 13))	('inflammatory diseases', 'Disease', 'MESH:D007249', (174, 195))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('ligand', 'molecular_function', 'GO:0005488', ('33', '39'))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('inflammatory diseases', 'Disease', (174, 195))	('Loss', 'Var', (0, 4))	('binding', 'Interaction', (40, 47))
8330	33108391	Downregulated CAV1 promotes glycolysis in adjacent cells leading to increased tumor growth via the reverse Warburg effect.	('Downregulated', 'Var', (0, 13))	('promotes', 'PosReg', (19, 27))	('CAV1', 'Gene', '857', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('glycolysis', 'biological_process', 'GO:0006096', ('28', '38'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('reverse Warburg effect', 'CPA', (99, 121))	('CAV1', 'Gene', (14, 18))	('glycolysis', 'MPA', (28, 38))	('tumor', 'Disease', (78, 83))	('increased', 'PosReg', (68, 77))
8331	33108391	Loss of stromal CAV1 has been associated with poorer prognosis among metastatic melanoma patients, and clinical studies of squamous cell carcinoma have demonstrated reconstitution of CAV1 and increased tumor cell apoptosis in patients treated with Metformin :a drug known to inhibit mitochondrial oxidative phosphorylation.	('Metformin', 'Chemical', 'MESH:D008687', (248, 257))	('squamous cell carcinoma', 'Disease', (123, 146))	('CAV1', 'Gene', (16, 20))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('297', '322'))	('tumor', 'Disease', (202, 207))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('patients', 'Species', '9606', (226, 234))	('apoptosis', 'biological_process', 'GO:0097194', ('213', '222'))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('apoptosis', 'biological_process', 'GO:0006915', ('213', '222'))	('CAV1', 'Gene', '857', (183, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('increased', 'PosReg', (192, 201))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('patients', 'Species', '9606', (89, 97))	('CAV1', 'Gene', '857', (16, 20))	('CAV1', 'Gene', (183, 187))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))
8335	33108391	demonstrated equally potent antiproliferative effects for N-acetylserotonin and melatonin; however, N-acetylserotonin only binds low affinity receptors whereas melatonin binds both high and low affinity sites.	('melatonin', 'Chemical', 'MESH:D008550', (160, 169))	('antiproliferative', 'CPA', (28, 45))	('low', 'NegReg', (129, 132))	('N-acetylserotonin', 'Chemical', 'MESH:C006389', (58, 75))	('N-acetylserotonin', 'Var', (100, 117))	('melatonin', 'Chemical', 'MESH:D008550', (80, 89))	('N-acetylserotonin', 'Chemical', 'MESH:C006389', (100, 117))
8351	33108391	In a recent study aimed at differentiating slow and fast proliferative states among melanoma cell lines compared to control media, glutamic acid was observed to play a supportive role in significantly accelerating proliferation, migration, and invasiveness among early stage melanoma cells, but not among metastatic melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('glutamic acid', 'Chemical', 'MESH:D018698', (131, 144))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('migration', 'CPA', (229, 238))	('proliferation', 'CPA', (214, 227))	('glutamic', 'Var', (131, 139))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('accelerating', 'PosReg', (201, 213))	('melanoma', 'Disease', (275, 283))	('invasiveness', 'CPA', (244, 256))
8467	32998469	UMs most often have a GNAQ or GNA11 mutation, while cutaneous melanomas usually have a BRAF, NRAS, KIT or NF1 mutation.	('KIT', 'Gene', (99, 102))	('GNAQ', 'Gene', '2776', (22, 26))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('KIT', 'molecular_function', 'GO:0005020', ('99', '102'))	('GNA11', 'Gene', (30, 35))	('GNAQ', 'Gene', (22, 26))	('NRAS', 'Gene', '4893', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('KIT', 'Gene', '3815', (99, 102))	('NF1', 'Gene', '4763', (106, 109))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('NRAS', 'Gene', (93, 97))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))	('melanomas', 'Disease', (62, 71))	('NF1', 'Gene', (106, 109))	('GNA11', 'Gene', '2767', (30, 35))	('mutation', 'Var', (36, 44))
8468	32998469	However, the same BRAF mutation as in cutaneous melanoma has been found in some iris melanomas and in a fraction of cells of some posterior UMs.	('found', 'Reg', (66, 71))	('iris melanomas', 'Disease', 'MESH:D008545', (80, 94))	('mutation', 'Var', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('iris melanomas', 'Phenotype', 'HP:0011524', (80, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('iris melanoma', 'Phenotype', 'HP:0011524', (80, 93))	('UM', 'Phenotype', 'HP:0007716', (140, 142))	('BRAF', 'Gene', (18, 22))	('cutaneous melanoma', 'Disease', (38, 56))	('iris melanomas', 'Disease', (80, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
8471	32998469	Rare UM with specific germline MBD4 mutations has been described to respond to anti-PD-1 therapy, probably because MBD4 mutations are associated with a high tumour mutation burden.	('MBD4', 'Gene', '8930', (115, 119))	('MBD4', 'Gene', (115, 119))	('respond', 'MPA', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('mutations', 'Var', (36, 45))	('UM', 'Phenotype', 'HP:0007716', (5, 7))	('tumour', 'Disease', (157, 163))	('MBD4', 'Gene', '8930', (31, 35))	('MBD4', 'Gene', (31, 35))	('PD-1', 'Gene', (84, 88))	('PD-1', 'Gene', '5133', (84, 88))
8478	32998469	A genetic risk factor is the presence of a germline mutation in the BAP1 gene, which is associated with the BAP1-tumor predisposition syndrome.	('BAP1-tumor', 'Disease', (108, 118))	('BAP1', 'Gene', '8314', (108, 112))	('BAP1-tumor', 'Disease', 'MESH:D009369', (108, 118))	('germline mutation', 'Var', (43, 60))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (108, 112))	('associated', 'Reg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BAP1', 'Gene', (68, 72))
8479	32998469	Patients with a mutation in this gene have an increased chance of developing UM, melanocytic cutaneous tumours, mesothelioma and renal cell carcinoma.	('mutation', 'Var', (16, 24))	('developing', 'PosReg', (66, 76))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('Patients', 'Species', '9606', (0, 8))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('mesothelioma and renal cell carcinoma', 'Disease', 'MESH:C538614', (112, 149))	('melanocytic cutaneous tumours', 'Disease', 'MESH:D009369', (81, 110))	('melanocytic cutaneous tumours', 'Disease', (81, 110))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
8487	32998469	It is known that posterior UMs carry specific mutations: in 94% of all tumours, a mutation in either the GNAQ or GNA11 gene has been found.	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('GNAQ', 'Gene', (105, 109))	('UM', 'Phenotype', 'HP:0007716', (27, 29))	('mutation', 'Var', (82, 90))	('tumours', 'Disease', (71, 78))	('GNA11', 'Gene', '2767', (113, 118))	('GNA11', 'Gene', (113, 118))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('GNAQ', 'Gene', '2776', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
8490	32998469	Among all UM, these are most associated with light-coloured eyes and they often have an A > T mutation in GNAQ Q209L or GNA11 Q209L.	('UM', 'Phenotype', 'HP:0007716', (10, 12))	('light-coloured eyes', 'Disease', (45, 64))	('Q209L', 'Mutation', 'rs121913492', (111, 116))	('GNA11', 'Gene', (120, 125))	('GNAQ', 'Gene', (106, 110))	('A > T', 'Var', (88, 93))	('light-coloured eyes', 'Phenotype', 'HP:0007730', (45, 64))	('GNA11', 'Gene', '2767', (120, 125))	('associated', 'Reg', (29, 39))	('Q209L', 'Mutation', 'rs121913492', (126, 131))	('GNAQ', 'Gene', '2776', (106, 110))
8491	32998469	Other common genetic aberrations in posterior UM are chromosomal changes, such as a loss of chromosome 3, loss of chromosome 8 p and a gain of chromosome 8 q, which are associated with a higher risk of developing metastases.	('chromosome', 'cellular_component', 'GO:0005694', ('114', '124'))	('loss', 'NegReg', (84, 88))	('loss', 'Var', (106, 110))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('gain', 'PosReg', (135, 139))	('metastases', 'Disease', (213, 223))	('metastases', 'Disease', 'MESH:D009362', (213, 223))
8492	32998469	Whereas GNAQ and GNA11 mutations occur early in tumour formation and are not associated with prognosis, EIF1AX, SF3B1 and BAP1 mutations occur later in the development of the tumour and are related to prognosis.	('EIF1AX', 'Gene', (104, 110))	('BAP1', 'Gene', (122, 126))	('GNAQ', 'Gene', (8, 12))	('EIF1AX', 'Gene', '1964', (104, 110))	('SF3B1', 'Gene', (112, 117))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('mutations', 'Var', (23, 32))	('GNA11', 'Gene', '2767', (17, 22))	('mutations', 'Var', (127, 136))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('SF3B1', 'Gene', '23451', (112, 117))	('tumour', 'Disease', (175, 181))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('BAP1', 'Gene', '8314', (122, 126))	('men', 'Species', '9606', (163, 166))	('related to', 'Reg', (190, 200))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (8, 12))
8493	32998469	A mutation in EIF1AX is present in 17% of primary UM, a mutation in SF3B1 in 25% and a mutation in BAP1 in about 45% of primary UM.	('BAP1', 'Gene', (99, 103))	('EIF1AX', 'Gene', '1964', (14, 20))	('primary UM', 'Disease', (42, 52))	('SF3B1', 'Gene', (68, 73))	('UM', 'Phenotype', 'HP:0007716', (128, 130))	('UM', 'Phenotype', 'HP:0007716', (50, 52))	('SF3B1', 'Gene', '23451', (68, 73))	('BAP1', 'Gene', '8314', (99, 103))	('mutation', 'Var', (56, 64))	('EIF1AX', 'Gene', (14, 20))
8494	32998469	EIF1AX mutations are associated with a good prognostic outcome; tumours with an SF3B1 mutation lead to an intermediate prognosis, in contrast to UMs with a BAP1 mutation.	('SF3B1', 'Gene', '23451', (80, 85))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('BAP1', 'Gene', '8314', (156, 160))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('SF3B1', 'Gene', (80, 85))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', (156, 160))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
8496	32998469	The EIF1AX mutation is responsible for unsuccessful protein translation, and the SF3B1 mutation affects gene splicing.	('SF3B1', 'Gene', (81, 86))	('gene splicing', 'MPA', (104, 117))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('SF3B1', 'Gene', '23451', (81, 86))	('protein translation', 'biological_process', 'GO:0006412', ('52', '71'))	('protein translation', 'MPA', (52, 71))	('affects', 'Reg', (96, 103))	('mutation', 'Var', (87, 95))	('EIF1AX', 'Gene', '1964', (4, 10))	('EIF1AX', 'Gene', (4, 10))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
8497	32998469	The lack of the BAP1 protein interferes with a wide range of normal cell processes such as DNA damage repair; 40% of UM metastases have a BAP1 mutation.	('BAP1', 'Gene', '8314', (138, 142))	('mutation', 'Var', (143, 151))	('BAP1', 'Gene', (138, 142))	('metastases', 'Disease', (120, 130))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('BAP1', 'Gene', '8314', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('metastases', 'Disease', 'MESH:D009362', (120, 130))	('BAP1', 'Gene', (16, 20))	('UM', 'Phenotype', 'HP:0007716', (117, 119))
8499	32998469	GNAQ and GNA11 mutations are detected in 77% to 84% of the iris tumours, which are not as frequent as in UM.	('GNA11', 'Gene', (9, 14))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('iris tumours', 'Disease', (59, 71))	('GNAQ', 'Gene', (0, 4))	('iris tumours', 'Disease', 'MESH:D015811', (59, 71))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('GNA11', 'Gene', '2767', (9, 14))
8501	32998469	More iris melanomas have a GNAQ mutation (47%) than a GNA11 mutation (30%).	('GNAQ', 'Gene', '2776', (27, 31))	('GNA11', 'Gene', (54, 59))	('iris melanomas', 'Disease', (5, 19))	('GNA11', 'Gene', '2767', (54, 59))	('iris melanomas', 'Disease', 'MESH:D008545', (5, 19))	('GNAQ', 'Gene', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('iris melanomas', 'Phenotype', 'HP:0011524', (5, 19))	('mutation', 'Var', (32, 40))	('iris melanoma', 'Phenotype', 'HP:0011524', (5, 18))
8502	32998469	As in UM, mutations in BAP1, EIF1AX and SF3B1 are frequently seen in iris tumours.	('SF3B1', 'Gene', (40, 45))	('BAP1', 'Gene', (23, 27))	('EIF1AX', 'Gene', '1964', (29, 35))	('EIF1AX', 'Gene', (29, 35))	('UM', 'Phenotype', 'HP:0007716', (6, 8))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('SF3B1', 'Gene', '23451', (40, 45))	('iris tumours', 'Disease', (69, 81))	('BAP1', 'Gene', '8314', (23, 27))	('iris tumours', 'Disease', 'MESH:D015811', (69, 81))	('seen', 'Reg', (61, 65))	('mutations', 'Var', (10, 19))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
8503	32998469	The frequency of BAP1 mutations seems comparable with UM.	('UM', 'Phenotype', 'HP:0007716', (54, 56))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('BAP1', 'Gene', (17, 21))
8505	32998469	Although not much data about these mutations are available, EIF1AX mutations seem to occur more often than in posterior UM.	('UM', 'Phenotype', 'HP:0007716', (120, 122))	('EIF1AX', 'Gene', '1964', (60, 66))	('EIF1AX', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))
8506	32998469	As EIF1AX mutations are correlated with a good prognosis in UM, this could be one of the explanations for the relatively good survival of patients with an iris tumour in comparison to more posteriorly located UM.	('UM', 'Phenotype', 'HP:0007716', (209, 211))	('iris tumour', 'Disease', (155, 166))	('iris tumour', 'Disease', 'MESH:D015811', (155, 166))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('EIF1AX', 'Gene', '1964', (3, 9))	('EIF1AX', 'Gene', (3, 9))	('mutations', 'Var', (10, 19))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('patients', 'Species', '9606', (138, 146))
8507	32998469	SF3B1 mutations are less common in iris tumours.	('common', 'Reg', (25, 31))	('SF3B1', 'Gene', (0, 5))	('iris tumours', 'Disease', (35, 47))	('SF3B1', 'Gene', '23451', (0, 5))	('iris tumours', 'Disease', 'MESH:D015811', (35, 47))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (6, 15))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
8508	32998469	In a study by Van Poppelen et al., 10 out of 30 iris tumours had mutations in NRAS, BRAF, PTEN, c-KIT and/or TP53.	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('c-KIT', 'Gene', (96, 101))	('PTEN', 'Gene', (90, 94))	('BRAF', 'Gene', (84, 88))	('PTEN', 'Gene', '5728', (90, 94))	('NRAS', 'Gene', (78, 82))	('TP53', 'Gene', '7157', (109, 113))	('iris tumours', 'Disease', (48, 60))	('c-KIT', 'Gene', '3815', (96, 101))	('NRAS', 'Gene', '4893', (78, 82))	('TP53', 'Gene', (109, 113))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('iris tumours', 'Disease', 'MESH:D015811', (48, 60))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('mutations', 'Var', (65, 74))
8509	32998469	Another study on 19 cases showed a BRAF mutation in 47% of the iris tumours.	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('iris tumours', 'Disease', (63, 75))	('iris tumours', 'Disease', 'MESH:D015811', (63, 75))
8510	32998469	As previously mentioned, mutations in BRAF and NRAS are common in cutaneous melanoma.	('mutations', 'Var', (25, 34))	('cutaneous melanoma', 'Disease', (66, 84))	('common', 'Reg', (56, 62))	('men', 'Species', '9606', (14, 17))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('NRAS', 'Gene', (47, 51))	('BRAF', 'Gene', (38, 42))	('NRAS', 'Gene', '4893', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
8513	32998469	Immunotherapy, which is helpful in UMs with a MBD4 mutation and a high mutation burden, is therefore probably also useful for iris melanomas, but luckily, these tumours do not often give rise to metastases.	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('MBD4', 'Gene', (46, 50))	('MBD4', 'Gene', '8930', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('iris melanomas', 'Disease', 'MESH:D008545', (126, 140))	('iris melanomas', 'Disease', (126, 140))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('iris melanoma', 'Phenotype', 'HP:0011524', (126, 139))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('iris melanomas', 'Phenotype', 'HP:0011524', (126, 140))	('mutation', 'Var', (51, 59))	('metastases', 'Disease', (195, 205))	('tumours', 'Disease', (161, 168))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))
8518	32998469	In a recent study, the C > T substitute in DNA (associated with UV light) was even higher in UM than in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (104, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('C > T substitute', 'Var', (23, 39))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('higher', 'PosReg', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
8533	32998469	Mutations of MC1R have been identified, of which the Arg151Cys, Arg160Trp and Asp294 variants have been reported to be over-represented in individuals with fair hair and skin, but they have not been associated with specific eye colours (see below).	('MC1R', 'Gene', (13, 17))	('associated', 'Reg', (199, 209))	('Arg151Cys', 'SUBSTITUTION', 'None', (53, 62))	('Arg160Trp', 'SUBSTITUTION', 'None', (64, 73))	('Arg151Cys', 'Var', (53, 62))	('Arg160Trp', 'Var', (64, 73))	('Asp294', 'Var', (78, 84))	('fair hair', 'Phenotype', 'HP:0002286', (156, 165))	('Asp294', 'Chemical', '-', (78, 84))	('MC1R', 'Gene', '4157', (13, 17))
8541	32998469	This suggests that specific MC1R gene variants do not play a major role in the susceptibility to develop UM.	('MC1R', 'Gene', '4157', (28, 32))	('MC1R', 'Gene', (28, 32))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('variants', 'Var', (38, 46))
8545	32998469	In the synthesis pathway of eumelanin, the addition of an amino group to DOPA quinone results in the formation of leucadopachrome.	('amino group', 'Var', (58, 69))	('leucadopachrome', 'MPA', (114, 129))	('synthesis', 'biological_process', 'GO:0009058', ('7', '16'))	('eumelanin', 'Chemical', 'MESH:C041877', (28, 37))	('formation', 'MPA', (101, 110))	('addition', 'Var', (43, 51))	('DOPA quinone', 'Chemical', '-', (73, 85))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))
8547	32998469	The presence of Zn2+ and Cu2+ ions leads to relatively higher conversion into DHICA than into DHI.	('DHI', 'Chemical', 'MESH:C071764', (78, 81))	('Cu2+', 'Chemical', '-', (25, 29))	('Zn2+', 'Var', (16, 20))	('Zn2+', 'Chemical', '-', (16, 20))	('DHICA', 'Chemical', 'MESH:C030692', (78, 83))	('conversion into DHICA', 'MPA', (62, 83))	('DHI', 'Chemical', 'MESH:C071764', (94, 97))	('higher', 'PosReg', (55, 61))
8554	32998469	When the MC1R gene is mutated, less cAMP is produced and less tyrosinase is activated.	('less', 'NegReg', (31, 35))	('cAMP', 'Chemical', '-', (36, 40))	('tyrosinase', 'Gene', '7299', (62, 72))	('activated', 'MPA', (76, 85))	('less', 'NegReg', (57, 61))	('mutated', 'Var', (22, 29))	('tyrosinase', 'Gene', (62, 72))	('cAMP', 'MPA', (36, 40))	('MC1R', 'Gene', '4157', (9, 13))	('MC1R', 'Gene', (9, 13))
8556	32998469	The incorporation of cysteine results in the formation of 5-S-cysteinyldopa (5-SCD) and 2-S-cysteinyldopa (5-SCD) in a ratio of 5:1.	('incorporation', 'Var', (4, 17))	('5-SCD', 'Chemical', 'MESH:D003548', (107, 112))	('5-S-cysteinyldopa', 'Chemical', 'MESH:D003548', (58, 75))	('5-SCD', 'Chemical', 'MESH:D003548', (77, 82))	('2-S-cysteinyldopa', 'Chemical', 'MESH:C034513', (88, 105))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('cysteine', 'Chemical', 'MESH:D003545', (21, 29))	('2-S-cysteinyldopa', 'MPA', (88, 105))
8560	32998469	BTZ is a stronger pro-oxidant and induces ROS production by reduction-oxidation (redox) cycling in the dark.	('ROS production', 'MPA', (42, 56))	('induces', 'Reg', (34, 41))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('BTZ', 'Var', (0, 3))	('BTZ', 'Chemical', '-', (0, 3))
8572	32998469	In a study on the development of cutaneous melanoma, a BRAF mutation was introduced in three different types of mice: red mice with an abundance of pheomelanin, albino mice with no melanin and black mice with an abundance of eumelanin.	('melanin', 'Chemical', 'MESH:D008543', (152, 159))	('mutation', 'Var', (60, 68))	('mice', 'Species', '10090', (122, 126))	('mice', 'Species', '10090', (199, 203))	('pheomelanin', 'Chemical', 'MESH:C018362', (148, 159))	('mice', 'Species', '10090', (168, 172))	('melanin', 'Chemical', 'MESH:D008543', (181, 188))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('mice', 'Species', '10090', (112, 116))	('eumelanin', 'Chemical', 'MESH:C041877', (225, 234))	('melanin', 'Chemical', 'MESH:D008543', (227, 234))	('men', 'Species', '9606', (25, 28))
8581	32998469	People with blue eyes often have specific single nucleotide polymorphisms (SNPs) in HERC2 and OCA2.	('single nucleotide polymorphisms', 'Var', (42, 73))	('blue eye', 'Phenotype', 'HP:0000635', (12, 20))	('HERC2', 'Gene', (84, 89))	('HERC2', 'Gene', '8924', (84, 89))	('People', 'Species', '9606', (0, 6))	('blue eyes', 'Phenotype', 'HP:0000635', (12, 21))	('OCA2', 'Gene', '4948', (94, 98))	('blue eyes', 'Species', '160493', (12, 21))	('OCA2', 'Gene', (94, 98))
8583	32998469	The specific SNP in the OCA2 gene, which is associated with blue eyes, causes a reduction in OCA2 transcription of that allele compared to the normal other allele.	('associated', 'Reg', (44, 54))	('blue eyes', 'Phenotype', 'HP:0000635', (60, 69))	('OCA2', 'Gene', '4948', (24, 28))	('blue eye', 'Phenotype', 'HP:0000635', (60, 68))	('reduction', 'NegReg', (80, 89))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('OCA2', 'Gene', '4948', (93, 97))	('OCA2', 'Gene', (24, 28))	('blue eyes', 'Disease', (60, 69))	('OCA2', 'Gene', (93, 97))	('SNP', 'Var', (13, 16))	('blue eyes', 'Species', '160493', (60, 69))	('transcription', 'MPA', (98, 111))
8591	32998469	They found six SNPs that functioned as major genetic predictors of eye colour on six different genes: in addition to the already mentioned HERC2 rs12913832 and OCA2 rs1800407, these were SLC24A4 rs12896399, SLC45A2 rs16891982, TYR rs1393350 and IRF4 rs12203592.	('HERC2', 'Gene', '8924', (139, 144))	('SLC45A2', 'Gene', (207, 214))	('men', 'Species', '9606', (129, 132))	('rs1800407', 'Mutation', 'rs1800407', (165, 174))	('HERC2', 'Gene', (139, 144))	('rs16891982', 'Mutation', 'rs16891982', (215, 225))	('SLC24A4', 'Gene', (187, 194))	('rs12203592', 'Mutation', 'rs12203592', (250, 260))	('rs1393350', 'Mutation', 'rs1393350', (231, 240))	('rs12913832', 'Mutation', 'rs12913832', (145, 155))	('OCA2', 'Gene', (160, 164))	('rs16891982', 'Var', (215, 225))	('rs12896399', 'Mutation', 'rs12896399', (195, 205))	('rs12203592', 'Var', (250, 260))	('rs12896399', 'Var', (195, 205))	('OCA2', 'Gene', '4948', (160, 164))	('IRF4', 'Gene', '3662', (245, 249))	('rs1800407', 'Var', (165, 174))	('TYR', 'Chemical', 'MESH:D014443', (227, 230))	('SLC45A2', 'Gene', '51151', (207, 214))	('SLC24A4', 'Gene', '123041', (187, 194))	('rs12913832', 'Var', (145, 155))	('IRF4', 'Gene', (245, 249))
8595	32998469	Of the 28 SNPs that had already been identified as risk factors for cutaneous melanoma, three had already been linked to iris colour: SNPs rs12913832, rs1129038 and rs916977, located on the pigmentation genes HERC2, OCA2 and IRF4, respectively.	('rs1129038', 'Mutation', 'rs1129038', (151, 160))	('rs1129038', 'Var', (151, 160))	('IRF4', 'Gene', '3662', (225, 229))	('pigmentation', 'Disease', 'MESH:D010859', (190, 202))	('HERC2', 'Gene', '8924', (209, 214))	('rs12913832', 'Mutation', 'rs12913832', (139, 149))	('OCA2', 'Gene', (216, 220))	('HERC2', 'Gene', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('IRF4', 'Gene', (225, 229))	('rs916977', 'Var', (165, 173))	('OCA2', 'Gene', '4948', (216, 220))	('pigmentation', 'Disease', (190, 202))	('pigmentation', 'biological_process', 'GO:0043473', ('190', '202'))	('rs12913832', 'Var', (139, 149))	('cutaneous melanoma', 'Disease', (68, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 86))	('rs916977', 'Mutation', 'rs916977', (165, 173))
8604	32998469	People with more pheomelanin compared to eumelanin have more efficient vitamin D synthesis.	('People', 'Species', '9606', (0, 6))	('eumelanin', 'Chemical', 'MESH:C041877', (41, 50))	('vitamin D', 'Chemical', 'MESH:D014807', (71, 80))	('vitamin D synthesis', 'biological_process', 'GO:0042368', ('71', '90'))	('pheomelanin', 'Chemical', 'MESH:C018362', (17, 28))	('vitamin D synthesis', 'MPA', (71, 90))	('pheomelanin', 'Var', (17, 28))
8631	31011493	Cancer in invertebrate and vertebrate organisms The prevailing consensus in oncology is that cancer arises when DNA mutations and nucleotide base rearrangements generate genetically distinct cells that target organs in a patchy and asymmetrical manner (Figure 2A, 2B).	('cancer', 'Disease', (93, 99))	('DNA', 'Gene', (112, 115))	('nucleotide base rearrangements', 'Var', (130, 160))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('oncology', 'Phenotype', 'HP:0002664', (76, 84))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))
8640	31011493	For example, the p53 signaling network suppresses tumor progression in humans, and accordingly, mutations of this network often lead to cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('suppresses', 'NegReg', (39, 49))	('humans', 'Species', '9606', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Disease', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('lead to', 'Reg', (128, 135))	('mutations', 'Var', (96, 105))
8647	31011493	Based on our current understanding, exposure to gamma rays, X-rays and the higher ultraviolet part of the electromagnetic spectrum causes DNA double-strand breaks, modifies histone architecture and generates reactive oxygen species that trigger genetic errors within somatic cells.	('genetic', 'Var', (245, 252))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (208, 231))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('rays', 'Species', '255564', (62, 66))	('histone architecture', 'Protein', (173, 193))	('trigger', 'Reg', (237, 244))	('reactive oxygen species', 'MPA', (208, 231))	('rays', 'Species', '255564', (54, 58))	('modifies', 'Reg', (164, 172))	('causes', 'Reg', (131, 137))	('DNA double-strand breaks', 'MPA', (138, 162))
8652	31011493	In this context, normal skin cells harbor a large degree of mutations, and accordingly, skin cutaneous melanoma has the highest mutational load among 23 human cancer types.	('cancer', 'Disease', (159, 165))	('skin cutaneous melanoma', 'Disease', (88, 111))	('mutational', 'Var', (128, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 111))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
8687	30028779	Genomic analysis revealed mutually exclusive mutations in TP53 and KIT in 25%, while 19% of cases demonstrated BRAF mutation.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (58, 62))	('KIT', 'Gene', (67, 70))	('TP53', 'Gene', (58, 62))	('BRAF', 'Gene', '673', (111, 115))	('KIT', 'molecular_function', 'GO:0005020', ('67', '70'))	('BRAF', 'Gene', (111, 115))	('KIT', 'Gene', '3815', (67, 70))
8689	30028779	Mutation in ATRX, previously undescribed in mucosal melanoma, was seen in 3/16 (10%) of patients.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('ATRX', 'Gene', '546', (12, 16))	('patients', 'Species', '9606', (88, 96))	('Mutation', 'Var', (0, 8))	('mucosal melanoma', 'Disease', (44, 60))	('ATRX', 'Gene', (12, 16))	('mucosal melanoma', 'Disease', 'MESH:D008545', (44, 60))
8691	30028779	Patients with three or more mutations had marginally worse overall survival rates than those with two or less (p=0.007).	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (28, 37))	('worse', 'NegReg', (53, 58))	('overall survival', 'MPA', (59, 75))
8701	30028779	The most widely studied adjuvant therapy is imatinib, targeting KIT mutations, has thus far shown modest response rates in mucosal melanoma trials.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('mucosal melanoma', 'Disease', 'MESH:D008545', (123, 139))	('KIT', 'Gene', '3815', (64, 67))	('imatinib', 'Chemical', 'MESH:C097613', (44, 52))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('KIT', 'Gene', (64, 67))	('mutations', 'Var', (68, 77))	('mucosal melanoma', 'Disease', (123, 139))
8704	30028779	Mutations and increased copy numbers encoding the receptor tyrosine kinase KIT have been described in up to 40% of mucosal melanomas.	('increased', 'PosReg', (14, 23))	('KIT', 'Gene', '3815', (75, 78))	('mucosal melanomas', 'Disease', 'MESH:D008545', (115, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('KIT', 'Gene', (75, 78))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tyrosine', 'Chemical', 'None', (59, 67))	('copy numbers', 'Var', (24, 36))	('mucosal melanomas', 'Disease', (115, 132))	('described', 'Reg', (89, 98))
8705	30028779	Mutations involving KIT and NRAS genes along with wild-type BRAF are present in approximately 20% of patient cases with vulvo-vaginal melanomas in another study.	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (126, 142))	('NRAS', 'Gene', '4893', (28, 32))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('vulvo-vaginal melanomas', 'Disease', 'MESH:D008545', (120, 143))	('vulvo-vaginal melanomas', 'Disease', (120, 143))	('Mutations', 'Var', (0, 9))	('KIT', 'Gene', (20, 23))	('KIT', 'Gene', '3815', (20, 23))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (126, 143))	('patient', 'Species', '9606', (101, 108))	('NRAS', 'Gene', (28, 32))
8706	30028779	In contrast, BRAF mutation involving the V600E locus was reported in around 40% of atypical genital nevi; this interesting finding implies that ultraviolet exposure is not essential in generating this mutation.	('BRAF', 'Gene', '673', (13, 17))	('atypical genital nevi', 'Disease', (83, 104))	('V600E', 'Var', (41, 46))	('BRAF', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (41, 46))	('nevi', 'Phenotype', 'HP:0003764', (100, 104))
8707	30028779	Identifying site-specific mutations involved in the pathogenesis of genitourinary tract melanoma can be contributory for further treatment options.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('genitourinary tract melanoma', 'Disease', (68, 96))	('pathogenesis', 'biological_process', 'GO:0009405', ('52', '64'))	('mutations', 'Var', (26, 35))	('genitourinary tract melanoma', 'Disease', 'MESH:C564424', (68, 96))	('men', 'Species', '9606', (134, 137))
8715	30028779	Targeted DNA sequencing was performed to identify somatic mutations in the coding regions of 151 cancer-associated genes, using 200 ng of DNA and the Agilent SureSelect XT ClearSeq Comprehensive Cancer Panel kit.	('mutations', 'Var', (58, 67))	('Cancer', 'Disease', (195, 201))	('cancer', 'Disease', (97, 103))	('Agilent SureSelect XT ClearSeq', 'Disease', 'None', (150, 180))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('Cancer', 'Disease', 'MESH:D009369', (195, 201))	('Cancer', 'Phenotype', 'HP:0002664', (195, 201))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('Agilent SureSelect XT ClearSeq', 'Disease', (150, 180))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('kit', 'Gene', (208, 211))	('kit', 'Gene', '3815', (208, 211))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
8742	30028779	Mutually exclusive TP53 and KIT mutations were most frequent, and were identified in four cases each (25%), equally divided between vulvar and vaginal origin.	('KIT', 'Gene', (28, 31))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mutations', 'Var', (32, 41))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('KIT', 'Gene', '3815', (28, 31))
8743	30028779	BRAF mutations were noted in 3 vulvar melanomas (10%); 2 were p.V600E and 1 was p.G466'V'.	('vulvar melanomas', 'Phenotype', 'HP:0030418', (31, 47))	("p.G466'V'", 'Var', (80, 89))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('p.V600E', 'Mutation', 'rs113488022', (62, 69))	('vulvar melanomas', 'Disease', 'MESH:D008545', (31, 47))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('vulvar melanomas', 'Disease', (31, 47))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (31, 46))	('BRAF', 'Gene', (0, 4))	('noted', 'Reg', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('p.V600E', 'Var', (62, 69))
8744	30028779	NRAS mutations were found in 2 vulvar melanomas (13%), one p.G13D and one p.G12S.	('p.G12S', 'Var', (74, 80))	('p.G13D', 'Mutation', 'rs112445441', (59, 65))	('vulvar melanomas', 'Phenotype', 'HP:0030418', (31, 47))	('mutations', 'Var', (5, 14))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (31, 46))	('p.G13D', 'Var', (59, 65))	('p.G12S', 'Mutation', 'rs121913250', (74, 80))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('vulvar melanomas', 'Disease', (31, 47))	('vulvar melanomas', 'Disease', 'MESH:D008545', (31, 47))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('NRAS', 'Gene', '4893', (0, 4))
8746	30028779	Truncating mutations in ATRX were found in 3 patients (pQ732X/p.Q770x in 2 and p.Q251X/p.Q289X in one); these accompanied a TP53 mutation in all 3 cases.	('p.Q251X', 'Mutation', 'p.Q251X', (79, 86))	('TP53', 'Gene', '7157', (124, 128))	('accompanied', 'Reg', (110, 121))	('ATRX', 'Gene', (24, 28))	('TP53', 'Gene', (124, 128))	('p.Q251X/p.Q289X', 'Var', (79, 94))	('p.Q289X', 'Mutation', 'p.Q289X', (87, 94))	('ATRX', 'Gene', '546', (24, 28))	('patients', 'Species', '9606', (45, 53))	('found', 'Reg', (34, 39))	('pQ732X/p.Q770x', 'Var', (55, 69))
8748	30028779	The patient with separate primary vulvar and vaginal melanomas showed distinct mutations in each: the vaginal melanoma showed KIT mutation and the vulvar melanoma NRAS mutation.	('NRAS', 'Gene', (163, 167))	('vulvar melanoma', 'Disease', 'MESH:D008545', (147, 162))	('vaginal melanoma', 'Disease', 'MESH:D008545', (102, 118))	('vaginal melanoma', 'Disease', 'MESH:D008545', (45, 61))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (102, 118))	('vulvar melanoma', 'Disease', (147, 162))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (45, 61))	('mutation', 'Var', (130, 138))	('vaginal melanoma', 'Disease', (102, 118))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('vaginal melanomas', 'Disease', 'MESH:D008545', (45, 62))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (147, 162))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('KIT', 'Gene', '3815', (126, 129))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (45, 62))	('vaginal melanomas', 'Disease', (45, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('NRAS', 'Gene', '4893', (163, 167))	('patient', 'Species', '9606', (4, 11))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('KIT', 'Gene', (126, 129))
8749	30028779	ZMYM3 mutational status was correlated with stromal invasion (p=0.034) in univariate analyses after Bonferroni correction.	('ZMYM3', 'Gene', (0, 5))	('stromal invasion', 'CPA', (44, 60))	('ZMYM3', 'Gene', '9203', (0, 5))	('correlated', 'Reg', (28, 38))	('mutational status', 'Var', (6, 23))
8754	30028779	There was a trend with worse overall survival outcome in patients with 3 or more mutations when these groups were compared by the log-rank test (p=0.07).	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (81, 90))	('worse', 'NegReg', (23, 28))
8755	30028779	The patients who developed lung metastases each had one mutation: one had a TP53 mutation and the other KIT mutation.	('lung metastases', 'Disease', (27, 42))	('lung metastases', 'Disease', 'MESH:D009362', (27, 42))	('KIT', 'Gene', (104, 107))	('TP53', 'Gene', '7157', (76, 80))	('mutation', 'Var', (81, 89))	('TP53', 'Gene', (76, 80))	('patients', 'Species', '9606', (4, 12))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('KIT', 'Gene', '3815', (104, 107))
8761	30028779	In this small series, we confirm that the most common mutations in FGTM affect the KIT and TP53 genes.	('TP53', 'Gene', (91, 95))	('affect', 'Reg', (72, 78))	('KIT', 'Gene', (83, 86))	('mutations', 'Var', (54, 63))	('FGTM', 'Disease', 'MESH:D052776', (67, 71))	('FGTM', 'Disease', (67, 71))	('KIT', 'molecular_function', 'GO:0005020', ('83', '86'))	('TP53', 'Gene', '7157', (91, 95))	('KIT', 'Gene', '3815', (83, 86))
8762	30028779	KIT alterations are more common in vulvar than vaginal melanoma, and our findings confirm this.	('vaginal melanoma', 'Phenotype', 'HP:0030418', (47, 63))	('common', 'Reg', (25, 31))	('alterations', 'Var', (4, 15))	('vaginal melanoma', 'Disease', (47, 63))	('vulvar', 'Disease', (35, 41))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('vaginal melanoma', 'Disease', 'MESH:D008545', (47, 63))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
8763	30028779	Historically, the incidence of c-KIT mutation in cutaneous melanoma is between 2-8% and the rate is increased to 15-20% in mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('mutation', 'Var', (37, 45))	('cutaneous melanoma', 'Disease', (49, 67))	('KIT', 'molecular_function', 'GO:0005020', ('33', '36'))	('mucosal melanomas', 'Disease', (123, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('c-KIT', 'Gene', (31, 36))	('c-KIT', 'Gene', '3815', (31, 36))	('mucosal melanomas', 'Disease', 'MESH:D008545', (123, 140))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))
8764	30028779	Amino acid substitution at positions W555R (10%), V559A (20%), V5590 (5%), L576P (25%), K642E (20%) and D816H (5%) are the common mutational loci; specific mutations may affect response to targeted therapy with nilotinib and imatinib in clinical trials.	('K642E', 'Mutation', 'rs121913512', (88, 93))	('V5590', 'Var', (63, 68))	('V559A', 'Var', (50, 55))	('imatinib', 'Chemical', 'MESH:C097613', (225, 233))	('D816H', 'SUBSTITUTION', 'None', (104, 109))	('L576P', 'SUBSTITUTION', 'None', (75, 80))	('affect', 'Reg', (170, 176))	('response to targeted therapy', 'MPA', (177, 205))	('D816H', 'Var', (104, 109))	('V559A', 'Chemical', 'MESH:C488478', (50, 55))	('K642E', 'Var', (88, 93))	('W555R', 'Mutation', 'p.W555R', (37, 42))	('V5590', 'Chemical', 'MESH:C494243', (63, 68))	('nilotinib', 'Chemical', 'MESH:C498826', (211, 220))	('L576P', 'Var', (75, 80))
8765	30028779	In our cases, the KIT mutations involved K642E, W557G and A529D loci.	('W557G', 'Mutation', 'rs121913235', (48, 53))	('KIT', 'Gene', '3815', (18, 21))	('KIT', 'Gene', (18, 21))	('K642E', 'Var', (41, 46))	('K642E', 'Mutation', 'rs121913512', (41, 46))	('A529D loci', 'Var', (58, 68))	('W557G', 'Var', (48, 53))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))	('A529D', 'Mutation', 'rs753212327', (58, 63))
8766	30028779	TP53 mutation was as frequent as KIT mutation in our cases, affecting four patients, with equal distribution between vulvar and vaginal lesions.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('KIT', 'molecular_function', 'GO:0005020', ('33', '36'))	('KIT', 'Gene', '3815', (33, 36))	('patients', 'Species', '9606', (75, 83))	('frequent', 'Reg', (21, 29))	('KIT', 'Gene', (33, 36))	('vaginal lesions', 'Disease', 'MESH:D014623', (128, 143))	('vaginal lesions', 'Disease', (128, 143))	('mutation', 'Var', (5, 13))
8767	30028779	Aberrations of this gene in cutaneous melanoma are typically associated with chronic sun damage, and TP53 mutation has been reported as rare to absent in acral and mucosal melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('mucosal melanoma', 'Disease', (164, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('TP53', 'Gene', '7157', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('Aberrations', 'Var', (0, 11))	('mucosal melanoma', 'Disease', 'MESH:D008545', (164, 180))	('TP53', 'Gene', (101, 105))	('associated', 'Reg', (61, 71))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('sun damage', 'Phenotype', 'HP:0000992', (85, 95))	('cutaneous melanoma', 'Disease', (28, 46))
8769	30028779	Aberrant TP53 expression is also more commonly associated with undifferentiated tumor cells in primary mucosal melanomas of the head and neck.	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('undifferentiated tumor', 'Disease', (63, 85))	('undifferentiated tumor', 'Disease', 'MESH:D002277', (63, 85))	('mucosal melanomas', 'Disease', (103, 120))	('expression', 'MPA', (14, 24))	('TP53', 'Gene', (9, 13))	('TP53', 'Gene', '7157', (9, 13))	('associated', 'Reg', (47, 57))	('mucosal melanomas', 'Disease', 'MESH:D008545', (103, 120))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
8771	30028779	One of the common mutations in cutaneous melanoma is the BRAF mutation; this confers sensitivity to BRAF therapy inhibitor, although patients typically ultimately develop drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (171, 186))	('develop', 'Reg', (163, 170))	('cutaneous melanoma', 'Disease', (31, 49))	('BRAF', 'Gene', '673', (57, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('drug resistance', 'biological_process', 'GO:0009315', ('171', '186'))	('patients', 'Species', '9606', (133, 141))	('BRAF', 'Gene', (57, 61))	('drug resistance', 'biological_process', 'GO:0042493', ('171', '186'))	('BRAF', 'Gene', '673', (100, 104))	('mutation', 'Var', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('BRAF', 'Gene', (100, 104))	('sensitivity to', 'MPA', (85, 99))
8772	30028779	We identified this mutation in 3 cases; two of these involved the V600E locus.	('V600E', 'Var', (66, 71))	('involved', 'Reg', (53, 61))	('V600E', 'Mutation', 'rs113488022', (66, 71))
8775	30028779	This mutation has been reported in neurocutaneous melanosis and a case of primary mesenchymal brain neoplasm, non-small cell lung carcinoma and colorectal carcinoma.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (144, 164))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (114, 139))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (110, 139))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (110, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mesenchymal brain neoplasm', 'Disease', 'MESH:C535700', (82, 108))	('mesenchymal brain neoplasm', 'Disease', (82, 108))	('brain neoplasm', 'Phenotype', 'HP:0030692', (94, 108))	('neurocutaneous melanosis', 'Disease', 'MESH:C537387', (35, 59))	('non-small cell lung carcinoma', 'Disease', (110, 139))	('colorectal carcinoma', 'Disease', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('reported', 'Reg', (23, 31))	('neurocutaneous melanosis', 'Disease', (35, 59))	('mutation', 'Var', (5, 13))
8777	30028779	Finally, the finding of NRAS mutation in two vulvar melanomas is in keeping with the reported incidence of this mutation in mucosal melanoma.	('NRAS', 'Gene', '4893', (24, 28))	('mutation', 'Var', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('vulvar melanomas', 'Phenotype', 'HP:0030418', (45, 61))	('mucosal melanoma', 'Disease', (124, 140))	('vulvar melanomas', 'Disease', (45, 61))	('mucosal melanoma', 'Disease', 'MESH:D008545', (124, 140))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (45, 60))	('vulvar melanomas', 'Disease', 'MESH:D008545', (45, 61))	('NRAS', 'Gene', (24, 28))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
8778	30028779	However, it is worth noting that BRAF and NRAS mutations were exclusive to the vulvar melanoma in our series, while TP53, KIT and ATRX were evenly distributed between the two sites.	('vulvar melanoma', 'Disease', (79, 94))	('TP53', 'Gene', (116, 120))	('BRAF', 'Gene', '673', (33, 37))	('NRAS', 'Gene', '4893', (42, 46))	('ATRX', 'Gene', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('BRAF', 'Gene', (33, 37))	('ATRX', 'Gene', '546', (130, 134))	('mutations', 'Var', (47, 56))	('KIT', 'Gene', '3815', (122, 125))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (79, 94))	('TP53', 'Gene', '7157', (116, 120))	('KIT', 'Gene', (122, 125))	('vulvar melanoma', 'Disease', 'MESH:D008545', (79, 94))	('NRAS', 'Gene', (42, 46))	('KIT', 'molecular_function', 'GO:0005020', ('122', '125'))
8780	30028779	For example, BRAF mutation is commonly associated with younger age in patients with metastatic melanoma.	('patients', 'Species', '9606', (70, 78))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('BRAF', 'Gene', (13, 17))	('associated', 'Reg', (39, 49))	('mutation', 'Var', (18, 26))
8781	30028779	NRAS mutation is associated with more aggressive disease and lower overall survival.	('lower', 'NegReg', (61, 66))	('overall survival', 'MPA', (67, 83))	('aggressive disease', 'Disease', 'MESH:D001523', (38, 56))	('NRAS', 'Gene', (0, 4))	('aggressive disease', 'Disease', (38, 56))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))
8783	30028779	One of the NRAS mutant cases was associated with brain metastasis in our series; this case also had KIT mutation.	('brain', 'Disease', (49, 54))	('KIT', 'Gene', (100, 103))	('NRAS', 'Gene', '4893', (11, 15))	('KIT', 'molecular_function', 'GO:0005020', ('100', '103'))	('associated', 'Reg', (33, 43))	('mutant', 'Var', (16, 22))	('KIT', 'Gene', '3815', (100, 103))	('NRAS', 'Gene', (11, 15))
8784	30028779	Male patients with high log-transformed missense mutation rates have better survival rates in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('patients', 'Species', '9606', (5, 13))	('cutaneous melanoma', 'Disease', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('better', 'PosReg', (69, 75))	('survival', 'CPA', (76, 84))	('missense mutation', 'Var', (40, 57))
8789	30028779	Mutations in cancer-associated genes are frequently found, and their role in choice of adjuvant treatment survival and determination of overall outcome certainly deserves larger-scale studies of this rare disease.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('men', 'Species', '9606', (101, 104))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))
8850	33932034	BNIP3 depletion halted mitophagy and enforced a PHD2-mediated downregulation of HIF-1alpha and its glycolytic program both in vitro and in vivo.	('halted', 'NegReg', (16, 22))	('mitophagy', 'CPA', (23, 32))	('HIF-1alpha', 'Protein', (80, 90))	('BNIP3', 'Gene', (0, 5))	('glycolytic program', 'MPA', (99, 117))	('mitophagy', 'biological_process', 'GO:0000423', ('23', '32'))	('PHD', 'molecular_function', 'GO:0050175', ('48', '51'))	('PHD2', 'Gene', '112405', (48, 52))	('depletion', 'Var', (6, 15))	('downregulation', 'NegReg', (62, 76))	('mitophagy', 'biological_process', 'GO:0000422', ('23', '32'))	('PHD2', 'Gene', (48, 52))
8866	33932034	In an MMTV-PyMT breast cancer model, loss of BNIP3 resulted in reactive oxygen species (ROS)-mediated stabilization of HIF-1alpha, due to the inability of cancer cells to perform mitophagy, which then fostered a HIF-1alpha-driven glycolytic shift and a more invasive breast cancer phenotype (Chourasia et al, 2015).	('BNIP3', 'Gene', (45, 50))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('invasive breast cancer', 'Disease', (258, 280))	('breast cancer', 'Disease', (16, 29))	('stabilization', 'MPA', (102, 115))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('loss', 'Var', (37, 41))	('invasive breast cancer', 'Disease', 'MESH:D001943', (258, 280))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (63, 86))	('inability of cancer', 'Disease', 'MESH:D007319', (142, 161))	('mitophagy', 'biological_process', 'GO:0000422', ('179', '188'))	('HIF-1alpha-driven glycolytic shift', 'MPA', (212, 246))	('mitophagy', 'biological_process', 'GO:0000423', ('179', '188'))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('fostered', 'Reg', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('inability of cancer', 'Disease', (142, 161))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('MMTV', 'Species', '11757', (6, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
8869	33932034	Together with the fact that constitutive HIF-1alpha levels have also been associated with poor prognosis in melanoma (Martinez-Garcia et al, 2017), these studies suggest that BNIP3 and HIF-1alpha jointly coordinate key metabolic and signaling nodes driving the aggressive phenotype of melanoma cells, yet whether and how the loss of BNIP3 affects HIF-1alpha signaling and melanoma growth in vivo have not been addressed.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('signaling', 'biological_process', 'GO:0023052', ('233', '242'))	('affects', 'Reg', (339, 346))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('loss', 'Var', (325, 329))	('melanoma', 'Disease', (285, 293))	('melanoma', 'Phenotype', 'HP:0002861', (372, 380))	('melanoma', 'Disease', (372, 380))	('melanoma growth', 'Disease', 'MESH:D008545', (372, 387))	('signaling', 'biological_process', 'GO:0023052', ('358', '367'))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))	('melanoma', 'Disease', 'MESH:D008545', (372, 380))	('BNIP3', 'Gene', (333, 338))	('Martinez-Garcia', 'Disease', 'MESH:C563346', (118, 133))	('HIF-1alpha signaling', 'MPA', (347, 367))	('melanoma growth', 'Disease', (372, 387))	('Martinez-Garcia', 'Disease', (118, 133))
8870	33932034	To shed light on these questions, we studied the effects of BNIP3 deletion on melanoma cell's mitochondria quality control, metabolic profile, and growth in vivo.	('BNIP3', 'Gene', (60, 65))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('deletion', 'Var', (66, 74))	('mitochondria', 'cellular_component', 'GO:0005739', ('94', '106'))
8886	33932034	Melanoma cells lacking essential autophagy genes, such as ATG5, have been shown to display reduced growth (Maes et al, 2014b; Mgrditchian et al, 2017), but how BNIP3 deficiency affects melanoma growth in vivo remains ill-defined.	('affects', 'Reg', (177, 184))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('ATG5', 'Gene', '11793', (58, 62))	('BNIP3', 'Gene', (160, 165))	('growth', 'MPA', (99, 105))	('Melanoma', 'Disease', (0, 8))	('melanoma growth', 'Disease', (185, 200))	('ATG5', 'Gene', (58, 62))	('melanoma growth', 'Disease', 'MESH:D008545', (185, 200))	('reduced', 'NegReg', (91, 98))	('autophagy', 'biological_process', 'GO:0016236', ('33', '42'))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('autophagy', 'biological_process', 'GO:0006914', ('33', '42'))	('deficiency', 'Var', (166, 176))
8894	33932034	In contrast, loss of BNIP3 caused an increase in the tumoral LC3B punctuated pattern (Fig 2G) suggestive of an altered LC3B turnover or enhanced autophagic flux in vivo.	('autophagic flux', 'CPA', (145, 160))	('LC3B', 'Gene', (61, 65))	('tumoral', 'Disease', (53, 60))	('enhanced', 'PosReg', (136, 144))	('tumoral', 'Disease', 'MESH:D009369', (53, 60))	('turnover', 'MPA', (124, 132))	('altered', 'Reg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('LC3B', 'Gene', '67443', (119, 123))	('increase', 'PosReg', (37, 45))	('BNIP3', 'Gene', (21, 26))	('LC3B', 'Gene', '67443', (61, 65))	('loss', 'Var', (13, 17))	('LC3B', 'Gene', (119, 123))
8896	33932034	Additionally, we found that BafA treatment increased cell death predominantly in BNIP3-silenced cells (Fig EV1F), suggesting that silencing BNIP3 levels renders melanoma cells particularly reliant on autophagy/lysosomal degradation for their survival, as also shown in previous studies using a breast cancer model (Chourasia et al, 2015).	('breast cancer', 'Disease', (294, 307))	('BNIP3', 'Gene', (140, 145))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('autophagy', 'biological_process', 'GO:0016236', ('200', '209'))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('BafA', 'Chemical', 'MESH:C057620', (28, 32))	('melanoma', 'Disease', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('degradation', 'biological_process', 'GO:0009056', ('220', '231'))	('silencing', 'Var', (130, 139))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))	('autophagy', 'biological_process', 'GO:0006914', ('200', '209'))	('autophagy/lysosomal', 'CPA', (200, 219))
8899	33932034	Consistent with this, along with Map1lc3b and Sqstm1, which in murine cells have been shown to belong to TFEB's transcriptional program (Wang et al, 2019), shBNIP3 cells displayed elevated protein levels of TFEB (Fig EV1H).	('TFEB', 'Gene', '21425', (207, 211))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('TFEB', 'Gene', '21425', (105, 109))	('1H', 'Chemical', '-', (219, 221))	('Sqstm1', 'Gene', (46, 52))	('TFEB', 'Gene', (105, 109))	('shBNIP3', 'Var', (156, 163))	('Sqstm1', 'Gene', '18412', (46, 52))	('Map1lc3b', 'Gene', '67443', (33, 41))	('Map1lc3b', 'Gene', (33, 41))	('protein levels', 'MPA', (189, 203))	('TFEB', 'Gene', (207, 211))	('elevated', 'PosReg', (180, 188))	('murine', 'Species', '10090', (63, 69))
8901	33932034	Both the in vitro data and the histological analysis of the tumors described above suggest that loss of BNIP3 may affect melanoma growth by altering specific cancer cell-autonomous processes.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('altering', 'Reg', (140, 148))	('loss', 'Var', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('affect', 'Reg', (114, 120))	('melanoma growth', 'Disease', (121, 136))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('melanoma growth', 'Disease', 'MESH:D008545', (121, 136))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('BNIP3', 'Gene', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', (60, 66))
8903	33932034	Consistent with these studies, under baseline conditions, BNIP3 silencing significantly impaired mitophagy, as shown by the reduced co-localization of GFP-LC3 with the mitochondrial marker TOMM20 (Fig 3A).	('mitophagy', 'biological_process', 'GO:0000423', ('97', '106'))	('reduced', 'NegReg', (124, 131))	('impaired', 'NegReg', (88, 96))	('TOMM20', 'Gene', '67952', (189, 195))	('BNIP3', 'Gene', (58, 63))	('mitophagy', 'biological_process', 'GO:0000422', ('97', '106'))	('co-localization', 'MPA', (132, 147))	('mitophagy', 'CPA', (97, 106))	('TOMM20', 'Gene', (189, 195))	('silencing', 'Var', (64, 73))	('localization', 'biological_process', 'GO:0051179', ('135', '147'))
8905	33932034	BNIP3 silencing resulted in the accumulation of the outer mitochondrial membrane mitophagy receptor NIX, a functional BNIP3 homolog (Vara-Perez et al, 2019a; Lee et al, 2020), in the absence of BafA, whereas BNIP3-proficient cells displayed increased amounts of both mitophagy receptors upon blockade of lysosomal degradation (Fig EV2D).	('increased', 'PosReg', (241, 250))	('NIX', 'Gene', '12177', (100, 103))	('outer mitochondrial membrane', 'cellular_component', 'GO:0005741', ('52', '80'))	('mitophagy', 'biological_process', 'GO:0000423', ('267', '276'))	('outer mitochondrial membrane', 'MPA', (52, 80))	('BNIP3', 'Gene', (0, 5))	('BafA', 'Chemical', 'MESH:C057620', (194, 198))	('mitophagy', 'biological_process', 'GO:0000422', ('81', '90'))	('degradation', 'biological_process', 'GO:0009056', ('314', '325'))	('amounts', 'MPA', (251, 258))	('NIX', 'Gene', (100, 103))	('accumulation', 'PosReg', (32, 44))	('mitophagy', 'biological_process', 'GO:0000423', ('81', '90'))	('silencing', 'Var', (6, 15))	('mitophagy', 'biological_process', 'GO:0000422', ('267', '276'))
8906	33932034	In contrast, while ATG5 silencing increased the presence of both mitochondrial receptors, NIX knockdown did not alter BNIP3 levels above control (Fig EV2E), suggesting that these mitochondrial proteins undergo degradation in association with BNIP3-regulated mitophagy.	('degradation', 'biological_process', 'GO:0009056', ('210', '221'))	('knockdown', 'Var', (94, 103))	('degradation', 'MPA', (210, 221))	('NIX', 'Gene', '12177', (90, 93))	('mitophagy', 'biological_process', 'GO:0000422', ('258', '267'))	('ATG5', 'Gene', '11793', (19, 23))	('NIX', 'Gene', (90, 93))	('mitophagy', 'biological_process', 'GO:0000423', ('258', '267'))	('increased', 'PosReg', (34, 43))	('ATG5', 'Gene', (19, 23))	('silencing', 'Var', (24, 33))
8907	33932034	Together, while these results do not exclude the contribution of alternative clearance pathways (Saita et al, 2013; Vincow et al, 2019), they indicate that the absence of BNIP3 disturbs mitochondrial homeostasis leading to the accumulation of dysfunctional mitochondria, under baseline/replete conditions.	('BNIP3', 'Gene', (171, 176))	('absence', 'Var', (160, 167))	('mitochondria', 'cellular_component', 'GO:0005739', ('257', '269'))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (243, 269))	('accumulation', 'PosReg', (227, 239))	('homeostasis', 'biological_process', 'GO:0042592', ('200', '211'))	('dysfunctional mitochondria', 'Disease', (243, 269))	('mitochondrial homeostasis', 'MPA', (186, 211))	('disturbs', 'NegReg', (177, 185))
8908	33932034	Defects in mitochondrial clearance or general autophagy not only impact mitochondrial functionalities but could alter the metabolic performance of melanoma cells.	('autophagy', 'biological_process', 'GO:0016236', ('46', '55'))	('alter', 'Reg', (112, 117))	('autophagy', 'biological_process', 'GO:0006914', ('46', '55'))	('mitochondrial functionalities', 'MPA', (72, 101))	('Defects', 'Var', (0, 7))	('mitochondrial clearance', 'CPA', (11, 34))	('autophagy', 'CPA', (46, 55))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('impact', 'Reg', (65, 71))
8911	33932034	However, under galactose, which forces the cells to rely further on mitochondrial oxidative phosphorylation (OXPHOS) (Aguer et al, 2011), shBNIP3 melanoma cells exhibited an increased basal OCR compared with their control and shATG5 counterparts (Fig 3C, Appendix Fig S2B).	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('galactose', 'Chemical', 'MESH:D005690', (15, 24))	('OXPHOS', 'biological_process', 'GO:0002082', ('109', '115'))	('increased', 'PosReg', (174, 183))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('82', '107'))	('shBNIP3', 'Var', (138, 145))	('ATG5', 'Gene', '11793', (228, 232))	('ATG5', 'Gene', (228, 232))	('basal OCR', 'CPA', (184, 193))
8913	33932034	To further validate these findings and discriminate the impact of defective BNIP3 or ATG5 expression on the metabolic profile of melanoma cells, we next analyzed melanoma cells' steady-state metabolism using complementary approaches: by proton nuclear magnetic resonance (1H-NMR; steady-state) and by gas chromatography coupled to mass spectrometry (GC-MS; steady-state 13C glucose labeling).	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('ATG5', 'Gene', (85, 89))	('melanoma', 'Disease', (162, 170))	('metabolism', 'biological_process', 'GO:0008152', ('191', '201'))	('1H', 'Chemical', '-', (272, 274))	('defective', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('13C', 'Chemical', 'MESH:C000615229', (370, 373))	('BNIP3', 'Gene', (76, 81))	('ATG5', 'Gene', '11793', (85, 89))	('glucose', 'Chemical', 'MESH:D005947', (374, 381))
8915	33932034	Furthermore, 13C-labeled lactate (m0+3 isotopologue) was significantly reduced in shBNIP3 cells when compared to both shCntl and shATG5 conditions (Fig 3H), indicating that less glucose is contributing to lactate production, as expected from cells with defective glycolysis.	('lactate', 'Chemical', 'MESH:D019344', (205, 212))	('shBNIP3', 'Var', (82, 89))	('lactate production', 'MPA', (205, 223))	('13C', 'Chemical', 'MESH:C000615229', (13, 16))	('reduced', 'NegReg', (71, 78))	('ATG5', 'Gene', '11793', (131, 135))	('glycolysis', 'biological_process', 'GO:0006096', ('263', '273'))	('ATG5', 'Gene', (131, 135))	('lactate', 'Chemical', 'MESH:D019344', (25, 32))	('13C-labeled lactate', 'MPA', (13, 32))	('glucose', 'Chemical', 'MESH:D005947', (178, 185))
8916	33932034	Altogether, these results indicate that:opposite to the metabolic effects observed upon blockade of canonical autophagy:silencing BNIP3 in melanoma cells results in a decreased glycolytic and fermentation ability.	('BNIP3', 'Gene', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('fermentation', 'biological_process', 'GO:0006113', ('192', '204'))	('autophagy', 'biological_process', 'GO:0016236', ('110', '119'))	('silencing', 'Var', (120, 129))	('autophagy', 'biological_process', 'GO:0006914', ('110', '119'))	('decreased', 'NegReg', (167, 176))
8918	33932034	Consistent with previous reports (Jiao et al, 2018), ATG5 removal induced a trend toward an upregulation:rather than downregulation:of some components of this pathway (Fig 3I), in line with the higher glycolytic metabolism of these autophagy-compromised melanoma cells.	('removal', 'Var', (58, 65))	('metabolism', 'biological_process', 'GO:0008152', ('212', '222'))	('ATG5', 'Gene', '11793', (53, 57))	('upregulation', 'PosReg', (92, 104))	('autophagy', 'biological_process', 'GO:0016236', ('232', '241'))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('melanoma', 'Disease', (254, 262))	('ATG5', 'Gene', (53, 57))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('autophagy', 'biological_process', 'GO:0006914', ('232', '241'))
8920	33932034	Our findings that BNIP3 depletion in melanoma cells reduced glycolytic fermentation and forced cells to rely on OXPHOS seemed at first inconsistent with the accumulation of their abnormal mitochondria and with the glycolytic shift usually observed in cells with compromised mitophagy (Vara-Perez et al, 2019a).	('mitochondria', 'cellular_component', 'GO:0005739', ('188', '200'))	('reduced', 'NegReg', (52, 59))	('mitophagy', 'biological_process', 'GO:0000423', ('274', '283'))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('glycolytic fermentation', 'biological_process', 'GO:0019660', ('60', '83'))	('melanoma', 'Disease', (37, 45))	('depletion', 'Var', (24, 33))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('BNIP3', 'Gene', (18, 23))	('OXPHOS', 'biological_process', 'GO:0002082', ('112', '118'))	('glycolytic fermentation', 'MPA', (60, 83))	('mitophagy', 'biological_process', 'GO:0000422', ('274', '283'))
8923	33932034	BNIP3 silencing, but not the knockdown of ATG5, caused a significant downregulation of HIF-1alpha protein levels, which was accompanied by a reduction in the LDHA protein expression (Fig 4A).	('LDHA', 'Gene', '16828', (158, 162))	('LDHA', 'Gene', (158, 162))	('ATG5', 'Gene', '11793', (42, 46))	('BNIP3', 'Gene', (0, 5))	('ATG5', 'Gene', (42, 46))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('HIF-1alpha protein levels', 'MPA', (87, 112))	('silencing', 'Var', (6, 15))	('downregulation', 'NegReg', (69, 83))	('reduction', 'NegReg', (141, 150))
8928	33932034	The effects of BNIP3 silencing on HIF-1alpha were mitigated but not completely abrogated under hypoxia (Appendix Fig S3C), suggesting that BNIP3-regulated mechanisms become overshadowed by the powerful HIF-1alpha stabilization under low oxygen levels (1% O2).	('hypoxia', 'Disease', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('oxygen', 'Chemical', 'MESH:D010100', (237, 243))	('low oxygen levels', 'Phenotype', 'HP:0012418', (233, 250))	('silencing', 'Var', (21, 30))	('O2', 'Chemical', 'MESH:D010100', (255, 257))	('BNIP3', 'Gene', (15, 20))
8933	33932034	Prolyl hydroxylases hydroxylate the alpha subunit of HIF-1 in two proline residues, tagging HIF-1alpha for proteasomal degradation (Lee et al, 2020).	('tagging', 'Var', (84, 91))	('HIF-1', 'Gene', '3091', (92, 97))	('HIF-1', 'Gene', '3091', (53, 58))	('proline', 'Chemical', 'MESH:D011392', (66, 73))	('HIF-1', 'Gene', (92, 97))	('HIF-1', 'Gene', (53, 58))	('degradation', 'biological_process', 'GO:0009056', ('119', '130'))
8934	33932034	Consistent with this, HIF-1alpha was more hydroxylated (on P564) upon BNIP3 knockdown in vitro and in vivo (Fig 4A, Appendix Fig S3B).	('S3B', 'Gene', (129, 132))	('knockdown', 'Var', (76, 85))	('more', 'PosReg', (37, 41))	('P564', 'Var', (59, 63))	('BNIP3', 'Gene', (70, 75))	('S3B', 'Gene', '11778', (129, 132))	('hydroxylated', 'MPA', (42, 54))
8936	33932034	Increased HIF-1alpha hydroxylation and downregulation of its main target genes were also observed in two human early-stage melanoma cell lines, the BRAFWT 530 and BRAFV600E mutant WM35, upon BNIP3 silencing (Fig EV3A-D), although these BNIP3-mediated effects were of a lower magnitude as compared to the murine B16-F10 cell line.	('BNIP3', 'Gene', (191, 196))	('B16-F10', 'CellLine', 'CVCL:0159', (311, 318))	('BRAFV600E', 'Var', (163, 172))	('silencing', 'NegReg', (197, 206))	('murine', 'Species', '10090', (304, 310))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('Increased', 'PosReg', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('human', 'Species', '9606', (105, 110))	('downregulation', 'NegReg', (39, 53))	('HIF-1alpha', 'Enzyme', (10, 20))
8938	33932034	This trend is in stark contrast to what was reported in breast cancer patients (Chourasia et al, 2015), where low BNIP3 levels and high HIF1A predicted poor patient survival better than high HIF1A alone.	('patients', 'Species', '9606', (70, 78))	('HIF1A', 'Gene', (136, 141))	('poor', 'NegReg', (152, 156))	('HIF1A', 'Gene', '3091', (136, 141))	('patient', 'Species', '9606', (157, 164))	('BNIP3 levels', 'MPA', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (70, 77))	('HIF1A', 'Gene', '3091', (191, 196))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('HIF1A', 'Gene', (191, 196))	('patient survival', 'CPA', (157, 173))	('high', 'Var', (131, 135))
8946	33932034	We focused on PHD2 because, among the three PHD isoforms, PHD2 showed a specific trend toward an upregulation upon loss of BNIP3 on RNA (Fig EV4A) and protein level both in vitro and in vivo (Fig 5A).	('PHD', 'Disease', (44, 47))	('upregulation', 'PosReg', (97, 109))	('PHD', 'Disease', (58, 61))	('PHD', 'Disease', 'MESH:D011547', (14, 17))	('PHD2', 'Gene', '112405', (58, 62))	('PHD2', 'Gene', (14, 18))	('PHD', 'molecular_function', 'GO:0050175', ('14', '17'))	('PHD', 'molecular_function', 'GO:0050175', ('44', '47'))	('PHD', 'Disease', 'MESH:D011547', (44, 47))	('PHD', 'Disease', 'MESH:D011547', (58, 61))	('protein level', 'MPA', (151, 164))	('RNA', 'MPA', (132, 135))	('BNIP3', 'Gene', (123, 128))	('PHD2', 'Gene', '112405', (14, 18))	('loss', 'Var', (115, 119))	('PHD2', 'Gene', (58, 62))	('PHD', 'molecular_function', 'GO:0050175', ('58', '61'))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('PHD', 'Disease', (14, 17))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))
8949	33932034	We first validated the functional role of PHD2 in our settings by chemical and genetic interference.	('genetic', 'Var', (79, 86))	('PHD', 'molecular_function', 'GO:0050175', ('42', '45'))	('PHD2', 'Gene', '112405', (42, 46))	('PHD2', 'Gene', (42, 46))
8951	33932034	The siRNA-based PHD2 knockdown (Fig 5E and Fig EV4B, Appendix Table S2) exerted similar rescuing effects though their magnitude was milder as compared to the PHD2 pharmacological inhibition and depended on the PHD2 knockdown efficiency.	('PHD2', 'Gene', '112405', (16, 20))	('PHD', 'molecular_function', 'GO:0050175', ('210', '213'))	('PHD', 'molecular_function', 'GO:0050175', ('16', '19'))	('PHD2', 'Gene', '112405', (210, 214))	('PHD2', 'Gene', '112405', (158, 162))	('PHD2', 'Gene', (16, 20))	('PHD', 'molecular_function', 'GO:0050175', ('158', '161'))	('PHD2', 'Gene', (158, 162))	('knockdown', 'Var', (21, 30))	('PHD2', 'Gene', (210, 214))
8955	33932034	Succinate levels were significantly higher in shBNIP3 cells, which would however suggest PHD2 inhibition and higher HIF-1alpha levels (Koivunen et al, 2007; Lee et al, 2020).	('higher', 'PosReg', (36, 42))	('inhibition', 'NegReg', (94, 104))	('higher', 'PosReg', (109, 115))	('shBNIP3', 'Var', (46, 53))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('PHD2', 'Gene', '112405', (89, 93))	('Succinate levels', 'MPA', (0, 16))	('PHD2', 'Gene', (89, 93))	('PHD', 'molecular_function', 'GO:0050175', ('89', '92'))	('HIF-1alpha levels', 'MPA', (116, 133))
8956	33932034	Instead, intracellular fumarate levels were reduced, although not significantly, by BNIP3 knockdown (Fig EV4C and D).	('fumarate', 'Chemical', 'MESH:D005650', (23, 31))	('knockdown', 'Var', (90, 99))	('intracellular fumarate levels', 'MPA', (9, 38))	('reduced', 'NegReg', (44, 51))	('BNIP3', 'Gene', (84, 89))	('intracellular', 'cellular_component', 'GO:0005622', ('9', '22'))
8959	33932034	We then reasoned that the specific changes in mitochondrial homeostasis, oxygen consumption, and clearance induced by the loss of BNIP3 could underlie the effector mechanism promoting PHD2-mediated HIF-1alpha downregulation.	('homeostasis', 'biological_process', 'GO:0042592', ('60', '71'))	('mitochondrial homeostasis', 'MPA', (46, 71))	('PHD2', 'Gene', (184, 188))	('BNIP3', 'Gene', (130, 135))	('downregulation', 'NegReg', (209, 223))	('PHD', 'molecular_function', 'GO:0050175', ('184', '187'))	('changes', 'Reg', (35, 42))	('oxygen', 'Chemical', 'MESH:D010100', (73, 79))	('clearance', 'MPA', (97, 106))	('loss', 'Var', (122, 126))	('oxygen consumption', 'MPA', (73, 91))	('PHD2', 'Gene', '112405', (184, 188))
8961	33932034	In line with this, only BNIP3-depleted cells:but not autophagy-compromised cells:displayed a significantly higher content of intracellular Fe2+ as imaged and quantitated by FerroOrange, a probe reacting specifically with intracellular Fe2+ ions (Fig 6A).	('intracellular', 'cellular_component', 'GO:0005622', ('125', '138'))	('autophagy', 'biological_process', 'GO:0016236', ('53', '62'))	('FerroOrange', 'Chemical', '-', (173, 184))	('intracellular', 'cellular_component', 'GO:0005622', ('221', '234'))	('autophagy', 'biological_process', 'GO:0006914', ('53', '62'))	('BNIP3-depleted', 'Var', (24, 38))	('Fe2+', 'Chemical', '-', (139, 143))	('Fe2+', 'Chemical', '-', (235, 239))	('higher', 'PosReg', (107, 113))	('content', 'MPA', (114, 121))
8963	33932034	This analysis showed that while the total iron content across these cell lines remained constant (Fig 6B; Appendix Table S3), shBNIP3 cells harbored a significantly higher proportion of Fe2+ when compared to Fe3+ (Fig 6B, Appendix Table S3).	('iron', 'Chemical', 'MESH:D007501', (42, 46))	('shBNIP3', 'Var', (126, 133))	('Fe2+', 'Chemical', '-', (186, 190))	('higher', 'PosReg', (165, 171))	('Fe2+', 'MPA', (186, 190))	('Fe3+', 'Chemical', '-', (208, 212))
8970	33932034	However, and irrespective of this, both NCOA4 and FTL accumulation were higher in shBNIP3 cells compared with shCntl or ATG5-depleted cells upon alkalinization of the lysosomes (Fig 6C, Appendix Table S2), thus suggesting that loss of BNIP3 enhances ferritinophagy.	('NCOA4', 'Gene', (40, 45))	('ATG5', 'Gene', (120, 124))	('loss', 'Var', (227, 231))	('NCOA4', 'Gene', '27057', (40, 45))	('FTL', 'Gene', '14325', (50, 53))	('shBNIP3', 'Gene', (82, 89))	('FTL', 'Gene', (50, 53))	('ATG5', 'Gene', '11793', (120, 124))	('higher', 'PosReg', (72, 78))	('enhances', 'PosReg', (241, 249))	('ferritinophagy', 'MPA', (250, 264))	('BNIP3', 'Gene', (235, 240))
8974	33932034	However, BNIP3 knockdown did not affect Ncoa4 mRNA levels (Fig EV4I) while it increased PHD2 (Egln1) expression (Fig EV4A).	('PHD2', 'Gene', '112405', (88, 92))	('Egln1', 'Gene', '112405', (94, 99))	('knockdown', 'Var', (15, 24))	('PHD2', 'Gene', (88, 92))	('PHD', 'molecular_function', 'GO:0050175', ('88', '91'))	('increased', 'PosReg', (78, 87))	('BNIP3', 'Gene', (9, 14))	('expression', 'MPA', (101, 111))	('Ncoa4', 'Gene', (40, 45))	('Egln1', 'Gene', (94, 99))	('Ncoa4', 'Gene', '27057', (40, 45))
8981	33932034	To this end, we downregulated NCOA4 by siRNA-mediated knockdown and analyzed iron content and HIF-1alpha levels in these melanoma cells by using both FerroOrange (Fig EV4J) and CE-ICP-MS-based Fe2+/Fe3+ speciation analysis (Fig 6E).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('NCOA4', 'Gene', (30, 35))	('knockdown', 'Var', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('NCOA4', 'Gene', '27057', (30, 35))	('FerroOrange', 'Chemical', '-', (150, 161))	('Fe2+', 'Chemical', '-', (193, 197))	('iron', 'Chemical', 'MESH:D007501', (77, 81))	('Fe3+', 'Chemical', '-', (198, 202))	('downregulated', 'NegReg', (16, 29))
8982	33932034	In line with this, NCOA4 silencing diminished intracellular Fe2+ levels (Fig 6E and Fig EV4J and Appendix Table S4) and completely abolished the striking increase in the Fe2+/Fe3+ ratio observed in the BNIP3-depleted cells.	('intracellular Fe2+ levels', 'MPA', (46, 71))	('silencing', 'Var', (25, 34))	('Fe2+/Fe3+ ratio', 'MPA', (170, 185))	('NCOA4', 'Gene', '27057', (19, 24))	('Fe3+', 'Chemical', '-', (175, 179))	('abolished', 'NegReg', (131, 140))	('intracellular', 'cellular_component', 'GO:0005622', ('46', '59'))	('Fe2+', 'Chemical', '-', (170, 174))	('Fe2+', 'Chemical', '-', (60, 64))	('diminished', 'NegReg', (35, 45))	('NCOA4', 'Gene', (19, 24))
8983	33932034	NCOA4 silencing also partially rescued the levels of HIF-1alpha and its downstream target LDHA in the BNIP3-depleted melanoma cells, whereas did not exert major effects in the shCntl and shATG5 (Fig 6F, Appendix Table S2).	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('NCOA4', 'Gene', (0, 5))	('ATG5', 'Gene', '11793', (189, 193))	('ATG5', 'Gene', (189, 193))	('NCOA4', 'Gene', '27057', (0, 5))	('LDHA', 'Gene', (90, 94))	('levels', 'MPA', (43, 49))	('rescued', 'PosReg', (31, 38))	('LDHA', 'Gene', '16828', (90, 94))	('HIF-1alpha', 'MPA', (53, 63))	('silencing', 'Var', (6, 15))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
8986	33932034	To this end, we transduced the melanoma cell lines with constructs overexpressing either a decoy protein (luciferase, Luc) or a human HIF-1alpha mutant which is no longer susceptible to PHD-mediated degradation, since both proline residues targeted for hydroxylation have been mutated into alanine residues (HIF-1alpha-AA), thereby leading to a constitutive HIF-1alpha transcriptional activation (Di Conza et al, 2017).	('PHD', 'Disease', (186, 189))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('alanine', 'Chemical', 'MESH:D000409', (290, 297))	('HIF-1alpha', 'Gene', (358, 368))	('degradation', 'biological_process', 'GO:0009056', ('199', '210'))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('human', 'Species', '9606', (128, 133))	('leading to', 'Reg', (332, 342))	('proline', 'Chemical', 'MESH:D011392', (223, 230))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('PHD', 'Disease', 'MESH:D011547', (186, 189))	('mutated', 'Var', (277, 284))	('PHD', 'molecular_function', 'GO:0050175', ('186', '189'))	('melanoma', 'Disease', (31, 39))
8987	33932034	Successful expression of the human HIF-1alpha-AA mutant in the murine B16-F10 cell lines (Fig EV5A and B) elevated overall HIF-1alpha levels, but not its hydroxylation, in shCntl and corrected HIF-1alpha protein levels in BNIP3-silenced cells, without overtly causing an overexpression (Fig 7A).	('human', 'Species', '9606', (29, 34))	('mutant', 'Var', (49, 55))	('corrected HIF-1alpha protein levels', 'MPA', (183, 218))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('B16-F10', 'CellLine', 'CVCL:0159', (70, 77))	('elevated', 'PosReg', (106, 114))	('HIF-1alpha-AA', 'Gene', (35, 48))	('murine', 'Species', '10090', (63, 69))	('HIF-1alpha levels', 'MPA', (123, 140))
8989	33932034	In contrast, BNIP3-mediated effects on the lysosomal NCOA4 turnover (ferritinophagy flux) were not affected by the expression of HIF-1alpha-AA (Fig 7E).	('BNIP3-mediated', 'Gene', (13, 27))	('HIF-1alpha-AA', 'Var', (129, 142))	('NCOA4', 'Gene', '27057', (53, 58))	('NCOA4', 'Gene', (53, 58))
8990	33932034	Taken together, these data show that in the BNIP3-depleted cells the glycolytic defect is secondary to HIF-1alpha downregulation and suggest that the effects on ferritinophagy are BNIP3-coordinated upstream events, ultimately stimulating PHD2 expression and function.	('ferritinophagy', 'Gene', (161, 175))	('HIF-1alpha', 'Gene', (103, 113))	('glycolytic defect', 'MPA', (69, 86))	('expression', 'MPA', (243, 253))	('PHD2', 'Gene', (238, 242))	('effects', 'Var', (150, 157))	('stimulating', 'PosReg', (226, 237))	('function', 'MPA', (258, 266))	('BNIP3-depleted', 'Gene', (44, 58))	('PHD', 'molecular_function', 'GO:0050175', ('238', '241'))	('downregulation', 'NegReg', (114, 128))	('PHD2', 'Gene', '112405', (238, 242))
9002	33932034	In this study, we show that depletion of BNIP3 decreases mitochondria clearance causing the accumulation of dysfunctional mitochondria.	('dysfunctional mitochondria', 'Disease', (108, 134))	('mitochondria', 'cellular_component', 'GO:0005739', ('122', '134'))	('depletion', 'Var', (28, 37))	('mitochondria', 'cellular_component', 'GO:0005739', ('57', '69'))	('BNIP3', 'Gene', (41, 46))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (108, 134))	('decreases', 'NegReg', (47, 56))	('mitochondria clearance', 'MPA', (57, 79))	('accumulation', 'PosReg', (92, 104))
9005	33932034	Furthermore, rescuing the basal expression of HIF-1alpha (by expressing an undegradable HIF-1alpha mutant) in BNIP3-silenced cells restores their glycolytic capability and corrects their delayed tumor growth in vivo.	('corrects', 'NegReg', (172, 180))	('glycolytic capability', 'MPA', (146, 167))	('tumor', 'Disease', (195, 200))	('HIF-1alpha', 'Gene', (88, 98))	('BNIP3-silenced', 'Gene', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('mutant', 'Var', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('restores', 'PosReg', (131, 139))
9006	33932034	Thus, compromising mitochondrial clearance while concomitantly preventing aerobic glycolysis in melanoma cells through the removal of BNIP3 has oncosuppressive ability.	('preventing', 'NegReg', (63, 73))	('BNIP3', 'Gene', (134, 139))	('mitochondrial clearance', 'MPA', (19, 42))	('aerobic glycolysis', 'MPA', (74, 92))	('compromising', 'NegReg', (6, 18))	('glycolysis', 'biological_process', 'GO:0006096', ('82', '92'))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('removal', 'Var', (123, 130))
9007	33932034	Consistent with this, studies in multiple tumor mouse models have shown that defects in mitophagy can cause tumor regression (Porporato et al, 2018; Vara-Perez et al, 2019a).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (42, 47))	('mouse', 'Species', '10090', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mitophagy', 'biological_process', 'GO:0000422', ('88', '97'))	('defects', 'Var', (77, 84))	('tumor', 'Disease', (108, 113))	('mitophagy', 'biological_process', 'GO:0000423', ('88', '97'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mitophagy', 'CPA', (88, 97))
9009	33932034	Future studies using autophagy blockers in vivo will be important to understand whether inhibiting autophagic flux contributes to accelerate tumor cell death and completely block the growth (or relapse) of the BNIP3-depleted tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('BNIP3-depleted', 'Gene', (210, 224))	('autophagy', 'biological_process', 'GO:0006914', ('21', '30'))	('accelerate', 'PosReg', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('tumor', 'Disease', (141, 146))	('block', 'NegReg', (173, 178))	('autophagic flux', 'CPA', (99, 114))	('inhibiting', 'Var', (88, 98))	('tumor', 'Disease', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('cell death', 'biological_process', 'GO:0008219', ('147', '157'))	('autophagy', 'biological_process', 'GO:0016236', ('21', '30'))	('tumors', 'Disease', (225, 231))
9013	33932034	Notably, in an MMTV-PyMT breast cancer model, loss of BNIP3 was shown to mitigate mitophagy, elevate ROS, and maintain autophagic flux under normoxic conditions (Chourasia et al, 2015), as observed in this study.	('mitophagy', 'CPA', (82, 91))	('BNIP3', 'Gene', (54, 59))	('mitigate', 'NegReg', (73, 81))	('mitophagy', 'biological_process', 'GO:0000422', ('82', '91'))	('ROS', 'MPA', (101, 104))	('MMTV', 'Species', '11757', (15, 19))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('loss', 'Var', (46, 50))	('mitophagy', 'biological_process', 'GO:0000423', ('82', '91'))	('breast cancer', 'Disease', (25, 38))	('autophagic flux', 'CPA', (119, 134))	('elevate', 'PosReg', (93, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('maintain', 'PosReg', (110, 118))
9018	33932034	Irrespective of this unknown, and supporting our patient and mechanistic data, high BNIP3 levels have been shown to promote cancer cell survival and metastatic dissemination in uveal melanomas (Jiang et al, 2018).	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('cancer', 'Disease', (124, 130))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('uveal melanomas', 'Disease', 'MESH:C536494', (177, 192))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('patient', 'Species', '9606', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('promote', 'PosReg', (116, 123))	('high', 'Var', (79, 83))	('metastatic dissemination', 'CPA', (149, 173))	('uveal melanomas', 'Disease', (177, 192))	('uveal melanomas', 'Phenotype', 'HP:0007716', (177, 192))	('BNIP3', 'Gene', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
9023	33932034	Using pharmacological and genetic tools, we show that BNIP3 depletion increases the hydroxylation of HIF-1alpha both in vitro and in vivo by elevating the expression and activity of PHD2.	('BNIP3', 'Gene', (54, 59))	('HIF-1alpha', 'Protein', (101, 111))	('elevating', 'PosReg', (141, 150))	('activity', 'MPA', (170, 178))	('increases', 'PosReg', (70, 79))	('depletion', 'Var', (60, 69))	('expression', 'MPA', (155, 165))	('hydroxylation', 'MPA', (84, 97))	('PHD2', 'Gene', '112405', (182, 186))	('PHD2', 'Gene', (182, 186))	('PHD', 'molecular_function', 'GO:0050175', ('182', '185'))
9029	33932034	Although we cannot rule out that, upon loss of BNIP3, subtle changes in the concentrations of cellular metabolites affecting PHD2 activity may further accentuate HIF-1alpha downregulation, our data suggest that deregulated iron metabolism is a crucial BNIP3-associated effector mechanism.	('HIF-1alpha', 'Protein', (162, 172))	('BNIP3', 'Gene', (47, 52))	('metabolism', 'biological_process', 'GO:0008152', ('228', '238'))	('iron', 'Chemical', 'MESH:D007501', (223, 227))	('PHD2', 'Gene', '112405', (125, 129))	('loss', 'Var', (39, 43))	('PHD', 'molecular_function', 'GO:0050175', ('125', '128'))	('deregulated iron metabolism', 'MPA', (211, 238))	('PHD2', 'Gene', (125, 129))	('downregulation', 'NegReg', (173, 187))
9031	33932034	We found that BNIP3 silencing in melanoma cells exacerbated the lysosomal turnover of NCOA4, resulting in an increase in the cytoplasmic Fe2+/Fe3+ ratio.	('exacerbated', 'PosReg', (48, 59))	('lysosomal turnover', 'MPA', (64, 82))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('increase', 'PosReg', (109, 117))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('BNIP3', 'Gene', (14, 19))	('NCOA4', 'Gene', (86, 91))	('Fe3+', 'Chemical', '-', (142, 146))	('cytoplasmic Fe2+/Fe3+ ratio', 'MPA', (125, 152))	('NCOA4', 'Gene', '27057', (86, 91))	('silencing', 'Var', (20, 29))	('Fe2+', 'Chemical', '-', (137, 141))
9032	33932034	Moreover, we also found that BNIP3 and NCOA4 physically interact and that the removal of NCOA4 rescued iron levels in BNIP3-silenced cells.	('NCOA4', 'Gene', (89, 94))	('rescued', 'PosReg', (95, 102))	('NCOA4', 'Gene', '27057', (39, 44))	('iron', 'Chemical', 'MESH:D007501', (103, 107))	('NCOA4', 'Gene', '27057', (89, 94))	('iron levels', 'MPA', (103, 114))	('BNIP3-silenced', 'Gene', (118, 132))	('removal', 'Var', (78, 85))	('NCOA4', 'Gene', (39, 44))
9038	33932034	Lastly, the elevation of the labile iron pool observed upon loss of BNIP3 suggests that melanoma cells harboring high levels of BNIP3 may be less vulnerable to ferroptosis, an emerging iron-mediated and lipid peroxidation-driven necrotic cell death with possible therapeutic implications in melanoma (Tsoi et al, 2018).	('necrotic cell death', 'biological_process', 'GO:0070265', ('229', '248'))	('iron', 'Chemical', 'MESH:D007501', (185, 189))	('ferroptosis', 'biological_process', 'GO:0097707', ('160', '171'))	('elevation', 'PosReg', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('BNIP3', 'Gene', (68, 73))	('lipid', 'Chemical', 'MESH:D008055', (203, 208))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('loss', 'Var', (60, 64))	('iron', 'Chemical', 'MESH:D007501', (36, 40))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('melanoma', 'Disease', (291, 299))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('necrotic cell death', 'Disease', 'MESH:D003643', (229, 248))	('labile iron pool', 'MPA', (29, 45))	('BNIP3', 'Var', (128, 133))	('necrotic cell death', 'Disease', (229, 248))
9061	33932034	For protein and RNA extraction, cells were seeded at a density of 150,000 (B16-F10 shCntl, B16-F10 shATG5), 200,000 (all human melanoma cell lines), or 300,000 (B16-F10 shBNIP3) cells/ well in a 6-well plate (Greiner Bio-One, Vilvoorde, Belgium) and cultured for 48 h (normoxic condition).	('B16-F10', 'CellLine', 'CVCL:0159', (91, 98))	('ATG5', 'Gene', '11793', (101, 105))	('B16-F10', 'Var', (91, 98))	('ATG5', 'Gene', (101, 105))	('human', 'Species', '9606', (121, 126))	('B16-F10', 'CellLine', 'CVCL:0159', (161, 168))	('F10 shBNIP3', 'Gene', '14058;12176', (165, 176))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('F10 shBNIP3', 'Gene', (165, 176))	('B16-F10', 'CellLine', 'CVCL:0159', (75, 82))
9069	33932034	Human HIF-1alpha mutant cDNA was PCR-amplified from the plasmid pLenti/V5-HIF-1alpha-mPPN and cloned into in-house pCHMWS-eGFP-ires-hygro after removal of eGFP.	('HIF-1alpha', 'Gene', (6, 16))	('Human', 'Species', '9606', (0, 5))	('mutant', 'Var', (17, 23))
9075	33932034	Cells were transiently transfected with 40 microM siRNA from the SMARTpool: ONtarget plus library from Dharmacon (Lafayette, CO, USA) either non-targeting (siScr, D-001810-10-05), targeting murine PHD2 (siPHD2, L-040757-01-0005) or murine NCOA4 (siNCOA4, L-049515-01-0005) using Dharmafect1 (Dharmacon) transfection reagent in serum-free medium according to the manufacturer's indications.	('siScr', 'Disease', 'None', (156, 161))	('PHD2', 'Gene', '112405', (197, 201))	('PHD2', 'Gene', (205, 209))	('murine', 'Species', '10090', (190, 196))	('NCOA4', 'Gene', '27057', (239, 244))	('PHD', 'molecular_function', 'GO:0050175', ('197', '200'))	('PHD2', 'Gene', (197, 201))	('murine', 'Species', '10090', (232, 238))	('NCOA4', 'Gene', (248, 253))	('NCOA4', 'Gene', '27057', (248, 253))	('L-049515-01-0005', 'Var', (255, 271))	('PHD2', 'Gene', '112405', (205, 209))	('siScr', 'Disease', (156, 161))	('non-targeting', 'MPA', (141, 154))	('NCOA4', 'Gene', (239, 244))
9090	33932034	Primary antibodies for ATG5 (1:1000, #12994), murine BNIP3 (1:1000, #3769), HIF-1alpha-OH P564 (1:500, #3434), LC3B (1:1,000, #3868), LDHA (1:1,000, #2012), NIX (1:1,000, #12396), PHD2 (1:1,000, #4835), and TFEB (1:500, #4240) were purchased from Cell Signaling Technologies (Danvers, MA, USA) and prepared in 5% (w/v) BSA in TBS-T buffer.	('NIX', 'Gene', '12177', (157, 160))	('TFEB', 'Gene', '21425', (207, 211))	('PHD2', 'Gene', (180, 184))	('LDHA', 'Gene', '16828', (134, 138))	('LC3B', 'Gene', '67443', (111, 115))	('ATG5', 'Gene', '11793', (23, 27))	('murine', 'Species', '10090', (46, 52))	('1:500', 'Var', (96, 101))	('Signaling', 'biological_process', 'GO:0023052', ('252', '261'))	('NIX', 'Gene', (157, 160))	('LC3B', 'Gene', (111, 115))	('PHD', 'molecular_function', 'GO:0050175', ('180', '183'))	('PHD2', 'Gene', '112405', (180, 184))	('TFEB', 'Gene', (207, 211))	('LDHA', 'Gene', (134, 138))	('ATG5', 'Gene', (23, 27))
9093	33932034	NCOA4 (1:1,000, A302-272A) was purchased from Bethyl Laboratories (Montgomery, TX, USA).	('A302-272A', 'Var', (16, 25))	('NCOA4', 'Gene', '27057', (0, 5))	('NCOA4', 'Gene', (0, 5))
9113	33932034	Cells were fixed with 4% PFA, permeabilized with 0.1% Triton X-100 (v/v) in PBS, blocked with 5% (v/v) FBS, 1% (w/v) BSA, 2.25% (w/v) glycine in PBS and incubated with selected primary (antiTOMM20, 1:100, #ab186735, Abcam) and secondary antibodies (1:200, #A27040, Life Technologies) in 5% (v/v) FBS, 1% (w/v) BSA in PBS.	('1:200', 'Var', (249, 254))	('TOMM20', 'Gene', (190, 196))	('PBS', 'Chemical', 'MESH:D007854', (145, 148))	('TOMM20', 'Gene', '67952', (190, 196))	('PBS', 'Chemical', 'MESH:D007854', (317, 320))	('PFA', 'Chemical', '-', (25, 28))	('PBS', 'Chemical', 'MESH:D007854', (76, 79))
9119	33932034	Inhibition of endogenous peroxidase was achieved by incubating the slides in 0.3% hydrogen peroxide in methanol for 20 min at -20 C. Sections were blocked in TNB blocking buffer (TSA kit, Perkin Elmer, Life Sciences, Zaventem, Belgium) supplemented with 20% (v/v) goat serum (Sigma-Aldrich) for 1 h at RT and then incubated overnight at 4 C with the primary antibody in TNB buffer: anti-Ki67 (1:100, #MA5-14520, Thermo Fisher Scientific), anti-HIF-1alpha (1:300, #10006421, Cayman Chemicals), anti-LC3B (1:100, #3868, Cell Signaling Technologies), anti-CD31 (1:100, #550274, BD Biosciences), anti-alpha-smooth muscle actin-Cy3 (1:250, #C6198, Sigma-Aldrich), or anti-hydroxyprobe (1:100, HP3-200Kit, Chemicon-Millipore).	('antibody', 'molecular_function', 'GO:0003823', ('358', '366'))	('LC3B', 'Gene', '67443', (498, 502))	('Kit', 'Gene', '16590', (695, 698))	('kit', 'Gene', (183, 186))	('LC3B', 'Gene', (498, 502))	('1:100', 'Var', (559, 564))	('antibody', 'cellular_component', 'GO:0042571', ('358', '366'))	('Cy3', 'Chemical', '-', (623, 626))	('Kit', 'Gene', (695, 698))	('Ki67', 'Gene', (387, 391))	('Signaling', 'biological_process', 'GO:0023052', ('523', '532'))	('kit', 'Gene', '16590', (183, 186))	('TSA', 'molecular_function', 'GO:0033984', ('179', '182'))	('antibody', 'cellular_component', 'GO:0019814', ('358', '366'))	('antibody', 'cellular_component', 'GO:0019815', ('358', '366'))	('1:250', 'Var', (628, 633))	('methanol', 'Chemical', 'MESH:D000432', (103, 111))	('Ki67', 'Gene', '17345', (387, 391))
9155	33932034	Intracellular iron content was measured using the dye FerroOrange (F374-10, Dojindo EU GmbH, Munich, Germany) according to the manufacturer's instructions.	('Intracellular', 'cellular_component', 'GO:0005622', ('0', '13'))	('iron', 'Chemical', 'MESH:D007501', (14, 18))	('FerroOrange', 'Chemical', '-', (54, 65))	('Intracellular iron content', 'MPA', (0, 26))	('F374-10', 'Var', (67, 74))
9174	19336521	Aberration in RUNX3 expression has not been described for cutaneous melanoma.	('RUNX3', 'Gene', (14, 19))	('cutaneous melanoma', 'Disease', (58, 76))	('RUNX3', 'Gene', '864', (14, 19))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('Aberration', 'Var', (0, 10))
9181	19336521	Assessment of RUNX3 promoter region methylation showed that only 5 of 17 (29%) melanoma lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas had hypermethylation of the promoter region.	('RUNX3', 'Gene', (14, 19))	('melanomas', 'Disease', (116, 125))	('RUNX3', 'Gene', '864', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('primary melanomas', 'Disease', (108, 125))	('melanomas', 'Disease', 'MESH:D008545', (156, 165))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('hypermethylation', 'Var', (170, 186))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('melanoma lines', 'Disease', 'MESH:D008545', (79, 93))	('primary melanomas', 'Disease', 'MESH:D008545', (108, 125))	('melanomas', 'Disease', (156, 165))	('melanoma lines', 'Disease', (79, 93))	('men', 'Species', '9606', (6, 9))
9194	19336521	Hypermethylation of the RUNX3 promoter region down-regulates its expression.	('down-regulates', 'NegReg', (46, 60))	('RUNX3', 'Gene', '864', (24, 29))	('RUNX3', 'Gene', (24, 29))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (65, 75))
9205	19336521	The study shows specific microRNA to a tumor suppressor gene may be a significant epigenetic mechanism in regulating tumor development and progression.	('progression', 'CPA', (139, 150))	('men', 'Species', '9606', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('microRNA', 'Var', (25, 33))	('tumor suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
9283	19336521	Because down-regulation of RUNX3 mRNA expression has been related to gene promoter region CpG island hypermethylation in other cancers, we examined this epigenetic regulatory mechanism in cell lines and primary and metastatic melanoma specimens.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('down-regulation', 'NegReg', (8, 23))	('men', 'Species', '9606', (240, 243))	('RUNX3', 'Gene', (27, 32))	('mRNA expression', 'MPA', (33, 48))	('RUNX3', 'Gene', '864', (27, 32))	('hypermethylation', 'Var', (101, 117))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Disease', (226, 234))	('examined', 'Reg', (139, 147))
9284	19336521	Aberrant promoter region hypermethylation of CpG islands is thought to play an important role in the inactivation of many tumor suppressor genes in cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('hypermethylation', 'Var', (25, 41))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', (148, 155))	('tumor suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('promoter', 'MPA', (9, 17))	('inactivation', 'NegReg', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
9285	19336521	Specifically, hypermethylation of the RUNX3 promoter region has been shown to down-regulate RUNX3 expression in other malignancies.	('RUNX3', 'Gene', (38, 43))	('down-regulate', 'NegReg', (78, 91))	('RUNX3', 'Gene', '864', (38, 43))	('hypermethylation', 'Var', (14, 30))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('RUNX3', 'Gene', (92, 97))	('RUNX3', 'Gene', '864', (92, 97))	('malignancies', 'Disease', (118, 130))	('expression', 'MPA', (98, 108))
9287	19336521	Five of 17 (29%) melanoma lines assayed showed evidence of RUNX3 promoter region methylation.	('RUNX3', 'Gene', (59, 64))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma lines', 'Disease', 'MESH:D008545', (17, 31))	('melanoma lines', 'Disease', (17, 31))	('RUNX3', 'Gene', '864', (59, 64))
9288	19336521	Of the 82 melanoma specimens assessed, 7 (9%) showed evidence of RUNX3 DNA hypermethylation.	('men', 'Species', '9606', (24, 27))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('RUNX3', 'Gene', (65, 70))	('RUNX3', 'Gene', '864', (65, 70))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('71', '91'))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('hypermethylation', 'Var', (75, 91))	('melanoma', 'Disease', (10, 18))
9289	19336521	Only 2 of 52 (4%) primary melanomas showed RUNX3 DNA hypermethylation, whereas 5 of 30 (16.7%) of metastatic melanomas showed hypermethylation.	('primary melanomas', 'Disease', (18, 35))	('melanomas', 'Disease', (26, 35))	('melanomas', 'Disease', (109, 118))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('melanomas', 'Disease', 'MESH:D008545', (109, 118))	('primary melanomas', 'Disease', 'MESH:D008545', (18, 35))	('melanomas', 'Disease', 'MESH:D008545', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('hypermethylation', 'Var', (53, 69))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('49', '69'))	('RUNX3', 'Gene', (43, 48))	('RUNX3', 'Gene', '864', (43, 48))
9291	19336521	However, the analysis showed that hypermethylation of RUNX3 frequency increased only slightly in metastatic tumors.	('metastatic', 'Disease', (97, 107))	('hypermethylation', 'Var', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('RUNX3', 'Gene', (54, 59))	('RUNX3', 'Gene', '864', (54, 59))
9306	19336521	These results showed that inhibition of miR-532-5p up-regulated the RUNX3 expression in melanoma cells at the mRNA and protein level and indicated that miR-532-5p can inhibit the RUNX3 at the mRNA level.	('RUNX3', 'Gene', '864', (179, 184))	('expression', 'MPA', (74, 84))	('RUNX3', 'Gene', '864', (68, 73))	('miR-532', 'Gene', (40, 47))	('up-regulated', 'PosReg', (51, 63))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('inhibition', 'Var', (26, 36))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('inhibit', 'NegReg', (167, 174))	('miR-532', 'Gene', '693124', (152, 159))	('miR-532', 'Gene', '693124', (40, 47))	('miR-532', 'Gene', (152, 159))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('RUNX3', 'Gene', (179, 184))	('RUNX3', 'Gene', (68, 73))
9319	19336521	have also recently identified in glioblastomas that RUNX3 promoter region was hypermethylated in 56% of tumors.	('glioblastomas', 'Phenotype', 'HP:0012174', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('RUNX3', 'Gene', (52, 57))	('glioblastomas', 'Disease', 'MESH:D005909', (33, 46))	('RUNX3', 'Gene', '864', (52, 57))	('glioblastomas', 'Disease', (33, 46))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('hypermethylated', 'Var', (78, 93))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
9321	19336521	Our results showed low frequency of hypermethylation of the RUNX3 promoter region in melanoma lines and melanoma tumors.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('hypermethylation', 'Var', (36, 52))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('RUNX3', 'Gene', (60, 65))	('RUNX3', 'Gene', '864', (60, 65))	('melanoma lines and melanoma tumors', 'Disease', 'MESH:D008545', (85, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
9323	19336521	RUNX3 is located on chromosome 1p36, which previously has been shown to be a site of genomic deletions in cutaneous melanoma.	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('RUNX3', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('deletions', 'Var', (93, 102))	('cutaneous melanoma', 'Disease', (106, 124))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (106, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (106, 124))	('RUNX3', 'Gene', '864', (0, 5))
9324	19336521	Previously, we have shown that allelic imbalance of the microsatellite region of 1p36 in melanoma tumors can be up to 38%.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('melanoma tumors', 'Disease', (89, 104))	('allelic imbalance', 'Var', (31, 48))	('microsatellite region', 'Var', (56, 77))	('imbalance', 'Phenotype', 'HP:0002172', (39, 48))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma tumors', 'Disease', 'MESH:D008545', (89, 104))
9329	19336521	Moreover, recent studies have shown a link between patterns of miRNA expression and the development of cancer and down-regulation of specific cancer-related genes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('development', 'CPA', (88, 99))	('patterns', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('regulation', 'biological_process', 'GO:0065007', ('119', '129'))	('men', 'Species', '9606', (95, 98))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('down-regulation', 'NegReg', (114, 129))
9345	19336521	We have shown in this study that RUNX3 can be suppressed by both miR and hypermethylation of the promoter region.	('hypermethylation', 'Var', (73, 89))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('RUNX3', 'Gene', (33, 38))	('RUNX3', 'Gene', '864', (33, 38))	('suppressed', 'NegReg', (46, 56))
9347	19336521	These three types of molecular aberrations collectively may suppress RUNX3 during development and metastasis of melanoma.	('aberrations', 'Var', (31, 42))	('RUNX3', 'Gene', (69, 74))	('RUNX3', 'Gene', '864', (69, 74))	('suppress', 'NegReg', (60, 68))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (98, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('men', 'Species', '9606', (89, 92))	('metastasis of melanoma', 'Disease', (98, 120))
9369	27829164	It is well known that UVB radiation induces DNA damage directly in epidermal cells, leading to mutagenesis; UVA radiation induces indirect genotoxicity through reactive oxygen species (ROS) and oxidative stress, and eventually leads to mutations that can trigger the carcinogenic process.	('oxidative stress', 'Phenotype', 'HP:0025464', (194, 210))	('carcinogenic process', 'Disease', 'MESH:D009385', (267, 287))	('leading to', 'Reg', (84, 94))	('ROS', 'Chemical', 'MESH:D017382', (185, 188))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (160, 183))	('leads to', 'Reg', (227, 235))	('mutagenesis', 'biological_process', 'GO:0006280', ('95', '106'))	('mutations', 'Var', (236, 245))	('trigger', 'Reg', (255, 262))	('carcinogenic process', 'Disease', (267, 287))	('oxidative', 'MPA', (194, 203))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('mutagenesis', 'MPA', (95, 106))
9371	27829164	CPD lesions are the most difficult to be repaired and, among them, dimers formed between adjacent cytosines (C-C) or between thymine and cytosine (T-C) are considered the most mutagenic.	('C', 'Chemical', 'MESH:D002244', (111, 112))	('C', 'Chemical', 'MESH:D002244', (149, 150))	('CPD lesions', 'Disease', (0, 11))	('CPD lesions', 'Disease', 'MESH:C565865', (0, 11))	('cytosine', 'Chemical', 'MESH:D003596', (137, 145))	('cytosine', 'Chemical', 'MESH:D003596', (98, 106))	('dimers', 'Var', (67, 73))	('cytosines', 'Chemical', 'MESH:D003596', (98, 107))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('mutagenic', 'Reg', (176, 185))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('thymine', 'Chemical', 'MESH:D013941', (125, 132))
9372	27829164	UVA radiation is an important oxidative stress inducer in epidermal cells through single and/or double DNA strand breaks and formation of 8-oxo-7,8-dihydroguanine (8-oxo-dG), which is strongly associated with cutaneous carcinogenesis due to generation of high genomic instability.	('8-oxo-7,8-dihydroguanine', 'Chemical', 'MESH:C024829', (138, 162))	('double DNA', 'Var', (96, 106))	('cutaneous carcinogenesis', 'Disease', (209, 233))	('cutaneous carcinogenesis', 'Disease', 'MESH:D063646', (209, 233))	('oxidative stress', 'Phenotype', 'HP:0025464', (30, 46))	('8-oxo-dG', 'Chemical', 'MESH:C024829', (164, 172))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('associated', 'Reg', (193, 203))
9389	27829164	The solar simulator lamp profile using the AM 1.5G filter, which lets through UVB, (280-320 nm), UVA (320-400 nm), visible light (400-700 nm) and infrared (700-1000 nm) irradiations, is similar to the mean global solar radiation that reaches the surface of the earth in the USA region.	('280-320 nm', 'Var', (84, 94))	('320-400 nm', 'Var', (102, 112))	('400-700 nm', 'Var', (130, 140))	('AM 1', 'Species', '408139', (43, 47))
9422	27829164	TaqMan probes used were CDKN1A (Hs00355782_m1), CCNE1 (Hs01026536_m1), GADD45A (Hs00169255_m1), GADD45B (Hs04188837_g1), EXO1 (Hs01116195_m1), BRCA1 (Hs01556193_m1), BRCA2 (Hs00609073_m1), MITF (Hs01117294_m1), MDM2 (Hs00242813_m1), PCNA (Hs00427214_g1), and HMOX1 (Hs01110250_m1).	('MDM2', 'Gene', (211, 215))	('Hs01116195_m1', 'Var', (127, 140))	('PCNA', 'molecular_function', 'GO:0003892', ('233', '237'))	('PCNA', 'Gene', (233, 237))	('CCNE1', 'Gene', '898', (48, 53))	('Hs00242813_m1', 'Var', (217, 230))	('MDM2', 'Gene', '4193', (211, 215))	('BRCA2', 'Gene', (166, 171))	('Hs00169255_m1', 'Var', (80, 93))	('CDKN1A', 'Gene', (24, 30))	('Hs01110250_m1', 'Var', (266, 279))	('EXO1', 'Gene', (121, 125))	('MITF', 'Gene', '4286', (189, 193))	('CDKN1A', 'Gene', '1026', (24, 30))	('PCNA', 'Gene', '5111', (233, 237))	('Hs00609073_m1', 'Var', (173, 186))	('Hs00427214_g1', 'Var', (239, 252))	('EXO1', 'Gene', '9156', (121, 125))	('BRCA2', 'Gene', '675', (166, 171))	('MITF', 'Gene', (189, 193))	('GADD45A', 'Gene', (71, 78))	('BRCA1', 'Gene', '672', (143, 148))	('Hs01117294_m1', 'Var', (195, 208))	('GADD45B', 'Gene', (96, 103))	('Hs00355782_m1', 'Var', (32, 45))	('BRCA1', 'Gene', (143, 148))	('Hs01556193_m1', 'Var', (150, 163))	('CCNE1', 'Gene', (48, 53))	('GADD45B', 'Gene', '4616', (96, 103))	('Hs04188837_g1', 'Var', (105, 118))	('GADD45A', 'Gene', '1647', (71, 78))	('Hs01026536_m1', 'Var', (55, 68))
9446	27829164	At 48 hours of treatment, in the group treated with carbaryl and solar radiation, there was a significant reduction in the percentage of cells in G0/G1 phase and a significant increase in S phase, while the percentage of G2 phase cells remained unaltered.	('S phase', 'CPA', (188, 195))	('increase', 'PosReg', (176, 184))	('G0/G1 phase', 'CPA', (146, 157))	('G2 phase', 'biological_process', 'GO:0051319', ('221', '229'))	('reduction', 'NegReg', (106, 115))	('carbaryl', 'Chemical', 'MESH:D012721', (52, 60))	('S phase', 'biological_process', 'GO:0051320', ('188', '195'))	('G1 phase', 'biological_process', 'GO:0051318', ('149', '157'))	('carbaryl', 'Var', (52, 60))
9456	27829164	Those authors demonstrated that Caucasian human melanocytes present limited cell death, mainly by apoptosis, even when exposed to high doses of solar radiation (1200 mJ/cm2 UVB and 11000 mJ/cm2 UVA).	('1200 mJ/cm2', 'Var', (161, 172))	('apoptosis', 'CPA', (98, 107))	('human', 'Species', '9606', (42, 47))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('cell death', 'CPA', (76, 86))	('apoptosis', 'biological_process', 'GO:0097194', ('98', '107'))	('apoptosis', 'biological_process', 'GO:0006915', ('98', '107'))	('cell death', 'biological_process', 'GO:0008219', ('76', '86'))
9490	27829164	demonstrated that the antioxidant acitivity of glutathione peroxidases occurs through direct neutralization of ROS, and their deficiency in knock-out mice induces endothelial and cardiomyocytes abnormalities due to high levels of oxidative stress.	('mice', 'Species', '10090', (150, 154))	('deficiency', 'Var', (126, 136))	('antioxidant acitivity', 'MPA', (22, 43))	('neutralization', 'MPA', (93, 107))	('cardiomyocytes abnormalities', 'Disease', 'MESH:D000014', (179, 207))	('oxidative stress', 'Phenotype', 'HP:0025464', (230, 246))	('induces', 'Reg', (155, 162))	('ROS', 'Chemical', 'MESH:D017382', (111, 114))	('ROS', 'Protein', (111, 114))	('cardiomyocytes abnormalities', 'Disease', (179, 207))	('oxidative stress', 'MPA', (230, 246))	('glutathione', 'Chemical', 'MESH:D005978', (47, 58))
9508	27829164	It is noteworthy that ROS can also cause DNA double strand breaks and oxidatively generated clustered DNA lesions (OCDLs), which are more complex lesions and represent great challenge for the repair system.	('DNA double strand breaks', 'MPA', (41, 65))	('clustered DNA lesions', 'Disease', (92, 113))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('ROS', 'Var', (22, 25))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('cause', 'Reg', (35, 40))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
9521	29725478	A joint effects analysis showed that the co-incidence of the high expression of GBP1-5 was correlated with favorable overall survival in SKCM patients.	('favorable', 'PosReg', (107, 116))	('high expression', 'Var', (61, 76))	('GBP1-5', 'Gene', (80, 86))	('SKCM', 'Disease', (137, 141))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (80, 86))	('patients', 'Species', '9606', (142, 150))
9522	29725478	Our findings suggest that GBP1-5 mRNAs in SKCM are associated with favorable prognosis and may be potential prognostic biomarkers.	('GBP1-5', 'Gene', (26, 32))	('mRNAs', 'Var', (33, 38))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (26, 32))
9537	29725478	The high expression of GBP1 was associated with high overall pathological stage in OSCC tissue.	('OS', 'Chemical', '-', (83, 85))	('GBP1', 'Gene', '2633', (23, 27))	('expression', 'MPA', (9, 19))	('GBP1', 'Gene', (23, 27))	('high', 'Var', (4, 8))	('associated', 'Reg', (32, 42))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('OSCC', 'Disease', (83, 87))
9543	29725478	However, overexpressed GBP1 was significantly associated with poorer prognosis in OSCC patients.	('overexpressed', 'Var', (9, 22))	('OSCC', 'Disease', (82, 86))	('GBP1', 'Gene', '2633', (23, 27))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('GBP1', 'Gene', (23, 27))	('OS', 'Chemical', '-', (82, 84))	('patients', 'Species', '9606', (87, 95))
9576	29725478	A high expression of GBP1-5 was significantly (P<0.001) associated with a favorable OS in SKCM patients (Fig.	('favorable OS', 'Disease', (74, 86))	('GBP1-5', 'Gene', (21, 27))	('patients', 'Species', '9606', (95, 103))	('SKCM', 'Disease', (90, 94))	('high', 'Var', (2, 6))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (21, 27))	('associated', 'Reg', (56, 66))	('OS', 'Chemical', '-', (84, 86))
9580	29725478	The co-overexpression of GBP1-5 in Group 6 (141 from 455) was found to be more highly correlated with a favorable OS than the co-overexpression of fewer GBP genes in other groups (P<0.0001).	('GBP', 'Gene', '54972', (25, 28))	('GBP1-5', 'Gene', (25, 31))	('co-overexpression', 'Var', (4, 21))	('OS', 'Chemical', '-', (114, 116))	('GBP', 'Gene', (153, 156))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (25, 31))	('favorable OS', 'MPA', (104, 116))	('GBP', 'Gene', '54972', (153, 156))	('GBP', 'Gene', (25, 28))
9595	29725478	The joint effects analysis showed that the co-expression of GBP1-5 all at high levels was correlated with a favorable OS in SKCM patients.	('SKCM', 'Disease', (124, 128))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (60, 66))	('patients', 'Species', '9606', (129, 137))	('OS', 'Chemical', '-', (118, 120))	('favorable OS', 'Disease', (108, 120))	('GBP1-5', 'Gene', (60, 66))	('co-expression', 'Var', (43, 56))
9596	29725478	In contrast, the co-expression of GBP1-5 at low levels was correlated with poor OS in SKCM patients.	('patients', 'Species', '9606', (91, 99))	('SKCM', 'Disease', (86, 90))	('OS', 'Chemical', '-', (80, 82))	('GBP1-5', 'Gene', '2633;2634;2635;115361;115362', (34, 40))	('co-expression', 'Var', (17, 30))	('poor OS', 'Disease', (75, 82))	('GBP1-5', 'Gene', (34, 40))
9675	28543136	Recently, mutations in the N-ras oncogene have been recognized as a common genetic mutation occurring in cutaneous melanoma with an incidence as high as 18%.	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (105, 123))	('N-ras', 'Gene', '4893', (27, 32))	('N-ras', 'Gene', (27, 32))	('cutaneous melanoma', 'Disease', (105, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('mutations', 'Var', (10, 19))
9676	28543136	This mutation has been associated with specific histologic subtypes of melanoma as well as distinctive tumor locations, predominately being found in nodular melanoma arising in the setting of areas of chronic sun-damaged skin secondary to exposure to ultraviolet radiation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('nodular melanoma', 'Disease', 'MESH:D020518', (149, 165))	('tumor', 'Disease', (103, 108))	('nodular melanoma', 'Disease', (149, 165))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('found', 'Reg', (140, 145))	('nodular melanoma', 'Phenotype', 'HP:0012058', (149, 165))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma', 'Disease', (157, 165))	('sun-damaged', 'Phenotype', 'HP:0000992', (209, 220))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('associated', 'Reg', (23, 33))	('mutation', 'Var', (5, 13))
9677	28543136	Head and neck melanoma, given their anatomic location and propensity for sun exposure, appears to be particularly susceptible to N-ras mutations.	('N-ras', 'Gene', '4893', (129, 134))	('N-ras', 'Gene', (129, 134))	('neck', 'cellular_component', 'GO:0044326', ('9', '13'))	('mutations', 'Var', (135, 144))	('neck melanoma', 'Disease', (9, 22))	('neck melanoma', 'Disease', 'MESH:D008545', (9, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
9678	28543136	compared frequencies of N-ras mutations between sun-exposed areas of the head and neck to unexposed regions of the body and found N-ras to be mutated in 32% of head and neck melanoma specimens, but only 7% of melanomas developing in unexposed sites.	('melanomas', 'Disease', (209, 218))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('mutated', 'Var', (142, 149))	('N-ras', 'Gene', '4893', (130, 135))	('N-ras', 'Gene', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('N-ras', 'Gene', '4893', (24, 29))	('neck melanoma', 'Disease', (169, 182))	('mutations', 'Var', (30, 39))	('N-ras', 'Gene', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Disease', 'MESH:D008545', (209, 218))	('neck', 'cellular_component', 'GO:0044326', ('169', '173'))	('neck melanoma', 'Disease', 'MESH:D008545', (169, 182))
9679	28543136	N-ras mutations have also been shown to be associated with thicker lesions and have higher rates of mitotic activity.	('thicker lesions', 'CPA', (59, 74))	('N-ras', 'Gene', '4893', (0, 5))	('mitotic activity', 'CPA', (100, 116))	('N-ras', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('higher', 'PosReg', (84, 90))
9680	28543136	Furthermore, N-ras mutation appears to be an independent adverse prognostic factor associated with decreased MSS (HR 2.96, p=0.04).	('decreased', 'NegReg', (99, 108))	('mutation', 'Var', (19, 27))	('N-ras', 'Gene', '4893', (13, 18))	('MSS', 'Gene', (109, 112))	('N-ras', 'Gene', (13, 18))	('MSS', 'Gene', '64374', (109, 112))
9702	33911146	According to the different expressions of LCP2, high LCP2 expression was positively correlated with more tumor-infiltrating CD8+ T cells.	('LCP2', 'Gene', '3937', (42, 46))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('LCP2', 'Gene', (53, 57))	('CD8', 'Gene', (124, 127))	('LCP2', 'Gene', '3937', (53, 57))	('CD8', 'Gene', '925', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('high', 'Var', (48, 52))	('tumor', 'Disease', (105, 110))	('LCP2', 'Gene', (42, 46))
9730	33911146	Furthermore, HPV-positive head and neck cancer (HNSC-HPV positive) had higher LCP2 expression than HPV-negative head and neck cancer.	('higher', 'PosReg', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('neck cancer', 'Disease', (35, 46))	('neck', 'cellular_component', 'GO:0044326', ('35', '39'))	('LCP2', 'Gene', (78, 82))	('head and neck cancer', 'Phenotype', 'HP:0012288', (26, 46))	('LCP2', 'Gene', '3937', (78, 82))	('expression', 'MPA', (83, 93))	('HPV-positive', 'Var', (13, 25))	('neck', 'cellular_component', 'GO:0044326', ('121', '125'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('neck cancer', 'Disease', 'MESH:D006258', (121, 132))	('neck cancer', 'Disease', 'MESH:D006258', (35, 46))	('neck cancer', 'Disease', (121, 132))	('head and neck cancer', 'Phenotype', 'HP:0012288', (112, 132))
9738	33911146	To investigate the prognostic value of LCP2 in the cohort, in which patients were received pharmacotherapy and radiation, TCGA-SKCM, GSE54467 and GSE65904 were included in this study.	('patients', 'Species', '9606', (68, 76))	('LCP2', 'Gene', (39, 43))	('LCP2', 'Gene', '3937', (39, 43))	('GSE54467', 'Var', (133, 141))	('GSE65904', 'Var', (146, 154))
9739	33911146	Kaplan-Meier curves showed that high LCP2 expression was significantly associated with a good overall survival in the SKCM and the SKCM-Metastasis cohorts, but not significant in the SKCM-Primary cohort (Fig.	('high', 'Var', (32, 36))	('LCP2', 'Gene', (37, 41))	('LCP2', 'Gene', '3937', (37, 41))
9740	33911146	Based on two metastatic melanoma datasets (GSE54467 and GSE65904), the prognostic value of LCP2 expression was consistent with the result from the SKCM-Metastasis cohort (Fig.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('GSE54467', 'Var', (43, 51))	('melanoma', 'Disease', (24, 32))	('LCP2', 'Gene', (91, 95))	('LCP2', 'Gene', '3937', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('GSE65904', 'Var', (56, 64))
9773	33911146	The high expression of LCP2 was associated with good survival of patients in SKCM-Metastasis cohort, in which patients received pharmacotherapy and radiation.	('LCP2', 'Gene', '3937', (23, 27))	('high expression', 'Var', (4, 19))	('LCP2', 'Gene', (23, 27))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (110, 118))
9774	33911146	Furthermore, LCP2 was involved in some immune-responses-related signaling pathways and high expression of LCP2 increased the infiltration of anti-tumor immune cells and thus helped to predict the progression-free survival of patients with metastatic skin cutaneous melanoma receiving anti-PD-1 immunotherapy.	('involved', 'Reg', (22, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (255, 273))	('increased', 'PosReg', (111, 120))	('helped', 'Reg', (174, 180))	('patients', 'Species', '9606', (225, 233))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('tumor', 'Disease', (146, 151))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (250, 273))	('LCP2', 'Gene', '3937', (106, 110))	('LCP2', 'Gene', '3937', (13, 17))	('LCP2', 'Gene', (13, 17))	('skin cutaneous melanoma', 'Disease', (250, 273))	('high expression', 'Var', (87, 102))	('LCP2', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('infiltration', 'CPA', (125, 137))
9776	33911146	High LCP2 protein expression is correlated with aggressive behavior in chronic lymphocytic leukemia cells.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (79, 99))	('lymphocytic leukemia', 'Disease', (79, 99))	('protein', 'Protein', (10, 17))	('High', 'Var', (0, 4))	('LCP2', 'Gene', '3937', (5, 9))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (71, 99))	('LCP2', 'Gene', (5, 9))	('aggressive behavior', 'Disease', (48, 67))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('aggressive behavior', 'Disease', 'MESH:D001523', (48, 67))	('aggressive behavior', 'biological_process', 'GO:0002118', ('48', '67'))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('correlated with', 'Reg', (32, 47))	('aggressive behavior', 'Phenotype', 'HP:0000718', (48, 67))
9778	33911146	The high LCP2 expression pattern also occurred in metastatic skin cutaneous melanoma and was correlated with good overall survival.	('skin cutaneous melanoma', 'Disease', (61, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('LCP2', 'Gene', (9, 13))	('LCP2', 'Gene', '3937', (9, 13))	('expression', 'MPA', (14, 24))	('high', 'Var', (4, 8))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 84))	('occurred', 'Reg', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
9782	33911146	Although mislocalization of LCP2 protein caused CD4+ T cells to skew towards the inflammatory Th1 and Th17 lineages, the role of LCP2 in Th17 cell differentiation is still unclear and is worth investigating.	('cell differentiation', 'biological_process', 'GO:0030154', ('142', '162'))	('LCP2', 'Gene', '3937', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('caused', 'Reg', (41, 47))	('CD4', 'Gene', (48, 51))	('mislocalization', 'Var', (9, 24))	('LCP2', 'Gene', (129, 133))	('LCP2', 'Gene', '3937', (129, 133))	('CD4', 'Gene', '920', (48, 51))	('protein', 'Protein', (33, 40))	('skew', 'Reg', (64, 68))	('LCP2', 'Gene', (28, 32))
9794	33911146	Excitingly, LCP2 was a good prognostic biomarker of progression-free survival for patients who received anti-PD1 immunotherapy.	('patients', 'Species', '9606', (82, 90))	('anti-PD1', 'Var', (104, 112))	('LCP2', 'Gene', (12, 16))	('LCP2', 'Gene', '3937', (12, 16))
9801	33911146	2 cohorts of metastatic melanoma with immunotherapy (Gide2019_PD1 (n = 41), Gide2019_PD1 + CTLA4 (n = 32)) were included to evaluate the prediction ability of LCP2.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('Gide2019_PD1', 'Var', (76, 88))	('LCP2', 'Gene', '3937', (159, 163))	('LCP2', 'Gene', (159, 163))	('CTLA4', 'Gene', '1493', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('CTLA4', 'Gene', (91, 96))
9804	33911146	The anti-LCP2 antibody (#DF7020, Biosciences, China) was used as the primary antibody.	('antibody', 'molecular_function', 'GO:0003823', ('14', '22'))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('antibody', 'cellular_component', 'GO:0042571', ('14', '22'))	('LCP2', 'Gene', (9, 13))	('LCP2', 'Gene', '3937', (9, 13))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('#DF7020', 'Var', (24, 31))	('antibody', 'cellular_component', 'GO:0019815', ('14', '22'))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('antibody', 'cellular_component', 'GO:0019814', ('14', '22'))
9820	33911146	Data were imported into GraphPad Prism 7 and the relative value of 22 types of immune cells was evaluated in both high- and low-LCP2 expression groups.	('high-', 'Var', (114, 119))	('LCP2', 'Gene', (128, 132))	('LCP2', 'Gene', '3937', (128, 132))
9824	33911146	GSE54467, GSE65904, Gide2019_PD1, Gide2019_PD1 + CTLA4 cohorts were used to evaluate the prognostic value of LCP2.	('CTLA4', 'Gene', '1493', (49, 54))	('LCP2', 'Gene', (109, 113))	('LCP2', 'Gene', '3937', (109, 113))	('CTLA4', 'Gene', (49, 54))	('Gide2019_PD1', 'Var', (34, 46))
9825	33911146	The Student's t-test is used to compare immune cell fractions in high- and low- LCP2-expression groups for statistical analysis.	('high-', 'Var', (65, 70))	('LCP2', 'Gene', (80, 84))	('LCP2', 'Gene', '3937', (80, 84))
9886	33437754	The newly obtained prediction accuracies caused by a gene were compared to the original prediction accuracy from the model for the cancer type labeled by TCGA data.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene', 'Var', (53, 57))
9904	33437754	The GCNN model with the PPI+singleton graph included all the 7,091 genes and demonstrated a >5% increase in prediction accuracy compared with the PPI graph with a smaller accuracy variation as shown in Table 2, suggesting that the additional 2,647 genes could be important in determining cancer type.	('PPI', 'biological_process', 'GO:0060134', ('146', '149'))	('GCNN', 'Chemical', '-', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('prediction', 'MPA', (108, 118))	('PPI+singleton', 'Var', (24, 37))	('increase', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('PPI', 'biological_process', 'GO:0060134', ('24', '27'))
9911	33437754	A total of 68%, 16%, 95.2%, and 72.9%, out of 166 READ samples were classified into COAD cancer type by the co-expression, co-expression+singleton, PPI, and PPI+singleton GCNN model respectively (confusion matrices in Figure 7 and, Figure 8, and further illustrated in Supplement 2, 3, 4, and 5).	('PPI', 'biological_process', 'GO:0060134', ('148', '151'))	('GCNN', 'Chemical', '-', (171, 175))	('D', 'Chemical', 'MESH:D003903', (87, 88))	('PPI', 'biological_process', 'GO:0060134', ('157', '160'))	('PPI+singleton', 'Var', (157, 170))	('COAD cancer', 'Disease', 'MESH:D029424', (84, 95))	('confusion', 'Phenotype', 'HP:0001289', (196, 205))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('COAD cancer', 'Disease', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
9919	33437754	UCS classification performed poorly (misclassification rate of 25%, 25%, 58.9%, and 21.4% for co-expression, co-expression+singleton, PPI model, and PPI+singleton GCNN model, respectively), and most of these misclassified samples were in UCEC as expected.	('PPI+singleton', 'Var', (149, 162))	('co-expression+singleton', 'Var', (109, 132))	('UCEC', 'Disease', (238, 242))	('GCNN', 'Chemical', '-', (163, 167))	('PPI', 'biological_process', 'GO:0060134', ('149', '152'))	('PPI', 'biological_process', 'GO:0060134', ('134', '137'))	('co-expression', 'Var', (94, 107))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))
10054	33071785	Concordantly, OA increased the levels of miR-193a-3p (targeting MCL1, c-KIT and K-RAS), miR-193a-5p (targeting PIK3R3 and mTOR), miR-34a-5p (targeting BCL2 and c-KIT) and miR-16-5p (miR-16-5p targeting BCL2, K-RAS and mTOR), while decreased miR-214-3p (targeting BAX).	('OA', 'Chemical', 'MESH:C578055', (14, 16))	('PIK3R3', 'Gene', (111, 117))	('mTOR', 'Gene', (218, 222))	('miR-16-5p', 'Var', (171, 180))	('mTOR', 'Gene', (122, 126))	('decreased', 'NegReg', (231, 240))	('BCL2', 'Gene', (202, 206))	('BCL2', 'molecular_function', 'GO:0015283', ('151', '155'))	('mTOR', 'Gene', '2475', (218, 222))	('miR-193a-3p', 'Var', (41, 52))	('mTOR', 'Gene', '2475', (122, 126))	('BCL2', 'Gene', '596', (151, 155))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('miR-34a-5p', 'Var', (129, 139))	('miR-214-3p', 'MPA', (241, 251))	('increased', 'PosReg', (17, 26))	('BCL2', 'Gene', (151, 155))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('PIK3R3', 'Gene', '8503', (111, 117))	('miR-193a-5p', 'Var', (88, 99))	('BCL2', 'Gene', '596', (202, 206))	('BCL2', 'molecular_function', 'GO:0015283', ('202', '206'))
10065	33071785	Indeed, for instance, oleuropein, the main secoiridoid glucoside present in the Olea europaea leaves and also olive oil, induces the downregulation of the pAKT/pS6 pathway enhancing the cytotoxicity activity of different antimelanoma chemotherapeutic drugs.	('oleuropein', 'Chemical', 'MESH:C002769', (22, 32))	('Olea europaea', 'Species', '4146', (80, 93))	('olive oil', 'Chemical', 'MESH:D000069463', (110, 119))	('glucoside', 'Chemical', 'MESH:D005960', (55, 64))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('enhancing', 'PosReg', (172, 181))	('melanoma', 'Disease', (225, 233))	('cytotoxicity', 'Disease', 'MESH:D064420', (186, 198))	('oleuropein', 'Var', (22, 32))	('downregulation', 'NegReg', (133, 147))	('pAKT/pS6 pathway', 'Pathway', (155, 171))	('cytotoxicity', 'Disease', (186, 198))
10066	33071785	Hydroxytyrosol, the most representative simple phenol of EVOO and Olea Europaea L. leaves, causes inhibition of melanoma cell proliferation activating caspase-3-dependent apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('Olea Europaea L', 'Species', '4146', (66, 81))	('inhibition', 'NegReg', (98, 108))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('EVOO', 'Chemical', '-', (57, 61))	('Hydroxytyrosol', 'Var', (0, 14))	('melanoma', 'Disease', (112, 120))	('phenol', 'Chemical', 'MESH:D019800', (47, 53))	('caspase-3-dependent apoptosis', 'CPA', (151, 180))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('Hydroxytyrosol', 'Chemical', 'MESH:C005975', (0, 14))
10096	33071785	To investigate the mechanism underlying the inhibition of melanoma cell viability by OA, the analysis of the cell cycle profile of OA-treated cells was investigated by the evaluation of Histone H3-pSer10, a marker of mitosis, and Cdk2-pTyr15, a marker of the G1/S transition.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('Cdk2-pTyr15', 'Var', (230, 241))	('OA', 'Chemical', 'MESH:C578055', (85, 87))	('mitosis', 'biological_process', 'GO:0000278', ('217', '224'))	('OA', 'Chemical', 'MESH:C578055', (131, 133))	('H3-pSer10', 'Chemical', '-', (194, 203))	('cell cycle', 'biological_process', 'GO:0007049', ('109', '119'))	('Cdk', 'molecular_function', 'GO:0004693', ('230', '233'))	('Tyr15', 'Chemical', '-', (236, 241))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
10100	33071785	In parallel, in OA treated cells we observed a significant increase (2.9 fold-increase) of the phosphorylation of Cdk2 on Tyr15 (Figure 2B), consistent with a cell cycle arrest in G1/S transition.	('Cdk', 'molecular_function', 'GO:0004693', ('114', '117'))	('OA', 'Chemical', 'MESH:C578055', (16, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (159, 176))	('Tyr15', 'Var', (122, 127))	('arrest', 'Disease', 'MESH:D006323', (170, 176))	('cell cycle', 'CPA', (159, 169))	('Cdk2', 'Gene', (114, 118))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('159', '176'))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('arrest', 'Disease', (170, 176))	('Tyr15', 'Chemical', '-', (122, 127))	('phosphorylation', 'MPA', (95, 110))	('increase', 'PosReg', (59, 67))
10101	33071785	Indeed, Cdk2 is a master regulator of G1/S transition which triggers out when it is in the dephosphorylated active form; the phosphorylation on Tyr15 leads to inactivation of this cyclin.	('phosphorylation on Tyr15', 'Var', (125, 149))	('Tyr15', 'Chemical', '-', (144, 149))	('cyclin', 'Protein', (180, 186))	('Cdk', 'molecular_function', 'GO:0004693', ('8', '11'))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('cyclin', 'molecular_function', 'GO:0016538', ('180', '186'))	('inactivation', 'MPA', (159, 171))
10111	33071785	Concordantly with gene modulation results, a significant 2-fold decrease of miR-214-3p, targeting BAX, and a significant upregulation of miR-34a-5p and miR-16-5p, both targeting BCL2, and of miR-193a-3p, targeting MCL-1 (Figure 3C) were observed.	('miR-16-5p', 'Var', (152, 161))	('BCL2', 'Gene', '596', (178, 182))	('decrease', 'NegReg', (64, 72))	('upregulation', 'PosReg', (121, 133))	('miR-214-3p', 'Gene', (76, 86))	('BCL2', 'Gene', (178, 182))	('miR-34a-5p', 'Var', (137, 147))	('BCL2', 'molecular_function', 'GO:0015283', ('178', '182'))
10115	33071785	In agreement with these data, a significant upregulation of miR-155-5p (targeting KRAS and PIK3R3) and miR-193a-5p (targeting mTOR) was evident after OA treatment (Figures 4B, C).	('OA', 'Chemical', 'MESH:C578055', (150, 152))	('PIK3R3', 'Gene', (91, 97))	('miR-193a-5p', 'Var', (103, 114))	('upregulation', 'PosReg', (44, 56))	('miR-155-5p', 'Gene', (60, 70))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('PIK3R3', 'Gene', '8503', (91, 97))
10117	33071785	Indeed, C-KIT is also targeted by miR-34a-5p and miR-193a-3p, K-RAS is also a target of miR-193a-3p and miR-16-5p, and the expression of mTOR is further regulated by miR-16-5p (Figure 4C).	('regulated', 'Reg', (153, 162))	('miR-16-5p', 'Var', (104, 113))	('expression', 'MPA', (123, 133))	('miR-193a-3p', 'Var', (88, 99))	('miR-34a-5p', 'Var', (34, 44))	('mTOR', 'Gene', (137, 141))	('mTOR', 'Gene', '2475', (137, 141))	('KIT', 'molecular_function', 'GO:0005020', ('10', '13'))	('miR-193a-3p', 'Var', (49, 60))	('targeted', 'Reg', (22, 30))	('C-KIT', 'Protein', (8, 13))
10138	33071785	Indeed, in OA-treated cells, we reported the decrease of the antiapoptotic BCL-2 and MCL1 mRNA expression and the increase of their experimentally validated inhibitory miRNAs, i.e., miR-34a-5p, miR-16-5p, and miR-193a-3p, (miRTarBase Accession ID: MIRT002298, MIRT001800, and MIRT002485) and the simultaneous increase of proapoptotic BAX expression and decrease of its silencing miR-214-3p (miRTarBase Accession ID: MIRT438124).	('BCL-2', 'Gene', (75, 80))	('BCL-2', 'molecular_function', 'GO:0015283', ('75', '80'))	('silencing miR-214-3p', 'MPA', (369, 389))	('miR-193a-3p', 'Var', (209, 220))	('MCL1', 'Gene', (85, 89))	('BAX', 'Gene', (334, 337))	('antiapoptotic', 'MPA', (61, 74))	('decrease', 'NegReg', (45, 53))	('MIRT001800', 'Var', (260, 270))	('miRTarBase Accession ID', 'Disease', (223, 246))	('decrease', 'NegReg', (353, 361))	('miRTarBase Accession ID', 'Disease', (391, 414))	('miRTarBase Accession ID', 'Disease', 'MESH:C537985', (223, 246))	('OA', 'Chemical', 'MESH:C578055', (11, 13))	('miRTarBase Accession ID', 'Disease', 'MESH:C537985', (391, 414))	('MIRT002485', 'Var', (276, 286))	('increase', 'PosReg', (114, 122))	('proapoptotic', 'MPA', (321, 333))	('miR-34a-5p', 'Var', (182, 192))	('expression', 'MPA', (338, 348))	('increase', 'PosReg', (309, 317))	('BCL-2', 'Gene', '596', (75, 80))
10141	33071785	The ability of OA to exert epigenetic modulation has been also demonstrated in other pathophysiological models, including adipocyte inflammation for miR-155 and miR-34a and multiple myeloma for miR-29b and miR-22 with the downregulation of several class I/II histone deacetylases.	('adipocyte inflammation', 'Phenotype', 'HP:0012490', (122, 144))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('miR-34a', 'Var', (161, 168))	('downregulation', 'NegReg', (222, 236))	('miR-29b', 'Var', (194, 201))	('class I/II histone deacetylases', 'Enzyme', (248, 279))	('miR-22', 'Gene', (206, 212))	('inflammation', 'Disease', (132, 144))	('multiple myeloma', 'Disease', 'MESH:D009101', (173, 189))	('inflammation', 'biological_process', 'GO:0006954', ('132', '144'))	('miR-155', 'Var', (149, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (173, 189))	('multiple myeloma', 'Disease', (173, 189))	('epigenetic modulation', 'MPA', (27, 48))	('OA', 'Chemical', 'MESH:C578055', (15, 17))
10145	33071785	Interestingly, high levels of mTOR expression can lead to apoptotic resistance by modulating several molecules, including Bcl-2 family members, and thus promoting tumor cell survival).	('modulating', 'Reg', (82, 92))	('lead to', 'Reg', (50, 57))	('apoptotic', 'MPA', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mTOR', 'Gene', '2475', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Bcl-2', 'molecular_function', 'GO:0015283', ('122', '127'))	('promoting', 'PosReg', (153, 162))	('tumor', 'Disease', (163, 168))	('Bcl-2', 'Gene', (122, 127))	('Bcl-2', 'Gene', '596', (122, 127))	('mTOR', 'Gene', (30, 34))	('expression', 'Var', (35, 45))
10146	33071785	The activated PI3K/Akt/mTOR pathway has been shown to induce upregulation of antiapoptotic Bcl-2 family member, such as MCL1, and the phosphorylation of BAX at the S184 site leading to BAX inactivation.	('inactivation', 'NegReg', (189, 201))	('MCL1', 'Gene', (120, 124))	('BAX', 'Gene', (185, 188))	('phosphorylation', 'Var', (134, 149))	('upregulation', 'PosReg', (61, 73))	('Bcl-2', 'Gene', '596', (91, 96))	('mTOR', 'Gene', (23, 27))	('Bcl-2', 'molecular_function', 'GO:0015283', ('91', '96'))	('mTOR', 'Gene', '2475', (23, 27))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('Bcl-2', 'Gene', (91, 96))	('BAX', 'Gene', (153, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))
10148	33071785	OA counteracts the expression of these genes by inducing an increase in the expression of miR-34a-5p, miR-193a-3p, miR-193a-5p, miR-16-5p, and miR-155-5p, which act as regulatory elements able to decrease transcriptional levels of these target genes (c-KIT, K-RAS, and PIK3R3) (miRTarBase Accession ID: MIRT438239, MIRT005100, MIRT502085, MIRT031485), and hence contrasting mTOR signaling.	('transcriptional levels', 'MPA', (205, 227))	('decrease', 'NegReg', (196, 204))	('MIRT005100', 'Var', (315, 325))	('MIRT438239', 'Var', (303, 313))	('MIRT502085', 'Var', (327, 337))	('PIK3R3', 'Gene', '8503', (269, 275))	('miR-155-5p', 'Var', (143, 153))	('miRTarBase Accession ID', 'Disease', (278, 301))	('miRTarBase Accession ID', 'Disease', 'MESH:C537985', (278, 301))	('increase', 'PosReg', (60, 68))	('PIK3R3', 'Gene', (269, 275))	('mTOR', 'Gene', (374, 378))	('miR-34a-5p', 'Gene', (90, 100))	('contrasting', 'NegReg', (362, 373))	('miR-193a-5p', 'Var', (115, 126))	('signaling', 'biological_process', 'GO:0023052', ('379', '388'))	('mTOR', 'Gene', '2475', (374, 378))	('OA', 'Chemical', 'MESH:C578055', (0, 2))	('miR-16-5p', 'Var', (128, 137))	('KIT', 'molecular_function', 'GO:0005020', ('253', '256'))	('miR-193a-3p', 'Var', (102, 113))	('expression', 'MPA', (76, 86))	('MIRT031485', 'Var', (339, 349))
10149	33071785	Moreover, mTOR expression levels were downregulated also through the increased expression of its silencing agents, miR-16-5p and miR-193a-5p, in OA-treated melanoma cells.	('silencing', 'NegReg', (97, 106))	('mTOR', 'Gene', (10, 14))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('increased', 'PosReg', (69, 78))	('miR-16-5p', 'Var', (115, 124))	('expression', 'MPA', (79, 89))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('downregulated', 'NegReg', (38, 51))	('expression levels', 'MPA', (15, 32))	('miR-193a-5p', 'Var', (129, 140))	('OA', 'Chemical', 'MESH:C578055', (145, 147))	('mTOR', 'Gene', '2475', (10, 14))
10232	32194688	High expression of STAT1 was significantly associated with immune response (normalized P=0.002; FDR=0.243; Fig.	('High', 'Var', (0, 4))	('immune response', 'biological_process', 'GO:0006955', ('59', '74'))	('STAT1', 'Gene', (19, 24))	('immune response', 'CPA', (59, 74))	('associated', 'Reg', (43, 53))	('STAT1', 'Gene', '6772', (19, 24))
10238	32194688	Dysfunction in the JAK-STAT signaling pathway is associated with diseases such as cancer and immune disorders.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Dysfunction', 'Var', (0, 11))	('JAK', 'Gene', '3716', (19, 22))	('signaling pathway', 'biological_process', 'GO:0007165', ('28', '45'))	('JAK', 'Gene', (19, 22))	('associated', 'Reg', (49, 59))	('immune disorders', 'Disease', 'MESH:D007154', (93, 109))	('STAT', 'Gene', (23, 27))	('immune disorders', 'Disease', (93, 109))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('JAK', 'molecular_function', 'GO:0004713', ('19', '22'))	('STAT', 'Gene', '6772', (23, 27))
10244	32194688	In papillary thyroid cancer, downregulation of JAK1 by miR-520a-3p inactivated the JAK-STAT signaling pathway.	('STAT', 'Gene', (87, 91))	('downregulation', 'NegReg', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('STAT', 'Gene', '6772', (87, 91))	('papillary thyroid cancer', 'Disease', (3, 27))	('JAK', 'molecular_function', 'GO:0004713', ('47', '50'))	('miR-520a-3p', 'Var', (55, 66))	('JAK1', 'Gene', (47, 51))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (3, 27))	('JAK1', 'Gene', '3716', (47, 51))	('JAK', 'Gene', (47, 50))	('JAK', 'Gene', '3716', (47, 50))	('signaling pathway', 'biological_process', 'GO:0007165', ('92', '109'))	('inactivated', 'NegReg', (67, 78))	('JAK', 'Gene', '3716', (83, 86))	('thyroid cancer', 'Phenotype', 'HP:0002890', (13, 27))	('JAK', 'molecular_function', 'GO:0004713', ('83', '86'))	('JAK', 'Gene', (83, 86))
10250	32194688	These results are consistent with other studies, in which high expression of STAT1 was associated with favorable prognosis in high-grade serous ovarian cancer (HGSC), colorectal cancer and esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (189, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('colorectal cancer', 'Disease', (167, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('high expression', 'Var', (58, 73))	('esophageal squamous cell carcinoma', 'Disease', (189, 223))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('serous ovarian cancer', 'Disease', (137, 158))	('STAT1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (137, 158))	('STAT1', 'Gene', '6772', (77, 82))
10251	32194688	In addition, high expression of STAT1 in HGSC was significantly associated with the recruitment of intraepithelial CD8+ T cells, which enhanced the prognostic and predictive value of intratumoral CD8+ T cells in HGSC, potentially due to tumors with high STAT1 mRNA expression exhibiting elevated expression of genes specific for tumor-associated macrophages and immunosuppressive T lymphocytes.	('tumor', 'Disease', (188, 193))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', (329, 334))	('STAT1', 'Gene', (254, 259))	('associated', 'Reg', (64, 74))	('tumors', 'Disease', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('STAT1', 'Gene', (32, 37))	('enhanced', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('STAT1', 'Gene', '6772', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('STAT1', 'Gene', '6772', (32, 37))	('high', 'Var', (249, 253))	('tumor', 'Disease', (237, 242))	('mRNA', 'MPA', (260, 264))	('tumor', 'Disease', 'MESH:D009369', (237, 242))
10253	32194688	However, high STAT1 expression was associated with poor prognosis in glioblastoma, and breast, ovarian, lung, blood and brain cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('expression', 'MPA', (20, 30))	('STAT1', 'Gene', (14, 19))	('STAT1', 'Gene', '6772', (14, 19))	('brain cancer', 'Phenotype', 'HP:0030692', (120, 132))	('breast, ovarian, lung, blood and brain cancer', 'Disease', 'MESH:D061325', (87, 132))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('high', 'Var', (9, 13))
10255	32194688	The majority of studies on STAT3 and cancer prognosis have demonstrated that phosphorylated STAT3 is associated with a poor outcome in colorectal cancer, multiple myeloma and urothelial carcinoma.	('phosphorylated', 'Var', (77, 91))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('STAT3', 'Gene', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('multiple myeloma and urothelial carcinoma', 'Disease', 'MESH:D009101', (154, 195))	('cancer', 'Disease', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('STAT3', 'Gene', '6774', (92, 97))	('STAT3', 'Gene', '6774', (27, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('STAT3', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('colorectal cancer', 'Disease', (135, 152))	('multiple myeloma', 'Phenotype', 'HP:0006775', (154, 170))
10259	32194688	For instance, colorectal carcinoma cell lines exhibiting low STAT1 and high STAT3 expression levels are associated with enhanced tumor growth in xenografts; by contrast, xenograft cell lines with high STAT1 and low STAT3 levels grew slowly.	('STAT3', 'Gene', '6774', (76, 81))	('STAT1', 'Gene', '6772', (61, 66))	('enhanced', 'PosReg', (120, 128))	('high', 'Var', (71, 75))	('STAT3', 'Gene', (76, 81))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (14, 34))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('STAT3', 'Gene', '6774', (215, 220))	('low', 'NegReg', (57, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('STAT1', 'Gene', (201, 206))	('STAT3', 'Gene', (215, 220))	('STAT1', 'Gene', (61, 66))	('tumor', 'Disease', (129, 134))	('STAT1', 'Gene', '6772', (201, 206))	('colorectal carcinoma', 'Disease', (14, 34))
10260	32194688	Thus, gene interactions may influence the cancer outcome.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('gene interactions', 'Var', (6, 23))	('influence', 'Reg', (28, 37))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
10278	29085693	The molecular study of the urinary bladder tumor specimen identified mutation of the GNAQ gene, which has been suggested to be an early molecular event in the pathogenetic course of over 80% of uveal melanomas.	('bladder tumor', 'Disease', 'MESH:D001749', (35, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (194, 209))	('melanomas', 'Phenotype', 'HP:0002861', (200, 209))	('bladder tumor', 'Phenotype', 'HP:0009725', (35, 48))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('mutation', 'Var', (69, 77))	('GNAQ', 'Gene', (85, 89))	('bladder tumor', 'Disease', (35, 48))	('uveal melanomas', 'Disease', 'MESH:C536494', (194, 209))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GNAQ', 'Gene', '2776', (85, 89))	('uveal melanomas', 'Disease', (194, 209))
10305	29085693	The genetic analysis proved positive for the exon 4 c.548G>A p.R183Q GNAQ mutation while it provided negative results for the rest of all.	('c.548G>A', 'Mutation', 'rs397514698', (52, 60))	('GNAQ', 'Gene', '2776', (69, 73))	('positive', 'Reg', (28, 36))	('c.548G>A p.R183Q', 'Var', (52, 68))	('GNAQ', 'Gene', (69, 73))	('p.R183Q', 'Var', (61, 68))	('p.R183Q', 'Mutation', 'rs397514698', (61, 68))
10319	29085693	In fact, it has been suggested that GNAQ mutations are an early event characterizing over 80% of uveal melanomas.	('mutations', 'Var', (41, 50))	('uveal melanomas', 'Disease', 'MESH:C536494', (97, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('GNAQ', 'Gene', '2776', (36, 40))	('uveal melanomas', 'Disease', (97, 112))	('uveal melanomas', 'Phenotype', 'HP:0007716', (97, 112))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('GNAQ', 'Gene', (36, 40))
10325	26850723	Some melanocortin 1 receptor (MC1R) gene variants play a direct role in the pathogenesis of cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma apart from their role in determining a cancer-prone pigmentory phenotype (fair skin, red hair, blue eyes) through their interactions with other genes regulating immuno-inflammatory responses, DNA repair or apoptosis.	('blue eyes', 'Phenotype', 'HP:0000635', (276, 285))	('apoptosis', 'biological_process', 'GO:0097194', ('387', '396'))	('apoptosis', 'biological_process', 'GO:0006915', ('387', '396'))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (102, 122))	('red hair, blue eyes', 'Disease', 'MESH:C567139', (266, 285))	('variants', 'Var', (41, 49))	('red hair', 'Phenotype', 'HP:0002297', (266, 274))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (124, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('MC1R', 'Gene', '4157', (30, 34))	('cutaneous basal cell carcinoma', 'Disease', (92, 122))	('MC1R', 'Gene', (30, 34))	('cutaneous melanoma', 'Disease', (162, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('DNA', 'cellular_component', 'GO:0005574', ('373', '376'))	('pathogenesis', 'biological_process', 'GO:0009405', ('76', '88'))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (92, 122))	('cancer', 'Disease', (220, 226))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('cutaneous squamous cell carcinoma', 'Disease', (124, 157))	('interactions', 'Interaction', (301, 313))	('fair skin', 'Phenotype', 'HP:0007513', (255, 264))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('DNA repair', 'biological_process', 'GO:0006281', ('373', '383'))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 157))	('melanocortin 1 receptor', 'Gene', '4157', (5, 28))	('melanocortin 1 receptor', 'Gene', (5, 28))
10336	26850723	Cutaneous squamous cell carcinoma, basal cell carcinoma and melanoma more frequently affect elderly, red haired, blue eyed and fair complexioned persons, and it has been consistently demonstrated that variants of the highly polymorphic melanocortin 1 receptor (MC1R) gene are associated with increased risk of these malignancies.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('variants', 'Var', (201, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (35, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('red hair', 'Phenotype', 'HP:0002297', (101, 109))	('MC1R', 'Gene', '4157', (261, 265))	('MC1R', 'Gene', (261, 265))	('associated', 'Reg', (276, 286))	('Cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (0, 33))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (35, 55))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('malignancies', 'Disease', 'MESH:D009369', (316, 328))	('blue eyed', 'Phenotype', 'HP:0000635', (113, 122))	('melanocortin 1 receptor', 'Gene', (236, 259))	('Cutaneous squamous cell carcinoma', 'Disease', (0, 33))	('malignancies', 'Disease', (316, 328))	('melanocortin 1 receptor', 'Gene', '4157', (236, 259))	('basal cell carcinoma', 'Disease', (35, 55))	('persons', 'Species', '9606', (145, 152))	('Cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
10337	26850723	The pathogenesis of cutaneous squamous cell carcinoma is associated with multiple local genetic alterations that may bring about dysregulation of the cell cycle, of apoptosis, of DNA repair, of cellular differentiation, of telomerase activity with evasion of cellular senescence, and of expression of the enzyme cyclo-oxygenase 2 (COX-2).	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 53))	('apoptosis', 'CPA', (165, 174))	('dysregulation', 'MPA', (129, 142))	('cellular senescence', 'biological_process', 'GO:0090398', ('259', '278'))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))	('evasion', 'MPA', (248, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('oxygenase', 'molecular_function', 'GO:0016701', ('318', '327'))	('cell cycle', 'CPA', (150, 160))	('alterations', 'Var', (96, 107))	('bring about', 'Reg', (117, 128))	('DNA repair', 'biological_process', 'GO:0006281', ('179', '189'))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (20, 53))	('telomerase activity', 'molecular_function', 'GO:0003720', ('223', '242'))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (129, 160))	('activity', 'MPA', (234, 242))	('cell cycle', 'biological_process', 'GO:0007049', ('150', '160'))	('DNA repair', 'MPA', (179, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('pathogenesis', 'biological_process', 'GO:0009405', ('4', '16'))	('cellular differentiation', 'CPA', (194, 218))	('cutaneous squamous cell carcinoma', 'Disease', (20, 53))
10338	26850723	In contrast, cutaneous basal cell carcinoma is primarily driven by genetic mutations causing uncontrolled activation of the hedgehog intracellular pathway leading to enhanced proliferative capacity of basal cells, and by molecular alterations in the p53 tumour-suppressor gene.	('molecular alterations', 'Var', (221, 242))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (13, 43))	('driven', 'Reg', (57, 63))	('proliferative capacity', 'CPA', (175, 197))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('intracellular', 'cellular_component', 'GO:0005622', ('133', '146'))	('tumour', 'Disease', (254, 260))	('p53', 'Gene', (250, 253))	('cutaneous basal cell carcinoma', 'Disease', (13, 43))	('p53', 'Gene', '7157', (250, 253))	('mutations', 'Var', (75, 84))	('enhanced', 'PosReg', (166, 174))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (23, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('activation', 'PosReg', (106, 116))	('hedgehog intracellular pathway', 'Pathway', (124, 154))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
10342	26850723	Skin melanoma cells show molecular alterations of the RAS-BRAF-MEK-ERK mitogen activated protein kinase (MAPK) signalling pathway, mediating uncontrolled proliferation of the affected malignant melanocytes; genetic alterations in the CDKN2A gene encoding the p16INK4A tumour suppressor protein; and MC1R genetic polymorphism.	('signalling pathway', 'biological_process', 'GO:0007165', ('111', '129'))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('CDKN2A', 'Gene', (234, 240))	('tumour', 'Disease', (268, 274))	('alterations', 'Var', (35, 46))	('MC1R', 'Gene', '4157', (299, 303))	('MAPK', 'molecular_function', 'GO:0004707', ('105', '109'))	('genetic alterations', 'Var', (207, 226))	('MC1R', 'Gene', (299, 303))	('protein', 'cellular_component', 'GO:0003675', ('286', '293'))	('CDKN2A', 'Gene', '1029', (234, 240))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('Skin melanoma', 'Disease', (0, 13))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('p16INK4A', 'Gene', (259, 267))	('ERK', 'molecular_function', 'GO:0004707', ('67', '70'))	('p16INK4A', 'Gene', '1029', (259, 267))	('Skin melanoma', 'Disease', 'MESH:D008545', (0, 13))	('BRAF', 'Gene', '673', (58, 62))	('MAPK) signalling', 'biological_process', 'GO:0000165', ('105', '121'))	('BRAF', 'Gene', (58, 62))
10351	26850723	The MC1R gene is highly polymorphic among White people with some genetic variants mediating the production of more pheomelanin and less eumelanin, resulting in the phenotype of red hair, blue eyes and fair skin.	('people', 'Species', '9606', (48, 54))	('eumelanin', 'Chemical', 'MESH:C041877', (136, 145))	('MC1R', 'Gene', '4157', (4, 8))	('less', 'NegReg', (131, 135))	('mediating', 'Reg', (82, 91))	('MC1R', 'Gene', (4, 8))	('fair skin', 'Phenotype', 'HP:0007513', (201, 210))	('variants', 'Var', (73, 81))	('fair skin', 'Disease', (201, 210))	('blue eyes', 'Phenotype', 'HP:0000635', (187, 196))	('pheomelanin', 'Chemical', 'MESH:C018362', (115, 126))	('red hair', 'Phenotype', 'HP:0002297', (177, 185))	('red hair, blue eyes', 'Disease', 'MESH:C567139', (177, 196))	('more', 'PosReg', (110, 114))
10352	26850723	Persons with a phenotype mediated by one of these MC1R genetic variants are at greater risk of UV-induced skin cancers, because pheomelanin not only provides less effective protection against UV than does eumelanin, but it also generates more mutagenic free radicals in response to UV.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('more', 'PosReg', (238, 242))	('protection', 'MPA', (173, 183))	('variants', 'Var', (63, 71))	('pheomelanin', 'Chemical', 'MESH:C018362', (128, 139))	('Persons', 'Species', '9606', (0, 7))	('free radicals', 'Chemical', 'MESH:D005609', (253, 266))	('skin cancers', 'Disease', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('skin cancers', 'Phenotype', 'HP:0008069', (106, 118))	('mutagenic free radicals', 'MPA', (243, 266))	('MC1R', 'Gene', '4157', (50, 54))	('skin cancers', 'Disease', 'MESH:D012878', (106, 118))	('response to UV', 'biological_process', 'GO:0009411', ('270', '284'))	('MC1R', 'Gene', (50, 54))	('eumelanin', 'Chemical', 'MESH:C041877', (205, 214))
10353	26850723	Apart from their role in determining a cancer-prone pigmentory phenotype, it has been demonstrated that certain MC1R variants play a direct role in the pathogenesis of cutaneous squamous cell carcinoma, cutaneous basal cell carcinoma and cutaneous melanoma.	('pathogenesis', 'biological_process', 'GO:0009405', ('152', '164'))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (168, 201))	('cutaneous melanoma', 'Disease', (238, 256))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (238, 256))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (238, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (213, 233))	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('role', 'Reg', (140, 144))	('cutaneous squamous cell carcinoma', 'Disease', (168, 201))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 201))	('cutaneous basal cell carcinoma', 'Disease', (203, 233))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (203, 233))	('variants', 'Var', (117, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('MC1R', 'Gene', '4157', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('MC1R', 'Gene', (112, 116))
10354	26850723	In fact, about 15 % of all cases of cutaneous melanoma are associated with some MC1R variants.	('variants', 'Var', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('associated', 'Reg', (59, 69))	('cutaneous melanoma', 'Disease', (36, 54))	('MC1R', 'Gene', '4157', (80, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('MC1R', 'Gene', (80, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))
10355	26850723	Non-pigmentory functions of MC1R mediated via the alphaMSH/MC1R pathway include regulation of local immuno-inflammatory responses brought about by several factors including modulation of NF-kappaB which is an important regulator of the production of inflammatory mediators, mediation of the proliferation and survival of melanocytes, induction of DNA repair following UV-induced DNA damage, and diminution of oxidative stress by reducing the generation of reactive oxidative species that have the capacity to cause oxidative damage to cellular DNA.	('MC1R', 'Gene', '4157', (59, 63))	('DNA repair', 'biological_process', 'GO:0006281', ('347', '357'))	('generation of reactive oxidative species', 'MPA', (442, 482))	('MC1R', 'Gene', (59, 63))	('DNA', 'cellular_component', 'GO:0005574', ('379', '382'))	('reducing', 'NegReg', (429, 437))	('MC1R', 'Gene', '4157', (28, 32))	('regulation', 'biological_process', 'GO:0065007', ('80', '90'))	('DNA', 'cellular_component', 'GO:0005574', ('544', '547'))	('MC1R', 'Gene', (28, 32))	('oxidative stress', 'Phenotype', 'HP:0025464', (409, 425))	('modulation', 'Var', (173, 183))	('DNA', 'cellular_component', 'GO:0005574', ('347', '350'))
10358	26850723	These non-pigmentory functions outlined in the above two paragraphs are dysregulated in melanocytes expressing those MC1R variants, thus promoting the risk of melanoma.	('melanoma', 'Disease', (159, 167))	('variants', 'Var', (122, 130))	('MC1R', 'Gene', '4157', (117, 121))	('MC1R', 'Gene', (117, 121))	('promoting', 'PosReg', (137, 146))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
10359	26850723	In fact, compared to melanocytes with mainstream MC1R it has become clear that in response to UV-induced DNA damage, melanocytes with MC1R variants have a lower DNA repair capacity, more DNA mutagenic photoproducts, increased oxidative DNA damage, and decreased apoptosis.	('DNA', 'cellular_component', 'GO:0005574', ('236', '239'))	('lower', 'NegReg', (155, 160))	('variants', 'Var', (139, 147))	('oxidative DNA damage', 'MPA', (226, 246))	('MC1R', 'Gene', '4157', (134, 138))	('MC1R', 'Gene', (134, 138))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('DNA repair capacity', 'MPA', (161, 180))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('increased', 'PosReg', (216, 225))	('response to UV', 'biological_process', 'GO:0009411', ('82', '96'))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('more', 'PosReg', (182, 186))	('DNA repair', 'biological_process', 'GO:0006281', ('161', '171'))	('decreased', 'NegReg', (252, 261))	('MC1R', 'Gene', '4157', (49, 53))	('DNA mutagenic photoproducts', 'MPA', (187, 214))	('MC1R', 'Gene', (49, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('262', '271'))	('apoptosis', 'biological_process', 'GO:0006915', ('262', '271'))	('apoptosis', 'CPA', (262, 271))
10360	26850723	Thus, the risk of melanoma is polygenetic comprising interactions between MC1R variants, other pigmentory gene variants, dysfunctional DNA repair genes and immuno-inflammatory genes.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('DNA repair', 'biological_process', 'GO:0006281', ('135', '145'))	('variants', 'Var', (79, 87))	('variants', 'Var', (111, 119))	('MC1R', 'Gene', '4157', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('MC1R', 'Gene', (74, 78))	('melanoma', 'Disease', (18, 26))	('interactions', 'Interaction', (53, 65))
10364	26850723	In general, if the damage to DNA affects oncogenes, tumour-suppressor genes (anti-oncogenes), or cell cycle checkpoint control genes, cellular genomic integrity will be destabilized with increased risk of acquiring additional cytogenetic alterations.	('DNA', 'Gene', (29, 32))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('destabilized', 'NegReg', (169, 181))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('97', '118'))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('cellular genomic integrity', 'CPA', (134, 160))	('damage', 'Var', (19, 25))	('tumour', 'Disease', (52, 58))	('oncogenes', 'Gene', (41, 50))
10365	26850723	Molecular alterations in oncogenes may permit uncontrolled cell proliferation in response to microenvironmental growth signals; and in tumour suppressor genes may result in dysregulated oncogenic activity.	('alterations', 'Var', (10, 21))	('result in', 'Reg', (163, 172))	('oncogenic activity', 'CPA', (186, 204))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('permit', 'Reg', (39, 45))	('oncogenes', 'Gene', (25, 34))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('dysregulated', 'MPA', (173, 185))	('tumour', 'Disease', (135, 141))
10369	26850723	Subsequent clonal divergence will result in the evolution of subclones which would have had multiple episodes of genetic mutations, one or more of which will eventually give rise to frank cutaneous squamous cell carcinoma in all its clinical variety.	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (188, 221))	('mutations', 'Var', (121, 130))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('cutaneous squamous cell carcinoma', 'Disease', (188, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('result in', 'Reg', (34, 43))	('give rise to', 'Reg', (169, 181))
10386	26850723	Dysregulation in the hedgehog intracellular signalling pathway is implicated in the pathogenesis of cutaneous basal cell carcinoma and is thought to be an early genetic factor in its tumourigenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('signalling pathway', 'biological_process', 'GO:0007165', ('44', '62'))	('tumour', 'Disease', (183, 189))	('Dysregulation', 'Var', (0, 13))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (110, 130))	('intracellular', 'cellular_component', 'GO:0005622', ('30', '43'))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (100, 130))	('pathogenesis', 'biological_process', 'GO:0009405', ('84', '96'))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('cutaneous basal cell carcinoma', 'Disease', (100, 130))	('implicated', 'Reg', (66, 76))	('hedgehog intracellular signalling pathway', 'Pathway', (21, 62))
10389	26850723	Clonal expansion of dysregulated cells within the keratinocytes stem cell niche is favoured by loss-of-function mutation in PTCH1 that allows upregulated activity of SMO, and by gain of function mutations in the SMO gene that render SMO protein resistant to inhibition by PTCH1.	('SMO', 'Gene', (212, 215))	('loss-of-function', 'NegReg', (95, 111))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('mutation', 'Var', (112, 120))	('PTCH1', 'Gene', '5727', (124, 129))	('PTCH1', 'Gene', (272, 277))	('Clonal expansion', 'CPA', (0, 16))	('gain of function', 'PosReg', (178, 194))	('SMO', 'Gene', '6608', (166, 169))	('SMO', 'Gene', (166, 169))	('mutations', 'Var', (195, 204))	('PTCH1', 'Gene', (124, 129))	('PTCH1', 'Gene', '5727', (272, 277))	('activity', 'MPA', (154, 162))	('SMO', 'Gene', '6608', (233, 236))	('upregulated', 'PosReg', (142, 153))	('SMO', 'Gene', (233, 236))	('SMO', 'Gene', '6608', (212, 215))
10391	26850723	Keratinocytes which show dysregulated expression of the hedgehog signalling pathway fail to undergo cell-cycle arrest in response to the p21 cell cycle inhibitor, and thus have enhanced proliferative capacity.	('p21', 'Gene', '644914', (137, 140))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('100', '117'))	('dysregulated', 'Var', (25, 37))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('signalling pathway', 'biological_process', 'GO:0007165', ('65', '83'))	('fail', 'NegReg', (84, 88))	('hedgehog', 'Gene', (56, 64))	('enhanced', 'PosReg', (177, 185))	('cell-cycle arrest', 'CPA', (100, 117))	('proliferative capacity', 'CPA', (186, 208))	('p21', 'Gene', (137, 140))
10393	26850723	About half of all cases of sporadic basal cell carcinoma also show mutations in the p53 tumour suppressor gene, but these seem to be late genetic events in the tumourigenesis of cutaneous basal cell carcinoma, which are related to its progression.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (160, 166))	('tumour', 'Disease', (88, 94))	('sporadic basal cell carcinoma', 'Disease', (27, 56))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (178, 208))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (36, 56))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('sporadic basal cell carcinoma', 'Disease', 'MESH:D002280', (27, 56))	('p53', 'Gene', (84, 87))	('cutaneous basal cell carcinoma', 'Disease', (178, 208))	('p53', 'Gene', '7157', (84, 87))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (188, 208))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
10414	26850723	Further factors are MC1R genetic polymorphism, and perhaps other yet ill-defined environmental factors, but some MC1R variants are associated with increased risk of cutaneous melanoma regardless of skin type and hair colour.	('MC1R', 'Gene', '4157', (20, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('variants', 'Var', (118, 126))	('MC1R', 'Gene', (20, 24))	('associated with', 'Reg', (131, 146))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('MC1R', 'Gene', '4157', (113, 117))	('MC1R', 'Gene', (113, 117))	('cutaneous melanoma regardless of skin type and hair colour', 'Disease', 'MESH:C562393', (165, 223))
10416	26850723	In contrast to malignant keratinocytes of cutaneous squamous cell carcinoma that show UV-induced signature-mutations, these are rare in cutaneous melanoma cells, and while mutations to tumour-suppressor gene p53 are frequent in UV-induced squamous cell carcinoma, in UV-induced cutaneous melanoma they are not.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cutaneous melanoma', 'Disease', (278, 296))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (278, 296))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (278, 296))	('p53', 'Gene', '7157', (208, 211))	('frequent', 'Reg', (216, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('cutaneous squamous cell carcinoma', 'Disease', (42, 75))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('p53', 'Gene', (208, 211))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (239, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('squamous cell carcinoma', 'Disease', (239, 262))	('tumour', 'Disease', (185, 191))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('mutations', 'Var', (172, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (42, 75))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))
10417	26850723	Cutaneous melanoma cells but not malignant keratinocytes show oncogenic mutations in either NRAS or BRAF.	('mutations', 'Var', (72, 81))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('NRAS', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (100, 104))	('NRAS', 'Gene', '4893', (92, 96))	('BRAF', 'Gene', (100, 104))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
10418	26850723	Except for acral and mucosal melanomas, BRAF mutations are an early genetic event of melanoma tumourigenesis and can be found in up to 60 % of frank melanomas.	('BRAF', 'Gene', '673', (40, 44))	('frank melanomas', 'Disease', (143, 158))	('mutations', 'Var', (45, 54))	('frank melanomas', 'Disease', 'MESH:D008545', (143, 158))	('melanoma tumourigenesis', 'Disease', (85, 108))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('mucosal melanomas', 'Disease', (21, 38))	('melanoma tumourigenesis', 'Disease', 'MESH:D008545', (85, 108))	('found', 'Reg', (120, 125))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mucosal melanomas', 'Disease', 'MESH:D008545', (21, 38))
10419	26850723	In contrast, in mucosal and acral melanomas there are gain-of-function mutations in the cKit receptor thyrosine kinase.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('acral melanomas', 'Disease', (28, 43))	('gain-of-function', 'PosReg', (54, 70))	('mucosal', 'Disease', (16, 23))	('mutations', 'Var', (71, 80))	('cKit receptor', 'Gene', (88, 101))	('acral melanoma', 'Phenotype', 'HP:0012060', (28, 42))	('acral melanomas', 'Disease', 'MESH:D008545', (28, 43))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('acral melanomas', 'Phenotype', 'HP:0012060', (28, 43))
10420	26850723	Inactivating mutations in the CDKN2A gene which encodes for p16INK4a tumour suppressor protein, pose a high risk for development of cutaneous melanoma.	('tumour', 'Disease', (69, 75))	('p16INK4a', 'Gene', (60, 68))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('CDKN2A', 'Gene', (30, 36))	('cutaneous melanoma', 'Disease', (132, 150))	('Inactivating mutations', 'Var', (0, 22))	('CDKN2A', 'Gene', '1029', (30, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('p16INK4a', 'Gene', '1029', (60, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
10421	26850723	Both BRAF and CDKN2A mutations in cutaneous melanoma cells are characteristic of indirect UV-induced oxidative damage.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('BRAF', 'Gene', '673', (5, 9))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (34, 52))	('CDKN2A', 'Gene', '1029', (14, 20))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('BRAF', 'Gene', (5, 9))	('cutaneous melanoma', 'Disease', (34, 52))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
10429	26850723	There is evidence of loss of integrity of membranes of the melanosomes in melanoma cells with consequent leakage of reactive oxygen species (ROS) and metabolic by-products of melanogenesis that may be cytotoxic, genotoxic or mutagenic into the cytoplasm of melanoma cells contributing to progressive DNA damage.	('integrity', 'MPA', (29, 38))	('DNA', 'cellular_component', 'GO:0005574', ('300', '303'))	('loss', 'NegReg', (21, 25))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (116, 139))	('leakage', 'MPA', (105, 112))	('ROS', 'Chemical', 'MESH:D017382', (141, 144))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('mutagenic', 'Var', (225, 234))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('DNA', 'Disease', (300, 303))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('melanoma', 'Disease', (257, 265))	('reactive oxygen species', 'MPA', (116, 139))	('cytoplasm', 'cellular_component', 'GO:0005737', ('244', '253'))
10434	26850723	However, it is established that polymorphic low-penetrance pigmentory genes governing pigmentation, genes involved in the mechanisms of breaking down UV-induced reactive oxygen species, genes encoding DNA-repair proteins, and UV-induced genetic mutations, all interact on a background of UV-induced local immunosuppression and other genetic and environmental factors in the initiation and progression of these malignancies.	('malignancies', 'Disease', (410, 422))	('breaking down', 'Phenotype', 'HP:0001061', (136, 149))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('mutations', 'Var', (245, 254))	('interact', 'Reg', (260, 268))	('pigmentation', 'Disease', 'MESH:D010859', (86, 98))	('pigmentation', 'biological_process', 'GO:0043473', ('86', '98'))	('pigmentation', 'Disease', (86, 98))	('malignancies', 'Disease', 'MESH:D009369', (410, 422))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (161, 184))	('DNA-repair', 'biological_process', 'GO:0006281', ('201', '211'))
10435	26850723	Thus, susceptibility to sporadic cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma and cutaneous melanoma is a polygenetic trait with each low-penetrance genetic variant contributing to the overall carcinogenic effect, and with extrinsic factors having the capacity to modify cancer risk by influencing the penetrance of the genetic variants.	('carcinogenic', 'Disease', 'MESH:D063646', (214, 226))	('cutaneous basal cell carcinoma', 'Disease', (33, 63))	('cutaneous melanoma', 'Disease', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('contributing', 'Reg', (186, 198))	('cutaneous basal cell carcinoma', 'Disease', 'MESH:D002280', (33, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cutaneous squamous cell carcinoma', 'Disease', (65, 98))	('modify', 'Reg', (285, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 98))	('cancer', 'Disease', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (43, 63))	('low-penetrance', 'NegReg', (155, 169))	('carcinogenic', 'Disease', (214, 226))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (65, 98))	('variant', 'Var', (178, 185))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (292, 298))
10445	29632737	This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy.	('melanoma', 'Disease', (65, 73))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('MI therapy', 'Var', (22, 32))	('regression', 'CPA', (93, 103))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('metastases', 'Disease', (117, 127))	('patients', 'Species', '9606', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
10449	29632737	This type of depigmentation in melanoma patients indicates breakage of tolerance against melanocytic antigens, leading to clinically active anti-melanocyte/melanoma immunity, consisting of melanoma-reactive T-cells and antibody responses.	('antibody', 'cellular_component', 'GO:0019814', ('219', '227'))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('antibody', 'cellular_component', 'GO:0019815', ('219', '227'))	('patients', 'Species', '9606', (40, 48))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('antibody', 'molecular_function', 'GO:0003823', ('219', '227'))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('antibody', 'cellular_component', 'GO:0042571', ('219', '227'))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', (31, 39))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('breakage', 'Var', (59, 67))
10516	29632737	Concerning the other 6 patients: patients MI-07 and MI-15 did not have an HLA type including HLA- A1, -A2 or -A3 and fig 4could therefore not be analyzed by the panel of HLA-peptide tetramers; 4 patients who received only 6 weeks of therapy were not included in the T cell analyses.	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (23, 31))	('MI-07', 'Var', (42, 47))	('MI-15', 'Disease', 'MESH:C567193', (52, 57))	('patients', 'Species', '9606', (195, 203))	('MI-15', 'Disease', (52, 57))
10521	29632737	The PBL data also includes patients MI-14 and MI-24, of whom PBMC were not evaluable.	('patients', 'Species', '9606', (27, 35))	('MI-14', 'Disease', (36, 41))	('MI-24', 'Var', (46, 51))	('MI-14', 'Disease', 'OMIM:615513', (36, 41))
10534	29632737	Pooled analyses of the percentages of melanoma-specific T-cells in MI-therapy-treated skin of 9 patients analyzed showed small but significant increases in melanoma-specific T-cell levels at baseline or 6 weeks (median 0.13, IQR 0.04-0.31) as compared to 12 weeks or later time points (median 0.23, IQR 0.06-0.47, p < 0.031).	('increases', 'PosReg', (143, 152))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('MI-therapy-treated', 'Var', (67, 85))	('patients', 'Species', '9606', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
10540	29632737	This is clearly illustrated by the observations that 3 patients (MI-04, MI-09, MI-24) achieved a CR upon prolonged treatment and that the clinical response in two patients (MI-16 and MI-24) started later than 12 weeks, achieving PR and CR, respectively.	('patients', 'Species', '9606', (163, 171))	('MI-04', 'Var', (65, 70))	('MI-09', 'Var', (72, 77))	('achieved', 'PosReg', (86, 94))	('patients', 'Species', '9606', (55, 63))	('MI-24', 'Var', (79, 84))
10550	29632737	Our preclinical data has shown that the addition of CpG greatly enhances systemic antimelanoma immunity induced by MI therapy.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('enhances', 'PosReg', (64, 72))	('systemic antimelanoma immunity', 'Disease', 'MESH:D007154', (73, 103))	('systemic antimelanoma immunity', 'Disease', (73, 103))	('CpG', 'Var', (52, 55))
10558	29632737	By its specific interaction with tyrosinase, either by quinone-modification increasing their immunogenicity, or by epitope spreading of the T-cell response, monobenzone can induce immunity against a range of melanocyte/melanoma antigens presented in patient-specific HLA types.	('immunity', 'MPA', (180, 188))	('tyrosinase', 'Gene', (33, 43))	('monobenzone', 'Chemical', 'MESH:C006429', (157, 168))	('monobenzone', 'Var', (157, 168))	('interaction', 'Interaction', (16, 27))	('increasing', 'PosReg', (76, 86))	('immunogenicity', 'MPA', (93, 107))	('induce', 'PosReg', (173, 179))	('tyrosinase', 'Gene', '7299', (33, 43))	('quinone', 'Chemical', 'MESH:C004532', (55, 62))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('patient', 'Species', '9606', (250, 257))	('melanoma', 'Disease', (219, 227))
10629	32731355	Gene set analysis of high KDM6A showed strong associations with immune responses and downregulation of genes associated with Myc and other oncogenic pathways.	('immune responses', 'CPA', (64, 80))	('downregulation', 'NegReg', (85, 99))	('KDM6A', 'Gene', '7403', (26, 31))	('high', 'Var', (21, 25))	('Myc', 'Gene', '4609', (125, 128))	('KDM6A', 'Gene', (26, 31))	('Myc', 'Gene', (125, 128))
10640	32731355	One such study from The Cancer Genome Atlas (TCGA) identified six X-linked genes that harbored loss of function mutations in cancers from males that, therefore, might play protective roles in females.	('loss of function', 'NegReg', (95, 111))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('Cancer', 'Disease', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (112, 121))
10645	32731355	H3K27me3 is generated by the methylase EZH2(Enhancer of Zesta Homolog-2), which is the catalytic subunit of the polycomb-repressive complex 2 (PRC2) that represses transcription of genes involved in differentiation and tumor suppression in many cancers, including melanoma.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('tumor', 'Disease', (219, 224))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('transcription', 'MPA', (164, 177))	('transcription', 'biological_process', 'GO:0006351', ('164', '177'))	('cancers', 'Disease', (245, 252))	('methylase', 'molecular_function', 'GO:0008168', ('29', '38'))	('H3K27me3', 'Var', (0, 8))	('represses', 'NegReg', (154, 163))	('EZH2', 'Gene', '2146', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('EZH2', 'Gene', (39, 43))	('melanoma', 'Disease', (264, 272))
10646	32731355	KDM6B also catalyzes the demethylation of H3K27me3, whereas UTY lacks demethylase activity due to the substitution of critical amino acids within the JmjC domain.	('UTY', 'Gene', '7404', (60, 63))	('demethylase activity', 'molecular_function', 'GO:0032451', ('70', '90'))	('KDM6B', 'Gene', (0, 5))	('UTY', 'Gene', (60, 63))	('demethylation', 'biological_process', 'GO:0070988', ('25', '38'))	('substitution', 'Var', (102, 114))	('H3K27me3', 'Protein', (42, 50))	('demethylase', 'Gene', (70, 81))	('demethylation', 'MPA', (25, 38))	('demethylase', 'Gene', '8932', (70, 81))	('KDM6B', 'Gene', '23135', (0, 5))
10665	32731355	High expression of ATRX was also associated with improved survival in melanoma patients.	('melanoma', 'Disease', (70, 78))	('improved', 'PosReg', (49, 57))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('High', 'Var', (0, 4))	('ATRX', 'Gene', '546', (19, 23))	('patients', 'Species', '9606', (79, 87))	('ATRX', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('survival', 'MPA', (58, 66))
10667	32731355	High ATRX was associated with improved survival regardless of KDM6A expression level and vice versa (Figure 2b), showing that ATRX is an independent predictor of survival, which was confirmed by univariate and multivariate cox regression analysis (Figure 2c).	('High', 'Var', (0, 4))	('KDM6A', 'Gene', (62, 67))	('ATRX', 'Gene', '546', (5, 9))	('ATRX', 'Gene', (126, 130))	('survival', 'MPA', (39, 47))	('ATRX', 'Gene', '546', (126, 130))	('KDM6A', 'Gene', '7403', (62, 67))	('ATRX', 'Gene', (5, 9))	('improved', 'PosReg', (30, 38))
10677	32731355	Patients with high KDM6A and low EZH2 levels had improved overall survival compared to low KDM6A and high EZH2 patients (log-rank p = 0.014).	('KDM6A', 'Gene', '7403', (19, 24))	('overall survival', 'MPA', (58, 74))	('improved', 'PosReg', (49, 57))	('EZH2', 'Gene', (106, 110))	('KDM6A', 'Gene', '7403', (91, 96))	('low', 'Var', (29, 32))	('Patients', 'Species', '9606', (0, 8))	('EZH2', 'Gene', '2146', (33, 37))	('KDM6A', 'Gene', (19, 24))	('EZH2', 'Gene', (33, 37))	('KDM6A', 'Gene', (91, 96))	('EZH2', 'Gene', '2146', (106, 110))	('patients', 'Species', '9606', (111, 119))
10686	32731355	These results were similar to those from the LMC cohort, in that patients with high KDM6A levels and low EZH2 levels had significantly better survival than patients with low KDM6A and EZH2 levels.	('patients', 'Species', '9606', (156, 164))	('KDM6A', 'Gene', (174, 179))	('KDM6A', 'Gene', '7403', (84, 89))	('EZH2', 'Gene', '2146', (184, 188))	('KDM6A', 'Gene', '7403', (174, 179))	('KDM6A', 'Gene', (84, 89))	('better', 'PosReg', (135, 141))	('high', 'Var', (79, 83))	('survival', 'CPA', (142, 150))	('EZH2', 'Gene', (184, 188))	('EZH2', 'Gene', '2146', (105, 109))	('patients', 'Species', '9606', (65, 73))	('EZH2', 'Gene', (105, 109))
10742	32731355	This was consistent with the preferential survival advantage in female melanoma patients with high KDM6A levels.	('patients', 'Species', '9606', (80, 88))	('KDM6A', 'Gene', '7403', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('high', 'Var', (94, 98))	('KDM6A', 'Gene', (99, 104))
10766	32731355	The relation to survival is somewhat surprising as KDM5C demethylase acts on H3K4 methylated histone marks, which are viewed as activating marks in euchromatin.	('euchromatin', 'cellular_component', 'GO:0000791', ('148', '159'))	('methylated', 'Var', (82, 92))	('H3K4', 'Protein', (77, 81))	('KDM5C', 'Gene', '8242', (51, 56))	('demethylase', 'Gene', '8932', (57, 68))	('acts', 'Reg', (69, 73))	('KDM5C', 'Gene', (51, 56))	('demethylase', 'Gene', (57, 68))
10771	32731355	It is possible that the female advantage in relation to DDX3X may result from the adverse effect of mutation or loss of DDX3X in male patients rather than effects on immune responses.	('DDX3X', 'Gene', (56, 61))	('DDX3X', 'Gene', '1654', (56, 61))	('patients', 'Species', '9606', (134, 142))	('DDX3X', 'Gene', (120, 125))	('mutation', 'Var', (100, 108))	('loss', 'NegReg', (112, 116))	('DDX3X', 'Gene', '1654', (120, 125))
10781	32731355	The present results also suggested that EZH2 inhibitors might have a role in the treatment of melanoma that expresses high EZH2 and low KDM6A as loss of KDM6A sensitizes bladder and lung cancer cells to treatment with EZH2 inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('lung cancer', 'Disease', (182, 193))	('KDM6A', 'Gene', (153, 158))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('bladder', 'Disease', 'MESH:D001745', (170, 177))	('KDM6A', 'Gene', (136, 141))	('sensitizes', 'Reg', (159, 169))	('men', 'Species', '9606', (208, 211))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('men', 'Species', '9606', (86, 89))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('bladder', 'Disease', (170, 177))	('melanoma', 'Disease', (94, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('EZH2', 'Gene', '2146', (123, 127))	('KDM6A', 'Gene', '7403', (153, 158))	('EZH2', 'Gene', (123, 127))	('KDM6A', 'Gene', '7403', (136, 141))	('loss', 'Var', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('EZH2', 'Gene', '2146', (218, 222))	('EZH2', 'Gene', (218, 222))
10928	21407133	Dominant-negative Akt cells were more sensitive to resveratrol and had diminished migratory properties.	('diminished', 'NegReg', (71, 81))	('migratory properties', 'CPA', (82, 102))	('resveratrol', 'Chemical', 'MESH:D000077185', (51, 62))	('sensitive', 'MPA', (38, 47))	('Akt cells', 'CPA', (18, 27))	('Dominant-negative', 'Var', (0, 17))	('more', 'PosReg', (33, 37))
10942	21407133	We studied the ability of resveratrol to affect these phenotypes in vitro with the highly malignant murine melanoma cell line variants B16F10, selected for its metastatic ability, and the more invasive variant B16BL6.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('B16BL6', 'CellLine', 'CVCL:0157', (210, 216))	('variants', 'Var', (126, 134))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('B16F10', 'CellLine', 'CVCL:0159', (135, 141))	('resveratrol', 'Chemical', 'MESH:D000077185', (26, 37))	('murine', 'Species', '10090', (100, 106))
10943	21407133	Using subcutaneous and tail vein injection of B16BL6 and B16F10 respectively, we further tested whether resveratrol treatment could affect tumor growth and reduce formation of lung metastasis in syngeneic mouse models of melanoma.	('reduce', 'NegReg', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('formation of lung metastasis', 'CPA', (163, 191))	('B16F10', 'Var', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('affect', 'Reg', (132, 138))	('melanoma', 'Disease', (221, 229))	('resveratrol', 'Chemical', 'MESH:D000077185', (104, 115))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('B16F10', 'CellLine', 'CVCL:0159', (57, 63))	('tested', 'Reg', (89, 95))	('B16BL6', 'CellLine', 'CVCL:0157', (46, 52))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mouse', 'Species', '10090', (205, 210))	('B16BL6', 'Var', (46, 52))
10984	21407133	Utilizing a filter (8 microm pore size) coated on the lower surface with fibronection and resveratrol in the medium, we show that the number of cells that migrated through the membrane decreased to nearly 40% and 5% in the presence of 50 microM and 100 microM resveratrol, respectively, compared to DMSO controls (Figure 2A).	('decreased', 'NegReg', (185, 194))	('pore', 'cellular_component', 'GO:0046930', ('29', '33'))	('resveratrol', 'Chemical', 'MESH:D000077185', (90, 101))	('50 microM', 'Var', (235, 244))	('DMSO', 'Chemical', 'MESH:D004121', (299, 303))	('membrane', 'cellular_component', 'GO:0016020', ('176', '184'))	('resveratrol', 'Chemical', 'MESH:D000077185', (260, 271))
10993	21407133	Treatment with resveratrol caused a decrease in both phospho (S473)-Akt and phospho (T308)-Akt within 1.5 hrs of resveratrol addition.	('phospho', 'CPA', (53, 60))	('resveratrol', 'Chemical', 'MESH:D000077185', (15, 26))	('phospho', 'Var', (76, 83))	('resveratrol', 'Chemical', 'MESH:D000077185', (113, 124))	('decrease', 'NegReg', (36, 44))
10995	21407133	A similar deactivation and attenuation of Akt was noted for both resveratrol and Ly294002.	('deactivation', 'NegReg', (10, 22))	('Ly294002', 'Var', (81, 89))	('Akt', 'Pathway', (42, 45))	('resveratrol', 'Chemical', 'MESH:D000077185', (65, 76))	('attenuation', 'NegReg', (27, 38))	('Ly294002', 'Chemical', 'MESH:C085911', (81, 89))
11012	21407133	As seen in the same figure, expression of dominant-negative Akt alone reduced cell migration to levels comparable to those obtained with 50 microM resveratrol.	('reduced', 'NegReg', (70, 77))	('resveratrol', 'Chemical', 'MESH:D000077185', (147, 158))	('dominant-negative', 'Var', (42, 59))	('cell migration', 'biological_process', 'GO:0016477', ('78', '92'))	('Akt', 'Gene', (60, 63))	('cell migration', 'CPA', (78, 92))
11015	21407133	These results demonstrate that inhibition of Akt, either with resveratrol or via the expression of a dominant-negative species, reduces the migratory behavior of the metastatic B16F10 melanoma cells.	('resveratrol', 'Chemical', 'MESH:D000077185', (62, 73))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('B16F10', 'CellLine', 'CVCL:0159', (177, 183))	('reduces', 'NegReg', (128, 135))	('inhibition', 'Var', (31, 41))	('Akt', 'Protein', (45, 48))
11051	21407133	PKB protein kinase B Ly294002 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one RIPA buffer Radio-Immunoprecipitation Assay buffer	('PKB', 'Gene', '11651', (0, 3))	('2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one', 'Chemical', 'MESH:C085911', (30, 78))	('Ly294002', 'Var', (21, 29))	('PKB', 'Gene', (0, 3))	('Ly294002', 'Chemical', 'MESH:C085911', (21, 29))	('RIPA buffer', 'Chemical', '-', (79, 90))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
11053	33378376	Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('tyrosine', 'Chemical', 'MESH:D014443', (227, 235))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('mutations', 'Var', (169, 178))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('skin cutaneous melanoma', 'Disease', (43, 66))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (43, 66))	('melanomas', 'Disease', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('gain-of-function', 'PosReg', (152, 168))
11054	33378376	In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2beta) functions as a partial agonist at ErbB4.	('partial agonist', 'MPA', (192, 207))	('Q43L', 'Mutation', 'p.Q43L', (96, 100))	('Neu', 'Gene', (149, 152))	('Q43L', 'Var', (96, 100))	('Neu', 'Gene', '13866', (149, 152))
11055	33378376	NRG2beta/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation.	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('tyrosine phosphorylation', 'MPA', (25, 49))	('cell proliferation', 'biological_process', 'GO:0008283', ('151', '169'))	('inhibits', 'NegReg', (110, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('stimulates', 'PosReg', (14, 24))	('NRG2beta/Q43L', 'Var', (0, 13))	('Q43L', 'Mutation', 'p.Q43L', (9, 13))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))	('agonist-induced ErbB4-dependent cell proliferation', 'CPA', (119, 169))
11058	33378376	In fact, recent studies with combination therapy using BRAF and MEK inhibitors and immunotherapies indicate rates of 5-year progression free survival and overall survival as high as 30-50% for metastatic melanoma patients whose tumors harbor a gain-of-function mutation in the BRAF gene.	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', (204, 212))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('BRAF', 'Gene', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutation', 'Var', (261, 269))	('gain-of-function', 'PosReg', (244, 260))	('tumors', 'Disease', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (213, 221))	('tumors', 'Disease', 'MESH:D009369', (228, 234))
11060	33378376	Our ongoing, unpublished analyses of the TCGA skin cutaneous melanoma genomic (SKCM) data set reveal that 70 of the 470 (15%) of the melanoma genomes harbor at least one non-synonymous missense mutation in the ERBB4 gene.	('missense mutation', 'Var', (185, 202))	('ERBB4', 'Gene', (210, 215))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 69))	('skin cutaneous melanoma', 'Disease', (46, 69))
11061	33378376	A total of 71 unique ERBB4 missense mutant alleles are observed; the R711C mutant allele is observed in five cases; the R106C mutant allele is observed in three cases; the E452K, P759L, D813N, R992C, and S975L mutant alleles are observed in two cases; the remaining 64 mutant alleles are observed in only one case each.	('R106C', 'Var', (120, 125))	('D813N', 'Var', (186, 191))	('E452K', 'Var', (172, 177))	('missense', 'Var', (27, 35))	('P759L', 'Mutation', 'p.P759L', (179, 184))	('E452K', 'Mutation', 'rs202247795', (172, 177))	('R106C', 'Mutation', 'rs751175543', (120, 125))	('S975L', 'Mutation', 'p.S975L', (204, 209))	('ERBB4', 'Gene', (21, 26))	('D813N', 'Mutation', 'p.D813N', (186, 191))	('R992C', 'Var', (193, 198))	('R992C', 'Mutation', 'rs143134749', (193, 198))	('S975L', 'Var', (204, 209))	('R711C', 'Var', (69, 74))	('P759L', 'Var', (179, 184))	('R711C', 'Mutation', 'rs267599191', (69, 74))
11062	33378376	Taken together, these data indicate that ERBB4 mutations appear to function as tumor drivers in BRAF wild-type melanomas by cooperating with elevated RAS signaling.	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('elevated', 'PosReg', (141, 149))	('tumor', 'Disease', (79, 84))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('mutations', 'Var', (47, 56))	('BRAF', 'Disease', (96, 100))	('melanomas', 'Disease', (111, 120))	('RAS signaling', 'MPA', (150, 163))	('ERBB4', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
11069	33378376	Our drug discovery strategy is driven by our observation that introducing the Q43L mutation into the gene that encodes the naturally-occurring ErbB4 full agonist NRG2beta creates a partial agonist of ErbB4; this NRG2beta/Q43L mutant stimulates ErbB4 tyrosine phosphorylation, yet it inhibits agonist-induced ErbB4-dependent cell proliferation.	('ErbB4', 'Protein', (244, 249))	('NRG2beta/Q43L mutant', 'Var', (212, 232))	('cell proliferation', 'biological_process', 'GO:0008283', ('324', '342'))	('agonist-induced ErbB4-dependent cell proliferation', 'CPA', (292, 342))	('stimulates', 'PosReg', (233, 243))	('inhibits', 'NegReg', (283, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (250, 258))	('Q43L', 'Mutation', 'p.Q43L', (221, 225))	('phosphorylation', 'biological_process', 'GO:0016310', ('259', '274'))	('Q43L', 'Mutation', 'p.Q43L', (78, 82))
11077	33378376	To evaluate the ELISA assay conditions, ErbB4 tyrosine phosphorylation stimulated by 10 nM NRG2beta, 10 nM NRG2beta/Q43L, or diluent (mock stimulation) was analyzed in eight independent ELISAs using a single batch of each of the three different lysates (Fig 1A).	('phosphorylation', 'biological_process', 'GO:0016310', ('55', '70'))	('tyrosine', 'Chemical', 'MESH:D014443', (46, 54))	('Q43L', 'Mutation', 'p.Q43L', (116, 120))	('NRG2beta', 'Var', (91, 99))	('ErbB4', 'Gene', (40, 45))
11078	33378376	Stimulation by 10 nM NRG2beta produces an average absorbance at 450 nm of 4.0 +- 0.3 AU, stimulation by 10 nM NRG2beta/Q43L produces an average absorbance at 450 nm of 1.6 +- 0.2 AU, and mock stimulation produces an average absorbance at 450 nm of 0.68 +- 0.06 AU.	('NRG2beta/Q43L', 'Var', (110, 123))	('1.6', 'Gene', '11801', (168, 171))	('Q43L', 'Mutation', 'p.Q43L', (119, 123))	('1.6', 'Gene', (168, 171))
11082	33378376	Thus, stimulation with either 10 nM NRG2beta or 10 nM NRG2beta/Q43L yields robust, reproducible levels of ErbB4 tyrosine phosphorylation as measured by the sandwich ELISA.	('NRG2beta', 'Var', (36, 44))	('NRG2beta/Q43L', 'Var', (54, 67))	('Q43L', 'Mutation', 'p.Q43L', (63, 67))	('tyrosine', 'Chemical', 'MESH:D014443', (112, 120))	('ErbB4', 'Protein', (106, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))
11087	33378376	Furthermore, the six trials of semi-automated stimulation with 10 nM NRG1beta yields an average ErbB4 tyrosine phosphorylation Z'-factor (Z') score in excess of 0.6 (Fig 1B), which indicates that semi-automated stimulation with 10 nM NRG1beta yields robust and reproducible ErbB4 tyrosine phosphorylation that is suitable for deployment in a high-throughput workflow.	('phosphorylation', 'biological_process', 'GO:0016310', ('289', '304'))	('ErbB4 tyrosine phosphorylation', 'MPA', (274, 304))	('tyrosine', 'Chemical', 'MESH:D014443', (280, 288))	('tyrosine', 'Chemical', 'MESH:D014443', (102, 110))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))	('NRG1beta', 'Var', (69, 77))	('NRG1beta', 'Var', (234, 242))
11122	33378376	The apparent false positivity rate (56%) of the DiscoverX PathHunter  U2OS ErbB4 Functional Assay illustrates the shortcoming of using this assay as the only means for identifying candidate ErbB4 partial agonists and the need for rigorous confirmatory assays to rule out false positives.	('false', 'biological_process', 'GO:0071878', ('271', '276'))	('partial', 'Var', (196, 203))	('false', 'biological_process', 'GO:0071878', ('13', '18'))	('U2OS', 'CellLine', 'CVCL:0042', (70, 74))	('ErbB4', 'Gene', (190, 195))	('false', 'biological_process', 'GO:0071877', ('271', '276'))	('false', 'biological_process', 'GO:0071877', ('13', '18'))
11129	33378376	Gefitinib shifts the EC50 for NRG1beta from 0.08 +- 0.02 nM to 0.12 +- 0.05 nM; this very minor decrease in agonist potency is consistent with the observation that gefitinib does not directly compete with NRG1beta for binding to the EGFR-ErbB4 heterodimer.	('gefitinib', 'Chemical', 'MESH:D000077156', (164, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('233', '237'))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('Gefitinib', 'Var', (0, 9))	('decrease', 'NegReg', (96, 104))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('binding', 'Interaction', (218, 225))	('agonist potency', 'MPA', (108, 123))
11131	33378376	In contrast, other compounds exhibit greater efficacy, such as SR-33487, which inhibits the NRG1beta Emax by 87% (Fig 5B and Table 2) and SR-33491, which inhibits the NRG1beta Emax by 72% (Fig 5C and Table 2).	('inhibits', 'NegReg', (154, 162))	('inhibits', 'NegReg', (79, 87))	('SR-33487', 'Chemical', '-', (63, 71))	('SR-33491', 'Chemical', '-', (138, 146))	('NRG1beta', 'Gene', (92, 100))	('SR-33491', 'Var', (138, 146))
11134	33378376	Gefitinib completely and potently (IC50 of 0.13 muM) inhibits the effect of stimulation with 0.3 nM NRG1beta yet fails to inhibit the effect of stimulation with 0.1 nM IL3.	('inhibits', 'NegReg', (53, 61))	('IL3', 'molecular_function', 'GO:0005135', ('168', '171'))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('NRG1beta', 'Var', (100, 108))
11136	33378376	The high-priority candidate, SR-33487, inhibits the stimulation of cell proliferation by 0.3 nM NRG1beta with an IC50 of 6.8 muM and is predicted to inhibit IL3-dependent cellular proliferation with an IC50 of 2100 muM (Figs 6B and 7 and Table 3).	('NRG1beta', 'Protein', (96, 104))	('inhibit', 'NegReg', (149, 156))	('SR-33487', 'Var', (29, 37))	('inhibits', 'NegReg', (39, 47))	('IL3', 'molecular_function', 'GO:0005135', ('157', '160'))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('52', '85'))	('SR-33487', 'Chemical', '-', (29, 37))	('cell proliferation', 'CPA', (67, 85))	('IL3-dependent cellular proliferation', 'CPA', (157, 193))
11137	33378376	Thus, SR-33487 is a much more potent inhibitor of ErbB4-dependent cell proliferation than of IL3-dependent cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('107', '125'))	('IL3', 'molecular_function', 'GO:0005135', ('93', '96'))	('SR-33487', 'Chemical', '-', (6, 14))	('SR-33487', 'Var', (6, 14))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('ErbB4-dependent', 'Gene', (50, 65))
11138	33378376	For example, SR-33486 inhibits the stimulation of cell proliferation by 0.3 nM NRG1beta with an IC50 of 0.11 uM and inhibits IL3-dependent cellular proliferation with an IC50 of 0.45 muM (Fig 8A and Table 3).	('NRG1beta', 'Protein', (79, 87))	('inhibits', 'NegReg', (116, 124))	('inhibits', 'NegReg', (22, 30))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('35', '68'))	('SR-33486', 'Chemical', '-', (13, 21))	('SR-33486', 'Var', (13, 21))	('IL3', 'molecular_function', 'GO:0005135', ('125', '128'))	('IL3-dependent cellular proliferation', 'CPA', (125, 161))	('cell proliferation', 'CPA', (50, 68))
11139	33378376	Thus, even though SR-33486 is a more potent inhibitor of ErbB4-dependent cell proliferation than is the high priority candidate (SR-33487), SR-33486 is much less selective for ErbB4 than is SR-33487.	('SR-33487', 'Chemical', '-', (190, 198))	('SR-33487', 'Chemical', '-', (129, 137))	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('SR-33486', 'Var', (18, 26))	('SR-33486', 'Chemical', '-', (18, 26))	('ErbB4-dependent', 'Gene', (57, 72))	('less', 'NegReg', (157, 161))	('SR-33486', 'Var', (140, 148))	('SR-33486', 'Chemical', '-', (140, 148))
11140	33378376	For example, SR-33507 inhibits the stimulation of cell proliferation by 0.3 nM NRG1beta with an IC50 of 0.39 muM and inhibits IL3-dependent cellular proliferation with an IC50 of 0.72 muM (S2 Fig and Table 3).	('NRG1beta', 'Protein', (79, 87))	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('35', '68'))	('inhibits', 'NegReg', (117, 125))	('IL3', 'molecular_function', 'GO:0005135', ('126', '129'))	('SR-33507', 'Chemical', '-', (13, 21))	('inhibits', 'NegReg', (22, 30))	('IL3-dependent cellular proliferation', 'CPA', (126, 162))	('SR-33507', 'Var', (13, 21))	('cell proliferation', 'CPA', (50, 68))
11141	33378376	Also, SR-33509 inhibits the stimulation of cell proliferation by 0.3 nM NRG1beta with an IC50 of 32 muM and fails to inhibit IL3-dependent cellular proliferation (S3 Fig and Table 3).	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('28', '61'))	('SR-33509', 'Var', (6, 14))	('SR-33509', 'Chemical', '-', (6, 14))	('NRG1beta', 'Gene', (72, 80))	('inhibits', 'NegReg', (15, 23))	('IL3', 'molecular_function', 'GO:0005135', ('125', '128'))	('cell proliferation', 'CPA', (43, 61))
11142	33378376	One molecule, SR-33528, is considered a special case as our initial analyses (Fig 9A; Table 3) indicate that it potently inhibits stimulation of cell proliferation by 0.3 nM NRG1beta (IC50 of less than 30 nM) and by 0.1 nM IL3 (IC50 of less than 30 nM).	('stimulation of cell proliferation', 'biological_process', 'GO:0008284', ('130', '163'))	('inhibits', 'NegReg', (121, 129))	('IL3', 'molecular_function', 'GO:0005135', ('223', '226'))	('cell proliferation', 'CPA', (145, 163))	('SR-33528', 'Var', (14, 22))	('SR-33528', 'Chemical', '-', (14, 22))	('NRG1beta', 'Protein', (174, 182))
11144	33378376	These data reveal that SR-33528 potently inhibits ErbB4-dependent cell proliferation (IC50 = 1.05 nM) and IL3-dependent cell proliferation (IC50 = 2.51 nM).	('inhibits', 'NegReg', (41, 49))	('SR-33528', 'Var', (23, 31))	('SR-33528', 'Chemical', '-', (23, 31))	('IL3', 'molecular_function', 'GO:0005135', ('106', '109'))	('cell proliferation', 'biological_process', 'GO:0008283', ('66', '84'))	('ErbB4-dependent cell proliferation', 'CPA', (50, 84))	('IL3-dependent cell proliferation', 'CPA', (106, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))
11145	33378376	Due to the similarity in SR-33528 potency against ErbB4- and IL3-dependent proliferation, we postulated that SR-33528 targets a convergence point downstream of ErbB4 and the IL3 receptor (S5 Fig).	('SR-33528', 'Var', (109, 117))	('SR-33528', 'Chemical', '-', (109, 117))	('IL3', 'molecular_function', 'GO:0005135', ('61', '64'))	('SR-33528', 'Chemical', '-', (25, 33))	('ErbB4', 'Gene', (160, 165))	('IL3', 'molecular_function', 'GO:0005135', ('174', '177'))
11148	33378376	In light of these results, it is clear that SR-33528 does not act upstream of either AKT or ERK.	('SR-33528', 'Chemical', '-', (44, 52))	('SR-33528', 'Var', (44, 52))	('AKT', 'Gene', '11651', (85, 88))	('ERK', 'Gene', '13844', (92, 95))	('ERK', 'Gene', (92, 95))	('AKT', 'Gene', (85, 88))	('ERK', 'molecular_function', 'GO:0004707', ('92', '95'))
11150	33378376	SR-33528 is structurally very similar to vinca alkaloids, particularly the FDA-approved anticancer agent vincristine (Fig 10).	('vinca alkaloids', 'Chemical', 'MESH:D014748', (41, 56))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('SR-33528', 'Var', (0, 8))	('SR-33528', 'Chemical', '-', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('vincristine', 'Chemical', 'MESH:D014750', (105, 116))
11151	33378376	This similarity suggests that SR-33528, like vincristine, non-specifically inhibits cell proliferation by preventing tubulin polymerization into microtubules just prior to cell division.	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('vincristine', 'Chemical', 'MESH:D014750', (45, 56))	('SR-33528', 'Var', (30, 38))	('SR-33528', 'Chemical', '-', (30, 38))	('preventing', 'NegReg', (106, 116))	('cell proliferation', 'CPA', (84, 102))	('cell division', 'biological_process', 'GO:0051301', ('172', '185'))	('inhibits', 'NegReg', (75, 83))
11154	33378376	As a result, six compounds (SR-33487, SR-33486, SR-33483, SR-33494, SR-33492, SR-33491) were identified that appear to selectively and potently inhibit ErbB4-dependent cell proliferation (Figs 6B and 8A-8E, Table 3).	('SR-33486', 'Chemical', '-', (38, 46))	('SR-33486', 'Var', (38, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('168', '186'))	('SR-33483', 'Var', (48, 56))	('SR-33491', 'Var', (78, 86))	('SR-33492', 'Var', (68, 76))	('SR-33494', 'Var', (58, 66))	('ErbB4-dependent cell proliferation', 'CPA', (152, 186))	('SR-33491', 'Chemical', '-', (78, 86))	('SR-33487', 'Chemical', '-', (28, 36))	('inhibit', 'NegReg', (144, 151))	('SR-33494', 'Chemical', '-', (58, 66))	('SR-33492', 'Chemical', '-', (68, 76))	('SR-33487', 'Var', (28, 36))	('SR-33483', 'Chemical', '-', (48, 56))
11157	33378376	To be explicit, EGFR or ErbB2 kinase activity, but NOT ErbB4 kinase activity, is required for the oncogenic activity of EGFR-ErbB4 or ErbB2-ErbB4 heterodimers, respectively.	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('kinase activity', 'molecular_function', 'GO:0016301', ('61', '76'))	('ErbB2', 'Gene', (134, 139))	('kinase activity', 'molecular_function', 'GO:0016301', ('30', '45'))	('EGFR-ErbB4', 'Var', (120, 130))	('ErbB2', 'Gene', (24, 29))	('ErbB2', 'Gene', '13866', (134, 139))	('ErbB2', 'Gene', '13866', (24, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('16', '20'))
11159	33378376	Instead, our strategy for identifying small molecule ErbB4 inhibitors was inspired by our observation that the Q43L mutant of the ErbB4 ligand NRG2beta is still able to stimulate ErbB4 tyrosine phosphorylation, but cannot stimulate the coupling of EGFR-ErbB4 heterodimers to cell proliferation.	('tyrosine', 'Chemical', 'MESH:D014443', (185, 193))	('Q43L', 'Var', (111, 115))	('ligand', 'molecular_function', 'GO:0005488', ('136', '142'))	('EGFR', 'molecular_function', 'GO:0005006', ('248', '252'))	('ErbB4 tyrosine phosphorylation', 'MPA', (179, 209))	('cell proliferation', 'biological_process', 'GO:0008283', ('275', '293'))	('NRG2beta', 'Gene', (143, 151))	('Q43L', 'Mutation', 'p.Q43L', (111, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('194', '209'))	('stimulate', 'PosReg', (169, 178))
11160	33378376	Moreover, the NRG2beta/Q43L ErbB4 partial agonist inhibits the agonistic activity of wild-type NRG2beta on EGFR-ErbB4 heterodimers.	('Q43L', 'Mutation', 'p.Q43L', (23, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('107', '111'))	('ErbB4', 'Gene', (28, 33))	('agonistic activity', 'MPA', (63, 81))	('inhibits', 'NegReg', (50, 58))	('NRG2beta/Q43L', 'Var', (14, 27))
11189	33378376	Our drug discovery approach was based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist NRG2beta functions as a partial agonist of ErbB4.	('partial agonist', 'NegReg', (143, 158))	('Q43L', 'Var', (66, 70))	('ErbB4', 'Gene', (105, 110))	('Q43L', 'Mutation', 'p.Q43L', (66, 70))
11190	33378376	NRG2beta/Q43L stimulates ErbB4 tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation.	('tyrosine', 'Chemical', 'MESH:D014443', (31, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('ErbB4', 'Protein', (25, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('157', '175'))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('stimulates', 'PosReg', (14, 24))	('NRG2beta/Q43L', 'Var', (0, 13))	('Q43L', 'Mutation', 'p.Q43L', (9, 13))	('inhibits', 'NegReg', (116, 124))
11191	33378376	ErbB4 partial agonists hold promise as therapies for ErbB4-dependent tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('partial agonists', 'Var', (6, 22))	('ErbB4-dependent', 'Gene', (53, 68))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('ErbB4', 'Gene', (0, 5))
11198	31496735	RARRES3 knockdown was achieved by siRNA transfection.	('knockdown', 'Var', (8, 17))	('RARRES3', 'Gene', (0, 7))	('RARRES3', 'Gene', '5920', (0, 7))
11206	31496735	RARRES3 knockdown partially abolished the anti-SKCM effect of HCP5 overexpression.	('abolished', 'NegReg', (28, 37))	('knockdown', 'Var', (8, 17))	('RARRES3', 'Gene', (0, 7))	('RARRES3', 'Gene', '5920', (0, 7))	('HCP5', 'Gene', '10866', (62, 66))	('anti-SKCM effect', 'MPA', (42, 58))	('HCP5', 'Gene', (62, 66))
11215	31496735	After querying some transcriptomic studies, we found that high expression of lncRNA HCP5 been proposed as a risk factor of SKCM progression.	('HCP5', 'Gene', '10866', (84, 88))	('risk factor', 'Reg', (108, 119))	('HCP5', 'Gene', (84, 88))	('SKCM', 'Disease', (123, 127))	('high', 'Var', (58, 62))
11237	31496735	The HCP5-overexpressing (OE) (LPP-Y1990-Lv105-400) and empty lentiviral particles were purchased from Genecopoeia (Rockville, MD, USA) and transduced into SKCM cells at log phase at the MOI of 5 TU/cell using EndoFectin Lenti transfection reagent (EF002, Genecopoeia) following the manufacturer's instructions.	('HCP5', 'Gene', '10866', (4, 8))	('LPP-Y1990-Lv105-400', 'Var', (30, 49))	('HCP5', 'Gene', (4, 8))
11243	31496735	HCP5 or RARRES3 mRNA in the total RNA was detected by qRT-PCR with 2-DeltaDeltaCt method using a one-step SYBR green RT-qPCR Kit (QP084, Genecopoeia) and the following primers (Genecopoeia): RARRES3 (HQP108527), GAPDH (HQP006940), HCP (Fw, CAGCCTGAGAGAAGTAGGGC; Rev, TCAGTCGCATTTCCAGGTAATTT; sequences from PrimerBank).	('GAPDH', 'Gene', (212, 217))	('RARRES3', 'Gene', '5920', (8, 15))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('HQP108527', 'Var', (200, 209))	('HCP5', 'Gene', '10866', (0, 4))	('HCP5', 'Gene', (0, 4))	('GAPDH', 'Gene', '2597', (212, 217))	('RARRES3', 'Gene', (191, 198))	('RARRES3', 'Gene', '5920', (191, 198))	('RARRES3', 'Gene', (8, 15))
11252	31496735	Three different reporter plasmids were constructed by Genecopoeia for the miRNA target luciferase reporter assay: for the wild-type (WT) plasmids, the cDNA of RARRES3 mRNA 3' UTR was inserted at the 3' flank of Gaussia luciferase (Gluc) gene on the reporter plasmids; for the Scrambled plasmids, the cDNA sequence of RARRES3 mRNA 3' UTR was scrambled; for mutant (MUT) plasmids, mutations were induced into the cDNA of RARRES3 mRNA 3' UTR (as demonstrated in Figure 5E).	('rat', 'Species', '10116', (450, 453))	('mutations', 'Var', (379, 388))	('RARRES3', 'Gene', '5920', (419, 426))	('RARRES3', 'Gene', '5920', (159, 166))	('flank of Gaussia luciferase', 'Disease', 'MESH:D021501', (202, 229))	('RARRES3', 'Gene', (419, 426))	('flank of Gaussia luciferase', 'Disease', (202, 229))	('RARRES3', 'Gene', (317, 324))	('RARRES3', 'Gene', '5920', (317, 324))	('RARRES3', 'Gene', (159, 166))	('mutant', 'Var', (356, 362))
11255	31496735	The cells were lysed on the plate with a mild lysis buffer (P0013, Beyotime), and the cell lysate was centrifuged at 15,000x g for 10 min at 4 C. The supernatant was then incubated with Protein A magnetic beads preloaded with rabbit anti-rat IgG antibody and rat anti-AGO2 antibody at 4 C for 16 hrs.	('antibody', 'cellular_component', 'GO:0042571', ('273', '281'))	('P0013', 'Var', (60, 65))	('AGO2', 'Gene', '27161', (268, 272))	('IgG antibody', 'Phenotype', 'HP:0003237', (242, 254))	('antibody', 'cellular_component', 'GO:0019815', ('273', '281'))	('rat', 'Species', '10116', (259, 262))	('antibody', 'cellular_component', 'GO:0019814', ('273', '281'))	('AGO2', 'Gene', (268, 272))	('antibody', 'molecular_function', 'GO:0003823', ('246', '254'))	('antibody', 'molecular_function', 'GO:0003823', ('273', '281'))	('rabbit', 'Species', '9986', (226, 232))	('IgG antibody', 'cellular_component', 'GO:0071736', ('242', '254'))	('lysis', 'biological_process', 'GO:0019835', ('46', '51'))	('rat', 'Species', '10116', (238, 241))
11258	31496735	Previous researches have implicated dysregulation of HCP5 in SKCM progression.	('dysregulation', 'Var', (36, 49))	('SKCM', 'Disease', (61, 65))	('HCP5', 'Gene', '10866', (53, 57))	('HCP5', 'Gene', (53, 57))
11260	31496735	After querying the TCGA-SKCM data, to our surprise, we found that high expression of HCP5 actually associated with increased survival of SKCM patients (Figure 1A), implying that HCP5 might limit SKCM progression.	('survival', 'MPA', (125, 133))	('increased', 'PosReg', (115, 124))	('HCP5', 'Gene', '10866', (85, 89))	('HCP5', 'Gene', (85, 89))	('SKCM', 'Disease', (137, 141))	('high', 'Var', (66, 70))	('HCP5', 'Gene', '10866', (178, 182))	('HCP5', 'Gene', (178, 182))	('SKCM', 'Disease', (195, 199))	('patients', 'Species', '9606', (142, 150))	('associated', 'Reg', (99, 109))
11277	31496735	Our data showed that OE HCP5 significantly increased the activity of Gluc, whose expression was governed by the WT 3' UTR of RARRES3 in SKCM cells, and scrambling the sequence of this 3' UTR of RARRES3 abolished the regulation of HCP5 on Gluc expression (Figure 5A).	('RARRES3', 'Gene', '5920', (125, 132))	('Gluc', 'Enzyme', (69, 73))	('RARRES3', 'Gene', (194, 201))	('RARRES3', 'Gene', '5920', (194, 201))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('scrambling', 'Var', (152, 162))	('HCP5', 'Gene', '10866', (24, 28))	('HCP5', 'Gene', '10866', (230, 234))	('activity', 'MPA', (57, 65))	('HCP5', 'Gene', (230, 234))	('increased', 'PosReg', (43, 52))	('HCP5', 'Gene', (24, 28))	('RARRES3', 'Gene', (125, 132))
11286	31496735	Previous studies described the potential association between high expression of HCP5 and SKCM patients' decreased survival.	('survival', 'MPA', (114, 122))	('high expression', 'Var', (61, 76))	('HCP5', 'Gene', '10866', (80, 84))	('HCP5', 'Gene', (80, 84))	('patients', 'Species', '9606', (94, 102))	('decreased', 'NegReg', (104, 113))	('SKCM', 'Disease', (89, 93))
11287	31496735	In the present research, however, we found that high expression of HCP5 might favor SKCM patients' good prognosis, and that this lncRNA was significantly decreased in SKCM pathologic tissue specimens comparing to normal tissue specimens.	('decreased', 'NegReg', (154, 163))	('good prognosis', 'CPA', (99, 113))	('HCP5', 'Gene', '10866', (67, 71))	('HCP5', 'Gene', (67, 71))	('SKCM', 'Disease', (84, 88))	('patients', 'Species', '9606', (89, 97))	('favor', 'PosReg', (78, 83))	('high', 'Var', (48, 52))
11295	31496735	We transfected the HCP5-OE SKCM cells with siRNA for RARRES3 knockdown at a series of continuously diluted concentrations to downregulate their RARRES3 expression to a "near wild-type" level.	('RARRES3', 'Gene', (53, 60))	('HCP5', 'Gene', '10866', (19, 23))	('RARRES3', 'Gene', '5920', (53, 60))	('rat', 'Species', '10116', (114, 117))	('HCP5', 'Gene', (19, 23))	('knockdown', 'Var', (61, 70))	('RARRES3', 'Gene', (144, 151))	('RARRES3', 'Gene', '5920', (144, 151))	('expression', 'MPA', (152, 162))	('downregulate', 'NegReg', (125, 137))
11323	23110010	We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors.	('BRAF', 'Gene', '673', (29, 33))	('formalin', 'Chemical', 'MESH:D005557', (259, 267))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('BRAF', 'Gene', (29, 33))	('paraffin', 'Chemical', 'MESH:D010232', (278, 286))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('mutation', 'Var', (34, 42))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 86))	('oligonucleotide', 'Chemical', 'MESH:D009841', (149, 164))	('tumors', 'Disease', (296, 302))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('primary cutaneous melanoma', 'Disease', (60, 86))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))
11324	23110010	The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma.	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('found', 'Reg', (22, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 88))	('patients', 'Species', '9606', (48, 56))	('non-cutaneous melanoma', 'Disease', (120, 142))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 142))	('primary cutaneous melanoma', 'Disease', (62, 88))
11325	23110010	The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))	('patient', 'Species', '9606', (114, 121))
11326	23110010	The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005).	('higher', 'PosReg', (53, 59))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('patients', 'Species', '9606', (63, 71))
11327	23110010	Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma.	('patients', 'Species', '9606', (115, 123))	('lower', 'NegReg', (106, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('mutation', 'Var', (82, 90))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('primary cutaneous melanoma', 'Disease', (129, 155))
11328	23110010	Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age.	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('mutation', 'Var', (64, 72))
11329	23110010	Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma.	('malignant melanoma', 'Disease', (256, 274))	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('pathogenesis', 'biological_process', 'GO:0009405', ('240', '252'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (256, 274))	('malignant melanoma', 'Disease', 'MESH:D008545', (256, 274))
11338	23110010	In more than 90% of total BRAF mutations, a glutamic acid for valine substitution at codon 600 in exon 15 has been identified up to present.	('glutamic acid for valine substitution at codon 600', 'Mutation', 'rs113488022', (44, 94))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (26, 30))
11339	23110010	This genetic alteration of BRAF sequentially induces constitutive extracellular signal-regulated kinase (ERK) signaling through a hyperactivation of the RAS/RAF/mitogen-activated protein kinase/ERK (MAPK/ERK) pathway that is involved in promoting the proliferation, survival and development of tumor cells.	('RAF', 'Gene', (28, 31))	('ERK', 'Gene', '5594', (105, 108))	('ERK', 'Gene', '5594', (194, 197))	('ERK', 'Gene', (204, 207))	('hyperactivation', 'PosReg', (130, 145))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('ERK', 'molecular_function', 'GO:0004707', ('194', '197'))	('induces', 'Reg', (45, 52))	('ERK', 'Gene', (105, 108))	('ERK', 'Gene', (194, 197))	('RAF', 'Gene', '22882', (157, 160))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('MAPK', 'molecular_function', 'GO:0004707', ('199', '203'))	('ERK', 'molecular_function', 'GO:0004707', ('105', '108'))	('mitogen-activated protein kinase/ERK', 'Gene', '5594', (161, 197))	('men', 'Species', '9606', (286, 289))	('extracellular', 'cellular_component', 'GO:0005576', ('66', '79'))	('extracellular signal-regulated kinase', 'Gene', (66, 103))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('RAF', 'Gene', (157, 160))	('tumor', 'Disease', (294, 299))	('extracellular signal-regulated kinase', 'Gene', '5594', (66, 103))	('ERK', 'Gene', '5594', (204, 207))	('genetic alteration', 'Var', (5, 23))	('RAF', 'Gene', '22882', (28, 31))	('mitogen-activated protein kinase/ERK', 'Gene', (161, 197))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('ERK', 'molecular_function', 'GO:0004707', ('204', '207'))	('promoting', 'PosReg', (237, 246))
11340	23110010	To date, several studies have been conducted to examine the relationship of BRAF mutation in MM with its clinicopathologic characteristics.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (81, 89))
11341	23110010	Nevertheless, to our knowledge, there are no reports about the associations between BRAF mutations in MM and its clinicopathologic features in the Korean population.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))
11342	23110010	Given the above background, we conducted this study to examine the frequency and potential clinicopathologic significance of the BRAF mutation in Korean patients with primary cutaneous or non-cutaneous melanoma.	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (188, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('patients', 'Species', '9606', (153, 161))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('mutation', 'Var', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('primary cutaneous', 'Disease', (167, 184))	('non-cutaneous melanoma', 'Disease', (188, 210))
11351	23110010	The BRAF mutation was detected using the Anyplex BRAF V600E real time detection system (Seegene Inc., Seoul, Korea).	('mutation', 'Var', (9, 17))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (49, 53))
11356	23110010	To evaluate the possible relationships between the BRAF mutation and various clinicopathologic parameters, we used either the Fisher's exact test or Mann-Whitney test.	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('BRAF', 'Gene', '673', (51, 55))
11357	23110010	Using the Mann-Whitney test, we analyzed the relationship between the BRAF mutation and ordinal clinicopathologic variables including Breslow thickness and tumor, node and metastasis (TNM) stage.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mutation', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NM', 'Phenotype', 'HP:0012058', (185, 187))	('tumor', 'Disease', (156, 161))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
11358	23110010	In addition, we used the Kaplan-Meier method to analyze the impact of the BRAF mutation on overall survival (OS) and disease-free survival (DFS).	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutation', 'Var', (79, 87))
11370	23110010	The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma (n=58).	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 88))	('patients', 'Species', '9606', (48, 56))	('primary cutaneous melanoma', 'Disease', (62, 88))
11372	23110010	In patients with primary cutaneous melanoma, the age was the only variable that had a significant correlation with the BRAF mutation.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('patients', 'Species', '9606', (3, 11))	('mutation', 'Var', (124, 132))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('primary cutaneous melanoma', 'Disease', (17, 43))
11373	23110010	The frequency of the BRAF mutation was significantly higher in patients aged 60 years or younger as compared with those aged 60 years or older (p=0.005).	('higher', 'PosReg', (53, 59))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('patients', 'Species', '9606', (63, 71))
11375	23110010	In addition, we also analyzed the correlation between the specific site of the occurrence of primary cutaneous melanoma and the frequency of the BRAF mutation.	('primary cutaneous melanoma', 'Disease', (93, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('BRAF', 'Gene', (145, 149))	('mutation', 'Var', (150, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 119))	('BRAF', 'Gene', '673', (145, 149))
11376	23110010	The BRAF mutation was found in 18.4% (7/38) of patients with ALM and 18.8% (3/16) of patients with NM.	('mutation', 'Var', (9, 17))	('NM', 'Phenotype', 'HP:0012058', (99, 101))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (85, 93))	('ALM', 'Phenotype', 'HP:0012060', (61, 64))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('ALM', 'Disease', (61, 64))
11379	23110010	The mean thickness of the tumors was smaller in patients with the BRAF mutation as compared with those without the BRAF mutation (4.8+-7.2 mm vs 6.0+-8.4 mm).	('BRAF', 'Gene', '673', (115, 119))	('smaller', 'NegReg', (37, 44))	('BRAF', 'Gene', (115, 119))	('mutation', 'Var', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('BRAF', 'Gene', '673', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('patients', 'Species', '9606', (48, 56))	('BRAF', 'Gene', (66, 70))	('tumors', 'Disease', (26, 32))
11380	23110010	The frequency of BRAF mutation was higher in patients with a Breslow thickness of <=2 mm as compared with those with a Breslow thickness of >2 mm (25.0% vs 13.2%).	('patients', 'Species', '9606', (45, 53))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))
11381	23110010	Neither the mean tumor thickness nor the Breslow thickness were variables that had a significant correlation with the frequency of BRAF mutation (p=0.328 and p=0.241, respectively).	('tumor', 'Disease', (17, 22))	('BRAF', 'Gene', (131, 135))	('mutation', 'Var', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('BRAF', 'Gene', '673', (131, 135))
11383	23110010	We also evaluated if the AJCC clinical stage, presence of ulceration, nodal metastasis and recurrence are significantly correlated with the frequency of the BRAF mutation.	('nodal', 'Gene', (70, 75))	('nodal', 'Gene', '4838', (70, 75))	('BRAF', 'Gene', '673', (157, 161))	('correlated', 'Reg', (120, 130))	('BRAF', 'Gene', (157, 161))	('mutation', 'Var', (162, 170))	('AJCC', 'Disease', (25, 29))
11384	23110010	But none of these factors had a statistically significant correlation with the frequency of the BRAF mutation.	('BRAF', 'Gene', '673', (96, 100))	('mutation', 'Var', (101, 109))	('BRAF', 'Gene', (96, 100))
11385	23110010	The frequency of BRAF mutation had no statistically significant impact on both the OS and DFS (p=0.561 and p=0.397, respectively).	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutation', 'Var', (22, 30))
11386	23110010	In patients with the BRAF mutation, however, there was a slightly increased tendency in the OS and DFS (Fig.	('increased', 'PosReg', (66, 75))	('DFS', 'Disease', (99, 102))	('mutation', 'Var', (26, 34))	('BRAF', 'Gene', '673', (21, 25))	('patients', 'Species', '9606', (3, 11))	('BRAF', 'Gene', (21, 25))
11387	23110010	The BRAF mutation was found in 11.1% (3/27) of patients with non-cutaneous melanoma.	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('patients', 'Species', '9606', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 83))	('non-cutaneous melanoma', 'Disease', (61, 83))
11389	23110010	Our results showed that the frequency of BRAF mutation was 17.2% in 58 patients with primary cutaneous melanoma.	('patients', 'Species', '9606', (71, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 111))	('BRAF', 'Gene', '673', (41, 45))	('primary cutaneous melanoma', 'Disease', (85, 111))	('BRAF', 'Gene', (41, 45))	('mutation', 'Var', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
11390	23110010	This methodological difference, however, is not sufficient to explain the low frequency of the BRAF mutation seen in our results.	('mutation', 'Var', (100, 108))	('BRAF', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (95, 99))
11391	23110010	compared the frequency of the BRAF mutation between the microdissected samples and those the DNA was extracted from an entire section without using a microdissection technique.	('BRAF', 'Gene', (30, 34))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('BRAF', 'Gene', '673', (30, 34))	('mutation', 'Var', (35, 43))
11392	23110010	There was no significant difference in the frequency of the BRAF mutation between the two groups.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutation', 'Var', (65, 73))
11393	23110010	Other reasons for the difference in the frequency of BRAF mutation may be that there is a variability in types of BRAF mutation, the proportion of histological subtypes and the sensitivity of the methods for detecting it.	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))
11394	23110010	Some of the previous studies have detected various types of BRAF mutations including exon 11 mutations (G465A, G465E, and G468S changes) as well as exon 15 mutations (V600E, V600K, V600R, V600G, and V600D changes) although the BRAF V600E mutation accounted for more than 90% of the detected mutations.	('G465A', 'Var', (104, 109))	('V600K', 'Mutation', 'rs121913227', (174, 179))	('V600D', 'Mutation', 'rs121913377', (199, 204))	('V600R', 'Var', (181, 186))	('V600K', 'Var', (174, 179))	('G468S', 'Mutation', 'p.G468S', (122, 127))	('G465E', 'Mutation', 'p.G465E', (111, 116))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('V600E', 'Mutation', 'rs113488022', (232, 237))	('V600E', 'Mutation', 'rs113488022', (167, 172))	('G465E', 'Var', (111, 116))	('V600R', 'Mutation', 'rs121913227', (181, 186))	('V600G', 'Mutation', 'rs113488022', (188, 193))	('G468S changes', 'Var', (122, 135))	('BRAF', 'Gene', (227, 231))	('BRAF', 'Gene', '673', (227, 231))	('V600G', 'Var', (188, 193))	('V600D changes', 'Var', (199, 212))	('G465A', 'Mutation', 'c.465G>A', (104, 109))	('V600E', 'Var', (167, 172))
11397	23110010	It has also been reported that ALM has a low frequency of BRAF mutation compared to other subtypes of melanomas.	('ALM', 'Disease', (31, 34))	('melanomas', 'Disease', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('mutation', 'Var', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('BRAF', 'Gene', '673', (58, 62))	('ALM', 'Phenotype', 'HP:0012060', (31, 34))	('BRAF', 'Gene', (58, 62))
11398	23110010	According to a recent study that has been conducted in the Asian population, the frequency of BRAF mutation was 15.0% and this value was similar to our results.	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (94, 98))	('mutation', 'Var', (99, 107))
11399	23110010	The above mentioned reasons make it more difficult to interpret our results that the frequency of BRAF mutation was relatively lower as compared with previous published studies.	('men', 'Species', '9606', (10, 13))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('lower', 'NegReg', (127, 132))	('mutation', 'Var', (103, 111))
11400	23110010	Our results showed that the age was the only clinicopathologic variable that has a significant correlation with the frequency of the BRAF mutation in patients with primary cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (172, 190))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('patients', 'Species', '9606', (150, 158))	('mutation', 'Var', (138, 146))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 190))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('primary cutaneous melanoma', 'Disease', (164, 190))
11401	23110010	Patients aged 60 years or younger had a higher frequency of the BRAF mutation as compared with those aged 60 years or older, which is consistent with previous reports.	('mutation', 'Var', (69, 77))	('Patients', 'Species', '9606', (0, 8))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', '673', (64, 68))
11405	23110010	In addition, to rule out the effects of histological subtypes, the site of occurrence and the degree of sunlight exposure, we also examined the correlation of the BRAF mutation with the age in patients with ALM.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('patients', 'Species', '9606', (193, 201))	('ALM', 'Phenotype', 'HP:0012060', (207, 210))	('sunlight exposure', 'Phenotype', 'HP:0000992', (104, 121))	('mutation', 'Var', (168, 176))	('examined', 'Reg', (131, 139))
11406	23110010	This showed that the frequency of the BRAF mutation was higher in patients younger than 60 years than those older than 60 years in cases of ALM (p=0.011).	('mutation', 'Var', (43, 51))	('BRAF', 'Gene', '673', (38, 42))	('ALM', 'Phenotype', 'HP:0012060', (140, 143))	('BRAF', 'Gene', (38, 42))	('patients', 'Species', '9606', (66, 74))
11407	23110010	These results indicate not only that the age is an independent variable that is correlated with the BRAF mutation but also that there is a difference in the pathogenesis between the two groups.	('BRAF', 'Gene', '673', (100, 104))	('pathogenesis', 'biological_process', 'GO:0009405', ('157', '169'))	('mutation', 'Var', (105, 113))	('BRAF', 'Gene', (100, 104))
11408	23110010	It can be speculated, however, that the difference in the pathogenesis between the two age groups may be due to the mutations of NRAS and BRAF, both of which are mutually exclusive events in the pathogenesis of MM.	('pathogenesis', 'biological_process', 'GO:0009405', ('58', '70'))	('due', 'Reg', (105, 108))	('NRAS', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (138, 142))	('NRAS', 'Gene', '4893', (129, 133))	('mutations', 'Var', (116, 125))	('BRAF', 'Gene', (138, 142))	('pathogenesis', 'biological_process', 'GO:0009405', ('195', '207'))
11409	23110010	Previous studies have demonstrated that the NRAS mutation is associated with older age, thicker tumor and poor clinical outcome as compared with the BRAF one.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('NRAS', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))	('NRAS', 'Gene', '4893', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
11410	23110010	Based on these reports, we can assume that the BRAF mutation is more commonly involved in the pathogenesis of melanoma in younger patients.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('involved', 'Reg', (78, 86))	('melanoma', 'Disease', (110, 118))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('patients', 'Species', '9606', (130, 138))	('mutation', 'Var', (52, 60))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))
11411	23110010	We can also presume that the NRAS mutation play a more predominant role in the pathogenesis of melanoma in older patients.	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('NRAS', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('melanoma', 'Disease', (95, 103))	('patients', 'Species', '9606', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('NRAS', 'Gene', '4893', (29, 33))
11413	23110010	These studies have reported that SSM and NM more frequently harbor BRAF mutations than ALM.	('ALM', 'Phenotype', 'HP:0012060', (87, 90))	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('SSM', 'Disease', (33, 36))	('BRAF', 'Gene', (67, 71))	('SSM', 'cellular_component', 'GO:1990843', ('33', '36'))	('NM', 'Phenotype', 'HP:0012058', (41, 43))	('SSM', 'Phenotype', 'HP:0012057', (33, 36))
11414	23110010	In the current study, as compared with previous published data, the frequency of BRAF mutation (18.4%) seen in patients with ALM was similar but that seen in patients with SSM or NM was relatively lower (0% and 18.8%, respectively).	('ALM', 'Phenotype', 'HP:0012060', (125, 128))	('SSM', 'Phenotype', 'HP:0012057', (172, 175))	('BRAF', 'Gene', '673', (81, 85))	('ALM', 'Disease', (125, 128))	('BRAF', 'Gene', (81, 85))	('NM', 'Phenotype', 'HP:0012058', (179, 181))	('mutation', 'Var', (86, 94))	('patients', 'Species', '9606', (158, 166))	('SSM', 'cellular_component', 'GO:1990843', ('172', '175'))	('patients', 'Species', '9606', (111, 119))
11416	23110010	Further large-scale studies are therefore warranted to identify the correlation between the frequency of BRAF mutation and histological subtypes in Korean patients with cutaneous melanoma.	('BRAF', 'Gene', '673', (105, 109))	('cutaneous melanoma', 'Disease', (169, 187))	('BRAF', 'Gene', (105, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (169, 187))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (169, 187))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))
11417	23110010	Our results showed that the frequency of BRAF mutation had an inverse correlation with tumor thickness despite a lack of the statistical significance.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('BRAF', 'Gene', '673', (41, 45))	('inverse', 'NegReg', (62, 69))	('BRAF', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutation', 'Var', (46, 54))
11418	23110010	Several previous reports have also shown that the frequency of BRAF mutation is associated with decreased tumor thickness.	('decreased tumor', 'Disease', (96, 111))	('mutation', 'Var', (68, 76))	('decreased tumor', 'Disease', 'MESH:D009369', (96, 111))	('BRAF', 'Gene', '673', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BRAF', 'Gene', (63, 67))
11419	23110010	These observations indicate that the frequency of BRAF mutation may be related to more differentiated forms of cutaneous melanoma and a slower cell proliferation rate.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('cutaneous melanoma', 'Disease', (111, 129))	('BRAF', 'Gene', (50, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 129))	('mutation', 'Var', (55, 63))	('slower cell proliferation rate', 'CPA', (136, 166))	('cell proliferation', 'biological_process', 'GO:0008283', ('143', '161'))	('BRAF', 'Gene', '673', (50, 54))
11420	23110010	In our series, the frequency of BRAF mutation had no significant correlations with the clinical stage, metastasis and cumulative survival rate.	('BRAF', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (32, 36))	('metastasis', 'CPA', (103, 113))	('mutation', 'Var', (37, 45))
11421	23110010	To date, several studies have also revealed that the frequency of BRAF mutation is not correlated with a prognosis and a survival in patients with primary cutaneous melanoma.	('primary cutaneous melanoma', 'Disease', (147, 173))	('mutation', 'Var', (71, 79))	('patients', 'Species', '9606', (133, 141))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('BRAF', 'Gene', '673', (66, 70))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (147, 173))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('BRAF', 'Gene', (66, 70))
11422	23110010	A lack of consistency and correlation may be due to the inclusion of a variety of histological subtypes and advanced tumors, as well as the inclusion or exclusion of NRAS mutant cases, known as an adverse prognostic factor, from the wild type category.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('NRAS', 'Gene', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('NRAS', 'Gene', '4893', (166, 170))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('mutant', 'Var', (171, 177))
11426	23110010	As described here, a lower prevalence of the BRAF mutation seen in patients with non-cutaneous melanoma is also in agreement with previous reports; the frequency of the BRAF mutation (0-9.5%) was relatively lower in non-cutaneous melanomas as compared with their cutaneous counterparts.	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('non-cutaneous melanoma', 'Disease', (81, 103))	('non-cutaneous melanoma', 'Disease', (216, 238))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('melanomas', 'Disease', 'MESH:D008545', (230, 239))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (220, 239))	('men', 'Species', '9606', (120, 123))	('melanomas', 'Disease', (230, 239))	('patients', 'Species', '9606', (67, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (220, 238))	('mutation', 'Var', (174, 182))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 103))	('lower', 'NegReg', (207, 212))	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (216, 238))	('melanomas', 'Phenotype', 'HP:0002861', (230, 239))
11427	23110010	Three previous studies could not detect a single BRAF mutation in a total of 83 patients with uveal melanoma.	('mutation', 'Var', (54, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('patients', 'Species', '9606', (80, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('BRAF', 'Gene', '673', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('BRAF', 'Gene', (49, 53))
11428	23110010	But, we detected the BRAF mutation in one case of uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutation', 'Var', (26, 34))	('detected', 'Reg', (8, 16))	('BRAF', 'Gene', '673', (21, 25))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('BRAF', 'Gene', (21, 25))	('uveal melanoma', 'Disease', (50, 64))
11430	23110010	elucidated the important role that the KIT plays in the pathogenesis of ALM and mucosal melanomas which harbor the BRAF mutations at lower frequencies.	('mucosal melanomas', 'Disease', 'MESH:D008545', (80, 97))	('BRAF', 'Gene', '673', (115, 119))	('ALM', 'Phenotype', 'HP:0012060', (72, 75))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('BRAF', 'Gene', (115, 119))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('ALM', 'Disease', (72, 75))	('mucosal melanomas', 'Disease', (80, 97))	('mutations', 'Var', (120, 129))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))
11431	23110010	According to these authors, mutations and/or copy number increases of KIT were observed in 39% of mucosal melanomas, 36% of ALM and 28% of melanomas that occurred on the skin which was vulnerable to chronic sun-damage.	('copy number increases', 'Var', (45, 66))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('mucosal melanomas', 'Disease', (98, 115))	('ALM', 'Disease', (124, 127))	('melanomas', 'Disease', (106, 115))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('KIT', 'Gene', (70, 73))	('mucosal melanomas', 'Disease', 'MESH:D008545', (98, 115))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('sun-damage', 'Phenotype', 'HP:0000992', (207, 217))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('observed', 'Reg', (79, 87))	('melanomas', 'Disease', (139, 148))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('mutations', 'Var', (28, 37))	('ALM', 'Phenotype', 'HP:0012060', (124, 127))
11437	23110010	BRAF-specific inhibitors, such as RAF-265 (CHIR-265) and PLX-4032 (Plexikkon), and MEK-specific inhibitors, such as PD0325901 (Pfizer Oncology) and ARRY-142886 (AZD6244), are currently being tested in clinical trials.	('RAF', 'Gene', '22882', (34, 37))	('PD0325901', 'Var', (116, 125))	('MEK', 'Gene', (83, 86))	('MEK', 'Gene', '5609', (83, 86))	('RAF', 'Gene', '22882', (1, 4))	('BRAF', 'Gene', '673', (0, 4))	('PD0325901', 'Chemical', 'MESH:C506614', (116, 125))	('Oncology', 'Phenotype', 'HP:0002664', (134, 142))	('RAF', 'Gene', (1, 4))	('BRAF', 'Gene', (0, 4))	('AZD6244', 'Chemical', 'MESH:C517975', (161, 168))	('RAF', 'Gene', (34, 37))
11438	23110010	Several preclinical and early clinical studies have shown that responses to these agents are associated with the BRAF mutation.	('BRAF', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (113, 117))	('associated', 'Reg', (93, 103))	('mutation', 'Var', (118, 126))
11440	23110010	In Korea, however, ALM is a more prevalent type of cutaneous melanoma and it demonstrates a decreased number of BRAF mutations as compared with SSM and NM.	('mutations', 'Var', (117, 126))	('NM', 'Phenotype', 'HP:0012058', (152, 154))	('SSM', 'Phenotype', 'HP:0012057', (144, 147))	('SSM', 'cellular_component', 'GO:1990843', ('144', '147'))	('cutaneous melanoma', 'Disease', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('ALM', 'Phenotype', 'HP:0012060', (19, 22))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('ALM', 'Disease', (19, 22))
11441	23110010	To facilitate the development of effective targeted therapies for the treatment of melanomas in the near future, it is imperative that further studies be conducted to examine the prevalence and clincopathologic significance of the alterations of several genes which may contribute to the pathogenesis of melanoma in a Korean population, including KIT, CCND1 and NRAS as well as BRAF gene.	('melanomas', 'Disease', (83, 92))	('CCND1', 'Gene', '595', (352, 357))	('men', 'Species', '9606', (25, 28))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('NRAS', 'Gene', '4893', (362, 366))	('CCND1', 'Gene', (352, 357))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('alterations', 'Var', (231, 242))	('BRAF', 'Gene', (378, 382))	('BRAF', 'Gene', '673', (378, 382))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('NRAS', 'Gene', (362, 366))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('contribute', 'Reg', (270, 280))	('melanoma', 'Disease', (304, 312))	('men', 'Species', '9606', (75, 78))	('pathogenesis', 'biological_process', 'GO:0009405', ('288', '300'))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('KIT', 'molecular_function', 'GO:0005020', ('347', '350'))
11442	23110010	In conclusion, our study provides preliminary results concerning the frequency of the BRAF mutation and its association with clinicopathologic parameters in Korean patients with primary cutaneous or non-cutaneous melanoma.	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (199, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('mutation', 'Var', (91, 99))	('BRAF', 'Gene', '673', (86, 90))	('patients', 'Species', '9606', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('primary cutaneous', 'Disease', (178, 195))	('BRAF', 'Gene', (86, 90))	('non-cutaneous melanoma', 'Disease', (199, 221))
11443	23110010	This will enable us to identify more accurate frequency of the alterations of each gene, to improve an understanding of the molecular pathogenesis of melanoma and to develop new diagnostic/prognostic markers and targeted drug therapies.	('alterations', 'Var', (63, 74))	('pathogenesis', 'biological_process', 'GO:0009405', ('134', '146'))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))
11483	33753855	Genetic mutations can generate tumor neoantigens that stimulate the immune response and enhance the response to ICIs.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('immune response', 'biological_process', 'GO:0006955', ('68', '83'))	('tumor', 'Disease', (31, 36))	('immune response', 'CPA', (68, 83))	('Genetic mutations', 'Var', (0, 17))	('stimulate', 'PosReg', (54, 63))	('response to ICIs', 'MPA', (100, 116))	('enhance', 'PosReg', (88, 95))
11500	33753855	We then generated the risk curve and scatterplot for the TIR risk score and the survival status of individual SKCM patients in the TCGA cohort, finding that the risk coefficient and mortality of patients with high TIR risk scores were higher than those with low TIR risk scores (Fig.	('patients', 'Species', '9606', (115, 123))	('higher', 'PosReg', (235, 241))	('mortality', 'Disease', 'MESH:D003643', (182, 191))	('high', 'Var', (209, 213))	('risk coefficient', 'MPA', (161, 177))	('patients', 'Species', '9606', (195, 203))	('mortality', 'Disease', (182, 191))
11502	33753855	To further validate the prognostic value of the TIR signature obtained from the TCGA melanoma cohort, we tested this signature in an independent melanoma dataset (GSE65904) (Supplementary Data 3), finding that patients with high TIR risk scores had worse OS, higher risk coefficient and mortality, and lower expression levels of SEL1L3, HAPLN3, BST2, and IFITM1 than those with low TIR risk scores (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('IFITM1', 'Gene', '8519', (355, 361))	('BST2', 'Gene', (345, 349))	('worse', 'PosReg', (249, 254))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('expression levels', 'MPA', (308, 325))	('higher', 'PosReg', (259, 265))	('IFITM1', 'Gene', (355, 361))	('patients', 'Species', '9606', (210, 218))	('risk coefficient', 'MPA', (266, 282))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('SEL1L3', 'Gene', (329, 335))	('mortality', 'Disease', (287, 296))	('SEL1L3', 'Gene', '23231', (329, 335))	('lower', 'NegReg', (302, 307))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('BST2', 'Gene', '684', (345, 349))	('HAPLN3', 'Gene', '145864', (337, 343))	('men', 'Species', '9606', (180, 183))	('HAPLN3', 'Gene', (337, 343))	('high', 'Var', (224, 228))	('mortality', 'Disease', 'MESH:D003643', (287, 296))
11516	33753855	The risk curve and scatterplot of this cohort demonstrated that the risk coefficient and mortality of patients with high TIR risk scores were higher than those with low TIR risk scores (Fig.	('mortality', 'Disease', 'MESH:D003643', (89, 98))	('high', 'Var', (116, 120))	('patients', 'Species', '9606', (102, 110))	('risk coefficient', 'MPA', (68, 84))	('mortality', 'Disease', (89, 98))	('higher', 'PosReg', (142, 148))
11520	33753855	There was no significant difference in SEL1L3 and HAPLN3 gene expression levels between the mutated group and the wild-type group (Fig.	('SEL1L3', 'Gene', (39, 45))	('SEL1L3', 'Gene', '23231', (39, 45))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('mutated', 'Var', (92, 99))	('HAPLN3', 'Gene', (50, 56))	('HAPLN3', 'Gene', '145864', (50, 56))
11523	33753855	6h), suggesting that DNA hypermethylation may underlie the underexpression of BST and IFITM1 in the L subtype (low immunity, high risk).	('hypermethylation', 'Var', (25, 41))	('IFITM1', 'Gene', '8519', (86, 92))	('IFITM1', 'Gene', (86, 92))	('BST', 'Gene', (78, 81))	('DNA', 'cellular_component', 'GO:0005574', ('21', '24'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('21', '41'))
11524	33753855	Consistently, patients with IFITM1 or BST2 hypermethylation, but not SEL1L3 or HAPLN3 hypermethylation, had significantly worse OS than the hypomethylation groups (Supplementary Fig.	('IFITM1', 'Gene', '8519', (28, 34))	('SEL1L3', 'Gene', '23231', (69, 75))	('HAPLN3', 'Gene', '145864', (79, 85))	('men', 'Species', '9606', (170, 173))	('HAPLN3', 'Gene', (79, 85))	('BST2', 'Gene', '684', (38, 42))	('hypermethylation', 'Var', (43, 59))	('patients', 'Species', '9606', (14, 22))	('SEL1L3', 'Gene', (69, 75))	('IFITM1', 'Gene', (28, 34))	('BST2', 'Gene', (38, 42))
11540	33753855	Interestingly, a recent study revealed an association between aberrant methylation of IFITM1 and poor disease-specific survival in patients with acral melanoma, an aggressive type of cutaneous melanoma.	('patients', 'Species', '9606', (131, 139))	('IFITM1', 'Gene', (86, 92))	('disease-specific survival', 'CPA', (102, 127))	('IFITM1', 'Gene', '8519', (86, 92))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('cutaneous melanoma', 'Disease', (183, 201))	('acral melanoma', 'Disease', 'MESH:D008545', (145, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (183, 201))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (183, 201))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('acral melanoma', 'Phenotype', 'HP:0012060', (145, 159))	('aberrant methylation', 'Var', (62, 82))	('acral melanoma', 'Disease', (145, 159))	('poor', 'NegReg', (97, 101))
11604	31749765	Similarly, QUICKI showed a negative correlation with a BMI both in the melanoma (r = -0.39, p < 0.001) and in the control group (r = -0.28, p < 0.001).	('negative', 'NegReg', (27, 35))	('QUICKI', 'Var', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))
11608	31749765	In the whole population, QUICKI resulted to be inversely correlated with insulinemia (r = -0.76, p < 0.0001), weight (r = -0.31, p < 0.0001), but not with glycaemia (r = -0.07, P = 0.25), sex (chi2 test, p = 0.63), age (r = 0.03, p = 0.60), and height (r = -0.06, p = 0.36).	('glycaemia', 'Disease', (155, 164))	('QUICKI', 'Var', (25, 31))	('insulinemia', 'Disease', (73, 84))	('correlated', 'Interaction', (57, 67))	('glycaemia', 'Disease', 'None', (155, 164))	('insulinemia', 'Disease', 'None', (73, 84))	('weight', 'MPA', (110, 116))
11626	31749765	Similarly, QUICKY values were strongly inversely correlated with insulinaemia (r = -0.76, p < 0.0001) and weight (r = -0.31, p < 0.0001), but not with the other variables considered.	('inversely', 'NegReg', (39, 48))	('insulinaemia', 'Disease', 'None', (65, 77))	('QUICKY', 'Var', (11, 17))	('correlated', 'Interaction', (49, 59))	('weight', 'Disease', (106, 112))	('insulinaemia', 'Disease', (65, 77))
11639	31749765	Alternatively, unbalances of the insulin/IGF-1/IGF-2 signaling pathways might be more important for the progression of the disease in its later stages.	('unbalances', 'Var', (15, 25))	('insulin', 'Gene', (33, 40))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('important', 'Reg', (86, 95))	('insulin', 'Gene', '3630', (33, 40))	('insulin', 'molecular_function', 'GO:0016088', ('33', '40'))	('IGF-1', 'Gene', '3479', (41, 46))	('IGF-2', 'Gene', (47, 52))	('IGF-1', 'Gene', (41, 46))	('IGF-2', 'Gene', '3481', (47, 52))
11667	30148988	Revisiting the clinical and biologic relevance of partial PTEN loss in melanoma The extent of PTEN loss that confers clinical and biological impact in melanoma is unclear.	('PTEN', 'Gene', '5728', (58, 62))	('PTEN', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma', 'Disease', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('loss', 'NegReg', (63, 67))	('partial', 'Var', (50, 57))	('PTEN', 'Gene', (58, 62))
11672	30148988	PTEN genomic alterations (deletion, mutation), promoter methylation, and protein destabilization did not fully explain PTEN loss in melanoma, whereas PTEN levels increased with treatment of melanoma cells with the histone deacetylase inhibitor LBH589.	('loss', 'NegReg', (124, 128))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('LBH', 'Gene', '81606', (244, 247))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('histone deacetylase', 'Gene', (214, 233))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('increased', 'PosReg', (162, 171))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('levels', 'MPA', (155, 161))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('PTEN', 'Gene', (119, 123))	('PTEN', 'MPA', (150, 154))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('LBH', 'Gene', (244, 247))	('protein destabilization', 'biological_process', 'GO:0031648', ('73', '96'))	('histone deacetylase', 'Gene', '9734', (214, 233))	('mutation', 'Var', (36, 44))
11673	30148988	Our data indicate that partial PTEN loss is due to modifiable epigenetic mechanisms and drives Akt activation and worse prognosis, suggesting a potential approach to improve the clinical outcome for a subset of advanced melanoma patients.	('patients', 'Species', '9606', (229, 237))	('Akt', 'Gene', '207', (95, 98))	('loss', 'NegReg', (36, 40))	('partial PTEN', 'Var', (23, 35))	('Akt', 'Gene', (95, 98))	('activation', 'PosReg', (99, 109))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma', 'Disease', (220, 228))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))
11684	30148988	What is the clinical and biological impact of partial PTEN loss in melanoma, and is there a significant threshold for reduced PTEN dosage?	('partial PTEN', 'Var', (46, 58))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('loss', 'NegReg', (59, 63))
11693	30148988	Activating BRAF and NRAS mutations were identified in 44.1% and 23.0% of tumors, respectively, consistent with their reported prevalence.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('NRAS', 'Gene', (20, 24))	('tumors', 'Disease', (73, 79))	('NRAS', 'Gene', '4893', (20, 24))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
11699	30148988	Several tumors with detectable PTEN expression using D4.3 or EPR9941-2 antibodies had absent PTEN staining using the 6H2.1 antibody.	('antibody', 'cellular_component', 'GO:0042571', ('123', '131'))	('EPR9941-2 antibodies', 'Var', (61, 81))	('antibody', 'cellular_component', 'GO:0019815', ('123', '131'))	('D4.3', 'Var', (53, 57))	('antibody', 'cellular_component', 'GO:0019814', ('123', '131'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('Several tumors', 'Disease', (0, 14))	('Several tumors', 'Disease', 'MESH:D009369', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('antibody', 'molecular_function', 'GO:0003823', ('123', '131'))	('PTEN', 'Protein', (31, 35))
11701	30148988	While BRAF mutations have been associated with loss of PTEN expression in primary melanoma, we did not observe a significant association between BRAF or NRAS mutation status and PTEN expression in our cohort (Table 1 and Supplementary Figure 3).	('expression', 'MPA', (60, 70))	('mutations', 'Var', (11, 20))	('BRAF', 'Gene', (145, 149))	('NRAS', 'Gene', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('BRAF', 'Gene', (6, 10))	('loss', 'NegReg', (47, 51))	('NRAS', 'Gene', '4893', (153, 157))	('BRAF', 'Gene', '673', (6, 10))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('Su', 'Chemical', 'MESH:C035067', (221, 223))	('PTEN', 'Protein', (55, 59))	('BRAF', 'Gene', '673', (145, 149))
11720	30148988	PTEN loss in melanoma has been attributed to gene deletions and mutations.	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('loss', 'NegReg', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('mutations', 'Var', (64, 73))	('PTEN', 'Gene', (0, 4))
11724	30148988	Complete PTEN deletion was identified in 5/48 (10.4%) of tumors and 1/17 (5.9%) of STCs, and hemizygous PTEN deletions in 13/48 (27.1%) of tumors and 6/17 (35.3%) of STCs (Figure 2A; data not shown for melanoma STCs).	('deletions', 'Var', (109, 118))	('PTEN', 'Gene', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('tumors', 'Disease', (139, 145))	('melanoma', 'Disease', (202, 210))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (57, 63))	('deletion', 'Var', (14, 22))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('PTEN', 'Gene', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
11726	30148988	18/287 tumors (6.3%) had deep PTEN deletions, and 24/87 tumors (8.4%) carried PTEN mutations (Figure 2B).	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('deep PTEN deletions', 'Var', (25, 44))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
11727	30148988	In contrast, deep PTEN deletions were observed in 150/242 (62.0%) of uterine tumors (UCEC), while 84/273 (30.8%) of glioblastomas (GBM) harbored PTEN mutations.	('tumors', 'Disease', (77, 83))	('deletions', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('GBM', 'Phenotype', 'HP:0012174', (131, 134))	('PTEN', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('glioblastomas', 'Phenotype', 'HP:0012174', (116, 129))	('PTEN', 'Gene', (145, 149))	('uterine tumors', 'Phenotype', 'HP:0010784', (69, 83))	('GBM', 'Disease', (131, 134))	('glioblastomas', 'Disease', (116, 129))	('glioblastomas', 'Disease', 'MESH:D005909', (116, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (150, 159))	('deep', 'Var', (13, 17))	('observed', 'Reg', (38, 46))	('GBM', 'Disease', 'MESH:D005909', (131, 134))
11728	30148988	Thus, genomic PTEN alterations are common in specific tumor types, but are relatively uncommon in melanoma and cannot explain the high frequency of PTEN loss.	('PTEN', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('alterations', 'Var', (19, 30))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
11729	30148988	PTEN transcriptional silencing by promoter hypermethylation has been reported in several cancer types, including melanoma.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('cancer', 'Disease', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('transcriptional', 'MPA', (5, 20))	('promoter hypermethylation', 'Var', (34, 59))	('PTEN', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
11743	30148988	Several reports suggest that PTEN function in cancers can be disrupted by aberrant activity of ubiquitin ligases and proteases that control PTEN protein stability.	('activity', 'MPA', (83, 91))	('function', 'MPA', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('PTEN', 'Gene', (29, 33))	('cancers', 'Disease', (46, 53))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('95', '104'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('ubiquitin', 'Protein', (95, 104))	('aberrant', 'Var', (74, 82))
11745	30148988	MG132 treatment (10 muM) rapidly induced expression of p27, an unstable protein that is rapidly degraded in cancer cell lines, but did not induce PTEN expression (Figure 3B; data not shown for SKMEL28 cells).	('MG132', 'Var', (0, 5))	('SKMEL28', 'CellLine', 'CVCL:0526', (193, 200))	('expression', 'MPA', (41, 51))	('induced', 'Reg', (33, 40))	('p27', 'Gene', '3429', (55, 58))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('p27', 'Gene', (55, 58))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
11750	30148988	These data are inconsistent with our observation that partial PTEN loss is associated with worse OS and Akt hyperactivation, and cannot be reconciled with PTEN functioning as a haploinsufficient tumor suppressor.	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (177, 200))	('partial', 'Var', (54, 61))	('Akt', 'Gene', (104, 107))	('haploinsufficient tumor', 'Disease', (177, 200))	('Akt', 'Gene', '207', (104, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('195', '211'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('195', '211'))	('loss', 'NegReg', (67, 71))	('worse', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
11753	30148988	We used the same RPPA platform to assess the relationship between PTEN dosage and Akt activity in melanoma cells with titrated PTEN knockdown, and in two large, independent melanoma cohorts (TCGA and Wistar PDX studies).	('knockdown', 'Var', (132, 141))	('Akt', 'Gene', '207', (82, 85))	('activity', 'MPA', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('Akt', 'Gene', (82, 85))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('PTEN', 'Gene', (127, 131))
11755	30148988	Data from our NYU cohort and TCGA suggest that PTEN mutations and deletions are relatively uncommon in melanoma and hence PTEN loss cannot be fully explained by genomic events.	('mutations', 'Var', (52, 61))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('PTEN', 'Gene', (47, 51))	('deletions', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
11756	30148988	Despite this, early reports suggested that PTEN disruption in melanoma cell lines was mediated by deletion or mutation, although parallel analysis of 49 matched melanoma/normal tissues found hemizygous PTEN deletions in 10 tumors (20%) and a single PTEN mutation, suggesting that genomic PTEN alterations are more common in cultured cells than non-cultured melanoma tissues.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('melanoma', 'Phenotype', 'HP:0002861', (357, 365))	('melanoma', 'Disease', (357, 365))	('PTEN', 'Gene', (202, 206))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('PTEN', 'Gene', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('disruption', 'NegReg', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('mutation', 'Var', (110, 118))	('melanoma', 'Disease', 'MESH:D008545', (357, 365))	('deletions', 'Var', (207, 216))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('deletion', 'Var', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
11758	30148988	PTEN promoter hypermethylation has also been associated with loss of PTEN in melanoma.	('promoter hypermethylation', 'Var', (5, 30))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('loss', 'NegReg', (61, 65))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', (69, 73))
11760	30148988	Interestingly, Roh and coworkers found PTEN promoter hypermethylation was independently associated with worse OS in Korean and TCGA melanoma cohorts, yet paradoxically PTEN mRNA expression was not correlated with PTEN methylation.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('methylation', 'biological_process', 'GO:0032259', ('218', '229'))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('worse OS', 'Disease', (104, 112))	('promoter hypermethylation', 'Var', (44, 69))	('PTEN', 'Gene', (39, 43))	('associated', 'Reg', (88, 98))
11762	30148988	Furthermore, Hesson and coworkers concluded that PTEN hypermethylation is rare in tumor cell lines and can be attributed to hypermethylation of PTENP1, a PTEN pseudogene sharing 91% identity with the PTEN promoter.	('hypermethylation', 'Var', (124, 140))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PTENP1', 'Gene', (144, 150))	('PTENP1', 'Gene', '11191', (144, 150))	('tumor', 'Disease', (82, 87))
11778	30148988	The importance of histone deacetylation to PTEN deregulation in melanoma supports the testing of combinations of immune checkpoint inhibitors and HDACi.	('HDAC', 'Gene', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('deregulation', 'Var', (48, 60))	('HDAC', 'Gene', '9734', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('histone deacetylation', 'biological_process', 'GO:0016575', ('18', '39'))
11792	30148988	Melanoma cell lines SKMEL19, SKMEL28, SKMEL103, SKMEL147, SKMEL173, SKMEL192 and SKMEL239 were from Memorial Sloan-Kettering Cancer Center (New York, NY).	('SKMEL103', 'CellLine', 'CVCL:6069', (38, 46))	('SKMEL19', 'CellLine', 'CVCL:6025', (20, 27))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('SKMEL192', 'CellLine', 'CVCL:6101', (68, 76))	('SKMEL28', 'CellLine', 'CVCL:0526', (29, 36))	('Melanoma', 'Disease', (0, 8))	('SKMEL173', 'CellLine', 'CVCL:6090', (58, 66))	('SKMEL147', 'CellLine', 'CVCL:3876', (48, 56))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SKMEL19', 'CellLine', 'CVCL:6025', (68, 75))	('SKMEL239', 'CellLine', 'CVCL:6122', (81, 89))	('SKMEL173', 'Var', (58, 66))
11799	30148988	The following antibodies (Cell Signaling Technology, Danvers, MA) were used: PTEN (D4.3 XP Rabbit mAb #9188), Total Akt (pan) (C67E7 Rabbit mAb #4691), Phospho-Akt (Ser473) (D9E XP Rabbit mAb #4060), p21 (12D1 Rabbit mAb #2947), p27 (D69C12 XP Rabbit mAb #3686), HSP90 (C45G5 Rabbit mAb #4877), and goat anti-rabbit IgG-HRP (#7074).	('Akt', 'Gene', '207', (160, 163))	('Signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('Ser', 'cellular_component', 'GO:0005790', ('165', '168'))	('p21', 'Gene', (200, 203))	('p27', 'Gene', '3429', (229, 232))	('p27', 'Gene', (229, 232))	('HSP90', 'Gene', '3320', (263, 268))	('Ser473', 'Chemical', 'MESH:C530429', (165, 171))	('Akt', 'Gene', (116, 119))	('Rabbit', 'Species', '9986', (276, 282))	('p21', 'Gene', '1026', (200, 203))	('Akt', 'Gene', '207', (116, 119))	('#7074', 'Var', (325, 330))	('Rabbit', 'Species', '9986', (133, 139))	('Rabbit', 'Species', '9986', (181, 187))	('rabbit', 'Species', '9986', (309, 315))	('Rabbit', 'Species', '9986', (244, 250))	('C45G5 Rabbit', 'Var', (270, 282))	('Rabbit', 'Species', '9986', (91, 97))	('Phospho', 'Chemical', 'MESH:C033601', (152, 159))	('Akt', 'Gene', (160, 163))	('Rabbit', 'Species', '9986', (210, 216))	('HSP90', 'Gene', (263, 268))
11807	33707472	Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.	('associations', 'Interaction', (122, 134))	('DNA methylation', 'biological_process', 'GO:0006306', ('92', '107'))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('survival time', 'CPA', (158, 171))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('gene expression', 'biological_process', 'GO:0010467', ('198', '213'))	('cancer', 'Disease', (16, 22))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
11809	33707472	This is likely because checkpoint inhibitors work by reinvigorating a pre-existing tumor immune response, which can be characterized by the cell types and the extent of immune cell infiltration in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('checkpoint', 'Gene', (23, 33))	('pre', 'molecular_function', 'GO:0003904', ('70', '73'))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (83, 88))	('inhibitors', 'Var', (34, 44))	('reinvigorating', 'PosReg', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('immune response', 'biological_process', 'GO:0006955', ('89', '104'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (197, 202))
11847	33707472	This is because larger  makes it easier for EMeth to separate the aberrant CpGs from the consistent ones and thus appropriately down-weighs their contributions to the final estimates.	('aberrant', 'Var', (66, 74))	('down-weighs', 'NegReg', (128, 139))	('EMeth', 'Chemical', '-', (44, 49))
11850	33707472	We also conducted additional simulations where the proportion of aberrant CpG probes varies from 5 to 35% and reached the same conclusion that EMeth consistently outperforms all the other methods (Supplementary Table S3).	('CpG', 'Gene', (74, 77))	('EMeth', 'Chemical', '-', (143, 148))	('aberrant', 'Var', (65, 73))
11871	33707472	A tumor cell with higher mutation burden may present more mutated peptides on its cell surface, and thus has higher chance to be recognized by the immune system.	('more', 'PosReg', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('higher', 'PosReg', (109, 115))	('mutation', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('mutated peptides', 'MPA', (58, 74))	('tumor', 'Disease', (2, 7))	('cell surface', 'cellular_component', 'GO:0009986', ('82', '94'))
11874	33707472	We observe that CD8T cells proportions (either the ones estimated using gene expression/CIBERSORTx or DNA methylation/EMeth) are indeed higher in the hypermutated subset (Fig.	('higher', 'PosReg', (136, 142))	('hypermutated', 'Var', (150, 162))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('EMeth', 'Chemical', '-', (118, 123))	('CD8', 'Gene', (16, 19))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))	('CD8', 'Gene', '925', (16, 19))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
11891	33707472	In fact, the Treg proportion estimates using LM22 has stronger correlation with SF11 estimates in 3 other cell types (correlation 0.74, 0.55, and 0.54 for B cells, CD4T, and monocyte, respectively) than with Treg itself (correlation 0.5).	('CD4', 'Gene', '920', (164, 167))	('Treg', 'Chemical', '-', (208, 212))	('Treg', 'Chemical', '-', (13, 17))	('correlation', 'Interaction', (63, 74))	('LM22', 'Var', (45, 49))	('LM22', 'CellLine', 'CVCL:5998', (45, 49))	('CD4', 'Gene', (164, 167))
11892	33707472	The Treg proportion estimates using either SF11 or LM22 have negative correlations with EMeth estimates (correlation -0.18 and -0.2 for SF11 and LM22 estimates, respectively, Figure S41).	('LM22', 'CellLine', 'CVCL:5998', (145, 149))	('correlations', 'Interaction', (70, 82))	('negative', 'NegReg', (61, 69))	('Treg', 'Chemical', '-', (4, 8))	('SF11', 'Var', (43, 47))	('LM22', 'CellLine', 'CVCL:5998', (51, 55))	('LM22', 'Var', (51, 55))	('EMeth', 'Chemical', '-', (88, 93))
12055	29229974	In particular, we emphasized pseudogenes potentially relevant to this cancer.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('pseudogenes', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
12060	29229974	One of the first discovery efforts in melanoma transcriptome studies revealed the emergence of genomic rearrangements behind novel gene fusions and identified somatic mutations responsible for disease progression.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('fusions', 'Var', (136, 143))	('melanoma', 'Disease', (38, 46))
12064	29229974	Following the seminal findings of two large-scale projects, ENCODE (https://www.encodeproject.org/) and GENCODE (http://www.gencodegenes.org/), the general attention has been gradually diverted away from genes and concentrated over other biotypes, such as long intergenic ncRNAs (lincRNAs), antisense RNAs, pseudogenes etc.	('ncRNA', 'Gene', '220202', (282, 287))	('antisense', 'Var', (291, 300))	('ncRNA', 'Gene', (272, 277))	('ncRNA', 'Gene', (282, 287))	('ncRNA', 'Gene', '220202', (272, 277))
12073	29229974	A recent large-scale analysis of pseudogene transcription in 13 cancer types (248 cancer samples, and 45 normal samples) showed the signature of 2082 distinct pseudogenes.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('pseudogenes', 'Var', (159, 170))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('transcription', 'biological_process', 'GO:0006351', ('44', '57'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
12079	29229974	By preserving proportions between LRM-selected regions and consensus ones, it clearly shows that LRM reduces enormously data redundancies, and likely also data complexities related to the algorithmic errors, noise effects, spurious detections etc.	('LRM', 'Var', (97, 100))	('algorithmic errors', 'Disease', (188, 206))	('algorithmic errors', 'Disease', 'MESH:D012030', (188, 206))	('reduces', 'NegReg', (101, 108))	('data redundancies', 'MPA', (120, 137))
12094	29229974	The mutated BRAF is V600E in 70-80% of all BRAF mutations in all cancers.	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('V600E', 'Var', (20, 25))
12096	29229974	Mutations in NRAS, occurring at limited frequency compared to BRAF, were considered too.	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('NRAS', 'Gene', '4893', (13, 17))
12097	29229974	We accounted for the fact that approximately 50% of melanomas of all clinical types present an activating mutation in the BRAF oncogene, while about 20% of the cases show an activating mutation in NRAS, leading to the activation of the MAPK signaling pathway (cellular proliferation and survival depend on such pathway).	('MAPK', 'Gene', (236, 240))	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('activating', 'PosReg', (174, 184))	('activation', 'PosReg', (218, 228))	('BRAF', 'Gene', '673', (122, 126))	('signaling pathway', 'biological_process', 'GO:0007165', ('241', '258'))	('mutation', 'Var', (106, 114))	('NRAS', 'Gene', (197, 201))	('mutation', 'Var', (185, 193))	('MAPK', 'molecular_function', 'GO:0004707', ('236', '240'))	('BRAF', 'Gene', (122, 126))	('melanomas', 'Disease', (52, 61))	('MAPK signaling', 'biological_process', 'GO:0000165', ('236', '250'))	('NRAS', 'Gene', '4893', (197, 201))	('MAPK', 'Gene', '5594', (236, 240))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('activating', 'PosReg', (95, 105))
12098	29229974	Previously, whole-genome sequencing of 25 metastatic melanomas and matched germline DNA revealed 11 genes significantly mutated, for BRAF in 16 samples and for NRAS in 9 samples.	('melanomas', 'Disease', (53, 62))	('NRAS', 'Gene', (160, 164))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('BRAF', 'Gene', '673', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('NRAS', 'Gene', '4893', (160, 164))	('BRAF', 'Gene', (133, 137))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('mutated', 'Var', (120, 127))
12100	29229974	Non-synonymous mutations on V600 of BRAF were detected on 57 cases, but 19 were then discarded due to the low sequencing depth (<5x) on the mutation site, thus remaining with 38 cases.	('BRAF', 'Gene', '673', (36, 40))	('BRAF', 'Gene', (36, 40))	('V600', 'Var', (28, 32))	('detected', 'Reg', (46, 54))
12101	29229974	Non-synonymous mutations on Q61 of NRAS were detected on 17 cases, but 2 were then discarded due to the low sequencing depth (<5x) on the mutation site, thus remaining with 15 cases.	('detected', 'Reg', (45, 53))	('NRAS', 'Gene', '4893', (35, 39))	('NRAS', 'Gene', (35, 39))	('Non-synonymous mutations', 'Var', (0, 24))
12102	29229974	Also, 33 cases have revealed no mutation on either V600 of BRAF or Q61 of NRAS, thus making the mutation-free group.	('NRAS', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (74, 78))	('V600', 'Var', (51, 55))	('Q61', 'Var', (67, 70))
12116	29229974	In biotypes (Table 2) we list ENSEMBL classes, and we may note the prevalence of antisense, lincRNA and pseudogenes over the other classes, with exclusion of protein coding genes (parental genes are a subset of them, reported apart to emphasize their target role).	('ncRNA', 'Gene', '220202', (94, 99))	('pseudogenes', 'Var', (104, 115))	('antisense', 'Var', (81, 90))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('ncRNA', 'Gene', (94, 99))
12134	29229974	Considering another scale, it has been demonstrated a combined regulative action of pseudogenes over a miRNA target, the tumor suppressor gene PTEN expression, through the mechanism known as ceRNA (competing endogenous RNA).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('121', '137'))	('RNA', 'cellular_component', 'GO:0005562', ('219', '222'))	('tumor', 'Disease', (121, 126))	('tumor suppressor', 'biological_process', 'GO:0051726', ('121', '137'))	('combined', 'Interaction', (54, 62))	('PTEN', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (143, 147))	('pseudogenes', 'Var', (84, 95))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
12164	31788049	Interleukin 1 receptor antagonist gene variable number of tandem repeats polymorphism and cutaneous melanoma Immunity and cytokines serve crucial roles in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (90, 108))	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('Interleukin 1', 'Gene', '3552', (0, 13))	('Interleukin 1', 'Gene', (0, 13))	('variable number of tandem repeats polymorphism', 'Var', (39, 85))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))
12165	31788049	The present study investigated whether a variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RA) gene (IL-1RN) located in intron 2 (rs2234663) is associated with cutaneous melanoma.	('cutaneous melanoma', 'Disease', (202, 220))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (202, 220))	('interleukin-1 receptor antagonist', 'Gene', (94, 127))	('interleukin-1 receptor antagonist', 'Gene', '3557', (94, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (202, 220))	('IL-1RN', 'Gene', '3557', (143, 149))	('IL-1RN', 'Gene', (143, 149))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('associated', 'Reg', (186, 196))	('rs2234663', 'Mutation', 'rs2234663', (172, 181))	('rs2234663', 'Var', (172, 181))	('IL-1RA', 'molecular_function', 'GO:0005152', ('129', '135'))	('IL-1', 'molecular_function', 'GO:0005149', ('143', '147'))
12168	31788049	According to the number of 86-bp repeats, five different IL-1RN alleles were identified: Allele 1 (4-repeats), allele 2 (2-repeats, short allele), allele 3 (5-repeats), allele 4 (3-repeats) and allele 5 (6-repeats).	('4-repeats', 'Var', (99, 108))	('IL-1RN', 'Gene', (57, 63))	('5-repeats', 'Var', (157, 166))	('3-repeats', 'Var', (179, 188))	('IL-1RN', 'Gene', '3557', (57, 63))	('2-repeats', 'Var', (121, 130))	('IL-1', 'molecular_function', 'GO:0005149', ('57', '61'))
12172	31788049	The present study first demonstrated that carriage of the 1/1 IL-1RN-VNTR genotype was protective, whereas 1/2 and 2/L was a risk factor for patients with cutaneous melanoma vs. healthy controls.	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('IL-1', 'molecular_function', 'GO:0005149', ('62', '66'))	('IL-1RN', 'Gene', '3557', (62, 68))	('IL-1RN', 'Gene', (62, 68))	('carriage', 'Var', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('patients', 'Species', '9606', (141, 149))
12173	31788049	The short allele 2 was associated with higher expression levels of IL-1RA, a potent competitive inhibitor of the proinflammatory cytokines IL-1alpha and IL-1beta.	('IL-1', 'molecular_function', 'GO:0005149', ('139', '143'))	('higher', 'PosReg', (39, 45))	('IL-1alpha', 'Gene', (139, 148))	('expression levels', 'MPA', (46, 63))	('IL-1', 'molecular_function', 'GO:0005149', ('153', '157'))	('IL-1RA', 'Gene', (67, 73))	('IL-1RA', 'molecular_function', 'GO:0005152', ('67', '73'))	('IL-1alpha', 'Gene', '3552', (139, 148))	('short', 'Var', (4, 9))
12174	31788049	VNTR-IL-1RN polymorphism may affect susceptibility to melanoma and, thus, it is a potential novel diagnostic biomarker for melanoma.	('IL-1RN', 'Gene', '3557', (5, 11))	('IL-1', 'molecular_function', 'GO:0005149', ('5', '9'))	('IL-1RN', 'Gene', (5, 11))	('affect', 'Reg', (29, 35))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('polymorphism', 'Var', (12, 24))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('susceptibility', 'MPA', (36, 50))
12186	31788049	Specifically, IL-1 cytokines promote increased levels of the main chemokine IL-8 (CXCL8) and consequently activate recruitment of neutrophils.	('IL-8', 'molecular_function', 'GO:0005153', ('76', '80'))	('IL-1', 'Gene', '3552', (14, 18))	('IL-1', 'molecular_function', 'GO:0005149', ('14', '18'))	('activate', 'PosReg', (106, 114))	('IL-1', 'Gene', (14, 18))	('cytokines', 'Var', (19, 28))	('recruitment of neutrophils', 'MPA', (115, 141))	('increased', 'PosReg', (37, 46))	('IL-8', 'Gene', '3576', (76, 80))	('CXCL8', 'Gene', '3576', (82, 87))	('levels of the', 'MPA', (47, 60))	('CXCL8', 'Gene', (82, 87))	('IL-8', 'Gene', (76, 80))
12189	31788049	Furthermore, blocking IL-1 receptor with IL-1RA or anti-IL-1R1 antibody inhibits tumor growth and metastasis accompanied by decreased accumulation of myeloid cells and expression of the PD-L1 molecule.	('IL-1R', 'molecular_function', 'GO:0004908', ('56', '61'))	('IL-1', 'Gene', (56, 60))	('IL-1RA', 'molecular_function', 'GO:0005152', ('41', '47'))	('inhibits', 'NegReg', (72, 80))	('antibody', 'cellular_component', 'GO:0019815', ('63', '71'))	('IL-1', 'Gene', '3552', (22, 26))	('blocking', 'Var', (13, 21))	('expression', 'MPA', (168, 178))	('IL-1', 'Gene', (22, 26))	('antibody', 'cellular_component', 'GO:0019814', ('63', '71'))	('tumor', 'Disease', (81, 86))	('IL-1', 'molecular_function', 'GO:0005149', ('22', '26'))	('IL-1', 'Gene', '3552', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('antibody', 'molecular_function', 'GO:0003823', ('63', '71'))	('PD-L1', 'Gene', (186, 191))	('IL-1', 'Gene', (41, 45))	('accumulation', 'PosReg', (134, 146))	('antibody', 'cellular_component', 'GO:0042571', ('63', '71'))	('IL-1', 'Gene', '3552', (56, 60))	('PD-L1', 'Gene', '29126', (186, 191))	('decreased', 'NegReg', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
12195	31788049	Increasing evidence showed that genetic polymorphisms of IL-1 family members can affect susceptibility to disease.	('genetic polymorphisms', 'Var', (32, 53))	('susceptibility', 'MPA', (88, 102))	('affect', 'Reg', (81, 87))	('IL-1', 'Gene', (57, 61))	('IL-1', 'Gene', '3552', (57, 61))	('IL-1', 'molecular_function', 'GO:0005149', ('57', '61'))
12200	31788049	So far, only one German study assessed the role of IL-1RN VNTR polymorphism in 97 melanoma patients and 343 controls.	('patients', 'Species', '9606', (91, 99))	('polymorphism', 'Var', (63, 75))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('IL-1', 'molecular_function', 'GO:0005149', ('51', '55'))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('IL-1RN', 'Gene', '3557', (51, 57))	('IL-1RN', 'Gene', (51, 57))
12218	31788049	The IL-1RN intron 2 VNTR polymorphism (rs2234663; also indicated as rs380092) was analyzed using 5'-CTCAGCAACACTCCTAT-3' and 5'-TCCTGGTCTGCAGGTAA-3' as primers.	('rs2234663', 'Mutation', 'rs2234663', (39, 48))	('rs2234663;', 'Var', (39, 49))	('IL-1RN', 'Gene', '3557', (4, 10))	('IL-1', 'molecular_function', 'GO:0005149', ('4', '8'))	('rs380092', 'Mutation', 'rs380092', (68, 76))	('IL-1RN', 'Gene', (4, 10))
12225	31788049	Conversely, heterozygous 1/2 genotype was almost twice more frequent in melanomas than in healthy patients (OR=1.84, P=0.003).	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('patients', 'Species', '9606', (98, 106))	('heterozygous', 'Var', (12, 24))	('melanomas', 'Disease', (72, 81))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
12234	31788049	No differences were noted between groups, however, the frequency of patients with a number of body nevi >50 tended to be higher in 2/L than non-2/L carriers (58.3% vs. 42.5%, OR=1.90, P=0.069).	('patients', 'Species', '9606', (68, 76))	('higher', 'PosReg', (121, 127))	('2/L', 'Var', (131, 134))	('nevi', 'Phenotype', 'HP:0003764', (99, 103))
12236	31788049	IL-1RA has been implicated in oncogenesis as mice deficient in IL-1RA develop the disease in response to carcinogens.	('deficient', 'Var', (50, 59))	('develop', 'PosReg', (70, 77))	('mice', 'Species', '10090', (45, 49))	('IL-1RA', 'molecular_function', 'GO:0005152', ('63', '69'))	('IL-1RA', 'Gene', (63, 69))	('oncogenesis', 'biological_process', 'GO:0007048', ('30', '41'))	('IL-1RA', 'molecular_function', 'GO:0005152', ('0', '6'))
12241	31788049	A general correlation between IL-1RN*2 allele and the presence of autoinflammatory disease strongly supports a role of VNTR IL-1RN polymorphism in the control of the inflammatory response.	('inflammatory response', 'biological_process', 'GO:0006954', ('166', '187'))	('IL-1', 'molecular_function', 'GO:0005149', ('30', '34'))	('IL-1RN', 'Gene', '3557', (30, 36))	('autoinflammatory disease', 'Disease', (66, 90))	('IL-1RN', 'Gene', (30, 36))	('polymorphism', 'Var', (131, 143))	('IL-1', 'molecular_function', 'GO:0005149', ('124', '128'))	('autoinflammatory disease', 'Phenotype', 'HP:0002960', (66, 90))	('IL-1RN', 'Gene', '3557', (124, 130))	('autoinflammatory disease', 'Disease', 'MESH:D056660', (66, 90))	('IL-1RN', 'Gene', (124, 130))
12250	31788049	However, we observed that among melanomas 58.3% of 2/L carries had more than 50 body nevi vs. 42.5% of non-2/L carriers OR=1.90, P=0.069.	('more than 50 body nevi', 'Phenotype', 'HP:0001054', (67, 89))	('melanomas', 'Disease', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('2/L', 'Var', (51, 54))	('melanomas', 'Disease', 'MESH:D008545', (32, 41))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))
12252	31788049	This study is the first investigation of VNTR IL-1RN polymorphism in Italian melanoma patients, and the second one on this polymorphism and melanoma after the study of Broer and colleagues.	('IL-1RN', 'Gene', (46, 52))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('polymorphism', 'Var', (53, 65))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('IL-1RN', 'Gene', '3557', (46, 52))	('patients', 'Species', '9606', (86, 94))
12260	31788049	The association of the VNTR IL-1RN polymorphism with cancer was examined by Zhang and colleagues who performed a meta-analysis including 14,854 cases and 19,337 controls from 71 published case-control studies.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('polymorphism', 'Var', (35, 47))	('IL-1RN', 'Gene', '3557', (28, 34))	('IL-1', 'molecular_function', 'GO:0005149', ('28', '32'))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('IL-1RN', 'Gene', (28, 34))
12265	31788049	It is apparent that further studies with large homogeneous patient populations will be needed to validate the association between VNTR IL-1RN gene polymorphism and human cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('polymorphism', 'Var', (147, 159))	('IL-1', 'molecular_function', 'GO:0005149', ('135', '139'))	('cancer', 'Disease', (170, 176))	('human', 'Species', '9606', (164, 169))	('patient', 'Species', '9606', (59, 66))	('association', 'Interaction', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('IL-1RN', 'Gene', '3557', (135, 141))	('IL-1RN', 'Gene', (135, 141))
12268	31788049	The presence of the IL-1RN*2 has been associated with enhanced IL-1beta production in vitro, and increased inflammatory response.	('IL-1', 'molecular_function', 'GO:0005149', ('20', '24'))	('increased', 'PosReg', (97, 106))	('inflammatory response', 'CPA', (107, 128))	('IL-1RN', 'Gene', '3557', (20, 26))	('IL-1beta production', 'biological_process', 'GO:0032611', ('63', '82'))	('IL-1RN', 'Gene', (20, 26))	('IL-1', 'molecular_function', 'GO:0005149', ('63', '67'))	('IL-1beta production', 'MPA', (63, 82))	('increased inflammatory response', 'Phenotype', 'HP:0012649', (97, 128))	('presence', 'Var', (4, 12))	('enhanced', 'PosReg', (54, 62))	('inflammatory response', 'biological_process', 'GO:0006954', ('107', '128'))
12271	31788049	A recent study showed that individuals with genotype 2/2 VNTR IL-1RN exhibited higher IL-1RA expression compared to 1/2 and 1/1 genotypes.	('IL-1RA expression', 'MPA', (86, 103))	('IL-1RA', 'molecular_function', 'GO:0005152', ('86', '92'))	('IL-1', 'molecular_function', 'GO:0005149', ('62', '66'))	('IL-1RN', 'Gene', '3557', (62, 68))	('IL-1RN', 'Gene', (62, 68))	('VNTR', 'Var', (57, 61))	('genotype 2/2 VNTR', 'Var', (44, 61))	('higher', 'PosReg', (79, 85))
12274	31788049	On the other hand, a study showed that blocking of IL-1R1 by treatment with IL-1R1 neutralizing antibody or IL-1 pathway-specific siRNAs led to growth arrest in IL-1-positive melanoma cells.	('IL-1', 'Gene', '3552', (108, 112))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('growth arrest', 'Phenotype', 'HP:0001510', (144, 157))	('melanoma', 'Disease', (175, 183))	('blocking', 'Var', (39, 47))	('growth arrest', 'CPA', (144, 157))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('IL-1', 'Gene', '3552', (51, 55))	('IL-1R', 'molecular_function', 'GO:0004908', ('76', '81'))	('IL-1', 'Gene', (108, 112))	('IL-1', 'Gene', '3552', (76, 80))	('IL-1', 'Gene', '3552', (161, 165))	('IL-1', 'Gene', (51, 55))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('IL-1', 'Gene', (76, 80))	('IL-1', 'molecular_function', 'GO:0005149', ('161', '165'))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('IL-1', 'molecular_function', 'GO:0005149', ('108', '112'))	('IL-1', 'Gene', (161, 165))	('IL-1R', 'molecular_function', 'GO:0004908', ('51', '56'))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))
12275	31788049	Furthermore, blocking the IL-1 pathway increased autophagy in IL-1-positive melanoma cells indicating that the endogenous IL-1 system is functional in most human melanoma and interrupting its signaling inhibits the growth of IL-1-positive melanoma cells.	('IL-1', 'Gene', '3552', (62, 66))	('autophagy', 'biological_process', 'GO:0006914', ('49', '58'))	('autophagy', 'CPA', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('blocking', 'Var', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('IL-1', 'Gene', (62, 66))	('IL-1', 'Gene', '3552', (225, 229))	('signaling', 'MPA', (192, 201))	('growth', 'CPA', (215, 221))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('IL-1', 'molecular_function', 'GO:0005149', ('26', '30'))	('IL-1', 'Gene', '3552', (122, 126))	('IL-1', 'molecular_function', 'GO:0005149', ('225', '229'))	('inhibits', 'NegReg', (202, 210))	('interrupting', 'Var', (175, 187))	('IL-1', 'molecular_function', 'GO:0005149', ('62', '66'))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('IL-1', 'Gene', (225, 229))	('IL-1', 'Gene', '3552', (26, 30))	('IL-1', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('autophagy', 'biological_process', 'GO:0016236', ('49', '58'))	('IL-1', 'molecular_function', 'GO:0005149', ('122', '126'))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('increased', 'PosReg', (39, 48))	('IL-1', 'Gene', (26, 30))	('human', 'Species', '9606', (156, 161))
12277	31788049	Such a hypothesis would fit with our present findings showing that 2/L genotype increases the risk to develop melanoma, but is not more frequent in metastatic than non-metastatic melanomas.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('melanomas', 'Disease', (179, 188))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanomas', 'Phenotype', 'HP:0002861', (179, 188))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanomas', 'Disease', 'MESH:D008545', (179, 188))	('melanoma', 'Disease', (179, 187))	('2/L', 'Var', (67, 70))
12281	31788049	Of note, anakinra (a recombinant form of IL-1RA used as an anti-inflammatory drug in certain diseases) or genetic inactivation of the IL-1beta-IL-1R1 system can lead to less melanoma growth in mice.	('less', 'NegReg', (169, 173))	('IL-1', 'molecular_function', 'GO:0005149', ('134', '138'))	('melanoma growth', 'Disease', (174, 189))	('melanoma growth', 'Disease', 'MESH:D008545', (174, 189))	('genetic inactivation', 'Var', (106, 126))	('IL-1RA', 'molecular_function', 'GO:0005152', ('41', '47'))	('IL-1R', 'molecular_function', 'GO:0004908', ('143', '148'))	('mice', 'Species', '10090', (193, 197))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))
12295	31788049	Our data highlighted that in terms of IL-1RN gene alteration by VNTR in intron 2, IL-1RA homeostasis plays roles in cutaneous melanoma.	('alteration', 'Var', (50, 60))	('IL-1RN', 'Gene', '3557', (38, 44))	('IL-1RN', 'Gene', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('homeostasis', 'biological_process', 'GO:0042592', ('89', '100'))	('cutaneous melanoma', 'Disease', (116, 134))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('IL-1', 'molecular_function', 'GO:0005149', ('38', '42'))	('IL-1RA', 'molecular_function', 'GO:0005152', ('82', '88'))
12298	31788049	Future studies should further explore IL-1RN polymorphisms for their inclusion in risk models for individualized prevention/susceptibility/prognosis in the practice of precision medicine applied in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('IL-1RN', 'Gene', '3557', (38, 44))	('cutaneous melanoma', 'Disease', (198, 216))	('polymorphisms', 'Var', (45, 58))	('IL-1RN', 'Gene', (38, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (198, 216))	('IL-1', 'molecular_function', 'GO:0005149', ('38', '42'))
12299	31788049	We first suggest that the heterozygous subjects having the short allele IL-1RN*2 are more prone to cutaneous malignant melanoma showing that (innate) immune mechanisms play a role in the susceptibility/pathogenesis of this cancer.	('IL-1', 'molecular_function', 'GO:0005149', ('72', '76'))	('short allele', 'Var', (59, 71))	('malignant melanoma', 'Disease', (109, 127))	('prone', 'Reg', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (99, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('IL-1RN', 'Gene', '3557', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('pathogenesis', 'biological_process', 'GO:0009405', ('202', '214'))	('cancer', 'Disease', (223, 229))	('IL-1RN', 'Gene', (72, 78))	('malignant melanoma', 'Phenotype', 'HP:0002861', (109, 127))	('malignant melanoma', 'Disease', 'MESH:D008545', (109, 127))
12304	31788049	Interestingly, in our study IL-1RN 2/L genotype appears to act as a risk factor for melanoma susceptibility independently by conventional risk factors for melanoma, with the possible exception of the elevated presence of nevi.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('genotype', 'Var', (39, 47))	('nevi', 'Phenotype', 'HP:0003764', (221, 225))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('IL-1RN', 'Gene', '3557', (28, 34))	('IL-1', 'molecular_function', 'GO:0005149', ('28', '32'))	('IL-1RN', 'Gene', (28, 34))	('risk factor', 'Reg', (68, 79))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))
12309	31788049	IL-1RA interleukin 1 receptor antagonist IL-1RN interleukin 1 receptor antagonist gene VNTR variable number of tandem repeats polymorphism FVG Friuli Venezia-Giulia MetM metastatic melanoma NMetM non-metastatic melanoma BMI body mass index TILs tumor infiltrating lymphocytes	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('polymorphism', 'Var', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Friuli Venezia-Giulia', 'Disease', (143, 164))	('IL-1RN', 'Gene', (41, 47))	('Friuli Venezia-Giulia', 'Disease', 'None', (143, 164))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('interleukin 1 receptor antagonist', 'Gene', (48, 81))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('interleukin 1 receptor antagonist', 'Gene', '3557', (48, 81))	('IL-1RA', 'molecular_function', 'GO:0005152', ('0', '6'))	('tumor', 'Disease', (245, 250))	('interleukin 1 receptor antagonist', 'Gene', (7, 40))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('FVG', 'Disease', 'None', (139, 142))	('IL-1RN', 'Gene', '3557', (41, 47))	('FVG', 'Disease', (139, 142))	('interleukin 1 receptor antagonist', 'Gene', '3557', (7, 40))	('IL-1', 'molecular_function', 'GO:0005149', ('41', '45'))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))
12310	27883956	Efficacy of BRAF Inhibitors in Asian Metastatic Melanoma Patients: Potential Implications of Genomic Sequencing in BRAF-Mutated Melanoma12 BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations.	('vemurafenib', 'Chemical', 'MESH:D000077484', (171, 182))	('V600 mutations', 'Var', (269, 283))	('Melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('Patients', 'Species', '9606', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('Melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('BRAF', 'Gene', '673', (155, 159))	('BRAF', 'Gene', '673', (115, 119))	('BRAF', 'Gene', (155, 159))	('dabrafenib', 'Chemical', 'MESH:C561627', (187, 197))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', (115, 119))	('BRAF', 'Gene', '673', (12, 16))	('Metastatic Melanoma', 'Disease', (37, 56))	('Metastatic Melanoma', 'Disease', 'MESH:D008545', (37, 56))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('BRAF', 'Gene', '673', (264, 268))	('BRAF', 'Gene', (264, 268))
12320	27883956	Targeted sequencing in five patients demonstrated NF1 mutations in three patients who did not respond to BRAF inhibitors.	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', (105, 109))	('NF1', 'Gene', (50, 53))	('mutations', 'Var', (54, 63))	('NF1', 'Gene', '4763', (50, 53))	('patients', 'Species', '9606', (28, 36))	('patients', 'Species', '9606', (73, 81))
12321	27883956	CONCLUSION: BRAF inhibitors were an effective therapeutic option for Korean patients with metastatic melanoma harboring a BRAF V600 mutation regardless of melanoma subtype (acral/mucosa versus cutaneous).	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('patients', 'Species', '9606', (76, 84))	('melanoma subtype', 'Disease', (155, 171))	('BRAF', 'Gene', (12, 16))	('V600 mutation', 'Var', (127, 140))	('melanoma', 'Disease', (101, 109))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', '673', (122, 126))	('melanoma subtype', 'Disease', 'MESH:D008545', (155, 171))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))
12326	27883956	For example, BRAF mutations commonly occur in cutaneous melanomas but are relatively uncommon in acral/mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mucosal melanomas', 'Disease', 'MESH:D008545', (103, 120))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('mucosal melanomas', 'Disease', (103, 120))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('occur', 'Reg', (37, 42))	('cutaneous melanomas', 'Disease', (46, 65))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('mutations', 'Var', (18, 27))
12327	27883956	BRAF mutations are discovered in approximately 50% of patients with malignant melanoma, and the BRAF V600E mutation is the most common (~80% of cases).	('V600E', 'Mutation', 'rs113488022', (101, 106))	('malignant melanoma', 'Disease', 'MESH:D008545', (68, 86))	('patients', 'Species', '9606', (54, 62))	('malignant melanoma', 'Disease', (68, 86))	('V600E', 'Var', (101, 106))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (0, 4))	('malignant melanoma', 'Phenotype', 'HP:0002861', (68, 86))
12328	27883956	The US Food and Drug Administration has approved single agents with vemurafenib, dabrafenib, and trametinib and the combination of dabrafenib and trametinib, vemurafenib, and cobimetinib in patients with unresectable or metastatic melanoma with a BRAF mutation.	('mutation', 'Var', (252, 260))	('BRAF', 'Gene', '673', (247, 251))	('dabrafenib', 'Chemical', 'MESH:C561627', (81, 91))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Disease', (231, 239))	('vemurafenib', 'Chemical', 'MESH:D000077484', (158, 169))	('patients', 'Species', '9606', (190, 198))	('BRAF', 'Gene', (247, 251))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('trametinib', 'Chemical', 'MESH:C560077', (97, 107))	('trametinib', 'Chemical', 'MESH:C560077', (146, 156))	('vemurafenib', 'Chemical', 'MESH:D000077484', (68, 79))	('dabrafenib', 'Chemical', 'MESH:C561627', (131, 141))	('unresectable', 'Disease', (204, 216))	('cobimetinib', 'Chemical', 'MESH:C574276', (175, 186))
12333	27883956	Numerous genetic and nongenetic alterations have been revealed, such as NRAS mutations, BRAF amplification, MEK1/2 mutations, and overexpression of COT or EGFR.	('amplification', 'Var', (93, 106))	('NRAS', 'Gene', (72, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('mutations', 'Var', (115, 124))	('EGFR', 'Gene', '1956', (155, 159))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('MEK1/2', 'Gene', '5604;5605', (108, 114))	('NRAS', 'Gene', '4893', (72, 76))	('overexpression', 'PosReg', (130, 144))	('COT', 'Gene', (148, 151))	('MEK1/2', 'Gene', (108, 114))	('EGFR', 'Gene', (155, 159))	('COT', 'Gene', '1326', (148, 151))	('mutations', 'Var', (77, 86))	('MEK1', 'molecular_function', 'GO:0004708', ('108', '112'))
12334	27883956	These genetic alterations are related to the mitogen-activated protein kinase pathway, which could drive melanoma progression, but driver mutations for resistance have not been well characterized.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('drive', 'Reg', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('related', 'Reg', (30, 37))	('melanoma', 'Disease', (105, 113))	('mitogen-activated protein kinase pathway', 'Pathway', (45, 85))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('genetic alterations', 'Var', (6, 25))
12339	27883956	We reviewed the medical records of all patients for clinical parameters, including sex, age, performance status, primary melanoma site, metastatic sites, serum lactate dehydrogenase level, BRAF mutation test results, and previous treatments.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('BRAF', 'Gene', '673', (189, 193))	('melanoma', 'Disease', (121, 129))	('mutation', 'Var', (194, 202))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('patients', 'Species', '9606', (39, 47))	('serum lactate dehydrogenase level', 'MPA', (154, 187))	('BRAF', 'Gene', (189, 193))
12357	27883956	All patients tested positive for the BRAF V600E mutation.	('V600E', 'Var', (42, 47))	('BRAF', 'Gene', '673', (37, 41))	('positive', 'Reg', (20, 28))	('BRAF', 'Gene', (37, 41))	('V600E', 'Mutation', 'rs113488022', (42, 47))	('patients', 'Species', '9606', (4, 12))
12362	27883956	The median PFS for patients with noncutaneous melanoma following treatment with BRAF inhibitors was 7.3 months (95% CI, 3.0-11.6), whereas the median PFS for cutaneous melanoma was 17.5 months (95% CI, 0.1-34.9).	('cutaneous melanoma', 'Disease', 'MESH:C562393', (158, 176))	('BRAF', 'Gene', (80, 84))	('patients', 'Species', '9606', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('inhibitors', 'Var', (85, 95))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))	('BRAF', 'Gene', '673', (80, 84))	('cutaneous melanoma', 'Disease', (158, 176))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (158, 176))
12376	27883956	IKZF1, ELMO1, and CDKN1B mutations were identified in Pat01.	('IKZF1', 'Gene', '10320', (0, 5))	('mutations', 'Var', (25, 34))	('ELMO1', 'Gene', (7, 12))	('CDKN1B', 'Gene', '1027', (18, 24))	('Pat', 'molecular_function', 'GO:0043894', ('54', '57'))	('IKZF1', 'Gene', (0, 5))	('CDKN1B', 'Gene', (18, 24))	('ELMO1', 'Gene', '9844', (7, 12))
12377	27883956	Patients with an NF1 mutation (Pats 01, 02, and 03) also demonstrated shorter duration of response than patients without an NF1 mutation (Pats 04 and 05).	('NF1', 'Gene', (124, 127))	('Pats', 'Species', '9606', (31, 35))	('Pats', 'Species', '9606', (138, 142))	('shorter', 'NegReg', (70, 77))	('mutation', 'Var', (21, 29))	('NF1', 'Gene', (17, 20))	('Patients', 'Species', '9606', (0, 8))	('duration', 'MPA', (78, 86))	('NF1', 'Gene', '4763', (17, 20))	('patients', 'Species', '9606', (104, 112))	('NF1', 'Gene', '4763', (124, 127))
12378	27883956	MAP2K2 mutation co-occurred with MYC and TMPRSS2 alterations in Pats 04 and 05, but the clinical significance was uncertain.	('co-occurred', 'Reg', (16, 27))	('MAP2K2', 'Gene', (0, 6))	('MYC', 'Gene', '4609', (33, 36))	('TMPRSS2', 'Gene', (41, 48))	('Pats', 'Species', '9606', (64, 68))	('mutation', 'Var', (7, 15))	('MAP2K', 'molecular_function', 'GO:0004708', ('0', '5'))	('MYC', 'Gene', (33, 36))	('MAP2K2', 'Gene', '5605', (0, 6))	('TMPRSS2', 'Gene', '7113', (41, 48))
12379	27883956	EGFR and PTEN mutations were identified in Pat 02, who had a relative short PR of 7.1 months.	('mutations', 'Var', (14, 23))	('Pat', 'molecular_function', 'GO:0043894', ('43', '46'))	('EGFR', 'Gene', (0, 4))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
12380	27883956	BRAF inhibitors have become a standard therapy for patients with metastatic melanoma and BRAF V600 mutation on the basis of recent multicenter, randomized trials.	('melanoma', 'Disease', (76, 84))	('BRAF', 'Gene', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('V600 mutation', 'Var', (94, 107))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', '673', (0, 4))	('patients', 'Species', '9606', (51, 59))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
12385	27883956	Our findings suggest that BRAF inhibitors might be a feasible and tolerable treatment option for Asian patients with noncutaneous metastatic melanoma who test positive for a BRAF V600 mutation.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('V600 mutation', 'Var', (179, 192))	('BRAF', 'Gene', '673', (26, 30))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (174, 178))	('patients', 'Species', '9606', (103, 111))
12403	27883956	One of our patients suspected to have primary resistance to BRAF inhibitors had mutations in CDKN1B, ELMO1, and IKZF1.	('CDKN1B', 'Gene', '1027', (93, 99))	('mutations', 'Var', (80, 89))	('BRAF', 'Gene', (60, 64))	('ELMO1', 'Gene', (101, 106))	('IKZF1', 'Gene', (112, 117))	('BRAF', 'Gene', '673', (60, 64))	('CDKN1B', 'Gene', (93, 99))	('patients', 'Species', '9606', (11, 19))	('IKZF1', 'Gene', '10320', (112, 117))	('ELMO1', 'Gene', '9844', (101, 106))
12406	27883956	A CDKN1B mutation could be related to trametinib resistance or tumor progression.	('mutation', 'Var', (9, 17))	('tumor', 'Disease', (63, 68))	('CDKN1B', 'Gene', '1027', (2, 8))	('trametinib', 'Chemical', 'MESH:C560077', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('related', 'Reg', (27, 34))	('CDKN1B', 'Gene', (2, 8))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
12407	27883956	A recent genomic study of esophageal cancer showed that ELMO1 mutation increases invasiveness and is related with tumorigenesis.	('ELMO1', 'Gene', '9844', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('esophageal cancer', 'Disease', 'MESH:D004938', (26, 43))	('ELMO1', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('mutation', 'Var', (62, 70))	('increases', 'PosReg', (71, 80))	('invasiveness', 'CPA', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('esophageal cancer', 'Disease', (26, 43))	('related', 'Reg', (101, 108))
12408	27883956	IKZF1 encodes the Ikaros transcription factor, a crucial element for hematopoiesis, and IKZF1 mutation is related to B-cell acute lymphoblastic leukemia.	('IKZF1', 'Gene', '10320', (0, 5))	('hematopoiesis', 'Disease', (69, 82))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (130, 152))	('Ikaros', 'Gene', (18, 24))	('lymphoblastic leukemia', 'Disease', (130, 152))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (124, 152))	('-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (118, 152))	('IKZF1', 'Gene', (88, 93))	('IKZF1', 'Gene', (0, 5))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (130, 152))	('related', 'Reg', (106, 113))	('transcription factor', 'molecular_function', 'GO:0000981', ('25', '45'))	('transcription', 'biological_process', 'GO:0006351', ('25', '38'))	('B-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (117, 152))	('Ikaros', 'Gene', '10320', (18, 24))	('hematopoiesis', 'Disease', 'MESH:C536227', (69, 82))	('IKZF1', 'Gene', '10320', (88, 93))	('hematopoiesis', 'biological_process', 'GO:0030097', ('69', '82'))	('mutation', 'Var', (94, 102))
12411	27883956	We observed that tumors with the NF1 mutation had an inferior response compared with NF1 wild-type melanoma.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (37, 45))	('NF1', 'Gene', (33, 36))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('NF1', 'Gene', (85, 88))	('NF1', 'Gene', '4763', (33, 36))	('NF1', 'Gene', '4763', (85, 88))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
12412	27883956	The patient who harbored EGFR and PTEN mutations showed a relatively short response of 7.7 months.	('EGFR', 'Gene', (25, 29))	('patient', 'Species', '9606', (4, 11))	('mutations', 'Var', (39, 48))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('PTEN', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (25, 29))	('PTEN', 'Gene', '5728', (34, 38))
12416	27883956	Although the sample size for this study was too small to definitely confirm the efficacy of BRAF inhibitors and resistance mechanism in metastatic noncutaneous melanoma, the treatment outcome parameters in this small cohort were comparable (ORR of 80% and a median PFS of 7.3 months in noncutaneous melanoma) to those reported in large phase III cutaneous melanoma trials.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('BRAF', 'Gene', '673', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('cutaneous melanoma', 'Disease', (289, 307))	('BRAF', 'Gene', (92, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (289, 307))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (289, 307))	('cutaneous melanoma', 'Disease', (346, 364))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (346, 364))	('melanoma', 'Phenotype', 'HP:0002861', (356, 364))	('cutaneous melanoma', 'Disease', (150, 168))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (346, 364))	('inhibitors', 'Var', (97, 107))
12417	27883956	Hence, BRAF inhibitors should be strongly considered as upfront treatment for metastatic melanoma with confirmed BRAF mutation regardless of site of origin (acral, mucosal, or cutaneous).	('BRAF', 'Gene', '673', (113, 117))	('BRAF', 'Gene', (113, 117))	('mutation', 'Var', (118, 126))	('BRAF', 'Gene', '673', (7, 11))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('BRAF', 'Gene', (7, 11))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
12419	27141884	Integrated Analysis of Multidimensional Omics Data on Cutaneous Melanoma Prognosis Multiple types of genetic, epigenetic, and genomic changes have been implicated in cutaneous melanoma prognosis.	('epigenetic', 'Var', (110, 120))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('Cutaneous Melanoma', 'Disease', (54, 72))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', (166, 184))	('implicated', 'Reg', (152, 162))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (166, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (64, 72))
12431	27141884	In the literature, multiple types of omics changes have been suggested as potentially associated with melanoma prognosis.	('changes', 'Var', (43, 50))	('associated', 'Reg', (86, 96))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))
12432	27141884	Studies of tumor cells in melanoma patients have characterized prognostic alterations with a panel of five genes in copy number alteration (CNA).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('copy number alteration', 'Var', (116, 138))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('patients', 'Species', '9606', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
12433	27141884	MicroRNA has also been implicated in melanoma prognosis.	('MicroRNA', 'Var', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('implicated', 'Reg', (23, 33))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))
12435	27141884	For genetic mutations, the associations of several somatic variants - such as BRAF V600E and NRAS Q61R/L/H - with prognosis have been reported.	('associations', 'Interaction', (27, 39))	('BRAF', 'Gene', '673', (78, 82))	('Q61R', 'Var', (98, 102))	('BRAF', 'Gene', (78, 82))	('NRAS', 'Gene', '4893', (93, 97))	('Q61R', 'SUBSTITUTION', 'None', (98, 102))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('NRAS', 'Gene', (93, 97))
12436	27141884	A whole-genome sequencing study found the RAC1 mutation as the third most frequent in sun-exposed melanomas and suggested its potential role in prognosis.	('melanomas', 'Disease', (98, 107))	('RAC1', 'Gene', (42, 46))	('frequent', 'Reg', (74, 82))	('mutation', 'Var', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('RAC1', 'Gene', '5879', (42, 46))
12437	27141884	For example, CNAs, microRNAs, methylation, and other changes affect gene expressions, which affect cancer outcomes/phenotypes through proteins.	('changes', 'Var', (53, 60))	('methylation', 'Var', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('cancer', 'Disease', (99, 105))	('affect', 'Reg', (61, 67))	('affect', 'Reg', (92, 98))	('gene expressions', 'MPA', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
12450	27141884	The loss and gain levels of copy number changes of tumors compared to normal tissues were identified using segmentation analysis and expressed in the log2 transformed form.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('segmentation', 'biological_process', 'GO:0035282', ('107', '119'))	('gain', 'PosReg', (13, 17))	('copy number changes', 'Var', (28, 47))
12482	27141884	For example with methylation, SPLS has a mean C-statistic of 0.702, compared to 0.605 of Enet and 0.668 of SPCA.	('PLS', 'Disease', 'MESH:D010214', (31, 34))	('PLS', 'Disease', (31, 34))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('methylation', 'Var', (17, 28))
12492	27141884	The model also includes BRAF and NRAS mutation status and methylation, which may affect prognosis through gene expression as well as other independent channels.	('NRAS', 'Gene', (33, 37))	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('NRAS', 'Gene', '4893', (33, 37))	('gene expression', 'MPA', (106, 121))	('methylation', 'Var', (58, 69))	('affect', 'Reg', (81, 87))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('BRAF', 'Gene', (24, 28))	('mutation', 'Var', (38, 46))	('BRAF', 'Gene', '673', (24, 28))	('prognosis', 'MPA', (88, 97))
12495	27141884	It is not surprising to observe that the gene expressions of samples with hypermethylated HLA.C status are significantly lower than those of the rest (p-value=1.687e-8).	('gene expressions', 'MPA', (41, 57))	('HLA.C', 'Gene', '3107', (90, 95))	('HLA.C', 'Gene', (90, 95))	('hypermethylated', 'Var', (74, 89))	('lower', 'NegReg', (121, 126))
12496	27141884	Samples with the hypermethylation of HLA.C tend to have a higher Clark level (p-value=0.007) and more advanced tumor status (p=0.012).	('Clark level', 'MPA', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HLA.C', 'Gene', '3107', (37, 42))	('HLA.C', 'Gene', (37, 42))	('tumor', 'Disease', (111, 116))	('higher', 'PosReg', (58, 64))	('hypermethylation', 'Var', (17, 33))
12498	27141884	Samples that have hypermethylated HLA.C and correlated genes tend to have a poorer survival.	('HLA.C', 'Gene', (34, 39))	('HLA.C', 'Gene', '3107', (34, 39))	('hypermethylated', 'Var', (18, 33))
12501	27141884	It has also been observed that genetic changes on chromosome 6 are highly associated with the expression of gene BCL2, which plays an important role in programmed cell death.	('BCL2', 'molecular_function', 'GO:0015283', ('113', '117'))	('genetic changes', 'Var', (31, 46))	('BCL2', 'Gene', '596', (113, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('50', '60'))	('expression', 'MPA', (94, 104))	('programmed cell death', 'biological_process', 'GO:0012501', ('152', '173'))	('BCL2', 'Gene', (113, 117))	('associated', 'Reg', (74, 84))
12511	27141884	Dysregulation of the MAPK pathway is partially due to the mutation of BRAF and RAS and other genetic modifications.	('RAS', 'Gene', (79, 82))	('due', 'Reg', (47, 50))	('mutation', 'Var', (58, 66))	('BRAF', 'Gene', '673', (70, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('21', '25'))	('MAPK pathway', 'Pathway', (21, 33))	('BRAF', 'Gene', (70, 74))
12528	27141884	Although methylation has been linked to the prognosis of melanoma and other cancer types, there is still a lack of study investigating its superior importance in prognosis.	('methylation', 'Var', (9, 20))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('linked', 'Reg', (30, 36))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
12538	33178610	The differentially expressed genes (DEGs) of melanoma in GSE15605, GSE46517, GSE7553, and the Cancer Genome Atlas (TCGA) datasets were analyzed.	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('GSE7553', 'Chemical', '-', (77, 84))	('GSE7553', 'Var', (77, 84))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('Cancer', 'Disease', (94, 100))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('GSE15605', 'Var', (57, 65))	('GSE46517', 'Var', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
12561	33178610	GSE15605, GSE46517, and GSE7553 themicroarray expression profiling datasets were downloaded from Gene Expression Omnibus.	('GSE15605', 'Var', (0, 8))	('GSE46517', 'Var', (10, 18))	('Gene Expression', 'biological_process', 'GO:0010467', ('97', '112'))	('GSE7553', 'Chemical', '-', (24, 31))	('GSE7553', 'Var', (24, 31))
12568	33178610	Intersect function in R was applied for identifying the common DEGs among GSE15605, GSE46517 and GSE7553 and TCGA.	('GSE15605', 'Var', (74, 82))	('GSE7553', 'Chemical', '-', (97, 104))	('GSE46517', 'Var', (84, 92))	('GSE7553', 'Var', (97, 104))
12577	33178610	According to the inclusion criteria, three GEO datasets and TCGA dataset were obtained in our study: GSE15605, GSE46517, GSE7553, and TCGA skin cutaneous melanoma data.	('GSE7553', 'Chemical', '-', (121, 128))	('GSE7553', 'Var', (121, 128))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (139, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('GSE15605', 'Var', (101, 109))	('GSE46517', 'Var', (111, 119))	('skin cutaneous melanoma', 'Disease', (139, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
12578	33178610	DEGs 1,078, 407, 892, and 2,148 from the expression profile datasets GSE15605, GSE46517, GSE7553, and TCGA dataset were extracted, respectively.	('DEGs 1', 'Gene', '8560', (0, 6))	('GSE15605', 'Var', (69, 77))	('GSE46517', 'Var', (79, 87))	('GSE7553', 'Chemical', '-', (89, 96))	('DEGs 1', 'Gene', (0, 6))
12600	33178610	Previous studies have found that the frequency of oncogenic mutations in the EGFR gene is closely related to the occurrence of melanoma.	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('related', 'Reg', (98, 105))	('EGFR', 'Gene', '1956', (77, 81))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('mutations', 'Var', (60, 69))	('EGFR', 'Gene', (77, 81))
12635	24491031	However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models.	('activating mutations', 'Var', (9, 29))	('Nrf2', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('promote', 'PosReg', (69, 76))	('tumor', 'Disease', (77, 82))
12642	24491031	Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1alpha destabilization and VEGFA repression.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('impaired', 'NegReg', (101, 109))	('VEGFA', 'Gene', '7422', (282, 287))	('Nrf2', 'Gene', (28, 32))	('HIF-1alpha', 'Gene', (251, 261))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (73, 96))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('sensitization', 'biological_process', 'GO:0046960', ('171', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('decreased', 'NegReg', (63, 72))	('destabilization', 'NegReg', (262, 277))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('decreased hypoxic', 'Disease', (205, 222))	('decreased hypoxic', 'Disease', 'MESH:D000860', (205, 222))	('VEGFA', 'Gene', (282, 287))	('HIF-1alpha', 'Gene', '3091', (251, 261))	('tumor', 'Disease', (118, 123))	('reactive oxygen species', 'MPA', (73, 96))	('restoration', 'Var', (13, 24))
12653	24491031	However, Nrf2 activation has also been proposed to play a role in cancer evolution , and induction of Nrf2 pathway due to genetic variants in Keap1 or Nrf2 might predispose to cancer .	('variants', 'Var', (130, 138))	('predispose', 'Reg', (162, 172))	('induction', 'PosReg', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Nrf2', 'Gene', (151, 155))	('Keap1', 'Gene', (142, 147))	('Keap1', 'Gene', '9817', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Nrf2 pathway', 'Pathway', (102, 114))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (66, 72))
12657	24491031	Moreover, Nrf2 expression was repressed in transformed MSC and breast cancer cells via activation of RAS/RAF/ERK pathway, and restoration of Nrf2 levels in transformed MSC induced the cellular antioxidant response and impaired in vivo tumor growth through mechanisms involving sensitization to apoptosis and destabilization of HIF-1alpha.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('breast cancer', 'Disease', (63, 76))	('sensitization', 'biological_process', 'GO:0046960', ('277', '290'))	('RAS/RAF/ERK pathway', 'Pathway', (101, 120))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('impaired', 'NegReg', (218, 226))	('Nrf2', 'Gene', (10, 14))	('HIF-1alpha', 'Gene', '3091', (327, 337))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('induced', 'PosReg', (172, 179))	('cellular antioxidant response', 'MPA', (184, 213))	('ERK', 'molecular_function', 'GO:0004707', ('109', '112'))	('apoptosis', 'biological_process', 'GO:0097194', ('294', '303'))	('HIF-1alpha', 'Gene', (327, 337))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('tumor', 'Disease', (235, 240))	('apoptosis', 'biological_process', 'GO:0006915', ('294', '303'))	('Nrf2', 'Gene', (141, 145))	('restoration', 'Var', (126, 137))
12691	24491031	While cell survival was not affected by the concentration of inhibitors used in this assay (Additional file 2: Figure S1), treatment with the ERK inhibitor U0126 led to a significant increase in the transcription of Nrf2 and NQO1 (Figure  3D).	('NQO1', 'Gene', (225, 229))	('transcription', 'MPA', (199, 212))	('U0126', 'Var', (156, 161))	('increase', 'PosReg', (183, 191))	('NQO1', 'Gene', '1728', (225, 229))	('Nrf2', 'Gene', (216, 220))	('NQO1', 'molecular_function', 'GO:0003955', ('225', '229'))	('ERK', 'molecular_function', 'GO:0004707', ('142', '145'))	('U0126', 'Chemical', 'MESH:C113580', (156, 161))	('transcription', 'biological_process', 'GO:0006351', ('199', '212'))
12692	24491031	However, inhibition of AKT with GSK690693, or PI3K with LY294002 and wortmannin did not induce expression of Nrf2 nor NQO1 (Figure  3D).	('GSK', 'molecular_function', 'GO:0050321', ('32', '35'))	('NQO1', 'Gene', (118, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('Nrf2', 'Gene', (109, 113))	('AKT', 'Gene', '207', (23, 26))	('NQO1', 'Gene', '1728', (118, 122))	('LY294002', 'Var', (56, 64))	('GSK690693', 'Chemical', 'MESH:C528328', (32, 41))	('GSK690693', 'Var', (32, 41))	('wortmannin', 'Chemical', 'MESH:D000077191', (69, 79))	('AKT', 'Gene', (23, 26))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))	('NQO1', 'molecular_function', 'GO:0003955', ('118', '122'))
12702	24491031	These results suggest that loss of Nrf2 expression contributes to both accumulation of intracellular ROS, and to MSC in vitro transformation.	('loss', 'Var', (27, 31))	('accumulation', 'PosReg', (71, 83))	('intracellular', 'cellular_component', 'GO:0005622', ('87', '100'))	('MSC in vitro transformation', 'CPA', (113, 140))	('intracellular', 'MPA', (87, 100))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('ROS', 'Protein', (101, 104))	('Nrf2', 'Gene', (35, 39))
12708	24491031	Over-expression of Nrf2 led to a slight, but significant reduction in tMSC viability (Figure  5E) and soft agarose growth (Figure  5F) when compared with tMSC expressing empty vector.	('agarose', 'Chemical', 'MESH:D012685', (107, 114))	('Nrf2', 'Gene', (19, 23))	('tMSC', 'Chemical', '-', (154, 158))	('reduction', 'NegReg', (57, 66))	('tMSC', 'Chemical', '-', (70, 74))	('Over-expression', 'Var', (0, 15))	('soft agarose growth', 'CPA', (102, 121))	('tMSC viability', 'CPA', (70, 84))
12709	24491031	Hence we inoculated tMSC over-expressing Nrf2 or empty vector into nude mice.	('over-expressing', 'Var', (25, 40))	('tMSC', 'Chemical', '-', (20, 24))	('nude mice', 'Species', '10090', (67, 76))	('Nrf2', 'Gene', (41, 45))
12722	24491031	This result suggests that loss of Nrf2 expression in tumor cells could facilitate the proliferation of endothelial cells within the tumor microenvironment in conditions when oxygen concentration becomes limited.	('oxygen', 'Chemical', 'MESH:D010100', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('proliferation of endothelial cells', 'CPA', (86, 120))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Nrf2', 'Gene', (34, 38))	('tumor', 'Disease', (132, 137))	('facilitate', 'PosReg', (71, 81))	('tumor', 'Disease', (53, 58))	('loss', 'Var', (26, 30))
12748	24491031	In this regard, oncogenic Ras might induce different biological responses depending on the status of tumor suppressors such as p53 and/or oncogenes such as Myc.	('biological responses', 'CPA', (53, 73))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('oncogenic Ras', 'Var', (16, 29))	('Myc', 'Gene', '4609', (156, 159))	('induce', 'Reg', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('p53', 'Gene', '7157', (127, 130))	('Myc', 'Gene', (156, 159))	('p53', 'Gene', (127, 130))
12751	24491031	These data differ from a report where Nrf2 knockdown by siRNA in human colon cancer cells inhibited tumor growth and led to a reduction in VEGF expression .	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('human', 'Species', '9606', (65, 70))	('VEGF', 'Gene', (139, 143))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (144, 154))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('knockdown', 'Var', (43, 52))	('Nrf2', 'Gene', (38, 42))	('colon cancer', 'Disease', (71, 83))	('reduction', 'NegReg', (126, 135))	('VEGF', 'Gene', '7422', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('inhibited', 'NegReg', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
12757	24491031	Moreover, analysis of available survival datasets obtained from GEO and TCGA databases shows that increased Nrf2 expression correlates with better survival in patients with melanoma, kidney and prostate cancers, further supporting our in vivo findings where restoration of Nrf2 expression in transformed MSC improved survival.	('expression', 'MPA', (113, 123))	('prostate cancers', 'Phenotype', 'HP:0012125', (194, 210))	('Nrf2', 'Gene', (273, 277))	('better', 'PosReg', (140, 146))	('survival', 'MPA', (317, 325))	('restoration', 'Var', (258, 269))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('kidney and prostate cancers', 'Disease', 'MESH:D011471', (183, 210))	('melanoma', 'Disease', (173, 181))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('increased', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('Nrf2', 'Gene', (108, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('survival', 'MPA', (147, 155))	('patients', 'Species', '9606', (159, 167))	('improved', 'PosReg', (308, 316))
12759	24491031	We also show that rescue of Nrf2 function in fully transformed cells is an effective strategy to tackle in vivo tumor growth, as Nrf2 expression sensitizes transformed cells to apoptosis and impairs the angiogenic response through destabilization of HIF-1alpha.	('sensitizes', 'Reg', (145, 155))	('apoptosis', 'CPA', (177, 186))	('Nrf2', 'Gene', (129, 133))	('HIF-1alpha', 'Gene', '3091', (250, 260))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('expression', 'Var', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('destabilization', 'MPA', (231, 246))	('angiogenic response', 'CPA', (203, 222))	('HIF-1alpha', 'Gene', (250, 260))	('tumor', 'Disease', (112, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('impairs', 'NegReg', (191, 198))
12776	24491031	24 hours later the cells were incubated with free serum standard media containing DMSO (Sigma) or the following chemicals: ERK kinases inhibitor U0126 (Calbiochem/MerckMillipore, Watford, UK); PI3K inhibitors LY294002 (Merck Biosciences Ltd, Nottingham, UK) and wortmannin (Cell Signaling Technology, Danvers, MA); and AKT inhibitor GSK690693 (Symansis, Timaru, NZ).	('LY294002', 'Var', (209, 217))	('ERK kinases', 'Enzyme', (123, 134))	('Signaling', 'biological_process', 'GO:0023052', ('279', '288'))	('GSK', 'molecular_function', 'GO:0050321', ('333', '336'))	('AKT', 'Gene', '207', (319, 322))	('DMSO', 'Chemical', 'MESH:D004121', (82, 86))	('U0126', 'Chemical', 'MESH:C113580', (145, 150))	('wortmannin', 'Chemical', 'MESH:D000077191', (262, 272))	('PI3K', 'molecular_function', 'GO:0016303', ('193', '197'))	('LY294002', 'Chemical', 'MESH:C085911', (209, 217))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('AKT', 'Gene', (319, 322))	('GSK690693', 'Chemical', 'MESH:C528328', (333, 342))
12795	31949127	Consistent with previous reports, ADT-OH inhibited IkappaBalpha degradation, resulting in reduced NF-kappaB activation and subsequent downregulation of the NF-kappaB-targeted anti-apoptotic proteins XIAP and Bcl-2.	('N', 'Chemical', 'MESH:D009584', (156, 157))	('IkappaBalpha', 'Gene', (51, 63))	('ADT-OH', 'Var', (34, 40))	('downregulation', 'NegReg', (134, 148))	('reduced', 'NegReg', (90, 97))	('ADT-OH', 'Chemical', 'MESH:C092798', (34, 40))	('IkappaBalpha', 'Gene', '18035', (51, 63))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('Bcl-2', 'molecular_function', 'GO:0015283', ('208', '213'))	('ADT', 'cellular_component', 'GO:0030956', ('34', '37'))	('XIAP', 'Gene', '11798', (199, 203))	('NF-kappaB', 'Protein', (98, 107))	('NF-kappaB-targeted anti-apoptotic proteins', 'MPA', (156, 198))	('degradation', 'biological_process', 'GO:0009056', ('64', '75'))	('inhibited', 'NegReg', (41, 50))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('98', '118'))	('XIAP', 'Gene', (199, 203))	('activation', 'PosReg', (108, 118))
12796	31949127	More importantly, we found that ADT-OH suppressed the ubiquitin-induced degradation of FADD by downregulating the expression of MKRN1, an E3 ubiquitin ligase of FADD.	('ADT', 'cellular_component', 'GO:0030956', ('32', '35'))	('ubiquitin-induced degradation', 'MPA', (54, 83))	('degradation', 'biological_process', 'GO:0009056', ('72', '83'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('141', '150'))	('MKRN1', 'Gene', (128, 133))	('ADT-OH', 'Chemical', 'MESH:C092798', (32, 38))	('suppressed', 'NegReg', (39, 49))	('expression', 'MPA', (114, 124))	('ADT-OH', 'Var', (32, 38))	('downregulating', 'NegReg', (95, 109))	('ubiquitin', 'molecular_function', 'GO:0031386', ('54', '63'))
12800	31949127	Taken together, our data suggest that ADT-OH is a promising cancer therapeutic drug that warrants further investigation into its potential clinical applications.	('ADT-OH', 'Chemical', 'MESH:C092798', (38, 44))	('ADT-OH', 'Var', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('ADT', 'cellular_component', 'GO:0030956', ('38', '41'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
12802	31949127	In recent decades, activating v-Raf murine sarcoma viral oncogene homologue B (BRAF) mutations were found in approximately one-half of all cutaneous melanomas.	('activating', 'PosReg', (19, 29))	('v-Raf', 'Gene', (30, 35))	('murine', 'Species', '10090', (36, 42))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (139, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (139, 158))	('BRAF', 'Gene', '109880', (79, 83))	('mutations', 'Var', (85, 94))	('v-Raf', 'Gene', '110157', (30, 35))	('cutaneous melanomas', 'Disease', (139, 158))	('BRAF', 'Gene', (79, 83))	('sarcoma', 'Disease', (43, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
12819	31949127	However, several studies have shown that H2S donors, including DATS, GYY4137 and ATB-346, markedly decrease the expression of anti-apoptotic genes, such as those encoding FLICE-inhibitory protein (c-FLIP) and B cell lymphoma gene-2 (Bcl-2), which can induce pro-apoptotic programmes in several cancer cell types.	('B cell lymphoma', 'Phenotype', 'HP:0012191', (209, 224))	('lymphoma', 'Phenotype', 'HP:0002665', (216, 224))	('ATB-346', 'Gene', (81, 88))	('c-FLIP', 'Gene', '12633', (197, 203))	('expression', 'MPA', (112, 122))	('B cell lymphoma gene-2', 'Gene', '12043', (209, 231))	('B cell lymphoma gene-2', 'Gene', (209, 231))	('cancer', 'Disease', (294, 300))	('c-FLIP', 'Gene', (197, 203))	('GYY4137', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('Bcl-2', 'Gene', (233, 238))	('decrease', 'NegReg', (99, 107))	('anti-apoptotic genes', 'Gene', (126, 146))	('H2S', 'Gene', (41, 44))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('Bcl-2', 'molecular_function', 'GO:0015283', ('233', '238'))	('H2S', 'Gene', '110798', (41, 44))	('donor', 'Species', '9606', (45, 50))	('GYY4137', 'Chemical', 'MESH:C529376', (69, 76))
12820	31949127	In addition, exogenous H2S can increase the activity of anion exchangers and sodium/proton exchangers to increase the production of metabolic acids to cause cancer cell death.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cell death', 'biological_process', 'GO:0008219', ('164', '174'))	('sodium', 'Chemical', 'MESH:D012964', (77, 83))	('sodium/proton exchangers', 'MPA', (77, 101))	('H2S', 'Gene', '110798', (23, 26))	('increase', 'PosReg', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('activity', 'MPA', (44, 52))	('production of metabolic acids', 'MPA', (118, 147))	('cancer', 'Disease', (157, 163))	('cause', 'Reg', (151, 156))	('anion exchangers', 'MPA', (56, 72))	('H2S', 'Gene', (23, 26))	('exogenous', 'Var', (13, 22))	('increase', 'PosReg', (31, 39))
12826	31949127	Intriguingly, ADT-OH markedly decreased the expression of makorin ring finger protein 1 (MKRN1), which is an E3 ubiquitin ligase of FADD, resulting in elevated protein levels of FADD.	('protein levels of FADD', 'MPA', (160, 182))	('expression', 'MPA', (44, 54))	('protein', 'cellular_component', 'GO:0003675', ('160', '167'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('112', '121'))	('ADT-OH', 'Var', (14, 20))	('ADT-OH', 'Chemical', 'MESH:C092798', (14, 20))	('makorin ring finger protein 1', 'Gene', '54484', (58, 87))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('ADT', 'cellular_component', 'GO:0030956', ('14', '17'))	('elevated', 'PosReg', (151, 159))	('makorin ring finger protein 1', 'Gene', (58, 87))	('MKRN1', 'Gene', (89, 94))	('decreased', 'NegReg', (30, 39))
12832	31949127	B16F10 and B16F1 (murine melanoma cells), LLC Lewis (murine lung carcinoma cells), 4T1 (murine breast cancer cells), A375 (human melanoma cells), A549, H446 and H1299 (human lung carcinoma cells), MCF-7 (human breast adenocarcinoma cell line), MDA-MB-231 (human breast cancer cells), HCT-116 (human colorectal carcinoma cells), HepG2 (human hepatocellular carcinoma cells), HaCaT (human immortalised epidermal cells), HK2 (human proximal tubule epithelial cells) and MEF (murine embryonic fibroblasts) cell lines were purchased from American Type Culture Collection (ATCC, USA) or maintained in our laboratory and cultured at 37  C in 5% CO2 in a humidified atmosphere in Dulbecco's modified Eagle's medium (DMEM, Gibco, Shanghai, China) with 10% foetal bovine serum (FBS, Gibco, Australia), penicillin (100 IU/ml) and streptomycin (100 mug/ml).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('mug', 'molecular_function', 'GO:0043739', ('837', '840'))	('H446', 'CellLine', 'CVCL:1562', (152, 156))	('human', 'Species', '9606', (423, 428))	('human', 'Species', '9606', (123, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (341, 365))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('LLC', 'cellular_component', 'GO:0038045', ('42', '45'))	('HCT-116', 'CellLine', 'CVCL:0291', (284, 291))	('HK2', 'molecular_function', 'GO:0008256', ('418', '421'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (244, 254))	('breast cancer', 'Disease', (262, 275))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('B16F1', 'CellLine', 'CVCL:0158', (11, 16))	('colorectal carcinoma', 'Disease', (299, 319))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('human', 'Species', '9606', (256, 261))	('human', 'Species', '9606', (335, 340))	('human', 'Species', '9606', (168, 173))	('breast cancer', 'Disease', (95, 108))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (299, 319))	('murine', 'Species', '10090', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('hepatocellular carcinoma', 'Disease', (341, 365))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('HaCaT', 'CellLine', 'CVCL:0038', (374, 379))	('lung carcinoma', 'Disease', 'MESH:D008175', (174, 188))	('lung carcinoma', 'Disease', (60, 74))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('B16F1', 'CellLine', 'CVCL:0158', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('100 IU/ml', 'Var', (804, 813))	('MCF-7', 'CellLine', 'CVCL:0031', (197, 202))	('murine', 'Species', '10090', (472, 478))	('breast adenocarcinoma', 'Disease', (210, 231))	('B16F10', 'CellLine', 'CVCL:0159', (0, 6))	('MEF', 'CellLine', 'CVCL:9115', (467, 470))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('streptomycin', 'Chemical', 'MESH:D013307', (819, 831))	('human', 'Species', '9606', (381, 386))	('penicillin', 'Chemical', 'MESH:D010406', (792, 802))	('HK2', 'Gene', (418, 421))	('HK2', 'Gene', '3099', (418, 421))	('human', 'Species', '9606', (204, 209))	('human', 'Species', '9606', (293, 298))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (210, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('murine', 'Species', '10090', (88, 94))	('CO2', 'Chemical', 'MESH:D002245', (638, 641))	('A375', 'CellLine', 'CVCL:0132', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (341, 365))	('melanoma', 'Disease', (129, 137))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('lung carcinoma', 'Disease', 'MESH:D008175', (60, 74))	('HepG2', 'CellLine', 'CVCL:0027', (328, 333))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('lung carcinoma', 'Disease', (174, 188))	('breast adenocarcinoma', 'Disease', 'MESH:D061325', (210, 231))	('melanoma', 'Disease', (25, 33))	('murine', 'Species', '10090', (18, 24))
12850	31949127	Then, 40 mug of total protein were used for immunoblotting analysis following standard conditions with the following primary antibodies: Bcl-2 (2876, Cell Signalling, USA; dilution 1:1000), Bax (2772, Cell Signalling, USA; dilution 1:1000), Bad (9292, Cell Signalling, USA; dilution 1:1000), FADD (ab124812, Abcam, Cambridge, UK; dilution 1:1000), MKRN1 (SAB2501717, Sigma-Aldrich; dilution 1:1000), IkappaBalpha (4812, Cell Signalling, USA; dilution 1:1000), cleaved caspase-8 (8592, Cell Signalling, USA; dilution 1:1000), XIAP (2042, Cell Signalling, USA; dilution 1:1000), cleaved caspase-3 (9662, Cell Signalling, USA; dilution 1:1000), PARP (9542, Cell Signalling, USA; dilution 1:1000); Flag (F3165 mouse; Sigma); ubiquitin (3933, Cell Signalling, USA; dilution 1:1000); beta-tubulin (Abgent, Suzhou, China) and beta-actin (Abgent, Suzhou, China).	('Signalling', 'biological_process', 'GO:0023052', ('490', '500'))	('Signalling', 'biological_process', 'GO:0023052', ('257', '267'))	('Signalling', 'biological_process', 'GO:0023052', ('155', '165'))	('PARP', 'Gene', (642, 646))	('IkappaBalpha', 'Gene', '18035', (400, 412))	('Bax', 'Gene', '12028', (190, 193))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('mouse', 'Species', '10090', (706, 711))	('Signalling', 'biological_process', 'GO:0023052', ('425', '435'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('137', '142'))	('caspase-3', 'Gene', (585, 594))	('beta-actin', 'Gene', (819, 829))	('Signalling', 'biological_process', 'GO:0023052', ('607', '617'))	('caspase-8', 'Gene', (468, 477))	('Bax', 'Gene', (190, 193))	('beta-actin', 'Gene', '11461', (819, 829))	('3933', 'Var', (732, 736))	('IkappaBalpha', 'Gene', (400, 412))	('beta-tubulin', 'Protein', (778, 790))	('XIAP', 'Gene', (525, 529))	('SAB2501717', 'Chemical', 'MESH:C504226', (355, 365))	('Signalling', 'biological_process', 'GO:0023052', ('743', '753'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('721', '730'))	('XIAP', 'Gene', '11798', (525, 529))	('Signalling', 'biological_process', 'GO:0023052', ('542', '552'))	('mug', 'molecular_function', 'GO:0043739', ('9', '12'))	('ubiquitin', 'Protein', (721, 730))	('Signalling', 'biological_process', 'GO:0023052', ('206', '216'))	('PARP', 'Gene', '11545', (642, 646))	('caspase-3', 'Gene', '12367', (585, 594))	('Signalling', 'biological_process', 'GO:0023052', ('659', '669'))	('caspase-8', 'Gene', '12370', (468, 477))
12869	31949127	To analyse the level of caspase-3 activation and FADD, tumour sections were stained with anti-cleaved caspase-3 (Cell Signalling Technology, USA) and FADD (Abcam, USA).	('tumour', 'Disease', (55, 61))	('caspase-3', 'Gene', '12367', (102, 111))	('caspase-3', 'Gene', '12367', (24, 33))	('anti-cleaved', 'Var', (89, 101))	('caspase-3', 'Gene', (102, 111))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('Signalling', 'biological_process', 'GO:0023052', ('118', '128'))	('caspase-3', 'Gene', (24, 33))
12873	31949127	We found that ADT-OH released H2S in a dose-dependent manner (Fig.	('ADT-OH', 'Var', (14, 20))	('H2S', 'Gene', '110798', (30, 33))	('ADT-OH', 'Chemical', 'MESH:C092798', (14, 20))	('ADT', 'cellular_component', 'GO:0030956', ('14', '17'))	('H2S', 'Gene', (30, 33))
12876	31949127	2, ADT-OH significantly inhibited the proliferation of a variety of tumour cells, including melanoma cells.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('ADT-OH', 'Var', (3, 9))	('ADT-OH', 'Chemical', 'MESH:C092798', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('inhibited', 'NegReg', (24, 33))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('tumour', 'Disease', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('ADT', 'cellular_component', 'GO:0030956', ('3', '6'))
12878	31949127	Moreover, ADT-OH strongly inhibited the proliferation of the B16F10 cells in a dose-dependent manner but had a slight effect on MEFs (Fig.	('inhibited', 'NegReg', (26, 35))	('ADT', 'cellular_component', 'GO:0030956', ('10', '13'))	('ADT-OH', 'Chemical', 'MESH:C092798', (10, 16))	('ADT-OH', 'Var', (10, 16))	('B16F10', 'CellLine', 'CVCL:0159', (61, 67))	('MEFs', 'CellLine', 'CVCL:9115', (128, 132))	('proliferation', 'CPA', (40, 53))
12879	31949127	Treatment with ADT-OH at a dose of 12.5 muM reduced MEF proliferation by 27.64% in and B16F10 cells by 55.74%, which implies that ADT-OH had a greater inhibitory effect on the proliferation of tumour cells than it did on normal cells.	('muM', 'Gene', (40, 43))	('ADT-OH', 'Chemical', 'MESH:C092798', (130, 136))	('ADT', 'cellular_component', 'GO:0030956', ('130', '133'))	('tumour', 'Disease', (193, 199))	('ADT', 'cellular_component', 'GO:0030956', ('15', '18'))	('B16F10', 'CellLine', 'CVCL:0159', (87, 93))	('MEF', 'CellLine', 'CVCL:9115', (52, 55))	('proliferation', 'CPA', (176, 189))	('inhibitory', 'NegReg', (151, 161))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('reduced', 'NegReg', (44, 51))	('MEF proliferation', 'CPA', (52, 69))	('muM', 'Gene', '56925', (40, 43))	('ADT-OH', 'Var', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('ADT-OH', 'Chemical', 'MESH:C092798', (15, 21))
12883	31949127	In a similar pattern to its effect on proliferation, ADT-OH induced tumour cell apoptosis but had a slight effect on the normal cells.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('tumour', 'Disease', (68, 74))	('ADT', 'cellular_component', 'GO:0030956', ('53', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('ADT-OH', 'Var', (53, 59))	('ADT-OH', 'Chemical', 'MESH:C092798', (53, 59))
12884	31949127	These results indicated that tumour cells are more sensitive to ADT-OH, although high concentrations of ADT-OH can induce apoptosis in normal cell lines.	('ADT-OH', 'Chemical', 'MESH:C092798', (64, 70))	('tumour', 'Disease', (29, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('ADT', 'cellular_component', 'GO:0030956', ('64', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('apoptosis', 'CPA', (122, 131))	('induce', 'Reg', (115, 121))	('ADT-OH', 'Chemical', 'MESH:C092798', (104, 110))	('ADT-OH', 'Var', (104, 110))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('ADT', 'cellular_component', 'GO:0030956', ('104', '107'))	('tumour', 'Disease', 'MESH:D009369', (29, 35))
12886	31949127	4, 50 muM ADT-OH increased ROS production slightly, but 12.5 muM ADT-OH did not affect ROS production.	('increased', 'PosReg', (17, 26))	('muM', 'Gene', '56925', (6, 9))	('ADT', 'cellular_component', 'GO:0030956', ('10', '13'))	('muM', 'Gene', (61, 64))	('muM', 'Gene', (6, 9))	('ADT', 'cellular_component', 'GO:0030956', ('65', '68'))	('ADT-OH', 'Var', (10, 16))	('ROS production', 'MPA', (27, 41))	('ADT-OH', 'Chemical', 'MESH:C092798', (10, 16))	('ADT-OH', 'Chemical', 'MESH:C092798', (65, 71))	('increased ROS production', 'Phenotype', 'HP:0025464', (17, 41))	('muM', 'Gene', '56925', (61, 64))
12890	31949127	These results showed that intrinsic apoptosis was activated by ADT-OH treatment, a finding that was consistent with that of other H2S donors reported in previous studies.	('H2S', 'Gene', (130, 133))	('intrinsic apoptosis', 'CPA', (26, 45))	('activated', 'PosReg', (50, 59))	('ADT-OH', 'Var', (63, 69))	('ADT', 'cellular_component', 'GO:0030956', ('63', '66'))	('donor', 'Species', '9606', (134, 139))	('ADT-OH', 'Chemical', 'MESH:C092798', (63, 69))	('H2S', 'Gene', '110798', (130, 133))	('intrinsic apoptosis', 'biological_process', 'GO:0097193', ('26', '45'))
12892	31949127	These results indicated that ADT-OH could induce apoptosis through exogenous stimulation.	('ADT', 'cellular_component', 'GO:0030956', ('29', '32'))	('ADT-OH', 'Chemical', 'MESH:C092798', (29, 35))	('induce', 'PosReg', (42, 48))	('ADT-OH', 'Var', (29, 35))	('apoptosis', 'biological_process', 'GO:0097194', ('49', '58'))	('apoptosis', 'biological_process', 'GO:0006915', ('49', '58'))	('exogenous stimulation', 'MPA', (67, 88))	('apoptosis', 'CPA', (49, 58))
12893	31949127	To explore the mechanisms, the extrinsic apoptosis pathway was analysed, and we found that the protein level of FADD was significantly elevated after ADT-OH treatment (Fig.	('ADT-OH', 'Var', (150, 156))	('ADT-OH', 'Chemical', 'MESH:C092798', (150, 156))	('elevated', 'PosReg', (135, 143))	('extrinsic apoptosis', 'biological_process', 'GO:0097191', ('31', '50'))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('ADT', 'cellular_component', 'GO:0030956', ('150', '153'))	('protein level', 'MPA', (95, 108))	('FADD', 'Protein', (112, 116))
12895	31949127	However, the qPCR results showed that the mRNA levels of FADD were not affected by ADT-OH (Fig.	('mRNA levels', 'MPA', (42, 53))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('ADT', 'cellular_component', 'GO:0030956', ('83', '86'))	('ADT-OH', 'Chemical', 'MESH:C092798', (83, 89))	('ADT-OH', 'Var', (83, 89))
12898	31949127	2e, the half-life of FADD was approximately 4 h; however, the degradation of FADD was almost completely blocked by MG132 treatment.	('degradation', 'biological_process', 'GO:0009056', ('62', '73'))	('MG132', 'Var', (115, 120))	('MG132', 'Chemical', 'MESH:C072553', (115, 120))	('blocked', 'NegReg', (104, 111))	('degradation', 'MPA', (62, 73))
12899	31949127	Interestingly, ADT-OH and NaHS also inhibited the degradation of FADD (Fig.	('degradation of FADD', 'MPA', (50, 69))	('inhibited', 'NegReg', (36, 45))	('ADT', 'cellular_component', 'GO:0030956', ('15', '18'))	('degradation', 'biological_process', 'GO:0009056', ('50', '61'))	('ADT-OH', 'Var', (15, 21))	('NaHS', 'Chemical', 'MESH:D012964', (26, 30))	('ADT-OH', 'Chemical', 'MESH:C092798', (15, 21))
12902	31949127	2f, ADT-OH significantly reduced the ubiquitination-mediated degradation of FADD.	('reduced', 'NegReg', (25, 32))	('ADT-OH', 'Var', (4, 10))	('ADT-OH', 'Chemical', 'MESH:C092798', (4, 10))	('degradation', 'biological_process', 'GO:0009056', ('61', '72'))	('ADT', 'cellular_component', 'GO:0030956', ('4', '7'))	('ubiquitination-mediated degradation of FADD', 'MPA', (37, 80))
12904	31949127	The mRNA and protein levels of MKRN1 were analysed to determine whether ADT-OH increased the protein level of FADD through MKRN1.	('protein level of FADD', 'MPA', (93, 114))	('increased', 'PosReg', (79, 88))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('ADT', 'cellular_component', 'GO:0030956', ('72', '75'))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('ADT-OH', 'Chemical', 'MESH:C092798', (72, 78))	('ADT-OH', 'Var', (72, 78))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('MKRN1', 'Gene', (123, 128))
12906	31949127	In summary, ADT-OH reduces the level of ubiquitination of FADD by decreasing the protein stability of MKRN1, which ultimately increases the protein level of FADD.	('increases', 'PosReg', (126, 135))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('level of ubiquitination', 'MPA', (31, 54))	('protein stability', 'MPA', (81, 98))	('ADT', 'cellular_component', 'GO:0030956', ('12', '15'))	('ADT-OH', 'Chemical', 'MESH:C092798', (12, 18))	('ADT-OH', 'Var', (12, 18))	('protein level of FADD', 'MPA', (140, 161))	('MKRN1', 'Protein', (102, 107))	('reduces', 'NegReg', (19, 26))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('decreasing', 'NegReg', (66, 76))
12915	31949127	Immunofluorescence staining of cleaved caspase-3 was performed and revealed that transfection with FADD alone or in combination with ADT-OH treatment induced the apoptosis of B16F10 cells.	('caspase-3', 'Gene', '12367', (39, 48))	('ADT', 'cellular_component', 'GO:0030956', ('133', '136'))	('ADT-OH', 'Chemical', 'MESH:C092798', (133, 139))	('caspase-3', 'Gene', (39, 48))	('transfection', 'Var', (81, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('B16F10', 'CellLine', 'CVCL:0159', (175, 181))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('apoptosis', 'CPA', (162, 171))
12924	31949127	The apoptosis rate of FADD-KO cells after treatment with 50 muM ADT-OH was 22.26%, whereas that of wild-type B16F10 cells was 41.95%.	('muM', 'Gene', (60, 63))	('ADT-OH', 'Var', (64, 70))	('ADT-OH', 'Chemical', 'MESH:C092798', (64, 70))	('ADT', 'cellular_component', 'GO:0030956', ('64', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('4', '13'))	('apoptosis', 'biological_process', 'GO:0097194', ('4', '13'))	('B16F10', 'CellLine', 'CVCL:0159', (109, 115))	('muM', 'Gene', '56925', (60, 63))	('apoptosis rate', 'CPA', (4, 18))
12927	31949127	Together with the above in vitro results, ADT-OH administration combined with overexpression of FADD seems to be a promising strategy for melanoma treatment.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('ADT-OH', 'Chemical', 'MESH:C092798', (42, 48))	('ADT-OH', 'Var', (42, 48))	('ADT', 'cellular_component', 'GO:0030956', ('42', '45'))
12933	31949127	On one hand, the stability of FADD in tumour cells would be increased by ADT-OH, and on the other hand, VNP-FADD would deliver FADD specifically to the tumour; thus, the antitumour effect would be more comprehensive and effective than either intervention alone.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('stability', 'MPA', (17, 26))	('tumour', 'Disease', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Disease', (174, 180))	('VNP', 'Gene', '380823', (104, 107))	('ADT-OH', 'Chemical', 'MESH:C092798', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('ADT', 'cellular_component', 'GO:0030956', ('73', '76'))	('ADT-OH', 'Var', (73, 79))	('tumour', 'Disease', (38, 44))	('VNP', 'Gene', (104, 107))	('increased', 'PosReg', (60, 69))
12939	31949127	The xenograft mice were randomly divided into six groups and treated with PBS, ADT-OH, VNP, VNP+ADT-OH, VNP-FADD and VNP-FADD+ADT-OH.	('VNP', 'Gene', '380823', (92, 95))	('ADT-OH', 'Chemical', 'MESH:C092798', (126, 132))	('mice', 'Species', '10090', (14, 18))	('ADT', 'cellular_component', 'GO:0030956', ('126', '129'))	('ADT-OH', 'Chemical', 'MESH:C092798', (96, 102))	('VNP', 'Gene', (92, 95))	('ADT', 'cellular_component', 'GO:0030956', ('96', '99'))	('VNP', 'Gene', '380823', (104, 107))	('ADT-OH', 'Var', (79, 85))	('ADT-OH', 'Chemical', 'MESH:C092798', (79, 85))	('VNP', 'Gene', '380823', (117, 120))	('VNP', 'Gene', '380823', (87, 90))	('VNP', 'Gene', (117, 120))	('ADT', 'cellular_component', 'GO:0030956', ('79', '82'))	('VNP', 'Gene', (87, 90))	('VNP', 'Gene', (104, 107))
12940	31949127	5b, d, the tumour volume in the group of mice that received ADT-OH treatment was significantly smaller than that of the non-ADT-OH treatment groups.	('smaller', 'NegReg', (95, 102))	('ADT-OH', 'Chemical', 'MESH:C092798', (60, 66))	('mice', 'Species', '10090', (41, 45))	('ADT', 'cellular_component', 'GO:0030956', ('124', '127'))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('ADT', 'cellular_component', 'GO:0030956', ('60', '63'))	('ADT-OH', 'Chemical', 'MESH:C092798', (124, 130))	('ADT-OH treatment', 'Var', (60, 76))	('tumour', 'Disease', (11, 17))
12946	31949127	In addition, the groups receiving the combined ADT-OH treatment had significantly increased tumour doubling time and tumour growth delay compared with the non-ADT-OH treatment groups (P < 0.05) (Fig.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('ADT-OH', 'Chemical', 'MESH:C092798', (47, 53))	('tumour', 'Disease', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour growth', 'Disease', (117, 130))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('ADT-OH', 'Chemical', 'MESH:C092798', (159, 165))	('tumour growth', 'Disease', 'MESH:D006130', (117, 130))	('growth delay', 'Phenotype', 'HP:0001510', (124, 136))	('increased', 'PosReg', (82, 91))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Disease', (117, 123))	('ADT-OH', 'Var', (47, 53))	('ADT', 'cellular_component', 'GO:0030956', ('47', '50'))	('ADT', 'cellular_component', 'GO:0030956', ('159', '162'))
12956	31949127	Next, to further demonstrate the role of FADD in the treatment of melanoma in vivo with ADT-OH, we constructed a mouse melanoma model by subcutaneously injecting B16F10 cells or B16F10 FADD-KO cells into C57BL/6 mice.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('mice', 'Species', '10090', (212, 216))	('ADT', 'cellular_component', 'GO:0030956', ('88', '91'))	('B16F10', 'CellLine', 'CVCL:0159', (162, 168))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('B16F10', 'Var', (178, 184))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('ADT-OH', 'Chemical', 'MESH:C092798', (88, 94))	('mouse', 'Species', '10090', (113, 118))	('B16F10', 'CellLine', 'CVCL:0159', (178, 184))
12961	31949127	Taken together, the data from our study suggest that FADD plays a critical role in the pro-apoptotic and antitumour effects of ADT-OH and that the absence of FADD greatly blunts these effects.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('pro-apoptotic', 'CPA', (87, 100))	('blunts', 'NegReg', (171, 177))	('ADT-OH', 'Chemical', 'MESH:C092798', (127, 133))	('tumour', 'Disease', (109, 115))	('absence', 'Var', (147, 154))	('ADT-OH', 'Gene', (127, 133))	('ADT', 'cellular_component', 'GO:0030956', ('127', '130'))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
12971	31949127	For example, GYY4137 (200-400 muM) treatment for 24 h triggered cell cycle arrest through the downregulation of cyclin D1 in HepG2 cells in a dose-dependent manner.	('HepG2', 'CellLine', 'CVCL:0027', (125, 130))	('muM', 'Gene', (30, 33))	('cyclin', 'molecular_function', 'GO:0016538', ('112', '118'))	('cyclin D1', 'Gene', '595', (112, 121))	('GYY4137', 'Var', (13, 20))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('cyclin D1', 'Gene', (112, 121))	('GYY4137', 'Chemical', 'MESH:C529376', (13, 20))	('muM', 'Gene', '56925', (30, 33))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('64', '81'))	('downregulation', 'NegReg', (94, 108))	('cell cycle arrest', 'CPA', (64, 81))
12975	31949127	Recently, several H2S donors and H2S-releasing hybrids, namely, DATS, ATB-346 and GYY4137, have been developed and designed as novel anticancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('H2S', 'Gene', '110798', (18, 21))	('GYY4137', 'Var', (82, 89))	('donor', 'Species', '9606', (22, 27))	('H2S', 'Gene', (18, 21))	('GYY4137', 'Chemical', 'MESH:C529376', (82, 89))	('H2S', 'Gene', '110798', (33, 36))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('H2S', 'Gene', (33, 36))
12976	31949127	For example, GYY4137 induced the apoptosis of various types of cancer cells, including HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS cells, with obvious inhibitory effects on tumour growth; however, limited application has been undertaken in melanoma treatment.	('GYY4137', 'Chemical', 'MESH:C529376', (13, 20))	('HL-60', 'CellLine', 'CVCL:0002', (110, 115))	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('HCT-116', 'CellLine', 'CVCL:0291', (93, 100))	('tumour growth', 'Disease', (182, 195))	('Hep G2', 'CellLine', 'CVCL:0027', (102, 108))	('MCF-7', 'CellLine', 'CVCL:0031', (117, 122))	('melanoma', 'Disease', 'MESH:D008545', (249, 257))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('GYY4137', 'Var', (13, 20))	('U2OS', 'CellLine', 'CVCL:0042', (135, 139))	('HeLa', 'CellLine', 'CVCL:0030', (87, 91))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('induced', 'Reg', (21, 28))	('apoptosis', 'CPA', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('melanoma', 'Disease', (249, 257))	('tumour growth', 'Disease', 'MESH:D006130', (182, 195))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
12980	31949127	In vitro, our results showed that ADT-OH induced more apoptosis in tumour cells than in normal cells, indicating that ADT-OH has potential in the treatment of melanoma with little side effects.	('apoptosis', 'CPA', (54, 63))	('melanoma', 'Disease', (159, 167))	('ADT-OH', 'Var', (34, 40))	('ADT-OH', 'Chemical', 'MESH:C092798', (34, 40))	('tumour', 'Disease', (67, 73))	('ADT', 'cellular_component', 'GO:0030956', ('34', '37'))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('ADT', 'cellular_component', 'GO:0030956', ('118', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('ADT-OH', 'Chemical', 'MESH:C092798', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
12981	31949127	Additionally, our study demonstrated that ADT-OH significantly increased the apoptosis of B16F10 cells by enhancing the activation of caspase-3.	('caspase-3', 'Gene', '12367', (134, 143))	('activation', 'MPA', (120, 130))	('B16F10', 'CellLine', 'CVCL:0159', (90, 96))	('enhancing', 'PosReg', (106, 115))	('apoptosis', 'CPA', (77, 86))	('ADT-OH', 'Var', (42, 48))	('ADT-OH', 'Chemical', 'MESH:C092798', (42, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('caspase-3', 'Gene', (134, 143))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('ADT', 'cellular_component', 'GO:0030956', ('42', '45'))
12983	31949127	Interestingly, in this study, we found that ADT-OH could not only induce apoptosis through this reported intrinsic apoptotic pathway but also enhance the extrinsic apoptotic pathway, as evidenced by the cleavage of caspase-8.	('ADT-OH', 'Var', (44, 50))	('ADT-OH', 'Chemical', 'MESH:C092798', (44, 50))	('intrinsic apoptotic pathway', 'Pathway', (105, 132))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('induce', 'PosReg', (66, 72))	('extrinsic apoptotic pathway', 'Pathway', (154, 181))	('apoptosis', 'CPA', (73, 82))	('extrinsic apoptotic pathway', 'biological_process', 'GO:0097191', ('154', '181'))	('enhance', 'PosReg', (142, 149))	('caspase-8', 'Gene', '12370', (215, 224))	('intrinsic apoptotic pathway', 'biological_process', 'GO:0097193', ('105', '132'))	('caspase-8', 'Gene', (215, 224))	('ADT', 'cellular_component', 'GO:0030956', ('44', '47'))
12984	31949127	Here, our study showed that ADT-OH significantly increased the protein level of FADD in several cancer cell lines, including B16F10 melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('protein level', 'MPA', (63, 76))	('melanoma', 'Disease', (132, 140))	('B16F10', 'CellLine', 'CVCL:0159', (125, 131))	('ADT', 'cellular_component', 'GO:0030956', ('28', '31'))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('increased', 'PosReg', (49, 58))	('ADT-OH', 'Var', (28, 34))	('ADT-OH', 'Chemical', 'MESH:C092798', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
12986	31949127	In addition, our results showed that ADT-OH significantly decreased the protein stability of MKRN1.	('MKRN1', 'Protein', (93, 98))	('protein stability', 'MPA', (72, 89))	('decreased', 'NegReg', (58, 67))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('ADT-OH', 'Var', (37, 43))	('ADT', 'cellular_component', 'GO:0030956', ('37', '40'))	('ADT-OH', 'Chemical', 'MESH:C092798', (37, 43))
12988	31949127	Interestingly, our results suggested that ADT-OH might increase the stability of FADD by decreasing the stability of MKRN1.	('stability of FADD', 'CPA', (68, 85))	('increase', 'PosReg', (55, 63))	('ADT-OH', 'Var', (42, 48))	('ADT-OH', 'Chemical', 'MESH:C092798', (42, 48))	('stability', 'MPA', (104, 113))	('decreasing', 'NegReg', (89, 99))	('ADT', 'cellular_component', 'GO:0030956', ('42', '45'))
12991	31949127	The data showed that the FADD-KO melanoma cells had little response to ADT-OH and that the level of apoptosis induced by ADT-OH was much lower than that of the wild-type cells.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('lower', 'NegReg', (137, 142))	('melanoma', 'Disease', (33, 41))	('ADT-OH', 'Var', (121, 127))	('ADT-OH', 'Chemical', 'MESH:C092798', (121, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('ADT', 'cellular_component', 'GO:0030956', ('71', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('ADT-OH', 'Chemical', 'MESH:C092798', (71, 77))	('response', 'MPA', (59, 67))	('ADT', 'cellular_component', 'GO:0030956', ('121', '124'))	('apoptosis', 'MPA', (100, 109))
12992	31949127	In addition, in vivo experiments showed that ADT-OH had no significant therapeutic effect on FADD-knockout melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('ADT-OH', 'Var', (45, 51))	('ADT-OH', 'Chemical', 'MESH:C092798', (45, 51))	('ADT', 'cellular_component', 'GO:0030956', ('45', '48'))
12993	31949127	Altogether, these results show that FADD knockout greatly blunts the pro-apoptotic effect of ADT-OH and indicate that FADD plays an important role in the treatment of melanoma with ADT-OH.	('ADT', 'cellular_component', 'GO:0030956', ('93', '96'))	('ADT-OH', 'Chemical', 'MESH:C092798', (181, 187))	('blunts', 'NegReg', (58, 64))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('knockout', 'Var', (41, 49))	('pro-apoptotic effect', 'MPA', (69, 89))	('ADT', 'cellular_component', 'GO:0030956', ('181', '184'))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('ADT-OH', 'Chemical', 'MESH:C092798', (93, 99))	('FADD', 'Gene', (36, 40))
12999	31949127	In addition, it should be noted that the dose of ADT-OH used in our study was less than one-half the dose of other H2S donors reportedly used in previous studies.	('H2S', 'Gene', '110798', (115, 118))	('ADT', 'cellular_component', 'GO:0030956', ('49', '52'))	('ADT-OH', 'Var', (49, 55))	('H2S', 'Gene', (115, 118))	('ADT-OH', 'Chemical', 'MESH:C092798', (49, 55))	('donor', 'Species', '9606', (119, 124))
13003	31949127	We also demonstrate that the combination of ADT-OH with VNP-FADD may provide a promising alternative therapy for melanoma, although further studies are needed to evaluate its potential in clinical applications.	('VNP', 'Gene', (56, 59))	('ADT-OH', 'Var', (44, 50))	('ADT-OH', 'Chemical', 'MESH:C092798', (44, 50))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('VNP', 'Gene', '380823', (56, 59))	('ADT', 'cellular_component', 'GO:0030956', ('44', '47'))
13015	29545914	Many studies, performed in animal models and in primary tumors, shed light on the complex genomic background involved in metastatic progression of MM; it has also been reported that mutation rate and gene modulation in melanoma are higher than in other solid malignancies.	('gene modulation', 'Var', (200, 215))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('malignancies', 'Disease', (259, 271))	('primary tumors', 'Disease', (48, 62))	('higher', 'Reg', (232, 238))	('primary tumors', 'Disease', 'MESH:D009369', (48, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (182, 190))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('malignancies', 'Disease', 'MESH:D009369', (259, 271))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('melanoma', 'Disease', (219, 227))
13041	29545914	As shown in Supplementary Figure 2 we found similar results even if A2P treatment affected cell viability also at a lower concentration In order to evaluate the involvement of the above genes in melanoma malignancy, we analyzed their expression levels in cancer and normal cells (melanocytes and fibroblasts); we also investigated the relationship between gene expression levels and migratory ability.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('melanoma malignancy', 'Disease', 'MESH:D008545', (195, 214))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('melanoma malignancy', 'Disease', (195, 214))	('A2P', 'Var', (68, 71))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('cancer', 'Disease', (255, 261))	('investigated', 'Reg', (318, 330))	('gene expression', 'biological_process', 'GO:0010467', ('356', '371'))
13044	29545914	SSBP1 instead was higher only in Colo853, compared to melanocytes and normal fibroblasts.	('Colo853', 'Var', (33, 40))	('SSBP1', 'Gene', '6742', (0, 5))	('Colo', 'Species', '307630', (33, 37))	('higher', 'PosReg', (18, 24))	('SSBP1', 'Gene', (0, 5))
13047	29545914	To confirm the relation between gene expression and migration ability we knocked down NMP1and PARK7 in A375 and Mewo cell lines by applying NMP1 and PARK7 specific shRNA sequences, respectively.	('NMP1and', 'Gene', (86, 93))	('PARK7', 'Gene', '11315', (149, 154))	('gene expression', 'biological_process', 'GO:0010467', ('32', '47'))	('A375', 'CellLine', 'CVCL:0132', (103, 107))	('PARK7', 'Gene', (94, 99))	('PARK7', 'Gene', (149, 154))	('PARK7', 'Gene', '11315', (94, 99))	('knocked', 'Var', (73, 80))
13048	29545914	In NMP1 and PARK 7 knock-down cells the expression of the above genes was reduced as well as migration ability, compared to A375 and Mewo WT cells (Supplementary Figure 3).	('expression', 'MPA', (40, 50))	('PARK 7', 'Gene', '11315', (12, 18))	('PARK 7', 'Gene', (12, 18))	('A375', 'CellLine', 'CVCL:0132', (124, 128))	('NMP1', 'Gene', (3, 7))	('migration ability', 'CPA', (93, 110))	('reduced', 'NegReg', (74, 81))	('knock-down', 'Var', (19, 29))
13056	29545914	Stathmin 1 showed a statistically significant (p-value = 1.069e-4; Q-value = 5.024e-3) over-expression compared to the unaltered group; Deglycase DJ-1 tended to be slightly under-expressed, although the result was not statistically significant (p-value = 0.783; Q-value = 0.876).	('Deglycase', 'Var', (136, 145))	('Stathmin 1', 'Gene', '3925', (0, 10))	('Stathmin 1', 'Gene', (0, 10))	('DJ-1', 'Gene', '11315', (146, 150))	('over-expression', 'PosReg', (87, 102))	('under-expressed', 'NegReg', (173, 188))	('DJ-1', 'Gene', (146, 150))
13074	29545914	Nucleophosmin results to be engaged in various processes such as chromosome maintenance (i.e., nucleosome assembly and telomerase maintenance), DNA repair (GO:0006281), DNA damage response via p53 (GO:0006977), intracellular protein (GO:0006886) and nucleocytoplasmic (GO:0006913) transport, response to stress (GO:0006950), cell aging (GO:0007569), and HIF1 alpha transcription factor network.	('transport', 'biological_process', 'GO:0006810', ('281', '290'))	('p53', 'Gene', (193, 196))	('GO:0006886', 'Var', (234, 244))	('nucleosome', 'cellular_component', 'GO:0000786', ('95', '105'))	('HIF1 alpha', 'Gene', (354, 364))	('Nucleophosmin', 'Gene', '4869', (0, 13))	('DNA', 'cellular_component', 'GO:0005574', ('169', '172'))	('intracellular protein', 'MPA', (211, 232))	('DNA repair', 'biological_process', 'GO:0006281', ('144', '154'))	('cell aging', 'biological_process', 'GO:0007569', ('325', '335'))	('nucleosome assembly', 'biological_process', 'GO:0006334', ('95', '114'))	('response to stress', 'biological_process', 'GO:0006950', ('292', '310'))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('transcription', 'biological_process', 'GO:0006351', ('365', '378'))	('GO:0006913', 'Var', (269, 279))	('HIF1 alpha', 'Gene', '3091', (354, 364))	('DNA damage response', 'biological_process', 'GO:0006974', ('169', '188'))	('GO:0006950', 'Var', (312, 322))	('GO:0006281', 'Var', (156, 166))	('GO:0006977', 'Var', (198, 208))	('intracellular', 'cellular_component', 'GO:0005622', ('211', '224'))	('GO:0007569', 'Var', (337, 347))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('p53', 'Gene', '7157', (193, 196))	('Nucleophosmin', 'Gene', (0, 13))	('transcription factor', 'molecular_function', 'GO:0000981', ('365', '385'))	('DNA', 'MPA', (169, 172))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
13078	29545914	This relation was confirmed by RNA interference assay as PARK7 knockdown reduced the migration ability.	('migration ability', 'CPA', (85, 102))	('PARK7', 'Gene', '11315', (57, 62))	('RNA interference', 'biological_process', 'GO:0016246', ('31', '47'))	('reduced', 'NegReg', (73, 80))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('PARK7', 'Gene', (57, 62))	('knockdown', 'Var', (63, 72))
13101	29545914	MtSSB protein is phosphorylated by CHEK1 that plays a role in DNA damage checkpoint (GO:0000077), G2/M transition of mitotic cell cycle (GO:0000086) and DNA repair (GO:0006281).	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('DNA repair', 'biological_process', 'GO:0006281', ('153', '163'))	('GO:0000086', 'Var', (137, 147))	('CHEK1', 'Gene', '1111', (35, 40))	('G2/M transition of mitotic cell cycle', 'biological_process', 'GO:0000086', ('98', '135'))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('MtSSB', 'Gene', (0, 5))	('mitotic cell cycle', 'CPA', (117, 135))	('MtSSB', 'Gene', '6742', (0, 5))	('DNA damage checkpoint', 'biological_process', 'GO:0000077', ('62', '83'))	('CHEK1', 'Gene', (35, 40))
13104	29545914	Furthermore SSBP1 associates with acetyltransferase p300 and promotes p53 acetylation.	('associates', 'Interaction', (18, 28))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('promotes', 'PosReg', (61, 69))	('SSBP1', 'Gene', '6742', (12, 17))	('acetylation', 'MPA', (74, 85))	('p300', 'Var', (52, 56))	('acetyltransferase', 'Enzyme', (34, 51))	('SSBP1', 'Gene', (12, 17))
13106	29545914	In particular we found that reduced cell viability and migration ability observed after AsA treatment in MeWo cells are associated to ENO1, PTGES3, NPM1, PARK7 and STMN1 genes dowregulation.	('reduced', 'NegReg', (28, 35))	('cell viability', 'CPA', (36, 50))	('STMN1', 'Gene', '3925', (164, 169))	('STMN1', 'Gene', (164, 169))	('NPM1', 'Gene', '4869', (148, 152))	('PARK7', 'Gene', '11315', (154, 159))	('PTGES3', 'Gene', (140, 146))	('AsA', 'Chemical', 'MESH:D001205', (88, 91))	('dowregulation', 'Var', (176, 189))	('migration ability', 'CPA', (55, 72))	('ENO1', 'Gene', (134, 138))	('ENO1', 'Gene', '2023', (134, 138))	('PTGES3', 'Gene', '10728', (140, 146))	('NPM1', 'Gene', (148, 152))	('PARK7', 'Gene', (154, 159))
13147	27167347	Targeted therapies such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and MEK inhibitors have shown significant survival advantage in BRAF-mutant melanoma 1, 2, 3, 4.	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (27, 73))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (27, 73))	('survival', 'CPA', (123, 131))	('BRAF-mutant', 'Var', (145, 156))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
13149	27167347	Ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) human monoclonal antibody (IgG1) that blocks the T-cell co-inhibitory signal 5, 6 demonstrated significant survival benefit in metastatic melanoma patients regardless of BRAF mutation status, whereas tremelimumab, another anti-CTLA-4 IgG2 monoclonal antibody, failed to show such benefit 7.	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('antibody', 'molecular_function', 'GO:0003823', ('323', '331'))	('patients', 'Species', '9606', (220, 228))	('antibody', 'cellular_component', 'GO:0042571', ('323', '331'))	('antibody', 'molecular_function', 'GO:0003823', ('90', '98'))	('antibody', 'cellular_component', 'GO:0042571', ('90', '98'))	('IgG1', 'cellular_component', 'GO:0071735', ('100', '104'))	('human', 'Species', '9606', (73, 78))	('mutation', 'Var', (248, 256))	('survival', 'CPA', (180, 188))	('antibody', 'cellular_component', 'GO:0019815', ('323', '331'))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('BRAF', 'Gene', (243, 247))	('antibody', 'cellular_component', 'GO:0019815', ('90', '98'))	('CTLA-4', 'Gene', '1493', (300, 306))	('CTLA-4', 'Gene', (300, 306))	('benefit', 'PosReg', (189, 196))	('tremelimumab', 'Chemical', 'MESH:C520704', (273, 285))	('CTLA-4', 'Gene', '1493', (20, 26))	('antibody', 'cellular_component', 'GO:0019814', ('323', '331'))	('IgG2', 'cellular_component', 'GO:0071735', ('307', '311'))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('antibody', 'cellular_component', 'GO:0019814', ('90', '98'))	('CTLA-4', 'Gene', (20, 26))
13156	27167347	The following information was extracted from individual trial reports: publication year, inclusion/exclusion criteria, sample size, median age, American Joint Committee on Cancer (AJCC) Stage, BRAF mutation status, PD-L1 positivity, number of prior systemic treatments, response to previous ipilimumab treatment, PFS, OS, ORR (defined as rate of complete remission or partial remission), adverse events, and mortality attributed to disease progression.	('BRAF', 'Gene', (193, 197))	('PFS', 'Disease', (313, 316))	('PD-L1', 'Gene', (215, 220))	('ORR', 'Disease', (322, 325))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', (172, 178))	('ipilimumab', 'Chemical', 'MESH:D000074324', (291, 301))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('PD-L1', 'Gene', '29126', (215, 220))	('positivity', 'Var', (221, 231))	('mutation', 'Var', (198, 206))
13158	27167347	Predefined criteria including experimental agent (anti-CTLA-4 vs. anti-PD-1), response to prior ipilimumab treatment (naive vs. refractory), BRAF mutation status (wild-type vs. V600E mutation), and PD-L1 positivity (expression level >5% vs. <=5%) were used for subgroup analyses to explore heterogeneity and to identify subgroups with differential benefit from the experimental agents (Table 2).	('PD-1', 'Gene', '5133', (71, 75))	('BRAF', 'Gene', (141, 145))	('PD-L1', 'Gene', (198, 203))	('V600E mutation', 'Var', (177, 191))	('ipilimumab', 'Chemical', 'MESH:D000074324', (96, 106))	('CTLA-4', 'Gene', (55, 61))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('PD-L1', 'Gene', '29126', (198, 203))	('CTLA-4', 'Gene', '1493', (55, 61))	('PD-1', 'Gene', (71, 75))
13167	27167347	BRAF mutation status and PD-L1 positivity were reported in three studies with anti-PD-1 treatment 12, 45, 46.	('PD-L1', 'Gene', '29126', (25, 30))	('PD-1', 'Gene', (83, 87))	('PD-1', 'Gene', '5133', (83, 87))	('PD-L1', 'Gene', (25, 30))	('mutation', 'Var', (5, 13))
13168	27167347	The numbers of patients with BRAF mutation, PD-L1 positivity, no prior systemic treatment, and ipilimumab refractory disease were 89, 407, 1373, and 945, respectively (Table S2).	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', (29, 33))	('mutation', 'Var', (34, 42))	('PD-L1', 'Gene', (44, 49))	('ipilimumab', 'Chemical', 'MESH:D000074324', (95, 105))	('PD-L1', 'Gene', '29126', (44, 49))
13187	27167347	In prior study of nivolumab, PD-L1 positivity, defined as more than 5% by immunohistochemistry staining, was associated with better response, although the association disappeared when a cutoff value of 1% was used as the positivity criteria 13.	('response', 'MPA', (132, 140))	('PD-L1', 'Gene', (29, 34))	('positivity', 'Var', (35, 45))	('better', 'PosReg', (125, 131))	('PD-L1', 'Gene', '29126', (29, 34))	('nivolumab', 'Chemical', 'MESH:D000077594', (18, 27))
13189	27167347	Similarly, in our meta-analysis, the subgroup with PD-L1 positivity (more than 5%) had a better treatment response to anti-PD-1 agents compared to the PD-L1-negative subgroup (Fig.	('PD-1', 'Gene', (123, 127))	('better', 'PosReg', (89, 95))	('PD-L1', 'Gene', '29126', (151, 156))	('PD-1', 'Gene', '5133', (123, 127))	('treatment response', 'MPA', (96, 114))	('PD-L1', 'Gene', '29126', (51, 56))	('PD-L1', 'Gene', (151, 156))	('positivity', 'Var', (57, 67))	('PD-L1', 'Gene', (51, 56))
13194	27167347	PD-L1 expression levels were shown to be variable in different metastatic lesions in the same patient and anti-PD-1 treatment response also seemed to be affected by tumor mutational load and preexisting intratumor CD8 +  T-cells based on preclinical studies 56, 57, 58.	('CD8', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mutational load', 'Var', (171, 186))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('expression', 'MPA', (6, 16))	('CD8', 'Gene', '925', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('PD-1', 'Gene', (111, 115))	('tumor', 'Disease', (208, 213))	('patient', 'Species', '9606', (94, 101))	('PD-1', 'Gene', '5133', (111, 115))	('PD-L1', 'Gene', '29126', (0, 5))	('affected', 'Reg', (153, 161))	('tumor', 'Disease', (165, 170))
13197	27167347	performed a pooled analysis from four studies including phase I and III trials to compare the clinical outcomes between patients with and without BRAF mutation who were treated with nivolumab 61.	('nivolumab 61', 'Chemical', '-', (182, 194))	('BRAF', 'Gene', (146, 150))	('patients', 'Species', '9606', (120, 128))	('mutation', 'Var', (151, 159))
13211	27167347	Second, BRAF inhibitor as a single agent and in combination with a MEK inhibitor was shown to improve survival in patients with BRAF mutation 1, 2, 3, 4, and immune check point inhibitors are effective regardless of BRAF mutation status 21, 59, 60.	('mutation', 'Var', (133, 141))	('survival', 'CPA', (102, 110))	('improve', 'PosReg', (94, 101))	('patients', 'Species', '9606', (114, 122))	('BRAF', 'Gene', (128, 132))
13212	27167347	Therefore, the optimal sequence for treatment, especially in patients with BRAF mutation, needs further investigation.	('BRAF', 'Gene', (75, 79))	('patients', 'Species', '9606', (61, 69))	('mutation', 'Var', (80, 88))
13214	27167347	In a meta-analysis of randomized controlled trials with unresectable cutaneous metastatic melanoma patients, agents targeting immune checkpoints were associated with better PFS, OS, and ORR compared to conventional treatments.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('cutaneous metastatic melanoma', 'Phenotype', 'HP:0012056', (69, 98))	('ORR', 'Disease', (186, 189))	('PFS', 'Disease', (173, 176))	('patients', 'Species', '9606', (99, 107))	('agents', 'Var', (109, 115))	('better', 'PosReg', (166, 172))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
13224	31892603	Furthermore, molecular and clinicopathological studies have demonstrated a correlation between defects in vitamin D signaling and progression of melanoma and disease outcome.	('vitamin D signaling', 'MPA', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('defects in vitamin D', 'Phenotype', 'HP:0100512', (95, 115))	('defects', 'Var', (95, 102))	('vitamin D', 'Chemical', 'MESH:D014807', (106, 115))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
13229	31892603	We also present the association of vitamin D and melanoma based on epidemiological, experimental and clinical evidence, showing that defects in vitamin D signaling correlate with progression of melanoma and disease outcome.	('vitamin D signaling', 'MPA', (144, 163))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('defects in vitamin D', 'Phenotype', 'HP:0100512', (133, 153))	('men', 'Species', '9606', (90, 93))	('vitamin D', 'Chemical', 'MESH:D014807', (35, 44))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('defects', 'Var', (133, 140))	('vitamin D', 'Chemical', 'MESH:D014807', (144, 153))	('melanoma', 'Disease', (49, 57))
13236	31892603	Inactivation of both 25(OH)D3 and 1,25(OH)2D3 is catalyzed by cytochrome P450 family 24 subfamily A member 1 (CYP24A1) via hydroxylation.	('cytochrome P450', 'molecular_function', 'GO:0019825', ('62', '77'))	('CYP24A1', 'Gene', (110, 117))	('CYP24A1', 'Gene', '1591', (110, 117))	('1,25(OH)2D3', 'Var', (34, 45))	('cytochrome P450 family 24 subfamily A member 1', 'Gene', '1591', (62, 108))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('62', '77'))	('25(OH)D3', 'Chemical', 'MESH:D002112', (21, 29))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (34, 45))	('cytochrome P450 family 24 subfamily A member 1', 'Gene', (62, 108))	('25(OH)D3', 'Var', (21, 29))	('hydroxylation', 'MPA', (123, 136))
13240	31892603	In the non-canonical pathway, vitamin D3 is activated by the action of steroidogenic enzyme CYP11A1 with initial production 20(OH)D3 and 22(OH)2D3, and further hydroxylation of the side chain by the same enzyme (Figure 1).	('20(OH)D3', 'Chemical', 'MESH:C480634', (124, 132))	('vitamin D3', 'Chemical', 'MESH:D002762', (30, 40))	('CYP11A1', 'Gene', '1583', (92, 99))	('CYP11A1', 'molecular_function', 'GO:0008386', ('92', '99'))	('20(OH)D3', 'Var', (124, 132))	('hydroxylation of the', 'MPA', (160, 180))	('activated', 'PosReg', (44, 53))	('CYP11A1', 'Gene', (92, 99))	('(OH)2D3', 'Chemical', '-', (139, 146))	('non-canonical pathway', 'Pathway', (7, 28))
13250	31892603	Individuals with genetically conditioned disease, such as xeroderma pigmentosum, related to mutations in XP and XPV genes, encoding proteins crucial for nucleotide excision repair whereby they are unable to repair UV-induced DNA damage, are more susceptible to both melanoma (more than 2,000-fold increased risk in comparison to the general population) and non-melanoma skin cancer (more than a 10,000-fold increased incidence in comparison to the general population).	('xeroderma pigmentosum', 'Disease', (58, 79))	('non-melanoma skin cancer', 'Disease', (357, 381))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('melanoma', 'Disease', 'MESH:D008545', (361, 369))	('increased', 'PosReg', (297, 306))	('XPV genes', 'Gene', (112, 121))	('DNA', 'cellular_component', 'GO:0005574', ('225', '228'))	('unable', 'NegReg', (197, 203))	('susceptible', 'Reg', (246, 257))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('mutations', 'Var', (92, 101))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('153', '179'))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (58, 79))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (357, 381))	('melanoma', 'Phenotype', 'HP:0002861', (361, 369))	('melanoma', 'Disease', (361, 369))	('skin cancer', 'Phenotype', 'HP:0008069', (370, 381))
13253	31892603	The mechanism involved in UV-induced carcinogenesis is complex and is related to such processes as immunosuppression, induction of mutations in a broad range of genes, stimulation of growth via altered expression of growth factors, cytokines, neuropetides and their receptors, and which can affect keratinocytes and melanocytes, and promote melanocyte-fibroblast interactions, and modify cadherins, integrins, melanoma inhibitory activity and expression of other genes (Figure 1).	('mutations', 'Var', (131, 140))	('cadherins', 'Protein', (388, 397))	('expression', 'MPA', (443, 453))	('carcinogenesis', 'Disease', 'MESH:D063646', (37, 51))	('carcinogenesis', 'Disease', (37, 51))	('promote', 'PosReg', (333, 340))	('melanoma', 'Disease', 'MESH:D008545', (410, 418))	('melanoma', 'Phenotype', 'HP:0002861', (410, 418))	('melanoma', 'Disease', (410, 418))	('stimulation of growth', 'biological_process', 'GO:0045927', ('168', '189'))	('integrins', 'Protein', (399, 408))	('affect', 'Reg', (291, 297))	('modify', 'Reg', (381, 387))	('melanocyte-fibroblast interactions', 'CPA', (341, 375))
13254	31892603	Although UV fingerprint mutations have been identified in genes p53 and cyclin-dependent kinase inhibitor 2A (CDKN2A) in BCC and SCC, the role of p53 in melanomagenesis is not defined [reviewed in ].	('CDKN2A', 'Gene', (110, 116))	('SCC', 'Disease', (129, 132))	('CDKN2A', 'Gene', '1029', (110, 116))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('p53', 'Gene', (64, 67))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('72', '105'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('89', '105'))	('mutations', 'Var', (24, 33))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (72, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (72, 108))	('BCC', 'Disease', (121, 124))	('p53', 'Gene', '7157', (64, 67))
13271	31892603	The involvement of UV in melanoma development is, in part, related to genetic factors, such as germline mutations, pigmentation, UV-induced mutations or inability to repair UV-induced DNA damages.	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('pigmentation', 'Disease', 'MESH:D010859', (115, 127))	('men', 'Species', '9606', (11, 14))	('men', 'Species', '9606', (118, 121))	('pigmentation', 'Disease', (115, 127))	('inability', 'Disease', 'MESH:D007319', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('men', 'Species', '9606', (41, 44))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('mutations', 'Var', (140, 149))	('pigmentation', 'biological_process', 'GO:0043473', ('115', '127'))	('melanoma', 'Disease', (25, 33))	('involvement', 'Reg', (4, 15))	('inability', 'Disease', (153, 162))
13274	31892603	About 20% of patients with susceptibility to melanoma are carriers of a CDKN2A (called also INK4a/ARF) gene mutation, coding two structurally distinct proteins, p14ARF and p16INK4a, involved in cell-cycle regulation, with mutations in p16INK4a.	('p16INK4a', 'Gene', '1029', (172, 180))	('INK4a/ARF', 'Gene', (92, 101))	('INK4a/ARF', 'Gene', '1029', (92, 101))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('194', '215'))	('p16INK4a', 'Gene', (235, 243))	('p16INK4a', 'Gene', (172, 180))	('p14ARF', 'Gene', (161, 167))	('patients', 'Species', '9606', (13, 21))	('CDKN2A', 'Gene', '1029', (72, 78))	('p16INK4a', 'Gene', '1029', (235, 243))	('mutations', 'Var', (222, 231))	('mutation', 'Var', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('p14ARF', 'Gene', '1029', (161, 167))	('CDKN2A', 'Gene', (72, 78))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
13275	31892603	Mutations in the cyclin-dependent kinase-4 (CDK4) gene confer susceptibility to cutaneous melanoma, but mutations in CDK4 are not as frequent as those in CDKN2A.	('CDK4', 'Gene', '1019', (117, 121))	('cyclin', 'molecular_function', 'GO:0016538', ('17', '23'))	('CDK', 'molecular_function', 'GO:0004693', ('117', '120'))	('cutaneous melanoma', 'Disease', (80, 98))	('CDKN2A', 'Gene', (154, 160))	('CDK4', 'Gene', '1019', (44, 48))	('susceptibility', 'Reg', (62, 76))	('CDK4', 'Gene', (44, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('cyclin-dependent kinase-4', 'Gene', (17, 42))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '1029', (154, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cyclin-dependent kinase-4', 'Gene', '1019', (17, 42))	('CDK4', 'Gene', (117, 121))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
13276	31892603	in addition, germline mutations in the tumor-suppressor BRCA-associated protein-1 (BAP1) gene, ubiquitin C-terminal hydrolase, encoding the protein interacting with BRCA1, have been identified in fewer than 1% of cutaneous melanomas.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ubiquitin C-terminal hydrolase', 'Gene', '7345', (95, 125))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (213, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (213, 231))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (213, 232))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('ubiquitin C-terminal hydrolase', 'molecular_function', 'GO:0036459', ('95', '125'))	('BRCA-associated protein-1', 'Gene', '8314', (56, 81))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('39', '55'))	('BAP1', 'Gene', '8314', (83, 87))	('identified', 'Reg', (182, 192))	('germline', 'Var', (13, 21))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('39', '55'))	('cutaneous melanomas', 'Disease', (213, 232))	('BRCA-associated protein-1', 'Gene', (56, 81))	('tumor', 'Disease', (39, 44))	('BRCA1', 'Gene', '672', (165, 170))	('ubiquitin C-terminal hydrolase', 'Gene', (95, 125))	('BRCA1', 'Gene', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BAP1', 'Gene', (83, 87))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('melanomas', 'Phenotype', 'HP:0002861', (223, 232))
13277	31892603	Melanocortin 1 receptor (MC1R) mutations increase susceptibility to melanoma in general population.	('MC1R', 'Gene', '4157', (25, 29))	('mutations', 'Var', (31, 40))	('MC1R', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('Melanocortin 1 receptor', 'Gene', (0, 23))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('susceptibility', 'MPA', (50, 64))	('Melanocortin 1 receptor', 'Gene', '4157', (0, 23))
13281	31892603	However recently mutations in BAP1 were found to be related to younger age (39-50 years) at diagnosis, and higher risk of second tumors (cutaneous melanoma, renal cell carcinoma) has been identified.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (157, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('tumors', 'Disease', (129, 135))	('BAP1', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('BAP1', 'Gene', '8314', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('renal cell carcinoma', 'Disease', (157, 177))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('cutaneous melanoma', 'Disease', (137, 155))	('mutations', 'Var', (17, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))
13304	31892603	1,25(OH)2D3 has antitumor properties affecting molecular pathways involved in proliferation, apoptosis and differentiation, but can also improve effectiveness of classical anticancer therapies.	('molecular pathways', 'Pathway', (47, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('differentiation', 'CPA', (107, 122))	('improve', 'PosReg', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('1,25(OH)2D3', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('proliferation', 'CPA', (78, 91))	('cancer', 'Disease', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('apoptosis', 'CPA', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Disease', (20, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
13309	31892603	Colston and co-workers showed VDR-expressing melanoma cells were inhibited by 1,25(OH)2D3.	('1,25(OH)2D3', 'Var', (78, 89))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (78, 89))	('inhibited', 'NegReg', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
13315	31892603	1,25(OH)2D3 also inhibited colony formation by SkMel-188 cells.	('1,25(OH)2D3', 'Var', (0, 11))	('inhibited', 'NegReg', (17, 26))	('colony formation', 'CPA', (27, 43))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))
13316	31892603	The antiproliferative activity of 1,25(OH)2D3l, calcipotriol and 25(OH)D3 are related to the expression VDR and CYP27B1.	('calcipotriol', 'Chemical', 'MESH:C055085', (48, 60))	('CYP27B1', 'Gene', '1594', (112, 119))	('25(OH)D3', 'Var', (65, 73))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (34, 45))	('CYP27B1', 'Gene', (112, 119))	('25(OH)D3', 'Chemical', 'MESH:D002112', (65, 73))	('antiproliferative', 'CPA', (4, 21))	('VDR', 'Gene', (104, 107))
13324	31892603	20,23(OH)2D3, and 1,20(OH)2D3 also inhibited proliferation and colony formation of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('formation', 'biological_process', 'GO:0009058', ('70', '79'))	('(OH)2D3', 'Chemical', '-', (5, 12))	('inhibited', 'NegReg', (35, 44))	('(OH)2D3', 'Chemical', '-', (22, 29))	('1,20(OH)2D3', 'Var', (18, 29))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
13328	31892603	The antitumorigenic activity of 1,25(OH)2D3 in an animal model was reported for the first time by Eisman and coworkers, demonstrating the inhibition by 1,25(OH)2D3 of the growth of human melanoma cells COLO 239F expressing VDR, which were injected into immunosuppressed mice.	('human', 'Species', '9606', (181, 186))	('inhibition', 'NegReg', (138, 148))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('growth', 'MPA', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (32, 43))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('COLO', 'Species', '307630', (202, 206))	('tumor', 'Disease', (8, 13))	('mice', 'Species', '10090', (270, 274))	('VDR', 'Gene', (223, 226))	('1,25(OH)2D3', 'Var', (152, 163))
13330	31892603	The VDR-positive SKMel-188 melanoma cell line, injected into immunocompromised mice, was inhibited by 20(OH)D3.	('inhibited', 'NegReg', (89, 98))	('mice', 'Species', '10090', (79, 83))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('20(OH)D3', 'Chemical', 'MESH:C480634', (102, 110))	('20(OH)D3', 'Var', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('SKMel-188', 'CellLine', 'CVCL:6098', (17, 26))
13331	31892603	1,25(OH)2D3 reduced lung metastasis of B16 melanoma cells injected into mouse by affecting the extracellular matrix, and 1(OH)D2 reduced tumor growth in Tyr-Tag transgenic mice, which develop pigmented ocular tumors, similar to human choroidal melanoma.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('choroidal melanoma', 'Disease', 'MESH:D008545', (234, 252))	('mouse', 'Species', '10090', (72, 77))	('reduced', 'NegReg', (129, 136))	('tumor', 'Disease', (209, 214))	('ocular tumors', 'Phenotype', 'HP:0100012', (202, 215))	('pigmented ocular tumors', 'Disease', 'MESH:D010859', (192, 215))	('choroidal melanoma', 'Disease', (234, 252))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('lung metastasis', 'CPA', (20, 35))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (234, 252))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('95', '115'))	('tumor', 'Disease', (137, 142))	('extracellular matrix', 'MPA', (95, 115))	('pigmented ocular tumors', 'Disease', (192, 215))	('Tyr', 'Chemical', 'MESH:D014443', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('human', 'Species', '9606', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('affecting', 'Reg', (81, 90))	('1(OH)D2', 'Var', (121, 128))	('reduced', 'NegReg', (12, 19))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('transgenic mice', 'Species', '10090', (161, 176))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
13334	31892603	Garland and Garland suggested that low-sun-exposure-related vitamin D insufficiency was correlated with higher colon cancer mortality rates.	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('mortality', 'Disease', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('colon cancer', 'Disease', (111, 123))	('mortality', 'Disease', 'MESH:D003643', (124, 133))	('low-sun-exposure-related', 'Var', (35, 59))	('insufficiency', 'Disease', 'MESH:D000309', (70, 83))	('higher', 'PosReg', (104, 110))	('vitamin D', 'Chemical', 'MESH:D014807', (60, 69))	('insufficiency', 'Disease', (70, 83))	('vitamin D insufficiency', 'Phenotype', 'HP:0100512', (60, 83))
13339	31892603	Subsequent studies confirmed that a lower vitamin D level was related to greater progression of melanoma (Breslow thickness, Clark level, the American Joint Committee on Cancer stage), the presences of poor prognostic markers (ulceration, higher mitotic index), shorter overall survival and increased risk for melanoma-specific death.	('lower', 'NegReg', (36, 41))	('Cancer', 'Disease', 'MESH:D009369', (170, 176))	('Clark level', 'MPA', (125, 136))	('vitamin D', 'Chemical', 'MESH:D014807', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('lower vitamin D', 'Phenotype', 'HP:0100512', (36, 51))	('melanoma', 'Disease', (310, 318))	('higher', 'PosReg', (239, 245))	('vitamin D level', 'MPA', (42, 57))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('shorter', 'NegReg', (262, 269))	('overall', 'MPA', (270, 277))	('presences', 'Var', (189, 198))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('Cancer', 'Disease', (170, 176))
13342	31892603	These authors suggested that melanomas associated with a low vitamin D level might be a different type from those associated with a higher nevi count, thus further studies are required to explain the association between nevi, melanoma and vitamin D level.	('nevi', 'Phenotype', 'HP:0003764', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('melanoma', 'Disease', (29, 37))	('low vitamin D', 'Phenotype', 'HP:0100512', (57, 70))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('nevi', 'Phenotype', 'HP:0003764', (139, 143))	('vitamin D', 'Chemical', 'MESH:D014807', (239, 248))	('low', 'Var', (57, 60))	('vitamin D', 'Chemical', 'MESH:D014807', (61, 70))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('vitamin D level', 'MPA', (61, 76))	('melanomas', 'Disease', (29, 38))
13356	31892603	Additionally, patients with melanoma showing poor prognostic markers such as nodular type, high mitotic index, ulceration and necrosis had low CYP24A1 expression.	('melanoma', 'Disease', (28, 36))	('necrosis', 'biological_process', 'GO:0001906', ('126', '134'))	('necrosis', 'Disease', (126, 134))	('low', 'NegReg', (139, 142))	('necrosis', 'biological_process', 'GO:0019835', ('126', '134'))	('necrosis', 'biological_process', 'GO:0008220', ('126', '134'))	('high', 'Var', (91, 95))	('necrosis', 'Disease', 'MESH:D009336', (126, 134))	('expression', 'MPA', (151, 161))	('necrosis', 'biological_process', 'GO:0070265', ('126', '134'))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('necrosis', 'biological_process', 'GO:0008219', ('126', '134'))	('patients', 'Species', '9606', (14, 22))	('CYP24A1', 'Gene', (143, 150))	('CYP24A1', 'Gene', '1591', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
13364	31892603	In summary, alterations in vitamin D activation, its local and systemic levels, and vitamin D-regulated signaling pathways can result in loss of anticancer protection provided by vitamin D and promote melanoma development.	('melanoma', 'Disease', (201, 209))	('promote', 'PosReg', (193, 200))	('cancer', 'Disease', (149, 155))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('men', 'Species', '9606', (217, 220))	('alterations', 'Var', (12, 23))	('activation', 'PosReg', (37, 47))	('vitamin D', 'Chemical', 'MESH:D014807', (27, 36))	('vitamin D', 'Gene', (27, 36))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('vitamin D', 'Chemical', 'MESH:D014807', (84, 93))	('loss', 'NegReg', (137, 141))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('vitamin D', 'Chemical', 'MESH:D014807', (179, 188))
13374	31892603	However, both experimental- and clinical-based studies clearly suggest that disturbances in vitamin D signaling may be related to melanoma development, progression and disease-free and overall survival of patients.	('disturbances', 'Var', (76, 88))	('patients', 'Species', '9606', (205, 213))	('related', 'Reg', (119, 126))	('men', 'Species', '9606', (146, 149))	('vitamin D', 'Chemical', 'MESH:D014807', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('melanoma', 'Disease', (130, 138))	('vitamin D signaling', 'MPA', (92, 111))	('men', 'Species', '9606', (20, 23))
13377	31892603	Since VDR, CYP27B1, CYP24A and ROR expression are related to the prognosis of patients with melanoma, they can be considered as potential biomarkers, similar to the serum vitamin D level.	('CYP27B1', 'Gene', (11, 18))	('ROR', 'Gene', (31, 34))	('CYP24A', 'Var', (20, 26))	('related', 'Reg', (50, 57))	('patients', 'Species', '9606', (78, 86))	('CYP27B1', 'Gene', '1594', (11, 18))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('VDR', 'Gene', (6, 9))	('vitamin D', 'Chemical', 'MESH:D014807', (171, 180))
13384	31741769	Our findings suggest L-EV cargo may serve as early mediators of tumor-induced immune subversion in regional lymph nodes, by preceding malignant cells and trafficking within the lymphatic vasculature to harbor the first pre-metastatic niche.	('tumor', 'Disease', (64, 69))	('L-EV', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cargo', 'molecular_function', 'GO:0140355', ('26', '31'))	('pre', 'molecular_function', 'GO:0003904', ('219', '222'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
13425	31741769	demonstrated in patients with metastatic disease lymphatic EVs have prognostic utility through the detection of BRAFV00E mutation on the lymphatic EVs and Broggi et al characterized the enrichment of tumor-associated factors including S100 proteins compared to plasma EVs, respectively While BRAF status was not clinically defined in the patients examined in the current study, future studies considering the influence of BRAF mutation on lymphatic EV cargo has the potential to highlight different mechanisms of action by which regional immunosuppression is mediated in the SLN.	('mutation', 'Var', (427, 435))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('S100', 'Gene', '6271', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('BRAF', 'Gene', (292, 296))	('BRAF', 'Gene', (112, 116))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', (422, 426))	('tumor', 'Disease', (200, 205))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', '673', (422, 426))	('cargo', 'molecular_function', 'GO:0140355', ('452', '457'))	('mutation', 'Var', (121, 129))	('BRAF', 'Gene', '673', (292, 296))	('patients', 'Species', '9606', (338, 346))	('S100', 'Gene', (235, 239))
13432	31741769	In this report, we propose a similar function for S100A9 in the pre-metastatic SLN whereby the lymphatic vasculature is utilized by the primary tumor in order to traffic subcellular factors including L-EV enriched with S100A9 from the primary tumor microenvironment to the pre-metastatic SLN (Figure 5).	('tumor', 'Disease', (144, 149))	('pre', 'molecular_function', 'GO:0003904', ('64', '67'))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('pre', 'molecular_function', 'GO:0003904', ('273', '276'))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('S100A9', 'Var', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
13462	30457212	The lncRNA RMEL3 protects immortalized cells from serum withdrawal-induced growth arrest and promotes melanoma cell proliferation and tumor growth RMEL3 is a recently identified lncRNA associated with BRAFV600E mutation and melanoma cell survival.	('melanoma cell', 'Disease', 'MESH:D008545', (102, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('growth arrest', 'Disease', 'MESH:D006323', (75, 88))	('melanoma cell', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('promotes', 'PosReg', (93, 101))	('growth arrest', 'Disease', (75, 88))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma cell', 'Disease', 'MESH:D008545', (224, 237))	('BRAFV600E', 'Mutation', 'rs113488022', (201, 210))	('tumor', 'Disease', (134, 139))	('melanoma cell', 'Disease', (224, 237))	('associated', 'Reg', (185, 195))	('BRAFV600E mutation', 'Var', (201, 219))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('growth arrest', 'Phenotype', 'HP:0001510', (75, 88))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
13463	30457212	Here, we demonstrate strong and moderate RMEL3 upregulation in BRAF and NRAS mutant melanoma cells, respectively, compared to melanocytes.	('NRAS', 'Gene', (72, 76))	('NRAS', 'Gene', '4893', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('upregulation', 'PosReg', (47, 59))	('RMEL3', 'Gene', (41, 46))	('BRAF', 'Gene', '673', (63, 67))	('mutant', 'Var', (77, 83))	('BRAF', 'Gene', (63, 67))
13464	30457212	High expression is also more frequent in cutaneous than in acral/mucosal melanomas, and analysis of an ICGC melanoma dataset showed that mutations in RMEL3 locus are preponderantly C > T substitutions at dipyrimidine sites including CC > TT, typical of UV signature.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('RMEL3', 'Gene', (150, 155))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mucosal melanomas', 'Disease', (65, 82))	('mutations', 'Var', (137, 146))	('dipyrimidine', 'Chemical', '-', (204, 216))	('CC > TT', 'Disease', (233, 240))	('mucosal melanomas', 'Disease', 'MESH:D008545', (65, 82))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('expression', 'Species', '29278', (5, 15))	('melanoma', 'Disease', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
13465	30457212	RMEL3 mutation does not correlate with RMEL3 levels, but does with poor patient survival, in TCGA melanoma dataset.	('RMEL3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('patient', 'Species', '9606', (72, 79))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))
13474	30457212	Whole exome sequencing led to the genomic classification of cutaneous melanoma into four subclasses according to cancer driver mutations: mutante BRAF (~52%), mutant RAS (~30%); mutant NF-1 (~14%); and triple wild-type, those with no mutations in any of the three genes.	('BRAF', 'Gene', (146, 150))	('mutant', 'Var', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mutant', 'Var', (159, 165))	('NF-1', 'Gene', (185, 189))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('mutante', 'Var', (138, 145))	('RAS', 'Gene', (166, 169))	('cancer', 'Disease', (113, 119))	('cutaneous melanoma', 'Disease', (60, 78))	('mutations', 'Var', (127, 136))	('BRAF', 'Gene', '673', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
13477	30457212	Therefore, mutations in BRAF, RAS, and NF-1 genes seem to lead to equivalent constitutive activation of the MAPK/ERK pathway, and for this reason, or perhaps due to deleterious effects of coexisting mutations, they almost always are found to be mutually exclusive.	('NF-1', 'Gene', (39, 43))	('mutations', 'Var', (11, 20))	('activation', 'PosReg', (90, 100))	('ERK', 'Gene', '5594', (113, 116))	('ERK', 'Gene', (113, 116))	('BRAF', 'Gene', (24, 28))	('RAS', 'Gene', (30, 33))	('BRAF', 'Gene', '673', (24, 28))	('ERK', 'molecular_function', 'GO:0004707', ('113', '116'))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))
13478	30457212	Activating mutations of genes implicated in the PI3K pathway are also highly frequent in melanoma, and activation of PI3K-AKT mTOR signaling pathway cooperates with the MAPK pathway to set the scenario of sustained growth and death resistance in melanoma.	('Activating mutations', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('MAPK', 'molecular_function', 'GO:0004707', ('169', '173'))	('melanoma', 'Disease', (246, 254))	('PI3K', 'molecular_function', 'GO:0016303', ('48', '52'))	('melanoma', 'Disease', 'MESH:D008545', (246, 254))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('AKT', 'Gene', '11651', (122, 125))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('signaling pathway', 'biological_process', 'GO:0007165', ('131', '148'))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('AKT', 'Gene', (122, 125))
13481	30457212	The discovery of new genes with tissue-specific expression and associated with genetic events of BRAF-activating mutations may provide new insights into the field and opportunities for novel therapeutic approaches.	('BRAF', 'Gene', '673', (97, 101))	('mutations', 'Var', (113, 122))	('BRAF', 'Gene', (97, 101))	('expression', 'Species', '29278', (48, 58))
13487	30457212	The later work also demonstrates that RMEL3 knockdown leads to alterations in the expression levels of mRNA and proteins of many components of the MAPK and PI3K pathways.	('expression', 'Species', '29278', (82, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('RMEL3', 'Gene', (38, 43))	('PI3K', 'molecular_function', 'GO:0016303', ('156', '160'))	('knockdown', 'Var', (44, 53))	('alterations', 'Reg', (63, 74))
13492	30457212	Human melanoma cell lines WM278 and WM1617 were kindly provided by Dr. Meenhard Herlyn (Wistar Institute, Philadelphia, PA), and we did an HLA typing for the cells that we carry in our laboratory and confirmed that they constitute a pair of cell lines originated from the same patient, as originally described.	('Human', 'Species', '9606', (0, 5))	('WM1617', 'Var', (36, 42))	('patient', 'Species', '9606', (277, 284))	('WM278', 'CellLine', 'CVCL:6473', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
13497	30457212	The melanoma cell lines VM10, WM2029, MeWo, Mel-Juso, LB373, WM451LU, IPC298, COLO792, Skmel-90, 501mel, Sk-mel-119, Sk-mel-2, MDAMB435S, WM1716, COLO829, A101D, C32, G361, MALME3M, Sk-mel-5, Skmel-28 and M14, Sk-mel30, LOX-IMVI, WM115, WM88, UACC62 e UACC257 were provided by Dr. David E Fisher's laboratory (MGH, Harvard Medical School).	('A101D', 'Var', (155, 160))	('MDAMB435S', 'CellLine', 'CVCL:0622', (127, 136))	('A101D', 'SUBSTITUTION', 'None', (155, 160))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
13535	30457212	SKMEL103 melanoma cells stably transduced with pLVX-TP (control) or pLVX-RMEL3 were cultured in complete media supplemented with 1 mug/ml doxycycline to confluence.	('doxycycline', 'Chemical', 'MESH:D004318', (138, 149))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('mug', 'molecular_function', 'GO:0043739', ('131', '134'))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('pLVX-RMEL3', 'Var', (68, 78))	('pLVX-TP', 'Var', (47, 54))	('SKMEL103', 'CellLine', 'CVCL:6069', (0, 8))
13543	30457212	Among the lines with high expression 15/19 (~79%) harbor BRAFV600E and 4/19 (~21%) NRASQ61L.	('NRAS', 'Gene', '4893', (83, 87))	('BRAFV600E', 'Var', (57, 66))	('BRAFV600E', 'Mutation', 'rs113488022', (57, 66))	('expression', 'Species', '29278', (26, 36))	('NRAS', 'Gene', (83, 87))
13544	30457212	Of the lines harboring BRAFV600E 15/24 (62,5%) showed high and 9/24 (37,5%) median/low RMEL3 expression.	('RMEL3', 'Protein', (87, 92))	('expression', 'Species', '29278', (93, 103))	('expression', 'MPA', (93, 103))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('BRAFV600E', 'Var', (23, 32))
13546	30457212	In order to clarify whether the RMEL3 locus (CTD-2023N9.1) could comprise a mutation hotspot associated with its upregulation in non-acral cutaneous melanoma, we searched for mutations in a region encompassing 20-kb upstream (including enhancer/ promoter regions) of the mapped start site of RMEL3, the entire body of the gene, and 20-kb downstream of the gene, both in a TCGA dataset of 450 melanomas (SKCM) and in an ICGC dataset of 129 melanomas (MELA-AU).	('melanomas', 'Disease', 'MESH:D008545', (392, 401))	('melanoma', 'Phenotype', 'HP:0002861', (392, 400))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (133, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Disease', (439, 448))	('cutaneous melanoma', 'Disease', (139, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (139, 157))	('melanomas', 'Disease', (392, 401))	('RMEL3', 'Gene', (292, 297))	('mutations', 'Var', (175, 184))	('melanomas', 'Disease', 'MESH:D008545', (439, 448))	('melanoma', 'Phenotype', 'HP:0002861', (439, 447))	('melanomas', 'Phenotype', 'HP:0002861', (439, 448))	('melanomas', 'Phenotype', 'HP:0002861', (392, 401))
13547	30457212	We found that 108 of 450 melanomas from TCGA presented mutation in the body of the gene, including ACTBL2 which maps within the intron 1 of RMEL3 gene, with 32 mutated melanomas (Table S1).	('melanomas', 'Disease', 'MESH:D008545', (168, 177))	('melanomas', 'Disease', 'MESH:D008545', (25, 34))	('RMEL3', 'Gene', (140, 145))	('melanomas', 'Disease', (168, 177))	('melanomas', 'Disease', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('mutation', 'Var', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('ACTBL2', 'Gene', (99, 105))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
13548	30457212	In the ICGC dataset, we found at least one mutation in 129 out of 129 melanomas, totaling 595 mutations, of which 28 mutations mapped upstream and 18 mutations downstream of the gene and the remaining majority of them were in the intronic regions, including ACTBL2 with 50 mutations (Table S2).	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('mutations', 'Var', (94, 103))	('ACTBL2', 'Gene', (258, 264))	('melanomas', 'Disease', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
13549	30457212	Then, we correlated the RMEL3 mutations (excluding the ACTBL2 mutations) found in TCGA samples with the RMEL3 expression levels from RNAseq data available in the TCGA, and as shown in Figure 1d, there was no statistically significant correlation between mutation and expression.	('RMEL3', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('expression', 'Species', '29278', (110, 120))	('expression', 'Species', '29278', (267, 277))
13551	30457212	Finally, using the TCGA dataset, we found that RMEL3 mutations are associated with poor patient survival rates (Figure 1e) (p < 0.05).	('patient', 'Species', '9606', (88, 95))	('RMEL3', 'Gene', (47, 52))	('patient survival rates', 'CPA', (88, 110))	('mutations', 'Var', (53, 62))	('poor', 'NegReg', (83, 87))
13554	30457212	RMEL3 RNA levels were reduced by approximately 50% in A375 and WM1617 BRAFV600E mutant cells after short-term, low-concentration treatment (Figure 2a) and 90% in Skmel19 and UACC62 after prolonged drug exposure (Figure 2b).	('RMEL3 RNA levels', 'MPA', (0, 16))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('mutant', 'Var', (80, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('BRAFV600E', 'Gene', (70, 79))	('reduced', 'NegReg', (22, 29))	('A375', 'CellLine', 'CVCL:0132', (54, 58))
13555	30457212	Paradoxically, the NRAS mutant WM1366 cells showed an increase in RMEL3 expression following short-term treatment (Figure 2a).	('mutant', 'Var', (24, 30))	('NRAS', 'Gene', (19, 23))	('expression', 'Species', '29278', (72, 82))	('increase', 'PosReg', (54, 62))	('NRAS', 'Gene', '4893', (19, 23))	('expression', 'MPA', (72, 82))	('RMEL3', 'Gene', (66, 71))	('WM1366', 'CellLine', 'CVCL:6789', (31, 37))
13556	30457212	FOXD3 (Forkhead Box D3), which was previously shown to be upregulated after mutant BRAF inhibition, was used here as positive control and confirmed to exhibit the expected expression pattern (Figure 2c,d).	('FOXD3', 'Gene', (0, 5))	('expression', 'Species', '29278', (172, 182))	('mutant', 'Var', (76, 82))	('upregulated', 'PosReg', (58, 69))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('inhibition', 'Var', (88, 98))
13558	30457212	Next, we showed that treatment of UACC62 cells with the MEK inhibitor PD98059 (25 muM for 48 hr) reduced RMEL3 RNA levels by 77%, a condition in which pERK levels were also efficiently decreased (Figure 2f).	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('ERK', 'Gene', '5594', (152, 155))	('muM', 'Gene', (82, 85))	('ERK', 'Gene', (152, 155))	('PD98059', 'Var', (70, 77))	('reduced', 'NegReg', (97, 104))	('PD98059', 'Chemical', 'MESH:C093973', (70, 77))	('MEK', 'Gene', (56, 59))	('MEK', 'Gene', '5609', (56, 59))	('RMEL3 RNA levels', 'MPA', (105, 121))	('muM', 'Gene', '56925', (82, 85))
13569	30457212	For stable expression of RMEL3 in melanoma cells, we chose VM10 line, one of the BRAFV600E mutant cells with the lowest RMEL3 expression levels (Figure 1a).	('expression', 'Species', '29278', (126, 136))	('expression', 'Species', '29278', (11, 21))	('melanoma', 'Disease', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (81, 90))	('mutant', 'Var', (91, 97))
13575	30457212	Proliferation rates upon serum starvation were measurably higher in pLVX-RMEL3-transduced cells compared to control (Figure 5b), as well as the colony formation capacity, analyzed by clonogenic assays in DMEM Complete Medium (Figure 5c).	('pLVX-RMEL3-transduced', 'Var', (68, 89))	('formation', 'biological_process', 'GO:0009058', ('151', '160'))	('Proliferation rates', 'CPA', (0, 19))	('colony formation capacity', 'CPA', (144, 169))	('DMEM', 'Chemical', '-', (204, 208))	('higher', 'PosReg', (58, 64))
13579	30457212	Previous work from our laboratory has shown that RMEL3 lncRNA is highly enriched in melanoma, particularly in tumors harboring the oncogenic BRAFV600E.	('BRAFV600E', 'Var', (141, 150))	('BRAFV600E', 'Mutation', 'rs113488022', (141, 150))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('melanoma', 'Disease', (84, 92))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('RMEL3', 'Gene', (49, 54))
13580	30457212	These studies have provided first evidence of the functional relevance of this lncRNA in melanoma owning to demonstration of its restricted expression pattern and the fact that its knockdown causes cell cycle arrest and dramatic decay of melanoma cell replicative survival, especially in BRAFV600E mutant cells, while treatment with the same siRNA preserves viability of cells that do not express detectable amounts of RMEL3.	('arrest', 'Disease', (209, 215))	('decay', 'NegReg', (229, 234))	('melanoma', 'Disease', (238, 246))	('expression', 'Species', '29278', (140, 150))	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (198, 215))	('BRAFV600E mutant', 'Var', (288, 304))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('198', '215'))	('knockdown', 'Var', (181, 190))	('arrest', 'Disease', 'MESH:D006323', (209, 215))	('melanoma', 'Disease', (89, 97))	('BRAFV600E', 'Mutation', 'rs113488022', (288, 297))	('mutant', 'Var', (298, 304))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
13581	30457212	Here, we add evidence that high RMEL3 expression is more often associated with extensive superficial/nodular cutaneous melanoma than mucosal and acral melanoma.	('expression', 'Species', '29278', (38, 48))	('nodular cutaneous melanoma than mucosal and acral melanoma', 'Disease', 'MESH:D008545', (101, 159))	('nodular cutaneous melanoma', 'Phenotype', 'HP:0012058', (101, 127))	('expression', 'MPA', (38, 48))	('associated', 'Reg', (63, 73))	('high', 'Var', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (109, 127))	('RMEL3', 'Gene', (32, 37))	('acral melanoma', 'Phenotype', 'HP:0012060', (145, 159))
13583	30457212	This and wealth of other evidence associating high content of UV signature mutations with cutaneous melanoma raised the possibility that the RMEL3 gene could be activated in the process of melanomagenesis due to the occurrence of a mutation hotspot, caused by UV exposure, in the promoter region of the gene itself.	('cutaneous melanoma', 'Disease', (90, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('activated', 'PosReg', (161, 170))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('RMEL3', 'Gene', (141, 146))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('melanoma', 'Disease', (100, 108))
13584	30457212	Analysis of TCGA and ICGC melanoma datasets, in fact, revealed a high content of UV signature mutations in the RMEL3 gene, however, lacking recurrent mutations that would characterize a hotspot.	('mutations', 'Var', (94, 103))	('RMEL3', 'Gene', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
13585	30457212	Also, RMEL3 mutation, in TCGA dataset, does not correlate with RMEL3 expression levels.	('expression', 'Species', '29278', (69, 79))	('mutation', 'Var', (12, 20))	('expression', 'MPA', (69, 79))	('RMEL3', 'Gene', (6, 11))
13586	30457212	Interestingly, however, RMEL3 mutation does correlate with poor patient survival raising the possibility that it could play a function as driver of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patient', 'Species', '9606', (64, 71))	('RMEL3', 'Gene', (24, 29))	('tumor', 'Disease', (148, 153))	('mutation', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
13587	30457212	Since we did not have access to expression data and survival information from ICGC, future studies should be pursued to answer whether mutations in the promoter region or additional mutations along the length of RMEL3 gene could influence its expression/function.	('expression', 'Species', '29278', (243, 253))	('influence', 'Reg', (229, 238))	('RMEL3', 'Gene', (212, 217))	('mutations', 'Var', (135, 144))	('expression', 'Species', '29278', (32, 42))	('expression/function', 'MPA', (243, 262))	('mutations', 'Var', (182, 191))
13588	30457212	We assume that, since mutation recurrence in the gene is rare, it is more likely that the association between RMEL3 mutation and poor patient survival rather than indicating a role of RMEL3 mutation as causative factor of tumorigenesis could just reflect an overall tumor mutational burden.	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('mutation', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('RMEL3', 'Gene', (110, 115))	('tumor', 'Disease', (266, 271))	('patient', 'Species', '9606', (134, 141))
13590	30457212	This is consistent with previous evidence that nearly 90% of cutaneous melanomas in contrast to 56% of acral and mucosal melanomas carry mutation in one of the three genes, BRAF, NRAS, or NF1.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mucosal melanomas', 'Disease', (113, 130))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('BRAF', 'Gene', '673', (173, 177))	('mutation', 'Var', (137, 145))	('mucosal melanomas', 'Disease', 'MESH:D008545', (113, 130))	('BRAF', 'Gene', (173, 177))	('NF1', 'Gene', (188, 191))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('NRAS', 'Gene', '4893', (179, 183))	('carry', 'Reg', (131, 136))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (61, 80))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (61, 80))	('NRAS', 'Gene', (179, 183))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanomas', 'Disease', (61, 80))
13591	30457212	Also, because RMEL3 expression in BRAF mutant melanoma cell lines clearly reverses to the levels observed in melanocytes upon treatments with BRAF or MEK inhibitors, we favor the hypothesis that an active status of the MAPK/ERK pathway is required for RMEL3 activation in the context of melanomagenesis.	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('RMEL3', 'Gene', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('melanoma', 'Disease', (287, 295))	('BRAF', 'Gene', '673', (142, 146))	('ERK', 'Gene', '5594', (224, 227))	('BRAF', 'Gene', (142, 146))	('expression', 'Species', '29278', (20, 30))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('mutant', 'Var', (39, 45))	('ERK', 'Gene', (224, 227))	('melanoma', 'Disease', 'MESH:D008545', (287, 295))	('reverses', 'NegReg', (74, 82))	('MEK', 'Gene', '5609', (150, 153))	('expression', 'MPA', (20, 30))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('MEK', 'Gene', (150, 153))	('ERK', 'molecular_function', 'GO:0004707', ('224', '227'))
13592	30457212	Moreover, the RMEL3 upregulation observed upon vemurafenib-induced paradoxical activation of ERK, in NRASQ61R mutant WM1366 cells, reinforces the notion that RMEL3 responds to ERK pathway activation and might be involved in the development of sporadic tumors or in the relapse of BRAFi-resistant melanoma.	('melanoma', 'Disease', (296, 304))	('ERK', 'Gene', (93, 96))	('sporadic tumors', 'Disease', 'MESH:D009369', (243, 258))	('RMEL3', 'Gene', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('ERK', 'Gene', '5594', (176, 179))	('NRAS', 'Gene', '4893', (101, 105))	('ERK', 'molecular_function', 'GO:0004707', ('176', '179'))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('ERK', 'molecular_function', 'GO:0004707', ('93', '96'))	('activation', 'PosReg', (79, 89))	('melanoma', 'Disease', 'MESH:D008545', (296, 304))	('ERK', 'Gene', (176, 179))	('involved', 'Reg', (212, 220))	('mutant', 'Var', (110, 116))	('upregulation', 'PosReg', (20, 32))	('WM1366', 'CellLine', 'CVCL:6789', (117, 123))	('vemurafenib', 'Chemical', 'MESH:D000077484', (47, 58))	('ERK', 'Gene', '5594', (93, 96))	('BRAF', 'Gene', '673', (280, 284))	('NRAS', 'Gene', (101, 105))	('BRAF', 'Gene', (280, 284))	('sporadic tumors', 'Disease', (243, 258))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
13597	30457212	Genomewide studies of transcription factor (TF) occupancy and histone modifications show evidence of chromatin accessibility typical of a primed enhancer (DNase I sensitivity, histone H3K27Ac, and H3K4me1) in a region 11- to 13-kb upstream of the presumed transcription start site of the gene (RMEL3/CTD-2023N9.1) in several cell lines used by ENCODE, such as K562, HUVEC, NT2-D1, and others.	('DNase I', 'molecular_function', 'GO:0004530', ('155', '162'))	('H3K27Ac', 'Var', (184, 191))	('K562', 'CellLine', 'CVCL:0004', (360, 364))	('transcription factor', 'molecular_function', 'GO:0000981', ('22', '42'))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('enhancer', 'PosReg', (145, 153))	('H3K4me1', 'Var', (197, 204))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('chromatin accessibility', 'MPA', (101, 124))	('transcription', 'biological_process', 'GO:0006351', ('256', '269'))
13602	30457212	Prompted by the evidence discussed above and having previously shown that RMEL3 is required for survival of BRAF mutant melanoma cells, the major focus of this work was on defining the effects provoked by ectopic expression of RMEL3 in different cell lines and under a variety of culture conditions, especially serum starvation.	('expression', 'Species', '29278', (213, 223))	('RMEL3', 'Gene', (227, 232))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('BRAF', 'Gene', '673', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('mutant', 'Var', (113, 119))	('BRAF', 'Gene', (108, 112))
13607	30457212	The results discussed above led us to hypothesize that overexpression of RMEL3 would potentially enhance malignant properties of either a BRAF wild-type or a BRAF mutant melanoma cell line expressing low RMEL3 levels.	('overexpression', 'PosReg', (55, 69))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('low RMEL3 levels', 'Phenotype', 'HP:0031037', (200, 216))	('BRAF', 'Gene', (138, 142))	('BRAF', 'Gene', '673', (138, 142))	('mutant', 'Var', (163, 169))	('malignant properties', 'CPA', (105, 125))	('expression', 'Species', '29278', (59, 69))	('BRAF', 'Gene', '673', (158, 162))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('enhance', 'PosReg', (97, 104))	('BRAF', 'Gene', (158, 162))	('RMEL3', 'Gene', (73, 78))
13608	30457212	Indeed, ectopic expression of RMEL3 using two different lentiviral vector systems enhanced cell proliferation in both cell lines, either cultured in complete media or under serum starvation.	('enhanced', 'PosReg', (82, 90))	('RMEL3', 'Gene', (30, 35))	('ectopic expression', 'Var', (8, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('91', '109'))	('expression', 'Species', '29278', (16, 26))	('cell proliferation', 'CPA', (91, 109))
13612	30457212	Previous findings link RMEL3 with BRAFV600E and the MAPK/ERK pathway activity.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('activity', 'MPA', (69, 77))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('ERK', 'Gene', '5594', (57, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('52', '56'))	('RMEL3', 'Var', (23, 28))	('ERK', 'Gene', (57, 60))	('BRAFV600E', 'Var', (34, 43))
13619	31983065	In SKCM regional LN tissues, the high expression of 32 types of chemokines and receptors, namely CCL2, 4-5, 7-8, 13, 22-25, CCR1-9, CXCL9-13, 16, CXCR3, 5, 6, XCL1-2 and XCR1 in LN was associated with favourable patient prognosis.	('XCL1-2', 'Gene', (159, 165))	('XCL1-2', 'Gene', '6375;6846', (159, 165))	('CXCL9-13', 'Gene', (132, 140))	('XCR1', 'Gene', '2829', (170, 174))	('CCL2', 'Gene', '6347', (97, 101))	('CCR1-9', 'Gene', (124, 130))	('patient', 'Species', '9606', (212, 219))	('CXCL9-13', 'Gene', '4283;3627;6373;6387;10563', (132, 140))	('CCL2', 'Gene', (97, 101))	('CCR1-9', 'Gene', '1230;729230;1232;1233;1234;1235;1236;1237;10803', (124, 130))	('CCL', 'molecular_function', 'GO:0044101', ('97', '100'))	('4-5', 'Var', (103, 106))	('XCR1', 'Gene', (170, 174))	('CCR', 'molecular_function', 'GO:0043880', ('124', '127'))	('CXCR3, 5, 6', 'Gene', '2833;643;10663', (146, 157))
13645	31983065	For the remaining 32 chemokine/receptor, high expression was associated with a better survival rate of the patients.	('chemokine/receptor', 'Gene', '7852', (21, 39))	('high', 'Var', (41, 45))	('better', 'PosReg', (79, 85))	('survival', 'CPA', (86, 94))	('patients', 'Species', '9606', (107, 115))	('chemokine/receptor', 'Gene', (21, 39))
13658	31983065	Among the chemokines and receptors analysed, we found CCR4, 6-9, CCL13, -22, -23, and XCR1 were positively correlated with the fractions of memory B cells and the naive T cells, and negatively correlated with M0 type macrophages and resting type MCs.	('negatively', 'NegReg', (182, 192))	('CCL', 'molecular_function', 'GO:0044101', ('65', '68'))	('M0 type macrophages', 'CPA', (209, 228))	('CCR4', 'Gene', (54, 58))	('CCR4', 'Gene', '1233', (54, 58))	('XCR1', 'Gene', '2829', (86, 90))	('memory', 'biological_process', 'GO:0007613', ('140', '146'))	('MCs', 'cellular_component', 'GO:0044232', ('246', '249'))	('correlated', 'Interaction', (107, 117))	('CCR', 'molecular_function', 'GO:0043880', ('54', '57'))	('CCL13', 'Gene', '6357', (65, 70))	('6-9', 'Var', (60, 63))	('XCR1', 'Gene', (86, 90))	('CCL13', 'Gene', (65, 70))
13666	31983065	T cell infiltration of the tumour is correlated with longer disease-free survival in stage III cancer patients.35 In addition, CXCR3 and its ligands CXCL9 and CXCL10 are closely related to the TH1 immune response, and CXCR3 mediates the anti-tumour response by recruiting into tumours NK cells, CD4-positive Th1 cells and CD8-positive cytotoxic T lymphocytes tumours.	('CD8', 'Gene', (322, 325))	('patients', 'Species', '9606', (102, 110))	('CXCL9', 'Gene', (149, 154))	('TH1', 'Gene', '51497', (193, 196))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('Th1', 'Gene', (308, 311))	('TH1 immune response', 'biological_process', 'GO:0042088', ('193', '212'))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('tumour', 'Disease', (242, 248))	('tumours', 'Disease', (359, 366))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('Th1', 'Gene', '51497', (308, 311))	('CXCL9', 'Gene', '4283', (149, 154))	('cancer', 'Disease', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (359, 365))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (359, 365))	('CXCR3', 'Var', (218, 223))	('tumour', 'Disease', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumours', 'Phenotype', 'HP:0002664', (359, 366))	('CXCL10', 'Gene', '3627', (159, 165))	('tumour', 'Disease', (359, 365))	('tumours', 'Disease', 'MESH:D009369', (359, 366))	('CD8', 'Gene', '925', (322, 325))	('tumours', 'Disease', (277, 284))	('tumour', 'Phenotype', 'HP:0002664', (277, 283))	('CXCL10', 'Gene', (159, 165))	('TH1', 'Gene', (193, 196))	('CD4', 'Gene', '920', (295, 298))	('tumours', 'Phenotype', 'HP:0002664', (277, 284))	('tumour', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (277, 283))	('tumours', 'Disease', 'MESH:D009369', (277, 284))	('recruiting', 'PosReg', (261, 271))	('CD4', 'Gene', (295, 298))
13710	32111241	Cells were also discarded if the TPM value of CD3D was < 3, TPM of CD8A < 3, or CD4 > 30 for fluorescence-activated cell sorting (FACS)-sorted CD8+ T cells and if the TPM of CD4 < 3 or CD8A > 30 for FACS-sorted CD4+ T cells.	('CD8A', 'Gene', (185, 189))	('CD3D', 'Gene', '915', (46, 50))	('CD3D', 'Gene', (46, 50))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('CD4 > 30', 'Var', (80, 88))	('CD8', 'Gene', (185, 188))	('CD8A', 'Gene', '925', (67, 71))	('CD8', 'Gene', '925', (185, 188))	('CD8A', 'Gene', (67, 71))	('CD8A', 'Gene', '925', (185, 189))	('CD8', 'Gene', (67, 70))	('CD8', 'Gene', '925', (67, 70))
13776	32111241	We found that neither PDCD1-high nor PDCD1-low subset were severely biased in distribution of cells from each patient in both single-cell transcriptome datasets reanalyzed, indicating that the observed differential expression is not based on patient-specific effect (Additional file 2: Figure S2).	('ran', 'Gene', '5901', (139, 142))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (242, 249))	('PDCD1-high', 'Var', (22, 32))	('ran', 'Gene', (139, 142))
13785	32111241	The distribution patterns of TOX-high cells and PDCD1-high cells were similar in the latent space of the tSNE plot for both melanoma and NSCLC, which were similar to the distribution patterns of IC genes (see Fig.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('NSCLC', 'Disease', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('PDCD1-high', 'Var', (48, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))
13808	32111241	Each population can be arranged in the following order of decreasing TOX expression: PD-1+TIM-3+ > PD-1+TIM-3- > PD-1-TIM-3- (Fig.	('PD-1+TIM-3+ > PD-1+TIM-3-', 'Var', (85, 110))	('PD-1+TIM-3-', 'Var', (99, 110))	('ran', 'Gene', (25, 28))	('ran', 'Gene', '5901', (25, 28))
13820	32111241	Interestingly, the knockdown of TOX in the TI CD8+ T cells resulted in a significant reduction of cells expressing IC molecules, such as PD-1, TIM-3, TIGIT, and CTLA-4.	('CD8', 'Gene', '925', (46, 49))	('cells expressing IC molecules', 'MPA', (98, 127))	('knockdown', 'Var', (19, 28))	('reduction', 'NegReg', (85, 94))	('CD8', 'Gene', (46, 49))
13823	32111241	Additionally, we observed that the frequency of TI CD8+ T cells that secrete effector cytokines (IFN-gamma and TNF-alpha) significantly increased upon TOX knockdown, suggesting that the anti-tumor function of TI CD8+ T cells could be restored upon TOX knockdown (Fig.	('knockdown', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('TNF-alpha', 'Gene', '7124', (111, 120))	('IFN-gamma', 'Gene', (97, 106))	('CD8', 'Gene', (212, 215))	('IFN-gamma', 'Gene', '3458', (97, 106))	('TNF-alpha', 'Gene', (111, 120))	('CD8', 'Gene', (51, 54))	('CD8', 'Gene', '925', (212, 215))	('tumor', 'Disease', (191, 196))	('CD8', 'Gene', '925', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('increased', 'PosReg', (136, 145))
13842	32111241	In the two NSCLC cohorts, the TOX expression level in the TILs of responders was significantly lower than that in the TILs of non-responders (P = 0.016 and 0.002, two-tailed Mann-Whitney U test).	('NSCLC cohort', 'Disease', (11, 23))	('lower', 'NegReg', (95, 100))	('responders', 'Var', (66, 76))	('TOX expression level', 'MPA', (30, 50))	('NSCLC cohort', 'Disease', 'MESH:D002289', (11, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))
13861	32111241	TOX knockdown in the TI CD8+ T cells significantly downregulated the expression of IC molecules, such as PD-1 (Fig.	('expression', 'MPA', (69, 79))	('CD8', 'Gene', (24, 27))	('downregulated', 'NegReg', (51, 64))	('CD8', 'Gene', '925', (24, 27))	('knockdown', 'Var', (4, 13))	('PD-1', 'Gene', (105, 109))
13875	32111241	This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018M3C9A5064709, 2018R1A5A2025079, 2019M3A9B6065189 to IL; 2017R1A5A1014560, 2018M3A9H3024850, 2018R1A2A1A05076997, 2019M3A9B6065221 to SJH).	('2018R1A5A2025079', 'Var', (139, 155))	('2019M3A9B6065221', 'Var', (238, 254))	('2018M3A9H3024850', 'Var', (199, 215))	('2019M3A9B6065189', 'Var', (157, 173))	('2018R1A2A1A05076997', 'Var', (217, 236))	('ran', 'Gene', (77, 80))	('ran', 'Gene', '5901', (77, 80))
13883	29152610	Mutations in Coagulation Factor VIII Are Associated with More Favorable Outcome in Patients with Cutaneous Melanoma Coagulation factor VIII (FVIII), von Willebrand factor (VWF), and ADAMTS13 play an important role in regulation of normal hemostasis.	('hemostasis', 'biological_process', 'GO:0007599', ('238', '248'))	('ADAMTS13', 'Gene', '11093', (182, 190))	('ADAMTS13', 'Gene', (182, 190))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (97, 115))	('Coagulation factor VIII', 'Gene', '2157', (116, 139))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (97, 115))	('Coagulation Factor VIII', 'Gene', '2157', (13, 36))	('Coagulation factor VIII', 'Gene', (116, 139))	('Melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('regulation', 'biological_process', 'GO:0065007', ('217', '227'))	('Mutations', 'Var', (0, 9))	('Coagulation', 'biological_process', 'GO:0050817', ('116', '127'))	('von Willebrand factor', 'Gene', (149, 170))	('Patients', 'Species', '9606', (83, 91))	('von Willebrand factor', 'Gene', '7450', (149, 170))	('Coagulation Factor VIII', 'Gene', (13, 36))	('Cutaneous Melanoma', 'Disease', (97, 115))	('Coagulation', 'biological_process', 'GO:0050817', ('13', '24'))
13887	29152610	Our results demonstrated that mutations in genes encoding FVIII, VWF, and ADAMTS13 were reported in 92 of 126 cancer genomic studies and high mutation rates in these three genes were observed in patients with cutaneous melanoma from three independent studies.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (209, 227))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (209, 227))	('cancer', 'Disease', (110, 116))	('VWF', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ADAMTS13', 'Gene', '11093', (74, 82))	('ADAMTS13', 'Gene', (74, 82))	('patients', 'Species', '9606', (195, 203))	('mutations', 'Var', (30, 39))	('FVIII', 'Gene', (58, 63))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cutaneous melanoma', 'Disease', (209, 227))
13888	29152610	Moreover, high mutation rates in FVIII, VWF, and ADAMTS13 were also found in patients with diffuse large B cell lymphoma (22.9%), lung small cell carcinoma (20.7%), and colon adenocarcinoma (19.4%).	('FVIII', 'Gene', (33, 38))	('lung small cell carcinoma', 'Phenotype', 'HP:0030357', (130, 155))	('found', 'Reg', (68, 73))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (105, 120))	('ADAMTS13', 'Gene', (49, 57))	('ADAMTS13', 'Gene', '11093', (49, 57))	('large B cell', 'Phenotype', 'HP:0005404', (99, 111))	('lung small', 'Phenotype', 'HP:0002089', (130, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (169, 189))	('patients', 'Species', '9606', (77, 85))	('VWF', 'Gene', (40, 43))	('B cell lymphoma', 'Disease', (105, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (130, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('mutation', 'Var', (15, 23))	('colon adenocarcinoma', 'Disease', (169, 189))	('lung small cell carcinoma', 'Disease', (130, 155))	('B cell lymphoma', 'Disease', 'MESH:D016393', (105, 120))
13890	29152610	There was a strong tendency for coexisting mutations of FVIII, VWF, and ADAMTS13.	('ADAMTS13', 'Gene', (72, 80))	('ADAMTS13', 'Gene', '11093', (72, 80))	('VWF', 'Gene', (63, 66))	('mutations', 'Var', (43, 52))	('FVIII', 'Gene', (56, 61))
13891	29152610	Kaplan-Meier survival analysis demonstrated that melanoma patients with FVIII mutations had a more favorable overall survival rate than those without FVIII mutations (p=0.02).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('mutations', 'Var', (78, 87))	('overall survival', 'CPA', (109, 125))	('favorable', 'PosReg', (99, 108))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('FVIII', 'Gene', (72, 77))
13892	29152610	These findings suggest for the first time that the FVIII mutation burden may have a prognostic value for patients with cutaneous melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('mutation', 'Var', (57, 65))	('patients', 'Species', '9606', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('FVIII', 'Gene', (51, 56))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
13899	29152610	When mutations persist in proto-oncogenes, an uncontrolled rate of mitosis could lead to cell transformation and tumor formation.	('tumor', 'Disease', (113, 118))	('lead to', 'Reg', (81, 88))	('mitosis', 'biological_process', 'GO:0000278', ('67', '74'))	('mitosis', 'Disease', (67, 74))	('mitosis', 'Disease', 'None', (67, 74))	('mutations', 'Var', (5, 14))	('uncontrolled', 'MPA', (46, 58))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('formation', 'biological_process', 'GO:0009058', ('119', '128'))	('cell transformation', 'CPA', (89, 108))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
13902	29152610	Previous studies have demonstrated that VWF, FVIII, platelets, and other procoagulants, such as tissue factor, factor X, and thrombin may not only result in the development of deep vein thromboembolism (DVT), but may also be associated with metastasis of malignant melanoma.	('metastasis', 'Disease', (241, 251))	('deep vein thromboembolism', 'Disease', (176, 201))	('deep vein thromboembolism', 'Phenotype', 'HP:0002625', (176, 201))	('malignant melanoma', 'Phenotype', 'HP:0002861', (255, 273))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('deep vein thromboembolism', 'Disease', 'MESH:D013923', (176, 201))	('malignant melanoma', 'Disease', 'MESH:D008545', (255, 273))	('thromboembolism', 'Phenotype', 'HP:0001907', (186, 201))	('FVIII', 'Var', (45, 50))	('VWF', 'Var', (40, 43))	('malignant melanoma', 'Disease', (255, 273))	('DVT', 'Phenotype', 'HP:0002625', (203, 206))	('associated with', 'Reg', (225, 240))	('result in', 'Reg', (147, 156))
13908	29152610	However, the association between the genetic alterations in the gene encoding FVIII, VWF, and ADAMTS13 and long-term outcomes in patients with cutaneous melanoma has not been investigated in a large cohort of datasets.	('VWF', 'Gene', (85, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('FVIII', 'Gene', (78, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('patients', 'Species', '9606', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('ADAMTS13', 'Gene', (94, 102))	('genetic alterations', 'Var', (37, 56))	('ADAMTS13', 'Gene', '11093', (94, 102))	('cutaneous melanoma', 'Disease', (143, 161))
13909	29152610	The present study takes advantage of the recent whole exome sequence (WES) datasets, mRNA expression (RNA-seq) data, and bioinformatics tools to determine the prognostic value of somatic mutations in FVIII, VWF and ADAMTS13 in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (227, 245))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (227, 245))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (227, 245))	('ADAMTS13', 'Gene', '11093', (215, 223))	('ADAMTS13', 'Gene', (215, 223))	('mutations', 'Var', (187, 196))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('VWF', 'Gene', (207, 210))	('FVIII', 'Gene', (200, 205))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))
13911	29152610	Further investigation of the molecular mechanism underlying how FVIII mutations are associated with a better outcome will help understand the pathogenesis of cutaneous melanoma, which may lead to the development of a novel therapeutic for such malignancy.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (158, 176))	('mutations', 'Var', (70, 79))	('pathogenesis', 'biological_process', 'GO:0009405', ('142', '154'))	('malignancy', 'Disease', 'MESH:D009369', (244, 254))	('malignancy', 'Disease', (244, 254))	('FVIII', 'Gene', (64, 69))	('associated', 'Reg', (84, 94))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('cutaneous melanoma', 'Disease', (158, 176))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (158, 176))
13919	29152610	The pathologic criteria used to determine any correlation with the mutations were based on the current WHO classification of human cutaneous melanoma and the AJCC cancer staging manual, 7th edition, including tumor depth (Clark level and Breslow thickness), tumor size, tumor site, lymph node, and metastasis status.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', (258, 263))	('cutaneous melanoma and the AJCC cancer', 'Disease', 'MESH:C562393', (131, 169))	('human', 'Species', '9606', (125, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', (270, 275))
13922	29152610	In all cancer studies, the mutations in FVIII, VWF, and ADAMTS13 were reported in 93 cancer studies.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('VWF', 'Gene', (47, 50))	('ADAMTS13', 'Gene', '11093', (56, 64))	('ADAMTS13', 'Gene', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('reported', 'Reg', (70, 78))	('FVIII', 'Gene', (40, 45))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
13924	29152610	High mutation rates in FVIII, VWF and ADAMTS13 were also reported in diffuse large B-cell lymphoma (22.9%), small cell lung carcinoma (20.7%), cholangiocarcinoma (20.0%), and colorectal adenocarcinoma (19.4%), etc.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('colorectal adenocarcinoma', 'Disease', (175, 200))	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (175, 200))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (83, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (108, 133))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (83, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (143, 161))	('VWF', 'Gene', (30, 33))	('cholangiocarcinoma', 'Disease', (143, 161))	('ADAMTS13', 'Gene', (38, 46))	('ADAMTS13', 'Gene', '11093', (38, 46))	('B-cell lymphoma', 'Disease', (83, 98))	('small cell lung carcinoma', 'Disease', (108, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (143, 161))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (108, 133))	('mutation', 'Var', (5, 13))
13925	29152610	In the provisional "TCGA skin cutaneous melanoma" dataset, 54 patients had FVIII mutations and 312 patients had no FVIII mutation.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 48))	('FVIII', 'Gene', (75, 80))	('skin cutaneous melanoma', 'Disease', (25, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (81, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('patients', 'Species', '9606', (62, 70))
13927	29152610	No significant difference was identified between patient's age, gender, Clark level, Breslow thickness, primary tumor ulceration, lymph node status, stage, overall copy number variation, and the percentage or post-operation chemo/radiation therapy in melanoma patients with and without FVIII mutations except for mutations counts (Table 1 and Suppl.	('patient', 'Species', '9606', (260, 267))	('mutations', 'Var', (292, 301))	('tumor ulceration', 'Disease', 'MESH:D014456', (112, 128))	('patient', 'Species', '9606', (49, 56))	('patients', 'Species', '9606', (260, 268))	('tumor ulceration', 'Disease', (112, 128))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))
13928	29152610	Furthermore, patients with the FVIII mutation are more likely to be in the tumor-free group (61.1% vs. 44.2%, p=0.042) (Table 1).	('mutation', 'Var', (37, 45))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('FVIII', 'Gene', (31, 36))	('tumor', 'Disease', (75, 80))
13931	29152610	The mutation rates in FVIII, VWF, and ADAMTS13 from the TCGA provisional data sets were 15%, 14%, and 5%, respectively (Fig.	('ADAMTS13', 'Gene', '11093', (38, 46))	('mutation', 'Var', (4, 12))	('ADAMTS13', 'Gene', (38, 46))
13934	29152610	The number of mutations in FVIII, VWF, and ADAMTS13 appeared to directly correlate with the length of coding regions of the genes (r2=0.993).	('VWF', 'Gene', (34, 37))	('ADAMTS13', 'Gene', (43, 51))	('FVIII', 'Gene', (27, 32))	('ADAMTS13', 'Gene', '11093', (43, 51))	('mutations', 'Var', (14, 23))
13936	29152610	All these gene mutations found by WES were verified with the RNA-Seq analysis in the same tumor samples, which were not present in the genomic DNA isolated from leukocytes of the patients.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
13938	29152610	Furthermore, there was a strong tendency of co-existence of mutations in both FVIII and VWF or in both VWF and ADAMTS13 in a single patient (not shown).	('patient', 'Species', '9606', (132, 139))	('co-existence', 'Interaction', (44, 56))	('FVIII', 'Gene', (78, 83))	('ADAMTS13', 'Gene', (111, 119))	('ADAMTS13', 'Gene', '11093', (111, 119))	('VWF', 'Gene', (103, 106))	('mutations', 'Var', (60, 69))	('VWF', 'Gene', (88, 91))
13941	29152610	In addition, no association was found between the combined mutations of VWF, FVIII, and ADAMTS13 with the long-term survival rate (Fig.	('FVIII', 'Gene', (77, 82))	('ADAMTS13', 'Gene', '11093', (88, 96))	('ADAMTS13', 'Gene', (88, 96))	('VWF', 'Gene', (72, 75))	('mutations', 'Var', (59, 68))
13942	29152610	Interestingly, low VWF, but not FVIII and ADAMTS13 mRNA expression in the melanoma tissue itself was associated with a better overall survival rate (p=0.02) (Fig.	('ADAMTS13', 'Gene', (42, 50))	('low', 'Var', (15, 18))	('VWF', 'MPA', (19, 22))	('better', 'PosReg', (119, 125))	('ADAMTS13', 'Gene', '11093', (42, 50))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('overall survival', 'MPA', (126, 142))
13943	29152610	4E), suggesting that the decreased VWF gene expression in association with FVIII mutations may have a protective effect in patients with melanoma.	('expression', 'MPA', (44, 54))	('VWF gene', 'Gene', (35, 43))	('FVIII', 'Gene', (75, 80))	('decreased', 'NegReg', (25, 34))	('patients', 'Species', '9606', (123, 131))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('mutations', 'Var', (81, 90))
13944	29152610	Specifically, patients with the FVIII mutations had a median survival of 269 months compared with the median survival of 67 months in those without the FVIII mutations (p=0.02).	('mutations', 'Var', (38, 47))	('patients', 'Species', '9606', (14, 22))	('FVIII', 'Disease', (32, 37))
13945	29152610	To investigate the possible underlying mechanism of the protective role of FVIII mutations in patients with cutaneous melanoma, we tested the effect of mutations in FVIII, VWF and ADAMTS13 on mRNA expression based on the RNA-Seq data.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (152, 161))	('RNA', 'cellular_component', 'GO:0005562', ('221', '224'))	('cutaneous melanoma', 'Disease', (108, 126))	('ADAMTS13', 'Gene', '11093', (180, 188))	('ADAMTS13', 'Gene', (180, 188))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (108, 126))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('FVIII', 'Gene', (165, 170))	('mutations', 'Var', (81, 90))	('tested', 'Reg', (131, 137))
13947	29152610	We furthered tested the entire mRNA expression profile in the tumor tissue from patients with FVIII mutations.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', (62, 67))	('tested', 'Reg', (13, 19))	('FVIII', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
13955	29152610	This study highlights the high mutation rates in genes encoding FVIII, VWF, and ADAMTS13 in patients with metastatic cutaneous melanoma (Figs.	('cutaneous melanoma', 'Disease', (117, 135))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('mutation', 'Var', (31, 39))	('ADAMTS13', 'Gene', (80, 88))	('patients', 'Species', '9606', (92, 100))	('FVIII', 'Gene', (64, 69))	('ADAMTS13', 'Gene', '11093', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('VWF', 'Gene', (71, 74))
13956	29152610	The presence of mutations in FVIII, but not in VWF and ADAMTS13 or a combined mutation rate of FVIII, VWF, and ADAMTS13, is associated with a more favorable overall survival in these patients (Fig.	('ADAMTS13', 'Gene', (55, 63))	('FVIII', 'Gene', (29, 34))	('ADAMTS13', 'Gene', '11093', (55, 63))	('ADAMTS13', 'Gene', (111, 119))	('FVIII', 'Gene', (95, 100))	('mutations', 'Var', (16, 25))	('ADAMTS13', 'Gene', '11093', (111, 119))	('overall survival', 'MPA', (157, 173))	('patients', 'Species', '9606', (183, 191))
13958	29152610	As shown in our data, patients with the FVIII mutations exhibited significantly lower expression of the FVIII mRNA, which may be translated with the reduced levels of FVIII procoagulant activity in situ around the tumors (Fig.	('mutations', 'Var', (46, 55))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('patients', 'Species', '9606', (22, 30))	('FVIII', 'Gene', (40, 45))	('reduced', 'NegReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('expression', 'MPA', (86, 96))	('lower', 'NegReg', (80, 85))	('tumors', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('levels', 'MPA', (157, 163))
13960	29152610	Further determination of FVIII synthesis and secretion from cultured melanoma cells with or without FVIII mutations may help better understand the pathophysiological relevance of the FVIII mutations.	('FVIII', 'Gene', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('synthesis', 'biological_process', 'GO:0009058', ('31', '40'))	('FVIII', 'Gene', (100, 105))	('mutations', 'Var', (106, 115))	('secretion', 'biological_process', 'GO:0046903', ('45', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
13968	29152610	While mutation rates in VWF are not associated with the long-term outcome in patients with melanoma, its plasma levels or the presence of ultra large VWF on endothelial surface are shown to be important for the development of thrombosis and tumor metastasis.	('thrombosis', 'Disease', (226, 236))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('mutation', 'Var', (6, 14))	('plasma levels', 'MPA', (105, 118))	('VWF', 'Gene', (24, 27))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('important', 'Reg', (193, 202))	('patients', 'Species', '9606', (77, 85))	('tumor metastasis', 'Disease', 'MESH:D009362', (241, 257))	('thrombosis', 'Disease', 'MESH:D013927', (226, 236))	('tumor metastasis', 'Disease', (241, 257))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
13974	29152610	Paradoxically, lung colonization by cancer cells was enhanced in the VWF-knockout mice and inhibition of platelet glycoprotein Ibalpha led to significant increase in the formation of pulmonary foci of tumor cells.	('mice', 'Species', '10090', (82, 86))	('glycoprotein Ibalpha', 'Gene', '14723', (114, 134))	('glycoprotein Ibalpha', 'Gene', (114, 134))	('inhibition', 'Var', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('pulmonary foci of tumor', 'Disease', 'MESH:D008175', (183, 206))	('cancer', 'Disease', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('formation', 'biological_process', 'GO:0009058', ('170', '179'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('increase', 'PosReg', (154, 162))	('pulmonary foci of tumor', 'Disease', (183, 206))	('enhanced', 'PosReg', (53, 61))
13979	29152610	We conclude that high mutation rates in FVIII, but not in VWF and ADAMTS13, may have a value in predicting a long-term outcome in patients with cutaneous metastatic melanoma.	('predicting', 'Reg', (96, 106))	('cutaneous metastatic melanoma', 'Phenotype', 'HP:0012056', (144, 173))	('ADAMTS13', 'Gene', (66, 74))	('ADAMTS13', 'Gene', '11093', (66, 74))	('FVIII', 'Gene', (40, 45))	('patients', 'Species', '9606', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('mutation rates', 'Var', (22, 36))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
13983	29152610	Using bioinformatics and whole genome sequencing and mortality data, a critical link between the long-term outcome of human cutaneous melanoma and the mutation burdens in factor VIII, but not in von Willebrand factor, and ADAMTS13 has been identified.	('von Willebrand factor', 'Gene', '7450', (195, 216))	('von Willebrand factor', 'Gene', (195, 216))	('cutaneous melanoma', 'Disease', (124, 142))	('factor VIII', 'Gene', '2157', (171, 182))	('mutation', 'Var', (151, 159))	('factor VIII', 'Gene', (171, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('ADAMTS13', 'Gene', (222, 230))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('human', 'Species', '9606', (118, 123))	('ADAMTS13', 'Gene', '11093', (222, 230))
14003	28666115	Mice with a DC-specific deficiency in the NFkappabeta sub-unit Ikappakappabeta fail to accumulate tissue-derived migDCs in the draining LNs and develop spontaneous autoimmune lupus-like disease.	('deficiency', 'Var', (24, 34))	('develop', 'Reg', (144, 151))	('autoimmune lupus-like disease', 'Disease', (164, 193))	('autoimmune lupus-like disease', 'Disease', 'MESH:D001327', (164, 193))	('Mice', 'Species', '10090', (0, 4))
14038	28666115	Little difference was appreciated between the transcriptome of steady-state migDC isolated from IL27Ralpha-/- and C57BL/6 WT mice, suggesting little basal signaling through IL-27Ralpha.	('IL-27', 'cellular_component', 'GO:0070744', ('173', '178'))	('basal signaling', 'biological_process', 'GO:0038034', ('149', '164'))	('basal signaling', 'MPA', (149, 164))	('mice', 'Species', '10090', (125, 129))	('IL-27', 'molecular_function', 'GO:0045523', ('173', '178'))	('IL27Ralpha-/-', 'Var', (96, 109))	('IL-27Ralpha', 'Gene', '50931', (173, 184))	('IL-27Ralpha', 'Gene', (173, 184))	('IL27', 'molecular_function', 'GO:0045523', ('96', '100'))	('little', 'NegReg', (142, 148))	('IL27', 'cellular_component', 'GO:0070744', ('96', '100'))
14055	28666115	Samples stratified as having high, medium, or low 150 IFNgamma signatures largely co-correlated with those having high, medium, or low 227 signatures but were distinct from those bearing a high, medium, or low somatic mutation rate (total non-silent missense and nonsense mutations [Figures 3F and S3B-S3G]).	('IFNgamma', 'Gene', (54, 62))	('nonsense', 'Var', (263, 271))	('S3B', 'Gene', (298, 301))	('medium', 'Var', (35, 41))	('low 150', 'Var', (46, 53))	('S3B', 'Gene', '11778', (298, 301))
14058	28666115	To isolate these cells, we used an enrichment strategy for lineage negative (lineage: CD3/CD20/CD56/ CD66b) CD45+CD11c+HLA+ cells, distinguishing CD14+ cells as enriched for monocytes from BDCA1+ and BDCA3+ expressing populations by flow cytometry.	('BDCA3', 'Gene', (200, 205))	('BDCA1', 'Gene', '911', (189, 194))	('CD3', 'Gene', (86, 89))	('CD45+CD11c+HLA+', 'Var', (108, 123))	('CD66b', 'Gene', (101, 106))	('BDCA3', 'Gene', '7056', (200, 205))	('CD3', 'Gene', '12501', (86, 89))	('BDCA1', 'Gene', (189, 194))	('CD66b', 'Gene', '1088', (101, 106))
14078	28666115	Strikingly we observed an increasing infiltrate of CD11c+ cells of a mononuclear phagocytic morphology bearing numerous dendrites, located within involved regions of dysplastic nevi and primary cutaneous melanoma specimens, which co-stained for SOCS2 (Figure 5G).	('CD11c+', 'Var', (51, 57))	('dysplastic nevi', 'Disease', (166, 181))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('dysplastic nevi', 'Disease', 'MESH:D004416', (166, 181))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (166, 181))	('cutaneous melanoma', 'Disease', (194, 212))	('nevi', 'Phenotype', 'HP:0003764', (177, 181))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (194, 212))
14085	28666115	SOCS2-/-, but not SOCS2+/+, mice had a 70%-90% reduction in intradermal EL4-OVA growth, with regression starting around day 8-12.	('SOCS2-/-', 'Var', (0, 8))	('mice', 'Species', '10090', (28, 32))	('reduction', 'NegReg', (47, 56))	('EL4', 'Gene', (72, 75))	('EL4', 'Gene', '111979', (72, 75))
14087	28666115	Testing B16-OVA melanoma, we also observed a roughly 40% reduction of intradermal tumor growth in SOCS2-/- animals (Figure S6E).	('SOCS2-/-', 'Var', (98, 106))	('reduction', 'NegReg', (57, 66))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('intradermal tumor', 'Disease', (70, 87))	('melanoma', 'Disease', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('intradermal tumor', 'Disease', 'MESH:D018330', (70, 87))
14088	28666115	Mice with a transient restriction to SOCS2-/- ZBTB46-dependent DC at the time of tumor implantation (Figure 6B and 6C) showed a significant reduction in B16-OVA melanoma growth.	('B16-OVA melanoma growth', 'Disease', 'MESH:D008546', (153, 176))	('B16-OVA melanoma growth', 'Disease', (153, 176))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('SOCS2-/- ZBTB46-dependent', 'Var', (37, 62))	('reduction', 'NegReg', (140, 149))	('Mice', 'Species', '10090', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
14096	28666115	CCR7-restricted loss of SOCS2 led to significantly higher contact sensitization as measured by ear swelling (Figure 7H).	('SOCS2', 'Gene', (24, 29))	('CCR', 'molecular_function', 'GO:0043880', ('0', '3'))	('ear swelling', 'Disease', 'MESH:D004427', (95, 107))	('sensitization', 'biological_process', 'GO:0046960', ('66', '79'))	('loss', 'Var', (16, 20))	('higher', 'PosReg', (51, 57))	('ear swelling', 'Disease', (95, 107))	('contact sensitization', 'CPA', (58, 79))
14098	28666115	Defects in DC apoptosis are linked to autoimmune disease.	('linked', 'Reg', (28, 34))	('Defects', 'Var', (0, 7))	('autoimmune disease', 'Disease', (38, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('14', '23'))	('apoptosis', 'biological_process', 'GO:0006915', ('14', '23'))	('autoimmune disease', 'Phenotype', 'HP:0002960', (38, 56))	('autoimmune disease', 'Disease', 'MESH:D001327', (38, 56))
14120	28666115	Hence, loss of SOCS2, a species-conserved transcript highly expressed by tissue migratory DC that was recently linked to suppression of autoimmunity, enables robust tumor-immune rejection.	('autoimmunity', 'Disease', 'MESH:D001327', (136, 148))	('loss', 'Var', (7, 11))	('autoimmunity', 'Phenotype', 'HP:0002960', (136, 148))	('SOCS2', 'Gene', (15, 20))	('autoimmunity', 'Disease', (136, 148))	('enables', 'PosReg', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
14171	28666115	All work on pigmented lesion specimens (nevi and melanoma) was IRB approved at Rockefeller University and obtained by informed consent and includes previously published data sets GEO: GSE53223 for common and dysplastic nevi and new data set GEO: GSE100050 for normal skin and melanoma.	('common', 'Disease', (197, 203))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('pigmented lesion', 'Disease', (12, 28))	('melanoma', 'Disease', (276, 284))	('pigmented lesion', 'Disease', 'MESH:D010859', (12, 28))	('dysplastic nevi', 'Disease', (208, 223))	('dysplastic nevi', 'Disease', 'MESH:D004416', (208, 223))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('GSE', 'Chemical', '-', (246, 249))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (208, 223))	('nevi', 'Phenotype', 'HP:0003764', (219, 223))	('nevi', 'Phenotype', 'HP:0003764', (40, 44))	('GSE', 'Chemical', '-', (184, 187))	('GSE53223', 'Var', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
14186	28666115	Expression data from GEO: GSE35459, GEO: GSE49358, GEO: GSE53588, GEO: GSE60782, and GEO: GSE66970 were analyzed using an unpaired t test.	('GSE', 'Chemical', '-', (90, 93))	('GSE', 'Chemical', '-', (56, 59))	('GSE66970', 'Var', (90, 98))	('GSE', 'Chemical', '-', (71, 74))	('GSE49358', 'Var', (41, 49))	('GSE', 'Chemical', '-', (26, 29))	('GSE35459', 'Var', (26, 34))	('GSE', 'Chemical', '-', (41, 44))	('GSE53588', 'Var', (56, 64))
14223	28078671	Genes described as mutated in single CMN (or possibly single samples taken from patients with multiple CMN) include NRAS,11, 12 BRAF,11, 13, 14, 15, 16, 17, 18 MC1R,11, 19 TP53 11 and GNAQ.20 However, in multiple CMN and CMN syndrome it is possible to assign causality to postzygotic mutations in NRAS in 80% of cases studied, as the same mutation is found in different cutaneous lesions from the same patient, and in affected neurological and malignant tissue.5 Causal mutations in multiple CMN usually lead to amino acid substitutions in codon 61, with p.Q61K being more common than p.Q61R, and with no distinguishable phenotypic differences between these two from existing data.	('patients', 'Species', '9606', (80, 88))	('CMN syndrome', 'Disease', (221, 233))	('NRAS', 'Gene', (297, 301))	('CMN', 'Gene', (492, 495))	('CMN', 'Phenotype', 'HP:0100814', (37, 40))	('TP53', 'Gene', (172, 176))	('lead to', 'Reg', (504, 511))	('substitutions', 'Var', (523, 536))	('NRAS', 'Gene', '4893', (116, 120))	('multiple CMN', 'Gene', (483, 495))	('patient', 'Species', '9606', (80, 87))	('CMN syndrome', 'Disease', 'MESH:D013577', (221, 233))	('p.Q61K', 'Var', (555, 561))	('patient', 'Species', '9606', (402, 409))	('p.Q61K', 'Mutation', 'rs121913254', (555, 561))	('NRAS', 'Gene', '4893', (297, 301))	('GNAQ', 'Gene', '2776', (184, 188))	('p.Q61R', 'Mutation', 'rs11554290', (585, 591))	('GNAQ', 'Gene', (184, 188))	('CMN', 'Phenotype', 'HP:0100814', (213, 216))	('TP53', 'Gene', '7157', (172, 176))	('CMN', 'Phenotype', 'HP:0100814', (492, 495))	('MC1R', 'Gene', '4157', (160, 164))	('CMN', 'Phenotype', 'HP:0100814', (103, 106))	('NRAS', 'Gene', (116, 120))	('MC1R', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (128, 132))	('CMN', 'Phenotype', 'HP:0100814', (221, 224))	('BRAF', 'Gene', (128, 132))
14224	28078671	However, numbers of p.Q61R are relatively low and this picture may change.18, 21 NRAS p.Q61H has also been described, but is confined to the rarer naevus spilus phenotypic subtype, a group that also so far contains a single report of a p.G13R mutation22 and a p.Q61L.23   BRAF p.V600E mutations can also be found in individuals with large or multiple CMN18 but thus far have not been found in more than one lesion in the same individual, and cannot therefore yet be assigned as causal.	('naevus spilus', 'Phenotype', 'HP:0025510', (147, 160))	('p.Q61R', 'Mutation', 'rs11554290', (20, 26))	('p.V600E', 'Mutation', 'rs113488022', (277, 284))	('NRAS', 'Gene', (81, 85))	('p.V600E', 'Var', (277, 284))	('CMN', 'Phenotype', 'HP:0100814', (351, 354))	('naevus', 'Phenotype', 'HP:0003764', (147, 153))	('p.Q61L', 'Mutation', 'rs11554290', (260, 266))	('BRAF', 'Gene', '673', (272, 276))	('p.G13R', 'Mutation', 'rs121434595', (236, 242))	('BRAF', 'Gene', (272, 276))	('NRAS', 'Gene', '4893', (81, 85))	('p.Q61H', 'Mutation', 'rs121913255', (86, 92))	('p.G13R mutation22', 'Var', (236, 253))
14226	28078671	Whether patients with CMN with germline MC1R variants are at an increased risk of melanoma development is not yet known.	('variants', 'Var', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('MC1R', 'Gene', '4157', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CMN', 'Phenotype', 'HP:0100814', (22, 25))	('MC1R', 'Gene', (40, 44))	('patients', 'Species', '9606', (8, 16))
14230	28078671	This clear distinction in copy-number patterns with benign and malignant behaviour from this first study has not always been replicated in other studies, with both histopathologically and clinically benign nodules occasionally exhibiting regional rather than whole chromosome copy-number changes, and clinically and histopathologically malignant nodules the opposite.26, 27 As with immunohistochemical studies, copy-number measurement can therefore be seen as a very useful adjunct to other assessment, rather than a definitive test of malignancy.	('copy-number', 'Var', (411, 422))	('malignancy', 'Disease', 'MESH:D009369', (536, 546))	('behaviour', 'biological_process', 'GO:0007610', ('73', '82'))	('chromosome', 'cellular_component', 'GO:0005694', ('265', '275'))	('malignancy', 'Disease', (536, 546))
14239	28078671	However, recent data have shown that the risk of melanoma appears to be higher in those with congenital abnormalities of the CNS.33 In line with this, melanoma incidence in the group of multiple CMN with an abnormal screening magnetic resonance imaging (MRI) of the CNS in the first year of life was still higher, at 12%, whereas in those with a normal screening scan it was 1-2% (Table 2).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('congenital abnormalities of the CNS', 'Disease', 'MESH:D000013', (93, 128))	('congenital abnormalities of the CNS', 'Disease', (93, 128))	('CMN', 'Phenotype', 'HP:0100814', (195, 198))	('abnormal', 'Var', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('higher', 'PosReg', (306, 312))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
14241	28078671	CNS screening MRI is therefore currently the best predictor of all adverse outcomes in children, with those with a normal scan being in a low-risk group for all complications, independent of the rest of their clinical phenotype.	('children', 'Species', '9606', (87, 95))	('MRI', 'Var', (14, 17))	('CNS screening MRI', 'Var', (0, 17))
14242	28078671	It is not yet clear why there is such a strong association between screening CNS MRI results and overall risk of melanoma.	('melanoma', 'Disease', (113, 121))	('screening CNS MRI', 'Var', (67, 84))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))
14244	28078671	Other possible explanations are that abnormal MRI is an indicator of a higher burden of mutated cells in the body as a whole, or that the mutation in those with complex congenital neurological disease happened at a particular stage of development, or that those with an abnormal MRI have other genetic risk factors predisposing both to congenital neurological disease and malignancy.	('congenital neurological disease', 'Disease', (169, 200))	('neurological disease', 'Phenotype', 'HP:0000707', (347, 367))	('congenital neurological disease', 'Disease', 'MESH:D019636', (169, 200))	('malignancy', 'Disease', 'MESH:D009369', (372, 382))	('neurological disease', 'Phenotype', 'HP:0000707', (180, 200))	('malignancy', 'Disease', (372, 382))	('MRI', 'Gene', (279, 282))	('abnormal', 'Var', (270, 278))	('abnormal', 'Var', (37, 45))	('congenital neurological disease', 'Disease', (336, 367))	('congenital neurological disease', 'Disease', 'MESH:D019636', (336, 367))
14253	28078671	Those described relating to NRAS are loss of the normal allele in NRAS,5 in that case not secondary to a deletion and therefore probably due to postmitotic recombination, and amplification of mutant NRAS.41 Mutations in BRAF have not been described in melanoma arising in a patient with CMN; however, given the availability and efficacy of BRAF inhibitors it is suggested that both NRAS and BRAF hotspots should be genotyped in cases of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (437, 445))	('melanoma', 'Disease', (437, 445))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('NRAS', 'Gene', (66, 70))	('NRAS', 'Gene', (382, 386))	('BRAF', 'Gene', '673', (220, 224))	('BRAF', 'Gene', (340, 344))	('BRAF', 'Gene', '673', (340, 344))	('BRAF', 'Gene', (220, 224))	('NRAS', 'Gene', (199, 203))	('NRAS', 'Gene', '4893', (28, 32))	('Mutations', 'Var', (207, 216))	('melanoma', 'Disease', 'MESH:D008545', (437, 445))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('patient', 'Species', '9606', (274, 281))	('CMN', 'Phenotype', 'HP:0100814', (287, 290))	('NRAS', 'Gene', '4893', (66, 70))	('NRAS', 'Gene', '4893', (382, 386))	('BRAF', 'Gene', '673', (391, 395))	('BRAF', 'Gene', (391, 395))	('NRAS', 'Gene', (28, 32))	('NRAS', 'Gene', '4893', (199, 203))
14261	28078671	However, regular contact with patients with multiple CMN is often required in childhood for skincare, neurodevelopmental follow-up, coordination of psychological support, treatment of pruritus or superficial infections where they arise, resection of small CMN where it can clearly improve cosmetic appearance, and to some degree reassurance of contact with a doctor in case it is needed.	('resection', 'Var', (237, 246))	('pruritus', 'Disease', 'MESH:D011537', (184, 192))	('superficial infections', 'Disease', (196, 218))	('small CMN', 'Var', (250, 259))	('improve', 'PosReg', (281, 288))	('child', 'Species', '9606', (78, 83))	('CMN', 'Phenotype', 'HP:0100814', (53, 56))	('cosmetic appearance', 'CPA', (289, 308))	('patients', 'Species', '9606', (30, 38))	('pruritus', 'Phenotype', 'HP:0000989', (184, 192))	('pruritus', 'Disease', (184, 192))	('CMN', 'Phenotype', 'HP:0100814', (256, 259))
14274	28078671	The recent introduction of routine genotyping for germline MC1R variants and somatic NRAS and BRAF mutations may also help to identify individuals at highest risk of melanoma development in the future.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('MC1R', 'Gene', '4157', (59, 63))	('melanoma', 'Disease', (166, 174))	('BRAF', 'Gene', (94, 98))	('MC1R', 'Gene', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('mutations', 'Var', (99, 108))	('NRAS', 'Gene', (85, 89))	('NRAS', 'Gene', '4893', (85, 89))	('BRAF', 'Gene', '673', (94, 98))	('variants', 'Var', (64, 72))
14295	28078671	(iii) Tissue sample: biopsy of suspected primary (CNS including leptomeningeal, or skin), for histopathology, NRAS and BRAF hotspot genotyping, copy-number analysis (array CGH or SNP array or FISH).	('NRAS', 'Gene', '4893', (110, 114))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('array CGH or SNP array', 'Disease', (166, 188))	('NRAS', 'Gene', (110, 114))	('array CGH or SNP array', 'Disease', 'MESH:C538388', (166, 188))	('copy-number', 'Var', (144, 155))
14296	28078671	Small single CMN are common birthmarks with very low risk of melanoma, and do not require routine resection for this reason.	('CMN', 'Phenotype', 'HP:0100814', (13, 16))	('Small single CMN', 'Var', (0, 16))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('birthmarks', 'Phenotype', 'HP:0000957', (28, 38))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
14297	28078671	Multiple CMN (two or more, of any size or site) can have extracutaneous associations, then termed 'CMN syndrome', and these phenotypes are caused by postzygotic mosaicism for NRAS mutations in 80% of cases.	('CMN', 'Phenotype', 'HP:0100814', (99, 102))	('caused by', 'Reg', (139, 148))	('mutations', 'Var', (180, 189))	('CMN syndrome', 'Disease', 'MESH:D013577', (99, 111))	('extracutaneous', 'Disease', (57, 71))	('CMN syndrome', 'Disease', (99, 111))	('NRAS', 'Gene', (175, 179))	('CMN', 'Phenotype', 'HP:0100814', (9, 12))	('NRAS', 'Gene', '4893', (175, 179))
14298	28078671	Individuals with multiple CMN do have an increased risk of melanoma, particularly in the presence of congenital neurological abnormalities on screening MRI in the first 6 months of life.	('multiple CMN', 'Var', (17, 29))	('congenital neurological abnormalities', 'Disease', 'MESH:D009461', (101, 138))	('congenital neurological abnormalities', 'Disease', (101, 138))	('CMN', 'Phenotype', 'HP:0100814', (26, 29))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('neurological abnormalities', 'Phenotype', 'HP:0000707', (112, 138))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
14323	24377047	CPA was reported to induce a fivefold enhancement of the tumor process, which was significantly reduced when CPA-treated animals were irradiated with MMWs.	('CPA', 'Chemical', 'MESH:D003520', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CPA', 'Chemical', 'MESH:D003520', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('enhancement', 'PosReg', (38, 49))	('CPA', 'Var', (0, 3))	('tumor', 'Disease', (57, 62))
14324	24377047	MMWs also increased NK cell activity suppressed by CPA, suggesting that the observed reduction of tumor metastasis is mediated through activation of NK cells.	('tumor metastasis', 'Disease', 'MESH:D009362', (98, 114))	('activation', 'PosReg', (135, 145))	('activity', 'MPA', (28, 36))	('tumor metastasis', 'Disease', (98, 114))	('NK cell', 'CPA', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('reduction', 'NegReg', (85, 94))	('CPA', 'Chemical', 'MESH:D003520', (51, 54))	('MMWs', 'Var', (0, 4))
14445	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))
14446	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))
14488	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))
14491	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'))
14533	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))
14558	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))
14568	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))
14570	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))	('melanoma', 'Disease', (110, 118))	('Variants', 'Var', (0, 8))	('patients', 'Species', '9606', (119, 127))	('CTLA-4', 'Gene', (32, 38))	('associate with', 'Reg', (39, 53))
14571	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))
14573	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'))
14574	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))
14577	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', 'Gene', '220972', (179, 182))	('miR-99b', 'Gene', (245, 252))	('miR-125a', 'Gene', '406910', (225, 233))	('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))	('resistance', 'CPA', (104, 114))	('miR-155', 'Gene', (189, 196))	('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', (198, 201))	('miR', 'Gene', '220972', (245, 248))	('predict', 'Reg', (79, 86))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('miR', 'Gene', '220972', (22, 25))	('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))
14586	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))
14587	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))	('TERT', 'Gene', '7015', (48, 52))	('uveal tumors', 'Disease', (120, 132))	('BRAF', 'Gene', '673', (32, 36))	('uveal tumors', 'Disease', 'MESH:D014604', (120, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('BRAF', 'Gene', (32, 36))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('NRAS', 'Gene', (38, 42))	('mutations', 'Var', (19, 28))	('TERT', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cutaneous melanoma', 'Disease', (81, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))
14588	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))
14638	18794153	Targeting (V600E) B-Raf and Akt3 using Nanoliposomal-siRNA Inhibits Cutaneous Melanocytic Lesion Development Most events promoting early melanoma development are yet to be identified but deregulation of the B-Raf and Akt3 signaling cascades are important regulators of this process.	('V600E', 'Var', (11, 16))	('Raf', 'Gene', '22882', (20, 23))	('signaling', 'biological_process', 'GO:0023052', ('222', '231'))	('Akt3', 'Gene', (28, 32))	('Cutaneous Melanocytic Lesion', 'Disease', 'MESH:D009508', (68, 96))	('Raf', 'Gene', (209, 212))	('Cutaneous Melanocytic Lesion', 'Disease', (68, 96))	('Raf', 'Gene', (20, 23))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('Akt3', 'Gene', '10000', (28, 32))	('melanoma', 'Disease', (137, 145))	('Inhibits', 'NegReg', (59, 67))	('Akt3', 'Gene', '10000', (217, 221))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('V600E', 'Mutation', 'rs113488022', (11, 16))	('Raf', 'Gene', '22882', (209, 212))	('Akt3', 'Gene', (217, 221))
14639	18794153	Approximately 90% of normal moles and ~60% of early invasive cutaneous melanomas contain a T1799A B-Raf mutation (V600EB-Raf), leading to 10X higher enzyme activity and constitutive activation of the MAP kinase pathway.	('T1799A', 'Mutation', 'rs113488022', (91, 97))	('T1799A', 'Var', (91, 97))	('invasive cutaneous melanomas', 'Disease', (52, 80))	('MAP', 'molecular_function', 'GO:0004239', ('200', '203'))	('V600EB-Raf', 'Gene', '22882', (114, 124))	('enzyme activity', 'molecular_function', 'GO:0003824', ('149', '164'))	('activity', 'MPA', (156, 164))	('invasive cutaneous melanomas', 'Disease', 'MESH:C562393', (52, 80))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('moles', 'Phenotype', 'HP:0003764', (28, 33))	('MAP kinase pathway', 'Pathway', (200, 218))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (61, 80))	('activation', 'PosReg', (182, 192))	('V600EB-Raf', 'Gene', (114, 124))	('enzyme', 'Enzyme', (149, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('higher', 'PosReg', (142, 148))
14642	18794153	Agents specifically targeting these proteins are needed, having fewer side effects than those inhibiting both normal and mutant B-Raf protein or targeting all three Akt isoforms.	('B-Raf protein', 'Protein', (128, 141))	('mutant', 'Var', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('Akt', 'Gene', '207', (165, 168))	('Akt', 'Gene', (165, 168))
14649	18794153	One frequent change occurring in ~90% of normal moles is a T1799A mutation of B-Raf in the MAP kinase pathway.	('B-Raf', 'Gene', (78, 83))	('T1799A', 'Mutation', 'rs113488022', (59, 65))	('moles', 'Phenotype', 'HP:0003764', (48, 53))	('T1799A', 'Var', (59, 65))	('MAP', 'molecular_function', 'GO:0004239', ('91', '94'))	('MAP kinase pathway', 'Pathway', (91, 109))
14650	18794153	Approximately 60% of advanced stage metastatic melanomas also contain the activating V600E mutation leading to 10.7 times higher activity than occurs in normal cells, thereby promoting cellular proliferation.	('higher', 'PosReg', (122, 128))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('activity', 'MPA', (129, 137))	('cellular proliferation', 'CPA', (185, 207))	('V600E', 'Var', (85, 90))	('promoting', 'PosReg', (175, 184))	('melanomas', 'Disease', (47, 56))
14656	18794153	Since these agents target specific genes, there would be fewer potential side effects than drugs inhibiting both mutant and wild-type B-Raf or all three Akt isoforms.	('mutant', 'Var', (113, 119))	('Akt', 'Gene', '207', (153, 156))	('Akt', 'Gene', (153, 156))
14659	18794153	One promising strategy for delivery through the keratinized layer utilizes low-frequency ultrasound to permeabilize skin enabling passage of macromolecules including antisense oligonucleotides without significant skin damage.	('skin damage', 'Disease', 'MESH:D012871', (213, 224))	('antisense oligonucleotides', 'Var', (166, 192))	('passage of macromolecules', 'MPA', (130, 155))	('oligonucleotides', 'Chemical', 'MESH:D009841', (176, 192))	('skin damage', 'Disease', (213, 224))
14672	18794153	Duration of siRNA-mediated protein knockdown at 0, 2, 4, 6, and 8 d following nucleofection was measured for B-Raf or C-Raf by Western blot analysis.	('knockdown', 'Var', (35, 44))	('C-Raf', 'Gene', (118, 123))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('C-Raf', 'Gene', '5894', (118, 123))
14673	18794153	Cells used in reconstructed skin were nucleofected with buffer, siMutB-Raf (100, 50, or 12.5 pmoles), siC-Raf (100 pmoles), or scrambled (100 pmoles) siRNA, plated into culture dishes and 2 d later mixed with keratinocytes, which was added onto the dermis as detailed below.	('C-Raf', 'Gene', '5894', (104, 109))	('100', 'Var', (76, 79))	('C-Raf', 'Gene', (104, 109))	('moles', 'Phenotype', 'HP:0003764', (116, 121))	('moles', 'Phenotype', 'HP:0003764', (143, 148))	('moles', 'Phenotype', 'HP:0003764', (94, 99))
14717	18794153	To verify specificity of siRNA targeting V600EB-Raf, 100 pmoles (1 muM) was nucleofected into melanoma cells containing mutant (UACC 903) or wild-type protein (C8161.Cl9).	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('muM', 'Gene', '56925', (67, 70))	('moles', 'Phenotype', 'HP:0003764', (58, 63))	('V600EB-Raf', 'Gene', (41, 51))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('muM', 'Gene', (67, 70))	('mutant', 'Var', (120, 126))	('V600EB-Raf', 'Gene', '22882', (41, 51))
14718	18794153	Western blot and densitometric analysis of cellular protein lysates showed that siRNA designed specifically against V600EB-Raf reduced protein levels ~50% in mutant UACC 903 (Fig.	('V600EB-Raf', 'Gene', (116, 126))	('reduced', 'NegReg', (127, 134))	('protein levels', 'MPA', (135, 149))	('V600EB-Raf', 'Gene', '22882', (116, 126))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('mutant', 'Var', (158, 164))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
14720	18794153	Thus, siRNA designed to specifically inhibit mutant V600EB-Raf or Akt3 reduces expression of mutant but not wild-type B-Raf protein and Akt3 but not Akt1 or Akt2, respectively.	('Akt3', 'Gene', (66, 70))	('expression', 'MPA', (79, 89))	('inhibit', 'NegReg', (37, 44))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('V600EB-Raf', 'Gene', (52, 62))	('mutant', 'Var', (93, 99))	('reduces', 'NegReg', (71, 78))	('V600EB-Raf', 'Gene', '22882', (52, 62))
14722	18794153	Examples of protein knockdown at 18 and 32 h following a single treatment showed a 50-60% decrease of V600EB-Raf protein compared to cells treated with scrambled siRNA-nanoliposomal complex (Fig.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('V600EB-Raf', 'Gene', (102, 112))	('V600EB-Raf', 'Gene', '22882', (102, 112))	('knockdown', 'Var', (20, 29))	('decrease', 'NegReg', (90, 98))
14723	18794153	Western blots were densitometrically scanned and knockdown of B-Raf protein compared to control cells nucleofected with siRNA targeting C-Raf.	('knockdown', 'Var', (49, 58))	('C-Raf', 'Gene', '5894', (136, 141))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('C-Raf', 'Gene', (136, 141))	('B-Raf protein', 'Protein', (62, 75))
14768	18794153	The era of personalized, targeted cancer treatment is near, but specific proteins playing key roles in particular cancer types need identification and demonstration that simultaneous targeting inhibits tumor development in a synergistically acting manner.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('targeting', 'Var', (183, 192))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (202, 207))	('particular cancer', 'Disease', 'MESH:D009369', (103, 120))	('inhibits', 'NegReg', (193, 201))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('particular cancer', 'Disease', (103, 120))	('cancer', 'Disease', (114, 120))
14775	18794153	Approximately 90% of nevi express V600EB-Raf but very few ever develop into melanoma due to the inhibitory effects associated with high MAP kinase pathway activity caused by the mutant protein.	('melanoma', 'Disease', (76, 84))	('mutant', 'Var', (178, 184))	('activity', 'MPA', (155, 163))	('V600EB-Raf', 'Gene', (34, 44))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('MAP', 'molecular_function', 'GO:0004239', ('136', '139'))	('V600EB-Raf', 'Gene', '22882', (34, 44))	('nevi', 'Phenotype', 'HP:0003764', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
14776	18794153	Akt3 has been shown to overcome this block by phosphorylating V600EB-Raf these melanocytes in order to lower activity of mutant protein and downstream MAP kinase pathway signaling to levels promoting rather than inhibiting melanoma development.	('melanoma', 'Disease', (223, 231))	('Akt3', 'Gene', (0, 4))	('V600EB-Raf', 'Gene', '22882', (62, 72))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('mutant', 'Var', (121, 127))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('promoting', 'PosReg', (190, 199))	('protein', 'Protein', (128, 135))	('lower', 'NegReg', (103, 108))	('MAP', 'molecular_function', 'GO:0004239', ('151', '154'))	('inhibiting', 'NegReg', (212, 222))	('V600EB-Raf', 'Gene', (62, 72))	('activity', 'MPA', (109, 117))	('phosphorylating', 'Var', (46, 61))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('MAP kinase pathway signaling', 'Pathway', (151, 179))
14778	18794153	Thus, this discovery demonstrates that siRNA can be used as a therapeutic, specifically targeting multiple aberrantly expressed or mutant cancer causing genes without inhibiting activity of normal proteins to more effectively treat melanoma.	('cancer', 'Disease', (138, 144))	('mutant', 'Var', (131, 137))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanoma', 'Disease', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
14794	32695793	The discovery of activating BRAF mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma.	('patients', 'Species', '9606', (197, 205))	('activating', 'PosReg', (17, 27))	('MEK', 'Gene', (141, 144))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('improved', 'PosReg', (176, 184))	('melanoma', 'Disease', (232, 240))	('mutations', 'Var', (33, 42))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('BRAF', 'Gene', '673', (220, 224))	('melanomas', 'Disease', (58, 67))	('BRAF', 'Gene', (220, 224))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', (28, 32))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('MEK', 'Gene', '5609', (141, 144))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
14796	32695793	Therefore, BRAF mutation testing has become a priority to determine the oncologist's choice and course of therapy.	('mutation', 'Var', (16, 24))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
14797	32695793	In this review, we will report the molecular biology-based strategies used for BRAF mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies.	('BRAF', 'Gene', (79, 83))	('BRAF', 'Gene', '673', (79, 83))	('mutation', 'Var', (84, 92))
14802	32695793	Indeed, cutaneous melanoma is characterized by a high prevalence of somatic mutations, both in the primary tumor and in the metastatic lesions, with a mean mutational burden over 20 mutations per megabase (Alexandrov et al.,; Akbani et al.,), one of the highest Tumor Mutation Burden (TMB) measurements among all solid tumors (Alexandrov et al.,; Zhang et al.,).	('tumor', 'Disease', (319, 324))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (319, 325))	('tumor', 'Disease', (107, 112))	('tumors', 'Disease', 'MESH:D009369', (319, 325))	('Tumor', 'Phenotype', 'HP:0002664', (262, 267))	('TMB', 'Chemical', '-', (285, 288))	('cutaneous melanoma', 'Disease', (8, 26))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (8, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('mutations', 'Var', (182, 191))	('tumors', 'Phenotype', 'HP:0002664', (319, 325))
14806	32695793	An activating mutation in BRAF, with a constitutive activation of the kinase, is found in about 50% of cutaneous melanomas, mostly the BRAF V600E (Tate et al.,).	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', '673', (26, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('BRAF', 'Gene', (135, 139))	('activating', 'PosReg', (3, 13))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (103, 122))	('BRAF', 'Gene', (26, 30))	('V600E', 'Mutation', 'rs113488022', (140, 145))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (103, 122))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('cutaneous melanomas', 'Disease', (103, 122))	('V600E', 'Var', (140, 145))	('activation', 'PosReg', (52, 62))
14809	32695793	Subsequently, the combination of BRAF inhibitors plus MEK inhibitors seemed to further improve the outcome in terms of Overall Survival (OS) among treated patients and combination therapy became the standard of treatment for BRAF mutant melanoma.	('melanoma', 'Disease', (237, 245))	('MEK', 'Gene', '5609', (54, 57))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (33, 37))	('Overall Survival', 'MPA', (119, 135))	('mutant', 'Var', (230, 236))	('BRAF', 'Gene', '673', (225, 229))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('BRAF', 'Gene', (33, 37))	('patients', 'Species', '9606', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('improve', 'PosReg', (87, 94))	('MEK', 'Gene', (54, 57))
14813	32695793	The dramatic improvements in the outcomes in BRAF-mutated melanoma patients receiving BRAF and MEK inhibitors highlights the need for molecular assessment, which has become a necessary step to identify patients who are best suitable for targeted therapies or immunotherapies.	('MEK', 'Gene', '5609', (95, 98))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('patients', 'Species', '9606', (67, 75))	('inhibitors', 'Var', (99, 109))	('BRAF', 'Gene', '673', (86, 90))	('patients', 'Species', '9606', (202, 210))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('improvements', 'PosReg', (13, 25))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('MEK', 'Gene', (95, 98))	('BRAF', 'Gene', (86, 90))	('melanoma', 'Disease', (58, 66))	('outcomes', 'MPA', (33, 41))
14816	32695793	Over the past few decades, growing efforts have shown that tumors often show recurrent oncogenic mutations, amplifications, and rearrangements in the genes that drive cell to proliferation and survival.	('oncogenic', 'CPA', (87, 96))	('mutations', 'Var', (97, 106))	('genes', 'Gene', (150, 155))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('rearrangements', 'Var', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('amplifications', 'Var', (108, 122))	('cell to proliferation', 'CPA', (167, 188))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
14817	32695793	These alterations can occur in different genes considered "drivers" and can be mutually exclusive within the same tumor, such as BRAF and NRAS gene mutations.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (148, 157))	('BRAF', 'Gene', '673', (129, 133))	('BRAF', 'Gene', (129, 133))	('NRAS', 'Gene', '4893', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('NRAS', 'Gene', (138, 142))
14820	32695793	Data published with TCGA Network, after the whole exome sequence analysis of 333 primary and/or metastatic melanoma patients, found that cutaneous melanomas could be classified into four genomic subgroups: mutant BRAF, mutant NRAS, mutant NF1, and triple-wild type (Berger et al.,; Furney et al.,; Akbani et al.,; Johansson et al.,; Hayward et al.,; Hintzsche et al.,; Lyu et al.,; Palmieri et al.,; Wilmott et al.,; Zhou et al.,).	('cutaneous melanomas', 'Disease', 'MESH:C562393', (137, 156))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('NF1', 'Gene', (239, 242))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('mutant', 'Var', (232, 238))	('cutaneous melanomas', 'Disease', (137, 156))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('patients', 'Species', '9606', (116, 124))	('Wilmott', 'Disease', 'None', (400, 407))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('NRAS', 'Gene', '4893', (226, 230))	('mutant', 'Var', (206, 212))	('Wilmott', 'Disease', (400, 407))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('mutant', 'Var', (219, 225))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('NF1', 'Gene', '4763', (239, 242))	('NRAS', 'Gene', (226, 230))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (137, 156))
14826	32695793	Mutations of RAS, RAF, and MEK were described in a large number of tumors: for example, RAS mutations have been found in about 1/3 of all human tumors and in 15-20% of melanomas, and BRAF is mutated in 8% of human tumors and in about 40-50% of melanomas.	('tumors', 'Disease', (144, 150))	('RAF', 'Gene', '22882', (18, 21))	('RAF', 'Gene', '22882', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('melanomas', 'Phenotype', 'HP:0002861', (244, 253))	('human', 'Species', '9606', (208, 213))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('RAF', 'Gene', (18, 21))	('found', 'Reg', (112, 117))	('BRAF', 'Gene', (183, 187))	('MEK', 'Gene', '5609', (27, 30))	('RAF', 'Gene', (184, 187))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanomas', 'Disease', 'MESH:D008545', (168, 177))	('MEK', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('melanomas', 'Disease', (168, 177))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('melanomas', 'Disease', 'MESH:D008545', (244, 253))	('tumors', 'Disease', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('melanomas', 'Disease', (244, 253))	('human', 'Species', '9606', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('BRAF', 'Gene', '673', (183, 187))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('RAS', 'Gene', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
14827	32695793	Moreover, a 15% of melanomas shows mutations of NF1 with loss of function.	('loss of function', 'NegReg', (57, 73))	('NF1', 'Gene', '4763', (48, 51))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('melanomas', 'Disease', (19, 28))	('NF1', 'Gene', (48, 51))	('mutations', 'Var', (35, 44))
14828	32695793	The identification of BRAF mutations is crucial for personalized treatment of melanoma, being an important tool for diagnosis, treatment, predictor of patient outcomes, and may have an impact on prognosis (Barbour et al.,).	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (22, 26))	('have', 'Reg', (177, 181))	('patient', 'Species', '9606', (151, 158))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('BRAF', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('impact', 'Reg', (185, 191))
14830	32695793	Despite this good purpose, to date, only BRAF mutations have FDA approved therapies in advanced cutaneous melanoma, whereas KIT mutations have the tyrosine kinase inhibitors Imatinib as off-label prescription.	('Imatinib', 'Chemical', 'MESH:D000068877', (174, 182))	('mutations', 'Var', (46, 55))	('KIT', 'Gene', (124, 127))	('cutaneous melanoma', 'Disease', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('KIT', 'molecular_function', 'GO:0005020', ('124', '127'))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('KIT', 'Gene', '3815', (124, 127))
14831	32695793	Based on recent ESMO Clinical Practice Guidelines, BRAF mutation testing is mandatory in patients with resectable or unresectable stage III or stage IV melanoma and is highly recommended in high-risk resected disease stage IIC patients (Michielin et al.,).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('stage IIC', 'Disease', (217, 226))	('stage IIC', 'Disease', 'MESH:C565261', (217, 226))	('patients', 'Species', '9606', (227, 235))	('patients', 'Species', '9606', (89, 97))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))	('mutation testing', 'Var', (56, 72))
14833	32695793	Additionally, the NCCN clinical practice guidelines recommend BRAF mutation testing in patients with resectable and unresectable or metastatic melanoma to guide treatment decisions (NCCN Clinical Practice Guidelines in Oncology3)?	('mutation testing', 'Var', (67, 83))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('patients', 'Species', '9606', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
14836	32695793	In case of melanomas arising on pre-existing nevi, particular care should be taken during the enrichment process to make sure that only melanoma cells are isolated from the tissue sample, as also melanocytic nevi can carry BRAF mutations.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('carry', 'Reg', (217, 222))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('pre', 'molecular_function', 'GO:0003904', ('32', '35'))	('mutations', 'Var', (228, 237))	('BRAF', 'Gene', '673', (223, 227))	('nevi', 'Phenotype', 'HP:0003764', (208, 212))	('melanomas', 'Disease', (11, 20))	('BRAF', 'Gene', (223, 227))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (196, 212))	('nevi', 'Phenotype', 'HP:0003764', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('melanoma', 'Disease', (11, 19))
14837	32695793	BRAF mutations occur quite often in melanomas, conferring to this kinase the ability to independently activate MEK, inducing its constitutive activation (Johnson and Sosman,).	('inducing', 'Reg', (116, 124))	('constitutive activation', 'MPA', (129, 152))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('MEK', 'Gene', (111, 114))	('MEK', 'Gene', '5609', (111, 114))	('BRAF', 'Gene', (0, 4))	('Johnson', 'Disease', 'MESH:C535882', (154, 161))	('Johnson', 'Disease', (154, 161))	('melanomas', 'Disease', (36, 45))
14838	32695793	However, mutations in BRAF are early and not sufficient to induce melanoma: there is a high frequency of these mutations in benign nevi (including congenital, intra-dermal, and dysplastic) (Pollock et al.,; Tschandl et al.,), and it seems that additional genetic events are necessary.	('mutations', 'Var', (111, 120))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('intra-dermal', 'Disease', (159, 171))	('dysplastic', 'Disease', 'MESH:D004416', (177, 187))	('mutations', 'Var', (9, 18))	('BRAF', 'Gene', '673', (22, 26))	('nevi', 'Phenotype', 'HP:0003764', (131, 135))	('BRAF', 'Gene', (22, 26))	('dysplastic', 'Disease', (177, 187))	('Pollock', 'Species', '8060', (190, 197))	('congenital', 'Disease', (147, 157))	('benign nevi', 'Disease', (124, 135))
14839	32695793	The discovery of BRAF mutation and its meaning occurred in 2002 and to date, about 300 BRAF mutations have been characterized, most in codon 600: this discovery paved the way for the development of new molecular-target drugs (Flaherty et al.,).	('BRAF', 'Gene', '673', (17, 21))	('mutations', 'Var', (92, 101))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
14841	32695793	Most BRAF mutations are missense variations that determine aminoacid substitution at valine 600.	('BRAF', 'Gene', '673', (5, 9))	('BRAF', 'Gene', (5, 9))	('valine', 'Chemical', 'MESH:D014633', (85, 91))	('mutations', 'Var', (10, 19))	('aminoacid', 'MPA', (59, 68))
14842	32695793	From 70, up to 88% of BRAF mutations are represented by V600E (valine to glutamic acid), but V600K (valine to lysine substitution) or V600D (valine to aspartic acid) and V600R (valine to arginine) are found in 5-12% and <= 5% of melanomas, respectively.	('mutations', 'Var', (27, 36))	('V600R', 'Mutation', 'rs121913227', (170, 175))	('melanomas', 'Phenotype', 'HP:0002861', (229, 238))	('lysine', 'Chemical', 'MESH:D008239', (110, 116))	('V600K', 'Mutation', 'rs121913227', (93, 98))	('V600E', 'Var', (56, 61))	('aspartic acid', 'Chemical', 'MESH:D001224', (151, 164))	('V600D', 'Mutation', 'rs121913377', (134, 139))	('valine', 'Chemical', 'MESH:D014633', (141, 147))	('valine', 'Chemical', 'MESH:D014633', (63, 69))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('V600D', 'Var', (134, 139))	('V600K', 'Var', (93, 98))	('valine', 'Chemical', 'MESH:D014633', (100, 106))	('glutamic acid', 'Chemical', 'MESH:D018698', (73, 86))	('BRAF', 'Gene', '673', (22, 26))	('melanomas', 'Disease', 'MESH:D008545', (229, 238))	('V600R', 'Var', (170, 175))	('BRAF', 'Gene', (22, 26))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('melanomas', 'Disease', (229, 238))	('valine', 'Chemical', 'MESH:D014633', (177, 183))	('arginine', 'Chemical', 'MESH:D001120', (187, 195))
14843	32695793	has further categorized BRAF mutations based on their MAPK pathway activation mechanisms into class-1 (high kinase activity involving codon 600), class-2 (high or intermediate kinase activity involving codons outside 600), and class-3 (impaired BRAF kinase activity) (Yao et al.,).	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('mutations', 'Var', (29, 38))	('kinase activity', 'molecular_function', 'GO:0016301', ('250', '265'))	('impaired', 'NegReg', (236, 244))	('kinase activity', 'molecular_function', 'GO:0016301', ('176', '191'))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('kinase activity', 'molecular_function', 'GO:0016301', ('108', '123'))
14844	32695793	Melanomas with BRAF class-1 (V600 mutations) respond well to current FDA-approved BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib), as well as combined BRAF/MEK inhibitor therapy.	('BRAF', 'Gene', '673', (15, 19))	('MEK', 'Gene', (167, 170))	('MEK', 'Gene', '5609', (167, 170))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (82, 86))	('V600 mutations', 'Var', (29, 43))	('dabrafenib', 'Chemical', 'MESH:C561627', (112, 122))	('Melanomas', 'Disease', (0, 9))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', '673', (162, 166))	('vemurafenib', 'Chemical', 'MESH:D000077484', (99, 110))	('encorafenib', 'Chemical', 'MESH:C000601108', (128, 139))	('BRAF', 'Gene', (162, 166))
14845	32695793	On the contrary, melanomas with BRAF class-2 mutations (non-V600 mutations) do not respond to first-generation BRAF inhibitors, which are monomer selective, but they could be of benefit to MEK/ERK inhibitors as well as the BRAF inhibitor PLX8394 (Dahlman et al.,; Bowyer et al.,; Marconcini et al.,; Janku et al.,).	('benefit', 'PosReg', (178, 185))	('BRAF', 'Gene', '673', (32, 36))	('mutations', 'Var', (45, 54))	('MEK', 'Gene', (189, 192))	('ERK', 'Gene', (193, 196))	('BRAF', 'Gene', (32, 36))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('melanomas', 'Disease', (17, 26))	('MEK', 'Gene', '5609', (189, 192))	('BRAF', 'Gene', '673', (223, 227))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('ERK', 'molecular_function', 'GO:0004707', ('193', '196'))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (223, 227))	('BRAF', 'Gene', (111, 115))	('melanomas', 'Disease', 'MESH:D008545', (17, 26))	('ERK', 'Gene', '5594', (193, 196))
14846	32695793	These class II mutations can be further subdivided into class IIa within the activation segment (L597 and K601) and IIb within the glycine-rich region (G466 and G469) (Dankner et al.,).	('K601', 'Var', (106, 110))	('glycine', 'Chemical', 'MESH:D005998', (131, 138))	('G466', 'Var', (152, 156))	('G469', 'Var', (161, 165))	('L597', 'Var', (97, 101))
14847	32695793	Finally, class III mutations (N581 and D594) have no kinase activity but facilitate RAS binding and CRAF activation (Yao et al.,).	('RAS', 'Protein', (84, 87))	('kinase activity', 'molecular_function', 'GO:0016301', ('53', '68'))	('CRAF', 'Gene', (100, 104))	('CRAF', 'Gene', '5894', (100, 104))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('N581', 'Var', (30, 34))	('facilitate', 'PosReg', (73, 83))	('CRAF', 'molecular_function', 'GO:0004709', ('100', '104'))	('D594', 'Var', (39, 43))
14848	32695793	To date, FDA approved only BRAF/MEK inhibitors alone or in combination in presence of BRAF V600 mutations.	('V600 mutations', 'Var', (91, 105))	('BRAF', 'Gene', '673', (86, 90))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))	('BRAF', 'Gene', (86, 90))
14849	32695793	Three combinations of BRAF/MEK inhibitors (vemurafenib plus cobimetinib, dabrafenib plus trametinib, and encorafenib plus binimetinib) are currently available for BRAF V600E/K metastatic melanomas, and one combination (dabrafenib plus trametinib) has been recently approved in the adjuvant, Stage III setting (Long et al.,; Schvartsman et al.,).	('V600E', 'Var', (168, 173))	('melanomas', 'Disease', 'MESH:D008545', (187, 196))	('cobimetinib', 'Chemical', 'MESH:C574276', (60, 71))	('melanomas', 'Disease', (187, 196))	('vemurafenib', 'Chemical', 'MESH:D000077484', (43, 54))	('encorafenib', 'Chemical', 'MESH:C000601108', (105, 116))	('dabrafenib', 'Chemical', 'MESH:C561627', (73, 83))	('MEK', 'Gene', '5609', (27, 30))	('V600E', 'SUBSTITUTION', 'None', (168, 173))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('MEK', 'Gene', (27, 30))	('trametinib', 'Chemical', 'MESH:C560077', (235, 245))	('BRAF', 'Gene', '673', (22, 26))	('melanomas', 'Phenotype', 'HP:0002861', (187, 196))	('BRAF', 'Gene', (22, 26))	('dabrafenib', 'Chemical', 'MESH:C561627', (219, 229))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('trametinib', 'Chemical', 'MESH:C560077', (89, 99))	('binimetinib', 'Chemical', 'MESH:C581313', (122, 133))
14850	32695793	Several methods have been developed and are currently used for the detection of BRAF mutations, including Sanger sequencing, immunohistochemistry (IHC), pyrosequencing, mutation-specific Polymerase Chain Reaction (PCR) and mutation-specific real-time PCR, digital PCR (dPCR), High-Resolution Melting curve analysis (HRM), Matrix Assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS; Sequenom), and Next-Generation Sequencing (NGS).	('mutations', 'Var', (85, 94))	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (80, 84))
14855	32695793	Moreover, the sensitivity of Sanger sequencing for V600E detection is 92.5% (Anderson et al.,), meaning that, using this technique alone, 7.5% of patients potentially eligible for treatment with BRAF and MEK inhibitors would be missed.	('V600E', 'Var', (51, 56))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('MEK', 'Gene', (204, 207))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('patients', 'Species', '9606', (146, 154))	('MEK', 'Gene', '5609', (204, 207))
14857	32695793	analyzed V600 mutations in 275 melanoma FFPE samples and displayed a higher sensitivity for Sanger sequencing than for Cobas 4800 test.	('V600 mutations', 'Var', (9, 23))	('melanoma FFPE', 'Disease', 'MESH:D008545', (31, 44))	('melanoma FFPE', 'Disease', (31, 44))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))
14860	32695793	examined BRAF mutations in 236 FFPE cutaneous melanoma lymph node metastases by Sanger sequencing tests and the Cobas  4800 BRAF V600 Mutation Test.	('BRAF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))	('BRAF', 'Gene', '673', (124, 128))	('melanoma lymph node metastases', 'Disease', 'MESH:D009362', (46, 76))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('BRAF', 'Gene', (124, 128))	('mutations', 'Var', (14, 23))	('melanoma lymph node metastases', 'Disease', (46, 76))	('BRAF', 'Gene', '673', (9, 13))
14861	32695793	Moreover, the sequencing demonstrated a superiority in the detection of mutations other than V600E but a higher susceptibility to DNA quality compared to Cobas 4800 test (Jurkowska et al.,).	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('V600E', 'Var', (93, 98))	('DNA quality', 'MPA', (130, 141))	('superiority', 'PosReg', (40, 51))	('Jurkowska', 'CellLine', 'None', (171, 180))	('susceptibility', 'MPA', (112, 126))	('V600E', 'Mutation', 'rs113488022', (93, 98))
14867	32695793	analyzed BRAF mutational status in 63 melanoma patients by HRM, pyrosequencing, allele specific PCR, NGS, and IHC reporting a cross-reactivity with no-V600E mutations (Ihle et al.,).	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (9, 13))	('mutational', 'Var', (14, 24))	('patients', 'Species', '9606', (47, 55))	('V600E', 'Mutation', 'rs113488022', (151, 156))	('melanoma', 'Disease', (38, 46))	('BRAF', 'Gene', '673', (9, 13))
14871	32695793	Pyrosequencing is commonly used to detect BRAF mutations and commercial kits are actually available for BRAF analysis on this platform, such as therascreen BRAF Pyro kit (Qiagen, Hilden, Germany) (Tan et al.,).	('BRAF', 'Gene', '673', (42, 46))	('BRAF', 'Gene', (156, 160))	('kit', 'Gene', (72, 75))	('mutations', 'Var', (47, 56))	('kit', 'Gene', (166, 169))	('kit', 'Gene', '3815', (72, 75))	('BRAF', 'Gene', '673', (104, 108))	('kit', 'Gene', '3815', (166, 169))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', (104, 108))	('BRAF', 'Gene', '673', (156, 160))
14875	32695793	The main limitation of these approaches is that they are optimized for the most common BRAF mutations.	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))	('mutations', 'Var', (92, 101))
14876	32695793	In particular, THxID-BRAF kit was approved for the detection of V600E and K mutations and is validated for DNA input ranging from 10 to 350 ng/mul (bioMerieux Corporate Website4).	('K mutations', 'Var', (74, 85))	('THxID-BRAF', 'Disease', 'None', (15, 25))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('kit', 'Gene', (26, 29))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('kit', 'Gene', '3815', (26, 29))	('THxID-BRAF', 'Disease', (15, 25))	('V600E', 'Var', (64, 69))
14877	32695793	On the contrary, the Cobas 4800 test is FDA approved only for V600E and has an analytical sensitivity of 95% for detecting the V600E mutation with a recommended DNA input of 125 ng total (125 ng/25 mul for the detection of BRAF V600E mutation at >= 5%) (Drugs@FDA: FDA-Approved Drugs5).	('V600E', 'Var', (127, 132))	('V600E', 'Mutation', 'rs113488022', (228, 233))	('V600E', 'Var', (62, 67))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('BRAF', 'Gene', '673', (223, 227))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('BRAF', 'Gene', (223, 227))	('V600E', 'Mutation', 'rs113488022', (62, 67))
14878	32695793	In contrast to the Cobas 4800 test, the THxID test has a high degree of sensitivity for both V600E and V600K.	('V600K', 'Var', (103, 108))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('V600K', 'Mutation', 'rs121913227', (103, 108))	('V600E', 'Var', (93, 98))
14880	32695793	Recently, CE-IVD real-time PCR tests have been developed to detect all BRAF V600 mutations with a sensitivity similar or superior to that observed with pyrosequencing.	('mutations', 'Var', (81, 90))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (71, 75))
14881	32695793	Indeed, PNA clamp real-time PCR detected a 0.5% BRAF V600E mutant in the background of the WT with high sensitivity since it is based on the principle that PNA inhibits WT by hybridizing normal sequences, and therefore mutant DNA is preferentially amplified.	('V600E', 'Mutation', 'rs113488022', (53, 58))	('V600E', 'Var', (53, 58))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
14883	32695793	The results indicated good agreement among all four methods about the presence of the BRAF V600E mutation reaching a concordance between Cobas  4800 and ddPCR of 88.9% for BRAF and 100% for WT patients.	('patients', 'Species', '9606', (193, 201))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))	('V600E', 'Var', (91, 96))	('BRAF', 'Gene', '673', (172, 176))	('BRAF', 'Gene', (172, 176))
14884	32695793	In addition, ddPCR was able to detect the BRAF V600E mutation in eight patients that would not have been identified by the others techniques thanks to its detection limit of 0.001% (Malicherova et al.,).	('BRAF', 'Gene', '673', (42, 46))	('patients', 'Species', '9606', (71, 79))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('V600E', 'Var', (47, 52))	('BRAF', 'Gene', (42, 46))
14885	32695793	Similarly, in another recent work, researchers compared ddPCR with Sanger sequencing and pyrosequencing in 40 melanoma FFPE tissues regarding the detection rates of mutations in BRAF, NRAS, and TERT promoter.	('TERT', 'Gene', (194, 198))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('NRAS', 'Gene', (184, 188))	('TERT', 'Gene', '7015', (194, 198))	('melanoma FFPE', 'Disease', (110, 123))	('BRAF', 'Gene', '673', (178, 182))	('NRAS', 'Gene', '4893', (184, 188))	('melanoma FFPE', 'Disease', 'MESH:D008545', (110, 123))	('BRAF', 'Gene', (178, 182))	('mutations', 'Var', (165, 174))
14886	32695793	Concordance between the platforms was high in tumors with high neoplastic cell content, whereas, at low tumor cellularity, the sensitivity offered by ddPCR allowed for the detection of mutations at low frequency abundance (McEvoy et al.,).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('low tumor', 'Disease', 'MESH:D009800', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('low tumor', 'Disease', (100, 109))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (185, 194))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
14887	32695793	analyzed BRAF V600E mutation in 47 metastatic melanoma biopsies by dPCR reaching a LOD of 0.0195% mutated allele.	('V600E', 'Var', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('BRAF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('LOD', 'molecular_function', 'GO:0033736', ('83', '86'))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (9, 13))
14890	32695793	analyzed 39 FFPE melanoma tissue samples collected by IHC using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific ddPCR Test, and the Idylla BRAF- Mutation Test (Idylla).	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', '673', (73, 77))	('antibody', 'cellular_component', 'GO:0042571', ('108', '116'))	('V600E', 'Mutation', 'rs113488022', (135, 140))	('BRAF', 'Gene', (118, 122))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('FFPE melanoma', 'Disease', (12, 25))	('antibody', 'cellular_component', 'GO:0019815', ('108', '116'))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('FFPE melanoma', 'Disease', 'MESH:D008545', (12, 25))	('antibody', 'cellular_component', 'GO:0019814', ('108', '116'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('antibody', 'molecular_function', 'GO:0003823', ('108', '116'))	('BRAF', 'Gene', (73, 77))	('V600E-specific', 'Var', (135, 149))
14894	32695793	HRM analysis is a PCR-based method for the identification of BRAF mutations.	('mutations', 'Var', (66, 75))	('BRAF', 'Gene', (61, 65))	('BRAF', 'Gene', '673', (61, 65))
14895	32695793	Indeed, HRM compared to other methods is an in-tube method in which the analysis is performed immediately after the amplification and is thus particularly suitable to give a quick response to oncologists on BRAF mutation status.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutation', 'Var', (212, 220))
14896	32695793	assessed and compared BRAF mutations in 59 FFPE melanoma samples using HRM PCR, real-time Allele-Specific Amplification (RT-ASA) PCR, NGS, IHC, and the diagnostics platform IdyllaTM.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (22, 26))	('FFPE melanoma', 'Disease', (43, 56))	('BRAF', 'Gene', (22, 26))	('FFPE melanoma', 'Disease', 'MESH:D008545', (43, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
14897	32695793	Sensitivity and specificity for HRM were 87.1 and 96.4%, respectively and was the less accurate assay for the detection of BRAF mutation on exon 15 (Harle et al.,; Franczak et al.,).	('mutation', 'Var', (128, 136))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))
14900	32695793	In 2014, a meta-analysis of 14 studies involving 1,324 samples in the detecting BRAF mutation indicated that the overall values of the sensitivity and specificity of HRM were 0.99 and 0.99, respectively (Chen et al.,).	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (80, 84))	('mutation', 'Var', (85, 93))
14901	32695793	carried out a blinded study to evaluate various BRAF mutation testing methodologies in FFPE melanoma samples using Sanger sequencing, single-strand conformation analysis (SSCA), HRM and Competitive Allele-Specific TaqMan  PCR (CAST-PCR).	('mutation', 'Var', (53, 61))	('FFPE melanoma', 'Disease', 'MESH:D008545', (87, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('FFPE melanoma', 'Disease', (87, 100))
14902	32695793	The iPLEX HS Melanoma panel (Agena Bioscience Inc., San Diego, CA) detects 97 clinically relevant variants in 11 melanoma relevant genes, including BRAF, at as low as 1% minor allele frequency from FFPE tissue.	('iPLEX HS Melanoma', 'Disease', 'MESH:C567159', (4, 21))	('iPLEX HS Melanoma', 'Disease', (4, 21))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('BRAF', 'Gene', '673', (148, 152))	('Melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('variants', 'Var', (98, 106))	('BRAF', 'Gene', (148, 152))
14903	32695793	compared the sensitivity of MALDI-TOF custom assay (Sequenom MassARRAY; Sequenom, San Diego, CA) with pyrosequencing in the detection of BRAF mutations in 145 specimens, including melanomas, finding a concordance between both assays of 99.3% (144/145).	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('mutations', 'Var', (142, 151))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('melanomas', 'Disease', (180, 189))
14910	32695793	For the external quality assessment, the European Molecular Genetics Quality Network (EMQN) provide several schemes, such as melanoma scheme to evaluate the capability to assess genotyping and clinical interpretation of BRAF gene mutations and NEXTGEN (S) for assessment of genotyping and quality of somatic NGS raw data (http://www.emqn.org/emqn/Home).	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('BRAF', 'Gene', '673', (220, 224))	('mutations', 'Var', (230, 239))	('BRAF', 'Gene', (220, 224))
14912	32695793	Actually, several companies developed CE-IVD NGS panels, but, to date, only Sentosa SQ Melanoma Panel (Vela Diagnostics) is specific for melanoma; it is able to detect 127 hot spot mutations and sequence variants in 10 melanoma genes with a mutation detection sensitivity of 5%.	('hot spot', 'PosReg', (172, 180))	('sequence variants', 'Var', (195, 212))	('Melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('Sentosa SQ Melanoma Panel', 'Disease', (76, 101))	('Sentosa SQ Melanoma Panel', 'Disease', 'MESH:D008545', (76, 101))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))
14913	32695793	Moreover, the only melanoma NGS panel approved by the FDA is the FoundationOne CDx  (F1CDx ) that it is able to detect substitutions, insertion and deletion alterations (indels), and Copy Number Alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures, including microsatellite instability and TMB using DNA isolated from FFPE tumor tissue.	('FFPE tumor', 'Disease', (359, 369))	('Copy Number Alterations', 'Var', (183, 206))	('insertion', 'Var', (134, 143))	('DNA', 'cellular_component', 'GO:0005574', ('341', '344'))	('melanoma NGS', 'Disease', (19, 31))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma NGS', 'Disease', 'MESH:D008545', (19, 31))	('deletion alterations', 'Var', (148, 168))	('FoundationOne CDx', 'Chemical', '-', (65, 82))	('TMB', 'Chemical', '-', (331, 334))	('microsatellite instability', 'Disease', 'MESH:D053842', (300, 326))	('FFPE tumor', 'Disease', 'MESH:D009369', (359, 369))	('microsatellite instability', 'Disease', (300, 326))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('substitutions', 'Var', (119, 132))
14917	32695793	In a study performed on 100 primary melanomas matched with 25 metastatic tumors aimed to identify the best combination of methods for detecting BRAF mutations (among PNA-clamping real-time PCR, IHC, and Sanger sequencing), a BRAF mutation frequency of 62%, based on the combination of at least two techniques was obtained (Bruno et al.,).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (225, 229))	('mutations', 'Var', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('BRAF', 'Gene', '673', (144, 148))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('BRAF', 'Gene', (144, 148))	('tumors', 'Disease', (73, 79))	('melanomas', 'Disease', (36, 45))
14923	32695793	As described above, an NGS approach to the detection of BRAF, NRAS, and KIT mutations in one single step can be considered in clinical practice, with the advantage of high sensitivity and quantitative information in terms of variant allele frequency and a lower cost compared to the single analysis of the three genes.	('mutations', 'Var', (76, 85))	('NRAS', 'Gene', '4893', (62, 66))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('KIT', 'Gene', (72, 75))	('BRAF', 'Gene', '673', (56, 60))	('NRAS', 'Gene', (62, 66))	('KIT', 'Gene', '3815', (72, 75))	('BRAF', 'Gene', (56, 60))
14940	32695793	As it is known, a requirement for administration of BRAFi/MEKi is the identification of a BRAF mutation in specific melanoma samples, which, however, may not represent the current somatic mutation status or tumor heterogeneity.	('BRAF', 'Gene', (90, 94))	('BRAF', 'Gene', '673', (90, 94))	('MEK', 'Gene', (58, 61))	('MEK', 'Gene', '5609', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('BRAF', 'Gene', '673', (52, 56))	('tumor', 'Disease', (207, 212))	('BRAF', 'Gene', (52, 56))	('mutation', 'Var', (95, 103))
14942	32695793	Indeed, the most common mistakes include the selection of the use of inappropriate blood collection tube (e.g., hemolysis or insufficient volume), wrong sample storage and transportation, and inappropriate DNA extraction and mutation detection tests.	('DNA extraction', 'CPA', (206, 220))	('tests', 'Reg', (244, 249))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('hemolysis', 'Disease', (112, 121))	('storage', 'biological_process', 'GO:0051235', ('160', '167'))	('hemolysis', 'Disease', 'MESH:D006461', (112, 121))	('mutation', 'Var', (225, 233))
14944	32695793	In addition, many standard molecular biology techniques for the detection of potentially targeting melanoma mutations are not suitable for the analysis of ctDNA due to their low sensitivity.	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('mutations', 'Var', (108, 117))
14946	32695793	For this reason, highly sensitive methodologies or modifications of pre-existing technologies have been developed in order to detect low-frequency mutations in cfDNA of melanoma patients, such as Allele-specific amplification Refractory Mutation System PCR (ARMS), Bead Emulsification Amplification and Magnetics (BEAMing) technology, Allele-Specific PCR (AS-PCR), PNA-PCR clamping technique, ddPCR, and NGS (Crowley et al.,; Volik et al.,; Busser et al.,; Table 2).	('mutations', 'Var', (147, 156))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('pre', 'molecular_function', 'GO:0003904', ('68', '71'))	('melanoma', 'Disease', (169, 177))	('patients', 'Species', '9606', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('Emulsification', 'Disease', (270, 284))	('Emulsification', 'Disease', 'None', (270, 284))
14949	32695793	It is notable that the liquid biopsy, and in particular cfDNA and CTCs, are not only important for the detection of clinically relevant mutations in melanoma but also for its prognostic and predictive value for patient outcome and response to therapy (Busser et al.,; Gaiser et al.,).	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('mutations', 'Var', (136, 145))	('patient', 'Species', '9606', (211, 218))
14951	32695793	Moreover, the typically only 1-10 CTCs can be found in 4 ml of blood of metastatic melanoma patients, and, for this reason, CTC enrichment methods and a highly sensitivity method are mandatory in order to identify melanoma mutations (Freeman et al.,).	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('patients', 'Species', '9606', (92, 100))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('mutations', 'Var', (223, 232))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
14956	32695793	In a more recent study, researchers used immunomagnetic beads for CTCs enrichment from metastatic melanoma patients blood with BRAF mutated tumors (Reid et al.,).	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('BRAF', 'Gene', '673', (127, 131))	('mutated', 'Var', (132, 139))	('BRAF', 'Gene', (127, 131))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (107, 115))
14957	32695793	The DNA extracted from CTCs has been subjected to Wool Genome Amplification (WGA) and tested for BRAF V600E or V600K mutations by ddPCRs.	('V600K', 'Var', (111, 116))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('V600K', 'Mutation', 'rs121913227', (111, 116))	('BRAF', 'Gene', (97, 101))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('V600E', 'Var', (102, 107))	('BRAF', 'Gene', '673', (97, 101))
14961	32695793	In particular, of 87 patients, 54 (62%) demonstrated positive immunostaining on ISET filters, and, among 46 (85%) patients with BRAF mutation, the V600E mutation was also identified in tissue specimen by pyrosequencing.	('V600E', 'Var', (147, 152))	('mutation', 'Var', (133, 141))	('patients', 'Species', '9606', (21, 29))	('BRAF', 'Gene', '673', (128, 132))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('patients', 'Species', '9606', (114, 122))	('BRAF', 'Gene', (128, 132))
14963	32695793	Finally, very few studies have been carried out on the BRAF mutation status in DNA inside exosomes in melanoma (Garcia-Silva et al.,).	('mutation', 'Var', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('Garcia-Silva', 'Disease', (112, 124))	('BRAF', 'Gene', '673', (55, 59))	('Garcia-Silva', 'Disease', 'MESH:C536767', (112, 124))	('BRAF', 'Gene', (55, 59))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
14965	32695793	found that the BRAF V600E mutation can be detected in exudative seroma (ES)-derived extracellular vesicles by quantitative PCR (LOD of 0.01%) and also correlated with risk of relapse.	('BRAF', 'Gene', '673', (15, 19))	('relapse', 'Disease', (175, 182))	('LOD', 'molecular_function', 'GO:0033736', ('128', '131'))	('BRAF', 'Gene', (15, 19))	('correlated with', 'Reg', (151, 166))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('seroma', 'Disease', 'MESH:D049291', (64, 70))	('extracellular', 'cellular_component', 'GO:0005576', ('84', '97'))	('seroma', 'Disease', (64, 70))	('V600E', 'Var', (20, 25))
14966	32695793	The researchers pointed out as the detection of BRAF mutation in ES vesicles obtained through lymphatic drainage may be a novel parameter to identify melanoma patients at risk of relapse probably due to the presence of residual disease (Garcia-Silva et al.,).	('Garcia-Silva', 'Disease', 'MESH:C536767', (237, 249))	('mutation', 'Var', (53, 61))	('Garcia-Silva', 'Disease', (237, 249))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('BRAF', 'Gene', '673', (48, 52))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('BRAF', 'Gene', (48, 52))	('patients', 'Species', '9606', (159, 167))
14970	32695793	Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy.	('mutations', 'Var', (38, 47))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (33, 37))
14974	32695793	In addition, intertumoral and intratumoral heterogeneity could lead to misinterpretation of BRAF mutational status; this is especially important if testing is performed on primary specimens, or micromestasis, when abundant metastatic lesions are unavailable.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('BRAF', 'Gene', '673', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (18, 23))	('BRAF', 'Gene', (92, 96))	('mutational', 'Var', (97, 107))	('tumor', 'Disease', (35, 40))	('lead', 'Reg', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
15083	29953437	Remarkably, we found that for three classes of cancers profiled by The Cancer Genome Atlas (TCGA):Uterine Corpus Endometrial Carcinoma, Colon and Rectal Adenocarcinomas, and Skin Cutaneous Melanoma:two specific, functionally important positions within zinc finger domains are mutated significantly more often than expected by chance, with alterations in 18%, 10% and 43% of tumors, respectively.	('tumors', 'Disease', (374, 380))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('mutated', 'Var', (276, 283))	('Carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('alterations', 'Reg', (339, 350))	('Cancer Genome Atlas', 'Disease', (71, 90))	('Corpus Endometrial Carcinoma, Colon and Rectal Adenocarcinomas', 'Disease', 'MESH:D016889', (106, 168))	('tumors', 'Disease', 'MESH:D009369', (374, 380))	('Skin Cutaneous Melanoma', 'Disease', (174, 197))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (179, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('Melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('tumors', 'Phenotype', 'HP:0002664', (374, 380))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (174, 197))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
15084	29953437	Further, the genes with these mutations also have high overall missense mutation rates, are expressed at levels comparable to those of known cancer genes, and together have biological process annotations that are consistent with roles in cancers.	('cancer', 'Disease', (238, 244))	('in cancers', 'Disease', (235, 245))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('in cancers', 'Disease', 'MESH:D009369', (235, 245))	('biological process', 'biological_process', 'GO:0008150', ('173', '191'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('missense mutation rates', 'MPA', (63, 86))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('cancer', 'Disease', (141, 147))
15085	29953437	Altogether, we introduce evidence broadly implicating mutations within a diverse set of zinc finger proteins as relevant for cancer, and propose that they contribute to the widespread transcriptional dysregulation observed in cancer cells.	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('zinc', 'Protein', (88, 92))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('transcriptional dysregulation', 'MPA', (184, 213))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('contribute', 'Reg', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
15091	29953437	Further, these mutations, observed across a wide range of transcription factors, converge on at least two processes:chromatin remodeling and dysregulation of retroelements:that are increasingly being linked to human cancers.	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('116', '136'))	('linked', 'Reg', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutations', 'Var', (15, 24))	('chromatin', 'cellular_component', 'GO:0000785', ('116', '125'))	('human', 'Species', '9606', (210, 215))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
15092	29953437	More generally, we propose that these uncovered mutations contribute to the widespread transcriptional dysregulation commonly observed in cancer cells.	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('transcriptional dysregulation', 'MPA', (87, 116))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
15095	29953437	Uncovering which of these mutations play a functional role in oncogenesis or tumor progression is critical for furthering our understanding of cancers and for uncovering new therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('oncogenesis', 'biological_process', 'GO:0007048', ('62', '73'))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('mutations', 'Var', (26, 35))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancers', 'Disease', (143, 150))	('tumor', 'Disease', (77, 82))
15096	29953437	While approaches based on identifying genes mutated across cancer samples more often than expected by chance have yielded both well-known and newly predicted cancer genes, the level of heterogeneity observed in cancers suggests that there are many genes that are mutated across smaller subsets of individuals but nevertheless play key roles in cancer progression.	('cancer', 'Disease', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('play', 'Reg', (326, 330))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Disease', (158, 164))	('mutated', 'Var', (263, 270))	('in cancers', 'Disease', (208, 218))	('in cancers', 'Disease', 'MESH:D009369', (208, 218))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
15097	29953437	Previously, analysis of protein structures revealed that many well-known cancer genes are enriched in mutations that affect protein stability or participation in interactions with nucleic acids, small molecules and peptides.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('protein', 'Protein', (124, 131))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (102, 111))	('interactions', 'Interaction', (162, 174))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('affect', 'Reg', (117, 123))	('nucleic acids', 'Protein', (180, 193))	('participation', 'Reg', (145, 158))
15098	29953437	Thus, these types of somatic mutations are promising as cancer-relevant candidates, even if they occur infrequently across patient cohorts.	('patient', 'Species', '9606', (123, 130))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
15099	29953437	Mutations of residues that affect the stability and specificity of DNA-binding domains are particularly noteworthy, as they can contribute to gene expression dysregulation, a widespread but highly varied phenomenon across tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('DNA-binding', 'molecular_function', 'GO:0003677', ('67', '78'))	('gene expression', 'biological_process', 'GO:0010467', ('142', '157'))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('gene expression dysregulation', 'MPA', (142, 171))	('tumors', 'Disease', (222, 228))	('contribute', 'Reg', (128, 138))
15100	29953437	Indeed, mutations within DNA-binding proteins such as p53, ARID1A, and GATA3 are prevalent in cancers.	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('GATA3', 'Gene', (71, 76))	('mutations', 'Var', (8, 17))	('p53', 'Gene', (54, 57))	('ARID1A', 'Gene', '8289', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ARID1A', 'Gene', (59, 65))	('prevalent', 'Reg', (81, 90))	('GATA3', 'Gene', '2625', (71, 76))	('p53', 'Gene', '7157', (54, 57))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('DNA-binding', 'molecular_function', 'GO:0003677', ('25', '36'))	('in cancers', 'Disease', (91, 101))	('in cancers', 'Disease', 'MESH:D009369', (91, 101))
15108	29953437	Our main finding is that two specific positions within ZF domains are mutated in three cancer types:Uterine Corpus Endometrial Carcinoma (UCEC), Colon and Rectal Adenocarcinomas (COAD/READ), and Skin Cutaneous Melanoma (SKCM):significantly more often than expected.	('Melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('cancer', 'Disease', (87, 93))	('READ', 'Disease', (184, 188))	('COAD', 'Disease', (179, 183))	('Skin Cutaneous Melanoma', 'Disease', (195, 218))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (200, 218))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (108, 136))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (115, 136))	('Corpus Endometrial Carcinoma', 'Disease', (108, 136))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (195, 218))	('Colon and Rectal Adenocarcinomas', 'Disease', 'MESH:D012004', (145, 177))	('READ', 'Disease', 'None', (184, 188))	('COAD', 'Disease', 'MESH:D029424', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('mutated', 'Var', (70, 77))
15109	29953437	We also demonstrate that genes affected by these mutations have high overall missense mutation rates, are expressed at levels comparable to those of known driver genes, and in aggregate have biological process annotations that are consistent with roles in cancers.	('in cancers', 'Disease', (253, 263))	('mutations', 'Var', (49, 58))	('missense mutation rates', 'MPA', (77, 100))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('biological process', 'biological_process', 'GO:0008150', ('191', '209'))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('in cancers', 'Disease', 'MESH:D009369', (253, 263))
15110	29953437	Overall, our work implicates a diverse set of ZF proteins as functionally relevant for cancer, and we propose that mutations within these proteins contribute to the pervasive transcriptional dysregulation observed in cancer cells.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (115, 124))	('transcriptional dysregulation', 'MPA', (175, 204))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('contribute', 'Reg', (147, 157))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
15113	29953437	Position 9 (p9, numbered relative to the start of the alpha-helix that binds DNA) is mutated frequently in the UCEC and COAD/READ cohorts, largely in the form of an arginine to isoleucine mutation (R9I).	('READ', 'Disease', (125, 129))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('COAD', 'Disease', (120, 124))	('arginine', 'Chemical', 'MESH:D001120', (165, 173))	('COAD', 'Disease', 'MESH:D029424', (120, 124))	('READ', 'Disease', 'None', (125, 129))	('arginine to isoleucine mutation', 'Var', (165, 196))	('isoleucine', 'Chemical', 'MESH:D007532', (177, 187))	('R9I', 'Mutation', 'p.R9I', (198, 201))
15115	29953437	These mutations affect a considerable fraction of tumors, with missense mutations at p9 found in 97 of 543 UCEC and 57 of 594 COAD/READ tumors, and missense mutations at p11 found in 204 of 470 SKCM tumors (Fig 1b).	('missense mutations at p9', 'Var', (63, 87))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', (199, 205))	('READ tumors', 'Disease', (131, 142))	('missense mutations at p11', 'Var', (148, 173))	('COAD', 'Disease', 'MESH:D029424', (126, 130))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('found', 'Reg', (88, 93))	('UCEC', 'Disease', (107, 111))	('READ tumors', 'Disease', 'MESH:D009369', (131, 142))	('COAD', 'Disease', (126, 130))	('SKCM tumors', 'Disease', (194, 205))	('SKCM tumors', 'Disease', 'MESH:D009369', (194, 205))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('affect', 'Reg', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', (50, 56))
15116	29953437	Further, a diverse set of ZF genes harbor these mutations, with p9 missense mutations in 367 and 228 genes in UCEC and COAD/READ, respectively, and p11 missense mutations in 199 genes in SKCM.	('READ', 'Disease', (124, 128))	('COAD', 'Disease', (119, 123))	('ZF genes', 'Gene', (26, 34))	('p9 missense mutations', 'Var', (64, 85))	('COAD', 'Disease', 'MESH:D029424', (119, 123))	('READ', 'Disease', 'None', (124, 128))	('p11 missense mutations', 'Var', (148, 170))	('mutations', 'Var', (48, 57))
15117	29953437	The histidine in p11 is one of four residues that coordinate zinc, and thereby is essential for stabilizing the domain; while this position can accomodate a cysteine and still coordinate zinc, substitutions of other residues lead to a loss of domain function.	('substitutions', 'Var', (193, 206))	('loss', 'NegReg', (235, 239))	('histidine', 'Chemical', 'MESH:D006639', (4, 13))	('cysteine', 'Chemical', 'MESH:D003545', (157, 165))	('domain function', 'MPA', (243, 258))
15118	29953437	Arginine in p9 stabilizes the docking of adjacent ZF domains via a contact with the backbone carbonyl or side chain at position -2 of the adjacent C-terminal ZF, and residues in p9 influence the orientation between these domains, an important factor in DNA recognition.	('orientation', 'MPA', (195, 206))	('residues', 'Var', (166, 174))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('Arginine', 'Var', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('253', '256'))	('influence', 'Reg', (181, 190))	('stabilizes', 'Reg', (15, 25))	('contact', 'Interaction', (67, 74))	('docking', 'MPA', (30, 37))
15119	29953437	Consistent with this functional role within arrays of ZF domains, ZF domains with R9I mutations have adjacent C-terminal ZF domains more often than expected, whereas this is not the case for ZF domains with H11Y mutations (S1 Fig).	('H11Y', 'Var', (207, 211))	('R9I', 'Mutation', 'p.R9I', (82, 85))	('H11Y', 'SUBSTITUTION', 'None', (207, 211))	('R9I mutations', 'Var', (82, 95))
15121	29953437	Further, since the number of these mutations observed in each tumor is positively correlated with the total number of missense mutations (Fig 2b), consideration of per-individual mutation rates is necessary to ascertain the significance of these two mutational peaks.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('missense mutations', 'Var', (118, 136))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('mutations', 'Var', (35, 44))
15123	29953437	The total actual number of missense mutations at p9 is 3.2 and 2.8 times the expected count for UCEC and COAD/READ, respectively, and at p11 is 1.9 times the expected count for SKCM (p < 0.0001, Fig 2c).	('READ', 'Disease', (110, 114))	('COAD', 'Disease', 'MESH:D029424', (105, 109))	('READ', 'Disease', 'None', (110, 114))	('missense mutations', 'Var', (27, 45))	('COAD', 'Disease', (105, 109))
15124	29953437	UCEC and COAD/READ tumors with mutations within the exonuclease domain of DNA polymerase epsilon (POLE) are ultramutated.	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('mutations', 'Var', (31, 40))	('COAD', 'Disease', 'MESH:D029424', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('UCEC', 'Disease', (0, 4))	('READ tumors', 'Disease', 'MESH:D009369', (14, 25))	('COAD', 'Disease', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('READ tumors', 'Disease', (14, 25))
15126	29953437	Notably, for all three cancers, other positions in the ZF domain have missense mutation frequencies that are roughly as expected using this permutation procedure (S2 Fig), indicating that after accounting for per-gene and per-individual mutational contexts, p9 and p11 are specifically enriched for mutation accumulation across these cancer cohorts.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('p11', 'Gene', (265, 268))	('cancers', 'Disease', (23, 30))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutation', 'Var', (299, 307))	('cancer', 'Disease', 'MESH:D009369', (334, 340))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (334, 340))
15128	29953437	Missense mutations at p9 cause arginine to isoleucine substitutions 67% and 66% of the time for UCEC and COAD/READ, respectively.	('READ', 'Disease', (110, 114))	('COAD', 'Disease', 'MESH:D029424', (105, 109))	('arginine', 'Chemical', 'MESH:D001120', (31, 39))	('READ', 'Disease', 'None', (110, 114))	('isoleucine', 'Chemical', 'MESH:D007532', (43, 53))	('cause', 'Reg', (25, 30))	('UCEC', 'Disease', (96, 100))	('arginine', 'MPA', (31, 39))	('COAD', 'Disease', (105, 109))	('Missense mutations', 'Var', (0, 18))
15130	29953437	Remarkably, the total numbers of p9 AGA mutations across cohorts of UCEC and COAD/READ individuals are 9.4 and 9.9 times higher than expected (both p-values < 1e-10, Poisson binomial test).	('READ', 'Disease', 'None', (82, 86))	('COAD', 'Disease', 'MESH:D029424', (77, 81))	('higher', 'PosReg', (121, 127))	('AGA', 'Gene', (36, 39))	('mutations', 'Var', (40, 49))	('READ', 'Disease', (82, 86))	('p9 AGA', 'Gene', (33, 39))	('COAD', 'Disease', (77, 81))
15131	29953437	UCEC and COAD/READ tumors with the POLE ultramutator phenotype show a significant increase in the G:C T:A transversion rate, particularly when flanked by an A:T base pair.	('COAD', 'Disease', 'MESH:D029424', (9, 13))	('G:C T:A', 'Var', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('UCEC', 'Disease', (0, 4))	('increase', 'PosReg', (82, 90))	('READ tumors', 'Disease', 'MESH:D009369', (14, 25))	('COAD', 'Disease', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('READ tumors', 'Disease', (14, 25))
15132	29953437	Indeed, of the 55 UCEC and 15 COAD/READ tumors with R9I mutations, 57 have missense mutations within the exonuclease domain of POLE, and an additional 3 have missense mutations elsewhere in POLE.	('15 COAD/READ tumors', 'Disease', (27, 46))	('missense mutations', 'Var', (75, 93))	('R9I', 'Mutation', 'p.R9I', (52, 55))	('R9I mutations', 'Var', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('15 COAD/READ tumors', 'Disease', 'MESH:D029424', (27, 46))	('UCEC', 'Disease', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
15133	29953437	When restricting our analysis to the 63 UCEC and COAD/READ samples with missense mutations in the exonuclease domain of POLE, the numbers of p9 AGA mutations remain enriched as compared to what is expected based upon the per-exome background rates of AGA mutations in these cancers (10.8 and 12.1 times higher, p = 1.0e-12 and p = 3.6e-13, Poisson binomial test).	('mutations', 'Var', (148, 157))	('AGA', 'Gene', (251, 254))	('AGA', 'Gene', (144, 147))	('cancers', 'Disease', 'MESH:D009369', (274, 281))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('READ', 'Disease', (54, 58))	('COAD', 'Disease', (49, 53))	('cancers', 'Disease', (274, 281))	('missense mutations in', 'Var', (72, 93))	('COAD', 'Disease', 'MESH:D029424', (49, 53))	('READ', 'Disease', 'None', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('higher', 'PosReg', (303, 309))	('mutations', 'Var', (255, 264))
15134	29953437	Thus, while these arginine to isoleucine mutations are consistent with the ultramutator phenotype, they accumulate at p9 of ZF domains at an unexpectedly high rate.	('isoleucine', 'Chemical', 'MESH:D007532', (30, 40))	('arginine to isoleucine', 'Var', (18, 40))	('arginine', 'Chemical', 'MESH:D001120', (18, 26))	('accumulate', 'PosReg', (104, 114))
15135	29953437	In SKCM, the H11Y mutations involve a Cytosine to Thymine mutation in the first position of the histidine codon, and occur when the Cytosine is preceded by a pyrimidine; the mutational patterns seen with ultraviolet light exposure and in melanoma consist of frequent CC CT and TC TT mutations.	('CC CT', 'Disease', (267, 272))	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('pyrimidine', 'Chemical', 'MESH:C030986', (158, 168))	('TC TT', 'Gene', (277, 282))	('mutations', 'Var', (283, 292))	('Cytosine', 'Chemical', 'MESH:D003596', (38, 46))	('H11Y', 'SUBSTITUTION', 'None', (13, 17))	('histidine', 'Chemical', 'MESH:D006639', (96, 105))	('Cytosine', 'Chemical', 'MESH:D003596', (132, 140))	('H11Y', 'Var', (13, 17))	('mutations', 'Var', (18, 27))
15136	29953437	However, ZF H11Y mutations occur 13.5 times more frequently than expected (p = 4.4e-11, Poisson binomial test) when considering the per-exome rates of CC CT and TC TT mutations.	('H11Y', 'SUBSTITUTION', 'None', (12, 16))	('mutations', 'Var', (17, 26))	('H11Y', 'Var', (12, 16))
15137	29953437	Thus, as with the R9I mutations and the ultramutator phenotype in UCEC and COAD/READ, the H11Y mutations are in concordance with the mutational profile characteristic of skin cancers but occur significantly more frequently than expected.	('R9I', 'Mutation', 'p.R9I', (18, 21))	('COAD', 'Disease', (75, 79))	('H11Y', 'SUBSTITUTION', 'None', (90, 94))	('skin cancers', 'Disease', 'MESH:D012878', (170, 182))	('READ', 'Disease', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('skin cancers', 'Phenotype', 'HP:0008069', (170, 182))	('COAD', 'Disease', 'MESH:D029424', (75, 79))	('H11Y', 'Var', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('READ', 'Disease', 'None', (80, 84))	('UCEC', 'Disease', (66, 70))	('skin cancers', 'Disease', (170, 182))
15139	29953437	Genes with a missense mutation at p9 (UCEC and COAD/READ) or p11 (SKCM) harbor missense mutations anywhere in their sequences in a moderate but clinically relevant range of individuals (each gene is mutated in, on average, 3.7%, 1.6% and 3.2% of UCEC, COAD/READ and SKCM tumors respectively).	('COAD', 'Disease', (252, 256))	('READ', 'Disease', (52, 56))	('missense mutation', 'Var', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('p11', 'Gene', (61, 64))	('READ', 'Disease', 'None', (257, 261))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('missense mutations', 'Var', (79, 97))	('SKCM tumors', 'Disease', (266, 277))	('UCEC', 'Disease', (246, 250))	('READ', 'Disease', 'None', (52, 56))	('COAD', 'Disease', 'MESH:D029424', (252, 256))	('COAD', 'Disease', 'MESH:D029424', (47, 51))	('SKCM tumors', 'Disease', 'MESH:D009369', (266, 277))	('READ', 'Disease', (257, 261))	('COAD', 'Disease', (47, 51))
15140	29953437	We next calculated for these genes the rate of missense mutations per coding sequence base, averaged across all tumor samples for each gene, while excluding the missense mutations at these ZF positions.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('missense mutations', 'Var', (47, 65))
15141	29953437	Missense mutation rates are significantly higher in these genes than in other genes (median values for the former are 16.8%, 33.5% and 19.0% higher than those of the latter, even though rates for the latter contain all missense mutations, with p-values 8.5e-15, 2.3e-14, and 1.6e-5 for UCEC, COAD/READ, and SKCM, respectively, Mann-Whitney U test).	('Missense mutation', 'MPA', (0, 17))	('READ', 'Disease', (297, 301))	('COAD', 'Disease', (292, 296))	('missense mutations', 'Var', (219, 237))	('higher', 'PosReg', (42, 48))	('COAD', 'Disease', 'MESH:D029424', (292, 296))	('READ', 'Disease', 'None', (297, 301))	('Mann-Whitney U test', 'Disease', (327, 346))
15142	29953437	For each cancer type, we divided the number of missense mutations in each gene by the total number of mutations that would lead to nonsynonymous changes in that gene, and likewise with synonymous mutations (see Methods).	('cancer', 'Disease', (9, 15))	('missense mutations', 'Var', (47, 65))	('lead', 'Reg', (123, 127))	('nonsynonymous changes', 'MPA', (131, 152))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
15143	29953437	While the overall distribution of the ratios of these two values are affected by the trinucleotide mutation profiles of each cancer type, they are comparable across genes within each cancer type since they account for both gene length and codon composition.	('trinucleotide', 'Var', (85, 98))	('trinucleotide', 'Chemical', '-', (85, 98))	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('affected', 'Reg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
15144	29953437	The ratios for ZF genes with at least one missense mutation at p9 (UCEC, COAD/READ) or p11 (SKCM) are higher than the ratios for all other genes with missense and synonymous mutations (one-sided Mann-Whitney p-values 2.4e-23, 1.1e-27, and 8.8e-28, respectively) (Fig 2d).	('missense mutation', 'Var', (42, 59))	('COAD', 'Disease', (73, 77))	('higher', 'PosReg', (102, 108))	('READ', 'Disease', (78, 82))	('COAD', 'Disease', 'MESH:D029424', (73, 77))	('READ', 'Disease', 'None', (78, 82))
15145	29953437	We conclude that the set of ZF genes with mutations at p9 and p11 generally have higher missense mutation rates than expected based upon their synonymous mutation rates, thereby ruling out the explanation that these genes or their genomic locations are simply more mutable, and instead lending support to the relevance of these genes to cancers.	('p11', 'Var', (62, 65))	('cancers', 'Disease', 'MESH:D009369', (337, 344))	('cancers', 'Phenotype', 'HP:0002664', (337, 344))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancers', 'Disease', (337, 344))	('mutations at p9', 'Var', (42, 57))	('higher', 'PosReg', (81, 87))	('missense mutation rates', 'MPA', (88, 111))	('ZF genes', 'Gene', (28, 36))
15146	29953437	To confirm that the uncovered mutations are affecting genes that are expressed, we analyzed RNA-seq data from TCGA for all ZF genes containing a missense mutation in at least one individual at p9 in COAD/READ and UCEC and p11 in SKCM (Fig 3).	('COAD', 'Disease', (199, 203))	('RNA', 'cellular_component', 'GO:0005562', ('92', '95'))	('READ', 'Disease', (204, 208))	('missense mutation', 'Var', (145, 162))	('mutations', 'Var', (30, 39))	('p11', 'Var', (222, 225))	('READ', 'Disease', 'None', (204, 208))	('COAD', 'Disease', 'MESH:D029424', (199, 203))
15147	29953437	For comparison, we also extracted gene expression values for genes that are identified in the abstracts of TCGA studies as significantly mutated in these cancers.	('gene expression', 'biological_process', 'GO:0010467', ('34', '49'))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('mutated', 'Var', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
15149	29953437	Further, for each ZF gene, the expression levels in samples where they are mutated in p9 (UCEC and COAD/READ) or p11 (SKCM) are similar to those where they are not, with 46% (UCEC), 53% (COAD/READ), and 50% (SKCM) of the values for affected samples falling within the interquartile range (i.e., the middle 50%) of the distribution of their respective genes.	('COAD', 'Disease', (99, 103))	('COAD', 'Disease', 'MESH:D029424', (187, 191))	('READ', 'Disease', 'None', (192, 196))	('READ', 'Disease', 'None', (104, 108))	('mutated', 'Var', (75, 82))	('COAD', 'Disease', (187, 191))	('expression', 'MPA', (31, 41))	('COAD', 'Disease', 'MESH:D029424', (99, 103))	('READ', 'Disease', (192, 196))	('falling', 'Phenotype', 'HP:0002527', (249, 256))	('READ', 'Disease', (104, 108))
15150	29953437	These results indicate that the ZF mutations are affecting genes that are expressed at levels sufficient to play an active role in cancer (Fig 3).	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (35, 44))
15151	29953437	We found 425 distinct ZF genes that had missense mutations in either p9 in COAD/READ or UCEC or in p11 in SKCM.	('missense mutations in', 'Var', (40, 61))	('COAD', 'Disease', (75, 79))	('ZF genes', 'Gene', (22, 30))	('READ', 'Disease', (80, 84))	('COAD', 'Disease', 'MESH:D029424', (75, 79))	('READ', 'Disease', 'None', (80, 84))	('p11', 'Var', (99, 102))
15154	29953437	To test whether p9 and p11 missense mutations disproportionately affect some ZF genes, we calculated the distribution of the number of genes that would be mutated in p9 or p11 by randomizing the mutations within all p9 or p11 sites while preserving trinucleotide context; these permutation tests account for both the number of ZF domains each gene contains and the nucleotide contexts in these positions of the domains (see Methods).	('affect', 'Reg', (65, 71))	('trinucleotide', 'Chemical', '-', (249, 262))	('mutations', 'Var', (36, 45))
15155	29953437	The actual mutations are concentrated in fewer genes than expected; they occur in 367 genes in UCEC, 228 genes in COAD/READ and 199 genes in SKCM, and these values are 16.4%, 18.0% and 24.4% lower than the average number observed in randomizations (all three empirical p-values < 0.0001).	('mutations', 'Var', (11, 20))	('READ', 'Disease', 'None', (119, 123))	('COAD', 'Disease', 'MESH:D029424', (114, 118))	('READ', 'Disease', (119, 123))	('COAD', 'Disease', (114, 118))
15157	29953437	Further, the actual fraction of missense mutations that occur at these positions in KRAB-containing genes is higher than expected by chance (empirical p-values <= 0.0001 for all three cancers using the p9 and p11 permutations described in the previous section).	('missense mutations', 'Var', (32, 50))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('KRAB-containing genes', 'Gene', (84, 105))
15158	29953437	Accordingly, GO functional enrichment on the sets of ZF genes with p9 or p11 missense mutations in each cancer type yielded only general terms, largely related to transcription and regulation.	('regulation', 'biological_process', 'GO:0065007', ('181', '191'))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('p11 missense mutations', 'Var', (73, 95))	('transcription', 'biological_process', 'GO:0006351', ('163', '176'))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
15159	29953437	Only 12 mutated ZF genes are associated with KEGG pathways; remarkably, however, all but one of these are associated either with cancer pathways or with signaling pathways regulating pluripotency of stem cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('ZF genes', 'Gene', (16, 24))	('associated', 'Reg', (106, 116))	('mutated', 'Var', (8, 15))	('KEGG pathways', 'Pathway', (45, 58))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
15160	29953437	Further, when analyzing the proteins that interact with mutated ZF genes (see Methods), the most significantly enriched KEGG pathways of the partners were Notch signaling pathway (UCEC, q = 2.1e-13 and COAD/READ, q = 0.12), a well-known cancer pathway and viral carcinogenesis (SKCM, q = 0.16).	('COAD', 'Disease', (202, 206))	('READ', 'Disease', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('mutated', 'Var', (56, 63))	('viral carcinogenesis', 'Disease', 'MESH:D063646', (256, 276))	('COAD', 'Disease', 'MESH:D029424', (202, 206))	('Notch signaling pathway', 'Pathway', (155, 178))	('READ', 'Disease', 'None', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('155', '178'))	('viral carcinogenesis', 'Disease', (256, 276))	('cancer', 'Disease', (237, 243))	('KEGG pathways', 'Pathway', (120, 133))
15162	29953437	Position 9 and 11 missense mutations are found in several known cancer genes.	('missense mutations', 'Var', (18, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
15164	29953437	Additionally, there are several other p9 and p11 mutated ZF proteins that are not in the CGC but nevertheless have some support for a role in cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('p11 mutated', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ZF proteins', 'Protein', (57, 68))	('cancer', 'Disease', (142, 148))
15165	29953437	For example, PEG3, which had a p9 missense mutation in three UCEC tumors and one COAD/READ tumor and an H11Y mutation in one SKCM tumor, has been implicated in the tumor necrosis factor response pathway as part of a protein complex that activates NFkappaB; it also plays a critical role in p53-mediated apoptosis.	('necrosis', 'biological_process', 'GO:0008220', ('170', '178'))	('PEG3', 'Gene', '5178', (13, 17))	('H11Y', 'Var', (104, 108))	('protein complex', 'cellular_component', 'GO:0032991', ('216', '231'))	('necrosis', 'biological_process', 'GO:0070265', ('170', '178'))	('tumor necrosis', 'Disease', 'MESH:D009336', (164, 178))	('READ tumor', 'Disease', 'MESH:D009369', (86, 96))	('H11Y', 'SUBSTITUTION', 'None', (104, 108))	('necrosis', 'biological_process', 'GO:0019835', ('170', '178'))	('COAD', 'Disease', (81, 85))	('necrosis', 'biological_process', 'GO:0001906', ('170', '178'))	('tumor necrosis', 'Disease', (164, 178))	('NFkappaB', 'Gene', '4790', (247, 255))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('164', '185'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('303', '312'))	('apoptosis', 'biological_process', 'GO:0006915', ('303', '312'))	('UCEC tumors', 'Disease', (61, 72))	('p9 missense mutation', 'Var', (31, 51))	('NFkappaB', 'Gene', (247, 255))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p53', 'Gene', '7157', (290, 293))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('UCEC tumors', 'Disease', 'MESH:D009369', (61, 72))	('necrosis', 'biological_process', 'GO:0008219', ('170', '178'))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SKCM tumor', 'Disease', 'MESH:D009369', (125, 135))	('COAD', 'Disease', 'MESH:D029424', (81, 85))	('PEG3', 'Gene', (13, 17))	('READ tumor', 'Disease', (86, 96))	('p53', 'Gene', (290, 293))	('SKCM tumor', 'Disease', (125, 135))
15166	29953437	ZNF382 had these mutations in six UCEC tumors and three COAD/READ tumors, and has been implicated as a tumor suppressor that is silenced in multiple carcinoma cell lines, including colon, cervical and gastric.	('UCEC tumors', 'Disease', 'MESH:D009369', (34, 45))	('COAD', 'Disease', 'MESH:D029424', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('multiple carcinoma', 'Disease', 'MESH:C537656', (140, 158))	('READ tumors', 'Disease', 'MESH:D009369', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gastric', 'Disease', (201, 208))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (66, 71))	('ZNF382', 'Gene', (0, 6))	('COAD', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('READ tumors', 'Disease', (61, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Disease', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor', 'Disease', (39, 44))	('ZNF382', 'Gene', '84911', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cervical', 'Disease', (188, 196))	('UCEC tumors', 'Disease', (34, 45))	('colon', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('multiple carcinoma', 'Disease', (140, 158))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
15167	29953437	ZNF420, also known as APAK, had missense mutations at p9 in five UCEC tumors and one COAD/READ tumor, and at p11 in one SKCM tumor; this protein interacts with p53 and in normal cells suppresses p53-mediated apoptosis.	('p53', 'Gene', (195, 198))	('UCEC tumors', 'Disease', (65, 76))	('p53', 'Gene', '7157', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('suppresses', 'NegReg', (184, 194))	('interacts', 'Interaction', (145, 154))	('missense mutations', 'Var', (32, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ZNF420', 'Gene', '147923', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('UCEC tumors', 'Disease', 'MESH:D009369', (65, 76))	('p53', 'Gene', (160, 163))	('COAD', 'Disease', 'MESH:D029424', (85, 89))	('SKCM tumor', 'Disease', 'MESH:D009369', (120, 130))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('READ tumor', 'Disease', (90, 100))	('APAK', 'Gene', (22, 26))	('SKCM tumor', 'Disease', (120, 130))	('ZNF420', 'Gene', (0, 6))	('COAD', 'Disease', (85, 89))	('p53', 'Gene', '7157', (195, 198))	('READ tumor', 'Disease', 'MESH:D009369', (90, 100))	('APAK', 'Gene', '147923', (22, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('208', '217'))	('apoptosis', 'biological_process', 'GO:0006915', ('208', '217'))
15168	29953437	Further, other p9 and p11 mutated proteins are implicated in the p53 pathway, including ZNF273, ZNF677 and ZFP28, which are the three ZF proteins recently found to interact with p53 binding protein p53bp1.	('p53', 'Gene', '7157', (65, 68))	('ZFP28', 'Gene', '140612', (107, 112))	('p53bp1', 'Gene', '7158', (198, 204))	('ZNF273', 'Gene', (88, 94))	('p53 binding', 'molecular_function', 'GO:0002039', ('178', '189'))	('p53', 'Gene', (65, 68))	('ZNF273', 'Gene', '10793', (88, 94))	('p53', 'Gene', '7157', (198, 201))	('ZFP28', 'Gene', (107, 112))	('p53bp1', 'Gene', (198, 204))	('proteins', 'Protein', (34, 42))	('interact', 'Interaction', (164, 172))	('ZNF677', 'Gene', '342926', (96, 102))	('implicated', 'Reg', (47, 57))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('p53', 'Gene', (198, 201))	('p11 mutated', 'Var', (22, 33))	('p53', 'Gene', '7157', (178, 181))	('ZNF677', 'Gene', (96, 102))	('p53', 'Gene', (178, 181))
15169	29953437	Three other genes with p9 or p11 missense mutations, ZNF281, ZNF148 (ZBP89), and ZEB1, have also been identified as ZF genes important in cancer onset and progression.	('ZNF148', 'Gene', '7707', (61, 67))	('cancer', 'Disease', (138, 144))	('ZNF281', 'Gene', '23528', (53, 59))	('ZNF148', 'Gene', (61, 67))	('ZNF281', 'Gene', (53, 59))	('ZBP89', 'Gene', '7707', (69, 74))	('p11 missense mutations', 'Var', (29, 51))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ZBP89', 'Gene', (69, 74))	('ZEB1', 'Gene', '6935', (81, 85))	('ZEB1', 'Gene', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
15170	29953437	Overall, many of the known biological processes and pathways of mutated ZF genes support their roles in cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutated', 'Var', (64, 71))	('ZF genes', 'Gene', (72, 80))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
15173	29953437	In contrast, we demonstrate that the mutations affect two functionally important positions within ZFs, and occur more often than expected when taking into account context-specific, per-gene, and per-patient mutation rates.	('mutations', 'Var', (37, 46))	('affect', 'Reg', (47, 53))	('patient', 'Species', '9606', (199, 206))	('ZFs', 'Gene', (98, 101))
15174	29953437	Further, we establish that the genes affected by these mutations tend to be more highly mutated than other genes, and are expressed at levels comparable to other cancer-relevant genes.	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (55, 64))
15175	29953437	Several factors seem to contribute to the enrichment of mutations seen at specific ZF domain positions in UCEC, COAD/READ, and SKCM.	('mutations', 'Var', (56, 65))	('READ', 'Disease', (117, 121))	('UCEC', 'Disease', (106, 110))	('COAD', 'Disease', 'MESH:D029424', (112, 116))	('SKCM', 'Disease', (127, 131))	('READ', 'Disease', 'None', (117, 121))	('COAD', 'Disease', (112, 116))
15179	29953437	While there do not appear to be specific, highly mutated positions within ZF domains when analyzing other cancer types (panel B in S5 Fig), the enrichment of missense mutations in relation to synonymous mutations in the set of affected ZF genes holds true for other cancer types as well (panel C in S5 Fig), suggesting that these ZF genes may be broadly affected across many cancer types.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', (266, 272))	('missense mutations', 'Var', (158, 176))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
15180	29953437	We thus expect that a wide spectrum of functions may be affected by the observed mutations; this is consistent with the fact that gene expression dysregulation is rampant in human cancers, and typically hundreds of genes are differentially expressed between normal and tumor samples.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('human', 'Species', '9606', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('tumor', 'Disease', (269, 274))	('gene expression', 'biological_process', 'GO:0010467', ('130', '145'))	('mutations', 'Var', (81, 90))
15182	29953437	Given that recent ChIP experiments have revealed that KRAB-containing ZF proteins can have up to 15,000 binding sites across the human genome, the mutations we observe can have a significant effect on widespread epigenetic changes.	('mutations', 'Var', (147, 156))	('binding sites', 'Interaction', (104, 117))	('effect', 'Reg', (191, 197))	('epigenetic changes', 'MPA', (212, 230))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('human', 'Species', '9606', (129, 134))
15183	29953437	Two recent large-scale ChIP-seq and ChIP-exo experiments on ZF proteins have determined genomic binding profiles for 231 of the 425 genes with p9 (UCEC, COAD/READ) or p11 (SKCM) missense mutations, and the ChIP binding peaks of 156 of them were found to overlap significantly with specific retroelements in at least one of these two studies.	('COAD', 'Disease', 'MESH:D029424', (153, 157))	('READ', 'Disease', 'None', (158, 162))	('binding', 'Interaction', (96, 103))	('missense mutations', 'Var', (178, 196))	('binding', 'molecular_function', 'GO:0005488', ('211', '218'))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('READ', 'Disease', (158, 162))	('COAD', 'Disease', (153, 157))	('p11', 'Var', (167, 170))
15184	29953437	Intriguingly, transposable element expression and insertions have been observed in cancers and have been proposed to provide a selective advantage for tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('observed', 'Reg', (71, 79))	('tumor', 'Disease', (151, 156))	('expression', 'MPA', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('in cancers', 'Disease', 'MESH:D009369', (80, 90))	('in cancers', 'Disease', (80, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('insertions', 'Var', (50, 60))	('transposable element', 'Var', (14, 34))
15186	29953437	We propose that these mutations are key contributors to widespread transcriptional deregulation in the tumors in which they are found.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('transcriptional deregulation', 'MPA', (67, 95))	('mutations', 'Var', (22, 31))
15187	29953437	The frequency, distribution and enrichment of these mutations across ZF domains strongly suggest that they confer a selective growth advantage to cancer cells.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('growth advantage', 'CPA', (126, 142))
15188	29953437	The specific ZF genes mutated vary across tumors, however, and while certain shared functions are likely involved, discovering the full range of downstream effects of these shared yet distinct mutations is an exciting avenue for future research.	('ZF genes', 'Gene', (13, 21))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutated', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
15190	29953437	The HMMER function hmmsearch (versions 2.3.2 and 3.0) was run on Ensembl human protein sequences using 12 Pfam HMM profiles from the Cys2-His2 ZF clan: PF00096, PF12756, PF13912, PF12171, PF13913, PF13909, PF12874, PF12907, PF02892, PF06220, PF09237, and PF11931.	('PF12756', 'Var', (161, 168))	('PF06220', 'Var', (233, 240))	('PF12907', 'Var', (215, 222))	('PF13912', 'Var', (170, 177))	('PF00096', 'Var', (152, 159))	('PF13909', 'Var', (197, 204))	('Cys2', 'Chemical', '-', (133, 137))	('PF09237', 'Var', (242, 249))	('human', 'Species', '9606', (73, 78))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('PF02892', 'Var', (224, 231))	('PF13913', 'Var', (188, 195))	('PF11931', 'Var', (255, 262))	('PF12171', 'Var', (179, 186))	('2-His', 'molecular_function', 'GO:0033770', ('136', '141'))	('PF12874', 'Var', (206, 213))
15191	29953437	These criteria only excluded a few mutations in each cancer type due to variations between Ensembl and RefSeq sequences.	('Ensembl', 'Gene', (91, 98))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('variations', 'Var', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RefSeq', 'Gene', (103, 109))
15193	29953437	We visually observed ZF p9 and p11 mutational peaks for UCEC, COAD/READ and SKCM.	('UCEC', 'Disease', (56, 60))	('ZF p9', 'Var', (21, 26))	('mutational', 'Var', (35, 45))	('SKCM', 'Disease', (76, 80))	('COAD', 'Disease', (62, 66))	('p11 mutational', 'Var', (31, 45))	('READ', 'Disease', (67, 71))	('COAD', 'Disease', 'MESH:D029424', (62, 66))	('READ', 'Disease', 'None', (67, 71))
15195	29953437	In particular, we repeatedly performed context-sensitive randomizations of the locations of p9 mutations in UCEC and COAD/READ samples across all p9 codons in the ZF genes considered in our analysis, and likewise for p11 mutations in SKCM samples across all p11 codons.	('COAD', 'Disease', 'MESH:D029424', (117, 121))	('READ', 'Disease', 'None', (122, 126))	('COAD', 'Disease', (117, 121))	('UCEC', 'Gene', (108, 112))	('p11', 'Gene', (217, 220))	('READ', 'Disease', (122, 126))	('mutations', 'Var', (95, 104))	('p9 mutations', 'Var', (92, 104))
15196	29953437	We used the Poisson binomial distribution to determine whether the cumulative numbers of mutations affecting ZF p9 in COAD/READ and UCEC and p11 in SKCM were significantly higher than expected when taking into account per-patient context-dependent mutation rates.	('SKCM', 'Disease', (148, 152))	('p11', 'Var', (141, 144))	('patient', 'Species', '9606', (222, 229))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('COAD', 'Disease', (118, 122))	('higher', 'PosReg', (172, 178))	('READ', 'Disease', (123, 127))	('mutations', 'Var', (89, 98))	('ZF p9', 'Gene', (109, 114))	('UCEC', 'Disease', (132, 136))	('READ', 'Disease', 'None', (123, 127))
15198	29953437	For each cancer type, we computed the per-gene missense mutation rate as the total number of missense mutations observed in a gene, divided by the number of nonsynonymous sites in the gene, and likewise with synonymous mutations and sites.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('missense mutations', 'Var', (93, 111))	('missense mutation', 'Var', (47, 64))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
15287	28912897	For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (177, 205))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (259, 278))	('CD8A', 'Gene', '925', (102, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 278))	('colorectal', 'Disease', 'MESH:D015179', (235, 245))	('tumor', 'Disease', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('melanoma', 'Disease', (284, 292))	('CD8A', 'Gene', '925', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CD8A', 'Gene', (102, 106))	('stomach', 'Disease', (247, 254))	('higher', 'PosReg', (132, 138))	('mutations', 'Var', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('neoantigens', 'Var', (162, 173))	('CD8A', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('breast and cervical cancer', 'Disease', 'MESH:D001943', (207, 233))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung adenocarcinoma', 'Disease', (259, 278))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('bladder urothelial carcinoma', 'Disease', (177, 205))	('colorectal', 'Disease', (235, 245))
15288	28912897	In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (68, 85))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (68, 85))	('liver hepatocellular', 'Disease', 'MESH:D056486', (42, 62))	('mutation burden', 'Var', (118, 133))	('negatively', 'NegReg', (91, 101))	('TMIT', 'Chemical', '-', (13, 17))	('thyroid carcinoma', 'Disease', (68, 85))	('liver hepatocellular', 'Disease', (42, 62))
15291	28912897	Inhibition of immune checkpoint proteins, primarily CTLA-4 or PD-1/PD-L1 may reduce the ability of the tumor microenvironment to suppress host antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CTLA-4', 'Gene', (52, 58))	('reduce', 'NegReg', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-1/PD-L1', 'Gene', (62, 72))	('tumor', 'Disease', (103, 108))	('suppress', 'NegReg', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Inhibition', 'Var', (0, 10))	('CTLA-4', 'Gene', '1493', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
15314	28912897	As per the study by Teng and colleagues, we classified TCGA samples of each cancer type into four TMITs by merging the mRNA expression levels of PD-L1 and CD8A, or PD-L1 and CYT as follows: type I, PD-L1 high expression and CD8A/CYT high expression; type II, PD-L1 low expression and CD8A/CYT low expression; type III, PD-L1 high expression and CD8A/CYT low expression; and type IV, PD-L1 low expression and CD8A/CYT high expression.	('CD8A', 'Gene', (408, 412))	('CD8A', 'Gene', (224, 228))	('CD8A', 'Gene', '925', (408, 412))	('CD8A', 'Gene', '925', (155, 159))	('CD8A', 'Gene', (155, 159))	('CD8A', 'Gene', '925', (345, 349))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CD8A', 'Gene', (345, 349))	('CD8A', 'Gene', '925', (284, 288))	('TMIT', 'Chemical', '-', (98, 102))	('low', 'NegReg', (389, 392))	('PD-L1', 'Var', (319, 324))	('CD8A', 'Gene', (284, 288))	('CD8A', 'Gene', '925', (224, 228))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
15320	28912897	TMIT was classified only for those tumor types with significant differences in mutation and/or neoantigen number in both PD-L1 and CD8A/CYT RPART subgroups.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('TMIT', 'Chemical', '-', (0, 4))	('neoantigen', 'MPA', (95, 105))	('differences', 'Reg', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD8A', 'Gene', '925', (131, 135))	('tumor', 'Disease', (35, 40))	('CD8A', 'Gene', (131, 135))	('mutation', 'Var', (79, 87))
15325	28912897	The number of mutations and neoantigens were significantly positively correlated, with a strong or very strong correlation for almost all tumors (R2 > 0.6), except for the LIHC and PRAD (relatively strong), and THCA (moderate; Supplementary Figure S1).	('almost all tumors', 'Disease', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (14, 23))	('almost all tumors', 'Disease', 'MESH:D009369', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
15331	28912897	Besides, RPART also better distinguished the different mutation number in the PD-L1 subgroups for BLCA, BRCA, CESC, LIHC, and SKCM; in the CD8A subgroups for BLCA, KIRC, and LIHC; and in CYT subgroups for BRCA, CESC, LUAD, SKCM, and STAD (Figure 2).	('BRCA', 'Gene', '672', (104, 108))	('BLCA', 'Chemical', '-', (158, 162))	('BRCA', 'Gene', (104, 108))	('BRCA', 'Gene', '672', (205, 209))	('PD-L1', 'Gene', (78, 83))	('CD8A', 'Gene', '925', (139, 143))	('BRCA', 'Gene', (205, 209))	('CD8A', 'Gene', (139, 143))	('mutation', 'Var', (55, 63))	('CESC', 'Disease', (110, 114))	('BLCA', 'Chemical', '-', (98, 102))
15332	28912897	In summary, for both mutation and neoantigen number, KIRC differs significantly in the PD-L1 and CD8A subgroups; BLCA, BRCA, SKCM, and STAD differ significantly in the PD-L1 and CYT subgroups; and CESC and LUAD differ significantly in the PD-L1, CD8A, and CYT subgroups.	('CD8A', 'Gene', '925', (97, 101))	('CD8A', 'Gene', (97, 101))	('mutation', 'Var', (21, 29))	('PD-L1', 'Disease', (87, 92))	('CD8A', 'Gene', '925', (246, 250))	('BLCA', 'Chemical', '-', (113, 117))	('BRCA', 'Gene', '672', (119, 123))	('CD8A', 'Gene', (246, 250))	('BRCA', 'Gene', (119, 123))
15336	28912897	Based on the abovementioned results, certain tumor samples were divided into four groups of tumor microenvironments according to the RPART cut-off values of PD-L1 and CD8A/CYT expression: PD-L1+CD8A for KIRC and LIHC; PD-L1+CYT for BLCA, BRCA, SKCM, STAD, and THCA; and PD-L1+CD8A/CYT for CESC, COAD, and LUAD.	('PD-L1+CYT', 'Var', (218, 227))	('COAD', 'Disease', (295, 299))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CD8A', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (45, 50))	('CD8A', 'Gene', '925', (276, 280))	('CD8A', 'Gene', '925', (194, 198))	('CD8A', 'Gene', '925', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD8A', 'Gene', (276, 280))	('COAD', 'Disease', 'MESH:D029424', (295, 299))	('BRCA', 'Gene', (238, 242))	('CD8A', 'Gene', (194, 198))	('tumor', 'Disease', (92, 97))	('BRCA', 'Gene', '672', (238, 242))	('BLCA', 'Chemical', '-', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
15341	28912897	Tumor samples with a higher mutation or neoantigen numbers than the median value also tended to have a higher proportion of TMIT I (Figures 4C-N).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMIT I', 'Disease', (124, 130))	('TMIT', 'Chemical', '-', (124, 128))	('neoantigen numbers', 'Var', (40, 58))	('mutation', 'Var', (28, 36))
15366	28912897	The objective response rate was also higher in patients with PD-L1 positive status than those with negative status (53% vs. 33%).	('objective response', 'CPA', (4, 22))	('higher', 'PosReg', (37, 43))	('PD-L1', 'Gene', (61, 66))	('patients', 'Species', '9606', (47, 55))	('positive status', 'Var', (67, 82))
15370	28912897	Overall, our results are generally consistent with those observed in clinical trials evaluating checkpoint inhibitor treatment, highlighting that the combination of PD-L1 and CD8A/CYT expression may help better identify subsets of patients who will benefit from anti-PD-1/PD-L1 therapy and avoid any potential toxicities and costs.	('toxicities', 'Disease', (310, 320))	('patients', 'Species', '9606', (231, 239))	('anti-PD-1/PD-L1', 'Var', (262, 277))	('PD-L1', 'Gene', (165, 170))	('toxicities', 'Disease', 'MESH:D064420', (310, 320))	('benefit', 'PosReg', (249, 256))	('CD8A', 'Gene', '925', (175, 179))	('CD8A', 'Gene', (175, 179))
15431	33671902	The high UV-dependent mutational loads may be associated with a growing number of genetic alterations, such as activating mutations in oncogenic genes, including N-ras and B-Raf in the mitogen-activated protein kinase (MAPK) signaling pathway, and inactivating mutations in tumor suppressor genes, including p16Ink4a/p19Arf and p53.	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('activating', 'PosReg', (111, 121))	('p53', 'Gene', (328, 331))	('signaling pathway', 'biological_process', 'GO:0007165', ('225', '242'))	('tumor', 'Disease', (274, 279))	('N-ras', 'Gene', (162, 167))	('inactivating mutations', 'Var', (248, 270))	('p19Arf', 'Gene', (317, 323))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('p16Ink4a', 'Gene', (308, 316))	('associated', 'Reg', (46, 56))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('219', '234'))	('p16Ink4a', 'Gene', '12578', (308, 316))	('N-ras', 'Gene', '18176', (162, 167))	('p19', 'cellular_component', 'GO:0070743', ('317', '320'))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('p19Arf', 'Gene', '12578', (317, 323))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('274', '290'))	('mutational', 'Var', (22, 32))	('mutations', 'Var', (122, 131))	('B-Raf', 'Gene', (172, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('274', '290'))
15432	33671902	Genomic alterations also inactivate phosphatase and tensin homolog (PTEN), thereby leading to the aberrant activation of the phosphoinositol-3-kinase (PI3K) pathway in melanoma.	('phosphoinositol-3-kinase', 'Gene', '18708', (125, 149))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('36', '66'))	('phosphatase', 'molecular_function', 'GO:0016791', ('36', '47'))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('alterations', 'Var', (8, 19))	('PTEN', 'Gene', '19211', (68, 72))	('PTEN', 'Gene', (68, 72))	('inactivate', 'NegReg', (25, 35))	('phosphatase and tensin homolog', 'Gene', '19211', (36, 66))	('activation', 'PosReg', (107, 117))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('phosphoinositol-3-kinase', 'Gene', (125, 149))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
15436	33671902	However, melanoma cells with a mutant B-Raf show resistance to most targeted inhibitors.	('mutant', 'Var', (31, 37))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('B-Raf', 'Protein', (38, 43))	('resistance', 'MPA', (49, 59))
15438	33671902	Moreover, treatment of B-RafV600-mutant melanoma using a B-Raf inhibitor or its combination with a MEK inhibitor typically elicits only partial responses due to the tumor cell-intrinsic reprogramming that attenuates the MAPK dependency.	('B-RafV600-mutant', 'Var', (23, 39))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('220', '224'))	('melanoma', 'Disease', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
15473	33671902	The IC50 values were 8.1 nM and 23.9 nM for BZ and CFZ, respectively (Table 1), and their differential effects on B16-F1 cell morphology and death were observed under an inverted microscope (Figure 1C).	('B16-F1', 'CellLine', 'CVCL:0158', (114, 120))	('CFZ', 'Var', (51, 54))	('effects', 'Reg', (103, 110))
15483	33671902	The concentration-dependent Western blotting data clearly showed that the levels of some of the ER stress markers, such as GRP78, ATF6alpha, and XBP1, were greater in the BZ-treated cells than in the CFZ-treated cells at the same concentration (Figure 3A, Figure S4).	('ATF6alpha', 'Gene', (130, 139))	('ATF6alpha', 'Gene', '226641', (130, 139))	('GRP78', 'Gene', (123, 128))	('XBP1', 'Gene', '22433', (145, 149))	('GRP78', 'Gene', '14828', (123, 128))	('XBP1', 'Gene', (145, 149))	('levels', 'MPA', (74, 80))	('greater', 'PosReg', (156, 163))	('BZ-treated', 'Var', (171, 181))
15491	33671902	The data showed that MMP loss was enhanced from 28.3% to 77.2% and 45.9% after 12 h of treatment with 100 nM BZ and CFZ, respectively (Figure 4B).	('MM', 'Disease', 'MESH:D009101', (21, 23))	('MMP', 'molecular_function', 'GO:0004235', ('21', '24'))	('100 nM', 'Var', (102, 108))	('enhanced', 'PosReg', (34, 42))
15492	33671902	To confirm that ROS are involved in BZ- and CFZ-induced ER stress and apoptosis in B16-F1 cells, cells were preincubated with a chemical antioxidant N-acetyl cysteine (NAC) for 1 h, followed by treatment with BZ or CFZ for 24 h. Since glutathione plays a major role in cellular defense against oxidative stress, we pretreated cells with the most commonly used gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO), which would reduce the levels of cellular oxidant scavenger glutathione and thus, amplify oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (524, 540))	('oxidative stress', 'Phenotype', 'HP:0025464', (294, 310))	('gamma-glutamylcysteine', 'Chemical', 'MESH:C017341;0.09979448647145767', (360, 382))	('buthionine sulfoximine', 'Chemical', 'MESH:D019328;0.8601814168083344', (404, 426))	('NAC', 'cellular_component', 'GO:0005854', ('168', '171'))	('B16-F1 cells', 'CellLine', 'CVCL:0158', (83, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('oxidative stress', 'MPA', (524, 540))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('reduce', 'NegReg', (446, 452))	('amplify', 'PosReg', (516, 523))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111;0.42519707168618087', (149, 166))	('levels of cellular oxidant scavenger glutathione', 'MPA', (457, 505))	('buthionine', 'Var', (404, 414))
15499	33671902	Based on these algorithms, CI < 1, CI = 1, and CI > 1 indicate synergism, additive effect, and antagonism, respectively, whereas DRI = 1, DRI > 1, and DRI < 1 indicate no dose-reduction, favorable dose-reduction, and not favorable dose-reduction, respectively, for each drug in the combination.	('DRI > 1', 'Gene', (138, 145))	('DRI > 1', 'Gene', '13496', (138, 145))	('additive effect', 'MPA', (74, 89))	('DRI < 1', 'Gene', (151, 158))	('CI > 1', 'Var', (47, 53))	('synergism', 'MPA', (63, 72))	('DRI = 1', 'Gene', '13496', (129, 136))	('DRI < 1', 'Gene', '13496', (151, 158))	('DRI = 1', 'Gene', (129, 136))
15503	33671902	Figure 6B and Figure S9 shows the enhanced activation of caspase 3, GRP78, ATF4, and XBP1 in the 25 + 25 nM combination.	('XBP1', 'Gene', (85, 89))	('enhanced activation', 'PosReg', (34, 53))	('caspase', 'Protein', (57, 64))	('GRP78', 'Gene', '14828', (68, 73))	('25 + 25 nM', 'Var', (97, 107))	('ATF4', 'Gene', (75, 79))	('XBP1', 'Gene', '22433', (85, 89))	('ATF4', 'Gene', '11911', (75, 79))	('GRP78', 'Gene', (68, 73))
15524	33671902	Among them, oncogenic somatic mutations in the B-Raf gene (i.e., V599E within the kinase domain) were found in approximately 60% of primary sporadic human melanomas, which result in constitutive activation of the Ser/Thr protein kinase.	('primary sporadic', 'Disease', (132, 148))	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('V599E', 'Mutation', 'p.V599E', (65, 70))	('B-Raf', 'Gene', (47, 52))	('Ser', 'cellular_component', 'GO:0005790', ('213', '216'))	('human', 'Species', '9606', (149, 154))	('found', 'Reg', (102, 107))	('activation', 'PosReg', (195, 205))	('mutations', 'Var', (30, 39))	('Ser/Thr protein kinase', 'Enzyme', (213, 235))	('melanomas', 'Disease', (155, 164))	('V599E', 'Var', (65, 70))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
15525	33671902	Oncogenic B-Raf leads to hyperactivation of the MEK and Erk/MAPK signaling pathways in a Ras-independent manner.	('hyperactivation', 'PosReg', (25, 40))	('Erk', 'Gene', (56, 59))	('Erk', 'molecular_function', 'GO:0004707', ('56', '59'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('60', '74'))	('B-Raf', 'Protein', (10, 15))	('MAPK', 'molecular_function', 'GO:0004707', ('60', '64'))	('Oncogenic', 'Var', (0, 9))	('Erk', 'Gene', '26413', (56, 59))
15526	33671902	Among the human melanoma cell lines, A375P and A375SM contain the constitutively active oncogenic B-RafV600E, whereas the mutational status of B-Raf in the human melanoma cell line DX3 is not known, with the p53 gene being intact and MEK appearing to be overexpressed.	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('human', 'Species', '9606', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('A375P', 'Var', (37, 42))	('A375SM', 'Var', (47, 53))	('melanoma', 'Disease', (16, 24))	('B-RafV600E', 'Var', (98, 108))	('human', 'Species', '9606', (156, 161))
15528	33671902	Instead, the expression of p16Ink4a and p19Arf tumor suppressor proteins was lost because of a large deletion spanning the Ink4a/Arf exons in the spontaneous B16-F1 melanoma cell line.	('Ink4a/Arf', 'Gene', '12578', (123, 132))	('p19Arf', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('melanoma', 'Disease', (165, 173))	('p19', 'cellular_component', 'GO:0070743', ('40', '43'))	('lost', 'NegReg', (77, 81))	('deletion', 'Var', (101, 109))	('B16-F1', 'CellLine', 'CVCL:0158', (158, 164))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('p19Arf', 'Gene', '12578', (40, 46))	('p16Ink4a', 'Gene', (27, 35))	('tumor', 'Disease', (47, 52))	('expression', 'MPA', (13, 23))	('Ink4a/Arf', 'Gene', (123, 132))	('p16Ink4a', 'Gene', '12578', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
15530	33671902	Inactivation of p19Arf in carcinogen-induced melanomas is accompanied by constitutive activation of MAPKs and/or mutation-associated activation of N-ras.	('p19Arf', 'Gene', '12578', (16, 22))	('N-ras', 'Gene', '18176', (147, 152))	('p19Arf', 'Gene', (16, 22))	('activation', 'PosReg', (133, 143))	('p19', 'cellular_component', 'GO:0070743', ('16', '19'))	('melanomas', 'Disease', (45, 54))	('N-ras', 'Gene', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('activation', 'PosReg', (86, 96))	('MAPKs', 'Protein', (100, 105))	('Inactivation', 'Var', (0, 12))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
15531	33671902	Inactivation of the Ink4a/Arf melanoma susceptibility locus has been identified in approximately 20-30% of familial melanoma cases and 15-30% of sporadic melanomas.	('familial melanoma', 'Disease', (107, 124))	('Arf melanoma', 'Disease', (26, 38))	('Arf melanoma', 'Disease', 'MESH:D008545', (26, 38))	('Ink4a/Arf', 'Gene', '12578', (20, 29))	('Ink4a/Arf', 'Gene', (20, 29))	('familial melanoma', 'Disease', 'MESH:C562393', (107, 124))	('sporadic melanomas', 'Disease', 'MESH:D008545', (145, 163))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('sporadic melanomas', 'Disease', (145, 163))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('Inactivation', 'Var', (0, 12))
15532	33671902	Therefore, genetic alterations in the p16Ink4a/p19Arf and ras-MAPK pathways may contribute to the development of murine melanoma.	('p19', 'cellular_component', 'GO:0070743', ('47', '50'))	('p19Arf', 'Gene', '12578', (47, 53))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('p19Arf', 'Gene', (47, 53))	('murine', 'Species', '10090', (113, 119))	('melanoma', 'Disease', (120, 128))	('p16Ink4a', 'Gene', '12578', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('p16Ink4a', 'Gene', (38, 46))	('genetic alterations', 'Var', (11, 30))	('contribute', 'Reg', (80, 90))	('ras-MAPK pathways', 'Pathway', (58, 75))
15533	33671902	Although B-Raf and MEK inhibitors are actively used for the treatment of metastatic melanoma in patients with B-RafV600E mutations, the development of resistance to these drugs has limited their therapeutic utilization in such patients.	('mutations', 'Var', (121, 130))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('B-RafV600E', 'Gene', (110, 120))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (227, 235))
15534	33671902	Moreover, some melanomas expressing wild type B-Raf have intrinsic resistance to B-Raf inhibitors.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('resistance', 'MPA', (67, 77))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('wild type B-Raf', 'Var', (36, 51))	('melanomas', 'Disease', (15, 24))
15545	33671902	In contrast, BZ and CFZ differentially induced apoptotic cell death, as judged by the increased DNA fragmentation (Figure 2A) and PI/annexin V-FITC double labeled cells (Figure 2B), and caspase activation (Figure 2D-F).	('apoptotic cell death', 'biological_process', 'GO:0006915', ('47', '67'))	('DNA fragmentation', 'CPA', (96, 113))	('increased', 'PosReg', (86, 95))	('CFZ', 'Var', (20, 23))	('activation', 'PosReg', (194, 204))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('96', '113'))	('induced', 'Reg', (39, 46))	('caspase', 'CPA', (186, 193))	('apoptotic cell death', 'CPA', (47, 67))	('caspase activation', 'biological_process', 'GO:0006919', ('186', '204'))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('annexin V', 'Gene', '11747', (133, 142))	('annexin V', 'Gene', (133, 142))
15549	33671902	CFZ was shown to induce apoptosis via activation of caspases 8, 9, 4, and 3 in BE(2)-M17 human neuroblastoma cells.	('human', 'Species', '9606', (89, 94))	('CFZ', 'Var', (0, 3))	('neuroblastoma', 'Disease', 'MESH:D009447', (95, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('neuroblastoma', 'Disease', (95, 108))	('caspases 8, 9, 4, and 3', 'Gene', '841;842;837;836', (52, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('activation', 'PosReg', (38, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (95, 108))
15553	33671902	Interestingly, CHOP expression (Figure 3A,B) and caspase 12 activation (Figure 2F) were decreased at the later time point (24 h) with a greater reduction in CFZ-treated cells compared to BZ-treated cells.	('caspase 12', 'Gene', (49, 59))	('CFZ-treated', 'Var', (157, 168))	('CHOP', 'Gene', (15, 19))	('caspase 12', 'Gene', '12364', (49, 59))	('decreased', 'NegReg', (88, 97))	('reduction', 'NegReg', (144, 153))	('CHOP', 'Gene', '13198', (15, 19))	('activation', 'MPA', (60, 70))
15566	33671902	However, intense and intermittent sun exposure (typical of sunburn history) or chronical sun exposure produces a high mutational load, which is associated with a high risk of cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('associated with', 'Reg', (144, 159))	('mutational', 'Var', (118, 128))	('cutaneous melanoma', 'Disease', (175, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))
15570	33671902	Therefore, our findings should be validated using other types of murine melanoma cell lines, such as the YUMM mouse melanoma cell lines, which are syngeneic to C57Bl/6J, have well defined human-relevant driver mutations, and are genomically stable.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('human', 'Species', '9606', (188, 193))	('melanoma', 'Disease', (72, 80))	('mutations', 'Var', (210, 219))	('MM', 'Disease', 'MESH:D009101', (107, 109))	('mouse', 'Species', '10090', (110, 115))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('murine', 'Species', '10090', (65, 71))
15574	33671902	Antibodies specific for cleaved caspase 3 (#9661), 8 (#8592) and 9 (#9509), caspase 12 (#2202), and phospho-elF2alpha (Ser51; #3597) were purchased from Cell Signaling (Beverly, MA, USA).	('#8592', 'Var', (54, 59))	('phospho', 'Chemical', 'MESH:C033601;-0.3922209334641923', (100, 107))	('#2202', 'Var', (88, 93))	('caspase 12', 'Gene', '12364', (76, 86))	('#9509', 'Var', (68, 73))	('#9661', 'Var', (43, 48))	('Signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('caspase', 'Protein', (32, 39))	('caspase 12', 'Gene', (76, 86))	('Ser', 'cellular_component', 'GO:0005790', ('119', '122'))
15623	31928951	Loss of Sfrp1 accelerates murine skin tumor initiation and SCC progression Sfrp1 loss enhances in vivo tumorigenic potential of murine skin CSCs We found enhanced EMT and Sox-2 in Sfrp1-/- murine skin SCC Sfrp1 and Sox-2 are inversely correlated in multiple human epithelial cancers Dr. Waghmare and his colleagues showed the importance of Sfrp1 in mouse skin tumor initiation and CSC regulation.	('murine', 'Species', '10090', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SCC', 'Disease', 'MESH:D002294', (201, 204))	('SCC', 'Disease', (59, 62))	('skin tumor initiation', 'Disease', (355, 376))	('SCC', 'Disease', (201, 204))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('mouse', 'Species', '10090', (349, 354))	('skin tumor initiation', 'Disease', 'MESH:D012878', (355, 376))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (360, 365))	('Sfrp1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('murine', 'Species', '10090', (189, 195))	('skin tumor', 'Phenotype', 'HP:0008069', (33, 43))	('tumor', 'Disease', (103, 108))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('loss', 'NegReg', (81, 85))	('Loss', 'Var', (0, 4))	('enhances', 'PosReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancers', 'Disease', (275, 282))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('skin tumor initiation', 'Disease', (33, 54))	('tumor', 'Disease', (38, 43))	('EMT', 'biological_process', 'GO:0001837', ('163', '166'))	('human', 'Species', '9606', (258, 263))	('Sfrp1', 'Gene', (8, 13))	('regulation', 'biological_process', 'GO:0065007', ('385', '395'))	('murine', 'Species', '10090', (26, 32))	('skin tumor initiation', 'Disease', 'MESH:D012878', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('skin tumor', 'Phenotype', 'HP:0008069', (355, 365))	('SCC', 'Disease', 'MESH:D002294', (59, 62))
15636	31928951	In oral squamous cell carcinoma (OSCC), silencing of the SFRP1, SFRP2, and SFRP5 genes was observed, due to methylation, in both oral cancer cell lines and tumor specimens.	('SFRP1', 'Gene', (57, 62))	('SFRP2', 'Gene', (64, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('OSCC', 'Disease', (33, 37))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Disease', (134, 140))	('SFRP5', 'Gene', '54612', (75, 80))	('methylation', 'Var', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('OSCC', 'Disease', 'MESH:D002294', (33, 37))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('SFRP2', 'Gene', '20319', (64, 69))	('silencing', 'NegReg', (40, 49))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('SFRP5', 'Gene', (75, 80))
15637	31928951	Further, methylation of the SFRP1 promoter was observed in esophageal squamous cell carcinoma and hepatocellular carcinoma.	('methylation', 'Var', (9, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('SFRP1', 'Gene', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('observed', 'Reg', (47, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (59, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('hepatocellular carcinoma', 'Disease', (98, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))
15638	31928951	SFRP1 loss was also observed in invasive breast cancer tissues and cell lines through either gene deletion or promoter hypermethylation.	('loss', 'NegReg', (6, 10))	('SFRP1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('promoter hypermethylation', 'Var', (110, 135))	('invasive breast cancer', 'Disease', 'MESH:D001943', (32, 54))	('gene deletion', 'Var', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('invasive breast cancer', 'Disease', (32, 54))
15639	31928951	In addition, SFRP (1, 2, 4, and 5) gene promoters are hypermethylated in cutaneous squamous cell carcinoma (SCC) in Chinese patient samples.	('cutaneous squamous cell carcinoma', 'Disease', (73, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('SFRP (1, 2, 4, and 5', 'Gene', '6422;6423;6424;6425', (13, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('hypermethylated', 'Var', (54, 69))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (73, 106))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 106))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('patient', 'Species', '9606', (124, 131))	('SCC', 'Disease', (108, 111))	('SCC', 'Disease', 'MESH:D002294', (108, 111))
15640	31928951	Moreover, microRNAs such as miR-1301-3p negatively target GSK-3beta and SFRP1, and promote the expansion of CSCs in prostate cancer.	('GSK-3beta', 'Gene', '606496', (58, 67))	('negatively target', 'NegReg', (40, 57))	('GSK-3beta', 'Gene', (58, 67))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-1301-3p', 'Var', (28, 39))	('SFRP1', 'Gene', (72, 77))	('prostate cancer', 'Disease', (116, 131))	('expansion', 'PosReg', (95, 104))	('CSCs', 'Gene', (108, 112))	('promote', 'PosReg', (83, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
15645	31928951	Further, Notch signaling drives the differentiation of keratin 5/14-positive basal epithelial cells into keratin 1/10-positive suprabasal cells in skin as well as oral epithelium.	('keratin 1', 'Gene', (105, 114))	('keratin 5', 'Gene', '110308', (55, 64))	('Notch', 'Var', (9, 14))	('differentiation', 'CPA', (36, 51))	('keratin 5', 'Gene', (55, 64))	('keratin 1', 'Gene', '16678', (105, 114))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
15646	31928951	Moreover, both tissues express similar kinds of integrins, such as alpha2beta1, alpha3beta1, and alpha6beta4 (in the basal layer), and terminal differentiation markers such as filaggrin (in the stratum corneum layer of the epidermis and gingiva/hard palate).	('alpha6beta4', 'Var', (97, 108))	('filaggrin', 'Gene', (176, 185))	('alpha2beta1', 'Var', (67, 78))	('filaggrin', 'Gene', '14246', (176, 185))	('alpha3beta1', 'Var', (80, 91))	('gingiva/hard palate', 'Disease', 'MESH:D018804', (237, 256))	('terminal differentiation', 'biological_process', 'GO:0048468', ('135', '159'))	('gingiva/hard palate', 'Disease', (237, 256))	('hard palate', 'Phenotype', 'HP:0410005', (245, 256))
15648	31928951	The basal/myoepithelial cells also express keratins such as K5 and K14, which are characteristic of the basal layer of stratified epithelia.	('keratins', 'Protein', (43, 51))	('K5', 'Gene', '110308', (60, 62))	('K14', 'Var', (67, 70))
15653	31928951	Significantly, SFRP1 loss due to hypermethylation is reported in skin cutaneous SCC, breast cancer, and OSCC.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('OSCC', 'Disease', 'MESH:D002294', (104, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('skin cutaneous SCC', 'Disease', 'MESH:D002294', (65, 83))	('hypermethylation', 'Var', (33, 49))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('OSCC', 'Disease', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SFRP1', 'Gene', (15, 20))	('loss', 'NegReg', (21, 25))	('skin cutaneous SCC', 'Disease', (65, 83))
15655	31928951	In the present study, we show that the loss of Sfrp1 in mouse skin leads to early tumor initiation with an early formation of papillomas and SCC.	('tumor initiation', 'Disease', (82, 98))	('papillomas', 'Phenotype', 'HP:0012740', (126, 136))	('mouse', 'Species', '10090', (56, 61))	('Sfrp1', 'Gene', (47, 52))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('papilloma', 'Phenotype', 'HP:0012740', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('formation', 'biological_process', 'GO:0009058', ('113', '122'))	('SCC', 'Disease', (141, 144))	('loss', 'Var', (39, 43))	('papillomas', 'Disease', (126, 136))	('papillomas', 'Disease', 'MESH:D010212', (126, 136))	('tumor initiation', 'Disease', 'MESH:D009369', (82, 98))	('SCC', 'Disease', 'MESH:D002294', (141, 144))
15662	31928951	The wild type (WT), Sfrp1+/- (heterozygous knockout), and Sfrp1-/- (homozygous knockout) mice were treated with DMBA and TPA at various postnatal days as shown in the schematic (Figure 1A).	('Sfrp1+/-', 'Var', (20, 28))	('TPA', 'molecular_function', 'GO:0031299', ('121', '124'))	('mice', 'Species', '10090', (89, 93))	('Sfrp1-/-', 'Gene', (58, 66))	('DMBA', 'Chemical', 'MESH:C082250', (112, 116))
15664	31928951	Thus, the study demonstrated that in Sfrp1-/- and Sfrp1+/- mice papilloma formation appears earlier by 3-4 weeks and 2-3 weeks, respectively, compared with WT mice (Figures 1C-1E).	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('mice', 'Species', '10090', (59, 63))	('papilloma', 'Phenotype', 'HP:0012740', (64, 73))	('Sfrp1+/-', 'Var', (50, 58))	('mice', 'Species', '10090', (159, 163))	('papilloma', 'Disease', (64, 73))	('Sfrp1-/-', 'Var', (37, 45))	('papilloma', 'Disease', 'MESH:D010212', (64, 73))
15665	31928951	Further, we counted the average number of tumors per mouse in the Sfrp1-/- and Sfrp1+/- mice compared with WT mice.	('Sfrp1+/-', 'Var', (79, 87))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mice', 'Species', '10090', (110, 114))	('Sfrp1-/-', 'Var', (66, 74))	('mouse', 'Species', '10090', (53, 58))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
15666	31928951	Although loss of Sfrp1 showed an early tumor initiation, it does not have any effect on the tumor burden (Figure 1F).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('loss', 'Var', (9, 13))	('tumor initiation', 'Disease', 'MESH:D009369', (39, 55))	('Sfrp1', 'Gene', (17, 22))	('tumor', 'Disease', (39, 44))	('tumor initiation', 'Disease', (39, 55))
15672	31928951	In this regard, we performed flow cytometry to analyze the CSCs from the Sfrp1-/- SCCs and WT SCCs, by using well-defined CSC markers (Lin-/Epcam+/alpha6-integrin+/CD34+) for skin SCC.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Disease', 'MESH:D002294', (180, 183))	('SCC', 'Disease', 'MESH:D002294', (94, 97))	('SCC', 'Disease', (82, 85))	('Lin-/Epcam+/alpha6-integrin+/CD34+', 'Var', (135, 169))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('SCC', 'Disease', (94, 97))	('SCC', 'Disease', 'MESH:D002294', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('Sfrp1-/-', 'Gene', (73, 81))	('SCC', 'Disease', (180, 183))
15675	31928951	The results showed that the Sfrp1-/- CSCs are able to give rise to tumor after 2-3 weeks of injection, but WT CSCs required 5-6 weeks for the tumor formation (Figures 3B and 3C).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('give rise', 'Reg', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (142, 147))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('Sfrp1-/-', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
15682	31928951	Further, mice with 5,000 Sfrp1-/- CSCs developed tumors after 6-7 weeks and no tumors were observed in mice with 5,000 WT CSCs (Figure S2B).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Sfrp1-/- CSCs', 'Var', (25, 38))	('mice', 'Species', '10090', (103, 107))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mice', 'Species', '10090', (9, 13))	('developed', 'PosReg', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15684	31928951	The TPC frequency was calculated as reported earlier, and we found that 1/8,442 (estimated value) Sfrp1-/- CSCs and 1/34,761 (estimated value) WT CSCs are able to form tumors when transplanted into NOD/SCID mice (Figure S2D).	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('SCID', 'Disease', 'MESH:D053632', (202, 206))	('SCID', 'Disease', (202, 206))	('mice', 'Species', '10090', (207, 211))	('Sfrp1-/- CSCs', 'Var', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
15685	31928951	These results suggest that loss of Sfrp1 results in aggressiveness of the CSCs with increased TPC frequency in Sfrp1-/- CSCs.	('TPC frequency', 'CPA', (94, 107))	('loss', 'Var', (27, 31))	('aggressiveness', 'Disease', 'MESH:D001523', (52, 66))	('aggressiveness', 'Disease', (52, 66))	('increased', 'PosReg', (84, 93))	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('Sfrp1', 'Gene', (35, 40))
15696	31928951	In addition, Sfrp1-/- CSCs showed a decrease in Wnt3A (canonical Wnt ligand) and increase in expression of Wnt7B (noncanonical Wnt ligand) (Figures S4A and S4B).	('ligand', 'molecular_function', 'GO:0005488', ('131', '137'))	('S4B', 'Chemical', 'MESH:D013455', (156, 159))	('Wnt7B', 'Gene', '22422', (107, 112))	('expression', 'MPA', (93, 103))	('Wnt3A', 'Gene', (48, 53))	('Wnt7B', 'Gene', (107, 112))	('increase', 'PosReg', (81, 89))	('Wnt3A', 'Gene', '22416', (48, 53))	('Sfrp1-/-', 'Var', (13, 21))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('decrease', 'NegReg', (36, 44))
15697	31928951	SFRP1 was shown to bind and inhibit WNT7B; therefore, loss of SFRP1 could enhance the WNT7B-mediated signaling cascade (WNT7B/JNK/c-JUN/c-FOS pathway) leading to the expression of Sox-2.	('c-FOS', 'Gene', '14281', (136, 141))	('WNT7B', 'Gene', (86, 91))	('JNK', 'Gene', '26419', (126, 129))	('c-JUN', 'Gene', (130, 135))	('WNT7B', 'Gene', '22422', (86, 91))	('c-JUN', 'Gene', '16476', (130, 135))	('c-FOS', 'Gene', (136, 141))	('loss', 'Var', (54, 58))	('SFRP1', 'Gene', (62, 67))	('JNK', 'Gene', (126, 129))	('signaling cascade', 'biological_process', 'GO:0007165', ('101', '118'))	('WNT7B', 'Gene', (36, 41))	('WNT7B', 'Gene', (120, 125))	('WNT7B', 'Gene', '22422', (36, 41))	('WNT7B', 'Gene', '22422', (120, 125))	('JNK', 'molecular_function', 'GO:0004705', ('126', '129'))	('enhance', 'PosReg', (74, 81))
15699	31928951	Overall, the data suggest the loss of Sfrp1 leads to accelerated tumor initiation with aggressiveness in CSCs by enhancing EMT signatures through altered signaling.	('tumor initiation', 'Disease', 'MESH:D009369', (65, 81))	('enhancing', 'PosReg', (113, 122))	('signaling', 'MPA', (154, 163))	('accelerated', 'PosReg', (53, 64))	('EMT signatures', 'MPA', (123, 137))	('altered', 'Reg', (146, 153))	('aggressiveness', 'Disease', 'MESH:D001523', (87, 101))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('signaling', 'biological_process', 'GO:0023052', ('154', '163'))	('tumor initiation', 'Disease', (65, 81))	('aggressiveness', 'Disease', (87, 101))	('aggressiveness', 'Phenotype', 'HP:0000718', (87, 101))	('Sfrp1', 'Gene', (38, 43))	('loss', 'Var', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
15701	31928951	In order to determine whether the loss of SFRP1 affects the stemness even in human skin cancers, we checked the expression levels of SFRP1 and SOX-2 in the human cutaneous SCC cell line A3886 and in the human keratinocyte cell line HaCaT.	('stemness', 'Disease', 'MESH:D020295', (60, 68))	('stemness', 'Disease', (60, 68))	('cutaneous SCC', 'Disease', 'MESH:D002294', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('SFRP1', 'Gene', (133, 138))	('HaCaT', 'CellLine', 'CVCL:0038', (232, 237))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('skin cancer', 'Phenotype', 'HP:0008069', (83, 94))	('cutaneous SCC', 'Disease', (162, 175))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('skin cancers', 'Phenotype', 'HP:0008069', (83, 95))	('human', 'Species', '9606', (77, 82))	('loss', 'Var', (34, 38))	('human', 'Species', '9606', (203, 208))	('SFRP1', 'Gene', (42, 47))	('skin cancers', 'Disease', (83, 95))	('affects', 'Reg', (48, 55))	('human', 'Species', '9606', (156, 161))	('skin cancers', 'Disease', 'MESH:D012878', (83, 95))
15702	31928951	The results showed a decrease in the expression of SFRP1 and increase in the expression of SOX-2, at both RNA and protein levels in A3886 compared with HaCaT.	('expression', 'MPA', (77, 87))	('SOX-2', 'Gene', (91, 96))	('decrease', 'NegReg', (21, 29))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('A3886', 'Var', (132, 137))	('SFRP1', 'Gene', (51, 56))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('increase', 'PosReg', (61, 69))	('expression', 'MPA', (37, 47))	('HaCaT', 'CellLine', 'CVCL:0038', (152, 157))
15720	31928951	The expression levels of SFRP1 were highly reduced, whereas SOX-2 was increased in MDA-MB-231 compared with MCF10A (Figure 6H).	('expression levels', 'MPA', (4, 21))	('increased', 'PosReg', (70, 79))	('MCF10A', 'CellLine', 'CVCL:0598', (108, 114))	('MDA-MB-231', 'Var', (83, 93))	('SFRP1', 'Gene', (25, 30))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (83, 93))	('reduced', 'NegReg', (43, 50))	('SOX-2', 'MPA', (60, 65))
15736	31928951	Moreover, high expression of Sfrp1 in WT HFSCs might also prevent tumor formation from HFSCs within these mice.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mice', 'Species', '10090', (106, 110))	('Sfrp1', 'Gene', (29, 34))	('prevent', 'NegReg', (58, 65))	('tumor', 'Disease', (66, 71))	('high expression', 'Var', (10, 25))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
15738	31928951	In the present study, Sfrp1-/- CSCs showed higher K8 expression compared with WT CSCs.	('K8', 'Gene', '16691', (50, 52))	('Sfrp1-/-', 'Var', (22, 30))	('higher', 'PosReg', (43, 49))
15740	31928951	Further, to explore whether the loss of Sfrp1 has any effect on CSC regulation, we checked the CSC percentage in the WT SCCs and Sfrp1-/- SCCs, which showed no alteration in the percentage of CSCs; however, the in vivo tumorigenesis assay showed increased tumorigenic potential of the Sfrp1-/- CSCs compared with control.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('SCC', 'Disease', 'MESH:D002294', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('Sfrp1-/-', 'Var', (285, 293))	('tumor', 'Disease', (219, 224))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('SCC', 'Disease', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('loss', 'Var', (32, 36))	('SCC', 'Disease', (138, 141))	('increased', 'PosReg', (246, 255))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('SCC', 'Disease', 'MESH:D002294', (120, 123))	('tumor', 'Disease', (256, 261))
15741	31928951	In addition, limiting dilution assay using 10,000, 5,000, and 1,000 CSCs from WT SCCs and Sfrp1-/- SCCs showed that Sfrp1-/- CSCs were able to form tumors in NOD/SCID mice at cell numbers as low as 10,000 and 5,000 CSCs with an estimated TPC efficiency of 1/8,442.	('mice', 'Species', '10090', (167, 171))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SCC', 'Disease', (99, 102))	('SCC', 'Disease', 'MESH:D002294', (81, 84))	('SCC', 'Disease', 'MESH:D002294', (99, 102))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('SCID', 'Disease', 'MESH:D053632', (162, 166))	('SCID', 'Disease', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('Sfrp1-/-', 'Var', (116, 124))	('SCC', 'Disease', (81, 84))
15743	31928951	Moreover, no tumors were observed with 1,000 CSCs of both the WT and the Sfrp1-/- SCCs.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('SCC', 'Disease', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('Sfrp1-/-', 'Var', (73, 81))	('SCC', 'Disease', 'MESH:D002294', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
15754	31928951	It was previously reported that SFRP1 binds and inhibits WNT7B; therefore, knockout of SFRP1 would enhance the WNT7B-mediated noncanonical signaling pathway.	('inhibits', 'NegReg', (48, 56))	('WNT7B', 'Gene', (111, 116))	('SFRP1', 'Gene', (87, 92))	('knockout', 'Var', (75, 83))	('WNT7B', 'Gene', '22422', (111, 116))	('WNT7B', 'Gene', (57, 62))	('WNT7B', 'Gene', '22422', (57, 62))	('signaling pathway', 'biological_process', 'GO:0007165', ('139', '156'))	('enhance', 'PosReg', (99, 106))
15762	31928951	Importantly, the data obtained from the murine skin model, i.e., the inverse correlation between Sfrp1 and Sox-2, was extrapolated to human skin cancer, as SFRP1 was shown to be lost due to promoter hypermethylation in human cutaneous SCC.	('skin cancer', 'Phenotype', 'HP:0008069', (140, 151))	('human', 'Species', '9606', (134, 139))	('human', 'Species', '9606', (219, 224))	('promoter hypermethylation', 'Var', (190, 215))	('skin cancer', 'Disease', (140, 151))	('murine', 'Species', '10090', (40, 46))	('skin cancer', 'Disease', 'MESH:D012878', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lost', 'NegReg', (178, 182))	('cutaneous SCC', 'Disease', 'MESH:D002294', (225, 238))	('SCC', 'Phenotype', 'HP:0002860', (235, 238))	('cutaneous SCC', 'Disease', (225, 238))
15765	31928951	Moreover, SFRP1 is also lost in OSCC and in breast cancer due to promoter hypermethylation.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('OSCC', 'Disease', (32, 36))	('breast cancer', 'Disease', (44, 57))	('lost', 'NegReg', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('SFRP1', 'Gene', (10, 15))	('OSCC', 'Disease', 'MESH:D002294', (32, 36))	('promoter hypermethylation', 'Var', (65, 90))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
15804	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))
15805	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))	('GNA11', 'Gene', (13, 18))	('GNAQ', 'Gene', (4, 8))	('GNA11', 'Gene', '2767', (13, 18))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
15837	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))
15859	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))
15969	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))
15976	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'))
15982	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))
15984	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))
15989	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))
16025	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))
16037	31848942	In this cutaneous melanoma cohort KIT mutation frequency was found to be 34/79 (43.04%) with a significantly higher rate in acrolentiginous melanoma (ALM) as compared to UV-induced common variants (20/34, 58.8% versus 14/45, 31.1%, p = 0.014).	('acrolentiginous melanoma', 'Phenotype', 'HP:0012060', (124, 148))	('higher rate', 'PosReg', (109, 120))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('ALM', 'Phenotype', 'HP:0012060', (150, 153))	('cutaneous melanoma', 'Disease', (8, 26))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('acrolentiginous melanoma', 'Disease', 'MESH:D008545', (124, 148))	('KIT', 'Gene', '3815', (34, 37))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (8, 26))	('mutation', 'Var', (38, 46))	('acrolentiginous melanoma', 'Disease', (124, 148))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('KIT', 'Gene', (34, 37))
16039	31848942	The actual frequency of KIT mutation in the original 227 patient cutaneous melanoma cohort was 34/227, 14.9%.	('KIT', 'molecular_function', 'GO:0005020', ('24', '27'))	('cutaneous melanoma', 'Disease', (65, 83))	('patient', 'Species', '9606', (57, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('mutation', 'Var', (28, 36))	('KIT', 'Gene', '3815', (24, 27))	('KIT', 'Gene', (24, 27))
16040	31848942	Exon 11 was the most frequent mutation site (44.7%) followed by exon 9 (21.1%) equally characterizing UV-induced common histotypes and ALM tumors.	('ALM tumors', 'Disease', 'MESH:D009369', (135, 145))	('ALM', 'Phenotype', 'HP:0012060', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ALM tumors', 'Disease', (135, 145))	('UV-induced', 'Disease', (102, 112))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('Exon', 'Var', (0, 4))
16042	31848942	KIT mutation hotspots were identified in exon 9 (c482/491/492), in exon 11 (c559,c572, c570), in exon 13 (c642), in exon 17 (c822) and in exon 18 (c853).	('c482/491/492', 'Var', (49, 61))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('c570', 'Var', (87, 91))	('c572', 'Var', (81, 85))	('c642', 'Var', (106, 110))	('c822', 'Var', (125, 129))	('KIT', 'Gene', (0, 3))	('c559', 'Var', (76, 80))
16043	31848942	The relatively high KIT mutation rate in cutaneous melanoma in this central-European cohort justifies regular testing of this molecular target in this entity, not only in mucosal variants.	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('cutaneous melanoma', 'Disease', (41, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (41, 59))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (41, 59))	('KIT', 'Gene', '3815', (20, 23))	('mutation', 'Var', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('KIT', 'Gene', (20, 23))
16044	31848942	KIT is the genetic driver of several malignant tumors: the majority of GIST and mastocytoses harbor this gene mutation and during the progression of AML, KIT mutation may also be acquired.	('KIT', 'molecular_function', 'GO:0005020', ('154', '157'))	('AML', 'Disease', (149, 152))	('malignant tumors', 'Disease', (37, 53))	('KIT', 'Gene', '3815', (154, 157))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('malignant tumors', 'Disease', 'MESH:D009369', (37, 53))	('KIT', 'Gene', (154, 157))	('mastocytoses', 'Disease', (80, 92))	('KIT', 'Gene', '3815', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutation', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('GIST', 'Disease', (71, 75))	('KIT', 'Gene', (0, 3))
16046	31848942	The major driver of skin melanoma is the mutant BRAF in almost half of the cases followed by NRAS mutation as the second most frequent one.	('skin melanoma', 'Disease', 'MESH:D008545', (20, 33))	('mutant', 'Var', (41, 47))	('skin melanoma', 'Disease', (20, 33))	('NRAS', 'Gene', '4893', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('NRAS', 'Gene', (93, 97))
16047	31848942	However, on the third place on the list of mutant oncogenes is KIT in skin melanoma, initially considered to occur in melanomas of the non-UV sites.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('skin melanoma', 'Disease', 'MESH:D008545', (70, 83))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('skin melanoma', 'Disease', (70, 83))	('mutant', 'Var', (43, 49))	('KIT', 'Gene', '3815', (63, 66))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('melanomas', 'Disease', (118, 127))	('KIT', 'Gene', (63, 66))
16048	31848942	Meanwhile, reports on various ethnicities and geographic areas of the world reported that the incidence rates of KIT mutation in skin melanoma are highly variable but still considered very low based on the initial observations.	('KIT', 'Gene', '3815', (113, 116))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('KIT', 'Gene', (113, 116))	('mutation', 'Var', (117, 125))	('skin melanoma', 'Disease', 'MESH:D008545', (129, 142))	('skin melanoma', 'Disease', (129, 142))
16053	31848942	However, involvement of exon 13 and 17 of KIT in mutational changes is also frequent in various cancer types.	('KIT', 'Gene', (42, 45))	('mutational changes', 'Var', (49, 67))	('involvement', 'Reg', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('KIT', 'Gene', '3815', (42, 45))	('cancer', 'Disease', (96, 102))	('frequent', 'Reg', (76, 84))
16054	31848942	The exon mutation pattern of KIT has significance in the sensitivity to KIT inhibitors since these mutations do not necessarily result in sensitivity but also in constitutive resistance to these drugs.	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('KIT', 'Gene', (72, 75))	('KIT', 'Gene', '3815', (29, 32))	('constitutive resistance to these drugs', 'MPA', (162, 200))	('KIT', 'Gene', (29, 32))	('mutations', 'Var', (99, 108))	('result', 'Reg', (128, 134))	('KIT', 'Gene', '3815', (72, 75))
16055	31848942	The purpose of this study was to asses the molecular epidemiology of KIT mutation in melanoma in a Central European country (Hungary), since data are almost absent with an exception of a Slovenian report on a small cohort.	('KIT', 'Gene', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('KIT', 'Gene', '3815', (69, 72))	('mutation', 'Var', (73, 81))
16058	31848942	Cases were enrolled from pathological FFPE archives of the primary tumors from Semmelweis University, Budapest tested diagnostically between 2014 and 2018 for BRAF and NRAS mutations.	('primary tumor', 'Disease', (59, 72))	('BRAF', 'Gene', (159, 163))	('NRAS', 'Gene', '4893', (168, 172))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('primary tumor', 'Disease', 'MESH:D001932', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mutations', 'Var', (173, 182))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('BRAF', 'Gene', '673', (159, 163))	('tumors', 'Disease', (67, 73))	('NRAS', 'Gene', (168, 172))
16066	31848942	This was analysed using restriction fragment length polymorphism (RFLP) by digestion with TspRI enzyme (New England Biolabs, Ipswich, MA) to screen for codon 600 mutant BRAF.	('BRAF', 'Gene', '673', (169, 173))	('BRAF', 'Gene', (169, 173))	('codon 600 mutant', 'Var', (152, 168))	('digestion', 'biological_process', 'GO:0007586', ('75', '84'))
16068	31848942	The basis of the method is that V600 mutation abolishes the restriction site resulting in a prominent band of 212 bp of the mutant allele, whereas wild type of BRAF is completely digested enzymatically, yielding DNA fragments at 125 bp.	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('restriction', 'MPA', (60, 71))	('mutant', 'Var', (124, 130))	('V600 mutation', 'Var', (32, 45))	('abolishes', 'NegReg', (46, 55))
16069	31848942	Samples bearing BRAF mutation by RFLP were evaluated by direct sequencing of the purified PCR product.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutation', 'Var', (21, 29))
16073	31848942	Chromas Lite Version 2.1 software was applied to detect mutations compared to NCBI (National Center for Biotechnology Information) Nucleotide BLAST (Basic Local Alignment Search Tool) Human Database.	('Chromas', 'Disease', (0, 7))	('mutations', 'Var', (56, 65))	('Human', 'Species', '9606', (184, 189))	('Chromas', 'Disease', 'None', (0, 7))
16079	31848942	of cutaneous melanoma cohort consecutively diagnostically tested between 2014 and 2018, we found that the BRAF mutation frequency in skin melanoma in Hungary is 45.4% (103/227) confirming data from other ethnicities and geographical regions.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('skin melanoma', 'Disease', (133, 146))	('mutation', 'Var', (111, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BRAF', 'Gene', '673', (106, 110))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('BRAF', 'Gene', (106, 110))	('skin melanoma', 'Disease', 'MESH:D008545', (133, 146))	('cutaneous melanoma', 'Disease', (3, 21))
16081	31848942	In this way we have collected a 79-case cohort of double-wild type skin melanoma, the pathological and clinical data of which are shown in Table 1.	('skin melanoma', 'Disease', 'MESH:D008545', (67, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('double-wild type', 'Var', (50, 66))	('skin melanoma', 'Disease', (67, 80))
16084	31848942	KIT mutation was found significantly more frequent in ALM as compared to UV-induced common variants (58.8% versus 31.1%, p = 0.014, Table 2).	('ALM', 'Phenotype', 'HP:0012060', (54, 57))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('mutation', 'Var', (4, 12))	('ALM', 'Disease', (54, 57))	('KIT', 'Gene', '3815', (0, 3))	('frequent', 'Reg', (42, 50))	('KIT', 'Gene', (0, 3))
16089	31848942	Analysis of mutations of skin melanoma in KIT exons indicated that, similar to GIST, exon 11 is the most frequently involved one (44.7%) followed by exon 9 (21.1%), exon 17 (15.8%) and exon 13 (13.2%) and exon 17 (13.2%) (Table 3) There were no significant differences between the UV- and non-UV melanomas in case of exon-9 and exon-11 involvements but exon 18 mutations found in UV melanoma exclusively and exon 13 and 17 mutations were more prevalent in non-UV melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (383, 391))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('melanomas', 'Disease', 'MESH:D008545', (296, 305))	('melanomas', 'Disease', 'MESH:D008545', (463, 472))	('exon 18', 'Gene', (353, 360))	('skin melanoma', 'Disease', 'MESH:D008545', (25, 38))	('melanomas', 'Disease', (296, 305))	('melanomas', 'Disease', (463, 472))	('melanoma', 'Phenotype', 'HP:0002861', (463, 471))	('KIT', 'Gene', (42, 45))	('melanoma exclusively', 'Disease', 'MESH:D008545', (383, 403))	('skin melanoma', 'Disease', (25, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanomas', 'Phenotype', 'HP:0002861', (296, 305))	('melanomas', 'Phenotype', 'HP:0002861', (463, 472))	('mutations', 'Var', (361, 370))	('melanoma exclusively', 'Disease', (383, 403))	('KIT', 'Gene', '3815', (42, 45))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
16091	31848942	(Table 3) In this form of melanoma also double mutations of KIT exons occured in one case.	('occured', 'Reg', (70, 77))	('KIT', 'Gene', '3815', (60, 63))	('KIT', 'Gene', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('double mutations', 'Var', (40, 56))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))
16092	31848942	It is of note that mutations in the nearest codons of such hot spots were also found to be clustered in KIT mutant melanomas (Table 4).	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('KIT', 'Gene', (104, 107))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mutant', 'Var', (108, 114))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', (115, 124))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('KIT', 'Gene', '3815', (104, 107))
16095	31848942	In our cohort, as well as in the one published recently, NRAS mutations rate was found to be 20%, a similar rate compared to other geographical regions reported.	('NRAS', 'Gene', '4893', (57, 61))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
16098	31848942	KIT mutation is associated with older age, with CSD melanoma, the mucosal and acrolentiginous forms.	('CSD melanoma', 'Disease', 'MESH:C562576', (48, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('acrolentiginous', 'Disease', (78, 93))	('CSD melanoma', 'Disease', (48, 60))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('acrolentiginous', 'Disease', 'None', (78, 93))	('mutation', 'Var', (4, 12))	('KIT', 'Gene', '3815', (0, 3))	('associated', 'Reg', (16, 26))	('KIT', 'Gene', (0, 3))	('mucosal', 'Disease', (66, 73))
16099	31848942	As an extreme example, recent data from Slovenia, a neighboring country to Hungary, KIT mutation frequency was found to be 1.3% while an analysis from Italy (UV-and non-UV forms) and France (mucosal only) found ~10%.	('mutation', 'Var', (88, 96))	('KIT', 'molecular_function', 'GO:0005020', ('84', '87'))	('KIT', 'Gene', '3815', (84, 87))	('KIT', 'Gene', (84, 87))
16103	31848942	We show here also, that the KIT mutation rate in double wild type mucosal melanoma in central Europe is comparable to the cutaneous variants.	('KIT', 'Gene', (28, 31))	('mucosal melanoma', 'Disease', (66, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (66, 82))	('KIT', 'Gene', '3815', (28, 31))	('mutation', 'Var', (32, 40))
16106	31848942	Unfortunately, most of the large melanoma cohorts on KIT mutation did not report completely the exon involvements.	('mutation', 'Var', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('KIT', 'Gene', '3815', (53, 56))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('KIT', 'Gene', (53, 56))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))
16107	31848942	In our skin melanoma cohort, similar to GIST, the most frequently mutated KIT exon is exon 11, although at lower frequency than in GIST (44.7%) followed by exon 9 (21.1%) and the other three exons (e13, e17, e18) with significant rates, suggesting a much broader carcinogenic targeting in melanoma.	('carcinogenic', 'Disease', (263, 275))	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('melanoma', 'Disease', (289, 297))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('KIT', 'Gene', '3815', (74, 77))	('skin melanoma', 'Disease', 'MESH:D008545', (7, 20))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('skin melanoma', 'Disease', (7, 20))	('e13', 'Var', (198, 201))	('KIT', 'Gene', (74, 77))	('carcinogenic', 'Disease', 'MESH:D063646', (263, 275))	('e18', 'Var', (208, 211))	('e17', 'Var', (203, 206))
16109	31848942	Concerning mutational hotspots, in GIST exon 9, codons 502-503 were identified unlike in our melanoma cohort where codons 491/492 were detected.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('codons 502-503', 'Var', (48, 62))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))
16110	31848942	It is of note that in exon 11, both in GIST and in our melanoma patients, codons 557/558 are common targets but nearby hotspot, c559, also exists in skin melanoma.	('codons 557/558', 'Var', (74, 88))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('patients', 'Species', '9606', (64, 72))	('skin melanoma', 'Disease', 'MESH:D008545', (149, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('skin melanoma', 'Disease', (149, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('c559', 'Var', (128, 132))	('melanoma', 'Disease', (55, 63))
16111	31848942	In exon 13 in GIST as well as in melanoma the hotspot is codon 642, but in melanoma the nearby codons are also frequent.	('codon 642', 'Var', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))
16112	31848942	Similarly, in exon 17 GIST and melanoma share codon 822 as hotspot unlike in exon 18 where GIST is characterized by codon 842 mutation unlike melanoma.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('codon 822', 'Var', (46, 55))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
16114	31848942	The best clinical experience with KIT inhibitor therapy we have is GIST where exon 11, exon 13 and exon 9 mutations have been shown to confer sensitivity to imatinib and sunitib.	('sunitib', 'Chemical', '-', (170, 177))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('exon', 'Var', (87, 91))	('KIT', 'Gene', (34, 37))	('KIT', 'Gene', '3815', (34, 37))	('mutations', 'Var', (106, 115))	('sensitivity to imatinib', 'MPA', (142, 165))	('imatinib', 'Chemical', 'MESH:D000068877', (157, 165))	('exon 11', 'Var', (78, 85))
16116	31848942	In KIT mutant thymic carcinoma exon 9/c490, exon 11/c553, c557, c559, c576 confers sensitivity, while exon 17/c820 mutation caused resistance to KIT inhitors.	('KIT', 'Gene', (145, 148))	('resistance', 'MPA', (131, 141))	('mutant', 'Var', (7, 13))	('thymic carcinoma', 'Disease', 'MESH:D013953', (14, 30))	('c559', 'Var', (64, 68))	('caused', 'Reg', (124, 130))	('sensitivity', 'MPA', (83, 94))	('KIT', 'molecular_function', 'GO:0005020', ('145', '148'))	('c576', 'Var', (70, 74))	('KIT', 'Gene', '3815', (3, 6))	('c557', 'Var', (58, 62))	('thymic carcinoma', 'Disease', (14, 30))	('KIT', 'Gene', '3815', (145, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('KIT', 'molecular_function', 'GO:0005020', ('3', '6'))	('KIT', 'Gene', (3, 6))	('exon', 'Var', (102, 106))
16119	31848942	On the other hand, responses were regularly detected in melanoma having exon 11 c576, c577, c557, c559, c560 mutations.	('c557', 'Var', (92, 96))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('c560 mutations', 'Var', (104, 118))	('c559', 'Var', (98, 102))	('detected', 'Reg', (44, 52))	('c576', 'Var', (80, 84))	('c577', 'Var', (86, 90))
16120	31848942	Furthermore, partial response was detected also in exon 13 c642 mutant melanoma in all the three trials.	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('c642 mutant', 'Var', (59, 70))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma', 'Disease', (71, 79))
16121	31848942	Since more than half of the KIT mutant melanomas harbor exon 11 and exon 13 mutations, this is a significant patient population which could be treated with KIT inhibitors.	('melanomas', 'Disease', (39, 48))	('KIT', 'Gene', (28, 31))	('patient', 'Species', '9606', (109, 116))	('KIT', 'Gene', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('KIT', 'molecular_function', 'GO:0005020', ('156', '159'))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('exon 13', 'Var', (68, 75))	('exon 11', 'Var', (56, 63))	('mutant', 'Var', (32, 38))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('KIT', 'Gene', '3815', (28, 31))	('KIT', 'Gene', '3815', (156, 159))
16122	31848942	Considering the relatively high mutation rate of KIT in melanoma, as compared to other mutated oncogens of other solid tumors where target therapy is available (see for example lung adenocarcinoma), it seems to be mandatory to screen BRAF/NRAS double wild type melanoma patients for KIT mutations at least in exon 11/13, irrespective of the type of melanoma.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('melanoma', 'Disease', (349, 357))	('mutations', 'Var', (287, 296))	('KIT', 'Gene', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('tumors', 'Disease', (119, 125))	('lung adenocarcinoma', 'Disease', (177, 196))	('NRAS', 'Gene', (239, 243))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('KIT', 'molecular_function', 'GO:0005020', ('283', '286'))	('KIT', 'Gene', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('KIT', 'Gene', '3815', (283, 286))	('BRAF', 'Gene', '673', (234, 238))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('melanoma', 'Disease', 'MESH:D008545', (349, 357))	('BRAF', 'Gene', (234, 238))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('patients', 'Species', '9606', (270, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('NRAS', 'Gene', '4893', (239, 243))	('KIT', 'Gene', '3815', (49, 52))
16124	31848942	Barbai T. was responsible for the technical analysis of BRAF, NRAS and KIT mutations.	('KIT', 'Gene', '3815', (71, 74))	('NRAS', 'Gene', '4893', (62, 66))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('BRAF', 'Gene', '673', (56, 60))	('KIT', 'Gene', (71, 74))	('mutations', 'Var', (75, 84))	('NRAS', 'Gene', (62, 66))	('BRAF', 'Gene', (56, 60))
16131	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))
16133	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))
16134	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))
16156	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))
16157	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'))	('activation', 'PosReg', (71, 81))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('lead to', 'Reg', (59, 66))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (13, 17))
16159	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))
16161	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))
16162	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))
16163	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'))
16164	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))
16166	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))
16167	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))	('tumors', 'Disease', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (191, 197))	('SF3B1', 'Gene', '23451', (31, 36))
16168	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))
16169	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))
16170	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))
16172	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))
16175	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))
16177	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))
16192	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))
16193	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))
16204	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))
16205	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))
16206	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))
16213	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))
16215	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))
16216	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))
16217	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))
16220	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'))
16221	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'))	('KIT', 'Gene', '3815', (85, 88))	('patients', 'Species', '9606', (71, 79))	('KIT', 'Gene', (85, 88))	('mutations', 'Var', (89, 98))
16237	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))
16245	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))
16255	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))
16261	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))
16262	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))
16263	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))
16269	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))	('mutations', 'Var', (18, 27))
16274	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))
16276	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))
16277	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))
16326	30813652	Furthermore, the median OS of TCGA-PCM cohort was significantly shorter than that of TCGA-MCM cohort (Figure 2A) and the opposite was true when the OBS was compared (Figure 2B).	('shorter', 'NegReg', (64, 71))	('OS', 'Chemical', '-', (24, 26))	('TCGA-PCM', 'Var', (30, 38))
16350	30813652	Stepwise multivariate Cox regression analyses, by considering the OBS to be the survival outcome and the 27 OBS associated miRNAs as covariates, revealed that hsa-miR-155-5p, hsa-miR-4461, hsa-miR-504-5p, hsa-miR-625-5p, and hsa-miR-664b-5p were independent prognostic miRNAs for patients with MCM (Table 2, upper part).	('hsa-miR-625', 'Gene', '693210', (205, 216))	('patients', 'Species', '9606', (280, 288))	('MCM', 'Disease', (294, 297))	('miR-4461', 'Gene', (179, 187))	('hsa-miR-625', 'Gene', (205, 216))	('miR-4461', 'Gene', '100616209', (179, 187))	('Cox', 'Gene', '1351', (22, 25))	('hsa-miR-155-5p', 'Var', (159, 173))	('Cox', 'Gene', (22, 25))
16369	29805686	KIT, NRAS, BRAF and FMNL2 mutations in oral mucosal melanoma and a systematic review of the literature Oral mucosal melanoma (OMM) is an aggressive malignant tumor derived from melanocytes in the oral cavity.	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Oral mucosal melanoma', 'Disease', 'MESH:D013280', (103, 124))	('tumor derived from melanocytes in the oral cavity', 'Phenotype', 'HP:0100649', (158, 207))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('malignant tumor', 'Disease', (148, 163))	('NRAS', 'Gene', '4893', (5, 9))	('oral mucosal melanoma', 'Disease', (39, 60))	('malignant tumor', 'Disease', 'MESH:D018198', (148, 163))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('FMNL2', 'Gene', (20, 25))	('FMNL2', 'Gene', '114793', (20, 25))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('oral mucosal melanoma', 'Disease', 'MESH:D013280', (39, 60))	('Oral mucosal melanoma', 'Disease', (103, 124))	('NRAS', 'Gene', (5, 9))	('BRAF', 'Gene', '673', (11, 15))	('OMM', 'Chemical', '-', (126, 129))	('BRAF', 'Gene', (11, 15))
16373	29805686	Among the 9 patients with OMM examined, KIT, BRAF and NRAS mutations were detected, and these mutations were all observed at a frequency of 11.1% (1/9 patients).	('patients', 'Species', '9606', (12, 20))	('NRAS', 'Gene', (54, 58))	('patients', 'Species', '9606', (151, 159))	('KIT', 'Gene', (40, 43))	('BRAF', 'Gene', (45, 49))	('NRAS', 'Gene', '4893', (54, 58))	('BRAF', 'Gene', '673', (45, 49))	('OMM', 'Chemical', '-', (26, 29))	('mutations', 'Var', (59, 68))	('KIT', 'molecular_function', 'GO:0005020', ('40', '43'))
16374	29805686	Notably, a novel FMNL2 mutation in 2 patients with OMM was identified by exome sequencing.	('OMM', 'Chemical', '-', (51, 54))	('FMNL2', 'Gene', '114793', (17, 22))	('mutation', 'Var', (23, 31))	('patients', 'Species', '9606', (37, 45))	('FMNL2', 'Gene', (17, 22))
16375	29805686	In conclusion, the current study observed KIT, BRAF, NRAS and FMNL2 mutations in patients with OMM, which may be of benefit for elucidating the underlying mechanism of OMM pathogenesis.	('KIT', 'Gene', (42, 45))	('FMNL2', 'Gene', '114793', (62, 67))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('patients', 'Species', '9606', (81, 89))	('NRAS', 'Gene', (53, 57))	('OMM', 'Chemical', '-', (95, 98))	('pathogenesis', 'biological_process', 'GO:0009405', ('172', '184'))	('NRAS', 'Gene', '4893', (53, 57))	('mutations', 'Var', (68, 77))	('OMM', 'Chemical', '-', (168, 171))	('OMM', 'Disease', (95, 98))	('FMNL2', 'Gene', (62, 67))
16390	29805686	Among all BRAF mutations, the V600E mutation accounted for >90% of cases.	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('V600E', 'Var', (30, 35))
16392	29805686	A number of BRAF inhibitors have been applied to clinical practice and have been demonstrated to inhibit melanoma proliferation.	('inhibit', 'NegReg', (97, 104))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('inhibitors', 'Var', (17, 27))	('melanoma proliferation', 'Disease', (105, 127))	('melanoma proliferation', 'Disease', 'MESH:D008545', (105, 127))
16395	29805686	The KIT mutation is more common in mucosal and acral melanomas than in cutaneous melanomas, and the percentage of KIT mutations detected in mucosal melanoma has been widely recognized to be 10-35%.	('mucosal melanoma', 'Disease', (140, 156))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (71, 90))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (71, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('KIT', 'Gene', (4, 7))	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('mutation', 'Var', (8, 16))	('cutaneous melanomas', 'Disease', (71, 90))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('acral melanomas', 'Disease', 'MESH:D008545', (47, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('acral melanomas', 'Phenotype', 'HP:0012060', (47, 62))	('KIT', 'molecular_function', 'GO:0005020', ('114', '117'))	('common', 'Reg', (25, 31))	('mucosal', 'Disease', (35, 42))	('mucosal melanoma', 'Disease', 'MESH:D008545', (140, 156))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('acral melanomas', 'Disease', (47, 62))
16396	29805686	The BRAF mutation is the most common mutation in cutaneous melanoma with a high incidence.	('mutation', 'Var', (9, 17))	('cutaneous melanoma', 'Disease', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
16397	29805686	However, several studies have demonstrated a low incidence of BRAF mutation in melanomas arising from non-hair-bearing skin, mucosa and internal organs that are totally sun protected, while the BRAF mutation is also rare in uveal melanomas.	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('BRAF', 'Gene', '673', (194, 198))	('melanomas', 'Disease', (230, 239))	('uveal melanomas', 'Disease', 'MESH:C536494', (224, 239))	('mutation', 'Var', (67, 75))	('BRAF', 'Gene', (194, 198))	('melanomas', 'Disease', (79, 88))	('uveal melanomas', 'Disease', (224, 239))	('uveal melanomas', 'Phenotype', 'HP:0007716', (224, 239))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Disease', 'MESH:D008545', (230, 239))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanomas', 'Phenotype', 'HP:0002861', (230, 239))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
16398	29805686	Furthermore, mutations in NRAS have been detected in 15-25% of melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('detected', 'Reg', (41, 49))	('NRAS', 'Gene', (26, 30))	('NRAS', 'Gene', '4893', (26, 30))	('mutations', 'Var', (13, 22))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('patients', 'Species', '9606', (72, 80))
16401	29805686	Thus, the aim of the present study was to detect the presence of KIT, BRAF and NRAS mutations in 9 OMM patients.	('KIT', 'Gene', (65, 68))	('NRAS', 'Gene', '4893', (79, 83))	('OMM', 'Disease', (99, 102))	('mutations', 'Var', (84, 93))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('OMM', 'Chemical', '-', (99, 102))	('BRAF', 'Gene', '673', (70, 74))	('patients', 'Species', '9606', (103, 111))	('NRAS', 'Gene', (79, 83))	('BRAF', 'Gene', (70, 74))
16408	29805686	Exons 11 and 15 of the BRAF gene (NG_007873.3), exons 1 and 2 of the NRAS gene (AH001530.2), and exons 11 and 13 of the KIT gene (NG_007456.1) were amplified by polymerase chain reaction (PCR) with six pairs of primers that covered the entire coding region of OMM.	('NRAS', 'Gene', '4893', (69, 73))	('BRAF', 'Gene', '673', (23, 27))	('NG_007873.3', 'Var', (34, 45))	('BRAF', 'Gene', (23, 27))	('OMM', 'Chemical', '-', (260, 263))	('NRAS', 'Gene', (69, 73))	('KIT', 'molecular_function', 'GO:0005020', ('120', '123'))
16417	29805686	Furthermore, a novel mutation was identified, namely L589M in exon 11 of the KIT gene, which had not been previously detected in melanomas or any other tumor types.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('KIT', 'molecular_function', 'GO:0005020', ('77', '80'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('KIT', 'Gene', (77, 80))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('tumor', 'Disease', (152, 157))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('L589M', 'Mutation', 'p.L589M', (53, 58))	('L589M in', 'Var', (53, 61))	('melanomas', 'Disease', (129, 138))
16418	29805686	The alteration in the BRAF gene was detected in exon 15 (D594G), which has been described in arcal melanoma.	('D594G', 'Var', (57, 62))	('arcal melanoma', 'Disease', (93, 107))	('BRAF', 'Gene', '673', (22, 26))	('arcal melanoma', 'Disease', 'MESH:D008545', (93, 107))	('D594G', 'Mutation', 'rs121913338', (57, 62))	('BRAF', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))
16420	29805686	Inclusion criteria for the literature review were as follows: i) Studies that included the key words 'oral and melanoma and (mutation OR mutated)'; ii) studies that examined gene mutations in patients with oral malignant mucosal melanoma; iii) studies that were only published in English.	('oral malignant mucosal melanoma', 'Disease', 'MESH:D008545', (206, 237))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('melanoma', 'Disease', (229, 237))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('patients', 'Species', '9606', (192, 200))	('oral malignant mucosal melanoma', 'Disease', (206, 237))	('mutations', 'Var', (179, 188))
16423	29805686	In the systematic review conducted in the present study, a total of five studies on gene mutations in OMM were identified, which satisfied the eligibility criteria.	('gene mutations', 'Var', (84, 98))	('OMM', 'Gene', (102, 105))	('OMM', 'Chemical', '-', (102, 105))
16424	29805686	The KIT, NRAS and BRAF mutations were detected in 3/28 (10.7%), 0/22 (0.0%), and 4/16 (25.0%) patients with OMM, respectively.	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('detected', 'Reg', (38, 46))	('OMM', 'Chemical', '-', (108, 111))	('patients', 'Species', '9606', (94, 102))	('NRAS', 'Gene', (9, 13))	('mutations', 'Var', (23, 32))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', (18, 22))	('KIT', 'Gene', (4, 7))
16426	29805686	In addition, 2 synonymous mutations (S645S and P585P) were detected in these 2 cases; however, they did not result in amino acid changes.	('P585P', 'Mutation', 'rs121913515', (47, 52))	('S645S', 'Mutation', 'p.S645S', (37, 42))	('P585P', 'Var', (47, 52))	('S645S', 'Var', (37, 42))
16429	29805686	In regards to BRAF, the classical V600E substitution that is typically identified in cutaneous melanoma was detected in 2 patients previously.	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('BRAF', 'Gene', '673', (14, 18))	('V600E', 'Var', (34, 39))	('patients', 'Species', '9606', (122, 130))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cutaneous melanoma', 'Disease', (85, 103))	('BRAF', 'Gene', (14, 18))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
16430	29805686	There was also another mutation located at codon 600, namely the V600L mutation, resulting in the replacement of the valine by leucine.	('leucine', 'Chemical', 'MESH:D007930', (127, 134))	('V600L', 'Var', (65, 70))	('leucine', 'MPA', (127, 134))	('V600L', 'Mutation', 'rs121913378', (65, 70))	('valine', 'MPA', (117, 123))	('valine', 'Chemical', 'MESH:D014633', (117, 123))
16431	29805686	No missense mutation of NRAS was reported in a previous study investigating OMM, but two synonymous mutations, K166K and F66F, were demonstrated in 2 patients.	('NRAS', 'Gene', '4893', (24, 28))	('F66F', 'Mutation', 'p.F66F', (121, 125))	('OMM', 'Chemical', '-', (76, 79))	('K166K', 'Mutation', 'p.K166K', (111, 116))	('K166K', 'Var', (111, 116))	('patients', 'Species', '9606', (150, 158))	('NRAS', 'Gene', (24, 28))	('F66F', 'Var', (121, 125))
16432	29805686	Exome sequencing was used to identify the potential pathogenic gene mutation in 6/9 patients in the present study, which were revealed not to be mutations in the KIT, BRAF or NRAS genes.	('patients', 'Species', '9606', (84, 92))	('mutation', 'Var', (68, 76))	('KIT', 'Gene', (162, 165))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('NRAS', 'Gene', (175, 179))	('NRAS', 'Gene', '4893', (175, 179))	('pathogenic', 'Reg', (52, 62))
16434	29805686	A total of 37 SNVs, as well as 5 insertion and deletion mutations, were detected in the 4 samples, while 22 mutations were observed in patient no.	('patient', 'Species', '9606', (135, 142))	('deletion mutations', 'Var', (47, 65))	('insertion', 'Var', (33, 42))	('SNVs', 'Disease', (14, 18))
16441	29805686	The V600E (Val600Glu) mutation that accounts for >90% of all BRAF mutations in cutaneous melanoma has been demonstrated to be activated by the RAS-guanosine triphosphate (GTP) protein, leading to ERK activation and stimulating the growth of melanoma cells.	('mutations', 'Var', (66, 75))	('cutaneous melanoma', 'Disease', (79, 97))	('stimulating', 'PosReg', (215, 226))	('melanoma', 'Disease', (241, 249))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (147, 169))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('activation', 'PosReg', (200, 210))	('Val600Glu', 'Mutation', 'rs113488022', (11, 20))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('ERK', 'molecular_function', 'GO:0004707', ('196', '199'))	('BRAF', 'Gene', '673', (61, 65))	('GTP', 'Chemical', '-', (171, 174))	('BRAF', 'Gene', (61, 65))	('ERK', 'Gene', '5594', (196, 199))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('ERK', 'Gene', (196, 199))
16443	29805686	Codon 61 is the major position for NRAS alterations in melanoma, such as Q61H, Q61K and Q61L.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('NRAS', 'Gene', (35, 39))	('Q61L', 'Mutation', 'rs11554290', (88, 92))	('NRAS', 'Gene', '4893', (35, 39))	('Q61H', 'Var', (73, 77))	('Q61L', 'Var', (88, 92))	('Q61K', 'Mutation', 'rs121913254', (79, 83))	('Q61K', 'Var', (79, 83))	('Q61H', 'Mutation', 'rs121913255', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
16444	29805686	The MAPK pathway may also be triggered by the activation of a KIT mutation, which participates in melanoma development through the induction of signaling proteins.	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('triggered', 'Reg', (29, 38))	('mutation', 'Var', (66, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('MAPK pathway', 'Pathway', (4, 16))	('KIT', 'Gene', (62, 65))
16446	29805686	The BRAF and NRAS mutations are the main genetic mutations in cutaneous melanoma cases, with a high incidence rate of 30-70 and 15-25%, respectively.	('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))	('NRAS', 'Gene', (13, 17))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('NRAS', 'Gene', '4893', (13, 17))	('mutations', 'Var', (18, 27))
16447	29805686	In contrast, a low incidence of BRAF and NRAS mutations has been described in mucosal melanoma patients.	('mucosal melanoma', 'Disease', 'MESH:D008545', (78, 94))	('NRAS', 'Gene', '4893', (41, 45))	('BRAF', 'Gene', '673', (32, 36))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (95, 103))	('BRAF', 'Gene', (32, 36))	('NRAS', 'Gene', (41, 45))	('mucosal melanoma', 'Disease', (78, 94))
16448	29805686	It appears that the BRAF mutation is quite rare in mucosal melanoma, whereas the NRAS mutation has a higher frequency in comparison with BRAF in this melanoma, although its percentage remains <20%.	('mucosal melanoma', 'Disease', (51, 67))	('mutation', 'Var', (25, 33))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('NRAS', 'Gene', (81, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (51, 67))	('BRAF', 'Gene', '673', (20, 24))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('BRAF', 'Gene', (20, 24))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('NRAS', 'Gene', '4893', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
16449	29805686	With regard to the mutation frequency in OMM, 1/9 patients (11.1%) presented a BRAF mutation, while the same incidence (1/9; 11.1%) of NRAS mutations was detected in the present study.	('NRAS', 'Gene', (135, 139))	('patients', 'Species', '9606', (50, 58))	('NRAS', 'Gene', '4893', (135, 139))	('OMM', 'Disease', (41, 44))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))	('OMM', 'Chemical', '-', (41, 44))	('mutation', 'Var', (84, 92))
16450	29805686	According to the results of the systematic review, 3/28 OMM patients (10.7%) were reported to exhibit a BRAF mutation, while no missense mutation of NRAS was reported among the 22 OMM patients (0.0%) included in previous studies.	('NRAS', 'Gene', (149, 153))	('OMM', 'Chemical', '-', (56, 59))	('patients', 'Species', '9606', (184, 192))	('OMM', 'Chemical', '-', (180, 183))	('patients', 'Species', '9606', (60, 68))	('NRAS', 'Gene', '4893', (149, 153))	('BRAF', 'Gene', '673', (104, 108))	('OMM', 'Disease', (56, 59))	('BRAF', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
16451	29805686	Thus, it is clear that the BRAF mutation in OMM occurs with a low incidence of <10%, which is consistent with the observations of previous studies on mucosal melanoma.	('BRAF', 'Gene', '673', (27, 31))	('OMM', 'Chemical', '-', (44, 47))	('mucosal melanoma', 'Disease', (150, 166))	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('mucosal melanoma', 'Disease', 'MESH:D008545', (150, 166))
16452	29805686	The distinction of BRAF mutations existing between cutaneous melanoma and OMM may therefore reveal a different molecular pathogenesis between these two melanoma types, and the different frequency of the NRAS mutation in mucosal melanoma and OMM may indicate that OMM has a distinctive pathogenesis and is a separate subtype.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('mutations', 'Var', (24, 33))	('OMM', 'Chemical', '-', (241, 244))	('OMM', 'Disease', (263, 266))	('OMM', 'Chemical', '-', (74, 77))	('NRAS', 'Gene', '4893', (203, 207))	('mutation', 'Var', (208, 216))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('mucosal melanoma', 'Disease', 'MESH:D008545', (220, 236))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', (228, 236))	('OMM', 'Chemical', '-', (263, 266))	('BRAF', 'Gene', '673', (19, 23))	('cutaneous melanoma', 'Disease', (51, 69))	('mucosal melanoma', 'Disease', (220, 236))	('BRAF', 'Gene', (19, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('pathogenesis', 'biological_process', 'GO:0009405', ('285', '297'))	('NRAS', 'Gene', (203, 207))
16454	29805686	Additionally, missense mutations of NRAS (p.S39F) with a relatively low peak on the sequencing map were identified in 6 patients, which may be associated with the tumor heterogeneity phenomenon.	('p.S39F', 'Var', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('NRAS', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('NRAS', 'Gene', '4893', (36, 40))	('missense mutations', 'Var', (14, 32))	('patients', 'Species', '9606', (120, 128))	('tumor', 'Disease', (163, 168))	('p.S39F', 'Mutation', 'rs139287106', (42, 48))
16456	29805686	This observation was also supported by the study of Beadling et al, who reported a higher incidence of KIT mutations in melanomas of the vulva, anorectum and vagina when compared with melanomas occurring at the head and neck sites.	('melanomas', 'Disease', 'MESH:D008545', (184, 193))	('melanomas of the vulva', 'Disease', (120, 142))	('mutations', 'Var', (107, 116))	('melanomas', 'Disease', (120, 129))	('KIT', 'Gene', (103, 106))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('neck', 'cellular_component', 'GO:0044326', ('220', '224'))	('melanomas of the vulva', 'Disease', 'MESH:D008545', (120, 142))	('melanomas', 'Disease', (184, 193))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))
16457	29805686	In addition, Schoenewolf et al identified a high frequency of KIT mutations (45%) in vulvovaginal melanomas and no mutation in 12 sinonasal melanomas.	('mutations', 'Var', (66, 75))	('melanomas', 'Disease', (98, 107))	('melanomas', 'Disease', (140, 149))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('vulvovaginal melanomas', 'Disease', (85, 107))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (85, 107))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (85, 107))	('KIT', 'Gene', (62, 65))
16458	29805686	On the basis of these previous findings, the frequency of KIT mutations in head and neck melanomas does not appear to be consistent, and this may be associated with differences in the sample quantity and the geographical region of patients.	('neck melanomas', 'Disease', (84, 98))	('patients', 'Species', '9606', (231, 239))	('neck', 'cellular_component', 'GO:0044326', ('84', '88'))	('associated', 'Reg', (149, 159))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('KIT', 'molecular_function', 'GO:0005020', ('58', '61'))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('KIT', 'Gene', (58, 61))	('neck melanomas', 'Disease', 'MESH:D008545', (84, 98))	('mutations', 'Var', (62, 71))
16459	29805686	The two novel mutations detected by sequencing in the present study, namely p.L589M of KIT and p.A59Tof NRAS, have not been reported in primary mucosa melanoma.	('KIT', 'Gene', (87, 90))	('NRAS', 'Gene', '4893', (104, 108))	('p.L589M', 'Mutation', 'p.L589M', (76, 83))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('p.L589M', 'Var', (76, 83))	('p.A59T', 'SUBSTITUTION', 'None', (95, 101))	('p.A59T', 'Var', (95, 101))	('mucosa melanoma', 'Disease', 'MESH:D008545', (144, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('NRAS', 'Gene', (104, 108))	('mucosa melanoma', 'Disease', (144, 159))
16462	29805686	In the present study cohort, 1 patient with a KIT mutation was observed, as well as 1 patient with an NRAS mutation and 1 patient with a BRAF mutation.	('KIT', 'molecular_function', 'GO:0005020', ('46', '49'))	('patient', 'Species', '9606', (122, 129))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('patient', 'Species', '9606', (86, 93))	('patient', 'Species', '9606', (31, 38))	('NRAS', 'Gene', (102, 106))	('NRAS', 'Gene', '4893', (102, 106))	('mutation', 'Var', (107, 115))	('mutation', 'Var', (50, 58))
16463	29805686	The mutation rate of all the 3 genes was 1/9 (11.1%), and this result was consistent with previous OMM studies identified in the systematic review, indicating that mutations of the KIT, NRAS and BRAF are associated with the occurrence of OMM.	('KIT', 'molecular_function', 'GO:0005020', ('181', '184'))	('NRAS', 'Gene', (186, 190))	('OMM', 'Chemical', '-', (238, 241))	('NRAS', 'Gene', '4893', (186, 190))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('associated with', 'Reg', (204, 219))	('mutations', 'Var', (164, 173))	('OMM', 'Chemical', '-', (99, 102))	('OMM', 'Disease', (238, 241))	('KIT', 'Gene', (181, 184))
16464	29805686	When compared with cutaneous melanoma, the distribution of KIT and BRAF mutations is markedly different in OMM.	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('OMM', 'Chemical', '-', (107, 110))	('cutaneous melanoma', 'Disease', (19, 37))	('BRAF', 'Gene', (67, 71))	('different', 'Reg', (94, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (19, 37))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (19, 37))	('OMM', 'Disease', (107, 110))	('KIT', 'Gene', (59, 62))
16465	29805686	In contrast to its role in cutaneous melanoma, the mutated KIT serves a more significant role in comparison with the BRAF gene in the occurrence of OMM.	('cutaneous melanoma', 'Disease', (27, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('KIT', 'molecular_function', 'GO:0005020', ('59', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('OMM', 'Chemical', '-', (148, 151))	('OMM', 'Disease', (148, 151))	('BRAF', 'Gene', '673', (117, 121))	('KIT', 'Gene', (59, 62))	('BRAF', 'Gene', (117, 121))	('mutated', 'Var', (51, 58))
16472	29805686	In consequence, the FMNL2 mutation may be regarded as a potential cause of the oral melanoma in these patients.	('mutation', 'Var', (26, 34))	('patients', 'Species', '9606', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('oral melanoma', 'Disease', 'MESH:D008545', (79, 92))	('FMNL2', 'Gene', (20, 25))	('cause', 'Reg', (66, 71))	('FMNL2', 'Gene', '114793', (20, 25))	('oral melanoma', 'Disease', (79, 92))
16473	29805686	In conclusion, despite a small cohort and a lack of extensive experimental repeat, the present study also revealed that KIT, NRAS and BRAF mutations may be associated with the occurrence of OMM, and that the FMNL2 mutations may be regarded as a potential cause of OMM.	('NRAS', 'Gene', (125, 129))	('OMM', 'Chemical', '-', (264, 267))	('FMNL2', 'Gene', (208, 213))	('mutations', 'Var', (139, 148))	('NRAS', 'Gene', '4893', (125, 129))	('BRAF', 'Gene', '673', (134, 138))	('OMM', 'Chemical', '-', (190, 193))	('BRAF', 'Gene', (134, 138))	('FMNL2', 'Gene', '114793', (208, 213))	('KIT', 'molecular_function', 'GO:0005020', ('120', '123'))	('associated with', 'Reg', (156, 171))	('KIT', 'Gene', (120, 123))	('OMM', 'Disease', (190, 193))
16477	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('protein/phosphoprotein', 'MPA', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
16481	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('mTOR', 'Gene', '2475', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
16482	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
16491	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('variants', 'Var', (198, 206))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
16494	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
16495	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
16503	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
16504	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
16505	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('losses', 'NegReg', (37, 43))	('tumor', 'Disease', (117, 122))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
16506	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (97, 106))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Disease', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
16507	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('EGFR', 'molecular_function', 'GO:0005006', ('309', '313'))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
16511	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('Variant', 'Var', (0, 7))	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'cellular_component', 'GO:0120206', ('105', '108'))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
16515	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SNP', 'Var', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
16516	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
16517	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
16518	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))
16520	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
16521	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
16525	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
16527	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
16528	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
16542	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
16549	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('mutagenesis', 'biological_process', 'GO:0006280', ('166', '177'))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
16550	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
16557	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('tumor', 'Disease', (9, 14))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
16558	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('variant', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DEPO', 'Disease', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
16559	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
16565	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
16566	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('variant/drug', 'Var', (48, 60))	('EGFR', 'Gene', '1956', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
16568	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
16569	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
16570	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
16572	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
16573	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
16574	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
16575	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
16576	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
16578	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
16579	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('PIK3CA', 'Gene', '5290', (38, 44))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('168', '172'))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
16581	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('EGFR', 'Gene', (12, 16))	('R108K', 'Var', (60, 65))	('associated', 'Reg', (151, 161))	('IDH1', 'Gene', (71, 75))	('A289V', 'Var', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('G598V', 'Var', (49, 54))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('IDH1', 'Gene', '3417', (71, 75))	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('extracellular', 'cellular_component', 'GO:0005576', ('17', '30'))
16582	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('EGFR', 'molecular_function', 'GO:0005006', ('109', '113'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('31', '35'))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
16583	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
16584	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
16586	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
16587	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
16590	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
16591	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('KRAS', 'Gene', '3845', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('98', '102'))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
16595	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
16598	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
16599	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
16600	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', (136, 140))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('136', '140'))
16601	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('mutations', 'Var', (107, 116))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('DEPO', 'Gene', (153, 157))	('EGFR', 'Gene', (33, 37))
16603	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('MAP2K', 'molecular_function', 'GO:0004708', ('82', '87'))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
16604	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
16605	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('BRAF', 'Gene', '673', (119, 123))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('binding', 'Interaction', (48, 55))	('BRAF', 'Gene', (68, 72))	('P34S', 'Var', (171, 175))	('BRAF', 'Gene', (119, 123))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
16606	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('E490D', 'Mutation', 'p.E490D', (101, 106))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('angiogenesis', 'biological_process', 'GO:0001525', ('248', '260'))	('S476G', 'Var', (115, 120))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('KIT', 'molecular_function', 'GO:0005020', ('240', '243'))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))	('E490D', 'Var', (101, 106))
16607	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('affect', 'Reg', (145, 151))	('binding affinity', 'Interaction', (152, 168))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('KIT', 'molecular_function', 'GO:0005020', ('206', '209'))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('angiogenesis', 'biological_process', 'GO:0001525', ('224', '236'))
16608	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('BRAF', 'Gene', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('BRAF', 'Gene', '673', (74, 78))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596R', 'Var', (125, 130))	('G596D', 'Var', (97, 102))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
16610	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('BRAF', 'Gene', '673', (26, 30))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('MEK1/2', 'Gene', (196, 202))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (222, 226))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', (222, 226))	('mutations', 'Var', (31, 40))	('phosphorylation', 'biological_process', 'GO:0016310', ('169', '184'))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('phosphorylation', 'MPA', (169, 184))	('MEK1', 'molecular_function', 'GO:0004708', ('196', '200'))
16611	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
16612	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('MEK1', 'molecular_function', 'GO:0004708', ('72', '76'))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
16613	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('MEK1', 'molecular_function', 'GO:0004708', ('105', '109'))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
16614	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('MEK1', 'molecular_function', 'GO:0004708', ('77', '81'))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('G596R', 'Var', (187, 192))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (204, 208))
16616	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('copy number amplification', 'Var', (72, 97))	('elevated', 'PosReg', (43, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('ESR1', 'Gene', (101, 105))	('protein expression', 'MPA', (130, 148))	('mRNA expression', 'MPA', (52, 67))	('elevated', 'PosReg', (121, 129))
16622	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('protein', 'cellular_component', 'GO:0003675', ('246', '253'))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
16634	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('ESR1', 'Gene', (80, 84))	('activity', 'MPA', (68, 76))	('elevated', 'PosReg', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
16637	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck', 'cellular_component', 'GO:0044326', ('66', '70'))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
16647	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('MEK1', 'molecular_function', 'GO:0004708', ('47', '51'))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('MEK1', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
16648	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('RAC1', 'Gene', (69, 73))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', (106, 110))	('RAC1', 'Gene', '5879', (69, 73))
16650	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('AKT1', 'Gene', '207', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
16652	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT', 'Gene', (110, 113))	('AKT1/2/3', 'Gene', (115, 123))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
16655	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('elevated', 'PosReg', (79, 87))	('activating', 'PosReg', (33, 43))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
16661	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
16663	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('variant/drug', 'Var', (63, 75))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
16665	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
16666	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
16681	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
16684	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
16688	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('tumors', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
16689	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
16692	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
16702	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('neck', 'cellular_component', 'GO:0044326', ('649', '653'))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('protein', 'cellular_component', 'GO:0003675', ('1171', '1178'))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('1396', '1412'))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('carcinoma', 'Disease', (19, 28))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('DCC', 'cellular_component', 'GO:0120206', ('356', '359'))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('Breast adenocarcinoma', 'Disease', (100, 121))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', (1107, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('carcinoma', 'Disease', (295, 304))	('AML', 'Disease', (34, 37))	('BRCA', 'Gene', (95, 99))	('LIHC', 'Disease', 'None', (829, 833))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('carcinoma', 'Disease', (182, 191))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('BRCA', 'Gene', '672', (95, 99))
16822	29923435	Patients with T1 melanomas were included in these analyses if they had clinical or pathological T1N0 melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanomas', 'Disease', (17, 26))	('T1N0', 'Var', (96, 100))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanomas', 'Disease', (101, 110))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('melanomas', 'Disease', 'MESH:D008545', (17, 26))
16823	29923435	Patients with T2-T4 melanomas were included only if they underwent lymphatic mapping and sentinel lymph node (SLN) biopsy and had no tumor-containing SLNs, and no microsatellites, satellites, or in-transit metastases at diagnosis or upon completion of initial treatment (pN0 melanoma).	('satellites', 'Species', '12877', (180, 190))	('microsatellites', 'Var', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('melanomas', 'Disease', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('Patients', 'Species', '9606', (0, 8))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('metastases', 'Disease', 'MESH:D009362', (206, 216))	('T2-T4', 'Var', (14, 19))	('tumor', 'Disease', (133, 138))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('satellites', 'Species', '12877', (168, 178))	('melanoma', 'Disease', (20, 28))	('metastases', 'Disease', (206, 216))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))
16846	29923435	The presence of non-nodal regional (microsatellite, satellite, or in-transit) metastases have been associated with adverse prognosis and also represent an N-category criterion in the eighth Edition AJCC staging system (Table 2).	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('microsatellite', 'Var', (36, 50))	('metastases', 'Disease', (78, 88))	('nodal', 'Gene', (20, 25))	('satellite', 'CPA', (52, 61))	('nodal', 'Gene', '4838', (20, 25))
16847	29923435	Microsatellites are defined as any microscopic focus of metastatic tumor cells in the skin or subcutis adjacent or deep to but discontinuous from the primary tumor.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor cells in the skin', 'Phenotype', 'HP:0008069', (67, 90))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('satellites', 'Species', '12877', (5, 15))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Microsatellites', 'Var', (0, 15))
16850	29923435	In the eighth edition analyses, microsatellites, satellites, and in-transit metastases are associated with similar survival outcomes and were grouped together for staging purposes (Figure 2c).	('satellites', 'Species', '12877', (49, 59))	('metastases', 'Disease', 'MESH:D009362', (76, 86))	('satellites', 'Species', '12877', (37, 47))	('microsatellites', 'Var', (32, 47))	('metastases', 'Disease', (76, 86))
16861	29923435	The exception is that the definition of stage IA and IB subgroups are refined such that patients with pathological T1bN0M0 melanoma are included in the pathological stage IA subgroup and not the pathological stage IB subgroup as in the seventh edition.	('patients', 'Species', '9606', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('T1bN0M0', 'Var', (115, 122))
16862	29923435	This change reflects the overall better prognosis of patients with T1b melanoma with pathologically negative nodes compared to patients with T1b melanoma with clinically negative nodes (some of whom will have pathological positive nodes).	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('patients', 'Species', '9606', (53, 61))	('negative', 'NegReg', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('patients', 'Species', '9606', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('T1b', 'Var', (67, 70))	('better', 'PosReg', (33, 39))
16865	29923435	adding tumor thickness along with ulceration) and N-category (number of tumor-involved lymph nodes, whether they were clinically detected or clinically occult, and the presence of microsatellite, satellite, and/or in-transit metastases) factors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (72, 77))	('microsatellite', 'Var', (180, 194))	('metastases', 'Disease', (225, 235))	('metastases', 'Disease', 'MESH:D009362', (225, 235))	('satellite', 'CPA', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
16876	29923435	In the eighth edition AJCC staging system, patients with T1b melanoma include many who in the seventh edition would have previously been classified as T1a.	('T1b', 'Var', (57, 60))	('patients', 'Species', '9606', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
16880	29923435	In the eighth edition, the Melanoma Expert Panel added further granularity throughout the N category by providing clarity of definitions, and increased subcategories from 5 to 9 to reflect factors associated with patient prognosis: (1) extent of regional node tumor involvement [clinically occult (N1a, N2a, N3a) vs clinically detected (N1b, N2b, N3b)], (2) number of tumor-involved regional nodes, and (3) presence of microsatellites, satellites, or in-transit metastases (N1c, N2c, N3c).	('tumor', 'Disease', (260, 265))	('satellites', 'Species', '12877', (436, 446))	('Melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumor', 'Disease', (368, 373))	('microsatellites', 'Var', (419, 434))	('metastases', 'Disease', (462, 472))	('patient', 'Species', '9606', (213, 220))	('Melanoma', 'Disease', (27, 35))	('Melanoma', 'Disease', 'MESH:D008545', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('satellites', 'Species', '12877', (424, 434))	('metastases', 'Disease', 'MESH:D009362', (462, 472))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('presence', 'Reg', (407, 415))	('satellites', 'CPA', (436, 446))
16915	30388455	We demonstrated that CDK4/6 inhibitors repress this program and sensitize melanoma tumors to ICIs in mouse models.	('CDK4/6', 'Protein', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mouse', 'Species', '10090', (101, 106))	('melanoma tumors', 'Disease', (74, 89))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('inhibitors', 'Var', (28, 38))	('sensitize', 'Reg', (64, 73))	('repress', 'NegReg', (39, 46))	('melanoma tumors', 'Disease', 'MESH:D008545', (74, 89))	('ICI', 'Chemical', 'MESH:C481040', (93, 96))
16937	30388455	Indeed, the programs are enriched for Myc targets, even after removing RP genes (p < 7.18 x 10-10) and are predicted to be repressed by MYC knockdown according to the Connectivity Map.	('MYC', 'Gene', (136, 139))	('RP genes', 'Gene', (71, 79))	('Myc', 'Gene', '4609', (38, 41))	('MYC', 'Gene', '4609', (136, 139))	('Myc', 'Gene', (38, 41))	('knockdown', 'Var', (140, 149))	('removing', 'NegReg', (62, 70))
16940	30388455	Second, inhibition of genes from the repressed component of the program in malignant melanoma cells conferred resistance to CD8+ T cells in a genome-wide CRISPR screen (p =1.67 x 10-3, hypergeometric test).	('malignant melanoma', 'Disease', (75, 93))	('genes', 'Gene', (22, 27))	('resistance', 'MPA', (110, 120))	('CD8', 'Gene', '926', (124, 127))	('malignant melanoma', 'Disease', 'MESH:D008545', (75, 93))	('CD8', 'Gene', (124, 127))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('inhibition', 'Var', (8, 18))	('malignant melanoma', 'Phenotype', 'HP:0002861', (75, 93))
16943	30388455	Moreover, there is a significant overlap between the perturbations that reverse the expression of the program's repressed and induced components (p = 4.35 x 10-6, hypergeometric test), including the overexpression of IFN-gamma and IFN-beta and the knockdown of MYC and CDK7.	('IFN-gamma', 'Gene', '3458', (217, 226))	('IFN-gamma', 'Gene', (217, 226))	('CDK7', 'Gene', (269, 273))	('MYC', 'Gene', (261, 264))	('IFN-beta', 'Gene', (231, 239))	('CDK', 'molecular_function', 'GO:0004693', ('269', '272'))	('overexpression', 'PosReg', (199, 213))	('CDK7', 'Gene', '1022', (269, 273))	('MYC', 'Gene', '4609', (261, 264))	('IFN-beta', 'Gene', '3456', (231, 239))	('knockdown', 'Var', (248, 257))
16990	30388455	Finally, analysis of published gene expression profiles of breast cancer cell lines and mouse models showed that CDK4/6i represses the resistance program (Figures 6B-6D).	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('represses', 'NegReg', (121, 130))	('breast cancer', 'Disease', (59, 72))	('CDK4/6i', 'Var', (113, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('mouse', 'Species', '10090', (88, 93))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))	('resistance', 'MPA', (135, 145))
17018	30388455	Thus, CDK4/6i administered in a phased fashion could potentially alleviate ICI resistance in some melanoma patients, consistent with a recent observation.	('ICI resistance', 'MPA', (75, 89))	('ICI', 'Chemical', 'MESH:C481040', (75, 78))	('CDK', 'molecular_function', 'GO:0004693', ('6', '9'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('alleviate', 'NegReg', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('CDK4/6i', 'Var', (6, 13))	('patients', 'Species', '9606', (107, 115))
17040	30388455	B16F10 was derived from a male mouse, MC38 and CT26 were derived from female mice.	('mice', 'Species', '10090', (77, 81))	('B16F10', 'CellLine', 'CVCL:0159', (0, 6))	('CT26', 'Gene', (47, 51))	('mouse', 'Species', '10090', (31, 36))	('B16F10', 'Var', (0, 6))	('CT26', 'Gene', '168400', (47, 51))
17130	30388455	We further refined the immune resistance program by integrating the scRNA-seq data with the results of a genome-scale CRISPR screen that identified gene KOs which sensitize malignant melanoma cells to T cell killing.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('sensitize', 'Reg', (163, 172))	('KOs', 'Var', (153, 156))	('T cell killing', 'CPA', (201, 215))	('malignant melanoma', 'Phenotype', 'HP:0002861', (173, 191))	('cell killing', 'biological_process', 'GO:0001906', ('203', '215'))	('malignant melanoma', 'Disease', 'MESH:D008545', (173, 191))	('malignant melanoma', 'Disease', (173, 191))
17169	30388455	Single-cell RNA-seq identifies an immune resistance program in malignant cells Multiple immune resistance mechanisms are co-regulated in the program The program predicts clinical responses to immunotherapy in melanoma patients CDK4/6 inhibitors repress the program and may sensitize melanoma to immunotherapy	('CDK', 'molecular_function', 'GO:0004693', ('227', '230'))	('patients', 'Species', '9606', (218, 226))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('sensitize', 'Reg', (273, 282))	('melanoma', 'Disease', (283, 291))	('CDK4/6', 'Var', (227, 233))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('repress', 'NegReg', (245, 252))
17171	25898173	Here we show that transcripts of hundreds of genes undergo site-specific C>U RNA editing in macrophages during M1 polarization and in monocytes in response to hypoxia and interferons.	('RNA editing', 'biological_process', 'GO:0009451', ('77', '88'))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('undergo', 'Reg', (51, 58))	('hypoxia', 'Disease', (159, 166))	('response to hypoxia', 'biological_process', 'GO:0001666', ('147', '166'))	('hypoxia', 'Disease', 'MESH:D000860', (159, 166))	('C>U RNA editing', 'Var', (73, 88))
17172	25898173	This editing alters the amino acid sequences for scores of proteins, including many that are involved in pathogenesis of viral diseases.	('proteins', 'Protein', (59, 67))	('viral diseases', 'Disease', 'MESH:D001102', (121, 135))	('editing', 'Var', (5, 12))	('alters', 'Reg', (13, 19))	('viral diseases', 'Disease', (121, 135))	('pathogenesis', 'biological_process', 'GO:0009405', ('105', '117'))	('amino acid sequences for', 'MPA', (24, 48))
17176	25898173	Aberrant RNA editing is linked to a range of neuropsychiatric and chronic diseases.	('neuropsychiatric and chronic diseases', 'Disease', 'MESH:D020945', (45, 82))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('Aberrant', 'Var', (0, 8))	('RNA editing', 'biological_process', 'GO:0009451', ('9', '20'))	('linked to', 'Reg', (24, 33))
17180	25898173	Aberrant RNA editing is linked to neuropsychiatric diseases such as epilepsy and schizophrenia, and chronic diseases such as cancer.	('epilepsy', 'Phenotype', 'HP:0001250', (68, 76))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('epilepsy', 'Disease', (68, 76))	('Aberrant', 'Var', (0, 8))	('linked', 'Reg', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('schizophrenia', 'Disease', 'MESH:D012559', (81, 94))	('schizophrenia', 'Disease', (81, 94))	('RNA editing', 'biological_process', 'GO:0009451', ('9', '20'))	('epilepsy', 'Disease', 'MESH:D004827', (68, 76))	('schizophrenia', 'Phenotype', 'HP:0100753', (81, 94))	('cancer', 'Disease', (125, 131))	('chronic diseases', 'Disease', 'MESH:D002908', (100, 116))	('chronic diseases', 'Disease', (100, 116))	('RNA', 'Protein', (9, 12))	('neuropsychiatric diseases', 'Disease', 'MESH:D020945', (34, 59))	('neuropsychiatric diseases', 'Disease', (34, 59))
17184	25898173	Although AID causes C>U deamination of DNA, multiple studies have failed to identify any RNA-editing activity for this protein.	('deamination', 'MPA', (24, 35))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('RNA-editing', 'biological_process', 'GO:0009451', ('89', '100'))	('causes', 'Reg', (13, 19))	('AID', 'Gene', (9, 12))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('AID', 'Gene', '57379', (9, 12))	('C>U', 'Var', (20, 23))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))
17187	25898173	C>U RNA editing alters hundreds of cytidines in chloroplasts and mitochondria of flowering plants, but the underlying deaminating enzymes are unknown.	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('flowering', 'biological_process', 'GO:0010228', ('81', '90'))	('C>U RNA editing', 'Var', (0, 15))	('flowering plants', 'Species', '3398', (81, 97))	('mitochondria', 'cellular_component', 'GO:0005739', ('65', '77'))	('RNA editing', 'biological_process', 'GO:0009451', ('4', '15'))	('cytidines', 'Chemical', 'MESH:D003562', (35, 44))	('alters', 'Reg', (16, 22))
17188	25898173	We have previously observed C>U editing of cytidine at c.136 (NCBI reference sequence NM_003000), which generates a nonsense codon (R46X), in ~6% of transcripts of the succinate dehydrogenase B (SDHB) gene in normal peripheral blood mononuclear cells (PBMCs) of humans.	('humans', 'Species', '9606', (262, 268))	('cytidine', 'Chemical', 'MESH:D003562', (43, 51))	('R46X', 'Mutation', 'rs74315370', (132, 136))	('succinate dehydrogenase B', 'Gene', '6390', (168, 193))	('succinate dehydrogenase B', 'Gene', (168, 193))	('Cs', 'Chemical', 'MESH:D002586', (255, 257))	('SDHB', 'Gene', '6390', (195, 199))	('R46X', 'Var', (132, 136))	('SDHB', 'Gene', (195, 199))
17190	25898173	Mutations in SDH genes are associated with both hereditary and non-hereditary paraganglioma and pheochromocytoma, renal carcinoma and gastrointestinal stromal tumours.	('tumours', 'Disease', (159, 166))	('renal carcinoma', 'Phenotype', 'HP:0005584', (114, 129))	('non-hereditary paraganglioma', 'Disease', (63, 91))	('SDH', 'Gene', (13, 16))	('associated', 'Reg', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('pheochromocytoma', 'Disease', (96, 112))	('Mutations', 'Var', (0, 9))	('hereditary', 'Disease', (48, 58))	('SDH', 'Gene', '6390', (13, 16))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('renal carcinoma', 'Disease', (114, 129))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))
17191	25898173	More recently, we found that hypoxia (1% O2) enhances the C>U editing of SDHB RNA at c.136 in monocytes, with an editing level of ~18% observed for monocyte-enriched PBMCs (MEPs) after 48 h of hypoxia.	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', (193, 200))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('RNA', 'cellular_component', 'GO:0005562', ('78', '81'))	('c.136', 'Var', (85, 90))	('C>U editing', 'MPA', (58, 69))	('Cs', 'Chemical', 'MESH:D002586', (169, 171))	('enhances', 'PosReg', (45, 53))	('SDHB', 'Gene', '6390', (73, 77))	('hypoxia', 'Disease', 'MESH:D000860', (193, 200))	('SDHB', 'Gene', (73, 77))	('O2', 'Chemical', 'MESH:D010100', (41, 43))
17193	25898173	C>U RNA editing of SDHB may therefore represent a hypoxia-adaptive mechanism that may have implications for the pathogenesis of chronic inflammatory diseases.	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('inflammatory diseases', 'Disease', 'MESH:D007249', (136, 157))	('SDHB', 'Gene', '6390', (19, 23))	('hypoxia', 'Disease', (50, 57))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('inflammatory diseases', 'Disease', (136, 157))	('SDHB', 'Gene', (19, 23))	('C>U RNA editing', 'Var', (0, 15))	('RNA editing', 'biological_process', 'GO:0009451', ('4', '15'))
17194	25898173	We show that transcripts of hundreds of genes including those implicated in viral pathogenesis and Alzheimer's disease are targets of editing in monocytes and macrophages.	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('editing', 'Var', (134, 141))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (99, 118))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (99, 118))	("Alzheimer's disease", 'Disease', (99, 118))
17197	25898173	These findings significantly expand our understanding of C>U RNA editing and open new avenues of inquiry on the role of APOBEC3 genes in viral and chronic diseases.	('C>U RNA', 'Var', (57, 64))	('RNA editing', 'biological_process', 'GO:0009451', ('61', '72'))	('APOBEC', 'cellular_component', 'GO:0030895', ('120', '126'))	('APOBEC3', 'Gene', '80287', (120, 127))	('chronic diseases', 'Disease', (147, 163))	('APOBEC3', 'Gene', (120, 127))	('chronic diseases', 'Disease', 'MESH:D002908', (147, 163))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))
17199	25898173	IFNs also upregulate expression of APOBEC3 CDAs, candidate enzymes that may be responsible for the SDHB c.136C>U RNA editing observed in monocytes.	('APOBEC3', 'Gene', '80287', (35, 42))	('CDA', 'Gene', '978', (43, 46))	('c.136C>U', 'Var', (104, 112))	('RNA editing', 'biological_process', 'GO:0009451', ('113', '124'))	('IFN', 'Gene', '3438', (0, 3))	('expression', 'MPA', (21, 31))	('SDHB', 'Gene', '6390', (99, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('35', '41'))	('IFN', 'Gene', (0, 3))	('SDHB', 'Gene', (99, 103))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('c.136C>U', 'SUBSTITUTION', 'None', (104, 112))	('upregulate', 'PosReg', (10, 20))	('CDA', 'Gene', (43, 46))	('APOBEC3', 'Gene', (35, 42))
17200	25898173	We therefore examined whether IFNs induce SDHB c.136C>U RNA editing.	('IFN', 'Gene', (30, 33))	('IFN', 'Gene', '3438', (30, 33))	('c.136C>U', 'SUBSTITUTION', 'None', (47, 55))	('c.136C>U', 'Var', (47, 55))	('RNA editing', 'biological_process', 'GO:0009451', ('56', '67'))	('SDHB', 'Gene', '6390', (42, 46))	('SDHB', 'Gene', (42, 46))	('RNA', 'cellular_component', 'GO:0005562', ('56', '59'))
17201	25898173	1a, treatment of MEPs with type 1 IFN (IFN1; 600 U ml-1) or IFNgamma (200 U ml-1) for 24 h induced SDHB c.136C>U RNA editing in MEPs, both in normoxia and hypoxia under 1% O2 (Mann-Whitney U-test P<0.01, comparing untreated and IFN-treated samples).	('IFN', 'Gene', '3438', (228, 231))	('IFN', 'Gene', (60, 63))	('IFN', 'Gene', '3438', (39, 42))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('IFNgamma', 'Gene', (60, 68))	('IFN', 'Gene', '3438', (60, 63))	('IFNgamma', 'Gene', '3458', (60, 68))	('IFN', 'Gene', (34, 37))	('IFN1', 'Gene', (39, 43))	('O2', 'Chemical', 'MESH:D010100', (172, 174))	('c.136C>U', 'Var', (104, 112))	('SDHB', 'Gene', '6390', (99, 103))	('IFN1', 'Gene', '3438', (39, 43))	('IFN', 'Gene', '3438', (34, 37))	('hypoxia', 'Disease', (155, 162))	('c.136C>U', 'SUBSTITUTION', 'None', (104, 112))	('IFN', 'Gene', (228, 231))	('RNA editing', 'biological_process', 'GO:0009451', ('113', '124'))	('IFN', 'Gene', (39, 42))	('hypoxia', 'Disease', 'MESH:D000860', (155, 162))	('SDHB', 'Gene', (99, 103))
17203	25898173	An additive effect of IFNs and hypoxia on SDHB c.136C>U RNA editing was observed and this was confirmed in an independent experiment in which matched MEPs of seven individuals were cultured under normoxia or hypoxia with 0, 300 or 1,500 U ml-1 IFN1 for 24 h. Editing level in cells treated with both hypoxia and IFN1 was higher than in cells treated with only hypoxia or IFN1 (Fig.	('IFN', 'Gene', '3438', (22, 25))	('c.136C>U', 'SUBSTITUTION', 'None', (47, 55))	('IFN1', 'Gene', '3438', (312, 316))	('hypoxia', 'Disease', (360, 367))	('IFN', 'Gene', '3438', (371, 374))	('IFN', 'Gene', '3438', (244, 247))	('hypoxia', 'Disease', (208, 215))	('IFN', 'Gene', (312, 315))	('hypoxia', 'Disease', 'MESH:D000860', (360, 367))	('hypoxia', 'Disease', (31, 38))	('hypoxia', 'Disease', (300, 307))	('IFN1', 'Gene', (371, 375))	('IFN1', 'Gene', (244, 248))	('RNA', 'cellular_component', 'GO:0005562', ('56', '59'))	('higher', 'PosReg', (321, 327))	('hypoxia', 'Disease', 'MESH:D000860', (208, 215))	('IFN', 'Gene', '3438', (312, 315))	('hypoxia', 'Disease', 'MESH:D000860', (300, 307))	('RNA editing', 'biological_process', 'GO:0009451', ('56', '67'))	('hypoxia', 'Disease', 'MESH:D000860', (31, 38))	('IFN1', 'Gene', '3438', (371, 375))	('SDHB', 'Gene', '6390', (42, 46))	('IFN1', 'Gene', '3438', (244, 248))	('Editing', 'MPA', (259, 266))	('SDHB', 'Gene', (42, 46))	('IFN', 'Gene', (22, 25))	('IFN', 'Gene', (371, 374))	('IFN1', 'Gene', (312, 316))	('c.136C>U', 'Var', (47, 55))	('IFN', 'Gene', (244, 247))
17206	25898173	We therefore examined and compared SDHB c.136C>U RNA editing in basal unpolarized (M0), M1 and M2 macrophages.	('c.136C>U', 'SUBSTITUTION', 'None', (40, 48))	('SDHB', 'Gene', (35, 39))	('c.136C>U', 'Var', (40, 48))	('RNA editing', 'biological_process', 'GO:0009451', ('49', '60'))	('SDHB', 'Gene', '6390', (35, 39))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
17214	25898173	C>U editing accounted for 73.3% of all non-synonymous editing upregulated by hypoxia in MEPs.	('hypoxia', 'Disease', (77, 84))	('C>U editing', 'Var', (0, 11))	('upregulated', 'PosReg', (62, 73))	('non-synonymous editing', 'MPA', (39, 61))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
17215	25898173	The average editing levels in hypoxic MEPs were >10% and >20%, respectively, for 93 (45%) and 25 (12%) of the 206 C>U sites for which editing was upregulated by hypoxia.	('editing', 'MPA', (12, 19))	('hypoxic MEP', 'Disease', (30, 41))	('hypoxia', 'Disease', 'MESH:D000860', (161, 168))	('hypoxia', 'Disease', (161, 168))	('upregulated', 'PosReg', (146, 157))	('C>U', 'Var', (114, 117))	('hypoxic MEP', 'Disease', 'MESH:D000860', (30, 41))
17219	25898173	C>U editing sites were most commonly present within a CCAUCG sequence motif (edited site underlined), with CAUC and its CACC, CCUC, CUUC and UAUC 1-nucleotide (nt) variants present for ~79% and 85% of the editing sites of MEPs and macrophages, respectively (Fig.	('CACC', 'Gene', '1179', (120, 124))	('variants', 'Var', (164, 172))	('1-nucleotide', 'Chemical', '-', (146, 158))	('CACC', 'Gene', (120, 124))
17220	25898173	As the UAUC motif containing the SDHB c.136 nucleotide was flanked by palindromic sequences (Fig.	('c.136 nucleotide', 'Var', (38, 54))	('SDHB', 'Gene', '6390', (33, 37))	('SDHB', 'Gene', (33, 37))
17223	25898173	These observations suggest that C>U RNA editing in MEPs and macrophages is catalysed by CDA(s) with particular target sequence and structure preference.	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('CDA', 'Gene', (88, 91))	('RNA editing', 'biological_process', 'GO:0009451', ('36', '47'))	('CDA', 'Gene', '978', (88, 91))	('C>U RNA', 'Var', (32, 39))
17231	25898173	In lymphocytes, RNA editing was seen for only two of the 34 genes (FAM89B and RHN1, ~8% level for each), suggesting that most of the differential C>U RNA editing in MEPs occurred in the monocytes.	('RNA editing', 'biological_process', 'GO:0009451', ('150', '161'))	('FAM89B', 'Gene', '23625', (67, 73))	('RNA', 'cellular_component', 'GO:0005562', ('150', '153'))	('RNA editing', 'biological_process', 'GO:0009451', ('16', '27'))	('MEPs', 'Gene', (165, 169))	('FAM89B', 'Gene', (67, 73))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('C>U RNA editing', 'Var', (146, 161))
17232	25898173	For two of the transcripts for which the editing results in a nonsense codon change, SDHB (NCBI reference sequence NM_003000, exon 2:p.R46X) and SIN3A (NM_001145357, exon 20:p.Q1197X), the effect of hypoxia-induced C>U RNA editing on protein level was examined by immunoblotting assays of whole-cell lysates of monocytes isolated from normoxic or hypoxic MEPs of three donors in a separate experiment.	('2:p.R46X', 'SUBSTITUTION', 'None', (131, 139))	('nonsense codon change', 'MPA', (62, 83))	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('20:p.Q1197X', 'SUBSTITUTION', 'None', (171, 182))	('2:p.R46X', 'Var', (131, 139))	('hypoxia', 'Disease', (199, 206))	('SDHB', 'Gene', '6390', (85, 89))	('SIN3A', 'Gene', (145, 150))	('results in', 'Reg', (49, 59))	('RNA editing', 'biological_process', 'GO:0009451', ('219', '230'))	('hypoxic MEP', 'Disease', 'MESH:D000860', (347, 358))	('SIN', 'biological_process', 'GO:0031028', ('145', '148'))	('RNA', 'cellular_component', 'GO:0005562', ('219', '222'))	('hypoxia', 'Disease', 'MESH:D000860', (199, 206))	('SDHB', 'Gene', (85, 89))	('20:p.Q1197X', 'Var', (171, 182))	('SIN3A', 'Gene', '25942', (145, 150))	('hypoxic MEP', 'Disease', (347, 358))	('editing', 'Var', (41, 48))	('NM_001145357', 'Var', (152, 164))
17235	25898173	Next, we examined whether expression of any CDA gene(s) was associated with SDHB c.136C>U RNA editing in monocytes and macrophages.	('SDHB', 'Gene', '6390', (76, 80))	('SDHB', 'Gene', (76, 80))	('RNA editing', 'biological_process', 'GO:0009451', ('90', '101'))	('c.136C>U', 'SUBSTITUTION', 'None', (81, 89))	('CDA', 'Gene', (44, 47))	('c.136C>U', 'Var', (81, 89))	('RNA', 'cellular_component', 'GO:0005562', ('90', '93'))	('associated', 'Reg', (60, 70))	('CDA', 'Gene', '978', (44, 47))
17241	25898173	To further understand the association of CDA gene expression with SDHB c.136C>U RNA editing, we evaluated RNA sequencing data in the Cancer Genome Atlas (TCGA) for three randomly chosen cancers, primary head and neck squamous cell carcinoma, lung adenocarcinoma and secondary skin cutaneous melanoma.	('SDHB', 'Gene', (66, 70))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('lung adenocarcinoma', 'Disease', (242, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('cancers', 'Disease', (186, 193))	('c.136C>U', 'SUBSTITUTION', 'None', (71, 79))	('CDA', 'Gene', (41, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (133, 152))	('CDA', 'Gene', '978', (41, 44))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (276, 299))	('RNA editing', 'biological_process', 'GO:0009451', ('80', '91'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('skin cutaneous melanoma', 'Disease', (276, 299))	('gene expression', 'biological_process', 'GO:0010467', ('45', '60'))	('neck squamous cell carcinoma', 'Disease', (212, 240))	('Cancer Genome Atlas', 'Disease', (133, 152))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (212, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('SDHB', 'Gene', '6390', (66, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (281, 299))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('neck', 'cellular_component', 'GO:0044326', ('212', '216'))	('c.136C>U', 'Var', (71, 79))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
17242	25898173	As tumours contain immune cells and can have hypoxic regions, we hypothesized that some degree of SDHB c.136C>U variation may be noticeable in the RNA sequences of the TCGA samples.	('c.136C>U', 'Var', (103, 111))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('SDHB', 'Gene', '6390', (98, 102))	('SDHB', 'Gene', (98, 102))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('c.136C>U', 'SUBSTITUTION', 'None', (103, 111))
17243	25898173	Somatic SDHB c.136C>T mutation has not been identified in any TCGA sample for these cancers (data release 17 of the International Cancer Genome Consortium).	('SDHB', 'Gene', '6390', (8, 12))	('c.136C>T', 'Mutation', 'rs74315370', (13, 21))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('SDHB', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('c.136C>T', 'Var', (13, 21))
17244	25898173	The scrutiny of TCGA's RNA sequencing data for the tumour tissues indicated putative C>U RNA editing of SDHB open reading frame (ORF) at c.136, but at no other site, in 30.2%, 26.4% and 9.6% of 298 primary head and neck squamous cell carcinoma, 220 lung adenocarcinoma and 187 secondary skin cutaneous melanoma cases that were examined, respectively (Fig.	('skin cutaneous melanoma', 'Disease', (287, 310))	('neck squamous cell carcinoma', 'Disease', (215, 243))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (215, 243))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (292, 310))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('lung adenocarcinoma', 'Disease', (249, 268))	('neck', 'cellular_component', 'GO:0044326', ('215', '219'))	('c.136', 'Var', (137, 142))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('editing', 'Var', (93, 100))	('tumour', 'Disease', (51, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('RNA editing', 'biological_process', 'GO:0009451', ('89', '100'))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('SDHB', 'Gene', '6390', (104, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (249, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (249, 268))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('C>U RNA editing', 'Var', (85, 100))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (287, 310))	('SDHB', 'Gene', (104, 108))
17247	25898173	Comparison of gene expression between the editing-positive and -negative samples showed that APOBEC3A was the only CDA gene whose expression was upregulated in the editing-positive samples in all three cancers.	('APOBEC3A', 'Gene', (93, 101))	('expression', 'MPA', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('editing-positive', 'Var', (164, 180))	('APOBEC3A', 'Gene', '200315', (93, 101))	('CDA', 'Gene', (115, 118))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('APOBEC', 'cellular_component', 'GO:0030895', ('93', '99'))	('upregulated', 'PosReg', (145, 156))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('CDA', 'Gene', '978', (115, 118))
17250	25898173	To test whether SDHB c.136C>U RNA editing can be induced by these two proteins, or by APOBEC3G whose expression is upregulated by M1 macrophage polarization, their complementary DNAs were exogenously expressed in the human 293T embryonic kidney cell line in which all three proteins were undetectable (Fig.	('293T', 'CellLine', 'CVCL:0063', (223, 227))	('APOBEC3G', 'Gene', (86, 94))	('embryonic kidney', 'Disease', 'MESH:D007674', (228, 244))	('human', 'Species', '9606', (217, 222))	('APOBEC3G', 'Gene', '60489', (86, 94))	('SDHB', 'Gene', '6390', (16, 20))	('SDHB', 'Gene', (16, 20))	('RNA editing', 'biological_process', 'GO:0009451', ('30', '41'))	('APOBEC', 'cellular_component', 'GO:0030895', ('86', '92'))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))	('embryonic kidney', 'Disease', (228, 244))	('c.136C>U', 'SUBSTITUTION', 'None', (21, 29))	('macrophage polarization', 'biological_process', 'GO:0042116', ('133', '156'))	('c.136C>U', 'Var', (21, 29))
17251	25898173	Transient transfection of 293T cells for exogenous expression of APOBEC3A, but not APOBEC3G or CDA, induced SDHB c.136C>U RNA editing in the cells (Fig.	('APOBEC3A', 'Gene', (65, 73))	('CDA', 'Gene', '978', (95, 98))	('SDHB', 'Gene', (108, 112))	('APOBEC3G', 'Gene', '60489', (83, 91))	('RNA editing', 'biological_process', 'GO:0009451', ('122', '133'))	('APOBEC', 'cellular_component', 'GO:0030895', ('83', '89'))	('APOBEC3A', 'Gene', '200315', (65, 73))	('APOBEC', 'cellular_component', 'GO:0030895', ('65', '71'))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('c.136C>U', 'SUBSTITUTION', 'None', (113, 121))	('c.136C>U', 'Var', (113, 121))	('induced', 'Reg', (100, 107))	('CDA', 'Gene', (95, 98))	('SDHB', 'Gene', '6390', (108, 112))	('APOBEC3G', 'Gene', (83, 91))	('293T', 'CellLine', 'CVCL:0063', (26, 30))
17253	25898173	Previous studies have shown that intronic sequences are essential for A>I RNA editing, but not for APOBEC1-mediated C>U editing of APOB, which occurs in the nucleus after the APOB pre-mRNA has been spliced.	('APOB', 'Gene', '338', (99, 103))	('APOB', 'Gene', (99, 103))	('APOB', 'Gene', '338', (175, 179))	('APOB', 'Gene', (175, 179))	('APOBEC1', 'Gene', (99, 106))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))	('APOBEC', 'cellular_component', 'GO:0030895', ('99', '105'))	('APOBEC1', 'Gene', '339', (99, 106))	('pre', 'molecular_function', 'GO:0003904', ('180', '183'))	('A>I RNA editing', 'Var', (70, 85))	('nucleus', 'cellular_component', 'GO:0005634', ('157', '164'))	('RNA editing', 'biological_process', 'GO:0009451', ('74', '85'))	('APOB', 'Gene', '338', (131, 135))	('APOB', 'Gene', (131, 135))
17254	25898173	We found evidence for c.136C>U RNA editing of transcripts generated in vivo from a co-transfected, intron-less SDHB ORF cDNA expression construct in APOBEC3A transfectants, indicating that intronic sequences are not required for APOBEC3A-mediated RNA editing (Supplementary Fig.	('SDHB', 'Gene', (111, 115))	('RNA', 'cellular_component', 'GO:0005562', ('247', '250'))	('APOBEC3A', 'Gene', (149, 157))	('APOBEC', 'cellular_component', 'GO:0030895', ('149', '155'))	('APOBEC3A', 'Gene', (229, 237))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('APOBEC', 'cellular_component', 'GO:0030895', ('229', '235'))	('RNA editing', 'biological_process', 'GO:0009451', ('247', '258'))	('c.136C>U', 'SUBSTITUTION', 'None', (22, 30))	('RNA editing', 'biological_process', 'GO:0009451', ('31', '42'))	('c.136C>U', 'Var', (22, 30))	('APOBEC3A', 'Gene', '200315', (229, 237))	('APOBEC3A', 'Gene', '200315', (149, 157))	('SDHB', 'Gene', '6390', (111, 115))
17255	25898173	Sanger sequencing of RT-PCR products of the 293T transfectants showed that exogenous APOBEC3A, but not CDA, also caused site-specific C>U RNA editing for 30 genes for which RNA editing was previously validated for MEPs (editing for EVI2B could not be examined because of low gene expression; Fig.	('APOBEC3A', 'Gene', '200315', (85, 93))	('CDA', 'Gene', (103, 106))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('RNA editing', 'biological_process', 'GO:0009451', ('138', '149'))	('gene expression', 'biological_process', 'GO:0010467', ('275', '290'))	('APOBEC', 'cellular_component', 'GO:0030895', ('85', '91'))	('RNA editing', 'biological_process', 'GO:0009451', ('173', '184'))	('exogenous', 'Var', (75, 84))	('CDA', 'Gene', '978', (103, 106))	('293T', 'CellLine', 'CVCL:0063', (44, 48))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('caused', 'Reg', (113, 119))	('C>U RNA editing', 'MPA', (134, 149))	('APOBEC3A', 'Gene', (85, 93))
17256	25898173	This suggests that APOBEC3A mediates the transcriptome-wide C>U RNA editing that was noted for MEPs and macrophages (Fig.	('RNA editing', 'biological_process', 'GO:0009451', ('64', '75'))	('C>U RNA editing', 'Var', (60, 75))	('mediates', 'Reg', (28, 36))	('APOBEC', 'cellular_component', 'GO:0030895', ('19', '25'))	('APOBEC3A', 'Gene', (19, 27))	('APOBEC3A', 'Gene', '200315', (19, 27))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
17259	25898173	Western blot assays of whole-cell lysates of the transfectants for three proteins, ASCC2, SDHB and TMEM109, whose RNA transcripts were predicted to have p.R121X (in exon 4; NCBI reference sequence NM_032204, which encodes a protein of 757 aa), p.R46X (in exon 2; NM_003000, 280 aa) and p.R37X (in exon 2; NM_024092, 243aa) nonsense codon changes, respectively, because of RNA editing showed that exogenous APOBEC3A expression reduced levels of the proteins in 293T cells (Fig.	('SDHB', 'Gene', (90, 94))	('levels of the proteins', 'MPA', (434, 456))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('RNA editing', 'biological_process', 'GO:0009451', ('372', '383'))	('p.R37X', 'Mutation', 'rs1392096081', (286, 292))	('ASCC2', 'Gene', '84164', (83, 88))	('p.R46X', 'Var', (244, 250))	('TMEM109', 'Gene', '79073', (99, 106))	('ASCC2', 'Gene', (83, 88))	('p.R46X', 'Mutation', 'rs74315370', (244, 250))	('protein', 'cellular_component', 'GO:0003675', ('224', '231'))	('APOBEC3A', 'Gene', (406, 414))	('RNA', 'cellular_component', 'GO:0005562', ('372', '375'))	('APOBEC', 'cellular_component', 'GO:0030895', ('406', '412'))	('APOBEC3A', 'Gene', '200315', (406, 414))	('p.R37X', 'Var', (286, 292))	('reduced', 'NegReg', (426, 433))	('SDHB', 'Gene', '6390', (90, 94))	('293T', 'CellLine', 'CVCL:0063', (460, 464))	('p.R121X', 'Var', (153, 160))	('TMEM109', 'Gene', (99, 106))	('p.R121X', 'Mutation', 'p.R121X', (153, 160))
17261	25898173	Notably, exogenous APOBEC3G also caused low-level, site-specific RNA editing for 11 genes in 293T transfectants (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('65', '68'))	('APOBEC', 'cellular_component', 'GO:0030895', ('19', '25'))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('exogenous', 'Var', (9, 18))	('APOBEC3G', 'Gene', (19, 27))	('caused', 'Reg', (33, 39))	('RNA editing', 'biological_process', 'GO:0009451', ('65', '76'))	('APOBEC3G', 'Gene', '60489', (19, 27))	('RNA editing', 'MPA', (65, 76))
17263	25898173	To validate that APOBEC3A mediates SDHB c.136C>U RNA editing in M1 macrophages (Fig.	('APOBEC3A', 'Gene', '200315', (17, 25))	('c.136C>U', 'SUBSTITUTION', 'None', (40, 48))	('SDHB', 'Gene', (35, 39))	('APOBEC', 'cellular_component', 'GO:0030895', ('17', '23'))	('c.136C>U', 'Var', (40, 48))	('RNA editing', 'biological_process', 'GO:0009451', ('49', '60'))	('APOBEC3A', 'Gene', (17, 25))	('SDHB', 'Gene', '6390', (35, 39))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))
17264	25898173	1b), we transfected M0 macrophages with small interfering RNA (siRNA) at 100 nM to knock down APOBEC3A RNA, induced their M1 polarization after a day and examined the M1-polarized cells after another 24 h. Transfection of cells with either of the two different siRNAs predicted to target APOBEC3A, or their equimolar mix, led to a significant reduction in APOBEC3A transcript and APOBEC3A protein levels compared with cells transfected with a control siRNA that is not predicted to target APOBEC3A (Fig.	('APOBEC3A', 'Gene', '200315', (380, 388))	('APOBEC3A', 'Gene', '200315', (356, 364))	('APOBEC3A', 'Gene', (94, 102))	('APOBEC3A', 'Gene', (489, 497))	('APOBEC3A', 'Gene', '200315', (489, 497))	('APOBEC3A', 'Gene', '200315', (94, 102))	('RNA', 'cellular_component', 'GO:0005562', ('103', '106'))	('APOBEC3A', 'Gene', (288, 296))	('Transfection', 'Var', (206, 218))	('protein', 'cellular_component', 'GO:0003675', ('389', '396'))	('APOBEC3A', 'Gene', '200315', (288, 296))	('APOBEC', 'cellular_component', 'GO:0030895', ('489', '495'))	('reduction', 'NegReg', (343, 352))	('APOBEC', 'cellular_component', 'GO:0030895', ('356', '362'))	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('APOBEC', 'cellular_component', 'GO:0030895', ('288', '294'))	('APOBEC', 'cellular_component', 'GO:0030895', ('94', '100'))	('APOBEC', 'cellular_component', 'GO:0030895', ('380', '386'))	('APOBEC3A', 'Gene', (380, 388))	('APOBEC3A', 'Gene', (356, 364))
17266	25898173	Reduction of APOBEC3A RNA level was associated with a significant reduction of SDHB c.136C>U RNA editing (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('APOBEC3A', 'Gene', '200315', (13, 21))	('c.136C>U', 'SUBSTITUTION', 'None', (84, 92))	('c.136C>U', 'Var', (84, 92))	('APOBEC', 'cellular_component', 'GO:0030895', ('13', '19'))	('RNA', 'cellular_component', 'GO:0005562', ('93', '96'))	('Reduction', 'NegReg', (0, 9))	('APOBEC3A', 'Gene', (13, 21))	('SDHB', 'Gene', '6390', (79, 83))	('RNA editing', 'biological_process', 'GO:0009451', ('93', '104'))	('reduction', 'NegReg', (66, 75))	('SDHB', 'Gene', (79, 83))
17269	25898173	The C101 residue of APOBEC3A is critical for binding of zinc and the C101S APOBEC3A mutant completely lacks deamination activity against cytidines of ssDNA in vitro.	('APOBEC3A', 'Gene', '200315', (75, 83))	('lacks', 'NegReg', (102, 107))	('APOBEC', 'cellular_component', 'GO:0030895', ('75', '81'))	('C101S', 'Mutation', 'p.C101S', (69, 74))	('APOBEC3A', 'Gene', '200315', (20, 28))	('deamination activity against cytidines', 'MPA', (108, 146))	('APOBEC', 'cellular_component', 'GO:0030895', ('20', '26'))	('cytidines', 'Chemical', 'MESH:D003562', (137, 146))	('APOBEC3A', 'Gene', (75, 83))	('binding', 'molecular_function', 'GO:0005488', ('45', '52'))	('APOBEC3A', 'Gene', (20, 28))	('C101S', 'Var', (69, 74))
17272	25898173	To test whether C101 residue is essential for the observed RNA editing, we transfected 293T cells with the mutant cDNA.	('mutant', 'Var', (107, 113))	('293T', 'CellLine', 'CVCL:0063', (87, 91))	('RNA editing', 'biological_process', 'GO:0009451', ('59', '70'))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('cDNA', 'Gene', (114, 118))
17273	25898173	SDHB c.136C>U RNA editing or site-specific C>U RNA editing for five other examined genes for which editing was observed in transfectants expressing the wild-type APOBEC3A was abolished in the C101S APOBEC3A transfectant (Fig.	('APOBEC3A', 'Gene', (162, 170))	('c.136C>U', 'SUBSTITUTION', 'None', (5, 13))	('APOBEC3A', 'Gene', (198, 206))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('c.136C>U', 'Var', (5, 13))	('abolished', 'NegReg', (175, 184))	('APOBEC', 'cellular_component', 'GO:0030895', ('162', '168'))	('C101S', 'Mutation', 'p.C101S', (192, 197))	('C101S', 'Var', (192, 197))	('SDHB', 'Gene', '6390', (0, 4))	('RNA', 'cellular_component', 'GO:0005562', ('47', '50'))	('APOBEC3A', 'Gene', '200315', (162, 170))	('APOBEC', 'cellular_component', 'GO:0030895', ('198', '204'))	('RNA editing', 'biological_process', 'GO:0009451', ('47', '58'))	('RNA editing', 'biological_process', 'GO:0009451', ('14', '25'))	('APOBEC3A', 'Gene', '200315', (198, 206))	('SDHB', 'Gene', (0, 4))
17274	25898173	The E72D and P134A variants of APOBEC3A were previously shown to variably impair the ssDNA deamination activity of the wild-type enzyme.	('impair', 'NegReg', (74, 80))	('E72D', 'Mutation', 'p.E72D', (4, 8))	('APOBEC3A', 'Gene', '200315', (31, 39))	('APOBEC', 'cellular_component', 'GO:0030895', ('31', '37'))	('P134A', 'Var', (13, 18))	('ssDNA deamination activity', 'MPA', (85, 111))	('APOBEC3A', 'Gene', (31, 39))	('E72D', 'Var', (4, 8))	('P134A', 'Mutation', 'rs1342585425', (13, 18))
17275	25898173	We found that whole-cell lysate of 293T transfectant of E72D, but not P134A, was moderately impaired in the ssDNA deamination assay (Fig.	('E72D', 'Mutation', 'p.E72D', (56, 60))	('E72D', 'Var', (56, 60))	('P134A', 'Mutation', 'rs1342585425', (70, 75))	('293T', 'CellLine', 'CVCL:0063', (35, 39))	('impaired', 'NegReg', (92, 100))	('ssDNA deamination assay', 'MPA', (108, 131))
17276	25898173	Unlike for C101S, the E72D variant was capable of C>U RNA editing of transcripts for SDHB and five other genes that were examined, although to lesser levels than the wild-type protein (Fig.	('C>U RNA editing', 'MPA', (50, 65))	('RNA editing', 'biological_process', 'GO:0009451', ('54', '65'))	('E72D', 'Mutation', 'p.E72D', (22, 26))	('E72D', 'Var', (22, 26))	('SDHB', 'Gene', '6390', (85, 89))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('SDHB', 'Gene', (85, 89))	('C101S', 'Mutation', 'p.C101S', (11, 16))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))
17277	25898173	The SDHB RNA editing level in transfectants of the P134A variant was ~80% of that of transfectants expressing the wild-type APOBEC3A (Fig.	('APOBEC3A', 'Gene', (124, 132))	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('APOBEC', 'cellular_component', 'GO:0030895', ('124', '130'))	('P134A', 'Mutation', 'rs1342585425', (51, 56))	('RNA editing', 'biological_process', 'GO:0009451', ('9', '20'))	('APOBEC3A', 'Gene', '200315', (124, 132))	('SDHB', 'Gene', '6390', (4, 8))	('P134A', 'Var', (51, 56))	('SDHB', 'Gene', (4, 8))
17280	25898173	To test whether RNA editing and retrotransposition-suppressing functions of APOBEC3A are linked, we tested the effect of mutations on LINE1 retrotransposition, using a previously described cell-based assay.	('mutations', 'Var', (121, 130))	('APOBEC3A', 'Gene', (76, 84))	('RNA editing', 'biological_process', 'GO:0009451', ('16', '27'))	('APOBEC', 'cellular_component', 'GO:0030895', ('76', '82'))	('APOBEC3A', 'Gene', '200315', (76, 84))	('retrotransposition', 'biological_process', 'GO:0032197', ('140', '158'))	('tested', 'Reg', (100, 106))	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('retrotransposition', 'biological_process', 'GO:0032197', ('32', '50'))
17281	25898173	We found that the ability of the E72D, C101S and P134A variants to inhibit retrotransposition paralleled their RNA-editing activities (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('inhibit', 'NegReg', (67, 74))	('C101S', 'Mutation', 'p.C101S', (39, 44))	('C101S', 'Var', (39, 44))	('E72D', 'Var', (33, 37))	('E72D', 'Mutation', 'p.E72D', (33, 37))	('P134A', 'Mutation', 'rs1342585425', (49, 54))	('retrotransposition', 'biological_process', 'GO:0032197', ('75', '93'))	('retrotransposition', 'MPA', (75, 93))	('RNA-editing', 'biological_process', 'GO:0009451', ('111', '122'))	('P134A', 'Var', (49, 54))
17282	25898173	These findings indicate that mutations in E72, C101 and P134 residues of APOBEC3A affect the protein's ssDNA and RNA deamination, and anti-LINE1 retrotransposition activities in a similar manner.	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('protein', 'Protein', (93, 100))	('mutations', 'Var', (29, 38))	('APOBEC3A', 'Gene', '200315', (73, 81))	('ssDNA', 'MPA', (103, 108))	('RNA deamination', 'MPA', (113, 128))	('E72', 'Var', (42, 45))	('P134', 'Var', (56, 60))	('anti-LINE1 retrotransposition activities', 'MPA', (134, 174))	('C101', 'Var', (47, 51))	('RNA', 'cellular_component', 'GO:0005562', ('113', '116'))	('retrotransposition', 'biological_process', 'GO:0032197', ('145', '163'))	('affect', 'Reg', (82, 88))	('APOBEC', 'cellular_component', 'GO:0030895', ('73', '79'))	('APOBEC3A', 'Gene', (73, 81))
17284	25898173	To demonstrate that APOBEC3A can edit c.136C>U in SDHB RNA in vitro, an SDHB ORF RNA of ~1.1 kb with an artificial sequence at its 5'-end was incubated with whole-cell lysates of 293T transfectants.	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))	('SDHB', 'Gene', '6390', (50, 54))	('c.136C>U', 'Var', (38, 46))	('artificial sequence', 'Species', '32630', (104, 123))	('SDHB', 'Gene', (50, 54))	('SDHB', 'Gene', (72, 76))	('APOBEC3A', 'Gene', '200315', (20, 28))	('APOBEC', 'cellular_component', 'GO:0030895', ('20', '26'))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))	('APOBEC3A', 'Gene', (20, 28))	('c.136C>U', 'SUBSTITUTION', 'None', (38, 46))	('293T', 'CellLine', 'CVCL:0063', (179, 183))	('SDHB', 'Gene', '6390', (72, 76))
17288	25898173	Incubation of in vitro-transcribed SDHB RNA with His6-tagged APOBEC3A protein showed site-specific editing of the SDHB RNA in vitro (Fig.	('APOBEC3A', 'Gene', '200315', (61, 69))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (35, 39))	('editing', 'Var', (99, 106))	('SDHB', 'Gene', (114, 118))	('His6', 'Chemical', 'MESH:C471213', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))	('APOBEC3A', 'Gene', (61, 69))	('SDHB', 'Gene', '6390', (35, 39))
17290	25898173	An ssDNA of 120 bases containing the SDHB cDNA sequence (c.37-c.156) too was deaminated at c.136 by the recombinant APOBEC3A protein.	('SDHB', 'Gene', '6390', (37, 41))	('c.136', 'Var', (91, 96))	('SDHB', 'Gene', (37, 41))	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('APOBEC3A', 'Gene', (116, 124))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('APOBEC3A', 'Gene', '200315', (116, 124))
17292	25898173	In contrast, cDNAs of the in vitro-synthesized SDHB RNA incubated with the APOBEC3A 293T transfectant cell lysates or the pure recombinant enzyme showed no evidence of additional mutations in Sanger sequence analysis of a 619 b segment that spanned exons 1-5 (Fig.	('APOBEC3A', 'Gene', '200315', (75, 83))	('APOBEC', 'cellular_component', 'GO:0030895', ('75', '81'))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('APOBEC3A', 'Gene', (75, 83))	('pure', 'molecular_function', 'GO:0034023', ('122', '126'))	('mutations', 'Var', (179, 188))	('293T', 'CellLine', 'CVCL:0063', (84, 88))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
17302	25898173	Replacement of the single murine APOBEC3 gene with either human APOBEC3A or APOBEC3G in mouse preserves APOBEC3-mediated restriction of the MMTV and MLV murine retroviruses, but a high level of viral DNA deamination is seen only with the latter.	('human', 'Species', '9606', (58, 63))	('restriction', 'MPA', (121, 132))	('Replacement', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('MMTV', 'Species', '11757', (140, 144))	('APOBEC3G', 'Gene', (76, 84))	('preserves', 'NegReg', (94, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('104', '110'))	('APOBEC', 'cellular_component', 'GO:0030895', ('64', '70'))	('DNA deamination', 'biological_process', 'GO:0045006', ('200', '215'))	('APOBEC3', 'Gene', '80287', (76, 83))	('APOBEC3', 'Gene', (76, 83))	('APOBEC3A', 'Gene', (64, 72))	('APOBEC', 'cellular_component', 'GO:0030895', ('33', '39'))	('APOBEC3', 'Gene', '80287', (104, 111))	('APOBEC3A', 'Gene', '200315', (64, 72))	('APOBEC3', 'Gene', (104, 111))	('murine', 'Species', '10090', (153, 159))	('APOBEC3', 'Gene', '80287', (33, 40))	('murine', 'Species', '10090', (26, 32))	('APOBEC', 'cellular_component', 'GO:0030895', ('76', '82'))	('APOBEC3G', 'Gene', '60489', (76, 84))	('APOBEC3', 'Gene', (33, 40))	('APOBEC3', 'Gene', (64, 71))	('APOBEC3', 'Gene', '80287', (64, 71))	('mouse', 'Species', '10090', (88, 93))
17303	25898173	Paradoxically, previous studies also show that CDA active site mutations such as H70R, C101S and C106S markedly diminish or abolish the virus-inhibiting activities of APOBEC3A.	('APOBEC3A', 'Gene', '200315', (167, 175))	('APOBEC', 'cellular_component', 'GO:0030895', ('167', '173'))	('virus-inhibiting activities', 'CPA', (136, 163))	('abolish', 'NegReg', (124, 131))	('CDA', 'Gene', '978', (47, 50))	('C106S', 'Var', (97, 102))	('C101S', 'Var', (87, 92))	('H70R', 'Mutation', 'p.H70R', (81, 85))	('diminish', 'NegReg', (112, 120))	('C106S', 'Mutation', 'p.C106S', (97, 102))	('APOBEC3A', 'Gene', (167, 175))	('H70R', 'Var', (81, 85))	('C101S', 'Mutation', 'p.C101S', (87, 92))	('CDA', 'Gene', (47, 50))
17305	25898173	We find that the RNA editing and anti-LINE-1 retrotransposition abilities of APOBEC3A are similarly affected by E72D, C101S and P134A mutations (Fig.	('anti-LINE-1 retrotransposition', 'MPA', (33, 63))	('retrotransposition', 'biological_process', 'GO:0032197', ('45', '63'))	('APOBEC', 'cellular_component', 'GO:0030895', ('77', '83'))	('C101S', 'Mutation', 'p.C101S', (118, 123))	('C101S', 'Var', (118, 123))	('RNA', 'cellular_component', 'GO:0005562', ('17', '20'))	('RNA editing', 'MPA', (17, 28))	('affected', 'Reg', (100, 108))	('E72D', 'Var', (112, 116))	('E72D', 'Mutation', 'p.E72D', (112, 116))	('P134A', 'Mutation', 'rs1342585425', (128, 133))	('APOBEC3A', 'Gene', (77, 85))	('RNA editing', 'biological_process', 'GO:0009451', ('17', '28'))	('P134A mutations', 'Var', (128, 143))	('APOBEC3A', 'Gene', '200315', (77, 85))
17307	25898173	The association established in this study between upregulation of APOBEC3A-mediated C>U RNA editing of cellular transcripts and hypoxia or IFN treatment of monocytes and M1 polarization of macrophages (Figs 1 and 2a) also supports this notion.	('APOBEC3A', 'Gene', (66, 74))	('C>U RNA', 'Var', (84, 91))	('IFN', 'Gene', (139, 142))	('APOBEC', 'cellular_component', 'GO:0030895', ('66', '72'))	('upregulation', 'PosReg', (50, 62))	('IFN', 'Gene', '3438', (139, 142))	('APOBEC3A', 'Gene', '200315', (66, 74))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('RNA editing', 'biological_process', 'GO:0009451', ('88', '99'))	('hypoxia', 'Disease', (128, 135))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))
17316	25898173	How hypoxia activates C>U RNA editing is currently unknown.	('C>U RNA editing', 'Var', (22, 37))	('RNA editing', 'biological_process', 'GO:0009451', ('26', '37'))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('hypoxia', 'Disease', (4, 11))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))
17318	25898173	Hypoxic stimulation of C>U RNA editing in these cells may therefore be caused by an alternative mechanism such as enhanced translocation of the enzyme to nucleus, where A>I and APOBEC1-mediated C>U RNA editing are known to occur.	('RNA editing', 'biological_process', 'GO:0009451', ('27', '38'))	('APOBEC1', 'Gene', (177, 184))	('translocation', 'MPA', (123, 136))	('C>U RNA editing', 'Var', (23, 38))	('RNA', 'cellular_component', 'GO:0005562', ('27', '30'))	('APOBEC1', 'Gene', '339', (177, 184))	('enhanced', 'PosReg', (114, 122))	('RNA editing', 'biological_process', 'GO:0009451', ('198', '209'))	('APOBEC', 'cellular_component', 'GO:0030895', ('177', '183'))	('nucleus', 'cellular_component', 'GO:0005634', ('154', '161'))	('RNA', 'cellular_component', 'GO:0005562', ('198', '201'))
17320	25898173	We find that RNAs encoding for both the SDHA and SDHB subunits of mitochondrial complex II are targets of hypoxia-induced C>U editing (Supplementary Data 1), suggesting that suppression of this complex facilitates hypoxia adaptation in pro-inflammatory monocytes and macrophages.	('SDHB', 'Gene', (49, 53))	('hypoxia', 'Disease', (214, 221))	('facilitates', 'PosReg', (202, 213))	('hypoxia', 'Disease', 'MESH:D000860', (214, 221))	('SDHA', 'Gene', '6389', (40, 44))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('suppression', 'Var', (174, 185))	('SDHA', 'Gene', (40, 44))	('SDHB', 'Gene', '6390', (49, 53))	('complex II', 'molecular_function', 'GO:0008177', ('80', '90'))
17340	25898173	Enhancement by hypoxia of SDHB c.136C>U RNA editing was not observed in cultures of previously cryopreserved CD14+ monocytes (Supplementary Fig.7a).	('Enhancement', 'PosReg', (0, 11))	('hypoxia', 'Disease', (15, 22))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('RNA editing', 'MPA', (40, 51))	('CD14', 'Gene', '929', (109, 113))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('RNA editing', 'biological_process', 'GO:0009451', ('40', '51'))	('SDHB', 'Gene', '6390', (26, 30))	('SDHB', 'Gene', (26, 30))	('c.136C>U', 'SUBSTITUTION', 'None', (31, 39))	('c.136C>U', 'Var', (31, 39))	('CD14', 'Gene', (109, 113))
17356	25898173	Paired comparison of pileups for the three pairs, from three different human donors, of normoxic and hypoxic MEP, or M2 and M1 macrophage samples was performed to identify genome sites with differential RNA editing in MEPs under hypoxia (test samples) compared with normoxia (control samples), or in M1 macrophages (test) compared with M2 macrophages (control).	('hypoxic MEP', 'Disease', (101, 112))	('hypoxia', 'Disease', (229, 236))	('hypoxia', 'Disease', 'MESH:D000860', (229, 236))	('hypoxic MEP', 'Disease', 'MESH:D000860', (101, 112))	('RNA editing', 'biological_process', 'GO:0009451', ('203', '214'))	('RNA', 'cellular_component', 'GO:0005562', ('203', '206'))	('differential', 'Var', (190, 202))	('human', 'Species', '9606', (71, 76))
17358	25898173	Variant sites with known maximum population prevalence >20% for identical sequence polymorphism (as per the popfreq_max ANNOVAR database, detailed below), or sites that did not map to a known RefSeq gene (www.ncbi.nlm.nih.gov/refseq), or mapped to either exons of >1 RefSeq genes on both chromosome strands, or mapped to only introns of >1 RefSeq genes on both chromosome strands were excluded.	('chromosome', 'cellular_component', 'GO:0005694', ('288', '298'))	('mum', 'Gene', '56925', (29, 32))	('mum', 'Gene', (29, 32))	('chromosome', 'cellular_component', 'GO:0005694', ('361', '371'))	('Variant', 'Var', (0, 7))
17361	25898173	For analyses of RNA-sequencing data of tumour samples of TCGA, genes with raw count value >0 for >=N samples, irrespective of group membership, where N equals the size of the SDHB c.136C>U editing-positive group, were considered as expressed, and values for prior.df and rowsum.filter parameters in estimateCommonDisp and estimateTagwiseDisp functions of edgeR were set at 0.2 and 4N, respectively.	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('c.136C>U', 'SUBSTITUTION', 'None', (180, 188))	('c.136C>U', 'Var', (180, 188))	('tumour', 'Disease', (39, 45))	('SDHB', 'Gene', '6390', (175, 179))	('SDHB', 'Gene', (175, 179))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
17362	25898173	Sequence-verified plasmid constructs in pCMV6 vector for cytomegalovirus (CMV) promoter-driven expression of human APOBEC3A, APOBEC3G, CDA and SDHB cDNAs, with sequences matching NCBI RefSeq sequences NM_145699.2, NM_021822.1, NM_001785.1 and NM_003000.2, respectively, for the generation of C-terminal Myc-DDK-tagged APOBEC3A and untagged APOBEC3G, CDA and SDHB proteins were obtained from OriGene (Rockville, MD; product numbers RC220995, SC122916, SC119015 and SC319204, respectively).	('SDHB', 'Gene', (358, 362))	('APOBEC3G', 'Gene', (125, 133))	('APOBEC', 'cellular_component', 'GO:0030895', ('340', '346'))	('SDHB', 'Gene', (143, 147))	('APOBEC3A', 'Gene', (115, 123))	('DDK', 'cellular_component', 'GO:0031431', ('307', '310'))	('APOBEC', 'cellular_component', 'GO:0030895', ('318', '324'))	('Myc', 'Gene', '4609', (303, 306))	('APOBEC3A', 'Gene', '200315', (115, 123))	('APOBEC3G', 'Gene', '60489', (340, 348))	('CDA', 'Gene', (350, 353))	('SC119015', 'Var', (451, 459))	('APOBEC3G', 'Gene', '60489', (125, 133))	('APOBEC3A', 'Gene', (318, 326))	('CDA', 'Gene', '978', (350, 353))	('RC220995', 'Var', (431, 439))	('CDA', 'Gene', (135, 138))	('APOBEC', 'cellular_component', 'GO:0030895', ('125', '131'))	('APOBEC3A', 'Gene', '200315', (318, 326))	('CDA', 'Gene', '978', (135, 138))	('SDHB', 'Gene', '6390', (358, 362))	('human', 'Species', '9606', (109, 114))	('APOBEC', 'cellular_component', 'GO:0030895', ('115', '121'))	('SC122916', 'Var', (441, 449))	('SDHB', 'Gene', '6390', (143, 147))	('Myc', 'Gene', (303, 306))	('APOBEC3G', 'Gene', (340, 348))
17364	25898173	Site-directed mutagenesis of APOBEC3A constructs (c.216G>C/p.E72D, c.301T>A/p.C101S or c.400C>G/p.P134A; primer sequences shown in Supplementary Table 10) was performed using Q5 site-directed mutagenesis kit (New England Biolabs, Ipswich, MA).	('c.216G>C', 'Mutation', 'c.216G>C', (50, 58))	('p.E72D', 'Mutation', 'p.E72D', (59, 65))	('c.400C>G', 'Mutation', 'c.400C>G', (87, 95))	('mutagenesis', 'biological_process', 'GO:0006280', ('192', '203'))	('mutagenesis', 'biological_process', 'GO:0006280', ('14', '25'))	('c.301T>A/p.C101S', 'Var', (67, 83))	('p.C101S', 'Mutation', 'p.C101S', (76, 83))	('APOBEC3A', 'Gene', (29, 37))	('c.400C>G/p.P134A', 'Var', (87, 103))	('APOBEC', 'cellular_component', 'GO:0030895', ('29', '35'))	('c.301T>A', 'Mutation', 'c.301T>A', (67, 75))	('p.P134A', 'Mutation', 'rs1342585425', (96, 103))	('APOBEC3A', 'Gene', '200315', (29, 37))	('c.216G>C/p.E72D', 'Var', (50, 65))
17376	25898173	TaqMan Gene Expression Assays from Life Technologies with identification numbers Hs00234140_m1, Hs00171149_m1, Hs00233627_m1 and Hs00267207_m1, or prepared in house were respectively used to quantify CCL2, CCL19, FCER2, MRC1 and ACTB with PCR performed on a 7900HT instrument (Life Technologies) and Cq values determined with automatic baseline and threshold detection by SDS 2.4 software (Life Technologies).	('Hs00267207_m1', 'Var', (129, 142))	('CCL2', 'Gene', '6347', (200, 204))	('Hs00171149_m1', 'Var', (96, 109))	('ACTB', 'Gene', '60', (229, 233))	('MRC1', 'CellLine', 'CVCL:0440', (220, 224))	('ACTB', 'Gene', (229, 233))	('Hs00233627_m1', 'Var', (111, 124))	('FCER2', 'Gene', '2208', (213, 218))	('Gene Expression', 'biological_process', 'GO:0010467', ('7', '22'))	('CCL', 'molecular_function', 'GO:0044101', ('200', '203'))	('CCL19', 'Gene', (206, 211))	('CCL19', 'Gene', '6363', (206, 211))	('CCL2', 'Gene', (200, 204))	('FCER2', 'Gene', (213, 218))	('CCL', 'molecular_function', 'GO:0044101', ('206', '209'))	('Hs00234140_m1', 'Var', (81, 94))
17378	25898173	Appropriateness of this method to estimate RNA-editing level was confirmed by comparing measurements of SDHB c.136C>U RNA-editing level obtained with it against those obtained with allele-specific RT-PCR (Supplementary Fig.	('c.136C>U', 'SUBSTITUTION', 'None', (109, 117))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('RNA-editing', 'biological_process', 'GO:0009451', ('43', '54'))	('c.136C>U', 'Var', (109, 117))	('RNA', 'cellular_component', 'GO:0005562', ('118', '121'))	('RNA-editing', 'biological_process', 'GO:0009451', ('118', '129'))	('SDHB', 'Gene', '6390', (104, 108))	('SDHB', 'Gene', (104, 108))
17400	25898173	The c.136C>U editing of the exogenous RNA was assessed by allele-specific RT-PCR as described previously but using a forward PCR primer (5'- GGAATTCGGCACGAGGAC -3') that does not bind the cDNA of endogenous SDHB RNA.	('SDHB', 'Gene', '6390', (207, 211))	('SDHB', 'Gene', (207, 211))	('RNA', 'cellular_component', 'GO:0005562', ('38', '41'))	('c.136C>U', 'SUBSTITUTION', 'None', (4, 12))	('RNA', 'cellular_component', 'GO:0005562', ('212', '215'))	('c.136C>U', 'Var', (4, 12))
17402	25898173	SDHB gene expression and c.136C>U RNA editing was quantified by RT-PCR.	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('RNA editing', 'biological_process', 'GO:0009451', ('34', '45'))	('gene expression', 'biological_process', 'GO:0010467', ('5', '20'))	('SDHB', 'Gene', '6390', (0, 4))	('c.136C>U', 'SUBSTITUTION', 'None', (25, 33))	('c.136C>U', 'Var', (25, 33))	('SDHB', 'Gene', (0, 4))
17404	25898173	designed the study with contributions from S.K.P and S.S. S.S. generated the expression constructs for mutant APOBEC3A and performed the experiments with 293T transfectants and APOBEC3A protein, and.	('APOBEC3A', 'Gene', (110, 118))	('mutant', 'Var', (103, 109))	('APOBEC3A', 'Gene', (177, 185))	('protein', 'cellular_component', 'GO:0003675', ('186', '193'))	('APOBEC3A', 'Gene', '200315', (110, 118))	('APOBEC', 'cellular_component', 'GO:0030895', ('177', '183'))	('APOBEC3A', 'Gene', '200315', (177, 185))	('APOBEC', 'cellular_component', 'GO:0030895', ('110', '116'))	('293T', 'CellLine', 'CVCL:0063', (154, 158))
17429	29100423	Then a prognostic lncRNA signature with six prognostic lncRNAs was constructed using a mathematical formula for survival prediction according to the expression of the six prognostic lncRNAs and using the multivariate Cox regression coefficient as the weight, as follows: Risk score= (-0.1779* expression value of LINC01260)+(-0.1522*expression of HCP5)+ (0.2537* expression value of PIGBOS1)+(-0.4409*expression of CTA-292E10.6)+ (-0.8444* expression value of RP11-247L20.4)+(-0.2056*expression of CTB-113P19.5).	('-0.1779*', 'Var', (284, 292))	('RP11', 'Gene', '26121', (460, 464))	('P19', 'cellular_component', 'GO:0070743', ('505', '508'))	('CTA-292E10.6', 'Gene', '84133', (415, 427))	('CTA-292E10.6', 'Gene', (415, 427))	('PIGBOS1', 'Gene', '101928527', (383, 390))	('Cox', 'Gene', (217, 220))	('LINC01260', 'Gene', '79015', (313, 322))	('Cox', 'Gene', '1351', (217, 220))	('LINC01260', 'Gene', (313, 322))	('HCP5', 'Gene', '10866', (347, 351))	('PIGBOS1', 'Gene', (383, 390))	('HCP5', 'Gene', (347, 351))	('RP11', 'Gene', (460, 464))
17546	26834525	Of those 25 had mutations at BRAF gene while 15 were wild type (see supplementary file for details).	('BRAF', 'Gene', '673', (29, 33))	('mutations', 'Var', (16, 25))	('men', 'Species', '9606', (74, 77))	('BRAF', 'Gene', (29, 33))
17547	26834525	Patients with mutant BRAF gene were significantly younger (average age 52 years) than those with wild type BRAF melanoma (average age 64 years; p = 0.03), in particular this observation was confirmed in females (p = 0.04), but not in males (p = 0.2) as shown in supplementary Table 2.	('type BRAF melanoma', 'Disease', (102, 120))	('BRAF', 'Gene', (107, 111))	('type BRAF melanoma', 'Disease', 'MESH:D008545', (102, 120))	('mutant', 'Var', (14, 20))	('men', 'Species', '9606', (268, 271))	('BRAF', 'Gene', '673', (21, 25))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (107, 111))	('younger', 'NegReg', (50, 57))
17548	26834525	BRAF mutational status was also related to anatomical sites (p = 0.03): in our sub-group of patients BRAF mutations prevail in melanoma of trunk compared to melanoma of the hand and foot that were all wild type for BRAF.	('BRAF', 'Gene', (101, 105))	('melanoma of the hand', 'Disease', (157, 177))	('BRAF', 'Gene', (215, 219))	('patients', 'Species', '9606', (92, 100))	('melanoma of trunk', 'Disease', 'MESH:D008545', (127, 144))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('trunk', 'cellular_component', 'GO:0043198', ('139', '144'))	('melanoma of the hand', 'Disease', 'MESH:D008545', (157, 177))	('mutations', 'Var', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (101, 105))	('melanoma of trunk', 'Disease', (127, 144))	('BRAF', 'Gene', '673', (215, 219))
17570	26834525	Regarding melanomas mutated at BRAF gene we observed a correlation between BRAF mutations and being young at the time of primary melanoma diagnosis in agreement with other authors, and our observation was confirmed particularly in women.	('women', 'Species', '9606', (231, 236))	('primary melanoma', 'Disease', (121, 137))	('mutations', 'Var', (80, 89))	('melanomas', 'Disease', (10, 19))	('BRAF', 'Gene', '673', (75, 79))	('men', 'Species', '9606', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('BRAF', 'Gene', (75, 79))	('primary melanoma', 'Disease', 'MESH:D008545', (121, 137))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('BRAF', 'Gene', '673', (31, 35))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))	('men', 'Species', '9606', (233, 236))	('mutated', 'Var', (20, 27))	('BRAF', 'Gene', (31, 35))
17571	26834525	BRAF mutations seem to be associated also to anatomical sites of the primary lesion, with melanomas on the trunk presenting higher rate of mutations at BRAF gene, as already shown.	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('BRAF', 'Gene', (152, 156))	('melanomas', 'Disease', 'MESH:D008545', (90, 99))	('mutations', 'Var', (139, 148))	('trunk', 'cellular_component', 'GO:0043198', ('107', '112'))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', (90, 99))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (152, 156))	('associated', 'Reg', (26, 36))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
17611	25922600	Relating more specifically to melanoma, it has been cited that asymmetry of the lymphatic and circulatory systems may influence the immune response against or patterns of melanoma spread.	('immune response', 'biological_process', 'GO:0006955', ('132', '147'))	('asymmetry', 'Var', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('immune response against', 'CPA', (132, 155))	('melanoma', 'Disease', (30, 38))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('patterns', 'CPA', (159, 167))	('influence', 'Reg', (118, 127))
17646	33724679	Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival.	('Critically', 'Disease', (0, 10))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('persister cells survival', 'CPA', (116, 140))	('chemical inhibition', 'Var', (12, 31))	('SMAD3', 'Gene', '4088', (35, 40))	('SMAD3', 'Gene', (35, 40))	('abrogates', 'NegReg', (106, 115))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
17655	33724679	Moreover, chemical inhibition of SMAD3 decreases persister cells population.	('chemical inhibition', 'Var', (10, 29))	('persister cells population', 'CPA', (49, 75))	('decreases', 'NegReg', (39, 48))	('SMAD3', 'Gene', '4088', (33, 38))	('SMAD3', 'Gene', (33, 38))
17660	33724679	Last year, the cancer genome atlas (TCGA) identified 299 driver genes by focusing on point mutations and small indels across 33 cancer types (Bailey et al, 2018).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('point mutations', 'Var', (85, 100))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Disease', (128, 134))
17661	33724679	It represents the most comprehensive effort thus far to identify cancer driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (79, 88))
17677	33724679	In addition, there is increased evidence that non-genetic reprogramming may confer drug-tolerant and/or resistant phenotypes to melanoma cells (Rambow et al, 2018; Corre et al, 2018; Tsoi et al, 2018; Hugo et al, 2015a; Talebi et al, 2018; Rapino et al, 2018; preprint: Marin-Bejar et al, 2020).	('resistant phenotypes', 'CPA', (104, 124))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('drug-tolerant', 'CPA', (83, 96))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('non-genetic', 'Var', (46, 57))	('melanoma', 'Disease', (128, 136))
17760	33724679	To reinforce the role of SMAD3 in BRAFi resistance, we showed that gain-of-function of SMAD3 significantly increases the BRAFi resistance of melanoma cells when compared to different control cells (parental 501Mel cells and the CRISPR-engineered cells: 501Mel cells expressing dCas9 and HSF1-p65-MS2 (named here 501Mel 2+) and the 501Mel 2+ cells expressing a control guide (named 3+ backbone; Fig 5D).	('p65', 'Gene', '5970', (292, 295))	('increases', 'PosReg', (107, 116))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('gain-of-function', 'PosReg', (67, 83))	('SMAD3', 'Gene', '4088', (87, 92))	('SMAD3', 'Gene', '4088', (25, 30))	('CRISPR', 'Gene', (228, 234))	('BRAFi', 'Chemical', '-', (34, 39))	('CRISPR', 'Gene', '70873', (228, 234))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('HSF1', 'Gene', (287, 291))	('dCas9', 'Var', (277, 282))	('HSF1', 'Gene', '3297', (287, 291))	('BRAFi', 'Chemical', '-', (121, 126))	('SMAD3', 'Gene', (87, 92))	('BRAFi resistance', 'CPA', (121, 137))	('SMAD3', 'Gene', (25, 30))	('p65', 'Gene', (292, 295))	('MS2', 'Species', '2710868', (296, 299))
17767	33724679	Surprisingly, the single SMAD3 depletion decreased the cell density in a similar magnitude than BRAFi treatment in these BRAFi-resistant cells (Figs 5G and H, and EV3B).	('BRAFi', 'Chemical', '-', (96, 101))	('cell density', 'CPA', (55, 67))	('BRAFi', 'Chemical', '-', (121, 126))	('decreased', 'NegReg', (41, 50))	('SMAD3', 'Gene', '4088', (25, 30))	('SMAD3', 'Gene', (25, 30))	('depletion', 'Var', (31, 40))
17768	33724679	The SMAD3 depletion did not modify the ERK pathway (Fig 5I) in contrast to the BRAFi.	('SMAD3', 'Gene', '4088', (4, 9))	('ERK', 'Gene', '5594', (39, 42))	('SMAD3', 'Gene', (4, 9))	('depletion', 'Var', (10, 19))	('ERK', 'Gene', (39, 42))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('BRAFi', 'Chemical', '-', (79, 84))
17783	33724679	We finally investigated the interest to combine BRAFi (Vem, alone or in combination with MEKi (Cobi)) and SMAD3i (SIS3) to eradicate the BRAFi-resistant cell lines (SKMel28R, M229R, and M238R) (Figs 5O and EV3K).	('M229R', 'Var', (175, 180))	('MEK', 'Gene', (89, 92))	('BRAFi', 'Chemical', '-', (48, 53))	('MEK', 'Gene', '5609', (89, 92))	('M238R', 'Var', (186, 191))	('SIS3', 'Chemical', '-', (114, 118))	('SMAD3', 'Gene', (106, 111))	('eradicate', 'NegReg', (123, 132))	('M238R', 'SUBSTITUTION', 'None', (186, 191))	('SMAD3', 'Gene', '4088', (106, 111))	('SKMel28R', 'Chemical', '-', (165, 173))	('BRAFi-resistant', 'Disease', (137, 152))	('M229R', 'SUBSTITUTION', 'None', (175, 180))	('BRAFi', 'Chemical', '-', (137, 142))	('SKMel28R', 'Var', (165, 173))
17814	33724679	In response to SMAD3 depletion, AXL and EGFR decreased in the two models in contrast to other genes such as MMP2, which decreased in only one model.	('MMP2', 'molecular_function', 'GO:0004228', ('108', '112'))	('AXL', 'Gene', (32, 35))	('decreased', 'NegReg', (45, 54))	('MMP2', 'Gene', (108, 112))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', '1956', (40, 44))	('depletion', 'Var', (21, 30))	('EGFR', 'Gene', (40, 44))	('SMAD3', 'Gene', '4088', (15, 20))	('MMP2', 'Gene', '4313', (108, 112))	('SMAD3', 'Gene', (15, 20))	('AXL', 'Gene', '558', (32, 35))
17865	33724679	AhR antagonists validated in mice are currently evaluated in clinical trials (NCT04200963, Ikena Oncology) and (NCT04069026, Bayer).	('NCT04200963', 'Var', (78, 89))	('Oncology', 'Phenotype', 'HP:0002664', (97, 105))	('NCT04069026', 'Var', (112, 123))	('mice', 'Species', '10090', (29, 33))
17867	33724679	Another option overcoming the potential pharmacological caveat would be to use antisense oligonucleotides (ASO) targeting AhR or SMAD3 (Leclerc et al, 2021).	('ASO', 'Chemical', 'MESH:D016376', (107, 110))	('SMAD3', 'Gene', '4088', (129, 134))	('oligonucleotides', 'Chemical', 'MESH:D009841', (89, 105))	('antisense', 'Var', (79, 88))	('AhR', 'Gene', (122, 125))	('SMAD3', 'Gene', (129, 134))
17869	33724679	In this study, we propose an AhR-SMAD3 impairment as a strategy to overcome melanoma resistance.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('impairment', 'Var', (39, 49))	('SMAD3', 'Gene', '4088', (33, 38))	('SMAD3', 'Gene', (33, 38))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
17892	33724679	M229S, M229R, M238S, M238R, and M249 were obtained from Thomas Graeber's laboratory at department of Molecular and Medical Pharmacology, University of California, Los Angeles, USA.	('M238R', 'SUBSTITUTION', 'None', (21, 26))	('M229R', 'Var', (7, 12))	('M229R', 'SUBSTITUTION', 'None', (7, 12))	('M238S', 'Var', (14, 19))	('M229S', 'Var', (0, 5))	('M238R', 'Var', (21, 26))	('M249', 'Var', (32, 36))	('M238S', 'Mutation', 'p.M238S', (14, 19))	('M229S', 'Mutation', 'p.M229S', (0, 5))
17894	33724679	HEK293T was grown in DMEM (Gibco BRL, Invitrogen, Paisley, UK) supplemented as melanoma cell lines media.	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('HEK293T', 'Var', (0, 7))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('DMEM', 'Chemical', '-', (21, 25))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
17895	33724679	SKMel28R, M229R, and M238R are cultivated in presence of 0.1 microM vemurafenib.	('M238R', 'SUBSTITUTION', 'None', (21, 26))	('M229R', 'Var', (10, 15))	('M238R', 'Var', (21, 26))	('vemurafenib', 'Chemical', 'MESH:D000077484', (68, 79))	('SKMel28R', 'Chemical', '-', (0, 8))	('M229R', 'SUBSTITUTION', 'None', (10, 15))
17917	33724679	For SMAD3i + vemurafenib combination treatment: 5,000 (501Mel) or 8,000 (M249, SKMel28R) cells were seeded in 96-well plates, in triplicates.	('SMAD3', 'Gene', '4088', (4, 9))	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('SKMel28R', 'Chemical', '-', (79, 87))	('501Mel', 'Var', (55, 61))	('M249, SKMel28R', 'Var', (73, 87))	('SMAD3', 'Gene', (4, 9))
17939	33724679	Patient's median expression of our 18 hits in baseline vs relapse (BRAFi) is based on expression data from GSE65186 (Hugo et al, 2015b) and GSE50509 (Rizos et al, 2014).	('Patient', 'Species', '9606', (0, 7))	('BRAFi', 'Chemical', '-', (67, 72))	('GSE50509', 'Var', (140, 148))	('GSE65186', 'Var', (107, 115))
17946	33724679	Gene Set Enrichment Analysis on Huh28 +- TGF-beta was realized based on GSE102109 (Merdrignac et al, 2018).	('Huh28 +-', 'Var', (32, 40))	('TGF-beta', 'Gene', '7039', (41, 49))	('TGF-beta', 'Gene', (41, 49))	('Huh28', 'CellLine', 'CVCL:0336', (32, 37))
17966	27706081	Given the central role of Golgi for various cell processes, its dysregulation is a likely feature in carcinogenesis.	('dysregulation', 'Var', (64, 77))	('Golgi', 'cellular_component', 'GO:0005794', ('26', '31'))	('carcinogenesis', 'Disease', (101, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))
17974	27706081	Binding of PI4P and MYO18A by GOLPH3 links Golgi membrane to F-actin cytoskeleton and is essential for vesicular trafficking.	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('63', '81'))	('MYO18A', 'Gene', '399687', (20, 26))	('Golgi membrane', 'cellular_component', 'GO:0000139', ('43', '57'))	('MYO18A', 'Gene', (20, 26))	('PI4P', 'Var', (11, 15))	('F-actin', 'cellular_component', 'GO:0031941', ('61', '68'))	('Binding', 'Interaction', (0, 7))	('GOLPH3', 'Gene', (30, 36))
18106	33643901	One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.	('tumor', 'Disease', (28, 33))	('reduce', 'NegReg', (130, 136))	('circulating levels', 'MPA', (137, 155))	('neutralize', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ENO1', 'Gene', (73, 77))	('ENO1', 'Gene', '2023', (73, 77))
18117	33643901	In this study, the cBio Cancer Genomics Portal (; accessed by April 30, 2020), which is a web tool for mutation analysis and visualization through TCGA cancer genomics profiles, was used for mutation analysis of ENO1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (24, 30))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ENO1', 'Gene', (212, 216))	('ENO1', 'Gene', '2023', (212, 216))	('mutation', 'Var', (191, 199))
18132	33643901	The highest ENO1 expression was found in EBV-transformed lymphocytes, whereas the lowest was observed in the left ventricle of the heart.	('ENO1', 'Gene', (12, 16))	('expression', 'MPA', (17, 27))	('ENO1', 'Gene', '2023', (12, 16))	('EBV-transformed', 'Var', (41, 56))
18139	33643901	The expression of ENO1 was significantly associated with the prognosis of eight types of cancers, including HNSC (HR = 1.32, P = 0.04), CESC (HR = 1.47, P = 0.04), BLCA (HR = 1.23, P = 0.04), LUAD (HR = 1.36, P = 0.01), SARC (HR = 1.36, P = 0.00), PAAD (HR = 1.65, P = 0.00), KICH (HR = 4.60, P = 0.00), and LIHC (HR = 1.63, P = 0.00), suggesting that high ENO1 expression might be an independent risk factor for these cancers (all HR > 1.00, P < 0.05).	('associated', 'Reg', (41, 51))	('high', 'Var', (352, 356))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', (89, 96))	('KICH', 'Disease', (276, 280))	('LUAD', 'Disease', (192, 196))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CESC', 'Disease', (136, 140))	('BLCA', 'Disease', (164, 168))	('ENO1', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('ENO1', 'Gene', (357, 361))	('cancers', 'Disease', (419, 426))	('ENO1', 'Gene', '2023', (18, 22))	('KICH', 'Disease', 'None', (276, 280))	('HNSC', 'Disease', (108, 112))	('SARC', 'Disease', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('ENO1', 'Gene', '2023', (357, 361))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
18141	33643901	High ENO1 expression was significantly associated with worse OS in CESC (log-rank P = 0.04), BLCA (log-rank P = 0.03), KICH (log-rank P = 0.01), LIHC (log-rank P = 0.00), and SARC (log-rank P = 0.04), and worse DFS in KICH (log-rank P = 0.03) and SARC (log-rank P = 0.07).	('SARC', 'Disease', (175, 179))	('LIHC', 'Disease', (145, 149))	('KICH', 'Disease', 'None', (218, 222))	('High', 'Var', (0, 4))	('ENO1', 'Gene', '2023', (5, 9))	('expression', 'MPA', (10, 20))	('ENO1', 'Gene', (5, 9))	('CESC', 'Disease', (67, 71))	('KICH', 'Disease', 'None', (119, 123))	('KICH', 'Disease', (218, 222))	('SARC', 'Disease', (247, 251))	('KICH', 'Disease', (119, 123))	('BLCA', 'Disease', (93, 97))
18146	33643901	Evidently, 195 samples in the altered group and 10,772 samples in the unaltered group were included for ENO1 mutation analysis.	('ENO1', 'Gene', '2023', (104, 108))	('mutation', 'Var', (109, 117))	('ENO1', 'Gene', (104, 108))
18147	33643901	The results demonstrated that ENO1 was altered in 1.8% of all the included samples, including inframe mutation, missense mutation, truncating mutation, fusion, amplification, and deep deletion ( Figure 6 ).	('truncating', 'MPA', (131, 141))	('amplification', 'Var', (160, 173))	('ENO1', 'Gene', (30, 34))	('deep deletion', 'Var', (179, 192))	('ENO1', 'Gene', '2023', (30, 34))	('altered', 'Reg', (39, 46))	('fusion', 'Var', (152, 158))	('missense mutation', 'Var', (112, 129))
18148	33643901	Furthermore, the prognostic significance of ENO1 mutation was estimated via Kaplan-Meier method.	('ENO1', 'Gene', '2023', (44, 48))	('mutation', 'Var', (49, 57))	('ENO1', 'Gene', (44, 48))
18180	33643901	These findings are consistent with a previous study showing that high ENO1 expression is significantly correlated with DNA replication and cell cycle in hepatocellular carcinoma.	('DNA replication', 'CPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('DNA replication', 'biological_process', 'GO:0006260', ('119', '134'))	('ENO1', 'Gene', (70, 74))	('ENO1', 'Gene', '2023', (70, 74))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('expression', 'MPA', (75, 85))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('cell cycle', 'CPA', (139, 149))	('high', 'Var', (65, 69))	('hepatocellular carcinoma', 'Disease', (153, 177))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('cell cycle', 'biological_process', 'GO:0007049', ('139', '149'))	('correlated', 'Reg', (103, 113))
18188	33643901	Furthermore, the knockdown of ENO1 has been shown to promote apoptosis and induce the arrest of cell cycle in gastric cancer cells.	('gastric cancer', 'Disease', (110, 124))	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'CPA', (61, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ENO1', 'Gene', (30, 34))	('ENO1', 'Gene', '2023', (30, 34))	('knockdown', 'Var', (17, 26))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('induce', 'Reg', (75, 81))	('promote', 'PosReg', (53, 60))
18193	33643901	Additionally, mutation of ENO1 was analysis, for it was proved that mutation could affect tumor progression; however, ENO1 mutation (1.8%) did not impact on prognosis in this study.	('affect', 'Reg', (83, 89))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ENO1', 'Gene', (118, 122))	('tumor', 'Disease', (90, 95))	('ENO1', 'Gene', '2023', (118, 122))	('ENO1', 'Gene', (26, 30))	('ENO1', 'Gene', '2023', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
18197	33643901	In consonance with our results, ENO1 expression was higher in late stages (stages III and IV), particularly that in KICH ( Figure 5E ), meanwhile, high ENO1 expression was significantly associated with worse OS in KICH ( Figure 4I ).	('worse OS', 'Disease', (202, 210))	('expression', 'MPA', (157, 167))	('ENO1', 'Gene', (152, 156))	('KICH', 'Disease', 'None', (214, 218))	('ENO1', 'Gene', '2023', (32, 36))	('ENO1', 'Gene', '2023', (152, 156))	('ENO1', 'Gene', (32, 36))	('KICH', 'Disease', 'None', (116, 120))	('high', 'Var', (147, 151))	('associated', 'Reg', (186, 196))	('higher', 'PosReg', (52, 58))	('KICH', 'Disease', (214, 218))	('expression', 'MPA', (37, 47))	('KICH', 'Disease', (116, 120))
18237	30171176	Several studies have shown that the number of non-synonymous somatic mutations (i.e., somatic mutation burden) was positively correlated with the level of immune cell infiltration in multiple cancer types.	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('non-synonymous somatic mutations', 'Var', (46, 78))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
18238	30171176	Other than somatic mutations, copy number variation has been found to negatively correlated with immune cell infiltration across multiple cancer types, which was particularly evident in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('cancer', 'Disease', (138, 144))	('melanoma', 'Disease', (186, 194))	('immune cell infiltration', 'CPA', (97, 121))	('negatively', 'NegReg', (70, 80))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('copy number variation', 'Var', (30, 51))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('correlated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
18254	30171176	GSE65904 and GSE19234 include information on disease-specific survival (DSS) and post recurrence survival respectively, while TCGA-SKCM, GSE54467, GSE22155 and GSE8401 datasets have overall survival (OS).	('overall', 'MPA', (182, 189))	('SKCM', 'Disease', (131, 135))	('disease-specific', 'MPA', (45, 61))	('GSE19234', 'Var', (13, 21))	('GSE65904', 'Var', (0, 8))	('SKCM', 'Disease', 'MESH:C562393', (131, 135))
18277	30171176	We then pursued four directions to examine the function of LIS in melanoma; (i) its prognostic role in metastatic melanoma, (ii) the prognostic role of LIS in stage III melanoma, (iii) the prediction of responsiveness to MAGE-A3 immunotherapy treatment, and (iv) the association between LIS and genomic aberrations, including copy number variation and total mutation burden.	('LIS', 'molecular_function', 'GO:0034007', ('59', '62'))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', (66, 74))	('copy number variation', 'Var', (326, 347))	('LIS', 'molecular_function', 'GO:0034007', ('287', '290'))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('MAGE-A3', 'Gene', (221, 228))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('LIS', 'molecular_function', 'GO:0034007', ('152', '155'))	('MAGE-A3', 'Gene', '4102', (221, 228))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('association', 'Interaction', (267, 278))	('melanoma', 'Disease', (114, 122))
18300	30171176	Indeed, LIS was prognostic in TCGA melanoma dataset, where patients with a high LIS had better overall survival than patients with low LIS (HR=0.65, P=0.007; Figure 3A).	('LIS', 'molecular_function', 'GO:0034007', ('135', '138'))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('high', 'Var', (75, 79))	('LIS', 'molecular_function', 'GO:0034007', ('80', '83'))	('LIS', 'molecular_function', 'GO:0034007', ('8', '11'))	('overall survival', 'MPA', (95, 111))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (117, 125))	('better', 'PosReg', (88, 94))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
18311	30171176	Taken together, we concluded that patients having high Breslow thickness tended to have low LIS in both primary and metastatic tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('low', 'NegReg', (88, 91))	('tumor', 'Disease', (127, 132))	('LIS', 'molecular_function', 'GO:0034007', ('92', '95'))	('patients', 'Species', '9606', (34, 42))	('high Breslow thickness', 'Var', (50, 72))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
18313	30171176	To follow up with the reported heterogeneity of this disease, we first examined the association between LIS and mutational subtypes, which included mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type) groups.	('RAS', 'Gene', (168, 171))	('mutant', 'Var', (161, 167))	('BRAF', 'Gene', (155, 159))	('NF1', 'Gene', (180, 183))	('NF1', 'Gene', '4763', (180, 183))	('mutant', 'Var', (148, 154))	('mutant', 'Var', (173, 179))	('LIS', 'molecular_function', 'GO:0034007', ('104', '107'))	('BRAF', 'Gene', '673', (155, 159))
18324	30171176	To determine whether LIS could consistently predict prognosis in metastatic melanoma, we extended our analyses into four publicly available metastatic melanoma datasets (GEO accession number GSE65904, GSE22155, GSE8401 and GSE19234).	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('metastatic', 'Disease', (140, 150))	('LIS', 'molecular_function', 'GO:0034007', ('21', '24'))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('GSE22155', 'Var', (201, 209))	('melanoma', 'Disease', (151, 159))	('GSE19234', 'Var', (223, 231))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('GSE8401', 'Var', (211, 218))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
18339	30171176	Immune cell infiltration was associated with genomic features such as tumor mutation burden (TMB) and copy number variation (CNV).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('copy number variation', 'Var', (102, 123))	('tumor', 'Disease', (70, 75))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
18351	30171176	Notably, CDK4 amplification events are associated with decreased immune cell infiltration in the primary samples.	('immune cell infiltration in the primary', 'CPA', (65, 104))	('CDK4', 'Gene', (9, 13))	('CDK4', 'Gene', '1019', (9, 13))	('amplification events', 'Var', (14, 34))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('CDK', 'molecular_function', 'GO:0004693', ('9', '12'))	('decreased', 'NegReg', (55, 64))	('decreased immune cell', 'Phenotype', 'HP:0002721', (55, 76))
18352	30171176	In metastatic tumor samples, amplification of oncogenic "driver", KRAS, as well as deletion of DDX3X or CDKN2A, are associated with decreased immune cell infiltration (P=6E-5, CDK4, P=1E-3, KRAS, P=7E-7, DDX3X, P=2E-5, CDKN2A).	('amplification', 'Var', (29, 42))	('DDX3X', 'Gene', (95, 100))	('CDKN2A', 'Gene', '1029', (219, 225))	('CDK', 'molecular_function', 'GO:0004693', ('174', '177'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('DDX3X', 'Gene', (204, 209))	('KRAS', 'Gene', '3845', (66, 70))	('CDKN2A', 'Gene', (104, 110))	('DDX3X', 'Gene', '1654', (95, 100))	('immune cell infiltration', 'CPA', (142, 166))	('KRAS', 'Gene', (66, 70))	('CDK4', 'Gene', (176, 180))	('KRAS', 'Gene', '3845', (190, 194))	('DDX3X', 'Gene', '1654', (204, 209))	('deletion', 'Var', (83, 91))	('CDKN2A', 'Gene', '1029', (104, 110))	('tumor', 'Disease', (14, 19))	('KRAS', 'Gene', (190, 194))	('CDK4', 'Gene', '1019', (176, 180))	('CDKN2A', 'Gene', (219, 225))	('decreased', 'NegReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('decreased immune cell', 'Phenotype', 'HP:0002721', (132, 153))
18375	30171176	Patients with high TMB was more likely to benefit from immunotherapy and presented a prolonged survival.	('prolonged', 'PosReg', (85, 94))	('benefit', 'PosReg', (42, 49))	('high TMB', 'Var', (14, 22))	('Patients', 'Species', '9606', (0, 8))	('immunotherapy', 'CPA', (55, 68))	('survival', 'CPA', (95, 103))
18384	30171176	CDK4 amplification was associated with low immune cell infiltration in primary melanoma samples (Figure 6E).	('low immune cell', 'Phenotype', 'HP:0002721', (39, 54))	('amplification', 'Var', (5, 18))	('low', 'NegReg', (39, 42))	('CDK4', 'Gene', '1019', (0, 4))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('CDK4', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
18386	30171176	We also found that deletion of DDX3X or CDKN2A, known to participate in innate immunity, were associated with immune cell infiltration (Figure 6G-H).	('DDX3X', 'Gene', (31, 36))	('deletion', 'Var', (19, 27))	('DDX3X', 'Gene', '1654', (31, 36))	('CDKN2A', 'Gene', (40, 46))	('innate immunity', 'biological_process', 'GO:0045087', ('72', '87'))	('associated', 'Reg', (94, 104))	('CDKN2A', 'Gene', '1029', (40, 46))	('immune cell infiltration', 'CPA', (110, 134))
18388	30171176	Our findings provide an understanding of cancer biology in melanoma by showing which somatic mutation might influence the immune cell infiltration in the melanoma microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('immune cell infiltration', 'CPA', (122, 146))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('cancer', 'Disease', (41, 47))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Disease', (59, 67))	('influence', 'Reg', (108, 117))	('somatic mutation', 'Var', (85, 101))
18392	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))
18395	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))
18396	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))
18397	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))
18406	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'))
18408	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))
18409	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))
18414	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))
18421	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))
18422	21941004	Five patients with apparent breast cancer predisposition were negative for pathogenic BRCA1 and BRCA2 gene mutations based on clinical testing.	('mutations', 'Var', (107, 116))	('patients', 'Species', '9606', (5, 13))	('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))
18429	21941004	The three patients had germline mutation in BAP1.	('BAP1', 'Gene', (44, 48))	('BAP1', 'Gene', '8314', (44, 48))	('germline mutation', 'Var', (23, 40))	('patients', 'Species', '9606', (10, 18))
18430	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'))
18439	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))	('c.650-26T A', 'Var', (232, 243))	('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+117_118delCC', 'Mutation', 'c.931+117_118delCC', (258, 276))	('variants', 'Var', (16, 24))	('c.931+70A G', 'Var', (245, 256))
18441	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))
18442	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))	('variants', 'Var', (17, 25))	('meningioma', 'Disease', (95, 105))	('cancer', 'Disease', (208, 214))	('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))
18443	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))	('patient', 'Species', '9606', (157, 164))	('abdominal adenocarcinoma', 'Disease', 'MESH:D000008', (99, 123))	('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))
18444	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))
18449	21941004	Sequencing of the tumour tissues showed loss of the normal allele, indicating biallelic inactivation of BAP1 in these tumours (figure 2).	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumour', 'Disease', (118, 124))	('tumours', 'Disease', (118, 125))	('BAP1', 'Gene', '8314', (104, 108))	('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))
18452	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))
18453	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))
18454	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))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('meningioma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 80))	('cancer', 'Disease', (125, 131))	('BAP1', 'Gene', '8314', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('biallelic inactivation', 'Var', (4, 26))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('UM', 'Phenotype', 'HP:0007716', (42, 44))
18455	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))
18456	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))	('cancers', 'Disease', (14, 21))	('cancer', 'Disease', (14, 20))	('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))
18458	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))
18461	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))
18463	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))
18466	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'))	('tumours', 'Disease', (89, 96))	('BAP1', 'Gene', (241, 245))	('BAP1', 'Gene', '8314', (133, 137))	('UM', 'Phenotype', 'HP:0007716', (3, 5))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (158, 165))	('mutation', 'Var', (121, 129))	('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))
18467	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))
18471	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))
18474	21941004	In conclusion, we report a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers.	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (33, 59))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('caused by', 'Reg', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', (81, 85))	('lung carcinoma', 'Disease', 'MESH:D008175', (128, 142))	('meningioma', 'Disease', (144, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('hereditary cancer syndrome', 'Disease', (33, 59))	('meningioma', 'Phenotype', 'HP:0002858', (144, 154))	('cancers', 'Disease', (175, 182))	('germline', 'Var', (72, 80))	('predisposes', 'Reg', (100, 111))	('meningioma', 'Disease', 'MESH:D008577', (144, 154))	('lung carcinoma', 'Disease', (128, 142))	('patients', 'Species', '9606', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('mutation', 'Var', (86, 94))	('BAP1', 'Gene', '8314', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
18507	33836680	The CheckMate-026 clinical trial, a retrospective analysis, reported that: among NSCLC patients administered with immunotherapy, the remission rate and progression-free survival outcomes of the high-TMB group were significantly better than those of the low-TMB group.	('TMB', 'Chemical', '-', (257, 260))	('TMB', 'Chemical', '-', (199, 202))	('progression-free survival outcomes', 'CPA', (152, 186))	('high-TMB', 'Var', (194, 202))	('remission rate', 'CPA', (133, 147))	('better', 'PosReg', (228, 234))	('NSCLC', 'Disease', (81, 86))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
18516	33836680	TMB refers to the total number of substitutions, insertions, deletions, and mutant genes per megabase in the coding region (exon) of the gene assessed in the tumor tissue.	('tumor', 'Disease', (158, 163))	('deletions', 'Var', (61, 70))	('TMB', 'Chemical', '-', (0, 3))	('insertions', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('substitutions', 'Var', (34, 47))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutant genes', 'Var', (76, 88))
18532	33836680	In the grouping, missense mutations were the most common (Fig.	('missense mutations', 'Var', (17, 35))	('common', 'Reg', (50, 56))	('common (Fig', 'Species', '3494', (50, 61))
18535	33836680	The optimal cutoff for samples classified into better and worse survival groups was established by the 'surv_cutpoint' algorithm of survival R package, consistent with the recognition that higher TMB enhances immune recognition and leads to better disease outcomes.	('enhances', 'PosReg', (200, 208))	('TMB', 'Chemical', '-', (196, 199))	('better', 'PosReg', (241, 247))	('immune', 'MPA', (209, 215))	('disease outcomes', 'CPA', (248, 264))	('higher', 'Var', (189, 195))	('TMB', 'MPA', (196, 199))
18548	33836680	Figure 3c shows that the low-TMB group was associated with immunity, and was mainly concentrated in autoimmune thyroid disease, B and T cell receptor signaling pathways, as well as intestinal immune network for the production of IGA, while the high-TMB group lacked this function (Supplementary Table S3-4).	('autoimmune thyroid disease', 'Disease', (100, 126))	('thyroid disease', 'Phenotype', 'HP:0000820', (111, 126))	('TMB', 'Chemical', '-', (29, 32))	('autoimmune thyroid disease', 'Disease', 'MESH:D013967', (100, 126))	('immunity', 'Disease', (59, 67))	('T cell receptor signaling pathways', 'Pathway', (134, 168))	('associated', 'Reg', (43, 53))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('low-TMB', 'Var', (25, 32))	('TMB', 'Chemical', '-', (249, 252))
18560	33836680	The K-M plot revealed that high TMB-IP score patients exhibited worse survival outcomes (Fig.	('TMB-IP score', 'Gene', (32, 44))	('survival', 'MPA', (70, 78))	('IP', 'Chemical', 'MESH:C041508', (36, 38))	('high', 'Var', (27, 31))	('patients', 'Species', '9606', (45, 53))	('TMB', 'Chemical', '-', (32, 35))
18569	33836680	The link between the mutants of the 4 hub genes and immune infiltrates in the SKCM microenvironment was assesssed.	('mutants', 'Var', (21, 28))	('hub', 'Gene', (38, 41))	('hub', 'Gene', '1993', (38, 41))
18570	33836680	Based on the findings, immune infiltrate inhibitions, such as CD8+ T cells, dendritic cells, CD4+ T cells, neutrophils, B-cells, and macrophages depended on the type of mutation exhibited by the genes, relative to the levels of immune infiltration in the wild type samples (Fig.	('mutation', 'Var', (169, 177))	('CD8', 'Gene', (62, 65))	('CD8', 'Gene', '925', (62, 65))	('CD4', 'Gene', (93, 96))	('CD4', 'Gene', '920', (93, 96))
18571	33836680	We have shown that the DEGs negatively impacted on immune pathways and that mutants of the four hub genes were inversely correlated with immune infiltrates.	('immune pathways', 'Pathway', (51, 66))	('DEGs', 'Gene', '8560', (23, 27))	('hub', 'Gene', '1993', (96, 99))	('mutants', 'Var', (76, 83))	('DEGs', 'Gene', (23, 27))	('immune infiltrates', 'Disease', (137, 155))	('hub', 'Gene', (96, 99))	('impacted', 'Reg', (39, 47))	('negatively', 'NegReg', (28, 38))
18574	33836680	Wilcoxon rank test revealed that infiltration levels of CD8+ T cells, CD4+ memory activated T cells, follicular helper T cells, monocytes and macrophage M1 cells were reduced in the high-TMB group, relative to those in the low-TMB group (Fig.	('TMB', 'Chemical', '-', (227, 230))	('CD4', 'Gene', (70, 73))	('infiltration levels', 'MPA', (33, 52))	('TMB', 'Chemical', '-', (187, 190))	('CD8', 'Gene', (56, 59))	('CD4', 'Gene', '920', (70, 73))	('CD8', 'Gene', '925', (56, 59))	('reduced', 'NegReg', (167, 174))	('high-TMB', 'Var', (182, 190))	('memory', 'biological_process', 'GO:0007613', ('75', '81'))
18583	33836680	found that TMB is correlated with clinical benefits of immunotherapy, that is, the greater the number of somatic mutations, the more likely the tumor is to respond to ICB.	('tumor', 'Disease', (144, 149))	('TMB', 'Chemical', '-', (11, 14))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('respond to ICB', 'MPA', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
18590	33836680	reported that NSCLC patients with elevated non-synonymous mutation burdens can achieve long-term remission by immunotherapy, which is of paramount importance for PFS.	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('non-synonymous mutation burdens', 'Var', (43, 74))	('NSCLC', 'Disease', (14, 19))	('patients', 'Species', '9606', (20, 28))
18591	33836680	The CheckMate-227 trial, comparing nivolumab+ipilimumab, nivolumab, and chemotherapy, revealed that patients with high TMBs (> 10 mutations/Mb) have the best OS outcomes, supporting the validity of TMB-based treatment stratification.	('TMB', 'Chemical', '-', (119, 122))	('nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('ipilimumab', 'Chemical', 'MESH:D000074324', (45, 55))	('TMBs', 'Gene', (119, 123))	('patients', 'Species', '9606', (100, 108))	('nivolumab', 'Chemical', 'MESH:D000077594', (35, 44))	('> 10 mutations/Mb', 'Var', (125, 142))	('TMB', 'Chemical', '-', (198, 201))
18592	33836680	Differential expression analysis and GSEA showed that the low-TMB group was correlated with autoimmune thyroid disease, B-and T-cell receptor signaling pathways, and intestinal immune networks for IGA production.	('thyroid disease', 'Phenotype', 'HP:0000820', (103, 118))	('B-and T-cell receptor signaling pathways', 'Pathway', (120, 160))	('TMB', 'Chemical', '-', (62, 65))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('autoimmune thyroid disease', 'Disease', (92, 118))	('GSEA', 'Chemical', '-', (37, 41))	('low-TMB', 'Var', (58, 65))	('autoimmune thyroid disease', 'Disease', 'MESH:D013967', (92, 118))
18595	33836680	The close relationships between low-TMB and multiple immune-related pathways have been reported, but the specific mechanisms should be further evaluated.	('immune-related pathways', 'Pathway', (53, 76))	('TMB', 'Chemical', '-', (36, 39))	('low-TMB', 'Var', (32, 39))
18601	33836680	High TMB-IP score means high risk, and it has a relatively shorter median survival outcomes than the low TMB-IP score (low risk) group.	('High', 'Var', (0, 4))	('shorter', 'NegReg', (59, 66))	('IP', 'Chemical', 'MESH:C041508', (109, 111))	('median survival outcomes', 'MPA', (67, 91))	('IP', 'Chemical', 'MESH:C041508', (9, 11))	('TMB', 'Chemical', '-', (105, 108))	('TMB', 'Chemical', '-', (5, 8))	('TMB-IP', 'Gene', (5, 11))
18602	33836680	Furthermore, mutants of these hub immune genes were associated with immune infiltrates, such as CD8+ T cells, CD4+ T cells, dendritic cells, macrophages, and B-cells in the SKCM microenvironment, implying that these immune infiltrate cells might be suppressed by mutations.	('CD4', 'Gene', (110, 113))	('hub', 'Gene', (30, 33))	('associated', 'Reg', (52, 62))	('CD8', 'Gene', (96, 99))	('CD4', 'Gene', '920', (110, 113))	('CD8', 'Gene', '925', (96, 99))	('immune infiltrates', 'Disease', (68, 86))	('mutants', 'Var', (13, 20))	('hub', 'Gene', '1993', (30, 33))
18606	33836680	It has been found that immune cell activation in the tumor microenvironment is not the same in different tumor types, even in the same mutation feature, therefore, a specific analysis is needed.	('tumor', 'Disease', (105, 110))	('immune cell activation', 'biological_process', 'GO:0045321', ('23', '45'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (53, 58))	('mutation', 'Var', (135, 143))
18608	33836680	There were immune cells with higher infiltration levels in the high-TMB group, and specific reasons for this outcome are worthy of further investigations.	('higher', 'PosReg', (29, 35))	('infiltration levels', 'MPA', (36, 55))	('high-TMB', 'Var', (63, 71))	('TMB', 'Chemical', '-', (68, 71))
18617	33836680	The four TMB-related immune gene model can effectively differentiate between high and low-risk patients, moreover, mutants of the four hub genes confer lower immune cell infiltration, which should be further validated.	('patients', 'Species', '9606', (95, 103))	('hub', 'Gene', (135, 138))	('immune cell infiltration', 'CPA', (158, 182))	('mutants', 'Var', (115, 122))	('lower', 'NegReg', (152, 157))	('TMB', 'Chemical', '-', (9, 12))	('hub', 'Gene', '1993', (135, 138))
18618	33836680	AUC Area under the curve CI Confidence interval DEGs Differentially expressed genes DSS Disease Specific Survival GO Gene ontology GSEA Gene Set Enrichment Analysis HR Hazard ratio ICB Immunocheck point blockade OS Overall Survival PFI Progression Free Interval ROC curve Receiver operating characteristic curve SKCM Skin Cutaneous Melanoma SNP Single nucleotide polymorphism SNV Single nucleotide variant TCGA The Cancer Genome Atlas TMB Tumor mutation burden (I) Conception and design: LWW and ZJY; (II) Performed data analysis and created the figures/tables: FC and RL; (III) Data analysis and interpretation: LWW, LS, and GSZ; (IV) Manuscript drafting and editing: All authors; (V) Final approval of manuscript: All authors.	('DSS', 'Gene', (84, 87))	('DEGs', 'Gene', (48, 52))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (317, 340))	('GSEA', 'Chemical', '-', (131, 135))	('DSS', 'Gene', '5376', (84, 87))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (322, 340))	('Gene ontology', 'biological_process', 'GO:0003673', ('117', '130'))	('Tumor', 'Phenotype', 'HP:0002664', (439, 444))	('Cancer', 'Disease', (415, 421))	('DEGs', 'Gene', '8560', (48, 52))	('Melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('Cancer', 'Disease', 'MESH:D009369', (415, 421))	('Cancer', 'Phenotype', 'HP:0002664', (415, 421))	('Skin Cutaneous Melanoma', 'Disease', (317, 340))	('PFI', 'molecular_function', 'GO:0034016', ('232', '235'))	('TMB', 'Chemical', '-', (435, 438))	('Single nucleotide variant', 'Var', (380, 405))
18625	25954764	NY-ESO-1 expression was also associated with reduced numbers and density of CD3+ tumor infiltrating lymphocytes (P = 0.017).	('expression', 'Var', (9, 19))	('NY-ESO-1', 'Gene', (0, 8))	('reduced', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('reduced numbers and density of CD3+ tumor', 'Phenotype', 'HP:0045080', (45, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('NY-ESO-1', 'Gene', '246100', (0, 8))
18626	25954764	When NY-ESO-1 protein was expressed, CD3+ T cells were less diffusely infiltrating the tumor and were more often arranged in small clusters (P = 0.010) or as isolated cells (P = 0.002) than in large clusters of more than five lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CD3+', 'Var', (37, 41))	('tumor', 'Disease', (87, 92))	('NY-ESO-1', 'Gene', '246100', (5, 13))	('NY-ESO-1', 'Gene', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('less', 'NegReg', (55, 59))
18659	25954764	We assessed cutaneous melanomas having all tumor thickness: <=1.0 mm (n = 24, 30%); 1.01-2.0 mm (n = 23, 29%); 2.01-4.0 mm (n = 6, 8%); and >4.0 mm (n = 26, 33%).	('>4.0 mm', 'Var', (140, 147))	('2.01-4.0 mm', 'Var', (111, 122))	('<=1.0 mm', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (12, 31))	('1.01-2.0 mm', 'Var', (84, 95))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (12, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (12, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('cutaneous melanomas', 'Disease', (12, 31))
18677	25954764	CD3+ T cells were more numerous in tumors negative for NY-ESO-1 (P = 0.017, Figure 4).	('NY-ESO-1', 'Gene', '246100', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NY-ESO-1', 'Gene', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('CD3+', 'Var', (0, 4))
18681	25954764	Given the dogma that cancer-testis antigens, such as NY-ESO-1, are associated only with cancer, any presence of NY-ESO-1 would indicate malignancy.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('malignancy', 'Disease', (136, 146))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('indicate', 'Reg', (127, 135))	('NY-ESO-1', 'Gene', '246100', (53, 61))	('NY-ESO-1', 'Gene', '246100', (112, 120))	('NY-ESO-1', 'Gene', (112, 120))	('cancer-testis', 'Disease', (21, 34))	('cancer', 'Disease', (21, 27))	('NY-ESO-1', 'Gene', (53, 61))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('cancer-testis', 'Disease', 'MESH:D013736', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('presence', 'Var', (100, 108))
18693	25954764	In another one, which analyzed 61 cutaneous melanomas, the NY-ESO-1 positive tumors had a median thickness of 4.7 mm versus 1.53 mm in the NY-ESO-1 negative group.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('positive', 'Var', (68, 76))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (34, 53))	('NY-ESO-1', 'Gene', (59, 67))	('NY-ESO-1', 'Gene', '246100', (59, 67))	('cutaneous melanomas', 'Disease', (34, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('NY-ESO-1', 'Gene', '246100', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NY-ESO-1', 'Gene', (139, 147))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (34, 53))
18706	25954764	It is well established that the presence of TIL is associated with better prognosis in melanoma.	('melanoma', 'Disease', (87, 95))	('presence', 'Var', (32, 40))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
18711	25954764	Similar to the protective effect reported for TIL in general, CD3+ cells in particular have been associated with improved survival in cancer.	('survival', 'CPA', (122, 130))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('CD3+ cells', 'Var', (62, 72))	('improved', 'PosReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
18787	16999866	As HMB45 is known to stain non-melanoma cells in SLN, incorporation of HMB45 in the cocktail used in this study may have contributed further to a reduction in the specificity.	('HMB45', 'Gene', (71, 76))	('specificity', 'MPA', (163, 174))	('incorporation', 'Var', (54, 67))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('reduction', 'NegReg', (146, 155))
18793	28380455	Targeted next generation sequencing of mucosal melanomas identifies frequent NF1 and RAS mutations Mucosal melanoma represents ~1% of all melanomas, frequently having a poor prognosis due to diagnosis at a late stage of disease.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('Mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('NF1', 'Gene', (77, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (39, 56))	('NF1', 'Gene', '4763', (77, 80))	('Mucosal melanoma', 'Disease', (99, 115))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('melanomas', 'Disease', (138, 147))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutations', 'Var', (89, 98))	('RAS', 'Gene', (85, 88))	('mucosal melanomas', 'Disease', (39, 56))	('melanomas', 'Disease', (47, 56))
18795	28380455	less BRAF and more frequent KIT mutations than cutaneous melanomas.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (47, 66))	('KIT', 'Gene', (28, 31))	('BRAF', 'Gene', '673', (5, 9))	('cutaneous melanomas', 'Disease', (47, 66))	('BRAF', 'Gene', (5, 9))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mutations', 'Var', (32, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('less', 'NegReg', (0, 4))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (47, 66))
18799	28380455	Mutations in BRAF were identified in 8.4% and KIT in 7.0% of tumor samples.	('BRAF', 'Gene', '673', (13, 17))	('KIT', 'molecular_function', 'GO:0005020', ('46', '49'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
18803	28380455	Our data indicate that in mucosal melanomas RAS/NF1 alterations are frequent, implying a significant pathogenetic role for MAPK and potentially PI3K pathway activation in these tumors.	('NF1', 'Gene', '4763', (48, 51))	('alterations', 'Var', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('MAPK', 'molecular_function', 'GO:0004707', ('123', '127'))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('PI3K', 'molecular_function', 'GO:0016303', ('144', '148'))	('activation', 'PosReg', (157, 167))	('mucosal melanomas RAS', 'Disease', (26, 47))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('tumors', 'Disease', (177, 183))	('mucosal melanomas RAS', 'Disease', 'MESH:D008545', (26, 47))	('NF1', 'Gene', (48, 51))
18810	28380455	gene amplifications or gain-of-function mutations of KIT are more frequently detected in mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('gain-of-function', 'PosReg', (23, 39))	('mucosal melanomas', 'Disease', (89, 106))	('mutations', 'Var', (40, 49))	('mucosal melanomas', 'Disease', 'MESH:D008545', (89, 106))	('KIT', 'Gene', (53, 56))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))
18813	28380455	NRAS mutations are somewhat less frequent in mucosal (10-20%) than cutaneous melanomas (20-30%).	('mucosal', 'Disease', (45, 52))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('NRAS', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('NRAS', 'Gene', '4893', (0, 4))	('cutaneous melanomas', 'Disease', (67, 86))
18816	28380455	Our study aimed to identify additional oncogenic driver mutations in mucosal melanoma in a larger cohort of patients to recognize additional molecular pathways with the potential to be exploited for establishing future therapeutic strategies.	('mutations', 'Var', (56, 65))	('mucosal melanoma', 'Disease', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (69, 85))	('patients', 'Species', '9606', (108, 116))
18819	28380455	NF1 and RAS were the most frequently mutated genes (Figure 2, Supplementary Figure 1 and 2, Table 2, Supplementary Table 1), with 15 NF1 mutations identified in 13 samples (18.3.%) and 12 RAS mutations identified in 12 samples (16.9%).	('identified', 'Reg', (147, 157))	('NF1', 'Gene', (133, 136))	('mutations', 'Var', (137, 146))	('NF1', 'Gene', '4763', (133, 136))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
18820	28380455	In 9 out of 13 samples (69.2%) a clearly inactivating NF1 mutation was present resulting in non-sense (synthesis stop) or frameshift mutations.	('frameshift mutations', 'Var', (122, 142))	('NF1', 'Gene', '4763', (54, 57))	('NF1', 'Gene', (54, 57))	('inactivating', 'NegReg', (41, 53))	('synthesis', 'biological_process', 'GO:0009058', ('103', '112'))
18821	28380455	Examples of some inactivating NF1 mutations detected in our cohort are shown in Supplementary Figure 1.	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('mutations', 'Var', (34, 43))	('inactivating', 'Reg', (17, 29))
18822	28380455	Two samples harbored multiple NF1 mutations (Table 2, Supplementary Table 1); one of them having two inactivating mutations, the other one having an inactivating and a D896N missense mutation.	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('D896N missense', 'Var', (168, 182))	('mutations', 'Var', (34, 43))	('D896N', 'Mutation', 'rs1189816828', (168, 173))
18823	28380455	RAS gene alterations were found in 12 out of 71 samples (16.9%), including 8 NRAS and 4 KRAS mutations.	('NRAS', 'Gene', (77, 81))	('RAS gene', 'Gene', (0, 8))	('alterations', 'Var', (9, 20))	('found', 'Reg', (26, 31))	('KRAS', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (77, 81))	('KRAS', 'Gene', '3845', (88, 92))
18824	28380455	Sanger sequencing was performed to validate the identified KRAS mutations (Supplementary Figure 3).	('KRAS', 'Gene', '3845', (59, 63))	('KRAS', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))
18825	28380455	Six samples (8.4%) harbored BRAF mutations, 5 of which were activating V600 mutations (4 V600E and 1 V600K) and 1 N188S mutation (Supplementary Table 2).	('activating', 'PosReg', (60, 70))	('BRAF', 'Gene', '673', (28, 32))	('V600K', 'Var', (101, 106))	('N188S', 'Mutation', 'rs770678769', (114, 119))	('V600', 'Gene', (71, 75))	('V600K', 'Mutation', 'rs121913227', (101, 106))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('BRAF', 'Gene', (28, 32))	('V600E', 'Var', (89, 94))
18826	28380455	The mutation pattern on protein level for the identified NRAS, KRAS and NF1 mutations are shown in Figure 2.	('NF1', 'Gene', (72, 75))	('KRAS', 'Gene', '3845', (63, 67))	('mutations', 'Var', (76, 85))	('NF1', 'Gene', '4763', (72, 75))	('NRAS', 'Gene', (57, 61))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('NRAS', 'Gene', '4893', (57, 61))	('KRAS', 'Gene', (63, 67))
18827	28380455	Another 4 samples carried known activating TERT-promoter mutations.	('mutations', 'Var', (57, 66))	('TERT', 'Gene', (43, 47))	('TERT', 'Gene', '7015', (43, 47))
18828	28380455	One GNA11 S267F mutation and 1 GNAQ R183Q mutation were identified.	('S267F', 'Mutation', 'rs765491785', (10, 15))	('GNAQ', 'Gene', (31, 35))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', (4, 9))	('R183Q', 'Mutation', 'rs397514698', (36, 41))	('GNA11', 'Gene', '2767', (4, 9))	('S267F', 'Var', (10, 15))
18829	28380455	Three samples harboring KRAS mutations also had concurrent NF1 mutations, 2 of which were clearly functionally inactivating.	('mutations', 'Var', (63, 72))	('KRAS', 'Gene', '3845', (24, 28))	('mutations', 'Var', (29, 38))	('NF1', 'Gene', (59, 62))	('NF1', 'Gene', '4763', (59, 62))	('KRAS', 'Gene', (24, 28))
18830	28380455	Additionally, 5 TP53, 7 SF3B1, 4 MITF and 3 PTEN mutations were identified.	('MITF', 'Gene', (33, 37))	('mutations', 'Var', (49, 58))	('MITF', 'Gene', '4286', (33, 37))	('SF3B1', 'Gene', (24, 29))	('PTEN', 'Gene', (44, 48))	('TP53', 'Gene', '7157', (16, 20))	('PTEN', 'Gene', '5728', (44, 48))	('SF3B1', 'Gene', '23451', (24, 29))	('TP53', 'Gene', (16, 20))
18831	28380455	Other less frequent mutations were identified in various genes including SMARC, BAP1, TERT, WT1, PIK3CA, MAP2K2, CDK4, CTNNB1, RAC1, ARID2 and ARID1A.	('WT1', 'Gene', (92, 95))	('BAP1', 'Gene', '8314', (80, 84))	('TERT', 'Gene', (86, 90))	('TERT', 'Gene', '7015', (86, 90))	('PIK3CA', 'Gene', '5290', (97, 103))	('WT1', 'Gene', '7490', (92, 95))	('ARID2', 'Gene', '196528', (133, 138))	('CDK4', 'Gene', (113, 117))	('MAP2K2', 'Gene', '5605', (105, 111))	('BAP1', 'Gene', (80, 84))	('CTNNB1', 'Gene', '1499', (119, 125))	('RAC1', 'Gene', (127, 131))	('CDK', 'molecular_function', 'GO:0004693', ('113', '116'))	('CDK4', 'Gene', '1019', (113, 117))	('SMARC', 'Gene', (73, 78))	('RAC1', 'Gene', '5879', (127, 131))	('ARID1A', 'Gene', (143, 149))	('ARID2', 'Gene', (133, 138))	('MAP2K', 'molecular_function', 'GO:0004708', ('105', '110'))	('PIK3CA', 'Gene', (97, 103))	('mutations', 'Var', (20, 29))	('CTNNB1', 'Gene', (119, 125))	('ARID1A', 'Gene', '8289', (143, 149))	('MAP2K2', 'Gene', (105, 111))
18832	28380455	We performed a statistical analysis to assess possible associations of clinical parameters such as gender, location of the primary tumor and sample type (primary, metastasis or recurrence) with the NF1, RAS and RAF mutational status.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('metastasis', 'Disease', 'MESH:D009362', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('NF1', 'Gene', (198, 201))	('RAS', 'Protein', (203, 206))	('mutational', 'Var', (215, 225))	('metastasis', 'Disease', (163, 173))	('RAF', 'Gene', (211, 214))	('tumor', 'Disease', (131, 136))	('NF1', 'Gene', '4763', (198, 201))	('RAF', 'Gene', '22882', (211, 214))
18833	28380455	In this study, 71 mucosal melanoma samples were screened for mutations in known recurrently mutated genes in cutaneous and uveal melanoma.	('mucosal melanoma', 'Disease', (18, 34))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (123, 137))	('mucosal melanoma', 'Disease', 'MESH:D008545', (18, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (123, 137))	('uveal melanoma', 'Disease', (123, 137))
18834	28380455	The most frequent mutations were identified in the NF1 gene and RAS gene family members, indicating that mucosal melanomas have a genetic mutation profile which is different from that of cutaneous or uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (200, 215))	('mucosal melanomas', 'Disease', 'MESH:D008545', (105, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (200, 214))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('uveal melanomas', 'Phenotype', 'HP:0007716', (200, 215))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('NF1', 'Gene', (51, 54))	('uveal melanomas', 'Disease', (200, 215))	('mucosal melanomas', 'Disease', (105, 122))	('NF1', 'Gene', '4763', (51, 54))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('mutations', 'Var', (18, 27))
18835	28380455	Our study identified an unexpectedly high number of NF1 mutations.	('NF1', 'Gene', (52, 55))	('mutations', 'Var', (56, 65))	('NF1', 'Gene', '4763', (52, 55))
18836	28380455	In 13 (18.3,%) out of 71 samples, NF1 mutations were identified.	('mutations', 'Var', (38, 47))	('NF1', 'Gene', '4763', (34, 37))	('NF1', 'Gene', (34, 37))
18837	28380455	To our knowledge, there is no previous data demonstrating that mucosal melanomas express such a high frequency of NF1 mutations.	('NF1', 'Gene', '4763', (114, 117))	('mutations', 'Var', (118, 127))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mucosal melanomas', 'Disease', (63, 80))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (63, 80))	('NF1', 'Gene', (114, 117))
18838	28380455	recently conducted a targeted sequencing analysis on 15 anorectal melanomas and identified that 3 of these tumors harbored an NF1 mutation.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('anorectal', 'Disease', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutation', 'Var', (130, 138))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('harbored', 'Reg', (114, 122))	('melanomas', 'Disease', (66, 75))	('NF1', 'Gene', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('NF1', 'Gene', '4763', (126, 129))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))
18840	28380455	In cutaneous melanomas, more than half of the mutations reported are loss-of-function (LoF) events.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (3, 22))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (3, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('mutations', 'Var', (46, 55))	('cutaneous melanomas', 'Disease', (3, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('loss-of-function', 'NegReg', (69, 85))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))
18841	28380455	In the mucosal melanomas studied here, 9 out of 13 cases carried NF1 LoF mutations (69.2%).	('LoF', 'NegReg', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('mucosal melanomas', 'Disease', (7, 24))	('mutations', 'Var', (73, 82))	('NF1', 'Gene', (65, 68))	('mucosal melanomas', 'Disease', 'MESH:D008545', (7, 24))	('NF1', 'Gene', '4763', (65, 68))
18843	28380455	As such, LoF mutations in NF1 are an important genetic mechanism for constitutive MAPK pathway activation.	('LoF', 'NegReg', (9, 12))	('NF1', 'Gene', (26, 29))	('activation', 'PosReg', (95, 105))	('NF1', 'Gene', '4763', (26, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('mutations', 'Var', (13, 22))
18844	28380455	A relevant role for NF1 mutations in cutaneous melanomas lacking conventional (i.e.	('cutaneous melanomas', 'Disease', (37, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (37, 56))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (37, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (37, 55))	('NF1', 'Gene', (20, 23))	('mutations', 'Var', (24, 33))	('NF1', 'Gene', '4763', (20, 23))
18846	28380455	demonstrated that desmoplastic melanomas frequently harbor NF1 mutations.	('mutations', 'Var', (63, 72))	('desmoplastic melanomas', 'Disease', (18, 40))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (18, 40))	('NF1', 'Gene', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('NF1', 'Gene', '4763', (59, 62))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))
18847	28380455	Desmoplastic melanomas are typically associated with high UV-exposure and high mutational loads.	('Desmoplastic melanomas', 'Disease', (0, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('Desmoplastic melanomas', 'Disease', 'MESH:D008545', (0, 22))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('associated', 'Reg', (37, 47))	('mutational loads', 'Var', (79, 95))
18848	28380455	described NF1 mutations in association with mutations in RASopathy genes (e.g.	('RASopathy', 'Disease', (57, 66))	('mutations', 'Var', (44, 53))	('NF1', 'Gene', '4763', (10, 13))	('RASopathy', 'Disease', 'None', (57, 66))	('NF1', 'Gene', (10, 13))	('association', 'Reg', (27, 38))	('mutations', 'Var', (14, 23))
18851	28380455	The association of UV-exposure with NF1 mutations observed in cutaneous melanoma is not to be expected in mucosal melanoma.	('cutaneous melanoma', 'Disease', (62, 80))	('NF1', 'Gene', (36, 39))	('mucosal melanoma', 'Disease', (106, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('NF1', 'Gene', '4763', (36, 39))	('mucosal melanoma', 'Disease', 'MESH:D008545', (106, 122))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
18852	28380455	Although mutational mechanisms may differ, these studies and our data support NF1 mutations being highly relevant in melanoma subgroups that rarely harbor BRAF or NRAS mutations.	('BRAF', 'Gene', (155, 159))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('NRAS', 'Gene', (163, 167))	('NRAS', 'Gene', '4893', (163, 167))	('NF1', 'Gene', (78, 81))	('mutations', 'Var', (82, 91))	('NF1', 'Gene', '4763', (78, 81))	('BRAF', 'Gene', '673', (155, 159))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
18853	28380455	Twelve out of 71 (16.9%) mucosal melanomas analyzed harbored RAS mutations, 8 in the NRAS and 4 in the KRAS gene.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mucosal melanomas', 'Disease', (25, 42))	('NRAS', 'Gene', (85, 89))	('harbored', 'Reg', (52, 60))	('NRAS', 'Gene', '4893', (85, 89))	('mucosal melanomas', 'Disease', 'MESH:D008545', (25, 42))	('RAS', 'Gene', (61, 64))	('mutations', 'Var', (65, 74))
18855	28380455	The frequency of NRAS mutations detected in our study with 11.2% is comparable.	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('NRAS', 'Gene', (17, 21))
18856	28380455	KRAS mutations have not been assessed in most previous studies of mucosal melanoma, however, accounted for one third of the mutations in RAS genes observed in our cohort.	('mutations', 'Var', (124, 133))	('mucosal melanoma', 'Disease', (66, 82))	('RAS genes', 'Gene', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mucosal melanoma', 'Disease', 'MESH:D008545', (66, 82))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
18858	28380455	Of the 6 mutations (8.4%) identified, 5 were well known V600 activating mutations, consisting of 4 V600E and 1 V600K mutation.	('V600K', 'Var', (111, 116))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('V600K', 'Mutation', 'rs121913227', (111, 116))	('V600', 'Gene', (56, 60))	('V600E', 'Var', (99, 104))
18860	28380455	These findings are in accordance with reports stating that activating BRAF mutations in mucosal melanomas are rare with a frequency between 5 and 17%.	('mucosal melanomas', 'Disease', (88, 105))	('mucosal melanomas', 'Disease', 'MESH:D008545', (88, 105))	('mutations', 'Var', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BRAF', 'Gene', '673', (70, 74))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('BRAF', 'Gene', (70, 74))
18863	28380455	Genetic alterations of KIT, including mutations and copy number increases, have been reported to occur in up to 39% of mucosal melanomas.	('mucosal melanomas', 'Disease', (119, 136))	('copy number increases', 'Var', (52, 73))	('occur', 'Reg', (97, 102))	('KIT', 'Gene', (23, 26))	('mucosal melanomas', 'Disease', 'MESH:D008545', (119, 136))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('mutations', 'Var', (38, 47))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))
18864	28380455	In our study, 5 out of 71 (7.0%) samples had a KIT mutation; 2 mutations in tumors of the head and neck region and 2 in vulvar melanomas.	('vulvar melanomas', 'Phenotype', 'HP:0030418', (120, 136))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('vulvar melanomas', 'Disease', (120, 136))	('vulvar melanomas', 'Disease', 'MESH:D008545', (120, 136))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('KIT', 'Gene', (47, 50))	('mutation', 'Var', (51, 59))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('neck', 'cellular_component', 'GO:0044326', ('99', '103'))
18865	28380455	reported KIT mutations in 17% (n=12) of primary mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mucosal melanomas', 'Disease', (48, 65))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (48, 65))	('mutations', 'Var', (13, 22))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
18866	28380455	They found that 35% (8 out of 23) of vulvar melanomas harbored KIT mutations.	('vulvar melanomas', 'Phenotype', 'HP:0030418', (37, 53))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('vulvar melanomas', 'Disease', (37, 53))	('vulvar melanomas', 'Disease', 'MESH:D008545', (37, 53))	('mutations', 'Var', (67, 76))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('harbored', 'Reg', (54, 62))	('KIT', 'Gene', (63, 66))
18868	28380455	Generally, our findings support existing literature stating that KIT mutations are more frequent in melanomas of the genital area followed by melanomas of the head and neck and the anorectal area.	('mutations', 'Var', (69, 78))	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('KIT', 'Gene', (65, 68))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('frequent', 'Reg', (88, 96))	('anorectal area', 'Phenotype', 'HP:0012732', (181, 195))	('neck', 'cellular_component', 'GO:0044326', ('168', '172'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanomas', 'Disease', (100, 109))	('melanomas', 'Disease', (142, 151))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
18869	28380455	TERT promoter mutations resulting in increased transcription of the TERT gene have been identified as the most common mutation in cutaneous melanoma.	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('transcription', 'MPA', (47, 60))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('increased', 'PosReg', (37, 46))	('cutaneous melanoma', 'Disease', (130, 148))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))	('mutations', 'Var', (14, 23))
18871	28380455	All TERT mutations were C>T mutations.	('C>T mutations', 'Var', (24, 37))	('TERT', 'Gene', '7015', (4, 8))	('TERT', 'Gene', (4, 8))
18872	28380455	As C>T alterations are classically associated with UV-exposure, the lower TERT mutation frequency may be due to the very limited UV-exposure of tumors arising in mucosal locations.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('TERT', 'Gene', '7015', (74, 78))	('C>T alterations', 'Var', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('TERT', 'Gene', (74, 78))
18874	28380455	Of those, only the GNAQ R183Q mutation is known to be functionally activating, resulting in increased mitogenic signaling in melanocytic tumors and rare vascular diseases such as Sturge-Weber syndrome and phakomatosis pigmentovascularis.	('Weber syndrome', 'Phenotype', 'HP:0002277', (186, 200))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GNAQ', 'Gene', (19, 23))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (179, 200))	('phakomatosis pigmentovascularis', 'Disease', 'MESH:D020752', (205, 236))	('mitogenic signaling', 'MPA', (102, 121))	('vascular diseases', 'Disease', (153, 170))	('melanocytic tumors', 'Disease', (125, 143))	('vascular diseases', 'Disease', 'MESH:D000783', (153, 170))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('increased', 'PosReg', (92, 101))	('GNAQ', 'Gene', '2776', (19, 23))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('phakomatosis pigmentovascularis', 'Disease', (205, 236))	('R183Q', 'Var', (24, 29))	('Sturge-Weber syndrome', 'Disease', (179, 200))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('R183Q', 'Mutation', 'rs397514698', (24, 29))
18876	28380455	While GNAQ and GNA11 mutations were recently reported to occur in 9.5% of mucosal melanomas, our study suggests these mutations are less frequent in this tumor entity.	('GNA11', 'Gene', (15, 20))	('mutations', 'Var', (21, 30))	('mucosal melanomas', 'Disease', 'MESH:D008545', (74, 91))	('GNAQ', 'Gene', '2776', (6, 10))	('GNA11', 'Gene', '2767', (15, 20))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('GNAQ', 'Gene', (6, 10))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mucosal melanomas', 'Disease', (74, 91))	('tumor', 'Disease', (154, 159))
18877	28380455	In out cohort, 31 samples presented mutations in the MAPK pathway (some of them harboring more than one mutation): 13 NF1, 12 RAS, 6 RAF, 5 KIT, 1 GNAQ and 1 GNA11 mutation.	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('mutations', 'Var', (36, 45))	('GNA11', 'Gene', (158, 163))	('NF1, 12 RAS, 6 RAF, 5 KIT, 1 GNAQ and 1', 'Gene', '4763', (118, 157))	('MAPK pathway', 'Pathway', (53, 65))	('KIT', 'molecular_function', 'GO:0005020', ('140', '143'))	('GNA11', 'Gene', '2767', (158, 163))
18878	28380455	In 23 of those samples mutations resulting in MAPK activation were found suggesting that this is a critical event in the pathogenesis of mucosal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('MAPK activation', 'biological_process', 'GO:0000187', ('46', '61'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (137, 153))	('mutations', 'Var', (23, 32))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('pathogenesis', 'biological_process', 'GO:0009405', ('121', '133'))	('MAPK', 'Gene', (46, 50))	('activation', 'PosReg', (51, 61))	('mucosal melanoma', 'Disease', (137, 153))
18882	28380455	Our results underline that mucosal melanomas are genetically distinct from cutaneous and uveal melanomas with frequent inactivating mutations in NF1 and activating mutations in RAS genes.	('NF1', 'Gene', '4763', (145, 148))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('uveal melanomas', 'Disease', (89, 104))	('uveal melanomas', 'Phenotype', 'HP:0007716', (89, 104))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('RAS', 'Gene', (177, 180))	('mucosal melanomas', 'Disease', (27, 44))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (89, 104))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('activating', 'PosReg', (153, 163))	('mucosal melanomas', 'Disease', 'MESH:D008545', (27, 44))	('inactivating mutations', 'Var', (119, 141))	('NF1', 'Gene', (145, 148))
18884	28380455	Taken into consideration that both NF1 and RAS alterations can additionally activate PI3K signaling, this pathway could be of particular significance in mucosal melanomas.	('PI3K signaling', 'Pathway', (85, 99))	('mucosal melanomas', 'Disease', 'MESH:D008545', (153, 170))	('PI3K', 'molecular_function', 'GO:0016303', ('85', '89'))	('activate', 'PosReg', (76, 84))	('PI3K signaling', 'biological_process', 'GO:0014065', ('85', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('alterations', 'Var', (47, 58))	('NF1', 'Gene', (35, 38))	('mucosal melanomas', 'Disease', (153, 170))	('NF1', 'Gene', '4763', (35, 38))
18885	28380455	It stands to reason that other, so far unidentified, mutations are present in mucosal melanomas and future whole-exome or whole-genome studies of larger tumor cohorts will be required to fully elucidate the landscape of genetic alterations involved.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mucosal melanomas', 'Disease', (78, 95))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('mucosal melanomas', 'Disease', 'MESH:D008545', (78, 95))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
18894	28380455	All known recurrent mutations in melanoma (incl.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))
18895	28380455	BRAF V600, NRAS G12, G13 and Q61 and KIT L576, K642 and N822) were repeatedly picked up by our NGS panel which showed a 100% concordance with mutations identified by Sanger sequencing, however demonstrated a higher level of sensitivity.	('Q61', 'Var', (29, 32))	('N822', 'Var', (56, 60))	('NRAS', 'Gene', '4893', (11, 15))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('K642 and N822', 'Var', (47, 60))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (11, 15))	('G13', 'Var', (21, 24))
18899	28380455	The CLC generated csv files were further analyzed manually with mutations affecting the protein-coding portion of the gene considered if predicted to result in non-synonymous amino acid changes.	('CLC', 'Gene', '1178', (4, 7))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('mutations', 'Var', (64, 73))	('CLC', 'Gene', (4, 7))
18901	28364002	Tissue-specific signaling networks rewired by major somatic mutations in human cancer revealed by proteome-wide discovery Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology.	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('human', 'Species', '9606', (73, 78))	('cancer', 'Disease', (168, 174))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('oncology', 'Phenotype', 'HP:0002664', (270, 278))
18902	28364002	Dysfunction of protein post-translational modification plays critical roles in tumorigenesis and drug responses.	('drug responses', 'CPA', (97, 111))	('Dysfunction', 'Var', (0, 11))	('tumor', 'Disease', (79, 84))	('post-translational modification', 'biological_process', 'GO:0043687', ('23', '54'))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('protein', 'Protein', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
18903	28364002	In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses.	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('signaling', 'biological_process', 'GO:0023052', ('194', '203'))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('signaling networks', 'Pathway', (194, 212))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('KNMPx', 'Chemical', '-', (136, 141))	('tumor', 'Disease', (239, 244))	('cancer', 'Disease', (261, 267))	('mutations', 'Var', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
18904	28364002	Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated non-redundant phosphorylation sites covering 18,610 proteins.	('tumor', 'Disease', (64, 69))	('missense mutations', 'Var', (36, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))	('Cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
18905	28364002	We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis.	('ERBB2', 'Gene', (36, 41))	('ERBB2', 'Gene', '2064', (36, 41))	('pan-cancer', 'Disease', 'MESH:C537931', (132, 142))	('missense mutations', 'Var', (79, 97))	('CTNNB1', 'Gene', '1499', (53, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('TP53', 'Gene', (43, 47))	('CTNNB1', 'Gene', (53, 59))	('pan-cancer', 'Disease', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
18908	28364002	Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways.	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('PI3K', 'molecular_function', 'GO:0016303', ('245', '249'))	('EGF', 'Pathway', (234, 237))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PI3K', 'Pathway', (245, 249))	('mutations', 'Var', (94, 103))	('EGF', 'molecular_function', 'GO:0005154', ('234', '237'))	('MAPK', 'molecular_function', 'GO:0004707', ('239', '243'))	('associations', 'Interaction', (169, 181))	('MAPK', 'Pathway', (239, 243))	('primary tumors', 'Disease', (118, 132))	('Wnt signaling pathways', 'Pathway', (261, 283))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mTOR', 'Gene', (251, 255))	('mTOR', 'Gene', '2475', (251, 255))	('primary tumors', 'Disease', 'MESH:D009369', (118, 132))	('signaling', 'biological_process', 'GO:0023052', ('265', '274'))
18912	28364002	Considering the existing observations that many somatic mutations promote tumorigenesis by rewiring protein signaling networks, one potential strategy is to incorporate somatic mutations with the protein structure information and investigate them at functional sites (e.g., phosphorylation sites).	('mutations', 'Var', (56, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('274', '289'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('rewiring', 'Reg', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('promote', 'PosReg', (66, 73))	('signaling', 'biological_process', 'GO:0023052', ('108', '117'))	('tumor', 'Disease', (74, 79))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('protein signaling networks', 'Pathway', (100, 126))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
18913	28364002	Phosphorylation-dependent signaling network is fundamental in cellular physiology and its dysfunction plays a critical role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('dysfunction', 'Var', (90, 101))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
18914	28364002	This provides us with a unique opportunity to interrogate the impact of somatic mutations on kinase-substrate phosphorylation sites to determine their pathophysiological roles in cancer and prioritize potentially actionable mutations.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (80, 89))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
18921	28364002	We examined over 740,000 missense mutations in nearly 5000 tumor-normal matching samples across 16 cancer types from TCGA.	('tumor', 'Disease', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('missense mutations', 'Var', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
18922	28364002	We found 47 statistically significantly mutated proteins (SMPs) that have enriched missense mutations at their phosphorylation sites in this pan-cancer analysis.	('proteins', 'Protein', (48, 56))	('pan-cancer', 'Disease', 'MESH:C537931', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('missense mutations', 'Var', (83, 101))	('pan-cancer', 'Disease', (141, 151))	('phosphorylation', 'biological_process', 'GO:0016310', ('111', '126'))
18923	28364002	Functional annotation analysis of these modules revealed the tissue-specific phosphorylation-related mechanisms of somatic mutations in cancer.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('mutations', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
18924	28364002	We found that the significantly mutated phosphorylation sites or proteins and their perturbed network modules were highly associated with patient survival and anticancer drug responses.	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('proteins', 'Protein', (65, 73))	('patient survival', 'CPA', (138, 154))	('associated with', 'Reg', (122, 137))	('mutated', 'Var', (32, 39))	('phosphorylation', 'Protein', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patient', 'Species', '9606', (138, 145))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
18932	28364002	We aim to integrate information from both kinase-substrate interaction network (KSIN) and co-expression networks to identify cancer-specific modules that are enriched for phosphorylation site mutations and highly co-expressed in the according tissue.	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('KSIN', 'Disease', 'None', (80, 84))	('phosphorylation', 'Var', (171, 186))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mutations', 'Var', (192, 201))	('KSIN', 'Disease', (80, 84))
18934	28364002	We proposed four following steps to detect densely mutated kinase-substrate modules in co-expressed KSIN: Start from one of the substrates with significantly mutated phosphorylation sites and its upstream kinase and downstream substrate as the seed.	('KSIN', 'Disease', 'None', (100, 104))	('KSIN', 'Disease', (100, 104))	('mutated', 'Var', (158, 165))	('phosphorylation sites', 'MPA', (166, 187))	('phosphorylation', 'biological_process', 'GO:0016310', ('166', '181'))
18937	28364002	In this study, we developed a novel computational oncoproteomics approach, namely kinome-wide network module for cancer pharmacogenomics (KNMPx), to identify novel actionable mutations that have rewired signaling networks and to further characterize tumorigenesis and anticancer drug responses.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('signaling', 'MPA', (203, 212))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('mutations', 'Var', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('cancer', 'Disease', (272, 278))	('KNMPx', 'Chemical', '-', (138, 143))	('tumor', 'Disease', (250, 255))
18939	28364002	In the present KNMPx approach, we investigated a total of 746,631 somatic mutations in 4,997 tumor samples across 16 major cancer types/subtypes from TCGA.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('investigated', 'Reg', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('KNMPx', 'Chemical', '-', (15, 20))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
18941	28364002	Overall, the average mutation rate across the 16 cancer types is 160.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('mutation', 'Var', (21, 29))
18949	28364002	We measured the functional impact scores of mutations using two popular and complementary tools: SIFT and PolyPhen-2.	('SIFT', 'Disease', (97, 101))	('mutations', 'Var', (44, 53))	('SIFT', 'Disease', 'None', (97, 101))
18950	28364002	We examined the cumulative distribution of SIFT and PolyPhen-2 scores for phosphorylation site mutations (direct position and seven flanking residues) and non-binding site mutations (amino acid positions excluding the binding sites and seven flanking residues).	('phosphorylation', 'MPA', (74, 89))	('mutations', 'Var', (172, 181))	('SIFT', 'Disease', 'None', (43, 47))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('SIFT', 'Disease', (43, 47))	('mutations', 'Var', (95, 104))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))
18952	28364002	We found that phosphorylation site mutations were more likely to be deleterious than non-phosphorylation site mutations when they were evaluated using both SIFT (P = 1.47x10-6, Fisher's exact test, Fig.	('phosphorylation', 'Var', (14, 29))	('SIFT', 'Disease', (156, 160))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('SIFT', 'Disease', 'None', (156, 160))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))
18953	28364002	By analyzing 746,631 missense mutations from 4,997 tumors across 16 cancer types from TCGA using KNMPx, we found that more than 50% tumor samples harbored phosphorylation-associated single nucleotide variants (SNVs), and further identified 47 proteins that harbored significantly mutated phosphorylation sites (false discovery rate q < 0.3) including several well-known cancer proteins: BRAF: p.T599 (q = 2.2x10-308), TP53: p.S269 (q = 2.2x10-45), and EGFR: p.T290 (q = 3.2x10-7) (Figure 3A).	('KNMPx', 'Chemical', '-', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('phosphorylation', 'biological_process', 'GO:0016310', ('288', '303'))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('p.S269', 'Var', (424, 430))	('tumor', 'Disease', (132, 137))	('EGFR', 'Gene', '1956', (452, 456))	('false', 'biological_process', 'GO:0071877', ('311', '316'))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('p.T599', 'Var', (393, 399))	('BRAF', 'Gene', '673', (387, 391))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('BRAF', 'Gene', (387, 391))	('EGFR', 'molecular_function', 'GO:0005006', ('452', '456'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('false', 'biological_process', 'GO:0071878', ('311', '316'))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (370, 376))	('EGFR', 'Gene', (452, 456))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('155', '170'))	('tumors', 'Disease', (51, 57))	('p.T290', 'Var', (458, 464))	('cancer', 'Disease', (68, 74))
18960	28364002	In the case of BRCA, we found 2 SMPs: ERBB2: Y772 (q = 0.00043), TP53: S269 (q = 0.0071).	('Y772', 'Var', (45, 49))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (38, 43))	('BRCA', 'Gene', '672', (15, 19))	('BRCA', 'Gene', (15, 19))
18962	28364002	For ERBB2, which encodes HER2, four mutations (V777L, D769Y, D769H, and I767M) may alter its phosphorylation site of p.Y772.	('I767M', 'Mutation', 'p.I767M', (72, 77))	('D769Y', 'Mutation', 'rs121913468', (54, 59))	('V777L', 'Mutation', 'rs121913471', (47, 52))	('I767M', 'Var', (72, 77))	('phosphorylation', 'biological_process', 'GO:0016310', ('93', '108'))	('phosphorylation site', 'MPA', (93, 113))	('ERBB2', 'Gene', '2064', (4, 9))	('p.Y772', 'Var', (117, 123))	('ERBB2', 'Gene', (4, 9))	('D769H', 'Var', (61, 66))	('D769Y', 'Var', (54, 59))	('V777L', 'Var', (47, 52))	('D769H', 'Mutation', 'rs121913468', (61, 66))	('HER2', 'Gene', (25, 29))	('alter', 'Reg', (83, 88))	('HER2', 'Gene', '2064', (25, 29))
18963	28364002	Three of them (V777L, D769Y and D769H) were functionally characterized as activating mutations in HER2 gene amplification-negative breast cancer.	('D769Y', 'Mutation', 'rs121913468', (22, 27))	('activating', 'PosReg', (74, 84))	('V777L', 'Mutation', 'rs121913471', (15, 20))	('D769H', 'Mutation', 'rs121913468', (32, 37))	('D769H', 'Var', (32, 37))	('D769Y', 'Var', (22, 27))	('HER2', 'Gene', (98, 102))	('V777L', 'Var', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('HER2', 'Gene', '2064', (98, 102))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))
18964	28364002	Interestingly, R273H on TP53 altering its phosphorylation site p.S269 was recently reported as an oncogenic mutation in the mouse model.	('TP53', 'Gene', (24, 28))	('phosphorylation', 'MPA', (42, 57))	('R273H', 'Var', (15, 20))	('R273H', 'Mutation', 'rs28934576', (15, 20))	('mouse', 'Species', '10090', (124, 129))	('p.S269', 'Var', (63, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))
18965	28364002	In the analysis of UCEC, we found 9 SMPs with q < 0.3 including CTNNB1: p.S37 (q = 1.7x10-93), CCND1: p.T286 (q = 0.00049), PIK3R1: p.T576 (q = 0.0024), and TP53: p.S269 (q = 0.0047).	('p.S37', 'Var', (72, 77))	('CTNNB1', 'Gene', (64, 70))	('p.T576', 'Var', (132, 138))	('p.S269', 'Var', (163, 169))	('PIK3R1', 'Gene', (124, 130))	('PIK3R1', 'Gene', '5295', (124, 130))	('CTNNB1', 'Gene', '1499', (64, 70))	('CCND1', 'Gene', (95, 100))	('CCND1', 'Gene', '595', (95, 100))	('T286', 'Chemical', '-', (104, 108))	('p.T286', 'Var', (102, 108))
18967	28364002	In BLCA, there were 4 SMPs: AHNAK: p.S1943 (q = 0.0012), TP53: p.T155 (q = 0.012), ILF3: p.S482 (q = 0.044) and ARID1A: p.S607 (q = 0.1).	('ARID1A', 'Gene', (112, 118))	('p.T155', 'Var', (63, 69))	('ILF3', 'Gene', '3609', (83, 87))	('AHNAK', 'Gene', '79026', (28, 33))	('p.S482', 'Var', (89, 95))	('p.S1943', 'Var', (35, 42))	('p.S607', 'Var', (120, 126))	('AHNAK', 'Gene', (28, 33))	('ILF3', 'Gene', (83, 87))	('ARID1A', 'Gene', '8289', (112, 118))
18971	28364002	Altogether, we demonstrated that KNMPx is a useful approach for identifying cancer-associated proteins harboring enriched somatic mutations at their phosphorylation sites.	('KNMPx', 'Chemical', '-', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (130, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('149', '164'))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
18975	28364002	Altogether, the clustering of phosphorylation site mutations in highly correlated kinase-substrate interactions that we observed might suggest tissue-specific patterns of phosphorylation site mutations in KSIN.	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('mutations', 'Var', (51, 60))	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('KSIN', 'Disease', 'None', (205, 209))	('KSIN', 'Disease', (205, 209))
18976	28364002	We hypothesized that phosphorylation site mutations rewired kinase-substrate interaction networks and further associated with tumorigenesis or anticancer drug responses.	('kinase-substrate interaction networks', 'Pathway', (60, 97))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('rewired', 'Reg', (52, 59))	('associated with', 'Reg', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Disease', (147, 153))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', (126, 131))
18981	28364002	In addition, genes in the consensus mutant modules for all the 16 individual cancer types were also significantly enriched in CGC (P values ranging from 2.8x10-11 to 0.017, hypergeometric test) and previously reported SMGs (P values ranging from 1.3x10-21 to 0.0035, hypergeometric test).	('SMGs', 'Chemical', '-', (218, 222))	('CGC', 'Disease', (126, 129))	('SMGs', 'Disease', (218, 222))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutant', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
18988	28364002	For instance, we found Bruton's tyrosine kinase (BTK), a key component of B cell receptor (BCR) signaling and functions as an important regulator of cell proliferation and cell survival in various B cell malignancies, has three somatic mutations around its phosphorylation site p.S21.	('signaling', 'biological_process', 'GO:0023052', ('96', '105'))	("Bruton's tyrosine kinase", 'Gene', (23, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('149', '167'))	("Bruton's tyrosine kinase", 'Gene', '695', (23, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('257', '272'))	('mutations', 'Var', (236, 245))	('BTK', 'Gene', (49, 52))	('BTK', 'Gene', '695', (49, 52))
18989	28364002	A previous study has reported that Btk phosphorylation at p.S21 creates a binding site for the prolyl isomerase Pin1, which modulates Btk activity in a cell cycle-dependent manner.	('Pin1', 'Gene', (112, 116))	('Btk', 'Gene', (134, 137))	('activity', 'MPA', (138, 146))	('p.S21', 'Var', (58, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('Btk', 'Gene', (35, 38))	('modulates', 'Reg', (124, 133))	('Btk', 'Gene', '695', (134, 137))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('cell cycle', 'biological_process', 'GO:0007049', ('152', '162'))	('Pin1', 'Gene', '5300', (112, 116))	('Btk', 'Gene', '695', (35, 38))	('binding', 'Interaction', (74, 81))
18990	28364002	We observed significant mutual exclusivity across the 11 genes in the module which was largely due to the previously reported mutual exclusivity between TP53 and CTNNB1 mutations in UCEC (Figure 4B).	('mutations', 'Var', (169, 178))	('CTNNB1', 'Gene', '1499', (162, 168))	('mutual', 'MPA', (24, 30))	('TP53', 'Gene', (153, 157))	('CTNNB1', 'Gene', (162, 168))	('UCEC', 'Disease', (182, 186))
18991	28364002	For example, 66 missense mutations on CTNNB1 in UCEC around site p.S37 (Figure 4C and 4D) might alter beta-catenin signaling in colon cancer.	('missense mutations', 'Var', (16, 34))	('colon cancer', 'Disease', (128, 140))	('beta-catenin', 'Gene', '1499', (102, 114))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('CTNNB1', 'Gene', (38, 44))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('alter', 'Reg', (96, 101))	('beta-catenin', 'Gene', (102, 114))	('colon cancer', 'Disease', 'MESH:D015179', (128, 140))	('CTNNB1', 'Gene', '1499', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
18993	28364002	Here, we analyzed putative somatic mutations across 1,001 human cancer cell lines and how their phosphorylation site mutations could correlate with drug sensitivity or resistance to the 265 drugs examined.	('mutations', 'Var', (117, 126))	('human', 'Species', '9606', (58, 63))	('correlate', 'Reg', (133, 142))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('resistance', 'MPA', (168, 178))	('drug sensitivity', 'Phenotype', 'HP:0020174', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
18997	28364002	Among the 277,073 putative somatic mutations revealed in these cancer cell lines, 29,821 were at the phosphorylation sites (locating at the direct phosphorylation sites or their 7-residue flanking regions) and half of them (15,626/29,821) also occurred in primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('101', '116'))	('phosphorylation', 'biological_process', 'GO:0016310', ('147', '162'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('cancer', 'Disease', (63, 69))	('mutations', 'Var', (35, 44))
18998	28364002	When comparing the 47 SMPs that we identified in primary tumor pan-cancer analysis, the correlation between the frequency of phosphorylation site mutations in cell lines and primary tumors was greater than 0.5 (from 0.53 in LAML to 0.97 in skin cutaneous melanoma [SKCM]) for all the 13 cancer types that had at least 10 samples with both variant and drug response data in primary tumors and the corresponding cell lines with the similar origins (Figure 5).	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (240, 263))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (245, 263))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('skin cutaneous melanoma', 'Disease', (240, 263))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('tumor', 'Disease', (57, 62))	('primary tumors', 'Disease', (174, 188))	('primary tumors', 'Disease', (373, 387))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('pan-cancer', 'Disease', 'MESH:C537931', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('variant', 'Var', (339, 346))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('mutations', 'Var', (146, 155))	('tumor', 'Disease', (182, 187))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (381, 386))	('primary tumors', 'Disease', 'MESH:D009369', (174, 188))	('primary tumors', 'Disease', 'MESH:D009369', (373, 387))	('pan-cancer', 'Disease', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (381, 386))
19001	28364002	As shown in Figure 6A and 6B, high sensitivity (low IC50 value) for four BRAF inhibitors: Dabrafenib (P = 1.7x10-57), PLX4720 (P = 1.0x10-26), SB590885 (P = 5.2x10-21), and AZ628 (P = 9.4x10-8), was significantly associated with BRAF p.T599 mutations.	('Dabrafenib', 'Chemical', 'MESH:C561627', (90, 100))	('BRAF', 'Gene', '673', (73, 77))	('PLX4720', 'Var', (118, 125))	('associated', 'Reg', (213, 223))	('BRAF', 'Gene', (229, 233))	('AZ628', 'Var', (173, 178))	('AZ628', 'Chemical', 'MESH:C000592454', (173, 178))	('p.T599 mutations', 'Var', (234, 250))	('BRAF', 'Gene', (73, 77))	('SB590885', 'Var', (143, 151))	('BRAF', 'Gene', '673', (229, 233))
19002	28364002	In addition, five MEK inhibitors, Bicalutamide (P = 1.7x10-57), RDEA119 (P = 1.2x10-14), PD-0325901 (P = 1.2x10-12), Trametinib (P = 8.8x10-9), and CI-1040 (P = 1.2x10-7), had a higher response to NRAS p.Y64 mutated cell lines in comparison with wild-type cell lines.	('Trametinib', 'Chemical', 'MESH:C560077', (117, 127))	('PD', 'Disease', 'MESH:D010300', (89, 91))	('higher', 'PosReg', (178, 184))	('response', 'MPA', (185, 193))	('Bicalutamide', 'Chemical', 'MESH:C053541', (34, 46))	('RDEA119', 'Var', (64, 71))
19003	28364002	Interestingly, one hotspot mutation site, TP53 p.S269 also lead to a higher response to Bicalutamide (P = 2.2x10-15) in TP53 p.S269 mutated cell lines compared to wild-type ones.	('TP53', 'Gene', (42, 46))	('Bicalutamide', 'Chemical', 'MESH:C053541', (88, 100))	('p.S269 mutated', 'Var', (125, 139))	('response to Bicalutamide', 'MPA', (76, 100))	('TP53', 'Gene', (120, 124))	('higher', 'PosReg', (69, 75))	('p.S269', 'Var', (47, 53))
19006	28364002	Figure 6A and 6B indicated that a higher response of Linifanib was significantly associated with several phosphorylation site mutations on energy homeostasis enzyme, creatine kinase, M-type (CKM) (P = 7.4x10-8) and a cell metabolism gene, SLC25A1 (P = 3.1x10-7).	('phosphorylation', 'MPA', (105, 120))	('metabolism', 'biological_process', 'GO:0008152', ('222', '232'))	('higher', 'PosReg', (34, 40))	('Linifanib', 'Chemical', 'MESH:C513486', (53, 62))	('Linifanib', 'Gene', (53, 62))	('SLC25A1', 'Gene', '6576', (239, 246))	('response', 'MPA', (41, 49))	('SLC25A1', 'Gene', (239, 246))	('creatine kinase, M-type (CKM', 'Gene', (166, 194))	('mutations', 'Var', (126, 135))	('creatine kinase, M-type (CKM)', 'Gene', '1158', (166, 195))	('energy homeostasis', 'biological_process', 'GO:0097009', ('139', '157'))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
19007	28364002	Furthermore, Quizartinib (AC220), a FDA-approved FLT3 inhibitor for the treatment of acute myeloid leukemia, was found significantly associated with a higher response in cancer cell lines harboring the rewired phosphorylation network by several proteins, such as MKNK1 p.S39 (P = 1.7x10-9), PKP2 p.Y161 (P = 1.6x10-8), CKM p.T313 (P = 2.5x10-7), and USP37 p.S170 (P = 2.2x10-7), in comparison with wild-type groups.	('cancer', 'Disease', (170, 176))	('PKP2 p', 'Gene', (291, 297))	('USP', 'molecular_function', 'GO:0051748', ('350', '353'))	('Quizartinib', 'Chemical', 'MESH:C544967', (13, 24))	('higher', 'PosReg', (151, 157))	('MKNK1 p', 'Gene', '8569', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('USP37', 'Gene', (350, 355))	('AC220', 'Chemical', 'MESH:C544967', (26, 31))	('CKM', 'Gene', '1158', (319, 322))	('PKP2 p', 'Gene', '5318', (291, 297))	('acute myeloid leukemia', 'Disease', (85, 107))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (91, 107))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('CKM', 'Gene', (319, 322))	('FLT3', 'Gene', (49, 53))	('MKNK1 p', 'Gene', (263, 270))	('USP37', 'Gene', '57695', (350, 355))	('phosphorylation', 'biological_process', 'GO:0016310', ('210', '225'))	('response', 'MPA', (158, 166))	('FLT3', 'Gene', '2322', (49, 53))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (85, 107))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (85, 107))	('p.S170', 'Var', (356, 362))
19011	28364002	In addition, QL-VIII-58, a mTOR inhibitor, presented high risk of resistance with somatic mutations altering ABLIM3 p.T276 (P = 1.1x10-7).	('p.T276', 'Var', (116, 122))	('ABLIM3', 'Gene', (109, 115))	('ABLIM3', 'Gene', '22885', (109, 115))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))
19013	28364002	Figure 6B displayed that mutations around APBB1IP p.S652 were significantly correlated with the resistance of FH535 in pan-cancer analysis.	('APBB1IP', 'Gene', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (25, 34))	('pan-cancer', 'Disease', (119, 129))	('p.S652', 'Var', (50, 56))	('APBB1IP', 'Gene', '54518', (42, 49))	('pan-cancer', 'Disease', 'MESH:C537931', (119, 129))	('FH535', 'Chemical', 'MESH:C575430', (110, 115))	('correlated', 'Reg', (76, 86))
19015	28364002	Collectively, rewired signaling network altered by phosphorylation site mutations is an important mechanism in mediating the resistance of cancer therapies for various signaling pathways, such as PI3K signaling and Wnt/beta-catenin signaling (Figure 7).	('beta-catenin', 'Gene', (219, 231))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('196', '210'))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('beta-catenin', 'Gene', '1499', (219, 231))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('PI3K', 'molecular_function', 'GO:0016303', ('196', '200'))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('phosphorylation site mutations', 'Var', (51, 81))	('cancer', 'Disease', (139, 145))
19016	28364002	In this study, we developed an oncoproteomics-based framework to perform systematic investigation of the somatic mutations by altering phosphorylation sites and the related signaling networks in approximately 5,000 tumor samples across 16 major cancer types.	('altering', 'Reg', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('cancer', 'Disease', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mutations', 'Var', (113, 122))	('phosphorylation sites', 'MPA', (135, 156))	('tumor', 'Disease', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('signaling', 'biological_process', 'GO:0023052', ('173', '182'))	('signaling', 'MPA', (173, 182))
19017	28364002	In our comparison of the mutational load distribution of missense mutations at phosphorylation sites versus other sites of the protein sequences, we found a higher mutation rate at phosphorylation sites than that of the remaining protein sites in nine cancer types we examined.	('missense mutations', 'Var', (57, 75))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('phosphorylation', 'biological_process', 'GO:0016310', ('181', '196'))	('cancer', 'Disease', (252, 258))	('phosphorylation', 'biological_process', 'GO:0016310', ('79', '94'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('higher', 'PosReg', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutation', 'MPA', (164, 172))	('protein', 'cellular_component', 'GO:0003675', ('230', '237'))
19018	28364002	Based on the significance test implemented in our kinome-wide network module for cancer pharmacogenomics, KNMPx, we reported 47 proteins that harbored significantly mutated phosphorylation sites in pan-cancer analysis and 74 proteins in 16 individual cancer type analysis.	('pan-cancer', 'Disease', (198, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('phosphorylation', 'biological_process', 'GO:0016310', ('173', '188'))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('KNMPx', 'Chemical', '-', (106, 111))	('pan-cancer', 'Disease', 'MESH:C537931', (198, 208))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (202, 208))	('phosphorylation', 'MPA', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (251, 257))	('mutated', 'Var', (165, 172))
19020	28364002	They showed that signaling networks are both dynamically (e.g., mutant molecular logic gates) and structurally rewired (e.g., both constitutive activation and inactivation of kinase and SH1 domains) in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('molecular logic gates', 'Gene', (71, 92))	('inactivation', 'NegReg', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('activation', 'PosReg', (144, 154))	('cancer', 'Disease', (202, 208))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('mutant', 'Var', (64, 70))
19021	28364002	Building on our observation of the clustering of phosphorylation site mutations in highly co-expressed kinase-substrate interactions, we proposed a new network algorithm to search for cancer-related modules consisting of a set of genes that are enriched with phosphorylation site mutations and tissue-specific kinase-substrate network.	('cancer', 'Disease', (184, 190))	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (280, 289))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('phosphorylation', 'biological_process', 'GO:0016310', ('259', '274'))
19022	28364002	We demonstrated that network module genes were significantly enriched in well-known cancers for both individual cancer and pan-cancer analyses, as well as were associated with patient survival.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pan-cancer', 'Disease', 'MESH:C537931', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('pan-cancer', 'Disease', (123, 133))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('genes', 'Var', (36, 41))	('cancers', 'Disease', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('enriched', 'Reg', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (127, 133))	('patient', 'Species', '9606', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (160, 170))
19024	28364002	Surprisingly, we found that mutation profiles in cell lines could highly reproduce the oncogenic phosphorylation site mutations identified in primary tumors (Figure 5).	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (118, 127))	('primary tumors', 'Disease', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('primary tumors', 'Disease', 'MESH:D009369', (142, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
19026	28364002	To our best knowledge, this is the first study of systematic oncoproteomics analysis for investigating phosphorylation site mutations mediating tumorigenesis and anticancer drug efficacy at the kinome-level.	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('phosphorylation', 'biological_process', 'GO:0016310', ('103', '118'))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
19028	28364002	Although two tumors may not have any phosphorylation site mutations in common, they may share the biological networks affected by these mutations.	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('mutations', 'Var', (136, 145))	('phosphorylation', 'biological_process', 'GO:0016310', ('37', '52'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
19029	28364002	By investigating phosphorylation site mutations in the context of network, we might be able to identify some rarely mutated proteins in the subnetworks linking to the well-characterized cancer-related proteins.	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
19030	28364002	All these mutations may also play important roles in altering phosphorylation sites and leading to tumor initiation and progression.	('leading to', 'Reg', (88, 98))	('phosphorylation sites', 'MPA', (62, 83))	('progression', 'CPA', (120, 131))	('tumor initiation', 'Disease', 'MESH:D009369', (99, 115))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('mutations', 'Var', (10, 19))	('tumor initiation', 'Disease', (99, 115))	('altering', 'Reg', (53, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))
19032	28364002	In our future work, we will investigate both phosphorylation signaling by kinases and dephosphorylation signaling by phosphatases altered by somatic mutations, which may medicate tumorigenesis and anticancer drug responses.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (149, 158))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('cancer', 'Disease', (201, 207))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('dephosphorylation signaling', 'MPA', (86, 113))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('dephosphorylation', 'biological_process', 'GO:0016311', ('86', '103'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('phosphorylation', 'biological_process', 'GO:0016310', ('45', '60'))	('tumor', 'Disease', (179, 184))
19033	28364002	CGC Cancer Gene Census FDR false discovery rate IC50 half maximal inhibitory concentration KSI kinase-substrate interactions KNMPx kinome-wide network module for cancer pharmacogenomics NAMs network-attacking mutations (NAMs) PCC Pearson correlation coefficient SMGs significantly mutated genes SMPs significantly mutated proteins SNVs single nucleotide variants TCGA The Cancer Genome Atlas	('Cancer', 'Disease', 'MESH:D009369', (372, 378))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('KNMPx', 'Chemical', '-', (125, 130))	('KSI', 'Chemical', '-', (91, 94))	('mutated', 'Reg', (281, 288))	('cancer', 'Disease', (162, 168))	('PCC', 'cellular_component', 'GO:0120205', ('226', '229'))	('Cancer', 'Phenotype', 'HP:0002664', (372, 378))	('false', 'biological_process', 'GO:0071878', ('27', '32'))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('single nucleotide variants', 'Var', (336, 362))	('SMGs', 'Chemical', '-', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('false', 'biological_process', 'GO:0071877', ('27', '32'))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Disease', (372, 378))
19052	26217116	There are many polymorphisms of the MC1R gene, resulting in the numerous skin-colour phenotypes seen in humans; variants such as the red hair, fair-skinned phenotype express low pigmentation, with a consequent increased sensitivity to ultraviolet (UV) light and associated increased melanoma risk.	('pigmentation', 'biological_process', 'GO:0043473', ('178', '190'))	('increased', 'PosReg', (210, 219))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('increased', 'PosReg', (273, 282))	('red hair', 'Phenotype', 'HP:0002297', (133, 141))	('MC1R', 'Gene', (36, 40))	('humans', 'Species', '9606', (104, 110))	('low pigmentation', 'Disease', (174, 190))	('variants', 'Var', (112, 120))	('low pigmentation', 'Disease', 'MESH:D010859', (174, 190))
19073	26217116	Observational studies suggest a strong association between high naevus counts and melanoma.	('naevus', 'Phenotype', 'HP:0003764', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('high', 'Var', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))
19077	26217116	This gene locus undergoes complex transcription (from alternate reading frames) and thus encodes two proteins, p16 and p14ARF; the majority of mutations affect the former protein.	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('p14ARF', 'Gene', (119, 125))	('affect', 'Reg', (153, 159))	('p16', 'Gene', '1029', (111, 114))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('p14ARF', 'Gene', '1029', (119, 125))	('p16', 'Gene', (111, 114))	('mutations', 'Var', (143, 152))
19081	26217116	Evidence also exists for a pro-melanomagenic effect of germline mutations affecting CDK4 and Rb1 directly.	('Rb', 'Phenotype', 'HP:0009919', (93, 95))	('Rb1', 'Gene', (93, 96))	('CDK4', 'Gene', (84, 88))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('CDK4', 'Gene', '1019', (84, 88))	('Rb1', 'Gene', '5925', (93, 96))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('germline mutations', 'Var', (55, 73))
19082	26217116	p14ARF also has an important role in down-regulating p53 activity (through increased activation of MDM2), thus also acting as a tumour suppressor; disruption of this activity through mutations could also be tumourigenic.	('tumour', 'Disease', (128, 134))	('tumour', 'Disease', (207, 213))	('p14ARF', 'Gene', '1029', (0, 6))	('mutations', 'Var', (183, 192))	('MDM2', 'Gene', '4193', (99, 103))	('MDM2', 'Gene', (99, 103))	('activation', 'PosReg', (85, 95))	('p14ARF', 'Gene', (0, 6))	('disruption', 'Var', (147, 157))	('p53', 'Gene', (53, 56))	('activity', 'MPA', (57, 65))	('down-regulating', 'NegReg', (37, 52))	('p53', 'Gene', '7157', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
19083	26217116	The actual prevalence of CDKN2A mutations is difficult to quantify.	('mutations', 'Var', (32, 41))	('CDKN2A', 'Gene', '1029', (25, 31))	('CDKN2A', 'Gene', (25, 31))
19086	26217116	There may also be interaction between genetic mutations to modulate melanoma risk further; for example, some MC1R gene variants can increase the penetrance of CDKN2A mutations, thus increasing risk further.	('CDKN2A', 'Gene', '1029', (159, 165))	('mutations', 'Var', (166, 175))	('increase', 'PosReg', (132, 140))	('risk', 'MPA', (193, 197))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('increasing', 'PosReg', (182, 192))	('melanoma', 'Disease', (68, 76))	('penetrance', 'MPA', (145, 155))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('MC1R', 'Gene', (109, 113))	('variants', 'Var', (119, 127))	('CDKN2A', 'Gene', (159, 165))
19090	26217116	Given that some studies suggest an increased risk of melanoma in the presence of mutations in this gene, whereas others have been unable to demonstrate this, no sound conclusions can be drawn regarding this gene.	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('mutations', 'Var', (81, 90))
19092	26217116	Genetic mutations affecting protagonists of the mitogen-activated protein kinase (MAPK) pathway have been found in many tumour types.	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('found', 'Reg', (106, 111))	('tumour', 'Disease', (120, 126))	('Genetic mutations', 'Var', (0, 17))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
19096	26217116	Homo- or hetero-dimer formation of RAF molecules ultimately leads to the activation of extracellular signal-regulated kinase (ERK) which in turn acts on numerous targets to promote cell growth and survival, as well as controlling further MAPK pathway signalling by inducing the expression of negative regulators, and directly inhibiting proteins such as CRAF.	('inducing', 'PosReg', (265, 273))	('extracellular signal-regulated kinase', 'Gene', '5594', (87, 124))	('CRAF', 'Gene', (354, 358))	('RAF', 'Gene', (35, 38))	('controlling', 'Reg', (218, 229))	('extracellular', 'cellular_component', 'GO:0005576', ('87', '100'))	('ERK', 'molecular_function', 'GO:0004707', ('126', '129'))	('expression', 'MPA', (278, 288))	('proteins', 'Protein', (337, 345))	('CRAF', 'molecular_function', 'GO:0004709', ('354', '358'))	('CRAF', 'Gene', '5894', (354, 358))	('promote', 'PosReg', (173, 180))	('inhibiting', 'NegReg', (326, 336))	('Homo-', 'Var', (0, 5))	('activation', 'PosReg', (73, 83))	('RAF', 'Gene', '22882', (355, 358))	('mole', 'Phenotype', 'HP:0003764', (39, 43))	('ERK', 'Gene', '5594', (126, 129))	('negative regulators', 'MPA', (292, 311))	('cell growth', 'CPA', (181, 192))	('MAPK pathway signalling', 'Pathway', (238, 261))	('signalling', 'biological_process', 'GO:0023052', ('251', '261'))	('RAF', 'Gene', '22882', (35, 38))	('cell growth', 'biological_process', 'GO:0016049', ('181', '192'))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('extracellular signal-regulated kinase', 'Gene', (87, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('238', '242'))	('RAF', 'Gene', (355, 358))	('hetero-dimer formation', 'Var', (9, 31))	('ERK', 'Gene', (126, 129))
19097	26217116	Mutations affecting this pathway are present in the vast majority of cutaneous melanomas, predominantly affecting the NRAS (approximately 20%) or BRAF (approximately 40-50%) proteins.	('BRAF', 'Gene', (146, 150))	('NRAS', 'Gene', (118, 122))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (69, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (69, 88))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('cutaneous melanomas', 'Disease', (69, 88))	('affecting', 'Reg', (104, 113))	('BRAF', 'Gene', '673', (146, 150))	('proteins', 'Protein', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
19098	26217116	In the case of BRAF, the vast majority of mutations constitute a single amino acid substitution from valine to glutamic acid at codon 600 (V600E), resulting in a constitutively active BRAF protein that is consequently able to signal in a continuous and unopposed fashion down the MAPK pathway, thus promoting melanomagenesis and preventing apoptosis.	('promoting', 'PosReg', (299, 308))	('BRAF', 'Gene', (184, 188))	('apoptosis', 'CPA', (340, 349))	('MAPK pathway', 'Pathway', (280, 292))	('melanomagenesis', 'Disease', 'None', (309, 324))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('BRAF', 'Gene', '673', (15, 19))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('BRAF', 'Gene', (15, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('340', '349'))	('apoptosis', 'biological_process', 'GO:0006915', ('340', '349'))	('preventing', 'NegReg', (329, 339))	('MAPK', 'molecular_function', 'GO:0004707', ('280', '284'))	('protein', 'Protein', (189, 196))	('V600E', 'Var', (139, 144))	('valine to glutamic acid at codon 600', 'Mutation', 'rs113488022', (101, 137))	('melanomagenesis', 'Disease', (309, 324))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', '673', (184, 188))
19099	26217116	Interestingly, a similar proportion of naevi also contain BRAF mutations, implying that these alone are not sufficient for malignant transformation.	('mutations', 'Var', (63, 72))	('naevi', 'Disease', (39, 44))	('BRAF', 'Gene', '673', (58, 62))	('naevi', 'Phenotype', 'HP:0003764', (39, 44))	('BRAF', 'Gene', (58, 62))
19100	26217116	It is hypothesised that whilst melanocyte acquisition of a BRAF mutation is not the founder event for oncogenesis, it occurs early in the development of invasive melanoma and further enhances the effects of other oncogenic stimuli; thus it facilitates malignant transformation, rather than initiating it.	('invasive melanoma', 'Disease', (153, 170))	('mutation', 'Var', (64, 72))	('men', 'Species', '9606', (145, 148))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('oncogenesis', 'biological_process', 'GO:0007048', ('102', '113'))	('facilitates', 'PosReg', (240, 251))	('effects', 'MPA', (196, 203))	('malignant transformation', 'CPA', (252, 276))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('invasive melanoma', 'Disease', 'MESH:D008545', (153, 170))	('enhances', 'PosReg', (183, 191))
19101	26217116	BRAF mutations are more commonly seen in melanomas arising in intermittently sun-exposed sites, implying that UV light (as described earlier) may be one such stimulus.	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', (41, 50))	('seen', 'Reg', (33, 37))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
19102	26217116	Additionally, as there is significant interaction between intracellular signalling pathways, further genetic aberrations affecting the PI3 kinase pathway, for example, may also be sufficient to induce melanoma development.	('melanoma', 'Disease', (201, 209))	('interaction', 'Reg', (38, 49))	('men', 'Species', '9606', (217, 220))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('signalling', 'biological_process', 'GO:0023052', ('72', '82'))	('genetic aberrations', 'Var', (101, 120))	('intracellular', 'cellular_component', 'GO:0005622', ('58', '71'))	('PI3 kinase pathway', 'Pathway', (135, 153))	('induce', 'PosReg', (194, 200))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
19104	26217116	Prognostic factors in cutaneous melanoma have been closely studied; they include histopathological characteristics, patient characteristics, biochemical measures and most recently genetic mutations.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('patient', 'Species', '9606', (116, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (22, 40))	('cutaneous melanoma', 'Disease', (22, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('genetic mutations', 'Var', (180, 197))
19122	26217116	The BRAF gene mutation - which as previously described is integral to melanoma pathogenesis - has been investigated as a prognostic marker too.	('melanoma', 'Disease', (70, 78))	('pathogenesis', 'biological_process', 'GO:0009405', ('79', '91'))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutation', 'Var', (14, 22))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
19123	26217116	In advanced disease, meta-analyses have demonstrated that the presence of a BRAF mutation is independently associated with a worse survival outcome.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (81, 89))	('presence', 'Var', (62, 70))
19132	26217116	Disruptions in a number of tumour suppressor genes and/or activation of oncogenes have been implicated in the development of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (125, 139))	('uveal melanoma', 'Disease', 'MESH:C536494', (125, 139))	('Disruptions', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('uveal melanoma', 'Disease', (125, 139))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('men', 'Species', '9606', (117, 120))	('implicated', 'Reg', (92, 102))	('tumour', 'Disease', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('activation', 'PosReg', (58, 68))	('oncogenes', 'Gene', (72, 81))
19133	26217116	Disruption of the activity of the retinoblastoma (Rb) tumour suppressor gene leads to uninhibited progression of melanocytes through the G1-S phase of the cell cycle, resulting in deregulated cell proliferation.	('retinoblastoma', 'Gene', (34, 48))	('deregulated', 'MPA', (180, 191))	('activity', 'MPA', (18, 26))	('retinoblastoma', 'Gene', '5925', (34, 48))	('cell proliferation', 'CPA', (192, 210))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('Rb', 'Gene', '5925', (50, 52))	('Rb', 'Phenotype', 'HP:0009919', (50, 52))	('uninhibited', 'MPA', (86, 97))	('tumour', 'Disease', (54, 60))	('S phase', 'biological_process', 'GO:0051320', ('140', '147'))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('155', '165'))	('cell proliferation', 'biological_process', 'GO:0008283', ('192', '210'))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('Disruption', 'Var', (0, 10))
19137	26217116	More recently mutually exclusive mutations in GNAQ and GNA11, genes encoding the alpha subunit of heterotrimeric cell surface G proteins, have been reported.	('GNAQ', 'Gene', (46, 50))	('cell surface', 'cellular_component', 'GO:0009986', ('113', '125'))	('mutations', 'Var', (33, 42))	('GNAQ', 'Gene', '2776', (46, 50))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))
19138	26217116	These alpha subunits are involved in mediating signals between G-protein-coupled receptors and downstream effectors such as protein kinases A and C. Mutations in codon 209 of GNAQ and GNA11 have been reported in approximately 46-49% and 32% of patients, respectively, and lead to constitutive activation of the G protein alpha subunit and activation of the MAPK signalling pathway (in human melanocyte cell lines), driving cell proliferation.	('Mutations in', 'Var', (149, 161))	('human', 'Species', '9606', (385, 390))	('cell proliferation', 'CPA', (423, 441))	('signalling pathway', 'biological_process', 'GO:0007165', ('362', '380'))	('patients', 'Species', '9606', (244, 252))	('GNA11', 'Gene', '2767', (184, 189))	('MAPK signalling pathway', 'Pathway', (357, 380))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('cell proliferation', 'biological_process', 'GO:0008283', ('423', '441'))	('driving', 'PosReg', (415, 422))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('protein', 'cellular_component', 'GO:0003675', ('313', '320'))	('GNAQ', 'Gene', '2776', (175, 179))	('GNA11', 'Gene', (184, 189))	('activation', 'PosReg', (293, 303))	('MAPK', 'molecular_function', 'GO:0004707', ('357', '361'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('357', '372'))	('GNAQ', 'Gene', (175, 179))	('activation', 'PosReg', (339, 349))
19139	26217116	The majority of substitutions at codon 209 of GNAQ and GNA11 involve substitutions of glutamine by leucine or glutamine by proline.	('leucine', 'Chemical', 'MESH:D007930', (99, 106))	('GNAQ', 'Gene', (46, 50))	('substitutions', 'Var', (69, 82))	('leucine', 'MPA', (99, 106))	('glutamine', 'Chemical', 'MESH:D005973', (110, 119))	('glutamine', 'Chemical', 'MESH:D005973', (86, 95))	('proline', 'Chemical', 'MESH:D011392', (123, 130))	('GNAQ', 'Gene', '2776', (46, 50))	('substitutions', 'Var', (16, 29))	('glutamine', 'MPA', (110, 119))	('GNA11', 'Gene', '2767', (55, 60))	('GNA11', 'Gene', (55, 60))	('glutamine', 'Protein', (86, 95))
19140	26217116	Mutations at codon 183 of GNAQ and GNA11 also occur, although less frequently, and involve the substitution of cytosine by thymine which is characteristic of ultraviolet-radiation-induced mutations, thereby supporting the role of UV-B radiation in the pathogenesis of a minority of uveal melanomas.	('cytosine', 'Chemical', 'MESH:D003596', (111, 119))	('uveal melanomas', 'Disease', 'MESH:C536494', (282, 297))	('GNAQ', 'Gene', (26, 30))	('thymine', 'MPA', (123, 130))	('GNA11', 'Gene', '2767', (35, 40))	('substitution', 'Var', (95, 107))	('cytosine', 'MPA', (111, 119))	('thymine', 'Chemical', 'MESH:D013941', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('Mutations', 'Var', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (288, 297))	('pathogenesis', 'biological_process', 'GO:0009405', ('252', '264'))	('uveal melanomas', 'Disease', (282, 297))	('uveal melanomas', 'Phenotype', 'HP:0007716', (282, 297))	('GNAQ', 'Gene', '2776', (26, 30))	('involve', 'Reg', (83, 90))	('GNA11', 'Gene', (35, 40))	('uveal melanoma', 'Phenotype', 'HP:0007716', (282, 296))
19141	26217116	As mutations in GNAQ and GNA11 are common in uveal melanoma, targeting these or downstream effectors such as protein kinase C or members of the MAPK signalling pathway are promising potential therapeutic options.	('MAPK', 'molecular_function', 'GO:0004707', ('144', '148'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('uveal melanoma', 'Disease', (45, 59))	('common', 'Reg', (35, 41))	('signalling pathway', 'biological_process', 'GO:0007165', ('149', '167'))	('GNAQ', 'Gene', (16, 20))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('144', '159'))	('GNAQ', 'Gene', '2776', (16, 20))	('GNA11', 'Gene', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (3, 12))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('GNA11', 'Gene', '2767', (25, 30))
19143	26217116	Inactivating somatic mutations of the gene coding for BRCA1-associated protein-1 (BAP1) have been found in up to 85% of metastasising uveal melanomas.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('BAP1', 'Gene', (82, 86))	('uveal melanomas', 'Disease', (134, 149))	('uveal melanomas', 'Phenotype', 'HP:0007716', (134, 149))	('BRCA1-associated protein-1', 'Gene', (54, 80))	('found', 'Reg', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('uveal melanomas', 'Disease', 'MESH:C536494', (134, 149))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))	('BAP1', 'Gene', '8314', (82, 86))	('BRCA1-associated protein-1', 'Gene', '8314', (54, 80))	('Inactivating somatic mutations', 'Var', (0, 30))
19146	26217116	Also families with germ-line mutations of BAP1 have been identified with an increased incidence of both uveal and cutaneous melanoma, as well as other malignancies.	('BAP1', 'Gene', '8314', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('uveal', 'Disease', (104, 109))	('cutaneous melanoma', 'Disease', (114, 132))	('BAP1', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('malignancies', 'Disease', (151, 163))
19154	26217116	Such patients with monosomy 3 uveal melanoma have a poor 5-year survival.	('monosomy 3', 'Var', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('patients', 'Species', '9606', (5, 13))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))
19156	26217116	It is likely that loss of chromosome 3 is an early event in tumourigenesis, predisposing to other cytogenetic aberrations such as gain of 8q.	('loss', 'Var', (18, 22))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('tumour', 'Disease', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('gain', 'PosReg', (130, 134))
19179	26217116	Unlike cutaneous melanoma, V600E BRAF or NRAS mutations are rare in mucosal melanoma.	('NRAS', 'Gene', '4893', (41, 45))	('cutaneous melanoma', 'Disease', (7, 25))	('V600E', 'Var', (27, 32))	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('BRAF', 'Gene', '673', (33, 37))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('BRAF', 'Gene', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('NRAS', 'Gene', (41, 45))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('mucosal melanoma', 'Disease', (68, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
19183	26217116	Although the exact mechanism of KIT signalling in melanocytes is not fully understood, studies have demonstrated that inactivating mutations in KIT can lead to amelanotic disorders and prevent normal melanocyte development and survival.	('KIT', 'Gene', (144, 147))	('signalling', 'biological_process', 'GO:0023052', ('36', '46'))	('amelanotic disorders', 'Disease', (160, 180))	('amelanotic disorders', 'Disease', 'MESH:D018328', (160, 180))	('normal melanocyte development', 'CPA', (193, 222))	('prevent', 'NegReg', (185, 192))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('inactivating mutations', 'Var', (118, 140))	('men', 'Species', '9606', (218, 221))	('lead to', 'Reg', (152, 159))	('KIT', 'molecular_function', 'GO:0005020', ('144', '147'))
19186	26217116	Subsequently, detailed studies comparing melanomas derived from different anatomical sites demonstrated gain-of-function mutations (such as K642E, D816H and V559A), amplifications or over-expression of c-KIT in 39% of mucosal melanomas.	('melanomas', 'Disease', (226, 235))	('KIT', 'molecular_function', 'GO:0005020', ('204', '207'))	('D816H', 'Var', (147, 152))	('V559A', 'Var', (157, 162))	('mucosal melanomas', 'Disease', 'MESH:D008545', (218, 235))	('K642E', 'Mutation', 'rs121913512', (140, 145))	('V559A', 'Mutation', 'rs121913517', (157, 162))	('D816H', 'Mutation', 'rs121913506', (147, 152))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('mucosal melanomas', 'Disease', (218, 235))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('K642E', 'Var', (140, 145))	('c-KIT', 'Gene', (202, 207))	('amplifications', 'Var', (165, 179))	('c-KIT', 'Gene', '3815', (202, 207))	('melanomas', 'Disease', (41, 50))	('over-expression', 'PosReg', (183, 198))	('gain-of-function', 'PosReg', (104, 120))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanomas', 'Disease', 'MESH:D008545', (226, 235))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
19187	26217116	This frequency is reported to vary markedly by site of melanoma; in one study 88% of oral mucosal melanomas were reported as expressing aberrant c-KIT, while others reported their highest rates (35%) amongst genital tract melanomas.	('expressing', 'Reg', (125, 135))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('aberrant', 'Var', (136, 144))	('KIT', 'molecular_function', 'GO:0005020', ('147', '150'))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('genital tract melanomas', 'Disease', 'MESH:D060737', (208, 231))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('c-KIT', 'Gene', (145, 150))	('genital tract melanomas', 'Disease', (208, 231))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (85, 107))	('c-KIT', 'Gene', '3815', (145, 150))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('oral mucosal melanomas', 'Disease', (85, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))
19189	26217116	Exon 11 mutations (including point mutations, in-frame deletions and insertions) are the most common KIT mutations; the L576P mutation in particular is found in approximately one third of these melanomas.	('L576P', 'Var', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('melanomas', 'Disease', 'MESH:D008545', (194, 203))	('KIT', 'molecular_function', 'GO:0005020', ('101', '104'))	('L576P', 'Mutation', 'rs121913513', (120, 125))	('melanomas', 'Disease', (194, 203))	('found', 'Reg', (152, 157))
19191	26217116	There is clearly still much to learn about the biology of mucosal melanoma, but the knowledge gained thus far about KIT mutations is encouraging further research in this area, focused particularly on exploiting this mutation in the pursuit of effective treatment options for this condition.	('men', 'Species', '9606', (258, 261))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('mucosal melanoma', 'Disease', (58, 74))	('KIT', 'molecular_function', 'GO:0005020', ('116', '119'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (58, 74))	('mutations', 'Var', (120, 129))	('KIT', 'Gene', (116, 119))
19192	26217116	KIT mutations have been successfully targeted in the treatment of other malignancies such as gastrointestinal stromal tumours (GIST), which also demonstrate an increased prevalence of KIT mutations.	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (93, 125))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'molecular_function', 'GO:0005020', ('184', '187'))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('KIT', 'Gene', (184, 187))	('malignancies', 'Disease', (72, 84))	('malignancies', 'Disease', 'MESH:D009369', (72, 84))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (188, 197))	('KIT', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('men', 'Species', '9606', (58, 61))	('gastrointestinal stromal tumours', 'Disease', (93, 125))
19194	26217116	Interestingly, patients with KIT mutations appear to have a poorer prognosis than wild-type patients.	('patients', 'Species', '9606', (15, 23))	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (33, 42))	('KIT', 'Gene', (29, 32))
19228	31318994	Patients with positive SLNB had significantly higher BT (2.4 mm vs. 1.6 mm in INN and negative SLNB, P < 0.001) and were therefore more frequently T3 or T4 stage (43.1% and 20.2% compared to 28.6% and 7.7% in negative SLNB and 27.1% and 5.8% in INN, P < 0.001).	('BT', 'Chemical', '-', (53, 55))	('higher', 'PosReg', (46, 52))	('T3 or T4 stage', 'CPA', (147, 161))	('Patients', 'Species', '9606', (0, 8))	('SLNB', 'Var', (23, 27))
19232	31318994	The OS curves showed significantly worse OS for patients with positive SLNB compared with patients with negative SLNB and only INN (Fig.	('SLNB', 'Var', (71, 75))	('patients', 'Species', '9606', (90, 98))	('positive SLNB', 'Var', (62, 75))	('patients', 'Species', '9606', (48, 56))
19247	27903500	Primary resistance to PD-1 blockade mediated by JAK1/2 mutations Loss of function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy.	('PD-1', 'Gene', (22, 26))	('JAK1/2', 'Gene', (95, 101))	('JAK1/2', 'Gene', '3716;3717', (48, 54))	('PD-1', 'Gene', '5133', (22, 26))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('mutations', 'Var', (55, 64))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('JAK1/2', 'Gene', (48, 54))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('mutations', 'Var', (82, 91))	('PD-1', 'Gene', (170, 174))	('JAK1/2', 'Gene', '3716;3717', (95, 101))	('PD-1', 'Gene', '5133', (170, 174))	('acquired resistance to anti-programmed', 'MPA', (114, 152))	('Loss of function', 'NegReg', (65, 81))
19249	27903500	JAK1/2 inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade.	('JAK1/2', 'Gene', '3716;3717', (0, 6))	('deficient colon cancer', 'Disease', 'MESH:D015179', (138, 160))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('deficient colon cancer', 'Disease', (138, 160))	('JAK1/2', 'Gene', (0, 6))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', (44, 49))	('patients', 'Species', '9606', (70, 78))	('mismatch repair', 'biological_process', 'GO:0006298', ('122', '137'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('deficient colon', 'Phenotype', 'HP:0005210', (138, 153))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (148, 160))	('inactivating mutations', 'Var', (7, 29))	('PD-1', 'Gene', (174, 178))	('PD-1', 'Gene', '5133', (174, 178))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
19250	27903500	Both cases had a high mutational load but did not respond to anti-PD-1 therapy.	('PD-1', 'Gene', (66, 70))	('mutational', 'Var', (22, 32))	('PD-1', 'Gene', '5133', (66, 70))
19251	27903500	Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway.	('mutations', 'Var', (51, 60))	('interferon gamma', 'molecular_function', 'GO:0005133', ('175', '191'))	('interferon gamma', 'Gene', (105, 121))	('lack', 'NegReg', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('expression', 'MPA', (89, 99))	('JAK', 'molecular_function', 'GO:0004713', ('44', '47'))	('inability', 'NegReg', (143, 152))	('JAK1/2', 'Gene', '3716;3717', (44, 50))	('JAK1/2', 'Gene', (44, 50))	('interferon gamma', 'Gene', (175, 191))	('human', 'Species', '9606', (14, 19))	('interferon gamma', 'Gene', '3458', (105, 121))	('PD-L1', 'Gene', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('interferon gamma', 'molecular_function', 'GO:0005133', ('105', '121'))	('PD-L1', 'Gene', '29126', (83, 88))	('signal', 'MPA', (156, 162))	('interferon gamma', 'Gene', '3458', (175, 191))
19252	27903500	JAK1/2 loss-of-function alterations in TCGA confer adverse outcomes in patients.	('JAK1/2', 'Gene', '3716;3717', (0, 6))	('alterations', 'Var', (24, 35))	('loss-of-function', 'NegReg', (7, 23))	('patients', 'Species', '9606', (71, 79))	('JAK1/2', 'Gene', (0, 6))	('TCGA', 'Gene', (39, 43))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))
19253	27903500	We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.	('loss-of-function', 'NegReg', (23, 39))	('PD-L1', 'Gene', (94, 99))	('PD-1', 'Gene', (178, 182))	('JAK1/2', 'Gene', (16, 22))	('PD-L1', 'Gene', '29126', (94, 99))	('expression', 'MPA', (100, 110))	('mutations', 'Var', (40, 49))	('interferon gamma', 'Gene', '3458', (127, 143))	('PD-1', 'Gene', '5133', (178, 182))	('JAK1/2', 'Gene', '3716;3717', (16, 22))	('JAK', 'molecular_function', 'GO:0004713', ('16', '19'))	('response to interferon gamma', 'biological_process', 'GO:0034341', ('115', '143'))	('lack', 'NegReg', (77, 81))	('interferon gamma', 'molecular_function', 'GO:0005133', ('127', '143'))	('interferon gamma', 'Gene', (127, 143))
19254	27903500	Blocking the programmed death 1 (PD-1) negative immune receptor results in unprecedented rates of long lasting anti-tumor activity in patients with metastatic cancers of different histologies, including melanoma, Hodgkin's disease, Merkel cell, head and neck, lung, esophageal, gastric, liver, kidney, ovarian, bladder and high mutational load cancers with defective mismatch repair, among others in a rapidly growing list.	('cancers', 'Disease', (344, 351))	('mismatch repair', 'biological_process', 'GO:0006298', ('367', '382'))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('Merkel cell', 'Disease', (232, 243))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('cancers', 'Disease', (159, 166))	('kidney', 'Disease', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	("Hodgkin's disease", 'Disease', (213, 230))	('PD-1', 'Gene', (33, 37))	('PD-1', 'Gene', '5133', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (344, 351))	('esophageal', 'Disease', (266, 276))	('programmed death 1', 'Gene', '5133', (13, 31))	('ovarian', 'Disease', (302, 309))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (213, 230))	("Hodgkin's disease", 'Phenotype', 'HP:0012189', (213, 230))	('gastric', 'Disease', (278, 285))	('bladder', 'Disease', (311, 318))	('programmed death 1', 'Gene', (13, 31))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('high mutational load', 'Var', (323, 343))	('lung', 'Disease', (260, 264))	('neck', 'cellular_component', 'GO:0044326', ('254', '258'))	('liver', 'Disease', (287, 292))	('tumor', 'Disease', (116, 121))	('cancers', 'Phenotype', 'HP:0002664', (344, 351))
19257	27903500	Most of these genes lead to beneficial antitumor effects, such as increased antigen presentation through inducible proteasome subunits, transporters associated with antigen processing (TAP) and the major histocompatibility complex (MHC), as well as increased production of chemokines attracting T cells and direct tumor growth arrest and apoptosis.	('growth arrest', 'Phenotype', 'HP:0001510', (320, 333))	('tumor', 'Disease', (314, 319))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('increased', 'PosReg', (249, 258))	('production', 'MPA', (259, 269))	('tumor growth arrest', 'Disease', 'MESH:D006323', (314, 333))	('apoptosis', 'CPA', (338, 347))	('tumor growth arrest', 'Disease', (314, 333))	('increased', 'PosReg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('antigen processing', 'biological_process', 'GO:0019882', ('165', '183'))	('apoptosis', 'biological_process', 'GO:0097194', ('338', '347'))	('antigen presentation', 'biological_process', 'GO:0019882', ('76', '96'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('338', '347'))	('beneficial', 'PosReg', (28, 38))	('proteasome', 'molecular_function', 'GO:0004299', ('115', '125'))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('198', '230'))	('genes', 'Var', (14, 19))	('proteasome', 'cellular_component', 'GO:0000502', ('115', '125'))	('antigen presentation', 'MPA', (76, 96))
19259	27903500	Acquired resistance to PD-1 blockade in patients with advanced melanoma can be associated with loss-of-function mutations with loss of heterozygosity in JAK1/2 or in beta 2-microglobulin (B2M).	('loss-of-function', 'NegReg', (95, 111))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('PD-1', 'Gene', (23, 27))	('B2M', 'Gene', '567', (188, 191))	('PD-1', 'Gene', '5133', (23, 27))	('beta 2-microglobulin', 'Gene', '567', (166, 186))	('B2M', 'Gene', (188, 191))	('patients', 'Species', '9606', (40, 48))	('JAK', 'molecular_function', 'GO:0004713', ('153', '156'))	('beta 2-microglobulin', 'Gene', (166, 186))	('mutations', 'Var', (112, 121))	('JAK1/2', 'Gene', '3716;3717', (153, 159))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('loss of', 'NegReg', (127, 134))	('melanoma', 'Disease', (63, 71))	('JAK1/2', 'Gene', (153, 159))
19260	27903500	The complex genetic changes leading to acquired resistance to PD-1 blockade, wherein one JAK1/2 allele was mutated and amplified and the other was lost, suggest a strong selective pressure induced by the therapeutic immune response.	('JAK', 'molecular_function', 'GO:0004713', ('89', '92'))	('lost', 'NegReg', (147, 151))	('JAK1/2', 'Gene', (89, 95))	('mutated', 'Var', (107, 114))	('PD-1', 'Gene', (62, 66))	('PD-1', 'Gene', '5133', (62, 66))	('immune response', 'biological_process', 'GO:0006955', ('216', '231'))	('JAK1/2', 'Gene', '3716;3717', (89, 95))
19264	27903500	We identified tumors with homozygous loss of function mutations in JAK1 and JAK2 and studied the functional effects of deficient interferon gamma receptor signaling that lead to a genetically-mediated absence of PD-L1 expression upon interferon gamma exposure.	('loss of function', 'NegReg', (37, 53))	('JAK2', 'Gene', (76, 80))	('interferon gamma', 'Gene', (234, 250))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('interferon gamma', 'Gene', (129, 145))	('JAK1', 'Gene', '3716', (67, 71))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('PD-L1', 'Gene', (212, 217))	('interferon gamma', 'molecular_function', 'GO:0005133', ('129', '145'))	('interferon gamma', 'Gene', '3458', (234, 250))	('interferon gamma', 'molecular_function', 'GO:0005133', ('234', '250'))	('PD-L1', 'Gene', '29126', (212, 217))	('JAK', 'molecular_function', 'GO:0004713', ('76', '79'))	('JAK', 'molecular_function', 'GO:0004713', ('67', '70'))	('interferon gamma', 'Gene', '3458', (129, 145))	('tumors', 'Disease', (14, 20))	('JAK2', 'Gene', '3717', (76, 80))	('absence', 'NegReg', (201, 208))	('deficient', 'NegReg', (119, 128))	('JAK1', 'Gene', (67, 71))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'MPA', (218, 228))
19265	27903500	Recent data indicates that tumors with high mutational burden are more likely to have clinical responses to PD-1 blockade therapy.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('high mutational burden', 'Var', (39, 61))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('PD-1', 'Gene', (108, 112))	('clinical responses', 'MPA', (86, 104))	('PD-1', 'Gene', '5133', (108, 112))
19269	27903500	We then assessed whether loss-of-function mutations in interferon receptor signaling molecules, which would prevent adaptive expression of PD-L1, might be present in tumors with relatively high mutational load that did not respond to therapy.	('PD-L1', 'Gene', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('interferon receptor', 'Gene', '3455', (55, 74))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('interferon receptor', 'Gene', (55, 74))	('loss-of-function', 'NegReg', (25, 41))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('PD-L1', 'Gene', '29126', (139, 144))	('expression', 'MPA', (125, 135))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (42, 51))
19270	27903500	A melanoma biopsy from the patient with the highest mutational load among the 9 non-responders (patient #15) had a somatic P429S missense mutation in the src-homology (SH2) domain of JAK1 (Fig.	('JAK1', 'Gene', '3716', (183, 187))	('JAK', 'molecular_function', 'GO:0004713', ('183', '186'))	('patient', 'Species', '9606', (96, 103))	('melanoma', 'Disease', 'MESH:D008545', (2, 10))	('patient', 'Species', '9606', (27, 34))	('melanoma', 'Phenotype', 'HP:0002861', (2, 10))	('melanoma', 'Disease', (2, 10))	('P429S', 'Mutation', 'p.P429S', (123, 128))	('P429S missense', 'Var', (123, 137))	('JAK1', 'Gene', (183, 187))
19272	27903500	None of the tumors from the other 22 patients had homozygous loss-of-function mutations or deletions in the interferon receptor pathway.	('interferon receptor', 'Gene', '3455', (108, 127))	('patients', 'Species', '9606', (37, 45))	('deletions', 'Var', (91, 100))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('interferon receptor', 'Gene', (108, 127))	('loss-of-function', 'NegReg', (61, 77))
19273	27903500	Rather, the other JAK2 mutations found in biopsies of responders had low variant allele frequency as shown in Fig.	('JAK', 'molecular_function', 'GO:0004713', ('18', '21'))	('variant', 'MPA', (73, 80))	('mutations', 'Var', (23, 32))	('JAK2', 'Gene', '3717', (18, 22))	('low', 'NegReg', (69, 72))	('JAK2', 'Gene', (18, 22))
19274	27903500	Two non-responders had IFNGR mutations, also of low allele frequency and therefore uncertain significance.	('IFNGR', 'Gene', (23, 28))	('IFNGR', 'Gene', '3459', (23, 28))	('mutations', 'Var', (29, 38))
19276	27903500	In contrast, the baseline biopsy from patient #15 with a high mutational load but with the JAK1 (P429S) missense mutation had undetectable CD8 infiltrates, PD-1 and PD-L1 expression (Supplementary Fig.	('expression', 'MPA', (171, 181))	('mutational', 'Var', (62, 72))	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('JAK1', 'Gene', (91, 95))	('patient', 'Species', '9606', (38, 45))	('PD-L1', 'Gene', (165, 170))	('JAK1', 'Gene', '3716', (91, 95))	('PD-1', 'Gene', '5133', (156, 160))	('JAK', 'molecular_function', 'GO:0004713', ('91', '94'))	('PD-1', 'Gene', (156, 160))	('PD-L1', 'Gene', '29126', (165, 170))	('P429S', 'Mutation', 'p.P429S', (97, 102))
19277	27903500	The amplification of PD-L1, PD-L2 and JAK2 (PDJ amplicon), which has been associated with a high response rate in Hodgkin's disease, was noted only in patient #16 who did not respond to PD-1 blockade therapy despite having the second highest mutational load and a high level of PD-L1 expression (Fig.	('JAK', 'molecular_function', 'GO:0004713', ('38', '41'))	("Hodgkin's disease", 'Disease', (114, 131))	('PD-L2', 'Gene', (28, 33))	('PD-L1', 'Gene', '29126', (278, 283))	('mutational', 'Var', (242, 252))	('patient', 'Species', '9606', (151, 158))	('JAK2', 'Gene', '3717', (38, 42))	("Hodgkin's disease", 'Phenotype', 'HP:0012189', (114, 131))	('PD-L1', 'Gene', (21, 26))	('PD-L2', 'Gene', '80380', (28, 33))	('JAK2', 'Gene', (38, 42))	('PD-1', 'Gene', '5133', (186, 190))	('PD-1', 'Gene', (186, 190))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (114, 131))	('PD-L1', 'Gene', (278, 283))	('PD-L1', 'Gene', '29126', (21, 26))
19286	27903500	Two cell lines had JAK1/2 homozygous loss of function mutations and did not respond to interferon gamma with upregulation of surface PD-L1 expression.	('loss of function', 'NegReg', (37, 53))	('JAK1/2', 'Gene', (19, 25))	('interferon gamma', 'Gene', '3458', (87, 103))	('PD-L1', 'Gene', (133, 138))	('surface', 'MPA', (125, 132))	('JAK', 'molecular_function', 'GO:0004713', ('19', '22'))	('upregulation', 'PosReg', (109, 121))	('mutations', 'Var', (54, 63))	('interferon gamma', 'molecular_function', 'GO:0005133', ('87', '103'))	('interferon gamma', 'Gene', (87, 103))	('PD-L1', 'Gene', '29126', (133, 138))	('JAK1/2', 'Gene', '3716;3717', (19, 25))	('expression', 'MPA', (139, 149))
19287	27903500	M368 had a mutation in JAK2 (20 out of 22 reads, variant allele frequency 0.91) that is predicted to disrupt and shift the D313 splice site acceptor in exon 8 by one nucleotide, changing the reading frame, and had loss of the wild type allele (Fig.	('JAK2', 'Gene', (23, 27))	('JAK', 'molecular_function', 'GO:0004713', ('23', '26'))	('reading frame', 'MPA', (191, 204))	('M368', 'Var', (0, 4))	('disrupt', 'NegReg', (101, 108))	('changing', 'Reg', (178, 186))	('D313 splice site acceptor', 'MPA', (123, 148))	('JAK2', 'Gene', '3717', (23, 27))
19288	27903500	M395 had an inactivating JAK1 D775N kinase domain mutation in exon 17 and loss of the other allele (140 out of 143 reads, variant allele frequency 0.98, Fig.	('inactivating', 'Reg', (12, 24))	('JAK', 'molecular_function', 'GO:0004713', ('25', '28'))	('M395', 'Var', (0, 4))	('JAK1', 'Gene', (25, 29))	('D775N', 'Var', (30, 35))	('JAK1', 'Gene', '3716', (25, 29))	('D775N', 'Mutation', 'p.D775N', (30, 35))
19289	27903500	M368 with the JAK2 loss of function mutation maintained signaling in response to interferon alpha and beta, but did not respond to interferon gamma (Fig.	('JAK', 'molecular_function', 'GO:0004713', ('14', '17'))	('JAK2', 'Gene', '3717', (14, 18))	('mutation', 'Var', (36, 44))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('response to interferon alpha', 'biological_process', 'GO:0035455', ('69', '97'))	('signaling', 'MPA', (56, 65))	('JAK2', 'Gene', (14, 18))	('interferon gamma', 'molecular_function', 'GO:0005133', ('131', '147'))	('loss of function', 'NegReg', (19, 35))
19291	27903500	M395 with the JAK1 loss of function mutation did not respond to downstream signaling to either interferon alpha, beta or gamma (Fig.	('JAK', 'molecular_function', 'GO:0004713', ('14', '17'))	('not', 'NegReg', (49, 52))	('interferon alpha, beta or gamma', 'Gene', '3456;3458', (95, 126))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('loss of function', 'NegReg', (19, 35))	('JAK1', 'Gene', (14, 18))	('JAK1', 'Gene', '3716', (14, 18))	('respond to downstream signaling', 'MPA', (53, 84))	('interferon alpha, beta', 'molecular_function', 'GO:0005132', ('95', '117'))	('mutation', 'Var', (36, 44))
19293	27903500	We were able to retrieve the tumor from which the cell line M395 had been established, and this tumor had absence of CD8 infiltration similar to the finding of patient #15 with a JAK1 loss of function mutation not responding to anti-PD-1 therapy (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss of function', 'NegReg', (184, 200))	('JAK', 'molecular_function', 'GO:0004713', ('179', '182'))	('PD-1', 'Gene', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (96, 101))	('PD-1', 'Gene', '5133', (233, 237))	('JAK1', 'Gene', (179, 183))	('JAK1', 'Gene', '3716', (179, 183))	('tumor', 'Disease', (29, 34))	('CD8', 'Gene', (117, 120))	('CD8', 'Gene', '925', (117, 120))	('mutation', 'Var', (201, 209))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
19295	27903500	To assess a causal relationship between loss of adaptive PD-L1 expression and loss-of-function JAK mutations, we transduced the M395 and M431 cell lines with a lentivirus vector expressing JAK1 wild-type (Supplementary Fig.	('M431', 'CellLine', 'CVCL:0037', (137, 141))	('JAK', 'Gene', (95, 98))	('PD-L1', 'Gene', (57, 62))	('PD-L1', 'Gene', '29126', (57, 62))	('mutations', 'Var', (99, 108))	('JAK1', 'Gene', (189, 193))	('JAK', 'molecular_function', 'GO:0004713', ('189', '192'))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('JAK1', 'Gene', '3716', (189, 193))	('loss-of-function', 'NegReg', (78, 94))
19296	27903500	Reintroducing the JAK1 wild-type protein corrected the interferon gamma-induced PD-L1 expression for M395, with a 4-fold increase in PD-L1 surface expression after interferon gamma exposure (Fig.	('JAK', 'molecular_function', 'GO:0004713', ('18', '21'))	('JAK1', 'Gene', '3716', (18, 22))	('PD-L1', 'Gene', (80, 85))	('interferon gamma', 'Gene', '3458', (164, 180))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('interferon gamma', 'Gene', (164, 180))	('PD-L1', 'Gene', (133, 138))	('increase', 'PosReg', (121, 129))	('interferon gamma', 'molecular_function', 'GO:0005133', ('55', '71'))	('interferon gamma', 'molecular_function', 'GO:0005133', ('164', '180'))	('interferon gamma', 'Gene', (55, 71))	('PD-L1', 'Gene', '29126', (80, 85))	('expression', 'MPA', (86, 96))	('PD-L1', 'Gene', '29126', (133, 138))	('JAK1', 'Gene', (18, 22))	('M395', 'Var', (101, 105))	('interferon gamma', 'Gene', '3458', (55, 71))
19297	27903500	For M431, the magnitude of change in PD-L1 expression after 18-hour interferon gamma exposure for M431 was modest after reintroducing the JAK1 wild-type protein (approximately 2-fold, compared to a 1.5 fold in the untransduced cell line) (Fig.	('JAK1', 'Gene', '3716', (138, 142))	('M431', 'CellLine', 'CVCL:0037', (98, 102))	('interferon gamma', 'molecular_function', 'GO:0005133', ('68', '84'))	('PD-L1', 'Gene', (37, 42))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('M431', 'CellLine', 'CVCL:0037', (4, 8))	('interferon gamma', 'Gene', '3458', (68, 84))	('PD-L1', 'Gene', '29126', (37, 42))	('JAK', 'molecular_function', 'GO:0004713', ('138', '141'))	('JAK1', 'Gene', (138, 142))	('M431', 'Var', (98, 102))	('interferon gamma', 'Gene', (68, 84))
19300	27903500	To determine whether JAK1/2 loss of function mutations are present and relate to response to PD-1 blockade therapy in another cancer histology, we analyzed whole exome sequencing data from 16 biopsies of patients with colon cancer, many with a high mutational load resultant from mismatch-repair deficiency.	('patients', 'Species', '9606', (204, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (218, 230))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mismatch-repair', 'biological_process', 'GO:0006298', ('280', '295'))	('JAK1/2', 'Gene', '3716;3717', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('colon cancer', 'Disease', 'MESH:D015179', (218, 230))	('JAK1/2', 'Gene', (21, 27))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('colon cancer', 'Disease', (218, 230))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('PD-1', 'Gene', (93, 97))	('mismatch-repair', 'Protein', (280, 295))	('JAK', 'molecular_function', 'GO:0004713', ('21', '24'))	('PD-1', 'Gene', '5133', (93, 97))	('cancer', 'Disease', (224, 230))
19301	27903500	One of the biopsies of a rare patient with high mutational load with neither an objective response nor disease control with anti-PD-1 had a homozygous JAK1 W690* nonsense loss-of-function mutation, expected to truncate the protein within the first kinase domain, and an accompanying loss of heterozygosity at the JAK1 locus (Fig.	('patient', 'Species', '9606', (30, 37))	('loss-of-function', 'NegReg', (171, 187))	('protein', 'Protein', (223, 230))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('W690*', 'SUBSTITUTION', 'None', (156, 161))	('JAK', 'molecular_function', 'GO:0004713', ('151', '154'))	('loss', 'NegReg', (283, 287))	('JAK1', 'Gene', (151, 155))	('W690*', 'Var', (156, 161))	('JAK', 'molecular_function', 'GO:0004713', ('313', '316'))	('JAK1', 'Gene', (313, 317))	('JAK1', 'Gene', '3716', (151, 155))	('JAK1', 'Gene', '3716', (313, 317))	('PD-1', 'Gene', (129, 133))	('PD-1', 'Gene', '5133', (129, 133))
19302	27903500	Although we observed other interferon-pathway and antigen presentation mutations in the high mutational load patients with a response to therapy in this cohort, they appeared to be heterozygous by allele frequency (adjusted VAF < 0.6) after adjustment for stromal content.	('patients', 'Species', '9606', (109, 117))	('high mutational load', 'Var', (88, 108))	('antigen presentation', 'Gene', (50, 70))	('mutations', 'Var', (71, 80))	('interferon-pathway', 'Gene', (27, 45))	('antigen presentation', 'biological_process', 'GO:0019882', ('50', '70'))
19303	27903500	Several samples bore two mutations in JAK1/2 or B2M, but either retained at least one wild-type copy (subjects #4 and #5), were too far apart to determine cis vs trans status (subject #6), or were of uncertain significance (subject #1, both near c-terminus).	('JAK1/2', 'Gene', '3716;3717', (38, 44))	('JAK', 'molecular_function', 'GO:0004713', ('38', '41'))	('mutations', 'Var', (25, 34))	('JAK1/2', 'Gene', (38, 44))	('B2M', 'Gene', '567', (48, 51))	('B2M', 'Gene', (48, 51))
19304	27903500	We then analyzed data from the Cancer Cell Line Encyclopedia (CCLE) from cBioPortal to determine the frequency of homozygous putative loss of function mutations in JAK1/2 in 905 cancer cell lines.	('JAK1/2', 'Gene', '3716;3717', (164, 170))	('JAK', 'molecular_function', 'GO:0004713', ('164', '167'))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('loss of function', 'NegReg', (134, 150))	('JAK1/2', 'Gene', (164, 170))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (31, 60))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer Cell Line Encyclopedia', 'Disease', (31, 60))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mutations', 'Var', (151, 160))
19305	27903500	The highest frequency of mutations was in endometrial cancers, as described previously.	('mutations', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('endometrial cancers', 'Disease', 'MESH:D016889', (42, 61))	('endometrial cancers', 'Disease', (42, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
19306	27903500	None of these cell lines had POLE or POLD1 mutations, but microsatellite instability and DNA damage gene mutations were present in the JAK1/2 mutant cell lines (Supplementary Fig.	('present', 'Reg', (120, 127))	('DNA damage gene', 'Gene', (89, 104))	('POLD1', 'Gene', (37, 42))	('JAK1/2', 'Gene', '3716;3717', (135, 141))	('POLD1', 'Gene', '5424', (37, 42))	('mutant', 'Var', (142, 148))	('JAK', 'molecular_function', 'GO:0004713', ('135', '138'))	('JAK1/2', 'Gene', (135, 141))	('mutations', 'Var', (105, 114))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('microsatellite instability', 'MPA', (58, 84))
19307	27903500	The frequency of JAK1/2 mutations across all cancers suggests that there is a fitness gain with loss of interferon responsiveness.	('JAK', 'molecular_function', 'GO:0004713', ('17', '20'))	('JAK1/2', 'Gene', '3716;3717', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('JAK1/2', 'Gene', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('fitness gain', 'Disease', (78, 90))	('fitness gain', 'Disease', 'MESH:D015430', (78, 90))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('mutations', 'Var', (24, 33))	('cancers', 'Disease', (45, 52))
19309	27903500	These include loss of function alterations in either JAK1 or JAK2 that would putatively diminish JAK1 or JAK2 signaling (homodeletions, truncating mutations or gene or protein downregulation).	('JAK1', 'Gene', (97, 101))	('JAK2', 'Gene', (105, 109))	('JAK', 'molecular_function', 'GO:0004713', ('97', '100'))	('JAK1', 'Gene', '3716', (53, 57))	('JAK', 'molecular_function', 'GO:0004713', ('105', '108'))	('JAK', 'molecular_function', 'GO:0004713', ('53', '56'))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('JAK2', 'Gene', '3717', (61, 65))	('JAK1', 'Gene', '3716', (97, 101))	('JAK1', 'Gene', (53, 57))	('diminish', 'NegReg', (88, 96))	('truncating mutations', 'Var', (136, 156))	('downregulation', 'NegReg', (176, 190))	('JAK2', 'Gene', '3717', (105, 109))	('JAK', 'molecular_function', 'GO:0004713', ('61', '64'))	('alterations', 'Var', (31, 42))	('loss of function', 'NegReg', (14, 30))	('JAK2', 'Gene', (61, 65))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))
19311	27903500	However, when only considering loss of function JAK1 or JAK2 alterations (homodeletions, truncating mutations or gene or protein downregulation), patients with tumors that had JAK1 or JAK2 alterations had significantly decreased overall survival (p = 0.009, log-rank test).	('JAK', 'molecular_function', 'GO:0004713', ('176', '179'))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('JAK2', 'Gene', '3717', (56, 60))	('JAK1', 'Gene', (48, 52))	('JAK2', 'Gene', (184, 188))	('overall survival', 'MPA', (229, 245))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('patients', 'Species', '9606', (146, 154))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('JAK2', 'Gene', (56, 60))	('JAK1', 'Gene', '3716', (176, 180))	('JAK', 'molecular_function', 'GO:0004713', ('56', '59'))	('JAK1', 'Gene', '3716', (48, 52))	('downregulation', 'NegReg', (129, 143))	('decreased', 'NegReg', (219, 228))	('JAK', 'molecular_function', 'GO:0004713', ('184', '187'))	('JAK2', 'Gene', '3717', (184, 188))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('JAK1', 'Gene', (176, 180))	('alterations', 'Var', (189, 200))
19312	27903500	When considered separately, the eight patients with truncating mutations in JAK1 or JAK2 and the 18 patients with JAK1 or JAK2 gene or protein downregulation also had significantly decreased overall survival (p=.016 and p<.001, respectively).	('JAK1', 'Gene', (114, 118))	('JAK', 'molecular_function', 'GO:0004713', ('122', '125'))	('downregulation', 'NegReg', (143, 157))	('JAK2', 'Gene', (122, 126))	('patients', 'Species', '9606', (100, 108))	('JAK', 'molecular_function', 'GO:0004713', ('84', '87'))	('patients', 'Species', '9606', (38, 46))	('truncating mutations', 'Var', (52, 72))	('JAK1', 'Gene', '3716', (76, 80))	('JAK', 'molecular_function', 'GO:0004713', ('114', '117'))	('overall', 'MPA', (191, 198))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('protein', 'Protein', (135, 142))	('JAK2', 'Gene', '3717', (84, 88))	('decreased', 'NegReg', (181, 190))	('JAK', 'molecular_function', 'GO:0004713', ('76', '79'))	('JAK1', 'Gene', '3716', (114, 118))	('JAK1', 'Gene', (76, 80))	('JAK2', 'Gene', '3717', (122, 126))	('JAK2', 'Gene', (84, 88))
19313	27903500	To assess the relevance of these findings in a broader set of malignancies, we examined the frequency of JAK1 and JAK2 alterations and their association with clinical outcome in TCGA datasets for four common malignancies (breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma', 'Disease', 'MESH:D000077192', (222, 293))	('JAK', 'molecular_function', 'GO:0004713', ('105', '108'))	('malignancies', 'Disease', (208, 220))	('JAK2', 'Gene', (114, 118))	('colorectal adenocarcinoma', 'Disease', (299, 324))	('JAK1', 'Gene', '3716', (105, 109))	('JAK', 'molecular_function', 'GO:0004713', ('114', '117'))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (274, 293))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (299, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('alterations', 'Var', (119, 130))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (222, 247))	('malignancies', 'Disease', (62, 74))	('JAK1', 'Gene', (105, 109))	('JAK2', 'Gene', '3717', (114, 118))
19314	27903500	Similar to findings in melanoma, alterations in JAK1 were found in 6%, 8%, 10% and 10% of patients with breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma and colorectal adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('breast invasive carcinoma, prostate adenocarcinoma, lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 175))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (104, 129))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('colorectal adenocarcinoma', 'Disease', (180, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('alterations', 'Var', (33, 44))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (180, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('found', 'Reg', (58, 63))	('patients', 'Species', '9606', (90, 98))	('JAK1', 'Gene', (48, 52))	('JAK1', 'Gene', '3716', (48, 52))
19317	27903500	However, for patients with breast invasive carcinoma harboring truncating mutations, there was an association with decreased survival (p=.006, log-rank test, Fig.	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (27, 52))	('survival', 'MPA', (125, 133))	('patients', 'Species', '9606', (13, 21))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (27, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('breast invasive carcinoma', 'Disease', (27, 52))	('decreased', 'NegReg', (115, 124))	('truncating mutations', 'Var', (63, 83))
19318	27903500	Likewise, patients with prostate adenocarcinoma harboring truncating mutations had worse overall survival (p=.009, log-rank test, Fig.	('worse', 'NegReg', (83, 88))	('prostate adenocarcinoma', 'Disease', (24, 47))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (24, 47))	('overall survival', 'MPA', (89, 105))	('patients', 'Species', '9606', (10, 18))	('truncating mutations', 'Var', (58, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
19319	27903500	6C), with a similar trend noted in patients harboring any loss of function JAK1 or JAK2 alteration (p=.083, Fig.	('JAK', 'molecular_function', 'GO:0004713', ('75', '78'))	('JAK1', 'Gene', (75, 79))	('JAK2', 'Gene', '3717', (83, 87))	('JAK1', 'Gene', '3716', (75, 79))	('patients', 'Species', '9606', (35, 43))	('JAK2', 'Gene', (83, 87))	('JAK', 'molecular_function', 'GO:0004713', ('83', '86'))	('alteration', 'Var', (88, 98))
19320	27903500	We did not observe differences in survival in patients with lung adenocarcinoma or colorectal adenocarcinoma harboring JAK1 or JAK2 loss of function alterations, either when considered separately or as a whole (Supplementary Fig.	('JAK2', 'Gene', '3717', (127, 131))	('alterations', 'Var', (149, 160))	('patients', 'Species', '9606', (46, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('JAK', 'molecular_function', 'GO:0004713', ('127', '130'))	('colorectal adenocarcinoma', 'Disease', (83, 108))	('JAK1', 'Gene', (119, 123))	('JAK1', 'Gene', '3716', (119, 123))	('JAK2', 'Gene', (127, 131))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (83, 108))	('lung adenocarcinoma', 'Disease', (60, 79))	('loss of function', 'NegReg', (132, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('JAK', 'molecular_function', 'GO:0004713', ('119', '122'))
19327	27903500	JAK kinases mediate signaling from many cytokine receptors, but the commonality between JAK1 and JAK2 homozygous loss of function mutations is that they are both required for signaling upon exposure to interferon gamma.	('JAK1', 'Gene', (88, 92))	('interferon gamma', 'Gene', (202, 218))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('JAK', 'molecular_function', 'GO:0004713', ('97', '100'))	('JAK1', 'Gene', '3716', (88, 92))	('interferon gamma', 'molecular_function', 'GO:0005133', ('202', '218'))	('mutations', 'Var', (130, 139))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('interferon gamma', 'Gene', '3458', (202, 218))	('JAK2', 'Gene', '3717', (97, 101))	('JAK', 'molecular_function', 'GO:0004713', ('88', '91'))	('loss of function', 'NegReg', (113, 129))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('JAK2', 'Gene', (97, 101))
19330	27903500	In that setting, T cells continued to recognize cancer cells with JAK1 or JAK2 mutations despite the known role of interferon gamma signaling in upregulating a series of genes involved in the antigen presenting machinery.	('JAK2', 'Gene', '3717', (74, 78))	('interferon gamma', 'Gene', '3458', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('JAK2', 'Gene', (74, 78))	('JAK', 'molecular_function', 'GO:0004713', ('74', '77'))	('interferon gamma', 'Gene', (115, 131))	('signaling', 'biological_process', 'GO:0023052', ('132', '141'))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('JAK', 'molecular_function', 'GO:0004713', ('66', '69'))	('JAK1', 'Gene', (66, 70))	('interferon gamma', 'molecular_function', 'GO:0005133', ('115', '131'))	('JAK1', 'Gene', '3716', (66, 70))	('mutations', 'Var', (79, 88))	('upregulating', 'PosReg', (145, 157))
19332	27903500	In primary resistance to checkpoint blockade therapy with the anti-CTLA-4 antibody ipilimumab, there is a higher frequency of mutations in the several molecules involved in the interferon signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('188', '205'))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('ipilimumab', 'Chemical', 'MESH:D000074324', (83, 93))	('CTLA-4', 'Gene', (67, 73))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('mutations', 'Var', (126, 135))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))	('CTLA-4', 'Gene', '1493', (67, 73))
19333	27903500	It is hypothesized that cancer cells lacking interferon receptor signaling would have a selective advantage because they evade T cells activated by CTLA-4 blockade, in particular through decreased antigen presentation and resistance to the anti-proliferative effects of interferons.	('CTLA-4', 'Gene', '1493', (148, 154))	('interferon receptor', 'Gene', '3455', (45, 64))	('antigen presentation', 'biological_process', 'GO:0019882', ('197', '217'))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('evade', 'NegReg', (121, 126))	('CTLA-4', 'Gene', (148, 154))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('blockade', 'Var', (155, 163))	('interferon receptor', 'Gene', (45, 64))	('decreased', 'NegReg', (187, 196))	('resistance', 'CPA', (222, 232))	('antigen presentation', 'MPA', (197, 217))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
19334	27903500	The same processes may have an important role in the lack of response to anti-PD-1 therapy in the cancers with JAK1/2 loss of function mutations in our series, as antitumor T cells would be anticipated to have lower ability to recognize and kill cancer cells.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('JAK', 'molecular_function', 'GO:0004713', ('111', '114'))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Disease', (167, 172))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('loss of function', 'NegReg', (118, 134))	('PD-1', 'Gene', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('PD-1', 'Gene', '5133', (78, 82))	('JAK1/2', 'Gene', '3716;3717', (111, 117))	('JAK1/2', 'Gene', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
19335	27903500	Loss of function mutations in JAK1/2 would likewise prevent the antitumor activity of any immunotherapy that results in the activation of T cells to attack cancer cells.	('tumor', 'Disease', (68, 73))	('JAK1/2', 'Gene', (30, 36))	('activation', 'PosReg', (124, 134))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('JAK', 'molecular_function', 'GO:0004713', ('30', '33'))	('Loss of function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('prevent', 'NegReg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('JAK1/2', 'Gene', '3716;3717', (30, 36))	('mutations', 'Var', (17, 26))	('T cells', 'CPA', (138, 145))
19338	27903500	Indeed, in both the patient in the melanoma series with a JAK1 loss of function and the biopsy from which we had derived a melanoma cell line with a JAK1 mutation were completely devoid of T cell infiltrates.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('JAK1', 'Gene', (149, 153))	('JAK', 'molecular_function', 'GO:0004713', ('149', '152'))	('JAK1', 'Gene', '3716', (149, 153))	('mutation', 'Var', (154, 162))	('loss of function', 'NegReg', (63, 79))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('patient', 'Species', '9606', (20, 27))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('JAK', 'molecular_function', 'GO:0004713', ('58', '61'))	('JAK1', 'Gene', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('JAK1', 'Gene', '3716', (58, 62))	('melanoma', 'Disease', (35, 43))
19339	27903500	As pre-existing T cells in the tumor are a requisite for response to anti-PD-1 therapy, then a JAK1/2 mutation may result in lack of response not only because PD-L1 cannot be reactively expressed but also because the cancer fails to attract T cells due to lack of chemokine production.	('PD-1', 'Gene', '5133', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('JAK1/2', 'Gene', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('PD-L1', 'Gene', '29126', (159, 164))	('mutation', 'Var', (102, 110))	('tumor', 'Disease', (31, 36))	('lack', 'NegReg', (125, 129))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('chemokine production', 'biological_process', 'GO:0032602', ('264', '284'))	('JAK1/2', 'Gene', '3716;3717', (95, 101))	('pre', 'molecular_function', 'GO:0003904', ('3', '6'))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('PD-L1', 'Gene', (159, 164))	('PD-1', 'Gene', (74, 78))
19340	27903500	Beyond a genetic mutation that prevented expression of JAK1/2, it is also possible that epigenetic silencing of JAKs could result in lack of response to interferon gamma, as previously reported for the LNCAP cell line.	('JAKs', 'Gene', '3716;3717', (112, 116))	('interferon gamma', 'Gene', '3458', (153, 169))	('interferon gamma', 'molecular_function', 'GO:0005133', ('153', '169'))	('response to interferon gamma', 'biological_process', 'GO:0034341', ('141', '169'))	('JAKs', 'Gene', (112, 116))	('JAK', 'molecular_function', 'GO:0004713', ('55', '58'))	('mutation', 'Var', (17, 25))	('JAK1/2', 'Gene', '3716;3717', (55, 61))	('JAK1/2', 'Gene', (55, 61))	('interferon gamma', 'Gene', (153, 169))	('epigenetic silencing', 'Var', (88, 108))	('lack', 'NegReg', (133, 137))
19342	27903500	This evidence suggests that the frequency of loss-of-function in JAK1/2 may be higher than can be estimated by exome sequencing analyses as it could occur epigenetically, and in these cases it would provide an option for pharmacological intervention.	('JAK1/2', 'Gene', '3716;3717', (65, 71))	('loss-of-function', 'NegReg', (45, 61))	('epigenetically', 'Var', (155, 169))	('JAK1/2', 'Gene', (65, 71))	('JAK', 'molecular_function', 'GO:0004713', ('65', '68'))
19343	27903500	In conclusion, we propose that JAK1/2 mutations that lead to loss of interferon gamma signaling and prevent adaptive PD-L1 expression upon interferon gamma exposure represent an immunoediting process that define patients with cancer that would not be good candidates for PD-1 blockade therapy.	('interferon gamma', 'molecular_function', 'GO:0005133', ('139', '155'))	('JAK1/2', 'Gene', '3716;3717', (31, 37))	('expression', 'MPA', (123, 133))	('patients', 'Species', '9606', (212, 220))	('JAK1/2', 'Gene', (31, 37))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('loss', 'NegReg', (61, 65))	('interferon gamma', 'Gene', (139, 155))	('interferon gamma', 'Gene', '3458', (69, 85))	('JAK', 'molecular_function', 'GO:0004713', ('31', '34'))	('PD-1', 'Gene', (271, 275))	('PD-1', 'Gene', '5133', (271, 275))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('PD-L1', 'Gene', (117, 122))	('mutations', 'Var', (38, 47))	('interferon gamma', 'molecular_function', 'GO:0005133', ('69', '85'))	('PD-L1', 'Gene', '29126', (117, 122))	('interferon gamma', 'Gene', '3458', (139, 155))	('interferon gamma', 'Gene', (69, 85))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
19345	27903500	The recognition that JAK1/2 loss of function mutations would lead to lack of response to PD-1 blockade therapy could be incorporated in oncogenic sequencing panels used to select patients for precision cancer treatments.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (45, 54))	('JAK1/2', 'Gene', '3716;3717', (21, 27))	('PD-1', 'Gene', (89, 93))	('lack', 'NegReg', (69, 73))	('PD-1', 'Gene', '5133', (89, 93))	('JAK1/2', 'Gene', (21, 27))	('loss of function', 'NegReg', (28, 44))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (202, 208))	('JAK', 'molecular_function', 'GO:0004713', ('21', '24'))
19367	27903500	Primary antibodies included pJak1 (Tyr1022/1023), pJAK2 (Tyr221), pSTAT1 (Tyr701), pSTAT3 (Tyr705), pSTAT5 (Tyr695) and their total proteins; PIAS1, IRF-1, SOCS1 and GAPDH (all from Cell Signaling Technology, Danvers, MA).	('Tyr221', 'Var', (57, 63))	('Tyr705', 'Var', (91, 97))	('IRF-1', 'Gene', '3659', (149, 154))	('PIAS1', 'Gene', (142, 147))	('Tyr701', 'Chemical', '-', (74, 80))	('Tyr1022/1023', 'Var', (35, 47))	('Tyr701', 'Var', (74, 80))	('GAPDH', 'Gene', '2597', (166, 171))	('IRF-1', 'Gene', (149, 154))	('Tyr705', 'Chemical', '-', (91, 97))	('SOCS1', 'Gene', (156, 161))	('Tyr221', 'Chemical', '-', (57, 63))	('JAK2', 'Gene', '3717', (51, 55))	('GAPDH', 'Gene', (166, 171))	('Tyr1022', 'Chemical', '-', (35, 42))	('PIAS1', 'Gene', '8554', (142, 147))	('Signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('Tyr695', 'Chemical', '-', (108, 114))	('Tyr695', 'Var', (108, 114))	('SOCS1', 'Gene', '8651', (156, 161))	('JAK2', 'Gene', (51, 55))
19388	27903500	For detection of potential JAK1 or JAK2 mutations, variants were detected using the Haplotype Caller, and noted for membership in dbSNP 146 and allele frequency from the 1000 Genomes project, and confirmed by visual inspection with the Integrated Genomics Viewer (IGV).	('JAK2', 'Gene', (35, 39))	('JAK', 'molecular_function', 'GO:0004713', ('27', '30'))	('mutations', 'Var', (40, 49))	('JAK1', 'Gene', (27, 31))	('JAK2', 'Gene', '3717', (35, 39))	('JAK1', 'Gene', '3716', (27, 31))	('JAK', 'molecular_function', 'GO:0004713', ('35', '38'))
19391	27903500	To determine the relevance of JAK1 and JAK2 alterations in a broader set of patients, we queried the TCGA skin cutaneous melanoma provisional dataset for the frequency of genetic and expression alterations in JAK1 and JAK2.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (106, 129))	('patients', 'Species', '9606', (76, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('JAK2', 'Gene', (218, 222))	('JAK', 'molecular_function', 'GO:0004713', ('209', '212'))	('JAK1', 'Gene', (30, 34))	('JAK2', 'Gene', (39, 43))	('skin cutaneous melanoma', 'Disease', (106, 129))	('JAK1', 'Gene', (209, 213))	('alterations', 'Var', (194, 205))	('JAK', 'molecular_function', 'GO:0004713', ('30', '33'))	('JAK', 'molecular_function', 'GO:0004713', ('39', '42'))	('JAK', 'molecular_function', 'GO:0004713', ('218', '221'))	('JAK1', 'Gene', '3716', (30, 34))	('JAK1', 'Gene', '3716', (209, 213))	('JAK2', 'Gene', '3717', (39, 43))	('JAK2', 'Gene', '3717', (218, 222))
19393	27903500	We then examined the association of various JAK1 and JAK2 alterations with overall survival for each dataset.	('JAK', 'molecular_function', 'GO:0004713', ('53', '56'))	('JAK', 'molecular_function', 'GO:0004713', ('44', '47'))	('JAK1', 'Gene', (44, 48))	('association', 'Interaction', (21, 32))	('JAK2', 'Gene', (53, 57))	('JAK1', 'Gene', '3716', (44, 48))	('examined', 'Reg', (8, 16))	('JAK2', 'Gene', '3717', (53, 57))	('alterations', 'Var', (58, 69))
19394	27903500	The Mutation Annotation Format (MAF) files containing JAK1 and JAK2 mutations in the TCGA datasets were obtained from Genomic Data Commons.	('JAK1', 'Gene', (54, 58))	('JAK', 'molecular_function', 'GO:0004713', ('63', '66'))	('JAK', 'molecular_function', 'GO:0004713', ('54', '57'))	('JAK1', 'Gene', '3716', (54, 58))	('JAK2', 'Gene', '3717', (63, 67))	('TCGA', 'Gene', (85, 89))	('JAK2', 'Gene', (63, 67))	('mutations', 'Var', (68, 77))
19395	27903500	The putative copy-number alterations (homodeletion events, in particular) available in cBioPortal were obtained from the TCGA datasets using Genomic Identification of Significant Targets in Cancer (GISTIC).	('Cancer', 'Disease', (190, 196))	('Cancer', 'Disease', 'MESH:D009369', (190, 196))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('copy-number', 'Var', (13, 24))
19399	27903500	A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes.	('interferon gamma', 'molecular_function', 'GO:0005133', ('102', '118'))	('PD-L1', 'Gene', (133, 138))	('JAK', 'molecular_function', 'GO:0004713', ('37', '40'))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inability', 'NegReg', (78, 87))	('interferon gamma', 'Gene', '3458', (102, 118))	('JAK1/2', 'Gene', '3716;3717', (37, 43))	('PD-L1', 'Gene', '29126', (133, 138))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('JAK1/2', 'Gene', (37, 43))	('interferon gamma', 'Gene', (102, 118))
19462	33707612	Inhibition of APJ signaling by MM54 significantly decreased the size (p = 0.0047; Fig.	('a', 'Gene', '16870', (44, 45))	('Inhibition', 'NegReg', (0, 10))	('MM54', 'Var', (31, 35))	('a', 'Gene', '16870', (55, 56))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('size', 'MPA', (64, 68))	('MM54', 'Chemical', '-', (31, 35))	('a', 'Gene', '16870', (22, 23))
19464	33707612	Histological analysis of the tumors revealed that blood and lymph vessel densities were higher in B16 Ap metastases (vs. B16 Mock metastases; p < 0.05) and, furthermore, that MM54 inhibited blood vessel formation significantly (p < 0.05; Fig.	('a', 'Gene', '16870', (13, 14))	('a', 'Gene', '16870', (172, 173))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('metastases', 'Disease', (130, 140))	('a', 'Gene', '16870', (108, 109))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('a', 'Gene', '16870', (10, 11))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('metastases', 'Disease', (105, 115))	('MM54', 'Chemical', '-', (175, 179))	('tumors', 'Disease', (29, 35))	('a', 'Gene', '16870', (136, 137))	('formation', 'biological_process', 'GO:0009058', ('203', '212'))	('a', 'Gene', '16870', (111, 112))	('a', 'Gene', '16870', (56, 57))	('a', 'Gene', '16870', (15, 16))	('a', 'Gene', '16870', (221, 222))	('a', 'Gene', '16870', (207, 208))	('Ap', 'Gene', '16870', (102, 104))	('a', 'Gene', '16870', (152, 153))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('MM54', 'Var', (175, 179))	('a', 'Gene', '16870', (47, 48))	('a', 'Gene', '16870', (40, 41))	('higher', 'PosReg', (88, 94))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('inhibited', 'NegReg', (180, 189))	('a', 'Gene', '16870', (133, 134))
19466	33707612	In line with these findings, the number of BrdU positive cells was also significantly increased in the B16 Ap metastases (vs. B16 Mock tumors; p < 0.0001) and MM54 decreased significantly the number of proliferating cells in apelin-overexpressing lung metastases, compared to apelin-overexpressing metastases treated with saline (p < 0.0001; Fig.	('metastases', 'Disease', 'MESH:D009362', (298, 308))	('a', 'Gene', '16870', (258, 259))	('Mock tumors', 'Disease', 'MESH:D009369', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('a', 'Gene', '16870', (155, 156))	('a', 'Gene', '16870', (225, 226))	('a', 'Gene', '16870', (67, 68))	('metastases', 'Disease', (298, 308))	('a', 'Gene', '16870', (304, 305))	('a', 'Gene', '16870', (312, 313))	('a', 'Gene', '16870', (91, 92))	('BrdU', 'Chemical', 'MESH:D001973', (43, 47))	('a', 'Gene', '16870', (210, 211))	('a', 'Gene', '16870', (169, 170))	('lung metastases', 'Disease', 'MESH:D009362', (247, 262))	('MM54', 'Chemical', '-', (159, 163))	('a', 'Gene', '16870', (113, 114))	('saline', 'Chemical', 'MESH:D012965', (322, 328))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('a', 'Gene', '16870', (255, 256))	('a', 'Gene', '16870', (80, 81))	('metastases', 'Disease', 'MESH:D009362', (252, 262))	('lung metastases', 'Disease', (247, 262))	('a', 'Gene', '16870', (301, 302))	('Ap', 'Gene', '16870', (107, 109))	('a', 'Gene', '16870', (64, 65))	('a', 'Gene', '16870', (182, 183))	('metastases', 'Disease', (110, 120))	('a', 'Gene', '16870', (268, 269))	('metastases', 'Disease', (252, 262))	('MM54', 'Var', (159, 163))	('a', 'Gene', '16870', (323, 324))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('a', 'Gene', '16870', (116, 117))	('Mock tumors', 'Disease', (130, 141))	('a', 'Gene', '16870', (276, 277))
19478	33707612	Studying the circulating apelin levels, we found that the plasma levels of apelin were significantly elevated in patients with melanoma (vs. healthy controls, 1.4590 +- 0.2676 ng/ml vs. 0.7704 +- 0.7117 ng/ml, respectively, p = 0.0011; Fig.	('a', 'Gene', '16870', (105, 106))	('a', 'Gene', '16870', (134, 135))	('a', 'Gene', '16870', (143, 144))	('a', 'Gene', '16870', (63, 64))	('a', 'Gene', '16870', (25, 26))	('1.4590 +- 0.2676 ng/ml', 'Var', (159, 181))	('patients', 'Species', '9606', (113, 121))	('a', 'Gene', '16870', (51, 52))	('a', 'Gene', '16870', (19, 20))	('a', 'Gene', '16870', (114, 115))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('a', 'Gene', '16870', (130, 131))	('a', 'Gene', '16870', (75, 76))	('a', 'Gene', '16870', (95, 96))	('a', 'Gene', '16870', (60, 61))
19480	33707612	Similarly, the concentration of vascular endothelial growth factor (VEGF), the key regulator of tumor angiogenesis, was also significantly elevated in patients with melanoma (vs. controls, 0.0689 +- 0.0086 ng/ml vs. 0.0454 +- 0.0128, respectively, p < 0.0001; Fig.	('vascular endothelial growth factor', 'Gene', '7422', (32, 66))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('a', 'Gene', '16870', (172, 173))	('a', 'Gene', '16870', (133, 134))	('0.0689 +- 0.0086 ng/ml', 'Var', (189, 211))	('VEGF', 'Gene', (68, 72))	('a', 'Gene', '16870', (5, 6))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('32', '66'))	('vascular endothelial growth factor', 'Gene', (32, 66))	('a', 'Gene', '16870', (33, 34))	('a', 'Gene', '16870', (88, 89))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('a', 'Gene', '16870', (50, 51))	('melanoma', 'Disease', (165, 173))	('a', 'Gene', '16870', (120, 121))	('a', 'Gene', '16870', (168, 169))	('tumor', 'Disease', (96, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('102', '114'))	('a', 'Gene', '16870', (23, 24))	('a', 'Gene', '16870', (152, 153))	('a', 'Gene', '16870', (102, 103))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('VEGF', 'Gene', '7422', (68, 72))	('a', 'Gene', '16870', (143, 144))	('a', 'Gene', '16870', (38, 39))	('a', 'Gene', '16870', (117, 118))	('patients', 'Species', '9606', (151, 159))	('a', 'Gene', '16870', (61, 62))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
19483	33707612	According to the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database, patients with high apelin expression levels (n = 229) have significantly impaired survival outcomes than those with low apelin-expressing tumors (n = 229; p = 0.038) in the case of patients with skin cutaneous melanoma (Supp Fig.	('A', 'Gene', '16870', (0, 1))	('a', 'Gene', '16870', (140, 141))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('a', 'Gene', '16870', (76, 77))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('a', 'Gene', '16870', (187, 188))	('A', 'Gene', '16870', (71, 72))	('a', 'Gene', '16870', (161, 162))	('a', 'Gene', '16870', (298, 299))	('patients', 'Species', '9606', (266, 274))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (285, 303))	('A', 'Gene', '16870', (55, 56))	('expression', 'MPA', (111, 121))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (280, 303))	('patients', 'Species', '9606', (85, 93))	('a', 'Gene', '16870', (57, 58))	('a', 'Gene', '16870', (288, 289))	('a', 'Gene', '16870', (48, 49))	('a', 'Gene', '16870', (302, 303))	('a', 'Gene', '16870', (104, 105))	('a', 'Gene', '16870', (80, 81))	('a', 'Gene', '16870', (152, 153))	('a', 'Gene', '16870', (78, 79))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('a', 'Gene', '16870', (86, 87))	('high', 'Var', (99, 103))	('a', 'Gene', '16870', (259, 260))	('a', 'Gene', '16870', (173, 174))	('a', 'Gene', '16870', (205, 206))	('Gene Expression', 'biological_process', 'GO:0010467', ('17', '32'))	('a', 'Gene', '16870', (267, 268))	('skin cutaneous melanoma', 'Disease', (280, 303))
19508	33707612	In our study, MM54, a competitive APJ antagonist, inhibited tumor (lymph)angiogenesis and tumor cell proliferation and thus attenuated apelin-induced growth of melanoma lung metastasis.	('melanoma lung metastasis', 'Disease', 'MESH:D009362', (160, 184))	('MM54', 'Var', (14, 18))	('a', 'Gene', '16870', (20, 21))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('a', 'Gene', '16870', (115, 116))	('a', 'Gene', '16870', (163, 164))	('a', 'Gene', '16870', (124, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('a', 'Gene', '16870', (130, 131))	('tumor', 'Disease', (60, 65))	('inhibited', 'NegReg', (50, 59))	('tumor', 'Disease', (90, 95))	('melanoma lung metastasis', 'Disease', (160, 184))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('a', 'Gene', '16870', (177, 178))	('a', 'Gene', '16870', (167, 168))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('a', 'Gene', '16870', (41, 42))	('a', 'Gene', '16870', (73, 74))	('MM54', 'Chemical', '-', (14, 18))	('a', 'Gene', '16870', (135, 136))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('a', 'Gene', '16870', (38, 39))	('a', 'Gene', '16870', (180, 181))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('a', 'Gene', '16870', (86, 87))	('a', 'Gene', '16870', (109, 110))	('angiogenesis', 'biological_process', 'GO:0001525', ('73', '85'))
19509	33707612	MM54 previously reduced glioblastoma growth in an ectopic xenograft tumor model and prolonged the survival of tumor-bearing mice.	('a', 'Gene', '16870', (30, 31))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Disease', (68, 73))	('a', 'Gene', '16870', (35, 36))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('reduced', 'NegReg', (16, 23))	('MM54', 'Chemical', '-', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('prolonged', 'PosReg', (84, 93))	('a', 'Gene', '16870', (104, 105))	('a', 'Gene', '16870', (80, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('a', 'Gene', '16870', (47, 48))	('MM54', 'Var', (0, 4))	('a', 'Gene', '16870', (64, 65))	('glioblastoma', 'Disease', (24, 36))	('tumor', 'Disease', (110, 115))	('a', 'Gene', '16870', (118, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (24, 36))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
19522	33707612	recently showed that apelin ablation enhances effectiveness of anti-angiogenic treatment in preclinical models of mammary and lung cancer and, furthermore, that blocking apelin prevents sunitinib-induced metastases.	('a', 'Gene', '16870', (28, 29))	('a', 'Gene', '16870', (21, 22))	('a', 'Gene', '16870', (138, 139))	('a', 'Gene', '16870', (170, 171))	('a', 'Gene', '16870', (115, 116))	('a', 'Gene', '16870', (132, 133))	('a', 'Gene', '16870', (82, 83))	('a', 'Gene', '16870', (122, 123))	('effectiveness', 'MPA', (46, 59))	('a', 'Gene', '16870', (68, 69))	('a', 'Gene', '16870', (210, 211))	('a', 'Gene', '16870', (18, 19))	('lung cancer', 'Disease', (126, 137))	('a', 'Gene', '16870', (63, 64))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('sunitinib', 'Chemical', 'MESH:D000077210', (186, 195))	('a', 'Gene', '16870', (207, 208))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('a', 'Gene', '16870', (40, 41))	('metastases', 'Disease', (204, 214))	('blocking', 'Var', (161, 169))	('a', 'Gene', '16870', (158, 159))	('prevents', 'NegReg', (177, 185))	('a', 'Gene', '16870', (31, 32))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('a', 'Gene', '16870', (118, 119))	('a', 'Gene', '16870', (101, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))
19618	33572647	(2) Methods: An in vitro model was based on two types of normal human melanocytes (HEMn-DP and HEMn-LP) and four melanoma cell lines (A375, WM1341D, Hs294T, and WM9).	('human', 'Species', '9606', (64, 69))	('A375', 'CellLine', 'CVCL:0132', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('WM9', 'CellLine', 'CVCL:6806', (161, 164))	('HEMn', 'molecular_function', 'GO:0051989', ('95', '99'))	('HEMn', 'molecular_function', 'GO:0051989', ('83', '87'))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('WM1341D', 'Var', (140, 147))	('WM1341D', 'Chemical', '-', (140, 147))
19621	33572647	High PARP1 expression was also associated with the invasiveness of tumor cells.	('High', 'Var', (0, 4))	('invasiveness of tumor', 'Disease', 'MESH:D009361', (51, 72))	('expression', 'MPA', (11, 21))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PARP1', 'Gene', (5, 10))	('invasiveness of tumor', 'Disease', (51, 72))
19624	33572647	In patients with nodal metastases, high PARP1 expression significantly correlated with the presence of microsatellitosis (p = 0.034), but we did not confirm the prognostic significance of PARP1 expression in these patients.	('microsatellitosis', 'Disease', 'None', (103, 120))	('metastases', 'Disease', 'MESH:D009362', (23, 33))	('patients', 'Species', '9606', (214, 222))	('nodal', 'Gene', '4838', (17, 22))	('microsatellitosis', 'Disease', (103, 120))	('correlated', 'Reg', (71, 81))	('metastases', 'Disease', (23, 33))	('patients', 'Species', '9606', (3, 11))	('PARP1', 'Gene', (40, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('nodal', 'Gene', (17, 22))
19627	33572647	In multivariate analysis, high PARP1 expression was an independent unfavorable prognosticator in lymph node-negative cutaneous melanoma patients.	('cutaneous melanoma', 'Disease', (117, 135))	('high', 'Var', (26, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('PARP1', 'Gene', (31, 36))	('patients', 'Species', '9606', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('expression', 'MPA', (37, 47))
19635	33572647	However, their effectiveness is limited due to resistance acquisition and/or the appearance of many different mutations in the tumor cells, varying from patient to patient and also within the tumor in the same patient.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (192, 197))	('mutations', 'Var', (110, 119))	('tumor', 'Disease', (127, 132))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patient', 'Species', '9606', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
19636	33572647	One of the new treatment options could be the application of poly (ADP-ribose) polymerase 1 (PARP1) inhibitors, which are already used in breast and ovarian cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('poly (ADP-ribose) polymerase 1', 'Gene', '142', (61, 91))	('PARP1', 'Gene', (93, 98))	('poly (ADP-ribose) polymerase 1', 'Gene', (61, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('inhibitors', 'Var', (100, 110))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (138, 163))
19645	33572647	Inhibition of PARP1 activity leads to a reduction in Snail1 and vimentin expression and upregulation of the E-cadherin level, which significantly abolished metastasis.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('PARP1', 'Gene', (14, 19))	('Snail1', 'Gene', (53, 59))	('Snail1', 'Gene', '6615', (53, 59))	('metastasis', 'CPA', (156, 166))	('vimentin', 'Gene', '7431', (64, 72))	('upregulation', 'PosReg', (88, 100))	('abolished', 'NegReg', (146, 155))	('reduction', 'NegReg', (40, 49))	('vimentin', 'cellular_component', 'GO:0045099', ('64', '72'))	('expression', 'MPA', (73, 83))	('vimentin', 'Gene', (64, 72))	('cadherin', 'molecular_function', 'GO:0008014', ('110', '118'))	('Inhibition', 'Var', (0, 10))	('vimentin', 'cellular_component', 'GO:0045098', ('64', '72'))
19653	33572647	To realize this purpose, we performed in vitro cell culture studies using two normal melanocyte cell cultures (HEMn-LP and HEMn-DP) and four malignant melanoma cell lines exhibiting various level of invasiveness (two skin-derived cell lines: A375 and WM1341D, and two metastatic lymph node-derived cell lines: Hs294T and WM9).	('HEMn', 'molecular_function', 'GO:0051989', ('111', '115'))	('HEMn', 'molecular_function', 'GO:0051989', ('123', '127'))	('WM9', 'CellLine', 'CVCL:6806', (321, 324))	('malignant melanoma', 'Phenotype', 'HP:0002861', (141, 159))	('malignant melanoma', 'Disease', 'MESH:D008545', (141, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('malignant melanoma', 'Disease', (141, 159))	('A375', 'CellLine', 'CVCL:0132', (242, 246))	('WM1341D', 'Var', (251, 258))	('WM1341D', 'Chemical', '-', (251, 258))
19663	33572647	Then, the membranes were blocked with 5% non-fat milk in Tris-Buffered Saline with Tween 20 (TBST) for 1 h at RT and incubated overnight at 4  C with primary mouse antibodies directed against PARP1 (SC-74470; dilution 1:500; clone B-10, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (SC-365062, Santa Cruz Biotechnology, Santa Cruz, CA, USA), which was used as an internal loading control.	('PARP1', 'Gene', (192, 197))	('mouse', 'Species', '10090', (158, 163))	('SC-365062', 'Var', (338, 347))	('CA', 'Gene', '12310', (275, 277))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '14433', (288, 328))	('CA', 'Gene', '12310', (387, 389))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (288, 328))
19691	33572647	In two normal human melanocyte cell cultures (HEMn-LP and HEMn-DP) and four melanoma cell lines (A375, WM1341D, Hs294T, and WM9), PARP1 protein localization was visualized using confocal microscopy.	('melanoma', 'Disease', (76, 84))	('WM1341D', 'Var', (103, 110))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('WM1341D', 'Chemical', '-', (103, 110))	('human', 'Species', '9606', (14, 19))	('HEMn', 'molecular_function', 'GO:0051989', ('58', '62'))	('protein localization', 'biological_process', 'GO:0008104', ('136', '156'))	('HEMn', 'molecular_function', 'GO:0051989', ('46', '50'))	('A375', 'CellLine', 'CVCL:0132', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('protein', 'Protein', (136, 143))	('WM9', 'CellLine', 'CVCL:6806', (124, 127))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
19695	33572647	Its elevated levels were observed in the A375 cell line, while the signal in WM1341D was comparable to the FI in normal melanocytes.	('A375', 'CellLine', 'CVCL:0132', (41, 45))	('WM1341D', 'Chemical', '-', (77, 84))	('WM1341D', 'Var', (77, 84))	('levels', 'MPA', (13, 19))	('elevated', 'PosReg', (4, 12))
19696	33572647	Again, the level of PARP1 was higher in WM9, Hs294T, and A375 cells compared with WM1341D cells and normal melanocytes (Figure 2a,b).	('WM9', 'CellLine', 'CVCL:6806', (40, 43))	('higher', 'PosReg', (30, 36))	('level', 'MPA', (11, 16))	('WM1341D', 'Chemical', '-', (82, 89))	('Hs294T', 'Var', (45, 51))	('A375', 'CellLine', 'CVCL:0132', (57, 61))	('PARP1', 'Gene', (20, 25))
19703	33572647	In patients without lymph node metastases, high PARP1 expression was significantly associated with thick (according to the Breslow scale), ulcerated, and highly mitogenic primary tumors (p = 0.0016, p = 0.023, and p < 0.001) (Table 3), whereas in patients with nodal metastases, upregulation of PARP1 correlated with the presence of microsatellitosis (p = 0.034) (Supplemental Table S1).	('nodal', 'Gene', (261, 266))	('nodal', 'Gene', '4838', (261, 266))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PARP1', 'Gene', (295, 300))	('microsatellitosis', 'Disease', (333, 350))	('PARP1', 'Gene', (48, 53))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('patients', 'Species', '9606', (247, 255))	('metastases', 'Disease', 'MESH:D009362', (267, 277))	('patients', 'Species', '9606', (3, 11))	('metastases', 'Disease', (31, 41))	('expression', 'MPA', (54, 64))	('thick', 'Disease', (99, 104))	('metastases', 'Disease', (267, 277))	('high', 'Var', (43, 47))	('tumors', 'Disease', (179, 185))	('ulcerated', 'Disease', (139, 148))	('microsatellitosis', 'Disease', 'None', (333, 350))	('upregulation', 'PosReg', (279, 291))
19705	33572647	High PARP1 expression in tumor cells was significantly correlated with shorter cancer-specific overall survival (p = 0.015) in lymph node-negative patients (Figure 4).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('expression', 'MPA', (11, 21))	('tumor', 'Disease', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('patients', 'Species', '9606', (147, 155))	('PARP1', 'Gene', (5, 10))	('shorter', 'NegReg', (71, 78))	('cancer', 'Disease', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
19708	33572647	After adjustment for Breslow thickness, high PARP1 expression was associated with shorter DFS (HR = 3.3, p = 0.005) in lymph node-negative patients (Figure 5).	('high', 'Var', (40, 44))	('patients', 'Species', '9606', (139, 147))	('PARP1', 'Gene', (45, 50))	('expression', 'MPA', (51, 61))	('DFS', 'MPA', (90, 93))	('shorter', 'NegReg', (82, 89))
19711	33572647	Moreover, the high PARP1 level was associated with increased invasiveness of tumor cells.	('increased', 'PosReg', (51, 60))	('invasiveness of tumor', 'Disease', (61, 82))	('PARP1', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('invasiveness of tumor', 'Disease', 'MESH:D009361', (61, 82))
19714	33572647	In our previous studies, we demonstrated that the WM1341D cell line exhibits lower invasive abilities than A375, WM9, and Hs294T cell lines.	('lower', 'NegReg', (77, 82))	('WM9', 'CellLine', 'CVCL:6806', (113, 116))	('WM1341D', 'Var', (50, 57))	('A375', 'CellLine', 'CVCL:0132', (107, 111))	('WM1341D', 'Chemical', '-', (50, 57))	('invasive abilities', 'CPA', (83, 101))
19715	33572647	Compared to other cells, WM1341D formed a lower number of invadopodia (adhesive structures with proteolytic activity), which are utilized by cancer cells to digest the extracellular matrix and invade tissue.	('WM1341D', 'Chemical', '-', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('168', '188'))	('cancer', 'Disease', (141, 147))	('WM1341D', 'Var', (25, 32))
19718	33572647	The smallest number of digesting cells as well as the lowest digestion area were observed in WM1341D cells.	('WM1341D', 'Chemical', '-', (93, 100))	('digestion area', 'MPA', (61, 75))	('WM1341D', 'Var', (93, 100))	('lowest', 'NegReg', (54, 60))	('digestion', 'biological_process', 'GO:0007586', ('61', '70'))
19732	33572647	showed that A375 cells treated with PARP1-i, AZD2461 in combination with onconase, a ribonuclease enzyme with strong antitumor activity in a number of cancers, inhibited the PARP1-NF-kappaB pathway, which resulted in reduced cell colony formation, migration, and invasion as well as elevated induction of apoptosis.	('AZD2461', 'Var', (45, 52))	('elevated', 'PosReg', (283, 291))	('AZD2461', 'Chemical', 'MESH:C000609611', (45, 52))	('A375', 'CellLine', 'CVCL:0132', (12, 16))	('cell colony formation', 'CPA', (225, 246))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('292', '314'))	('tumor', 'Disease', (121, 126))	('PARP1-i', 'Var', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('inhibited', 'NegReg', (160, 169))	('NF-kappaB', 'Gene', (180, 189))	('cancers', 'Disease', (151, 158))	('formation', 'biological_process', 'GO:0009058', ('237', '246'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('invasion', 'CPA', (263, 271))	('apoptosis', 'CPA', (305, 314))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('NF-kappaB', 'Gene', '4790', (180, 189))	('migration', 'CPA', (248, 257))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('reduced', 'NegReg', (217, 224))
19734	33572647	In another study utilizing uveal melanoma cell lines, it was reported that inhibition of PARP1 led to retardation or almost complete inhibition of tumor development.	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('uveal melanoma', 'Disease', (27, 41))	('tumor', 'Disease', (147, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inhibition', 'Var', (75, 85))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('inhibition', 'NegReg', (133, 143))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('retardation', 'Disease', (102, 113))	('retardation', 'Disease', 'MESH:D008607', (102, 113))	('PARP1', 'Gene', (89, 94))
19736	33572647	In acute myeloid leukemia, inhibition of PARP1 induced neoplastic cell apoptosis and arrested cell cycle in G2/M phase.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('cell cycle in G2/M phase', 'CPA', (94, 118))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('PARP1', 'Gene', (41, 46))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('M phase', 'biological_process', 'GO:0000279', ('111', '118'))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('neoplastic cell apoptosis', 'CPA', (55, 80))	('inhibition', 'Var', (27, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('acute myeloid leukemia', 'Disease', (3, 25))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('arrest', 'Disease', (85, 91))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
19738	33572647	Due to the significant correlation between high PARP1 expression and enhanced mitotic activity, potential inhibition of PAPR1 in cutaneous melanoma patients could be beneficial.	('expression', 'MPA', (54, 64))	('PAPR1', 'Gene', (120, 125))	('patients', 'Species', '9606', (148, 156))	('mitotic activity', 'CPA', (78, 94))	('PARP1', 'Gene', (48, 53))	('high', 'Var', (43, 47))	('enhanced', 'PosReg', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('cutaneous melanoma', 'Disease', (129, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 147))
19791	23563206	Additionally, these tumors rarely show mutation of BRAF V600E, however can show various mutations of c-KIT, which may provide a specific target for systemic therapy in a subgroup of patients.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (88, 97))	('c-KIT', 'Gene', (101, 106))	('BRAF', 'Gene', '673', (51, 55))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('BRAF', 'Gene', (51, 55))	('c-KIT', 'Gene', '3815', (101, 106))
19805	23563206	In contrast to cutaneous melanoma, anal melanoma is rarely associated with BRAF mutations.	('mutations', 'Var', (80, 89))	('BRAF', 'Gene', '673', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('cutaneous melanoma', 'Disease', (15, 33))	('associated', 'Reg', (59, 69))	('melanoma', 'Disease', (40, 48))	('BRAF', 'Gene', (75, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (15, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('anal melanoma', 'Phenotype', 'HP:0030444', (35, 48))
19806	23563206	However, studies demonstrate a subset of anal melanomas with KIT mutations, which may be susceptible to tyrosine kinase inhibitors.	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('anal melanoma', 'Phenotype', 'HP:0030444', (41, 54))	('KIT', 'molecular_function', 'GO:0005020', ('61', '64'))	('KIT', 'Gene', (61, 64))	('melanomas', 'Disease', (46, 55))	('mutations', 'Var', (65, 74))
19813	23563206	Regional nodal metastases do not carry the same prognostic significance as in cutaneous melanoma; however, resection of all clinically evident disease can result in long-term cure in a small subset of patients.	('patients', 'Species', '9606', (201, 209))	('metastases', 'Disease', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('resection', 'Var', (107, 116))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('cutaneous melanoma', 'Disease', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))
19817	23563206	Again noted is the extreme rare occurrence of BRAF mutations in the female genital tract variant.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('mutations', 'Var', (51, 60))	('female genital tract', 'Disease', (68, 88))
19818	23563206	However mutations in KIT (exons 11, 13, and 17) have been demonstrated in vulva/vagina melanoma and with commercially available agents targeted towards this mutation (i.e imatinib) may provide another target for treatment of metastatic disease in this population.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('vagina melanoma', 'Phenotype', 'HP:0030418', (80, 95))	('mutations', 'Var', (8, 17))	('vagina melanoma', 'Disease', 'MESH:D008545', (80, 95))	('vagina melanoma', 'Disease', (80, 95))	('KIT', 'molecular_function', 'GO:0005020', ('21', '24'))	('imatinib', 'Chemical', 'MESH:D000068877', (171, 179))	('KIT', 'Gene', (21, 24))	('demonstrated', 'Reg', (58, 70))
19841	23563206	Additionally while BRAF mutations are exceedingly rare in uveal melanomas, there are certain patients whose tumors will exhibit mutations of either KIT or GNAQ , which may offer potential other targets of systemic therapy.	('KIT', 'molecular_function', 'GO:0005020', ('148', '151'))	('BRAF', 'Gene', '673', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (128, 137))	('KIT', 'Gene', (148, 151))	('BRAF', 'Gene', (19, 23))	('GNAQ', 'Gene', '2776', (155, 159))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('uveal melanomas', 'Disease', (58, 73))	('uveal melanomas', 'Phenotype', 'HP:0007716', (58, 73))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('uveal melanomas', 'Disease', 'MESH:C536494', (58, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (58, 72))	('patients', 'Species', '9606', (93, 101))	('GNAQ', 'Gene', (155, 159))
19882	23563206	Use of SLNB, immuno-histochemical stains for Gp100 and Ki67, and molecular analysis for BRAF and NRAS mutations have all been investigated as potential markers.	('NRAS', 'Gene', (97, 101))	('BRAF', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (97, 101))	('BRAF', 'Gene', '673', (88, 92))	('Gp100', 'Gene', (45, 50))	('mutations', 'Var', (102, 111))	('Gp100', 'Gene', '6490', (45, 50))
19908	23563206	The most well-studied specific gene mutation that causes Familial Melanoma Syndrome is cyclin-dependent kinase inhibitor (CDKN)2A (p16), a cyclin-dependent tumor suppressor gene on the short arm of chromosome nine (9p21).	('Familial Melanoma Syndrome', 'Disease', 'OMIM:155600', (57, 83))	('Melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cyclin', 'molecular_function', 'GO:0016538', ('139', '145'))	('Familial Melanoma Syndrome', 'Disease', (57, 83))	('mutation', 'Var', (36, 44))	('p16', 'Gene', '1029', (131, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('87', '120'))	('short arm', 'Phenotype', 'HP:0009824', (185, 194))	('chromosome', 'cellular_component', 'GO:0005694', ('198', '208'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('104', '120'))	('tumor', 'Disease', (156, 161))	('CDKN)2A', 'Gene', '1029', (122, 129))	('p16', 'Gene', (131, 134))	('causes', 'Reg', (50, 56))
19909	23563206	Depending on the family history, up to 40% of patients with a genetic predisposition to melanoma may have a CDKN2A mutation.	('patients', 'Species', '9606', (46, 54))	('CDKN2A', 'Gene', '1029', (108, 114))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('mutation', 'Var', (115, 123))	('CDKN2A', 'Gene', (108, 114))
19910	23563206	In addition, CDKN2A mutation carriers appear to have an increased risk for a variety of other cancers; for instance, pancreatic cancer risk is estimated to be 58% by age 80.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('pancreatic cancer', 'Disease', (117, 134))	('mutation', 'Var', (20, 28))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('CDKN2A', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('CDKN2A', 'Gene', '1029', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
19912	23563206	Since the majority of families with an inherited predisposition to melanoma do not have a mutation in either of these two genes, other yet unidentified loci may contribute to some inherited cases.	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutation', 'Var', (90, 98))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))
19914	23563206	Melanoma risk is multifactorial, influenced by factors such as exposure to ultraviolet light, fair skin type, number of nevi and modifier gene mutations in melanocortin-1 receptor (MC1R).	('MC1R', 'Gene', '4157', (181, 185))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('MC1R', 'Gene', (181, 185))	('melanocortin-1 receptor', 'Gene', '4157', (156, 179))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('influenced', 'Reg', (33, 43))	('fair skin', 'Phenotype', 'HP:0007513', (94, 103))	('Melanoma', 'Disease', (0, 8))	('nevi', 'Phenotype', 'HP:0003764', (120, 124))	('mutations', 'Var', (143, 152))	('melanocortin-1 receptor', 'Gene', (156, 179))
20075	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
20076	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
20114	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))
20153	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
20167	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
20177	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
20214	29144507	The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability.	('melanoma', 'Disease', (90, 98))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('lacking', 'NegReg', (156, 163))	('fragile X mental retardation protein', 'Gene', (109, 145))	('FXS', 'Disease', (216, 219))	('mental retardation', 'Phenotype', 'HP:0001249', (14, 32))	('fragile X mental retardation protein', 'Gene', '2332', (109, 145))	('intellectual disability', 'Phenotype', 'HP:0001249', (258, 281))	('FXS', 'Disease', 'MESH:D005600', (216, 219))	('fragile X syndrome', 'Disease', (196, 214))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('intellectual disability', 'Disease', 'MESH:D008607', (258, 281))	('fragile X mental retardation protein', 'Gene', (4, 40))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('fragile X mental retardation protein', 'Gene', '2332', (4, 40))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('fragile X syndrome', 'Disease', 'MESH:D005600', (196, 214))	('mental retardation', 'Phenotype', 'HP:0001249', (119, 137))	('mutated', 'Var', (167, 174))	('intellectual disability', 'Disease', (258, 281))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
20221	29144507	Mutations or absence of FMRP cause the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability in humans.	('intellectual disability', 'Disease', (101, 124))	('FXS', 'Disease', (59, 62))	('fragile X syndrome', 'Disease', (39, 57))	('intellectual disability', 'Disease', 'MESH:D008607', (101, 124))	('fragile X syndrome', 'Disease', 'MESH:D005600', (39, 57))	('intellectual disability', 'Phenotype', 'HP:0001249', (101, 124))	('FXS', 'Disease', 'MESH:D005600', (59, 62))	('absence', 'NegReg', (13, 20))	('Mutations', 'Var', (0, 9))	('FMRP', 'Gene', (24, 28))	('cause', 'Reg', (29, 34))	('humans', 'Species', '9606', (128, 134))
20239	29144507	Moreover, a survival analysis, comparing high- (Figure 1j) and low-expressing FMR1 primary melanoma (N=47), showed a significant decreased disease-free survival in patients with FMR1-overexpressing tumors (Figure 1l).	('FMR1', 'Gene', '2332', (178, 182))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('high-', 'Var', (41, 46))	('melanoma', 'Disease', (91, 99))	('FMR1', 'Gene', '2332', (78, 82))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('FMR1', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('disease-free survival', 'CPA', (139, 160))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('patients', 'Species', '9606', (164, 172))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('decreased', 'NegReg', (129, 138))	('FMR1', 'Gene', (78, 82))
20248	29144507	To verify whether lack of FMRP might lead to different capacity of melanoma cells to migrate, invade and/or adhere, we knocked down FMRP expression in 501 mel (Supplementary Figure 1a) or A375 cells (Supplementary Figure 1b), treating the cells for 24, 48 or 72 h with a scrambled or specific small interfering RNAs (siRNAs) (FMR1 siRNA).	('FMRP', 'Gene', (132, 136))	('FMR1', 'Gene', (326, 330))	('Supplementary Figure 1a', 'Disease', 'MESH:D017034', (160, 183))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('knocked', 'Var', (119, 126))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('A375', 'CellLine', 'CVCL:0132', (188, 192))	('Supplementary Figure 1a', 'Disease', (160, 183))	('FMR1', 'Gene', '2332', (326, 330))
20249	29144507	After FMRP silencing, migration of 501 mel or A375 cells was followed for 9 h in a wound-healing assay (Figures 3a and b).	('silencing', 'Var', (11, 20))	('FMRP', 'Gene', (6, 10))	('A375', 'CellLine', 'CVCL:0132', (46, 50))	('wound-healing', 'biological_process', 'GO:0042060', ('83', '96'))
20255	29144507	Taken together, these results indicate that FMRP knockdown significantly affects migration, invasion and adhesion properties of melanoma cells, suggesting a role for FMRP in tumor cell invasiveness.	('tumor', 'Disease', (174, 179))	('knockdown', 'Var', (49, 58))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('FMRP', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('affects', 'Reg', (73, 80))	('migration', 'CPA', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
20259	29144507	A quantification of FMRP-gold particles in perinuclear (PN) and under membrane (UM) area (x 20 000 magnification) of 501 mel cells showed that FMRP-gold particles were enriched in the region underlying the plasma membrane (Figure 6i and k) and often aggregated forming multicomponent complexes (Figure 6j, red arrows).	('PN', 'Disease', 'MESH:C565820', (56, 58))	('FMRP-gold', 'Var', (143, 152))	('aggregated', 'Reg', (250, 260))	('plasma membrane', 'cellular_component', 'GO:0005886', ('206', '221'))	('membrane', 'cellular_component', 'GO:0016020', ('70', '78'))
20287	29144507	In particular, FMRP is able to modulate the expression of several mRNAs encoding proteins capable of remodeling the extracellular matrix such as matrix metalloproteinase-8, MMP8, the disintegrins and metalloproteases ADAM19 and ADAM23 and the metalloprotease inhibitor TIMP2 (Supplementary Table 1).	('ADAM23', 'Gene', (228, 234))	('MMP8', 'Gene', '4317', (173, 177))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('116', '136'))	('expression', 'MPA', (44, 54))	('TIMP2', 'Gene', '7077', (269, 274))	('ADAM19', 'Gene', (217, 223))	('matrix metalloproteinase-8', 'Gene', '4317', (145, 171))	('metalloprotease inhibitor', 'molecular_function', 'GO:0008191', ('243', '268'))	('matrix metalloproteinase-8', 'molecular_function', 'GO:0051405', ('145', '171'))	('TIMP2', 'Gene', (269, 274))	('ADAM23', 'Gene', '8745', (228, 234))	('MMP8', 'molecular_function', 'GO:0008130', ('173', '177'))	('modulate', 'Reg', (31, 39))	('mRNAs encoding', 'Gene', (66, 80))	('FMRP', 'Var', (15, 19))	('matrix metalloproteinase-8', 'Gene', (145, 171))	('ADAM19', 'Gene', '8728', (217, 223))	('MMP8', 'Gene', (173, 177))
20298	29144507	Additionally, anticancer therapies that modulate FMRP levels or FMRP-related genes relevant to the biology of the invasive melanoma could represent a promising option for treatment.	('invasive melanoma', 'Disease', (114, 131))	('FMRP-related genes', 'Gene', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('modulate', 'Var', (40, 48))	('invasive melanoma', 'Disease', 'MESH:D008545', (114, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
20306	29144507	The MM001, MM011, MM031, MM032, MM034, MM047, MM057, MM074, MM087, MM099, MM117 and MM118 melanoma cell lines were derived from patients with invasive and metastatic melanomas, upon being shortly cultured in F10 medium with 5% fetal bovine serum (FBS; (HyClone Laboratories, UT, USA) and 5% calf bovine serum (HyClone Laboratories).	('melanoma', 'Disease', (90, 98))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('bovine', 'Species', '9913', (233, 239))	('calf', 'Species', '9913', (291, 295))	('bovine', 'Species', '9913', (296, 302))	('MM034', 'Var', (32, 37))	('MM087', 'Var', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('MM031', 'Var', (18, 23))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanomas', 'Disease', 'MESH:D008545', (166, 175))	('MM057', 'Var', (46, 51))	('MM074', 'Var', (53, 58))	('MM032', 'Var', (25, 30))	('melanomas', 'Disease', (166, 175))	('patients', 'Species', '9606', (128, 136))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
20331	29144507	Membranes were incubated using specific antibodies for FMRP (1 : 500), beta-actin (1 : 1000; Cell Signaling (Leiden, The Netherlands)) and alpha-tubulin (1 : 5000; DSHB, Iowa City, IA, USA) and the signal was detected using an Enhanced Chemiluminescence Kit (GE Healthcare, Little Chalfont, UK).	('1 : 1000;', 'Var', (83, 92))	('1 : 5000;', 'Var', (154, 163))	('alpha-tubulin', 'Protein', (139, 152))	('beta-actin', 'Gene', (71, 81))	('Cell', 'MPA', (93, 97))	('beta-actin', 'Gene', '728378', (71, 81))	('Signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('FMRP', 'Gene', (55, 59))
20368	29034516	Gene PTMA has been suggested as a possible molecular signature underlying melanoma in vivo growth rate, for which increased levels have been found in primary and metastatic melanoma tissues.	('growth', 'MPA', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('Gene', 'Var', (0, 4))	('PTMA', 'Gene', (5, 9))	('PTMA', 'Gene', '5757', (5, 9))
20369	29034516	Inherited mutations in gene CDK4 have been documented in some families with hereditary melanomas and confer a 60%-90% lifetime risk of cutaneous melanoma.	('hereditary melanomas', 'Disease', (76, 96))	('CDK4', 'Gene', '1019', (28, 32))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('hereditary melanomas', 'Disease', 'MESH:D008545', (76, 96))	('cutaneous melanoma', 'Disease', (135, 153))	('CDK', 'molecular_function', 'GO:0004693', ('28', '31'))	('documented', 'Reg', (43, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('mutations', 'Var', (10, 19))	('CDK4', 'Gene', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
20372	29034516	The absence of gene NLRC4, which is an important regulator of key inflammatory signaling pathways in macrophages, has been shown to play a critical role in suppressing tumor growth in cutaneous melanoma.	('NLRC4', 'Gene', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('cutaneous melanoma', 'Disease', (184, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (184, 202))	('tumor growth', 'CPA', (168, 180))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('absence', 'Var', (4, 11))	('suppressing', 'NegReg', (156, 167))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('NLRC4', 'Gene', '58484', (20, 25))
20375	29034516	The DNA hypermethylation of gene EVX1 at precancerous stages has been observed to be strengthened during progression to lung adenocarcinomas and significantly correlated with tumor aggressiveness.	('tumor aggressiveness', 'Disease', (175, 195))	('strengthened', 'PosReg', (85, 97))	('hypermethylation', 'Var', (8, 24))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('4', '24'))	('EVX1', 'Gene', '2128', (33, 37))	('aggressiveness', 'Phenotype', 'HP:0000718', (181, 195))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('correlated with', 'Reg', (159, 174))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (175, 195))	('DNA', 'MPA', (4, 7))	('lung adenocarcinomas', 'Disease', (120, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('EVX1', 'Gene', (33, 37))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (120, 140))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (120, 140))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
20379	29034516	Published analysis has also suggested the strong association between gene BRCA2 and lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('gene', 'Var', (69, 73))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('lung adenocarcinoma', 'Disease', (84, 103))
20384	25484917	We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('K36M', 'Var', (44, 48))	('H3.1', 'Gene', '8352', (60, 64))	('chromatin', 'cellular_component', 'GO:0000785', ('247', '256'))	('K36M', 'Mutation', 'p.K36M', (44, 48))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('247', '267'))	('histone methylation', 'biological_process', 'GO:0016571', ('212', '231'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('defective', 'NegReg', (237, 246))	('chromatin remodeling', 'CPA', (247, 267))	('increased', 'PosReg', (173, 182))	('H3.1', 'Gene', (60, 64))	('transcriptionally repressive histone methylation', 'MPA', (183, 231))
20386	25484917	Epigenetic control of gene expression dictates cell fate in health and disease, and dysregulation of epigenetic signals is associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('associated', 'Reg', (123, 133))	('dysregulation', 'Var', (84, 97))	('dictates', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Epigenetic', 'Var', (0, 10))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))	('cell fate', 'CPA', (47, 56))	('cancer', 'Disease', (139, 145))
20387	25484917	Two observations support pharmacological targeting of the 'cancer epigenome': (1) some cancer-associated epigenetic aberrations drive cancer initiation or progression; and (2) unlike genetic information, epigenetic states are reversible.	('cancer', 'Disease', (87, 93))	("'cancer", 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('epigenetic aberrations', 'Var', (105, 127))	('cancer initiation', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	("'cancer", 'Disease', (58, 65))	('progression', 'CPA', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer initiation', 'Disease', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (59, 65))	('drive', 'Reg', (128, 133))
20389	25484917	Cancer associated overexpression, mutation, or aberrant recruitment of chromatin factors (defined here as proteins that participate in the chemical modification of DNA, histones, or control nucleosome occupancy), represent emerging opportunities for cancer therapy.	('aberrant', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('recruitment', 'MPA', (56, 67))	('cancer', 'Disease', (250, 256))	('mutation', 'Var', (34, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('nucleosome', 'cellular_component', 'GO:0000786', ('190', '200'))	('overexpression', 'PosReg', (18, 32))
20390	25484917	For instance, inhibitors of EZH2 - a histone 3 lysine 27 (H3K27) methyltransferase that is overexpressed in a number of solid tumors and is the site of recurrent gain-of-function mutations in lymphoma - are raising considerable interest as potential anti-cancer agents, and have recently advanced to the clinic.	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('H3K27', 'Gene', '126961', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('lymphoma', 'Disease', 'MESH:D008223', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('EZH2', 'Gene', '2146', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('EZH2', 'Gene', (28, 32))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('cancer', 'Disease', (255, 261))	('mutations', 'Var', (179, 188))	('inhibitors', 'Var', (14, 24))	('gain-of-function', 'PosReg', (162, 178))	('H3K27', 'Gene', (58, 63))	('lymphoma', 'Disease', (192, 200))
20391	25484917	Chromosomal aberrations and altered expression of chromatin factors that are recurrent in specific cancer types have been reported in the literature, some extensively, and recently reviewed.	('Chromosomal aberrations', 'Var', (0, 23))	('altered', 'Reg', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Disease', (99, 105))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('expression', 'MPA', (36, 46))
20396	25484917	This systematic and integrated approach identifies many oncogenic aberrations already recorded in the literature, but also uncovers novel alterations recurrently affecting chromatin factors in specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('alterations', 'Var', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('affecting', 'Reg', (162, 171))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('cancer', 'Disease', (202, 208))	('chromatin factors', 'MPA', (172, 189))
20397	25484917	Overall our results provide novel insight into the cancer epigenome revealing a tendency toward alterations predicted to result in greater transcriptional repression, decreased transcriptional activation and reduced chromatin remodeling.	('chromatin remodeling', 'MPA', (216, 236))	('alterations', 'Var', (96, 107))	('chromatin', 'cellular_component', 'GO:0000785', ('216', '225'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('216', '236'))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('transcriptional activation', 'MPA', (177, 203))	('reduced', 'NegReg', (208, 215))	('greater', 'PosReg', (131, 138))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('transcriptional repression', 'MPA', (139, 165))	('decreased', 'NegReg', (167, 176))
20406	25484917	As shown in Additional file 2: Figure S1 and Table 1, our analysis retrieved a number of known cancer-associated aberrations in chromatin factors.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('chromatin factors', 'Protein', (128, 145))	('chromatin', 'cellular_component', 'GO:0000785', ('128', '137'))	('aberrations', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
20409	25484917	Other examples include recurrent mutations of the chromatin remodeling protein ATRX in lower grade glioblastoma (40% of patient), or DNMT3A and TET2 in acute myeloid leukemia (25% and 8.6% of patients, respectively), mutations of the H3K4 methyltransferase MLL3 in 7.7% of breast cancer patients, or mutations of the bromodomain containing protein PBRM1 in 28.5% of kidney renal clear cell carcinoma.	('patient', 'Species', '9606', (192, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('acute myeloid leukemia', 'Disease', (152, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('DNMT3A', 'Gene', (133, 139))	('mutations', 'Var', (33, 42))	('TET2', 'Gene', '54790', (144, 148))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (366, 399))	('MLL3', 'Gene', '58508', (257, 261))	('glioblastoma', 'Disease', (99, 111))	('patient', 'Species', '9606', (287, 294))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('patient', 'Species', '9606', (120, 127))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (158, 174))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (152, 174))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (152, 174))	('kidney renal clear cell carcinoma', 'Disease', (366, 399))	('PBRM1', 'Gene', '55193', (348, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutations', 'Var', (300, 309))	('patients', 'Species', '9606', (192, 200))	('DNMT3A', 'Gene', '1788', (133, 139))	('MLL3', 'Gene', (257, 261))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', (273, 286))	('TET2', 'Gene', (144, 148))	('PBRM1', 'Gene', (348, 353))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('protein', 'cellular_component', 'GO:0003675', ('340', '347'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('50', '70'))	('patients', 'Species', '9606', (287, 295))	('H3', 'Gene', '126961', (234, 236))	('ATRX', 'Gene', (79, 83))	('ATRX', 'Gene', '546', (79, 83))	('mutations', 'Var', (217, 226))
20413	25484917	Another PMT, MLL2, and the HAT EP300 are found mutated in 18% and 7.8% of head and neck tumors, respectively (Table 1).	('head and neck tumors', 'Phenotype', 'HP:0012288', (74, 94))	('neck tumors', 'Disease', (83, 94))	('MLL2', 'Gene', '9757', (13, 17))	('PMT', 'molecular_function', 'GO:0030736', ('8', '11'))	('EP300', 'Gene', '2033', (31, 36))	('MLL2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EP300', 'Gene', (31, 36))	('mutated', 'Var', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('neck tumors', 'Disease', 'MESH:D006258', (83, 94))	('neck', 'cellular_component', 'GO:0044326', ('83', '87'))
20419	25484917	Again, the rationale here may be that since chromatin factors control the transcriptional profile of the cancer genome, mutations affecting a single chromatin factor may have a strong impact on the expression of a combination of genes involved in cell fate, survival, or DNA damage response.	('chromatin', 'cellular_component', 'GO:0000785', ('44', '53'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('DNA damage response', 'biological_process', 'GO:0006974', ('271', '290'))	('chromatin', 'cellular_component', 'GO:0000785', ('149', '158'))	('transcriptional', 'MPA', (74, 89))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (198, 208))	('DNA', 'cellular_component', 'GO:0005574', ('271', '274'))	('impact', 'Reg', (184, 190))
20425	25484917	It has been proposed that site-specific missense mutations that recur across a sizable cohort of cancer patients are indicative of an oncogenic role for the targeted gene, while genes that are frequently mutated at random positions are more likely to act as tumor suppressors.	('missense mutations', 'Var', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
20426	25484917	For instance, we did not have access to lymphoma data, and failed to retrieve known Y641 mutants that increase the trimethylase activity of EZH2 in this cancer type.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('lymphoma', 'Disease', 'MESH:D008223', (40, 48))	('cancer', 'Disease', (153, 159))	('EZH2', 'Gene', '2146', (140, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('EZH2', 'Gene', (140, 144))	('trimethylase activity', 'MPA', (115, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Y641', 'Var', (84, 88))	('increase', 'PosReg', (102, 110))	('lymphoma', 'Disease', (40, 48))
20429	25484917	For instance, genes coding for the histone variant H3.1, are mutated in 17 out of 270 head and neck squamous cell carcinoma samples (HNSC), and four of these mutations replace a lysine with methionine at position 36 (twice in HIST1H3C, once in HIST1H3E and once in HIST1H3I) suggesting that H3K36M is an oncogenic mutation that drives tumor initiation or progression in a fraction of HNSC patients.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('mutations replace', 'Var', (158, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('replace', 'Var', (168, 175))	('HIST1H3C', 'Gene', '8352', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('H3.1', 'Gene', '8352', (51, 55))	('HIST1H3C', 'Gene', (226, 234))	('tumor initiation', 'Disease', 'MESH:D009369', (335, 351))	('tumor initiation', 'Disease', (335, 351))	('HIST1H3E', 'Gene', (244, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('HIST1H3E', 'Gene', '8353', (244, 252))	('HIST1H3I', 'Gene', (265, 273))	('patients', 'Species', '9606', (389, 397))	('H3.1', 'Gene', (51, 55))	('H3K36M', 'Var', (291, 297))	('HIST1H3I', 'Gene', '8354', (265, 273))	('lysine with methionine at position 36', 'Mutation', 'p.K36M', (178, 215))	('head', 'Disease', (86, 90))	('neck', 'cellular_component', 'GO:0044326', ('95', '99'))
20434	25484917	We also found a H3K36M mutation in a colorectal cancer sample, suggesting that this mechanism may extend to other cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('colorectal cancer', 'Disease', (37, 54))	('found', 'Reg', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('H3K36M', 'Var', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('cancer', 'Disease', (114, 120))
20435	25484917	Though statistically significant, we note that the H3K36M mutation rate of 24% out of the 6.2% HNSC samples carrying a mutation at H3.1 remains low.	('mutation', 'Var', (119, 127))	('H3.1', 'Gene', (131, 135))	('H3.1', 'Gene', '8352', (131, 135))	('H3K36M', 'Gene', (51, 57))
20436	25484917	As a comparison, over 40% of cutaneous melanoma samples carry a mutation in BRAF, 90% of which are at the hotspot V600E.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('V600E', 'Mutation', 'rs113488022', (114, 119))
20437	25484917	Another histone, H2B is mutated in seven out of 377 glioblastoma multiform patients, resulting in a G53D mutant in three cases (in HIST1H2BE, HIST1H2BL and HIST1H2BF) (Figure 2A,B).	('H2B', 'Gene', (147, 150))	('H2B', 'Gene', '8349', (136, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('HIST1H2BF', 'Gene', '8343', (156, 165))	('H2B', 'Gene', (161, 164))	('H2B', 'Gene', (17, 20))	('HIST1H2BL', 'Gene', '8340', (142, 151))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('H2B', 'Gene', (136, 139))	('HIST1H2BL', 'Gene', (142, 151))	('patients', 'Species', '9606', (75, 83))	('H2B', 'Gene', '8349', (147, 150))	('HIST1H2BE', 'Gene', (131, 140))	('G53D', 'Mutation', 'p.G53D', (100, 104))	('G53D', 'Var', (100, 104))	('HIST1H2BF', 'Gene', (156, 165))	('H2B', 'Gene', '8349', (161, 164))	('H2B', 'Gene', '8349', (17, 20))	('HIST1H2BE', 'Gene', '8344', (131, 140))
20438	25484917	This mutation places an acidic residue in the minor groove of the DNA wrapped around the histone octamer (Additional file 4: Figure S3), which should destabilize nucleosomal H2B, and possibly nucleosome fluctuation or chromatin architecture.	('nucleosomal', 'MPA', (162, 173))	('chromatin', 'cellular_component', 'GO:0000785', ('218', '227'))	('nucleosome', 'cellular_component', 'GO:0000786', ('192', '202'))	('destabilize', 'NegReg', (150, 161))	('H2B', 'Gene', '8349', (174, 177))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('groove', 'cellular_component', 'GO:0097610', ('52', '58'))	('mutation', 'Var', (5, 13))	('H2B', 'Gene', (174, 177))
20440	25484917	We find that WHSC1, an H3K36 di-methylase that harbors two PWWP domains, is mutated in eight HNSC samples.	('WHSC1', 'Gene', (13, 18))	('H3', 'Gene', '126961', (23, 25))	('mutated', 'Var', (76, 83))	('WHSC1', 'Gene', '7468', (13, 18))	('methylase', 'molecular_function', 'GO:0008168', ('32', '41'))
20441	25484917	In four cases, this produces a frameshift insertion at position G944 of the C-terminal PWWP domain (Figure 2B).	('frameshift', 'Var', (31, 41))	('G944 of the C', 'Mutation', 'rs775942317', (64, 77))	('produces', 'Reg', (20, 28))
20442	25484917	This results in deletion of the C-terminal helix of the WHSC1 PWWP domain, expected to cap the methyl-lysine binding aromatic cage, and may also cause truncation of the methyltransferase domain of WHSC1, located on a downstream exon.	('methyl-lysine binding aromatic cage', 'MPA', (95, 130))	('WHSC1', 'Gene', '7468', (56, 61))	('cap', 'PosReg', (87, 90))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('deletion', 'Var', (16, 24))	('WHSC1', 'Gene', (56, 61))	('methyltransferase', 'Enzyme', (169, 186))	('results in', 'Reg', (5, 15))	('WHSC1', 'Gene', '7468', (197, 202))	('truncation', 'MPA', (151, 161))	('cause', 'Reg', (145, 150))	('methyl-lysine', 'Chemical', '-', (95, 108))	('WHSC1', 'Gene', (197, 202))
20444	25484917	We find that the H3K36M mutation and WHSC1 frameshifts are mutually exclusive in HNSC tumor samples.	('HNSC tumor', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HNSC tumor', 'Disease', (81, 91))	('H3K36M mutation', 'Var', (17, 32))	('WHSC1', 'Gene', '7468', (37, 42))	('frameshifts', 'Var', (43, 54))	('WHSC1', 'Gene', (37, 42))
20445	25484917	Both aberrations are expected to affect H3K36me2 signaling and may represent alternate pathways to the same molecular endpoint.	('affect', 'Reg', (33, 39))	('aberrations', 'Var', (5, 16))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('H3', 'Gene', '126961', (40, 42))
20446	25484917	While mutation hotspots are expected to reveal oncogenes, tumor suppressors are generally targeted by mutations that are more distributed over the gene in cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('targeted', 'Reg', (90, 98))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
20450	25484917	In total, six of the most mutated genes in various cancer types methylate H3K4 or H3K36 (Additional file 2: Figure S1A, Table 1).	('H3', 'Gene', '126961', (82, 84))	('H3', 'Gene', '126961', (74, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylate', 'Var', (64, 73))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
20454	25484917	Importantly, we observe that D328 makes critical electrostatic interactions with both H3K4 and H3K9 in the DPF3 complex, and is conserved in MLL3 (corresponding residue: D400 - Figure 2C - Bottom).	('H3', 'Gene', '126961', (95, 97))	('MLL3', 'Gene', '58508', (141, 145))	('D328', 'Chemical', '-', (29, 33))	('electrostatic interactions', 'MPA', (49, 75))	('D328', 'Var', (29, 33))	('H3', 'Gene', '126961', (86, 88))	('DPF3', 'Gene', (107, 111))	('MLL3', 'Gene', (141, 145))	('DPF3', 'Gene', '8110', (107, 111))
20455	25484917	Intriguingly, D400N is one of the three mutations affecting the triple PHD finger of MLL3 in colorectal cancer, and, based on these structural observations, should significantly affect histone binding.	('D400N', 'Mutation', 'p.D400N', (14, 19))	('histone', 'MPA', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('MLL3', 'Gene', (85, 89))	('histone binding', 'molecular_function', 'GO:0042393', ('185', '200'))	('colorectal cancer', 'Disease', (93, 110))	('D400N', 'Var', (14, 19))	('MLL3', 'Gene', '58508', (85, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('PHD', 'molecular_function', 'GO:0050175', ('71', '74'))	('affect', 'Reg', (178, 184))
20458	25484917	The C347G mutation will irremediably affect the structure of this domain, expected to participate in substrate binding.	('structure', 'MPA', (48, 57))	('affect', 'Reg', (37, 43))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('C347G', 'Var', (4, 9))	('participate', 'Reg', (86, 97))	('C347G', 'Mutation', 'rs754368331', (4, 9))
20459	25484917	Somatic mutations affecting MLL3 in colorectal cancer seem therefore to target with high precision residues involved in recruiting the enzyme to appropriately marked loci.	('MLL3', 'Gene', '58508', (28, 32))	('colorectal cancer', 'Disease', (36, 53))	('mutations', 'Var', (8, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('MLL3', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))
20460	25484917	Selective targeting of H3K4 and H3K36 methylation by oncogenic mutations was also observed in other studies that are not yet available from TCGA; for instance, mutations in SETD2 and genes affecting H3K36 methylation are recurrent in high-grade gliomas.	('H3', 'Gene', '126961', (23, 25))	('recurrent', 'Reg', (221, 230))	('mutations', 'Var', (160, 169))	('SETD2', 'Gene', (173, 178))	('gliomas', 'Disease', (245, 252))	('H3', 'Gene', '126961', (199, 201))	('methylation', 'biological_process', 'GO:0032259', ('205', '216'))	('gliomas', 'Disease', 'MESH:D005910', (245, 252))	('gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('H3', 'Gene', '126961', (32, 34))	('SETD2', 'Gene', '29072', (173, 178))
20461	25484917	Together, these results show that H3K36 and H3K4 mediated signaling is highly targeted in cancer via hotspot mutations of oncogenes and random mutation of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('H3', 'Gene', '126961', (44, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('H3', 'Gene', '126961', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('oncogenes', 'Gene', (122, 131))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
20462	25484917	To identify cancer-associated chromatin factor alterations that are either synergistic or redundant, we searched for co-occurring and mutually exclusive mutation patterns, respectively (Additional file 5: Table S2).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('alterations', 'Var', (47, 58))	('chromatin', 'cellular_component', 'GO:0000785', ('30', '39'))
20463	25484917	We find that mutations are co-occurring in ATRX, TP53, and IDH1, and that these are mutually exlusive with mutations in PTEN and EGFR in glioblatoma multiform (GBM) and lower grade glioma (LGG) (Figure 3; Additional file 5: Table S2).	('IDH1', 'Gene', '3417', (59, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('TP53', 'Gene', (49, 53))	('IDH1', 'Gene', (59, 63))	('ATRX', 'Gene', '546', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioblatoma multiform', 'Disease', (137, 158))	('EGFR', 'Gene', '1956', (129, 133))	('PTEN', 'Gene', (120, 124))	('glioblatoma multiform', 'Disease', 'MESH:D004892', (137, 158))	('PTEN', 'Gene', '5728', (120, 124))	('mutations', 'Var', (13, 22))	('EGFR', 'Gene', (129, 133))	('glioma', 'Disease', (181, 187))	('ATRX', 'Gene', (43, 47))
20464	25484917	For example, TP53 is mutated in 50% of all LGG samples, but in 95% of the 80 ATRX-mutated samples.	('TP53', 'Gene', (13, 17))	('ATRX', 'Gene', '546', (77, 81))	('TP53', 'Gene', '7157', (13, 17))	('LGG', 'Disease', (43, 46))	('mutated', 'Var', (21, 28))	('ATRX', 'Gene', (77, 81))
20466	25484917	Interestingly, it was found that mutations in IDH1, ATRX, or TP53 were recurrent only in glioma-CpG island methylator phenotype-positive tumors (a phenotype probably attributable to the competitive inhibition of TET demethylases, following accumulation of 2-hydroxyglutarate caused by IDH1 mutation), while mutations in EGFR and PTEN were only observed in other tumor subtypes, which is in agreement with the pattern that we observe.	('tumors', 'Disease', (137, 143))	('mutation', 'Var', (290, 298))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (362, 367))	('IDH1', 'Gene', (285, 289))	('TP53', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('IDH1', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('EGFR', 'Gene', (320, 324))	('ATRX', 'Gene', (52, 56))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (256, 274))	('PTEN', 'Gene', (329, 333))	('glioma', 'Disease', (89, 95))	('ATRX', 'Gene', '546', (52, 56))	('IDH1', 'Gene', '3417', (285, 289))	('tumor', 'Disease', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('320', '324'))	('IDH1', 'Gene', '3417', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PTEN', 'Gene', '5728', (329, 333))	('TP53', 'Gene', '7157', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('EGFR', 'Gene', '1956', (320, 324))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
20467	25484917	An important mutation that is missed in our exome-centric analysis is an upregulating mutation in the promoter of the telomerase reverse transcriptase (TERT), observed in 58% to 84% of primary glioblastomas, suggesting that telomere lengthening plays an important role in tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('TERT', 'Gene', '7015', (152, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (193, 206))	('telomere', 'cellular_component', 'GO:0005696', ('224', '232'))	('transcriptase', 'molecular_function', 'GO:0034062', ('137', '150'))	('tumor', 'Disease', (272, 277))	('telomerase reverse transcriptase', 'Gene', (118, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('glioblastomas', 'Disease', (193, 206))	('telomerase reverse transcriptase', 'Gene', '7015', (118, 150))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('upregulating', 'PosReg', (73, 85))	('mutation', 'Var', (86, 94))	('TERT', 'Gene', (152, 156))	('transcriptase', 'molecular_function', 'GO:0003968', ('137', '150'))	('glioblastomas', 'Phenotype', 'HP:0012174', (193, 206))	('telomere', 'cellular_component', 'GO:0000781', ('224', '232'))	('transcriptase', 'molecular_function', 'GO:0003899', ('137', '150'))
20468	25484917	Interestingly, ATRX is required for accumulation at telomeres, and ATRX mutations promote telomere lengthening and cellular proliferation.	('mutations', 'Var', (72, 81))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (15, 19))	('cellular proliferation', 'CPA', (115, 137))	('ATRX', 'Gene', '546', (67, 71))	('promote', 'PosReg', (82, 89))	('telomere', 'cellular_component', 'GO:0000781', ('90', '98'))	('telomere lengthening', 'CPA', (90, 110))	('telomere', 'cellular_component', 'GO:0005696', ('90', '98'))	('ATRX', 'Gene', (15, 19))
20469	25484917	Similarly TP53 deficiency favors telomere lengthening.	('telomere lengthening', 'CPA', (33, 53))	('TP53', 'Gene', (10, 14))	('favors', 'PosReg', (26, 32))	('telomere', 'cellular_component', 'GO:0000781', ('33', '41'))	('telomere', 'cellular_component', 'GO:0005696', ('33', '41'))	('deficiency', 'Var', (15, 25))	('TP53', 'Gene', '7157', (10, 14))
20470	25484917	This suggests complementary pressures towards an oncogenic pathway depending on telomere lengthening by mutations co-occurring at ATRX, TP53 and (hypothetically) IDH1 in adult brain tumors where the PTEN/EGFR surface signaling axis is not altered.	('PTEN', 'Gene', '5728', (199, 203))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('IDH1', 'Gene', '3417', (162, 166))	('TP53', 'Gene', '7157', (136, 140))	('brain tumors', 'Disease', 'MESH:D001932', (176, 188))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (104, 113))	('telomere', 'cellular_component', 'GO:0000781', ('80', '88'))	('telomere', 'cellular_component', 'GO:0005696', ('80', '88'))	('EGFR', 'Gene', '1956', (204, 208))	('oncogenic pathway', 'Pathway', (49, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))	('brain tumors', 'Disease', (176, 188))	('telomere', 'MPA', (80, 88))	('ATRX', 'Gene', (130, 134))	('ATRX', 'Gene', '546', (130, 134))	('TP53', 'Gene', (136, 140))	('PTEN', 'Gene', (199, 203))	('IDH1', 'Gene', (162, 166))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('EGFR', 'Gene', (204, 208))
20471	25484917	Other intriguing observations include a mutual exclusion in lower grade glioma between ATRX and CIC, a transcriptional repressor that may play a role in development of the central nervous system, and mutual exclusion in uterine corpus endometrial carcinoma between mutations at TP53 and SWI/SNF remodeling complex protein ARID1A (Additional file 5: Table S2).	('glioma', 'Disease', (72, 78))	('mutations', 'Var', (265, 274))	('TP53', 'Gene', '7157', (278, 282))	('TP53', 'Gene', (278, 282))	('SWI/SNF', 'Gene', (287, 294))	('ATRX', 'Gene', '546', (87, 91))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('ATRX', 'Gene', (87, 91))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (235, 256))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('CIC', 'Gene', '23152', (96, 99))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('ARID1A', 'Gene', '8289', (322, 328))	('endometrial carcinoma', 'Disease', (235, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('ARID1A', 'Gene', (322, 328))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (235, 256))	('CIC', 'Gene', (96, 99))
20473	25484917	We find that some of the changes observed in the cancer epigenome can be associated with a hyperproliferative phenotype, a hallmark of cancer.	('hallmark of cancer', 'Disease', 'MESH:D009369', (123, 141))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (73, 83))	('hyperproliferative phenotype', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('changes', 'Var', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('hallmark of cancer', 'Disease', (123, 141))	('cancer', 'Disease', (49, 55))
20476	25484917	We also find that the only two proteins known to act as direct links between histone methylation and the DNA replication machinery, ORC1 (that binds to H4K20me3 and recruits the origin of replication complex at replication origins) and UHRF1 (that binds H3K9me3 and recruits DNMT1 to hemi-methylated cytosines), are among the five most frequently overexpressed chromatin factors across all cancer types studied (Additional file 2: Figure S1B).	('DNMT1', 'Gene', (275, 280))	('ORC1', 'Gene', '4998', (132, 136))	('UHRF1', 'Gene', (236, 241))	('UHRF1', 'Gene', '29128', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (390, 396))	('DNMT1', 'Gene', '1786', (275, 280))	('histone methylation', 'biological_process', 'GO:0016571', ('77', '96'))	('cancer', 'Disease', (390, 396))	('H3', 'Gene', '126961', (254, 256))	('chromatin', 'cellular_component', 'GO:0000785', ('361', '370'))	('DNA replication', 'biological_process', 'GO:0006260', ('105', '120'))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('ORC1', 'Gene', (132, 136))	('recruits', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('H4K20me3', 'Var', (152, 160))	('ORC', 'cellular_component', 'GO:0000808', ('132', '135'))
20477	25484917	Another histone chaperone that is significantly overexpressed - actually the most frequently overexpressed chromatin factor in cancer - is HJURP, a chaperone of the histone H3 variant CENP-A, which facilitates aneuploidy and genome instability, another hallmark of cancer (Additional file 2: Figure S1B; Table 1).	('CENP-A', 'Gene', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('hallmark of cancer', 'Disease', (253, 271))	('histone chaperone', 'biological_process', 'GO:0006334', ('8', '25'))	('aneuploidy', 'Disease', (210, 220))	('variant', 'Var', (176, 183))	('genome instability', 'CPA', (225, 243))	('HJURP', 'Gene', '55355', (139, 144))	('cancer', 'Disease', (127, 133))	('H3', 'Gene', '126961', (173, 175))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('CENP-A', 'Gene', '1058', (184, 190))	('histone chaperone', 'biological_process', 'GO:0043486', ('8', '25'))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HJURP', 'Gene', (139, 144))	('chromatin', 'cellular_component', 'GO:0000785', ('107', '116'))	('hallmark of cancer', 'Disease', 'MESH:D009369', (253, 271))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('aneuploidy', 'Disease', 'MESH:D000782', (210, 220))	('cancer', 'Disease', (265, 271))	('facilitates', 'PosReg', (198, 209))
20486	25484917	Additionally, ATRX is responsible for the incorporation H3.3 at telomeres, and its mutation can cause alternative telomere lengthening, associated with increased genomic instability.	('increased', 'PosReg', (152, 161))	('ATRX', 'Gene', (14, 18))	('H3', 'Gene', '126961', (56, 58))	('cause', 'Reg', (96, 101))	('mutation', 'Var', (83, 91))	('telomere', 'cellular_component', 'GO:0005696', ('114', '122'))	('genomic', 'MPA', (162, 169))	('ATRX', 'Gene', '546', (14, 18))	('alternative telomere lengthening', 'MPA', (102, 134))	('telomere', 'cellular_component', 'GO:0000781', ('114', '122'))
20487	25484917	These observations strongly suggest that genetic or transcriptional aberrations targeting chromatin factors in cancer favor replication and contribute to genome instability.	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('contribute', 'Reg', (140, 150))	('favor', 'PosReg', (118, 123))	('chromatin factors', 'Protein', (90, 107))	('replication', 'CPA', (124, 135))	('aberrations', 'Var', (68, 79))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('genome instability', 'MPA', (154, 172))
20489	25484917	Cancer genomes generally have large numbers of 'passenger' mutations and a small number of driver genetic events.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (59, 68))	("'passenger'", 'PosReg', (47, 58))
20491	25484917	To identify candidate drivers affecting epigenetic mechanisms, we looked for correlations between copy number gains and overexpression of chromatin factors in cancer samples compared with matched normal samples.	('cancer', 'Disease', (159, 165))	('chromatin', 'cellular_component', 'GO:0000785', ('138', '147'))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('copy number', 'Var', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
20494	25484917	Amplification of the SETDB1 gene in lung cancer was recently shown to contribute to lung tumorigenesis, and shRNA-mediated depletion of SETDB1 in amplified cells reduced tumor growth in a mouse xenograft model.	('SETDB1', 'Gene', (136, 142))	('lung cancer', 'Disease', (36, 47))	('mouse', 'Species', '10090', (188, 193))	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('reduced', 'NegReg', (162, 169))	('SETDB1', 'Gene', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (170, 175))	('depletion', 'Var', (123, 132))	('contribute', 'Reg', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
20498	25484917	Interestingly, knockdown of WHSC1L1 results in profound loss of growth survival of 8p11-12 amplified breast cancer cells, but not control MCF10A cells.	('MCF10A', 'CellLine', 'CVCL:0598', (138, 144))	('loss', 'NegReg', (56, 60))	('knockdown', 'Var', (15, 24))	('WHSC1L1', 'Gene', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('WHSC1L1', 'Gene', '54904', (28, 35))	('growth survival', 'CPA', (64, 79))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
20499	25484917	These results suggest that amplification of WHSC1L1 drives cancer in a subset of breast cancer patients.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('breast cancer', 'Disease', (81, 94))	('WHSC1L1', 'Gene', '54904', (44, 51))	('patients', 'Species', '9606', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('drives', 'Reg', (52, 58))	('amplification', 'Var', (27, 40))	('WHSC1L1', 'Gene', (44, 51))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
20506	25484917	Together, these results show that overall copy number variation do not appear to drive transcriptional de-regulation of most chromatin factors and are therefore likely to be passenger events in cancer.	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('cancer', 'Disease', (194, 200))	('transcriptional', 'MPA', (87, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('125', '134'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('copy number variation', 'Var', (42, 63))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
20511	25484917	Specific combinations of post-translational modifications of DNA and histones at distinct genomic elements control chromatin compaction, nucleosome occupancy, and gene activation status: histone acetylation and H3K4 di- or tri-methylation at promoters, H3K4 mono-methylation at enhancers and tri-methylation of H3K36 as well as DNA methylation in gene bodies are associated with transcriptionally active genes.	('methylation', 'biological_process', 'GO:0032259', ('227', '238'))	('associated', 'Reg', (363, 373))	('chromatin', 'cellular_component', 'GO:0000785', ('115', '124'))	('H3', 'Gene', '126961', (311, 313))	('H3', 'Gene', '126961', (253, 255))	('DNA', 'cellular_component', 'GO:0005574', ('328', '331'))	('histone acetylation', 'biological_process', 'GO:0016573', ('187', '206'))	('methylation', 'biological_process', 'GO:0032259', ('263', '274'))	('DNA methylation', 'biological_process', 'GO:0006306', ('328', '343'))	('methylation', 'biological_process', 'GO:0032259', ('296', '307'))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('tri-methylation', 'Var', (292, 307))	('nucleosome', 'cellular_component', 'GO:0000786', ('137', '147'))	('H3', 'Gene', '126961', (211, 213))
20512	25484917	Promoters tri-methylated at H3K4 and H3K27 are thought to be in a state that is transcriptionally repressed, but 'poised' for rapid activation upon demethylation of H3K37.	('demethylation', 'biological_process', 'GO:0070988', ('148', '161'))	('H3', 'Gene', '126961', (165, 167))	('H3K27', 'Gene', '126961', (37, 42))	('H3K27', 'Gene', (37, 42))	('H3', 'Gene', '126961', (28, 30))	('H3', 'Gene', '126961', (37, 39))	('tri-methylated', 'Var', (10, 24))
20513	25484917	Finally, tri-methylated H3K9 and methylated DNA at enhancers, or a combination of these two marks with trimethylated H3K27 at promoters, is associated with gene silencing (Figure 6A,B).	('H3K27', 'Gene', (117, 122))	('H3K27', 'Gene', '126961', (117, 122))	('gene', 'MPA', (156, 160))	('gene silencing', 'biological_process', 'GO:0016458', ('156', '170'))	('H3', 'Gene', '126961', (117, 119))	('H3', 'Gene', '126961', (24, 26))	('methylated', 'Var', (33, 43))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))
20514	25484917	Intriguingly, we find that enzymes that deposit histone marks associated with gene activation, such as the H3K4 trimethylases MLL1-4 and SETD1A/B, or the H3K36 trimethylase SETD2 are more often repressed and mutated in cancer (Figure 6C).	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('SETD2', 'Gene', (173, 178))	('MLL1', 'Gene', '4297', (126, 130))	('H3', 'Gene', '126961', (154, 156))	('SETD1A/B', 'Gene', (137, 145))	('H3', 'Gene', '126961', (107, 109))	('SETD1A/B', 'Gene', '9739', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutated', 'Var', (208, 215))	('cancer', 'Disease', (219, 225))	('MLL1', 'Gene', (126, 130))	('repressed', 'MPA', (194, 203))	('SETD2', 'Gene', '29072', (173, 178))
20522	25484917	Some of the emerging epigenetic drugs, such as bromodomain, protein methyltransferase, or IDH1 inhibitors, are targeting patient group with clear oncogenic chromosomal aberrations such as gene fusions at BRD4 and MLL1, or mutations at IDH1.	('IDH1', 'Gene', (90, 94))	('chromosomal aberrations', 'Disease', (156, 179))	('BRD4', 'Gene', (204, 208))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (156, 179))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (156, 179))	('IDH1', 'Gene', (235, 239))	('MLL1', 'Gene', '4297', (213, 217))	('IDH1', 'Gene', '3417', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('IDH1', 'Gene', '3417', (235, 239))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (156, 178))	('mutations', 'Var', (222, 231))	('BRD4', 'Gene', '23476', (204, 208))	('patient', 'Species', '9606', (121, 128))	('MLL1', 'Gene', (213, 217))
20523	25484917	Translocations are not included in our analysis, but IDH1 mutations are high on our chromatin factor mutation landscape (Additional file 2: Figure S1A).	('chromatin', 'cellular_component', 'GO:0000785', ('84', '93'))	('mutations', 'Var', (58, 67))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
20524	25484917	Other peaks, such as ATRX mutations in lower grade glioma or ARID1A mutations in endometrial cancer and stomach adenocarcinoma may represent other points of entry for therapeutic intervention.	('stomach adenocarcinoma', 'Disease', (104, 126))	('endometrial cancer', 'Phenotype', 'HP:0012114', (81, 99))	('glioma', 'Disease', (51, 57))	('ARID1A', 'Gene', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ATRX', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('mutations', 'Var', (26, 35))	('ATRX', 'Gene', '546', (21, 25))	('endometrial cancer', 'Disease', (81, 99))	('mutations', 'Var', (68, 77))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (104, 126))	('ARID1A', 'Gene', '8289', (61, 67))
20529	25484917	It has been proposed that most epigenetic-associated mutations are observed in hematological, in pediatric, or in rare and aggressive variants of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('observed', 'Reg', (67, 75))	('mutations', 'Var', (53, 62))	('hematological', 'Disease', (79, 92))	('solid tumors', 'Disease', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic-associated mutations', 'Var', (31, 62))
20545	25484917	This is in agreement with previous work showing that some cancer types are particularly enriched in false mutation calling.	('false mutation calling', 'Var', (100, 122))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('false', 'biological_process', 'GO:0071878', ('100', '105'))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('false', 'biological_process', 'GO:0071877', ('100', '105'))
20552	25484917	GISTIC values are used to evaluate copy number variations relative to the reference genome (hg18 for COAD/READ, LAML and OV; hg19 for all other cancer types).	('COAD', 'Disease', 'MESH:D029424', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('cancer', 'Disease', (144, 150))	('COAD', 'Disease', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('copy number variations', 'Var', (35, 57))
20557	25484917	Mutation hotspots were defined as aminoacids affected by a minimum of three mutations representing at least 20% of non-silent mutations for that gene in a given cancer type.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))
20589	20607422	Categories were made for SN tumor burden as follows: <0.1 mm (submicrometastases), 0.1-1.0 mm, and >1.0 mm.	('SN tumor', 'Disease', (25, 33))	('metastases', 'Disease', 'MESH:D009362', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('0.1-1.0 mm', 'Var', (83, 93))	('SN tumor', 'Disease', 'None', (25, 33))	('metastases', 'Disease', (70, 80))
20612	20607422	The distribution of SN tumor burden according the Rotterdam criteria was (Table 1): <0.1 mm, 7 cases (2.2%); 0.1-1.0 mm, 105 cases (32.7%); and >1.0 mm, 209 cases (65.1%).	('0.1-1.0 mm', 'Var', (109, 119))	('>1.0 mm', 'Var', (144, 151))	('<0.1 mm', 'Var', (84, 91))	('SN tumor', 'Disease', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SN tumor', 'Disease', 'None', (20, 28))
20621	20607422	There is a worldwide agreement about the negative prognostic implications of node positivity in cutaneous melanoma, but the clinical significance of tiny tumor deposits is still debatable.	('cutaneous melanoma', 'Disease', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('tiny tumor', 'Disease', 'MESH:D009369', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tiny tumor', 'Disease', (149, 159))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('node positivity', 'Var', (77, 92))
20648	30622534	The analysis revealed different patterns of immune infiltration in different cancers driven by restricted expression of chemoattractant genes and by pathways dysregulated as a result of mutations in oncogenes and tumor suppressor genes.	('tumor', 'Disease', (213, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('213', '229'))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('mutations', 'Var', (186, 195))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('213', '229'))	('cancers', 'Disease', (77, 84))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('oncogenes', 'Gene', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
20659	30622534	Next, we tested our signatures on single-cell sequencing data from tumor-infiltrated lymphocytes (B-cell, Macrophages, CD8+ T cells, and NK cells) in melanoma patients (GSE72056) and observed higher scores for the cognate cell types (Supplementary Figure 1C).	('CD8', 'Gene', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CD8', 'Gene', '925', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('tumor', 'Disease', (67, 72))	('melanoma', 'Disease', (150, 158))	('patients', 'Species', '9606', (159, 167))	('tested', 'Reg', (9, 15))	('GSE72056', 'Var', (169, 177))
20672	30622534	Kidney renal cell carcinoma (KIRC) being an immune-sensitive tumor had a high infiltration of all the immune cell types except Treg cells (Figure 2A, right panel), dark red Q1 boxes, whereas kidney renal papillary cell carcinoma (KIRP) showed lesser infiltration of most immune cell types (Figure 2A, right panel), white Q1 boxes.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('Kidney renal cell carcinoma', 'Disease', 'MESH:D007674', (0, 27))	('kidney renal papillary cell carcinoma', 'Disease', (191, 228))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (191, 228))	('Kidney renal cell carcinoma', 'Disease', (0, 27))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (7, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (198, 228))	('tumor', 'Disease', (61, 66))	('dark red', 'Var', (164, 172))
20675	30622534	For example, the co-occurrence of T cells and NK cells in tumors enhances the efficacy of cancer immunotherapy drugs.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('co-occurrence', 'Var', (17, 30))	('enhances', 'PosReg', (65, 73))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
20683	30622534	Next, we considered mutations in oncogenes and tumor suppressor genes as possible drivers of immune cell infiltration through the expression of chemoattractant genes, or by other mechanisms, such as changes in the tumor stroma, or directly impeding the migratory behavior of immune cells.	('migratory behavior of immune cells', 'CPA', (253, 287))	('tumor', 'Disease', (47, 52))	('tumor stroma', 'Disease', (214, 226))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (214, 219))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('immune cell infiltration', 'CPA', (93, 117))	('mutations', 'Var', (20, 29))	('impeding', 'NegReg', (240, 248))	('tumor stroma', 'Disease', 'MESH:D009369', (214, 226))
20684	30622534	We selected tumor samples across different cancers enriched or depleted for different immune cells and analyzed mutations in all genes.	('analyzed', 'Reg', (103, 111))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancers', 'Disease', (43, 50))	('mutations', 'Var', (112, 121))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', (12, 17))
20685	30622534	We identified mutations in known and novel genes associated with enrichment or depletion of specific immune cells in different cancers (T-test: P-value < 0.05; Figure 2D and Supplementary Figure 4.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (49, 59))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('mutations', 'Var', (14, 23))	('depletion', 'MPA', (79, 88))
20686	30622534	We observed that the same mutation affected the infiltration of distinct immune cell populations in two different cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutation', 'Var', (26, 34))	('affected', 'Reg', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('infiltration of', 'CPA', (48, 63))
20687	30622534	For example, in LUAD, higher Treg infiltration was seen in samples harboring oncogenic KRAS mutation (G12V/D), whereas the same mutation in pancreatic adenocarcinoma (PAAD) correlated with high infiltration of CD8+, CD4+ T cells, and Neutrophils.	('higher', 'PosReg', (22, 28))	('KRAS', 'Gene', (87, 91))	('Treg infiltration', 'CPA', (29, 46))	('CD4', 'Gene', (216, 219))	('CD4', 'Gene', '920', (216, 219))	('KRAS', 'Gene', '3845', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('CD8', 'Gene', (210, 213))	('G12V', 'Var', (102, 106))	('G12V', 'SUBSTITUTION', 'None', (102, 106))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (140, 165))	('CD8', 'Gene', '925', (210, 213))
20688	30622534	Several novel dependencies of clinical relevance were detected between mutations and infiltration of specific immune cells.	('dependencies', 'Disease', 'MESH:D019966', (14, 26))	('mutations', 'Var', (71, 80))	('dependencies', 'Disease', (14, 26))
20689	30622534	For example, loss of function mutations in RNF43 and DOCK-3 genes were associated with higher infiltration of CD8+ T cells in colon adenocarcinoma (COAD; Figure 2D and Supplementary Figure 4A).	('COAD', 'Disease', 'MESH:D029424', (148, 152))	('loss of function', 'NegReg', (13, 29))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (126, 146))	('infiltration', 'CPA', (94, 106))	('RNF43', 'Gene', (43, 48))	('RNF43', 'Gene', '54894', (43, 48))	('DOCK-3', 'Gene', (53, 59))	('COAD', 'Disease', (148, 152))	('CD8', 'Gene', (110, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('mutations', 'Var', (30, 39))	('DOCK-3', 'Gene', '1795', (53, 59))	('CD8', 'Gene', '925', (110, 113))	('colon adenocarcinoma', 'Disease', (126, 146))	('higher', 'PosReg', (87, 93))
20691	30622534	NK cell infiltration was higher in COAD samples carrying BRAF V600E and a frameshift mutation in RNF43 (Figure 2D, Supplementary Figure 4B).	('RNF43', 'Gene', (97, 102))	('higher', 'PosReg', (25, 31))	('COAD', 'Disease', 'MESH:D029424', (35, 39))	('BRAF', 'Gene', '673', (57, 61))	('frameshift mutation', 'Var', (74, 93))	('BRAF', 'Gene', (57, 61))	('COAD', 'Disease', (35, 39))	('NK cell infiltration', 'CPA', (0, 20))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('RNF43', 'Gene', '54894', (97, 102))
20692	30622534	A snapshot showing the impact of other oncogenic mutations such as KRAS, BRAF, and FGFR3 on the composition of the tumor-associated immune infiltrate is shown in Figure 2D and Supplementary Figures 4C-E. A complete list of mutations significantly associated with enrichment or depletion of immune cells is provided in Supplementary Table 3.	('BRAF', 'Gene', '673', (73, 77))	('FGFR3', 'Gene', '2261', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (115, 120))	('FGFR', 'molecular_function', 'GO:0005007', ('83', '87'))	('KRAS', 'Gene', (67, 71))	('KRAS', 'Gene', '3845', (67, 71))	('FGFR3', 'Gene', (83, 88))	('depletion of immune cells', 'Phenotype', 'HP:0002721', (277, 302))	('BRAF', 'Gene', (73, 77))	('mutations', 'Var', (223, 232))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
20693	30622534	We demonstrate that the relationship between driver mutations and their impact on immune infiltration is complex and is centrally dependent on the cancer type.	('mutations', 'Var', (52, 61))	('immune infiltration', 'MPA', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
20694	30622534	Our analysis further reiterates that both chemoattractant gene expression and oncogenic mutations act together for the recruitment of specific immune cells in the TME and therefore contribute to the changes in the TME as the tumor develops over time.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('mutations', 'Var', (88, 97))	('contribute', 'Reg', (181, 191))	('tumor', 'Disease', (225, 230))	('changes', 'Reg', (199, 206))	('TME', 'MPA', (214, 217))	('recruitment', 'MPA', (119, 130))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))
20715	30622534	As expected, cluster-3 containing exclusively of LAML (Acute Myeloid Leukemia) samples had significantly lower macrophage content than all other clusters (Figure 4D).	('lower', 'NegReg', (105, 110))	('LAML', 'Var', (49, 53))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (61, 77))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (55, 77))	('Acute Myeloid Leukemia', 'Disease', (55, 77))	('macrophage content', 'CPA', (111, 129))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (55, 77))	('Leukemia', 'Phenotype', 'HP:0001909', (69, 77))
20716	30622534	The mutational burden was slightly higher in cluster-4 tumors (Figure 4E), which correlated with higher CD8+ T cell infiltration in cluster-4.	('higher', 'PosReg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('CD8', 'Gene', (104, 107))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('CD8', 'Gene', '925', (104, 107))	('mutational', 'Var', (4, 14))	('higher', 'Reg', (35, 41))
20717	30622534	Tumors with high mutation burden, such as MSI+ tumors showed higher CD8+ T cell infiltration.	('tumors', 'Disease', (47, 53))	('MSI', 'Gene', '5928', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CD8', 'Gene', (68, 71))	('mutation burden', 'Var', (17, 32))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD8', 'Gene', '925', (68, 71))	('higher', 'PosReg', (61, 67))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('MSI', 'Gene', (42, 45))
20719	30622534	Cluster-4 tumors showed slightly better prognosis compared to cluster-1, or cluster-2, confirming that infiltration of CD8+ T cells is associated with long-term survival benefit (Supplementary Figures 5A,B).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('CD8', 'Gene', (119, 122))	('survival', 'CPA', (161, 169))	('CD8', 'Gene', '925', (119, 122))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('benefit', 'PosReg', (170, 177))	('infiltration', 'Var', (103, 115))
20738	30622534	The survival analysis showed that high T-cell activation score was associated with an improved survival independent of age, stage and cancertype (p-value: 2e-07; Figure 5C).	('T-cell', 'MPA', (39, 45))	('T-cell activation', 'biological_process', 'GO:0042110', ('39', '56'))	('improved', 'PosReg', (86, 94))	('cancer', 'Disease', (134, 140))	('survival', 'MPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('high', 'Var', (34, 38))	('high T-cell activation', 'Phenotype', 'HP:0005419', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
20755	30622534	Our analysis shows that tumors have distinct immune cell infiltration profiles that cannot be predicted apriori from analysis of tumor mutation burden or from mutations in oncogenes and tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumor', 'Disease', (24, 29))	('mutations', 'Var', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))
20757	30622534	In addition, our study reveals that associations between specific genetic alterations in oncogenes and tumor suppressor genes and the impact of such alterations on immune cell infiltration are cancer-specific.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', (103, 108))	('oncogenes', 'Gene', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('associations', 'Interaction', (36, 48))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('genetic alterations', 'Var', (66, 85))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
20758	30622534	For example, a novel association was detected between mutations in two different modulators of the Wnt signaling pathway (RNF-43 and DOCK3) and increased CD8+ T cell infiltration in colorectal adenocarcinoma (COAD).	('DOCK3', 'Gene', (133, 138))	('COAD', 'Disease', (209, 213))	('CD8', 'Gene', (154, 157))	('colorectal adenocarcinoma', 'Disease', (182, 207))	('CD8', 'Gene', '925', (154, 157))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('99', '120'))	('RNF-43', 'Gene', (122, 128))	('mutations', 'Var', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (182, 207))	('DOCK3', 'Gene', '1795', (133, 138))	('COAD', 'Disease', 'MESH:D029424', (209, 213))	('increased', 'PosReg', (144, 153))	('RNF-43', 'Gene', '54894', (122, 128))
20761	30622534	We postulate that the frameshift mutations in RNF-43 and DOCK3 genes identified in the study are expected to increase Wnt signaling:the former by stabilizing the FZD receptors on the membrane and the latter by releasing beta-catenin for nuclear translocation.	('FZD', 'Gene', (162, 165))	('DOCK3', 'Gene', (57, 62))	('nuclear translocation', 'MPA', (237, 258))	('RNF-43', 'Gene', (46, 52))	('beta-catenin', 'Gene', '1499', (220, 232))	('increase', 'PosReg', (109, 117))	('releasing', 'PosReg', (210, 219))	('frameshift mutations', 'Var', (22, 42))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('membrane', 'cellular_component', 'GO:0016020', ('183', '191'))	('stabilizing', 'Reg', (146, 157))	('Wnt signaling', 'MPA', (118, 131))	('FZD', 'Gene', '7855', (162, 165))	('DOCK3', 'Gene', '1795', (57, 62))	('beta-catenin', 'Gene', (220, 232))	('RNF-43', 'Gene', '54894', (46, 52))
20762	30622534	Our observation that increased infiltration of CD8+ T-cells correlated with loss of function mutations in RNF-43 and DOCK3 in human colon adenocarcinoma contrasts with the findings described in Spranger et al.. Further work is needed to delineate the complex role of Wnt signaling in immune cell infiltration.	('human', 'Species', '9606', (126, 131))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('mutations', 'Var', (93, 102))	('colon adenocarcinoma', 'Disease', (132, 152))	('RNF-43', 'Gene', '54894', (106, 112))	('CD8', 'Gene', (47, 50))	('DOCK3', 'Gene', '1795', (117, 122))	('CD8', 'Gene', '925', (47, 50))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (132, 152))	('RNF-43', 'Gene', (106, 112))	('DOCK3', 'Gene', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))
20764	30622534	This study stands out to be one of the largest analysis where the impact of all mutations across 33 cancers have been systematically associated with the enrichment or depletion of a variety of immune cells uncovering novel targets for immunopotentiation.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('depletion of', 'MPA', (167, 179))	('enrichment', 'MPA', (153, 163))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('associated', 'Reg', (133, 143))	('cancers', 'Disease', (100, 107))
20782	30622534	RNA-Seq expression data was downloaded from the GEO database for the studies GSE60424, ERR431583, and GSE100382 (details of the data can be found in Supplementary Table 1).	('ERR431583', 'Chemical', '-', (87, 96))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('GSE100382', 'Var', (102, 111))	('GSE60424', 'Var', (77, 85))
20807	28868012	Contrary to cutaneous melanoma, primary oral melanoma more commonly harbors mutations in c-KIT.	('c-KIT', 'Gene', (89, 94))	('primary oral melanoma', 'Disease', 'MESH:D008545', (32, 53))	('mutations', 'Var', (76, 85))	('cutaneous melanoma', 'Disease', (12, 30))	('c-KIT', 'Gene', '3815', (89, 94))	('primary oral melanoma', 'Disease', (32, 53))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (12, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (12, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('KIT', 'molecular_function', 'GO:0005020', ('91', '94'))	('harbors', 'Reg', (68, 75))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
20810	28868012	In molecular analysis, a c-KIT mutation was proven and a CT scan revealed pulmonary metastases.	('mutation', 'Var', (31, 39))	('c-KIT', 'Gene', (25, 30))	('c-KIT', 'Gene', '3815', (25, 30))	('pulmonary metastases', 'Disease', 'MESH:D009362', (74, 94))	('pulmonary metastases', 'Disease', (74, 94))	('KIT', 'molecular_function', 'GO:0005020', ('27', '30'))
20820	28868012	A molecular analysis of the specimens showed a c-KIT V560D mutation.	('c-KIT', 'Gene', '3815', (47, 52))	('V560D', 'Var', (53, 58))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('V560D', 'Mutation', 'rs121913521', (53, 58))	('c-KIT', 'Gene', (47, 52))
20842	28868012	Fifth, in contrast to cutaneous melanoma, which shows BRAF mutation in 50% and NRAS mutation in about 20% of cases, primary oral melanoma more commonly harbors mutations in c-KIT.	('harbors', 'Reg', (152, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('mutations', 'Var', (160, 169))	('NRAS', 'Gene', '4893', (79, 83))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('primary oral melanoma', 'Disease', 'MESH:D008545', (116, 137))	('cutaneous melanoma', 'Disease', (22, 40))	('c-KIT', 'Gene', (173, 178))	('primary oral melanoma', 'Disease', (116, 137))	('c-KIT', 'Gene', '3815', (173, 178))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (22, 40))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))	('NRAS', 'Gene', (79, 83))
20848	28868012	Altogether, 27 patients with BRAFV600E-mutated metastatic melanoma were included; 19 of them suffered from mucosal and acral melanoma.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('acral melanoma', 'Disease', 'MESH:D008545', (119, 133))	('patients', 'Species', '9606', (15, 23))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('mucosal', 'Disease', (107, 114))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('suffered from', 'Reg', (93, 106))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('acral melanoma', 'Phenotype', 'HP:0012060', (119, 133))	('BRAFV600E-mutated', 'Var', (29, 46))	('acral melanoma', 'Disease', (119, 133))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
20852	28868012	However, BRAF mutations are rarely seen in mucosal melanomas, with a reported frequency of 3.6-16.5%.	('mucosal melanomas', 'Disease', (43, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('BRAF', 'Gene', (9, 13))	('mucosal melanomas', 'Disease', 'MESH:D008545', (43, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
20853	28868012	Instead, nearly 25% of mucosal melanomas show a genetic aberration in KIT, a receptor tyrosine kinase.	('KIT', 'Gene', (70, 73))	('mucosal melanomas', 'Disease', 'MESH:D008545', (23, 40))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('genetic aberration', 'Var', (48, 66))	('mucosal melanomas', 'Disease', (23, 40))
20857	28868012	Besides its application in metastatic, KIT-mutated melanoma, it is used in patients with chronic myeloid leukemia and gastrointestinal stromal tumors.	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (118, 149))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('KIT-mutated', 'Var', (39, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (97, 113))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (89, 113))	('patients', 'Species', '9606', (75, 83))	('chronic myeloid leukemia', 'Disease', (89, 113))	('gastrointestinal stromal tumors', 'Disease', (118, 149))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (89, 113))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (118, 149))	('melanoma', 'Disease', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
20859	28868012	Overall, 24 patients were included; 8 patients had a KIT mutation, 11 showed KIT amplification, and 5 had both.	('patients', 'Species', '9606', (12, 20))	('KIT', 'molecular_function', 'GO:0005020', ('77', '80'))	('KIT amplification', 'MPA', (77, 94))	('KIT mutation', 'Var', (53, 65))	('patients', 'Species', '9606', (38, 46))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))
20860	28868012	The response rates to imatinib amounted to 54% in the mutated group and 0% in the amplified group.	('imatinib', 'Chemical', 'MESH:D000068877', (22, 30))	('mutated', 'Var', (54, 61))	('response', 'MPA', (4, 12))
20861	28868012	Furthermore, 4 patients in this study had an NRAS mutation before treatment; none of these had a response to or sustained stable disease with imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (142, 150))	('patients', 'Species', '9606', (15, 23))	('abl', 'Gene', '25', (124, 127))	('abl', 'Gene', (124, 127))	('NRAS', 'Gene', (45, 49))	('NRAS', 'Gene', '4893', (45, 49))	('mutation', 'Var', (50, 58))
20879	28868012	In contrast to BRAF mutations, KIT mutations are more common in mucosal melanomas, and good response rates to the tyrosine kinase inhibitor imatinib have been described.	('BRAF', 'Gene', '673', (15, 19))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('123', '139'))	('KIT', 'Gene', (31, 34))	('mucosal melanomas', 'Disease', (64, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('BRAF', 'Gene', (15, 19))	('mucosal melanomas', 'Disease', 'MESH:D008545', (64, 81))	('common', 'Reg', (54, 60))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('imatinib', 'Chemical', 'MESH:D000068877', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('mutations', 'Var', (35, 44))
20880	28868012	These data, however, are exclusively valid for KIT-mutated mucosal melanoma and not for KIT-amplified tumors (RR 54 vs. 0%).	('mucosal melanoma', 'Disease', (59, 75))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('KIT-mutated', 'Var', (47, 58))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (59, 75))	('KIT', 'molecular_function', 'GO:0005020', ('88', '91'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
20899	22532924	Malignant melanoma is a highly malignant tumor, and NRAS and BRAF mutations are mainly involved in the pathogenesis of melanoma.	('NRAS', 'Gene', (52, 56))	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('malignant tumor', 'Disease', (31, 46))	('malignant tumor', 'Disease', 'MESH:D018198', (31, 46))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('involved', 'Reg', (87, 95))	('Malignant melanoma', 'Phenotype', 'HP:0002861', (0, 18))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('NRAS', 'Gene', '4893', (52, 56))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (61, 65))	('Malignant melanoma', 'Disease', 'MESH:D008545', (0, 18))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('Malignant melanoma', 'Disease', (0, 18))	('pathogenesis', 'biological_process', 'GO:0009405', ('103', '115'))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))
20903	22532924	Since KIT and PDGFRA genes are mapped to 4q12, it is anticipated that PDGFRA gene mutations are involved in the tumorigenesis of melanoma, as in the case of gastrointestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('PDGFRA', 'Gene', '5156', (70, 76))	('involved', 'Reg', (96, 104))	('PDGFRA', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('PDGFRA', 'Gene', (14, 20))	('PDGFRA', 'Gene', '5156', (14, 20))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (157, 188))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (157, 188))	('tumor', 'Disease', (182, 187))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (82, 91))	('KIT', 'molecular_function', 'GO:0005020', ('6', '9'))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('gastrointestinal stromal tumors', 'Disease', (157, 188))
20920	22532924	The present study is the forth report of PDGFRA mutations in melanoma; the first was reported by Curtin et al., who found no PDGFR mutations in 26 cutaneous melanomas.	('PDGFR', 'Gene', '5159', (41, 46))	('PDGFRA', 'Gene', (41, 47))	('PDGFR', 'Gene', '5159', (125, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (147, 165))	('PDGFRA', 'Gene', '5156', (41, 47))	('cutaneous melanomas', 'Disease', (147, 166))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (147, 166))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (147, 166))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('mutations', 'Var', (48, 57))	('PDGFR', 'Gene', (41, 46))	('PDGFR', 'Gene', (125, 130))
20921	22532924	The second was reported by Sihto et al., who demonstrated no PDGFRA gene mutations in 14 cutaneous melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanomas', 'Disease', (89, 108))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('PDGFRA', 'Gene', (61, 67))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (89, 108))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (89, 108))	('PDGFRA', 'Gene', '5156', (61, 67))	('mutations', 'Var', (73, 82))
20924	22532924	Studies of KIT mutations are scant in number in cutaneous melanoma, and are none in conjunctival melanoma.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('mutations', 'Var', (15, 24))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (84, 105))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (84, 105))	('conjunctival melanoma', 'Disease', (84, 105))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
20925	22532924	showed only 2% of melanomas had KIT mutations.	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('melanomas', 'Disease', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('KIT mutations', 'Var', (32, 45))
20926	22532924	showed no KIT mutations in 14 cutaneous melanomas.	('cutaneous melanomas', 'Disease', (30, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('KIT', 'molecular_function', 'GO:0005020', ('10', '13'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('mutations', 'Var', (14, 23))
20927	22532924	showed that KIT mutations were present in 39% of mucosal melanomas, in 36% of acral melanomas, 28% in melanomas of sun-damaged skin, and in 0% of melanomas of non-sun-damaged skin.	('melanomas', 'Disease', 'MESH:D008545', (146, 155))	('melanomas', 'Disease', (84, 93))	('KIT', 'Gene', (12, 15))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanomas', 'Disease', (146, 155))	('KIT', 'molecular_function', 'GO:0005020', ('12', '15'))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('mutations', 'Var', (16, 25))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('mucosal melanomas', 'Disease', 'MESH:D008545', (49, 66))	('sun-damaged', 'Phenotype', 'HP:0000992', (163, 174))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('melanomas', 'Disease', (57, 66))	('acral melanomas', 'Disease', 'MESH:D008545', (78, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('mucosal melanomas', 'Disease', (49, 66))	('acral melanomas', 'Phenotype', 'HP:0012060', (78, 93))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Disease', (102, 111))	('sun-damaged', 'Phenotype', 'HP:0000992', (115, 126))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('acral melanomas', 'Disease', (78, 93))
20928	22532924	recently reported that KIT mutations were present in 23% of acral melanomas, 15.6% of mucosal melanomas, 1.7% of cutaneous melanomas, and 0% of choroidal melanomas.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (144, 163))	('acral melanomas', 'Disease', (60, 75))	('mucosal melanomas', 'Disease', (86, 103))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))	('cutaneous melanomas', 'Disease', (113, 132))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('choroidal melanomas', 'Disease', 'MESH:D008545', (144, 163))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('acral melanomas', 'Disease', 'MESH:D008545', (60, 75))	('acral melanomas', 'Phenotype', 'HP:0012060', (60, 75))	('KIT', 'Gene', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (113, 132))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (113, 132))	('mucosal melanomas', 'Disease', 'MESH:D008545', (86, 103))	('choroidal melanomas', 'Disease', (144, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))
20930	22532924	reported that KIT mutations were present in 2% of melanomas and that KIT mutations were frequent in acral and sun-damaged skin melanomas and mucosal melanomas while it was very rare in non-sun-damaged skin melanoma.	('KIT', 'Gene', (69, 72))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('skin melanoma', 'Disease', (201, 214))	('mucosal melanomas', 'Disease', (141, 158))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanomas', 'Disease', (50, 59))	('sun-damaged', 'Phenotype', 'HP:0000992', (110, 121))	('frequent', 'Reg', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('acral', 'Disease', (100, 105))	('sun-damaged', 'Phenotype', 'HP:0000992', (189, 200))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Disease', 'MESH:D008545', (127, 136))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))	('skin melanomas', 'Disease', (122, 136))	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('skin melanomas', 'Disease', 'MESH:D008545', (122, 136))	('melanomas', 'Disease', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('skin melanoma', 'Disease', 'MESH:D008545', (201, 214))	('melanomas', 'Disease', (149, 158))	('mutations', 'Var', (73, 82))	('skin melanoma', 'Disease', 'MESH:D008545', (122, 135))	('mucosal melanomas', 'Disease', 'MESH:D008545', (141, 158))
20936	22532924	More studies of the relationship between KIT gene mutations and KIT protein expression in conjunctival melanoma remain to be performed.	('mutations', 'Var', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (90, 111))	('conjunctival melanoma', 'Disease', (90, 111))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (41, 44))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (90, 111))
20939	15928660	Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours.	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (401, 408))	('uveal melanoma', 'Phenotype', 'HP:0007716', (291, 305))	('latter tumours', 'Disease', 'MESH:D009369', (394, 408))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mutations', 'Var', (192, 201))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('MAPK pathway', 'Pathway', (18, 30))	('uveal melanomas', 'Disease', 'MESH:C536494', (52, 67))	('cutaneous melanoma', 'Disease', (141, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (141, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('274', '278'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('BRAF', 'Gene', '673', (187, 191))	('BRAF', 'Gene', (187, 191))	('latter tumours', 'Disease', (394, 408))	('uveal melanomas', 'Disease', (52, 67))	('uveal melanomas', 'Phenotype', 'HP:0007716', (52, 67))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (291, 305))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('uveal melanoma', 'Disease', (291, 305))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumour', 'Phenotype', 'HP:0002664', (401, 407))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
20947	15928660	Notable exceptions are hypermethylation of CDKN2A, which is more common in tumours from patients who develop metastatic disease (van der Velden et al, 2001), and germline BRCA2 gene mutations, which occur in 3% of patients younger than 50 years of age (Scott et al, 2002).	('common', 'Reg', (65, 71))	('patients', 'Species', '9606', (214, 222))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('CDKN2A', 'Gene', (43, 49))	('tumours', 'Disease', (75, 82))	('patients', 'Species', '9606', (88, 96))	('metastatic disease', 'Disease', (109, 127))	('CDKN2A', 'Gene', '1029', (43, 49))	('BRCA2', 'Gene', (171, 176))	('van der Velden', 'Disease', 'MESH:C536528', (129, 143))	('hypermethylation', 'Var', (23, 39))	('van der Velden', 'Disease', (129, 143))	('germline', 'Var', (162, 170))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('BRCA2', 'Gene', '675', (171, 176))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
20952	15928660	Of three RAS genes found to be activated by mutation in human tumours, NRAS (neuroblastoma RAS viral (v-ras) oncogene homologue) is most commonly mutated in cutaneous melanomas (van Elsas et al, 1996).	('cutaneous melanomas', 'Disease', 'MESH:C562393', (157, 176))	('mutation', 'Var', (44, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('mutated', 'Var', (146, 153))	('cutaneous melanomas', 'Disease', (157, 176))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('neuroblastoma RAS viral', 'Disease', (77, 100))	('NRAS', 'Gene', (71, 75))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (77, 100))	('human', 'Species', '9606', (56, 61))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('NRAS', 'Gene', '4893', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (77, 90))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (157, 176))	('tumours', 'Disease', (62, 69))
20956	15928660	It has emerged that BRAF (v-raf murine sarcoma viral oncogene homologue B1) is very frequently activated by mutation in cutaneous melanomas (Brose et al, 2002; Davies et al, 2002; Alsina et al, 2003; Dong et al, 2003; Gorden et al, 2003; Kumar et al, 2003a, 2003b; Maldonado et al, 2003; Omholt et al, 2003; Pollock et al, 2003; Rimoldi et al, 2003; Satyamoorthy et al, 2003; Weber et al, 2003; Cohen et al, 2004; Reifenberger et al, 2004; Shinozaki et al, 2004; Tsao et al, 2004).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (120, 139))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (120, 139))	('v-raf', 'Gene', (26, 31))	('sarcoma viral', 'Disease', (39, 52))	('Pollock', 'Species', '8060', (308, 315))	('murine', 'Species', '10090', (32, 38))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('cutaneous melanomas', 'Disease', (120, 139))	('activated', 'PosReg', (95, 104))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('v-raf', 'Gene', '110157', (26, 31))	('sarcoma viral', 'Disease', 'MESH:D001102', (39, 52))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('mutation', 'Var', (108, 116))	('BRAF', 'Gene', (20, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))
20957	15928660	Notably, the frequency of BRAF mutations is also high in benign melanocytic naevi (Dong et al, 2003; Pollock et al, 2003; Uribe et al, 2003; Yazdi et al, 2003), indicating that constitutive activation of the MAPK pathway is an early event in melanomagenesis.	('benign melanocytic naevi', 'Disease', (57, 81))	('mutations', 'Var', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('melanocytic naevi', 'Phenotype', 'HP:0000995', (64, 81))	('BRAF', 'Gene', (26, 30))	('naevi', 'Phenotype', 'HP:0003764', (76, 81))	('MAPK', 'molecular_function', 'GO:0004707', ('208', '212'))	('Pollock', 'Species', '8060', (101, 108))
20958	15928660	All BRAF mutations in cutaneous pigmented neoplasms occur within the kinase domain.	('mutations', 'Var', (9, 18))	('occur', 'Reg', (52, 57))	('cutaneous pigmented neoplasms', 'Disease', 'MESH:D010859', (22, 51))	('BRAF', 'Gene', (4, 8))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('cutaneous pigmented neoplasms', 'Disease', (22, 51))
20959	15928660	The most frequently found mutation in BRAF (V599E) consists of a 1796T   A transversion in exon 15 (Davies et al, 2002).	('V599E', 'Mutation', 'p.V599E', (44, 49))	('1796T   A transversion', 'Var', (65, 87))	('BRAF', 'Gene', (38, 42))
20960	15928660	Various other mutations have been described in this exon in melanocytic tumours (V599D (Brose et al, 2002; Davies et al, 2002; Pollock et al, 2003); V599K (Pollock et al, 2003, Uribe et al, 2003); V599R (Pollock et al, 2003); K600E (Brose et al, 2002, Satyamoorthy et al, 2003)).	('Pollock', 'Species', '8060', (156, 163))	('Pollock', 'Species', '8060', (204, 211))	('V599R', 'Mutation', 'p.V599R', (197, 202))	('V599K', 'Mutation', 'p.V599K', (149, 154))	('V599K', 'Var', (149, 154))	('melanocytic tumours', 'Disease', 'MESH:D009508', (60, 79))	('K600E', 'Var', (226, 231))	('V599R', 'Var', (197, 202))	('Pollock', 'Species', '8060', (127, 134))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('K600E', 'Mutation', 'p.K600E', (226, 231))	('V599D', 'Mutation', 'p.V599D', (81, 86))	('melanocytic tumours', 'Disease', (60, 79))
20961	15928660	The latter consist of a 1352A   C transversion (K438Q) (Brose et al, 2002), a 1402G   A transition (G468R) and a 1402/1403GG   TC tandem transversion (Gorden et al, 2003), a 1394G   A transition (G465E) and a 1394G   C transversion (G465A) (Davies et al, 2002).	('K438Q', 'Mutation', 'p.K438Q', (48, 53))	('G465A', 'Mutation', 'rs1379583365', (233, 238))	('1402G', 'Var', (78, 83))	('G465E', 'Mutation', 'p.G465E', (196, 201))	('G468R', 'Mutation', 'p.G468R', (100, 105))	('G465E', 'Var', (196, 201))	('1402/1403GG   TC', 'Var', (113, 129))	('K438Q', 'Var', (48, 53))	('1394G', 'Var', (174, 179))	('1394G   C', 'Var', (209, 218))
20962	15928660	Furthermore, it is not surprising that since they activate the same pathway, mutations in NRAS and BRAF are almost mutually exclusive (Brose et al, 2002; Davies et al, 2002; Alsina et al, 2003; Dong et al, 2003; Gorden et al, 2003; Kumar et al, 2003a, 2003b; Omholt et al, 2003; Pollock et al, 2003; Satyamoorthy et al, 2003; Reifenberger et al, 2004; Tsao et al, 2004).	('NRAS', 'Gene', (90, 94))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', (99, 103))	('Pollock', 'Species', '8060', (279, 286))	('mutations', 'Var', (77, 86))	('activate', 'PosReg', (50, 58))
20983	15928660	After blocking with 5% skim milk in PBS-Tween solution, the membranes were probed overnight at 4 C with the following primary antibodies specific to each antigen: phospho-MEK1/2 (dilution 1 : 1000), phospho-ERK1/2 (p44/42) (#9106, dilution 1 : 5000), total ERK1/2 (#9102, dilution 1 : 1000) and phospho-ELK1 (dilution 1 : 1000) antibody (all from Cell Signaling Technology, Hertfordshire, UK).	('Tween', 'Chemical', 'MESH:D011136', (40, 45))	('ELK1', 'Gene', '2002', (303, 307))	('p44', 'Gene', (215, 218))	('antibody', 'cellular_component', 'GO:0019815', ('328', '336'))	('p44', 'Gene', '10561', (215, 218))	('dilution 1 : 1000', 'Var', (309, 326))	('ERK1', 'molecular_function', 'GO:0004707', ('207', '211'))	('antibody', 'cellular_component', 'GO:0019814', ('328', '336'))	('antibody', 'molecular_function', 'GO:0003823', ('328', '336'))	('MEK1/2', 'Gene', '5604;5605', (171, 177))	('ERK1', 'molecular_function', 'GO:0004707', ('257', '261'))	('Signaling', 'biological_process', 'GO:0023052', ('352', '361'))	('MEK1/2', 'Gene', (171, 177))	('MEK1', 'molecular_function', 'GO:0004708', ('171', '175'))	('PBS', 'Chemical', 'MESH:D007854', (36, 39))	('#9102', 'Var', (265, 270))	('antibody', 'cellular_component', 'GO:0042571', ('328', '336'))	('ELK1', 'Gene', (303, 307))
20993	15928660	Of the 11 uveal melanoma cell lines under study, only one cell line (Ocm 1) carried a BRAF mutation, the common V599E (also described by Calipel et al and Kilic et al).	('uveal melanoma', 'Disease', 'MESH:C536494', (10, 24))	('mutation', 'Var', (91, 99))	('V599E', 'Mutation', 'p.V599E', (112, 117))	('uveal melanoma', 'Phenotype', 'HP:0007716', (10, 24))	('uveal melanoma', 'Disease', (10, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('Ocm 1', 'Species', '83984', (69, 74))
20997	15928660	In response to the constitutively activating BRAF mutation in Ocm 1, downstream members of the MAPK pathway show activation (phosphorylated MEK, ERK and ELK).	('ERK', 'Gene', (145, 148))	('ELK', 'Gene', '2047', (153, 156))	('Ocm 1', 'Species', '83984', (62, 67))	('MEK', 'Gene', (140, 143))	('MEK', 'Gene', '5609', (140, 143))	('activating BRAF', 'PosReg', (34, 49))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('activation', 'PosReg', (113, 123))	('MAPK pathway', 'Pathway', (95, 107))	('ERK', 'Gene', '5594', (145, 148))	('ERK', 'molecular_function', 'GO:0004707', ('145', '148'))	('Ocm 1', 'Gene', (62, 67))	('ELK', 'Gene', (153, 156))	('mutation', 'Var', (50, 58))
20999	15928660	Interestingly, compared to the phosphorylation status of these members in Ocm 1, most cell lines show activation of MEK, ERK and ELK; however, these cell lines show this activation in the absence of mutations in the upstream RAS and BRAF genes.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('ELK', 'Gene', '2047', (129, 132))	('ELK', 'Gene', (129, 132))	('activation', 'PosReg', (170, 180))	('MEK', 'Gene', (116, 119))	('MEK', 'Gene', '5609', (116, 119))	('Ocm 1', 'Species', '83984', (74, 79))	('activation', 'PosReg', (102, 112))	('BRAF', 'Gene', (233, 237))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('mutations', 'Var', (199, 208))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
21006	15928660	In the uveal melanoma cell lines and primary uveal melanomas analysed in our study, only cell line Ocm 1 carried a mutation in BRAF (V599E), thus confirming the documentation of a mutation in this cell line by Calipel et al (2003) and Kilic et al (2004).	('uveal melanoma', 'Disease', (7, 21))	('V599E', 'Mutation', 'p.V599E', (133, 138))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (45, 59))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('uveal melanomas', 'Phenotype', 'HP:0007716', (45, 60))	('primary uveal melanomas', 'Disease', 'MESH:C536494', (37, 60))	('primary uveal melanomas', 'Disease', (37, 60))	('Ocm 1', 'Species', '83984', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('mutation', 'Var', (115, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (45, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
21007	15928660	Similarly, our observation of a complete lack of BRAF mutations in primary uveal tumours mirrors the findings of several recent reports (Cohen et al, 2003; Cruz et al, 2003; Edmunds et al, 2003; Rimoldi et al, 2003; Weber et al, 2003; Kilic et al, 2004).	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('uveal tumours', 'Disease', 'MESH:D014604', (75, 88))	('mutations', 'Var', (54, 63))	('uveal tumours', 'Disease', (75, 88))	('BRAF', 'Gene', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
21008	15928660	Table 3 contains a summary of published reports on RAS and BRAF mutations, as well as studies on other members of the MAPK pathway, in uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('RAS', 'Gene', (51, 54))	('uveal melanomas', 'Disease', 'MESH:C536494', (135, 150))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('MAPK', 'molecular_function', 'GO:0004707', ('118', '122'))	('BRAF', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))	('uveal melanomas', 'Disease', (135, 150))	('uveal melanomas', 'Phenotype', 'HP:0007716', (135, 150))
21010	15928660	It is somewhat surprising therefore that three out of three uveal melanoma cell lines studied by Calipel et al (2003) carried the V599E mutation in BRAF, especially since only one out of 11 cell lines in the panel we analysed was found to have this mutation.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('V599E', 'Mutation', 'p.V599E', (130, 135))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('V599E', 'Var', (130, 135))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('BRAF', 'Gene', (148, 152))
21011	15928660	Taken together, these data suggest that while a BRAF mutation is not required for uveal melanoma development in vivo, such mutations confer a cellular growth advantage and are hence selected if they occur in cell lines cultured in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('cellular growth advantage', 'CPA', (142, 167))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('cellular growth', 'biological_process', 'GO:0016049', ('142', '157'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('mutations', 'Var', (123, 132))
21012	15928660	In our study, none of the cell lines or primary tumours carried mutations in any of the three RAS genes (N, H and K), a finding consistent with a previous report (Soparker et al, 1993).	('primary tumours', 'Disease', (40, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('RAS', 'Gene', (94, 97))	('mutations', 'Var', (64, 73))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('primary tumours', 'Disease', 'MESH:D009369', (40, 55))
21017	15928660	It is tempting to speculate that MAPK activation in uveal melanoma may arise via crosstalk with the PI3K/PTEN/AKT pathway, possibly as a consequence of mutation of some of its components (other than PTEN, which is not mutated in this tumour type).	('PTEN', 'Gene', '5728', (199, 203))	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('AKT', 'Gene', (110, 113))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('PI3K', 'molecular_function', 'GO:0016303', ('100', '104'))	('MAPK activation', 'biological_process', 'GO:0000187', ('33', '48'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('PTEN', 'Gene', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('tumour', 'Disease', (234, 240))	('mutation', 'Var', (152, 160))	('MAPK', 'Gene', (33, 37))	('AKT', 'Gene', '207', (110, 113))	('PTEN', 'Gene', '5728', (105, 109))	('activation', 'PosReg', (38, 48))	('PTEN', 'Gene', (199, 203))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
21021	15928660	Although many uveal melanoma samples have been studied for BRAF and NRAS mutations, few have been analysed for MAPK activation and there is the implicit assumption that this pathway is not involved in uveal melanoma genesis.	('uveal melanoma genesis', 'Disease', (201, 223))	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (201, 215))	('uveal melanoma', 'Disease', (14, 28))	('NRAS', 'Gene', (68, 72))	('uveal melanoma', 'Disease', 'MESH:C536494', (201, 215))	('MAPK activation', 'biological_process', 'GO:0000187', ('111', '126'))	('BRAF', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (68, 72))	('uveal melanoma genesis', 'Disease', 'MESH:C536494', (201, 223))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('mutations', 'Var', (73, 82))
21058	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
21059	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
21063	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))	('pre', 'molecular_function', 'GO:0003904', ('203', '206'))
21095	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('downregulated', 'NegReg', (178, 191))	('SRPX', 'Gene', (9, 13))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('DRS', 'Gene', (80, 83))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('ETX1', 'Gene', (72, 76))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
21104	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
21105	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mRNA expression', 'MPA', (24, 39))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
21140	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
21148	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('advantage', 'PosReg', (99, 108))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('MYC', 'Gene', (43, 46))
21159	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('pre', 'molecular_function', 'GO:0003904', ('172', '175'))	('HDAC4', 'Gene', (134, 139))	('GSE120040', 'Var', (141, 150))	('pre', 'molecular_function', 'GO:0003904', ('57', '60'))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
21170	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'molecular_function', 'GO:0004298', ('424', '427'))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'molecular_function', 'GO:0004298', ('352', '355'))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
21175	31378787	Moreover, we demonstrate that the importance of c-Jun depends on melanoma stage and mutation status of the tumor suppressor PTEN.	('c-Jun', 'Gene', (48, 53))	('PTEN', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('c-Jun', 'Gene', '3725', (48, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))	('mutation', 'Var', (84, 92))
21187	31378787	However, it remains unclear which direct target genes of AP-1 homodimer or heterodimer cause the functional effects that support melanomagenesis.	('AP-1', 'Gene', (57, 61))	('AP-1', 'cellular_component', 'GO:0005907', ('57', '61'))	('heterodimer', 'Var', (75, 86))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('si', 'Chemical', 'MESH:D012825', (141, 143))
21189	31378787	We have previously demonstrated that the microRNA miR-125b directly regulates the transcription factor c-Jun, affecting the proliferative and migratory potential of melanoma cells.	('transcription factor', 'molecular_function', 'GO:0000981', ('82', '102'))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))	('regulates', 'Reg', (68, 77))	('c-Jun', 'Gene', '3725', (103, 108))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('affecting', 'Reg', (110, 119))	('melanoma', 'Disease', (165, 173))	('miR-125b', 'Var', (50, 58))	('c-Jun', 'Gene', (103, 108))
21193	31378787	Deregulation of c-Jun is one of the most important events in malignant melanoma and many other cancer entities, but the functional relevance of c-Jun deregulation and its molecular effects on target gene expression have not been determined in detail to date.	('malignant melanoma', 'Disease', (61, 79))	('c-Jun', 'Gene', '3725', (16, 21))	('malignant melanoma', 'Disease', 'MESH:D008545', (61, 79))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('c-Jun', 'Gene', '3725', (144, 149))	('c-Jun', 'Gene', (16, 21))	('gene expression', 'biological_process', 'GO:0010467', ('199', '214'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('malignant melanoma', 'Phenotype', 'HP:0002861', (61, 79))	('si', 'Chemical', 'MESH:D012825', (210, 212))	('c-Jun', 'Gene', (144, 149))
21195	31378787	Mutations in the PTEN gene and thus the loss of this tumor suppressor protein are prevalent in melanoma and lead to upregulation of AKT activity.	('AKT', 'Gene', '207', (132, 135))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('melanoma', 'Disease', (95, 103))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('prevalent', 'Reg', (82, 91))	('AKT', 'Gene', (132, 135))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (17, 21))	('upregulation', 'PosReg', (116, 128))	('tumor', 'Disease', (53, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
21199	31378787	Given that melanomas gain different properties during their progression, we selected six different melanoma cell lines (Sbcl-2, WM3211, WM793, WM1366, WM1158, WM9) categorized by tumor stage (PT, MET) and their previously described BRAF and PTEN mutation status.	('BRAF', 'Gene', '673', (232, 236))	('WM1158', 'Var', (151, 157))	('BRAF', 'Gene', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('melanomas gain', 'Disease', 'MESH:D008545', (11, 25))	('Sbcl', 'Chemical', '-', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanomas gain', 'Disease', (11, 25))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('PTEN', 'Gene', (241, 245))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('melanoma', 'Disease', (11, 19))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('WM9', 'CellLine', 'CVCL:6806', (159, 162))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('tumor', 'Disease', (179, 184))
21200	31378787	1Aii) of four melanoma cell lines exhibiting different tumor stages, BRAF mutation statuses, and PTEN deletions.	('melanoma', 'Disease', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutation', 'Var', (74, 82))	('PTEN', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('deletions', 'Var', (102, 111))	('tumor', 'Disease', (55, 60))	('BRAF', 'Gene', '673', (69, 73))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('BRAF', 'Gene', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
21210	31378787	Due to the fact that PTEN is known to inhibit AKT activity (predominantly AKT3 in melanoma) and thus promotes melanoma cell apoptosis, loss of PTEN is a crucial event during melanoma development and progression.	('AKT', 'Gene', '207', (74, 77))	('AKT', 'Gene', (46, 49))	('loss', 'Var', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('promotes', 'PosReg', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('AKT3', 'Gene', '10000', (74, 78))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('inhibit', 'NegReg', (38, 45))	('AKT', 'Gene', '207', (46, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('AKT3', 'Gene', (74, 78))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('PTEN', 'Gene', (143, 147))	('AKT', 'Gene', (74, 77))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('activity', 'MPA', (50, 58))	('PTEN', 'Gene', (21, 25))
21217	31378787	Our analysis showed a significant induction of c-Jun peak-associated genes in each sequenced c-Jun expressing melanoma cell line (Sbcl2, WM3211, WM1366, WM793, and WM1158), suggesting a positive regulatory activity of c-Jun (Fig.	('c-Jun', 'Gene', '3725', (218, 223))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('c-Jun', 'Gene', (93, 98))	('melanoma', 'Disease', (110, 118))	('c-Jun', 'Gene', '3725', (47, 52))	('WM793', 'Var', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('induction', 'PosReg', (34, 43))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('c-Jun', 'Gene', (218, 223))	('WM3211', 'Var', (137, 143))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('c-Jun', 'Gene', (47, 52))	('Sbcl', 'Chemical', '-', (130, 134))	('c-Jun', 'Gene', '3725', (93, 98))	('WM1366', 'Var', (145, 151))
21219	31378787	Most interestingly, our c-Jun ChIP-Seq data clearly revealed differences in DNA-binding activity of c-Jun based on the cell line-specific PTEN copy number alteration.	('PTEN', 'Gene', (138, 142))	('differences', 'Reg', (61, 72))	('c-Jun', 'Gene', (100, 105))	('c-Jun', 'Gene', (24, 29))	('c-Jun', 'Gene', '3725', (24, 29))	('DNA-binding', 'molecular_function', 'GO:0003677', ('76', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('c-Jun', 'Gene', '3725', (100, 105))	('DNA-binding', 'Interaction', (76, 87))	('copy number alteration', 'Var', (143, 165))
21259	31378787	Interestingly, AKT-siPool transfection in PTEN-/c-Jun- WM9 melanoma cells to mimic PTEN re-expression increased c-Jun protein expression (Fig.	('c-Jun', 'Gene', (48, 53))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('AKT', 'Gene', '207', (15, 18))	('transfection', 'Var', (26, 38))	('c-Jun', 'Gene', '3725', (112, 117))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('WM9', 'CellLine', 'CVCL:6806', (55, 58))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))	('c-Jun', 'Gene', '3725', (48, 53))	('c-Jun', 'Gene', (112, 117))	('AKT', 'Gene', (15, 18))	('increased', 'PosReg', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
21262	31378787	5e, f) and inhibition of c-Jun after siRNA transfection resulted in a significant decrease in cell number compared to sictrl-transfected cells (Fig.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('c-Jun', 'Gene', (25, 30))	('transfection', 'Var', (43, 55))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('decrease', 'NegReg', (82, 90))	('c-Jun', 'Gene', '3725', (25, 30))	('cell number', 'CPA', (94, 105))	('inhibition', 'NegReg', (11, 21))
21265	31378787	The data reveal a significant downregulation of c-Jun in patients with PTENHomDel and an almost unchanged c-Jun expression pattern in those with PTENHemDel compared to PTENWT patients, supporting our findings (Fig.	('c-Jun', 'Gene', (48, 53))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('c-Jun', 'Gene', '3725', (106, 111))	('patients', 'Species', '9606', (57, 65))	('PTENHomDel', 'Var', (71, 81))	('downregulation', 'NegReg', (30, 44))	('patients', 'Species', '9606', (175, 183))	('c-Jun', 'Gene', '3725', (48, 53))	('c-Jun', 'Gene', (106, 111))
21267	31378787	Further, we investigated overall survival of 471 skin cutaneous melanoma patients based on the PTEN and c-Jun expression status, and could clearly show that melanoma patients with alterations in both, c-Jun and PTEN, belong to the high risk group, whereas patients with either PTENWT or c-JunWT belong to the low risk group (Fig.	('c-Jun', 'Gene', '3725', (287, 292))	('alterations', 'Var', (180, 191))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('PTEN', 'Gene', (211, 215))	('c-Jun', 'Gene', (201, 206))	('melanoma', 'Disease', (64, 72))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 72))	('skin cutaneous melanoma', 'Disease', (49, 72))	('c-Jun', 'Gene', (287, 292))	('c-Jun', 'Gene', '3725', (104, 109))	('c-Jun', 'Gene', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (256, 264))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('patients', 'Species', '9606', (166, 174))	('c-Jun', 'Gene', '3725', (201, 206))
21281	31378787	Mutations in members of the PI3K pathway have been extensively studied in many cancer entities.	('PI3K', 'molecular_function', 'GO:0016303', ('28', '32'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PI3K pathway', 'Pathway', (28, 40))	('Mutations', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
21282	31378787	In melanoma, PTEN inactivation could be identified as the crucial step activating the PI3K pathway.	('PI3K pathway', 'Pathway', (86, 98))	('inactivation', 'Var', (18, 30))	('PTEN', 'Protein', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
21303	31378787	Previous data from Chen and colleagues support our results, revealing that PTEN inactivation results in cellular senescence in mouse embryonic fibroblasts.	('mouse', 'Species', '10090', (127, 132))	('results in', 'Reg', (93, 103))	('cellular senescence', 'biological_process', 'GO:0090398', ('104', '123'))	('PTEN', 'Gene', (75, 79))	('cellular senescence', 'CPA', (104, 123))	('inactivation', 'Var', (80, 92))
21304	31378787	Given that melanomas preferentially activate the PI3K pathway through inactivation of PTEN, it can be hypothesized that c-Jun expression in early melanoma stages protects melanoma cells with decreasing PTEN levels from this growth arrest.	('c-Jun', 'Gene', '3725', (120, 125))	('PTEN', 'Gene', (86, 90))	('inactivation', 'Var', (70, 82))	('PI3K', 'molecular_function', 'GO:0016303', ('49', '53'))	('activate', 'PosReg', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('c-Jun', 'Gene', (120, 125))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('melanomas', 'Disease', (11, 20))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('PI3K pathway', 'Pathway', (49, 61))	('PTEN levels', 'MPA', (202, 213))	('melanoma', 'Disease', (146, 154))	('si', 'Chemical', 'MESH:D012825', (132, 134))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('decreasing', 'NegReg', (191, 201))	('growth arrest', 'Phenotype', 'HP:0001510', (224, 237))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
21316	31378787	We applied "si-POOL-AKT", "si-POOL-PTEN", and "si-POOL-c-Jun" (functionally verified, by siTOOLs Biotech GmbH, Planegg, Germany) for specific knockdown of AKT1, AKT2, AKT3, PTEN, and c-Jun, respectively.	('AKT', 'Gene', (167, 170))	('PTEN', 'Gene', (173, 177))	('AKT', 'Gene', '207', (161, 164))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('AKT2', 'Gene', '208', (161, 165))	('c-Jun', 'Gene', '3725', (183, 188))	('AKT', 'Gene', (155, 158))	('c-Jun', 'Gene', (183, 188))	('AKT1', 'Gene', '207', (155, 159))	('AKT', 'Gene', '207', (167, 170))	('c-Jun', 'Gene', '3725', (55, 60))	('AKT2', 'Gene', (161, 165))	('AKT', 'Gene', (20, 23))	('c-Jun', 'Gene', (55, 60))	('AKT1', 'Gene', (155, 159))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('AKT', 'Gene', '207', (155, 158))	('AKT3', 'Gene', '10000', (167, 171))	('knockdown', 'Var', (142, 151))	('AKT', 'Gene', (161, 164))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('AKT', 'Gene', '207', (20, 23))	('AKT3', 'Gene', (167, 171))	('si', 'Chemical', 'MESH:D012825', (27, 29))
21322	31378787	ChIP was performed with the human melanoma cell lines Sbcl-2, WM3211, WM1366, WM793, WM1158, WM9 and NHEM that had not exceeded six passages.	('WM793', 'Var', (78, 83))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('human', 'Species', '9606', (28, 33))	('Sbcl', 'Chemical', '-', (54, 58))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('WM9', 'CellLine', 'CVCL:6806', (93, 96))
21331	31378787	After preclearing with Sepharose CL-4B beads (Sigma) for 2 h, chromatin samples from 10 x 106 cells were immunoprecipitated overnight with 5 mug of rabbit polyclonal antibody anti-c-Jun (Santa Cruz Biotechnology Inc.) or anti- H3K37ac (Abcam).	('chromatin', 'cellular_component', 'GO:0000785', ('62', '71'))	('c-Jun', 'Gene', (180, 185))	('antibody', 'cellular_component', 'GO:0019814', ('166', '174'))	('rabbit', 'Species', '9986', (148, 154))	('antibody', 'molecular_function', 'GO:0003823', ('166', '174'))	('anti- H3K37ac', 'Var', (221, 234))	('antibody', 'cellular_component', 'GO:0042571', ('166', '174'))	('c-Jun', 'Gene', '3725', (180, 185))	('Sepharose CL-4B', 'Chemical', 'MESH:C035771', (23, 38))	('mug', 'molecular_function', 'GO:0043739', ('141', '144'))	('antibody', 'cellular_component', 'GO:0019815', ('166', '174'))
21362	31949145	We show that KDELR3 regulates the metastasis suppressor, KAI1, and report an interaction with the E3 ubiquitin-protein ligase gp78, a regulator of KAI1 degradation.	('KAI1', 'Gene', (57, 61))	('KAI1', 'Gene', (147, 151))	('degradation', 'biological_process', 'GO:0009056', ('152', '163'))	('regulates', 'Reg', (20, 29))	('KAI1', 'Gene', '3732', (57, 61))	('metastasis', 'CPA', (34, 44))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('interaction', 'Interaction', (77, 88))	('ubiquitin', 'molecular_function', 'GO:0031386', ('101', '110'))	('KAI1', 'Gene', '3732', (147, 151))	('KDELR3', 'Var', (13, 19))
21377	31949145	Employing this approach, we identify a 43-gene embryonic melanoblast signature that predicts metastatic melanoma patient survival, and we introduce a role for KDELR3 that is distinct from KDELR1.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('patient', 'Species', '9606', (113, 120))	('melanoma', 'Disease', (104, 112))	('KDELR3', 'Var', (159, 165))	('KDELR1', 'Gene', (188, 194))	('KDELR1', 'Gene', '10945', (188, 194))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
21379	31949145	We observe that KDELR3 regulates KAI1 protein levels and post-translational modification.	('regulates', 'Reg', (23, 32))	('KAI1', 'Gene', '3732', (33, 37))	('post-translational modification', 'MPA', (57, 88))	('KDELR3', 'Var', (16, 22))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('post-translational modification', 'biological_process', 'GO:0043687', ('57', '88'))	('KAI1', 'Gene', (33, 37))
21390	31949145	To this end, we interrogated our 467 putative MetDev genes by using a Cox proportional hazards model to associate their expression with overall survival in a training dataset of human patient samples derived from melanoma metastases (stages III and IV; GSE19234).	('melanoma metastases', 'Disease', (213, 232))	('human', 'Species', '9606', (178, 183))	('GSE19234', 'Var', (253, 261))	('melanoma metastases', 'Disease', 'MESH:D009362', (213, 232))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('patient', 'Species', '9606', (184, 191))	('MetDev genes', 'Gene', (46, 58))
21393	31949145	Notably, gene expression levels in samples derived from early-stage (stages I and II) primary melanoma lesions did not predict patient outcome, suggesting that MetDev genes play a key role in late-stage disease specifically (GSE8401; Fig.	('melanoma lesions', 'Disease', 'MESH:D008545', (94, 110))	('MetDev genes', 'Gene', (160, 172))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('melanoma lesions', 'Disease', (94, 110))	('patient', 'Species', '9606', (127, 134))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('GSE8401;', 'Var', (225, 233))
21406	31949145	We showed that KDELR3 is localized to both the cis- and trans-Golgi compartments in metastatic melanoma cells (Supplementary Fig.	('Golgi', 'cellular_component', 'GO:0005794', ('62', '67'))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma cells', 'Disease', 'MESH:D008545', (95, 109))	('KDELR3', 'Var', (15, 21))	('melanoma cells', 'Disease', (95, 109))
21408	31949145	Moreover, within the KDELR family only KDELR3 demonstrated a melanoblast-specific expression pattern and showed consistent upregulation in melanoma cell lines (Fig.	('expression pattern', 'MPA', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('upregulation', 'PosReg', (123, 135))	('KDELR3', 'Var', (39, 45))	('melanoblast-specific', 'CPA', (61, 81))
21414	31949145	KDELR3 was therefore validated as a mediator of anchorage-independent growth in melanoma cells, a process required for metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma cells', 'Disease', 'MESH:D008545', (80, 94))	('melanoma cells', 'Disease', (80, 94))	('KDELR3', 'Var', (0, 6))
21417	31949145	Stable shRNA knockdown of KDELR3 also resulted in a reduction in lung colonization following tail vein metastasis and significantly fewer mice characterized with high metastatic burden (Supplementary Fig.	('lung colonization following tail vein metastasis', 'CPA', (65, 113))	('mice', 'Species', '10090', (138, 142))	('fewer', 'NegReg', (132, 137))	('KDELR3', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))	('reduction', 'NegReg', (52, 61))
21419	31949145	6g-i), suggesting that the KDELR3-mediated metastatic phenotype cannot be attributed to a change in proliferation, and that KDELR3 is a genuine melanoma metastasis progression gene.	('KDELR3', 'Var', (124, 130))	('melanoma metastasis', 'Disease', 'MESH:D009362', (144, 163))	('metastatic', 'CPA', (43, 53))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma metastasis', 'Disease', (144, 163))
21425	31949145	As PERK is a protein kinase and GADD34 a protein phosphatase, which both act on EIF2alpha, we hypothesized that KDELR3-low cells are primed to activate the PERK-EIF2alpha arm of the UPR.	('PERK-EIF2alpha', 'Var', (156, 170))	('GADD34', 'Gene', '17872', (32, 38))	('EIF2', 'cellular_component', 'GO:0005850', ('80', '84'))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('activate', 'PosReg', (143, 151))	('EIF2', 'cellular_component', 'GO:0005850', ('161', '165'))	('phosphatase', 'molecular_function', 'GO:0016791', ('49', '60'))	('GADD34', 'Gene', (32, 38))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))
21427	31949145	6b) and found that loss of KDELR3 expression resulted in increased PERK and EIF2alpha protein levels in untreated cells, corroborating our mouse model data (Fig.	('KDELR3', 'Gene', (27, 33))	('EIF2alpha protein levels', 'MPA', (76, 100))	('mouse', 'Species', '10090', (139, 144))	('loss', 'Var', (19, 23))	('increased', 'PosReg', (57, 66))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('EIF2', 'cellular_component', 'GO:0005850', ('76', '80'))	('PERK', 'MPA', (67, 71))
21431	31949145	To test this, we asked if KDELR3 knockdown sensitizes metastatic melanoma cells to ER stress-induced death.	('melanoma cells', 'Disease', (65, 79))	('knockdown', 'Var', (33, 42))	('sensitizes', 'Reg', (43, 53))	('melanoma cells', 'Disease', 'MESH:D008545', (65, 79))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('KDELR3 knockdown', 'Var', (26, 42))
21433	31949145	We observed that siRNA-mediated knockdown of KDELR3 expression resulted in a ~5-fold increase in metastatic melanoma cell death over controls (8.3%, siKDELR3; 1.6%, siControl; Fig.	('melanoma cell death', 'Disease', (108, 127))	('KDELR3', 'Gene', (45, 51))	('knockdown', 'Var', (32, 41))	('melanoma cell death', 'Disease', 'MESH:D003643', (108, 127))	('cell death', 'biological_process', 'GO:0008219', ('117', '127'))	('increase', 'PosReg', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
21435	31949145	However, KDELR3-knockdown cells have an enhanced sensitivity to ER stress induction with tunicamycin (>13-fold difference in cell death: 28.4%, siKDELR3; 2.1%, siControl; Fig.	('siKDELR3', 'Var', (144, 152))	('sensitivity', 'MPA', (49, 60))	('tunicamycin', 'Chemical', 'MESH:D014415', (89, 100))	('cell death', 'biological_process', 'GO:0008219', ('125', '135'))	('enhanced', 'PosReg', (40, 48))	('KDELR3-knockdown', 'Var', (9, 25))
21436	31949145	If our hypothesis is correct, we expect KDELR3 to be critical to metastatic melanoma viability, but not to normal melanocytes.	('melanoma viability', 'Disease', (76, 94))	('KDELR3', 'Var', (40, 46))	('melanoma viability', 'Disease', 'MESH:D008545', (76, 94))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
21439	31949145	These data indicate that the ability of KDELR3 to relieve ER stress is crucial for adaptation and survival of metastatic melanoma and may be instrumental to the metastatic phenotype.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('KDELR3', 'Var', (40, 46))	('ER stress', 'MPA', (58, 67))
21440	31949145	To further understand the role of KDELR3 in metastasis, we queried if KDELR3 knockdown would increase expression of known metastasis suppressors in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('expression', 'MPA', (102, 112))	('increase', 'PosReg', (93, 101))	('KDELR3', 'Gene', (70, 76))	('knockdown', 'Var', (77, 86))
21442	31949145	Of these, only KAI1 demonstrated a marked increase in expression following KDELR3 knockdown (Fig.	('expression', 'MPA', (54, 64))	('KDELR3 knockdown', 'Var', (75, 91))	('KAI1', 'Gene', '3732', (15, 19))	('KAI1', 'Gene', (15, 19))	('increase', 'PosReg', (42, 50))
21443	31949145	Moreover, we observed a change in KAI1 molecular weight distribution following KDELR3 knockdown, suggesting alterations in KAI1 post-translational modification.	('KAI1', 'Gene', (123, 127))	('knockdown', 'Var', (86, 95))	('change', 'Reg', (24, 30))	('alterations', 'Reg', (108, 119))	('post-translational modification', 'MPA', (128, 159))	('post-translational modification', 'biological_process', 'GO:0043687', ('128', '159'))	('KDELR3', 'Gene', (79, 85))	('KAI1', 'Gene', (34, 38))	('KAI1', 'Gene', '3732', (123, 127))	('KAI1', 'Gene', '3732', (34, 38))
21446	31949145	To further validate the role of KDELR3 on KAI1 protein regulation, we exogenously expressed KAI1 protein in 1205Lu metastatic melanoma cells (in which endogenous KAI1 expression is relatively low) and co-expressed KDELR3-001, KDELR3-002, or a vector control.	('KAI1', 'Gene', (92, 96))	('KAI1', 'Gene', '3732', (162, 166))	('KAI1', 'Gene', '3732', (42, 46))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('KAI1', 'Gene', (42, 46))	('KDELR3-001', 'Var', (214, 224))	('melanoma cells', 'Disease', 'MESH:D008545', (126, 140))	('KAI1', 'Gene', '3732', (92, 96))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('KAI1', 'Gene', (162, 166))	('protein', 'Protein', (97, 104))	('melanoma cells', 'Disease', (126, 140))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))
21449	31949145	KAI1 protein glycosylation pattern was impacted reciprocally by knockdown and overexpression experiments, supporting the notion that KAI1 post-translational modification pathways are regulated by KDELR3, including an upregulation of a high-molecular-weight band in KDELR3-knockdown cells (Fig.	('regulated', 'Reg', (183, 192))	('KAI1', 'Gene', (133, 137))	('high-molecular-weight band', 'MPA', (235, 261))	('KAI1', 'Gene', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('KAI1', 'Gene', '3732', (133, 137))	('post-translational modification', 'biological_process', 'GO:0043687', ('138', '169'))	('protein glycosylation', 'biological_process', 'GO:0006486', ('5', '26'))	('KDELR3', 'Var', (196, 202))	('KAI1', 'Gene', '3732', (0, 4))	('upregulation', 'PosReg', (217, 229))
21451	31949145	Glycosylated KAI1 has been linked to inhibition of cell motility and promotion of cell death, and has been shown to influence N-cadherin clustering and bone metastasis in acute myeloid leukemia.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (171, 193))	('KAI1', 'Gene', (13, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (177, 193))	('influence', 'Reg', (116, 125))	('cell death', 'CPA', (82, 92))	('N-cadherin', 'Protein', (126, 136))	('acute myeloid leukemia', 'Disease', (171, 193))	('inhibition', 'NegReg', (37, 47))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('cell motility', 'CPA', (51, 64))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (171, 193))	('cell death', 'biological_process', 'GO:0008219', ('82', '92'))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('KAI1', 'Gene', '3732', (13, 17))	('cell motility', 'biological_process', 'GO:0048870', ('51', '64'))	('bone metastasis', 'CPA', (152, 167))	('Glycosylated', 'Var', (0, 12))
21453	31949145	We asked if KDELR3 regulates expression of the E3 ubiquitin ligase known to target KAI1, gp78/autocrine motility factor receptor (AMFR), hereafter referred to as gp78.	('regulates', 'Reg', (19, 28))	('KAI1', 'Gene', '3732', (83, 87))	('ubiquitin', 'molecular_function', 'GO:0031386', ('50', '59'))	('gp78/autocrine motility factor receptor', 'Gene', (89, 128))	('KDELR3', 'Var', (12, 18))	('gp78/autocrine motility factor receptor', 'Gene', '267', (89, 128))	('KAI1', 'Gene', (83, 87))	('E3 ubiquitin ligase', 'Enzyme', (47, 66))	('expression', 'MPA', (29, 39))
21454	31949145	Interestingly, gp78 was first identified as a motility factor associated with metastasis in several cancers, including melanoma.	('gp78', 'Var', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('associated with', 'Reg', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('metastasis', 'CPA', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
21456	31949145	To assess how KDELR3 contributes to melanoma progression in patients, we utilized multiple melanoma patient databases, TCGA and Gene Expression Omnibus (GEO; GSE8401, GSE19234).	('patient', 'Species', '9606', (60, 67))	('melanoma progression', 'Disease', (36, 56))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('melanoma', 'Disease', (91, 99))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('GSE19234', 'Var', (167, 175))	('patient', 'Species', '9606', (100, 107))	('melanoma progression', 'Disease', 'MESH:D008545', (36, 56))	('Gene Expression', 'biological_process', 'GO:0010467', ('128', '143'))
21459	31949145	Metastatic melanoma patients with KDELR3 copy number amplifications demonstrated reduced survival relative to patients without such alterations (Supplementary Fig.	('patients', 'Species', '9606', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('patients', 'Species', '9606', (20, 28))	('reduced', 'NegReg', (81, 88))	('KDELR3 copy number amplifications', 'Var', (34, 67))	('survival', 'MPA', (89, 97))	('Metastatic melanoma', 'Disease', (0, 19))	('Metastatic melanoma', 'Disease', 'MESH:D008545', (0, 19))
21461	31949145	High KDELR3-expressing late-stage metastatic melanomas showed statistically significant association with poor patient outcome, whereas KDELR3 expression levels in early-stage primary tumor samples did not (Fig.	('High KDELR3-expressing', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('patient', 'Species', '9606', (110, 117))	('melanomas', 'Disease', (45, 54))	('tumor', 'Disease', (183, 188))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
21468	31949145	These data intimate that KDELR1 and KDELR3 play different roles in melanoma progression.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('KDELR1', 'Gene', (25, 31))	('melanoma progression', 'Disease', 'MESH:D008545', (67, 87))	('KDELR3', 'Var', (36, 42))	('KDELR1', 'Gene', '10945', (25, 31))	('melanoma progression', 'Disease', (67, 87))
21470	31949145	Notably, in contrast to KDELR3 knockdown, which predictably diminished metastasis, KDELR1 knockdown actually increased metastasis, suggesting that KDELR1 contributes in a very different way to melanoma etiology and can function as a metastasis suppressor (Fig.	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('knockdown', 'Var', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('metastasis', 'MPA', (119, 129))	('KDELR1', 'Gene', (147, 153))	('KDELR1', 'Gene', '10945', (147, 153))	('KDELR1', 'Gene', (83, 89))	('increased', 'PosReg', (109, 118))	('KDELR1', 'Gene', '10945', (83, 89))
21474	31949145	The genetic/epigenetic reactivation of pathways that allow embryonic melanocytes to migrate, invade, and colonize would represent an efficient strategy for melanoma cells to successfully metastasize.	('genetic/epigenetic reactivation', 'Var', (4, 35))	('melanoma cells', 'Disease', 'MESH:D008545', (156, 170))	('melanoma cells', 'Disease', (156, 170))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))
21476	31949145	KDELR3 has neither been previously associated with cutaneous melanoma metastasis nor investigated in depth in the literature.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma metastasis', 'Disease', (51, 80))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('cutaneous melanoma metastasis', 'Disease', 'MESH:D009362', (51, 80))	('KDELR3', 'Var', (0, 6))
21478	31949145	Our data demonstrating reduced BiP protein in stable KDELR3-knockdown cells suggest that BiP is a genuine substrate for KDELR3 retrograde trafficking, and that without KDELR3 expression melanoma cells are unable to maintain normal BiP levels.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('BiP', 'Gene', '2662', (231, 234))	('melanoma cells', 'Disease', 'MESH:D008545', (186, 200))	('BiP', 'Gene', (89, 92))	('melanoma cells', 'Disease', (186, 200))	('BiP', 'Gene', '2662', (89, 92))	('BiP', 'Gene', '2662', (31, 34))	('BiP', 'Gene', (31, 34))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('reduced', 'NegReg', (23, 30))	('KDELR3', 'Var', (120, 126))	('BiP', 'Gene', (231, 234))
21488	31949145	KAI1 glycosylation leads to changes in its membrane organization and therefore its ability to mediate this extracellular/intercellular signaling.	('mediate', 'MPA', (94, 101))	('membrane organization', 'biological_process', 'GO:0061024', ('43', '64'))	('signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('KAI1', 'Gene', (0, 4))	('membrane organization', 'MPA', (43, 64))	('extracellular', 'cellular_component', 'GO:0005576', ('107', '120'))	('membrane', 'cellular_component', 'GO:0016020', ('43', '51'))	('glycosylation', 'biological_process', 'GO:0070085', ('5', '18'))	('changes', 'Reg', (28, 35))	('glycosylation', 'Var', (5, 18))	('ability', 'MPA', (83, 90))	('KAI1', 'Gene', '3732', (0, 4))
21493	31949145	Here we link KDELR3 to post-translational modification (glycosylation) and degradation of the metastasis suppressor, KAI1.	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('post-translational modification', 'biological_process', 'GO:0043687', ('23', '54'))	('KAI1', 'Gene', '3732', (117, 121))	('post-translational modification', 'MPA', (23, 54))	('KAI1', 'Gene', (117, 121))	('degradation', 'MPA', (75, 86))	('KDELR3', 'Var', (13, 19))	('glycosylation', 'biological_process', 'GO:0070085', ('56', '69'))
21494	31949145	This biology may be informative for developing therapeutics for KDELR3-high metastatic melanoma patients.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('patients', 'Species', '9606', (96, 104))	('KDELR3-high', 'Var', (64, 75))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
21495	31949145	We found that two such genes, KDELR3 and P4HA2 (a collagen prolyl 4-hydroxylase involved in ECM remodeling and associated with worse clinical outcome in melanoma patients), from our four-gene functional validation screen are tightly co-expressed in four independent mouse models and in human melanoma patients.	('collagen', 'molecular_function', 'GO:0005202', ('50', '58'))	('patients', 'Species', '9606', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (292, 300))	('prolyl 4-hydroxylase', 'molecular_function', 'GO:0031545', ('59', '79'))	('HA2', 'cellular_component', 'GO:0030122', ('43', '46'))	('prolyl', 'Chemical', 'MESH:C065612', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('human', 'Species', '9606', (286, 291))	('patients', 'Species', '9606', (301, 309))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('KDELR3', 'Var', (30, 36))	('P4HA2', 'Gene', (41, 46))	('mouse', 'Species', '10090', (266, 271))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('melanoma', 'Disease', (292, 300))
21499	31949145	We anticipate that further exploration of KDELR3 and other now-uncovered embryonic genes/pathways will facilitate the development of more effective treatment strategies for patients with advanced melanoma, and perhaps other tumor types.	('KDELR3', 'Var', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('patients', 'Species', '9606', (173, 181))	('tumor', 'Disease', (224, 229))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
21511	31949145	4a were derived from the following four mouse melanoma models: M1, albino female C57BL/6 background, with BrafCA/+; Ptenflox/+; Cdkn2aflox/+; Tyr-CreERT2-tg transgenic alleles.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('Tyr', 'Chemical', 'MESH:C042696', (142, 145))	('mouse', 'Species', '10090', (40, 45))	('Ptenflox', 'Chemical', 'None', (116, 124))	('Tyr-CreERT2-tg', 'Var', (142, 156))	('Ptenflox/+; Cdkn2aflox/+; Tyr-CreERT2-tg', 'Var', (116, 156))
21513	31949145	M2, C57BL/6 female background, with BrafCA/+; Cdkn2aflox/+; Tyr-CreERT2-tg; Hgf-tg transgenic alleles.	('Hgf', 'Gene', (76, 79))	('Tyr-CreERT2-tg', 'Var', (60, 74))	('Hgf', 'Gene', '3082', (76, 79))	('Tyr', 'Chemical', 'MESH:C042696', (60, 63))
21515	31949145	M3, C57BL/6 female background, Cdk4R24C; Hgf-tg transgenic alleles.	('Hgf', 'Gene', '3082', (41, 44))	('Hgf', 'Gene', (41, 44))	('Cdk4R24C', 'Var', (31, 39))	('Cdk', 'molecular_function', 'GO:0004693', ('31', '34'))
21531	31949145	Among the late-stage patients, the patients with high expression signature had significant poor survival compared with those with low expression (P = 3.486e - 5, log-rank test, Fig.	('survival', 'CPA', (96, 104))	('patients', 'Species', '9606', (21, 29))	('poor', 'NegReg', (91, 95))	('high expression', 'Var', (49, 64))	('patients', 'Species', '9606', (35, 43))
21554	31949145	Human 1205Lu cells were transduced with a high multiplicity of infection (MOI) of FerH-ffLuc-IRES-H2B-eGFP-expressing lentivirus (11346-M04-653, Frederick National Laboratory for Cancer Research, Proteomics Facility, courtesy of Dominic Esposito).	('Human', 'Species', '9606', (0, 5))	('infection', 'Disease', (63, 72))	('H2B', 'Chemical', 'MESH:D006859', (98, 101))	('infection', 'Disease', 'MESH:D007239', (63, 72))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('11346-M04-653', 'Var', (130, 143))
21556	31949145	TOPO cloning was used to clone place this sequence into the Gateway cloning system and the pENTR L1/L2 plasmid was combined with C413-E19 pPol2 L4/R1 and pDEST-658 R4/R2 destination plasmids.	('C413-E19', 'Var', (129, 137))	('L1/L2', 'Gene', (97, 102))	('L1/L2', 'Gene', '28938', (97, 102))	('C413', 'Chemical', 'MESH:C102734', (129, 133))
21564	31949145	Primary melanocytes, of which there were 234 (gifted by Meenhard Herlyn, Wistar Institute), were immortalized through a one-step infection with MSCV-pic2 retroviral vector that co-express the catalytic subunit of hTERT and a shRNA CDKN2A gene locus that knocks down both p16INK4A and p14ARF (hTERT-sh_p16).	('hTERT', 'Gene', (213, 218))	('MSCV', 'Species', '258023', (144, 148))	('p16INK4A', 'Var', (271, 279))	('hTERT', 'Gene', '7015', (292, 297))	('infection', 'Disease', (129, 138))	('hTERT', 'Gene', (292, 297))	('pic', 'cellular_component', 'GO:0097550', ('149', '152'))	('p14ARF', 'Var', (284, 290))	('knocks down', 'NegReg', (254, 265))	('hTERT', 'Gene', '7015', (213, 218))	('infection', 'Disease', 'MESH:D007239', (129, 138))	('pic', 'cellular_component', 'GO:0019035', ('149', '152'))
21571	31949145	All other assays were performed using both the siGENOME siRNAs, including siGENOME Human AMFR siRNA SMARTpool (M-006522-01-0005, Dharmacon ) and ON-TARGET Plus SMARTpool siRNAs for human KDELR3 (L-012316-00-0005, Dharmacon ), human KDELR1 (L-019136-01-0005, Dharmacon ), and ON-TARGET plus  Control Pool (Non-targeting control, D-001810-10-20, Dharmacon ).	('human', 'Species', '9606', (181, 186))	('L-019136-01-0005', 'Var', (240, 256))	('KDELR1', 'Gene', (232, 238))	('M-006522-01-0005, Dharmacon', 'Chemical', 'MESH:C000598011', (111, 138))	('human', 'Species', '9606', (226, 231))	('KDELR1', 'Gene', '10945', (232, 238))	('L-019136-01-0005, Dharmacon', 'Chemical', 'MESH:C000598011', (240, 267))	('L-012316-00-0005, Dharmacon', 'Chemical', 'MESH:C000598011', (195, 222))	('M-006522-01-0005', 'Var', (111, 127))	('Human', 'Species', '9606', (83, 88))	('L-012316-00-0005', 'Var', (195, 211))	('D-001810-10-20', 'Chemical', 'MESH:C480634', (328, 342))
21577	31949145	1205Lu human melanoma cells transduced with mPol2p> Hs.AMFR-mCherry and mPol2p> Hs.KDELR3-GFP were plated on chamber slides (Nunc Lab-Tek) coated with 0.1% gelatin (Stemcell) and imaged by confocal microscopy.	('Tek', 'Gene', (134, 137))	('mPol2p> Hs.KDELR3-GFP', 'Var', (72, 93))	('human', 'Species', '9606', (7, 12))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mPol2p', 'Var', (44, 50))	('melanoma cells', 'Disease', 'MESH:D008545', (13, 27))	('melanoma cells', 'Disease', (13, 27))	('Tek', 'Gene', '7010', (134, 137))
21619	31949145	Individual human genes tested: KDELR3 F, 5'-TCCCAGTCATTGGCCTTTCC-3' and KDELR3 R, 5'-CCAGTTAGCCAGGTAGAGTGC-3'; KDELR1 F, 5'-TCAAAGCTACTTACGATGGGAAC-3' and KDELR1 R, 5'-ATTGACCAGGAACGCCAGAAT-3'; KDELR2 F, 5'-GCACTGGTCTTCACAACTCGT-3' and KDELR2 R, 5'-AGATCAGGTACACTGTGGCATA-3'; KDELR3-001 F, 5'-TGACCAAATTGCAGTCGTGT-3' and KDELR3-001 R, 5'-TCAGATTGGCATTGGAAGACT-3'; AMFR F, 5'-GGTTCTAGTAAATACCGCTTGCT-3' and AMFR R, 5'-TCTCACTCACTCGAAGAGGGC-3'; CD82 F, 5'-TGTCCTGCAAACCTCCTCCA-3' and CD82 R, 5'-CCATGAGCATAGTGACTGCC-3'.	('CAT', 'Gene', '847', (500, 503))	('KDELR2', 'Gene', '11014', (236, 242))	('human', 'Species', '9606', (11, 16))	('CAT', 'Gene', (267, 270))	('KDELR1', 'Gene', (155, 161))	('KDELR1', 'Gene', '10945', (155, 161))	('CAT', 'Gene', (51, 54))	('KDELR2', 'Gene', '11014', (194, 200))	("5'-TCAAAGCTACTTACGATGGGAAC", 'Chemical', 'MESH:C068492', (121, 147))	('CAT', 'Gene', (494, 497))	('CD82 F', 'Var', (443, 449))	('KDELR2', 'Gene', (236, 242))	('CAT', 'Gene', '847', (347, 350))	('CAT', 'Gene', '847', (267, 270))	('CAT', 'Gene', (500, 503))	('KDELR2', 'Gene', (194, 200))	('KDELR1', 'Gene', (111, 117))	('CAT', 'Gene', '847', (51, 54))	('KDELR1', 'Gene', '10945', (111, 117))	("5'-TCTCACTCACTCGAAGAGGGC", 'Chemical', 'MESH:C068492', (414, 438))	('CD82 R', 'Var', (482, 488))	('CAT', 'Gene', '847', (494, 497))	('CAT', 'Gene', (347, 350))
21647	31949145	G.M., K.L.M., P.J.M., A.S., A.M.M., C.-P.D., A.M.W., Y.C.T., H.T.M., S.D., P.S.M.	('P.S.M', 'Var', (75, 80))	('P.J.M.', 'Var', (14, 20))	('H.T', 'Disease', (61, 64))	('C.-P.D.', 'Var', (36, 43))	('H.T', 'Disease', 'MESH:D000848', (61, 64))	('Y.C.T.', 'Var', (53, 59))
21648	31949145	K.L.M., P.J.M., A.S., A.M.M., H.T.M., T.G., Y.C.T., M.R.Z., E.P.-G., S.D., L.M.J., S.M.H., K.Y.	('L.M.J.', 'Var', (75, 81))	('H.T', 'Disease', 'MESH:D000848', (30, 33))	('H.T', 'Disease', (30, 33))
21651	33923757	Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma In this study we investigated the role of cannabinoid receptor 2 (CB2R) on immune cells in melanoma and found significantly improved overall survival in patients with high intra-tumoral CB2R gene expression.	('improved', 'PosReg', (209, 217))	('CB2R', 'Gene', '12802', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('CB2R', 'Gene', (271, 275))	('tumor', 'Disease', (263, 268))	('CB2R', 'Gene', (151, 155))	('Associated', 'Reg', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('gene expression', 'biological_process', 'GO:0010467', ('276', '291'))	('high', 'Var', (252, 256))	('Melanoma', 'Disease', 'MESH:D008545', (76, 84))	('patients', 'Species', '9606', (238, 246))	('CB2R', 'Gene', '12802', (271, 275))	('Tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('overall survival', 'MPA', (218, 234))	('Melanoma', 'Disease', (76, 84))
21660	33923757	In a murine melanoma model, CB2R expression reduced the growth of melanoma as well as the B cell frequencies in the tumor microenvironment (TME), compared to CB2R-deficient mice.	('CB2R', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('CB2R', 'Gene', '12802', (158, 162))	('expression', 'Var', (33, 43))	('CB2R', 'Gene', '12802', (28, 32))	('melanoma', 'Disease', (12, 20))	('growth', 'CPA', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('murine', 'Species', '10090', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('reduced', 'NegReg', (44, 51))	('CB2R', 'Gene', (158, 162))	('tumor', 'Disease', (116, 121))	('mice', 'Species', '10090', (173, 177))
21671	33923757	The ECS consists of the endocannabinoid ligands 2-arachidonglycerol (2-AG) and N-arachidonoylethanolamine (anandamide) which activate the G-protein coupled receptors, cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), which were first cloned in the 1990s.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('CB1R', 'Gene', (196, 200))	('2-arachidonglycerol', 'Chemical', '-', (48, 67))	('G-protein coupled', 'Protein', (138, 155))	('anandamide', 'Chemical', 'MESH:C078814', (107, 117))	('N-arachidonoylethanolamine', 'Var', (79, 105))	('2-AG', 'Chemical', '-', (69, 73))	('CB2R', 'Gene', (235, 239))	('cannabinoid receptor type-1', 'Gene', '12801', (167, 194))	('activate', 'PosReg', (125, 133))	('cannabinoid receptor type-1', 'Gene', (167, 194))	('CB2R', 'Gene', '12802', (235, 239))	('N-arachidonoylethanolamine', 'Chemical', 'MESH:C557222', (79, 105))
21688	33923757	injection of anti-CD19 (clone 1D3) and anti-B220 (clone RA3.3A1/6.1) monoclonal antibodies (Bio X Cell) every 5 days, starting three weeks before tumor inoculation.	('B220', 'Gene', '19264', (44, 48))	('B220', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('anti-CD19', 'Var', (13, 22))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
21695	33923757	The following antibodies targeting mouse surface antigens were used: anti-CD45.2 (104), anti-CD3 (145-2C11), anti-CD4 (RM4-5), anti-CD8 (53-6.7), anti-CD19 (6D5), anti-NK1.1 (PK136), anti-CD11b (M1/70) and anti-Gr-1 (RB6-8C5).	('CD4', 'Gene', '12504', (74, 77))	('CD45', 'Gene', '5788', (74, 78))	('CD11b', 'Gene', '16409', (188, 193))	('NK1.1', 'Gene', '17059', (168, 173))	('anti-CD8', 'Var', (127, 135))	('CD4', 'Gene', (114, 117))	('CD45', 'Gene', (74, 78))	('CD4', 'Gene', '12504', (114, 117))	('anti-CD19', 'Var', (146, 155))	('mouse', 'Species', '10090', (35, 40))	('CD3', 'Gene', (93, 96))	('NK1.1', 'Gene', (168, 173))	('CD4', 'Gene', (74, 77))	('CD3', 'Gene', '28134', (93, 96))	('CD11b', 'Gene', (188, 193))
21703	33923757	This resulted in 4568 wt and 5273 Cnr2-/- B cells.	('4568 wt', 'Var', (17, 24))	('Cnr2', 'Gene', '12802', (34, 38))	('Cnr2', 'Gene', (34, 38))
21732	33923757	Upon B cell depletion using anti-CD19 and anti-B220 depleting antibodies, Treg frequencies were reduced (Figure 4C, Supplemental Figure S1), suggesting that CB2R regulates tumor immunity by reducing Breg-mediated Treg induction.	('B220', 'Gene', '19264', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CB2R', 'Gene', '12802', (157, 161))	('reduced', 'NegReg', (96, 103))	('B220', 'Gene', (47, 51))	('Treg', 'Chemical', '-', (74, 78))	('anti-CD19', 'Var', (28, 37))	('tumor', 'Disease', (172, 177))	('regulates', 'Reg', (162, 171))	('CB2R', 'Gene', (157, 161))	('Treg', 'Chemical', '-', (213, 217))	('Breg-mediated Treg induction', 'CPA', (199, 227))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('reducing', 'NegReg', (190, 198))	('Treg frequencies', 'CPA', (74, 90))
21735	33923757	Using the B16F10 murine cutaneous melanoma model, a remarkable reduction in tumor growth upon treatment with the selective CB2R agonists GW833972A and JWH-133 was found.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (24, 42))	('GW833972A', 'Var', (137, 146))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('JWH-133', 'Chemical', 'MESH:C432747', (151, 158))	('murine', 'Species', '10090', (17, 23))	('CB2R', 'Gene', (123, 127))	('reduction', 'NegReg', (63, 72))	('GW833972A', 'Chemical', 'MESH:C533061', (137, 146))	('CB2R', 'Gene', '12802', (123, 127))	('cutaneous melanoma', 'Disease', (24, 42))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (24, 42))
21742	33923757	Therefore, CB2R deficiency leads to impaired B cell development and differentiation, inducing a release of immature B cells into the circulation.	('CB2R', 'Gene', (11, 15))	('impaired', 'NegReg', (36, 44))	('release of immature B cells into the circulation', 'MPA', (96, 144))	('inducing', 'Reg', (85, 93))	('B cell development', 'CPA', (45, 63))	('CB2R', 'Gene', '12802', (11, 15))	('differentiation', 'CPA', (68, 83))	('impaired B cell development', 'Phenotype', 'HP:0005357', (36, 63))	('B cell development', 'biological_process', 'GO:0030183', ('45', '63'))	('deficiency', 'Var', (16, 26))
21747	33923757	Based on these findings, we hypothesize that CB2R deficiency triggers the infiltration of immature B cells and the induction of Treg, thereby dampening the tumor-specific immune response.	('CB2R', 'Gene', '12802', (45, 49))	('Treg', 'CPA', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('infiltration', 'CPA', (74, 86))	('triggers', 'Reg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('deficiency', 'Var', (50, 60))	('tumor', 'Disease', (156, 161))	('Treg', 'Chemical', '-', (128, 132))	('CB2R', 'Gene', (45, 49))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))	('dampening', 'NegReg', (142, 151))
21781	25506846	A BRAF V600 mutation was detected (Fig.	('BRAF', 'Gene', (2, 6))	('V600', 'Var', (7, 11))	('BRAF', 'Gene', '673', (2, 6))
21813	32533054	Since immunosuppression from abnormalities of the TME critically interrupts immunotherapeutic approaches, understanding the TME and characterizing novel immune subtypes have been extensively researched to predict immunotherapy responses and enhance antitumor activity by targeting TME-induced ICI resistance.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('abnormalities', 'Var', (29, 42))	('enhance', 'PosReg', (241, 248))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('immunotherapeutic approaches', 'CPA', (76, 104))	('targeting', 'Reg', (271, 280))	('tumor', 'Disease', (253, 258))	('interrupts', 'NegReg', (65, 75))
21861	32533054	We identified significantly amplified or deleted loci and genes within both subtypes across 7 cancers except few subtypes (Supplementary Table 3 and 4, respectively), and recurrent amplifications and deletions at several loci with immune checkpoint genes were found in KIRP, PAAD, PCPG, SARC and SKCM (Supplementary Fig.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('SKCM', 'Disease', (296, 300))	('PCPG', 'Disease', (281, 285))	('KIRP', 'Disease', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PAAD', 'Disease', (275, 279))	('deletions', 'Var', (200, 209))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('SARC', 'Disease', (287, 291))	('cancers', 'Disease', (94, 101))
21885	32533054	At gene levels, recurrent amplifications and deletions at immune checkpoint genes were found in several subtypes of cancers but not in TME-dependent manner.	('immune checkpoint genes', 'Gene', (58, 81))	('deletions', 'Var', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('found', 'Reg', (87, 92))	('amplifications', 'Var', (26, 40))
21904	32533054	GISTIC analysis was conducted to find recurrent amplification and deletion in the subtypes of 7 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('deletion', 'Var', (66, 74))	('amplification', 'Var', (48, 61))
21960	32057296	To correlate the gene expression measured by qPCR with the actual protein expression, we performed a proteomic analysis on the microdissected material in three representative cases, that is one with high IFNg expression ('IFNg-high'), one with the high LAG3 and no IFNg expression ('LAG3-high'), and one with none of the four markers strongly expressed ('none').	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('IFNg', 'Gene', (204, 208))	('LAG3', 'Gene', (283, 287))	('LAG3', 'Gene', (253, 257))	('LAG3', 'Gene', '3902', (283, 287))	('LAG3', 'Gene', '3902', (253, 257))	('IFNg', 'Gene', '3458', (265, 269))	('IFNg', 'Gene', (222, 226))	('IFNg', 'Gene', '3458', (204, 208))	('high', 'Var', (199, 203))	('IFNg', 'Gene', '3458', (222, 226))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('IFNg', 'Gene', (265, 269))
22048	32057296	This dataset included 4645 cells from 19 tumors, each annotated with 23684 gene IDs (HGNC format).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('23684', 'Var', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))
22195	23166783	A multivariate Cox proportional hazards model revealed these genes as a potential independent predictor, which may possibly add (both p = 0.01) to the predictive value of the most important morphological indicator, Breslow depth.	('genes', 'Var', (61, 66))	('Cox', 'Gene', '1351', (15, 18))	('Cox', 'Gene', (15, 18))
22222	23166783	The two probe sets with the best predictive value comprised the Affymetrix probe set IDs 217838_s_at (HR = 0.288, p = 0.001) and 208651_x_at (HR = 2.034, p = 0.016) matching the genes encoding Ena/vasodilator-stimulated phosphoprotein-like (EVL) and CD24 antigen (CD24), respectively (Table 1).	('EVL', 'Gene', (241, 244))	('208651_x_at', 'Var', (129, 140))	('Ena/vasodilator-stimulated phosphoprotein-like', 'Gene', '51466', (193, 239))	('EVL', 'Gene', '51466', (241, 244))	('Ena/vasodilator-stimulated phosphoprotein-like', 'Gene', (193, 239))	('IDs 217838_s_at', 'Var', (85, 100))
22252	23166783	Furthermore, the mutual functional compensation of family members, the modulation of activity by expression and intracellular distribution of their respective ligands as well as by signaling pathways such as EGF-R signaling and additional functions such as the recently described involvement of EVL in homologous recombinational repair of double-strand DNA breaks, may all have significant and sometimes opposite impact on tumor cell development and progression.	('DNA', 'cellular_component', 'GO:0005574', ('353', '356'))	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('EVL', 'Gene', '51466', (295, 298))	('tumor', 'Disease', (423, 428))	('intracellular', 'cellular_component', 'GO:0005622', ('112', '125'))	('cell development', 'biological_process', 'GO:0048468', ('429', '445'))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('EGF', 'molecular_function', 'GO:0005154', ('208', '211'))	('signaling', 'biological_process', 'GO:0023052', ('214', '223'))	('activity', 'MPA', (85, 93))	('homologous recombinational repair', 'biological_process', 'GO:0000724', ('302', '335'))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('double-strand', 'Var', (339, 352))	('EVL', 'Gene', (295, 298))
22301	20398247	Although Ki-67 positivity is a marker of proliferative cells, it is uncertain how many of the cells expressing Ki-67 will actually undergo mitosis.	('mitosis', 'Disease', (139, 146))	('Ki-67', 'Var', (111, 116))	('mitosis', 'Disease', 'None', (139, 146))	('Ki-67', 'Chemical', '-', (111, 116))	('Ki-67', 'Chemical', '-', (9, 14))	('mitosis', 'biological_process', 'GO:0000278', ('139', '146'))
22306	20398247	In a series of lymph node negative breast cancer patients, PHH3 was the strongest prognostic variable.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PHH3', 'Var', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('PHH3', 'Chemical', '-', (59, 63))	('breast cancer', 'Disease', (35, 48))	('patients', 'Species', '9606', (49, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
22316	20398247	In our series, loss of p16 expression is previously shown to be associated with increased Ki-67 expression and poor outcome.	('p16', 'Gene', (23, 26))	('Ki-67', 'Protein', (90, 95))	('increased', 'PosReg', (80, 89))	('expression', 'MPA', (96, 106))	('loss', 'Var', (15, 19))	('p16', 'Gene', '1029', (23, 26))	('Ki-67', 'Chemical', '-', (90, 95))
22375	20398247	Furthermore, the level of Ki-67 expression was correlated with high EZH2 expression (p = 0.002, Mann-Whitney test; data not shown).	('EZH2', 'Gene', (68, 72))	('Ki-67', 'Chemical', '-', (26, 31))	('expression', 'MPA', (73, 83))	('EZH2', 'Gene', '2146', (68, 72))	('expression', 'MPA', (32, 42))	('Ki-67', 'Var', (26, 31))
22389	20398247	In the group with high Cdc6 expression, there was significant higher level of PHH3 positivity than the group with low Cdc6 expression (p = 0.042, Mann-Whitney test; data not shown).	('Cdc6', 'Gene', (118, 122))	('PHH3', 'Chemical', '-', (78, 82))	('Cdc6', 'Gene', '990', (118, 122))	('Cdc6', 'Gene', (23, 27))	('Cdc6', 'Gene', '990', (23, 27))	('higher', 'PosReg', (62, 68))	('high', 'Var', (18, 22))	('PHH3', 'Protein', (78, 82))
22396	20398247	In the melanoma group (n = 113), the median value of MCM4 positivity was 36.8% in contrast to 2.0% in nevi (n = 31) (p < 0.001, Mann-Whitney test).	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('positivity', 'Var', (58, 68))	('MCM4', 'Gene', '4173', (53, 57))	('nevi', 'Phenotype', 'HP:0003764', (102, 106))	('MCM4', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))
22417	20398247	High mitotic count was a predictor of poor prognosis in univariate analysis, while increased percentage of Ki-67 positivity in tumor cells was stronger in multivariate survival models.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Ki-67', 'Protein', (107, 112))	('High', 'Var', (0, 4))	('tumor', 'Disease', (127, 132))	('Ki-67', 'Chemical', '-', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
22423	20398247	Still, in a systematic review and meta-analysis of published literature on prognostic immunohistochemical biomarkers in cutaneous melanoma, Ki-67 was among the most promising.	('Ki-67', 'Chemical', '-', (140, 145))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('Ki-67', 'Var', (140, 145))
22425	20398247	Since only a subset of the cells expressing Ki-67 in fact will go through mitosis, one important aim of this study was to investigate whether mitotic count was a better way to estimate proliferation and prognosis, and to compare the impact of Ki-67 with mitotic count and a selection of more recently introduced proliferation markers.	('Ki-67', 'Chemical', '-', (44, 49))	('Ki-67', 'Chemical', '-', (243, 248))	('mitosis', 'biological_process', 'GO:0000278', ('74', '81'))	('mitosis', 'Disease', (74, 81))	('mitosis', 'Disease', 'None', (74, 81))	('Ki-67', 'Var', (44, 49))
22429	20398247	found 5 cases with high Ki-67 expression (>=25% positive tumor cells) of which 4 developed metastases, and in the multivariate analyses, no other factors, included mitotic count, turned out to be independently predictive.	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('Ki-67', 'Gene', (24, 29))	('metastases', 'Disease', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Ki-67', 'Chemical', '-', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('tumor', 'Disease', (57, 62))
22431	20398247	In this respect, the mitotic marker anti-PHH3 is interesting, as it lightens up mitosis that appear as sharply stained figures, whereas apoptotic cells remain negative.	('anti-PHH3', 'Var', (36, 45))	('mitosis', 'Disease', (80, 87))	('lightens up', 'NegReg', (68, 79))	('PHH3', 'Chemical', '-', (41, 45))	('mitosis', 'biological_process', 'GO:0000278', ('80', '87'))	('mitosis', 'Disease', 'None', (80, 87))
22468	30717708	Additionally, high CD133 expression signatures were found in intestinal subtypes and low tumor stage GCs as well as in those with microsatellite instabilities and high mutation burdens.	('expression signatures', 'MPA', (25, 46))	('GCs', 'Phenotype', 'HP:0012126', (101, 104))	('CD133', 'Gene', (19, 24))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('CD133', 'Gene', '8842', (19, 24))	('low tumor', 'Disease', 'MESH:D009800', (85, 94))	('microsatellite', 'Var', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('low tumor', 'Disease', (85, 94))
22474	30717708	Immunohistochemistry (IHC)-based quantification of expressed CD133 protein levels has been proposed as a GC prognostic marker and CD133 positivity indicates poor prognosis as well as chemoresistance and disease progression of GC.	('positivity', 'Var', (136, 146))	('GC', 'Phenotype', 'HP:0012126', (226, 228))	('disease progression', 'CPA', (203, 222))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('chemoresistance', 'CPA', (183, 198))	('CD133', 'Gene', (61, 66))	('CD133', 'Gene', (130, 135))	('CD133', 'Gene', '8842', (130, 135))	('CD133', 'Gene', '8842', (61, 66))	('poor prognosis', 'CPA', (157, 171))	('GC', 'Phenotype', 'HP:0012126', (105, 107))
22478	30717708	In this study, we performed microarray-based transcriptome analyses of CD133+ vs. CD133- cells obtained by cell sorting from three GC cell lines (KATO-III, SNU216 and SNU601).	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('CD133', 'Gene', '8842', (82, 87))	('CD133', 'Gene', (82, 87))	('CD133', 'Gene', (71, 76))	('CD133', 'Gene', '8842', (71, 76))	('SNU601', 'Var', (167, 173))	('SNU216', 'Var', (156, 162))	('SNU216', 'CellLine', 'CVCL:3946', (156, 162))
22503	30717708	To evaluate the gene expression associated with the CD133 stem cell marker in GCs, we performed gene expression profiling of three gastric cancer cell lines (KATO-III, SNU216, and SNU601).	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (52, 57))	('SNU601', 'Var', (180, 186))	('SNU216', 'CellLine', 'CVCL:3946', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gene expression', 'biological_process', 'GO:0010467', ('96', '111'))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('GCs', 'Phenotype', 'HP:0012126', (78, 81))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('gastric cancer', 'Disease', (131, 145))
22541	30717708	Among the major mutations of GC, mutations of TP53, PIK3CA, KRAS, ARID1A, and RHOA were evaluated, whereas only ARID1A mutations were significantly associated with CD133 expression signature (P = 0.0007; Fig.	('ARID1A', 'Gene', (112, 118))	('CD133', 'Gene', '8842', (164, 169))	('TP53', 'Gene', '7157', (46, 50))	('RHOA', 'Gene', '387', (78, 82))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (52, 58))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	('KRAS', 'Gene', (60, 64))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('TP53', 'Gene', (46, 50))	('RHOA', 'Gene', (78, 82))	('associated', 'Reg', (148, 158))	('KRAS', 'Gene', '3845', (60, 64))	('PIK3CA', 'Gene', '5290', (52, 58))	('ARID1A', 'Gene', '8289', (112, 118))	('CD133', 'Gene', (164, 169))
22593	30717708	In general, IHC-based CD133 positivity in GC has been regarded as a feature associated with high-stage and high-grade tumors with poor prognosis.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('high-stage', 'Disease', (92, 102))	('CD133', 'Gene', (22, 27))	('associated', 'Reg', (76, 86))	('CD133', 'Gene', '8842', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
22611	29523541	Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers.	('cancers', 'Disease', (223, 230))	('localization', 'biological_process', 'GO:0051179', ('125', '137'))	('activity', 'MPA', (142, 150))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('human', 'Species', '9606', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Peli1', 'Var', (41, 46))	('modulating', 'Reg', (98, 108))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('rat', 'Species', '10116', (31, 34))	('subcellular localization', 'MPA', (113, 137))
22614	29523541	The important roles of p53 in tumor suppression have been well established by the fact that more than 50% of human tumors have p53 mutation or loss of heterozygosity.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('loss of', 'NegReg', (143, 150))	('tumor', 'Disease', (30, 35))	('p53', 'Gene', (127, 130))	('mutation', 'Var', (131, 139))
22615	29523541	In addition, mice or humans harboring germline p53 mutations have the predisposition for early tumorigenesis and death.	('mice', 'Species', '10090', (13, 17))	('mutations', 'Var', (51, 60))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('germline', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('humans', 'Species', '9606', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p53', 'Gene', (47, 50))	('tumor', 'Disease', (95, 100))
22616	29523541	The critical roles of Mdm2 and Mdmx in regulating p53 are best demonstrated by studies carried out in mice where inactivation of p53 was shown to completely rescue the embryonic lethality caused by the loss of either Mdm2 or Mdmx.	('loss', 'Var', (202, 206))	('mice', 'Species', '10090', (102, 106))	('rat', 'Species', '10116', (70, 73))	('embryonic lethality', 'Disease', 'MESH:D020964', (168, 187))	('embryonic lethality', 'Disease', (168, 187))	('inactivation', 'Var', (113, 125))	('Mdmx', 'Gene', (225, 229))	('p53', 'Gene', (129, 132))	('Mdm2', 'Gene', (217, 221))	('rescue', 'PosReg', (157, 163))
22618	29523541	In addition, Mdm2 functions as a Ring domain E3 ubiquitin ligase to promote p53 degradation by poly-ubiquitination and nuclear export by mono-ubiquitination.	('degradation', 'MPA', (80, 91))	('nuclear export', 'biological_process', 'GO:0051168', ('119', '133'))	('promote', 'PosReg', (68, 75))	('p53', 'Gene', (76, 79))	('-ub', 'Chemical', '-', (99, 102))	('ubiquitin', 'molecular_function', 'GO:0031386', ('48', '57'))	('Mdm2', 'Gene', (13, 17))	('degradation', 'biological_process', 'GO:0009056', ('80', '91'))	('nuclear export', 'MPA', (119, 133))	('poly-ubiquitination', 'MPA', (95, 114))	('-ub', 'Chemical', '-', (141, 144))	('mono-ubiquitination', 'Var', (137, 156))
22642	29523541	For the different Mdmx and Peli1 deletion mutant constructs, DNA sequences corresponding to different regions were amplified by PCR from the above constructs and cloned into pCIN4-FLAG-HA or pCMV-Myc expression vectors.	('Peli1', 'Gene', (27, 32))	('mutant', 'Var', (42, 48))	('Mdmx', 'Gene', (18, 22))	('deletion mutant', 'Var', (33, 48))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('expression vectors', 'Species', '29278', (200, 218))
22643	29523541	Myc-Mdmx and Mdmx Delta200-274 constructs were obtained from Jiandong Chen's laboratory.	('Myc-Mdmx', 'Gene', '4194', (0, 8))	('rat', 'Species', '10116', (81, 84))	('Delta200-274', 'Var', (18, 30))	('Myc-Mdmx', 'Gene', (0, 8))
22644	29523541	Myc-Peli1 C395/398A mutant was generated by Quick Change Site-Directed Mutagenesis Kit (Stratagene) according to the manufacturer's protocol.	('Myc-Peli1', 'Gene', (0, 9))	('C395/398A', 'Var', (10, 19))	('Mutagenesis', 'biological_process', 'GO:0006280', ('71', '82'))	('Myc-Peli1', 'Gene', '57162', (0, 9))	('rat', 'Species', '10116', (35, 38))	('rat', 'Species', '10116', (90, 93))
22667	29523541	Ablation of p53 and Mdmx was performed by transfection of U2OS cells with siRNA duplex oligo sets (On-Target-Plus Smart pool L00332900 for p53 and L-00653600 for Mdmx, Dharmacon).	('L00332900', 'Var', (125, 134))	('L-00653600', 'Var', (147, 157))	('U2OS', 'CellLine', 'CVCL:0042', (58, 62))
22687	29523541	Mice heterozygous for Peli1 deletion (Peli1+/-) were bred to generate age-matched mice homozygous for Peli1 deletion (Peli1-/-) and wild-type mice.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (142, 146))	('Mice', 'Species', '10090', (0, 4))	('Peli1', 'Gene', (22, 27))	('deletion', 'Var', (28, 36))	('Peli1', 'Gene', (102, 107))	('deletion', 'Var', (108, 116))	('rat', 'Species', '10116', (65, 68))
22696	29523541	Previous studies indicated that p53 is not frequently mutated in human melanomas, partially caused by Mdmx amplification.	('melanomas', 'Disease', (71, 80))	('human', 'Species', '9606', (65, 70))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('p53', 'Gene', (32, 35))	('Mdmx', 'Var', (102, 106))	('caused', 'Reg', (92, 98))
22700	29523541	As expected, FH-Mdmx, CK1alpha, 14-3-3, p53, Mdm2 and p73 were identified as major components of the complexes (Fig.	('Mdm2', 'Var', (45, 49))	('p53', 'Var', (40, 43))	('CK1', 'Species', '2498238', (22, 25))	('p73', 'Var', (54, 57))	('CK1alpha', 'Var', (22, 30))
22709	29523541	The expression constructs for FH-Mdmx and deletion mutants were co-transfected with Myc-Peli1 into H1299 cells.	('expression', 'Species', '29278', (4, 14))	('Myc-Peli1', 'Gene', '57162', (84, 93))	('H1299', 'CellLine', 'CVCL:0060', (99, 104))	('deletion mutants', 'Var', (42, 58))	('FH-Mdmx', 'Gene', (30, 37))	('Myc-Peli1', 'Gene', (84, 93))
22711	29523541	To map Peli1 domains for Mdmx binding, Myc-Peli1 and deletion mutants were co-transfected with FH-Mdmx in H1299 cells.	('deletion mutants', 'Var', (53, 69))	('Myc-Peli1', 'Gene', '57162', (39, 48))	('Mdmx binding', 'molecular_function', 'GO:0070216', ('25', '37'))	('H1299', 'CellLine', 'CVCL:0060', (106, 111))	('Myc-Peli1', 'Gene', (39, 48))
22713	29523541	To this end, the expression constructs for FH-Mdmx or FLAG tagged p53 are co-transfected with Myc-Peli1 into H1299 cells.	('expression', 'Species', '29278', (17, 27))	('Myc-Peli1', 'Gene', '57162', (94, 103))	('H1299', 'CellLine', 'CVCL:0060', (109, 114))	('Myc-Peli1', 'Gene', (94, 103))	('FH-Mdmx', 'Var', (43, 50))	('p53', 'Gene', (66, 69))
22716	29523541	Lysine 48 (K48) linked poly-ubiquitination chain targets protein for destruction by 26S proteasome whereas other types of poly-ubiquitination, for example, K63 linked poly-ubiquitination is not associated with protein degradation.	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('protein degradation', 'biological_process', 'GO:0030163', ('210', '229'))	('K63 linked poly-ubiquitination', 'Var', (156, 186))	('26S proteasome', 'cellular_component', 'GO:0000504', ('84', '98'))	('-ub', 'Chemical', '-', (171, 174))	('26S proteasome', 'cellular_component', 'GO:0005837', ('84', '98'))	('26S', 'MPA', (84, 87))	('-ub', 'Chemical', '-', (126, 129))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('-ub', 'Chemical', '-', (27, 30))	('proteasome', 'molecular_function', 'GO:0004299', ('88', '98'))	('26S proteasome', 'cellular_component', 'GO:0000502', ('84', '98'))	('protein', 'Protein', (57, 64))
22717	29523541	As shown in Supplementary Figure 3A, although Peli1 induced K63-linked poly-ubiquitination by using Ub-K63 only (lysine to arginine mutations on all other lysine residues except K63), Peli1 was also able to promote Mdmx poly-ubiquitination with either K48R-ub or K63R-ub (lysine to arginine mutation only at either K48 or K63, respectively).	('K63R', 'SUBSTITUTION', 'None', (263, 267))	('promote', 'PosReg', (207, 214))	('K63R', 'Var', (263, 267))	('lysine', 'Chemical', 'MESH:D008239', (155, 161))	('K48R', 'Var', (252, 256))	('-ub', 'Chemical', '-', (75, 78))	('arginine', 'Chemical', 'MESH:D001120', (123, 131))	('-ub', 'Chemical', '-', (267, 270))	('-ub', 'Chemical', '-', (256, 259))	('K63-linked poly-ubiquitination', 'MPA', (60, 90))	('Ub-K63', 'Chemical', '-', (100, 106))	('lysine', 'Chemical', 'MESH:D008239', (113, 119))	('Mdmx poly-ubiquitination', 'MPA', (215, 239))	('arginine', 'Chemical', 'MESH:D001120', (282, 290))	('induced', 'Reg', (52, 59))	('K48R', 'SUBSTITUTION', 'None', (252, 256))	('-ub', 'Chemical', '-', (224, 227))	('lysine', 'Chemical', 'MESH:D008239', (272, 278))
22731	29523541	The results demonstrated that Peli1 null cells grow faster than the control cells (Supplementary Fig.	('grow', 'CPA', (47, 51))	('faster', 'PosReg', (52, 58))	('rat', 'Species', '10116', (19, 22))	('null', 'Var', (36, 40))	('Peli1', 'Gene', (30, 35))
22743	29523541	Loss of one Mdmx allele or Mdmx modifications affects the onset of c-Myc induced lymphomagenesis, suggesting Mdmx function is crucial for c-Myc induced tumorigenesis.	('lymphoma', 'Disease', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Mdmx', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('affects', 'Reg', (46, 53))	('c-Myc', 'Gene', (138, 143))	('lymphoma', 'Disease', 'MESH:D008223', (81, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	('tumor', 'Disease', (152, 157))	('c-Myc', 'Gene', '4609', (67, 72))	('modifications', 'Var', (32, 45))	('c-Myc', 'Gene', (67, 72))	('c-Myc', 'Gene', '4609', (138, 143))
22744	29523541	Since Peli1 is an Mdmx regulator, we next evaluated whether loss of Peli1 modulated oncogene-induced tumorigenesis using a mouse Emu-Myc lymphoma model.	('Peli1', 'Gene', (68, 73))	('mouse', 'Species', '10090', (123, 128))	('modulated', 'Reg', (74, 83))	('tumor', 'Disease', (101, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('loss', 'Var', (60, 64))	('Emu-Myc lymphoma', 'Disease', 'MESH:D008223', (129, 145))	('Emu-Myc lymphoma', 'Disease', (129, 145))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
22746	29523541	However, Peli1 null Emu-Myc mice developed significant early-onset B-cell lymphoma compared with Peli1 wild-type Emu-Myc mice (Fig.	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('mice', 'Species', '10090', (28, 32))	('Peli1', 'Var', (9, 14))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (67, 82))	('B-cell lymphoma', 'Disease', (67, 82))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('mice', 'Species', '10090', (121, 125))
22752	29523541	It is well established that the p53 pathway is inactivated in Emu-Myc lymphomas either by p53 mutation, loss of Arf, or overexpression of Mdm2.	('lymphoma', 'Phenotype', 'HP:0002665', (70, 78))	('loss', 'NegReg', (104, 108))	('inactivated', 'NegReg', (47, 58))	('p53', 'Gene', (90, 93))	('overexpression', 'PosReg', (120, 134))	('Arf', 'Protein', (112, 115))	('Emu-Myc lymphomas', 'Disease', 'MESH:D008223', (62, 79))	('expression', 'Species', '29278', (124, 134))	('p53 pathway', 'Pathway', (32, 43))	('Emu-Myc lymphomas', 'Disease', (62, 79))	('lymphomas', 'Phenotype', 'HP:0002665', (70, 79))	('mutation', 'Var', (94, 102))
22754	29523541	Of note, we detected mutant p53 only from one of 20 Peli1 null mice with lymphomas.	('p53', 'Gene', (28, 31))	('lymphomas', 'Disease', 'MESH:D008223', (73, 82))	('mutant', 'Var', (21, 27))	('lymphomas', 'Phenotype', 'HP:0002665', (73, 82))	('detected', 'Reg', (12, 20))	('mice', 'Species', '10090', (63, 67))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('lymphomas', 'Disease', (73, 82))
22758	29523541	Real-time PCR analysis demonstrated that mRNA levels for both Puma and p21 were markedly decreased in Peli1 null lymphoma tissues (Fig.	('lymphoma', 'Disease', 'MESH:D008223', (113, 121))	('p21', 'Var', (71, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('rat', 'Species', '10116', (30, 33))	('lymphoma', 'Disease', (113, 121))	('mRNA levels', 'MPA', (41, 52))	('decreased', 'NegReg', (89, 98))
22770	29523541	The results showed that the patients with higher Peli1 expression have a better overall survival in comparison with those with lower Peli1 expression in the wild-type p53 population (Fig.	('overall survival', 'MPA', (80, 96))	('expression', 'Species', '29278', (55, 65))	('expression', 'Species', '29278', (139, 149))	('better', 'PosReg', (73, 79))	('patients', 'Species', '9606', (28, 36))	('Peli1 expression', 'Var', (49, 65))
22771	29523541	We did not observe significant difference in overall survival between the patients with higher and lower Peli1 expression in p53 mutant population (Fig.	('lower', 'NegReg', (99, 104))	('expression', 'Species', '29278', (111, 121))	('patients', 'Species', '9606', (74, 82))	('p53', 'Gene', (125, 128))	('expression', 'MPA', (111, 121))	('mutant', 'Var', (129, 135))	('Peli1', 'Protein', (105, 110))
22775	29523541	Importantly, deletion of Peli1 accelerates oncogene induced mouse lymphomagenesis.	('Peli1', 'Gene', (25, 30))	('rat', 'Species', '10116', (37, 40))	('deletion', 'Var', (13, 21))	('lymphoma', 'Disease', (66, 74))	('accelerates', 'PosReg', (31, 42))	('lymphoma', 'Disease', 'MESH:D008223', (66, 74))	('mouse', 'Species', '10090', (60, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (66, 74))
22785	29523541	Many previous studies indicate that Peli1 catalyzes ubiquitination of substrate proteins by K48 and/or K63-linked poly-ubiquitin chains.	('K48', 'Var', (92, 95))	('-ub', 'Chemical', '-', (118, 121))	('K63-linked', 'Var', (103, 113))	('rat', 'Species', '10116', (75, 78))	('ubiquitination of substrate proteins', 'MPA', (52, 88))	('ubiquitin', 'molecular_function', 'GO:0031386', ('119', '128'))	('Peli1', 'Gene', (36, 41))
22786	29523541	We found that Peli1 promotes Mdmx both K48 and K63 linked poly-ubiquitination, suggested that Peli1 mediated ubiquitination is non-canonical and degradation-independent.	('K48', 'MPA', (39, 42))	('Peli1', 'Gene', (14, 19))	('Mdmx', 'MPA', (29, 33))	('K63', 'Var', (47, 50))	('promotes', 'PosReg', (20, 28))	('-ub', 'Chemical', '-', (62, 65))	('degradation', 'biological_process', 'GO:0009056', ('145', '156'))
22793	29523541	Deletion of either p53 or Arf expression in Emu-Myc mice markedly accelerates the onset of lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (91, 99))	('rat', 'Species', '10116', (72, 75))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('Arf', 'Gene', (26, 29))	('mice', 'Species', '10090', (52, 56))	('p53', 'Gene', (19, 22))	('accelerates', 'PosReg', (66, 77))	('lymphoma', 'Disease', (91, 99))	('expression', 'Species', '29278', (30, 40))	('Deletion', 'Var', (0, 8))
22794	29523541	In contrast, loss of one copy of Mdm2 delays the tumor formation, whereas overexpression of Mdm2 accelerates the onset of B cell lymphoma in Emu-Myc mice.	('accelerates', 'PosReg', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Mdm2', 'Gene', (33, 37))	('Mdm2', 'Gene', (92, 96))	('rat', 'Species', '10116', (103, 106))	('delays', 'NegReg', (38, 44))	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('B cell lymphoma', 'Disease', 'MESH:D016393', (122, 137))	('B cell lymphoma', 'Disease', (122, 137))	('tumor', 'Disease', (49, 54))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (122, 137))	('formation', 'biological_process', 'GO:0009058', ('55', '64'))	('mice', 'Species', '10090', (149, 153))	('loss', 'Var', (13, 17))	('expression', 'Species', '29278', (78, 88))
22795	29523541	Recently, losing one copy of Mdmx also exhibited the increased lymphoma latency, suggesting Mdmx crucial roles in Myc-induced lymphomagenesis.	('losing', 'Var', (10, 16))	('lymphoma', 'Disease', (126, 134))	('lymphoma', 'Disease', (63, 71))	('lymphoma', 'Disease', 'MESH:D008223', (126, 134))	('increased', 'PosReg', (53, 62))	('lymphoma', 'Disease', 'MESH:D008223', (63, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))
22796	29523541	Considering that Peli1 functions in regulating Mdmx-p53 axis, our findings that Peli1 deletion contributes to Myc-induced lymphomagenesis, provides an example for Mdmx regulation in tumor suppression.	('contributes', 'Reg', (95, 106))	('lymphoma', 'Disease', (122, 130))	('tumor', 'Disease', (182, 187))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('Peli1', 'Gene', (80, 85))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('regulation', 'biological_process', 'GO:0065007', ('168', '178'))	('deletion', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
22797	29523541	Although either deletion of Arf or p53 mutations is frequently observed in Emu-Myc lymphoma, the majority of Peli1 null Emu-Myc lymphoma exhibits a wild type p53 and intact Arf expression.	('Emu-Myc lymphoma', 'Disease', (75, 91))	('Emu-Myc lymphoma', 'Disease', (120, 136))	('p53', 'MPA', (158, 161))	('p53', 'Gene', (35, 38))	('deletion', 'Var', (16, 24))	('mutations', 'Var', (39, 48))	('Arf expression', 'MPA', (173, 187))	('expression', 'Species', '29278', (177, 187))	('lymphoma', 'Phenotype', 'HP:0002665', (83, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('Peli1', 'Gene', (109, 114))	('observed', 'Reg', (63, 71))	('Arf', 'Gene', (28, 31))	('Emu-Myc lymphoma', 'Disease', 'MESH:D008223', (75, 91))	('Emu-Myc lymphoma', 'Disease', 'MESH:D008223', (120, 136))
22814	26334503	Moreover RASSF8 was found to induce apoptosis in melanoma cells by activating the P53-P21 pathway, and also in vivo studies demonstrated that inhibiting RASSF8 increases the tumorigenic properties of human melanoma xenografts.	('P53', 'Gene', '7157', (82, 85))	('human', 'Species', '9606', (200, 205))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('melanoma', 'Disease', (206, 214))	('increases', 'PosReg', (160, 169))	('inhibiting', 'Var', (142, 152))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('RASSF8', 'Gene', (153, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('P21', 'Gene', '1026', (86, 89))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('activating', 'Reg', (67, 77))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('P21', 'Gene', (86, 89))	('tumor', 'Disease', (174, 179))	('P53', 'Gene', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
22820	26334503	Our group has previously demonstrated the correlation between transcriptional inactivation of the RASSF1 gene in cutaneous melanoma and hypermethylation of CpG promoter region, and relation to disease progression.	('transcriptional', 'MPA', (62, 77))	('RASSF1', 'Gene', '11186', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('RASSF1', 'Gene', (98, 104))	('hypermethylation', 'Var', (136, 152))	('cutaneous melanoma', 'Disease', (113, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 131))
22827	26334503	In comparison to early stage melanoma, promoter region methylation in advanced melanoma resulted in lower expression of RASSF8.	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('expression', 'MPA', (106, 116))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('lower', 'NegReg', (100, 105))	('RASSF8', 'Gene', (120, 126))	('methylation', 'Var', (55, 66))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
22842	26334503	Functional assays were also performed to compare colony formation in soft agar, cell growth, migration and invasion: Wm266-4 control, Wm266-4 RASSF8, M24 control, M24 RASSF8 shRNA, Wp-0614 Cntl, Wp-0614 RASSF8, M101 Cntl and M101 shRNA.	('Wp-0614 RASSF8', 'Var', (195, 209))	('M101', 'Var', (225, 229))	('M101', 'Var', (211, 215))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('M24 RASSF8', 'Var', (163, 173))	('agar', 'Chemical', 'MESH:D000362', (74, 78))
22847	26334503	As shown in Figure 3D while RASSF8 induced the expression of P53 and P21, it downregulated Cyclin D1 expression in Wm266-4 cells; these observations were confirmed by RASSF8 knockdown resulting in opposite signaling pathways; RASSF8 knockdown in M24 cells lead to reduced P53 and P21 expression, and increased Cyclin D1 expression (Supplementary Figure 9B).	('Cyclin', 'molecular_function', 'GO:0016538', ('91', '97'))	('P21', 'Gene', (69, 72))	('increased', 'PosReg', (300, 309))	('expression', 'MPA', (320, 330))	('P53', 'Gene', '7157', (272, 275))	('P21', 'Gene', '1026', (280, 283))	('Cyclin D1', 'Gene', '595', (310, 319))	('reduced', 'NegReg', (264, 271))	('Cyclin D1', 'Gene', (310, 319))	('P21', 'Gene', (280, 283))	('RASSF8', 'Gene', (226, 232))	('knockdown', 'Var', (233, 242))	('P53', 'Gene', (61, 64))	('expression', 'MPA', (284, 294))	('Cyclin', 'molecular_function', 'GO:0016538', ('310', '316'))	('downregulated', 'NegReg', (77, 90))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('Cyclin D1', 'Gene', '595', (91, 100))	('P53', 'Gene', '7157', (61, 64))	('P21', 'Gene', '1026', (69, 72))	('P53', 'Gene', (272, 275))	('Cyclin D1', 'Gene', (91, 100))
22849	26334503	In summary, these results support the findings of apoptosis induced through RASSF8 overexpression regulating the P53-P21 pathway.	('RASSF8', 'Gene', (76, 82))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('regulating', 'Reg', (98, 108))	('P21', 'Gene', (117, 120))	('overexpression', 'Var', (83, 97))	('P53', 'Gene', (113, 116))	('P53', 'Gene', '7157', (113, 116))	('P21', 'Gene', '1026', (117, 120))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('apoptosis', 'CPA', (50, 59))
22850	26334503	Previous studies have demonstrated RASSF8 depletion leading to the loss of adheren junction (AJ) components, beta-catenin and P65 from sites of cell-cell contact followed by their relocalization to the nucleus (16).	('RASSF8', 'Gene', (35, 41))	('P65', 'Gene', '5970', (126, 129))	('P65', 'Gene', (126, 129))	('beta-catenin', 'Protein', (109, 121))	('relocalization', 'MPA', (180, 194))	('loss', 'NegReg', (67, 71))	('depletion', 'Var', (42, 51))	('nucleus', 'cellular_component', 'GO:0005634', ('202', '209'))
22852	26334503	Compared to Wm266-4 Cntl, expression of P65 and p-P65 was reduced while IkappaBalpha expression was increased in Wm266-4 RASSF8 (Figure 4A).	('expression', 'MPA', (26, 36))	('increased', 'PosReg', (100, 109))	('Wm266-4 RASSF8', 'Var', (113, 127))	('IkappaBalpha', 'Gene', (72, 84))	('reduced', 'NegReg', (58, 65))	('P65', 'Gene', '5970', (50, 53))	('P65', 'Gene', (50, 53))	('P65', 'Gene', '5970', (40, 43))	('P65', 'Gene', (40, 43))	('IkappaBalpha', 'Gene', '4792', (72, 84))
22854	26334503	Expression of P65 increased when RASSF8 was knocked down by RASSF8 shRNA in M24 and M101 cells (Figure 4B and Supplementary Figure 10B).	('increased', 'PosReg', (18, 27))	('knocked', 'Var', (44, 51))	('Expression', 'MPA', (0, 10))	('RASSF8', 'Gene', (33, 39))	('P65', 'Gene', '5970', (14, 17))	('RASSF8', 'Gene', (60, 66))	('P65', 'Gene', (14, 17))
22855	26334503	IL-6 mRNA expression (downstream target of P65) in M24 RASSF8 shRNA treated was significantly increased compared to M24 Cntl (Supplementary Figure 11).	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('RASSF8', 'Gene', (55, 61))	('mRNA expression', 'MPA', (5, 20))	('increased', 'PosReg', (94, 103))	('IL-6', 'Gene', (0, 4))	('M24', 'Var', (51, 54))	('P65', 'Gene', '5970', (43, 46))	('IL-6', 'Gene', '3569', (0, 4))	('P65', 'Gene', (43, 46))
22859	26334503	As shown in Figure 4D and 4E, migration and invasion of M24-RASSF8 shRNA were significantly reduced by BAY 11-7082 compared to that of M24 control.	('invasion', 'CPA', (44, 52))	('BAY 11-7082', 'Var', (103, 114))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (103, 114))	('reduced', 'NegReg', (92, 99))
22860	26334503	p-IkappaBalpha and p65 were more inhibited in M24 shRNA than that in M24 Cntl, while no change in IkappaBalpha was observed upon treatment by BAY 11-7082 (Figure 4F).	('p65', 'Gene', (19, 22))	('IkappaBalpha', 'Gene', '4792', (2, 14))	('IkappaBalpha', 'Gene', '4792', (98, 110))	('p65', 'Gene', '5970', (19, 22))	('IkappaBalpha', 'Gene', (2, 14))	('M24', 'Var', (46, 49))	('IkappaBalpha', 'Gene', (98, 110))	('inhibited', 'NegReg', (33, 42))	('BAY 11-7082', 'Chemical', 'MESH:C434003', (142, 153))
22867	26334503	These results suggest that RASSF8 promoter region methylation regulates its expression in melanoma during tumor progression.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('methylation', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('expression', 'MPA', (76, 86))	('regulates', 'Reg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('RASSF8', 'Gene', (27, 33))	('tumor', 'Disease', (106, 111))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
22872	26334503	As shown in the Kaplan-Meier survival analysis, patients with high RASSF8 expression (AJCC stage IV) have a higher survival rate than patients with low RASSF8 expression (Figure 6C).	('survival', 'MPA', (115, 123))	('expression', 'Var', (74, 84))	('RASSF8', 'Gene', (67, 73))	('patients', 'Species', '9606', (134, 142))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('higher', 'PosReg', (108, 114))
22873	26334503	These findings support that RASSF8 plays a major role in the progression of melanoma metastasis To assess whether RASSF8 suppresses the tumorigenic properties of cell lines, M24 control and M24-RASSF8 shRNA were injected subdermally into the thigh of male nude-BALB/c mice (6 mice/cell line).	('melanoma metastasis', 'Disease', (76, 95))	('mice', 'Species', '10090', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mice', 'Species', '10090', (276, 280))	('M24-RASSF8', 'Var', (190, 200))	('melanoma metastasis', 'Disease', 'MESH:D009362', (76, 95))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('RASSF8', 'Var', (114, 120))	('suppresses', 'NegReg', (121, 131))	('tumor', 'Disease', (136, 141))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
22875	26334503	Inhibition of RASSF8 also increased the volume and weight of tumors (Figure 7).	('weight of tumors', 'Disease', (51, 67))	('weight of tumors', 'Disease', 'MESH:D015431', (51, 67))	('increased', 'PosReg', (26, 35))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RASSF8', 'Gene', (14, 20))
22876	26334503	Here we have demonstrated RASSF8 knockdown leading to the significant increase in growth rate and tumorigenicity of a human melanoma cells in a nude mice xenograft model.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('growth rate', 'CPA', (82, 93))	('increase', 'PosReg', (70, 78))	('knockdown', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('RASSF8', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('nude mice', 'Species', '10090', (144, 153))	('human', 'Species', '9606', (118, 123))	('tumor', 'Disease', (98, 103))
22880	26334503	In the present study, for the first time, we report RASSF8 tumor suppressor role by regulating P65 expression and P53-P21 pathway in melanoma; here we have demonstrated the correlation between the methylation and expression of RASSF8 gene, corresponding to aggressive tumor progression and function in melanoma.	('aggressive tumor', 'Disease', 'MESH:D001523', (257, 273))	('tumor', 'Disease', (59, 64))	('methylation', 'biological_process', 'GO:0032259', ('197', '208'))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('RASSF8', 'Gene', (227, 233))	('methylation', 'Var', (197, 208))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('aggressive tumor', 'Disease', (257, 273))	('melanoma', 'Disease', (133, 141))	('P65', 'Gene', '5970', (95, 98))	('P65', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))	('expression', 'MPA', (213, 223))	('P21', 'Gene', '1026', (118, 121))	('P53', 'Gene', (114, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('P21', 'Gene', (118, 121))	('tumor', 'Disease', (268, 273))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('P53', 'Gene', '7157', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
22890	26334503	Based on this study, P65 is lost from sites of cell-cell contact and gets relocated to the nucleus following RASSF8 depletion.	('depletion', 'Var', (116, 125))	('P65', 'Gene', '5970', (21, 24))	('RASSF8', 'Gene', (109, 115))	('P65', 'Gene', (21, 24))	('nucleus', 'cellular_component', 'GO:0005634', ('91', '98'))
22892	26334503	Conversely, knockdown of RASSF8 shRNA was associated with a significant increase in P65 expression.	('increase', 'PosReg', (72, 80))	('knockdown', 'Var', (12, 21))	('RASSF8', 'Gene', (25, 31))	('P65', 'Gene', '5970', (84, 87))	('P65', 'Gene', (84, 87))
22895	26334503	Our results also showed expression of IL-6 (downstream target of P65) increasing upon RASSF8 reduced expression by RASSF8 shRNA in M24.	('IL-6', 'Gene', '3569', (38, 42))	('expression', 'MPA', (24, 34))	('reduced', 'NegReg', (93, 100))	('P65', 'Gene', '5970', (65, 68))	('P65', 'Gene', (65, 68))	('increasing', 'PosReg', (70, 80))	('IL-6', 'Gene', (38, 42))	('IL-6', 'molecular_function', 'GO:0005138', ('38', '42'))	('expression', 'MPA', (101, 111))	('RASSF8', 'Var', (115, 121))
22898	26334503	Most members of RASSF family have CpG islands in the promoter region of their genes.	('RASSF', 'Gene', (16, 21))	('RASSF', 'Gene', '11186;9770;283349;83593;83937;83593;283349;166824;8045;11228;71323;9182;644943', (16, 21))	('CpG islands', 'Var', (34, 45))
22901	26334503	Epigenetic inactivation of RASSF6 and RASSF10 is an extremely frequent event in the pathogenesis of childhood leukemia.	('RASSF6', 'Gene', '166824', (27, 33))	('RASSF10', 'Gene', '644943', (38, 45))	('RASSF10', 'Gene', (38, 45))	('leukemia', 'Disease', (110, 118))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('RASSF6', 'Gene', (27, 33))	('leukemia', 'Disease', 'MESH:D007938', (110, 118))	('pathogenesis', 'biological_process', 'GO:0009405', ('84', '96'))	('Epigenetic inactivation', 'Var', (0, 23))
22903	26334503	This is the first report on methylation of RASSF8 in cutaneous melanoma as a metastasis progression factor.	('RASSF8', 'Gene', (43, 49))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('cutaneous melanoma', 'Disease', (53, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (53, 71))	('methylation', 'Var', (28, 39))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
22904	26334503	Decreased expression of RASSF8 due to methylation was also found to be related to progression of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('methylation', 'Var', (38, 49))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('RASSF8', 'Gene', (24, 30))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
22908	26334503	Xenograft studies confirmed that tumors grew faster in the RASSF8 knockdown group than in the control group.	('faster', 'PosReg', (45, 51))	('tumors', 'Disease', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('knockdown', 'Var', (66, 75))	('RASSF8', 'Gene', (59, 65))
22909	26334503	This study is a first report showing that inhibiting RASSF8 can increase the development of xenograft tumors in vivo, supporting its role as a tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('xenograft tumors', 'Disease', (92, 108))	('tumor', 'Disease', (143, 148))	('inhibiting', 'Var', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('RASSF8', 'Gene', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('increase', 'PosReg', (64, 72))	('xenograft tumors', 'Disease', 'MESH:D009369', (92, 108))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
22911	26334503	Our study also confirms that methylation of RASSF8 promoter occurs in advanced melanoma.	('methylation', 'Var', (29, 40))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('occurs', 'Reg', (60, 66))	('RASSF8', 'Gene', (44, 50))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
22914	26334503	We assessed expression of RASSF8 in 24 well-established, early-passaged cutaneous melanoma metastasis cell lines: M24, M101, FD0836, TG0873, M14, JH1173, ME7, M16, M20, CS0169, WP0614, ME35, BD0548, SR0488, AB0801, DP0574, M8133, LM0615, ME16, M21, ME9, M12, M211, and M13 established from AJCC stage III and IV melanoma patients who received surgery at JWCI.	('patients', 'Species', '9606', (321, 329))	('DP0574', 'Var', (215, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('M211', 'Var', (259, 263))	('IV melanoma', 'Disease', (309, 320))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('M101', 'Var', (119, 123))	('IV melanoma', 'Disease', 'MESH:D008545', (309, 320))	('cutaneous melanoma metastasis', 'Disease', (72, 101))	('cutaneous melanoma metastasis', 'Disease', 'MESH:D009362', (72, 101))	('LM0615', 'CellLine', 'CVCL:5998', (230, 236))	('M8133', 'Var', (223, 228))
22915	26334503	Melanocyte line (HEM-M, Catalog #2216) was purchased from ScienCell (Carlsbad, CA), Wm266-4 from ATCC (Manassas, VA), and primary cell lines (WC00060, WC00080, WC00081) obtained from Coriell institute (Camden, NJ).	('WC00060', 'Var', (142, 149))	('WC00081', 'Var', (160, 167))	('WC00080', 'Var', (151, 158))	('HEM', 'Disease', 'MESH:C535858', (17, 20))	('HEM', 'Disease', (17, 20))
22977	22892755	Exciting developments in metabolomics and exon sequencing (http://www.ornl.gov/sci/techresources/Human_Genome/faq/seqfacts.shtml) will surely result in more detailed mutations of the genes, which may yield more relevant cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('mutations', 'Var', (166, 175))	('result', 'Reg', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('yield', 'Reg', (200, 205))
22988	22892755	They found that the cells plated on ordinary tissue culture plastic became spindled with little metastatic potential when injected into the tail vein of BALB/c C57B/6 mice.	('C57B', 'SUBSTITUTION', 'None', (160, 164))	('metastatic potential', 'CPA', (96, 116))	('C57B', 'Var', (160, 164))	('little', 'NegReg', (89, 95))	('mice', 'Species', '10090', (167, 171))
23007	22892755	One of the most studied and important pathways is the mitogen-activated protein (MAP) kinase pathway and the BRAF mutation.	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('mutation', 'Var', (114, 122))	('MAP', 'molecular_function', 'GO:0004239', ('81', '84'))
23008	22892755	80 % of these mutations involve a single substitution of glutamate for valine (V600E).	('V600E', 'Var', (79, 84))	('valine', 'Chemical', 'MESH:D014633', (71, 77))	('V600E', 'Mutation', 'rs113488022', (79, 84))	('glutamate', 'Protein', (57, 66))	('involve', 'Reg', (24, 31))	('glutamate', 'Chemical', 'MESH:D018698', (57, 66))
23027	22892755	For example, DOC180 through activation of RAC1 and JNK activity directly affects the actin cytoskeleton and formation of MMP.	('RAC1', 'Gene', (42, 46))	('JNK', 'Gene', '5599', (51, 54))	('actin', 'MPA', (85, 90))	('DOC180', 'Chemical', '-', (13, 19))	('MMP', 'Gene', (121, 124))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('85', '103'))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('MMP', 'molecular_function', 'GO:0004235', ('121', '124'))	('JNK', 'molecular_function', 'GO:0004705', ('51', '54'))	('activation', 'PosReg', (28, 38))	('DOC180', 'Var', (13, 19))	('RAC1', 'Gene', '5879', (42, 46))	('affects', 'Reg', (73, 80))	('JNK', 'Gene', (51, 54))	('MMP', 'Gene', '4313;4314;4318;4322', (121, 124))
23031	22892755	The NEDD-9 overexpression also shows an increase in pERK and some increase in Stat2 activation.	('increase', 'PosReg', (66, 74))	('Stat2', 'Gene', '6773', (78, 83))	('overexpression', 'Var', (11, 25))	('NEDD-9', 'Gene', (4, 10))	('increase', 'PosReg', (40, 48))	('pERK', 'Gene', (52, 56))	('Stat2', 'Gene', (78, 83))	('pERK', 'Gene', '9451', (52, 56))	('NEDD-9', 'Gene', '4739', (4, 10))
23036	22892755	In vitro, SOX2 expression is associated with invasive function, and knockdown of the gene and protein inhibit invasion.	('SOX2', 'Gene', (10, 14))	('invasive function', 'CPA', (45, 62))	('knockdown', 'Var', (68, 77))	('expression', 'MPA', (15, 25))	('inhibit', 'NegReg', (102, 109))	('associated', 'Reg', (29, 39))	('invasion', 'CPA', (110, 118))	('SOX2', 'Gene', '6657', (10, 14))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
23072	22892755	SLN positivity has been shown to be associated with an immunosuppressed state of the lymph node probably induced by secretogogues of the primary tumor, possibly TGF-beta, that induce plasmacytoid dendritic cell formation and leads to an increase in the production of IDO, indoleamine-2,3-deoxygenase, the inhibitor of T cell function.	('IDO', 'Gene', '3620', (267, 270))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('production', 'MPA', (253, 263))	('increase', 'PosReg', (237, 245))	('IDO', 'molecular_function', 'GO:0047719', ('267', '270'))	('plasmacytoid dendritic cell formation', 'CPA', (183, 220))	('IDO', 'Gene', (267, 270))	('SLN', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('positivity', 'Var', (4, 14))	('formation', 'biological_process', 'GO:0009058', ('211', '220'))	('tumor', 'Disease', (145, 150))	('TGF-beta', 'Gene', '7040', (161, 169))	('IDO', 'molecular_function', 'GO:0033754', ('267', '270'))	('TGF-beta', 'Gene', (161, 169))
23083	22892755	Epigenomic aberrations can be used as bio-markers for prognosis and prediction in early and late stage melanomas.	('Epigenomic aberrations', 'Var', (0, 22))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Disease', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
23085	22892755	CpG site hypermethylation of gene promoter regions is one of the most significant mechanisms, whereby melanoma-related genes are turned on and off.	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('CpG', 'Var', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))
23101	22892755	We recently determined that microRNA 29C could regulate DNMT3s and is related to melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('regulate', 'Reg', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('microRNA', 'Var', (28, 36))	('related', 'Reg', (70, 77))	('DNMT3s', 'MPA', (56, 62))
23104	22892755	In this observation, low microRNA 29 and high DNMT3 were correlated with a poorer prognosis in stage III melanoma patients.	('microRNA 29', 'Protein', (25, 36))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('low', 'NegReg', (21, 24))	('DNMT3', 'Gene', (46, 51))	('high', 'Var', (41, 45))	('III melanoma', 'Disease', (101, 113))	('III melanoma', 'Disease', 'MESH:D008545', (101, 113))	('patients', 'Species', '9606', (114, 122))
23105	22892755	In summary, we have shown that epigenomic events play a significant role in melanoma progression and are highly integrated together.	('melanoma', 'Disease', (76, 84))	('epigenomic', 'Var', (31, 41))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
23111	22892755	Intriguingly, while mutations in the BRAF gene have emerged as a rational target for therapy of advanced melanoma, they are not able to successively distinguish between these various stages of melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('BRAF', 'Gene', '673', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('BRAF', 'Gene', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('mutations', 'Var', (20, 29))
23210	22892755	Significant improvements in both hepatic progression-free survival (hPFS), overall PFS, and ORR were seen in patients treated with CS-PHP compared with patients treated with BAC.	('CS-PHP', 'Chemical', '-', (131, 137))	('improvements', 'PosReg', (12, 24))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (152, 160))	('PFS', 'MPA', (83, 86))	('CS-PHP', 'Var', (131, 137))	('hepatic progression-free survival', 'MPA', (33, 66))	('ORR', 'MPA', (92, 95))
23211	22892755	Median hepatic PFS in the CS-PHP arm was significantly higher (HR 0.34, P < 0.001) at 8.1 months compared with 1.6 months in the BAC arm Overall PFS was also improved in the CS-PHP arm at 6.4 vs. 16 months (HR 0.41, P < 0.001).	('CS-PHP', 'Var', (26, 32))	('improved', 'PosReg', (158, 166))	('CS-PHP', 'Chemical', '-', (26, 32))	('hepatic PFS', 'MPA', (7, 18))	('PFS', 'MPA', (145, 148))	('CS-PHP', 'Chemical', '-', (174, 180))	('higher', 'PosReg', (55, 61))
23214	22892755	The subset of patients treated (4 CS-PHP and 4 BAC) at Moffitt Cancer Center mirror imaged the results of the entire cohort in the phase III trial with a median hepatic PFS in the CS-PHP group of 310 days versus the BAC group of 48 days.	('CS-PHP', 'Chemical', '-', (34, 40))	('hepatic PFS', 'MPA', (161, 172))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CS-PHP', 'Var', (180, 186))	('patients', 'Species', '9606', (14, 22))	('CS-PHP', 'Chemical', '-', (180, 186))
23219	22892755	Stanley P. L. Leong, MD SLN status in melanoma is a powerful predictor of clinical outcome.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('P. L. Leong', 'Var', (8, 19))	('MD SLN status', 'Var', (21, 34))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
23229	22892755	Following adjustment for age and gender, the hazard ratio (HR) associated with MMS was 1.09 per mm increase (P = 0.05) for PFS, and 6.30 (P = 0.014) and 5.41 (P = 0.048) for OS in patients, respectively, with MMS of 0.6-5.5 mm and MMS >= 5.5 mm compared with those with MMS < 0.6 mm.	('MMS', 'Var', (79, 82))	('PFS', 'Disease', (123, 126))	('OS', 'Chemical', '-', (174, 176))	('increase', 'PosReg', (99, 107))	('patients', 'Species', '9606', (180, 188))
23230	22892755	When patients were stratified by their PMT, the risk for disease progression and OS was substantially worse for the group with PMT >= 4.5 mm (HR = 13.10 and P = 0.022 for PFS; HR = 17.26 and P < 0.001 for OS) relative to the baseline group with PMT < 1.6 mm.	('worse', 'NegReg', (102, 107))	('PMT', 'molecular_function', 'GO:0030736', ('39', '42'))	('patients', 'Species', '9606', (5, 13))	('PMT >= 4.5 mm', 'Var', (127, 140))	('OS', 'Chemical', '-', (205, 207))	('disease', 'Disease', (57, 64))	('OS', 'Chemical', '-', (81, 83))	('PMT', 'molecular_function', 'GO:0030736', ('127', '130'))	('PMT', 'molecular_function', 'GO:0030736', ('245', '248'))
23243	22892755	The greatest risk reductions were observed in patients with ulceration and stage IIb/III-N1 with estimated HR for RFS, DMFS, and OS of 0.69 (P = 0.003), 0.59 (P < 0.0001) and 0.58 (P < 0.0001).	('reductions', 'NegReg', (18, 28))	('patients', 'Species', '9606', (46, 54))	('ulceration', 'Disease', (60, 70))	('OS', 'Chemical', '-', (129, 131))	('DMFS', 'Var', (119, 123))	('DMFS', 'Chemical', '-', (119, 123))	('RFS', 'Var', (114, 117))
23246	22892755	Based on this pivotal trial FDA has approved pegylated interfere or Sylatron for stage III melanoma.	('III melanoma', 'Disease', 'MESH:D008545', (87, 99))	('pegylated', 'Var', (45, 54))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('III melanoma', 'Disease', (87, 99))
23249	22892755	The findings of Curtin and co-workers of melanomas carrying distinct "driver" mutations based on etiologic factors paved the way for a new molecular understanding of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('mutations', 'Var', (78, 87))	('melanomas', 'Disease', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
23250	22892755	Activating BRAF mutations have been observed in approximately 40-50 % of all melanomas, particularly in cutaneous melanomas arising on intermittently sun-exposed skin.	('Activating', 'PosReg', (0, 10))	('melanomas', 'Disease', (77, 86))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (104, 123))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (104, 123))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('mutations', 'Var', (16, 25))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('cutaneous melanomas', 'Disease', (104, 123))	('BRAF', 'Gene', '673', (11, 15))	('melanomas', 'Disease', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('BRAF', 'Gene', (11, 15))
23251	22892755	The majority of BRAF mutations (over 85 %) are located in codon 600, mostly V600E mutations but with a minority of V600K, V600D and V600R mutations, as well as a small number in other codons.	('V600E', 'Mutation', 'rs113488022', (76, 81))	('V600D', 'Mutation', 'rs121913377', (122, 127))	('V600K', 'Var', (115, 120))	('V600R', 'Mutation', 'rs121913227', (132, 137))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('V600E', 'Var', (76, 81))	('V600K', 'Mutation', 'rs121913227', (115, 120))	('V600D', 'Var', (122, 127))	('V600R', 'Var', (132, 137))	('mutations', 'Var', (21, 30))
23252	22892755	Among melanomas that do not have BRAF mutations, 15-20 % harbor NRAS mutations, predominantly Q61R or Q61K mutations.	('BRAF', 'Gene', '673', (33, 37))	('Q61R', 'Mutation', 'rs11554290', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BRAF', 'Gene', (33, 37))	('melanomas', 'Disease', (6, 15))	('NRAS', 'Gene', (64, 68))	('Q61K', 'Mutation', 'rs121913254', (102, 106))	('NRAS', 'Gene', '4893', (64, 68))	('Q61K mutations', 'Var', (102, 116))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('Q61R', 'Var', (94, 98))
23253	22892755	Simultaneous mutations of BRAF and NRAS are highly unusual, presumably because either mutation alone is sufficient to drive the malignant phenotype.	('BRAF', 'Gene', '673', (26, 30))	('NRAS', 'Gene', (35, 39))	('NRAS', 'Gene', '4893', (35, 39))	('BRAF', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))
23254	22892755	Acral lentiginous melanomas and mucosal melanomas are more likely than other types to harbor activating c-KIT mutations (8-17 % of such tumors).	('tumors', 'Disease', (136, 142))	('Acral lentiginous melanomas and mucosal melanomas', 'Disease', 'MESH:D008545', (0, 49))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (110, 119))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('c-KIT', 'Gene', (104, 109))	('Acral lentiginous melanomas', 'Phenotype', 'HP:0012060', (0, 27))	('activating', 'PosReg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('c-KIT', 'Gene', '3815', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
23255	22892755	Some of the activating c-KIT mutations are sensitive to treatment with imatinib mesylate, but many are either insensitive to that drug or more sensitive to other kinase inhibitors such as sorafenib or dasatanib.	('c-KIT', 'Gene', '3815', (23, 28))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (71, 88))	('mutations', 'Var', (29, 38))	('c-KIT', 'Gene', (23, 28))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))	('activating', 'PosReg', (12, 22))	('sorafenib', 'Chemical', 'MESH:D000077157', (188, 197))	('dasatanib', 'Chemical', '-', (201, 210))
23256	22892755	The oral BRAF inhibitor vemurafenib (Zelboraf , Genentech, South San Francisco, CA) is relatively specific for the V600E mutant form of the BRAF protein.	('V600E', 'Mutation', 'rs113488022', (115, 120))	('BRAF', 'Gene', (9, 13))	('vemurafenib', 'Chemical', 'MESH:D000077484', (24, 35))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('BRAF', 'Gene', '673', (140, 144))	('V600E', 'Var', (115, 120))	('BRAF', 'Gene', (140, 144))	('BRAF', 'Gene', '673', (9, 13))
23260	22892755	A phase II trial is evaluating vemurafenib in patients suffering from brain metastases with and without previous brain-directed therapies, and other phase II trials are planned for patients with mutations in codon V600 that are not V600E and in children with V600E BRAF mutated melanoma.	('melanoma', 'Disease', 'MESH:D008545', (278, 286))	('patients', 'Species', '9606', (46, 54))	('vemurafenib', 'Chemical', 'MESH:D000077484', (31, 42))	('V600E', 'Mutation', 'rs113488022', (259, 264))	('V600E', 'Mutation', 'rs113488022', (232, 237))	('brain metastases', 'Disease', 'MESH:D009362', (70, 86))	('BRAF', 'Gene', '673', (265, 269))	('children', 'Species', '9606', (245, 253))	('brain metastases', 'Disease', (70, 86))	('V600E', 'Var', (259, 264))	('V600E', 'Var', (232, 237))	('patients', 'Species', '9606', (181, 189))	('melanoma', 'Phenotype', 'HP:0002861', (278, 286))	('melanoma', 'Disease', (278, 286))	('BRAF', 'Gene', (265, 269))
23277	22892755	As mentioned previously, some acral lentiginous and mucosal melanomas carry activating c-KIT mutations.	('acral lentiginous', 'Disease', 'MESH:D007911', (30, 47))	('mutations', 'Var', (93, 102))	('c-KIT', 'Gene', (87, 92))	('acral lentiginous', 'Disease', (30, 47))	('activating', 'PosReg', (76, 86))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mucosal melanomas', 'Disease', (52, 69))	('c-KIT', 'Gene', '3815', (87, 92))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mucosal melanomas', 'Disease', 'MESH:D008545', (52, 69))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))
23286	22892755	The discovery of specific mutations in different types of melanomas led to the development and testing of clinically useful inhibitors in a very short time frame.	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('mutations', 'Var', (26, 35))	('melanomas', 'Disease', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))
23316	22892755	Hussein Tawbi presented to ASCO 2 years ago that methylation patterns combined with gene expression profiling may predict who will respond to temozolomide or dacarbazine.	('predict', 'Reg', (114, 121))	('dacarbazine', 'Chemical', 'MESH:D003606', (158, 169))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('temozolomide', 'Chemical', 'MESH:D000077204', (142, 154))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('methylation', 'Var', (49, 60))	('respond to temozolomide', 'MPA', (131, 154))
23323	22892755	Patients without measurable disease, have by contrast, a consistent Th1 biased T cell response pattern when evaluated in relation to a half dozen peptide vaccine antigens, in vitro using Elispot T cell assays.	('Patients', 'Species', '9606', (0, 8))	('T cell response', 'MPA', (79, 94))	('Th1', 'Var', (68, 71))
23333	22892755	Enhancement of the immune response against cancer using monoclonal antibody blockade of CTLA-4 has resulted in a significant survival benefit for patients with metastatic melanoma.	('Enhancement', 'PosReg', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('survival benefit', 'CPA', (125, 141))	('cancer', 'Disease', (43, 49))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('immune response', 'MPA', (19, 34))	('CTLA-4', 'Gene', (88, 94))	('blockade', 'NegReg', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('immune response', 'biological_process', 'GO:0006955', ('19', '34'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('patients', 'Species', '9606', (146, 154))	('monoclonal antibody', 'Var', (56, 75))
23352	22892755	Of interest, ulceration appears to be associated with benefit from the pegylated and other regimens of low-dose or intermediate-dose IFN.	('pegylated', 'Var', (71, 80))	('IFN', 'Gene', '3439', (133, 136))	('IFN', 'Gene', (133, 136))	('ulceration', 'Disease', (13, 23))
23356	22892755	You've seen these discussed at this symposium already, and I think the fact that the BRAF mutation status is a pivot for therapeutic decision-making for patients with metastatic symptomatic disease may give rise to analyses of BRAF mutation status, PTEN, c-Kit and NRAS status, as the basis for more personalized therapy of melanoma.	('NRAS', 'Gene', (265, 269))	('patients', 'Species', '9606', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (324, 332))	('melanoma', 'Disease', (324, 332))	('NRAS', 'Gene', '4893', (265, 269))	('melanoma', 'Disease', 'MESH:D008545', (324, 332))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('PTEN', 'Gene', (249, 253))	('c-Kit', 'Gene', '3815', (255, 260))	('PTEN', 'Gene', '5728', (249, 253))	('BRAF', 'Gene', '673', (227, 231))	('c-Kit', 'Gene', (255, 260))	('mutation', 'Var', (90, 98))	('BRAF', 'Gene', (227, 231))
23357	22892755	Brain disease is a further major obstacle that we are approaching systematically using new BRAF inhibitors from GSK, where we thought we would never be able to hope to remit disease in patients with predictable regularity, but now see more than 50 % of patients showing antitumor benefit in brain metastases.	('brain metastases', 'Disease', 'MESH:D009362', (291, 307))	('Brain disease', 'Disease', 'MESH:D001927', (0, 13))	('remit disease', 'Disease', 'MESH:C535355', (168, 181))	('BRAF', 'Gene', '673', (91, 95))	('Brain disease', 'Disease', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('patients', 'Species', '9606', (253, 261))	('remit disease', 'Disease', (168, 181))	('BRAF', 'Gene', (91, 95))	('GSK', 'Chemical', '-', (112, 115))	('inhibitors', 'Var', (96, 106))	('patients', 'Species', '9606', (185, 193))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('brain metastases', 'Disease', (291, 307))	('GSK', 'Gene', (112, 115))
23358	22892755	Abrogation of resistance using combinations such as combinations that impact parallel pathways, or that may be collimated in the MAP/MEK pathway, have early suggestions of added benefit and perhaps reduced toxicity.	('MEK', 'Gene', (133, 136))	('MEK', 'Gene', '5609', (133, 136))	('parallel pathways', 'Pathway', (77, 94))	('toxicity', 'Disease', 'MESH:D064420', (206, 214))	('toxicity', 'Disease', (206, 214))	('combinations', 'Var', (52, 64))	('impact', 'Reg', (70, 76))	('MAP', 'molecular_function', 'GO:0004239', ('129', '132'))
23372	22892755	Anti-CTLA-4 blocking antibodies given together with interferon alpha has been a combination of interest to us at the University of Pittsburgh for several years, and we've completed a trial of Pfizer's Tremelimumab combined with IFN alfa-2b.	('Anti-CTLA-4', 'Var', (0, 11))	('IFN', 'Gene', '3439', (228, 231))	('IFN', 'Gene', (228, 231))
23390	22892755	Interferon is the standard, but IL-2 we've had before this, and anti-CTLA-4 blocking antibodies, all three of these induce autoimmunity.	('IL-2', 'molecular_function', 'GO:0005134', ('32', '36'))	('anti-CTLA-4', 'Var', (64, 75))	('autoimmunity', 'Phenotype', 'HP:0002960', (123, 135))	('IL-2', 'Gene', '3558', (32, 36))	('IL-2', 'Gene', (32, 36))	('autoimmunity', 'Disease', (123, 135))	('induce', 'Reg', (116, 122))	('autoimmunity', 'Disease', 'MESH:D001327', (123, 135))
23391	22892755	And so I think the paradigm shifts are that we have now an understanding of the role of driver mutations, BRAF for sure we need to assail.	('BRAF', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (106, 110))	('mutations', 'Var', (95, 104))
23393	22892755	Dasatinib, tested in the ECOG trial 2607, is moving from enrollment of patients with acral and mucosal melanomas, to enrollment only of patients with specifically proven c-Kit mutations that appear to be more sensitive to the molecular inhibitors.	('mutations', 'Var', (176, 185))	('mucosal melanomas', 'Disease', (95, 112))	('patients', 'Species', '9606', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('mucosal melanomas', 'Disease', 'MESH:D008545', (95, 112))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('patients', 'Species', '9606', (136, 144))	('c-Kit', 'Gene', (170, 175))	('c-Kit', 'Gene', '3815', (170, 175))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
23396	22892755	Now we have cutaneous melanoma:and multiple pathway driven distinctions of BRAF mutant vs. wild type, and clinical variables that are likely to be important in driving the decision of whether to use BRAF inhibitors:such as whether the patient is symptomatic?	('patient', 'Species', '9606', (235, 242))	('mutant', 'Var', (80, 86))	('BRAF', 'Gene', '673', (75, 79))	('cutaneous melanoma', 'Disease', (12, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (12, 30))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (12, 30))	('BRAF', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))
23398	22892755	If they are asymptomatic, BRAF mutation or not, I think the immunotherapies still take top drawer.	('mutation', 'Var', (31, 39))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (26, 30))
23404	33064882	Recurrent co-alteration of HDGF and SETDB1 on chromosome 1q drives cutaneous melanoma progression and poor prognosis A progressive increase in copy number variation (CNV) characterizes the natural history of cutaneous melanoma progression toward later disease stages, but our understanding of genetic drivers underlying chromosomal arm-level CNVs remains limited.	('HDGF', 'Gene', '3068', (27, 31))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('SETDB1', 'Gene', (36, 42))	('co-alteration', 'Var', (10, 23))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('SETDB1', 'Gene', '9869', (36, 42))	('melanoma', 'Disease', (77, 85))	('cutaneous melanoma', 'Disease', (67, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (67, 85))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('copy number', 'MPA', (143, 154))	('melanoma', 'Disease', (218, 226))	('cutaneous melanoma', 'Disease', (208, 226))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (208, 226))	('HDGF', 'Gene', (27, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (208, 226))
23413	33064882	Our work identifies the co-amplification of HDGF and SETDB1 as a functional driver of melanoma progression and poor patient prognosis.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('HDGF', 'Gene', (44, 48))	('patient', 'Species', '9606', (116, 123))	('co-amplification', 'Var', (24, 40))	('SETDB1', 'Gene', (53, 59))
23415	33064882	While genomic analysis has identified several recurrently mutated drivers that define malignant initiation of the disease (e.g., oncogenic BRAF mutations) (; Cancer Genome Atlas, 2015), mutational burden does not correlate with disease stage.	('BRAF', 'Gene', (139, 143))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('malignant initiation of the disease', 'Disease', (86, 121))	('Cancer', 'Disease', (158, 164))	('malignant initiation of the disease', 'Disease', 'MESH:D009369', (86, 121))	('Cancer', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (144, 153))	('BRAF', 'Gene', '673', (139, 143))
23419	33064882	Such is the case of chromosome 1q amplification, which is observed in >20% of all metastatic pancancer samples, and is the second most significant arm-level amplification observed in cutaneous melanoma (Amp q = 4.29e-9, Amp z score = 6.24).	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cutaneous melanoma', 'Disease', (183, 201))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (183, 201))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (183, 201))	('Amp', 'Chemical', 'MESH:D000249', (220, 223))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('amplification', 'Var', (34, 47))	('Amp', 'Chemical', 'MESH:D000249', (203, 206))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))	('cancer', 'Disease', (96, 102))
23420	33064882	We have previously utilized mosaic transgenesis in the BRAFV600E-driven MiniCoopR (MCR) melanoma model in zebrafish to screen 17 genes located on a focally amplified region of 1q21 (chr1: 147.2-149.2 Mb), and identified SETDB1 as a driver accelerating melanoma development in vivo.	('accelerating', 'PosReg', (239, 251))	('zebrafish', 'Species', '7955', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('SETDB1', 'Gene', (220, 226))	('melanoma', 'Disease', (252, 260))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('BRAFV600E-driven', 'Var', (55, 71))
23426	33064882	Given that HDGF alteration in melanoma patients co-occurs with BRAF and NRAS driver mutations (Figure S2a-b), we leveraged the zebrafish MCR model (Figure 1c) to test the functional effect of HDGF on melanoma progression in vivo.	('NRAS', 'Gene', (72, 76))	('zebrafish', 'Species', '7955', (127, 136))	('patients', 'Species', '9606', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('NRAS', 'Gene', '4893', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('melanoma', 'Disease', (200, 208))	('mutations', 'Var', (84, 93))	('BRAF', 'Gene', '673', (63, 67))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('HDGF', 'Gene', (11, 15))	('BRAF', 'Gene', (63, 67))	('alteration', 'Var', (16, 26))
23438	33064882	Interestingly, TCGA SKCM patients with HDGF amplification or overexpression have a higher Buffa Hypoxia score than patients without HDGF alterations (Figure S3 C, p = 3.925e-4, q = 0.0151).	('patients', 'Species', '9606', (115, 123))	('TCGA', 'Gene', (15, 19))	('Hypoxia', 'Disease', (96, 103))	('amplification', 'Var', (44, 57))	('patients', 'Species', '9606', (25, 33))	('overexpression', 'Var', (61, 75))	('higher', 'PosReg', (83, 89))	('Hypoxia', 'Disease', 'MESH:D000860', (96, 103))
23443	33064882	Immunohistochemistry analysis on fixed tumors showed a ~ 6-fold increase in mCherry + vessels in MCR:NRASQ61R + MCR:HDGF tumors compared to MCR:NRASQ61R + MCR:EGFP controls (p = .0187, Figure 2d-e) at 8-10 weeks post-injection, thus confirming HDGF to induce an increase in tumor vascularization.	('NRAS', 'Gene', '4893', (144, 148))	('HDGF tumors', 'Disease', 'MESH:D009369', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', (274, 279))	('tumors', 'Disease', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('NRAS', 'Gene', '4893', (101, 105))	('tumor', 'Disease', (121, 126))	('NRAS', 'Gene', (144, 148))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('NRAS', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MCR', 'Var', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', (121, 127))	('increase', 'PosReg', (64, 72))	('mCherry', 'MPA', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('HDGF tumors', 'Disease', (116, 127))
23445	33064882	As expected, given their proximity (5.7 Mb distance) on chromosome 1q, SETDB1 and HDGF are significantly co-altered by amplification and/or overexpression in 8% of patients (p < .001, q < 0.001) (Figure 3a-b).	('HDGF', 'Gene', (82, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('56', '66'))	('amplification', 'Var', (119, 132))	('co-altered', 'Reg', (105, 115))	('SETDB1', 'Gene', (71, 77))	('patients', 'Species', '9606', (164, 172))	('overexpression', 'Var', (140, 154))
23446	33064882	In the TCGA dataset, which includes a mixture of stages and primary versus metastatic tumors as a tissues source, HDGF and SETDB1 co-amplification is observed in ~ 3% of patients (Figure S4a-b).	('patients', 'Species', '9606', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SETDB1', 'Gene', (123, 129))	('HDGF', 'Gene', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('co-amplification', 'Var', (130, 146))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))
23449	33064882	Interestingly, patients in the TCGA SKCM dataset with both genes overexpressed and/or amplified have worse disease-specific survival (Figure 3a,e) (SETDB1 and HDGF co-altered versus.	('patients', 'Species', '9606', (15, 23))	('overexpressed', 'PosReg', (65, 78))	('amplified', 'Var', (86, 95))	('worse', 'NegReg', (101, 106))	('disease-specific survival', 'CPA', (107, 132))
23450	33064882	Given the two driver genes' independent mechanistic effects (HDGF on angiogenesis and SETDB1 on senescence), we hypothesized that co-alteration of both by amplification and/or overexpression might result in a more aggressive disease, causing poor patient survival.	('amplification', 'Var', (155, 168))	('senescence', 'biological_process', 'GO:0010149', ('96', '106'))	('angiogenesis', 'biological_process', 'GO:0001525', ('69', '81'))	('aggressive disease', 'Disease', (214, 232))	('result in', 'Reg', (197, 206))	('patient', 'Species', '9606', (247, 254))	('aggressive disease', 'Disease', 'MESH:D001523', (214, 232))	('more', 'PosReg', (209, 213))	('SETDB1', 'Gene', (86, 92))	('co-alteration', 'Var', (130, 143))	('overexpression', 'PosReg', (176, 190))
23452	33064882	MCR:HDGF + MCR:SETDB1 co-injection resulted in a stronger acceleration in malignant melanoma formation (median onset 8 weeks) than either MCR:HDGF (median onset 11 weeks) or MCR:SETDB1 (median onset 11 weeks) vector alone (HDGF + SETDB1 versus SETDB1 p = .0013, HDGF + SETDB1 versus HDGF p < .0001, HDGF versus SETDB1 p = .25, HDGF + SETDB1, HDGF, SETDB1 versus EGFP all p < .0001) (Figure 3f).	('malignant melanoma', 'Disease', 'MESH:D008545', (74, 92))	('acceleration', 'PosReg', (58, 70))	('malignant melanoma', 'Disease', (74, 92))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('SETDB1', 'Var', (15, 21))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
23457	33064882	We show for the first time that recurrent co-alteration of HDGF and SETDB1 drives cutaneous melanoma progression and poor patient outcome.	('SETDB1', 'Gene', (68, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('patient', 'Species', '9606', (122, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('HDGF', 'Gene', (59, 63))	('cutaneous melanoma', 'Disease', (82, 100))	('co-alteration', 'Var', (42, 55))
23458	33064882	We speculate that recurrent amplification of chromosome 1q frequently observed in malignant melanoma may confer an evolutionary advantage in part though HDGF/SETDB1 amplification that results in its selection during disease progression.	('selection', 'MPA', (199, 208))	('malignant melanoma', 'Disease', 'MESH:D008545', (82, 100))	('HDGF/SETDB1', 'Gene', (153, 164))	('malignant melanoma', 'Disease', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('amplification', 'Var', (165, 178))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('amplification', 'Var', (28, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (82, 100))
23461	33064882	A progressive accumulation of copy number changes has been described in late disease stages, but our understanding of which specific events drive melanoma progression remains incomplete.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('copy number changes', 'Var', (30, 49))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))
23463	33064882	Our study pinpoints an evolutionary advantage that might underlie the recurrent amplification of chromosome 1q in malignant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('amplification', 'Var', (80, 93))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (114, 132))	('malignant melanoma', 'Disease', 'MESH:D008545', (114, 132))	('malignant melanoma', 'Disease', (114, 132))
23487	31235702	Vitamin D is activated through sequential hydroxylations at C25 (by CYP27A1 and/or CYP2R) with following hydroxylation at C12 by CYP27B1 and inactivated by CYP24A1 through hydroxylation at C24 with further shortening at the side chain to produce calcitroic acid.	('CYP27A1', 'molecular_function', 'GO:0047749', ('68', '75'))	('CYP27A1', 'Gene', (68, 75))	('calcitroic acid', 'Chemical', 'MESH:C021640', (246, 261))	('CYP27B1', 'Gene', '1594', (129, 136))	('CYP24A1', 'Gene', (156, 163))	('CYP2R', 'Var', (83, 88))	('CYP24A1', 'Gene', '1591', (156, 163))	('CYP27A1', 'Gene', '1593', (68, 75))	('CYP27B1', 'Gene', (129, 136))	('activated', 'PosReg', (13, 22))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
23493	31235702	It was shown that vitamin D deficiency or dysregulated vitamin D signaling can play an important role in oncogenesis, clinical advancement and prognosis in such neoplasms as cutaneous melanomas, bladder, breast, lung, ovarian, pancreatic, thyroid, prostate and colorectal cancers.	('deficiency', 'Disease', (28, 38))	('neoplasms', 'Disease', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('dysregulated vitamin D', 'Phenotype', 'HP:0100512', (42, 64))	('breast', 'Disease', (204, 210))	('colorectal cancers', 'Disease', (261, 279))	('thyroid', 'Disease', (239, 246))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (174, 193))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (174, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('pancreatic', 'Disease', (227, 237))	('vitamin D', 'Chemical', 'MESH:D014807', (18, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (161, 170))	('oncogenesis', 'biological_process', 'GO:0007048', ('105', '116'))	('bladder', 'Disease', (195, 202))	('ovarian', 'Disease', (218, 225))	('ovarian', 'Disease', 'MESH:D010051', (218, 225))	('lung', 'Disease', (212, 216))	('dysregulated', 'Var', (42, 54))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))	('cutaneous melanomas', 'Disease', (174, 193))	('prostate', 'Disease', (248, 256))	('colorectal cancers', 'Disease', 'MESH:D015179', (261, 279))	('neoplasms', 'Disease', 'MESH:D009369', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('deficiency', 'Disease', 'MESH:D007153', (28, 38))	('vitamin D', 'Chemical', 'MESH:D014807', (55, 64))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (18, 38))	('pancreatic', 'Disease', 'MESH:D010195', (227, 237))
23555	31235702	Our study provides evidence showing the presence of VDR and CYB27B1 and CYP24A1, hydroxylases taking part in vitamin D metabolism, as well as RORalpha and RORgamma, alternative receptors for vitamin D-hydroxyderivatives.	('CYP24A1', 'Gene', '1591', (72, 79))	('VDR', 'Gene', (52, 55))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('109', '129'))	('eta', 'Gene', (120, 123))	('RORalpha and RORgamma', 'Gene', '6095', (142, 163))	('VDR', 'Gene', '7421', (52, 55))	('vitamin D', 'Chemical', 'MESH:D014807', (191, 200))	('vitamin D', 'Chemical', 'MESH:D014807', (109, 118))	('eta', 'Gene', '1909', (120, 123))	('CYP24A1', 'Gene', (72, 79))	('CYB27B1', 'Var', (60, 67))
23556	31235702	In all of the tissues examined the presence of nuclear receptors for vitamin D (VDRn), RORalphan and RORgamman, as well as CYB27B1 and CYP24A1, were confirmed.	('vitamin D', 'Chemical', 'MESH:D014807', (69, 78))	('RORalphan', 'Chemical', '-', (87, 96))	('VDR', 'Gene', (80, 83))	('CYB27B1', 'Var', (123, 130))	('CYP24A1', 'Gene', (135, 142))	('CYP24A1', 'Gene', '1591', (135, 142))	('VDR', 'Gene', '7421', (80, 83))	('RORgamman', 'Chemical', '-', (101, 110))
23565	31235702	Also in skin melanoma, a significantly decrease in the expression of VDR, CYB27B1, CYP24A1, RORalpha and RORgamma was observed in comparison to normal melanocytes or perilesional keratinocytes.	('CYP24A1', 'Gene', (83, 90))	('CYB27B1', 'Var', (74, 81))	('decrease', 'NegReg', (39, 47))	('CYP24A1', 'Gene', '1591', (83, 90))	('VDR', 'Gene', '7421', (69, 72))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('expression', 'MPA', (55, 65))	('skin melanoma', 'Disease', 'MESH:D008545', (8, 21))	('RORalpha and RORgamma', 'Gene', '6095', (92, 113))	('VDR', 'Gene', (69, 72))	('skin melanoma', 'Disease', (8, 21))
23596	31235702	In conclusion, we provide an evidence for the presence of the VDR, CYB27B1, CYP24A1, RORalpha and RORgamma in uveal cells, which changes in uveal melanomas and suggest that these proteins are involved in clinical presentation and represent targets for novel therapeutic approaches.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('uveal melanomas', 'Disease', (140, 155))	('uveal melanomas', 'Phenotype', 'HP:0007716', (140, 155))	('VDR', 'Gene', '7421', (62, 65))	('CYP24A1', 'Gene', (76, 83))	('CYP24A1', 'Gene', '1591', (76, 83))	('uveal melanomas', 'Disease', 'MESH:C536494', (140, 155))	('uveal melanoma', 'Phenotype', 'HP:0007716', (140, 154))	('VDR', 'Gene', (62, 65))	('RORalpha and RORgamma', 'Gene', '6095', (85, 106))	('CYB27B1', 'Var', (67, 74))
23631	27141983	The occurrence of non-melanoma malignant skin lesions and non-cutaneous squamous-cell carcinoma among metastatic melanoma patients: an observational cohort study in Denmark Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations.	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Disease', 'MESH:D008545', (260, 268))	('non-melanoma malignant skin lesions', 'Disease', (18, 53))	('patients', 'Species', '9606', (235, 243))	('squamous-cell carcinoma', 'Disease', (72, 95))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('patients', 'Species', '9606', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('melanoma', 'Disease', (260, 268))	('non-melanoma malignant skin lesions', 'Disease', 'MESH:D008545', (18, 53))	('BRAF', 'Gene', '673', (194, 198))	('BRAF', 'Gene', (194, 198))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('mutant', 'Var', (187, 193))	('melanoma', 'Disease', (113, 121))	('cutaneous squamous-cell carcinoma', 'Phenotype', 'HP:0006739', (62, 95))	('non-melanoma malignant skin lesions', 'Phenotype', 'HP:0008069', (18, 53))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))
23632	27141983	However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('SCC', 'Gene', '6317', (82, 85))	('BRAF', 'Gene', (9, 13))	('induce', 'PosReg', (38, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 78))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (45, 78))	('inhibitors', 'Var', (14, 24))	('cuSCC', 'Phenotype', 'HP:0006739', (80, 85))	('SCC', 'Gene', (82, 85))	('cutaneous squamous cell carcinoma', 'Disease', (45, 78))	('BRAF', 'Gene', '673', (9, 13))
23647	27141983	Recently, treatment with immunotherapy or inhibition of the mitogen-activated protein kinase (MAPK) pathway has demonstrated clinical benefit by prolonging OS and progression-free survival (PFS) in randomized trials.	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('prolonging', 'PosReg', (145, 155))	('OS', 'Chemical', 'MESH:D009992', (156, 158))	('inhibition', 'Var', (42, 52))	('progression-free survival', 'CPA', (163, 188))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))
23739	27141983	In conclusion, our results suggest that metastatic melanoma patients may further develop non-melanoma skin lesions and non-cuSCC; however, the incidence is low.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('metastatic', 'Var', (40, 50))	('melanoma', 'Disease', (93, 101))	('non-melanoma skin lesions', 'Disease', 'MESH:D012871', (89, 114))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('patients', 'Species', '9606', (60, 68))	('non-melanoma skin lesions', 'Phenotype', 'HP:0008069', (89, 114))	('cuSCC', 'Phenotype', 'HP:0006739', (123, 128))	('SCC', 'Gene', (125, 128))	('develop', 'PosReg', (81, 88))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('SCC', 'Gene', '6317', (125, 128))	('melanoma', 'Disease', (51, 59))	('non-melanoma skin lesions', 'Disease', (89, 114))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
23772	30652536	As shown by survival curves for BRCA (Fig 2E), MESO (Fig 2F), and PAAD (Fig 2G), the OS of patients with high levels of MAP2K1 and CDK4/6 was significantly lower than the OS of patients with low levels of MAP2K1 and CDK4/6.	('PAAD', 'Disease', 'MESH:D010195', (66, 70))	('MESO', 'Disease', 'MESH:D008654', (47, 51))	('CDK', 'molecular_function', 'GO:0004693', ('131', '134'))	('lower', 'NegReg', (156, 161))	('MAP2K1', 'Gene', '5604', (205, 211))	('patients', 'Species', '9606', (91, 99))	('MAP2K', 'molecular_function', 'GO:0004708', ('120', '125'))	('MESO', 'Disease', (47, 51))	('MAP2K1', 'Gene', (205, 211))	('PAAD', 'Disease', (66, 70))	('CDK4/6', 'Gene', (131, 137))	('MAP2K', 'molecular_function', 'GO:0004708', ('205', '210'))	('BRCA', 'Gene', '672', (32, 36))	('high', 'Var', (105, 109))	('patients', 'Species', '9606', (177, 185))	('CDK', 'molecular_function', 'GO:0004693', ('216', '219'))	('MAP2K1', 'Gene', '5604', (120, 126))	('BRCA', 'Gene', (32, 36))	('MAP2K1', 'Gene', (120, 126))
23776	30652536	As shown in Figure 3, synergistic effect was predicted for several MAPK1 combinations evidenced by short OS in the high (ie, more than the median) MAPK1-high other gene-expression group and significantly better OS within the cohort in which expression of both of these genes is low (ie, below median).	('MAPK1', 'Gene', (67, 72))	('gene-expression', 'biological_process', 'GO:0010467', ('164', '179'))	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('MAPK1', 'Gene', (147, 152))	('MAPK1', 'Gene', '5594', (67, 72))	('combinations', 'Var', (73, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('67', '71'))	('MAPK1', 'Gene', '5594', (147, 152))
23799	30652536	ERK inhibitors are being tested in the clinic for the treatment of tumors with aberrant MAPK pathway signaling; however, combination therapies will probably be necessary to achieve durable tumor control.	('tumor', 'Disease', (189, 194))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('MAPK pathway signaling', 'Pathway', (88, 110))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('aberrant', 'Var', (79, 87))	('ERK', 'Gene', '5594', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('ERK', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', (67, 73))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))
23801	30652536	ERK inhibition may also be the best way to disrupt this pathway in other RAS-driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ERK', 'Gene', '5594', (0, 3))	('inhibition', 'Var', (4, 14))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ERK', 'Gene', (0, 3))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))
23802	30652536	Our results show that expression of multiple novel targets might synergistically affect patient survival, and inhibition of these genes may increase the efficacy of ERK inhibitors.	('patient', 'Species', '9606', (88, 95))	('efficacy', 'MPA', (153, 161))	('ERK', 'Gene', '5594', (165, 168))	('ERK', 'molecular_function', 'GO:0004707', ('165', '168'))	('affect', 'Reg', (81, 87))	('inhibition', 'Var', (110, 120))	('patient survival', 'CPA', (88, 104))	('increase', 'PosReg', (140, 148))	('ERK', 'Gene', (165, 168))
23803	30652536	We demonstrate that expression of MAPK1 and PKN3 both have to be low to predict better OS, and PKN3 inhibition may increase efficacy of the MAPK inhibitor sorafenib.	('MAPK', 'Enzyme', (140, 144))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('MAPK1', 'Gene', (34, 39))	('PKN3', 'Gene', '263803', (44, 48))	('PKN3', 'Gene', (44, 48))	('PKN3', 'Gene', (95, 99))	('sorafenib', 'Chemical', 'MESH:C471405', (155, 164))	('increase', 'PosReg', (115, 123))	('PKN3', 'Gene', '263803', (95, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('inhibition', 'Var', (100, 110))	('efficacy', 'MPA', (124, 132))	('MAPK1', 'Gene', '5594', (34, 39))
23809	30365005	Tumor sequence surveys have frequently ranked the importance of substitutions to cancer growth by P value or a false-discovery conversion thereof.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('false', 'biological_process', 'GO:0071877', ('111', '116'))	('cancer', 'Disease', (81, 87))	('substitutions', 'Var', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('false', 'biological_process', 'GO:0071878', ('111', '116'))
23813	30365005	Then we bring to bear recent advances that draw upon an understanding of the development of cancer as an evolutionary process to estimate the effect size of somatic variants leading to cancer.	('variants', 'Var', (165, 173))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (185, 191))
23814	30365005	We demonstrate the estimation of the effect sizes of all recurrent single nucleotide variants in 22 cancer types, quantifying relative importance within and between driver genes.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('single nucleotide variants', 'Var', (67, 93))
23815	30365005	Since the advent of whole-exome and whole-genome sequencing of tumor tissues, studies of somatic mutations have revealed the underlying genetic architecture of cancer, producing lists of statistically significantly mutated genes whose ordering implies their relative importance to tumorigenesis and cancer development.	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('mutated', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('tumor', 'Disease', (281, 286))
23816	30365005	Typically, differentiation of selected mutations from neutral mutations is performed by quantifying the overrepresentation of mutations within specific genes in tumor tissue relative to normal tissue, and disproportionate prevalence of somatic mutations in a gene has been taken as prima facie evidence of a causative role for that gene.	('prima', 'Gene', '145270', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutations', 'Var', (126, 135))	('tumor', 'Disease', (161, 166))	('prima', 'Gene', (282, 287))
23817	30365005	Two quantifications have implicitly ordered the importance of discovered cancer "driver" genes: the prevalence of the mutation among tumor tissues sequenced from that tumor type, the statistical significance (P value) of the disproportionality of mutation frequency, or both.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
23820	30365005	Although prevalence of a somatic mutation in a cancer type has important consequences for biomarker studies and identification of the therapeutic population for a targeted therapy, there is only a correlative:rather than causal:link between prevalence of mutation and its contribution to tumorigenesis and cancer development.	('tumor', 'Disease', (288, 293))	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (255, 263))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Disease', (306, 312))
23821	30365005	The lack of causal linkage is easily seen by considering the mutated genes that, despite their high prevalence in tumor populations, are universally regarded as false positives.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('false', 'biological_process', 'GO:0071878', ('161', '166'))	('tumor', 'Disease', (114, 119))	('false', 'biological_process', 'GO:0071877', ('161', '166'))	('mutated genes', 'Var', (61, 74))
23825	30365005	Any consideration of whether mutated genes are contributing to tumorigenesis and cancer development:or of the degree to which they are contributing:must address the issue of their underlying mutation rate.	('tumor', 'Disease', (63, 68))	('contributing', 'Reg', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('mutated', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
23826	30365005	As in the divergence of species, synonymous site mutations are presumably neutral (or nearly so) to the success of cancer lineages during the divergence from normal to resectable tumor.	('cancer', 'Disease', (115, 121))	('mutations', 'Var', (49, 58))	('synonymous site mutations', 'Var', (33, 58))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Disease', (179, 184))
23829	30365005	Although approaches accounting for genic mutation rates will eliminate false positives, and the P value will serve to exclude genes like TTN that have no role in tumorigenesis and cancer development, the rank order by P value of genes that do have a role in tumorigenesis and cancer development will remain highly affected by mutation rate.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('false', 'biological_process', 'GO:0071878', ('71', '76'))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TTN', 'Gene', (137, 140))	('mutation', 'Var', (326, 334))	('cancer', 'Disease', (276, 282))	('tumor', 'Disease', (258, 263))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (162, 167))	('TTN', 'Gene', '7273', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('false', 'biological_process', 'GO:0071877', ('71', '76'))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('cancer', 'Disease', (180, 186))
23830	30365005	Genes with higher mutation rate will (correctly) be more likely to achieve statistical significance, and thus will appear deceptively high on a ranked list whose ordering suggests importance in tumorigenesis and cancer development.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', (194, 199))	('mutation', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
23833	30365005	By applying an evolutionary concept, the importance of a mutation to tumorigenesis and cancer development can be quantified by its "selective effect" on the cancer lineage.	('mutation', 'Var', (57, 65))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
23834	30365005	Mutations are a major source of variation contributing to tumorigenesis, yet we do not conduct genomic tumor sequence surveys to discover neutral mutation rates: we conduct them to determine which mutations spread within cancer tissues because of the effects of mutations on proliferation and survival.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (221, 227))	('tumor', 'Disease', (103, 108))	('proliferation', 'CPA', (275, 288))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('survival', 'CPA', (293, 301))	('effects', 'Reg', (251, 258))	('mutations', 'Var', (262, 271))
23837	30365005	The flux of substitutions among tumors at a nucleotide site that occurs above the baseline silent rate represents the intensity of selection on that mutation within the tumor population.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('substitutions', 'Var', (12, 25))	('tumor', 'Disease', (169, 174))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
23838	30365005	These selection intensities quantify the survival and proliferative advantage conferred by variants, facilitating comparisons of the relative importance of drivers among and within tumor types.	('tumor', 'Disease', (181, 186))	('survival', 'CPA', (41, 49))	('proliferative advantage', 'CPA', (54, 77))	('variants', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
23843	30365005	Head and neck squamous cell carcinoma (HNSC) tumors with variant data obtained from the NCI TCGA database were designated as positive for human papillomavirus (HPV) if they contained greater than 100 HPV RNA viral transcript reads per hundred million, and one of the 17 tumors obtained from Hedberg et al.	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Disease', (270, 276))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('neck squamous cell carcinoma (HNSC) tumors', 'Disease', 'MESH:D000077195', (9, 51))	('variant', 'Var', (57, 64))	('human papillomavirus', 'Species', '10566', (138, 158))	('RNA', 'cellular_component', 'GO:0005562', ('204', '207'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('HPV', 'Species', '10566', (200, 203))	('HPV', 'Species', '10566', (160, 163))	('Head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (0, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('neck', 'cellular_component', 'GO:0044326', ('9', '13'))	('HNSC', 'Phenotype', 'HP:0012288', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
23851	30365005	The intensity of selection, or cancer effect size, per variant is then equivalent to the substitution rate divided by the mutation rate.	('variant', 'Var', (55, 62))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
23855	30365005	To calculate the cancer effect sizes of all recurrent single-nucleotide variants in 22 cancer types, we compared the rate of observed substitutions to the rate that substitutions would be expected to arise in the absence of selection in data that either were obtained from TCGA projects downloaded from the National Cancer Institute's Genomic Data Commons (Supplementary Table 2, available online) or were derived from whole exome sequencing of tumors as part of a collaboration with Gilead Sciences (Supplementary Table 1, Methods, available online).	('cancer', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (445, 451))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('variants', 'Var', (72, 80))	('Cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (17, 23))	('Cancer', 'Disease', (316, 322))	('tumor', 'Phenotype', 'HP:0002664', (445, 450))	('tumors', 'Phenotype', 'HP:0002664', (445, 451))	('Cancer', 'Disease', 'MESH:D009369', (316, 322))	('tumors', 'Disease', (445, 451))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
23859	30365005	For instance, even though lung tissues encounter similar mutagens and hence mutations arise through similar mutational signatures, lung adenocarcinoma and lung squamous cell carcinoma variants conferring the largest effect sizes are markedly different among the two cancers (Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (155, 183))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancers', 'Disease', (266, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (131, 183))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('variants', 'Var', (184, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))
23860	30365005	Moreover, within a tumor type, the selection intensity decouples the effects of mutation rate on frequency: Even though EGFR L858R variants are approximately twice as prevalent as KRAS G12A variants in lung adenocarcinoma tumors, KRAS G12A is estimated to have a higher effect size, because of its much lower baseline mutation rate.	('KRAS', 'Gene', (180, 184))	('variants', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (19, 24))	('lung adenocarcinoma tumors', 'Disease', 'MESH:D000077192', (202, 228))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('G12A', 'Mutation', 'rs121913529', (235, 239))	('EGFR', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumor', 'Disease', (222, 227))	('variants', 'Var', (190, 198))	('KRAS', 'Gene', (230, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('G12A', 'Mutation', 'rs121913529', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('baseline mutation rate', 'MPA', (309, 331))	('KRAS', 'Gene', '3845', (180, 184))	('EGFR', 'Gene', '1956', (120, 124))	('lung adenocarcinoma tumors', 'Disease', (202, 228))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('L858R', 'Mutation', 'rs121434568', (125, 130))
23863	30365005	This calculation yielded cancer effect sizes for all fixed substitutions (Supplementary Figure 1, Supplementary Table 3, available online) that quantify contribution to the cancer phenotype within 22 tumor types.	('substitutions', 'Var', (59, 72))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (25, 31))
23867	30365005	Several substitutions within genes that are not statistically significantly overmutated are interspersed among more prevalent substitutions within genes that are estimated to be statistically significantly mutated, for instance, Mastermind-like3 (MAML3) G1073A in rectum adenocarcinoma, a protein that is known to bind to and stabilize the DNA-binding complex of the Notch intracellular domain and ubiquitin ligase Cullin-3 (CUL3) M299R in prostate adenocarcinoma, which was only recently implicated as a driver of prostate cancer by an even higher sample-size tumor sequence analysis.	('prostate adenocarcinoma', 'Disease', (440, 463))	('CUL3', 'Gene', (425, 429))	('MAML3', 'Gene', '55534', (247, 252))	('bind', 'Interaction', (314, 318))	('Cullin-3', 'Gene', (415, 423))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('tumor', 'Phenotype', 'HP:0002664', (561, 566))	('DNA-binding', 'molecular_function', 'GO:0003677', ('340', '351'))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (440, 463))	('rectum adenocarcinoma', 'Disease', (264, 285))	('M299R', 'Var', (431, 436))	('Mastermind-like3', 'Gene', (229, 245))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('protein', 'cellular_component', 'GO:0003675', ('289', '296'))	('Mastermind-like3', 'Gene', '55534', (229, 245))	('ubiquitin', 'molecular_function', 'GO:0031386', ('398', '407'))	('M299R', 'Mutation', 'p.M299R', (431, 436))	('CUL3', 'Gene', '8452', (425, 429))	('G1073A', 'Var', (254, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (515, 530))	('prostate cancer', 'Phenotype', 'HP:0012125', (515, 530))	('prostate cancer', 'Disease', (515, 530))	('G1073A', 'Mutation', 'rs770136825', (254, 260))	('DNA', 'cellular_component', 'GO:0005574', ('340', '343'))	('intracellular', 'cellular_component', 'GO:0005622', ('373', '386'))	('tumor', 'Disease', (561, 566))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (264, 285))	('MAML3', 'Gene', (247, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (454, 463))	('Cullin-3', 'Gene', '8452', (415, 423))	('tumor', 'Disease', 'MESH:D009369', (561, 566))
23869	30365005	For instance, HPV+ and HPV- HNSC and estrogen receptor-positive and estrogen receptor-negative BRCA each have distinct variants of high cancer effect size (notably, variants within TP53 rank among the highest effect sizes within HNSC and BRCA tumors negative for HPV and negative for ER, respectively; Supplementary Figure 1, available online).	('TP53', 'Gene', (181, 185))	('HPV', 'Species', '10566', (14, 17))	('BRCA tumors', 'Disease', (238, 249))	('BRCA tumors', 'Disease', 'MESH:D009369', (238, 249))	('estrogen receptor', 'Gene', (37, 54))	('BRCA', 'Gene', (238, 242))	('HNSC', 'Phenotype', 'HP:0012288', (28, 32))	('estrogen receptor', 'Gene', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('high cancer', 'Disease', 'MESH:D009369', (131, 142))	('BRCA', 'Gene', (95, 99))	('high cancer', 'Disease', (131, 142))	('HPV', 'Species', '10566', (23, 26))	('variants', 'Var', (119, 127))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('BRCA', 'Phenotype', 'HP:0003002', (238, 242))	('HPV', 'Species', '10566', (263, 266))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('estrogen receptor', 'Gene', '2099', (37, 54))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('estrogen receptor', 'Gene', '2099', (68, 85))	('variants', 'Var', (165, 173))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('HPV- HNSC', 'Disease', (23, 32))	('BRCA', 'Gene', '672', (238, 242))	('BRCA', 'Gene', '672', (95, 99))	('HPV- HNSC', 'Disease', 'MESH:D030361', (23, 32))
23872	30365005	We derive the appropriate metric: the cancer effect size of mutations.	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
23873	30365005	This effect size:quantifying the intensity of selection on mutations in cancer cells in patients:conveys the replicative and survival benefit conferred by genetic variants, and therefore is a direct metric of the contribution of a variant to the cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('replicative', 'CPA', (109, 120))	('cancer', 'Disease', (246, 252))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('variants', 'Var', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
23874	30365005	Using our approach, we estimated the effect size of all recurrent single-nucleotide variants in 22 cancer types, reevaluating their importance across single-nucleotide variant effect size to cancer in disparate tumor types projected to account for approximately 82% of all new cancer cases within the United States in 2017.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('single-nucleotide variants', 'Var', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
23876	30365005	For instance, FBXW7 R505G was estimated to have the highest selection intensity in HPV+ HNSC, BRAF V600E was estimated to have the seventh highest selection intensity in low-grade glioma, and BRAF G469A was estimated to have the 12th highest selection intensity in prostate adenocarcinoma, yet these two genes were not classified as statistically significantly mutated at the gene level within these three cancer types.	('prostate adenocarcinoma', 'Disease', (265, 288))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('FBXW7 R505G', 'Var', (14, 25))	('HPV', 'Species', '10566', (83, 86))	('cancer', 'Disease', (406, 412))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (265, 288))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('BRAF', 'Gene', '673', (94, 98))	('R505G', 'Mutation', 'rs149680468', (20, 25))	('HPV+ HNSC', 'Disease', (83, 92))	('BRAF', 'Gene', (94, 98))	('HNSC', 'Phenotype', 'HP:0012288', (88, 92))	('G469A', 'Mutation', 'rs121913355', (197, 202))	('glioma', 'Disease', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (406, 412))	('BRAF', 'Gene', '673', (192, 196))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('BRAF', 'Gene', (192, 196))
23877	30365005	Mutations within these two well-known oncogenes were estimated to confer large effect sizes, and these genes were determined to be statistically significantly mutated in other cancer types, yet their importance in patients who have these rarer somatic variants within HPV+ HNSC, low-grade glioma, and prostate adenocarcinoma has been poorly illuminated by gene-wide analyses of statistically significant mutation burden across patients.	('glioma', 'Disease', (289, 295))	('variants', 'Var', (252, 260))	('patients', 'Species', '9606', (427, 435))	('patients', 'Species', '9606', (214, 222))	('HPV+ HNSC', 'Gene', (268, 277))	('HPV', 'Species', '10566', (268, 271))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('HNSC', 'Phenotype', 'HP:0012288', (273, 277))	('prostate adenocarcinoma', 'Disease', (301, 324))	('glioma', 'Disease', 'MESH:D005910', (289, 295))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (289, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (301, 324))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
23878	30365005	Thus, calculating the cancer effect size at the level of single nucleotide variants identifies drivers with an underwhelming, low prevalence that potentially exert a very large effect in different tumor types.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', (22, 28))	('single nucleotide variants', 'Var', (57, 83))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (197, 202))
23879	30365005	Targeted therapies are often developed for, and necessarily tested in, a single tumor type with the targeted variant at high frequency.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('variant', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (80, 85))
23882	30365005	Targets for therapies that were originally developed for variants at high prevalence in one tumor type are expected to be effective when treating the same variant in a secondary tumor type if the variant has similarly high selection intensity in the second tumor type, even if it is at low prevalence in the newly considered tumor type.	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('variants', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (92, 97))	('variant', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
23884	30365005	For instance, the relative ranking of the effect sizes of the somatic variants within a tumor indicates the variants that, when targeted, would have the largest predicted effect on tumor progression.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('variants', 'Var', (108, 116))	('variants', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
23886	30365005	Furthermore, when a therapy abrogates novel oncogenic function primarily by disabling a gain-of-function mutation, the upper limit of the efficacy of the precision-targeted treatment will be dictated by the selection intensity that the somatic variant imparted to the cancer cell lineage.	('cancer', 'Disease', (268, 274))	('mutation', 'Var', (105, 113))	('gain-of-function', 'PosReg', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('disabling', 'Var', (76, 85))	('prima', 'Gene', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('prima', 'Gene', '145270', (63, 68))
23887	30365005	Therefore, precision treatments can be selected in clinical decision making on tumor boards to target mutations with the greatest cancer effect size, incorporating other knowledge regarding the pharmacokinetics, efficacy, side effects, and the evolution of resistance to therapies.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
23891	30365005	that are effective in providing a systematic and experimentally controlled methodology to assess functional impact of many tumorigenic genomic variants.	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (123, 128))	('variants', 'Var', (143, 151))
23892	30365005	Context-specific variation introduced via a model system causes imperfect capture of the functional impact of all variants; results from model systems should be considered alongside human cancer effect sizes.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (182, 187))	('variants', 'Var', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))
23893	30365005	The effect sizes of cancer mutations can inform nearly every aspect of basic research related to oncology, including which genes and pathways deserve greater attention in basic research.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('oncology', 'Phenotype', 'HP:0002664', (97, 105))	('inform', 'Reg', (41, 47))
23894	30365005	Although network interactions, epigenetic and tumor microenvironment interactions, and aspects of cellular differentiation and cellular plasticity mean that quantification of the selective effect of mutations does not provide an upper bound on the importance of a gene or pathway in the molecular biology of particular cases of cancer, its quantification does provide a lower bound on its importance across a cancer type, as the role of genes with a somatic variant can be no lower in importance than the selection intensity the variant imparts.	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('mutations', 'Var', (199, 208))	('cancer', 'Disease', 'MESH:D009369', (409, 415))	('cancer', 'Disease', (409, 415))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
23895	30365005	By focusing on single-nucleotide variants, we have dealt with only a subset of the mutational processes observed in cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('single-nucleotide variants', 'Var', (15, 41))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
23925	30229459	Overall, BRAF mutations are found in 50% of tumors and are more common in melanomas developing on intermittently sun-exposed skin (i.e., trunk).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('BRAF', 'Gene', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('melanomas', 'Disease', 'MESH:D008545', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('common', 'Reg', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('trunk', 'cellular_component', 'GO:0043198', ('137', '142'))	('mutations', 'Var', (14, 23))	('melanomas', 'Disease', (74, 83))	('BRAF', 'Gene', '673', (9, 13))
23926	30229459	NRAS mutations are found in approximately 20% of melanomas and are more frequently found in chronically sun-exposed skin (i.e., face).	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('NRAS', 'Gene', '4893', (0, 4))
23927	30229459	In contrast, ALM occurs on relatively sun-protected sites, including the palms, soles, and nail apparatus, and has comparatively lower numbers of point mutations than do melanomas occurring on sun-exposed sites.	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('point', 'Var', (146, 151))	('ALM', 'Phenotype', 'HP:0012060', (13, 16))	('ALM', 'Disease', (13, 16))	('melanomas', 'Disease', (170, 179))	('lower', 'NegReg', (129, 134))
23978	33798262	UM is known to have driver mutations in GNAQ/11, CYSLTR2, and PLCB4, with subsequent mutations in BAP1 (associated with adverse prognosis), SF3B1 (associated with late metastasis), or EIF1AX (associated with good prognosis).	('BAP1', 'Gene', (98, 102))	('mutations', 'Var', (27, 36))	('GNAQ', 'Gene', (40, 44))	('SF3B1', 'Gene', (140, 145))	('associated', 'Reg', (147, 157))	('CYSLTR2', 'Gene', '57105', (49, 56))	('PLCB4', 'Gene', '5332', (62, 67))	('CYSLTR2', 'Gene', (49, 56))	('associated', 'Reg', (104, 114))	('mutations', 'Var', (85, 94))	('SF3B1', 'Gene', '23451', (140, 145))	('GNAQ', 'Gene', '2776', (40, 44))	('BAP1', 'Gene', '8314', (98, 102))	('UM', 'Phenotype', 'HP:0007716', (0, 2))	('PLCB4', 'Gene', (62, 67))	('EIF1AX', 'Gene', '1964', (184, 190))	('EIF1AX', 'Gene', (184, 190))
23979	33798262	CoM on the other hand resembles cutaneous melanoma and has driver mutations in BRAF, NRAS, Kit, TERT, or NF1.	('mutations', 'Var', (66, 75))	('NF1', 'Gene', (105, 108))	('TERT', 'Gene', (96, 100))	('NF1', 'Gene', '4763', (105, 108))	('Kit', 'Gene', (91, 94))	('NRAS', 'Gene', (85, 89))	('CoM', 'Phenotype', 'HP:0007716', (0, 3))	('TERT', 'Gene', '7015', (96, 100))	('cutaneous melanoma', 'Disease', (32, 50))	('Kit', 'Gene', '3815', (91, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('NRAS', 'Gene', '4893', (85, 89))	('BRAF', 'Gene', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
23985	33798262	In various cancers, including cutaneous melanoma, increased activity of the YAP/TAZ pathway has been related to worse survival, and inhibition of YAP/TAZ has been suggested as a potential new therapy.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('increased', 'PosReg', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('YAP/TAZ pathway', 'Pathway', (76, 91))	('activity', 'MPA', (60, 68))	('cutaneous melanoma', 'Disease', (30, 48))	('cancers', 'Disease', (11, 18))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('inhibition', 'Var', (132, 142))
23991	33798262	Approximately 90% of UM harbor a GNAQ/11 mutation, which was found to activate the YAP/TAZ cascade.	('GNAQ', 'Gene', (33, 37))	('mutation', 'Var', (41, 49))	('GNAQ', 'Gene', '2776', (33, 37))	('activate', 'PosReg', (70, 78))	('YAP/TAZ', 'MPA', (83, 90))	('UM', 'Phenotype', 'HP:0007716', (21, 23))
23992	33798262	Inhibition of this pathway by shRNA or drugs led to decreased cell growth in vitro as well as tumor regression in mouse models carrying a GNAQ/11 mutation.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Inhibition', 'NegReg', (0, 10))	('GNAQ', 'Gene', '2776', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('decreased', 'NegReg', (52, 61))	('tumor', 'Disease', (94, 99))	('mouse', 'Species', '10090', (114, 119))	('GNAQ', 'Gene', (138, 142))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('mutation', 'Var', (146, 154))	('cell growth', 'CPA', (62, 73))
23994	33798262	YAP1 expression was detected in cutaneous melanoma cell lines lacking a GNAQ/11 mutation (but harboring BRAF or NRAS mutations instead), and in human cutaneous melanoma tissue where a high expression was related to worse survival.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('mutations', 'Var', (117, 126))	('YAP1', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (112, 116))	('YAP1', 'Gene', '10413', (0, 4))	('human', 'Species', '9606', (144, 149))	('GNAQ', 'Gene', '2776', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lacking', 'NegReg', (62, 69))	('NRAS', 'Gene', (112, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', (32, 50))	('cutaneous melanoma', 'Disease', (150, 168))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('mutation', 'Var', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('GNAQ', 'Gene', (72, 76))
23997	33798262	This mechanism is poorly understood, however, and it is unknown if the YAP/TAZ pathway (activated by the early GNAQ/11 mutation) is altered by chromosome changes or other mutations, such as in BAP1, which is known to be related to adverse prognosis.	('YAP/TAZ pathway', 'Pathway', (71, 86))	('mutation', 'Var', (119, 127))	('BAP1', 'Gene', '8314', (193, 197))	('GNAQ', 'Gene', '2776', (111, 115))	('GNAQ', 'Gene', (111, 115))	('chromosome', 'cellular_component', 'GO:0005694', ('143', '153'))	('BAP1', 'Gene', (193, 197))	('mutations', 'Var', (171, 180))
24001	33798262	Next, we studied the effect of YAP1-inhibition using VP without light activation on multiple UM cell lines with different genetic profiles (including cell lines with and without BAP1 expression), and included CoM cell lines with either a BRAF or NRAS mutation as a control.	('BAP1', 'Gene', '8314', (178, 182))	('VP', 'Chemical', 'MESH:D000077362', (53, 55))	('BAP1', 'Gene', (178, 182))	('mutation', 'Var', (251, 259))	('YAP1', 'Gene', (31, 35))	('YAP1', 'Gene', '10413', (31, 35))	('CoM', 'Phenotype', 'HP:0007716', (209, 212))	('UM', 'Phenotype', 'HP:0007716', (93, 95))	('NRAS', 'Gene', (246, 250))	('NRAS', 'Gene', '4893', (246, 250))
24031	33798262	Antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA): YAP (4912S), TEAD1 (12292S), and c-Myc (9402S).	('12292S', 'Var', (97, 103))	('c-Myc', 'Gene', '4609', (110, 115))	('4912S', 'Var', (82, 87))	('TEAD1', 'Gene', '7003', (90, 95))	('c-Myc', 'Gene', (110, 115))	('TEAD1', 'Gene', (90, 95))	('Signaling', 'biological_process', 'GO:0023052', ('36', '45'))
24039	33798262	As the YAP/TAZ pathway is activated by mutations in GNAQ/11, we examined the expression of mRNA in tumors with and without these mutations.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('GNAQ', 'Gene', '2776', (52, 56))	('mutations', 'Var', (39, 48))	('YAP/TAZ pathway', 'Pathway', (7, 22))	('activated', 'PosReg', (26, 35))	('GNAQ', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
24040	33798262	In the TCGA dataset, tumors with either a GNAQ or GNA11 mutation (n = 72) did not differ in their expression of YAP1-related genes compared with tumors without these mutations (n = 6; see Table 1).	('YAP1', 'Gene', '10413', (112, 116))	('GNAQ', 'Gene', '2776', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('GNA11', 'Gene', '2767', (50, 55))	('GNA11', 'Gene', (50, 55))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('GNAQ', 'Gene', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutation', 'Var', (56, 64))	('YAP1', 'Gene', (112, 116))	('expression', 'MPA', (98, 108))
24041	33798262	In the Leiden dataset, the four tumors that lacked a GNAQ/11 mutation had a higher YAP1 expression, but a similar TEAD4 expression, than the tumors with a GNAQ/11 mutation (n = 60, P = 0.033 and P = 0.84, respectively; see Table 2); the interpretation of this finding is hampered, however, due to low numbers of cases lacking a GNAQ/11-mutation.	('lacked', 'NegReg', (44, 50))	('mutation', 'Var', (61, 69))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('GNAQ', 'Gene', '2776', (53, 57))	('tumors', 'Disease', (32, 38))	('expression', 'MPA', (88, 98))	('GNAQ', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('GNAQ', 'Gene', '2776', (155, 159))	('tumors', 'Disease', (141, 147))	('TEAD4', 'Gene', (114, 119))	('higher', 'PosReg', (76, 82))	('GNAQ', 'Gene', (155, 159))	('GNAQ', 'Gene', '2776', (328, 332))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('GNAQ', 'Gene', (328, 332))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('YAP1', 'Gene', '10413', (83, 87))	('TEAD4', 'Gene', '7004', (114, 119))	('YAP1', 'Gene', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
24042	33798262	We then tested whether YAP1 activity relates to the genetic status of UM, such as monosomy 3 (M3)/BAP1-loss, or gain of chromosome 8q, two adverse prognostic factors.	('BAP1', 'Gene', (98, 102))	('tested', 'Reg', (8, 14))	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('monosomy', 'Var', (82, 90))	('gain', 'Var', (112, 116))	('BAP1', 'Gene', '8314', (98, 102))	('YAP1', 'Gene', '10413', (23, 27))	('YAP1', 'Gene', (23, 27))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))
24050	33798262	First, we analyzed the inhibitory effect of VP treatment on BAP1-positive UM cell lines with a mutation in GNAQ or GNA11.	('GNA11', 'Gene', '2767', (115, 120))	('VP', 'Chemical', 'MESH:D000077362', (44, 46))	('GNAQ', 'Gene', '2776', (107, 111))	('BAP1', 'Gene', '8314', (60, 64))	('UM', 'Phenotype', 'HP:0007716', (74, 76))	('GNAQ', 'Gene', (107, 111))	('GNA11', 'Gene', (115, 120))	('BAP1', 'Gene', (60, 64))	('mutation', 'Var', (95, 103))
24053	33798262	We compared the results in the UM cell lines with the effect on cell lines with a BRAF or NRAS mutation (i.e.	('NRAS', 'Gene', (90, 94))	('UM', 'Phenotype', 'HP:0007716', (31, 33))	('NRAS', 'Gene', '4893', (90, 94))	('BRAF', 'Gene', (82, 86))	('mutation', 'Var', (95, 103))
24060	33798262	We included two recently developed UM cell lines with a GNAQ/11 mutation, which lack expression of BAP1 (i.e.	('expression', 'MPA', (85, 95))	('BAP1', 'Gene', (99, 103))	('UM', 'Phenotype', 'HP:0007716', (35, 37))	('mutation', 'Var', (64, 72))	('GNAQ', 'Gene', '2776', (56, 60))	('BAP1', 'Gene', '8314', (99, 103))	('GNAQ', 'Gene', (56, 60))
24073	33798262	It can be deduced that, in order to be susceptible to VP, cell lines need a certain amount of cell growth, and a GNAQ/11 mutation may lower the threshold for VP sensitivity.	('GNAQ', 'Gene', (113, 117))	('lower', 'NegReg', (134, 139))	('VP', 'Chemical', 'MESH:D000077362', (54, 56))	('VP', 'Chemical', 'MESH:D000077362', (158, 160))	('mutation', 'Var', (121, 129))	('GNAQ', 'Gene', '2776', (113, 117))	('cell growth', 'biological_process', 'GO:0016049', ('94', '105'))	('threshold for VP sensitivity', 'MPA', (144, 172))
24086	33798262	Our experiments showed that exposure to VP decreased cell viability in BAP1-positive UM cell lines harboring mutations in GNAQ/11, as has been reported before.	('VP', 'Chemical', 'MESH:D000077362', (40, 42))	('GNAQ', 'Gene', (122, 126))	('BAP1', 'Gene', '8314', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('mutations', 'Var', (109, 118))	('cell viability', 'CPA', (53, 67))	('BAP1', 'Gene', (71, 75))	('decreased', 'NegReg', (43, 52))	('GNAQ', 'Gene', '2776', (122, 126))
24087	33798262	A mutation in GNAQ/11 was no exclusive predictor of a response to VP, however, as we report on cell lines with a GNAQ/11 mutation without a clear response (MM28 and MP46), and a cell line lacking GNAQ/11 mutations that did demonstrate decreased survival (OCM3).	('GNAQ', 'Gene', '2776', (196, 200))	('GNAQ', 'Gene', (113, 117))	('GNAQ', 'Gene', '2776', (14, 18))	('GNAQ', 'Gene', (196, 200))	('GNAQ', 'Gene', (14, 18))	('mutation', 'Var', (121, 129))	('GNAQ', 'Gene', '2776', (113, 117))	('VP', 'Chemical', 'MESH:D000077362', (66, 68))
24092	33798262	We also studied cell lines lacking a mutation in GNAQ/11.	('GNAQ', 'Gene', '2776', (49, 53))	('GNAQ', 'Gene', (49, 53))	('mutation', 'Var', (37, 45))
24093	33798262	We identified no convincing effect of VP in the two CoM cell lines with either a BRAF or NRAS mutation (CRMM1 and CRMM2), whereas the cutaneous melanoma cell line OCM3 did show a response to VP.	('NRAS', 'Gene', '4893', (89, 93))	('VP', 'Chemical', 'MESH:D000077362', (191, 193))	('BRAF', 'Gene', (81, 85))	('VP', 'Chemical', 'MESH:D000077362', (38, 40))	('NRAS', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Disease', (134, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('mutation', 'Var', (94, 102))	('CoM', 'Phenotype', 'HP:0007716', (52, 55))
24117	33798262	Even so, knockdown of YAP and TAZ caused reduced expression of PD-L1 in cutaneous melanoma cell lines, which would theoretically make these cells more vulnerable to CD8+ T cell attack.	('reduced', 'NegReg', (41, 48))	('cutaneous melanoma', 'Disease', (72, 90))	('make', 'Reg', (129, 133))	('knockdown', 'Var', (9, 18))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('expression', 'MPA', (49, 59))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('CD8', 'Gene', (165, 168))	('PD-L1', 'Gene', (63, 68))	('CD8', 'Gene', '925', (165, 168))	('PD-L1', 'Gene', '29126', (63, 68))
24125	33798262	YAP1 inhibition may be used as a cotreatment with both targeted and immunotherapy, to overcome mechanisms of resistance and escape.	('YAP1', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('YAP1', 'Gene', '10413', (0, 4))
24126	32526884	Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib.	('Patched Drug Efflux', 'MPA', (14, 33))	('vemurafenib', 'Chemical', 'MESH:D000077484', (175, 186))	('Efflux', 'biological_process', 'GO:0140352', ('27', '33'))	('Melanoma', 'Disease', (98, 106))	('BrafV600E', 'Mutation', 'rs113488022', (88, 97))	('BrafV600E', 'Var', (88, 97))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (44, 55))	('patients', 'Species', '9606', (116, 124))	('Melanoma', 'Disease', 'MESH:D008545', (107, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('Effectiveness', 'MPA', (56, 69))	('BRAFV600E', 'Var', (139, 148))	('BRAFV600E', 'Mutation', 'rs113488022', (139, 148))	('Increases', 'PosReg', (34, 43))	('Melanoma', 'Disease', (107, 115))	('Efflux', 'biological_process', 'GO:0140115', ('27', '33'))	('Melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('Melanoma', 'Disease', 'MESH:D008545', (98, 106))
24150	32526884	These discoveries suggest that the use of inhibitors of Ptch1 drug efflux activity in combination with classical chemotherapy, such as doxorubicin, could be a novel way to circumvent drug resistance, recurrence and metastasis of tumors expressing Ptch1.	('drug resistance', 'biological_process', 'GO:0009315', ('183', '198'))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('drug resistance', 'biological_process', 'GO:0042493', ('183', '198'))	('drug efflux activity', 'MPA', (62, 82))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('recurrence', 'CPA', (200, 210))	('doxorubicin', 'Chemical', 'MESH:D004317', (135, 146))	('drug resistance', 'MPA', (183, 198))	('circumvent', 'NegReg', (172, 182))	('metastasis of tumors', 'Disease', (215, 235))	('drug resistance', 'Phenotype', 'HP:0020174', (183, 198))	('Ptch1', 'Gene', (247, 252))	('efflux', 'biological_process', 'GO:0140115', ('67', '73'))	('metastasis of tumors', 'Disease', 'MESH:D009362', (215, 235))	('Ptch1', 'Gene', (56, 61))	('Ptch1', 'Gene', '5727', (247, 252))	('inhibitors', 'Var', (42, 52))	('Ptch1', 'Gene', '5727', (56, 61))	('efflux', 'biological_process', 'GO:0140352', ('67', '73'))
24151	32526884	Around 45-50% of cutaneous melanomas have mutations in the BRAF serine/threonine kinase.	('serine', 'Chemical', 'MESH:D012694', (64, 70))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (17, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (17, 36))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('cutaneous melanomas', 'Disease', (17, 36))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('mutations', 'Var', (42, 51))
24159	32526884	We did not observe a significant difference in the distribution of PTCH1 gene expression between tumors carrying or not BRAFV600 mutation for primary or metastatic samples (Figure 1A middle).	('PTCH1', 'Gene', (67, 72))	('mutation', 'Var', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRAF', 'Gene', '673', (120, 124))	('PTCH1', 'Gene', '5727', (67, 72))	('BRAF', 'Gene', (120, 124))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gene expression', 'biological_process', 'GO:0010467', ('73', '88'))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
24160	32526884	In this cohort, the Kaplan-Meier analysis for a subset of patients with metastatic disease who did not receive immunotherapy indicated that a high level of Ptch1 in patient samples significantly correlated with a lower overall survival time (Figure 1A right).	('lower', 'NegReg', (213, 218))	('Ptch1', 'Gene', '5727', (156, 161))	('metastatic disease', 'Disease', 'MESH:C538445', (72, 90))	('patient', 'Species', '9606', (58, 65))	('Ptch1', 'Gene', (156, 161))	('patient', 'Species', '9606', (165, 172))	('metastatic disease', 'Disease', (72, 90))	('high', 'Var', (142, 146))	('patients', 'Species', '9606', (58, 66))	('overall', 'MPA', (219, 226))
24164	32526884	Interestingly, the depletion of Ptch1 using specific silencing RNA in the MeWo melanoma cell line induced cell retention of doxorubicin (dxr), a fluorescent chemotherapeutic drug commonly used to treat many types of cancers, while control cells showed a strong decrease of intracellular dxr fluorescence 30 min after the removal of this drug from the medium (Figure 1C).	('Ptch1', 'Gene', '5727', (32, 37))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('silencing', 'NegReg', (53, 62))	('induced', 'Reg', (98, 105))	('cell retention', 'CPA', (106, 120))	('intracellular', 'cellular_component', 'GO:0005622', ('273', '286'))	('MeWo melanoma', 'Disease', 'MESH:D008545', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('intracellular dxr fluorescence', 'MPA', (273, 303))	('dxr', 'Chemical', 'MESH:D004317', (137, 140))	('depletion', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('doxorubicin', 'MPA', (124, 135))	('retention', 'biological_process', 'GO:0051235', ('111', '120'))	('C', 'Chemical', 'MESH:D002244', (367, 368))	('dxr', 'Chemical', 'MESH:D004317', (287, 290))	('MeWo melanoma', 'Disease', (74, 87))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('Ptch1', 'Gene', (32, 37))	('decrease', 'NegReg', (261, 269))
24173	32526884	Melanoma cells from the MeWo cell line and the BRAFV600E mutant cell line A375 were treated with increasing concentrations of dxr, with or without natural or synthetic PAH for either 48 or 24 h, before assessment of cell viability.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('dxr', 'Chemical', 'MESH:D004317', (126, 129))	('Melanoma', 'Disease', (0, 8))	('PAH', 'Chemical', '-', (168, 171))	('BRAFV600E', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('A375', 'CellLine', 'CVCL:0132', (74, 78))	('PAH', 'molecular_function', 'GO:0033972', ('168', '171'))
24175	32526884	Interestingly, our results showed that sPAH also strongly increased drx cytotoxicity in MeWo cells rendered resistant to dxr (MeWo-DxrR) (Figure 2C, Table 1).	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('increased', 'PosReg', (58, 67))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('dxr', 'Chemical', 'MESH:D004317', (121, 124))	('cytotoxicity', 'Disease', (72, 84))	('sPAH', 'Chemical', '-', (39, 43))	('sPAH', 'Var', (39, 43))
24194	32526884	These results show that the hydroquinone moiety is essential for sPAH activity as a Ptch1 drug efflux inhibitor, and that the loss of the double bond slightly reduces its activity.	('double', 'Protein', (138, 144))	('Ptch1', 'Gene', '5727', (84, 89))	('hydroquinone', 'Chemical', 'MESH:C031927', (28, 40))	('Ptch1', 'Gene', (84, 89))	('sPAH', 'Chemical', '-', (65, 69))	('efflux', 'biological_process', 'GO:0140115', ('95', '101'))	('reduces', 'NegReg', (159, 166))	('efflux', 'biological_process', 'GO:0140352', ('95', '101'))	('activity', 'MPA', (171, 179))	('loss', 'Var', (126, 130))
24206	32526884	Interestingly, the IC50 of cisplatin was significantly decreased in the presence of sPAH in both MeWo and A375 cells, indicating that sPAH also increases the cytotoxicity of cisplatin against melanoma cells (Figure S2).	('sPAH', 'Chemical', '-', (134, 138))	('increases', 'PosReg', (144, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('sPAH', 'Var', (134, 138))	('A375', 'CellLine', 'CVCL:0132', (106, 110))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('decreased', 'NegReg', (55, 64))	('cytotoxicity', 'Disease', (158, 170))	('melanoma', 'Disease', (192, 200))	('IC50', 'MPA', (19, 23))	('sPAH', 'Chemical', '-', (84, 88))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))
24207	32526884	Vemurafenib is a targeted chemotherapy agent which interrupts the BRAF/MEK step in the BRAF/MEK/ERK pathway when BRAF has the V600E mutation.	('V600E', 'Var', (126, 131))	('BRAF', 'Gene', '673', (113, 117))	('MEK', 'Gene', (92, 95))	('BRAF', 'Gene', (66, 70))	('MEK', 'Gene', '5609', (92, 95))	('ERK', 'molecular_function', 'GO:0004707', ('96', '99'))	('BRAF', 'Gene', (113, 117))	('MEK', 'Gene', (71, 74))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('ERK', 'Gene', '5594', (96, 99))	('BRAF', 'Gene', '673', (66, 70))	('interrupts', 'NegReg', (51, 61))	('BRAF', 'Gene', (87, 91))	('MEK', 'Gene', '5609', (71, 74))	('ERK', 'Gene', (96, 99))	('BRAF', 'Gene', '673', (87, 91))
24211	32526884	Remarkably, sPAH also increased the effectiveness of vemurafenib against WM9 cells rendered resistant to vemurafenib (WM9R) with a decrease by a factor of ten of the IC50 of vemurafenib in the presence of sPAH 20 microM (Figure 5A).	('vemurafenib', 'Chemical', 'MESH:D000077484', (174, 185))	('effectiveness', 'MPA', (36, 49))	('decrease', 'NegReg', (131, 139))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('IC50', 'MPA', (166, 170))	('sPAH', 'Chemical', '-', (205, 209))	('increased', 'PosReg', (22, 31))	('sPAH', 'Chemical', '-', (12, 16))	('vemurafenib', 'Chemical', 'MESH:D000077484', (53, 64))	('sPAH', 'Var', (12, 16))	('vemurafenib', 'Chemical', 'MESH:D000077484', (105, 116))
24219	32526884	Using microscale thermophoresis (MST), we showed that sPAH binds to membranes prepared from yeast expressing human Ptch1 with a Kd around 7 microM, while sPAH does not bind to membranes prepared from yeast expressing another human membrane protein, Smoothened (Figure 6A).	('Ptch1', 'Gene', (115, 120))	('yeast', 'Species', '4932', (200, 205))	('sPAH', 'Chemical', '-', (154, 158))	('binds', 'Interaction', (59, 64))	('yeast', 'Species', '4932', (92, 97))	('human', 'Species', '9606', (109, 114))	('membrane', 'cellular_component', 'GO:0016020', ('231', '239'))	('protein', 'cellular_component', 'GO:0003675', ('240', '247'))	('human', 'Species', '9606', (225, 230))	('sPAH', 'Chemical', '-', (54, 58))	('human', 'Var', (109, 114))	('Ptch1', 'Gene', '5727', (115, 120))
24224	32526884	Figure 6C reports the mean percentage of dxr accumulated in cells in the presence of vemurafenib relative to dxr accumulated in the absence of vemurafenib.	('vemurafenib', 'Chemical', 'MESH:D000077484', (143, 154))	('dxr', 'Chemical', 'MESH:D004317', (41, 44))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('vemurafenib', 'Var', (85, 96))	('dxr accumulated', 'MPA', (41, 56))	('dxr', 'Chemical', 'MESH:D004317', (109, 112))	('vemurafenib', 'Chemical', 'MESH:D000077484', (85, 96))
24229	32526884	Among the amino acids surrounding the cholesterol in the central cavity, five are conserved in proteins from Patched family, of which two have side chains directed toward the cholesterol (Leu427 and Ala497; Figure S3).	('cholesterol', 'Chemical', 'MESH:D002784', (38, 49))	('cholesterol', 'Chemical', 'MESH:D002784', (175, 186))	('Ala497', 'Chemical', '-', (199, 205))	('Ala497', 'Var', (199, 205))	('Leu427', 'Var', (188, 194))	('Leu427', 'Chemical', '-', (188, 194))
24230	32526884	We also observed that single nucleotide variations in seven of the residues surrounding the cholesterol are responsible for diseases according to the BioMuta database (Table 3).	('cholesterol', 'Chemical', 'MESH:D002784', (92, 103))	('diseases', 'Disease', (124, 132))	('responsible', 'Reg', (108, 119))	('single nucleotide variations', 'Var', (22, 50))
24231	32526884	Being built between loops, this cavity is flexible and should be able to accommodate many types of ligands thanks to a large number of aromatic amino acids with polar groups (tyrosines and tryptophans) and some polar residues among the hydrophobic ones.	('aromatic', 'Var', (135, 143))	('tyrosines', 'Chemical', 'MESH:D014443', (175, 184))	('polar residues', 'Var', (211, 225))	('aromatic amino acids', 'Chemical', 'MESH:D024322', (135, 155))	('tryptophans', 'Chemical', 'MESH:D014364', (189, 200))
24233	32526884	We observed at least one hydrogen bond with nearby amino acids for dxr, vemurafenib, and PAH (Leu775 or Asp776), both with the oxygen of the peptide bond.	('Asp776', 'Var', (104, 110))	('Leu775', 'Chemical', '-', (94, 100))	('hydrogen', 'Interaction', (25, 33))	('PAH', 'molecular_function', 'GO:0033972', ('89', '92'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (72, 83))	('oxygen', 'Chemical', 'MESH:D010100', (127, 133))	('PAH', 'Chemical', '-', (89, 92))	('hydrogen', 'Chemical', 'MESH:D006859', (25, 33))	('dxr', 'Chemical', 'MESH:D004317', (67, 70))	('Leu775', 'Var', (94, 100))	('Asp776', 'Chemical', '-', (104, 110))
24234	32526884	Interestingly, when Asp776 is mutated to glycine, the probability of a damaging phenotype is high (with a score of 0.87 according to the BioMuta database) supporting the importance of this amino acid for Ptch1 function.	('Asp776 is mutated to glycine', 'Mutation', 'p.D776G', (20, 48))	('Ptch1', 'Gene', '5727', (204, 209))	('Asp776', 'Var', (20, 26))	('Ptch1', 'Gene', (204, 209))
24235	32526884	Another amino acid predicted to interact with dxr, vemurafenib and PAH is Trp129, either by pi-stacking or hydrophobic interaction.	('PAH', 'molecular_function', 'GO:0033972', ('67', '70'))	('pi-stacking', 'Var', (92, 103))	('Trp129', 'Chemical', '-', (74, 80))	('interact', 'Interaction', (32, 40))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('Trp129', 'Gene', (74, 80))	('dxr', 'Chemical', 'MESH:D004317', (46, 49))	('PAH', 'Chemical', '-', (67, 70))
24246	32526884	A formulation of 2.44 mg of encapsulated sPAH/mL (7 mM) was tested on melanoma cells and results show that sPAH encapsulated in i-Particles (iP-sPAH) was able to increase the cytotoxicity of vemurafenib against A375 cells in a manner that was comparable to the free sPAH (Figure 8A).	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('increase', 'PosReg', (162, 170))	('sPAH', 'Chemical', '-', (41, 45))	('sPAH', 'Chemical', '-', (144, 148))	('sPAH', 'Chemical', '-', (107, 111))	('cytotoxicity', 'Disease', (175, 187))	('sPAH', 'Chemical', '-', (266, 270))	('sPAH', 'Var', (107, 111))	('vemurafenib', 'Chemical', 'MESH:D000077484', (191, 202))	('A375', 'CellLine', 'CVCL:0132', (211, 215))	('cytotoxicity', 'Disease', 'MESH:D064420', (175, 187))	('iP-sPAH', 'Chemical', '-', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
24258	32526884	Moreover, quantification of the vemurafenib contained within the tumors showed that extracts from all the tumors treated with the combination iP-sPAH + vemurafenib exhibited a vemurafenib peak area that was greater than 106 units, corresponding to approximately 100 nM, while extracts from two of seven tumors treated with vemurafenib alone showed a vemurafenib peak area of 2.105 to 4.105 units corresponding to the background signal (Figure 8E).	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (176, 187))	('iP-sPAH', 'Var', (142, 149))	('vemurafenib', 'Chemical', 'MESH:D000077484', (32, 43))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('vemurafenib', 'Chemical', 'MESH:D000077484', (152, 163))	('iP-sPAH', 'Chemical', '-', (142, 149))	('vemurafenib', 'Chemical', 'MESH:D000077484', (350, 361))	('vemurafenib', 'MPA', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (323, 334))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
24260	32526884	Interestingly, this analysis revealed that tumors treated with iP-sPAH contained significantly more cholesterol than the other tumors (Figure 8F).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('cholesterol', 'MPA', (100, 111))	('more', 'PosReg', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('iP-sPAH', 'Var', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cholesterol', 'Chemical', 'MESH:D002784', (100, 111))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('iP-sPAH', 'Chemical', '-', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
24262	32526884	Vemurafenib is known to selectively block the RAF/MEK/ERK pathway in BRAF mutant cells.	('MEK', 'Gene', '5609', (50, 53))	('ERK', 'Gene', '5594', (54, 57))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('RAF', 'Gene', (70, 73))	('RAF', 'Gene', (46, 49))	('ERK', 'Gene', (54, 57))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('RAF', 'Gene', '673', (70, 73))	('RAF', 'Gene', '673', (46, 49))	('BRAF', 'Gene', '673', (69, 73))	('mutant', 'Var', (74, 80))	('MEK', 'Gene', (50, 53))	('BRAF', 'Gene', (69, 73))	('block', 'NegReg', (36, 41))
24272	32526884	Nearly half of patients with metastatic melanomas harbor a valine-glutamine substitution in codon 600 of the serine/threonine kinase BRAF.	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('melanomas', 'Disease', (40, 49))	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', '673', (133, 137))	('valine-glutamine', 'Var', (59, 75))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('BRAF', 'Gene', (133, 137))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('valine', 'Chemical', 'MESH:D014633', (59, 65))	('glutamine', 'Chemical', 'MESH:D005973', (66, 75))
24277	32526884	Both intrinsic and acquired resistances can be driven by genetic and epigenetic alterations that drive gene expression changes and intratumor heterogeneity which, in turn, enable tumor regrowth and disease relapse.	('epigenetic alterations', 'Var', (69, 91))	('disease relapse', 'CPA', (198, 213))	('changes', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('gene expression', 'MPA', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('tumor', 'Disease', (136, 141))	('enable', 'PosReg', (172, 178))	('tumor', 'Disease', (179, 184))
24297	32526884	We also observed that sPAH was able to increase the cytotoxicity of cisplatin, another chemotherapeutic agent that we previously identified as a substrate of Ptch1, against melanoma cells in vitro (Figure S2).	('sPAH', 'Var', (22, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (52, 64))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('increase', 'PosReg', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('Ptch1', 'Gene', '5727', (158, 163))	('Ptch1', 'Gene', (158, 163))	('cytotoxicity', 'Disease', (52, 64))	('sPAH', 'Chemical', '-', (22, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
24298	32526884	We then wanted to know if sPAH could also enhance the efficiency of targeted chemotherapy such as vemurafenib against BRAFV600E melanoma cells, and found that sPAH strongly increased the cytotoxicity of vemurafenib, even in resistant BRAFV600E melanoma cells (Figure 5).	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('cytotoxicity', 'Disease', 'MESH:D064420', (187, 199))	('vemurafenib', 'Chemical', 'MESH:D000077484', (203, 214))	('sPAH', 'Chemical', '-', (159, 163))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('BRAFV600E', 'Mutation', 'rs113488022', (234, 243))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('increased', 'PosReg', (173, 182))	('sPAH', 'Chemical', '-', (26, 30))	('sPAH', 'Var', (159, 163))	('cytotoxicity', 'Disease', (187, 199))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('vemurafenib', 'Chemical', 'MESH:D000077484', (98, 109))	('melanoma', 'Disease', (244, 252))	('melanoma', 'Disease', (128, 136))
24302	32526884	Altogether, our in vitro results suggest that sPAH increases doxorubicin and vemurafenib efficacy by binding to the same pocket as these chemotherapeutic agents on Ptch1 and inhibiting their efflux by Ptch1.	('Ptch1', 'Gene', (201, 206))	('inhibiting', 'NegReg', (174, 184))	('Ptch1', 'Gene', '5727', (201, 206))	('doxorubicin', 'Chemical', 'MESH:D004317', (61, 72))	('increases', 'PosReg', (51, 60))	('efflux', 'biological_process', 'GO:0140115', ('191', '197'))	('sPAH', 'Chemical', '-', (46, 50))	('efflux', 'biological_process', 'GO:0140352', ('191', '197'))	('efficacy', 'MPA', (89, 97))	('doxorubicin', 'MPA', (61, 72))	('binding', 'Interaction', (101, 108))	('sPAH', 'Var', (46, 50))	('Ptch1', 'Gene', (164, 169))	('Ptch1', 'Gene', '5727', (164, 169))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (77, 88))	('efflux', 'MPA', (191, 197))
24303	32526884	The fact that sPAH also inhibited cholesterol efflux strengthens this interpretation.	('sPAH', 'Chemical', '-', (14, 18))	('cholesterol', 'Chemical', 'MESH:D002784', (34, 45))	('cholesterol efflux', 'MPA', (34, 52))	('sPAH', 'Var', (14, 18))	('inhibited', 'NegReg', (24, 33))	('cholesterol efflux', 'biological_process', 'GO:0033344', ('34', '52'))
24310	32526884	We injected immune-compromised mice with BRAFV600E A375 melanoma, which is a cell line typically used as a model of xenograft melanoma for testing novel anti-melanoma compounds.	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('A375', 'CellLine', 'CVCL:0132', (51, 55))	('melanoma', 'Disease', (56, 64))	('BRAFV600E', 'Var', (41, 50))	('mice', 'Species', '10090', (31, 35))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
24311	32526884	Experiments performed on these mice showed that the addition of iP-sPAH to the vemurafenib treatment inhibited tumor growth more significantly than vemurafenib alone (Figure 8B).	('iP-sPAH', 'Var', (64, 71))	('vemurafenib', 'Gene', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('iP-sPAH', 'Chemical', '-', (64, 71))	('vemurafenib', 'Chemical', 'MESH:D000077484', (79, 90))	('tumor', 'Disease', (111, 116))	('mice', 'Species', '10090', (31, 35))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('inhibited', 'NegReg', (101, 110))
24315	32526884	Analyses of tumor extracts revealed that the addition of iP-sPAH to vemurafenib treatment more significantly inhibited the phosphorylation of ERK1/2 than vemurafenib alone, indicating an increase in the effectiveness of vemurafenib.	('vemurafenib', 'Chemical', 'MESH:D000077484', (154, 165))	('iP-sPAH', 'Var', (57, 64))	('phosphorylation', 'MPA', (123, 138))	('increase', 'PosReg', (187, 195))	('vemurafenib', 'Chemical', 'MESH:D000077484', (220, 231))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('ERK1/2', 'Gene', (142, 148))	('inhibited', 'NegReg', (109, 118))	('iP-sPAH', 'Chemical', '-', (57, 64))	('ERK1/2', 'Gene', '5595;5594', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('vemurafenib', 'Chemical', 'MESH:D000077484', (68, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))	('ERK1', 'molecular_function', 'GO:0004707', ('142', '146'))
24323	32526884	We therefore quantified the amount of cholesterol in tumor extracts and, indeed, found that tumors treated with iP-sPAH contained significantly more cholesterol than other tumors (Figure 8F), indicating that sPAH inhibited cholesterol efflux mediated by Ptch1 in this system.	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (92, 97))	('cholesterol efflux', 'biological_process', 'GO:0033344', ('223', '241'))	('sPAH', 'Chemical', '-', (115, 119))	('cholesterol', 'Chemical', 'MESH:D002784', (223, 234))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('iP-sPAH', 'Var', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('iP-sPAH', 'Chemical', '-', (112, 119))	('cholesterol', 'Chemical', 'MESH:D002784', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cholesterol efflux', 'MPA', (223, 241))	('more', 'PosReg', (144, 148))	('sPAH', 'Chemical', '-', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cholesterol', 'Chemical', 'MESH:D002784', (149, 160))	('tumors', 'Disease', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('cholesterol', 'MPA', (149, 160))	('Ptch1', 'Gene', (254, 259))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('inhibited', 'NegReg', (213, 222))	('Ptch1', 'Gene', '5727', (254, 259))	('tumor', 'Disease', (53, 58))
24326	32526884	Indeed, in healthy cells, accumulation of free cholesterol has been shown to induce many mechanisms of cellular toxicity, including disrupted function of the integral membrane proteins and signaling proteins that reside in membrane domains, intracellular cholesterol crystallization, oxysterol formation, and the triggering of apoptotic signaling pathways.	('toxicity', 'Disease', (112, 120))	('cholesterol', 'Chemical', 'MESH:D002784', (47, 58))	('intracellular', 'cellular_component', 'GO:0005622', ('241', '254'))	('integral membrane proteins', 'Protein', (158, 184))	('signaling', 'biological_process', 'GO:0023052', ('337', '346'))	('oxysterol', 'Chemical', 'MESH:D000072376', (284, 293))	('free cholesterol', 'Var', (42, 58))	('function', 'MPA', (142, 150))	('cholesterol', 'Chemical', 'MESH:D002784', (255, 266))	('membrane', 'cellular_component', 'GO:0016020', ('167', '175'))	('formation', 'biological_process', 'GO:0009058', ('294', '303'))	('apoptotic signaling pathways', 'Pathway', (327, 355))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('accumulation', 'Var', (26, 38))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('membrane', 'cellular_component', 'GO:0016020', ('223', '231'))
24376	32526884	MeWo cells were transfected with 400 pmol of human Ptch1 Silencer  Select pre-designed siRNA (Ambion, #4392420, s11441 (sense: 5'GCACUUACUUUACGACCUAtt3'; as: 5'UAGGUCGUAAAGUAAGUGCtg3') or control (medium GC) siRNA oligos (Invitrogen) using Lipofectamine RNAiMAX reagent (Invitrogen) following the manufacturer's protocol, then seeded in 24-well plates and incubated at 37  C and 5% CO2 for 16 h before Western blotting and dxr efflux measurements.	('C', 'Chemical', 'MESH:D002244', (132, 133))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('efflux', 'biological_process', 'GO:0140352', ('427', '433'))	('CO2', 'Chemical', 'MESH:D002245', (382, 385))	('pre', 'molecular_function', 'GO:0003904', ('74', '77'))	('C', 'Chemical', 'MESH:D002244', (178, 179))	('C', 'Chemical', 'MESH:D002244', (145, 146))	('dxr', 'Chemical', 'MESH:D004317', (423, 426))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('Ptch1', 'Gene', (51, 56))	('C', 'Chemical', 'MESH:D002244', (382, 383))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('Ptch1', 'Gene', '5727', (51, 56))	('C', 'Chemical', 'MESH:D002244', (373, 374))	('s11441', 'Var', (112, 118))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('human', 'Species', '9606', (45, 50))	('C', 'Chemical', 'MESH:D002244', (205, 206))	('efflux', 'biological_process', 'GO:0140115', ('427', '433'))
24398	32526884	Titration of sPAH results in a gradual change in MST signal, which is plotted as Fnorm against the sPAH concentration to yield a dose-response curve, which has been fitted to derive binding constants (Kd).	('sPAH', 'Gene', (13, 17))	('MST signal', 'MPA', (49, 59))	('Titration', 'Var', (0, 9))	('binding', 'molecular_function', 'GO:0005488', ('182', '189'))	('change', 'Reg', (39, 45))	('sPAH', 'Chemical', '-', (99, 103))	('sPAH', 'Chemical', '-', (13, 17))
24463	32526884	We conclude that sPAH is a very promising lead for vemurafenib resistant BRAFV600E melanoma where Ptch1 is overexpressed.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))	('Ptch1', 'Gene', '5727', (98, 103))	('Ptch1', 'Gene', (98, 103))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('sPAH', 'Chemical', '-', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
24468	32526884	Dxr-IC50 values calculated in the presence of sPAH or sPAH analogue 13 are presented, Figure S2: sPAH increases cisplatin cytotoxicity against MeWo and A375 melanoma cell lines.	('cytotoxicity', 'Disease', (122, 134))	('sPAH', 'Chemical', '-', (97, 101))	('sPAH', 'Var', (97, 101))	('sPAH', 'Chemical', '-', (46, 50))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('melanoma', 'Disease', (157, 165))	('A375', 'CellLine', 'CVCL:0132', (152, 156))	('sPAH', 'Chemical', '-', (54, 58))	('cytotoxicity', 'Disease', 'MESH:D064420', (122, 134))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('increases', 'PosReg', (102, 111))
24497	27403562	Germline MC1R status influences somatic mutation burden in melanoma The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene.	('MC1R', 'Gene', '4157', (220, 224))	('variants', 'Var', (167, 175))	('melanocortin 1 receptor', 'Gene', '4157', (195, 218))	('MC1R', 'Gene', (220, 224))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('MC1R', 'Gene', '4157', (9, 13))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('MC1R', 'Gene', (9, 13))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanocortin 1 receptor', 'Gene', (195, 218))
24500	27403562	We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('non-C>T mutation', 'Var', (51, 67))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))
24502	27403562	Here, the authors investigate melanoma samples from patients with and without these variants and find that their presence is predictive of a higher overall mutation prevalence.	('mutation prevalence', 'MPA', (156, 175))	('higher', 'PosReg', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('variants', 'Var', (84, 92))	('melanoma', 'Disease', (30, 38))	('patients', 'Species', '9606', (52, 60))
24507	27403562	Population sequencing studies have revealed a number of null or hypomorphic MC1R alleles, which are collectively referred to as R alleles and are strongly associated with the red hair and light skin phenotype.	('light skin phenotype', 'Disease', (188, 208))	('associated with', 'Reg', (155, 170))	('MC1R', 'Gene', (76, 80))	('light skin', 'Phenotype', 'HP:0001010', (188, 198))	('red hair', 'Disease', (175, 183))	('red hair', 'Phenotype', 'HP:0002297', (175, 183))	('red hair', 'Disease', 'MESH:C567091', (175, 183))	('alleles', 'Var', (81, 88))
24510	27403562	Collectively these factors link MC1R variants to increased melanoma risk.	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('variants', 'Var', (37, 45))	('melanoma', 'Disease', (59, 67))	('MC1R', 'Gene', (32, 36))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
24514	27403562	Mutations found in melanomas are predominantly C>T transitions due to the production of cyclobutane pyrimidine dimers (CPDs) in response to solar UV damage, but other mutational classes such as C>A transversions have also been observed.	('UV damage', 'Disease', 'MESH:C563466', (146, 155))	('C>T', 'Disease', (47, 50))	('ran', 'Gene', (199, 202))	('UV damage', 'Disease', (146, 155))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('ran', 'Gene', '5901', (199, 202))	('cyclobutane pyrimidine dimers', 'MPA', (88, 117))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('ran', 'Gene', (52, 55))	('Mutations', 'Var', (0, 9))	('CPD', 'Disease', (119, 122))	('cyclobutane pyrimidine', 'Chemical', '-', (88, 110))	('CPD', 'Disease', 'MESH:C565865', (119, 122))	('ran', 'Gene', '5901', (52, 55))	('melanomas', 'Disease', (19, 28))
24515	27403562	Indeed, hotspot mutations in key driver genes, such as BRAF and KIT, are almost exclusively acquired as non-C>T mutations.	('mutations', 'Var', (16, 25))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('KIT', 'Gene', (64, 67))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))
24517	27403562	We analysed somatic single-nucleotide variants (SNVs) from two independent melanoma cohorts: melanoma samples from The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) collection, and a data set from the Yale Melanoma Genome Project.	('Melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (119, 138))	('Melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (151, 169))	('Cancer Genome Atlas', 'Disease', (119, 138))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('single-nucleotide variants', 'Var', (20, 46))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Melanoma', 'Disease', 'MESH:D008545', (218, 226))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 169))	('melanoma', 'Disease', (75, 83))	('skin cutaneous melanoma', 'Disease', (146, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))
24522	27403562	Since MC1R disruptive variants segregate on separate haplotypes, we assumed persons with two R alleles to be homozygotes or compound heterozygotes.	('persons', 'Species', '9606', (76, 83))	('variants', 'Var', (22, 30))	('MC1R', 'Gene', (6, 10))
24528	27403562	Eight mutational signatures explained 97.5% of mutations in the combined TCGA and Yale melanoma data set (Supplementary Figs 6 and 7).	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('mutations', 'Var', (47, 56))	('TCGA', 'Gene', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
24529	27403562	The sample group with one or two MC1R R alleles had a significantly lower prevalence of the signature linked to age-associated 5-methylcytosine deamination, a result presumably explained in part by their younger age at diagnosis (57.6 versus 62.2 years on average; Supplementary Table 5).	('5-methylcytosine', 'Chemical', 'MESH:D044503', (127, 143))	('alleles', 'Var', (40, 47))	('MC1R R', 'Gene', (33, 39))	('lower', 'NegReg', (68, 73))
24530	27403562	We next considered whether the increased number of mutations observed in tumours from MC1R variant carriers could be due to differential DNA repair ability in primary human melanocytes (HPMs).	('tumours', 'Disease', (73, 80))	('variant', 'Var', (91, 98))	('DNA repair', 'biological_process', 'GO:0006281', ('137', '147'))	('MC1R', 'Gene', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('DNA', 'cellular_component', 'GO:0005574', ('137', '140'))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('human', 'Species', '9606', (167, 172))	('tumours', 'Disease', 'MESH:D009369', (73, 80))
24532	27403562	Irradiation of cell lines with escalating doses of UV light (302 nm) resulted in significantly reduced survival of MC1R knockdown cells compared with cells transfected with a scrambled shRNA control (Fig.	('ran', 'Gene', (157, 160))	('ran', 'Gene', '5901', (157, 160))	('knockdown', 'Var', (120, 129))	('survival', 'CPA', (103, 111))	('reduced', 'NegReg', (95, 102))	('MC1R', 'Gene', (115, 119))
24536	27403562	Most mutations found in melanoma genomes are likely to be passengers, and are thus reflective of the UV exposure and other mutagenic processes operative over a patient's lifetime.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('mutations', 'Var', (5, 14))	('patient', 'Species', '9606', (160, 167))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))
24537	27403562	Our regression analyses suggest that the estimated increase in expected SNV count associated with the presence of an MC1R R allele for the C>T mutation class is comparable to the estimated increase associated with an additional 21 years of age in the combined data set, with similar estimates across the other mutation classes (range 18-29 years; Table 1).	('increase', 'PosReg', (51, 59))	('ran', 'Gene', (328, 331))	('ran', 'Gene', '5901', (328, 331))	('SNV count', 'MPA', (72, 81))	('presence', 'Var', (102, 110))	('MC1R R', 'Gene', (117, 123))
24540	27403562	Our study finds that melanomas from individuals carrying MC1R R variants associated with red hair and freckling have a significantly higher somatic mutational burden than melanomas from individuals with no MC1R R variants.	('red hair', 'Disease', 'MESH:C567091', (89, 97))	('freckling', 'Phenotype', 'HP:0001480', (102, 111))	('MC1R R', 'Gene', (57, 63))	('melanomas', 'Disease', (171, 180))	('somatic mutational burden', 'MPA', (140, 165))	('higher', 'PosReg', (133, 139))	('melanomas', 'Disease', (21, 30))	('associated', 'Reg', (73, 83))	('freckling', 'Disease', (102, 111))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('red hair', 'Disease', (89, 97))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('variants', 'Var', (64, 72))	('red hair', 'Phenotype', 'HP:0002297', (89, 97))
24541	27403562	This might reflect a form of 'collateral damage' resulting from a decreased ability of cells in patients with R alleles to protect themselves from UV damage, or indicate that other mutational processes are operative in melanocytes from these patients.	('UV damage', 'Disease', (147, 156))	('decreased', 'NegReg', (66, 75))	('protect', 'MPA', (123, 130))	('patients', 'Species', '9606', (96, 104))	('R alleles', 'Var', (110, 119))	('UV damage', 'Disease', 'MESH:C563466', (147, 156))	("'collateral damage'", 'Disease', (29, 48))	('patients', 'Species', '9606', (242, 250))
24548	27403562	While CPDs and 6-4PP are primarily associated with C>T and CC>TT mutations, they have also been associated with non-C>T mutations, and thus may contribute to the elevated levels of these mutations observed in R allele carriers.	('6-4PP', 'Chemical', '-', (15, 20))	('associated', 'Reg', (35, 45))	('C>T', 'Var', (51, 54))	('CC>TT', 'Gene', (59, 64))	('CPD', 'Disease', (6, 9))	('CPD', 'Disease', 'MESH:C565865', (6, 9))	('mutations', 'Var', (65, 74))
24550	27403562	Thus, the enrichment of the non-C>T signatures we observe are likely to be the result of multiple mutagenic processes such as lipid peroxidation and ROS activity, together with the effects of ultraviolet photoproducts such as 6-4PP.	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('lipid', 'MPA', (126, 131))	('ROS', 'Chemical', '-', (149, 152))	('6-4PP', 'Chemical', '-', (226, 231))	('ROS', 'Enzyme', (149, 152))	('non-C>T signatures', 'Var', (28, 46))	('activity', 'MPA', (153, 161))
24551	27403562	In summary, we find a role for germline MC1R variants in influencing the somatic mutational landscape of melanoma.	('somatic mutational landscape', 'MPA', (73, 101))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('variants', 'Var', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('influencing', 'Reg', (57, 68))	('MC1R', 'Gene', (40, 44))
24558	27403562	To identify the precise variants carried by each individual, for each normal/germline BAM, we called variants in the MC1R region with samtools mpileup -Dsu -C50 -m2 -F0.0005 -d1000 and bcftools view -p 0.99 -vcgN, applying the standard set of vcf-annotate filters, and applying the Ensembl Variant Effect Predictor to the canonical MC1R transcript (ENST00000555147) including SIFT and PolyPhen scores.	('SIFT', 'Disease', (376, 380))	('ran', 'Gene', (338, 341))	('ran', 'Gene', '5901', (338, 341))	('variants', 'Var', (101, 109))	('SIFT', 'Disease', 'None', (376, 380))
24559	27403562	For each normal BAM, we extracted MC1R polymorphisms that passed all filters, including the nine canonical MC1R missense polymorphisms, nonsense or frameshift mutations and variants predicted to be deleterious or damaging by SIFT or PolyPhen (details below).	('missense polymorphisms', 'Var', (112, 134))	('frameshift mutations', 'Var', (148, 168))	('SIFT', 'Disease', (225, 229))	('nonsense', 'Var', (136, 144))	('MC1R', 'Gene', (107, 111))	('SIFT', 'Disease', 'None', (225, 229))	('variants', 'Var', (173, 181))
24561	27403562	Of note, a recent report quantified membrane expression levels and cAMP induction by the rare MC1R alleles p.Gly89Arg, p.Thr95Met, p.Asp121Glu and p.Arg213Trp, found in patients from the TCGA cohort, as well as p.Ser83Leu, in the same position as a variant found in a patient from the Yale cohort (p.Ser83Pro).	('p.Asp121Glu', 'Var', (131, 142))	('p.Thr95Met', 'Var', (119, 129))	('p.Thr95Met', 'Mutation', 'rs34158934', (119, 129))	('cAMP', 'Chemical', '-', (67, 71))	('membrane', 'cellular_component', 'GO:0016020', ('36', '44'))	('cAMP induction', 'MPA', (67, 81))	('MC1R', 'Gene', (94, 98))	('p.Arg213Trp', 'Mutation', 'rs200000734', (147, 158))	('p.Ser83Leu', 'Mutation', 'rs777024553', (211, 221))	('ran', 'Gene', (40, 43))	('ran', 'Gene', '5901', (40, 43))	('p.Arg213Trp', 'Var', (147, 158))	('p.Gly89Arg', 'Mutation', 'rs34540312', (107, 117))	('Ser', 'cellular_component', 'GO:0005790', ('213', '216'))	('patient', 'Species', '9606', (268, 275))	('p.Gly89Arg', 'Var', (107, 117))	('patients', 'Species', '9606', (169, 177))	('p.Ser83Pro', 'Mutation', 'rs34474212', (298, 308))	('p.Asp121Glu', 'Mutation', 'rs200616835', (131, 142))	('patient', 'Species', '9606', (169, 176))	('Ser', 'cellular_component', 'GO:0005790', ('300', '303'))
24574	27403562	CPD and 6-4PP ELISA were performed by using anti-CPD and anti-6-4PP antibodies, the purified anti-mouse IgG mAb was diluted to 2 mug ml-1 in PBS and added into an enhanced protein-binding ELISA plate (for example, Falcon Labware plate).	('CPD', 'Disease', 'MESH:C565865', (49, 52))	('mug', 'molecular_function', 'GO:0043739', ('129', '132'))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('protein-binding', 'molecular_function', 'GO:0005515', ('172', '187'))	('6-4PP', 'Chemical', '-', (62, 67))	('CPD', 'Disease', (49, 52))	('mouse', 'Species', '10090', (98, 103))	('CPD', 'Disease', (0, 3))	('anti-6-4PP', 'Var', (57, 67))	('CPD', 'Disease', 'MESH:C565865', (0, 3))	('6-4PP', 'Chemical', '-', (8, 13))
24581	26825879	GNA11 Mutation in a Patient With Cutaneous Origin Melanoma The rapid advances in the molecular biology and genetics have improved the understanding of molecular pathogenesis of v-Raf murine sarcoma viral oncogene homolog B (BRAF), feline sarcoma viral oncogene v-kit (KIT), and neuroblastoma v-Ras oncogene homolog (NRAS) mutant melanomas with the subsequent development of targeted therapeutic agents.	('v-kit', 'Gene', '16590', (261, 266))	('Mutation', 'Var', (6, 14))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (177, 222))	('Cutaneous Origin Melanoma', 'Disease', (33, 58))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('v-kit', 'Gene', (261, 266))	('melanomas', 'Disease', 'MESH:D008545', (329, 338))	('Melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('Cutaneous Origin Melanoma', 'Disease', 'MESH:C562393', (33, 58))	('neuroblastoma', 'Disease', (278, 291))	('KIT', 'molecular_function', 'GO:0005020', ('268', '271'))	('neuroblastoma', 'Phenotype', 'HP:0003006', (278, 291))	('melanomas', 'Disease', (329, 338))	('pathogenesis', 'biological_process', 'GO:0009405', ('161', '173'))	('GNA11', 'Gene', '2767', (0, 5))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (177, 222))	('neuroblastoma', 'Disease', 'MESH:D009447', (278, 291))	('sarcoma', 'Phenotype', 'HP:0100242', (190, 197))	('Patient', 'Species', '9606', (20, 27))	('sarcoma viral', 'Disease', 'MESH:D001102', (190, 203))	('sarcoma viral', 'Disease', 'MESH:D001102', (238, 251))	('melanomas', 'Phenotype', 'HP:0002861', (329, 338))	('mutant', 'Var', (322, 328))	('sarcoma viral', 'Disease', (238, 251))	('GNA11', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (329, 337))
24582	26825879	However, only limited data are available for melanoma harboring other somatic than BRAF, KIT, and NRAS mutations.	('mutations', 'Var', (103, 112))	('NRAS', 'Gene', (98, 102))	('KIT', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('BRAF', 'Gene', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))
24583	26825879	Mutations in guanine nucleotide-binding protein Q polypeptide (GNAQ) and guanine nucleotide-binding protein alpha-11 (GNA11), alpha subunits of heterotrimeric G proteins, constitutively activate mitogen-activated protein kinase (MAPK) pathway in uveal melanoma.	('GNA11', 'Gene', (118, 123))	('guanine nucleotide-binding protein alpha-11', 'Gene', (73, 116))	('MAPK', 'molecular_function', 'GO:0004707', ('229', '233'))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', '2776', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('21', '39'))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('guanine nucleotide-binding protein alpha-11', 'Gene', '2767', (73, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (246, 260))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', (246, 260))	('uveal melanoma', 'Disease', 'MESH:C536494', (246, 260))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('activate', 'PosReg', (186, 194))	('GNAQ', 'Gene', (63, 67))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('81', '99'))
24584	26825879	However, there are no reports of GNA11 mutations in cutaneous melanomas.	('GNA11', 'Gene', (33, 38))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (52, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (52, 71))	('GNA11', 'Gene', '2767', (33, 38))	('mutations', 'Var', (39, 48))	('cutaneous melanomas', 'Disease', (52, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
24586	26825879	Mutation analysis of the tumor revealed a GNA11 Q209L mutation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Q209L', 'Mutation', 'rs1057519742', (48, 53))	('tumor', 'Disease', (25, 30))	('Q209L', 'Var', (48, 53))	('GNA11', 'Gene', (42, 47))	('GNA11', 'Gene', '2767', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
24588	26825879	To our knowledge, this is the first case report to demonstrate cutaneous origin melanoma harboring a GNA11 Q209L mutation.	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('Q209L', 'Mutation', 'rs1057519742', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('Q209L', 'Var', (107, 112))
24592	26825879	The discovery of BRAF mutations in melanoma and the development of BRAF inhibitors have changed the landscape of advanced melanoma treatment.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('BRAF', 'Gene', (17, 21))	('changed', 'Reg', (88, 95))	('mutations', 'Var', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanoma', 'Disease', (35, 43))
24593	26825879	With the remarkable success of targeted therapy in BRAFV600 mutant melanoma, extensive research efforts have been made to discover targetable somatic mutations other than BRAF in melanoma.	('BRAFV600', 'Gene', (51, 59))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('mutant', 'Var', (60, 66))	('melanoma', 'Disease', (179, 187))
24594	26825879	The rapid advances in the molecular and genetic analysis of melanoma with the extensive research efforts have improved the understanding of clinicopathologic features of BRAF, KIT, and NRAS mutations in melanoma, which helps with development of targeted therapeutic agents.	('NRAS', 'Gene', (185, 189))	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('BRAF', 'Gene', (170, 174))	('KIT', 'Gene', (176, 179))	('improved', 'PosReg', (110, 118))	('mutations', 'Var', (190, 199))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
24598	26825879	The mutations of GNAQ/GNA11 have been reported exclusively in primary uveal melanoma and they are critical for the development and progression of uveal melanoma by activation of the mitogen-activated protein kinase (MAPK) pathway.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('GNA11', 'Gene', (22, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('reported', 'Reg', (38, 46))	('GNA11', 'Gene', '2767', (22, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('GNAQ', 'Gene', (17, 21))	('activation', 'PosReg', (164, 174))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('mutations', 'Var', (4, 13))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (62, 84))	('primary uveal melanoma', 'Disease', (62, 84))	('GNAQ', 'Gene', '2776', (17, 21))
24599	26825879	Although GNAQ/GNA11 mutations are not rare in benign and malignant blue nevus,GNA11 mutations have never been reported in patients with cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('GNAQ', 'Gene', (9, 13))	('nevus', 'Phenotype', 'HP:0003764', (72, 77))	('GNA11', 'Gene', (78, 83))	('GNA11', 'Gene', '2767', (78, 83))	('blue nevus', 'Phenotype', 'HP:0100814', (67, 77))	('GNA11', 'Gene', (14, 19))	('patients', 'Species', '9606', (122, 130))	('GNAQ', 'Gene', '2776', (9, 13))	('cutaneous melanoma', 'Disease', (136, 154))	('GNA11', 'Gene', '2767', (14, 19))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('mutations', 'Var', (20, 29))
24600	26825879	Here, we report a patient with cutaneous origin melanoma harboring GNA11 mutation.	('melanoma', 'Disease', (48, 56))	('GNA11', 'Gene', (67, 72))	('GNA11', 'Gene', '2767', (67, 72))	('patient', 'Species', '9606', (18, 25))	('mutation', 'Var', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
24615	26825879	A molecular analysis of the liver lesion revealed a GNA11 mutation with wild-type BRAF, wild-type KIT, and wild-type NRAS genes.	('liver lesion', 'Disease', 'MESH:D017093', (28, 40))	('mutation', 'Var', (58, 66))	('revealed', 'Reg', (41, 49))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))	('GNA11', 'Gene', (52, 57))	('liver lesion', 'Disease', (28, 40))	('GNA11', 'Gene', '2767', (52, 57))
24617	26825879	As GNA11 mutations have been reported in uveal melanoma frequently, extensive ophthalmology exams and a magnetic resonance imaging (MRI) of the brain were performed, which revealed no evidence of uveal melanoma (Figure 3).	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('mutations', 'Var', (9, 18))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('GNA11', 'Gene', (3, 8))	('reported', 'Reg', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('GNA11', 'Gene', '2767', (3, 8))	('uveal melanoma', 'Disease', 'MESH:C536494', (196, 210))	('uveal melanoma', 'Phenotype', 'HP:0007716', (196, 210))	('uveal melanoma', 'Disease', (196, 210))
24628	26825879	GNAQ or GNA11 mutations occur at either exon 4 R183 or exon 5 Q209 mostly, and these hotspot mutations are considered driver mutations in uveal melanoma by blocking intrinsic GTPase activity and activating downstream pathways constitutively.	('activating', 'Reg', (195, 205))	('activity', 'MPA', (182, 190))	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('intrinsic', 'Protein', (165, 174))	('GNA11', 'Gene', (8, 13))	('uveal melanoma', 'Disease', (138, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (138, 152))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Phenotype', 'HP:0007716', (138, 152))	('GNA11', 'Gene', '2767', (8, 13))	('blocking', 'NegReg', (156, 164))	('downstream pathways', 'Pathway', (206, 225))	('GNAQ', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('GTPase activity', 'molecular_function', 'GO:0003924', ('175', '190'))	('mutations', 'Var', (14, 23))
24629	26825879	In our patient, GNA11 Q209L mutation was detected by a next-generation sequencing platform.	('Q209L', 'Var', (22, 27))	('GNA11', 'Gene', (16, 21))	('patient', 'Species', '9606', (7, 14))	('GNA11', 'Gene', '2767', (16, 21))	('Q209L', 'Mutation', 'rs1057519742', (22, 27))
24630	26825879	Most cutaneous melanomas (up to 70%) have a dysregulated MAPK pathway via BRAF (50%) or NRAS mutations (15-20%), which promote uncontrolled proliferation and growth.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('cutaneous melanomas', 'Disease', (5, 24))	('dysregulated', 'Reg', (44, 56))	('mutations', 'Var', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', (74, 78))	('growth', 'CPA', (158, 164))	('promote', 'PosReg', (119, 126))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('NRAS', 'Gene', (88, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('57', '61'))	('MAPK pathway', 'Pathway', (57, 69))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))	('uncontrolled', 'MPA', (127, 139))
24631	26825879	However, cutaneous melanomas rarely harbor GNAQ/GNA11 mutations which were reported in primary uveal melanoma at a frequency up to 80%.	('primary uveal melanoma', 'Disease', 'MESH:C536494', (87, 109))	('primary uveal melanoma', 'Disease', (87, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('GNAQ', 'Gene', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('mutations', 'Var', (54, 63))	('GNA11', 'Gene', '2767', (48, 53))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('GNA11', 'Gene', (48, 53))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (9, 28))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (9, 28))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('cutaneous melanomas', 'Disease', (9, 28))	('GNAQ', 'Gene', '2776', (43, 47))
24635	26825879	Recently, GNA11 R183C mutation has been identified in 1 cutaneous origin melanoma cell line.	('melanoma', 'Disease', (73, 81))	('R183C', 'Mutation', 'p.R183C', (16, 21))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('GNA11', 'Gene', '2767', (10, 15))	('GNA11', 'Gene', (10, 15))	('R183C', 'Var', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
24636	26825879	However, it is not clear whether the original cutaneous melanoma sample harbors GNA11 mutation as several studies have demonstrated significant genomic difference between cancer cell lines and original tissue samples.	('GNA11', 'Gene', '2767', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', (46, 64))	('mutation', 'Var', (86, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('GNA11', 'Gene', (80, 85))
24637	26825879	In addition, Griewank et al reported abnormally high frequency of BRAF V600E mutations in uveal melanoma cell lines; suggesting contamination in laboratories that handle both cutaneous and uveal melanoma samples; furthermore, multiple studies failed to identify BRAF mutations in original uveal melanoma tissue, which also suggests genomic difference between melanoma cell lines and original melanoma tissues.	('melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('melanoma', 'Disease', (359, 367))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('melanoma', 'Disease', (295, 303))	('original melanoma', 'Disease', (383, 400))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (289, 303))	('melanoma', 'Disease', 'MESH:D008545', (392, 400))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('V600E mutations', 'Var', (71, 86))	('BRAF', 'Gene', (66, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('original melanoma', 'Disease', 'MESH:D008545', (383, 400))	('uveal melanoma', 'Phenotype', 'HP:0007716', (289, 303))	('melanoma', 'Disease', 'MESH:D008545', (359, 367))	('mutations', 'Var', (77, 86))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('uveal melanoma', 'Disease', 'MESH:C536494', (189, 203))	('melanoma', 'Phenotype', 'HP:0002861', (392, 400))	('uveal melanoma', 'Disease', (189, 203))	('melanoma', 'Disease', (392, 400))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('original uveal melanoma', 'Disease', (280, 303))	('original uveal melanoma', 'Disease', 'MESH:C536494', (280, 303))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('uveal melanoma', 'Phenotype', 'HP:0007716', (189, 203))	('melanoma', 'Disease', (96, 104))
24638	26825879	Another possibility is that our patient has malignant blue nevus as GNAQ/GNA11 mutations have been described in benign and malignant blue nevus.	('GNA11', 'Gene', (73, 78))	('GNA11', 'Gene', '2767', (73, 78))	('GNAQ', 'Gene', (68, 72))	('malignant blue nevus', 'Disease', (44, 64))	('blue nevus', 'Phenotype', 'HP:0100814', (54, 64))	('blue nevus', 'Phenotype', 'HP:0100814', (133, 143))	('nevus', 'Phenotype', 'HP:0003764', (59, 64))	('patient', 'Species', '9606', (32, 39))	('GNAQ', 'Gene', '2776', (68, 72))	('mutations', 'Var', (79, 88))	('nevus', 'Phenotype', 'HP:0003764', (138, 143))
24640	26825879	Previously, an increase in frequency of GNA11 mutations from primary to metastatic uveal melanomas has been reported.	('uveal melanoma', 'Phenotype', 'HP:0007716', (83, 97))	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('GNA11', 'Gene', '2767', (40, 45))	('primary', 'Disease', (61, 68))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('uveal melanomas', 'Disease', (83, 98))	('uveal melanomas', 'Phenotype', 'HP:0007716', (83, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('uveal melanomas', 'Disease', 'MESH:C536494', (83, 98))
24642	26825879	Unfortunately, the GNA11 mutation test of the primary lesion and metastatic lymph nodes was not performed due to insufficient samples.	('GNA11', 'Gene', '2767', (19, 24))	('mutation', 'Var', (25, 33))	('GNA11', 'Gene', (19, 24))
24643	26825879	As GNAQ/GNA11 mutations are associated with activation of the MAPK pathway similar to BRAF and NRAS mutations, and a selective MEK inhibitor has demonstrated activity in metastatic uveal melanoma with GNAQ/GNA11 mutations in a Phase II clinical trial, the patient might have experienced clinical benefit from an MEK inhibitor.	('GNA11', 'Gene', (8, 13))	('MEK', 'Gene', (127, 130))	('activation', 'PosReg', (44, 54))	('GNA11', 'Gene', (206, 211))	('GNAQ', 'Gene', '2776', (201, 205))	('mutations', 'Var', (212, 221))	('GNAQ', 'Gene', (201, 205))	('mutations', 'Var', (14, 23))	('activity', 'MPA', (158, 166))	('GNAQ', 'Gene', '2776', (3, 7))	('MEK', 'Gene', '5609', (312, 315))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('GNA11', 'Gene', '2767', (8, 13))	('GNAQ', 'Gene', (3, 7))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('uveal melanoma', 'Disease', (181, 195))	('GNA11', 'Gene', '2767', (206, 211))	('MEK', 'Gene', (312, 315))	('MAPK pathway', 'Pathway', (62, 74))	('MEK', 'Gene', '5609', (127, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('patient', 'Species', '9606', (256, 263))
24644	26825879	There is no data regarding any effects of GNAQ/11 mutations on BRAF or NRAS mutations, which are the most common oncogenic mutations in cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('mutations', 'Var', (76, 85))	('cutaneous melanomas', 'Disease', (136, 155))	('GNAQ', 'Gene', '2776', (42, 46))	('NRAS', 'Gene', (71, 75))	('GNAQ', 'Gene', (42, 46))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (136, 155))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (136, 155))	('BRAF', 'Gene', (63, 67))
24645	26825879	However, it is possible that mutations in GNAQ/11, BRAF, or NRAS are mutually exclusive similar to BRAF and NRAS mutations as co-mutations of GNAQ/11 and BRAF or NRAS have not been reported, and all these mutations activate the same MAPK pathway.	('MAPK pathway', 'Pathway', (233, 245))	('GNAQ', 'Gene', '2776', (42, 46))	('mutations', 'Var', (29, 38))	('mutations', 'Var', (205, 214))	('GNAQ', 'Gene', (142, 146))	('GNAQ', 'Gene', '2776', (142, 146))	('GNAQ', 'Gene', (42, 46))	('activate', 'PosReg', (215, 223))	('MAPK', 'molecular_function', 'GO:0004707', ('233', '237'))
24646	26825879	As far as we are aware, our case is the first documented cutaneous origin melanoma harboring a GNA11 mutation.	('GNA11', 'Gene', (95, 100))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('GNA11', 'Gene', '2767', (95, 100))	('mutation', 'Var', (101, 109))
24707	32902917	We also found that patients with high immune scores had longer survival time than did patients in the low immune score group (Figure S2, P = .0125).	('patients', 'Species', '9606', (19, 27))	('survival time', 'CPA', (63, 76))	('low immune score', 'Phenotype', 'HP:0002721', (102, 118))	('high immune scores', 'Var', (33, 51))	('longer', 'PosReg', (56, 62))	('patients', 'Species', '9606', (86, 94))
24709	32902917	SKCM is believed to be mostly driven by functionally based mutations of BRAF.	('SKCM', 'Disease', (0, 4))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
24710	32902917	26  In our assessments, we found that both immune and stromal scores were relatively higher in such types of BRAF mutants (Figure 2A).	('mutants', 'Var', (114, 121))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', (109, 113))	('higher', 'PosReg', (85, 91))
24722	32902917	Moreover, gene alteration in UBE2L6, PARP14, IFIH1, IRF2, and GBP4 were found to have occurred in only 1.4%, 4%, 4%, 4%, and 2.1% of sequenced cases respectively for data acquired from the OncoPrint schematic of cBioPortal (Figure 5C).	('UBE2L6', 'Gene', (29, 35))	('UBE2L6', 'Gene', '9246', (29, 35))	('gene alteration', 'Var', (10, 25))	('IRF2', 'Gene', (52, 56))	('PARP14', 'Gene', '54625', (37, 43))	('GBP4', 'Gene', (62, 66))	('IRF2', 'Gene', '3660', (52, 56))	('IFIH1', 'Gene', '64135', (45, 50))	('IFIH1', 'Gene', (45, 50))	('PARP14', 'Gene', (37, 43))	('GBP4', 'Gene', '115361', (62, 66))
24731	32902917	To validate the ability of the prognostic signature to predict immunotherapeutic benefits, we assigned 27 patients treated with PD-1 inhibitors in the GSE78220 cohort to high- and low-risk subgroups.	('patients', 'Species', '9606', (106, 114))	('inhibitors', 'Var', (133, 143))	('PD-1', 'Gene', (128, 132))	('PD-1', 'Gene', '5133', (128, 132))
24788	31217906	Our study started with the analysis of various genetic alterations (amplifications, mutations/deletion) as well as RNA overexpression of these RNA modification regulatory proteins in The Cancer Genome Atlas melanoma database.	('Cancer Genome Atlas melanoma', 'Disease', (187, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('Cancer Genome Atlas melanoma', 'Disease', 'MESH:C563985', (187, 215))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('RNA', 'cellular_component', 'GO:0005562', ('143', '146'))	('mutations/deletion', 'Var', (84, 102))	('RNA modification', 'biological_process', 'GO:0009451', ('143', '159'))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))
24792	31217906	Therefore, we functionally validated METTL4 and DNMT3A using shRNA-mediated knockdown and found that their knockdown in melanoma cells led to melanoma cells growth inhibition.	('knockdown', 'Var', (107, 116))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('METTL4', 'Gene', (37, 43))	('DNMT3A', 'Gene', (48, 54))	('METTL4', 'Gene', '64863', (37, 43))	('DNMT3A', 'Gene', '1788', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
24797	31217906	Among these, activating mutations in BRAF and NRAS gene and inactivating mutations in NF1 gene accounts for over 80% of melanoma and results in the activation of MAP kinase pathway.	('NRAS', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (37, 41))	('activation', 'PosReg', (148, 158))	('NRAS', 'Gene', '4893', (46, 50))	('BRAF', 'Gene', (37, 41))	('MAP kinase pathway', 'Pathway', (162, 180))	('NF1', 'Gene', '4763', (86, 89))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('activating mutations', 'Var', (13, 33))	('NF1', 'Gene', (86, 89))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('inactivating mutations', 'Var', (60, 82))	('MAP', 'molecular_function', 'GO:0004239', ('162', '165'))	('activation of MAP kinase', 'biological_process', 'GO:0000187', ('148', '172'))
24798	31217906	Based on the findings that MAPK pathway is activated in a large percentage of melanoma, clinically effective BRAF kinase and MEK1/2 kinase inhibitors have been developed and are being used to treat metastatic melanoma patients with BRAF mutations.	('MEK1/2', 'Gene', '5604;5605', (125, 131))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('MEK1/2', 'Gene', (125, 131))	('patients', 'Species', '9606', (218, 226))	('activated', 'PosReg', (43, 52))	('BRAF', 'Gene', '673', (232, 236))	('BRAF', 'Gene', (232, 236))	('MEK1', 'molecular_function', 'GO:0004708', ('125', '129'))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('mutations', 'Var', (237, 246))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('MAPK pathway', 'Pathway', (27, 39))
24801	31217906	Similar to other RNAs, mRNAs also contain different types of internal modifications such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C) and inosine (I).	('N6-methyladenosine', 'Var', (92, 110))	('5-hydroxymethylcytosine', 'MPA', (142, 165))	('5-methylcytosine', 'MPA', (118, 134))	('inosine', 'Chemical', 'MESH:D007288', (177, 184))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (118, 134))	('hm5C', 'Chemical', '-', (167, 171))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (142, 165))	('m6A', 'Gene', '56339', (112, 115))	('m6A', 'Gene', (112, 115))	('m5C', 'Chemical', '-', (168, 171))	('inosine', 'Disease', (177, 184))	('m5C', 'Chemical', '-', (136, 139))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (92, 110))
24802	31217906	Because these modifications affect the mRNA stability, localization and/or function of various RNA species, deregulations in these processes are implicated in various pathological conditions, including cancer, cardiovascular diseases and neurological disorders.	('modifications', 'Var', (14, 27))	('affect', 'Reg', (28, 34))	('implicated', 'Reg', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('function', 'MPA', (75, 83))	('RNA', 'cellular_component', 'GO:0005562', ('95', '98'))	('neurological disorders', 'Disease', (238, 260))	('localization', 'MPA', (55, 67))	('cardiovascular diseases', 'Disease', (210, 233))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (210, 233))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (210, 233))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('localization', 'biological_process', 'GO:0051179', ('55', '67'))	('cancer', 'Disease', (202, 208))	('mRNA stability', 'MPA', (39, 53))	('neurological disorders', 'Disease', 'MESH:D009422', (238, 260))
24810	31217906	Using the TCGA melanoma dataset, we identified various genetic alterations in m1A writers and erasers in melanoma (Figure 1B).	('genetic alterations', 'Var', (55, 74))	('m1A', 'Gene', (78, 81))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))
24811	31217906	N6-methyladenosine modification of RNA (also known as m6A) is also the most abundant internal modification of mRNA.	('m6A', 'Gene', (54, 57))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('m6A', 'Gene', '56339', (54, 57))	('N6-methyladenosine modification', 'Var', (0, 31))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
24816	31217906	These studies have shown that m6A modifications were typically found clustered around stop codons, in 3'UTRs, and within long internal exons and play a role in translational control.	('play', 'Reg', (145, 149))	('modifications', 'Var', (34, 47))	('m6A', 'Gene', (30, 33))	('m6A', 'Gene', '56339', (30, 33))
24820	31217906	m5C is methylation of RNA has been reported to be abundant in tRNA and rRNA and is shown to stabilizes the RNA secondary structure and affects translational fidelity.	('RNA', 'cellular_component', 'GO:0005562', ('22', '25'))	('stabilizes', 'Reg', (92, 102))	('RNA', 'Gene', (22, 25))	('affects', 'Reg', (135, 142))	('methylation', 'Var', (7, 18))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('translational fidelity', 'MPA', (143, 165))	('tRNA', 'molecular_function', 'GO:0030533', ('62', '66'))	('RNA secondary structure', 'MPA', (107, 130))	('m5C', 'Chemical', '-', (0, 3))	('m5C is methylation', 'Var', (0, 18))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
24825	31217906	TCGA melanoma dataset revealed that a large percentage of m5C RNA modification regulatory proteins were upregulated in melanoma, with some also showing mutations, although not recurrent (Figure 1D).	('mutations', 'Var', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('RNA modification', 'biological_process', 'GO:0009451', ('62', '78'))	('melanoma', 'Disease', (5, 13))	('m5C RNA modification', 'Protein', (58, 78))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('upregulated', 'PosReg', (104, 115))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('m5C', 'Chemical', '-', (58, 61))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))
24831	31217906	This modification also changes the informational content of the RNA molecule, as inosine preferentially base pairs with cytidine and is therefore interpreted as guanosine by the translational and splicing machinery.	('modification', 'Var', (5, 17))	('base pairs with cytidine', 'MPA', (104, 128))	('cytidine', 'Chemical', 'MESH:D003562', (120, 128))	('changes', 'Reg', (23, 30))	('splicing', 'biological_process', 'GO:0045292', ('196', '204'))	('inosine', 'Chemical', 'MESH:D007288', (81, 88))	('informational content', 'MPA', (35, 56))	('guanosine', 'Chemical', 'MESH:D006151', (161, 170))	('preferentially', 'PosReg', (89, 103))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
24862	31217906	We found that the knockdown of RNA modification regulatory protein encoding genes (METTL4 and DNMT3A) inhibited the ability of melanoma cells to form colonies in soft agar (Figure 5B-5G).	('knockdown', 'Var', (18, 27))	('METTL4', 'Gene', '64863', (83, 89))	('RNA modification', 'biological_process', 'GO:0009451', ('31', '47'))	('inhibited', 'NegReg', (102, 111))	('agar', 'Chemical', 'MESH:D000362', (167, 171))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('DNMT3A', 'Gene', (94, 100))	('METTL4', 'Gene', (83, 89))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('DNMT3A', 'Gene', '1788', (94, 100))
24872	31217906	Although, the traditional view has been that a driver oncogenic event typically occur as an activating mutation in protooncogene, such as in NRAS and BRAF genes in case of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('NRAS', 'Gene', '4893', (141, 145))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('mutation', 'Var', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('activating', 'PosReg', (92, 102))	('NRAS', 'Gene', (141, 145))
24913	33863293	High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('High expression', 'Var', (0, 15))	('LUSC', 'Disease', (100, 104))	('ocular melanomas', 'Phenotype', 'HP:0025534', (131, 147))	('prostate cancer', 'Disease', (229, 244))	('LGG', 'Disease', (199, 202))	('ocular melanomas', 'Disease', 'MESH:D008545', (131, 147))	('LGG', 'Disease', (73, 76))	('GMFG', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('GBM', 'Disease', (46, 49))	('ocular melanomas', 'Disease', (131, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))
24914	33863293	In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003).	('THYM', 'Phenotype', 'HP:0100522', (137, 141))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 93))	('GMFG', 'Gene', (32, 36))	('bile duct cancer', 'Phenotype', 'HP:0030153', (193, 209))	('high expression', 'Var', (13, 28))	('bile duct cancer', 'Disease', (193, 209))	('thymoma', 'Phenotype', 'HP:0100522', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('skin cutaneous melanoma', 'Disease', (70, 93))	('thymoma', 'Disease', 'MESH:D013945', (128, 135))	('bile duct cancer', 'Disease', 'MESH:D001650', (193, 209))	('thymoma', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('CHOL', 'Disease', (211, 215))	('CHOL', 'Disease', 'None', (211, 215))
24916	33863293	Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).	('iron', 'Chemical', 'MESH:D007501', (192, 196))	('immune response', 'biological_process', 'GO:0006955', ('135', '150'))	('immune response', 'CPA', (135, 150))	('tumor', 'Disease', (178, 183))	('GMFG', 'Var', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('survivals', 'Disease', (65, 74))	('cancers', 'Disease', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (116, 121))	('modulating', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
24922	33863293	These two studies demonstrated that GMFG could promote the migration and proliferation of ovarian and colorectal cancer cells, and the high expression of GMFG was related to poor survival outcome for ovarian cancer patients.	('ovarian', 'Disease', 'MESH:D010049', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('related', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('high', 'Var', (135, 139))	('ovarian', 'Disease', (90, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('migration', 'CPA', (59, 68))	('ovarian cancer', 'Disease', (200, 214))	('colorectal cancer', 'Disease', (102, 119))	('promote', 'PosReg', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('ovarian', 'Disease', (200, 207))	('patients', 'Species', '9606', (215, 223))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('proliferation', 'CPA', (73, 86))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))
24940	33863293	1c, high expression of GMFG was correlated with early pathological stage in bladder cancer (BLCA) (P = 0.016), LUAD (P = 0.015), skin cutaneous melanoma (SKCM) (P = 0.006) and thyroid cancer (THCA) (P = 0.01), but was linked with advanced pathological stage in stomach cancer (STAD) (P = 0.028).	('skin cutaneous melanoma', 'Disease', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('high expression', 'Var', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('thyroid cancer', 'Disease', (176, 190))	('stomach cancer', 'Disease', 'MESH:D013274', (261, 275))	('stomach cancer', 'Phenotype', 'HP:0012126', (261, 275))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('thyroid cancer', 'Disease', 'MESH:D013964', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('correlated', 'Reg', (32, 42))	('LUAD', 'Disease', (111, 115))	('GMFG', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('thyroid cancer', 'Phenotype', 'HP:0002890', (176, 190))	('stomach cancer', 'Disease', (261, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 152))	('BLCA', 'Phenotype', 'HP:0009725', (92, 96))
24941	33863293	For survival outcome, high expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and UVM (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('high expression', 'Var', (22, 37))	('LGG', 'Disease', (202, 205))	('prostate cancer', 'Disease', (232, 247))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('GBM', 'Disease', (68, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LGG', 'Disease', (95, 98))	('GMFG', 'Gene', (41, 45))	('UVM', 'Disease', (153, 156))	('LUSC', 'Disease', (122, 126))
24942	33863293	In contrast, high expression of GMFG was associated with better OS in SKCM (HR = 0.59, P < 0.001) and THYM (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003) (Fig.	('bile duct cancer', 'Disease', 'MESH:D001650', (157, 173))	('CHOL', 'Disease', 'None', (175, 179))	('THYM', 'Phenotype', 'HP:0100522', (102, 106))	('SKCM', 'Disease', (70, 74))	('CHOL', 'Disease', (175, 179))	('GMFG', 'Gene', (32, 36))	('high expression', 'Var', (13, 28))	('THYM', 'Disease', (102, 106))	('bile duct cancer', 'Phenotype', 'HP:0030153', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bile duct cancer', 'Disease', (157, 173))
24948	33863293	We also summarized the top 10 most significant items of GO/KEGG pathways for each individual cancer (Supplementary file 1-4: Table S1-S4), and we found that GMFG was notably associated with the biological process of immune response in most cancers, so we decided to analyze the correlation between GMFG and its immunomodulators co-expression genes.	('cancer', 'Disease', (93, 99))	('associated with', 'Reg', (174, 189))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('immune response', 'biological_process', 'GO:0006955', ('216', '231'))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GMFG', 'Var', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('biological process', 'biological_process', 'GO:0008150', ('194', '212'))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
24950	33863293	As for co-stimulators, GMFG was highly associated with CD80 and CD28 in most cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('CD28', 'Gene', (64, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GMFG', 'Var', (23, 27))	('cancers', 'Disease', (77, 84))	('CD28', 'Gene', '940', (64, 68))	('CD80', 'Gene', (55, 59))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CD80', 'Gene', '941', (55, 59))
24960	33863293	In addition, high expression of GMFG was associated with early pathological stage in four cancers (BLCA, LUAD, SKCM, and THCA), but was correlated with advanced pathological stage in STAD.	('cancers', 'Disease', (90, 97))	('SKCM', 'Disease', (111, 115))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('high', 'Var', (13, 17))	('BLCA', 'Phenotype', 'HP:0009725', (99, 103))	('GMFG', 'Gene', (32, 36))	('LUAD', 'Disease', (105, 109))	('THCA', 'Phenotype', 'HP:0002890', (121, 125))	('correlated', 'Reg', (136, 146))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
24961	33863293	Moreover, the associations of GMFG expression with OS and DFS were also investigated, and high expression of GMFG predicted worse OS in four cancers (GBM, LGG, LUSC, and UVM), and worse DFS for LGG and PRAD, but was associated with better OS in SKCM and THYM, better DFS in CHOL.	('better OS', 'Disease', (232, 241))	('PRAD', 'Disease', (202, 206))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('high expression', 'Var', (90, 105))	('SKCM', 'Disease', (245, 249))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('CHOL', 'Disease', 'None', (274, 278))	('cancers', 'Disease', (141, 148))	('LGG', 'Disease', (155, 158))	('THYM', 'Phenotype', 'HP:0100522', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('GMFG', 'Gene', (109, 113))	('CHOL', 'Disease', (274, 278))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('worse OS', 'Disease', (124, 132))	('LUSC', 'Disease', (160, 164))	('LGG', 'Disease', (194, 197))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('THYM', 'Disease', (254, 258))
24969	33863293	Taken together, that GMFG enhances both the cancer progression and the immune defense, and patients' survival outcome may depend on the balance between the speed of cancer development and the ability of immune system against cancer tissues.	('immune defense', 'CPA', (71, 85))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GMFG', 'Var', (21, 25))	('enhances', 'PosReg', (26, 34))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
24972	33863293	Recent studies reported that GMFG regulates monocyte migration by modulating ITGB1, and functions as a negative regulator of Toll-like receptor 4 (TLR4) signaling through facilitating TLR4 endocytic trafficking in macrophages.	('ITGB1', 'Gene', (77, 82))	('signaling', 'biological_process', 'GO:0023052', ('153', '162'))	('GMFG', 'Var', (29, 33))	('TLR4', 'Gene', (147, 151))	('TLR4', 'Gene', '7099', (184, 188))	('modulating', 'Reg', (66, 76))	('regulates', 'Reg', (34, 43))	('facilitating', 'PosReg', (171, 183))	('ITGB1', 'Gene', '3688', (77, 82))	('TLR4', 'Gene', (184, 188))	('Toll-like receptor 4', 'Gene', '7099', (125, 145))	('TLR4', 'Gene', '7099', (147, 151))	('Toll-like receptor 4', 'Gene', (125, 145))	('monocyte migration', 'CPA', (44, 62))
25045	24033424	The antibody to leptin yielded positive immunostaining of dog adipose tissue which served as a positive control (Fig.	('antibody', 'cellular_component', 'GO:0042571', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019815', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019814', ('4', '12'))	('immunostaining', 'MPA', (40, 54))	('antibody', 'molecular_function', 'GO:0003823', ('4', '12'))	('dog', 'Species', '9615', (58, 61))	('antibody', 'Var', (4, 12))
25075	24033424	For example, BRAF mutations are common in cutaneous melanoma in humans but found infrequently in OM in dogs and mucosal melanomas in humans .	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('mutations', 'Var', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRAF', 'Gene', '673', (13, 17))	('mucosal melanomas', 'Disease', 'MESH:D008545', (112, 129))	('humans', 'Species', '9606', (64, 70))	('dogs', 'Species', '9615', (103, 107))	('BRAF', 'Gene', (13, 17))	('humans', 'Species', '9606', (133, 139))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('OM', 'Chemical', '-', (97, 99))	('mucosal melanomas', 'Disease', (112, 129))	('cutaneous melanoma', 'Disease', (42, 60))
25076	24033424	In contrast KIT mutations are found at low but consistent rates in OM in dogs and mucosal melanomas in humans.	('mucosal melanomas', 'Disease', (82, 99))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('mucosal melanomas', 'Disease', 'MESH:D008545', (82, 99))	('mutations', 'Var', (16, 25))	('dogs', 'Species', '9615', (73, 77))	('humans', 'Species', '9606', (103, 109))	('KIT', 'molecular_function', 'GO:0005020', ('12', '15'))	('OM', 'Chemical', '-', (67, 69))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
25083	31673075	This study reveals the genes C7, MMP3, KRT14, LOC642587, CASP7, S100A7 and miRNAs hsa-mir-205 and hsa-mir-203b as the key genomic features that may substantially contribute to the oncogenesis of melanoma.	('hsa-mir-205', 'Gene', (82, 93))	('contribute', 'Reg', (162, 172))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('S10', 'Gene', '6204', (64, 67))	('MMP3', 'molecular_function', 'GO:0004248', ('33', '37'))	('LOC642587', 'Var', (46, 55))	('MMP3', 'Gene', (33, 37))	('LOC642587', 'Chemical', 'MESH:C492399', (46, 55))	('oncogenesis', 'biological_process', 'GO:0007048', ('180', '191'))	('C7', 'Gene', '730', (29, 31))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('hsa-mir-205', 'Gene', '406988', (82, 93))	('melanoma', 'Disease', (195, 203))	('CASP7', 'Gene', (57, 62))	('KRT14', 'Gene', '3861', (39, 44))	('S10', 'Gene', (64, 67))	('hsa-mir-203b', 'Gene', (98, 110))	('MMP3', 'Gene', '4314', (33, 37))	('KRT14', 'Gene', (39, 44))	('hsa-mir-203b', 'Gene', '100616173', (98, 110))	('CASP7', 'Gene', '840', (57, 62))
25095	31673075	The core study on SKCM done by TCGA has revealed four subtypes of cancer, which include mutant BRAF, mutant RAS, mutant NF1, triple WT (wild-type) based on mutant genes.	('SKCM', 'Disease', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('BRAF', 'Gene', '673', (95, 99))	('SKCM', 'Disease', 'MESH:C562393', (18, 22))	('NF1', 'Gene', (120, 123))	('BRAF', 'Gene', (95, 99))	('mutant', 'Var', (88, 94))	('core', 'cellular_component', 'GO:0019013', ('4', '8'))	('NF1', 'Gene', '4763', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutant', 'Var', (113, 119))	('mutant RAS', 'Var', (101, 111))	('cancer', 'Disease', (66, 72))
25097	31673075	Further, it has been observed that the mutational rate of these genes is much higher in melanoma patients than other cancer types of TCGA.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('mutational', 'Var', (39, 49))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('higher', 'Reg', (78, 84))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (97, 105))
25098	31673075	Interestingly, over 50% of melanoma patients have BRAF kinase (BRAF proto-oncogene, serine/threonine kinase) mutations.	('BRAF', 'Gene', (50, 54))	('threonine', 'Chemical', 'MESH:C061951', (91, 100))	('serine', 'Chemical', 'MESH:C047902', (84, 90))	('patients', 'Species', '9606', (36, 44))	('BRAF', 'Gene', '673', (63, 67))	('mutations', 'Var', (109, 118))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (50, 54))
25099	31673075	In addition, various studies have demonstrated that the SKCM arises from the anomalies in transcriptomic and epigenetic factors such as expression of mRNAs, miRNAs, the aberration in methylation patterns of CpG islands of genes and histone modifications, which paves the way for the development of potential molecular biomarkers in melanoma.	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('SKCM', 'Disease', (56, 60))	('CpG', 'Gene', (207, 210))	('anomalies', 'Var', (77, 86))	('melanoma', 'Disease', 'MESH:D008545', (332, 340))	('melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('melanoma', 'Disease', (332, 340))	('SKCM', 'Disease', 'MESH:C562393', (56, 60))	('aberration', 'Var', (169, 179))	('methylation', 'Var', (183, 194))
25168	31673075	The C7, S100A7, LOC642587, CASP14 and MMP3 are among the top 5 mRNA expression features that can discriminate metastatic and primary tumor samples with AUROC 0.81, 0.78, 0.77, 0.77 and 0.77 at thresholds 4.3, 3.1, 0.9, 0.9 and 3.7 (log2 RSEM values), respectively.	('S10', 'Gene', '6204', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('LOC642587', 'Chemical', 'MESH:C492399', (16, 25))	('MMP3', 'molecular_function', 'GO:0004248', ('38', '42'))	('metastatic', 'CPA', (110, 120))	('C7', 'Gene', '730', (4, 6))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CASP14', 'Gene', '23581', (27, 33))	('MMP3', 'Gene', (38, 42))	('S10', 'Gene', (8, 11))	('tumor', 'Disease', (133, 138))	('LOC642587', 'Var', (16, 25))	('MMP3', 'Gene', '4314', (38, 42))	('CASP14', 'Gene', (27, 33))
25178	31673075	Furthermore, RPS27 has been reported to have mutations in untranslated region and shown to have an impact in the progression of melanoma.	('RPS27', 'Gene', '6232', (13, 18))	('mutations', 'Var', (45, 54))	('melanoma', 'Disease', (128, 136))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('impact', 'Reg', (99, 105))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('RPS27', 'Gene', (13, 18))
25394	31850079	Publicly available datasets were analyzed in this study: TCGA-BRCA data (found at The Cancer Genome Atlas), GSE63557 (found at Gene Expression Omnibus) and GSE35640 (found at Gene Expression Omnibus).	('Gene Expression', 'biological_process', 'GO:0010467', ('175', '190'))	('TCGA-BRCA', 'Gene', (57, 66))	('GSE35640', 'Var', (156, 164))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Disease', (86, 92))	('GSE63557', 'Var', (108, 116))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))	('Gene Expression', 'biological_process', 'GO:0010467', ('127', '142'))
25592	24212638	The tumorigenicity of these cells was dramatically blocked by a neutralizing monoclonal antibody to VEGF.	('tumor', 'Disease', (4, 9))	('neutralizing', 'Var', (64, 76))	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('blocked', 'NegReg', (51, 58))	('VEGF', 'Gene', (100, 104))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))
25617	24212638	reported that in a human ovarian cancer model, presence of tumor suppressor gene ARHI induced autophagy, which kept tumor cells dormant in vivo, as xenografts.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ARHI', 'Gene', '9077', (81, 85))	('autophagy', 'biological_process', 'GO:0016236', ('94', '103'))	('autophagy', 'CPA', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ovarian cancer', 'Disease', 'MESH:D010051', (25, 39))	('induced', 'Reg', (86, 93))	('presence', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('59', '75'))	('ARHI', 'Gene', (81, 85))	('autophagy', 'biological_process', 'GO:0006914', ('94', '103'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('59', '75'))	('ovarian cancer', 'Disease', (25, 39))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('human', 'Species', '9606', (19, 24))	('tumor', 'Disease', (116, 121))
25726	24212638	Moreover, targeted therapy against CSC markers may eliminate dormant tumor cells at distant metastatic sites.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('eliminate', 'NegReg', (51, 60))	('targeted', 'Var', (10, 18))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
25738	33076392	Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers.	('Melanoma', 'Disease', 'MESH:D008545', (55, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (222, 246))	('lung', 'Disease', (248, 252))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (266, 283))	('INK4a/ARF', 'Gene', '1029', (27, 36))	('cancer', 'Disease', (277, 283))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('cancer', 'Disease', (174, 180))	('Melanoma', 'Disease', (55, 63))	('neck', 'cellular_component', 'GO:0044326', ('217', '221'))	('INK4a/ARF', 'Gene', (27, 36))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (208, 246))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (266, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck squamous cell carcinomas', 'Disease', (217, 246))	('INK4a/ARF', 'Gene', '1029', (119, 128))	('Melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('pancreatic cancers', 'Disease', (266, 284))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('carcinomas', 'Phenotype', 'HP:0030731', (236, 246))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (217, 246))	('breast', 'Disease', (254, 260))	('reported', 'Reg', (157, 165))	('pancreatic cancers', 'Disease', 'MESH:D010190', (266, 284))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('INK4a/ARF', 'Gene', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Effects', 'Reg', (44, 51))	('alterations', 'Var', (100, 111))
25739	33076392	In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma.	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('cutaneous melanoma', 'Disease', (214, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (214, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (214, 232))	('alterations', 'Var', (37, 48))	('melanomas', 'Disease', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('loss of function', 'NegReg', (13, 29))	('melanomas', 'Disease', (102, 111))	('CDKN2A', 'Gene', (30, 36))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
25740	33076392	The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('86', '102'))	('p14ARF', 'Gene', (134, 140))	('p53', 'Gene', '7157', (120, 123))	('p16INK4a', 'Var', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('p53', 'Gene', (120, 123))	('cyclin', 'Gene', '5111', (69, 75))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('69', '102'))	('p14ARF', 'Gene', '1029', (134, 140))	('CDKN2A', 'Gene', (4, 10))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('cyclin', 'Gene', (69, 75))
25741	33076392	The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('p14ARF', 'Gene', (126, 132))	('CDKN2A', 'Gene', (16, 22))	('affect', 'Reg', (78, 84))	('alterations', 'Var', (23, 34))	('coding sequence', 'MPA', (89, 104))	('p14ARF', 'Gene', '1029', (126, 132))	('target', 'Reg', (59, 65))	('p16INK4a', 'Var', (113, 121))	('melanoma', 'Disease', (38, 46))	('p16INK4a', 'Protein', (66, 74))
25742	33076392	There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions.	('alterations', 'Var', (69, 80))	('affect', 'Reg', (86, 92))	('INK4a/ARF', 'Gene', '1029', (59, 68))	('p14ARF', 'Gene', '1029', (93, 99))	('INK4a/ARF', 'Gene', (59, 68))	('p14ARF', 'Gene', (93, 99))
25743	33076392	In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development.	('alterations', 'Var', (63, 74))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (205, 213))	('melanoma', 'Disease', (105, 113))	('familial melanoma', 'Disease', (149, 166))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('familial melanoma', 'Disease', 'MESH:C562393', (149, 166))	('CDKN2A', 'Gene', (89, 95))	('alterations', 'Var', (134, 145))	('CDKN2A', 'Gene', (127, 133))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))
25746	33076392	The transformation of melanocytes into melanoma, termed melanomagenesis, involves the sequential selection of genetic and epigenetic alterations that promote proliferation, invasion, and immune escape.	('invasion', 'CPA', (173, 181))	('promote', 'PosReg', (150, 157))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (4, 33))	('immune escape', 'CPA', (187, 200))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('epigenetic alterations', 'Var', (122, 144))	('proliferation', 'CPA', (158, 171))
25747	33076392	Cutaneous melanoma has the highest median coding mutation rate of any cancer type (14.4 coding mutations per megabase) and this reflects the high proportion of ultraviolet (UV)-induced C>T substitutions that occur at pyrimidines.	('pyrimidines', 'Chemical', 'MESH:D011743', (217, 228))	('C>T substitutions', 'Var', (185, 202))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('coding mutation', 'MPA', (42, 57))	('Cutaneous melanoma', 'Disease', (0, 18))
25751	33076392	This is one of the most commonly altered sequences in cancer and is mutated, deleted, or methylated in 40-70% of sporadic melanomas.	('sporadic melanomas', 'Disease', (113, 131))	('methylated', 'Var', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('deleted', 'Var', (77, 84))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('sporadic melanomas', 'Disease', 'MESH:D008545', (113, 131))
25754	33076392	p16INK4a forms binary complexes with the cyclin-dependent kinases 4 and 6 (CDK4/6) to inhibit cyclin D-CDK4/6-mediated phosphorylation of the retinoblastoma protein and, thus, prevents G1 to S phase cell cycle transition.	('p16INK4a', 'Var', (0, 8))	('cyclin', 'molecular_function', 'GO:0016538', ('41', '47'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('S phase', 'biological_process', 'GO:0051320', ('191', '198'))	('inhibit', 'NegReg', (86, 93))	('cyclin', 'Gene', (41, 47))	('retinoblastoma', 'Phenotype', 'HP:0009919', (142, 156))	('cell cycle transition', 'biological_process', 'GO:0044771', ('199', '220'))	('cyclin', 'Gene', '5111', (94, 100))	('G1 to S phase cell cycle transition', 'CPA', (185, 220))	('retinoblastoma', 'Disease', (142, 156))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('cyclin', 'Gene', (94, 100))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('prevents', 'NegReg', (176, 184))	('complexes', 'Interaction', (22, 31))	('retinoblastoma', 'Disease', 'MESH:D012175', (142, 156))	('cyclin-dependent kinases 4 and 6', 'Gene', '1019;1021', (41, 73))	('cell cycle transition', 'biological_process', 'GO:0044770', ('199', '220'))	('cyclin', 'Gene', '5111', (41, 47))	('cyclin', 'molecular_function', 'GO:0016538', ('94', '100'))
25756	33076392	In this review, we examine genetic alterations affecting the CDKN2A locus in melanoma, the functional impact of altered CDKN2A, and the contribution of this locus to melanoma development and progression.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('CDKN2A', 'Gene', (61, 67))	('CDKN2A', 'Gene', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('altered', 'Var', (112, 119))
25758	33076392	Inactivation of the CDKN2A locus has been detected in approximately 50% of primary melanomas and over 75% of metastatic melanomas.	('melanomas', 'Disease', (120, 129))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (120, 129))	('CDKN2A', 'Gene', (20, 26))	('melanomas', 'Disease', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('Inactivation', 'Var', (0, 12))	('detected', 'Reg', (42, 50))
25759	33076392	The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequences of both p16INK4a and p14ARF.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('p14ARF', 'Gene', '1029', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('CDKN2A', 'Gene', (16, 22))	('coding sequences', 'MPA', (89, 105))	('p14ARF', 'Gene', (127, 133))	('p16INK4a', 'Var', (114, 122))	('affect', 'Reg', (78, 84))	('alterations', 'Var', (23, 34))	('target', 'Reg', (59, 65))	('melanoma', 'Disease', (38, 46))	('p16INK4a', 'Protein', (66, 74))
25760	33076392	Somatic CDKN2A alterations that solely affect p14ARF without compromising the syntenic p16INK4a coding region are rare.	('p14ARF', 'Gene', (46, 52))	('CDKN2A', 'Gene', (8, 14))	('affect', 'Reg', (39, 45))	('p14ARF', 'Gene', '1029', (46, 52))	('alterations', 'Var', (15, 26))
25761	33076392	For example, analysis of the mutation spectrum of primary and metastatic cutaneous melanoma in The Cancer Genome Atlas (TCGA) (n = 363, data derived through the Memorial Sloan Kettering Cancer Center cBioPortal for Cancer Genomics identified CDKN2A genetic alterations in approximately 45% (162/363) of melanoma cases; these included missense mutations (21/363, 5.8%), truncating mutations (34/363, 9.4%), in-frame deletions (2/363, 0.6%), amplifications (1/363, 0.3%), and homozygous deletions (112/363, 30.8%).	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('CDKN2A', 'Gene', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('Cancer', 'Phenotype', 'HP:0002664', (215, 221))	('truncating', 'MPA', (369, 379))	('cutaneous melanoma', 'Disease', (73, 91))	('in-frame deletions', 'Var', (406, 424))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('amplifications', 'Var', (440, 454))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Disease', (303, 311))	('missense mutations', 'Var', (334, 352))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('alterations', 'Reg', (257, 268))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
25762	33076392	Almost 43% of the missense, truncating, and in-frame mutations specifically affected p16INK4a, 57% affected both p14ARF and p16INK4a, and mutations that altered p14ARF alone were not observed.	('p14ARF', 'Gene', (113, 119))	('p14ARF', 'Gene', (161, 167))	('missense', 'Var', (18, 26))	('p16INK4a', 'Gene', (85, 93))	('affected', 'Reg', (99, 107))	('mutations', 'Var', (53, 62))	('truncating', 'MPA', (28, 38))	('affected', 'Reg', (76, 84))	('p14ARF', 'Gene', '1029', (113, 119))	('p14ARF', 'Gene', '1029', (161, 167))
25763	33076392	It is worth noting that alterations that appear to specifically alter one of the CDKN2A-encoded proteins may impact the co-ordinated regulation of p14ARF and/or p16INK4a.	('alterations', 'Var', (24, 35))	('p16INK4a', 'Var', (161, 169))	('impact', 'Reg', (109, 115))	('CDKN2A-encoded', 'Gene', (81, 95))	('alter', 'Reg', (64, 69))	('p14ARF', 'Gene', (147, 153))	('regulation', 'biological_process', 'GO:0065007', ('133', '143'))	('co-ordinated regulation', 'MPA', (120, 143))	('p14ARF', 'Gene', '1029', (147, 153))
25764	33076392	These mutation frequencies are consistent with previous reports and confirm that homozygous CDKN2A deletions are the most common alterations affecting this locus in melanoma (reviewed in reference).	('CDKN2A', 'Gene', (92, 98))	('deletions', 'Var', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
25765	33076392	Promoter hypermethylation of CDKN2A leading to transcription silencing and loss of protein expression increases during melanoma progression and has been identified in approximately 19-60% of vertical-growth-phase melanomas, 40% of radial-growth-phase melanomas, and 25-33% of melanoma metastases.	('protein expression', 'MPA', (83, 101))	('identified', 'Reg', (153, 163))	('melanomas', 'Disease', (251, 260))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('Promoter hypermethylation', 'Var', (0, 25))	('transcription', 'MPA', (47, 60))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('melanoma', 'Disease', (276, 284))	('vertical-growth-phase', 'CPA', (191, 212))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('loss', 'NegReg', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('melanomas', 'Phenotype', 'HP:0002861', (251, 260))	('melanoma metastases', 'Disease', 'MESH:D009362', (276, 295))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('transcription', 'biological_process', 'GO:0006351', ('47', '60'))	('melanomas', 'Disease', 'MESH:D008545', (213, 222))	('increases', 'PosReg', (102, 111))	('melanoma metastases', 'Disease', (276, 295))	('CDKN2A', 'Gene', (29, 35))	('melanomas', 'Disease', (213, 222))	('melanoma', 'Disease', 'MESH:D008545', (276, 284))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanomas', 'Disease', 'MESH:D008545', (251, 260))
25767	33076392	In this study, only 16/60 (27%) metastases displayed p16INK4a promoter methylation and seven of these tumors showed concurrent methylation on both the p16INK4a and p14ARF promoters.	('methylation', 'Var', (71, 82))	('p16INK4a', 'Gene', (53, 61))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('p14ARF', 'Gene', (164, 170))	('metastases', 'Disease', (32, 42))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('p14ARF', 'Gene', '1029', (164, 170))
25768	33076392	Intriguingly, the epigenetic modifications affecting p14ARF and p16INK4a may vary in melanoma, with 5' CpG promoter hypermethylation reported to be predominant in p16INK4a gene inactivation, whereas histone hypoacetylation is more commonly associated with p14ARF gene silencing.	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('p14ARF', 'Gene', '1029', (256, 262))	('p14ARF', 'Gene', '1029', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('p16INK4a', 'Var', (163, 171))	('melanoma', 'Disease', (85, 93))	('gene silencing', 'biological_process', 'GO:0016458', ('263', '277'))	('inactivation', 'NegReg', (177, 189))	('p14ARF', 'Gene', (256, 262))	('p14ARF', 'Gene', (53, 59))
25769	33076392	In the TCGA cohort, methylation of three CpG islands in the p16INK4a exon 1alpha [cg12840719, cg13601799, cg04026675] and five CpG islands in p14ARF exon 1beta [cg03079681, cg07562918, cg00718440, cg10848754, cg14430974] were analyzed.	('p14ARF exon 1beta', 'Gene', '1029', (142, 159))	('[cg12840719', 'Var', (81, 92))	('p14ARF exon 1beta', 'Gene', (142, 159))	('cg04026675]', 'Var', (106, 117))	('cg14430974]', 'Var', (209, 220))	('[cg03079681', 'Var', (160, 171))	('cg07562918', 'Var', (173, 183))	('cg00718440', 'Var', (185, 195))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('cg10848754', 'Var', (197, 207))
25771	33076392	The co-operative binding of PRC1 (including the BMI1 subunit) and the long noncoding RNA ANRIL to H3K27me3 compacts the CDKN2A genomic locus and represses transcription, in particular the transcription of p16INK4a.	('transcription', 'MPA', (188, 201))	('p16INK4a', 'Gene', (205, 213))	('ANRIL', 'Gene', '100048912', (89, 94))	('binding', 'Interaction', (17, 24))	('CDKN2A', 'Gene', (120, 126))	('PRC1', 'Gene', (28, 32))	('BMI1', 'Gene', '648', (48, 52))	('PRC1', 'Gene', '9055', (28, 32))	('H3K27me3', 'Var', (98, 106))	('represses', 'NegReg', (145, 154))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('binding', 'molecular_function', 'GO:0005488', ('17', '24'))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('ANRIL', 'Gene', (89, 94))	('transcription', 'MPA', (155, 168))	('BMI1', 'Gene', (48, 52))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))
25772	33076392	In line with these data, the levels of H3K27me3 increase from primary to metastatic melanoma, and high H3K27me3 is an independent poor prognostic marker in melanoma.	('H3K27me3', 'Protein', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('levels', 'MPA', (29, 35))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('primary', 'Disease', (62, 69))	('high H3K27me3', 'Var', (98, 111))	('increase', 'PosReg', (48, 56))
25773	33076392	Mutations in the BRAF, NRAS, and NF1 genes are the predominant drivers in cutaneous melanoma, and CDKN2A genetic alterations are distributed evenly amongst these genetic melanoma subtypes, with CDKN2A genetic alterations detected in 48.9% (92/188) of BRAF-mutant, 44.7% (51/114) of NRAS-mutant, and 50% (33/66) of NF1-mutant cutaneous melanomas (Table 1).	('NF1', 'Gene', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (325, 344))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (325, 344))	('NRAS', 'Gene', '4893', (23, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (325, 343))	('melanoma', 'Disease', (335, 343))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (325, 343))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (251, 255))	('BRAF', 'Gene', '673', (251, 255))	('cutaneous melanomas', 'Disease', (325, 344))	('NRAS', 'Gene', '4893', (282, 286))	('NRAS', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('NF1', 'Gene', '4763', (314, 317))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('NF1', 'Gene', (314, 317))	('BRAF', 'Gene', '673', (17, 21))	('NF1', 'Gene', '4763', (33, 36))	('BRAF', 'Gene', (17, 21))	('melanomas', 'Phenotype', 'HP:0002861', (335, 344))	('cutaneous melanoma', 'Disease', (74, 92))	('NRAS', 'Gene', (282, 286))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 92))
25776	33076392	Interestingly CDKN2A methylation was rarely detected in sporadic primary melanoma and has not been identified in melanocytic nevi.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('nevi', 'Phenotype', 'HP:0003764', (125, 129))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('methylation', 'Var', (21, 32))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (113, 129))	('CDKN2A', 'Gene', (14, 20))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
25777	33076392	Altogether, CDKN2A alterations (including mutation, deletion, and promoter hypermethylation) appear to be differentially distributed across the cutaneous melanoma genomic subtypes, and have been identified in 58% of BRAF-mutant, 72% of NRAS-mutant, and 71% of NF1-mutant melanoma but only in 37% of triple wild-type melanomas.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('CDKN2A', 'Gene', (12, 18))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('NF1', 'Gene', '4763', (260, 263))	('melanomas', 'Phenotype', 'HP:0002861', (316, 325))	('NF1', 'Gene', (260, 263))	('alterations', 'Var', (19, 30))	('mutation', 'Var', (42, 50))	('NRAS', 'Gene', '4893', (236, 240))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('promoter hypermethylation', 'MPA', (66, 91))	('deletion', 'Var', (52, 60))	('identified', 'Reg', (195, 205))	('melanomas', 'Disease', 'MESH:D008545', (316, 325))	('NRAS', 'Gene', (236, 240))	('BRAF', 'Gene', '673', (216, 220))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (271, 279))	('melanoma', 'Disease', (154, 162))	('melanomas', 'Disease', (316, 325))	('BRAF', 'Gene', (216, 220))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
25780	33076392	In particular, 50% of melanoma patients aged 31-50, 41% of patients aged 51-70, and 36% of patients aged > 71 had somatic CDKN2A genetic changes.	('patients', 'Species', '9606', (91, 99))	('CDKN2A', 'Gene', (122, 128))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (31, 39))	('genetic changes', 'Var', (129, 144))
25781	33076392	Further, CDKN2A mutation status is not associated with overall survival in melanoma; melanoma patients with somatic CDKN2A alterations had a median overall survival of 112 months compared to a median overall survival of 79 months in patients with wild-type CDKN2A (Figure 2).	('patients', 'Species', '9606', (94, 102))	('CDKN2A', 'Gene', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('patients', 'Species', '9606', (233, 241))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('alterations', 'Var', (123, 134))
25783	33076392	For instance, CDKN2A mutations are present in 20% (4 out of 20 cases; 3 truncating mutations and one missense mutation) of desmoplastic melanoma, and these alterations predominantly affected either p16INK4a alone or p16INK4a along with p14ARF.	('p14ARF', 'Gene', (236, 242))	('p16INK4a', 'Var', (216, 224))	('p14ARF', 'Gene', '1029', (236, 242))	('affected', 'Reg', (182, 190))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('p16INK4a', 'Var', (198, 206))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (123, 144))	('desmoplastic melanoma', 'Disease', (123, 144))	('CDKN2A', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
25784	33076392	CDKN2A mutations are less common in acral melanoma, with only 9-18% of acral melanomas showing somatic CDKN2A alterations, and these alterations were predominantly homozygous deletions.	('acral melanomas', 'Disease', 'MESH:D008545', (71, 86))	('alterations', 'Var', (110, 121))	('acral melanoma', 'Phenotype', 'HP:0012060', (71, 85))	('acral melanoma', 'Phenotype', 'HP:0012060', (36, 50))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('acral melanoma', 'Disease', (36, 50))	('acral melanomas', 'Disease', (71, 86))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('acral melanomas', 'Phenotype', 'HP:0012060', (71, 86))	('CDKN2A', 'Gene', (103, 109))	('acral melanoma', 'Disease', 'MESH:D008545', (71, 85))	('acral melanoma', 'Disease', 'MESH:D008545', (36, 50))	('CDKN2A', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
25785	33076392	CDKN2A mutation rates were similarly low in uveal melanoma, with only one missense mutation (V28G within exon 1alpha) detected in the 80 uveal melanomas included in TCGA uveal melanoma cohort.	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('V28G', 'Mutation', 'rs775176191', (93, 97))	('uveal melanoma', 'Disease', (170, 184))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('uveal melanoma', 'Disease', (44, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (137, 151))	('uveal melanoma', 'Disease', (137, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (137, 151))	('CDKN2A', 'Gene', (0, 6))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('uveal melanomas', 'Phenotype', 'HP:0007716', (137, 152))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanomas', 'Disease', (143, 152))	('mutation', 'Var', (7, 15))
25787	33076392	Loss of function alterations affecting the CDKN2A locus have been identified in the germline of multiple-case melanoma kindreds around the world.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('CDKN2A', 'Gene', (43, 49))	('Loss of function', 'NegReg', (0, 16))	('alterations', 'Var', (17, 28))
25789	33076392	The systematic analysis of 80 melanoma-prone families identified 37 distinct mutations affecting the CDKN2A locus.	('CDKN2A', 'Gene', (101, 107))	('mutations', 'Var', (77, 86))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))
25790	33076392	Half of these mutations were in exon 1alpha (these will not affect the p14ARF coding sequence) and half were in exon 2.	('p14ARF', 'Gene', (71, 77))	('mutations', 'Var', (14, 23))	('p14ARF', 'Gene', '1029', (71, 77))
25791	33076392	Whereas all exon 2 mutations altered the p16INK4a protein, only 14/20 of these exon 2 mutations also impacted the p14ARF protein sequence.	('mutations', 'Var', (86, 95))	('p14ARF', 'Gene', '1029', (114, 120))	('p16INK4a protein', 'Protein', (41, 57))	('mutations', 'Var', (19, 28))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('impacted', 'Reg', (101, 109))	('altered', 'Reg', (29, 36))	('p14ARF', 'Gene', (114, 120))
25793	33076392	Germline inactivation of p14ARF is mostly due to whole gene deletions, insertions, or splice mutations.	('p14ARF', 'Gene', (25, 31))	('insertions', 'Var', (71, 81))	('p14ARF', 'Gene', '1029', (25, 31))	('splice mutations', 'Var', (86, 102))
25794	33076392	For instance, a germline deletion of p14ARF exon 1beta coding sequence and a germline mutation (Gly16Asp) in exon 1beta were identified in families with melanoma-neural system tumor syndrome; a frameshift mutation (16 base pair insertion) was detected in a Spanish female who developed multiple primary melanomas at a young age; a splice mutation resulting in haploinsufficiency was associated with melanoma in a single family; and a mutation coding for the missense Arg54His mutation in p14ARF was found in an Italian melanoma family.	('Gly16Asp', 'Mutation', 'rs1444669684', (96, 104))	('haploinsufficiency', 'Disease', 'MESH:D058495', (360, 378))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('p14ARF exon 1beta', 'Gene', (37, 54))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (399, 407))	('melanoma', 'Disease', (399, 407))	('haploinsufficiency', 'Disease', (360, 378))	('melanomas', 'Disease', 'MESH:D008545', (303, 312))	('missense Arg54His', 'Var', (458, 475))	('p14ARF', 'Gene', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (519, 527))	('p14ARF', 'Gene', (488, 494))	('melanomas', 'Disease', (303, 312))	('neural system tumor', 'Phenotype', 'HP:0004375', (162, 181))	('melanoma', 'Disease', 'MESH:D008545', (303, 311))	('Arg54His', 'Mutation', 'p.R54H', (467, 475))	('melanoma', 'Disease', 'MESH:D008545', (399, 407))	('melanoma-neural system tumor syndrome', 'Disease', (153, 190))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('melanoma-neural system tumor syndrome', 'Disease', 'MESH:C536149', (153, 190))	('melanomas', 'Phenotype', 'HP:0002861', (303, 312))	('melanoma', 'Phenotype', 'HP:0002861', (519, 527))	('melanoma', 'Disease', (519, 527))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('p14ARF', 'Gene', '1029', (37, 43))	('p14ARF exon 1beta', 'Gene', '1029', (37, 54))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanoma', 'Disease', (303, 311))	('p14ARF', 'Gene', '1029', (488, 494))
25795	33076392	Large germline CDKN2A deletions encompassing exon 1alpha, 2, and/or 3 which affect both p14ARF and p16INK4a have also been identified in melanoma-prone kindreds, although these are uncommon and account for only 2% of germline CDKN2A alterations.	('affect', 'Reg', (76, 82))	('deletions', 'Var', (22, 31))	('CDKN2A', 'Gene', (15, 21))	('p14ARF', 'Gene', '1029', (88, 94))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('p14ARF', 'Gene', (88, 94))
25796	33076392	A germline splice site mutation removing exon 2 of CDKN2A was identified in a family with melanoma and multiple dysplastic nevi.	('melanoma and multiple dysplastic', 'Disease', 'MESH:D008545', (90, 122))	('multiple dysplastic nevi', 'Phenotype', 'HP:0001054', (103, 127))	('mutation removing', 'Var', (23, 40))	('nevi', 'Phenotype', 'HP:0003764', (123, 127))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (112, 127))	('CDKN2A', 'Gene', (51, 57))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
25797	33076392	The penetrance of germline CDKN2A mutations for melanoma also varies according to geographical locations, with penetrance increasing with higher baseline melanoma incidence rates.	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('CDKN2A', 'Gene', (27, 33))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('mutations', 'Var', (34, 43))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
25799	33076392	A GenoMEL study that screened for CDKN2A mutations in Australian, European, and North American families reported increased mutation frequency in families with melanoma and pancreatic cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('CDKN2A', 'Gene', (34, 40))	('melanoma and pancreatic cancer', 'Disease', 'MESH:C563985', (159, 189))	('increased', 'PosReg', (113, 122))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
25800	33076392	A prospective study examining cancer diagnoses in Swedish carriers of the Arg112dup alteration in CDKN2A concluded that mutation carriers had a significantly elevated risk of developing pancreatic, lung, head and neck, and gastro-oesophageal carcinomas.	('gastro-oesophageal carcinomas', 'Disease', (223, 252))	('neck', 'cellular_component', 'GO:0044326', ('213', '217'))	('pancreatic', 'Disease', (186, 196))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Arg112dup', 'Var', (74, 83))	('CDKN2A', 'Gene', (98, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('developing', 'PosReg', (175, 185))	('lung', 'Disease', (198, 202))	('gastro-oesophageal carcinomas', 'Disease', 'MESH:D005764', (223, 252))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('pancreatic', 'Disease', 'MESH:D010195', (186, 196))
25802	33076392	developed the CDKN2A Mutation (CM) score to predict CDKN2A germline mutation status among melanoma prone families; a CM score > 35 out of 49 possible points was associated with a > 90% probability of a melanoma-prone family sharing a CDKN2A mutation.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('CM score', 'Var', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
25803	33076392	Importantly, CDKN2A mutation carriers have been reported to be at increased risk of developing other cancers, including breast, lung, and non-melanoma skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (156, 163))	('skin cancer', 'Phenotype', 'HP:0008069', (151, 162))	('cancers', 'Disease', (101, 108))	('lung', 'Disease', (128, 132))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('mutation', 'Var', (20, 28))	('skin cancers', 'Phenotype', 'HP:0008069', (151, 163))	('CDKN2A', 'Gene', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (138, 163))	('breast', 'Disease', (120, 126))	('non-melanoma skin cancers', 'Disease', (138, 163))
25804	33076392	These additional cancer risks are not consistently observed, however, and this may indicate that the risk of other cancer types reflects the specific germline CDKN2A mutation.	('cancer', 'Disease', (115, 121))	('germline', 'Var', (150, 158))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('CDKN2A', 'Gene', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
25805	33076392	For instance, whereas 25-36% of melanoma-prone families with Arg24Pro, c.34G>T, or Gly101Trp had pancreatic cancer, none of the 30 families with Met53Ile, c.IVS2-104A>G, or c.32_33ins9-32 developed pancreatic cancer.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('Met53Ile', 'Var', (145, 153))	('pancreatic cancer', 'Disease', (198, 215))	('c.34G>T', 'Mutation', 'rs121913250', (71, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))	('c.IVS2-104A>G', 'Var', (155, 168))	('Gly101Trp', 'Var', (83, 92))	('c.IVS2-104A>G', 'Mutation', 'c.IVS2-104A>G', (155, 168))	('Arg24Pro', 'SUBSTITUTION', 'None', (61, 69))	('Arg24Pro', 'Var', (61, 69))	('c.32_33ins9-32', 'Var', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('c.32_33ins9', 'Mutation', 'c.32_33ins9', (173, 184))	('Gly101Trp', 'SUBSTITUTION', 'None', (83, 92))	('c.34G>T', 'Var', (71, 78))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (198, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (198, 215))	('Met53Ile', 'Mutation', 'rs104894095', (145, 153))
25806	33076392	Finally, a CDKN2A germline deletion of the p14ARF-specific exon 1ss was associated with excess risk for melanoma, astrocytoma, neurofibromas, and schwannomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('p14ARF', 'Gene', (43, 49))	('melanoma', 'Disease', (104, 112))	('schwannomas', 'Disease', (146, 157))	('astrocytoma', 'Disease', 'MESH:D001254', (114, 125))	('associated', 'Reg', (72, 82))	('p14ARF', 'Gene', '1029', (43, 49))	('germline deletion', 'Var', (18, 35))	('neurofibromas', 'Phenotype', 'HP:0001067', (127, 140))	('astrocytoma', 'Disease', (114, 125))	('schwannomas', 'Disease', 'MESH:D009442', (146, 157))	('astrocytoma', 'Phenotype', 'HP:0009592', (114, 125))	('CDKN2A', 'Gene', (11, 17))	('neurofibromas', 'Disease', (127, 140))	('neurofibromas', 'Disease', 'MESH:D009455', (127, 140))	('schwannomas', 'Phenotype', 'HP:0100008', (146, 157))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
25807	33076392	Modifier genes for melanoma kindreds carrying CDKN2A mutations have also been reported.	('CDKN2A', 'Gene', (46, 52))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('mutations', 'Var', (53, 62))
25808	33076392	In an early study on Dutch melanoma families, the melanocortin-1 receptor (MC1R) variant Arg151Cys increased the risk of melanoma in carriers of a p16INK4a-inactivating deletion (known as p16-Leiden).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanocortin-1 receptor', 'Gene', '4157', (50, 73))	('MC1R', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('p16', 'Gene', (188, 191))	('p16', 'Gene', (147, 150))	('Arg151Cys', 'SUBSTITUTION', 'None', (89, 98))	('p16', 'Gene', '1029', (147, 150))	('Arg151Cys', 'Var', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('increased', 'PosReg', (99, 108))	('melanoma', 'Disease', (27, 35))	('p16', 'Gene', '1029', (188, 191))	('MC1R', 'Gene', '4157', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('melanocortin-1 receptor', 'Gene', (50, 73))
25809	33076392	This increased risk of melanoma was not wholly attributed to the fair skin type associated with this MC1R variant.	('fair skin', 'Phenotype', 'HP:0007513', (65, 74))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('MC1R', 'Gene', '4157', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('MC1R', 'Gene', (101, 105))	('variant', 'Var', (106, 113))
25810	33076392	A later study confirmed that four frequent MC1R variants (Val60Leu, Val92Met, Arg151Cys, Arg160Tro) were associated with an increased melanoma risk in CDKN2A mutation carriers.	('MC1R', 'Gene', (43, 47))	('MC1R', 'Gene', '4157', (43, 47))	('Arg151Cys', 'SUBSTITUTION', 'None', (78, 87))	('Val92Met', 'SUBSTITUTION', 'None', (68, 76))	('Arg160Tro', 'Var', (89, 98))	('Arg151Cys', 'Var', (78, 87))	('Val60Leu', 'SUBSTITUTION', 'None', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('CDKN2A', 'Gene', (151, 157))	('melanoma', 'Disease', (134, 142))	('Val60Leu', 'Var', (58, 66))	('associated', 'Reg', (105, 115))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('Val92Met', 'Var', (68, 76))
25811	33076392	Polymorphisms in genes involved in DNA repair (POLN, PRKDC), immune regulation (IL9), and apoptosis (BCL7A, BCL2L1) have also been associated with increased melanoma risk, and in some instances, these polymorphisms (IL9 and BCL7A) have stronger risks in CDKN2A-positive families.	('IL9', 'molecular_function', 'GO:0005140', ('216', '219'))	('POLN', 'Gene', '353497', (47, 51))	('BCL7A', 'Gene', (224, 229))	('IL9', 'Gene', '3578', (216, 219))	('BCL2L1', 'Gene', '598', (108, 114))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('Polymorphisms', 'Var', (0, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('BCL7A', 'Gene', (101, 106))	('IL9', 'Gene', (216, 219))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('IL9', 'molecular_function', 'GO:0005140', ('80', '83'))	('IL9', 'Gene', '3578', (80, 83))	('PRKDC', 'Gene', '5591', (53, 58))	('POLN', 'Gene', (47, 51))	('associated', 'Reg', (131, 141))	('BCL7A', 'Gene', '605', (224, 229))	('PRKDC', 'Gene', (53, 58))	('BCL2L1', 'Gene', (108, 114))	('IL9', 'Gene', (80, 83))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('BCL7A', 'Gene', '605', (101, 106))	('BCL2', 'molecular_function', 'GO:0015283', ('108', '112'))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))
25812	33076392	Melanoma-associated CDKN2A missense mutations commonly diminish the capacity of p16INK4a to bind and inhibit CDK4/6.	('diminish', 'NegReg', (55, 63))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('inhibit', 'NegReg', (101, 108))	('p16INK4a', 'Protein', (80, 88))	('CDK', 'molecular_function', 'GO:0004693', ('109', '112'))	('Melanoma', 'Disease', (0, 8))	('missense mutations', 'Var', (27, 45))	('bind', 'Interaction', (92, 96))	('CDK4/6', 'Protein', (109, 115))	('CDKN2A', 'Gene', (20, 26))
25813	33076392	described germline CDKN2A substitutions that impaired the ability of p16INK4a to inhibit the catalytic activity of cyclin D1/CDK4 and cyclin D1/CDK6 complexes.	('cyclin', 'molecular_function', 'GO:0016538', ('115', '121'))	('CDK4', 'Gene', (125, 129))	('cyclin D1', 'Gene', '595', (115, 124))	('cyclin D1', 'Gene', (115, 124))	('CDK4', 'Gene', '1019', (125, 129))	('CDKN2A', 'Gene', (19, 25))	('catalytic activity', 'molecular_function', 'GO:0003824', ('93', '111'))	('CDK6', 'Gene', (144, 148))	('inhibit', 'NegReg', (81, 88))	('cyclin D1', 'Gene', '595', (134, 143))	('CDK6', 'Gene', '1021', (144, 148))	('cyclin D1', 'Gene', (134, 143))	('cyclin', 'molecular_function', 'GO:0016538', ('134', '140'))	('substitutions', 'Var', (26, 39))	('CDK', 'molecular_function', 'GO:0004693', ('144', '147'))	('CDK', 'molecular_function', 'GO:0004693', ('125', '128'))	('impaired', 'NegReg', (45, 53))	('catalytic activity', 'MPA', (93, 111))
25814	33076392	The Met53Ile and Arg24Pro germline mutants of p16INK4a have diminished capacity to bind CDK4 compared to wild-type p16INK4a.	('Met53Ile', 'Var', (4, 12))	('bind', 'Interaction', (83, 87))	('p16INK4a', 'Gene', (46, 54))	('diminished', 'NegReg', (60, 70))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('CDK4', 'Gene', '1019', (88, 92))	('CDK4', 'Gene', (88, 92))	('Arg24Pro', 'Var', (17, 25))	('Met53Ile', 'Mutation', 'rs104894095', (4, 12))	('Arg24Pro', 'SUBSTITUTION', 'None', (17, 25))	('capacity', 'MPA', (71, 79))
25815	33076392	Although, it is worth noting that the CDK4-binding affinity of the Arg24Pro mutation is controversial.	('Arg24Pro', 'SUBSTITUTION', 'None', (67, 75))	('Arg24Pro', 'Var', (67, 75))	('CDK', 'molecular_function', 'GO:0004693', ('38', '41'))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (38, 42))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))
25816	33076392	The somatic missense p16INK4a mutation (Pro48Leu) decreased the ability of the protein to bind and inhibit CDK6 kinase activity, thus, failing to arrest melanoma cell growth.	('p16INK4a', 'Var', (21, 29))	('arrest melanoma', 'Disease', (146, 161))	('bind', 'Interaction', (90, 94))	('missense p16INK4a', 'Var', (12, 29))	('kinase activity', 'molecular_function', 'GO:0016301', ('112', '127'))	('ability', 'MPA', (64, 71))	('cell growth', 'biological_process', 'GO:0016049', ('162', '173'))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('inhibit', 'NegReg', (99, 106))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('decreased', 'NegReg', (50, 59))	('arrest melanoma', 'Disease', 'MESH:D006323', (146, 161))	('CDK6', 'Gene', (107, 111))	('CDK6', 'Gene', '1021', (107, 111))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('Pro48Leu', 'Mutation', 'p.P48L', (40, 48))
25817	33076392	Melanoma cell lines with a Pro81Leu missense mutation in p16INK4a also showed defective binding ability to CDK4, and these cells had more aggressive cell growth compared to the wild-type cells.	('Pro81Leu missense mutation', 'Var', (27, 53))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('CDK4', 'Gene', '1019', (107, 111))	('defective', 'NegReg', (78, 87))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('p16INK4a', 'Gene', (57, 65))	('binding', 'molecular_function', 'GO:0005488', ('88', '95'))	('more', 'PosReg', (133, 137))	('Melanoma', 'Disease', (0, 8))	('Pro81Leu', 'Mutation', 'rs11552823', (27, 35))	('cell growth', 'biological_process', 'GO:0016049', ('149', '160'))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('aggressive cell growth', 'CPA', (138, 160))	('binding', 'Interaction', (88, 95))	('CDK4', 'Gene', (107, 111))
25818	33076392	There is some evidence that CDKN2A mutations do not only impact the binding affinity of p16INK4a for CDK4 or CDK6.	('CDK6', 'Gene', (109, 113))	('impact', 'Reg', (57, 63))	('CDK4', 'Gene', (101, 105))	('CDK6', 'Gene', '1021', (109, 113))	('CDK4', 'Gene', '1019', (101, 105))	('CDK', 'molecular_function', 'GO:0004693', ('109', '112'))	('CDK', 'molecular_function', 'GO:0004693', ('101', '104'))	('CDKN2A', 'Gene', (28, 34))	('binding affinity', 'Interaction', (68, 84))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('mutations', 'Var', (35, 44))
25819	33076392	Indeed, several melanoma-associated mutations (e.g., N-terminal 24bp p16INK4a duplication, Arg24Pro, Leu117Pro) retained CDK4 and/or CDK6 binding activity even though they displayed diminished cell cycle inhibitory activity, suggesting that other p16INK4a binding interactions may be important in melanoma susceptibility.	('Leu117Pro', 'Var', (101, 110))	('p16INK4a', 'Gene', (69, 77))	('binding', 'molecular_function', 'GO:0005488', ('256', '263'))	('Arg24Pro', 'SUBSTITUTION', 'None', (91, 99))	('Arg24Pro', 'Var', (91, 99))	('CDK6', 'Gene', '1021', (133, 137))	('melanoma', 'Disease', 'MESH:D008545', (297, 305))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('binding', 'Interaction', (138, 145))	('melanoma', 'Disease', (16, 24))	('CDK4', 'Gene', (121, 125))	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('CDK6', 'Gene', (133, 137))	('Leu117Pro', 'SUBSTITUTION', 'None', (101, 110))	('cell cycle', 'biological_process', 'GO:0007049', ('193', '203'))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))	('CDK4', 'Gene', '1019', (121, 125))	('activity', 'MPA', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('melanoma', 'Disease', (297, 305))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))
25821	33076392	Various p16INK4a mutants, including the melanoma-associated germline mutations Ala36Pro and Ala57Val, were also associated with impaired oxidative regulatory functions, and intracellular oxidative dysregulation in melanocytes can lead to genetic damage that contributes to increased melanoma susceptibility.	('intracellular', 'cellular_component', 'GO:0005622', ('173', '186'))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('intracellular oxidative dysregulation', 'MPA', (173, 210))	('Ala57Val', 'Var', (92, 100))	('increased', 'PosReg', (273, 282))	('impaired', 'NegReg', (128, 136))	('genetic damage', 'Disease', 'MESH:D030342', (238, 252))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('Ala36Pro', 'SUBSTITUTION', 'None', (79, 87))	('p16INK4a', 'Gene', (8, 16))	('Ala36Pro', 'Var', (79, 87))	('genetic damage', 'Disease', (238, 252))	('lead to', 'Reg', (230, 237))	('Ala57Val', 'SUBSTITUTION', 'None', (92, 100))	('oxidative regulatory functions', 'MPA', (137, 167))
25822	33076392	Inactivation of p16INK4a has been shown to contribute to the failure of senescence and progression from normal melanocytes to malignant melanoma via benign nevi, dysplastic nevi, radial growth phase, and vertical growth phase stages.	('malignant melanoma', 'Disease', 'MESH:D008545', (126, 144))	('p16INK4a', 'Gene', (16, 24))	('malignant melanoma', 'Disease', (126, 144))	('senescence', 'CPA', (72, 82))	('dysplastic', 'Disease', 'MESH:D004416', (162, 172))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (162, 177))	('dysplastic', 'Disease', (162, 172))	('nevi', 'Phenotype', 'HP:0003764', (156, 160))	('senescence', 'biological_process', 'GO:0010149', ('72', '82'))	('nevi', 'Phenotype', 'HP:0003764', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('malignant melanoma', 'Phenotype', 'HP:0002861', (126, 144))	('vertical growth phase', 'CPA', (204, 225))	('radial growth phase', 'CPA', (179, 198))	('progression', 'CPA', (87, 98))	('Inactivation', 'Var', (0, 12))	('benign nevi', 'Disease', (149, 160))
25823	33076392	Loss of p16INK4a as a single event is not sufficient to induce melanomagenesis but does predispose one to melanoma development, especially in the presence of other driver mutations.	('p16INK4a', 'Protein', (8, 16))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('predispose', 'Reg', (88, 98))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('Loss', 'Var', (0, 4))	('melanoma', 'Disease', (63, 71))
25824	33076392	For instance, loss of p16INK4a cooperates with BRAFV600E oncogenic mutation to promote melanoma progression in genetic mouse models.	('melanoma', 'Disease', (87, 95))	('loss', 'Var', (14, 18))	('mouse', 'Species', '10090', (119, 124))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('p16INK4a', 'Protein', (22, 30))	('promote', 'PosReg', (79, 86))	('BRAFV600E', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
25828	33076392	A 16 base pair insertion (60ins16) caused by a duplication of a CG-rich region within exon 1beta was detected in a Spanish female who had multiple primary melanomas.	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('60ins16', 'Var', (26, 33))	('CG-rich region', 'Gene', (64, 78))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('duplication', 'Var', (47, 58))	('60ins16', 'Mutation', 'c.60ins16', (26, 33))	('melanomas', 'Disease', (155, 164))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
25830	33076392	In contrast, another p14ARF variant (Gly16Asp) in exon 1beta retained its ability to bind HDM2 and stabilize p53.	('p14ARF', 'Gene', '1029', (21, 27))	('ability', 'MPA', (74, 81))	('p14ARF', 'Gene', (21, 27))	('HDM2', 'Gene', (90, 94))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('Gly16Asp', 'Var', (37, 45))	('Gly16Asp', 'Mutation', 'rs1444669684', (37, 45))	('bind', 'Interaction', (85, 89))	('HDM2', 'Gene', '4193', (90, 94))
25831	33076392	A splice site mutation in exon 1beta was shown to cause p14ARF haploinsufficiency and was associated with melanoma susceptibility.	('cause', 'Reg', (50, 55))	('haploinsufficiency', 'Disease', (63, 81))	('p14ARF', 'Gene', '1029', (56, 62))	('haploinsufficiency', 'Disease', 'MESH:D058495', (63, 81))	('associated with', 'Reg', (90, 105))	('p14ARF', 'Gene', (56, 62))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('splice site mutation', 'Var', (2, 22))
25832	33076392	There have been several studies investigating the role of CDKN2A exon 2 mutations that impact the p14ARF coding sequence.	('p14ARF', 'Gene', '1029', (98, 104))	('mutations', 'Var', (72, 81))	('CDKN2A', 'Gene', (58, 64))	('p14ARF', 'Gene', (98, 104))
25833	33076392	In one study, 3/7 p14ARF mutations, encoded by CDKN2A exon 2 mutations, altered the subcellular distribution of p14ARF and diminished its ability to stabilize p53.	('p14ARF', 'Gene', (112, 118))	('mutations', 'Var', (25, 34))	('altered', 'Reg', (72, 79))	('p53', 'Gene', (159, 162))	('p53', 'Gene', '7157', (159, 162))	('diminished', 'NegReg', (123, 133))	('CDKN2A', 'Gene', (47, 53))	('p14ARF', 'Gene', '1029', (18, 24))	('subcellular distribution', 'MPA', (84, 108))	('mutations', 'Var', (61, 70))	('p14ARF', 'Gene', '1029', (112, 118))	('p14ARF', 'Gene', (18, 24))	('ability', 'MPA', (138, 145))
25834	33076392	The restoration of p14ARF and/or p16INK4a functions has not yet been possible, and most therapeutic strategies involve modulating downstream cell cycle regulators or pathways to overcome the loss of CDKN2A-encoded functions.	('p14ARF', 'Gene', (19, 25))	('modulating', 'Reg', (119, 129))	('cell cycle', 'biological_process', 'GO:0007049', ('141', '151'))	('p14ARF', 'Gene', '1029', (19, 25))	('p16INK4a', 'Var', (33, 41))
25847	33076392	The combination of ribociclib and MDM2 inhibition also enhanced tumor regression and overcame resistance to CDK4/6 inhibitors in a melanoma xenograft model.	('inhibition', 'Var', (39, 49))	('tumor', 'Disease', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('CDK', 'molecular_function', 'GO:0004693', ('108', '111'))	('enhanced', 'PosReg', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('MDM2', 'Gene', '4193', (34, 38))	('ribociclib', 'Chemical', 'MESH:C000589651', (19, 29))	('MDM2', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
25851	33076392	Loss of CDKN2A has been shown to predict response to CDK4/6 inhibitors in melanoma, glioblastoma, ovarian, and rhabdoid tumor cells.	('rhabdoid tumor', 'Disease', (111, 125))	('CDKN2A', 'Gene', (8, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('CDK4/6', 'Gene', (53, 59))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('response to', 'MPA', (41, 52))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (111, 125))	('Loss', 'Var', (0, 4))	('melanoma, glioblastoma, ovarian', 'Disease', 'MESH:D005909', (74, 105))
25853	33076392	The presence of an activating Arg24Cys CDK4 mutation, which abolishes the ability of CDK4 to bind to p16INK4 was also associated with melanoma cell sensitivity to CDK4/6 inhibition.	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('Arg24Cys', 'SUBSTITUTION', 'None', (30, 38))	('activating', 'PosReg', (19, 29))	('CDK4', 'Gene', (163, 167))	('CDK4', 'Gene', '1019', (163, 167))	('CDK4', 'Gene', '1019', (39, 43))	('CDK4', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('CDK4', 'Gene', (85, 89))	('melanoma', 'Disease', (134, 142))	('p16INK4', 'Gene', '1029', (101, 108))	('p16INK4', 'Gene', (101, 108))	('associated', 'Reg', (118, 128))	('CDK4', 'Gene', '1019', (85, 89))	('Arg24Cys', 'Var', (30, 38))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('CDK', 'molecular_function', 'GO:0004693', ('163', '166'))	('CDK', 'molecular_function', 'GO:0004693', ('85', '88'))
25855	33076392	Considering that CDKN2A methylation can lead to p14ARF and p16INK4a loss, epigenetic reactivation of CDKN2A has also been attempted with inhibitors of DNA methyltransferase (DNMT), histone deacetylase (HDAC), histone methyltransferase, and histone acetyltransferase.	('DNA methyltransferase', 'Gene', (151, 172))	('p14ARF', 'Gene', (48, 54))	('methylation', 'Var', (24, 35))	('CDKN2A', 'Gene', (17, 23))	('DNA methyltransferase', 'Gene', '1786', (151, 172))	('p16INK4a', 'Gene', (59, 67))	('DNMT', 'Gene', '1786', (174, 178))	('loss', 'NegReg', (68, 72))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('DNMT', 'Gene', (174, 178))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))	('p14ARF', 'Gene', '1029', (48, 54))
25856	33076392	These inhibitors have been shown to induce p14ARF and p16INK4a expression in cancer cell lines and preclinical models (reviewed in reference).	('p14ARF', 'Gene', (43, 49))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('p14ARF', 'Gene', '1029', (43, 49))	('expression', 'MPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('p16INK4a', 'Var', (54, 62))	('induce', 'PosReg', (36, 42))
25858	33076392	However, given that these epigenetic modulators have promiscuous effects, it is difficult to attribute the consequent melanoma control on modulation of p14ARF and p16INK4a function alone.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('p14ARF', 'Gene', '1029', (152, 158))	('p16INK4a', 'Var', (163, 171))	('p14ARF', 'Gene', (152, 158))
25862	33076392	Despite the high frequency of CDKN2A alterations in melanomas, the impact of CDKN2A mutations on patient responses to BRAF/MEK inhibitors is not well established.	('BRAF', 'Gene', '673', (118, 122))	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('MEK', 'Gene', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('MEK', 'Gene', '5609', (123, 126))	('BRAF', 'Gene', (118, 122))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', (30, 36))	('melanomas', 'Disease', (52, 61))	('alterations', 'Var', (37, 48))	('patient', 'Species', '9606', (97, 104))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
25863	33076392	For instance, in melanoma cell studies, the presence of p16INK4a-resistant CDK4 mutations (including the melanoma-associated germline CDK4 Arg24Cys mutation) did not alter cell sensitivity to BRAF inhibitors.	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('melanoma', 'Disease', (105, 113))	('BRAF', 'Gene', '673', (192, 196))	('CDK4', 'Gene', (75, 79))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', (192, 196))	('Arg24Cys', 'Var', (139, 147))	('melanoma', 'Disease', (17, 25))	('CDK4', 'Gene', '1019', (75, 79))	('CDK4', 'Gene', '1019', (134, 138))	('CDK4', 'Gene', (134, 138))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('Arg24Cys', 'SUBSTITUTION', 'None', (139, 147))	('p16INK4a-resistant', 'Var', (56, 74))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))
25864	33076392	Conversely, the overexpression of cyclin D1 was associated with BRAF inhibitor resistance and resistance was enhanced when cyclin D1 overexpression was combined with the CDK4 Arg24Cys mutation.	('resistance', 'MPA', (94, 104))	('cyclin D1', 'Gene', (34, 43))	('CDK4', 'Gene', (170, 174))	('Arg24Cys', 'SUBSTITUTION', 'None', (175, 183))	('BRAF', 'Gene', '673', (64, 68))	('cyclin', 'molecular_function', 'GO:0016538', ('123', '129'))	('overexpression', 'PosReg', (16, 30))	('CDK4', 'Gene', '1019', (170, 174))	('associated', 'Reg', (48, 58))	('CDK', 'molecular_function', 'GO:0004693', ('170', '173'))	('BRAF', 'Gene', (64, 68))	('cyclin D1', 'Gene', (123, 132))	('cyclin', 'molecular_function', 'GO:0016538', ('34', '40'))	('cyclin D1', 'Gene', '595', (34, 43))	('cyclin D1', 'Gene', '595', (123, 132))	('Arg24Cys', 'Var', (175, 183))	('enhanced', 'PosReg', (109, 117))
25867	33076392	It is important to mention that 15-40% of mucosal and acral melanomas show activating mutations or amplification of the receptor tyrosine kinase KIT, and the kinase inhibitor imatinib has shown efficacy in KIT-mutant melanoma with an overall response rate of 54%.	('KIT', 'molecular_function', 'GO:0005020', ('206', '209'))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('KIT', 'Gene', '3815', (206, 209))	('KIT', 'Gene', (145, 148))	('amplification', 'Var', (99, 112))	('acral melanomas', 'Disease', 'MESH:D008545', (54, 69))	('mutations', 'Var', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('acral melanomas', 'Phenotype', 'HP:0012060', (54, 69))	('melanoma', 'Disease', (60, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('KIT', 'Gene', '3815', (145, 148))	('KIT', 'Gene', (206, 209))	('activating', 'PosReg', (75, 85))	('KIT', 'molecular_function', 'GO:0005020', ('145', '148'))	('acral melanomas', 'Disease', (54, 69))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('158', '174'))	('imatinib', 'Chemical', 'MESH:D000068877', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
25868	33076392	Imatinib is also used commonly in the treatment of BCR-ABL chronic myelogenous leukemia but has not been as successful in BCR-ABL positive acute lymphoblastic leukemia showing deletion in the CDKN2A gene, suggesting that expression of p14ARF and/or p16INK4a may sensitize cancer cells to imatinib treatment.	('deletion', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('p14ARF', 'Gene', '1029', (235, 241))	('BCR-ABL', 'Gene', (51, 58))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (145, 167))	('BCR-ABL', 'Gene', (122, 129))	('CDKN2A', 'Gene', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (67, 87))	('lymphoblastic leukemia', 'Disease', (145, 167))	('sensitize', 'Reg', (262, 271))	('p14ARF', 'Gene', (235, 241))	('myelogenous leukemia', 'Disease', (67, 87))	('positive acute lymphoblastic leukemia', 'Phenotype', 'HP:0004848', (130, 167))	('imatinib', 'Chemical', 'MESH:D000068877', (288, 296))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (139, 167))	('BCR-ABL', 'Gene', '25', (51, 58))	('p16INK4a', 'Var', (249, 257))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (145, 167))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (59, 87))	('leukemia', 'Phenotype', 'HP:0001909', (159, 167))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (67, 87))	('BCR-ABL', 'Gene', '25', (122, 129))	('cancer', 'Disease', (272, 278))
25869	33076392	Thus, it is tempting to speculate that CDKN2A inactivation in melanoma may analogously diminish sensitivity to imatinib in melanoma.	('melanoma', 'Disease', (62, 70))	('diminish', 'NegReg', (87, 95))	('CDKN2A', 'Gene', (39, 45))	('imatinib', 'Chemical', 'MESH:D000068877', (111, 119))	('sensitivity to imatinib', 'MPA', (96, 119))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('inactivation', 'Var', (46, 58))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
25872	33076392	Response rates are higher with PD-1 inhibitors (up to 45%) and the combination of CTLA-4 and PD-1 inhibitors further enhances the response rate to 60%.	('inhibitors', 'Var', (36, 46))	('inhibitors', 'Var', (98, 108))	('higher', 'PosReg', (19, 25))	('Response', 'MPA', (0, 8))	('CTLA-4', 'Gene', '1493', (82, 88))	('PD-1', 'Gene', (31, 35))	('PD-1', 'Gene', (93, 97))	('PD-1', 'Gene', '5133', (31, 35))	('PD-1', 'Gene', '5133', (93, 97))	('CTLA-4', 'Gene', (82, 88))	('enhances', 'PosReg', (117, 125))
25874	33076392	In this context, knockout of the CDKN2A gene in mice resulted in increased inflammatory cytokine expression in the skin following chronic UVB irradiation.	('increased', 'PosReg', (65, 74))	('CDKN2A', 'Gene', (33, 39))	('mice', 'Species', '10090', (48, 52))	('inflammatory cytokine expression in', 'MPA', (75, 110))	('knockout', 'Var', (17, 25))	('increased inflammatory cytokine expression', 'Phenotype', 'HP:0012649', (65, 107))
25877	33076392	JAK2 is a critical transcription factor in IFNgamma signaling, and the loss of JAK2 is associated with PD-1 inhibitor resistance.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('IFNgamma', 'Gene', (43, 51))	('JAK', 'molecular_function', 'GO:0004713', ('79', '82'))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', '3717', (79, 83))	('PD-1', 'Gene', (103, 107))	('IFNgamma', 'Gene', '3458', (43, 51))	('associated', 'Reg', (87, 97))	('PD-1', 'Gene', '5133', (103, 107))	('transcription factor', 'molecular_function', 'GO:0000981', ('19', '39'))	('JAK2', 'Gene', (0, 4))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('transcription', 'biological_process', 'GO:0006351', ('19', '32'))	('loss', 'Var', (71, 75))	('JAK2', 'Gene', (79, 83))
25879	33076392	Hence, loss of CDKN2A may increase inflammatory responses, which may augment response to immune checkpoint blockade, but also confer susceptibility to immunotherapy resistance through IFNgamma suppression.	('inflammatory responses', 'CPA', (35, 57))	('response to immune checkpoint blockade', 'MPA', (77, 115))	('IFNgamma', 'Gene', (184, 192))	('CDKN2A', 'Gene', (15, 21))	('loss', 'Var', (7, 11))	('increase inflammatory responses', 'Phenotype', 'HP:0012649', (26, 57))	('susceptibility', 'Reg', (133, 147))	('IFNgamma', 'Gene', '3458', (184, 192))	('augment', 'PosReg', (69, 76))	('increase', 'PosReg', (26, 34))
25880	33076392	Given the complexity of the immune response and the heterogeneity of immune cell subsets, it is unclear if and how p14ARF and/or p16INK4a regulate melanoma response to immunotherapy.	('p14ARF', 'Gene', '1029', (115, 121))	('regulate', 'Reg', (138, 146))	('p14ARF', 'Gene', (115, 121))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('immune response', 'biological_process', 'GO:0006955', ('28', '43'))	('p16INK4a', 'Var', (129, 137))
25881	33076392	CDKN2A mutations were not significantly associated with clinical outcomes such as median time to progression, overall survival, and disease control rate in a cohort of 102 cutaneous melanoma patients treated with immune checkpoint inhibitors.	('patients', 'Species', '9606', (191, 199))	('cutaneous melanoma', 'Disease', (172, 190))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (172, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (172, 190))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('mutations', 'Var', (7, 16))
25882	33076392	However, this study did report a trend towards improved time to progression and disease control rate in patients with CDKN2A mutations.	('CDKN2A', 'Gene', (118, 124))	('mutations', 'Var', (125, 134))	('improved', 'PosReg', (47, 55))	('disease control rate', 'CPA', (80, 100))	('patients', 'Species', '9606', (104, 112))	('time to progression', 'MPA', (56, 75))
25883	33076392	Similarly, melanoma patients with CDKN2A germline mutations also showed improved response to immune checkpoint blockade; approximately 58% of carriers responded to therapy, with 32% showing complete response, suggesting that CDKN2A mutation may be associated with better immunotherapy response rates.	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('immunotherapy response', 'CPA', (271, 293))	('mutation', 'Var', (232, 240))	('CDKN2A', 'Gene', (225, 231))	('CDKN2A', 'Gene', (34, 40))	('patients', 'Species', '9606', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
25884	33076392	Although the mechanism for improved immunotherapy responsiveness in CDKN2A mutation carriers remains unclear, melanomas with somatic CDKN2A mutations have an increased mutational burden, and this may result in more neoantigens and stronger immune responses.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('immune responses', 'CPA', (240, 256))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('mutation', 'Var', (75, 83))	('CDKN2A', 'Gene', (68, 74))	('more', 'PosReg', (210, 214))	('CDKN2A', 'Gene', (133, 139))	('neoantigens', 'MPA', (215, 226))	('mutational burden', 'MPA', (168, 185))	('melanomas', 'Disease', (110, 119))	('mutations', 'Var', (140, 149))	('stronger', 'PosReg', (231, 239))	('increased', 'PosReg', (158, 167))
25891	33076392	Similar to p14ARF, ectopic expression of p16INK4a in glioma cell lines also sensitized cells to the chemotherapy drug vincristine.	('p16INK4a', 'Var', (41, 49))	('p14ARF', 'Gene', '1029', (11, 17))	('ectopic expression', 'Var', (19, 37))	('glioma', 'Disease', (53, 59))	('sensitized', 'Reg', (76, 86))	('p14ARF', 'Gene', (11, 17))	('vincristine', 'Chemical', 'MESH:D014750', (118, 129))	('glioma', 'Disease', 'MESH:D005910', (53, 59))	('glioma', 'Phenotype', 'HP:0009733', (53, 59))
25892	33076392	In melanoma cells, CDKN2A expression was associated with better response to chemotherapy in the form of melphalan or actinomycin-D, and enforced accumulation of p16INK4a induced cell death by augmenting response to these cytotoxic drugs.	('death', 'Disease', (183, 188))	('response to these cytotoxic drugs', 'MPA', (203, 236))	('p16INK4a', 'Var', (161, 169))	('better', 'PosReg', (57, 63))	('CDKN2A', 'Gene', (19, 25))	('actinomycin', 'Chemical', 'MESH:D003609', (117, 128))	('melphalan', 'Chemical', 'MESH:D008558', (104, 113))	('cell death', 'biological_process', 'GO:0008219', ('178', '188'))	('response to chemotherapy', 'MPA', (64, 88))	('accumulation', 'PosReg', (145, 157))	('induced', 'PosReg', (170, 177))	('augmenting', 'PosReg', (192, 202))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('death', 'Disease', 'MESH:D003643', (183, 188))
25894	33076392	Many CDKN2A genetic and epigenetic changes impact both the p16INK4a and p14ARF protein products encoded by this locus, and although early studies confirmed the major contribution of p16INK4a in CDKN2A-associated melanoma, there is now significant evidence that p14ARF plays an important and additional role in melanomagenesis.	('p14ARF', 'Gene', '1029', (261, 267))	('impact', 'Reg', (43, 49))	('p14ARF', 'Gene', '1029', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('p16INK4a', 'Var', (182, 190))	('melanoma', 'Disease', (310, 318))	('CDKN2A', 'Gene', (5, 11))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('p14ARF', 'Gene', (261, 267))	('p14ARF', 'Gene', (72, 78))	('CDKN2A-associated', 'Gene', (194, 211))	('melanoma', 'Disease', (212, 220))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('changes', 'Var', (35, 42))
25895	33076392	CDKN2A loss is associated with histological features predictive of poor prognosis in melanoma and also correlates with diminished patient response to treatment, with loss of CDKN2A associated with poor response to BRAF/MEK inhibitors and chemotherapy but potentially improved responses to immune checkpoint inhibitors.	('associated', 'Reg', (181, 191))	('loss', 'NegReg', (7, 11))	('patient', 'Species', '9606', (130, 137))	('BRAF', 'Gene', '673', (214, 218))	('BRAF', 'Gene', (214, 218))	('MEK', 'Gene', (219, 222))	('diminished', 'NegReg', (119, 129))	('CDKN2A', 'Gene', (174, 180))	('loss', 'Var', (166, 170))	('MEK', 'Gene', '5609', (219, 222))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('patient response to treatment', 'MPA', (130, 159))
25896	33076392	The loss of the CDKN2A sequence also co-operates with the BRAF and NRAS oncogenes to promote melanoma development.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('promote', 'PosReg', (85, 92))	('CDKN2A', 'Gene', (16, 22))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', '673', (58, 62))	('NRAS', 'Gene', '4893', (67, 71))	('BRAF', 'Gene', (58, 62))	('loss', 'Var', (4, 8))
25897	33076392	Thus, there is renewed interest in restoring the functional loss of p16INK4a and p14ARF in melanoma, and the frequent loss of this locus in melanoma may provide unique therapeutic opportunities, as the downstream targets retinoblastoma protein and p53 are often retained.	('retinoblastoma', 'Phenotype', 'HP:0009919', (221, 235))	('p16INK4a', 'Var', (68, 76))	('p14ARF', 'Gene', (81, 87))	('p53', 'Gene', (248, 251))	('p53', 'Gene', '7157', (248, 251))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('loss', 'NegReg', (118, 122))	('loss', 'NegReg', (60, 64))	('retinoblastoma', 'Disease', (221, 235))	('retinoblastoma', 'Disease', 'MESH:D012175', (221, 235))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('p14ARF', 'Gene', '1029', (81, 87))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))
25900	32226530	Copy Number Amplification of DNA Damage Repair Pathways Potentiates Therapeutic Resistance in Cancer Rationale: Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy.	('Copy Number', 'Var', (0, 11))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('Loss', 'NegReg', (112, 116))	('DNA', 'MPA', (120, 123))	('tumor', 'Disease', (151, 156))	('Cancer', 'Disease', (94, 100))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('Cancer', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
25902	32226530	This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome.	('DDR genes', 'Gene', (75, 84))	('occurs', 'Reg', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('copy number amplification', 'Var', (46, 71))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('patient', 'Species', '9606', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
25906	32226530	Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors.	('global mutation load', 'MPA', (60, 80))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('amplification', 'Var', (26, 39))	('DDR', 'Gene', (17, 20))	('increased', 'PosReg', (145, 154))	('Tumors', 'Disease', (0, 6))	('decreased', 'NegReg', (50, 59))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
25910	32226530	Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response.	('drug resistance', 'biological_process', 'GO:0009315', ('216', '231'))	('correlations', 'Interaction', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('copy number amplification', 'Var', (182, 207))	('patient', 'Species', '9606', (277, 284))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('drug resistance', 'biological_process', 'GO:0042493', ('216', '231'))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('DDR drug resistance', 'MPA', (212, 231))	('DDR', 'Gene', (173, 176))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
25912	32226530	Tumors with DNA damage repair (DDR) deficiency demonstrate sensitivity to genome-instability targeting chemotherapies through "synthetic lethality".	('DDR', 'Gene', (31, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('deficiency', 'Var', (36, 46))
25915	32226530	This led to the FDA's consecutive approval of olaparib (2014), rucaparib (2016), niraparib (2017), and talazoparib (2018), for the treatment of advanced ovarian cancer and metastatic breast cancer patients with germline BRCA mutation.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (197, 205))	('BRCA', 'Gene', (220, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('advanced ovarian cancer', 'Disease', (144, 167))	('talazoparib', 'Chemical', 'MESH:C586365', (103, 114))	('niraparib', 'Chemical', 'MESH:C545685', (81, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('rucaparib', 'Chemical', 'MESH:C531549', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('olaparib', 'Chemical', 'MESH:C531550', (46, 54))	('advanced ovarian cancer', 'Disease', 'MESH:D010051', (144, 167))	('breast cancer', 'Disease', (183, 196))	('germline', 'Var', (211, 219))	('BRCA', 'Gene', '672', (220, 224))
25917	32226530	Despite the previously well-established connections between DDR loss-of-function and cancer development and treatment, how frequently the gain-of-function alterations in DDR pathways occur in cancer, and to what extent they affect the DNA damage repair clinical outcome and even drug response remain elusive.	('DNA', 'cellular_component', 'GO:0005574', ('235', '238'))	('affect', 'Reg', (224, 230))	('alterations', 'Var', (155, 166))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gain-of-function', 'PosReg', (138, 154))	('DDR', 'Gene', (170, 173))	('DNA damage repair', 'MPA', (235, 252))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('loss-of-function', 'NegReg', (64, 80))
25918	32226530	In this study, we aimed to characterize the landscape of copy number amplification across nine DDR pathways in cancer by integrating the multi-dimensional genomic data from primary cancer samples and cancer cell lines across 32 cancer types.	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('copy number amplification', 'Var', (57, 82))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
25919	32226530	By further integrating the DDR gene data with tumor mutation burden, mutation signature, clinical treatment information and cancer cell line pharmacogenomics data, we sought to determine the DDR gene amplifications' impacts on the tumor genome instability, patient prognosis and drug responses.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('patient', 'Species', '9606', (257, 264))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', (231, 236))	('amplifications', 'Var', (200, 214))	('impacts', 'Reg', (216, 223))	('DDR', 'Gene', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
25921	32226530	The copy number segmentation data (SCNA score) were obtained from the Circular Binary Segmentation (CBS) algorithm, and the GISTIC (Genomic Identification of Significant Targets in Cancer) calls comprising -2 (deletion), -1 (loss), 0 (diploid), 1 (gain), and 2 (amplification) were made using GISTIC2.0.	('Circular Binary Segmentation (CBS) algorithm', 'Disease', 'MESH:C537538', (70, 114))	('segmentation', 'biological_process', 'GO:0035282', ('16', '28'))	('loss', 'NegReg', (225, 229))	('gain', 'PosReg', (248, 252))	('Cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cancer', 'Disease', (181, 187))	('deletion', 'Var', (210, 218))	('Cancer', 'Disease', 'MESH:D009369', (181, 187))	('Segmentation', 'biological_process', 'GO:0035282', ('86', '98'))
25923	32226530	Genes with over 5% of samples harboring GISTIC call = -2 or 2 in more than two cancer types were defined as recurrently copy number deleted or amplified.	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('GISTIC call = -2', 'Var', (40, 56))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
25925	32226530	Gene Set Enrichment Analysis (GSEA) was performed to further interpret the association between DDR gene amplification and mRNA overexpression (see Supplementary Methods).	('mRNA overexpression', 'MPA', (122, 141))	('GSEA', 'Chemical', '-', (30, 34))	('DDR', 'Gene', (95, 98))	('amplification', 'Var', (104, 117))
25927	32226530	GSEA analysis was performed on the gene list ranked by the correlation between the gene copy number and mutation burden to determine whether DDR pathways are enriched in the top genes whose copy number gain/amplification could decrease genome instability.	('genome instability', 'MPA', (236, 254))	('decrease', 'NegReg', (227, 235))	('copy number', 'Var', (190, 201))	('GSEA', 'Chemical', '-', (0, 4))	('gain/amplification', 'PosReg', (202, 220))
25930	32226530	Overall survival rates were estimated by Kaplan-Meier curves between patients with or without specific gene copy number amplification/gain (CNAmp; GISTIC calls = 1 and 2) versus others and compared in the specific cancer types using a Cox regression model stratified by the DDR gene SNCA score.	('gene copy number amplification/gain', 'Var', (103, 138))	('SNCA', 'Gene', '6622', (283, 287))	('cancer', 'Disease', (214, 220))	('CNAmp', 'Chemical', '-', (140, 145))	('SNCA', 'Gene', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
25943	32226530	Intriguingly, we observed recurrent DDR gene copy number amplifications/gains (CNAmps) among the 10,489 TCGA cancer samples across 32 tumor types (Figure 1A, 1B, Table S1, and Figure S1A).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('copy number amplifications/gains', 'Var', (45, 77))	('DDR gene', 'Gene', (36, 44))	('cancer', 'Disease', (109, 115))	('CNAmp', 'Chemical', '-', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (134, 139))
25952	32226530	The overexpression of all 13 of the recurrently amplified DDR genes was significantly driven by copy number amplification in the cancer cell lines (Figure S1C and Tables S2 and S3).	('copy number amplification', 'Var', (96, 121))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('DDR genes', 'Gene', (58, 67))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('overexpression', 'PosReg', (4, 18))
25953	32226530	With the observation of significantly recurrent overexpression and amplification of DDR genes in both primary tumors and cancer cell lines, we wondered if CNAmp and overexpression of DDR genes would increase the DDR function in tumor cells.	('primary tumors', 'Disease', 'MESH:D009369', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('amplification', 'Var', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('DDR function', 'MPA', (212, 224))	('tumor', 'Disease', (228, 233))	('overexpression', 'PosReg', (48, 62))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CNAmp', 'Chemical', '-', (155, 160))	('increase', 'PosReg', (199, 207))	('cancer', 'Disease', (121, 127))	('primary tumors', 'Disease', (102, 116))	('DDR genes', 'Gene', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
25955	32226530	This analysis revealed that tumors harboring CNAmp of 11 individual DDR genes (4 of which are recurrently amplified among multiple cancer types, UBE2T, PARP1, PRKDC, and RAD52) exhibited significantly reduced mutation burden versus those without CNAmp of these 11 DDR genes (Figure 2A), suggesting that the amplification of DDR genes might lead to an increased DDR function in those tumors.	('CNAmp', 'Var', (45, 50))	('RAD', 'biological_process', 'GO:1990116', ('170', '173'))	('RAD52', 'Gene', '5893', (170, 175))	('reduced', 'NegReg', (201, 208))	('mutation burden', 'MPA', (209, 224))	('tumors', 'Disease', 'MESH:D009369', (383, 389))	('PRKDC', 'Gene', '5591', (159, 164))	('PARP1', 'Gene', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('multiple cancer', 'Disease', (122, 137))	('PRKDC', 'Gene', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CNAmp', 'Chemical', '-', (246, 251))	('increased', 'PosReg', (351, 360))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (383, 389))	('UBE2T', 'Gene', (145, 150))	('DDR function', 'MPA', (361, 373))	('PARP1', 'Gene', '142', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('DDR genes', 'Gene', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('RAD52', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (383, 388))	('UBE2T', 'Gene', '29089', (145, 150))	('CNAmp', 'Chemical', '-', (45, 50))	('tumors', 'Disease', (383, 389))	('multiple cancer', 'Disease', 'MESH:D009369', (122, 137))	('amplification', 'Var', (307, 320))
25956	32226530	For example, the amplification of the BER pathway, including the genes UNG, POLE, TDG, and PARP1, is prominently correlated with genome stability in the OVs, as tumors with a stable genome were significantly enriched in the BER pathway gene amplified sample set (NES = 1.802, FDR = 0.007) (Figure 2B).	('TDG', 'Gene', (82, 85))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('BER pathway', 'Pathway', (38, 49))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('BER', 'biological_process', 'GO:0006284', ('224', '227'))	('PARP1', 'Gene', (91, 96))	('correlated', 'Reg', (113, 123))	('PARP1', 'Gene', '142', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('amplification', 'Var', (17, 30))	('BER', 'biological_process', 'GO:0006284', ('38', '41'))	('UNG', 'Gene', (71, 74))
25958	32226530	Its loss-of-function mutations have been established to cause a hyper-mutator phenotype in multiple cancer types.	('multiple cancer', 'Disease', (91, 106))	('loss-of-function', 'NegReg', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('multiple cancer', 'Disease', 'MESH:D009369', (91, 106))	('hyper-mutator phenotype', 'MPA', (64, 87))	('mutations', 'Var', (21, 30))
25961	32226530	When considering all the 21 previously defined mutation signatures, including smoking-, UVB exposure-, and POLE deficiency-induced mutation signatures, we observed that tumors with DDR gene amplification have a significantly lower incidence of the aforementioned DNA damage (Figure 2D-H and Figure S2B).	('gene amplification', 'Var', (185, 203))	('DDR', 'Gene', (181, 184))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Figure 2D-H', 'Disease', 'MESH:D004062', (275, 286))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lower', 'NegReg', (225, 230))	('Figure 2D-H', 'Disease', (275, 286))	('tumors', 'Disease', (169, 175))	('DNA', 'cellular_component', 'GO:0005574', ('263', '266'))
25963	32226530	Tumors bearing amplification of FA pathway genes (FANCB, FANCC and FANCM in LGG and UBE2T in GBM) and HDR genes (ATM, CHECK1, MRE11A in GBM and GEN1 in skin cutaneous melanoma [SKCM]) showed significantly reduced temozolomide-induced signature score (Figure 2G), indicating the critical role of DSB-associated recombinational repair in attenuating alkylating agent-induced genome lesions.	('FANCB', 'Gene', '2187', (50, 55))	('ATM', 'Gene', (113, 116))	('FANCC', 'Gene', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 175))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MRE11A', 'Gene', (126, 132))	('FA', 'Phenotype', 'HP:0001994', (57, 59))	('GEN1', 'Gene', '348654', (144, 148))	('UBE2T', 'Gene', (84, 89))	('FA', 'Phenotype', 'HP:0001994', (50, 52))	('skin cutaneous melanoma', 'Disease', (152, 175))	('Tumors', 'Disease', (0, 6))	('FA', 'Phenotype', 'HP:0001994', (32, 34))	('UBE2T', 'Gene', '29089', (84, 89))	('FANCB', 'Gene', (50, 55))	('HDR', 'biological_process', 'GO:0000724', ('102', '105'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('temozolomide', 'Chemical', 'MESH:D000077204', (213, 225))	('temozolomide-induced signature score', 'MPA', (213, 249))	('reduced', 'NegReg', (205, 212))	('FANCM', 'Gene', '57697', (67, 72))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ATM', 'Gene', '472', (113, 116))	('FANCM', 'Gene', (67, 72))	('recombinational repair', 'biological_process', 'GO:0000725', ('310', '332'))	('MRE11A', 'Gene', '4361', (126, 132))	('FANCC', 'Gene', '2176', (57, 62))	('amplification', 'Var', (15, 28))	('FA pathway genes', 'Gene', (32, 48))	('HDR genes', 'Gene', (102, 111))	('FA', 'Phenotype', 'HP:0001994', (67, 69))	('GEN1', 'Gene', (144, 148))
25964	32226530	These observations suggest that the CNAmp of DDR genes would restore the DDR function in tumor cells, thus alleviating the genome lesions and maintaining genome stability in the tumor.	('tumor', 'Disease', (178, 183))	('alleviating', 'NegReg', (107, 118))	('CNAmp', 'Chemical', '-', (36, 41))	('restore', 'PosReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('DDR genes', 'Gene', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('genome lesions', 'MPA', (123, 137))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('genome', 'MPA', (154, 160))	('DDR function', 'MPA', (73, 85))	('CNAmp', 'Var', (36, 41))	('tumor', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
25968	32226530	Amplification of the PMS2 gene is frequently found in glioblastoma multiforme (GBM, 454 [79.5%] of 571), lower grade glioma (LGG, 134 [22.4%] of 510), HNSC (205 [39.7%] of 517) and OV (132 [23.5%] of 562).	('PMS2', 'Gene', (21, 25))	('Amplification', 'Var', (0, 13))	('glioblastoma multiforme', 'Disease', (54, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('PMS2', 'Gene', '5395', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HNSC', 'Phenotype', 'HP:0012288', (151, 155))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (54, 77))	('glioma', 'Disease', (117, 123))	('found', 'Reg', (45, 50))	('HNSC', 'Disease', (151, 155))
25969	32226530	Those patients with PMS2 gene amplification have significantly shorter survival compared to non-CNAmp patients in each cancer type (GBM, HR = 1.53, 95% CI 1.22 to 1.92, P = 1.98x10-4; LGG, HR = 2.32, 95% CI 1.69 to 3.19, P = 2.33x10-7; HNSC, HR = 1.58, 95% CI 1.24 to 2.02, P = 2.22x10-4; OV, HR = 1.42, 95% CI 1.12 to 1.79, P = 3.48x10-3) (Figure 3B).	('PMS2', 'Gene', (20, 24))	('PMS2', 'Gene', '5395', (20, 24))	('gene amplification', 'Var', (25, 43))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('shorter', 'NegReg', (63, 70))	('HNSC', 'Phenotype', 'HP:0012288', (236, 240))	('cancer', 'Disease', (119, 125))	('patients', 'Species', '9606', (6, 14))	('CNAmp', 'Chemical', '-', (96, 101))	('survival', 'MPA', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
25971	32226530	Poor survival was observed in patients with POLM amplification in multiple cancer types (HNSC: CNAmp frequency = 36.4% [188 of 517], HR = 1.40, 95% CI 1.09 to 1.81, P = 9.17x10-3; LGG: CNAmp frequency = 23.5% [120 of 510], HR = 2.47, 95% CI 1.78 to 3.44, P = 6.83x10-3; and LUAD: CNAmp frequency = 51.9% [265 of 511], HR = 1.52, 95% CI 1.15 to 2.03, P = 3.83x10-3) (Figure 3C).	('amplification', 'Var', (49, 62))	('CNAmp', 'Chemical', '-', (280, 285))	('CNAmp', 'Chemical', '-', (95, 100))	('POLM', 'Gene', '27434', (44, 48))	('CNAmp', 'Chemical', '-', (185, 190))	('multiple cancer', 'Disease', (66, 81))	('patients', 'Species', '9606', (30, 38))	('HNSC', 'Phenotype', 'HP:0012288', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('POLM', 'Gene', (44, 48))	('multiple cancer', 'Disease', 'MESH:D009369', (66, 81))
25972	32226530	PRKDC amplification also significantly correlated with poor patient survival in multiple cancer types (sarcoma [SARC]: CNAmp frequency = 35.2% [89 of 253], HR = 2.15, 95% CI 1.46 to 3.18, P = 1.12x10-4; uterine corpus endometrial carcinoma [UCEC]: CNAmp frequency = 31.5% [165 of 523], HR = 1.72, 95% CI 1.21 to 2.44, P = 2.50x10-3) (Figure 3D).	('patient', 'Species', '9606', (60, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (218, 239))	('poor', 'NegReg', (55, 59))	('PRKDC', 'Gene', (0, 5))	('multiple cancer', 'Disease', 'MESH:D009369', (80, 95))	('sarcoma', 'Disease', (103, 110))	('CNAmp', 'Chemical', '-', (119, 124))	('CNAmp', 'Chemical', '-', (248, 253))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (218, 239))	('PRKDC', 'Gene', '5591', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('multiple cancer', 'Disease', (80, 95))	('amplification', 'Var', (6, 19))	('endometrial carcinoma', 'Disease', (218, 239))	('sarcoma', 'Disease', 'MESH:D012509', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
25974	32226530	The observation of significant positive correlations between DDR gene CNAmp and reduced tumor mutation burden, mechanism specific mutation signatures, and poor patient survival lead to our hypothesis that CNAmp of these DDR genes may cause poor patient survival by augmenting DDR function and consequently chemotherapy resistance in the tumor.	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('augmenting', 'PosReg', (265, 275))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('DDR function', 'MPA', (276, 288))	('DDR genes', 'Gene', (220, 229))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', (337, 342))	('chemotherapy resistance', 'CPA', (306, 329))	('CNAmp', 'Chemical', '-', (205, 210))	('CNAmp', 'Chemical', '-', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CNAmp', 'Var', (205, 210))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('patient', 'Species', '9606', (245, 252))
25977	32226530	Moreover, NBN CNAmp is most prominently correlated with poor overall survival in OV patients (HR = 1.36, 95% CI 1.13 to 1.64, P = 9.62x10-4) (Figure 4A).	('poor', 'NegReg', (56, 60))	('NBN CNAmp', 'Var', (10, 19))	('patients', 'Species', '9606', (84, 92))	('CNAmp', 'Chemical', '-', (14, 19))	('overall survival', 'MPA', (61, 77))
25981	32226530	Since platinum-based drugs and PARP inhibitors have been extensively used as the DSB-targeting chemotherapy of ovarian cancer, we performed a correlation analysis between NBN copy number alterations and the drug treatment response to cisplatin and PARPis across 505 cancer cell lines from the GDSC database.	('PARP', 'Gene', '142', (31, 35))	('alterations', 'Var', (187, 198))	('PARP', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', (119, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('PARP', 'Gene', '142', (248, 252))	('PARP', 'Gene', (248, 252))	('response to cisplatin', 'biological_process', 'GO:0072718', ('222', '243'))	('platinum', 'Chemical', 'MESH:D010984', (6, 14))	('NBN', 'Gene', (171, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('ovarian cancer', 'Disease', (111, 125))	('cancer', 'Disease', (266, 272))	('copy', 'Var', (175, 179))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
25982	32226530	This analysis revealed that NBN copy number is highly correlated with cellular viability responses to cisplatin treatment (rho = 0.25, P = 1.60x10-3), which is the most commonly used chemotherapy for OV patients.	('copy number', 'Var', (32, 43))	('NBN', 'Gene', (28, 31))	('patients', 'Species', '9606', (203, 211))	('correlated', 'Reg', (54, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))
25983	32226530	Moreover, the cancer cell lines with NBN amplification showed significantly increased resistance to PARP inhibitors olaparib and veliparib (Figure 4C).	('cancer', 'Disease', (14, 20))	('olaparib', 'MPA', (116, 124))	('veliparib', 'MPA', (129, 138))	('increased', 'PosReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('resistance to', 'MPA', (86, 99))	('PARP', 'Gene', (100, 104))	('veliparib', 'Chemical', 'MESH:C521013', (129, 138))	('amplification', 'Var', (41, 54))	('NBN', 'Gene', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('PARP', 'Gene', '142', (100, 104))	('olaparib', 'Chemical', 'MESH:C531550', (116, 124))
25986	32226530	Consistently, NBN depletion significantly sensitized these cancer cells to cisplatin or olaparib treatment (Figure 4K-N and Figure S3D).	('sensitized', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('depletion', 'Var', (18, 27))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('olaparib', 'Chemical', 'MESH:C531550', (88, 96))
25989	32226530	Our analysis also found a strong association between NBN amplification and AZD7762 (inhibitor for ATM substrate CHECK1/2) resistance (Figure 4C).	('AZD7762', 'Gene', (75, 82))	('AZD7762', 'Chemical', 'MESH:C532363', (75, 82))	('ATM', 'Gene', (98, 101))	('amplification', 'Var', (57, 70))	('resistance', 'MPA', (122, 132))	('ATM', 'Gene', '472', (98, 101))	('NBN', 'Gene', (53, 56))
25996	32226530	In this regard, we further integrated the copy number alterations data across 505 cancer cell lines and their responses to 37 genome-instability targeting drugs (i.e., 23 DNA-damaging drugs and 14 cell cycle/TP53 targeting agents) in GDSC.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('197', '207'))	('copy', 'Var', (42, 46))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('genome-instability', 'MPA', (126, 144))
25998	32226530	Among the 468 significant associations, 430 (92%) significant positive correlations indicated that DDR gene CNAmp lead to drug resistance (Table S4), suggesting that the CNAmp of DDR genes might induce a resistant phenotype to chemotherapy targeting genome-instability.	('induce', 'Reg', (195, 201))	('DDR', 'Gene', (99, 102))	('drug resistance', 'Phenotype', 'HP:0020174', (122, 137))	('DDR', 'Gene', (179, 182))	('CNAmp', 'Var', (170, 175))	('drug resistance', 'biological_process', 'GO:0009315', ('122', '137'))	('resistant phenotype', 'MPA', (204, 223))	('drug resistance', 'MPA', (122, 137))	('CNAmp', 'Chemical', '-', (108, 113))	('drug resistance', 'biological_process', 'GO:0042493', ('122', '137'))	('CNAmp', 'Chemical', '-', (170, 175))	('lead to', 'Reg', (114, 121))
26004	32226530	Six (29% of 21) HDR genes (NBN, GEN1, BARD1, RAD50, BRCA1, and BRIP1) showed significant positive correlations between the gene copy number alterations and cell line responses to veliparib and olaparib treatments respectively (P < 0.05) (Table S4).	('BRIP1', 'Gene', '83990', (63, 68))	('GEN1', 'Gene', '348654', (32, 36))	('BRCA1', 'Gene', '672', (52, 57))	('gene copy number alterations', 'Var', (123, 151))	('RAD', 'biological_process', 'GO:1990116', ('45', '48'))	('HDR', 'biological_process', 'GO:0000724', ('16', '19'))	('veliparib', 'Chemical', 'MESH:C521013', (179, 188))	('GEN1', 'Gene', (32, 36))	('RAD50', 'Gene', (45, 50))	('BRCA1', 'Gene', (52, 57))	('BARD1', 'Gene', '580', (38, 43))	('RAD50', 'Gene', '10111', (45, 50))	('cell line responses', 'CPA', (156, 175))	('olaparib', 'Chemical', 'MESH:C531550', (193, 201))	('HDR genes', 'Gene', (16, 25))	('BARD1', 'Gene', (38, 43))	('BRIP1', 'Gene', (63, 68))
26006	32226530	In the current study, by integrating multi-dimensional genomics and clinical data in cancer patients and cancer cell lines, we demonstrated that DNA damage repair (DDR) genes' copy number amplification/gain (CNAmp) and overexpression not only recurrently occur across 32 cancer types, but also lead to elevated DNA repair capacity and increased chemotherapy resistance.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('amplification/gain', 'PosReg', (188, 206))	('overexpression', 'PosReg', (219, 233))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (271, 277))	('DNA repair capacity', 'MPA', (311, 330))	('CNAmp', 'Chemical', '-', (208, 213))	('DNA repair', 'biological_process', 'GO:0006281', ('311', '321'))	('copy number', 'Var', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('patients', 'Species', '9606', (92, 100))	('DNA', 'cellular_component', 'GO:0005574', ('311', '314'))	('chemotherapy resistance', 'CPA', (345, 368))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('increased', 'PosReg', (335, 344))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('elevated', 'PosReg', (302, 310))
26008	32226530	DDR pathway deficiencies have been well-established as drug-actionable targets for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('DDR pathway', 'Pathway', (0, 11))	('deficiencies', 'Var', (12, 24))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
26010	32226530	Previous studies reported that the restoration of homology-dependent recombination (HDR) function by somatic reversion of germline BRCA1/2 mutations confers platinum and PARPi resistance in ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (190, 204))	('ovarian cancer', 'Disease', (190, 204))	('HDR', 'biological_process', 'GO:0000724', ('84', '87'))	('mutations', 'Var', (139, 148))	('PARP', 'Gene', '142', (170, 174))	('platinum', 'CPA', (157, 165))	('BRCA1', 'Gene', '672', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('BRCA1', 'Gene', (131, 136))	('homology-dependent', 'MPA', (50, 68))	('PARP', 'Gene', (170, 174))
26013	32226530	Since the genome instability has been intensively reported as a prognosis marker for the cancer patient, we further adjusted the survival analysis using the genome instability data and confirmed that the strong connection between DDR gene amplification and poor patient survival still stood (data not shown).	('DDR', 'Gene', (230, 233))	('amplification', 'Var', (239, 252))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('patient', 'Species', '9606', (96, 103))	('cancer', 'Disease', (89, 95))	('patient', 'Species', '9606', (262, 269))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
26027	21557225	Prognostic Molecular Biomarkers for Cutaneous Malignant Melanoma Molecular signatures of melanoma have propelled new approaches to early diagnosis, monitoring of treatment response, and targeted therapy.	('Cutaneous Malignant Melanoma', 'Disease', 'MESH:C562393', (36, 64))	('Cutaneous Malignant Melanoma', 'Disease', (36, 64))	('Malignant Melanoma', 'Phenotype', 'HP:0002861', (46, 64))	('Cutaneous Malignant Melanoma', 'Phenotype', 'HP:0012056', (36, 64))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('Molecular', 'Var', (65, 74))
26030	21557225	Although molecular alterations have been investigated as potential biomarkers of cancer progression or outcome, only a handful of prognostic biomarkers have been validated in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('alterations', 'Var', (19, 30))	('cutaneous melanoma', 'Disease', (175, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))
26034	21557225	Genomic biomarkers such as mutation (mt), single nucleotide polymorphism (SNP), and loss of heterozygosity (LOH) have been found in high frequency in melanoma.	('mutation', 'Var', (27, 35))	('single nucleotide polymorphism', 'Var', (42, 72))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('loss of heterozygosity', 'Var', (84, 106))
26089	21557225	Although IHC using anti-S100p, HMB45, and MART-1 antibodies is standard, a significant number of patients with histopathology-negative SLNs subsequently develop recurrent disease.	('MART-1', 'Gene', (42, 48))	('anti-S100p', 'Var', (19, 29))	('SLNs', 'Disease', (135, 139))	('develop', 'Reg', (153, 160))	('MART-1', 'Gene', '2315', (42, 48))	('patients', 'Species', '9606', (97, 105))
26108	21557225	Separately, they also assessed serial blood specimens collected from 87 patients before and during induction biochemotherapy and maintenance biotherapy for stage IV melanoma; changes in CTC detection were significantly correlated with treatment response, progression-free survival, and overall survival (Figure 3B).	('progression-free survival', 'CPA', (255, 280))	('treatment response', 'CPA', (235, 253))	('overall survival', 'CPA', (286, 302))	('IV melanoma', 'Disease', (162, 173))	('changes', 'Var', (175, 182))	('CTC detection', 'MPA', (186, 199))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('correlated', 'Reg', (219, 229))	('IV melanoma', 'Disease', 'MESH:D008545', (162, 173))	('patients', 'Species', '9606', (72, 80))
26115	21557225	Recently, epigenetic alterations have become a hot topic in melanoma.	('melanoma', 'Disease', (60, 68))	('epigenetic alterations', 'Var', (10, 32))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))
26117	21557225	BRAF kinase has become a key target of interest in melanoma because of its high frequency of mutation.	('mutation', 'Var', (93, 101))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
26118	21557225	BRAF kinase is a component of the Ras-MAPK-ERK pathway; BRAF mutation occurs frequently in exons 11 V600E.	('MAPK', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (56, 60))	('MAPK', 'Gene', '5595;5594;5595', (38, 42))	('V600E', 'Var', (100, 105))	('mutation', 'Var', (61, 69))	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('ERK', 'Gene', '5594', (43, 46))	('ERK', 'Gene', (43, 46))	('BRAF', 'Gene', '673', (0, 4))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (100, 105))	('BRAF', 'Gene', (56, 60))
26123	21557225	Assessment of melanoma BRAFmt has gained importance because of the effectiveness of PLX4032 and GSK2118436, new agents that target BRAFmt.	('melanoma', 'Disease', (14, 22))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (23, 27))	('GSK2118436', 'Var', (96, 106))	('BRAF', 'Gene', (23, 27))	('GSK', 'molecular_function', 'GO:0050321', ('96', '99'))	('PLX4032', 'Gene', (84, 91))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('BRAF', 'Gene', '673', (131, 135))
26128	21557225	Several germline mutations of RET play an important role in development of multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma.	('germline mutations', 'Var', (8, 26))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (84, 103))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (147, 174))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (157, 174))	('MEN', 'Species', '9606', (127, 130))	('MEN', 'Species', '9606', (120, 123))	('RET', 'Gene', '5979', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('MEN2A', 'Gene', (120, 125))	('RET', 'Gene', (30, 33))	('MEN2B', 'Gene', (127, 132))	('MEN2A', 'Gene', '5979', (120, 125))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (157, 174))	('neoplasia', 'Phenotype', 'HP:0002664', (94, 103))	('MEN2B', 'Gene', '5979', (127, 132))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (75, 103))	('thyroid carcinoma', 'Disease', (157, 174))	('multiple endocrine neoplasia', 'Disease', (75, 103))	('MEN', 'Species', '9606', (105, 108))
26129	21557225	G691S RET polymorphism (RETp) is a single nucleotide germline polymorphism in exon 11 of the juxtamembrane region of RET, which enhances the response of RET to GDNF in pancreatic cancer.	('pancreatic cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('G691S', 'Mutation', 'rs1799939', (0, 5))	('RET', 'Gene', '5979', (153, 156))	('enhances', 'PosReg', (128, 136))	('RET', 'Gene', '5979', (24, 27))	('G691S', 'Var', (0, 5))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('RET', 'Gene', (153, 156))	('RET', 'Gene', '5979', (6, 9))	('RET', 'Gene', '5979', (117, 120))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('93', '106'))	('GDNF', 'Gene', (160, 164))	('RET', 'Gene', (24, 27))	('GDNF', 'Gene', '2668', (160, 164))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('93', '106'))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('response', 'MPA', (141, 149))	('RETp', 'Gene', '5979', (24, 28))	('RETp', 'Gene', (24, 28))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('93', '106'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('93', '106'))	('RET', 'Gene', (6, 9))	('RET', 'Gene', (117, 120))
26136	21557225	The frequency of loss of heterozygosity (LOH) in tumors, along with specific gene function in tumor cells, suggests that LOH may play a significant role in regulating tumor-suppressor genes and oncogenes.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('167', '183'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('loss', 'Var', (17, 21))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('167', '183'))
26137	21557225	Frequent LOH of DNA microsatellites on specific chromosomal regions has been reported in cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('microsatellites', 'Var', (20, 35))	('cutaneous melanoma', 'Disease', (89, 107))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('LOH', 'NegReg', (9, 12))
26139	21557225	We found that LOH of microsatellites covering the APAF-1 locus (12q22-23) was significantly more common in metastatic tumors (36 of 98 specimens; 37%) than in primary melanomas (10 of 54 specimens; 19%).	('APAF-1', 'Gene', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('common', 'Reg', (97, 103))	('LOH', 'Var', (14, 17))	('melanomas', 'Disease', 'MESH:D008545', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('APAF-1', 'Gene', '317', (50, 56))	('microsatellites', 'Var', (21, 36))	('melanomas', 'Disease', (167, 176))
26143	21557225	FABP7 expression is significantly decreased in metastases of melanoma due to LOH, and its decrease is associated with significantly poorer disease outcome.	('FABP7', 'Gene', '2173', (0, 5))	('decreased', 'NegReg', (34, 43))	('metastases of melanoma', 'Disease', 'MESH:D009362', (47, 69))	('expression', 'MPA', (6, 16))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('metastases of melanoma', 'Disease', (47, 69))	('FABP7', 'Gene', (0, 5))	('decrease', 'NegReg', (90, 98))	('LOH', 'Var', (77, 80))
26146	21557225	CpG island methylation can result in suppression of gene expression, and contribute to tumorigenesis and cancer progression.	('contribute', 'Reg', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (87, 92))	('methylation', 'Var', (11, 22))	('suppression', 'NegReg', (37, 48))	('CpG', 'Protein', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gene expression', 'MPA', (52, 67))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
26147	21557225	Epigenetic suppression can occur by methylation of specific CpG islands in the promoter region, histone methylation or acetylation and/or miR activation.	('acetylation', 'MPA', (119, 130))	('histone methylation', 'biological_process', 'GO:0016571', ('96', '115'))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('histone', 'Protein', (96, 103))	('Epigenetic', 'MPA', (0, 10))	('methylation', 'Var', (36, 47))
26148	21557225	In melanoma, more than 50 genes have been reported to demonstrate aberrant hypermethylation of promoter CpG islands.	('hypermethylation', 'MPA', (75, 91))	('aberrant', 'Var', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
26149	21557225	We were the first group to identify and verify the inactivation of RAS association domain family protein 1A, RASSF1A, which is a human tumor suppressor gene in melanoma.	('RASSF1A', 'Gene', '11186', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('melanoma', 'Disease', (160, 168))	('inactivation', 'Var', (51, 63))	('tumor', 'Disease', (135, 140))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('human', 'Species', '9606', (129, 134))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('RASSF1A', 'Gene', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
26151	21557225	Methylation of the RASSF1A CpG island was detected in 57% of tumors.	('tumors', 'Disease', (61, 67))	('RASSF1A', 'Gene', '11186', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RASSF1A', 'Gene', (19, 26))	('detected', 'Reg', (42, 50))
26152	21557225	Hypermethylation of CpG regions correlated with no expression of the RASSF1A gene.	('RASSF1A', 'Gene', '11186', (69, 76))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (51, 61))	('RASSF1A', 'Gene', (69, 76))
26155	21557225	The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRGs) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CIMP', 'Chemical', '-', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('inactivation', 'NegReg', (112, 124))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('128', '144'))	('methylation', 'Var', (180, 191))	('tumor', 'Disease', (229, 234))	('tumor suppressor', 'biological_process', 'GO:0051726', ('128', '144'))	('tumor', 'Disease', (128, 133))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (149, 154))	('TRGs', 'Gene', (170, 174))	('associated', 'Reg', (50, 60))	('malignancy', 'Disease', (81, 91))
26156	21557225	These epigenetic changes create a distinct CIMP pattern that has been linked to progression and disease outcome in gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (115, 139))	('linked', 'Reg', (70, 76))	('CIMP', 'Chemical', '-', (43, 47))	('epigenetic changes', 'Var', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('gastrointestinal cancers', 'Disease', (115, 139))
26162	21557225	These events strongly indicate that specific epigenetic aberrations in melanoma progression are very significant, thus new potential targets.	('epigenetic aberrations', 'Var', (45, 67))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))
26168	21557225	Evidence of RUNX3 promoter region methylation was demonstrated in 5 of 17 (29%) melanoma cell lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas.	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('RUNX3', 'Gene', '864', (12, 17))	('melanomas', 'Disease', (162, 171))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanomas', 'Disease', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('methylation', 'Var', (34, 45))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('RUNX3', 'Gene', (12, 17))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))
26182	21557225	The BRAF V600Emt can be useful for monitoring melanoma patients receiving biochemotherapy.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('Emt', 'biological_process', 'GO:0001837', ('13', '16'))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('V600Emt', 'Var', (9, 16))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('patients', 'Species', '9606', (55, 63))
26183	21557225	Methylation detected in serum DNA can predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy for metastatic melanoma.	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('patients', 'Species', '9606', (90, 98))	('predict', 'Reg', (38, 45))
26185	21557225	In a study of RASSF1A, RAR-beta2 and MGMT, we found that circulating methylated RASSF1A was significantly less frequent in biochemotherapy responders (3 of 23, 13%) than nonresponders (10 of 24, 42%), and it was significantly correlated with overall survival (Figure 5).	('RASSF1A', 'Gene', '11186', (80, 87))	('RASSF1A', 'Gene', (14, 21))	('MGMT', 'molecular_function', 'GO:0003908', ('37', '41'))	('correlated with', 'Reg', (226, 241))	('overall', 'MPA', (242, 249))	('MGMT', 'Gene', '4255', (37, 41))	('less', 'NegReg', (106, 110))	('methylated', 'Var', (69, 79))	('RASSF1A', 'Gene', (80, 87))	('MGMT', 'Gene', (37, 41))	('RASSF1A', 'Gene', '11186', (14, 21))
26186	21557225	Patients with RASSF1A, RAR-beta2, or at least one of the three biomarkers had significantly worse overall survival than patients with no biomarkers.	('RASSF1A', 'Gene', (14, 21))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (120, 128))	('RASSF1A', 'Gene', '11186', (14, 21))	('overall survival', 'MPA', (98, 114))	('worse', 'NegReg', (92, 97))	('RAR-beta2', 'Var', (23, 32))
26187	21557225	In a separate study, we demonstrated serum estrogen receptor alpha hypermethylation was detected more frequently in advanced melanomas than localized melanomas and was the only factor predicting progression-free and overall survival in patients receiving biochemotherapy.	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanomas', 'Disease', (150, 159))	('patients', 'Species', '9606', (236, 244))	('estrogen receptor alpha', 'Gene', (43, 66))	('detected', 'Reg', (88, 96))	('hypermethylation', 'Var', (67, 83))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('melanomas', 'Disease', (125, 134))	('estrogen receptor alpha', 'Gene', '2099', (43, 66))	('melanomas', 'Disease', 'MESH:D008545', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))
26191	21557225	CTC were detected in 13 of 15 (86%) patients with serum tumor-related methylated DNA, and in 13 of 35 (37%) patients without methylated DNA.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', (56, 61))	('methylated', 'Var', (70, 80))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('patients', 'Species', '9606', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
26192	21557225	Patients with both CTC and methylated DNA showed significantly poorer response to biochemotherapy and poorer progression.	('CTC', 'Var', (19, 22))	('methylated', 'Var', (27, 37))	('poorer', 'NegReg', (63, 69))	('Patients', 'Species', '9606', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))
26222	31212865	In contrast, expression of MHC-II by tumor cells was also reported to associate with higher metastatic dissemination, increased tumor stage and reduced survival in melanoma.	('reduced', 'NegReg', (144, 151))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('higher', 'PosReg', (85, 91))	('MHC-II', 'Gene', (27, 33))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('expression', 'Var', (13, 23))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('metastatic dissemination', 'CPA', (92, 116))	('survival', 'CPA', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))
26252	31212865	The survival analysis of 15 HLA class II genes in cutaneous melanoma by online databases UALCAN revealed patients with cutaneous melanoma in high expression group of all HLA class II genes had longer survival as compared with patients in low/medium expression group (Figure 3).	('longer', 'PosReg', (193, 199))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('patients', 'Species', '9606', (105, 113))	('HLA', 'Gene', '3128', (28, 31))	('HLA', 'Gene', (170, 173))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cutaneous melanoma', 'Disease', (50, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('HLA', 'Gene', '3128', (170, 173))	('patients', 'Species', '9606', (226, 234))	('high expression', 'Var', (141, 156))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))	('HLA', 'Gene', (28, 31))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
26255	31212865	Hazard ratios of <1.0 indicated patients with high HLA class II gene expressions had better overall survival.	('better', 'PosReg', (85, 91))	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('HLA', 'Gene', '3128', (51, 54))	('overall survival', 'CPA', (92, 108))	('HLA', 'Gene', (51, 54))
26288	31212865	In metastatic melanoma, positive staining for MHC-II expression in Stage III and IV cutaneous melanoma correlated with longer overall survival.	('melanoma', 'Disease', (14, 22))	('Stage III', 'Disease', (67, 76))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('longer', 'PosReg', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('cutaneous melanoma', 'Disease', (84, 102))	('positive staining', 'Var', (24, 41))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('overall survival', 'MPA', (126, 142))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('MHC-II', 'Gene', (46, 52))
26302	31212865	The high expression of APOL3 was reported to predict worse clinical outcome in patients with acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (93, 115))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (99, 115))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (93, 115))	('APOL3', 'Gene', (23, 28))	('high', 'Var', (4, 8))	('patients', 'Species', '9606', (79, 87))	('acute myeloid leukemia', 'Disease', (93, 115))	('APOL3', 'Gene', '80833', (23, 28))	('clinical', 'Species', '191496', (59, 67))
26312	31212865	Blockade of CD74 related immunosuppressive signaling may restore anti-tumor immune response in metastatic melanoma, suggesting the crucial role of CD74 in immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('restore', 'PosReg', (57, 64))	('immune response', 'biological_process', 'GO:0006955', ('76', '91'))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (70, 75))	('signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('CD74', 'Gene', '972', (147, 151))	('CD74', 'Gene', (12, 16))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('CD74', 'Gene', '972', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CD74', 'Gene', (147, 151))
26314	31212865	C1q appears to have pro-tumorigenic and anti-tumorigenic role in cancer, depending on the context of the disease.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
26333	30026606	Telomere length and survival in primary cutaneous melanoma patients Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age-dependent attrition.	('Telomere', 'cellular_component', 'GO:0000781', ('68', '76'))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('Telomere', 'cellular_component', 'GO:0005696', ('68', '76'))	('Telomere', 'cellular_component', 'GO:0000781', ('0', '8'))	('cutaneous melanoma', 'Disease', (40, 58))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (40, 58))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (40, 58))	('Telomere', 'cellular_component', 'GO:0005696', ('0', '8'))	('Telomere repeats', 'Var', (68, 84))
26334	30026606	Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('associated', 'Reg', (45, 55))	('Telomere', 'cellular_component', 'GO:0000781', ('0', '8'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Telomere', 'cellular_component', 'GO:0005696', ('0', '8'))	('Telomere', 'Var', (0, 8))
26335	30026606	In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers.	('poor', 'NegReg', (159, 163))	('patients', 'Species', '9606', (176, 184))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (76, 83))	('short telomeres', 'Phenotype', 'HP:0031413', (135, 150))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('cancers', 'Disease', (200, 207))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('short telomeres', 'Var', (135, 150))
26336	30026606	In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('short telomeres', 'Var', (121, 136))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('II cutaneous melanoma', 'Disease', 'MESH:C562393', (40, 61))	('short telomeres', 'Phenotype', 'HP:0031413', (121, 136))	('patients', 'Species', '9606', (213, 221))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('II cutaneous melanoma', 'Disease', (40, 61))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (107, 115))	('poor', 'NegReg', (141, 145))
26345	30026606	The melanoma genome in general is characterized by one of the highest prevalence of somatic mutations in human cancers and several genetic alterations have been shown to predict outcome in melanoma.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('human', 'Species', '9606', (105, 110))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (92, 101))	('predict', 'Reg', (170, 177))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
26346	30026606	In particular, the most frequent somatic mutations in cutaneous melanoma like those in the TERT promoter and BRAF/NRAS reportedly associate with poor disease-free and melanoma-specific survival.	('poor', 'NegReg', (145, 149))	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', (109, 113))	('TERT', 'Gene', (91, 95))	('BRAF', 'Gene', '673', (109, 113))	('NRAS', 'Gene', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('NRAS', 'Gene', '4893', (114, 118))	('TERT', 'Gene', '7015', (91, 95))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Disease', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('cutaneous melanoma', 'Disease', (54, 72))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
26348	30026606	Inherent limitations of DNA replication and telomerase suppression in most somatic cells through epigenetic reprogramming of the telomerase reverse transcriptase (TERT) gene, cause telomeres to undergo age-dependent incremental attrition.	('TERT', 'Gene', '7015', (163, 167))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('transcriptase', 'molecular_function', 'GO:0003899', ('148', '161'))	('epigenetic', 'Var', (97, 107))	('transcriptase', 'molecular_function', 'GO:0003968', ('148', '161'))	('men', 'Species', '9606', (221, 224))	('transcriptase', 'molecular_function', 'GO:0034062', ('148', '161'))	('DNA replication', 'biological_process', 'GO:0006260', ('24', '39'))	('TERT', 'Gene', (163, 167))	('telomerase reverse transcriptase', 'Gene', (129, 161))	('telomerase reverse transcriptase', 'Gene', '7015', (129, 161))
26352	30026606	Different investigations over the years, in contrast, have suggested that short telomeres associate with poor patient survival.	('short telomeres', 'Var', (74, 89))	('poor', 'NegReg', (105, 109))	('patient survival', 'CPA', (110, 126))	('short telomeres', 'Phenotype', 'HP:0031413', (74, 89))	('patient', 'Species', '9606', (110, 117))
26354	30026606	Despite a confounding effect of the age at diagnosis, our results suggest an association between short telomeres and poor patient survival, particularly for melanoma patients in younger age groups.	('poor', 'NegReg', (117, 121))	('patient survival', 'CPA', (122, 138))	('short telomeres', 'Phenotype', 'HP:0031413', (97, 112))	('patient', 'Species', '9606', (122, 129))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('short telomeres', 'Var', (97, 112))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('patient', 'Species', '9606', (166, 173))	('patients', 'Species', '9606', (166, 174))
26361	30026606	The patients included in the study were further genotyped for rs1317082, rs7726159 and rs6060627 polymorphisms that have been shown to associate with telomere length in genome wide association studies.	('telomere', 'cellular_component', 'GO:0005696', ('150', '158'))	('rs6060627', 'Mutation', 'rs6060627', (87, 96))	('telomere', 'cellular_component', 'GO:0000781', ('150', '158'))	('associate', 'Reg', (135, 144))	('rs1317082', 'Mutation', 'rs1317082', (62, 71))	('rs7726159', 'Var', (73, 82))	('rs7726159', 'Mutation', 'rs7726159', (73, 82))	('rs1317082', 'Var', (62, 71))	('rs6060627', 'Var', (87, 96))	('patients', 'Species', '9606', (4, 12))
26363	30026606	The computed weighted genetic risk score due to genotypes with variant alleles for three polymorphisms ranged from -0.34 to 0.39 for rs1317082, -0.61 to 0.00 for rs7726159 and -0.46 to 0.20 for rs6060627 (Supplementary Table S2).	('S', 'Chemical', 'MESH:D013455', (225, 226))	('rs7726159', 'Var', (162, 171))	('rs1317082', 'Var', (133, 142))	('men', 'Species', '9606', (211, 214))	('rs6060627', 'Mutation', 'rs6060627', (194, 203))	('S', 'Chemical', 'MESH:D013455', (205, 206))	('rs7726159', 'Mutation', 'rs7726159', (162, 171))	('rs1317082', 'Mutation', 'rs1317082', (133, 142))	('rs6060627', 'Var', (194, 203))
26364	30026606	In univariate Cox regression analysis with telomere length as a continuous variable, an improved melanoma-specific patient survival was observed with increased telomere length (HR 0.65, 95% CI 0.42-1.00, P 0.05).	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('telomere length', 'Var', (160, 175))	('telomere', 'cellular_component', 'GO:0005696', ('43', '51'))	('telomere', 'cellular_component', 'GO:0000781', ('160', '168'))	('increased telomere length', 'Phenotype', 'HP:0031413', (150, 175))	('telomere', 'cellular_component', 'GO:0005696', ('160', '168'))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('improved', 'PosReg', (88, 96))	('increased', 'PosReg', (150, 159))	('patient', 'Species', '9606', (115, 122))	('telomere', 'cellular_component', 'GO:0000781', ('43', '51'))
26366	30026606	The data analysis with telomere length as a dichotomous variable based on median distribution also showed that the patients with short telomeres (<=1.20) were at risk of poor survival (log rank P 0.001; HR 2.05, 95% CI 1.33-3.16, Fig.	('poor', 'NegReg', (170, 174))	('patients', 'Species', '9606', (115, 123))	('telomere', 'cellular_component', 'GO:0000781', ('23', '31'))	('telomere', 'cellular_component', 'GO:0005696', ('23', '31'))	('short', 'Var', (129, 134))	('short telomeres', 'Phenotype', 'HP:0031413', (129, 144))
26377	30026606	The results showed that the patients below 30 years of age at diagnosis (first quantile) with short telomeres were at risk of poor survival (HR 3.91, 95% CI 1.25-12.29) compared to the patients with long telomeres within that sub-group.	('short telomeres', 'Phenotype', 'HP:0031413', (94, 109))	('poor', 'NegReg', (126, 130))	('patients', 'Species', '9606', (185, 193))	('short telomeres', 'Var', (94, 109))	('patients', 'Species', '9606', (28, 36))
26379	30026606	The association between patients with short telomeres and poor melanoma-specific survival in the fourth quantile (50-60 years) was also statistically significant (HR 1.57, 95% CI 1.00-2.47).	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('short telomeres', 'Var', (38, 53))	('patients', 'Species', '9606', (24, 32))	('poor', 'NegReg', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('short telomeres', 'Phenotype', 'HP:0031413', (38, 53))
26381	30026606	Multivariate analysis that included age, composite genetic risk score, sex, nevus number, tumor localization, and tumor stage showed that the association of patients with short telomeres (compared to patients with long telomeres) with decreased melanoma-specific survival was not statistically significant (HR 1.17, 95% CI 0.71-1.94, P 0.53; Table 2).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('nevus', 'Phenotype', 'HP:0003764', (76, 81))	('patients', 'Species', '9606', (200, 208))	('short telomeres', 'Var', (171, 186))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('melanoma', 'Disease', (245, 253))	('tumor', 'Disease', (90, 95))	('localization', 'biological_process', 'GO:0051179', ('96', '108'))	('patients', 'Species', '9606', (157, 165))	('tumor', 'Disease', (114, 119))	('decreased', 'NegReg', (235, 244))	('short telomeres', 'Phenotype', 'HP:0031413', (171, 186))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
26383	30026606	Further, multivariate analysis using telomere length and composite genetic risk score as a combined variable showed that the patients under high-risk category with both short and long telomeres showed an increased mortality compared to patients in low-risk category with long telomeres (Table 3).	('telomere', 'cellular_component', 'GO:0005696', ('37', '45'))	('patients', 'Species', '9606', (236, 244))	('long telomeres', 'Var', (179, 193))	('short', 'Var', (169, 174))	('telomere', 'cellular_component', 'GO:0000781', ('37', '45'))	('patients', 'Species', '9606', (125, 133))
26384	30026606	Similarly, a multivariate model that included all confounders showed that the patients with short telomeres in the age group below 30 years (first quantile) were at statistically significant risk of poor survival (HR 3.82, 95% CI 1.10-13.30) compared to patients with long telomeres within the same group.	('short telomeres', 'Var', (92, 107))	('patients', 'Species', '9606', (78, 86))	('short telomeres', 'Phenotype', 'HP:0031413', (92, 107))	('poor', 'NegReg', (199, 203))	('patients', 'Species', '9606', (254, 262))	('S', 'Chemical', 'MESH:D013455', (0, 1))
26385	30026606	A similar statistically significant association between patients with short telomeres and poor melanoma-specific survival was also observed in the age group 30-40 years (HR 2.69, 95% CI 1.03-7.03).	('patients', 'Species', '9606', (56, 64))	('poor', 'NegReg', (90, 94))	('short telomeres', 'Phenotype', 'HP:0031413', (70, 85))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('short telomeres', 'Var', (70, 85))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))
26389	30026606	Cox regression analysis on the age matched group showed that the patients with short telomeres compared to those with long telomere were at statistically significant risk of poor survival (univariate HR 1.89, 95% CI 1.10-3.25, P 0.02).	('short telomeres', 'Phenotype', 'HP:0031413', (79, 94))	('telomere', 'cellular_component', 'GO:0000781', ('123', '131'))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('telomere', 'cellular_component', 'GO:0005696', ('123', '131'))	('short telomeres', 'Var', (79, 94))	('patients', 'Species', '9606', (65, 73))	('poor', 'NegReg', (174, 178))
26390	30026606	Multivariate data analysis also showed in age-matched groups, the patients with short telomeres were at the risk of poor survival (HR 1.79, 95% CI 1.01-3.17, P 0.05; Table 4) compared to the patients with long telomeres.	('patients', 'Species', '9606', (191, 199))	('short telomeres', 'Phenotype', 'HP:0031413', (80, 95))	('poor', 'NegReg', (116, 120))	('short telomeres', 'Var', (80, 95))	('patients', 'Species', '9606', (66, 74))
26391	30026606	In this study based on stage I and II incident melanoma patients, we observed that short telomeres predispose patients to poor melanoma-specific survival, which contrasts with reported association of long telomere with increased risk of melanoma.	('melanoma', 'Disease', (237, 245))	('patients', 'Species', '9606', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('telomere', 'cellular_component', 'GO:0000781', ('205', '213'))	('short telomeres', 'Var', (83, 98))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('poor', 'NegReg', (122, 126))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('melanoma', 'Disease', (127, 135))	('short telomeres', 'Phenotype', 'HP:0031413', (83, 98))	('telomere', 'cellular_component', 'GO:0005696', ('205', '213'))	('patients', 'Species', '9606', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))
26392	30026606	Despite a strong inverse correlation between telomere length and age, we observed that the effect of short compared to long telomeres on poor survival was pronounced in patients below 40 years at diagnosis.	('poor survival', 'MPA', (137, 150))	('patients', 'Species', '9606', (169, 177))	('telomere', 'cellular_component', 'GO:0005696', ('45', '53'))	('short', 'Var', (101, 106))	('telomere', 'cellular_component', 'GO:0000781', ('45', '53'))
26394	30026606	The polymorphisms that had been previously shown to be associated with telomere length and risk of various cancers through genome wide association studies did not per se show any impact on melanoma-specific survival in this study.	('telomere', 'cellular_component', 'GO:0000781', ('71', '79'))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('telomere', 'cellular_component', 'GO:0005696', ('71', '79'))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (55, 65))	('polymorphisms', 'Var', (4, 17))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
26396	30026606	Our results were further corroborated through use of age-matched analysis, which showed that patients with short telomeres were at a statistically significant poorer risk of survival than the patients with long telomeres.	('short telomeres', 'Phenotype', 'HP:0031413', (107, 122))	('patients', 'Species', '9606', (192, 200))	('poorer', 'NegReg', (159, 165))	('short telomeres', 'Var', (107, 122))	('survival', 'MPA', (174, 182))	('patients', 'Species', '9606', (93, 101))
26397	30026606	Increased risk of melanoma due to increased telomere length has been postulated as a paradox where sufficient telomere length allows cells to survive until crisis point through continuous division and consequent acquisition of driver mutations.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('telomere', 'cellular_component', 'GO:0005696', ('110', '118'))	('telomere', 'cellular_component', 'GO:0000781', ('44', '52'))	('increased telomere length', 'Phenotype', 'HP:0031413', (34, 59))	('telomere', 'cellular_component', 'GO:0005696', ('44', '52'))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('telomere', 'cellular_component', 'GO:0000781', ('110', '118'))	('mutations', 'Var', (234, 243))	('melanoma', 'Disease', (18, 26))
26399	30026606	In previous studies on breast cancer, multiple myeloma and renal cell carcinoma, short telomeres were shown to be associated with poor overall survival.	('breast cancer', 'Disease', (23, 36))	('multiple myeloma and renal cell carcinoma', 'Disease', 'MESH:C538614', (38, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('overall survival', 'MPA', (135, 151))	('short telomeres', 'Phenotype', 'HP:0031413', (81, 96))	('poor', 'NegReg', (130, 134))	('associated', 'Reg', (114, 124))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (59, 79))	('short telomeres', 'Var', (81, 96))	('multiple myeloma', 'Phenotype', 'HP:0006775', (38, 54))
26402	30026606	The observed association of short telomeres with poor melanoma-specific survival seems to be in conformity with emerging data.	('short telomeres', 'Phenotype', 'HP:0031413', (28, 43))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('short telomeres', 'Var', (28, 43))	('poor', 'NegReg', (49, 53))
26403	30026606	Studies have shown that despite ubiquitous telomerase rejuvenation, a continued shortening of telomeres in tumor cells, particularly in presence of the TERT promoter mutations, in the initial stages lead to chromosomal fusions and aneuploidy.	('chromosomal fusions', 'CPA', (207, 226))	('aneuploidy', 'Disease', 'MESH:D000782', (231, 241))	('TERT', 'Gene', '7015', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutations', 'Var', (166, 175))	('tumor', 'Disease', (107, 112))	('shortening of telomeres', 'Phenotype', 'HP:0031413', (80, 103))	('shortening', 'NegReg', (80, 90))	('aneuploidy', 'Disease', (231, 241))	('lead to', 'Reg', (199, 206))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TERT', 'Gene', (152, 156))	('S', 'Chemical', 'MESH:D013455', (0, 1))
26405	30026606	Evidence suggests that genetic instability drives tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (50, 55))	('genetic instability', 'Var', (23, 42))
26407	30026606	Previously, we have shown that the TERT promoter mutations associated with poor survival in patients with primary melanoma and our subsequent data showed shorter telomeres in tumors with than without the TERT promoter mutations.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (49, 58))	('TERT', 'Gene', '7015', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('poor', 'NegReg', (75, 79))	('patients', 'Species', '9606', (92, 100))	('associated', 'Reg', (59, 69))	('TERT', 'Gene', '7015', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('TERT', 'Gene', (35, 39))	('telomeres', 'MPA', (162, 171))	('TERT', 'Gene', (204, 208))	('shorter', 'NegReg', (154, 161))	('melanoma', 'Disease', (114, 122))
26408	30026606	In this study, telomere length was measured in blood cells and not in tumor tissues; therefore, the association of short telomere length with decreased survival cannot be directly explained by an effect in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('telomere', 'cellular_component', 'GO:0005696', ('121', '129'))	('short telomere length', 'Phenotype', 'HP:0031413', (115, 136))	('telomere', 'cellular_component', 'GO:0000781', ('15', '23'))	('tumor', 'Disease', (206, 211))	('survival', 'MPA', (152, 160))	('tumor', 'Disease', (70, 75))	('decreased', 'NegReg', (142, 151))	('short', 'Var', (115, 120))	('telomere', 'cellular_component', 'GO:0005696', ('15', '23'))	('telomere', 'cellular_component', 'GO:0000781', ('121', '129'))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
26410	30026606	In this study, however, we show that in contrast to the association between long telomeres and increased melanoma risk, short telomeres predict poor melanoma-specific survival.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (149, 157))	('melanoma', 'Disease', (105, 113))	('short telomeres', 'Var', (120, 135))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('poor', 'NegReg', (144, 148))	('short telomeres', 'Phenotype', 'HP:0031413', (120, 135))
26413	30026606	With age as a strong confounder, the risk of poor survival due to short telomeres on survival was in particularly pronounced in younger patients.	('patients', 'Species', '9606', (136, 144))	('poor', 'NegReg', (45, 49))	('short telomeres', 'Phenotype', 'HP:0031413', (66, 81))	('short telomeres', 'Var', (66, 81))
26478	30396920	Moreover, expression of NME1 is associated with better overall clinical outcome in several cancer types.	('cancer', 'Disease', (91, 97))	('better', 'PosReg', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NME1', 'Gene', (24, 28))	('expression', 'Var', (10, 20))
26479	30396920	In addition, we have demonstrated that ablation of the Nme1-Nme2 locus in mice confers strong metastatic activity in a model of ultraviolet light-induced melanoma, providing in vivo validation of metastasis suppressor functions for the Nme1 and/or Nme2 genes.	('Nme2', 'Gene', (248, 252))	('Nme2', 'Gene', '18103', (60, 64))	('Nme1-Nme2', 'Gene', (55, 64))	('metastatic activity', 'CPA', (94, 113))	('Nme1', 'Gene', '18102', (236, 240))	('ablation', 'Var', (39, 47))	('Nme1', 'Gene', (55, 59))	('Nme1-Nme2', 'Gene', '18102;18103', (55, 64))	('Nme2', 'Gene', (60, 64))	('Nme2', 'Gene', '18103', (248, 252))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('Nme1', 'Gene', '18102', (55, 59))	('light-induced melanoma', 'Phenotype', 'HP:0031420', (140, 162))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('mice', 'Species', '10090', (74, 78))	('Nme1', 'Gene', (236, 240))
26502	30396920	M14 cells were transiently transfected with 100 ng of a Renilla luciferase pLightSwitch promoter plasmid containing the transcriptional regulatory region of ALDOC (-880 to +118) (SwitchGear Genomics, Menlo Park, CA, USA).	('ALDOC', 'Gene', (157, 162))	('ALDOC', 'Gene', '230', (157, 162))	('-880 to +118', 'Var', (164, 176))
26510	30396920	Immunoblot analysis demonstrated a NME1-induced increase (4.9-fold) in ALDOC protein levels (Figure 1A, right).	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('ALDOC', 'Gene', '230', (71, 76))	('NME1-induced', 'Var', (35, 47))	('ALDOC', 'Gene', (71, 76))	('increase', 'PosReg', (48, 56))
26513	30396920	Finally, to further confirm the regulatory axis between NME1 and ALDOC, the impact of silencing NME1 expression was examined in the melanoma cell line WM278, which expresses NME1 at normal levels.	('WM278', 'CellLine', 'CVCL:6473', (151, 156))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('silencing', 'Var', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('ALDOC', 'Gene', (65, 70))	('ALDOC', 'Gene', '230', (65, 70))	('NME1', 'Gene', (96, 100))
26515	30396920	Treatment with the anti-NME1 shRNA sequence indeed elicited a significant decrease (62%) in expression of ALDOC protein (Figure 1C).	('ALDOC', 'Gene', (106, 111))	('decrease', 'NegReg', (74, 82))	('ALDOC', 'Gene', '230', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('anti-NME1', 'Var', (19, 28))
26528	30396920	A significant increase in ALDOC pre-mRNA levels was observed in both the M14 and WM1158-NME1 expressing cells (Figure 2A), strongly suggesting that NME1-dependent induction of ALDOC occurred at the transcriptional level.	('ALDOC', 'Gene', (26, 31))	('pre', 'molecular_function', 'GO:0003904', ('32', '35'))	('WM1158-NME1', 'Var', (81, 92))	('ALDOC', 'Gene', (176, 181))	('ALDOC', 'Gene', '230', (26, 31))	('WM1158-NME1', 'CellLine', 'CVCL:6785', (81, 92))	('ALDOC', 'Gene', '230', (176, 181))	('increase', 'PosReg', (14, 22))
26534	30396920	To further assess the impact of NME1 on transcription of the ALDOC gene, chromatin immunoprecipitation (ChIP) analysis was conducted with three different DNA amplicons located upstream and downstream of the transcription start site of ALDOC gene (-542 to -398, -188 to -4, and +31 to +244).	('ALDOC', 'Gene', (61, 66))	('ALDOC', 'Gene', '230', (235, 240))	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('ALDOC', 'Gene', '230', (61, 66))	('transcription', 'biological_process', 'GO:0006351', ('40', '53'))	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	('-542 to -398', 'Var', (247, 259))	('ALDOC', 'Gene', (235, 240))	('chromatin', 'cellular_component', 'GO:0000785', ('73', '82'))
26535	30396920	Likely targets of epigenetic modification within the ALDOC gene were identified prior to the study using the University of California, Santa Cruz (USCS) genome browser and ChIPseq data from the Encyclopedia of DNA Elements (ENCODE) project.	('epigenetic modification', 'Var', (18, 41))	('ALDOC', 'Gene', (53, 58))	('DNA', 'cellular_component', 'GO:0005574', ('210', '213'))	('ALDOC', 'Gene', '230', (53, 58))
26538	30396920	While ChIP analysis conducted in control M14 cells failed to detect the H3K27ac modification, forced NME1 expression resulted in a significant increase of H3K27ac across all three regions analyzed (Figure 3B), consistent with NME1-mediated activation of the ALDOC promoter.	('NME1', 'Gene', (101, 105))	('H3K27ac', 'Var', (155, 162))	('ALDOC', 'Gene', (258, 263))	('expression', 'Var', (106, 116))	('ALDOC', 'Gene', '230', (258, 263))	('increase', 'PosReg', (143, 151))
26539	30396920	NME1 expression also resulted in significant enrichment of the transcription activation mark H3K4me3 within the +31 to +244 region of the ALDOC gene (Figure 3B), consistent with predictions from the ENCODE site.	('transcription', 'MPA', (63, 76))	('ALDOC', 'Gene', (138, 143))	('expression', 'Var', (5, 15))	('H3K4me3', 'Protein', (93, 100))	('ALDOC', 'Gene', '230', (138, 143))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('NME1', 'Gene', (0, 4))
26541	30396920	Taken together, the ChIP analyses demonstrate that NME1 expression results in the activation of ALDOC promoter, with inducible recruitment of NME1 to the promoter region strongly suggesting its participation in the activation mechanism.	('activation', 'PosReg', (82, 92))	('ALDOC', 'Gene', (96, 101))	('NME1', 'Gene', (51, 55))	('recruitment', 'MPA', (127, 138))	('ALDOC', 'Gene', '230', (96, 101))	('expression', 'Var', (56, 66))
26555	30396920	Other studies employing ChIP analysis have indeed reported physical association of NME1 with DNA motifs in a number of genes with potential relevance to cancer phenotype, but none has analyzed the impact of the DNA binding interactions on transcriptional activity.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('association', 'Interaction', (68, 79))	('cancer', 'Disease', (153, 159))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('DNA motifs', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('DNA binding', 'molecular_function', 'GO:0003677', ('211', '222'))	('NME1', 'Gene', (83, 87))
26556	30396920	Our current study provides the novel observations of inducible recruitment of NME1 to the promoter region of its target gene, ALDOC, and a strong association between occupancy of NME1 and an epigenetically active state at the ALDOC promoter.	('ALDOC', 'Gene', (226, 231))	('ALDOC', 'Gene', (126, 131))	('epigenetically active state', 'MPA', (191, 218))	('ALDOC', 'Gene', '230', (226, 231))	('ALDOC', 'Gene', '230', (126, 131))	('NME1', 'Gene', (78, 82))	('occupancy', 'Var', (166, 175))	('NME1', 'Gene', (179, 183))	('recruitment', 'MPA', (63, 74))
26560	30396920	The possibility cannot be formally excluded; however, the procedure detected an indirect interaction of NME1 with the ALDOC gene via crosslinking to a primary DNA binding protein.	('NME1', 'Gene', (104, 108))	('ALDOC', 'Gene', '230', (118, 123))	('interaction', 'Interaction', (89, 100))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('crosslinking', 'Var', (133, 145))	('ALDOC', 'Gene', (118, 123))	('DNA binding', 'molecular_function', 'GO:0003677', ('159', '170'))
26561	30396920	Recruitment of NME1 was associated with activation of ALDOC transcription, most likely by promoting assembly of a coactivator complex composed of histone acetylases and methylases that promote epigenetic activation of the locus.	('ALDOC', 'Gene', (54, 59))	('ALDOC', 'Gene', '230', (54, 59))	('transcription', 'biological_process', 'GO:0006351', ('60', '73'))	('Recruitment', 'Var', (0, 11))	('assembly', 'MPA', (100, 108))	('NME1', 'Gene', (15, 19))	('promoting', 'PosReg', (90, 99))	('activation', 'PosReg', (40, 50))
26571	30396920	Herein, we observed that silencing of ALDOC mRNA expression in M14 melanoma cells with shRNA constructs fails to disrupt the motility-suppressing activity of NME1 (data not shown).	('silencing', 'Var', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('ALDOC', 'Gene', (38, 43))	('melanoma', 'Disease', (67, 75))	('motility-suppressing activity', 'CPA', (125, 154))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('ALDOC', 'Gene', '230', (38, 43))
26596	27533448	While oncogenic BRAF and NRAS mutations are seen in 50% and 15% of cutaneous melanomas respectively, these mutations are rare in uveal melanoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma tumors', 'Disease', (129, 150))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('mutations', 'Var', (30, 39))	('NRAS', 'Gene', (25, 29))	('uveal melanoma tumors', 'Disease', 'MESH:C536494', (129, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('NRAS', 'Gene', '4893', (25, 29))	('cutaneous melanomas', 'Disease', (67, 86))
26597	27533448	Instead, 90% harbor mutations in either the GNAQ or GNA11 components of the guanine nucleotide binding protein subunit alpha.	('GNAQ', 'Gene', (44, 48))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('84', '102'))	('GNA11', 'Gene', (52, 57))	('GNAQ', 'Gene', '2776', (44, 48))	('GNA11', 'Gene', '2767', (52, 57))	('mutations', 'Var', (20, 29))
26613	27533448	Uveal melanoma patients were included in several of the initial studies of PD-1 antibodies, but data are limited because these patients were excluded from most subsequent clinical trials.	('patients', 'Species', '9606', (15, 23))	('PD-1', 'Gene', (75, 79))	('PD-1', 'Gene', '5133', (75, 79))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('patients', 'Species', '9606', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', (0, 14))	('antibodies', 'Var', (80, 90))
26689	27533448	One patient had no detectable exon 5 GNAQ or GNA11 mutations, and an additional patient was found to be negative for GNAQ mutations with no record of GNA11 mutation analysis.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (117, 121))	('GNAQ', 'Gene', (37, 41))	('GNA11', 'Gene', (150, 155))	('GNAQ', 'Gene', '2776', (117, 121))	('patient', 'Species', '9606', (4, 11))	('GNA11', 'Gene', '2767', (150, 155))	('GNA11', 'Gene', (45, 50))	('GNAQ', 'Gene', '2776', (37, 41))	('patient', 'Species', '9606', (80, 87))	('GNA11', 'Gene', '2767', (45, 50))
26690	27533448	None of the patients with PD or SD after treatment with PD-1 or PD-L1 antibodies were tested for GNAQ or GNA11 mutations.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (12, 20))	('GNA11', 'Gene', (105, 110))	('GNAQ', 'Gene', '2776', (97, 101))	('men', 'Species', '9606', (46, 49))	('GNA11', 'Gene', '2767', (105, 110))	('PD-L1', 'Gene', (64, 69))	('PD-1', 'Gene', (56, 60))	('SD', 'Disease', 'MESH:D029461', (32, 34))	('PD-1', 'Gene', '5133', (56, 60))	('PD-L1', 'Gene', '29126', (64, 69))	('GNAQ', 'Gene', (97, 101))
26699	27533448	As described in cutaneous melanoma, there did not seem to be a clear association between clinical benefit from PD-1 or PD-L1 antibodies and benefit from prior treatment with other immune therapies, including ipilimumab.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('ipilimumab', 'Chemical', 'MESH:D000074324', (208, 218))	('PD-L1', 'Gene', (119, 124))	('cutaneous melanoma', 'Disease', (16, 34))	('PD-1', 'Gene', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('PD-1', 'Gene', '5133', (111, 115))	('antibodies', 'Var', (125, 135))	('PD-L1', 'Gene', '29126', (119, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (16, 34))	('men', 'Species', '9606', (164, 167))
26714	27533448	In patients with metastatic cutaneous melanoma and other advanced malignancies, tumors expressing high levels of PD-L1 (i.e., "PD-L1 positive") are more likely to respond to anti-PD-1 monotherapy than those with low expression (i.e., "PD-L1 negative").	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-1', 'Gene', (179, 183))	('PD-1', 'Gene', '5133', (179, 183))	('PD-L1', 'Gene', (113, 118))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('tumors', 'Disease', (80, 86))	('malignancies', 'Disease', (66, 78))	('PD-L1', 'Gene', '29126', (113, 118))	('PD-L1', 'Gene', (127, 132))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('PD-L1', 'Gene', '29126', (127, 132))	('cutaneous melanoma', 'Disease', (28, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('PD-L1', 'Gene', (235, 240))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('PD-L1', 'Gene', '29126', (235, 240))	('patients', 'Species', '9606', (3, 11))	('respond', 'MPA', (163, 170))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('high levels', 'Var', (98, 109))
26734	26733611	We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR 0.56, 95%CI 0.41-0.77; P=0.0002) and rs6695772, controlling the expression of BATF3 (HR 1.64, 95%CI 1.19-2.24; P=0.0019).	('IL19', 'molecular_function', 'GO:0045516', ('95', '99'))	('impacting', 'Reg', (85, 94))	('rs6673928', 'Mutation', 'rs6673928', (74, 83))	('IL19', 'Gene', (95, 99))	('rs6695772', 'Var', (152, 161))	('melanoma OS', 'Disease', (58, 69))	('expression', 'MPA', (100, 110))	('melanoma OS', 'Disease', 'MESH:C567932', (58, 69))	('BATF3', 'Gene', '55509', (193, 198))	('rs6695772', 'Mutation', 'rs6695772', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('IL19', 'Gene', '29949', (95, 99))	('BATF3', 'Gene', (193, 198))	('rs6673928', 'Var', (74, 83))
26745	26733611	Findings from genome-wide association studies (GWAS) estimate that 88% of disease/trait-associated germline variants are non-coding, and 12% and 34% of them overlap with transcription factor-binding regions and DNase I Hypersensitive sites (i.e.	('DNase I', 'molecular_function', 'GO:0004530', ('211', '218'))	('Hypersensitive', 'Disease', (219, 233))	('Hypersensitive', 'Disease', 'MESH:D004342', (219, 233))	('overlap', 'Reg', (157, 164))	('transcription factor-binding', 'molecular_function', 'GO:0008134', ('170', '198'))	('variants', 'Var', (108, 116))	('transcription', 'biological_process', 'GO:0006351', ('170', '183'))
26746	26733611	These large analyses generated comprehensive maps of inherited genetic variation that regulate gene expression, thus representing plausible biological candidates for association with human traits, including common diseases.	('genetic variation', 'Var', (63, 80))	('gene expression', 'MPA', (95, 110))	('gene expression', 'biological_process', 'GO:0010467', ('95', '110'))	('human', 'Species', '9606', (183, 188))	('regulate', 'Reg', (86, 94))
26747	26733611	While most eQTL studies were conducted on a relatively small sample size, a recent study by Grundberg et al (2013) identified cis-eQTL SNPs in three selected tissues, including lymphoblastoid cell lines (LCLs) derived from a large population of 857 well-phenotyped healthy female twins of the MuTHER (Multiple Tissue Human Expression Resource) project.	('SNPs', 'Var', (135, 139))	('cis-eQTL SNPs', 'Var', (126, 139))	('Human', 'Species', '9606', (317, 322))
26749	26733611	By interrogating 382 immunomodulatory genes against eQTL data from MuTHER, we have evaluated 40 expression-regulating polymorphisms and their cumulative effects for association with melanoma clinical outcomes in a large population sample of 1,221 CM patients.	('CM', 'Phenotype', 'HP:0012056', (247, 249))	('association', 'Interaction', (165, 176))	('patients', 'Species', '9606', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('polymorphisms', 'Var', (118, 131))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
26756	26733611	Probes were designed and synthesized by NanoString nCounter technologies to probe the following sequences of target transcripts: CCACAGACATGCACCATATAGAAGAGAGTTTCCAAGAAATCAAAAGAGCCATCCAAGCTAAGGACACC TTCCCAAATGTCACTATCCTGTCCACATTGGA for IL19 (NM_013371.3), GCAAGAAGTATGCTGAGGCTGTCACTCGGGCTAAGCAGATTGTGTGGAATGGTCCTGTGGGGGTATTT GAATGGGAAGCTTTTGCCCGGGGAACCAAAGC for PGK1 (NM_000291.2) and CGGTCGTGATGTGGTCTGTGGCCAACGAGCCTGCGTCCCACCTAGAATCTGCTGGCTACTACTTGAAG ATGGTGATCGCTCACACCAAATCCTTGGACCC for GUSB (NM_000181.1).	('NM_013371.3', 'Var', (241, 252))	('PGK', 'molecular_function', 'GO:0004618', ('361', '364'))	('GUSB', 'Gene', (490, 494))	('PGK1', 'Gene', '5230', (361, 365))	('PGK1', 'Gene', (361, 365))	('IL19', 'Gene', '29949', (235, 239))	('IL19', 'molecular_function', 'GO:0045516', ('235', '239'))	('IL19', 'Gene', (235, 239))	('GUSB', 'Gene', '2990', (490, 494))
26775	26733611	In the RFS analysis, the most significant association was observed for rs9921791, an eQTL controlling expression of MLST8 in LCLs (Figure 1A) and ranking #16 among the top 50 eQTLs in the study (Supplementary Table 2), where carriers of at least one copy of minor T allele were associated with better outcome under the dominant model (HR= 0.52, 95% CI 0.35 to 0.79; P=0.0009).	('better', 'PosReg', (294, 300))	('MLST8', 'Gene', '64223', (116, 121))	('RFS', 'Chemical', '-', (7, 10))	('MLST8', 'Gene', (116, 121))	('rs9921791', 'Var', (71, 80))	('rs9921791', 'Mutation', 'rs9921791', (71, 80))
26776	26733611	While other variants show nominal significance under different genetic models of analysis, including rs6695772 (IL19, P=0.005), rs6695772 (BATF3, P=0.006), rs841718 (STAT6, P=0.015), rs11539345 (CD40, P=0.016) and rs2276645 (ZAP70, P=0.048), after adjusting for multiple testing none of the variants remained statistically significant in RFS analyses.	('STAT6', 'Gene', (166, 171))	('rs2276645', 'Mutation', 'rs2276645', (214, 223))	('BATF3', 'Gene', '55509', (139, 144))	('BATF3', 'Gene', (139, 144))	('rs11539345', 'Mutation', 'rs11539345', (183, 193))	('ZAP70', 'Gene', (225, 230))	('CD4', 'Gene', '920', (195, 198))	('STAT6', 'Gene', '6778', (166, 171))	('ZAP70', 'Gene', '7535', (225, 230))	('IL19', 'molecular_function', 'GO:0045516', ('112', '116'))	('CD4', 'Gene', (195, 198))	('rs6695772', 'Var', (128, 137))	('RFS', 'Chemical', '-', (338, 341))	('rs11539345', 'Var', (183, 193))	('IL19', 'Gene', '29949', (112, 116))	('rs6695772', 'Mutation', 'rs6695772', (128, 137))	('IL19', 'Gene', (112, 116))	('rs2276645', 'Var', (214, 223))	('rs6695772', 'Var', (101, 110))	('rs841718', 'Mutation', 'rs841718', (156, 164))	('rs841718', 'Var', (156, 164))	('rs6695772', 'Mutation', 'rs6695772', (101, 110))
26778	26733611	The most significant association with OS was observed for rs6673928 (an eQTL impacting expression of IL19 [Figure 1B] and ranking #12 among the top 50 eQTLs in the study [Supplementary Table 2]), under the dominant model, in which the variant T allele was associated with improved OS (HR=0.56, 95% CI 0.41 to 0.77, P=0.0002).	('rs6673928', 'Mutation', 'rs6673928', (58, 67))	('improved', 'PosReg', (272, 280))	('impacting', 'Reg', (77, 86))	('IL19', 'Gene', '29949', (101, 105))	('variant', 'Var', (235, 242))	('IL19', 'Gene', (101, 105))	('expression', 'MPA', (87, 97))	('rs6673928', 'Var', (58, 67))	('IL19', 'molecular_function', 'GO:0045516', ('101', '105'))	('OS', 'Chemical', '-', (38, 40))	('OS', 'Chemical', '-', (281, 283))
26779	26733611	Moreover, comparably significant association between OS and rs6673928 was also observed in an analysis adjusted by only age and gender (see Methods), suggesting that survival effect of rs6673928 is independent of other AJCC clinical variables (HR=0.61, 95% CI 0.45 to 0.82; P=0.0008).	('AJCC', 'Disease', (219, 223))	('rs6673928', 'Var', (185, 194))	('OS', 'Chemical', '-', (53, 55))	('rs6673928', 'Mutation', 'rs6673928', (60, 69))	('rs6673928', 'Mutation', 'rs6673928', (185, 194))
26780	26733611	Our second most significant OS association, reaching the level of multiple testing adjusted significance, was observed for rs6695772 (influencing BATF3 expression levels, Figure 1C).	('OS', 'Chemical', '-', (28, 30))	('rs6695772', 'Var', (123, 132))	('BATF3', 'Gene', '55509', (146, 151))	('rs6695772', 'Mutation', 'rs6695772', (123, 132))	('expression levels', 'MPA', (152, 169))	('BATF3', 'Gene', (146, 151))	('influencing', 'Reg', (134, 145))
26781	26733611	The carriers of the rs6695772 minor C allele were associated with worse survival under the dominant model (HR=1.64, 95% CI 1.19 to 2.24; P=0.0019).	('rs6695772', 'Var', (20, 29))	('rs6695772', 'Mutation', 'rs6695772', (20, 29))	('worse', 'NegReg', (66, 71))	('survival', 'MPA', (72, 80))
26782	26733611	Polymorphisms rs6673928 and rs6695772, both exhibiting most significant association with OS, are located ~6 Mb apart on chromosome 1q32, previously suggested for association with melanoma outcome.	('rs6695772', 'Var', (28, 37))	('rs6673928', 'Var', (14, 23))	('rs6695772', 'Mutation', 'rs6695772', (28, 37))	('OS', 'Chemical', '-', (89, 91))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('rs6673928', 'Mutation', 'rs6673928', (14, 23))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))
26783	26733611	Linkage disequilibrium (LD) analysis showed that the two SNPs are independent (r2=0.002, D'=0.099), which we further confirmed by performing association between OS and rs6695772 using multivariate Cox regression analysis while also adjusting for the rs6673928 variant and found no difference in effect size and significance.	('OS', 'Chemical', '-', (161, 163))	('rs6673928', 'Var', (250, 259))	('rs6695772', 'Var', (168, 177))	('association', 'Interaction', (141, 152))	('rs6673928', 'Mutation', 'rs6673928', (250, 259))	('rs6695772', 'Mutation', 'rs6695772', (168, 177))	('Cox', 'Gene', '1351', (197, 200))	('Cox', 'Gene', (197, 200))
26784	26733611	Moreover, as per MuTHER data, there is no correlation between rs6673928 (eQTL for IL19) and BATF3 expression and similarly no association is observed between rs6695772 (eQTL for BATF3) and expression levels of IL19.	('rs6695772', 'Var', (158, 167))	('IL19', 'Gene', '29949', (210, 214))	('IL19', 'Gene', (210, 214))	('BATF3', 'Gene', (178, 183))	('IL19', 'molecular_function', 'GO:0045516', ('210', '214'))	('rs6695772', 'Mutation', 'rs6695772', (158, 167))	('IL19', 'molecular_function', 'GO:0045516', ('82', '86'))	('expression', 'MPA', (189, 199))	('BATF3', 'Gene', '55509', (92, 97))	('rs6673928', 'Var', (62, 71))	('IL19', 'Gene', '29949', (82, 86))	('IL19', 'Gene', (82, 86))	('BATF3', 'Gene', (92, 97))	('BATF3', 'Gene', '55509', (178, 183))	('rs6673928', 'Mutation', 'rs6673928', (62, 71))	('expression', 'MPA', (98, 108))
26785	26733611	Other associations with OS, not reaching the adjustments for multiple testing, were observed for rs841718 (STAT6, Pdominant model=0.007), rs2701652 (IRAK3, P=0.035), rs7720838 (PTGER4, Precessive model=0.037) and rs11569345 (CD40, Pdominant model=0.040).	('PTGER4', 'Gene', (177, 183))	('rs11569345', 'Var', (213, 223))	('rs7720838', 'Var', (166, 175))	('STAT6', 'Gene', (107, 112))	('associations', 'Reg', (6, 18))	('rs841718', 'Mutation', 'rs841718', (97, 105))	('OS', 'Chemical', '-', (24, 26))	('STAT6', 'Gene', '6778', (107, 112))	('IRAK3', 'Gene', (149, 154))	('rs841718', 'Var', (97, 105))	('CD4', 'Gene', (225, 228))	('rs7720838', 'Mutation', 'rs7720838', (166, 175))	('rs11569345', 'Mutation', 'rs11569345', (213, 223))	('IRAK3', 'Gene', '11213', (149, 154))	('CD4', 'Gene', '920', (225, 228))	('PTGER4', 'Gene', '5734', (177, 183))	('rs2701652', 'Var', (138, 147))	('rs2701652', 'Mutation', 'rs2701652', (138, 147))
26786	26733611	Of note, SNPs rs11569345 (CD40), rs6673928 (IL19), rs6695772 (BATF3) and rs841718 (STAT6) exhibited association with both RFS and OS, and the directionality of associations was comparable between RFS and OS for all analyzed SNPs (Table 3).	('rs6673928', 'Mutation', 'rs6673928', (33, 42))	('RFS', 'Chemical', '-', (122, 125))	('IL19', 'Gene', '29949', (44, 48))	('IL19', 'Gene', (44, 48))	('rs841718', 'Mutation', 'rs841718', (73, 81))	('association', 'Interaction', (100, 111))	('rs6695772', 'Var', (51, 60))	('rs841718', 'Var', (73, 81))	('rs6695772', 'Mutation', 'rs6695772', (51, 60))	('CD4', 'Gene', '920', (26, 29))	('STAT6', 'Gene', (83, 88))	('IL19', 'molecular_function', 'GO:0045516', ('44', '48'))	('RFS', 'Chemical', '-', (196, 199))	('OS', 'Chemical', '-', (204, 206))	('CD4', 'Gene', (26, 29))	('rs6673928', 'Var', (33, 42))	('rs11569345', 'Mutation', 'rs11569345', (14, 24))	('BATF3', 'Gene', '55509', (62, 67))	('RFS', 'Disease', (122, 125))	('STAT6', 'Gene', '6778', (83, 88))	('BATF3', 'Gene', (62, 67))	('rs11569345', 'Var', (14, 24))	('OS', 'Chemical', '-', (130, 132))
26787	26733611	We further assessed the cumulative effect of two eQTL SNPs, rs6673928 (IL19) and rs6695772 (BATF3) on OS, as these were the most significant associations in the single SNP analysis after adjustment for multiple testing, and, interestingly, both variants, albeit genetically independent (not in LD), map in the same locus at 1q32.	('OS', 'Chemical', '-', (102, 104))	('IL19', 'molecular_function', 'GO:0045516', ('71', '75'))	('rs6673928', 'Var', (60, 69))	('rs6695772', 'Mutation', 'rs6695772', (81, 90))	('associations', 'Reg', (141, 153))	('BATF3', 'Gene', '55509', (92, 97))	('rs6673928', 'Mutation', 'rs6673928', (60, 69))	('IL19', 'Gene', '29949', (71, 75))	('IL19', 'Gene', (71, 75))	('BATF3', 'Gene', (92, 97))	('rs6695772', 'Var', (81, 90))
26789	26733611	The following genotypes were considered as unfavorable: rs6673928 (wild-type) and rs6695772 (heterozygotes and variant homozygotes).	('rs6695772', 'Mutation', 'rs6695772', (82, 91))	('rs6695772', 'Var', (82, 91))	('rs6673928', 'Mutation', 'rs6673928', (56, 65))	('rs6673928', 'Var', (56, 65))
26791	26733611	To further validate the genotype-expression correlation of our most significant eQTL in melanoma survival analysis, we tested the correlation of rs6679328 with IL19 expression in CD4+ T cells purified from a subset of 43 melanoma patients from a population genotyped in this study.	('rs6679328', 'Var', (145, 154))	('CD4', 'Gene', (179, 182))	('rs6679328', 'Mutation', 'rs6679328', (145, 154))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (221, 229))	('melanoma', 'Disease', (88, 96))	('CD4', 'Gene', '920', (179, 182))	('tested', 'Reg', (119, 125))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('patients', 'Species', '9606', (230, 238))	('IL19', 'Gene', '29949', (160, 164))	('IL19', 'Gene', (160, 164))	('IL19', 'molecular_function', 'GO:0045516', ('160', '164'))	('correlation', 'Interaction', (130, 141))
26797	26733611	MC1R, vitamin D-binding protein ], in general, almost exclusively, the genetic variants identified to date for associations with melanoma risk (i.e.	('MC1R', 'Gene', '4157', (0, 4))	('vitamin D-binding protein', 'Gene', (6, 31))	('vitamin D-binding protein', 'Gene', '2638', (6, 31))	('vitamin D-binding', 'molecular_function', 'GO:0005499', ('6', '23'))	('MC1R', 'Gene', (0, 4))	('variants', 'Var', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('associations', 'Interaction', (111, 123))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))
26800	26733611	Considering the fact that melanomas are highly immunogenic, the genetic variants in immunomodulatory genes that are significantly and reproducibly associated with gene expression in immune cells as validated eQTLs may have a strong potential to serve as clinically actionable prognostic markers.	('melanomas', 'Disease', (26, 35))	('associated', 'Reg', (147, 157))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('variants', 'Var', (72, 80))	('melanomas', 'Disease', 'MESH:D008545', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('gene expression', 'biological_process', 'GO:0010467', ('163', '178'))
26802	26733611	Our study provides a first in-depth analysis aimed at mapping the functionally important germline variants in immunomodulatory networks as potential markers of melanoma prognosis.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('markers', 'Reg', (149, 156))	('variants', 'Var', (98, 106))
26804	26733611	Our approach for the first time identified several eQTL variants that were significantly associated with melanoma survival.	('associated with', 'Reg', (89, 104))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('variants', 'Var', (56, 64))	('eQTL', 'Gene', (51, 55))
26805	26733611	The most significant finding in our study is the association of melanoma overall survival (OS) with eQTL variant rs6673928 at 1q32.1, impacting the expression of IL19 gene (linear regression coefficient [beta]= 0.12, P=5.66x10-23).	('impacting', 'Reg', (134, 143))	('IL19', 'Gene', '29949', (162, 166))	('rs6673928', 'Var', (113, 122))	('IL19', 'Gene', (162, 166))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('association', 'Interaction', (49, 60))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('rs6673928', 'Mutation', 'rs6673928', (113, 122))	('OS', 'Chemical', '-', (91, 93))	('IL19', 'molecular_function', 'GO:0045516', ('162', '166'))	('expression', 'MPA', (148, 158))	('variant rs6673928', 'Var', (105, 122))	('eQTL', 'Gene', (100, 104))
26806	26733611	We observed a strong association of rs6673928 with better survival for the carriers of a minor T allele (HR=0.56, 95% CI 0.41 to 0.77; P=0.0002), which correlated with increased expression of IL19 in LCLs from MuTHER dataset, and this correlation was also validated in CD4+ T cells purified from a subset of melanoma patients from our study population (Figure 3).	('increased', 'PosReg', (168, 177))	('rs6673928', 'Var', (36, 45))	('expression', 'MPA', (178, 188))	('CD4', 'Gene', (269, 272))	('CD4', 'Gene', '920', (269, 272))	('survival', 'CPA', (58, 66))	('rs6673928', 'Mutation', 'rs6673928', (36, 45))	('melanoma', 'Disease', (308, 316))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('better', 'PosReg', (51, 57))	('IL19', 'molecular_function', 'GO:0045516', ('192', '196'))	('melanoma', 'Disease', 'MESH:D008545', (308, 316))	('patients', 'Species', '9606', (317, 325))	('IL19', 'Gene', '29949', (192, 196))	('IL19', 'Gene', (192, 196))
26811	26733611	Interestingly, eQTL data from MuTHER project show that our most significant variant rs6673928 also associates with expression of IL10, albeit with less significance (P<2.5x10-6) compared to the effect on IL19 expression.	('rs6673928', 'Var', (84, 93))	('rs6673928', 'Mutation', 'rs6673928', (84, 93))	('IL19', 'Gene', (204, 208))	('expression', 'MPA', (115, 125))	('IL10', 'Gene', (129, 133))	('IL10', 'Gene', '3586', (129, 133))	('associates', 'Reg', (99, 109))	('IL19', 'Gene', '29949', (204, 208))	('IL19', 'molecular_function', 'GO:0045516', ('204', '208'))	('IL10', 'molecular_function', 'GO:0005141', ('129', '133'))
26812	26733611	This is interesting, as we have recently identified strong association with CM survival for a variant near IL10, rs3024493.	('IL10', 'molecular_function', 'GO:0005141', ('107', '111'))	('IL10', 'Gene', (107, 111))	('IL10', 'Gene', '3586', (107, 111))	('rs3024493', 'Mutation', 'rs3024493', (113, 122))	('rs3024493', 'Var', (113, 122))	('CM', 'Phenotype', 'HP:0012056', (76, 78))	('association', 'Reg', (59, 70))	('CM survival', 'Disease', (76, 87))
26813	26733611	In that recent report we showed that the association with improved OS is driven by rs3024493 heterozygotes, which secrete medium levels of IL10, as compared to low-secreting minor allele homozygotes conversely associated with worse outcome, which is consistent with directionality of the effects for IL19 in the current study.	('improved', 'PosReg', (58, 66))	('associated', 'Reg', (210, 220))	('IL10', 'Gene', (139, 143))	('IL19', 'Gene', '29949', (300, 304))	('IL10', 'molecular_function', 'GO:0005141', ('139', '143'))	('IL19', 'Gene', (300, 304))	('OS', 'Chemical', '-', (67, 69))	('IL10', 'Gene', '3586', (139, 143))	('rs3024493', 'Var', (83, 92))	('IL19', 'molecular_function', 'GO:0045516', ('300', '304'))	('rs3024493', 'Mutation', 'rs3024493', (83, 92))
26814	26733611	Other prior smaller scale studies also reported associations at 1q32.1 with melanoma survival for a set of three highly correlated polymorphisms in IL10 promoter: rs1800896, rs1800871 and rs1800872.	('melanoma', 'Disease', (76, 84))	('rs1800871', 'Var', (174, 183))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('rs1800872', 'Var', (188, 197))	('IL10', 'Gene', (148, 152))	('IL10', 'Gene', '3586', (148, 152))	('associations', 'Interaction', (48, 60))	('rs1800896', 'Var', (163, 172))	('rs1800872', 'Mutation', 'rs1800872', (188, 197))	('rs1800871', 'Mutation', 'rs1800871', (174, 183))	('IL10', 'molecular_function', 'GO:0005141', ('148', '152'))	('rs1800896', 'Mutation', 'rs1800896', (163, 172))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
26816	26733611	These consistent reports clearly suggest that the genetic variation at 1q32 may result in specific gene-expression patterns regulating several interleukin candidates in the locus with an impact on melanoma clinical outcome, likely via modulation of melanoma immune surveillance.	('result in', 'Reg', (80, 89))	('impact', 'Reg', (187, 193))	('gene-expression patterns', 'MPA', (99, 123))	('interleukin candidates', 'Gene', (143, 165))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('gene-expression', 'biological_process', 'GO:0010467', ('99', '114'))	('melanoma', 'Disease', (197, 205))	('melanoma', 'Disease', 'MESH:D008545', (249, 257))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('genetic variation', 'Var', (50, 67))	('melanoma', 'Disease', (249, 257))
26817	26733611	Using the data from 1000 Genomes Pilot project we found that rs1800896 [previous studies, ], rs3024493 [our recent study, ], and rs6673928 [current study] show little to no correlation (r2rs1800896-rs3024493= 0.31, r2rs1800896-rs6673928= 0.24 and r2rs6673928-rs3024493= 0.07), which was also confirmed in our study population (data not shown).	('rs3024493', 'Var', (93, 102))	('rs6673928', 'Var', (129, 138))	('rs3024493', 'Mutation', 'rs3024493', (93, 102))	('rs1800896', 'Mutation', 'rs1800896', (188, 197))	('rs3024493', 'Mutation', 'rs3024493', (259, 268))	('rs1800896', 'Mutation', 'rs1800896', (217, 226))	('r2rs6673928-rs3024493=', 'Var', (247, 269))	('rs6673928', 'Mutation', 'rs6673928', (129, 138))	('rs6673928', 'Mutation', 'rs6673928', (249, 258))	('rs3024493', 'Mutation', 'rs3024493', (198, 207))	('rs1800896', 'Var', (61, 70))	('rs1800896', 'Mutation', 'rs1800896', (61, 70))	('r2rs1800896-rs6673928=', 'Var', (215, 237))	('rs6673928', 'Mutation', 'rs6673928', (227, 236))
26818	26733611	The region of associated variants shows the presence of several strong DNase I hypersensitive sites in T cells, involving multiple transcription factors spread across a 30 kbp region (Supplementary Figure 2).	('variants', 'Var', (25, 33))	('hypersensitive', 'Disease', (79, 93))	('transcription', 'biological_process', 'GO:0006351', ('131', '144'))	('DNase I', 'molecular_function', 'GO:0004530', ('71', '78'))	('hypersensitive', 'Disease', 'MESH:D004342', (79, 93))
26819	26733611	We found another variant on chromosome 1, rs6695772, which was associated with OS.	('OS', 'Chemical', '-', (79, 81))	('associated', 'Reg', (63, 73))	('rs6695772', 'Var', (42, 51))	('rs6695772', 'Mutation', 'rs6695772', (42, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('28', '38'))
26821	26733611	The MuTHER eQTL data in LCLs associate minor C allele of rs6695772 with decreased expression levels of BATF3 gene (basic leucine zipper transcription factor, ATF-like 3) in a dose-dependent manner (linear regression coefficient [beta]=-0.16, P=6.93x10-10) (Figure 1C).	('rs6695772', 'Mutation', 'rs6695772', (57, 66))	('BATF3', 'Gene', '55509', (103, 108))	('expression levels', 'MPA', (82, 99))	('decreased', 'NegReg', (72, 81))	('BATF3', 'Gene', (103, 108))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('transcription factor', 'molecular_function', 'GO:0000981', ('136', '156'))	('rs6695772', 'Var', (57, 66))
26824	26733611	Interestingly, rs6695772 maps ~6Mb downstream from our most significantly associated variant, rs6673928, and although not in LD (r2=0.002), the comparably significant association effects observed with melanoma survival and relatively close proximity of both loci might suggest common genetic or biological underpinnings.	('melanoma', 'Disease', (201, 209))	('rs6695772', 'Mutation', 'rs6695772', (15, 24))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('rs6673928', 'Mutation', 'rs6673928', (94, 103))	('rs6695772', 'Var', (15, 24))	('rs6673928', 'Var', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
26826	26733611	Moreover, knocking down BATF3 in Th2 cells dramatically decreased expression of IL4 and IL10 cytokines.	('BATF3', 'Gene', '55509', (24, 29))	('knocking down', 'Var', (10, 23))	('BATF3', 'Gene', (24, 29))	('IL10', 'molecular_function', 'GO:0005141', ('88', '92'))	('IL4', 'molecular_function', 'GO:0005136', ('80', '83'))	('decreased', 'NegReg', (56, 65))	('IL10', 'Gene', (88, 92))	('expression', 'MPA', (66, 76))	('IL4', 'Gene', '3565', (80, 83))	('IL4', 'Gene', (80, 83))	('IL10', 'Gene', '3586', (88, 92))
26828	26733611	These findings therefore align with our observations that minor T allele carriers of germline eQTL rs6695772, associated with worse OS, express low levels of BATF3 which may in turn down-regulate IL4 and IL10.	('rs6695772', 'Var', (99, 108))	('IL10', 'molecular_function', 'GO:0005141', ('204', '208'))	('BATF3', 'Gene', (158, 163))	('IL4', 'Gene', (196, 199))	('eQTL', 'Gene', (94, 98))	('rs6695772', 'Mutation', 'rs6695772', (99, 108))	('IL4', 'Gene', '3565', (196, 199))	('OS', 'Chemical', '-', (132, 134))	('IL10', 'Gene', (204, 208))	('down-regulate', 'NegReg', (182, 195))	('IL4', 'molecular_function', 'GO:0005136', ('196', '199'))	('IL10', 'Gene', '3586', (204, 208))	('BATF3', 'Gene', '55509', (158, 163))
26832	26733611	Due to functional commonalities and putative mutual interaction between the two loci (rs6673928 and rs6695772) most significantly associated with melanoma OS in our study, we explored possible cumulative effects of these two variants.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('rs6673928', 'Mutation', 'rs6673928', (86, 95))	('rs6695772', 'Mutation', 'rs6695772', (100, 109))	('rs6695772', 'Var', (100, 109))	('melanoma OS', 'Disease', (146, 157))	('rs6673928', 'Var', (86, 95))	('melanoma OS', 'Disease', 'MESH:C567932', (146, 157))	('associated', 'Reg', (130, 140))
26833	26733611	We found that the joint effect of both variants on OS is substantially stronger (HR =1.92, 95% CI 1.43 to 2.60; P=1.87x10-5) (Figure 2), when compared to single SNP analysis.	('stronger', 'PosReg', (71, 79))	('OS', 'Chemical', '-', (51, 53))	('variants', 'Var', (39, 47))
26836	26733611	Significant association was also noted for rs9921791, located nearby MLST8 (mammalian lethal with SEC13 protein 8).	('mammalian lethal with SEC13 protein 8', 'Gene', '64223', (76, 113))	('mammalian lethal with SEC13 protein 8', 'Gene', (76, 113))	('MLST8', 'Gene', '64223', (69, 74))	('rs9921791', 'Var', (43, 52))	('MLST8', 'Gene', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('rs9921791', 'Mutation', 'rs9921791', (43, 52))
26837	26733611	The carriers of minor T allele (associated with increased expression of MLST8) recurred significantly later compared to patients with CC genotypes (Figure 1A).	('increased', 'PosReg', (48, 57))	('minor T', 'Var', (16, 23))	('expression', 'MPA', (58, 68))	('MLST8', 'Gene', '64223', (72, 77))	('patients', 'Species', '9606', (120, 128))	('MLST8', 'Gene', (72, 77))
26839	26733611	This suggest that upregulation of MLST8 expression among rs99212791-T allele carriers with CM, may stimulate immune tumoral response via mTOR pathway-mediated T cell activation, leading to suppression of CM recurrence.	('expression', 'MPA', (40, 50))	('upregulation', 'PosReg', (18, 30))	('rs99212791', 'Mutation', 'rs99212791', (57, 67))	('T cell activation', 'biological_process', 'GO:0042110', ('159', '176'))	('activation', 'PosReg', (166, 176))	('suppression', 'NegReg', (189, 200))	('stimulate', 'PosReg', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('MLST8', 'Gene', '64223', (34, 39))	('CM', 'Phenotype', 'HP:0012056', (204, 206))	('MLST8', 'Gene', (34, 39))	('mTOR', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mTOR', 'Gene', '2475', (137, 141))	('CM', 'Phenotype', 'HP:0012056', (91, 93))	('rs99212791-T', 'Var', (57, 69))	('tumor', 'Disease', (116, 121))
26841	26733611	Although all our analyses were adjusted for gender, the gender-stratified tests for our most significant associations revealed a gender-specific effect for some variants, in particular rs6695772 (BATF3) association with OS observed only in males.	('rs6695772', 'Var', (185, 194))	('OS', 'Chemical', '-', (220, 222))	('BATF3', 'Gene', (196, 201))	('rs6695772', 'Mutation', 'rs6695772', (185, 194))	('BATF3', 'Gene', '55509', (196, 201))
26842	26733611	As it is difficult to draw reliable conclusions at this stage, to confirm their potential biological meaning, the gender-specific testing of rs6695772 (BATF3) in a larger melanoma population will be needed in subsequent efforts.	('BATF3', 'Gene', '55509', (152, 157))	('rs6695772', 'Var', (141, 150))	('BATF3', 'Gene', (152, 157))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('rs6695772', 'Mutation', 'rs6695772', (141, 150))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))
26848	26733611	Here we provide a novel approach for identification of biologically and clinically impactful germline variants associated with melanoma prognosis.	('variants', 'Var', (102, 110))	('associated', 'Reg', (111, 121))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))
26849	26733611	As immunogenicity is an important hallmark of melanoma progression, in our strategy we interrogated publically available resources to identify genetic variants strongly associated with the expression of immune related genes and tested their effect on modulation of survival in 1,221 melanoma patients.	('tested', 'Reg', (228, 234))	('variants', 'Var', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('expression', 'MPA', (189, 199))	('melanoma', 'Disease', (283, 291))	('associated', 'Reg', (169, 179))	('patients', 'Species', '9606', (292, 300))
26850	26733611	We have identified novel significant associations of gene-expression correlated variants with melanoma OS, and propose that their joint interaction may provide a clinically relevant effect independent of the current clinicopathological markers.	('gene-expression', 'MPA', (53, 68))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('gene-expression', 'biological_process', 'GO:0010467', ('53', '68'))	('melanoma OS', 'Disease', (94, 105))	('variants', 'Var', (80, 88))	('associations', 'Interaction', (37, 49))	('melanoma OS', 'Disease', 'MESH:C567932', (94, 105))
26857	32839509	FAM83H-AS1 silencing impairs two important breast cancer related pathways: cell migration and cell death.	('silencing', 'Var', (11, 20))	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('impairs', 'NegReg', (21, 28))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cell migration', 'CPA', (75, 89))	('cell death', 'CPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cell migration', 'biological_process', 'GO:0016477', ('75', '89'))	('FAM83H-AS1', 'Gene', (0, 10))	('cell death', 'biological_process', 'GO:0008219', ('94', '104'))
26858	32839509	Among the most relevant potential FAM83H-AS1 gene targets, we found p63 and claudin 1 (CLDN1) to be deregulated after FAM83H-AS1 knockdown.	('FAM83H-AS1', 'Gene', '100128338', (34, 44))	('FAM83H-AS1', 'Gene', (118, 128))	('CLDN1', 'Gene', '9076', (87, 92))	('knockdown', 'Var', (129, 138))	('p63', 'Gene', '8626', (68, 71))	('claudin 1', 'Gene', '9076', (76, 85))	('FAM83H-AS1', 'Gene', (34, 44))	('CLDN1', 'Gene', (87, 92))	('FAM83H-AS1', 'Gene', '100128338', (118, 128))	('deregulated', 'PosReg', (100, 111))	('claudin 1', 'Gene', (76, 85))	('p63', 'Gene', (68, 71))
26869	32839509	In this regard, recent papers have focused on the role of long non coding RNAs (lncRNAs) in cancer biology and in the role of specific lncRNAs in breast cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('long non coding RNAs', 'Var', (58, 78))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
26870	32839509	FAM83H-AS1 is a lncRNA whose expression impairs important cancer-related pathways such as cell proliferation, migration, invasion and cell death in lung, colorectal, glial, bladder, ovarian and cervical cancer cells.	('expression', 'Var', (29, 39))	('bladder', 'Disease', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cell proliferation', 'CPA', (90, 108))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('migration', 'CPA', (110, 119))	('glial', 'Disease', (166, 171))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('invasion', 'CPA', (121, 129))	('cell death', 'CPA', (134, 144))	('cell death', 'biological_process', 'GO:0008219', ('134', '144'))	('lung', 'Disease', (148, 152))	('cancer', 'Disease', (203, 209))	('ovarian and cervical cancer', 'Disease', 'MESH:D002575', (182, 209))	('FAM83H-AS1', 'Gene', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('impairs', 'NegReg', (40, 47))	('colorectal', 'Disease', (154, 164))	('cancer', 'Disease', (58, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
26871	32839509	At the molecular level, one report showed that MET/EGFR signaling is regulated by FAM83H-AS1, and showed that FAM83H-AS1 epigenetically silenced CDKN1A by binding to EZH2 in glioma cells.	('FAM83H-AS1', 'Gene', '100128338', (82, 92))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('EGFR', 'Gene', (51, 55))	('binding', 'Interaction', (155, 162))	('CDKN1A', 'Gene', (145, 151))	('CDKN1A', 'Gene', '1026', (145, 151))	('FAM83H-AS1', 'Gene', (82, 92))	('EZH2', 'Gene', (166, 170))	('EZH2', 'Gene', '2146', (166, 170))	('FAM83H-AS1', 'Gene', '100128338', (110, 120))	('EGFR', 'Gene', '1956', (51, 55))	('binding', 'molecular_function', 'GO:0005488', ('155', '162'))	('glioma', 'Disease', (174, 180))	('FAM83H-AS1', 'Gene', (110, 120))	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('silenced', 'NegReg', (136, 144))	('epigenetically', 'Var', (121, 135))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
26890	32839509	Altogether, these widespread alterations in FAM83H-AS1 expression suggested that its expression could be a prognostic biomarker for all BRCA subtypes: but as mentioned above, FAM83H-AS1 was previously reported to have particular prognostic association with the BRCA luminal subtype.	('FAM83H-AS1', 'Gene', '100128338', (44, 54))	('FAM83H-AS1', 'Gene', '100128338', (175, 185))	('BRCA', 'Phenotype', 'HP:0003002', (261, 265))	('BRCA', 'Gene', '672', (261, 265))	('FAM83H-AS1', 'Gene', (44, 54))	('FAM83H-AS1', 'Gene', (175, 185))	('alterations', 'Var', (29, 40))	('BRCA', 'Gene', (261, 265))	('luminal', 'Chemical', 'MESH:D010634', (266, 273))	('BRCA', 'Gene', '672', (136, 140))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
26938	32839509	Caspase 3 assays identified a significantly increase in enzymatic activity (T-test; p = 0.032) after 72 h of FAM83H-AS1 silencing, which corroborates its role in apoptosis mediated cell death.	('FAM83H-AS1', 'Gene', '100128338', (109, 119))	('cell death', 'biological_process', 'GO:0008219', ('181', '191'))	('enzymatic activity', 'MPA', (56, 74))	('Caspase 3', 'Gene', (0, 9))	('increase', 'PosReg', (44, 52))	('FAM83H-AS1', 'Gene', (109, 119))	('silencing', 'Var', (120, 129))	('Caspase 3', 'Gene', '836', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))
26953	32839509	4) or after FAM83H-AS1 knockdown in MCF7 cells (Fig.	('FAM83H-AS1', 'Gene', '100128338', (12, 22))	('FAM83H-AS1', 'Gene', (12, 22))	('knockdown', 'Var', (23, 32))	('MCF7', 'CellLine', 'CVCL:0031', (36, 40))
26956	32839509	Long non-coding RNAs are molecules that exert numerous roles in human cancers, as their biological activities involve regulation of cell proliferation, cell death, differentiation, migration and invasion.	('differentiation', 'CPA', (164, 179))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Long non-coding', 'Var', (0, 15))	('invasion', 'CPA', (195, 203))	('cell proliferation', 'CPA', (132, 150))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cell death', 'biological_process', 'GO:0008219', ('152', '162'))	('migration', 'CPA', (181, 190))	('cancers', 'Disease', (70, 77))	('cell death', 'CPA', (152, 162))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('118', '150'))
26968	32839509	Accordingly, we also found that FAM83H-AS1 knockdown significantly deregulates migration and apoptosis-related genes, such as TP63 and CLND1.	('FAM83H-AS1', 'Gene', (32, 42))	('CLND1', 'Gene', (135, 140))	('deregulates', 'NegReg', (67, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('knockdown', 'Var', (43, 52))	('TP63', 'Gene', (126, 130))	('TP63', 'Gene', '8626', (126, 130))	('migration and', 'CPA', (79, 92))	('FAM83H-AS1', 'Gene', '100128338', (32, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
26973	32839509	FAM83H-AS1 was involved in regulation of cell proliferation, migration and invasion processes that were decreased after FAM83H-AS1 knockdown in lung cancer cells.	('FAM83H-AS1', 'Gene', '100128338', (120, 130))	('knockdown', 'Var', (131, 140))	('lung cancer', 'Disease', (144, 155))	('invasion processes', 'CPA', (75, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('regulation of cell proliferation', 'biological_process', 'GO:0042127', ('27', '59'))	('cell proliferation', 'CPA', (41, 59))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('decreased', 'NegReg', (104, 113))	('FAM83H-AS1', 'Gene', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('migration', 'CPA', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('FAM83H-AS1', 'Gene', (0, 10))
26976	32839509	In vitro assays also show that FAM83H-AS1 silencing increases cellular death, possibly by up regulating genes like p63.	('silencing', 'Var', (42, 51))	('up regulating', 'PosReg', (90, 103))	('increases', 'PosReg', (52, 61))	('FAM83H-AS1', 'Gene', '100128338', (31, 41))	('p63', 'Gene', (115, 118))	('cellular death', 'CPA', (62, 76))	('FAM83H-AS1', 'Gene', (31, 41))	('p63', 'Gene', '8626', (115, 118))
26977	32839509	One previous report showed that cell death was markedly increased after with FAM83H-AS1 knockdown in colorectal cell lines.	('cell death', 'CPA', (32, 42))	('increased', 'PosReg', (56, 65))	('FAM83H-AS1', 'Gene', (77, 87))	('knockdown', 'Var', (88, 97))	('cell death', 'biological_process', 'GO:0008219', ('32', '42'))	('FAM83H-AS1', 'Gene', '100128338', (77, 87))
26979	32839509	Cell proliferation was inhibited with FAM83H-AS1 knockdown and this effect mediated by FAM83H-AS1 could be reversed by Notch1 regulators.	('Notch1', 'Gene', (119, 125))	('knockdown', 'Var', (49, 58))	('Cell proliferation', 'biological_process', 'GO:0008283', ('0', '18'))	('FAM83H-AS1', 'Gene', (87, 97))	('inhibited', 'NegReg', (23, 32))	('Notch1', 'Gene', '4851', (119, 125))	('FAM83H-AS1', 'Gene', '100128338', (38, 48))	('FAM83H-AS1', 'Gene', (38, 48))	('FAM83H-AS1', 'Gene', '100128338', (87, 97))	('Cell proliferation', 'CPA', (0, 18))
26981	32839509	In this regard, it has been shown that FAM83H-AS1 epigenetically silenced CDKN1A by binding to EZH2 in glioma cells.	('silenced', 'NegReg', (65, 73))	('epigenetically', 'Var', (50, 64))	('EZH2', 'Gene', (95, 99))	('CDKN1A', 'Gene', (74, 80))	('FAM83H-AS1', 'Gene', (39, 49))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('CDKN1A', 'Gene', '1026', (74, 80))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('FAM83H-AS1', 'Gene', '100128338', (39, 49))	('binding', 'Interaction', (84, 91))	('glioma', 'Disease', (103, 109))	('EZH2', 'Gene', '2146', (95, 99))
26989	32839509	FAM83H-AS1 deregulation is associated with migration and cell death impairment in BRCA samples and breast cancer cells, and may regulate a plethora of cancer-related gene targets, such as p63, BAX, LEP and CLDN1.	('CLDN1', 'Gene', '9076', (206, 211))	('LEP', 'Gene', '3952', (198, 201))	('cancer', 'Disease', (106, 112))	('BRCA', 'Phenotype', 'HP:0003002', (82, 86))	('LEP', 'Gene', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('plethora', 'Phenotype', 'HP:0001050', (139, 147))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cancer', 'Disease', (151, 157))	('death impairment', 'Disease', 'MESH:D003643', (62, 78))	('BRCA', 'Gene', '672', (82, 86))	('p63', 'Gene', (188, 191))	('cell death', 'biological_process', 'GO:0008219', ('57', '67'))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('p63', 'Gene', '8626', (188, 191))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('CLDN1', 'Gene', (206, 211))	('regulate', 'Reg', (128, 136))	('migration', 'CPA', (43, 52))	('FAM83H-AS1', 'Gene', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('BRCA', 'Gene', (82, 86))	('breast cancer', 'Disease', (99, 112))	('deregulation', 'Var', (11, 23))	('associated', 'Reg', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('death impairment', 'Disease', (62, 78))	('BAX', 'Gene', (193, 196))	('BAX', 'Gene', '581', (193, 196))
27025	32839509	GAPDH (Hs99999905) and SCARNA5 (Hs03391742_cn) transcripts were used as endogenous controls.	('SCARNA5', 'Gene', '677775', (23, 30))	('SCARNA5', 'Gene', (23, 30))	('GAPDH', 'Gene', '2597', (0, 5))	('Hs03391742_cn', 'Var', (32, 45))	('Hs99999905', 'Var', (7, 17))	('GAPDH', 'Gene', (0, 5))
27056	32688345	In this study, we systematically analyzed the differential expression and genetic alterations in ferroptosis-related genes (FRGs) in 32 cancer types.	('ferroptosis', 'biological_process', 'GO:0097707', ('97', '108'))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FRGs', 'Gene', (124, 128))	('cancer', 'Disease', (136, 142))	('genetic alterations', 'Var', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
27062	32688345	Ferroptosis is also triggered by perturbations in lipid metabolism.	('lipid metabolism', 'biological_process', 'GO:0006629', ('50', '66'))	('perturbations', 'Var', (33, 46))	('triggered by', 'Reg', (20, 32))	('lipid metabolism', 'MPA', (50, 66))	('Ferroptosis', 'Disease', (0, 11))	('Ferroptosis', 'biological_process', 'GO:0097707', ('0', '11'))	('lipid', 'Chemical', 'MESH:D008055', (50, 55))
27063	32688345	We then used the GSCA database to determine the single nucleotide variations (SNV) and copy number variations (CNV) in the 36 FRGs in the 32 cancer types.	('copy number variations', 'Var', (87, 109))	('FRGs', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('single nucleotide variations', 'Var', (48, 76))	('cancer', 'Disease', (141, 147))
27065	32688345	The average mutation rate of TP53 was the highest among all FRGs at 82%; majority of the genetic aberrations were missense mutations and were more common in lung adenocarcinoma (LUAD) and squamous cell carcinoma(LUSC) (Supplementary Figure 1A, 1B).	('common', 'Reg', (147, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('TP53', 'Gene', '7157', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('TP53', 'Gene', (29, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('lung adenocarcinoma', 'Disease', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('squamous cell carcinoma', 'Disease', (188, 211))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('missense mutations', 'Var', (114, 132))
27066	32688345	We also analyzed the CNVs in the FRGs among the 32 cancer types and found heterozygous mutations in TP53 and ALOX15B and heterozygous amplifications in RPL8 and PTGS2 (Supplementary Figure 1C).	('RPL8', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (100, 104))	('PTGS2', 'Gene', '5743', (161, 166))	('RPL8', 'Gene', '6132', (152, 156))	('PTGS', 'biological_process', 'GO:0016441', ('161', '165'))	('ALOX15B', 'Gene', (109, 116))	('TP53', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('ALOX15B', 'Gene', '247', (109, 116))	('cancer', 'Disease', (51, 57))	('PTGS2', 'Gene', (161, 166))	('mutations', 'Var', (87, 96))
27099	32688345	CCK8 proliferation assay shows that CARS knockdown 786-O cells showed significant reduction in proliferation compared to the control 786-O cells (Figure 7D).	('reduction', 'NegReg', (82, 91))	('CARS', 'Gene', (36, 40))	('proliferation', 'CPA', (95, 108))	('knockdown', 'Var', (41, 50))	('CARS', 'Gene', '833', (36, 40))
27129	30115691	Furthermore, ErbB3-ErbB2 signaling was adaptively upregulated following MEK inhibition.	('upregulated', 'PosReg', (50, 61))	('ErbB2', 'Gene', '2064', (19, 24))	('MEK', 'Gene', (72, 75))	('inhibition', 'Var', (76, 86))	('signaling', 'biological_process', 'GO:0023052', ('25', '34'))	('ErbB2', 'Gene', (19, 24))
27135	30115691	Approximately one-third of WT/WT melanoma harbor NF1 alterations; cKIT, cyclin D1 and CDK4 amplifications are also detected.	('CDK4', 'Gene', (86, 90))	('cyclin D1', 'Gene', (72, 81))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (27, 41))	('CDK4', 'Gene', '1019', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('alterations', 'Var', (53, 64))	('cyclin', 'molecular_function', 'GO:0016538', ('72', '78'))	('WT/WT melanoma', 'Disease', (27, 41))	('CDK', 'molecular_function', 'GO:0004693', ('86', '89'))	('NF1', 'Gene', (49, 52))	('cyclin D1', 'Gene', '595', (72, 81))	('NF1', 'Gene', '4763', (49, 52))
27137	30115691	This contrasts with the efficacy of MEK inhibitors in V600E/K BRAF-harboring melanoma, for which trametinib is FDA-approved alone and in combination with BRAF inhibitor.	('BRAF', 'Gene', '673', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('BRAF', 'Gene', (154, 158))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('V600E', 'Var', (54, 59))	('V600E', 'SUBSTITUTION', 'None', (54, 59))	('trametinib', 'Chemical', 'MESH:C560077', (97, 107))
27138	30115691	Additionally, the MEK inhibitor, binimetinib, showed improved response rates and progression-free survival compared to dacarbazine in mutant NRAS melanoma patients.	('progression-free survival', 'CPA', (81, 106))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('NRAS', 'Gene', '4893', (141, 145))	('dacarbazine', 'Chemical', 'MESH:D003606', (119, 130))	('binimetinib', 'Chemical', 'MESH:C581313', (33, 44))	('response rates', 'CPA', (62, 76))	('patients', 'Species', '9606', (155, 163))	('improved', 'PosReg', (53, 61))	('mutant', 'Var', (134, 140))	('NRAS', 'Gene', (141, 145))
27139	30115691	The standard of care for WT/WT melanoma patients is immune checkpoint inhibitor therapy with anti-CTLA-4 (ipilimumab) and/or anti-PD-1 (pembrolizumab or nivolumab).	('ipilimumab', 'Chemical', 'MESH:D000074324', (106, 116))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (25, 39))	('patients', 'Species', '9606', (40, 48))	('anti-PD-1', 'Var', (125, 134))	('CTLA-4', 'Gene', '1493', (98, 104))	('WT/WT melanoma', 'Disease', (25, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('CTLA-4', 'Gene', (98, 104))	('pembrolizumab', 'Chemical', 'MESH:C582435', (136, 149))	('nivolumab', 'Chemical', 'MESH:D000077594', (153, 162))
27142	30115691	In mutant BRAF melanoma and thyroid carcinoma, ErbB3/HER3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3/human epidermal receptor 3) up-regulation is a cellular adaptation to BRAF/MEK inhibition.	('mutant', 'Var', (3, 9))	('up-regulation', 'PosReg', (145, 158))	('BRAF melanoma', 'Disease', 'MESH:D008545', (10, 23))	('BRAF melanoma', 'Disease', (10, 23))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (28, 45))	('thyroid carcinoma', 'Disease', (28, 45))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('regulation', 'biological_process', 'GO:0065007', ('148', '158'))	('b2 erythroblastic leukemia', 'Phenotype', 'HP:0004812', (65, 91))	('HER3', 'Gene', '2065', (53, 57))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (28, 45))	('BRAF', 'Gene', '673', (187, 191))	('BRAF', 'Gene', (187, 191))	('human', 'Species', '9606', (117, 122))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('erythroblastic leukemia viral', 'Disease', (68, 97))	('erythroblastic leukemia viral', 'Disease', 'MESH:D004915', (68, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('HER3', 'Gene', (53, 57))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))
27147	30115691	While up-regulated expression of ErbB3 and other RTKs are linked to resistance to BRAF and MEK inhibitors in BRAF mutant melanoma, the mechanisms underlying resistance in WT/WT melanoma remain unclear.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('expression', 'MPA', (19, 29))	('WT/WT melanoma', 'Disease', (171, 185))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('BRAF', 'Gene', '673', (82, 86))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('BRAF', 'Gene', (82, 86))	('mutant', 'Var', (114, 120))	('melanoma', 'Disease', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (171, 185))	('up-regulated', 'PosReg', (6, 18))	('ErbB3', 'Gene', (33, 38))
27152	30115691	These findings provide pre-clinical data to support the use of anti-ErbB2 and/or anti-ErbB3 antibodies to maximize the effects of MEK inhibitors in WT/WT cutaneous melanoma patients.	('effects', 'MPA', (119, 126))	('WT cutaneous melanoma', 'Disease', 'MESH:C562393', (151, 172))	('patients', 'Species', '9606', (173, 181))	('ErbB2', 'Gene', (68, 73))	('WT cutaneous melanoma', 'Disease', (151, 172))	('ErbB2', 'Gene', '2064', (68, 73))	('pre', 'molecular_function', 'GO:0003904', ('23', '26'))	('anti-ErbB3', 'Var', (81, 91))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))
27153	30115691	Human melanoma biopsies (TJUMEL40 and TJUMEL45) were obtained from Thomas Jefferson University Hospital under IRB-approved protocol (#10D.341) that include written informed consent and was in accordance with recognized ethical guidelines.	('Human', 'Species', '9606', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('TJUMEL45', 'Var', (38, 46))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
27172	30115691	Following two washes with FACS buffer (PBS with 1% FBS and 0.5% sodium azide), cells were stained with either ErbB3-PE or ErbB2-PE (Biolegend) for 30 min at room temperature.	('ErbB2', 'Gene', (122, 127))	('ErbB3-PE', 'Var', (110, 118))	('PBS', 'Disease', 'MESH:D011535', (39, 42))	('PBS', 'Disease', (39, 42))	('ErbB2', 'Gene', '2064', (122, 127))	('sodium azide', 'Chemical', 'MESH:D019810', (64, 76))
27202	30115691	Samples with both pErbB2 and pErbB3 z-scores >1 and >-1 were classified as high and mid, respectively.	('pErbB3', 'Gene', (29, 35))	('ErbB2', 'Gene', '2064', (19, 24))	('z-scores >1', 'Var', (36, 47))	('>-1', 'Var', (52, 55))	('ErbB2', 'Gene', (19, 24))
27212	30115691	A comparable co-expression was observed in BRAF mutant melanoma samples and similar results were also observed in NRAS mutant melanoma samples (Supplemental Fig.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('mutant', 'Var', (48, 54))	('BRAF', 'Gene', '673', (43, 47))	('NRAS', 'Gene', (114, 118))	('BRAF', 'Gene', (43, 47))	('NRAS', 'Gene', '4893', (114, 118))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('mutant', 'Var', (119, 125))	('melanoma', 'Disease', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
27213	30115691	Similar findings were evident when the z-score was calculated based on the Pan-Cancer 19 RPPA data collected from The Cancer Proteome Atlas (TCPA) with nearly 60% of patients co-expressing phospho-ErbB3 and phospho-ErbB2 (Supplemental Fig.	('ErbB2', 'Gene', (215, 220))	('TCPA', 'Chemical', '-', (141, 145))	('Cancer Proteome Atlas', 'Disease', (118, 139))	('ErbB2', 'Gene', '2064', (215, 220))	('Cancer Proteome Atlas', 'Disease', 'MESH:D009369', (118, 139))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('phospho-ErbB3', 'Var', (189, 202))	('patients', 'Species', '9606', (166, 174))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
27216	30115691	74% of Stage III and Stage IV WT/WT melanoma patient samples expressed phosphorylated ErbB2.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('WT/WT melanoma', 'Disease', (30, 44))	('ErbB2', 'Gene', (86, 91))	('patient', 'Species', '9606', (45, 52))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (30, 44))	('ErbB2', 'Gene', '2064', (86, 91))	('phosphorylated', 'Var', (71, 85))
27228	30115691	We also tested the effect of four additional growth factors (EGF, HGF, IGF, and PDGFbb), which have been implicated in resistance to targeted therapies in mutant BRAF melanoma.	('tested', 'Reg', (8, 14))	('EGF', 'molecular_function', 'GO:0005154', ('61', '64'))	('EGF', 'Gene', (61, 64))	('mutant', 'Var', (155, 161))	('HGF', 'Gene', (66, 69))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('HGF', 'Gene', '3082', (66, 69))	('EGF', 'Gene', '1950', (61, 64))	('BRAF melanoma', 'Disease', 'MESH:D008545', (162, 175))	('BRAF melanoma', 'Disease', (162, 175))
27242	30115691	In contrast to some findings on ERK1/2 pathway re-activation in mutant BRAF melanoma, NRG1 elicited minimal effects on ERK1/2 phosphorylation in MEK-inhibited WT/WT melanoma cells (Fig.	('BRAF melanoma', 'Disease', 'MESH:D008545', (71, 84))	('ERK1', 'molecular_function', 'GO:0004707', ('119', '123'))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (159, 173))	('NRG1', 'Gene', '3084', (86, 90))	('BRAF melanoma', 'Disease', (71, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('ERK1/2 phosphorylation', 'MPA', (119, 141))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('mutant', 'Var', (64, 70))	('WT/WT melanoma', 'Disease', (159, 173))	('NRG1', 'Gene', (86, 90))	('ERK1', 'molecular_function', 'GO:0004707', ('32', '36'))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
27245	30115691	NRG1-stimulated AKT phosphorylation was lower and transient in WM3928 compared to the other cell lines, consistent with the lower activation of ErbB2 (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('AKT', 'Gene', '207', (16, 19))	('ErbB2', 'Gene', (144, 149))	('activation', 'PosReg', (130, 140))	('NRG1', 'Gene', (0, 4))	('WM3928', 'Var', (63, 69))	('lower', 'NegReg', (124, 129))	('AKT', 'Gene', (16, 19))	('ErbB2', 'Gene', '2064', (144, 149))	('NRG1', 'Gene', '3084', (0, 4))	('lower', 'NegReg', (40, 45))
27250	30115691	Since NRAS mutant melanoma patients showed similar co-expressed medium-high levels of both phosphorylated ErbB3 and ErbB2 compared to WT/WT (Supplemental Fig.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('mutant', 'Var', (11, 17))	('ErbB2', 'Gene', (116, 121))	('ErbB2', 'Gene', '2064', (116, 121))	('patients', 'Species', '9606', (27, 35))	('NRAS', 'Gene', (6, 10))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('NRAS', 'Gene', '4893', (6, 10))
27251	30115691	S1B), we next analyzed the effect of NRG1 in MEK-inhibited NRAS mutant cell lines.	('NRG1', 'Gene', (37, 41))	('NRG1', 'Gene', '3084', (37, 41))	('NRAS', 'Gene', (59, 63))	('mutant', 'Var', (64, 70))	('NRAS', 'Gene', '4893', (59, 63))
27252	30115691	Out of 4 cell lines just one expressed ErbB3 and ErbB2 and showed adaptive activation of ErbB3/ErbB2 pathways in the presence of trametinib and NRG, confirming that NRG1 effects rely on the expression of ErbB3 and its co-receptor, ErbB2 (Supplemental Fig.	('ErbB2', 'Gene', '2064', (49, 54))	('ErbB2', 'Gene', '2064', (231, 236))	('trametinib', 'Chemical', 'MESH:C560077', (129, 139))	('ErbB2', 'Gene', (95, 100))	('activation', 'PosReg', (75, 85))	('NRG1', 'Gene', (165, 169))	('NRG1', 'Gene', '3084', (165, 169))	('ErbB2', 'Gene', '2064', (95, 100))	('ErbB2', 'Gene', (49, 54))	('ErbB2', 'Gene', (231, 236))	('ErbB3', 'Var', (39, 44))
27261	30115691	ErbB3 cell surface expression levels were also reduced following NRG1 stimulation (Fig.	('NRG1', 'Gene', (65, 69))	('cell surface', 'cellular_component', 'GO:0009986', ('6', '18'))	('ErbB3 cell surface expression levels', 'MPA', (0, 36))	('reduced', 'NegReg', (47, 54))	('stimulation', 'Var', (70, 81))	('NRG1', 'Gene', '3084', (65, 69))
27266	30115691	LJM716 and pertuzumab individually reduced NRG1-induced phosphorylation of ErbB3, ErbB2 and AKT (Fig.	('ErbB2', 'Gene', (82, 87))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('NRG1', 'Gene', (43, 47))	('reduced', 'NegReg', (35, 42))	('ErbB3', 'Protein', (75, 80))	('AKT', 'Gene', '207', (92, 95))	('ErbB2', 'Gene', '2064', (82, 87))	('LJM716', 'Chemical', '-', (0, 6))	('NRG1', 'Gene', '3084', (43, 47))	('phosphorylation', 'MPA', (56, 71))	('pertuzumab', 'Chemical', 'MESH:C485206', (11, 21))	('AKT', 'Gene', (92, 95))	('LJM716', 'Var', (0, 6))
27274	30115691	6C) and LJM716 did not affect their proliferation in the presence of NRG1 (Supplemental Fig.	('LJM716', 'Var', (8, 14))	('NRG1', 'Gene', '3084', (69, 73))	('NRG1', 'Gene', (69, 73))	('LJM716', 'Chemical', '-', (8, 14))
27280	30115691	Conditioned media derived from CAF40 and CAF45 stimulated phosphorylation of ErbB3, ErbB2 and AKT in MEK-inhibited WT/WT melanoma cells (Fig.	('AKT', 'Gene', '207', (94, 97))	('CAF45', 'Chemical', '-', (41, 46))	('ErbB3', 'Gene', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('ErbB2', 'Gene', '2064', (84, 89))	('phosphorylation', 'MPA', (58, 73))	('CAF40', 'Gene', (31, 36))	('CAF45', 'Var', (41, 46))	('WT/WT melanoma', 'Disease', 'MESH:C536751', (115, 129))	('AKT', 'Gene', (94, 97))	('stimulated', 'PosReg', (47, 57))	('WT/WT melanoma', 'Disease', (115, 129))	('CAF40', 'Gene', '9125', (31, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('ErbB2', 'Gene', (84, 89))
27281	30115691	ErbB3, ErbB2 and AKT phosphorylation induced by fibroblast and CAF conditioned media was reversed by LJM716 or pertuzumab treatment (Fig.	('pertuzumab', 'Chemical', 'MESH:C485206', (111, 121))	('AKT', 'Gene', (17, 20))	('LJM716', 'Chemical', '-', (101, 107))	('ErbB3', 'Gene', (0, 5))	('LJM716', 'Var', (101, 107))	('ErbB2', 'Gene', (7, 12))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('AKT', 'Gene', '207', (17, 20))	('CAF', 'Gene', (63, 66))	('CAF', 'Gene', '8850', (63, 66))	('ErbB2', 'Gene', '2064', (7, 12))
27289	30115691	MEK inhibitor reduced tumor growth in both models, which was significantly further delayed when LJM716 was combined with MEK inhibitor treatment (Fig.	('reduced', 'NegReg', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('LJM716', 'Chemical', '-', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('delayed', 'NegReg', (83, 90))	('tumor', 'Disease', (22, 27))	('LJM716', 'Var', (96, 102))
27293	30115691	Major advances have been made for the treatment of V600-mutant BRAF melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('BRAF melanoma', 'Disease', (63, 76))	('V600-mutant', 'Var', (51, 62))	('BRAF melanoma', 'Disease', 'MESH:D008545', (63, 76))
27294	30115691	By contrast, targeted inhibitor trials in non-mutant BRAF melanoma have elicited poor response rates.	('BRAF melanoma', 'Disease', (53, 66))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('BRAF melanoma', 'Disease', 'MESH:D008545', (53, 66))	('non-mutant', 'Var', (42, 52))
27295	30115691	In a study from Falchook and colleagues, a 20% response rate to the MEK inhibitor, trametinib, was observed in WT/WT (although 2 of these samples harbored atypical BRAF mutations).	('BRAF', 'Gene', '673', (164, 168))	('trametinib', 'Chemical', 'MESH:C560077', (83, 93))	('mutations', 'Var', (169, 178))	('BRAF', 'Gene', (164, 168))
27297	30115691	Our findings may extend to mutant NRAS melanoma.	('mutant', 'Var', (27, 33))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('NRAS', 'Gene', (34, 38))	('extend', 'Reg', (17, 23))	('NRAS', 'Gene', '4893', (34, 38))
27298	30115691	While bioinformatic analysis showed strong basal pErbB3 and pErbB2 levels in mutant NRAS melanoma, cell-based studies showed various levels of ErbB3 adaptive responses.	('ErbB2', 'Gene', (61, 66))	('NRAS', 'Gene', (84, 88))	('pErbB3', 'MPA', (49, 55))	('NRAS', 'Gene', '4893', (84, 88))	('ErbB2', 'Gene', '2064', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('mutant', 'Var', (77, 83))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('strong', 'PosReg', (36, 42))
27299	30115691	These data reflect the high level of heterogeneity present in NRAS mutant melanoma and need further investigation to clarify the role of NRG1 in driving resistance to MEK inhibitor in this subgroup.	('NRAS', 'Gene', '4893', (62, 66))	('NRG1', 'Gene', (137, 141))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('mutant', 'Var', (67, 73))	('NRG1', 'Gene', '3084', (137, 141))	('NRAS', 'Gene', (62, 66))
27300	30115691	In the mutant BRAF setting, multiple growth factors and their cognate receptors have been shown the mediate resistance to BRAF inhibitors.	('resistance', 'MPA', (108, 118))	('mutant', 'Var', (7, 13))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))
27303	30115691	By contrast, other growth factors linked to resistance to BRAF inhibitors in mutant BRAF melanoma, elicit little to no reversal of growth inhibition.	('BRAF', 'Gene', '673', (84, 88))	('BRAF melanoma', 'Disease', (84, 97))	('BRAF', 'Gene', (84, 88))	('BRAF', 'Gene', '673', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mutant', 'Var', (77, 83))	('BRAF', 'Gene', (58, 62))	('BRAF melanoma', 'Disease', 'MESH:D008545', (84, 97))
27305	30115691	Indeed, LJM716 and pertuzumab partially, but not completely, reversed the effects of CAF conditioned medium on cell growth in MEK-inhibited cells.	('cell growth', 'biological_process', 'GO:0016049', ('111', '122'))	('LJM716', 'Var', (8, 14))	('CAF', 'Gene', (85, 88))	('pertuzumab', 'Chemical', 'MESH:C485206', (19, 29))	('CAF', 'Gene', '8850', (85, 88))	('LJM716', 'Chemical', '-', (8, 14))	('cell growth', 'MPA', (111, 122))
27307	30115691	Clinical grade anti-ErbB3 targeting agents are being developed and tested in clinical trials for many solid malignancies (NCT02387216, NCT02167854, NCT01602406, NCT02980341).	('NCT02167854', 'Var', (135, 146))	('NCT01602406', 'Var', (148, 159))	('NCT02387216', 'Var', (122, 133))	('solid malignancies', 'Disease', 'MESH:D009369', (102, 120))	('NCT02980341', 'Var', (161, 172))	('solid malignancies', 'Disease', (102, 120))
27312	30115691	Recent studies in breast cancer cells demonstrate ErbB2 is inactivated by ERK1/2-dependent phosphorylation of threonine 677 in the juxtamembrane region.	('ErbB2', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('inactivated', 'NegReg', (59, 70))	('phosphorylation', 'Var', (91, 106))	('threonine', 'Chemical', 'MESH:D013912', (110, 119))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('131', '144'))	('breast cancer', 'Disease', (18, 31))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('131', '144'))	('ErbB2', 'Gene', '2064', (50, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('ERK1', 'molecular_function', 'GO:0004707', ('74', '78'))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('131', '144'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('131', '144'))
27313	30115691	By contrast, in MEK-inhibited cells, dephosphorylation of threonine 677 enables ErbB2 to be a more effective co-receptor for ErbB3.	('threonine', 'Chemical', 'MESH:D013912', (58, 67))	('ErbB2', 'Gene', '2064', (80, 85))	('threonine 677', 'Var', (58, 71))	('dephosphorylation', 'biological_process', 'GO:0016311', ('37', '54'))	('ErbB2', 'Gene', (80, 85))	('dephosphorylation of', 'MPA', (37, 57))
27324	30115691	The transcription factor SOX10 has been described as a direct regulator of ErbB3 in neural crest-derived cells; however, SOX10 in mutant BRAF melanoma cells is associated with repression of EGFR and PDGFR.	('BRAF melanoma', 'Disease', 'MESH:D008545', (137, 150))	('associated', 'Reg', (160, 170))	('repression', 'MPA', (176, 186))	('BRAF melanoma', 'Disease', (137, 150))	('EGFR', 'Gene', '1956', (190, 194))	('EGFR', 'molecular_function', 'GO:0005006', ('190', '194'))	('transcription', 'biological_process', 'GO:0006351', ('4', '17'))	('transcription factor', 'molecular_function', 'GO:0000981', ('4', '24'))	('EGFR', 'Gene', (190, 194))	('SOX10', 'Gene', '6663', (25, 30))	('PDGFR', 'Gene', (199, 204))	('PDGFR', 'Gene', '5159', (199, 204))	('mutant', 'Var', (130, 136))	('SOX10', 'Gene', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('SOX10', 'Gene', (121, 126))	('SOX10', 'Gene', '6663', (121, 126))
27333	30236595	In summary, PD-L1/PD-L2/JAK2 amplification was associated with durable response to therapy for both cases and this genomic signature is a potential valuable metric in predicting response to immunotherapy.	('PD-L1', 'Gene', (12, 17))	('associated with', 'Reg', (47, 62))	('amplification', 'Var', (29, 42))	('JAK2', 'Gene', '3717', (24, 28))	('PD-L1', 'Gene', '29126', (12, 17))	('JAK', 'molecular_function', 'GO:0004713', ('24', '27'))	('JAK2', 'Gene', (24, 28))	('PD-L2', 'Gene', (18, 23))	('PD-L2', 'Gene', '80380', (18, 23))
27343	30236595	A more recent study involving various 9p24.1 amplified solid tumors with a low to intermediate TMB (based on sequencing of 1.2Mb of the genome; low TMB defined as <=5 mutations/megabase, intermediate TMB defined as 6-19 mutations/megabase, high TMB defined as >=20 mutations/megabase) documented objective responses to the administration of immune checkpoint blockade agents for 6 of 9 (66.7%) cases, emphasizing the importance of this genomic signature.	('mutations/megabase', 'Var', (167, 185))	('solid tumors', 'Disease', (55, 67))	('TMB', 'Chemical', '-', (148, 151))	('TMB', 'Chemical', '-', (200, 203))	('TMB', 'Chemical', '-', (245, 248))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('solid tumors', 'Disease', 'MESH:D009369', (55, 67))	('TMB', 'Chemical', '-', (95, 98))	('mutations/megabase', 'Var', (220, 238))
27344	30236595	Herein, we report two patients with metastatic melanoma that had a 9p24.1 amplification that showed a durable response to immunotherapy.	('amplification', 'Var', (74, 87))	('patients', 'Species', '9606', (22, 30))	('9p24.1', 'Gene', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
27353	30236595	Molecular profiling by MSK-IMPACT revealed a high TMB of 52.7 mt/MB (average TMB for melanomas in the MSK-IMPACT clinical sequencing cohort: 7.9 mt/MB), an abundance of G>A and C>T transitions, consistent with UV exposure, and no clear driver alteration (Table 1).	('G>A', 'Var', (169, 172))	('melanomas', 'Disease', (85, 94))	('mt/MB', 'Var', (62, 67))	('TMB', 'MPA', (50, 53))	('C>T', 'Var', (177, 180))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('TMB', 'Chemical', '-', (77, 80))	('TMB', 'Chemical', '-', (50, 53))
27358	30236595	MSK-IMPACT testing revealed a low TMB of 3.9 mt/MB (Table 1), KIT/PDGFRA amplification at 4q12 likely serving as a driver alteration, and 3.6-fold amplification at 9p24.1 (Table 1, Figure 2C).	('PDGFRA', 'Gene', '5156', (66, 72))	('TMB', 'Chemical', '-', (34, 37))	('PDGFRA', 'Gene', (66, 72))	('amplification at', 'Var', (73, 89))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('KIT', 'Gene', '3815', (62, 65))	('TMB', 'MPA', (34, 37))	('KIT', 'Gene', (62, 65))
27368	30236595	While cutaneous melanomas often have a high TMB secondary to UV exposure, characterized by an abundance of G>A and C>T transitions; non-cutaneous melanomas, such as mucosal melanomas, lack a similar mutational signature and tend to exhibit a lower TMB.	('melanomas', 'Disease', 'MESH:D008545', (146, 155))	('melanomas', 'Disease', (173, 182))	('mucosal melanomas', 'Disease', (165, 182))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('melanomas', 'Disease', (146, 155))	('C>T', 'Var', (115, 118))	('TMB', 'Chemical', '-', (44, 47))	('lower', 'NegReg', (242, 247))	('TMB', 'MPA', (248, 251))	('cutaneous melanoma', 'Disease', (6, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (6, 24))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 24))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (6, 25))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('TMB', 'Chemical', '-', (248, 251))	('melanomas', 'Disease', 'MESH:D008545', (16, 25))	('melanomas', 'Disease', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Disease', 'MESH:D008545', (173, 182))	('mucosal melanomas', 'Disease', 'MESH:D008545', (165, 182))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (136, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))
27372	30236595	Although the literature is limited in regards to treatment outcomes for solid tumors with 9p24.1 amplifications, a few case series and reports suggest that such a signature is likely to predict favorable response to immunotherapy.	('solid tumors', 'Disease', 'MESH:D009369', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('solid tumors', 'Disease', (72, 84))	('amplifications', 'Var', (97, 111))
27374	30236595	A high TMB, as defined by >=20 mutations/Mb by Goodman et al, was associated with favorable response to immunotherapy for the metastatic cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('TMB', 'Chemical', '-', (7, 10))	('metastatic cutaneous melanoma', 'Disease', 'MESH:C562393', (126, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('metastatic cutaneous melanoma', 'Disease', (126, 155))	('mutations/Mb', 'Var', (31, 43))
27385	31842801	Among these genes, ZAP70, CD3E, CD3G, CD3D, and CD247 were part of the TCR 'signal-triggering module'; (3) High expression of the PIGs involved in the TCR signaling pathway was associated with improved OS in 5 cancer types (breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and sarcoma (SARC)), but was associated with decreased OS in brain lower-grade glioma (LGG).	('BRCA', 'Gene', '672', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (331, 368))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCR', 'Gene', '6962', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('lung adenocarcinoma', 'Disease', (377, 396))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (331, 368))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (224, 249))	('BRCA', 'Gene', (251, 255))	('TCR', 'Gene', (71, 74))	('TCR', 'cellular_component', 'GO:0042101', ('151', '154'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (258, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('sarcoma', 'Disease', 'MESH:D012509', (409, 416))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('glioma', 'Disease', (484, 490))	('TCR', 'Gene', (151, 154))	('sarcoma', 'Disease', (409, 416))	('decreased', 'NegReg', (450, 459))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (377, 396))	('glioma', 'Disease', 'MESH:D005910', (484, 490))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (377, 396))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('151', '172'))	('PIGs', 'Species', '9823', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('glioma', 'Phenotype', 'HP:0009733', (484, 490))	('breast invasive carcinoma', 'Disease', (224, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (409, 416))	('TCR', 'cellular_component', 'GO:0042101', ('71', '74'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('improved', 'PosReg', (193, 201))	('High expression', 'Var', (107, 122))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (224, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('TCR', 'biological_process', 'GO:0006283', ('71', '74'))	('cancer', 'Disease', (210, 216))	('TCR', 'Gene', '6962', (71, 74))	('neck', 'cellular_component', 'GO:0044326', ('340', '344'))
27397	31842801	In addition, pembrolizumab was associated with a significantly longer OS for platinum-refractory advanced urothelial carcinoma than standard therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('urothelial carcinoma', 'Disease', (106, 126))	('pembrolizumab', 'Var', (13, 26))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (106, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))
27444	31842801	Eleven genes (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were identified as participating in the TCR signaling pathway (Fig.	('participating', 'Reg', (107, 120))	('TCR', 'cellular_component', 'GO:0042101', ('128', '131'))	('CD40LG', 'Gene', (69, 75))	('ZAP70', 'Var', (14, 19))	('TCR', 'Gene', (128, 131))	('GRAP2', 'Gene', (81, 86))	('CD3G', 'Gene', (45, 49))	('PTPRC', 'Gene', '100522631', (21, 26))	('ICOS', 'Gene', (33, 37))	('ITK', 'Gene', (57, 60))	('CD3E', 'Gene', (39, 43))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('128', '149'))	('CD247', 'Var', (62, 67))	('PTPRC', 'Gene', (21, 26))	('GRAP2', 'Gene', '100516438', (81, 86))	('ICOS', 'Gene', '733597', (33, 37))	('CD40LG', 'Gene', '397231', (69, 75))	('TCR', 'Gene', '6962', (128, 131))	('CD3D', 'Gene', (51, 55))	('ITK', 'Gene', '100523474', (57, 60))
27446	31842801	ZAP70, CD3E, CD3G, CD3D, and CD247 were classified into a 'TCR signal triggering module' by Acuto et al., which was crucial to the successful initiation of T cell activation.	('CD3E', 'Var', (7, 11))	('CD3G', 'Var', (13, 17))	('CD3D', 'Var', (19, 23))	('T cell activation', 'biological_process', 'GO:0042110', ('156', '173'))	('TCR', 'cellular_component', 'GO:0042101', ('59', '62'))	('ZAP70', 'Var', (0, 5))	('TCR', 'Gene', '6962', (59, 62))	('CD247', 'Var', (29, 34))	('TCR', 'biological_process', 'GO:0006283', ('59', '62'))	('TCR', 'Gene', (59, 62))
27449	31842801	Second, 6 (LCK, ZAP70, CD3E, CD3G, CD3D, and CD247) out of 11 PIGs played crucial roles in activating T cell activation.	('CD247', 'Var', (45, 50))	('activating T cell activation', 'MPA', (91, 119))	('T cell activation', 'biological_process', 'GO:0042110', ('102', '119'))	('PIGs', 'Species', '9823', (62, 66))
27460	31842801	High-level expression of the PIGs participating in the TCR signaling pathway was associated with improved OS in 5 cancer types (BRCA, CESC, HNSC, LUAD, and SARC), but with decreased OS in LGG.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('HNSC', 'Disease', (140, 144))	('TCR', 'cellular_component', 'GO:0042101', ('55', '58'))	('cancer', 'Disease', (114, 120))	('improved', 'PosReg', (97, 105))	('BRCA', 'Gene', (128, 132))	('LUAD', 'Disease', (146, 150))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TCR', 'Gene', '6962', (55, 58))	('CESC', 'Disease', (134, 138))	('PIGs', 'Species', '9823', (29, 33))	('High-level expression', 'Var', (0, 21))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('55', '76'))	('TCR', 'Gene', (55, 58))
27479	31842801	Eleven PIGs (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were mainly shared by the 6 cancer types (BRCA, CESC, HNSC, LUAD, SARC, and LGG) involved in the TCR signaling pathway.	('CD40LG', 'Gene', '397231', (68, 74))	('CD3D', 'Var', (50, 54))	('ITK', 'Gene', '100523474', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PIGs', 'Species', '9823', (7, 11))	('ZAP70', 'Var', (13, 18))	('CD40LG', 'Gene', (68, 74))	('TCR', 'Gene', (184, 187))	('TCR', 'cellular_component', 'GO:0042101', ('184', '187'))	('PTPRC', 'Gene', '100522631', (20, 25))	('BRCA', 'Gene', '672', (129, 133))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('184', '205'))	('GRAP2', 'Gene', (80, 85))	('ICOS', 'Gene', (32, 36))	('BRCA', 'Gene', (129, 133))	('CD3G', 'Var', (44, 48))	('PTPRC', 'Gene', (20, 25))	('cancer', 'Disease', (115, 121))	('ITK', 'Gene', (56, 59))	('ICOS', 'Gene', '733597', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CD247', 'Var', (61, 66))	('GRAP2', 'Gene', '100516438', (80, 85))	('TCR', 'Gene', '6962', (184, 187))
27480	31842801	Six genes (ZAP70, LCK, CD3E, CD3G, CD3D, and CD247) played a key role in triggering the TCR signaling pathway.	('CD3D', 'Gene', (35, 39))	('CD3G', 'Gene', (29, 33))	('LCK', 'Gene', (18, 21))	('CD247', 'Gene', (45, 50))	('TCR', 'Gene', (88, 91))	('ZAP70', 'Var', (11, 16))	('TCR signaling pathway', 'biological_process', 'GO:0050852', ('88', '109'))	('triggering', 'Reg', (73, 83))	('TCR', 'cellular_component', 'GO:0042101', ('88', '91'))	('TCR', 'Gene', '6962', (88, 91))	('CD3E', 'Gene', (23, 27))
27486	31842801	In this study, there was no significant difference between the OS in patients with high expression of CTLA4 and PD1 and that of patients with low expression of CTLA4 and PD1 in most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CTLA4', 'Gene', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('high expression', 'Var', (83, 98))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (128, 136))	('PD1', 'Gene', (112, 115))
27488	31842801	High expression of 11 PIGs was associated with good prognosis in BRCA, CESC, HNSC, LUAD, and SARC but poor prognosis in LGG.	('High expression', 'Var', (0, 15))	('LUAD', 'Disease', (83, 87))	('BRCA', 'Gene', (65, 69))	('SARC but', 'Disease', (93, 101))	('CESC', 'Disease', (71, 75))	('BRCA', 'Gene', '672', (65, 69))	('PIGs', 'Species', '9823', (22, 26))	('HNSC', 'Disease', (77, 81))
27493	31842801	Among them, CD45 can modulate LCK activation or inactivation by the dephosphorylation of Tyr505 of LCK or the dephosphorylation of Tyr394 of LCK.	('CD45', 'Var', (12, 16))	('Tyr505', 'Var', (89, 95))	('LCK', 'Protein', (141, 144))	('inactivation', 'NegReg', (48, 60))	('Tyr394', 'Chemical', '-', (131, 137))	('dephosphorylation', 'MPA', (110, 127))	('dephosphorylation', 'biological_process', 'GO:0016311', ('68', '85'))	('Tyr505', 'Chemical', '-', (89, 95))	('activation', 'PosReg', (34, 44))	('LCK', 'Protein', (99, 102))	('LCK', 'Protein', (30, 33))	('modulate', 'Reg', (21, 29))	('dephosphorylation', 'biological_process', 'GO:0016311', ('110', '127'))	('dephosphorylation', 'MPA', (68, 85))
27512	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('118', '141'))	('EGFR', 'molecular_function', 'GO:0005006', ('243', '247'))	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
27513	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('EGFR', 'molecular_function', 'GO:0005006', ('88', '92'))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('DNA methylation', 'biological_process', 'GO:0006306', ('135', '150'))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
27515	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('199', '203'))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('DNA methylation', 'biological_process', 'GO:0006306', ('180', '195'))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
27517	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))
27519	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
27520	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
27521	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('EGFR', 'molecular_function', 'GO:0005006', ('60', '64'))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
27522	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('associated', 'Reg', (113, 123))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('short', 'NegReg', (129, 134))
27524	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('EGFR', 'molecular_function', 'GO:0005006', ('43', '47'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('associated', 'Reg', (27, 37))	('expression', 'MPA', (48, 58))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
27526	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('EGFR', 'molecular_function', 'GO:0005006', ('246', '250'))	('affects', 'Reg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (6, 15))
27528	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('177-338aa', 'Var', (174, 183))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
27530	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('angiogenesis', 'biological_process', 'GO:0001525', ('427', '439'))	('survival', 'CPA', (319, 327))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', (397, 403))	('activation', 'PosReg', (146, 156))	('proliferation', 'CPA', (292, 305))	('EGFR', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('contribute', 'Reg', (353, 363))	('autophosphorylation', 'MPA', (161, 180))	('rat', 'Species', '10116', (299, 302))	('promote', 'PosReg', (284, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('457', '466'))	('intracellular', 'cellular_component', 'GO:0005622', ('116', '129'))	('dimerization', 'Var', (33, 45))	('metastasis', 'CPA', (441, 451))	('activates', 'PosReg', (218, 227))	('apoptosis', 'biological_process', 'GO:0006915', ('457', '466'))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('growth', 'CPA', (307, 313))	('signaling', 'biological_process', 'GO:0023052', ('251', '260'))
27532	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('regulation', 'biological_process', 'GO:0065007', ('95', '105'))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
27534	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('94', '98'))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('aggressive behavior', 'biological_process', 'GO:0002118', ('196', '215'))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
27537	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('146', '150'))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
27539	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
27542	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
27546	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))
27556	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('EGFR', 'Gene', (25, 29))	('alterations', 'Var', (30, 41))	('rat', 'Species', '10116', (34, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
27557	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('12', '16'))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
27558	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
27559	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('EGFR', 'molecular_function', 'GO:0005006', ('237', '241'))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
27561	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('8', '12'))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('160', '164'))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
27563	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
27564	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('located', 'Reg', (71, 78))	('Furin', 'Gene', (86, 91))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
27565	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
27566	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('neck', 'cellular_component', 'GO:0044326', ('53', '57'))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
27567	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
27568	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
27569	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
27570	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('G598E', 'Var', (159, 164))	('G598A', 'Var', (100, 105))	('G598V', 'Var', (82, 87))
27571	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
27573	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('L858R', 'Var', (170, 175))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
27577	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
27579	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('HNSC', 'Disease', (106, 110))	('BLCA', 'Disease', (161, 165))	('rat', 'Species', '10116', (78, 81))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('ESCA', 'Disease', (92, 96))	('STAD', 'Disease', (119, 123))
27581	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR', 'molecular_function', 'GO:0005006', ('93', '97'))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
27582	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (155, 158))	('alterations', 'Var', (55, 66))	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (141, 144))	('patient', 'Species', '9606', (80, 87))
27583	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('58', '62'))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median OS', 'MPA', (100, 109))
27584	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('patients', 'Species', '9606', (125, 133))
27585	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EGFR', 'molecular_function', 'GO:0005006', ('126', '130'))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
27586	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('short survival', 'MPA', (79, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('40', '44'))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
27588	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (282, 286))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('increased', 'PosReg', (337, 346))	('cancers', 'Disease', (128, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('100', '104'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('EGFR', 'molecular_function', 'GO:0005006', ('197', '201'))	('mutation', 'Var', (287, 295))	('EGFR', 'molecular_function', 'GO:0005006', ('282', '286'))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('EGFR', 'molecular_function', 'GO:0005006', ('255', '259'))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('EGFR expression', 'MPA', (347, 362))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('EGFR', 'molecular_function', 'GO:0005006', ('347', '351'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('65', '69'))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', (232, 238))
27608	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))	('gene expression', 'biological_process', 'GO:0010467', ('110', '125'))
27609	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
27612	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
27614	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))
27617	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('EGFR', 'Gene', (30, 34))	('alterations', 'Var', (35, 46))	('alteration', 'Var', (122, 132))	('EGFR', 'molecular_function', 'GO:0005006', ('30', '34'))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
27619	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
27620	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
27621	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
27622	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
27624	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
27625	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
27627	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('extracellular', 'cellular_component', 'GO:0005576', ('63', '76'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('transmembrane', 'cellular_component', 'GO:0016021', ('99', '112'))	('mutations', 'Var', (30, 39))	('transmembrane', 'cellular_component', 'GO:0044214', ('99', '112'))	('tumor', 'Disease', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))
27628	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('9', '13'))
27629	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('patient', 'Species', '9606', (74, 81))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', (42, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('short patient survival', 'CPA', (68, 90))
27630	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
27631	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('27', '31'))
27632	32067422	However, high EGFR expression was significantly associated with short patient survival.	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('patient', 'Species', '9606', (70, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('high', 'Var', (9, 13))
27634	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('EGFR', 'molecular_function', 'GO:0005006', ('172', '176'))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('neck', 'cellular_component', 'GO:0044326', ('41', '45'))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
27639	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('cancer', 'Disease', (152, 158))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('EGFR', 'molecular_function', 'GO:0005006', ('46', '50'))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
27640	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
27641	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('45', '49'))
27645	31357729	Some studies have shown that DNA methylation is associated with cancer development, progression, and metastasis.	('methylation', 'Var', (33, 44))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('progression', 'CPA', (84, 95))	('associated', 'Reg', (48, 58))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('metastasis', 'CPA', (101, 111))	('DNA', 'Protein', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
27662	31357729	DNA methylation is an important epigenetic modification that does not alter the DNA sequence, which is essential for the development, progression, and metastasis of cancer.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('methylation', 'Var', (4, 15))	('DNA', 'Disease', (0, 3))	('metastasis of cancer', 'Disease', (151, 171))	('metastasis of cancer', 'Disease', 'MESH:D009362', (151, 171))
27736	31357729	The degree of methylation of the RCHY1 gene is significantly correlated with the prognosis of breast cancer patients (cox p-value = 0.0098), and the prognosis of patients with a higher degree of methylation of RCHY1 is better than that of patients with lower methylation of RCHY1.	('RCHY1', 'Gene', '25898', (274, 279))	('methylation', 'MPA', (14, 25))	('RCHY1', 'Gene', '25898', (210, 215))	('methylation', 'biological_process', 'GO:0032259', ('259', '270'))	('RCHY1', 'Gene', (274, 279))	('RCHY1', 'Gene', '25898', (33, 38))	('patients', 'Species', '9606', (108, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('RCHY1', 'Gene', (210, 215))	('RCHY1', 'Gene', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('methylation', 'biological_process', 'GO:0032259', ('195', '206'))	('breast cancer', 'Disease', (94, 107))	('patients', 'Species', '9606', (162, 170))	('methylation', 'Var', (195, 206))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('cox', 'Gene', '1351', (118, 121))	('cox', 'Gene', (118, 121))	('patients', 'Species', '9606', (239, 247))	('correlated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
27739	31357729	The expression of the gene RCHY1 in higher-methylation group and lower-methylation group was shown in Figure 7c.	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('RCHY1', 'Gene', '25898', (27, 32))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('higher-methylation', 'Var', (36, 54))	('RCHY1', 'Gene', (27, 32))
27740	31357729	It can be clearly seen that the RCHY1 expression of patients in lower-methylation group is significantly higher than that in the higher-methylation group (MWW test p-value = 6.5e-03).	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('higher', 'PosReg', (105, 111))	('expression', 'MPA', (38, 48))	('RCHY1', 'Gene', (32, 37))	('lower-methylation', 'Var', (64, 81))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('RCHY1', 'Gene', '25898', (32, 37))	('patients', 'Species', '9606', (52, 60))
27745	31357729	The p-values of cox regression were 0.001, 5e-05, 7e-04, and 3e-05, respectively, and patients with a higher methylation degree of these genes had a better prognosis than those with a lower degree of methylation.	('methylation', 'Var', (109, 120))	('methylation', 'biological_process', 'GO:0032259', ('200', '211'))	('cox', 'Gene', (16, 19))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('cox', 'Gene', '1351', (16, 19))	('patients', 'Species', '9606', (86, 94))
27748	31357729	The p-value of Cox regression was 0.016, and the prognosis of patients with a lower degree of methylation was better than that of patients with higher methylation.	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('methylation', 'Var', (94, 105))	('patients', 'Species', '9606', (130, 138))	('Cox', 'Gene', '1351', (15, 18))	('patients', 'Species', '9606', (62, 70))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))	('Cox', 'Gene', (15, 18))
27754	31357729	Currently, the abnormality of DNA methylation has been shown to be associated with cancer prognosis, and the accumulation of DNA methylation data provides an opportunity to study cancer at the epigenetic level.	('abnormality of DNA methylation', 'Phenotype', 'HP:0003254', (15, 45))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('methylation', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA methylation', 'biological_process', 'GO:0006306', ('125', '140'))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('abnormality', 'Var', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('DNA', 'Gene', (30, 33))	('cancer', 'Disease', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('cancer', 'Disease', (83, 89))
27762	31357729	In addition, after analyzing the topology of the core module networks in three cancers, we identified DNA methylation prognostic biomarkers in three cancers.	('cancers', 'Disease', (79, 86))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('core', 'cellular_component', 'GO:0019013', ('49', '53'))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('methylation', 'Var', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA methylation', 'biological_process', 'GO:0006306', ('102', '117'))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('DNA', 'cellular_component', 'GO:0005574', ('102', '105'))
27888	19887476	The breakdown of tumor thickness within this 141-patient cohort was as follows: T1-27%; T2-28%; T3-30%; T4-15%.	('tumor', 'Disease', (17, 22))	('patient', 'Species', '9606', (49, 56))	('T3-30', 'Var', (96, 101))	('breakdown', 'biological_process', 'GO:0009056', ('4', '13'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
27907	19887476	By Cox regression analysis, the multi-marker index was significantly predictive of reduced DSS (P<0.001).	('Cox', 'Gene', '1351', (3, 6))	('DSS', 'Gene', (91, 94))	('reduced', 'NegReg', (83, 90))	('DSS', 'Gene', '5376', (91, 94))	('Cox', 'Gene', (3, 6))	('multi-marker', 'Var', (32, 44))
27949	19887476	Many individual biomarkers (reviewed in reference) have been suggested as molecular prognostic factors for melanoma, including Ki67 and p16, which have been shown to have independent prognostic significance in distinct cohorts.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('Ki67', 'Var', (127, 131))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('p16', 'Gene', (136, 139))	('p16', 'Gene', '1029', (136, 139))
27950	19887476	However, whether addition of Ki-67, p16, or other markers could improve the prognostic efficacy of the current multi-marker assay could be the subject of future studies.	('Ki-67', 'Chemical', '-', (29, 34))	('improve', 'PosReg', (64, 71))	('p16', 'Gene', '1029', (36, 39))	('prognostic efficacy', 'MPA', (76, 95))	('Ki-67', 'Var', (29, 34))	('p16', 'Gene', (36, 39))
27968	28851416	Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age >= 16 years, successful GEP result and >=1 follow-up visit for inclusion in this interim analysis.	('CM', 'Disease', 'MESH:D009202', (25, 27))	('NCT02355587', 'Var', (61, 72))	('NCT02355574', 'Var', (89, 100))	('CM', 'Phenotype', 'HP:0012056', (25, 27))	('patients', 'Species', '9606', (28, 36))
27972	28851416	1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each).	('OS', 'Chemical', '-', (24, 26))	('RFS', 'Gene', '65211', (9, 12))	('DMFS', 'Var', (14, 18))	('DMFS', 'Chemical', '-', (14, 18))	('RFS', 'Gene', (9, 12))
28004	28851416	A class 2 profile was observed in 23% (74 of 322) of cases, and was associated with older age, male gender, higher Breslow thickness, ulceration, advanced clinical stage, and positive SLN status (all p < 0.01).	('associated', 'Reg', (68, 78))	('positive', 'Var', (175, 183))	('ulceration', 'Disease', (134, 144))	('higher', 'PosReg', (108, 114))	('SLN', 'Gene', (184, 187))	('SLN', 'Gene', '6588', (184, 187))
28037	28851416	The advantages of molecular testing for enhanced prognosis are well documented for other diseases, including breast cancer and ocular melanoma.	('ocular melanoma', 'Disease', (127, 142))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ocular melanoma', 'Phenotype', 'HP:0007716', (127, 142))	('molecular testing', 'Var', (18, 35))	('ocular melanoma', 'Disease', 'MESH:D008545', (127, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
28050	26176707	RAC1 P29S regulates PD-L1 expression in melanoma Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear.	('RAC1', 'Gene', '5879', (180, 184))	('RAC1', 'Gene', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('RAC1', 'Gene', '5879', (139, 143))	('mutations', 'Var', (126, 135))	('RAC1', 'Gene', (0, 4))	('P29', 'Gene', '25949', (5, 8))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('P29', 'Gene', (5, 8))	('PD-L1', 'Gene', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', (202, 210))	('cutaneous melanoma', 'Disease', (75, 93))	('RAC1', 'Gene', '5879', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('PD-L1', 'Gene', '29126', (20, 25))	('RAC1', 'Gene', (180, 184))	('P29', 'Gene', '25949', (122, 125))	('P29', 'Gene', (122, 125))	('P29', 'Gene', '25949', (185, 188))	('P29', 'Gene', (185, 188))
28051	26176707	Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion.	('downregulated', 'NegReg', (215, 228))	('P29S', 'Mutation', 'rs1057519874', (239, 243))	('Syk', 'Gene', '6850', (148, 151))	('cyclin B1', 'Gene', (119, 128))	('RAC1', 'Gene', (190, 194))	('P29S', 'Mutation', 'rs1057519874', (195, 199))	('cyclin', 'molecular_function', 'GO:0016538', ('119', '125'))	('PD-L1', 'Gene', (130, 135))	('P29S expression', 'Var', (195, 210))	('Ets-1', 'Gene', '2113', (137, 142))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('Syk', 'Gene', (148, 151))	('PD-L1', 'Gene', '29126', (130, 135))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('cyclin B1', 'Gene', '891', (119, 128))	('upregulated', 'PosReg', (173, 184))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('Ets-1', 'Gene', (137, 142))
28052	26176707	Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants.	('RAC1', 'Gene', (103, 107))	('patient', 'Species', '9606', (113, 120))	('PD-L1', 'Gene', (53, 58))	('patient', 'Species', '9606', (19, 26))	('increased', 'PosReg', (90, 99))	('P29S', 'Var', (108, 112))	('patients', 'Species', '9606', (113, 121))	('PD-L1', 'Gene', '29126', (53, 58))	('expression', 'MPA', (59, 69))	('P29S', 'Mutation', 'rs1057519874', (108, 112))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))
28053	26176707	The finding that PD-L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response.	('promote', 'PosReg', (76, 83))	('RAC1', 'Gene', (62, 66))	('PD-L1', 'Gene', '29126', (17, 22))	('upregulated', 'PosReg', (26, 37))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('immune response', 'biological_process', 'GO:0006955', ('113', '128'))	('suppression', 'CPA', (84, 95))	('oncogenic', 'Var', (52, 61))	('PD-L1', 'Gene', (17, 22))	('P29S', 'Var', (67, 71))	('P29S', 'Mutation', 'rs1057519874', (67, 71))
28054	26176707	This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD-L1 is a candidate biomarker for increased benefit from treatment with anti-PD1 or anti-PD-L1 antibodies.	('PD-L1', 'Gene', (114, 119))	('PD-L1', 'Gene', '29126', (204, 209))	('P29S', 'Mutation', 'rs1057519874', (59, 63))	('PD-L1', 'Gene', '29126', (114, 119))	('RAC1', 'Gene', (54, 58))	('P29S mutations', 'Var', (59, 73))	('PD1', 'Gene', '5133', (192, 195))	('PD1', 'Gene', (192, 195))	('PD-L1', 'Gene', (204, 209))
28055	26176707	New efforts in sequencing the exomes of cutaneous melanomas led to the detection of recurrent P29S mutations in Ras-related C3 botulinum toxin substrate (RAC1) in 5-9% of samples, making this the third most frequent activating mutation in sun-exposed melanoma after BRAF V600 and NRAS Q61 mutations.	('NRAS', 'Gene', (280, 284))	('activating', 'PosReg', (216, 226))	('P29S', 'Mutation', 'rs1057519874', (94, 98))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (40, 59))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (40, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (40, 58))	('RAC1', 'Gene', (154, 158))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Disease', (251, 259))	('cutaneous melanomas', 'Disease', (40, 59))	('BRAF', 'Gene', '673', (266, 270))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('BRAF', 'Gene', (266, 270))	('NRAS', 'Gene', '4893', (280, 284))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('P29S', 'Var', (94, 98))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))
28061	26176707	The P29S mutation in the RAC1 protein leads to a fast cycling GTPase, with increased inherent GDP/GTP nucleotide exchange.	('P29S', 'Var', (4, 8))	('GTP', 'Chemical', 'MESH:D006160', (98, 101))	('GTP', 'Chemical', 'MESH:D006160', (62, 65))	('GDP/GTP nucleotide exchange', 'MPA', (94, 121))	('GTPase', 'Enzyme', (62, 68))	('leads to', 'Reg', (38, 46))	('P29S', 'Mutation', 'rs1057519874', (4, 8))	('fast cycling', 'MPA', (49, 61))	('GDP', 'Chemical', 'MESH:D006153', (94, 97))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('increased', 'PosReg', (75, 84))	('RAC1', 'Gene', (25, 29))
28063	26176707	Therefore, the P29S mutation in the switch I region may have other effects on signal transduction beyond the observed fast cycling phenotype.	('signal transduction', 'biological_process', 'GO:0007165', ('78', '97'))	('effects', 'Reg', (67, 74))	('P29S', 'Var', (15, 19))	('P29S', 'Mutation', 'rs1057519874', (15, 19))	('signal transduction', 'MPA', (78, 97))
28064	26176707	There have been limited biochemical studies showing RAC1 P29S to have increased binding to downstream effectors as well as enhanced migration and proliferation.	('enhanced', 'PosReg', (123, 131))	('RAC1', 'Gene', (52, 56))	('increased', 'PosReg', (70, 79))	('binding', 'molecular_function', 'GO:0005488', ('80', '87'))	('migration', 'CPA', (132, 141))	('binding', 'Interaction', (80, 87))	('P29S', 'Var', (57, 61))	('P29S', 'Mutation', 'rs1057519874', (57, 61))
28065	26176707	Given the prevalence of RAC1 mutations in melanoma and the relative dearth of knowledge on the mechanism through which RAC1 P29S transforms murine melanocytes, we examined the signaling pathways associated with RAC1 expression.	('melanoma', 'Disease', (42, 50))	('P29S', 'Var', (124, 128))	('mutations', 'Var', (29, 38))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('murine', 'Species', '10090', (140, 146))	('RAC1', 'Gene', (119, 123))	('P29S', 'Mutation', 'rs1057519874', (124, 128))	('examined', 'Reg', (163, 171))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('RAC1', 'Gene', (24, 28))
28066	26176707	Through reverse phase protein array (RPPA) analysis, we found that cyclin B1, PD-L1, Ets-1, and Syk were significantly upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion.	('downregulated', 'NegReg', (161, 174))	('upregulated', 'PosReg', (119, 130))	('PD-L1', 'Gene', (78, 83))	('Syk', 'Gene', (96, 99))	('P29S', 'Mutation', 'rs1057519874', (185, 189))	('Ets-1', 'Gene', (85, 90))	('RAC1 P29S', 'Var', (136, 145))	('Ets-1', 'Gene', '2113', (85, 90))	('cyclin B1', 'Gene', '891', (67, 76))	('P29S', 'Mutation', 'rs1057519874', (141, 145))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('PD-L1', 'Gene', '29126', (78, 83))	('cyclin', 'molecular_function', 'GO:0016538', ('67', '73'))	('Syk', 'Gene', '6850', (96, 99))	('cyclin B1', 'Gene', (67, 76))
28067	26176707	Western blot and flow cytometry analyses revealed a robust increase in PD-L1 specifically with RAC1 P29S expression.	('P29S', 'Var', (100, 104))	('PD-L1', 'Gene', (71, 76))	('P29S', 'Mutation', 'rs1057519874', (100, 104))	('PD-L1', 'Gene', '29126', (71, 76))	('RAC1', 'Gene', (95, 99))	('increase', 'PosReg', (59, 67))
28068	26176707	Using the Skin Cutaneous Melanoma (SKCM) database in The Cancer Genome Atlas (TCGA), we found PD-L1 expression to be significantly increased in RAC1 P29S compared to RAC1 WT melanoma patients.	('PD-L1', 'Gene', (94, 99))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('Cancer Genome Atlas', 'Disease', (57, 76))	('WT melanoma', 'Disease', (171, 182))	('increased', 'PosReg', (131, 140))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (57, 76))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('WT melanoma', 'Disease', 'MESH:D008545', (171, 182))	('PD-L1', 'Gene', '29126', (94, 99))	('expression', 'MPA', (100, 110))	('Skin Cutaneous Melanoma', 'Disease', (10, 33))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('RAC1 P29S', 'Var', (144, 153))	('P29S', 'Mutation', 'rs1057519874', (149, 153))	('Melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('patients', 'Species', '9606', (183, 191))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (10, 33))
28069	26176707	Thus, our data provide new insight into the biological function of RAC1 P29S mutations as being involved in suppressing the antitumor immune response.	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('immune response', 'biological_process', 'GO:0006955', ('134', '149'))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('RAC1', 'Gene', (67, 71))	('P29S', 'Mutation', 'rs1057519874', (72, 76))	('P29S mutations', 'Var', (72, 86))	('suppressing', 'NegReg', (108, 119))
28072	26176707	Previous studies have identified RAC1 mutations in 5-9% of cutaneous melanoma samples.	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('RAC1', 'Gene', (33, 37))	('identified', 'Reg', (22, 32))	('mutations', 'Var', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
28073	26176707	Of these, 47.6% of the mutations are P29S and 19.0% of the mutations are P29L, making a total of 66.6% of the mutations occurring at the P29 codon (Figure 1A).	('P29', 'Gene', '25949', (73, 76))	('mutations', 'Var', (110, 119))	('P29', 'Gene', (37, 40))	('P29L', 'Mutation', 'rs1057519948', (73, 77))	('P29', 'Gene', '25949', (37, 40))	('P29', 'Gene', (137, 140))	('mutations', 'Var', (23, 32))	('P29', 'Gene', '25949', (137, 140))	('P29', 'Gene', (73, 76))	('P29S', 'Mutation', 'rs1057519874', (37, 41))
28074	26176707	The other mutations identified are V14E, E31D, P34S, S71F, P87L, N92K, and P140L.	('N92K', 'Var', (65, 69))	('P140L', 'Mutation', 'rs771808903', (75, 80))	('P34S', 'Var', (47, 51))	('S71F', 'Mutation', 'p.S71F', (53, 57))	('E31D', 'Mutation', 'p.E31D', (41, 45))	('V14E', 'Mutation', 'rs1438192629', (35, 39))	('V14E', 'Var', (35, 39))	('S71F', 'Var', (53, 57))	('P140L', 'Var', (75, 80))	('P87L', 'Var', (59, 63))	('P34S', 'Mutation', 'rs759370979', (47, 51))	('N92K', 'Mutation', 'p.N92K', (65, 69))	('E31D', 'Var', (41, 45))	('P87L', 'Mutation', 'rs750014957', (59, 63))
28075	26176707	Interestingly, none of these mutations occur at the Q61 or G12 codon, which are known Ras family activating mutations seen in other cancer types.	('G12', 'Var', (59, 62))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
28076	26176707	In the cutaneous melanoma dataset from the TCGA, we found the rate of co-existing BRAF mutation to be 42.9% (9/21) and that of co-existing NRAS mutation to be 33.3% (7/21) (Figure 1B).	('cutaneous melanoma', 'Disease', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('BRAF', 'Gene', '673', (82, 86))	('NRAS', 'Gene', (139, 143))	('BRAF', 'Gene', (82, 86))	('NRAS', 'Gene', '4893', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutation', 'Var', (87, 95))
28077	26176707	The rate of BRAF mutations in the entire dataset is 46.3% (177/382) and that of NRAS is 24.9% (95/382).	('NRAS', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('NRAS', 'Gene', '4893', (80, 84))	('mutations', 'Var', (17, 26))
28078	26176707	Compared to all melanoma patients, those with the RAC1 mutation have 1.37 the odds of having a co-existing NRAS mutation but only 0.87 the odds of having a co-existing BRAF mutation.	('mutation', 'Var', (112, 120))	('NRAS', 'Gene', '4893', (107, 111))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('BRAF', 'Gene', '673', (168, 172))	('patients', 'Species', '9606', (25, 33))	('BRAF', 'Gene', (168, 172))	('NRAS', 'Gene', (107, 111))
28079	26176707	Therefore, there is significant overlap between NRAS and BRAF mutations with RAC1 mutations, and the rate of co-existing NRAS mutation is higher than expected.	('NRAS', 'Gene', '4893', (48, 52))	('NRAS', 'Gene', '4893', (121, 125))	('mutations', 'Var', (62, 71))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('RAC1', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', (48, 52))	('NRAS', 'Gene', (121, 125))
28081	26176707	We used site-directed mutagenesis to introduce a P29S mutation in wild-type (WT) RAC1 with an eGFP tag (Figure S1).	('mutagenesis', 'biological_process', 'GO:0006280', ('22', '33'))	('P29S', 'Var', (49, 53))	('RAC1', 'Gene', (81, 85))	('P29S', 'Mutation', 'rs1057519874', (49, 53))
28084	26176707	Expression of RAC1 increased levels of phospho-Pak1.	('RAC1', 'Gene', (14, 18))	('Pak1', 'Gene', (47, 51))	('Expression', 'Var', (0, 10))	('increased', 'PosReg', (19, 28))	('Pak1', 'Gene', '5058', (47, 51))
28085	26176707	Fluorescence staining of the actin cytoskeleton with phalloidin indicated that the expression of RAC1 P29S and Q61L led to more cells with membrane ruffling (Figures 2B and S2).	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('29', '47'))	('RAC1', 'Gene', (97, 101))	('more', 'PosReg', (123, 127))	('Q61L', 'Var', (111, 115))	('P29S', 'Mutation', 'rs1057519874', (102, 106))	('Q61L', 'Mutation', 'rs11554290', (111, 115))	('cells with membrane ruffling', 'CPA', (128, 156))	('phalloidin', 'Chemical', 'MESH:D010590', (53, 63))	('membrane', 'cellular_component', 'GO:0016020', ('139', '147'))	('membrane ruffling', 'biological_process', 'GO:0097178', ('139', '156'))	('P29S', 'Var', (102, 106))
28086	26176707	Compared to RAC1 WT, both RAC1 P29S and RAC1 Q61L have been shown to increase proliferation.	('increase', 'PosReg', (69, 77))	('P29S', 'Var', (31, 35))	('P29S', 'Mutation', 'rs1057519874', (31, 35))	('proliferation', 'CPA', (78, 91))	('Q61L', 'Mutation', 'rs11554290', (45, 49))
28087	26176707	In colony proliferation assays, we noted a similar increase in cell growth with RAC1 Q61L (P < 0.001) > RAC1 P29S (P = 0.001) > RAC1 WT (P = 0.069) compared to parental cells (Figure 2C, D. We examined the effect of RAC1 expression on growth in soft agar, an indicator of the ability of tumor cells to escape the requirement for interactions with the extracellular matrix.	('increase', 'PosReg', (51, 59))	('cell growth', 'biological_process', 'GO:0016049', ('63', '74'))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('351', '371'))	('tumor', 'Disease', (287, 292))	('agar', 'Chemical', 'MESH:D000362', (250, 254))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('RAC1', 'Gene', (216, 220))	('Q61L', 'Var', (85, 89))	('RAC1 Q61L', 'Var', (80, 89))	('P29S', 'Mutation', 'rs1057519874', (109, 113))	('cell growth', 'CPA', (63, 74))	('Q61L', 'Mutation', 'rs11554290', (85, 89))
28088	26176707	Studies from other groups indicate that RAC1 P29S is a mode of resistance to RAF inhibitors in mutant BRAF melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('RAF', 'Gene', '22882', (103, 106))	('BRAF melanoma', 'Disease', 'MESH:D008545', (102, 115))	('P29S', 'Mutation', 'rs1057519874', (45, 49))	('RAF', 'Gene', (103, 106))	('BRAF melanoma', 'Disease', (102, 115))	('RAF', 'Gene', '22882', (77, 80))	('mutant', 'Var', (95, 101))	('RAF', 'Gene', (77, 80))
28089	26176707	It is important to understand how RAC1 mutations alter the response to targeted therapies in subsets of melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('response to targeted therapies', 'MPA', (59, 89))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('mutations', 'Var', (39, 48))	('melanomas', 'Disease', (104, 113))	('alter', 'Reg', (49, 54))	('RAC1', 'Gene', (34, 38))
28092	26176707	The expression of RAC1, either wild type or mutant, did not affect the level of apoptosis induced by trametinib.	('RAC1', 'Gene', (18, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('mutant', 'Var', (44, 50))	('trametinib', 'Chemical', 'MESH:C560077', (101, 111))
28093	26176707	Given that melan-a cells were insensitive to trametinib, we were not able to test the protective effects of RAC1 mutants in cell death assays.	('trametinib', 'Chemical', 'MESH:C560077', (45, 55))	('mutants', 'Var', (113, 120))	('cell death', 'biological_process', 'GO:0008219', ('124', '134'))	('RAC1', 'Gene', (108, 112))
28094	26176707	Mutant NRAS melanoma cells have varied response to MEK inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('MEK', 'Gene', (51, 54))	('NRAS', 'Gene', (7, 11))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('response', 'MPA', (39, 47))	('MEK', 'Gene', '5609', (51, 54))	('Mutant', 'Var', (0, 6))	('NRAS', 'Gene', '4893', (7, 11))
28095	26176707	Therefore, we generated two mutant NRAS cell lines with inducible expression of RAC1 WT, RAC1 P29S or RAC1 Q61L (Figure 3B).	('Q61L', 'Mutation', 'rs11554290', (107, 111))	('NRAS', 'Gene', (35, 39))	('RAC1', 'Gene', (80, 84))	('NRAS', 'Gene', '4893', (35, 39))	('RAC1 Q61L', 'Var', (102, 111))	('RAC1 P29S', 'Var', (89, 98))	('P29S', 'Mutation', 'rs1057519874', (94, 98))
28096	26176707	In 3D culture systems, the two mutant NRAS human melanoma cell lines, WM1346 TR and WM1361A TR, were sensitive to trametinib, as indicated by increased annexin V positivity following trametinib treatment (Figure 3C).	('NRAS', 'Gene', '4893', (38, 42))	('positivity', 'MPA', (162, 172))	('WM1361A', 'Var', (84, 91))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('increased', 'PosReg', (142, 151))	('annexin V', 'Gene', (152, 161))	('annexin V', 'Gene', '308', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('trametinib', 'Chemical', 'MESH:C560077', (114, 124))	('NRAS', 'Gene', (38, 42))	('trametinib', 'Chemical', 'MESH:C560077', (183, 193))	('sensitive', 'MPA', (101, 110))	('melanoma', 'Disease', (49, 57))	('human', 'Species', '9606', (43, 48))
28097	26176707	Inducible expression of RAC1 WT, P29S, or Q61L did not significantly change the degree of apoptosis induced by trametinib (Figure 3C).	('Q61L', 'Mutation', 'rs11554290', (42, 46))	('Q61L', 'Var', (42, 46))	('apoptosis', 'biological_process', 'GO:0097194', ('90', '99'))	('apoptosis', 'biological_process', 'GO:0006915', ('90', '99'))	('P29S', 'Var', (33, 37))	('trametinib', 'Chemical', 'MESH:C560077', (111, 121))	('P29S', 'Mutation', 'rs1057519874', (33, 37))	('RAC1', 'Gene', (24, 28))
28098	26176707	In YUHEF cells, a melanoma cell line wild type for both BRAF and NRAS with an endogenous RAC1 P29S mutation, we depleted endogenous RAC1 by siRNA transfection (Figure 3D) to determine whether RAC1 loss sensitized the cells to MEK inhibition.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('NRAS', 'Gene', '4893', (65, 69))	('depleted', 'NegReg', (112, 120))	('MEK', 'Gene', (226, 229))	('YUHEF', 'CellLine', 'CVCL:G326', (3, 8))	('MEK', 'Gene', '5609', (226, 229))	('BRAF', 'Gene', '673', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('loss', 'NegReg', (197, 201))	('RAC1', 'Gene', (89, 93))	('P29S mutation', 'Var', (94, 107))	('P29S', 'Mutation', 'rs1057519874', (94, 98))	('RAC1', 'Gene', (192, 196))	('melanoma', 'Disease', (18, 26))	('NRAS', 'Gene', (65, 69))	('BRAF', 'Gene', (56, 60))
28100	26176707	RAC1 depletion increased apoptosis in YUHEF cells, and this was further enhanced by 21.8% following addition of trametinib.	('depletion', 'Var', (5, 14))	('YUHEF', 'CellLine', 'CVCL:G326', (38, 43))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('apoptosis', 'CPA', (25, 34))	('RAC1', 'Gene', (0, 4))	('trametinib', 'Chemical', 'MESH:C560077', (112, 122))
28101	26176707	The similar increase in trametinib-induced apoptosis in the absence and presence of RAC1 depletion indicated that RAC1 depletion did not increase sensitivity to trametinib.	('apoptosis', 'CPA', (43, 52))	('depletion', 'Var', (89, 98))	('increase', 'PosReg', (12, 20))	('trametinib', 'Chemical', 'MESH:C560077', (24, 34))	('trametinib', 'Chemical', 'MESH:C560077', (161, 171))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('trametinib-induced', 'Gene', (24, 42))
28103	26176707	With RAC1 WT expression, there were 71 proteins that were upregulated and 40 that were downregulated; with RAC1 P29S expression, 87 were upregulated and 38 downregulated; and with RAC1 Q61L expression, 17 were upregulated and 36 were downregulated.	('P29S', 'Mutation', 'rs1057519874', (112, 116))	('upregulated', 'PosReg', (137, 148))	('downregulated', 'NegReg', (234, 247))	('upregulated', 'PosReg', (58, 69))	('upregulated', 'PosReg', (210, 221))	('RAC1 P29S expression', 'Var', (107, 127))	('proteins', 'Protein', (39, 47))	('downregulated', 'NegReg', (156, 169))	('Q61L', 'Mutation', 'rs11554290', (185, 189))
28104	26176707	There were 42 different proteins and phospho-proteins that were similarly regulated with the expression of the RAC1 WT, RAC1 P29S, and RAC1 Q61L compared to parental melan-a cells (Figure 4B).	('RAC1 Q61L', 'Var', (135, 144))	('RAC1', 'Gene', (111, 115))	('regulated', 'Reg', (74, 83))	('P29S', 'Var', (125, 129))	('RAC1 P29S', 'Var', (120, 129))	('P29S', 'Mutation', 'rs1057519874', (125, 129))	('Q61L', 'Mutation', 'rs11554290', (140, 144))
28106	26176707	The enrichment of pathways involved in cell cycle and cancer signaling likely reflects the increase in cell growth seen with RAC1 expression (Figure 2C-E).	('cell cycle', 'biological_process', 'GO:0007049', ('39', '49'))	('RAC1', 'Gene', (125, 129))	('cell growth', 'CPA', (103, 114))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('expression', 'Var', (130, 140))	('increase', 'PosReg', (91, 99))	('cancer', 'Disease', (54, 60))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
28107	26176707	The majority of the up- or downregulated proteins were shared in common between or among RAC1 WT, RAC1 P29S, and RAC1 Q61L.	('P29S', 'Var', (103, 107))	('up-', 'PosReg', (20, 23))	('Q61L', 'Mutation', 'rs11554290', (118, 122))	('RAC1 Q61L', 'Var', (113, 122))	('P29S', 'Mutation', 'rs1057519874', (103, 107))	('downregulated', 'NegReg', (27, 40))	('RAC1', 'Gene', (98, 102))	('RAC1', 'Gene', (89, 93))	('proteins', 'Protein', (41, 49))
28108	26176707	However, several proteins were uniquely regulated, specifically 8 with RAC1 WT, 21 with RAC1 P29S, and 5 with RAC1 Q61L (Figure 4B).	('RAC1 WT', 'Var', (71, 78))	('RAC1 P29S', 'Var', (88, 97))	('Q61L', 'Mutation', 'rs11554290', (115, 119))	('regulated', 'Reg', (40, 49))	('P29S', 'Mutation', 'rs1057519874', (93, 97))	('proteins', 'Protein', (17, 25))
28109	26176707	To define a protein signature specific to RAC1 P29S, we compared the changes with RAC1 P29S overexpression in melan-a cells and the changes with RAC1 depletion in YUHEF melanoma cells, which harbor an endogenous RAC1 P29S mutation.	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('P29S', 'Mutation', 'rs1057519874', (47, 51))	('P29S', 'Var', (217, 221))	('P29S', 'Var', (87, 91))	('overexpression', 'PosReg', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('P29S', 'Mutation', 'rs1057519874', (217, 221))	('P29S', 'Mutation', 'rs1057519874', (87, 91))	('RAC1', 'Gene', (82, 86))	('YUHEF', 'CellLine', 'CVCL:G326', (163, 168))
28110	26176707	SAM showed 18 proteins that were upregulated and 72 that were downregulated with RAC1 depletion in YUHEF cells (Figure 5A).	('upregulated', 'PosReg', (33, 44))	('proteins', 'Protein', (14, 22))	('YUHEF', 'CellLine', 'CVCL:G326', (99, 104))	('downregulated', 'NegReg', (62, 75))	('RAC1', 'Gene', (81, 85))	('depletion', 'Var', (86, 95))
28111	26176707	Nineteen proteins were upregulated with RAC1 P29S expression and downregulated with RAC1 depletion, and one protein was downregulated with RAC1 P29S expression and upregulated with RAC1 depletion (Figure 5B).	('upregulated', 'PosReg', (23, 34))	('P29S', 'Mutation', 'rs1057519874', (144, 148))	('upregulated', 'PosReg', (164, 175))	('P29S', 'Mutation', 'rs1057519874', (45, 49))	('proteins', 'Protein', (9, 17))	('RAC1 P29S', 'Var', (40, 49))	('downregulated', 'NegReg', (65, 78))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('P29S', 'Var', (45, 49))
28112	26176707	Of the 20 proteins differentially regulated, four are part of the 21 protein subset that were uniquely changed with the expression of RAC1 P29S: cyclin B1, Pdcd-1L1 (aka PD-L1, CD274), Ets-1, and Syk (boxed in Figure 5B).	('changed', 'Reg', (103, 110))	('Syk', 'Gene', (196, 199))	('PD-L1', 'Gene', (170, 175))	('PD-L1', 'Gene', '29126', (170, 175))	('CD274', 'Gene', (177, 182))	('Pdcd-1L1', 'Gene', (156, 164))	('cyclin B1', 'Gene', '891', (145, 154))	('cyclin B1', 'Gene', (145, 154))	('Pdcd-1L1', 'Gene', '29126', (156, 164))	('cyclin', 'molecular_function', 'GO:0016538', ('145', '151'))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('P29S', 'Var', (139, 143))	('Ets-1', 'Gene', '2113', (185, 190))	('Syk', 'Gene', '6850', (196, 199))	('CD274', 'Gene', '29126', (177, 182))	('RAC1', 'Gene', (134, 138))	('P29S', 'Mutation', 'rs1057519874', (139, 143))	('Ets-1', 'Gene', (185, 190))
28116	26176707	With RAC1 depletion, there were decreases in PD-L1, Ets-1, and Syk that correlate with the degree of RAC1 knockdown.	('Ets-1', 'Gene', (52, 57))	('RAC1', 'Gene', (101, 105))	('PD-L1', 'Gene', '29126', (45, 50))	('Syk', 'Gene', (63, 66))	('depletion', 'Var', (10, 19))	('knockdown', 'Var', (106, 115))	('Syk', 'Gene', '6850', (63, 66))	('decreases', 'NegReg', (32, 41))	('Ets-1', 'Gene', '2113', (52, 57))	('PD-L1', 'Gene', (45, 50))
28117	26176707	The specificity of the PD-L1 antibodies used for Western blot analysis was validated with PD-L1 knockdown in both a human melanoma cell line and melan-a cells (Figure S3A,B).	('knockdown', 'Var', (96, 105))	('PD-L1', 'Gene', (23, 28))	('PD-L1', 'Gene', '29126', (90, 95))	('PD-L1', 'Gene', '29126', (23, 28))	('human', 'Species', '9606', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('PD-L1', 'Gene', (90, 95))
28119	26176707	As was seen with Western blot analysis, surface staining of PD-L1 in melan-a cells expressing RAC1 WT and RAC1 Q61L was similar to that of parental cells melan-a, but expression of RAC1 P29S led to a significant increase in surface PD-L1 expression (Figure 5E, F. To extend our studies to human patient samples, we evaluated the mutant RAC1 subset for PD-L1 expression in the SKCM database in the TCGA.	('PD-L1', 'Gene', (232, 237))	('PD-L1', 'Gene', (352, 357))	('Q61L', 'Mutation', 'rs11554290', (111, 115))	('patient', 'Species', '9606', (295, 302))	('PD-L1', 'Gene', (60, 65))	('PD-L1', 'Gene', '29126', (232, 237))	('PD-L1', 'Gene', '29126', (352, 357))	('human', 'Species', '9606', (289, 294))	('RAC1 P29S', 'Var', (181, 190))	('increase', 'PosReg', (212, 220))	('expression', 'MPA', (238, 248))	('P29S', 'Mutation', 'rs1057519874', (186, 190))	('PD-L1', 'Gene', '29126', (60, 65))
28120	26176707	There was no significant difference in PD-L1 expression between the wild-type RAC1 and mutant RAC1 patients when accounting for the full spectrum of RAC1 mutations (P = 0.292).	('PD-L1', 'Gene', (39, 44))	('RAC1', 'Gene', (94, 98))	('PD-L1', 'Gene', '29126', (39, 44))	('patients', 'Species', '9606', (99, 107))	('mutant', 'Var', (87, 93))	('RAC1', 'Gene', (78, 82))
28122	26176707	For the RAC1 P29S subset, we found a significant increase in PD-L1 mRNA (P = 0.005) compared to wild-type RAC1 patients.	('increase', 'PosReg', (49, 57))	('P29S', 'Mutation', 'rs1057519874', (13, 17))	('PD-L1', 'Gene', (61, 66))	('RAC1', 'Gene', (8, 12))	('PD-L1', 'Gene', '29126', (61, 66))	('P29S', 'Var', (13, 17))	('patients', 'Species', '9606', (111, 119))
28124	26176707	With both exogenous expression of RAC1 P29S in vitro and endogenous expression of RAC1 P29S in melanoma patients, we found that RAC1 P29S expression is correlated with an increase in PD-L1 expression.	('PD-L1', 'Gene', (183, 188))	('P29S', 'Mutation', 'rs1057519874', (133, 137))	('RAC1 P29S', 'Var', (128, 137))	('P29S', 'Mutation', 'rs1057519874', (39, 43))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('PD-L1', 'Gene', '29126', (183, 188))	('melanoma', 'Disease', (95, 103))	('expression', 'MPA', (189, 199))	('P29S', 'Mutation', 'rs1057519874', (87, 91))	('increase', 'PosReg', (171, 179))	('patients', 'Species', '9606', (104, 112))
28125	26176707	In recent years, advances in DNA sequencing have led to the identification of many new mutations in melanomas.	('melanomas', 'Disease', 'MESH:D008545', (100, 109))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))	('melanomas', 'Disease', (100, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('mutations', 'Var', (87, 96))
28126	26176707	Previously, it was found that in RAC1 mutant melanomas, the rate of co-existing NRAS mutation (30%) is higher than expected, whereas the rate of co-existing BRAF mutation was only 26%.	('NRAS', 'Gene', (80, 84))	('mutant', 'Var', (38, 44))	('RAC1', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (157, 161))	('NRAS', 'Gene', '4893', (80, 84))	('mutation', 'Var', (85, 93))	('melanomas', 'Disease', (45, 54))	('BRAF', 'Gene', (157, 161))	('higher', 'PosReg', (103, 109))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
28127	26176707	In the cutaneous melanoma dataset from the TCGA, we found the rate of co-existing BRAF mutation to be 42.9% (9/21) and that of co-existing NRAS mutation to be 33.3% (7/21).	('cutaneous melanoma', 'Disease', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('BRAF', 'Gene', '673', (82, 86))	('NRAS', 'Gene', (139, 143))	('BRAF', 'Gene', (82, 86))	('NRAS', 'Gene', '4893', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutation', 'Var', (87, 95))
28128	26176707	Thus, there is a high degree of overlap between melanomas with mutations in RAC1 and those with mutations in BRAF or NRAS.	('mutations', 'Var', (63, 72))	('NRAS', 'Gene', (117, 121))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('RAC1', 'Gene', (76, 80))	('NRAS', 'Gene', '4893', (117, 121))	('melanomas', 'Disease', (48, 57))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
28129	26176707	RAC1 is known to positively regulate cell proliferation, and the P29S mutant has been shown to enhance cell growth.	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('P29S', 'Var', (65, 69))	('cell growth', 'CPA', (103, 114))	('P29S', 'Mutation', 'rs1057519874', (65, 69))	('cell growth', 'biological_process', 'GO:0016049', ('103', '114'))	('RAC1', 'Gene', (0, 4))	('cell proliferation', 'CPA', (37, 55))	('enhance', 'PosReg', (95, 102))
28130	26176707	Morphologically, expression of RAC1 P29S and RAC1 Q61L led to an increase in membrane ruffling, a phenotype commonly attributed to RAC1 activating mutations due to their regulation of F-actin reorganization.	('increase', 'PosReg', (65, 73))	('membrane', 'cellular_component', 'GO:0016020', ('77', '85'))	('membrane ruffling', 'MPA', (77, 94))	('F-actin', 'cellular_component', 'GO:0031941', ('184', '191'))	('regulation', 'biological_process', 'GO:0065007', ('170', '180'))	('Q61L', 'Mutation', 'rs11554290', (50, 54))	('RAC1', 'Gene', (31, 35))	('membrane ruffling', 'biological_process', 'GO:0097178', ('77', '94'))	('RAC1', 'Gene', (131, 135))	('Q61L', 'Var', (50, 54))	('P29S', 'Var', (36, 40))	('RAC1', 'Gene', (45, 49))	('P29S', 'Mutation', 'rs1057519874', (36, 40))
28131	26176707	While some have found melanoma cell lines with RAC1 P29S mutation to be resistant to RAF and MEK inhibitors, others have found that RAC1 mutation status does not predict sensitivity to RAF or MEK inhibitors.	('MEK', 'Gene', (192, 195))	('MEK', 'Gene', '5609', (192, 195))	('RAF', 'Gene', '22882', (185, 188))	('RAF', 'Gene', (185, 188))	('P29S', 'Var', (52, 56))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('MEK', 'Gene', (93, 96))	('melanoma', 'Disease', (22, 30))	('RAC1', 'Gene', (47, 51))	('P29S', 'Mutation', 'rs1057519874', (52, 56))	('MEK', 'Gene', '5609', (93, 96))	('RAF', 'Gene', '22882', (85, 88))	('RAF', 'Gene', (85, 88))
28132	26176707	Given the heterogeneity of responses, we analyzed the response of mutant NRAS melanoma to MEK inhibitors and found that RAC1 expression does not decrease cell death in the presence of the MEK inhibitor, trametinib.	('NRAS', 'Gene', '4893', (73, 77))	('MEK', 'Gene', (188, 191))	('mutant', 'Var', (66, 72))	('cell death', 'CPA', (154, 164))	('MEK', 'Gene', '5609', (188, 191))	('trametinib', 'Chemical', 'MESH:C560077', (203, 213))	('MEK', 'Gene', (90, 93))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Disease', (78, 86))	('RAC1', 'Gene', (120, 124))	('MEK', 'Gene', '5609', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('cell death', 'biological_process', 'GO:0008219', ('154', '164'))	('NRAS', 'Gene', (73, 77))
28133	26176707	Conversely, RAC1 depletion in a melanoma cell line with an endogenous RAC1 P29S mutation does not lead to an increase in cell death upon MEK inhibition.	('P29S', 'Mutation', 'rs1057519874', (75, 79))	('MEK', 'Gene', (137, 140))	('MEK', 'Gene', '5609', (137, 140))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('RAC1', 'Gene', (70, 74))	('melanoma', 'Disease', (32, 40))	('cell death', 'CPA', (121, 131))	('cell death', 'biological_process', 'GO:0008219', ('121', '131'))	('P29S', 'Var', (75, 79))
28134	26176707	Of the 218 validated antibodies, 42 were similarly regulated with RAC1 WT, RAC1 P29S, and RAC1 Q61L expression.	('RAC1 Q61L', 'Var', (90, 99))	('P29S', 'Var', (80, 84))	('P29S', 'Mutation', 'rs1057519874', (80, 84))	('Q61L', 'Mutation', 'rs11554290', (95, 99))
28135	26176707	Twenty-one of the proteins were uniquely regulated by RAC1 P29S expression.	('proteins', 'Protein', (18, 26))	('P29S', 'Mutation', 'rs1057519874', (59, 63))	('RAC1', 'Gene', (54, 58))	('P29S expression', 'Var', (59, 74))	('regulated', 'Reg', (41, 50))
28136	26176707	Of these 21, four upregulated proteins (cyclin B1, PD-L1, Ets-1, and Syk) were also downregulated by RAC1 depletion in YUHEF melanoma cells, which harbor an endogenous RAC1 P29S mutation.	('YUHEF', 'CellLine', 'CVCL:G326', (119, 124))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('PD-L1', 'Gene', '29126', (51, 56))	('depletion', 'MPA', (106, 115))	('P29S', 'Mutation', 'rs1057519874', (173, 177))	('proteins', 'Protein', (30, 38))	('Ets-1', 'Gene', (58, 63))	('RAC1', 'Gene', (168, 172))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('upregulated', 'PosReg', (18, 29))	('Syk', 'Gene', '6850', (69, 72))	('cyclin', 'molecular_function', 'GO:0016538', ('40', '46'))	('downregulated', 'NegReg', (84, 97))	('Syk', 'Gene', (69, 72))	('P29S', 'Var', (173, 177))	('Ets-1', 'Gene', '2113', (58, 63))	('cyclin B1', 'Gene', '891', (40, 49))	('cyclin B1', 'Gene', (40, 49))	('PD-L1', 'Gene', (51, 56))
28140	26176707	Mutations in melanoma likely contribute to the immunogenicity of this cancer, and the expression of mutated antigens in melanoma cells can be recognized by tumor infiltrating lymphocytes.	('contribute', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('Mutations', 'Var', (0, 9))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('tumor', 'Disease', (156, 161))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
28141	26176707	Inhibition of the MEK-ERK1/2 pathway has been shown to decrease the production of immunosuppressive soluble factors such as IL-10, IL-6, and IL-1 in mutant BRAF melanoma.	('IL-1', 'Gene', '3552', (124, 128))	('IL-1', 'Gene', '3552', (141, 145))	('IL-6', 'molecular_function', 'GO:0005138', ('131', '135'))	('IL-1', 'Gene', (124, 128))	('IL-1', 'Gene', (141, 145))	('IL-6', 'Gene', '3569', (131, 135))	('ERK1', 'molecular_function', 'GO:0004707', ('22', '26'))	('soluble', 'cellular_component', 'GO:0005625', ('100', '107'))	('production of immunosuppressive soluble factors', 'MPA', (68, 115))	('IL-6', 'Gene', (131, 135))	('mutant', 'Var', (149, 155))	('IL-10', 'Gene', '3586', (124, 129))	('ERK1/2', 'Gene', (22, 28))	('IL-10', 'molecular_function', 'GO:0005141', ('124', '129'))	('MEK', 'Gene', '5609', (18, 21))	('BRAF melanoma', 'Disease', 'MESH:D008545', (156, 169))	('ERK1/2', 'Gene', '5595;5594', (22, 28))	('IL-10', 'Gene', (124, 129))	('IL-1', 'molecular_function', 'GO:0005149', ('141', '145'))	('BRAF melanoma', 'Disease', (156, 169))	('MEK', 'Gene', (18, 21))	('decrease', 'NegReg', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))
28144	26176707	To the best of our knowledge, our observation that PD-L1 is increased with RAC1 P29S is the first of a role for the RAC1 P29S oncogene in modulating the immunogenicity of melanoma.	('PD-L1', 'Gene', '29126', (51, 56))	('modulating', 'Reg', (138, 148))	('P29S', 'Var', (80, 84))	('P29S', 'Mutation', 'rs1057519874', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('P29S', 'Mutation', 'rs1057519874', (80, 84))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('RAC1', 'Gene', (75, 79))	('increased', 'PosReg', (60, 69))	('PD-L1', 'Gene', (51, 56))
28153	26176707	Given the correlation between RAC1 P29S expression and PD-L1 expression, it would be interesting to evaluate the response to anti-PD-L1 or anti-PD-1 therapies in this subgroup.	('PD-L1', 'Gene', '29126', (55, 60))	('PD-L1', 'Gene', (130, 135))	('P29S', 'Var', (35, 39))	('P29S', 'Mutation', 'rs1057519874', (35, 39))	('PD-L1', 'Gene', '29126', (130, 135))	('RAC1', 'Gene', (30, 34))	('PD-L1', 'Gene', (55, 60))
28154	26176707	In summary, we show a novel role for RAC1 P29S in modulating the expression of PD-L1 in melanoma.	('P29S', 'Var', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('RAC1', 'Gene', (37, 41))	('P29S', 'Mutation', 'rs1057519874', (42, 46))	('PD-L1', 'Gene', (79, 84))	('expression', 'MPA', (65, 75))	('PD-L1', 'Gene', '29126', (79, 84))	('modulating', 'Reg', (50, 60))
28156	26176707	Additionally, given the role of anti-PD-1 and PD-L1 antibodies, RAC1 P29S may be a useful predictor of response to such therapies.	('PD-L1', 'Gene', (46, 51))	('P29S', 'Var', (69, 73))	('PD-L1', 'Gene', '29126', (46, 51))	('P29S', 'Mutation', 'rs1057519874', (69, 73))	('RAC1', 'Gene', (64, 68))	('anti-PD-1', 'Gene', (32, 41))
28164	26176707	Lentiviral particles and melan-a and tetracycline repressor-expressing (TR expressing) sublines WM1346 TR and WM1361A TR expressing RAC1 WT-eGFP and RAC1 P29S-eGFP and RAC1 Q61L-eGFP were generated, as previously described.	('RAC1', 'Var', (132, 136))	('P29S', 'Mutation', 'rs1057519874', (154, 158))	('Q61L', 'Mutation', 'rs11554290', (173, 177))	('tetracycline', 'Chemical', 'MESH:D013752', (37, 49))	('RAC1 P29S-eGFP', 'Var', (149, 163))	('RAC1 Q61L-eGFP', 'Var', (168, 182))
28175	26176707	Mutant NRAS cells (4 x 103) were plated per six-well plate in complete medium with or without inhibitors, which were replenished every 2 days.	('NRAS', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('NRAS', 'Gene', '4893', (7, 11))
28183	26176707	A one-way anova analysis of PD-L1 mRNA expression levels was performed on 9 RAC1 P29S mutants, 4 RAC1 P29L mutants, 7 non-P29 RAC1 mutants, and 282 RAC1 WT.	('P29L', 'Mutation', 'rs1057519948', (102, 106))	('mutants', 'Var', (86, 93))	('PD-L1', 'Gene', '29126', (28, 33))	('P29S', 'Mutation', 'rs1057519874', (81, 85))	('P29', 'Gene', '25949', (81, 84))	('P29', 'Gene', (81, 84))	('RAC1', 'Gene', (76, 80))	('P29', 'Gene', '25949', (102, 105))	('P29', 'Gene', '25949', (122, 125))	('P29', 'Gene', (102, 105))	('P29', 'Gene', (122, 125))	('PD-L1', 'Gene', (28, 33))
28185	26176707	Dunnett's one-tailed multiple comparison post hoc tests were performed to determine the statistical significance of the RAC1 P29S samples compared to the other groups.	('P29S', 'Var', (125, 129))	('RAC1', 'Gene', (120, 124))	('P29S', 'Mutation', 'rs1057519874', (125, 129))
28186	26176707	Recent efforts in exome sequencing of cutaneous melanoma samples identified a recurrent RAC1 P29S mutation.	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('P29S', 'Var', (93, 97))	('RAC1', 'Gene', (88, 92))	('P29S', 'Mutation', 'rs1057519874', (93, 97))	('cutaneous melanoma', 'Disease', (38, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
28187	26176707	We utilized an unbiased protein array to determine proteins regulated by RAC1 P29S and identified a correlation between PD-L1, a negative immune modulator, and RAC1 P29S.	('P29S', 'Var', (165, 169))	('RAC1', 'Gene', (73, 77))	('RAC1', 'Gene', (160, 164))	('P29S', 'Mutation', 'rs1057519874', (165, 169))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (120, 125))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('P29S', 'Var', (78, 82))	('P29S', 'Mutation', 'rs1057519874', (78, 82))
28188	26176707	This finding provides novel insight into the biology of RAC1 P29S, with a potential role in evading the antitumor immune response.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('P29S', 'Mutation', 'rs1057519874', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RAC1', 'Gene', (56, 60))	('tumor', 'Disease', (108, 113))	('immune response', 'biological_process', 'GO:0006955', ('114', '129'))	('P29S', 'Var', (61, 65))
28189	26176707	Additionally, RAC1 P29S melanoma patients may derive increased benefit from immune therapies that target PD-L1 or its receptor, PD-1.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('patients', 'Species', '9606', (33, 41))	('PD-L1', 'Gene', (105, 110))	('PD-L1', 'Gene', '29126', (105, 110))	('RAC1 P29S', 'Var', (14, 23))	('P29S', 'Mutation', 'rs1057519874', (19, 23))	('melanoma', 'Disease', (24, 32))
28195	26134500	We demonstrate that high ALCAM expression in primary melanoma cells (IRS >=8) is strongly correlated with unfavorable prognosis as compared with patients with lower ALCAM immunoreactivity in tumor compartment as regards cancer specific overall survival (CSOS) (P = 0.001) and disease free survival (DFS) (P < 0.001).	('ALCAM', 'Gene', (165, 170))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('correlated', 'Reg', (90, 100))	('ALCAM', 'Gene', '214', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('tumor', 'Disease', (191, 196))	('CSOS', 'Chemical', '-', (254, 258))	('cancer', 'Disease', (220, 226))	('ALCAM', 'Gene', '214', (165, 170))	('patients', 'Species', '9606', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('disease free survival', 'CPA', (276, 297))	('ALCAM', 'Gene', (25, 30))	('lower ALCAM', 'Phenotype', 'HP:0003282', (159, 170))
28199	26134500	High ALCAM expression in melanoma cells of the primary tumor can be used as a marker of negative outcome and may indicate a more invasive phenotype of cancer cells, which would require a more intensive therapeutic strategy.	('primary tumor', 'Disease', 'MESH:D009369', (47, 60))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('expression', 'MPA', (11, 21))	('indicate', 'Reg', (113, 121))	('ALCAM', 'Gene', '214', (5, 10))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('primary tumor', 'Disease', (47, 60))	('ALCAM', 'Gene', (5, 10))
28202	26134500	All disturbances of this extremely precise homeostasis may lead to abnormal expression of adhesion proteins and molecules involved in intercellular communication, which may in turn initiate melanomagenesis.	('adhesion proteins', 'Protein', (90, 107))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('disturbances', 'Var', (4, 16))	('lead to', 'Reg', (59, 66))	('expression', 'MPA', (76, 86))	('homeostasis', 'biological_process', 'GO:0042592', ('43', '54'))	('initiate', 'Reg', (181, 189))
28223	26134500	Inhibition of ALCAM expression resulted in significantly decreased MMP-2 activity, and thus in decreased metastatic potential.	('decreased', 'NegReg', (95, 104))	('metastatic potential', 'CPA', (105, 125))	('ALCAM', 'Gene', (14, 19))	('MMP-2', 'molecular_function', 'GO:0004228', ('67', '72'))	('MMP-2', 'Gene', '4313', (67, 72))	('Inhibition', 'Var', (0, 10))	('ALCAM', 'Gene', '214', (14, 19))	('decreased', 'NegReg', (57, 66))	('MMP-2', 'Gene', (67, 72))
28269	26134500	High ALCAM expression in cancer cells of the primary tumor (IRS >=8) is closely correlated with unfavorable prognosis in cutaneous melanoma patients as regards cancer specific overall survival and particularly disease free survival (P = 0.001 and P < 0.001, respectively) (Fig.	('correlated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('High', 'Var', (0, 4))	('cutaneous melanoma', 'Disease', (121, 139))	('primary tumor', 'Disease', (45, 58))	('cancer', 'Disease', (160, 166))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (121, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (121, 139))	('ALCAM', 'Gene', '214', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('primary tumor', 'Disease', 'MESH:D009369', (45, 58))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (25, 31))	('ALCAM', 'Gene', (5, 10))
28276	26134500	We demonstrate that high ALCAM expression in primary tumor cancer cells (IRS >=8) is strongly correlated with unfavorable prognosis as compared with patients with lower ALCAM immunoreactivity in tumor compartment as regards cancer specific overall survival (CSOS) (P = 0.001) and disease free survival (DFS) (P < 0.001).	('tumor', 'Disease', (195, 200))	('primary tumor', 'Disease', (45, 58))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor cancer', 'Disease', 'MESH:D009369', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('CSOS', 'Chemical', '-', (258, 262))	('cancer', 'Disease', (224, 230))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('disease free survival', 'CPA', (280, 301))	('ALCAM', 'Gene', '214', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('lower ALCAM', 'Phenotype', 'HP:0003282', (163, 174))	('ALCAM', 'Gene', '214', (25, 30))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('ALCAM', 'Gene', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('overall survival', 'CPA', (240, 256))	('correlated', 'Reg', (94, 104))	('primary tumor', 'Disease', 'MESH:D009369', (45, 58))	('ALCAM', 'Gene', (25, 30))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', (59, 65))	('tumor cancer', 'Disease', (53, 65))
28307	25953768	Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (269, 277))	('Notch', 'Gene', '4851', (124, 129))	('Notch', 'Gene', (124, 129))	('MAML2', 'Gene', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('promote', 'PosReg', (207, 214))	('NCSTN', 'Gene', (50, 55))	('growth', 'CPA', (215, 221))	('MAML2', 'Gene', '84441', (61, 66))	('Patients', 'Species', '9606', (87, 95))	('NCOR2', 'Gene', (43, 48))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (101, 119))	('melanoma', 'Disease', (269, 277))	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('Melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('NCSTN', 'Gene', '23385', (50, 55))	('Notch', 'Gene', '4851', (23, 28))	('NCOR2', 'Gene', '9612', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('Notch', 'Gene', (23, 28))	('cutaneous melanoma', 'Disease', (185, 203))	('human', 'Species', '9606', (179, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (185, 203))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (185, 203))	('Variants', 'Var', (11, 19))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('124', '147'))	('Cutaneous Melanoma', 'Disease', (101, 119))
28308	25953768	Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients.	('cutaneous melanoma', 'Disease', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('affect', 'Reg', (55, 61))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('Notch', 'Gene', '4851', (31, 36))	('patients', 'Species', '9606', (98, 106))	('Notch', 'Gene', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('genetic variants', 'Var', (11, 27))	('prognosis', 'CPA', (66, 75))
28309	25953768	We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset.	('Notch', 'Gene', '4851', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('SNPs', 'Var', (20, 24))	('Notch', 'Gene', (31, 36))	('cutaneous melanoma', 'Disease', (50, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('patients', 'Species', '9606', (69, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))	('cutaneous melanoma', 'Disease', (113, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 131))
28311	25953768	Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('cutaneous melanoma', 'Disease', (111, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 129))	('SNPs', 'Var', (25, 29))	('patients', 'Species', '9606', (130, 138))	('Notch', 'Gene', '4851', (33, 38))	('Notch', 'Gene', (33, 38))
28312	25953768	The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73-4.23; Ptrend = 9.62 x 10-7), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively).	('rs7953425', 'Mutation', 'rs7953425', (197, 206))	('NCOR2', 'Gene', (165, 170))	('NCOR2', 'Gene', '9612', (33, 38))	('rs1124379 G>A', 'Var', (150, 163))	('rs10846684', 'Mutation', 'rs10846684', (171, 181))	('rs2342924', 'Mutation', 'rs2342924', (39, 48))	('MAML2', 'Gene', '84441', (191, 196))	('rs2342924 T>C', 'Var', (39, 52))	('rs10846684 G>A', 'Var', (171, 185))	('rs1124379', 'Mutation', 'rs1124379', (150, 159))	('rs7953425 G>A', 'Var', (197, 210))	('NCOR2', 'Gene', '9612', (165, 170))	('MAML2', 'Gene', (191, 196))	('NCSTN', 'Gene', (144, 149))	('NCSTN', 'Gene', '23385', (144, 149))	('NCOR2', 'Gene', (33, 38))
28313	25953768	Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival.	('cutaneous melanoma disease', 'Disease', (74, 100))	('cutaneous melanoma disease', 'Disease', 'MESH:C562393', (74, 100))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('SNPs', 'Var', (25, 29))	('Notch', 'Gene', '4851', (33, 38))	('Notch', 'Gene', (33, 38))	('predictors', 'Reg', (60, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))
28314	25953768	Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients.	('Notch', 'Gene', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('genetic variants', 'Var', (57, 73))	('patients', 'Species', '9606', (230, 238))	('cutaneous melanoma', 'Disease', (211, 229))	('Notch', 'Gene', '4851', (77, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (211, 229))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (211, 229))
28318	25953768	Considering the diversity of genetic and epigenetic factors involved in the origin and progress of cutaneous melanoma, it is very likely that SNPs in other developmental and oncogenic pathways may contribute to the variation in treatment outcomes of cutaneous melanoma patients and thus affect the survival of cutaneous melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (320, 328))	('contribute', 'Reg', (197, 207))	('cutaneous melanoma', 'Disease', (310, 328))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (310, 328))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (310, 328))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('affect', 'Reg', (287, 293))	('patients', 'Species', '9606', (269, 277))	('cutaneous melanoma', 'Disease', (250, 268))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('patients', 'Species', '9606', (329, 337))	('cutaneous melanoma', 'Disease', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (250, 268))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (250, 268))	('SNPs', 'Var', (142, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
28325	25953768	Thus, we took a pathway-based multigene approach to identify putatively functional SNPs in genes involved in the Notch pathway and examined their associations with survival of cutaneous melanoma patients by using the available genotyping data from a previously published GWAS study of cutaneous melanoma.	('Notch', 'Gene', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('cutaneous melanoma', 'Disease', (176, 194))	('cutaneous melanoma', 'Disease', (285, 303))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (285, 303))	('associations', 'Interaction', (146, 158))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (285, 303))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('patients', 'Species', '9606', (195, 203))	('SNPs', 'Var', (83, 87))	('Notch', 'Gene', '4851', (113, 118))
28347	25953768	Kaplan-Meier survival curves and log-rank tests were used to evaluate the effects of genetic variants on the cumulative probability of DSS and overall survival (OS).	('OS', 'Chemical', '-', (161, 163))	('DSS', 'Gene', (135, 138))	('DSS', 'Gene', '5376', (135, 138))	('variants', 'Var', (93, 101))	('overall survival', 'CPA', (143, 159))
28349	25953768	We first performed multivariate Cox models to assess the associations of 4,949 SNPs (Supplementary Table S1) of the Notch pathway genes with DSS in the presence of age, sex, tumor stage, Breslow thickness, SLNB, Clark level, ulceration of tumor, and tumor cell mitotic rate.	('Cox', 'Gene', (32, 35))	('Notch', 'Gene', (116, 121))	('Clark', 'MPA', (212, 217))	('SLNB', 'MPA', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('ulceration of tumor', 'Disease', 'MESH:D014456', (225, 244))	('tumor', 'Disease', (239, 244))	('associations', 'Interaction', (57, 69))	('ulceration of tumor', 'Disease', (225, 244))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('DSS', 'Gene', (141, 144))	('Cox', 'Gene', '1351', (32, 35))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Notch', 'Gene', '4851', (116, 121))	('SNPs', 'Var', (79, 83))	('DSS', 'Gene', '5376', (141, 144))
28353	25953768	When we applied the 13 significant SNPs in RegulomeDB, four were predicted to be putatively functional, including two NOCR2 SNPs (rs2342924 T>C and rs10846684 G>A), one NCSTN SNP (rs1124379 G>A), and one MAML2 SNP (rs79453425 G>A).	('NCSTN', 'Gene', '23385', (169, 174))	('rs79453425', 'Mutation', 'rs79453425', (215, 225))	('rs1124379', 'Mutation', 'rs1124379', (180, 189))	('rs10846684 G>A', 'Var', (148, 162))	('NCSTN', 'Gene', (169, 174))	('rs2342924', 'Mutation', 'rs2342924', (130, 139))	('rs2342924 T>C', 'Var', (130, 143))	('rs10846684', 'Mutation', 'rs10846684', (148, 158))	('MAML2', 'Gene', '84441', (204, 209))	('MAML2', 'Gene', (204, 209))	('rs79453425 G>A', 'Var', (215, 229))	('rs1124379 G>A', 'Var', (180, 193))
28357	25953768	The associations of NCOR2 rs2342924C and rs10846684A, NCSTN rs1124379A, and MAML2 rs79453425A with DSS were statistically significant in a trend test (P = 9.62E-07, 0.005, 0.005, and 0.013, respectively; Table 1).	('NCOR2', 'Gene', (20, 25))	('rs10846684', 'Mutation', 'rs10846684', (41, 51))	('DSS', 'Gene', (99, 102))	('rs79453425', 'Mutation', 'rs79453425', (82, 92))	('NCSTN', 'Gene', '23385', (54, 59))	('DSS', 'Gene', '5376', (99, 102))	('NCSTN', 'Gene', (54, 59))	('rs1124379A', 'Var', (60, 70))	('MAML2', 'Gene', (76, 81))	('rs2342924', 'Mutation', 'rs2342924', (26, 35))	('significant', 'Reg', (122, 133))	('NCOR2', 'Gene', '9612', (20, 25))	('MAML2', 'Gene', '84441', (76, 81))	('rs79453425A', 'Var', (82, 93))	('rs10846684A', 'Var', (41, 52))	('rs2342924C', 'Var', (26, 36))	('associations', 'Interaction', (4, 16))	('rs1124379', 'Mutation', 'rs1124379', (60, 69))
28358	25953768	Compared with their homozygous genotypes, these unfavorable (variant) genotypes in a dominant genetic model were significantly associated with a poor DSS [HR, 2.71, 95% confidence interval (95% CI), 1.73-4.23, and P = 1.28E-05 for rs2342924 CC+CT; 1.64, 1.07-2.51, and 0.022 for rs10846684 AA+AG; 2.36, 1.28-4.36 and 0.006 for rs1124379 AG+GG; and 1.77, 1.09-2.89, and 0.021 for rs79453425 AA+AG; Table 1].	('rs10846684 AA+AG', 'Var', (279, 295))	('rs1124379', 'Mutation', 'rs1124379', (327, 336))	('rs2342924 CC+CT', 'Var', (231, 246))	('rs2342924', 'Mutation', 'rs2342924', (231, 240))	('rs10846684', 'Mutation', 'rs10846684', (279, 289))	('DSS', 'Gene', (150, 153))	('DSS', 'Gene', '5376', (150, 153))	('rs79453425', 'Mutation', 'rs79453425', (379, 389))	('rs79453425 AA+AG', 'Var', (379, 395))	('rs1124379 AG+GG', 'Var', (327, 342))
28362	25953768	To better estimate the joint effect of the four SNPs on patients' clinic outcomes, we assessed the DSS associated with the combined unfavorable genotypes (a genotype score under a dominant genetic model) of rs2342924 CC+CT, rs10846684 AA+AG, rs1124379 AG+GG (this was under a recessive model), and rs79453425 AA+AG.	('patients', 'Species', '9606', (56, 64))	('rs1124379 AG+GG', 'Var', (242, 257))	('rs2342924 CC+CT', 'Var', (207, 222))	('rs79453425 AA+AG', 'Var', (298, 314))	('rs79453425', 'Mutation', 'rs79453425', (298, 308))	('rs2342924', 'Mutation', 'rs2342924', (207, 216))	('DSS', 'Gene', (99, 102))	('rs10846684', 'Mutation', 'rs10846684', (224, 234))	('rs1124379', 'Mutation', 'rs1124379', (242, 251))	('DSS', 'Gene', '5376', (99, 102))	('rs10846684 AA+AG', 'Var', (224, 240))
28375	25953768	Such expression data are available for NCOR2 rs2342924 and rs10846684, and NCSTN rs1124379 but not for MAML2 rs79453425.	('NCOR2', 'Gene', '9612', (39, 44))	('rs2342924', 'Var', (45, 54))	('rs79453425', 'Mutation', 'rs79453425', (109, 119))	('NCSTN', 'Gene', '23385', (75, 80))	('rs10846684', 'Mutation', 'rs10846684', (59, 69))	('MAML2', 'Gene', '84441', (103, 108))	('MAML2', 'Gene', (103, 108))	('NCSTN', 'Gene', (75, 80))	('rs1124379', 'Mutation', 'rs1124379', (81, 90))	('rs10846684', 'Var', (59, 69))	('rs2342924', 'Mutation', 'rs2342924', (45, 54))	('rs1124379', 'Var', (81, 90))	('NCOR2', 'Gene', (39, 44))
28376	25953768	4, the rs2342924C allele was associated with significantly lower levels of mRNA expression of NCOR2 (P = 0.044), but such a genotype-phenotype correlation was not evident for rs10846684 and rs1124379.	('levels', 'MPA', (65, 71))	('mRNA expression', 'MPA', (75, 90))	('NCOR2', 'Gene', '9612', (94, 99))	('rs2342924C', 'Var', (7, 17))	('rs1124379', 'Mutation', 'rs1124379', (190, 199))	('lower', 'NegReg', (59, 64))	('NCOR2', 'Gene', (94, 99))	('rs2342924', 'Mutation', 'rs2342924', (7, 16))	('rs10846684', 'Mutation', 'rs10846684', (175, 185))
28377	25953768	In the present study, we comprehensively investigated the predictive role of putatively functional variants in the Notch pathway genes in cutaneous melanoma DSS using the published GWAS dataset.	('cutaneous melanoma DSS', 'Disease', 'MESH:D015417', (138, 160))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('variants', 'Var', (99, 107))	('Notch', 'Gene', '4851', (115, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (138, 156))	('Notch', 'Gene', (115, 120))	('cutaneous melanoma DSS', 'Disease', (138, 160))
28378	25953768	We found that NCOR2 rs2342924 T>C, rs10846684 G>A, NCSTN rs1124379 G>A, and MAML2 rs79453425 G>A independently or jointly modulated survival of cutaneous melanoma patients.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('rs10846684', 'Mutation', 'rs10846684', (35, 45))	('NCOR2', 'Gene', (14, 19))	('rs1124379', 'Mutation', 'rs1124379', (57, 66))	('modulated', 'Reg', (122, 131))	('rs2342924', 'Mutation', 'rs2342924', (20, 29))	('rs2342924 T>C', 'Var', (20, 33))	('NCOR2', 'Gene', '9612', (14, 19))	('rs79453425 G>A', 'Var', (82, 96))	('NCSTN', 'Gene', (51, 56))	('rs79453425', 'Mutation', 'rs79453425', (82, 92))	('MAML2', 'Gene', (76, 81))	('NCSTN', 'Gene', '23385', (51, 56))	('patients', 'Species', '9606', (163, 171))	('rs10846684 G>A', 'Var', (35, 49))	('MAML2', 'Gene', '84441', (76, 81))	('rs1124379 G>A', 'Var', (57, 70))	('survival', 'MPA', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('cutaneous melanoma', 'Disease', (144, 162))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
28383	25953768	However, no study has reported a role of genetic variants of Notch pathway genes in predicting clinical outcomes of cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('genetic variants', 'Var', (41, 57))	('clinical', 'Species', '191496', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Notch', 'Gene', '4851', (61, 66))	('Notch', 'Gene', (61, 66))
28384	25953768	In the present study, three putatively functional SNPs of Notch coregulators were found to be significantly associated with cutaneous melanoma DSS and OS.	('cutaneous melanoma DSS', 'Disease', (124, 146))	('SNPs', 'Var', (50, 54))	('OS', 'Chemical', '-', (151, 153))	('Notch', 'Gene', (58, 63))	('cutaneous melanoma DSS', 'Disease', 'MESH:D015417', (124, 146))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('associated', 'Reg', (108, 118))	('Notch', 'Gene', '4851', (58, 63))
28385	25953768	Specifically, carriers of the NOCR2 rs2342924T and rs10846684G and MAML2 rs79453425G variant genotypes had a better DSS, compared with those with CC, AA, and AA homozygous genotypes, respectively.	('MAML2', 'Gene', '84441', (67, 72))	('rs10846684G', 'Var', (51, 62))	('rs2342924T', 'Var', (36, 46))	('rs10846684', 'Mutation', 'rs10846684', (51, 61))	('rs2342924', 'Mutation', 'rs2342924', (36, 45))	('DSS', 'Gene', (116, 119))	('DSS', 'Gene', '5376', (116, 119))	('rs79453425', 'Mutation', 'rs79453425', (73, 83))	('MAML2', 'Gene', (67, 72))	('rs79453425G', 'Var', (73, 84))	('NOCR2', 'Gene', (30, 35))	('better', 'PosReg', (109, 115))
28386	25953768	Among these three SNPs, rs10846684 and rs2342924 are located at the first and third introns of NCOR2, respectively, whereas rs79453425 is located at the second intron of MAML2.	('NCOR2', 'Gene', (95, 100))	('rs2342924', 'Mutation', 'rs2342924', (39, 48))	('MAML2', 'Gene', '84441', (170, 175))	('MAML2', 'Gene', (170, 175))	('rs79453425', 'Var', (124, 134))	('rs10846684', 'Var', (24, 34))	('NCOR2', 'Gene', '9612', (95, 100))	('rs79453425', 'Mutation', 'rs79453425', (124, 134))	('rs2342924', 'Var', (39, 48))	('rs10846684', 'Mutation', 'rs10846684', (24, 34))
28387	25953768	The online prediction tool RegulomeDB for analysis of DNase-seq showed that rs2342924, rs10846684, and rs79453425 are located in the DNase I hypersensitive sites, which represent open and active chromatins.	('hypersensitive', 'Disease', 'MESH:D004342', (141, 155))	('rs2342924', 'Mutation', 'rs2342924', (76, 85))	('hypersensitive', 'Disease', (141, 155))	('rs10846684', 'Mutation', 'rs10846684', (87, 97))	('DNase I', 'molecular_function', 'GO:0004530', ('133', '140'))	('rs79453425', 'Mutation', 'rs79453425', (103, 113))	('rs2342924', 'Var', (76, 85))	('rs79453425', 'Var', (103, 113))	('rs10846684', 'Var', (87, 97))
28388	25953768	By searching a published expression data containing 270 HapMap of lymphoblastoid cell lines derived from diverse populations, we found that the unfavorable CC+TT genotypes of rs2342924 were shown to be associated with lower mRNA expression levels of NCOR2.	('rs2342924', 'Var', (175, 184))	('NCOR2', 'Gene', (250, 255))	('NCOR2', 'Gene', '9612', (250, 255))	('rs2342924', 'Mutation', 'rs2342924', (175, 184))	('mRNA expression levels', 'MPA', (224, 246))	('lower', 'NegReg', (218, 223))
28389	25953768	This genotype-phenotype correlation also provides additional biologic evidence that NCOR2 expression may be mediated by this putatively functional SNP rs2342924, a possible explanation for the observed association with cutaneous melanoma DSS.	('mediated by', 'Reg', (108, 119))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('NCOR2', 'Gene', '9612', (84, 89))	('rs2342924', 'Var', (151, 160))	('expression', 'MPA', (90, 100))	('cutaneous melanoma DSS', 'Disease', (219, 241))	('NCOR2', 'Gene', (84, 89))	('rs2342924', 'Mutation', 'rs2342924', (151, 160))	('cutaneous melanoma DSS', 'Disease', 'MESH:D015417', (219, 241))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (219, 237))
28392	25953768	Mechanistic studies have shown that recruitment of NCOR2 can downregulate the IL6-mediated cancer cell growth and gene expression by transcriptionally inactivating STAT3, whereas silencing NCOR2 could lead to cell circle progression.	('NCOR2', 'Gene', (189, 194))	('inactivating', 'NegReg', (151, 163))	('cell circle progression', 'CPA', (209, 232))	('NCOR2', 'Gene', '9612', (189, 194))	('downregulate', 'NegReg', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('silencing', 'Var', (179, 188))	('cell growth', 'biological_process', 'GO:0016049', ('98', '109'))	('IL6', 'Gene', '3569', (78, 81))	('lead to', 'Reg', (201, 208))	('STAT3', 'Gene', (164, 169))	('NCOR2', 'Gene', (51, 56))	('recruitment', 'Var', (36, 47))	('STAT3', 'Gene', '6774', (164, 169))	('IL6', 'molecular_function', 'GO:0005138', ('78', '81'))	('NCOR2', 'Gene', '9612', (51, 56))	('IL6', 'Gene', (78, 81))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gene expression', 'biological_process', 'GO:0010467', ('114', '129'))
28395	25953768	The oncogenic role of MAML2 was first described in mucoepidermoid carcinoma, in which translocation of MAML2 in mucoepidermoid carcinoma will create a fusion oncogene mucoepidermoid carcinoma translocated 1 (MECT1):MAML2 that is involved in disrupting the normal cell cycle, differentiation, and tumor development.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('translocation', 'Var', (86, 99))	('MAML2', 'Gene', '84441', (103, 108))	('mucoepidermoid carcinoma', 'Disease', (51, 75))	('cell cycle', 'CPA', (263, 273))	('MAML2', 'Gene', (22, 27))	('MAML2', 'Gene', '84441', (215, 220))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (51, 75))	('tumor', 'Disease', (296, 301))	('MECT1', 'Gene', '23373', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('MAML2', 'Gene', '84441', (22, 27))	('mucoepidermoid carcinoma', 'Disease', (112, 136))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (112, 136))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (167, 191))	('MECT1', 'Gene', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cell cycle', 'biological_process', 'GO:0007049', ('263', '273'))	('MAML2', 'Gene', (103, 108))	('mucoepidermoid carcinoma translocated 1', 'Gene', '23373', (167, 206))	('mucoepidermoid carcinoma translocated 1', 'Gene', (167, 206))	('MAML2', 'Gene', (215, 220))
28400	25953768	The other SNP associated with DSS of cutaneous melanoma patients in the Notch pathway was NCSTN rs1124379, located in intron 7 of the gene.	('NCSTN', 'Gene', '23385', (90, 95))	('patients', 'Species', '9606', (56, 64))	('DSS', 'Gene', (30, 33))	('Notch', 'Gene', '4851', (72, 77))	('NCSTN', 'Gene', (90, 95))	('rs1124379', 'Var', (96, 105))	('associated', 'Reg', (14, 24))	('Notch', 'Gene', (72, 77))	('DSS', 'Gene', '5376', (30, 33))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('cutaneous melanoma', 'Disease', (37, 55))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (37, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (37, 55))	('rs1124379', 'Mutation', 'rs1124379', (96, 105))
28401	25953768	Carriers of rs1124379 A variant allele had a better DSS compared with those GG homozygotes in cutaneous melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('DSS', 'Gene', '5376', (52, 55))	('cutaneous melanoma', 'Disease', (94, 112))	('better', 'PosReg', (45, 51))	('patients', 'Species', '9606', (113, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('rs1124379', 'Mutation', 'rs1124379', (12, 21))	('rs1124379 A', 'Var', (12, 23))	('DSS', 'Gene', (52, 55))
28402	25953768	ChIP-seq data on RegulomeDB suggested that rs1124379 may influence the binding activity of transcriptional factor RFX5, as the SNP is located in its binding sites.	('binding', 'molecular_function', 'GO:0005488', ('149', '156'))	('influence', 'Reg', (57, 66))	('RFX5', 'Gene', (114, 118))	('rs1124379', 'Mutation', 'rs1124379', (43, 52))	('RFX5', 'Gene', '5993', (114, 118))	('binding', 'Interaction', (71, 78))	('rs1124379', 'Var', (43, 52))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
28411	25953768	In fact, through stratified analyses, we found that the genotype-survival association was more pronounced in the presence of clinicopathologic risk factors, such as late tumor stage, presence of ulceration and positive SLNB.	('SLNB', 'Gene', (219, 223))	('ulceration', 'Disease', (195, 205))	('late tumor', 'Disease', (165, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('positive', 'Var', (210, 218))	('late tumor', 'Disease', 'MESH:D009369', (165, 175))
28412	25953768	These results suggest that these SNPs in the Notch pathway may aggregate the existing genomic instability of highly malignant melanoma, promoting melanoma development, and progression in the high-risk populations.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('SNPs', 'Var', (33, 37))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('Notch', 'Gene', '4851', (45, 50))	('Notch', 'Gene', (45, 50))	('promoting', 'PosReg', (136, 145))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('malignant melanoma', 'Phenotype', 'HP:0002861', (116, 134))
28426	33392203	Moreover, we ran CMap analysis to select a list of small molecule drugs for SKCM, such as EGFR inhibitor AG-490, growth factor receptor inhibitor GW-441756 and apoptosis stimulant betulinic-acid, which have shown therapeutic effect in the treatment of melanoma.	('betulinic-acid', 'Chemical', 'MESH:C002070', (180, 194))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('GW-441756', 'Var', (146, 155))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('GW-441756', 'Chemical', 'MESH:C000606649', (146, 155))	('EGFR', 'Gene', '1956', (90, 94))	('AG-490', 'Chemical', 'MESH:C095512', (105, 111))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('90', '94'))	('melanoma', 'Disease', (252, 260))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('EGFR', 'Gene', (90, 94))
28435	33392203	Mutations in the CDKN2A gene are the most common alteration in hereditary melanoma (Aoude et al.,).	('hereditary melanoma', 'Disease', (63, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('CDKN2A', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', '1029', (17, 23))	('hereditary melanoma', 'Disease', 'MESH:D008545', (63, 82))	('common', 'Reg', (42, 48))
28451	33392203	Transcription of lncRNA may influence local chromatin states and transcription factor (TF) binding on promoter and enhancer regions (Kopp and Mendell,).	('ncRNA', 'Gene', '54719', (18, 23))	('chromatin', 'cellular_component', 'GO:0000785', ('44', '53'))	('Transcription', 'Var', (0, 13))	('TF) binding', 'molecular_function', 'GO:0008134', ('87', '98'))	('binding', 'Interaction', (91, 98))	('influence', 'Reg', (28, 37))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('transcription factor', 'molecular_function', 'GO:0000981', ('65', '85'))	('ncRNA', 'Gene', (18, 23))	('local chromatin states', 'MPA', (38, 60))
28455	33392203	In this paper, we set about to investigate the interactions between aberrantly expressed lncRNA and mRNA to uncover their regulation functions in SKCM.	('SKCM', 'Disease', (146, 150))	('regulation', 'biological_process', 'GO:0065007', ('122', '132'))	('ncRNA', 'Gene', '54719', (90, 95))	('aberrantly expressed', 'Var', (68, 88))	('ncRNA', 'Gene', (90, 95))
28489	33392203	Another weighted gene co-expression network analysis show that the PI3K subunit PI3KCD exhibited excellent efficacy for diagnosing primary and metastatic tumor tissue (Wang et al.,).	('PI3K', 'molecular_function', 'GO:0016303', ('67', '71'))	('PI3KCD', 'Var', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
28499	33392203	FGD1 has been verified that it plays a direct role in the proliferation or invasion of melanoma cells (Hou et al.,), thereby the patients with high FGD1 expression frequently showed worse prognosis (Zeng et al.,).	('melanoma', 'Disease', (87, 95))	('FGD1', 'Gene', '2245', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('invasion', 'CPA', (75, 83))	('patients', 'Species', '9606', (129, 137))	('high', 'Var', (143, 147))	('FGD1', 'Gene', (0, 4))	('FGD1', 'Gene', '2245', (148, 152))	('FGD1', 'Gene', (148, 152))	('expression', 'MPA', (153, 163))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
28507	33392203	The expression levels of CD52, CD53, and LAPTM5 are positively correlated with the survival rate, while DSC3 is correlated with adverse prognosis.	('correlated', 'Reg', (63, 73))	('survival rate', 'CPA', (83, 96))	('DSC3', 'Gene', (104, 108))	('DSC3', 'Gene', '1825', (104, 108))	('LAPTM5', 'Gene', '7805', (41, 47))	('expression', 'MPA', (4, 14))	('LAPTM5', 'Gene', (41, 47))	('CD53', 'Var', (31, 35))	('CD52', 'Var', (25, 29))
28512	33392203	Inhibition of FOXD2-AS1 can suppress cutaneous melanoma cell proliferation, migration and invasion through regulating phospho-Akt expression (Ren et al.,).	('suppress', 'NegReg', (28, 36))	('FOXD2', 'Gene', '2306', (14, 19))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('Ren', 'Gene', (142, 145))	('Akt', 'Gene', '207', (126, 129))	('FOXD2', 'Gene', (14, 19))	('regulating', 'Reg', (107, 117))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('cutaneous melanoma', 'Disease', (37, 55))	('Inhibition', 'Var', (0, 10))	('Ren', 'Gene', '5972', (142, 145))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (37, 55))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (37, 55))	('AS1', 'Gene', '5729', (20, 23))	('AS1', 'Gene', (20, 23))	('Akt', 'Gene', (126, 129))	('invasion', 'CPA', (90, 98))
28524	33392203	Also, previous studies have shown that some of the deregulated mRNAs are involved in melanoma.	('mRNAs', 'MPA', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('involved', 'Reg', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('deregulated', 'Var', (51, 62))
28542	33392203	have revealed that melanoma cell proliferation, migration and invasion can be suppressed by the inhibition of FOXD2-AS1 that regulates phospho-Akt expression in cutaneous melanoma.	('migration', 'CPA', (48, 57))	('cutaneous melanoma', 'Disease', (161, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('expression', 'MPA', (147, 157))	('Akt', 'Gene', '207', (143, 146))	('FOXD2', 'Gene', '2306', (110, 115))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('invasion', 'CPA', (62, 70))	('AS1', 'Gene', '5729', (116, 119))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('inhibition', 'Var', (96, 106))	('AS1', 'Gene', (116, 119))	('FOXD2', 'Gene', (110, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('suppressed', 'NegReg', (78, 88))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('Akt', 'Gene', (143, 146))	('regulates', 'Reg', (125, 134))
28545	33392203	have verified that knockdown of MALAT1 can attenuate the migrational ability of melanoma cells via in vitro studies as early as 2014, indicating the correlation between MALAT1 and melanoma metastasis (Tian et al.,).	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('knockdown', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('MALAT1', 'Gene', '378938', (32, 38))	('MALAT1', 'Gene', '378938', (169, 175))	('correlation', 'Interaction', (149, 160))	('melanoma metastasis', 'Disease', (180, 199))	('MALAT1', 'Gene', (169, 175))	('melanoma metastasis', 'Disease', 'MESH:D009362', (180, 199))	('MALAT1', 'Gene', (32, 38))	('attenuate', 'NegReg', (43, 52))
28554	33392203	For instance, EGFR inhibitor AG-490 can effectively suppress tumor cell proliferation by limiting the expression of cyclin D1 (Kamran et al.,).	('limiting', 'NegReg', (89, 97))	('EGFR', 'Gene', '1956', (14, 18))	('suppress', 'NegReg', (52, 60))	('EGFR', 'Gene', (14, 18))	('AG-490', 'Chemical', 'MESH:C095512', (29, 35))	('expression', 'MPA', (102, 112))	('cyclin', 'molecular_function', 'GO:0016538', ('116', '122'))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cyclin D1', 'Gene', '595', (116, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cyclin D1', 'Gene', (116, 125))	('tumor', 'Disease', (61, 66))	('AG-490', 'Var', (29, 35))
28561	33392203	The functional and pathway annotations demonstrate that the aberrantly expressed genes participate in melanoma-related biological processes, such as epidermis and skin development, keratinocyte differentiation, and cornification.	('participate', 'Reg', (87, 98))	('keratinocyte differentiation', 'biological_process', 'GO:0030216', ('181', '209'))	('skin development', 'biological_process', 'GO:0043588', ('163', '179'))	('skin development', 'CPA', (163, 179))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('keratinocyte differentiation', 'CPA', (181, 209))	('aberrantly expressed genes', 'Var', (60, 86))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('cornification', 'CPA', (215, 228))	('cornification', 'biological_process', 'GO:0070268', ('215', '228'))
28639	31797612	GO:0048020 and GO:0008009 are associated with chemokines, which are implicated in glioblastoma development.	('associated', 'Reg', (30, 40))	('GO:0048020', 'Var', (0, 10))	('chemokines', 'Gene', (46, 56))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('GO:0008009', 'Var', (15, 25))
28656	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
28663	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('signaling', 'biological_process', 'GO:0023052', ('189', '198'))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
28703	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
28721	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
28773	25995384	Genetic alterations, such as recurrent chromosomal alterations, can be primary causes for many human cancers.	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('chromosomal alterations', 'Var', (39, 62))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('causes', 'Reg', (79, 85))
28774	25995384	Chromosomal focal amplifications or deletions often produce copy number variation (CNV) of genes, which may contribute to tumor progression.	('produce', 'Reg', (52, 59))	('deletions', 'Var', (36, 45))	('genes', 'Gene', (91, 96))	('copy number variation', 'MPA', (60, 81))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('contribute', 'Reg', (108, 118))
28775	25995384	These chromosomal alterations can lead to deregulation of gene structure, function, and expression that functionally contribute to the pathogenesis of cancer.	('chromosomal alterations', 'Var', (6, 29))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pathogenesis', 'biological_process', 'GO:0009405', ('135', '147'))	('expression', 'MPA', (88, 98))	('cancer', 'Disease', (151, 157))	('gene structure', 'MPA', (58, 72))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('contribute', 'Reg', (117, 127))	('function', 'MPA', (74, 82))	('deregulation', 'MPA', (42, 54))
28776	25995384	A recent study by The Cancer Genome Atlas (TCGA) Pan-Cancer Analysis Working Group performed an integrative analysis of somatic copy number alterations across 12 tumor types and provided a public resource of highly curated data and information.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Cancer Genome Atlas', 'Disease', (22, 41))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', (162, 167))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (22, 41))	('copy number alterations', 'Var', (128, 151))	('Cancer', 'Disease', (53, 59))
28780	25995384	ZBTB7A binding sites in human MCAM promoter region were mutated with Q5  Site-Directed Mutagenesis Kit (New England Biolabs).	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('human', 'Species', '9606', (24, 29))	('Mutagenesis', 'biological_process', 'GO:0006280', ('87', '98'))	('mutated', 'Var', (56, 63))	('ZBTB7A', 'Gene', (0, 6))
28797	25995384	Consistent with the close association of metastasis with mortality, data derived from TCGA Skin Cutaneous Melanoma datasets reveal that decreased chromosome 19p13.3 copy number correlates with poor prognoses in melanoma patients (Fig.	('Skin Cutaneous Melanoma', 'Disease', (91, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('146', '156'))	('chromosome', 'Gene', (146, 156))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('copy number', 'Var', (165, 176))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (91, 114))	('patients', 'Species', '9606', (220, 228))	('Melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('decreased', 'NegReg', (136, 145))
28817	25995384	We observed that cell lines with low levels of ZBTB7A (A375, SK-Mel-2, UACC62 and UACC257) express approximately 20 fold more MCAM mRNA than cells with high ZBTB7A expression levels (1205Lu, Lox-IM VI, MeWo and WM155) (Fig.	('ZBTB7A', 'Gene', (47, 53))	('Lox', 'Gene', (191, 194))	('1205Lu', 'Var', (183, 189))	('A375', 'CellLine', 'CVCL:0132', (55, 59))	('MCAM mRNA', 'MPA', (126, 135))	('Lox', 'Gene', '4015', (191, 194))	('UACC62', 'Chemical', '-', (71, 77))	('more', 'PosReg', (121, 125))
28820	25995384	ZBTB7A knockdown was associated with a robust induction of the expression of MCAM at both protein and mRNA levels in all 4 melanoma cell lines (Fig.	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('MCAM', 'Gene', (77, 81))	('expression', 'MPA', (63, 73))	('ZBTB7A', 'Gene', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('induction', 'PosReg', (46, 55))	('knockdown', 'Var', (7, 16))
28823	25995384	Immunohistochemical staining of tumor sections derived from implanted cells confirmed that knockdown of ZBTB7A was associated with a robust increase in MCAM expression (Fig.	('MCAM expression', 'MPA', (152, 167))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('knockdown', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ZBTB7A', 'Gene', (104, 110))	('increase', 'PosReg', (140, 148))	('tumor', 'Disease', (32, 37))
28829	25995384	Indeed, unlike its wild type counterpart, ZBTB7A (R399L) failed to repress the expression of MCAM, as shown in the luciferase-based assay (Fig.	('R399L', 'Mutation', 'p.R399L', (50, 55))	('R399L', 'Var', (50, 55))	('MCAM', 'Gene', (93, 97))
28834	25995384	Two melanoma cell lines, M14 and UACC62 that express relatively low and high levels of MCAM respectively, were used to experimentally test the effects of ZBTB7A knockdown or overexpression.	('ZBTB7A', 'Gene', (154, 160))	('UACC62', 'Chemical', '-', (33, 39))	('knockdown', 'Var', (161, 170))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
28838	25995384	The results indicate that ZBTB7A knockdown stimulated cell invasion and this effect of ZBTB7A-deficiency was mitigated by the use of the anti-MCAM antibody.	('ZBTB7A', 'Gene', (26, 32))	('antibody', 'molecular_function', 'GO:0003823', ('147', '155'))	('stimulated', 'PosReg', (43, 53))	('knockdown', 'Var', (33, 42))	('ZBTB7A-deficiency', 'Disease', (87, 104))	('ZBTB7A-deficiency', 'Disease', 'MESH:D007153', (87, 104))	('antibody', 'cellular_component', 'GO:0042571', ('147', '155'))	('antibody', 'cellular_component', 'GO:0019815', ('147', '155'))	('cell invasion', 'CPA', (54, 67))	('antibody', 'cellular_component', 'GO:0019814', ('147', '155'))
28840	25995384	When compared to control shRNA expressing M14 cells, the shZBTB7A expressing melanoma cells developed much more lung metastasis, which was completely diminished by MCAM knockdown (Fig.	('shZBTB7A', 'Chemical', '-', (57, 65))	('diminished', 'NegReg', (150, 160))	('knockdown', 'Var', (169, 178))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('lung metastasis', 'Disease', (112, 127))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('MCAM', 'Gene', (164, 168))	('lung metastasis', 'Disease', 'MESH:D009362', (112, 127))
28858	25995384	MCAM, a critical regulator of melanoma metastasis and progression, was among the significantly up-regulated genes in ZBTB7A deficient cells.	('melanoma metastasis', 'Disease', 'MESH:D009362', (30, 49))	('ZBTB7A', 'Gene', (117, 123))	('up-regulated', 'PosReg', (95, 107))	('MCAM', 'Gene', (0, 4))	('melanoma metastasis', 'Disease', (30, 49))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('deficient', 'Var', (124, 133))
28867	25995384	Among the melanoma lines, MeWo harbors wild type BRAF, NRAS and PTEN; A375, Lox-IM VI, M14, SK-MEL-2, SK-MEL-5, WM155, and UACC257 have mutations in BRAF or NRAS, but wild type for PTEN; SK-MEL-28 and UACC62 have mutations in BRAF or NRAS, and homozygous or heterozygous loss of PTEN, representing more advanced stage of melanoma.	('melanoma lines', 'Disease', (10, 24))	('NRAS', 'Gene', '4893', (55, 59))	('melanoma', 'Disease', 'MESH:D008545', (321, 329))	('mutations', 'Var', (136, 145))	('PTEN', 'Gene', '5728', (181, 185))	('NRAS', 'Gene', '4893', (157, 161))	('SK-MEL-5', 'CellLine', 'CVCL:0527', (102, 110))	('Lox', 'Gene', '4015', (76, 79))	('NRAS', 'Gene', (55, 59))	('loss', 'NegReg', (271, 275))	('NRAS', 'Gene', '4893', (234, 238))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma lines', 'Disease', 'MESH:D008545', (10, 24))	('BRAF', 'Gene', (149, 153))	('PTEN', 'Gene', (279, 283))	('BRAF', 'Gene', '673', (149, 153))	('BRAF', 'Gene', '673', (226, 230))	('melanoma', 'Phenotype', 'HP:0002861', (321, 329))	('SK-MEL-28', 'Chemical', '-', (187, 196))	('melanoma', 'Disease', (321, 329))	('NRAS', 'Gene', (157, 161))	('BRAF', 'Gene', (226, 230))	('PTEN', 'Gene', (64, 68))	('Lox', 'Gene', (76, 79))	('PTEN', 'Gene', '5728', (279, 283))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (187, 195))	('UACC62', 'Chemical', '-', (201, 207))	('A375', 'CellLine', 'CVCL:0132', (70, 74))	('NRAS', 'Gene', (234, 238))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (92, 100))	('PTEN', 'Gene', '5728', (64, 68))	('BRAF', 'Gene', '673', (49, 53))	('PTEN', 'Gene', (181, 185))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('BRAF', 'Gene', (49, 53))	('melanoma', 'Disease', (10, 18))
28873	25995384	ZBTB7A underexpression in melanoma cells was associated with enhanced cell adhesion and invasion, both of which were completely blocked by the use of anti-MCAM antibody.	('enhanced', 'PosReg', (61, 69))	('invasion', 'CPA', (88, 96))	('cell adhesion', 'CPA', (70, 83))	('underexpression', 'Var', (7, 22))	('antibody', 'cellular_component', 'GO:0042571', ('160', '168'))	('ZBTB7A', 'Gene', (0, 6))	('antibody', 'cellular_component', 'GO:0019814', ('160', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('antibody', 'cellular_component', 'GO:0019815', ('160', '168'))	('melanoma', 'Disease', (26, 34))	('cell adhesion', 'biological_process', 'GO:0007155', ('70', '83'))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('antibody', 'molecular_function', 'GO:0003823', ('160', '168'))
28879	32290321	In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alter', 'Reg', (53, 58))	('dysfunctions', 'Var', (26, 38))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic modifications', 'Var', (94, 118))	('genetic', 'Var', (79, 86))	('expression', 'MPA', (65, 75))	('cancer', 'Disease', (3, 9))	('PRDM genes', 'Gene', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
28880	32290321	They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed.	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('alternative splicing', 'Var', (29, 49))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
28893	32290321	Some evidence suggests that PRDMs are involved in human malignancy through modulation of several processes such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('inflammation', 'Disease', (164, 176))	('inflammation', 'biological_process', 'GO:0006954', ('164', '176'))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('modulation', 'Reg', (75, 85))	('involved', 'Reg', (38, 46))	('PRDMs', 'Chemical', '-', (28, 33))	('malignancy', 'Disease', (56, 66))	('genetic reprogramming', 'CPA', (141, 162))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('metabolic homeostasis', 'CPA', (182, 203))	('epigenetic modifications', 'Var', (115, 139))	('human', 'Species', '9606', (50, 55))	('homeostasis', 'biological_process', 'GO:0042592', ('192', '203'))
28894	32290321	These two isoforms, generated by either alternative splicing or alternative use of different promoters, play opposite roles, particularly in cancer.	('alternative splicing', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('splicing', 'biological_process', 'GO:0045292', ('52', '60'))	('cancer', 'Disease', (141, 147))
28896	32290321	The imbalance in favor of PR- is observed in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR- form.	('inactivating mutations', 'Var', (90, 112))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('human', 'Species', '9606', (50, 55))	('increased', 'PosReg', (157, 166))	('silencing', 'Var', (116, 125))	('malignancies', 'Disease', (56, 68))	('expression', 'MPA', (167, 177))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
28898	32290321	An overview of cancer-specific alterations affecting PRDM family members, taking into account putative causes, produced effects, and underlying molecular mechanisms, is detailed below and summarized in Table 1.	('alterations', 'Var', (31, 42))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PRDM', 'Gene', (53, 57))
28905	32290321	Particularly, disruption of PRDM1/BLIMP1 function is frequently observed in the activated B-cell-like (ABC) subtype of DLBCL by distinct mechanisms including inactivating mutations, chromosomal deletion, and epigenetic silencing.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('inactivating mutations', 'Var', (158, 180))	('BLIMP1', 'Gene', '639', (34, 40))	('function', 'MPA', (41, 49))	('ABC', 'Gene', (103, 106))	('ABC', 'Gene', '10058', (103, 106))	('activated B-cell-like', 'Disease', (80, 101))	('epigenetic silencing', 'Var', (208, 228))	('BLIMP1', 'Gene', (34, 40))	('chromosomal deletion', 'Var', (182, 202))	('disruption', 'NegReg', (14, 24))
28906	32290321	Of note, a more recent study demonstrated that its genetic loss could contribute to the overall poor prognosis for ABC-DLBCL but not germinal center B-cell-like (GCB)-DLBCLs.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('BCL', 'Phenotype', 'HP:0012191', (169, 172))	('ABC', 'Gene', (115, 118))	('ABC', 'Gene', '10058', (115, 118))	('genetic loss', 'Var', (51, 63))
28907	32290321	Furthermore, the lack of BLIMP1 expression correlated with an impaired p53 signaling pathway and Myc overexpression; gene expression profiling data also indicated that inactivated BLIMP1 could facilitate DLBCL progression through Myc and BCR (B cell receptor) signaling, which are essential for ABC-DLBCL survival.	('DLBCL', 'Disease', (204, 209))	('BLIMP1', 'Gene', (25, 31))	('BCL', 'Phenotype', 'HP:0012191', (301, 304))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('BLIMP1', 'Gene', (180, 186))	('ABC', 'Gene', '10058', (295, 298))	('BLIMP1', 'Gene', '639', (25, 31))	('gene expression', 'biological_process', 'GO:0010467', ('117', '132'))	('BLIMP1', 'Gene', '639', (180, 186))	('BCL', 'Phenotype', 'HP:0012191', (206, 209))	('inactivated', 'Var', (168, 179))	('facilitate', 'PosReg', (193, 203))	('p53 signaling pathway', 'biological_process', 'GO:0030330', ('71', '92'))	('Myc', 'MPA', (230, 233))	('ABC', 'Gene', (295, 298))
28910	32290321	In addition, PRDM1 ectopic expression in a DLBCL-derived cell line triggered cell cycle arrest.	('PRDM1', 'Gene', (13, 18))	('ectopic expression', 'Var', (19, 37))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('77', '94'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('BCL', 'Phenotype', 'HP:0012191', (45, 48))	('triggered', 'Reg', (67, 76))
28912	32290321	Consistently, an in vivo study showed that mouse Prdm1 deletion cooperated with constitutive activation of the NF-kappaB pathway to support a neoplastic phenotype.	('activation', 'PosReg', (93, 103))	('support', 'PosReg', (132, 139))	('Prdm1', 'Gene', '12142', (49, 54))	('NF-kappaB', 'Gene', '18033', (111, 120))	('Prdm1', 'Gene', (49, 54))	('deletion', 'Var', (55, 63))	('neoplastic phenotype', 'CPA', (142, 162))	('mouse', 'Species', '10090', (43, 48))	('NF-kappaB', 'Gene', (111, 120))
28914	32290321	For instance, array comparative genomic hybridization and gene expression profiling in extranodal NK/T-cell lymphoma (EN-NK/T) revealed that the most frequently deleted chromosomal region 6q21-6q25, induced a downregulation of several tumor-suppressor genes including PRDM1.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('235', '251'))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (101, 116))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (98, 116))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('235', '251'))	('NK/T-cell lymphoma', 'Disease', (98, 116))	('downregulation', 'NegReg', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cell lymphoma', 'Phenotype', 'HP:0012191', (103, 116))	('tumor-suppressor', 'Gene', (235, 251))	('PRDM1', 'Gene', (268, 273))	('6q21-6q25', 'Var', (188, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('tumor-suppressor', 'Gene', '7248', (235, 251))	('chromosomal region', 'cellular_component', 'GO:0098687', ('169', '187'))
28918	32290321	PRDM1 mutations occurred in patients with plasmablastic lymphoma; interestingly, in this rare neoplasm, PRDM1 genetic alterations did not impair terminal B-cell differentiation, but contributed to the oncogenicity of MYC, which is usually dysregulated by translocation or amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('plasmablastic lymphoma', 'Disease', (42, 64))	('MYC', 'Gene', '4609', (217, 220))	('genetic alterations', 'Var', (110, 129))	('MYC', 'Gene', (217, 220))	('neoplasm', 'Disease', (94, 102))	('B-cell differentiation', 'biological_process', 'GO:0030183', ('154', '176'))	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (42, 64))	('PRDM1', 'Gene', (104, 109))	('oncogenicity', 'MPA', (201, 213))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('patients', 'Species', '9606', (28, 36))	('contributed to', 'Reg', (182, 196))
28931	32290321	In colorectal tumor cells, PRDM1 knockdown by small-interfering RNA (siRNA) results in both apoptosis and growth arrest through regulation of p53 transcription.	('apoptosis', 'biological_process', 'GO:0097194', ('92', '101'))	('regulation', 'biological_process', 'GO:0065007', ('128', '138'))	('apoptosis', 'biological_process', 'GO:0006915', ('92', '101'))	('transcription', 'biological_process', 'GO:0006351', ('146', '159'))	('apoptosis', 'CPA', (92, 101))	('p53', 'Gene', (142, 145))	('growth arrest', 'Disease', (106, 119))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))	('knockdown', 'Var', (33, 42))	('growth arrest', 'Disease', 'MESH:D006323', (106, 119))	('PRDM1', 'Gene', (27, 32))	('regulation', 'Reg', (128, 138))	('growth arrest', 'Phenotype', 'HP:0001510', (106, 119))	('transcription', 'MPA', (146, 159))	('colorectal tumor', 'Disease', (3, 19))	('colorectal tumor', 'Disease', 'MESH:D015179', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('small-interfering', 'Var', (46, 63))
28932	32290321	Interestingly, both p53 mRNA and protein levels are considerably increased after PRDM1/BLIMP1 depletion, which is accompanied by the induction of p53 target genes.	('increased', 'PosReg', (65, 74))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('BLIMP1', 'Gene', (87, 93))	('BLIMP1', 'Gene', '639', (87, 93))	('depletion', 'Var', (94, 103))
28939	32290321	In addition, PRDM1 reduced the expression of DKK1 thus exerting its antitumor effect via antagonizing the activity of Wnt/beta-catenin pathway (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('beta-catenin', 'Gene', '1499', (122, 134))	('antagonizing', 'NegReg', (89, 101))	('tumor', 'Disease', (72, 77))	('DKK1', 'Gene', '22943', (45, 49))	('DKK1', 'Gene', (45, 49))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduced', 'NegReg', (19, 26))	('activity', 'MPA', (106, 114))	('beta-catenin', 'Gene', (122, 134))	('PRDM1', 'Var', (13, 18))
28941	32290321	Specifically, the ectopic expression of the transcription factor Aiolos induced anoikis resistance to cancer cells by downregulating PRDM1.	('Aiolos', 'Gene', '22806', (65, 71))	('ectopic expression', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induced', 'PosReg', (72, 79))	('transcription factor', 'molecular_function', 'GO:0000981', ('44', '64'))	('PRDM1', 'Gene', (133, 138))	('cancer', 'Disease', (102, 108))	('downregulating', 'NegReg', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('transcription', 'biological_process', 'GO:0006351', ('44', '57'))	('Aiolos', 'Gene', (65, 71))	('anoikis', 'biological_process', 'GO:0043276', ('80', '87'))
28944	32290321	Additionally, mutations were revealed in some solid tumors, such as skin cutaneous melanoma and uterine carcinosarcoma, which displayed more than 5% of patients carrying PRDM1 mutations.	('revealed', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (176, 185))	('skin cutaneous melanoma', 'Disease', (68, 91))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (104, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (96, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PRDM1', 'Gene', (170, 175))	('carcinosarcoma', 'Disease', (104, 118))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (152, 160))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
28950	32290321	Indeed, both genetic inactivation or epigenetic silencing of RIZ1 and/or an increase of RIZ2 expression levels were frequently revealed in many human cancer tissues and cell lines.	('increase', 'PosReg', (76, 84))	('human', 'Species', '9606', (144, 149))	('revealed', 'Reg', (127, 135))	('genetic inactivation', 'Var', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('expression levels', 'MPA', (93, 110))	('cancer', 'Disease', (150, 156))	('RIZ2', 'Gene', '7799', (88, 92))	('RIZ2', 'Gene', (88, 92))	('RIZ1', 'Gene', (61, 65))	('epigenetic silencing', 'Var', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
28954	32290321	Riz1 knockout mice, carrying normal Riz2, were tumor prone in both wild-type and mutant p53 genetic backgrounds.	('prone', 'PosReg', (53, 58))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p53', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutant', 'Var', (81, 87))	('Riz2', 'Gene', '7799', (36, 40))	('Riz2', 'Gene', (36, 40))	('tumor', 'Disease', (47, 52))
28955	32290321	Indeed, an accelerated tumorigenesis was associated with Riz1 deficiency (Riz1-/-) on the p53+/- background.	('Riz1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('deficiency', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('accelerated', 'PosReg', (11, 22))	('tumor', 'Disease', (23, 28))
28958	32290321	Indeed, frameshift mutations of microsatellite repeats localized in the C-terminal coding region were frequently detected in colorectal, gastric, endometrial, and pancreatic microsatellite instability (MIN) positive cancers.	('gastric', 'Disease', (137, 144))	('colorectal', 'Disease', (125, 135))	('endometrial', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('frameshift mutations', 'Var', (8, 28))	('pancreatic microsatellite instability (MIN) positive cancers', 'Disease', 'MESH:D053842', (163, 223))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('detected', 'Reg', (113, 121))
28962	32290321	Despite their high occurrence, the functional significance in tumorigenesis of these C-terminal PRDM2 truncated forms induced by frameshift mutations is still unknown and deserves investigation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PRDM2', 'Gene', (96, 101))	('frameshift mutations', 'Var', (129, 149))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('induced', 'Reg', (118, 125))
28963	32290321	Interestingly, the restoration of the wild-type PRDM2 gene sequence of one mutant c.4467delA allele by genome editing in homozygous mutant human colorectal cancer cells, repaired its H3K9me2 activity, impaired tumor cell growth, reduced anchorage-independent growth, cellular migration, and colony forming ability in vitro, as well as decreased the tumor growth in a mouse xenograft model.	('colony forming ability in vitro', 'CPA', (291, 322))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('mouse', 'Species', '10090', (367, 372))	('activity', 'MPA', (191, 199))	('impaired tumor', 'Disease', 'MESH:D060825', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('colorectal cancer', 'Disease', (145, 162))	('decreased', 'NegReg', (335, 344))	('tumor', 'Disease', (210, 215))	('H3K9me2', 'Protein', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('cell growth', 'biological_process', 'GO:0016049', ('216', '227'))	('c.4467delA', 'Var', (82, 92))	('PRDM2', 'Gene', (48, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('reduced', 'NegReg', (229, 236))	('repaired', 'NegReg', (170, 178))	('cellular migration', 'CPA', (267, 285))	('tumor', 'Disease', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('anchorage-independent growth', 'CPA', (237, 265))	('mutant', 'Var', (132, 138))	('impaired tumor', 'Disease', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (139, 144))	('c.4467delA', 'Mutation', 'rs57173229', (82, 92))
28964	32290321	Furthermore, H3K9me2 activity restoration determined the downregulation of several genes involved in cancer pathways, mostly of EMT, thus contributing to a more aggressive cancer phenotype (Figure 1E).	('downregulation', 'NegReg', (57, 71))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('H3K9me2', 'Protein', (13, 20))	('cancer', 'Disease', (101, 107))	('EMT', 'biological_process', 'GO:0001837', ('128', '131'))	('aggressive cancer', 'Disease', 'MESH:D009369', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', (172, 178))	('aggressive cancer', 'Disease', (161, 178))	('more', 'PosReg', (156, 160))
28965	32290321	In addition, frameshift mutations in the (A)9 tract were also found in samples of malignant melanoma and nevi and in leukemia cell lines.	('nevi', 'Disease', (105, 109))	('malignant melanoma', 'Disease', 'MESH:D008545', (82, 100))	('malignant melanoma', 'Disease', (82, 100))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('nevi', 'Phenotype', 'HP:0003764', (105, 109))	('leukemia', 'Disease', (117, 125))	('frameshift mutations', 'Var', (13, 33))	('found', 'Reg', (62, 67))	('malignant melanoma', 'Phenotype', 'HP:0002861', (82, 100))	('A)9', 'Gene', (42, 45))
28966	32290321	Interestingly, in most cases of MIN pathway cancers these frameshift mutations were biallelic or homozygous/hemizygous, indicating that PRDM2 follows the two-hit model of tumor suppressor genes, with one hit achieved either by mutations/deletions affecting the PR domain or by frameshift mutations in the 3' end affecting the interactions between the N-terminal PR domain of RIZ1 and its C-terminal region, including the PR-binding motif.	('affecting', 'Reg', (312, 321))	('RIZ1', 'Gene', (375, 379))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations/deletions', 'Var', (227, 246))	('binding', 'molecular_function', 'GO:0005488', ('424', '431'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('171', '187'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('171', '187'))	('frameshift mutations', 'Var', (277, 297))	('interactions', 'Interaction', (326, 338))
28968	32290321	Interestingly, some PRDM2 polymorphisms have also been associated with carcinogenesis.	('polymorphisms', 'Var', (26, 39))	('PRDM2', 'Gene', (20, 25))	('carcinogenesis', 'Disease', (71, 85))	('associated', 'Reg', (55, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
28970	32290321	A CpG island in the PRDM2/RIZ1 promoter is frequently methylated in many cancer types, such as breast carcinomas and liver tumors, as well as in colon and lung cancer cell lines.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (160, 166))	('liver tumors', 'Disease', 'MESH:D008113', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('liver tumors', 'Phenotype', 'HP:0002896', (117, 129))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('methylated', 'Var', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinomas', 'Disease', (95, 112))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('liver tumors', 'Disease', (117, 129))	('PRDM2/RIZ1', 'Gene', (20, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('colon and lung cancer', 'Disease', 'MESH:D008175', (145, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
28971	32290321	Additionally, epigenetic silencing of RIZ1 expression was also detected in pituitary adenomas and nasopharyngeal carcinoma specimens.	('detected', 'Reg', (63, 71))	('epigenetic silencing', 'Var', (14, 34))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('men', 'Species', '9606', (128, 131))	('pituitary adenomas', 'Disease', 'MESH:D010911', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (98, 122))	('RIZ1', 'Gene', (38, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (75, 93))	('carcinoma', 'Disease', (113, 122))	('pituitary adenomas', 'Disease', (75, 93))
28978	32290321	Noteworthy, a later study demonstrated that estradiol induced the preferential synthesis of transcripts with exon 9a, whereas it reduced those containing exons 9b and 10.	('synthesis', 'biological_process', 'GO:0009058', ('79', '88'))	('synthesis', 'MPA', (79, 88))	('preferential', 'PosReg', (66, 78))	('exon 9a', 'Var', (109, 116))	('reduced', 'NegReg', (129, 136))	('estradiol', 'Chemical', 'MESH:D004958', (44, 53))
28987	32290321	Specifically, tumor suppressor function requires the establishment of the H4K20me1-H3K9me1 trans-tail 'histone code' at specific loci through the direct interaction of RIZ1 PR-binding motif to PR-Set7 monomethyltransferase, an essential component of the mammalian cell cycle, which is needed for proper DNA replication and mitosis, thus hypothesizing an additional mechanism of action.	('mitosis', 'biological_process', 'GO:0000278', ('323', '330'))	('cell cycle', 'biological_process', 'GO:0007049', ('264', '274'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PR-Set7', 'Gene', '387893', (193, 200))	('mitosis', 'Disease', (323, 330))	('binding', 'molecular_function', 'GO:0005488', ('176', '183'))	('mammalian', 'Species', '9606', (254, 263))	('men', 'Species', '9606', (62, 65))	('mitosis', 'Disease', 'None', (323, 330))	('DNA replication', 'biological_process', 'GO:0006260', ('303', '318'))	('DNA', 'cellular_component', 'GO:0005574', ('303', '306'))	('interaction', 'Interaction', (153, 164))	('PR-Set7', 'Gene', (193, 200))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('H4K20me1-H3K9me1', 'Var', (74, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('RIZ1', 'Gene', (168, 172))
28989	32290321	Since the loss of PR-Set7 produced persistent DNA double-strand breaks (DSBs), it was conceivable that H4K20me1, and possibly Riz1-mediated H3K9me1, had a role in DNA repair.	('loss', 'Var', (10, 14))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('DNA double-strand breaks', 'MPA', (46, 70))	('DSBs', 'Chemical', '-', (72, 76))	('H4K20me1', 'Var', (103, 111))	('PR-Set7', 'Gene', (18, 25))	('PR-Set7', 'Gene', '387893', (18, 25))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('DNA repair', 'biological_process', 'GO:0006281', ('163', '173'))
29000	32290321	It is well established that chromosomal rearrangements or proviral insertion at the PRDM3 locus gene, MECOM, are found in up to 10% of acute myeloid leukemia (AML) cases with poor survival outcomes.	('men', 'Species', '9606', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (159, 162))	('AML', 'Disease', (159, 162))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (135, 157))	('MECOM', 'Gene', (102, 107))	('found', 'Reg', (113, 118))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (141, 157))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (135, 157))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('acute myeloid leukemia', 'Disease', (135, 157))	('chromosomal rearrangements', 'Var', (28, 54))
29004	32290321	Later, in ovarian tumors a high frequency of aberrant EVI1 splicing, generating novel isoforms, could contribute to the pathophysiology of these cancers.	('cancers', 'Disease', (145, 152))	('ovarian tumors', 'Disease', (10, 24))	('EVI1', 'Gene', (54, 58))	('ovarian tumors', 'Phenotype', 'HP:0100615', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('aberrant', 'Var', (45, 53))	('ovarian tumors', 'Disease', 'MESH:D010051', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('isoforms', 'MPA', (86, 94))	('contribute', 'Reg', (102, 112))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('EVI1', 'Gene', '14013', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
29005	32290321	EVI1 is usually upregulated through the generation of oncogenic fusion proteins as a consequence of rearrangements; alternatively, it can also be upregulated by leukemogenic factors at the transcriptional level.	('upregulated', 'PosReg', (16, 27))	('rearrangements', 'Var', (100, 114))	('EVI1', 'Gene', (0, 4))	('upregulated', 'PosReg', (146, 157))	('men', 'Species', '9606', (109, 112))	('EVI1', 'Gene', '14013', (0, 4))
29016	32290321	For instance, the proximal set of EVI1 zinc fingers is able to bind the N-terminal domain of the zinc finger transcription factor hypermethylated in cancer 1 (HIC1); in turn, this interaction deregulates the DNA binding and transcriptional activity of EVI1 on the BCL-XL promoter, thus compromising the anti-apoptotic activity of EVI1 (Figure 2).	('transcriptional', 'MPA', (224, 239))	('hypermethylated in cancer 1', 'Gene', (130, 157))	('EVI1', 'Gene', (252, 256))	('EVI1', 'Gene', '14013', (252, 256))	('BCL-XL', 'Gene', (264, 270))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('compromising', 'NegReg', (286, 298))	('anti-apoptotic activity', 'CPA', (303, 326))	('EVI1', 'Gene', (34, 38))	('deregulates', 'NegReg', (192, 203))	('HIC1', 'Gene', (159, 163))	('EVI1', 'Gene', '14013', (34, 38))	('BCL-XL', 'Gene', '598', (264, 270))	('hypermethylated in cancer 1', 'Gene', '3090', (130, 157))	('interaction', 'Var', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA binding', 'Interaction', (208, 219))	('HIC1', 'Gene', '3090', (159, 163))	('DNA binding', 'molecular_function', 'GO:0003677', ('208', '219'))	('transcription', 'biological_process', 'GO:0006351', ('109', '122'))	('transcription factor', 'molecular_function', 'GO:0000981', ('109', '129'))	('EVI1', 'Gene', (330, 334))	('BCL', 'Phenotype', 'HP:0012191', (264, 267))	('EVI1', 'Gene', '14013', (330, 334))
29019	32290321	EVI1 knockdown impaired PC cell proliferation through a cell cycle progression blockade.	('blockade', 'NegReg', (79, 87))	('cell cycle progression', 'CPA', (56, 78))	('impaired', 'NegReg', (15, 23))	('knockdown', 'Var', (5, 14))	('PC', 'Phenotype', 'HP:0012125', (24, 26))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('EVI1', 'Gene', (0, 4))	('EVI1', 'Gene', '14013', (0, 4))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))
29020	32290321	Mechanistically, these changes might be at least in part mediated by reactivation of SMAD3, a known transcriptional target of EVI1.	('SMAD3', 'Gene', '4088', (85, 90))	('SMAD3', 'Gene', (85, 90))	('EVI1', 'Gene', (126, 130))	('reactivation', 'Var', (69, 81))	('EVI1', 'Gene', '14013', (126, 130))
29021	32290321	EVI1 knockdown in PC cells also reduced migratory potential and anchorage-independent growth while enhancing apoptosis sensitivity.	('enhancing', 'PosReg', (99, 108))	('apoptosis sensitivity', 'CPA', (109, 130))	('anchorage-independent growth', 'CPA', (64, 92))	('migratory potential', 'CPA', (40, 59))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (32, 39))	('EVI1', 'Gene', (0, 4))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('PC', 'Phenotype', 'HP:0012125', (18, 20))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('EVI1', 'Gene', '14013', (0, 4))
29032	32290321	In addition, EVI1 knockdown demonstrated its requirement for metastasis of colon cancer cells.	('knockdown', 'Var', (18, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('men', 'Species', '9606', (52, 55))	('EVI1', 'Gene', (13, 17))	('metastasis of colon cancer', 'Disease', (61, 87))	('EVI1', 'Gene', '14013', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (61, 87))
29037	32290321	Recent findings have suggested MECOM as a novel candidate gene for hereditary hematological malignancies; indeed, a novel germline mutation within the ninth zinc finger motif was reported in a family with developed myeloid malignancies.	('reported', 'Reg', (179, 187))	('myeloid malignancies', 'Disease', 'MESH:D009369', (215, 235))	('hematological malignancies', 'Phenotype', 'HP:0004377', (78, 104))	('hereditary hematological malignancies', 'Disease', (67, 104))	('myeloid malignancies', 'Disease', (215, 235))	('hereditary hematological malignancies', 'Disease', 'MESH:D019337', (67, 104))	('germline mutation within', 'Var', (122, 146))
29038	32290321	As for PRDM2 gene, a mononucleotide repeat (A7) in exon 8 of MECOM coding sequences was found to be a target for frameshift mutation (loss-of-function mutation) in colorectal cancers with MIN.	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (164, 182))	('mononucleotide', 'Chemical', '-', (21, 35))	('colorectal cancers', 'Disease', (164, 182))	('PRDM2', 'Gene', (7, 12))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('frameshift mutation', 'Var', (113, 132))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
29039	32290321	In the same study, the authors also observed intratumor heterogeneity (an important cancer hallmark) of MECOM mutations in four of 16 analyzed cases (25%).	('MECOM', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer hallmark', 'Disease', (84, 99))	('cancer hallmark', 'Disease', 'MESH:D009369', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
29047	32290321	PRDM5 is silenced in human breast, ovarian, and liver cancers by CpG island methylation of its promoter region.	('ovarian', 'Disease', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('breast', 'Disease', (27, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (48, 60))	('human', 'Species', '9606', (21, 26))	('silenced', 'NegReg', (9, 17))	('liver cancers', 'Phenotype', 'HP:0002896', (48, 61))	('liver cancers', 'Disease', (48, 61))	('liver cancers', 'Disease', 'MESH:D006528', (48, 61))	('methylation', 'Var', (76, 87))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PRDM5', 'Gene', (0, 5))
29049	32290321	Later, epigenetic PRDM5 silencing was also shown in gastric and colorectal cancers, where its ectopic expression determined a cell growth suppression.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('suppression', 'NegReg', (138, 149))	('epigenetic PRDM5', 'Var', (7, 23))	('gastric', 'Disease', (52, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cell growth', 'biological_process', 'GO:0016049', ('126', '137'))	('silencing', 'NegReg', (24, 33))	('cell growth', 'CPA', (126, 137))
29050	32290321	Of note, PRDM5 promoter methylation was detected in both primary colorectal and gastric cancers but not in noncancerous tissue specimens collected from areas adjacent to the tumors.	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cancerous', 'Disease', (110, 119))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (65, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('detected', 'Reg', (40, 48))	('methylation', 'Var', (24, 35))	('men', 'Species', '9606', (132, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('PRDM5', 'Gene', (9, 14))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('gastric cancers', 'Phenotype', 'HP:0012126', (80, 95))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
29053	32290321	Recently, a significant PRDM5 promoter methylation was observed in BRAF mutant cancers of the serrated pathway whereas minimal levels of methylation were detected in the BRAF wild-type cancers of the traditional pathway; moreover, PRDM5 methylation was evident in a small proportion of serrated type polyps indicating that this may be an early event in tumorigenesis.	('polyps', 'Disease', (300, 306))	('serrated pathway', 'Pathway', (94, 110))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('tumor', 'Disease', (353, 358))	('mutant', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('serrated type', 'Disease', (286, 299))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('polyps', 'Disease', 'MESH:D011127', (300, 306))	('methylation', 'biological_process', 'GO:0032259', ('237', '248'))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('PRDM5', 'Gene', (231, 236))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('BRAF', 'Gene', '673', (170, 174))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (170, 174))	('PRDM5', 'Gene', (24, 29))	('serrated type polyps', 'Phenotype', 'HP:0032222', (286, 306))	('BRAF', 'Gene', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
29055	32290321	For example, aberrant DNA methylation reduced PRDM5 expression in about 40.5% of cervical cancers, whereas normal tissues were unmethylated.	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancers', 'Disease', (81, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('PRDM5', 'Gene', (46, 51))	('cervical cancers', 'Disease', 'MESH:D002583', (81, 97))	('expression', 'MPA', (52, 62))	('aberrant DNA methylation', 'Var', (13, 37))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))
29056	32290321	Similarly, PRDM5 was frequently silenced by promoter methylation in multiple cancer cell lines and tumor specimens, including nasopharyngeal, esophageal, gastric, cervical, and hepatocellular carcinoma.	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cervical', 'Disease', (163, 171))	('esophageal', 'Disease', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('tumor', 'Disease', (99, 104))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('promoter methylation', 'Var', (44, 64))	('nasopharyngeal', 'Disease', (126, 140))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (77, 83))	('PRDM5', 'Gene', (11, 16))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('silenced', 'NegReg', (32, 40))	('hepatocellular carcinoma', 'Disease', (177, 201))	('gastric', 'Disease', (154, 161))
29062	32290321	Accordingly, this concept is also supported by a study in which repression of PRDM5 function, due to deletions in its locus along with miR-182 sequence amplification, was shown to play a co-operative role in ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (208, 223))	('miR-182', 'Gene', '406958', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('deletions', 'Var', (101, 110))	('repression', 'NegReg', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (208, 222))	('PRDM5', 'Gene', (78, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (208, 223))	('ovarian cancers', 'Disease', (208, 223))	('miR-182', 'Gene', (135, 142))
29068	32290321	Noteworthy, a meta-analysis of genome-wide association studies correlated a single nucleotide polymorphism in PRDM6 gene with both mammographic density and breast cancer susceptibility.	('PRDM6', 'Gene', (110, 115))	('PRDM6', 'Gene', '93166', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('single nucleotide polymorphism', 'Var', (76, 106))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('mammographic density', 'Disease', (131, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
29072	32290321	A whole-exome sequencing analysis on a small group of pituitary adenomas revealed genetic variants in several genes, including PRDM8.	('pituitary adenomas', 'Disease', (54, 72))	('PRDM8', 'Gene', (127, 132))	('variants', 'Var', (90, 98))	('PRDM8', 'Gene', '56978', (127, 132))	('pituitary adenomas', 'Disease', 'MESH:D010911', (54, 72))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (54, 72))
29084	32290321	Indeed, meiotic recombination is crucial for accurate chromosomal disjunction and genomic stability maintenance during meiosis; likewise, homologous recombination also promotes genomic stability by repairing DSBs in cells undergoing mitosis.	('homologous recombination', 'Var', (138, 162))	('meiosis', 'biological_process', 'GO:0051321', ('119', '126'))	('DSBs', 'Disease', (208, 212))	('meiosis', 'Disease', 'MESH:C536875', (119, 126))	('mitosis', 'biological_process', 'GO:0000278', ('233', '240'))	('DSBs', 'Chemical', '-', (208, 212))	('promotes', 'PosReg', (168, 176))	('genomic stability', 'CPA', (177, 194))	('homologous recombination', 'biological_process', 'GO:0035825', ('138', '162'))	('mitosis', 'Disease', (233, 240))	('repairing', 'NegReg', (198, 207))	('mitosis', 'Disease', 'None', (233, 240))	('meiosis', 'Disease', (119, 126))
29085	32290321	Furthermore, the two processes involve overlapping molecular machinery and comparable mechanisms whose dysregulation can often lead to diseases, including cancer.	('diseases', 'Disease', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lead to', 'Reg', (127, 134))	('dysregulation', 'Var', (103, 116))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
29091	32290321	Since PRDM9 variability has been suggested to influence genomic instability, the authors of this study argued that these rare allelic forms could be involved in the development of preleukemic clones in B-ALL patients and proposed that an altered PRDM9 function in the parental germline could lead to the genomic instability associated with childhood ALL.	('PRDM9', 'Gene', '56979', (6, 11))	('function', 'MPA', (252, 260))	('LL', 'Phenotype', 'HP:0005526', (351, 353))	('patients', 'Species', '9606', (208, 216))	('childhood ALL', 'Disease', (340, 353))	('LL', 'Phenotype', 'HP:0005526', (205, 207))	('genomic instability', 'MPA', (304, 323))	('B-ALL', 'Phenotype', 'HP:0004812', (202, 207))	('altered', 'Var', (238, 245))	('PRDM9', 'Gene', (246, 251))	('lead to', 'Reg', (292, 299))	('PRDM9', 'Gene', '56979', (246, 251))	('involved', 'Reg', (149, 157))	('PRDM9', 'Gene', (6, 11))	('men', 'Species', '9606', (172, 175))
29092	32290321	PRDM9 mutations have also been correlated with specific solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('PRDM9', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('correlated', 'Reg', (31, 41))	('PRDM9', 'Gene', '56979', (0, 5))
29093	32290321	Indeed, in a study defining a landscape of non-coding RNA (ncRNA) in the head and neck squamous cell carcinoma (HNSCC), 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with known gene mutations and chromosome alterations, including PRDM9 mutations; particularly, piR-34736 was upregulated two-fold in HNSCC and correlated to patient survival and PRDM9 mutation.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('HNSCC', 'Disease', (382, 387))	('mutation', 'Var', (433, 441))	('PRDM9', 'Gene', (427, 432))	('patient', 'Species', '9606', (216, 223))	('mutations', 'Var', (319, 328))	('PRDM9', 'Gene', '56979', (427, 432))	('patient', 'Species', '9606', (406, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('PRDM9', 'Gene', (313, 318))	('PRDM9', 'Gene', '56979', (313, 318))	('correlated', 'Reg', (200, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (382, 387))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('upregulated', 'PosReg', (358, 369))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('piR-34736', 'Var', (344, 353))	('chromosome', 'cellular_component', 'GO:0005694', ('279', '289'))
29094	32290321	Very recently, a mutation analysis of histone lysine methyltransferases in bladder cancer from TCGA datasets identified PRDM9 among the six genes with a potential critical role in oncogenesis and prognosis of this cancer type.	('PRDM9', 'Gene', '56979', (120, 125))	('cancer', 'Disease', (214, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (17, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('oncogenesis', 'biological_process', 'GO:0007048', ('180', '191'))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PRDM9', 'Gene', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
29095	32290321	Noteworthy, our pan-cancer mutation analysis recognized PRDM9 as one of the most mutated genes of the PRDM family with frequencies ranging from 0.5% to 15.4% and higher than 5% in multiple cancers, such as DLBCL, HNSCC, endometrial, esophageal, stomach, and colon carcinomas, kidney and lung tumors, and melanoma.	('colon carcinomas', 'Disease', (258, 274))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('BCL', 'Phenotype', 'HP:0012191', (208, 211))	('lung tumors', 'Phenotype', 'HP:0100526', (287, 298))	('multiple cancers', 'Disease', (180, 196))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('colon carcinomas', 'Disease', 'MESH:D003110', (258, 274))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('lung tumors', 'Disease', (287, 298))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('DLBCL', 'Disease', (206, 211))	('HNSCC', 'Disease', (213, 218))	('esophageal', 'Disease', (233, 243))	('cancer', 'Disease', (20, 26))	('multiple cancers', 'Disease', 'MESH:D009369', (180, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (213, 218))	('endometrial', 'Disease', (220, 231))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PRDM9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (304, 312))	('PRDM9', 'Gene', '56979', (56, 61))	('lung tumors', 'Disease', 'MESH:D008175', (287, 298))	('stomach', 'Disease', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (264, 274))
29096	32290321	In a newly published pan-cancer analysis of TCGA data the authors revealed that aberrant expression of PRDM9 was associated with an enrichment of somatic structural variants at sites of binding and activity in several cancer types, thus hypothesizing a novel mechanism underlying genomic instability during tumorigenesis based on the possibility that there are putative uncharacterized genomic features and binding sites leading to these variants.	('men', 'Species', '9606', (138, 141))	('tumor', 'Disease', (307, 312))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('expression', 'MPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('activity', 'MPA', (198, 206))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('binding', 'Interaction', (186, 193))	('aberrant', 'Var', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('binding', 'molecular_function', 'GO:0005488', ('407', '414'))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('PRDM9', 'Gene', (103, 108))	('variants', 'Var', (165, 173))	('cancer', 'Disease', (218, 224))	('PRDM9', 'Gene', '56979', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('associated', 'Reg', (113, 123))
29098	32290321	Using RNA-seq and other methodologies, analysis of 84 soft tissue sarcomas revealed that a significant subset of low-grade undifferentiated pleomorphic sarcoma (UPS) showed a gene fusion of PRDM10 either with MED12 or CITED2, suggesting that these rearrangements were specific for this less aggressive UPS subset.	('men', 'Species', '9606', (257, 260))	('aggressive UPS', 'Disease', 'MESH:D017118', (291, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('PRDM10', 'Gene', (190, 196))	('undifferentiated pleomorphic sarcoma', 'Disease', (123, 159))	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('gene fusion', 'Var', (175, 186))	('MED12', 'Gene', (209, 214))	('PRDM10', 'Gene', '56980', (190, 196))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('CITED2', 'Gene', (218, 224))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('CITED2', 'Gene', '10370', (218, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('sarcomas', 'Disease', (66, 74))	('MED12', 'Gene', '9968', (209, 214))	('aggressive UPS', 'Disease', (291, 305))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (123, 159))
29102	32290321	In childhood ALL, whole-exome-sequencing and whole-genome-sequencing revealed that homozygous non-synonymous coding mutations negatively affected PRDM11 function.	('non-synonymous coding mutations', 'Var', (94, 125))	('PRDM11', 'Gene', (146, 152))	('LL', 'Phenotype', 'HP:0005526', (14, 16))	('affected', 'Reg', (137, 145))	('PRDM11', 'Chemical', '-', (146, 152))	('negatively', 'NegReg', (126, 136))	('function', 'MPA', (153, 161))
29104	32290321	Indeed, deletion of PRDM11 accelerated Myc-driven lymphomagenesis, while its overexpression induced apoptosis and delayed lymphoma onset.	('PRDM11', 'Chemical', '-', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('overexpression', 'PosReg', (77, 91))	('delayed lymphoma', 'Disease', (114, 130))	('lymphoma', 'Disease', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('PRDM11', 'Gene', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('accelerated', 'PosReg', (27, 38))	('delayed lymphoma', 'Disease', 'MESH:D008223', (114, 130))	('lymphoma', 'Disease', (50, 58))	('apoptosis', 'CPA', (100, 109))	('deletion', 'Var', (8, 16))
29109	32290321	Several studies indicated that PRDM12 might act as a tumor suppressor gene in human chronic myeloid leukemia with derivative chromosome 9 deletions or rearrangements.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('chronic myeloid leukemia', 'Disease', (84, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('rearrangements', 'Var', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('PRDM12', 'Gene', '59335', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRDM12', 'Gene', (31, 37))	('deletions', 'Var', (138, 147))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (160, 163))	('human', 'Species', '9606', (78, 83))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (84, 108))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (84, 108))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
29124	32290321	The analysis of gene copy number suggested that the mechanism could be gene amplification on chromosome 8q13, a region frequently altered in a wide variety of human tumors.	('tumors', 'Disease', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('human', 'Species', '9606', (159, 164))	('gene amplification', 'Var', (71, 89))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
29126	32290321	In vitro experiments showed that while ectopic PRDM14 expression enhanced cancer cell growth and resistance to chemotherapeutic drugs, PRDM14 knockdown was able to induce apoptosis and increase sensitivity to chemotherapeutic drugs.	('increase', 'PosReg', (185, 193))	('PRDM14', 'Gene', (47, 53))	('sensitivity to chemotherapeutic drugs', 'MPA', (194, 231))	('ectopic', 'Var', (39, 46))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('induce', 'PosReg', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('apoptosis', 'CPA', (171, 180))	('enhanced', 'PosReg', (65, 73))	('resistance to chemotherapeutic drugs', 'MPA', (97, 133))	('cancer', 'Disease', (74, 80))	('men', 'Species', '9606', (15, 18))	('PRDM14', 'Gene', (135, 141))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('knockdown', 'Var', (142, 151))
29127	32290321	More recently, in vitro and in vivo experiments were set up to ascertain whether and how PRDM14 could also confer stem cell-like properties and epigenetic changes to cancer cells.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (42, 45))	('confer', 'Reg', (107, 113))	('stem cell-like properties', 'CPA', (114, 139))	('epigenetic changes', 'Var', (144, 162))	('PRDM14', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
29131	32290321	PRDM14 silencing strongly reduced the stem cell phenotype and inhibited breast cancer cell line proliferation, tumorsphere formation, and suppressed cell growth in the presence of low concentrations of anticancer drugs.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('PRDM14', 'Gene', (0, 6))	('reduced', 'NegReg', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('silencing', 'Var', (7, 16))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (79, 85))	('cell growth', 'CPA', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cell growth', 'biological_process', 'GO:0016049', ('149', '160'))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('stem cell phenotype', 'CPA', (38, 57))	('inhibited', 'NegReg', (62, 71))	('suppressed', 'NegReg', (138, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
29134	32290321	In particular, miR-424 knockdown induces cdc42 expression that in turn positively regulates PRDM14 through the activation of p-21-activated kinase 1 (pak1) and stat5 (Figure 1F).	('activation', 'PosReg', (111, 121))	('pak1', 'Gene', '5058', (150, 154))	('regulates', 'Reg', (82, 91))	('knockdown', 'Var', (23, 32))	('p-21-activated kinase 1', 'Gene', '5058', (125, 148))	('stat5', 'Gene', (160, 165))	('cdc42', 'Gene', '998', (41, 46))	('p-21-activated kinase 1', 'Gene', (125, 148))	('pak1', 'Gene', (150, 154))	('miR-424', 'Gene', '494336', (15, 22))	('cdc42', 'Gene', (41, 46))	('miR-424', 'Gene', (15, 22))	('induces', 'PosReg', (33, 40))	('stat5', 'Gene', '6776', (160, 165))	('expression', 'MPA', (47, 57))	('PRDM14', 'Gene', (92, 98))
29141	32290321	As in human ALL, mice with LL induced by Prdm14 aberrant expression showed widespread aneuploidy and copy number alterations, indicating significant chromosomal damage due to failure to activate genes involved in chromosomal stability and DNA repair pathways.	('DNA', 'cellular_component', 'GO:0005574', ('239', '242'))	('human', 'Species', '9606', (6, 11))	('mice', 'Species', '10090', (17, 21))	('aneuploidy', 'Disease', (86, 96))	('DNA repair', 'biological_process', 'GO:0006281', ('239', '249'))	('LL', 'Phenotype', 'HP:0005526', (13, 15))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('aberrant expression', 'Var', (48, 67))	('copy number alterations', 'CPA', (101, 124))	('activate', 'PosReg', (186, 194))	('Prdm14', 'Gene', (41, 47))	('LL', 'Phenotype', 'HP:0005526', (27, 29))
29149	32290321	Consistently, PRDM14 overexpression promoted cell migration through extracellular matrix degradation in a human lung cancer cell line.	('human', 'Species', '9606', (106, 111))	('overexpression', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('degradation', 'biological_process', 'GO:0009056', ('89', '100'))	('lung cancer', 'Disease', (112, 123))	('cell migration', 'biological_process', 'GO:0016477', ('45', '59'))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cell migration', 'CPA', (45, 59))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('68', '88'))	('extracellular matrix degradation', 'CPA', (68, 100))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('PRDM14', 'Gene', (14, 20))	('promoted', 'PosReg', (36, 44))
29152	32290321	More recently, overexpression of PRDM14 was observed also in pancreatic cancer, where it could sustain cell pluripotency; indeed, PRDM14 knockdown suppressed cancer stem-like phenotypes, including liver metastasis, via miR-125a-3p regulating Fyn expression (Figure 1F).	('PRDM14', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppressed', 'NegReg', (147, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('cancer', 'Disease', (158, 164))	('knockdown', 'Var', (137, 146))	('Fyn', 'Gene', (242, 245))	('liver metastasis', 'Disease', 'MESH:D009362', (197, 213))	('Fyn', 'Gene', '2534', (242, 245))	('expression', 'MPA', (246, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('liver metastasis', 'Disease', (197, 213))	('pancreatic cancer', 'Disease', (61, 78))	('cancer', 'Disease', (72, 78))
29154	32290321	Alterations of the 8q13.2 region with PRDM14 copy number gain were also found in intracranial germ cell tumors and in head and neck cancer.	('head and neck cancer', 'Disease', 'MESH:D006258', (118, 138))	('found', 'Reg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('neck', 'cellular_component', 'GO:0044326', ('127', '131'))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PRDM14', 'Gene', (38, 44))	('tumors', 'Disease', (104, 110))	('copy number', 'Var', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (94, 110))	('gain', 'PosReg', (57, 61))
29160	32290321	Later, PRDM14 silencing was found through hypermethylation of its promoter in HPV-positive cancers, and ectopic expression of PRDM14 in HPV16-positive cancer cell lines induced apoptosis, possibly due to a direct upregulation of the pro-apoptotic genes NOXA and PUMA.	('hypermethylation', 'Var', (42, 58))	('PRDM14', 'Gene', (126, 132))	('PUMA', 'Gene', '27113', (262, 266))	('PRDM14', 'Gene', (7, 13))	('HPV-positive cancers', 'Disease', 'MESH:D030361', (78, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (151, 157))	('upregulation', 'PosReg', (213, 225))	('PUMA', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HPV16', 'Species', '333760', (136, 141))	('HPV-positive cancers', 'Disease', (78, 98))	('NOXA', 'Gene', '5366', (253, 257))	('ectopic expression', 'Var', (104, 122))	('apoptosis', 'CPA', (177, 186))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('induced', 'PosReg', (169, 176))	('NOXA', 'Gene', (253, 257))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('silencing', 'NegReg', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))
29167	32290321	PRDM15 was identified as a candidate tumor suppressor gene, since localized homozygous deletions were revealed at 21q22 chromosome region in several pancreatic cancer cell lines.	('PRDM15', 'Gene', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('tumor', 'Disease', (37, 42))	('deletions', 'Var', (87, 96))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('chromosome region', 'cellular_component', 'GO:0098687', ('120', '137'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('PRDM15', 'Gene', '63977', (0, 6))
29176	32290321	Moreover, the aberrant expression of MEL1S/sPRDM16, associated with DNA hypomethylation, was correlated with dysregulation of TGF-beta-mediated signaling suggesting that MEL1S might be responsible for TGF-beta resistance in leukemogenesis of adult T-cell leukemia.	('TGF-beta', 'Gene', (126, 134))	('leukemogenesis of adult T-cell leukemia', 'Disease', 'MESH:D015459', (224, 263))	('correlated', 'Reg', (93, 103))	('MEL1', 'Gene', '63976', (37, 41))	('TGF-beta', 'Gene', '7039', (201, 209))	('leukemogenesis of adult T-cell leukemia', 'Disease', (224, 263))	('MEL1', 'Gene', '63976', (170, 174))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('68', '87'))	('TGF-beta', 'Gene', (201, 209))	('MEL1', 'Gene', (37, 41))	('associated', 'Reg', (52, 62))	('aberrant', 'Var', (14, 22))	('expression', 'MPA', (23, 33))	('MEL1', 'Gene', (170, 174))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('TGF-beta', 'Gene', '7039', (126, 134))	('dysregulation', 'MPA', (109, 122))
29180	32290321	In addition, cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion were detected in a case of progressive CML suggesting that different mechanisms of chromosomal rearrangement may occur in these malignancies.	('CML', 'Phenotype', 'HP:0005506', (154, 157))	('men', 'Species', '9606', (219, 222))	('malignancies', 'Disease', (243, 255))	('CML', 'Disease', (154, 157))	('t(1;21)(p36;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 87))	('cryptic', 'Gene', '55997', (13, 20))	('RUNX1', 'Gene', (57, 62))	('PRDM16', 'Gene', (46, 52))	('cryptic', 'Gene', (13, 20))	('partial deletions', 'Var', (25, 42))	('RUNX1', 'Gene', (95, 100))	('RUNX1', 'Gene', '861', (57, 62))	('RUNX1', 'Gene', '861', (95, 100))	('detected', 'Reg', (120, 128))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
29181	32290321	Successively, additional PRDM16 translocation partners, fusion transcripts and other rearrangements have been detected in leukemia cases with a poor prognosis, most of them showing an upregulation of this gene as a common feature.	('detected', 'Reg', (110, 118))	('PRDM16', 'Gene', (25, 31))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('men', 'Species', '9606', (94, 97))	('upregulation', 'PosReg', (184, 196))	('fusion transcripts', 'Var', (56, 74))
29182	32290321	Actually, several studies have established that high PRDM16 expression is independently associated with adverse outcomes in both adult and pediatric AML patients.	('expression', 'MPA', (60, 70))	('AML', 'Disease', (149, 152))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('patients', 'Species', '9606', (153, 161))	('PRDM16', 'Gene', (53, 59))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('high', 'Var', (48, 52))	('associated with', 'Reg', (88, 103))
29187	32290321	The mouse model of conditional Prdm16 deletion elucidated the role of these two isoforms in normal and leukemic hematopoiesis and identified sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.	('leukemic hematopoiesis', 'Disease', (103, 125))	('mouse', 'Species', '10090', (4, 9))	('inflammation', 'Disease', 'MESH:D007249', (197, 209))	('leukemia', 'Disease', (213, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('leukemia', 'Disease', 'MESH:D007938', (213, 221))	('inflammation', 'Disease', (197, 209))	('leukemic hematopoiesis', 'Disease', 'MESH:C536227', (103, 125))	('Prdm16', 'Gene', (31, 37))	('hematopoiesis', 'biological_process', 'GO:0030097', ('112', '125'))	('deletion', 'Var', (38, 46))	('inflammation', 'biological_process', 'GO:0006954', ('197', '209'))
29188	32290321	To date, rearrangements of the chromosomal region encompassing PRDM16 have been observed not only in hematopoietic malignancies but also in several solid tumors though with different and/or conflicting results, which altogether indicate this gene may function as both oncogene and tumor suppressor gene.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('PRDM16', 'Gene', (63, 69))	('observed', 'Reg', (80, 88))	('men', 'Species', '9606', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('281', '297'))	('rearrangements', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('281', '297'))	('chromosomal region', 'cellular_component', 'GO:0098687', ('31', '49'))	('malignancies', 'Disease', (115, 127))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', (154, 159))
29189	32290321	For instance, genome-wide array based comparative genomic hybridization (array-CGH) defined distinct amplifications in osteosarcoma, involving PRDM16.	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('amplifications', 'Var', (101, 115))	('osteosarcoma', 'Disease', (119, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('PRDM16', 'Gene', (143, 149))
29190	32290321	Otherwise, array-CGH integrated with gene expression analysis of leiomyosarcoma revealed a frequent loss at 1p36, which contains PRDM16, suggesting that this defect could promote muscle differentiation in this context.	('p36', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 79))	('p36', 'Gene', '51251', (109, 112))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('promote', 'PosReg', (171, 178))	('muscle differentiation', 'CPA', (179, 201))	('leiomyosarcoma', 'Disease', (65, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (65, 79))	('defect', 'Var', (158, 164))	('loss', 'NegReg', (100, 104))	('PRDM16', 'Gene', (129, 135))
29191	32290321	Similarly, integrated analysis of uterine leiomyosarcoma revealed PRDM16 deletions and/or reduced expression.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('reduced', 'NegReg', (90, 97))	('PRDM16', 'Gene', (66, 72))	('deletions', 'Var', (73, 82))	('leiomyosarcoma', 'Disease', (42, 56))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (34, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (42, 56))	('expression', 'MPA', (98, 108))
29197	32290321	A possible role as a tumor suppressor gene has been proposed in lung cancer where PRDM16 is aberrantly methylated and its expression is low or absent.	('PRDM16', 'Gene', (82, 88))	('lung cancer', 'Disease', (64, 75))	('absent', 'NegReg', (143, 149))	('expression', 'MPA', (122, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('tumor', 'Disease', (21, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('21', '37'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrantly methylated', 'Var', (92, 113))	('low', 'NegReg', (136, 139))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('21', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
29198	32290321	Accordingly, the median overall survival of both non-small cell lung cancer and LUAD patients with high levels of PRDM16 was significantly longer than that of cases with low levels of this gene.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PRDM16', 'Gene', (114, 120))	('patients', 'Species', '9606', (85, 93))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('longer', 'PosReg', (139, 145))	('high levels', 'Var', (99, 110))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('non-small cell lung cancer', 'Disease', (49, 75))
29203	32290321	Altogether, these findings indicate that PRDM16 methylation status, both hypermethylation and hypomethylation, is often affected in distinct cancers, where this gene can play alternatively a role as an oncogene or as a tumor suppressor gene.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('PRDM16', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('hypermethylation', 'Var', (73, 89))	('tumor', 'Disease', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('219', '235'))	('affected', 'Reg', (120, 128))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('219', '235'))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('hypomethylation', 'MPA', (94, 109))	('methylation', 'Var', (48, 59))	('cancers', 'Disease', (141, 148))
29205	32290321	Additionally, PRDM16 is highly overexpressed also in atypical teratoid/rhabdoid tumor, a highly malignant brain tumor predominantly arising in infants; moreover, it could have a functional role in human rhabdoid tumor cells since PRDM16 knockdown resulted in reduced metabolic activity and proliferation.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (71, 85))	('rhabdoid tumor', 'Disease', (71, 85))	('PRDM16', 'Gene', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('infants', 'Species', '9606', (143, 150))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (203, 217))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('malignant brain tumor', 'Disease', 'MESH:D001932', (96, 117))	('malignant brain tumor', 'Disease', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('metabolic activity', 'CPA', (267, 285))	('rhabdoid tumor', 'Disease', (203, 217))	('reduced', 'NegReg', (259, 266))	('knockdown', 'Var', (237, 246))	('proliferation', 'CPA', (290, 303))	('human', 'Species', '9606', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
29213	32290321	Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production.	('oxygen consumption', 'MPA', (92, 110))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Disease', (59, 64))	('ciRS-133 reduced cancer cachexia', 'Disease', (23, 55))	('decreasing', 'NegReg', (81, 91))	('heat production', 'MPA', (115, 130))	('cachexia', 'Phenotype', 'HP:0004326', (47, 55))	('ciRS-133 reduced cancer cachexia', 'Disease', 'MESH:D002100', (23, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('knockdown', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
29215	32290321	Our TCGA analysis found that PRDM16 gene was mutated in about 6-7% of DLBCL and it was frequently altered in many cases of skin cutaneous melanoma (7.8%) and endometrial carcinoma (5.6%).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (158, 179))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BCL', 'Phenotype', 'HP:0012191', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('skin cutaneous melanoma', 'Disease', (123, 146))	('endometrial carcinoma', 'Disease', (158, 179))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (158, 179))	('PRDM16', 'Gene', (29, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('DLBCL', 'Disease', (70, 75))	('altered', 'Reg', (98, 105))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 146))	('mutated', 'Var', (45, 52))
29235	32290321	Moreover, high expression of ZFPM1 was related with good prognosis of LUAD through the analysis of RNA-seq, DNA methylation, and miRNA-seq data of squamous cell cancer samples downloaded from TCGA.	('DNA methylation', 'biological_process', 'GO:0006306', ('108', '123'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('related', 'Reg', (39, 46))	('LUAD', 'Disease', (70, 74))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('expression', 'MPA', (15, 25))	('squamous cell cancer', 'Disease', (147, 167))	('high', 'Var', (10, 14))	('ZFPM1', 'Gene', (29, 34))	('squamous cell cancer', 'Disease', 'MESH:D002294', (147, 167))	('ZFPM1', 'Gene', '161882', (29, 34))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (147, 167))
29237	32290321	Indeed, our pan-cancer analysis revealed ZFPM1/FOG1 mutation occurrence in about 50% of ACC patients.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('ZFPM1', 'Gene', (41, 46))	('patients', 'Species', '9606', (92, 100))	('ACC', 'Disease', (88, 91))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('ZFPM1', 'Gene', '161882', (41, 46))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
29238	32290321	Interestingly, these mutations were localized in a hotspot region and OncodriveCLUST results suggested it could be putatively considered a cancer driver gene in this malignancy.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('malignancy', 'Disease', (166, 176))	('cancer', 'Disease', (139, 145))
29239	32290321	These results were confirmed by a complete analysis of the mutational data of ACC, which was performed on the same public database and validated through further algorithms (Mutsig and 20/20 rule); this study identified a new ACC-specific gene mutation signature, also comprising ZFPM1 among the six genes.	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('mutation', 'Var', (243, 251))	('ACC-specific', 'Disease', (225, 237))	('ZFPM1', 'Gene', (279, 284))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('ZFPM1', 'Gene', '161882', (279, 284))
29240	32290321	In addition, in our analysis we found that ZFPM1 is mutated also in colorectal cancers at relatively high frequencies.	('colorectal cancers', 'Disease', 'MESH:D015179', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutated', 'Var', (52, 59))	('colorectal cancers', 'Disease', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('ZFPM1', 'Gene', '161882', (43, 48))	('ZFPM1', 'Gene', (43, 48))
29247	32290321	It is known that GATA3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation; FOG2 was shown to act during mammary development even though the consequences of Gata3 gene ablation in murine models were more severe than that of Fog2, whose excision induced premature mammary gland involution.	('induced', 'Reg', (283, 290))	('cell differentiation', 'biological_process', 'GO:0030154', ('92', '112'))	('murine', 'Species', '10090', (218, 224))	('Fog2', 'Gene', '22762', (262, 266))	('Fog2', 'Gene', (262, 266))	('mammary-gland morphogenesis', 'biological_process', 'GO:0060443', ('52', '79'))	('gene', 'Var', (201, 205))	('Gata3', 'Gene', (195, 200))	('Gata3', 'Gene', '14462', (195, 200))	('mammary gland involution', 'biological_process', 'GO:0060056', ('301', '325'))	('men', 'Species', '9606', (158, 161))
29251	32290321	Bioinformatics analysis of microarray data and genotyping of a ZFPM2 polymorphism indicated its possible role in glioma and glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('polymorphism', 'Var', (69, 81))	('ZFPM2', 'Gene', (63, 68))	('role', 'Reg', (105, 109))	('glioma', 'Disease', (113, 119))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
29258	32290321	Indeed, we found that, after PRDM9, ZFPM2/FOG2 was the most mutated PRDM gene with pan-cancer frequencies of protein-affecting mutations higher than 1%; specifically, we detected mutation frequencies higher than 5% in patients with skin cutaneous melanoma, lung tumors, uterine carcinosarcoma, esophageal carcinoma, and stomach and rectum adenocarcinomas.	('skin cutaneous melanoma', 'Disease', (232, 255))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('PRDM9', 'Gene', (29, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (344, 354))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('mutation', 'Var', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('PRDM9', 'Gene', '56979', (29, 34))	('lung tumors', 'Disease', (257, 268))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (294, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (270, 292))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('mutations', 'Var', (127, 136))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 255))	('cancer', 'Disease', (87, 93))	('patients', 'Species', '9606', (218, 226))	('rectum adenocarcinomas', 'Disease', 'MESH:D012004', (332, 354))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinosarcoma', 'Disease', (278, 292))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (294, 314))	('carcinosarcoma', 'Disease', 'MESH:D002296', (278, 292))	('lung tumors', 'Disease', 'MESH:D008175', (257, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('lung tumors', 'Phenotype', 'HP:0100526', (257, 268))	('esophageal carcinoma', 'Disease', (294, 314))	('rectum adenocarcinomas', 'Disease', (332, 354))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
29263	32290321	In this scenario, being involved in a multitude of pathways regulating several cancer-related processes, ranging from cell metabolism to stemness, the pharmacological control of PRDM epigenetic modulators represent a potential multi-target approach in cancer therapy (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (252, 258))	('metabolism', 'biological_process', 'GO:0008152', ('123', '133'))	('epigenetic modulators', 'Var', (183, 204))	('PRDM', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
29264	32290321	A hallmark of cancer is the genomic instability that accounts for the increase in mutation frequency.	('cancer', 'Disease', (14, 20))	('increase', 'PosReg', (70, 78))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('genomic', 'MPA', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
29268	32290321	For instance, PRDM2a/RIZ1 was shown to counteract the IGF-1 receptor and the downstream components ERK1/2 and AKT (Figure 3B).	('ERK1', 'molecular_function', 'GO:0004707', ('99', '103'))	('AKT', 'Gene', (110, 113))	('IGF-1', 'Gene', '3479', (54, 59))	('IGF-1', 'Gene', (54, 59))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('ERK1/2', 'Gene', (99, 105))	('PRDM2a/RIZ1', 'Var', (14, 25))	('AKT', 'Gene', '207', (110, 113))
29292	32290321	PRDM14 knockdown decreased cancer stem-like phenotypes through upregulation of miR-125a-3p that subsequently downregulated Fyna mechanism that is reported to regulate tumor phenotypes in pancreatic cancer (Figure 1F).	('Fyn', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('PRDM14', 'Gene', (0, 6))	('upregulation', 'PosReg', (63, 75))	('decreased', 'NegReg', (17, 26))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', (167, 172))	('Fyn', 'Gene', '2534', (123, 126))	('miR-125a-3p', 'Gene', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('pancreatic cancer', 'Disease', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('downregulated', 'NegReg', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (27, 33))	('knockdown', 'Var', (7, 16))
29300	32290321	Indeed, its silencing in breast cancer cells reduces cancer stem cells phenotype and tumorsphere formation (Table 1 and Figure 1).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (32, 38))	('reduces', 'NegReg', (45, 52))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('silencing', 'Var', (12, 21))	('breast cancer', 'Disease', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
29304	32290321	MAGL blockade impairs migration, invasiveness, and tumorigenicity in aggressive human cancer.	('blockade', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAGL', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (51, 56))	('invasiveness', 'CPA', (33, 45))	('migration', 'CPA', (22, 31))	('impairs', 'NegReg', (14, 21))	('human', 'Species', '9606', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (86, 92))
29309	32290321	Additionally, since some PRDMs (e.g., PRDM1, 9, 11, 14, 16) are able to orchestrate the differentiation of B and T lymphocytes, their involvement in the control of a more incisive immune response to neoplasia cannot be excluded.	('PRDM1', 'Var', (38, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('men', 'Species', '9606', (141, 144))	('neoplasia', 'Disease', 'MESH:D009369', (199, 208))	('immune response', 'biological_process', 'GO:0006955', ('180', '195'))	('neoplasia', 'Disease', (199, 208))	('PRDMs', 'Chemical', '-', (25, 30))
29311	32290321	Currently, as reported for other families, many studies have highlighted the consequences of aberrant isoform expression in triggering tumorigenesis and drug resistance, suggesting that dysregulation of alternative transcription may be a key mechanism leading to cancer progression and drug resistance.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('drug resistance', 'biological_process', 'GO:0042493', ('153', '168'))	('cancer', 'Disease', (263, 269))	('tumor', 'Disease', (135, 140))	('drug resistance', 'biological_process', 'GO:0009315', ('286', '301'))	('drug resistance', 'CPA', (286, 301))	('leading', 'Reg', (252, 259))	('aberrant', 'Var', (93, 101))	('drug resistance', 'CPA', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('drug resistance', 'biological_process', 'GO:0042493', ('286', '301'))	('dysregulation', 'Var', (186, 199))	('transcription', 'biological_process', 'GO:0006351', ('215', '228'))	('drug resistance', 'biological_process', 'GO:0009315', ('153', '168'))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
20899	22355509	Malignant melanoma is a highly malignant tumor, and NRAS and BRAF mutations are mainly involved in the pathogenesis of melanoma.	('NRAS', 'Gene', (52, 56))	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('malignant tumor', 'Disease', (31, 46))	('malignant tumor', 'Disease', 'MESH:D018198', (31, 46))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('involved', 'Reg', (87, 95))	('Malignant melanoma', 'Phenotype', 'HP:0002861', (0, 18))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('NRAS', 'Gene', '4893', (52, 56))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (61, 65))	('Malignant melanoma', 'Disease', 'MESH:D008545', (0, 18))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('Malignant melanoma', 'Disease', (0, 18))	('pathogenesis', 'biological_process', 'GO:0009405', ('103', '115'))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))
20903	22355509	Since KIT and PDGFRA genes are mapped to 4q12, it is anticipated that PDGFRA gene mutations are involved in the tumorigenesis of melanoma, as in the case of gastrointestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('PDGFRA', 'Gene', '5156', (70, 76))	('involved', 'Reg', (96, 104))	('PDGFRA', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('PDGFRA', 'Gene', (14, 20))	('PDGFRA', 'Gene', '5156', (14, 20))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (157, 188))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (157, 188))	('tumor', 'Disease', (182, 187))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (82, 91))	('KIT', 'molecular_function', 'GO:0005020', ('6', '9'))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('gastrointestinal stromal tumors', 'Disease', (157, 188))
29341	22355509	The present study is the forth report of PDGFRA mutations in melanoma; the first was reported by Curtin et al., who found no PDGFRA mutations in 26 cutaneous melanomas.	('PDGFRA', 'Gene', (41, 47))	('PDGFRA', 'Gene', '5156', (41, 47))	('PDGFRA', 'Gene', '5156', (125, 131))	('PDGFRA', 'Gene', (125, 131))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (148, 167))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (148, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('cutaneous melanomas', 'Disease', (148, 167))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('mutations', 'Var', (48, 57))	('melanoma', 'Disease', (158, 166))
20921	22355509	The second was reported by Sihto et al., who demonstrated no PDGFRA gene mutations in 14 cutaneous melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanomas', 'Disease', (89, 108))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('PDGFRA', 'Gene', (61, 67))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (89, 108))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (89, 108))	('PDGFRA', 'Gene', '5156', (61, 67))	('mutations', 'Var', (73, 82))
29345	22355509	Studies of KIT mutations are scant in number in cutaneous melanoma, and there are none in nasal melanoma.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('nasal melanoma', 'Disease', (90, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('mutations', 'Var', (15, 24))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('nasal melanoma', 'Disease', 'MESH:D008545', (90, 104))
20925	22355509	showed only 2% of melanomas had KIT mutations.	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('melanomas', 'Disease', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('KIT mutations', 'Var', (32, 45))
29347	22355509	showed that KIT mutations are present in 39% of mucosal melanomas, in 36% of acral melanomas, 28% in melanomas of sun-damaged skin, and in 0% of melanomas of non-sun-damaged skin.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('KIT', 'Gene', (12, 15))	('melanomas', 'Disease', (83, 92))	('KIT', 'molecular_function', 'GO:0005020', ('12', '15'))	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', 'MESH:D008545', (145, 154))	('mutations', 'Var', (16, 25))	('melanomas', 'Disease', (145, 154))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('acral melanomas', 'Disease', 'MESH:D008545', (77, 92))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('acral melanomas', 'Phenotype', 'HP:0012060', (77, 92))	('melanomas', 'Disease', (56, 65))	('mucosal melanomas', 'Disease', 'MESH:D008545', (48, 65))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('sun-damaged', 'Phenotype', 'HP:0000992', (114, 125))	('sun-damaged', 'Phenotype', 'HP:0000992', (162, 173))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('mucosal melanomas', 'Disease', (48, 65))	('acral melanomas', 'Disease', (77, 92))	('melanomas', 'Disease', (101, 110))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
29348	22355509	recently reported that KIT mutations were present in 23% of acral melanomas, 15.6% of mucosal melanomas, 1.7% of cutaneous melanomas, 7.7% of conjunctival melanomas, and 0% of choroidal melanomas.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('acral melanomas', 'Disease', (60, 75))	('mucosal melanomas', 'Disease', (86, 103))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))	('cutaneous melanomas', 'Disease', (113, 132))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('choroidal melanomas', 'Disease', 'MESH:D008545', (176, 195))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (142, 164))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('acral melanomas', 'Disease', 'MESH:D008545', (60, 75))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('choroidal melanomas', 'Disease', (176, 195))	('acral melanomas', 'Phenotype', 'HP:0012060', (60, 75))	('KIT', 'Gene', (23, 26))	('conjunctival melanomas', 'Disease', (142, 164))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (113, 132))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (113, 132))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (176, 195))	('mucosal melanomas', 'Disease', 'MESH:D008545', (86, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))
29349	22355509	reported that KIT mutation was present in 2% of melanomas and that KIT mutation is frequent in acral and sun-damaged skin melanomas and mucosal melanomas while it was very rare in non-sun-damaged skin melanoma.	('acral', 'Disease', (95, 100))	('KIT', 'Gene', (67, 70))	('sun-damaged', 'Phenotype', 'HP:0000992', (184, 195))	('skin melanoma', 'Disease', (196, 209))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanomas', 'Disease', (122, 131))	('KIT', 'molecular_function', 'GO:0005020', ('67', '70'))	('skin melanomas', 'Disease', (117, 131))	('skin melanomas', 'Disease', 'MESH:D008545', (117, 131))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('melanomas', 'Disease', (144, 153))	('skin melanoma', 'Disease', 'MESH:D008545', (117, 130))	('mucosal melanomas', 'Disease', 'MESH:D008545', (136, 153))	('melanomas', 'Disease', (48, 57))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('KIT', 'molecular_function', 'GO:0005020', ('14', '17'))	('skin melanoma', 'Disease', 'MESH:D008545', (196, 209))	('mutation', 'Var', (71, 79))	('mucosal melanomas', 'Disease', (136, 153))	('sun-damaged', 'Phenotype', 'HP:0000992', (105, 116))	('frequent', 'Reg', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))
29353	22355509	More studies of the relationship between KIT gene mutations and KIT protein expression in nasal melanoma remain to be performed.	('mutations', 'Var', (50, 59))	('nasal melanoma', 'Disease', (90, 104))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('nasal melanoma', 'Disease', 'MESH:D008545', (90, 104))
29366	33202944	The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations.	('worst', 'NegReg', (62, 67))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('overall survival', 'MPA', (68, 84))	('patients', 'Species', '9606', (103, 111))	('BRAF-mutations', 'Gene', (122, 136))	('alteration', 'Var', (16, 26))
29370	33202944	Selective inhibitors of V600E BRAF-mutated melanoma, such as vemurafenib, dabrafenib and encorafenib, prolong survival of patients harboring the V600E mutation.	('V600E', 'Mutation', 'rs113488022', (145, 150))	('V600E', 'Var', (24, 29))	('survival', 'MPA', (110, 118))	('encorafenib', 'Chemical', 'MESH:C000601108', (89, 100))	('V600E', 'Var', (145, 150))	('dabrafenib', 'Chemical', 'MESH:C561627', (74, 84))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('patients', 'Species', '9606', (122, 130))	('BRAF-mutated', 'Gene', (30, 42))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('vemurafenib', 'Chemical', 'MESH:D000077484', (61, 72))	('prolong', 'PosReg', (102, 109))	('V600E', 'Mutation', 'rs113488022', (24, 29))
29371	33202944	However, the onset of tumor resistance observed following this treatment, which was found to be related to the emergence of bypass mutations in resistant tumors that often cause reactivation of the RAS/BRAF/MEK pathway, led to the development of combo therapies with BRAF and MEK inhibitors as the current standard of care.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (22, 27))	('reactivation', 'MPA', (178, 190))	('RAS/BRAF/MEK pathway', 'Pathway', (198, 218))	('tumor', 'Disease', (154, 159))
29386	33202944	According to the first model tumor cells acquire mutations linearly in a step-wise process leading to more malignant stages of cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (49, 58))	('more', 'PosReg', (102, 106))	('leading to', 'Reg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', (29, 34))	('cancer', 'Disease', (127, 133))
29389	33202944	Finally, and differently from the other models, the theory of "punctuate equilibrium" assumes that mutations are not acquired gradually and sequentially over time but in short bursts of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))
29391	33202944	Interestingly, a recent mathematical modeling has revealed that bursts of mutations are the best models able to recapitulate the long-stemmed clonal trees of the evolution of different cancers.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (74, 83))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Disease', (185, 192))
29405	33202944	In this paper we have tried to interpret available data using a bioinformatic approach directed to identify novel targets to selectively hit CSCs in BRAF mutated cutaneous melanomas.	('BRAF', 'Gene', (149, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (162, 181))	('melanomas', 'Disease', (172, 181))	('mutated', 'Var', (154, 161))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))
29407	33202944	Importantly, the signature of genes belonging to this network showed a prognostic potential for BRAF-mutant melanoma patients based on The Cancer Genome Atlas (TCGA) data.	('BRAF-mutant', 'Var', (96, 107))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('BRAF-mutant', 'Gene', (96, 107))	('Cancer', 'Disease', (139, 145))	('patients', 'Species', '9606', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('melanoma', 'Disease', (108, 116))
29413	33202944	(3) These publications were screened to finally obtain a list of 25 top genes, which potentially sustain melanoma stem cell fitness.	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('sustain', 'PosReg', (97, 104))	('melanoma stem cell fitness', 'Disease', 'MESH:D008545', (105, 131))	('genes', 'Var', (72, 77))	('melanoma stem cell fitness', 'Disease', (105, 131))
29421	33202944	have suggested that NF-kappaB inhibition reduces the ability of CSCs to maintain their population within the tumor mass.	('inhibition', 'Var', (30, 40))	('NF-kappaB', 'Gene', '4790', (20, 29))	('reduces', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('NF-kappaB', 'Gene', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
29426	33202944	Paradoxically, inhibition of TP53 was shown to sensitize melanoma cells to BRAF/MEK inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('sensitize', 'Reg', (47, 56))	('melanoma', 'Disease', (57, 65))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('inhibition', 'Var', (15, 25))
29436	33202944	Hence, it is not surprising that the mTORC1/2 inhibitor AZD8055, which triggers MITF cytoplasmic retention, was able to decrease PGC1alpha expression and OXPHOS in melanoma.	('MITF', 'Gene', (80, 84))	('mTORC1/2', 'Gene', (37, 45))	('OXPHOS', 'biological_process', 'GO:0002082', ('154', '160'))	('PGC1alpha', 'Gene', (129, 138))	('decrease', 'NegReg', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('AZD8055', 'Var', (56, 63))	('AZD8055', 'Chemical', 'MESH:C546624', (56, 63))	('mTORC1', 'cellular_component', 'GO:0031931', ('37', '43'))	('mTORC1/2', 'Gene', '74343;382056', (37, 45))	('expression', 'MPA', (139, 149))	('MITF', 'Gene', '4286', (80, 84))	('PGC1alpha', 'Gene', '10891', (129, 138))	('retention', 'biological_process', 'GO:0051235', ('97', '106'))	('OXPHOS', 'MPA', (154, 160))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))
29438	33202944	In line with this finding the novel mitochondrial complex I inhibitor IACS-010759 demonstrated a significant anti-tumor activity as single-agent of in high OXPHOS MAPKi-resistant melanoma models in vivo.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('complex I', 'cellular_component', 'GO:0030964', ('50', '59'))	('tumor', 'Disease', (114, 119))	('OXPHOS', 'biological_process', 'GO:0002082', ('156', '162'))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('IACS-010759', 'Var', (70, 81))
29440	33202944	CSCs maintenance also seems to depend upon the size of the pool of monounsaturated fatty acids (MUFAs) generated by the activity of the stearoyl-CoA desaturase 1 (SCD1) because SCD1 inhibition was shown to selectively eliminate CSCs in lung cancer, both alone and in synergy with chemotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('SCD1', 'Gene', (163, 167))	('stearoyl-CoA desaturase 1', 'Gene', (136, 161))	('CSCs', 'MPA', (228, 232))	('eliminate', 'NegReg', (218, 227))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('inhibition', 'Var', (182, 192))	('SCD1', 'Gene', (177, 181))	('SCD1', 'Gene', '6319', (163, 167))	('monounsaturated fatty acids', 'Chemical', 'MESH:D005229', (67, 94))	('MUFAs', 'Chemical', 'MESH:D005229', (96, 101))	('SCD1', 'Gene', '6319', (177, 181))	('stearoyl-CoA desaturase 1', 'Gene', '6319', (136, 161))	('lung cancer', 'Disease', (236, 247))
29444	33202944	Exposure of BRAF-mutated melanoma cells to inhibitors of the MAPK pathway enhanced stemness features by increasing the expression of YAP/TAZ and downstream genes, but not SCD1.	('SCD1', 'Gene', '6319', (171, 175))	('YAP', 'Gene', (133, 136))	('MAPK', 'Gene', (61, 65))	('inhibitors', 'Var', (43, 53))	('expression', 'MPA', (119, 129))	('TAZ', 'Gene', (137, 140))	('TAZ', 'Gene', '6901', (137, 140))	('YAP', 'Gene', '10413', (133, 136))	('stemness', 'Disease', 'MESH:D020295', (83, 91))	('stemness', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('SCD1', 'Gene', (171, 175))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('melanoma', 'Disease', (25, 33))	('increasing', 'PosReg', (104, 114))	('enhanced', 'PosReg', (74, 82))
29446	33202944	These findings, albeit limited to in vitro studies, underscore the potential role of SCD1 in melanoma progression and suggest the opportunity to further SCD1 inhibitors in combination with MAPK inhibitors for the control of resistance to targeted therapy.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('SCD1', 'Gene', '6319', (85, 89))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('SCD1', 'Gene', (153, 157))	('inhibitors', 'Var', (158, 168))	('MAPK', 'molecular_function', 'GO:0004707', ('189', '193'))	('SCD1', 'Gene', (85, 89))	('SCD1', 'Gene', '6319', (153, 157))
29451	33202944	However, in apparent contrast with Pisanu et al., in this model, loss of SCD1 was accompanied by an increase in cells with an invasive phenotype.	('SCD1', 'Gene', (73, 77))	('loss', 'Var', (65, 69))	('SCD1', 'Gene', '6319', (73, 77))	('cells with an invasive phenotype', 'CPA', (112, 144))	('increase', 'PosReg', (100, 108))
29474	33202944	It is important to point out that the effects of the three most common driver mutations (BRAFmut, RASmut, NF1mut) are influenced by additional mutations in other genes, such as CDKN2A and PTEN.	('CDKN2A', 'Gene', (177, 183))	('RASmut', 'Disease', (98, 104))	('influenced', 'Reg', (118, 128))	('CDKN2A', 'Gene', '1029', (177, 183))	('PTEN', 'Gene', (188, 192))	('PTEN', 'Gene', '5728', (188, 192))	('mutations', 'Var', (143, 152))
29480	33202944	Our results shown as Kaplan-Meyer curves demonstrated that the alteration of the 25 genes is statistically correlated with the worst overall survival (OS) only in the specific subset of BRAFmut melanoma patients (Figure 5).	('correlated', 'Reg', (107, 117))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('patients', 'Species', '9606', (203, 211))	('overall survival', 'MPA', (133, 149))	('alteration', 'Var', (63, 73))	('worst', 'NegReg', (127, 132))
29491	33202944	This hypothesis is supported by the finding that alterations of the expression of genes belonging to "MSCsign" is associated with the worst OS for BRAF mutated melanoma patients based on TCGA data.	('alterations', 'Var', (49, 60))	('patients', 'Species', '9606', (169, 177))	('expression', 'MPA', (68, 78))	('mutated', 'Var', (152, 159))	('melanoma', 'Disease', (160, 168))	('MSCsign', 'Disease', 'None', (102, 109))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('MSCsign', 'Disease', (102, 109))
29495	33202944	Very recently, it has been reported that the inhibition of the fatty acid transporter FATP2 using the specific inhibitor lipofermata reduces the accumulation of lipids and also challenges the mitochondrial metabolism in an aged melanoma microenvironment.	('fatty acid', 'Chemical', 'MESH:D005227', (63, 73))	('reduces', 'NegReg', (133, 140))	('accumulation of lipids', 'MPA', (145, 167))	('FATP2', 'Gene', '11001', (86, 91))	('metabolism', 'biological_process', 'GO:0008152', ('206', '216'))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('inhibition', 'Var', (45, 55))	('mitochondrial metabolism', 'MPA', (192, 216))	('challenges', 'NegReg', (177, 187))	('FATP2', 'Gene', (86, 91))	('lipids', 'Chemical', 'MESH:D008055', (161, 167))
29497	33202944	This study paves the way to additional combinatorial strategies using FATP2 inhibitors together with inhibitors of enzymes involved in MUFAs synthesis, such as SCD itself.	('synthesis', 'biological_process', 'GO:0009058', ('141', '150'))	('inhibitors', 'Var', (76, 86))	('FATP2', 'Gene', (70, 75))	('SCD', 'Gene', '6319', (160, 163))	('SCD', 'Gene', (160, 163))	('FATP2', 'Gene', '11001', (70, 75))	('MUFAs', 'Chemical', 'MESH:D005229', (135, 140))
29503	33202944	Finally, CSCs may also be directly tackled thanks to the use of specific inhibitors of JARID1B despite in this case their clinical development being far from being successfully accomplished.	('CSCs', 'Disease', (9, 13))	('JARID1B', 'Gene', (87, 94))	('inhibitors', 'Var', (73, 83))	('JARID1B', 'Gene', '10765', (87, 94))
29515	31832188	Induction of G0/G1 phase arrest and apoptosis by CRISPR/Cas9-mediated knockout of CDK2 in A375 melanocytes Cutaneous melanoma is one of the most common malignant skin tumors, with a continuously increasing incidence.	('Cas', 'cellular_component', 'GO:0005650', ('56', '59'))	('skin tumors', 'Phenotype', 'HP:0008069', (162, 173))	('CDK2', 'Gene', '1017', (82, 86))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('skin tumor', 'Phenotype', 'HP:0008069', (162, 172))	('arrest', 'Disease', 'MESH:D006323', (25, 31))	('CDK2', 'Gene', (82, 86))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('A375', 'CellLine', 'CVCL:0132', (90, 94))	('G1 phase', 'biological_process', 'GO:0051318', ('16', '24'))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('apoptosis', 'CPA', (36, 45))	('malignant skin tumors', 'Disease', 'MESH:D009369', (152, 173))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('arrest', 'Disease', (25, 31))	('Cutaneous melanoma', 'Disease', (107, 125))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('knockout', 'Var', (70, 78))	('malignant skin tumors', 'Disease', (152, 173))
29517	31832188	In the present study, a lentivirus expressing single-guide RNA (sgRNA) was constructed to knock out CDK2 using CRISP/Cas9 technology, in order to confirm the role of CDK2 in A375 human melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('human', 'Species', '9606', (179, 184))	('A375', 'CellLine', 'CVCL:0132', (174, 178))	('CDK2', 'Gene', (100, 104))	('CDK', 'molecular_function', 'GO:0004693', ('100', '103'))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('Cas', 'cellular_component', 'GO:0005650', ('117', '120'))	('CDK', 'molecular_function', 'GO:0004693', ('166', '169'))	('knock out', 'Var', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
29518	31832188	The results demonstrated that CDK2 knockout induced G0/G1 phase arrest and early apoptosis by downregulating the expression of CDK4 and cyclin A2, and by upregulating the expression of cyclin D1.	('arrest', 'Disease', (64, 70))	('CDK2', 'Gene', (30, 34))	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('G1 phase', 'biological_process', 'GO:0051318', ('55', '63'))	('downregulating', 'NegReg', (94, 108))	('cyclin D1', 'Gene', (185, 194))	('cyclin D1', 'Gene', '595', (185, 194))	('knockout', 'Var', (35, 43))	('expression', 'MPA', (113, 123))	('cyclin', 'molecular_function', 'GO:0016538', ('136', '142'))	('upregulating', 'PosReg', (154, 166))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('CDK', 'molecular_function', 'GO:0004693', ('30', '33'))	('cyclin', 'molecular_function', 'GO:0016538', ('185', '191'))	('CDK4', 'Gene', (127, 131))	('cyclin A2', 'Gene', (136, 145))	('expression', 'MPA', (171, 181))	('CDK', 'molecular_function', 'GO:0004693', ('127', '130'))	('CDK4', 'Gene', '1019', (127, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('cyclin A2', 'Gene', '890', (136, 145))
29527	31832188	Other studies have indicated that the role of CDK2 in cancer is debatable, as CDK2 knockdown failed to inhibit the proliferation of colon cancer cells, and cell proliferation may occur in the absence of CDK2.	('cancer', 'Disease', (138, 144))	('CDK', 'molecular_function', 'GO:0004693', ('46', '49'))	('colon cancer', 'Disease', (132, 144))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))	('knockdown', 'Var', (83, 92))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CDK', 'molecular_function', 'GO:0004693', ('78', '81'))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('cell proliferation', 'CPA', (156, 174))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('CDK2', 'Gene', (78, 82))	('inhibit', 'NegReg', (103, 110))	('CDK', 'molecular_function', 'GO:0004693', ('203', '206'))
29547	31832188	A375 cells were seeded in 6-well plates and infected with sgCDK2-108 or sgCDK2-NC lentivirus.	('sgCDK2-NC', 'Var', (72, 81))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('infected', 'Disease', (44, 52))	('infected', 'Disease', 'MESH:D007239', (44, 52))
29549	31832188	The cells were resuspended in PBS containing RNase A (100 microg/ml) at 37 C for 30 min, then stained with propidium iodide (WLA010a; Wanleibio) at 4 C for 30 min.	('propidium iodide', 'Chemical', 'MESH:D011419', (107, 123))	('RNase A', 'Gene', (45, 52))	('RNase A', 'Gene', '6035', (45, 52))	('100 microg/ml', 'Var', (54, 67))	('WLA010a', 'Chemical', '-', (125, 132))
29553	31832188	The results demonstrated that >80% of A375 cells expressed GFP among the sgCDK2-110, sgCDK2-108 and sgCDK2-NC groups (Fig.	('A375', 'CellLine', 'CVCL:0132', (38, 42))	('sgCDK2-108', 'Var', (85, 95))	('GFP', 'Var', (59, 62))
29554	31832188	The qPCR results revealed that the mRNA levels of CDK2 were significantly downregulated in A375 cells infected by lentiviruses sgCDK2-110 and sgCDK2-108 compared with sgCDK2-NC (P<0.05; Fig.	('infected', 'Disease', 'MESH:D007239', (102, 110))	('A375', 'CellLine', 'CVCL:0132', (91, 95))	('mRNA levels', 'MPA', (35, 46))	('sgCDK2-110', 'Gene', (127, 137))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('infected', 'Disease', (102, 110))	('sgCDK2-108', 'Var', (142, 152))	('CDK2', 'Gene', (50, 54))	('downregulated', 'NegReg', (74, 87))
29555	31832188	The results were further confirmed by western blotting, which demonstrated that the CDK2 was knocked out in A375 cells infected by lentiviruses sgCDK2-110 and sgCDK2-108, particularly sgCDK2-108 (P<0.05; Fig.	('infected', 'Disease', (119, 127))	('sgCDK2-108', 'Var', (159, 169))	('sgCDK2-110', 'Gene', (144, 154))	('A375', 'CellLine', 'CVCL:0132', (108, 112))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('knocked out', 'NegReg', (93, 104))	('CDK2', 'Gene', (84, 88))	('infected', 'Disease', 'MESH:D007239', (119, 127))
29559	31832188	The percentage of cells in the G0/G1 phase among lentivirus sgCDK2-108-infected A375 cells was significantly higher (81.78%) compared with lentivirus sgCDK2-NC (69.06%); however, the percentage of S phase cells in the sgCDK2-108 group was significantly reduced (7.85%) compared with the sgCDK2-NC group (15.38%) (P<0.05; Fig.	('infected', 'Disease', 'MESH:D007239', (71, 79))	('S phase', 'biological_process', 'GO:0051320', ('197', '204'))	('lentivirus', 'Var', (49, 59))	('infected', 'Disease', (71, 79))	('higher', 'PosReg', (109, 115))	('S phase cells', 'CPA', (197, 210))	('G1 phase', 'biological_process', 'GO:0051318', ('34', '42'))	('A375', 'CellLine', 'CVCL:0132', (80, 84))	('reduced', 'NegReg', (253, 260))
29560	31832188	These results indicated that CDK2 knockout induces G0/G1 phase arrest in A375 cells.	('induces', 'Reg', (43, 50))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('G1 phase', 'biological_process', 'GO:0051318', ('54', '62'))	('A375', 'CellLine', 'CVCL:0132', (73, 77))	('arrest', 'Disease', (63, 69))	('knockout', 'Var', (34, 42))	('CDK2', 'Gene', (29, 33))	('CDK', 'molecular_function', 'GO:0004693', ('29', '32'))
29561	31832188	Apoptosis was then analyzed in A375 cells infected with lentiviruses sgCDK2-108 or sgCDK2-NC.	('infected', 'Disease', 'MESH:D007239', (42, 50))	('sgCDK2-NC', 'Var', (83, 92))	('infected', 'Disease', (42, 50))	('A375', 'CellLine', 'CVCL:0132', (31, 35))
29564	31832188	3B), suggesting that knockout of CDK2 induces early apoptosis in A375 cells.	('CDK', 'molecular_function', 'GO:0004693', ('33', '36'))	('A375', 'CellLine', 'CVCL:0132', (65, 69))	('induces', 'Reg', (38, 45))	('knockout', 'Var', (21, 29))	('CDK2', 'Gene', (33, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
29569	31832188	Previous studies demonstrated that the colony-forming ability and cell viability were markedly inhibited by knockdown of myosin VI using lentivirus-mediated shRNA in A375 melanocytes.	('myosin VI', 'Gene', '4646', (121, 130))	('knockdown', 'Var', (108, 117))	('myosin VI', 'Gene', (121, 130))	('cell viability', 'CPA', (66, 80))	('inhibited', 'NegReg', (95, 104))	('A375', 'CellLine', 'CVCL:0132', (166, 170))	('colony-forming ability', 'CPA', (39, 61))
29572	31832188	CRISP/Cas9 technology is a reliable method for gene editing, and CRISP/Cas9-mediated knockout of the PDEF gene significantly inhibited the migration and invasion of AGS human gastric cancer cells by transfection with pX459-PDEF-sgRNA plasmids.	('Cas', 'cellular_component', 'GO:0005650', ('6', '9'))	('PDEF', 'Gene', (101, 105))	('gastric cancer', 'Disease', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('knockout', 'Var', (85, 93))	('human', 'Species', '9606', (169, 174))	('PDEF', 'Gene', '25803', (223, 227))	('gastric cancer', 'Disease', 'MESH:D013274', (175, 189))	('Cas', 'cellular_component', 'GO:0005650', ('71', '74'))	('inhibited', 'NegReg', (125, 134))	('PDEF', 'Gene', '25803', (101, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('PDEF', 'Gene', (223, 227))
29574	31832188	CDK2 is a key regulator of the G1/S and S/G2 cell cycle transitions; however, genetic deletion of CDK2 in p27 (Kip1)-null mice failed to suppress the development of pituitary tumors.	('pituitary tumors', 'Disease', 'MESH:D010911', (165, 181))	('mice', 'Species', '10090', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('p27', 'Gene', (106, 109))	('development', 'CPA', (150, 161))	('pituitary tumors', 'Disease', (165, 181))	('Kip1', 'Gene', '12576', (111, 115))	('S/G2', 'Var', (40, 44))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('S/G2', 'SUBSTITUTION', 'None', (40, 44))	('suppress', 'NegReg', (137, 145))	('CDK', 'molecular_function', 'GO:0004693', ('98', '101'))	('p27', 'Gene', '12576', (106, 109))	('cell cycle', 'biological_process', 'GO:0007049', ('45', '55'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CDK2', 'Gene', (98, 102))	('Kip1', 'Gene', (111, 115))
29576	31832188	Additionally, ablation of CDK2 significantly delayed S-M progression and downregulated the expression of CDK6.	('CDK6', 'Gene', '1021', (105, 109))	('expression', 'MPA', (91, 101))	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('CDK6', 'Gene', (105, 109))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('delayed', 'NegReg', (45, 52))	('downregulated', 'NegReg', (73, 86))	('CDK2', 'Gene', (26, 30))	('S-M progression', 'CPA', (53, 68))	('ablation', 'Var', (14, 22))
29581	31832188	The results revealed a successful lentivirus-mediated knockout of CDK2 using CRISP/Cas9 technology; the expression of CDK2 was also completely knocked out in A375 cells.	('A375', 'CellLine', 'CVCL:0132', (158, 162))	('knockout', 'Var', (54, 62))	('Cas', 'cellular_component', 'GO:0005650', ('83', '86'))	('CDK2', 'Gene', (66, 70))	('CDK', 'molecular_function', 'GO:0004693', ('66', '69'))	('expression', 'MPA', (104, 114))	('CDK2', 'Gene', (118, 122))	('knocked out', 'NegReg', (143, 154))	('CDK', 'molecular_function', 'GO:0004693', ('118', '121'))
29583	31832188	Further study demonstrated that the loss of CDK2 function significantly increased the percentage of cells in the G0/G1 phase and induced G0/G1 phase arrest.	('G1 phase', 'biological_process', 'GO:0051318', ('116', '124'))	('increased', 'PosReg', (72, 81))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('induced', 'Reg', (129, 136))	('loss', 'Var', (36, 40))	('arrest', 'Disease', (149, 155))	('G1 phase', 'biological_process', 'GO:0051318', ('140', '148'))	('CDK2', 'Gene', (44, 48))	('CDK', 'molecular_function', 'GO:0004693', ('44', '47'))
29591	31832188	In the present study, apoptosis of A375 cells occurred following knockout of CDK2 by flow cytometry, but the changes of apoptotic-related proteins, such PARP, caspase-3 and BCL-2, were not evaluated by western blotting, which is another limitation of this study.	('CDK2', 'Gene', (77, 81))	('caspase-3', 'Gene', (159, 168))	('BCL-2', 'molecular_function', 'GO:0015283', ('173', '178'))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('apoptosis', 'CPA', (22, 31))	('A375', 'CellLine', 'CVCL:0132', (35, 39))	('caspase-3', 'Gene', '836', (159, 168))	('PARP', 'Gene', '1302', (153, 157))	('BCL-2', 'Gene', '596', (173, 178))	('knockout', 'Var', (65, 73))	('PARP', 'Gene', (153, 157))	('BCL-2', 'Gene', (173, 178))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))
29592	31832188	Further research will focus on the mechanism of apoptosis of A375 cells following CDK2 knockout by a lentiviral CRISP/Cas9 system.	('knockout', 'Var', (87, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('Cas', 'cellular_component', 'GO:0005650', ('118', '121'))	('A375', 'CellLine', 'CVCL:0132', (61, 65))	('CDK2', 'Gene', (82, 86))
29595	31832188	Therefore, knockout of CDK2 by CRISPR/Cas9 technology may provide a novel therapeutic approach to cutaneous melanoma.	('Cas', 'cellular_component', 'GO:0005650', ('38', '41'))	('cutaneous melanoma', 'Disease', (98, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))	('knockout', 'Var', (11, 19))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('CDK2', 'Gene', (23, 27))
29663	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))	('melanoma', 'Disease', (250, 258))	('genes', 'Var', (58, 63))	('pigmentation', 'Disease', (105, 117))	('nevi', 'Disease', (89, 93))	('MTAP', 'Gene', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('pigmentation', 'biological_process', 'GO:0043473', ('105', '117'))	('MTAP', 'Gene', '4507', (95, 99))
29691	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))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('NRAS', 'Gene', '4893', (17, 21))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
29693	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))	('KRAS', 'Gene', '3845', (128, 132))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))	('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))
29695	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))
29696	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))
29697	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))
29698	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))
29702	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))	('NRAS', 'Gene', (9, 13))	('tumor', 'Disease', (70, 75))	('NRAS', 'Gene', '4893', (9, 13))	('associated', 'Reg', (54, 64))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
29703	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))
29707	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.	('BRAF', 'Gene', (153, 157))	('melanocytic neoplasia', 'Disease', (220, 241))	('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))
29709	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))
29711	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))
29712	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))	('melanomas', 'Disease', (43, 52))	('BRAF', 'Gene', (186, 190))	('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))
29714	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))
29716	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))
29717	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))
29718	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))
29719	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))
29720	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))
29729	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))
29734	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))
29736	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))	('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))	('mucosal melanomas', 'Disease', 'MESH:D008545', (271, 288))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanomas', 'Phenotype', 'HP:0002861', (279, 288))
29738	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))
29740	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))
29741	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))
29742	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))	('malignant melanocytic neoplasms', 'Disease', (33, 64))	('blue nevi', 'Disease', (107, 116))	('uveal melanomas', 'Disease', (121, 136))	('GNAQ', 'Gene', (99, 103))	('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))
29743	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))	('affected', 'Reg', (114, 122))	('GTP', 'Chemical', 'MESH:D006160', (177, 180))	('codon 209', 'Var', (123, 132))	('GTPase', 'Enzyme', (177, 183))	('mutations', 'Var', (4, 13))	('GTP-bound', 'MPA', (215, 224))	('GTP', 'Chemical', 'MESH:D006160', (215, 218))	('crippled', 'NegReg', (164, 172))
29744	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))
29745	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))
29746	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))
29747	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))
29748	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))
29749	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))
29783	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'))
29784	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'))
29790	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))
29793	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))
29794	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))	('GNAQ', 'Gene', (99, 103))	('NRAS', 'Gene', (157, 161))	('uveal melanoma', 'Disease', (26, 40))	('KIT pathways', 'Pathway', (166, 178))	('BRAF', 'Gene', (151, 155))	('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))
29795	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))
29797	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))
29798	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))
29799	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))
29800	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))
29802	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))
29804	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))
29811	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))
29818	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))
29824	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))
29826	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))
29831	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))
29832	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))
29833	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))
29834	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))
29835	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))
29836	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))
29839	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))
29841	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))
29850	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))
29851	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))
29854	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))
29858	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))	('lesions', 'MPA', (322, 329))	('mutations', 'Var', (140, 149))	('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))
29859	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))	('neoplasm', 'Phenotype', 'HP:0002664', (180, 188))	('neoplasms', 'Disease', 'MESH:D009369', (180, 189))	('neoplasms', 'Disease', (180, 189))	('mutations', 'Var', (209, 218))	('give rise', 'Reg', (158, 167))
29862	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))
29863	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))
29866	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))
29867	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))
29922	33679809	DNA methylation is a form of DNA chemical modification, and as an essential regulator of gene transcription, can be carcinogenic.	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('carcinogenic', 'Disease', 'MESH:D063646', (116, 128))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('transcription', 'biological_process', 'GO:0006351', ('94', '107'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('carcinogenic', 'Disease', (116, 128))	('methylation', 'Var', (4, 15))
29945	33679809	Kaplan-Meier survival analysis also demonstrated that among patients with CESC (Figure 3D; p = 0.021), DLBC (Figure 3E; p = 0.009), LUAD (Figure 3H; p = 0.020), THCA (Figure 3I; p = 0.013), and SKCM (Figure 3G, p = 0.029), those with high levels of TREM2 had longer survival times, while in patients with LGG (Figure 3B; P = 0.003), LIHC (Figure 3C; p = 0.006), and KIRC (Figure 3F; p = 0.014), high TREM2 expression was associated with poor OS.	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('patients', 'Species', '9606', (60, 68))	('THCA', 'Phenotype', 'HP:0002890', (161, 165))	('high', 'Var', (395, 399))	('patients', 'Species', '9606', (291, 299))	('poor OS', 'Disease', (437, 444))	('survival times', 'CPA', (266, 280))	('longer', 'PosReg', (259, 265))	('expression', 'MPA', (406, 416))	('TREM2', 'Gene', (400, 405))
29950	33679809	KM analysis showed that individuals with in CESC (Figure 5B; p = 0.001) and DLBC (Figure 5E; p = 0.003) and high levels of TREM2 expression had longer survival times, while patients with LGG (Figure 5C; p = 0.005) and PRAD (Figure 5D; p < 0.001) and high TREM2 expression had poor PFI.	('survival times', 'CPA', (151, 165))	('patients', 'Species', '9606', (173, 181))	('longer', 'PosReg', (144, 150))	('expression', 'MPA', (261, 271))	('PFI', 'molecular_function', 'GO:0034016', ('281', '284'))	('high', 'Var', (108, 112))	('TREM2', 'Gene', (123, 128))	('TREM2', 'Gene', (255, 260))
29980	33679809	TREM2 methylation level was a protective factor in patients with mesothelioma, uveal melanoma, and liver cancer, in terms of OS (Figure 12B).	('methylation level', 'Var', (6, 23))	('liver cancer', 'Disease', (99, 111))	('mesothelioma', 'Disease', (65, 77))	('TREM2', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('patients', 'Species', '9606', (51, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (99, 111))	('liver cancer', 'Disease', 'MESH:D006528', (99, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
29990	33679809	The results demonstrate that TREM2 expression is positively associated with several immune cell-related pathways, including B, CD4 T, and CD8 T cells, and immune factor-related pathways such as TNF, cell migration, and synaptic pruning.	('cell migration', 'CPA', (199, 213))	('immune cell-related pathways', 'Pathway', (84, 112))	('TREM2', 'Gene', (29, 34))	('CD4', 'Gene', '920', (127, 130))	('synaptic pruning', 'CPA', (219, 235))	('associated', 'Reg', (60, 70))	('CD8', 'Gene', (138, 141))	('TNF', 'Gene', (194, 197))	('CD8', 'Gene', '925', (138, 141))	('TNF', 'Gene', '7124', (194, 197))	('cell migration', 'biological_process', 'GO:0016477', ('199', '213'))	('CD4', 'Gene', (127, 130))	('expression', 'Var', (35, 45))
29999	33679809	Similarly, TREM2 expression was previously reported as associated with shorter survival time in patients with gastric cancer.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('survival time', 'CPA', (79, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TREM2', 'Gene', (11, 16))	('expression', 'Var', (17, 27))	('patients', 'Species', '9606', (96, 104))	('shorter', 'NegReg', (71, 78))
30002	33679809	In contrast, high TREM2 expression is associated with good prognosis in patients with CESC, LUAD, and THCA.	('CESC', 'Disease', (86, 90))	('THCA', 'Phenotype', 'HP:0002890', (102, 106))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('THCA', 'Disease', (102, 106))	('LUAD', 'Disease', (92, 96))	('TREM2', 'Gene', (18, 23))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('patients', 'Species', '9606', (72, 80))
30014	33679809	High-frequency MSI in colorectal cancer is an independent predictor of clinical characteristics and prognosis.	('colorectal cancer', 'Disease', (22, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('High-frequency MSI', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))
30026	33679809	These results all indicate that expression of TREM2 is closely related to immune infiltration of tumor cells, affects patient prognosis, and proposes new targets for the development of immunosuppressants.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patient prognosis', 'CPA', (118, 135))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'Var', (32, 42))	('tumor', 'Disease', (97, 102))	('affects', 'Reg', (110, 117))	('related', 'Reg', (63, 70))	('patient', 'Species', '9606', (118, 125))	('TREM2', 'Gene', (46, 51))
30036	31754644	Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers Malignant cells reconfigure their metabolism to support oncogenic processes such as accelerated growth and proliferation.	('cancers', 'Disease', (93, 100))	('metabolism', 'MPA', (135, 145))	('Metabolic gene', 'Gene', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('accelerated growth', 'CPA', (185, 203))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('alterations', 'Var', (15, 26))	('aggressiveness', 'Phenotype', 'HP:0000718', (47, 61))	('proliferation', 'CPA', (208, 221))	('metabolism', 'biological_process', 'GO:0008152', ('135', '145'))	('drug responses', 'CPA', (66, 80))	('impact', 'Reg', (27, 33))	('aggressiveness', 'Disease', 'MESH:D001523', (47, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('aggressiveness', 'Disease', (47, 61))
30038	31754644	We find that mutations and copy number variations of metabolic genes are pervasive across all human cancers.	('metabolic genes', 'Gene', (53, 68))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (94, 99))	('mutations', 'Var', (13, 22))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('copy number variations', 'Var', (27, 49))	('cancers', 'Disease', (100, 107))
30039	31754644	Based on the frequencies of metabolic gene alterations, we further find that there are two distinct cancer supertypes that tend to be associated with different clinical outcomes.	('metabolic gene', 'Gene', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
30045	31754644	Although many of the metabolic processes occurring in cancer cells are similar to those occurring in healthy proliferating cells, a series of genetic and epigenetic modifications in cancer cells can result in the aberrant regulation of these processes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('regulation', 'MPA', (222, 232))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('genetic', 'Var', (142, 149))	('cancer', 'Disease', (182, 188))	('aberrant', 'Reg', (213, 221))	('result in', 'Reg', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('regulation', 'biological_process', 'GO:0065007', ('222', '232'))	('epigenetic modifications', 'Var', (154, 178))
30046	31754644	These alterations include diverse driver mutations and gene copy number alterations, which can impart a substantial degree of metabolic heterogeneity to different tumours of the same cancer type.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (183, 189))	('tumours', 'Disease', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gene copy number alterations', 'Var', (55, 83))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumours', 'Disease', 'MESH:D009369', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
30048	31754644	These and other studies have also yielded a growing appreciation of how the aberrant metabolic changes in cancer cells influence the anticancer drug responses of different tumours.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('metabolic changes', 'CPA', (85, 102))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('influence', 'Reg', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('aberrant', 'Var', (76, 84))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (137, 143))	('tumours', 'Disease', (172, 179))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
30055	31754644	Valuable in this regard, are large-scale drug response screening projects such as the Genomics of Drug Sensitivity in Cancer (GDSC;) and the Cancer Cell Line Encyclopedia which provide transcriptome and epigenetic profiles for over one thousand human cancer cell lines together with their dose-response profiles to hundreds of anticancer drugs.	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (98, 114))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('human', 'Species', '9606', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('epigenetic', 'Var', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', (251, 257))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
30066	31754644	For instance, mutations of PIK3CA reprogramme metabolism and are associated with poorer survival outcomes in several cancers, including those of the colon, rectum, breast and lungs.	('rectum', 'Disease', (156, 162))	('lungs', 'Disease', (175, 180))	('breast', 'Disease', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('metabolism', 'biological_process', 'GO:0008152', ('46', '56'))	('PIK3CA', 'Gene', (27, 33))	('associated', 'Reg', (65, 75))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('reprogramme', 'Reg', (34, 45))	('PIK3CA', 'Gene', '5290', (27, 33))	('colon', 'Disease', (149, 154))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('mutations', 'Var', (14, 23))	('poorer', 'NegReg', (81, 87))	('cancers', 'Disease', (117, 124))
30072	31754644	We clustered the 32 human cancers based on the frequencies of gene alterations of metabolic pathways.	('human', 'Species', '9606', (20, 25))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gene alterations', 'Var', (62, 78))	('metabolic pathways', 'Pathway', (82, 100))
30083	31754644	We found that alterations to genes involved in second-tier pathways were more frequent in the HM cancers than in the LM cancers (Fig.	('alterations', 'Var', (14, 25))	('genes', 'Gene', (29, 34))	('HM cancers', 'Disease', (94, 104))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HM cancers', 'Disease', 'MESH:D009369', (94, 104))	('frequent', 'Reg', (78, 86))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('second-tier', 'Pathway', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('LM cancer', 'Phenotype', 'HP:0002665', (117, 126))
30091	31754644	We anticipate that studying alterations of selenoamino acid metabolism could yield targets for the development of new therapeutics and predictive biomarkers that would aid the treatment of various cancers.	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('selenoamino acid', 'Chemical', 'MESH:D000596', (43, 59))	('alterations', 'Var', (28, 39))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancers', 'Disease', (197, 204))	('selenoamino acid metabolism', 'MPA', (43, 70))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('metabolism', 'biological_process', 'GO:0008152', ('60', '70'))
30095	31754644	Since the changes in phospholipid metabolism can affect the proliferation of cancer cells and their responses to drugs, it is plausible that at least some of the observed alterations in genes involved in phospholipid metabolism may have biological and clinical relevance.	('responses to drugs', 'MPA', (100, 118))	('affect', 'Reg', (49, 55))	('proliferation', 'CPA', (60, 73))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('phospholipid metabolism', 'biological_process', 'GO:0006644', ('204', '227'))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('phospholipid metabolism', 'MPA', (21, 44))	('changes', 'Var', (10, 17))	('phospholipid metabolism', 'biological_process', 'GO:0006644', ('21', '44'))
30100	31754644	We discovered that 78% of all tumours harbour alteration in these genes (Fig.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('alteration', 'Var', (46, 56))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
30103	31754644	Collectively these results reiterate that alterations within genes involved in particular aspects of lipid, carbohydrate and amino acid metabolism are found in many different cancers.	('carbohydrate', 'Chemical', 'MESH:D002241', (108, 120))	('alterations', 'Var', (42, 53))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('metabolism', 'biological_process', 'GO:0008152', ('136', '146'))	('cancers', 'Disease', (175, 182))	('found', 'Reg', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
30130	31754644	Among these, afatinib, CP724714 and gefitinib target the EGFR signalling pathway, whereas TAK-715 targets JNK and p38 signalling, and vinorelbine inhibits mitosis by destabilising microtubules (Supplementary file 2).	('destabilising', 'NegReg', (166, 179))	('mitosis', 'biological_process', 'GO:0000278', ('155', '162'))	('CP724714', 'Var', (23, 31))	('target', 'Reg', (46, 52))	('p38', 'Gene', (114, 117))	('EGFR', 'Gene', (57, 61))	('afatinib', 'Chemical', 'MESH:C522924', (13, 21))	('inhibits', 'NegReg', (146, 154))	('microtubules', 'MPA', (180, 192))	('CP724714', 'Chemical', 'MESH:C521104', (23, 31))	('mitosis', 'CPA', (155, 162))	('p38', 'Gene', '1432', (114, 117))	('signalling pathway', 'biological_process', 'GO:0007165', ('62', '80'))	('JNK', 'MPA', (106, 109))	('EGFR', 'molecular_function', 'GO:0005006', ('57', '61'))	('vinorelbine', 'Chemical', 'MESH:C030852', (134, 145))	('signalling', 'biological_process', 'GO:0023052', ('118', '128'))	('EGFR', 'Gene', '1956', (57, 61))	('JNK', 'molecular_function', 'GO:0004705', ('106', '109'))	('gefitinib', 'Chemical', 'MESH:C419708', (36, 45))
30138	31754644	Since the frequencies of alterations to genes involved in metabolic pathways are likely to influence the responses of patients to anticancer drugs, we identified GDSC cancer cell lines displaying similar gene alterations to those found in individual primary tumours to test whether this might be the case (see methods section).	('alterations', 'Var', (25, 36))	('primary tumours', 'Disease', (250, 265))	('primary tumours', 'Disease', 'MESH:D009369', (250, 265))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('influence', 'Reg', (91, 100))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('responses', 'MPA', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (118, 126))
30142	31754644	Also, cell lines of lung adenocarcinoma with alterations in genes involved in the biological oxidation pathways are more resistant to 52 anticancer drugs than are those without alterations to these genes (Fig.	('alterations', 'Var', (45, 56))	('lung adenocarcinoma', 'Disease', (20, 39))	('resistant', 'CPA', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (20, 39))	('cancer', 'Disease', (141, 147))
30143	31754644	Altogether, we found 2186 instances where alterations to genes involved in a specific metabolic pathway are associated with the efficacy of anticancer drugs in the cancer cell lines (Supplementary file 2).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('alterations', 'Var', (42, 53))	('genes', 'Gene', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (164, 170))	('associated', 'Reg', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('efficacy', 'MPA', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
30146	31754644	Given that we had found that tumours displaying different numbers of alterations to metabolic genes exhibit different clinical and survival outcomes, we decided to examine this in more detail for particular cancer types.	('alterations', 'Var', (69, 80))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('metabolic genes', 'Gene', (84, 99))	('tumours', 'Disease', (29, 36))	('particular cancer', 'Disease', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('particular cancer', 'Disease', 'MESH:D009369', (196, 213))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
30147	31754644	Using data of primary cancers from the TCGA, for patients' tumours with or without alterations in genes involved in abacavir metabolism, we found that the durations of the disease-free progression periods were significantly lower for oesophageal adenocarcinoma patients with alterations to these genes (log rank p = 0.004; Fig.	('patients', 'Species', '9606', (261, 269))	('abacavir', 'Chemical', 'MESH:C106538', (116, 124))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('metabolism', 'biological_process', 'GO:0008152', ('125', '135'))	('cancers', 'Disease', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('oesophageal adenocarcinoma', 'Disease', (234, 260))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('lower', 'NegReg', (224, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('patients', 'Species', '9606', (49, 57))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (234, 260))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', (59, 66))	('alterations', 'Var', (275, 286))
30148	31754644	Conversely, disease-free progression periods were higher for uterine corpus endometrial carcinoma patients with alterations to genes involved in abacavir metabolism (log rank p = 0.041; Fig.	('higher', 'PosReg', (50, 56))	('disease-free progression periods', 'CPA', (12, 44))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (76, 97))	('metabolism', 'biological_process', 'GO:0008152', ('154', '164'))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('endometrial carcinoma', 'Disease', (76, 97))	('abacavir', 'Chemical', 'MESH:C106538', (145, 153))	('alterations', 'Var', (112, 123))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))
30149	31754644	This then indicates that, even within each cancer type, the numbers of alterations found in metabolic genes involved in particular pathways can, in addition to influencing anticancer drug responses, detectably impact patient survival.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patient survival', 'CPA', (217, 233))	('cancer', 'Disease', (43, 49))	('metabolic genes', 'Gene', (92, 107))	('patient', 'Species', '9606', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('alterations', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('influencing', 'Reg', (160, 171))	('impact', 'Reg', (210, 216))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
30150	31754644	We examined the relationships between the numbers of alterations within the metabolic genes of primary tumours and cell lines of 32 different human cancer types and both clinical outcomes and likely drug responses.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('primary tumours', 'Disease', (95, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('alterations', 'Var', (53, 64))	('human', 'Species', '9606', (142, 147))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('metabolic genes', 'Gene', (76, 91))	('primary tumours', 'Disease', 'MESH:D009369', (95, 110))
30155	31754644	Just as others have shown that alterations of genes involved in signalling pathways can have clinical implications, we show here that individuals with HM tumours tend to have worse clinical outcomes than those afflicted with LM tumours.	('LM tumours', 'Disease', (225, 235))	('alterations', 'Var', (31, 42))	('worse', 'NegReg', (175, 180))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('HM tumours', 'Disease', 'MESH:D009369', (151, 161))	('signalling', 'biological_process', 'GO:0023052', ('64', '74'))	('HM tumours', 'Disease', (151, 161))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('LM tumours', 'Disease', 'MESH:D009369', (225, 235))	('tumours', 'Phenotype', 'HP:0002664', (228, 235))
30157	31754644	Our analyses indicate that alterations of genes involved in the central metabolic pathways and the regulators of these pathways are pervasive across all human cancers (Fig.	('cancers', 'Disease', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('alterations', 'Var', (27, 38))
30159	31754644	In various cancers, MYC and HIF1A alterations dysregulate multiple metabolic enzymes including, hexokinase, isocitrate dehydrogenase, pyruvate dehydrogenase kinase and lactate dehydrogenase.	('MYC', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HIF1A', 'Gene', '3091', (28, 33))	('isocitrate dehydrogenase', 'Enzyme', (108, 132))	('alterations', 'Var', (34, 45))	('pyruvate', 'Chemical', 'MESH:D011773', (134, 142))	('MYC', 'Gene', '4609', (20, 23))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('pyruvate dehydrogenase kinase', 'Enzyme', (134, 163))	('hexokinase', 'Gene', (96, 106))	('lactate dehydrogenase', 'Enzyme', (168, 189))	('HIF1A', 'Gene', (28, 33))	('isocitrate', 'Chemical', 'MESH:D007523', (108, 118))	('dysregulate', 'Reg', (46, 57))	('metabolic enzymes', 'Enzyme', (67, 84))	('hexokinase', 'Gene', '3098', (96, 106))	('lactate', 'Chemical', 'MESH:D019344', (168, 175))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))
30173	31754644	Taking a step back, we are reminded that among tumours that are derived from any particular tissue, there exist distinct tumour subtypes that differ from one another both in the gene alterations they display, and in the actual metabolic perturbations that these gene alterations cause.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('gene alterations', 'MPA', (178, 194))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumour', 'Disease', (47, 53))	('alterations', 'Var', (267, 278))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumours', 'Disease', (47, 54))	('tumour', 'Disease', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
30176	31754644	This then supports the assertion that for any given cancer patient, the overall landscape of metabolic gene alterations could be used to identify generally applicable anticancer drug classes, following which alterations to specific metabolic genes could be used to eliminate the remaining drug choices that have the highest chances of failure.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('alterations', 'Var', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('patient', 'Species', '9606', (59, 66))	('cancer', 'Disease', (171, 177))	('alterations', 'Var', (208, 219))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
30177	31754644	Our results have revealed that within each of the 32 cancer types, there exist subtypes that have alterations in genes that are involved in metabolic pathways that are less commonly associated with cancers (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (198, 204))	('genes', 'Gene', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('alterations', 'Var', (98, 109))
30178	31754644	Interestingly, we found that for different cancer types, alterations of genes involved in a particular metabolic pathway may not produce similar clinical outcomes.	('alterations', 'Var', (57, 68))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
30179	31754644	For example, we found that for patients with alterations to genes involved in abacavir metabolism, those afflicted with oesophageal adenocarcinoma present with worse outcomes whereas those afflicted with uterine corpora endometrial carcinoma present with better outcomes (Fig.	('alterations', 'Var', (45, 56))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (220, 241))	('oesophageal adenocarcinoma', 'Disease', (120, 146))	('endometrial carcinoma', 'Disease', (220, 241))	('metabolism', 'biological_process', 'GO:0008152', ('87', '97'))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (220, 241))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (120, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('patients', 'Species', '9606', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('abacavir', 'Chemical', 'MESH:C106538', (78, 86))
30182	31754644	Altogether, we have shown both that metabolic gene alterations which potentially dysregulate metabolic pathways are a pervasive phenomenon across all 32 of the investigated human cancer types, and that numbers of metabolic gene alterations are linked to treatment outcomes.	('dysregulate', 'Reg', (81, 92))	('alterations', 'Var', (51, 62))	('metabolic pathways', 'Pathway', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('linked', 'Reg', (244, 250))	('alterations', 'Var', (228, 239))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('human', 'Species', '9606', (173, 178))	('metabolic gene', 'Gene', (36, 50))	('cancer', 'Disease', (179, 185))
30183	31754644	Further, our analysis of the drug response profiles of well-characterised cancer cell lines suggests that alterations of genes of various metabolic pathways may also be predictive of drug responses.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('drug', 'Disease', (183, 187))	('cancer', 'Disease', (74, 80))	('alterations', 'Var', (106, 117))	('genes', 'Gene', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
30189	31754644	For each of the 32 human cancers, we calculated the overall percentage of samples with mutations and/or copy number alterations in genes that belong to each of the sixteen first-tier metabolic pathway as defined in the Reactome pathway database (see the spreadsheet, "Metabolic Pathways - First Tier", of Supplementary file 2).	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('copy number alterations', 'Var', (104, 127))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('genes', 'Gene', (131, 136))	('cancers', 'Disease', (25, 32))	('human', 'Species', '9606', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('mutations', 'Var', (87, 96))
30195	31754644	Again, we used the approach for determining the extent of gene alterations (as described above) to calculate the fraction of tumours with alterations to genes involved in second-tier metabolic pathways across each cancer type (Fig.	('cancer', 'Disease', (214, 220))	('tumours', 'Disease', (125, 132))	('alterations', 'Var', (138, 149))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
30196	31754644	Also, using the same approach, we calculated the fraction of tumours with alterations in the genes that encode enzymes of the central metabolic pathway and their regulators (Fig.	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('tumours', 'Disease', (61, 68))	('alterations', 'Var', (74, 85))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
30238	28404758	Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001).	('patients', 'Species', '9606', (103, 111))	('regional recurrence', 'CPA', (77, 96))	('regional RT', 'Var', (29, 40))	('lower', 'NegReg', (63, 68))
30239	28404758	Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('low', 'Var', (75, 78))	('gene expression', 'biological_process', 'GO:0010467', ('41', '56'))	('survival', 'MPA', (146, 154))	('tumor', 'Disease', (104, 109))	('patients', 'Species', '9606', (27, 35))	('improved', 'PosReg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
30282	28404758	On subset analysis, regional RT was associated with a lower risk of regional recurrence for patients with an AJCC nodal N1b/N2b/N3 stage (Figure 1B; n=175; 1-, 2-, and 5-year regional control rates: 95.7%, 94.1%, and 94.1% vs 85.3%, 79.1%, and 69.5%, respectively; P=.003) and those with ECE (Figure 1C; n=141; 1-, 2-, and 5-year regional control rates: 98.4%, 96.7%, and 96.7% vs 82.3%, 75.5%, and 62.2%, respectively; P<.001).	('regional recurrence', 'MPA', (68, 87))	('nodal', 'Gene', (114, 119))	('nodal', 'Gene', '4838', (114, 119))	('patients', 'Species', '9606', (92, 100))	('N1b/N2b/N3', 'Var', (120, 130))	('lower', 'NegReg', (54, 59))	('AJCC', 'Var', (109, 113))
30292	28404758	Among 213 patients (52.0%) at the highest risk of regional recurrence, including those with either AJCC N1b/N2b/N3 disease or ECE, postoperative RT was associated with a lower risk of additional treatment for regional recurrence at 1, 2, and 5 years posttreatment (2.7%, 2.7%, and 2.7% vs 12.7%, 18.1%, and 26.0%, respectively; HR, 0.12; 95% CI, 0.03-0.50; P=.004).	('AJCC N1b/N2b/N3', 'Var', (99, 114))	('postoperative', 'Var', (131, 144))	('lower', 'NegReg', (170, 175))	('patients', 'Species', '9606', (10, 18))
30295	28404758	Variables associated with distant metastasis-free survival on multivariate analysis included AJCC N1b/N2b/N3 nodal stage (HR, 1.497; 95% CI, 1.033-2.170; P=.033), ECE (HR, 2.079; 95% CI, 1.432-3.017; P<.001).	('AJCC', 'Gene', (93, 97))	('distant metastasis-free survival', 'CPA', (26, 58))	('N1b/N2b/N3', 'Var', (98, 108))	('nodal', 'Gene', '4838', (109, 114))	('nodal', 'Gene', (109, 114))
30299	28404758	Variables associated with OS on multivariate analysis included older patient age (HR, 1.010; 95% CI, 1.000-1.019; P=.042), male sex (HR, 1.518; 95% CI, 1.136-2.028; P=.005), AJCC T3/4 tumor status (HR, 2.354; 95% CI, 1.559-3.554; P<.001), AJCC N1b/N2b/N3 nodal stage (HR, 1.439; 95% CI, 1.060-1.954; P=.02), increasing lymph nodes involved (HR, 1.041; 95% CI, 1.008-1.075; P=.01), ECE (HR, 1.751; 95% CI, 1.277-2.399; P<.001), nodal size >2 cm (HR, 1.405; 95% CI, 1.045-1.889; P=.02), and adjuvant immunotherapy (to be reported separately).	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('nodal', 'Gene', '4838', (255, 260))	('adjuvant immunotherapy', 'CPA', (489, 511))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('ECE', 'CPA', (381, 384))	('nodal', 'Gene', (427, 432))	('tumor', 'Disease', (184, 189))	('nodal', 'Gene', '4838', (427, 432))	('patient', 'Species', '9606', (69, 76))	('AJCC N1b/N2b/N3', 'Var', (239, 254))	('nodal', 'Gene', (255, 260))
30302	28404758	Among the 11 patients treated with postoperative RT, patients with a low RSI GES (radiosensitive) had significantly better survival than those with a high RSI GES (less radiosensitive; Figure 2A), with 1-, 2-, and 5-year estimated survival rates of 100%, 100%, and 75.0% compared with 85.7%, 14.3%, and 0%, respectively (HR, 10.68; 95% CI, 1.24-92.14).	('better', 'PosReg', (116, 122))	('survival', 'CPA', (123, 131))	('patients', 'Species', '9606', (53, 61))	('low RSI', 'Var', (69, 76))	('patients', 'Species', '9606', (13, 21))
30393	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))	('GNAQ', 'Gene', '2776', (65, 69))	('uveal melanoma', 'Disease', (153, 167))	('BRAF', 'Gene', '673', (102, 106))	('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))
30400	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))
30401	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))	('metastasis', 'CPA', (451, 461))	('high', 'Var', (357, 361))	('Twist1 gene', 'Gene', (362, 373))	('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))
30403	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))
30414	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))	('Snail1', 'Var', (197, 203))	('promote', 'PosReg', (213, 220))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('uveal melanoma', 'Phenotype', 'HP:0007716', (233, 247))	('uveal melanoma', 'Disease', 'MESH:C536494', (233, 247))	('invasion', 'CPA', (221, 229))
30426	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))	('promoting', 'PosReg', (231, 240))	('tumor', 'Disease', (15, 20))	('survival', 'MPA', (171, 179))	('metastatic', 'CPA', (241, 251))
30432	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))
30433	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))
30435	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.	('uveal melanoma', 'Disease', (24, 38))	('BAP1', 'Gene', (85, 89))	('mutations', 'Var', (72, 81))	('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))
30436	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))
30440	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))
30446	30782194	Up to 95% of GCMNs harbor NRAS mutations, and mutations in the BRAF, MC1R, TP53, and GNAQ genes have also been described.	('mutations', 'Var', (31, 40))	('TP53', 'Gene', '7157', (75, 79))	('MC1R', 'Gene', '4157', (69, 73))	('GNAQ', 'Gene', (85, 89))	('MC1R', 'Gene', (69, 73))	('NRAS', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (63, 67))	('NRAS', 'Gene', '4893', (26, 30))	('GNAQ', 'Gene', '2776', (85, 89))	('BRAF', 'Gene', (63, 67))	('TP53', 'Gene', (75, 79))
30449	30782194	The first case revealed only a non-pathogenic P72R polymorphism of the TP53 gene in the homozygote condition.	('TP53', 'Gene', '7157', (71, 75))	('P72R', 'Mutation', 'rs1042522', (46, 50))	('TP53', 'Gene', (71, 75))	('P72R', 'Var', (46, 50))
30450	30782194	For the second case, a Q61K mutation was detected in the NRAS gene.	('Q61K', 'Mutation', 'rs121913254', (23, 27))	('NRAS', 'Gene', '4893', (57, 61))	('Q61K', 'Var', (23, 27))	('NRAS', 'Gene', (57, 61))
30452	30782194	The most frequent genetic event in giant CMNs is NRAS mutations, which was discovered in one of our cases.	('NRAS', 'Gene', '4893', (49, 53))	('NRAS', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))
30465	30782194	Mutations in this network, such as in genes MITF and KIT and probably in the hepatocyte growth factor/c-Met signaling pathway, might deregulate the pigmentation system during embryogenesis, resulting in various congenital disorders.	('pigmentation system', 'MPA', (148, 167))	('embryogenesis', 'biological_process', 'GO:0009790', ('175', '188'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('77', '101'))	('KIT', 'Gene', (53, 56))	('embryogenesis', 'biological_process', 'GO:0009793', ('175', '188'))	('pigmentation', 'biological_process', 'GO:0043473', ('148', '160'))	('embryogenesis', 'biological_process', 'GO:0009792', ('175', '188'))	('congenital disorders', 'Disease', (211, 231))	('Mutations', 'Var', (0, 9))	('resulting in', 'Reg', (190, 202))	('c-Met', 'Gene', (102, 107))	('c-Met', 'Gene', '4233', (102, 107))	('deregulate', 'Reg', (133, 143))	('congenital disorders', 'Disease', 'MESH:D000013', (211, 231))	('MITF', 'Gene', '4286', (44, 48))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))	('hepatocyte growth factor', 'Gene', '3082', (77, 101))	('MITF', 'Gene', (44, 48))	('Met signaling pathway', 'biological_process', 'GO:0048012', ('104', '125'))	('hepatocyte growth factor', 'Gene', (77, 101))
30468	30782194	Postzygotic mutations in the NRAS gene are thought to be responsible for CMN formation in 80% of cases because the same mutation is found in different cutaneous lesions from the same individual and in affected neurological and malignant tissue.	('responsible', 'Reg', (57, 68))	('CMN formation', 'Disease', (73, 86))	('NRAS', 'Gene', (29, 33))	('Postzygotic mutations', 'Var', (0, 21))	('NRAS', 'Gene', '4893', (29, 33))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))
30469	30782194	The NRAS mutations often result in an amino acid substitution in codon 61.	('amino acid substitution', 'Var', (38, 61))	('mutations', 'Var', (9, 18))	('NRAS', 'Gene', (4, 8))	('result in', 'Reg', (25, 34))	('NRAS', 'Gene', '4893', (4, 8))
30470	30782194	The BRAF V600E mutation can also be found but in no more than one lesion of the same patient and therefore cannot be assigned as causal.	('patient', 'Species', '9606', (85, 92))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
30471	30782194	Additionally, mutations in MC1R and TP53 have been identified in CMN and might be involved in its formation.	('CMN', 'Disease', (65, 68))	('involved', 'Reg', (82, 90))	('MC1R', 'Gene', '4157', (27, 31))	('identified', 'Reg', (51, 61))	('MC1R', 'Gene', (27, 31))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('formation', 'biological_process', 'GO:0009058', ('98', '107'))	('mutations', 'Var', (14, 23))
30472	30782194	The presence of BRAF or NRAS mutations does not confer an increased risk of malignant transformation, and further mutations are required to cause melanoma formation in a CMN.	('NRAS', 'Gene', '4893', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('cause', 'Reg', (140, 145))	('BRAF', 'Gene', (16, 20))	('mutations', 'Var', (29, 38))	('BRAF', 'Gene', '673', (16, 20))	('formation', 'biological_process', 'GO:0009058', ('155', '164'))	('NRAS', 'Gene', (24, 28))
30493	30782194	Genetic analysis of tumor tissue was performed using a diagnostic biochip (EIMB RAS, Russia) for the detection of most common somatic mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1, and MAP2K2 genes.	('KIT', 'Gene', (163, 166))	('BRAF', 'Gene', '673', (151, 155))	('GNA11', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('BRAF', 'Gene', (151, 155))	('NRAS', 'Gene', '4893', (157, 161))	('MAP2K', 'molecular_function', 'GO:0004708', ('181', '186'))	('MAP2K2', 'Gene', '5605', (193, 199))	('MAP2K1', 'Gene', '5604', (181, 187))	('mutations', 'Var', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KIT', 'molecular_function', 'GO:0005020', ('163', '166'))	('MAP2K1', 'Gene', (181, 187))	('NRAS', 'Gene', (157, 161))	('GNA11', 'Gene', '2767', (174, 179))	('GNAQ', 'Gene', '2776', (168, 172))	('MAP2K', 'molecular_function', 'GO:0004708', ('193', '198'))	('MAP2K2', 'Gene', (193, 199))	('GNAQ', 'Gene', (168, 172))	('tumor', 'Disease', (20, 25))
30496	30782194	As a result, only Arg/Arg polymorphism at codon 72 of the TP53 gene, which is not pathogenic, was revealed.	('Arg', 'Chemical', 'MESH:D001120', (18, 21))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('Arg', 'Chemical', 'MESH:D001120', (22, 25))	('Arg/Arg polymorphism at', 'Var', (18, 41))
30516	30782194	Genetic analysis of the tumor was performed using a diagnostic biochip for the detection of somatic mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1, and MAP2K2 genes, Sanger sequencing for searching germinal mutations in the CDKN2A gene.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MAP2K2', 'Gene', (159, 165))	('GNAQ', 'Gene', (134, 138))	('MAP2K', 'molecular_function', 'GO:0004708', ('159', '164'))	('GNA11', 'Gene', (140, 145))	('KIT', 'Gene', (129, 132))	('NRAS', 'Gene', '4893', (123, 127))	('BRAF', 'Gene', '673', (117, 121))	('BRAF', 'Gene', (117, 121))	('MAP2K2', 'Gene', '5605', (159, 165))	('tumor', 'Disease', (24, 29))	('CDKN2A', 'Gene', (231, 237))	('MAP2K1', 'Gene', '5604', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('mutations', 'Var', (100, 109))	('MAP2K1', 'Gene', (147, 153))	('KIT', 'molecular_function', 'GO:0005020', ('129', '132'))	('NRAS', 'Gene', (123, 127))	('CDKN2A', 'Gene', '1029', (231, 237))	('MAP2K', 'molecular_function', 'GO:0004708', ('147', '152'))	('GNA11', 'Gene', '2767', (140, 145))	('GNAQ', 'Gene', '2776', (134, 138))
30517	30782194	Eventually, a Q61K mutation was revealed in the NRAS gene.	('Q61K', 'Mutation', 'rs121913254', (14, 18))	('Q61K', 'Var', (14, 18))	('NRAS', 'Gene', (48, 52))	('NRAS', 'Gene', '4893', (48, 52))
30545	30782194	For patient M (Case 1), we evaluated the presence of somatic and germline mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1/2, PDGFRA, RASA1, RAC1, MET, PTEN, AKT1, TP53, and TERT genes and somatic mutations in the GNAQ and GNA11 genes.	('RAC1', 'Gene', (146, 150))	('GNAQ', 'Gene', '2776', (108, 112))	('TP53', 'Gene', '7157', (169, 173))	('MET', 'Gene', (152, 155))	('GNAQ', 'Gene', (108, 112))	('RAC1', 'Gene', '5879', (146, 150))	('PTEN', 'Gene', '5728', (157, 161))	('NRAS', 'Gene', (97, 101))	('GNAQ', 'Gene', '2776', (219, 223))	('GNA11', 'Gene', (228, 233))	('GNA11', 'Gene', '2767', (114, 119))	('TERT', 'Gene', (179, 183))	('PDGFRA', 'Gene', (131, 137))	('TERT', 'Gene', '7015', (179, 183))	('MAP2K', 'molecular_function', 'GO:0004708', ('121', '126'))	('PDGFRA', 'Gene', '5156', (131, 137))	('AKT1', 'Gene', '207', (163, 167))	('GNAQ', 'Gene', (219, 223))	('MAP2K1/2', 'Gene', (121, 129))	('RASA1', 'Gene', '5921', (139, 144))	('MAP2K1/2', 'Gene', '5604;5605', (121, 129))	('TP53', 'Gene', (169, 173))	('AKT1', 'Gene', (163, 167))	('GNA11', 'Gene', (114, 119))	('KIT', 'Gene', (103, 106))	('BRAF', 'Gene', '673', (91, 95))	('GNA11', 'Gene', '2767', (228, 233))	('NRAS', 'Gene', '4893', (97, 101))	('mutations', 'Var', (74, 83))	('patient', 'Species', '9606', (4, 11))	('RASA1', 'Gene', (139, 144))	('BRAF', 'Gene', (91, 95))	('PTEN', 'Gene', (157, 161))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))
30547	30782194	Only non-pathogenic TP53 codon 72 Arg/Arg polymorphism was detected.	('Arg', 'Chemical', 'MESH:D001120', (38, 41))	('TP53', 'Gene', (20, 24))	('codon 72 Arg/Arg', 'Var', (25, 41))	('Arg', 'Chemical', 'MESH:D001120', (34, 37))	('TP53', 'Gene', '7157', (20, 24))
30548	30782194	For patient L (Case2), an analysis was performed to determine the somatic mutations in the BRAF, NRAS, KIT, GNAQ, GNA11, MAP2K1, and MAP2K2 genes and germline mutations in the CDKN2A gene.	('GNAQ', 'Gene', '2776', (108, 112))	('CDKN2A', 'Gene', (176, 182))	('GNAQ', 'Gene', (108, 112))	('NRAS', 'Gene', (97, 101))	('GNA11', 'Gene', '2767', (114, 119))	('MAP2K', 'molecular_function', 'GO:0004708', ('121', '126'))	('MAP2K2', 'Gene', (133, 139))	('CDKN2A', 'Gene', '1029', (176, 182))	('germline', 'Var', (150, 158))	('MAP2K1', 'Gene', '5604', (121, 127))	('GNA11', 'Gene', (114, 119))	('MAP2K1', 'Gene', (121, 127))	('KIT', 'Gene', (103, 106))	('BRAF', 'Gene', '673', (91, 95))	('NRAS', 'Gene', '4893', (97, 101))	('mutations', 'Var', (74, 83))	('patient', 'Species', '9606', (4, 11))	('BRAF', 'Gene', (91, 95))	('MAP2K2', 'Gene', '5605', (133, 139))	('MAP2K', 'molecular_function', 'GO:0004708', ('133', '138'))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))
30549	30782194	Ultimately, only a Q61K mutation in the NRAS gene was found.	('NRAS', 'Gene', '4893', (40, 44))	('NRAS', 'Gene', (40, 44))	('Q61K', 'Mutation', 'rs121913254', (19, 23))	('Q61K', 'Var', (19, 23))
30550	30782194	Mutations in the NRAS gene occur in 80-95% of giant CMNs and are considered one of the causes of CMN formation, although other factors are needed for malignant transformation.	('occur', 'Reg', (27, 32))	('NRAS', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (17, 21))	('formation', 'biological_process', 'GO:0009058', ('101', '110'))
30555	30782194	There were 9 patients who developed melanoma in the first 5 years of life, and 7 patients revealed a Q61K mutation in the NRAS gene.	('Q61K', 'Mutation', 'rs121913254', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (81, 89))	('NRAS', 'Gene', (122, 126))	('NRAS', 'Gene', '4893', (122, 126))	('Q61K', 'Var', (101, 105))
30556	30782194	In 3 cases of cutaneous melanoma in one patient, Q61K was found as in our Case 2.	('patient', 'Species', '9606', (40, 47))	('cutaneous melanoma', 'Disease', (14, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (14, 32))	('Q61K', 'Mutation', 'rs121913254', (49, 53))	('Q61K', 'Var', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))
30577	30782194	The histopathology by at least two experts in the field and genetic analysis of driver mutations can help to differentiate melanoma from benign proliferative nodules in the skin.	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('mutations', 'Var', (87, 96))
30578	30782194	The most frequent genetic event in giant CMNs are NRAS mutations (up to 95%), which was discovered in one of our cases.	('NRAS', 'Gene', (50, 54))	('NRAS', 'Gene', '4893', (50, 54))	('mutations', 'Var', (55, 64))
30587	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))
30588	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))
30610	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))
30617	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))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('tumor suppressor', 'Gene', '7248', (71, 87))	('NRAS', 'Gene', '4893', (59, 63))
30618	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))	('MAPK', 'Pathway', (102, 106))	('mutations', 'Var', (82, 91))	('develop from', 'Reg', (59, 71))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
30619	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))
30621	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))
30623	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))
30624	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.	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('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))	('result from', 'Reg', (35, 46))	('EIF1AX', 'Gene', (161, 167))	('GNA11', 'Gene', (66, 71))	('melanoma', 'Disease', (6, 14))	('GNA11', 'Gene', '2767', (66, 71))	('mutation', 'Var', (72, 80))	('BAP1', 'Gene', '8314', (144, 148))
30627	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))
30629	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))
30632	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))
30634	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))	('signaling', 'MPA', (56, 65))	('overamplification', 'PosReg', (35, 52))	('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))
30636	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))
30638	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))
30641	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))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('GNA11', 'Gene', '2767', (15, 20))	('GNAQ', 'Gene', '2776', (6, 10))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('found', 'Reg', (43, 48))	('GNAQ', 'Gene', (6, 10))	('mutations', 'Var', (21, 30))
30642	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))
30643	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))
30645	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))
30647	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))
30648	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))
30650	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))
30651	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))	('dysregulation', 'Var', (26, 39))	('mutations', 'Var', (70, 79))	('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))	('increase tumor aggression', 'Disease', (115, 140))	('exacerbate', 'PosReg', (84, 94))	('cell cycle', 'CPA', (47, 57))	('CDKN2A', 'Gene', (63, 69))
30653	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))	('monosomy 3', 'Disease', (35, 45))	('BAP1', 'Gene', (0, 4))	('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))
30654	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))
30655	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))
30656	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))
30658	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))
30660	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))
30663	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))
30667	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'))	('PARP', 'Gene', '142', (129, 133))	('poly (ADP-ribose) polymerase', 'Gene', '142', (99, 127))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('poly (ADP-ribose) polymerase', 'Gene', (99, 127))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('PARP', 'Gene', (129, 133))
30669	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'))
30670	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))
30671	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))
30672	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))
30675	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))
30677	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'))	('inhibiting', 'NegReg', (67, 77))	('proliferation', 'CPA', (78, 91))	('apoptosis', 'CPA', (142, 151))	('apoptosis', 'biological_process', 'GO:0097194', ('142', '151'))	('apoptosis', 'biological_process', 'GO:0006915', ('142', '151'))	('1,25(OH)2D3', 'Var', (9, 20))	('regulating', 'Reg', (93, 103))	('melanoma', 'Disease', (55, 63))
30683	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))
30684	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))	('single-nucleotide polymorphisms', 'Var', (28, 59))	('associated', 'Reg', (101, 111))	('VDR', 'Gene', (24, 27))
30687	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))	('VDR', 'Gene', (36, 39))	('low', 'NegReg', (164, 167))	('vitamin D levels', 'MPA', (168, 184))	('low vitamin D', 'Phenotype', 'HP:0100512', (164, 177))	('VDR', 'Gene', '7421', (36, 39))	('patients', 'Species', '9606', (124, 132))
30688	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))
30693	32429485	were the first to discover that 1,25(OH)2D3 inhibits the proliferation of human melanoma cells.	('human', 'Species', '9606', (74, 79))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (32, 43))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('inhibits', 'NegReg', (44, 52))	('1,25(OH)2D3', 'Var', (32, 43))
30699	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))
30711	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))
30713	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'))
30714	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))
30715	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))
30716	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))
30717	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))
30718	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))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('MC1R', 'Gene', '4157', (48, 52))	('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))
30719	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))
30722	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))
30723	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))	('mouse', 'Species', '10090', (30, 35))	('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))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
30726	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))
30728	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))
30730	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))
30744	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))	('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))	('sensitivity to', 'MPA', (123, 137))
30745	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))
30749	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))
30753	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))
30760	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))
30761	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))
30762	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))
30763	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))	('superficial spreading subtype', 'Disease', (64, 93))	('patient', 'Species', '9606', (103, 110))	('V600E', 'Mutation', 'rs113488022', (24, 29))
30764	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'))
30766	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))
30767	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))
30768	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))
30769	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))
30770	32429485	Accordingly, BRAF mutations are associated with melanomas from anatomic locations with intermittent sun exposure, such as the trunk and extremities.	('mutations', 'Var', (18, 27))	('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', 'Phenotype', 'HP:0002861', (48, 57))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
30771	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))
30772	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))
30773	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))
30774	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))
30775	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'))
30783	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))
30786	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))
30788	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))	('propagate downstream signals', 'MPA', (118, 146))	('G protein', 'Protein', (105, 114))	('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'))
30789	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))
30793	32429485	The prognostic value of identification of NRAS mutation is unclear.	('mutation', 'Var', (47, 55))	('NRAS', 'Gene', (42, 46))	('NRAS', 'Gene', '4893', (42, 46))
30796	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))
30797	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))
30798	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))
30799	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))
30804	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))
30805	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))
30809	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))
30810	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))
30811	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'))
30813	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))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('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))
30814	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))
30817	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))
30829	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))
30845	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
30885	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
30889	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
30899	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
30909	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
30915	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('MMR', 'biological_process', 'GO:0006298', ('234', '237'))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('methylation', 'biological_process', 'GO:0032259', ('250', '261'))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
30925	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
30930	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('YIF1B', 'Gene', (108, 113))	('LIHC', 'Disease', (64, 68))	('tumor', 'Disease', (159, 164))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('expression', 'MPA', (114, 124))	('YIF1B', 'Gene', '90522', (108, 113))
30932	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('172', '193'))	('vesicle', 'cellular_component', 'GO:0031982', ('66', '73'))	('YIF1B', 'Gene', '90522', (33, 38))	('cell membrane', 'cellular_component', 'GO:0005886', ('201', '214'))	('cell membrane', 'cellular_component', 'GO:0005886', ('245', '258'))	('cargo', 'molecular_function', 'GO:0140355', ('106', '111'))	('YIF1B', 'Gene', '90522', (308, 313))	('Golgi apparatus', 'cellular_component', 'GO:0005794', ('223', '238'))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('localization', 'biological_process', 'GO:0051179', ('259', '271'))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
30935	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('HTR', 'Gene', (33, 36))	('signaling', 'biological_process', 'GO:0023052', ('10', '19'))	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('specific proteins', 'MPA', (130, 147))	('YIF1B', 'Gene', (87, 92))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('encephalopathy', 'Disease', (175, 189))
30950	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('COAD', 'Disease', (13, 17))	('high MSI', 'Var', (32, 40))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
30962	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('proteolysis', 'biological_process', 'GO:0006508', ('126', '137'))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
30974	33204327	Alterations in such regulation lead to melanoma development.	('Alterations', 'Var', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('lead to', 'Reg', (31, 38))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))
30975	33204327	Methods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts.	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 54))	('skin cutaneous melanoma', 'Disease', (31, 54))	('Cadherin', 'Protein', (9, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('Cadherin', 'molecular_function', 'GO:0008014', ('9', '17'))	('mutations', 'Var', (18, 27))
30976	33204327	Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software.	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('GROMACS', 'Gene', (133, 140))	('Mutations', 'Var', (0, 9))	('GROMACS', 'Gene', '54453', (133, 140))
30978	33204327	Cell-based fluorescence reporter assay was used to validate beta-catenin activity in the presence of cadherin mutations.	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (101, 109))	('cadherin', 'Gene', (101, 109))	('mutations', 'Var', (110, 119))	('activity', 'MPA', (73, 81))	('cadherin', 'molecular_function', 'GO:0008014', ('101', '109'))	('beta-catenin', 'Protein', (60, 72))
30980	33204327	Results: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca2+-binding and cell-cell contacts.	('S524L', 'Var', (125, 130))	('Ca2+', 'Chemical', 'MESH:D000069285', (192, 196))	('mutations', 'Var', (25, 34))	('cadherin', 'Gene', (56, 64))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('found', 'Reg', (71, 76))	('Ca2+-binding', 'MPA', (192, 204))	('melanoma', 'Disease', (80, 88))	('CDH6', 'Gene', (155, 159))	('CDH6', 'Gene', '1004', (155, 159))	('binding', 'molecular_function', 'GO:0005488', ('197', '204'))	('destabilizes', 'NegReg', (179, 191))	('S524L', 'Mutation', 'rs202247793', (125, 130))	('cell-cell contacts', 'CPA', (209, 227))
30982	33204327	Mutations in the intracellular domains significantly disturbed CDH6/beta-catenin complex formation, resulting in beta-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/beta-catenin signaling.	('formation', 'biological_process', 'GO:0009058', ('89', '98'))	('signaling', 'biological_process', 'GO:0023052', ('212', '221'))	('Wnt', 'Gene', '7471', (195, 198))	('intracellular', 'cellular_component', 'GO:0005622', ('17', '30'))	('CDH6', 'Gene', (63, 67))	('beta-catenin translocation into cytosol or nucleus', 'MPA', (113, 163))	('CDH6', 'Gene', '1004', (63, 67))	('nucleus', 'cellular_component', 'GO:0005634', ('156', '163'))	('Wnt', 'Gene', (195, 198))	('Mutations', 'Var', (0, 9))	('disturbed', 'Reg', (53, 62))	('dysregulation', 'MPA', (168, 181))	('catenin complex', 'cellular_component', 'GO:0016342', ('73', '88'))	('cytosol', 'cellular_component', 'GO:0005829', ('145', '152'))
30983	33204327	Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type.	('core', 'cellular_component', 'GO:0019013', ('22', '26'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (9, 18))	('disease-free survival times', 'CPA', (117, 144))	('correlated', 'Reg', (37, 47))	('longer', 'PosReg', (168, 174))	('CDH', 'Gene', (27, 30))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (178, 186))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CDH', 'Gene', '55349', (27, 30))	('lymph node invasion', 'CPA', (80, 99))
30984	33204327	Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy.	('cadherin', 'Gene', (105, 113))	('neo-antigen potentials', 'MPA', (71, 93))	('mutated', 'Var', (97, 104))	('associated with', 'Reg', (122, 137))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (105, 113))	('increased', 'PosReg', (61, 70))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('T-lymphocyte infiltration', 'CPA', (138, 163))
30985	33204327	Conclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development.	('Changes', 'Reg', (12, 19))	('cadherin', 'Gene', (75, 83))	('trigger', 'PosReg', (118, 125))	('cell-cell', 'CPA', (23, 32))	('mutations', 'Var', (59, 68))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
30986	33204327	Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times.	('benefit', 'PosReg', (78, 85))	('AJs', 'Gene', (21, 24))	('mutations', 'Var', (8, 17))	('patients', 'Species', '9606', (86, 94))
30993	33204327	Clustering of core cadherin-catenin complexes can further strengthen cell-cell adhesion, allowing cadherins to nucleate signaling hubs and establish the regulatory Hippo network.	('core', 'cellular_component', 'GO:0019013', ('14', '18'))	('strengthen', 'PosReg', (58, 68))	('cadherin', 'Gene', (19, 27))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (19, 27))	('cadherin', 'Gene', (98, 106))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (98, 106))	('cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('cell-cell adhesion', 'CPA', (69, 87))	('Clustering', 'Var', (0, 10))	('signaling hubs', 'MPA', (120, 134))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('69', '87'))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
31000	33204327	With advanced whole genome sequencing and other integrative technologies, a set of major driver mutations in cutaneous melanoma, e.g.	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('cutaneous melanoma', 'Disease', (109, 127))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (109, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (109, 127))	('mutations', 'Var', (96, 105))
31007	33204327	To map the key pathways associated with cadherin mutations, normalized gene expression data were applied for gene set enrichment analysis (GSEA) by using GSEA Java (version 2.2.3) from Broad Institute.	('mutations', 'Var', (49, 58))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (40, 48))	('cadherin', 'Gene', (40, 48))	('GSEA', 'Chemical', '-', (139, 143))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('GSEA', 'Chemical', '-', (154, 158))
31008	33204327	Prediction of peptide-binding affinity onto MHC-I complex, with the peptide length of nine amino acids, was performed to estimate the neo-antigen potentials of mutations in cadherin genes by using NetMHCpan algorithm.	('cadherin', 'molecular_function', 'GO:0008014', ('173', '181'))	('mutations', 'Var', (160, 169))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (173, 181))	('cadherin', 'Gene', (173, 181))	('peptide-binding', 'molecular_function', 'GO:0042277', ('14', '29'))	('NetMHCpan', 'Chemical', '-', (197, 206))
31012	33204327	Among the 22 tissues, 9 of them showed mutations in classical cadherin genes in the Taiwanese cohort (Table S1).	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (62, 70))	('cadherin', 'Gene', (62, 70))	('mutations', 'Var', (39, 48))
31020	33204327	In this study, CDH6 (PDB ID: 5VEB) was selected as the template for predicting the structure of S524L-EC5, p120-catenin in complex with E-cadherin (PDB ID: 3L6X) was selected as template for predicting the structures of WT-, D661N-, and E662K-JMD in complex with p120-catenin, and beta-catenin with desmosomal-cadherin (PDB ID: 3IFQ) was selected as the other template for predicting the structures of WT-, R689Q-, D691N-, E722K-, D726N-, S749F-, R773Q-CBD in complex with beta-catenin.	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('cadherin', 'Gene', (310, 318))	('E722K', 'Mutation', 'rs780971188', (423, 428))	('p120-catenin', 'Gene', '1500', (263, 275))	('PDB', 'Gene', (21, 24))	('p120-catenin', 'Gene', (263, 275))	('E662K', 'Mutation', 'rs755912714', (237, 242))	('D726N', 'Mutation', 'p.D726N', (431, 436))	('PDB', 'Gene', '5131', (21, 24))	('R773Q', 'Mutation', 'rs1239863031', (447, 452))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (310, 318))	('E722K-', 'Var', (423, 429))	('PDB', 'Gene', (148, 151))	('PDB', 'Gene', '5131', (148, 151))	('cadherin', 'Gene', (138, 146))	('CDH6', 'Gene', '1004', (15, 19))	('S749F-', 'Var', (439, 445))	('PDB', 'Gene', (320, 323))	('D691N-', 'Var', (415, 421))	('E-cadherin', 'Gene', (136, 146))	('R773Q-CBD', 'Var', (447, 456))	('E-cadherin', 'Gene', '999', (136, 146))	('D691N', 'Mutation', 'p.D691N', (415, 420))	('PDB', 'Gene', '5131', (320, 323))	('CDH6', 'Gene', (15, 19))	('S524L', 'Mutation', 'rs202247793', (96, 101))	('D726N-', 'Var', (431, 437))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (138, 146))	('S749F', 'Mutation', 'p.S749F', (439, 444))	('p120-catenin', 'Gene', '1500', (107, 119))	('D661N', 'Mutation', 'rs748299287', (225, 230))	('R689Q-', 'Var', (407, 413))	('cadherin', 'molecular_function', 'GO:0008014', ('310', '318'))	('p120-catenin', 'Gene', (107, 119))	('R689Q', 'Mutation', 'rs138589959', (407, 412))
31029	33204327	CDH6 with mutations in the CBD domain were generated by site directed mutagenesis (F541; Thermo Fisher Scientific Inc.).	('CDH6', 'Gene', (0, 4))	('CDH6', 'Gene', '1004', (0, 4))	('mutations', 'Var', (10, 19))	('mutagenesis', 'biological_process', 'GO:0006280', ('70', '81'))
31030	33204327	To monitor complex formation in live cells, beta-catenin-mCherry and CDH6 variants gagged with GFP were co-transfected into A375 cells using Lipofectamine 2000 (Thermo Fisher Scientific Inc.) by 1:1 molar ratio.	('formation', 'biological_process', 'GO:0009058', ('19', '28'))	('A375', 'CellLine', 'CVCL:0132', (124, 128))	('CDH6', 'Gene', (69, 73))	('CDH6', 'Gene', '1004', (69, 73))	('variants', 'Var', (74, 82))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (141, 159))
31031	33204327	Dysregulation in interactions between melanocyte and keratinocyte or melanocyte and matrix is a key step during melanoma malignant transition.	('interactions', 'Interaction', (17, 29))	('Dysregulation', 'Var', (0, 13))	('melanoma malignant transition', 'Disease', (112, 141))	('melanoma malignant transition', 'Disease', 'MESH:D008545', (112, 141))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))
31036	33204327	Surprisingly, frequent mutations (>= 10%) were found in 5 classical cadherin genes (CDH6, CDH18, CDH10, CDH9 and CDH4) (Figure 2B).	('CDH18', 'Gene', (90, 95))	('CDH9', 'Gene', '1007', (104, 108))	('CDH10', 'Gene', (97, 102))	('CDH10', 'Gene', '1008', (97, 102))	('CDH4', 'Gene', (113, 117))	('mutations', 'Var', (23, 32))	('cadherin', 'Gene', (68, 76))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (68, 76))	('CDH4', 'Gene', '1002', (113, 117))	('CDH9', 'Gene', (104, 108))	('CDH18', 'Gene', '1016', (90, 95))	('CDH6', 'Gene', (84, 88))	('CDH6', 'Gene', '1004', (84, 88))	('cadherin', 'molecular_function', 'GO:0008014', ('68', '76'))
31037	33204327	Although no mutually exclusive pattern, genetic alterations in the classic cadherin genes sum up a total mutation rate of 56% in melanoma tissues.	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('cadherin', 'Gene', (75, 83))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('genetic alterations', 'Var', (40, 59))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (75, 83))
31038	33204327	Consistent with previous findings indicating rare E-cadherin (CDH1) mutations in cancer, only 2.7% of melanomas carry CDH1 mutations.	('CDH1', 'Gene', '999', (118, 122))	('melanomas', 'Disease', (102, 111))	('CDH1', 'Gene', (62, 66))	('E-cadherin', 'Gene', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('CDH1', 'Gene', '999', (62, 66))	('cancer', 'Disease', (81, 87))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('E-cadherin', 'Gene', '999', (50, 60))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('CDH1', 'Gene', (118, 122))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cadherin', 'molecular_function', 'GO:0008014', ('52', '60'))	('mutations', 'Var', (123, 132))
31040	33204327	Mutation rates in other minor AJ genes including nectins and nectin-like molecules were also relatively low (< 10%) (Figure S2), suggesting that mutations in classical cadherins play more important roles in melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('mutations', 'Var', (145, 154))	('cadherin', 'Gene', (168, 176))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (168, 176))
31042	33204327	Significantly, the top-four mutated genes (core CDHs) are all type-II classical cadherins, suggesting alterations in heterophilic interactions may function as one possible mechanism to drive melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('cadherin', 'Gene', (80, 88))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (80, 88))	('melanoma', 'Disease', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('drive', 'PosReg', (185, 190))	('heterophilic interactions', 'MPA', (117, 142))	('CDHs', 'Chemical', '-', (48, 52))	('alterations', 'Var', (102, 113))	('core', 'cellular_component', 'GO:0019013', ('43', '47'))
31043	33204327	At nucleotide levels, most of the detected substitutions (around 90%) were G to A or C to T, a signature for DNA damage repair after UV-induced DNA adducts (Figure 2C), indicating the etiological relevance of mutations in those adhesion genes during melanoma development.	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('substitutions', 'Var', (43, 56))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))
31044	33204327	Mutational profiles revealed that somatic mutations in cadherins could be detected at a variety of positions throughout coding regions with the existence of some truncations and out-of-frame insertions/deletions (Figure 3A, left panel).	('truncations', 'Var', (162, 173))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (55, 63))	('out-of-frame insertions/deletions', 'Var', (178, 211))	('cadherin', 'Gene', (55, 63))	('mutations', 'Var', (42, 51))
31045	33204327	The feature of most detected somatic mutations suggests a tumor suppressor role for those adhesion proteins in cancer development.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
31046	33204327	Nevertheless, the S524L substitution on the fifth extracellular (EC5) domain of CDH6 (K-cadherin) stood out to be a unique mutation with a relatively higher frequency, indicating its potent role in melanoma development.	('extracellular', 'cellular_component', 'GO:0005576', ('50', '63'))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('cadherin', 'Gene', (88, 96))	('melanoma', 'Disease', (198, 206))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (88, 96))	('cadherin', 'molecular_function', 'GO:0008014', ('88', '96'))	('S524L', 'Mutation', 'rs202247793', (18, 23))	('CDH6', 'Gene', (80, 84))	('CDH6', 'Gene', '1004', (80, 84))	('S524L', 'Var', (18, 23))
31047	33204327	On the other hand, mutations in the intracellular domains of top-five cadherins show mutual exclusivity with beta-catenin (CTNNB1) mutations (Figure 3B), suggesting potent effects of cadherin mutations on canonical Wnt/beta-catenin signaling.	('effects', 'Reg', (172, 179))	('cadherin', 'Gene', (183, 191))	('mutations', 'Var', (131, 140))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (183, 191))	('cadherin', 'Gene', (70, 78))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (70, 78))	('Wnt', 'Gene', (215, 218))	('CTNNB1', 'Gene', (123, 129))	('canonical', 'MPA', (205, 214))	('mutations', 'Var', (19, 28))	('intracellular', 'cellular_component', 'GO:0005622', ('36', '49'))	('cadherin', 'molecular_function', 'GO:0008014', ('183', '191'))	('CTNNB1', 'Gene', '1499', (123, 129))	('Wnt', 'Gene', '7471', (215, 218))	('signaling', 'biological_process', 'GO:0023052', ('232', '241'))	('mutations', 'Var', (192, 201))
31048	33204327	Co-occurrence analysis among the core CDHs (CDH6, CDH9, CDH10 and CDH10) indicated the association of CDH6 mutations with mutations in CDH9, CDH10 and CDH18 (Figure 3C).	('CDH9', 'Gene', (50, 54))	('CDH10', 'Gene', (56, 61))	('association', 'Interaction', (87, 98))	('CDH9', 'Gene', '1007', (50, 54))	('core', 'cellular_component', 'GO:0019013', ('33', '37'))	('CDH10', 'Gene', '1008', (66, 71))	('CDH18', 'Gene', '1016', (151, 156))	('CDH10', 'Gene', (141, 146))	('CDH9', 'Gene', (135, 139))	('CDH6', 'Gene', '1004', (102, 106))	('CDH10', 'Gene', '1008', (56, 61))	('CDH9', 'Gene', '1007', (135, 139))	('CDH6', 'Gene', (102, 106))	('CDH18', 'Gene', (151, 156))	('CDH6', 'Gene', '1004', (44, 48))	('mutations', 'Var', (107, 116))	('CDH10', 'Gene', '1008', (141, 146))	('CDH10', 'Gene', (66, 71))	('CDHs', 'Chemical', '-', (38, 42))	('mutations', 'Var', (122, 131))	('CDH6', 'Gene', (44, 48))
31053	33204327	Thus, mutations in type-II cadherins, especially in CDH6, may gain functional advantages during melanoma development.	('gain', 'PosReg', (62, 66))	('CDH6', 'Gene', (52, 56))	('cadherin', 'Gene', (27, 35))	('CDH6', 'Gene', '1004', (52, 56))	('functional', 'MPA', (67, 77))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (27, 35))	('melanoma', 'Disease', (96, 104))	('mutations', 'Var', (6, 15))
31054	33204327	To know functional impacts of mutations in CDH6, the structure of the EC5 domain (CDH6-EC5) was constructed by MODELLER program using the published human CDH6 crystal structure (Protein Data Bank ID: 5VEB) as the template.	('CDH6', 'Gene', '1004', (43, 47))	('CDH6', 'Gene', (154, 158))	('CDH6', 'Gene', (43, 47))	('CDH6', 'Gene', '1004', (82, 86))	('CDH6', 'Gene', '1004', (154, 158))	('human', 'Species', '9606', (148, 153))	('mutations', 'Var', (30, 39))	('CDH6', 'Gene', (82, 86))
31055	33204327	To compare the similarity in three-dimensional structure of the EC5, Root-Mean-Square Deviation (RMSD) analyses indicated longer average distances between the atoms in the S524L mutant as compared to wild type (WT) CDH6, suggesting its impacts on the EC5 structure (Figure 4A, upper).	('longer', 'PosReg', (122, 128))	('impacts', 'Reg', (236, 243))	('CDH6', 'Gene', (215, 219))	('S524L', 'Var', (172, 177))	('S524L', 'Mutation', 'rs202247793', (172, 177))	('CDH6', 'Gene', '1004', (215, 219))
31056	33204327	Analyses of the residue-specific Root-Mean-Square Fluctuations (RMSF) (Figure 4A, lower) further revealed higher atomic fluctuations of the S524L mutant at the beta2/beta3 loop, a region for Ca2+-binding, when compared with the WT.	('binding', 'molecular_function', 'GO:0005488', ('196', '203'))	('atomic fluctuations', 'MPA', (113, 132))	('beta2/beta3', 'Gene', (160, 171))	('S524L', 'Var', (140, 145))	('higher', 'PosReg', (106, 112))	('Ca2+', 'Chemical', 'MESH:D000069285', (191, 195))	('S524L', 'Mutation', 'rs202247793', (140, 145))	('beta2/beta3', 'Gene', '170589', (160, 171))
31057	33204327	The beta4/beta5 loop, which was predicted to stabilize the Ca2+-binding, was also found less stable in this mutant due to its higher RMSF and B-factors (Figure 4A-B).	('Ca2+', 'Chemical', 'MESH:D000069285', (59, 63))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('B-factors', 'CPA', (142, 151))	('higher', 'PosReg', (126, 132))	('beta4/beta5', 'Gene', (4, 15))	('mutant', 'Var', (108, 114))	('RMSF', 'MPA', (133, 137))	('beta4/beta5', 'Gene', '28898', (4, 15))
31059	33204327	The double-free energy was calculated according to DeltaG1 (Ca2+-bound) - DeltaG2 (Ca2+-free), as shown in the thermodynamic cycle (Figure 4C).	('DeltaG1', 'DELETION', 'None', (51, 58))	('DeltaG2', 'DELETION', 'None', (74, 81))	('DeltaG2', 'Var', (74, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (83, 87))	('DeltaG1', 'Var', (51, 58))	('Ca2+', 'Chemical', 'MESH:D000069285', (60, 64))
31060	33204327	The data indicated that the Ca2+-binding affinity toward CDH6-EC5 was reduced by S524L substitution (DeltaDeltaG = 4.4 kJ/mol).	('CDH6', 'Gene', '1004', (57, 61))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('reduced', 'NegReg', (70, 77))	('Ca2+', 'Chemical', 'MESH:D000069285', (28, 32))	('S524L', 'Mutation', 'rs202247793', (81, 86))	('S524L', 'Var', (81, 86))	('Ca2+-binding affinity', 'MPA', (28, 49))	('CDH6', 'Gene', (57, 61))
31061	33204327	These analyses conclude that S524L substitution may induce additional fluctuations in the beta2/beta3 and beta4/beta5 loop regions, which can promote instability in this region and thus hamper Ca2+-binding.	('Ca2+-binding', 'MPA', (193, 205))	('beta2/beta3', 'Gene', (90, 101))	('fluctuations', 'MPA', (70, 82))	('induce', 'Reg', (52, 58))	('beta4/beta5', 'Gene', (106, 117))	('S524L', 'Mutation', 'rs202247793', (29, 34))	('hamper', 'NegReg', (186, 192))	('S524L', 'Var', (29, 34))	('Ca2+', 'Chemical', 'MESH:D000069285', (193, 197))	('binding', 'molecular_function', 'GO:0005488', ('198', '205'))	('instability', 'MPA', (150, 161))	('promote', 'PosReg', (142, 149))	('beta4/beta5', 'Gene', '28898', (106, 117))	('beta2/beta3', 'Gene', '170589', (90, 101))
31063	33204327	To study functional roles of mutations in the intracellular domain (CDH-C), we performed sequence alignment across cadherins involved in the cadherin interactome core.	('core', 'cellular_component', 'GO:0019013', ('162', '166'))	('cadherin', 'Gene', (115, 123))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (115, 123))	('cadherin', 'Gene', (141, 149))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (141, 149))	('mutations', 'Var', (29, 38))	('intracellular', 'cellular_component', 'GO:0005622', ('46', '59'))	('CDH', 'Gene', (68, 71))	('CDH', 'Gene', '55349', (68, 71))	('cadherin', 'molecular_function', 'GO:0008014', ('141', '149'))
31065	33204327	We next predicted 3-D structures of CDH6-JMD (residues 660-677) and CDH6-CBD (residues 687-784) in complexes with p120-catenin and beta-catenin, respectively, in which orange spheres indicate the mutations (Figure 5B).	('residues 660-677', 'Var', (46, 62))	('CDH6', 'Gene', '1004', (68, 72))	('residues 687-784', 'Var', (78, 94))	('beta-catenin', 'Protein', (131, 143))	('p120-catenin', 'Gene', '1500', (114, 126))	('complexes', 'Interaction', (99, 108))	('CDH6', 'Gene', (36, 40))	('p120-catenin', 'Gene', (114, 126))	('CDH6', 'Gene', '1004', (36, 40))	('CDH6', 'Gene', (68, 72))
31066	33204327	Significantly, most of the mutations can change the charge (D661N, E662K, R689Q, D691N, E722K, D762N, and R773Q); therefore, the salt bridge interactions between cadherins and catenins can be interrupted, which may consequently reduce cadherin/catenin complex formation.	('E722K', 'Var', (88, 93))	('salt bridge', 'MPA', (129, 140))	('D762N', 'Var', (95, 100))	('D762N', 'Mutation', 'p.D762N', (95, 100))	('E722K', 'Mutation', 'rs780971188', (88, 93))	('reduce', 'NegReg', (228, 234))	('R773Q', 'Mutation', 'rs1239863031', (106, 111))	('cadherin', 'Gene', (235, 243))	('E662K', 'Var', (67, 72))	('R689Q', 'Var', (74, 79))	('D691N', 'Var', (81, 86))	('cadherin', 'Gene', (162, 170))	('interrupted', 'NegReg', (192, 203))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (235, 243))	('R689Q', 'Mutation', 'rs138589959', (74, 79))	('E662K', 'Mutation', 'rs755912714', (67, 72))	('R773Q)', 'Var', (106, 112))	('formation', 'biological_process', 'GO:0009058', ('260', '269'))	('cadherin', 'molecular_function', 'GO:0008014', ('235', '243'))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (162, 170))	('D691N', 'Mutation', 'p.D691N', (81, 86))	('catenin complex', 'cellular_component', 'GO:0016342', ('244', '259'))	('change', 'Reg', (41, 47))	('D661N', 'Var', (60, 65))	('D661N', 'Mutation', 'rs748299287', (60, 65))
31068	33204327	The catenin binding affinity differences  were calculated according to DeltaG1 (catenin-bound) - DeltaG2 (catenin-free), as shown in the thermodynamic cycle when placed in one simulation box (Figure S1A).	('DeltaG2', 'Var', (97, 104))	('DeltaG1', 'Var', (71, 78))	('catenin', 'Protein', (4, 11))	('DeltaG1', 'DELETION', 'None', (71, 78))	('DeltaG2', 'DELETION', 'None', (97, 104))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))
31069	33204327	The resulting binding free energy differences  in mutants as compared to WT CDH6 were 4.60 (D661N) and 7.50 (E662K) kJ/mol for p120-catenin (Figure 5C and Figure S8), whereas 8.17 (R689Q), 5.96 (D691N), -0.07 (E722K), 5.98 (D762N), and 8.70 (R773Q) kJ/mol for beta-catenin (Figure 5C and Figure S9), suggesting that the binding affinity for both p120-catenin and beta-catenin were disrupted in most mutants .	('D762N', 'Mutation', 'p.D762N', (224, 229))	('E722K', 'Mutation', 'rs780971188', (210, 215))	('CDH6', 'Gene', (76, 80))	('beta-catenin', 'Protein', (363, 375))	('R773Q', 'Mutation', 'rs1239863031', (242, 247))	('p120-catenin', 'Gene', '1500', (127, 139))	('binding affinity', 'Interaction', (320, 336))	('R689Q', 'Mutation', 'rs138589959', (181, 186))	('mutants', 'Var', (399, 406))	('p120-catenin', 'Gene', (127, 139))	('D691N', 'Mutation', 'p.D691N', (195, 200))	('mutants', 'Var', (50, 57))	('binding', 'molecular_function', 'GO:0005488', ('320', '327'))	('E662K', 'Mutation', 'rs755912714', (109, 114))	('D661N', 'Mutation', 'rs748299287', (92, 97))	('disrupted', 'NegReg', (381, 390))	('p120-catenin', 'Gene', '1500', (346, 358))	('binding', 'molecular_function', 'GO:0005488', ('14', '21'))	('p120-catenin', 'Gene', (346, 358))	('CDH6', 'Gene', '1004', (76, 80))
31070	33204327	The residue S749 lies within the invariant cadherin sequence 749Ser-Leu-Ser-Ser-Leu753, which has been shown as an important phosphorylation site to form hydrogen bonds with beta-catenin.	('cadherin', 'Gene', (43, 51))	('Leu', 'Chemical', 'MESH:D007930', (80, 83))	('Ser', 'Chemical', 'MESH:D012694', (72, 75))	('hydrogen', 'Chemical', 'MESH:D006859', (154, 162))	('Ser', 'Chemical', 'MESH:D012694', (76, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('beta-catenin', 'Protein', (174, 186))	('749Ser-Leu-Ser-Ser-Leu753', 'Var', (61, 86))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (43, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('125', '140'))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))	('Leu', 'Chemical', 'MESH:D007930', (68, 71))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))	('Leu753', 'Chemical', '-', (80, 86))	('S749', 'Var', (12, 16))	('Ser', 'cellular_component', 'GO:0005790', ('64', '67'))
31071	33204327	The S749F substitution therefore can block the phosphorylation in this region, and consequently reduce cadherin/beta-catenin complex formation.	('S749F', 'Mutation', 'p.S749F', (4, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('cadherin', 'Gene', (103, 111))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (103, 111))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('reduce cadherin/beta-catenin complex', 'Phenotype', 'HP:0040209', (96, 132))	('phosphorylation', 'MPA', (47, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('catenin complex', 'cellular_component', 'GO:0016342', ('117', '132'))	('reduce', 'NegReg', (96, 102))	('block', 'NegReg', (37, 42))	('S749F', 'Var', (4, 9))
31072	33204327	Similar strategies were also applied to calculate cadherin-catenin binding free energy differences caused by somatic mutations in other top-four mutated genes.	('mutations', 'Var', (117, 126))	('binding', 'molecular_function', 'GO:0005488', ('67', '74'))	('cadherin', 'Gene', (50, 58))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (50, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('binding', 'Interaction', (67, 74))
31073	33204327	Except CDH10, most substitutions in JMD and CBD domains of those type-II CDHs resulted in less stable cadherin-catenin complexes with increased free energy differences (Table S2).	('less', 'NegReg', (90, 94))	('free energy differences', 'MPA', (144, 167))	('CDH10', 'Gene', '1008', (7, 12))	('CDH10', 'Gene', (7, 12))	('substitutions', 'Var', (19, 32))	('CDHs', 'Gene', (73, 77))	('cadherin', 'Gene', (102, 110))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (102, 110))	('CDHs', 'Chemical', '-', (73, 77))	('increased', 'PosReg', (134, 143))	('cadherin', 'molecular_function', 'GO:0008014', ('102', '110'))
31074	33204327	To study the functional relevance, GFP-tagged CDH6 mutants with different known mutations in CDH-C were prepared individually and co-transfected with wild type beta-catenin tagged with mCherry into A375 cells, a melanoma cell line proven to express the lowest CDH6 level in cell line screening.	('CDH', 'Gene', (46, 49))	('CDH', 'Gene', '55349', (93, 96))	('mutants', 'Var', (51, 58))	('CDH', 'Gene', (260, 263))	('mutations', 'Var', (80, 89))	('CDH6', 'Gene', (260, 264))	('CDH', 'Gene', (93, 96))	('CDH', 'Gene', '55349', (46, 49))	('CDH6', 'Gene', '1004', (260, 264))	('CDH', 'Gene', '55349', (260, 263))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('A375', 'CellLine', 'CVCL:0132', (198, 202))	('CDH6', 'Gene', (46, 50))	('CDH6', 'Gene', '1004', (46, 50))
31076	33204327	Except D691N, CDH6 mutants with mutations in beta-catenin-binding domain significantly reduced complex formation on cell membrane by promoting beta-catenin translocation into cytosol and/or nucleus, indicating destabilization of CDH6/beta-catenin complex.	('catenin complex', 'cellular_component', 'GO:0016342', ('239', '254'))	('CDH6', 'Gene', (14, 18))	('reduced', 'NegReg', (87, 94))	('cytosol', 'cellular_component', 'GO:0005829', ('175', '182'))	('complex formation on cell membrane', 'MPA', (95, 129))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('CDH6', 'Gene', '1004', (14, 18))	('mutations', 'Var', (32, 41))	('CDH6', 'Gene', (229, 233))	('beta-catenin-binding', 'molecular_function', 'GO:0008013', ('45', '65'))	('mutants', 'Var', (19, 26))	('nucleus', 'cellular_component', 'GO:0005634', ('190', '197'))	('promoting', 'PosReg', (133, 142))	('cell membrane', 'cellular_component', 'GO:0005886', ('116', '129'))	('D691N', 'Mutation', 'p.D691N', (7, 12))	('CDH6', 'Gene', '1004', (229, 233))
31077	33204327	For D661N and E662K, the portions of nuclear beta-catenin were also increased, which could be due to indirect effects of unstable CDH6/p120-catenin complex formation (Figure 6A-B).	('CDH6', 'Gene', (130, 134))	('formation', 'biological_process', 'GO:0009058', ('156', '165'))	('catenin complex', 'cellular_component', 'GO:0016342', ('140', '155'))	('E662K', 'Mutation', 'rs755912714', (14, 19))	('CDH6', 'Gene', '1004', (130, 134))	('D661N', 'Var', (4, 9))	('p120-catenin', 'Gene', '1500', (135, 147))	('D661N', 'Mutation', 'rs748299287', (4, 9))	('E662K', 'Var', (14, 19))	('nuclear beta-catenin', 'Protein', (37, 57))	('increased', 'PosReg', (68, 77))	('p120-catenin', 'Gene', (135, 147))
31080	33204327	However, nuclear and cytosol beta-catenin staining as found in the cell-based study can be frequently detected in melanoma samples with mutated core CDHs (Figure 6C and Figures S4-S7).	('core CDHs', 'Protein', (144, 153))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('core', 'cellular_component', 'GO:0019013', ('144', '148'))	('cytosol', 'cellular_component', 'GO:0005829', ('21', '28'))	('detected', 'Reg', (102, 110))	('mutated', 'Var', (136, 143))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('CDHs', 'Chemical', '-', (149, 153))	('melanoma', 'Disease', (114, 122))
31081	33204327	We also analyzed mRNA levels of genes involved in Hippo and Wnt/beta-catenin signaling in patients with mutations in top-four cadherins (MT core CDHs).	('CDHs', 'Chemical', '-', (145, 149))	('mutations', 'Var', (104, 113))	('Wnt', 'Gene', (60, 63))	('Wnt', 'Gene', '7471', (60, 63))	('core', 'cellular_component', 'GO:0019013', ('140', '144'))	('cadherin', 'Gene', (126, 134))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (126, 134))	('patients', 'Species', '9606', (90, 98))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))
31090	33204327	In general, patients with mutations in core CDH genes showed better overall (p = 0.008; Figure 7B, upper) and disease-free (p = 0.002; Figure 7B, lower) survival times.	('patients', 'Species', '9606', (12, 20))	('CDH', 'Gene', (44, 47))	('better', 'PosReg', (61, 67))	('CDH', 'Gene', '55349', (44, 47))	('disease-free', 'CPA', (110, 122))	('mutations', 'Var', (26, 35))	('core', 'cellular_component', 'GO:0019013', ('39', '43'))
31091	33204327	To know possible signaling signatures in melanomas with mutations in core CDH genes, gene set enrichment analysis (GSEA) was performed using WT group as the control.	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mutations', 'Var', (56, 65))	('CDH', 'Gene', (74, 77))	('GSEA', 'Chemical', '-', (115, 119))	('CDH', 'Gene', '55349', (74, 77))	('melanomas', 'Disease', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('core', 'cellular_component', 'GO:0019013', ('69', '73'))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
31092	33204327	Several up-regulated pathways were found to contribute to cancer progression, DNA replication/cell proliferation, and cell cycle regulation (Table S3 and Figure S10), indicating the pro-oncogenic activity of cadherin mutations.	('cadherin', 'molecular_function', 'GO:0008014', ('208', '216'))	('cell cycle regulation', 'CPA', (118, 139))	('DNA replication', 'biological_process', 'GO:0006260', ('78', '93'))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('DNA replication/cell proliferation', 'CPA', (78, 112))	('pathways', 'Pathway', (21, 29))	('cadherin', 'Gene', (208, 216))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('up-regulated', 'PosReg', (8, 20))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (208, 216))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('118', '139'))	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (217, 226))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))
31093	33204327	These data may explain why melanomas with cadherin mutations correlate with advanced tumor stages and metastatic potentials.	('tumor', 'Disease', (85, 90))	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('mutations', 'Var', (51, 60))	('metastatic potentials', 'CPA', (102, 123))	('cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (42, 50))	('melanomas', 'Disease', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('cadherin', 'Gene', (42, 50))
31097	33204327	Our data revealed higher T-lymphocyte (CD3+) infiltrations in melanoma lesions with mutations in core CDH genes as compared to tissues with wild type CDHs (Figure 7E).	('CDH', 'Gene', (102, 105))	('CDH', 'Gene', (150, 153))	('CDH', 'Gene', '55349', (150, 153))	('CDHs', 'Chemical', '-', (150, 154))	('CDH', 'Gene', '55349', (102, 105))	('mutations', 'Var', (84, 93))	('core', 'cellular_component', 'GO:0019013', ('97', '101'))	('melanoma lesions', 'Disease', 'MESH:D008545', (62, 78))	('higher', 'PosReg', (18, 24))	('melanoma lesions', 'Disease', (62, 78))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
31098	33204327	Our data suggest that cadherin mutations can potentially trigger anti-cancer immunity in patients via promoting lymphocyte infiltration, resulting in prolonged survival times.	('mutations', 'Var', (31, 40))	('prolonged', 'PosReg', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cadherin', 'Gene', (22, 30))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('patients', 'Species', '9606', (89, 97))	('promoting', 'PosReg', (102, 111))	('survival times', 'CPA', (160, 174))	('cancer', 'Disease', (70, 76))	('lymphocyte infiltration', 'CPA', (112, 135))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))	('trigger', 'PosReg', (57, 64))
31099	33204327	To understand how cadherin mutations activate T-cell immunity, we used machine-learning-based neo-antigen prediction program, NetMHCpan, to score neo-antigen potentials of defined mutations.	('activate', 'PosReg', (37, 45))	('mutations', 'Var', (27, 36))	('NetMHCpan', 'Chemical', '-', (126, 135))	('cadherin', 'Gene', (18, 26))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (18, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))
31100	33204327	Notably, the recurrent S524L substitution on CDH6 was found to be a potent neo-antigen due to increased MHC-I binding affinity and less antigen-tolerance (Figure 8A).	('binding', 'molecular_function', 'GO:0005488', ('110', '117'))	('S524L', 'Mutation', 'rs202247793', (23, 28))	('less', 'NegReg', (131, 135))	('S524L', 'Var', (23, 28))	('CDH6', 'Gene', (45, 49))	('increased', 'PosReg', (94, 103))	('MHC-I', 'Protein', (104, 109))	('CDH6', 'Gene', '1004', (45, 49))	('increased MHC', 'Phenotype', 'HP:0025548', (94, 107))	('antigen-tolerance', 'CPA', (136, 153))	('binding affinity', 'Interaction', (110, 126))
31102	33204327	This finding indicated higher immunogenic potentials generated by mutations in core CDH genes.	('mutations', 'Var', (66, 75))	('CDH', 'Gene', (84, 87))	('immunogenic potentials', 'MPA', (30, 52))	('CDH', 'Gene', '55349', (84, 87))	('higher', 'PosReg', (23, 29))	('core', 'cellular_component', 'GO:0019013', ('79', '83'))
31103	33204327	Accumulating evidence have revealed that tumors with higher mutational burdens correlate with the likelihood of higher neo-antigen loads, leading to better therapeutic outcome for patients after immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('neo-antigen loads', 'MPA', (119, 136))	('mutational burdens', 'Var', (60, 78))	('therapeutic outcome', 'MPA', (156, 175))	('higher', 'PosReg', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('better', 'PosReg', (149, 155))	('patients', 'Species', '9606', (180, 188))
31104	33204327	By using immunogenetic datasets from MSKCC and UCLA groups, we found that mutations in core CDH genes highly correlated with total mutational and neo-antigen loads in patients with metastatic melanoma (Figure 8B-C).	('core', 'cellular_component', 'GO:0019013', ('87', '91'))	('CDH', 'Gene', (92, 95))	('mutations', 'Var', (74, 83))	('patients', 'Species', '9606', (167, 175))	('neo-antigen loads', 'MPA', (146, 163))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('correlated', 'Reg', (109, 119))	('melanoma', 'Disease', (192, 200))	('CDH', 'Gene', '55349', (92, 95))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))
31105	33204327	Those findings suggest an anti-tumor microenvironment immune type associated with mutations in core CDH genes that favors a better clinical response to immunotherapeutic agents (Figure S12).	('favors', 'PosReg', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('core', 'cellular_component', 'GO:0019013', ('95', '99'))	('CDH', 'Gene', (100, 103))	('mutations', 'Var', (82, 91))	('better', 'PosReg', (124, 130))	('CDH', 'Gene', '55349', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
31106	33204327	To confirm this, we also compared clinical outcomes of anti-CTLA4 (Ipilimumab) and anti-PD1 (Pembrolizumab) therapies between patients with and without mutations in core CDH genes.	('Ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('CDH', 'Gene', (170, 173))	('CTLA4', 'Gene', (60, 65))	('mutations', 'Var', (152, 161))	('CDH', 'Gene', '55349', (170, 173))	('core', 'cellular_component', 'GO:0019013', ('165', '169'))	('patients', 'Species', '9606', (126, 134))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (93, 106))	('CTLA4', 'Gene', '1493', (60, 65))
31107	33204327	Consistent with higher mutational and neo-antigen loads, patients with CDH mutations usually showed longer therapeutic duration times for Ipilimumab treatment (Figure 8D) and better drug responses for Pembrolizumab therapy (Figure 8E).	('CDH', 'Gene', (71, 74))	('better', 'PosReg', (175, 181))	('drug responses', 'MPA', (182, 196))	('CDH', 'Gene', '55349', (71, 74))	('patients', 'Species', '9606', (57, 65))	('longer', 'PosReg', (100, 106))	('therapeutic duration times', 'MPA', (107, 133))	('mutations', 'Var', (75, 84))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (138, 148))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (201, 214))
31111	33204327	Through data mining using TCGA dataset, we discovered high mutation frequencies in cadherin genes which can be validated by using data from non-TCGA cohort (Figure 2 and Figure S3A).	('mutation frequencies', 'Var', (59, 79))	('cadherin', 'Gene', (83, 91))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (83, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))
31114	33204327	Even though mutation rate of CDH4 (R-cadherin) was also high (the fifth highly mutated gene) and defined as a type-I cadherin, the heterophilic interaction between CDH4 and CDH2 has been previously reported.	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (117, 125))	('CDH2', 'Gene', (173, 177))	('cadherin', 'Gene', (37, 45))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (37, 45))	('CDH4', 'Gene', '1002', (164, 168))	('CDH2', 'Gene', '1000', (173, 177))	('CDH4', 'Gene', (29, 33))	('R-cadherin', 'Gene', '1002', (35, 45))	('cadherin', 'molecular_function', 'GO:0008014', ('37', '45'))	('cadherin', 'molecular_function', 'GO:0008014', ('117', '125'))	('R-cadherin', 'Gene', (35, 45))	('mutation', 'Var', (12, 20))	('cadherin', 'Gene', (117, 125))	('CDH4', 'Gene', '1002', (29, 33))	('CDH4', 'Gene', (164, 168))
31115	33204327	Dislike CDH1 being genetically deleted or epigenetically silenced during cancer development, those top-four cadherins were consistently expressed to form cell-cell contacts during the transition from melanocyte to melanoma.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('CDH1', 'Gene', (8, 12))	('CDH1', 'Gene', '999', (8, 12))	('epigenetically silenced', 'Var', (42, 65))	('cadherin', 'Gene', (108, 116))
31116	33204327	Breaking such balance by mutations in key cadherins may serve as a newly-defined driving force to promote melanomagenesis, which could be a possible common mechanism shared by other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (25, 34))	('promote', 'PosReg', (98, 105))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('cadherin', 'Gene', (42, 50))
31121	33204327	Both tumor-suppressing and pro-oncogenic activities were associated with CDH6 expression in cancer development.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('expression', 'Var', (78, 88))	('pro-oncogenic activities', 'CPA', (27, 51))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CDH6', 'Gene', (73, 77))	('CDH6', 'Gene', '1004', (73, 77))	('tumor', 'Disease', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
31124	33204327	Based on our study, recurrent mutation S524L and functional mutations in the intracellular domain of CDH6 can result in loss of cell-cell contacts and beta-catenin translocation into nucleus, which associate with tumors at more advanced stages and lymph node invasion (Figures 6 and 7), suggesting those mutations as active drivers but not passengers during melanogenesis.	('intracellular', 'cellular_component', 'GO:0005622', ('77', '90'))	('S524L', 'Mutation', 'rs202247793', (39, 44))	('CDH6', 'Gene', '1004', (101, 105))	('mutation S524L', 'Var', (30, 44))	('tumors', 'Disease', (213, 219))	('S524L', 'Var', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('beta-catenin translocation into nucleus', 'MPA', (151, 190))	('nucleus', 'cellular_component', 'GO:0005634', ('183', '190'))	('CDH6', 'Gene', (101, 105))	('cell-cell contacts', 'CPA', (128, 146))	('associate with', 'Reg', (198, 212))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('loss', 'NegReg', (120, 124))	('lymph node invasion', 'CPA', (248, 267))
31125	33204327	To our knowledge, this is the first report to address the functional impacts of CDH6 and its mutations on melanoma development.	('mutations', 'Var', (93, 102))	('CDH6', 'Gene', (80, 84))	('CDH6', 'Gene', '1004', (80, 84))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))
31126	33204327	Interestingly, we also found nuclear staining for mutated CDH6 in tumor samples (Figure 6C), which could be novel phenomena in certain types of melanoma awaiting further investigation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('CDH6', 'Gene', (58, 62))	('CDH6', 'Gene', '1004', (58, 62))	('mutated', 'Var', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
31132	33204327	For examples, fibroblast-like synoviocytes can migrate and invade into pigmented villonodular synovitis by expressing CDH11, Silencing of CDH10 was also found as another mechanism to enhance breast tumor cell mobility in hypoxic conditions.	('pigmented villonodular synovitis', 'Disease', (71, 103))	('Silencing', 'Var', (125, 134))	('CDH10', 'Gene', '1008', (138, 143))	('breast tumor', 'Disease', 'MESH:D001943', (191, 203))	('CDH10', 'Gene', (138, 143))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (221, 239))	('breast tumor', 'Disease', (191, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('enhance', 'PosReg', (183, 190))	('CDH11', 'Gene', '1009', (118, 123))	('hypoxic conditions', 'Disease', (221, 239))	('pigmented villonodular synovitis', 'Disease', 'MESH:D013586', (71, 103))	('migrate', 'CPA', (47, 54))	('CDH11', 'Gene', (118, 123))	('synovitis', 'Phenotype', 'HP:0100769', (94, 103))	('breast tumor', 'Phenotype', 'HP:0100013', (191, 203))
31133	33204327	These studies support our findings that mutations in core type-II cadherins may provide advantages for melanoma cells to alter the original connecting networks with keratinocytes, enabling them to further migrate out of melanocyte stem cell niche and form tumor lesions on the skin.	('original connecting networks', 'MPA', (131, 159))	('cadherin', 'Gene', (66, 74))	('advantages', 'PosReg', (88, 98))	('tumor lesions', 'Disease', (256, 269))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (66, 74))	('form', 'Reg', (251, 255))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('tumor lesions', 'Disease', 'MESH:D009369', (256, 269))	('core', 'cellular_component', 'GO:0019013', ('53', '57'))	('tumor lesions on the skin', 'Phenotype', 'HP:0008069', (256, 281))	('mutations', 'Var', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('alter', 'Reg', (121, 126))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
31134	33204327	Based on genetic analyses, molecular modeling and experimental investigations, our data highly suggest the causal consequence of mutations in CDH-C domains with activation of Wnt/beta-catenin signaling.	('Wnt', 'Gene', '7471', (175, 178))	('mutations', 'Var', (129, 138))	('Wnt', 'Gene', (175, 178))	('CDH', 'Gene', (142, 145))	('signaling', 'biological_process', 'GO:0023052', ('192', '201'))	('activation', 'PosReg', (161, 171))	('CDH', 'Gene', '55349', (142, 145))
31135	33204327	Firstly, mutations in CDH-C domains of the core CDHs showed mutual exclusivity with beta-catenin (CTNNB1) mutations (Figure 3B), suggesting that they share redundant biological functions; secondly, CDH-C mutations correlated with increased thermodynamics of the CDH-C/beta-catenin or CDH-C/p120-catenin complexes (Figure 5C and Figures S8-S9), indicating higher levels of free beta-catenin in cells; finally, live imaging study confirmed an overall increased nuclear beta-catenin in cells expressing CDH6 mutants with mutations in the CDH-C domain (Figure 6A-B).	('mutants', 'Var', (505, 512))	('CDH', 'Gene', '55349', (535, 538))	('mutations', 'Var', (518, 527))	('CTNNB1', 'Gene', '1499', (98, 104))	('CDH', 'Gene', (500, 503))	('CDH6', 'Gene', '1004', (500, 504))	('increased', 'PosReg', (449, 458))	('CDH', 'Gene', (262, 265))	('CDH', 'Gene', (48, 51))	('CDH6', 'Gene', (500, 504))	('CDH', 'Gene', (284, 287))	('CDH', 'Gene', (22, 25))	('CDH', 'Gene', (198, 201))	('CDH', 'Gene', '55349', (500, 503))	('CTNNB1', 'Gene', (98, 104))	('mutations', 'Var', (204, 213))	('p120-catenin', 'Gene', '1500', (290, 302))	('CDHs', 'Chemical', '-', (48, 52))	('CDH', 'Gene', '55349', (262, 265))	('CDH', 'Gene', '55349', (48, 51))	('core', 'cellular_component', 'GO:0019013', ('43', '47'))	('p120-catenin', 'Gene', (290, 302))	('CDH', 'Gene', (535, 538))	('CDH', 'Gene', '55349', (22, 25))	('CDH', 'Gene', '55349', (284, 287))	('CDH', 'Gene', '55349', (198, 201))	('nuclear beta-catenin', 'MPA', (459, 479))
31136	33204327	Consistent with this, the recurrent S524L mutation in CDH6-EC5 also affect the stability and organization of CDH6-mediated AJ complex (Figure 4A-C), leading to beta-catenin release from the membrane and translocation into cell nucleus as well as loss of contact inhibition (Figure 6B-D).	('CDH6', 'Gene', '1004', (54, 58))	('cell nucleus', 'cellular_component', 'GO:0005634', ('222', '234'))	('contact inhibition', 'biological_process', 'GO:0060242', ('254', '272'))	('stability', 'MPA', (79, 88))	('membrane', 'cellular_component', 'GO:0016020', ('190', '198'))	('S524L', 'Mutation', 'rs202247793', (36, 41))	('translocation into cell nucleus', 'MPA', (203, 234))	('beta-catenin release from the membrane', 'MPA', (160, 198))	('S524L', 'Var', (36, 41))	('organization', 'MPA', (93, 105))	('contact inhibition', 'MPA', (254, 272))	('loss', 'NegReg', (246, 250))	('affect', 'Reg', (68, 74))	('CDH6', 'Gene', (109, 113))	('CDH6', 'Gene', '1004', (109, 113))	('CDH6', 'Gene', (54, 58))
31137	33204327	Especially, there is a 510-His-Ala-Val-512 (HAV) motif at the EC5 domain which is considered responsible for stabilization and clustering of adjacent cadherin monomers in a calcium-dependent fashion.	('calcium', 'Chemical', 'MESH:D002118', (173, 180))	('510-His-Ala-Val-512', 'Var', (23, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('150', '158'))	('cadherin', 'Gene', (150, 158))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (150, 158))
31138	33204327	Also, the EC5 is the only extracellular domain that contains critical cysteine residues (at the positions of 497, 589, 591, and 600) in CDH6 for possible cis- and trans-dimerization of neighboring cadherins.	('CDH6', 'Gene', (136, 140))	('cysteine', 'Chemical', 'MESH:D003545', (70, 78))	('cadherin', 'Gene', (197, 205))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (197, 205))	('591', 'Var', (119, 122))	('CDH6', 'Gene', '1004', (136, 140))	('extracellular', 'cellular_component', 'GO:0005576', ('26', '39'))
31139	33204327	Therefore, S524L mutation may restrain calcium-induced CDH6 rigidification and dimerization, leading to reduced cell contacts with neighboring cells.	('reduced', 'NegReg', (104, 111))	('cell contacts with neighboring cells', 'CPA', (112, 148))	('calcium-induced', 'MPA', (39, 54))	('S524L mutation', 'Var', (11, 25))	('rigidification', 'MPA', (60, 74))	('calcium', 'Chemical', 'MESH:D002118', (39, 46))	('CDH6', 'Gene', (55, 59))	('CDH6', 'Gene', '1004', (55, 59))	('S524L', 'Mutation', 'rs202247793', (11, 16))	('dimerization', 'MPA', (79, 91))	('restrain', 'NegReg', (30, 38))
31140	33204327	Although mutations in the core CDH genes showed pro-oncogenic activity, patients with such mutations showed better overall and disease-free survival times (Figure 7B).	('overall', 'CPA', (115, 122))	('pro-oncogenic activity', 'CPA', (48, 70))	('disease-free survival times', 'CPA', (127, 154))	('mutations', 'Var', (9, 18))	('CDH', 'Gene', (31, 34))	('mutations', 'Var', (91, 100))	('better', 'PosReg', (108, 114))	('CDH', 'Gene', '55349', (31, 34))	('core', 'cellular_component', 'GO:0019013', ('26', '30'))	('patients', 'Species', '9606', (72, 80))
31141	33204327	These results indicate possible complications associated with mutations in those type-II cadherins in controlling immunosurveillance.	('mutations', 'Var', (62, 71))	('cadherin', 'Gene', (89, 97))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (89, 97))
31145	33204327	By using the immunogenetic dataset from MSKCC group, we also noticed patients with mutations in CDH6 or other core CDH genes showed more gammadeltaT cell recruitments in melanoma lesions with more activated CD4+ memory T cells and higher cytolytic scores (Figure S12).	('melanoma lesions', 'Disease', (170, 186))	('higher', 'PosReg', (231, 237))	('CDH6', 'Gene', '1004', (96, 100))	('CDH', 'Gene', (96, 99))	('core', 'cellular_component', 'GO:0019013', ('110', '114'))	('patients', 'Species', '9606', (69, 77))	('CDH', 'Gene', '55349', (115, 118))	('CDH6', 'Gene', (96, 100))	('cytolytic scores', 'CPA', (238, 254))	('CDH', 'Gene', '55349', (96, 99))	('memory', 'biological_process', 'GO:0007613', ('212', '218'))	('CD4', 'Gene', '920', (207, 210))	('more activated', 'PosReg', (192, 206))	('more', 'PosReg', (132, 136))	('gammadeltaT cell recruitments', 'CPA', (137, 166))	('mutations', 'Var', (83, 92))	('melanoma lesions', 'Disease', 'MESH:D008545', (170, 186))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('CD4', 'Gene', (207, 210))	('CDH', 'Gene', (115, 118))
31146	33204327	Accordingly, there could be a possibility that mutations in cadherins, when the melanoma cells spread through the blood or lymph, can stimulate gammadeltaT cell activation and enhance lymphocyte recruitment into core tumor lesions, leading to up-regulation of T-lymphocyte and antigen responses which were evidenced in our study (Figure 7C-E).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('stimulate', 'PosReg', (134, 143))	('gammadeltaT cell activation', 'MPA', (144, 171))	('tumor lesions', 'Disease', (217, 230))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('cadherin', 'Gene', (60, 68))	('mutations', 'Var', (47, 56))	('enhance', 'PosReg', (176, 183))	('tumor lesions', 'Disease', 'MESH:D009369', (217, 230))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (60, 68))	('up-regulation', 'PosReg', (243, 256))	('cell activation', 'biological_process', 'GO:0001775', ('156', '171'))	('lymphocyte', 'CPA', (184, 194))	('core', 'cellular_component', 'GO:0019013', ('212', '216'))	('regulation', 'biological_process', 'GO:0065007', ('246', '256'))
31147	33204327	Since most of detected CDH mutations in melanoma are highly relevant to UV exposure, CDH mutations should play certain key roles in triggering anti-tumor immunity in patients.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CDH', 'Gene', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CDH', 'Gene', (85, 88))	('tumor', 'Disease', (148, 153))	('CDH', 'Gene', '55349', (23, 26))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('CDH', 'Gene', '55349', (85, 88))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('patients', 'Species', '9606', (166, 174))
31148	33204327	Especially, the S524L substitution in CDH6 has been predicted to be a strong neo-antigen (Figure 8A), peptides with such substitution could be utilized as potent adjuvants to trigger stronger anti-melanoma immunity when co-treated with other immuno-therapeutics such as anti-PD-1/L1 or anti-CTLA4 Abs.	('CTLA4', 'Gene', (291, 296))	('CDH6', 'Gene', (38, 42))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('S524L', 'Mutation', 'rs202247793', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('S524L', 'Var', (16, 21))	('CDH6', 'Gene', '1004', (38, 42))	('CTLA4', 'Gene', '1493', (291, 296))	('stronger', 'PosReg', (183, 191))
31149	33204327	Whether mutations in cadherins can change cytokine profiles in the local microenvironment to direct lymphocyte homing and activate anti-melanoma immunity will be investigated in our future study.	('lymphocyte homing', 'biological_process', 'GO:0097022', ('100', '117'))	('activate', 'PosReg', (122, 130))	('mutations', 'Var', (8, 17))	('change', 'Reg', (35, 41))	('cadherin', 'Gene', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('lymphocyte homing', 'biological_process', 'GO:0097021', ('100', '117'))	('melanoma', 'Disease', (136, 144))	('cadherin', 'Gene', '999;1008;1009;1015;1015;1016;1000;1016;1001;1002;1004;12563;1005;1007', (21, 29))	('cytokine profiles', 'MPA', (42, 59))
31152	33204327	Secondly, CDH mutations alone may not be the only contributor to make melanoma becoming more immunogenic.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('CDH', 'Gene', (10, 13))	('CDH', 'Gene', '55349', (10, 13))	('mutations', 'Var', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
31161	33266349	No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('PD-L1', 'Gene', (23, 28))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('NRAS', 'Gene', (84, 88))	('tumour', 'Disease', (44, 50))	('NRAS', 'Gene', '4893', (84, 88))	('PD-L1', 'Gene', '29126', (23, 28))	('mutations', 'Var', (89, 98))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
31169	33266349	Notably, genetic studies have reported mutations in BRAF, NRAS, and KIT, and implication of ultraviolet radiation as a risk factor for CM.	('NRAS', 'Gene', '4893', (58, 62))	('reported', 'Reg', (30, 38))	('risk', 'Reg', (119, 123))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('mutations', 'Var', (39, 48))	('KIT', 'Gene', '3815', (68, 71))	('BRAF', 'Gene', '673', (52, 56))	('KIT', 'Gene', (68, 71))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (52, 56))
31170	33266349	Indeed, large cohorts of CM patients have identified BRAF and NRAS mutations in 29-50% and in 18%, respectively.	('NRAS', 'Gene', '4893', (62, 66))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (28, 36))	('NRAS', 'Gene', (62, 66))
31188	33266349	The inter-observer coefficient of agreement (Cohen Kappa) was performed to compare the expression of PD-L1 in IC with SP142 and SP263 Abs.	('SP142', 'Chemical', '-', (118, 123))	('PD-L1', 'Gene', '29126', (101, 106))	('SP263', 'Chemical', '-', (128, 133))	('SP142', 'Var', (118, 123))	('IC', 'Chemical', '-', (110, 112))	('SP263 Abs', 'Var', (128, 137))	('PD-L1', 'Gene', (101, 106))
31189	33266349	A good correlation was observed for IC between the SP263 and SP142 Abs (0.74).	('SP263', 'Var', (51, 56))	('SP263', 'Chemical', '-', (51, 56))	('SP142 Abs', 'Var', (61, 70))	('SP142', 'Chemical', '-', (61, 66))	('IC', 'Chemical', '-', (36, 38))
31201	33266349	The mutations BRAFV600E and NRASQ61R were mutually exclusive.	('NRASQ61R', 'Var', (28, 36))	('BRAFV600E', 'Var', (14, 23))	('BRAFV600E', 'Mutation', 'rs113488022', (14, 23))
31203	33266349	SP142/PD-L1-IC and SP263/PD-L1-IC positivity (>=1%) correlated with CD8+ TILs and with PD-1+ TILs (p = 0.04 and p < 0.001, respectively for SP142, and p = 0.0006 and p = 0.0002 for SP263, respectively).	('IC', 'Chemical', '-', (12, 14))	('PD-1+ TILs', 'Disease', (87, 97))	('CD8', 'Gene', (68, 71))	('PD-L1', 'Gene', '29126', (25, 30))	('CD8', 'Gene', '925', (68, 71))	('SP263', 'Chemical', '-', (19, 24))	('IC', 'Chemical', '-', (31, 33))	('PD-1+ TILs', 'Disease', 'MESH:D010300', (87, 97))	('PD-L1', 'Gene', (6, 11))	('SP142', 'Chemical', '-', (0, 5))	('SP142', 'Chemical', '-', (140, 145))	('SP263', 'Chemical', '-', (181, 186))	('SP142', 'Var', (140, 145))	('PD-L1', 'Gene', '29126', (6, 11))	('PD-L1', 'Gene', (25, 30))
31205	33266349	No correlation was found between PD-L1 expression (SP142 or SP263) or PD-1+ or CD8+ TILs and BRAF or NRAS mutations.	('BRAF', 'Gene', (93, 97))	('PD-L1', 'Gene', (33, 38))	('SP142', 'Chemical', '-', (51, 56))	('NRAS', 'Gene', (101, 105))	('SP142', 'Var', (51, 56))	('NRAS', 'Gene', '4893', (101, 105))	('PD-L1', 'Gene', '29126', (33, 38))	('CD8', 'Gene', (79, 82))	('CD8', 'Gene', '925', (79, 82))	('PD-1', 'Gene', (70, 74))	('mutations', 'Var', (106, 115))	('SP263', 'Chemical', '-', (60, 65))	('PD-1', 'Gene', '5133', (70, 74))	('BRAF', 'Gene', '673', (93, 97))	('SP263', 'Var', (60, 65))
31218	33266349	Finally, negative or weak staining of IC with SP142 and with CD8 was significantly associated with a pathological-Tumour 1 (pT1) stage and a bulbar localization.	('SP142', 'Chemical', '-', (46, 51))	('bulbar', 'Disease', (141, 147))	('SP142', 'Var', (46, 51))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('IC', 'Chemical', '-', (38, 40))	('localization', 'biological_process', 'GO:0051179', ('148', '160'))	('associated', 'Reg', (83, 93))	('negative', 'NegReg', (9, 17))	('Tumour', 'Phenotype', 'HP:0002664', (114, 120))	('weak', 'NegReg', (21, 25))
31221	33266349	No significant association with DFS was noted with SP142 IC and SP263 IC or TC.	('SP142', 'Chemical', '-', (51, 56))	('SP263', 'Chemical', '-', (64, 69))	('SP142', 'Var', (51, 56))	('IC', 'Chemical', '-', (70, 72))	('TC', 'Chemical', '-', (76, 78))	('SP263 IC', 'Var', (64, 72))	('IC', 'Chemical', '-', (57, 59))
31222	33266349	No significant association with DSS was noted with SP142 and SP263 IC.	('SP142', 'Chemical', '-', (51, 56))	('SP142', 'Var', (51, 56))	('SP263', 'Chemical', '-', (61, 66))	('DSS', 'Chemical', '-', (32, 35))	('DSS', 'Disease', (32, 35))	('IC', 'Chemical', '-', (67, 69))	('SP263 IC', 'Var', (61, 69))
31223	33266349	No significant association was found for BRAFV600E or NRASQ61R mutations and clinical or pathological parameters.	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('NRASQ61R', 'Var', (54, 62))	('BRAFV600E', 'Gene', (41, 50))
31224	33266349	There was no significant association of a BRAF mutation with DSS or DFS but a NRAS mutation was significantly associated with shorter DSS (p = 0.03).	('BRAF', 'Gene', '673', (42, 46))	('shorter DSS', 'Disease', (126, 137))	('DSS', 'Chemical', '-', (61, 64))	('DSS', 'Chemical', '-', (134, 137))	('NRAS', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('NRAS', 'Gene', '4893', (78, 82))	('BRAF', 'Gene', (42, 46))
31225	33266349	Finally, a multifactorial analysis showed that metastasis (pM1) was independently associated with worse DFS (p = 0.01, hazard ratio = 5.54, IC95% OR (1.31-23.30)).	('IC', 'Chemical', '-', (140, 142))	('pM1', 'Gene', '8834', (59, 62))	('pM1', 'Gene', (59, 62))	('DFS', 'Disease', (104, 107))	('metastasis', 'Var', (47, 57))
31228	33266349	The purpose of our study was to analyse PD-L1 expression alone or in combination with CD8 and PD-1 expression and the BRAFV600E and NRASQ61R status, as a prognostic factor in CM.	('PD-L1', 'Gene', (40, 45))	('BRAFV600E', 'Var', (118, 127))	('CD8', 'Gene', (86, 89))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('CD8', 'Gene', '925', (86, 89))	('PD-L1', 'Gene', '29126', (40, 45))	('PD-1', 'Gene', (94, 98))	('PD-1', 'Gene', '5133', (94, 98))
31229	33266349	We tested 2 PD-L1 clones (SP142 and SP263) on 65 CM.	('PD-L1', 'Gene', (12, 17))	('SP142', 'Chemical', '-', (26, 31))	('PD-L1', 'Gene', '29126', (12, 17))	('SP263', 'Chemical', '-', (36, 41))	('SP142', 'Var', (26, 31))	('SP263', 'Var', (36, 41))
31233	33266349	Finally, the administration of therapeutic molecules targeting PD1/PD-L1 for some solid tumours is linked to specific biomarkers used as FDA approved companion diagnostic tests (SP142 for atezolizumab and SP263 for pembrolizumab treatment).	('atezolizumab', 'Chemical', 'MESH:C000594389', (188, 200))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('PD-L1', 'Gene', (67, 72))	('solid tumours', 'Disease', 'MESH:D009369', (82, 95))	('SP263', 'Chemical', '-', (205, 210))	('solid tumours', 'Disease', (82, 95))	('PD-L1', 'Gene', '29126', (67, 72))	('SP263', 'Var', (205, 210))	('pembrolizumab', 'Chemical', 'MESH:C582435', (215, 228))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('SP142', 'Chemical', '-', (178, 183))	('SP142', 'Var', (178, 183))
31235	33266349	The tumours with PD-L1/IC+ were practically the same with the SP142 and SP263 clones.	('SP142', 'Chemical', '-', (62, 67))	('SP263', 'Chemical', '-', (72, 77))	('SP142', 'Var', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('SP263', 'Var', (72, 77))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('PD-L1/IC', 'Gene', (17, 25))	('PD-L1/IC', 'Gene', '29126', (17, 25))	('tumours', 'Disease', (4, 11))
31240	33266349	We also found preferential labelling on IC, with clone SP142 (44%) and clone SP263 (58%).	('IC', 'Chemical', '-', (40, 42))	('preferential', 'PosReg', (14, 26))	('SP142', 'Chemical', '-', (55, 60))	('clone SP263', 'Var', (71, 82))	('SP263', 'Chemical', '-', (77, 82))	('clone SP142', 'Var', (49, 60))	('labelling', 'MPA', (27, 36))
31246	33266349	We found a significant correlation between the positivity to PD-L1 (SP142 and SP263 clones) and CD8+ TILs and between the positivity of PD-L1 (SP142 and SP263 clones) and PD-1+ TILs.	('SP142', 'Var', (143, 148))	('PD-L1', 'Gene', (61, 66))	('CD8', 'Gene', (96, 99))	('SP263', 'Chemical', '-', (153, 158))	('PD-L1', 'Gene', (136, 141))	('PD-1+ TILs', 'Disease', (171, 181))	('SP263', 'Chemical', '-', (78, 83))	('PD-L1', 'Gene', '29126', (61, 66))	('CD8', 'Gene', '925', (96, 99))	('PD-1+ TILs', 'Disease', 'MESH:D010300', (171, 181))	('SP142', 'Chemical', '-', (68, 73))	('PD-L1', 'Gene', '29126', (136, 141))	('SP142', 'Chemical', '-', (143, 148))
31256	33266349	showed that PD-L1 positive staining in the tumour was associated with worse CM-related survival.	('CM-related survival', 'CPA', (76, 95))	('PD-L1', 'Gene', (12, 17))	('worse', 'NegReg', (70, 75))	('tumour', 'Disease', (43, 49))	('PD-L1', 'Gene', '29126', (12, 17))	('positive staining', 'Var', (18, 35))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
31262	33266349	In addition to immunotherapy, patients with melanoma can also benefit from anti-BRAF therapy when a mutation is detected.	('BRAF', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('mutation', 'Var', (100, 108))	('patients', 'Species', '9606', (30, 38))	('BRAF', 'Gene', '673', (80, 84))
31265	33266349	Moreover, some BRAF and NRAS mutations could be missed by using IHC alone since the anti-BRAF and anti-NRAS antibodies allow detecting only some specific BRAF and NRAS mutations.	('BRAF', 'Gene', '673', (15, 19))	('NRAS', 'Gene', '4893', (24, 28))	('NRAS', 'Gene', '4893', (103, 107))	('NRAS', 'Gene', (163, 167))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (154, 158))	('NRAS', 'Gene', '4893', (163, 167))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (154, 158))	('BRAF', 'Gene', (89, 93))	('NRAS', 'Gene', (24, 28))	('NRAS', 'Gene', (103, 107))	('mutations', 'Var', (168, 177))
31277	33266349	Formalin-Fixed Paraffin Embedded (FFPE) freshly cut serial tissue sections of 3microm thickness, mounted on positively charged slides were stained for PD-L1 with two anti-human PD-L1 rabbit monoclonal Ab, according to the manufacturer's recommendations: SP263 and SP142 antibodies (Abs) (Ventana, Tucson, AZ, USA).	('SP263', 'Var', (254, 259))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('PD-L1', 'Gene', '29126', (151, 156))	('PD-L1', 'Gene', (177, 182))	('SP142 antibodies', 'Var', (264, 280))	('PD-L1', 'Gene', '29126', (177, 182))	('Paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('PD-L1', 'Gene', (151, 156))	('SP263', 'Chemical', '-', (254, 259))	('SP142', 'Chemical', '-', (264, 269))
31290	33266349	NRASQ61R and BRAFV600E IHC expression was evaluated as previously described.	('BRAFV600E', 'Var', (13, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (13, 22))	('NRASQ61R', 'Var', (0, 8))
31295	33266349	The impact of the following factors: patient age, gender, localization, NRAS status, BRAF status, associated lesion, histological type, thickness, mitosis, pTNM stage, and immunohistochemical markers SP142 IC and TC, SP263 IC and TC, PD-1 TILs, CD8+ TILs, NKP46 TILs were investigated by univariate and multivariate analysis.	('SP142', 'Chemical', '-', (200, 205))	('NRAS', 'Gene', '4893', (72, 76))	('IC', 'Chemical', '-', (223, 225))	('localization', 'biological_process', 'GO:0051179', ('58', '70'))	('mitosis', 'biological_process', 'GO:0000278', ('147', '154'))	('CD8', 'Gene', '925', (245, 248))	('IC', 'Chemical', '-', (206, 208))	('NRAS', 'Gene', (72, 76))	('TC', 'Chemical', '-', (213, 215))	('BRAF', 'Gene', (85, 89))	('TC', 'Chemical', '-', (230, 232))	('BRAF', 'Gene', '673', (85, 89))	('PD-1 TILs', 'Disease', 'MESH:D010300', (234, 243))	('SP142 IC', 'Var', (200, 208))	('PD-1 TILs', 'Disease', (234, 243))	('CD8', 'Gene', (245, 248))	('NKP46', 'Gene', (256, 261))	('SP263', 'Chemical', '-', (217, 222))	('NKP46', 'Gene', '9437', (256, 261))	('patient', 'Species', '9606', (37, 44))
31306	32532044	Oncogenic mutations in both GPCRs and G proteins (GNAS, GNAQ or GNA11) encoding genes have been identified in a significant number of tumors.	('tumors', 'Disease', (134, 140))	('GNAS', 'Gene', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('GPCR', 'Gene', '23566', (28, 32))	('identified', 'Reg', (96, 106))	('GNA11', 'Gene', (64, 69))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GPCR', 'Gene', (28, 32))	('GNAQ', 'Gene', (56, 60))
31307	32532044	Interestingly, uveal melanoma driver mutations in GNAQ/GNA11 were identified for a decade, but their discovery did not lead to mutation-specific drug development, unlike it the case for BRAF mutations in cutaneous melanoma which saw enormous success.	('BRAF', 'Gene', (186, 190))	('GNAQ/GNA11', 'Gene', (50, 60))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('uveal melanoma', 'Phenotype', 'HP:0007716', (15, 29))	('uveal melanoma', 'Disease', (15, 29))	('cutaneous melanoma', 'Disease', (204, 222))	('uveal melanoma', 'Disease', 'MESH:C536494', (15, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (204, 222))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (204, 222))	('mutations', 'Var', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BRAF', 'Gene', '673', (186, 190))
31308	32532044	In this review, we summarize the current knowledge on cancer-associated alterations of GPCRs and G proteins and we focus on the case of uveal melanoma.	('alterations', 'Var', (72, 83))	('GPCR', 'Gene', '23566', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('G proteins', 'Protein', (97, 107))	('cancer', 'Disease', (54, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (136, 150))	('uveal melanoma', 'Disease', (136, 150))	('uveal melanoma', 'Disease', 'MESH:C536494', (136, 150))	('GPCR', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
31316	32532044	In this review, we describe first the G protein-encoding gene alterations that have been identified in malignancies.	('malignancies', 'Disease', (103, 115))	('alterations', 'Var', (62, 73))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))
31317	32532044	Second, we focus on the role of alterations in GNAQ/11 specifically in uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (71, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('alterations', 'Var', (32, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (71, 85))	('uveal melanoma', 'Disease', (71, 85))	('GNAQ/11', 'Gene', (47, 54))
31322	32532044	In the case of GPCRs stimulation and after conformation change of the receptors, the Galpha unit will load GTP instead of GDP, leading to its release from the Gbetagamma unit and from the receptor.	('GPCR', 'Gene', (15, 19))	('Galpha', 'Gene', (85, 91))	('GDP', 'Chemical', 'MESH:D006153', (122, 125))	('GPCR', 'Gene', '23566', (15, 19))	('GTP', 'Chemical', 'MESH:D006160', (107, 110))	('conformation change', 'Var', (43, 62))	('Gbeta', 'Gene', (159, 164))	('Galpha', 'Gene', '8802', (85, 91))	('release', 'MPA', (142, 149))	('Gbeta', 'Gene', '8801', (159, 164))
31328	32532044	Oncogenic mutations in these genes usually impair their GTPase activity, leading to constitutively active forms of GTP-bound proteins and to extended downstream signaling.	('extended', 'PosReg', (141, 149))	('activity', 'MPA', (63, 71))	('GTPase', 'Enzyme', (56, 62))	('GTP', 'Chemical', 'MESH:D006160', (56, 59))	('signaling', 'biological_process', 'GO:0023052', ('161', '170'))	('GTPase activity', 'molecular_function', 'GO:0003924', ('56', '71'))	('GTP-bound', 'Protein', (115, 124))	('GTP', 'Chemical', 'MESH:D006160', (115, 118))	('mutations', 'Var', (10, 19))	('impair', 'NegReg', (43, 49))	('downstream signaling', 'MPA', (150, 170))	('constitutively active forms of', 'MPA', (84, 114))
31330	32532044	Nonetheless, it was recently suggested that Galphas gain-of-function mutation can bypass the need for GTP binding and directly activate GDP-bound Galphas.	('Galphas', 'Gene', (44, 51))	('GTP', 'Chemical', 'MESH:D006160', (102, 105))	('activate', 'PosReg', (127, 135))	('GDP', 'Chemical', 'MESH:D006153', (136, 139))	('GTP', 'Protein', (102, 105))	('mutation', 'Var', (69, 77))	('Galphas', 'Gene', '79447', (146, 153))	('Galphas', 'Gene', (146, 153))	('gain-of-function', 'PosReg', (52, 68))	('GTP binding', 'molecular_function', 'GO:0005525', ('102', '113'))	('Galphas', 'Gene', '79447', (44, 51))
31331	32532044	Based on deep sequencing studies, it is known that mutations in GNAS occur in a wide range of tumors.	('GNAS', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('occur', 'Reg', (69, 74))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
31336	32532044	Interestingly, GNAS is described as a driver oncogene in a subset of colon adenomas and adenocarcinomas, and mutations in this gene can promote hyperplasia of endocrine cells in thyroid and pituitary tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hyperplasia', 'Disease', 'MESH:D006965', (144, 155))	('adenocarcinomas', 'Disease', (88, 103))	('promote', 'PosReg', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('colon adenomas', 'Disease', (69, 83))	('pituitary tumors', 'Disease', 'MESH:D010911', (190, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('hyperplasia', 'Disease', (144, 155))	('mutations', 'Var', (109, 118))	('adenocarcinomas', 'Disease', 'MESH:D000230', (88, 103))	('colon adenomas', 'Disease', 'MESH:D000236', (69, 83))	('pituitary tumors', 'Disease', (190, 206))
31338	32532044	Since COX2 has a known protumorigenic role in colon neoplasia, oncogenic mutations in GNAS may therefore activate a proinflammatory response, which favors tumor development.	('colon neoplasia', 'Disease', (46, 61))	('favors', 'PosReg', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('colon neoplasia', 'Disease', 'MESH:D003110', (46, 61))	('neoplasia', 'Phenotype', 'HP:0002664', (52, 61))	('proinflammatory response', 'MPA', (116, 140))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (155, 160))	('COX2', 'Gene', '5743', (6, 10))	('COX2', 'Gene', (6, 10))	('colon neoplasia', 'Phenotype', 'HP:0100273', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('GNAS', 'Gene', (86, 90))	('activate', 'PosReg', (105, 113))	('mutations', 'Var', (73, 82))
31339	32532044	GNAQ and GNA11 mutations are mutually exclusives and occur in about 2% of human cancers.	('GNA11', 'Gene', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (15, 24))	('cancers', 'Disease', (80, 87))	('GNAQ', 'Gene', (0, 4))	('human', 'Species', '9606', (74, 79))	('occur', 'Reg', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
31340	32532044	Mutations in GNAQ and GNA11 were mostly identified at residues involved in GTPase activity (Q209 or R183).	('GNA11', 'Gene', (22, 27))	('Q209', 'Var', (92, 96))	('GNAQ', 'Gene', (13, 17))	('GTPase activity', 'molecular_function', 'GO:0003924', ('75', '90'))	('GTPase', 'Protein', (75, 81))	('Mutations', 'Var', (0, 9))	('R183', 'Var', (100, 104))	('activity', 'MPA', (82, 90))	('GTP', 'Chemical', 'MESH:D006160', (75, 78))
31342	32532044	Details on the role of these mutations in uveal melanoma will be discussed in the next paragraph.	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
31343	32532044	Several mutations in other Galpha encoding genes have been identified at a much lower frequency in human cancers and might not be activating.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('Galpha', 'Gene', '8802', (27, 33))	('mutations', 'Var', (8, 17))	('Galpha', 'Gene', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
31344	32532044	As an example, GNA15 (encoding Galphaq subunits) is significantly mutated in skin melanomas that do not often carry GNAQ or GNA11 mutations.	('mutated', 'Var', (66, 73))	('Galphaq', 'Gene', '2776', (31, 38))	('skin melanomas', 'Disease', 'MESH:D008545', (77, 91))	('Galphaq', 'Gene', (31, 38))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('skin melanomas', 'Disease', (77, 91))	('GNA15', 'Gene', '2769', (15, 20))	('GNA15', 'Gene', (15, 20))
31346	32532044	However, mutations in GPCRs encoding genes were identified in almost 20% human cancers.	('identified', 'Reg', (48, 58))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (9, 18))	('GPCR', 'Gene', (22, 26))	('human', 'Species', '9606', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('GPCR', 'Gene', '23566', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
31347	32532044	Although many of these mutations are still uncharacterized regarding the impact on tumorigenesis, the most frequent were found in the thyroid-stimulating hormone receptor (TSHR), smoothened (SMO), glutamate metabotropic receptors (GRMs), the lysophosphatidic acid receptor (LPA) and the sphingosine-1-phosphate (S1P) receptor.	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (287, 310))	('TSHR', 'Gene', '7253', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('smoothened', 'Gene', (179, 189))	('thyroid-stimulating hormone receptor', 'Gene', (134, 170))	('tumor', 'Disease', (83, 88))	('smoothened', 'Gene', '6608', (179, 189))	('TSHR', 'Gene', (172, 176))	('GRMs', 'Gene', (231, 235))	('SMO', 'Gene', '6608', (191, 194))	('SMO', 'Gene', (191, 194))	('mutations', 'Var', (23, 32))	('thyroid-stimulating hormone receptor', 'Gene', '7253', (134, 170))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (242, 263))	('LPA', 'Gene', (274, 277))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('frequent', 'Reg', (107, 115))
31350	32532044	In sum, hotspot mutations in GNAS, GNAQ and GNA11 have been identified in human tumors; however, a better characterization of the mutations on the other G protein-encoding genes is still needed.	('GNAQ', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GNA11', 'Gene', (44, 49))	('mutations', 'Var', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (74, 79))	('GNAS', 'Gene', (29, 33))
31355	32532044	Moreover, by using different Galpha variants in which GTPase activity was lost, they could observe the formation of stable complexes with Gbetagamma and a prevention of its downstream interaction with PREX1.	('lost', 'NegReg', (74, 78))	('prevention', 'NegReg', (155, 165))	('GTPase activity', 'molecular_function', 'GO:0003924', ('54', '69'))	('PREX1', 'Gene', '57580', (201, 206))	('GTPase', 'Protein', (54, 60))	('complexes', 'Interaction', (123, 132))	('Galpha', 'Gene', '8802', (29, 35))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('interaction', 'Interaction', (184, 195))	('variants', 'Var', (36, 44))	('Gbeta', 'Gene', (138, 143))	('activity', 'MPA', (61, 69))	('GTP', 'Chemical', 'MESH:D006160', (54, 57))	('Gbeta', 'Gene', '8801', (138, 143))	('Galpha', 'Gene', (29, 35))	('PREX1', 'Gene', (201, 206))
31358	32532044	Silencing of Gialpha2 in pancreatic cancer cells reduced the migration dependent on TGFbeta, oxytocin, SDF-1alpha, and EGF.	('TGFbeta', 'Gene', (84, 91))	('oxytocin', 'Gene', (93, 101))	('pancreatic cancer', 'Disease', (25, 42))	('reduced', 'NegReg', (49, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (25, 42))	('EGF', 'Gene', (119, 122))	('oxytocin', 'Gene', '5020', (93, 101))	('TGFbeta', 'Gene', '7039', (84, 91))	('Gialpha2', 'Gene', (13, 21))	('EGF', 'Gene', '1950', (119, 122))	('migration', 'CPA', (61, 70))	('EGF', 'molecular_function', 'GO:0005154', ('119', '122'))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (25, 42))	('Silencing', 'Var', (0, 9))
31359	32532044	In addition, silencing of Gialpha2 in cells that overexpressed active RAC1 abolished their migration without affecting the basal RAC1 activation.	('Gialpha2', 'Protein', (26, 34))	('RAC1', 'Gene', '5879', (129, 133))	('RAC1', 'Gene', (70, 74))	('abolished', 'NegReg', (75, 84))	('RAC1', 'Gene', (129, 133))	('active', 'Var', (63, 69))	('migration', 'CPA', (91, 100))	('RAC1', 'Gene', '5879', (70, 74))	('silencing', 'Var', (13, 22))
31361	32532044	Indeed, genetically engineered mouse models could show cooperation between GnasR201C and KrasG12D mutations to promote the initiation of intraductal papillary mucinous neoplasms (IPMNs), the latter progressing into pancreatic ductal adenocarcinomas (PDAs) after additional Tp53 loss.	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (215, 248))	('loss', 'NegReg', (278, 282))	('papillary mucinous neoplasms', 'Disease', (149, 177))	('GnasR201C', 'Var', (75, 84))	('mouse', 'Species', '10090', (31, 36))	('KrasG12D', 'Gene', (89, 97))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (159, 177))	('progressing', 'Reg', (198, 209))	('pancreatic ductal adenocarcinomas', 'Disease', (215, 248))	('mutations', 'Var', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (149, 177))	('Tp53', 'Gene', (273, 277))	('neoplasms', 'Phenotype', 'HP:0002664', (168, 177))	('promote', 'PosReg', (111, 118))
31362	32532044	The authors not only observed an essential role of mutant Gnas in tumor maintenance but also a mechanism of protein kinase A-mediated suppression of salt-inducible kinases (Sik1-3), in association with lipid remodeling.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Gnas', 'Gene', (58, 62))	('tumor', 'Disease', (66, 71))	('lipid', 'Chemical', 'MESH:D008055', (202, 207))	('mutant', 'Var', (51, 57))	('suppression', 'NegReg', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('Sik1-3', 'Gene', (173, 179))
31363	32532044	As increased intracellular ROS levels are known to induce cell cycle arrest, senescence, and apoptosis, the deregulation of ROS levels may lead to tumorigenesis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('apoptosis', 'CPA', (93, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('tumor', 'Disease', (147, 152))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('deregulation', 'Var', (108, 120))	('senescence', 'CPA', (77, 87))	('arrest', 'Disease', (69, 75))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('58', '75'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('increased', 'PosReg', (3, 12))	('lead to', 'Reg', (139, 146))	('increased intracellular ROS levels', 'Phenotype', 'HP:0025464', (3, 37))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('senescence', 'biological_process', 'GO:0010149', ('77', '87'))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))
31379	32532044	In sum, multiple recent studies indicate a key role of GNA mutations in processes such as cell migration, promoter hypermethylation and ultimately tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cell migration', 'biological_process', 'GO:0016477', ('90', '104'))	('cell migration', 'CPA', (90, 104))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutations', 'Var', (59, 68))	('promoter', 'MPA', (106, 114))	('GNA', 'Gene', (55, 58))
31381	32532044	Four main groups have been proposed as follows: mutant BRAF, mutant RAS, mutant NF1, and triple BRAF/RAS/NF1 wildtype (which includes mutations in other genes such as GNA).	('mutant', 'Var', (48, 54))	('NF1', 'Gene', (105, 108))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (105, 108))	('NF1', 'Gene', '4763', (80, 83))	('mutant', 'Var', (73, 79))	('BRAF', 'Gene', (96, 100))	('mutant', 'Var', (61, 67))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))
31382	32532044	For example, several zebrafish models of uveal melanoma have shown that melanocyte-specific expression of driver mutations GNAQ/GNA11(Q209L) led to considerable changes in the melanocyte biology of the fish.	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('zebrafish', 'Species', '7955', (21, 30))	('melanocyte biology of the fish', 'CPA', (176, 206))	('GNAQ/GNA11', 'Gene', (123, 133))	('Q209L', 'SUBSTITUTION', 'None', (134, 139))	('Q209L', 'Var', (134, 139))	('changes', 'Reg', (161, 168))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutations', 'Var', (113, 122))
31386	32532044	In a mouse model of leptomeningeal melanocytic neoplasms, the inducible expression of Gnaq(Q209L) variant at the neural crest stage before melanocyte differentiation, could favor the development of blue nevus-like lesions in the dermis, various melanocytic neoplasms in the cranium and spine but also melanoma of the central nervous system.	('Q209L', 'SUBSTITUTION', 'None', (91, 96))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (35, 56))	('leptomeningeal melanocytic neoplasms', 'Disease', (20, 56))	('blue nevus', 'Phenotype', 'HP:0100814', (198, 208))	('variant', 'Var', (98, 105))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (35, 56))	('leptomeningeal melanocytic neoplasms', 'Disease', 'MESH:D008577', (20, 56))	('spine', 'cellular_component', 'GO:0044309', ('286', '291'))	('favor', 'PosReg', (173, 178))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (245, 266))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('blue nevus-like lesions', 'Disease', (198, 221))	('mouse', 'Species', '10090', (5, 10))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('139', '165'))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (245, 266))	('neoplasms', 'Phenotype', 'HP:0002664', (257, 266))	('melanocytic neoplasms', 'Disease', (245, 266))	('melanoma of the central nervous system', 'Disease', (301, 339))	('melanoma of the central nervous system', 'Disease', 'MESH:D002493', (301, 339))	('nevus', 'Phenotype', 'HP:0003764', (203, 208))	('Q209L', 'Var', (91, 96))	('neoplasms', 'Phenotype', 'HP:0002664', (47, 56))	('melanoma of the central nervous system', 'Phenotype', 'HP:0100836', (301, 339))
31388	32532044	Thus, these results suggest an essential role of GNAQ mutations in the tumorigenesis of the melanocyte lineage.	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GNAQ', 'Gene', (49, 53))	('tumor', 'Disease', (71, 76))
31389	32532044	Nevertheless, these data do not explain the GNAQ/GNA11 selective mutational pressure observed in uveal melanoma compared to cutaneous melanoma or why they are considered to be oncogenic.	('mutational', 'Var', (65, 75))	('GNAQ/GNA11', 'Gene', (44, 54))	('cutaneous melanoma', 'Disease', (124, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', (97, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
31391	32532044	GNAQ and GNA11 mutations were amplified by real-time PCR in the circulating DNA from the plasma of 22 patients with uveal melanoma, and Q209 mutations were detected by ultradeep sequencing in 9 of these.	('GNA11', 'Gene', (9, 14))	('patients', 'Species', '9606', (102, 110))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))
31392	32532044	More recently, the identification of additional somatic mutations in uveal melanoma which could not be detected by classical NGS led to a tumor classification in four molecular and clinical subgroups that will allow a stratification of uveal melanoma patient management.	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('tumor', 'Disease', (138, 143))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('patient', 'Species', '9606', (251, 258))	('uveal melanoma', 'Disease', 'MESH:C536494', (236, 250))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (236, 250))	('uveal melanoma', 'Disease', (236, 250))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
31393	32532044	Moreover, "secondary" driver mutations in the GNA pathway have also been detected in uveal melanoma at low frequencies, but might account for tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('tumor', 'Disease', (142, 147))	('account', 'Reg', (130, 137))	('GNA pathway', 'Pathway', (46, 57))	('mutations', 'Var', (29, 38))	('uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('uveal melanoma', 'Disease', 'MESH:C536494', (85, 99))	('uveal melanoma', 'Disease', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
31394	32532044	Of note, a retrospective study identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma, which showed lower tumor mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas.	('metastatic GNAQ/11', 'Gene', (59, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (194, 213))	('tumor', 'Disease', (123, 128))	('ultraviolet', 'MPA', (157, 168))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanomas', 'Phenotype', 'HP:0002861', (204, 213))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('uveal melanoma', 'Phenotype', 'HP:0007716', (88, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (88, 102))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('uveal melanoma', 'Disease', (88, 102))	('patients', 'Species', '9606', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (194, 213))	('mutant', 'Var', (78, 84))	('cutaneous melanomas', 'Disease', (194, 213))
31396	32532044	The authors concluded that primary GNAQ/11 mutant nonuveal melanoma is a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('mutant', 'Var', (43, 49))	('melanoma', 'Disease', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
31398	32532044	In uveal melanoma, hot spot somatic mutations in GNAQ/GNA11 lead to amino acid substitutions in exon 5 (p.Q209L or p.Q209P) or in exon 4 (p.R183C).	('p.R183C', 'SUBSTITUTION', 'None', (138, 145))	('p.Q209L', 'SUBSTITUTION', 'None', (104, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('p.R183C', 'Var', (138, 145))	('lead', 'Reg', (60, 64))	('p.Q209P', 'SUBSTITUTION', 'None', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('p.Q209P', 'Var', (115, 122))	('GNAQ/GNA11', 'Gene', (49, 59))	('p.Q209L', 'Var', (104, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
31399	32532044	While the first group of mutations prevents the intrinsic GTPase activity and therefore constitutively activates the protein, the second group leads to only a partial loss of GTPase activity.	('activity', 'MPA', (65, 73))	('mutations', 'Var', (25, 34))	('activates', 'PosReg', (103, 112))	('activity', 'MPA', (182, 190))	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('GTP', 'Chemical', 'MESH:D006160', (58, 61))	('GTPase', 'Protein', (175, 181))	('protein', 'Protein', (117, 124))	('GTPase activity', 'molecular_function', 'GO:0003924', ('58', '73'))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('GTPase', 'Protein', (58, 64))	('prevents', 'NegReg', (35, 43))	('GTPase activity', 'molecular_function', 'GO:0003924', ('175', '190'))
31400	32532044	In the first described uveal melanoma mouse model, an oncogenic Gnaq mutant under the control of the Rosa26 promoter was conditionally expressed by the cre recombinase under the control of melanocyte specific-promoter Mitf, and could initiate tumors which progressed to intravasation and metastases in 100% offspring.	('Mitf', 'Gene', '17342', (218, 222))	('mouse', 'Species', '10090', (38, 43))	('tumors', 'Disease', (243, 249))	('Gnaq', 'Gene', (64, 68))	('Mitf', 'Gene', (218, 222))	('mutant', 'Var', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('Rosa26', 'Gene', '14910', (101, 107))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('metastases', 'Disease', (288, 298))	('uveal melanoma', 'Disease', (23, 37))	('Rosa26', 'Gene', (101, 107))	('metastases', 'Disease', 'MESH:D009362', (288, 298))	('initiate', 'PosReg', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
31402	32532044	Interestingly, the overexpression of mutant Gnaq(Q209L) led to a loss of cutaneous melanocytes in adult mice, which could explain why this mutation is not found in cutaneous melanoma.	('overexpression', 'PosReg', (19, 33))	('loss', 'NegReg', (65, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('Gnaq', 'Gene', (44, 48))	('mice', 'Species', '10090', (104, 108))	('mutant', 'Var', (37, 43))	('Q209L', 'Var', (49, 54))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('Q209L', 'SUBSTITUTION', 'None', (49, 54))	('cutaneous melanoma', 'Disease', (164, 182))	('cutaneous melanocytes', 'CPA', (73, 94))
31403	32532044	In another mouse model, melanocyte-specific expression of Gna11(Q209L) led to pigmented neoplastic lesions from melanocytes of the skin and noncutaneous organs, including the eye and leptomeninges.	('Gna11', 'Gene', (58, 63))	('pigmented neoplastic lesions', 'Disease', 'MESH:D010859', (78, 106))	('mouse', 'Species', '10090', (11, 16))	('Q209L', 'Var', (64, 69))	('led to', 'Reg', (71, 77))	('Q209L', 'SUBSTITUTION', 'None', (64, 69))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (88, 106))	('Gna11', 'Gene', '14672', (58, 63))	('pigmented neoplastic lesions', 'Disease', (78, 106))	('pigmented neoplastic lesions from melanocytes of the skin', 'Phenotype', 'HP:0002861', (78, 135))
31408	32532044	Interestingly, other members in the GNA signaling have also been identified with mutations specifically in uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('mutations', 'Var', (81, 90))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))
31410	32532044	Recurrent mutations on codon 129 and 136 have been identified in uveal melanoma, but only the first one is oncogenic.	('uveal melanoma', 'Phenotype', 'HP:0007716', (65, 79))	('uveal melanoma', 'Disease', (65, 79))	('identified', 'Reg', (51, 61))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutations', 'Var', (10, 19))	('uveal melanoma', 'Disease', 'MESH:C536494', (65, 79))
31413	32532044	Mutations in members of this family, PLCB4 and PLCB3, were identified in patient-derived uveal melanoma samples.	('identified', 'Reg', (59, 69))	('PLCB3', 'Gene', (47, 52))	('PLCB4', 'Gene', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (73, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (89, 103))	('uveal melanoma', 'Disease', (89, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (89, 103))	('PLCB4', 'Gene', '5332', (37, 42))	('PLCB3', 'Gene', '5331', (47, 52))
31422	32532044	The combination of BRAF/MEK inhibitors is not possible due to the absence of BRAF mutations in uveal melanoma.	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (19, 23))	('MEK', 'Gene', (24, 27))	('MEK', 'Gene', '5609', (24, 27))	('BRAF', 'Gene', (77, 81))	('absence', 'NegReg', (66, 73))	('uveal melanoma', 'Disease', 'MESH:C536494', (95, 109))	('mutations', 'Var', (82, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (95, 109))	('uveal melanoma', 'Disease', (95, 109))
31423	32532044	Clinical trials for MEK inhibitors in combination with chemotherapy or other candidate targets (PKC, AKT) have shown no significant improvement in the progression free survival.	('AKT', 'Gene', '207', (101, 104))	('PKC', 'Gene', (96, 99))	('PKC', 'Gene', '112476', (96, 99))	('MEK', 'Gene', (20, 23))	('PKC', 'molecular_function', 'GO:0004697', ('96', '99'))	('MEK', 'Gene', '5609', (20, 23))	('AKT', 'Gene', (101, 104))	('inhibitors', 'Var', (24, 34))
31424	32532044	Indeed, the observed heterogeneity of MAPK activation in uveal melanoma with GNAQ/11 mutations could explain at least in part this phenomenon and, therefore, it does not allow this mutational status to be an efficient biomarker of MEK inhibitors' sensitivity.	('MAPK activation', 'biological_process', 'GO:0000187', ('38', '53'))	('MAPK', 'Gene', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('activation', 'PosReg', (43, 53))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('mutations', 'Var', (85, 94))	('uveal melanoma', 'Disease', (57, 71))	('GNAQ/11', 'Gene', (77, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('MEK', 'Gene', (231, 234))	('MEK', 'Gene', '5609', (231, 234))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
31426	32532044	Nevertheless, in light of the data discussed above, it appears quite obvious that the inhibition of oncogenic G proteins and their downstream targets should lead to the efficient killing of tumors that developed from driver GNA mutations.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('oncogenic', 'Protein', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (228, 237))	('killing', 'CPA', (179, 186))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('inhibition', 'NegReg', (86, 96))
31428	32532044	Of these, GNAQ family-specific inhibitors FR900359 (FR) and YM254890 (YM) were described to block the downstream signaling of GNAQ variants in cancer cells with high GNAQ activity.	('downstream signaling', 'MPA', (102, 122))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('GNAQ', 'Gene', (126, 130))	('variants', 'Var', (131, 139))	('YM254890', 'Chemical', 'MESH:C475455', (60, 68))	('block', 'NegReg', (92, 97))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('FR900359', 'Chemical', 'MESH:C000607068', (42, 50))
31430	32532044	In uveal melanoma-specific mutations, both identified hotspots are located in the GTPase domain and play a key role in stabilizing the transition state for GTP hydrolysis.	('mutations', 'Var', (27, 36))	('GTP', 'Chemical', 'MESH:D006160', (82, 85))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GTP hydrolysis', 'MPA', (156, 170))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('156', '170'))	('GTP', 'Chemical', 'MESH:D006160', (156, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
31431	32532044	As discussed above, these variants differ because the R183C variant is still able to be regulated by receptor stimulation, whereas Q209L/P variants are uncoupled from GPCRs.	('GPCR', 'Gene', (167, 171))	('R183C', 'SUBSTITUTION', 'None', (54, 59))	('Q209L', 'Var', (131, 136))	('R183C', 'Var', (54, 59))	('Q209L', 'SUBSTITUTION', 'None', (131, 136))	('GPCR', 'Gene', '23566', (167, 171))
31438	32532044	It is therefore likely that these inhibitors will be tested in uveal melanoma with GPCR mutations in the future.	('GPCR', 'Gene', '23566', (83, 87))	('uveal melanoma', 'Disease', (63, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (63, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('mutations', 'Var', (88, 97))	('GPCR', 'Gene', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
31439	32532044	GDIs such as FR or YM are also expected to have an impact on tumors with aberrant activation of the G proteins, whether they carry a mutation on GNA genes or upstream their receptor.	('G proteins', 'Protein', (100, 110))	('tumors', 'Disease', (61, 67))	('mutation', 'Var', (133, 141))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('GNA genes', 'Gene', (145, 154))	('activation', 'PosReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('impact', 'Reg', (51, 57))
31440	32532044	Mutations in GNAQ and CYSTR2 represent the vast majority of uveal melanoma tumors and they activate downstream targets such as TRIO or ARF6.	('ARF6', 'Gene', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('CYSTR2', 'Gene', (22, 28))	('TRIO', 'Gene', (127, 131))	('ARF6', 'Gene', '382', (135, 139))	('TRIO', 'Gene', '7204', (127, 131))	('melanoma tumors', 'Disease', 'MESH:D008545', (66, 81))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('activate', 'PosReg', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('melanoma tumors', 'Disease', (66, 81))
31441	32532044	Inhibitors of these two proteins have been developed, and it would make sense to test them in uveal melanoma  The observation that one of the direct causes for cancer development is the alteration of genes encoding for G proteins, leading to inactivate their GTPase function, has been known for a while.	('GTPase', 'Protein', (259, 265))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('inactivate', 'NegReg', (242, 252))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('alteration', 'Var', (186, 196))	('function', 'MPA', (266, 274))	('GTP', 'Chemical', 'MESH:D006160', (259, 262))
31443	32532044	The development of specific inhibitors for GNAQ, efficacy of which was shown in vitro and in vivo, has paved the road for a rational therapeutic approach in cancers carrying alterations in this particular protein.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('GNAQ', 'Protein', (43, 47))	('cancers', 'Disease', (157, 164))	('alterations', 'Var', (174, 185))
31448	32532044	The vast majority of tumors carry activating mutations in GNAQ/11, which leads to the overactivation of signaling such as ARF6/TRIO/RHO/RAC/YAP and PLCB/PKC/ERK.	('RAC', 'Gene', (136, 139))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('overactivation', 'PosReg', (86, 100))	('signaling', 'MPA', (104, 113))	('PKC', 'Gene', '112476', (153, 156))	('ARF6', 'Gene', '382', (122, 126))	('GNAQ/11', 'Gene', (58, 65))	('YAP', 'Gene', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('TRIO', 'Gene', (127, 131))	('RAC', 'Gene', '5879', (136, 139))	('tumors', 'Disease', (21, 27))	('ARF6', 'Gene', (122, 126))	('ERK', 'Gene', '5594', (157, 160))	('PKC', 'Gene', (153, 156))	('mutations', 'Var', (45, 54))	('ERK', 'molecular_function', 'GO:0004707', ('157', '160'))	('activating', 'PosReg', (34, 44))	('TRIO', 'Gene', '7204', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('PKC', 'molecular_function', 'GO:0004697', ('153', '156'))	('ERK', 'Gene', (157, 160))	('YAP', 'Gene', '10413', (140, 143))
31449	32532044	In addition, 40% uveal melanoma present genetic alterations in BAP1, which are associated with metastasis.	('associated', 'Reg', (79, 89))	('BAP1', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('genetic alterations', 'Var', (40, 59))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('BAP1', 'Gene', '8314', (63, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
31451	23760049	Do not underestimate nucleotide excision repair: It not only predicts melanoma risk but also survival outcome Nucleotide excision repair (NER) removes UV-induced DNA damage and other bulky DNA lesions thereby maintaining genomic integrity.	('melanoma', 'Disease', (70, 78))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('21', '47'))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('removes', 'NegReg', (143, 150))	('DNA', 'cellular_component', 'GO:0005574', ('162', '165'))	('Nucleotide', 'Var', (110, 120))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('NER', 'biological_process', 'GO:0006289', ('138', '141'))	('genomic', 'MPA', (221, 228))	('Nucleotide excision repair', 'biological_process', 'GO:0006289', ('110', '136'))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
31452	23760049	Dr. Qingyi Wei's group demonstrated over the last decade that NER fidelity and single nucleotide polymorphisms (SNPs) in NER genes constitute melanoma risk biomarkers.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('NER genes', 'Gene', (121, 130))	('single nucleotide polymorphisms', 'Var', (79, 110))	('NER', 'biological_process', 'GO:0006289', ('121', '124'))	('NER', 'biological_process', 'GO:0006289', ('62', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
31453	23760049	they provide evidence that SNPs in NER genes may also predict melanoma survival.	('melanoma', 'Disease', (62, 70))	('NER genes', 'Gene', (35, 44))	('predict', 'Reg', (54, 61))	('SNPs', 'Var', (27, 31))	('NER', 'biological_process', 'GO:0006289', ('35', '38'))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
31465	23760049	If not repaired, these DNA lesions may lead to UV "fingerprint" mutations at adjacent pyrimidines.	('lead to', 'Reg', (39, 46))	('lesions', 'Var', (27, 34))	('pyrimidines', 'Chemical', 'MESH:D011743', (86, 97))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
31480	23760049	Interestingly, the hallmark acute burning on minimal sun exposure may not be present in 30-40% of all XP patients, mainly in those patients with defects in the XPC or polymerase eta genes.	('patients', 'Species', '9606', (131, 139))	('defects', 'Var', (145, 152))	('patients', 'Species', '9606', (105, 113))	('XPC', 'Gene', (160, 163))	('XPC', 'Gene', '7508', (160, 163))
31485	23760049	Unrepaired DNA damage may lead to somatic mutations that play a role in cancer induction and progression.	('lead to', 'Reg', (26, 33))	('somatic mutations', 'Var', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
31487	23760049	Multiple melanomas with the same exposure history and genetic background can be studied in few patients where the effects of UV-damage are amplified due to the NER deficiency.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('patients', 'Species', '9606', (95, 103))	('Multiple melanomas', 'Disease', (0, 18))	('Multiple melanomas', 'Disease', 'MESH:D008545', (0, 18))	('UV-damage', 'Disease', 'MESH:C563466', (125, 134))	('deficiency', 'Var', (164, 174))	('NER', 'Gene', (160, 163))	('UV-damage', 'Disease', (125, 134))	('NER', 'biological_process', 'GO:0006289', ('160', '163'))
31488	23760049	For example, it was shown that more than 90% of melanomas in XP patients carried UV-type "fingerprint" mutations in the PTEN melanoma suppressor gene.	('melanoma', 'Disease', (48, 56))	('mutations', 'Var', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('patients', 'Species', '9606', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('melanomas', 'Disease', (48, 57))	('PTEN', 'Gene', (120, 124))	('PTEN', 'Gene', '5728', (120, 124))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
31498	23760049	The efficacy of the "standard" chemotherapeutic treatment of metastasized melanoma with dacarbazine or temozolomide depends on low O-6-methylguanine-DNA-methyltransferase (MGMT) repair and on high mismatch repair.	('MGMT', 'Gene', '4255', (172, 176))	('MGMT', 'Gene', (172, 176))	('high mismatch repair', 'Var', (192, 212))	('O-6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (131, 170))	('O-6-methylguanine-DNA-methyltransferase', 'Gene', (131, 170))	('metastasized melanoma', 'Disease', (61, 82))	('dacarbazine', 'Chemical', 'MESH:D003606', (88, 99))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('low', 'NegReg', (127, 130))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('MGMT', 'molecular_function', 'GO:0003908', ('170', '174'))	('temozolomide', 'Chemical', 'MESH:D000077204', (103, 115))	('metastasized melanoma', 'Disease', 'MESH:D009362', (61, 82))	('mismatch repair', 'biological_process', 'GO:0006298', ('195', '210'))
31506	23760049	SNPs in the XPC NER gene have been shown by Dr. Wei's group to confer an increased risk for melanoma development.	('XPC', 'Gene', (12, 15))	('SNPs', 'Var', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('NER', 'biological_process', 'GO:0006289', ('16', '19'))	('XPC', 'Gene', '7508', (12, 15))
31507	23760049	SNPs in other genes and pathways have also been implicated in an increased melanoma risk.	('SNPs', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('implicated', 'Reg', (48, 58))
31511	23760049	They identified novel chromosomal loci predisposing to cutaneous melanoma including 15q13.1 (HERC2/OCA2 region), 16q24.3 (MC1R region), 9p21.3 (p16/ARF region), and 1q21.3 (ARNT/LASS2/ANXA9 region).	('LASS2', 'Gene', (178, 183))	('1q21.3', 'Var', (165, 171))	('ANXA9', 'Gene', '8416', (184, 189))	('ANXA9', 'Gene', (184, 189))	('9p21.3', 'Var', (136, 142))	('LASS2', 'Gene', '29956', (178, 183))	('ARNT', 'Gene', '405', (173, 177))	('cutaneous melanoma', 'Disease', (55, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (55, 73))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (55, 73))	('OCA2', 'Gene', (99, 103))	('OCA2', 'Gene', '4948', (99, 103))	('ARNT', 'Gene', (173, 177))	('ARF', 'Disease', (148, 151))	('p16', 'Gene', (144, 147))	('HERC2', 'Gene', '8924', (93, 98))	('p16', 'Gene', '1029', (144, 147))	('MC1R', 'Gene', '4157', (122, 126))	('MC1R', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('HERC2', 'Gene', (93, 98))	('ARF', 'Disease', 'MESH:D058186', (148, 151))
31515	23760049	The XPE and ERCC5/XPG polymorphisms were associated with 4- to11- fold increased hazard of early death while the XPC and ERCC2/XPD polymorphisms were associated with about a doubling of risk of death.	('death', 'Disease', (194, 199))	('ERCC2', 'Gene', '2068', (121, 126))	('polymorphisms', 'Var', (22, 35))	('XPD', 'Gene', (127, 130))	('XPG', 'Gene', '2073', (18, 21))	('XPE', 'Gene', '1643', (4, 7))	('XPD', 'Gene', '2068', (127, 130))	('XPE', 'Gene', (4, 7))	('XPG', 'Gene', (18, 21))	('ERCC5', 'Gene', (12, 17))	('ERCC2', 'Gene', (121, 126))	('XPC', 'Gene', (113, 116))	('ERCC5', 'Gene', '2073', (12, 17))	('death', 'Disease', 'MESH:D003643', (194, 199))	('death', 'Disease', 'MESH:D003643', (97, 102))	('death', 'Disease', (97, 102))	('XPC', 'Gene', '7508', (113, 116))
31517	23760049	Presence of these variant SNPs was associated with additional risk of death in melanoma patients with unfavorable histopathological risk factors such as increased tumor thickness, involvement of lymph nodes, increased mitotic rate, presence of ulceration, and stage III or IV.	('increased tumor', 'Disease', (153, 168))	('mitotic rate', 'CPA', (218, 230))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('increased', 'PosReg', (208, 217))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('increased tumor', 'Disease', 'MESH:D009369', (153, 168))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('variant', 'Var', (18, 25))
31519	23760049	The rare genetic disorder, XP, has mutations in these same NER genes resulting in greatly increased melanoma risk.	('genetic disorder', 'Disease', (9, 25))	('increased', 'PosReg', (90, 99))	('genetic disorder', 'Disease', 'MESH:D030342', (9, 25))	('NER', 'biological_process', 'GO:0006289', ('59', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('NER genes', 'Gene', (59, 68))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('mutations', 'Var', (35, 44))
31523	23760049	Common single nucleotide polymorphisms (SNPs) in NER genes may be associated with increased melanoma risk and decreased melanoma survival in the general population.	('single nucleotide polymorphisms', 'Var', (7, 38))	('NER', 'Gene', (49, 52))	('decreased melanoma', 'Disease', (110, 128))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', (92, 100))	('decreased melanoma', 'Disease', 'MESH:D008545', (110, 128))	('increased', 'PosReg', (82, 91))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('NER', 'biological_process', 'GO:0006289', ('49', '52'))
31576	28938534	The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM).	('nevi', 'Disease', (46, 50))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('V600E', 'Var', (9, 14))	('melanomas', 'Disease', (62, 71))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('melanosis', 'Disease', 'MESH:D008548', (101, 110))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanosis', 'Disease', (101, 110))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
31578	28938534	Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death.	('growth', 'MPA', (32, 38))	('BRAF', 'Gene', '673', (5, 9))	('mutant', 'Var', (52, 58))	('BRAF', 'Gene', (5, 9))	('BRAF', 'Gene', (47, 51))	('suppressed', 'NegReg', (21, 31))	('BRAF', 'Gene', '673', (47, 51))	('CM', 'Phenotype', 'HP:0007716', (59, 61))	('cell death', 'biological_process', 'GO:0008219', ('95', '105'))
31579	28938534	MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('proliferation', 'CPA', (28, 41))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('cell death', 'biological_process', 'GO:0008219', ('162', '172'))	('cell death', 'CPA', (162, 172))	('inhibited', 'NegReg', (18, 27))	('MEK162', 'Gene', (0, 6))	('inhibition', 'NegReg', (147, 157))	('MK2206', 'Var', (11, 17))	('combination', 'Interaction', (90, 101))	('CM', 'Phenotype', 'HP:0007716', (45, 47))	('growth', 'CPA', (140, 146))	('CM', 'Phenotype', 'HP:0007716', (180, 182))
31581	28938534	While BRAF inhibitors prohibited cell growth, they were not always cytotoxic.	('prohibited', 'NegReg', (22, 32))	('cell growth', 'CPA', (33, 44))	('BRAF', 'Gene', '673', (6, 10))	('inhibitors', 'Var', (11, 21))	('cell growth', 'biological_process', 'GO:0016049', ('33', '44'))	('BRAF', 'Gene', (6, 10))
31592	28938534	Like cutaneous melanoma, CM frequently harbors a BRAF mutation, as opposed to GNAQ/GNA11 mutations which are found in most cases of uveal melanoma.	('mutation', 'Var', (54, 62))	('cutaneous melanoma', 'Disease', (5, 23))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('GNAQ', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('harbors', 'Reg', (39, 46))	('uveal melanoma', 'Phenotype', 'HP:0007716', (132, 146))	('uveal melanoma', 'Disease', (132, 146))	('uveal melanoma', 'Disease', 'MESH:C536494', (132, 146))	('CM', 'Phenotype', 'HP:0007716', (25, 27))	('BRAF', 'Gene', '673', (49, 53))	('GNA11', 'Gene', (83, 88))	('GNAQ', 'Gene', '2776', (78, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (5, 23))	('BRAF', 'Gene', (49, 53))	('GNA11', 'Gene', '2767', (83, 88))
31593	28938534	In a recent study, a BRAF V600E mutation was found in 29% of CM, and an NRAS mutation in 18%.	('NRAS', 'Gene', (72, 76))	('CM', 'Phenotype', 'HP:0007716', (61, 63))	('NRAS', 'Gene', '4893', (72, 76))	('BRAF', 'Gene', '673', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', (21, 25))	('V600E', 'Var', (26, 31))
31594	28938534	C-KIT mutations are seldom found in CM.	('CM', 'Phenotype', 'HP:0007716', (36, 38))	('C-KIT', 'Gene', '3815', (0, 5))	('C-KIT', 'Gene', (0, 5))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('mutations', 'Var', (6, 15))
31595	28938534	Mutant BRAF and NRAS are both known to activate the downstream kinases MEK1/2 and ERK1/2, thereby promoting tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ERK1', 'molecular_function', 'GO:0004707', ('82', '86'))	('NRAS', 'Gene', (16, 20))	('MEK1/2', 'Gene', '5604;5605', (71, 77))	('tumor', 'Disease', (108, 113))	('MEK1', 'molecular_function', 'GO:0004708', ('71', '75'))	('MEK1/2', 'Gene', (71, 77))	('promoting', 'PosReg', (98, 107))	('NRAS', 'Gene', '4893', (16, 20))	('BRAF', 'Gene', '673', (7, 11))	('Mutant', 'Var', (0, 6))	('BRAF', 'Gene', (7, 11))	('ERK1/2', 'Gene', (82, 88))	('activate', 'PosReg', (39, 47))
31600	28938534	Overactivity of PI3K/AKT pathway can be induced by loss of activity of PTEN or by activating mutations in oncogene NRAS.	('Overactivity', 'PosReg', (0, 12))	('loss of activity', 'NegReg', (51, 67))	('NRAS', 'Gene', (115, 119))	('mutations', 'Var', (93, 102))	('NRAS', 'Gene', '4893', (115, 119))	('PTEN', 'Gene', (71, 75))	('AKT', 'Gene', '207', (21, 24))	('PTEN', 'Gene', '5728', (71, 75))	('activating', 'Reg', (82, 92))	('AKT', 'Gene', (21, 24))	('PI3K', 'molecular_function', 'GO:0016303', ('16', '20'))
31602	28938534	To determine whether the above-mentioned inhibitors are of use in CM, we tested the effect of several potentially useful drugs on three CM cell lines, each of which has either a BRAF or NRAS mutation.	('BRAF', 'Gene', (178, 182))	('tested', 'Reg', (73, 79))	('NRAS', 'Gene', (186, 190))	('CM', 'Phenotype', 'HP:0007716', (136, 138))	('NRAS', 'Gene', '4893', (186, 190))	('BRAF', 'Gene', '673', (178, 182))	('CM', 'Phenotype', 'HP:0007716', (66, 68))	('mutation', 'Var', (191, 199))
31604	28938534	We determined the presence of BRAF V600E mutation in 131 pigmented conjunctival lesions from 129 patients and analyzed the expression of phosphorylated (p)-ERK and p-AKT by immunohistochemistry (Table 1).	('ERK', 'Gene', '5594', (156, 159))	('AKT', 'Gene', '207', (166, 169))	('ERK', 'Gene', (156, 159))	('V600E', 'Var', (35, 40))	('BRAF', 'Gene', (30, 34))	('AKT', 'Gene', (166, 169))	('BRAF', 'Gene', '673', (30, 34))	('ERK', 'molecular_function', 'GO:0004707', ('156', '159'))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('patients', 'Species', '9606', (97, 105))
31605	28938534	We observed BRAF V600E mutation in 19% of nevi (n=51) and 26% of melanoma (n=42) (Figure 1G).	('nevi', 'Phenotype', 'HP:0003764', (42, 46))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('nevi', 'Disease', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
31606	28938534	No BRAF V600E mutation was seen in any case of PAM without atypia (n=20) or PAM with atypia (n=18).	('V600E', 'Mutation', 'rs113488022', (8, 13))	('V600E', 'Var', (8, 13))	('BRAF', 'Gene', '673', (3, 7))	('PAM', 'Disease', (47, 50))	('BRAF', 'Gene', (3, 7))
31607	28938534	One of the BRAF mutated melanomas evolved from a background of PAM.	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanomas', 'Disease', (24, 33))	('mutated', 'Var', (16, 23))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('BRAF', 'Gene', '673', (11, 15))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('BRAF', 'Gene', (11, 15))
31614	28938534	In groups of nevi and CM, neither cytoplasmic nor nuclear expression was associated with the presence of a BRAF mutation.	('BRAF', 'Gene', (107, 111))	('CM', 'Phenotype', 'HP:0007716', (22, 24))	('mutation', 'Var', (112, 120))	('nevi', 'Disease', (13, 17))	('nevi', 'Phenotype', 'HP:0003764', (13, 17))	('BRAF', 'Gene', '673', (107, 111))
31625	28938534	Low concentrations of MK2206 (CRMM1 0.5 muM, CRMM2 2muM and CM2005.1 4muM) reduced the level of p-AKT, but higher concentrations were needed to suppress cell growth (Figure 3).	('cell growth', 'CPA', (153, 164))	('MK2206', 'Var', (22, 28))	('CM2005.1', 'Var', (60, 68))	('level', 'MPA', (87, 92))	('reduced', 'NegReg', (75, 82))	('AKT', 'Gene', '207', (98, 101))	('CM', 'Phenotype', 'HP:0007716', (60, 62))	('cell growth', 'biological_process', 'GO:0016049', ('153', '164'))	('suppress', 'NegReg', (144, 152))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('AKT', 'Gene', (98, 101))
31626	28938534	To investigate whether the AKT pathway was effectively inhibited by MK2206, we determined the p-PRAS40 level, since PRAS40 is a direct downstream target molecule of AKT.	('AKT', 'Gene', (165, 168))	('MK2206', 'Chemical', 'MESH:C548887', (68, 74))	('PRAS40', 'Gene', '84335', (116, 122))	('AKT', 'Gene', (27, 30))	('PRAS40', 'Gene', (116, 122))	('MK2206', 'Var', (68, 74))	('PRAS40', 'Gene', '84335', (96, 102))	('AKT', 'Gene', '207', (27, 30))	('AKT', 'Gene', '207', (165, 168))	('PRAS40', 'Gene', (96, 102))
31627	28938534	As shown in Figure 3E, levels of p-PRAS40 were strongly reduced in all three cell lines upon MK2206 treatment at relative low concentrations, indicating that AKT activity was decreased by MK2206; however, this inhibition was not sufficient to decrease the cell growth of CRMM2 and CM2005.1.	('MK2206', 'Var', (93, 99))	('MK2206', 'Chemical', 'MESH:C548887', (188, 194))	('reduced', 'NegReg', (56, 63))	('activity', 'MPA', (162, 170))	('MK2206', 'Var', (188, 194))	('cell growth', 'biological_process', 'GO:0016049', ('256', '267'))	('AKT', 'Gene', '207', (158, 161))	('levels', 'MPA', (23, 29))	('MK2206', 'Chemical', 'MESH:C548887', (93, 99))	('CM', 'Phenotype', 'HP:0007716', (281, 283))	('PRAS40', 'Gene', '84335', (35, 41))	('PRAS40', 'Gene', (35, 41))	('decreased', 'NegReg', (175, 184))	('AKT', 'Gene', (158, 161))
31629	28938534	MEK162 and MK2206 inhibited growth of all CM cell lines in a dose-dependent manner, although only high concentrations of MK2206 were able to suppress the proliferation of CRMM2 and CM2005.1.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('growth', 'CPA', (28, 34))	('MK2206', 'Chemical', 'MESH:C548887', (121, 127))	('suppress', 'NegReg', (141, 149))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('CM', 'Phenotype', 'HP:0007716', (42, 44))	('inhibited', 'NegReg', (18, 27))	('MK2206', 'Var', (11, 17))	('CM', 'Phenotype', 'HP:0007716', (181, 183))	('proliferation', 'CPA', (154, 167))	('MK2206', 'Var', (121, 127))
31630	28938534	Although CRMM1 and CM2005.1 both harbor the BRAF V600E mutation, their sensitivity to BRAFi differed very much.	('BRAF', 'Gene', '673', (44, 48))	('V600E', 'Var', (49, 54))	('BRAF', 'Gene', (44, 48))	('CM', 'Phenotype', 'HP:0007716', (19, 21))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (86, 90))	('V600E', 'Mutation', 'rs113488022', (49, 54))
31632	28938534	However, we did find a deletion in exon 2 of PTEN in the NRAS mutant cell line CRMM2.	('deletion', 'Var', (23, 31))	('NRAS', 'Gene', (57, 61))	('NRAS', 'Gene', '4893', (57, 61))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))
31634	28938534	MEK162 and MK2206 increased the sub-G1 fraction, indicating that these two drugs were able to induce cell death.	('MEK162', 'Chemical', 'MESH:C581313', (0, 6))	('cell death', 'CPA', (101, 111))	('increased', 'PosReg', (18, 27))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('MEK162', 'Var', (0, 6))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('sub-G1 fraction', 'MPA', (32, 47))	('MK2206', 'Var', (11, 17))
31636	28938534	Both MEK162 and MK2206 treatment led to G1 arrest, a modest increase in the sub-G1 fraction and a reduced number of S-phase cells (Supplementary Figure S2), although the effect of MK2206 was not very strong.	('MEK162', 'Var', (5, 11))	('MK2206', 'Var', (16, 22))	('increase', 'PosReg', (60, 68))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('MK2206', 'Chemical', 'MESH:C548887', (180, 186))	('S-phase', 'biological_process', 'GO:0051320', ('116', '123'))	('MEK162', 'Chemical', 'MESH:C581313', (5, 11))	('arrest', 'Disease', (43, 49))	('reduced', 'NegReg', (98, 105))	('sub-G1 fraction', 'CPA', (76, 91))	('MK2206', 'Chemical', 'MESH:C548887', (16, 22))
31637	28938534	In CM2005.1, G1 arrest and depletion of S-phase cells were found after all drug treatments, although MK2206 treatment did not result in a reduced G2/M phase.	('G2/M phase', 'CPA', (146, 156))	('arrest', 'Disease', 'MESH:D006323', (16, 22))	('M phase', 'biological_process', 'GO:0000279', ('149', '156'))	('CM2005.1', 'Var', (3, 11))	('CM', 'Phenotype', 'HP:0007716', (3, 5))	('S-phase', 'biological_process', 'GO:0051320', ('40', '47'))	('arrest', 'Disease', (16, 22))	('MK2206', 'Chemical', 'MESH:C548887', (101, 107))	('depletion', 'MPA', (27, 36))
31639	28938534	Poly (ADP-ribose) polymerase (PARP) cleavage is often associated with apoptotic cell death and has served as a marker for apoptosis and caspase activity.	('caspase activity', 'molecular_function', 'GO:0030693', ('136', '152'))	('apoptosis', 'biological_process', 'GO:0097194', ('122', '131'))	('apoptosis', 'biological_process', 'GO:0006915', ('122', '131'))	('PARP', 'Gene', (30, 34))	('Poly (ADP-ribose) polymerase', 'Gene', '142', (0, 28))	('cleavage', 'Var', (36, 44))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('70', '90'))	('PARP', 'Gene', '142', (30, 34))	('caspase activity', 'molecular_function', 'GO:0097153', ('136', '152'))	('caspase activity', 'molecular_function', 'GO:0004197', ('136', '152'))	('Poly (ADP-ribose) polymerase', 'Gene', (0, 28))	('associated', 'Reg', (54, 64))	('apoptotic cell death', 'CPA', (70, 90))
31646	28938534	We treated CRMM1, CRMM2 and CM2005.1 with varied concentrations of MEK162, MK2206 or the combination of MEK162 and MK2206 for 72 hours, and evaluated cell growth.	('MEK162', 'Chemical', 'MESH:C581313', (104, 110))	('MK2206', 'Var', (115, 121))	('MEK162', 'Chemical', 'MESH:C581313', (67, 73))	('MK2206', 'Chemical', 'MESH:C548887', (115, 121))	('cell growth', 'biological_process', 'GO:0016049', ('150', '161'))	('cell growth', 'CPA', (150, 161))	('MK2206', 'Chemical', 'MESH:C548887', (75, 81))	('CM', 'Phenotype', 'HP:0007716', (28, 30))	('evaluated', 'Reg', (140, 149))
31647	28938534	Figure 5 shows that MEK162 and MK2206 were synergistic in all cell lines, with synergy confirmed by CI values.	('MK2206', 'Var', (31, 37))	('MEK162', 'Chemical', 'MESH:C581313', (20, 26))	('MEK162', 'Var', (20, 26))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))
31648	28938534	In all cell lines, the combination of MEK162 and MK2206 at low concentrations caused slightly stronger G1 arrest and depletion of S-phase compared to single treatments (Figure 6).	('MEK162', 'Var', (38, 44))	('arrest', 'Disease', (106, 112))	('S-phase', 'biological_process', 'GO:0051320', ('130', '137'))	('depletion of S-phase', 'MPA', (117, 137))	('MK2206', 'Chemical', 'MESH:C548887', (49, 55))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('stronger', 'PosReg', (94, 102))	('MK2206', 'Var', (49, 55))	('MEK162', 'Chemical', 'MESH:C581313', (38, 44))
31649	28938534	Uveal melanomas, in contrast to conjunctival melanomas, lack BRAF or NRAS mutations but frequently have mutations in GNAQ, GNA11, BAP1, SF3B1 or EIF1AX.	('BAP1', 'Gene', (130, 134))	('EIF1AX', 'Gene', '1964', (145, 151))	('conjunctival melanomas', 'Disease', (32, 54))	('GNAQ', 'Gene', '2776', (117, 121))	('melanomas', 'Disease', (45, 54))	('GNA11', 'Gene', '2767', (123, 128))	('GNAQ', 'Gene', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('NRAS', 'Gene', '4893', (69, 73))	('SF3B1', 'Gene', (136, 141))	('mutations', 'Var', (104, 113))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (32, 53))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))	('BRAF', 'Gene', '673', (61, 65))	('SF3B1', 'Gene', '23451', (136, 141))	('BRAF', 'Gene', (61, 65))	('GNA11', 'Gene', (123, 128))	('BAP1', 'Gene', '8314', (130, 134))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('NRAS', 'Gene', (69, 73))	('EIF1AX', 'Gene', (145, 151))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (32, 54))	('melanomas', 'Disease', (6, 15))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))
31654	28938534	Furthermore, similar to the findings in melanocytic nevi and cutaneous melanoma, we report that BRAF mutations do not determine the tumor's ERK phosphorylation status.	('ERK', 'molecular_function', 'GO:0004707', ('140', '143'))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('144', '159'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (40, 56))	('ERK', 'Gene', '5594', (140, 143))	('tumor', 'Disease', (132, 137))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('ERK', 'Gene', (140, 143))
31656	28938534	Recently, loss of function mutations in NF1 have been described in a high percentage of cutaneous melanoma.	('mutations', 'Var', (27, 36))	('loss of function', 'NegReg', (10, 26))	('NF1', 'Gene', (40, 43))	('cutaneous melanoma', 'Disease', (88, 106))	('NF1', 'Gene', '4763', (40, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))
31664	28938534	Although CRMM1 and CM2005.1 both harbor a BRAF V600E mutation, their sensitivity to BRAFi differed greatly: CRMM1 required a much higher dose of Dabrafenib to inhibit cell growth compared to CM2005.1.	('BRAF', 'Gene', '673', (42, 46))	('CM', 'Phenotype', 'HP:0007716', (191, 193))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('V600E', 'Mutation', 'rs113488022', (47, 52))	('CM', 'Phenotype', 'HP:0007716', (19, 21))	('Dabrafenib', 'Chemical', 'MESH:C561627', (145, 155))	('cell growth', 'CPA', (167, 178))	('V600E', 'Var', (47, 52))	('BRAF', 'Gene', (42, 46))	('cell growth', 'biological_process', 'GO:0016049', ('167', '178'))	('inhibit', 'NegReg', (159, 166))
31669	28938534	This finding is in agreement with other preclinical studies in other malignancies, in which selective BRAFi stimulated cell growth and ERK phosphorylation in BRAF WT and NRAS mutant cutaneous melanoma cell lines.	('NRAS', 'Gene', (170, 174))	('mutant', 'Var', (175, 181))	('stimulated', 'PosReg', (108, 118))	('cutaneous melanoma', 'Disease', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('BRAF', 'Gene', '673', (158, 162))	('cell growth', 'CPA', (119, 130))	('ERK', 'molecular_function', 'GO:0004707', ('135', '138'))	('BRAF', 'Gene', (158, 162))	('ERK', 'Gene', '5594', (135, 138))	('malignancies', 'Disease', 'MESH:D009369', (69, 81))	('NRAS', 'Gene', '4893', (170, 174))	('malignancies', 'Disease', (69, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('ERK', 'Gene', (135, 138))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('cell growth', 'biological_process', 'GO:0016049', ('119', '130'))
31673	28938534	Furthermore, the data of cell cycle profiles and PARP cleavage show that in addition to cytostatic effects, MEK162 alone can prompt apoptosis, regardless of BRAF or NRAS mutations.	('apoptosis', 'CPA', (132, 141))	('PARP', 'Gene', '142', (49, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('MEK162', 'Chemical', 'MESH:C581313', (108, 114))	('BRAF', 'Gene', '673', (157, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('PARP', 'Gene', (49, 53))	('BRAF', 'Gene', (157, 161))	('MEK162', 'Var', (108, 114))	('cell cycle', 'biological_process', 'GO:0007049', ('25', '35'))	('NRAS', 'Gene', (165, 169))	('prompt', 'PosReg', (125, 131))	('NRAS', 'Gene', '4893', (165, 169))
31677	28938534	The PI3K/AKT signal transduction pathway is considered a potential co-target for BRAF and NRAS mutant cutaneous melanoma.	('AKT', 'Gene', '207', (9, 12))	('NRAS', 'Gene', (90, 94))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('BRAF', 'Gene', '673', (81, 85))	('NRAS', 'Gene', '4893', (90, 94))	('AKT signal transduction', 'biological_process', 'GO:0043491', ('9', '32'))	('BRAF', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('AKT', 'Gene', (9, 12))	('mutant', 'Var', (95, 101))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))
31679	28938534	Our results show that MK2206 inhibited proliferation in all CM cell lines, but at variable doses, and independent of their effect on p-AKT and p-PRAS40, indicating that the growth inhibitory effect induced by MK2206 is not specific or at least partly caused by off-target effects.	('inhibited', 'NegReg', (29, 38))	('AKT', 'Gene', '207', (135, 138))	('MK2206', 'Var', (22, 28))	('MK2206', 'Chemical', 'MESH:C548887', (209, 215))	('AKT', 'Gene', (135, 138))	('CM', 'Phenotype', 'HP:0007716', (60, 62))	('proliferation', 'CPA', (39, 52))	('MK2206', 'Var', (209, 215))	('PRAS40', 'Gene', '84335', (145, 151))	('MK2206', 'Chemical', 'MESH:C548887', (22, 28))	('PRAS40', 'Gene', (145, 151))	('growth', 'MPA', (173, 179))
31680	28938534	With the clinical availability of PI3K, AKT and mTOR inhibitors, a number of trials are now ongoing in cutaneous melanoma.	('mTOR', 'Gene', '2475', (48, 52))	('PI3K', 'Var', (34, 38))	('cutaneous melanoma', 'Disease', (103, 121))	('mTOR', 'Gene', (48, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('AKT', 'Gene', '207', (40, 43))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('34', '38'))	('AKT', 'Gene', (40, 43))
31681	28938534	Our studies show that combining MEK162 with MK2206 has a synergistic inhibitory effect on proliferation of three CM cell lines, regardless of their sensitivity to the individual agents.	('proliferation', 'CPA', (90, 103))	('CM', 'Phenotype', 'HP:0007716', (113, 115))	('MK2206', 'Var', (44, 50))	('inhibitory', 'NegReg', (69, 79))	('MEK162', 'Chemical', 'MESH:C581313', (32, 38))	('MEK162', 'Var', (32, 38))	('MK2206', 'Chemical', 'MESH:C548887', (44, 50))
31682	28938534	Mutations in the G-alpha-proteins GNAQ and GNA11 that occur in 91% of uveal melanoma also activate MAPK and PI3K/AKT pathways, which implies that the combination of MEK and AKT inhibitors may also be profitable for this patient group.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('AKT', 'Gene', '207', (113, 116))	('MEK', 'Gene', '5609', (165, 168))	('AKT', 'Gene', (173, 176))	('GNA11', 'Gene', '2767', (43, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('G-alpha-proteins', 'Protein', (17, 33))	('MEK', 'Gene', (165, 168))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (34, 38))	('AKT', 'Gene', '207', (173, 176))	('GNA11', 'Gene', (43, 48))	('patient', 'Species', '9606', (220, 227))	('activate', 'PosReg', (90, 98))	('GNAQ', 'Gene', (34, 38))	('AKT', 'Gene', (113, 116))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('108', '112'))
31695	28938534	Briefly, following deparaffinization and heat-induced antigen retrieval for 60 minutes, the tissue sections were incubated with primary antibody anti-MAP kinase diphosphorylated ERK 1/2 (1:1000; M8159, Sigma-Aldrich, St. Louis, MO, USA), p-AKT Ser473 (sc-135651; 1:25, Santa Cruz Biotechnology; Dallas, TX, USA), p-AKT Thr 308 (sc-135650, 1:50, Santa Cruz Biotechnology), BRAF-V600E (26039, 1:50, NewEast Biosciences, Malvern, PA, USA) or Melan A (clone A103, Ventana) for 1 hour at 36 C. A subsequent amplification step was followed by incubation with hematoxylin II counter stain for 8 minutes and then bluing reagent for 8 minutes according to the manufacturer's instructions (Ventana).	('paraffin', 'Chemical', 'MESH:D010232', (21, 29))	('Ser473', 'Chemical', '-', (244, 250))	('Ser', 'cellular_component', 'GO:0005790', ('244', '247'))	('ERK 1/2', 'Gene', (178, 185))	('hematoxylin', 'Chemical', 'MESH:D006416', (553, 564))	('antibody', 'cellular_component', 'GO:0019815', ('136', '144'))	('AKT', 'Gene', (315, 318))	('BRAF', 'Gene', '673', (372, 376))	('BRAF', 'Gene', (372, 376))	('AKT', 'Gene', '207', (240, 243))	('ERK 1', 'molecular_function', 'GO:0004707', ('178', '183'))	('V600E', 'Mutation', 'rs113488022', (377, 382))	('antibody', 'cellular_component', 'GO:0019814', ('136', '144'))	('MAP', 'molecular_function', 'GO:0004239', ('150', '153'))	('sc-135650', 'Var', (328, 337))	('ERK 1/2', 'Gene', '5595;5594', (178, 185))	('Thr', 'Chemical', 'MESH:D013912', (319, 322))	('AKT', 'Gene', '207', (315, 318))	('antibody', 'molecular_function', 'GO:0003823', ('136', '144'))	('AKT', 'Gene', (240, 243))	('antibody', 'cellular_component', 'GO:0042571', ('136', '144'))
31697	28938534	Vemurafenib (PLX4032, S1267), Dabrafenib (GSK2118436, S2807), MEK162 (ARRY-162, S7007) and MK2206 (S1078) were purchased from Selleck Chemicals (Huissen, The Netherlands).	('MEK162', 'Chemical', 'MESH:C581313', (62, 68))	('PLX4032', 'Var', (13, 20))	('GSK2118436, S2807', 'Var', (42, 59))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('Dabrafenib', 'Chemical', 'MESH:C561627', (30, 40))	('GSK2118436', 'Chemical', 'MESH:C561627', (42, 52))	('MK2206', 'Chemical', 'MESH:C548887', (91, 97))	('GSK', 'molecular_function', 'GO:0050321', ('42', '45'))
31701	28938534	Our previous studies have shown that CRMM1 and CM2005.1 harbor a BRAF V600E mutation, and CRMM2 contains an NRAS Q61L mutation.	('NRAS', 'Gene', (108, 112))	('V600E', 'Var', (70, 75))	('NRAS', 'Gene', '4893', (108, 112))	('Q61L', 'Mutation', 'rs11554290', (113, 117))	('BRAF', 'Gene', '673', (65, 69))	('CM', 'Phenotype', 'HP:0007716', (47, 49))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (65, 69))
31702	28938534	Inactivating molecular changes in PTEN were tested by NGS as decribed before.	('PTEN', 'Gene', '5728', (34, 38))	('PTEN', 'Gene', (34, 38))	('Inactivating', 'Var', (0, 12))
31703	28938534	Cells were lysed in M-PER Mammalian Protein Extraction Reagent (78501, Thermo Scientific, OH, USA), supplemented with protease and phosphatase inhibitors (78415 and 78420, Thermo Scientific).	('phosphatase', 'molecular_function', 'GO:0016791', ('131', '142'))	('78501', 'Var', (64, 69))	('Mammalian', 'Species', '9606', (26, 35))	('78415', 'Var', (155, 160))
31761	30548543	The prognostic accuracy of the three-protein marker was subsequently validated in a cohort of 248 patients enrolled in the Eastern Cooperative Oncology Group 1690 (E1690) clinical trial.47 Although protein expression significantly correlated with recurrence and survival and all high-risk patients had events within 5 years, the E1690 cohort was primarily composed of high-risk tumors with five-year survival rates that approached 50% among low-risk patients.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('tumors', 'Disease', (378, 384))	('tumors', 'Disease', 'MESH:D009369', (378, 384))	('tumors', 'Phenotype', 'HP:0002664', (378, 384))	('Oncology', 'Phenotype', 'HP:0002664', (143, 151))	('patients', 'Species', '9606', (98, 106))	('survival', 'CPA', (262, 270))	('patients', 'Species', '9606', (450, 458))	('E1690', 'Var', (329, 334))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('recurrence', 'CPA', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (378, 383))	('protein', 'Protein', (198, 205))	('correlated with', 'Reg', (231, 246))	('patients', 'Species', '9606', (289, 297))
31792	30548543	Studies of contemporary anti-melanoma therapies suggest greater efficacy of these drugs in patients with lower tumor burden.4, 6, 8 For patients with low-risk disease, avoidance of unnecessary physician visits, laboratory tests, and imaging studies decreases cost, anxiety, and time lost from work and family.	('anxiety', 'Disease', (265, 272))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patients', 'Species', '9606', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('anxiety', 'Phenotype', 'HP:0000739', (265, 272))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('tumor', 'Disease', (111, 116))	('avoidance', 'Var', (168, 177))	('decreases', 'NegReg', (249, 258))	('patients', 'Species', '9606', (136, 144))	('anxiety', 'Disease', 'MESH:D001008', (265, 272))
31797	30548543	These data also suggest that the 31-GEP could increase the yield of actionable SLN-positive outcomes, which are currently only in the 15%-20% range for intermediate thickness tumors, and lower for thin tumors.	('31-GEP', 'Var', (33, 39))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('increase', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('SLN-positive', 'Gene', (79, 91))	('thickness tumors', 'Disease', 'MESH:C535655', (165, 181))	('thickness tumors', 'Disease', (165, 181))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
31799	30548543	Efforts toward this end have been focused on the identification of actionable genetic alterations in cancer drivers of cell-cycle regulation, PI3K/AKT, MAPK, and other pathways.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('PI3K', 'molecular_function', 'GO:0016303', ('142', '146'))	('cancer', 'Disease', (101, 107))	('cell-cycle', 'MPA', (119, 129))	('MAPK', 'Gene', (152, 156))	('AKT', 'Gene', '207', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cell-cycle regulation', 'biological_process', 'GO:0051726', ('119', '140'))	('genetic alterations', 'Var', (78, 97))	('MAPK', 'molecular_function', 'GO:0004707', ('152', '156'))	('AKT', 'Gene', (147, 150))
31806	30548543	Advances in genomic sequencing technologies, coupled with the development of effective melanoma therapies, have identified genes with specific driver mutations as predictors of response.	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (150, 159))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
31807	30548543	The best-studied example in melanoma is the BRAF V600 mutation that promotes constitutive activation of the MAPK pathway and is present in approximately 50% of melanoma tumors.83, 84 To date, two PCR-based companion diagnostics (CDx), the Cobas 4800 (Roche Diagnostics, Indianapolis, IN) and the THxID kit (BioMerieux, Marcy-l'Etoile, France), have been FDA approved for the detection of the V600E and/or V600K BRAF mutations, allowing for the appropriate use of BRAF and MEK inhibitors in patients with mutations.85, 86 It should also be noted that NGS detection of BRAF and NRAS driver mutations is widely available through other laboratory developed test technologies that do not require FDA approval.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('MEK', 'Gene', '5609', (472, 475))	('melanoma tumors', 'Disease', 'MESH:D008545', (160, 175))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('V600E', 'Mutation', 'rs113488022', (392, 397))	('patients', 'Species', '9606', (490, 498))	('CDx', 'Chemical', '-', (229, 232))	('melanoma tumors', 'Disease', (160, 175))	('BRAF', 'Gene', '673', (411, 415))	('BRAF', 'Gene', (411, 415))	('MEK', 'Gene', (472, 475))	('NRAS', 'Gene', '4893', (576, 580))	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BRAF', 'Gene', '673', (567, 571))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (28, 36))	('BRAF', 'Gene', (567, 571))	('V600K', 'Mutation', 'rs121913227', (405, 410))	('NRAS', 'Gene', (576, 580))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BRAF', 'Gene', '673', (463, 467))	('BRAF', 'Gene', (463, 467))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('mutations', 'Var', (416, 425))
31808	30548543	The emergence of NGS technologies has allowed for the detection of BRAF mutations in combination with other predictive markers for melanoma (Table 4).	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('BRAF', 'Gene', (67, 71))
31809	30548543	The US FDA premarket approval of CDx from FoundationOne allows for more accurate determination of BRAF mutation status.	('mutation', 'Var', (103, 111))	('CDx', 'Chemical', '-', (33, 36))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))
31810	30548543	Although the approval specifies the indication for BRAF targeted therapy in melanoma, CDx also assesses mutations in 324 genes, gene rearrangements, as well as microsatellite instability and tumor mutation burden (TMB).	('melanoma', 'Disease', (76, 84))	('mutations', 'Var', (104, 113))	('CDx', 'Chemical', '-', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('324 genes', 'Gene', (117, 126))	('BRAF', 'Gene', '673', (51, 55))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('microsatellite instability', 'MPA', (160, 186))	('BRAF', 'Gene', (51, 55))	('TMB', 'Chemical', '-', (214, 217))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
31850	30548543	For patients who have node-negative disease after SLNBx and fall in the Stage I and Stage II range, having an additional biologic prognosticator, to be used with or without further probabilistic predictors, may allow both the development and more rational use of new adjuvant drugs in the subset of high-risk node-negative patients.	('node-negative', 'Disease', (22, 35))	('patients', 'Species', '9606', (323, 331))	('fall', 'Phenotype', 'HP:0002527', (60, 64))	('SLNBx', 'Var', (50, 55))	('SLNBx', 'Chemical', '-', (50, 55))	('patients', 'Species', '9606', (4, 12))
31924	29666643	The correlation of IGSF9 positivity with other continuous variables, such as age, tumor size in cm, depth of myometrium invasion as percentage of total myometrium thickness, and Ki67 labeling index were plotted in Figure 7.	('positivity', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('IGSF9', 'Gene', (19, 24))
31941	29666643	It is reported to be a tumor suppressor; the deficiency of WISP2 promotes breast cancer growth and WISP2 RNA expression was decreased in 79% of human colon cancers, but no studies of WISP2 in endometrial cancer have been reported.	('endometrial cancer', 'Disease', (192, 210))	('RNA', 'cellular_component', 'GO:0005562', ('105', '108'))	('endometrial cancer', 'Disease', 'MESH:D016889', (192, 210))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('WISP2', 'Gene', '8839', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('WISP2', 'Gene', (99, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('human', 'Species', '9606', (144, 149))	('deficiency', 'Var', (45, 55))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('colon cancers', 'Phenotype', 'HP:0003003', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('WISP2', 'Gene', '8839', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('WISP2', 'Gene', (183, 188))	('promotes', 'PosReg', (65, 73))	('tumor', 'Disease', (23, 28))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('breast cancer', 'Disease', (74, 87))	('WISP2', 'Gene', '8839', (99, 104))	('colon cancers', 'Disease', 'MESH:D015179', (150, 163))	('endometrial cancer', 'Phenotype', 'HP:0012114', (192, 210))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('decreased', 'NegReg', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colon cancers', 'Disease', (150, 163))	('WISP2', 'Gene', (59, 64))
31952	29666643	The positivity of IGSF9 is also higher in cancer with myometrium invasion than those without, likely an indicator of cancer aggressiveness.	('myometrium', 'Disease', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('higher', 'Reg', (32, 38))	('positivity', 'Var', (4, 14))	('IGSF9', 'Gene', (18, 23))	('cancer aggressiveness', 'Disease', (117, 138))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (117, 138))	('cancer', 'Disease', (117, 123))	('aggressiveness', 'Phenotype', 'HP:0000718', (124, 138))
31957	29666643	Overexpression of IGSF9 is an indicator of poor prognosis in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('IGSF9', 'Gene', (18, 23))	('endometrial cancer', 'Disease', (61, 79))	('Overexpression', 'Var', (0, 14))	('endometrial cancer', 'Phenotype', 'HP:0012114', (61, 79))
31967	29399853	in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('melanoma', 'Disease', (73, 81))	('patients', 'Species', '9606', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('BRAF', 'Gene', '673', (26, 30))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('V600E', 'Var', (31, 36))	('V600E', 'SUBSTITUTION', 'None', (31, 36))	('BRAF', 'Gene', (26, 30))	('solid tumors', 'Disease', (46, 58))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
31973	29399853	Melanomas are the most aggressive form of skin cancers which account for 80% of skin cancer-induced deaths.1 The origin and progression of melanoma has been associated with genetic mutations in several genes, including BRAF, NRAS, MITF and KIT, that are involved in different signaling pathways regulating survival, growth and proliferation in cells.	('MITF', 'Gene', '4286', (231, 235))	('NRAS', 'Gene', (225, 229))	('skin cancers', 'Disease', (42, 54))	('skin cancers', 'Disease', 'MESH:D012878', (42, 54))	('MITF', 'Gene', (231, 235))	('deaths', 'Disease', (100, 106))	('signaling', 'biological_process', 'GO:0023052', ('276', '285'))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('mutations', 'Var', (181, 190))	('skin cancer', 'Disease', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('deaths', 'Disease', 'MESH:D003643', (100, 106))	('KIT', 'Gene', (240, 243))	('associated', 'Reg', (157, 167))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('skin cancer', 'Phenotype', 'HP:0008069', (42, 53))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('NRAS', 'Gene', '4893', (225, 229))	('skin cancer', 'Phenotype', 'HP:0008069', (80, 91))	('BRAF', 'Gene', (219, 223))	('BRAF', 'Gene', '673', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('Melanomas', 'Disease', (0, 9))	('melanoma', 'Disease', (139, 147))	('skin cancers', 'Phenotype', 'HP:0008069', (42, 54))	('skin cancer', 'Disease', 'MESH:D012878', (80, 91))	('KIT', 'molecular_function', 'GO:0005020', ('240', '243'))	('skin cancer', 'Disease', 'MESH:D012878', (42, 53))
31974	29399853	The recent discovery of these mutations not only resulted in better understanding of melanoma and its progression but also resulted in advancement of targeted therapies.2 BRAF mutation, occurring in approximately 50% of patients with melanoma, constitutively activates the mitogen-activated protein kinase (MAPK; RAS RAF MEK ERK) signaling pathway, which plays a vital role in regulating the cell proliferation and survival in human tumors including cutaneous melanoma.2, 3, 4  Melanoma is relatively more common in Caucasian populations and hence analyses of characteristics of patients with BRAF mutations in detail have been restricted to these patients.5, 6 Studies involving China, Korea and Japan revealed that there may be some differences in incidence of melanoma compared with the findings in Caucasians, including frequency and an age association with BRAF mutation.7, 8, 9, 10 In a recent study conducted in Japan, the detection rates of BRAF, NRAS and KIT mutations were 30.4%, 12.3% and 12.9%, respectively.11  Dabrafenib, a potent and selective inhibitor of BRAF kinase activity, was approved based on the results of a phase 3 trial which demonstrated significant improvement in progression-free survival (PFS) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma.12, 13 Trametinib, a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase activity was approved for use in the treatment of adult patients with unresectable or metastatic melanoma containing BRAF V600E/K mutations based on the results demonstrated in a phase 3 trial.14, 15 Owing to the modest improvement in PFS with BRAF- and MEK-inhibitor monotherapies, development of resistance to BRAF inhibition, poor outcome in patients with BRAF-mutant melanoma after development of resistance to BRAF-inhibitor monotherapy, and the associated severe cutaneous toxicity, there was an interest in combining oncogenic BRAF inhibition with downstream MEK inhibition in the MAPK pathway to help in improving the patient outcomes.	('men', 'Species', '9606', (1185, 1188))	('ERK', 'molecular_function', 'GO:0004707', ('325', '328'))	('kinase activity', 'molecular_function', 'GO:0016301', ('1077', '1092'))	('Trametinib', 'Chemical', 'MESH:C560077', (1314, 1324))	('MEK', 'Gene', (1381, 1384))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('melanoma', 'Disease', 'MESH:D008545', (1298, 1306))	('protein', 'cellular_component', 'GO:0003675', ('291', '298'))	('NRAS', 'Gene', (955, 959))	('men', 'Species', '9606', (1455, 1458))	('patient', 'Species', '9606', (579, 586))	('patients', 'Species', '9606', (648, 656))	('RAF', 'Gene', '22882', (863, 866))	('melanoma', 'Disease', (1784, 1792))	('toxicity', 'Disease', 'MESH:D064420', (1892, 1900))	('tumor', 'Phenotype', 'HP:0002664', (433, 438))	('RAF', 'Gene', '22882', (172, 175))	('men', 'Species', '9606', (142, 145))	('tumors', 'Disease', (433, 439))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (450, 468))	('ERK', 'Gene', (325, 328))	('BRAF', 'Gene', '673', (1828, 1832))	('melanoma', 'Phenotype', 'HP:0002861', (1298, 1306))	('MEK', 'Gene', (1979, 1982))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('MEK2', 'molecular_function', 'GO:0004708', ('1386', '1390'))	('BRAF', 'Gene', '673', (949, 953))	('men', 'Species', '9606', (1806, 1809))	('patient', 'Species', '9606', (648, 655))	('RAF', 'Gene', '22882', (1243, 1246))	('RAF', 'Gene', (172, 175))	('V600E', 'Var', (1535, 1540))	('RAF', 'Gene', '22882', (1773, 1776))	('Melanoma', 'Disease', 'MESH:D008545', (478, 486))	('patients', 'Species', '9606', (1469, 1477))	('MEK', 'Gene', (1667, 1670))	('BRAF', 'Gene', (1947, 1951))	('BRAF', 'Gene', '673', (1947, 1951))	('BRAF', 'Gene', '673', (1772, 1776))	('MEK', 'Gene', '5609', (1386, 1389))	('RAF', 'Gene', (1243, 1246))	('patient', 'Species', '9606', (1469, 1476))	('RAF', 'Gene', (1773, 1776))	('MAPK', 'Gene', '5594', (307, 311))	('patients', 'Species', '9606', (1228, 1236))	('V600E', 'SUBSTITUTION', 'None', (1535, 1540))	('RAF', 'Gene', '22882', (1073, 1076))	('patients', 'Species', '9606', (220, 228))	('RAF', 'Gene', '22882', (1658, 1661))	('BRAF', 'Gene', (1072, 1076))	('BRAF', 'Gene', '673', (1072, 1076))	('melanoma', 'Phenotype', 'HP:0002861', (460, 468))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', '673', (1530, 1534))	('MEK1', 'Gene', (1381, 1385))	('patient', 'Species', '9606', (2039, 2046))	('tumors', 'Phenotype', 'HP:0002664', (433, 439))	('ERK', 'Gene', '5594', (325, 328))	('Melanoma', 'Phenotype', 'HP:0002861', (478, 486))	('BRAF', 'Gene', (593, 597))	('BRAF', 'Gene', '673', (593, 597))	('RAF', 'Gene', (1073, 1076))	('RAF', 'Gene', (1658, 1661))	('V600E', 'Mutation', 'rs113488022', (1535, 1540))	('MEK', 'Gene', (321, 324))	('melanoma', 'Disease', 'MESH:D008545', (1510, 1518))	('RAF', 'Gene', '22882', (594, 597))	('patient', 'Species', '9606', (1228, 1235))	('RAF', 'Gene', '22882', (1829, 1832))	('BRAF', 'Gene', '673', (862, 866))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('MAPK', 'Gene', '5594', (2001, 2005))	('BRAF', 'Gene', (1828, 1832))	('human', 'Species', '9606', (427, 432))	('BRAF', 'Gene', (1725, 1729))	('BRAF', 'Gene', '673', (1725, 1729))	('signaling pathway', 'biological_process', 'GO:0007165', ('330', '347'))	('BRAF', 'Gene', (949, 953))	('RAF', 'Gene', (594, 597))	('patients', 'Species', '9606', (579, 587))	('patient', 'Species', '9606', (1758, 1765))	('melanoma', 'Disease', 'MESH:D008545', (1784, 1792))	('RAF', 'Gene', (1829, 1832))	('MEK', 'Gene', '5609', (1381, 1384))	('RAF', 'Gene', '22882', (1726, 1729))	('melanoma', 'Disease', (763, 771))	('BRAF', 'Gene', (1772, 1776))	('kinase activity', 'molecular_function', 'GO:0016301', ('1406', '1421'))	('inhibition', 'NegReg', (1952, 1962))	('Melanoma', 'Disease', (478, 486))	('RAF', 'Gene', (1726, 1729))	('RAF', 'Gene', '22882', (1531, 1534))	('RAF', 'Gene', '22882', (317, 320))	('BRAF', 'Gene', (1530, 1534))	('MEK', 'Gene', '5609', (1979, 1982))	('MEK1', 'molecular_function', 'GO:0004708', ('1381', '1385'))	('RAF', 'Gene', (1531, 1534))	('MEK2', 'Gene', '5605', (1386, 1390))	('RAF', 'Gene', (317, 320))	('RAF', 'Gene', '22882', (1948, 1951))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (450, 468))	('BRAF', 'Gene', '673', (171, 175))	('BRAF', 'Gene', (1242, 1246))	('BRAF', 'Gene', '673', (1242, 1246))	('men', 'Species', '9606', (1640, 1643))	('melanoma', 'Disease', (234, 242))	('melanoma', 'Disease', (1298, 1306))	('BRAF', 'Gene', (862, 866))	('NRAS', 'Gene', '4893', (955, 959))	('V600E', 'Var', (1247, 1252))	('RAF', 'Gene', (1948, 1951))	('MAPK', 'Gene', (307, 311))	('men', 'Species', '9606', (1703, 1706))	('MAPK', 'molecular_function', 'GO:0004707', ('307', '311'))	('V600E', 'SUBSTITUTION', 'None', (1247, 1252))	('MEK', 'Gene', (1386, 1389))	('melanoma', 'Disease', (460, 468))	('MEK', 'Gene', '5609', (321, 324))	('KIT', 'molecular_function', 'GO:0005020', ('964', '967'))	('MAPK', 'molecular_function', 'GO:0004707', ('2001', '2005'))	('patients', 'Species', '9606', (1758, 1766))	('RAF', 'Gene', '22882', (950, 953))	('V600E', 'Mutation', 'rs113488022', (1247, 1252))	('MAPK', 'Gene', (2001, 2005))	('MEK2', 'Gene', (1386, 1390))	('cutaneous melanoma', 'Disease', (450, 468))	('melanoma', 'Disease', 'MESH:D008545', (763, 771))	('BRAF', 'Gene', (1657, 1661))	('BRAF', 'Gene', '673', (1657, 1661))	('RAF', 'Gene', (863, 866))	('cell proliferation', 'biological_process', 'GO:0008283', ('392', '410'))	('patient', 'Species', '9606', (220, 227))	('BRAF', 'Gene', (171, 175))	('melanoma', 'Disease', (85, 93))	('MEK1', 'Gene', '5604', (1381, 1385))	('melanoma', 'Disease', 'MESH:D008545', (460, 468))	('RAF', 'Gene', (950, 953))	('MEK', 'Gene', '5609', (1667, 1670))	('toxicity', 'Disease', (1892, 1900))	('tumors', 'Disease', 'MESH:D009369', (433, 439))	('Dabrafenib', 'Chemical', 'MESH:C561627', (1024, 1034))	('melanoma', 'Disease', (1510, 1518))	('melanoma', 'Phenotype', 'HP:0002861', (763, 771))
31975	29399853	A synergistic effect of the combination of dabrafenib and trametinib, via concomitant inhibition of the ERK, was observed in BRAF V600-mutant melanoma cell lines, and delayed emergence of resistance was observed in BRAF V600-mutant melanoma xenografts in vivo along with a decrease in skin toxicities compared with monotherapy.16 In a phase 2 study, the dabrafenib and trametinib combination significantly improved PFS and decreased the frequency of known BRAF inhibitor-induced hyperproliferative skin lesions such as cutaneous squamous cell carcinoma, papilloma and hyperkeratosis, compared with dabrafenib monotherapy in patients with BRAF inhibitor-naive metastatic melanoma.17  The combination of dabrafenib and trametinib in the pivotal phase 3 studies revealed statistically significant and clinically relevant improvements in PFS, overall survival (OS) in patients with BRAF V600 mutation-positive melanoma.18, 19, 20, 21 As the data in Asian patients are very limited, this study was conducted to determine the safety and preliminary efficacy of dabrafenib plus trametinib in Japanese patients with BRAF V600E/K mutation-positive solid tumors, including melanoma.	('patients', 'Species', '9606', (864, 872))	('hyperkeratosis', 'Disease', (568, 582))	('cutaneous squamous cell carcinoma', 'Disease', (519, 552))	('papilloma', 'Disease', (554, 563))	('BRAF', 'Gene', (215, 219))	('dabrafenib', 'Chemical', 'MESH:C561627', (598, 608))	('hyperproliferative skin lesions', 'Disease', 'MESH:D012871', (479, 510))	('patients', 'Species', '9606', (1094, 1102))	('V600E', 'SUBSTITUTION', 'None', (1113, 1118))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanoma', 'Disease', (232, 240))	('papilloma', 'Disease', 'MESH:D010212', (554, 563))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (519, 552))	('melanoma', 'Disease', 'MESH:D008545', (1163, 1171))	('trametinib', 'Chemical', 'MESH:C560077', (1071, 1081))	('hyperkeratosis', 'Disease', 'MESH:D017488', (568, 582))	('ERK', 'Gene', '5594', (104, 107))	('melanoma', 'Disease', 'MESH:D008545', (670, 678))	('papilloma', 'Phenotype', 'HP:0012740', (554, 563))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))	('solid tumors', 'Disease', (1139, 1151))	('dabrafenib', 'Chemical', 'MESH:C561627', (1055, 1065))	('ERK', 'molecular_function', 'GO:0004707', ('104', '107'))	('patients', 'Species', '9606', (624, 632))	('skin toxicities', 'Disease', (285, 300))	('melanoma', 'Disease', 'MESH:D008545', (906, 914))	('trametinib', 'Chemical', 'MESH:C560077', (369, 379))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (568, 582))	('BRAF', 'Gene', (125, 129))	('hyperproliferative skin lesions', 'Disease', (479, 510))	('BRAF', 'Gene', '673', (125, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (529, 552))	('ERK', 'Gene', (104, 107))	('BRAF', 'Gene', '673', (878, 882))	('solid tumors', 'Disease', 'MESH:D009369', (1139, 1151))	('BRAF', 'Gene', (1108, 1112))	('BRAF', 'Gene', '673', (1108, 1112))	('BRAF', 'Gene', (878, 882))	('melanoma', 'Phenotype', 'HP:0002861', (1163, 1171))	('BRAF', 'Gene', '673', (456, 460))	('melanoma', 'Disease', (1163, 1171))	('trametinib', 'Chemical', 'MESH:C560077', (58, 68))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('men', 'Species', '9606', (825, 828))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (519, 552))	('BRAF', 'Gene', (456, 460))	('skin toxicities', 'Disease', 'MESH:D012871', (285, 300))	('melanoma', 'Phenotype', 'HP:0002861', (670, 678))	('melanoma', 'Disease', (670, 678))	('carcinoma', 'Phenotype', 'HP:0030731', (543, 552))	('V600E', 'Var', (1113, 1118))	('dabrafenib', 'Chemical', 'MESH:C561627', (354, 364))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('dabrafenib', 'Chemical', 'MESH:C561627', (43, 53))	('trametinib', 'Chemical', 'MESH:C560077', (717, 727))	('tumors', 'Phenotype', 'HP:0002664', (1145, 1151))	('dabrafenib', 'Chemical', 'MESH:C561627', (702, 712))	('BRAF', 'Gene', '673', (638, 642))	('patients', 'Species', '9606', (951, 959))	('tumor', 'Phenotype', 'HP:0002664', (1145, 1150))	('BRAF', 'Gene', (638, 642))	('melanoma', 'Phenotype', 'HP:0002861', (906, 914))	('melanoma', 'Disease', (906, 914))	('BRAF', 'Gene', '673', (215, 219))
31978	29399853	combination in patients with BRAF V600E/K mutation-positive advanced solid tumors (phase 1) and BRAF V600E/K mutation-positive cutaneous melanoma (phase 2) were evaluated (Fig.	('BRAF', 'Gene', '673', (29, 33))	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('patients', 'Species', '9606', (15, 23))	('BRAF', 'Gene', (29, 33))	('V600E', 'SUBSTITUTION', 'None', (34, 39))	('V600E', 'Var', (101, 106))	('solid tumors', 'Disease', (69, 81))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('BRAF', 'Gene', (96, 100))	('V600E', 'SUBSTITUTION', 'None', (101, 106))	('BRAF', 'Gene', '673', (96, 100))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (127, 145))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('cutaneous melanoma', 'Disease', (127, 145))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (127, 145))	('V600E', 'Var', (34, 39))
31982	29399853	In phase 1, patients aged 20 years or more with histologically confirmed BRAF V600E/K mutation-positive advanced solid tumors, which are not responsive to standard therapies or for which there was no approved or curative therapy, were included.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('BRAF', 'Gene', '673', (73, 77))	('patients', 'Species', '9606', (12, 20))	('mutation-positive', 'Reg', (86, 103))	('V600E', 'SUBSTITUTION', 'None', (78, 83))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('V600E', 'Var', (78, 83))	('BRAF', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('solid tumors', 'Disease', (113, 125))
31983	29399853	In phase 2, patients aged 20 years or more with histologically confirmed BRAF V600E/K mutation-positive unresectable (stage IIIC) or metastatic (stage IV) cutaneous melanoma were included.	('BRAF', 'Gene', '673', (73, 77))	('patients', 'Species', '9606', (12, 20))	('V600E', 'SUBSTITUTION', 'None', (78, 83))	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('unresectable', 'Disease', (104, 116))	('metastatic', 'CPA', (133, 143))	('V600E', 'Var', (78, 83))	('BRAF', 'Gene', (73, 77))
32033	29399853	in patients with BRAF V600E/K mutation-positive advanced solid tumors, dabrafenib seemed to be rapidly absorbed with the median plasma Tmax of approximately 2 h. Plasma AUC0-12 h on day 21 was lower than that after a single dose on day 1 (Fig.	('solid tumors', 'Disease', (57, 69))	('BRAF', 'Gene', '673', (17, 21))	('dabrafenib', 'Chemical', 'MESH:C561627', (71, 81))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Plasma AUC0-12 h', 'MPA', (162, 178))	('BRAF', 'Gene', (17, 21))	('patients', 'Species', '9606', (3, 11))	('solid tumors', 'Disease', 'MESH:D009369', (57, 69))	('V600E', 'Var', (22, 27))	('V600E', 'SUBSTITUTION', 'None', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lower', 'NegReg', (193, 198))
32034	29399853	Plasma trough concentrations of dabrafenib and its metabolites seemed to reach a steady state by week 3 (percent coefficient of variation [%CV] of 149% [dabrafenib], 82% [GSK2285403, hydroxylated form], 52% [GSK2298683, carboxylate form] and 84% [GSK2167542, demethylated form]).	('dabrafenib', 'Chemical', 'MESH:C561627', (153, 163))	('[GSK2285403', 'Var', (170, 181))	('dabrafenib', 'Chemical', 'MESH:C561627', (32, 42))	('GSK2167542', 'Chemical', '-', (247, 257))	('GSK', 'molecular_function', 'GO:0050321', ('171', '174'))	('GSK', 'molecular_function', 'GO:0050321', ('247', '250'))	('carboxylate', 'Chemical', '-', (220, 231))	('GSK2285403', 'Chemical', '-', (171, 181))	('GSK2298683', 'Chemical', '-', (208, 218))	('GSK', 'molecular_function', 'GO:0050321', ('208', '211'))	('[GSK2298683', 'Var', (207, 218))
32061	29399853	The advancement of BRAF-targeted therapies has transformed the treatment of BRAF-mutant metastatic melanoma by improving outcomes for the treated patients.23 The purpose of this Japanese phase 1/2 study was to assess the safety and preliminary efficacy of dabrafenib and trametinib combination in 12 Japanese patients with BRAF V600E/K mutation-positive advanced solid tumors (phase 1) and BRAF V600E/K mutation-positive cutaneous melanoma (phase 2).	('solid tumors', 'Disease', (363, 375))	('BRAF', 'Gene', (390, 394))	('cutaneous melanoma', 'Disease', (421, 439))	('dabrafenib', 'Chemical', 'MESH:C561627', (256, 266))	('V600E', 'SUBSTITUTION', 'None', (328, 333))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (421, 439))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (421, 439))	('V600E', 'Var', (395, 400))	('melanoma', 'Disease', 'MESH:D008545', (431, 439))	('solid tumors', 'Disease', 'MESH:D009369', (363, 375))	('tumors', 'Phenotype', 'HP:0002664', (369, 375))	('BRAF', 'Gene', '673', (323, 327))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('patients', 'Species', '9606', (146, 154))	('BRAF', 'Gene', (323, 327))	('V600E', 'SUBSTITUTION', 'None', (395, 400))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('V600E', 'Var', (328, 333))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('BRAF', 'Gene', '673', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (431, 439))	('BRAF', 'Gene', (19, 23))	('melanoma', 'Disease', (431, 439))	('trametinib', 'Chemical', 'MESH:C560077', (271, 281))	('BRAF', 'Gene', '673', (390, 394))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('patients', 'Species', '9606', (309, 317))	('men', 'Species', '9606', (68, 71))	('men', 'Species', '9606', (11, 14))
32079	29399853	All of the patients enrolled in this study are patients with V600E mutation-positive malignant melanoma, and clinical data from V600K mutation-positive malignant melanoma patients were not obtained.	('malignant melanoma', 'Disease', (152, 170))	('malignant melanoma', 'Disease', 'MESH:D008545', (85, 103))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('malignant melanoma', 'Disease', (85, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('patients', 'Species', '9606', (47, 55))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('patients', 'Species', '9606', (171, 179))	('malignant melanoma', 'Phenotype', 'HP:0002861', (152, 170))	('V600K', 'Mutation', 'rs121913227', (128, 133))	('V600E', 'Var', (61, 66))	('malignant melanoma', 'Phenotype', 'HP:0002861', (85, 103))	('patients', 'Species', '9606', (11, 19))	('malignant melanoma', 'Disease', 'MESH:D008545', (152, 170))
32080	29399853	Therefore, moving forward, clinical data needs to be accumulated to evaluate efficacy in Japanese patients with V600K mutation-positive malignant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('malignant melanoma', 'Disease', 'MESH:D008545', (136, 154))	('malignant melanoma', 'Disease', (136, 154))	('patients', 'Species', '9606', (98, 106))	('V600K', 'Var', (112, 117))	('malignant melanoma', 'Phenotype', 'HP:0002861', (136, 154))	('V600K', 'Mutation', 'rs121913227', (112, 117))
32083	29399853	in patients with V600E or V600K mutation-positive advanced solid cancer, dabrafenib seemed to be rapidly absorbed.	('dabrafenib', 'Chemical', 'MESH:C561627', (73, 83))	('V600E', 'Var', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('V600K', 'Var', (26, 31))	('patients', 'Species', '9606', (3, 11))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('cancer', 'Disease', (65, 71))	('V600K', 'Mutation', 'rs121913227', (26, 31))
32090	29399853	In conclusion, the safety, efficacy and PK of this combination therapy in Japanese patients with unresectable or metastatic BRAF mutation-positive cutaneous malignant melanoma could be analogically inferred from the global clinical study results.	('malignant melanoma', 'Phenotype', 'HP:0002861', (157, 175))	('mutation-positive', 'Var', (129, 146))	('BRAF', 'Gene', (124, 128))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (147, 175))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('patients', 'Species', '9606', (83, 91))	('BRAF', 'Gene', '673', (124, 128))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (147, 175))	('cutaneous malignant melanoma', 'Disease', (147, 175))
32112	33256089	UV signatures were detected in cutaneous melanoma, and consist of C > T transitions at dipyrimidine sites and CC > TT or (C/T)C > (C/T)T mutations.	('cutaneous melanoma', 'Disease', (31, 49))	('C > T transitions', 'Var', (66, 83))	('CC > TT', 'Var', (110, 117))	('C/T)C > (C/T)T mutations', 'Var', (122, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('dipyrimidine', 'Chemical', '-', (87, 99))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))
32114	33256089	Melanoma is a disease of old age and the stochastic accumulation of mutations within melanocytes either inherited or acquired, result in melanocyte transformation into melanoma.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('result in', 'Reg', (127, 136))	('mutations', 'Var', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanocyte transformation', 'CPA', (137, 162))
32139	33256089	The genetic abnormalities commonly associated with these two subtypes of cutaneous melanoma are neurofibromin 1 (NF1), NRAS, BRAF non-V600E mutations, or KIT in CSID, while non-CSID is associated with BRAF V600E mutations, suggesting that the non-CSID might originate from nevi (Figure 1).	('cutaneous melanoma', 'Disease', (73, 91))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('KIT', 'Gene', (154, 157))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('NRAS', 'Gene', (119, 123))	('non-V600E mutations', 'Var', (130, 149))	('BRAF', 'Gene', (125, 129))	('KIT', 'Gene', '3815', (154, 157))	('genetic abnormalities', 'Disease', 'MESH:D030342', (4, 25))	('BRAF', 'Var', (201, 205))	('genetic abnormalities', 'Disease', (4, 25))	('NF1', 'Gene', '4763', (113, 116))	('nevi', 'Phenotype', 'HP:0003764', (273, 277))	('neurofibromin 1', 'Gene', '4763', (96, 111))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('KIT', 'molecular_function', 'GO:0005020', ('154', '157'))	('associated', 'Reg', (35, 45))	('neurofibromin 1', 'Gene', (96, 111))	('NF1', 'Gene', (113, 116))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('NRAS', 'Gene', '4893', (119, 123))	('V600E', 'Mutation', 'rs113488022', (206, 211))
32141	33256089	The BRAF subtype is characterized by the presence of BRAF hot-spot mutations (V600E, V600K, V600R, and K601E) and is mutually exclusive with NRAS hot spot mutations.	('K601E', 'Var', (103, 108))	('V600K', 'Mutation', 'rs121913227', (85, 90))	('NRAS', 'Gene', '4893', (141, 145))	('BRAF', 'Gene', (53, 57))	('V600R', 'Mutation', 'rs121913227', (92, 97))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('BRAF', 'Disease', (4, 8))	('V600K', 'Var', (85, 90))	('V600E', 'Var', (78, 83))	('V600R', 'Var', (92, 97))	('K601E', 'Mutation', 'rs121913364', (103, 108))	('NRAS', 'Gene', (141, 145))
32142	33256089	Additionally, non-hotspot mutations in BRAF occurred together with N/H/K-RAS hotspot mutations and NF1 mutations.	('mutations', 'Var', (103, 112))	('BRAF', 'Gene', (39, 43))	('NF1', 'Gene', (99, 102))	('NF1', 'Gene', '4763', (99, 102))	('K-RAS', 'Gene', '3845', (71, 76))	('K-RAS', 'Gene', (71, 76))
32143	33256089	Hot-spot mutations in BRAF and N/H/K-RAS show increased MAPK and PI3K/AKT signaling cascade activation.	('AKT', 'Gene', '207', (70, 73))	('activation', 'PosReg', (92, 102))	('K-RAS', 'Gene', '3845', (35, 40))	('increased', 'PosReg', (46, 55))	('mutations', 'Var', (9, 18))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('AKT signaling cascade', 'biological_process', 'GO:0043491', ('70', '91'))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('AKT', 'Gene', (70, 73))	('K-RAS', 'Gene', (35, 40))	('BRAF', 'Gene', (22, 26))
32144	33256089	NF1 mutations are detected in 15% of melanoma and the majority of them are from older patients with a higher mutational burden.	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))	('patients', 'Species', '9606', (86, 94))
32145	33256089	More than half of the NF1 mutations are associated with a loss of function.	('mutations', 'Var', (26, 35))	('NF1', 'Gene', (22, 25))	('NF1', 'Gene', '4763', (22, 25))	('loss of function', 'NegReg', (58, 74))
32146	33256089	Mutations in NF1 also lead to the activation of the MAPK pathway.	('MAPK pathway', 'Pathway', (52, 64))	('NF1', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', '4763', (13, 16))	('MAPK', 'molecular_function', 'GO:0004707', ('52', '56'))	('activation', 'PosReg', (34, 44))
32156	33256089	Common mutations found in uveal melanoma include CYSLTR2, PLCB4, and GNAQ/GNA11; all promote activation of the MAPK and PI3K/AKT signaling cascades (Figure 1).	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('GNA11', 'Gene', '2767', (74, 79))	('GNAQ', 'Gene', '2776', (69, 73))	('PLCB4', 'Gene', '5332', (58, 63))	('GNAQ', 'Gene', (69, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('AKT signaling', 'biological_process', 'GO:0043491', ('125', '138'))	('AKT', 'Gene', (125, 128))	('uveal melanoma', 'Disease', (26, 40))	('uveal melanoma', 'Disease', 'MESH:C536494', (26, 40))	('mutations', 'Var', (7, 16))	('GNA11', 'Gene', (74, 79))	('CYSLTR2', 'Gene', '57105', (49, 56))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('promote activation', 'PosReg', (85, 103))	('uveal melanoma', 'Phenotype', 'HP:0007716', (26, 40))	('PLCB4', 'Gene', (58, 63))	('AKT', 'Gene', '207', (125, 128))	('CYSLTR2', 'Gene', (49, 56))
32157	33256089	Activating mutations in GNAQ/GNA11 also lead to activation of several transcriptional factors associated with RNA splicing, DNA damage response, and cellular proliferation.	('GNA11', 'Gene', (29, 34))	('mutations', 'Var', (11, 20))	('GNAQ', 'Gene', '2776', (24, 28))	('GNA11', 'Gene', '2767', (29, 34))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('GNAQ', 'Gene', (24, 28))	('RNA splicing', 'biological_process', 'GO:0008380', ('110', '122'))	('transcriptional factors', 'MPA', (70, 93))	('DNA damage response', 'biological_process', 'GO:0006974', ('124', '143'))	('activation', 'PosReg', (48, 58))
32162	33256089	Amplification or deletion of many genes is a common carcinogenic process involved in acral melanoma.	('acral melanoma', 'Disease', 'MESH:D008545', (85, 99))	('Amplification', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('acral melanoma', 'Phenotype', 'HP:0012060', (85, 99))	('carcinogenic', 'Disease', 'MESH:D063646', (52, 64))	('acral melanoma', 'Disease', (85, 99))	('carcinogenic', 'Disease', (52, 64))
32163	33256089	Genetic alterations commonly found within acral melanoma are correlated with the signaling pathways associated with cell cycle progression and cell growth.	('Genetic alterations', 'Var', (0, 19))	('signaling pathways', 'Pathway', (81, 99))	('cell growth', 'biological_process', 'GO:0016049', ('143', '154'))	('acral melanoma', 'Disease', 'MESH:D008545', (42, 56))	('signaling', 'biological_process', 'GO:0023052', ('81', '90'))	('correlated', 'Reg', (61, 71))	('acral melanoma', 'Phenotype', 'HP:0012060', (42, 56))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('acral melanoma', 'Disease', (42, 56))	('cell cycle', 'CPA', (116, 126))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
32164	33256089	Interestingly, like cutaneous melanoma, mutations in the TERT promoter and TERT amplification might upregulate telomerase activity in acral melanoma cells, allowing them to become replicative immortal (Figure 1).	('melanoma cells', 'Disease', (140, 154))	('mutations', 'Var', (40, 49))	('acral melanoma', 'Disease', (134, 148))	('telomerase activity', 'molecular_function', 'GO:0003720', ('111', '130'))	('cutaneous melanoma', 'Disease', (20, 38))	('upregulate', 'PosReg', (100, 110))	('telomerase', 'Enzyme', (111, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (20, 38))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 38))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma cells', 'Disease', 'MESH:D008545', (140, 154))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('acral melanoma', 'Disease', 'MESH:D008545', (134, 148))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', '7015', (57, 61))	('acral melanoma', 'Phenotype', 'HP:0012060', (134, 148))	('activity', 'MPA', (122, 130))
32167	33256089	Similar to other non-cutaneous melanoma subtypes, mucosal melanoma is characterized by a low mutational burden (2.64 mutations per Mb compared to cutaneous melanoma with 49.17 mutations per Mb), high copy number variations, and increased chromosomal structural variations.	('mucosal melanoma', 'Disease', 'MESH:D008545', (50, 66))	('mutations', 'Var', (117, 126))	('cutaneous melanoma', 'Disease', (21, 39))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (21, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (21, 39))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('cutaneous melanoma', 'Disease', (146, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('high', 'Var', (195, 199))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (146, 164))	('mucosal melanoma', 'Disease', (50, 66))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
32171	33256089	identified mutations that were not previously identified in mucosal melanoma: MUC2, UBE4A, PTPRT, NRK, NALCN, MUC4, MAP4K4, LRRC7, LRP1B, FURIN, CNBD1, CDH13, CACNA1C, AHNAK, ABH1B, KIR2DL1, MGAM, and SELPLG.	('mutations', 'Var', (11, 20))	('MAP4K4', 'Gene', (116, 122))	('FURIN', 'Gene', '5045', (138, 143))	('KIR2DL1', 'Gene', (182, 189))	('NRK', 'Gene', '203447', (98, 101))	('SELPLG', 'Gene', '6404', (201, 207))	('MUC2', 'Gene', '4583', (78, 82))	('CDH13', 'Gene', (152, 157))	('CACNA1C', 'Gene', '775', (159, 166))	('PTPRT', 'Gene', (91, 96))	('LRRC7', 'Gene', (124, 129))	('LRRC7', 'Gene', '57554', (124, 129))	('LRP1B', 'Gene', (131, 136))	('MAP', 'molecular_function', 'GO:0004239', ('116', '119'))	('MUC2', 'Gene', (78, 82))	('NALCN', 'Gene', (103, 108))	('MGAM', 'Gene', '8972', (191, 195))	('CNBD1', 'Gene', '168975', (145, 150))	('NALCN', 'Gene', '259232', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('CACNA1C', 'Gene', (159, 166))	('UBE4A', 'Gene', (84, 89))	('SELPLG', 'Gene', (201, 207))	('AHNAK', 'Gene', '79026', (168, 173))	('UBE4A', 'Gene', '9354', (84, 89))	('FURIN', 'Gene', (138, 143))	('CNBD1', 'Gene', (145, 150))	('MGAM', 'Gene', (191, 195))	('MUC4', 'Gene', '4585', (110, 114))	('mucosal melanoma', 'Disease', 'MESH:D008545', (60, 76))	('MAP4K4', 'Gene', '9448', (116, 122))	('LRP1B', 'Gene', '53353', (131, 136))	('PTPRT', 'Gene', '11122', (91, 96))	('KIR2DL1', 'Gene', '3802', (182, 189))	('MUC4', 'Gene', (110, 114))	('CDH13', 'Gene', '1012', (152, 157))	('AHNAK', 'Gene', (168, 173))	('ABH1B', 'Gene', (175, 180))	('NRK', 'Gene', (98, 101))	('mucosal melanoma', 'Disease', (60, 76))
32175	33256089	In the course of constructing transgenic mice with a fragment of genomic DNA (Clone B), which demonstrated adipocyte differentiation in vitro, resulted in concomitant deletion of 70 kb of host DNA and insertion of Clone B.	('adipocyte', 'MPA', (107, 116))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('adipocyte differentiation', 'biological_process', 'GO:0045444', ('107', '132'))	('transgenic mice', 'Species', '10090', (30, 45))	('deletion', 'Var', (167, 175))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('insertion', 'Var', (201, 210))	('men', 'Species', '9606', (57, 60))	('host DNA', 'Gene', (188, 196))
32179	33256089	To confirm that the aberrant mGluR1 expression in melanocytes drives the tumor phenotype, a second transgenic line was made with GRM1 cDNA, under a melanocyte-specific promoter, dopachrome tautomerase (DCT).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('drives', 'Reg', (62, 68))	('aberrant', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('DC', 'Gene', '13179', (202, 204))	('dopachrome tautomerase', 'Gene', '13190', (178, 200))	('transgenic', 'Species', '10090', (99, 109))	('tumor', 'Disease', (73, 78))	('dopachrome tautomerase', 'Gene', (178, 200))	('mGluR1', 'Gene', (29, 35))
32180	33256089	This second transgenic line displays similar tumor onset and progression as the first one, confirming that the aberrant expression of mGluR1 in melanocytes was sufficient to promote melanocyte hyperplasia and transformation into malignant melanoma, similar to human melanoma development.	('transgenic', 'Species', '10090', (12, 22))	('tumor', 'Disease', (45, 50))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('men', 'Species', '9606', (282, 285))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('mGluR1', 'Gene', (134, 140))	('malignant melanoma', 'Disease', (229, 247))	('promote', 'PosReg', (174, 181))	('aberrant', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('malignant melanoma', 'Phenotype', 'HP:0002861', (229, 247))	('transformation', 'CPA', (209, 223))	('human', 'Species', '9606', (260, 265))	('malignant melanoma', 'Disease', 'MESH:D008545', (229, 247))	('hyperplasia', 'Disease', (193, 204))	('hyperplasia', 'Disease', 'MESH:D006965', (193, 204))
32200	33256089	Chemotherapy induces mitotic catastrophe in cancer cells and if not repaired rapidly, it can induce apoptosis or necrosis, depending on the extent of the damage.	('necrosis', 'Disease', 'MESH:D009336', (113, 121))	('necrosis', 'biological_process', 'GO:0070265', ('113', '121'))	('necrosis', 'biological_process', 'GO:0019835', ('113', '121'))	('induces', 'Reg', (13, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('necrosis', 'biological_process', 'GO:0008220', ('113', '121'))	('induce', 'Reg', (93, 99))	('mitotic catastrophe', 'CPA', (21, 40))	('necrosis', 'biological_process', 'GO:0001906', ('113', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('Chemotherapy', 'Var', (0, 12))	('necrosis', 'Disease', (113, 121))	('necrosis', 'biological_process', 'GO:0008219', ('113', '121'))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('21', '40'))	('apoptosis', 'CPA', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
32206	33256089	In 2011, the FDA approved the first in-class targeted therapy for melanoma, vemurafenib.. Vemurafenib was specifically approved for melanomas with BRAF V600E-activating mutation, this agent inhibits the kinase activity that is responsible for hyperactivating the MAPK pathway.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('inhibits', 'NegReg', (190, 198))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('melanomas', 'Disease', (132, 141))	('BRAF V600E-activating mutation', 'Var', (147, 177))	('MAPK pathway', 'Pathway', (263, 275))	('MAPK', 'molecular_function', 'GO:0004707', ('263', '267'))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('kinase activity', 'MPA', (203, 218))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Disease', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('kinase activity', 'molecular_function', 'GO:0016301', ('203', '218'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (76, 87))	('hyperactivating', 'PosReg', (243, 258))
32209	33256089	Dabrafenib is approved for melanoma tumors with BRAF V600E/K mutations.	('melanoma tumors', 'Disease', 'MESH:D008545', (27, 42))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF V600E/K', 'Var', (48, 60))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('melanoma tumors', 'Disease', (27, 42))
32211	33256089	The mutated BRAF melanomas had a 33% response while the wild-type BRAF tumors only had a 10% response.	('mutated', 'Var', (4, 11))	('BRAF melanomas', 'Disease', (12, 26))	('BRAF tumors', 'Disease', 'MESH:D009369', (66, 77))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('BRAF tumors', 'Disease', (66, 77))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('BRAF melanomas', 'Disease', 'MESH:D008545', (12, 26))
32212	33256089	In 2012, the FDA approved trametinib for mutated BRAF melanoma, based on the improved patient survival in the trametinib arm, compared to the standard of care.	('BRAF melanoma', 'Disease', (49, 62))	('mutated', 'Var', (41, 48))	('trametinib', 'Chemical', 'MESH:C560077', (26, 36))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('patient', 'Species', '9606', (86, 93))	('trametinib', 'Chemical', 'MESH:C560077', (110, 120))	('BRAF melanoma', 'Disease', 'MESH:D008545', (49, 62))	('improved', 'PosReg', (77, 85))
32213	33256089	Evidence suggests that in patients with mutated BRAF, the combination of BRAF and MEK inhibitors yields greater benefit and prolongs the development of resistance.	('BRAF', 'Gene', (73, 77))	('men', 'Species', '9606', (144, 147))	('MEK', 'Gene', '5609', (82, 85))	('patients', 'Species', '9606', (26, 34))	('mutated', 'Var', (40, 47))	('development of resistance', 'MPA', (137, 162))	('prolongs', 'NegReg', (124, 132))	('BRAF', 'Gene', (48, 52))	('MEK', 'Gene', (82, 85))
32217	33256089	A small subset of melanoma patients have DNA alterations in KIT that manifest as point mutations and amplifications in less than 7% of cutaneous melanoma patients, and in approximately 40% of mucosal and acral melanoma patients.	('acral melanoma', 'Phenotype', 'HP:0012060', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('cutaneous melanoma', 'Disease', (135, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('KIT', 'Gene', (60, 63))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('amplifications', 'MPA', (101, 115))	('patients', 'Species', '9606', (27, 35))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('patients', 'Species', '9606', (219, 227))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('point mutations', 'Var', (81, 96))	('acral melanoma', 'Disease', (204, 218))	('KIT', 'Gene', '3815', (60, 63))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('patients', 'Species', '9606', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('acral melanoma', 'Disease', 'MESH:D008545', (204, 218))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
32218	33256089	KIT, a tyrosine kinase, when stimulated by binding of stem cell factor (SCF) or when mutated, activates the MAPK and PI3K/AKT pathway.	('binding', 'Interaction', (43, 50))	('stimulated', 'PosReg', (29, 39))	('activates', 'PosReg', (94, 103))	('SCF', 'Gene', (72, 75))	('SCF', 'Gene', '4254', (72, 75))	('stem cell factor', 'Gene', (54, 70))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('stem cell factor', 'Gene', '4254', (54, 70))	('stem cell factor', 'molecular_function', 'GO:0005173', ('54', '70'))	('binding', 'molecular_function', 'GO:0005488', ('43', '50'))	('KIT', 'Gene', '3815', (0, 3))	('AKT', 'Gene', '207', (122, 125))	('mutated', 'Var', (85, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('SCF', 'molecular_function', 'GO:0005173', ('72', '75'))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('KIT', 'Gene', (0, 3))	('AKT', 'Gene', (122, 125))
32232	33256089	In cancer, the interactions between PD-1 on cytotoxic T-lymphocytes and PD-L1 on tumor cells or tumor macrophages, NK cells, dendritic cells, and various other immune cells, result in an exhausted T-cell phenotype, rendering the immune system unable to detect and eliminate tumors via epigenetic changes within T-cells (Figure 3).	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (274, 279))	('PD-L1', 'Gene', (72, 77))	('T-cell phenotype', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic changes', 'Var', (285, 303))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('interactions', 'Interaction', (15, 27))	('tumors', 'Disease', (274, 280))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('PD-1', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
32237	33256089	Furthermore, glycosylation in PD-L1 was shown to improve the half-life of PD-L1, and strengthen its engagement with PD-1, thereby improving its ability to exhaust T-cells.	('strengthen', 'PosReg', (85, 95))	('PD-L1', 'Gene', (74, 79))	('glycosylation', 'Var', (13, 26))	('engagement', 'Interaction', (100, 110))	('PD-L1', 'Gene', (30, 35))	('improving', 'PosReg', (130, 139))	('glycosylation', 'biological_process', 'GO:0070085', ('13', '26'))	('improve', 'PosReg', (49, 56))	('men', 'Species', '9606', (106, 109))	('half-life', 'MPA', (61, 70))	('exhaust T-cells', 'MPA', (155, 170))	('PD-1', 'Protein', (116, 120))
32242	33256089	However, in the context of cancer, when PD-L1/PD-L2 interact with PD-1 on cytotoxic T-cells, it leads to SHP1/2 recruitment to the TCR and modulates numerous phosphorylation activities, resulting in defective cytolytic T-cell function and metabolism.	('cytolytic T-cell function', 'CPA', (209, 234))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('phosphorylation', 'biological_process', 'GO:0016310', ('158', '173'))	('leads to', 'Reg', (96, 104))	('phosphorylation activities', 'MPA', (158, 184))	('interact', 'Interaction', (52, 60))	('metabolism', 'biological_process', 'GO:0008152', ('239', '249'))	('TCR', 'biological_process', 'GO:0006283', ('131', '134'))	('SHP1/2', 'Gene', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (27, 33))	('PD-L1/PD-L2', 'Var', (40, 51))	('defective', 'NegReg', (199, 208))	('recruitment', 'MPA', (112, 123))	('modulates', 'Reg', (139, 148))	('men', 'Species', '9606', (119, 122))	('metabolism', 'CPA', (239, 249))	('TCR', 'cellular_component', 'GO:0042101', ('131', '134'))
32244	33256089	Disruption between PD-1 and one or more of these molecules result in defective development of cytotoxic memory T-cells and exhaustion of CD8+ T cells.	('men', 'Species', '9606', (86, 89))	('CD8', 'Gene', (137, 140))	('cytotoxic memory T', 'Disease', (94, 112))	('CD8', 'Gene', '925', (137, 140))	('cytotoxic memory T', 'Disease', 'MESH:D064420', (94, 112))	('memory', 'biological_process', 'GO:0007613', ('104', '110'))	('mole', 'Phenotype', 'HP:0003764', (49, 53))	('defective', 'NegReg', (69, 78))	('PD-1', 'Gene', (19, 23))	('Disruption', 'Var', (0, 10))
32259	33256089	MDSCs are critical in cancer progression, as they support tumor cell dissemination, and inhibit T-cell function.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('MDSCs', 'Var', (0, 5))	('support', 'PosReg', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('T-cell function', 'CPA', (96, 111))	('inhibit', 'NegReg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
32261	33256089	MDSCs reduce cytotoxic T-cell function in the tumor microenvironment by disrupting key metabolic pathways required for proper T cell function, which eventually result in T-cell apoptosis.	('MDSCs', 'Var', (0, 5))	('T-cell apoptosis', 'CPA', (170, 186))	('result in', 'Reg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('key metabolic', 'MPA', (83, 96))	('cytotoxic T-cell function', 'CPA', (13, 38))	('reduce', 'NegReg', (6, 12))	('disrupting', 'NegReg', (72, 82))	('men', 'Species', '9606', (64, 67))	('T-cell apoptosis', 'biological_process', 'GO:0070231', ('170', '186'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
32262	33256089	Depletion of MDSCs might improve anti-melanoma immunity, since MDSCs were shown to negative correlate with survival.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('MDSCs', 'Gene', (13, 18))	('improve', 'PosReg', (25, 32))	('Depletion', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
32291	33256089	During genetic/epigenetic changes or immune editing, melanoma subclones can successfully downregulate key components of their MHC I antigen presentation pathways, and effectively escape immune surveillance (Figure 3).	('escape', 'Reg', (179, 185))	('antigen presentation', 'biological_process', 'GO:0019882', ('132', '152'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('immune editing', 'Var', (37, 51))	('downregulate', 'NegReg', (89, 101))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('MHC I antigen presentation pathways', 'Pathway', (126, 161))	('immune', 'MPA', (186, 192))	('genetic/epigenetic changes', 'Var', (7, 33))
32296	33256089	Our lab developed various spontaneous melanoma-prone mouse models, driven by aberrant mGluR1 expression in melanocytes, which mimic melanoma development and progression in humans.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('men', 'Species', '9606', (148, 151))	('mGluR1', 'Gene', (86, 92))	('humans', 'Species', '9606', (172, 178))	('mouse', 'Species', '10090', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('aberrant', 'Var', (77, 85))
32305	33256089	UV-induced accumulation of stochastic mutations in melanocytes leads to cell transformation and tumor formation.	('cell transformation', 'CPA', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('leads to', 'Reg', (63, 71))	('tumor', 'Disease', (96, 101))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('stochastic mutations', 'Var', (27, 47))
32324	33256089	MiR-125b-5p detected in the melanoma exosome cargo can induce TAM formation, to support melanoma growth.	('MiR-125b-5p', 'Var', (0, 11))	('melanoma growth', 'Disease', (88, 103))	('melanoma', 'Disease', (28, 36))	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('support', 'PosReg', (80, 87))	('melanoma growth', 'Disease', 'MESH:D008545', (88, 103))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('exosome', 'cellular_component', 'GO:0070062', ('37', '44'))	('cargo', 'molecular_function', 'GO:0140355', ('45', '50'))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('TAM', 'Chemical', '-', (62, 65))	('MiR-125b-5p', 'Chemical', '-', (0, 11))	('induce', 'PosReg', (55, 61))	('TAM formation', 'CPA', (62, 75))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
32327	33256089	Our lab demonstrated that inhibition of mGluR1 expression or function by genetic or pharmacological inhibitors in melanoma cells, did not modulate the number of exosomes released, but rather reduced the functions of the exosomes on the recipient cells in cell migration, invasion, and anchorage-independent growth, perhaps through cargo sorting into exosomes.	('mGluR1', 'Gene', (40, 46))	('melanoma cells', 'Disease', 'MESH:D008545', (114, 128))	('cell migration', 'CPA', (255, 269))	('melanoma cells', 'Disease', (114, 128))	('cell migration', 'biological_process', 'GO:0016477', ('255', '269'))	('inhibition', 'Var', (26, 36))	('reduced', 'NegReg', (191, 198))	('invasion', 'CPA', (271, 279))	('cargo', 'molecular_function', 'GO:0140355', ('331', '336'))	('anchorage-independent growth', 'CPA', (285, 313))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('functions', 'MPA', (203, 212))
32347	33256089	The triple combination of atezolizumab, vemurafenib (BRAF V600E inhibitor), and cobimetnib (MEK inhibitor) was approved by the FDA as a first line therapy for BRAF V600 unresectable or metastatic melanoma.	('MEK', 'Gene', (92, 95))	('MEK', 'Gene', '5609', (92, 95))	('atezolizumab', 'Chemical', 'MESH:C000594389', (26, 38))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('BRAF V600', 'Var', (159, 168))	('melanoma', 'Disease', (196, 204))	('V600E', 'Mutation', 'rs113488022', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('vemurafenib', 'Chemical', 'MESH:D000077484', (40, 51))	('cobimetnib', 'Chemical', '-', (80, 90))	('metastatic', 'CPA', (185, 195))
32352	33256089	PD-1 antibodies show response rates in the range of 30%-40% which are higher than ipilimumab and showed improved overall survival.	('ipilimumab', 'Chemical', 'MESH:D000074324', (82, 92))	('improved', 'PosReg', (104, 112))	('antibodies', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))
32356	33256089	Furthermore, detailed characterization of melanoma patients who are sensitive to immune checkpoint therapy would improve response rates and survival outcomes for future patients, given anti-CTLA-4/anti-PD-1/anti-PD-L1 antibodies.	('melanoma', 'Disease', (42, 50))	('patients', 'Species', '9606', (169, 177))	('response rates', 'CPA', (121, 135))	('anti-CTLA-4/anti-PD-1/anti-PD-L1', 'Var', (185, 217))	('patients', 'Species', '9606', (51, 59))	('survival outcomes', 'CPA', (140, 157))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('improve', 'PosReg', (113, 120))
32377	33256089	Genomic instability is associated with treatment responses to anti-PD-1/anti-PD-L1 antibodies in melanoma (and other cancers), specifically by examining the tumor mutational burden.	('tumor', 'Disease', (157, 162))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('men', 'Species', '9606', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Genomic instability', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('anti-PD-1/anti-PD-L1', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('associated', 'Reg', (23, 33))	('cancers', 'Disease', (117, 124))
32378	33256089	This concept revolves around the fact that these tumors have a higher mutation rate that increases their likelihood of presenting neoepitopes for surveying immune cells, to recognize and mount an anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('presenting neoepitopes for surveying immune cells', 'MPA', (119, 168))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('immune response', 'biological_process', 'GO:0006955', ('207', '222'))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (201, 206))	('mutation', 'Var', (70, 78))	('increases', 'PosReg', (89, 98))
32380	33256089	proposed that if there are specific mutations that make a tumor more responsive to immune checkpoint therapy, "immune checkpoint activating mutation threshold (iCAM)".	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('activating', 'PosReg', (129, 139))
32392	33256089	Similar results were observed when the patients were stratified based on the PD-L1 positivity of their tumors, high tumor mutational burden or high T-cell inflamed gene expression profiles showed improved responses and survival.	('responses', 'CPA', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('survival', 'CPA', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('tumor', 'Disease', (116, 121))	('improved', 'PosReg', (196, 204))	('high', 'Var', (111, 115))
32396	33256089	These subtypes can be divided into cutaneous melanoma; CSID and non-CSID with a higher mutational burden, as compared to non-cutaneous melanoma that include acral, mucosal, and uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('cutaneous melanoma', 'Disease', (125, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('mutational', 'Var', (87, 97))	('cutaneous melanoma', 'Disease', (35, 53))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (35, 53))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (35, 53))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('uveal melanoma', 'Disease', (177, 191))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
32419	33256089	CAR T cell therapy was shown to be remarkably successful in treating patients with B-cell malignancies, however, for solid tumors like melanoma, it was met with low response rates (19% for CARs targeting gp100 and 30% for CARs targeting DMF5), and the toxicities associated with the destruction of normal melanocytes.	('CARs', 'Gene', '833', (189, 193))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('patients', 'Species', '9606', (69, 77))	('malignancies', 'Disease', (90, 102))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('solid tumors like melanoma', 'Disease', (117, 143))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('CAR', 'Gene', (0, 3))	('CAR', 'Gene', '9970', (0, 3))	('solid tumors like melanoma', 'Disease', 'MESH:D008545', (117, 143))	('toxicities', 'Disease', 'MESH:D064420', (252, 262))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('CAR', 'Gene', (222, 225))	('gp100', 'Gene', (204, 209))	('CAR', 'Gene', '9970', (222, 225))	('CARs', 'Gene', (222, 226))	('gp100', 'Gene', '6490', (204, 209))	('CAR', 'cellular_component', 'GO:0005826', ('0', '3'))	('toxicities', 'Disease', (252, 262))	('CAR', 'Gene', (189, 192))	('CARs', 'Gene', (189, 193))	('CAR', 'Gene', '9970', (189, 192))	('DMF5', 'Var', (237, 241))	('CARs', 'Gene', '833', (222, 226))
32432	33256089	Preclinical studies suggest that oncolytic viruses can induce an abscopal-like effect; with tumor regression occurring at the site of injection, and induction of a systemic anti-tumor immune response that affects distant tumors.	('tumor', 'Disease', (178, 183))	('abscopal-like effect', 'Disease', (65, 85))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('immune response', 'biological_process', 'GO:0006955', ('184', '199'))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('oncolytic viruses', 'Var', (33, 50))	('tumors', 'Disease', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
32441	33256089	The rationale for combining these two immune checkpoint blockade therapies is to expand anti-tumor cytotoxic T-cells within the lymph nodes through anti-CTLA-4 treatment, and anti-PD-1 releases the "breaks" of these effector T-cells at the tumor site to overcome the immune suppressive environment created by tumor cells (Figure 7).	('men', 'Species', '9606', (165, 168))	('tumor', 'Disease', (309, 314))	('expand', 'PosReg', (81, 87))	('tumor', 'Disease', (240, 245))	('tumor cytotoxic', 'Disease', (93, 108))	('tumor cytotoxic', 'Disease', 'MESH:D064420', (93, 108))	('men', 'Species', '9606', (293, 296))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('anti-PD-1', 'Var', (175, 184))
32447	33256089	Similarly, the rational of sequential administration of T-VEC, anti-CTLA-4, and anti-PD-1, radiation therapy could be given first to promote tumor necrosis, and to induce an anti-tumor adaptive immune response.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor necrosis', 'Disease', 'MESH:D009336', (141, 155))	('adaptive immune response', 'biological_process', 'GO:0002250', ('185', '209'))	('induce', 'Reg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('necrosis', 'biological_process', 'GO:0070265', ('147', '155'))	('promote', 'PosReg', (133, 140))	('necrosis', 'biological_process', 'GO:0008219', ('147', '155'))	('necrosis', 'biological_process', 'GO:0019835', ('147', '155'))	('tumor', 'Disease', (141, 146))	('anti-CTLA-4', 'Var', (63, 74))	('necrosis', 'biological_process', 'GO:0008220', ('147', '155'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('anti-PD-1', 'Var', (80, 89))	('tumor necrosis', 'Disease', (141, 155))	('necrosis', 'biological_process', 'GO:0001906', ('147', '155'))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
32450	33256089	Preclinical evidence suggest that adoptive T-cell transfer along with the dual treatment of anti-CTLA-4 and anti-PD-1, can improve tumor-antigen-specific cytotoxic T-cell infiltration and function within the tumor site, corresponding to the improved survival in experimental animal models (Figure 7).	('tumor-antigen', 'molecular_function', 'GO:0008222', ('131', '144'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('function within the', 'CPA', (188, 207))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('improved', 'PosReg', (241, 249))	('anti-CTLA-4', 'Gene', (92, 103))	('improve', 'PosReg', (123, 130))	('adoptive T-cell transfer', 'CPA', (34, 58))	('men', 'Species', '9606', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (131, 136))	('anti-PD-1', 'Var', (108, 117))	('men', 'Species', '9606', (84, 87))	('tumor', 'Disease', (208, 213))
32454	33256089	Interestingly, vemurafenib, the inhibitor for mutated BRAF, paradoxically activates the MAPK pathway in adoptively transferred T-cells in a mutant BRAF-driven mouse melanoma model.	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('BRAF', 'Gene', (54, 58))	('activates', 'PosReg', (74, 83))	('mouse', 'Species', '10090', (159, 164))	('mutated', 'Var', (46, 53))	('MAPK pathway', 'Pathway', (88, 100))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('vemurafenib', 'Chemical', 'MESH:D000077484', (15, 26))	('melanoma', 'Disease', (165, 173))	('mutant', 'Var', (140, 146))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
32455	33256089	In this model, the inhibitor, vemurafenib, acts within its canonical function to inhibit mutant BRAF in melanoma cells but also paradoxically activates the MAPK pathway in T-cells to enhance the anti-tumor cytotoxic function of the tumor recognizing T-cells.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('activates', 'PosReg', (142, 151))	('MAPK', 'molecular_function', 'GO:0004707', ('156', '160'))	('mutant', 'Var', (89, 95))	('melanoma cells', 'Disease', 'MESH:D008545', (104, 118))	('tumor cytotoxic', 'Disease', 'MESH:D064420', (200, 215))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('vemurafenib', 'Chemical', 'MESH:D000077484', (30, 41))	('tumor cytotoxic', 'Disease', (200, 215))	('melanoma cells', 'Disease', (104, 118))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('inhibit', 'NegReg', (81, 88))	('MAPK pathway', 'Pathway', (156, 168))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('enhance', 'PosReg', (183, 190))	('BRAF', 'Gene', (96, 100))
32462	33256089	However, with the ongoing biomarker studies uncovering key molecular markers such as tumor mutational burden, molecular marker expression on tumor or immune cells, circulating soluble markers, and pro- or anti-tumor immune cell populations, at baseline or on treatment, would advance the identification of responders vs. non-responders.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (85, 90))	('advance', 'PosReg', (276, 283))	('men', 'Species', '9606', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (141, 146))	('mutational', 'Var', (91, 101))	('mole', 'Phenotype', 'HP:0003764', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('responders', 'Disease', (306, 316))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mole', 'Phenotype', 'HP:0003764', (110, 114))	('soluble', 'cellular_component', 'GO:0005625', ('176', '183'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
32488	31923345	Although these advances resulted in more refined diagnoses and classifications of glioma tumors, integrating histological and molecular information (e.g., IDH1/2 mutations and 1p/19q codeletion) (Louis et al., 2016), significant improvements in therapies that truly impact on patient outcomes are still lacking.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (162, 171))	('IDH1/2', 'Gene', (155, 161))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma tumors', 'Disease', (82, 95))	('glioma tumors', 'Disease', 'MESH:D005910', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patient', 'Species', '9606', (276, 283))
32490	31923345	Functionally, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, resistance to TMZ, and stemness capacity (Goncalves et al., 2018).	('resistance to TMZ', 'CPA', (116, 133))	('invasion', 'CPA', (95, 103))	('stemness capacity', 'CPA', (139, 156))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('GBM cell viability', 'CPA', (60, 78))	('increased', 'PosReg', (50, 59))	('proliferation', 'CPA', (80, 93))	('expression', 'Var', (19, 29))	('migration', 'CPA', (105, 114))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('WNT6', 'Gene', (14, 18))
32491	31923345	In vivo, WNT6 accelerated GBM-associated death in mice.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('WNT6', 'Var', (9, 13))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (14, 25))
32495	31923345	Agilent G4502A 244K data were used for LGG and GBM (WNT6 and HOXA9-high expression was considered when TCGA level 3 value >= 0 [GBM median value] or 3, respectively), while RNAseq data (Illumina HiSeq 2000 Sequencing System) were downloaded for all cancers (WNT6-high expression was considered when TCGA FPKM-UQ value >= 6800 [GBM median value]) (The Cancer Genome Atlas Research Network, 2008).	('G4502A', 'Var', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('cancers', 'Disease', (249, 256))	('Cancer', 'Disease', (351, 357))	('G4502A', 'SUBSTITUTION', 'None', (8, 14))	('Cancer', 'Disease', 'MESH:D009369', (351, 357))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('GBM', 'Phenotype', 'HP:0012174', (327, 330))
32529	31923345	The raw expression data profile (Agilent G4502A 244K) of all GBM patients from TCGA (n = 573) was used, employing a continuous phenotype profile to find gene sets from the MSigDb C6 collection that correlates with WNT6 (gene neighbors).	('G4502A', 'SUBSTITUTION', 'None', (41, 47))	('GBM', 'Phenotype', 'HP:0012174', (61, 64))	('GBM', 'Gene', (61, 64))	('patients', 'Species', '9606', (65, 73))	('G4502A', 'Var', (41, 47))
32530	31923345	For beta-catenin IF (610153; BD Transduction Laboratories, San Jose, CA, USA, 1 : 200), U87-MSCV and U87-HOXA9 cells plated on coverslips were fixed in 95% EtOH and 5% acetic acid (v/v), followed by incubation in 1% BSA in PBS-0.1% Tween for 1 h, and overnight at 4  C with the primary antibody.	('antibody', 'cellular_component', 'GO:0019815', ('286', '294'))	('610153;', 'Var', (21, 28))	('Transduction', 'biological_process', 'GO:0009293', ('32', '44'))	('antibody', 'cellular_component', 'GO:0019814', ('286', '294'))	('beta-catenin', 'Protein', (4, 16))	('EtOH', 'Chemical', 'MESH:D000431', (156, 160))	('acetic acid', 'Chemical', 'MESH:D019342', (168, 179))	('antibody', 'molecular_function', 'GO:0003823', ('286', '294'))	('PBS', 'Chemical', 'MESH:D007854', (223, 226))	('MSCV', 'Species', '258023', (92, 96))	('Tween', 'Chemical', 'MESH:D011136', (232, 237))	('antibody', 'cellular_component', 'GO:0042571', ('286', '294'))
32550	31923345	Together, these results show that high WNT6 expression associates with higher glioma grades independently of IDH mutation and 1p/19q codeletion status.	('higher', 'PosReg', (71, 77))	('IDH', 'Gene', '3417', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('WNT6', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('glioma', 'Disease', (78, 84))	('IDH', 'Gene', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
32551	31923345	To understand the mechanisms responsible for WNT6 overexpression in glioma, we started by investigating copy number alterations of the WNT6 locus in LGG (n = 509) and GBM (n = 565) patients from TCGA (Fig.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('WNT6', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('copy number alterations', 'Var', (104, 127))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (68, 74))
32559	31923345	Interestingly, looking for the 28 DNA methylation sites within the WNT6 locus, in 516 LGG and 141 GBM patients, we identified regions that are consistently hypomethylated (e.g., from the 4th probe [cg16256504] to the 8th probe [cg02175741]) or hypermethylated (e.g., 16th probe [cg05618201]) both in LGG and in GBM (Figs 2A and S2), showing a remarkable homogeneity of DNA methylation levels of these particular regions across very heterogeneous glioma samples of different grades.	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (446, 452))	('glioma', 'Phenotype', 'HP:0009733', (446, 452))	('[cg16256504]', 'Var', (197, 209))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('glioma', 'Disease', (446, 452))	('DNA methylation', 'biological_process', 'GO:0006306', ('369', '384'))	('DNA methylation', 'biological_process', 'GO:0006306', ('34', '49'))	('DNA', 'cellular_component', 'GO:0005574', ('369', '372'))	('[cg02175741]', 'Var', (227, 239))
32563	31923345	MSP analyses showed that five of the seven cell lines presented 5-Aza-mediated demethylation (A172, SNB19, KNS42, SW1783, and Res186; Fig.	('5-Aza', 'Chemical', 'MESH:D000077209', (64, 69))	('demethylation', 'biological_process', 'GO:0070988', ('79', '92'))	('A172', 'Var', (94, 98))	('SW1783', 'CellLine', 'CVCL:1722', (114, 120))	('SNB19', 'Var', (100, 105))	('SW1783', 'Var', (114, 120))	('5-Aza-mediated demethylation', 'MPA', (64, 92))
32564	31923345	Interestingly, 5-Aza treatment successfully increased WNT6 expression in four of these five cell lines (fold changes between 1.7 and 3.15; for KNS42, SW1783, A172, and Res186).	('WNT6 expression', 'MPA', (54, 69))	('increased', 'PosReg', (44, 53))	('5-Aza', 'Chemical', 'MESH:D000077209', (15, 20))	('SW1783', 'CellLine', 'CVCL:1722', (150, 156))	('SW1783', 'Var', (150, 156))
32573	31923345	Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6-associated genes in GBM patients (Goncalves et al., 2018), we found that WNT6-negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = -0.26 and false discovery rate, FDR = 0.18; Fig.	('knockdown', 'Var', (261, 270))	('GSEA', 'Chemical', '-', (31, 35))	('false', 'biological_process', 'GO:0071878', ('306', '311'))	('upregulated', 'PosReg', (224, 235))	('false', 'biological_process', 'GO:0071877', ('306', '311'))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('patients', 'Species', '9606', (118, 126))
32575	31923345	This association was not only observed in vitro but also in vivo, as U87+/-HOXA9 tumors grown subcutaneously in nude mice also showed significantly higher expression of WNT6 and beta-catenin (mainly in the nucleus) in HOXA9-positive tumors when compared to HOXA9-negative tumors (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('nude mice', 'Species', '10090', (112, 121))	('WNT6', 'Protein', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Protein', (178, 190))	('higher', 'PosReg', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('nucleus', 'cellular_component', 'GO:0005634', ('206', '213'))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('HOXA9-positive', 'Var', (218, 232))	('tumors', 'Disease', (272, 278))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
32576	31923345	In addition, cyclin D1, a known transcriptional target of the canonical WNT/beta-catenin pathway, was also upregulated in HOXA9-positive tumors when compared to negative tumors (Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin D1', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HOXA9-positive', 'Var', (122, 136))	('cyclin', 'molecular_function', 'GO:0016538', ('13', '19'))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cyclin D1', 'Gene', '595', (13, 22))	('upregulated', 'PosReg', (107, 118))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
32580	31923345	Thus, the clinical impact of WNT6 in GBM was evaluated using a multivariable Cox model to adjust to potential confounding effects of other putative prognostic factors, namely patient age, KPS, gender, therapy, IDH mutation status, and HOXA9 expression (Tables 2 and S2).	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (214, 222))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (175, 182))	('IDH', 'Gene', (210, 213))
32582	31923345	Importantly, IDHwt GBM patients with both WNT6-high and HOXA9-high expression presented a shorter OS (median OS = 290 days) when compared to all other patients (median OS = 425; log-rank P = 0.002; Fig.	('IDH', 'Gene', '3417', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (151, 159))	('HOXA9-high expression', 'Var', (56, 77))	('IDH', 'Gene', (13, 16))
32594	31923345	In contrast, our findings demonstrated that DNA methylation, a critical epigenetic mechanism, associates with WNT6 expression levels in glioma (Figs 2, S2 and S3), similarly to what was observed for other WNT ligands in other cancer types (Carmona et al., 2013; Jung et al., 2015; Kim et al., 2015a; Liu et al., 2016; Xu et al., 2005).	('WNT6', 'Gene', (110, 114))	('DNA', 'MPA', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', (226, 232))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('methylation', 'Var', (48, 59))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
32596	31923345	Interestingly, most of the CpG sites are more frequently methylated in LGG than GBM patients (19 out of 28; Fig.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('LGG', 'Disease', (71, 74))	('methylated', 'Var', (57, 67))	('patients', 'Species', '9606', (84, 92))
32598	31923345	Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal.	('glioma', 'Disease', (72, 78))	('methylation', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('WNT6', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('associated', 'Reg', (37, 47))	('DNA', 'MPA', (9, 12))
32608	31923345	Interestingly, WNT6 was also shown to be associated with shorter survival in LGG patients (Dao Trong et al., 2018), where HOXA9 overexpression is not frequent (Pojo et al., 2015).	('patients', 'Species', '9606', (81, 89))	('WNT6', 'Var', (15, 19))	('LGG', 'Disease', (77, 80))	('survival', 'MPA', (65, 73))	('shorter', 'NegReg', (57, 64))
32626	24573402	For example, miR-7 and miR-331-3p have been shown to regulate the expression of epidermal growth factor receptor (EGFR) and human EGFR, which are biomarkers of human tumors.	('human tumors', 'Disease', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('expression', 'MPA', (66, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('human tumors', 'Disease', 'MESH:D009369', (160, 172))	('epidermal growth factor receptor', 'Gene', (80, 112))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('80', '103'))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('EGFR', 'Gene', (130, 134))	('epidermal growth factor receptor', 'Gene', '1956', (80, 112))	('regulate', 'Reg', (53, 61))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('EGFR', 'Gene', (114, 118))	('miR-7', 'Gene', (13, 18))	('human', 'Species', '9606', (160, 165))	('miR-331-3p', 'Var', (23, 33))	('EGFR', 'Gene', '1956', (130, 134))	('miR-7', 'Gene', '10859', (13, 18))	('EGFR', 'Gene', '1956', (114, 118))	('human', 'Species', '9606', (124, 129))
32630	24573402	Given the detrimental effects of metastatic tumors and the growing development of sequencing technology, small RNA sequencing was adopted in our study to identify the differentially expressed miRNAs in metastatic melanoma compared with primary cutaneous melanoma samples.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 262))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (244, 262))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('primary cutaneous melanoma', 'Disease', (236, 262))	('miRNAs', 'Var', (192, 198))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Disease', (254, 262))	('melanoma', 'Disease', (213, 221))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))
32647	24573402	The 4 differentially expressed miRNAs were hsa-miR-146, hsa-miR-27, hsa-miR-877 and hsa-miR-186.	('hsa-miR-877', 'Gene', '100126314', (68, 79))	('hsa-miR-146', 'Var', (43, 54))	('miR-27', 'Gene', '407018', (60, 66))	('miR-27', 'Gene', (60, 66))	('hsa-miR-877', 'Gene', (68, 79))	('miR-186', 'Gene', '406962', (88, 95))	('miR-186', 'Gene', (88, 95))
32649	24573402	Katakowski et al demonstrated that the expression of miR-146b-5p inversely correlated with glioma invasiveness in the brain.	('glioma invasiveness', 'Disease', (91, 110))	('glioma', 'Phenotype', 'HP:0009733', (91, 97))	('inversely', 'NegReg', (65, 74))	('miR-146b-5p', 'Var', (53, 64))	('correlated with', 'Reg', (75, 90))	('glioma invasiveness', 'Disease', 'MESH:D005910', (91, 110))
32650	24573402	The study by Mertens-Talcott et al indicated that miR-27a is overexpressed in breast cancer cells, and that cell proliferation is decreased by the inhibition of this miRNA using antisense molecules in MDA-MB-231 cells.	('Mertens-Talcott', 'Disease', (13, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('Mertens-Talcott', 'Disease', 'MESH:D020386', (13, 28))	('miR-27a', 'Gene', (50, 57))	('miR-27a', 'Gene', '407018', (50, 57))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (201, 211))	('antisense', 'Var', (178, 187))	('inhibition', 'NegReg', (147, 157))	('cell proliferation', 'CPA', (108, 126))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('overexpressed', 'PosReg', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('decreased', 'NegReg', (130, 139))	('breast cancer', 'Disease', (78, 91))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
32651	24573402	Scott et al reported that in SKBr3 breast cancer cells, the inhibitor of histone deacetylases, LAQ824, rapidly decreased miR-27a levels.	('miR-27a', 'Gene', (121, 128))	('SKBr3', 'CellLine', 'CVCL:0033', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('decreased', 'NegReg', (111, 120))	('miR-27a', 'Gene', '407018', (121, 128))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('LAQ824', 'Var', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
32667	29641532	Germline mutations in candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers While a number of autosomal dominant and autosomal recessive cancer syndromes have an associated spectrum of cancers, the prevalence and variety of cancer predisposition mutations in patients with multiple primary cancers have not been extensively investigated.	('Germline mutations', 'Var', (0, 18))	('cutaneous melanoma', 'Disease', (73, 91))	('cancer syndromes', 'Disease', (209, 225))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('autosomal recessive cancer syndrome', 'Disease', 'MESH:D009386', (189, 224))	('autosomal recessive cancer syndrome', 'Disease', (189, 224))	('patients', 'Species', '9606', (331, 339))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('cancers', 'Disease', 'MESH:D009369', (362, 369))	('cancer syndromes', 'Disease', 'MESH:D009369', (209, 225))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('primary cancers', 'Disease', 'MESH:D009369', (354, 369))	('primary cancers', 'Disease', 'MESH:D009369', (132, 147))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('cancer', 'Disease', (140, 146))	('cancers', 'Disease', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (362, 369))	('cancers', 'Disease', (362, 369))	('cancer', 'Disease', (362, 368))	('primary cancers', 'Disease', (354, 369))	('cancer', 'Disease', (257, 263))	('primary cancers', 'Disease', (132, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Disease', (209, 215))	('cancers', 'Disease', (140, 147))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancer', 'Disease', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
32668	29641532	An understanding of the variants predisposing to more than one cancer type could improve patient care, including screening and genetic counselling, as well as advancing the understanding of tumour development.	('tumour', 'Disease', (190, 196))	('improve', 'PosReg', (81, 88))	('patient', 'Species', '9606', (89, 96))	('variants', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
32671	29641532	We focussed on variants in 525 pre-selected genes, including 65 autosomal dominant and 31 autosomal recessive cancer predisposition genes, 116 genes involved in the DNA repair pathway, and 313 commonly somatically mutated in cancer.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('DNA repair', 'biological_process', 'GO:0006281', ('165', '175'))	('autosomal recessive cancer', 'Disease', (90, 116))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (90, 116))	('variants', 'Var', (15, 23))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('autosomal dominant', 'Disease', (64, 82))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
32674	29641532	Variants typically found somatically in haematological malignancies (in JAK1, JAK2, SF3B1, SRSF2, TET2 and TYK2) were present in lymphocyte DNA of patients with multiple primary cancers, all of whom had a history of haematological malignancy and cutaneous melanoma, as well as colorectal cancer and/or prostate cancer.	('Variants', 'Var', (0, 8))	('SF3B1', 'Gene', '23451', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('JAK', 'molecular_function', 'GO:0004713', ('78', '81'))	('primary cancers', 'Disease', (170, 185))	('TYK2', 'Gene', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('JAK', 'molecular_function', 'GO:0004713', ('72', '75'))	('cutaneous melanoma', 'Disease', (246, 264))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (246, 264))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (246, 264))	('haematological malignancy', 'Disease', 'MESH:D019337', (216, 241))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('JAK2', 'Gene', '3717', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('JAK1', 'Gene', (72, 76))	('prostate cancer', 'Disease', 'MESH:D011471', (302, 317))	('TYK2', 'Gene', '7297', (107, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (302, 317))	('colorectal cancer', 'Disease', 'MESH:D015179', (277, 294))	('patients', 'Species', '9606', (147, 155))	('TET2', 'Gene', (98, 102))	('SRSF2', 'Gene', '6427', (91, 96))	('prostate cancer', 'Disease', (302, 317))	('haematological malignancies', 'Disease', (40, 67))	('colorectal cancer', 'Disease', (277, 294))	('SRSF2', 'Gene', (91, 96))	('JAK2', 'Gene', (78, 82))	('primary cancers', 'Disease', 'MESH:D009369', (170, 185))	('SF3B1', 'Gene', (84, 89))	('JAK1', 'Gene', '3716', (72, 76))	('TET2', 'Gene', '54790', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('haematological malignancy', 'Disease', (216, 241))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('haematological malignancies', 'Disease', 'MESH:D019337', (40, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (277, 294))
32675	29641532	Other potentially pathogenic variants were discovered in BUB1B, POLE2, ROS1 and DNMT3A.	('BUB1B', 'Gene', (57, 62))	('ROS1', 'Gene', '6098', (71, 75))	('pathogenic', 'Reg', (18, 28))	('variants', 'Var', (29, 37))	('BUB1B', 'Gene', '701', (57, 62))	('POLE2', 'Gene', (64, 69))	('DNMT3A', 'Gene', (80, 86))	('DNMT3A', 'Gene', '1788', (80, 86))	('ROS1', 'Gene', (71, 75))	('POLE2', 'Gene', '5427', (64, 69))
32676	29641532	Compared to controls, multiple cancer cases had significantly more likely damaging mutations (nonsense, frameshift ins/del) in tumour suppressor and tyrosine kinase genes and higher overall burden of mutations in all cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('frameshift ins/del', 'Var', (104, 122))	('higher', 'PosReg', (175, 181))	('multiple cancer', 'Disease', 'MESH:D009369', (22, 37))	('tyrosine kinase', 'Gene', '7294', (149, 164))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('tyrosine kinase', 'Gene', (149, 164))	('tumour', 'Disease', (127, 133))	('cancer', 'Disease', (31, 37))	('multiple cancer', 'Disease', (22, 37))
32677	29641532	We identified several pathogenic variants that likely predispose to at least one of the tumours in patients with multiple cancers.	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('tumours', 'Disease', 'MESH:D009369', (88, 95))	('pathogenic', 'Reg', (22, 32))	('patients', 'Species', '9606', (99, 107))	('multiple cancers', 'Disease', (113, 129))	('tumours', 'Disease', (88, 95))	('predispose', 'Reg', (54, 64))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('multiple cancers', 'Disease', 'MESH:D009369', (113, 129))	('variants', 'Var', (33, 41))
32678	29641532	We additionally present evidence that there may be a higher burden of variants of unknown significance in 'cancer genes' in patients with multiple cancer types.	('multiple cancer', 'Disease', 'MESH:D009369', (138, 153))	("'cancer", 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (70, 78))	("'cancer", 'Disease', (106, 113))	('multiple cancer', 'Disease', (138, 153))	('patients', 'Species', '9606', (124, 132))
32679	29641532	Further screens of this nature need to be carried out to build evidence to show if the cancers observed in these patients form part of a cancer spectrum associated with single germline variants in these genes, whether multiple layers of susceptibility exist (oligogenic or polygenic), or if the occurrence of multiple different cancers is due to random chance.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', (87, 94))	('cancer', 'Disease', (87, 93))	('variants', 'Var', (185, 193))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (328, 335))	('cancers', 'Phenotype', 'HP:0002664', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (328, 334))	('cancers', 'Disease', (328, 335))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('associated', 'Reg', (153, 163))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
32681	29641532	CM risk is heritable and high penetrance germline mutations in CDKN2A, CDK4, BAP1, MITF, TERT, POT1, ACD, TERF2IP and POLE have been reported to contribute to CM development in some high density melanoma families.	('ACD', 'Gene', '65057', (101, 104))	('CDKN2A', 'Gene', '1029', (63, 69))	('TERF2IP', 'Gene', '54386', (106, 113))	('POT1', 'Gene', '25913', (95, 99))	('CDK4', 'Gene', '1019', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('POT1', 'Gene', (95, 99))	('BAP1', 'Gene', '8314', (77, 81))	('ACD', 'Gene', (101, 104))	('contribute', 'Reg', (145, 155))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('MITF', 'Gene', '4286', (83, 87))	('CDKN2A', 'Gene', (63, 69))	('BAP1', 'Gene', (77, 81))	('CDK4', 'Gene', (71, 75))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('MITF', 'Gene', (83, 87))	('germline mutations', 'Var', (41, 59))	('TERF2IP', 'Gene', (106, 113))
32683	29641532	Notably, GWAS hits have been proximal to three genes involved in DNA repair, ATM, also an autosomal recessive cancer gene, (11q22-q23; rs73008229, genome-wide significance = 1.4x10-12), PARP1 (1q42.12; rs3219090, genome-wide significance = 7.1x10-12) and RAD23B (9q31.2; rs10739221, genome-wide significance = 9.6x10-9); however the exact mechanisms behind risks associated with these GWAS hits have yet to be ascertained.	('11q22-q23; rs73008229', 'Var', (124, 145))	('RAD', 'biological_process', 'GO:1990116', ('255', '258'))	('ATM', 'Gene', (77, 80))	('autosomal recessive cancer', 'Disease', (90, 116))	('PARP1', 'Gene', '142', (186, 191))	('PARP1', 'Gene', (186, 191))	('RAD23B', 'Gene', '5887', (255, 261))	('rs73008229', 'Var', (135, 145))	('ATM', 'Gene', '472', (77, 80))	('rs3219090', 'Var', (202, 211))	('rs3219090', 'Mutation', 'rs3219090', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs73008229', 'Mutation', 'rs73008229', (135, 145))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	('autosomal recessive cancer', 'Disease', 'MESH:D009369', (90, 116))	('RAD23B', 'Gene', (255, 261))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('rs10739221', 'Mutation', 'rs10739221', (271, 281))
32684	29641532	Additionally, pathogenic variants in BRCA1 and BRCA2, autosomal dominant cancer risk genes, both crucial in the process of homologous recombination DNA repair, increase risks to CM and uveal melanoma (UM), as well as several other cancer types including breast and ovarian cancer).	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('uveal melanoma', 'Disease', (185, 199))	('uveal melanoma', 'Disease', 'MESH:C536494', (185, 199))	('homologous recombination', 'biological_process', 'GO:0035825', ('123', '147'))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (254, 279))	('cancer', 'Disease', (73, 79))	('variants', 'Var', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('BRCA2', 'Gene', (47, 52))	('DNA repair', 'biological_process', 'GO:0006281', ('148', '158'))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('uveal melanoma', 'Phenotype', 'HP:0007716', (185, 199))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (265, 279))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (54, 79))	('autosomal dominant cancer', 'Disease', (54, 79))	('BRCA2', 'Gene', '675', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA1', 'Gene', (37, 42))
32686	29641532	Together, these data suggest a potential role for aberrations in DNA repair genes in the susceptibility to CM, UM and other cancers.	('aberrations', 'Var', (50, 61))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA repair genes', 'Gene', (65, 81))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
32687	29641532	Recent evidence has shown an increased burden in pathogenic/probably pathogenic mutations in previously described 'cancer' genes (associated with autosomal dominant, autosomal recessive, cancer predisposition GWAS hits, or somatic driver events) in patients with paediatric cancer, compared to two control populations.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (115, 121))	('autosomal recessive', 'Disease', (166, 185))	('pathogenic/probably', 'CPA', (49, 68))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (274, 280))	("'cancer", 'Disease', 'MESH:D009369', (114, 121))	('autosomal dominant', 'Disease', (146, 164))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	("'cancer", 'Disease', (114, 121))
32693	29641532	Here, we hypothesise that mutations in a curated 'cancer gene' list and/or DNA repair genes are key elements to the cancer susceptibility in individuals with three or more primary cancers.	('primary cancers', 'Disease', (172, 187))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	("'cancer", 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('primary cancers', 'Disease', 'MESH:D009369', (172, 187))	('DNA repair genes', 'Gene', (75, 91))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('mutations', 'Var', (26, 35))	("'cancer", 'Disease', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA repair', 'biological_process', 'GO:0006281', ('75', '85'))	('cancer', 'Disease', (180, 186))
32694	29641532	We have therefore undertaken an investigation of 525 'cancer' or DNA repair genes and describe the prevalence and spectrum of germline variants in this cohort of multiple cancer patients, compared to a control (non-cancer) cohort.	("'cancer", 'Disease', (53, 60))	('multiple cancer', 'Disease', 'MESH:D009369', (162, 177))	('non-cancer', 'Disease', (211, 221))	('non-cancer', 'Disease', 'MESH:D009369', (211, 221))	('patients', 'Species', '9606', (178, 186))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('DNA repair genes', 'Gene', (65, 81))	('variants', 'Var', (135, 143))	('DNA repair', 'biological_process', 'GO:0006281', ('65', '75'))	("'cancer", 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('multiple cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
32707	29641532	Sanger validation was performed on frameshift mutations in the multiple cancer cohort to ensure the correct base pairs were called for the in/del.	('multiple cancer', 'Disease', 'MESH:D009369', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('frameshift mutations', 'Var', (35, 55))	('multiple cancer', 'Disease', (63, 78))
32708	29641532	Variants were assessed using four in silico tools that predict whether an amino acid alteration affects protein function: SIFT, PolyPhen-2, likelihood ratio test and Mutation Taster.	('SIFT', 'Disease', 'None', (122, 126))	('protein function', 'MPA', (104, 120))	('affects', 'Reg', (96, 103))	('SIFT', 'Disease', (122, 126))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('amino acid alteration', 'Var', (74, 95))
32715	29641532	Of the 57 individuals with three or more distinct primary tumours, 53 instances of non-silent mutation were identified from the 63 autosomal dominant cancer predisposition genes at a Kaviar aggregate population frequency of less than 1:100 (47 missense, 1 splicing, 1 nonsense, and 4 non-frameshift ins/dels).	('primary tumours', 'Disease', (50, 65))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('missense', 'Var', (244, 252))	('non-frameshift ins/dels', 'Var', (284, 307))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (131, 156))	('splicing', 'biological_process', 'GO:0045292', ('256', '264'))	('splicing', 'Var', (256, 264))	('autosomal dominant cancer', 'Disease', (131, 156))	('nonsense', 'Var', (268, 276))	('primary tumours', 'Disease', 'MESH:D009369', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
32716	29641532	The nonsense mutation (CBL p.E658X) results in the termination of the protein product 249 amino acids prematurely and the removal of the vital tyrosinases at p. 700, 731 and 774, which are the key phosphorylation sites.	('protein', 'Protein', (70, 77))	('tyrosinases', 'Enzyme', (143, 154))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('termination', 'MPA', (51, 62))	('p.E658X', 'Var', (27, 34))	('p.E658X', 'Mutation', 'p.E658X', (27, 34))	('removal', 'NegReg', (122, 129))	('CBL', 'Gene', (23, 26))	('CBL', 'Gene', '867', (23, 26))
32718	29641532	Pathogenic mutations described to date require a functional tyrosine kinase binding domain (TKB, from p.51 - 349) and disruption of the alpha-helix formed between the TKB and RING domains; the truncating mutation in our cohort (p.Glu658X) does not disrupt this interaction.	('mutations', 'Var', (11, 20))	('tyrosine kinase', 'Gene', (60, 75))	('alpha-helix formed', 'MPA', (136, 154))	('p.Glu658X', 'Var', (228, 237))	('tyrosine kinase binding', 'molecular_function', 'GO:1990782', ('60', '83'))	('tyrosine kinase', 'Gene', '7294', (60, 75))	('p.Glu658X', 'Mutation', 'p.E658X', (228, 237))
32719	29641532	Additionally, the RASopathy associated mutations cluster around the RING domain, with described mutations occurring from p.Q367-R420, which is before the protein disruption described in our patient.	('p.Q367-R420', 'Var', (121, 132))	('RASopathy', 'Disease', 'None', (18, 27))	('mutations', 'Var', (39, 48))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('RASopathy', 'Disease', (18, 27))	('mutations', 'Var', (96, 105))	('patient', 'Species', '9606', (190, 197))
32721	29641532	Of the 47 missense mutations observed, 1 was present in <1:2000 in the Kaviar population and predicted as damaging by all four in silico prediction algorithms (BRCA2 p.A75P rs28897701).	('rs28897701', 'DBSNP_MENTION', 'None', (173, 183))	('BRCA2', 'Gene', (160, 165))	('p.A75P', 'Var', (166, 172))	('missense mutations', 'Var', (10, 28))	('BRCA2', 'Gene', '675', (160, 165))	('p.A75P', 'SUBSTITUTION', 'None', (166, 172))	('rs28897701', 'Var', (173, 183))
32722	29641532	The BRCA2 p.A75P mutation is, however, not classified as predisposing to breast/ovarian cancer by LOVD, or ClinVar.	('p.A75P', 'Var', (10, 16))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (73, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('p.A75P', 'SUBSTITUTION', 'None', (10, 16))	('breast/ovarian cancer', 'Disease', (73, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BRCA2', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (4, 9))
32723	29641532	Additionally, a variant in APC (p.E2445D rs587782127) was predicted as damaging by the three algorithms able to assess it; this variant is classified as being of unknown significance by three submitters in ClinVar and the individual carrying the variant has not had colorectal cancer, commonly associated with APC germline mutations, to date.	('APC', 'Disease', (310, 313))	('colorectal cancer', 'Disease', (266, 283))	('p.E2445D', 'Var', (32, 40))	('APC', 'Disease', 'MESH:D011125', (27, 30))	('rs587782127', 'Var', (41, 52))	('rs587782127', 'DBSNP_MENTION', 'None', (41, 52))	('variant', 'Var', (246, 253))	('APC', 'cellular_component', 'GO:0005680', ('310', '313'))	('APC', 'Disease', (27, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (266, 283))	('APC', 'cellular_component', 'GO:0005680', ('27', '30'))	('p.E2445D', 'SUBSTITUTION', 'None', (32, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (266, 283))	('APC', 'Disease', 'MESH:D011125', (310, 313))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
32724	29641532	The type and frequency of rare germline mutations in AD genes were then assessed in a control cohort (n = 1358); 1201 occurrences of non-silent mutation were identified from the 65 autosomal dominant cancer predisposition genes at a Kaviar aggregate population frequency of less than 1:100 (1132 missense mutations, 12 splicing, 5 nonsense, 18 frameshift and 34 non-frameshift ins/dels).	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (181, 206))	('non-frameshift ins/dels', 'Var', (362, 385))	('autosomal dominant cancer', 'Disease', (181, 206))	('nonsense', 'Var', (331, 339))	('frameshift', 'Var', (344, 354))	('AD', 'Disease', 'MESH:D000544', (53, 55))	('AD', 'Disease', (53, 55))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('1132', 'Var', (291, 295))	('missense mutations', 'Var', (296, 314))	('splicing', 'biological_process', 'GO:0045292', ('319', '327'))
32725	29641532	Two of the nonsense mutations (p.C675X and p.E1013X) in BRCA1, 7 of the frameshift (p.N1626*11, p.N3024*16, p.Q1429*8, p.L2092*6, p.K1057*7 (x2), and p.F1546*21) in BRCA2 and a single frameshift (p.Q60*6) in PALB2 would predispose the carrier to breast/ovarian cancer.	('p.N1626*', 'Var', (84, 92))	('p.F1546*', 'Var', (150, 158))	('predispose', 'Reg', (220, 230))	('p.L2092*', 'SUBSTITUTION', 'None', (119, 127))	('PALB2', 'Gene', '79728', (208, 213))	('p.E1013X', 'Var', (43, 51))	('p.C675X', 'Mutation', 'rs80356920', (31, 38))	('breast/ovarian cancer', 'Disease', (246, 267))	('p.L2092*', 'Var', (119, 127))	('p.N3024*', 'SUBSTITUTION', 'None', (96, 104))	('p.N3024*', 'Var', (96, 104))	('p.E1013X', 'Mutation', 'rs80357424', (43, 51))	('p.F1546*', 'SUBSTITUTION', 'None', (150, 158))	('p.N1626*', 'SUBSTITUTION', 'None', (84, 92))	('p.C675X', 'Var', (31, 38))	('p.K1057*', 'Var', (130, 138))	('BRCA2', 'Gene', (165, 170))	('BRCA1', 'Gene', '672', (56, 61))	('p.Q60*', 'SUBSTITUTION', 'None', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carrier', 'molecular_function', 'GO:0005215', ('235', '242'))	('BRCA1', 'Gene', (56, 61))	('p.Q1429*', 'SUBSTITUTION', 'None', (108, 116))	('BRCA2', 'Gene', '675', (165, 170))	('p.Q60*', 'Var', (196, 202))	('p.K1057*', 'SUBSTITUTION', 'None', (130, 138))	('PALB2', 'Gene', (208, 213))	('p.Q1429*', 'Var', (108, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))	('breast/ovarian cancer', 'Disease', 'MESH:D010051', (246, 267))
32726	29641532	Finally of note, a p.Q12X variant in TP53 results in early protein truncation (full length protein is 394 amino acids long) and would result in Li-Fraumeni syndrome in the carrier.	('Li-Fraumeni syndrome', 'Disease', (144, 164))	('protein', 'Protein', (59, 66))	('p.Q12X', 'Var', (19, 25))	('result in', 'Reg', (134, 143))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('results in', 'Reg', (42, 52))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (144, 164))	('carrier', 'molecular_function', 'GO:0005215', ('172', '179'))	('p.Q12X', 'Mutation', 'rs757274881', (19, 25))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
32727	29641532	A total of 109 instances of missense variants of a frequency <1:2000 in the Kaviar population were predicted as damaging by all four prediction algorithms; of these, only one of which has been reported as pathogenic in ClinVar (RET p.I852M rs377767426).	('rs377767426', 'DBSNP_MENTION', 'None', (240, 251))	('p.I852M', 'Var', (232, 239))	('RET', 'Gene', '5979', (228, 231))	('missense variants', 'Var', (28, 45))	('RET', 'Gene', (228, 231))	('p.I852M', 'SUBSTITUTION', 'None', (232, 239))	('rs377767426', 'Var', (240, 251))
32728	29641532	Examination of the autosomal recessive (AR) cancer predisposition gene variants from WES/WGS in all cohorts can only reveal where an individual has more than one variant in the same gene, but not whether they are on the same chromosome.	('variants', 'Var', (71, 79))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('225', '235'))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
32729	29641532	In the multiple cancer case cohort, one individual had two missense variants in the same gene (BRIP1; S3 Table, highlighted yellow); neither of these variants were classified as damaging by all four prediction tools.	('multiple cancer', 'Disease', (7, 22))	('missense variants', 'Var', (59, 76))	('BRIP1', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('BRIP1', 'Gene', '83990', (95, 100))
32731	29641532	It is plausible that heterozygous variant(s) in AR genes could cause a more subtle effect, such as inducing haploinsufficiency that increases susceptibility to cancer without causing an overt cancer syndrome.	('inducing', 'Reg', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('haploinsufficiency', 'Disease', (108, 126))	('cancer', 'Disease', (160, 166))	('susceptibility', 'MPA', (142, 156))	('heterozygous variant', 'Var', (21, 41))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer syndrome', 'Disease', 'MESH:D009369', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('AR genes', 'Gene', (48, 56))	('haploinsufficiency', 'Disease', 'MESH:D058495', (108, 126))	('cancer syndrome', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
32732	29641532	In the multiple cancer cases, truncating variants were seen in FANCC (p.R484X) and in FANCF (c.484/485 AG deletion).	('FANCF', 'Gene', '2188', (86, 91))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('truncating', 'MPA', (30, 40))	('c.484/485 AG deletion', 'Var', (93, 114))	('multiple cancer', 'Disease', (7, 22))	('FANCC', 'Gene', '2176', (63, 68))	('FANCC', 'Gene', (63, 68))	('FANCF', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p.R484X', 'Mutation', 'rs768988593', (70, 77))	('p.R484X', 'Var', (70, 77))
32733	29641532	In the UK10K population, there are truncating mutations in 61 individuals, in 21 genes, including: ATM, BRIP1, MUTYH, NBN, NTHL1, RAD51C, RECQL4, WRN, XPC, members of the ERCC gene family (ERCC1, ERCC3, ERCC5) and members of the FANC gene family (FANCA, FANCC, FANCD2, FANCF, FANCG, FANCI, FANCM).	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (269, 273))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (261, 265))	('NBN', 'Gene', '4683', (118, 121))	('RECQL4', 'Gene', (138, 144))	('BRIP1', 'Gene', '83990', (104, 109))	('NTHL1', 'Gene', '4913', (123, 128))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (290, 294))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (283, 287))	('FANCC', 'Gene', (254, 259))	('ERCC3', 'Gene', (196, 201))	('truncating mutations', 'Var', (35, 55))	('MUTYH', 'Gene', (111, 116))	('FANCF', 'Gene', (269, 274))	('FANC', 'Gene', (247, 251))	('mutations', 'Var', (46, 55))	('FANCG', 'Gene', (276, 281))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (247, 251))	('NBN', 'Gene', (118, 121))	('ATM', 'Gene', '472', (99, 102))	('MUTYH', 'Gene', '4595', (111, 116))	('ERCC5', 'Gene', '2073', (203, 208))	('FANC', 'Gene', (254, 258))	('ERCC1', 'Gene', '2067', (189, 194))	('WRN', 'Gene', (146, 149))	('WRN', 'Gene', '7486', (146, 149))	('BRIP1', 'Gene', (104, 109))	('ERCC3', 'Gene', '2071', (196, 201))	('FANCI', 'Gene', (283, 288))	('RAD51C', 'Gene', '5889', (130, 136))	('FANC', 'Gene', (276, 280))	('FANC', 'Gene', (229, 233))	('FANCM', 'Gene', '57697', (290, 295))	('RAD', 'biological_process', 'GO:1990116', ('130', '133'))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (254, 258))	('FANCM', 'Gene', (290, 295))	('ERCC5', 'Gene', (203, 208))	('FANCD2', 'Gene', (261, 267))	('ERCC1', 'Gene', (189, 194))	('XPC', 'Gene', '7508', (151, 154))	('FANCI', 'Gene', '55215', (283, 288))	('FANCG', 'Gene', '2189', (276, 281))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (276, 280))	('FANC', 'Gene', '2176;675;2177;2188;2189;55215;83990;57697;79728;5889;2072;672', (229, 233))	('ATM', 'Gene', (99, 102))	('NTHL1', 'Gene', (123, 128))	('FANCF', 'Gene', '2188', (269, 274))	('FANCC', 'Gene', '2176', (254, 259))	('FANC', 'Gene', (269, 273))	('FANC', 'Gene', (261, 265))	('RAD51C', 'Gene', (130, 136))	('XPC', 'Gene', (151, 154))	('RECQL4', 'Gene', '9401', (138, 144))	('FANC', 'Gene', (290, 294))	('FANC', 'Gene', (283, 287))	('FANCD2', 'Gene', '2177', (261, 267))
32735	29641532	Examination of the TSG that are not otherwise classified as AD or AR cancer syndrome genes (n = 49) in the multiple cancer cohort revealed 50 missense, 1 nonsense, 2 frameshift and 6 non-frameshift in/del variants at a frequency of <1:100 in the Kaviar control population.	('multiple cancer', 'Disease', 'MESH:D009369', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('AD', 'Disease', 'MESH:D000544', (60, 62))	('AD', 'Disease', (60, 62))	('frameshift', 'Var', (166, 176))	('missense', 'Var', (142, 150))	('multiple cancer', 'Disease', (107, 122))	('nonsense', 'Var', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('non-frameshift in/del', 'Var', (183, 204))	('cancer syndrome', 'Disease', 'MESH:D009369', (69, 84))	('cancer syndrome', 'Disease', (69, 84))
32736	29641532	Of all the missense mutations, two variants were predicted as damaging by all tools (PMS1 p.T75I rs61756360 and TNFAIP3 p.R761H rs368859219) and another variant was predicted as damaging by the 3 tools that could assess it (TET2 p.I1873T rs116519313).	('p.I1873T', 'Var', (229, 237))	('rs116519313', 'DBSNP_MENTION', 'None', (238, 249))	('p.I1873T', 'SUBSTITUTION', 'None', (229, 237))	('TNFAIP3', 'Gene', '7128', (112, 119))	('rs116519313', 'Var', (238, 249))	('missense', 'Var', (11, 19))	('rs61756360', 'DBSNP_MENTION', 'None', (97, 107))	('p.T75I', 'Var', (90, 96))	('rs61756360', 'Var', (97, 107))	('TNFAIP3', 'Gene', (112, 119))	('p.R761H', 'Var', (120, 127))	('TET2', 'Gene', '54790', (224, 228))	('rs368859219', 'Var', (128, 139))	('rs368859219', 'DBSNP_MENTION', 'None', (128, 139))	('p.R761H', 'SUBSTITUTION', 'None', (120, 127))	('TET2', 'Gene', (224, 228))	('p.T75I', 'SUBSTITUTION', 'None', (90, 96))
32738	29641532	The nonsense variant (p.L737X; rs759242053) occurred in BUB1B.	('p.L737X', 'Mutation', 'rs759242053', (22, 29))	('BUB1B', 'Gene', '701', (56, 61))	('occurred', 'Reg', (44, 52))	('rs759242053', 'Mutation', 'rs759242053', (31, 42))	('p.L737X; rs759242053', 'Var', (22, 42))	('BUB1B', 'Gene', (56, 61))
32739	29641532	Variants in this gene can cause the AR disorder mosaic variegated aneuploidy, however, when a single deleterious mutation is present, this can result in a premature chromatid separation trait (OMIM entry 176430), which can lead to an increased susceptibility to tumour development.	('premature chromatid separation', 'Phenotype', 'HP:0200024', (155, 185))	('tumour', 'Disease', (262, 268))	('Variants', 'Var', (0, 8))	('mutation', 'Var', (113, 121))	('cause', 'Reg', (26, 31))	('aneuploidy', 'Disease', (66, 76))	('chromatid', 'cellular_component', 'GO:0005694', ('165', '174'))	('aneuploidy', 'Disease', 'MESH:D000782', (66, 76))	('premature chromatid separation trait', 'CPA', (155, 191))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('result in', 'Reg', (143, 152))	('chromatid', 'cellular_component', 'GO:0005695', ('165', '174'))
32740	29641532	Two variants in TET2 are of note; the first, p.I1873T (rs116519313), is commonly reported as a somatic mutation (COSMIC ID = COSM41741 in haematopoietic/lymphocyte cancer x18); this patient had CM, colorectal cancer and mast cell leukaemia as distinct primary tumours and the second, an AT deletion at c.4874/4875, causing a frameshift at p.T1626, is in a patient with myeloproliferative disorder at age 65 years.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('myeloproliferative disorder', 'Disease', (369, 396))	('mast cell leukaemia', 'Phenotype', 'HP:0100495', (220, 239))	('p.I1873T', 'Var', (45, 53))	('mast cell leukaemia', 'Disease', 'MESH:D007946', (220, 239))	('rs116519313', 'Mutation', 'rs116519313', (55, 66))	('mast cell leukaemia', 'Disease', (220, 239))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('p.T1626', 'Var', (339, 346))	('p.I1873T', 'SUBSTITUTION', 'None', (45, 53))	('TET2', 'Gene', '54790', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('patient', 'Species', '9606', (182, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (198, 215))	('primary tumours', 'Disease', 'MESH:D009369', (252, 267))	('primary tumours', 'Disease', (252, 267))	('colorectal cancer', 'Disease', (198, 215))	('frameshift at p.T1626', 'Var', (325, 346))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (369, 396))	('patient', 'Species', '9606', (356, 363))	('cancer', 'Disease', (164, 170))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (369, 396))	('tumours', 'Phenotype', 'HP:0002664', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (209, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('TET2', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
32742	29641532	One of the nonsense mutations observed was in BUB1B (p.R770X; rs750364303), which as previously described could cause premature chromatid separation trait.	('cause', 'Reg', (112, 117))	('rs750364303', 'Var', (62, 73))	('BUB1B', 'Gene', '701', (46, 51))	('premature chromatid separation', 'Phenotype', 'HP:0200024', (118, 148))	('rs750364303', 'Mutation', 'rs750364303', (62, 73))	('chromatid', 'cellular_component', 'GO:0005695', ('128', '137'))	('p.R770X; rs750364303', 'Var', (53, 73))	('p.R770X', 'Mutation', 'rs750364303', (53, 60))	('chromatid', 'cellular_component', 'GO:0005694', ('128', '137'))	('BUB1B', 'Gene', (46, 51))	('premature chromatid separation trait', 'CPA', (118, 154))
32743	29641532	A variant in ASXL1 (p.R693X rs373221034) has been reported to be somatically mutated 38 times in haematopoietic/lymphoid tissue/28 times in pancreatic cancer (ID = COSM51388) in the COSMIC database.	('p.R693X', 'SUBSTITUTION', 'None', (20, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('rs373221034', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('p.R693X', 'Var', (20, 27))	('ASXL1', 'Gene', '171023', (13, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('rs373221034', 'DBSNP_MENTION', 'None', (28, 39))	('ASXL1', 'Gene', (13, 18))	('pancreatic cancer', 'Disease', (140, 157))
32745	29641532	Of particular note in the multiple cancer case patients is the variant in JAK2 (p.V617F rs77375493), which is very highly somatically mutated in haematopoietic and lymphoid tissues (reported over 40,000 times in COSMIC, ID = COSM12600) and has been reported as a gain of function variant in myeloproliferative disorders, as well as acting as a predisposition variant in the germline.	('p.V617F', 'Var', (80, 87))	('multiple cancer', 'Disease', (26, 41))	('myeloproliferative disorders', 'Disease', (291, 319))	('gain of function', 'PosReg', (263, 279))	('rs77375493', 'Var', (88, 98))	('JAK2', 'Gene', '3717', (74, 78))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (291, 319))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('JAK2', 'Gene', (74, 78))	('patients', 'Species', '9606', (47, 55))	('JAK', 'molecular_function', 'GO:0004713', ('74', '77'))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (291, 319))	('multiple cancer', 'Disease', 'MESH:D009369', (26, 41))	('rs77375493', 'DBSNP_MENTION', 'None', (88, 98))	('p.V617F', 'SUBSTITUTION', 'None', (80, 87))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (291, 318))
32746	29641532	The individual with this variant had myeloproliferative disorder at age 44.	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (37, 64))	('myeloproliferative disorder', 'Disease', (37, 64))	('variant', 'Var', (25, 32))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (37, 64))
32747	29641532	Additionally of potential functional impact: a frameshift variant in JAK1 (c.3031insC) in an individual who had a history of CM (n = 2), lymphoma (at 75 years of age) and prostate cancer (at 83 years of age); a frameshift variant in TYK2 (c.1725-1728delinsTT), in an individual with a history of CM (at 42 years of age), lymphoma and clear cell renal carcinoma (both at 58 years of age), colorectal cancer (at 63 years of age) and prostate cancer (at 64 years of age); and a nonsense variant in ROS1 (p.L1209X) in an individual who had CM (at 63 years of age), stomach cancer (at 67 years of age), colorectal cancer (at 68 years of age), Merkel cell carcinoma (at 78 years of age) and thyroid cancer (at 79 years of age).	('prostate cancer', 'Disease', 'MESH:D011471', (171, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('frameshift variant', 'Var', (211, 229))	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('colorectal cancer', 'Phenotype', 'HP:0003003', (388, 405))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (334, 360))	('JAK', 'molecular_function', 'GO:0004713', ('69', '72'))	('colorectal cancer', 'Disease', 'MESH:D015179', (598, 615))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('prostate cancer', 'Disease', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('Merkel cell carcinoma', 'Disease', (638, 659))	('prostate cancer', 'Disease', 'MESH:D011471', (431, 446))	('stomach cancer', 'Disease', (561, 575))	('prostate cancer', 'Phenotype', 'HP:0012125', (431, 446))	('lymphoma', 'Disease', (321, 329))	('colorectal cancer', 'Disease', (598, 615))	('prostate cancer', 'Disease', (431, 446))	('TYK2', 'Gene', (233, 237))	('lymphoma', 'Disease', 'MESH:D008223', (321, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (650, 659))	('thyroid cancer', 'Disease', (685, 699))	('colorectal cancer', 'Disease', 'MESH:D015179', (388, 405))	('JAK1', 'Gene', (69, 73))	('TYK2', 'Gene', '7297', (233, 237))	('ROS1', 'Gene', '6098', (495, 499))	('frameshift variant', 'Var', (47, 65))	('lymphoma', 'Disease', (137, 145))	('p.L1209X', 'Var', (501, 509))	('stomach cancer', 'Disease', 'MESH:D013274', (561, 575))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('p.L1209X', 'Mutation', 'rs35302901', (501, 509))	('renal carcinoma', 'Phenotype', 'HP:0005584', (345, 360))	('colorectal cancer', 'Disease', (388, 405))	('stomach cancer', 'Phenotype', 'HP:0012126', (561, 575))	('cancer', 'Phenotype', 'HP:0002664', (609, 615))	('colorectal cancer', 'Phenotype', 'HP:0003003', (598, 615))	('c.3031insC', 'Mutation', 'c.3031insC', (75, 85))	('thyroid cancer', 'Disease', 'MESH:D013964', (685, 699))	('cancer', 'Phenotype', 'HP:0002664', (569, 575))	('c.1725-1728del', 'Var', (239, 253))	('lymphoma', 'Phenotype', 'HP:0002665', (321, 329))	('thyroid cancer', 'Phenotype', 'HP:0002890', (685, 699))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (638, 659))	('c.1725-1728del', 'DELETION', 'None', (239, 253))	('clear cell renal carcinoma', 'Disease', (334, 360))	('ROS1', 'Gene', (495, 499))	('JAK1', 'Gene', '3716', (69, 73))
32748	29641532	As shown in S3 Table, none of the variants in these kinase genes found in the UK10K control data have been reported as significantly mutated somatically in any cancer type.	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('variants', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
32751	29641532	In the multiple cancer cases, several interesting variants are revealed, including in DNMT3A (p.R693H rs147001633 reported 121 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM442676), SF3B1 (p.K666N rs377023736 reported 31 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM132937) and SRSF2 p.P95L r751713049 reported 134 times in haematopoietic/lymphoid tissue in COSMIC, ID = COSM146288).	('p.P95L', 'Mutation', 'rs751713049', (313, 319))	('rs147001633', 'DBSNP_MENTION', 'None', (102, 113))	('p.R693H', 'SUBSTITUTION', 'None', (94, 101))	('COSM146288', 'Chemical', '-', (400, 410))	('SF3B1', 'Gene', '23451', (196, 201))	('p.K666N', 'SUBSTITUTION', 'None', (203, 210))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))	('SRSF2', 'Gene', '6427', (307, 312))	('DNMT3A', 'Gene', '1788', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('p.R693H', 'Var', (94, 101))	('SRSF2', 'Gene', (307, 312))	('rs377023736', 'DBSNP_MENTION', 'None', (211, 222))	('multiple cancer', 'Disease', (7, 22))	('p.K666N', 'Var', (203, 210))	('p.P95L', 'Var', (313, 319))	('SF3B1', 'Gene', (196, 201))	('rs147001633', 'Var', (102, 113))	('rs377023736', 'Var', (211, 222))	('DNMT3A', 'Gene', (86, 92))
32752	29641532	The individual with the DNMT3A p.R693H variant had not had any haematological malignancy prior to death (at age 89 years), while the individual with the SF3B1 p.K666N variant had chronic myeloid leukaemia.	('chronic myeloid leukaemia', 'Disease', (179, 204))	('SF3B1', 'Gene', '23451', (153, 158))	('p.R693H', 'SUBSTITUTION', 'None', (31, 38))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (187, 204))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (179, 204))	('DNMT3A', 'Gene', (24, 30))	('DNMT3A', 'Gene', '1788', (24, 30))	('haematological malignancy', 'Disease', (63, 88))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (179, 204))	('p.R693H', 'Var', (31, 38))	('SF3B1', 'Gene', (153, 158))	('haematological malignancy', 'Disease', 'MESH:D019337', (63, 88))	('p.K666N', 'SUBSTITUTION', 'None', (159, 166))	('p.K666N', 'Var', (159, 166))
32753	29641532	A second individual, who had CM (at age 76 years), prostate cancer (at 86 years) and chronic myeloid leukaemia (at age 88 years), had a novel splice variant, 2bp into the intron after exon 18 of DNMT3A; this variant is of unknown functional consequence.	('2bp into', 'Var', (158, 166))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (85, 110))	('DNMT3A', 'Gene', (195, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('DNMT3A', 'Gene', '1788', (195, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (85, 110))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('chronic myeloid leukaemia', 'Disease', (85, 110))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (93, 110))
32754	29641532	The individual with the SRSF2 p.P95L variant is the same patient with the TET2 p.I1873T variant and mast cell leukaemia/colorectal cancer.	('SRSF2', 'Gene', '6427', (24, 29))	('leukaemia/colorectal cancer', 'Disease', (110, 137))	('patient', 'Species', '9606', (57, 64))	('TET2', 'Gene', '54790', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('p.I1873T', 'Var', (79, 87))	('mast cell leukaemia', 'Phenotype', 'HP:0100495', (100, 119))	('TET2', 'Gene', (74, 78))	('p.P95L', 'Mutation', 'rs751713049', (30, 36))	('mast cell leukaemia', 'Disease', 'MESH:D007946', (100, 119))	('SRSF2', 'Gene', (24, 29))	('p.P95L', 'Var', (30, 36))	('leukaemia/colorectal cancer', 'Disease', 'MESH:D015179', (110, 137))	('mast cell leukaemia', 'Disease', (100, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('p.I1873T', 'SUBSTITUTION', 'None', (79, 87))
32755	29641532	None of the variants in the multiple cancer cases have been classified as pathogenic by ClinVar.	('variants', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('multiple cancer', 'Disease', 'MESH:D009369', (28, 43))	('multiple cancer', 'Disease', (28, 43))
32756	29641532	In the UK10K cohort, several variants are classified as pathogenic in ClinVar (S3 Table); however, none of these are associated with cancer predisposition by germline mutation.	('associated', 'Reg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('variants', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
32757	29641532	Two individuals in the UK10K control cohort had the same variant in DNMT3A (p.R693H) and two individuals had the same variant in SF3B1 (p.K666N) described in the multiple cancer cases.	('SF3B1', 'Gene', (129, 134))	('multiple cancer', 'Disease', 'MESH:D009369', (162, 177))	('p.K666N', 'Mutation', 'rs377023736', (136, 143))	('DNMT3A', 'Gene', (68, 74))	('SF3B1', 'Gene', '23451', (129, 134))	('DNMT3A', 'Gene', '1788', (68, 74))	('p.R693H', 'Mutation', 'rs147001633', (76, 83))	('variant', 'Var', (57, 64))	('multiple cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
32758	29641532	Additionally, an individual had the PIK3CA p.H1047L rs121913279 variant, which has been reported at high frequency in breast (n = 183), large intestine (n = 64) and endometrial (n = 43) cancers in COSMIC, ID = COSM776 and COSM94987.	('rs121913279', 'Var', (52, 63))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('PIK3CA', 'Gene', '5290', (36, 42))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('large intestine', 'Disease', (136, 151))	('p.H1047L', 'Var', (43, 51))	('breast', 'Disease', (118, 124))	('rs121913279', 'DBSNP_MENTION', 'None', (52, 63))	('p.H1047L', 'SUBSTITUTION', 'None', (43, 51))	('endometrial', 'Disease', (165, 176))	('PIK3CA', 'Gene', (36, 42))
32759	29641532	Many identified cancer predisposition genes encode DNA damage repair molecules; we have therefore additionally examined variants in genes not previously described as cancer genes, but which have a direct role in DNA damage repair.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('212', '215'))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('variants', 'Var', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancer', 'Disease', (16, 22))	('Man', 'Species', '9606', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
32760	29641532	In the multiple cancer cases, there were 55 missense, 4 splicing, 6 nonsense, and 3 non-frameshift ins/del variants with a frequency of <1:100 in the Kaviar control population; of these, 31 missense, 2 splicing, 3 nonsense, and 1 non-frameshift ins/del variants had a frequency of <1:2000.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('splicing', 'biological_process', 'GO:0045292', ('202', '210'))	('missense', 'Var', (44, 52))	('splicing', 'biological_process', 'GO:0045292', ('56', '64'))	('multiple cancer', 'Disease', (7, 22))	('missense', 'Var', (190, 198))	('splicing', 'Var', (202, 210))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))
32761	29641532	A total of 6 missense variants at a frequency <1:2000 were predicted as damaging by all four algorithms, of which a single individual had two rare variants in WRNIP1 and another had a missense variant in POLE2 (p.L249I).	('missense', 'Var', (13, 21))	('POLE2', 'Gene', (204, 209))	('POLE2', 'Gene', '5427', (204, 209))	('WRNIP1', 'Gene', (159, 165))	('p.L249I', 'Mutation', 'rs141483427', (211, 218))	('WRNIP1', 'Gene', '56897', (159, 165))	('missense', 'Var', (184, 192))	('p.L249I', 'Var', (211, 218))
32762	29641532	The individual with two WRNIP missense variants (p.R537W rs145167237 and p.P615L rs372821009) had early onset cancers (Thyroid cancer at 31, CM at 42 and multifocal clear cell renal cancer at 58 years of age).	('WRN', 'Gene', (24, 27))	('Thyroid cancer', 'Disease', 'MESH:D013964', (119, 133))	('WRN', 'Gene', '7486', (24, 27))	('rs145167237', 'DBSNP_MENTION', 'None', (57, 68))	('rs372821009', 'Var', (81, 92))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('clear cell renal cancer', 'Disease', (165, 188))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('rs372821009', 'DBSNP_MENTION', 'None', (81, 92))	('cancers', 'Disease', (110, 117))	('rs145167237', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (165, 188))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('p.R537W', 'SUBSTITUTION', 'None', (49, 56))	('renal cancer', 'Phenotype', 'HP:0009726', (176, 188))	('p.R537W', 'Var', (49, 56))	('p.P615L', 'SUBSTITUTION', 'None', (73, 80))	('p.P615L', 'Var', (73, 80))	('Thyroid cancer', 'Disease', (119, 133))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
32764	29641532	The missense variant in POLE2 occurred in an individual who had colorectal cancer at age 59 years.	('POLE2', 'Gene', '5427', (24, 29))	('colorectal cancer', 'Disease', (64, 81))	('missense variant', 'Var', (4, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('occurred', 'Reg', (30, 38))	('POLE2', 'Gene', (24, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
32766	29641532	Exploration of the proportion of individuals from each cohort with variants previously observed in the Kaviar control population was carried out to assess whether there were a greater proportion of variants never/rarely previously observed in the Kaviar control cohort (n = 77,301) in the multiple cancer cases, compared to the UK10K population control cohort.	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('multiple cancer', 'Disease', 'MESH:D009369', (289, 304))	('variants', 'Var', (198, 206))	('multiple cancer', 'Disease', (289, 304))
32768	29641532	there was not an over-representation of very rare/novel mutations in cancer/DNA repair genes in multiple cancer patients compared to an unselected cohort of individuals.	('multiple cancer', 'Disease', 'MESH:D009369', (96, 111))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('DNA repair', 'biological_process', 'GO:0006281', ('76', '86'))	('multiple cancer', 'Disease', (96, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
32771	29641532	This revealed that a greater number of multiple cancer cases carried multiple variants in cancer genes (Mann-Whitney P = 0.0012; Fig 2A) and in all genes combined (Mann-Whitney P = 0.0014), but not the DNA repair genes alone (Mann-Whitney P = 0.092; Fig 2B), compared to those in the UK10K control population.	('multiple cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('DNA repair', 'biological_process', 'GO:0006281', ('202', '212'))	('Man', 'Species', '9606', (164, 167))	('Man', 'Species', '9606', (226, 229))	('multiple cancer', 'Disease', 'MESH:D009369', (39, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Man', 'Species', '9606', (104, 107))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('variants', 'Var', (78, 86))
32773	29641532	The low frequency of germline mutations in TP53 or BRCA1/2, respectively means that statistical evidence supporting these associations is rather weak.	('BRCA1/2', 'Gene', '672;675', (51, 58))	('germline mutations', 'Var', (21, 39))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('BRCA1/2', 'Gene', (51, 58))
32780	29641532	It is of interest that in the UK10K data, 2 deleterious variants were identified in BRCA1 and 7 in BRCA2 (a frequency of 0.15% and 0.52%, respectively); the estimated population frequency of pathogenic BRCA1/2 mutations is 1:800 (0.125%) to 1:1000 (0.1%) per gene, although the prevalence varies between ethnic groups and geographical areas.	('BRCA1', 'Gene', '672', (202, 207))	('mutations', 'Var', (210, 219))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('pathogenic', 'Reg', (191, 201))	('BRCA1', 'Gene', (202, 207))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA2', 'Gene', (99, 104))	('BRCA1', 'Gene', (84, 89))	('BRCA1/2', 'Gene', (202, 209))	('BRCA2', 'Gene', '675', (99, 104))
32781	29641532	A frequency of pathogenic variants in approximately 1:200 individuals for BRCA2 is therefore higher than might be expected from a population of individuals selected for non-cancer studies.	('non-cancer', 'Disease', (169, 179))	('non-cancer', 'Disease', 'MESH:D009369', (169, 179))	('pathogenic', 'Reg', (15, 25))	('BRCA2', 'Gene', (74, 79))	('BRCA2', 'Gene', '675', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('variants', 'Var', (26, 34))
32783	29641532	In the UK10K cohort, 4 individuals had truncating mutations in MSH6 (0.29%, approximately 1:350), which would cause an increase in colorectal cancer risk (by 8 times) and in endometrial cancer risk (26 times) more than the general population in these individuals.	('MSH6', 'Gene', (63, 67))	('endometrial cancer', 'Phenotype', 'HP:0012114', (174, 192))	('truncating mutations', 'Var', (39, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('endometrial cancer', 'Disease', 'MESH:D016889', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('MSH6', 'Gene', '2956', (63, 67))	('increase', 'PosReg', (119, 127))	('endometrial cancer', 'Disease', (174, 192))	('colorectal cancer', 'Disease', (131, 148))
32784	29641532	Finally, truncating or previously functionally described deleterious missense mutations were observed in CBL (predisposing to Noonan syndrome, OMIM ID: 613563), EPCAM (Lynch syndrome/hereditary nonpolyposis colorectal cancer, OMIM ID: 613244), NF1 (Neurofibromatosis, OMIM ID: 162200), PALB2 (breast cancer, OMIM ID: 114480), TP53 (Li Fraumeni Syndrome, OMIM ID: 151623) and TSC2 (Tuberous sclerosis type 2, OMIM ID: 613254) in the UK10K control cohort.	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (249, 266))	('Lynch syndrome', 'Disease', 'MESH:D003123', (168, 182))	('Neurofibromatosis', 'Disease', (249, 266))	('EPCAM', 'Gene', '4072', (161, 166))	('TP53', 'Gene', '7157', (326, 330))	('PALB2', 'Gene', '79728', (286, 291))	('CBL', 'Gene', '867', (105, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('NF1', 'Gene', '4763', (244, 247))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (183, 224))	('Neurofibromatosis', 'Disease', 'MESH:C537392', (249, 266))	('Li Fraumeni Syndrome', 'Disease', 'MESH:D016864', (332, 352))	('breast cancer', 'Disease', (293, 306))	('NF1', 'Gene', (244, 247))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('Li Fraumeni Syndrome', 'Disease', (332, 352))	('EPCAM', 'Gene', (161, 166))	('CBL', 'Gene', (105, 108))	('Noonan syndrome', 'Disease', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('TSC2', 'Gene', '7249', (375, 379))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('missense mutations', 'Var', (69, 87))	('Lynch syndrome', 'Disease', (168, 182))	('TP53', 'Gene', (326, 330))	('nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (194, 224))	('Tuberous sclerosis type 2', 'Disease', 'MESH:C566021', (381, 406))	('hereditary nonpolyposis colorectal cancer', 'Disease', (183, 224))	('TSC2', 'Gene', (375, 379))	('Noonan syndrome', 'Disease', 'MESH:D009634', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('Tuberous sclerosis type 2', 'Disease', (381, 406))	('PALB2', 'Gene', (286, 291))
32785	29641532	If we take these data as indicative of the types of deleterious genetic mutations present in a collection of individuals collated from non-cancer focused cohorts, it is clear that the multiple cancer cohort has a significant under-representation of such variants, and therefore no unidentified underlying cancer syndrome predisposition.	('non-cancer', 'Disease', (135, 145))	('mutations', 'Var', (72, 81))	('non-cancer', 'Disease', 'MESH:D009369', (135, 145))	('cancer syndrome', 'Disease', 'MESH:D009369', (305, 320))	('variants', 'Var', (254, 262))	('multiple cancer', 'Disease', 'MESH:D009369', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('under-representation', 'NegReg', (225, 245))	('cancer syndrome', 'Disease', (305, 320))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('multiple cancer', 'Disease', (184, 199))
32787	29641532	These cancer syndromes require homozygous or compound heterozygous mutations and often have a severe phenotype.	('cancer syndromes', 'Disease', (6, 22))	('compound heterozygous mutations', 'Var', (45, 76))	('cancer syndromes', 'Disease', 'MESH:D009369', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))
32790	29641532	In the multiple cancer patients, a nonsense variant in FANCC and a frameshift in FANCF were observed; three frameshifts were observed in these genes in the UK10 data.	('FANCC', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('patients', 'Species', '9606', (23, 31))	('frameshift', 'Var', (67, 77))	('FANCF', 'Gene', (81, 86))	('multiple cancer', 'Disease', (7, 22))	('FANCF', 'Gene', '2188', (81, 86))	('FANCC', 'Gene', '2176', (55, 60))	('multiple cancer', 'Disease', 'MESH:D009369', (7, 22))
32792	29641532	In the tumour suppressor, tyrosine kinase and 'other' categories of genes, several variants robustly described as somatic events in haematological malignancies were observed.	('variants', 'Var', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tyrosine kinase', 'Gene', (26, 41))	('haematological malignancies', 'Disease', (132, 159))	('haematological malignancies', 'Disease', 'MESH:D019337', (132, 159))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tyrosine kinase', 'Gene', '7294', (26, 41))	('tumour', 'Disease', (7, 13))
32793	29641532	As the JAK2 p.V617F, TET2 p.I1873T, SF3B1 p.K666N, SRSF2 p.P95L and DNMT3A p.R693H variants are frequent somatically mutated hotpots in haematological malignancy and have not been previously reported in the germline, it is plausible that our screen of buffy coat derived DNA detected somatic mutations.	('JAK', 'molecular_function', 'GO:0004713', ('7', '10'))	('SF3B1', 'Gene', (36, 41))	('p.I1873T', 'Mutation', 'rs116519313', (26, 34))	('p.P95L', 'Mutation', 'rs751713049', (57, 63))	('haematological malignancy', 'Disease', (136, 161))	('DNMT3A', 'Gene', (68, 74))	('JAK2', 'Gene', '3717', (7, 11))	('TET2', 'Gene', '54790', (21, 25))	('SF3B1', 'Gene', '23451', (36, 41))	('haematological malignancy', 'Disease', 'MESH:D019337', (136, 161))	('p.R693H', 'SUBSTITUTION', 'None', (75, 82))	('p.V617F', 'Var', (12, 19))	('SRSF2', 'Gene', '6427', (51, 56))	('JAK2', 'Gene', (7, 11))	('SRSF2', 'Gene', (51, 56))	('p.K666N', 'Mutation', 'rs377023736', (42, 49))	('DNA', 'cellular_component', 'GO:0005574', ('271', '274'))	('p.R693H', 'Var', (75, 82))	('p.V617F', 'Mutation', 'rs77375493', (12, 19))	('p.I1873T', 'Var', (26, 34))	('DNMT3A', 'Gene', '1788', (68, 74))	('p.P95L', 'Var', (57, 63))	('TET2', 'Gene', (21, 25))	('p.K666N', 'Var', (42, 49))
32794	29641532	The participant with the JAK2 p.V617F variant previously had myeloproliferative disorder at age 44, and had their blood drawn for DNA extraction approximately 20 years later; at their death aged 85 years, had no reported diagnosis of recurrent haematological malignancy.	('haematological malignancy', 'Disease', 'MESH:D019337', (244, 269))	('JAK', 'molecular_function', 'GO:0004713', ('25', '28'))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('p.V617F', 'Var', (30, 37))	('JAK2', 'Gene', '3717', (25, 29))	('myeloproliferative disorder', 'Disease', (61, 88))	('myeloproliferative disorder', 'Disease', 'MESH:D009196', (61, 88))	('haematological malignancy', 'Disease', (244, 269))	('JAK2', 'Gene', (25, 29))	('p.V617F', 'SUBSTITUTION', 'None', (30, 37))	('myeloproliferative disorder', 'Phenotype', 'HP:0005547', (61, 88))	('participant', 'Species', '9606', (4, 15))
32795	29641532	The participants with a) the SF3B1 p.K666N and b) SRSF2 p.P95L/TET2 p.I1873T variants, respectively, both had haematological malignancies diagnosed in a closer timeframe after blood draw (exact date unknown) and therefore, tumour cells may have been detected.	('p.I1873T', 'Var', (68, 76))	('TET2', 'Gene', (63, 67))	('SF3B1', 'Gene', '23451', (29, 34))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('SRSF2', 'Gene', (50, 55))	('haematological malignancies', 'Disease', 'MESH:D019337', (110, 137))	('haematological malignancies', 'Disease', (110, 137))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('participants', 'Species', '9606', (4, 16))	('tumour', 'Disease', (223, 229))	('TET2', 'Gene', '54790', (63, 67))	('p.K666N', 'SUBSTITUTION', 'None', (35, 42))	('p.I1873T', 'SUBSTITUTION', 'None', (68, 76))	('SRSF2', 'Gene', '6427', (50, 55))	('SF3B1', 'Gene', (29, 34))	('p.K666N', 'Var', (35, 42))	('p.P95L', 'Mutation', 'rs751713049', (56, 62))
32796	29641532	The variant in DNMT3A observed in haematological malignancies (p.R693H, as reported in COSMIC), was detected in an individual who had not developed such a tumour type prior to their death aged 89 years (previous cancers are: CM, prostate cancer and mesothelioma).	('DNMT3A', 'Gene', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('mesothelioma', 'Disease', (249, 261))	('tumour', 'Disease', (155, 161))	('mesothelioma', 'Disease', 'MESH:D008654', (249, 261))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('haematological malignancies', 'Disease', 'MESH:D019337', (34, 61))	('DNMT3A', 'Gene', '1788', (15, 21))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('prostate cancer', 'Disease', (229, 244))	('p.R693H', 'Mutation', 'rs147001633', (63, 70))	('variant', 'Var', (4, 11))	('haematological malignancies', 'Disease', (34, 61))
32798	29641532	Frameshift or splice variants in JAK1, DNMT3A, TET2 and TYK2 all occurred in individuals with a history of CM and lymphoma/leukaemia and are not previously described as haematological malignancy hotspots; each of these individuals additionally had prostate and/or colorectal cancer, suggesting a potential phenotype associated with these variants.	('colorectal cancer', 'Disease', 'MESH:D015179', (264, 281))	('JAK1', 'Gene', (33, 37))	('colorectal cancer', 'Disease', (264, 281))	('occurred', 'Reg', (65, 73))	('lymphoma/leukaemia', 'Disease', 'MESH:D007938', (114, 132))	('DNMT3A', 'Gene', '1788', (39, 45))	('haematological malignancy', 'Disease', 'MESH:D019337', (169, 194))	('TET2', 'Gene', '54790', (47, 51))	('lymphoma/leukaemia', 'Disease', (114, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('JAK1', 'Gene', '3716', (33, 37))	('TYK2', 'Gene', (56, 60))	('JAK', 'molecular_function', 'GO:0004713', ('33', '36'))	('Frameshift', 'Var', (0, 10))	('DNMT3A', 'Gene', (39, 45))	('TYK2', 'Gene', '7297', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('TET2', 'Gene', (47, 51))	('prostate', 'Disease', (248, 256))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('haematological malignancy', 'Disease', (169, 194))
32800	29641532	A variant in BUB1B (p.L373X) occurred in an individual with CM, breast cancer and mesothelioma.	('mesothelioma', 'Disease', (82, 94))	('p.L373X', 'Mutation', 'p.L373X', (20, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('mesothelioma', 'Disease', 'MESH:D008654', (82, 94))	('BUB1B', 'Gene', (13, 18))	('occurred', 'Reg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('BUB1B', 'Gene', '701', (13, 18))	('breast cancer', 'Disease', (64, 77))	('p.L373X', 'Var', (20, 27))
32803	29641532	Whether these variants additionally confer increased risk to the other malignancies in these individuals (which include cutaneous melanoma, colorectal cancer, clear cell renal carcinoma and prostate cancer), or there are further genetic predispositions in these individuals leading to the development of these independent primary tumours is an intriguing question.	('risk', 'Reg', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('clear cell renal carcinoma and prostate cancer', 'Disease', 'MESH:C538614', (159, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('renal carcinoma', 'Phenotype', 'HP:0005584', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('malignancies', 'Disease', (71, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (190, 205))	('primary tumours', 'Disease', (322, 337))	('colorectal cancer', 'Disease', (140, 157))	('primary tumours', 'Disease', 'MESH:D009369', (322, 337))	('variants', 'Var', (14, 22))	('tumours', 'Phenotype', 'HP:0002664', (330, 337))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
32804	29641532	Also in these two classifications of genes, the frequency of damaging variants (frameshift in/dels and nonsense) were higher in the multiple cancer cases at frequencies of <1:100 and <1:2000 compared to the UK10K cohort.	('higher', 'PosReg', (118, 124))	('multiple cancer', 'Disease', 'MESH:D009369', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('multiple cancer', 'Disease', (132, 147))	('nonsense', 'Var', (103, 111))
32806	29641532	We observed a variant in POLE2, which was predicted as damaging by all in silico tools, in a patient who had colorectal cancer at age 59 years old.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('POLE2', 'Gene', (25, 30))	('POLE2', 'Gene', '5427', (25, 30))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('patient', 'Species', '9606', (93, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('variant', 'Var', (14, 21))
32807	29641532	Variants in this gene have recently been associated with the development of colorectal cancer and polyposis.	('Variants', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('associated with', 'Reg', (41, 56))	('polyposis', 'Disease', 'MESH:D011125', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('polyposis', 'Disease', (98, 107))
32808	29641532	POLE2 is a subunit of the polymerase epsilon enzyme complex; we have previously demonstrated that a deleterious variant in another member of this complex, POLE, was associated with cutaneous melanoma development.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (181, 199))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('POLE', 'Gene', (155, 159))	('associated with', 'Reg', (165, 180))	('variant', 'Var', (112, 119))	('POLE2', 'Gene', (0, 5))	('enzyme complex', 'cellular_component', 'GO:1902494', ('45', '59'))	('cutaneous melanoma', 'Disease', (181, 199))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (181, 199))	('POLE2', 'Gene', '5427', (0, 5))
32809	29641532	There is therefore an indication that variants in POLE and POLE2 might be associated with susceptibility to multiple cancer types.	('POLE2', 'Gene', '5427', (59, 64))	('multiple cancer', 'Disease', 'MESH:D009369', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('variants', 'Var', (38, 46))	('POLE', 'Gene', (50, 54))	('susceptibility', 'Reg', (90, 104))	('multiple cancer', 'Disease', (108, 123))	('POLE2', 'Gene', (59, 64))	('associated', 'Reg', (74, 84))
32810	29641532	Also of interest were two variants in WRNIP1 that were predicted as damaging by all in silico tools, which occurred in the same individual, who had early onset cancers (thyroid cancer at 31, CM at 42 and multifocal clear cell renal cancer at 58 years of age.	('clear cell renal cancer', 'Disease', (215, 238))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('WRNIP1', 'Gene', (38, 44))	('thyroid cancer', 'Disease', (169, 183))	('cancers', 'Disease', (160, 167))	('renal cancer', 'Phenotype', 'HP:0009726', (226, 238))	('thyroid cancer', 'Phenotype', 'HP:0002890', (169, 183))	('WRNIP1', 'Gene', '56897', (38, 44))	('thyroid cancer', 'Disease', 'MESH:D013964', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (215, 238))	('variants', 'Var', (26, 34))
32812	29641532	There are a large number of missense (n = 22) and frameshift (n = 4) variants in WRNIP1 in the UK10K cohort, which could be suggestive of a degree of plasticity in the ability of the protein to withstand mutation.	('WRNIP1', 'Gene', '56897', (81, 87))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('variants', 'Var', (69, 77))	('missense', 'Var', (28, 36))	('frameshift', 'Var', (50, 60))	('WRNIP1', 'Gene', (81, 87))
32813	29641532	The most intriguing implication from our observations is that there is a higher burden of variants in 'cancer' genes in patients with multiple primary cancers than in the control population.	("'cancer", 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('primary cancers', 'Disease', 'MESH:D009369', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	("'cancer", 'Disease', (102, 109))	('variants', 'Var', (90, 98))	('patients', 'Species', '9606', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('primary cancers', 'Disease', (143, 158))
32814	29641532	It is plausible that a number of rare mutations in different genes can act synergistically or additively together to increase susceptibility to cancer development.	('susceptibility', 'Reg', (126, 140))	('increase', 'PosReg', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('act', 'Reg', (71, 74))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
32815	29641532	This potential mechanism by which the combination of variants leads to an increased susceptibility to cancer development is intriguing and would require very careful dissection and functional assessment, and perhaps with the advent of Cas9/CRISPR technology, this type of complex genetic manipulation might be more feasible in the future.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cas', 'cellular_component', 'GO:0005650', ('235', '238'))	('variants', 'Var', (53, 61))
32821	29641532	Another possibility is that the increased burden in missense variants detected in the DNA of individuals with multiple primary cancers is as a somatic event as a consequence to the treatment of their previous tumour(s).	('primary cancers', 'Disease', 'MESH:D009369', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('primary cancers', 'Disease', (119, 134))	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('tumour', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumour', 'Disease', (209, 215))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('missense variants', 'Var', (52, 69))
32825	29641532	It is clear from the genetic data that there are individuals present in the UK10K cohort who have cancer syndromes caused by deleterious mutations (such as BRCA1 nonsense, BRCA2 frameshift and APC frameshift variants).	('nonsense', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer syndromes', 'Disease', (98, 114))	('BRCA2', 'Gene', '675', (172, 177))	('APC', 'cellular_component', 'GO:0005680', ('193', '196'))	('BRCA1', 'Gene', '672', (156, 161))	('cancer syndromes', 'Disease', 'MESH:D009369', (98, 114))	('APC', 'Disease', 'MESH:D011125', (193, 196))	('BRCA2', 'Gene', (172, 177))	('APC', 'Disease', (193, 196))	('frameshift', 'Var', (178, 188))	('BRCA1', 'Gene', (156, 161))	('caused by', 'Reg', (115, 124))
32826	29641532	This does, however, also indicate that the UK10K cohort is a representative cross-section of the general population and therefore any difference between this cohort and the multiple cancer cohort are potentially important.	('multiple cancer', 'Disease', (173, 188))	('UK10K', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('multiple cancer', 'Disease', 'MESH:D009369', (173, 188))
32827	29641532	An example of this is at chr2:47637479, rs63749984, in MSH2.	('rs63749984', 'Mutation', 'rs63749984', (40, 50))	('MSH2', 'Gene', (55, 59))	('rs63749984', 'Var', (40, 50))	('MSH2', 'Gene', '4436', (55, 59))
32829	29641532	This variant (rs63749984) and chromosomal location are therefore both currently classified as 'pathogenic' by ClinVar and without further scrutiny, the incorrect conclusion would be reached.	("'pathogenic'", 'PosReg', (94, 106))	('rs63749984', 'Mutation', 'rs63749984', (14, 24))	('rs63749984', 'Var', (14, 24))
32830	29641532	For example, while the truncation observed in CBL (p.E658X) in the multiple cancer cohort and the frameshift in the UK10K cohort (a 7bp deletion at p.M222) could be automatically designated as damaging, there is no evidence in the literature of pathogenicity being conferred by truncation of CBL protein.	('truncation', 'MPA', (23, 33))	('CBL', 'Gene', (292, 295))	('CBL', 'Gene', '867', (292, 295))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('multiple cancer', 'Disease', 'MESH:D009369', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('p.E658X', 'Var', (51, 58))	('multiple cancer', 'Disease', (67, 82))	('CBL', 'Gene', (46, 49))	('CBL', 'Gene', '867', (46, 49))	('p.E658X', 'Mutation', 'p.E658X', (51, 58))
32831	29641532	Given the observations of single pathogenic variants predisposing to multiple tumour types arising in distinct tissues, such as with BAP1 (uveal melanoma, mesothelioma, meningioma, clear cell renal cell carcinoma and cholangiocarcinoma), BRCA1 or BRCA2 (breast, ovarian, uveal melanoma), it is plausible that other examples exist that have diverse effects that have yet to be described.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (181, 212))	('tumour', 'Disease', (78, 84))	('uveal melanoma', 'Disease', (139, 153))	('BAP1', 'Gene', '8314', (133, 137))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (217, 235))	('BRCA2', 'Gene', (247, 252))	('meningioma', 'Disease', (169, 179))	('cholangiocarcinoma', 'Disease', (217, 235))	('meningioma', 'Phenotype', 'HP:0002858', (169, 179))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (217, 235))	('breast, ovarian, uveal melanoma', 'Disease', 'MESH:C536494', (254, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (181, 212))	('BAP1', 'Gene', (133, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (271, 285))	('BRCA2', 'Gene', '675', (247, 252))	('uveal melanoma', 'Disease', (271, 285))	('meningioma', 'Disease', 'MESH:D008577', (169, 179))	('BRCA1', 'Gene', '672', (238, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('BRCA1', 'Gene', (238, 243))	('clear cell renal cell carcinoma', 'Disease', (181, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('uveal melanoma', 'Phenotype', 'HP:0007716', (271, 285))	('mesothelioma', 'Disease', (155, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('variants', 'Var', (44, 52))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
32833	29641532	We identified a number of variants likely to have caused increased susceptibility to at least one of the primary tumours observed and have additionally shown an increased burden of mutation in affected individuals.	('primary tumours', 'Disease', (105, 120))	('primary tumours', 'Disease', 'MESH:D009369', (105, 120))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('variants', 'Var', (26, 34))
32834	29641532	Given the later age of onset of many of these tumours, it is plausible that these variants, either alone or in combination, do not have high impact on protein function and instead have more subtle cellular effects.	('variants', 'Var', (82, 90))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('protein function', 'MPA', (151, 167))	('tumours', 'Disease', (46, 53))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('have', 'Reg', (180, 184))
32837	29641532	The implication from this and other recent studies is that there are a significant number of germline genetic variations in genes known to be associated with cancer processes in individuals with a wide variety of tumour types.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('genetic variations', 'Var', (102, 120))	('cancer', 'Disease', (158, 164))	('tumour', 'Disease', (213, 219))	('associated', 'Reg', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
32838	28486107	RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma Constitutive activation of Galphaq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK.	('MAPK Pathway', 'Pathway', (17, 29))	('GNAQ', 'Gene', '2776', (132, 136))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('GNAQ', 'Gene', '2776', (44, 48))	('GNAQ', 'Gene', (132, 136))	('GNAQ', 'Gene', (44, 48))	('Melanoma', 'Disease', 'MESH:D008545', (62, 70))	('GNA11', 'Gene', (140, 145))	('RasGRP3', 'Gene', '25780', (0, 7))	('uveal melanomas', 'Disease', 'MESH:C536494', (168, 183))	('mutations', 'Var', (119, 128))	('Mutant', 'Var', (49, 55))	('MAPK', 'molecular_function', 'GO:0004707', ('204', '208'))	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('UMs', 'Phenotype', 'HP:0007716', (185, 188))	('RasGRP3', 'Gene', (0, 7))	('activates', 'PosReg', (194, 203))	('Galphaq signaling', 'MPA', (98, 115))	('Melanoma', 'Disease', (62, 70))	('MAPK', 'Enzyme', (204, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (168, 182))	('Melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('activation', 'PosReg', (84, 94))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('uveal melanomas', 'Disease', (168, 183))	('uveal melanomas', 'Phenotype', 'HP:0007716', (168, 183))	('Activation', 'PosReg', (30, 40))	('GNA11', 'Gene', '2767', (140, 145))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
32840	28486107	We identified PKC delta and epsilon as required and sufficient to activate MAPK in GNAQ mutant melanomas.	('PKC delta', 'Gene', (14, 23))	('MAPK', 'Gene', (75, 79))	('melanomas', 'Disease', (95, 104))	('PKC delta', 'Gene', '5580', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('activate', 'PosReg', (66, 74))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('mutant', 'Var', (88, 94))	('GNAQ', 'Gene', (83, 87))
32841	28486107	MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM.	('mutation', 'Var', (133, 141))	('Ras', 'Chemical', 'MESH:D011883', (27, 30))	('MAPK', 'Gene', (0, 4))	('Ras', 'Chemical', 'MESH:D011883', (48, 51))	('activation', 'PosReg', (5, 15))	('UM', 'Phenotype', 'HP:0007716', (145, 147))	('GNAQ/11', 'Gene', (125, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('MAPK activation', 'biological_process', 'GO:0000187', ('0', '15'))
32844	28486107	find that Ras is required for GNAQ-mediated MAPK activation and identify PKC delta, epsilon and RasGRP3 as components of a signaling module necessary and sufficient to activate the Ras/MAPK pathway in GNAQ mutant uveal melanoma (UM).	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('Ras', 'Chemical', 'MESH:D011883', (181, 184))	('PKC delta', 'Gene', '5580', (73, 82))	('MAPK activation', 'biological_process', 'GO:0000187', ('44', '59'))	('GNAQ', 'Gene', (201, 205))	('Ras/MAPK pathway', 'Pathway', (181, 197))	('PKC delta', 'Gene', (73, 82))	('mutant', 'Var', (206, 212))	('PKC', 'molecular_function', 'GO:0004697', ('73', '76'))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('uveal melanoma', 'Disease', 'MESH:C536494', (213, 227))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('uveal melanoma', 'Disease', (213, 227))	('Ras', 'Chemical', 'MESH:D011883', (96, 99))	('Ras', 'Chemical', 'MESH:D011883', (10, 13))	('activate', 'PosReg', (168, 176))	('UM', 'Phenotype', 'HP:0007716', (229, 231))	('uveal melanoma', 'Phenotype', 'HP:0007716', (213, 227))
32848	28486107	Instead, UM harbors mutually exclusive mutations in GNAQ, GNA11, PLCB4, or cysteinyl leukotriene receptor 2 (CYSLTR2).	('CYSLTR2', 'Gene', (109, 116))	('cysteinyl leukotriene receptor 2', 'Gene', (75, 107))	('PLCB4', 'Gene', '5332', (65, 70))	('CYSLTR2', 'Gene', '57105', (109, 116))	('mutations', 'Var', (39, 48))	('GNA11', 'Gene', (58, 63))	('UM', 'Phenotype', 'HP:0007716', (9, 11))	('PLCB4', 'Gene', (65, 70))	('GNAQ', 'Gene', (52, 56))	('cysteinyl leukotriene receptor 2', 'Gene', '57105', (75, 107))	('GNA11', 'Gene', '2767', (58, 63))
32851	28486107	Approximately 95% of GNAQ and GNA11 mutations in melanoma affect codons 209 (Q209) of the G proteins with only 5% affecting codon 183 (R183) in the Ras-like domain.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('GNA11', 'Gene', (30, 35))	('G proteins', 'Protein', (90, 100))	('mutations', 'Var', (36, 45))	('GNAQ', 'Gene', (21, 25))	('Ras', 'Chemical', 'MESH:D011883', (148, 151))	('GNA11', 'Gene', '2767', (30, 35))	('codons', 'MPA', (65, 71))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('affect', 'Reg', (58, 64))
32852	28486107	The respective mutations result in complete or partial loss of GTPase activity, thereby locking GNAQ/11 into its active protein, GTP-bound conformation, resulting in a dominant acting oncogene that transforms melanocytes.	('loss', 'NegReg', (55, 59))	('activity', 'MPA', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('GTPase', 'Enzyme', (63, 69))	('mutations', 'Var', (15, 24))	('oncogene', 'CPA', (184, 192))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('GTPase activity', 'molecular_function', 'GO:0003924', ('63', '78'))	('GTP', 'Chemical', 'MESH:D006160', (129, 132))
32854	28486107	Recently, mutations in the CYSLTR2, a Gq-coupled GPCR, and the downstream effector of Galphaq PLCB4, encoding a phospholipase C beta(PLC beta) isoform, have been reported in the small percentage of UMs without GNAQ or GNA11 mutations.	('PLC', 'cellular_component', 'GO:0042824', ('133', '136'))	('CYSLTR2', 'Gene', '57105', (27, 34))	('GNA11', 'Gene', '2767', (218, 223))	('GNA11', 'Gene', (218, 223))	('CYSLTR2', 'Gene', (27, 34))	('eta', 'Gene', '1909', (138, 141))	('eta', 'Gene', (138, 141))	('PLCB4', 'Gene', '5332', (94, 99))	('reported', 'Reg', (162, 170))	('UM', 'Phenotype', 'HP:0007716', (198, 200))	('UMs', 'Phenotype', 'HP:0007716', (198, 201))	('eta', 'Gene', '1909', (129, 132))	('eta', 'Gene', (129, 132))	('mutations', 'Var', (10, 19))	('PLCB4', 'Gene', (94, 99))
32855	28486107	In the TCGA, 78 out of 80 human UMs have mutations in either GNAQ, GNA11, PLCB4, or CYSLTR2, indicating that UM is defined by activating mutations in the GNAQ/11 pathway.	('mutations', 'Var', (41, 50))	('PLCB4', 'Gene', (74, 79))	('GNA11', 'Gene', (67, 72))	('UMs', 'Phenotype', 'HP:0007716', (32, 35))	('GNA11', 'Gene', '2767', (67, 72))	('GNAQ', 'Gene', (61, 65))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('CYSLTR2', 'Gene', '57105', (84, 91))	('UM', 'Phenotype', 'HP:0007716', (109, 111))	('PLCB4', 'Gene', '5332', (74, 79))	('CYSLTR2', 'Gene', (84, 91))	('human', 'Species', '9606', (26, 31))	('activating', 'PosReg', (126, 136))
32857	28486107	PLC beta, a direct downstream effector of mutant GNAQ/11, hydrolyzes the membrane phospholipid phosphatidylinositol 4,5-bisphosphate to release two potent second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).	('mutant', 'Var', (42, 48))	('phospholipid phosphatidylinositol 4,5-bisphosphate', 'Chemical', '-', (82, 132))	('GNAQ/11', 'Gene', (49, 56))	('membrane', 'cellular_component', 'GO:0016020', ('73', '81'))	('release two potent second messengers', 'MPA', (136, 172))	('inositol 1,4,5-trisphosphate', 'Chemical', 'MESH:D015544', (174, 202))	('PLC', 'cellular_component', 'GO:0042824', ('0', '3'))	('IP3', 'Chemical', 'MESH:D015544', (204, 207))	('eta', 'Gene', '1909', (5, 8))	('DAG', 'Chemical', 'MESH:D004075', (229, 232))	('diacylglycerol', 'MPA', (213, 227))	('diacylglycerol', 'Chemical', 'MESH:D004075', (213, 227))	('eta', 'Gene', (5, 8))
32863	28486107	The specific PKC isoforms that mediate the activating effect on the MAPK pathway in the context of GNAQ or GNA11 mutations remain unclear.	('PKC', 'Gene', '112476', (13, 16))	('GNAQ', 'Gene', (99, 103))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('mutations', 'Var', (113, 122))	('MAPK pathway', 'Pathway', (68, 80))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('PKC', 'Gene', (13, 16))	('GNA11', 'Gene', '2767', (107, 112))	('GNA11', 'Gene', (107, 112))
32864	28486107	Recent studies have also demonstrated that mutant GNAQ/11 promote UM tumorigenesis by activating YAP independent of PLC beta.	('YAP', 'Gene', '10413', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('tumor', 'Disease', (69, 74))	('promote', 'PosReg', (58, 65))	('eta', 'Gene', '1909', (121, 124))	('activating', 'Reg', (86, 96))	('PLC', 'cellular_component', 'GO:0042824', ('116', '119'))	('YAP', 'Gene', (97, 100))	('mutant', 'Var', (43, 49))	('eta', 'Gene', (121, 124))	('GNAQ/11', 'Gene', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
32865	28486107	Furthermore, prior studies have shown that PKC inhibition alone in UM cell lines is not sufficient to completely suppress MAPK signaling, suggesting that PKC-independent effectors may be involved that mediate MAPK signaling in GNAQ/11 mutant cells.	('MAPK', 'molecular_function', 'GO:0004707', ('209', '213'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('122', '136'))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('PKC', 'molecular_function', 'GO:0004697', ('43', '46'))	('PKC', 'Gene', '112476', (43, 46))	('MAPK signaling', 'MPA', (122, 136))	('suppress', 'NegReg', (113, 121))	('PKC', 'molecular_function', 'GO:0004697', ('154', '157'))	('UM', 'Phenotype', 'HP:0007716', (67, 69))	('MAPK signaling', 'biological_process', 'GO:0000165', ('209', '223'))	('PKC', 'Gene', (154, 157))	('PKC', 'Gene', (43, 46))	('mutant', 'Var', (235, 241))	('PKC', 'Gene', '112476', (154, 157))
32867	28486107	Studies in BRAFV600E melanomas suggest that therapeutically meaningful responses in patients can only be expected if marked suppression of the MAPK pathway is achieved.	('BRAFV600E', 'Var', (11, 20))	('BRAFV600E', 'Mutation', 'rs113488022', (11, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('patients', 'Species', '9606', (84, 92))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('MAPK pathway', 'Pathway', (143, 155))
32868	28486107	To achieve this goal in UM, a more refined understanding of the connection between MAPK signaling and GNAQ/11 mutant in uveal melanoma is required to develop more effective targeting strategies.	('GNAQ/11', 'Gene', (102, 109))	('UM', 'Phenotype', 'HP:0007716', (24, 26))	('MAPK signaling', 'biological_process', 'GO:0000165', ('83', '97'))	('mutant', 'Var', (110, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (120, 134))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (120, 134))	('uveal melanoma', 'Disease', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))
32869	28486107	Here, the goal of the current study is to investigate which PKC isoforms activate MAPK signaling and how PKC signaling relays to the MAPK pathway in GNAQ/11 mutant melanoma, thus identifying specific therapeutic targets for cancers driven by oncogenic GNAQ/11.	('PKC', 'molecular_function', 'GO:0004697', ('105', '108'))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('GNAQ/11', 'Gene', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('MAPK signaling', 'biological_process', 'GO:0000165', ('82', '96'))	('PKC', 'Gene', (60, 63))	('PKC', 'Gene', '112476', (105, 108))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('PKC', 'Gene', (105, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('activate', 'PosReg', (73, 81))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))	('mutant', 'Var', (157, 163))	('PKC', 'molecular_function', 'GO:0004697', ('60', '63'))	('PKC', 'Gene', '112476', (60, 63))	('MAPK signaling', 'Pathway', (82, 96))
32872	28486107	To overcome this limitation we tested the specificity of commercially available PKC antibodies by transfecting HA-tagged full-length PKC isoforms or their catalytic subunits (Figures S1A and S1B) into 293FT cells and identified a panel of specific antibodies that was used to screen a panel of melanoma cells with or without GNAQ/11 mutations.	('PKC', 'molecular_function', 'GO:0004697', ('80', '83'))	('PKC', 'Gene', '112476', (133, 136))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('PKC', 'molecular_function', 'GO:0004697', ('133', '136'))	('PKC', 'Gene', (80, 83))	('PKC', 'Gene', '112476', (80, 83))	('tested', 'Reg', (31, 37))	('293FT', 'CellLine', 'CVCL:6911', (201, 206))	('mutations', 'Var', (333, 342))	('GNAQ/11', 'Gene', (325, 332))	('PKC', 'Gene', (133, 136))
32873	28486107	As shown in Figure 1A, five PKC isoforms (PKC alpha, delta, epsilon, zeta, and iota) were consistently expressed throughout all six UM cells with GNAQ/11 mutations tested (MEL202, 92-1, OMM1.3, and MEL270 with GNAQ mutations, and OMM-GN11 and UPMD-1 with GNA11 mutations).	('mutations', 'Var', (261, 270))	('PKC alpha, delta, epsilon, zeta, and iota', 'Gene', '5578;5580;5581;5590', (42, 83))	('MEL270', 'Var', (198, 204))	('PKC', 'Gene', (42, 45))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', '112476', (42, 45))	('GNAQ/11', 'Gene', (146, 153))	('PKC', 'Gene', '112476', (28, 31))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('GNAQ', 'Gene', (210, 214))	('mutations', 'Var', (154, 163))	('PKC', 'molecular_function', 'GO:0004697', ('42', '45'))	('GNA11', 'Gene', '2767', (255, 260))	('GNA11', 'Gene', (255, 260))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))
32878	28486107	While PKC beta II showed differential expression between melanoma cell lines with and without GNAQ/11 mutations, it was not expressed in all GNAQ/11 mutant cell lines, ruling it out as a universal effector downstream of mutant GNAQ/11.	('PKC', 'molecular_function', 'GO:0004697', ('6', '9'))	('PKC beta', 'Gene', '5579', (6, 14))	('GNAQ/11', 'Gene', (94, 101))	('expression', 'MPA', (38, 48))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('mutations', 'Var', (102, 111))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('PKC beta', 'Gene', (6, 14))
32879	28486107	While PKC zeta and iota, where found to be expressed in GNAQ/11 mutant cell lines, are classified as atypical PKCs as they are not activated by either calcium or DAG, making them unlikely candidate effectors of mutant Galphaq.	('PKC zeta', 'Gene', (6, 14))	('PKC', 'Gene', (6, 9))	('PKC', 'Gene', '112476', (6, 9))	('PKC', 'molecular_function', 'GO:0004697', ('6', '9'))	('GNAQ/11', 'Gene', (56, 63))	('PKC', 'Gene', (110, 113))	('PKC zeta', 'Gene', '5590', (6, 14))	('PKC', 'Gene', '112476', (110, 113))	('iota', 'Chemical', '-', (19, 23))	('calcium', 'Chemical', 'MESH:D002118', (151, 158))	('DAG', 'Chemical', 'MESH:D004075', (162, 165))	('mutant', 'Var', (64, 70))
32880	28486107	By contrast, PKC alpha, delta, and epsilon, which were consistently expressed in all UM cell lines with GNAQ or GNA11 mutations, are candidates to mediate MAPK signaling in GNAQ mutant melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('GNA11', 'Gene', (112, 117))	('melanomas', 'Disease', (185, 194))	('MAPK signaling', 'biological_process', 'GO:0000165', ('155', '169'))	('mutations', 'Var', (118, 127))	('mediate', 'Reg', (147, 154))	('GNA11', 'Gene', '2767', (112, 117))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('PKC alpha, delta, and epsilon', 'Gene', '5578;5580;5581', (13, 42))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('GNAQ', 'Gene', (104, 108))	('UM', 'Phenotype', 'HP:0007716', (85, 87))	('PKC', 'molecular_function', 'GO:0004697', ('13', '16'))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))
32881	28486107	To determine which of these PKC isoforms mediate MAPK signaling in GNAQ/11 mutant cells, we performed small interfering RNAs (siRNA)-mediated knockdown of PKC isoforms (PKC alpha, delta, epsilon as well as zeta used as control) alone or in combination in three GNAQ mutant cell lines (92-1, OMM1.3, and MEL202) and examined MAPK signaling at the level of pMEK and pERK.	('PKC', 'Gene', (155, 158))	('PKC', 'Gene', '112476', (28, 31))	('MEK', 'Gene', '5609', (356, 359))	('PKC', 'Gene', '112476', (169, 172))	('MAPK signaling', 'biological_process', 'GO:0000165', ('49', '63'))	('MAPK', 'molecular_function', 'GO:0004707', ('324', '328'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('324', '338'))	('PKC', 'molecular_function', 'GO:0004697', ('155', '158'))	('PKC alpha, delta, epsilon as well as zeta', 'Gene', '5578;5580', (169, 210))	('MAPK', 'molecular_function', 'GO:0004707', ('49', '53'))	('MEK', 'Gene', (356, 359))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', (169, 172))	('PKC', 'molecular_function', 'GO:0004697', ('28', '31'))	('pERK', 'Gene', (364, 368))	('PKC', 'molecular_function', 'GO:0004697', ('169', '172'))	('pERK', 'Gene', '9451', (364, 368))	('PKC', 'Gene', '112476', (155, 158))	('mutant', 'Var', (75, 81))
32882	28486107	As shown in Figures 1B and S1C, knockdown of either PKC delta or epsilon alone resulted in partial inhibition of pMEK and pERK, whereas knockdown of PKC alpha and PKC zeta had no significant effect.	('pERK', 'Gene', (122, 126))	('PKC alpha', 'Gene', (149, 158))	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('PKC delta', 'Gene', (52, 61))	('pERK', 'Gene', '9451', (122, 126))	('PKC', 'molecular_function', 'GO:0004697', ('149', '152'))	('knockdown', 'Var', (32, 41))	('MEK', 'Gene', (114, 117))	('inhibition', 'NegReg', (99, 109))	('MEK', 'Gene', '5609', (114, 117))	('PKC zeta', 'Gene', (163, 171))	('PKC delta', 'Gene', '5580', (52, 61))	('PKC alpha', 'Gene', '5578', (149, 158))	('PKC', 'molecular_function', 'GO:0004697', ('163', '166'))	('PKC zeta', 'Gene', '5590', (163, 171))
32883	28486107	Combined knockdown of PKC delta and epsilon inhibited pMEK and pERK levels similar to knockdown of GNAQ itself.	('PKC delta', 'Gene', '5580', (22, 31))	('knockdown', 'Var', (9, 18))	('epsilon', 'Enzyme', (36, 43))	('PKC', 'molecular_function', 'GO:0004697', ('22', '25'))	('inhibited', 'NegReg', (44, 53))	('pERK', 'Gene', '9451', (63, 67))	('pERK', 'Gene', (63, 67))	('MEK', 'Gene', (55, 58))	('MEK', 'Gene', '5609', (55, 58))	('PKC delta', 'Gene', (22, 31))
32886	28486107	By contrast, knockdown of PKC betaII in 92-1 with GNAQ mutation (Figure 1B) and OMM-GN11 and UPMD-2 cell lines with GNA11 mutation (Figure S1E) had no effect on pMEK and pERK.	('PKC beta', 'Gene', '5579', (26, 34))	('GNA11', 'Gene', (116, 121))	('UPMD-2', 'CellLine', 'CVCL:C298', (93, 99))	('GNA11', 'Gene', '2767', (116, 121))	('PKC beta', 'Gene', (26, 34))	('pERK', 'Gene', '9451', (170, 174))	('pERK', 'Gene', (170, 174))	('MEK', 'Gene', (162, 165))	('MEK', 'Gene', '5609', (162, 165))	('mutation', 'Var', (55, 63))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('GNAQ', 'Gene', (50, 54))
32887	28486107	To establish an initial connection between specific PKC isoforms and mutant GNAQ, we co-transfected PKC isoforms (alpha, delta, epsilon, zeta, iota) together with GNAQQ209L into the 293FT model cell line.	('PKC', 'molecular_function', 'GO:0004697', ('52', '55'))	('PKC isoforms (alpha, delta, epsilon, zeta, iota', 'Gene', '5578;5580;5581;5590', (100, 147))	('293FT', 'CellLine', 'CVCL:6911', (182, 187))	('PKC', 'Gene', (100, 103))	('mutant', 'Var', (69, 75))	('PKC', 'Gene', '112476', (100, 103))	('PKC', 'Gene', (52, 55))	('PKC', 'Gene', '112476', (52, 55))	('GNAQQ209L', 'Chemical', '-', (163, 172))	('PKC', 'molecular_function', 'GO:0004697', ('100', '103'))
32889	28486107	We confirmed that the synergistic effect was dependent on the kinase activity of PKC delta and epsilon, by using kinase-dead mutants of PKC delta and epsilon (Figure S2A).	('PKC delta', 'Gene', '5580', (136, 145))	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('PKC delta', 'Gene', '5580', (81, 90))	('kinase activity', 'molecular_function', 'GO:0016301', ('62', '77'))	('mutants', 'Var', (125, 132))	('PKC', 'molecular_function', 'GO:0004697', ('136', '139'))	('dependent', 'Reg', (45, 54))	('PKC delta', 'Gene', (136, 145))	('PKC delta', 'Gene', (81, 90))
32890	28486107	Furthermore, only GNAQQ209L, but not wild-type GNAQ, synergized with PKC delta and epsilon, indicating that the synergy depended on active GNAQ (Figure S2B).	('PKC delta', 'Gene', (69, 78))	('PKC delta', 'Gene', '5580', (69, 78))	('GNAQQ209L', 'Chemical', '-', (18, 27))	('GNAQQ209L', 'Var', (18, 27))	('PKC', 'molecular_function', 'GO:0004697', ('69', '72'))
32894	28486107	In UM cell lines with GNAQ/11 mutations, PKC alpha and zeta were localized in the cytosolic fraction, while a considerable portion of the PKC delta and epsilon signal was localized at the membrane (Figure S2E).	('PKC delta', 'Gene', (138, 147))	('PKC', 'molecular_function', 'GO:0004697', ('41', '44'))	('PKC alpha', 'Gene', '5578', (41, 50))	('PKC delta', 'Gene', '5580', (138, 147))	('eta', 'Gene', '1909', (56, 59))	('eta', 'Gene', (56, 59))	('mutations', 'Var', (30, 39))	('GNAQ/11', 'Gene', (22, 29))	('PKC', 'molecular_function', 'GO:0004697', ('138', '141'))	('PKC alpha', 'Gene', (41, 50))	('membrane', 'cellular_component', 'GO:0016020', ('188', '196'))	('UM', 'Phenotype', 'HP:0007716', (3, 5))
32895	28486107	These data further support the notion that the main active isoforms in the context of GNAQ/11 mutations are PKC delta and epsilon.	('GNAQ/11', 'Gene', (86, 93))	('mutations', 'Var', (94, 103))	('PKC delta', 'Gene', (108, 117))	('epsilon', 'Enzyme', (122, 129))	('PKC delta', 'Gene', '5580', (108, 117))	('PKC', 'molecular_function', 'GO:0004697', ('108', '111'))
32896	28486107	As previously shown, cell proliferation of GNAQ mutant UM cells depends on GNAQ and PKC as knockdown of GNAQ or PKC inhibition suppress cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('21', '39'))	('mutant', 'Var', (48, 54))	('cell proliferation', 'CPA', (21, 39))	('GNAQ', 'Gene', (43, 47))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('PKC', 'molecular_function', 'GO:0004697', ('84', '87'))	('PKC', 'molecular_function', 'GO:0004697', ('112', '115'))	('PKC', 'Gene', (84, 87))	('PKC', 'Gene', '112476', (84, 87))	('suppress', 'NegReg', (127, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('PKC', 'Gene', (112, 115))	('PKC', 'Gene', '112476', (112, 115))	('cell proliferation', 'CPA', (136, 154))
32898	28486107	Combined knockdown of PKC delta and epsilon, but not alpha, reduced cell proliferation similar to knockdown of GNAQ in GNAQ mutant cell lines (92-1 and OMM1.3), while the knockdown had no effect in cell lines without GNAQ mutations (Figure 1E).	('PKC delta', 'Gene', '5580', (22, 31))	('PKC', 'molecular_function', 'GO:0004697', ('22', '25'))	('cell proliferation', 'CPA', (68, 86))	('GNAQ', 'Gene', (119, 123))	('mutant', 'Var', (124, 130))	('reduced', 'NegReg', (60, 67))	('PKC delta', 'Gene', (22, 31))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
32900	28486107	Taken together, these experiments indicate that PKC delta and epsilon are essential for MAPK signaling and proliferation of UM cell lines with GNAQ mutations, but not in related cell lines without GNAQ mutations.	('PKC delta', 'Gene', (48, 57))	('mutations', 'Var', (148, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('GNAQ', 'Gene', (143, 147))	('UM', 'Phenotype', 'HP:0007716', (124, 126))	('PKC delta', 'Gene', '5580', (48, 57))	('MAPK signaling', 'biological_process', 'GO:0000165', ('88', '102'))
32901	28486107	To determine at which level mutant GNAQ activates the MAP-kinase pathway, we investigated whether the activation depended on Ras.	('mutant', 'Var', (28, 34))	('MAP', 'molecular_function', 'GO:0004239', ('54', '57'))	('activates', 'PosReg', (40, 49))	('Ras', 'Chemical', 'MESH:D011883', (125, 128))	('MAP-kinase pathway', 'Pathway', (54, 72))	('GNAQ', 'Gene', (35, 39))
32902	28486107	We found that 293FT cells transfected with GNAQQ209L had increased levels of Ras-GTP compared with controls, which could be further increased by co-transfection of PKC delta and epsilon compared with co-transfection of GFP (Figure 2A), while PKC alpha or zeta together with GNAQQ209L also increased Ras-GTP level, albeit to a lesser extent (Figure S2H).	('PKC delta', 'Gene', '5580', (164, 173))	('Ras-GTP level', 'MPA', (299, 312))	('PKC', 'molecular_function', 'GO:0004697', ('242', '245'))	('eta', 'Gene', (256, 259))	('PKC delta', 'Gene', (164, 173))	('increased', 'PosReg', (132, 141))	('Ras-GTP', 'Chemical', '-', (77, 84))	('GNAQQ209L', 'Var', (43, 52))	('Ras-GTP', 'Chemical', '-', (299, 306))	('PKC alpha', 'Gene', (242, 251))	('increased', 'PosReg', (289, 298))	('levels', 'MPA', (67, 73))	('increased', 'PosReg', (57, 66))	('Ras-GTP', 'MPA', (77, 84))	('293FT', 'CellLine', 'CVCL:6911', (14, 19))	('GNAQQ209L', 'Chemical', '-', (43, 52))	('PKC', 'molecular_function', 'GO:0004697', ('164', '167'))	('GNAQQ209L', 'Chemical', '-', (274, 283))	('PKC alpha', 'Gene', '5578', (242, 251))	('eta', 'Gene', '1909', (256, 259))
32906	28486107	These results indicate that activation of MAPK signaling in GNAQ mutant cells requires the presence of Ras, with little or no specific preference of any specific Ras family member.	('GNAQ', 'Gene', (60, 64))	('mutant', 'Var', (65, 71))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('Ras', 'Chemical', 'MESH:D011883', (103, 106))	('Ras', 'Chemical', 'MESH:D011883', (162, 165))	('activation', 'PosReg', (28, 38))	('Ras', 'Protein', (103, 106))	('MAPK signaling', 'biological_process', 'GO:0000165', ('42', '56'))	('MAPK signaling', 'MPA', (42, 56))
32907	28486107	To determine how mutant GNAQ activates Ras/MAPK signaling, we compared gene expression profiles between five GNAQ or GNA11 mutant melanoma cells (GNAQmt: 92-1, MEL202, OMM1.3; GNA11mt: UPMD-1, OMM-GN11) and five GNAQ/11 wild-type melanoma cells with either NRAS (SK-MEL-2, MM415, and MM485, all from cutaneous origins) or BRAF mutations (SK-MEL-5 from cutaneous origin and MUM2C from uveal origin).	('mutations', 'Var', (327, 336))	('GNAQ', 'Gene', (109, 113))	('gene expression', 'biological_process', 'GO:0010467', ('71', '86'))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('GNA11', 'Gene', (117, 122))	('Ras', 'Chemical', 'MESH:D011883', (39, 42))	('mutant', 'Var', (17, 23))	('GNA11', 'Gene', '2767', (176, 181))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('UM', 'Phenotype', 'HP:0007716', (374, 376))	('melanoma', 'Disease', (130, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))	('NRAS', 'Gene', '4893', (257, 261))	('BRAF', 'Gene', (322, 326))	('BRAF', 'Gene', '673', (322, 326))	('MAPK signaling', 'biological_process', 'GO:0000165', ('43', '57'))	('GNA11', 'Gene', '2767', (117, 122))	('GNA11', 'Gene', (176, 181))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('NRAS', 'Gene', (257, 261))	('mutant', 'Var', (123, 129))
32910	28486107	qRT-PCR experiments confirmed that RasGRP3 mRNA is markedly upregulated (>100-fold) in melanoma cell lines with GNAQ or GNA11 mutations, compared with normal melanocytes or melanoma cell lines with other mutations.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('upregulated', 'PosReg', (60, 71))	('GNAQ', 'Gene', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('GNA11', 'Gene', (120, 125))	('melanoma', 'Disease', (173, 181))	('mRNA', 'MPA', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('GNA11', 'Gene', '2767', (120, 125))	('RasGRP3', 'Gene', (35, 42))	('mutations', 'Var', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
32911	28486107	Other RasGRP family members, as well as the RasGEF SOS1, did not show any increased expression levels in melanoma cell lines with GNAQ or GNA11 mutations or showed differential expression differences in these cells (Figure S3A).	('SOS1', 'Gene', '6654', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('GNAQ', 'Gene', (130, 134))	('Ras', 'Chemical', 'MESH:D011883', (6, 9))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('GNA11', 'Gene', (138, 143))	('Ras', 'Chemical', 'MESH:D011883', (44, 47))	('SOS1', 'Gene', (51, 55))	('RasGRP', 'Gene', '10125', (6, 12))	('mutations', 'Var', (144, 153))	('GNA11', 'Gene', '2767', (138, 143))	('RasGRP', 'Gene', (6, 12))
32913	28486107	Interestingly, the four samples in the 478 samples of cutaneous melanoma samples that harbor GNAQ or GNA11 hotspot mutations, also had elevated RasGRP3 mRNA with levels comparable with those present in UM (Figure 3D).	('GNA11', 'Gene', '2767', (101, 106))	('GNA11', 'Gene', (101, 106))	('UM', 'Phenotype', 'HP:0007716', (202, 204))	('mutations', 'Var', (115, 124))	('elevated', 'PosReg', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('cutaneous melanoma', 'Disease', (54, 72))	('RasGRP3', 'Protein', (144, 151))	('GNAQ', 'Gene', (93, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
32915	28486107	We found that both RasGRP3 and p-RasGRP3 (T133) protein levels in melanoma cell lines with GNAQ mutations were significantly higher than in cell lines without GNAQ mutations, including SK-MEL-5 and UACC257 (Figure S3D).	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('T133', 'Chemical', '-', (42, 46))	('GNAQ', 'Gene', (91, 95))	('higher', 'PosReg', (125, 131))	('protein levels', 'MPA', (48, 62))	('mutations', 'Var', (96, 105))
32917	28486107	As shown in Figure S3E, two conjunctival melanoma cell lines that had no GNAQ/11 mutations (CRMM1 and CRMM2) had no detectable expression of RasGRP3 protein by western blot and immunohistochemistry (Figure 3F), while UM cell lines with GNAQ mutation (92-1, MEL270) or GNA11 mutation (OMM1) showed strong RasGRP3 immunoreactivity (Figures 3F and S3F).	('GNA11', 'Gene', '2767', (268, 273))	('mutation', 'Var', (274, 282))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('GNAQ/11', 'Gene', (73, 80))	('conjunctival melanoma', 'Disease', (28, 49))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (28, 49))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (28, 49))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mutations', 'Var', (81, 90))	('RasGRP3 immunoreactivity', 'MPA', (304, 328))	('GNA11', 'Gene', (268, 273))	('UM', 'Phenotype', 'HP:0007716', (217, 219))
32918	28486107	RasGRP3 protein expression was also detected by immunohistochemistry in UM tissues with GNAQ and GNA11 mutations (Figure 3G).	('mutations', 'Var', (103, 112))	('GNAQ', 'Gene', (88, 92))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('GNA11', 'Gene', '2767', (97, 102))	('GNA11', 'Gene', (97, 102))
32919	28486107	Conversely, expression of GNAQQ209L or GNA11Q209L, but not BRAFV600E, in human melanocytes significantly increased total RasGRP3 and p-RasGRP3 levels (Figure 4B).	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('GNA11', 'Gene', (39, 44))	('GNAQQ209L', 'Chemical', '-', (26, 35))	('GNAQQ209L', 'Var', (26, 35))	('p-RasGRP3 levels', 'MPA', (133, 149))	('GNA11', 'Gene', '2767', (39, 44))	('human', 'Species', '9606', (73, 78))	('RasGRP3', 'MPA', (121, 128))	('increased', 'PosReg', (105, 114))
32923	28486107	The effect of PKC inhibition on RasGRP3 expression levels and p-RasGRP3 levels was dose dependent in three different GNAQ mutant cell lines incubated with two different PKC inhibitors, AEB071 and AHT956 for 24 hr (Figures 4D and S4B), but had no effects on RasGRP3 expression while inhibiting p-RasGRP3 in melanoma cell lines with BrafV600E or NRAS mutations (Figure S4C), which have very weak expression of RasGRP3 compared with GNAQ mutant cells.	('BrafV600E', 'Mutation', 'rs113488022', (331, 340))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('melanoma', 'Disease', (306, 314))	('NRAS', 'Gene', (344, 348))	('PKC', 'Gene', (14, 17))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('PKC', 'Gene', '112476', (14, 17))	('PKC', 'molecular_function', 'GO:0004697', ('169', '172'))	('PKC', 'Gene', (169, 172))	('PKC', 'Gene', '112476', (169, 172))	('NRAS', 'Gene', '4893', (344, 348))	('PKC', 'molecular_function', 'GO:0004697', ('14', '17'))	('inhibiting', 'NegReg', (282, 292))	('mutant', 'Var', (122, 128))	('BrafV600E', 'Var', (331, 340))
32925	28486107	TPA also increased RasGRP3 expression in human melanoma cells with BRAF mutations (Figure S4D).	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', '673', (67, 71))	('TPA', 'Gene', '5327', (0, 3))	('TPA', 'molecular_function', 'GO:0031299', ('0', '3'))	('BRAF', 'Gene', (67, 71))	('RasGRP3', 'Protein', (19, 26))	('human', 'Species', '9606', (41, 46))	('increased', 'PosReg', (9, 18))	('expression', 'MPA', (27, 37))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('TPA', 'Gene', (0, 3))
32926	28486107	These data indicate that activation of PKC in melanocytic cells results in upregulation of RasGRP3 expression as well as T133 phosphorylation of RasGRP3, and that the markedly elevated protein and phosphorylation levels found in GNAQ mutant melanoma cells are a consequence of Galphaq-mediated upregulation of PKC activity.	('GNAQ', 'Gene', (229, 233))	('mutant', 'Var', (234, 240))	('melanoma', 'Disease', (241, 249))	('expression', 'MPA', (99, 109))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('T133', 'Chemical', '-', (121, 125))	('PKC activity', 'molecular_function', 'GO:0004697', ('310', '322'))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('upregulation', 'PosReg', (294, 306))	('T133 phosphorylation', 'MPA', (121, 141))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('elevated', 'PosReg', (176, 184))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('PKC', 'Gene', '112476', (310, 313))	('RasGRP3', 'Enzyme', (91, 98))	('PKC', 'Gene', '112476', (39, 42))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('PKC', 'Gene', (310, 313))	('upregulation', 'PosReg', (75, 87))	('PKC', 'Gene', (39, 42))	('PKC', 'molecular_function', 'GO:0004697', ('39', '42'))
32927	28486107	Among the four PKC isoforms, PKC alpha, delta, epsilon, and zeta, which we found to be invariably expressed in GNAQ or GNA11 mutant UM cell lines, only PKC delta and epsilon robustly phosphorylated T133 of RasGRP3, whereas PKC alpha and zeta had weaker effects with no significant consequences on MAPK signaling (Figures 4F and S4F).	('eta', 'Gene', (61, 64))	('PKC alpha, delta, epsilon, and zeta', 'Gene', '5578;5580;5581;5590', (29, 64))	('PKC', 'molecular_function', 'GO:0004697', ('152', '155'))	('eta', 'Gene', '1909', (238, 241))	('UM', 'Phenotype', 'HP:0007716', (132, 134))	('GNA11', 'Gene', (119, 124))	('PKC', 'Gene', '112476', (29, 32))	('PKC', 'Gene', (29, 32))	('RasGRP3', 'Enzyme', (206, 213))	('PKC alpha', 'Gene', '5578', (223, 232))	('PKC alpha', 'Gene', (29, 38))	('PKC', 'molecular_function', 'GO:0004697', ('223', '226'))	('phosphorylated', 'MPA', (183, 197))	('T133', 'Chemical', '-', (198, 202))	('eta', 'Gene', (238, 241))	('PKC delta', 'Gene', '5580', (152, 161))	('PKC', 'Gene', '112476', (152, 155))	('T133', 'Var', (198, 202))	('MAPK', 'molecular_function', 'GO:0004707', ('297', '301'))	('mutant', 'Var', (125, 131))	('PKC', 'Gene', '112476', (223, 226))	('PKC delta', 'Gene', (152, 161))	('GNA11', 'Gene', '2767', (119, 124))	('PKC', 'Gene', (152, 155))	('PKC alpha', 'Gene', '5578', (29, 38))	('PKC', 'Gene', '112476', (15, 18))	('eta', 'Gene', '1909', (61, 64))	('PKC', 'molecular_function', 'GO:0004697', ('29', '32'))	('PKC', 'molecular_function', 'GO:0004697', ('15', '18'))	('MAPK signaling', 'MPA', (297, 311))	('PKC', 'Gene', (223, 226))	('PKC', 'Gene', (15, 18))	('MAPK signaling', 'biological_process', 'GO:0000165', ('297', '311'))	('PKC alpha', 'Gene', (223, 232))
32929	28486107	We ruled out a positive feedback loop involving MAPK activation and RasGRP3 regulation by suppressing MAP-kinase signaling using the two different MEK inhibitors PD0325901 and Trametinib (Figures 4H and S4G).	('MAPK', 'molecular_function', 'GO:0004707', ('48', '52'))	('Trametinib', 'Chemical', 'MESH:C560077', (176, 186))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('MAP-kinase signaling', 'MPA', (102, 122))	('MEK', 'Gene', (147, 150))	('MEK', 'Gene', '5609', (147, 150))	('MAP', 'molecular_function', 'GO:0004239', ('102', '105'))	('MAPK activation', 'biological_process', 'GO:0000187', ('48', '63'))	('regulation', 'biological_process', 'GO:0065007', ('76', '86'))	('suppressing', 'NegReg', (90, 101))	('PD0325901', 'Var', (162, 171))	('PD0325901', 'Chemical', 'MESH:C506614', (162, 171))
32930	28486107	The YAP1 pathway has been shown to play an important role in GNAQ mutant melanoma development.	('melanoma', 'Disease', (73, 81))	('YAP1', 'Gene', (4, 8))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('YAP1', 'Gene', '10413', (4, 8))	('GNAQ', 'Gene', (61, 65))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
32932	28486107	Combined inhibition of the YAP1 and PKC/MAPK pathways neither synergistically suppressed MAPK signaling nor increased cleaved PARP levels, compared with combined inhibition of PKC and MEK (Figures S5B and S5C).	('MAPK signaling', 'biological_process', 'GO:0000165', ('89', '103'))	('PARP', 'Gene', (126, 130))	('MAPK', 'molecular_function', 'GO:0004707', ('40', '44'))	('MAPK signaling', 'MPA', (89, 103))	('PKC', 'Gene', (36, 39))	('inhibition', 'Var', (9, 19))	('increased', 'PosReg', (108, 117))	('PKC', 'molecular_function', 'GO:0004697', ('36', '39'))	('PKC', 'Gene', '112476', (176, 179))	('S5B', 'Gene', (197, 200))	('YAP1', 'Gene', '10413', (27, 31))	('suppressed', 'NegReg', (78, 88))	('PKC', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (184, 187))	('PARP', 'Gene', '1302', (126, 130))	('YAP1', 'Gene', (27, 31))	('PKC', 'molecular_function', 'GO:0004697', ('176', '179'))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('MEK', 'Gene', (184, 187))	('PKC', 'Gene', '112476', (36, 39))	('S5B', 'Gene', '5711', (197, 200))
32934	28486107	However, knockdown of MET or inhibition with the MET inhibitor INC280 had no effect on RasGRP3 and p-RasGRP3 levels or pERK in UM cell lines (Figures S5D and S5E).	('pERK', 'Gene', (119, 123))	('knockdown', 'Var', (9, 18))	('p-RasGRP3 levels', 'MPA', (99, 115))	('RasGRP3', 'MPA', (87, 94))	('INC280', 'Gene', (63, 69))	('INC280', 'Chemical', 'MESH:C000613976', (63, 69))	('UM', 'Phenotype', 'HP:0007716', (127, 129))	('pERK', 'Gene', '9451', (119, 123))
32937	28486107	By contrast, the knockdown had no effect on the RASGEF SOS1.	('SOS1', 'Gene', (55, 59))	('SOS1', 'Gene', '6654', (55, 59))	('knockdown', 'Var', (17, 26))
32938	28486107	The PKC inhibitors AEB071 and AHT956 also both decreased RasGRP3 mRNA, also with no effect on SOS1 mRNAs (Figure S6G).	('SOS1', 'Gene', (94, 98))	('PKC', 'Gene', (4, 7))	('PKC', 'Gene', '112476', (4, 7))	('SOS1', 'Gene', '6654', (94, 98))	('AEB071', 'Var', (19, 25))	('RasGRP3', 'Protein', (57, 64))	('PKC', 'molecular_function', 'GO:0004697', ('4', '7'))	('AHT956', 'Var', (30, 36))	('decreased', 'NegReg', (47, 56))
32939	28486107	Conversely, overexpression of GNAQQ209L or GNA11Q209L in melanocytes increased RasGRP3 mRNA (Figure S6F).	('increased', 'PosReg', (69, 78))	('GNA11', 'Gene', (43, 48))	('GNAQQ209L', 'Chemical', '-', (30, 39))	('GNAQQ209L', 'Var', (30, 39))	('GNA11', 'Gene', '2767', (43, 48))	('RasGRP3 mRNA', 'MPA', (79, 91))
32941	28486107	Together, these data suggest that RasGRP3 regulation in the context of GNAQ mutations occurs transcriptionally and involves PKC signaling.	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('mutations', 'Var', (76, 85))	('GNAQ', 'Gene', (71, 75))	('PKC', 'Gene', (124, 127))	('PKC', 'Gene', '112476', (124, 127))	('RasGRP3', 'Gene', (34, 41))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('PKC', 'molecular_function', 'GO:0004697', ('124', '127'))
32942	28486107	The consistently elevated expression levels implicated RasGRP3 as a candidate protein involved in activation of Ras signaling downstream of mutant GNAQ/11.	('GNAQ/11', 'Gene', (147, 154))	('Ras signaling', 'Pathway', (112, 125))	('activation', 'PosReg', (98, 108))	('Ras', 'Chemical', 'MESH:D011883', (55, 58))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('elevated', 'PosReg', (17, 25))	('RasGRP3', 'Gene', (55, 62))	('expression levels', 'MPA', (26, 43))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('Ras', 'Chemical', 'MESH:D011883', (112, 115))	('mutant', 'Var', (140, 146))
32943	28486107	Knockdown of RasGRP3 in GNAQ mutant melanoma cell lines significantly reduced levels of pMEK and pERK, but not pAKT (Figures 5A and S7A), but had no effect in other melanoma cell lines (Figure 5B).	('MEK', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('reduced', 'NegReg', (70, 77))	('melanoma', 'Disease', (36, 44))	('MEK', 'Gene', '5609', (89, 92))	('RasGRP3', 'Gene', (13, 20))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('mutant', 'Var', (29, 35))	('GNAQ', 'Gene', (24, 28))	('pERK', 'Gene', '9451', (97, 101))	('pERK', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
32945	28486107	Knockdown of SOS1 only slightly reduced pMEK and pERK levels (Figure S7D).	('MEK', 'Gene', (41, 44))	('Knockdown', 'Var', (0, 9))	('MEK', 'Gene', '5609', (41, 44))	('pERK', 'Gene', '9451', (49, 53))	('SOS1', 'Gene', (13, 17))	('reduced', 'NegReg', (32, 39))	('pERK', 'Gene', (49, 53))	('SOS1', 'Gene', '6654', (13, 17))
32946	28486107	Knockdown of either GNAQ or RasGRP3 also decreased Ras-GTP levels in GNAQ mutant UM cell lines (Figure S7E).	('Ras-GTP levels', 'MPA', (51, 65))	('Ras-GTP', 'Chemical', '-', (51, 58))	('decreased', 'NegReg', (41, 50))	('UM', 'Phenotype', 'HP:0007716', (81, 83))	('GNAQ', 'Gene', (69, 73))	('mutant', 'Var', (74, 80))
32947	28486107	siRNA-mediated knockdown of RasGRP3 also significantly decreased proliferation of GNAQ mutant cells during a 5-day proliferation assay, whereas it had no significant effect on other melanoma cell lines (Figure 5C).	('proliferation', 'CPA', (65, 78))	('GNAQ', 'Gene', (82, 86))	('RasGRP3', 'Gene', (28, 35))	('mutant', 'Var', (87, 93))	('decreased', 'NegReg', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
32949	28486107	To further confirm that RasGRP3 modulates MAPK signaling in the setting of GNAQ mutation, we co-transfected 293FT cells with GNAQQ209L combined with individual RasGRP isoforms and examined their effects on MAPK signaling.	('RasGRP', 'Gene', '10125', (160, 166))	('RasGRP', 'Gene', (160, 166))	('GNAQ', 'Gene', (75, 79))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('RasGRP', 'Gene', '10125', (24, 30))	('GNAQQ209L', 'Var', (125, 134))	('293FT', 'CellLine', 'CVCL:6911', (108, 113))	('RasGRP', 'Gene', (24, 30))	('MAPK signaling', 'biological_process', 'GO:0000165', ('206', '220'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('42', '56'))	('examined', 'Reg', (180, 188))	('MAPK signaling', 'MPA', (42, 56))	('GNAQQ209L', 'Chemical', '-', (125, 134))	('modulates', 'Reg', (32, 41))	('mutation', 'Var', (80, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('206', '210'))
32950	28486107	As shown in Figure 5G, RasGRP1, RasGRP3, and RasGRP4 alone, but not RasGRP2, induced pERK, while only co-transfection GNAQQ209L with RasGRP1 or RasGRP3 potentiated MAPK signaling as demonstrated by markedly increased pMEK and pERK levels.	('pERK', 'Gene', (226, 230))	('pERK', 'Gene', '9451', (85, 89))	('pERK', 'Gene', (85, 89))	('pERK', 'Gene', '9451', (226, 230))	('RasGRP1', 'Gene', (23, 30))	('RasGRP1', 'Gene', (133, 140))	('GNAQQ209L', 'Var', (118, 127))	('RasGRP1', 'Gene', '10125', (23, 30))	('RasGRP1', 'Gene', '10125', (133, 140))	('MEK', 'Gene', '5609', (218, 221))	('GNAQQ209L', 'Chemical', '-', (118, 127))	('induced', 'Reg', (77, 84))	('potentiated', 'PosReg', (152, 163))	('RasGRP4', 'Gene', (45, 52))	('MAPK signaling', 'MPA', (164, 178))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))	('MEK', 'Gene', (218, 221))	('increased', 'PosReg', (207, 216))	('RasGRP4', 'Gene', '115727', (45, 52))	('MAPK signaling', 'biological_process', 'GO:0000165', ('164', '178'))
32951	28486107	In contrast, co-transfection GNAQQ209L with RasGRP2 had no synergistic effect on MAPK signaling, consistent with the notion that RasGRP2 activates Rap, but not Ras.	('GNAQQ209L', 'Chemical', '-', (29, 38))	('GNAQQ209L', 'Var', (29, 38))	('Rap', 'Gene', '4043', (147, 150))	('RasGRP2', 'Var', (129, 136))	('activates', 'PosReg', (137, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('MAPK signaling', 'MPA', (81, 95))	('Rap', 'Gene', (147, 150))	('Ras', 'Chemical', 'MESH:D011883', (160, 163))	('MAPK signaling', 'biological_process', 'GO:0000165', ('81', '95'))	('Ras', 'Chemical', 'MESH:D011883', (44, 47))	('Ras', 'Chemical', 'MESH:D011883', (129, 132))
32953	28486107	GNAQQ209L increased p-RasGRP1 (T184) and p-RasGRP3 (T133) levels in RasGRP1-and RasGRP3-expressing cells, respectively, indicating that oncogenic GNAQ can in principle activate both RasGRP1 and RasGRP3.	('T133', 'Chemical', '-', (52, 56))	('GNAQQ209L', 'Chemical', '-', (0, 9))	('GNAQQ209L', 'Var', (0, 9))	('activate', 'PosReg', (168, 176))	('RasGRP1', 'Gene', '10125', (22, 29))	('RasGRP1', 'Gene', (22, 29))	('RasGRP1', 'Gene', '10125', (68, 75))	('RasGRP1', 'Gene', (68, 75))	('RasGRP1', 'Gene', '10125', (182, 189))	('increased', 'PosReg', (10, 19))	('RasGRP1', 'Gene', (182, 189))
32955	28486107	In B cells, it has been shown that PKC can phosphorylate RasGRP3 at T133, located near the amino terminal region of CDC25 Ras activator domain.	('Ras', 'Chemical', 'MESH:D011883', (122, 125))	('PKC', 'molecular_function', 'GO:0004697', ('35', '38'))	('T133', 'Var', (68, 72))	('PKC', 'Gene', (35, 38))	('PKC', 'Gene', '112476', (35, 38))	('CDC25', 'Gene', (116, 121))	('CDC25', 'Gene', '995', (116, 121))	('T133', 'Chemical', '-', (68, 72))	('Ras', 'Chemical', 'MESH:D011883', (57, 60))
32956	28486107	A phosphorylation site mutant RasGRP3T133A substantially reduces but does not abrogate all RasGRP3 activity in B cells.	('RasGRP3T133A', 'Gene', (30, 42))	('T133A', 'Mutation', 'rs760130608', (37, 42))	('activity', 'MPA', (99, 107))	('mutant', 'Var', (23, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('2', '17'))
32957	28486107	To determine the role of T133 phosphorylation in the context of mutant GNAQ/11, we introduced RasGRP3T133A into 293FT cells.	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('T133', 'Chemical', '-', (101, 105))	('GNAQ/11', 'Gene', (71, 78))	('293FT', 'CellLine', 'CVCL:6911', (112, 117))	('mutant', 'Var', (64, 70))	('T133', 'Chemical', '-', (25, 29))
32958	28486107	RasGRP3 T133A also was less effective in synergizing with GNAQQ209L in activating the MAP-kinase pathway (Figure 6A) and Ras (Figures S7G) than wild-type RasGRP3.	('Ras', 'MPA', (121, 124))	('Ras', 'Chemical', 'MESH:D011883', (0, 3))	('T133A', 'Var', (8, 13))	('MAP', 'molecular_function', 'GO:0004239', ('86', '89'))	('MAP-kinase pathway', 'Pathway', (86, 104))	('Ras', 'Chemical', 'MESH:D011883', (121, 124))	('T133A', 'Mutation', 'rs760130608', (8, 13))	('GNAQQ209L', 'Chemical', '-', (58, 67))	('activating', 'MPA', (71, 81))	('Ras', 'Chemical', 'MESH:D011883', (154, 157))
32960	28486107	These data indicate that PKC phosphorylation at T133 also contributes to RasGRP3-mediated Ras/MAPK signaling in the context of mutant GNAQ.	('mutant', 'Var', (127, 133))	('PKC', 'Gene', (25, 28))	('PKC', 'Gene', '112476', (25, 28))	('MAPK', 'molecular_function', 'GO:0004707', ('94', '98'))	('T133', 'Chemical', '-', (48, 52))	('Ras', 'Chemical', 'MESH:D011883', (90, 93))	('contributes', 'Reg', (58, 69))	('MAPK signaling', 'biological_process', 'GO:0000165', ('94', '108'))	('PKC', 'molecular_function', 'GO:0004697', ('25', '28'))	('phosphorylation', 'biological_process', 'GO:0016310', ('29', '44'))	('Ras', 'Chemical', 'MESH:D011883', (73, 76))	('RasGRP3-mediated Ras/MAPK signaling', 'MPA', (73, 108))
32961	28486107	However, the phosphorylation site mutant of RasGRP3 had a residual activating effect on the MAP-kinase pathway, indicating that some RasGRP3 activity may be PKC independent.	('RasGRP3', 'Gene', (44, 51))	('PKC', 'molecular_function', 'GO:0004697', ('157', '160'))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('activating effect', 'MPA', (67, 84))	('MAP-kinase pathway', 'Pathway', (92, 110))	('phosphorylation', 'Var', (13, 28))	('PKC', 'Gene', '112476', (157, 160))	('MAP', 'molecular_function', 'GO:0004239', ('92', '95'))	('PKC', 'Gene', (157, 160))	('mutant', 'Var', (34, 40))
32962	28486107	To resolve this, we inhibited PKC activity using the pan-PKC inhibitor AEB071 in 293FT cells transfected with combinations of mutant or wild-type RasGRP3 with mutant GNAQ (Figure 6B).	('combinations', 'Interaction', (110, 122))	('mutant', 'Var', (159, 165))	('PKC activity', 'molecular_function', 'GO:0004697', ('30', '42'))	('mutant', 'Var', (126, 132))	('PKC', 'molecular_function', 'GO:0004697', ('57', '60'))	('PKC', 'Gene', (30, 33))	('inhibited', 'NegReg', (20, 29))	('RasGRP3', 'Gene', (146, 153))	('PKC', 'Gene', '112476', (30, 33))	('293FT', 'CellLine', 'CVCL:6911', (81, 86))	('PKC', 'Gene', (57, 60))	('PKC', 'Gene', '112476', (57, 60))
32963	28486107	At a concentration of 1 muM AEB071 was able to completely abrogate T133 phosphorylation of RasGRP3, consistent with prior studies showing complete extinction of PKC activity at this concentration.	('PKC', 'Gene', (161, 164))	('RasGRP3', 'Gene', (91, 98))	('PKC', 'Gene', '112476', (161, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('PKC activity', 'molecular_function', 'GO:0004697', ('161', '173'))	('T133', 'Chemical', '-', (67, 71))	('AEB071', 'Var', (28, 34))	('abrogate', 'NegReg', (58, 66))	('T133 phosphorylation', 'MPA', (67, 87))
32964	28486107	By contrast, AEB071 had no significant effect on MAP-kinase pathway activation of wild-type RasGRP3 or RasGRP3T133A in the absence of mutant GNAQ, indicating that this residual activity was PKC independent.	('MAP-kinase pathway', 'Pathway', (49, 67))	('activation', 'PosReg', (68, 78))	('AEB071', 'Var', (13, 19))	('T133A', 'Mutation', 'rs760130608', (110, 115))	('PKC', 'molecular_function', 'GO:0004697', ('190', '193'))	('PKC', 'Gene', (190, 193))	('PKC', 'Gene', '112476', (190, 193))	('MAP', 'molecular_function', 'GO:0004239', ('49', '52'))
32965	28486107	As a control, addition of a MEK inhibitor, PD0325901, in this experiment blocked all MAPK activation (Figure 6C).	('PD0325901', 'Var', (43, 52))	('activation', 'PosReg', (90, 100))	('MAPK activation', 'biological_process', 'GO:0000187', ('85', '100'))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('PD0325901', 'Chemical', 'MESH:C506614', (43, 52))	('MEK', 'Gene', (28, 31))	('MAPK', 'Protein', (85, 89))	('MEK', 'Gene', '5609', (28, 31))	('blocked', 'NegReg', (73, 80))
32968	28486107	As shown in Figure 6D, deletion of the C1 domain of RasGRP3 significantly reduces the ability of mutant GNAQ to activate the MAP-kinase pathway, and the RasGRP3 activity could be further reduced by mutating the T133 phosphorylation site.	('phosphorylation', 'biological_process', 'GO:0016310', ('216', '231'))	('MAP-kinase pathway', 'Pathway', (125, 143))	('deletion', 'Var', (23, 31))	('MAP', 'molecular_function', 'GO:0004239', ('125', '128'))	('T133', 'Chemical', '-', (211, 215))	('mutating', 'Var', (198, 206))	('ability', 'MPA', (86, 93))	('RasGRP3', 'Gene', (52, 59))	('reduces', 'NegReg', (74, 81))	('activate', 'PosReg', (112, 120))
32969	28486107	The effect of C1 deletion could be completely rescued by adding Fyn or Src membrane binding motifs to the RasGRP3 C1 deletion mutants (Figure 6E), indicating that C1-mediated membrane binding is essential for GNAQ-mediated activation of MAP-kinase signaling.	('Fyn', 'Gene', (64, 67))	('RasGRP3 C1', 'Gene', (106, 116))	('binding', 'molecular_function', 'GO:0005488', ('184', '191'))	('signaling', 'biological_process', 'GO:0023052', ('248', '257'))	('membrane', 'cellular_component', 'GO:0016020', ('175', '183'))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('deletion', 'Var', (17, 25))	('activation of MAP-kinase', 'biological_process', 'GO:0000187', ('223', '247'))	('membrane', 'cellular_component', 'GO:0016020', ('75', '83'))	('Fyn', 'Gene', '2534', (64, 67))	('deletion mutants', 'Var', (117, 133))	('mutants', 'Var', (126, 133))	('MAP', 'molecular_function', 'GO:0004239', ('237', '240'))
32970	28486107	Together, these data demonstrate that membrane binding via the C1 domain and T133 phosphorylation cooperate in RasGRP3-mediated activation of MAPK signaling in the setting of GNAQ mutations.	('activation', 'PosReg', (128, 138))	('MAPK signaling', 'MPA', (142, 156))	('mutations', 'Var', (180, 189))	('MAPK signaling', 'biological_process', 'GO:0000165', ('142', '156'))	('GNAQ', 'Gene', (175, 179))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('T133', 'Chemical', '-', (77, 81))	('membrane', 'cellular_component', 'GO:0016020', ('38', '46'))	('RasGRP3-mediated', 'Protein', (111, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))
32971	28486107	Constitutive activation of the MAPK pathway (RAS/RAF/MEK/ERK) is common in cutaneous melanoma and typically occurs through mutations and/or amplification of signaling modules such as BRAF or NRAS.	('RAF', 'Gene', '22882', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('RAF', 'Gene', '22882', (184, 187))	('amplification', 'Var', (140, 153))	('MEK', 'Gene', '5609', (53, 56))	('NRAS', 'Gene', (191, 195))	('RAF', 'Gene', (49, 52))	('ERK', 'Gene', '5594', (57, 60))	('RAF', 'Gene', (184, 187))	('MEK', 'Gene', (53, 56))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('MAPK pathway', 'Pathway', (31, 43))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('ERK', 'Gene', (57, 60))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('NRAS', 'Gene', '4893', (191, 195))	('activation', 'PosReg', (13, 23))	('BRAF', 'Gene', '673', (183, 187))	('BRAF', 'Gene', (183, 187))	('mutations', 'Var', (123, 132))
32976	28486107	Among the more than ten different PKC isoforms we found that, irrespective of GNAQ or GNA11 mutation status, PKC alpha, delta, epsilon, or zeta were ubiquitously expressed in melanoma cells, while PKC iota was only weakly expressed, mostly consistent with published reports.	('PKC', 'Gene', (34, 37))	('PKC', 'Gene', '112476', (34, 37))	('mutation', 'Var', (92, 100))	('GNAQ', 'Gene', (78, 82))	('PKC', 'molecular_function', 'GO:0004697', ('34', '37'))	('PKC alpha, delta, epsilon, or zeta', 'Gene', '5578;5580;5581;5590', (109, 143))	('PKC', 'Gene', '112476', (109, 112))	('iota', 'Chemical', '-', (201, 205))	('PKC', 'Gene', (197, 200))	('PKC', 'Gene', '112476', (197, 200))	('PKC', 'Gene', (109, 112))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('GNA11', 'Gene', (86, 91))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('PKC', 'molecular_function', 'GO:0004697', ('109', '112'))	('GNA11', 'Gene', '2767', (86, 91))	('PKC', 'molecular_function', 'GO:0004697', ('197', '200'))
32978	28486107	Only knockdown of PKC delta or epsilon, but not other PKC isoforms significantly reduced MAPK signaling in GNAQ mutant melanoma cells.	('PKC delta', 'Gene', (18, 27))	('MAPK signaling', 'biological_process', 'GO:0000165', ('89', '103'))	('mutant', 'Var', (112, 118))	('PKC', 'Gene', (18, 21))	('reduced', 'NegReg', (81, 88))	('PKC', 'Gene', '112476', (18, 21))	('PKC delta', 'Gene', '5580', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('MAPK signaling', 'MPA', (89, 103))	('melanoma', 'Disease', (119, 127))	('PKC', 'molecular_function', 'GO:0004697', ('54', '57'))	('epsilon', 'Enzyme', (31, 38))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('PKC', 'Gene', (54, 57))	('PKC', 'Gene', '112476', (54, 57))
32979	28486107	Only combined depletion of PKC delta and epsilon, but not combined knockdown of either PKC zeta with delta or epsilon, or PKC alpha with delta or epsilon extinguished MAP-kinase pathway signaling and inhibited proliferation of GNAQ mutant melanoma cell lines but had no such effect on melanoma cell lines with other mutations.	('PKC', 'molecular_function', 'GO:0004697', ('27', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('MAP-kinase pathway', 'Pathway', (167, 185))	('PKC', 'molecular_function', 'GO:0004697', ('87', '90'))	('mutant', 'Var', (232, 238))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('MAP', 'molecular_function', 'GO:0004239', ('167', '170'))	('PKC zeta', 'Gene', (87, 95))	('PKC delta', 'Gene', '5580', (27, 36))	('GNAQ', 'Gene', (227, 231))	('inhibited', 'NegReg', (200, 209))	('PKC delta', 'Gene', (27, 36))	('extinguished', 'NegReg', (154, 166))	('depletion', 'NegReg', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('PKC alpha', 'Gene', (122, 131))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))	('proliferation', 'CPA', (210, 223))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('PKC', 'molecular_function', 'GO:0004697', ('122', '125'))	('PKC zeta', 'Gene', '5590', (87, 95))	('PKC alpha', 'Gene', '5578', (122, 131))
32980	28486107	Concordantly, co-transfection of GNAQQ209L with PKC delta or epsilon, but not PKC alpha, zeta, and iota potentiated MAPK signaling in 293FT cells.	('PKC delta', 'Gene', (48, 57))	('GNAQQ209L', 'Chemical', '-', (33, 42))	('PKC', 'molecular_function', 'GO:0004697', ('48', '51'))	('PKC delta', 'Gene', '5580', (48, 57))	('epsilon', 'Enzyme', (61, 68))	('PKC', 'molecular_function', 'GO:0004697', ('78', '81'))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('MAPK signaling', 'MPA', (116, 130))	('PKC alpha, zeta, and iota', 'Gene', '5578;5590', (78, 103))	('MAPK signaling', 'biological_process', 'GO:0000165', ('116', '130'))	('potentiated', 'PosReg', (104, 115))	('GNAQQ209L', 'Var', (33, 42))	('293FT', 'CellLine', 'CVCL:6911', (134, 139))
32987	28486107	We show that the significantly increased expression level of RasGRP3 in UM is a direct consequence of Galphaq signaling, and that Galphaq signaling not only increases RasGRP3 transcription in a PKC-dependent manner but activates RasGRP3 by two independent mechanisms: membrane recruitment and phosphorylation by PKC delta and epsilon.	('transcription', 'MPA', (175, 188))	('increased', 'PosReg', (31, 40))	('PKC', 'Gene', '112476', (194, 197))	('PKC', 'Gene', '112476', (312, 315))	('PKC', 'molecular_function', 'GO:0004697', ('312', '315'))	('PKC delta', 'Gene', '5580', (312, 321))	('PKC', 'Gene', (194, 197))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('phosphorylation', 'MPA', (293, 308))	('PKC delta', 'Gene', (312, 321))	('PKC', 'Gene', (312, 315))	('activates', 'PosReg', (219, 228))	('UM', 'Phenotype', 'HP:0007716', (72, 74))	('RasGRP3', 'Gene', (167, 174))	('increases', 'PosReg', (157, 166))	('phosphorylation', 'biological_process', 'GO:0016310', ('293', '308'))	('PKC', 'molecular_function', 'GO:0004697', ('194', '197'))	('RasGRP3', 'Gene', (229, 236))	('Galphaq', 'Var', (130, 137))	('membrane', 'cellular_component', 'GO:0016020', ('268', '276'))	('signaling', 'biological_process', 'GO:0023052', ('110', '119'))	('membrane recruitment', 'MPA', (268, 288))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('expression level', 'MPA', (41, 57))
32989	28486107	Here we show that the expression level of RasGRP3 in GNAQ or GNA11 mutant melanoma cell lines and human UM tissues by far exceeds the expression levels of the previously reported tissue types, indicating a specific role of this protein in UM.	('expression', 'MPA', (134, 144))	('GNAQ', 'Gene', (53, 57))	('UM', 'Phenotype', 'HP:0007716', (104, 106))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('GNA11', 'Gene', '2767', (61, 66))	('GNA11', 'Gene', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('expression level', 'MPA', (22, 38))	('RasGRP3', 'Gene', (42, 49))	('melanoma', 'Disease', (74, 82))	('mutant', 'Var', (67, 73))	('UM', 'Phenotype', 'HP:0007716', (239, 241))	('human', 'Species', '9606', (98, 103))
32990	28486107	Our results indicate that GNAQ signaling and PKC delta and epsilon are involved in upregulating RasGRP3 expression, and that this effect is restricted to melanocytes, as mutant GNAQ did not increase RasGRP3 expression levels in 293FT (data not shown).	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('GNAQ', 'Gene', (177, 181))	('PKC', 'molecular_function', 'GO:0004697', ('45', '48'))	('PKC delta', 'Gene', (45, 54))	('PKC delta', 'Gene', '5580', (45, 54))	('upregulating', 'PosReg', (83, 95))	('expression', 'MPA', (104, 114))	('RasGRP3', 'Protein', (96, 103))	('mutant', 'Var', (170, 176))	('293FT', 'CellLine', 'CVCL:6911', (228, 233))
32993	28486107	Phosphorylation of RasGRP3 at threonine 133 by PKC enhances the ability of RasGRP3 to maximally activate Ras signaling in antigen receptor-stimulated B cells, and in that context is suggested to be mediated by PKC theta and PKC beta.	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('PKC', 'Gene', '112476', (210, 213))	('PKC beta', 'Gene', '5579', (224, 232))	('threonine 133', 'Var', (30, 43))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('PKC', 'molecular_function', 'GO:0004697', ('210', '213'))	('PKC', 'molecular_function', 'GO:0004697', ('47', '50'))	('RasGRP3', 'Gene', (19, 26))	('PKC', 'Gene', (210, 213))	('eta', 'Gene', (216, 219))	('PKC', 'Gene', '112476', (224, 227))	('eta', 'Gene', '1909', (229, 232))	('PKC beta', 'Gene', (224, 232))	('Ras', 'Chemical', 'MESH:D011883', (75, 78))	('threonine', 'Chemical', 'MESH:D013912', (30, 39))	('PKC', 'molecular_function', 'GO:0004697', ('224', '227'))	('PKC', 'Gene', (224, 227))	('activate', 'PosReg', (96, 104))	('ability', 'MPA', (64, 71))	('eta', 'Gene', (229, 232))	('Ras signaling', 'MPA', (105, 118))	('Ras', 'Chemical', 'MESH:D011883', (105, 108))	('Ras', 'Chemical', 'MESH:D011883', (19, 22))	('PKC', 'Gene', '112476', (47, 50))	('Phosphorylation', 'MPA', (0, 15))	('enhances', 'PosReg', (51, 59))	('PKC', 'Gene', (47, 50))	('eta', 'Gene', '1909', (216, 219))
32994	28486107	We confirm the critical role of RasGRP3 phosphorylation at T133 in the setting of GNAQ mutations with PKC delta and epsilon as the relevant PKC isoforms for this modification in UM.	('PKC delta', 'Gene', '5580', (102, 111))	('PKC', 'Gene', '112476', (102, 105))	('PKC', 'Gene', (140, 143))	('PKC', 'Gene', '112476', (140, 143))	('UM', 'Phenotype', 'HP:0007716', (178, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('GNAQ', 'Gene', (82, 86))	('PKC', 'molecular_function', 'GO:0004697', ('140', '143'))	('PKC', 'molecular_function', 'GO:0004697', ('102', '105'))	('PKC delta', 'Gene', (102, 111))	('PKC', 'Gene', (102, 105))	('mutations', 'Var', (87, 96))	('T133', 'Chemical', '-', (59, 63))	('phosphorylation', 'MPA', (40, 55))
32995	28486107	We show that mutating the PKC phosphorylation site of RasGRP3 (T133A) partially, but not completely, attenuated RasGRP3-mediated MAPK signaling.	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('T133A', 'Mutation', 'rs760130608', (63, 68))	('MAPK signaling', 'biological_process', 'GO:0000165', ('129', '143'))	('attenuated', 'NegReg', (101, 111))	('mutating', 'Var', (13, 21))	('PKC', 'Gene', (26, 29))	('PKC', 'Gene', '112476', (26, 29))	('PKC', 'molecular_function', 'GO:0004697', ('26', '29'))	('RasGRP3-mediated MAPK signaling', 'MPA', (112, 143))	('MAPK', 'molecular_function', 'GO:0004707', ('129', '133'))
32999	28486107	This PKC-independent activity may explain why PKC inhibition fails to induce sustained suppression of MAPK signaling in GNAQ mutant melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanomas', 'Phenotype', 'HP:0002861', (132, 141))	('mutant', 'Var', (125, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('GNAQ', 'Gene', (120, 124))	('MAPK signaling', 'MPA', (102, 116))	('melanomas', 'Disease', 'MESH:D008545', (132, 141))	('MAPK signaling', 'biological_process', 'GO:0000165', ('102', '116'))	('PKC', 'Gene', (46, 49))	('PKC', 'Gene', '112476', (46, 49))	('PKC', 'molecular_function', 'GO:0004697', ('5', '8'))	('PKC', 'molecular_function', 'GO:0004697', ('46', '49'))	('PKC', 'Gene', (5, 8))	('PKC', 'Gene', '112476', (5, 8))	('melanomas', 'Disease', (132, 141))
33024	28486107	PD0325901 and Trametinib were obtained from Chemie TEK(Indianapolis, IN).	('Trametinib', 'Chemical', 'MESH:C560077', (14, 24))	('TEK', 'Gene', '7010', (51, 54))	('PD0325901', 'Var', (0, 9))	('TEK', 'Gene', (51, 54))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))
33030	28486107	After 48 hr transfection, cells were counted using TC10 automated cell counter (Bio-Rad, Hercules, CA) and plated in triplicate into 6-well plates at 5x104 cells/well and cultured for the indicated times.	('Rad', 'biological_process', 'GO:1990116', ('84', '87'))	('Rad', 'Gene', '6236', (84, 87))	('TC10', 'Gene', (51, 55))	('Rad', 'Gene', (84, 87))	('TC10', 'Gene', '23433', (51, 55))	('transfection', 'Var', (12, 24))
33040	28486107	SOS1 (Hs00362308_m1), RasGRP2 (Hs00183378_m1), 3 (Hs00209808_m1) and 4 (Hs01073182_m1) probes and primers were obtained at Applied Bio System.	('Hs00183378_m1', 'Var', (31, 44))	('Hs00362308_m1', 'Var', (6, 19))	('SOS1', 'Gene', (0, 4))	('Hs00209808_m1', 'Var', (50, 63))	('SOS1', 'Gene', '6654', (0, 4))
33043	28486107	Gene level differential expression was compared between 5 GNAQ/11 mutant melanoma cells and 5 BRAF/Nras mutant melanoma cells by using Affymetrix transcriptome Analysis Console (TAC) software.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('BRAF', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('Nras', 'Gene', (99, 103))	('TAC', 'cellular_component', 'GO:0120121', ('178', '181'))	('Nras', 'Gene', '4893', (99, 103))	('BRAF', 'Gene', '673', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
33059	28486107	The cohort of patients included in this paper were as follows: GNAQ mutant: male 78 years, male 78 years, male 77 years, male 51 years; GNA11 mutant: female 73 years, female 73 years, female 53 years, female 43 years.	('GNA11', 'Gene', (136, 141))	('mutant', 'Var', (142, 148))	('GNA11', 'Gene', '2767', (136, 141))	('GNAQ', 'Gene', (63, 67))	('patients', 'Species', '9606', (14, 22))	('mutant', 'Var', (68, 74))
33068	28486107	PKC delta/epsilon mediate ERK activation in uveal melanoma with Galphaq pathway mutations The RAS exchange factor RasGRP3 is a critical module for ERK activation PKC delta, PKC epsilon, and RasGRP3 are novel therapeutic targets for uveal melanoma Uveal melanoma (UM) is the most lethal form of melanoma with a 10-year survival rate of approximately 50%.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('PKC epsilon', 'Gene', '5581', (173, 184))	('melanoma', 'Disease', (238, 246))	('ERK', 'Gene', '5594', (26, 29))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('melanoma', 'Disease', (294, 302))	('PKC delta', 'Gene', '5580', (162, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('ERK', 'Gene', (147, 150))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('uveal melanoma', 'Disease', (44, 58))	('PKC', 'molecular_function', 'GO:0004697', ('162', '165'))	('PKC delta', 'Gene', (162, 171))	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('melanoma', 'Disease', (253, 261))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('UM', 'Phenotype', 'HP:0007716', (263, 265))	('ERK', 'Gene', (26, 29))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('uveal melanoma', 'Disease', (232, 246))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (247, 261))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('PKC epsilon', 'Gene', (173, 184))	('PKC delta', 'Gene', '5580', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('PKC', 'molecular_function', 'GO:0004697', ('173', '176'))	('PKC delta', 'Gene', (0, 9))	('PKC', 'molecular_function', 'GO:0004697', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('ERK', 'Gene', '5594', (147, 150))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))
33075	31683701	CjM is commonly characterized by mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF), neurofibromin 1 (NF1) and telomerase reverse transcriptase (TERT), high expression of mammalian target of rapamycin (mTOR) and heat shock protein 90 (HSP90), frequent phosphatase and tensin homolog (PTEN) loss and upregulation of specific miRNAs.	('PTEN', 'Gene', (300, 304))	('CjM', 'Phenotype', 'HP:0007716', (0, 3))	('mutations', 'Var', (33, 42))	('CjM', 'Disease', (0, 3))	('transcriptase', 'molecular_function', 'GO:0003899', ('146', '159'))	('mTOR', 'Gene', (218, 222))	('mammalian target of rapamycin', 'Gene', '2475', (187, 216))	('neurofibromin 1', 'Gene', '4763', (101, 116))	('loss', 'NegReg', (306, 310))	('PTEN', 'Gene', '5728', (300, 304))	('mTOR', 'Gene', '2475', (218, 222))	('heat shock protein 90', 'Gene', '3320', (228, 249))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('268', '298'))	('phosphatase', 'Enzyme', (268, 279))	('neurofibromin 1', 'Gene', (101, 116))	('high', 'PosReg', (168, 172))	('mammalian target of rapamycin', 'Gene', (187, 216))	('telomerase reverse transcriptase', 'Gene', (127, 159))	('phosphatase', 'molecular_function', 'GO:0016791', ('268', '279'))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (46, 92))	('HSP90', 'Gene', (251, 256))	('telomerase reverse transcriptase', 'Gene', '21752', (127, 159))	('transcriptase', 'molecular_function', 'GO:0003968', ('146', '159'))	('upregulation', 'PosReg', (315, 327))	('transcriptase', 'molecular_function', 'GO:0034062', ('146', '159'))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('CjM', 'Disease', 'MESH:D003229', (0, 3))	('HSP90', 'Gene', '3320', (251, 256))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (46, 92))	('heat shock protein 90', 'Gene', (228, 249))	('shock', 'Phenotype', 'HP:0031273', (233, 238))
33094	31683701	V-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation characterizes up to 50% of conjunctival melanomas as an early event in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (96, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('conjunctival melanomas', 'Disease', (96, 118))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (96, 118))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (0, 46))	('BRAF', 'Gene', (48, 52))	('V600E', 'Var', (54, 59))	('V-raf murine sarcoma viral oncogene homolog B1', 'Gene', (0, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (13, 20))	('tumor', 'Disease', (140, 145))
33095	31683701	NF1 mutations can be detected in about 30% of conjunctival melanomas.	('conjunctival melanomas', 'Disease', 'MESH:D003229', (46, 68))	('conjunctival melanomas', 'Disease', (46, 68))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (46, 67))
33096	31683701	Neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS) mutations occur in about 20% of the cases and are mutually exclusive with BRAF mutations.	('mutations', 'Var', (56, 65))	('NRAS', 'Gene', (50, 54))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (0, 13))	('Neuroblastoma', 'Disease', 'MESH:D009447', (0, 13))	('NRAS', 'Gene', '4893', (50, 54))	('Neuroblastoma', 'Disease', (0, 13))
33097	31683701	KIT mutations are more seldomly detected (lower than 7%) and are mutually exclusive with NRAS and BRAF mutations.	('NRAS', 'Gene', '4893', (89, 93))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', '3815', (0, 3))	('NRAS', 'Gene', (89, 93))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))
33101	31683701	In addition, molecular features of this tumor may also include the overexpression of HSP90 and Bcl-2, the inactivation of p16, other minor chromosome abnormalities and miRNAs upregulation.	('inactivation', 'Var', (106, 118))	('HSP90', 'Gene', (85, 90))	('overexpression', 'PosReg', (67, 81))	('p16', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HSP90', 'Gene', '3320', (85, 90))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (139, 163))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (139, 163))	('chromosome abnormalities', 'Disease', (139, 163))	('upregulation', 'PosReg', (175, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('139', '149'))	('p16', 'Gene', '1029', (122, 125))	('tumor', 'Disease', (40, 45))	('Bcl-2', 'Gene', (95, 100))	('miRNAs', 'CPA', (168, 174))	('Bcl-2', 'Gene', '596', (95, 100))	('Bcl-2', 'molecular_function', 'GO:0015283', ('95', '100'))
33102	31683701	However, none of these genetic or epigenetic alterations seems to have a prognostic role in CjM.	('CjM', 'Disease', (92, 95))	('CjM', 'Phenotype', 'HP:0007716', (92, 95))	('epigenetic alterations', 'Var', (34, 56))	('CjM', 'Disease', 'MESH:D003229', (92, 95))
33111	31683701	The frequency of BRAF, NRAS and KIT mutations in CjM is more similar to cutaneous melanoma than uveal/mucosal melanoma.	('cutaneous melanoma than uveal/mucosal melanoma', 'Disease', (72, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('KIT', 'Gene', '3815', (32, 35))	('CjM', 'Phenotype', 'HP:0007716', (49, 52))	('NRAS', 'Gene', (23, 27))	('KIT', 'Gene', (32, 35))	('cutaneous melanoma than uveal/mucosal melanoma', 'Disease', 'MESH:C536494', (72, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('mutations', 'Var', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('CjM', 'Disease', 'MESH:D003229', (49, 52))	('BRAF', 'Gene', (17, 21))	('CjM', 'Disease', (49, 52))	('uveal/mucosal melanoma', 'Phenotype', 'HP:0007716', (96, 118))	('NRAS', 'Gene', '4893', (23, 27))
33112	31683701	BRAF mutations have been detected in up to 50% of primary and metastatic conjunctival melanomas as in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('metastatic conjunctival melanomas', 'Phenotype', 'HP:0007716', (62, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (73, 94))	('BRAF', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (73, 95))	('conjunctival melanomas', 'Disease', (73, 95))	('detected', 'Reg', (25, 33))
33115	31683701	Other uncommon BRAF mutations are detectable in <6% of conjunctival melanomas.	('BRAF', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (55, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (55, 77))	('conjunctival melanomas', 'Disease', (55, 77))	('mutations', 'Var', (20, 29))
33116	31683701	These BRAF mutations found in CjM are similar to cutaneous melanoma, in which V600E represents the most typical mutation (almost 70% of cases), followed by V600K (about 20% of cases) and less frequent mutations, such as V600D and V600R.	('V600D', 'Var', (220, 225))	('CjM', 'Disease', 'MESH:D003229', (30, 33))	('CjM', 'Disease', (30, 33))	('cutaneous melanoma', 'Disease', (49, 67))	('V600D', 'Mutation', 'rs121913377', (220, 225))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('V600R', 'Mutation', 'rs121913227', (230, 235))	('V600K', 'Var', (156, 161))	('CjM', 'Phenotype', 'HP:0007716', (30, 33))	('V600E', 'Var', (78, 83))	('V600K', 'Mutation', 'rs121913227', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('V600R', 'Var', (230, 235))
33117	31683701	Acral and mucosal melanomas more rarely harbor BRAF mutations (respectively, 10-15% and 5% of cases), which, on the contrary, have never been reported in uveal melanoma.	('mutations', 'Var', (52, 61))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('BRAF', 'Gene', (47, 51))	('mucosal melanomas', 'Disease', (10, 27))	('uveal melanoma', 'Phenotype', 'HP:0007716', (154, 168))	('uveal melanoma', 'Disease', (154, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (154, 168))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
33118	31683701	BRAF mutations are frequently associated with melanocytic nevi (up to 67%) and probably occur in early stages of CjM development from nevi.	('associated', 'Reg', (30, 40))	('CjM', 'Disease', 'MESH:D003229', (113, 116))	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('CjM', 'Disease', (113, 116))	('melanocytic nevi', 'Disease', (46, 62))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (46, 62))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', (0, 4))	('nevi', 'Phenotype', 'HP:0003764', (134, 138))	('CjM', 'Phenotype', 'HP:0007716', (113, 116))
33119	31683701	Indeed, up to 50% of conjunctival nevi harbor BRAF mutations, which are less common in PAM.	('BRAF', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('PAM', 'Gene', '5066', (87, 90))	('conjunctival nevi', 'Disease', (21, 38))	('PAM', 'Gene', (87, 90))	('nevi', 'Phenotype', 'HP:0003764', (34, 38))
33121	31683701	Similarly, in cutaneous melanoma BRAF mutations are more predominant among younger patients.	('cutaneous melanoma BRAF', 'Disease', 'MESH:C562393', (14, 37))	('cutaneous melanoma BRAF', 'Disease', (14, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('patients', 'Species', '9606', (83, 91))	('mutations', 'Var', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))
33123	31683701	BRAF mutations are not significantly associated with increased recurrence, regional metastases or mortality from CjM, but they are correlated with reduced distant metastases free-survival.	('CjM', 'Disease', 'MESH:D003229', (113, 116))	('metastases', 'Disease', (163, 173))	('CjM', 'Disease', (113, 116))	('metastases', 'Disease', (84, 94))	('mutations', 'Var', (5, 14))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('BRAF', 'Gene', (0, 4))	('reduced', 'NegReg', (147, 154))	('CjM', 'Phenotype', 'HP:0007716', (113, 116))
33124	31683701	In vitro, Vemurafenib and Dabrafenib inhibit BRAF-mutant CjM cell lines, similarly to cutaneous melanoma cells.	('CjM', 'Phenotype', 'HP:0007716', (57, 60))	('cutaneous melanoma', 'Disease', (86, 104))	('Vemurafenib', 'Chemical', 'MESH:C551177', (10, 21))	('CjM', 'Disease', 'MESH:D003229', (57, 60))	('inhibit', 'NegReg', (37, 44))	('CjM', 'Disease', (57, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('Dabrafenib', 'Chemical', 'MESH:C561627', (26, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BRAF-mutant', 'Var', (45, 56))
33125	31683701	In vivo, several BRAF mutated conjunctival melanomas were effectively treated with BRAF inhibitors in monotherapy or in combination with MEK inhibitors.	('MEK', 'Gene', (137, 140))	('inhibitors', 'Var', (88, 98))	('MEK', 'Gene', '5609', (137, 140))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (30, 51))	('conjunctival melanomas', 'Disease', (30, 52))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (30, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('mutated', 'Var', (22, 29))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', (83, 87))
33127	31683701	In conclusion, we believe that tests for BRAF mutations should be included in the management of CjM and that clinical studies with BRAF and MEK inhibitors are required in this setting.	('MEK', 'Gene', (140, 143))	('mutations', 'Var', (46, 55))	('CjM', 'Phenotype', 'HP:0007716', (96, 99))	('MEK', 'Gene', '5609', (140, 143))	('CjM', 'Disease', 'MESH:D003229', (96, 99))	('CjM', 'Disease', (96, 99))	('BRAF', 'Gene', (41, 45))
33129	31683701	NRAS mutations have been found in almost 20% of conjunctival melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('conjunctival melanomas', 'Disease', (48, 70))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (48, 70))	('NRAS', 'Gene', (0, 4))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (48, 69))	('found', 'Reg', (25, 30))	('NRAS', 'Gene', '4893', (0, 4))
33130	31683701	Regarding the other types of melanoma, NRAS mutations have been found in about 20% of cutaneous melanomas, 5-13% of mucosal melanomas and 10% of acral melanomas.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('acral melanomas', 'Phenotype', 'HP:0012060', (145, 160))	('mucosal melanomas', 'Disease', 'MESH:D008545', (116, 133))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('NRAS', 'Gene', '4893', (39, 43))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('acral melanomas', 'Disease', (145, 160))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (86, 105))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (86, 105))	('mucosal melanomas', 'Disease', (116, 133))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('melanoma', 'Disease', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('NRAS', 'Gene', (39, 43))	('cutaneous melanomas', 'Disease', (86, 105))	('found', 'Reg', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('mutations', 'Var', (44, 53))	('acral melanomas', 'Disease', 'MESH:D008545', (145, 160))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
33132	31683701	It is worth noting that benign cutaneous nevi can harbor NRAS mutations.	('harbor', 'Reg', (50, 56))	('NRAS', 'Gene', (57, 61))	('NRAS', 'Gene', '4893', (57, 61))	('mutations', 'Var', (62, 71))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))
33133	31683701	In CjM, NRAS mutations are mutually exclusive with BRAF mutations, similarly to cutaneous melanoma, in which concomitant BRAF and NRAS mutations occur in less than 0.6% of cases.	('mutations', 'Var', (56, 65))	('CjM', 'Phenotype', 'HP:0007716', (3, 6))	('NRAS', 'Gene', (8, 12))	('cutaneous melanoma', 'Disease', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('CjM', 'Disease', 'MESH:D003229', (3, 6))	('NRAS', 'Gene', '4893', (8, 12))	('CjM', 'Disease', (3, 6))	('NRAS', 'Gene', (130, 134))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
33134	31683701	c-KIT mutations have been detected in almost 2-7% of conjunctival melanomas and they are mutually exclusive with NRAS and BRAF mutations, as in cutaneous melanoma.	('c-KIT', 'Gene', (0, 5))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 162))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (53, 75))	('conjunctival melanomas', 'Disease', (53, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (53, 74))	('c-KIT', 'Gene', '3815', (0, 5))	('NRAS', 'Gene', (113, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('NRAS', 'Gene', '4893', (113, 117))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('detected', 'Reg', (26, 34))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('cutaneous melanoma', 'Disease', (144, 162))	('mutations', 'Var', (6, 15))
33135	31683701	Similarly, in cutaneous melanomas, the incidence of KIT mutations ranges from 5.1% for non 'sun-exposed' patients to 9.8% for chronically 'sun-exposed' patients.	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (105, 113))	('to 9', 'Species', '1214577', (114, 118))	('KIT', 'Gene', (52, 55))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (14, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (14, 33))	('cutaneous melanomas', 'Disease', (14, 33))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('patients', 'Species', '9606', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('KIT', 'Gene', '3815', (52, 55))
33136	31683701	KIT mutations are more frequently detected in mucosal (about 11.5% of cases) and acral (10.8% of cases) melanomas while they have not been reported in uveal melanoma.	('detected', 'Reg', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('acral', 'Disease', (81, 86))	('uveal melanoma', 'Disease', (151, 165))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('mucosal', 'Disease', (46, 53))	('KIT', 'Gene', '3815', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanomas', 'Disease', (104, 113))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))
33139	31683701	It is noteworthy that KIT mutations are not directly correlated with KIT gene copy number or CD117, the KIT gene product, expression.	('KIT', 'Gene', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('KIT', 'Gene', (104, 107))	('KIT', 'Gene', '3815', (22, 25))	('CD117', 'Gene', '3815', (93, 98))	('KIT', 'Gene', (22, 25))	('CD117', 'Gene', (93, 98))	('mutations', 'Var', (26, 35))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('KIT', 'Gene', '3815', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('KIT', 'Gene', '3815', (104, 107))
33141	31683701	Consequently, we can assume that not all KIT mutations are drivers in melanomas and are not principal therapeutic targets.	('mutations', 'Var', (45, 54))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('KIT', 'Gene', '3815', (41, 44))	('melanomas', 'Disease', (70, 79))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
33144	31683701	NF1 mutations, leading to neurofibromin 1 dysfunction, occur in up to 30% of CjM and can be found simultaneously with BRAF and RAS mutations.	('CjM', 'Disease', (77, 80))	('CjM', 'Disease', 'MESH:D003229', (77, 80))	('neurofibromin 1', 'Gene', '4763', (26, 41))	('NF1', 'Gene', (0, 3))	('CjM', 'Phenotype', 'HP:0007716', (77, 80))	('mutations', 'Var', (4, 13))	('neurofibromin 1', 'Gene', (26, 41))
33147	31683701	NF1 mutations are particularly frequent in CjM that have been exposed to UVs, highlighting the possible pathogenetic role of sunlight exposure.	('CjM', 'Disease', 'MESH:D003229', (43, 46))	('CjM', 'Disease', (43, 46))	('frequent', 'Reg', (31, 39))	('NF1', 'Gene', (0, 3))	('sunlight exposure', 'Phenotype', 'HP:0000992', (125, 142))	('mutations', 'Var', (4, 13))	('CjM', 'Phenotype', 'HP:0007716', (43, 46))
33148	31683701	NF1 mutations are associated with sunlight exposure also in cutaneous melanoma and are more frequent in the desmoplastic subtype.	('frequent', 'Reg', (92, 100))	('sunlight exposure', 'Phenotype', 'HP:0000992', (34, 51))	('associated', 'Reg', (18, 28))	('cutaneous melanoma', 'Disease', (60, 78))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
33149	31683701	It has been demonstrated that cutaneous melanomas with NF1 mutations harbor a higher mutational load.	('cutaneous melanomas', 'Disease', (30, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('mutational load', 'MPA', (85, 100))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('mutations', 'Var', (59, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('NF1', 'Gene', (55, 58))
33154	31683701	These kinases activate AKT through the phosphorylation of its residues Threonine-308 (Thr308) and Serine-473 (Ser473).	('phosphorylation', 'MPA', (39, 54))	('Ser', 'Chemical', 'MESH:C530429', (98, 101))	('AKT', 'Gene', '207', (23, 26))	('activate', 'PosReg', (14, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('Ser', 'cellular_component', 'GO:0005790', ('110', '113'))	('kinases', 'Disease', 'MESH:D058495', (6, 13))	('kinases', 'Disease', (6, 13))	('Ser', 'Chemical', 'MESH:C530429', (110, 113))	('AKT', 'Gene', (23, 26))	('Threonine', 'Chemical', 'MESH:C061951', (71, 80))	('Serine-473', 'MPA', (98, 108))	('Serine', 'Chemical', 'MESH:C047902', (98, 104))	('Thr308', 'Var', (86, 92))
33162	31683701	S6 and its phosphorylated form (Ser235/236) are expressed in 100% and 75% of CjM cells, respectively.	('CjM', 'Disease', (77, 80))	('CjM', 'Disease', 'MESH:D003229', (77, 80))	('CjM', 'Phenotype', 'HP:0007716', (77, 80))	('Ser235', 'Chemical', 'MESH:C530429', (32, 38))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('Ser235/236', 'Var', (32, 42))
33166	31683701	The association between mTOR nonsynonymous mutations and a short survival has been reported in cutaneous and mucosal melanoma patients.	('mucosal melanoma', 'Disease', 'MESH:D008545', (109, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('association', 'Interaction', (4, 15))	('nonsynonymous mutations', 'Var', (29, 52))	('patients', 'Species', '9606', (126, 134))	('mucosal melanoma', 'Disease', (109, 125))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
33167	31683701	In mTOR mutant cell lines, high levels of phosphorylated S6, AKT and 4E-BP1 have been found.	('mTOR', 'Gene', '2475', (3, 7))	('found', 'Reg', (86, 91))	('mutant', 'Var', (8, 14))	('AKT and 4E-BP1', 'Gene', '207;1978', (61, 75))	('mTOR', 'Gene', (3, 7))
33191	31683701	TERT promoter mutations, which cause an increased TERT expression, are detectable in 32-41% of conjunctival melanomas and in 8% of PAM cases.	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (95, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (95, 116))	('TERT promoter', 'Gene', (0, 13))	('conjunctival melanomas', 'Disease', (95, 117))	('PAM', 'Gene', '5066', (131, 134))	('TERT expression', 'MPA', (50, 65))	('mutations', 'Var', (14, 23))	('PAM', 'Gene', (131, 134))
33192	31683701	Indeed, while several conjunctival melanocytic nevi harbor BRAF mutations, TERT promoter mutations are detectable only in melanomas and premalignant lesions (such as PAM with atypia), playing a role in tumor progression.	('PAM', 'Gene', '5066', (166, 169))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('mutations', 'Var', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanomas', 'Disease', (122, 131))	('tumor', 'Disease', (202, 207))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('PAM', 'Gene', (166, 169))	('premalignant lesions', 'Disease', (136, 156))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('BRAF', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (35, 51))	('several conjunctival melanocytic nevi', 'Phenotype', 'HP:0005603', (14, 51))	('TERT promoter', 'Gene', (75, 88))	('premalignant lesions', 'Disease', 'MESH:D051437', (136, 156))	('conjunctival melanocytic nevi', 'Disease', (22, 51))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
33193	31683701	TERT promoter mutations detected in CjM consist of C>T or CC>TT nucleotide changes.	('CjM', 'Disease', 'MESH:D003229', (36, 39))	('CjM', 'Disease', (36, 39))	('C>T', 'Var', (51, 54))	('CjM', 'Phenotype', 'HP:0007716', (36, 39))
33195	31683701	The occurrence of TERT promoter mutations in CjM is similar to cutaneous melanoma in which TERT mutations can be found in 64-68% of lesions, both in primary and metastases, and are associated with a shorter survival.	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('shorter', 'NegReg', (199, 206))	('CjM', 'Phenotype', 'HP:0007716', (45, 48))	('cutaneous melanoma', 'Disease', (63, 81))	('survival', 'MPA', (207, 215))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (63, 81))	('CjM', 'Disease', (45, 48))	('mutations', 'Var', (32, 41))	('CjM', 'Disease', 'MESH:D003229', (45, 48))	('metastases', 'Disease', (161, 171))	('metastases', 'Disease', 'MESH:D009362', (161, 171))
33198	31683701	The detection of TERT promoter mutations reveals future therapeutic options for CjM.	('CjM', 'Disease', (80, 83))	('mutations', 'Var', (31, 40))	('TERT promoter', 'Gene', (17, 30))	('CjM', 'Phenotype', 'HP:0007716', (80, 83))	('CjM', 'Disease', 'MESH:D003229', (80, 83))
33199	31683701	Thus, reverse transcriptase inhibitors, such as azidothymidine (AZT), may become possible candidates for therapies directed against TERT-promoter mutant conjunctival melanomas (Figure 4A).	('conjunctival melanomas', 'Disease', 'MESH:D003229', (153, 175))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('conjunctival melanomas', 'Disease', (153, 175))	('TERT-promoter mutant', 'Var', (132, 152))	('AZT', 'Chemical', 'MESH:D015215', (64, 67))	('transcriptase', 'molecular_function', 'GO:0034062', ('14', '27'))	('transcriptase', 'molecular_function', 'GO:0003899', ('14', '27'))	('transcriptase', 'molecular_function', 'GO:0003968', ('14', '27'))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (153, 174))	('azidothymidine', 'Chemical', 'MESH:D015215', (48, 62))
33202	31683701	CDKN2A mutations can be found both in cutaneous and in CjM.	('CjM', 'Phenotype', 'HP:0007716', (55, 58))	('CjM', 'Disease', 'MESH:D003229', (55, 58))	('CjM', 'Disease', (55, 58))	('cutaneous', 'Disease', (38, 47))	('CDKN2A', 'Gene', (0, 6))	('found', 'Reg', (24, 29))	('CDKN2A', 'Gene', '1029', (0, 6))	('mutations', 'Var', (7, 16))
33203	31683701	Furthermore, CDKN2A germline mutations are associated with familiar melanomas.	('melanomas', 'Disease', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('CDKN2A', 'Gene', (13, 19))	('germline mutations', 'Var', (20, 38))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('CDKN2A', 'Gene', '1029', (13, 19))	('associated', 'Reg', (43, 53))	('melanomas', 'Disease', 'MESH:D008545', (68, 77))
33204	31683701	Acral melanoma expresses mutations of the CDK4/6 pathway in about 82.7% of the cases.	('mutations', 'Var', (25, 34))	('Acral melanoma', 'Disease', (0, 14))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('CDK4/6', 'Gene', '1019;1021', (42, 48))	('Acral melanoma', 'Disease', 'MESH:D008545', (0, 14))	('CDK4/6', 'Gene', (42, 48))	('Acral melanoma', 'Phenotype', 'HP:0012060', (0, 14))
33205	31683701	CDKN2A alterations have been also found in mucosal melanoma of the oral cavity, but they are not related to specific clinicopathological subsets.	('mucosal melanoma', 'Disease', 'MESH:D008545', (43, 59))	('found', 'Reg', (34, 39))	('CDKN2A', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('alterations', 'Var', (7, 18))	('CDKN2A', 'Gene', '1029', (0, 6))	('mucosal melanoma', 'Disease', (43, 59))
33206	31683701	To date, CDKN2A mutations have never been reported in uveal melanoma.	('CDKN2A', 'Gene', '1029', (9, 15))	('mutations', 'Var', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))	('uveal melanoma', 'Disease', 'MESH:C536494', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('CDKN2A', 'Gene', (9, 15))
33209	31683701	In conclusion, we believe that CDKN2A mutations can be of interest as a potential therapeutic target for CjM and can also be useful for the differential diagnosis between CjM and benign atypical conjunctival nevi.	('CjM', 'Disease', (105, 108))	('CjM', 'Phenotype', 'HP:0007716', (171, 174))	('CjM', 'Disease', 'MESH:D003229', (171, 174))	('CjM', 'Disease', (171, 174))	('nevi', 'Phenotype', 'HP:0003764', (208, 212))	('CjM', 'Phenotype', 'HP:0007716', (105, 108))	('CDKN2A', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('CjM', 'Disease', 'MESH:D003229', (105, 108))	('CDKN2A', 'Gene', '1029', (31, 37))
33214	31683701	Furthermore, metastatic CjM conjunctival melanoma shows the amplification of MLH1 (3p22.1) and TIMP2 (17q25.3) and the deletion of MGMT (20q26.3) and ECHS1 (10q26.3).	('TIMP2', 'Gene', (95, 100))	('MGMT', 'molecular_function', 'GO:0003908', ('131', '135'))	('MLH1', 'Gene', '4292', (77, 81))	('ECHS1', 'Gene', '1892', (150, 155))	('MLH1', 'Gene', (77, 81))	('CjM', 'Phenotype', 'HP:0007716', (24, 27))	('deletion', 'Var', (119, 127))	('MGMT', 'Gene', '4255', (131, 135))	('MGMT', 'Gene', (131, 135))	('conjunctival melanoma', 'Disease', (28, 49))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (28, 49))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (28, 49))	('CjM', 'Disease', 'MESH:D003229', (24, 27))	('ECHS1', 'Gene', (150, 155))	('CjM', 'Disease', (24, 27))	('TIMP2', 'Gene', '7077', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))
33217	31683701	Deletion of MGMT, which is involved in genome stability, has been detected in many cancer types, including cutaneous melanoma.	('cutaneous melanoma', 'Disease', (107, 125))	('detected', 'Reg', (66, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MGMT', 'Gene', (12, 16))	('MGMT', 'Gene', '4255', (12, 16))	('MGMT', 'molecular_function', 'GO:0003908', ('12', '16'))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('cancer', 'Disease', (83, 89))	('Deletion', 'Var', (0, 8))
33220	31683701	The deletion of 10q only was correlated with shorter metastases-free survival, lymphatic invasion and major tumor thickness in 59 CjM patients.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CjM', 'Phenotype', 'HP:0007716', (130, 133))	('deletion of', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('metastases', 'Disease', (53, 63))	('shorter', 'NegReg', (45, 52))	('CjM', 'Disease', 'MESH:D003229', (130, 133))	('CjM', 'Disease', (130, 133))	('patients', 'Species', '9606', (134, 142))	('tumor', 'Disease', (108, 113))	('metastases', 'Disease', 'MESH:D009362', (53, 63))	('lymphatic invasion', 'CPA', (79, 97))
33222	31683701	Moreover, there is a higher frequency of 10q loss in BRAF mutant CjM.	('mutant', 'Var', (58, 64))	('10q', 'CPA', (41, 44))	('CjM', 'Phenotype', 'HP:0007716', (65, 68))	('BRAF', 'Gene', (53, 57))	('CjM', 'Disease', (65, 68))	('CjM', 'Disease', 'MESH:D003229', (65, 68))
33223	31683701	In uveal melanoma, typically BRAF-wild type, the most frequent chromosome abnormalities, such as chromosome 3 monosomy and gain of chromosome 8q, demonstrated a prognostic value for relapse, but they did not predict response to treatment.	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('chromosome abnormalities', 'Disease', (63, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('131', '141'))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('chromosome 3 monosomy', 'Var', (97, 118))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (63, 87))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('monosomy', 'Var', (110, 118))	('gain', 'PosReg', (123, 127))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (63, 87))
33229	31683701	We could assume that tumors with BRAF mutation need a further genetic event, which induces AKT pathway, for their development.	('AKT', 'Gene', '207', (91, 94))	('BRAF', 'Gene', (33, 37))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('induces', 'Reg', (83, 90))	('AKT', 'Gene', (91, 94))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
33234	31683701	High EZH2 is correlated with CjM thickness and poor prognosis.	('CjM', 'Disease', 'MESH:D003229', (29, 32))	('CjM', 'Disease', (29, 32))	('High', 'Var', (0, 4))	('CjM', 'Phenotype', 'HP:0007716', (29, 32))	('EZH2', 'Gene', (5, 9))
33236	31683701	In zebrafish xenografts, genetic and pharmacological knockdown of EZH2, through molecules such as GSK503 or UNC1999, reduces tumor growth and colony formation of CjM cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('zebrafish', 'Species', '7955', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('knockdown', 'Var', (53, 62))	('EZH2', 'Gene', (66, 70))	('reduces', 'NegReg', (117, 124))	('tumor', 'Disease', (125, 130))	('GSK', 'molecular_function', 'GO:0050321', ('98', '101'))	('CjM', 'Phenotype', 'HP:0007716', (162, 165))	('formation', 'biological_process', 'GO:0009058', ('149', '158'))	('CjM', 'Disease', 'MESH:D003229', (162, 165))	('CjM', 'Disease', (162, 165))
33237	31683701	Inactivation of EZH2 upregulates the oncogene p21/CDKN1A, that controls cellular transition from the G1 to S phase.	('EZH2', 'Gene', (16, 20))	('CDKN1A', 'Gene', (50, 56))	('S phase', 'biological_process', 'GO:0051320', ('107', '114'))	('CDKN1A', 'Gene', '1026', (50, 56))	('p21', 'Gene', '1026', (46, 49))	('p21', 'Gene', (46, 49))	('upregulates', 'PosReg', (21, 32))	('Inactivation', 'Var', (0, 12))
33239	31683701	Inhibition of EZH2 in CjM cells slows the cellular progression to the S-phase and determines cell death through apoptosis and autophagy.	('CjM', 'Disease', 'MESH:D003229', (22, 25))	('CjM', 'Disease', (22, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('EZH2', 'Gene', (14, 18))	('determines', 'Reg', (82, 92))	('autophagy', 'biological_process', 'GO:0016236', ('126', '135'))	('autophagy', 'biological_process', 'GO:0006914', ('126', '135'))	('Inhibition', 'Var', (0, 10))	('slows', 'NegReg', (32, 37))	('cellular progression to the S-phase', 'CPA', (42, 77))	('CjM', 'Phenotype', 'HP:0007716', (22, 25))	('S-phase', 'biological_process', 'GO:0051320', ('70', '77'))	('autophagy', 'CPA', (126, 135))	('cell death', 'biological_process', 'GO:0008219', ('93', '103'))
33241	31683701	In conclusion, EZH2 knockdown in CjM cells leads to an S-phase depletion with G1 arrest and accumulation of cells in the G2/M phase.	('S-phase', 'biological_process', 'GO:0051320', ('55', '62'))	('CjM', 'Disease', 'MESH:D003229', (33, 36))	('CjM', 'Disease', (33, 36))	('M phase', 'biological_process', 'GO:0000279', ('124', '131'))	('CjM', 'Phenotype', 'HP:0007716', (33, 36))	('S-phase depletion', 'MPA', (55, 72))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('knockdown', 'Var', (20, 29))	('EZH2', 'Gene', (15, 19))	('arrest', 'Disease', (81, 87))	('leads to', 'Reg', (43, 51))	('accumulation', 'PosReg', (92, 104))
33257	31683701	The association between the upregulation of mir-3916 and an increased risk of local recurrence of CjM has been pointed out.	('CjM', 'Phenotype', 'HP:0007716', (98, 101))	('mir-3916', 'Var', (44, 52))	('CjM', 'Disease', 'MESH:D003229', (98, 101))	('CjM', 'Disease', (98, 101))	('local recurrence', 'Disease', (78, 94))	('upregulation', 'PosReg', (28, 40))
33260	31683701	Overall, CjM is commonly characterized by mutations of BRAF, NF1 and TERT, high expression of mTOR and HSP90, frequent PTEN loss and upregulation of specific miRNAs.	('loss', 'NegReg', (124, 128))	('CjM', 'Disease', 'MESH:D003229', (9, 12))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('HSP90', 'Gene', (103, 108))	('NF1', 'Gene', (61, 64))	('upregulation', 'PosReg', (133, 145))	('CjM', 'Disease', (9, 12))	('PTEN', 'Gene', (119, 123))	('CjM', 'Phenotype', 'HP:0007716', (9, 12))	('HSP90', 'Gene', '3320', (103, 108))	('PTEN', 'Gene', '5728', (119, 123))	('expression', 'MPA', (80, 90))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (55, 59))
33261	31683701	The anti-BRAF and anti-MEK combination could be a therapeutic option in case of BRAF mutations.	('MEK', 'Gene', '5609', (23, 26))	('mutations', 'Var', (85, 94))	('MEK', 'Gene', (23, 26))	('BRAF', 'Disease', (80, 84))
33267	31683701	The challenge for the future is the identification of the driver molecular alterations to achieve a clinically relevant therapeutic effect in CjM patients.	('CjM', 'Phenotype', 'HP:0007716', (142, 145))	('alterations', 'Var', (75, 86))	('CjM', 'Disease', (142, 145))	('CjM', 'Disease', 'MESH:D003229', (142, 145))	('patients', 'Species', '9606', (146, 154))
33270	30216763	Overexpression of sorcin has been reported to be associated with different cancers such as breast cancer, colorectal cancer, gastric cancer, leukemia, lung cancer, nasopharyngeal cancer, ovarian cancer, etc.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('colorectal cancer', 'Disease', (106, 123))	('associated', 'Reg', (49, 59))	('lung cancer', 'Disease', (151, 162))	('Overexpression', 'Var', (0, 14))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (164, 185))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('ovarian cancer', 'Disease', (187, 201))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('sorcin', 'Protein', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (164, 185))	('leukemia', 'Disease', 'MESH:D007938', (141, 149))	('leukemia', 'Disease', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('breast cancer', 'Disease', (91, 104))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('nasopharyngeal cancer', 'Disease', (164, 185))
33273	30216763	Sorcin was also found to regulate apoptosis, as silencing of the same resulted in increased levels of proapoptotic genes and induced mitochondrial apoptotic pathway in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('silencing', 'Var', (48, 57))	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('levels of proapoptotic genes', 'MPA', (92, 120))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('induced', 'PosReg', (125, 132))	('mitochondrial apoptotic pathway', 'Pathway', (133, 164))	('increased', 'PosReg', (82, 91))	('cancer', 'Disease', (168, 174))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))
33274	30216763	Interestingly, mutations in the sorcin gene have been closely linked with poor overall survival in bladder cancer, brain lower-grade glioma, glioblastoma, glioblastoma multiforme, kidney renal clear cell carcinoma, and stomach adenocarcinoma.	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioblastoma', 'Disease', (155, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('poor', 'NegReg', (74, 78))	('mutations', 'Var', (15, 24))	('glioblastoma multiforme', 'Disease', (155, 178))	('stomach adenocarcinoma', 'Disease', (219, 241))	('linked', 'Reg', (62, 68))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (180, 213))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (219, 241))	('glioma', 'Disease', (133, 139))	('bladder cancer', 'Disease', (99, 113))	('sorcin', 'Gene', (32, 38))	('kidney renal clear cell carcinoma', 'Disease', (180, 213))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
33290	30216763	In addition, silencing of this protein resulted in apoptosis and reverted MDR of cancer cells, and additionally, sorcin depletion reduced the levels of various proteins involved in angiogenesis, invasion, and metastasis.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('levels of various proteins', 'MPA', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('angiogenesis', 'biological_process', 'GO:0001525', ('181', '193'))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('cancer', 'Disease', (81, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('depletion', 'MPA', (120, 129))	('reduced', 'NegReg', (130, 137))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('MDR of', 'CPA', (74, 80))	('apoptosis', 'CPA', (51, 60))	('MDR', 'molecular_function', 'GO:0004745', ('74', '77'))	('silencing', 'Var', (13, 22))
33301	30216763	These five EF-hands were found to pair with each other (EF1 with EF2 and EF3 with EF4).	('EF2', 'Gene', '1938', (65, 68))	('EF4', 'Gene', '60558', (82, 85))	('EF2', 'Gene', (65, 68))	('EF3', 'Var', (73, 76))	('EF4', 'Gene', (82, 85))
33318	30216763	Calcium (Ca2+) plays significant roles in neurons, including synaptic plasticity and apoptosis, and deregulation of this neuronal calcium signaling was known to be one of the central mechanisms of different neurodegenerative diseases such as Alzheimer's disease (AD).	('AD', 'Phenotype', 'HP:0002511', (263, 265))	('AD', 'Disease', 'MESH:D000544', (263, 265))	('deregulation', 'Var', (100, 112))	('AD', 'Disease', (263, 265))	('calcium', 'Chemical', 'MESH:D002118', (130, 137))	('neurodegenerative diseases', 'Disease', (207, 233))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (242, 261))	('calcium signaling', 'biological_process', 'GO:0019722', ('130', '147'))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	("Alzheimer's disease", 'Disease', (242, 261))	('Ca2+', 'Chemical', 'MESH:D000069285', (9, 13))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (207, 233))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (242, 261))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (207, 233))
33320	30216763	Sorcin expression enhances the concentration of calcium in endoplasmic reticulum (ER), inhibits ER stress, and induces the resistance to apoptosis.	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('59', '80'))	('calcium', 'Chemical', 'MESH:D002118', (48, 55))	('concentration of calcium', 'MPA', (31, 55))	('Sorcin', 'Gene', (0, 6))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('inhibits', 'NegReg', (87, 95))	('expression', 'Var', (7, 17))	('induces', 'Reg', (111, 118))	('resistance to apoptosis', 'CPA', (123, 146))	('ER stress', 'MPA', (96, 105))	('enhances', 'PosReg', (18, 26))
33321	30216763	Apart from calcium homeostasis, sorcin was also found to have a key role in the activation of mitosis and cytokinesis as loss of sorcin highly compromised the normal process of mitosis and cytokinesis.	('mitosis', 'Disease', 'None', (94, 101))	('activation of mitosis', 'biological_process', 'GO:0045840', ('80', '101'))	('compromised', 'NegReg', (143, 154))	('mitosis', 'Disease', (177, 184))	('mitosis', 'biological_process', 'GO:0000278', ('177', '184'))	('loss', 'Var', (121, 125))	('mitosis', 'Disease', 'None', (177, 184))	('homeostasis', 'biological_process', 'GO:0042592', ('19', '30'))	('cytokinesis', 'biological_process', 'GO:0000910', ('189', '200'))	('calcium', 'Chemical', 'MESH:D002118', (11, 18))	('cytokinesis', 'biological_process', 'GO:0000910', ('106', '117'))	('sorcin', 'Protein', (129, 135))	('mitosis', 'Disease', (94, 101))
33326	30216763	Apart from this, sorcin also targets the sarcolemmal NCX1 (sodium/ calcium exchanger) and induces its expression in the cardiac muscles, and silencing of sorcin by miR-1 helps to regulate the myocardial contraction through calcium signaling.	('calcium', 'Chemical', 'MESH:D002118', (223, 230))	('sorcin', 'Gene', (154, 160))	('silencing', 'Var', (141, 150))	('calcium', 'Chemical', 'MESH:D002118', (67, 74))	('expression', 'MPA', (102, 112))	('induces', 'PosReg', (90, 97))	('calcium signaling', 'biological_process', 'GO:0019722', ('223', '240'))	('myocardial contraction', 'CPA', (192, 214))	('NCX1', 'Gene', (53, 57))	('sodium/ calcium exchanger', 'molecular_function', 'GO:0005432', ('59', '84'))	('regulate', 'Reg', (179, 187))	('miR-1', 'Gene', '79187', (164, 169))	('NCX1', 'Gene', '6546', (53, 57))	('calcium signaling', 'MPA', (223, 240))	('miR-1', 'Gene', (164, 169))
33339	30216763	As observed from the cBioPortal for Cancer Genomics data, several mutations of sorcin protein are associated with different kind of cancers including bladder cancer, colorectal adenocarcinoma, prostate adenocarcinoma, skin cutaneous melanoma, sarcoma, and uterine corpus endometrial carcinoma, etc.	('mutations', 'Var', (66, 75))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (223, 241))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal adenocarcinoma, prostate adenocarcinoma', 'Disease', 'MESH:D000230', (166, 216))	('sorcin', 'Gene', (79, 85))	('Cancer', 'Disease', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('endometrial carcinoma', 'Disease', (271, 292))	('protein', 'Protein', (86, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (150, 164))	('bladder cancer', 'Disease', (150, 164))	('sarcoma', 'Disease', 'MESH:D012509', (243, 250))	('sarcoma', 'Disease', (243, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('bladder cancer', 'Phenotype', 'HP:0009725', (150, 164))	('Cancer', 'Disease', 'MESH:D009369', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (271, 292))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (243, 250))	('skin cutaneous melanoma', 'Disease', (218, 241))	('associated', 'Reg', (98, 108))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (271, 292))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))
33340	30216763	In line with this, RNA sequencing analysis of patient samples revealed amplification of SRI gene to be associated with various cancers, which was evident from the TCGA cBioPortal database.	('patient', 'Species', '9606', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (103, 113))	('amplification', 'Var', (71, 84))	('SRI', 'Gene', (88, 91))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('SRI', 'Gene', '6717', (88, 91))	('cancers', 'Disease', (127, 134))
33343	30216763	In addition to gene amplification, different mutations of SRI gene were also reported in the TCGA database, and frequency of SRI gene mutation observed in different cancers is as follows: colorectal cancer 0.16%, uterine cancer 0.36%, prostate cancer 0.4%, and sarcoma 0.38%.	('sarcoma', 'Disease', (261, 268))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('prostate cancer', 'Disease', (235, 250))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (199, 205))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('sarcoma', 'Phenotype', 'HP:0100242', (261, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('uterine cancer', 'Phenotype', 'HP:0010784', (213, 227))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('SRI', 'Gene', '6717', (125, 128))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cancer', 'Disease', (244, 250))	('SRI', 'Gene', '6717', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('mutation', 'Var', (134, 142))	('SRI', 'Gene', (125, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('SRI', 'Gene', (58, 61))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))	('sarcoma', 'Disease', 'MESH:D012509', (261, 268))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))
33345	30216763	As mentioned earlier, according to the TCGA database, sorcin shows different mutations in different cancers such as X84_splice (splice mutation) in bladder cancer, D157N (missense mutation) in colorectal adenocarcinoma, A161T (missense mutation) & Q48*(nonsense mutation) in prostate adenocarcinoma, P28L (missense mutation) & C162F (missense mutation) in skin cutaneous melanoma, Y13Tfs *30(FS del mutation) in sarcoma, and A161T (missense mutation) & R106I (missense mutation) in uterine corpus endometrial carcinoma.	('D157N', 'Var', (164, 169))	('A161T', 'Mutation', 'rs1457132903', (220, 225))	('P28L', 'Mutation', 'p.P28L', (300, 304))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('A161T', 'Mutation', 'rs1457132903', (425, 430))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('Y13Tfs *30(FS del', 'Mutation', 'p.13,FSdelT', (381, 398))	('sarcoma', 'Phenotype', 'HP:0100242', (412, 419))	('C162F', 'Mutation', 'p.C162F', (327, 332))	('endometrial carcinoma', 'Disease', (497, 518))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (193, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (509, 518))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (497, 518))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (497, 518))	('melanoma', 'Phenotype', 'HP:0002861', (371, 379))	('X84_splice', 'Var', (116, 126))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (356, 379))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (361, 379))	('skin cutaneous melanoma', 'Disease', (356, 379))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('P28', 'cellular_component', 'GO:0070744', ('300', '303'))	('R106I', 'Mutation', 'p.R106I', (453, 458))	('cancers', 'Disease', (100, 107))	('prostate adenocarcinoma', 'Disease', (275, 298))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('D157N', 'Mutation', 'rs754279084', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('sarcoma', 'Disease', 'MESH:D012509', (412, 419))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('colorectal adenocarcinoma', 'Disease', (193, 218))	('sarcoma', 'Disease', (412, 419))	('A161T', 'Var', (220, 225))
33348	30216763	However, in some of the cancers, patients with altered sorcin showed more median month survival such as breast cancer (163.1 months), esophageal carcinoma (44.71 months), head and neck squamous cell carcinoma (71.16 months), ovarian serous cystadenocarcinoma (50.33 months), and skin cutaneous melanoma (297.67 months) (Table 1).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (279, 302))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (134, 154))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (225, 258))	('breast cancer', 'Disease', (104, 117))	('skin cutaneous melanoma', 'Disease', (279, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('neck', 'cellular_component', 'GO:0044326', ('180', '184'))	('altered', 'Var', (47, 54))	('esophageal carcinoma', 'Disease', (134, 154))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (284, 302))	('cancers', 'Disease', (24, 31))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (134, 154))	('neck squamous cell carcinoma', 'Disease', (180, 208))	('more', 'PosReg', (69, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (180, 208))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (225, 258))	('patients', 'Species', '9606', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('ovarian serous cystadenocarcinoma', 'Disease', (225, 258))
33354	30216763	Cancer cells acquire MDR through ABC transporter family, resistance to apoptosis induction, autophagy, cancer stem cells, miRNA, hypoxia, DNA damage and repair, and epigenetic regulation.	('epigenetic', 'Var', (165, 175))	('hypoxia', 'Disease', (129, 136))	('ABC transporter', 'molecular_function', 'GO:0140359', ('33', '48'))	('MDR', 'molecular_function', 'GO:0004745', ('21', '24'))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (103, 109))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('hypoxia', 'Disease', 'MESH:D000860', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('autophagy', 'biological_process', 'GO:0016236', ('92', '101'))	('autophagy', 'CPA', (92, 101))	('MDR', 'Gene', (21, 24))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('autophagy', 'biological_process', 'GO:0006914', ('92', '101'))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('regulation', 'biological_process', 'GO:0065007', ('176', '186'))	('Cancer', 'Disease', (0, 6))
33361	30216763	Silencing of sorcin resulted in the downregulation of these genes in addition to p-Akt and NF-kappaB levels inducing chemoresistance in myeloma cells (Figure 3).	('sorcin', 'Gene', (13, 19))	('downregulation', 'NegReg', (36, 50))	('NF-kappaB', 'Gene', '4790', (91, 100))	('NF-kappaB', 'Gene', (91, 100))	('myeloma', 'Disease', (136, 143))	('inducing', 'Reg', (108, 116))	('p-Akt', 'MPA', (81, 86))	('Silencing', 'Var', (0, 9))	('myeloma', 'Disease', 'MESH:D009101', (136, 143))	('chemoresistance', 'CPA', (117, 132))
33364	30216763	Likewise, chemoresistance to cisplatin in MDR cells is also associated with the co-amplification of sorcin.	('MDR', 'molecular_function', 'GO:0004745', ('42', '45'))	('sorcin', 'Protein', (100, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('chemoresistance', 'CPA', (10, 25))	('co-amplification', 'Var', (80, 96))	('associated', 'Reg', (60, 70))
33366	30216763	Similarly, co-amplification of sorcin and MDR1 gene observed in leukemia can be taken as a good indicator of clinical drug resistance and prognosis of the disease.	('leukemia', 'Disease', (64, 72))	('MDR', 'molecular_function', 'GO:0004745', ('42', '45'))	('sorcin', 'Gene', (31, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('MDR1', 'Gene', (42, 46))	('drug resistance', 'biological_process', 'GO:0009315', ('118', '133'))	('co-amplification', 'Var', (11, 27))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('MDR1', 'Gene', '5243', (42, 46))	('leukemia', 'Disease', 'MESH:D007938', (64, 72))	('drug resistance', 'biological_process', 'GO:0042493', ('118', '133'))
33367	30216763	Further proving the importance of sorcin in MDR, overexpression of sorcin in K562 cells by gene transfection led to the increase in drug resistance, from 4.1- to 22.5-fold, to various chemotherapeutic drugs such as doxorubicin, etoposide, homoharringtonine, and vincristine.	('drug resistance', 'biological_process', 'GO:0042493', ('132', '147'))	('K562', 'CellLine', 'CVCL:0004', (77, 81))	('doxorubicin', 'Chemical', 'MESH:D004317', (215, 226))	('drug resistance', 'MPA', (132, 147))	('increase', 'PosReg', (120, 128))	('etoposide', 'Chemical', 'MESH:D005047', (228, 237))	('gene transfection', 'Var', (91, 108))	('vincristine', 'Chemical', 'MESH:D014750', (262, 273))	('drug resistance', 'Phenotype', 'HP:0020174', (132, 147))	('homoharringtonine', 'Chemical', 'MESH:D000077863', (239, 256))	('overexpression', 'PosReg', (49, 63))	('drug resistance', 'biological_process', 'GO:0009315', ('132', '147'))	('MDR', 'molecular_function', 'GO:0004745', ('44', '47'))
33380	30216763	Upregulation of sorcin in malignant cells significantly induces the cell proliferation, migration, and invasion, and knockdown of the same diminished the proliferation, migration, and invasion of cancer cells, revealing the importance of sorcin in the development and progression of cancer.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cell proliferation', 'CPA', (68, 86))	('cancer', 'Disease', (283, 289))	('migration', 'CPA', (169, 178))	('induces', 'PosReg', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('migration', 'CPA', (88, 97))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('sorcin', 'Gene', (16, 22))	('diminished', 'NegReg', (139, 149))	('invasion', 'CPA', (103, 111))	('knockdown', 'Var', (117, 126))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
33383	30216763	TCGA data analysis also showed alteration status of sorcin gene to be significantly associated with survival of cancer patients, suggesting the prognostic value of this protein.	('sorcin gene', 'Gene', (52, 63))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('patients', 'Species', '9606', (119, 127))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('survival', 'Disease', (100, 108))	('associated', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('alteration status', 'Var', (31, 48))
33512	28719033	Identification of driver copy number alterations in diverse cancer types and application in drug repositioning Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression.	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number alterations', 'Var', (25, 48))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
33559	28719033	a + b + c + d is the total number of genes in the expression profile, and a + b is the number of census cancer genes in the expression profile.	('a + b + c + d', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('census cancer', 'Disease', (97, 110))	('census cancer', 'Disease', 'MESH:D009369', (97, 110))	('a + b', 'Var', (74, 79))
33572	28719033	Second, alterations, including SCNAs, that affect expression levels of other genes in the cancer genome have been used to identify key events for carcinogenesis (Masica and Karchin, 2011).	('carcinogenesis', 'Disease', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alterations', 'Var', (8, 19))	('affect', 'Reg', (43, 49))	('expression levels', 'MPA', (50, 67))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
33591	28719033	The drivers with deletions also significantly overlapped with tumor suppressor genes in the TSGene database in 11 of the 18 cancer types (Fig.	('overlapped', 'Reg', (46, 56))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('deletions', 'Var', (17, 26))	('tumor', 'Disease', (62, 67))	('tumor suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
33598	28719033	Many studies have reported aberrations in POU5F1B in cancer, such as in gastric and prostate cancer (Hayashi et al., 2015; Kastler et al., 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('gastric and prostate cancer', 'Disease', 'MESH:D013274', (72, 99))	('cancer', 'Disease', (53, 59))	('POU5F1B', 'Gene', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('POU5F1B', 'Gene', '5462', (42, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('aberrations', 'Var', (27, 38))
33599	28719033	5C, a total of nine non-coding drivers (hsa-mir-106b, hsa-mir-218-2, hsa-mir-548k, AP006216.10, CAPN10-AS1, RP11-1191J2.4, RP11-191L9.4, RP11-443B7.1 and RP11-794P6.1) were shared by two cancer types, and three non-coding drivers (PVT1, SOX2-OT and hsa-mir-429) by three cancer types.	('AS1', 'Gene', (103, 106))	('RP11', 'Gene', (108, 112))	('RP11', 'Gene', '26121', (154, 158))	('PVT1', 'Gene', '5820', (231, 235))	('RP11', 'Gene', (123, 127))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('RP11', 'Gene', (137, 141))	('RP11', 'Gene', (154, 158))	('SOX2-OT', 'Gene', (237, 244))	('AS1', 'Gene', '5729', (103, 106))	('CAPN10', 'Gene', (96, 102))	('SOX2-OT', 'Gene', '347689', (237, 244))	('RP11', 'Gene', '26121', (108, 112))	('CAPN10', 'Gene', '11132', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('hsa-mir-218-2', 'Gene', '407001', (54, 67))	('RP11', 'Gene', '26121', (123, 127))	('hsa-mir-218-2', 'Gene', (54, 67))	('cancer', 'Disease', (187, 193))	('AP006216.10', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hsa-mir-429', 'Gene', '554210', (249, 260))	('PVT1', 'Gene', (231, 235))	('RP11', 'Gene', '26121', (137, 141))	('hsa-mir-429', 'Gene', (249, 260))
33603	28719033	In total, seven drivers (MYC with amplification, PER2, HDAC4, PTPRG, PIK3R1, RAPGEF1 and PPP5C with deletion) were detected in both BRCA and OV.	('BRCA', 'Gene', '672', (132, 136))	('PIK3R1', 'Gene', (69, 75))	('MYC', 'Gene', (25, 28))	('HDAC4', 'Gene', '9759', (55, 60))	('RAPGEF1', 'Gene', '2889', (77, 84))	('PPP5C', 'Gene', (89, 94))	('PPP5C', 'Gene', '5536', (89, 94))	('BRCA', 'Gene', (132, 136))	('OV', 'Phenotype', 'HP:0100615', (141, 143))	('amplification', 'Var', (34, 47))	('deletion', 'Var', (100, 108))	('HDAC4', 'Gene', (55, 60))	('PIK3R1', 'Gene', '5295', (69, 75))	('MYC', 'Gene', '4609', (25, 28))	('PTPRG', 'Gene', (62, 67))	('PER2', 'Gene', (49, 53))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('RAPGEF1', 'Gene', (77, 84))	('PER2', 'Gene', '8864', (49, 53))	('PTPRG', 'Gene', '5793', (62, 67))
33614	28719033	Copy number alterations of non-coding RNAs play important roles in the progression of diverse types of cancer (Du et al., 2016).	('RNAs', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Copy number alterations', 'Var', (0, 23))	('roles', 'Reg', (58, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
33617	28719033	For example, driver lncRNA GAS5 with amplification in liver hepatocellular carcinoma (LIHC) identified in our work has been reported with oncogenic roles in LIHC by Tao et al.	('GAS5', 'Gene', '60674', (27, 31))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 84))	('LIHC', 'Disease', (86, 90))	('LIHC', 'Disease', 'None', (86, 90))	('amplification', 'Var', (37, 50))	('GAS5', 'Gene', (27, 31))	('GAS', 'molecular_function', 'GO:0034005', ('27', '30'))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LIHC', 'Disease', (157, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('LIHC', 'Disease', 'None', (157, 161))	('liver hepatocellular carcinoma', 'Disease', (54, 84))
33618	28719033	Hsa-mir-134, a driver miRNA with a deletion in LUAD, was found to suppress NSCLC progression through down-regulation of CCND1 (Sun et al., 2016).	('LUAD', 'Gene', (47, 51))	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('suppress', 'NegReg', (66, 74))	('down-regulation', 'NegReg', (101, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('Hsa-mir-134', 'Gene', '406924', (0, 11))	('CCND1', 'Gene', (120, 125))	('NSCLC', 'Disease', (75, 80))	('deletion', 'Var', (35, 43))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('Hsa-mir-134', 'Gene', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('CCND1', 'Gene', '595', (120, 125))
33642	28719033	Afatinib, another FDA approved drug, is used to treat late stage (metastatic) NSCLC with EGFR mutations (Dungo and Keating, 2013) (Fig.	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('mutations', 'Var', (94, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('NSCLC', 'Disease', (78, 83))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('EGFR', 'Gene', '1956', (89, 93))
33643	28719033	LUSC cell lines with amplification of EGFR show marginally significant sensitivity to lapatinib compared with those of LUSC cell lines with wild-type EGFR in the CCLE database (P = 0.049, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('38', '42'))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', (38, 42))	('lapatinib', 'Chemical', 'MESH:D000077341', (86, 95))	('sensitivity to lapatinib', 'MPA', (71, 95))	('EGFR', 'molecular_function', 'GO:0005006', ('150', '154'))	('CCLE', 'Chemical', '-', (162, 166))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (21, 34))	('EGFR', 'Gene', '1956', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
33644	28719033	LGG cell lines with amplification of EGFR show significant sensitivity to lapatinib compared with those of LGG cell lines with wild-type EGFR in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', (137, 141))	('EGFR', 'molecular_function', 'GO:0005006', ('37', '41'))	('sensitivity to lapatinib', 'MPA', (59, 83))	('EGFR', 'Gene', '1956', (37, 41))	('lapatinib', 'Chemical', 'MESH:D000077341', (74, 83))	('EGFR', 'Gene', '1956', (137, 141))	('amplification', 'Var', (20, 33))	('EGFR', 'Gene', (37, 41))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))
33645	28719033	BRCA cell lines with amplification of ERBB2 show significantly lower IC50 levels of afatinib compared with those of BRCA cell lines with wild-type ERBB2 in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('IC50 levels of afatinib', 'MPA', (69, 92))	('lower', 'NegReg', (63, 68))	('BRCA', 'Gene', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (38, 43))	('ERBB2', 'Gene', '2064', (147, 152))	('afatinib', 'Chemical', 'MESH:D000077716', (84, 92))	('BRCA', 'Phenotype', 'HP:0003002', (116, 120))	('amplification', 'Var', (21, 34))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))	('BRCA', 'Gene', '672', (0, 4))
33657	28719033	Both CDKN2A and RB1 were reported to have deletions in BRCA and LGG (Bieche and Lidereau, 2000; Debniak et al., 2004).	('BRCA', 'Phenotype', 'HP:0003002', (55, 59))	('BRCA', 'Gene', '672', (55, 59))	('CDKN2A', 'Gene', (5, 11))	('BRCA', 'Gene', (55, 59))	('RB1', 'Gene', (16, 19))	('LGG', 'Gene', (64, 67))	('CDKN2A', 'Gene', '1029', (5, 11))	('deletions', 'Var', (42, 51))	('RB1', 'Gene', '5925', (16, 19))
33659	28719033	Notably, our work investigated the similarity and specificity of different cancer types from copy number alterations, which only represents one kind of molecular feature of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
33662	28719033	The drivers with amplifications in BRCA identified by our work significantly overlapped those detected by the Helios method (P = 9.46 x 10-10, hypergeometric test), including CCND1, MYC, ERBB2, ERLIN2, FOXA1, RAD52 and TOMM20.	('TOMM20', 'Gene', '9804', (219, 225))	('amplifications', 'Var', (17, 31))	('RAD', 'biological_process', 'GO:1990116', ('209', '212'))	('CCND1', 'Gene', '595', (175, 180))	('RAD52', 'Gene', '5893', (209, 214))	('BRCA', 'Phenotype', 'HP:0003002', (35, 39))	('CCND1', 'Gene', (175, 180))	('ERLIN2', 'Gene', '11160', (194, 200))	('MYC', 'Gene', (182, 185))	('BRCA', 'Gene', '672', (35, 39))	('FOXA1', 'Gene', '3169', (202, 207))	('ERBB2', 'Gene', (187, 192))	('ERLIN2', 'Gene', (194, 200))	('FOXA1', 'Gene', (202, 207))	('BRCA', 'Gene', (35, 39))	('TOMM20', 'Gene', (219, 225))	('MYC', 'Gene', '4609', (182, 185))	('RAD52', 'Gene', (209, 214))	('ERBB2', 'Gene', '2064', (187, 192))
33664	28719033	(2016) reported that gistic 2.0 tends to call larger deletion regions than amplification regions and identifies more drivers in deleted regions than in amplified regions for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('deletion', 'Var', (53, 61))
33665	28719033	Generally, our methods identified more drivers with deletions than drivers with amplifications for each cancer type, except for LIHC, which has 77 amplified drivers and 41 deleted drivers (Table S2).	('LIHC', 'Disease', 'None', (128, 132))	('LIHC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('deletions', 'Var', (52, 61))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
33667	28719033	Some studies have also found that deletions or losses are more common than amplifications or gains in cancer (Cancer Genome Atlas Network, 2012; Schoch et al., 2002), which is an interesting phenomenon that warrants further exploration.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('deletions', 'Var', (34, 43))	('losses', 'NegReg', (47, 53))	('Cancer Genome Atlas', 'Disease', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gains in cancer', 'Disease', (93, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (110, 129))	('gains in cancer', 'Disease', 'MESH:D015430', (93, 108))
33672	28719033	The mutation status of known cancer genes may affect the expression of CDEGs.	('expression', 'MPA', (57, 67))	('cancer', 'Disease', (29, 35))	('mutation', 'Var', (4, 12))	('CDEGs', 'Gene', (71, 76))	('affect', 'Reg', (46, 52))	('CDEGs', 'Chemical', '-', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
33702	18655191	Our findings suggest that plasticity of aggressive melanoma can enable autopoiesis of critical vascular-mimicking elements within the tumor infrastructure, and may reflect in part the implications of current anti-angiogenic treatments.	('aggressive melanoma', 'Disease', 'MESH:D008545', (40, 59))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('enable', 'PosReg', (64, 70))	('aggressive melanoma', 'Disease', (40, 59))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('plasticity', 'Var', (26, 36))	('autopoiesis of', 'CPA', (71, 85))	('tumor', 'Disease', (134, 139))
33725	18655191	After fixation with -10 C methanol for 5 min, air drying, and washing (3x) with PBS, the specimens were incubated for 20 min with 10% blocking serum-PBS, washed with PBS, and then incubated for 60 min with one of the following rabbit-derived primary antibodies at 4mug/ml in 1.5% blocking serum-PBS: anti-ephrin-A1 (sc-911), -A3 (sc-1012), -B2 (sc-1010) (Santa Cruz); or 12 mug/ml anti-ephrin-A3 (ZMD.322; Invitrogen); or 12 mug/ml goat-derived anti-ephrin-B2 (AF496; R&D).	('ephrin', 'molecular_function', 'GO:0005106', ('450', '456'))	('ephrin', 'molecular_function', 'GO:0005106', ('386', '392'))	('ephrin', 'molecular_function', 'GO:0005106', ('305', '311'))	('mug', 'molecular_function', 'GO:0043739', ('374', '377'))	('ephrin-A3', 'Gene', (386, 395))	('AF', 'Disease', 'MESH:D001281', (461, 463))	('ephrin-A3', 'Gene', '100358959', (386, 395))	('anti-ephrin-A1', 'Var', (300, 314))	('PBS', 'Chemical', 'MESH:D007854', (295, 298))	('ephrin', 'molecular_function', 'GO:0046875', ('450', '456'))	('PBS', 'Chemical', 'MESH:D007854', (149, 152))	('ethanol', 'Chemical', 'MESH:D000431', (27, 34))	('PBS', 'Chemical', 'MESH:D007854', (166, 169))	('PBS', 'Chemical', 'MESH:D007854', (80, 83))	('ephrin', 'molecular_function', 'GO:0046875', ('386', '392'))	('ephrin', 'molecular_function', 'GO:0046875', ('305', '311'))	('goat', 'Species', '9925', (432, 436))	('mug', 'molecular_function', 'GO:0043739', ('265', '268'))	('mug', 'molecular_function', 'GO:0043739', ('425', '428'))	('rabbit', 'Species', '9986', (227, 233))
33801	18655191	It is documented that AUM-2 (or MUM2B) disseminates hematogenously while C8161 metastasizes hematogenously and/or via the lymphatics.	('AUM-2', 'Gene', (22, 27))	('disseminates', 'CPA', (39, 51))	('AUM', 'cellular_component', 'GO:0120001', ('22', '25'))	('metastasizes', 'CPA', (79, 91))	('MUM2B', 'CellLine', 'CVCL:3447', (32, 37))	('C8161', 'Var', (73, 78))
33805	32659961	Melanoma demonstrates relatively frequent MET aberrations, including MET gene amplification.	('Melanoma', 'Disease', (0, 8))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('MET gene amplification', 'Var', (69, 91))
33816	32659961	Dysregulation of the HGF/MET signaling pathway has been demonstrated in a wide range of malignancies, including malignant melanoma.	('malignant melanoma', 'Disease', 'MESH:D008545', (112, 130))	('malignant melanoma', 'Disease', (112, 130))	('Dysregulation', 'Var', (0, 13))	('malignancies', 'Disease', (88, 100))	('HGF', 'Gene', (21, 24))	('HGF', 'Gene', '3082', (21, 24))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('malignant melanoma', 'Phenotype', 'HP:0002861', (112, 130))	('MET signaling pathway', 'biological_process', 'GO:0048012', ('25', '46'))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
33817	32659961	A recent large whole genome sequencing (WGS) analysis of melanomas has demonstrated relatively frequent MET aberrations, including MET gene amplification, single nucleotide variations/deletions, and structural variants.	('melanomas', 'Disease', (57, 66))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('single nucleotide variations/deletions', 'Var', (155, 193))	('structural variants', 'Var', (199, 218))	('MET gene amplification', 'Var', (131, 153))
33823	32659961	For example, mutations in receptor tyrosine kinase pathways, such as epidermal growth factor receptor (EGFR), have been shown to induce PD-L1 expression in lung tumors and this overexpression in cancer cells can block anti-tumor immunity, resulting in immune escape, which can be overcome by PD-1/PD-L1 inhibition by restoring tumor-specific T-cell immunity.	('lung tumors', 'Disease', (156, 167))	('EGFR', 'Gene', '1956', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('69', '92'))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('PD-L1', 'Gene', (136, 141))	('receptor tyrosine kinase', 'Gene', '5979', (26, 50))	('PD-L1', 'Gene', '29126', (136, 141))	('tumor', 'Disease', (161, 166))	('induce', 'PosReg', (129, 135))	('epidermal growth factor receptor', 'Gene', (69, 101))	('tumor', 'Disease', (327, 332))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('receptor tyrosine kinase', 'Gene', (26, 50))	('epidermal growth factor receptor', 'Gene', '1956', (69, 101))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Disease', (223, 228))	('EGFR', 'Gene', (103, 107))	('cancer', 'Disease', (195, 201))	('lung tumors', 'Disease', 'MESH:D008175', (156, 167))	('immune escape', 'CPA', (252, 265))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('expression', 'MPA', (142, 152))	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('PD-L1', 'Gene', (297, 302))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('lung tumors', 'Phenotype', 'HP:0100526', (156, 167))	('PD-1', 'Gene', (292, 296))	('PD-1', 'Gene', '5133', (292, 296))	('PD-L1', 'Gene', '29126', (297, 302))	('lung tumor', 'Phenotype', 'HP:0100526', (156, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('block', 'NegReg', (212, 217))
33825	32659961	For example, MET expression has been shown to promote upregulation of PD-L1 in renal cancer cells and expression of PD-L1 and PD-L2 are upregulated in MET-amplified gastric and lung tumor cells.	('upregulated', 'PosReg', (136, 147))	('PD-L1', 'Gene', '29126', (70, 75))	('renal cancer', 'Disease', (79, 91))	('lung tumor', 'Disease', (177, 187))	('renal cancer', 'Phenotype', 'HP:0009726', (79, 91))	('lung tumor', 'Disease', 'MESH:D008175', (177, 187))	('upregulation', 'PosReg', (54, 66))	('PD-L1', 'Gene', (116, 121))	('renal cancer', 'Disease', 'MESH:D007680', (79, 91))	('PD-L2', 'Gene', (126, 131))	('lung tumor', 'Phenotype', 'HP:0100526', (177, 187))	('PD-L1', 'Gene', '29126', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('MET', 'Var', (13, 16))	('PD-L1', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
33854	32659961	For example, in a case of acral melanoma with KIT mutation, targeting MET with a selective inhibitor successfully overcame resistance to KIT inhibition, as confirmed also in cell line studies.	('acral melanoma', 'Disease', 'MESH:D008545', (26, 40))	('KIT', 'Gene', '3815', (46, 49))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('KIT', 'molecular_function', 'GO:0005020', ('46', '49'))	('KIT', 'Gene', (46, 49))	('acral melanoma', 'Disease', (26, 40))	('KIT', 'Gene', '3815', (137, 140))	('acral melanoma', 'Phenotype', 'HP:0012060', (26, 40))	('KIT', 'Gene', (137, 140))	('overcame', 'PosReg', (114, 122))	('KIT', 'molecular_function', 'GO:0005020', ('137', '140'))	('mutation', 'Var', (50, 58))
33855	32659961	Another study has established that MAPK pathway inhibition following BRAF inhibitor treatment induced rapid increases in MET and GAB1 expression and MET amplification was also observed to co-exist with BRAF hotspot mutations and represent the most common amplification among RTKs in melanomas.	('MAPK pathway', 'Pathway', (35, 47))	('increases', 'PosReg', (108, 117))	('MET', 'Gene', (121, 124))	('melanomas', 'Phenotype', 'HP:0002861', (283, 292))	('mutations', 'Var', (215, 224))	('BRAF', 'Gene', '673', (69, 73))	('GAB1', 'Gene', '2549', (129, 133))	('BRAF', 'Gene', (69, 73))	('expression', 'MPA', (134, 144))	('BRAF', 'Gene', '673', (202, 206))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('BRAF', 'Gene', (202, 206))	('RTK', 'Gene', (275, 278))	('RTK', 'Gene', '5979', (275, 278))	('melanomas', 'Disease', 'MESH:D008545', (283, 292))	('GAB1', 'Gene', (129, 133))	('inhibition', 'NegReg', (48, 58))	('melanomas', 'Disease', (283, 292))
33856	32659961	Moreover, downstream effects of MET phosphorylation include activation of the MAPK signaling pathway, where more than 80% of melanomas harbors alterations.	('MAPK signaling', 'biological_process', 'GO:0000165', ('78', '92'))	('phosphorylation', 'biological_process', 'GO:0016310', ('36', '51'))	('melanomas harbors alterations', 'Disease', 'MESH:C537062', (125, 154))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('phosphorylation', 'Var', (36, 51))	('melanomas harbors alterations', 'Disease', (125, 154))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('signaling pathway', 'biological_process', 'GO:0007165', ('83', '100'))	('activation', 'PosReg', (60, 70))	('MAPK signaling pathway', 'Pathway', (78, 100))	('MET phosphorylation', 'Var', (32, 51))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))
33877	32659961	This is exemplified by the assessment, in melanoma tissue samples, of the expression of BRAF mutations, which is currently the most robust predictive biomarker influencing eligibility to targeted therapy with vemurafenib and dabrafenib.	('melanoma', 'Disease', (42, 50))	('mutations', 'Var', (93, 102))	('dabrafenib', 'Chemical', 'MESH:C561627', (225, 235))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('vemurafenib', 'Chemical', 'MESH:D000077484', (209, 220))
33881	32659961	For MET, for example, in a phase I clinical trial testing the humanized anti-MET antibody Onartuzumab, patients with metastatic, chemotherapy-resistant gastric carcinomas, and high MET expression (defined qualitatively as > 50% of tumor cells with 2+ and 3+ staining) showed complete response with improved progression free survival (PFS) and overall survival (OS).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('antibody', 'cellular_component', 'GO:0042571', ('81', '89'))	('high MET', 'Var', (176, 184))	('Onartuzumab', 'Chemical', 'MESH:C584058', (90, 101))	('gastric carcinomas', 'Disease', (152, 170))	('gastric carcinomas', 'Disease', 'MESH:D013274', (152, 170))	('human', 'Species', '9606', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('antibody', 'cellular_component', 'GO:0019815', ('81', '89'))	('tumor', 'Disease', (231, 236))	('antibody', 'cellular_component', 'GO:0019814', ('81', '89'))	('progression free survival', 'CPA', (307, 332))	('patients', 'Species', '9606', (103, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('antibody', 'molecular_function', 'GO:0003823', ('81', '89'))	('overall survival', 'CPA', (343, 359))	('improved', 'PosReg', (298, 306))
33890	32659961	The WM35, WM115, WM164, WM278, WM793, WM852, WM1341D, 451Lu, and 1205Lu cell lines were obtained from the Wistar Institute and cultured with tumor specialized media containing 2% FBS.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('WM278', 'Var', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('WM852', 'Var', (38, 43))	('WM115', 'Var', (10, 15))	('tumor', 'Disease', (141, 146))	('WM164', 'Var', (17, 22))	('WM793', 'Var', (31, 36))	('WM1341D', 'Var', (45, 52))
33932	32825219	Moreover, miR-26b-5p overexpression induced a decreased T cell recognition.	('T cell recognition', 'CPA', (56, 74))	('cell recognition', 'biological_process', 'GO:0008037', ('58', '74'))	('miR-26b-5p', 'Var', (10, 20))	('overexpression', 'PosReg', (21, 35))	('miR-26b-5p', 'Chemical', '-', (10, 20))	('decreased T cell', 'Phenotype', 'HP:0005403', (46, 62))	('decreased', 'NegReg', (46, 55))
33933	32825219	Furthermore, an inverse expression of miR-26b-5p and miR-21-3p with TAP1 was found in primary melanoma lesions, which was linked with the frequency of CD8+ T cell infiltration.	('TAP1', 'Gene', (68, 72))	('melanoma lesions', 'Disease', 'MESH:D008545', (94, 110))	('miR-26b-5p', 'Chemical', '-', (38, 48))	('melanoma lesions', 'Disease', (94, 110))	('miR-21-3p', 'Gene', '406995', (53, 62))	('CD8', 'Gene', (151, 154))	('miR-26b-5p', 'Var', (38, 48))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('CD8', 'Gene', '925', (151, 154))	('miR-21-3p', 'Gene', (53, 62))
33934	32825219	Thus, miR-26-5p and miR-21-3p are involved in the HLA class I-mediated immune escape and might be used as biomarkers or therapeutic targets for HLA class Ilow melanoma cells.	('melanoma', 'Disease', (159, 167))	('involved', 'Reg', (34, 42))	('miR-21-3p', 'Gene', '406995', (20, 29))	('miR-26-5p', 'Chemical', '-', (6, 15))	('miR-21-3p', 'Gene', (20, 29))	('miR-26-5p', 'Var', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
33953	32825219	However, melanoma cells escape T cell recognition by different mechanisms, like inefficient antigen processing and presentation, modulation of immune stimulatory or immune suppressive molecules and alterations in the cellular composition of the TME.	('antigen', 'Protein', (92, 99))	('cell recognition', 'biological_process', 'GO:0008037', ('33', '49'))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('inefficient', 'NegReg', (80, 91))	('alterations', 'Reg', (198, 209))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('92', '127'))	('modulation', 'Var', (129, 139))
33983	32825219	Immunodetection was performed using the following specific primary antibodies (Ab): anti-TAP1 (ab13516, Abcam, Cambridge, UK), anti-TAP2, kindly provided by Soldano Ferrone, anti-AGO2 (ab156870, Abcam) and anti-MBP Abs (ab9084, Abcam).	('Soldano Ferrone', 'Chemical', '-', (157, 172))	('AGO2', 'Gene', (179, 183))	('ab156870', 'Var', (185, 193))	('MBP', 'Gene', '4155', (211, 214))	('AGO2', 'Gene', '27161', (179, 183))	('TAP2', 'Gene', (132, 136))	('TAP2', 'Gene', '6891', (132, 136))	('MBP', 'Gene', (211, 214))
33988	32825219	For the deletion of the binding side of miR-26b-5p or miR-21-3p in the TAP1 3' UTR, specific primers were designed according to the NEBaseChanger software (, NEB) (Supplementary Table S1).	('miR-26b-5p', 'Var', (40, 50))	('miR-21-3p', 'Gene', '406995', (54, 63))	('miR-21-3p', 'Gene', (54, 63))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('miR-26b-5p', 'Chemical', '-', (40, 50))	('deletion', 'Var', (8, 16))
34014	32825219	These data demonstrated a correlation of high levels of TAP1 and HLA class I loci with an increased overall survival (OS) of tumor patients including melanoma, with the exception of cancers in immune privileged organs (brain, eye, thymus).	('patients', 'Species', '9606', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('increased', 'PosReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('high', 'Var', (41, 45))	('tumor', 'Disease', (125, 130))	('TAP1', 'Gene', (56, 60))	('HLA class I', 'Protein', (65, 76))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('melanoma', 'Disease', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('overall survival', 'MPA', (100, 116))
34027	32825219	In order to select the candidate miRs, several criteria were applied, such as (i) that a specific binding site for the respective candidate miRs within the TAP1 3'-UTR should be predicted by at least four out of the six selected bioinformatic tools, (ii) the tpm counts observed in the TAP1 3' UTR miTRAP eluate should be higher than 1000, while (iii) the tpm counts observed in the MS2 control miTRAP eluate should be less than 100 and (iv) the enrichment ratio should be higher than 50.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('binding', 'molecular_function', 'GO:0005488', ('98', '105'))	('MS2', 'Species', '2710868', (383, 386))	('TAP1', 'Var', (286, 290))
34030	32825219	These include miR-21-3p, miR-22-3p, miR-140-3p, miR-590-3p, miR-26b-5p, miR-532-5p and miR-26a-5p (Table 2).	('miR-140', 'Gene', (36, 43))	('miR-26b-5p', 'Var', (60, 70))	('miR-22-3p', 'Gene', '407008', (25, 34))	('5p', 'Chemical', '-', (80, 82))	('miR-26a-5p', 'Chemical', '-', (87, 97))	('miR-532', 'Gene', '693124', (72, 79))	('miR-140', 'Gene', '406932', (36, 43))	('miR-26b-5p', 'Chemical', '-', (60, 70))	('miR-532', 'Gene', (72, 79))	('5p', 'Chemical', '-', (95, 97))	('miR-590-3p', 'Chemical', '-', (48, 58))	('miR-21-3p', 'Gene', '406995', (14, 23))	('5p', 'Chemical', '-', (68, 70))	('miR-590-3p', 'Var', (48, 58))	('miR-21-3p', 'Gene', (14, 23))	('miR-22-3p', 'Gene', (25, 34))	('miR-26a-5p', 'Var', (87, 97))
34032	32825219	Moreover, miR-26a-5p, miR-532-5p and miR-590-3p had lower binding energy and/or enrichment ratios than miR-26b-5p or miR-21-3p, while the miTRAP ratio of miR-22-3p was lower than the miTRAP ratios of miR-26b-5p or miR-21-3p.	('enrichment ratios', 'MPA', (80, 97))	('miR-590-3p', 'Chemical', '-', (37, 47))	('5p', 'Chemical', '-', (111, 113))	('miR-21-3p', 'Gene', '406995', (214, 223))	('5p', 'Chemical', '-', (30, 32))	('lower', 'NegReg', (52, 57))	('miR-26b-5p', 'Chemical', '-', (103, 113))	('miR-22-3p', 'Gene', (154, 163))	('miR-21-3p', 'Gene', '406995', (117, 126))	('miR-26a-5p', 'Var', (10, 20))	('binding', 'Interaction', (58, 65))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('miR-532', 'Gene', '693124', (22, 29))	('miR-532', 'Gene', (22, 29))	('miR-26a-5p', 'Chemical', '-', (10, 20))	('5p', 'Chemical', '-', (208, 210))	('miR-590-3p', 'Var', (37, 47))	('miR-21-3p', 'Gene', (214, 223))	('miR-21-3p', 'Gene', (117, 126))	('5p', 'Chemical', '-', (18, 20))	('miR-26b-5p', 'Chemical', '-', (200, 210))	('miR-22-3p', 'Gene', '407008', (154, 163))
34042	32825219	As expected, the deletion of the binding sites of the candidate miR within the TAP1 3' UTR altered neither the luc activity in the presence of the miR nor that of the NC (Figure 3a,b).	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))	('altered', 'Reg', (91, 98))	('deletion', 'Var', (17, 25))	('luc activity', 'MPA', (111, 123))
34046	32825219	Overexpression of miR-26b-5p in BUF1379 and FM3 cells decreased the TAP1 mRNA and protein levels with approximately 30% when compared to controls (Figure 4c,g,h).	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('miR-26b-5p', 'Chemical', '-', (18, 28))	('FM3', 'Gene', '10316', (44, 47))	('decreased', 'NegReg', (54, 63))	('miR-26b-5p', 'Var', (18, 28))	('FM3', 'Gene', (44, 47))
34048	32825219	As expected, the expression of other APM components, such as TAP2, was not affected by miR-26b-5p and miR-21-3p overexpression (Figure 4e-g).	('expression', 'MPA', (17, 27))	('miR-21-3p', 'Gene', '406995', (102, 111))	('TAP2', 'Gene', (61, 65))	('TAP2', 'Gene', '6891', (61, 65))	('miR-21-3p', 'Gene', (102, 111))	('miR-26b-5p', 'Var', (87, 97))	('miR-26b-5p', 'Chemical', '-', (87, 97))
34051	32825219	As shown in Figure 5e, HLA-A2 surface expression was also significantly downregulated upon miR-26b-5p overexpression, whereas no effects were visible upon miR-21-3p overexpression.	('HLA-A', 'Gene', (23, 28))	('miR-26b-5p overexpression', 'Var', (91, 116))	('miR-21-3p', 'Gene', '406995', (155, 164))	('downregulated', 'NegReg', (72, 85))	('overexpression', 'Var', (102, 116))	('surface expression', 'MPA', (30, 48))	('HLA-A', 'Gene', '3105', (23, 28))	('miR-26b-5p', 'Chemical', '-', (91, 101))	('miR-21-3p', 'Gene', (155, 164))
34056	32825219	MiR expression levels were significantly reduced (between 30-50%) both in the BUF1379 and FM3 transfectants when compared to cells transfected with NC inhibitors or parental cells (Figure 6a,b).	('MiR', 'Gene', (0, 3))	('reduced', 'NegReg', (41, 48))	('FM3', 'Gene', '10316', (90, 93))	('MiR', 'Gene', '220972', (0, 3))	('FM3', 'Gene', (90, 93))	('BUF1379', 'Var', (78, 85))	('transfectants', 'Var', (94, 107))
34059	32825219	Inhibition of miR-26b-5p or miR-21-3p in BUF1379 and FM3 cells increased HLA-A2 surface antigens (Figure 6i,j), while HLA-BC surface expression remained unchanged (Figure 6k,l).	('HLA-A', 'Gene', (73, 78))	('increased', 'PosReg', (63, 72))	('HLA-B', 'Gene', (118, 123))	('miR-26b-5p', 'Var', (14, 24))	('FM3', 'Gene', '10316', (53, 56))	('miR-21-3p', 'Gene', '406995', (28, 37))	('HLA-B', 'Gene', '3106', (118, 123))	('HLA-A', 'Gene', '3105', (73, 78))	('miR-26b-5p', 'Chemical', '-', (14, 24))	('miR-21-3p', 'Gene', (28, 37))	('FM3', 'Gene', (53, 56))
34061	32825219	Lower levels of CD107a positive T cells were found in response to BUF1379 cells overexpressing miR-26b-5p when compared to control transfectants (Figure 7).	('miR-26b-5p', 'Var', (95, 105))	('miR-26b-5p', 'Chemical', '-', (95, 105))	('CD107a', 'Gene', '3916', (16, 22))	('CD107a', 'Gene', (16, 22))
34065	32825219	As shown in Figure 8c,d, the TAP1 expression scores were directly correlated with the frequency of CD8+ immune cells, with TAP1low and TAP1high melanoma lesions exhibiting the low and high frequency of CD8+ T cells respectively.	('TAP1low', 'Var', (123, 130))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('CD8', 'Gene', (202, 205))	('CD8', 'Gene', '925', (202, 205))	('TAP1high', 'Var', (135, 143))	('melanoma lesions', 'Disease', 'MESH:D008545', (144, 160))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('TAP1', 'Gene', (29, 33))	('melanoma lesions', 'Disease', (144, 160))
34066	32825219	Furthermore, a direct link between TAP1low and CD8low infiltration with high miR-26b-5p and miR-21-3p expression and vice versa exists (Figure 8c,d).	('high', 'PosReg', (72, 76))	('miR-21-3p', 'Gene', (92, 101))	('CD8', 'Gene', (47, 50))	('miR-21-3p', 'Gene', '406995', (92, 101))	('CD8', 'Gene', '925', (47, 50))	('TAP1low', 'Gene', (35, 42))	('miR-26b-5p', 'Var', (77, 87))	('miR-26b-5p', 'Chemical', '-', (77, 87))
34078	32825219	Moreover, the overexpression of miR-21-3p or miR-26b-5p resulted in a reduced TAP1 protein expression in melanoma cells.	('expression', 'MPA', (91, 101))	('reduced', 'NegReg', (70, 77))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('miR-21-3p', 'Gene', (32, 41))	('miR-21-3p', 'Gene', '406995', (32, 41))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('miR-26b-5p', 'Chemical', '-', (45, 55))	('miR-26b-5p', 'Var', (45, 55))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('overexpression', 'PosReg', (14, 28))	('TAP1', 'Gene', (78, 82))
34080	32825219	Particularly, upon miR-26b-5p overexpression, HLA-A2 surface expression was specifically downregulated, resulting in a decreased recognition of the transfected melanoma cells by HLA-A2-restricted CD8+ T cells.	('decreased', 'NegReg', (119, 128))	('HLA-A', 'Gene', '3105', (178, 183))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('CD8', 'Gene', (196, 199))	('downregulated', 'NegReg', (89, 102))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('CD8', 'Gene', '925', (196, 199))	('HLA-A', 'Gene', (178, 183))	('HLA-A', 'Gene', '3105', (46, 51))	('recognition', 'MPA', (129, 140))	('overexpression', 'Var', (30, 44))	('miR-26b-5p overexpression', 'Var', (19, 44))	('HLA-A', 'Gene', (46, 51))	('miR-26b-5p', 'Chemical', '-', (19, 29))
34092	32825219	Ectopic expression of miR-26b-5p can inhibit proliferation, induce apoptosis, suppress angiogenesis and/or decrease tumorigenicity and is therefore involved in controlling carcinogenesis and tumor progression in hepatocellular and bladder cancer.	('induce', 'PosReg', (60, 66))	('hepatocellular', 'Disease', (212, 226))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('bladder cancer', 'Disease', 'MESH:D001749', (231, 245))	('bladder cancer', 'Disease', (231, 245))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('decrease', 'NegReg', (107, 115))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('miR-26b-5p', 'Chemical', '-', (22, 32))	('angiogenesis', 'biological_process', 'GO:0001525', ('87', '99'))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('bladder cancer', 'Phenotype', 'HP:0009725', (231, 245))	('angiogenesis', 'CPA', (87, 99))	('apoptosis', 'CPA', (67, 76))	('proliferation', 'CPA', (45, 58))	('inhibit', 'NegReg', (37, 44))	('suppress', 'NegReg', (78, 86))	('tumor', 'Disease', (191, 196))	('involved', 'Reg', (148, 156))	('miR-26b-5p', 'Var', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (116, 121))
34093	32825219	So far, little information exists on the function of miR-26b-5p in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('miR-26b-5p', 'Var', (53, 63))	('miR-26b-5p', 'Chemical', '-', (53, 63))
34095	32825219	Recently, miR-26b-5p has been shown to target the MAPK and AKT/mTOR signaling pathways by binding to the 3' UTR of TRAF5 or TRIM44, respectively, which are involved in the malignant progression of melanoma cells.	('TRIM44', 'Gene', '54765', (124, 130))	('TRIM44', 'Gene', (124, 130))	('miR-26b-5p', 'Chemical', '-', (10, 20))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('binding', 'Interaction', (90, 97))	('miR-26b-5p', 'Var', (10, 20))	('TRAF5', 'Gene', (115, 120))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('mTOR', 'Gene', (63, 67))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('AKT', 'Gene', (59, 62))	('involved', 'Reg', (156, 164))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('mTOR', 'Gene', '2475', (63, 67))	('TRAF5', 'Gene', '7188', (115, 120))	('MAPK', 'Pathway', (50, 54))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('AKT', 'Gene', '207', (59, 62))
34096	32825219	However, no direct effects of miR-26b-5p on the expression of immune modulatory molecules have been described neither in melanoma nor in other tumor types.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('miR-26b-5p', 'Var', (30, 40))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('miR-26b-5p', 'Chemical', '-', (30, 40))
34098	32825219	By directly targeting the 3' UTR of TAP1, miR-26b-5p decreased TAP1 mRNA and protein expression and negatively interferes with the immunogenicity of tumor cells demonstrating that miR-26b-5p could have, instead of the published tumor suppressive activity, also a tumor-promoting activity by including an immune escape phenotype in melanoma cells.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('melanoma', 'Disease', 'MESH:D008545', (331, 339))	('miR-26b-5p', 'Var', (42, 52))	('TAP1', 'Gene', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('miR-26b-5p', 'Chemical', '-', (180, 190))	('tumor', 'Disease', (263, 268))	('TAP1', 'Gene', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (331, 339))	('melanoma', 'Disease', (331, 339))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('miR-26b-5p', 'Var', (180, 190))	('decreased', 'NegReg', (53, 62))	('miR-26b-5p', 'Chemical', '-', (42, 52))	('interferes', 'NegReg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('immune escape', 'CPA', (304, 317))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (228, 233))
34100	32825219	These data suggest a dual role for miR-26b-5p in tumors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('miR-26b-5p', 'Var', (35, 45))	('miR-26b-5p', 'Chemical', '-', (35, 45))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))
34110	32820147	Moreover, knockdown of TTN partially abrogated lncRNA-TTN-AS1 induced SKCM tumorigenesis.	('SKCM tumor', 'Disease', 'MESH:D009369', (70, 80))	('lncRNA-TTN-AS1', 'Gene', '100506866', (47, 61))	('lncRNA-TTN-AS1', 'Gene', (47, 61))	('SKCM tumor', 'Disease', (70, 80))	('abrogated', 'NegReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('knockdown', 'Var', (10, 19))
34111	32820147	Mechanistically, hypomethylation of transcription initiation site was responsible for lncRNA-TTN-AS1 high expression levels.	('lncRNA-TTN-AS1', 'Gene', (86, 100))	('hypomethylation', 'Var', (17, 32))	('responsible', 'Reg', (70, 81))	('lncRNA-TTN-AS1', 'Gene', '100506866', (86, 100))	('transcription', 'biological_process', 'GO:0006351', ('36', '49'))
34136	32820147	As a result, TTN expression was markedly reduced at mRNA and protein levels after knockdown of lncRNA-TTN-AS1 (Figs.	('reduced', 'NegReg', (41, 48))	('TTN expression', 'MPA', (13, 27))	('lncRNA-TTN-AS1', 'Gene', '100506866', (95, 109))	('lncRNA-TTN-AS1', 'Gene', (95, 109))	('knockdown', 'Var', (82, 91))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
34147	32820147	Similarly, knockdown of TTN and lncRNA-TTN-AS1 led to apoptosis of B16F10 cells (Fig.	('apoptosis', 'CPA', (54, 63))	('lncRNA-TTN-AS1', 'Gene', '100506866', (32, 46))	('lncRNA-TTN-AS1', 'Gene', (32, 46))	('TTN', 'Gene', (24, 27))	('B16F10', 'CellLine', 'CVCL:0159', (67, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('knockdown', 'Var', (11, 20))
34156	32820147	We found that knockdown of TTN and lncRNA-TTN-AS1 significantly suppressed SKCM tumor growth (Fig.	('SKCM tumor', 'Disease', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TTN', 'Gene', (27, 30))	('suppressed', 'NegReg', (64, 74))	('SKCM tumor', 'Disease', 'MESH:D009369', (75, 85))	('knockdown', 'Var', (14, 23))	('lncRNA-TTN-AS1', 'Gene', '100506866', (35, 49))	('lncRNA-TTN-AS1', 'Gene', (35, 49))
34158	32820147	The results showed that knockdown of TTN and lncRNA-TTN-AS1 decreased the expression of Ki-67 (Fig.	('lncRNA-TTN-AS1', 'Gene', '100506866', (45, 59))	('expression', 'MPA', (74, 84))	('decreased', 'NegReg', (60, 69))	('Ki-67', 'Gene', '17345', (88, 93))	('Ki-67', 'Gene', (88, 93))	('lncRNA-TTN-AS1', 'Gene', (45, 59))	('knockdown', 'Var', (24, 33))
34160	32820147	Moreover, knockdown of lncRNA-TTN-AS1 decreased the expression of TTN protein (Fig.	('decreased', 'NegReg', (38, 47))	('lncRNA-TTN-AS1', 'Gene', '100506866', (23, 37))	('lncRNA-TTN-AS1', 'Gene', (23, 37))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('TTN protein', 'Protein', (66, 77))	('expression', 'MPA', (52, 62))	('knockdown', 'Var', (10, 19))
34172	32820147	Our results showed that lncRNA-TTN-AS1 induced SKCM cell proliferation and metastasis in vitro, while knockdown of TTN eliminated the discrepant cell properties triggered by lncRNA-TTN-AS1 overexpression, indicating that TTN was required for lncRNA-TTN-AS1-mediated SKCM cell maintenance and expansion (Fig.	('lncRNA-TTN-AS1', 'Gene', '100506866', (242, 256))	('lncRNA-TTN-AS1', 'Gene', (242, 256))	('SKCM cell proliferation', 'CPA', (47, 70))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('lncRNA-TTN-AS1', 'Gene', '100506866', (174, 188))	('knockdown', 'Var', (102, 111))	('lncRNA-TTN-AS1', 'Gene', (174, 188))	('metastasis', 'CPA', (75, 85))	('lncRNA-TTN-AS1', 'Gene', '100506866', (24, 38))	('lncRNA-TTN-AS1', 'Gene', (24, 38))
34173	32820147	Previous studies have showed that malignant proliferation of tumor cells is often accompanied with hypomethylation of both coding and noncoding regions genome-wide.	('hypomethylation', 'Var', (99, 114))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('malignant proliferation', 'CPA', (34, 57))	('accompanied', 'Reg', (82, 93))	('tumor', 'Disease', (61, 66))
34177	32820147	6a upper panel), and was lower in lncRNA-TTN-AS1 overexpressed cell lines than in the control cells (Fig.	('overexpressed', 'Var', (49, 62))	('lncRNA-TTN-AS1', 'Gene', '100506866', (34, 48))	('lncRNA-TTN-AS1', 'Gene', (34, 48))	('lower', 'NegReg', (25, 30))
34178	32820147	6a bottom panel), indicating that hypomethylation of transcription initiation site was responsible for lncRNA-TTN-AS1 overexpression.	('overexpression', 'PosReg', (118, 132))	('transcription', 'biological_process', 'GO:0006351', ('53', '66'))	('lncRNA-TTN-AS1', 'Gene', '100506866', (103, 117))	('lncRNA-TTN-AS1', 'Gene', (103, 117))	('hypomethylation', 'Var', (34, 49))	('responsible', 'Reg', (87, 98))
34186	32820147	Opposite results were obtained after knockdown of lncRNA-TTN-AS1 (Fig.	('knockdown', 'Var', (37, 46))	('lncRNA-TTN-AS1', 'Gene', '100506866', (50, 64))	('lncRNA-TTN-AS1', 'Gene', (50, 64))
34196	32820147	For examples, H3K27 acetylation-mediated activation results in high expression of lncRNA colon cancer-associated transcript-1 (CCAT1) in ESCC, whereas high methylation of its gene promoter leads to decreased expression of p53-induced lncRNA TP53 target 1 (TP53TG1) in human cancer.	('expression', 'MPA', (68, 78))	('expression', 'MPA', (208, 218))	('H3K27', 'Protein', (14, 19))	('lncRNA', 'Gene', (82, 88))	('TP53 target 1', 'Gene', '11257', (241, 254))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('cancer', 'Disease', (95, 101))	('ESCC', 'Disease', (137, 141))	('high methylation', 'Var', (151, 167))	('CCAT1', 'Gene', '100507056', (127, 132))	('activation', 'PosReg', (41, 51))	('TP53TG1', 'Gene', (256, 263))	('p53', 'Gene', '7157', (222, 225))	('decreased', 'NegReg', (198, 207))	('TP53TG1', 'Gene', '11257', (256, 263))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('CCAT1', 'Gene', (127, 132))	('human', 'Species', '9606', (268, 273))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('p53', 'Gene', (222, 225))	('TP53 target 1', 'Gene', (241, 254))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (274, 280))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
34197	32820147	In this study, we found that hypomethylation of transcription initiation site was responsible for lncRNA-TTN-AS1 overexpression.	('lncRNA-TTN-AS1', 'Gene', '100506866', (98, 112))	('lncRNA-TTN-AS1', 'Gene', (98, 112))	('transcription', 'biological_process', 'GO:0006351', ('48', '61'))	('overexpression', 'PosReg', (113, 127))	('responsible', 'Reg', (82, 93))	('hypomethylation', 'Var', (29, 44))
34200	32820147	It was reported that the transition from N2BA to N2B was coupled to specific changes in the expression pattern of TTN.	('N2BA', 'Var', (41, 45))	('changes', 'Reg', (77, 84))	('TTN', 'Gene', (114, 117))	('N2BA', 'Chemical', '-', (41, 45))	('expression pattern', 'MPA', (92, 110))
34227	32820147	The biotin-labeled lncRNA (both wild type and mutant type) and the antisense RNA were in vitro transcribed with a Biotin RNA Labeling Mix (Roche, CA, USA) and the T7 RNA polymerase (Roche), treated with RNase-free DNase I (Roche) and purified with an RNeasy Mini Kit (Qiagen).	('DNase I', 'Gene', (214, 221))	('Kit', 'Gene', '16590', (263, 266))	('DNase I', 'molecular_function', 'GO:0004530', ('214', '221'))	('CA', 'Gene', '12310', (146, 148))	('biotin', 'Chemical', 'MESH:D001710', (4, 10))	('Kit', 'Gene', (263, 266))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('mutant', 'Var', (46, 52))	('RNA', 'cellular_component', 'GO:0005562', ('166', '169'))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('antisense RNA', 'molecular_function', 'GO:0009388', ('67', '80'))	('DNase I', 'Gene', '13419', (214, 221))
34252	32820147	Firefly (Fluc) and Renilla (Rluc) luciferase activities were determined after 48 h. LncRNA-TTN-AS1 was knocked down or overexpressed in B16F10 cells.	('TTN-AS1', 'Gene', '100506866', (91, 98))	('knocked down', 'Var', (103, 115))	('TTN-AS1', 'Gene', (91, 98))	('B16F10', 'CellLine', 'CVCL:0159', (136, 142))
34256	32820147	Antibodies against Cyclin D1 (# WL01435a), CDK2 (# WL01543), CDK4 (# WL01711), Bax (# WL01637), pro-caspase 3 (# WL02117), cleaved-caspase 3 (# WL02117), pro-caspase 9 (# WL03421), and cleaved-caspase 9 (# WL03421) were purchased from Wanleibio (Shenyang, Liaoning, China).	('Bax', 'Gene', '12028', (79, 82))	('CDK4', 'Gene', (61, 65))	('Cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))	('CDK2', 'Gene', (43, 47))	('# WL01435a', 'Var', (30, 40))	('caspase 9', 'Gene', (193, 202))	('# WL01637', 'Var', (84, 93))	('# WL03421', 'Var', (204, 213))	('CDK4', 'Gene', '12567', (61, 65))	('# WL01711', 'Var', (67, 76))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('Cyclin D1', 'Gene', '12443', (19, 28))	('Bax', 'Gene', (79, 82))	('# WL02117', 'Var', (111, 120))	('# WL02117', 'Var', (142, 151))	('caspase 9', 'Gene', (158, 167))	('# WL01543', 'Var', (49, 58))	('caspase 9', 'Gene', '12371', (193, 202))	('CDK2', 'Gene', '12566', (43, 47))	('Cyclin D1', 'Gene', (19, 28))	('CDK', 'molecular_function', 'GO:0004693', ('61', '64'))	('# WL03421', 'Var', (169, 178))	('caspase 9', 'Gene', '12371', (158, 167))
34257	32820147	Antibody against Titin/CMD1G (# bs-9861R) was purchased from Bioss (Beijing, China).	('# bs-9861R', 'Var', (30, 40))	('Titin', 'Gene', '22138', (17, 22))	('Titin', 'Gene', (17, 22))
34262	33668805	Here, we used in silico analyses of multi-Omics data to map out the role of epigenetic and genetic alterations of STAT3/CDK2/4/6 in tumor immune infiltrations, immunotherapy response, and prognosis of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('STAT3', 'Gene', '6774', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('patients', 'Species', '9606', (208, 216))	('cancer', 'Disease', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('STAT3', 'Gene', (114, 119))	('CDK', 'molecular_function', 'GO:0004693', ('120', '123'))	('genetic alterations', 'Var', (91, 110))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CDK2/4/6', 'Gene', '1017;1019;1021', (120, 128))	('CDK2/4/6', 'Gene', (120, 128))
34269	33668805	Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts.	('genetic alterations', 'Var', (10, 29))	('CDK', 'molecular_function', 'GO:0004693', ('39', '42'))	('STAT3', 'Gene', '6774', (33, 38))	('associated', 'Reg', (111, 121))	('CDK2/4/6', 'Gene', '1017;1019;1021', (39, 47))	('STAT3', 'Gene', (33, 38))	('CDK2/4/6', 'Gene', (39, 47))	('co-occurred', 'Reg', (48, 59))
34285	33668805	CDKs are multi-functional proteins whose role includes metabolism, epigenetic regulations, spermatogenesis cell cycle transition, and stem cell self-renewal.	('cell cycle transition', 'biological_process', 'GO:0044771', ('107', '128'))	('epigenetic regulations', 'Var', (67, 89))	('metabolism', 'biological_process', 'GO:0008152', ('55', '65'))	('spermatogenesis', 'biological_process', 'GO:0007283', ('91', '106'))	('CDK', 'Gene', (0, 3))	('spermatogenesis cell cycle transition', 'CPA', (91, 128))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (0, 3))	('stem cell self-renewal', 'CPA', (134, 156))	('cell cycle transition', 'biological_process', 'GO:0044770', ('107', '128'))
34289	33668805	However, epigenetic factors and genetic factors including the loss of cyclin D-CDK4/6 negative regulators, overexpression of cyclin D, amplification and/or mutation of CDK4/6, compromises the regulatory integrity of the CDKs leading to hyper complexation of the catalytic and regulatory unit and consequently un-control cell cycle progression, cancer initiation and developments.	('cancer', 'Disease', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('CDK', 'Gene', (168, 171))	('overexpression', 'PosReg', (107, 121))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (79, 82))	('compromises', 'NegReg', (176, 187))	('CDK', 'molecular_function', 'GO:0004693', ('168', '171'))	('cell cycle', 'biological_process', 'GO:0007049', ('320', '330'))	('cyclin', 'Gene', (70, 76))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (220, 223))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('CDK', 'Gene', (79, 82))	('cyclin', 'Gene', (125, 131))	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('hyper complexation', 'MPA', (236, 254))	('cell cycle progression', 'CPA', (320, 342))	('CDK', 'Gene', (220, 223))	('cyclin', 'molecular_function', 'GO:0016538', ('70', '76'))	('amplification', 'Var', (135, 148))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (168, 171))	('un-control', 'NegReg', (309, 319))	('cyclin', 'molecular_function', 'GO:0016538', ('125', '131'))	('developments', 'CPA', (366, 378))	('regulatory integrity', 'MPA', (192, 212))	('mutation', 'Var', (156, 164))
34290	33668805	Aberrant CDKs expressions, therefore, constitute an important event in cancer development, progression, and aggressiveness.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (71, 77))	('CDK', 'Gene', (9, 12))	('aggressiveness', 'Disease', 'MESH:D001523', (108, 122))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aggressiveness', 'Disease', (108, 122))	('aggressiveness', 'Phenotype', 'HP:0000718', (108, 122))
34296	33668805	Genetic alteration of STAT3/CDK2/4/6 co-occurred with other gene alteration and are associated with poorer prognosis of the cohorts.	('CDK2/4/6', 'Gene', (28, 36))	('CDK2/4/6', 'Gene', '1017;1019;1021', (28, 36))	('co-occurred', 'Reg', (37, 48))	('Genetic alteration', 'Var', (0, 18))	('CDK', 'molecular_function', 'GO:0004693', ('28', '31'))	('STAT3', 'Gene', '6774', (22, 27))	('STAT3', 'Gene', (22, 27))	('associated', 'Reg', (84, 94))
34309	33668805	We obtained the transcriptomic and clinical data with the response to anti-PD1 ICB or anti-CTL4A treatments in melanoma patients and anti-PD1 ICB treatment in brain cancer patients.	('anti-PD1', 'Var', (133, 141))	('brain cancer', 'Disease', (159, 171))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('brain cancer', 'Disease', 'MESH:D001932', (159, 171))	('brain cancer', 'Phenotype', 'HP:0030692', (159, 171))	('patients', 'Species', '9606', (120, 128))	('anti-PD1', 'Gene', (70, 78))	('patients', 'Species', '9606', (172, 180))
34342	33668805	The results showed that the arm-level gain and high amplification of CDK2 in GBM was negatively (p < 0.05) associated with B-cell, macrophages, CD4+ T cell dendritic cell infiltration (Supplementary Figure S5), while CDK4 SCNAs showed no or weak relationship with infiltration of the above six immune cell types.	('CDK', 'molecular_function', 'GO:0004693', ('217', '220'))	('gain', 'PosReg', (38, 42))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('CD4', 'Gene', (144, 147))	('B-cell', 'CPA', (123, 129))	('associated', 'Reg', (107, 117))	('CD4', 'Gene', '920', (144, 147))	('CDK2', 'Gene', (69, 73))	('macrophages', 'CPA', (131, 142))	('high amplification', 'Var', (47, 65))	('CDK2', 'Gene', '1017', (69, 73))	('CDK4', 'Gene', '1019', (217, 221))	('CDK4', 'Gene', (217, 221))	('negatively', 'NegReg', (85, 95))
34343	33668805	Conversely, Arm level gain of CDK6 shows a positive (p < 0.05) correlation with increase CD4+ T cell, CD4+ T cell, macrophages, and dendritic cell infiltration, while arm level deletion shows a strong negative correlation (p < 0.001) with B-cell infiltrations in GBM patient.	('CDK', 'molecular_function', 'GO:0004693', ('30', '33'))	('CD4', 'Gene', '920', (89, 92))	('patient', 'Species', '9606', (267, 274))	('increase', 'PosReg', (80, 88))	('deletion', 'Var', (177, 185))	('CDK6', 'Gene', (30, 34))	('CDK6', 'Gene', '1021', (30, 34))	('CD4', 'Gene', (89, 92))	('CD4', 'Gene', (102, 105))	('gain', 'PosReg', (22, 26))	('CD4', 'Gene', '920', (102, 105))
34353	33668805	Among, 10953 patients/10967 samples of all type of human cancers publicly available in the online cancer genomic database cBioPortal, genetic alterations of CDK2/4/6 and STAT3 occurs in 825 (8%) patients, comprising 127 (1.2%) CDK2, 307 (2.8%) CDK4, 266 (2.4%) CDK6, and 220 (2%) STAT3 and (Figure 7A).	('cancer', 'Disease', (57, 63))	('patients', 'Species', '9606', (13, 21))	('CDK', 'molecular_function', 'GO:0004693', ('261', '264'))	('CDK2', 'Gene', (227, 231))	('STAT3', 'Gene', '6774', (280, 285))	('human', 'Species', '9606', (51, 56))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CDK4', 'Gene', '1019', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CDK', 'molecular_function', 'GO:0004693', ('227', '230'))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('genetic alterations', 'Var', (134, 153))	('patients', 'Species', '9606', (195, 203))	('CDK2/4/6', 'Gene', '1017;1019;1021', (157, 165))	('CDK6', 'Gene', '1021', (261, 265))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('STAT3', 'Gene', (170, 175))	('CDK2', 'Gene', '1017', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('CDK', 'molecular_function', 'GO:0004693', ('157', '160'))	('CDK6', 'Gene', (261, 265))	('CDK2', 'Gene', (157, 161))	('STAT3', 'Gene', '6774', (170, 175))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('CDK', 'molecular_function', 'GO:0004693', ('244', '247'))	('CDK2/4/6', 'Gene', (157, 165))	('STAT3', 'Gene', (280, 285))	('CDK4', 'Gene', (244, 248))	('CDK2', 'Gene', '1017', (227, 231))
34354	33668805	The CDK2 alterations (127; 1.2%) occur in 22 cancer types, mostly in endometrial carcinoma (4.1%), esophagogastric carcinoma (3.11%), and ovarian epithelial tumor (2.91%).	('esophagogastric carcinoma', 'Phenotype', 'HP:0011459', (99, 124))	('CDK2', 'Gene', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (69, 90))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ovarian epithelial tumor', 'Disease', 'MESH:D010051', (138, 162))	('carcinoma', 'Disease', 'MESH:D009369', (115, 124))	('occur', 'Reg', (33, 38))	('epithelial tumor', 'Phenotype', 'HP:0031492', (146, 162))	('carcinoma', 'Disease', (81, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (69, 90))	('ovarian epithelial tumor', 'Phenotype', 'HP:0025318', (138, 162))	('carcinoma', 'Disease', 'MESH:D009369', (81, 90))	('alterations', 'Var', (9, 20))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('endometrial carcinoma', 'Disease', (69, 90))	('carcinoma', 'Disease', (115, 124))	('CDK2', 'Gene', '1017', (4, 8))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))	('ovarian epithelial tumor', 'Disease', (138, 162))
34355	33668805	The most common alterations in CDK2 is amplification (85 cases, 66.92%), mutation (35 cases, 27.55%), while deep deletion (four cases, 3.14%), and multiple alterations (three cases, 2.36%) are the least occurred (Figure 7B).	('amplification', 'MPA', (39, 52))	('deep deletion', 'Var', (108, 121))	('CDK2', 'Gene', (31, 35))	('CDK2', 'Gene', '1017', (31, 35))	('mutation', 'Var', (73, 81))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))
34356	33668805	The CDK4 alterations occur in 23 cancer types, mostly in sarcoma (17.65%), glioblastoma (13.85), and adrenocortical carcinoma (6.59%).	('glioblastoma', 'Disease', (75, 87))	('sarcoma', 'Disease', (57, 64))	('adrenocortical carcinoma', 'Disease', (101, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('occur', 'Reg', (21, 26))	('sarcoma', 'Disease', 'MESH:D012509', (57, 64))	('alterations', 'Var', (9, 20))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (101, 125))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CDK4', 'Gene', '1019', (4, 8))	('CDK4', 'Gene', (4, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))
34357	33668805	Amplification (246 cases, 79.15%), and mutation (55 cases, 17.91%), are the most common CDK alterations while multiple alterations (eight cases, 2.60%) and deep deletion (one case, 0.32%) are least occurred.	('Amplification', 'Var', (0, 13))	('mutation', 'Var', (39, 47))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('CDK', 'Gene', (88, 91))	('CDK', 'Gene', '983;1017;1019;12567;1021;12571', (88, 91))
34358	33668805	CDK6 alterations occur in 26 cancer types, mostly in esophageal squamous cell carcinoma (95, 12.63%), esophagogastric adenocarcinoma (514 cases, 9.14%), and head and neck squamous cell carcinoma (523 cases, 4.78%).	('neck', 'cellular_component', 'GO:0044326', ('166', '170'))	('CDK', 'molecular_function', 'GO:0004693', ('0', '3'))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (53, 87))	('CDK6', 'Gene', '1021', (0, 4))	('alterations', 'Var', (5, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('adenocarcinoma', 'Disease', (118, 132))	('occur', 'Reg', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('CDK6', 'Gene', (0, 4))	('neck squamous cell carcinoma', 'Disease', (166, 194))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (166, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 132))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (157, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
34359	33668805	The most common alterations in CDK6 is amplification (199 cases, 74.81%), mutation (46 cases, 17.29%), deep deletion (13 cases, 4.88%) while multiple alterations (seven cases, 2.63%) and fusion (one case, 0.37%) occurred the least.	('amplification', 'MPA', (39, 52))	('mutation', 'Var', (74, 82))	('deep deletion', 'Var', (103, 116))	('CDK6', 'Gene', (31, 35))	('CDK6', 'Gene', '1021', (31, 35))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))
34360	33668805	The STAT3 alterations occur in 27 cancer types, comprising of mutation (136 cases, 61.81%), amplification (48 cases, 21.81%), deep deletion (25 cases, 11.36%), fusion (seven cases, 3.18%), and multiple alterations (four cases, 1.81%) occurred the least (Figure 7B).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('amplification', 'MPA', (92, 105))	('alterations', 'Var', (10, 21))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('mutation', 'Var', (62, 70))	('cancer', 'Disease', (34, 40))	('STAT3', 'Gene', '6774', (4, 9))	('deep deletion', 'Var', (126, 139))	('fusion', 'Var', (160, 166))	('STAT3', 'Gene', (4, 9))
34361	33668805	Specific mutation profiling indicated that out of the total CDK2 mutation in the database, 75.60% were missense, 19.51%, were truncating while 4.87% cases were fusion mutations (Figure 7C).	('fusion mutations', 'Var', (160, 176))	('CDK2', 'Gene', '1017', (60, 64))	('missense', 'Var', (103, 111))	('truncating', 'MPA', (126, 136))	('mutation', 'Var', (65, 73))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('CDK2', 'Gene', (60, 64))
34362	33668805	For CDK4 mutation, 52 (75.36%) were missense, 10 (14.49%) fusion, five (7.24%) truncating while two (2.89) cases were inframe mutations).	('mutation', 'Var', (9, 17))	('fusion', 'Var', (58, 64))	('CDK4', 'Gene', (4, 8))	('missense', 'Var', (36, 44))	('CDK4', 'Gene', '1019', (4, 8))	('truncating', 'MPA', (79, 89))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))
34363	33668805	Of the total CDK6 mutation in the database, 81.96%, 8.19%, and 9.83% were missense, truncating, and fusion, respectively (Figure 7C).	('truncating', 'MPA', (84, 94))	('CDK6', 'Gene', (13, 17))	('CDK6', 'Gene', '1021', (13, 17))	('fusion', 'Var', (100, 106))	('mutation', 'Var', (18, 26))	('missense', 'Var', (74, 82))	('CDK', 'molecular_function', 'GO:0004693', ('13', '16'))
34364	33668805	We analyzed the prognostic relevance of CDK2, CDK4, and CDK6 genetic alterations and found that CDK4 and CDK6 alterations are associated with low overall survival, disease-free survival, and progression-free survival of cancer cohorts (p < 0.05).	('CDK', 'molecular_function', 'GO:0004693', ('46', '49'))	('CDK4', 'Gene', '1019', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('CDK6', 'Gene', '1021', (56, 60))	('CDK2', 'Gene', '1017', (40, 44))	('CDK', 'molecular_function', 'GO:0004693', ('105', '108'))	('low', 'NegReg', (142, 145))	('CDK4', 'Gene', (96, 100))	('CDK2', 'Gene', (40, 44))	('CDK6', 'Gene', (56, 60))	('overall survival', 'CPA', (146, 162))	('disease-free survival', 'CPA', (164, 185))	('CDK', 'molecular_function', 'GO:0004693', ('40', '43'))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('cancer', 'Disease', (220, 226))	('CDK4', 'Gene', '1019', (96, 100))	('CDK6', 'Gene', '1021', (105, 109))	('alterations', 'Var', (110, 121))	('CDK4', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('CDK', 'molecular_function', 'GO:0004693', ('56', '59'))	('progression-free survival', 'CPA', (191, 216))	('CDK6', 'Gene', (105, 109))
34365	33668805	However, genetic alteration in CDK2 was not associated (p > 0.05) with low overall survival, disease-free survival, and progression-free survival of the cohorts (Figure 7D).	('low', 'NegReg', (71, 74))	('CDK2', 'Gene', (31, 35))	('overall survival', 'CPA', (75, 91))	('CDK2', 'Gene', '1017', (31, 35))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('genetic alteration', 'Var', (9, 27))
34366	33668805	We also analyzed the frequency of gene alteration co-occurrence with CDK2, CDK4, CDK6, and STAT3 genetic alteration (Figure 8A,B), and found co-occurrence of genetic alterations in a total of 19434 genes, enriched in CDK2/4/6 and STAT3 altered and non-altered cohorts.	('CDK2/4/6', 'Gene', '1017;1019;1021', (217, 225))	('CDK6', 'Gene', '1021', (81, 85))	('STAT3', 'Gene', '6774', (230, 235))	('CDK2', 'Gene', '1017', (217, 221))	('CDK', 'molecular_function', 'GO:0004693', ('217', '220'))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('CDK6', 'Gene', (81, 85))	('CDK2', 'Gene', (217, 221))	('CDK4', 'Gene', (75, 79))	('genetic alterations', 'Var', (158, 177))	('CDK2/4/6', 'Gene', (217, 225))	('19434', 'Gene', (192, 197))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CDK4', 'Gene', '1019', (75, 79))	('STAT3', 'Gene', (91, 96))	('CDK2', 'Gene', '1017', (69, 73))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('CDK2', 'Gene', (69, 73))	('STAT3', 'Gene', '6774', (91, 96))	('STAT3', 'Gene', (230, 235))
34367	33668805	However, only, 12676, 9265, 14130, and 17416 altered genes were significantly enriched in CDK2, CDK4, CDK6, and STAT3 altered cohorts respectively, while no gene alteration was significantly (all p > 0.05) enriched in CDK2/4/6/STAT3 unaltered cohorts (Figure 8A).	('CDK2', 'Gene', '1017', (218, 222))	('STAT3', 'Gene', '6774', (112, 117))	('9265', 'Var', (22, 26))	('CDK2', 'Gene', (218, 222))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('CDK2', 'Gene', '1017', (90, 94))	('CDK', 'molecular_function', 'GO:0004693', ('218', '221'))	('CDK6', 'Gene', '1021', (102, 106))	('CDK2', 'Gene', (90, 94))	('CDK2/4/6', 'Gene', (218, 226))	('CDK4', 'Gene', (96, 100))	('17416', 'Var', (39, 44))	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('STAT3', 'Gene', (227, 232))	('CDK6', 'Gene', (102, 106))	('CDK', 'molecular_function', 'GO:0004693', ('96', '99'))	('12676', 'Var', (15, 20))	('STAT3', 'Gene', '6774', (227, 232))	('CDK4', 'Gene', '1019', (96, 100))	('14130', 'Var', (28, 33))	('CDK2/4/6', 'Gene', '1017;1019;1021', (218, 226))	('STAT3', 'Gene', (112, 117))
34369	33668805	However, TP53, TTN, MUC16, and FLG were the most frequently mutated genes in all CDK2, CDK4, and CDK6 altered and non-altered cohorts, while TTN, TP53, MUC16, SYNE1, RYR2, CSMD3, HMCN1, LRP1B, ZFHXA, and FAT4 are the most frequently mutated genes in both STAT3 altered and non-altered cohorts (Figure 8C).	('STAT3', 'Gene', (255, 260))	('CDK6', 'Gene', '1021', (97, 101))	('HMCN1', 'Gene', (179, 184))	('SYNE1', 'Gene', (159, 164))	('MUC16', 'Gene', '94025', (152, 157))	('TP53', 'Gene', '7157', (9, 13))	('FLG', 'Gene', '2312', (31, 34))	('MUC16', 'Gene', (20, 25))	('CDK6', 'Gene', (97, 101))	('STAT3', 'Gene', '6774', (255, 260))	('altered', 'Var', (102, 109))	('TTN', 'Gene', '7273', (141, 144))	('RYR2', 'Gene', (166, 170))	('SYNE1', 'Gene', '23345', (159, 164))	('CSMD3', 'Gene', '114788', (172, 177))	('TTN', 'Gene', '7273', (15, 18))	('CDK', 'molecular_function', 'GO:0004693', ('97', '100'))	('FAT4', 'Gene', (204, 208))	('CDK2', 'Gene', '1017', (81, 85))	('TP53', 'Gene', (146, 150))	('TTN', 'Gene', (141, 144))	('RYR2', 'Gene', '6262', (166, 170))	('TTN', 'Gene', (15, 18))	('LRP1B', 'Gene', (186, 191))	('mutated', 'Reg', (60, 67))	('CSMD3', 'Gene', (172, 177))	('MUC16', 'Gene', (152, 157))	('CDK2', 'Gene', (81, 85))	('HMCN1', 'Gene', '83872', (179, 184))	('CDK', 'molecular_function', 'GO:0004693', ('87', '90'))	('TP53', 'Gene', (9, 13))	('CDK4', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (146, 150))	('MUC16', 'Gene', '94025', (20, 25))	('LRP1B', 'Gene', '53353', (186, 191))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('FAT4', 'Gene', '79633', (204, 208))	('FLG', 'Gene', (31, 34))	('RYR', 'cellular_component', 'GO:1990425', ('166', '169'))	('CDK4', 'Gene', '1019', (87, 91))
34370	33668805	Analysis of the promoter DNA methylation indicated that among 30 TCGA cancer type hypo-methylation of CDK2 are significantly associated with T cell dysfunctional phenotype high death risk and shorter survival durations in melanoma, kidney, and brain cancer only (Figure 9A).	('T cell dysfunctional', 'Disease', (141, 161))	('death', 'Disease', (177, 182))	('brain cancer', 'Disease', 'MESH:D001932', (244, 256))	('T cell dysfunctional', 'Disease', 'MESH:C536780', (141, 161))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('associated', 'Reg', (125, 135))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('cancer', 'Disease', (70, 76))	('death', 'Disease', 'MESH:D003643', (177, 182))	('brain cancer', 'Disease', (244, 256))	('shorter', 'NegReg', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CDK2', 'Gene', '1017', (102, 106))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('hypo-methylation', 'Var', (82, 98))	('CDK2', 'Gene', (102, 106))	('cancer', 'Disease', (250, 256))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('brain cancer', 'Phenotype', 'HP:0030692', (244, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('kidney', 'Disease', (232, 238))	('DNA methylation', 'biological_process', 'GO:0006306', ('25', '40'))
34371	33668805	Similarly, hypo-methylation of CDK2 is associated with T cell dysfunctional phenotype and worse prognosis of the brain, melanoma, metastatic melanoma, liver, and sarcoma patient while in colorectal cancer patients, it shows a negative association with dysfunctional T cells and predicts a good prognosis of the cohorts (Figure 9A).	('colorectal cancer', 'Disease', (187, 204))	('patients', 'Species', '9606', (205, 213))	('dysfunctional T', 'Disease', (252, 267))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('associated', 'Reg', (39, 49))	('negative', 'NegReg', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('patient', 'Species', '9606', (205, 212))	('association', 'Interaction', (235, 246))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('sarcoma', 'Disease', (162, 169))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('T cell dysfunctional', 'Disease', (55, 75))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('CDK2', 'Gene', '1017', (31, 35))	('dysfunctional T', 'Disease', 'MESH:D009461', (252, 267))	('T cell dysfunctional', 'Disease', 'MESH:C536780', (55, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('hypo-methylation', 'Var', (11, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('CDK2', 'Gene', (31, 35))	('patient', 'Species', '9606', (170, 177))
34372	33668805	Hypo-methylation of CDK6 is associated with T cell dysfunctional phenotype high death risk and low survival duration in lymphoma, cervical, and brain cancer patients (Figure 9A,B).	('T cell dysfunctional', 'Disease', (44, 64))	('Hypo-methylation', 'Var', (0, 16))	('patients', 'Species', '9606', (157, 165))	('T cell dysfunctional', 'Disease', 'MESH:C536780', (44, 64))	('brain cancer', 'Disease', (144, 156))	('death', 'Disease', (80, 85))	('cervical', 'Disease', (130, 138))	('low', 'NegReg', (95, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('brain cancer', 'Phenotype', 'HP:0030692', (144, 156))	('CDK6', 'Gene', '1021', (20, 24))	('death', 'Disease', 'MESH:D003643', (80, 85))	('lymphoma', 'Disease', (120, 128))	('brain cancer', 'Disease', 'MESH:D001932', (144, 156))	('lymphoma', 'Disease', 'MESH:D008223', (120, 128))	('CDK6', 'Gene', (20, 24))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('CDK', 'molecular_function', 'GO:0004693', ('20', '23'))
34373	33668805	Hyper methylation of STAT3, on the other hand, predicted high death risk and poor survival of melanoma, metastatic melanoma, endometrial, head and neck cancer, and lung cancer patients while predicting low death risk and longer survival duration in the brain, breast, and uveal cancers (Figure 9B).	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('poor', 'NegReg', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('breast', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('lung cancer', 'Disease', (164, 175))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('head and neck cancer', 'Phenotype', 'HP:0012288', (138, 158))	('neck', 'cellular_component', 'GO:0044326', ('147', '151'))	('death', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('death', 'Disease', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('STAT3', 'Gene', (21, 26))	('Hyper methylation', 'Var', (0, 17))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('uveal cancers', 'Disease', (272, 285))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('head and neck cancer', 'Disease', 'MESH:D006258', (138, 158))	('STAT3', 'Gene', '6774', (21, 26))	('patients', 'Species', '9606', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('endometrial', 'Disease', (125, 136))	('uveal cancers', 'Disease', 'MESH:D009369', (272, 285))	('death', 'Disease', 'MESH:D003643', (62, 67))	('death', 'Disease', 'MESH:D003643', (206, 211))
34374	33668805	Copy number alteration of CDK2 is associated with dysfunctional T-cell phenotype, high death risk, and shorter survival of lymphoma, leukemia, and breast cancer patients while CDK4 predicted a worse prognosis of the brain, lymphoma, and breast cancer patients.	('CDK', 'molecular_function', 'GO:0004693', ('26', '29'))	('patients', 'Species', '9606', (251, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('death', 'Disease', (87, 92))	('CDK', 'molecular_function', 'GO:0004693', ('176', '179'))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('lymphoma', 'Disease', (123, 131))	('Copy number alteration', 'Var', (0, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('lymphoma', 'Disease', 'MESH:D008223', (123, 131))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('CDK2', 'Gene', '1017', (26, 30))	('breast cancer', 'Disease', (237, 250))	('lymphoma', 'Phenotype', 'HP:0002665', (223, 231))	('CDK2', 'Gene', (26, 30))	('leukemia', 'Disease', (133, 141))	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('CDK4', 'Gene', (176, 180))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Disease', (147, 160))	('death', 'Disease', 'MESH:D003643', (87, 92))	('patients', 'Species', '9606', (161, 169))	('dysfunctional T-cell', 'Disease', 'MESH:C536780', (50, 70))	('associated', 'Reg', (34, 44))	('CDK4', 'Gene', '1019', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('lymphoma', 'Disease', (223, 231))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('shorter', 'NegReg', (103, 110))	('dysfunctional T-cell', 'Disease', (50, 70))	('lymphoma', 'Disease', 'MESH:D008223', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
34382	33668805	In the present study, we identified the frequencies of genetic alterations of STAT3/CDK2/4/6 in multiple cancer types, identified the gene signature as oncogenic prognosticators of CAFs and tumor immune infiltration, and poor prognoses of clinical cancer cohorts.	('multiple cancer', 'Disease', 'MESH:D009369', (96, 111))	('cancer', 'Disease', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CDK2/4/6', 'Gene', (84, 92))	('STAT3', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (248, 254))	('CAFs', 'Gene', (181, 185))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('STAT3', 'Gene', '6774', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('multiple cancer', 'Disease', (96, 111))	('CAFs', 'Gene', '6899', (181, 185))	('genetic alterations', 'Var', (55, 74))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CDK2/4/6', 'Gene', '1017;1019;1021', (84, 92))	('tumor', 'Disease', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', 'MESH:D009369', (190, 195))
34385	33668805	Aberrant CDK2/4/6 expression may enhance cancer progression, in part, through influence on mechanisms that maintain cell cycle progression.	('influence', 'Reg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Aberrant', 'Var', (0, 8))	('CDK2/4/6', 'Gene', '1017;1019;1021', (9, 17))	('CDK2/4/6', 'Gene', (9, 17))	('CDK', 'molecular_function', 'GO:0004693', ('9', '12'))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('expression', 'MPA', (18, 28))	('cell cycle progression', 'CPA', (116, 138))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('enhance', 'PosReg', (33, 40))
34386	33668805	Furthermore, it is worth noting that genetic alterations in CDK2/4/6 are associated with a poorer prognosis of the cancer cohorts.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('associated', 'Reg', (73, 83))	('CDK2/4/6', 'Gene', (60, 68))	('genetic alterations', 'Var', (37, 56))	('CDK2/4/6', 'Gene', '1017;1019;1021', (60, 68))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
34387	33668805	Indeed, we found that genetic alterations in CDK2/4/6 co-occurred with a number of other genetic alterations in the cancer cohorts.	('CDK2/4/6', 'Gene', (45, 53))	('co-occurred', 'Reg', (54, 65))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('genetic alterations', 'Var', (22, 41))	('CDK', 'molecular_function', 'GO:0004693', ('45', '48'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CDK2/4/6', 'Gene', '1017;1019;1021', (45, 53))
34388	33668805	While we have yet to establish a cause of the co-occurrence relationship here, the genetic alterations in CDK2/4/6 could conceivably synergize with the observed gene alteration co-occurrence to promote tumor progression and hence could be responsible for the observed poorer survival of the CDK2/4/6 altered cohorts than the non-altered cohorts.	('genetic alterations', 'Var', (83, 102))	('promote', 'PosReg', (194, 201))	('CDK', 'molecular_function', 'GO:0004693', ('106', '109'))	('tumor', 'Disease', (202, 207))	('alterations', 'Var', (91, 102))	('CDK2/4/6', 'Gene', '1017;1019;1021', (291, 299))	('CDK', 'molecular_function', 'GO:0004693', ('291', '294'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CDK2/4/6', 'Gene', (291, 299))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('CDK2/4/6', 'Gene', (106, 114))	('CDK2/4/6', 'Gene', '1017;1019;1021', (106, 114))
34395	33668805	Taking together, these results not only pointed out the potential roles of aberrant CDK2/4/6 expression in the initiation and development of multiple cancer but also suggest that STAT3 and CDK2/4/6 expression may alter tumor immune microenvironment and hence involved in cancer immune responses.	('CDK2/4/6', 'Gene', (189, 197))	('aberrant', 'Var', (75, 83))	('tumor', 'Disease', (219, 224))	('CDK2/4/6', 'Gene', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancer', 'Disease', (271, 277))	('multiple cancer', 'Disease', 'MESH:D009369', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('cancer', 'Disease', (150, 156))	('STAT3', 'Gene', (179, 184))	('CDK2/4/6', 'Gene', '1017;1019;1021', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('alter', 'Reg', (213, 218))	('CDK2/4/6', 'Gene', '1017;1019;1021', (84, 92))	('STAT3', 'Gene', '6774', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('multiple cancer', 'Disease', (141, 156))	('involved', 'Reg', (259, 267))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('CDK', 'molecular_function', 'GO:0004693', ('189', '192'))
34401	33668805	Our result is supported by preclinical studies which revealed that aberrant STAT3 expression mediates immunosuppression of tumor cells.	('STAT3', 'Gene', '6774', (76, 81))	('tumor', 'Disease', (123, 128))	('STAT3', 'Gene', (76, 81))	('mediates', 'Reg', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('aberrant', 'Var', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
34405	33668805	Collectively this study suggested that the immune cell infiltrations of GBM and melanoma are inversely associated with CDK2/4/6 and STAT3 expression or genetic alterations.	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('genetic alterations', 'Var', (152, 171))	('associated', 'Reg', (103, 113))	('immune cell infiltrations', 'CPA', (43, 68))	('STAT3', 'Gene', '6774', (132, 137))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('STAT3', 'Gene', (132, 137))	('CDK2/4/6', 'Gene', (119, 127))	('expression', 'MPA', (138, 148))	('CDK2/4/6', 'Gene', '1017;1019;1021', (119, 127))
34407	33668805	DNA methylation is a key epigenetic modification in the mammalian genomes which plays an important role in the regulation of gene expression and therefore can serve as a non-invasive biomarker for cancer diagnosis and prognosis.	('regulation', 'MPA', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Disease', (197, 203))	('methylation', 'Var', (4, 15))	('DNA', 'Disease', (0, 3))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('111', '140'))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mammalian', 'Species', '9606', (56, 65))
34408	33668805	Consequently, we found that differential-methylation and copy number alterations of STAT3/CDK2/4/6 are associated with dysfunctional T-cell phenotypes, high death risk, and short survival duration of multiple cancer cohorts, hence providing preliminary evidence for the use of STAT3/CDK2/4/6 signature for DNA methylation-based biomarkers of dysfunctional T-cell phenotypes.	('dysfunctional T-cell', 'Disease', 'MESH:C536780', (119, 139))	('CDK2/4/6', 'Gene', '1017;1019;1021', (90, 98))	('associated', 'Reg', (103, 113))	('dysfunctional T-cell', 'Disease', 'MESH:C536780', (342, 362))	('CDK', 'molecular_function', 'GO:0004693', ('283', '286'))	('CDK2/4/6', 'Gene', (283, 291))	('dysfunctional T-cell', 'Disease', (119, 139))	('STAT3', 'Gene', (277, 282))	('multiple cancer', 'Disease', (200, 215))	('dysfunctional T-cell', 'Disease', (342, 362))	('copy number alterations', 'Var', (57, 80))	('differential-methylation', 'Var', (28, 52))	('DNA', 'cellular_component', 'GO:0005574', ('306', '309'))	('death', 'Disease', (157, 162))	('STAT3', 'Gene', (84, 89))	('STAT3', 'Gene', '6774', (277, 282))	('DNA methylation', 'biological_process', 'GO:0006306', ('306', '321'))	('CDK', 'molecular_function', 'GO:0004693', ('90', '93'))	('STAT3', 'Gene', '6774', (84, 89))	('CDK2/4/6', 'Gene', (90, 98))	('CDK2/4/6', 'Gene', '1017;1019;1021', (283, 291))	('death', 'Disease', 'MESH:D003643', (157, 162))	('multiple cancer', 'Disease', 'MESH:D009369', (200, 215))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
34410	33668805	We found that patients with high expression of STAT3, CDK2, CDK4, or CDK6 yield poor clinical benefit to anti-PD1 or anti-CTLA4 therapy and had shorter survival time than those patients with low expression profiles.	('CDK4', 'Gene', (60, 64))	('STAT3', 'Gene', (47, 52))	('high expression', 'Var', (28, 43))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))	('patients', 'Species', '9606', (14, 22))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('STAT3', 'Gene', '6774', (47, 52))	('CDK4', 'Gene', '1019', (60, 64))	('CDK6', 'Gene', '1021', (69, 73))	('CTLA4', 'Gene', '1493', (122, 127))	('CDK2', 'Gene', '1017', (54, 58))	('CDK6', 'Gene', (69, 73))	('CDK2', 'Gene', (54, 58))	('survival time', 'CPA', (152, 165))	('poor', 'NegReg', (80, 84))	('CTLA4', 'Gene', (122, 127))	('shorter', 'NegReg', (144, 151))	('patients', 'Species', '9606', (177, 185))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))
34413	33668805	In line with this rationale, a combined preclinical and clinical study have reported that PD-L1 protein abundance and tumor-infiltrating lymphocyte is regulated by cell cycle kinases and that the Inhibition of CDK4/6 increases PD-L1 protein and reduced the numbers of tumor-infiltrating lymphocytes in mouse and in human cancer specimens.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mouse', 'Species', '10090', (302, 307))	('increases', 'PosReg', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CDK', 'molecular_function', 'GO:0004693', ('210', '213'))	('PD-L1 protein', 'Protein', (227, 240))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('increases PD', 'Phenotype', 'HP:0008151', (217, 229))	('reduced', 'NegReg', (245, 252))	('CDK4/6', 'Gene', (210, 216))	('human', 'Species', '9606', (315, 320))	('tumor', 'Disease', (268, 273))	('cancer', 'Disease', (321, 327))	('Inhibition', 'Var', (196, 206))	('tumor', 'Disease', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('cell cycle', 'biological_process', 'GO:0007049', ('164', '174'))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('PD-L1', 'Gene', (90, 95))
34415	33668805	In addition, there are several ongoing trials testing combinations of CDK4/6 inhibitors with immunotherapy, including avelumab and pembrolizumab (e.g., NCT02778685; NCT02779751; and NCT03147287).	('NCT02779751', 'Var', (165, 176))	('CDK4/6', 'Protein', (70, 76))	('NCT03147287', 'Var', (182, 193))	('CDK', 'molecular_function', 'GO:0004693', ('70', '73'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (131, 144))	('avelumab', 'Chemical', 'MESH:C000609138', (118, 126))	('combinations', 'Interaction', (54, 66))	('NCT02778685', 'Var', (152, 163))
34423	33668805	In addition, it's associated with poor response to immunotherapy Genetic alteration of STAT3/CDK2/4/6 co-occurred with other gene alteration and are associated with poorer prognosis of the cohorts.	('STAT3', 'Gene', (87, 92))	('CDK', 'molecular_function', 'GO:0004693', ('93', '96'))	('CDK2/4/6', 'Gene', (93, 101))	('poor response to immunotherapy', 'Phenotype', 'HP:0002721', (34, 64))	('CDK2/4/6', 'Gene', '1017;1019;1021', (93, 101))	('co-occurred', 'Reg', (102, 113))	('Genetic alteration', 'Var', (65, 83))	('associated', 'Reg', (149, 159))	('STAT3', 'Gene', '6774', (87, 92))
34432	33668805	Figure S5: Box plots showing tumor immune infiltration levels in GBM patients with different somatic copy number alterations for CDK2/CDK4/CDK6/STAT3.	('CDK6', 'Gene', (139, 143))	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('CDK6', 'Gene', '1021', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CDK2', 'Gene', '1017', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patients', 'Species', '9606', (69, 77))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('copy number alterations', 'Var', (101, 124))	('tumor', 'Disease', (29, 34))	('CDK4', 'Gene', '1019', (134, 138))	('CDK4', 'Gene', (134, 138))	('CDK2', 'Gene', (129, 133))	('STAT3', 'Gene', '6774', (144, 149))	('CDK', 'molecular_function', 'GO:0004693', ('139', '142'))	('STAT3', 'Gene', (144, 149))
34434	33207206	Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma Somatic mutations in skin cancers and other ultraviolet (UV)-exposed cells are typified by C>T and CC>TT substitutions at dipyrimidine sequences; however, many oncogenic "driver" mutations in melanoma do not fit this UV signature.	('mutations', 'Var', (117, 126))	('Melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('skin cancers', 'Phenotype', 'HP:0008069', (130, 142))	('skin cancers', 'Disease', (130, 142))	('Melanoma', 'Disease', (100, 108))	('Melanoma', 'Disease', 'MESH:D008545', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('melanoma', 'Disease', 'MESH:D008545', (301, 309))	('substitutions', 'Var', (214, 227))	('skin cancers', 'Disease', 'MESH:D012878', (130, 142))	('CC>TT substitutions', 'Var', (208, 227))	('melanoma', 'Disease', (301, 309))	('C>T', 'Var', (200, 203))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('dipyrimidine', 'Chemical', '-', (231, 243))	('Mutations', 'Var', (87, 96))	('skin cancer', 'Phenotype', 'HP:0008069', (130, 141))
34436	33207206	Analysis of ~50,000 UV-induced mutations reveals abundant non-canonical mutations, including T>C, T>A, and AC>TT substitutions.	('mutations', 'Var', (31, 40))	('T>C', 'Var', (93, 96))	('AC', 'Chemical', 'MESH:D000186', (107, 109))	('AC>TT substitutions', 'Var', (107, 126))	('T>A', 'Var', (98, 101))	('non-canonical', 'MPA', (58, 71))
34439	33207206	These include multiple driver mutations, most prominently the recurrent BRAF V600E and V600K substitutions, suggesting that mutations arising from rare, atypical UV photoproducts may play a role in melanomagenesis.	('BRAF', 'Gene', (72, 76))	('V600K', 'Mutation', 'rs121913227', (87, 92))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('role', 'Reg', (190, 194))	('melanoma', 'Disease', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('BRAF', 'Gene', '673', (72, 76))	('V600K', 'Var', (87, 92))	('play', 'Reg', (183, 187))
34440	33207206	UV mutagenesis has been well studied, but many driver mutations in melanoma do not fit the canonical UV signature.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mutations', 'Var', (54, 63))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutagenesis', 'biological_process', 'GO:0006280', ('3', '14'))
34441	33207206	Non-canonical UV mutations are likely caused by atypical photoproducts, which may contribute to melanomagenesis.	('Non-canonical', 'Var', (0, 13))	('contribute', 'Reg', (82, 92))	('mutations', 'Var', (17, 26))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
34442	33207206	Exposure to ultraviolet (UV) light causes a unique signature of mutations in skin cancers and other UV-irradiated cells.	('skin cancers', 'Phenotype', 'HP:0008069', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('skin cancers', 'Disease', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('skin cancers', 'Disease', 'MESH:D012878', (77, 89))	('mutations', 'Var', (64, 73))	('skin cancer', 'Phenotype', 'HP:0008069', (77, 88))
34443	33207206	UV-induced mutations primarily consist of C-to-T (C>T) substitutions in cytosine-containing dipyrimidine (Dipyr) sequences (i.e., TC, CT, or CC).	('mutations', 'Var', (11, 20))	('TC', 'Chemical', 'MESH:D013667', (130, 132))	('C-to-T (C>T', 'Var', (42, 53))	('Dipyr', 'Chemical', '-', (106, 111))	('cytosine', 'Chemical', 'MESH:D003596', (72, 80))	('dipyrimidine', 'Chemical', '-', (92, 104))
34444	33207206	Hence CC>TT and C>T substitutions in Dipyr sequences comprise the canonical signature of short- or medium-wavelength UV light (i.e., UVC or UVB).	('Dipyr', 'Chemical', '-', (37, 42))	('CC>TT', 'Var', (6, 11))	('Dipyr sequences', 'Gene', (37, 52))	('C>T substitutions', 'Var', (16, 33))	('substitutions', 'Var', (20, 33))
34445	33207206	UV signature mutations arise from mutagenic bypass of UV-induced DNA lesions, primarily consisting of cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs), which form exclusively at Dipyr sequences.	('CPDs', 'Disease', (133, 137))	('Dipyr', 'Chemical', '-', (199, 204))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('CPDs', 'Disease', 'MESH:C565866', (133, 137))	('cyclobutane pyrimidine dimers', 'MPA', (102, 131))	('mutations', 'Var', (13, 22))	('cyclobutane pyrimidine', 'Chemical', '-', (102, 124))
34446	33207206	Although the vast majority of somatic mutations in skin cancers such as melanoma are UV signature mutations, many of the identified driver mutations in melanoma are not.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('skin cancers', 'Phenotype', 'HP:0008069', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('skin cancers', 'Disease', (51, 63))	('mutations', 'Var', (38, 47))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('skin cancers', 'Disease', 'MESH:D012878', (51, 63))
34448	33207206	Although these are among the most recurrent mutations in melanoma and are associated with carcinogenesis, neither is a canonical UV signature mutation: NRAS Q61R is caused by a T>C mutation, while BRAF V600E is caused by a T>A mutation in a non-Dipyr context.	('Dipyr', 'Chemical', '-', (245, 250))	('NRAS', 'Gene', (152, 156))	('BRAF', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (197, 201))	('T>C', 'Var', (177, 180))	('NRAS', 'Gene', '4893', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('caused by', 'Reg', (165, 174))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('Q61R', 'Mutation', 'rs11554290', (157, 161))	('V600E', 'Mutation', 'rs113488022', (202, 207))	('carcinogenesis', 'Disease', (90, 104))	('associated', 'Reg', (74, 84))
34451	33207206	As a whole, fewer than 50% of putative driver mutations in melanoma are UV signature mutations, which is surprising given the known association between acute UV exposure (i.e., blistering sunburns) and melanomagenesis.	('mutations', 'Var', (46, 55))	('blistering', 'Phenotype', 'HP:0008066;HP:0200037', (177, 187))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('blistering sunburns', 'Phenotype', 'HP:0008066', (177, 196))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
34452	33207206	Genome sequencing of mutations arising in mammalian cells following experimental UV exposure (typically a single low dose of UV) has confirmed that UVB or UVC light primarily induces UV signature mutations.	('mammalian', 'Species', '9606', (42, 51))	('UV signature mutations', 'MPA', (183, 205))	('induces', 'Reg', (175, 182))	('mutations', 'Var', (21, 30))
34453	33207206	However, these studies have not provided insight into the origin of the atypical substitution patterns that cause many of the driver mutations in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('mutations', 'Var', (133, 142))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))
34454	33207206	Non-UV signature driver mutations in BRAF (and potentially other genes) could arise from a neighboring UV lesion, but support for this hypothesis has been difficult to ascertain given the limited numbers of non-UV signature mutations in melanoma and other UV-exposed cells, and because of the difficulty in establishing their UV origin.	('melanoma', 'Disease', (237, 245))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('mutations', 'Var', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))
34455	33207206	For example, genetic defects in the NER pathway in xeroderma pigmentosum (XP) patients cause elevated frequency of UV mutations, which translates to a >1,000-fold increased risk for skin cancer.	('xeroderma pigmentosum', 'Disease', (51, 72))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (51, 72))	('skin cancer', 'Phenotype', 'HP:0008069', (182, 193))	('mutations', 'Var', (118, 127))	('genetic defects', 'Disease', (13, 28))	('NER pathway', 'Pathway', (36, 47))	('skin cancer', 'Disease', (182, 193))	('patients', 'Species', '9606', (78, 86))	('genetic defects', 'Disease', 'MESH:D030342', (13, 28))	('skin cancer', 'Disease', 'MESH:D012878', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NER', 'biological_process', 'GO:0006289', ('36', '39'))
34458	33207206	Genome sequencing of cutaneous squamous cell carcinomas (cSCC) and melanomas has revealed that UV signature mutations have significant transcriptional asymmetry.	('melanomas', 'Disease', (67, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('cutaneous squamous cell carcinomas', 'Disease', 'MESH:D002294', (21, 55))	('mutations', 'Var', (108, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('cSCC', 'Phenotype', 'HP:0006739', (57, 61))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('cutaneous squamous cell carcinomas', 'Disease', (21, 55))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (31, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('cutaneous squamous cell carcinomas', 'Phenotype', 'HP:0006739', (21, 55))
34459	33207206	This asymmetry is elevated in tumors derived from individuals with germline deficiencies in the XPC gene, because XPC is required for the global genomic-NER (GG-NER) sub-pathway, which repairs UV photoproducts in intergenic DNA and the non-transcribed strand (NTS) of genes.	('XPC', 'Gene', (114, 117))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('GG-NER', 'biological_process', 'GO:0070911', ('158', '164'))	('XPC', 'Gene', '7508', (96, 99))	('NER', 'biological_process', 'GO:0006289', ('153', '156'))	('XPC', 'Gene', '7508', (114, 117))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('deficiencies', 'Var', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('XPC', 'Gene', (96, 99))
34460	33207206	We sequenced the genomes of >150 independent isolates of wild-type (WT) or NER-deficient yeast strains and identified in total more than 50,000 UV-induced mutations.	('UV-induced', 'Gene', (144, 154))	('NER', 'biological_process', 'GO:0006289', ('75', '78'))	('mutations', 'Var', (155, 164))	('yeast', 'Species', '4932', (89, 94))
34461	33207206	Although canonical UV signature mutations are prevalent in our dataset, we also observe other mutation classes likely associated with atypical UV lesions, including a thymine-adenine (TA) photoproduct, which we mapped at single-nucleotide resolution across UV-irradiated yeast genomes.	('thymine-adenine', 'Chemical', '-', (167, 182))	('TA', 'Chemical', '-', (184, 186))	('mutations', 'Var', (32, 41))	('yeast', 'Species', '4932', (271, 276))	('associated', 'Reg', (118, 128))
34463	33207206	These non-canonical mutation classes include NRAS Q61R and BRAF V600K and V600E, which are among the most common driver mutations in melanoma, indicating that mutations caused by atypical photoproducts may promote melanomagenesis.	('V600K', 'Mutation', 'rs121913227', (64, 69))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('Q61R', 'Mutation', 'rs11554290', (50, 54))	('mutations', 'Var', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('promote', 'PosReg', (206, 213))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('V600E', 'Var', (74, 79))	('V600K', 'Var', (64, 69))	('NRAS', 'Gene', (45, 49))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('NRAS', 'Gene', '4893', (45, 49))
34465	33207206	This treatment has a minor effect on WT yeast survival (Figure 1B) but induces a highly reproducible, dose-dependent increase in mutation in both whole-genome sequencing analysis (Figures 1C and S1A) and using a CAN1 forward mutation reporter (Figure S1B).	('CAN1', 'Gene', '856646', (212, 216))	('increase', 'PosReg', (117, 125))	('mutation', 'Var', (129, 137))	('yeast', 'Species', '4932', (40, 45))	('CAN1', 'Gene', (212, 216))
34466	33207206	The >10-fold higher mutation density in UV-irradiated yeast compared with non-irradiated controls indicates that the vast majority of the mutations in exposed isolates are UV induced.	('yeast', 'Species', '4932', (54, 59))	('higher', 'PosReg', (13, 19))	('mutations', 'Var', (138, 147))
34468	33207206	Of the 14,285 single-nucleotide substitutions, 32% are C>T mutations at either the 5' position (5' Dipyr) or 3' position (3' Dipyr) of Dipyr sequences, consistent with the traditional UV signature (Figures 1D, S1C, and S1D).	('Dipyr', 'Chemical', '-', (99, 104))	('single-nucleotide substitutions', 'Var', (14, 45))	('Dipyr', 'Chemical', '-', (125, 130))	('C>T mutations', 'Var', (55, 68))	('Dipyr', 'Chemical', '-', (135, 140))
34469	33207206	However, we also identified similarly high levels of T>C (42%) and T>A (18%) mutations (Figure 1D), each enriched at specific trinucleotide contexts.	('C (42', 'molecular_function', 'GO:0003813', ('55', '60'))	('trinucleotide', 'Chemical', '-', (126, 139))	('T>A', 'Gene', (67, 70))	('mutations', 'Var', (77, 86))	('T>C', 'Var', (53, 56))
34470	33207206	T>C substitutions are primarily associated with TTA, TTC, TTG, and TTT sequences (i.e., TTN), as well as CTN trinucleotides (Figure 1D), and thus mostly occur in the 3' position of a Dipyr (Figure S1D), indicating that they likely arise from known UV photoproducts (e.g., CPDs or 6-4PPs).	('TTC', 'Disease', (53, 56))	('trinucleotides', 'Chemical', '-', (109, 123))	('TC', 'Chemical', 'MESH:D013667', (54, 56))	('TTA', 'Disease', (48, 51))	('TTT', 'Gene', (67, 70))	('CPDs', 'Disease', (272, 276))	('TTA', 'Chemical', 'MESH:C062078', (48, 51))	('associated', 'Reg', (32, 42))	('substitutions', 'Var', (4, 17))	('Dipyr', 'Chemical', '-', (183, 188))	('CPDs', 'Disease', 'MESH:C565866', (272, 276))
34471	33207206	In contrast, T>A substitutions primarily occur at ATA and TTA trinucleotide sequences (Figure 1D).	('TA', 'Chemical', '-', (59, 61))	('TA', 'Chemical', '-', (51, 53))	('occur', 'Reg', (41, 46))	('TTA trinucleotide', 'Chemical', '-', (58, 75))	('substitutions', 'Var', (17, 30))
34472	33207206	The high abundance of T>A substitutions at non-Dipyr contexts ("No" in Figure S1D) suggests that these mutations may be caused by damage other than the canonical UV photoproducts.	('T>A', 'Gene', (22, 25))	('Dipyr', 'Chemical', '-', (47, 52))	('substitutions', 'Var', (26, 39))
34474	33207206	The rad16Delta and rad26Delta mutant strains were treated, respectively, with 15 doses of 12.5 or 25 J/m2 UV light (rad16Delta yeast were treated with a lower dose because of their greater UV sensitivity; see Figure S2A), and the genomes of individual isolates from each strain were sequenced.	('rad', 'biological_process', 'GO:1990116', ('116', '119'))	('rad16Delta', 'Var', (4, 14))	('rad26Delta', 'Var', (19, 29))	('yeast', 'Species', '4932', (127, 132))	('rad', 'biological_process', 'GO:1990116', ('19', '22'))	('rad', 'biological_process', 'GO:1990116', ('4', '7'))
34475	33207206	Consistent with single-dose mutation frequencies measured in the CAN1 gene (Figure S2B), WT and rad26Delta strains displayed nearly equal numbers of mutations per genome, whereas mutations in rad16Delta yeast increased ~2-fold despite the lower UV dose (Figure 2A).	('mutations', 'Var', (149, 158))	('CAN1', 'Gene', '856646', (65, 69))	('rad', 'biological_process', 'GO:1990116', ('96', '99'))	('yeast', 'Species', '4932', (203, 208))	('mutations', 'Var', (179, 188))	('rad', 'biological_process', 'GO:1990116', ('192', '195'))	('CAN1', 'Gene', (65, 69))
34476	33207206	The rad26Delta cells displayed a mutation spectrum very similar to WT (Figure S2E), consistent with the limited role of Rad26 and of the TC-NER pathway in the repair of UV damage in yeast.	('Rad26', 'Gene', '853492', (120, 125))	('TC-NER', 'biological_process', 'GO:0006283', ('137', '143'))	('Rad26', 'Gene', (120, 125))	('TC-NER', 'Chemical', '-', (137, 143))	('Rad', 'biological_process', 'GO:1990116', ('120', '123'))	('rad26Delta', 'Var', (4, 14))	('yeast', 'Species', '4932', (182, 187))	('rad', 'biological_process', 'GO:1990116', ('4', '7'))
34477	33207206	In contrast, specific classes of mutations are elevated in the GG-NER-deficient rad16Delta yeast (Figure 2B).	('yeast', 'Species', '4932', (91, 96))	('rad', 'biological_process', 'GO:1990116', ('80', '83'))	('elevated', 'PosReg', (47, 55))	('rad16Delta', 'Var', (80, 90))	('GG-NER', 'biological_process', 'GO:0070911', ('63', '69'))
34478	33207206	The greatest increase is observed for C>T mutations in a Dipyr context, which increase 2.5-fold (5' Dipyr) and 3.2-fold (3' Dipyr) in the rad16Delta mutant.	('Dipyr', 'Chemical', '-', (57, 62))	('increase', 'PosReg', (78, 86))	('rad16Delta', 'Var', (138, 148))	('C>T mutations', 'Var', (38, 51))	('Dipyr', 'Chemical', '-', (100, 105))	('Dipyr', 'Chemical', '-', (124, 129))	('rad', 'biological_process', 'GO:1990116', ('138', '141'))
34480	33207206	Surprisingly, T>A mutations (in a 3' Dipyr and "No" Dipyr context) and T>C mutations (5' and 3' Dipyr contexts) also increased in the rad16Delta mutant (Figure 2B), suggesting that these non-canonical UV-induced mutations may also originate from UV photoproducts repaired by the NER pathway.	('Dipyr', 'Chemical', '-', (37, 42))	('increased', 'PosReg', (117, 126))	('rad', 'biological_process', 'GO:1990116', ('132', '135'))	('NER', 'biological_process', 'GO:0006289', ('277', '280'))	('Dipyr', 'Chemical', '-', (96, 101))	('rad16Delta mutant', 'Var', (134, 151))	('mutations', 'Var', (212, 221))	('Dipyr', 'Chemical', '-', (52, 57))	('T>C', 'Gene', (71, 74))
34481	33207206	For this analysis, we assigned the mutation to the DNA strand containing the pyrimidine base, because UV mutations are primarily associated with lesions at pyrimidine sequences.	('pyrimidine', 'Chemical', 'MESH:C030986', (77, 87))	('associated', 'Reg', (129, 139))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('lesions', 'Var', (145, 152))	('mutations', 'Var', (105, 114))	('pyrimidine', 'Var', (156, 166))	('pyrimidine', 'Chemical', 'MESH:C030986', (156, 166))
34482	33207206	In WT cells, mutation density as a whole is ~1.9-fold lower on the TS relative to the NTS across ~5,000 yeast genes (p < 0.0001; Figure S3A), consistent with faster repair of the TS by the TC-NER pathway.	('TC-NER', 'biological_process', 'GO:0006283', ('189', '195'))	('mutation', 'Var', (13, 21))	('TC-NER', 'Chemical', '-', (189, 195))	('yeast', 'Species', '4932', (104, 109))	('lower', 'NegReg', (54, 59))
34483	33207206	Deletion of RAD16, which is required for GG-NER (Figure 2A, inset), increases mutation density on the NTS (Figure S3B), resulting in an elevated transcriptional asymmetry (~6.2-fold asymmetry).	('increases', 'PosReg', (68, 77))	('RAD16', 'Gene', '852411', (12, 17))	('RAD', 'biological_process', 'GO:1990116', ('12', '15'))	('mutation density', 'MPA', (78, 94))	('transcriptional asymmetry', 'MPA', (145, 170))	('elevated', 'PosReg', (136, 144))	('RAD16', 'Gene', (12, 17))	('GG-NER', 'biological_process', 'GO:0070911', ('41', '47'))	('Deletion', 'Var', (0, 8))
34484	33207206	In contrast, deletion of RAD26, which plays a role in transcription-coupled repair of the TS (Figure 2A, inset), nearly eliminates the transcriptional asymmetry of UV-induced mutations (~1.2-fold asymmetry; Figure S3C).	('RAD26', 'Gene', '853492', (25, 30))	('eliminates', 'NegReg', (120, 130))	('RAD', 'biological_process', 'GO:1990116', ('25', '28'))	('transcriptional asymmetry', 'MPA', (135, 160))	('deletion', 'Var', (13, 21))	('RAD26', 'Gene', (25, 30))	('mutations', 'Var', (175, 184))	('transcription-coupled repair', 'biological_process', 'GO:0006283', ('54', '82'))
34486	33207206	As expected for canonical UV signature mutations, all trinucleotide classes that contain C>T mutations in Dipyr sequences (red circles with black outline in Figure 2C) show significant transcriptional asymmetry in WT cells, with ~2- to 3-fold higher mutation density on the NTS.	('transcriptional', 'MPA', (185, 200))	('mutations', 'Var', (93, 102))	('Dipyr', 'Chemical', '-', (106, 111))	('higher', 'PosReg', (243, 249))	('Dipyr sequences', 'Gene', (106, 121))	('trinucleotide', 'Chemical', '-', (54, 67))
34487	33207206	Transcriptional asymmetry of these C>T mutations is elevated in the rad16Delta mutant (>10-fold asymmetry) and diminished in the rad26Delta mutant (Figure 2C), consistent with prior reports that these mutations arise from CPDs or 6-4PPs that are repaired by both NER sub-pathways.	('Transcriptional asymmetry', 'MPA', (0, 25))	('rad16Delta', 'Var', (68, 78))	('CPDs', 'Disease', (222, 226))	('NER', 'biological_process', 'GO:0006289', ('263', '266'))	('rad', 'biological_process', 'GO:1990116', ('68', '71'))	('rad', 'biological_process', 'GO:1990116', ('129', '132'))	('C>T', 'Gene', (35, 38))	('rad26Delta', 'Var', (129, 139))	('mutations', 'Var', (39, 48))	('CPDs', 'Disease', 'MESH:C565866', (222, 226))	('diminished', 'NegReg', (111, 121))	('elevated', 'PosReg', (52, 60))
34488	33207206	Similarly, certain classes of C>A mutations (Figure 2C; primarily TCN trinucleotide classes) and non-canonical UV-induced T>C mutations (Figure 2D) also show transcriptional asymmetry in WT cells that is further elevated in the rad16Delta mutant (Figures 2C-2E), indicating that these mutations also likely arise from bulky UV photoproducts.	('TCN trinucleotide', 'Chemical', '-', (66, 83))	('rad', 'biological_process', 'GO:1990116', ('228', '231'))	('rad16Delta mutant', 'Var', (228, 245))	('elevated', 'PosReg', (212, 220))	('C>A', 'Gene', (30, 33))	('transcriptional', 'MPA', (158, 173))	('mutations', 'Var', (34, 43))
34489	33207206	Lower abundance T>A mutations associated with TTC, TTG, and TTT sequences show transcriptional asymmetry favoring the NTS relative to the TS (Figures 2D and 2F), similar to T>C substitutions in these sequence contexts.	('TC', 'Chemical', 'MESH:D013667', (47, 49))	('favoring', 'PosReg', (105, 113))	('T>A', 'Gene', (16, 19))	('TTT', 'Gene', (60, 63))	('mutations', 'Var', (20, 29))
34490	33207206	In contrast, high-abundance T>A mutations in TTA trinucleotide sequences display transcriptional asymmetry favoring the TS (Figures 2D and 2F).	('TTA trinucleotide', 'Chemical', '-', (45, 62))	('TTA', 'Gene', (45, 48))	('mutations', 'Var', (32, 41))
34491	33207206	Moreover, T>A mutations in contexts ending with a TA sequence (e.g., ATA, CTA, GTA, TTA) are all elevated on the TS relative to the NTS (Figures 2D and 2F).	('elevated', 'PosReg', (97, 105))	('TA', 'Chemical', '-', (85, 87))	('T>A', 'Gene', (10, 13))	('ATA', 'Disease', (69, 72))	('TTA', 'Chemical', 'MESH:C062078', (84, 87))	('TA', 'Chemical', '-', (70, 72))	('CTA', 'Disease', (74, 77))	('TA', 'Chemical', '-', (80, 82))	('TA', 'Chemical', '-', (50, 52))	('TA', 'Chemical', '-', (75, 77))	('mutations', 'Var', (14, 23))
34492	33207206	This analysis indicates that collectively "NTA" mutations originate from a DNA lesion on the opposite DNA strand, at a corresponding TAN consensus sequence (Figure 2G), and that the central adenine in this consensus is mutated to thymine (i.e., A>T mutation).	('TA', 'Chemical', '-', (133, 135))	('TA', 'Chemical', '-', (44, 46))	('originate from', 'Reg', (58, 72))	('thymine', 'Chemical', 'MESH:D013941', (230, 237))	('adenine', 'Chemical', 'MESH:D000225', (190, 197))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('mutated', 'Var', (219, 226))	('mutations', 'Var', (48, 57))
34493	33207206	T>A substitutions in an NTA sequence context total 1,677 mutations in WT cells, comprising 66% of T>A mutations and 12% of all mutations in our WT dataset, and therefore are a frequent UV-induced mutation.	('T>A', 'Gene', (98, 101))	('TA', 'Chemical', '-', (25, 27))	('mutations', 'Var', (57, 66))	('mutations', 'Var', (102, 111))	('substitutions', 'Var', (4, 17))
34501	33207206	UVDE-seq reads were enriched at Dipyr sequences (Figure 3F), with the highest levels at TC sequences, followed by TT, CC, and CT.	('Dipyr', 'Chemical', '-', (32, 37))	('Dipyr sequences', 'Var', (32, 47))	('TC', 'Chemical', 'MESH:D013667', (88, 90))	('TC sequences', 'Var', (88, 100))	('UVDE', 'Chemical', '-', (0, 4))
34505	33207206	These data indicate that UV irradiation induces significant levels of TA photoproducts in vitro and across the yeast genome, which provides a plausible mechanism for the generation of UV mutations at TA sequences.	('TA photoproducts', 'MPA', (70, 86))	('TA', 'Chemical', '-', (70, 72))	('TA', 'Chemical', '-', (200, 202))	('mutations', 'Var', (187, 196))	('yeast', 'Species', '4932', (111, 116))
34506	33207206	UV irradiation also induced many tandem double substitutions (399 in WT) in yeast, but surprisingly, canonical UV-induced CC>TT mutations are only the second most frequent tandem mutation in this dataset (Figure 4A).	('mutations', 'Var', (128, 137))	('tandem double substitutions', 'Var', (33, 60))	('yeast', 'Species', '4932', (76, 81))
34509	33207206	Most of these novel tandem mutations also show significant transcriptional asymmetry favoring the NTS (Figure 4C), which is exacerbated in rad16Delta mutant yeast (Figure 4D).	('rad', 'biological_process', 'GO:1990116', ('139', '142'))	('yeast', 'Species', '4932', (157, 162))	('exacerbated', 'PosReg', (124, 135))	('rad16Delta mutant', 'Var', (139, 156))
34510	33207206	These results indicate that along with the well-established CC>TT mutations, novel tandem mutations at AC and CT sequences may originate from UV lesions that are repaired by NER.	('NER', 'biological_process', 'GO:0006289', ('174', '177'))	('originate from', 'Reg', (127, 141))	('AC', 'Chemical', 'MESH:D000186', (103, 105))	('tandem mutations', 'Var', (83, 99))
34513	33207206	Indeed, 50 of the AC>NN mutations occur in a TACA sequence context, which has no overlapping Dipyr sequences.	('occur', 'Reg', (34, 39))	('TA', 'Chemical', '-', (45, 47))	('Dipyr', 'Chemical', '-', (93, 98))	('AC', 'Chemical', 'MESH:D000186', (18, 20))	('AC>NN', 'Gene', (18, 23))	('mutations', 'Var', (24, 33))	('AC', 'Chemical', 'MESH:D000186', (46, 48))
34514	33207206	Therefore, AC>NN mutations are unlikely to be caused by mutagenic bypass of canonical UV photoproducts at neighboring or overlapping Dipyr sequences and, similar to A>T mutations in NTA sequences, are likely to be caused by an atypical UV photoproduct.	('AC>NN', 'Disease', (11, 16))	('Dipyr', 'Chemical', '-', (133, 138))	('AC', 'Chemical', 'MESH:D000186', (11, 13))	('TA', 'Chemical', '-', (183, 185))	('mutations', 'Var', (17, 26))
34515	33207206	Given the striking abundance of non-canonical UV-induced mutations in our yeast dataset, we next assessed whether similar types of mutations are present in the genomes of human cancers associated with UV exposure.	('associated', 'Reg', (185, 195))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('human', 'Species', '9606', (171, 176))	('yeast', 'Species', '4932', (74, 79))
34516	33207206	Initially, we analyzed single-nucleotide substitutions derived from whole-genome sequencing of 140 cutaneous melanoma tumors in a manner similar to our yeast data.	('single-nucleotide substitutions', 'Var', (23, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('yeast', 'Species', '4932', (152, 157))	('melanoma tumors', 'Disease', (109, 124))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('cutaneous melanoma tumor', 'Disease', (99, 123))	('melanoma tumors', 'Disease', 'MESH:D008545', (109, 124))	('cutaneous melanoma tumor', 'Disease', 'MESH:C562393', (99, 123))
34517	33207206	This effort revealed T>C and T>A substitutions comprise only 5% and 4% of total single-nucleotide substitutions, respectively, because the vast majority of substitutions in these tumors are UV signature mutations (Figure 5A).	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('substitutions', 'Var', (156, 169))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('T>C', 'Var', (21, 24))
34518	33207206	Despite their lower abundance compared with our yeast dataset, T>C and T>A mutations are enriched in cutaneous melanomas relative to acral melanomas (which are not typically UV exposed).	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('T>C', 'Var', (63, 66))	('acral melanomas', 'Disease', 'MESH:D008545', (133, 148))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (101, 120))	('yeast', 'Species', '4932', (48, 53))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (101, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('acral melanomas', 'Disease', (133, 148))	('acral melanoma', 'Phenotype', 'HP:0012060', (133, 147))	('mutations', 'Var', (75, 84))	('T>A', 'Gene', (71, 74))	('acral melanomas', 'Phenotype', 'HP:0012060', (133, 148))	('cutaneous melanomas', 'Disease', (101, 120))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
34519	33207206	T>C and T>A mutation classes are elevated ~6- to 12-fold in cutaneous relative to acral melanoma (Figure 5B).	('acral melanoma', 'Disease', 'MESH:D008545', (82, 96))	('T>C', 'Var', (0, 3))	('T>A', 'Var', (8, 11))	('elevated', 'PosReg', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('cutaneous', 'Disease', (60, 69))	('acral melanoma', 'Phenotype', 'HP:0012060', (82, 96))	('acral melanoma', 'Disease', (82, 96))
34520	33207206	Abundances of T>C and T>A mutations similar to those in cutaneous melanoma were also observed in a group of sun-exposed cSCCs (Figures S5A and S5B), which, although they differ from melanoma in terms of causative driver mutations, share an association with UV exposure.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('cutaneous melanoma', 'Disease', (56, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (56, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (56, 74))	('association', 'Interaction', (240, 251))	('cSCC', 'Phenotype', 'HP:0006739', (120, 124))	('mutations', 'Var', (26, 35))	('T>A', 'Gene', (22, 25))	('T>C', 'Gene', (14, 17))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
34521	33207206	Importantly, this dataset also contains sequenced cSCCs derived from patients with germline mutations in XPC, which like Rad16 in yeast, is required for GG-NER in human cells.	('cSCC', 'Phenotype', 'HP:0006739', (50, 54))	('Rad16', 'Gene', (121, 126))	('XPC', 'Gene', (105, 108))	('yeast', 'Species', '4932', (130, 135))	('mutations', 'Var', (92, 101))	('human', 'Species', '9606', (163, 168))	('XPC', 'Gene', '7508', (105, 108))	('patients', 'Species', '9606', (69, 77))	('Rad16', 'Gene', '852411', (121, 126))	('GG-NER', 'biological_process', 'GO:0070911', ('153', '159'))	('Rad', 'biological_process', 'GO:1990116', ('121', '124'))
34523	33207206	The frequency of UV signature C>T mutations is elevated in NER-deficient XPC-/- cSCCs relative to repair-proficient cSCCs (Figure S5C), as expected.	('XPC', 'Gene', (73, 76))	('NER-deficient', 'Disease', (59, 72))	('NER', 'biological_process', 'GO:0006289', ('59', '62'))	('cSCC', 'Phenotype', 'HP:0006739', (116, 120))	('elevated', 'PosReg', (47, 55))	('XPC', 'Gene', '7508', (73, 76))	('UV signature', 'Gene', (17, 29))	('mutations', 'Var', (34, 43))	('cSCC', 'Phenotype', 'HP:0006739', (80, 84))
34525	33207206	In particular, T>A mutations in an NTA sequence context (i.e., ATA, CTA, GTA, and TTA) are highly elevated in XPC-/- cSCCs (Figure S5E).	('TA', 'Chemical', '-', (74, 76))	('cSCC', 'Phenotype', 'HP:0006739', (117, 121))	('XPC', 'Gene', (110, 113))	('ATA', 'Disease', (63, 66))	('XPC', 'Gene', '7508', (110, 113))	('TTA', 'Chemical', 'MESH:C062078', (82, 85))	('mutations', 'Var', (19, 28))	('elevated', 'PosReg', (98, 106))	('TA', 'Chemical', '-', (83, 85))	('TA', 'Chemical', '-', (69, 71))	('T>A', 'Gene', (15, 18))	('S5E', 'Mutation', 'p.S5E', (131, 134))	('TA', 'Chemical', '-', (64, 66))	('TA', 'Chemical', '-', (36, 38))
34526	33207206	Analysis of canonical UV signature C>T mutations revealed significant transcriptional asymmetry in genes that are highly expressed in keratinocytes (top quartile) in the XPC-/- cSCCs (Figure 5C).	('cSCC', 'Phenotype', 'HP:0006739', (177, 181))	('XPC', 'Gene', (170, 173))	('mutations', 'Var', (39, 48))	('XPC', 'Gene', '7508', (170, 173))	('transcriptional', 'MPA', (70, 85))
34528	33207206	Similarly, non-canonical UV-induced T>C mutations revealed a significant transcriptional asymmetry for most Dipyr mutation classes among high-expressed genes (Figure 5E), but not in low-expressed genes (Figure 5F), although the magnitude of transcriptional asymmetry for T>C mutations is somewhat lower than C>T mutations.	('Dipyr mutation', 'Gene', (108, 122))	('mutations', 'Var', (40, 49))	('transcriptional', 'MPA', (73, 88))	('Dipyr', 'Chemical', '-', (108, 113))
34529	33207206	As in yeast, T>A mutations in an "NTA" sequence context are elevated on the TS in highly expressed genes (Figure 5G), but not in lowly expressed genes (Figure 5H), suggesting that many of the T>A mutations may arise from atypical TA photoproducts (Figure 2G).	('TA', 'Chemical', '-', (230, 232))	('T>A', 'Gene', (192, 195))	('elevated', 'PosReg', (60, 68))	('TA', 'Chemical', '-', (35, 37))	('yeast', 'Species', '4932', (6, 11))	('mutations', 'Var', (17, 26))	('T>A', 'Gene', (13, 16))	('mutations', 'Var', (196, 205))
34530	33207206	Similar trends in transcriptional asymmetry are apparent for T>C and T>A mutations in cutaneous melanoma (Figures S6A-S6D), although the magnitude of transcriptional asymmetry is decreased, presumably because of active GG-NER in these tumors.	('cutaneous melanoma', 'Disease', (86, 104))	('transcriptional', 'MPA', (18, 33))	('T>A', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('GG-NER', 'biological_process', 'GO:0070911', ('219', '225'))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('T>C', 'Var', (61, 64))	('tumors', 'Disease', (235, 241))
34531	33207206	These findings are consistent with the hypothesis that many T>C and T>A mutations in cutaneous melanoma and cSCC are induced by UV exposure.	('cSCC', 'Disease', (108, 112))	('mutations', 'Var', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('cSCC', 'Phenotype', 'HP:0006739', (108, 112))	('cutaneous melanoma', 'Disease', (85, 103))	('T>C', 'Var', (60, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
34533	33207206	Although CC>TT tandem mutations are by far the most common double substitution in cutaneous melanoma, as expected, significant numbers of AC>TT, CT>TA, and CT>TC tandem mutations are also present (Figure 6A).	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('CT>TC', 'Var', (156, 161))	('AC>TT', 'Var', (138, 143))	('TA', 'Chemical', '-', (148, 150))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('AC', 'Chemical', 'MESH:D000186', (138, 140))	('TC', 'Chemical', 'MESH:D013667', (159, 161))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('CT>TA', 'Var', (145, 150))
34534	33207206	Among melanoma driver genes, however, AC>TT is the most common tandem mutation (Figure 6B).	('AC', 'Chemical', 'MESH:D000186', (38, 40))	('AC>TT', 'Var', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
34536	33207206	For example, UV signature CC>TT mutations are 90-fold more abundant in cutaneous relative to acral melanoma.	('acral melanoma', 'Phenotype', 'HP:0012060', (93, 107))	('acral melanoma', 'Disease', (93, 107))	('cutaneous', 'Disease', (71, 80))	('mutations', 'Var', (32, 41))	('acral melanoma', 'Disease', 'MESH:D008545', (93, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))
34537	33207206	Similar or even higher levels of enrichment were observed for AC>TT and CT>TA tandem substitutions (Figure 6C).	('AC>TT', 'Var', (62, 67))	('AC', 'Chemical', 'MESH:D000186', (62, 64))	('TA', 'Chemical', '-', (75, 77))	('CT>TA', 'Var', (72, 77))
34541	33207206	Oncogenic BRAF and NRAS mutations are the most common melanoma driver mutations, yet these mutations typically do not match the UV signature.	('NRAS', 'Gene', (19, 23))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('NRAS', 'Gene', '4893', (19, 23))	('melanoma', 'Disease', (54, 62))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('mutations', 'Var', (24, 33))
34542	33207206	We wondered whether the non-canonical UV-induced mutations identified in this study could explain the occurrence of some BRAF and NRAS mutations, thereby providing a functional link between UV exposure and melanomagenesis.	('BRAF', 'Gene', (121, 125))	('mutations', 'Var', (135, 144))	('NRAS', 'Gene', '4893', (130, 134))	('NRAS', 'Gene', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('BRAF', 'Gene', '673', (121, 125))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
34544	33207206	Because skin cancers are the predominant cancer type whose etiology is associated with exposure to UV irradiation, mutations for which UV-induced damage was a key underlying cause would be expected to be highly enriched within skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (8, 19))	('cancer', 'Disease', (232, 238))	('skin cancer', 'Phenotype', 'HP:0008069', (227, 238))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', (41, 47))	('skin cancers', 'Disease', (8, 20))	('associated', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('skin cancers', 'Disease', 'MESH:D012878', (8, 20))	('skin cancer', 'Disease', 'MESH:D012878', (227, 238))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (13, 19))	('skin cancer', 'Phenotype', 'HP:0008069', (8, 19))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (115, 124))	('skin cancer', 'Disease', (227, 238))	('skin cancers', 'Phenotype', 'HP:0008069', (8, 20))
34545	33207206	As expected, the BRAF mutations within our dataset primarily cluster at the known oncogenic V600 position (Figure 7A).	('V600', 'Var', (92, 96))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('cluster', 'Reg', (61, 68))
34546	33207206	Of the BRAF V600 variants, the minor variant V600M is the only UV signature mutation (i.e., C>T substitution in a Dipyr context).	('V600M', 'Mutation', 'rs121913378', (45, 50))	('V600M', 'Var', (45, 50))	('BRAF', 'Gene', '673', (7, 11))	('C>T substitution', 'Var', (92, 108))	('BRAF', 'Gene', (7, 11))	('Dipyr', 'Chemical', '-', (114, 119))
34547	33207206	V600M is 4.9-fold more likely to occur in skin cancers as opposed to non-skin cancers, consistent with its potential induction by UV exposure.	('skin cancers', 'Disease', 'MESH:D012878', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-skin cancers', 'Disease', 'MESH:D012878', (69, 85))	('V600M', 'Mutation', 'rs121913378', (0, 5))	('V600M', 'Var', (0, 5))	('skin cancer', 'Phenotype', 'HP:0008069', (42, 53))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('skin cancer', 'Phenotype', 'HP:0008069', (73, 84))	('skin cancers', 'Phenotype', 'HP:0008069', (42, 54))	('skin cancers', 'Disease', (42, 54))	('skin cancers', 'Phenotype', 'HP:0008069', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('skin cancers', 'Disease', 'MESH:D012878', (42, 54))	('occur', 'Reg', (33, 38))	('non-skin cancers', 'Disease', (69, 85))
34548	33207206	Although the remaining BRAF V600 variants are non-UV signature mutations, many of these are highly enriched in skin cancers.	('BRAF', 'Gene', '673', (23, 27))	('skin cancers', 'Disease', 'MESH:D012878', (111, 123))	('BRAF', 'Gene', (23, 27))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('skin cancers', 'Disease', (111, 123))	('skin cancers', 'Phenotype', 'HP:0008069', (111, 123))	('variants', 'Var', (33, 41))
34550	33207206	The BRAF V600K mutation is the second most common BRAF variant in the analyzed dataset (occurring in 537 samples) and is an AC>TT (or GT>AA) tandem substitution.	('BRAF', 'Gene', (50, 54))	('V600K', 'Var', (9, 14))	('BRAF', 'Gene', (4, 8))	('V600K', 'Mutation', 'rs121913227', (9, 14))	('BRAF', 'Gene', '673', (4, 8))	('AC', 'Chemical', 'MESH:D000186', (124, 126))	('BRAF', 'Gene', '673', (50, 54))
34552	33207206	Our analysis of AC>CT and AC>TT mutations in yeast and human cells indicate that these driver mutations are likely induced by an atypical UV photoproduct occurring at the AC dinucleotide on the TS of the BRAF gene.	('AC', 'Chemical', 'MESH:D000186', (26, 28))	('BRAF', 'Gene', (204, 208))	('mutations', 'Var', (94, 103))	('AC', 'Chemical', 'MESH:D000186', (171, 173))	('human', 'Species', '9606', (55, 60))	('mutations', 'Var', (32, 41))	('AC dinucleotide', 'Chemical', '-', (171, 186))	('yeast', 'Species', '4932', (45, 50))	('AC', 'Chemical', 'MESH:D000186', (16, 18))	('BRAF', 'Gene', '673', (204, 208))
34553	33207206	Among non-V600 variants, the BRAF L597S, which is due to a non-UV signature CT>TC tandem substitution, is also highly enriched in skin cancers.	('BRAF', 'Gene', '673', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('CT>TC tandem', 'Var', (76, 88))	('BRAF', 'Gene', (29, 33))	('skin cancers', 'Phenotype', 'HP:0008069', (130, 142))	('skin cancers', 'Disease', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('skin cancers', 'Disease', 'MESH:D012878', (130, 142))	('TC', 'Chemical', 'MESH:D013667', (79, 81))	('L597S', 'Mutation', 'rs121913368', (34, 39))	('skin cancer', 'Phenotype', 'HP:0008069', (130, 141))
34554	33207206	Tandem oncogenic mutations in BRAF are also enriched in skin cancers relative to thyroid cancer, which also commonly involves oncogenic BRAF mutations (Table S1).	('skin cancers', 'Disease', 'MESH:D012878', (56, 68))	('skin cancers', 'Phenotype', 'HP:0008069', (56, 68))	('BRAF', 'Gene', '673', (136, 140))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('BRAF', 'Gene', (136, 140))	('thyroid cancer', 'Disease', (81, 95))	('BRAF', 'Gene', (30, 34))	('thyroid cancer', 'Disease', 'MESH:D013964', (81, 95))	('BRAF', 'Gene', '673', (30, 34))	('skin cancer', 'Phenotype', 'HP:0008069', (56, 67))	('thyroid cancer', 'Phenotype', 'HP:0002890', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('skin cancers', 'Disease', (56, 68))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
34555	33207206	Similarly to recurrent BRAF mutations, non-canonical C>T, C>A, T>A, and T>C mutations in NRAS are 2.6- to 38-fold enriched within skin cancers compared with non-skin cancers (Figure S7).	('NRAS', 'Gene', '4893', (89, 93))	('skin cancers', 'Disease', (130, 142))	('non-skin cancers', 'Disease', (157, 173))	('skin cancers', 'Disease', 'MESH:D012878', (130, 142))	('skin cancers', 'Disease', 'MESH:D012878', (161, 173))	('skin cancer', 'Phenotype', 'HP:0008069', (130, 141))	('T>C mutations', 'Var', (72, 85))	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('NRAS', 'Gene', (89, 93))	('T>A', 'Var', (63, 66))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('skin cancer', 'Phenotype', 'HP:0008069', (161, 172))	('non-skin cancers', 'Disease', 'MESH:D012878', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('skin cancers', 'Phenotype', 'HP:0008069', (130, 142))	('skin cancers', 'Phenotype', 'HP:0008069', (161, 173))	('C>A', 'Var', (58, 61))	('C>T', 'Var', (53, 56))
34556	33207206	NRAS Q61R and Q61L involve T>C and T>A substitutions, respectively, within a TTG context, which are consistent with experimentally derived UV-induced mutations we observed in yeast (Figure 2).	('T>C', 'Var', (27, 30))	('T>A', 'Var', (35, 38))	('NRAS', 'Gene', '4893', (0, 4))	('Q61R', 'Mutation', 'rs11554290', (5, 9))	('yeast', 'Species', '4932', (175, 180))	('NRAS', 'Gene', (0, 4))	('Q61L', 'Mutation', 'rs11554290', (14, 18))	('Q61L', 'Var', (14, 18))
34559	33207206	To test whether a single dose of either type of UV light can induce the tandem substitution required to cause oncogenic BRAF V600K mutations, we engineered a yeast strain to contain an inactive ura3 allele, in which the catalytic K93 residue of Ura3 is mutated to valine by an AA-to-GT change in the coding strand (Figure 7B).	('valine', 'Chemical', 'MESH:D014633', (264, 270))	('mutations', 'Var', (131, 140))	('BRAF', 'Gene', '673', (120, 124))	('V600K', 'Mutation', 'rs121913227', (125, 130))	('yeast', 'Species', '4932', (158, 163))	('Ura3', 'Gene', (245, 249))	('ura3', 'Gene', '856692', (194, 198))	('BRAF', 'Gene', (120, 124))	('Ura3', 'Gene', '856692', (245, 249))	('ura3', 'Gene', (194, 198))	('K93', 'Var', (230, 233))
34560	33207206	Reversion of this mutant Ura3 to an active form would therefore require a V93K mutation and mimic the mutational process required to generate a BRAF V600K mutation.	('V93K', 'Var', (74, 78))	('Ura3', 'Gene', '856692', (25, 29))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('V600K', 'Mutation', 'rs121913227', (149, 154))	('Ura3', 'Gene', (25, 29))	('V93K', 'Mutation', 'p.V93K', (74, 78))
34566	33207206	The BRAF V600E mutation is the most frequent driver mutation in melanoma.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('V600E', 'Var', (9, 14))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
34567	33207206	Despite this mutation primarily involving a T-to-A substitution in a GTG sequence context, the V600E mutation was 3.6-fold more frequent in skin cancers than in non-skin cancers (nearly as enriched as V600M), suggesting that some of these mutations may be induced by UV exposure in skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('skin cancers', 'Disease', 'MESH:D012878', (282, 294))	('skin cancer', 'Phenotype', 'HP:0008069', (140, 151))	('skin cancer', 'Phenotype', 'HP:0008069', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('non-skin cancers', 'Disease', 'MESH:D012878', (161, 177))	('V600E', 'Var', (95, 100))	('skin cancers', 'Phenotype', 'HP:0008069', (165, 177))	('skin cancer', 'Phenotype', 'HP:0008069', (282, 293))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('skin cancers', 'Phenotype', 'HP:0008069', (140, 152))	('GTG', 'Chemical', '-', (69, 72))	('non-skin cancers', 'Disease', (161, 177))	('V600M', 'Mutation', 'rs121913378', (201, 206))	('skin cancers', 'Phenotype', 'HP:0008069', (282, 294))	('skin cancers', 'Disease', 'MESH:D012878', (165, 177))	('skin cancers', 'Disease', (140, 152))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('skin cancers', 'Disease', 'MESH:D012878', (140, 152))	('skin cancers', 'Disease', (282, 294))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
34568	33207206	Analysis of sequenced cutaneous melanomas revealed that T>A substitutions in a GTG sequence context show significant transcriptional asymmetry in highly expressed genes (Figure 7C), with mutations being elevated on the TS.	('mutations', 'MPA', (187, 196))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('GTG', 'Chemical', '-', (79, 82))	('highly expressed genes', 'MPA', (146, 168))	('substitutions', 'Var', (60, 73))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (22, 41))	('transcriptional', 'MPA', (117, 132))	('cutaneous melanomas', 'Disease', (22, 41))
34569	33207206	This analysis suggests that at least a subset of these mutations may arise from a UV-induced photoproduct occurring in the CAC sequence on the opposite strand.	('AC', 'Chemical', 'MESH:D000186', (124, 126))	('arise from', 'Reg', (69, 79))	('mutations', 'Var', (55, 64))
34570	33207206	The BRAF V600E mutation is also occasionally caused by a CA>TT (i.e., TG>AA) tandem substitution, which, although infrequent, is highly enriched in skin cancers (~130-fold; Figure 7A).	('skin cancers', 'Disease', 'MESH:D012878', (148, 160))	('caused', 'Reg', (45, 51))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('skin cancer', 'Phenotype', 'HP:0008069', (148, 159))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('skin cancers', 'Phenotype', 'HP:0008069', (148, 160))	('skin cancers', 'Disease', (148, 160))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
34571	33207206	To test the hypothesis that the BRAF V600E mutation is UV inducible, we adapted a published mutation reporter, in which the yeast TRP5 gene is inactivated by an E50V mutation.	('TRP5', 'Gene', '852858', (130, 134))	('BRAF', 'Gene', '673', (32, 36))	('E50V', 'Var', (161, 165))	('inactivated', 'NegReg', (143, 154))	('BRAF', 'Gene', (32, 36))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('E50V', 'Mutation', 'p.E50V', (161, 165))	('V600E', 'Var', (37, 42))	('TRP5', 'Gene', (130, 134))	('yeast', 'Species', '4932', (124, 129))
34572	33207206	We measured the frequency in which the mutant trp5 gene in yeast is reverted to an active form (i.e., TRP+) by a V50E substitution.	('V50E', 'Mutation', 'p.V50E', (113, 117))	('trp5', 'Gene', (46, 50))	('yeast', 'Species', '4932', (59, 64))	('TRP', 'Chemical', 'MESH:D014364', (102, 105))	('trp5', 'Gene', '852858', (46, 50))	('V50E substitution', 'Var', (113, 130))
34573	33207206	This reversion would require a T>A substitution in a GTG context, thereby modeling the BRAF V600E substitution (Figure 7D).	('GTG', 'Chemical', '-', (53, 56))	('V600E', 'Mutation', 'rs113488022', (92, 97))	('V600E', 'Var', (92, 97))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
34576	33207206	Sequencing of the UV-induced TRP+ colonies revealed a mix of T>A (80%, 39 out of 49 TRP+ colonies, for UVC; 89%, 41 out of 46 TRP+ colonies, for UVB) and TG>AA (i.e., CA>TT on TS; 20%, 10 out of 49 TRP+ colonies, for UVC; 11%, 5 out of 46 TRP+ colonies, for UVB) substitutions, indicating that UV light can induce both types of BRAF V600E mutations.	('BRAF', 'Gene', '673', (328, 332))	('TRP', 'Chemical', 'MESH:D014364', (239, 242))	('TRP', 'Chemical', 'MESH:D014364', (198, 201))	('TRP', 'Chemical', 'MESH:D014364', (84, 87))	('substitutions', 'Var', (263, 276))	('BRAF', 'Gene', (328, 332))	('TRP', 'Chemical', 'MESH:D014364', (29, 32))	('V600E', 'Mutation', 'rs113488022', (333, 338))	('TRP', 'Chemical', 'MESH:D014364', (126, 129))
34577	33207206	The three TRP+ colonies isolated following no UV irradiation (0 J/m2 UVC) were all T>A substitutions.	('T>A', 'Var', (83, 86))	('TRP', 'Chemical', 'MESH:D014364', (10, 13))	('TRP+', 'Gene', (10, 14))
34581	33207206	Surprisingly, non-canonical mutation signatures detected in UV-irradiated yeast provide a potential mechanism for some of the most frequent oncogenic mutations in melanoma (Table S2).	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('mutations', 'Var', (150, 159))	('yeast', 'Species', '4932', (74, 79))
34583	33207206	In contrast with the results reported here, prior studies of UV mutagenesis in mammalian cells have concluded that short- or medium-wavelength UV light (i.e., UVC and UVB) specifically induce C>T and CC>TT substitutions.	('mammalian', 'Species', '9606', (79, 88))	('C>T', 'Var', (192, 195))	('substitutions', 'Var', (206, 219))	('mutagenesis', 'biological_process', 'GO:0006280', ('64', '75'))	('induce', 'PosReg', (185, 191))
34585	33207206	Similarly, non-UV signature mutations are abundant in skin cancers, but these mutation classes have been overshadowed by the predominance of UV signature mutations in these tumors.	('skin cancers', 'Phenotype', 'HP:0008069', (54, 66))	('skin cancers', 'Disease', (54, 66))	('skin cancers', 'Disease', 'MESH:D012878', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('non-UV', 'Var', (11, 17))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('skin cancer', 'Phenotype', 'HP:0008069', (54, 65))
34594	33207206	However, many of the T>C mutations in human cells are associated with NTT sequences (i.e., the 5' position of a Dipyr sequence is mutated, not the 3' position), and therefore may represent a distinct mutational signature, possibly because of differences in lesion bypass by translesion DNA polymerases.	('mutations', 'Var', (25, 34))	('human', 'Species', '9606', (38, 43))	('Dipyr', 'Chemical', '-', (112, 117))	('DNA', 'cellular_component', 'GO:0005574', ('286', '289'))	('T>C', 'Gene', (21, 24))	('associated', 'Reg', (54, 64))	('NTT sequences', 'Disease', (70, 83))
34597	33207206	This mutation class is highly relevant to melanoma, because these tandem substitutions are responsible for the oncogenic BRAF V600R and V600K mutations.	('melanoma', 'Disease', (42, 50))	('BRAF', 'Gene', (121, 125))	('responsible', 'Reg', (91, 102))	('V600R', 'Mutation', 'rs121913227', (126, 131))	('V600K', 'Var', (136, 141))	('BRAF', 'Gene', '673', (121, 125))	('V600R', 'Var', (126, 131))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('V600K', 'Mutation', 'rs121913227', (136, 141))
34598	33207206	Our analysis indicates that the BRAF V600R and V600K mutations occur almost exclusively in skin cancers, consistent with their UV origin.	('V600K', 'Mutation', 'rs121913227', (47, 52))	('BRAF', 'Gene', '673', (32, 36))	('V600R', 'Mutation', 'rs121913227', (37, 42))	('BRAF', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('skin cancers', 'Disease', 'MESH:D012878', (91, 103))	('V600K', 'Var', (47, 52))	('V600R', 'Var', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('skin cancers', 'Phenotype', 'HP:0008069', (91, 103))	('skin cancers', 'Disease', (91, 103))	('skin cancer', 'Phenotype', 'HP:0008069', (91, 102))
34600	33207206	It has been previously suggested that these tandem BRAF mutations arise from mutagenic bypass of canonical UV lesions occurring at neighboring/overlapping Dipyr.	('BRAF', 'Gene', (51, 55))	('mutations', 'Var', (56, 65))	('Dipyr', 'Chemical', '-', (155, 160))	('BRAF', 'Gene', '673', (51, 55))
34602	33207206	Moreover, AC>TT mutations occur frequently in sequence contexts that lack any neighboring Dipyr sequences.	('AC', 'Chemical', 'MESH:D000186', (10, 12))	('Dipyr', 'Chemical', '-', (90, 95))	('mutations', 'Var', (16, 25))	('AC>', 'Gene', (10, 13))
34605	33207206	For example, multiple lines of evidence indicate that UV-induced A>T substitutions in yeast are primarily due to non-canonical TA photoproducts.	('TA', 'Chemical', '-', (127, 129))	('A>T substitutions', 'Var', (65, 82))	('substitutions', 'Var', (69, 82))	('yeast', 'Species', '4932', (86, 91))
34606	33207206	Perhaps the most convincing line of evidence is that UV-induced A>T mutations in TA sequences have significant strand asymmetry in transcribed genes, both in yeast and human cells, which is modulated by the NER pathway.	('human', 'Species', '9606', (168, 173))	('yeast', 'Species', '4932', (158, 163))	('transcribed genes', 'MPA', (131, 148))	('NER', 'biological_process', 'GO:0006289', ('207', '210'))	('A>T mutations', 'Var', (64, 77))	('TA sequences', 'Gene', (81, 93))	('strand asymmetry', 'MPA', (111, 127))	('TA', 'Chemical', '-', (81, 83))
34607	33207206	This analysis highlights the power of transcriptional asymmetry to elucidate novel mutational processes or mutagenic lesions, particularly when applied to mutation data from repair-deficient cells (e.g., rad16Delta or XPC-/-) or high- versus low-expressed genes.	('XPC', 'Gene', (218, 221))	('XPC', 'Gene', '7508', (218, 221))	('rad', 'biological_process', 'GO:1990116', ('204', '207'))	('rad16Delta', 'Var', (204, 214))
34609	33207206	Our data indicate that TA photoproducts are highly mutagenic in vivo due to misinsertion of an adenine nucleotide opposite the 3' adenine base in the TA photoproduct.	('misinsertion', 'Var', (76, 88))	('adenine nucleotide', 'Chemical', 'MESH:D000227', (95, 113))	('adenine nucleotide', 'MPA', (95, 113))	('mutagenic', 'MPA', (51, 60))	('adenine', 'Chemical', 'MESH:D000225', (130, 137))	('adenine', 'Chemical', 'MESH:D000225', (95, 102))	('TA', 'Chemical', '-', (150, 152))	('TA', 'Chemical', '-', (23, 25))
34612	33207206	This is the most frequent driver mutation in melanoma, yet it is not thought to originate from UV damage because of its non-canonical substitution pattern and non-Dipyr sequence context.	('mutation', 'Var', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('Dipyr', 'Chemical', '-', (163, 168))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
34613	33207206	Using a yeast reversion reporter, we show that T>A mutations in a GTG context are UV inducible.	('yeast', 'Species', '4932', (8, 13))	('mutations', 'Var', (51, 60))	('GTG', 'Chemical', '-', (66, 69))	('T>A', 'Gene', (47, 50))
34615	33207206	One possibility is that the putative photoproduct at AC dinucleotides may cause not only AC>TT mutations, but also single A>T substitutions.	('single A>T substitutions', 'Var', (115, 139))	('AC', 'Chemical', 'MESH:D000186', (89, 91))	('cause', 'Reg', (74, 79))	('AC dinucleotides', 'Chemical', '-', (53, 69))	('AC>', 'Disease', (89, 92))	('AC', 'Chemical', 'MESH:D000186', (53, 55))
34617	33207206	Consistent with this hypothesis, a significant fraction of the UV-induced TRP+ revertants in our yeast assay were CA>TT tandem substitutions, a mutation class that causes the complex BRAF V600E variant in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('TRP', 'Chemical', 'MESH:D014364', (74, 77))	('melanoma', 'Disease', (205, 213))	('BRAF', 'Gene', '673', (183, 187))	('V600E', 'Mutation', 'rs113488022', (188, 193))	('CA>TT tandem substitutions', 'Var', (114, 140))	('yeast', 'Species', '4932', (97, 102))	('BRAF', 'Gene', (183, 187))
34618	33207206	The yeast reversion assays described in this study could be used to investigate whether other mutagens cause these recurrent BRAF mutations, essentially as a type of Ames test for the causes of oncogenic mutations found in melanoma and other cancers.	('melanoma', 'Disease', (223, 231))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('cancers', 'Disease', (242, 249))	('yeast', 'Species', '4932', (4, 9))	('mutations', 'Var', (130, 139))	('BRAF', 'Gene', '673', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('BRAF', 'Gene', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
34621	33207206	Our model suggests that the high UV dose associated with severe sunburn may be required to generate the rare atypical photoproducts needed to induce the BRAF (or NRAS) driver mutations important for melanomagenesis.	('BRAF', 'Gene', (153, 157))	('NRAS', 'Gene', '4893', (162, 166))	('severe sunburn', 'Phenotype', 'HP:0007537', (57, 71))	('melanoma', 'Disease', (199, 207))	('mutations', 'Var', (175, 184))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('NRAS', 'Gene', (162, 166))	('BRAF', 'Gene', '673', (153, 157))
34632	33207206	Yeast stains utilized in this study were constructed in either the BY4741, BY4742 or ySR128 genetic backgrounds.	('ySR128', 'Chemical', '-', (85, 91))	('BY4741', 'Chemical', '-', (67, 73))	('BY4742', 'Chemical', '-', (75, 81))	('Yeast', 'Species', '4932', (0, 5))	('BY4742', 'Var', (75, 81))	('BY4741', 'Var', (67, 73))
34638	33207206	The wild-type BY4743 is a product of mating BY4741 and BY4742.	('BY4742', 'Var', (55, 61))	('BY4741', 'Var', (44, 50))	('mating', 'biological_process', 'GO:1990277', ('37', '43'))	('BY4743', 'Var', (14, 20))	('BY4741', 'Chemical', '-', (44, 50))	('mating', 'biological_process', 'GO:0007618', ('37', '43'))	('mating', 'biological_process', 'GO:0000747', ('37', '43'))	('BY4742', 'Chemical', '-', (55, 61))
34639	33207206	The rad26Delta diploid strain was created by mating rad26Delta yeast in the BY4741 and BY4742 backgrounds (made by TRP1 and LEU2 insertion, respectively) with each other and confirming by selection on plates and PCR analysis.	('BY4742', 'Chemical', '-', (87, 93))	('mating', 'biological_process', 'GO:1990277', ('45', '51'))	('BY4742', 'Var', (87, 93))	('BY4741', 'Chemical', '-', (76, 82))	('rad', 'biological_process', 'GO:1990116', ('52', '55'))	('LEU2', 'Gene', (124, 128))	('TRP1', 'Gene', (115, 119))	('mating', 'biological_process', 'GO:0000747', ('45', '51'))	('mating', 'biological_process', 'GO:0007618', ('45', '51'))	('BY4741', 'Var', (76, 82))	('yeast', 'Species', '4932', (63, 68))	('LEU2', 'Gene', '850342', (124, 128))	('TRP1', 'Gene', '851570', (115, 119))	('rad26Delta', 'Var', (52, 62))	('TRP1', 'molecular_function', 'GO:0004167', ('115', '119'))	('rad', 'biological_process', 'GO:1990116', ('4', '7'))
34640	33207206	The rad16Delta diploid strain was created by mating knockout strains (again, using TRP1 and LEU2 selection) created in BY4741 and BY4742 backgrounds and confirming by selection on plates and PCR analysis.	('TRP1', 'Gene', (83, 87))	('mating', 'biological_process', 'GO:1990277', ('45', '51'))	('LEU2', 'Gene', '850342', (92, 96))	('TRP1', 'molecular_function', 'GO:0004167', ('83', '87'))	('BY4741', 'Var', (119, 125))	('BY4742', 'Chemical', '-', (130, 136))	('BY4742', 'Var', (130, 136))	('TRP1', 'Gene', '851570', (83, 87))	('mating', 'biological_process', 'GO:0000747', ('45', '51'))	('mating', 'biological_process', 'GO:0007618', ('45', '51'))	('LEU2', 'Gene', (92, 96))	('BY4741', 'Chemical', '-', (119, 125))	('rad', 'biological_process', 'GO:1990116', ('4', '7'))
34641	33207206	ura3 reversion strains were constructed in the yeast strain ySR128, which contains ADE2, URA3, and CAN1 deleted from their normal chromosomal positions and re-inserted as an array into the LYS2 gene on chromosome 2.	('ura3', 'Gene', '856692', (0, 4))	('ADE2', 'Gene', '854295', (83, 87))	('ySR128', 'Chemical', '-', (60, 66))	('ADE2', 'molecular_function', 'GO:0004638', ('83', '87'))	('CAN1', 'Gene', '856646', (99, 103))	('yeast', 'Species', '4932', (47, 52))	('LYS2', 'Gene', (189, 193))	('ADE2', 'Gene', (83, 87))	('ura3', 'Gene', (0, 4))	('deleted', 'Var', (104, 111))	('LYS2', 'Gene', '852412', (189, 193))	('CAN1', 'Gene', (99, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('202', '212'))	('URA3', 'Gene', '856692', (89, 93))	('URA3', 'Gene', (89, 93))
34644	33207206	Strains containing only the intended AA to GT tandem substitution and a second benign substitution were subsequently diploidized by transformation of the yeast with the YEpHO plasmid that results in expression of the HO endonuclease.	('tandem substitution', 'Var', (46, 65))	('yeast', 'Species', '4932', (154, 159))	('results in', 'Reg', (188, 198))	('expression', 'MPA', (199, 209))
34647	33207206	A trp5 E50V point mutant was generated in BY4741 using Cas9 genome editing.	('trp5', 'Gene', '852858', (2, 6))	('Cas', 'cellular_component', 'GO:0005650', ('55', '58'))	('trp5', 'Gene', (2, 6))	('E50V', 'Mutation', 'p.E50V', (7, 11))	('E50V point', 'Var', (7, 17))	('BY4741', 'Chemical', '-', (42, 48))
34649	33207206	The resulting plasmid was then transformed into BY4741 along with pJH001 and a template oligonucleotide OHSM001 (CTATTCTCAAGGGTTTCCAGGATGGTGGTGTAGATATCATCGTGTTAGGTATGCCCTTCTCTGATCCAATTGCAGATGGTCCTACAATTC), which, upon recombination resulted in a GAA>GTG mutation in addition to inactivation of the downstream PAM sequence.	('GTG', 'Chemical', '-', (137, 140))	('TC', 'Chemical', 'MESH:D013667', (119, 121))	('TC', 'Chemical', 'MESH:D013667', (117, 119))	('GAA>GTG mutation', 'Var', (246, 262))	('TC', 'Chemical', 'MESH:D013667', (149, 151))	('TA', 'Chemical', '-', (147, 149))	('TA', 'Chemical', '-', (114, 116))	('TA', 'Chemical', '-', (162, 164))	('TC', 'Chemical', 'MESH:D013667', (172, 174))	('oligonucleotide', 'Chemical', 'MESH:D009841', (88, 103))	('BY4741', 'Chemical', '-', (48, 54))	('resulted in', 'Reg', (232, 243))	('mutation', 'Var', (254, 262))	('GTG', 'Chemical', '-', (250, 253))	('TC', 'Chemical', 'MESH:D013667', (177, 179))	('GTG', 'Chemical', '-', (154, 157))	('TC', 'Chemical', 'MESH:D013667', (170, 172))	('TC', 'Chemical', 'MESH:D013667', (201, 203))	('TA', 'Chemical', '-', (158, 160))	('TA', 'Chemical', '-', (143, 145))	('AC', 'Chemical', 'MESH:D000186', (196, 198))	('GTG', 'Chemical', '-', (140, 143))	('TC', 'Chemical', 'MESH:D013667', (192, 194))	('TC', 'Chemical', 'MESH:D013667', (128, 130))	('TA', 'Chemical', '-', (195, 197))	('TC', 'Chemical', 'MESH:D013667', (152, 154))
34650	33207206	The trp5 E50V mutant was confirmed by DNA sequencing.	('E50V', 'Mutation', 'p.E50V', (9, 13))	('trp5', 'Gene', '852858', (4, 8))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('E50V', 'Var', (9, 13))	('trp5', 'Gene', (4, 8))
34654	33207206	Plates were exposed to 12.5 J/m2 (rad16Delta) or 25 J/m2 (wild-type and rad26Delta) of UVC radiation and then incubated in the dark for about 2 to 3 days at 30thC.	('rad16Delta', 'Var', (34, 44))	('thC', 'Chemical', 'MESH:D013759', (159, 162))	('rad', 'biological_process', 'GO:1990116', ('34', '37'))	('rad26Delta', 'Var', (72, 82))	('rad', 'biological_process', 'GO:1990116', ('72', '75'))
34656	33207206	To assess the survival of rad16Delta, rad26Delta, and wild-type (BY4741) haploid strains, cultures were grown to mid to late log phase in YPD medium and OD600 readings were obtained to determine approximate cell density.	('rad', 'biological_process', 'GO:1990116', ('26', '29'))	('BY4741', 'Chemical', '-', (65, 71))	('rad26Delta', 'Var', (38, 48))	('rad', 'biological_process', 'GO:1990116', ('38', '41'))	('YPD medium', 'Chemical', '-', (138, 148))	('rad16Delta', 'Var', (26, 36))
34665	33207206	Single nucleotide substitutions were classified according to the pyrimidine-containing DNA strand (i.e., C or T).	('pyrimidine', 'Chemical', 'MESH:C030986', (65, 75))	('pyrimidine-containing', 'Var', (65, 86))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('Single nucleotide substitutions', 'Var', (0, 31))
34668	33207206	Genes overlapping with repetitive rDNA (i.e., YLR154C-G, YLR155C, YLR161W, YLR162W-A) and CUP1 (i.e., YHR053C, YHR054C, YHR055C) loci were also excluded.	('CUP1', 'Gene', '856450', (90, 94))	('YHR054C', 'Var', (111, 118))	('YLR154C-G', 'Var', (46, 55))	('YLR162W-A', 'Var', (75, 84))	('YLR161W', 'Gene', '850858', (66, 73))	('YLR155C', 'Var', (57, 64))	('YHR055C', 'Var', (120, 127))	('YLR161W', 'Gene', (66, 73))	('CUP1', 'Gene', (90, 94))
34670	33207206	To estimate the abundance of UV-induced mutations occurring on a genomic scale, CAN1 mutation assays were performed on rad16Delta, rad26Delta, and wild-type (WT) haploid strains.	('CAN1', 'Gene', (80, 84))	('rad16Delta', 'Var', (119, 129))	('rad', 'biological_process', 'GO:1990116', ('131', '134'))	('mutations', 'Var', (40, 49))	('CAN1', 'Gene', '856646', (80, 84))	('rad26Delta', 'Var', (131, 141))	('rad', 'biological_process', 'GO:1990116', ('119', '122'))
34676	33207206	To assess whether UV light could revert the ura3 K93V mutant, yeast cultures were grown in YPD until mid to late log phase and harvested via centrifugation.	('K93V', 'Mutation', 'p.K93V', (49, 53))	('K93V', 'Var', (49, 53))	('yeast', 'Species', '4932', (62, 67))	('ura3', 'Gene', '856692', (44, 48))	('ura3', 'Gene', (44, 48))
34680	33207206	URA+ reversion mutations were confirmed by sequencing the URA3 gene and PCR amplifying a DNA fragment between the ADE2 and URA3 genes to ensure URA+ isolates were derived from the originating yeast strain and contained the expected GT to AA substitution.	('URA3', 'Gene', '856692', (58, 62))	('ADE2', 'molecular_function', 'GO:0004638', ('114', '118'))	('URA3', 'Gene', (58, 62))	('URA', 'Chemical', '-', (123, 126))	('ADE2', 'Gene', '854295', (114, 118))	('mutations', 'Var', (15, 24))	('yeast', 'Species', '4932', (192, 197))	('URA', 'Chemical', '-', (144, 147))	('URA', 'Chemical', '-', (58, 61))	('URA', 'Chemical', '-', (0, 3))	('ADE2', 'Gene', (114, 118))	('URA3', 'Gene', '856692', (123, 127))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('URA3', 'Gene', (123, 127))
34681	33207206	To test the reversion frequency of the trp5 E50V mutant upon irradiation with UV light, cultures were grown in YPD medium until mid or late log phase and harvested via centrifugation.	('trp5', 'Gene', '852858', (39, 43))	('E50V', 'Mutation', 'p.E50V', (44, 48))	('trp5', 'Gene', (39, 43))	('YPD medium', 'Chemical', '-', (111, 121))	('E50V', 'Var', (44, 48))
34724	33207206	DNA fragments were then end-repaired (NEB, E6050L) and dA-tailed (NEB, E6053L), and a double stranded trP1 adaptor was ligated to both ends of the fragments via a quick ligase module (NEB, E6056L).	('trP1', 'molecular_function', 'GO:0004167', ('102', '106'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('E6053L', 'Var', (71, 77))	('E6053L', 'SUBSTITUTION', 'None', (71, 77))	('E6050L', 'Var', (43, 49))	('E6056L', 'SUBSTITUTION', 'None', (189, 195))	('E6056L', 'Var', (189, 195))	('trP1', 'Gene', (102, 106))	('trP1', 'Gene', '851570', (102, 106))	('E6050L', 'SUBSTITUTION', 'None', (43, 49))
34726	33207206	Following confirmation, free 3'-OH groups were blocked with Terminal Transferase (NEB, M0315L) either dideoxyATP or dideoxyGTP (Roche Diagnostics, 03732738001).	('dideoxyGTP', 'Chemical', 'MESH:C031709', (116, 126))	('M0315L', 'Mutation', 'p.M0315L', (87, 93))	('dideoxyGTP', 'Var', (116, 126))	('dideoxyATP', 'Chemical', '-', (102, 112))	('dideoxyATP', 'Var', (102, 112))
34741	33207206	Analysis of mutations in the coding exons of driver genes used driver genes identified in two recent papers, namely ARID2, BRAF, CDK4, CDKN2A, DDX3X, GNAQ, HRAS, KIT, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PPP6C, PTEN, RAC1, RASA2, RB1, SF3B1, SNX31, STK19, TACC1, and TP53.	('CDKN2A', 'Gene', (135, 141))	('MAP2K', 'molecular_function', 'GO:0004708', ('181', '186'))	('AC', 'Chemical', 'MESH:D000186', (253, 255))	('NRAS', 'Gene', (194, 198))	('STK19', 'molecular_function', 'GO:0004686', ('245', '250'))	('STK19', 'Gene', (245, 250))	('mutations', 'Var', (12, 21))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('SNX31', 'Gene', (238, 243))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('NRAS', 'Gene', '4893', (194, 198))	('AC', 'Chemical', 'MESH:D000186', (214, 216))	('TA', 'Chemical', '-', (252, 254))	('MAP2K', 'molecular_function', 'GO:0004708', ('173', '178'))
34745	33207206	For each mutation occurring at least 10 times in the dataset an odds-ratio for its representation among human skin cancers was calculated as the ratio of skin cancer samples containing the mutation to skin cancers without the mutation divided by the ratio of non-skin cancers that contain the mutation to non-skin cancers without the mutation.	('skin cancers', 'Phenotype', 'HP:0008069', (263, 275))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('skin cancer', 'Disease', (154, 165))	('skin cancers', 'Disease', 'MESH:D012878', (201, 213))	('skin cancer', 'Disease', 'MESH:D012878', (263, 274))	('skin cancers', 'Phenotype', 'HP:0008069', (309, 321))	('skin cancers', 'Phenotype', 'HP:0008069', (110, 122))	('non-skin cancers', 'Disease', 'MESH:D012878', (305, 321))	('skin cancer', 'Disease', 'MESH:D012878', (110, 121))	('skin cancer', 'Disease', 'MESH:D012878', (309, 320))	('skin cancer', 'Phenotype', 'HP:0008069', (154, 165))	('non-skin cancers', 'Disease', (259, 275))	('skin cancers', 'Disease', 'MESH:D012878', (263, 275))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('human', 'Species', '9606', (104, 109))	('skin cancer', 'Phenotype', 'HP:0008069', (201, 212))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('skin cancers', 'Disease', (110, 122))	('skin cancers', 'Disease', 'MESH:D012878', (309, 321))	('skin cancers', 'Disease', 'MESH:D012878', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('skin cancer', 'Disease', 'MESH:D012878', (154, 165))	('non-skin cancers', 'Disease', (305, 321))	('skin cancers', 'Phenotype', 'HP:0008069', (201, 213))	('skin cancer', 'Phenotype', 'HP:0008069', (263, 274))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('skin cancer', 'Disease', 'MESH:D012878', (201, 212))	('skin cancer', 'Phenotype', 'HP:0008069', (309, 320))	('non-skin cancers', 'Disease', 'MESH:D012878', (259, 275))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('skin cancer', 'Phenotype', 'HP:0008069', (110, 121))	('mutation', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('skin cancers', 'Disease', (201, 213))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
34746	33207206	Similarly, the incidence of specific BRAF mutations in skin and thyroid cancers were compared by calculating odds-ratios for mutations occurring at least 10 times in either of these two cancer types.	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('thyroid cancers', 'Disease', 'MESH:D013964', (64, 79))	('BRAF', 'Gene', '673', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BRAF', 'Gene', (37, 41))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('thyroid cancers', 'Disease', (64, 79))	('thyroid cancer', 'Phenotype', 'HP:0002890', (64, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('skin', 'Disease', (55, 59))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', (72, 78))
34747	33207206	Odds-ratios were calculated as the ratio of the number of skin cancer samples with a mutation to the number of skin cancers without the mutation divided by the ratio of number of thyroid cancers with a mutation to thyroid cancers without the mutation.	('skin cancer', 'Disease', (58, 69))	('thyroid cancer', 'Phenotype', 'HP:0002890', (214, 228))	('mutation', 'Var', (85, 93))	('thyroid cancers', 'Disease', (214, 229))	('skin cancers', 'Phenotype', 'HP:0008069', (111, 123))	('skin cancer', 'Disease', 'MESH:D012878', (111, 122))	('skin cancer', 'Phenotype', 'HP:0008069', (58, 69))	('thyroid cancers', 'Disease', 'MESH:D013964', (179, 194))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('skin cancers', 'Disease', (111, 123))	('thyroid cancer', 'Phenotype', 'HP:0002890', (179, 193))	('skin cancers', 'Disease', 'MESH:D012878', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('skin cancer', 'Disease', 'MESH:D012878', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('thyroid cancers', 'Disease', 'MESH:D013964', (214, 229))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('thyroid cancers', 'Disease', (179, 194))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
34773	28879661	Cases of melanoma were identified by specifying site "melanoma of the skin," which included cases with International Classification of Diseases for Oncology, Third Edition (ICD-0-3) codes 8720-8723, 8726-8727, 8730, 8740-8746, 8760-8761, 8770-8773, 8780, and 8790.	('8770-8773', 'Var', (238, 247))	('8726-8727', 'Var', (199, 208))	('8760-8761', 'Var', (227, 236))	('8730', 'Var', (210, 214))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('8720-8723', 'Var', (188, 197))	('melanoma of the skin', 'Disease', (54, 74))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('8790', 'Var', (259, 263))	('8780', 'Var', (249, 253))	('melanoma of the skin', 'Disease', 'MESH:D008545', (54, 74))	('8740-8746', 'Var', (216, 225))	('Oncology', 'Phenotype', 'HP:0002664', (148, 156))
34779	28879661	Anatomic sites were classified as face/ear (C440-C443), scalp and neck (C444), trunk (C445), extremities (C446-C447), and not otherwise specified/overlapping codes (C448-C449).	('neck', 'cellular_component', 'GO:0044326', ('66', '70'))	('C446-C447', 'Var', (106, 115))	('trunk', 'cellular_component', 'GO:0043198', ('79', '84'))	('C445', 'Var', (86, 90))	('C448-C449', 'Var', (165, 174))	('C444', 'Var', (72, 76))	('C440-C443', 'Var', (44, 53))	('scalp', 'Disease', 'MESH:C538225', (56, 61))	('scalp', 'Disease', (56, 61))
34905	22922842	Flow cytometry was used to confirm the populations as CD133+ or CD133- using the monospecific mouse mAb CD133/2 (Miltenyi Biotech).	('CD133-', 'Var', (64, 70))	('CD133/2', 'Gene', (104, 111))	('mouse', 'Species', '10090', (94, 99))	('CD133/2', 'Gene', '19126;12481', (104, 111))
34913	22922842	1, CD133 and CD166 specific mAb stained the membrane as well as the cytoplasm to a lesser degree, while Nestin and ABCB5 mAbs predominantly stained cytoplasm of MSCs.	('Nestin', 'Gene', (104, 110))	('cytoplasm', 'cellular_component', 'GO:0005737', ('148', '157'))	('ABCB5', 'Gene', (115, 120))	('MSCs', 'molecular_function', 'GO:0043854', ('161', '165'))	('CD166', 'Gene', (13, 18))	('ABCB5', 'Gene', '340273', (115, 120))	('CD133', 'Var', (3, 8))	('cytoplasm', 'cellular_component', 'GO:0005737', ('68', '77'))	('Nestin', 'Gene', '10763', (104, 110))	('CD166', 'Gene', '214', (13, 18))	('membrane', 'cellular_component', 'GO:0016020', ('44', '52'))
34968	31142788	In addition, mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) encoding two tumour suppressor proteins, p16 and p14, as well as genes involved in the DNA repair mechanism or the melanocortin-1 receptor (MC1R) play an important role in the onset of melanoma.	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('43', '59'))	('DNA repair', 'biological_process', 'GO:0006281', ('159', '169'))	('tumour', 'Disease', (85, 91))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (26, 62))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('p16', 'Gene', (113, 116))	('MC1R', 'Gene', '4157', (212, 216))	('MC1R', 'Gene', (212, 216))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (26, 62))	('p16', 'Gene', '1029', (113, 116))	('p14', 'Gene', '1029', (121, 124))	('CDKN2A', 'Gene', (64, 70))	('p14', 'Gene', (121, 124))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('mutations', 'Var', (13, 22))	('melanoma', 'Disease', (257, 265))	('CDKN2A', 'Gene', '1029', (64, 70))	('melanocortin-1 receptor', 'Gene', (187, 210))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('26', '59'))	('melanocortin-1 receptor', 'Gene', '4157', (187, 210))
35001	31142788	fatty acid synthase (FASN), chloride intracellular channel protein-4 (CLIC4), heat shock protein beta-1 (HSPB1), Rho guanine nucleotide exchange factor 1 (ARHGEF1), D-3-phosphoglycerate dehydrogenase (PHGDH), myosin-1c (MYO1C), and caveolin-1 (CAV1) for missense, truncating and in-frame mutations, amplification and deletions, mRNA up- and downregulation and protein up- and down regulation by reverse phase protein array (RPPA) assay.	('CAV1', 'Gene', '857', (244, 248))	('protein', 'Protein', (360, 367))	('FASN', 'Gene', (21, 25))	('up-', 'PosReg', (368, 371))	('CLIC4', 'Gene', '25932', (70, 75))	('mRNA', 'MPA', (328, 332))	('mutations', 'Var', (288, 297))	('intracellular', 'cellular_component', 'GO:0005622', ('37', '50'))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('heat shock protein beta-1', 'Gene', (78, 103))	('HSPB1', 'Gene', (105, 110))	('D-3-phosphoglycerate dehydrogenase', 'Gene', '26227', (165, 199))	('fatty acid synthase', 'Gene', (0, 19))	('down regulation', 'NegReg', (376, 391))	('heat shock protein beta-1', 'Gene', '3315', (78, 103))	('Rho guanine nucleotide exchange factor', 'molecular_function', 'GO:0005089', ('113', '151'))	('CAV1', 'Gene', (244, 248))	('myosin-1c', 'Gene', (209, 218))	('MYO1C', 'Gene', '4641', (220, 225))	('CLIC4', 'Gene', (70, 75))	('Rho guanine nucleotide exchange factor 1', 'Gene', '9138', (113, 153))	('D-3-phosphoglycerate dehydrogenase', 'Gene', (165, 199))	('HSPB1', 'Gene', '3315', (105, 110))	('Rho guanine nucleotide exchange factor 1', 'Gene', (113, 153))	('up-', 'PosReg', (333, 336))	('missense', 'Var', (254, 262))	('FASN', 'Gene', '2194', (21, 25))	('regulation', 'biological_process', 'GO:0065007', ('381', '391'))	('myosin-1c', 'Gene', '4641', (209, 218))	('caveolin-1', 'Gene', (232, 242))	('deletions', 'Var', (317, 326))	('MYO1C', 'Gene', (220, 225))	('ARHGEF1', 'Gene', (155, 162))	('chloride intracellular channel protein-4', 'Gene', '25932', (28, 68))	('caveolin-1', 'Gene', '857', (232, 242))	('fatty acid synthase', 'Gene', '2194', (0, 19))	('chloride intracellular channel protein-4', 'Gene', (28, 68))	('PHGDH', 'Gene', '26227', (201, 206))	('shock', 'Phenotype', 'HP:0031273', (83, 88))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))	('PHGDH', 'Gene', (201, 206))	('ARHGEF1', 'Gene', '9138', (155, 162))	('protein', 'cellular_component', 'GO:0003675', ('360', '367'))	('protein', 'cellular_component', 'GO:0003675', ('409', '416'))	('amplification', 'Var', (299, 312))	('downregulation', 'NegReg', (341, 355))
35002	31142788	For endoglin (CD105, Hs00923996_m1), platelet endothelial cell adhesion molecule (CD31, Hs1065279_m1), and VEGF-A (Hs00900055_m1) expression analysis, we used TaqMan  probes (Life Technologies LTD, CA, USA) and TaqMan  Universal Master Mix (Life Technologies LTD, CA, USA).	('cell adhesion', 'biological_process', 'GO:0007155', ('58', '71'))	('LTD', 'biological_process', 'GO:0060292', ('193', '196'))	('platelet endothelial cell adhesion', 'Phenotype', 'HP:0008352', (37, 71))	('LTD', 'biological_process', 'GO:0060292', ('259', '262'))	('VEGF-A', 'Gene', '7422', (107, 113))	('VEGF-A', 'Gene', (107, 113))	('CD31', 'Gene', (82, 86))	('endoglin', 'molecular_function', 'GO:0070123', ('4', '12'))	('CD31', 'Gene', '5175', (82, 86))	('Hs00900055_m1', 'Var', (115, 128))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('58', '80'))
35015	31142788	To reveal signalling pathways and interaction networks perturbed by inhibition of Runx2 DNA-binding function, we performed a bioinformatics analysis on the proteins whose expression significantly changed between A375 and 3G8 melanoma cells.	('expression', 'MPA', (171, 181))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('inhibition', 'Var', (68, 78))	('melanoma', 'Disease', (225, 233))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('signalling', 'biological_process', 'GO:0023052', ('10', '20'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('88', '99'))	('changed', 'Reg', (196, 203))	('Runx2', 'Gene', (82, 87))	('Runx2', 'Gene', '860', (82, 87))	('A375', 'CellLine', 'CVCL:0132', (212, 216))
35024	31142788	We observed that HUVEC co-cultured with 3G8 cells had a significant reduction in the capillary forming features with few connecting structures when compared with A375 cells (p < 0.05, Fig.	('capillary forming features', 'CPA', (85, 111))	('A375', 'CellLine', 'CVCL:0132', (162, 166))	('3G8', 'Var', (40, 43))	('reduction', 'NegReg', (68, 77))
35027	31142788	Using TCGA cohort survival data in univariate analysis, alterations in all these genes were not associated with reduced patient overall survival (Fig.	('reduced', 'NegReg', (112, 119))	('patient', 'Species', '9606', (120, 127))	('alterations', 'Var', (56, 67))
35028	31142788	6B), while there was significantly lower overall survival among melanoma patients with alterations of MYO1C gene (Logrank test p-value: 0.0019) (Fig.	('MYO1C', 'Gene', '4641', (102, 107))	('alterations', 'Var', (87, 98))	('MYO1C', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('lower', 'NegReg', (35, 40))	('patients', 'Species', '9606', (73, 81))
35029	31142788	Our previous study showed that Runt domain KO melanoma cells are characterized by reduced proliferation, epithelial-mesenchymal transition and metastasis, suggesting that the Runt domain of Runx2 may represent an oncotarget in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('Runt domain KO', 'Var', (31, 45))	('Runx2', 'Gene', '860', (190, 195))	('Runx2', 'Gene', (190, 195))	('reduced', 'NegReg', (82, 89))	('metastasis', 'CPA', (143, 153))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('105', '138'))	('epithelial-mesenchymal transition', 'CPA', (105, 138))
35030	31142788	In the present study, with the aim of deepening the understanding of Runt domain-dependent effects on melanoma cells biology, we carried out a proteomic analysis of A375 and del-Runt (3G8) melanoma whole-cell extracts to investigate the intracellular molecular mechanisms characterizing the deletion of the DNA-binding domain from RUNX2.	('DNA-binding', 'molecular_function', 'GO:0003677', ('307', '318'))	('A375', 'CellLine', 'CVCL:0132', (165, 169))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('deletion', 'Var', (291, 299))	('melanoma', 'Disease', (102, 110))	('RUNX2', 'Gene', (331, 336))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('intracellular', 'cellular_component', 'GO:0005622', ('237', '250'))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('DNA', 'cellular_component', 'GO:0005574', ('307', '310'))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
35031	31142788	One of the interesting observations was that the most significant deregulated pathways in cells with the deletion of Runt domain of Runx2 is the "Granzyme A signalling".	('deregulated', 'Reg', (66, 77))	('Granzyme A', 'Gene', '3001', (146, 156))	('deletion', 'Var', (105, 113))	('Runx2', 'Gene', '860', (132, 137))	('Runx2', 'Gene', (132, 137))	('Granzyme A', 'Gene', (146, 156))
35061	31142788	We also detected a reduced number of network-like structures, as well as reduced expression of CD105 and CD31 endothelial markers in HUVEC cells co-cultured with 3G8 as compared to that co-cultured with A375 melanoma cells (Fig.	('CD105', 'Gene', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('CD31', 'Gene', (105, 109))	('melanoma', 'Disease', (208, 216))	('reduced', 'NegReg', (73, 80))	('A375', 'CellLine', 'CVCL:0132', (203, 207))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('CD31', 'Gene', '5175', (105, 109))	('3G8', 'Var', (162, 165))	('reduced', 'NegReg', (19, 26))	('network-like structures', 'CPA', (37, 60))	('expression', 'MPA', (81, 91))
35065	31142788	Finally, we also found upregulation of Caveolin-1 (CAV1, +2.11 fold change) as a result of the deletion of the Runt domain of Runx-2 in 3G8 cells.	('Runx-2', 'Gene', (126, 132))	('deletion', 'Var', (95, 103))	('upregulation', 'PosReg', (23, 35))	('CAV1', 'Gene', (51, 55))	('Caveolin-1', 'Gene', '857', (39, 49))	('Runx-2', 'Gene', '860', (126, 132))	('Caveolin-1', 'Gene', (39, 49))	('CAV1', 'Gene', '857', (51, 55))
35068	31142788	The most common alteration found in patients for all these targets is the mRNA transcriptional upregulation of their encoding genes, hence the fact that the deletions of Runt domain leads to a downregulation at protein level for all of them (with the exception of CAV1 which is upregulated) seems particularly interesting in confirming the key role of Runx2 in the development of melanoma.	('downregulation', 'NegReg', (193, 207))	('mRNA transcriptional', 'MPA', (74, 94))	('deletions', 'Var', (157, 166))	('patients', 'Species', '9606', (36, 44))	('CAV1', 'Gene', '857', (264, 268))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('protein level', 'MPA', (211, 224))	('upregulation', 'PosReg', (95, 107))	('Runx2', 'Gene', (352, 357))	('Runt domain', 'Gene', (170, 181))	('melanoma', 'Disease', (380, 388))	('Runx2', 'Gene', '860', (352, 357))	('melanoma', 'Phenotype', 'HP:0002861', (380, 388))	('CAV1', 'Gene', (264, 268))	('melanoma', 'Disease', 'MESH:D008545', (380, 388))
35072	31142788	It should however be emphasized that the findings here reported are related to the consequences of deleting the Runt domain of Runx2, and not to Runx2 full knockout.	('Runx2', 'Gene', (127, 132))	('Runx2', 'Gene', '860', (127, 132))	('Runx2', 'Gene', (145, 150))	('Runt domain', 'MPA', (112, 123))	('deleting', 'Var', (99, 107))	('Runx2', 'Gene', '860', (145, 150))
35073	31142788	Indeed, the mutant Runx2 protein in 3G8 cells could still alter gene expression through indirect mechanisms, which are still relevant in understanding the role that Runx2 plays in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('gene expression', 'MPA', (64, 79))	('melanoma', 'Disease', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('protein', 'Protein', (25, 32))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('mutant', 'Var', (12, 18))	('alter', 'Reg', (58, 63))	('Runx2', 'Gene', (19, 24))	('Runx2', 'Gene', '860', (19, 24))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('Runx2', 'Gene', '860', (165, 170))	('Runx2', 'Gene', (165, 170))
35079	31069961	Enhanced reduced representation bisulfite sequencing-based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells.	('expression', 'MPA', (160, 170))	('abnormal', 'Var', (122, 130))	('bisulfite', 'Chemical', 'MESH:C042345', (32, 41))	('gene expression', 'biological_process', 'GO:0010467', ('155', '170'))	('VEGFC', 'Gene', (131, 136))	('SIX1', 'Gene', (150, 154))	('ANGPT2', 'Gene', (138, 144))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
35080	31069961	In patients, VEGFC (P-value = 0.031), ANGPT2 (P-value < 0.001), and SIX1 (P-value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival.	('overall survival', 'MPA', (163, 179))	('VEGFC', 'Gene', (13, 18))	('ANGPT2', 'Gene', (38, 44))	('shorter', 'NegReg', (155, 162))	('patients', 'Species', '9606', (3, 11))	('promoter hypomethylation', 'Var', (91, 115))
35098	31069961	Here, we show that the aggressiveness of murine melanoma cells is closely associated with high expression of angiogenic factors and that blockade of the VEGF pathway abrogates the tumorigenic potential of metastatic melanoma cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('melanoma', 'Disease', (48, 56))	('aggressiveness', 'Phenotype', 'HP:0000718', (23, 37))	('blockade', 'Var', (137, 145))	('abrogates', 'NegReg', (166, 175))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('VEGF', 'Gene', (153, 157))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('tumor', 'Disease', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('aggressiveness', 'Disease', 'MESH:D001523', (23, 37))	('melanoma', 'Disease', (216, 224))	('murine', 'Species', '10090', (41, 47))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('aggressiveness', 'Disease', (23, 37))	('VEGF', 'Gene', '22339', (153, 157))	('expression', 'MPA', (95, 105))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
35102	31069961	Murine melanoma cell lines 4C11- (nonmetastatic) and 4C11+ (metastatic) were cultured in RPMI 1640 medium supplemented with 5% FBS and 1% penicillin (100U mL-1) and streptomycin (100 mug mL-1) at 37  C in 5% CO2 humidified atmosphere.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('mL-1', 'Gene', (155, 159))	('mL-1', 'Gene', (187, 191))	('penicillin', 'Chemical', 'MESH:D010406', (138, 148))	('CO2', 'Chemical', '-', (208, 211))	('mL-1', 'Gene', '16728', (155, 159))	('RPMI 1640 medium', 'Chemical', '-', (89, 105))	('mug', 'molecular_function', 'GO:0043739', ('183', '186'))	('mL-1', 'Gene', '16728', (187, 191))	('streptomycin', 'Chemical', 'MESH:D013307', (165, 177))	('100', 'Var', (179, 182))	('melanoma', 'Disease', (7, 15))
35143	31069961	However, 4C11+ cells at day 3 had already given rise to a tumor mass with an extensive network of blood vessels.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('4C11+', 'Var', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
35147	31069961	In average, 4C11+ tumor volume was 11-fold bigger than 4C11- tumors at the evaluated time points (Fig.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('4C11+', 'Var', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
35152	31069961	In contrast, 4C11+ tumors presented hyperchromatic nuclei, pleomorphic cells, extensive necrosis, and a hypervascularized and invasive tumor growth pattern (Fig.	('necrosis', 'Disease', 'MESH:D009336', (88, 96))	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('hyperchromatic nuclei', 'CPA', (36, 57))	('tumor growth', 'Disease', 'MESH:D006130', (135, 147))	('necrosis', 'Disease', (88, 96))	('necrosis', 'biological_process', 'GO:0008219', ('88', '96'))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('necrosis', 'biological_process', 'GO:0008220', ('88', '96'))	('growth pattern', 'biological_process', 'GO:0007150', ('141', '155'))	('tumor growth', 'Disease', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('invasive tumor', 'Disease', (126, 140))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('necrosis', 'biological_process', 'GO:0070265', ('88', '96'))	('necrosis', 'biological_process', 'GO:0019835', ('88', '96'))	('necrosis', 'biological_process', 'GO:0001906', ('88', '96'))	('growth pattern', 'biological_process', 'GO:0040007', ('141', '155'))	('pleomorphic cells', 'CPA', (59, 76))	('4C11+', 'Var', (13, 18))	('invasive tumor', 'Disease', 'MESH:D009369', (126, 140))
35153	31069961	There was also a variable pigment formation in 4C11+ samples, which was clearly recognizable in the macroscopic tumor and in the HE staining.	('pigment', 'MPA', (26, 33))	('pigment formation', 'biological_process', 'GO:0046148', ('26', '43'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('HE', 'Chemical', '-', (129, 131))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('4C11+', 'Var', (47, 52))	('tumor', 'Disease', (112, 117))
35154	31069961	Abundant positive immunohistochemical staining for pH3, an important mitosis marker, was observed in 4C11+ cells (Fig.	('mitosis', 'Disease', 'None', (69, 76))	('4C11+', 'Var', (101, 106))	('pH3', 'Gene', (51, 54))	('mitosis', 'biological_process', 'GO:0000278', ('69', '76'))	('mitosis', 'Disease', (69, 76))
35157	31069961	All 4C11- tumor samples contained few and well-defined intratumoral vessels; however, 4C11+ tumor samples presented large and irregular vessels and several hemorrhagic areas within the tumor masses (Fig.	('hemorrhagic areas within the tumor', 'Disease', (156, 190))	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('4C11+', 'Var', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('hemorrhagic areas within the tumor', 'Disease', 'MESH:D001929', (156, 190))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (60, 65))
35162	31069961	Interestingly, a String analysis showed that among the 10 most upregulated genes in 4C11+ compared with 4C11- cells, there is an association among the proteins encoded by Vegfc (the most upregulated gene), Angpt2, Shc4, and Met.	('Met', 'Gene', (224, 227))	('Angpt2', 'Gene', '11601', (206, 212))	('Shc4', 'Gene', '271849', (214, 218))	('4C11+', 'Var', (84, 89))	('Vegfc', 'Gene', (171, 176))	('upregulated', 'PosReg', (63, 74))	('Shc4', 'Gene', (214, 218))	('Vegfc', 'Gene', '22341', (171, 176))	('Angpt2', 'Gene', (206, 212))	('upregulated', 'PosReg', (187, 198))
35166	31069961	We validated that Vegfa is downregulated in 4C11+ cells in comparison with 4C11- cells, while Vegfb and Vegfc are upregulated, the latter to a much higher extent.	('Vegfb', 'Gene', (94, 99))	('Vegfb', 'Gene', '22340', (94, 99))	('Vegfc', 'Gene', (104, 109))	('Vegfa', 'Gene', '22339', (18, 23))	('Vegfc', 'Gene', '22341', (104, 109))	('downregulated', 'NegReg', (27, 40))	('Vegfa', 'Gene', (18, 23))	('4C11+', 'Var', (44, 49))	('upregulated', 'PosReg', (114, 125))
35167	31069961	Considering the receptors, Vegfr-1 and Nrp2 were downregulated in 4C11+ cells compared with 4C11- cells; Vegfr-2 could not be detected in either one of the cell lines and Vegfr-3 was highly upregulated in 4C11+ cells.	('Vegfr-3', 'Gene', (171, 178))	('4C11+', 'Var', (66, 71))	('Vegfr-1', 'Gene', '14254', (27, 34))	('Nrp', 'biological_process', 'GO:0085015', ('39', '42'))	('Nrp2', 'Gene', '18187', (39, 43))	('Nrp2', 'Gene', (39, 43))	('downregulated', 'NegReg', (49, 62))	('Vegfr-2', 'Gene', (105, 112))	('Vegfr-1', 'Gene', (27, 34))	('Vegfr-2', 'Gene', '16542', (105, 112))	('upregulated', 'PosReg', (190, 201))	('Vegfr-3', 'Gene', '14257', (171, 178))
35178	31069961	From 11 samples grown from axitinib-pretreated 4C11+ cells, two were able to develop tumors, although much smaller than tumors generated by untreated 4C11+ cells.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('axitinib', 'Chemical', 'MESH:D000077784', (27, 35))	('develop', 'PosReg', (77, 84))	('4C11+', 'Var', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
35181	31069961	After adjustment for age, tumor primary site, presence of metastasis in lymph nodes, ulceration, and Breslow depth value, high expression of VEGFR-3 (HR = 1.199; P-value = 0.044) and ANGPT2 (HR = 1.189; P-value = 0.002) was shown to be predictors of shorter overall survival (Fig.	('overall survival', 'MPA', (258, 274))	('shorter', 'NegReg', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('high expression', 'Var', (122, 137))	('VEGFR-3', 'Gene', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('ANGPT2', 'Gene', (183, 189))
35187	31069961	The number of CpGs differentially methylated in Vegfc, Angpt2, and Six1 promoters was four (distant from 147-222 nucleotides downstream of the TSS), 11 (located from 1129 to 1370 nucleotides upstream of the TSS), and 72 (-1499 to +203 distant from the TSS), respectively.	('Angpt2', 'Gene', (55, 61))	('Vegfc', 'Gene', '22341', (48, 53))	('-1499', 'Var', (221, 226))	('Six1', 'Gene', '20471', (67, 71))	('Angpt2', 'Gene', '11601', (55, 61))	('Six1', 'Gene', (67, 71))	('Vegfc', 'Gene', (48, 53))
35188	31069961	In the analyzed region, Vegfr-3 and Met did not show any differential methylation in 4C11+ in comparison with 4C11- cells.	('4C11+', 'Var', (85, 90))	('Vegfr-3', 'Gene', (24, 31))	('Vegfr-3', 'Gene', '14257', (24, 31))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))
35190	31069961	Demethylation caused by the treatment enhanced the expression of the three genes analyzed, most prominently of Angpt2 and Six1 (Fig.	('Angpt2', 'Gene', '11601', (111, 117))	('Demethylation', 'biological_process', 'GO:0070988', ('0', '13'))	('enhanced', 'PosReg', (38, 46))	('Six1', 'Gene', '20471', (122, 126))	('Demethylation', 'Var', (0, 13))	('expression', 'MPA', (51, 61))	('Angpt2', 'Gene', (111, 117))	('Six1', 'Gene', (122, 126))
35198	31069961	In vivo, 4C11+ cells gave rise to larger tumors, which were highly proliferative and vascularized.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('4C11+ cells', 'Var', (9, 20))	('vascularized', 'CPA', (85, 97))
35200	31069961	These data are consistent and enrich our previous results showing different growth rate and metastasis capability of 4C11- and 4C11+ cells in a mouse model (Souza et al., 2012).	('metastasis capability', 'CPA', (92, 113))	('mouse', 'Species', '10090', (144, 149))	('growth rate', 'CPA', (76, 87))	('4C11-', 'Var', (117, 122))
35203	31069961	The high VM capability of 4C11+ cells is consistent with their excessive bleeding observed in the CAM assay and can contribute to it.	('bleeding', 'Disease', (73, 81))	('CAM', 'Disease', (98, 101))	('bleeding', 'Disease', 'MESH:D006470', (73, 81))	('high VM capability', 'MPA', (4, 22))	('4C11+', 'Var', (26, 31))
35209	31069961	Conversely, Bmp4 is a known inhibitor of angiogenesis (Tsuchida et al., 2014); thus, its downregulation probably contributes to 4C11+ tumor vascularization.	('Bmp4', 'Gene', (12, 16))	('downregulation', 'NegReg', (89, 103))	('4C11+', 'Var', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Bmp4', 'Gene', '12159', (12, 16))	('tumor', 'Disease', (134, 139))
35240	31069961	In melanoma, one study demonstrated high levels of circulating ANGPT2 to be associated with poor patient overall survival (Helfrich et al., 2009).	('poor', 'NegReg', (92, 96))	('ANGPT2', 'Gene', (63, 69))	('associated', 'Reg', (76, 86))	('high levels', 'Var', (36, 47))	('patient', 'Species', '9606', (97, 104))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
35242	31069961	Furthermore, we detected that Vegfc, Angpt2, and Six1 promoters were hypomethylated in 4C11+ cells compared with 4C11- cells.	('hypomethylated', 'Var', (69, 83))	('Angpt2', 'Gene', (37, 43))	('4C11+ cells', 'Var', (87, 98))	('Six1', 'Gene', (49, 53))	('Angpt2', 'Gene', '11601', (37, 43))	('Six1', 'Gene', '20471', (49, 53))	('Vegfc', 'Gene', (30, 35))	('Vegfc', 'Gene', '22341', (30, 35))
35244	31069961	VEGFC expression has previously been shown to predict melanoma patient survival (Boone et al., 2008; Liu et al., 2008), and its expression has been shown to be regulated by DNA methylation in gastric cancer (Matsumura et al., 2007).	('regulated', 'Reg', (160, 169))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('DNA methylation', 'Var', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('predict', 'Reg', (46, 53))	('patient', 'Species', '9606', (63, 70))	('gastric cancer', 'Disease', (192, 206))	('expression', 'MPA', (128, 138))	('DNA methylation', 'biological_process', 'GO:0006306', ('173', '188'))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('gastric cancer', 'Disease', 'MESH:D013274', (192, 206))	('VEGFC', 'Gene', (0, 5))
35246	31069961	Concerning ANGPT2, the methylation status of 6 CpGs near the gene transcription site (four of which were analyzed in this study) has already been shown to predict overall survival of chronic lymphocytic leukemia patients (Martinelli et al., 2013).	('methylation', 'Var', (23, 34))	('ANGPT2', 'Gene', (11, 17))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (183, 211))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('leukemia', 'Phenotype', 'HP:0001909', (203, 211))	('patients', 'Species', '9606', (212, 220))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (183, 211))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('chronic lymphocytic leukemia', 'Disease', (183, 211))	('predict', 'Reg', (155, 162))
35248	31069961	Methylation of SIX1 promoter has previously been reported as a transcription regulatory mechanism in the porcine and bovine muscle (Wei et al., 2018; Wu et al., 2013).	('bovine', 'Species', '9913', (117, 123))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('SIX1', 'Gene', (15, 19))
35258	23691346	Melanoma M (Zero): Diagnosis and Therapy This paper reviews the epidemiology, diagnosis, and treatment of M zero cutaneous melanoma including the most recent developments.	('men', 'Species', '9606', (165, 168))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('M zero', 'Var', (106, 112))	('men', 'Species', '9606', (98, 101))	('cutaneous melanoma', 'Disease', (113, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 131))
35284	23691346	The development of CM results from complex interaction between mutations in various genes and constitutional and/or inherited factors combined with environmental factors, mainly UV-radiations.	('mutations', 'Var', (63, 72))	('CM', 'Phenotype', 'HP:0012056', (19, 21))	('interaction', 'Reg', (43, 54))	('men', 'Species', '9606', (155, 158))	('results from', 'Reg', (22, 34))	('CM', 'Disease', 'MESH:D009202', (19, 21))	('men', 'Species', '9606', (11, 14))
35297	23691346	Mutations or epigenetic silencing of cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) are common genetic abnormality in patients with family history of melanoma.	('epigenetic silencing', 'Var', (13, 33))	('p16', 'Gene', (85, 88))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('54', '70'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (37, 73))	('CDKN2A', 'Gene', (75, 81))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (37, 73))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('abnormality', 'Disease', 'MESH:D000014', (109, 120))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('37', '70'))	('CDKN2A', 'Gene', '1029', (75, 81))	('Mutations', 'Var', (0, 9))	('abnormality', 'Disease', (109, 120))	('p16', 'Gene', '1029', (85, 88))	('patients', 'Species', '9606', (124, 132))
35298	23691346	Moreover, over two-thirds of melanomas have activating mutations in B-RAF gene, leading to constitutive activation of the B-Raf/MKK/ERK signaling pathway.	('ERK', 'Gene', '5594', (132, 135))	('ERK', 'molecular_function', 'GO:0004707', ('132', '135'))	('activation', 'PosReg', (104, 114))	('activating', 'PosReg', (44, 54))	('B-RAF', 'Gene', '673', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('mutations', 'Var', (55, 64))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('ERK', 'Gene', (132, 135))	('B-Raf', 'Gene', (122, 127))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('B-RAF', 'Gene', (68, 73))	('B-Raf', 'Gene', '673', (122, 127))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('melanomas', 'Disease', (29, 38))	('MKK', 'molecular_function', 'GO:0004708', ('128', '131'))
35299	23691346	Melanomas on skin without chronic sun-induced damage had frequent mutations in BRAF, on the contrary acral and mucosal melanoma and melanoma on the skin with chronic sun damage frequently are characterized by Kit mutations.	('mutations', 'Var', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('mucosal melanoma', 'Disease', (111, 127))	('sun damage', 'Phenotype', 'HP:0000992', (166, 176))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('BRAF', 'Gene', '673', (79, 83))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('mucosal melanoma', 'Disease', 'MESH:D008545', (111, 127))	('BRAF', 'Gene', (79, 83))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))
35300	23691346	These mutations are responsible of cancer cell behavior through mechanisms that are still to be defined.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('responsible', 'Reg', (20, 31))	('cancer', 'Disease', (35, 41))	('mutations', 'Var', (6, 15))
35301	23691346	Furthermore, PTEN (phosphatase and tensin homolog) deleted on chromosome 10 can be found mutated, deleted, or epigenetically silenced in melanoma.	('epigenetically silenced', 'Var', (110, 133))	('phosphatase', 'molecular_function', 'GO:0016791', ('19', '30'))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('19', '49'))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('deleted', 'Var', (98, 105))
35305	23691346	In particular, Melanocortin 1 receptor (MCR1) variants seems to be associated with red hair color phenotype and melanoma.	('red hair', 'Phenotype', 'HP:0002297', (83, 91))	('Melanocortin 1 receptor', 'Gene', (15, 38))	('MCR1', 'Gene', '4157', (40, 44))	('Melanocortin 1 receptor', 'Gene', '4157', (15, 38))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('variants', 'Var', (46, 54))	('MCR1', 'Gene', (40, 44))	('melanoma', 'Disease', (112, 120))	('associated', 'Reg', (67, 77))	('red hair color', 'Disease', 'MESH:D003117', (83, 97))	('red hair color', 'Disease', (83, 97))
35399	23691346	Significant treatment-related adverse events (AEs) favored the investigation of low-dose IFN-alpha given for a longer duration in the aim to improve the toxicity profile.	('IFN-alpha', 'Gene', '3439', (89, 98))	('IFN-alpha', 'Gene', (89, 98))	('low-dose', 'Var', (80, 88))	('toxicity', 'Disease', 'MESH:D064420', (153, 161))	('toxicity', 'Disease', (153, 161))	('men', 'Species', '9606', (17, 20))
35414	23691346	In patients harboring BRAF mutations, the unequivocal clinical benefit obtained by BRAF inhibitors (vemurafenib or dabrafenib) in respect to Deticene in the treatment of advanced disease raised the question of the opportunity of testing the efficacy in the adjuvant setting.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (22, 26))	('vemurafenib', 'Chemical', 'MESH:D000077484', (100, 111))	('men', 'Species', '9606', (162, 165))	('BRAF', 'Gene', (22, 26))	('patients', 'Species', '9606', (3, 11))	('BRAF', 'Gene', '673', (83, 87))	('Deticene', 'Chemical', 'MESH:D003606', (141, 149))	('BRAF', 'Gene', (83, 87))	('dabrafenib', 'Chemical', 'MESH:C561627', (115, 125))
35513	12735792	However, it is important to note that a significant number of melanomas are also non-immunoreactive for HMB45.	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanomas', 'Disease', (62, 71))	('non-immunoreactive', 'Var', (81, 99))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('HMB45', 'Protein', (104, 109))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
35563	24249545	Fenestrations in the catheter between the two occlusion balloons allow for venous outflow from the hepatic veins to be shunted extracorporeally, and using a perfusion bypass machine the venoveno bypass circuit passes blood through the chemotherapy filtration device, and then returns it via the IJ venous catheter thus completing the veno-veno bypass circuit.	('occlusion balloons', 'Disease', 'MESH:D054549', (46, 64))	('Fenestrations', 'Var', (0, 13))	('venous outflow from the', 'MPA', (75, 98))	('occlusion balloons', 'Disease', (46, 64))
35647	30759888	A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('cytosine deaminases', 'Enzyme', (123, 142))	('cytosine', 'Chemical', 'MESH:D003596', (123, 131))	('RNA editing', 'biological_process', 'GO:0009451', ('111', '122'))	('activity', 'MPA', (95, 103))	('mutations', 'Var', (30, 39))	('off-target', 'NegReg', (84, 94))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))
35650	30759888	We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('APOBEC', 'cellular_component', 'GO:0030895', ('56', '62'))	('mutable', 'Var', (120, 127))	('APOBEC3B', 'Gene', (66, 74))	('cancer', 'Disease', (111, 117))	('APOBEC', 'cellular_component', 'GO:0030895', ('66', '72'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('APOBEC1', 'Gene', (47, 54))	('APOBEC3G', 'Gene', '60489', (80, 88))	('AID', 'Disease', 'None', (225, 228))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('AID', 'Disease', (225, 228))	('APOBEC1', 'Gene', '339', (47, 54))	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('APOBEC3B', 'Gene', '9582', (66, 74))	('humoral immune response', 'biological_process', 'GO:0006959', ('171', '194'))	('APOBEC3A', 'Gene', (56, 64))	('APOBEC3G', 'Gene', (80, 88))	('APOBEC3A', 'Gene', '200315', (56, 64))	('APOBEC', 'cellular_component', 'GO:0030895', ('80', '86'))	('cancer', 'Disease', (320, 326))
35652	30759888	The sequencing of genomes of solid tumors and liquid malignancies associated with different types and stages of cancer has revealed a plethora of genetic changes, from nucleotide substitutions and insertions/deletions to chromosomal rearrangements and chromosome copy number alterations.	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('malignancies', 'Disease', (53, 65))	('cancer', 'Disease', (112, 118))	('chromosome copy number alterations', 'CPA', (252, 286))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('changes', 'Reg', (154, 161))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('chromosomal rearrangements', 'CPA', (221, 247))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('252', '262'))	('plethora', 'Phenotype', 'HP:0001050', (134, 142))	('nucleotide substitutions', 'Var', (168, 192))	('insertions/deletions', 'Var', (197, 217))	('solid tumors', 'Disease', (29, 41))
35654	30759888	The underlying causes of this mutagenesis are diverse, from the appearance of mutator mutations to DNA damage by intrinsic or environmental mutagens (e.g., oxidative stress, tobacco smoke, UV light, etc.).	('mutations', 'Var', (86, 95))	('tobacco', 'Species', '4097', (174, 181))	('mutator', 'Gene', (78, 85))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('mutagenesis', 'biological_process', 'GO:0006280', ('30', '41'))	('oxidative stress', 'Phenotype', 'HP:0025464', (156, 172))	('DNA', 'Gene', (99, 102))
35655	30759888	Somatic genome instability leads to the activation of oncogenes and inactivation of tumor suppressors and helps tumor cells to emerge, proliferate, elude immune surveillance, and acquire resistance to anticancer drugs.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('elude', 'Reg', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', (205, 211))	('oncogenes', 'Protein', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('activation', 'PosReg', (40, 50))	('tumor', 'Disease', (84, 89))	('acquire', 'Reg', (179, 186))	('proliferate', 'CPA', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('emerge', 'CPA', (127, 133))	('tumor', 'Disease', (112, 117))	('inactivation', 'NegReg', (68, 80))	('genome instability', 'Var', (8, 26))
35656	30759888	In some cancers, the number of single nucleotide variations (SNVs) is in the order of tens of thousands per genome.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('single nucleotide variations', 'Var', (31, 59))
35657	30759888	A few driver mutations ultimately lead to cancer, while the role, if any, of the vast majority of mutations, termed "passengers", during tumor development is poorly understood.	('tumor', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lead to', 'Reg', (34, 41))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
35659	30759888	One of the clearest mutational signatures, found in breast and other cancers, is characterized by C:G to T:A or C:G to G:C substitutions that are found predominantly in the 5'-TC sequence motif (signatures #2 and 13; listed in the COSMIC database).	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('breast', 'Disease', (52, 58))	('C:G to T:A', 'Var', (98, 108))	("5'-TC", 'Chemical', '-', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('substitutions', 'Var', (123, 136))	('C:G to G:C substitutions', 'Var', (112, 136))	('cancers', 'Disease', (69, 76))
35661	30759888	These enzymes, collectively called APOBECs, deaminate cytosine in single-stranded DNA, yielding uracil.	('cytosine', 'Chemical', 'MESH:D003596', (54, 62))	('uracil', 'Chemical', 'MESH:D014498', (96, 102))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('yielding', 'Reg', (87, 95))	('uracil', 'MPA', (96, 102))	('deaminate', 'Var', (44, 53))
35663	30759888	Also, abasic sites that are produced as intermediates of uracil repair are bypassed by the cytidine transferase activity of REV1 translesion DNA polymerase, leading to C:G to G:C transversions.	('REV1', 'Gene', (124, 128))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('C:G to G:C transversions', 'Var', (168, 192))	('transferase activity', 'molecular_function', 'GO:0016740', ('100', '120'))	('abasic', 'Var', (6, 12))	('leading to', 'Reg', (157, 167))	('uracil', 'Chemical', 'MESH:D014498', (57, 63))	('REV1', 'Gene', '51455', (124, 128))
35666	30759888	Mutational signatures of cytosine deaminases are detected in many cancers.	('detected', 'Reg', (49, 57))	('Mutational', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cytosine', 'Chemical', 'MESH:D003596', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
35668	30759888	It should be noted that if deaminases act on 5-methylcytosine generating "T", a specialized G:T mismatch repair mechanism operates, and the genetic consequences could be different because of the disappearance of an epigenetic mark.	('disappearance', 'NegReg', (195, 208))	('mismatch repair', 'biological_process', 'GO:0006298', ('94', '109'))	('epigenetic mark', 'Var', (215, 230))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (45, 61))
35670	30759888	It is not usually possible to define the DNA strand upon which the vast majority of mutations has occurred (but see); for example, both a C>T change on one strand and a G>A change on the opposite strand lead to the same CG to TA transition.	('CG to TA transition', 'MPA', (220, 239))	('CG', 'Chemical', 'MESH:C028505', (220, 222))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('C>T change', 'Var', (138, 148))
35671	30759888	Analysis of the mutational spectra of context-dependent mutations in cancer genomes involves pooling all the mutations from cancer samples into a discrete distribution according to the mutation types, while further analysis involves the so-called non-negative matrix factorization (NMF) method.	('cancer', 'Disease', (124, 130))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (69, 75))
35688	30759888	Thus, weight matrices properly represent the DNA sequence context of mutations induced by various AID/APOBEC proteins, as noted in previous studies where a simple consensus approach was used.	('AID', 'Disease', 'None', (98, 101))	('mutations', 'Var', (69, 78))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('induced', 'Reg', (79, 86))	('APOBEC', 'cellular_component', 'GO:0030895', ('102', '108'))	('AID', 'Disease', (98, 101))
35692	30759888	We examined the correlation of the sites of C:G>T:A mutations in cancers and AID/APOBEC mutable motifs.	('APOBEC', 'cellular_component', 'GO:0030895', ('81', '87'))	('C:G>T:A', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('AID', 'Disease', 'None', (77, 80))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('AID', 'Disease', (77, 80))	('cancers', 'Disease', (65, 72))
35693	30759888	A correlation between the mutable motifs of (at least one) deaminase(s) and the sites of somatic C:G>T:A mutations was found for all cancer tissues (Figure 2 and Supplementary Table S6).	('mutable', 'Var', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
35696	30759888	For example, estimated fractions of APOBEC1-associated mutations (0.66, 0.48, 0.74, 0.39, and 0.62) look consistent with the smallest value of 0.39 corresponding to the lowest ratio value (1.064, APOBEC1, lung), although this method sometimes yielded potentially underestimated values (0.17, APOBEC3G, cervix, ratio = 1.113) and overestimated values (0.92, APOBEC3G, bladder, ratio = 1.101) (Supplementary Table S6).	('APOBEC3G', 'Gene', '60489', (357, 365))	('APOBEC', 'cellular_component', 'GO:0030895', ('36', '42'))	('APOBEC', 'cellular_component', 'GO:0030895', ('292', '298'))	('APOBEC3G', 'Gene', '60489', (292, 300))	('mutations', 'Var', (55, 64))	('APOBEC1', 'Gene', (36, 43))	('APOBEC1', 'Gene', '339', (36, 43))	('APOBEC', 'cellular_component', 'GO:0030895', ('357', '363'))	('APOBEC1', 'Gene', (196, 203))	('APOBEC3G', 'Gene', (357, 365))	('APOBEC', 'cellular_component', 'GO:0030895', ('196', '202'))	('APOBEC1', 'Gene', '339', (196, 203))	('underestimated', 'NegReg', (263, 277))	('APOBEC3G', 'Gene', (292, 300))
35698	30759888	This result suggests that a substantial proportion of somatic mutations is associated with AID/APOBEC mutagenesis.	('somatic', 'Disease', (54, 61))	('associated', 'Reg', (75, 85))	('APOBEC', 'cellular_component', 'GO:0030895', ('95', '101'))	('AID', 'Disease', 'None', (91, 94))	('mutagenesis', 'biological_process', 'GO:0006280', ('102', '113'))	('AID', 'Disease', (91, 94))	('mutagenesis', 'Var', (102, 113))
35699	30759888	Many C:G > G:C transversions were suggested to be the result of processing abasic sites after the removal of uracils originating via DNA deamination by AID/APOBEC proteins.	('C:G > G:C transversions', 'Var', (5, 28))	('AID', 'Disease', (152, 155))	('DNA deamination', 'biological_process', 'GO:0045006', ('133', '148'))	('AID', 'Disease', 'None', (152, 155))	('APOBEC', 'cellular_component', 'GO:0030895', ('156', '162'))	('uracil', 'Chemical', 'MESH:D014498', (109, 115))	('transversions', 'Var', (15, 28))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))
35700	30759888	Consistent with this idea, a significant correlation of these mutations with mutable motifs was found in many cancers (Figure 3 and Supplementary Table S7).	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('correlation', 'Reg', (41, 52))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
35701	30759888	The transversions associated with APOBEC1, APOBEC3A, and APOBEC3B were found to be more abundant in comparison with APOBEC3G and AID, suggesting a role of these three deaminases in generating C:G>G:C somatic mutations in human cancer.	('APOBEC', 'cellular_component', 'GO:0030895', ('116', '122'))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('APOBEC3G', 'Gene', (116, 124))	('C:G>G', 'Var', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('APOBEC1', 'Gene', '339', (34, 41))	('APOBEC3B', 'Gene', (57, 65))	('APOBEC3A', 'Gene', (43, 51))	('human', 'Species', '9606', (221, 226))	('AID', 'Disease', 'None', (129, 132))	('APOBEC3A', 'Gene', '200315', (43, 51))	('cancer', 'Disease', (227, 233))	('APOBEC3G', 'Gene', '60489', (116, 124))	('APOBEC', 'cellular_component', 'GO:0030895', ('57', '63'))	('AID', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('APOBEC3B', 'Gene', '9582', (57, 65))	('APOBEC', 'cellular_component', 'GO:0030895', ('43', '49'))	('APOBEC1', 'Gene', (34, 41))
35703	30759888	Although it has been proposed that C:G>A:T mutations are a less likely outcome of AID/APOBEC enzymatic action, we found a significant excess of these transversions in many cancers (Figure 4 and Supplementary Table S8), suggesting that a significant portion of C:G>A:T mutations may be caused by processes initiated by deamination by AID/APOBEC enzymes.	('AID', 'Disease', (333, 336))	('AID', 'Disease', 'None', (82, 85))	('mutations', 'Var', (268, 277))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('caused', 'Reg', (285, 291))	('C:G', 'Gene', (260, 263))	('APOBEC', 'cellular_component', 'GO:0030895', ('337', '343'))	('APOBEC', 'cellular_component', 'GO:0030895', ('86', '92'))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('AID', 'Disease', 'None', (333, 336))	('AID', 'Disease', (82, 85))
35704	30759888	That the APOBEC3A, APOBEC3B, and APOBEC3G footprints are more abundant in comparison with the APOBEC1 and AID motifs suggests an important role for these three deaminases in generating somatic C:G>A:T mutations in human cancers.	('APOBEC3B', 'Gene', (19, 27))	('APOBEC', 'cellular_component', 'GO:0030895', ('19', '25'))	('APOBEC3G', 'Gene', '60489', (33, 41))	('C:G>A:T', 'Var', (193, 200))	('APOBEC1', 'Gene', (94, 101))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('human', 'Species', '9606', (214, 219))	('APOBEC1', 'Gene', '339', (94, 101))	('AID', 'Disease', 'None', (106, 109))	('APOBEC3B', 'Gene', '9582', (19, 27))	('APOBEC3A', 'Gene', (9, 17))	('APOBEC3G', 'Gene', (33, 41))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('APOBEC3A', 'Gene', '200315', (9, 17))	('APOBEC', 'cellular_component', 'GO:0030895', ('33', '39'))	('cancers', 'Disease', (220, 227))	('APOBEC', 'cellular_component', 'GO:0030895', ('9', '15'))	('AID', 'Disease', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('APOBEC', 'cellular_component', 'GO:0030895', ('94', '100'))
35710	30759888	A significant excess of somatic mutations in AID mutable motifs was detected in acute myeloid leukemia (Table 2).	('acute myeloid leukemia', 'Disease', (80, 102))	('AID', 'Disease', (45, 48))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (80, 102))	('AID', 'Disease', 'None', (45, 48))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (80, 102))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('mutable', 'Var', (49, 56))
35714	30759888	An overwhelming excess of somatic mutations in APOBEC1 and APOBEC3A/B/G mutable motifs (Table 2) is likely to be due to the known excess of mutations in dipyrimidine dinucleotides (for example, TC) in skin cutaneous melanoma caused by mutagenic UV photoproducts.	('TC', 'Chemical', 'MESH:D013667', (194, 196))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (206, 224))	('dipyrimidine dinucleotides', 'Chemical', '-', (153, 179))	('APOBEC1', 'Gene', (47, 54))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (201, 224))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (59, 69))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('APOBEC1', 'Gene', '339', (47, 54))	('APOBEC3A/B', 'Gene', (59, 69))	('mutations', 'Var', (140, 149))	('skin cutaneous melanoma', 'Disease', (201, 224))	('mutations', 'Var', (34, 43))	('APOBEC', 'cellular_component', 'GO:0030895', ('59', '65'))	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))
35715	30759888	Accordingly, we interpreted the excess of mutations in the AID/APOBEC3A/B/G contexts (Table 2) to be the result of false positives (as was already suggested by the results of the control experiments; for details, see Section 4.7), but we are also aware of evidence for the direct role of deaminases in skin cancer.	('APOBEC3A/B', 'Gene', (63, 73))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (63, 73))	('false', 'biological_process', 'GO:0071878', ('115', '120'))	('AID', 'Disease', 'None', (59, 62))	('AID', 'Disease', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('skin cancer', 'Phenotype', 'HP:0008069', (302, 313))	('APOBEC', 'cellular_component', 'GO:0030895', ('63', '69'))	('false', 'biological_process', 'GO:0071877', ('115', '120'))	('skin cancer', 'Disease', (302, 313))	('skin cancer', 'Disease', 'MESH:D012878', (302, 313))	('mutations', 'Var', (42, 51))
35721	30759888	This distorted normal distribution (another problem is a much larger number of sites in the last bin compared with the previous bin) may be a reason why two distributions (Figure 5A) were incorrectly classified (mixed together) yielding an obvious overestimate for the APOBEC3G mutable motifs (see Section 3).	('mutable', 'Var', (278, 285))	('APOBEC', 'cellular_component', 'GO:0030895', ('269', '275'))	('APOBEC3G', 'Gene', (269, 277))	('APOBEC3G', 'Gene', '60489', (269, 277))	('overestimate', 'PosReg', (248, 260))
35722	30759888	We confirm that while the mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the humoral immune response somatic hypermutation machine, AID, are the most widespread feature of the somatic mutation spectra attributed to APOBECs in cancer genomes.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('APOBEC', 'cellular_component', 'GO:0030895', ('60', '66'))	('APOBEC3G', 'Gene', (84, 92))	('APOBEC', 'cellular_component', 'GO:0030895', ('84', '90'))	('APOBEC3A', 'Gene', (60, 68))	('APOBEC3B', 'Gene', '9582', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('APOBEC3A', 'Gene', '200315', (60, 68))	('cancer', 'Disease', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('humoral immune response', 'biological_process', 'GO:0006959', ('161', '184'))	('mutable', 'Var', (124, 131))	('APOBEC', 'cellular_component', 'GO:0030895', ('51', '57'))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('AID', 'Disease', 'None', (216, 219))	('APOBEC', 'cellular_component', 'GO:0030895', ('70', '76'))	('APOBEC3G', 'Gene', '60489', (84, 92))	('APOBEC1', 'Gene', (51, 58))	('APOBEC3B', 'Gene', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', (115, 121))	('AID', 'Disease', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('APOBEC1', 'Gene', '339', (51, 58))
35724	30759888	The blood subset of mutations stands apart because only AID mutable motifs are detected (Figure 2, Figure 3 and Figure 4 and Table 2).	('AID', 'Disease', (56, 59))	('AID', 'Disease', 'None', (56, 59))	('mutations', 'Var', (20, 29))
35732	30759888	Randomly sampled sites from yeast chromosomes are far from being a good "negative" set, because distributions of mutations across yeast chromosomes are too sparse and may contain a lot of mutable motifs.	('contain', 'Reg', (171, 178))	('mutations', 'Var', (113, 122))	('yeast', 'Species', '4932', (130, 135))	('yeast', 'Species', '4932', (28, 33))
35733	30759888	Another issue is the need to take into account the much higher A:T content of the mutation sites in the yeast genome as compared with the human genome; this should be implemented as a part of a learning procedure.	('mutation', 'Var', (82, 90))	('human', 'Species', '9606', (138, 143))	('yeast', 'Species', '4932', (104, 109))	('A:T content', 'MPA', (63, 74))
35745	30759888	Coordinates and types of mutations induced by various APOBEC/AID proteins in yeast were obtained from previously published SNV datasets (see legend to Supplementary Table S1).	('AID', 'Disease', (61, 64))	('mutations', 'Var', (25, 34))	('yeast', 'Species', '4932', (77, 82))	('APOBEC', 'cellular_component', 'GO:0030895', ('54', '60'))	('AID', 'Disease', 'None', (61, 64))
35747	30759888	We calculated the weight matrices for 6f different AID/APOBEC mutational signatures in the yeast genome (Supplementary Table S1).	('mutational', 'Var', (62, 72))	('yeast', 'Species', '4932', (91, 96))	('APOBEC', 'cellular_component', 'GO:0030895', ('55', '61'))	('AID', 'Disease', (51, 54))	('AID', 'Disease', 'None', (51, 54))
35750	30759888	We also performed another control experiment: we randomly extracted sequences from the yeast genome, maintaining the nucleotide composition and the size of sequence sets for each set of mutation sites with AID/APOBEC-induced mutations.	('APOBEC', 'cellular_component', 'GO:0030895', ('210', '216'))	('AID', 'Disease', 'None', (206, 209))	('mutations', 'Var', (225, 234))	('AID', 'Disease', (206, 209))	('yeast', 'Species', '4932', (87, 92))
35755	30759888	A dataset of somatic mutations in mitochondrial DNA in various cancer types was extracted from.	('mitochondrial', 'Gene', (34, 47))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('34', '51'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('mutations', 'Var', (21, 30))
35756	30759888	We used only the nucleotides immediately flanking the mutations, because the AID/APOBEC enzymes are thought to scan a very limited region of DNA to deaminate (methyl)cytosines in a preferred motif.	('cytosine', 'Chemical', 'MESH:D003596', (166, 174))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('APOBEC', 'cellular_component', 'GO:0030895', ('81', '87'))	('mutations', 'Var', (54, 63))	('AID', 'Disease', 'None', (77, 80))	('AID', 'Disease', (77, 80))
35764	30759888	To test the robustness of the normalization, a simple control experiment was designed: we randomly shuffled the sequences of the AID/APOBEC mutation sites (Supplementary Table S1).	('AID', 'Disease', 'None', (129, 132))	('APOBEC', 'cellular_component', 'GO:0030895', ('133', '139'))	('mutation', 'Var', (140, 148))	('AID', 'Disease', (129, 132))
35772	30759888	The analysis of mutations in various tissues suggested that the weight matrix technique may also produce misleading results for bladder, cervix, and skin tumors (Figure 6).	('bladder', 'Disease', (128, 135))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('skin tumors', 'Disease', (149, 160))	('mutations', 'Var', (16, 25))	('skin tumors', 'Disease', 'MESH:D012878', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cervix', 'Disease', (137, 143))	('skin tumors', 'Phenotype', 'HP:0008069', (149, 160))
35773	30759888	The analysis of nucleotide frequencies for the region +-3 suggested that skin, cervix, and bladder tumors are characterized by a high frequency of T nucleotides around the sites of mutation (Supplementary Table S5), and this is likely to be a reason for the high rate of false positives.	('cervix', 'Disease', (79, 85))	('false', 'biological_process', 'GO:0071878', ('271', '276'))	('bladder tumors', 'Disease', 'MESH:D001749', (91, 105))	('T nucleotides', 'Var', (147, 160))	('bladder tumors', 'Phenotype', 'HP:0009725', (91, 105))	('bladder tumors', 'Disease', (91, 105))	('false', 'biological_process', 'GO:0071877', ('271', '276'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('skin', 'Disease', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
35777	30759888	Indeed, a significant association between the AID mutable motif and mutations was found in all three studied sets of somatic mutations (Table 3), suggesting that the AID weight matrix is a reliable descriptor of AID-induced mutagenesis.	('AID', 'Disease', (212, 215))	('AID', 'Disease', 'None', (212, 215))	('mutagenesis', 'biological_process', 'GO:0006280', ('224', '235'))	('AID', 'Disease', (166, 169))	('AID', 'Disease', 'None', (46, 49))	('AID', 'Disease', 'None', (166, 169))	('mutations', 'Var', (68, 77))	('AID', 'Disease', (46, 49))
35782	30759888	We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of the somatic mutation spectra attributed to APOBECs in cancer genomes.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('APOBEC', 'cellular_component', 'GO:0030895', ('56', '62'))	('cancer', 'Disease', (319, 325))	('mutable', 'Var', (120, 127))	('cancer', 'Disease', (111, 117))	('APOBEC3B', 'Gene', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('APOBEC', 'cellular_component', 'GO:0030895', ('66', '72'))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('APOBEC1', 'Gene', (47, 54))	('APOBEC3G', 'Gene', '60489', (80, 88))	('AID', 'Disease', 'None', (225, 228))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('AID', 'Disease', (225, 228))	('APOBEC1', 'Gene', '339', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('APOBEC3B', 'Gene', '9582', (66, 74))	('humoral immune response', 'biological_process', 'GO:0006959', ('171', '194'))	('APOBEC3A', 'Gene', (56, 64))	('APOBEC3G', 'Gene', (80, 88))	('APOBEC3A', 'Gene', '200315', (56, 64))	('APOBEC', 'cellular_component', 'GO:0030895', ('80', '86'))	('APOBEC', 'cellular_component', 'GO:0030895', ('47', '53'))
35783	30759888	The AID and APOBEC3A mutable motifs are the most prominent features of the C:G>T:A transitions that constitute the vast majority of somatic mutations in studied cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('AID', 'Disease', (4, 7))	('APOBEC3A', 'Gene', (12, 20))	('C:G>T:A', 'Var', (75, 82))	('AID', 'Disease', 'None', (4, 7))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('APOBEC3A', 'Gene', '200315', (12, 20))	('cancers', 'Disease', (161, 168))
35784	30759888	We also demonstrated an abundance of APOBEC3A/3B/3G mutable motifs in DNA contexts of C:G>A:T transversions.	('APOBEC', 'cellular_component', 'GO:0030895', ('37', '43'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('APOBEC3A', 'Gene', (37, 45))	('C:G>A:T transversions', 'Var', (86, 107))	('APOBEC3A', 'Gene', '200315', (37, 45))	('mutable', 'Var', (52, 59))
35786	30759888	Overall, the weight matrix approach revealed that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in the studied cancer types.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('associated', 'Reg', (86, 96))	('AID', 'Disease', 'None', (115, 118))	('AID', 'Disease', (115, 118))	('APOBEC', 'cellular_component', 'GO:0030895', ('119', '125'))	('somatic mutations', 'Var', (50, 67))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
35810	33336008	Cutaneous melanoma is a highly malignant and invasive skin cancer, in which melanocytes switch to cancerous cells through variations at molecular and biochemical levels.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variations', 'Var', (122, 132))	('invasive skin cancer', 'Phenotype', 'HP:0030447', (45, 65))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cancerous', 'Disease', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (54, 65))	('invasive skin cancer', 'Disease', 'MESH:D012878', (45, 65))	('invasive skin cancer', 'Disease', (45, 65))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('cancerous', 'Disease', 'MESH:D009369', (98, 107))	('Cutaneous melanoma', 'Disease', (0, 18))
35850	33336008	Kan Zhai's study revealed that the gene mutation in 3'-UTR regulates POU2AF1 expression and subsequently gives rise to lymphoma.	('mutation', 'Var', (40, 48))	('expression', 'MPA', (77, 87))	('POU2AF1', 'Gene', (69, 76))	('lymphoma', 'Disease', 'MESH:D008223', (119, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	("3'-UTR", 'Gene', (52, 58))	('regulates', 'Reg', (59, 68))	('gives rise to', 'Reg', (105, 118))	('POU2AF1', 'Gene', '5450', (69, 76))	('lymphoma', 'Disease', (119, 127))
35862	33336008	This finding is consistent with the results of the present study, in which the high expression of ITGAL is a prognostic risk factor for metastatic melanoma.	('ITGAL', 'Gene', '3683', (98, 103))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('high expression', 'Var', (79, 94))	('melanoma', 'Disease', (147, 155))	('ITGAL', 'Gene', (98, 103))
35889	33336008	Furthermore, the rate of lymph node metastasis is higher in the MZB1 high expression group than in the low expression group.	('lymph node metastasis', 'CPA', (25, 46))	('higher', 'PosReg', (50, 56))	('MZB1', 'Gene', (64, 68))	('MZB1', 'Gene', '51237', (64, 68))	('high expression', 'Var', (69, 84))
35891	33336008	The number of patients exhibiting a tumor-free status was higher in the MZB1 high expression group than in the low expression group.	('high expression', 'Var', (77, 92))	('MZB1', 'Gene', (72, 76))	('MZB1', 'Gene', '51237', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('higher', 'PosReg', (58, 64))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', (36, 41))
35982	25580155	Adjuvant cryotherapy induces necrosis of tumor cells during the thawing portion due to the efflux of intracellular contents, and reduces recurrence in comparison to excision alone.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('necrosis', 'biological_process', 'GO:0019835', ('29', '37'))	('necrosis', 'biological_process', 'GO:0001906', ('29', '37'))	('efflux of intracellular contents', 'MPA', (91, 123))	('necrosis', 'biological_process', 'GO:0008220', ('29', '37'))	('efflux', 'biological_process', 'GO:0140115', ('91', '97'))	('efflux', 'biological_process', 'GO:0140352', ('91', '97'))	('cryotherapy', 'Var', (9, 20))	('recurrence', 'CPA', (137, 147))	('necrosis of tumor', 'Disease', (29, 46))	('necrosis', 'biological_process', 'GO:0070265', ('29', '37'))	('necrosis', 'biological_process', 'GO:0008219', ('29', '37'))	('necrosis of tumor', 'Disease', 'MESH:D009336', (29, 46))	('reduces', 'NegReg', (129, 136))
35989	25580155	Less commonly, damage to the eyelids, uvea, and extraocular muscles may result in ectropion, uveitis, and possible paralysis of extraocular muscles especially if muscle insertion sites are involved.	('paralysis', 'Phenotype', 'HP:0003470', (115, 124))	('uvea', 'Disease', 'MESH:C536494', (38, 42))	('ectropion', 'Disease', (82, 91))	('paralysis', 'Disease', 'MESH:D010243', (115, 124))	('uveitis', 'Phenotype', 'HP:0000554', (93, 100))	('ectropion', 'Phenotype', 'HP:0000656', (82, 91))	('result in', 'Reg', (72, 81))	('uveitis', 'Disease', 'MESH:D014605', (93, 100))	('uvea', 'Disease', (38, 42))	('paralysis', 'Disease', (115, 124))	('damage', 'Var', (15, 21))	('uveitis', 'Disease', (93, 100))
36004	25580155	The regimen in this case is most commonly 0.04% four times a day for cycles of 14 consecutive days with 1-week intervals in between cycles to avoid toxicity from prolonged exposure to MMC.	('MMC', 'Chemical', 'MESH:D016685', (184, 187))	('toxicity', 'Disease', (148, 156))	('0.04%', 'Var', (42, 47))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))
36015	25580155	The regimens when MMC was used as adjuvant therapy following surgical excision of CMM, were 0.04% MMC four times a day for 1 week, for three weeks followed by one week of topical corticosteroid, for 4 weeks, or for 3 weeks followed by 3 weeks without MMC over an average of 2.0 cycles.	('CMM', 'Gene', (82, 85))	('topical', 'molecular_function', 'GO:0003809', ('171', '178'))	('CMM', 'Gene', '1243', (82, 85))	('MMC', 'Chemical', 'MESH:D016685', (98, 101))	('0.04%', 'Var', (92, 97))	('CMM', 'Phenotype', 'HP:0007716', (82, 85))	('MMC', 'Chemical', 'MESH:D016685', (251, 254))	('MMC', 'Chemical', 'MESH:D016685', (18, 21))
36019	25580155	In a study of 91 patients with OSSN treated with 0.04% MMC four times a day for 1-3 cycles of 7 consecutive days, patients most commonly complained of an allergic reaction (31/91 or 34%) after the second or third cycle, and epiphora secondary to punctal stenosis after a median of 2 months (14/91 or 15%).	('epiphora', 'Phenotype', 'HP:0009926', (224, 232))	('allergic reaction', 'Phenotype', 'HP:0012393', (154, 171))	('0.04%', 'Var', (49, 54))	('epiphora secondary to punctal stenosis', 'Disease', 'MESH:D007766', (224, 262))	('MMC', 'Chemical', 'MESH:D016685', (55, 58))	('allergic reaction', 'Disease', 'MESH:D004342', (154, 171))	('epiphora secondary to punctal stenosis', 'Disease', (224, 262))	('patients', 'Species', '9606', (17, 25))	('punctal stenosis', 'Phenotype', 'HP:0025572', (246, 262))	('complained', 'Reg', (137, 147))	('patients', 'Species', '9606', (114, 122))	('allergic reaction', 'Disease', (154, 171))	('OSSN', 'Chemical', '-', (31, 35))
36039	25580155	Brachytherapy has also been reported to reduce recurrence in comparison to excision alone, excision with cryotherapy, or excision with MMC, although results were only statistically significant when compared against excision with cryotherapy.	('reduce', 'NegReg', (40, 46))	('MMC', 'Chemical', 'MESH:D016685', (135, 138))	('Brachytherapy', 'Var', (0, 13))	('recurrence', 'MPA', (47, 57))
36074	25580155	A trial is currently underway to evaluate SLNB through the outcome measures of: frequency of SLNB positivity in CMM, false negative rate for this measure, and identifying any ocular or periocular complications of the technique and risk of facial nerve damage (ClinicalTrials.gov Identifier: NCT00386906).	('false', 'biological_process', 'GO:0071878', ('117', '122'))	('facial nerve damage', 'Disease', 'MESH:D005155', (239, 258))	('facial nerve damage', 'Phenotype', 'HP:0010628', (239, 258))	('CMM', 'Gene', '1243', (112, 115))	('CMM', 'Phenotype', 'HP:0007716', (112, 115))	('SLNB', 'Gene', (93, 97))	('false', 'biological_process', 'GO:0071877', ('117', '122'))	('facial nerve damage', 'Disease', (239, 258))	('positivity', 'Var', (98, 108))	('CMM', 'Gene', (112, 115))
36102	25580155	The treatment of cutaneous melanoma has been revolutionized by the discovery of unique genetic mutations in affected tissues, and the novel biological therapies that have been developed to target the downstream effects of these mutations.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (17, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('mutations', 'Var', (95, 104))	('cutaneous melanoma', 'Disease', (17, 35))
36109	25580155	Vemurafenib and dabrafenib are highly selective BRAF-kinase inhibitors, a mutation found in 60 percent of cutaneous melanomas, primarily at the V600E position.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (106, 125))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (106, 125))	('V600E', 'Var', (144, 149))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('cutaneous melanomas', 'Disease', (106, 125))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('V600E', 'Mutation', 'rs113488022', (144, 149))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (106, 124))
36115	25580155	BRAF has received the most attention, due to a high level of concordance in the BRAF mutation between cutaneous and conjunctival melanoma.	('BRAF', 'Gene', (80, 84))	('conjunctival melanoma', 'Disease', (116, 137))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (116, 137))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (116, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('cutaneous', 'Disease', (102, 111))	('mutation', 'Var', (85, 93))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (80, 84))
36116	25580155	A total of 6 case series were found in the literature assessing the presence of BRAF mutations in CMM, covering a total of 163 cases (Table 9).	('BRAF', 'Gene', (80, 84))	('CMM', 'Gene', '1243', (98, 101))	('CMM', 'Phenotype', 'HP:0007716', (98, 101))	('mutations', 'Var', (85, 94))	('BRAF', 'Gene', '673', (80, 84))	('CMM', 'Gene', (98, 101))
36120	25580155	Interestingly, the idea has been proposed that there is the potential for synergistic effect should ipilimumab and vemurafenib be combined, as BRAF inhibitors can cause higher tumor recognition by T-cells which would be activated by the effects of ipilimumab, and this treatment may be explored in clinical trials in the future.	('inhibitors', 'Var', (148, 158))	('higher', 'PosReg', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ipilimumab', 'Chemical', 'MESH:D000074324', (100, 110))	('ipilimumab', 'Chemical', 'MESH:D000074324', (248, 258))	('tumor', 'Disease', (176, 181))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('vemurafenib', 'Chemical', 'MESH:D000077484', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
36130	25580155	NRAS is an oncogene in the Ras family that encodes a GTPase which, when mutated, activates a signal transduction pathway that leads to unregulated cell division.	('mutated', 'Var', (72, 79))	('leads to', 'Reg', (126, 134))	('signal transduction', 'biological_process', 'GO:0007165', ('93', '112'))	('signal transduction pathway', 'Pathway', (93, 120))	('activates', 'PosReg', (81, 90))	('NRAS', 'Gene', (0, 4))	('unregulated', 'MPA', (135, 146))	('cell division', 'biological_process', 'GO:0051301', ('147', '160'))	('NRAS', 'Gene', '4893', (0, 4))
36134	25580155	Other genetic patterns in CMM reported include amplification of copy numbers CDKN1A and RUNX2 in primary tumors, and amplification of MLH1 and TIMP2, and deletion of MGMT and ECHS1 in metastasis-origin tumors.	('tumors', 'Disease', (105, 111))	('ECHS1', 'Gene', '1892', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('metastasis-origin', 'CPA', (184, 201))	('MLH1', 'Gene', (134, 138))	('amplification', 'Reg', (47, 60))	('CMM', 'Gene', (26, 29))	('RUNX2', 'Gene', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('TIMP2', 'Gene', (143, 148))	('RUNX2', 'Gene', '860', (88, 93))	('MLH1', 'Gene', '4292', (134, 138))	('MGMT', 'Gene', '4255', (166, 170))	('primary tumors', 'Disease', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('CMM', 'Gene', '1243', (26, 29))	('ECHS1', 'Gene', (175, 180))	('primary tumors', 'Disease', 'MESH:D009369', (97, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('MGMT', 'molecular_function', 'GO:0003908', ('166', '170'))	('TIMP2', 'Gene', '7077', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CDKN1A', 'Gene', (77, 83))	('MGMT', 'Gene', (166, 170))	('CMM', 'Phenotype', 'HP:0007716', (26, 29))	('tumors', 'Disease', (202, 208))	('CDKN1A', 'Gene', '1026', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('deletion', 'Var', (154, 162))	('amplification', 'Var', (117, 130))
36137	25580155	found that monosomy 3 was found in uveal melanoma whereas losses in 9p, gains in chromosome 7 or amplifications of CCND1 centromere proximal chromosomal areas of chromosome 11 favored CMM.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('CCND1', 'Gene', (115, 120))	('gains', 'PosReg', (72, 77))	('CMM', 'Gene', '1243', (184, 187))	('uveal melanoma', 'Disease', (35, 49))	('chromosome 7', 'Gene', (81, 93))	('CMM', 'Phenotype', 'HP:0007716', (184, 187))	('centromere', 'cellular_component', 'GO:0005698', ('121', '131'))	('chromosome', 'cellular_component', 'GO:0005694', ('81', '91'))	('monosomy', 'Disease', (11, 19))	('CCND1', 'Gene', '595', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('CMM', 'Gene', (184, 187))	('centromere', 'cellular_component', 'GO:0000775', ('121', '131'))	('losses', 'NegReg', (58, 64))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('amplifications', 'Var', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
36146	25580155	The exciting advent of tumor specific mutations, and biological therapies that combat these mutations, have yielded promising results in cutaneous melanoma and this approach is currently being mirrored in CMM.	('CMM', 'Gene', '1243', (205, 208))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('CMM', 'Phenotype', 'HP:0007716', (205, 208))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('CMM', 'Gene', (205, 208))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('tumor', 'Disease', (23, 28))	('cutaneous melanoma', 'Disease', (137, 155))
36150	25580155	With regards to treatment, genetic evaluation of tumor and tumor specific biological therapies to combat mutations are an exciting new frontier.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
36164	32185171	Some others are specific for one or more skin cancer types, like miR-21 and miR-221 for cutaneous melanoma and cutaneous squamous carcinoma or miR-155 for melanoma and cutaneous lymphoma.	('miR-221', 'Gene', '407006', (76, 83))	('cutaneous lymphoma', 'Phenotype', 'HP:0012192', (168, 186))	('miR-155', 'Var', (143, 150))	('cutaneous squamous carcinoma', 'Disease', 'MESH:D002294', (111, 139))	('melanoma and cutaneous lymphoma', 'Disease', 'MESH:C562393', (155, 186))	('skin cancer', 'Disease', (41, 52))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (121, 139))	('miR-21', 'Gene', '406991', (65, 71))	('cutaneous squamous carcinoma', 'Disease', (111, 139))	('skin cancer', 'Phenotype', 'HP:0008069', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cutaneous squamous carcinoma', 'Phenotype', 'HP:0006739', (111, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('miR-221', 'Gene', (76, 83))	('miR-21', 'Gene', (65, 71))	('cutaneous melanoma', 'Disease', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('skin cancer', 'Disease', 'MESH:D012878', (41, 52))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))
36167	32185171	In the last decade, the dramatic increase of diseases that are linked to changes in RNA modifications has shown that the epitranscriptomic domain will impact health science.	('RNA modifications', 'Gene', (84, 101))	('increase of diseases', 'Disease', 'MESH:D019586', (33, 53))	('RNA', 'cellular_component', 'GO:0005562', ('84', '87'))	('impact', 'Reg', (151, 157))	('health science', 'MPA', (158, 172))	('changes', 'Var', (73, 80))	('increase of diseases', 'Disease', (33, 53))
36169	32185171	Through this action, miRNAs are involved in many physiological processes, and any deregulations at this level will trigger abnormalities and further human diseases.	('abnormalities', 'CPA', (123, 136))	('human', 'Species', '9606', (149, 154))	('deregulations', 'Var', (82, 95))	('involved', 'Reg', (32, 40))	('trigger', 'Reg', (115, 122))
36182	32185171	miR-205-5p overexpression in spindle cancer cells was shown to decrease tumor cell proliferation and invasiveness.	('miR-205-5p', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('cancer', 'Disease', (37, 43))	('tumor', 'Disease', (72, 77))	('invasiveness', 'CPA', (101, 113))	('decrease', 'NegReg', (63, 71))	('spindle', 'cellular_component', 'GO:0005819', ('29', '36'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('overexpression', 'PosReg', (11, 25))
36189	32185171	Almost concomitantly, another group has shown that skin cancer is associated with the methylation status of miRNA-148a.	('miRNA-148a', 'Gene', (108, 118))	('methylation status', 'Var', (86, 104))	('associated', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('skin cancer', 'Disease', (51, 62))	('skin cancer', 'Disease', 'MESH:D012878', (51, 62))
36192	32185171	age, pathological differentiation, and lymph node metastasis) and with patient's survival; therefore, miR-148a methylation status can be a candidate for a prognostic biomarker in skin cancer.	('miR-148a', 'Gene', '406940', (102, 110))	('methylation status', 'Var', (111, 129))	('skin cancer', 'Phenotype', 'HP:0008069', (179, 190))	('miR-148a', 'Gene', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('skin cancer', 'Disease', (179, 190))	('skin cancer', 'Disease', 'MESH:D012878', (179, 190))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('patient', 'Species', '9606', (71, 78))
36199	32185171	Dissimilarly, if deletion, mutations, or epigenetic silencing is active on a tumor-suppressive miRNA that would normally regulate oncogenes, this may lead to enhanced oncogenic activity.	('mutations', 'Var', (27, 36))	('epigenetic silencing', 'Var', (41, 61))	('enhanced', 'PosReg', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('oncogenic activity', 'CPA', (167, 185))	('deletion', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
36210	32185171	Especially for primary melanomas, this approach showed the downregulation of intra-tumor expression for several miRNA species, such as miR-125b, miR-182, miR-200c, and miR-205, which could promote tumor dissemination.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (83, 88))	('intra-tumor', 'Disease', 'MESH:D009369', (77, 88))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('miR-125b', 'Var', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('miR-205', 'Var', (168, 175))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('miR-200c', 'Gene', '406985', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('downregulation', 'NegReg', (59, 73))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('miR-182', 'Gene', (145, 152))	('miR-200c', 'Gene', (154, 162))	('promote', 'PosReg', (189, 196))	('intra-tumor', 'Disease', (77, 88))	('miR-182', 'Gene', '406958', (145, 152))	('melanomas', 'Disease', (23, 32))	('tumor', 'Disease', (197, 202))
36211	32185171	The TaqMan method could label miRNA-125b, miRNA-200c, and miRNA-205 as useful prognostic biomarkers correlated with shorter survival and, thus, able to select high-risk patients.	('shorter', 'NegReg', (116, 123))	('patients', 'Species', '9606', (169, 177))	('miRNA-125b', 'Var', (30, 40))	('miRNA-200c', 'Var', (42, 52))	('miRNA-205', 'Var', (58, 67))
36235	32185171	Therefore, there are conflicting results that show a miRNA as an oncomir in one type of cancer while in others the same molecule is a tumor suppressor.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('134', '150'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('miRNA', 'Var', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor suppressor', 'biological_process', 'GO:0051726', ('134', '150'))	('tumor', 'Disease', (134, 139))
36241	32185171	But not only genetic alterations, which characterize this skin cancer, epigenetic deregulation was also identified concerning melanoma initiation and progression.	('melanoma initiation', 'Disease', (126, 145))	('epigenetic deregulation', 'Var', (71, 94))	('skin cancer', 'Phenotype', 'HP:0008069', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('skin cancer', 'Disease', (58, 69))	('skin cancer', 'Disease', 'MESH:D012878', (58, 69))	('melanoma initiation', 'Disease', 'MESH:D008545', (126, 145))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))
36246	32185171	In melanoma, miR-21, miR-125b, miR-150, miR-155, miR-205, and miR-211 were the molecules that were searched for their prognostic value and for which targeted therapy was developed to obliviate their onco-miRNA action.	('miR-21', 'Gene', (13, 19))	('miR-125b', 'Var', (21, 29))	('miR-21', 'Gene', (62, 68))	('miR-205', 'Var', (49, 56))	('miR-21', 'Gene', '406991', (13, 19))	('miR-155', 'Var', (40, 47))	('miR-21', 'Gene', '406991', (62, 68))	('miR-150', 'Gene', (31, 38))	('melanoma', 'Disease', (3, 11))	('miR-150', 'Gene', '406942', (31, 38))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
36266	32185171	This was one of the first studies to identify circulating miRNAs in melanoma, and this finding would indicate the prognostic value of circulating miR-199a-5p, miR-33a, and miR-424.	('miR-33a', 'Gene', (159, 166))	('miR-424', 'Gene', '494336', (172, 179))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('miR-199a-5p', 'Var', (146, 157))	('miR-33a', 'Gene', '407039', (159, 166))	('miR-424', 'Gene', (172, 179))
36279	32185171	Aberrant genes associated with melanoma (e.g.	('Aberrant genes', 'Var', (0, 14))	('associated', 'Reg', (15, 25))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))
36281	32185171	let-7a and b, miR-148, miR-155, miR-182, miR-200c, miR-211, miR-214, miR-221, and miR-222) and can aid the large set of potential biomarkers and/or therapeutic targets in melanoma.	('miR-222', 'Gene', '407007', (82, 89))	('miR-221', 'Gene', (69, 76))	('let-7a', 'Gene', (0, 6))	('miR-211', 'Var', (51, 58))	('miR-214', 'Gene', (60, 67))	('miR-182', 'Gene', '406958', (32, 39))	('miR-222', 'Gene', (82, 89))	('miR-148', 'Var', (14, 21))	('miR-200c', 'Gene', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('miR-200c', 'Gene', '406985', (41, 49))	('miR-221', 'Gene', '407006', (69, 76))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('miR-214', 'Gene', '406996', (60, 67))	('miR-155', 'Var', (23, 30))	('miR-182', 'Gene', (32, 39))
36284	32185171	MELmiR-7 consists of miR-16, miR-211-5p, miR-4487, miR-4706, miR-4731, and miR-509-5p.	('miR-509-5p', 'Gene', '100616458', (75, 85))	('miR-4487', 'Gene', '100616222', (41, 49))	('miR-4731', 'Gene', '100616125', (61, 69))	('miR-211-5p', 'Var', (29, 39))	('miR-7', 'Gene', '10859', (3, 8))	('miR-16', 'Gene', (21, 27))	('miR-4706', 'Gene', (51, 59))	('miR-16', 'Gene', '51573', (21, 27))	('miR-4706', 'Gene', '100616490', (51, 59))	('miR-4487', 'Gene', (41, 49))	('miR-509-5p', 'Gene', (75, 85))	('miR-4731', 'Gene', (61, 69))	('miR-7', 'Gene', (3, 8))
36287	32185171	Using quantitative in situ hybridization (qISH) on over 100 primary melanomas, a test that was further validated on over 200 additional samples, low levels of miR-205 were shown to be correlated with lower survival in patients.	('patients', 'Species', '9606', (218, 226))	('melanomas', 'Disease', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('miR-205', 'Var', (159, 166))	('lower', 'NegReg', (200, 205))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('survival', 'MPA', (206, 214))	('melanomas', 'Disease', 'MESH:D008545', (68, 77))
36288	32185171	Thus, miR-205 was reported as a tumor suppressor miRNA in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('miR-205', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
36303	32185171	This mechanistic study proved that polymorphisms in the 3'-UTR of TYRP1 mRNA affect the regulation performed by miR-155 and, further, its translation into the protein.	('TYRP1', 'Gene', '7306', (66, 71))	('translation', 'biological_process', 'GO:0006412', ('138', '149'))	('miR-155', 'Gene', (112, 119))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('affect', 'Reg', (77, 83))	('regulation', 'biological_process', 'GO:0065007', ('88', '98'))	('regulation performed', 'MPA', (88, 108))	('polymorphisms', 'Var', (35, 48))	('translation', 'MPA', (138, 149))	('TYRP1', 'Gene', (66, 71))
36305	32185171	In an experimental mouse model, it was shown that miR-155 increased the expression and silenced WEE1, leading to decreased metastases.	('WEE1', 'Gene', (96, 100))	('increased', 'PosReg', (58, 67))	('silenced', 'Var', (87, 95))	('expression', 'MPA', (72, 82))	('miR-155', 'Var', (50, 57))	('metastases', 'Disease', (123, 133))	('mouse', 'Species', '10090', (19, 24))	('metastases', 'Disease', 'MESH:D009362', (123, 133))	('decreased', 'NegReg', (113, 122))
36318	32185171	The combination of miR-125b, miR-200c, and miR-205 was found to be correlated with shorter survival.	('miR-200c', 'Gene', (29, 37))	('miR-125b', 'Var', (19, 27))	('miR-200c', 'Gene', '406985', (29, 37))	('shorter', 'NegReg', (83, 90))	('miR-205', 'Var', (43, 50))
36320	32185171	The panel of miR-125b, miR-200c, and miR-205 can be developed in a prognostic biomarker panel and for selecting high-risk-recurrence patients.	('miR-125b', 'Var', (13, 21))	('miR-200c', 'Gene', (23, 31))	('patients', 'Species', '9606', (133, 141))	('miR-200c', 'Gene', '406985', (23, 31))	('miR-205', 'Var', (37, 44))
36321	32185171	Earlier studies have shown that global miRNA expression profiles are differentially expressed in correlation with BRAF mutation.	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('global miRNA expression profiles', 'MPA', (32, 64))
36322	32185171	Therefore, when BRAF mutation appears, several miRNAs were found underexpressed, namely, miR-193a, miR-338, and miR-565.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('miR-338', 'Gene', (99, 106))	('mutation', 'Var', (21, 29))	('miR-565', 'Var', (112, 119))	('miR-338', 'Gene', '442906', (99, 106))	('miR-193a', 'Gene', '406968', (89, 97))	('miR-193a', 'Gene', (89, 97))
36325	32185171	This panel of miRNAs comprised the following molecules: miR-150, miR-342-3p, miR-455-3p, miR-145, miR-155, and miR-497.	('miR-342-3p', 'Var', (65, 75))	('miR-150', 'Gene', '406942', (56, 63))	('miR-455-3p', 'Var', (77, 87))	('miR-145', 'Gene', (89, 96))	('miR-145', 'Gene', '406937', (89, 96))	('miR-497', 'Gene', (111, 118))	('miR-155', 'Var', (98, 105))	('miR-497', 'Gene', '574456', (111, 118))	('miR-150', 'Gene', (56, 63))
36333	32185171	MiR-146a-5p regulates several important cellular pathways like Toll-like receptor, NF-kappaB, and ErB.	('regulates', 'Reg', (12, 21))	('Toll-like receptor', 'Pathway', (63, 81))	('NF-kappaB', 'Pathway', (83, 92))	('ErB', 'Gene', (98, 101))	('ErB', 'Gene', '2100', (98, 101))	('MiR-146a-5p', 'Var', (0, 11))
36334	32185171	Actually, miRNA-146a-5p targets almost 40 genes, one of them being the well-known NRAS gene.	('NRAS', 'Gene', '4893', (82, 86))	('miRNA-146a-5p', 'Var', (10, 23))	('NRAS', 'Gene', (82, 86))
36336	32185171	Cross-validation between these two datasets revealed five miRNAs (miR-142-5p, miR-150-5p, miR-342-3p, miR-155-5p, and miR-146b-5p) that were highly and reproducibly associated with clinical patient prognosis.	('miR-342-3p', 'Var', (90, 100))	('miR-142', 'Gene', (66, 73))	('miR-150', 'Gene', (78, 85))	('associated', 'Reg', (165, 175))	('miR-146b', 'Gene', (118, 126))	('miR-150', 'Gene', '406942', (78, 85))	('miR-146b', 'Gene', '574447', (118, 126))	('miR-142', 'Gene', '406934', (66, 73))	('miR-155-5p', 'Var', (102, 112))	('patient', 'Species', '9606', (190, 197))
36352	32185171	Using microarray analysis validated by qRT-PCR, improved molecular tissue markers were reported when three miRNAs (namely, miR-200c, miR-205, and miR-211) were found differentially expressed in primary compared to metastatic melanomas, these miRNAs acting like tumor suppressors.	('miR-205', 'Var', (133, 140))	('melanomas', 'Phenotype', 'HP:0002861', (225, 234))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('melanomas', 'Disease', 'MESH:D008545', (225, 234))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('miR-211', 'Var', (146, 153))	('miR-200c', 'Gene', (123, 131))	('miR-200c', 'Gene', '406985', (123, 131))	('melanomas', 'Disease', (225, 234))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
36357	32185171	Particular determinants like genetic mutation(s), particular epigenetic features, and the host's immune response are important criteria for predicting patient outcomes.	('patient', 'Species', '9606', (151, 158))	('epigenetic features', 'Var', (61, 80))	('immune response', 'biological_process', 'GO:0006955', ('97', '112'))	('genetic mutation', 'Var', (29, 45))
36358	32185171	With the advent of targeted therapy in melanoma, namely, BRAF kinase inhibitors for BRAF mutant tumors, epigenetic studies emerged focusing on the processes that underlie therapy resistance.	('BRAF', 'Gene', '673', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BRAF', 'Gene', '673', (57, 61))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('tumors', 'Disease', (96, 102))	('melanoma', 'Disease', (39, 47))	('BRAF', 'Gene', (84, 88))	('BRAF', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutant', 'Var', (89, 95))
36365	32185171	MiR-579-3p targets the 3'-UTR region of oncoproteins BRAF and E3 ubiquitin-protein ligase, MDM2.	('BRAF', 'Gene', '673', (53, 57))	('MDM2', 'Gene', '4193', (91, 95))	('BRAF', 'Gene', (53, 57))	('MDM2', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('MiR-579-3p', 'Var', (0, 10))	('oncoproteins', 'Protein', (40, 52))	('ubiquitin', 'molecular_function', 'GO:0031386', ('65', '74'))
36366	32185171	In tumor samples harvested before and after therapy resistance occurrence, miR-579-3p is strongly downregulated upon resistance installment.	('downregulated', 'NegReg', (98, 111))	('tumor', 'Disease', (3, 8))	('miR-579-3p', 'Var', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
36369	32185171	Bisulfite sequencing PCR technology indicated that DNA hypermethylation induced the downregulation of miR-211 in tumor tissues.	('tumor', 'Disease', (113, 118))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('51', '71'))	('DNA hypermethylation', 'Var', (51, 71))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('miR-211', 'Gene', (102, 109))	('downregulation', 'NegReg', (84, 98))
36370	32185171	Reversing the process, namely, the epigenetic modification that downregulates miR-211, chemosensitivity of melanoma cells can be achieved.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('downregulates', 'NegReg', (64, 77))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('chemosensitivity', 'CPA', (87, 103))	('epigenetic modification', 'Var', (35, 58))	('miR-211', 'Gene', (78, 85))
36371	32185171	Resistance to MAK inhibitors was shown to be associated with another miRNA, namely, miR-214.	('miR-214', 'Gene', (84, 91))	('associated', 'Reg', (45, 55))	('miR-214', 'Gene', '406996', (84, 91))	('Resistance', 'Var', (0, 10))	('MAK', 'Enzyme', (14, 17))
36379	32185171	miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, and miR-99b) is related to MDSCs and immune checkpoint inhibitor resistance.	('MDSCs', 'Disease', (93, 98))	('miR-99b', 'Gene', '407056', (70, 77))	('miR-125b', 'Var', (19, 27))	('miR-125a', 'Gene', (46, 54))	('MDSCs', 'Disease', 'None', (93, 98))	('miR-146a', 'Gene', (0, 8))	('let-7e', 'Gene', (38, 44))	('miR-155', 'Var', (10, 17))	('miR-100', 'Gene', '406892', (29, 36))	('miR-146b', 'Gene', (56, 64))	('related', 'Reg', (82, 89))	('miR-100', 'Gene', (29, 36))	('miR-146b', 'Gene', '574447', (56, 64))	('miR-125a', 'Gene', '406910', (46, 54))	('let-7e', 'Gene', '406887', (38, 44))	('miR-146a', 'Gene', '406938', (0, 8))	('miR-99b', 'Gene', (70, 77))
36403	32185171	As miRNAs regulate over 60% of human genes and since cutaneous melanoma has a high genetic heterogeneity, miRNA alterations, stable and detectable in tissue/body fluids, make them robust candidate biomarkers in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (211, 219))	('human', 'Species', '9606', (31, 36))	('cutaneous melanoma', 'Disease', (53, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (53, 71))	('alterations', 'Var', (112, 123))	('melanoma', 'Disease', (63, 71))
36436	32185171	The group of Maj has identified, after isolation, reverse transcriptase reactions, and cDNA amplification, a panel of miRNAs: miR-15a, miR-16, miR-155, let-7a, let-7d, and let-7f.	('miR-155', 'Var', (143, 150))	('let-7f', 'Var', (172, 178))	('let-7d', 'Gene', '406886', (160, 166))	('let-7d', 'Gene', (160, 166))	('let-7a', 'Var', (152, 158))	('miR-16', 'Gene', (135, 141))	('transcriptase', 'molecular_function', 'GO:0003899', ('58', '71'))	('transcriptase', 'molecular_function', 'GO:0003968', ('58', '71'))	('miR-16', 'Gene', '51573', (135, 141))	('miR-15a', 'Gene', (126, 133))	('miR-15a', 'Gene', '406948', (126, 133))	('transcriptase', 'molecular_function', 'GO:0034062', ('58', '71'))
36437	32185171	MF was characterized by a miR-155 overexpression, and metastatic MF was found with lower concentrations of let-7a, let-7d, and let-7f.	('let-7d', 'Gene', '406886', (115, 121))	('let-7d', 'Gene', (115, 121))	('let-7f', 'Var', (127, 133))	('overexpression', 'PosReg', (34, 48))	('MF', 'Disease', 'MESH:D009182', (0, 2))	('let-7a', 'Var', (107, 113))	('MF', 'Disease', 'MESH:D009182', (65, 67))
36439	32185171	Low Drosha expression seems to be an independent predictor biomarker for advanced stages.	('Drosha expression', 'Disease', (4, 21))	('Drosha expression', 'Disease', 'MESH:D001039', (4, 21))	('Low', 'Var', (0, 3))
36447	32185171	Low levels of miR-155 and miR-150 were found associated with shorter progression-free survival in primary cutaneous marginal zone B cell lymphomas type.	('shorter', 'NegReg', (61, 68))	('miR-150', 'Gene', (26, 33))	('miR-155', 'Var', (14, 21))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (130, 145))	('miR-150', 'Gene', '406942', (26, 33))	('progression-free survival', 'CPA', (69, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (130, 146))	('cell lymphoma', 'Phenotype', 'HP:0012191', (132, 145))	('lymphomas', 'Disease', (137, 146))	('lymphomas', 'Disease', 'MESH:D008223', (137, 146))	('lymphomas', 'Phenotype', 'HP:0002665', (137, 146))
36545	31660262	found that miRNA-25 directly regulates P57 (a tumor suppressor gene), and the abnormal expression of this miRNA in gastric cancer patients can advance cancer cells from G1 to S phase.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('advance', 'PosReg', (143, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('miR', 'Gene', '220972', (11, 14))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('abnormal', 'Var', (78, 86))	('S phase', 'biological_process', 'GO:0051320', ('175', '182'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', (11, 14))	('cancer', 'Disease', (151, 157))	('gastric cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR', 'Gene', (106, 109))	('tumor', 'Disease', (46, 51))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('P57', 'MPA', (39, 42))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('G1 to S phase', 'CPA', (169, 182))	('regulates', 'Reg', (29, 38))
36562	31660262	Early research of miR-510 did not examine its relationship with cancer, only its aberrant expression in irritable bowel syndrome.	('irritable bowel syndrome', 'Disease', 'MESH:D043183', (104, 128))	('aberrant expression', 'Var', (81, 100))	('irritable', 'Phenotype', 'HP:0000737', (104, 113))	('irritable bowel syndrome', 'Disease', (104, 128))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('miR-510', 'Gene', '574515', (18, 25))	('miR-510', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
36574	31660262	For example, abnormal PI3K-Akt-mTOR signaling is one of the most common dysfunctions present in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('human', 'Species', '9606', (96, 101))	('Akt', 'Gene', '207', (27, 30))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('signaling', 'biological_process', 'GO:0023052', ('36', '45'))	('cancers', 'Disease', (102, 109))	('Akt', 'Gene', (27, 30))	('abnormal', 'Var', (13, 21))
36580	31660262	increased the sensitivity of hepatoma stem cells to TRAIL (Tumor necrosis factor (TNF) -related apoptosis-inducing ligand), reducing apoptosis by knocking out miR-25.	('apoptosis', 'CPA', (133, 142))	('TRAIL', 'Gene', (52, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('miR-25', 'Gene', (159, 165))	('necrosis', 'biological_process', 'GO:0008219', ('65', '73'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('hepatoma', 'Disease', (29, 37))	('Tumor', 'Phenotype', 'HP:0002664', (59, 64))	('Tumor necrosis factor', 'molecular_function', 'GO:0005164', ('59', '80'))	('necrosis', 'biological_process', 'GO:0008220', ('65', '73'))	('reducing', 'NegReg', (124, 132))	('Tumor necrosis', 'Disease', 'MESH:D009336', (59, 73))	('miR-25', 'Gene', '407014', (159, 165))	('necrosis', 'biological_process', 'GO:0070265', ('65', '73'))	('ligand', 'molecular_function', 'GO:0005488', ('115', '121'))	('Tumor necrosis', 'Disease', (59, 73))	('necrosis', 'biological_process', 'GO:0019835', ('65', '73'))	('knocking out', 'Var', (146, 158))	('TRAIL', 'Gene', '8743', (52, 57))	('necrosis', 'biological_process', 'GO:0001906', ('65', '73'))	('sensitivity', 'MPA', (14, 25))	('hepatoma', 'Disease', 'MESH:D006528', (29, 37))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
36597	29385676	Somewhat distinct from sun exposure-related human cutaneous melanomas, there is growing evidence that a variety of gene copy number alterations and protein structure/function mutations play roles in canine melanomas, in circumstances more analogous to human mucosal melanomas and to some extent other melanomas with murine sarcoma viral oncogene homolog B (BRAF), Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog (NRAS), and neurofibromin 1 tumor suppressor NF1 triple wild-type genotype.	('human', 'Species', '9606', (44, 49))	('neurofibromin 1 tumor', 'Phenotype', 'HP:0001067', (425, 446))	('Neuroblastoma RAS Viral', 'Disease', (364, 387))	('Neuroblastoma RAS Viral', 'Disease', 'MESH:D009447', (364, 387))	('melanomas', 'Phenotype', 'HP:0002861', (301, 310))	('mutations', 'Var', (175, 184))	('melanomas', 'Disease', 'MESH:D008545', (266, 275))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('441', '457'))	('tumor', 'Disease', (441, 446))	('mucosal melanomas', 'Disease', 'MESH:D008545', (258, 275))	('sarcoma', 'Disease', 'MESH:D012509', (323, 330))	('murine', 'Species', '10090', (316, 322))	('cutaneous melanomas', 'Disease', (50, 69))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('melanomas', 'Disease', (266, 275))	('sarcoma', 'Disease', (323, 330))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('melanomas', 'Disease', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (441, 446))	('mucosal melanomas', 'Disease', (258, 275))	('tumor suppressor', 'biological_process', 'GO:0051726', ('441', '457'))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('canine', 'Species', '9615', (199, 205))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanomas', 'Phenotype', 'HP:0002861', (266, 275))	('melanomas', 'Disease', 'MESH:D008545', (301, 310))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('human', 'Species', '9606', (252, 257))	('melanomas', 'Disease', (301, 310))	('melanomas', 'Disease', 'MESH:D008545', (206, 215))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (50, 69))	('melanomas', 'Disease', (206, 215))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (50, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (364, 377))
36608	29385676	Large burdens of mutations typically characterize cutaneous melanomas, a feature that adds to the complexity of identifying driver mutations.	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (50, 69))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (50, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mutations', 'Var', (17, 26))	('cutaneous melanomas', 'Disease', (50, 69))
36609	29385676	A significant proportion of cutaneous melanomas harbor recurring (hot spot) mutations in BRAF (approximately 50%), RAS (approximately 20%), and/or NF1 (approximately 25%) genes, and these mutations can be associated with constitutive activation of the MAPK signaling pathway.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('mutations', 'Var', (76, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('252', '256'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('MAPK signaling pathway', 'Pathway', (252, 274))	('RAS', 'Gene', (115, 118))	('cutaneous melanomas', 'Disease', (28, 47))	('NF1', 'Gene', (147, 150))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('signaling pathway', 'biological_process', 'GO:0007165', ('257', '274'))	('BRAF', 'Gene', (89, 93))	('MAPK signaling', 'biological_process', 'GO:0000165', ('252', '266'))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))
36610	29385676	There is also a subgroup of cutaneous melanomas characterized by a lack of BRAF, N/H/K-RAS, or NF1 mutations, which are referred to as the triple wild-type (TWT) subtype.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('NF1', 'Gene', (95, 98))	('BRAF', 'Gene', (75, 79))	('mutations', 'Var', (99, 108))	('cutaneous melanomas', 'Disease', (28, 47))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('N/H/K-RAS', 'Gene', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('lack', 'NegReg', (67, 71))
36614	29385676	Melanoma has been modeled in mice (and zebrafish) engineered to carry defined mutations such as BRAFV600E or NRASQ61R/K (or G12V), or in some cases through inactivation of tumor suppressor genes such as CDKN2A or PTEN to model cutaneous melanomas.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('BRAFV600E', 'Mutation', 'rs113488022', (96, 105))	('tumor', 'Disease', (172, 177))	('CDKN2A', 'Gene', '1029', (203, 209))	('melanomas', 'Phenotype', 'HP:0002861', (237, 246))	('mice', 'Species', '10090', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('inactivation', 'Var', (156, 168))	('G12V', 'Var', (124, 128))	('Melanoma', 'Disease', (0, 8))	('zebrafish', 'Species', '7955', (39, 48))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('G12V', 'Mutation', 'p.G12V', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (227, 246))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (227, 246))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (227, 245))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('BRAFV600E', 'Var', (96, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('172', '188'))	('cutaneous melanomas', 'Disease', (227, 246))	('CDKN2A', 'Gene', (203, 209))	('tumor suppressor', 'biological_process', 'GO:0051726', ('172', '188'))	('PTEN', 'Gene', (213, 217))
36644	29385676	UV exposure is not a risk factor for MM, so tumors lack the high number of UV-signature type mutations found in cutaneous melanoma.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (93, 102))	('cutaneous melanoma', 'Disease', (112, 130))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('MM', 'Phenotype', 'HP:0002861', (37, 39))
36645	29385676	Copy number variants appear to more common in human MM than are BRAF or NRAS mutations, although a few examples with NRAS mutations have been documented (Table 1).	('human', 'Species', '9606', (46, 51))	('Copy number variants', 'Var', (0, 20))	('common', 'Reg', (36, 42))	('MM', 'Phenotype', 'HP:0002861', (52, 54))
36651	29385676	As examples, loss of SPRED1, as well as copy number gains or mutation of V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene (KIT) and V-Myc Avian Myelocytomatosis Viral Oncogene Homolog (MYC), could all contribute to alternative means of promoting MAPK pathway activation in MM.	('V-Myc Avian Myelocytomatosis Viral', 'Disease', (137, 171))	('Sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('mutation', 'Var', (61, 69))	('KIT', 'molecular_function', 'GO:0005020', ('128', '131'))	('SPRED1', 'Gene', (21, 27))	('activation', 'PosReg', (264, 274))	('loss', 'Var', (13, 17))	('SPRED1', 'Gene', '487485', (21, 27))	('Sarcoma Viral', 'Disease', 'MESH:D001102', (104, 117))	('Sarcoma Viral', 'Disease', (104, 117))	('MM', 'Phenotype', 'HP:0002861', (278, 280))	('MYC', 'Gene', '403924', (190, 193))	('MAPK', 'molecular_function', 'GO:0004707', ('251', '255'))	('KIT', 'Gene', (128, 131))	('promoting', 'PosReg', (241, 250))	('MYC', 'Gene', (190, 193))	('V-Myc Avian Myelocytomatosis Viral', 'Disease', 'MESH:D001715', (137, 171))	('MAPK pathway', 'Pathway', (251, 263))	('copy number gains', 'Var', (40, 57))
36652	29385676	Manifestly, despite the relative infrequency of BRAF and NRAS mutations, MAPK pathway activation appears to be a feature exhibited fairly commonly in both canine and human MM.	('activation', 'PosReg', (86, 96))	('canine', 'Species', '9615', (155, 161))	('MM', 'Phenotype', 'HP:0002861', (172, 174))	('MAPK pathway', 'Pathway', (73, 85))	('NRAS', 'Gene', (57, 61))	('human', 'Species', '9606', (166, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('73', '77'))	('BRAF', 'Gene', (48, 52))	('mutations', 'Var', (62, 71))
36654	29385676	Altered signaling of this nature can be influenced by inactivation of the tumor suppressor PTEN.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('influenced', 'Reg', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('signaling', 'biological_process', 'GO:0023052', ('8', '17'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('signaling', 'MPA', (8, 17))	('inactivation', 'Var', (54, 66))
36655	29385676	In addition to PTEN, genes including TP53 and ubiquitin ligase proto-oncogene (MDM2) were found to be mutated in some of the eight human MM studied.	('ubiquitin', 'molecular_function', 'GO:0031386', ('46', '55'))	('MM', 'Phenotype', 'HP:0002861', (137, 139))	('human', 'Species', '9606', (131, 136))	('PTEN', 'Gene', (15, 19))	('MDM2', 'Gene', (79, 83))	('MDM2', 'Gene', '4193', (79, 83))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('mutated', 'Var', (102, 109))
36660	29385676	In some canine MM melanomas, pathway activation may be due loss of PTEN, mutations in NRAS occur in a few cases (similar to human MM), or over-expression of receptor tyrosine kinases, such as platelet derived growth factor receptor (PDGFR) could be possible.	('NRAS', 'Gene', (86, 90))	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('PDGFR', 'Gene', '5159', (233, 238))	('platelet derived growth factor', 'molecular_function', 'GO:0005161', ('192', '222'))	('canine', 'Species', '9615', (8, 14))	('pathway activation', 'PosReg', (29, 47))	('platelet derived growth factor receptor', 'Gene', (192, 231))	('PTEN', 'Protein', (67, 71))	('platelet derived growth factor receptor', 'Gene', '5159', (192, 231))	('melanomas', 'Disease', (18, 27))	('human', 'Species', '9606', (124, 129))	('MM', 'Phenotype', 'HP:0002861', (130, 132))	('PDGFR', 'Gene', (233, 238))	('loss', 'NegReg', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('mutations', 'Var', (73, 82))	('MM', 'Phenotype', 'HP:0002861', (15, 17))
36662	29385676	In light of the emerging recognition that copy number variations appear to underpin a component of mucosal melanomagenesis in both species, future focus of melanoma genomics should shift towards a wider survey of the genetic landscape.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('underpin', 'Reg', (75, 83))	('copy number variations', 'Var', (42, 64))	('mucosal melanomagenesis', 'Disease', (99, 122))	('mucosal melanomagenesis', 'Disease', 'MESH:D052016', (99, 122))
36676	29385676	Identification of the V600E canonical BRAF mutations in human cutaneous melanoma led to the development of efficacious small molecule inhibitors.	('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))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('human', 'Species', '9606', (56, 61))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (22, 27))
36679	29385676	Comparatively, in vitro studies of canine urinary bladder transitional cell carcinoma harboring orthologous BRAFV600E mutations (e.g., canine V595E) have shown response to the BRAF kinase inhibitor Vemurafenib, while tumor cells with wild-type BRAF were unresponsive to the drug.	('bladder transitional cell carcinoma', 'Phenotype', 'HP:0006740', (50, 85))	('tumor', 'Disease', (217, 222))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (198, 209))	('canine', 'Species', '9615', (135, 141))	('canine', 'Species', '9615', (35, 41))	('carcinoma', 'Disease', 'MESH:D002277', (76, 85))	('V595E', 'Mutation', 'p.V595E', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('response', 'MPA', (160, 168))	('mutations', 'Var', (118, 127))	('BRAFV600E', 'Mutation', 'rs113488022', (108, 117))	('bladder transitional', 'Phenotype', 'HP:0100645', (50, 70))	('carcinoma', 'Disease', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('181', '197'))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('BRAFV600E', 'Gene', (108, 117))	('BRAF', 'Enzyme', (176, 180))
36680	29385676	Although canine MM would likely be unresponsive to this BRAF kinase inhibitor, since the ortholog to the V600E mutant is not a frequent event in this tumor type, the rational targeting of the BRAF mutant is validated in canine cancer.	('canine', 'Species', '9615', (220, 226))	('canine', 'Species', '9615', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('V600E', 'Var', (105, 110))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('MM', 'Phenotype', 'HP:0002861', (16, 18))	('tumor', 'Disease', (150, 155))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('61', '77'))
36681	29385676	The existence of activating mutations or gene amplification of the proto-oncogene KIT in human MM makes KIT a putative therapeutic target.	('human', 'Species', '9606', (89, 94))	('gene amplification', 'Var', (41, 59))	('activating', 'PosReg', (17, 27))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('MM', 'Phenotype', 'HP:0002861', (95, 97))
36683	29385676	Interestingly, clinical response to Imatinib was limited to mucosal melanomas with KIT mutations, while tumors with amplification of wild-type KIT had no response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('mucosal melanomas', 'Disease', 'MESH:D008545', (60, 77))	('KIT', 'Gene', (83, 86))	('KIT', 'molecular_function', 'GO:0005020', ('143', '146'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('KIT', 'molecular_function', 'GO:0005020', ('83', '86'))	('tumors', 'Disease', (104, 110))	('Imatinib', 'Chemical', 'MESH:D000068877', (36, 44))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('mucosal melanomas', 'Disease', (60, 77))	('mutations', 'Var', (87, 96))
36685	29385676	As an example of translational medicine, masitinib mesylate (AB1010) was initially approved in veterinary medicine for the treatment of unresectable canine mast cell tumors activated by KIT mutation.	('mutation', 'Var', (190, 198))	('mast cell tumors', 'Phenotype', 'HP:0100495', (156, 172))	('KIT', 'molecular_function', 'GO:0005020', ('186', '189'))	('canine', 'Species', '9615', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KIT', 'Gene', (186, 189))	('mast cell tumor', 'Phenotype', 'HP:0100495', (156, 171))	('masitinib mesylate', 'Chemical', 'MESH:C526575', (41, 59))	('activated by', 'Reg', (173, 185))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
36693	29385676	Through apparent signaling crosstalk analogous to several human cancers, targeting PI3K/mTOR in canine MM, which resulted in diminished downstream p-S6 and eIF4E expression, induced reciprocal activation of p-ERK in some cell lines.	('human', 'Species', '9606', (58, 63))	('eIF4E', 'Gene', (156, 161))	('ERK', 'Gene', (209, 212))	('p-S6', 'Protein', (147, 151))	('PI3K/mTOR', 'Var', (83, 92))	('MM', 'Phenotype', 'HP:0002861', (103, 105))	('activation', 'PosReg', (193, 203))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('eIF4', 'cellular_component', 'GO:0008304', ('156', '160'))	('canine', 'Species', '9615', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('diminished', 'NegReg', (125, 135))	('reciprocal', 'MPA', (182, 192))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('eIF4E', 'Gene', '487870', (156, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('ERK', 'Gene', '5594', (209, 212))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('expression', 'MPA', (162, 172))	('ERK', 'molecular_function', 'GO:0004707', ('209', '212'))
36695	29385676	In addition, such inhibitor combinations synergistically decreased cell survival and solid tumor growth in canine MM xenografts in mice.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('combinations', 'Var', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cell survival', 'CPA', (67, 80))	('decreased', 'NegReg', (57, 66))	('MM', 'Phenotype', 'HP:0002861', (114, 116))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Disease', (91, 96))	('canine', 'Species', '9615', (107, 113))
36714	29385676	Objective anti-tumor responses were observed in one of seven dogs with oral malignant melanoma and one of two dogs with undifferentiated sarcoma when treated with chimeric anti-PD-L1 at 2 or 5 mg/kg every 2 weeks in a pilot clinical study.	('oral malignant melanoma', 'Disease', 'MESH:D008545', (71, 94))	('undifferentiated sarcoma', 'Disease', (120, 144))	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('PD-L1', 'Gene', '484186', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('chimeric', 'Var', (163, 171))	('PD-L1', 'Gene', (177, 182))	('dogs', 'Species', '9615', (110, 114))	('malignant melanoma', 'Phenotype', 'HP:0002861', (76, 94))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('oral malignant melanoma', 'Disease', (71, 94))	('tumor', 'Disease', (15, 20))	('undifferentiated sarcoma', 'Disease', 'MESH:D002277', (120, 144))	('dogs', 'Species', '9615', (61, 65))
36841	31717496	More than 50% of sporadic melanomas carry mutations in Ras/Raf/mitogen-activated protein kinase (MAPK/MEK) pathway, which may represent aims of novel targeted therapies.	('mi', 'Phenotype', 'HP:0000568', (63, 65))	('MEK', 'Gene', '5609', (102, 105))	('Ras/Raf/mitogen-activated', 'Pathway', (55, 80))	('sporadic melanomas', 'Disease', (17, 35))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('97', '101'))	('mutations', 'Var', (42, 51))	('sporadic melanomas', 'Disease', 'MESH:D008545', (17, 35))	('MEK', 'Gene', (102, 105))
36874	31717496	The discovery of melanoma susceptibility genes and their mutations could lead to development of more accurate prediction and screening tools to identify high-risk populations and to identify new therapeutic targets or prevention strategies.	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (57, 66))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))
36882	31717496	Currently, germline CDKN2A mutations are observed in 20-40% of families with hereditary melanoma across continents.	('mutations', 'Var', (27, 36))	('hereditary melanoma', 'Disease', 'MESH:D008545', (77, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('hereditary melanoma', 'Disease', (77, 96))	('CDKN2A', 'Gene', (20, 26))	('mi', 'Phenotype', 'HP:0000568', (65, 67))
36883	31717496	More than 60 different mutations in the CDKN2A gene were found in hereditary melanoma families, with the majority of them represented by missense mutations in p16.	('represented', 'Reg', (122, 133))	('found', 'Reg', (57, 62))	('missense mutations', 'Var', (137, 155))	('CDKN2A', 'Gene', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mi', 'Phenotype', 'HP:0000568', (88, 90))	('mi', 'Phenotype', 'HP:0000568', (137, 139))	('p16', 'Gene', (159, 162))	('mutations', 'Var', (23, 32))	('hereditary melanoma', 'Disease', 'MESH:D008545', (66, 85))	('hereditary melanoma', 'Disease', (66, 85))
36884	31717496	In contrast, incidence of somatic CDKN2A mutations in sporadic melanomas is very low.	('mutations', 'Var', (41, 50))	('sporadic melanomas', 'Disease', (54, 72))	('CDKN2A', 'Gene', (34, 40))	('sporadic melanomas', 'Disease', 'MESH:D008545', (54, 72))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
36885	31717496	In 1995, a mutated CDK4 was found in cultured melanoma cells and metastatic tissue.	('CDK', 'molecular_function', 'GO:0004693', ('19', '22'))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('CDK4', 'Gene', (19, 23))	('melanoma', 'Disease', (46, 54))	('mutated', 'Var', (11, 18))
36886	31717496	This mutation prevented binding of p16INK4A to CDK4, thus obstructing inhibition of the CDK4 enzyme activity.	('CDK', 'molecular_function', 'GO:0004693', ('47', '50'))	('CDK4', 'Protein', (47, 51))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('binding', 'Interaction', (24, 31))	('inhibition', 'MPA', (70, 80))	('prevented', 'NegReg', (14, 23))	('obstructing', 'NegReg', (58, 69))	('p16INK4A', 'Gene', (35, 43))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('CDK4 enzyme', 'Enzyme', (88, 99))	('enzyme activity', 'molecular_function', 'GO:0003824', ('93', '108'))	('mutation', 'Var', (5, 13))	('activity', 'MPA', (100, 108))	('p16INK4A', 'Gene', '1029', (35, 43))
36887	31717496	A CDK4 mutation was later found in two unrelated melanoma families, and the role of CDK4 mutations in melanoma development was confirmed.	('melanoma development', 'Disease', (102, 122))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('CDK4', 'Gene', (84, 88))	('CDK', 'molecular_function', 'GO:0004693', ('84', '87'))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('mi', 'Phenotype', 'HP:0000568', (60, 62))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('mutations', 'Var', (89, 98))	('CDK', 'molecular_function', 'GO:0004693', ('2', '5'))	('melanoma development', 'Disease', 'MESH:D008545', (102, 122))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
36889	31717496	Both CDKN2A and CDK4 represent high-susceptibility genes for malignant melanoma, i.e., mutation in such genes greatly increases the chance of melanoma development.	('malignant melanoma', 'Disease', (61, 79))	('CDK', 'molecular_function', 'GO:0004693', ('16', '19'))	('malignant melanoma', 'Disease', 'MESH:D008545', (61, 79))	('CDKN2A', 'Gene', (5, 11))	('melanoma development', 'Disease', 'MESH:D008545', (142, 162))	('CDK4', 'Gene', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma development', 'Disease', (142, 162))	('increases', 'PosReg', (118, 127))	('mutation', 'Var', (87, 95))	('malignant melanoma', 'Phenotype', 'HP:0002861', (61, 79))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
36890	31717496	Additional gene mutations were identified as causal for predisposition to melanoma itself or in combination with other cancers in the last decade.	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('mutations', 'Var', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('cancers', 'Disease', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
36893	31717496	However, the exact mechanism of BAP1 mutations that promote melanoma genesis is yet to be elucidated.	('melanoma genesis', 'Disease', 'MESH:D008545', (60, 76))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (37, 46))	('melanoma genesis', 'Disease', (60, 76))	('BAP1', 'Gene', (32, 36))	('promote', 'PosReg', (52, 59))
36894	31717496	Germline mutation in telomerase reverse transcriptase (TERT gene) and other proteins, which protect the ends of chromosomes from deterioration and the cells from senescence, were also reported in melanoma affected families.	('transcriptase', 'molecular_function', 'GO:0003899', ('40', '53'))	('senescence', 'biological_process', 'GO:0010149', ('162', '172'))	('transcriptase', 'molecular_function', 'GO:0034062', ('40', '53'))	('reported', 'Reg', (184, 192))	('mi', 'Phenotype', 'HP:0000568', (216, 218))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('TERT', 'Gene', (55, 59))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('Germline mutation', 'Var', (0, 17))	('transcriptase', 'molecular_function', 'GO:0003968', ('40', '53'))
36895	31717496	Loss-of-function, missense mutations or other POT1 variants were observed in familial melanoma patients in the United Kingdom, the Netherlands, and Australia and in another study also in Italy, USA, and France.	('Loss-of-function', 'NegReg', (0, 16))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('POT1', 'Gene', (46, 50))	('patients', 'Species', '9606', (95, 103))	('variants', 'Var', (51, 59))	('familial melanoma', 'Disease', (77, 94))	('familial melanoma', 'Disease', 'MESH:C562393', (77, 94))	('missense mutations', 'Var', (18, 36))	('mi', 'Phenotype', 'HP:0000568', (79, 81))	('mi', 'Phenotype', 'HP:0000568', (18, 20))
36897	31717496	Mutations in the microphthalmia (mi) locus in mice are causative for several defects, including small unpigmented eyes and lack of skin melanocytes.	('mi', 'Phenotype', 'HP:0000568', (28, 30))	('mi', 'Phenotype', 'HP:0000568', (33, 35))	('small unpigmented eyes', 'Disease', (96, 118))	('microphthalmia', 'Disease', 'MESH:D008850', (17, 31))	('microphthalmia', 'Disease', (17, 31))	('mi', 'Phenotype', 'HP:0000568', (46, 48))	('Mutations', 'Var', (0, 9))	('causative', 'Reg', (55, 64))	('mice', 'Species', '10090', (46, 50))	('mi', 'Phenotype', 'HP:0000568', (17, 19))	('microphthalmia', 'Phenotype', 'HP:0000568', (17, 31))	('small unpigmented eyes', 'Disease', 'MESH:D000853', (96, 118))
36902	31717496	MITF amplification is more prevalent in metastatic disease and correlated with decreased patient survival.	('patient survival', 'CPA', (89, 105))	('patient', 'Species', '9606', (89, 96))	('metastatic disease', 'Disease', (40, 58))	('decreased', 'NegReg', (79, 88))	('amplification', 'Var', (5, 18))	('MITF', 'Gene', (0, 4))	('prevalent', 'Reg', (27, 36))
36903	31717496	Mutations in the MITF gene are found not only in melanomas but also in other cancers, such as renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('cancers', 'Disease', (77, 84))	('MITF', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('melanomas', 'Disease', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('found', 'Reg', (31, 36))	('renal cell carcinoma', 'Disease', (94, 114))
36904	31717496	As mutations in high-susceptibility genes greatly increase risk of melanoma development, individuals carrying CDKN2A, CDK4, BAP1, POT1, or MITF mutations should be educated on the importance of melanoma prevention and early detection and should undergo regular medical skin examination.	('CDKN2A', 'Gene', (110, 116))	('MITF', 'Gene', (139, 143))	('CDK4', 'Gene', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma development', 'Disease', 'MESH:D008545', (67, 87))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('POT1', 'Gene', (130, 134))	('BAP1', 'Gene', (124, 128))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('increase', 'PosReg', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mi', 'Phenotype', 'HP:0000568', (277, 279))	('melanoma development', 'Disease', (67, 87))	('mutations', 'Var', (144, 153))	('mutations', 'Var', (3, 12))	('CDK', 'molecular_function', 'GO:0004693', ('118', '121'))
36905	31717496	Unfortunately, it still remains uncertain how these mutations influence patient phenotypes, as the melanoma risk is influenced by variations in penetrance, environmental exposure, and coinheritance with low-susceptibility genes.	('variations', 'Var', (130, 140))	('mutations', 'Var', (52, 61))	('patient', 'Species', '9606', (72, 79))	('iron', 'Chemical', 'MESH:D007501', (159, 163))	('influenced by', 'Reg', (116, 129))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('influence', 'Reg', (62, 71))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
36907	31717496	Melanocortin 1 receptor (MC1R) gene variants are associated with red hair and fair skin, a skin phototype with higher risk of melanoma development.	('red hair', 'Phenotype', 'HP:0002297', (65, 73))	('melanoma development', 'Disease', (126, 146))	('associated', 'Reg', (49, 59))	('MC1R', 'Gene', (25, 29))	('Melanocortin 1 receptor', 'Gene', (0, 23))	('fair skin', 'Phenotype', 'HP:0007513', (78, 87))	('variants', 'Var', (36, 44))	('fair skin', 'Disease', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('Melanocortin 1 receptor', 'Gene', '494018', (0, 23))	('red hair', 'Disease', (65, 73))	('melanoma development', 'Disease', 'MESH:D008545', (126, 146))
36908	31717496	Presence of MC1R variants, together with CDKN2A mutations, significantly increases melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('variants', 'Var', (17, 25))	('increases', 'PosReg', (73, 82))	('MC1R', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
36910	31717496	Several polymorphisms of the vitamin D receptor (VDR) gene have a supporting effect in melanoma formation and correlate with a negative outcome in affected patients.	('patients', 'Species', '9606', (156, 164))	('melanoma', 'Disease', (87, 95))	('mi', 'Phenotype', 'HP:0000568', (33, 35))	('formation', 'biological_process', 'GO:0009058', ('96', '105'))	('vitamin D receptor', 'Gene', (29, 47))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('VDR', 'Gene', '7421', (49, 52))	('VDR', 'Gene', (49, 52))	('vitamin D receptor', 'Gene', '7421', (29, 47))	('polymorphisms', 'Var', (8, 21))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
36913	31717496	Many other gene variants may increase melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('increase', 'PosReg', (29, 37))	('variants', 'Var', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
36920	31717496	In the majority of sporadic human melanomas, mutations activating the mitogen-activated protein kinase (MAPK/MEK) pathway (Figure 1) are present, affecting mainly BRAF, NRAS, or neurofibromin 1 (NF1) genes (see below).	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('MEK', 'Gene', (109, 112))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('NRAS', 'Gene', (169, 173))	('melanomas', 'Disease', (34, 43))	('activating', 'PosReg', (55, 65))	('affecting', 'Reg', (146, 155))	('neurofibromin 1', 'Gene', '4763', (178, 193))	('mi', 'Phenotype', 'HP:0000568', (70, 72))	('neurofibromin 1', 'Gene', (178, 193))	('mi', 'Phenotype', 'HP:0000568', (188, 190))	('NF1', 'Gene', (195, 198))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('BRAF', 'Gene', (163, 167))	('mutations', 'Var', (45, 54))	('human', 'Species', '9606', (28, 33))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('MEK', 'Gene', '5609', (109, 112))
36922	31717496	About 50% of cutaneous melanomas carry a mutation in BRAF gene, which is in approximately 50% cases represented by V600E substitution, followed by V600K (10-15%) and several less frequent mutations.	('V600E', 'Mutation', 'rs113488022', (115, 120))	('V600K', 'Mutation', 'rs121913227', (147, 152))	('cutaneous melanomas', 'Disease', (13, 32))	('BRAF gene', 'Gene', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('V600E', 'Var', (115, 120))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('V600K', 'Var', (147, 152))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (13, 32))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (13, 32))
36925	31717496	In 10-15% of melanomas, mutations in NRAS occur, predominantly in codon 61.	('NRAS', 'Gene', (37, 41))	('melanomas', 'Disease', (13, 22))	('mi', 'Phenotype', 'HP:0000568', (54, 56))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('mutations', 'Var', (24, 33))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
36926	31717496	Mutations in KRAS are rare in cutaneous melanoma (2% of cases), in contrast to other cancers such as colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('Mutations', 'Var', (0, 9))	('cutaneous melanoma', 'Disease', (30, 48))	('KRAS', 'Gene', (13, 17))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('colorectal cancer', 'Disease', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
36927	31717496	Interestingly, KRAS mutations were detected in several mouse melanoma models and melanoma cell lines.	('KRAS', 'Gene', (15, 19))	('mouse', 'Species', '10090', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('mutations', 'Var', (20, 29))
36929	31717496	Mutations inactivating NF1 were reported in approximately 50% of melanomas.	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('Mutations inactivating', 'Var', (0, 22))	('NF1', 'Gene', (23, 26))	('melanomas', 'Disease', (65, 74))	('reported', 'Reg', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))
36931	31717496	Less than 2% of cutaneous melanomas carry mutation in transmembrane receptor tyrosine kinase KIT.	('transmembrane', 'cellular_component', 'GO:0044214', ('54', '67'))	('KIT', 'molecular_function', 'GO:0005020', ('93', '96'))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('transmembrane', 'cellular_component', 'GO:0016021', ('54', '67'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (16, 35))	('mutation', 'Var', (42, 50))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (16, 35))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('cutaneous melanomas', 'Disease', (16, 35))
36932	31717496	Amplifications of the MITF gene were observed in 20% of metastatic melanomas and are associated with decreased five-year survival.	('melanomas', 'Disease', (67, 76))	('five-year survival', 'CPA', (111, 129))	('MITF', 'Gene', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('observed', 'Reg', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('decreased', 'NegReg', (101, 110))	('melanomas', 'Disease', 'MESH:D008545', (67, 76))	('Amplifications', 'Var', (0, 14))
36934	31717496	Mutation in other molecules and pathways outside of the MAPK pathway were also reported in sporadic melanoma, e.g., mutations and deletions in phosphatase and tensin homolog (PTEN), which encodes a phosphatase and a key regulator of the PI3K signaling pathway, as well as mutations in p53, telomerase catalytic subunit TERT, cell-cycle regulating proteins, and many others.	('mutations', 'Var', (272, 281))	('sporadic', 'Disease', (91, 99))	('p53', 'Gene', '397276', (285, 288))	('signaling pathway', 'biological_process', 'GO:0007165', ('242', '259'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('143', '173'))	('deletions', 'Var', (130, 139))	('phosphatase', 'molecular_function', 'GO:0016791', ('143', '154'))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('phosphatase', 'molecular_function', 'GO:0016791', ('198', '209'))	('phosphatase', 'Gene', (143, 154))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('cell-cycle', 'biological_process', 'GO:0007049', ('325', '335'))	('p53', 'Gene', (285, 288))	('reported', 'Reg', (79, 87))	('phosphatase', 'Gene', (198, 209))	('phosphatase', 'Gene', '5728', (143, 154))	('mutations', 'Var', (116, 125))	('PI3K', 'molecular_function', 'GO:0016303', ('237', '241'))	('PTEN', 'Gene', (175, 179))	('phosphatase', 'Gene', '5728', (198, 209))	('PI3K signaling', 'biological_process', 'GO:0014065', ('237', '251'))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
36935	31717496	According to the most prevalent significantly mutated genes, The Cancer Genome Atlas Network recently provided a schema for cutaneous melanoma genomic classification into four subtypes: mutant BRAF, mutant RAS, mutant NF1, and triple-WT (wild-type).	('BRAF', 'Gene', (193, 197))	('cutaneous melanoma', 'Disease', (124, 142))	('mutant RAS', 'Var', (199, 209))	('NF1', 'Gene', (218, 221))	('mutant', 'Var', (186, 192))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('Cancer', 'Disease', (65, 71))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('mutant', 'Var', (211, 217))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('Cancer', 'Disease', 'MESH:D009369', (65, 71))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mi', 'Phenotype', 'HP:0000568', (147, 149))
36936	31717496	Elucidation of important mutations in melanoma led in the last decade to the development of targeted therapies that improved survival of melanoma and also other cancer patients.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('mutations', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('survival', 'MPA', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (161, 167))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('improved', 'PosReg', (116, 124))
36937	31717496	The examples include B-Raf inhibitors that are used in B-Raf V600E and V600K mutated cancers or MEK inhibitors for treatment cancers with activated upper parts of the MAPK cascade.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('MAPK cascade', 'biological_process', 'GO:0000165', ('167', '179'))	('V600K', 'Var', (71, 76))	('B-Raf', 'Gene', '100514612', (55, 60))	('V600E', 'Var', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('MEK', 'Gene', '5609', (96, 99))	('cancers', 'Disease', (85, 92))	('B-Raf', 'Gene', '100514612', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('B-Raf', 'Gene', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('MAPK', 'molecular_function', 'GO:0004707', ('167', '171'))	('MEK', 'Gene', (96, 99))	('B-Raf', 'Gene', (21, 26))	('V600K', 'Mutation', 'rs121913227', (71, 76))
36953	31717496	The identification of mutations in the B-Raf kinase constitutively activating the MAPK pathway triggered new targeted therapies with small-molecule inhibitors of B-Raf and/or MEK kinases.	('B-Raf', 'Gene', '100514612', (39, 44))	('B-Raf', 'Gene', (39, 44))	('MEK', 'Gene', (175, 178))	('MEK', 'Gene', '5609', (175, 178))	('mutations', 'Var', (22, 31))	('MAPK pathway', 'Pathway', (82, 94))	('activating', 'PosReg', (67, 77))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('B-Raf', 'Gene', '100514612', (162, 167))	('B-Raf', 'Gene', (162, 167))
36965	31717496	In melanoma, fruit fly was used to study the effect of Tum1 (tumorous-lethal) mutation on melanotic neoplasm growth.	('neoplasm', 'Disease', (100, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (100, 108))	('mutation', 'Var', (78, 86))	('melanotic neoplasm', 'Phenotype', 'HP:0002861', (90, 108))	('Tum1', 'Gene', (55, 59))	('neoplasm', 'Disease', 'MESH:D009369', (100, 108))	('fruit fly', 'Species', '7227', (13, 22))	('Tum1', 'Gene', '32080', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumorous', 'Disease', 'MESH:D009369', (61, 69))	('melanoma', 'Disease', (3, 11))	('tumorous', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
36969	31717496	In Xiphophorus, melanoma can be also induced by various physical and chemical means, such as ultraviolet (UV) radiation, X-rays, N-methyl-N-nitrosourea, or N-ethyl-N-nitrosourea.	('N-methyl-N-nitrosourea', 'Var', (129, 151))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (156, 177))	('induced', 'Reg', (37, 44))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (129, 151))	('mi', 'Phenotype', 'HP:0000568', (72, 74))
37003	31717496	Genetically engineered mouse models are extensively used to study the effects of genetic alterations in melanoma initiation, progression, and metastasis, as well as for drug efficacy assessment.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma initiation', 'Disease', (104, 123))	('genetic alterations', 'Var', (81, 100))	('mouse', 'Species', '10090', (23, 28))	('melanoma initiation', 'Disease', 'MESH:D008545', (104, 123))
37005	31717496	The presence of germline mutations in genetically engineered mouse models may affect developmental and reproductive fitness, as well as lead to the formation of tumors in other tissues.	('tumors', 'Disease', (161, 167))	('germline mutations', 'Var', (16, 34))	('lead to', 'Reg', (136, 143))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('affect', 'Reg', (78, 84))	('fitness', 'Disease', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mouse', 'Species', '10090', (61, 66))	('presence', 'Var', (4, 12))	('fitness', 'Disease', 'MESH:D012640', (116, 123))
37023	31717496	Transcriptomic analysis of canine oral melanoma revealed mutations in NRAS and PTEN genes, but not in BRAF, as well as upregulation of matrix metalloproteinase 2 (MMP2) and downregulation of MMP7.	('NRAS', 'Gene', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('MMP7', 'Gene', '489432', (191, 195))	('upregulation', 'PosReg', (119, 131))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('mi', 'Phenotype', 'HP:0000568', (11, 13))	('mutations', 'Var', (57, 66))	('MMP2', 'Gene', (163, 167))	('MMP7', 'molecular_function', 'GO:0004235', ('191', '195'))	('MMP2', 'molecular_function', 'GO:0004228', ('163', '167'))	('MMP7', 'Gene', (191, 195))	('PTEN', 'Gene', (79, 83))	('canine', 'Species', '9615', (27, 33))	('downregulation', 'NegReg', (173, 187))
37025	31717496	In a genomic study of 27 canine malignant melanoma tumors, mutations in genes including BAP1, KIT, KRAS, NRAS, PTEN, and TP53 were found, while no mutation in TERT promoter, BRAF, CDK4, MITF, or NF1 genes was detected.	('found', 'Reg', (131, 136))	('NRAS', 'Gene', (105, 109))	('CDK', 'molecular_function', 'GO:0004693', ('180', '183'))	('BAP1', 'Gene', (88, 92))	('mi', 'Phenotype', 'HP:0000568', (9, 11))	('malignant melanoma', 'Phenotype', 'HP:0002861', (32, 50))	('KRAS', 'Gene', (99, 103))	('canine', 'Species', '9615', (25, 31))	('malignant melanoma tumors', 'Disease', (32, 57))	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('TP53', 'Gene', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('malignant melanoma tumors', 'Disease', 'MESH:D008545', (32, 57))	('mutations', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PTEN', 'Gene', (111, 115))	('KIT', 'Gene', (94, 97))	('TP53', 'Gene', '403869', (121, 125))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
37026	31717496	In approximately 20% tumors, mutations in PTPRJ (protein tyrosine phosphatase, receptor type J), a putative tumor suppressor gene not previously shown to have frequent inactivating point mutations in cancer, was observed.	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('observed', 'Reg', (212, 220))	('PTPRJ', 'Gene', '100524973', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PTPRJ', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('phosphatase', 'molecular_function', 'GO:0016791', ('66', '77'))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', (21, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('protein tyrosine phosphatase, receptor type J', 'Gene', '100524973', (49, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (200, 206))
37034	31717496	The 4.6-kb duplication in the intron of the syntaxin 17 (STX17) gene was found to cause the graying in horses and is associated with a high incidence of melanoma and vitiligo-like skin depigmentation.	('cause', 'Reg', (82, 87))	('vitiligo', 'Phenotype', 'HP:0001045', (166, 174))	('STX17', 'Gene', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('associated with', 'Reg', (117, 132))	('graying', 'Disease', (92, 99))	('vitiligo-like skin depigmentation', 'Disease', (166, 199))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('4.6-kb duplication in', 'Var', (4, 25))	('vitiligo-like skin depigmentation', 'Disease', 'MESH:D014820', (166, 199))	('graying', 'Species', '36185', (92, 99))	('horses', 'Species', '9796', (103, 109))
37071	31717496	The melanoma-producing allele at this locus is inherited in the heterozygous state and requires a somatic mutation of the normal allele to initiate melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('melanoma development', 'Disease', 'MESH:D008545', (148, 168))	('mutation', 'Var', (106, 114))	('melanoma development', 'Disease', (148, 168))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
37084	31717496	This is explained by a mutation of the KIT gene, leading to a failure of melanoblast migration and subsequent lack of melanocytes in the skin of white pigs.	('lack', 'NegReg', (110, 114))	('mutation', 'Var', (23, 31))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('mi', 'Phenotype', 'HP:0000568', (85, 87))	('pigs', 'Species', '9823', (151, 155))	('melanoblast migration', 'CPA', (73, 94))	('KIT', 'Gene', (39, 42))	('failure', 'NegReg', (62, 69))
37143	31717496	Application of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) revealed four ion peaks, m/z 3044, 6011, 6140, and 10180, which were overexpressed in MeLiM melanoma tissue in comparison to healthy skin.	('6011', 'Var', (132, 136))	('m/z 3044', 'Var', (122, 130))	('10180', 'Var', (148, 153))	('MeLiM melanoma tissue', 'Disease', 'MESH:D008545', (183, 204))	('overexpressed', 'PosReg', (166, 179))	('MeLiM melanoma tissue', 'Disease', (183, 204))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('6140', 'Var', (138, 142))
37145	31717496	Overexpression of metallothioneins was associated with a poor prognosis in human cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('metallothioneins', 'Protein', (18, 34))	('Overexpression', 'Var', (0, 14))	('cutaneous melanoma', 'Disease', (81, 99))	('human', 'Species', '9606', (75, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))
37183	31717496	The CDKN2A locus causative in human familial melanoma was studied in MeLiM pigs; however, haplotype analysis, allelic association, and linkage analysis led to exclusion of this gene from candidates for melanoma susceptibility.	('human', 'Species', '9606', (30, 35))	('exclusion', 'NegReg', (159, 168))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('pigs', 'Species', '9823', (75, 79))	('MeLiM', 'Chemical', '-', (69, 74))	('mi', 'Phenotype', 'HP:0000568', (38, 40))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('familial melanoma', 'Disease', (36, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('familial melanoma', 'Disease', 'MESH:C562393', (36, 53))	('melanoma', 'Disease', (45, 53))	('haplotype', 'Var', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
37187	31717496	For the black coat color, a variant allele of the MC1R gene was found (marked as MC1R*2) to be associated with melanoma development.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma development', 'Disease', 'MESH:D008545', (111, 131))	('melanoma development', 'Disease', (111, 131))	('MC1R', 'Gene', (50, 54))	('associated with', 'Reg', (95, 110))	('variant', 'Var', (28, 35))
37188	31717496	This is in agreement with the fact that human variant alleles of MC1R may increase melanoma risk independently of UV exposure.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('human variant', 'Species', '9606', (40, 53))	('variant', 'Var', (46, 53))	('MC1R', 'Gene', (65, 69))	('increase', 'PosReg', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
37193	31717496	Diverse KIT mutations were found in various human cancers, including melanoma, and one variant showed a significant association with cutaneous invasion, melanoma development, and tumor ulceration in the MeLiM strain.	('human', 'Species', '9606', (44, 49))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('cancers', 'Disease', (50, 57))	('melanoma', 'Disease', (153, 161))	('cutaneous invasion', 'CPA', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('found', 'Reg', (27, 32))	('MeLiM', 'Chemical', '-', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('KIT', 'Gene', (8, 11))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('KIT', 'molecular_function', 'GO:0005020', ('8', '11'))	('association', 'Reg', (116, 127))	('melanoma development', 'Disease', (153, 173))	('tumor ulceration', 'Disease', (179, 195))	('tumor ulceration', 'Disease', 'MESH:D014456', (179, 195))	('mutations', 'Var', (12, 21))	('melanoma development', 'Disease', 'MESH:D008545', (153, 173))
37205	31717496	Mutations in TERT promoter are associated with both familial and sporadic melanoma.	('mi', 'Phenotype', 'HP:0000568', (54, 56))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('TERT promoter', 'Gene', (13, 26))	('associated', 'Reg', (31, 41))	('melanoma', 'Disease', (74, 82))	('familial', 'Disease', (52, 60))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))
37208	31717496	HERC3 mutations were observed in gastric and colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('HERC3', 'Gene', (0, 5))	('colorectal cancers', 'Disease', 'MESH:D015179', (45, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('observed', 'Reg', (21, 29))	('HERC3', 'Gene', '100517903', (0, 5))	('colorectal cancers', 'Disease', (45, 63))	('gastric', 'Disease', (33, 40))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('mutations', 'Var', (6, 15))
37292	31717496	Long-term overexpression of HSPs, followed by significant tumor lymphocyte infiltration, suggests that melanoma devitalization in the MeLiM model elicits a cell-mediated anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (175, 180))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('MeLiM', 'Chemical', '-', (134, 139))	('elicits', 'Reg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('devitalization', 'Var', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('immune response', 'biological_process', 'GO:0006955', ('181', '196'))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
37344	33863315	In this study, the inclusion criteria were as follows: 1) patients had a confirmed diagnosis of malignant cutaneous melanoma with ICD-O-3/WHO 2008 morphology codes 8721-8723, 8726-8728, 8730, 8740-8746, 8760-8761, 8770-8774, 8780 and 8790; 2) the codes of the primary site were C440-C447; 3) patients acquired a diagnosis with a living status; and 4) patients had active follow-up.	('8760-8761', 'Var', (203, 212))	('malignant cutaneous melanoma', 'Disease', (96, 124))	('8770-8774', 'Var', (214, 223))	('C440-C447', 'Var', (278, 287))	('malignant cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 124))	('8721-8723', 'Var', (164, 173))	('patients', 'Species', '9606', (292, 300))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('8726-8728', 'Var', (175, 184))	('8730', 'Var', (186, 190))	('8740-8746', 'Var', (192, 201))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (351, 359))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (106, 124))
37350	33863315	Patients with anatomic site codes C440- Skin of lip, C441- Eyelid, C442- External ear, C443- Skin other/unspecific parts of face, or C444- Skin of scalp and neck were assigned to the HNM group, while those whose site was coded as C445- Skin of trunk, C446- Skin of upper limb and shoulder, or C447- Skin of lower limb and hip were assigned to the BM group.	('lower limb', 'Phenotype', 'HP:0006385', (307, 317))	('C440- Skin', 'Var', (34, 44))	('C442-', 'Var', (67, 72))	('- Skin of scalp', 'Phenotype', 'HP:0010541', (137, 152))	('Patients', 'Species', '9606', (0, 8))	('parts of face', 'Phenotype', 'HP:0005323', (115, 128))	('HNM', 'biological_process', 'GO:0030989', ('183', '186'))	('C444-', 'Var', (133, 138))	('neck', 'cellular_component', 'GO:0044326', ('157', '161'))	('C443- Skin', 'Var', (87, 97))	('trunk', 'cellular_component', 'GO:0043198', ('244', '249'))	('C441-', 'Var', (53, 58))
37365	33863315	Superficial spreading melanoma (SSM) was the most common histological type in both groups, but lentigo maligna melanoma (LMM) was much more frequent in the HNM group than in the BM group (31.8% vs. 6.6%).	('lentigo maligna melanoma', 'Disease', 'MESH:D018327', (95, 119))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('HNM', 'biological_process', 'GO:0030989', ('156', '159'))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('HNM', 'Var', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('lentigo maligna melanoma', 'Disease', (95, 119))	('SSM', 'cellular_component', 'GO:1990843', ('32', '35'))	('lentigo maligna melanoma', 'Phenotype', 'HP:0012059', (95, 119))
37422	32846966	Here, we characterized how TPC2 knockout (KO) affected human melanoma cells derived from a metastatic site.	('knockout', 'Var', (32, 40))	('human', 'Species', '9606', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('TPC2', 'Gene', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('affected', 'Reg', (46, 54))
37423	32846966	TPC2 KO increased these cells' ability to invade the extracelullar matrix and was associated with the increased expression of mesenchymal markers ZEB-1, Vimentin and N-Cadherin, and the enhanced secretion of MMP9.	('increased', 'PosReg', (102, 111))	('Vimentin', 'cellular_component', 'GO:0045099', ('153', '161'))	('N-Cadherin', 'Protein', (166, 176))	('secretion', 'MPA', (195, 204))	('secretion', 'biological_process', 'GO:0046903', ('195', '204'))	('MMP9', 'molecular_function', 'GO:0004229', ('208', '212'))	('increased', 'PosReg', (8, 17))	('Vimentin', 'Protein', (153, 161))	('ZEB-1', 'Gene', (146, 151))	('ZEB-1', 'Gene', '6935', (146, 151))	('enhanced', 'PosReg', (186, 194))	('TPC2 KO', 'Var', (0, 7))	('Vimentin', 'cellular_component', 'GO:0045098', ('153', '161'))	('MMP9', 'Protein', (208, 212))	('Cadherin', 'molecular_function', 'GO:0008014', ('168', '176'))	('expression', 'MPA', (112, 122))
37424	32846966	TPC2 KO also activated genes regulated by YAP/TAZ, which are key regulators of tumourigenesis and metastasis.	('genes', 'Gene', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('activated', 'PosReg', (13, 22))	('TPC2', 'Var', (0, 4))	('tumour', 'Disease', (79, 85))	('YAP/TAZ', 'Gene', (42, 49))
37425	32846966	Expression levels of ORAI1, a component of store-operated Ca2+ entry (SOCE), and PKC-betaII, part of the HIPPO pathway that negatively regulates YAP/TAZ activity, were reduced by TPC2 KO and RNA interference knockdown.	('PKC', 'molecular_function', 'GO:0004697', ('81', '84'))	('PKC-betaII', 'Disease', (81, 91))	('PKC-betaII', 'Disease', 'MESH:C537180', (81, 91))	('YAP/TAZ activity', 'MPA', (145, 161))	('knockdown', 'Var', (208, 217))	('Expression levels', 'MPA', (0, 17))	('RNA interference', 'biological_process', 'GO:0016246', ('191', '207'))	('Ca2', 'Gene', '760', (58, 61))	('SOCE', 'biological_process', 'GO:0002115', ('70', '74'))	('RNA', 'Protein', (191, 194))	('RNA', 'cellular_component', 'GO:0005562', ('191', '194'))	('TPC2 KO', 'Var', (179, 186))	('ORAI1', 'Gene', '84876', (21, 26))	('ORAI1', 'Gene', (21, 26))	('Ca2', 'Gene', (58, 61))	('reduced', 'NegReg', (168, 175))
37436	32846966	Thus contrasting studies have indicated that TPCs are highly selective for Na+ and are regulated by [PI(3,5)P2] but not NAADP, or alternatively that TPCs mediate Ca2+ release evoked by NAADP.	('PI(3,5)P2', 'Chemical', 'MESH:C106336', (101, 110))	('NAADP', 'Chemical', 'MESH:C024376', (120, 125))	('NAADP', 'Chemical', 'MESH:C024376', (185, 190))	('mediate', 'Reg', (154, 161))	('NAADP', 'Var', (185, 190))	('Na+', 'MPA', (75, 78))	('Ca2', 'Gene', (162, 165))	('Ca2', 'Gene', '760', (162, 165))
37450	32846966	TFEB knockdown reduced the number of lysosomes and their localization to the plasma membrane.	('knockdown', 'Var', (5, 14))	('TFEB', 'Gene', '7942', (0, 4))	('number of lysosomes', 'MPA', (27, 46))	('reduced', 'NegReg', (15, 22))	('TFEB', 'Gene', (0, 4))	('plasma membrane', 'cellular_component', 'GO:0005886', ('77', '92'))	('localization', 'MPA', (57, 69))	('localization', 'biological_process', 'GO:0051179', ('57', '69'))
37454	32846966	Interestingly, the hyperactivation of YAP has been shown to be associated with poor cancer prognosis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('YAP', 'Gene', (38, 41))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('hyperactivation', 'Var', (19, 34))
37474	32846966	Melanocyte Inducing Transcription Factor (MITF) expression promotes melanoma cell survival and migration.	('Melanocyte Inducing Transcription Factor', 'Gene', (0, 40))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('promotes', 'PosReg', (59, 67))	('Melanocyte Inducing Transcription Factor', 'Gene', '4286', (0, 40))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('MITF', 'Gene', (42, 46))	('expression', 'Var', (48, 58))	('migration', 'CPA', (95, 104))
37494	32846966	We also observed that ORAI1 expression is reduced after TPC2 transient silencing (Figure 5D).	('reduced', 'NegReg', (42, 49))	('expression', 'MPA', (28, 38))	('ORAI1', 'Gene', (22, 27))	('ORAI1', 'Gene', '84876', (22, 27))	('transient silencing', 'Var', (61, 80))	('TPC2', 'Gene', (56, 60))
37501	32846966	have shown that silencing and pharmacologically inhibiting this channel impaired the migration of urinary bladder and hepatic human carcinoma cells in vitro, and of murine breast cancer cells both in vitro and in an in vivo mouse model.	('impaired', 'NegReg', (72, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('inhibiting', 'NegReg', (48, 58))	('mouse', 'Species', '10090', (224, 229))	('breast cancer', 'Disease', (172, 185))	('silencing', 'Var', (16, 25))	('hepatic human carcinoma', 'Disease', 'MESH:D006525', (118, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('murine', 'Species', '10090', (165, 171))	('migration', 'CPA', (85, 94))	('hepatic human carcinoma', 'Disease', (118, 141))
37507	32846966	They expressed a wild-type BRAF kinase and a mutant TP53 protein.	('mutant', 'Var', (45, 51))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein', 'Protein', (57, 64))
37514	32846966	It has also been shown that high levels of YAP are correlated with a decrease in survival for melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('high levels', 'Var', (28, 39))	('melanoma', 'Disease', (94, 102))	('decrease', 'NegReg', (69, 77))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (103, 111))
37515	32846966	Importantly, we also confirmed that the transient inhibition of TPC2 in the CHL1 and MeWo metastatic human cell lines via RNAi using anti-TPC2 siRNAs, has similar effects on the expression of YAP/TAZ target genes.	('expression', 'MPA', (178, 188))	('inhibition', 'NegReg', (50, 60))	('RNAi', 'biological_process', 'GO:0016246', ('122', '126'))	('human', 'Species', '9606', (101, 106))	('anti-TPC2', 'Var', (133, 142))
37529	32846966	However, it remains to be shown how such a change in endolysosomal pH would affect the HIPPO pathway, which is the primary mediator of YAP/TAZ activity.	('HIPPO pathway', 'Pathway', (87, 100))	('affect', 'Reg', (76, 82))	('pH', 'Gene', '5053', (67, 69))	('change', 'Var', (43, 49))
37530	32846966	Given previous evidence that TPC2 is a mediator of Ca2+ signalling responses, one obvious possibility is that changes in such responses underlie how a loss of, or a reduction in, TPC2 expression levels are associated with an increase in YAP/TAZ activity, and as a consequence, an enhancement of metastatic traits.	('metastatic traits', 'CPA', (295, 312))	('Ca2', 'Gene', (51, 54))	('increase', 'PosReg', (225, 233))	('Ca2', 'Gene', '760', (51, 54))	('enhancement', 'PosReg', (280, 291))	('TPC2', 'Gene', (179, 183))	('YAP/TAZ activity', 'CPA', (237, 253))	('reduction', 'NegReg', (165, 174))	('signalling', 'biological_process', 'GO:0023052', ('56', '66'))	('expression', 'MPA', (184, 194))	('changes', 'Var', (110, 117))	('loss', 'NegReg', (151, 155))
37534	32846966	We found that in TPC2 KO or anti-TPC2 siRNA-treated cells, both ORAI1 and PKC-betaII levels decreased.	('anti-TPC2', 'Var', (28, 37))	('PKC-betaII', 'Disease', 'MESH:C537180', (74, 84))	('ORAI1', 'Gene', '84876', (64, 69))	('PKC-betaII', 'Disease', (74, 84))	('PKC', 'molecular_function', 'GO:0004697', ('74', '77'))	('ORAI1', 'Gene', (64, 69))	('decreased', 'NegReg', (92, 101))
37536	32846966	This raises the question of how changes in the expression of TPC2, an endolysosomal ion channel, could cause such a change in the levels of expression of ORAI1 and PKC-betaII.	('levels of expression', 'MPA', (130, 150))	('PKC', 'molecular_function', 'GO:0004697', ('164', '167'))	('PKC-betaII', 'Disease', 'MESH:C537180', (164, 174))	('PKC-betaII', 'Disease', (164, 174))	('TPC2', 'Gene', (61, 65))	('cause', 'Reg', (103, 108))	('ORAI1', 'Gene', (154, 159))	('ORAI1', 'Gene', '84876', (154, 159))	('changes', 'Var', (32, 39))	('change', 'Reg', (116, 122))
37540	32846966	The membranes were incubated with the following primary antibodies overnight at 4  C: anti-MITF (Santacruz Biotch, Dallas, TX, USA), anti-YAP (Cell Signalling, Danvers, MA, USA); anti-TAZ (Sigma, St. Louis, MO, USA); anti-N-Cadherin (Abcam, Cambridge, UK); and anti-ORAI1 (ProSci IncTM, San Diego, CA, USA).	('Cadherin', 'molecular_function', 'GO:0008014', ('224', '232'))	('anti-TAZ', 'Var', (179, 187))	('anti-N-Cadherin', 'Protein', (217, 232))	('ORAI1', 'Gene', '84876', (266, 271))	('ORAI1', 'Gene', (266, 271))	('Signalling', 'biological_process', 'GO:0023052', ('148', '158'))
37557	32846966	GEO2R, an online analysing tool of GEO DataSets, was utilized to analyse differentially expressed genes between A375 melanoma cells harbouring the BRAF V600E oncogenic mutation, and which had been treated, or not, with the BRAF inhibitor Vemurafenib.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('V600E', 'Var', (152, 157))	('A375', 'CellLine', 'CVCL:0132', (112, 116))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('BRAF', 'Gene', '673', (223, 227))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (238, 249))	('BRAF', 'Gene', (223, 227))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('melanoma', 'Disease', (117, 125))
37594	29992995	The frequency of BRAF and NRAS mutations differs among the cutaneous melanoma subtypes.	('mutations', 'Var', (31, 40))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('NRAS', 'Gene', '30380', (26, 30))	('NRAS', 'Gene', (26, 30))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '403065', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
37599	29992995	Mutually exclusive mutations in GNAQ or in GNA11, the principal driver oncogenes in uveal melanoma, occur in approximately 85% of cases.	('GNAQ', 'Gene', (32, 36))	('GNAQ', 'Gene', '570108', (32, 36))	('GNA11', 'Gene', (43, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('mutations', 'Var', (19, 28))	('occur', 'Reg', (100, 105))	('GNA11', 'Gene', '563953', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
37600	29992995	Moreover, inactivating mutations in the tumour suppressor BAP1 occur in ~85% of metastatic tumours and are associated with disease dissemination and poor prognosis.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('inactivating mutations', 'Var', (10, 32))	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('occur', 'Reg', (63, 68))	('BAP1', 'Gene', (58, 62))	('tumour', 'Disease', (40, 46))	('tumour', 'Disease', (91, 97))	('tumours', 'Disease', (91, 98))	('BAP1', 'Gene', '558885', (58, 62))	('disease dissemination', 'CPA', (123, 144))	('associated with', 'Reg', (107, 122))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
37679	29992995	For this purpose, C8161-GFP or Hermes 2B-GFP cells were injected in the yolk of zebrafish embryos two days post-fertilization (dpf), and the differential migration was evaluated via live imaging after 2-3 days post-injection (dpi).	('fertilization', 'biological_process', 'GO:0009566', ('112', '125'))	('dpi', 'Chemical', '-', (226, 229))	('C8161-GFP', 'Var', (18, 27))	('zebrafish', 'Species', '7955', (80, 89))	('differential migration', 'CPA', (141, 163))	('yolk', 'cellular_component', 'GO:0060417', ('72', '76'))	('dpf', 'Chemical', '-', (127, 130))
37699	29992995	It is known that aberrant expression of embryonic epithelial-mesenchymal transition (EMT) factors triggers extensive plasticity of cancer cells, including melanoma cells via EMT plasticity, invading melanoma cells can use a broad spectrum of invasion strategies depending upon many environmental determinants leading to tumour resistance and metastasis.	('cancer', 'Disease', (131, 137))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('aberrant', 'Var', (17, 25))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('50', '83'))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('tumour', 'Phenotype', 'HP:0002664', (320, 326))	('plasticity', 'MPA', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EMT', 'biological_process', 'GO:0001837', ('174', '177'))	('tumour', 'Disease', 'MESH:D009369', (320, 326))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('tumour', 'Disease', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Disease', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
37738	27533633	Over the past 5 years, however, treatment of cutaneous melanoma has been revolutionized by targeted therapy against mutant BRAF and immune-checkpoint inhibitors expressed on T lymphocytes and other immune cells that enhance anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('enhance', 'PosReg', (216, 223))	('cutaneous melanoma', 'Disease', (45, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (45, 63))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (45, 63))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('tumor', 'Disease', (229, 234))	('mutant', 'Var', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
37743	27533633	Recent data investigating the efficacy of immune-checkpoint inhibition in cutaneous melanoma, non-small cell lung cancer, and microsatellite unstable colorectal and gynecologic carcinomas suggest that tumors with a higher mutational burden are more likely to respond to these therapies.	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('carcinomas', 'Disease', 'MESH:D002277', (177, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('colorectal', 'Disease', (150, 160))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('mutational', 'Var', (222, 232))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('carcinomas', 'Disease', (177, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('colorectal', 'Disease', 'MESH:D015179', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cutaneous melanoma', 'Disease', (74, 92))	('tumors', 'Disease', (201, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 92))
37748	27533633	Relevant clinical data were retrieved from electronic medical records including: sex; age, stage, Eastern Cooperative Oncology Group (ECOG) performance status, and sites of metastatic disease at anti-PD1 treatment initiation; presence of BRAF, NRAS, and KIT mutations; number and characteristics of prior and subsequent systemic therapies; treatment-related variables (anti-PD-1 agent used, duration of treatment, reason for discontinuation, toxicities), and survival status.	('mutations', 'Var', (258, 267))	('BRAF', 'Gene', '673', (238, 242))	('NRAS', 'Gene', '4893', (244, 248))	('KIT', 'Gene', (254, 257))	('KIT', 'molecular_function', 'GO:0005020', ('254', '257'))	('BRAF', 'Gene', (238, 242))	('PD-1', 'Gene', (374, 378))	('PD1', 'Gene', '5133', (200, 203))	('PD-1', 'Gene', '5133', (374, 378))	('toxicities', 'Disease', (442, 452))	('PD1', 'Gene', (200, 203))	('Oncology', 'Phenotype', 'HP:0002664', (118, 126))	('NRAS', 'Gene', (244, 248))	('toxicities', 'Disease', 'MESH:D064420', (442, 452))
37764	27533633	An alteration in BRAF, KIT or NRAS was identified in 17 out of 52 tumors (33%) tested for at least one genomic aberration (BRAF n=2; KIT n=5; NRAS n=10); see Supplemental Table 1 for detailed mutational data.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('NRAS', 'Gene', (142, 146))	('NRAS', 'Gene', '4893', (142, 146))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (123, 127))	('tumors', 'Disease', (66, 72))	('alteration', 'Var', (3, 13))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('KIT', 'Gene', (23, 26))	('BRAF', 'Gene', '673', (123, 127))	('BRAF', 'Gene', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('NRAS', 'Gene', (30, 34))	('KIT', 'molecular_function', 'GO:0005020', ('133', '136'))	('NRAS', 'Gene', '4893', (30, 34))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))
37782	27533633	Among the 17 patients whose tumors had a known driver in BRAF, NRAS, or KIT, 4/10 patients with NRAS mutations responded to PD-1 blockade versus 0/5 and 0/2 with KIT or BRAF, respectively.	('NRAS', 'Gene', '4893', (63, 67))	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('BRAF', 'Gene', '673', (57, 61))	('responded', 'MPA', (111, 120))	('patients', 'Species', '9606', (13, 21))	('BRAF', 'Gene', (57, 61))	('NRAS', 'Gene', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('NRAS', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutations', 'Var', (101, 110))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('tumors', 'Disease', (28, 34))	('patients', 'Species', '9606', (82, 90))	('NRAS', 'Gene', '4893', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('PD-1', 'Gene', (124, 128))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('PD-1', 'Gene', '5133', (124, 128))
37824	27533633	In a retrospective analysis of a prospective trial of cutaneous melanoma treated with pembrolizumab, patients with pre-treatment tumors that had higher densities of CD8+ T cells at the invasive margin, particularly those expressing PD-1, or more clonal expansion of the T cell receptor were more likely to obtain objective responses.	('patients', 'Species', '9606', (101, 109))	('PD-1', 'Gene', (232, 236))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('PD-1', 'Gene', '5133', (232, 236))	('pembrolizumab', 'Chemical', 'MESH:C582435', (86, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('T cell receptor', 'Protein', (270, 285))	('pre', 'molecular_function', 'GO:0003904', ('115', '118'))	('clonal', 'CPA', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cutaneous melanoma', 'Disease', (54, 72))	('CD8+ T', 'Var', (165, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('higher', 'PosReg', (145, 151))
37828	27533633	The presence of TILs was associated with superior clinical outcomes in retrospective analyses of primary acral melanomas and oral cavity mucosal melanomas.	('TILs', 'Gene', (16, 20))	('acral melanomas', 'Disease', 'MESH:D008545', (105, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mucosal melanomas', 'Disease', (137, 154))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('mucosal melanomas', 'Disease', 'MESH:D008545', (137, 154))	('acral melanoma', 'Phenotype', 'HP:0012060', (105, 119))	('acral melanomas', 'Disease', (105, 120))	('acral melanomas', 'Phenotype', 'HP:0012060', (105, 120))	('superior', 'PosReg', (41, 49))	('presence', 'Var', (4, 12))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
37849	29257259	LINE1 hypermethylation in peripheral blood of cutaneous melanoma patients is associated with metastasis.	('hypermethylation', 'Var', (6, 22))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('LINE1', 'Gene', (0, 5))	('metastasis', 'CPA', (93, 103))	('cutaneous melanoma', 'Disease', (46, 64))	('patients', 'Species', '9606', (65, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('associated', 'Reg', (77, 87))
37858	29257259	Two gene expression datasets (GSE46517 and GSE7553) were retrieved from Gene Expression Omnibus (GEO) with key words 'cutaneous melanoma', 'homo sapiens' and 'metastasis' by the end of May 13th, 2016.	("'cutaneous melanoma", 'Phenotype', 'HP:0012056', (117, 136))	('GSE46517', 'Var', (30, 38))	('cutaneous melanoma', 'Disease', (118, 136))	('GSE7553', 'Chemical', '-', (43, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('GSE7553', 'Var', (43, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('Gene Expression', 'biological_process', 'GO:0010467', ('72', '87'))	('homo sapiens', 'Species', '9606', (140, 152))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))
37868	29257259	The SVM classifier was validated using dataset GSE46517 and GSE7553.	('GSE7553', 'Chemical', '-', (60, 67))	('GSE7553', 'Var', (60, 67))	('GSE46517', 'Var', (47, 55))
37888	29257259	A previous study has reported that a RAC1 mutant (Pro29 to serine, P29S) promotes melanocyte proliferation and migration.	('Pro29 to', 'Var', (50, 58))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('82', '106'))	('RAC1', 'Gene', '5879', (37, 41))	('Pro29 to serine', 'Mutation', 'rs1057519874', (50, 65))	('melanocyte proliferation', 'CPA', (82, 106))	('RAC1', 'Gene', (37, 41))	('promotes', 'PosReg', (73, 81))	('P29S', 'Var', (67, 71))	('P29S', 'Mutation', 'rs1057519874', (67, 71))
37897	29257259	Inhibition of VAV1 can attenuate metastasis of pancreatic cancer.	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (33, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('VAV1', 'Gene', (14, 18))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (47, 64))	('metastasis of pancreatic cancer', 'Disease', (33, 64))	('Inhibition', 'Var', (0, 10))	('VAV1', 'Gene', '7409', (14, 18))	('attenuate', 'NegReg', (23, 32))
37967	27344178	In our study, we divided cutaneous melanoma patients into two groups according to clinical status of lymph nodes: (1) Clinically-positive nodes (2015); and (2) Clinically-negative nodes (54270).	('54270', 'Var', (187, 192))	('patients', 'Species', '9606', (44, 52))	('cutaneous melanoma', 'Disease', (25, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
37993	32370744	However, even immune checkpoint inhibitors (ICIs) such as antibodies targeting either the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed death 1 (PD1) immune checkpoints, yet approximately 50% of the patients do not respond to treatment.	('CTLA-4', 'Gene', (135, 141))	('programmed death 1', 'Gene', (150, 168))	('PD1', 'Gene', '5133', (170, 173))	('antibodies', 'Var', (58, 68))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (90, 133))	('PD1', 'Gene', (170, 173))	('patients', 'Species', '9606', (224, 232))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (90, 133))	('programmed death 1', 'Gene', '5133', (150, 168))	('CTLA-4', 'Gene', '1493', (135, 141))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
38044	32370744	In the present study, we found that the expression of SRGN was positively associated with the immune infiltrates and the survival rate of SKCM and SCKM-metastasis patients.	('immune infiltrates', 'CPA', (94, 112))	('patients', 'Species', '9606', (163, 171))	('SKCM', 'Chemical', '-', (138, 142))	('expression', 'Var', (40, 50))	('survival rate', 'CPA', (121, 134))	('SRGN', 'Gene', '5552', (54, 58))	('SRGN', 'Gene', (54, 58))	('associated', 'Reg', (74, 84))
38055	32370744	A former study once demonstrated that neutrophil infiltration and CD123+ dendritic cell infiltration in primary melanoma were independently associated with poor prognosis.	('neutrophil infiltration', 'Var', (38, 61))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('CD123', 'Gene', (66, 71))	('melanoma', 'Disease', (112, 120))	('CD123', 'Gene', '3563', (66, 71))
38067	32370744	In previous studies, most researches found that high SRGN expression was correlated with low survival rate of most tumors such as breast cancer, prostate cancer, colorectal cancer, nasopharyngeal carcinoma, glioma, and primary lung adenocarcinomas.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (181, 205))	('expression', 'MPA', (58, 68))	('low', 'NegReg', (89, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('carcinoma', 'Disease', 'MESH:D009369', (196, 205))	('prostate cancer', 'Disease', (145, 160))	('high', 'Var', (48, 52))	('SRGN', 'Gene', '5552', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (227, 246))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('carcinoma', 'Disease', (237, 246))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (227, 247))	('glioma', 'Disease', (207, 213))	('tumors', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('SRGN', 'Gene', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (130, 143))	('survival', 'MPA', (93, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('carcinoma', 'Disease', (196, 205))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (227, 247))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('colorectal cancer', 'Disease', (162, 179))	('carcinoma', 'Disease', 'MESH:D009369', (237, 246))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('lung adenocarcinomas', 'Disease', (227, 247))
38070	32370744	Interestingly, we found that high SRGN expression was associated with improved survival which seems opposite to previous studies.	('high', 'Var', (29, 33))	('SRGN', 'Gene', (34, 38))	('SRGN', 'Gene', '5552', (34, 38))	('improved', 'PosReg', (70, 78))	('survival', 'CPA', (79, 87))	('expression', 'MPA', (39, 49))
38096	24729470	To this end, our prior work showed that manipulation of hPNPaseold-35 expression in melanoma cells, i.e., its depletion or overexpression, caused genome wide alterations in numerous genes and pathways, with some of the most significant changes associated with mitochondrial function, cholesterol biosynthesis, cell cycle and cellular growth and proliferation.	('changes', 'Reg', (236, 243))	('hPNPaseold-35', 'Gene', '87178', (56, 69))	('manipulation', 'Var', (40, 52))	('cholesterol', 'Chemical', 'MESH:D002784', (284, 295))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cholesterol biosynthesis', 'biological_process', 'GO:0006695', ('284', '308'))	('melanoma', 'Disease', (84, 92))	('cellular growth', 'biological_process', 'GO:0016049', ('325', '340'))	('overexpression', 'PosReg', (123, 137))	('alterations', 'Reg', (158, 169))	('genes', 'Gene', (182, 187))	('depletion', 'NegReg', (110, 119))	('hPNPaseold-35', 'Gene', (56, 69))	('cell cycle', 'biological_process', 'GO:0007049', ('310', '320'))
38129	24729470	After washing three times with TBS-T for 10 minutes each, the membranes were incubated with primary antibodies overnight at 4 C. The primary antibodies used were anti-HA (mouse, 1:1000), anti-hPNPaseold-35 (chicken; 1:5000), anti-EF1alpha (mouse, 1:1000).	('mouse', 'Species', '10090', (240, 245))	('anti-HA', 'Var', (162, 169))	('EF1alpha', 'Gene', '373963', (230, 238))	('TBS-T', 'Chemical', '-', (31, 36))	('hPNPaseold-35', 'Gene', (192, 205))	('chicken', 'Species', '9031', (207, 214))	('mouse', 'Species', '10090', (171, 176))	('hPNPaseold-35', 'Gene', '87178', (192, 205))	('EF1alpha', 'Gene', (230, 238))
38149	24729470	Transient knockdown of hPNPaseold-35 in HeLa cells also resulted in a 1.4 and ~2 fold elevation of SYNCRIP and CENPA RNA levels respectively (Figure 3C), proving that these gene dysregulations are neither cell line specific effect, nor an indirect effect due to stable knockdown.	('HeLa', 'CellLine', 'CVCL:0030', (40, 44))	('CENPA', 'Gene', (111, 116))	('hPNPaseold-35', 'Gene', (23, 36))	('SYNCRIP', 'Gene', (99, 106))	('hPNPaseold-35', 'Gene', '87178', (23, 36))	('CENPA', 'Gene', '1058', (111, 116))	('SYNCRIP', 'Gene', '10492', (99, 106))	('RNA', 'cellular_component', 'GO:0005562', ('117', '120'))	('knockdown', 'Var', (10, 19))	('elevation', 'PosReg', (86, 95))
38163	24729470	As the heat maps indicate, opposite expression trends (compared to hPNPaseold-35) were observed for the genes KI1644 (OV, COAD, PRAD), ADARB1 (OV, COAD), HMG20B (COAD), IGFBP3 (COAD, PRAD), DDIT4 (COAD, PRAD), EMR2 (COAD, SKCM), SLC1A3 (COAD, PRAD), and DHRS2 (PRAD).	('COAD', 'Disease', (216, 220))	('COAD', 'Disease', (122, 126))	('EMR2', 'Gene', (210, 214))	('EMR2', 'Gene', '30817', (210, 214))	('SLC1A3', 'Gene', '6507', (229, 235))	('COAD', 'Disease', (177, 181))	('COAD', 'Disease', 'MESH:D029424', (237, 241))	('IGFBP3', 'Gene', '3486', (169, 175))	('DDIT4', 'Gene', (190, 195))	('ADARB1', 'Gene', '104', (135, 141))	('COAD', 'Disease', 'MESH:D029424', (197, 201))	('DDIT4', 'Gene', '54541', (190, 195))	('COAD', 'Disease', 'MESH:D029424', (147, 151))	('HMG20B', 'Gene', (154, 160))	('COAD', 'Disease', 'MESH:D029424', (162, 166))	('KI1644', 'Var', (110, 116))	('ADARB1', 'Gene', (135, 141))	('DHRS2', 'Gene', (254, 259))	('hPNPaseold-35', 'Gene', (67, 80))	('COAD', 'Disease', (237, 241))	('COAD', 'Disease', 'MESH:D029424', (216, 220))	('COAD', 'Disease', 'MESH:D029424', (122, 126))	('COAD', 'Disease', (197, 201))	('COAD', 'Disease', (147, 151))	('SLC1A3', 'Gene', (229, 235))	('COAD', 'Disease', 'MESH:D029424', (177, 181))	('hPNPaseold-35', 'Gene', '87178', (67, 80))	('COAD', 'Disease', (162, 166))	('IGFBP3', 'Gene', (169, 175))	('HMG20B', 'Gene', '10362', (154, 160))	('DHRS2', 'Gene', '10202', (254, 259))
38202	24729470	Our bioinformatics analysis points to hPNPaseold-35 overexpression tipping the balance towards growth arrest, perhaps due to the resulting downregulation of cellular proliferation-related genes such as E2F3, MCM4, MCM7 and EIF4G1, and the upregulation of pro-apoptotic transcripts like FAS.	('overexpression', 'Var', (52, 66))	('EIF4', 'cellular_component', 'GO:0008304', ('223', '227'))	('upregulation', 'PosReg', (239, 251))	('cellular', 'CPA', (157, 165))	('hPNPaseold-35', 'Gene', (38, 51))	('MCM7', 'Gene', (214, 218))	('E2F3', 'Gene', '1871', (202, 206))	('MCM4', 'Gene', '4173', (208, 212))	('EIF4G1', 'Gene', '1981', (223, 229))	('MCM7', 'Gene', '4176', (214, 218))	('growth arrest', 'Phenotype', 'HP:0001510', (95, 108))	('downregulation', 'NegReg', (139, 153))	('hPNPaseold-35', 'Gene', '87178', (38, 51))	('growth arrest', 'Disease', 'MESH:D006323', (95, 108))	('MCM4', 'Gene', (208, 212))	('tipping', 'Reg', (67, 74))	('growth arrest', 'Disease', (95, 108))	('EIF4G1', 'Gene', (223, 229))	('FAS', 'Disease', (286, 289))	('E2F3', 'Gene', (202, 206))
38207	31143514	This meta-analysis confirmed the favorable prognostic role of the CD3+, CD4+, CD8+, FOXP3+, and CD20+ TILs in the overall survival of melanoma patients and found an association between the TILs present and improved overall survival.	('TIL', 'Gene', (102, 105))	('overall survival', 'MPA', (215, 231))	('CD4', 'Gene', (72, 75))	('TIL', 'Gene', (189, 192))	('FOXP3', 'Gene', '50943', (84, 89))	('improved', 'PosReg', (206, 214))	('CD8', 'Gene', '925', (78, 81))	('CD20', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('CD3+', 'Var', (66, 70))	('CD20', 'Gene', '931', (96, 100))	('TIL', 'Gene', '7096', (102, 105))	('CD8', 'Gene', (78, 81))	('TIL', 'Gene', '7096', (189, 192))	('patients', 'Species', '9606', (143, 151))	('FOXP3', 'Gene', (84, 89))	('CD4', 'Gene', '920', (72, 75))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
38219	31143514	Many studies have indicated that TILs are a favorable prognostic factor for melanoma patients, and the presence of TILs might lead to a better prognosis.	('melanoma', 'Disease', (76, 84))	('TIL', 'Gene', (115, 118))	('presence', 'Var', (103, 111))	('TIL', 'Gene', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('patients', 'Species', '9606', (85, 93))	('lead to', 'Reg', (126, 133))	('TIL', 'Gene', '7096', (115, 118))	('TIL', 'Gene', '7096', (33, 36))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
38231	31143514	Additionally, CD3+ T-cell infiltration into the primary tumor has also been observed as an excellent early predictor of longer survival in metastatic melanoma patients receiving DC-based immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('CD3+', 'Var', (14, 18))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
38258	31143514	Additionally, we assessed the prognostic roles of different TIL grades for the OS of melanoma patients, and the results indicated that an advantageous prognostic role for non-brisk TILs [HR: 0.71 (0.55-0.90)] and brisk TILs [HR: 0.61 (0.52-0.72)] but not moderate TILs [HR: 0.81 (0.32-2.07)] for OS (Figure 3).	('TIL', 'Gene', (60, 63))	('patients', 'Species', '9606', (94, 102))	('advantageous', 'PosReg', (138, 150))	('OS', 'Chemical', '-', (296, 298))	('OS', 'Chemical', '-', (79, 81))	('TIL', 'Gene', '7096', (219, 222))	('non-brisk', 'Var', (171, 180))	('TIL', 'Gene', '7096', (264, 267))	('TIL', 'Gene', '7096', (181, 184))	('TIL', 'Gene', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('TIL', 'Gene', '7096', (60, 63))	('melanoma', 'Disease', (85, 93))	('TIL', 'Gene', (219, 222))	('TIL', 'Gene', (264, 267))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
38263	31143514	The prognostic value of brisk TILs was assessed in 3 studies, and the meta-analysis demonstrated brisk TILs to be a favorable prognostic factor for RFS [HR: 0.50 (0.27-0.94)] (Figure 5(b)).	('TIL', 'Gene', (30, 33))	('TIL', 'Gene', '7096', (103, 106))	('brisk', 'Var', (97, 102))	('TIL', 'Gene', '7096', (30, 33))	('TIL', 'Gene', (103, 106))	('RFS', 'Disease', (148, 151))	('RFS', 'Chemical', '-', (148, 151))
38288	31143514	The results indicated a better OS in melanoma patients with high FOXP3 TIL infiltration [HR: 0.57 (0.40-0.82)] (Table 3, Supplement Figure 8).	('TIL', 'Gene', (71, 74))	('OS', 'Chemical', '-', (31, 33))	('patients', 'Species', '9606', (46, 54))	('FOXP3', 'Gene', (65, 70))	('high', 'Var', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('FOXP3', 'Gene', '50943', (65, 70))	('TIL', 'Gene', '7096', (71, 74))
38293	31143514	The meta-analysis showed a markedly favorable prognostic value for patients with high CD20 TIL infiltration [HR: 0.49 (0.34-0.71)] (Table 3, Supplement Figure 9).	('TIL', 'Gene', (91, 94))	('patients', 'Species', '9606', (67, 75))	('high', 'Var', (81, 85))	('CD20', 'Gene', '931', (86, 90))	('TIL', 'Gene', '7096', (91, 94))	('CD20', 'Gene', (86, 90))
38311	31143514	This finding is consistent with the reports of Clemente et al and Clark et al, both of whom observed that the survival rate of melanoma patients with a brisk TIL response compared with those with a non-brisk response was higher, and the TIL response was an independent prognostic indicator.	('TIL', 'Gene', (158, 161))	('TIL', 'Gene', (237, 240))	('brisk', 'Var', (152, 157))	('TIL', 'Gene', '7096', (237, 240))	('patients', 'Species', '9606', (136, 144))	('survival', 'CPA', (110, 118))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('TIL', 'Gene', '7096', (158, 161))	('higher', 'PosReg', (221, 227))
38313	31143514	In addition, the presence of TILs would decrease the involvement of regional lymph nodes and distant metastasis to lead a positive outcome.	('decrease', 'NegReg', (40, 48))	('TIL', 'Gene', (29, 32))	('involvement', 'CPA', (53, 64))	('presence', 'Var', (17, 25))	('TIL', 'Gene', '7096', (29, 32))
38346	31143514	The specific mechanism of CD3+ TILs as favorable prognostic factor is unclear, and additional large-sample studies are needed to confirm the results due to the small number of enrolled studies.	('CD3+', 'Var', (26, 30))	('TIL', 'Gene', (31, 34))	('TIL', 'Gene', '7096', (31, 34))
38356	31143514	In conclusion, our meta-analysis confirmed the favorable prognostic role of CD3+, CD4+, CD8+, FOXP3+, and CD20+ TILs in the overall survival of melanoma patients.	('CD8', 'Gene', '925', (88, 91))	('CD4', 'Gene', '920', (82, 85))	('FOXP3', 'Gene', '50943', (94, 99))	('patients', 'Species', '9606', (153, 161))	('TIL', 'Gene', (112, 115))	('CD20', 'Gene', (106, 110))	('CD20', 'Gene', '931', (106, 110))	('FOXP3', 'Gene', (94, 99))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('TIL', 'Gene', '7096', (112, 115))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('CD4', 'Gene', (82, 85))	('CD3+', 'Var', (76, 80))	('CD8', 'Gene', (88, 91))
38381	19649148	Patients with the least advanced disease (other than melanoma in situ), that is, in stage IA disease (i.e., T1aN0M0, lesion less than 1 mm thick, without ulceration and extending into reticular dermis [Clark level II/III]) have a 94% 5-year and an 86% 10-year survival.	('stage IA disease', 'Disease', 'MESH:C536041', (84, 100))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('T1aN0M0', 'Var', (108, 115))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('Patients', 'Species', '9606', (0, 8))	('stage IA disease', 'Disease', (84, 100))
38384	19649148	Patients with stage IIIA disease (i.e., T1-4aN1a-2aM0, lesion of any thickness, without ulceration, with microscopic metastasis) have a 67% 5-year survival rate.	('T1-4aN1a-2aM0', 'Var', (40, 53))	('stage IIIA disease', 'Disease', (14, 32))	('Patients', 'Species', '9606', (0, 8))
38385	19649148	Patients with stage IIIC disease (any TN3M0, four or more metastatic lymph nodes, matted lymph nodes, in-transit metastasis with metastatic lymph nodes) have a 28% 5-year survival rate (Figure 3).	('Patients', 'Species', '9606', (0, 8))	('TN3M0', 'Var', (38, 43))	('stage IIIC', 'Disease', (14, 24))
38395	19649148	'Field cells' were characterized by Bastian et al.. Epidermis adjacent to the acral lentiginous melanoma can harbor cells with a high level of DNA amplifications (11q13, 5p15) that can be detected by fluorescent in situ hybridization.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('p15', 'Gene', (171, 174))	('p15', 'Gene', '1030', (171, 174))	('acral lentiginous melanoma', 'Phenotype', 'HP:0012060', (78, 104))	('acral lentiginous melanoma', 'Disease', (78, 104))	('acral lentiginous melanoma', 'Disease', 'MESH:D007911', (78, 104))	('11q13', 'Var', (163, 168))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
38411	19649148	According to systematic review and meta-analysis by Mocellin et al., positive reverse transcription PCR status correlated with both TNM stage (stage I or II vs III; PCR positivity, 95.1 vs 46.6%; p < 0001) and disease recurrence (PCR positive vs negative; relapse rate, 16.8 vs 8.7%; p < 0001).	('TNM', 'Gene', (132, 135))	('disease', 'Disease', (210, 217))	('reverse transcription', 'biological_process', 'GO:0001171', ('78', '99'))	('positive', 'Var', (69, 77))	('reverse transcription PCR status', 'Gene', (78, 110))	('TNM', 'Gene', '10178', (132, 135))
38438	19649148	Markers used to detect circulating melanoma cells used in different studies included tyrosine, Melan-A, MAGE-3, melanoma cell-adhesion molecule-18, p97 and gp100.	('gp100', 'Gene', (156, 161))	('Melan-A', 'Gene', (95, 102))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('gp100', 'Gene', '6490', (156, 161))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('MAGE-3', 'Gene', (104, 110))	('MAGE-3', 'Gene', '4102', (104, 110))	('cell-adhesion molecule', 'molecular_function', 'GO:0098631', ('121', '143'))	('tyrosine', 'Chemical', 'MESH:D014443', (85, 93))	('melanoma cells', 'Disease', (35, 49))	('tyrosine', 'Var', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('p97', 'Gene', '4241', (148, 151))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('p97', 'Gene', (148, 151))	('Melan-A', 'Gene', '2315', (95, 102))	('melanoma cells', 'Disease', 'MESH:D008545', (35, 49))	('cell-adhesion', 'biological_process', 'GO:0007155', ('121', '134'))
38461	19649148	Of note, recent attention of the scientific (including melanoma) community shifted from progressive changes of neoplastic clones (accumulation of new mutations leading to more aggressive phenotypes) to the concept of neoplastic stem cells (Figure 4).	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('leading to', 'Reg', (160, 170))	('mutations', 'Var', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
38464	19649148	Fusion would result in activation of master regulatory genes that activate multiple pathways, particularly related to epithelial-mesenchymal transition, such as SNAIL, SLUG, SPARC and TWIST.	('TWIST', 'Gene', '7291', (184, 189))	('SPARC', 'Gene', '6678', (174, 179))	('master regulatory genes', 'Gene', (37, 60))	('Fusion', 'Var', (0, 6))	('TWIST', 'Gene', (184, 189))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('118', '151'))	('SPARC', 'Gene', (174, 179))	('activation', 'PosReg', (23, 33))	('activate', 'PosReg', (66, 74))	('SNAIL', 'Gene', (161, 166))	('SLUG', 'Gene', (168, 172))	('SNAIL', 'Gene', '6615', (161, 166))	('SLUG', 'Gene', '6591', (168, 172))
38509	19649148	On the other hand, melanomas expressing integrin alpha4beta1 develop lymph node metastases.	('metastases', 'Disease', (80, 90))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('integrin', 'Var', (40, 48))	('develop', 'PosReg', (61, 68))	('melanomas', 'Disease', (19, 28))
38549	19649148	B-Raf encodes a Ras-regulated kinase that regulates cell proliferation and is mutated in a specific site (glutamic acid for valine substitution at codon 600 in exon 15).	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell proliferation', 'CPA', (52, 70))	('B-Raf', 'Gene', (0, 5))	('B-Raf', 'Gene', '673', (0, 5))	('glutamic acid for valine substitution at codon 600', 'Mutation', 'rs113488022', (106, 156))	('regulates', 'Reg', (42, 51))	('glutamic acid for valine substitution', 'Var', (106, 143))
38551	19649148	However, only highly metastatic melanoma cells expressing alpha4beta1 bind to vascular cell-adhesion molecule (VCAM)-1 on endothelial cells as opposed to non-metastatic melanoma cells expressing similar levels of alpha4beta1.	('alpha4beta1', 'Var', (58, 69))	('bind', 'Interaction', (70, 74))	('melanoma cells', 'Disease', 'MESH:D008545', (169, 183))	('melanoma cells', 'Disease', (169, 183))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma cells', 'Disease', 'MESH:D008545', (32, 46))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma cells', 'Disease', (32, 46))	('cell-adhesion molecule (VCAM)-1', 'Gene', '7412', (87, 118))	('cell-adhesion', 'biological_process', 'GO:0007155', ('87', '100'))	('cell-adhesion molecule', 'molecular_function', 'GO:0098631', ('87', '109'))
38557	19649148	Ln-5 can then render poorly aggressive melanoma cells more aggressive.	('aggressive melanoma', 'Disease', (28, 47))	('melanoma cells', 'Disease', 'MESH:D008545', (39, 53))	('aggressive', 'CPA', (59, 69))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma cells', 'Disease', (39, 53))	('aggressive melanoma', 'Disease', 'MESH:D008545', (28, 47))	('Ln-5', 'Var', (0, 4))
38577	19649148	Protease-activated thrombin receptor is a receptor with serpentine structure, activated through the cleavage of the extracellular amino terminus by thrombin.	('cleavage', 'Var', (100, 108))	('thrombin', 'Gene', (148, 156))	('thrombin', 'Gene', (19, 27))	('thrombin', 'Gene', '2147', (148, 156))	('extracellular', 'cellular_component', 'GO:0005576', ('116', '129'))	('thrombin', 'Gene', '2147', (19, 27))
38598	19649148	Inhibition of melanogenesis should therefore decrease melanoma aggressiveness and act as an enhancer of current therapy protocols.	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (54, 77))	('decrease', 'NegReg', (45, 53))	('Inhibition', 'Var', (0, 10))	('melanogenesis', 'Gene', (14, 27))	('melanoma aggressiveness', 'Disease', (54, 77))	('aggressiveness', 'Phenotype', 'HP:0000718', (63, 77))
38599	19649148	We have recently shown that the inhibition of melanogenesis by phenylthiourea and d-penicillamine enhanced cytoxicity of cyclophosphamide and IL-2-activated lymphocytes against melanoma cells.	('enhanced', 'PosReg', (98, 106))	('d-penicillamine', 'Chemical', 'MESH:D010396', (82, 97))	('melanogenesis', 'Gene', (46, 59))	('phenylthiourea', 'Var', (63, 77))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (121, 137))	('d-penicillamine', 'Var', (82, 97))	('IL-2', 'molecular_function', 'GO:0005134', ('142', '146'))	('inhibition', 'NegReg', (32, 42))	('melanoma cells', 'Disease', 'MESH:D008545', (177, 191))	('melanoma cells', 'Disease', (177, 191))	('IL-2', 'Gene', '3558', (142, 146))	('cytoxicity of cyclophosphamide', 'MPA', (107, 137))	('phenylthiourea', 'Chemical', 'MESH:D010670', (63, 77))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('IL-2', 'Gene', (142, 146))
38617	19649148	Anti-BCL-2 antisense oligonucleotide (oblimersen sodium) inhibits antiapoptotic protein BCL-2 (Figure 12).	('BCL-2', 'Gene', (5, 10))	('BCL-2', 'molecular_function', 'GO:0015283', ('88', '93'))	('antisense oligonucleotide', 'Var', (11, 36))	('BCL-2', 'molecular_function', 'GO:0015283', ('5', '10'))	('oligonucleotide', 'Chemical', 'MESH:D009841', (21, 36))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('oblimersen sodium', 'Chemical', 'MESH:C408162', (38, 55))	('BCL-2', 'Gene', '596', (5, 10))	('inhibits', 'NegReg', (57, 65))	('BCL-2', 'Gene', '596', (88, 93))	('BCL-2', 'Gene', (88, 93))
38618	19649148	Combination therapy with anti-BCL-2 antisense oligonucleotide and dacarbazine achieved a 13.5% overall response rate.	('BCL-2', 'Gene', (30, 35))	('BCL-2', 'molecular_function', 'GO:0015283', ('30', '35'))	('antisense oligonucleotide', 'Var', (36, 61))	('dacarbazine', 'Chemical', 'MESH:D003606', (66, 77))	('oligonucleotide', 'Chemical', 'MESH:D009841', (46, 61))	('BCL-2', 'Gene', '596', (30, 35))
38621	19649148	Stimulation of TLR9 activates plasmacytoid dendritic cells, thus inducing an innate immune response.	('inducing', 'PosReg', (65, 73))	('TLR9', 'Gene', (15, 19))	('innate immune response', 'biological_process', 'GO:0045087', ('77', '99'))	('Stimulation', 'Var', (0, 11))	('innate', 'CPA', (77, 83))	('TLR9', 'Gene', '54106', (15, 19))	('plasmacytoid dendritic cells', 'CPA', (30, 58))	('activates', 'PosReg', (20, 29))
38622	19649148	Overall 15% of melanoma patients treated with TLR9 activating nucleotide (PF-3512676) achieved stable disease.	('TLR9', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('stable disease', 'MPA', (95, 109))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('TLR9', 'Gene', '54106', (46, 50))	('PF', 'Chemical', 'MESH:C002997', (74, 76))	('patients', 'Species', '9606', (24, 32))	('PF-3512676', 'Var', (74, 84))
38650	19649148	Modification of the receptor of oncostatin M on melanoma cells renders it resistant to the action of antiproliferative cytokine.	('Modification', 'Var', (0, 12))	('oncostatin M', 'Gene', '5008', (32, 44))	('oncostatin M', 'Gene', (32, 44))	('resistant', 'MPA', (74, 83))	('melanoma cells', 'Disease', 'MESH:D008545', (48, 62))	('melanoma cells', 'Disease', (48, 62))	('oncostatin M', 'molecular_function', 'GO:0005147', ('32', '44'))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
38671	23431289	Some observational studies have suggested that excess dietary intake of polyunsaturated fatty acids such as linoleic acid increases cutaneous melanoma risk.	('linoleic acid', 'Var', (108, 121))	('oleic acid', 'Chemical', 'MESH:D019301', (111, 121))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (72, 99))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (76, 99))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('linoleic acid', 'Chemical', 'MESH:D019787', (108, 121))	('fatty acid', 'Chemical', 'MESH:D005227', (88, 98))	('cutaneous melanoma', 'Disease', (132, 150))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('saturated fat', 'Chemical', '-', (78, 91))	('saturated fatty acids', 'Chemical', 'MESH:D005227', (78, 99))	('linoleic', 'Chemical', '-', (108, 116))	('fatty acids', 'Chemical', 'MESH:D005227', (88, 99))	('oleic', 'Chemical', '-', (111, 116))	('increases', 'PosReg', (122, 131))	('melanoma', 'Disease', (142, 150))
38674	23431289	Conditional logistic regression was used to estimate the relative risk of melanoma associated with tertiles of percentage composition of each fatty acid as well as groupings including saturated, monounsaturated, and polyunsaturated fatty acids.	('percentage composition', 'Var', (111, 133))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('saturated, monounsaturated, and polyunsaturated fatty acids', 'Chemical', '-', (184, 243))	('polyunsaturated fatty acids', 'Var', (216, 243))	('monounsaturated', 'Var', (195, 210))
38675	23431289	We found a slightly increased melanoma risk for stearic and arachidic acids proportion, with and without adjustment for potential confounders.	('arachidic acids', 'Chemical', 'MESH:D004537', (60, 75))	('stearic', 'Chemical', '-', (48, 55))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('arachidic acids', 'Var', (60, 75))	('arachidic acid', 'Chemical', 'MESH:C094477', (60, 74))	('stearic', 'Var', (48, 55))
38676	23431289	For an n-3 polyunsaturated fatty acid, docosapentaenoic acid, we found a male-specific direct association with melanoma risk.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('docosapentaenoic acid', 'Chemical', 'MESH:C026219', (39, 60))	('melanoma', 'Disease', (111, 119))	('docosapentaenoic', 'Var', (39, 55))	('n-3 polyunsaturated fatty acid', 'Chemical', 'MESH:D015525', (7, 37))
38681	23431289	In epidermal reconstructs, n-6 PUFAs administration resulted in increased epidermal oxidative damage, possibly leading to accumulated mutations and increased risk of skin cancer, especially melanoma.	('especially melanoma', 'Disease', 'MESH:D008545', (179, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('n-6 PUFAs', 'Chemical', '-', (27, 36))	('skin cancer', 'Disease', 'MESH:D012878', (166, 177))	('especially melanoma', 'Disease', (179, 198))	('epidermal oxidative damage', 'MPA', (74, 100))	('mutations', 'Var', (134, 143))	('skin cancer', 'Phenotype', 'HP:0008069', (166, 177))	('increased', 'PosReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('skin cancer', 'Disease', (166, 177))
38702	26744134	Similar to uveal melanoma and blue nevi, they frequently harbor activating GNAQ or GNA11 mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (11, 25))	('uveal melanoma', 'Disease', (11, 25))	('activating', 'PosReg', (64, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (11, 25))	('nevi', 'Phenotype', 'HP:0003764', (35, 39))	('GNAQ', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('mutations', 'Var', (89, 98))	('GNA11', 'Gene', (83, 88))	('GNA11', 'Gene', '2767', (83, 88))	('GNAQ', 'Gene', '2776', (75, 79))	('blue nevi', 'Phenotype', 'HP:0100814', (30, 39))
38703	26744134	Rare NRAS mutations have also been reported.	('mutations', 'Var', (10, 19))	('NRAS', 'Gene', '4893', (5, 9))	('NRAS', 'Gene', (5, 9))
38705	26744134	In concordance with previous studies, cutaneous melanoma samples showed frequent NRAS or BRAF mutations, as well as mutations in other genes (e.g.	('mutations', 'Var', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('NRAS', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('cutaneous melanoma', 'Disease', (38, 56))	('NRAS', 'Gene', '4893', (81, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
38707	26744134	Metastasized uveal melanomas exhibited mutations in GNAQ, GNA11 and BAP1.	('uveal melanomas', 'Phenotype', 'HP:0007716', (13, 28))	('Metastasized uveal melanomas', 'Disease', (0, 28))	('GNAQ', 'Gene', '2776', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('exhibited', 'Reg', (29, 38))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', '8314', (68, 72))	('Metastasized uveal melanomas', 'Disease', 'MESH:D009362', (0, 28))	('GNA11', 'Gene', (58, 63))	('GNA11', 'Gene', '2767', (58, 63))	('GNAQ', 'Gene', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('BAP1', 'Gene', (68, 72))
38708	26744134	In contrast, MT-CNS almost exclusively demonstrated mutations in GNAQ (71 %) or GNA11 (12 %).	('mutations', 'Var', (52, 61))	('GNA11', 'Gene', '2767', (80, 85))	('GNAQ', 'Gene', '2776', (65, 69))	('demonstrated', 'Reg', (39, 51))	('GNAQ', 'Gene', (65, 69))	('GNA11', 'Gene', (80, 85))
38709	26744134	Interestingly both GNA11 mutations identified were detected in MT-CNS diagnosed as intermediate grade melanocytomas which also recurred.	('detected', 'Reg', (51, 59))	('mutations', 'Var', (25, 34))	('GNA11', 'Gene', (19, 24))	('melanocytomas', 'Disease', (102, 115))	('GNA11', 'Gene', '2767', (19, 24))	('melanocytomas', 'Disease', 'None', (102, 115))
38710	26744134	One of these recurrent cases also harbored an inactivating BAP1 mutation and was found to have lost one copy of chromosome 3.	('lost', 'NegReg', (95, 99))	('inactivating', 'Var', (46, 58))	('mutation', 'Var', (64, 72))	('BAP1', 'Gene', (59, 63))	('harbored', 'Reg', (34, 42))	('BAP1', 'Gene', '8314', (59, 63))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
38711	26744134	Our findings show that while MT-CNS do have GNAQ or GNA11 mutations, they rarely harbor other recurrent mutations found in uveal or cutaneous melanomas.	('mutations', 'Var', (58, 67))	('uveal or cutaneous melanomas', 'Phenotype', 'HP:0007716', (123, 151))	('GNAQ', 'Gene', (44, 48))	('uveal or cutaneous melanomas', 'Disease', (123, 151))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (132, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('GNA11', 'Gene', (52, 57))	('GNAQ', 'Gene', '2776', (44, 48))	('GNA11', 'Gene', '2767', (52, 57))	('uveal or cutaneous melanomas', 'Disease', 'MESH:C536494', (123, 151))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))
38721	26744134	In uveal melanoma, activating mutations in GNAQ and GNA11 were identified, as well as mutations in BAP1 , SF3B1  and EIF1AX .	('mutations', 'Var', (86, 95))	('BAP1', 'Gene', (99, 103))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('SF3B1', 'Gene', (106, 111))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GNAQ', 'Gene', (43, 47))	('SF3B1', 'Gene', '23451', (106, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('EIF1AX', 'Gene', '1964', (117, 123))	('mutations', 'Var', (30, 39))	('GNA11', 'Gene', (52, 57))	('BAP1', 'Gene', '8314', (99, 103))	('GNAQ', 'Gene', '2776', (43, 47))	('GNA11', 'Gene', '2767', (52, 57))	('uveal melanoma', 'Disease', (3, 17))	('EIF1AX', 'Gene', (117, 123))
38722	26744134	Inactivating BAP1 mutations are associated with poor prognosis, whereas SF3B1 and EIF1AX mutations primarily occur in tumors which do not metastasize.	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Inactivating', 'Var', (0, 12))	('SF3B1', 'Gene', (72, 77))	('BAP1', 'Gene', '8314', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('SF3B1', 'Gene', '23451', (72, 77))	('mutations', 'Var', (18, 27))
38723	26744134	In MT-CNS, the occurrence of activating GNAQ and GNA11 mutations has been well documented.	('GNAQ', 'Gene', (40, 44))	('mutations', 'Var', (55, 64))	('GNAQ', 'Gene', '2776', (40, 44))	('activating', 'PosReg', (29, 39))	('GNA11', 'Gene', '2767', (49, 54))	('GNA11', 'Gene', (49, 54))
38724	26744134	The common occurrence of these mutations in uveal melanoma and their rarity in cutaneous melanoma points toward a pathogenetic relationship of MT-CNS with uveal melanomas.	('uveal melanoma', 'Disease', 'MESH:C536494', (155, 169))	('cutaneous melanoma', 'Disease', (79, 97))	('mutations', 'Var', (31, 40))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (155, 169))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('uveal melanomas', 'Disease', 'MESH:C536494', (155, 170))	('uveal melanomas', 'Disease', (155, 170))	('uveal melanomas', 'Phenotype', 'HP:0007716', (155, 170))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('uveal melanoma', 'Disease', (44, 58))
38726	26744134	In rare, mainly pediatric MT-CNS cases, NRAS mutations have been reported.	('NRAS', 'Gene', '4893', (40, 44))	('mutations', 'Var', (45, 54))	('NRAS', 'Gene', (40, 44))	('MT-CNS', 'Disease', (26, 32))
38727	26744134	Recent work by Kusters-Vandevelde et al.. demonstrated GNAQ and GNA11 mutations in CNS melanocytomas and found at least one tumor to have copy number alterations similar to uveal melanoma (loss of chromosome 3 and gains of chromosome 8q).	('uveal melanoma', 'Phenotype', 'HP:0007716', (173, 187))	('copy', 'MPA', (138, 142))	('tumor', 'Disease', (124, 129))	('gains', 'PosReg', (214, 219))	('GNA11', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('197', '207'))	('CNS melanocytomas', 'Disease', 'MESH:D002493', (83, 100))	('CNS melanocytomas', 'Disease', (83, 100))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GNA11', 'Gene', '2767', (64, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('223', '233'))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('uveal melanoma', 'Disease', (173, 187))	('GNAQ', 'Gene', '2776', (55, 59))	('uveal melanoma', 'Disease', 'MESH:C536494', (173, 187))	('GNAQ', 'Gene', (55, 59))	('loss', 'NegReg', (189, 193))
38729	26744134	analyzed copy number alterations, methylation profiles and individual activating gene mutations in melanocytomas, schwannomas and melanomas.	('mutations', 'Var', (86, 95))	('schwannomas', 'Phenotype', 'HP:0100008', (114, 125))	('methylation', 'Var', (34, 45))	('activating', 'PosReg', (70, 80))	('melanocytomas, schwannomas and melanomas', 'Disease', 'MESH:D009442', (99, 139))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('copy number alterations', 'Var', (9, 32))
38732	26744134	The aim of our study was to analyze the occurrence of gene mutations known to be frequent in cutaneous or uveal melanoma in a cohort of MT-CNS using a next generation targeted sequencing approach.	('frequent', 'Reg', (81, 89))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutations', 'Var', (59, 68))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))
38761	26744134	The sequencing of all samples with the 29 gene assay identified recurrent activating Q209 mutations in GNAQ and GNA11 in the MT-CNS (Table 1; Fig.	('activating', 'PosReg', (74, 84))	('GNAQ', 'Gene', '2776', (103, 107))	('GNA11', 'Gene', (112, 117))	('Q209 mutations', 'Var', (85, 99))	('GNA11', 'Gene', '2767', (112, 117))	('GNAQ', 'Gene', (103, 107))
38762	26744134	Mutations in GNAQ were identified in 13 samples from 12 patients (12 of 17 = 71 %).	('patients', 'Species', '9606', (56, 64))	('GNAQ', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (23, 33))	('GNAQ', 'Gene', '2776', (13, 17))
38763	26744134	Mutations in GNA11 were found in three samples from two patients (2 of 17 = 12 %).	('patients', 'Species', '9606', (56, 64))	('GNA11', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (13, 18))	('found', 'Reg', (24, 29))
38764	26744134	An inactivating BAP1 mutation leading to the formation of a stop codon at residue 60 (R60*) was identified in two samples of the same patient (the primary tumor and a recurrence, shown in Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('R60*', 'SUBSTITUTION', 'None', (86, 90))	('tumor', 'Disease', (155, 160))	('BAP1', 'Gene', '8314', (16, 20))	('formation', 'biological_process', 'GO:0009058', ('45', '54'))	('BAP1', 'Gene', (16, 20))	('patient', 'Species', '9606', (134, 141))	('R60*', 'Var', (86, 90))
38766	26744134	The uveal melanoma samples harbored recurrent GNAQ (n = 2, 29 %) and GNA11 mutations (n = 4, 57 %).	('GNAQ', 'Gene', (46, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (4, 18))	('uveal melanoma', 'Disease', (4, 18))	('GNAQ', 'Gene', '2776', (46, 50))	('mutations', 'Var', (75, 84))	('GNA11', 'Gene', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('GNA11', 'Gene', '2767', (69, 74))	('uveal melanoma', 'Disease', 'MESH:C536494', (4, 18))
38767	26744134	BAP1 mutations were identified in 4 samples (57 %), of which 3 (75 %) were clearly inactivating, leading to loss of the functional protein (Supplemental Fig.	('loss', 'NegReg', (108, 112))	('BAP1', 'Gene', (0, 4))	('functional protein', 'MPA', (120, 138))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('BAP1', 'Gene', '8314', (0, 4))
38768	26744134	BRAF V600 mutations were detected in 10 of 19 (53 %) samples, including 7 V600E, 2 V600K and 1 T599_V600insT alterations.	('V600K', 'Var', (83, 88))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('V600K', 'Mutation', 'rs121913227', (83, 88))	('T599_V600insT', 'Var', (95, 108))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (74, 79))	('BRAF', 'Gene', (0, 4))	('V600insT', 'Mutation', 'c.600insV,T', (100, 108))	('detected', 'Reg', (25, 33))
38769	26744134	Another two samples carried N581S and P239L mutations of unclear functional significance.	('N581S', 'Mutation', 'rs121913370', (28, 33))	('P239L', 'Var', (38, 43))	('P239L', 'Mutation', 'rs1471878830', (38, 43))	('N581S', 'Var', (28, 33))
38770	26744134	NRAS mutations were found mutually exclusively with BRAF mutations in 5 (26 %) samples and included 4 Q61K and 1 Q61R alterations.	('Q61R', 'Var', (113, 117))	('NRAS', 'Gene', '4893', (0, 4))	('Q61R', 'Mutation', 'rs11554290', (113, 117))	('Q61K', 'Var', (102, 106))	('mutations', 'Var', (5, 14))	('Q61K', 'Mutation', 'rs121913254', (102, 106))	('mutations', 'Var', (57, 66))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
38771	26744134	Other rarer mutations were identified, including NF1, PTEN, ARID1A, RAC1, KIT, SF3B1 and other mutations (see Table 1; Supplemental Table 3 reporting mutations with an allelic frequency >=15 %).	('ARID1A', 'Gene', (60, 66))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('NF1', 'Gene', '4763', (49, 52))	('RAC1', 'Gene', '5879', (68, 72))	('SF3B1', 'Gene', (79, 84))	('PTEN', 'Gene', (54, 58))	('RAC1', 'Gene', (68, 72))	('KIT', 'Gene', (74, 77))	('PTEN', 'Gene', '5728', (54, 58))	('mutations', 'Var', (150, 159))	('mutations', 'Var', (95, 104))	('SF3B1', 'Gene', '23451', (79, 84))	('NF1', 'Gene', (49, 52))	('ARID1A', 'Gene', '8289', (60, 66))
38772	26744134	In 14 of the MT-CNS samples, exon 1 of the gene EIF1AX, which was not covered in the next gen sequencing panel, was sequenced by Sanger-sequencing, in search of recurrent mutations which are frequently seen in primary uveal melanoma samples; no EIF1AX mutations were identified.	('EIF1AX', 'Gene', '1964', (245, 251))	('EIF1AX', 'Gene', (245, 251))	('uveal melanoma', 'Disease', 'MESH:C536494', (218, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (218, 232))	('uveal melanoma', 'Disease', (218, 232))	('mutations', 'Var', (171, 180))	('EIF1AX', 'Gene', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('EIF1AX', 'Gene', '1964', (48, 54))
38775	26744134	In two samples, the primary and recurrent tumor from the same patient harboring the BAP1 R60* mutations, BAP1 IHC showed absent nuclear expression (Fig.	('R60*', 'SUBSTITUTION', 'None', (89, 93))	('tumor', 'Disease', (42, 47))	('absent', 'NegReg', (121, 127))	('BAP1', 'Gene', '8314', (105, 109))	('patient', 'Species', '9606', (62, 69))	('BAP1', 'Gene', '8314', (84, 88))	('R60*', 'Var', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('BAP1', 'Gene', (84, 88))	('nuclear expression', 'MPA', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BAP1', 'Gene', (105, 109))
38776	26744134	Genome wide chromosomal copy number analysis was performed on both samples identified as having inactivating BAP1 c.178C > T, p.R60* mutations as well as two other MT-CNS (also intermediate-grade melanocytoma) samples, both harboring GNAQ c.626A > T, p.Q209L mutations.	('melanocytoma', 'Disease', (196, 208))	('p.R60*', 'Mutation', 'p.R60*', (126, 132))	('GNAQ', 'Gene', '2776', (234, 238))	('c.178C > T', 'Var', (114, 124))	('BAP1', 'Gene', '8314', (109, 113))	('melanocytoma', 'Disease', 'None', (196, 208))	('p.Q209L', 'Var', (251, 258))	('p.R60*', 'Var', (126, 132))	('GNAQ', 'Gene', (234, 238))	('c.178C > T', 'Mutation', 'rs587777021', (114, 124))	('inactivating', 'Var', (96, 108))	('BAP1', 'Gene', (109, 113))	('p.Q209L', 'Mutation', 'rs121913492', (251, 258))	('c.626A > T', 'Mutation', 'rs121913492', (239, 249))
38779	26744134	In our study, a larger cohort of MT-CNS was screened for mutations in a range of genes known to be recurrently mutated in other melanocytic tumors, in particular cutaneous and uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (176, 190))	('uveal melanoma', 'Disease', (176, 190))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (57, 66))	('melanocytic tumors', 'Disease', 'MESH:D009508', (128, 146))	('melanocytic tumors', 'Disease', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('uveal melanoma', 'Disease', 'MESH:C536494', (176, 190))
38780	26744134	Other than the known mutations in GNAQ and GNA11, none of the other genes analyzed were found to harbor recurrent mutations in MT-CNS from different patients.	('patients', 'Species', '9606', (149, 157))	('mutations', 'Var', (114, 123))	('GNA11', 'Gene', (43, 48))	('GNA11', 'Gene', '2767', (43, 48))	('MT-CNS', 'Gene', (127, 133))	('GNAQ', 'Gene', (34, 38))	('GNAQ', 'Gene', '2776', (34, 38))
38782	26744134	In the uveal melanoma samples analyzed, 4 out of 7 (57 %) had mutations in BAP1.	('uveal melanoma', 'Disease', (7, 21))	('BAP1', 'Gene', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('uveal melanoma', 'Disease', 'MESH:C536494', (7, 21))	('BAP1', 'Gene', '8314', (75, 79))	('mutations', 'Var', (62, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (7, 21))
38783	26744134	Potentially events inactivating BAP1, such as promoter methylation or homozygous deletions, not detected by our sequencing approach, may have taken place in some of the remaining samples.	('deletions', 'Var', (81, 90))	('BAP1', 'Gene', '8314', (32, 36))	('promoter', 'MPA', (46, 54))	('BAP1', 'Gene', (32, 36))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
38785	26744134	The mutations identified in cutaneous melanomas reflect those described in previous studies with activating BRAF and NRAS mutations in 53 and 26 % of samples, respectively.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('NRAS', 'Gene', (117, 121))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('NRAS', 'Gene', '4893', (117, 121))	('cutaneous melanomas', 'Disease', (28, 47))	('mutations', 'Var', (122, 131))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('activating', 'PosReg', (97, 107))	('BRAF', 'Gene', '673', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRAF', 'Gene', (108, 112))
38786	26744134	Additionally, our screen identified a number of other recently described mutations such as two hotspot R29 RAC1 mutations, 3 inactivating NF1 mutations, 2 inactivating ARID1A mutations and 2 KIT mutations.	('mutations', 'Var', (142, 151))	('inactivating', 'NegReg', (125, 137))	('RAC1', 'Gene', (107, 111))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('ARID1A', 'Gene', '8289', (168, 174))	('ARID1A', 'Gene', (168, 174))	('mutations', 'Var', (112, 121))	('mutations', 'Var', (175, 184))	('NF1', 'Gene', (138, 141))	('inactivating', 'NegReg', (155, 167))	('mutations', 'Var', (73, 82))	('NF1', 'Gene', '4763', (138, 141))	('RAC1', 'Gene', '5879', (107, 111))
38787	26744134	One KIT mutation, K642E, is clearly activating and was identified in an NRAS and BRAF wild-type sample.	('NRAS', 'Gene', (72, 76))	('KIT', 'molecular_function', 'GO:0005020', ('4', '7'))	('NRAS', 'Gene', '4893', (72, 76))	('BRAF', 'Gene', '673', (81, 85))	('K642E', 'Var', (18, 23))	('BRAF', 'Gene', (81, 85))	('K642E', 'Mutation', 'rs121913512', (18, 23))	('activating', 'MPA', (36, 46))
38789	26744134	The high mutation frequency of GNAQ and GNA11 mutations detected in MT-CNS is intriguing.	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', '2767', (40, 45))	('GNAQ', 'Gene', (31, 35))
38790	26744134	As we previously reported, in contrast to uveal melanomas, MT-CNS samples much more commonly harbor GNAQ mutations than GNA11 mutations.	('GNAQ', 'Gene', '2776', (100, 104))	('harbor', 'Reg', (93, 99))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('GNA11', 'Gene', (120, 125))	('MT-CNS', 'Disease', (59, 65))	('GNAQ', 'Gene', (100, 104))	('mutations', 'Var', (105, 114))	('GNA11', 'Gene', '2767', (120, 125))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
38791	26744134	Concordant with our previous study, our targeted next generation sequencing in the current study identified 71 % GNAQ and 12 % GNA11 mutations.	('GNAQ', 'Gene', (113, 117))	('mutations', 'Var', (133, 142))	('GNA11', 'Gene', '2767', (127, 132))	('GNA11', 'Gene', (127, 132))	('GNAQ', 'Gene', '2776', (113, 117))
38792	26744134	also recently reported more frequent GNAQ mutations (37 %) than GNA11 mutations (10 %) in MT-CNS.	('GNAQ', 'Gene', (37, 41))	('MT-CNS', 'Disease', (90, 96))	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('GNAQ', 'Gene', '2776', (37, 41))	('mutations', 'Var', (42, 51))
38793	26744134	Blue nevi, benign melanocytic proliferations of the skin, also show a similar distribution with 55 % GNAQ and 7 % GNA11 mutations reported in one study.	('GNA11', 'Gene', '2767', (114, 119))	('melanocytic', 'Disease', (18, 29))	('GNAQ', 'Gene', '2776', (101, 105))	('Blue nevi', 'Disease', (0, 9))	('melanocytic', 'Disease', 'MESH:D009508', (18, 29))	('Blue nevi', 'Phenotype', 'HP:0100814', (0, 9))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('mutations', 'Var', (120, 129))	('GNAQ', 'Gene', (101, 105))	('GNA11', 'Gene', (114, 119))
38794	26744134	The distribution of mutations in primary uveal melanoma samples is more evenly distributed, however still shows slightly more GNAQ (45-47 %) than GNA11 (32-44 %) mutations .	('GNAQ', 'Gene', '2776', (126, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (41, 55))	('uveal melanoma', 'Disease', (41, 55))	('mutations', 'Var', (162, 171))	('GNA11', 'Gene', '2767', (146, 151))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('GNA11', 'Gene', (146, 151))
38795	26744134	In contrast, a higher frequency of GNA11 (57-60 %) to GNAQ (20-22 %) mutations has been reported in uveal melanoma metastases .	('mutations', 'Var', (69, 78))	('GNAQ', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma metastases', 'Disease', (100, 125))	('uveal melanoma metastases', 'Disease', 'MESH:D009362', (100, 125))	('GNAQ', 'Gene', '2776', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('GNA11', 'Gene', '2767', (35, 40))	('GNA11', 'Gene', (35, 40))
38796	26744134	The shift in mutation frequencies from GNAQ to GNA11 from benign to increasingly malignant tumors may indicate GNA11 mutations are associated with a more malignant phenotype in this entity.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (117, 126))	('GNAQ', 'Gene', (39, 43))	('malignant tumors', 'Disease', (81, 97))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('associated', 'Reg', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('malignant tumors', 'Disease', 'MESH:D018198', (81, 97))	('GNAQ', 'Gene', '2776', (39, 43))	('GNA11', 'Gene', '2767', (111, 116))	('GNA11', 'Gene', (111, 116))
38797	26744134	Interestingly, both of the two mutant GNA11 cases (three samples from two patients) we observed in MT-CNS were rated intermediate grade melanocytomas.	('mutant', 'Var', (31, 37))	('melanocytomas', 'Disease', (136, 149))	('patients', 'Species', '9606', (74, 82))	('GNA11', 'Gene', '2767', (38, 43))	('GNA11', 'Gene', (38, 43))	('melanocytomas', 'Disease', 'None', (136, 149))
38798	26744134	Furthermore, both mutant GNA11 MT-CNS cases were tumors that recurred.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutant', 'Var', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('GNA11', 'Gene', (25, 30))	('GNA11', 'Gene', '2767', (25, 30))
38799	26744134	One of these cases also harbored an inactivating BAP1 mutation.	('mutation', 'Var', (54, 62))	('BAP1', 'Gene', '8314', (49, 53))	('BAP1', 'Gene', (49, 53))	('inactivating', 'Var', (36, 48))
38800	26744134	also reported that all melanocytomas in their cohort with GNA11 mutations were of intermediate grade.	('melanocytomas', 'Disease', (23, 36))	('melanocytomas', 'Disease', 'None', (23, 36))	('mutations', 'Var', (64, 73))	('GNA11', 'Gene', '2767', (58, 63))	('GNA11', 'Gene', (58, 63))
38801	26744134	If future studies with larger case numbers report similar findings to our study, this could signify GNA11 mutations are also associated with a more aggressive phenotype in MT-CNS.	('MT-CNS', 'Disease', (172, 178))	('associated with', 'Reg', (125, 140))	('mutations', 'Var', (106, 115))	('GNA11', 'Gene', (100, 105))	('GNA11', 'Gene', '2767', (100, 105))
38802	26744134	Considering the similar occurrence of GNAQ and GNA11 mutations in a high frequency of MT-CNS and uveal melanomas, it would seem likely that MT-CNS could potentially also harbor mutations in other genes known to be relevant in uveal melanoma, in particular the recently identified mutations in SF3B1, EIF1AX and BAP1.	('GNAQ', 'Gene', '2776', (38, 42))	('SF3B1', 'Gene', '23451', (293, 298))	('GNA11', 'Gene', (47, 52))	('mutations', 'Var', (177, 186))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('GNAQ', 'Gene', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (226, 240))	('EIF1AX', 'Gene', (300, 306))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('BAP1', 'Gene', (311, 315))	('EIF1AX', 'Gene', '1964', (300, 306))	('uveal melanomas', 'Disease', 'MESH:C536494', (97, 112))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('GNA11', 'Gene', '2767', (47, 52))	('mutations', 'Var', (53, 62))	('SF3B1', 'Gene', (293, 298))	('harbor', 'Reg', (170, 176))	('mutations', 'Var', (280, 289))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (226, 240))	('uveal melanoma', 'Disease', (226, 240))	('BAP1', 'Gene', '8314', (311, 315))	('uveal melanomas', 'Disease', (97, 112))	('uveal melanomas', 'Phenotype', 'HP:0007716', (97, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
38803	26744134	Mutations in these genes are found in most uveal melanoma samples and with rare exceptions are mutually exclusive.	('found', 'Reg', (29, 34))	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('Mutations', 'Var', (0, 9))	('uveal melanoma', 'Disease', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
38804	26744134	BAP1 mutations are associated with metastasis and poor prognosis, whereas SF3B1 and EIF1AX mutations primarily occur in tumors with a favorable prognosis.	('associated', 'Reg', (19, 29))	('metastasis', 'Disease', 'MESH:D009362', (35, 45))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('BAP1', 'Gene', (0, 4))	('EIF1AX', 'Gene', (84, 90))	('SF3B1', 'Gene', '23451', (74, 79))	('metastasis', 'Disease', (35, 45))	('EIF1AX', 'Gene', '1964', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('BAP1', 'Gene', '8314', (0, 4))	('SF3B1', 'Gene', (74, 79))
38805	26744134	As MT-CNS are mostly benign tumors with a favorable prognosis, it would seem likely that they could also harbor SF3B1 or EIF1AX mutations.	('MT-CNS', 'Disease', (3, 9))	('mutations', 'Var', (128, 137))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('SF3B1', 'Gene', '23451', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('harbor', 'Reg', (105, 111))	('EIF1AX', 'Gene', '1964', (121, 127))	('EIF1AX', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SF3B1', 'Gene', (112, 117))
38807	26744134	These results suggest that mutations in uveal melanoma genes other than GNAQ and GNA11 are rare in MT-CNS.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('GNAQ', 'Gene', '2776', (72, 76))	('GNA11', 'Gene', '2767', (81, 86))	('GNA11', 'Gene', (81, 86))	('uveal melanoma', 'Phenotype', 'HP:0007716', (40, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (40, 54))	('uveal melanoma', 'Disease', (40, 54))	('GNAQ', 'Gene', (72, 76))
38808	26744134	Although only identified in one MT-CNS case (1 of 17 = 6 %), the case with BAP1 inactivation and Chr.	('inactivation', 'Var', (80, 92))	('BAP1', 'Gene', '8314', (75, 79))	('BAP1', 'Gene', (75, 79))
38809	26744134	Similar to our findings, the chromosomal alterations in these cases are highly reminiscent of uveal melanomas with a poor prognosis.	('uveal melanomas', 'Disease', 'MESH:C536494', (94, 109))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('chromosomal alterations', 'Var', (29, 52))	('uveal melanomas', 'Disease', (94, 109))	('uveal melanomas', 'Phenotype', 'HP:0007716', (94, 109))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanomas', 'Phenotype', 'HP:0002861', (100, 109))
38810	26744134	As such, screening for inactivating BAP1 mutations and/or Chr.	('inactivating', 'Var', (23, 35))	('BAP1', 'Gene', (36, 40))	('BAP1', 'Gene', '8314', (36, 40))	('mutations', 'Var', (41, 50))
38811	26744134	3 and an inactivating BAP1 mutation, both patient history and MRI scans showed no sign of uveal melanoma.	('uveal melanoma', 'Phenotype', 'HP:0007716', (90, 104))	('uveal melanoma', 'Disease', (90, 104))	('uveal melanoma', 'Disease', 'MESH:C536494', (90, 104))	('inactivating', 'Var', (9, 21))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (42, 49))	('BAP1', 'Gene', '8314', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('BAP1', 'Gene', (22, 26))
38815	26744134	Our study screened for the presence of mutations in many genes known to be recurrently mutated in cutaneous and uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('uveal melanomas', 'Disease', (112, 127))	('uveal melanomas', 'Phenotype', 'HP:0007716', (112, 127))	('mutations', 'Var', (39, 48))	('uveal melanoma', 'Phenotype', 'HP:0007716', (112, 126))	('uveal melanomas', 'Disease', 'MESH:C536494', (112, 127))
38817	26744134	Although MT-CNS share frequent GNAQ and GNA11 mutations with uveal melanomas, mutations in other uveal melanoma genes were very rare.	('uveal melanomas', 'Disease', (61, 76))	('uveal melanomas', 'Phenotype', 'HP:0007716', (61, 76))	('mutations', 'Var', (46, 55))	('GNA11', 'Gene', (40, 45))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (61, 76))	('GNAQ', 'Gene', '2776', (31, 35))	('GNA11', 'Gene', '2767', (40, 45))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('uveal melanoma', 'Disease', (97, 111))	('uveal melanoma', 'Disease', 'MESH:C536494', (61, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (97, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (61, 75))	('GNAQ', 'Gene', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
38819	26744134	The identification of novel gene mutations unique to MT-CNS would be a valuable diagnostic tool to help distinguish MT-CNS from metastases of melanocytic tumors from other sites.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('metastases of melanocytic tumors', 'Disease', 'MESH:D009362', (128, 160))	('mutations', 'Var', (33, 42))	('metastases of melanocytic tumors', 'Disease', (128, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
38820	31765370	GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs.	('copy number variation', 'Var', (77, 98))	('solid tumors', 'Disease', (102, 114))	('GPCR', 'Gene', '148', (144, 148))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GPCR', 'Gene', (144, 148))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
38828	31765370	Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage.	('GPCR', 'Gene', '148', (8, 12))	('mutated', 'Var', (29, 36))	('GPCR', 'Gene', (8, 12))
38833	31765370	Expression of certain GPCRs appears to have prognostic relevance, and many GPCRs undergo widespread mutation and copy number variation.	('GPCR', 'Gene', '148', (75, 79))	('copy number variation', 'Var', (113, 134))	('undergo', 'Reg', (81, 88))	('GPCR', 'Gene', (75, 79))	('GPCR', 'Gene', (22, 26))	('GPCR', 'Gene', '148', (22, 26))
38837	31765370	One reason for their limited use is the notion that GPCRs are rarely mutated in cancer :although mutations occur in heterotrimeric GTP binding (G) proteins that GPCRs activate :and that GPCRs regulate pathways, such as Wnt, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-Kinase (PI3K) signaling, with mutations in cancer.	('mutations', 'Var', (97, 106))	('Wnt', 'Pathway', (219, 222))	('mutations', 'Var', (318, 327))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GPCR', 'Gene', '148', (52, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('258', '262'))	('GPCR', 'Gene', '148', (186, 190))	('PI3K', 'molecular_function', 'GO:0016303', ('296', '300'))	('Phosphoinositide 3-Kinase', 'Gene', '5293', (269, 294))	('GPCR', 'Gene', (52, 56))	('GPCR', 'Gene', '148', (161, 165))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('GPCR', 'Gene', (186, 190))	('regulate', 'Reg', (192, 200))	('GPCR', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Phosphoinositide 3-Kinase', 'Gene', (269, 294))	('cancer', 'Disease', (331, 337))	('GTP binding', 'molecular_function', 'GO:0005525', ('131', '142'))	('PI3K) signaling', 'biological_process', 'GO:0014065', ('296', '311'))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
38839	31765370	To define the landscape of GPCRs in cancer, we undertook an integrated analysis of Differential Expression (DE), mutations, and copy number variation (CNV) of GPCRs, which are annotated by the Guide to Pharmacology database (GtoPdb), in 20 types of solid tumors (Table 1 and S1 and S2 Tables).	('GPCR', 'Gene', '148', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Disease', (36, 42))	('solid tumors', 'Disease', 'MESH:D009369', (249, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('GPCR', 'Gene', (27, 31))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('GPCR', 'Gene', '148', (159, 163))	('copy number variation', 'Var', (128, 149))	('solid tumors', 'Disease', (249, 261))	('GPCR', 'Gene', (159, 163))
38880	31765370	We compiled a list of GPCRs overexpressed in solid tumors with fold-changes and FDR along with expression in TPM (for median expression and within-group comparisons of different genes) and Counts Per Million (CPM; for intergroup comparisons of the same gene).	('TPM', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GPCR', 'Gene', (22, 26))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('TPM', 'Chemical', '-', (109, 112))	('GPCR', 'Gene', '148', (22, 26))	('fold-changes', 'Var', (63, 75))
38931	31765370	EDNRB, which is highly overexpressed in SKCM, promotes migration and transformation of melanocytes and melanoma cells, and inhibition of EDNRB is pro-apoptotic.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('EDNRB', 'Gene', (0, 5))	('inhibition', 'Var', (123, 133))	('migration', 'CPA', (55, 64))	('EDNRB', 'Gene', (137, 142))	('transformation', 'CPA', (69, 83))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (69, 98))	('EDNRB', 'Gene', '1910', (0, 5))	('promotes', 'PosReg', (46, 54))	('EDNRB', 'Gene', '1910', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
38945	31765370	GPCR expression appears largely independent of driver mutations, such as in BRCA HR+ IDC tumors with either PI3KA or TP53 mutations (Fig 7A-7C); both groups have similar GPCR expression and DE of the same GPCRs compared to normal breast tissue.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('GPCR', 'Gene', '148', (0, 4))	('PI3KA', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('BRCA HR+ IDC tumors', 'Disease', 'MESH:D001919', (76, 95))	('BRCA', 'Phenotype', 'HP:0003002', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GPCR', 'Gene', '148', (205, 209))	('GPCR', 'Gene', (0, 4))	('BRCA HR+ IDC tumors', 'Disease', (76, 95))	('mutations', 'Var', (122, 131))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (205, 209))	('GPCR', 'Gene', (170, 174))
38946	31765370	Similar results occur for lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD) that have or lack TP53 mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('stomach adenocarcinoma', 'Disease', (57, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (57, 79))
38970	31765370	In SKCM, which has the highest mutation burden among TCGA tumor types, the most highly overexpressed GPCRs (GPR143, EDNRB, and GPR56) are mutated in <2% of SKCM tumors, whereas frequently mutated GPCRs (e.g., GPR98, mutated in nearly 40% of tumors) typically have low expression.	('GPCR', 'Gene', '148', (196, 200))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('GPCR', 'Gene', (196, 200))	('GPCR', 'Gene', '148', (101, 105))	('GPR98', 'Gene', (209, 214))	('tumor', 'Disease', (161, 166))	('GPR56', 'Gene', (127, 132))	('GPCR', 'Gene', (101, 105))	('tumor', 'Disease', (58, 63))	('GPR143', 'Gene', (108, 114))	('tumor', 'Disease', (241, 246))	('SKCM tumors', 'Disease', (156, 167))	('SKCM tumors', 'Disease', 'MESH:D009369', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EDNRB', 'Gene', '1910', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('EDNRB', 'Gene', (116, 121))	('GPR98', 'Gene', '84059', (209, 214))	('mutated', 'Var', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('overexpressed', 'PosReg', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('GPR56', 'Gene', '9289', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (241, 247))	('GPR143', 'Gene', '4935', (108, 114))
38974	31765370	Furthermore, as discussed in the following sections on GPCR mutation, mutations to these GPCRs are predicted to have no functional impact and are not enriched significantly for mutations at specific sites; thus, overexpressed GPCRs in tumors are not expected to be altered in their function by mutations.	('GPCR', 'Gene', '148', (226, 230))	('mutations', 'Var', (70, 79))	('GPCR', 'Gene', '148', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('GPCR', 'Gene', (226, 230))	('GPCR', 'Gene', '148', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('GPCR', 'Gene', (89, 93))	('GPCR', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('overexpressed', 'PosReg', (212, 225))
38976	31765370	Tissues and tumors typically express >150 GPCRs (at detection thresholds >0.1 TPM) that couple to the major types of G proteins (Gs, Gi/o, Gq/11, G12/13), most frequently Gi/Go and Gq/G11 (S7A and S7B Fig).	('Gi/Go', 'Var', (171, 176))	('S7', 'Gene', '6264', (189, 191))	('TPM', 'Chemical', '-', (78, 81))	('GPCR', 'Gene', '148', (42, 46))	('S7', 'Gene', '6264', (197, 199))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('GPCR', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('couple', 'Reg', (88, 94))
39018	31765370	Analysis of 5,103 TCGA samples in 20 tumor types (S3 Table; 21 tumor types if one divides ESCA into esophageal adenocarcinoma and squamous cell carcinomas) revealed many GPCRs with frequent nonsilent mutations (Figs 11A and S8A), including a more frequently mutated subset (Fig 11A, inset).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('squamous cell carcinomas', 'Disease', (130, 154))	('mutations', 'Var', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (100, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (170, 174))	('tumor', 'Disease', (63, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (130, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (130, 154))	('tumor', 'Disease', (37, 42))	('adenocarcinoma', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
39021	31765370	SKCM has the highest frequency: approximately 40% of SKCM tumors have GPR98 mutations (Fig 11C and 11H).	('GPR98', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SKCM tumors', 'Disease', (53, 64))	('SKCM tumors', 'Disease', 'MESH:D009369', (53, 64))	('GPR98', 'Gene', '84059', (70, 75))
39023	31765370	Certain GPCRs are mutated in >10% of specific tumor types (Fig 11C).	('GPCR', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (46, 51))	('GPCR', 'Gene', '148', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
39025	31765370	Frequently mutated GPCRs (e.g., GPR98, GPR112, and BAI3) are more likely to be mutated as Nmut increases (Fig 11E, SKCM as an example).	('BAI3', 'Gene', (51, 55))	('GPCR', 'Gene', (19, 23))	('mutated', 'Var', (79, 86))	('GPR112', 'Gene', '139378', (39, 45))	('GPR98', 'Gene', (32, 37))	('GPR112', 'Gene', (39, 45))	('GPCR', 'Gene', '148', (19, 23))	('GPR98', 'Gene', '84059', (32, 37))	('BAI3', 'Gene', '577', (51, 55))
39026	31765370	The relationship between Nmut and likelihood of GPR98 mutation is similar in SKCM and other cancers (Fig 11F); this is also observed for other frequently mutated GPCRs.	('mutation', 'Var', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('GPR98', 'Gene', '84059', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('GPCR', 'Gene', '148', (162, 166))	('SKCM', 'Disease', (77, 81))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('GPCR', 'Gene', (162, 166))	('GPR98', 'Gene', (48, 53))
39027	31765370	Hence, the likelihood of a GPCR being mutated appears to depend on the accumulation of genome damage and to be independent of the mechanisms for the mutations.	('GPCR', 'Gene', (27, 31))	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (27, 31))
39029	31765370	Mutations of certain GPCRs, such as GPR98, may thus serve as a bellwether for genome-wide DNA damage.	('GPCR', 'Gene', '148', (21, 25))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('GPCR', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('GPR98', 'Gene', (36, 41))	('GPR98', 'Gene', '84059', (36, 41))
39030	31765370	Missense mutations and in-frame deletions are the most frequent nonsilent mutations in GPCR genes (S8C and S8D Fig and S5 Table).	('in-frame deletions', 'Var', (23, 41))	('GPCR', 'Gene', (87, 91))	('GPCR', 'Gene', '148', (87, 91))	('Missense mutations', 'Var', (0, 18))
39031	31765370	Mutations in frequently mutated GPCRs occur at many sites (S9A Fig), which contrasts with the smaller number of such sites in common oncogenes, e.g., KRAS.	('mutated', 'Var', (24, 31))	('GPCR', 'Gene', (32, 36))	('occur', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('GPCR', 'Gene', '148', (32, 36))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
39032	31765370	Certain GPCR genes (e.g., GPR98) may be in genomic regions vulnerable to dysregulation of DNA damage and repair and belong to a subset of mutated genes; GPR98 mutations frequently occur alongside other frequently mutated genes such as TTN and MUC16 (S10A-S10G Fig).	('TTN', 'Gene', (235, 238))	('GPR98', 'Gene', '84059', (26, 31))	('GPCR', 'Gene', (8, 12))	('TTN', 'Gene', '7273', (235, 238))	('MUC16', 'Gene', '94025', (243, 248))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('mutations', 'Var', (159, 168))	('occur', 'Reg', (180, 185))	('GPR98', 'Gene', (153, 158))	('S10A', 'SUBSTITUTION', 'None', (250, 254))	('GPR98', 'Gene', (26, 31))	('GPR98', 'Gene', '84059', (153, 158))	('GPCR', 'Gene', '148', (8, 12))	('MUC16', 'Gene', (243, 248))	('S10G', 'Mutation', 'p.S10G', (255, 259))	('S10A', 'Var', (250, 254))
39038	31765370	Survival analysis of metastatic SKCM samples was performed in order to evaluate the impact on tumors of somatic nonsilent mutations to GPR98, GPR112, or other frequently mutated GPCRs.	('GPCR', 'Gene', '148', (178, 182))	('GPR112', 'Gene', '139378', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GPR98', 'Gene', (135, 140))	('GPR112', 'Gene', (142, 148))	('mutations', 'Var', (122, 131))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('GPR98', 'Gene', '84059', (135, 140))	('GPCR', 'Gene', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
39041	31765370	We find the same result in other tumor types as well and thus conclude that somatic nonsilent mutations to GPCRs have no impact on patient survival.	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GPCR', 'Gene', '148', (107, 111))	('tumor', 'Disease', (33, 38))	('patient', 'Species', '9606', (131, 138))	('GPCR', 'Gene', (107, 111))
39044	31765370	As cell-surface receptors, frequently mutated, well-expressed GPCRs may represent neo-antigens.	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (62, 66))	('cell-surface', 'Protein', (3, 15))	('GPCR', 'Gene', (62, 66))	('cell-surface', 'cellular_component', 'GO:0009986', ('3', '15'))
39045	31765370	For SKCM, which has the most GPCR mutations among tumors types surveyed, DE analysis of primary melanomas and distant metastases that have or lack GPCR mutations (e.g., GPR98 and LPHN2) revealed little evidence that these mutations alter the tumor transcriptome, implying that such GPCR mutations are likely passenger, rather than driver, mutations (Figs 11H and S8C and S8D).	('LPHN2', 'Gene', '23266', (179, 184))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('mutations', 'Var', (287, 296))	('tumor', 'Disease', (242, 247))	('GPCR', 'Gene', '148', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('GPCR', 'Gene', '148', (147, 151))	('GPCR', 'Gene', (29, 33))	('alter', 'Reg', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('GPCR', 'Gene', '148', (282, 286))	('GPR98', 'Gene', (169, 174))	('GPCR', 'Gene', (147, 151))	('mutations', 'Var', (222, 231))	('GPCR', 'Gene', (282, 286))	('tumor', 'Disease', (50, 55))	('LPHN2', 'Gene', (179, 184))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanomas', 'Disease', (96, 105))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('GPR98', 'Gene', '84059', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('metastases', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', (50, 56))
39046	31765370	Conversely, previous work has suggested that for known oncogenes (e.g., for TP53), there are often widespread transcriptomic changes associated with specific mutations.	('transcriptomic changes', 'MPA', (110, 132))	('mutations', 'Var', (158, 167))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (76, 80))
39047	31765370	We found similar behavior for other tumors (e.g., BLCA) that have frequent GPCR mutations.	('GPCR', 'Gene', '148', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (80, 89))	('GPCR', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('BLCA', 'Phenotype', 'HP:0009725', (50, 54))
39048	31765370	As a further approach, we evaluated GPCR mutations, predicting the likelihood of functional consequences and site-specific enrichment of the mutations via MutSig 2CV version 3.1 (gdac.broadinstitute.org).	('GPCR', 'Gene', '148', (36, 40))	('GPCR', 'Gene', (36, 40))	('mutations', 'Var', (141, 150))
39049	31765370	The majority of GPCRs frequently mutated (Fig 11I, SKCM as example) show nonsilent mutations that are nonsignificant in terms of enrichment (compared to the background mutation rate of silent mutations over the same regions) for individual mutation sites.	('GPCR', 'Gene', '148', (16, 20))	('GPCR', 'Gene', (16, 20))	('mutated', 'Var', (33, 40))
39050	31765370	These mutations are not predicted to be functional (calculated from estimations of functional impact of mutations based on whether mutated regions are highly evolutionarily conserved) by MutSig 2CV, consistent with the idea that the frequent GPCR mutations are likely passenger and not driver mutations.	('mutations', 'Var', (247, 256))	('GPCR', 'Gene', '148', (242, 246))	('GPCR', 'Gene', (242, 246))
39056	31765370	Single-copy/heterozygous deletions of GPCRs are widespread, whereas homozygous deletions are rare (Fig 13A and 13D).	('GPCR', 'Gene', '148', (38, 42))	('Single-copy/heterozygous', 'Var', (0, 24))	('GPCR', 'Gene', (38, 42))
39057	31765370	GPCR genes with single-copy deletions are generally not significantly expressed in tumors or normal tissues, implying that such deletions lack functional effects, but exceptions exist.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('GPCR', 'Gene', '148', (0, 4))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('GPCR', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('single-copy deletions', 'Var', (16, 37))
39066	31765370	However, tumors with amplification of GPR160 show a higher likelihood (approximately 33%, p = 0.003, Fig 13H) of expressing GPR160 at levels above the median for OV.	('GPR160', 'Gene', '26996', (124, 130))	('GPR160', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('OV', 'Phenotype', 'HP:0100615', (162, 164))	('GPR160', 'Gene', (38, 44))	('amplification', 'Var', (21, 34))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('GPR160', 'Gene', '26996', (38, 44))
39071	31765370	In this study, we identified mutations, CNVs, and alterations in mRNA expression of GPCRs in a range of solid tumors.	('GPCR', 'Gene', (84, 88))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('alterations', 'Reg', (50, 61))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mRNA expression', 'MPA', (65, 80))	('GPCR', 'Gene', '148', (84, 88))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
39073	31765370	Mutations of certain GPCRs have been implicated in cancer, but a comprehensive analysis of GPCR amplification, expression, and DE has been lacking.	('GPCR', 'Gene', '148', (21, 25))	('implicated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('GPCR', 'Gene', (21, 25))	('GPCR', 'Gene', (91, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GPCR', 'Gene', '148', (91, 95))
39078	31765370	GPCR mutations appear to reflect accumulation of DNA damage and mutations across the genome and may be tumor markers for this process.	('DNA damage', 'MPA', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Disease', (103, 108))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('accumulation', 'PosReg', (33, 45))
39084	31765370	Known driver mutations do not appear to influence GPCR expression in tumors, but we excluded rare mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GPCR', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GPCR', 'Gene', '148', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('mutations', 'Var', (13, 22))
39116	31765370	GPCR mutations, CNV, and DE thus occur at a high frequency in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GPCR', 'Gene', '148', (0, 4))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('occur', 'Reg', (33, 38))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
39133	31765370	The two methods yielded nearly identical results (S11C and S11D Fig).	('S11D', 'SUBSTITUTION', 'None', (59, 63))	('S11D', 'Var', (59, 63))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11C', 'Var', (50, 54))
39135	31765370	EBseq and edgeR yielded very similar results (S11A and S11B Fig), in particular for GPCRs, implying that assumptions implicit in the DE analysis via edgeR/TMM normalization do not skew or bias the results.	('GPCR', 'Gene', (84, 88))	('S11B', 'SUBSTITUTION', 'None', (55, 59))	('S11B', 'Var', (55, 59))	('S11A', 'Var', (46, 50))	('GPCR', 'Gene', '148', (84, 88))	('S11A', 'SUBSTITUTION', 'None', (46, 50))
39169	31765370	In general, DE of GPCRs is similar whether TCGA normal tissue or GTEx tissue is compared to TCGA tumor samples (e.g., S11E and S11F Fig), suggesting that such differences are unlikely to impact upon the general conclusions of this study.	('S11F', 'Mutation', 'p.S11F', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('S11F', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GPCR', 'Gene', '148', (18, 22))	('tumor', 'Disease', (97, 102))	('S11E', 'Mutation', 'p.S11E', (118, 122))	('GPCR', 'Gene', (18, 22))	('GTEx', 'Chemical', '-', (65, 69))
39180	31765370	This method was also used to evaluate the significance of associations between expression of GPCRs and presence of specific driver mutations (e.g., presence or absence of mutations to TP53 or KRAS) and association between GPCR mRNA expression and the thresholded GISTIC 2.0 CNV call.	('absence', 'NegReg', (160, 167))	('association', 'Interaction', (202, 213))	('GPCR', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (184, 188))	('GPCR', 'Gene', '148', (93, 97))	('TP53', 'Gene', (184, 188))	('GPCR', 'Gene', '148', (222, 226))	('KRAS', 'Gene', (192, 196))	('mutations', 'Var', (171, 180))	('GPCR', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (192, 196))
39197	30662871	We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.	('SPEN', 'Gene', (166, 170))	('CDKN2A', 'Gene', '1029', (128, 134))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('BRAF', 'Gene', '673', (117, 121))	('RAC1', 'Gene', '5879', (157, 161))	('mutations', 'Var', (35, 44))	('significance', 'Reg', (192, 204))	('RAC1', 'Gene', (157, 161))	('SPEN', 'Gene', '23013', (166, 170))	('PTEN', 'Gene', (136, 140))	('PTEN', 'Gene', '5728', (136, 140))	('CDKN2A', 'Gene', (128, 134))	('BRAF', 'Gene', (117, 121))	('RAS', 'Gene', (123, 126))
39202	30662871	Even if studies are focused in metastatic melanoma (MM) specimens and for the most abundant BRAF and NRAS mutations, the prognostic significance in MM is less understood and, in some cases, controversial.	('NRAS', 'Gene', (101, 105))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('metastatic melanoma', 'Disease', (31, 50))	('NRAS', 'Gene', '4893', (101, 105))	('mutations', 'Var', (106, 115))	('metastatic melanoma', 'Disease', 'MESH:D008545', (31, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
39205	30662871	We have restricted our analysis to samples procured from MM for three reasons: (1) metastatic tumors are more likely to have mutations in driver genes; (2) passenger mutations that are associated with ultraviolet signature may be significantly less in MM; and (3) although not all patients with primary melanoma will succumb to their disease, patients with MM have a worse prognosis.	('mutations', 'Var', (125, 134))	('MM', 'Disease', (252, 254))	('mutations', 'Var', (166, 175))	('driver genes', 'Gene', (138, 150))	('patients', 'Species', '9606', (343, 351))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patients', 'Species', '9606', (281, 289))	('primary melanoma', 'Disease', (295, 311))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('less', 'NegReg', (244, 248))	('primary melanoma', 'Disease', 'MESH:D008545', (295, 311))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))
39211	30662871	The variants were also annotated with the Catalog of Somatic Mutations in Cancer (COSMIC, v77) and ExAC (v0.3) to obtain the allele frequency of the variants.	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('variants', 'Var', (4, 12))	('OS', 'Chemical', '-', (83, 85))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))
39228	30662871	Kaplan-Meier curves were constructed using GraphPad Prism (v 8.0, GraphPad, La Jolla, CA) to estimate the melanoma-specific overall survival (OS) in patients with high (>2+) nuclear plus cytoplasmic nuclear-only signal vs. high (>2+) nuclear-only signal vs. low (<= 2+) expression of SPEN protein by melanoma cells.	('SPEN', 'Gene', '23013', (284, 288))	('high (>2+', 'Var', (163, 172))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('patients', 'Species', '9606', (149, 157))	('melanoma', 'Disease', (300, 308))	('melanoma', 'Disease', 'MESH:D008545', (300, 308))	('OS', 'Chemical', '-', (142, 144))	('SPEN', 'Gene', (284, 288))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('protein', 'cellular_component', 'GO:0003675', ('289', '296'))
39231	30662871	25,102,889 mutations, both somatic and presumed germline, were identified in 474 tumors.	('mutations', 'Var', (11, 20))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
39233	30662871	For the OS-original diagnosis analysis, 5,351 mutations (0.22% total; 5,285 single nucleotide variations, 37 dinucleotide variants, and 29 insertions/deletions) in 537 genes were found in 356 tumors [median, 10 mutations, ~95% confidence interval (~95CI) 9-11 mutations; range, 0-132 mutations].	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('OS', 'Chemical', '-', (8, 10))	('found', 'Reg', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
39235	30662871	We observed similar findings in the OS-specimen collection analysis [5,481 mutations in 541 genes were found in 363 tumor specimens; median follow-up 53.0 months (~95CI, 47.8-59.2 months); 190 (52.3%) patients were deceased].	('patients', 'Species', '9606', (201, 209))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (75, 84))	('OS', 'Chemical', '-', (36, 38))	('found', 'Reg', (103, 108))
39237	30662871	To assess whether our filtering strategy retained known somatic mutations, we tested the impact of this strategy on the hotspot mutations in five known cancer-associated genes: BRAF, RAS family (HRAS, NRAS, and KRAS), and stop-gain NF1 gene mutations.	('cancer', 'Disease', (152, 158))	('NRAS', 'Gene', (201, 205))	('HRAS', 'Gene', (195, 199))	('NF1', 'Gene', (232, 235))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('mutations', 'Var', (128, 137))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('NF1', 'Gene', '4763', (232, 235))	('NRAS', 'Gene', '4893', (201, 205))	('KRAS', 'Gene', (211, 215))	('tested', 'Reg', (78, 84))	('KRAS', 'Gene', '3845', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HRAS', 'Gene', '3265', (195, 199))	('mutations', 'Var', (241, 250))
39239	30662871	Incidence of ultraviolet signature mutations (C>T substitutions) is significantly higher in unfiltered primary melanomas compared to MM samples (Figure 3, left panel, p < 2.2 x 10-16, Wilcoxon rank-sum test).	('primary melanoma', 'Disease', (103, 119))	('ultraviolet', 'MPA', (13, 24))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('higher', 'PosReg', (82, 88))	('C>T substitutions', 'Var', (46, 63))	('melanomas', 'Disease', (111, 120))	('primary melanoma', 'Disease', 'MESH:D008545', (103, 119))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
39240	30662871	Overall, C>T transitions, C>T transitions at a dipyrimidine site, and CC   TT accounted for 79.4%, 77.8%, and 0.11% of the total 5,322 mutations, respectively.	('C>T transitions', 'Var', (9, 24))	('C>T transitions', 'Var', (26, 41))	('dipyrimidine', 'Chemical', '-', (47, 59))
39256	30662871	There was significant difference in the frequency of ultraviolet signature mutations seen in the 22 genes compared to the remaining 111 genes that were mutated in >=3% of patients in either OS analyses (p = 0.04, Wilcoxon).	('ultraviolet signature', 'MPA', (53, 74))	('OS', 'Chemical', '-', (190, 192))	('mutations', 'Var', (75, 84))	('patients', 'Species', '9606', (171, 179))
39258	30662871	However, while the MAF of BRAFV600 mutations was higher in primary as opposed to MM samples, the corresponding MAF for most of the 22 genes was the opposite:namely, higher in MM compared to primary melanoma specimens (Supplemental Material, Figure S3, panel B).	('primary melanoma', 'Disease', 'MESH:D008545', (190, 206))	('BRAF', 'Gene', '673', (26, 30))	('primary melanoma', 'Disease', (190, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('BRAF', 'Gene', (26, 30))	('higher', 'PosReg', (165, 171))	('mutations', 'Var', (35, 44))
39259	30662871	The higher frequency of BRAFV600 mutations in SKCM suggests their founder status in this disease, while supporting the notion that mutations in the other 22 genes are potentially clonal or subclonal events that occur more frequently in MM samples.	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('mutations', 'Var', (33, 42))
39260	30662871	Mutated RAC1, FGFR1, AFF3, and NTRK1 genes were more frequently seen in MM samples from patients who died within 5 years from the original diagnosis.	('AFF3', 'Gene', (21, 25))	('NTRK1', 'Gene', (31, 36))	('RAC1', 'Gene', '5879', (8, 12))	('patients', 'Species', '9606', (88, 96))	('RAC1', 'Gene', (8, 12))	('FGFR1', 'Gene', (14, 19))	('NTRK1', 'Gene', '4914', (31, 36))	('AFF3', 'Gene', '3899', (21, 25))	('FGFR1', 'Gene', '2260', (14, 19))	('seen', 'Reg', (64, 68))	('Mutated', 'Var', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))
39261	30662871	In contrast, mutated CIITA was more frequently seen in MM samples from patients who have lived >5 years after original diagnosis (Figure 6).	('mutated', 'Var', (13, 20))	('patients', 'Species', '9606', (71, 79))	('CIITA', 'Gene', (21, 26))	('CIITA', 'Gene', '4261', (21, 26))
39266	30662871	To validate our findings related to the 22 genes from the TCGA cohort in a separate MM cohort, we analyzed the presence of these mutations in a cohort of 33 stage III/IV patients with SKCM who were followed at the UNC-CH Melanoma Program and had consented to the UNCseq  project (Supplemental Material, Table S2), combined with 6 other previously published melanoma datasets.	('patients', 'Species', '9606', (170, 178))	('CH Melanoma', 'Disease', (218, 229))	('mutations', 'Var', (129, 138))	('CH Melanoma', 'Disease', 'MESH:D008545', (218, 229))	('melanoma', 'Phenotype', 'HP:0002861', (357, 365))	('Melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Disease', (357, 365))	('melanoma', 'Disease', 'MESH:D008545', (357, 365))
39267	30662871	Table 2 shows the non-synonymous somatic mutations from MM tumor samples of cutaneous or unknown primaries that were subjected to next generation sequencing analysis and grouped according to primary (n = 107) vs. metastatic (n = 417) status.	('MM tumor', 'Disease', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('non-synonymous', 'Var', (18, 32))	('MM tumor', 'Disease', 'MESH:D009369', (56, 64))
39269	30662871	In contrast with the TCGA SKCM cohort, however, more mutated genes were seen in primaries compared to metastases (2/22 in the TCGA cohort vs. 10/22 in the validation cohort).	('mutated', 'Var', (53, 60))	('metastases', 'Disease', (102, 112))	('metastases', 'Disease', 'MESH:D009362', (102, 112))
39270	30662871	Of the 9 mutated genes whose mutations were confirmed by RNA-seq, all but one (i.e., AFF4) were equivocally found to be expressed in the other two datasets that reported both RNA and DNA sequencing analysis.	('AFF4', 'Gene', '27125', (85, 89))	('mutations', 'Var', (29, 38))	('AFF4', 'Gene', (85, 89))	('RNA', 'cellular_component', 'GO:0005562', ('57', '60'))	('RNA', 'cellular_component', 'GO:0005562', ('175', '178'))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))
39273	30662871	Cox analysis for each of the 8 mutated genes whose RNA expression was confirmed across all studies showed trends of mutations in RAC1 in MM with worse prognosis (HR = 2.1, 95CI 0.66-6.63, log-rank p = 0.07), whereas mutations in SPEN showed trends of mutations with better prognosis (HR = 0.50, range 0.27-0.93, log-rank p = 0.09) (Figure 7).	('RAC1', 'Gene', '5879', (129, 133))	('SPEN', 'Gene', (229, 233))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('RAC1', 'Gene', (129, 133))	('mutations', 'Var', (116, 125))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('SPEN', 'Gene', '23013', (229, 233))
39275	30662871	Figure 8 shows integrated analysis of somatic mutations, copy number alterations, and gene expression alterations for RAC1 and SPEN for the 357 TCGA MM samples.	('SPEN', 'Gene', '23013', (127, 131))	('RAC1', 'Gene', '5879', (118, 122))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('RAC1', 'Gene', (118, 122))	('SPEN', 'Gene', (127, 131))	('copy number alterations', 'Var', (57, 80))
39277	30662871	The unfavorable outcome of patients with any genetic aberrations in RAC1 is in line with a report on the adverse prognostic significance of high RAC1 protein expression by immunohistochemistry in primary cutaneous melanoma samples.	('RAC1', 'Gene', '5879', (145, 149))	('genetic aberrations', 'Disease', 'MESH:D030342', (45, 64))	('expression', 'MPA', (158, 168))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('high', 'Var', (140, 144))	('cutaneous melanoma', 'Disease', (204, 222))	('RAC1', 'Gene', (145, 149))	('RAC1', 'Gene', '5879', (68, 72))	('RAC1', 'Gene', (68, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (204, 222))	('patients', 'Species', '9606', (27, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (204, 222))	('genetic aberrations', 'Disease', (45, 64))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('protein', 'Protein', (150, 157))
39286	30662871	Given that SPEN somatic mutations do not associate with significant differences in RNA expression, we speculate that distinct yet-to-be identified SPEN mutations may regulate SPEN localization.	('RNA', 'cellular_component', 'GO:0005562', ('83', '86'))	('SPEN', 'Gene', (175, 179))	('mutations', 'Var', (152, 161))	('SPEN', 'Gene', '23013', (175, 179))	('SPEN', 'Gene', '23013', (147, 151))	('localization', 'biological_process', 'GO:0051179', ('180', '192'))	('localization', 'MPA', (180, 192))	('SPEN', 'Gene', '23013', (11, 15))	('SPEN', 'Gene', (147, 151))	('regulate', 'Reg', (166, 174))	('SPEN', 'Gene', (11, 15))
39291	30662871	Less well-known genes in melanoma biology not only may be significantly mutated due to the random effect of ultraviolet radiation, but their mutated status may have potential prognostic significance [e.g., the Spen homolog transcriptional regulator (SPEN)].	('mutated', 'Var', (141, 148))	('Spen homolog transcriptional regulator', 'Gene', '23013', (210, 248))	('SPEN', 'Gene', (250, 254))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('SPEN', 'Gene', '23013', (250, 254))	('Spen homolog transcriptional regulator', 'Gene', (210, 248))
39293	30662871	The neoantigens provoke an immune response, which may account for the immunogenicity of cutaneous melanoma and other cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('neoantigens', 'Var', (4, 15))	('provoke', 'Reg', (16, 23))	('cutaneous melanoma', 'Disease', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('immune', 'MPA', (27, 33))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('immune response', 'biological_process', 'GO:0006955', ('27', '42'))	('cancers', 'Disease', (117, 124))
39295	30662871	The lack of mutations with high functional impact does not mitigate the importance of such missense mutations in protein function, as in the case of KEAP1 in lung cancer.	('missense mutations', 'Var', (91, 109))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('KEAP1', 'Gene', '9817', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('KEAP1', 'Gene', (149, 154))
39296	30662871	Instead, it may provide an explanation about the lack of association between high somatic mutation burden with host immune response and OS in melanoma, which is complex: somatic mutations in genes associated with immune surveillance (e.g., PTPRC/CD45, FCRL4, CARD11) may be associated with favorable prognosis because potentially damaging mutations are not ultimately expressed.	('CARD11', 'Gene', (259, 265))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('immune response', 'biological_process', 'GO:0006955', ('116', '131'))	('PTPRC', 'Gene', (240, 245))	('FCRL4', 'Gene', (252, 257))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('CD45', 'Gene', (246, 250))	('OS', 'Chemical', '-', (136, 138))	('PTPRC', 'Gene', '5788', (240, 245))	('CD45', 'Gene', '5788', (246, 250))	('FCRL4', 'Gene', '83417', (252, 257))	('mutations', 'Var', (178, 187))	('CARD11', 'Gene', '84433', (259, 265))	('melanoma', 'Disease', (142, 150))
39298	30662871	Our validation cohort was comprised of patient samples with significant heterogeneity with respect to selection for BRAFV600 mutations and, systemic treatment type (i.e., FDA approved treatments before or after 2011), which may have influenced OS, and the geopolitical origin of patients.	('mutations', 'Var', (125, 134))	('patient', 'Species', '9606', (39, 46))	('OS', 'Chemical', '-', (244, 246))	('BRAF', 'Gene', '673', (116, 120))	('BRAF', 'Gene', (116, 120))	('patient', 'Species', '9606', (279, 286))	('influenced', 'Reg', (233, 243))	('patients', 'Species', '9606', (279, 287))
39299	30662871	Nevertheless, certain mutated genes were confirmed by RNA-seq across all datasets (e.g., RAC1, MAP2K1, SPEN, CUX1, TSC2, CNTRL, AKAP9, and STAG2) whereas others were found not to be expressed, irrespective of the RNA-seq validation algorithm used (e.g., FCRL4, CARD11, PDGFRB).	('PDGFRB', 'Gene', '5159', (269, 275))	('RNA', 'cellular_component', 'GO:0005562', ('213', '216'))	('MAP2K1', 'Gene', '5604', (95, 101))	('PDGFRB', 'Gene', (269, 275))	('mutated', 'Var', (22, 29))	('MAP2K', 'molecular_function', 'GO:0004708', ('95', '100'))	('MAP2K1', 'Gene', (95, 101))	('SPEN', 'Gene', (103, 107))	('TSC2', 'Gene', '7249', (115, 119))	('RAC1', 'Gene', (89, 93))	('CARD11', 'Gene', (261, 267))	('CNTRL', 'Gene', '11064', (121, 126))	('CUX1', 'Gene', '1523', (109, 113))	('STAG2', 'Gene', '10735', (139, 144))	('CUX1', 'Gene', (109, 113))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))	('TSC2', 'Gene', (115, 119))	('AKAP9', 'Gene', '10142', (128, 133))	('CARD11', 'Gene', '84433', (261, 267))	('FCRL4', 'Gene', (254, 259))	('AKAP9', 'Gene', (128, 133))	('CNTRL', 'Gene', (121, 126))	('RAC1', 'Gene', '5879', (89, 93))	('FCRL4', 'Gene', '83417', (254, 259))	('SPEN', 'Gene', '23013', (103, 107))	('STAG2', 'Gene', (139, 144))
39300	30662871	For example, assuming that a given gene whose incidence of mutation is 5.3% in the study population (e.g., NTRK1) and is associated with worse OS (HR = 1.93), the power to detect significant prognostic difference if n = 245 and 70% of patients had an event (e.g., death) is only 0.64.	('NTRK1', 'Gene', (107, 112))	('patients', 'Species', '9606', (235, 243))	('death', 'Disease', 'MESH:D003643', (264, 269))	('mutation', 'Var', (59, 67))	('death', 'Disease', (264, 269))	('NTRK1', 'Gene', '4914', (107, 112))	('OS', 'Chemical', '-', (143, 145))
39303	30662871	A recent study has shown that high expression of RAC1 protein in primary cutaneous melanoma samples was associated with thinner melanomas, BRAFV600 mutation and with RAC1 mutation.	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('cutaneous melanoma', 'Disease', (73, 91))	('mutation', 'Var', (171, 179))	('expression', 'MPA', (35, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('associated', 'Reg', (104, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('RAC1', 'Gene', (49, 53))	('protein', 'Protein', (54, 61))	('RAC1', 'Gene', '5879', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('melanomas', 'Disease', 'MESH:D008545', (128, 137))	('RAC1', 'Gene', (166, 170))	('melanomas', 'Disease', (128, 137))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('BRAF', 'Gene', '673', (139, 143))	('RAC1', 'Gene', '5879', (166, 170))	('BRAF', 'Gene', (139, 143))	('high', 'PosReg', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
39313	30662871	The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2018.00584/full#supplementary-material SKCM Skin Cutaneous Melanoma MM metastatic melanoma TCGA The Cancer Genome Atlas Project VCF variant call format UNC-CH the University of North Carolina at Chapel Hill OS overall survival RNA-seq RNA sequencing 95CI 95% confidence intervals FDR false discovery rate MAF mutant allele frequency MAC mutant allele count.	('MAC', 'cellular_component', 'GO:0005579', ('451', '454'))	('Cancer', 'Disease', 'MESH:D009369', (218, 224))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (167, 185))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('RNA', 'cellular_component', 'GO:0005562', ('345', '348'))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (162, 185))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('false', 'biological_process', 'GO:0071877', ('402', '407'))	('metastatic melanoma', 'Disease', 'MESH:D008545', (189, 208))	('MAC', 'cellular_component', 'GO:0097423', ('451', '454'))	('metastatic melanoma', 'Disease', (189, 208))	('OS', 'Chemical', '-', (325, 327))	('Melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('RNA', 'cellular_component', 'GO:0005562', ('353', '356'))	('false', 'biological_process', 'GO:0071878', ('402', '407'))	('mutant', 'Var', (427, 433))	('Skin Cutaneous Melanoma', 'Disease', (162, 185))	('Cancer', 'Disease', (218, 224))
39321	30373609	In two patients we identified resistance-associated variants explaining lack of therapy response.	('resistance-associated', 'Reg', (30, 51))	('patients', 'Species', '9606', (7, 15))	('variants', 'Var', (52, 60))
39329	30373609	Prominent examples are BRAF mutations in metastatic melanoma and HER2 overexpression in breast cancer, which can be targeted by specific kinase inhibitors or monoclonal antibodies, e.g.	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('HER2', 'Gene', '2064', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('BRAF', 'Gene', '673', (23, 27))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('BRAF', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('overexpression', 'PosReg', (70, 84))	('HER2', 'Gene', (65, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('mutations', 'Var', (28, 37))
39333	30373609	This allows us to detect not only cancer type specific alterations, but also mutations common in other cancer types, or mutations with associated therapies that are currently in clinical development.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('alterations', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
39376	30373609	These types of information help to prioritize variants with respect to their significance for tumor development or treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('treatment resistance', 'CPA', (115, 135))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('variants', 'Var', (46, 54))
39377	30373609	For instance, in colorectal cancer new mutations in the MAPK signaling pathway can confer resistance against combined RAF/MEK therapy by sustaining the activity of the pathway.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MEK', 'Gene', (122, 125))	('activity', 'MPA', (152, 160))	('RAF', 'Gene', '22882', (118, 121))	('MEK', 'Gene', '5609', (122, 125))	('colorectal cancer', 'Disease', (17, 34))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('RAF', 'Gene', (118, 121))	('mutations', 'Var', (39, 48))	('signaling pathway', 'biological_process', 'GO:0007165', ('61', '78'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('56', '70'))	('MAPK', 'Gene', (56, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('sustaining', 'PosReg', (137, 147))
39382	30373609	The clinical report is intended to only present the relevant subset of variants found in a tumor.	('variants', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
39386	30373609	For instance, the status of BRAF in melanoma (mutations prevalent in 40-50% of all cases) or ALK in lung cancer (rearrangements prevalent in 4-5% of all non-small cell lung cancers) influences eligibility for clinical trials.	('ALK', 'Gene', '238', (93, 96))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('ALK', 'Gene', (93, 96))	('mutations', 'Var', (46, 55))	('influences', 'Reg', (182, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancer', 'Disease', (100, 111))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('cell lung cancers', 'Disease', 'MESH:D008175', (163, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cell lung cancers', 'Disease', (163, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))
39388	30373609	For instance, various TP53 mutations have been reported to confer resistance to platinum-based chemotherapy in ovarian cancer.	('mutations', 'Var', (27, 36))	('ovarian cancer', 'Disease', (111, 125))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('TP53', 'Gene', '7157', (22, 26))	('resistance to platinum-based chemotherapy', 'MPA', (66, 107))	('TP53', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
39394	30373609	The BRAF mutation observed in our example patient illustrates how the clinical report can be utilized to facilitate clinical decision making.	('mutation', 'Var', (9, 17))	('patient', 'Species', '9606', (42, 49))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
39395	30373609	BRAF V600E is a well-known therapy target in melanoma and thus assigned the highest confidence.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
39413	30373609	A high mutational load above 100 non-synonymous coding mutations has been shown to be predictive of positive response to ipilimumab therapy in melanoma.	('ipilimumab', 'Chemical', 'MESH:D000074324', (121, 131))	('mutational load', 'Var', (7, 22))	('positive', 'PosReg', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
39416	30373609	Furthermore, the patient's tumor harbored amplifications of BRAF, EGFR, MET, and CDK6, which provides a rationale for this tumor's acquired resistance to the triple BRAF/MEK/CDK4&6 inhibitor treatment applied before sequencing.	('CDK6', 'Gene', '1021', (81, 85))	('patient', 'Species', '9606', (17, 24))	('CDK', 'molecular_function', 'GO:0004693', ('174', '177'))	('tumor', 'Disease', (123, 128))	('CDK6', 'Gene', (81, 85))	('tumor', 'Disease', (27, 32))	('EGFR', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('MET', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MEK', 'Gene', '5609', (170, 173))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('MEK', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EGFR', 'Gene', '1956', (66, 70))	('amplifications', 'Var', (42, 56))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('EGFR', 'molecular_function', 'GO:0005006', ('66', '70'))
39425	30373609	PXR knockdown in cancer cells induces increased paclitaxel sensitivity and apoptotic cell death.	('paclitaxel sensitivity', 'MPA', (48, 70))	('apoptotic cell death', 'CPA', (75, 95))	('PXR', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('75', '95'))	('cancer', 'Disease', (17, 23))	('PXR', 'Gene', '8856', (0, 3))	('knockdown', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('increased', 'PosReg', (38, 47))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
39451	30373609	For patient 13 several damaging variants were identified in genes associated with the MAPK signaling pathway.	('MAPK signaling pathway', 'Pathway', (86, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('86', '90'))	('patient', 'Species', '9606', (4, 11))	('MAPK signaling', 'biological_process', 'GO:0000165', ('86', '100'))	('variants', 'Var', (32, 40))	('signaling pathway', 'biological_process', 'GO:0007165', ('91', '108'))
39455	30373609	For patient 14 the SwissMTB molecular diagnostic identified a variant in the WD40 domain of the tumor suppressor gene FBXW7.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('FBXW7', 'Gene', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('FBXW7', 'Gene', '55294', (118, 123))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('variant in the WD40 domain', 'Var', (62, 88))
39458	30373609	Since in the panel-based analysis the observed FBXW7 variant appeared as the only mutation, a therapy with mTOR inhibitors such as everolimus might be justified.	('everolimus', 'Chemical', 'MESH:D000068338', (131, 141))	('mTOR', 'Gene', (107, 111))	('FBXW7', 'Gene', (47, 52))	('variant', 'Var', (53, 60))	('mTOR', 'Gene', '2475', (107, 111))	('FBXW7', 'Gene', '55294', (47, 52))
39464	30373609	In case of disease progression the SwissMTB report recommends off-label treatment with palbociclib to target the observed loss-of-function variant R80* in CDKN2A.	('CDKN2A', 'Gene', '1029', (155, 161))	('R80*', 'Var', (147, 151))	('loss-of-function', 'NegReg', (122, 138))	('R80*', 'SUBSTITUTION', 'None', (147, 151))	('CDKN2A', 'Gene', (155, 161))
39465	30373609	Patient 17 presented four different resistance mutations, namely ALK G1202R, KRAS S65 N, TP53 C275Y, and TP53 G245D.	('C275Y', 'Var', (94, 99))	('ALK', 'Gene', '238', (65, 68))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('C275Y', 'Mutation', 'rs863224451', (94, 99))	('KRAS', 'Gene', (77, 81))	('S65 N', 'Mutation', 'p.S65N', (82, 87))	('ALK', 'Gene', (65, 68))	('TP53', 'Gene', (105, 109))	('TP53', 'Gene', '7157', (105, 109))	('KRAS', 'Gene', '3845', (77, 81))	('G1202R', 'Mutation', 'rs1057519783', (69, 75))	('G245D', 'Var', (110, 115))	('Patient', 'Species', '9606', (0, 7))	('G245D', 'Mutation', 'rs121912656', (110, 115))
39467	30373609	Instead, we recommended treatment with tyrosine kinase and mTOR inhibitors such as pazopanib and everolimus based on several variants in genes associated to the MAPK signaling pathway and mTOR signaling pathway.	('MAPK signaling', 'biological_process', 'GO:0000165', ('161', '175'))	('tyrosine kinase', 'Gene', (39, 54))	('signaling pathway', 'biological_process', 'GO:0007165', ('166', '183'))	('everolimus', 'Chemical', 'MESH:D000068338', (97, 107))	('pazopanib', 'Chemical', 'MESH:C516667', (83, 92))	('variants', 'Var', (125, 133))	('tyrosine kinase', 'Gene', '7294', (39, 54))	('signaling pathway', 'biological_process', 'GO:0007165', ('193', '210'))	('mTOR', 'Gene', (188, 192))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('mTOR', 'Gene', '2475', (188, 192))	('mTOR', 'Gene', '2475', (59, 63))	('mTOR', 'Gene', (59, 63))
39469	30373609	Patient 19 presented a lung adenocarcinoma with an ALK G1202R variant, a mutation associated with general resistance against ALK inhibition.	('ALK', 'Gene', '238', (51, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('ALK', 'Gene', '238', (125, 128))	('lung adenocarcinoma', 'Disease', (23, 42))	('ALK', 'Gene', (51, 54))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (23, 42))	('Patient', 'Species', '9606', (0, 7))	('G1202R', 'Mutation', 'rs1057519783', (55, 61))	('G1202R', 'Var', (55, 61))	('ALK', 'Gene', (125, 128))
39472	30373609	Here, the only two identified variants were TP53 R342* and TP53 R248Q.	('R248Q', 'Var', (64, 69))	('TP53', 'Gene', (59, 63))	('R248Q', 'Mutation', 'rs11540652', (64, 69))	('R342*', 'SUBSTITUTION', 'None', (49, 54))	('TP53', 'Gene', '7157', (44, 48))	('R342*', 'Var', (49, 54))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', (44, 48))
39475	30373609	For patient 22 we identified TP53 R273S, a variant associated to cisplatin therapy resistance in a variety of cancer types.	('R273S', 'Mutation', 'rs121913343', (34, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('cancer', 'Disease', (110, 116))	('R273S', 'Var', (34, 39))	('patient', 'Species', '9606', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
39478	30373609	with sunitinib or regorafenib, based on multiple variants in the MAPK signaling pathway and a KIT exon11 variant.	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('signaling pathway', 'biological_process', 'GO:0007165', ('70', '87'))	('variants', 'Var', (49, 57))	('MAPK signaling pathway', 'Pathway', (65, 87))	('variant', 'Var', (105, 112))	('sunitinib', 'Chemical', 'MESH:D000077210', (5, 14))	('regorafenib', 'Chemical', 'MESH:C559147', (18, 29))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('65', '79'))
39526	30373609	We identified actionable targets in 86% of the patients, and in addition identified several resistance-causing variants.	('resistance-causing', 'Reg', (92, 110))	('patients', 'Species', '9606', (47, 55))	('variants', 'Var', (111, 119))
39530	30373609	Proteomic analysis would provide information on the translated proteins in the tumor, thereby verifying variants identified on the genomic and transcriptomic level and additionally detecting post-translational modifications.	('tumor', 'Disease', (79, 84))	('variants', 'Var', (104, 112))	('detecting', 'Reg', (181, 190))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
39531	30373609	Post-translational modifications, such as phosphorylation or histone modifications, have been shown to play a critical role in the development of a variety of cancer types and in drug resistance development.	('cancer', 'Disease', (159, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('drug resistance', 'biological_process', 'GO:0009315', ('179', '194'))	('drug resistance', 'biological_process', 'GO:0042493', ('179', '194'))	('histone', 'Protein', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('phosphorylation', 'Var', (42, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('role', 'Reg', (119, 123))	('play', 'Reg', (103, 107))
39543	30373609	Given the appropriate consent, variants found in a certain tumor type, as well as chosen therapies and their outcomes, can form a resource which facilitates and improves therapy recommendations for new patients.	('variants', 'Var', (31, 39))	('tumor', 'Disease', (59, 64))	('improves', 'PosReg', (161, 169))	('patients', 'Species', '9606', (202, 210))	('facilitates', 'PosReg', (145, 156))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
39550	30373609	CNV Copy number variant DKFZ Deutsches Krebsforschungszentrum DNA Deoxyribonucleic acid FFPE Formalin-fixed paraffin embedded HLA Human leukocyte antigen InDel Insertion and deletion IRB Institutional review board NCT Nationales Centrum fur Tumorerkrankungen NGS Next-generation sequencing RNA Ribonucleic acid RNA-seq RNA sequencing SKCM Skin cutaneous melanoma SNV Single nucleotide variant SwissMTB Swiss Molecular Tumor Board TCGA The Cancer Genome Atlas UNC Uniform naming convention UVM Uveal melanoma WES Whole exome sequencing WGS Whole genome sequening FS developed the WES/WGS pipeline, contributed to report design, and analyzed patient samples.	('RNA', 'cellular_component', 'GO:0005562', ('311', '314'))	('melanoma', 'Disease', 'MESH:D008545', (354, 362))	('melanoma', 'Disease', 'MESH:D008545', (499, 507))	('paraffin', 'Chemical', 'MESH:D010232', (108, 116))	('Skin cutaneous melanoma', 'Disease', (339, 362))	('Cancer', 'Phenotype', 'HP:0002664', (439, 445))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (339, 362))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (493, 507))	('InDel', 'Chemical', '-', (154, 159))	('variant', 'Var', (16, 23))	('Cancer', 'Disease', (439, 445))	('RNA', 'cellular_component', 'GO:0005562', ('319', '322'))	('melanoma', 'Phenotype', 'HP:0002861', (354, 362))	('melanoma', 'Disease', (354, 362))	('Tumor', 'Phenotype', 'HP:0002664', (418, 423))	('melanoma', 'Phenotype', 'HP:0002861', (499, 507))	('melanoma', 'Disease', (499, 507))	('Cancer', 'Disease', 'MESH:D009369', (439, 445))	('Human', 'Species', '9606', (130, 135))	('patient', 'Species', '9606', (640, 647))	('Tumor', 'Phenotype', 'HP:0002664', (241, 246))	('RNA', 'cellular_component', 'GO:0005562', ('290', '293'))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('UVM', 'Phenotype', 'HP:0007716', (489, 492))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (344, 362))	('Formalin', 'Chemical', 'MESH:D005557', (93, 101))	('variant', 'Var', (385, 392))
39585	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
39595	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
39596	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
39597	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
39607	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
39608	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('HR value', 'MPA', (15, 23))	('CDCA3', 'Gene', (76, 81))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))
39619	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('CDCA3', 'Gene', '83461', (68, 73))	('0.30-0.59', 'Var', (169, 178))	('association', 'Interaction', (48, 59))	('CDCA3', 'Gene', (68, 73))
39625	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
39647	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('CDCA3', 'Gene', (87, 92))	('gastric cancer', 'Disease', (148, 162))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
39650	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('high', 'Var', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('tumor', 'Disease', (198, 203))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('HCC', 'Disease', (149, 152))
39657	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
39661	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', '83461', (160, 165))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
39663	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
39664	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
39671	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
39674	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
39702	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
39706	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
39717	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
39769	22959032	Furthermore, curcumin treatment reduced lung metastasis of B16F-10 melanoma cells in experimental models of metastasis and increased the lifespan of animals.	('increased', 'PosReg', (123, 132))	('B16F', 'SUBSTITUTION', 'None', (59, 63))	('lung metastasis', 'CPA', (40, 55))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('reduced', 'NegReg', (32, 39))	('melanoma', 'Disease', (67, 75))	('curcumin', 'Chemical', 'MESH:D003474', (13, 21))	('B16F', 'Var', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('men', 'Species', '9606', (91, 94))	('men', 'Species', '9606', (27, 30))
39776	22959032	This study evaluated the efficacy of curcumin coupled to a melanoma surface antigen recognizing Muc18 antibody, through a cleavable arm, for preventing B16F-10 melanoma tumor growth in mice.	('preventing', 'NegReg', (141, 151))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('curcumin', 'Chemical', 'MESH:D003474', (37, 45))	('antibody', 'cellular_component', 'GO:0019814', ('102', '110'))	('Muc18', 'Gene', (96, 101))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma tumor', 'Disease', 'MESH:D008545', (160, 174))	('antibody', 'molecular_function', 'GO:0003823', ('102', '110'))	('B16F', 'Var', (152, 156))	('antibody', 'cellular_component', 'GO:0042571', ('102', '110'))	('B16F', 'SUBSTITUTION', 'None', (152, 156))	('mice', 'Species', '10090', (185, 189))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('Muc18', 'Gene', '84004', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma tumor', 'Disease', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('antibody', 'cellular_component', 'GO:0019815', ('102', '110'))
39818	22959032	In addition, EGCG also reduced the expression of the proliferation regulator cyclin-D1 and induced cell cycle inhibitors p16, p21 and p27.	('p16', 'Gene', '1029', (121, 124))	('cell cycle', 'CPA', (99, 109))	('cyclin-D1', 'Gene', '595', (77, 86))	('induced', 'Reg', (91, 98))	('p27', 'Gene', (134, 137))	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('p27', 'Gene', '3429', (134, 137))	('cyclin-D1', 'Gene', (77, 86))	('cell cycle', 'biological_process', 'GO:0007049', ('99', '109'))	('expression', 'MPA', (35, 45))	('EGCG', 'Var', (13, 17))	('p16', 'Gene', (121, 124))	('reduced', 'NegReg', (23, 30))	('p21', 'Gene', '1026', (126, 129))	('cyclin', 'molecular_function', 'GO:0016538', ('77', '83'))	('p21', 'Gene', (126, 129))
39819	22959032	Furthermore, in murine models of melanoma, EGCG reduced cell migration, induced apoptosis and triggered cell cycle arrest thereby inhibiting melanoma tumor growth and the metastatic potential of the cells.	('murine', 'Species', '10090', (16, 22))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('cell cycle arrest', 'CPA', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('induced', 'Reg', (72, 79))	('inhibiting', 'NegReg', (130, 140))	('metastatic potential of the cells', 'CPA', (171, 204))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('melanoma tumor', 'Disease', 'MESH:D008545', (141, 155))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('cell migration', 'CPA', (56, 70))	('reduced', 'NegReg', (48, 55))	('EGCG', 'Var', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('triggered', 'Reg', (94, 103))	('cell migration', 'biological_process', 'GO:0016477', ('56', '70'))	('apoptosis', 'CPA', (80, 89))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('104', '121'))	('EGCG', 'Chemical', 'MESH:C045651', (43, 47))	('melanoma tumor', 'Disease', (141, 155))
39825	22959032	But, results from secondary end-point analyses showed that supplemental selenium might reduce the incidence (77 cancers in the selenium group and 119 in controls) and mortality rates from carcinomas (29 deaths in the selenium treatment group and 57 deaths in controls).	('death', 'Disease', 'MESH:D003643', (203, 208))	('mortality', 'CPA', (167, 176))	('selenium', 'Chemical', 'MESH:D012643', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reduce', 'NegReg', (87, 93))	('death', 'Disease', 'MESH:D003643', (249, 254))	('carcinomas', 'Disease', (188, 198))	('selenium', 'Chemical', 'MESH:D012643', (72, 80))	('men', 'Species', '9606', (65, 68))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('men', 'Species', '9606', (231, 234))	('cancers', 'Disease', (112, 119))	('death', 'Disease', (203, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('death', 'Disease', (249, 254))	('carcinomas', 'Disease', 'MESH:D002277', (188, 198))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('supplemental', 'Var', (59, 71))	('selenium', 'Chemical', 'MESH:D012643', (217, 225))
39844	22959032	Several other studies also have shown the ability of selenomethionine to inhibit metastasis development in animal models (Figure 3).	('selenomethionine', 'Chemical', 'MESH:D012645', (53, 69))	('selenomethionine', 'Var', (53, 69))	('metastasis development', 'CPA', (81, 103))	('men', 'Species', '9606', (99, 102))	('inhibit', 'NegReg', (73, 80))
39845	22959032	For example, diet containing selenomethionine, one of the major constituents of selenized yeast, has been shown to inhibit pulmonary metastasis in a mouse model.	('selenomethionine', 'Chemical', 'MESH:D012645', (29, 45))	('inhibit', 'NegReg', (115, 122))	('selenomethionine', 'Var', (29, 45))	('pulmonary metastasis', 'CPA', (123, 143))	('mouse', 'Species', '10090', (149, 154))	('yeast', 'Species', '4932', (90, 95))
39851	22959032	Mechanistic studies found that p-XSC could induce apoptosis in melanoma cells without affecting neighboring epithelial cells thereby reducing tumor development in the lungs.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('p-XSC', 'Var', (31, 36))	('men', 'Species', '9606', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('tumor', 'Disease', (142, 147))	('induce', 'Reg', (43, 49))	('apoptosis', 'CPA', (50, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('melanoma', 'Disease', (63, 71))	('reducing', 'NegReg', (133, 141))
39852	22959032	Further studies have demonstrated that p-XSC can also inhibit tumor angiogenesis as well as proliferation of melanoma cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibit', 'NegReg', (54, 61))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('tumor', 'Disease', (62, 67))	('melanoma', 'Disease', (109, 117))	('p-XSC', 'Var', (39, 44))	('angiogenesis', 'biological_process', 'GO:0001525', ('68', '80'))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
39864	22959032	In melanomas, ISC-4 reduced the Akt3 signaling activity thereby inhibiting melanoma cell proliferation and inducing apoptosis.	('reduced', 'NegReg', (20, 27))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))	('apoptosis', 'CPA', (116, 125))	('melanomas', 'Disease', (3, 12))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('Akt3', 'Gene', (32, 36))	('signaling', 'biological_process', 'GO:0023052', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('inhibiting', 'NegReg', (64, 74))	('cell proliferation', 'biological_process', 'GO:0008283', ('84', '102'))	('inducing', 'Reg', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('ISC-4', 'Var', (14, 19))	('melanoma', 'Disease', (3, 11))	('Akt3', 'Gene', '10000', (32, 36))
39870	22959032	Mechanistically, PBISe inhibited iNOS and Akt3 pathways, while inducing pErk1/2 expression.	('inducing', 'Reg', (63, 71))	('inhibited', 'NegReg', (23, 32))	('Akt3', 'Gene', (42, 46))	('PBISe', 'Chemical', '-', (17, 22))	('Erk1/2', 'Gene', '5595;5594', (73, 79))	('PBISe', 'Var', (17, 22))	('Akt3', 'Gene', '10000', (42, 46))	('iNOS', 'Gene', (33, 37))	('expression', 'MPA', (80, 90))	('iNOS', 'Gene', '4843', (33, 37))	('Erk1/2', 'Gene', (73, 79))
39885	22959032	Acetyl salicylic acid (ASA) has been reported to half the risk of developing cutaneous melanoma compared to non-users or those who used ASA for < 2 years (Figure 3).	('Acetyl', 'Var', (0, 6))	('ASA', 'Chemical', 'MESH:D001241', (136, 139))	('Acetyl salicylic acid', 'Chemical', 'MESH:D001241', (0, 21))	('cutaneous melanoma', 'Disease', (77, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('ASA', 'Chemical', 'MESH:D001241', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
39921	22959032	For example a preclinical study evaluating the efficacy of DFMO in malignant mouse B16 amelanotic melanoma (B16a) showed a dose-dependent decrease in the tumor growth and pulmonary metastasis development.	('men', 'Species', '9606', (199, 202))	('amelanotic melanoma', 'Disease', 'MESH:D018328', (87, 106))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('decrease', 'NegReg', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('DFMO', 'Chemical', 'MESH:D000518', (59, 63))	('pulmonary metastasis development', 'CPA', (171, 203))	('DFMO', 'Var', (59, 63))	('mouse', 'Species', '10090', (77, 82))	('amelanotic melanoma', 'Disease', (87, 106))	('tumor', 'Disease', (154, 159))
39922	22959032	Administration of 0.5, 1 and 2% DFMO in water, inhibited tumor growth by 0, 24.5 and 60%, while the same doses reduced metastasis by 55, 83 and 96%.	('inhibited', 'NegReg', (47, 56))	('DFMO', 'Chemical', 'MESH:D000518', (32, 36))	('DFMO', 'Var', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('water', 'Chemical', 'MESH:D014867', (40, 45))	('reduced', 'NegReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('metastasis', 'CPA', (119, 129))	('tumor', 'Disease', (57, 62))
39926	22959032	For example, treatment of B16 melanoma cells with DFMO inhibited the growth with an IC50 of 31.1 muM.	('men', 'Species', '9606', (18, 21))	('DFMO', 'Chemical', 'MESH:D000518', (50, 54))	('DFMO', 'Var', (50, 54))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('growth', 'MPA', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('inhibited', 'NegReg', (55, 64))
39936	22959032	DFMO, tilorone, or poly(l) X poly(C), when administered alone, showed 85, 39, and 39% of inhibition of tumor growth, respectively.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('poly(l) X poly(C', 'Var', (19, 35))	('tilorone', 'Chemical', 'MESH:D013994', (6, 14))	('inhibition', 'NegReg', (89, 99))	('poly(l) X poly(C)', 'Chemical', '-', (19, 36))	('DFMO', 'Chemical', 'MESH:D000518', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
39937	22959032	However, a combination of DFMO and tilorone or poly(l) X poly(C) resulted in 98 and 95% growth inhibition.	('growth', 'MPA', (88, 94))	('DFMO', 'Chemical', 'MESH:D000518', (26, 30))	('poly(l) X poly(C', 'Var', (47, 63))	('poly(l) X poly(C)', 'Chemical', '-', (47, 64))	('tilorone', 'Chemical', 'MESH:D013994', (35, 43))
39939	22959032	A combination of DFMO and tilorone led to 78% inhibition of tumor growth and 99.5% inhibition of metastases, but the mechanisms remain to be fully elucidated.	('inhibition', 'NegReg', (83, 93))	('metastases', 'Disease', (97, 107))	('inhibition', 'NegReg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DFMO', 'Chemical', 'MESH:D000518', (17, 21))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('DFMO', 'Var', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tilorone', 'Chemical', 'MESH:D013994', (26, 34))	('tumor', 'Disease', (60, 65))
39976	22959032	Other studies have suggested involvement of reactive oxygen species, inhibition of topoisomerase I, activation of Erk1/2 phosphorylation, suppression of tumor angiogenesis, and modulation of pro-growth transcriptional activators as well as aminopeptidase N activity for betulinic acid chemopreventive activity.	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('phosphorylation', 'CPA', (121, 136))	('Erk1/2', 'Gene', '5595;5594', (114, 120))	('tumor', 'Disease', (153, 158))	('modulation', 'Var', (177, 187))	('inhibition', 'NegReg', (69, 79))	('topoisomerase', 'molecular_function', 'GO:0003917', ('83', '96'))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Erk1', 'molecular_function', 'GO:0004707', ('114', '118'))	('reactive oxygen species', 'MPA', (44, 67))	('aminopeptidase N activity', 'molecular_function', 'GO:0004179', ('240', '265'))	('betulinic acid', 'Chemical', 'MESH:C002070', (270, 284))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('topoisomerase I', 'Enzyme', (83, 98))	('topoisomerase', 'molecular_function', 'GO:0003918', ('83', '96'))	('suppression', 'NegReg', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (44, 67))	('men', 'Species', '9606', (36, 39))	('Erk1/2', 'Gene', (114, 120))	('activation', 'PosReg', (100, 110))
39986	22959032	Targeted inhibition of EGFR using PD153035 decreased betulinic acid induced EGFR phosphorylation and inhibited Akt activation to promote cancer cell destruction.	('phosphorylation', 'MPA', (81, 96))	('promote', 'PosReg', (129, 136))	('Akt', 'Gene', (111, 114))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (76, 80))	('cancer', 'Disease', (137, 143))	('Akt', 'Gene', '207', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('betulinic acid induced', 'MPA', (53, 75))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('76', '80'))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('EGFR', 'Gene', (23, 27))	('PD153035', 'Chemical', 'MESH:C088860', (34, 42))	('PD153035', 'Var', (34, 42))	('betulinic acid', 'Chemical', 'MESH:C002070', (53, 67))	('inhibited', 'NegReg', (101, 110))	('decreased', 'NegReg', (43, 52))
39993	22959032	Furthermore, a large case-control study using dietary vitamin-D found it reduced melanoma risk.	('reduced', 'NegReg', (73, 80))	('vitamin-D', 'Var', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('vitamin-D', 'Chemical', 'MESH:D014807', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
39997	22959032	If vitamin D inhibits a signaling pathway involved in the development of melanoma, such as V600EBRAF protein involved in cell proliferation, then oral vitamin D could be explored further as a chemoprevention.	('melanoma', 'Disease', (73, 81))	('signaling pathway', 'Pathway', (24, 41))	('vitamin D', 'Chemical', 'MESH:D014807', (3, 12))	('vitamin D', 'Chemical', 'MESH:D014807', (151, 160))	('V600EBRAF', 'Var', (91, 100))	('men', 'Species', '9606', (65, 68))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('121', '139'))	('protein', 'Protein', (101, 108))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('signaling pathway', 'biological_process', 'GO:0007165', ('24', '41'))	('inhibits', 'NegReg', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
40018	31861976	We used two cohorts with acute myeloid leukemia (AML), one exclusively with individuals over the age of 60 (GSE6891) (461 patients) with samples collected from both blood and bone marrow and the second (GSE15434) of exclusively normal karyotype (NK) AML (251 patients) with samples collected from mononuclear cells.	('AML', 'Disease', (49, 52))	('patients', 'Species', '9606', (259, 267))	('AML', 'Disease', 'MESH:D015470', (250, 253))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (25, 47))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (31, 47))	('AML', 'Disease', (250, 253))	('patients', 'Species', '9606', (122, 130))	('acute myeloid leukemia', 'Disease', (25, 47))	('GSE15434', 'Var', (203, 211))	('AML', 'Phenotype', 'HP:0004808', (250, 253))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('leukemia', 'Phenotype', 'HP:0001909', (39, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (25, 47))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
40063	31861976	We hypothesize that deviations between the methylation of loci between patient sub-groups creates tail regions.	('methylation', 'Var', (43, 54))	('patient', 'Species', '9606', (71, 78))	('deviations', 'Var', (20, 30))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))
40086	28787433	This study aimed to determine if BRAF and NRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('BRAF', 'Gene', '673', (33, 37))	('NRAS', 'Gene', '4893', (42, 46))	('tumour metastasis', 'Disease', (106, 123))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('BRAF', 'Gene', (33, 37))	('NRAS', 'Gene', (42, 46))	('type tumours', 'Disease', 'MESH:D009369', (63, 75))	('tumour metastasis', 'Disease', 'MESH:D009362', (106, 123))	('type tumours', 'Disease', (63, 75))	('mutant', 'Var', (47, 53))
40090	28787433	BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07-5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14-2.10, P=0.005).	('sentinel lymph node positivity', 'CPA', (105, 135))	('aOR', 'molecular_function', 'GO:0033726', ('158', '161'))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('lymph node metastasis', 'CPA', (34, 55))	('mutation', 'Var', (5, 13))
40091	28787433	BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49-6.42, P=0.003; aOR 3.17, 95% CI 1.32-7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23-9.69, P<0.001; aOR 4.03, 95% CI 1.72-9.44, P=0.001).	('aOR', 'molecular_function', 'GO:0033726', ('218', '221'))	('liver metastasis', 'Disease', 'MESH:D009362', (82, 98))	('liver metastasis', 'Disease', (82, 98))	('mutation', 'Var', (23, 31))	('NRAS', 'Gene', '4893', (18, 22))	('aOR', 'molecular_function', 'GO:0033726', ('100', '103'))	('central nervous system (CNS) metastasis', 'Disease', 'MESH:D009362', (177, 216))	('BRAF', 'Gene', '673', (0, 4))	('aOR', 'molecular_function', 'GO:0033726', ('255', '258'))	('aOR', 'molecular_function', 'GO:0033726', ('137', '140'))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (18, 22))
40092	28787433	NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21-4.93, P=0.01).	('aOR', 'molecular_function', 'GO:0033726', ('51', '54'))	('lung metastasis', 'Disease', 'MESH:D009362', (34, 49))	('associated', 'Reg', (18, 28))	('lung metastasis', 'Disease', (34, 49))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))
40093	28787433	BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity.	('associated', 'Reg', (30, 40))	('sentinel lymph node positivity', 'CPA', (92, 122))	('lymph node metastasis', 'CPA', (46, 67))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
40094	28787433	BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis.	('lung metastasis', 'Disease', (93, 108))	('liver metastasis', 'Disease', (53, 69))	('lung metastasis', 'Disease', 'MESH:D009362', (93, 108))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', (74, 78))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', '4893', (74, 78))	('associated', 'Reg', (29, 39))	('BRAF', 'Gene', (0, 4))	('liver metastasis', 'Disease', 'MESH:D009362', (53, 69))	('mutations', 'Var', (14, 23))	('CNS', 'Disease', (45, 48))
40103	28787433	It is well-recognised that 40-50% and 15% of cutaneous melanomas harbour activating mutations of BRAF and NRAS, respectively.	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('NRAS', 'Gene', '4893', (106, 110))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (45, 64))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (45, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (45, 63))	('cutaneous melanomas', 'Disease', (45, 64))	('NRAS', 'Gene', (106, 110))	('mutations', 'Var', (84, 93))	('activating', 'PosReg', (73, 83))	('BRAF', 'Gene', '673', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('BRAF', 'Gene', (97, 101))
40104	28787433	Mutations in BRAF and NRAS oncogenes are associated with distinct phenotypic and histopathological characteristics.	('associated', 'Reg', (41, 51))	('BRAF', 'Gene', '673', (13, 17))	('NRAS', 'Gene', (22, 26))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (22, 26))
40106	28787433	The primary aim of this study was to determine if BRAF and NRAS mutant tumours compared to wild-type tumours have a propensity to metastasise as satellite/in-transit, regional lymph node or distant metastasis as the first site of metastasis and if these tumours behave differently in their anatomical metastatic pathways.	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('metastasise', 'CPA', (130, 141))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('type tumours', 'Disease', (96, 108))	('distant metastasis', 'CPA', (190, 208))	('tumours', 'Disease', (71, 78))	('mutant', 'Var', (64, 70))	('NRAS', 'Gene', '4893', (59, 63))	('tumours', 'Disease', (254, 261))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('regional lymph node', 'CPA', (167, 186))	('type tumours', 'Disease', 'MESH:D009369', (96, 108))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Disease', 'MESH:D009369', (254, 261))	('BRAF', 'Gene', '673', (50, 54))	('BRAF', 'Gene', (50, 54))	('tumours', 'Disease', (101, 108))	('NRAS', 'Gene', (59, 63))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
40114	28787433	The primary melanomas of 73% of all patients enroled in MMP were tested for the presence of a BRAF and NRAS mutation.	('NRAS', 'Gene', '4893', (103, 107))	('BRAF', 'Gene', (94, 98))	('patients', 'Species', '9606', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('NRAS', 'Gene', (103, 107))	('mutation', 'Var', (108, 116))	('MMP', 'molecular_function', 'GO:0004235', ('56', '59'))	('melanomas', 'Disease', (12, 21))	('BRAF', 'Gene', '673', (94, 98))	('tested', 'Reg', (65, 71))
40118	28787433	The sample was checked for multiple known mutations in BRAF (exon 11 and 15), NRAS (exon 2, 3 and 4) and KIT (exon 11, 13 and 17) using Sequenom (Agena) Mass ARRAY OncoFocus panel (Version 3).	('KIT', 'Gene', (105, 108))	('NRAS', 'Gene', (78, 82))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('BRAF', 'Gene', '673', (55, 59))	('NRAS', 'Gene', '4893', (78, 82))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (55, 59))
40129	28787433	Univariate and multivariate multinomial regression analyses were conducted to compare various clinical and pathological variables between patients with BRAF mutations, NRAS mutations and BRAF/NRAS wild-type tumours with the associations summarised as relative risk ratios (RRR) and 95% confidence intervals (CI).	('BRAF', 'Gene', (152, 156))	('NRAS', 'Gene', '4893', (168, 172))	('BRAF', 'Gene', '673', (187, 191))	('type tumours', 'Disease', 'MESH:D009369', (202, 214))	('mutations', 'Var', (173, 182))	('mutations', 'Var', (157, 166))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('NRAS', 'Gene', (192, 196))	('type tumours', 'Disease', (202, 214))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('BRAF', 'Gene', '673', (152, 156))	('NRAS', 'Gene', '4893', (192, 196))	('patients', 'Species', '9606', (138, 146))	('NRAS', 'Gene', (168, 172))	('BRAF', 'Gene', (187, 191))
40130	28787433	Logistic regression was used to assess associations of various clinicopathological characteristics with BRAF V600E and V600K mutational subtypes and with sentinel lymph node positivity, summarised as odds ratios (OR).	('V600K', 'Mutation', 'rs121913227', (119, 124))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('BRAF', 'Gene', '673', (104, 108))	('V600K', 'Var', (119, 124))	('associations', 'Interaction', (39, 51))	('BRAF', 'Gene', (104, 108))	('V600E', 'Var', (109, 114))
40131	28787433	Melanoma-specific survival (MSS) was compared between patients with BRAF mutant, NRAS mutant and wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('BRAF', 'Gene', '673', (68, 72))	('mutant', 'Var', (86, 92))	('patients', 'Species', '9606', (54, 62))	('type tumours', 'Disease', 'MESH:D009369', (102, 114))	('Melanoma', 'Disease', (0, 8))	('BRAF', 'Gene', (68, 72))	('NRAS', 'Gene', (81, 85))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('mutant', 'Var', (73, 79))	('MSS', 'Disease', 'MESH:D013132', (28, 31))	('type tumours', 'Disease', (102, 114))	('MSS', 'Disease', (28, 31))	('NRAS', 'Gene', '4893', (81, 85))
40139	28787433	Among the 1048 primary melanomas, 48.6% were BRAF mutant, 19.0% were NRAS mutant and 32.4% were BRAF/NRAS wild type.	('NRAS', 'Gene', '4893', (69, 73))	('melanomas', 'Disease', (23, 32))	('NRAS', 'Gene', (101, 105))	('NRAS', 'Gene', '4893', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (96, 100))	('mutant', 'Var', (50, 56))	('BRAF', 'Gene', '673', (96, 100))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('mutant', 'Var', (74, 80))	('NRAS', 'Gene', (69, 73))
40140	28787433	Among the BRAF mutant tumours, the most common genotype was V600E (70.0%), followed by V600K (24.2%) and less common genotypes (5.8%).	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('V600K', 'Mutation', 'rs121913227', (87, 92))	('tumours', 'Disease', (22, 29))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', (10, 14))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('V600E', 'Var', (60, 65))	('V600K', 'Var', (87, 92))
40141	28787433	The majority (93.2%) of NRAS mutant tumours had an NRAS codon 61 mutation.	('NRAS', 'Gene', '4893', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mutant', 'Var', (29, 35))	('tumours', 'Disease', (36, 43))	('NRAS', 'Gene', (51, 55))	('NRAS', 'Gene', (24, 28))	('NRAS', 'Gene', '4893', (51, 55))
40142	28787433	Clinical and pathological characteristics are described by BRAF and NRAS mutation status in Table 1 with corresponding estimates of associations presented in Table 2.	('mutation status', 'Var', (73, 88))	('NRAS', 'Gene', (68, 72))	('NRAS', 'Gene', '4893', (68, 72))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))
40143	28787433	Median age differed between patients with BRAF mutant, NRAS mutant and BRAF/NRAS wild-type tumours (53 vs 62 vs 61 years, respectively).	('BRAF', 'Gene', '673', (42, 46))	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('NRAS', 'Gene', (76, 80))	('type tumours', 'Disease', (86, 98))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('BRAF', 'Gene', '673', (71, 75))	('NRAS', 'Gene', '4893', (55, 59))	('NRAS', 'Gene', '4893', (76, 80))	('BRAF', 'Gene', (71, 75))	('patients', 'Species', '9606', (28, 36))	('type tumours', 'Disease', 'MESH:D009369', (86, 98))	('BRAF', 'Gene', (42, 46))	('mutant', 'Var', (60, 66))	('NRAS', 'Gene', (55, 59))	('mutant', 'Var', (47, 53))
40144	28787433	Even when adjusted for other factors, compared to those aged >50 years, patients aged <50 years had 2.48-fold higher relative risk of having a BRAF mutant tumour than a BRAF/NRAS wild-type tumour and a 3.59-fold higher relative risk of having a BRAF mutant tumour than a NRAS mutant tumour (RRR 2.48, 95% CI 1.82-3.38, P<0.001; RRR 3.59, 95% CI 2.39-5.41, P<0.001, respectively).	('tumour', 'Disease', 'MESH:D009369', (283, 289))	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('tumour', 'Disease', (283, 289))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('NRAS', 'Gene', (271, 275))	('tumour', 'Disease', (189, 195))	('NRAS', 'Gene', '4893', (174, 178))	('tumour', 'Disease', (155, 161))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Disease', (257, 263))	('NRAS', 'Gene', (174, 178))	('NRAS', 'Gene', '4893', (271, 275))	('mutant', 'Var', (148, 154))	('tumour', 'Phenotype', 'HP:0002664', (283, 289))	('patients', 'Species', '9606', (72, 80))
40145	28787433	Compared to BRAF/NRAS wild-type tumours, BRAF mutation was associated with truncal location and superficial spreading subtype after adjustment for other variables (Tables 1 and 2).	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('type tumours', 'Disease', 'MESH:D009369', (27, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('associated', 'Reg', (59, 69))	('NRAS', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (41, 45))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('BRAF', 'Gene', (41, 45))	('type tumours', 'Disease', (27, 39))	('superficial spreading subtype', 'Disease', (96, 125))	('NRAS', 'Gene', '4893', (17, 21))	('truncal location', 'Disease', (75, 91))	('mutation', 'Var', (46, 54))
40146	28787433	Compared to BRAF mutations, NRAS mutations were more common in tumours on the upper extremities (adjusted RRR (aRRR) 2.38, 95% CI 1.38-4.10, P=0.002) and lower extremities (aRRR 1.77 95% CI 1.02-3.09, P=0.04) than the head and neck region.	('tumours', 'Disease', (63, 70))	('RRR 1', 'Gene', (174, 179))	('NRAS', 'Gene', '4893', (28, 32))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('RRR 1', 'Gene', '147906', (174, 179))	('common', 'Reg', (53, 59))	('mutations', 'Var', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('neck', 'cellular_component', 'GO:0044326', ('227', '231'))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('NRAS', 'Gene', (28, 32))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
40147	28787433	Compared to patients with BRAF V600E mutant tumours, patients with BRAF V600K mutant tumours had an increased odds of being male (OR 2.04, 95% CI 1.33-3.19, P<0.001), older (OR >=50 years 6.38, 95% CI 3.78-10.79, P<0.001) and having tumours located on the head and neck region compared to the trunk (RR 2.45, 95% CI 1.42-4.22, P=0.001).	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('BRAF', 'Gene', '673', (26, 30))	('neck', 'cellular_component', 'GO:0044326', ('265', '269'))	('BRAF', 'Gene', (26, 30))	('tumours', 'Phenotype', 'HP:0002664', (233, 240))	('tumours', 'Disease', 'MESH:D009369', (233, 240))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (12, 20))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('trunk', 'cellular_component', 'GO:0043198', ('293', '298'))	('patients', 'Species', '9606', (53, 61))	('tumours located on the head and neck', 'Phenotype', 'HP:0012288', (233, 269))	('tumours', 'Disease', (233, 240))	('tumours', 'Disease', (85, 92))	('mutant', 'Var', (78, 84))	('BRAF', 'Gene', '673', (67, 71))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('BRAF', 'Gene', (67, 71))	('V600K', 'Mutation', 'rs121913227', (72, 77))	('tumours', 'Disease', (44, 51))	('V600E', 'Mutation', 'rs113488022', (31, 36))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
40150	28787433	BRAF V600K mutant tumours, compared to V600E tumours, had an increased odds of being thick tumours than thin tumours (OR 2.39, 95% CI 1.27-4.50, P=0.007) and having a high mitotic rate (OR >=10/mm2 compared to <5/mm2 2.05 95% CI 1.19-3.54, P=0.01).	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('tumours than thin tumours', 'Disease', (91, 116))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('V600E', 'Var', (39, 44))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600K', 'Mutation', 'rs121913227', (5, 10))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumours than thin tumours', 'Disease', 'MESH:D009369', (91, 116))	('tumours', 'Disease', (18, 25))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('V600E', 'SUBSTITUTION', 'None', (39, 44))	('tumours', 'Disease', 'MESH:D009369', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('V600K', 'Var', (5, 10))	('tumours', 'Disease', (109, 116))	('tumours', 'Disease', (45, 52))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('tumours', 'Disease', (91, 98))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
40151	28787433	The relationship between V600K mutation and greater tumour thickness (aOR thick compared to thin tumours 1.69, 95% CI 0.74-3.84, P=0.2) and mitotic rate (aOR >=10/mm2 compared to <5/mm2 1.41 95% CI 0.71-2.80, P=0.3) were partially explained by other factors.	('V600K', 'Var', (25, 30))	('tumours', 'Disease', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('aOR', 'molecular_function', 'GO:0033726', ('70', '73'))	('mitotic rate', 'CPA', (140, 152))	('V600K', 'Mutation', 'rs121913227', (25, 30))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumour thickness', 'Disease', (52, 68))	('aOR', 'molecular_function', 'GO:0033726', ('154', '157'))	('greater', 'PosReg', (44, 51))	('tumour thickness', 'Disease', 'MESH:D009369', (52, 68))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
40152	28787433	There was no evidence to suggest that ulceration was related to BRAF V600 subtype (univariate OR V600K 1.18, 95% CI 0.75-1.86, P=0.5).	('V600K', 'Var', (97, 102))	('BRAF', 'Gene', '673', (64, 68))	('BRAF', 'Gene', (64, 68))	('ulceration', 'Disease', (38, 48))	('V600K', 'Mutation', 'rs121913227', (97, 102))
40155	28787433	After adjusting for age, sex, mitotic rate, ulceration, Breslow thickness, histologic subtype and anatomical site of primary tumour, BRAF mutant tumours had 1.55 times increased odds (aOR 1.55, 95% CI 1.14-2.10, P=0.005) of having a positive SLNB compared to BRAF/NRAS wild-type tumours.	('mutant', 'Var', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('NRAS', 'Gene', (264, 268))	('tumours', 'Disease', 'MESH:D009369', (145, 152))	('tumours', 'Disease', (279, 286))	('type tumours', 'Disease', 'MESH:D009369', (274, 286))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (133, 137))	('tumours', 'Phenotype', 'HP:0002664', (279, 286))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('tumours', 'Disease', 'MESH:D009369', (279, 286))	('tumour', 'Disease', (145, 151))	('BRAF', 'Gene', (259, 263))	('BRAF', 'Gene', '673', (259, 263))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))	('aOR', 'molecular_function', 'GO:0033726', ('184', '187'))	('SLNB', 'MPA', (242, 246))	('NRAS', 'Gene', '4893', (264, 268))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('type tumours', 'Disease', (274, 286))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('tumours', 'Disease', (145, 152))
40156	28787433	There were similar odds of SLNB positivity between NRAS mutant and BRAF/NRAS wild-type tumours (aOR 1.06, 95% CI 0.73-1.56, P=0.8).	('NRAS', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (67, 71))	('SLNB', 'Gene', (27, 31))	('type tumours', 'Disease', 'MESH:D009369', (82, 94))	('NRAS', 'Gene', '4893', (72, 76))	('mutant', 'Var', (56, 62))	('BRAF', 'Gene', (67, 71))	('type tumours', 'Disease', (82, 94))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('aOR', 'molecular_function', 'GO:0033726', ('96', '99'))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('NRAS', 'Gene', (51, 55))	('NRAS', 'Gene', '4893', (51, 55))
40164	28787433	The site of first metastasis was similar in both NRAS mutant and BRAF/NRAS wild-type mutant groups (Table 4).	('NRAS', 'Gene', '4893', (49, 53))	('NRAS', 'Gene', (70, 74))	('NRAS', 'Gene', '4893', (70, 74))	('BRAF', 'Gene', '673', (65, 69))	('mutant', 'Var', (54, 60))	('NRAS', 'Gene', (49, 53))	('BRAF', 'Gene', (65, 69))
40165	28787433	BRAF mutant tumours, compared to BRAF/NRAS wild-type tumours, had increased risk of developing regional lymph node metastasis rather than satellite/in-transit metastasis as first metastasis (univariate RRR 3.24, 95% CI 1.49-7.08, P=0.003), This increased risk remained statistically significant after adjustments (RRR 2.46 95% CI 1.07-5.69, P=0.04; Table 4).	('type tumours', 'Disease', (48, 60))	('NRAS', 'Gene', '4893', (38, 42))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('BRAF', 'Gene', '673', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('BRAF', 'Gene', (33, 37))	('tumours', 'Disease', (12, 19))	('regional lymph node metastasis', 'CPA', (95, 125))	('BRAF', 'Gene', '673', (0, 4))	('type tumours', 'Disease', 'MESH:D009369', (48, 60))	('mutant', 'Var', (5, 11))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (38, 42))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
40166	28787433	BRAF mutant tumours had increased risk of developing regional lymph node metastasis rather than distant metastasis as the site of first metastasis; however, this increased risk was not statistically significant (RRR 1.32, 95% CI 0.70-2.49, P=0.4).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('RRR 1', 'Gene', '147906', (212, 217))	('regional lymph node metastasis', 'CPA', (53, 83))	('tumours', 'Disease', (12, 19))	('BRAF', 'Gene', '673', (0, 4))	('mutant', 'Var', (5, 11))	('RRR 1', 'Gene', (212, 217))	('BRAF', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))
40171	28787433	Of the 103 patients who died from metastatic melanoma, 24.3% of tumours had an NRAS mutation, 59.2% had a BRAF mutation and 16.5% had BRAF/NRAS wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('NRAS', 'Gene', '4893', (79, 83))	('NRAS', 'Gene', (139, 143))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('type tumours', 'Disease', 'MESH:D009369', (149, 161))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('BRAF', 'Gene', '673', (134, 138))	('tumours', 'Disease', (64, 71))	('BRAF', 'Gene', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('NRAS', 'Gene', (79, 83))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('NRAS', 'Gene', '4893', (139, 143))	('patients', 'Species', '9606', (11, 19))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('type tumours', 'Disease', (149, 161))	('BRAF', 'Gene', '673', (106, 110))	('tumours', 'Disease', (154, 161))	('BRAF', 'Gene', (106, 110))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('mutation', 'Var', (84, 92))
40172	28787433	In univariate analysis, both patients with BRAF mutant and NRAS mutant melanomas had a worse MSS than patients with BRAF/NRAS wild-type tumours (hazard ratio (HR) 2.46 95% CI 1.43-4.20, P=0.001; HR 2.70, 95% CI 1.46-5.00, P=0.002, respectively).	('type tumours', 'Disease', (131, 143))	('patients', 'Species', '9606', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('NRAS', 'Gene', (121, 125))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('patients', 'Species', '9606', (29, 37))	('mutant', 'Var', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('type tumours', 'Disease', 'MESH:D009369', (131, 143))	('MSS', 'Disease', (93, 96))	('mutant', 'Var', (64, 70))	('NRAS', 'Gene', '4893', (59, 63))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('BRAF', 'Gene', '673', (116, 120))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('BRAF', 'Gene', (116, 120))	('MSS', 'Disease', 'MESH:D013132', (93, 96))	('melanomas', 'Disease', (71, 80))	('NRAS', 'Gene', '4893', (121, 125))	('BRAF', 'Gene', '673', (43, 47))	('BRAF', 'Gene', (43, 47))	('NRAS', 'Gene', (59, 63))
40173	28787433	When adjusted for age, sex, ulceration, Breslow thickness, histologic subtype and mitotic rate, the relationship between BRAF mutation and MSS was slightly strengthened (HR 2.95, 95% CI 1.64-5.29, P<0.001).	('BRAF', 'Gene', (121, 125))	('MSS', 'Disease', 'MESH:D013132', (139, 142))	('MSS', 'Disease', (139, 142))	('mutation', 'Var', (126, 134))	('strengthened', 'PosReg', (156, 168))	('BRAF', 'Gene', '673', (121, 125))
40174	28787433	After adjustments, patients with NRAS mutant melanomas had a worse MSS than patients with BRAF/NRAS wild-type melanomas (HR 3.08, 95% CI 1.56-6.08, P=0.001).	('BRAF', 'Gene', (90, 94))	('melanomas', 'Disease', (45, 54))	('NRAS', 'Gene', '4893', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('NRAS', 'Gene', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('MSS', 'Disease', (67, 70))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))	('mutant', 'Var', (38, 44))	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (19, 27))	('NRAS', 'Gene', (95, 99))	('MSS', 'Disease', 'MESH:D013132', (67, 70))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('NRAS', 'Gene', '4893', (33, 37))	('melanomas', 'Disease', (110, 119))	('BRAF', 'Gene', '673', (90, 94))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))
40176	28787433	With respect to patients who developed central nervous system (CNS) metastasis, 50/77 (65%) had a BRAF mutant tumour and 17/77 (22%) had a NRAS mutant tumour.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('NRAS', 'Gene', (139, 143))	('mutant', 'Var', (103, 109))	('patients', 'Species', '9606', (16, 24))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('central nervous system (CNS) metastasis', 'Disease', 'MESH:D009362', (39, 78))	('NRAS', 'Gene', '4893', (139, 143))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
40177	28787433	BRAF mutation and NRAS mutation were associated with increased odds of developing CNS metastasis compared to BRAF/NRAS wild-type tumours (BRAF aOR 4.65, 95% CI 2.23-9.69, P<0.001; NRAS aOR 4.03, 95% CI 1.72-9.44, P=0.001).	('BRAF', 'Gene', '673', (0, 4))	('type tumours', 'Disease', 'MESH:D009369', (124, 136))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (18, 22))	('CNS metastasis', 'Disease', (82, 96))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('NRAS', 'Gene', (114, 118))	('NRAS', 'Gene', '4893', (180, 184))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('aOR', 'molecular_function', 'GO:0033726', ('185', '188'))	('aOR', 'molecular_function', 'GO:0033726', ('143', '146'))	('type tumours', 'Disease', (124, 136))	('NRAS', 'Gene', (180, 184))	('mutation', 'Var', (23, 31))	('NRAS', 'Gene', '4893', (18, 22))	('CNS metastasis', 'Disease', 'MESH:D009362', (82, 96))	('NRAS', 'Gene', '4893', (114, 118))	('mutation', 'Var', (5, 13))
40178	28787433	Among patients who developed liver metastasis, 40/65 (62%) had a BRAF mutant tumour and 14/65 (21%) had an NRAS mutant tumour.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('mutant', 'Var', (70, 76))	('tumour', 'Disease', (77, 83))	('NRAS', 'Gene', '4893', (107, 111))	('tumour', 'Disease', (119, 125))	('patients', 'Species', '9606', (6, 14))	('BRAF', 'Gene', '673', (65, 69))	('liver metastasis', 'Disease', 'MESH:D009362', (29, 45))	('liver metastasis', 'Disease', (29, 45))	('BRAF', 'Gene', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('NRAS', 'Gene', (107, 111))
40179	28787433	There was evidence to suggest that the presence of either a BRAF or NRAS mutation was associated with an increased odds of developing liver metastasis compared to BRAF/NRAS wild-type tumours (BRAF aOR 3.09, 95% CI 1.49-6.42, P=0.003; NRAS aOR 3.17, 95% CI 1.32-7.58, P=0.01).	('NRAS', 'Gene', '4893', (168, 172))	('aOR', 'molecular_function', 'GO:0033726', ('197', '200'))	('liver metastasis', 'Disease', (134, 150))	('type tumours', 'Disease', 'MESH:D009369', (178, 190))	('NRAS', 'Gene', '4893', (68, 72))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('mutation', 'Var', (73, 81))	('NRAS', 'Gene', '4893', (234, 238))	('NRAS', 'Gene', (168, 172))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('liver metastasis', 'Disease', 'MESH:D009362', (134, 150))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('aOR', 'molecular_function', 'GO:0033726', ('239', '242'))	('BRAF', 'Gene', '673', (192, 196))	('NRAS', 'Gene', (68, 72))	('type tumours', 'Disease', (178, 190))	('BRAF', 'Gene', (192, 196))	('NRAS', 'Gene', (234, 238))
40180	28787433	Among patients who developed lung metastasis, 50/98 (51%) had a BRAF mutant tumour and 23/98 (24%) had a NRAS mutant tumour.	('BRAF', 'Gene', '673', (64, 68))	('NRAS', 'Gene', (105, 109))	('lung metastasis', 'Disease', (29, 44))	('mutant', 'Var', (69, 75))	('lung metastasis', 'Disease', 'MESH:D009362', (29, 44))	('BRAF', 'Gene', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('NRAS', 'Gene', '4893', (105, 109))	('patients', 'Species', '9606', (6, 14))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (117, 123))	('tumour', 'Disease', (76, 82))
40181	28787433	While there was evidence to suggest that NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21-4.93, P=0.013), there was uncertainty regarding an association between BRAF mutation and the development of lung metastasis (aOR 1.78, 95% CI 0.98-3.25 P=0.06).	('NRAS', 'Gene', '4893', (41, 45))	('aOR', 'molecular_function', 'GO:0033726', ('239', '242'))	('aOR', 'molecular_function', 'GO:0033726', ('92', '95'))	('lung metastasis', 'Disease', (75, 90))	('BRAF', 'Gene', (185, 189))	('lung metastasis', 'Disease', 'MESH:D009362', (75, 90))	('associated', 'Reg', (59, 69))	('lung metastasis', 'Disease', (222, 237))	('lung metastasis', 'Disease', 'MESH:D009362', (222, 237))	('NRAS', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (185, 189))	('mutation', 'Var', (46, 54))
40184	28787433	Excluding patients with a tumour-positive SLNB, the median time to first metastasis was shorter in patients with BRAF mutant tumours (12.5 months, IQR 5.0-22.5 months) compared to NRAS mutant (13.4 months, IQR 5.6-21.7) and BRAF/NRAS wild-type tumours (18.1 months, IQR 7.4-32.3 months) (P=0.14).	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('NRAS', 'Gene', '4893', (229, 233))	('NRAS', 'Gene', '4893', (180, 184))	('tumour-positive SLNB', 'Disease', 'MESH:D009369', (26, 46))	('type tumours', 'Disease', (239, 251))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('NRAS', 'Gene', (229, 233))	('patients', 'Species', '9606', (99, 107))	('mutant', 'Var', (118, 124))	('patients', 'Species', '9606', (10, 18))	('tumour-positive SLNB', 'Disease', (26, 46))	('tumours', 'Disease', (244, 251))	('shorter', 'NegReg', (88, 95))	('BRAF', 'Gene', '673', (113, 117))	('type tumours', 'Disease', 'MESH:D009369', (239, 251))	('NRAS', 'Gene', (180, 184))	('BRAF', 'Gene', (113, 117))	('tumours', 'Disease', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('BRAF', 'Gene', (224, 228))	('BRAF', 'Gene', '673', (224, 228))	('tumours', 'Disease', 'MESH:D009369', (244, 251))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
40185	28787433	The median time to distant metastasis was similar among patients with BRAF mutant (15.0 months (IQR 8.5-26.4)) NRAS mutant (16.2 months (IQR 10.8-25.1)) and BRAF/NRAS wild-type (17.2 months [IQR 11.5-29.2]) tumours (P=0.7).	('NRAS', 'Gene', (111, 115))	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('patients', 'Species', '9606', (56, 64))	('distant metastasis', 'CPA', (19, 37))	('NRAS', 'Gene', '4893', (111, 115))	('NRAS', 'Gene', '4893', (162, 166))	('tumours', 'Disease', (207, 214))	('BRAF', 'Gene', '673', (157, 161))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('BRAF', 'Gene', (157, 161))	('mutant', 'Var', (75, 81))	('BRAF', 'Gene', '673', (70, 74))	('mutant', 'Var', (116, 122))	('NRAS', 'Gene', (162, 166))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('BRAF', 'Gene', (70, 74))
40192	28787433	Consistent with the existing literature, our study found that BRAF positivity is associated with younger age and superficial spreading subtype.	('BRAF', 'Gene', (62, 66))	('superficial', 'Disease', (113, 124))	('positivity', 'Var', (67, 77))	('BRAF', 'Gene', '673', (62, 66))
40193	28787433	In the multivariate regression analysis, BRAF mutation was not associated with Breslow thickness.	('mutation', 'Var', (46, 54))	('Breslow thickness', 'Disease', (79, 96))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', '673', (41, 45))
40194	28787433	Previous work on a subset of this cohort suggested that BRAF mutant tumours were thinner at diagnosis compared to BRAF wild-type tumours.	('BRAF wild-type tumours', 'Disease', (114, 136))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('BRAF wild-type tumours', 'Disease', 'MESH:D009369', (114, 136))	('thinner', 'NegReg', (81, 88))	('BRAF', 'Gene', '673', (56, 60))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (129, 136))	('tumours', 'Disease', (68, 75))	('mutant', 'Var', (61, 67))	('BRAF', 'Gene', (56, 60))
40195	28787433	However, other studies have found no relationship between Breslow thickness and BRAF mutation.	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (80, 84))	('mutation', 'Var', (85, 93))
40196	28787433	Among BRAF mutant tumours, the frequency (24%) of BRAF V600K in our cohort was somewhat higher than expected.	('higher', 'PosReg', (88, 94))	('mutant', 'Var', (11, 17))	('V600K', 'Var', (55, 60))	('BRAF', 'Gene', (50, 54))	('tumours', 'Disease', (18, 25))	('tumours', 'Phenotype', 'HP:0002664', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('BRAF', 'Gene', '673', (6, 10))	('V600K', 'Mutation', 'rs121913227', (55, 60))	('BRAF', 'Gene', (6, 10))	('BRAF', 'Gene', '673', (50, 54))	('tumours', 'Disease', 'MESH:D009369', (18, 25))
40197	28787433	The frequency of BRAF V600K mutation has been reported to range between 6 and 30%.	('V600K', 'Mutation', 'rs121913227', (22, 27))	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('V600K', 'Var', (22, 27))
40200	28787433	For instance, studies using methods with lower sensitivities for reliably detecting non-V600E mutations (such as Sanger sequencing) or with lower specificities in distinguishing variant mutations may underestimate the frequency of mutations in V600K.	('V600E', 'Mutation', 'rs113488022', (88, 93))	('V600K', 'Mutation', 'rs121913227', (244, 249))	('non-V600E', 'Var', (84, 93))	('V600K', 'Var', (244, 249))	('underestimate', 'NegReg', (200, 213))
40201	28787433	Moreover, mutations in V600K may be more frequent in Australian populations due to high ultraviolet exposure given the higher proportion of melanomas arising in chronic sun-damaged skin.	('melanomas', 'Disease', (140, 149))	('V600K', 'Var', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('V600K', 'Mutation', 'rs121913227', (23, 28))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))	('sun-damaged', 'Phenotype', 'HP:0000992', (169, 180))
40203	28787433	Previous studies have similarly demonstrated associations between V600K genotype with older patient age and head and neck location.	('V600K', 'Var', (66, 71))	('associations', 'Interaction', (45, 57))	('patient', 'Species', '9606', (92, 99))	('neck', 'cellular_component', 'GO:0044326', ('117', '121'))	('V600K', 'Mutation', 'rs121913227', (66, 71))
40204	28787433	These findings suggest that different genotypes exist within BRAF mutant melanoma, whereby V600K and V600E genotypes may represent biologically and clinically distinct entities.	('melanoma', 'Disease', (73, 81))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('mutant', 'Var', (66, 72))	('BRAF', 'Gene', '673', (61, 65))	('V600E', 'Var', (101, 106))	('BRAF', 'Gene', (61, 65))	('V600K', 'Var', (91, 96))	('V600K', 'Mutation', 'rs121913227', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
40205	28787433	In our study, NRAS positivity was more common in older patients and in tumour located on the extremities compared to the head and necsk region.	('positivity', 'Var', (19, 29))	('NRAS', 'Gene', '4893', (14, 18))	('tumour', 'Disease', (71, 77))	('common', 'Reg', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (55, 63))	('NRAS', 'Gene', (14, 18))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
40206	28787433	Several other studies have demonstrated an association between NRAS mutation and older patient age; however, a meta-analysis did not demonstrate this association.	('mutation', 'Var', (68, 76))	('NRAS', 'Gene', (63, 67))	('patient', 'Species', '9606', (87, 94))	('NRAS', 'Gene', '4893', (63, 67))
40207	28787433	Other studies have similarly revealed that NRAS mutant melanomas have a propensity to develop on the extremities compared to the head and neck region.	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('mutant', 'Var', (48, 54))	('develop on the extremities', 'CPA', (86, 112))	('melanomas', 'Disease', 'MESH:D008545', (55, 64))	('NRAS', 'Gene', (43, 47))	('neck', 'cellular_component', 'GO:0044326', ('138', '142'))	('melanomas', 'Disease', (55, 64))	('NRAS', 'Gene', '4893', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
40208	28787433	Thomas et al's cohort study demonstrated an inverse relationship between NRAS mutant melanomas and scalp/neck location.	('melanomas', 'Disease', (85, 94))	('NRAS', 'Gene', '4893', (73, 77))	('inverse', 'NegReg', (44, 51))	('scalp', 'Disease', (99, 104))	('scalp', 'Disease', 'MESH:C538225', (99, 104))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('neck', 'cellular_component', 'GO:0044326', ('105', '109'))	('mutant', 'Var', (78, 84))	('NRAS', 'Gene', (73, 77))
40209	28787433	Furthermore, even when adjusted for other factors, BRAF mutant tumours had an increased risk of regional lymph node metastasis compared to satellite/in-transit metastasis as the site of first metastasis.	('tumours', 'Disease', (63, 70))	('mutant', 'Var', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('BRAF', 'Gene', '673', (51, 55))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('BRAF', 'Gene', (51, 55))	('tumours', 'Disease', 'MESH:D009369', (63, 70))	('regional lymph node metastasis', 'CPA', (96, 126))
40210	28787433	Our study has also demonstrated that patients with melanomas harbouring a BRAF mutation had increased odds of a tumour-positive SLNB.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('BRAF', 'Gene', (74, 78))	('patients', 'Species', '9606', (37, 45))	('BRAF', 'Gene', '673', (74, 78))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (79, 87))	('melanomas', 'Disease', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('tumour-positive SLNB', 'Disease', 'MESH:D009369', (112, 132))	('tumour-positive SLNB', 'Disease', (112, 132))
40211	28787433	The fact that BRAF mutation was associated on multivariate analysis with nodal disease, whether detected clinically or by a tumour-positive SLNB, suggests that this is likely to be a true association.	('nodal disease', 'Disease', 'MESH:D013611', (73, 86))	('nodal disease', 'Disease', (73, 86))	('mutation', 'Var', (19, 27))	('tumour-positive SLNB', 'Disease', 'MESH:D009369', (124, 144))	('tumour-positive SLNB', 'Disease', (124, 144))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('BRAF', 'Gene', '673', (14, 18))	('associated', 'Reg', (32, 42))	('BRAF', 'Gene', (14, 18))
40212	28787433	We have previously reported an association between BRAF mutation status and nodal involvement at diagnosis in a subset of the MMP cohort.	('nodal involvement', 'Disease', (76, 93))	('BRAF', 'Gene', '673', (51, 55))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('MMP', 'molecular_function', 'GO:0004235', ('126', '129'))
40213	28787433	Broekaert et al suggested that BRAF mutant tumours metastasise more frequently to regional lymph nodes, with BRAF wild-type tumours more likely to metastasise to non-nodal sites.	('BRAF', 'Gene', (109, 113))	('metastasise', 'CPA', (51, 62))	('BRAF', 'Gene', '673', (109, 113))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('BRAF', 'Gene', (31, 35))	('BRAF wild-type tumours', 'Disease', (109, 131))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Disease', 'MESH:D009369', (43, 50))	('tumours', 'Disease', (43, 50))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('mutant', 'Var', (36, 42))	('BRAF wild-type tumours', 'Disease', 'MESH:D009369', (109, 131))	('BRAF', 'Gene', '673', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
40214	28787433	In contrast, another study found that BRAF mutant melanomas were most likely to recur with distant metastasis as the site of first recurrence and that isolated regional lymph node metastasis was rare.	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('BRAF', 'Gene', '673', (38, 42))	('distant metastasis', 'CPA', (91, 109))	('mutant', 'Var', (43, 49))	('BRAF', 'Gene', (38, 42))	('melanomas', 'Disease', (50, 59))
40215	28787433	Our study indicated that BRAF mutation and NRAS mutation were associated with the subsequent development of CNS metastasis (aOR 4.65, 95% CI 2.23-9.69 P<0.001; aOR 4.03, 95% CI 1.72-9.44, P=0.001, respectively) and liver metastasis (aOR 3.09, 95% CI 1.49-6.42 P=0.003; aOR 3.17, 95% CI 1.32-7.58, P=0.01, respectively).	('aOR', 'molecular_function', 'GO:0033726', ('233', '236'))	('aOR', 'molecular_function', 'GO:0033726', ('124', '127'))	('associated', 'Reg', (62, 72))	('mutation', 'Var', (30, 38))	('NRAS', 'Gene', (43, 47))	('BRAF', 'Gene', '673', (25, 29))	('aOR', 'molecular_function', 'GO:0033726', ('269', '272'))	('CNS metastasis', 'Disease', (108, 122))	('mutation', 'Var', (48, 56))	('aOR', 'molecular_function', 'GO:0033726', ('160', '163'))	('BRAF', 'Gene', (25, 29))	('NRAS', 'Gene', '4893', (43, 47))	('liver metastasis', 'Disease', 'MESH:D009362', (215, 231))	('CNS metastasis', 'Disease', 'MESH:D009362', (108, 122))	('liver metastasis', 'Disease', (215, 231))
40216	28787433	Compared to BRAF/NRAS wild-type tumours, NRAS mutation was also associated with lung metastasis (aOR 2.44, 95% CI 1.21-4.93, P=0.013).	('associated', 'Reg', (64, 74))	('NRAS', 'Gene', '4893', (41, 45))	('aOR', 'molecular_function', 'GO:0033726', ('97', '100'))	('lung metastasis', 'Disease', (80, 95))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('type tumours', 'Disease', 'MESH:D009369', (27, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('NRAS', 'Gene', (17, 21))	('NRAS', 'Gene', (41, 45))	('type tumours', 'Disease', (27, 39))	('NRAS', 'Gene', '4893', (17, 21))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('mutation', 'Var', (46, 54))	('lung metastasis', 'Disease', 'MESH:D009362', (80, 95))
40217	28787433	Consistent with our finding of an association between liver metastasis and BRAF mutation, a small retrospective study found that melanomas harbouring BRAF mutations were more likely than BRAF wild-type tumours to metastasise to the liver.	('BRAF wild-type tumours', 'Disease', (187, 209))	('metastasise to the liver', 'CPA', (213, 237))	('mutations', 'Var', (155, 164))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('BRAF', 'Gene', '673', (187, 191))	('BRAF wild-type tumours', 'Disease', 'MESH:D009369', (187, 209))	('BRAF', 'Gene', '673', (75, 79))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (150, 154))	('liver metastasis', 'Disease', 'MESH:D009362', (54, 70))	('liver metastasis', 'Disease', (54, 70))	('melanomas', 'Disease', (129, 138))	('BRAF', 'Gene', (187, 191))
40219	28787433	Jakob et al study revealed that tumour mutation was associated with an increased risk of CNS involvement at diagnosis of stage IV disease (P=0.008), with melanomas harbouring BRAF and NRAS mutations more likely to have CNS involvement compared to BRAF/NRAS wild-type patients (24.1%, 23.1% and 12.4%, respectively).	('CNS involvement', 'Disease', (89, 104))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('melanomas', 'Disease', 'MESH:D008545', (154, 163))	('CNS', 'Disease', (219, 222))	('NRAS', 'Gene', (184, 188))	('patients', 'Species', '9606', (267, 275))	('melanomas', 'Disease', (154, 163))	('NRAS', 'Gene', '4893', (252, 256))	('mutations', 'Var', (189, 198))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('BRAF', 'Gene', '673', (247, 251))	('NRAS', 'Gene', '4893', (184, 188))	('tumour', 'Disease', (32, 38))	('BRAF', 'Gene', (247, 251))	('NRAS', 'Gene', (252, 256))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))
40234	28787433	The median time to the development of distant metastatic disease in patients with BRAF mutant tumours was shorter than in patients with BRAF/NRAS wild-type tumours; however, this difference was not statistically significant.	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('BRAF', 'Gene', '673', (136, 140))	('BRAF', 'Gene', (136, 140))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('NRAS', 'Gene', '4893', (141, 145))	('patients', 'Species', '9606', (68, 76))	('type tumours', 'Disease', (151, 163))	('tumours', 'Disease', (94, 101))	('shorter', 'NegReg', (106, 113))	('mutant', 'Var', (87, 93))	('patients', 'Species', '9606', (122, 130))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumours', 'Disease', 'MESH:D009369', (94, 101))	('NRAS', 'Gene', (141, 145))	('BRAF', 'Gene', '673', (82, 86))	('distant metastatic disease', 'CPA', (38, 64))	('tumours', 'Disease', (156, 163))	('type tumours', 'Disease', 'MESH:D009369', (151, 163))	('BRAF', 'Gene', (82, 86))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))
40240	28787433	To conclude, patients with BRAF mutant tumours have an increased risk of regional lymph node metastasis as the site of first metastasis and sentinel lymph node positivity.	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('patients', 'Species', '9606', (13, 21))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('tumours', 'Disease', (39, 46))	('BRAF', 'Gene', '673', (27, 31))	('mutant', 'Var', (32, 38))	('BRAF', 'Gene', (27, 31))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('regional lymph node metastasis', 'CPA', (73, 103))
40241	28787433	The presence of either a BRAF or NRAS mutation was associated with the development of CNS and liver metastasis and the presence of an NRAS mutation was associated with the development of lung metastasis.	('lung metastasis', 'Disease', 'MESH:D009362', (187, 202))	('associated with', 'Reg', (152, 167))	('lung metastasis', 'Disease', (187, 202))	('NRAS', 'Gene', (33, 37))	('NRAS', 'Gene', '4893', (33, 37))	('associated', 'Reg', (51, 61))	('BRAF', 'Gene', '673', (25, 29))	('liver metastasis', 'Disease', 'MESH:D009362', (94, 110))	('liver metastasis', 'Disease', (94, 110))	('NRAS', 'Gene', (134, 138))	('mutation', 'Var', (38, 46))	('BRAF', 'Gene', (25, 29))	('NRAS', 'Gene', '4893', (134, 138))
40249	32274887	The catalyst for the development of targeted therapy modalities was the identification of activating NRAS mutations and BRAF mutations in 1984 and 2002, respectively, which paved the way for molecular stratification of the melanoma patient population.	('melanoma', 'Disease', (223, 231))	('mutations', 'Var', (125, 134))	('NRAS', 'Gene', (101, 105))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('men', 'Species', '9606', (28, 31))	('BRAF', 'Gene', '673', (120, 124))	('NRAS', 'Gene', '4893', (101, 105))	('BRAF', 'Gene', (120, 124))	('activating', 'PosReg', (90, 100))	('mutations', 'Var', (106, 115))	('patient', 'Species', '9606', (232, 239))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
40250	32274887	Approximately 45%-50% of non-acral lentiginous (AL) cutaneous melanoma patients have tumors that harbor activating BRAF mutations, with a single amino acid substitution of valine for glutamic acid at codon 600 (V600E) occurring in 90% of cases (Figure 1a).	('BRAF', 'Gene', '673', (115, 119))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('BRAF', 'Gene', (115, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('patients', 'Species', '9606', (71, 79))	('valine for glutamic acid at codon 600', 'Mutation', 'rs113488022', (172, 209))	('V600E', 'Mutation', 'rs113488022', (211, 216))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('AL', 'Chemical', '-', (48, 50))	('activating', 'PosReg', (104, 114))	('V600E', 'Var', (211, 216))	('mutations', 'Var', (120, 129))	('non-acral lentiginous', 'Disease', (25, 46))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
40251	32274887	Activating NRAS mutations at codon 12, 13, or 61 are detectable in 15%-20% of non-AL cutaneous melanoma patients and serve as an independent predictor of worse patient overall survival.	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', '4893', (11, 15))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 103))	('AL cutaneous melanoma', 'Disease', (82, 103))	('mutations', 'Var', (16, 25))	('patient', 'Species', '9606', (104, 111))	('patient', 'Species', '9606', (160, 167))	('NRAS', 'Gene', (11, 15))	('patients', 'Species', '9606', (104, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))
40253	32274887	To date, it remains unclear whether the same melanoma cell can harbor both a BRAF and an NRAS mutation, or at the single-cell level, these mutations are indeed mutually exclusive.	('NRAS', 'Gene', '4893', (89, 93))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', (77, 81))	('NRAS', 'Gene', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('mutation', 'Var', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
40254	32274887	With discoveries revealing that ~70% of non-AL cutaneous melanomas contain mutations constitutively activating the mitogen-activated protein kinase (MAPK) pathway came intense development of inhibitors capable of targeting various nodes of the mitogen-activated protein kinase (MAPK) pathway (i.e., BRAF, MEK, and ERK inhibitors) that continues to date.	('ERK', 'Gene', '5594', (314, 317))	('ERK', 'molecular_function', 'GO:0004707', ('314', '317'))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('MEK', 'Gene', '5609', (305, 308))	('men', 'Species', '9606', (183, 186))	('ERK', 'Gene', (314, 317))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('BRAF', 'Gene', '673', (299, 303))	('MEK', 'Gene', (305, 308))	('BRAF', 'Gene', (299, 303))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (47, 66))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (47, 66))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 65))	('AL cutaneous melanoma', 'Disease', (44, 65))	('activating', 'PosReg', (100, 110))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))	('MAPK', 'molecular_function', 'GO:0004707', ('278', '282'))	('cutaneous melanomas', 'Disease', (47, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('mutations', 'Var', (75, 84))
40255	32274887	The first targeted therapy approved for the treatment of patients with BRAFV600E/K mutant melanoma was the small molecule inhibitor vemurafenib, an agent designed to have high specificity against the mutant V600E, V600K, V600D, and V600R forms of BRAF.	('melanoma', 'Disease', (90, 98))	('V600E', 'Var', (207, 212))	('V600D', 'Mutation', 'rs121913377', (221, 226))	('BRAFV600E', 'Mutation', 'rs113488022', (71, 80))	('men', 'Species', '9606', (49, 52))	('V600D', 'Var', (221, 226))	('V600R', 'Mutation', 'rs121913227', (232, 237))	('BRAF', 'Gene', '673', (71, 75))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('BRAF', 'Gene', (71, 75))	('V600K', 'Var', (214, 219))	('V600E/K', 'Mutation', 'rs113488022', (75, 82))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('V600E', 'Mutation', 'rs113488022', (207, 212))	('patients', 'Species', '9606', (57, 65))	('BRAF', 'Gene', '673', (247, 251))	('vemurafenib', 'Chemical', 'MESH:D000077484', (132, 143))	('BRAF', 'Gene', (247, 251))	('V600R', 'Var', (232, 237))	('V600K', 'Mutation', 'rs121913227', (214, 219))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
40259	32274887	For patients with wild-type BRAF, treatment with BRAF inhibitors that specifically target V600E/K mutant BRAF may increase melanoma aggressiveness due to the paradoxical activation of wild-type BRAF and downstream MAPK pathway signaling.	('melanoma aggressiveness', 'Disease', (123, 146))	('aggressiveness', 'Phenotype', 'HP:0000718', (132, 146))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('MAPK', 'molecular_function', 'GO:0004707', ('214', '218'))	('V600E', 'SUBSTITUTION', 'None', (90, 95))	('activation', 'PosReg', (170, 180))	('patients', 'Species', '9606', (4, 12))	('increase', 'PosReg', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('BRAF', 'Gene', '673', (28, 32))	('men', 'Species', '9606', (39, 42))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', '673', (194, 198))	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', (194, 198))	('V600E', 'Var', (90, 95))	('BRAF', 'Gene', '673', (49, 53))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (123, 146))	('BRAF', 'Gene', (49, 53))
40288	32274887	A 2009 SEER study found the overall incidence rates of AL melanoma were similar between non-Hispanic Whites and Blacks; however, Hispanic Whites have statistically higher incidence rates relative to non-Hispanic Whites.	('AL melanoma', 'Disease', 'MESH:D009101', (55, 66))	('higher', 'PosReg', (164, 170))	('Hispanic Whites', 'Var', (129, 144))	('AL melanoma', 'Disease', (55, 66))	('incidence', 'MPA', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
40295	32274887	BRAF mutations in are found in 1 in every 5 Al melanoma patients, leaving ~80% ineligible to receive BRAF inhibitor and combination BRAF/MEK inhibitor strategies (; Figure 1b).	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', (132, 136))	('patients', 'Species', '9606', (56, 64))	('MEK', 'Gene', (137, 140))	('MEK', 'Gene', '5609', (137, 140))	('mutations in', 'Var', (5, 17))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', '673', (132, 136))
40297	32274887	80% of AL melanomas display genetic aberrations of cyclin-dependent kinase 4/6 (CDK4/6) pathway-related genes (i.e., amplification of CDK4 and CCND1, and/or loss of CDK2NA), representing the most frequent copy number alteration detected.	('CDK4', 'Gene', (80, 84))	('CDK', 'molecular_function', 'GO:0004693', ('165', '168'))	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))	('CDK4', 'Gene', '1019', (80, 84))	('CCND1', 'Gene', '595', (143, 148))	('CDK2NA', 'Gene', '1017', (165, 171))	('CDK', 'molecular_function', 'GO:0004693', ('80', '83'))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('AL melanomas', 'Disease', (7, 19))	('CDK2NA', 'Gene', (165, 171))	('CDK4', 'Gene', '1019', (134, 138))	('CDK4', 'Gene', (134, 138))	('CCND1', 'Gene', (143, 148))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('loss', 'NegReg', (157, 161))	('AL melanomas', 'Disease', 'MESH:D009101', (7, 19))	('amplification', 'Var', (117, 130))
40298	32274887	Additionally, activating KIT mutations are present in ~6% of cases.	('KIT', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))	('activating', 'PosReg', (14, 24))	('KIT', 'Gene', '3815', (25, 28))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))
40299	32274887	AL melanoma displays similar incidence of NRAS mutations as non-AL cutaneous melanoma, detectable in 15%-28% of AL melanoma patients, and NRAS mutations are an independent prognostic factor of worse overall survival.	('NRAS', 'Gene', '4893', (42, 46))	('AL melanoma', 'Disease', 'MESH:D009101', (112, 123))	('NRAS', 'Gene', '4893', (138, 142))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 85))	('AL cutaneous melanoma', 'Disease', (64, 85))	('AL melanoma', 'Disease', 'MESH:D009101', (0, 11))	('mutations', 'Var', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('AL melanoma', 'Disease', (112, 123))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('AL melanoma', 'Disease', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('NRAS', 'Gene', (42, 46))	('patients', 'Species', '9606', (124, 132))	('mutations', 'Var', (143, 152))	('NRAS', 'Gene', (138, 142))
40305	32274887	Although AL melanoma patients with Kit mutations can be treated with a KIT inhibitor per National Comprehensive Cancer Network (NCCN) guidelines, resistance mechanisms that reactivate downstream MAPK and PI3K pathway signaling have been suggested to blunt long-term durability (Table 1).	('KIT', 'Gene', '3815', (71, 74))	('patients', 'Species', '9606', (21, 29))	('AL melanoma', 'Disease', (9, 20))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reactivate', 'NegReg', (173, 183))	('PI3K', 'molecular_function', 'GO:0016303', ('204', '208'))	('mutations', 'Var', (39, 48))	('blunt', 'NegReg', (250, 255))	('AL melanoma', 'Disease', 'MESH:D009101', (9, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('195', '199'))	('Cancer', 'Disease', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('KIT', 'Gene', (71, 74))	('Kit', 'Gene', (35, 38))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('Kit', 'Gene', '3815', (35, 38))	('PI3K pathway signaling', 'Pathway', (204, 226))
40306	32274887	Due to the high percentage of AL melanoma tumors with CDK4/6-pathway aberrations, CDK4/6 inhibition represents one of the most promising targeted therapy strategies for AL melanomas clinically (NCT03454919).	('AL melanomas', 'Disease', (169, 181))	('aberrations', 'Var', (69, 80))	('AL melanoma tumors', 'Disease', (30, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('AL melanomas', 'Disease', 'MESH:D009101', (169, 181))	('CDK4', 'Gene', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('CDK4', 'Gene', '1019', (82, 86))	('CDK4', 'Gene', (82, 86))	('CDK4', 'Gene', '1019', (54, 58))	('CDK', 'molecular_function', 'GO:0004693', ('54', '57'))	('AL melanoma tumors', 'Disease', 'MESH:D009101', (30, 48))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))
40316	32274887	This is in contrast to non-AL cutaneous melanomas where <10% of BRAF mutations are outside of the V600 codon, and more closely resembles the high prevalence of non-V600 mutations found in 48% of lung adenocarcinomas.	('mutations', 'Var', (69, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (195, 215))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (195, 215))	('cutaneous melanomas', 'Disease', (30, 49))	('BRAF', 'Gene', '673', (64, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('BRAF', 'Gene', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (30, 49))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 49))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 48))	('AL cutaneous melanoma', 'Disease', (27, 48))	('lung adenocarcinomas', 'Disease', (195, 215))
40317	32274887	A closer analysis of the most common non-V600 mutations reveals (a) a difference between the frequency of mutations on D594, G469, and K601 between non-AL cutaneous melanomas and MMs, and (b) convergence in the non-V600 mutational landscape between MM and lung cancers where mutations are often associated with genotoxic agents.	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 173))	('AL cutaneous melanoma', 'Disease', (152, 173))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (155, 174))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (155, 174))	('lung cancers', 'Disease', 'MESH:D008175', (256, 268))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('lung cancers', 'Phenotype', 'HP:0100526', (256, 268))	('cutaneous melanomas', 'Disease', (155, 174))	('MMs', 'Disease', (179, 182))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('mutations', 'Var', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('lung cancers', 'Disease', (256, 268))	('D594', 'Var', (119, 123))	('G469', 'Var', (125, 129))	('K601', 'Var', (135, 139))
40319	32274887	There is also a divergence in the location of NRAS mutations between MM and cutaneous melanoma, with 54% located on codon 61 in MM versus 88% in cutaneous melanoma, and 46% located on codons 12 and 13 in MM versus 12% for cutaneous melanomas.	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', '4893', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (222, 241))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (222, 240))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (222, 241))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (222, 240))	('located', 'Reg', (173, 180))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('cutaneous melanomas', 'Disease', (222, 241))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('NRAS', 'Gene', (46, 50))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('cutaneous melanoma', 'Disease', (145, 163))	('melanomas', 'Phenotype', 'HP:0002861', (232, 241))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (145, 163))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 163))	('located', 'Reg', (105, 112))
40320	32274887	Approximately 7%-22% of MMs have v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) somatic mutations or amplifications.	('amplifications', 'Var', (122, 136))	('kit', 'Gene', (35, 38))	('kit', 'Gene', '3815', (35, 38))	('sarcoma', 'Disease', 'MESH:D012509', (64, 71))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('sarcoma', 'Disease', (64, 71))	('KIT', 'Gene', '3815', (96, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('MMs', 'Disease', (24, 27))	('KIT', 'Gene', (96, 99))
40321	32274887	MMs located in the genital area appear to be driven by mutations in SF3B1 which encodes the subunit 1 of splicing factor 3b, a component of the spliceosome that processes pre-mRNA into mature transcripts.	('splicing', 'biological_process', 'GO:0045292', ('105', '113'))	('SF3B1', 'Gene', (68, 73))	('mutations', 'Var', (55, 64))	('pre', 'molecular_function', 'GO:0003904', ('171', '174'))	('driven by', 'Reg', (45, 54))	('MMs', 'Disease', (0, 3))	('SF3B1', 'Gene', '23451', (68, 73))	('spliceosome', 'cellular_component', 'GO:0005681', ('144', '155'))
40322	32274887	A recent study analyzing the mutational landscape of MM identified IGF2R mutations in 31.7% of MM samples relative to 6.3% of SSM cases.	('SSM', 'cellular_component', 'GO:1990843', ('126', '129'))	('mutations', 'Var', (73, 82))	('IGF2R', 'Gene', '3482', (67, 72))	('IGF2R', 'Gene', (67, 72))
40328	32274887	Clinical trials targeting KIT with imatinib show no clear effect in unselected metastatic melanoma patient populations, but encouraging clinical benefit has been observed with KIT inhibition specifically in patients with melanomas harboring KIT mutations (not in patients whose melanoma harbor KIT amplification only; Table 1).	('KIT', 'Gene', '3815', (176, 179))	('melanoma', 'Disease', (90, 98))	('melanomas', 'Phenotype', 'HP:0002861', (221, 230))	('KIT', 'Gene', '3815', (294, 297))	('KIT', 'molecular_function', 'GO:0005020', ('294', '297'))	('patient', 'Species', '9606', (207, 214))	('inhibition', 'NegReg', (180, 190))	('melanoma', 'Phenotype', 'HP:0002861', (278, 286))	('melanoma', 'Disease', (278, 286))	('KIT', 'Gene', (241, 244))	('patient', 'Species', '9606', (263, 270))	('KIT', 'molecular_function', 'GO:0005020', ('241', '244'))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Disease', (221, 229))	('mutations', 'Var', (245, 254))	('melanoma harbor KIT', 'Disease', 'MESH:C537062', (278, 297))	('KIT', 'molecular_function', 'GO:0005020', ('26', '29'))	('KIT', 'Gene', (26, 29))	('imatinib', 'Chemical', 'MESH:D000068877', (35, 43))	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('melanoma harbor KIT', 'Disease', (278, 297))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanomas', 'Disease', 'MESH:D008545', (221, 230))	('KIT', 'Gene', (176, 179))	('KIT', 'Gene', (294, 297))	('melanomas', 'Disease', (221, 230))	('KIT', 'Gene', '3815', (241, 244))	('patient', 'Species', '9606', (99, 106))	('melanoma', 'Disease', 'MESH:D008545', (278, 286))	('patients', 'Species', '9606', (207, 215))	('KIT', 'Gene', '3815', (26, 29))	('patients', 'Species', '9606', (263, 271))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
40329	32274887	These data support the practice of determining KIT mutational status for MM patients to have a higher chance of receiving additional clinical benefit.	('patients', 'Species', '9606', (76, 84))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('mutational status', 'Var', (51, 68))	('KIT', 'Gene', '3815', (47, 50))	('KIT', 'Gene', (47, 50))
40331	32274887	For the relatively small number of MM patients whose tumors harbor BRAF mutations (relative to the ~50% in non-AL cutaneous melanoma patients), treatment with combination BRAF inhibitor and MEK inhibitor therapy is available.	('mutations', 'Var', (72, 81))	('AL cutaneous melanoma', 'Disease', 'MESH:C562393', (111, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('BRAF', 'Gene', '673', (67, 71))	('tumors harbor BRAF', 'Disease', (53, 71))	('men', 'Species', '9606', (149, 152))	('BRAF', 'Gene', (67, 71))	('patients', 'Species', '9606', (133, 141))	('BRAF', 'Gene', '673', (171, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors harbor BRAF', 'Disease', 'MESH:C537062', (53, 71))	('BRAF', 'Gene', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('MEK', 'Gene', (190, 193))	('patients', 'Species', '9606', (38, 46))	('AL cutaneous melanoma', 'Disease', (111, 132))	('MEK', 'Gene', '5609', (190, 193))
40347	32274887	In contrast, the main drivers for UM are activating mutations of guanine nucleotide-binding protein G (GNAQ/11), splicing factor 3B subunit 1 (SF3B1), eukaryotic translation initiation factor (EIF1AX), and inactivating mutations of the tumor suppressor BRCA-associated protein-1 (BAP1).	('translation initiation', 'biological_process', 'GO:0006413', ('162', '184'))	('EIF1AX', 'Gene', '1964', (193, 199))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('236', '252'))	('activating', 'PosReg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('73', '91'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('236', '252'))	('splicing factor 3B subunit 1', 'Gene', '23451', (113, 141))	('BRCA-associated protein-1', 'Gene', '8314', (253, 278))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('splicing', 'biological_process', 'GO:0045292', ('113', '121'))	('BAP1', 'Gene', '8314', (280, 284))	('SF3B1', 'Gene', (143, 148))	('protein', 'cellular_component', 'GO:0003675', ('269', '276'))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('BRCA-associated protein-1', 'Gene', (253, 278))	('mutations', 'Var', (52, 61))	('inactivating mutations', 'Var', (206, 228))	('GNAQ', 'Gene', '2776', (103, 107))	('EIF1AX', 'Gene', (193, 199))	('BAP1', 'Gene', (280, 284))	('splicing factor 3B subunit 1', 'Gene', (113, 141))	('SF3B1', 'Gene', '23451', (143, 148))	('GNAQ', 'Gene', (103, 107))	('tumor', 'Disease', (236, 241))
40349	32274887	GNAQ and GNA11 mutations are mutually exclusive, and thus in total are detected in 85%-94% of UM across all stages of disease (Figure 1d).	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('GNAQ', 'Gene', (0, 4))	('detected', 'Reg', (71, 79))	('GNA11', 'Gene', '2767', (9, 14))
40350	32274887	Due to their detection in benign uveal nevi, GNAQ/11 mutations are thought to be early mutational events.	('GNAQ', 'Gene', '2776', (45, 49))	('nevi', 'Phenotype', 'HP:0003764', (39, 43))	('GNAQ', 'Gene', (45, 49))	('mutations', 'Var', (53, 62))
40351	32274887	BAP1 (located on the short arm of chromosome 3) loss-of-function mutations are posited to serve as a predisposing factor for diverse hereditary cancers including mesothelioma, cutaneous melanoma, renal cell carcinoma, and UM.	('mesothelioma', 'Disease', (162, 174))	('short arm', 'Phenotype', 'HP:0009824', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (162, 174))	('BAP1', 'Gene', (0, 4))	('chromosome', 'cellular_component', 'GO:0005694', ('34', '44'))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('hereditary cancers', 'Disease', (133, 151))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('hereditary cancers', 'Disease', 'MESH:D009369', (133, 151))	('loss-of-function', 'NegReg', (48, 64))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('cutaneous melanoma', 'Disease', (176, 194))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (176, 194))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (176, 194))	('renal cell carcinoma', 'Disease', (196, 216))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('BAP1', 'Gene', '8314', (0, 4))	('mutations', 'Var', (65, 74))
40352	32274887	A recent comprehensive review identified that among 174 patients harboring germline BAP1 mutations, 130 developed tumors that were either UM (31% of cases), cutaneous melanoma (13% of cases), renal cell carcinoma (10% of cases), or MM (22% of cases).	('cutaneous melanoma', 'Disease', (157, 175))	('patients', 'Species', '9606', (56, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 175))	('germline', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('BAP1', 'Gene', '8314', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('developed', 'Reg', (104, 113))	('renal cell carcinoma', 'Disease', (192, 212))	('mutations', 'Var', (89, 98))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('BAP1', 'Gene', (84, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))
40353	32274887	In UM, loss of BAP1 returns melanoma cells to a more stem cell-like state as BAP1 is involved in melanocyte differentiation.	('loss', 'Var', (7, 11))	('returns melanoma', 'Disease', 'MESH:D008545', (20, 36))	('returns melanoma', 'Disease', (20, 36))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', '8314', (77, 81))	('melanocyte differentiation', 'biological_process', 'GO:0030318', ('97', '123'))	('BAP1', 'Gene', (15, 19))	('BAP1', 'Gene', (77, 81))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
40354	32274887	BAP1 is frequently mutated in metastasizing uveal melanomas, which supports the growing evidence that stem-like melanoma cell states drive elements of the metastatic cascade.	('uveal melanomas', 'Phenotype', 'HP:0007716', (44, 59))	('men', 'Species', '9606', (142, 145))	('BAP1', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('metastasizing uveal melanomas', 'Disease', 'MESH:D009362', (30, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('mutated', 'Var', (19, 26))	('metastasizing uveal melanomas', 'Disease', (30, 59))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('BAP1', 'Gene', '8314', (0, 4))
40358	32274887	UM patients that possess GNAQ or GNA11 mutations can be treated in clinical trials with targeted therapy approaches specific for the MAPK pathway (i.e., MEK inhibitor, ERK inhibitor) as these tumors display elevated MAPK activity.	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('tumors', 'Disease', (192, 198))	('ERK', 'Gene', '5594', (168, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('MEK', 'Gene', (153, 156))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('GNA11', 'Gene', '2767', (33, 38))	('mutations', 'Var', (39, 48))	('ERK', 'Gene', (168, 171))	('GNAQ', 'Gene', '2776', (25, 29))	('elevated', 'PosReg', (207, 215))	('ERK', 'molecular_function', 'GO:0004707', ('168', '171'))	('GNAQ', 'Gene', (25, 29))	('patients', 'Species', '9606', (3, 11))	('MEK', 'Gene', '5609', (153, 156))	('GNA11', 'Gene', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('MAPK', 'Enzyme', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
40361	32274887	Additionally, preclinical studies identified that targeting the PI3K/AKT pathway (in GNAQ and GNA11 mutant xenograft models) in combination with a MEK inhibitor may be an effective treatment strategy for patients with GNAQ or GNA11 mutations; however, clinical trials using this combination have stopped due to low response rates and high toxicity (; Table 1).	('men', 'Species', '9606', (186, 189))	('mutations', 'Var', (232, 241))	('GNAQ', 'Gene', '2776', (85, 89))	('GNA11', 'Gene', (94, 99))	('patients', 'Species', '9606', (204, 212))	('AKT', 'Gene', (69, 72))	('MEK', 'Gene', '5609', (147, 150))	('GNA11', 'Gene', (226, 231))	('GNAQ', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (218, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('MEK', 'Gene', (147, 150))	('GNAQ', 'Gene', (218, 222))	('toxicity', 'Disease', 'MESH:D064420', (339, 347))	('AKT', 'Gene', '207', (69, 72))	('GNA11', 'Gene', '2767', (94, 99))	('mutant', 'Var', (100, 106))	('toxicity', 'Disease', (339, 347))	('GNA11', 'Gene', '2767', (226, 231))
40363	32274887	For UM with BAP1 mutations, it has been shown preclinically that treatment with a histone deacetylase (HDAC) inhibitor could be beneficial.	('histone deacetylase', 'Gene', '9734', (82, 101))	('HDAC', 'Gene', '9734', (103, 107))	('histone deacetylase', 'Gene', (82, 101))	('men', 'Species', '9606', (70, 73))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('HDAC', 'Gene', (103, 107))
40364	32274887	Because BAP1 mutations are associated with loss of melanocytic differentiation, treatment with HDAC inhibitors (valproic acid) are postulated to inhibit the growth of uveal melanoma in vivo by inducing morphological differentiation.	('valproic acid', 'Chemical', 'MESH:D014635', (112, 125))	('inducing', 'PosReg', (193, 201))	('loss of melanocytic', 'Disease', (43, 62))	('loss of melanocytic', 'Disease', 'MESH:D009508', (43, 62))	('morphological differentiation', 'CPA', (202, 231))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('BAP1', 'Gene', '8314', (8, 12))	('HDAC', 'Gene', '9734', (95, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('growth', 'MPA', (157, 163))	('men', 'Species', '9606', (85, 88))	('uveal melanoma', 'Disease', (167, 181))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('HDAC', 'Gene', (95, 99))	('inhibit', 'NegReg', (145, 152))
40377	32274887	Activating BRAF mutations are detected in patients with NM at a slightly lower frequency relative to SSM, with 43%-47% of patients possessing mutations mostly (88% of cases) in V600E (; Figure 1e).	('Activating', 'PosReg', (0, 10))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('patients', 'Species', '9606', (122, 130))	('V600E', 'Var', (177, 182))	('SSM', 'cellular_component', 'GO:1990843', ('101', '104'))	('BRAF', 'Gene', '673', (11, 15))	('patients', 'Species', '9606', (42, 50))	('BRAF', 'Gene', (11, 15))
40378	32274887	A recent study identified evidence that BRAFV600E expression may serve as a prognostic marker in primary NM associated with ulceration and reduced survival.	('primary NM associated', 'Disease', (97, 118))	('BRAFV600E', 'Mutation', 'rs113488022', (40, 49))	('reduced', 'NegReg', (139, 146))	('ulceration', 'Disease', (124, 134))	('survival', 'MPA', (147, 155))	('BRAFV600E', 'Var', (40, 49))
40380	32274887	Activating NRAS mutations are detected at a significantly elevated frequency in NM relative to SSM in 30%-33% vs. 19% of cases, respectively.	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', '4893', (11, 15))	('mutations', 'Var', (16, 25))	('SSM', 'cellular_component', 'GO:1990843', ('95', '98'))	('NRAS', 'Gene', (11, 15))
40397	32274887	The frequency of activating BRAF mutations in LM is unclear, with reports finding 16.7%-53.4% of LM patients harboring BRAF mutations (; Figure 1f).	('BRAF', 'Gene', '673', (28, 32))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('patients', 'Species', '9606', (100, 108))	('BRAF', 'Gene', (28, 32))
40399	32274887	In a Greek cohort, 16.7% of LM melanoma cases expressed BRAF mutations and 50% of LM cases in a Japanese cohort expressed BRAF mutations.	('LM melanoma', 'Disease', 'MESH:D008545', (28, 39))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', '673', (122, 126))	('mutations', 'Var', (61, 70))	('BRAF', 'Gene', (122, 126))	('LM melanoma', 'Disease', (28, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BRAF', 'Gene', (56, 60))
40400	32274887	When BRAF mutations are present, the V600K substitution is frequently observed (~77%) relative to the V600E (~23%) as observed in SSM, in this small set of 13 LM patient tumor samples.	('BRAF', 'Gene', '673', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('BRAF', 'Gene', (5, 9))	('V600K', 'Var', (37, 42))	('SSM', 'Disease', (130, 133))	('tumor', 'Disease', (170, 175))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('SSM', 'cellular_component', 'GO:1990843', ('130', '133'))	('V600K', 'Mutation', 'rs121913227', (37, 42))	('patient', 'Species', '9606', (162, 169))
40402	32274887	Activating NRAS mutations have been reported to occur in ~8.1%-16% of LM cases.	('NRAS', 'Gene', '4893', (11, 15))	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))
40426	33718105	However, existing markers such as S100 protein, BRAF, and NRAS mutation have hints on the diagnosis and prognosis of patients.	('NRAS', 'Gene', '4893', (58, 62))	('S100', 'Gene', '6285', (34, 38))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('S100', 'Gene', (34, 38))	('mutation', 'Var', (63, 71))	('patients', 'Species', '9606', (117, 125))	('BRAF', 'Gene', '673', (48, 52))	('BRAF', 'Gene', (48, 52))	('NRAS', 'Gene', (58, 62))
40431	33718105	The absence of tumor antigens, antigen presentation defects, mismatch repair deficiency, overall mutational load, neoantigen load, PD-L1 levels, intestinal microbiota, etc.	('defects', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('deficiency', 'NegReg', (77, 87))	('PD-L1', 'Gene', '29126', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('antigen presentation', 'MPA', (31, 51))	('mutational', 'Var', (97, 107))	('tumor', 'Disease', (15, 20))	('absence', 'NegReg', (4, 11))	('mismatch repair', 'biological_process', 'GO:0006298', ('61', '76'))	('neoantigen load', 'MPA', (114, 129))	('antigen presentation', 'biological_process', 'GO:0019882', ('31', '51'))	('mismatch repair', 'Protein', (61, 76))	('PD-L1', 'Gene', (131, 136))
40444	33718105	RNA-seq and sample profiles used for identification of BTLA expression and prognostic value [GSE65904, GSE53118, GSE98394 ], validation of BTLA predictive value in metastatic melanoma patients treated with the anti-PD-1 agent [GSE91061 and Liu et al.	('GSE53118', 'Var', (103, 111))	('patients', 'Species', '9606', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('[GSE65904', 'Var', (92, 101))	('melanoma', 'Disease', (175, 183))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
40445	33718105	], and MAGE-A3 blocker [GSE35640 ] were obtained from the Gene Expression Omnibus (GEO) database.	('[GSE35640 ]', 'Var', (23, 34))	('MAGE-A3', 'Gene', (7, 14))	('MAGE-A3', 'Gene', '4102', (7, 14))	('Gene Expression', 'biological_process', 'GO:0010467', ('58', '73'))
40474	33718105	There was no significant association between BTLA expression and OS in primary melanoma, whereas high BTLA expression was associated with better OS in metastatic melanoma ( Figure 3A ).	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('BTLA', 'Gene', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('high', 'Var', (97, 101))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
40496	33718105	In primary SKCM, M0 macrophage, M1 macrophage, M2 macrophage, myeloid activated dendrite cells, NK cells, and CD8+ T cells showed a higher proportion in the BTLAhigh group than in the low BTLAlow group ( Figures 6A, B ).	('higher', 'PosReg', (132, 138))	('dendrite', 'cellular_component', 'GO:0030425', ('80', '88'))	('SKCM', 'Chemical', '-', (11, 15))	('CD8', 'Gene', (110, 113))	('CD8', 'Gene', '925', (110, 113))	('BTLAhigh', 'Var', (157, 165))
40503	33718105	In both primary and metastatic SKCM samples, we observed that the BTLAhigh group had higher anti-cancer immune scores in the trafficking of T cells to tumors (step 4), infiltration of T cells into tumors (step 5), killing of cancer cells (step 7), except the recognition of cancer cells by T cells (step 6).	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (225, 231))	('killing', 'CPA', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', (97, 103))	('higher', 'PosReg', (85, 91))	('BTLAhigh', 'Var', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Disease', (151, 157))	('SKCM', 'Chemical', '-', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('infiltration', 'CPA', (168, 180))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('trafficking', 'MPA', (125, 136))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
40507	33718105	It seemed that high BTLA expression led to more recruitment of T cells in SKCM, especially in metastatic SKCM.	('high', 'Var', (15, 19))	('recruitment', 'MPA', (48, 59))	('more', 'PosReg', (43, 47))	('metastatic SKCM', 'Disease', (94, 109))	('SKCM', 'Chemical', '-', (74, 78))	('SKCM', 'Chemical', '-', (105, 109))	('BTLA', 'Protein', (20, 24))
40532	33718105	A previous study revealed that BTLA detected in epithelial ovarian carcinoma (EOC) tissues can predict poor outcomes of patients, and BTLA inhibitor combined with chemotherapy could enhance immune activation and produce effective anti-tumor effects.	('epithelial ovarian carcinoma', 'Disease', (48, 76))	('enhance', 'PosReg', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D010051', (48, 76))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('BTLA', 'Gene', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('immune', 'CPA', (190, 196))	('tumor', 'Disease', (235, 240))	('inhibitor', 'Var', (139, 148))	('patients', 'Species', '9606', (120, 128))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (59, 76))
40579	30591049	Mutated BRAFV600E represents a major target in the current therapeutic strategies, despite the fact that more than half of melanomas do not harbor this mutation.	('melanomas', 'Disease', (123, 132))	('BRAFV600E', 'Mutation', 'rs113488022', (8, 17))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('Mutated', 'Var', (0, 7))	('BRAFV600E', 'Gene', (8, 17))
40583	30591049	On the other hand, MMP-9 activation was associated with cancer growth and dissemination, its role in cutaneous melanoma was reported and its activation, mediated by NF-kappaB, was associated with the BRAFV600E mutation status.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('NF-kappaB', 'Gene', '4790', (165, 174))	('BRAFV600E', 'Mutation', 'rs113488022', (200, 209))	('associated', 'Reg', (180, 190))	('BRAFV600E mutation', 'Var', (200, 218))	('NF-kappaB', 'Gene', (165, 174))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('MMP-9', 'Gene', '4318', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MMP-9', 'molecular_function', 'GO:0004229', ('19', '24'))	('MMP-9', 'Gene', (19, 24))	('activation', 'PosReg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('associated', 'Reg', (40, 50))	('activation', 'PosReg', (141, 151))	('cancer', 'Disease', (56, 62))
40584	30591049	Another recent study reports the correlation of MMP-9 hypermethylation with its overexpression in melanoma indicating novel molecular mechanisms underlying the MMPs activity and their modulatory role in melanoma aggressiveness.	('overexpression', 'PosReg', (80, 94))	('MMP-9', 'Gene', '4318', (48, 53))	('melanoma aggressiveness', 'Disease', (203, 226))	('MMP-9', 'Gene', (48, 53))	('MMP-9', 'molecular_function', 'GO:0004229', ('48', '53'))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('hypermethylation', 'Var', (54, 70))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (212, 226))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma aggressiveness', 'Disease', 'MESH:D008545', (203, 226))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
40591	30591049	Moreover, a link between high levels of TNF-alpha and increased risk of tumor formation and development has been described in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('formation', 'biological_process', 'GO:0009058', ('78', '87'))	('tumor', 'Disease', (72, 77))	('TNF-alpha', 'Protein', (40, 49))	('high', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
40601	30591049	to bear or not a V600E BRAF mutation, alone or together with others), and also with the anatomical site where the primary tumor occurs or, in addition, with the immunological status of patients observed in different cases of patients receiving immunosuppressive therapies.	('patients', 'Species', '9606', (225, 233))	('V600E', 'Var', (17, 22))	('BRAF', 'Gene', '673', (23, 27))	('BRAF', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('patients', 'Species', '9606', (185, 193))	('V600E', 'Mutation', 'rs113488022', (17, 22))	('tumor', 'Disease', (122, 127))
40607	30591049	In detail, A375, Preyer, SK-MEL-30, MEWO, MEL501 and ME665 were propagated in complete Dulbecco's modified Eagle's medium (DMEM; Hyclone, South Logan, UT) supplemented with 10% fetal bovine serum (FBS, HyClone), 2 mM L-glutamine and 100 IU/ml penicillin/streptomycin (Invitrogen, Carlsbad, CA) in humidified 5% CO2 atmosphere, at 37  C for the specified time and, when required, under serum deprivation.	('streptomycin', 'Chemical', 'MESH:D013307', (254, 266))	('SK-MEL', 'Chemical', '-', (25, 31))	('L-glutamine', 'Chemical', 'MESH:D005973', (217, 228))	('ME665', 'Chemical', '-', (53, 58))	('A375', 'CellLine', 'CVCL:0132', (11, 15))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (87, 121))	('ME665', 'Var', (53, 58))	('FBS', 'Disease', (197, 200))	('penicillin', 'Chemical', 'MESH:D010406', (243, 253))	('bovine', 'Species', '9913', (183, 189))	('DMEM', 'Chemical', '-', (123, 127))	('FBS', 'Disease', 'MESH:D005198', (197, 200))
40641	30591049	1a).Different growth rates were observed in the 10 different cell lines; they were then clustered in three main groups, namely: high proliferation rate (SK-MEL-110, A375, A375M, MEL501), low proliferation rate (ME665, SK-MEL-30, Preyer, SK-MEL-28) and very low proliferation rate (Mel 397 and MeWo) cells (Fig.	('SK-MEL-28', 'Chemical', '-', (237, 246))	('A375', 'CellLine', 'CVCL:0132', (171, 175))	('ME665', 'Chemical', '-', (211, 216))	('SK-MEL', 'Chemical', '-', (237, 243))	('A375', 'CellLine', 'CVCL:0132', (165, 169))	('SK-MEL', 'Chemical', '-', (218, 224))	('ME665', 'Var', (211, 216))	('SK-MEL', 'Chemical', '-', (153, 159))	('low', 'NegReg', (257, 260))	('low proliferation rate', 'CPA', (187, 209))	('high proliferation rate', 'CPA', (128, 151))	('SK-MEL-30', 'Var', (218, 227))
40651	30591049	Since this assay allows to evaluate the stem traits of tumor cells that is related to resistance to extreme conditions and treatments, these experiments confirmed that the biological features of the selected cell lines, under our experimental conditions, were strikingly different, with the A375 showing a more aggressive phenotype compared to SK-MEL-28.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('A375', 'CellLine', 'CVCL:0132', (291, 295))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SK-MEL-28', 'Chemical', '-', (344, 353))	('A375', 'Var', (291, 295))	('tumor', 'Disease', (55, 60))	('aggressive phenotype', 'CPA', (311, 331))
40668	30591049	Namely, PDGF-BB, IL-1beta, IL-9, IP-10, IL-8, IL-1ra and G-CSF resulted significantly down-regulated in A375 as compared to SK-MEL-28, while IL-6, IL-12, EOTAXIN, RANTES, INF-gamma, TNF-alpha and VEGF were significantly up-regulated in A375 as compared to SK-MEL-28 (see Table 2).	('G-CSF', 'Gene', (57, 62))	('EOTAXIN', 'Gene', '6356', (154, 161))	('IL-6', 'Gene', '3569', (141, 145))	('IL-1', 'Gene', (46, 50))	('IL-1ra', 'Gene', (46, 52))	('A375', 'Var', (104, 108))	('IL-8', 'molecular_function', 'GO:0005153', ('40', '44'))	('IL-1', 'Gene', '3553', (46, 50))	('IL-6', 'molecular_function', 'GO:0005138', ('141', '145'))	('up-regulated', 'PosReg', (220, 232))	('IL-6', 'Gene', (141, 145))	('A375', 'CellLine', 'CVCL:0132', (236, 240))	('PDGF', 'molecular_function', 'GO:0005161', ('8', '12'))	('IL-8', 'Gene', (40, 44))	('A375', 'CellLine', 'CVCL:0132', (104, 108))	('IL-1ra', 'Gene', '3554', (46, 52))	('IL-1beta', 'Gene', '3553', (17, 25))	('down-regulated', 'NegReg', (86, 100))	('IL-1', 'Gene', (147, 151))	('IL-1ra', 'molecular_function', 'GO:0005152', ('46', '52'))	('IL-1', 'molecular_function', 'GO:0005149', ('17', '21'))	('IL-1', 'Gene', '3553', (147, 151))	('SK-MEL-28', 'Chemical', '-', (124, 133))	('IL-1beta', 'Gene', (17, 25))	('PDGF-BB', 'Gene', (8, 15))	('IL-1', 'Gene', (17, 21))	('IL-9', 'Gene', '3578', (27, 31))	('IL-8', 'Gene', '3576', (40, 44))	('EOTAXIN', 'Gene', (154, 161))	('IL-1', 'Gene', '3553', (17, 21))	('VEGF', 'Gene', '7422', (196, 200))	('IL-12', 'molecular_function', 'GO:0005143', ('147', '152'))	('IL-9', 'molecular_function', 'GO:0005140', ('27', '31'))	('SK-MEL-28', 'Chemical', '-', (256, 265))	('RANTES', 'Gene', (163, 169))	('RANTES', 'Gene', '6352', (163, 169))	('VEGF', 'Gene', (196, 200))	('IL-9', 'Gene', (27, 31))	('G-CSF', 'Gene', '1440', (57, 62))
40815	27184066	In melanoma cells, a reduced amount of HAS1 positivity was associated with decreased disease-specific survival (DSS) (p = 0.013; Fig.	('reduced', 'NegReg', (21, 28))	('disease-specific survival', 'CPA', (85, 110))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('HAS1', 'Gene', '3036', (39, 43))	('DSS', 'Gene', (112, 115))	('DSS', 'Gene', '5376', (112, 115))	('HAS1', 'Gene', (39, 43))	('melanoma', 'Disease', (3, 11))	('positivity', 'Var', (44, 54))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('decreased', 'NegReg', (75, 84))
40848	27184066	Silencing of versican increases cell proliferation and migration, whereas silencing of fibronectin increases drug sensitivity of melanoma cells.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('migration', 'CPA', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('drug sensitivity', 'Phenotype', 'HP:0020174', (109, 125))	('melanoma', 'Disease', (129, 137))	('fibronectin', 'Gene', (87, 98))	('silencing', 'Var', (74, 83))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('versican', 'Gene', (13, 21))	('fibronectin', 'Gene', '2335', (87, 98))	('increases', 'PosReg', (22, 31))	('Silencing', 'Var', (0, 9))	('increases', 'PosReg', (99, 108))	('cell proliferation', 'CPA', (32, 50))	('drug sensitivity', 'CPA', (109, 125))	('versican', 'Gene', '1462', (13, 21))
40853	27184066	The results suggest that loss of hyaluronan is associated with the acquisition of a motile, invasive tumor cell phenotype.	('loss', 'Var', (25, 29))	('hyaluronan', 'Protein', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('invasive tumor', 'Disease', 'MESH:D009369', (92, 106))	('invasive tumor', 'Disease', (92, 106))	('hyaluronan', 'Chemical', 'MESH:D006820', (33, 43))	('associated', 'Reg', (47, 57))	('motile', 'CPA', (84, 90))
40860	27184066	Moreover, our unpublished in vitro observations support the idea that hyaluronan overexpression tends to restrict melanoma cell growth, and melanoma cell lines (MV3 and C8161) overexpressing HAS3 show reduced cell motility and proliferation.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('cell motility', 'biological_process', 'GO:0048870', ('209', '222'))	('HAS3', 'Gene', '3038', (191, 195))	('cell motility', 'CPA', (209, 222))	('hyaluronan', 'Chemical', 'MESH:D006820', (70, 80))	('restrict', 'NegReg', (105, 113))	('reduced', 'NegReg', (201, 208))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('cell growth', 'biological_process', 'GO:0016049', ('123', '134'))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('hyaluronan', 'Protein', (70, 80))	('overexpressing', 'Var', (176, 190))	('HAS3', 'Gene', (191, 195))	('melanoma', 'Disease', (114, 122))
40876	27184066	In addition to CD44 shedding, the expression of certain CD44 variants has been shown to induce disease dissemination.	('CD44', 'Gene', '960', (15, 19))	('CD44', 'Gene', (56, 60))	('CD44', 'Gene', (15, 19))	('disease dissemination', 'CPA', (95, 116))	('induce', 'Reg', (88, 94))	('CD44', 'Gene', '960', (56, 60))	('variants', 'Var', (61, 69))
40877	27184066	Indeed, the expression of receptor variant CD44v6 associates strongly with brain metastases.	('brain metastases', 'Disease', (75, 91))	('CD44', 'Gene', '960', (43, 47))	('CD44', 'Gene', (43, 47))	('expression', 'MPA', (12, 22))	('variant', 'Var', (35, 42))	('brain metastases', 'Disease', 'MESH:D009362', (75, 91))
40882	27184066	In melanoma, hyaluronan may increase leukocyte infiltration, and therefore, the loss of hyaluronan could contribute to a reduction in TILs, thereby worsening the prognosis.	('hyaluronan', 'Chemical', 'MESH:D006820', (13, 23))	('increase leukocyte', 'Phenotype', 'HP:0001974', (28, 46))	('hyaluronan', 'Protein', (88, 98))	('worsening', 'Reg', (148, 157))	('loss', 'Var', (80, 84))	('hyaluronan', 'Protein', (13, 23))	('TILs', 'MPA', (134, 138))	('leukocyte infiltration', 'MPA', (37, 59))	('hyaluronan', 'Chemical', 'MESH:D006820', (88, 98))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('reduction', 'NegReg', (121, 130))	('increase', 'PosReg', (28, 36))
40919	25242350	Recent data suggests an increased frequency of c-KIT (CD117) aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not seem to be of pathogenetic importance.	('c-KIT', 'Gene', '3815', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (126, 144))	('mucosal melanomas', 'Disease', 'MESH:D008545', (76, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('mucosal melanomas', 'Disease', (76, 93))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('aberrations', 'Var', (61, 72))	('CD117', 'Gene', '3815', (54, 59))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (126, 145))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (126, 145))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('CD117', 'Gene', (54, 59))	('c-KIT', 'Gene', (103, 108))	('cutaneous melanomas', 'Disease', (126, 145))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('c-KIT', 'Gene', '3815', (103, 108))	('c-KIT', 'Gene', (47, 52))
40921	25242350	Downstream in the c-KIT signaling pathway, microphthalmia-associated transcription factor (MITF) is involved in melanocyte development, and amplification of this gene is found in approximately 15% to 20% of PMMs.	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('microphthalmia-associated transcription factor', 'Gene', (43, 89))	('c-KIT', 'Gene', (18, 23))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('microphthalmia', 'Phenotype', 'HP:0000568', (43, 57))	('MITF', 'Gene', '4286', (91, 95))	('MITF', 'Gene', (91, 95))	('c-KIT', 'Gene', '3815', (18, 23))	('microphthalmia-associated transcription factor', 'Gene', '4286', (43, 89))	('amplification', 'Var', (140, 153))	('transcription factor', 'molecular_function', 'GO:0000981', ('69', '89'))	('KIT signaling pathway', 'biological_process', 'GO:0038109', ('20', '41'))	('men', 'Species', '9606', (130, 133))
40922	25242350	The Genome-Wide Cancer Sequencing Program (the Sanger Institute's Cancer Genome Project) detected frequent mutations of B-type Raf (BRAF; proto-oncogene B-Raf) in 50% to 70% of cutaneous melanomas.	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cutaneous melanomas', 'Disease', (177, 196))	('Cancer', 'Disease', (66, 72))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanomas', 'Phenotype', 'HP:0002861', (187, 196))	('B-type Raf', 'Gene', '673', (120, 130))	('proto-oncogene B-Raf', 'Gene', '673', (138, 158))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('proto-oncogene B-Raf', 'Gene', (138, 158))	('Cancer', 'Disease', (16, 22))	('mutations', 'Var', (107, 116))	('B-type Raf', 'Gene', (120, 130))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (177, 196))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (177, 196))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (177, 195))
40923	25242350	Nearly 90% of reported BRAF alterations are oncogenic mutations that lie in the region that encodes the kinase domains, in which valine is replaced by glutamic acid at codon 600 (V600E) and usually occur in melanomas that develop in sites that are chronically sun exposed or have intermittent UV exposure compared with lesions that form in mucosal membranes or unexposed sites.	('BRAF', 'Gene', '673', (23, 27))	('alterations', 'Var', (28, 39))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanomas', 'Disease', 'MESH:D008545', (207, 216))	('BRAF', 'Gene', (23, 27))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('valine is replaced by glutamic acid at codon 600', 'Mutation', 'rs113488022', (129, 177))	('melanomas', 'Disease', (207, 216))	('occur', 'Reg', (198, 203))
40924	25242350	Conversely, BRAF mutations in PMMs are uncommon; mutations in this gene have been detected in <10% of PMMs.	('PMMs', 'Disease', (102, 106))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
40925	25242350	Alterations in the CDKN2A locus, encoding the tumor suppressor protein p16/INK4A, are frequently present in patients with hereditary cutaneous melanoma.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('INK4A', 'Gene', '1029', (75, 80))	('Alterations', 'Var', (0, 11))	('hereditary cutaneous melanoma', 'Disease', (122, 151))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('present', 'Reg', (97, 104))	('hereditary cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 151))	('patients', 'Species', '9606', (108, 116))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('CDKN2A', 'Gene', (19, 25))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('INK4A', 'Gene', (75, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))	('p16', 'Gene', (71, 74))	('tumor', 'Disease', (46, 51))	('CDKN2A', 'Gene', '1029', (19, 25))	('p16', 'Gene', '1029', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
40927	25242350	Somatic inactivation of INK4A by point mutation, deletion, or promoter hypermethylation is found in most sporadic melanomas and in 24% to 40% of melanoma-prone families.	('INK4A', 'Gene', (24, 29))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('promoter', 'MPA', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('inactivation', 'NegReg', (8, 20))	('INK4A', 'Gene', '1029', (24, 29))	('point mutation', 'Var', (33, 47))	('deletion', 'Var', (49, 57))	('melanomas', 'Disease', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
40928	25242350	Loss of p16 expression, CDKN2A mutations, and loss of heterozygosity are observed in up to 50% of PMMs.	('mutations', 'Var', (31, 40))	('p16', 'Gene', '1029', (8, 11))	('PMMs', 'Disease', (98, 102))	('CDKN2A', 'Gene', (24, 30))	('Loss', 'NegReg', (0, 4))	('CDKN2A', 'Gene', '1029', (24, 30))	('p16', 'Gene', (8, 11))	('expression', 'MPA', (12, 22))
40951	25242350	The comparative genomic hybridization profiles can help in diagnosing sinonasal PMMs because these tumors have consistent alterations: chromosome 1q is gained in all tumors, and gains of 6p and 8q are present in 93% and 57% of cases, respectively.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('chromosome', 'Var', (135, 145))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('135', '145'))	('sinonasal PMMs', 'Disease', (70, 84))	('gained', 'PosReg', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumors', 'Disease', (99, 105))
40995	25242350	Loree et al found that the 5-year overall survival (OS) rate of patients with T1 and T2 PMMs of the head and neck was 32% and for T3 and T4 tumors was 0% (p =.05).	('T2 PMMs', 'Var', (85, 92))	('OS', 'Chemical', '-', (52, 54))	('neck', 'cellular_component', 'GO:0044326', ('109', '113'))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('patients', 'Species', '9606', (64, 72))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
41063	25242350	Unlike cutaneous melanoma, PMMs have infrequent BRAF mutations and do not seem sensitive to therapies targeting BRAF.	('cutaneous melanoma', 'Disease', (7, 25))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (7, 25))	('PMMs', 'Disease', (27, 31))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('mutations', 'Var', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
41064	25242350	There is emerging evidence indicating that melanomas with c-KIT alterations of proven functional relevance may respond to c-KIT inhibitors, such as imatinib, sorafenib, dasatinib, or sunitinib.	('melanomas', 'Disease', (43, 52))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))	('c-KIT', 'Gene', (58, 63))	('c-KIT', 'Gene', '3815', (122, 127))	('imatinib', 'Chemical', 'MESH:D000068877', (148, 156))	('KIT', 'molecular_function', 'GO:0005020', ('124', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('respond', 'MPA', (111, 118))	('sunitinib', 'Chemical', 'MESH:D000077210', (183, 192))	('c-KIT', 'Gene', '3815', (58, 63))	('alterations', 'Var', (64, 75))	('melanomas', 'Disease', 'MESH:D008545', (43, 52))	('dasatinib', 'Chemical', 'MESH:D000069439', (169, 178))	('sorafenib', 'Chemical', 'MESH:D000077157', (158, 167))	('c-KIT', 'Gene', (122, 127))
41065	25242350	Some trials investigating the response to imatinib in patients with unresectable melanoma harboring somatic alterations of c-KIT are currently ongoing.	('c-KIT', 'Gene', (123, 128))	('imatinib', 'Chemical', 'MESH:D000068877', (42, 50))	('alterations', 'Var', (108, 119))	('patients', 'Species', '9606', (54, 62))	('c-KIT', 'Gene', '3815', (123, 128))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))
41066	25242350	In a published phase II study of imatinib in 43 patients with unresectable melanoma harboring mutations or amplification of c-KIT (including 11 patients with PMMs), imatinib was associated with a 23% objective response rate, suggesting a targeted treatment option for molecularly selected patients.	('amplification', 'Var', (107, 120))	('mutations', 'Var', (94, 103))	('objective', 'MPA', (200, 209))	('men', 'Species', '9606', (252, 255))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('c-KIT', 'Gene', (124, 129))	('patients', 'Species', '9606', (144, 152))	('melanoma', 'Disease', (75, 83))	('imatinib', 'Chemical', 'MESH:D000068877', (33, 41))	('patients', 'Species', '9606', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('c-KIT', 'Gene', '3815', (124, 129))	('imatinib', 'Var', (165, 173))	('imatinib', 'Chemical', 'MESH:D000068877', (165, 173))	('patients', 'Species', '9606', (289, 297))
41083	25242350	Finally, patients with lower Ki67 scores showed better survival than those with higher Ki67 scores; also, high survivin (an inhibitor of apoptosis) scores have correlated significantly with a poor prognosis.	('patients', 'Species', '9606', (9, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('high', 'Var', (106, 110))	('survivin', 'Protein', (111, 119))
41102	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))
41106	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))	('CTLA-4', 'Gene', '1493', (43, 49))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('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))
41175	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))	('CTLA-4', 'Gene', '1493', (218, 224))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (239, 257))	('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))
41205	29924232	Currently, it is recommended for lesions thicker than 0.76mm, with a mitotic index above1 and/or ulcerated lesions of 1 mm or larger and clinical examination with no evidence of lymph node enlargement.	('men', 'Species', '9606', (196, 199))	('lymph node enlargement', 'Disease', (178, 200))	('above1', 'Var', (83, 89))	('lymph node enlargement', 'Disease', 'MESH:D000072717', (178, 200))	('men', 'Species', '9606', (22, 25))	('mitotic index', 'CPA', (69, 82))	('lymph node enlargement', 'Phenotype', 'HP:0002716', (178, 200))
41295	28107203	Malignant transformation of tissue destroys its normal structure and leads to an immune response that includes infiltration of the tissue with immune cells that target tumor cells.	('destroys', 'NegReg', (35, 43))	('tumor', 'Disease', (168, 173))	('immune response', 'CPA', (81, 96))	('normal structure', 'MPA', (48, 64))	('leads to', 'Reg', (69, 77))	('Malignant transformation', 'Var', (0, 24))	('immune response', 'biological_process', 'GO:0006955', ('81', '96'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
41322	28107203	In details, patients with high P-LS also had fewer mitotic counts (<= 5 per 10 high-power fields) than patients with low P-LS (P = 0.01).	('patients', 'Species', '9606', (12, 20))	('fewer', 'NegReg', (45, 50))	('LS', 'Chemical', '-', (123, 125))	('mitotic counts', 'CPA', (51, 65))	('high P-LS', 'Var', (26, 35))	('patients', 'Species', '9606', (103, 111))	('LS', 'Chemical', '-', (33, 35))
41331	28107203	With respect to LS, the cases were divided into four subgroups (Supplementary Table 6 in Supplementary Data): Low LS in both compartments (92 cases, 51.9%), high LS only in the intratumoral compartment (9 cases, 5.1%), high LS only in the peritumoral compartment (58 cases, 32.8%), and high LS in both compartments (18 cases, 10.2%).	('LS', 'Chemical', '-', (162, 164))	('LS', 'Chemical', '-', (291, 293))	('LS', 'Chemical', '-', (16, 18))	('tumor', 'Disease', (182, 187))	('high LS', 'Var', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('LS', 'Chemical', '-', (224, 226))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('LS', 'Chemical', '-', (114, 116))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', (243, 248))
41333	28107203	In addition, these two subgroups with high P-LS tended toward lower mitotic counts (<= 5 per 10 high-power fields) compared with other subgroups (P = 0.06).	('lower', 'NegReg', (62, 67))	('high P-LS', 'Var', (38, 47))	('mitotic counts', 'CPA', (68, 82))	('LS', 'Chemical', '-', (45, 47))
41339	28107203	BRAF mutations were frequently observed in patients with NMs (P = 0.06, Table 1).	('NM', 'Phenotype', 'HP:0012058', (57, 59))	('patients', 'Species', '9606', (43, 51))	('NMs', 'Disease', (57, 60))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('observed', 'Reg', (31, 39))	('BRAF', 'Gene', (0, 4))
41340	28107203	In addition, BRAF mutations tended to be associated with the presence of peritumoral lymphocytes, although this was not significant (P = 0.13, Table 2).	('associated', 'Reg', (41, 51))	('BRAF', 'Gene', '673', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('BRAF', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('mutations', 'Var', (18, 27))
41344	28107203	Considering the group together, patients with peritumoral lymphocytes and a high P-LS tended to have longer DFS than those without peritumoral lymphocytes or low P-LS, but the differences were not significant (P = 0.07, Figure 3A and P = 0.14, Figure 3B, respectively).	('longer', 'PosReg', (101, 107))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('LS', 'Chemical', '-', (164, 166))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('LS', 'Chemical', '-', (83, 85))	('DFS', 'MPA', (108, 111))	('high', 'Var', (76, 80))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
41363	28107203	Finally, we interpret our findings to indicate that high LS is a favorable prognostic factor in ALM but not in other subtypes, although a previous study identified immune signatures associated with improved survival independent of subtypes of cutaneous melanoma.	('LS', 'Chemical', '-', (57, 59))	('ALM', 'Disease', (96, 99))	('survival', 'MPA', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('ALM', 'Phenotype', 'HP:0012060', (96, 99))	('improved', 'PosReg', (198, 206))	('cutaneous melanoma', 'Disease', (243, 261))	('high LS', 'Var', (52, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (243, 261))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (243, 261))
41366	28107203	For instance, the NRAS mutation has been more frequently detected in NM than in other subtypes.	('NRAS', 'Gene', '4893', (18, 22))	('mutation', 'Var', (23, 31))	('detected', 'Reg', (57, 65))	('NM', 'Phenotype', 'HP:0012058', (69, 71))	('NRAS', 'Gene', (18, 22))
41367	28107203	Activation of the oncogenic RAS pathway by the NRAS mutation suppresses the immune response by decreasing expression of major histocompatibility complex on tumor-cell surfaces and recruitment of regulatory T lymphocytes.	('immune response', 'biological_process', 'GO:0006955', ('76', '91'))	('decreasing', 'NegReg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('suppresses', 'NegReg', (61, 71))	('oncogenic RAS pathway', 'Pathway', (18, 39))	('NRAS', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('expression of major histocompatibility complex on', 'MPA', (106, 155))	('immune response', 'CPA', (76, 91))	('NRAS', 'Gene', '4893', (47, 51))	('mutation', 'Var', (52, 60))	('tumor', 'Disease', (156, 161))	('recruitment', 'CPA', (180, 191))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('120', '152'))
41368	28107203	In a large-series study performed in the United States and Australia, when the NRAS mutation was present in melanoma, the tumor infiltrating lymphocyte grade was lower.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('NRAS', 'Gene', '4893', (79, 83))	('melanoma', 'Disease', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lower', 'NegReg', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('tumor', 'Disease', (122, 127))	('NRAS', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
41369	28107203	To our knowledge, this study is the first report on the prognostic impact of high LS in ALM.	('high LS', 'Var', (77, 84))	('ALM', 'Disease', (88, 91))	('LS', 'Chemical', '-', (82, 84))	('ALM', 'Phenotype', 'HP:0012060', (88, 91))
41370	28107203	Although the mechanism is uncertain, we can assume that there was a lower incidence of the BRAF or NRAS mutations in these cases, which have poor prognoses.	('mutations', 'Var', (104, 113))	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', (91, 95))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))
41373	28107203	Unlike ALM, other cutaneous melanoma subtypes frequently present ultraviolet signatures and harbor mutations in BRAF, RAS, and NF.	('ultraviolet signatures', 'MPA', (65, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('mutations', 'Var', (99, 108))	('RAS', 'Gene', (118, 121))	('ALM', 'Phenotype', 'HP:0012060', (7, 10))	('cutaneous melanoma subtypes', 'Disease', 'MESH:C562393', (18, 45))	('cutaneous melanoma subtypes', 'Disease', (18, 45))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
41374	28107203	Mutations in these genes can facilitate escape from immune responses via several mechanisms: suppression of antigen expression, recruitment of regulatory T lymphocytes, and impaired dendritic cell maturation.	('impaired dendritic', 'Disease', (173, 191))	('impaired dendritic', 'Disease', 'MESH:D009422', (173, 191))	('suppression', 'NegReg', (93, 104))	('antigen', 'Protein', (108, 115))	('immune responses', 'CPA', (52, 68))	('Mutations', 'Var', (0, 9))	('recruitment', 'CPA', (128, 139))	('cell maturation', 'biological_process', 'GO:0048469', ('192', '207'))	('escape', 'CPA', (40, 46))
41375	28107203	In addition to immunoediting, NRAS mutations decrease Fas receptor expression and the susceptibility to Fas-mediated apoptosis in melanoma.	('NRAS', 'Gene', '4893', (30, 34))	('Fas receptor', 'Protein', (54, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('NRAS', 'Gene', (30, 34))	('decrease', 'NegReg', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('expression', 'MPA', (67, 77))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('mutations', 'Var', (35, 44))
41380	28107203	However, BRAF mutations tended to be associated with the presence of peritumoral lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('BRAF', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('associated', 'Reg', (37, 47))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
41381	28107203	According to previous studies, cutaneous melanomas with mutations in RAS had less lymphocytic infiltration than those with the BRAF mutation.	('lymphocytic infiltration', 'CPA', (82, 106))	('mutations', 'Var', (56, 65))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (31, 50))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (31, 50))	('RAS', 'Gene', (69, 72))	('BRAF', 'Gene', '673', (127, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('BRAF', 'Gene', (127, 131))	('less', 'NegReg', (77, 81))	('cutaneous melanomas', 'Disease', (31, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))
41419	29673314	For instance, the mutation rate at TC* sites is particularly high in skin cutaneous melanoma, with the largest proportion of mutations at TCC positions of all cancer types.	('cancer', 'Disease', (159, 165))	('TCC', 'cellular_component', 'GO:0005579', ('138', '141'))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 92))	('skin cutaneous melanoma', 'Disease', (69, 92))	('high', 'Reg', (61, 65))	('mutation', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))
41421	29673314	In colorectal cancer, we observe a high proportion of mutations at TCG and TCT sites.	('TCG', 'Chemical', '-', (67, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
41422	29673314	These can be attributed to mutations in the POLE gene that cause DNA polymerase epsilon deficiency: we find an increased overall mutation rate, a very high proportion of T[C >A]T and T[C >T]G mutations and a high contribution of COSMIC signature 10 in six out of 42 colon cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('colon cancer', 'Disease', 'MESH:D015179', (266, 278))	('increased', 'PosReg', (111, 120))	('epsilon deficiency', 'Disease', (80, 98))	('epsilon deficiency', 'Disease', 'MESH:D001321', (80, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (266, 278))	('T[C >A]', 'Var', (170, 177))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('colon cancer', 'Disease', (266, 278))	('mutation', 'MPA', (129, 137))	('T[C >T]G mutations', 'Var', (183, 201))
41423	29673314	Five of those (and three of the other colon cancer samples) have a nonsynonymous mutation in POLE and one of them in addition in POLD1, which encodes the DNA polymerase delta (Additional file 1: Figure S1).	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('nonsynonymous mutation', 'Var', (67, 89))	('POLE', 'Gene', (93, 97))	('DNA polymerase delta', 'Gene', '5424', (154, 174))	('POLD1', 'Gene', (129, 134))	('POLD1', 'Gene', '5424', (129, 134))	('DNA polymerase delta', 'Gene', (154, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('colon cancer', 'Disease', 'MESH:D015179', (38, 50))	('colon cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
41425	29673314	Coding regions tend to have fewer mutations in all cancer types.	('fewer', 'NegReg', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (34, 43))
41445	29673314	Here, the observed mutations are more spread than in KRAS, but they mainly occur in highly conserved exonic regions, where the neutral model predicts a low mutation rate.	('KRAS', 'Gene', '3845', (53, 57))	('occur', 'Reg', (75, 80))	('KRAS', 'Gene', (53, 57))	('mutations', 'Var', (19, 28))
41450	29673314	In breast cancer, head and neck squamous cell carcinoma, kidney chromophobe and thyroid carcinoma, this difference is much more pronounced at A:T positions than at G:C positions, but there is no general pattern with respect to the mutation type.	('A:T positions', 'Var', (142, 155))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('neck', 'cellular_component', 'GO:0044326', ('27', '31'))	('thyroid carcinoma', 'Disease', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (18, 55))	('kidney chromophobe', 'Disease', (57, 75))	('kidney chromophobe', 'Disease', 'MESH:D000238', (57, 75))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (80, 97))
41451	29673314	2c; later replicating regions have more mutations), but the regression coefficient varies significantly between the different cancer types and the mutation types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('varies', 'Reg', (83, 89))	('mutations', 'Var', (40, 49))
41455	29673314	The most extreme example is the probability of a C > T mutation in highly expressed regions in melanoma, which is only one fifth of the probability in lowly expressed ones (Fig.	('C > T mutation', 'Var', (49, 63))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))
41458	29673314	We find that the mutation rates differ between the different types of mutations, but also between the specific contexts that we consider: CpG, to capture the pattern of spontaneous deamination, and TpCp[AT], to capture the APOBEC signature.	('mutations', 'Var', (70, 79))	('TpCp', 'Gene', (198, 202))	('APOBEC', 'MPA', (223, 229))	('spontaneous deamination', 'MPA', (169, 192))	('TpCp', 'Gene', '8030', (198, 202))	('APOBEC', 'cellular_component', 'GO:0030895', ('223', '229'))	('AT', 'Disease', 'None', (203, 205))
41459	29673314	We find that the C > T mutation rate is higher in CpG sites than in other sites in all cancer types.	('cancer', 'Disease', (87, 93))	('CpG', 'Disease', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'Reg', (40, 46))	('C > T mutation', 'Var', (17, 31))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
41460	29673314	In skin cutaneous melanoma, we also observe elevated mutation rate for CC context, which is related to the elevated CC > TT mutation rate due to UV light.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 26))	('mutation', 'Var', (53, 61))	('elevated', 'PosReg', (44, 52))	('skin cutaneous melanoma', 'Disease', (3, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
41461	29673314	We observe elevated rates of mutations that fit the APOBEC pattern in breast cancer, bladder urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma and skin cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('lung squamous cell carcinoma', 'Disease', (154, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (115, 152))	('bladder urothelial carcinoma', 'Disease', (85, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('neck', 'cellular_component', 'GO:0044326', ('124', '128'))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (187, 210))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (85, 113))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('skin cutaneous melanoma', 'Disease', (187, 210))	('APOBEC', 'cellular_component', 'GO:0030895', ('52', '58'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))
41472	29673314	Since TCR is a subpathway of nucleotide excision repair (NER), it is expected to act on helix-distorting mutations like for example the well-known UV light induced CC > TT mutations in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('mutations', 'Var', (172, 181))	('TCR', 'biological_process', 'GO:0006283', ('6', '9'))	('NER', 'biological_process', 'GO:0006289', ('57', '60'))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('29', '55'))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('TCR', 'cellular_component', 'GO:0042101', ('6', '9'))	('melanoma', 'Disease', (185, 193))
41473	29673314	Thus, the cancer specific differences that we see might be explained by varying effectiveness of TCR, but also by different proportions of mutations that create bulky distortions.	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('TCR', 'cellular_component', 'GO:0042101', ('97', '100'))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('TCR', 'biological_process', 'GO:0006283', ('97', '100'))	('cancer', 'Disease', (10, 16))
41474	29673314	For example, the rate of C > T mutations is further decreased in highly expressed regions in melanoma than the other mutation types.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('decreased', 'NegReg', (52, 61))	('C > T mutations', 'Var', (25, 40))
41481	29673314	Known somatic or germline mutations that are associated with specific mutational processes or repair pathways can also be used as explanatory variables, e. g. a germline deletion of APOBEC3B that fuses APOBEC3A with the 3' UTR of APOBEC3B has been found to be associated with an increased number of APOBEC-type mutations.	('APOBEC3A', 'Gene', '200315', (202, 210))	('APOBEC', 'cellular_component', 'GO:0030895', ('202', '208'))	('APOBEC', 'cellular_component', 'GO:0030895', ('299', '305'))	('APOBEC', 'cellular_component', 'GO:0030895', ('230', '236'))	('APOBEC3B', 'Gene', (182, 190))	('APOBEC3B', 'Gene', (230, 238))	('APOBEC-type mutations', 'Disease', (299, 320))	('APOBEC3B', 'Gene', '9582', (230, 238))	('APOBEC3B', 'Gene', '9582', (182, 190))	('APOBEC3A', 'Gene', (202, 210))	('associated', 'Reg', (260, 270))	('APOBEC', 'cellular_component', 'GO:0030895', ('182', '188'))	('deletion', 'Var', (170, 178))
41514	21698147	Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('deregulation', 'Var', (14, 26))	('Dicer', 'Gene', '23405', (30, 35))	('Dicer', 'Gene', (30, 35))	('patients', 'Species', '9606', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
41516	21698147	Specific miRNAs can function as tumor suppressor genes or oncogenes (oncomirs) where deregulated miRNA expression has been demonstrated in a variety of human cancers including chronic lymphocytic leukemia, lung cancer, colorectal neoplasia and pancreatic endocrine and acinar tumors.	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('lung cancer', 'Disease', (206, 217))	('human', 'Species', '9606', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('leukemia', 'Phenotype', 'HP:0001909', (196, 204))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (176, 204))	('cancers', 'Disease', (158, 165))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (184, 204))	('neoplasia', 'Phenotype', 'HP:0002664', (230, 239))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('miRNA expression', 'MPA', (97, 113))	('colorectal neoplasia and pancreatic endocrine and acinar tumors', 'Disease', 'MESH:D010190', (219, 282))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('tumor', 'Disease', (276, 281))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('deregulated', 'Var', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('lymphocytic leukemia', 'Disease', (184, 204))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
41521	21698147	For example, high dicer expression is a poor prognostic factor in patients with prostate adenocarcinoma, whereas low Dicer expression is a poor prognostic factor in lung and ovarian carcinoma.	('Dicer', 'Gene', '23405', (117, 122))	('Dicer', 'Gene', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('high', 'Var', (13, 17))	('prostate adenocarcinoma', 'Disease', (80, 103))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (80, 103))	('patients', 'Species', '9606', (66, 74))	('dicer', 'Gene', '23405', (18, 23))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (174, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('lung and ovarian carcinoma', 'Disease', 'MESH:D010051', (165, 191))	('dicer', 'Gene', (18, 23))
41548	21698147	Scores for multiple cores from one case were averaged, and final Dicer scores were categorized into a three-level grouping of Negative, Low (>0 and <=1.5) or High (>1.6) for analyses that included all 404 patients.	('patients', 'Species', '9606', (205, 213))	('Dicer', 'Gene', '23405', (65, 70))	('Dicer', 'Gene', (65, 70))	('>0', 'Var', (141, 143))
41554	21698147	These two studies used whole genome oligo-microarray platforms: GPL1708 Agilent-012391 Whole Human Genome Oligo Microarray G4112A and GPL570 Affymetrix GeneChip Human Genome U133 Plus 2.0 Array.	('Human', 'Species', '9606', (161, 166))	('G4112A', 'Mutation', 'g.4112G>A', (123, 129))	('GPL570', 'Var', (134, 140))	('Human', 'Species', '9606', (93, 98))	('G4112A', 'Var', (123, 129))
41557	21698147	A2058, A375P, C32, A375SM and HEK 293 cells (embryonic kidney 293) were kindly provided by Dr. Stanley N. Cohen, Stanford school of medicine, CA.	('embryonic kidney', 'Disease', (45, 61))	('A375P', 'Var', (7, 12))	('HEK 293', 'CellLine', 'CVCL:0045', (30, 37))	('A375SM', 'Var', (19, 25))	('embryonic kidney', 'Disease', 'MESH:D007674', (45, 61))	('C32', 'Gene', (14, 17))	('C32', 'Gene', '51192', (14, 17))
41610	21698147	Western blot analysis combined with measured relative band intensity, normalized against succinate dehydrogenase (SDHA), showed >2 to 4-fold higher Dicer levels in melanoma cell lines (WM278, WM1552C and A375P) when compared to melanocyte-L or other melanoma cell lines (WM35 and A375M) (Fig.	('WM278', 'Var', (185, 190))	('Dicer', 'Gene', '23405', (148, 153))	('Dicer', 'Gene', (148, 153))	('SDHA', 'Gene', '6389', (114, 118))	('succinate dehydrogenase', 'Gene', (89, 112))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('A375P', 'Var', (204, 209))	('melanoma', 'Disease', (250, 258))	('SDHA', 'Gene', (114, 118))	('higher', 'PosReg', (141, 147))	('succinate dehydrogenase', 'Gene', '6389', (89, 112))	('melanoma', 'Disease', (164, 172))	('WM278', 'CellLine', 'CVCL:6473', (185, 190))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('WM1552C', 'Var', (192, 199))
41616	21698147	Neither Dicer mRNA nor Dicer protein levels correlated with any of the mature miRNAs tested (let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, left-7g or let-7i).	('let-7e', 'Gene', '406887', (125, 131))	('let-7a', 'Var', (93, 99))	('let-7b', 'Gene', (101, 107))	('let-7i', 'Gene', (152, 158))	('Dicer', 'Gene', '23405', (23, 28))	('let-7e', 'Gene', (125, 131))	('let-7i', 'Gene', '406891', (152, 158))	('Dicer', 'Gene', '23405', (8, 13))	('Dicer', 'Gene', (8, 13))	('let-7c', 'Gene', (109, 115))	('Dicer', 'Gene', (23, 28))	('left-7g', 'Var', (141, 148))	('let-7d', 'Gene', '406886', (117, 123))	('let-7c', 'Gene', '406885', (109, 115))	('let-7d', 'Gene', (117, 123))	('let-7b', 'Gene', '406884', (101, 107))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('let-7f', 'Var', (133, 139))
41647	21698147	Deregulation of Dicer, or other enzymes in the miRNA biogenesis pathway, maybe a common central feature shared by several solid cancers to globally regulate the biogenesis of oncomirs.	('biogenesis', 'MPA', (161, 171))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('Deregulation', 'Var', (0, 12))	('Dicer', 'Gene', '23405', (16, 21))	('Dicer', 'Gene', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('47', '63'))	('regulate', 'Reg', (148, 156))
41648	21698147	From our pooled analysis focusing on all known enzymes that participate in the biogenesis and maturation of canonical miRNAs, we also propose the possibility of a more general phenomenon where several deregulated RNAi enzymes, in addition to Dicer, may influence the various steps in melanoma progression (Fig.	('deregulated', 'Var', (201, 212))	('RNAi', 'biological_process', 'GO:0016246', ('213', '217'))	('influence', 'Reg', (253, 262))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('melanoma', 'Disease', (284, 292))	('RNAi', 'Gene', (213, 217))	('Dicer', 'Gene', (242, 247))	('Dicer', 'Gene', '23405', (242, 247))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))
41651	21698147	Beyond this, a combined understanding of deregulated Dicer and its influence on the expression pattern of mature miRNAs may lead to indications of directions in which small RNA modulations may contribute therapeutically in melanoma treatment.	('melanoma', 'Disease', (223, 231))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('contribute', 'Reg', (193, 203))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('Dicer', 'Gene', '23405', (53, 58))	('Dicer', 'Gene', (53, 58))	('deregulated', 'Var', (41, 52))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
41664	33072607	Results: The most common mutation was C > T, and the top three frequently mutated genes were TTN, MUC16, and BRAF.	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('TTN', 'Gene', (93, 96))	('MUC16', 'Gene', (98, 103))	('MUC16', 'Gene', '94025', (98, 103))	('C > T', 'Var', (38, 43))	('TTN', 'Gene', '7273', (93, 96))
41667	33072607	As for immune infiltration, the proportion was higher for macrophages M1 and M2 in the high-TMB group, while lower for memory B cells and regulatory T cells.	('high-TMB', 'Var', (87, 95))	('lower', 'NegReg', (109, 114))	('higher', 'PosReg', (47, 53))	('memory', 'biological_process', 'GO:0007613', ('119', '125'))	('macrophages M1', 'CPA', (58, 72))	('TMB', 'Chemical', '-', (92, 95))
41680	33072607	Since melanocytes are usually exposed to a large amount of ultraviolet radiation and the accumulated mutations, melanomas have a higher mutational load than other tumors, which may increase the efficacy of ICIs by generating and presenting immunogenic neoantigens.	('melanomas', 'Disease', (112, 121))	('efficacy', 'MPA', (194, 202))	('mutational load', 'MPA', (136, 151))	('mutations', 'Var', (101, 110))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('ICIs', 'CPA', (206, 210))	('increase', 'PosReg', (181, 189))
41681	33072607	Tumor mutation burden (TMB), defined as the total number of somatic coding errors, base substitutions, and indel mutations per million bases, can effectively estimate overall mutational load and neoantigenic load.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('base substitutions', 'Var', (83, 101))	('neoantigenic load', 'MPA', (195, 212))	('TMB', 'Chemical', '-', (23, 26))
41705	33072607	As for external validation, according to the filter criteria as: patients had been diagnosed as melanoma, the datasets include complete survival information, and include enough sample sizes (n > 50), three melanoma datasets were chosen, GSE65904 (n = 210), GSE54467 (n = 79), and GSE22153 (n = 54) as validation sets in the GEO database.	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('GSE22153', 'Var', (280, 288))	('patients', 'Species', '9606', (65, 73))	('GSE65904', 'Var', (237, 245))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (206, 214))	('GSE54467', 'Var', (257, 265))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Disease', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
41711	33072607	In melanoma, for each hub gene involved in the risk score model, Somatic Copy Number Alterations (SCNA) module of TIMER tool was used to compare the infiltration levels among samples with different SCNA, including deep deletion, arm-level deletion, diploid/normal, arm-level gain, and high amplification.	('hub', 'Gene', '1993', (22, 25))	('hub', 'Gene', (22, 25))	('diploid/normal', 'Disease', (249, 263))	('deep deletion', 'Var', (214, 227))	('high', 'Disease', (285, 289))	('arm-level gain', 'Disease', (265, 279))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('arm-level', 'Disease', (229, 238))
41720	33072607	According to the K-M curve, the high-TMB group had significantly better survival outcomes, with the log-rank test of P < 0.0001 (Figure 2B).	('survival outcomes', 'CPA', (72, 89))	('better', 'PosReg', (65, 71))	('high-TMB', 'Var', (32, 40))	('TMB', 'Chemical', '-', (37, 40))
41726	33072607	Furthermore, we explored the TMB-related pathway through GSEA, using TMB level as the phenotype label, and found that cell cycle, DNA replication, mismatch repair, and nucleotide excision were significantly enriched in the high-TMB group, with FDR < 0.025 (Figure 4C).	('high-TMB', 'Var', (223, 231))	('nucleotide excision', 'Var', (168, 187))	('DNA', 'cellular_component', 'GO:0005574', ('130', '133'))	('TMB', 'Chemical', '-', (69, 72))	('mismatch repair', 'biological_process', 'GO:0006298', ('147', '162'))	('DNA', 'MPA', (130, 133))	('GSEA', 'Chemical', '-', (57, 61))	('TMB', 'Chemical', '-', (228, 231))	('cell cycle', 'CPA', (118, 128))	('TMB', 'Chemical', '-', (29, 32))	('mismatch repair', 'MPA', (147, 162))	('cell cycle, DNA replication', 'biological_process', 'GO:0044786', ('118', '145'))
41744	33072607	As for the relationship between prognosis-related genes and immune cell infiltration, we explored the changes of infiltration in the samples with copy number alteration of IFNG and BIRC5, respectively.	('BIRC5', 'Gene', '332', (181, 186))	('copy number alteration', 'Var', (146, 168))	('BIRC5', 'Gene', (181, 186))	('IFNG', 'Gene', '3458', (172, 176))	('IFNG', 'Gene', (172, 176))
41745	33072607	Overall, compared to melanoma samples with diploid/normal expression of IFNG and BIRC5, samples with bidirectional copy number variation of BIRC5 and increased copy number variation of IFNG had a lower level of immune infiltration, including B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells (Figure 9A).	('IFNG', 'Gene', (72, 76))	('CD4', 'Gene', '920', (251, 254))	('lower', 'NegReg', (196, 201))	('CD8', 'Gene', (265, 268))	('BIRC5', 'Gene', '332', (140, 145))	('IFNG', 'Gene', '3458', (185, 189))	('BIRC5', 'Gene', (140, 145))	('copy number variation', 'Var', (160, 181))	('CD4', 'Gene', (251, 254))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('IFNG', 'Gene', '3458', (72, 76))	('BIRC5', 'Gene', '332', (81, 86))	('BIRC5', 'Gene', (81, 86))	('CD8', 'Gene', '925', (265, 268))	('immune infiltration', 'MPA', (211, 230))	('IFNG', 'Gene', (185, 189))	('lower level of immune infiltration', 'Phenotype', 'HP:0002721', (196, 230))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
41756	33072607	The C > T mutations accounted for the vast majority, consistent with ultraviolet exposure leading to the formation of pyrimidine dimers.	('pyrimidine', 'Chemical', 'MESH:C030986', (118, 128))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('C > T', 'Var', (4, 9))	('formation of pyrimidine dimers', 'MPA', (105, 135))
41758	33072607	TTN, mutations of which are often detected in solid tumors, is associated with increased TMB and better response to ICIs, and patients with mutant TTN have a better prognosis.	('response to ICIs', 'MPA', (104, 120))	('solid tumor', 'Disease', (46, 57))	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('TTN', 'Gene', (147, 150))	('TTN', 'Gene', (0, 3))	('solid tumor', 'Disease', 'MESH:D009369', (46, 57))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (5, 14))	('TTN', 'Gene', '7273', (147, 150))	('TTN', 'Gene', '7273', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('TMB', 'MPA', (89, 92))	('patients', 'Species', '9606', (126, 134))	('TMB', 'Chemical', '-', (89, 92))	('mutant', 'Var', (140, 146))
41761	33072607	The BRAF mutation is obviously the most common carcinogenic driver in melanoma, by activating the mitogen-activated protein kinase (MAPK) pathway, which is a pivotal regulator of cellular growth and proliferation.	('mutation', 'Var', (9, 17))	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('carcinogenic', 'Disease', 'MESH:D063646', (47, 59))	('carcinogenic', 'Disease', (47, 59))	('cellular growth', 'biological_process', 'GO:0016049', ('179', '194'))	('MAPK', 'molecular_function', 'GO:0004707', ('132', '136'))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('activating', 'PosReg', (83, 93))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
41769	33072607	Moreover, abnormal adhesion of tumor cells is associated with tumor progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('abnormal', 'Var', (10, 18))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (62, 67))	('metastasis', 'CPA', (84, 94))	('adhesion', 'MPA', (19, 27))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
41789	33072607	TAMs provide a promising target for immunotherapy, and TAMs targeting can enhance the response to other immunotherapies when used synergistically.	('TAMs', 'Chemical', '-', (0, 4))	('targeting', 'Var', (60, 69))	('TAMs', 'Chemical', '-', (55, 59))	('response', 'CPA', (86, 94))	('enhance', 'PosReg', (74, 81))
41793	33072607	Tumor infiltrating B cells play a critical role in regulating the anti-tumor immune response in melanoma, and the absence of B cells is associated with a poor response to ICIs.	('absence', 'Var', (114, 121))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('absence of B cells', 'Phenotype', 'HP:0005365', (114, 132))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('immune response', 'biological_process', 'GO:0006955', ('77', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('tumor', 'Disease', (71, 76))	('melanoma', 'Disease', (96, 104))
41809	28193624	The melanoma was driven by biallelic inactivation of NF1.	('biallelic inactivation', 'Var', (27, 49))	('NF1', 'Gene', (53, 56))	('driven by', 'Reg', (17, 26))	('NF1', 'Gene', '4763', (53, 56))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
41811	28193624	Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes.	('gene expression', 'biological_process', 'GO:0010467', ('211', '226'))	('dictate', 'Reg', (245, 252))	('PD-1', 'Gene', (258, 262))	('lesional', 'Var', (202, 210))	('PD-1', 'Gene', '5133', (258, 262))
41816	28193624	This approach has been applied to pancreatic and other cancer types, revealing diverse patterns of clonal evolution from the primary lesion to metastases, in which intratumoral subclones and metastatic tumors accumulate private mutations superimposed on shared or ubiquitous mutations.	('metastases', 'Disease', (143, 153))	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('accumulate', 'PosReg', (209, 219))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('private mutations', 'Var', (220, 237))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('pancreatic', 'Disease', 'MESH:D010195', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('pancreatic', 'Disease', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
41833	28193624	Whole exome sequencing of all 26 specimens confirmed that this tumor was wildtype for canonical activating mutations in RAS, RAF, and KIT, and was NF1-driven with clonal biallelic inactivation of the gene present in all primary, recurrent, and metastatic specimens collected pre- and post-mortem.	('tumor', 'Disease', (63, 68))	('RAS', 'Gene', (120, 123))	('mutations', 'Var', (107, 116))	('activating', 'PosReg', (96, 106))	('biallelic inactivation', 'Var', (170, 192))	('RAF', 'Gene', '22882', (125, 128))	('RAF', 'Gene', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('NF1', 'Gene', (147, 150))	('pre', 'molecular_function', 'GO:0003904', ('275', '278'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('NF1', 'Gene', '4763', (147, 150))	('KIT', 'Gene', (134, 137))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))
41834	28193624	All tumors harbored a truncating NF1 Q519* mutation that was accompanied by a focal heterozygous loss of the single remaining wildtype allele (Figure 2).	('NF1', 'Gene', (33, 36))	('Q519*', 'Var', (37, 42))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('NF1', 'Gene', '4763', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('Q519*', 'SUBSTITUTION', 'None', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
41837	28193624	All tumors possessed a high burden, but very stable pattern, of copy number changes, with few changes acquired after diagnosis (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (128, 151))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('Supplementary Figure S1', 'Disease', (128, 151))	('copy number changes', 'Var', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
41935	28193624	In total, 21,550 candidate somatic mutations were detected, of which 2207 were unique variants across the tumor samples.	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('mutations', 'Var', (35, 44))
41936	28193624	Finally, the purity and integer copy number results from FACETS analysis, along with coverage levels and allele frequencies, were used to estimate the fraction of cancer cells harboring each mutation (cancer cell fraction, CCF) in all specimens.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cell fraction', 'cellular_component', 'GO:0000267', ('208', '221'))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (191, 199))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
41937	28193624	To identify driver gene mutations, we utilized multiple methods to cross-reference the somatic variants relying on two pan-cancer studies.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
41943	28193624	Phylogeny construction was based on the subset of somatic mutations (n=795) with greater than 20-fold coverage in every tumor and normal specimen, with a minimum allelic fraction of 10% in at least one tumor specimen, and no more than a single variant read or 2% allelic fraction in both the frozen and FFPE matched normal samples.	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
42071	32990318	Lately, several institutions have reported clinical results using Cf-252 neutron brachytherapy or proton/carbon-ion radiotherapy for cutaneous or mucosal melanoma, which enables much higher radiation doses to be delivered to the target.	('Cf-252', 'Var', (66, 72))	('cutaneous', 'Disease', (133, 142))	('mucosal melanoma', 'Disease', (146, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('mucosal melanoma', 'Disease', 'MESH:D008545', (146, 162))	('carbon', 'Chemical', 'MESH:D002244', (105, 111))
42198	32256700	Although we identified an increased risk to develop tumours with Breslow >1 mm in patients with residence in both Northern regions, the lower melanoma mortality in the North West could be the result of a lower incidence of CM, due to the high prevalence of indigenous ancestors with darker skin, but there was no data to confirm this hypothesis.	('lower', 'NegReg', (136, 141))	('tumours', 'Disease', (52, 59))	('patients', 'Species', '9606', (82, 90))	('CM', 'Phenotype', 'HP:0012056', (223, 225))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('Breslow', 'Var', (65, 72))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('lower', 'NegReg', (204, 209))	('melanoma mortality', 'Disease', (142, 160))	('melanoma mortality', 'Disease', 'MESH:D003643', (142, 160))	('darker skin', 'Phenotype', 'HP:0000953', (283, 294))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
42212	32764384	Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma There is an urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations.	('V600E', 'Var', (274, 279))	('BCL2', 'Gene', (26, 30))	('V600E', 'SUBSTITUTION', 'None', (274, 279))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('Patients', 'Species', '9606', (68, 76))	('Inhibiting', 'NegReg', (15, 25))	('patients', 'Species', '9606', (150, 158))	('BCL2', 'molecular_function', 'GO:0015283', ('26', '30'))	('Melanoma', 'Disease', 'MESH:D008545', (91, 99))	('patients', 'Species', '9606', (251, 259))	('BCL2', 'Gene', '596', (26, 30))	('Melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('MCL1', 'Gene', (35, 39))	('MCL1', 'Gene', '4170', (35, 39))	('Melanoma', 'Disease', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))
42214	32764384	Here, we analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations.	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('melanomas', 'Disease', (188, 197))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('cutaneous melanoma', 'Disease', (32, 50))	('Cancer', 'Disease', (55, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('expression', 'MPA', (146, 156))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('mutations', 'Var', (227, 236))
42216	32764384	We explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo.	('acral melanomas', 'Disease', (172, 187))	('S63845', 'Chemical', 'MESH:C000614727', (121, 127))	('S64315', 'Chemical', '-', (131, 137))	('S63845', 'Var', (121, 127))	('myeloid cell leukemia sequence 1', 'Gene', '4170', (70, 102))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (70, 91))	('myeloid cell leukemia sequence 1', 'Gene', (70, 102))	('acral melanomas', 'Disease', 'MESH:D008545', (172, 187))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('BH3', 'Chemical', 'MESH:C006008', (42, 45))	('acral melanoma', 'Phenotype', 'HP:0012060', (172, 186))	('melanomas', 'Phenotype', 'HP:0002861', (178, 187))	('acral melanomas', 'Phenotype', 'HP:0012060', (172, 187))	('S64315/MIK665', 'Var', (131, 144))	('ABT-199', 'Chemical', 'MESH:C579720', (56, 63))
42217	32764384	Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('cell death', 'CPA', (43, 53))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('V600E', 'Var', (194, 199))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('V600E', 'SUBSTITUTION', 'None', (194, 199))	('cell death', 'biological_process', 'GO:0008219', ('43', '53'))
42226	32764384	While the efficacy of signal transduction inhibitors that target BRAF-V600E/K mutation is well described for patients with melanoma, treatments for patients that do not harbor a BRAF-V600E/K mutation are limited to immunotherapy and lack other clinical options.	('patients', 'Species', '9606', (148, 156))	('V600E', 'Var', (70, 75))	('patients', 'Species', '9606', (109, 117))	('signal transduction', 'biological_process', 'GO:0007165', ('22', '41'))	('V600E', 'SUBSTITUTION', 'None', (70, 75))	('V600E', 'Var', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('V600E', 'SUBSTITUTION', 'None', (183, 188))
42228	32764384	In this study, we analyzed the cutaneous melanoma TCGA transcriptomic and proteomic database for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations.	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('cutaneous melanoma', 'Disease', (31, 49))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('mutations', 'Var', (191, 200))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanomas', 'Disease', (152, 161))
42231	32764384	We then explored the efficacy of combining two BH3 mimetics, an MCL1 inhibitor (S63845 or S64315/MIK665) and a BCL2 inhibitor (ABT-199/venetoclax) in cutaneous, mucosal and acral melanomas in vitro and in vivo.	('S63845', 'Chemical', 'MESH:C000614727', (80, 86))	('acral melanoma', 'Phenotype', 'HP:0012060', (173, 187))	('acral melanomas', 'Phenotype', 'HP:0012060', (173, 188))	('acral melanomas', 'Disease', (173, 188))	('S63845', 'Var', (80, 86))	('BH3', 'Chemical', 'MESH:C006008', (47, 50))	('ABT-199', 'Chemical', 'MESH:C579720', (127, 134))	('BCL2', 'molecular_function', 'GO:0015283', ('111', '115'))	('melanomas', 'Phenotype', 'HP:0002861', (179, 188))	('S64315/MIK665', 'Var', (90, 103))	('acral melanomas', 'Disease', 'MESH:D008545', (173, 188))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('S64315', 'Chemical', '-', (90, 96))
42234	32764384	To identify other potential therapeutic targets, we analyzed the TCGA data for differences in gene and/or protein expression between BRAF-MUT and BRAF-WT melanoma.	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('differences', 'Reg', (79, 90))	('BRAF-WT melanoma', 'Disease', (146, 162))	('BRAF-MUT', 'Var', (133, 141))	('BRAF-WT melanoma', 'Disease', 'MESH:D008545', (146, 162))
42241	32764384	In melanoma, knocking down BCL2 sensitized cells to the MCL1 inhibitor S63845, and conversely knocking down MCL1 sensitized cells to the BCL2 inhibitor ABT-199 (Figure 1c-e).	('sensitized', 'Reg', (113, 123))	('ABT-199', 'Chemical', 'MESH:C579720', (152, 159))	('BCL2', 'molecular_function', 'GO:0015283', ('27', '31'))	('BCL2', 'Gene', (27, 31))	('S63845', 'Chemical', 'MESH:C000614727', (71, 77))	('BCL2', 'molecular_function', 'GO:0015283', ('137', '141'))	('knocking down', 'Var', (94, 107))	('melanoma', 'Disease', (3, 11))	('MCL1', 'Gene', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('sensitized', 'Reg', (32, 42))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('knocking', 'Var', (13, 21))
42243	32764384	We tested the treatment efficacy of combining MCL1 inhibitors with ABT-199 in melanomas with or without BRAF-V600 hotspot mutations (MUT vs WT groups).	('melanomas', 'Disease', (78, 87))	('ABT-199', 'Chemical', 'MESH:C579720', (67, 74))	('ABT-199', 'Gene', (67, 74))	('BRAF-V600', 'Gene', (104, 113))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('tested', 'Reg', (3, 9))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutations', 'Var', (122, 131))
42245	32764384	We first utilized ATP assays to examine the in vitro viability following the treatments with S63845 and ABT-199, either as a single agent or in combination, in a panel of fifteen human melanoma lines and primary melanocytes (Figure 2a-d).	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('human', 'Species', '9606', (179, 184))	('ABT-199', 'Gene', (104, 111))	('S63845', 'Chemical', 'MESH:C000614727', (93, 99))	('ATP', 'Chemical', 'MESH:D000255', (18, 21))	('S63845', 'Var', (93, 99))	('ABT-199', 'Chemical', 'MESH:C579720', (104, 111))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
42247	32764384	Overall, single drug treatments of either ABT-199 or S63845 alone (up to 2.5 muM), had little effect on cell viability.	('ABT-199', 'Chemical', 'MESH:C579720', (42, 49))	('ABT-199', 'Gene', (42, 49))	('S63845', 'Chemical', 'MESH:C000614727', (53, 59))	('S63845', 'Var', (53, 59))
42249	32764384	Interestingly, the combination treatment showed a greater efficacy on the BRAF-WT melanomas, as compared to the melanomas with BRAF-V600E (MUT).	('melanomas', 'Disease', (112, 121))	('V600E', 'Mutation', 'rs113488022', (132, 137))	('melanomas', 'Disease', (82, 91))	('BRAF-V600E', 'Var', (127, 137))	('BRAF-WT melanomas', 'Disease', 'MESH:D008545', (74, 91))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('BRAF-WT melanomas', 'Disease', (74, 91))
42251	32764384	The combination also increased the ratio of cleaved/full-length poly ADP-ribose polymerase (PARP) and caused rounded morphology of cells (Figure 2e, Figure S2), indicating the induction of apoptosis.	('induction of apoptosis', 'biological_process', 'GO:0006915', ('176', '198'))	('rounded morphology', 'CPA', (109, 127))	('increased', 'PosReg', (21, 30))	('combination', 'Var', (4, 15))	('poly ADP-ribose polymerase', 'Gene', (64, 90))	('ratio', 'MPA', (35, 40))	('poly ADP-ribose polymerase', 'Gene', '142', (64, 90))	('caused', 'Reg', (102, 108))
42253	32764384	We next evaluated the in vivo efficacy of the combination therapy in a mouse xenograft model of MB 3616, which has a NRAS-Q61K mutation and does not have a BRAF-V600E/K mutation (Figure 3a,b).	('NRAS', 'Gene', (117, 121))	('Q61K', 'Mutation', 'rs121913254', (122, 126))	('V600E', 'SUBSTITUTION', 'None', (161, 166))	('mouse', 'Species', '10090', (71, 76))	('V600E', 'Var', (161, 166))	('NRAS', 'Gene', '18176', (117, 121))
42257	32764384	Immunoblot of lysates from the tumors post-treatment showed that S63845 alone increased MCL1 expression 2.9-fold (Figure S4), which has been reported previously by others.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('S63845', 'Chemical', 'MESH:C000614727', (65, 71))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('S63845', 'Var', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('increased', 'PosReg', (78, 87))	('MCL1 expression', 'MPA', (88, 103))
42258	32764384	Our in vitro data suggested that the combination of an MCL1 inhibitor and ABT-199 was effective against all melanomas, but higher concentrations were necessary for the BRAF-MUT compared to the BRAF-WT (Figure 2 and Figure S1).	('BRAF-MUT', 'Var', (168, 176))	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('ABT-199', 'Chemical', 'MESH:C579720', (74, 81))	('ABT-199', 'Gene', (74, 81))	('melanomas', 'Disease', (108, 117))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
42259	32764384	In vivo, this combination was also successful in inhibiting tumor growth for BRAF-V600E melanoma, when ABT-199 was administered at an increased frequency of three times per week (Figure S5a).	('BRAF-V600E', 'Var', (77, 87))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('V600E', 'Mutation', 'rs113488022', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibiting', 'NegReg', (49, 59))	('ABT-199', 'Chemical', 'MESH:C579720', (103, 110))	('tumor', 'Disease', (60, 65))
42266	32764384	Similar to the ATP assay (Figure 2c), the combination was more successful in inhibiting the primary spheres in lines with BRAF-WT (WT) genotypes than those with BRAF-V600E (MUT) (Figure 4c and Table S5).	('inhibiting', 'NegReg', (77, 87))	('BRAF-V600E', 'Var', (161, 171))	('primary spheres in', 'CPA', (92, 110))	('BRAF-WT', 'Var', (122, 129))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))	('V600E', 'Mutation', 'rs113488022', (166, 171))
42268	32764384	These results suggest that the combination of ABT-199 and S63845 can play an important role in preventing relapse caused by MICs.	('ABT-199', 'Chemical', 'MESH:C579720', (46, 53))	('relapse', 'Disease', (106, 113))	('ABT-199', 'Gene', (46, 53))	('S63845', 'Var', (58, 64))	('MICs', 'Disease', (124, 128))	('S63845', 'Chemical', 'MESH:C000614727', (58, 64))
42270	32764384	In B cell lymphoma cells, genomic amplification or pharmacologic induction of NOXA sensitizes cells to BCL2 inhibitors, including ABT-199.	('BCL2', 'molecular_function', 'GO:0015283', ('103', '107'))	('sensitizes', 'Reg', (83, 93))	('B cell lymphoma', 'Disease', 'MESH:D016393', (3, 18))	('B cell lymphoma', 'Disease', (3, 18))	('ABT-199', 'Chemical', 'MESH:C579720', (130, 137))	('BCL2 inhibitors', 'MPA', (103, 118))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (3, 18))	('cell lymphoma', 'Phenotype', 'HP:0012191', (5, 18))	('NOXA', 'Gene', (78, 82))	('lymphoma', 'Phenotype', 'HP:0002665', (10, 18))	('NOXA', 'Gene', '5366', (78, 82))	('genomic amplification', 'Var', (26, 47))
42272	32764384	In acute myeloid leukemia (AML), BIM is an important mediator for S63845-induced apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('S63845', 'Chemical', 'MESH:C000614727', (66, 72))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('S63845-induced', 'Var', (66, 80))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('acute myeloid leukemia', 'Disease', (3, 25))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('AML', 'Disease', (27, 30))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
42274	32764384	Thus, we investigated the roles of BIM and NOXA in the S63845+ABT-199 mediated cell death with cell lines genetically modified with shRNA or CRISPR-Cas9 technology.	('S63845+ABT-199', 'Gene', (55, 69))	('S63845', 'Chemical', 'MESH:C000614727', (55, 61))	('Cas', 'cellular_component', 'GO:0005650', ('148', '151'))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))	('ABT-199', 'Chemical', 'MESH:C579720', (62, 69))	('S63845+ABT-199', 'Var', (55, 69))	('NOXA', 'Gene', (43, 47))	('NOXA', 'Gene', '5366', (43, 47))
42275	32764384	Knocking down or knocking out BIM or NOXA partially protected melanoma cells from the combination treatment but did not eliminate the killing effects (Figure 5a-c).	('melanoma', 'Disease', (62, 70))	('Knocking down', 'Var', (0, 13))	('BIM', 'Gene', (30, 33))	('knocking out', 'Var', (17, 29))	('NOXA', 'Gene', (37, 41))	('NOXA', 'Gene', '5366', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
42277	32764384	Therefore, we performed knockdown experiments to investigate the role of BID in ABT-199 plus S63845 induced killing.	('ABT-199', 'Chemical', 'MESH:C579720', (80, 87))	('ABT-199', 'Gene', (80, 87))	('S63845', 'Var', (93, 99))	('S63845', 'Chemical', 'MESH:C000614727', (93, 99))
42278	32764384	Like NOXA and BIM, knockdown of BID also enhanced melanoma resistance to the combination (Figure 5a).	('knockdown', 'Var', (19, 28))	('enhanced', 'PosReg', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('NOXA', 'Gene', (5, 9))	('BID', 'Gene', (32, 35))	('NOXA', 'Gene', '5366', (5, 9))
42280	32764384	S64315 (MIK665), which is derived from S63845, has similar chemical properties to inhibit MCL1, and is currently in clinical trials for AML ( NCT02992483; NCT02979366; ; ).	(' NCT02992483;', 'Var', (141, 154))	('S64315', 'Chemical', '-', (0, 6))	('inhibit', 'NegReg', (82, 89))	('S63845', 'Chemical', 'MESH:C000614727', (39, 45))	('AML', 'Disease', 'MESH:D015470', (136, 139))	('S64315', 'Var', (0, 6))	('AML', 'Disease', (136, 139))	('MCL1', 'Gene', (90, 94))
42281	32764384	Thus, we performed a comparative analysis of S64315 and S63845, either alone or in combination with ABT-199 in multiple melanoma cell lines.	('S63845', 'Chemical', 'MESH:C000614727', (56, 62))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('S63845', 'Var', (56, 62))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('ABT-199', 'Chemical', 'MESH:C579720', (100, 107))	('S64315', 'Var', (45, 51))	('S64315', 'Chemical', '-', (45, 51))
42282	32764384	Overall, S64315 exhibited similar or better efficacy than S63845 (Figure 6 and Table S6).	('better', 'PosReg', (37, 43))	('S64315', 'Chemical', '-', (9, 15))	('S64315', 'Var', (9, 15))	('S63845', 'Chemical', 'MESH:C000614727', (58, 64))
42284	32764384	Patients with metastatic or unresectable melanoma treated with combination immune checkpoint blockade (Ipilimumab/Nivolumab) or BRAF/MEK inhibition demonstrate 5-year overall survival of 52% and 34%, respectively.	('MEK', 'Gene', (133, 136))	('MEK', 'Gene', '5609', (133, 136))	('inhibition', 'Var', (137, 147))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (103, 113))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('Nivolumab', 'Chemical', 'MESH:D000077594', (114, 123))	('metastatic', 'Disease', (14, 24))
42287	32764384	In addition, patients with rare melanoma subtypes, such as acral and mucosal, are genetically distinct from cutaneous melanomas and typically lack BRAF-V600E/K mutations, making them ineligible for BRAF/MEK inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('MEK', 'Gene', (203, 206))	('V600E', 'Var', (152, 157))	('melanoma', 'Disease', (32, 40))	('patients', 'Species', '9606', (13, 21))	('acral', 'Disease', (59, 64))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (108, 127))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('cutaneous melanomas', 'Disease', (108, 127))	('lack', 'NegReg', (142, 146))	('V600E', 'SUBSTITUTION', 'None', (152, 157))	('MEK', 'Gene', '5609', (203, 206))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (108, 127))
42292	32764384	These data led us to explore BH3 mimetics in advanced melanomas, especially those without BRAF-V600E/K.	('V600E', 'SUBSTITUTION', 'None', (95, 100))	('BH3', 'Chemical', 'MESH:C006008', (29, 32))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanomas', 'Disease', (54, 63))	('V600E', 'Var', (95, 100))
42294	32764384	Our in vitro and in vivo data showed that the simultaneous targeting of BCL2 and MCL1 is effective in treating advanced melanoma, and this combination is more potent in melanomas without the BRAF-V600E/K variant.	('BCL2', 'molecular_function', 'GO:0015283', ('72', '76'))	('V600E', 'Var', (196, 201))	('melanomas', 'Disease', 'MESH:D008545', (169, 178))	('V600E', 'SUBSTITUTION', 'None', (196, 201))	('MCL1', 'Gene', (81, 85))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanomas', 'Disease', (169, 178))	('BCL2', 'Gene', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
42298	32764384	For our BRAF-V600E melanoma in vivo model, we needed to utilize higher doses and/or increase the frequency of administration for these compounds to achieve similar results:i.e., a reduction in cell viability in vitro and inhibition of tumor growth in vivo (Figure 2, Figure 3 and Figures S1 and S5).	('reduction', 'NegReg', (180, 189))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('inhibition', 'NegReg', (221, 231))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('V600E', 'Mutation', 'rs113488022', (13, 18))	('tumor', 'Disease', (235, 240))	('BRAF-V600E', 'Var', (8, 18))	('cell viability', 'CPA', (193, 207))
42305	32764384	Lee et al., in 2019, reported the in vitro efficacy of the S63845 with ABT-199 in combination in a limited number of cutaneous melanoma cell lines.	('ABT-199', 'Chemical', 'MESH:C579720', (71, 78))	('ABT-199', 'Gene', (71, 78))	('cutaneous melanoma', 'Disease', (117, 135))	('S63845', 'Chemical', 'MESH:C000614727', (59, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('S63845', 'Var', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))
42306	32764384	We are the first to study the efficacy of the combination of S63845 with ABT-199 in vivo in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('S63845', 'Chemical', 'MESH:C000614727', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('ABT-199', 'Chemical', 'MESH:C579720', (73, 80))	('S63845', 'Var', (61, 67))	('ABT-199', 'Gene', (73, 80))
42307	32764384	Moreover, our current study also includes in vitro data that tests a clinic-ready version of the MCL1 inhibitor, S64315 (MIK665), in combination with the FDA approved ABT-199, further justifying the use of this therapeutic option for patients with advanced melanoma.	('ABT-199', 'Chemical', 'MESH:C579720', (167, 174))	('S64315', 'Var', (113, 119))	('patients', 'Species', '9606', (234, 242))	('S64315', 'Chemical', '-', (113, 119))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))
42312	32764384	safely administered S63845 (25 mg/kg) and ABT-199 (50 mg/kg) simultaneously in a mouse model of AML for five days.	('AML', 'Disease', (96, 99))	('S63845', 'Var', (20, 26))	('ABT-199', 'Chemical', 'MESH:C579720', (42, 49))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('mouse', 'Species', '10090', (81, 86))	('S63845', 'Chemical', 'MESH:C000614727', (20, 26))	('ABT-199', 'Gene', (42, 49))
42316	32764384	A phase 1 study  (NCT03672695) examining the combination of S64315 with ABT-199 is underway for patients with AML.	('AML', 'Disease', (110, 113))	('S64315', 'Var', (60, 66))	('S64315', 'Chemical', '-', (60, 66))	('patients', 'Species', '9606', (96, 104))	('AML', 'Disease', 'MESH:D015470', (110, 113))	('ABT-199', 'Chemical', 'MESH:C579720', (72, 79))	('ABT-199', 'Gene', (72, 79))
42322	32764384	Although knockdown of BID decreased cell sensitivity to this treatment, our data indicate that a BID-null state will not prevent killing completely, as we could not detect BID in the moderately sensitive cell line MB 2141 (Figure S6).	('MB 2141', 'CellLine', 'CVCL:K903', (214, 221))	('decreased', 'NegReg', (26, 35))	('knockdown', 'Var', (9, 18))	('cell sensitivity', 'MPA', (36, 52))
42328	32764384	This is consistent with previous finding that BRAF-V600E can downregulate BIM expression in melanoma.	('downregulate', 'NegReg', (61, 73))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('BIM', 'Gene', (74, 77))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('BRAF-V600E', 'Var', (46, 56))
42329	32764384	Considering that our data showing BIM knockout or knockdown results in decreased melanoma sensitivity to this combination, we speculate that higher BIM expression may be a contributing factor for a better response in BRAF-WT melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('knockdown', 'Var', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('BRAF-WT melanoma', 'Disease', (217, 233))	('BRAF-WT melanoma', 'Disease', 'MESH:D008545', (217, 233))	('decreased melanoma', 'Disease', (71, 89))	('knockout', 'Var', (38, 46))	('expression', 'MPA', (152, 162))	('decreased melanoma', 'Disease', 'MESH:D008545', (71, 89))
42331	32764384	All drugs (S63845, S64315, and ABT-199) used for the study were purchased from MedChem Express (Monmouth Junction, NJ, USA) or from Selleck Chem (Houston, TX, USA).	('S63845', 'Var', (11, 17))	('S64315', 'Var', (19, 25))	('S64315', 'Chemical', '-', (19, 25))	('ABT-199', 'Chemical', 'MESH:C579720', (31, 38))	('S63845', 'Chemical', 'MESH:C000614727', (11, 17))
42340	32764384	The following antibodies were purchased from Cell Signaling Technologies (Danvers, MA, USA): PARP (#9532), BID (#2002), BIM (#2933), BCL2 (#15071), alpha/beta tubulin (#2148), and HRP-conjugated goat anti-mouse and anti-rabbit antibodies.	('#9532', 'Var', (99, 104))	('#2148', 'Var', (168, 173))	('mouse', 'Species', '10090', (205, 210))	('BCL2', 'molecular_function', 'GO:0015283', ('133', '137'))	('Signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('#15071', 'Var', (139, 145))	('#2933', 'Var', (125, 130))
42341	32764384	The NOXA antibody (# OP180) was obtained from Millipore Sigma (St. Louis, MO, USA) and MCL1 antibody (#819) was purchased from Santa Cruz Biotechnology (Dallas, TX, USA).	('antibody', 'cellular_component', 'GO:0042571', ('92', '100'))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('NOXA', 'Gene', '5366', (4, 8))	('antibody', 'cellular_component', 'GO:0019815', ('92', '100'))	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('antibody', 'cellular_component', 'GO:0019814', ('92', '100'))	('antibody', 'molecular_function', 'GO:0003823', ('92', '100'))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('NOXA', 'Gene', (4, 8))	('# OP180', 'Var', (19, 26))
42351	32764384	The antibodies used in the study are Cleaved Caspase 3, (1:200, #9664, Cell Signaling Technology, (Danvers, MA, USA) and Ki67, (1:100, #RM-9106-S1, Thermo Fisher Scientific, (Waltham, MA, USA).	('1:100', 'Var', (128, 133))	('1:200', 'Var', (57, 62))	('Ki67', 'Gene', '17345', (121, 125))	('Caspase 3', 'Protein', (45, 54))	('Signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('Ki67', 'Gene', (121, 125))
42358	32764384	The following are available online at Supplementary Data , Figure S1: The combination of S63845 + ABT-199 kills BRAF-WT melanoma cell in vitro at sub-micromolar dose, Figure S2: S63845 combined with ABT-199 induced apoptosis in melanoma cells, Figure S3: Representative bright-field images of Ki67 and Cleaved Caspase 3 staining from tumor sections derived from mouse xenografts experiments of Figure 3, Figure S4: Immunoblot with tumor cell lysates collected from the mouse xenograft experiment of Figure 3, Figure S5: The combination of S63845 + ABT-199 kills BRAF-V600E melanoma cells in vivo at higher frequency of treatment, Figure S6: Endogenous level of BID in melanoma cell lines and patient samples, Figure S7: Full immunoblot images of bands shown in Figure 1e, Figure S8: Full immunoblot images of bands shown in Figure 2e, Figure S9: Full immunoblot images of bands shown in Supplementary Figure S4, Figure S10: Full immunoblot images of bands shown in Figure 5, Figure S11: Full immunoblot images of bands shown in Supplementary Figure S6, Table S1: Comparison of the mRNA expression from the TCGA cutaneous melanoma data set, Table S2: Comparison of the protein expression from the TCGA cutaneous melanoma RPPA data set, Table S3: Details of the melanoma lines used in the study and IC50 of indicated drugs, Table S4: p values for ATP assay of S63845+ABT-199 Combination (Figure 2a), Table S5: p values for Figure 4, Table S6: p values for Figure 6.	('patient', 'Species', '9606', (692, 699))	('BRAF-WT melanoma cell', 'Disease', 'MESH:D008545', (112, 133))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('melanoma', 'Phenotype', 'HP:0002861', (668, 676))	('melanoma', 'Disease', (668, 676))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('protein', 'cellular_component', 'GO:0003675', ('1168', '1175'))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('cutaneous melanoma', 'Disease', (1111, 1129))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (1111, 1129))	('melanoma', 'Disease', 'MESH:D008545', (1211, 1219))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1111, 1129))	('melanoma', 'Phenotype', 'HP:0002861', (573, 581))	('V600E', 'Mutation', 'rs113488022', (567, 572))	('S63845', 'Chemical', 'MESH:C000614727', (178, 184))	('melanoma', 'Disease', (573, 581))	('ATP', 'Chemical', 'MESH:D000255', (1345, 1348))	('Ki67', 'Gene', (293, 297))	('S63845+ABT-199', 'Var', (1358, 1372))	('apoptosis', 'biological_process', 'GO:0097194', ('215', '224'))	('apoptosis', 'biological_process', 'GO:0006915', ('215', '224'))	('ABT-199', 'Chemical', 'MESH:C579720', (98, 105))	('melanoma', 'Disease', 'MESH:D008545', (1121, 1129))	('melanoma', 'Disease', (1260, 1268))	('S63845', 'Chemical', 'MESH:C000614727', (89, 95))	('tumor', 'Disease', (431, 436))	('ABT-199', 'Chemical', 'MESH:C579720', (1365, 1372))	('Ki67', 'Gene', '17345', (293, 297))	('tumor', 'Disease', 'MESH:D009369', (431, 436))	('ABT-199', 'Chemical', 'MESH:C579720', (548, 555))	('tumor', 'Disease', (334, 339))	('melanoma', 'Disease', (1211, 1219))	('melanoma', 'Disease', (228, 236))	('cutaneous melanoma', 'Disease', (1201, 1219))	('ABT-199', 'Chemical', 'MESH:C579720', (199, 206))	('S63845', 'Chemical', 'MESH:C000614727', (539, 545))	('S63845', 'Chemical', 'MESH:C000614727', (1358, 1364))	('melanoma', 'Disease', 'MESH:D008545', (668, 676))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('BRAF-WT melanoma cell', 'Disease', (112, 133))	('mouse', 'Species', '10090', (362, 367))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1201, 1219))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (1201, 1219))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('melanoma', 'Disease', 'MESH:D008545', (573, 581))	('melanoma', 'Phenotype', 'HP:0002861', (1121, 1129))	('melanoma', 'Disease', (1121, 1129))	('mouse', 'Species', '10090', (469, 474))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))	('melanoma', 'Disease', 'MESH:D008545', (1260, 1268))
42361	28884047	BsmI (rs1544410) and FokI (rs2228570) vitamin D receptor polymorphisms, smoking, and body mass index as risk factors of cutaneous malignant melanoma in northeast Italy : To investigate whether vitamin D receptor gene (VDR) BsmI-rs1544410 and FokI-rs2228570 polymorphisms, smoking duration, and body mass index (BMI) are risk factors for cutaneous melanoma, especially metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (347, 355))	('vitamin D receptor', 'Gene', '7421', (193, 211))	('malignant melanoma', 'Disease', 'MESH:D008545', (130, 148))	('rs1544410', 'Mutation', 'rs1544410', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (379, 387))	('vitamin D receptor', 'Gene', (38, 56))	('FokI-rs2228570', 'Var', (242, 256))	('VDR', 'Gene', (218, 221))	('rs1544410', 'Mutation', 'rs1544410', (228, 237))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('rs2228570', 'Mutation', 'rs2228570', (27, 36))	('vitamin D receptor', 'Gene', '7421', (38, 56))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (120, 148))	('rs2228570', 'Mutation', 'rs2228570', (247, 256))	('malignant melanoma', 'Disease', (130, 148))	('VDR', 'Gene', '7421', (218, 221))	('melanoma', 'Phenotype', 'HP:0002861', (347, 355))	('melanoma', 'Disease', (347, 355))	('melanoma', 'Phenotype', 'HP:0002861', (379, 387))	('cutaneous melanoma', 'Disease', (337, 355))	('melanoma', 'Disease', (379, 387))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (337, 355))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (337, 355))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('vitamin D receptor', 'Gene', (193, 211))	('malignant melanoma', 'Phenotype', 'HP:0002861', (130, 148))
42365	28884047	Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk: >=20 years of smoking (OR=2.43); >=20 years of smoking combined with bb (OR=4.78), Bb+bb (OR=2.30), Ff (OR=3.04), and Ff+ff (OR=3.08); obesity (BMI>30 kg/m2) alone (OR=3.54); and obesity combined with Bb+bb (OR=3.52), Ff (OR=4.78), and Ff+ff (OR=6.56).	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('Bb+bb', 'Chemical', '-', (308, 313))	('>=20', 'Var', (107, 111))	('obesity', 'Disease', (286, 293))	('obesity', 'Disease', (242, 249))	('bb', 'Chemical', '-', (176, 178))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('obesity', 'Phenotype', 'HP:0001513', (286, 293))	('obesity', 'Phenotype', 'HP:0001513', (242, 249))	('patients', 'Species', '9606', (27, 35))	('bb', 'Chemical', '-', (193, 195))	('Bb+bb', 'Chemical', '-', (190, 195))	('bb', 'Chemical', '-', (311, 313))	('melanoma', 'Disease', (18, 26))	('obesity', 'Disease', 'MESH:D009765', (286, 293))	('obesity', 'Disease', 'MESH:D009765', (242, 249))
42366	28884047	Comparison of MetM vs NMetM patients revealed that the following biomarkers were at risk: >=20 years of smoking (OR=2.39), >=20 years of smoking combined with bb (OR=5.13), Bb+bb (OR=3.07), and Ff+ff (OR=2.66); and obesity combined with Bb+bb (OR=5.27), Ff (OR=6.28), and Ff+ff (OR=9.18).	('obesity', 'Disease', 'MESH:D009765', (215, 222))	('bb', 'Chemical', '-', (176, 178))	('>=20', 'Var', (90, 94))	('Bb+bb', 'Chemical', '-', (237, 242))	('bb', 'Chemical', '-', (240, 242))	('obesity', 'Disease', (215, 222))	('>=20 years', 'Var', (123, 133))	('bb', 'Chemical', '-', (159, 161))	('Bb+bb', 'Chemical', '-', (173, 178))	('obesity', 'Phenotype', 'HP:0001513', (215, 222))	('patients', 'Species', '9606', (28, 36))
42390	28884047	Most clinical studies that explored association of VDR polymorphisms with diseases focused on two VDR single-nucleotide polymorphisms (SNPs), namely, BsmI-rs1544410 G>A located in intron 8 and FokI-rs2228570 C>T located in exon 2.	('FokI-rs2228570 C>T', 'Var', (193, 211))	('VDR', 'Gene', (51, 54))	('rs2228570', 'Mutation', 'rs2228570', (198, 207))	('BsmI-rs1544410 G>A', 'Var', (150, 168))	('rs1544410', 'Mutation', 'rs1544410', (155, 164))	('VDR', 'Gene', '7421', (51, 54))	('VDR', 'Gene', (98, 101))	('VDR', 'Gene', '7421', (98, 101))
42408	28884047	To compare MetM and NMetM, adjusted analyses included indicators that resulted in risk of metastasis development: (3) trunk location, Breslow's thickness, ulceration, mitosis>1, absence of tumor-infiltrating lymphocytes (TILs), and epithelioid variant; (4) >=20 years of smoking; and (5) BMI>30 kg/m2 (i.e., obesity).	('metastasis development', 'CPA', (90, 112))	('TIL', 'Gene', (221, 224))	('tumor', 'Disease', (189, 194))	('BMI>30 kg/m2', 'Var', (288, 300))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('absence', 'NegReg', (178, 185))	('obesity', 'Disease', 'MESH:D009765', (308, 315))	('men', 'Species', '9606', (108, 111))	('mitosis', 'biological_process', 'GO:0000278', ('167', '174'))	('obesity', 'Disease', (308, 315))	('mitosis', 'Disease', (167, 174))	('ulceration', 'Disease', (155, 165))	('TIL', 'Gene', '7096', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mitosis', 'Disease', 'None', (167, 174))	('Breslow', 'Disease', (134, 141))	('obesity', 'Phenotype', 'HP:0001513', (308, 315))	('trunk', 'cellular_component', 'GO:0043198', ('118', '123'))
42438	28884047	Genotype bb combined with >=20 years of smoking was more frequent among all melanoma patients than healthy controls (OR=4.78), in MetM than NMetM patients (OR=5.13), and in MetM patients than healthy controls (OR=9.18).	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('Genotype', 'Var', (0, 8))	('patients', 'Species', '9606', (178, 186))	('frequent', 'Reg', (57, 65))	('patients', 'Species', '9606', (85, 93))	('bb', 'Chemical', '-', (9, 11))	('patients', 'Species', '9606', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
42444	28884047	Notably, Ff genotype combined with >=20 years of smoking acted as risk factor for all melanoma patients (OR=3.04 for melanoma patients vs. healthy controls) and MetM patients (OR=4.84 for MetM patients vs. healthy controls).	('risk factor', 'Reg', (66, 77))	('genotype', 'Var', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Disease', (86, 94))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (166, 174))	('melanoma', 'Disease', (117, 125))
42447	28884047	Finally, obese carriers of Ff+ff presented an increased risk for all melanomas (OR=6.56 for all melanoma patients vs. healthy controls) and for MetM (OR=9.18 for MetM patients vs. healthy controls).	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('patients', 'Species', '9606', (105, 113))	('obese', 'Disease', (9, 14))	('MetM', 'Disease', (144, 148))	('Ff+ff', 'Var', (27, 32))	('patients', 'Species', '9606', (167, 175))	('melanomas', 'Disease', (69, 78))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('obese', 'Disease', 'MESH:D009765', (9, 14))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('melanoma', 'Disease', (69, 77))
42466	28884047	Paradoxically, by comparison with healthy controls, carriage of bb genotype posed risk to MetM, but was protective for NMetM cases.	('risk', 'Reg', (82, 86))	('bb', 'Chemical', '-', (64, 66))	('MetM', 'Disease', (90, 94))	('carriage', 'Var', (52, 60))
42469	28884047	The study indicated increased frequencies of Bb and bb genotypes in melanoma patients compared with healthy controls (BB 23.8%, Bb 50.5%, bb 25.7%) and demonstrated an association between VDR-BsmI bb genotype and increased Breslow's thickness, a parameter that is consistently associated with metastasis and poor prognosis.	('increased', 'PosReg', (20, 29))	('VDR', 'Gene', '7421', (188, 191))	('bb', 'Chemical', '-', (52, 54))	('Bb', 'Chemical', '-', (128, 130))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	("Breslow's thickness", 'Disease', (223, 242))	('melanoma', 'Disease', (68, 76))	('BB', 'Chemical', '-', (118, 120))	('patients', 'Species', '9606', (77, 85))	('VDR', 'Gene', (188, 191))	('bb', 'Chemical', '-', (138, 140))	('Bb', 'Chemical', '-', (45, 47))	('bb', 'Chemical', '-', (197, 199))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('increased', 'PosReg', (213, 222))	('genotype', 'Var', (200, 208))
42470	28884047	A meta-analysis showed that BsmI B allele is associated with reduced melanoma risk with OR=0.81 and 95% CI=0.72-0.92.	('allele', 'Var', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('reduced', 'NegReg', (61, 68))	('BsmI B', 'Gene', (28, 34))
42475	28884047	Functional effect of VDR-BsmI polymorphism remains unclear.	('VDR', 'Gene', '7421', (21, 24))	('polymorphism', 'Var', (30, 42))	('VDR', 'Gene', (21, 24))
42477	28884047	Thus, VDR-BsmI polymorphism cannot directly change the protein sequence of the VDR receptor.	('VDR', 'Gene', '7421', (6, 9))	('polymorphism', 'Var', (15, 27))	('VDR', 'Gene', '7421', (79, 82))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('VDR', 'Gene', (6, 9))	('VDR', 'Gene', (79, 82))
42482	28884047	In general, inconsistent findings were reported for association of VDR-FokI polymorphism with melanoma.	('VDR', 'Gene', (67, 70))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('association', 'Interaction', (52, 63))	('polymorphism', 'Var', (76, 88))	('VDR', 'Gene', '7421', (67, 70))
42483	28884047	In one meta-analysis, FokI polymorphism was associated with an overall significantly increased risk of skin cancer (Ff vs. FF: OR=1.20, 95% CI=1.01-1.44; ff vs. FF: OR=1.41, 95% CI=1.08-1.84; Ff+ff vs. FF: OR=1.26, 95% CI=1.04-1.53).	('polymorphism', 'Var', (27, 39))	('skin cancer', 'Disease', 'MESH:D012878', (103, 114))	('FokI', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('skin cancer', 'Phenotype', 'HP:0008069', (103, 114))	('skin cancer', 'Disease', (103, 114))
42485	28884047	Notably, in our study, Ff+ff (f allele carriers), when combined with >=20 years of smoking or with obesity, exhibited adjusted OR=4 and ORs from 8 to 18, respectively, for MetM patients vs. healthy controls.	('obesity', 'Disease', 'MESH:D009765', (99, 106))	('patients', 'Species', '9606', (177, 185))	('obesity', 'Disease', (99, 106))	('MetM', 'Disease', (172, 176))	('obesity', 'Phenotype', 'HP:0001513', (99, 106))	('Ff+ff', 'Var', (23, 28))
42489	28884047	We also observed that >=20 years of ever in life smoking combined with certain genetic traits, specifically, with bb, Bb+bb (b allele carriers), Ff, and Ff+ff (f allele carriers) are associated with significant crude ORs ranging from 4 to 9 for MetM cases vs healthy controls.	('MetM', 'Disease', (245, 249))	('bb', 'Chemical', '-', (121, 123))	('to 9', 'Species', '1214577', (236, 240))	('Ff+ff', 'Var', (153, 158))	('bb', 'Chemical', '-', (114, 116))	('Bb+bb', 'Chemical', '-', (118, 123))	('Bb+bb', 'Gene', (118, 123))
42494	28884047	revealed that smoking duration at diagnosis (hazard ratio=1.11, 95% CI=1.03-1.20, P=0.009) is associated with risk of death from melanoma; and that lower vitamin D levels and smoking are associated with ulceration (a well-known poor prognostic factor) of primary melanomas and poor melanoma-specific survival.	('lower vitamin D', 'Phenotype', 'HP:0100512', (148, 163))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('ulceration', 'Disease', (203, 213))	('melanoma', 'Disease', (263, 271))	('primary melanoma', 'Disease', (255, 271))	('primary melanoma', 'Disease', 'MESH:D008545', (255, 271))	('vitamin D', 'Chemical', 'MESH:D014807', (154, 163))	('melanoma', 'Disease', 'MESH:D008545', (282, 290))	('melanomas', 'Disease', 'MESH:D008545', (263, 272))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('smoking', 'Var', (175, 182))	('melanomas', 'Disease', (263, 272))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('melanoma', 'Phenotype', 'HP:0002861', (282, 290))	('melanoma', 'Disease', (282, 290))	('vitamin D levels', 'MPA', (154, 170))	('melanomas', 'Phenotype', 'HP:0002861', (263, 272))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('lower', 'NegReg', (148, 153))
42506	28884047	A recent study on melanoma cells observed a role for epigenetic mechanisms in VDR-miRNAs regulation.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('epigenetic', 'Var', (53, 63))	('VDR', 'Gene', (78, 81))	('regulation', 'biological_process', 'GO:0065007', ('89', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('VDR', 'Gene', '7421', (78, 81))
42512	28884047	A large-cohort Italian study demonstrated that BMI>=25 kg/m2 is associated with Breslow's thickness>1 mm among melanoma patients.	('BMI>=25 kg/m2', 'Var', (47, 60))	('associated', 'Reg', (64, 74))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	("Breslow's thickness>1 mm", 'Disease', (80, 104))	('melanoma', 'Disease', (111, 119))	('patients', 'Species', '9606', (120, 128))
42523	28884047	Thus, any modification of VDR activities induced by VDR polymorphisms can affect vitamin D functions.	('VDR', 'Gene', (52, 55))	('vitamin D functions', 'MPA', (81, 100))	('VDR', 'Gene', (26, 29))	('VDR', 'Gene', '7421', (52, 55))	('modification', 'Reg', (10, 22))	('affect', 'Reg', (74, 80))	('vitamin D', 'Chemical', 'MESH:D014807', (81, 90))	('polymorphisms', 'Var', (56, 69))	('VDR', 'Gene', '7421', (26, 29))
42524	28884047	Deletion of VDR results in increased susceptibility to tumor formation and reduces ability of keratinocytes to clear UVB-induced DNA mutations.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('increased', 'PosReg', (27, 36))	('VDR', 'Gene', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('tumor', 'Disease', (55, 60))	('VDR', 'Gene', '7421', (12, 15))	('reduces', 'NegReg', (75, 82))	('ability', 'MPA', (83, 90))	('susceptibility', 'Reg', (37, 51))	('formation', 'biological_process', 'GO:0009058', ('61', '70'))	('Deletion', 'Var', (0, 8))
42527	28884047	VDR cistrome analyses suggested that altered expression of VDR in colon cancer changes actions of VDR, thus affecting patient outcome.	('colon cancer', 'Disease', (66, 78))	('VDR', 'Gene', '7421', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('VDR', 'Gene', '7421', (59, 62))	('VDR', 'Gene', (98, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('affecting', 'Reg', (108, 117))	('VDR', 'Gene', (0, 3))	('VDR', 'Gene', (59, 62))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('changes', 'Reg', (79, 86))	('altered', 'Var', (37, 44))	('patient', 'Species', '9606', (118, 125))	('VDR', 'Gene', '7421', (98, 101))
42537	28884047	We first suggest gene-environment effects, including smoking duration and obesity, and VDR genetic polymorphisms with cutaneous malignant melanoma in general and specifically with MetM.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (118, 146))	('cutaneous malignant melanoma', 'Disease', (118, 146))	('polymorphisms', 'Var', (99, 112))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('VDR', 'Gene', '7421', (87, 90))	('malignant melanoma', 'Phenotype', 'HP:0002861', (128, 146))	('obesity', 'Disease', (74, 81))	('men', 'Species', '9606', (29, 32))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (118, 146))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))	('VDR', 'Gene', (87, 90))	('MetM', 'Disease', (180, 184))
42539	28884047	Such management may include screening of VDR polymorphisms and detailed assessment of smoking habits and BMI.	('VDR', 'Gene', '7421', (41, 44))	('polymorphisms', 'Var', (45, 58))	('VDR', 'Gene', (41, 44))	('men', 'Species', '9606', (78, 81))	('men', 'Species', '9606', (11, 14))
42582	30374897	Firstly, analysis of the biopsy group indicated that the 10-year melanoma-specific survival rate was significantly lower among SLN-positive patients than among SLN-negative patients for intermediate-thickness melanomas (62.1+-4.8% versus 85.1+-1.5%).	('SLN-positive', 'Var', (127, 139))	('melanomas', 'Disease', (209, 218))	('patients', 'Species', '9606', (173, 181))	('intermediate-thickness melanoma', 'Phenotype', 'HP:0012057', (186, 217))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('lower', 'NegReg', (115, 120))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('patients', 'Species', '9606', (140, 148))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Disease', 'MESH:D008545', (209, 218))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
42583	30374897	Multivariate analysis for intermediate-thickness melanoma patients confirmed that SLN status was the most powerful prognostic factor, with about a 2.5-fold higher risk of recurrence or death from melanoma for SLN-positive patients than for the SLN-negative patients in the biopsy group (p < 0.001).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('SLN-positive', 'Var', (209, 221))	('intermediate-thickness melanoma', 'Phenotype', 'HP:0012057', (26, 57))	('death', 'Disease', 'MESH:D003643', (185, 190))	('death', 'Disease', (185, 190))	('patients', 'Species', '9606', (222, 230))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('patients', 'Species', '9606', (257, 265))	('patients', 'Species', '9606', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
42584	30374897	Secondly, analysis of data from patients who developed nodal metastases indicated that early intervention for nodal disease had a significant positive impact on survival: patients with intermediate-thickness melanomas in the observation group who developed a palpable nodal recurrence and had a TLND had a significantly lower 10-year melanoma-specific survival rate than those in the SLNB group with a positive SLN and immediate CLND (41.5% versus 62.1%, p = 0.006).	('intermediate-thickness', 'Var', (185, 207))	('melanoma', 'Disease', 'MESH:D008545', (334, 342))	('patients', 'Species', '9606', (32, 40))	('intermediate-thickness melanoma', 'Phenotype', 'HP:0012057', (185, 216))	('nodal metastases', 'Disease', (55, 71))	('nodal disease', 'Disease', 'MESH:D013611', (110, 123))	('melanoma', 'Disease', (208, 216))	('melanomas', 'Phenotype', 'HP:0002861', (208, 217))	('nodal disease', 'Disease', (110, 123))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('patients', 'Species', '9606', (171, 179))	('melanomas', 'Disease', 'MESH:D008545', (208, 217))	('nodal metastases', 'Disease', 'MESH:D009362', (55, 71))	('lower', 'NegReg', (320, 325))	('melanoma', 'Phenotype', 'HP:0002861', (334, 342))	('melanomas', 'Disease', (208, 217))	('melanoma', 'Disease', (334, 342))
42591	30374897	The study showed that S1-stage (1 <= n <= 2 and d <= 1 mm, with clustered subcapsular metastatic deposits) and S2-stage (n > 2 and d <= 1 mm, with more extended peripheral metastases) patients had a 5-year survival rate without distant metastases of over 90%, similar to that of S0-stage (no detectable metastases) patients.	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('metastases', 'Disease', (303, 313))	('patients', 'Species', '9606', (184, 192))	('S2-stage', 'Var', (111, 119))	('metastases', 'Disease', 'MESH:D009362', (303, 313))	('metastases', 'Disease', (236, 246))	('S1-stage', 'Var', (22, 30))	('metastases', 'Disease', 'MESH:D009362', (236, 246))	('patients', 'Species', '9606', (315, 323))	('metastases', 'Disease', (172, 182))
42592	30374897	In contrast, S3-stage (n > 2 and d > 1 mm, and deeper infiltration of metastatic cells in the parenchyma) patients had a very poor prognosis with a 5-year survival rate of around 30%.	('S3-stage', 'Var', (13, 21))	('patients', 'Species', '9606', (106, 114))	('d > 1 mm', 'Var', (33, 41))
42615	30374897	The most important disadvantage of CLND was lymphedema, which occurred in 24% of the patients in the dissection group compared with 6% in the observation group.	('lymphedema', 'Phenotype', 'HP:0001004', (44, 54))	('lymphedema', 'Disease', (44, 54))	('patients', 'Species', '9606', (85, 93))	('lymphedema', 'Disease', 'MESH:D008209', (44, 54))	('dissection', 'Var', (101, 111))
42624	30374897	In this study, patients who received ipilimumab (n = 475) had significantly higher rates of 5-year recurrence-free survival (40.8% versus 30.3%, p < 0.001), 5-year distant metastasis-free survival (48.3 versus 38.9, p = 0.002) and 5-year overall survival (65.4% versus 54.4%; HR for death = 0.72, p = 0.001) than patients who were prescribed the placebo (n = 476).	('patients', 'Species', '9606', (15, 23))	('ipilimumab', 'Var', (37, 47))	('overall survival', 'CPA', (238, 254))	('distant metastasis-free survival', 'CPA', (164, 196))	('ipilimumab', 'Chemical', 'MESH:D000074324', (37, 47))	('higher', 'PosReg', (76, 82))	('patients', 'Species', '9606', (313, 321))	('death', 'Disease', 'MESH:D003643', (283, 288))	('death', 'Disease', (283, 288))
42626	30374897	Recurrence-free survival at 1 year was significantly higher in patients treated with nivolumab than in those treated with ipilimumab (70.5% versus 60.8%), and the risk of recurrence or death was lower (34.0% versus 45.5% respectively, HR=0.65, 97.56% CI, 0.51-0.83; p < 0.001).	('Recurrence-free survival', 'CPA', (0, 24))	('higher', 'PosReg', (53, 59))	('death', 'Disease', 'MESH:D003643', (185, 190))	('nivolumab', 'Chemical', 'MESH:D000077594', (85, 94))	('death', 'Disease', (185, 190))	('patients', 'Species', '9606', (63, 71))	('ipilimumab', 'Chemical', 'MESH:D000074324', (122, 132))	('nivolumab', 'Var', (85, 94))
42627	30374897	In addition, as BRAF mutations are found in approximately 40% of melanomas, a double-blind placebo-controlled phase 3 trial (COMBI-AD: N = 870, median follow up: 2.8 years) investigated the efficacy of a combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.	('melanomas', 'Disease', 'MESH:D008545', (65, 74))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('MEK', 'Gene', '5609', (267, 270))	('trametinib', 'Chemical', 'MESH:C560077', (281, 291))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('melanomas', 'Disease', (65, 74))	('BRAF', 'Gene', (233, 237))	('BRAF', 'Gene', '673', (233, 237))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('MEK', 'Gene', (267, 270))	('dabrafenib', 'Chemical', 'MESH:C561627', (248, 258))	('mutations', 'Var', (21, 30))
42628	30374897	This treatment improved the estimated 3-year rate of relapse-free survival compared with a placebo (58% versus 39%; HR for relapse or death = 0.47; 95% CI, 0.39-0.58; p < 0.001) in patients with stage III melanoma with BRAF V600E or V600K mutations who had undergone CLND.	('stage III melanoma', 'Disease', 'MESH:D008545', (195, 213))	('death', 'Disease', 'MESH:D003643', (134, 139))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('death', 'Disease', (134, 139))	('V600K', 'Mutation', 'rs121913227', (233, 238))	('stage III melanoma', 'Disease', (195, 213))	('patients', 'Species', '9606', (181, 189))	('BRAF', 'Gene', (219, 223))	('improved', 'PosReg', (15, 23))	('BRAF', 'Gene', '673', (219, 223))	('V600K', 'Var', (233, 238))	('V600E', 'Mutation', 'rs113488022', (224, 229))
42641	33596955	We observed that patients with high TMB, high IFNgammaRes and high MacReg had significantly better OS compared to high TMB, low IFNgammaRes and low MacReg (HR = 2.8, p = 3.55E-08).	('TMB', 'Chemical', '-', (119, 122))	('high TMB', 'Var', (31, 39))	('high MacReg', 'Var', (62, 73))	('patients', 'Species', '9606', (17, 25))	('TMB', 'Chemical', '-', (36, 39))	('high IFNgammaRes', 'Var', (41, 57))	('better', 'PosReg', (92, 98))
42648	33596955	It has been established that the immunogenicity of melanoma is driven by one of the highest somatic mutation rates among all cancers, and a high overall TMB is associated with improved ICI therapy outcomes in melanoma, non-small cell lung cancer (NSCLC), and other cancers.	('NSCLC', 'Disease', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('improved', 'PosReg', (176, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('NSCLC', 'Phenotype', 'HP:0030358', (247, 252))	('ICI therapy', 'MPA', (185, 196))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('TMB', 'MPA', (153, 156))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancer', 'Disease', (234, 245))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('TMB', 'Chemical', '-', (153, 156))	('melanoma', 'Disease', (51, 59))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('NSCLC', 'Disease', 'MESH:D002289', (247, 252))	('mutation', 'Var', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('cancers', 'Disease', (265, 272))	('lung cancer', 'Disease', 'MESH:D008175', (234, 245))
42649	33596955	Since ICI therapies boost immune priming and activation, the level of neo-epitope burden (NB) resulting from tumor-specific somatic mutations may be associated with improved immune detection of tumor cells.	('improved', 'PosReg', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('immune detection', 'MPA', (174, 190))	('mutations', 'Var', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
42666	33596955	In order to predict which neo-epitopes, derived from somatic mutations, would be presented by MHC class I, and hence may represent cancer-specific antigens, we inferred the major MHC class I alleles (for HLA-A, HLA-B, and HLA-C) for each sample from WXS.	('cancer', 'Disease', (131, 137))	('HLA-A', 'Gene', (204, 209))	('MHC class', 'Gene', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (61, 70))	('HLA-B', 'Gene', (211, 216))	('HLA-A', 'Gene', '3105', (204, 209))	('HLA-B', 'Gene', '3106', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
42669	33596955	Using the MuTect2 aggregated protected MAF file, TMB for each patient was calculated as the total number of non-silent mutations present on autosomal chromosomes (frameshift or in-frame indels, missense mutations, nonsense mutations, nonstop mutations, or mutations in RNA-splice or transcription start sites).	('nonstop mutations', 'Var', (234, 251))	('RNA', 'cellular_component', 'GO:0005562', ('269', '272'))	('MAF', 'Gene', (39, 42))	('frameshift', 'Var', (163, 173))	('transcription', 'biological_process', 'GO:0006351', ('283', '296'))	('patient', 'Species', '9606', (62, 69))	('TMB', 'Chemical', '-', (49, 52))	('nonsense mutations', 'Var', (214, 232))	('mutations in', 'Var', (256, 268))	('missense mutations', 'Var', (194, 212))	('MAF', 'Gene', '4094', (39, 42))	('in-frame indels', 'Var', (177, 192))
42699	33596955	To define TMB cut-off most significantly associated with OS, in the discovery set we tested thresholds of 50, 75, 100, 125, 150, 200, 250 mutations per exome per patient (Table 1).	('patient', 'Species', '9606', (162, 169))	('TMB', 'Chemical', '-', (10, 13))	('associated', 'Reg', (41, 51))	('mutations', 'Var', (138, 147))
42703	33596955	We then used 125 mutations as our cutoff in the validation 1 set and observed that patients with 125 or fewer mutations had significantly worse median OS (3.6 years, p = 0.01, HR = 2.86, 95% CI 1.23-6.62) when compared to those with more than 125 mutations (9.8 years) (Table 1 and Additional file 1: Figure S1B).	('fewer', 'NegReg', (104, 109))	('patients', 'Species', '9606', (83, 91))	('worse', 'NegReg', (138, 143))	('mutations', 'Var', (110, 119))
42728	33596955	KM analysis of the high TMB group showed that patients with high levels of MacReg (defined as greater than the overall median value of 0.25) and IFNgammaRes (greater than the overall median value of - 0.05) had significantly (p = 0.0001) improved survival when compared to those patients with high TMB who had low levels of MacReg (<= 0.25) and IFNgammaRes (<= -0.05) (Fig.	('TMB', 'Chemical', '-', (298, 301))	('patients', 'Species', '9606', (46, 54))	('survival', 'CPA', (247, 255))	('high', 'Var', (60, 64))	('improved', 'PosReg', (238, 246))	('TMB', 'Chemical', '-', (24, 27))	('patients', 'Species', '9606', (279, 287))
42729	33596955	These data clearly show that high TMB patients have different survival outcomes based on their status of MacReg and IFNgammaRes; the high TMB patients with high levels of MacReg and IFNgammaRes have significantly better OS compared to those patients with low levels of each, and this association is statistically significant in a univariate Cox PH model (log-rank p = 6.82E-06, HR = 0.31, 95% CI 0.18-0.53) and even more significant in a multivariate Cox PH model (log-rank p = 3.84E-08, HR = 0.35, 95% CI 0.20-0.60).	('better', 'PosReg', (213, 219))	('TMB', 'Chemical', '-', (34, 37))	('TMB', 'Chemical', '-', (138, 141))	('patients', 'Species', '9606', (38, 46))	('high levels', 'Var', (156, 167))	('patients', 'Species', '9606', (142, 150))	('PH', 'Gene', '5053', (345, 347))	('patients', 'Species', '9606', (241, 249))	('PH', 'Gene', '5053', (455, 457))
42747	33596955	In a sample of 278 metastatic tumors from melanoma patients from publicly available resources at TCGA who had not been previously treated by ICI therapies, we found that low TMB was associated with worse OS (discovery p = 1.30E-05, HR = 3.52, 95% CI 2.00-6.20 and validation 1 p = 0.01, HR = 2.86, 95% CI 1.23-6.62).	('melanoma', 'Disease', (42, 50))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('low', 'Var', (170, 173))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('patients', 'Species', '9606', (51, 59))	('TMB', 'MPA', (174, 177))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('TMB', 'Chemical', '-', (174, 177))
42749	33596955	Specifically, our findings show that melanoma OS is significantly prolonged in patients with metastatic tumors harboring > 125 mutations, a threshold that is consistent with prior studies focused on ICI outcomes: a meta-analysis of three ICI metastatic melanoma studies determined that 192 mutations best differentiated responses to ICI therapy.	('melanoma OS', 'Disease', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma OS', 'Disease', 'MESH:C567932', (37, 48))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('melanoma', 'Disease', (253, 261))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))	('tumors', 'Disease', (104, 110))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (290, 299))
42751	33596955	found similar results with response to ICI therapy by defining low and high TMB by the median of 209 mutations and found that the high mutation load was associated with both improved progression-free survival and response to ICI therapy.	('TMB', 'Chemical', '-', (76, 79))	('progression-free survival', 'CPA', (183, 208))	('improved', 'PosReg', (174, 182))	('high mutation load', 'Var', (130, 148))
42763	33596955	This is shown by our findings that IFNgammaRes and MacReg levels modulate survival differently in patients with high or low TMB (Fig.	('TMB', 'Chemical', '-', (124, 127))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))	('survival', 'MPA', (74, 82))	('modulate', 'Reg', (65, 73))
42765	33596955	This shows that among patients with high TMB, which has been considered to be a favorable prognostic indicator, there is further stratification of survival based on the status of other pro-inflammatory tumor intrinsic pathways.	('TMB', 'Chemical', '-', (41, 44))	('tumor', 'Disease', (202, 207))	('patients', 'Species', '9606', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('high', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
42772	33596955	However, the opposite effects for the increased levels of IFNgammaRes (associated with OS in the TMB high group) and MacReg (associated with OS in the TMB low group), suggest different biological mechanisms of anti-tumor immunity in tumors with low TMB, likely supporting a model of a direct stimulation of MacReg that is independent of IFNgammaRes signaling.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('TMB', 'Chemical', '-', (151, 154))	('tumors', 'Disease', (233, 239))	('low', 'Var', (245, 248))	('tumor', 'Disease', (233, 238))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('TMB', 'Chemical', '-', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('TMB', 'Gene', (249, 252))	('signaling', 'biological_process', 'GO:0023052', ('349', '358'))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('increased', 'PosReg', (38, 47))	('TMB', 'Chemical', '-', (249, 252))
42820	28707459	Skin cancer was defined according to site as "C43" and "C44" according to the International Classification of Diseases, 10th revision (ICD-10) code.	('C44', 'Var', (56, 59))	('Skin cancer', 'Disease', (0, 11))	('Skin cancer', 'Phenotype', 'HP:0008069', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Skin cancer', 'Disease', 'MESH:D012878', (0, 11))
42822	28707459	Skin cancer with a morphology code of "8050-8078" or "8083-8084" was classified as squamous cell carcinoma and skin cancer coded as "8090-8098" was classified as basal cell carcinoma according to the International Classification of Diseases for Oncology, third edition (ICD-O-3) code.	('skin cancer', 'Disease', 'MESH:D012878', (111, 122))	('Oncology', 'Phenotype', 'HP:0002664', (245, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('basal cell carcinoma', 'Disease', (162, 182))	('squamous cell carcinoma', 'Disease', (83, 106))	('8083-8084', 'Var', (54, 63))	('Skin cancer', 'Disease', 'MESH:D012878', (0, 11))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (162, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (162, 182))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('Skin cancer', 'Disease', (0, 11))	('Skin cancer', 'Phenotype', 'HP:0008069', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('skin cancer', 'Disease', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
42823	28707459	Skin cancer sites were categorized into sun-exposed sites (face and neck: ICD-10 codes for C430-C433, C440-C443), and sites that are usually not exposed to sun (trunk and lower limbs: ICD-10 codes for C435, C437, C445, C447), to perform subgroup analysis.	('neck', 'cellular_component', 'GO:0044326', ('68', '72'))	('trunk', 'cellular_component', 'GO:0043198', ('161', '166'))	('Skin cancer', 'Disease', (0, 11))	('C430-C433', 'Var', (91, 100))	('Skin cancer', 'Phenotype', 'HP:0008069', (0, 11))	('C440-C443', 'Var', (102, 111))	('Skin cancer', 'Disease', 'MESH:D012878', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('lower limbs', 'Phenotype', 'HP:0006385', (171, 182))
42883	28707459	Indeed, a population-based study in Germany (SCREEN project) showed that skin cancer screening could increase the incidence of melanoma.	('screening', 'Var', (85, 94))	('increase', 'PosReg', (101, 109))	('skin cancer', 'Phenotype', 'HP:0008069', (73, 84))	('skin cancer', 'Disease', (73, 84))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('skin cancer', 'Disease', 'MESH:D012878', (73, 84))
42915	28831681	Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination.	('antagonizes', 'NegReg', (104, 115))	('RAD18', 'Gene', (71, 76))	('ubiquitin', 'Gene', '850620', (120, 129))	('PCNA', 'molecular_function', 'GO:0003892', ('87', '91'))	('PCNA', 'molecular_function', 'GO:0003892', ('17', '21'))	('NEDDylation', 'Var', (92, 103))	('RAD18', 'Gene', '56852', (71, 76))	('RAD', 'biological_process', 'GO:1990116', ('71', '74'))	('ubiquitin', 'Gene', (120, 129))
42916	28831681	In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination.	('NEDP1', 'Gene', (13, 18))	('NEDDylation', 'MPA', (85, 96))	('ubiquitin', 'Gene', '850620', (113, 122))	('NEDP1', 'Gene', (56, 61))	('enhances', 'PosReg', (71, 79))	('reduces', 'NegReg', (101, 108))	('PCNA', 'molecular_function', 'GO:0003892', ('80', '84'))	('NEDP1', 'Gene', '123228', (13, 18))	('ubiquitin', 'Gene', (113, 122))	('PCNA', 'molecular_function', 'GO:0003892', ('46', '50'))	('deletion', 'Var', (62, 70))	('NEDP1', 'Gene', '123228', (56, 61))
42918	28831681	Impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-poleta interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-poleta interaction and blocks poleta foci formation.	('PCNA-poleta interaction', 'MPA', (86, 109))	('poleta', 'Chemical', '-', (265, 271))	('ubiquitin', 'Gene', '850620', (226, 235))	('NEDP1', 'Gene', (173, 178))	('poleta', 'Chemical', '-', (295, 301))	('knockout', 'Var', (35, 43))	('Ubc12', 'Gene', '9040', (29, 34))	('inhibits', 'NegReg', (251, 259))	('Ubc12', 'Gene', (29, 34))	('NEDP1', 'Gene', '123228', (173, 178))	('promotes', 'PosReg', (77, 85))	('ubiquitin', 'Gene', (226, 235))	('NEDDylation', 'MPA', (14, 25))	('ubiquitin', 'Gene', '850620', (58, 67))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))	('blocks', 'NegReg', (288, 294))	('PCNA', 'molecular_function', 'GO:0003892', ('240', '244'))	('poleta foci formation', 'CPA', (295, 316))	('accumulation', 'MPA', (210, 222))	('deletion', 'Var', (179, 187))	('PCNA', 'molecular_function', 'GO:0003892', ('260', '264'))	('PCNA-poleta interaction', 'CPA', (260, 283))	('ubiquitin', 'Gene', (58, 67))	('reduces', 'NegReg', (188, 195))	('enhances', 'PosReg', (44, 52))	('PCNA', 'molecular_function', 'GO:0003892', ('86', '90'))	('PCNA', 'molecular_function', 'GO:0003892', ('53', '57'))	('poleta', 'Chemical', '-', (91, 97))	('formation', 'biological_process', 'GO:0009058', ('307', '316'))
42919	28831681	Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity.	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('NEDP1', 'Gene', '123228', (90, 95))	('cell sensitivity to H2O2-induced oxidative stress', 'MPA', (35, 84))	('oxidative stress', 'Phenotype', 'HP:0025464', (68, 84))	('decreases', 'NegReg', (25, 34))	('NEDP1', 'Gene', (90, 95))	('knockout', 'Var', (16, 24))	('Ubc12', 'Gene', '9040', (10, 15))	('deletion', 'Var', (96, 104))	('aggravates', 'PosReg', (105, 115))	('Ubc12', 'Gene', (10, 15))
42932	28831681	Moreover, other studies have shown that yeast PCNA is modified by small ubiquitin-like modifier (SUMO) on Lys164 and Lys127, and SUMOylated PCNA can recruit a helicase Srs2 to prevent undesired recombination (Pfander et al.,).	('Srs2', 'Gene', '853353', (168, 172))	('ubiquitin', 'Gene', (72, 81))	('Lys127', 'Chemical', '-', (117, 123))	('Lys127', 'Var', (117, 123))	('Srs2', 'Gene', (168, 172))	('yeast', 'Species', '4932', (40, 45))	('PCNA', 'molecular_function', 'GO:0003892', ('46', '50'))	('ubiquitin', 'Gene', '850620', (72, 81))	('PCNA', 'molecular_function', 'GO:0003892', ('140', '144'))	('Lys164', 'Var', (106, 112))	('Lys164', 'Chemical', '-', (106, 112))	('ubiquitin', 'molecular_function', 'GO:0031386', ('72', '81'))	('recruit', 'Interaction', (149, 156))
42940	28831681	By contrast, we did not observe modified PCNA in cells expressing a mutant NEDD8-DeltaGG that lacked the last two-glycine residues (Figs.	('NEDD8-DeltaGG', 'Gene', (75, 88))	('PCNA', 'molecular_function', 'GO:0003892', ('41', '45'))	('glycine', 'Chemical', 'MESH:D005998', (114, 121))	('mutant', 'Var', (68, 74))
42941	28831681	Moreover, we investigated whether NEDD8-activating enzyme inhibitor MLN4924 affected PCNA NEDDylation.	('PCNA', 'Disease', (85, 89))	('MLN4924', 'Chemical', 'MESH:C539933', (68, 75))	('PCNA', 'molecular_function', 'GO:0003892', ('85', '89'))	('MLN4924', 'Var', (68, 75))	('affected', 'Reg', (76, 84))
42942	28831681	1B, MLN4924 abolished PCNA NEDDylation compared to that in untreated cells, indicating that the NEDD8 activating E1 is utilized for PCNA NEDDylation.	('MLN4924', 'Var', (4, 11))	('PCNA', 'molecular_function', 'GO:0003892', ('22', '26'))	('abolished', 'NegReg', (12, 21))	('PCNA', 'molecular_function', 'GO:0003892', ('132', '136'))	('MLN4924', 'Chemical', 'MESH:C539933', (4, 11))
42943	28831681	As the lysine 164 of PCNA is the modification site for both ubiquitin and SUMO (Bergink and Jentsch,), to investigate whether NEDD8 also targets PCNA at Lys164, we constructed a mutant, PCNA-K164R, and examined its NEDDylation.	('PCNA', 'molecular_function', 'GO:0003892', ('21', '25'))	('Lys164', 'Chemical', '-', (153, 159))	('ubiquitin', 'Gene', '850620', (60, 69))	('K164R', 'SUBSTITUTION', 'None', (191, 196))	('PCNA', 'molecular_function', 'GO:0003892', ('145', '149'))	('examined', 'Reg', (202, 210))	('PCNA', 'molecular_function', 'GO:0003892', ('186', '190'))	('K164R', 'Var', (191, 196))	('ubiquitin', 'Gene', (60, 69))	('lysine', 'Chemical', 'MESH:D008239', (7, 13))	('ubiquitin', 'molecular_function', 'GO:0031386', ('60', '69'))
42962	28831681	The Cys28 in the RING domain of RAD18 is the key site essential for its E3 ligase activity (Huang et al.,), we constructed two RAD18 mutants, C28F and DeltaRING, and detected their effects on PCNA NEDDylation.	('effects', 'Reg', (181, 188))	('C28F', 'Var', (142, 146))	('DeltaRING', 'Var', (151, 160))	('PCNA NEDDylation', 'MPA', (192, 208))	('Cys28', 'Chemical', '-', (4, 9))	('RAD18', 'Gene', (32, 37))	('PCNA', 'molecular_function', 'GO:0003892', ('192', '196'))	('RAD18', 'Gene', '56852', (32, 37))	('RAD', 'biological_process', 'GO:1990116', ('127', '130'))	('C28F', 'Mutation', 'p.C28F', (142, 146))	('ligase activity', 'molecular_function', 'GO:0016874', ('75', '90'))	('RAD18', 'Gene', (127, 132))	('RAD', 'biological_process', 'GO:1990116', ('32', '35'))	('RAD18', 'Gene', '56852', (127, 132))
42963	28831681	The mutants diminished the activity of RAD18 in mediating PCNA NEDDylation (Fig.	('mutants', 'Var', (4, 11))	('RAD18', 'Gene', (39, 44))	('activity', 'MPA', (27, 35))	('RAD18', 'Gene', '56852', (39, 44))	('RAD', 'biological_process', 'GO:1990116', ('39', '42'))	('PCNA', 'molecular_function', 'GO:0003892', ('58', '62'))	('mediating PCNA NEDDylation', 'MPA', (48, 74))	('diminished', 'NegReg', (12, 22))
42964	28831681	2E, lines 1-4), demonstrating that Cys28 is essential for RAD18 to catalyze NEDDylation pathway.	('RAD18', 'Gene', '56852', (58, 63))	('RAD', 'biological_process', 'GO:1990116', ('58', '61'))	('NEDDylation pathway', 'Pathway', (76, 95))	('Cys28', 'Var', (35, 40))	('Cys28', 'Chemical', '-', (35, 40))	('RAD18', 'Gene', (58, 63))
42967	28831681	With Rad18 depletion, PCNA NEDDylation was abolished totally compared to that in WT cells, and only WT RAD18 but not the mutants could recover PCNA NEDDylation (Fig.	('RAD18', 'Gene', '56852', (103, 108))	('PCNA', 'molecular_function', 'GO:0003892', ('143', '147'))	('Rad18', 'Gene', '56852', (5, 10))	('RAD', 'biological_process', 'GO:1990116', ('103', '106'))	('PCNA', 'molecular_function', 'GO:0003892', ('22', '26'))	('Rad18', 'Gene', (5, 10))	('PCNA', 'MPA', (143, 147))	('Rad', 'biological_process', 'GO:1990116', ('5', '8'))	('depletion', 'Var', (11, 20))	('RAD18', 'Gene', (103, 108))	('abolished', 'NegReg', (43, 52))
42975	28831681	3C), indicating that the increased NEDDylation of PCNA is dependent on the conserved modification residue Lys164.	('NEDDylation', 'MPA', (35, 46))	('PCNA', 'molecular_function', 'GO:0003892', ('50', '54'))	('Lys164', 'Chemical', '-', (106, 112))	('Lys164', 'Var', (106, 112))
42979	28831681	S2C, in MLN4924-treated 293T cells, we performed Ni2+ pull-down assay and observed a significant inhibition of MLN4924 on PCNA NEDDylation but not its ubiqitination, suggesting that PCNA NEDDylation utilizes the NEDD8 E1 under oxidative stress.	('PCNA', 'molecular_function', 'GO:0003892', ('182', '186'))	('Ni2+', 'Chemical', '-', (49, 53))	('MLN4924', 'Chemical', 'MESH:C539933', (111, 118))	('MLN4924', 'Chemical', 'MESH:C539933', (8, 15))	('293T', 'CellLine', 'CVCL:0063', (24, 28))	('inhibition', 'NegReg', (97, 107))	('PCNA', 'molecular_function', 'GO:0003892', ('122', '126'))	('MLN4924', 'Var', (111, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (227, 243))
42981	28831681	Moreover, in Ubc12 -/- cells, we did not detect the increase of PCNA NEDDylation, while expression of UBC12 recovered the accumulation of NEDDylated PCNA (Fig.	('NEDDylated', 'MPA', (138, 148))	('UBC12', 'Gene', '9040', (102, 107))	('expression', 'Var', (88, 98))	('accumulation', 'MPA', (122, 134))	('recovered', 'PosReg', (108, 117))	('UBC12', 'Gene', (102, 107))	('Ubc12', 'Gene', '9040', (13, 18))	('Ubc12', 'Gene', (13, 18))	('PCNA', 'molecular_function', 'GO:0003892', ('149', '153'))	('PCNA', 'molecular_function', 'GO:0003892', ('64', '68'))
42986	28831681	Moreover, expression of NEDP1 abolished PCNA NEDDylation and inhibited NEDDylated PCNA under oxidative stress (Fig.	('inhibited', 'NegReg', (61, 70))	('NEDDylated', 'MPA', (71, 81))	('NEDP1', 'Gene', (24, 29))	('abolished', 'NegReg', (30, 39))	('PCNA', 'molecular_function', 'GO:0003892', ('40', '44'))	('NEDP1', 'Gene', '123228', (24, 29))	('oxidative stress', 'Phenotype', 'HP:0025464', (93, 109))	('PCNA', 'Disease', (40, 44))	('expression', 'Var', (10, 20))	('PCNA', 'molecular_function', 'GO:0003892', ('82', '86'))
42990	28831681	In H2O2 treated WT cells, we observed an obvious increase in modified PCNA in the TIF, while in Rad18 -/- cells, we did not detect modified bands of PCNA under oxidative stress (Fig.	('Rad18', 'Gene', (96, 101))	('increase', 'PosReg', (49, 57))	('H2O2', 'Chemical', 'MESH:D006861', (3, 7))	('modified', 'MPA', (61, 69))	('Rad', 'biological_process', 'GO:1990116', ('96', '99'))	('PCNA', 'Protein', (70, 74))	('PCNA', 'molecular_function', 'GO:0003892', ('70', '74'))	('Rad18', 'Gene', '56852', (96, 101))	('PCNA', 'molecular_function', 'GO:0003892', ('149', '153'))	('H2O2', 'Var', (3, 7))	('oxidative stress', 'Phenotype', 'HP:0025464', (160, 176))
42994	28831681	In addition, WT RAD18 but not the inactive enzyme mutants of RAD18, C28F or DeltaRING could rescue PCNA NEDDylation (Fig.	('C28F', 'Mutation', 'p.C28F', (68, 72))	('RAD18', 'Gene', (16, 21))	('DeltaRING', 'Var', (76, 85))	('RAD18', 'Gene', (61, 66))	('RAD18', 'Gene', '56852', (16, 21))	('RAD', 'biological_process', 'GO:1990116', ('61', '64'))	('C28F', 'Var', (68, 72))	('RAD18', 'Gene', '56852', (61, 66))	('rescue', 'PosReg', (92, 98))	('RAD', 'biological_process', 'GO:1990116', ('16', '19'))	('PCNA', 'molecular_function', 'GO:0003892', ('99', '103'))	('PCNA NEDDylation', 'Disease', (99, 115))
43005	28831681	5B, expression of NEDD8 inhibited PCNA ubiquitination (line 2 vs. line 1, left panel), and vice versa (line 2 vs. line 1, right panel), suggesting that PCNA NEDDylation antagonizes its ubiquitination.	('PCNA', 'molecular_function', 'GO:0003892', ('152', '156'))	('ubiquitin', 'Gene', '850620', (39, 48))	('antagonizes', 'NegReg', (169, 180))	('ubiquitin', 'Gene', '850620', (185, 194))	('inhibited', 'NegReg', (24, 33))	('PCNA', 'molecular_function', 'GO:0003892', ('34', '38'))	('NEDD8', 'Gene', (18, 23))	('ubiquitin', 'Gene', (39, 48))	('PCNA', 'Var', (152, 156))	('expression', 'Var', (4, 14))	('ubiquitin', 'Gene', (185, 194))
43008	28831681	Moreover, in Ubc12 -/- cells, we found that PCNA ubiquitination increased, which was reduced by UBC12 re-expression (Fig.	('re-expression', 'Var', (102, 115))	('ubiquitin', 'Gene', (49, 58))	('UBC12', 'Gene', '9040', (96, 101))	('Ubc12', 'Gene', '9040', (13, 18))	('Ubc12', 'Gene', (13, 18))	('PCNA', 'molecular_function', 'GO:0003892', ('44', '48'))	('UBC12', 'Gene', (96, 101))	('increased', 'PosReg', (64, 73))	('ubiquitin', 'Gene', '850620', (49, 58))
43012	28831681	Moreover, we assessed whether Nedp1 knockout and Ubc12 knockout affected PCNA ubiquitination induced by H2O2 treatment.	('Ubc12', 'Gene', '9040', (49, 54))	('ubiquitin', 'Gene', '850620', (78, 87))	('affected', 'Reg', (64, 72))	('Nedp1', 'Gene', (30, 35))	('ubiquitin', 'Gene', (78, 87))	('knockout', 'Var', (55, 63))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))	('Ubc12', 'Gene', (49, 54))	('PCNA', 'molecular_function', 'GO:0003892', ('73', '77'))
43023	28831681	Moreover, in cells not treated with H2O2, expression of ubiquitin but not NEDD8 promoted the recruitment of poleta to PCNA (Fig.	('ubiquitin', 'Gene', (56, 65))	('promoted', 'PosReg', (80, 88))	('poleta', 'Chemical', '-', (108, 114))	('recruitment', 'MPA', (93, 104))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('PCNA', 'molecular_function', 'GO:0003892', ('118', '122'))	('expression', 'Var', (42, 52))	('ubiquitin', 'Gene', '850620', (56, 65))	('ubiquitin', 'molecular_function', 'GO:0031386', ('56', '65'))	('NEDD8', 'Gene', (74, 79))
43026	28831681	6B, Nedp1 knockout reduced the interaction between PCNA and poleta, suggesting that enhanced NEDDylation reduced PCNA ubiquitination, thus impeded poleta recruitment.	('impeded', 'NegReg', (139, 146))	('interaction', 'Interaction', (31, 42))	('ubiquitin', 'Gene', (118, 127))	('knockout', 'Var', (10, 18))	('reduced', 'NegReg', (105, 112))	('reduced', 'NegReg', (19, 26))	('Nedp1', 'Gene', (4, 9))	('poleta', 'Chemical', '-', (60, 66))	('PCNA', 'molecular_function', 'GO:0003892', ('113', '117'))	('enhanced', 'PosReg', (84, 92))	('PCNA', 'molecular_function', 'GO:0003892', ('51', '55'))	('poleta', 'Chemical', '-', (147, 153))	('NEDDylation', 'MPA', (93, 104))	('ubiquitin', 'Gene', '850620', (118, 127))
43028	28831681	6C), indicating that loss of PCNA NEDDylation promotes poleta recruitment.	('loss', 'Var', (21, 25))	('poleta recruitment', 'CPA', (55, 73))	('poleta', 'Chemical', '-', (55, 61))	('PCNA NEDDylation', 'Protein', (29, 45))	('promotes', 'PosReg', (46, 54))	('PCNA', 'molecular_function', 'GO:0003892', ('29', '33'))
43029	28831681	In addition, Immunofluorescence assay showed that NEDD8 expression blocked poleta foci formation under oxidative stress (Fig.	('NEDD8', 'Gene', (50, 55))	('poleta foci formation', 'CPA', (75, 96))	('blocked', 'NegReg', (67, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('poleta', 'Chemical', '-', (75, 81))	('expression', 'Var', (56, 66))	('formation', 'biological_process', 'GO:0009058', ('87', '96'))
43030	28831681	Together, these results demonstrate that up-regulation of NEDDylation by NEDD8 overexpression or Nedp1 knockout antagonizes PCNA ubiquitination and thus inhibits poleta recruitment, while Ubc12 knockout promotes PCNA ubiquitination and enhances poleta recruitment.	('Nedp1', 'Gene', (97, 102))	('poleta', 'Chemical', '-', (162, 168))	('NEDD8', 'Gene', (73, 78))	('ubiquitin', 'Gene', '850620', (129, 138))	('poleta recruitment', 'MPA', (162, 180))	('PCNA', 'molecular_function', 'GO:0003892', ('212', '216'))	('Ubc12', 'Gene', '9040', (188, 193))	('promotes', 'PosReg', (203, 211))	('Ubc12', 'Gene', (188, 193))	('ubiquitin', 'Gene', '850620', (217, 226))	('ubiquitin', 'Gene', (129, 138))	('poleta', 'Chemical', '-', (245, 251))	('NEDDylation', 'MPA', (58, 69))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))	('antagonizes', 'NegReg', (112, 123))	('knockout', 'Var', (103, 111))	('ubiquitin', 'Gene', (217, 226))	('poleta recruitment', 'MPA', (245, 263))	('enhances', 'PosReg', (236, 244))	('PCNA', 'molecular_function', 'GO:0003892', ('124', '128'))	('inhibits', 'NegReg', (153, 161))	('up-regulation', 'PosReg', (41, 54))
43035	28831681	While in Ubc12 -/- cells, we found that UBC12 deletion increased cell survival while UBC12 re-expression increased cell sensitivity to oxidative stress induced by H2O2 treatment (Fig.	('UBC12', 'Gene', '9040', (40, 45))	('UBC12', 'Gene', '9040', (85, 90))	('Ubc12', 'Gene', (9, 14))	('cell survival', 'CPA', (65, 78))	('deletion', 'Var', (46, 54))	('increased', 'PosReg', (55, 64))	('UBC12', 'Gene', (40, 45))	('H2O2', 'Chemical', 'MESH:D006861', (163, 167))	('UBC12', 'Gene', (85, 90))	('cell sensitivity to oxidative stress induced', 'MPA', (115, 159))	('increased', 'PosReg', (105, 114))	('Ubc12', 'Gene', '9040', (9, 14))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
43037	28831681	These data indicate that in Ubc12 -/- cells, impaired NEDDylation increases cell survival in response to DNA damaging agents.	('increases', 'PosReg', (66, 75))	('NEDDylation', 'MPA', (54, 65))	('cell survival', 'CPA', (76, 89))	('Ubc12', 'Gene', '9040', (28, 33))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('Ubc12', 'Gene', (28, 33))	('response to DNA damaging agents', 'MPA', (93, 124))	('impaired', 'Var', (45, 53))
43042	28831681	More importantly, Ubc12 knockout promotes PCNA ubiquitination while Nedp1 knockout or NEDD8 expression inhibits PCNA ubiquitination and further reduces poleta recruitment.	('promotes', 'PosReg', (33, 41))	('ubiquitin', 'Gene', '850620', (47, 56))	('knockout', 'Var', (74, 82))	('PCNA', 'molecular_function', 'GO:0003892', ('112', '116'))	('ubiquitin', 'Gene', (117, 126))	('reduces', 'NegReg', (144, 151))	('poleta recruitment', 'MPA', (152, 170))	('inhibits', 'NegReg', (103, 111))	('poleta', 'Chemical', '-', (152, 158))	('NEDD8', 'Gene', (86, 91))	('ubiquitin', 'Gene', (47, 56))	('Nedp1', 'Gene', (68, 73))	('ubiquitin', 'Gene', '850620', (117, 126))	('Ubc12', 'Gene', (18, 23))	('Ubc12', 'Gene', '9040', (18, 23))	('knockout', 'Var', (24, 32))	('PCNA', 'molecular_function', 'GO:0003892', ('42', '46'))
43044	28831681	Interestingly, our results show that PCNA NEDDylation also occurs at Lys164 and utilizes the same E3 ligase RAD18, suggesting a close relationship between PCNA ubiquitination and NEDDylation.	('PCNA', 'molecular_function', 'GO:0003892', ('155', '159'))	('Lys164', 'Var', (69, 75))	('RAD18', 'Gene', '56852', (108, 113))	('PCNA', 'molecular_function', 'GO:0003892', ('37', '41'))	('ubiquitin', 'Gene', (160, 169))	('RAD', 'biological_process', 'GO:1990116', ('108', '111'))	('ubiquitin', 'Gene', '850620', (160, 169))	('RAD18', 'Gene', (108, 113))	('Lys164', 'Chemical', '-', (69, 75))
43055	28831681	In addition, Ubc12 knockout enhanced PCNA-poleta interaction, but NEDD8 expression or NEDP1 deletion reduced the recruitment of poleta (Fig.	('knockout', 'Var', (19, 27))	('PCNA', 'molecular_function', 'GO:0003892', ('37', '41'))	('NEDP1', 'Gene', (86, 91))	('poleta', 'Chemical', '-', (128, 134))	('enhanced', 'PosReg', (28, 36))	('deletion', 'Var', (92, 100))	('Ubc12', 'Gene', '9040', (13, 18))	('Ubc12', 'Gene', (13, 18))	('NEDD8', 'Gene', (66, 71))	('PCNA-poleta interaction', 'MPA', (37, 60))	('reduced', 'NegReg', (101, 108))	('NEDP1', 'Gene', '123228', (86, 91))	('poleta', 'Chemical', '-', (42, 48))	('recruitment of poleta', 'MPA', (113, 134))
43061	28831681	This result indicates that the dissociation of NEDP1 from PCNA contributes to the increase of NEDDylated PCNA.	('dissociation', 'Var', (31, 43))	('NEDP1', 'Gene', '123228', (47, 52))	('PCNA', 'molecular_function', 'GO:0003892', ('105', '109'))	('increase', 'PosReg', (82, 90))	('NEDDylated PCNA', 'Disease', (94, 109))	('PCNA', 'molecular_function', 'GO:0003892', ('58', '62'))	('NEDP1', 'Gene', (47, 52))
43062	28831681	Moreover, NEDP1 deletion reduced PCNA-poleta interaction, thus prevented TLS pathway and increased cell sensitivity to H2O2-induced oxidative stress (Figs.	('reduced', 'NegReg', (25, 32))	('NEDP1', 'Gene', (10, 15))	('PCNA-poleta interaction', 'MPA', (33, 56))	('deletion', 'Var', (16, 24))	('prevented', 'NegReg', (63, 72))	('TLS pathway', 'Pathway', (73, 84))	('cell sensitivity to H2O2-induced oxidative stress', 'MPA', (99, 148))	('H2O2', 'Chemical', 'MESH:D006861', (119, 123))	('PCNA', 'molecular_function', 'GO:0003892', ('33', '37'))	('NEDP1', 'Gene', '123228', (10, 15))	('oxidative stress', 'Phenotype', 'HP:0025464', (132, 148))	('increased', 'PosReg', (89, 98))	('poleta', 'Chemical', '-', (38, 44))
43064	28831681	As both the increased ratio of free NEDD8 over ubiquitin and oxidative stress induce global atypical NEDDylation using ubiquitin enzyme UBE1, which could transfer NEDD8 to RAD6B (also called UBE2B), the E2 of PCNA ubiquitination (Hjerpe et al.,; Leidecker et al.,), it is possible that the ubiquitin enzymes cascade UBE1-RAD6B-RAD18 can also be utilized to mediate oxidative stress-induced PCNA NEDDylation.	('UBE2B', 'Gene', '7320', (191, 196))	('UBE1', 'Gene', '7317', (136, 140))	('RAD18', 'Gene', '56852', (327, 332))	('ubiquitin', 'Gene', (214, 223))	('ubiquitin', 'Gene', (47, 56))	('ubiquitin', 'molecular_function', 'GO:0031386', ('119', '128'))	('RAD6B', 'Gene', '7320', (172, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (365, 381))	('ubiquitin', 'Gene', (119, 128))	('UBE1', 'Gene', (316, 320))	('RAD6B', 'Gene', '7320', (321, 326))	('ubiquitin', 'Gene', '850620', (290, 299))	('PCNA', 'molecular_function', 'GO:0003892', ('390', '394'))	('RAD6B', 'Gene', (172, 177))	('UBE1', 'Gene', '7317', (316, 320))	('RAD', 'biological_process', 'GO:1990116', ('321', '324'))	('RAD6B', 'Gene', (321, 326))	('ubiquitin', 'molecular_function', 'GO:0031386', ('290', '299'))	('oxidative stress', 'Phenotype', 'HP:0025464', (61, 77))	('UBE2B', 'Gene', (191, 196))	('ubiquitin', 'Gene', (290, 299))	('RAD18', 'Gene', (327, 332))	('ubiquitin', 'Gene', '850620', (214, 223))	('ubiquitin', 'Gene', '850620', (47, 56))	('RAD', 'biological_process', 'GO:1990116', ('172', '175'))	('PCNA', 'molecular_function', 'GO:0003892', ('209', '213'))	('ubiquitin', 'Gene', '850620', (119, 128))	('NEDD8', 'Var', (163, 168))	('ubiquitin', 'molecular_function', 'GO:0031386', ('47', '56'))	('UBE1', 'Gene', (136, 140))	('RAD', 'biological_process', 'GO:1990116', ('327', '330'))
43066	28831681	2C and 2D) and MLN4924 could inhibit PCNA NEDDylation significantly when NEDD8 was overexpressed or under oxidative stress (Figs.	('PCNA NEDDylation', 'MPA', (37, 53))	('overexpressed', 'PosReg', (83, 96))	('PCNA', 'molecular_function', 'GO:0003892', ('37', '41'))	('oxidative stress', 'Phenotype', 'HP:0025464', (106, 122))	('inhibit', 'NegReg', (29, 36))	('MLN4924', 'Chemical', 'MESH:C539933', (15, 22))	('MLN4924', 'Var', (15, 22))	('NEDD8', 'Gene', (73, 78))
43068	28831681	As mutation and inactivation of poleta cause xeroderma pigmentosum variant (XPV), a type of autosomal recessive disease, which is prone to developing malignant skin cancer (Johnson et al.,; Han et al.,), we evaluated the clinical relevance of NEDDylation in skin cancer by bioinformatics analysis using SKCM (Skin Cutaneous Melanoma) dataset from GEPIA (gene expression profiling interactive analysis) (http://gepia.cancer-pku.cn/).	('xeroderma pigmentosum variant', 'Disease', 'MESH:C536766', (45, 74))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (309, 332))	('skin cancer', 'Disease', 'MESH:D012878', (160, 171))	('autosomal recessive disease', 'Disease', (92, 119))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('gene expression', 'biological_process', 'GO:0010467', ('354', '369'))	('skin cancer', 'Disease', (258, 269))	('skin cancer', 'Phenotype', 'HP:0008069', (258, 269))	('Skin Cutaneous Melanoma', 'Disease', (309, 332))	('mutation', 'Var', (3, 11))	('gepia.cancer-pku', 'Disease', 'MESH:C567494', (410, 426))	('poleta', 'Chemical', '-', (32, 38))	('malignant skin cancer', 'Disease', 'MESH:D012878', (150, 171))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (314, 332))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (92, 119))	('inactivation', 'Var', (16, 28))	('skin cancer', 'Phenotype', 'HP:0008069', (160, 171))	('skin cancer', 'Disease', 'MESH:D012878', (258, 269))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('gepia.cancer-pku', 'Disease', (410, 426))	('xeroderma pigmentosum variant', 'Disease', (45, 74))	('malignant skin cancer', 'Disease', (150, 171))	('poleta', 'Gene', (32, 38))	('Melanoma', 'Phenotype', 'HP:0002861', (324, 332))
43070	28831681	Meanwhile, correlative analysis revealed that low level of poleta is associated with higher survival of SKCM patients (Fig.	('poleta', 'Chemical', '-', (59, 65))	('higher', 'PosReg', (85, 91))	('patients', 'Species', '9606', (109, 117))	('low level', 'Var', (46, 55))	('survival', 'MPA', (92, 100))	('SKCM', 'Disease', (104, 108))
43073	28831681	In addition, in response to H2O2 or cisplatin treatment, as UBC12 deletion reduced cell sensitivity while UBC12 re-expression reduced cell survival (Fig.	('UBC12', 'Gene', '9040', (60, 65))	('cell survival', 'CPA', (134, 147))	('H2O2', 'Chemical', 'MESH:D006861', (28, 32))	('UBC12', 'Gene', '9040', (106, 111))	('cell sensitivity', 'CPA', (83, 99))	('UBC12', 'Gene', (60, 65))	('reduced', 'NegReg', (75, 82))	('UBC12', 'Gene', (106, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('deletion', 'Var', (66, 74))	('reduced', 'NegReg', (126, 133))
43079	28831681	3Flag-PCNA, 3Flag-PCNA-K164R, 3Flag-RAD18, 3Flag-RAD18-C28F, 3Flag-RAD18-DeltaRING, 3Flag-NEDP1, and 3Flag-NEDP1-C163S were cloned into the pCDNA-3Flag vector through restriction sites EcoRI and XhoI.	('RAD', 'biological_process', 'GO:1990116', ('36', '39'))	('RAD', 'biological_process', 'GO:1990116', ('67', '70'))	('PCNA', 'molecular_function', 'GO:0003892', ('6', '10'))	('RAD18', 'Gene', '56852', (49, 54))	('NEDP1', 'Gene', (107, 112))	('NEDP1', 'Gene', '123228', (107, 112))	('RAD', 'biological_process', 'GO:1990116', ('49', '52'))	('C163S', 'Mutation', 'rs751982875', (113, 118))	('RAD18', 'Gene', (36, 41))	('NEDP1', 'Gene', (90, 95))	('RAD18', 'Gene', (67, 72))	('C28F', 'Mutation', 'p.C28F', (55, 59))	('NEDP1', 'Gene', '123228', (90, 95))	('K164R', 'SUBSTITUTION', 'None', (23, 28))	('PCNA', 'molecular_function', 'GO:0003892', ('18', '22'))	('RAD18', 'Gene', '56852', (67, 72))	('K164R', 'Var', (23, 28))	('RAD18', 'Gene', '56852', (36, 41))	('RAD18', 'Gene', (49, 54))
43092	28831681	HEK293T cells transfected with the indicated plasmids were lysed in 6 mL lysis buffer for 30 min and then incubated with 80 muL Ni2+ resin for 4 h. The lysates were washed with buffers 1, 2, 3, and 4 in turn, and then the modified proteins were eluted in 30 muL elution buffer and boiled in 30 muL 2x SDS loading buffer.	('Ni2+', 'Chemical', '-', (128, 132))	('modified', 'Var', (222, 230))	('SDS', 'Chemical', 'MESH:D012967', (301, 304))	('boiled', 'Phenotype', 'HP:0020083', (281, 287))	('proteins', 'Protein', (231, 239))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('lysis', 'biological_process', 'GO:0019835', ('73', '78'))
43107	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))
43109	28781888	In addition, risk variants from this region were positively associated with higher expression of CLPTM1L.	('variants', 'Var', (18, 26))	('CLPTM1L', 'Gene', (97, 104))	('CLPTM1L', 'Gene', '81037', (97, 104))	('expression', 'MPA', (83, 93))	('higher', 'PosReg', (76, 82))
43111	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', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('malignant tumor', 'Disease', 'MESH:D018198', (95, 110))	('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))
43112	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))
43113	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'))
43115	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', (139, 146))	('CLPTM1L', 'Gene', (36, 43))	('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))
43120	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))
43121	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))	('SF3B1', 'Gene', '23451', (74, 79))	('BAP1', 'Gene', '8314', (142, 146))	('metastasis', 'CPA', (191, 201))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (142, 146))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', (68, 72))	('associated', 'Reg', (160, 170))	('SF3B1', 'Gene', (74, 79))
43127	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))
43128	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'))
43130	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))
43131	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))
43132	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))
43133	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))
43134	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))
43136	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))
43137	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))
43138	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))
43140	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))
43142	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))
43145	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))
43146	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))
43148	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))	('CLPTM1L', 'Gene', (17, 24))	('negatively', 'NegReg', (46, 56))	('positively', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('variants', 'Var', (5, 13))	('associated', 'Reg', (71, 81))
43150	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))
43151	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))
43152	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))	('rs421284', 'Mutation', 'rs421284', (105, 113))	('CLPTM1L', 'Gene', '81037', (24, 31))
43153	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', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('CLPTM1L', 'Gene', (86, 93))	('expression', 'MPA', (94, 104))	('rs421284', 'Var', (73, 81))
43154	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))
43155	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))
43156	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))
43157	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))
43158	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))
43170	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))
43172	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))
43173	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))	('OCA2', 'Gene', (39, 43))	('rs3930739', 'Var', (79, 88))	('rs12913832', 'Var', (51, 61))	('OCA2', 'Gene', '4948', (39, 43))	('rs12913832', 'Mutation', 'rs12913832', (51, 61))	('rs11074306', 'Mutation', 'rs11074306', (63, 73))
43174	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))
43175	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))
43176	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))
43180	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))
43182	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'))
43203	30119689	Expression of the myogenic regulatory factors required to promote differentiation, MYOD and MYOG, was downregulated in the absence of JARID2, even though decreases in the methylation of histone H3 lysine 27 (H3K27me3) were observed on both promoters.	('downregulated', 'NegReg', (102, 115))	('methylation', 'MPA', (171, 182))	('MYOG', 'CPA', (92, 96))	('H3', 'Chemical', 'MESH:C012616', (208, 210))	('Expression', 'MPA', (0, 10))	('H3', 'Chemical', 'MESH:C012616', (194, 196))	('absence', 'Var', (123, 130))	('lysine', 'Chemical', 'MESH:D008239', (197, 203))	('myogenic regulatory factors', 'Gene', (18, 45))	('decreases', 'NegReg', (154, 163))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
43206	30119689	We show that the Wnt antagonist SFRP1 is highly upregulated in the absence of JARID2 and is a direct target of JARID2 and the PRC2 complex.	('JARID2', 'Gene', (78, 84))	('absence', 'Var', (67, 74))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('126', '138'))	('Wnt', 'Gene', '35975', (17, 20))	('Wnt', 'Gene', (17, 20))	('upregulated', 'PosReg', (48, 59))	('SFRP1', 'Gene', (32, 37))
43220	30119689	Methylation of H3K27 recruits PRC1, which then catalyzes the ubiquitination of H2AK119.	('PRC1', 'Gene', (30, 34))	('H2AK119', 'Chemical', '-', (79, 86))	('Methylation', 'Var', (0, 11))	('H3K27', 'Protein', (15, 20))	('H3', 'Chemical', 'MESH:C012616', (15, 17))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('ubiquitination', 'MPA', (61, 75))	('PRC1', 'Gene', '233406', (30, 34))
43222	30119689	Di- and trimethylation of H3K27 is primarily associated with facultative heterochromatin, while mono-methylation is associated with intergenic heterochromatin.	('facultative heterochromatin', 'Disease', (61, 88))	('Di-', 'Var', (0, 3))	('intergenic heterochromatin', 'Disease', (132, 158))	('trimethylation', 'Var', (8, 22))	('H3', 'Chemical', 'MESH:C012616', (26, 28))	('associated', 'Reg', (45, 55))	('H3K27', 'Protein', (26, 31))	('heterochromatin', 'cellular_component', 'GO:0000792', ('143', '158'))	('heterochromatin', 'cellular_component', 'GO:0000792', ('73', '88'))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('associated', 'Reg', (116, 126))
43223	30119689	Promoters and enhancers of many lineage-specific genes contain di- and trimethylated H3K27, and many of these elements lose the methylation profile upon differentiation (reviewed in).	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('lose', 'NegReg', (119, 123))	('methylation profile', 'MPA', (128, 147))	('H3', 'Chemical', 'MESH:C012616', (85, 87))	('trimethylated', 'Var', (71, 84))	('H3K27', 'Protein', (85, 90))	('di-', 'MPA', (63, 66))
43227	30119689	In embryonic stem (ES) cells, deletion of Jarid2 shows a severe differentiation block due to an upregulation of Nanog mRNA and an inhibition of Wnt signaling.	('Jarid2', 'Gene', (42, 48))	('Jarid2', 'Gene', '16468', (42, 48))	('differentiation block', 'Disease', (64, 85))	('Nanog', 'Gene', '71950', (112, 117))	('differentiation block', 'Disease', 'MESH:D006327', (64, 85))	('Wnt', 'Gene', '35975', (144, 147))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('inhibition', 'NegReg', (130, 140))	('deletion', 'Var', (30, 38))	('Nanog', 'Gene', (112, 117))	('Wnt', 'Gene', (144, 147))	('upregulation', 'PosReg', (96, 108))
43231	30119689	Sfrp1 was one of a panel of Wnt signaling genes shown to be upregulated in embryonic stem (ES) cells upon JARID2 deletion.	('upregulated', 'PosReg', (60, 71))	('JARID2', 'Gene', (106, 112))	('deletion', 'Var', (113, 121))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('Sfrp1', 'Gene', (0, 5))	('Wnt', 'Gene', '35975', (28, 31))	('Sfrp1', 'Gene', '20377', (0, 5))	('Wnt', 'Gene', (28, 31))
43251	30119689	We found that H3K27 methylation could be observed at the DRR, CE and PRR of the Myod1 promoter and that depletion of JARID2 leads to a loss of H3K27me3 on each of these regions (Additional file 1: Figure S1 a-c).	('depletion', 'MPA', (104, 113))	('loss', 'NegReg', (135, 139))	('H3K27me3', 'Protein', (143, 151))	('Myod1', 'Gene', (80, 85))	('JARID2', 'Gene', (117, 123))	('PRR', 'molecular_function', 'GO:0038187', ('69', '72'))	('methylation', 'Var', (20, 31))	('H3', 'Chemical', 'MESH:C012616', (143, 145))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('H3K27', 'Protein', (14, 19))	('Myod1', 'Gene', '17927', (80, 85))	('H3', 'Chemical', 'MESH:C012616', (14, 16))
43254	30119689	As a control for these experiments, we show that H3K27me3 is observed on the HoxB7 promoter (Additional file 1: Figure S1 f), a known target of the PRC2 complex.	('PRC2 complex', 'cellular_component', 'GO:0035098', ('148', '160'))	('HoxB7', 'Gene', '15415', (77, 82))	('H3K27me3', 'Var', (49, 57))	('HoxB7', 'Gene', (77, 82))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
43256	30119689	Significantly, we also show here that JARID2 is required to guide the PRC2-mediated H3K27 methylation responsible for repressing both Myod1 and Myog and that JARID2 does not inhibit PRC2 complex activity on these promoters.	('H3K27', 'Protein', (84, 89))	('Myog', 'Gene', (144, 148))	('H3', 'Chemical', 'MESH:C012616', (84, 86))	('Myod1', 'Gene', '17927', (134, 139))	('Myog', 'Gene', '17928', (144, 148))	('methylation', 'biological_process', 'GO:0032259', ('90', '101'))	('methylation', 'Var', (90, 101))	('Myod1', 'Gene', (134, 139))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('182', '194'))
43264	30119689	Other work has shown no change in Myog mRNA expression upon a transient siEZH2 depletions and a delay in Myog mRNA expression upon transient siSUZ12 depletion.	('Myog', 'Gene', '17928', (105, 109))	('Myog', 'Gene', (34, 38))	('siEZH2', 'Gene', (72, 78))	('SUZ12', 'Gene', (143, 148))	('SUZ12', 'Gene', '52615', (143, 148))	('Myog', 'Gene', '17928', (34, 38))	('delay', 'NegReg', (96, 101))	('depletions', 'Var', (79, 89))	('Myog', 'Gene', (105, 109))
43272	30119689	We next examined Myog mRNA expression and found that expression of MYOD also upregulated Myog mRNA (Additional file 2: Figure S2 b).	('Myog', 'Gene', (89, 93))	('Myog', 'Gene', '17928', (17, 21))	('upregulated', 'PosReg', (77, 88))	('MYOD', 'Gene', (67, 71))	('expression', 'Var', (53, 63))	('Myog', 'Gene', '17928', (89, 93))	('Myog', 'Gene', (17, 21))
43273	30119689	Analysis of a differentiation-specific marker, Mylpf, also showed upregulation upon expression of MYOD (Additional file 2: Figure S2 c).	('expression', 'Var', (84, 94))	('upregulation', 'PosReg', (66, 78))	('Mylpf', 'Gene', (47, 52))	('MYOD', 'Gene', (98, 102))	('Mylpf', 'Gene', '17907', (47, 52))
43277	30119689	Inhibition of GSK3beta by LiCl is known to enhance myotube formation in C2C12 cells.	('GSK3beta', 'Gene', (14, 22))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('LiCl', 'Chemical', 'MESH:D018021', (26, 30))	('Inhibition of GSK', 'biological_process', 'GO:1902948', ('0', '17'))	('GSK3beta', 'Gene', '56637', (14, 22))	('C2C12 cells', 'CellLine', 'CVCL:0188', (72, 83))	('GSK', 'molecular_function', 'GO:0050321', ('14', '17'))	('Inhibition', 'Var', (0, 10))	('myotube formation', 'CPA', (51, 68))	('enhance', 'PosReg', (43, 50))
43306	30119689	Previous work has shown that beta-catenin binds to the DRR of the Myod1 promoter.	('beta-catenin', 'Gene', '12387', (29, 41))	('binds', 'Interaction', (42, 47))	('Myod1', 'Gene', (66, 71))	('DRR', 'Var', (55, 58))	('beta-catenin', 'Gene', (29, 41))	('Myod1', 'Gene', '17927', (66, 71))
43315	30119689	We also found that H3K27me3 was present at the Sfrp1 promoter in normal cells, indicating that it is normally repressed by the PRC2 complex (Fig.	('H3K27me3', 'Var', (19, 27))	('H3', 'Chemical', 'MESH:C012616', (19, 21))	('Sfrp1', 'Gene', (47, 52))	('Sfrp1', 'Gene', '20377', (47, 52))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('127', '139'))
43316	30119689	Upon JARID2 depletion, H3K27me3 was reduced on the Sfrp1 promoter (Fig.	('H3K27me3', 'Protein', (23, 31))	('Sfrp1', 'Gene', '20377', (51, 56))	('H3', 'Chemical', 'MESH:C012616', (23, 25))	('reduced', 'NegReg', (36, 43))	('Sfrp1', 'Gene', (51, 56))	('depletion', 'Var', (12, 21))
43319	30119689	However, our mRNA expression data show that the loss of H3K27me3 on the Nkd1 promoter is not sufficient for activation of this gene.	('H3K27me3', 'Var', (56, 64))	('H3', 'Chemical', 'MESH:C012616', (56, 58))	('loss', 'Var', (48, 52))
43322	30119689	We also found that ectopic expression of SFRP1 was sufficient to inhibit the mRNA expression of Myod1 (Fig.	('Myod1', 'Gene', (96, 101))	('ectopic expression', 'Var', (19, 37))	('mRNA expression', 'MPA', (77, 92))	('SFRP1', 'Gene', (41, 46))	('Myod1', 'Gene', '17927', (96, 101))	('inhibit', 'NegReg', (65, 72))
43327	30119689	We found that ectopic expression of SFRP1 was sufficient to inhibit the nuclear translocation and increase the cytosolic localization of beta-catenin (Fig.	('SFRP1', 'Gene', (36, 41))	('localization', 'biological_process', 'GO:0051179', ('121', '133'))	('beta-catenin', 'Gene', '12387', (137, 149))	('inhibit', 'NegReg', (60, 67))	('nuclear translocation', 'MPA', (72, 93))	('cytosolic localization', 'MPA', (111, 133))	('increase', 'PosReg', (98, 106))	('beta-catenin', 'Gene', (137, 149))	('ectopic expression', 'Var', (14, 32))
43341	30119689	The importance of canonical Wnt signaling in myogenesis has been demonstrated through series of loss- and gain-of-function assays that showed loss of beta-catenin delayed differentiation, while constitutive overexpression of beta-catenin results in precocious differentiation.	('myogenesis', 'biological_process', 'GO:0042692', ('45', '55'))	('loss', 'Var', (142, 146))	('beta-catenin', 'Gene', '12387', (150, 162))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('beta-catenin', 'Gene', (225, 237))	('Wnt', 'Gene', '35975', (28, 31))	('myogenesis', 'biological_process', 'GO:0048740', ('45', '55'))	('delayed', 'NegReg', (163, 170))	('beta-catenin', 'Gene', '12387', (225, 237))	('myogenesis', 'biological_process', 'GO:0007519', ('45', '55'))	('Wnt', 'Gene', (28, 31))	('loss-', 'NegReg', (96, 101))	('beta-catenin', 'Gene', (150, 162))	('differentiation', 'CPA', (171, 186))
43348	30119689	Significantly, while decreases in promoter methylation at genes such as Mck were observed upon EZH2 depletion, a corresponding increase in protein expression was not observed, consistent with our work.	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('decreases', 'NegReg', (21, 30))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('Mck', 'Gene', (72, 75))	('promoter methylation', 'MPA', (34, 54))	('depletion', 'Var', (100, 109))	('Mck', 'Gene', '12715', (72, 75))
43349	30119689	Other studies have also observed the anticipated increased expression of myogenin and downstream targets upon Suz12 depletion, but this study utilized a transient siRNA approach.	('Suz12', 'Gene', (110, 115))	('depletion', 'Var', (116, 125))	('Suz12', 'Gene', '52615', (110, 115))	('myogenin', 'Gene', (73, 81))	('increased', 'PosReg', (49, 58))	('myogenin', 'Gene', '17928', (73, 81))	('expression', 'MPA', (59, 69))
43351	30119689	A conditional ablation of Ezh2 in satellite cells using a Pax7-Cre driver showed an increase in the MYOG-positive satellite cell pool, indicating precocious differentiation, but a delay in MYOG-positive cells following injury.	('Pax7', 'Gene', (58, 62))	('Ezh2', 'Gene', (26, 30))	('Ezh2', 'Gene', '14056', (26, 30))	('MYOG-positive cells', 'CPA', (189, 208))	('MYOG-positive satellite cell pool', 'CPA', (100, 133))	('increase', 'PosReg', (84, 92))	('delay', 'NegReg', (180, 185))	('Pax7', 'Gene', '18509', (58, 62))	('ablation', 'Var', (14, 22))
43352	30119689	Other studies have shown that siRNA against EZH2 in isolated satellite cells leads to a downregulation of myogenin and inhibition of EZH2 in these cells leads to decreases in downstream targets such as MCK.	('EZH2', 'Gene', (133, 137))	('downregulation', 'NegReg', (88, 102))	('myogenin', 'Gene', '17928', (106, 114))	('downstream targets', 'MPA', (175, 193))	('decreases', 'NegReg', (162, 171))	('MCK', 'Gene', '12715', (202, 205))	('inhibition', 'Var', (119, 129))	('EZH2', 'Gene', (44, 48))	('myogenin', 'Gene', (106, 114))	('MCK', 'Gene', (202, 205))
43361	30119689	In our study, while we observed a decrease in H3K27me3 status on the promoter of Nkd1 upon depletion of JARID2, we saw no upregulation in mRNA expression.	('H3K27me3 status', 'Var', (46, 61))	('H3', 'Chemical', 'MESH:C012616', (46, 48))	('decrease', 'NegReg', (34, 42))	('depletion', 'MPA', (91, 100))	('Nkd1', 'Gene', (81, 85))	('mRNA expression', 'MPA', (138, 153))
43364	30119689	In contrast, at the majority of targets we studied in C2C12 cells, we did not see any significant changes in H3K9me status upon JARID2 depletion.	('depletion', 'Var', (135, 144))	('C2C12 cells', 'CellLine', 'CVCL:0188', (54, 65))	('H3K9me', 'Protein', (109, 115))	('H3', 'Chemical', 'MESH:C012616', (109, 111))
43366	30119689	However, earlier studies with ES cells showed that loss of Jarid2 delayed ES cell differentiation, while loss of PRC2 enhanced differentiation.	('loss', 'Var', (51, 55))	('ES cell differentiation', 'CPA', (74, 97))	('cell differentiation', 'biological_process', 'GO:0030154', ('77', '97'))	('delayed', 'NegReg', (66, 73))	('Jarid2', 'Gene', (59, 65))	('enhanced', 'PosReg', (118, 126))	('Jarid2', 'Gene', '16468', (59, 65))	('loss', 'Var', (105, 109))	('PRC2', 'Gene', (113, 117))	('differentiation', 'CPA', (127, 142))
43371	30119689	Deregulated Wnt signaling has also shown to be correlated with poor survival in many cancer studies (reviewed in).	('Wnt', 'Gene', (12, 15))	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('Wnt', 'Gene', '35975', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
43403	30119689	The following antibodies were used: anti-Jarid2 (Cell Signaling), anti-H3K27me3 (Cell Signaling), anti-pan methyl H3K9 (D54, Cell Signaling) and anti-beta-catenin (E-5, SCBT).	('Signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('H3', 'Chemical', 'MESH:C012616', (114, 116))	('E-5', 'Gene', (164, 167))	('beta-catenin', 'Gene', '12387', (150, 162))	('Jarid2', 'Gene', (41, 47))	('Jarid2', 'Gene', '16468', (41, 47))	('H3', 'Chemical', 'MESH:C012616', (71, 73))	('Signaling', 'biological_process', 'GO:0023052', ('54', '63'))	('Signaling', 'biological_process', 'GO:0023052', ('130', '139'))	('E-5', 'Gene', '100035928', (164, 167))	('anti-pan methyl H3K9', 'Var', (98, 118))	('beta-catenin', 'Gene', (150, 162))	('anti-H3K27me3', 'Var', (66, 79))
43501	32330367	Gene/environment interactions have previously been demonstrated for other melanoma subtypes, for which both genetic variants in genes such as MC1R and environmental exposures such as UV light are established risk factors.	('variants', 'Var', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('MC1R', 'Gene', '4157', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('MC1R', 'Gene', (142, 146))
43527	32330367	Misdiagnosis has been observed to be associated with increased median tumour thickness, more advanced stage at diagnosis and lower 5-year survival (Soon et al., 2003).	('tumour thickness', 'Disease', (70, 86))	('tumour thickness', 'Disease', 'MESH:D009369', (70, 86))	('5-year', 'MPA', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('Misdiagnosis', 'Var', (0, 12))	('increased', 'PosReg', (53, 62))	('lower', 'NegReg', (125, 130))
43554	32330367	One possible explanation for the high local recurrence rate is the finding of genetically abnormal melanocytes in histologically normal epidermis adjacent to melanomas on the non-hair-bearing skin of the palms and soles (Bastian et al., 2000; North, Kageshita, Pinkel, LeBoit, & Bastian, 2008).	('abnormal melanocyte', 'Phenotype', 'HP:0002861', (90, 109))	('melanomas', 'Disease', (158, 167))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanomas', 'Phenotype', 'HP:0002861', (158, 167))	('abnormal melanocytes', 'Phenotype', 'HP:0002861', (90, 110))	('genetically abnormal', 'Var', (78, 98))	('melanomas', 'Disease', 'MESH:D008545', (158, 167))
43560	32330367	Interestingly, melanoblasts harbouring CCND1 amplification have been detected in the secretory portion of eccrine glands among human melanoma cells, suggesting that these cells could originate acral melanomas.	('human', 'Species', '9606', (127, 132))	('CCND1', 'Gene', (39, 44))	('acral melanoma', 'Phenotype', 'HP:0012060', (193, 207))	('acral melanomas', 'Disease', (193, 208))	('acral melanomas', 'Phenotype', 'HP:0012060', (193, 208))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('acral melanomas', 'Disease', 'MESH:D008545', (193, 208))	('CCND1', 'Gene', '595', (39, 44))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))	('melanoma', 'Disease', (199, 207))	('amplification', 'Var', (45, 58))
43583	32330367	Sequencing and copy-number profiling studies of ALM tumours have identified characteristic tumour-promoting mutations implicating several genes.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('ALM', 'Phenotype', 'HP:0012060', (48, 51))	('ALM tumours', 'Disease', (48, 59))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', (91, 97))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('tumour', 'Disease', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('ALM tumours', 'Disease', 'MESH:D009369', (48, 59))
43585	32330367	In this regard, a study over 514 ALM samples identified that these tumours frequently display a dysregulated CDK4 pathway, a product of either gains of CDK4/CCND1 or loss of CDKN2A that, in turn, promote G1 to S cell cycle transition and thus contribute to tumour proliferation (Kong et al., 2017) (Figure 3).	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('ALM', 'Phenotype', 'HP:0012060', (33, 36))	('loss', 'Var', (166, 170))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('gains', 'PosReg', (143, 148))	('cell cycle transition', 'biological_process', 'GO:0044770', ('212', '233'))	('dysregulated', 'MPA', (96, 108))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('contribute', 'Reg', (243, 253))	('CDK', 'molecular_function', 'GO:0004693', ('152', '155'))	('CCND1', 'Gene', '595', (157, 162))	('tumour proliferation', 'Disease', (257, 277))	('CDK', 'molecular_function', 'GO:0004693', ('109', '112'))	('cell cycle transition', 'biological_process', 'GO:0044771', ('212', '233'))	('CDKN2A', 'Gene', (174, 180))	('promote', 'PosReg', (196, 203))	('CCND1', 'Gene', (157, 162))	('tumour proliferation', 'Disease', 'MESH:D009369', (257, 277))	('tumours', 'Disease', (67, 74))	('CDK4 pathway', 'Pathway', (109, 121))	('CDKN2A', 'Gene', '1029', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('G1 to S cell cycle transition', 'CPA', (204, 233))
43588	32330367	(2019) observed a low frequency of TERT promoter mutations but amplification of the TERT locus in 10.3% of the cases, and 3.3% cases with copy-number transitions with relative gain of TERT, although the comprehensive role of telomere regulation specific to ALM has not been clarified (Hayward et al., 2017; Liang et al., 2017).	('regulation', 'biological_process', 'GO:0065007', ('234', '244'))	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('mutations', 'Var', (49, 58))	('copy-number', 'Var', (138, 149))	('ALM', 'Phenotype', 'HP:0012060', (257, 260))	('telomere', 'cellular_component', 'GO:0000781', ('225', '233'))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))	('TERT', 'Gene', (184, 188))	('telomere', 'cellular_component', 'GO:0005696', ('225', '233'))	('TERT', 'Gene', '7015', (184, 188))
43589	32330367	ALM stands out from other melanoma subtypes as it carries a large number of structural variants including duplications, deletions, translocations and inversions.	('deletions', 'Var', (120, 129))	('translocations', 'Var', (131, 145))	('duplications', 'Var', (106, 118))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('inversions', 'Var', (150, 160))	('melanoma', 'Disease', (26, 34))	('ALM', 'Phenotype', 'HP:0012060', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
43596	32330367	Overall, the frequency of RAS, BRAF or neurofibromin 1 (NF1) mutations resulting in the activation of the MAPK pathway seems to be lower in ALM than in other subtypes of melanoma (Hayward et al., 2017; Vazquez et al., 2015; Yun et al., 2011), and other drivers such as KIT, PAK1 and SPRED1 may be more important (Curtin et al., 2006; Liang et al., 2017; Yeh et al., 2019) (Figure 3).	('NF1', 'Gene', '4763', (56, 59))	('PAK1', 'Gene', '5058', (274, 278))	('neurofibromin 1', 'Gene', '4763', (39, 54))	('lower', 'NegReg', (131, 136))	('KIT', 'Gene', '3815', (269, 272))	('MAPK pathway', 'Pathway', (106, 118))	('NF1', 'Gene', (56, 59))	('neurofibromin 1', 'Gene', (39, 54))	('activation', 'PosReg', (88, 98))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))	('mutations', 'Var', (61, 70))	('ALM', 'Phenotype', 'HP:0012060', (140, 143))	('RAS', 'Gene', (26, 29))	('SPRED1', 'Gene', '161742', (283, 289))	('KIT', 'Gene', (269, 272))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('PAK1', 'Gene', (274, 278))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('KIT', 'molecular_function', 'GO:0005020', ('269', '272'))	('SPRED1', 'Gene', (283, 289))	('ALM', 'Disease', (140, 143))
43599	32330367	These studies also suggest that chromosomal instability is a contributing factor to the aetiology of ALM and that it is different from that of melanomas in sun-exposed skin.	('ALM', 'Phenotype', 'HP:0012060', (101, 104))	('melanomas', 'Disease', (143, 152))	('ALM', 'Disease', (101, 104))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('chromosomal instability', 'Var', (32, 55))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('chromosomal instability', 'Phenotype', 'HP:0040012', (32, 55))
43621	32330367	Of major clinical importance, drug intervention experiments conducted with melanoma PDXs and derived cell lines clearly show that these models can recapitulate the therapeutic response observed in patients, can help identify the causal role of genetic alterations in therapy resistance and may be used to test drug combinations (Einarsdottir et al., 2014; Girotti et al., 2016; Kemper et al., 2016; Krepler et al., 2017).	('melanoma PDXs', 'Disease', (75, 88))	('patients', 'Species', '9606', (197, 205))	('melanoma PDXs', 'Disease', 'MESH:D008545', (75, 88))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('genetic', 'Var', (244, 251))
43622	32330367	(2017), genetic alterations in TERT were found in more than 40% of acral melanomas in patients.	('found', 'Reg', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('acral melanoma', 'Phenotype', 'HP:0012060', (67, 81))	('acral melanomas', 'Disease', (67, 82))	('genetic alterations', 'Var', (8, 27))	('acral melanomas', 'Phenotype', 'HP:0012060', (67, 82))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('acral melanomas', 'Disease', 'MESH:D008545', (67, 82))	('patients', 'Species', '9606', (86, 94))
43627	32330367	This is consistent with the presence of KIT alterations in ALM and other melanoma subtypes and has supported the development of studies exploring its role as a therapeutic target in melanoma (Curtin et al., 2006; Hodi et al., 2013).	('melanoma', 'Disease', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('KIT', 'Gene', '3815', (40, 43))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('KIT', 'Gene', (40, 43))	('alterations', 'Var', (44, 55))	('KIT', 'molecular_function', 'GO:0005020', ('40', '43'))	('ALM', 'Phenotype', 'HP:0012060', (59, 62))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
43631	32330367	Oncogenic activation of the CDK4 pathway through copy-number gains in CDK4, CCND1 and loss of CDKN2A is a common genetic feature of acral melanomas (Bastian et al., 2000; Curtin et al., 2005; Furney et al., 2012; Kong et al., 2017; Liang et al., 2017).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('acral melanoma', 'Phenotype', 'HP:0012060', (132, 146))	('CDK4', 'Gene', (70, 74))	('CCND1', 'Gene', (76, 81))	('loss', 'NegReg', (86, 90))	('CDKN2A', 'Gene', '1029', (94, 100))	('CDK', 'molecular_function', 'GO:0004693', ('70', '73'))	('acral melanomas', 'Phenotype', 'HP:0012060', (132, 147))	('CDK', 'molecular_function', 'GO:0004693', ('28', '31'))	('acral melanomas', 'Disease', (132, 147))	('copy-number', 'Var', (49, 60))	('CCND1', 'Gene', '595', (76, 81))	('CDKN2A', 'Gene', (94, 100))	('gains', 'PosReg', (61, 66))	('acral melanomas', 'Disease', 'MESH:D008545', (132, 147))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('CDK4 pathway', 'Pathway', (28, 40))	('activation', 'PosReg', (10, 20))
43632	32330367	(2017) used ALM PDX with different CDK4 pathway aberrations to test response to either the pan-CDK inhibitor AT7519 or the specific CDK4/6 inhibitor PD0332991 (palbociclib).	('CDK', 'Gene', '1019;12567;1021', (132, 135))	('CDK4/6', 'Gene', (132, 138))	('CDK', 'Gene', (132, 135))	('PD0332991', 'Chemical', 'MESH:C500026', (149, 158))	('CDK', 'Gene', (95, 98))	('test', 'Reg', (63, 67))	('AT7519', 'Chemical', 'MESH:C531230', (109, 115))	('ALM', 'Phenotype', 'HP:0012060', (12, 15))	('CDK', 'Gene', '1019;12567;1021', (95, 98))	('PD0332991', 'Var', (149, 158))	('CDK', 'molecular_function', 'GO:0004693', ('35', '38'))	('CDK', 'molecular_function', 'GO:0004693', ('132', '135'))	('CDK inhibitor', 'molecular_function', 'GO:0004861', ('95', '108'))	('palbociclib', 'Chemical', 'MESH:C500026', (160, 171))	('CDK4/6', 'Gene', '1019;1021', (132, 138))	('CDK', 'Gene', (35, 38))	('CDK', 'Gene', '1019;12567;1021', (35, 38))
43633	32330367	While ALM PDXs with no alterations in the CDK4 pathway showed no significant response, tumour volume was decreased in PDXs harbouring CDK4 gain/CDKN2A loss or CCND1 gain/CDKN2A loss and, to a larger extent, in PDXs with copy-number gains in both CDK4 and CCND1.	('tumour', 'Disease', (87, 93))	('decreased', 'NegReg', (105, 114))	('CDKN2A', 'Gene', (170, 176))	('CCND1', 'Gene', '595', (255, 260))	('CCND1', 'Gene', '595', (159, 164))	('CDKN2A', 'Gene', (144, 150))	('ALM', 'Phenotype', 'HP:0012060', (6, 9))	('CCND1', 'Gene', (255, 260))	('CCND1', 'Gene', (159, 164))	('CDKN2A', 'Gene', '1029', (170, 176))	('copy-number gains', 'Var', (220, 237))	('CDK', 'molecular_function', 'GO:0004693', ('246', '249'))	('loss', 'NegReg', (177, 181))	('CDKN2A', 'Gene', '1029', (144, 150))	('loss', 'NegReg', (151, 155))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('CDK4', 'Gene', (134, 138))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('CDK', 'molecular_function', 'GO:0004693', ('134', '137'))
43638	32330367	Furthermore, activation of CDK4 pathway, in the case of acral melanoma patients achieved via CCND1 copy-number gains, was associated with response to PD-1 blockade (Yu et al., 2019).	('PD-1 blockade', 'Disease', 'MESH:D010300', (150, 163))	('CCND1', 'Gene', '595', (93, 98))	('patients', 'Species', '9606', (71, 79))	('copy-number gains', 'Var', (99, 116))	('acral melanoma', 'Disease', 'MESH:D008545', (56, 70))	('activation', 'PosReg', (13, 23))	('PD-1 blockade', 'Disease', (150, 163))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('acral melanoma', 'Phenotype', 'HP:0012060', (56, 70))	('CDK4 pathway', 'Pathway', (27, 39))	('CCND1', 'Gene', (93, 98))	('acral melanoma', 'Disease', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
43646	32330367	However, their study has already highlighted palbociclib as a possible agent in treating ALM patients with aberrations in the CDK4 pathway, which highlights the power of these kinds of preclinical studies and calls for more research for this subtype of melanoma.	('patients', 'Species', '9606', (93, 101))	('palbociclib', 'Chemical', 'MESH:C500026', (45, 56))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('aberrations', 'Var', (107, 118))	('melanoma', 'Disease', (253, 261))	('CDK', 'molecular_function', 'GO:0004693', ('126', '129'))	('melanoma', 'Disease', 'MESH:D008545', (253, 261))	('ALM', 'Phenotype', 'HP:0012060', (89, 92))	('CDK4 pathway', 'Pathway', (126, 138))	('ALM', 'Disease', (89, 92))
43651	29317335	The association signal for BRCA2 was driven primarily by likely gene disrupting (LGD) variants, with an Odds Ratio (OR) of 5.62 (95% Confidence Interval (CI) 1.03 - 30.1).	('gene disrupting', 'Reg', (64, 79))	('BRCA2', 'Gene', '675', (27, 32))	('BRCA2', 'Gene', (27, 32))	('variants', 'Var', (86, 94))
43652	29317335	In contrast, the association signals for MC1R and MITF were driven primarily by predicted pathogenic non-LGD coding variants, with estimated ORs of 1.4 to 3.0 for MC1R and 4.1 for MITF.	('MITF', 'Gene', '4286', (50, 54))	('variants', 'Var', (116, 124))	('MITF', 'Gene', (50, 54))	('MC1R', 'Gene', (41, 45))	('MC1R', 'Gene', '4157', (41, 45))	('MC1R', 'Gene', '4157', (163, 167))	('MC1R', 'Gene', (163, 167))	('MC1R and 4.1', 'Gene', '4157', (163, 175))	('MITF', 'Gene', '4286', (180, 184))	('MITF', 'Gene', (180, 184))
43653	29317335	MTAP exhibited an excess of both LGD and predicted damaging non-LGD variants among cases, with ORs of 5.62 and 3.72, respectively, although neither category was significant.	('variants', 'Var', (68, 76))	('MTAP', 'Gene', (0, 4))	('MTAP', 'Gene', '4507', (0, 4))
43654	29317335	For individuals with known or predicted damaging variants, age of disease onset was significantly lower for two of the four genes, MC1R (p=0.005) and MTAP (p=0.035).	('variants', 'Var', (49, 57))	('MTAP', 'Gene', (150, 154))	('MC1R', 'Gene', '4157', (131, 135))	('MC1R', 'Gene', (131, 135))	('MTAP', 'Gene', '4507', (150, 154))	('lower', 'NegReg', (98, 103))
43655	29317335	In an analysis of germline carrier status and overlapping copy number alterations, we observed no evidence to support a two-hit model of carcinogenesis in any of the four genes.	('copy number alterations', 'Var', (58, 81))	('carcinogenesis', 'Disease', (137, 151))	('carrier', 'molecular_function', 'GO:0005215', ('27', '34'))	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))
43656	29317335	Although MC1R carriers were represented proportionally among the four molecular tumor subtypes, these individuals accounted for 69% of ultraviolet (UV) radiation mutational signatures among triple-wild type tumors (p = 0.040), highlighting the increased sensitivity to UV exposure among individuals with loss-of-function variants in MC1R.	('loss-of-function', 'NegReg', (304, 320))	('mutational', 'Var', (162, 172))	('type tumors', 'Disease', 'MESH:D009369', (202, 213))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('type tumors', 'Disease', (202, 213))	('MC1R', 'Gene', (9, 13))	('MC1R', 'Gene', '4157', (333, 337))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MC1R', 'Gene', (333, 337))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('increased sensitivity to UV exposure', 'Phenotype', 'HP:0003224', (244, 280))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('MC1R', 'Gene', '4157', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('variants', 'Var', (321, 329))	('tumor', 'Disease', (207, 212))
43661	29317335	A number of intermediate risk melanoma-susceptibility genes, with variants conferring a 2-fold to 8-fold increased risk, have been identified through a combination of case-control and familial studies, including MC1R, MITF, BRCA2 , TERT, BAP1, POT1, and MTAP.	('MC1R', 'Gene', '4157', (212, 216))	('MITF', 'Gene', (218, 222))	('TERT', 'Gene', (232, 236))	('MC1R', 'Gene', (212, 216))	('TERT', 'Gene', '7015', (232, 236))	('POT1', 'Gene', (244, 248))	('BRCA2', 'Gene', '675', (224, 229))	('MITF', 'Gene', '4286', (218, 222))	('variants', 'Var', (66, 74))	('MTAP', 'Gene', '4507', (254, 258))	('BAP1', 'Gene', '8314', (238, 242))	('MTAP', 'Gene', (254, 258))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('POT1', 'Gene', '25913', (244, 248))	('melanoma', 'Disease', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('BAP1', 'Gene', (238, 242))	('BRCA2', 'Gene', (224, 229))
43662	29317335	Detailed characterization of genomic alterations in melanoma has revealed four major tumor subtypes defined by the occurrence of somatic point mutations, mutant BRAF, mutant RAS, mutant NF1, and triple-WT (wild-type).	('RAS', 'Gene', (174, 177))	('tumor', 'Disease', (85, 90))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('mutant', 'Var', (179, 185))	('NF1', 'Gene', (186, 189))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('NF1', 'Gene', '4763', (186, 189))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutant', 'Var', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutant', 'Var', (154, 160))
43664	29317335	In contrast, only 30% of triple-WT tumors are known to harbor a UV mutational signature.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('WT tumors', 'Disease', (32, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('mutational', 'Var', (67, 77))	('WT tumors', 'Disease', 'MESH:C536751', (32, 41))
43675	29317335	We injected the normal phasing into each (paired) tumor sample file and applied hapLOH to infer allelic imbalance and copy number alterations in all tumor samples.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('imbalance', 'Phenotype', 'HP:0002172', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (149, 154))	('copy number alterations', 'Var', (118, 141))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
43678	29317335	MC1R and MITF exhibited no meaningful change in association signal, while BRCA2 exhibited only a modest attenuation in signal, (Table 1), suggesting that missense variants with unconfirmed pathogenicity in these genes increase melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('MC1R', 'Gene', '4157', (0, 4))	('MITF', 'Gene', '4286', (9, 13))	('melanoma', 'Disease', (227, 235))	('MITF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('missense variants', 'Var', (154, 171))	('BRCA2', 'Gene', (74, 79))	('MC1R', 'Gene', (0, 4))	('BRCA2', 'Gene', '675', (74, 79))	('increase', 'PosReg', (218, 226))
43686	29317335	Both MTAP and MC1R carriers were diagnosed with melanoma at significantly younger ages, with p = 0.035 and 0.005, respectively (see Figure 3B and 3C).	('melanoma', 'Disease', (48, 56))	('MTAP', 'Gene', (5, 9))	('MC1R', 'Gene', '4157', (14, 18))	('MC1R', 'Gene', (14, 18))	('carriers', 'Var', (19, 27))	('MTAP', 'Gene', '4507', (5, 9))	('diagnosed', 'Reg', (33, 42))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
43687	29317335	The mean age at diagnosis was 35.5 among MTAP carriers, 53.9 among MC1R carriers, and 57.7 among non-carriers.	('MTAP', 'Gene', '4507', (41, 45))	('carriers', 'Var', (46, 54))	('MTAP', 'Gene', (41, 45))	('MC1R', 'Gene', '4157', (67, 71))	('MC1R', 'Gene', (67, 71))
43692	29317335	In this study, we considered three functional variant categories for gene-based rare variant effect size estimates: LGD and known pathogenic variants, non-LGD variants predicted to be damaging by both CASM and PP2, and non-LGD variants predicted to be benign by both CASM and PP2.	('PP2', 'Gene', (210, 213))	('PP2', 'Gene', '4888', (210, 213))	('PP2', 'Gene', (276, 279))	('variants', 'Var', (141, 149))	('PP2', 'Gene', '4888', (276, 279))
43693	29317335	Although the confidence intervals were wide, LGD variants in BRCA2 and predicted damaging non-LGD variants in MITF all exhibited odds ratios of greater than 1.	('variants', 'Var', (49, 57))	('BRCA2', 'Gene', (61, 66))	('MITF', 'Gene', '4286', (110, 114))	('MITF', 'Gene', (110, 114))	('BRCA2', 'Gene', '675', (61, 66))
43694	29317335	Missense variants in MC1R are associated with phenotypical features such as light skin pigmentation and red hair, in addition to an increased risk of cutaneous melanoma.	('associated', 'Reg', (30, 40))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('skin pigmentation', 'Disease', 'MESH:D010859', (82, 99))	('red hair', 'Disease', (104, 112))	('red hair', 'Phenotype', 'HP:0002297', (104, 112))	('MC1R', 'Gene', '4157', (21, 25))	('pigmentation', 'biological_process', 'GO:0043473', ('87', '99'))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('MC1R', 'Gene', (21, 25))	('Missense variants', 'Var', (0, 17))	('cutaneous melanoma', 'Disease', (150, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('skin pigmentation', 'Phenotype', 'HP:0000953', (82, 99))	('light skin', 'Phenotype', 'HP:0001010', (76, 86))	('skin pigmentation', 'Disease', (82, 99))
43695	29317335	We identified four MC1R variants (rs1805006, rs1805007, rs1805008, rs1805009) with ORs significantly greater than 1 in this study (Table 2).	('rs1805007', 'Mutation', 'rs1805007', (45, 54))	('rs1805008', 'Mutation', 'rs1805008', (56, 65))	('rs1805009', 'Mutation', 'rs1805009', (67, 76))	('rs1805009', 'Var', (67, 76))	('rs1805008', 'Var', (56, 65))	('rs1805006', 'Var', (34, 43))	('rs1805007', 'Var', (45, 54))	('MC1R', 'Gene', '4157', (19, 23))	('rs1805006', 'Mutation', 'rs1805006', (34, 43))	('MC1R', 'Gene', (19, 23))
43696	29317335	All four variants are known melanoma risk factors and are strongly associated with red hair.	('melanoma', 'Disease', (28, 36))	('red hair', 'Phenotype', 'HP:0002297', (83, 91))	('associated', 'Reg', (67, 77))	('variants', 'Var', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('red hair', 'Disease', (83, 91))
43697	29317335	The association between MC1R carrier status and increased UV mutational signatures in triple-WT tumors is likely due to an interaction between lighter skin pigmentation and UV exposure.	('increased', 'PosReg', (48, 57))	('skin pigmentation', 'Disease', (151, 168))	('MC1R', 'Gene', '4157', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('carrier', 'Var', (29, 36))	('MC1R', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('WT tumors', 'Disease', 'MESH:C536751', (93, 102))	('skin pigmentation', 'Disease', 'MESH:D010859', (151, 168))	('pigmentation', 'biological_process', 'GO:0043473', ('156', '168'))	('mutational', 'Var', (61, 71))	('carrier', 'molecular_function', 'GO:0005215', ('29', '36'))	('WT tumors', 'Disease', (93, 102))	('skin pigmentation', 'Phenotype', 'HP:0000953', (151, 168))
43699	29317335	The modest but significant relationship between MC1R carrier status and younger age at melanoma diagnosis could be explained by age-specific increases in relative risk or by earlier detection due to recognized phenotypic risk factors.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('relative', 'MPA', (154, 162))	('increases', 'PosReg', (141, 150))	('carrier status', 'Var', (53, 67))	('MC1R', 'Gene', '4157', (48, 52))	('MC1R', 'Gene', (48, 52))	('carrier', 'molecular_function', 'GO:0005215', ('53', '60'))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
43701	29317335	We identified an association between melanoma and a rare functional non-synonymous SNV (rs149617956), with an adjusted OR of 4.48 (95% CI: 1.57 to 12.78).	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('rs149617956', 'Var', (88, 99))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('rs149617956', 'Mutation', 'rs149617956', (88, 99))
43702	29317335	This variant is also associated with a higher incidence of renal cancer, increased nevus count, and non-blue eye color.	('increased', 'PosReg', (73, 82))	('renal cancer', 'Disease', (59, 71))	('renal cancer', 'Phenotype', 'HP:0009726', (59, 71))	('variant', 'Var', (5, 12))	('renal cancer', 'Disease', 'MESH:D007680', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('blue eye', 'Phenotype', 'HP:0000635', (104, 112))	('nevus', 'Phenotype', 'HP:0003764', (83, 88))	('non-blue eye color', 'Disease', (100, 118))	('nevus count', 'CPA', (83, 94))
43705	29317335	Previous studies have reported multiple variants associated with occurrence of cutaneous melanoma.	('cutaneous melanoma', 'Disease', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('associated', 'Reg', (49, 59))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('variants', 'Var', (40, 48))
43706	29317335	In this study, VAAST identified two additional potential risk variants in MTAP, one LGD and one non-LGD.	('MTAP', 'Gene', '4507', (74, 78))	('variants', 'Var', (62, 70))	('MTAP', 'Gene', (74, 78))
43707	29317335	Although only two MTAP carriers were identified in this study, the age at diagnosis was significantly different between carriers and non-carriers.	('MTAP', 'Gene', '4507', (18, 22))	('MTAP', 'Gene', (18, 22))	('carriers', 'Var', (120, 128))
43708	29317335	Both MTAP carriers were diagnosed with melanoma before the age of 45, compared to an average age at diagnosis among all study participants of 56.7.	('MTAP', 'Gene', (5, 9))	('diagnosed with', 'Reg', (24, 38))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('participants', 'Species', '9606', (126, 138))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('MTAP', 'Gene', '4507', (5, 9))	('carriers', 'Var', (10, 18))
43709	29317335	To our knowledge, associations with MTAP susceptibility variants and early-onset melanoma have not been previously reported.	('associations', 'Interaction', (18, 30))	('MTAP', 'Gene', (36, 40))	('MTAP', 'Gene', '4507', (36, 40))	('variants', 'Var', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
43712	29317335	The estimated effect size for LGD variants in BRCA2 was somewhat higher than previously reported, with a crude OR of 5.6 and an adjusted OR of 3.4.	('BRCA2', 'Gene', '675', (46, 51))	('variants', 'Var', (34, 42))	('BRCA2', 'Gene', (46, 51))
43713	29317335	However, given the wide confidence intervals, these results are consistent with previous relative risk estimate of 2.6 (95% CI 1.3 to 5.2) for pathogenic BRCA2 variants .	('BRCA2', 'Gene', (154, 159))	('variants', 'Var', (160, 168))	('BRCA2', 'Gene', '675', (154, 159))
43714	29317335	We also replicated the association with the BRCA2 coding variant rs1799944, which had a MAF of 0.03 among controls.	('BRCA2', 'Gene', '675', (44, 49))	('rs1799944', 'Var', (65, 74))	('BRCA2', 'Gene', (44, 49))	('rs1799944', 'Mutation', 'rs1799944', (65, 74))
43715	29317335	Note that rs766173 and rs1799944 are in near complete linkage disequilibrium (r2 = .89), which complicates interpretations of causality.	('rs766173', 'Var', (10, 18))	('rs1799944', 'Var', (23, 32))	('rs1799944', 'Mutation', 'rs1799944', (23, 32))	('rs766173', 'Mutation', 'rs766173', (10, 18))
43718	29317335	Coding variants in both FANCA and BRCA2 have been previously associated with overall survival of melanoma patients.	('associated with', 'Reg', (61, 76))	('BRCA2', 'Gene', '675', (34, 39))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('FANCA', 'Gene', '2175', (24, 29))	('patients', 'Species', '9606', (106, 114))	('Coding variants', 'Var', (0, 15))	('BRCA2', 'Gene', (34, 39))	('FANCA', 'Gene', (24, 29))
43727	29317335	CASM conservation-controlled amino acid substitution matrix CI confidence interval CNA copy number alteration ExAC Exome Aggregation Consortium GATK Genome Analysis Toolkit LGD likely gene-disrupting NDAR National Database for Autism Research OR odds ratio PCA principle component analysis QC quality control SGI somatic-germline interaction SKCM skin cutaneous Melanoma SNP single nucleotide polymorphism SNV single nucleotide variant SSC Simons Simplex Collection TCGA The Cancer Genome Atlas VAAST2 The Variant Annotation, Analysis and Search Tool XPAT The cross-Platform Association Toolkit Rare, protein-coding variants in MC1R, MITF, BRCA2, and MTAP confer between a 1.4-fold to 6-fold increase in melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (704, 712))	('MC1R', 'Gene', '4157', (628, 632))	('Autism', 'Disease', 'MESH:D001321', (227, 233))	('MC1R', 'Gene', (628, 632))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (475, 494))	('MITF', 'Gene', '4286', (634, 638))	('MTAP', 'Gene', (651, 655))	('MTAP', 'Gene', '4507', (651, 655))	('Cancer Genome Atlas', 'Disease', (475, 494))	('Autism', 'Disease', (227, 233))	('melanoma', 'Phenotype', 'HP:0002861', (704, 712))	('skin cutaneous Melanoma', 'Disease', 'MESH:C562393', (347, 370))	('melanoma', 'Disease', (704, 712))	('Autism', 'Phenotype', 'HP:0000717', (227, 233))	('MITF', 'Gene', (634, 638))	('BRCA2', 'Gene', (640, 645))	('cutaneous Melanoma', 'Phenotype', 'HP:0012056', (352, 370))	('Cancer', 'Phenotype', 'HP:0002664', (475, 481))	('protein', 'cellular_component', 'GO:0003675', ('601', '608'))	('Melanoma', 'Phenotype', 'HP:0002861', (362, 370))	('variants', 'Var', (616, 624))	('BRCA2', 'Gene', '675', (640, 645))	('skin cutaneous Melanoma', 'Disease', (347, 370))	('increase', 'PosReg', (692, 700))
43728	29317335	Susceptibility variants within MC1R are associated with ultraviolet (UV) radiation mutational signatures in triple-wildtype tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MC1R', 'Gene', '4157', (31, 35))	('MC1R', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('variants', 'Var', (15, 23))	('type tumors', 'Disease', 'MESH:D009369', (119, 130))	('type tumors', 'Disease', (119, 130))
43729	29317335	Susceptibility variants in MC1R and MTAP are associated with earlier age of melanoma diagnosis.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('MC1R', 'Gene', '4157', (27, 31))	('MTAP', 'Gene', (36, 40))	('MC1R', 'Gene', (27, 31))	('MTAP', 'Gene', '4507', (36, 40))	('variants', 'Var', (15, 23))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
43786	27549193	TAM numbers have been reported to be a predictor of worse outcome in many cancers.	('TAM numbers', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('TAM', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
43792	27549193	Non-synonymous somatic mutations in the tumor genome can generate immunogenic neoantigens that trigger antitumor response through T-cell activation.	('T-cell', 'CPA', (130, 136))	('T-cell activation', 'biological_process', 'GO:0042110', ('130', '147'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Non-synonymous somatic mutations', 'Var', (0, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (40, 45))	('immunogenic neoantigens', 'MPA', (66, 89))	('trigger', 'PosReg', (95, 102))
43796	27549193	In addition, we observed that dendritic cell infiltration is correlated with the total mutation load in breast cancer (Spearman's rho = 0.11, q = 0.037), as is B-cell infiltration (rho = 0.13, q = 0.018), suggesting cancer-specific roles for these cell types in antitumor immunity.	('dendritic cell', 'CPA', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('breast cancer', 'Disease', (104, 117))	('mutation load', 'Var', (87, 100))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (266, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
43799	27549193	MSI typically generates small indels across the genome, producing non-self antigens that may be recognized by the host immune system.	('MSI', 'Disease', 'None', (0, 3))	('non-self antigens', 'MPA', (66, 83))	('indels', 'Var', (30, 36))	('MSI', 'Disease', (0, 3))	('producing', 'Reg', (56, 65))
43840	27549193	More importantly, we found that tumors with high TIM3 expression can be divided into two distinct groups with different levels of infiltrating CD8 T cells (Fig.	('TIM3', 'Gene', '84868', (49, 53))	('high', 'Var', (44, 48))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('TIM3', 'Gene', (49, 53))
43856	27549193	Systematic exploration of tumor-immune interactions revealed cancer genetic alterations and chemokine/receptor expression networks are potential regulators of immune cell infiltration heterogeneity.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('genetic alterations', 'Var', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (26, 31))
43910	27549193	We investigated the expression levels of the B-cell markers CD19 and CD20 in OV and discovered that tumor purity is not negatively correlated with gene expression levels for both genes, indicating that aneuploid cells in ovarian cancer may also express B-cell markers.	('aneuploid', 'Var', (202, 211))	('express', 'Reg', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CD19', 'Gene', (60, 64))	('tumor', 'Disease', (100, 105))	('ovarian cancer', 'Disease', (221, 235))	('CD20', 'Gene', '54474', (69, 73))	('CD19', 'Gene', '930', (60, 64))	('gene expression', 'biological_process', 'GO:0010467', ('147', '162'))	('CD20', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('OV', 'Phenotype', 'HP:0012887', (77, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))
43926	33347579	Variable interplay of UV-induced DNA damage and repair at transcription factor binding sites An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('transcription', 'biological_process', 'GO:0006351', ('58', '71'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('TFBS', 'Chemical', '-', (194, 198))	('melanomas', 'Disease', 'MESH:D008545', (207, 216))	('UV-light related', 'Gene', (120, 136))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('58', '86'))	('mutations', 'Var', (137, 146))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('158', '186'))	('melanomas', 'Disease', (207, 216))
43930	33347579	We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies.	('formation', 'MPA', (133, 142))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('TF', 'Gene', '2152', (74, 76))	('increased', 'PosReg', (115, 124))	('dipyrimidine', 'Chemical', '-', (24, 36))	('dipyrimidine positions', 'Var', (24, 46))	('binding', 'molecular_function', 'GO:0005488', ('58', '65'))	('UV-induced lesions', 'MPA', (146, 164))	('Tryptophan', 'Chemical', 'MESH:D014364', (85, 95))
43937	33347579	Both processes thus result in C-G>T-A mutations in cytosines within dipyrimidine contexts, leaving a distinctive mutational pattern known as the UV mutational signature (COSMIC signatures 7a-c).	('leaving', 'Reg', (91, 98))	('result in', 'Reg', (20, 29))	('C-G>T-A mutations', 'Var', (30, 47))	('mutations', 'Var', (38, 47))	('dipyrimidine', 'Chemical', '-', (68, 80))
43939	33347579	The rate of mutations in TFBS in certain cell types, such as melanocytes (and the derived tumor type melanomas), is abnormally high in comparison to that observed in their flanking regions.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('mutations', 'Var', (12, 21))	('TFBS', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor type melanomas', 'Disease', 'MESH:D008545', (90, 110))	('TFBS', 'Chemical', '-', (25, 29))	('tumor type melanomas', 'Disease', (90, 110))
43940	33347579	Several studies have reported an unexpected increase of the mutations in active TFBS in melanomas linked to a reduced accessibility of the NER machinery to these regions.	('accessibility', 'MPA', (118, 131))	('TFBS', 'Chemical', '-', (80, 84))	('reduced', 'NegReg', (110, 117))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('increase', 'PosReg', (44, 52))	('melanomas', 'Disease', (88, 97))	('mutations', 'Var', (60, 69))	('TFBS', 'Gene', (80, 84))	('NER', 'biological_process', 'GO:0006289', ('139', '142'))
43942	33347579	The relative contribution of these two factors to the increased rate of mutations at the binding sites of different TFs, and across the whole TFBSs genomic compartment in melanomas is not completely understood.	('mutations', 'Var', (72, 81))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('TF', 'Gene', '2152', (116, 118))	('melanomas', 'Disease', (171, 180))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('TF', 'Gene', '2152', (142, 144))	('TFBS', 'Chemical', '-', (142, 146))
43956	33347579	The probability of a trinucleotide or pentanucleotide to be mutated was determined using the whole genome mutations of all 136 UV induced melanomas, normalized by the abundance of each trinucleotide or pentanucleotide in the genome.	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('pentanucleotide', 'Chemical', '-', (38, 53))	('trinucleotide', 'Chemical', '-', (185, 198))	('pentanucleotide', 'Chemical', '-', (202, 217))	('melanomas', 'Disease', (138, 147))	('trinucleotide', 'Chemical', '-', (21, 34))	('mutations', 'Var', (106, 115))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))
43962	33347579	Then, for each position, we counted the number of observed and expected mutations, and also CPDs at different timepoints after UV exposure.	('CPDs', 'Disease', (92, 96))	('mutations', 'Var', (72, 81))	('CPDs', 'Disease', 'MESH:C565866', (92, 96))
43969	33347579	Mutations and CPDs found to overlap this set of sampled dipyrimidines were used as reference for those observed in dipyrimidines within the motif.	('CPDs', 'Disease', (14, 18))	('dipyrimidines', 'Chemical', '-', (56, 69))	('Mutations', 'Var', (0, 9))	('dipyrimidines', 'Chemical', '-', (115, 128))	('CPDs', 'Disease', 'MESH:C565866', (14, 18))
43977	33347579	When comparing the observed number of mutations or CPDs in a specific region with an expected distribution, being the simulated number of mutations or the CPDs in the naked DNA respectively, a chi-squared goodness of fit test was used.	('CPDs', 'Disease', 'MESH:C565866', (155, 159))	('CPDs', 'Disease', (51, 55))	('CPDs', 'Disease', 'MESH:C565866', (51, 55))	('DNA', 'cellular_component', 'GO:0005574', ('173', '176'))	('CPDs', 'Disease', (155, 159))	('mutations', 'Var', (138, 147))
43990	33347579	From a cohort of 136 UV-exposed melanomas we obtained the mutations overlapping these 598,987 2001-nucleotide wide regions.	('mutations', 'Var', (58, 67))	('melanomas', 'Disease', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('melanomas', 'Disease', 'MESH:D008545', (32, 41))
43998	33347579	The mutation rate of the motifs of most basic leucine zipper and fork head TFs, on the other hand, is significantly lower than expected.	('lower', 'NegReg', (116, 121))	('TF', 'Gene', '2152', (75, 77))	('mutation', 'Var', (4, 12))	('leucine', 'Chemical', 'MESH:D007930', (46, 53))	('basic leucine zipper', 'Protein', (40, 60))
44004	33347579	The increase of observed mutation rate (with respect to the expectation) tends to be more apparent at the motifs of TFs with higher expression:a proxy of higher occupancy of their binding sites:across melanomas (Supplementary Figure S5).	('melanomas', 'Disease', 'MESH:D008545', (201, 210))	('TF', 'Gene', '2152', (116, 118))	('mutation', 'Var', (25, 33))	('increase', 'PosReg', (4, 12))	('melanomas', 'Disease', (201, 210))	('expression', 'MPA', (132, 142))	('binding', 'molecular_function', 'GO:0005488', ('180', '187'))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))
44008	33347579	At some TF binding motifs -as previously observed for ETS1:the increase in the number of UV-induced mutations with respect to the expectation is mainly driven by one or few dipyrimidines (Figure 2A-D; Supplementary Figure S6 and Supplementary Table S2).	('mutations', 'Var', (100, 109))	('increase', 'PosReg', (63, 71))	('dipyrimidines', 'Chemical', '-', (173, 186))	('UV-induced', 'Gene', (89, 99))	('dipyrimidines', 'Var', (173, 186))	('TF binding', 'molecular_function', 'GO:0008134', ('8', '18'))	('ETS1', 'Gene', '2113', (54, 58))	('ETS1', 'Gene', (54, 58))	('TF', 'Gene', '2152', (8, 10))
44009	33347579	Specifically, some dipyrimidine sites within Tryptophan Cluster and C2H2 Zinc Fingers TF motifs tend to bear more mutations than expected (Figure 2E).	('mutations', 'MPA', (114, 123))	('Tryptophan', 'Chemical', 'MESH:D014364', (45, 55))	('C2H2', 'Gene', (68, 72))	('TF', 'Gene', '2152', (86, 88))	('dipyrimidine', 'Chemical', '-', (19, 31))	('dipyrimidine', 'Var', (19, 31))
44010	33347579	At these sites features other than sequence context influence the rate of mutations, pointing at the influence of bound TFs on the formation of UV-induced photoproducts and/or their repair.	('TF', 'Gene', '2152', (120, 122))	('mutations', 'Var', (74, 83))	('influence', 'Reg', (52, 61))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))	('influence', 'Reg', (101, 110))
44029	33347579	Only a few motifs presented large higher- (some Tryptophan Cluster TFs) or lower-than-expected (some C2H2 Zinc Finger and Basic Leucine Zipper TFs) rates of CPD formation.	('C2H2', 'Var', (101, 105))	('Tryptophan', 'Chemical', 'MESH:D014364', (48, 58))	('TF', 'Gene', '2152', (67, 69))	('lower-than-expected', 'NegReg', (75, 94))	('Leucine', 'Chemical', 'MESH:D007930', (128, 135))	('Tryptophan Cluster', 'MPA', (48, 66))	('TF', 'Gene', '2152', (143, 145))	('formation', 'biological_process', 'GO:0009058', ('161', '170'))	('CPD formation', 'MPA', (157, 170))	('Basic Leucine Zipper', 'Var', (122, 142))
44031	33347579	Summing up, CPD formation rate is higher than expected in the motifs of TFs of the Tryptophan Cluster family, which could contribute to their higher-than-expected rate of mutations.	('motifs', 'Var', (62, 68))	('higher', 'PosReg', (34, 40))	('Tryptophan', 'Chemical', 'MESH:D014364', (83, 93))	('TF', 'Gene', '2152', (72, 74))	('CPD formation', 'CPA', (12, 25))	('formation', 'biological_process', 'GO:0009058', ('16', '25'))
44047	33347579	Intriguingly, we observed that CPDs involving CC dipyrimidines tend to occupy lowly-repaired positions (Figure 4G), while those of TT or TC dipyrimidines were at highly repaired positions.	('CPDs', 'Disease', 'MESH:C565866', (31, 35))	('TC dipyrimidines', 'Chemical', '-', (137, 153))	('CC dipyrimidines', 'Chemical', '-', (46, 62))	('CC dipyrimidines', 'Var', (46, 62))	('CPDs', 'Disease', (31, 35))
44051	33347579	This hypothesis is based on the assumption that the rate of mutations across TFBS is ultimately shaped by the rate of CPDs generated by UV within each TFBS and the efficiency of NER correcting them.	('CPDs', 'Disease', 'MESH:C565866', (118, 122))	('TFBS', 'Chemical', '-', (77, 81))	('NER', 'biological_process', 'GO:0006289', ('178', '181'))	('TFBS', 'Chemical', '-', (151, 155))	('mutations', 'Var', (60, 69))	('CPDs', 'Disease', (118, 122))
44055	33347579	The observation that the burden of mutations at promoter regions:and in particular in TFBS:in melanomas was unexpectedly high paved the way for the dissection of the detailed influence of the bound TF on the formation of UV-induced lesions and their repair.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('TFBS', 'Chemical', '-', (86, 90))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('TF', 'Gene', '2152', (198, 200))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('formation', 'biological_process', 'GO:0009058', ('208', '217'))	('TF', 'Gene', '2152', (86, 88))	('melanomas', 'Disease', (94, 103))	('mutations', 'Var', (35, 44))
44066	33347579	A second limitation of the analysis stems from the fact that while CPDs have been mapped in a fibroblast cell line, the source of mutations are melanomas, which derive from melanocytes, a different cell type.	('CPDs', 'Disease', (67, 71))	('melanomas', 'Disease', (144, 153))	('CPDs', 'Disease', 'MESH:C565866', (67, 71))	('mutations', 'Var', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))
44070	33347579	the distribution of mutations across different areas that results from the interplay between the formation of the CPDs and their repair:is complex, and varies widely between families of TFs.	('CPDs', 'Disease', (114, 118))	('CPDs', 'Disease', 'MESH:C565866', (114, 118))	('formation', 'biological_process', 'GO:0009058', ('97', '106'))	('TF', 'Gene', '2152', (186, 188))	('mutations', 'Var', (20, 29))
44077	33347579	We also found that the decreased accessibility of NER that results in a reduced activity of repair of UV-induced lesions is observed across the binding sites of TFs of most families and is thus a more widespread cause of their increased mutation rate.	('reduced', 'NegReg', (72, 79))	('accessibility', 'MPA', (33, 46))	('lesions', 'Var', (113, 120))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('TF', 'Gene', '2152', (161, 163))	('UV-induced', 'Gene', (102, 112))	('repair', 'MPA', (92, 98))	('activity', 'MPA', (80, 88))	('NER', 'Protein', (50, 53))	('NER', 'biological_process', 'GO:0006289', ('50', '53'))	('decreased', 'NegReg', (23, 32))
44083	33347579	This raises the intriguing possibility that the significant increase in the rate of DNA repair registered at the binding sites of Tryptophan cluster TFs:an exception in this regard (Table 1):is caused by the TF vacating the site, due to the distortion of the DNA double helix.	('TF', 'Gene', '2152', (208, 210))	('distortion', 'Var', (241, 251))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('DNA repair', 'biological_process', 'GO:0006281', ('84', '94'))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('259', '262'))	('increase', 'PosReg', (60, 68))	('TF', 'Gene', '2152', (149, 151))	('Tryptophan', 'Chemical', 'MESH:D014364', (130, 140))
44130	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))
44144	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))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
44152	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))
44162	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))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('hallmark characteristics', 'MPA', (70, 94))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('TRIM44', 'Gene', '54765', (18, 24))	('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'))
44164	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))
44166	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'))
44167	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.	('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))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('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', 'Gene', (125, 131))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (111, 117))
44169	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('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))
44170	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))	('activated', 'PosReg', (99, 108))	('glioma', 'Disease', (112, 118))	('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))
44171	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
44172	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))
44183	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))	('CADM1', 'Gene', (103, 108))	('DDIT4', 'Gene', (130, 135))	('knockdown', 'Var', (39, 48))	('CDK19', 'Gene', '23097', (96, 101))	('DDIT4', 'Gene', '54541', (130, 135))
44192	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))
44199	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))
44215	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
44217	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
44225	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
44244	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
44245	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
44246	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
44248	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
44249	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('E59K', 'Var', (0, 4))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
44250	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
44251	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('R238C', 'Var', (117, 122))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('NTNG1', 'Gene', '22854', (33, 38))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
44252	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('EGF', 'molecular_function', 'GO:0005154', ('352', '355'))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
44253	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('NTN3', 'Gene', '4917', (224, 228))	('patients', 'Species', '9606', (76, 84))	('NTN1', 'Gene', (138, 142))	('NTN4', 'Gene', '59277', (301, 305))	('NTN3', 'Gene', (224, 228))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
44254	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('patient', 'Species', '9606', (75, 82))	('patients', 'Species', '9606', (118, 126))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('NTNG1', 'Gene', '22854', (104, 109))	('patient', 'Species', '9606', (118, 125))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
44255	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (84, 91))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('NTNG2', 'Gene', '84628', (204, 209))	('NTN1', 'Gene', '9423', (195, 199))
44256	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
44257	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
44258	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
44259	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
44260	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
44261	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
44262	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('EGF', 'molecular_function', 'GO:0005154', ('15', '18'))	('NTN4', 'Gene', (42, 46))	('EGF', 'molecular_function', 'GO:0005154', ('93', '96'))	('NTN3', 'Gene', '4917', (36, 40))	('NTN5', 'Gene', '126147', (52, 56))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
44263	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('EGF', 'molecular_function', 'GO:0005154', ('58', '61'))	('EGF', 'molecular_function', 'GO:0005154', ('21', '24'))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('EGF', 'molecular_function', 'GO:0005154', ('154', '157'))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('EGF', 'molecular_function', 'GO:0005154', ('117', '120'))	('NTNG1', 'Gene', (7, 12))
44264	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
44274	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('MLK1', 'Gene', (14, 18))	('transcription', 'MPA', (96, 109))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'molecular_function', 'GO:0004229', ('91', '95'))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('epigenetic activation', 'Var', (66, 87))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cell migration', 'biological_process', 'GO:0016477', ('35', '49'))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('MMP9', 'Gene', '4318', (91, 95))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('enhanced', 'PosReg', (19, 27))
44309	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTN1', 'Gene', '9423', (57, 61))	('NTN1', 'Gene', '9423', (238, 242))	('NTN1', 'Gene', (57, 61))	('NTNG1', 'Gene', '22854', (255, 260))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
44312	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
44314	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('NTN4', 'Gene', '59277', (46, 50))	('associated', 'Reg', (55, 65))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('NTN4', 'Gene', (46, 50))
44315	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
44317	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('radiation therapy', 'Disease', (49, 66))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
44318	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('associated', 'Reg', (24, 34))	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', '4917', (15, 19))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN3', 'Gene', (15, 19))
44319	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (104, 114))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
44320	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
44324	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('EZH2', 'Gene', '2146', (102, 106))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
44339	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
44345	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('eQTL', 'Var', (39, 43))	('affected', 'Reg', (27, 35))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
44348	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('non-obstructive azoospermia', 'Disease', (96, 123))	('AIDS', 'Disease', (55, 59))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
44351	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('EBF1', 'Gene', '1879', (108, 112))	('rs9901637', 'Var', (33, 42))	('binding', 'molecular_function', 'GO:0005488', ('85', '92'))	('EBF1', 'Gene', (108, 112))	('MYC', 'Gene', (96, 99))	('rs9894790', 'Var', (22, 31))	('NR2F2', 'Gene', '7026', (124, 129))	('NR2F2', 'Gene', (124, 129))	('TCF12', 'Gene', (101, 106))	('TCF12', 'Gene', '6938', (101, 106))	('MYC', 'Gene', '4609', (96, 99))	('affect', 'Reg', (74, 80))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('EGR1', 'Gene', (114, 118))	('EGR1', 'Gene', '1958', (114, 118))	('binding', 'Interaction', (85, 92))
44352	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('high', 'Var', (14, 18))	('NTN1', 'Gene', '9423', (33, 37))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
44360	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
44372	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('126', '135'))	('apoptosis', 'biological_process', 'GO:0006915', ('126', '135'))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
44381	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
44384	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Netrin', 'Gene', (112, 118))
44385	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
44386	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('localization', 'biological_process', 'GO:0051179', ('195', '207'))	('EGF', 'molecular_function', 'GO:0005154', ('127', '130'))	('NTR', 'Gene', (215, 218))
44389	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
44397	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
44405	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('NTNG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('methylation', 'Var', (36, 47))
44406	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('EMT', 'biological_process', 'GO:0001837', ('148', '151'))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
44408	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
44409	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
44413	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
44487	32201538	The wild-type and mutated 3'UTRs of STAT3 were subcloned into the pGL3 vector (Promega, WI, USA).	('pGL3', 'Gene', (66, 70))	('mutated', 'Var', (18, 25))	('STAT3', 'Gene', '6774', (36, 41))	('pGL3', 'Gene', '6391', (66, 70))	('STAT3', 'Gene', (36, 41))	('pGL', 'molecular_function', 'GO:0004598', ('66', '69'))
44488	32201538	Cells were co-transfected with the plasmid constructs of pGL3-STAT3-3'UTR or pGL3-STAT3-3'UTR-mut and ad-miR-181 or ad-control using Lipofectamine 3000 (Invitrogen, CA, USA).	('STAT3', 'Gene', (62, 67))	('pGL', 'molecular_function', 'GO:0004598', ('57', '60'))	('pGL', 'molecular_function', 'GO:0004598', ('77', '80'))	('STAT3', 'Gene', '6774', (82, 87))	('pGL3', 'Gene', (77, 81))	('STAT3', 'Gene', '6774', (62, 67))	('pGL3', 'Gene', (57, 61))	('STAT3', 'Gene', (82, 87))	('ad-miR-181', 'Var', (102, 112))	('pGL3', 'Gene', '6391', (57, 61))	('pGL3', 'Gene', '6391', (77, 81))
44509	32201538	To further confirm whether miR-181 directly targets STAT3, a firefly luciferase reporter was constructed containing a wild type or mutated type fragment of the 3'-UTR of STAT3 mRNA.	('STAT3', 'Gene', (52, 57))	('STAT3', 'Gene', '6774', (170, 175))	('mutated', 'Var', (131, 138))	('STAT3', 'Gene', (170, 175))	('STAT3', 'Gene', '6774', (52, 57))
44531	32201538	There are growing evidences that altered expression of miRNAs is strongly linked with carcinogenesis and progression of human malignancies including CM32.	('carcinogenesis', 'Disease', (86, 100))	('human', 'Species', '9606', (120, 125))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('expression', 'MPA', (41, 51))	('CM', 'Disease', 'MESH:C562393', (149, 151))	('malignancies', 'Disease', (126, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('CM', 'Phenotype', 'HP:0012056', (149, 151))	('miRNAs', 'Protein', (55, 61))	('altered', 'Var', (33, 40))	('linked', 'Reg', (74, 80))
44536	32201538	Although miR-181 miRNA family was report with clear effects on CD4+T cell development and homeostasis, at least partly, similar to the functions as IL-22 shown; our results demonstrate that miR-181 could be employed as a prognostic biomarker for CM development, as well as a predictor for CM outcome.	('homeostasis', 'biological_process', 'GO:0042592', ('90', '101'))	('IL-22', 'molecular_function', 'GO:0045518', ('148', '153'))	('CD4', 'Gene', (63, 66))	('CM', 'Disease', 'MESH:C562393', (289, 291))	('CD4', 'Gene', '920', (63, 66))	('T cell development', 'biological_process', 'GO:0030217', ('67', '85'))	('CM', 'Disease', 'MESH:C562393', (246, 248))	('CM', 'Phenotype', 'HP:0012056', (289, 291))	('IL-22', 'Gene', '50616', (148, 153))	('miR-181', 'Var', (190, 197))	('IL-22', 'Gene', (148, 153))	('CM', 'Phenotype', 'HP:0012056', (246, 248))
44541	32201538	Moreover, IL22 treatment significantly inhibited the expression of STAT3, while miR-181 knockdown significantly reversed this effect.	('IL22', 'molecular_function', 'GO:0045518', ('10', '14'))	('inhibited', 'NegReg', (39, 48))	('STAT3', 'Gene', '6774', (67, 72))	('knockdown', 'Var', (88, 97))	('STAT3', 'Gene', (67, 72))	('expression', 'MPA', (53, 63))	('miR-181', 'Gene', (80, 87))
44542	32201538	Furthermore, IL22 treatment elevated expression of p-AKT, p-beta-catenin and MMP-4; however, miR-181 knockdown significantly inhibited phosphorylation of Akt and beta-catenin, and expression of MMP-4 as well.	('MMP-4', 'Gene', (77, 82))	('MMP', 'molecular_function', 'GO:0004235', ('194', '197'))	('elevated', 'PosReg', (28, 36))	('IL22', 'molecular_function', 'GO:0045518', ('13', '17'))	('MMP-4', 'Gene', (194, 199))	('Akt', 'Gene', (154, 157))	('MMP-4', 'Gene', '3609', (77, 82))	('MMP', 'molecular_function', 'GO:0004235', ('77', '80'))	('miR-181', 'Gene', (93, 100))	('phosphorylation', 'MPA', (135, 150))	('AKT', 'Gene', (53, 56))	('Akt', 'Gene', '207', (154, 157))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('MMP-4', 'Gene', '3609', (194, 199))	('expression', 'MPA', (180, 190))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('expression', 'MPA', (37, 47))	('beta-catenin', 'Gene', (162, 174))	('AKT', 'Gene', '207', (53, 56))	('beta-catenin', 'Gene', '1499', (162, 174))	('inhibited', 'NegReg', (125, 134))	('knockdown', 'Var', (101, 110))
44543	32201538	Although our results showed IL-22 treatment indeed as an activator of STAT3/Akt signing pathway, interestingly, we noticed that the activation of STAT3/Akt pathway in CM cells was mainly mediated directly by miR-181.	('activation', 'PosReg', (132, 142))	('miR-181', 'Var', (208, 215))	('STAT3', 'Gene', (70, 75))	('STAT3', 'Gene', (146, 151))	('Akt', 'Gene', (76, 79))	('IL-22', 'Gene', '50616', (28, 33))	('Akt', 'Gene', (152, 155))	('IL-22', 'molecular_function', 'GO:0045518', ('28', '33'))	('CM', 'Phenotype', 'HP:0012056', (167, 169))	('IL-22', 'Gene', (28, 33))	('CM', 'Disease', 'MESH:C562393', (167, 169))	('Akt', 'Gene', '207', (76, 79))	('STAT3', 'Gene', '6774', (146, 151))	('Akt', 'Gene', '207', (152, 155))	('STAT3', 'Gene', '6774', (70, 75))
44546	32201538	Consistently, we observed increased expression of p-beta-catenin and MMP-4 in CM cells under IL22 treatment, revealing the underlying mechanism of IL22-induced CM progression.	('CM', 'Phenotype', 'HP:0012056', (78, 80))	('treatment', 'Var', (98, 107))	('beta-catenin', 'Gene', (52, 64))	('CM', 'Phenotype', 'HP:0012056', (160, 162))	('IL22', 'molecular_function', 'GO:0045518', ('93', '97'))	('IL22', 'molecular_function', 'GO:0045518', ('147', '151'))	('MMP', 'molecular_function', 'GO:0004235', ('69', '72'))	('CM', 'Disease', 'MESH:C562393', (160, 162))	('beta-catenin', 'Gene', '1499', (52, 64))	('increased', 'PosReg', (26, 35))	('CM', 'Disease', 'MESH:C562393', (78, 80))	('MMP-4', 'Gene', (69, 74))	('expression', 'MPA', (36, 46))	('MMP-4', 'Gene', '3609', (69, 74))
44565	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))
44566	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))
44571	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))
44572	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))
44647	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))
44661	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))
44662	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.	('mutation', 'Var', (111, 119))	('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))	('loss-of-function', 'NegReg', (94, 110))	('mutational burden', 'MPA', (141, 158))
44695	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))	('PRAME', 'Gene', '23532', (225, 230))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('increase', 'PosReg', (15, 23))	('PRAME', 'Gene', (225, 230))	('tumor', 'Disease', (55, 60))	('MART-1', 'Gene', '2315', (249, 255))	('MART-1', 'Gene', (249, 255))	('efficacy', 'MPA', (24, 32))
44696	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))
44697	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))
44710	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))	('checkpoint', 'MPA', (59, 69))	('NCT03408587', 'Var', (280, 291))	('NCT02913417', 'Var', (116, 127))	('NCT02831933', 'Var', (217, 228))
44714	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))
44725	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))
44762	22759494	While UVC radiation is ecologically not relevant since it is absorbed by oxygen and ozone in the Earth's atmosphere, the longer wavelength UV-B (280-315 nm) and UV-A (315-400 nm) radiation have significant effects on the biota.	('effects', 'Reg', (206, 213))	('biota', 'Species', '131567', (221, 226))	('oxygen', 'Chemical', 'MESH:D010100', (73, 79))	('biota', 'CPA', (221, 226))	('280-315 nm', 'Var', (145, 155))
44784	22759494	During DNA replication, DNA polymerase incorporates an incorrect base opposite to an aberrant base, causing a mutation.	('DNA replication', 'biological_process', 'GO:0006260', ('7', '22'))	('rat', 'Species', '10116', (46, 49))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('causing', 'Reg', (100, 107))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('mutation', 'Var', (110, 118))
44785	22759494	The mutation caused by direct DNA damage can lead to skin cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('skin cancers', 'Disease', (53, 65))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('skin cancers', 'Disease', 'MESH:D012878', (53, 65))	('mutation', 'Var', (4, 12))	('lead to', 'Reg', (45, 52))	('skin cancer', 'Phenotype', 'HP:0008069', (53, 64))	('skin cancers', 'Phenotype', 'HP:0008069', (53, 65))
44796	22759494	Oxidative stress is caused by imbalance between ROS production and a biological system's ability to readily detoxify these reactive intermediates or easily repair the resulting damage.	('detoxify', 'MPA', (108, 116))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('ROS', 'Chemical', 'MESH:D017382', (48, 51))	('Oxidative stress', 'Disease', (0, 16))	('ROS', 'Protein', (48, 51))	('imbalance', 'Var', (30, 39))	('caused by', 'Reg', (20, 29))	('imbalance', 'Phenotype', 'HP:0002172', (30, 39))
44800	22759494	Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G --> T and G --> C conversions.	('G --> T', 'Var', (105, 112))	('men', 'Species', '9606', (32, 35))	('causing', 'Reg', (97, 104))	('Sp', 'Chemical', 'MESH:C408822', (58, 60))	('G --> C', 'Var', (117, 124))
44831	22759494	Components of temporary tattoos and hair dye ingredients, namely para-aminophenol (PAP) and para-phenylenediamine (PPD), have been reported to be carcinogenic and transformed in human skin.	('PAP', 'Chemical', 'MESH:C026729', (83, 86))	('para-phenylenediamine', 'Var', (92, 113))	('PPD', 'Chemical', 'MESH:C029728', (115, 118))	('human', 'Species', '9606', (178, 183))	('PAP', 'molecular_function', 'GO:0043751', ('83', '86'))	('transformed', 'CPA', (163, 174))	('para-aminophenol', 'Var', (65, 81))	('para-aminophenol', 'Chemical', 'MESH:C026729', (65, 81))	('para-phenylenediamine', 'Chemical', 'MESH:C029728', (92, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (146, 158))	('carcinogenic', 'Disease', (146, 158))	('tattoos and hair dye', 'Disease', 'MESH:C567128', (24, 44))
44836	22759494	It is supposed that indoor solar UVA exposure, which causes mutations, depletes vitamin D3 in the skin.	('depletes', 'NegReg', (71, 79))	('mutations', 'Var', (60, 69))	('vitamin D3', 'MPA', (80, 90))	('vitamin D3', 'Chemical', 'MESH:D002762', (80, 90))
44885	22759494	Worldwide, approximately 20-40% of kins with familial melanoma harbour germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence.	('CDKN2A', 'Gene', (97, 103))	('familial melanoma', 'Disease', 'OMIM:155600', (45, 62))	('mutations', 'Var', (80, 89))	('p14ARF', 'Gene', (188, 194))	('chromosome', 'cellular_component', 'GO:0005694', ('121', '131'))	('CDKN2A', 'Gene', '1029', (97, 103))	('p16INK4', 'Gene', '1029', (176, 183))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('p16INK4', 'Gene', (176, 183))	('senescence', 'biological_process', 'GO:0010149', ('267', '277'))	('regulation of cell cycle progression', 'biological_process', 'GO:0051726', ('213', '249'))	('p14ARF', 'Gene', '1029', (188, 194))	('familial melanoma', 'Disease', (45, 62))
44886	22759494	There are geographical variations in the incidence of CDKN2A mutations.	('CDKN2A', 'Gene', '1029', (54, 60))	('CDKN2A', 'Gene', (54, 60))	('mutations', 'Var', (61, 70))
44887	22759494	The risk of melanoma in CDKN2A mutation carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population.	('higher', 'Reg', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('mutation', 'Var', (31, 39))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('CDKN2A', 'Gene', (24, 30))	('CDKN2A', 'Gene', '1029', (24, 30))
44888	22759494	Another melanoma susceptibility gene, CDK4, accounts for only small number of families with germ mutations on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A.	('mutations', 'Var', (97, 106))	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('cyclin', 'molecular_function', 'GO:0016538', ('139', '145'))	('p16INK4A', 'Gene', '1029', (193, 201))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('CDK', 'molecular_function', 'GO:0004693', ('38', '41'))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (38, 42))	('p16INK4A', 'Gene', (193, 201))
44890	22759494	A panel of polymorphisms that appears to confer low-to-moderate risk for melanoma has been assessed through functional and genome-wide association studies.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('polymorphisms', 'Var', (11, 24))	('rat', 'Species', '10116', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
44892	22759494	Vitamin D receptor (VDR) gene SNPs the FokI T allele was associated with increased melanoma risk (OR 1.42, 95% confidence interval CI 1.06-1.91).	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('VDR', 'Gene', '7421', (20, 23))	('FokI T', 'Var', (39, 45))	('Vitamin D receptor', 'Gene', (0, 18))	('SNPs', 'Var', (30, 34))	('Vitamin D receptor', 'Gene', '7421', (0, 18))	('VDR', 'Gene', (20, 23))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
44894	22759494	However, other study showed opposite results: a significant association between the BsmI VDR polymorphism and increased melanoma risk (OR, 1.30, 95% CI, 1.11-1.53, the population attributable risk 9.2%.).	('polymorphism', 'Var', (93, 105))	('VDR', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('VDR', 'Gene', '7421', (89, 92))
44895	22759494	Mutations in the cell cycle gene CDKN2A (gene or mono-allelic loss at the locus) were connected with high risk of melanoma but results are not clear.	('CDKN2A', 'Gene', (33, 39))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('cell cycle', 'biological_process', 'GO:0007049', ('17', '27'))	('CDKN2A', 'Gene', '1029', (33, 39))	('Mutations', 'Var', (0, 9))	('connected', 'Reg', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
44896	22759494	The oncogenic mutations in the B-RAF and N-RAS genes constitute the initiating somatic events followed by loss of a major check point gene mainly CDKN2A or in some cases p53 or PTEN.	('CDKN2A', 'Gene', (146, 152))	('N-RAS', 'Gene', '4893', (41, 46))	('CDKN2A', 'Gene', '1029', (146, 152))	('p53', 'Gene', (170, 173))	('B-RAF', 'Gene', '673', (31, 36))	('PTEN', 'Gene', (177, 181))	('p53', 'Gene', '7157', (170, 173))	('PTEN', 'Gene', '5728', (177, 181))	('loss', 'NegReg', (106, 110))	('B-RAF', 'Gene', (31, 36))	('mutations', 'Var', (14, 23))	('N-RAS', 'Gene', (41, 46))
44898	22759494	Recent reviews show links between the DNA repair pathways and cancer, particularly the association between nucleotide excision repair and melanoma development (154, 155, 156).	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('links', 'Interaction', (20, 25))	('DNA repair', 'biological_process', 'GO:0006281', ('38', '48'))	('nucleotide excision repair', 'Var', (107, 133))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('107', '133'))	('men', 'Species', '9606', (154, 157))	('cancer', 'Disease', (62, 68))	('association', 'Interaction', (87, 98))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('DNA repair pathways', 'Pathway', (38, 57))
44899	22759494	Nucleotide excision repair gene xeroderma pigmentosum variant (XPV), the c.1783G, p.595V alleles were associated with melanoma (OR 1.86 CI 1.27-2.71, and OR 1.84 1.29-2.63 respectively).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('associated', 'Reg', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('p.595V', 'Var', (82, 88))	('xeroderma pigmentosum', 'Disease', (32, 53))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (32, 53))	('Nucleotide excision repair', 'biological_process', 'GO:0006289', ('0', '26'))	('c.1783G', 'Var', (73, 80))
44900	22759494	XPD/ERCC2 SNP rs1318, variant C allele was associated with slightly increased melanoma risk (OR = 1.12, 95% CI 1.03-1.21, population attributable risk = 9.6%).	('ERCC2', 'Gene', (4, 9))	('rs1318', 'Var', (14, 20))	('XPD', 'Disease', 'MESH:C562591', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('ERCC2', 'Gene', '2068', (4, 9))	('rs1318', 'Mutation', 'rs1318', (14, 20))	('XPD', 'Disease', (0, 3))
44901	22759494	Some of the genetic variants in the DNA repair gene XRCC1 have also been associated with melanoma.	('variants', 'Var', (20, 28))	('XRCC1', 'Gene', '7515', (52, 57))	('associated', 'Reg', (73, 83))	('XRCC1', 'Gene', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
44902	22759494	Patients with variant genotype had better overall survival.	('overall', 'MPA', (42, 49))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (35, 41))	('variant', 'Var', (14, 21))
44903	22759494	MC1R variants were associated with susceptibility to basal cell carcinoma of skin and there is an interaction with host factors and the XRCC3 gene.	('associated', 'Reg', (19, 29))	('MC1R', 'Gene', '4157', (0, 4))	('interaction with host', 'biological_process', 'GO:0051701', ('98', '119'))	('MC1R', 'Gene', (0, 4))	('XRCC3', 'Gene', (136, 141))	('basal cell carcinoma of skin', 'Disease', (53, 81))	('XRCC3', 'Gene', '7517', (136, 141))	('basal cell carcinoma of skin', 'Disease', 'MESH:D002280', (53, 81))	('carcinoma of skin', 'Phenotype', 'HP:0008069', (64, 81))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (53, 73))	('variants', 'Var', (5, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
44904	22759494	ASIP and TYR pigmentation variants are also associated with cutaneous melanoma and basal cell carcinoma.	('associated', 'Reg', (44, 54))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (83, 103))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (83, 103))	('basal cell carcinoma', 'Disease', (83, 103))	('TYR', 'Chemical', 'MESH:D014443', (9, 12))	('ASIP', 'Gene', '434', (0, 4))	('cutaneous melanoma', 'Disease', (60, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('pigmentation', 'biological_process', 'GO:0043473', ('13', '25'))	('ASIP', 'Gene', (0, 4))	('variants', 'Var', (26, 34))
44905	22759494	These results suggest that both nucleotide as well as base excision repair deficiency may contribute to the development of cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('base excision repair', 'MPA', (54, 74))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 141))	('base excision repair', 'biological_process', 'GO:0006284', ('54', '74'))	('men', 'Species', '9606', (115, 118))	('nucleotide', 'Var', (32, 42))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('cutaneous melanoma', 'Disease', (123, 141))	('contribute', 'Reg', (90, 100))	('deficiency', 'Disease', (75, 85))	('deficiency', 'Disease', 'MESH:D007153', (75, 85))
44938	26618123	Tumors were divided into five groups according to their Breslow thickness: in situ, <=1 mm, 1.01-2.00 mm, 2.01-4.00 mm, and >=4.01 mm.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('2.01-4.00 mm', 'Var', (106, 118))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('>=4.01 mm', 'Var', (124, 133))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('1.01-2.00 mm', 'Var', (92, 104))
45024	28092363	In vitro studies show that UVB causes the formation of 6-4 photoproducts and signature CC>TT mutations at dipyrimidine sites through the formation of cyclobutane pyrimidine dimers (CPDs), although other patterns, including C>T transitions at dipyrimidine sites, are also seen in vitro (Figure 1b).	('mutations', 'Var', (93, 102))	('dipyrimidine', 'Chemical', '-', (106, 118))	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('dipyrimidine', 'Chemical', '-', (242, 254))	('CPDs', 'Chemical', 'MESH:D011740', (181, 185))	('CC>TT', 'Gene', (87, 92))	('cyclobutane pyrimidine', 'Chemical', '-', (150, 172))	('cyclobutane pyrimidine dimers', 'MPA', (150, 179))	('formation', 'biological_process', 'GO:0009058', ('42', '51'))
45026	28092363	Human cutaneous melanomas are highly mutated with a predominance of C>T transitions at dipyrimidine sites but fewer CC>TT transitions, which is consistent with UVR mutagenesis.	('CC>', 'MPA', (116, 119))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (6, 25))	('Human', 'Species', '9606', (0, 5))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (6, 24))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (6, 25))	('cutaneous melanomas', 'Disease', (6, 25))	('dipyrimidine', 'Chemical', '-', (87, 99))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('mutagenesis', 'biological_process', 'GO:0006280', ('164', '175'))	('C>T transitions', 'Var', (68, 83))
45028	28092363	Interestingly, the driver mutations in the RAS/RAF pathway, including BRAF V600E, present in 60-90% of nevi and approximately 50% of melanomas, are not UVR-type mutations.	('RAF', 'Gene', '387609', (47, 50))	('melanomas', 'Disease', (133, 142))	('nevi', 'Phenotype', 'HP:0003764', (103, 107))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('nevi', 'Disease', (103, 107))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('RAF', 'Gene', (71, 74))	('V600E', 'Var', (75, 80))	('RAF', 'Gene', '387609', (71, 74))	('RAF', 'Gene', (47, 50))
45029	28092363	Regardless, BRAF mutations are most common in sun-exposed nevi and melanoma, suggesting a link to UVR.	('nevi', 'Phenotype', 'HP:0003764', (58, 62))	('BRAF', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('sun-exposed nevi', 'Disease', (46, 62))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutations', 'Var', (17, 26))
45041	28092363	Interestingly, some of the melanomas and nevi in these mice had NRAS mutations near the sixty-first codon, which is a hotspot for human congenital nevi and melanomas.	('mutations', 'Var', (69, 78))	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('melanomas', 'Disease', 'MESH:D008545', (156, 165))	('NRAS', 'Gene', (64, 68))	('mice', 'Species', '10090', (55, 59))	('melanomas', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('nevi', 'Phenotype', 'HP:0003764', (147, 151))	('melanomas', 'Disease', (156, 165))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))	('human', 'Species', '9606', (130, 135))
45042	28092363	In the past decade, technological advances have generated GEM models that harbor oncogenic mutations associated with human melanoma to prospectively investigate clinically relevant questions about the role of UVR in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (216, 234))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (216, 234))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (216, 234))	('human', 'Species', '9606', (117, 122))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mutations', 'Var', (91, 100))	('melanoma', 'Disease', (123, 131))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))
45073	28092363	Mice broadly expressing an HGF transgene gain constitutive activation of pathways downstream of MET, resulting in increased skin pigmentation owing to survival of melanocytes at the epidermal-dermal junction, which persists into adulthood.	('gain', 'PosReg', (41, 45))	('increased', 'PosReg', (114, 123))	('skin pigmentation', 'Disease', (124, 141))	('HGF', 'Gene', (27, 30))	('skin pigmentation', 'Disease', 'MESH:D010859', (124, 141))	('pigmentation', 'biological_process', 'GO:0043473', ('129', '141'))	('pathways', 'Pathway', (73, 81))	('transgene', 'Var', (31, 40))	('Mice', 'Species', '10090', (0, 4))	('activation', 'PosReg', (59, 69))	('increased skin pigmentation', 'Phenotype', 'HP:0000953', (114, 141))
45080	28092363	Melanocytic nevi and melanomas arising in the HGF-tg model are histologically heterogeneous and recapitulate the variety seen in human cutaneous melanocytic lesions.	('cutaneous melanocytic lesions', 'Disease', 'MESH:D009508', (135, 164))	('Melanocytic nevi', 'Phenotype', 'HP:0000995', (0, 16))	('nevi', 'Phenotype', 'HP:0003764', (12, 16))	('melanomas', 'Disease', (21, 30))	('Melanocytic nevi', 'Disease', (0, 16))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('human', 'Species', '9606', (129, 134))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('cutaneous melanocytic lesions', 'Disease', (135, 164))	('HGF-tg', 'Var', (46, 52))
45081	28092363	Disruptions of the CDKN2A locus or activation of CDK4 accelerate melanoma development following neonatal UVR in the HGF model.	('accelerate', 'PosReg', (54, 64))	('Disruptions', 'Var', (0, 11))	('CDKN2A', 'Gene', '12578', (19, 25))	('CDKN2A', 'Gene', (19, 25))	('CDK', 'molecular_function', 'GO:0004693', ('49', '52'))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('CDK4', 'Gene', (49, 53))	('melanoma', 'Disease', (65, 73))	('CDK4', 'Gene', '12567', (49, 53))	('activation', 'PosReg', (35, 45))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
45087	28092363	In contrast to the use of neonatal UVR in the HGF-tg mouse models, studies examining the role of UVR in melanocytic nevi and melanomas with a dominant oncogenic driver mutation have primarily focused on adult UVR exposure.	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (104, 120))	('melanomas', 'Disease', (125, 134))	('mutation', 'Var', (168, 176))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('mouse', 'Species', '10090', (53, 58))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))
45088	28092363	Mice with mutations in the RAS/RAF pathways (HRAS, NRAS, or BRAF) show melanocytic hyperplasia and increased numbers of extrafollicular melanocytes within the dermis compared with wild-type mice.	('RAF', 'Gene', '387609', (61, 64))	('melanocytic hyperplasia', 'Disease', 'MESH:D006965', (71, 94))	('RAF', 'Gene', (31, 34))	('melanocytic hyperplasia', 'Disease', (71, 94))	('RAF', 'Gene', '387609', (31, 34))	('increased', 'PosReg', (99, 108))	('Mice', 'Species', '10090', (0, 4))	('mice', 'Species', '10090', (190, 194))	('mutations', 'Var', (10, 19))	('RAF', 'Gene', (61, 64))
45089	28092363	These models are consistent with the theory that RAS/RAF mutations are founding mutations in melanocytic nevi and melanomas.	('melanocytic nevi', 'Disease', (93, 109))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (93, 109))	('nevi', 'Phenotype', 'HP:0003764', (105, 109))	('mutations', 'Var', (57, 66))	('RAF', 'Gene', (53, 56))	('melanomas', 'Disease', (114, 123))	('RAF', 'Gene', '387609', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
45096	28092363	RAS mutations (primarily NRAS but occasionally HRAS) are common in human congenital nevi and cutaneous melanoma, and Chin et al observed that mice expressing a mutant HRAS transgene by virtue of the mouse tyrosinase promoter (TPras) and loss of p16 Ink4a developed melanoma without additional carcinogens.	('mouse', 'Species', '10090', (199, 204))	('Ink4a', 'Gene', '12578', (249, 254))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('melanoma', 'Disease', (103, 111))	('Ink4a', 'Gene', (249, 254))	('cutaneous melanoma', 'Disease', (93, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('p16', 'Gene', '12578', (245, 248))	('mutant', 'Var', (160, 166))	('nevi', 'Phenotype', 'HP:0003764', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('HRAS', 'Gene', (167, 171))	('p16', 'Gene', (245, 248))	('tyrosinase', 'Gene', (205, 215))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('tyrosinase', 'Gene', '22173', (205, 215))	('developed', 'Reg', (255, 264))	('mice', 'Species', '10090', (142, 146))	('human', 'Species', '9606', (67, 72))
45102	28092363	Other studies using TPras mice have investigated the role of neonatal UVR and cell cycle checkpoints on the development of RAS mutant melanomas.	('mutant', 'Var', (127, 133))	('melanomas', 'Disease', (134, 143))	('cell cycle', 'biological_process', 'GO:0007049', ('78', '88'))	('RAS', 'Gene', (123, 126))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('mice', 'Species', '10090', (26, 30))
45105	28092363	Hacker et al reported that neonatal UVR exposure also increased the frequency and accelerated the development of melanomas in TPras mice carrying a Cdk4R24C mutation.	('melanomas', 'Disease', (113, 122))	('Cdk', 'molecular_function', 'GO:0004693', ('148', '151'))	('accelerated', 'PosReg', (82, 93))	('increased', 'PosReg', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('mice', 'Species', '10090', (132, 136))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('Cdk4R24C mutation', 'Var', (148, 165))
45106	28092363	These studies indicate that functional disruption of the p16 Ink4a/CDK4/CDK6/RB pathway can facilitate mutant RAS-driven melanomagenesis in UVR-associated and non UVR-associated pathways.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('disruption', 'Var', (39, 49))	('melanoma', 'Disease', (121, 129))	('Ink4a', 'Gene', '12578', (61, 66))	('CDK6', 'Gene', '12571', (72, 76))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('p16', 'Gene', (57, 60))	('CDK4', 'Gene', (67, 71))	('Ink4a', 'Gene', (61, 66))	('CDK4', 'Gene', '12567', (67, 71))	('CDK', 'molecular_function', 'GO:0004693', ('67', '70'))	('mutant RAS-driven', 'Var', (103, 120))	('facilitate', 'PosReg', (92, 102))	('CDK6', 'Gene', (72, 76))	('p16', 'Gene', '12578', (57, 60))
45107	28092363	BRAFV600E mutations are the most common driver mutations in human cutaneous melanoma.	('BRAFV600E mutations', 'Var', (0, 19))	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('human', 'Species', '9606', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
45109	28092363	To test this hypothesis, Viros et al induced BRAFV600E mutations using tyrosinase-driven Cre-Lox recombination in 2-month-old mice followed by weekly broad-spectrum UVR starting at 3 months.	('Lox', 'Gene', (93, 96))	('mice', 'Species', '10090', (126, 130))	('BRAFV600E', 'Mutation', 'rs113488022', (45, 54))	('tyrosinase', 'Gene', (71, 81))	('mutations', 'Var', (55, 64))	('Lox', 'Gene', '16948', (93, 96))	('tyrosinase', 'Gene', '22173', (71, 81))	('BRAFV600E', 'Gene', (45, 54))
45112	28092363	Exclusively in the UVR-exposed tumors, Trp53 mutations were additionally identified.	('Trp53', 'Gene', '22059', (39, 44))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('Trp53', 'Gene', (39, 44))
45113	28092363	Trp53 is known to be a mutational target of UVR, and the p19Arf/p53 pathway facilitates BRAFV600E mutant mouse melanoma.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('p19', 'cellular_component', 'GO:0070743', ('57', '60'))	('p53', 'Gene', (2, 5))	('facilitates', 'PosReg', (76, 87))	('p19Arf', 'Gene', '12578', (57, 63))	('p19Arf', 'Gene', (57, 63))	('Trp53', 'Gene', '22059', (0, 5))	('BRAFV600E mutant', 'Var', (88, 104))	('p53', 'Gene', '22059', (2, 5))	('BRAFV600E', 'Mutation', 'rs113488022', (88, 97))	('p53', 'Gene', '22059', (64, 67))	('p53', 'Gene', (64, 67))	('mouse', 'Species', '10090', (105, 110))	('Trp53', 'Gene', (0, 5))
45125	28092363	The differences in the types of mutations induced within the tumors by the two wavebands may have clinical implications.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
45154	28092363	Although UVR is thought to impact melanocytes predominantly, but not exclusively, through mutagenesis, the indirect consequences of UVR are complex and multifaceted, promoting melanoma formation and progression through a variety of mechanisms.	('mutagenesis', 'biological_process', 'GO:0006280', ('90', '101'))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('formation', 'biological_process', 'GO:0009058', ('185', '194'))	('melanoma', 'Disease', (176, 184))	('promoting', 'PosReg', (166, 175))	('progression', 'CPA', (199, 210))	('UVR', 'Var', (132, 135))	('impact', 'Reg', (27, 33))
45169	24130734	In various murine tumor models including melanoma models, ectopic expression of IL-27 has been shown to play an anti-tumoral role and to favor tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('IL-27', 'Gene', (80, 85))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (18, 23))	('IL-27', 'cellular_component', 'GO:0070744', ('80', '85'))	('tumor', 'Disease', (117, 122))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('IL-27', 'molecular_function', 'GO:0045523', ('80', '85'))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ectopic expression', 'Var', (58, 76))	('murine', 'Species', '10090', (11, 17))	('favor', 'PosReg', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
45203	24130734	EBI3 was detected using 2G4H6 mouse mAb (IgG2a), in parallel with an isotype-matched control mAb (UPC10, IgG2a, ICN Pharmaceuticals).	('EBI3', 'cellular_component', 'GO:0070744', ('0', '4'))	('EBI3', 'Gene', '10148', (0, 4))	('EBI3', 'Gene', (0, 4))	('2G4H6', 'Var', (24, 29))	('IgG2a', 'cellular_component', 'GO:0071735', ('41', '46'))	('EBI3', 'cellular_component', 'GO:0070745', ('0', '4'))	('mouse', 'Species', '10090', (30, 35))	('IgG2a', 'cellular_component', 'GO:0071735', ('105', '110'))
45242	24130734	Positivity for IL-27 in tumor cells was observed in 2/8 cases of stage 1, 7/12 cases of stage 2, 10/12 cases of stage 3, and 9/11 cases of stage 4 (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('IL-27', 'cellular_component', 'GO:0070744', ('15', '20'))	('tumor', 'Disease', (24, 29))	('IL-27', 'Gene', (15, 20))	('observed', 'Reg', (40, 48))	('IL-27', 'molecular_function', 'GO:0045523', ('15', '20'))	('Positivity', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('stage 1', 'Disease', (65, 72))
45259	24130734	To test the hypothesis that IL-27 could promote melanoma progression by inducing IL-10 expression in melanoma cells, we tested the effect of exogenous recombinant IL-27, alone or in combination with TGF-ss1, on IL-10 expression in 4 melanoma cell lines that express the two subunits of the IL-27 receptor, IL-27Ralpha and gp130 (Figure 4A), but do not express IL-27 (not shown).	('IL-10', 'Gene', (81, 86))	('IL-10', 'molecular_function', 'GO:0005141', ('211', '216'))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('IL-27', 'molecular_function', 'GO:0045523', ('306', '311'))	('IL-27', 'cellular_component', 'GO:0070744', ('290', '295'))	('IL-27', 'cellular_component', 'GO:0070744', ('163', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('promote', 'PosReg', (40, 47))	('melanoma', 'Disease', (48, 56))	('IL-27', 'molecular_function', 'GO:0045523', ('360', '365'))	('IL-27Ralpha', 'Var', (306, 317))	('melanoma cells', 'Disease', (101, 115))	('inducing', 'Reg', (72, 80))	('IL-27', 'cellular_component', 'GO:0070744', ('28', '33'))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('gp130', 'molecular_function', 'GO:0004921', ('322', '327'))	('IL-27', 'molecular_function', 'GO:0045523', ('290', '295'))	('gp130', 'molecular_function', 'GO:0004898', ('322', '327'))	('IL-27', 'molecular_function', 'GO:0045523', ('163', '168'))	('expression', 'MPA', (87, 97))	('gp130', 'molecular_function', 'GO:0004897', ('322', '327'))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('IL-10', 'molecular_function', 'GO:0005141', ('81', '86'))	('IL-27', 'molecular_function', 'GO:0045523', ('28', '33'))	('IL-27', 'cellular_component', 'GO:0070744', ('306', '311'))	('gp130', 'Var', (322, 327))	('gp130', 'molecular_function', 'GO:0004915', ('322', '327'))	('melanoma cells', 'Disease', 'MESH:D008545', (101, 115))	('tested', 'Reg', (120, 126))	('IL-27', 'cellular_component', 'GO:0070744', ('360', '365'))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))
45280	24130734	In patients with acute myeloid leukemia, IL-27Ralpha has been linked to transformation through its ability to dimerize and to constitutively activate a mutant form of Jak2.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (23, 39))	('ability', 'MPA', (99, 106))	('IL-27', 'cellular_component', 'GO:0070744', ('41', '46'))	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('Jak2', 'Gene', (167, 171))	('Jak', 'molecular_function', 'GO:0004713', ('167', '170'))	('Jak2', 'Gene', '3717', (167, 171))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (17, 39))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (17, 39))	('IL-27Ralpha', 'Gene', (41, 52))	('mutant', 'Var', (152, 158))	('patients', 'Species', '9606', (3, 11))	('acute myeloid leukemia', 'Disease', (17, 39))	('activate', 'PosReg', (141, 149))	('IL-27', 'molecular_function', 'GO:0045523', ('41', '46'))	('dimerize', 'MPA', (110, 118))	('linked', 'Reg', (62, 68))
45294	24130734	Patients with advanced melanoma treated with anti-PD1 or anti-PD-L1 Abs showed an objective response in 28% and 17% of cases, respectively, the highest percentages among the various tumors tested.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('Patients', 'Species', '9606', (0, 8))	('anti-PD1', 'Var', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('anti-PD-L1', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
45367	16787533	Thus, this attribute was annotated with "depth" (NCI C25333) as the property because it was considered to be the characteristic being defined, and "tumor cell invasion" (NCI C20625) as the property qualifier because it was considered to be a modifier of "depth".	('tumor', 'Disease', (148, 153))	('C20625', 'Var', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))
45431	32873829	Positivity for both VISTA and PD-1 predicted worse survival.	('VISTA', 'Gene', '64115', (20, 25))	('VISTA', 'Gene', (20, 25))	('Positivity', 'Var', (0, 10))	('PD-1', 'Gene', (30, 34))
45457	32873829	Paraffin-embedded sections were immunostained with anti-VISTA (1:200, ProSci Incorporation, CA, USA), anti-CD33 (1:100, Leica Biosystems, Newcastle, UK), or anti-PD-1 (1:100, Ventana, Tucson, AZ, USA) antibodies.	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('VISTA', 'Gene', '64115', (56, 61))	('CD33', 'Gene', '945', (107, 111))	('CD33', 'Gene', (107, 111))	('1:200', 'Var', (63, 68))	('VISTA', 'Gene', (56, 61))
45478	32873829	High CD33 expression was also associated with a higher likelihood of LN involvement (P = 0.001) and an advanced AJCC stage (P = 0.005; Table 1).	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('CD33', 'Gene', '945', (5, 9))	('CD33', 'Gene', (5, 9))	('AJCC', 'Disease', (112, 116))
45480	32873829	There was a significant association between high expression of VISTA and pathological features such as a deeper Breslow thickness (P = 0.002), the presence of ulceration (P = 0.015) and higher frequency of vertical growth phase (P = 0.041).	('high', 'Var', (44, 48))	('VISTA', 'Gene', (63, 68))	('vertical growth phase', 'CPA', (206, 227))	('ulceration', 'Disease', (159, 169))	('VISTA', 'Gene', '64115', (63, 68))
45490	32873829	Median OS was significantly shorter in patients with high expression of CD33 (56.0 months; 95% CI 38.51-73.49 months) compared with those with low expression of CD33 (81.0 months; 95% CI 64.64-97.35 months) (P = 0.004, Fig.	('CD33', 'Gene', (161, 165))	('patients', 'Species', '9606', (39, 47))	('CD33', 'Gene', '945', (72, 76))	('shorter', 'NegReg', (28, 35))	('CD33', 'Gene', (72, 76))	('CD33', 'Gene', '945', (161, 165))	('high expression', 'Var', (53, 68))
45491	32873829	PFS was also significantly better in patients with low expression of CD33 (P < 0.001).	('CD33', 'Gene', '945', (69, 73))	('CD33', 'Gene', (69, 73))	('patients', 'Species', '9606', (37, 45))	('better', 'PosReg', (27, 33))	('low expression', 'Var', (51, 65))	('PFS', 'CPA', (0, 3))
45492	32873829	Patients with high expression of VISTA (58.0 months; 95% CI 30.55-85.47 months) had inferior median OS compared with patients with low expression of VISTA (79.0 months; 95% CI 62.00-95.42 months) (P = 0.017, Fig.	('inferior', 'NegReg', (84, 92))	('VISTA', 'Gene', '64115', (149, 154))	('VISTA', 'Gene', '64115', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('patients', 'Species', '9606', (117, 125))	('VISTA', 'Gene', (149, 154))	('VISTA', 'Gene', (33, 38))
45497	32873829	When survival was evaluated with respect to PD-1 expression, high expression of both VISTA and PD-1 was associated with worse median OS (VISTAhighPD-1high: 44.0 months, 95% CI 30.4-57.59 months; and non-VISTAhighPD-1high: 71.0 months, 95% CI 59.49-82.50 months) (P = 0.033).	('high expression', 'Var', (61, 76))	('VISTA', 'Gene', (85, 90))	('PD-1', 'Gene', (95, 99))	('VISTA', 'Gene', (137, 142))	('VISTA', 'Gene', (203, 208))	('VISTA', 'Gene', '64115', (85, 90))	('VISTA', 'Gene', '64115', (203, 208))	('VISTA', 'Gene', '64115', (137, 142))
45503	32873829	MDSCs can contribute to tumor invasion by inhibiting T-cell proliferation as well as by promoting tumor metastasis and angiogenesis.	('T-cell proliferation', 'CPA', (53, 73))	('tumor metastasis', 'Disease', 'MESH:D009362', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MDSCs', 'Var', (0, 5))	('tumor', 'Disease', (24, 29))	('tumor metastasis', 'Disease', (98, 114))	('inhibiting', 'NegReg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('angiogenesis', 'CPA', (119, 131))	('angiogenesis', 'biological_process', 'GO:0001525', ('119', '131'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promoting', 'PosReg', (88, 97))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('53', '73'))
45507	32873829	Therefore, blocking MDSCs could be a novel anticancer strategy that could enhance the antitumor effects of PD-1/PD-L1 inhibitors.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('MDSCs', 'Gene', (20, 25))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('blocking', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('enhance', 'PosReg', (74, 81))
45513	32873829	Furthermore, high expression of CD33 was associated with poor clinicopathological variables and was an independent prognostic factor in melanoma.	('high', 'Var', (13, 17))	('CD33', 'Gene', '945', (32, 36))	('CD33', 'Gene', (32, 36))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))
45516	32873829	The inhibitory function of VISTA in anticancer immunity was demonstrated in mice transplanted with melanoma, in which blocking of VISTA induced antitumor immunity by increasing tumor-specific CD4+ and CD8+ T cells and decreasing FoxP3+ regulatory T cells in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('FoxP3+ regulatory T cells in the', 'CPA', (229, 261))	('blocking', 'Var', (118, 126))	('CD8', 'Gene', (201, 204))	('VISTA', 'Gene', '64115', (130, 135))	('VISTA', 'Gene', '64115', (27, 32))	('increasing', 'PosReg', (166, 176))	('decreasing', 'NegReg', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('VISTA', 'Gene', (130, 135))	('VISTA', 'Gene', (27, 32))	('cancer', 'Disease', (40, 46))	('mice', 'Species', '10090', (76, 80))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (262, 267))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CD8', 'Gene', '925', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
45523	32873829	VISTA blockade in the B16 melanoma model reduced the number of tumor-infiltrating monocytic MDSCs and increased the density of tumor-infiltrating effector T cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (63, 68))	('reduced', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (127, 132))	('VISTA', 'Gene', '64115', (0, 5))	('VISTA', 'Gene', (0, 5))	('density', 'MPA', (116, 123))	('blockade', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('increased', 'PosReg', (102, 111))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
45526	32873829	Furthermore, patients with high expression of both CD33 and VISTA had the worst survival in our cohort.	('CD33', 'Gene', (51, 55))	('VISTA', 'Gene', (60, 65))	('patients', 'Species', '9606', (13, 21))	('survival', 'MPA', (80, 88))	('worst', 'NegReg', (74, 79))	('high expression', 'Var', (27, 42))	('VISTA', 'Gene', '64115', (60, 65))	('CD33', 'Gene', '945', (51, 55))
45529	32873829	The frequency of high expression was higher in PD-1 than VISTA in presenting study.	('high expression', 'MPA', (17, 32))	('PD-1', 'Var', (47, 51))	('VISTA', 'Gene', '64115', (57, 62))	('VISTA', 'Gene', (57, 62))
45531	32873829	Among patients with high expression of PD-1, patients with high expression of VISTA (VISTAhighPD-1high) had a worse prognosis than patients with low expression of VISTA (VISTAlowPD-1high).	('VISTA', 'Gene', (170, 175))	('PD-1', 'Gene', (39, 43))	('patients', 'Species', '9606', (131, 139))	('VISTA', 'Gene', (85, 90))	('VISTA', 'Gene', '64115', (170, 175))	('VISTA', 'Gene', '64115', (163, 168))	('high expression', 'Var', (20, 35))	('VISTA', 'Gene', '64115', (78, 83))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (6, 14))	('VISTAlowPD', 'Disease', (170, 180))	('VISTA', 'Gene', (163, 168))	('VISTA', 'Gene', '64115', (85, 90))	('VISTAlowPD', 'Disease', 'None', (170, 180))	('VISTA', 'Gene', (78, 83))
45533	32873829	This finding also suggests that combination therapy with anti-VISTA and anti-PD-1 antibodies may be an effective approach for immunotherapy of cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('VISTA', 'Gene', '64115', (62, 67))	('combination', 'Interaction', (32, 43))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('anti-PD-1', 'Var', (72, 81))	('VISTA', 'Gene', (62, 67))	('cutaneous melanoma', 'Disease', (143, 161))
45534	32873829	The combination of VISTA and PD-1 inhibitors synergistically enhanced antitumor immune responses in mouse models.	('enhanced', 'PosReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mouse', 'Species', '10090', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibitors', 'Var', (34, 44))	('VISTA', 'Gene', '64115', (19, 24))	('tumor', 'Disease', (74, 79))	('VISTA', 'Gene', (19, 24))	('PD-1', 'Gene', (29, 33))
45542	32561704	Defects in TBX21 gene can cause Th1/Th2 imbalance, which is closely related to tumorigenesis.	('cause', 'Reg', (26, 31))	('tumor', 'Disease', (79, 84))	('Defects', 'Var', (0, 7))	('TBX21', 'Gene', (11, 16))	('Th1/Th2 imbalance', 'MPA', (32, 49))	('imbalance', 'Phenotype', 'HP:0002172', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
45554	32561704	Among the Asian Eastern populations, the incidence of SKCM occurs mostly at the extremities, and the V-raf murine sarcoma viral oncogene homolog (BRAF) gene mutation rate is about 24.3%.	('BRAF', 'Gene', (146, 150))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('sarcoma', 'Disease', (114, 121))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('mutation', 'Var', (157, 165))	('SKCM', 'Disease', (54, 58))	('SKCM', 'Chemical', '-', (54, 58))	('BRAF', 'Gene', '109880', (146, 150))	('murine', 'Species', '10090', (107, 113))
45555	32561704	While in the Caucasian Western populations, it is more common in the head and face, and the BRAF gene mutation rate about 50%.	('mutation', 'Var', (102, 110))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '109880', (92, 96))
45556	32561704	Some genes and their effects have been shown to be related to SKCM and its metastasis, such as the chemokine C-X-C receptor 4 (CXCR4) gene silencing of melanoma invasion and metastasis, the promotion of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways on the progression of SKCM, and the prediction of distant metastasis by serum lactate dehydrogenase (LDH).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma invasion', 'Disease', 'MESH:D008545', (152, 169))	('gene silencing', 'biological_process', 'GO:0016458', ('134', '148'))	('CXCR4', 'Gene', '7852', (127, 132))	('SKCM', 'Disease', (311, 315))	('CXCR4', 'Gene', (127, 132))	('metastasis', 'CPA', (174, 184))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('SKCM', 'Chemical', '-', (62, 66))	('PI3K', 'molecular_function', 'GO:0016303', ('274', '278'))	('silencing', 'NegReg', (139, 148))	('promotion', 'PosReg', (190, 199))	('CXCR4', 'molecular_function', 'GO:0038147', ('127', '132'))	('SKCM', 'Disease', (62, 66))	('distant metastasis', 'CPA', (339, 357))	('MAPK', 'molecular_function', 'GO:0004707', ('237', '241'))	('gene', 'Var', (134, 138))	('melanoma invasion', 'Disease', (152, 169))	('SKCM', 'Chemical', '-', (311, 315))
45566	32561704	Using GSEA, we first generated an orderly gene list according to the correlation between all genes and TBX21 expression, and then identified the significant survival difference between high TBX21 group and low TBX21 group through GSEA.	('TBX21', 'Gene', (103, 108))	('high', 'Var', (185, 189))	('TBX21', 'Gene', (190, 195))	('GSEA', 'Chemical', '-', (230, 234))	('GSEA', 'Chemical', '-', (6, 10))
45595	32561704	reported that TBX21-deficient mice were more sensitive to tumor development due to dysfunction of immune cells such as Th1 dysfunction; restoration of TBX21 suppressed tumor growth in mice.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Disease', (168, 173))	('suppressed', 'NegReg', (157, 167))	('TBX21', 'Gene', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('restoration', 'Var', (136, 147))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
45602	32561704	T-bet can control the type of immunoglobulin (Ig) expressed by B cells, and the expression of T-bet can promote the production of IgG2a, IgG2b, and IgG3 and inhibit the production of IgG1 and IgE.	('IgG2a', 'cellular_component', 'GO:0071735', ('130', '135'))	('IgG3', 'Gene', '3502', (148, 152))	('T-bet', 'Gene', '30009', (94, 99))	('promote', 'PosReg', (104, 111))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('30', '44'))	('IgG2a', 'Protein', (130, 135))	('IgG3', 'Gene', (148, 152))	('inhibit', 'NegReg', (157, 164))	('T-bet', 'Gene', (0, 5))	('IgG3', 'cellular_component', 'GO:0071735', ('148', '152'))	('IgG2b', 'cellular_component', 'GO:0071735', ('137', '142'))	('IgG1', 'cellular_component', 'GO:0071735', ('183', '187'))	('production', 'MPA', (116, 126))	('IgG2b', 'Protein', (137, 142))	('IgE', 'MPA', (192, 195))	('expression', 'Var', (80, 90))	('T-bet', 'Gene', (94, 99))	('T-bet', 'Gene', '30009', (0, 5))	('production', 'MPA', (169, 179))
45630	31065009	Direct photon irradiation of a tumor from radioisotopes such as 125I or 106Ru is the main form of treatment in the management of uveal melanoma known as brachytherapy.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('tumor', 'Disease', (31, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (129, 143))	('106Ru', 'Var', (72, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('uveal melanoma', 'Disease', (129, 143))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
45639	31065009	A similar effect was also observed in the case of endothelial cells irradiated with X-rays, in which these modifications lead to lower motile activity of the cells.	('modifications', 'Var', (107, 120))	('motile activity of the cells', 'CPA', (135, 163))	('lower', 'NegReg', (129, 134))	('rays', 'Species', '255564', (86, 90))
45650	31065009	Untreated Mel270 and BLM cells exhibited a normal distribution of the Young's modulus values, although the mean value of Mel270 cells was almost two times higher than that of BLM cells (1.5 vs 0.8 kPa, respectively, Fig.	('BLM', 'Gene', '641', (175, 178))	('BLM', 'Gene', '641', (21, 24))	('Mel270', 'Var', (121, 127))	('BLM', 'Gene', (175, 178))	('higher', 'PosReg', (155, 161))	('BLM', 'Gene', (21, 24))
45652	31065009	For the highest dose of the low-LET proton beam, Mel270 were approximately 1.5-times more elastic and BLM 5 times more elastic than control (at 20 days post-radiation).	('more', 'PosReg', (85, 89))	('BLM', 'Gene', '641', (102, 105))	('elastic', 'MPA', (90, 97))	('elastic', 'MPA', (119, 126))	('BLM', 'Gene', (102, 105))	('Mel270', 'Var', (49, 55))
45675	31065009	Mechanical softening of cancer cells and modification of their adhesion to extracellular matrix increased their capacity to escape the primary tumor.	('increased', 'PosReg', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('adhesion', 'CPA', (63, 71))	('tumor', 'Disease', (143, 148))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('modification', 'Var', (41, 53))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('75', '95'))	('capacity', 'MPA', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
45681	31065009	In general, the changes in cellular elasticity in Mel270 choroidal melanoma were much less pronounced.	('Mel270', 'Var', (50, 56))	('choroidal melanoma', 'Disease', (57, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('cellular elasticity', 'MPA', (27, 46))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (57, 75))	('choroidal melanoma', 'Disease', 'MESH:D008545', (57, 75))
45699	31065009	GNAQ mutation induces viability and migration of uveal melanoma cells via Notch signaling activation, which is mediated by YAP dephosphorylation and nuclear translocation.	('uveal melanoma', 'Disease', 'MESH:C536494', (49, 63))	('activation', 'PosReg', (90, 100))	('dephosphorylation', 'biological_process', 'GO:0016311', ('127', '144'))	('GNAQ', 'Gene', '2776', (0, 4))	('uveal melanoma', 'Disease', (49, 63))	('induces', 'PosReg', (14, 21))	('Notch', 'Pathway', (74, 79))	('YAP', 'Gene', '10413', (123, 126))	('migration', 'CPA', (36, 45))	('GNAQ', 'Gene', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('viability', 'CPA', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('mutation', 'Var', (5, 13))	('YAP', 'Gene', (123, 126))	('uveal melanoma', 'Phenotype', 'HP:0007716', (49, 63))
45717	31065009	The primary antibodies used for staining were Vimentin (D21H3) Rabbit mAbs (Cell Signaling Technology, USA) in 0.1% BSA at a concentration 1:300.	('D21H3', 'Var', (56, 61))	('Rabbit', 'Species', '9986', (63, 69))	('Vimentin', 'cellular_component', 'GO:0045098', ('46', '54'))	('Vimentin', 'Protein', (46, 54))	('Vimentin', 'cellular_component', 'GO:0045099', ('46', '54'))	('Signaling', 'biological_process', 'GO:0023052', ('81', '90'))
45720	31065009	The membranes were blocked with 5% skim milk or in 5% BSA in a TBS buffer with 1% of Tween 20 for 1 h and incubated with primary antibodies against ICAM-1 and Tenascin C (D16C4) (Cell Signaling Technology, MA, USA), LAMB3 (CL3363) (Thermo Fisher Scientific) at 4  C overnight.	('TBS', 'Chemical', 'MESH:D013725', (63, 66))	('LAMB3', 'Gene', (216, 221))	('Tween 20', 'Chemical', 'MESH:D011136', (85, 93))	('LAMB3', 'Gene', '3914', (216, 221))	('Signaling', 'biological_process', 'GO:0023052', ('184', '193'))	('D16C4', 'Var', (171, 176))	('Tenascin C', 'cellular_component', 'GO:0090733', ('159', '169'))
45751	30726463	Patients with moderate/marked TIL in the primary melanoma lesion had a five-fold lower risk for the presence of one positive lymph node when compared to individuals with absent or few TIL in the lesion.	('moderate/marked', 'Var', (14, 29))	('lower', 'NegReg', (81, 86))	('melanoma lesion', 'Disease', (49, 64))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma lesion', 'Disease', 'MESH:D008545', (49, 64))
45782	33621202	The anti-melanoma effects of exogenous IL-33 could also be mediated by eosinophils and dendritic cells (DCs).	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('exogenous', 'Var', (29, 38))	('IL-33', 'molecular_function', 'GO:0002112', ('39', '44'))	('IL-33', 'Gene', (39, 44))
45793	33621202	In the LN metastasis sub-cohort, samples with lower mutation count or from younger patients have higher expression level of IL-33 (Figure 1B).	('IL-33', 'Protein', (124, 129))	('higher', 'PosReg', (97, 103))	('lower', 'NegReg', (46, 51))	('mutation', 'Var', (52, 60))	('patients', 'Species', '9606', (83, 91))	('IL-33', 'molecular_function', 'GO:0002112', ('124', '129'))	('expression level', 'MPA', (104, 120))
45796	33621202	Only three types of immune cells accumulate differently between the high and low IL-33 groups in the primary melanoma sub-cohort, with type 1 T helper (Th1) cells and natural killer T (NKT) cells more abundant in samples from the low IL-33 group, and conventional DCs more abundant in samples from the high IL-33 group.	('IL-33', 'molecular_function', 'GO:0002112', ('81', '86'))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('IL-33', 'molecular_function', 'GO:0002112', ('234', '239'))	('melanoma', 'Disease', (109, 117))	('low', 'Var', (230, 233))	('IL-33', 'molecular_function', 'GO:0002112', ('307', '312'))
45797	33621202	In the LN metastasis sub-cohort, 24 types of immune cells, including B cells, CD4+ T cells, CD8+ T cells, Th2 cells, NK cells, M1 macrophages, DCs et al., are more abundant in samples from the high IL-33 group; while three types of immune cells, including Th1 cells, NKT cells and basophils, are more abundant in samples from the low IL-33 group.	('high IL-33', 'Var', (193, 203))	('CD8', 'Gene', (92, 95))	('CD4', 'Gene', '920', (78, 81))	('Th2', 'Chemical', '-', (106, 109))	('IL-33', 'molecular_function', 'GO:0002112', ('334', '339'))	('CD8', 'Gene', '925', (92, 95))	('CD4', 'Gene', (78, 81))	('IL-33', 'molecular_function', 'GO:0002112', ('198', '203'))
45798	33621202	In the other metastasis sub-cohort, 16 types of immune cells including B cells, CD4+ T cells, CD8+ T cells, NK cells, M1 macrophages, DCs et al., are more abundant in samples from the high IL-33 group; while Th1 cells and NKT cells are more abundant in samples from the low IL-33 group.	('IL-33', 'molecular_function', 'GO:0002112', ('274', '279'))	('IL-33', 'molecular_function', 'GO:0002112', ('189', '194'))	('CD4', 'Gene', (80, 83))	('CD8', 'Gene', (94, 97))	('CD8', 'Gene', '925', (94, 97))	('high IL-33', 'Var', (184, 194))	('CD4', 'Gene', '920', (80, 83))
45800	33621202	Excluding IL-33, we found that 1158, 1366, and 1012 genes are expressed at higher levels in the high IL-33 group than in the low IL-33 group in the primary melanoma, LN metastasis, and other metastasis sub-cohorts, respectively (Figure 4A).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('higher', 'PosReg', (75, 81))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('IL-33', 'molecular_function', 'GO:0002112', ('129', '134'))	('high IL-33', 'Var', (96, 106))	('IL-33', 'molecular_function', 'GO:0002112', ('10', '15'))	('IL-33', 'molecular_function', 'GO:0002112', ('101', '106'))
45801	33621202	Consistent with analyses of immune cells abundance, pathways enriched in the high IL-33 group of the LN and other metastasis sub-cohorts are mostly related to the process of immune response and inflammation.	('immune response', 'biological_process', 'GO:0006955', ('174', '189'))	('inflammation', 'biological_process', 'GO:0006954', ('194', '206'))	('high', 'Var', (77, 81))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('inflammation', 'Disease', (194, 206))	('IL-33', 'molecular_function', 'GO:0002112', ('82', '87'))
45802	33621202	However, pathways enriched in the high IL-33 group of the primary melanoma sub-cohort are less associated with the immune response.	('less', 'NegReg', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Disease', (66, 74))	('immune response', 'biological_process', 'GO:0006955', ('115', '130'))	('high', 'Var', (34, 38))	('IL-33', 'molecular_function', 'GO:0002112', ('39', '44'))
45808	33621202	The differences of pathways enriched in the high IL-33 group between the primary melanoma and the metastasis sub-cohorts also reveal the context-specificity of IL-33's effects.	('high', 'Var', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('differences', 'Reg', (4, 15))	('IL-33', 'molecular_function', 'GO:0002112', ('160', '165'))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('IL-33', 'molecular_function', 'GO:0002112', ('49', '54'))
45810	33621202	In the metastasis sub-cohorts, the high expression of IL-33 is associated with more infiltrations of CD8+ T cells, NK cells and DCs in tumor samples, and these immune components have been proven to be important mediators of the anti-tumor effects of IL-33 in mouse melanoma models.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CD8', 'Gene', '925', (101, 104))	('IL-33', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (135, 140))	('IL-33', 'molecular_function', 'GO:0002112', ('54', '59'))	('IL-33', 'molecular_function', 'GO:0002112', ('250', '255'))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('mouse', 'Species', '10090', (259, 264))	('more', 'PosReg', (79, 83))	('infiltrations', 'CPA', (84, 97))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('high', 'Var', (35, 39))	('CD8', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
45813	33621202	B cells, CD4+ T cells and M1 macrophages also accumulate more in the high IL-33 tumors than in the low IL-33 tumors, which may partially explain the better prognosis of the high IL-33 groups.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('IL-33', 'molecular_function', 'GO:0002112', ('178', '183'))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('IL-33', 'molecular_function', 'GO:0002112', ('74', '79'))	('CD4', 'Gene', (9, 12))	('accumulate', 'PosReg', (46, 56))	('tumors', 'Disease', (80, 86))	('high', 'Var', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('CD4', 'Gene', '920', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('IL-33', 'molecular_function', 'GO:0002112', ('103', '108'))	('tumors', 'Disease', (109, 115))
45814	33621202	Notably, Th1 cells are more abundant in the low IL-33 samples rather than in the high IL-33 samples, which may be due to the enhanced Th2 polarization in the high IL-33 environment.	('low IL-33', 'Var', (44, 53))	('Th2 polarization', 'CPA', (134, 150))	('Th2', 'Chemical', '-', (134, 137))	('Th1 cells', 'CPA', (9, 18))	('IL-33', 'molecular_function', 'GO:0002112', ('86', '91'))	('enhanced', 'PosReg', (125, 133))	('IL-33', 'molecular_function', 'GO:0002112', ('48', '53'))	('IL-33', 'molecular_function', 'GO:0002112', ('163', '168'))
45815	33621202	However, considering that Th1 cells and NKT cells are downregulated in the high IL-33 tumor samples in both the primary and metastatic settings, IL-33 itself may not account for the downregulation of Th1 cells and NKT cells.	('IL-33', 'molecular_function', 'GO:0002112', ('80', '85'))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('high', 'Var', (75, 79))	('IL-33', 'molecular_function', 'GO:0002112', ('145', '150'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('IL-33', 'Gene', (80, 85))	('downregulated', 'NegReg', (54, 67))
45816	33621202	Ectopic expression of IL-33 in melanoma cells can induce effective anti-tumor immune responses.	('IL-33', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('Ectopic expression', 'Var', (0, 18))	('IL-33', 'molecular_function', 'GO:0002112', ('22', '27'))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('induce', 'PosReg', (50, 56))
45842	29977240	PD-1 inhibition in melanoma promotes tumor regression and prolonged overall survival in 30-40% of patients with advanced disease.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('inhibition', 'Var', (5, 15))	('PD-1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('prolonged', 'PosReg', (58, 67))	('melanoma', 'Disease', (19, 27))	('PD-1', 'Gene', '5133', (0, 4))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('promotes', 'PosReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('overall survival', 'CPA', (68, 84))
45851	29977240	Genetic alterations affecting IFNGR1, IFNGR2, IRF1, and JAK2, and amplifications of the IFNgamma inhibitor genes, SOCS1 and PIAS4, are also enriched in patients not responding to checkpoint inhibition.	('Genetic alterations', 'Var', (0, 19))	('JAK2', 'Gene', (56, 60))	('SOCS1', 'Gene', '8651', (114, 119))	('IRF1', 'Gene', '3659', (46, 50))	('IFNgamma', 'Gene', (88, 96))	('IFNGR2', 'Gene', '3460', (38, 44))	('IFNgamma', 'Gene', '3458', (88, 96))	('IFNGR1', 'Gene', (30, 36))	('SOCS1', 'Gene', (114, 119))	('PIAS4', 'Gene', '51588', (124, 129))	('JAK', 'molecular_function', 'GO:0004713', ('56', '59'))	('IFNGR2', 'Gene', (38, 44))	('JAK2', 'Gene', '3717', (56, 60))	('PIAS4', 'Gene', (124, 129))	('patients', 'Species', '9606', (152, 160))	('IRF1', 'Gene', (46, 50))
45852	29977240	Furthermore, loss-of-function mutations in the upstream IFNgamma-signaling regulators JAK1 and JAK2, concurrent with deletion of the wild type alleles, have been identified in two melanoma patients who failed anti-PD-1 therapy.	('IFNgamma', 'Gene', (56, 64))	('JAK1', 'Gene', (86, 90))	('PD-1', 'Gene', (214, 218))	('melanoma', 'Disease', (180, 188))	('loss-of-function', 'NegReg', (13, 29))	('PD-1', 'Gene', '5133', (214, 218))	('JAK2', 'Gene', '3717', (95, 99))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('IFNgamma', 'Gene', '3458', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('JAK', 'molecular_function', 'GO:0004713', ('86', '89'))	('JAK2', 'Gene', (95, 99))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (189, 197))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('signaling', 'biological_process', 'GO:0023052', ('65', '74'))
45853	29977240	The loss of IFNgamma signaling limits immune cell recruitment and immune recognition of tumor cells by suppressing the production of IFNgamma-dependent chemokines and diminishing antigen presentation.	('IFNgamma', 'Gene', (12, 20))	('limits', 'NegReg', (31, 37))	('diminishing', 'NegReg', (167, 178))	('antigen presentation', 'biological_process', 'GO:0019882', ('179', '199'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('IFNgamma', 'Gene', '3458', (12, 20))	('immune', 'CPA', (66, 72))	('IFNgamma', 'Gene', (133, 141))	('antigen presentation', 'MPA', (179, 199))	('IFNgamma', 'Gene', '3458', (133, 141))	('immune cell recruitment', 'CPA', (38, 61))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))	('tumor', 'Disease', (88, 93))	('suppressing', 'NegReg', (103, 114))	('loss', 'Var', (4, 8))
45858	29977240	Furthermore, our data confirm that measuring IFNgamma output with a select number of targets may be useful for detecting intrinsic defects in the IFNgamma/JAK/STAT pathway, including JAK and STAT mutations which are associated with PD-1 inhibitor resistance.	('IFNgamma', 'Gene', (146, 154))	('PD-1', 'Gene', (232, 236))	('defects', 'NegReg', (131, 138))	('JAK', 'molecular_function', 'GO:0004713', ('183', '186'))	('PD-1', 'Gene', '5133', (232, 236))	('IFNgamma', 'Gene', '3458', (146, 154))	('associated', 'Reg', (216, 226))	('JAK', 'molecular_function', 'GO:0004713', ('155', '158'))	('JAK', 'Var', (183, 186))	('IFNgamma', 'Gene', (45, 53))	('IFNgamma', 'Gene', '3458', (45, 53))
45875	29977240	Expression of five well-defined IFNgamma targets, the PD-1 ligands PD-L1 and PD-L2, NGFR, antigen-presenting HLA-A, -B, and -C (HLA-ABC), and HLA-DR molecules was examined in a panel of 39 human melanoma cell lines with defined oncogenic driver mutations (Figure 1A; Figure S1 in Supplementary Material).	('HLA-DR', 'Gene', (142, 148))	('HLA-A', 'Gene', (109, 114))	('PD-L2', 'Gene', (77, 82))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (109, 126))	('HLA-A', 'Gene', '3105', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('NGFR', 'Gene', (84, 88))	('mutations', 'Var', (245, 254))	('HLA-A', 'Gene', '3105', (109, 114))	('human', 'Species', '9606', (189, 194))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('PD-1', 'Gene', (54, 58))	('HLA-A', 'Gene', (128, 133))	('PD-1', 'Gene', '5133', (54, 58))	('IFNgamma', 'Gene', (32, 40))	('HLA-DR', 'Gene', '3122', (142, 148))	('IFNgamma', 'Gene', '3458', (32, 40))	('PD-L1', 'Gene', (67, 72))	('NGFR', 'Gene', '4804', (84, 88))	('PD-L2', 'Gene', '80380', (77, 82))	('PD-L1', 'Gene', '29126', (67, 72))
45881	29977240	Three cell lines, the BRAFV600-mutant C060M1 and BRAF/NRASWT D24M and SMU15-0217, had a bimodal expression of both HLA-DR and NGFR (data not shown).	('D24M', 'Mutation', 'p.D24M', (61, 65))	('NGFR', 'Gene', (126, 130))	('HLA-DR', 'Gene', '3122', (115, 121))	('BRAF', 'Gene', '673', (22, 26))	('NRAS', 'Gene', (54, 58))	('HLA-DR', 'Gene', (115, 121))	('C060M1', 'Var', (38, 44))	('BRAF', 'Gene', (22, 26))	('NRAS', 'Gene', '4893', (54, 58))	('NGFR', 'Gene', '4804', (126, 130))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
45908	29977240	Whole exome sequencing of this cell line identified a damaging missense mutation resulting in a P44R substitution in the extracellular portion of the IFNGR1 (Figure 6B).	('P44R', 'Mutation', 'rs587776853', (96, 100))	('extracellular', 'cellular_component', 'GO:0005576', ('121', '134'))	('P44R', 'Var', (96, 100))	('IFNGR1', 'Gene', (150, 156))
45913	29977240	The remaining 23 melanoma cell lines, including the IFNGR1-mutant D22M1 cells, showed minimal cell cycle profile changes when exposed to IFNgamma (Table 2).	('cell cycle profile', 'CPA', (94, 112))	('IFNgamma', 'Gene', (137, 145))	('D22M1', 'Gene', (66, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('IFNgamma', 'Gene', '3458', (137, 145))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('IFNGR1-mutant', 'Var', (52, 65))	('IFNGR1-mutant D22M1', 'Gene', (52, 71))
45928	29977240	In particular, nuclear expression of the IFNgamma transcription factor IRF1 is associated with better response to anti-PD-1 therapy in melanoma and loss-of-function mutations in IFNgamma pathway modulators (JAK1, JAK2) are associated with resistance to anti-PD-1 treatment.	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('PD-1', 'Gene', (258, 262))	('PD-1', 'Gene', '5133', (258, 262))	('nuclear expression', 'MPA', (15, 33))	('JAK', 'molecular_function', 'GO:0004713', ('213', '216'))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('JAK2', 'Gene', '3717', (213, 217))	('IFNgamma', 'Gene', (178, 186))	('JAK', 'molecular_function', 'GO:0004713', ('207', '210'))	('IFNgamma', 'Gene', '3458', (178, 186))	('mutations', 'Var', (165, 174))	('PD-1', 'Gene', (119, 123))	('PD-1', 'Gene', '5133', (119, 123))	('IRF1', 'Gene', (71, 75))	('IFNgamma', 'Gene', '3458', (41, 49))	('JAK2', 'Gene', (213, 217))	('IFNgamma', 'Gene', (41, 49))	('transcription factor', 'molecular_function', 'GO:0000981', ('50', '70'))	('better', 'PosReg', (95, 101))	('IRF1', 'Gene', '3659', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('loss-of-function', 'NegReg', (148, 164))
45940	29977240	Loss of MHC class I expression is another established mechanism of immune escape, often involving genetic alterations in the B2M gene and we noted that the SMU15-0217 melanoma cell line showed loss of B2M expression, concurrent with loss of HLA-ABC expression.	('MHC class I', 'Gene', (8, 19))	('expression', 'MPA', (249, 259))	('B2M', 'Gene', '567', (125, 128))	('loss', 'NegReg', (193, 197))	('B2M', 'Gene', (201, 204))	('B2M', 'Gene', (125, 128))	('HLA-A', 'Gene', '3105', (241, 246))	('Loss', 'NegReg', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('B2M', 'Gene', '567', (201, 204))	('HLA-A', 'Gene', (241, 246))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('genetic alterations', 'Var', (98, 117))	('alterations', 'Var', (106, 117))	('expression', 'MPA', (205, 215))	('loss', 'NegReg', (233, 237))
45941	29977240	Only one cell line (i.e., D22M1) failed to respond to IFNgamma, and this was associated with a homozygous, predicted loss-of-function mutation in the IFNGR1 gene.	('IFNgamma', 'Gene', (54, 62))	('mutation', 'Var', (134, 142))	('IFNgamma', 'Gene', '3458', (54, 62))	('IFNGR1', 'Gene', (150, 156))	('loss-of-function', 'NegReg', (117, 133))	('respond', 'MPA', (43, 50))
45943	29977240	We show that incomplete IFNgamma signaling occurs in almost 70% of immunotherapy-naive melanoma, and previous reports have confirmed that pre-existing alterations affecting IFNgamma signaling have the potential to confer resistance to immune checkpoint inhibitors.	('melanoma', 'Disease', (87, 95))	('pre', 'molecular_function', 'GO:0003904', ('138', '141'))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('IFNgamma', 'Gene', (173, 181))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('resistance', 'MPA', (221, 231))	('IFNgamma', 'Gene', '3458', (173, 181))	('IFNgamma', 'Gene', '3458', (24, 32))	('signaling', 'biological_process', 'GO:0023052', ('33', '42'))	('IFNgamma', 'Gene', (24, 32))	('alterations', 'Var', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
45944	29977240	In fact, we identified two well-recognized mechanisms of immunotherapy resistance; the loss of B2M expression, resulting in absence of cell surface HLA-ABC, and a missense mutation in the IFNGR1 gene, resulting in loss of cell surface IFNGR1.	('loss', 'NegReg', (87, 91))	('B2M', 'Gene', (95, 98))	('cell surface IFNGR1', 'MPA', (222, 241))	('expression', 'MPA', (99, 109))	('B2M', 'Gene', '567', (95, 98))	('missense mutation', 'Var', (163, 180))	('loss', 'NegReg', (214, 218))	('cell surface', 'cellular_component', 'GO:0009986', ('222', '234'))	('IFNGR1', 'Gene', (188, 194))	('absence', 'NegReg', (124, 131))	('HLA-A', 'Gene', '3105', (148, 153))	('cell surface', 'cellular_component', 'GO:0009986', ('135', '147'))	('HLA-A', 'Gene', (148, 153))
45958	26991400	While certain somatic mutations are associated with neoplastic growth and distant metastasis (see below) the malignancy is not inherited in a traditional genetic fashion although individuals with germline BAP1 mutations are thought to be at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.	('uveal and cutaneous melanoma', 'Disease', 'MESH:C536494', (257, 285))	('malignancy', 'Disease', (109, 119))	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancers', 'Phenotype', 'HP:0002664', (320, 327))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (267, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('BAP1', 'Gene', (205, 209))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('associated', 'Reg', (36, 46))	('mesothelioma and renal cancers', 'Disease', 'MESH:D007680', (297, 327))	('neoplastic growth', 'Disease', (52, 69))	('neoplastic growth', 'Disease', 'MESH:D006130', (52, 69))
46010	26991400	Those whose primary tumors have a Class 2 gene expression profile, monosomy 3 or were greater than 8 mm in apical dimension are in the highest risk group.	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('primary tumors', 'Disease', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('monosomy 3', 'Var', (67, 77))	('primary tumors', 'Disease', 'MESH:D009369', (12, 26))
46060	26991400	The ligation of PD-1 and PD-L1 inhibits T cell proliferation and activation and induces apoptosis of antigen specific T cells to suppress anti-tumor immunity.	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('tumor', 'Disease', (143, 148))	('inhibits', 'NegReg', (31, 39))	('T cell proliferation', 'CPA', (40, 60))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('activation', 'CPA', (65, 75))	('suppress', 'NegReg', (129, 137))	('T cell proliferation', 'biological_process', 'GO:0042098', ('40', '60'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ligation', 'Var', (4, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('PD-L1', 'Gene', (25, 30))	('induces', 'Reg', (80, 87))	('PD-1', 'Gene', (16, 20))
46066	26991400	Since there are many differences in the tumor-immune microenvironment (nearly always the liver) as well as tumor biology (far fewer mutations and different mutational spectrum) of uveal melanoma compared with cutaneous (and other, such as mucosal) sites of primary melanoma, it is likely that outcomes reported for metastatic cutaneous melanoma will not be replicated in uveal melanoma, and that other trial designs will need to be considered.	('tumor', 'Disease', (107, 112))	('uveal melanoma', 'Phenotype', 'HP:0007716', (180, 194))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('melanoma', 'Disease', 'MESH:D008545', (377, 385))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('uveal melanoma', 'Phenotype', 'HP:0007716', (371, 385))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('melanoma', 'Disease', 'MESH:D008545', (336, 344))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (377, 385))	('melanoma', 'Disease', (377, 385))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('tumor', 'Disease', (40, 45))	('melanoma', 'Disease', (265, 273))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('uveal melanoma', 'Disease', (180, 194))	('uveal melanoma', 'Disease', 'MESH:C536494', (180, 194))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cutaneous melanoma', 'Disease', (326, 344))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (326, 344))	('melanoma', 'Phenotype', 'HP:0002861', (336, 344))	('melanoma', 'Disease', (336, 344))	('fewer', 'NegReg', (126, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (326, 344))	('uveal melanoma', 'Disease', (371, 385))	('uveal melanoma', 'Disease', 'MESH:C536494', (371, 385))
46067	26991400	Uveal melanomas are not known to harbor BRAF or NRAS mutations.	('BRAF', 'Gene', '673', (40, 44))	('NRAS', 'Gene', '4893', (48, 52))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('BRAF', 'Gene', (40, 44))	('melanomas', 'Disease', (6, 15))	('mutations', 'Var', (53, 62))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('NRAS', 'Gene', (48, 52))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
46068	26991400	Instead, 80% of uveal melanomas have oncogenic mutations in GNAQ or GNA11, which are potential drivers of MAPK activation similar to oncogenic BRAF mutations in cutaneous melanoma.	('uveal melanomas', 'Disease', (16, 31))	('cutaneous melanoma', 'Disease', (161, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 179))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('GNA11', 'Gene', '2767', (68, 73))	('GNAQ', 'Gene', '2776', (60, 64))	('GNAQ', 'Gene', (60, 64))	('mutations', 'Var', (47, 56))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('MAPK activation', 'biological_process', 'GO:0000187', ('106', '121'))	('GNA11', 'Gene', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('106', '110'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))
46079	26991400	Cytogenetic changes in uveal melanoma are nonrandom and are characterized by monosomy 3, trisomy 8, deletions in chromosome 1 and structural or numerical abnormalities of chromosome 6.	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('uveal melanoma', 'Phenotype', 'HP:0007716', (23, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (23, 37))	('structural', 'Var', (130, 140))	('trisomy 8', 'Disease', (89, 98))	('uveal melanoma', 'Disease', (23, 37))	('monosomy 3', 'Disease', (77, 87))	('deletions', 'Var', (100, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))
46080	26991400	Cytogenetic investigation of uveal melanoma has revealed that monosomy 3 is the most frequent karyotypic abnormality, present in approximately 50-60% of cases.	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('monosomy 3', 'Var', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
46081	26991400	The pattern of loss of heterozygosity in these tumors indicates the presence of deletions around 3p25-26 and on 3q, and a region at 3p11-14 is preferentially deleted.	('tumors', 'Disease', (47, 53))	('3p25-26', 'Gene', (97, 104))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('deletions', 'Var', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
46084	26991400	The loss of the entire short arm of chromosome 1 was only observed in tumors with monosomy 3 and 1p31 was proposed to be involved in progression of monosomy 3 uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (159, 173))	('monosomy 3', 'Var', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (159, 173))	('uveal melanoma', 'Disease', (159, 173))	('short arm', 'Phenotype', 'HP:0009824', (23, 32))	('p31', 'Gene', (98, 101))	('tumors', 'Disease', (70, 76))	('involved', 'Reg', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('p31', 'Gene', '529', (98, 101))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('chromosome', 'cellular_component', 'GO:0005694', ('36', '46'))
46086	26991400	The combination of monosomy 3 with cell type analysis or tumor diameter has been shown to have a greater prognostic impact than monosomy 3 alone.	('monosomy 3', 'Var', (19, 29))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
46088	26991400	Abdel-Rahman et.al., in their study of 47 uveal melanomas and median follow-up of 36 months, showed that partial chromosome 3 alteration is not associated with the highly aggressive uveal melanoma that metastasizes within the first 3 years post treatment.	('associated', 'Reg', (144, 154))	('uveal melanomas', 'Disease', (42, 57))	('uveal melanomas', 'Phenotype', 'HP:0007716', (42, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (182, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('partial chromosome', 'Var', (105, 123))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanomas', 'Disease', 'MESH:C536494', (42, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('uveal melanoma', 'Disease', 'MESH:C536494', (182, 196))	('uveal melanoma', 'Disease', (182, 196))
46097	26991400	Oncogene and tumor suppressor mutations that are common in other cancers are mostly absent in uveal melanoma, a disease characterized by low mutation burden.	('tumor', 'Disease', (13, 18))	('uveal melanoma', 'Disease', 'MESH:C536494', (94, 108))	('uveal melanoma', 'Phenotype', 'HP:0007716', (94, 108))	('uveal melanoma', 'Disease', (94, 108))	('absent', 'NegReg', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mutations', 'Var', (30, 39))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Oncogene', 'Gene', (0, 8))	('cancers', 'Disease', (65, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
46099	26991400	These "driver" mutations that control the biology of up to 70% of cutaneous melanomas are absent/rare in uveal melanoma.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (66, 85))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (66, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('mutations', 'Var', (15, 24))	('cutaneous melanomas', 'Disease', (66, 85))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('to 7', 'Species', '1214577', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
46101	26991400	analyzed 50 cases of primary uveal melanoma obtained from enucleation for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT.	('primary uveal melanoma', 'Disease', (21, 43))	('SF3B1', 'Gene', (116, 121))	('GNA11', 'Gene', '2767', (103, 108))	('TERT', 'Gene', (134, 138))	('GNAQ', 'Gene', '2776', (97, 101))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('mutations', 'Var', (74, 83))	('SF3B1', 'Gene', '23451', (116, 121))	('BAP1', 'Gene', (110, 114))	('enucleation', 'biological_process', 'GO:0090601', ('58', '69'))	('TERT', 'Gene', '7015', (134, 138))	('GNA11', 'Gene', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (21, 43))	('GNAQ', 'Gene', (97, 101))
46102	26991400	They found that 42.2% of uveal melanomas harbored mutated GNAQ, 32.6% GNA11, 31.5% BAP1, 9.7% SF3B1, 18.9% EIF1AX and 1% TERT.	('SF3B1', 'Gene', '23451', (94, 99))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('GNAQ', 'Gene', '2776', (58, 62))	('TERT', 'Gene', '7015', (121, 125))	('uveal melanomas', 'Disease', (25, 40))	('uveal melanomas', 'Phenotype', 'HP:0007716', (25, 40))	('mutated', 'Var', (50, 57))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('SF3B1', 'Gene', (94, 99))	('GNAQ', 'Gene', (58, 62))	('TERT', 'Gene', (121, 125))	('GNA11', 'Gene', (70, 75))	('uveal melanomas', 'Disease', 'MESH:C536494', (25, 40))	('EIF1AX and 1', 'Gene', '1964;10209', (107, 119))	('GNA11', 'Gene', '2767', (70, 75))
46103	26991400	Of these, GNAQ and GNA11 are usually mutually exclusive but both can co-exist with BAP1 or SF3B1 mutations.	('mutations', 'Var', (97, 106))	('SF3B1', 'Gene', (91, 96))	('GNAQ', 'Gene', '2776', (10, 14))	('GNA11', 'Gene', (19, 24))	('BAP1', 'Gene', (83, 87))	('GNA11', 'Gene', '2767', (19, 24))	('SF3B1', 'Gene', '23451', (91, 96))	('GNAQ', 'Gene', (10, 14))	('co-exist', 'Reg', (69, 77))
46104	26991400	Likewise, BAP1 and SF3B1 are mutually exclusive as are EIF1AX and SF3B1 mutations, TERT mutations appear to co-exist specifically with GNA11 or EIF1AX mutations.	('mutations', 'Var', (72, 81))	('GNA11', 'Gene', '2767', (135, 140))	('EIF1AX', 'Gene', (55, 61))	('EIF1AX', 'Gene', '1964', (55, 61))	('SF3B1', 'Gene', '23451', (19, 24))	('EIF1AX', 'Gene', (144, 150))	('SF3B1', 'Gene', (66, 71))	('TERT', 'Gene', (83, 87))	('EIF1AX', 'Gene', '1964', (144, 150))	('TERT', 'Gene', '7015', (83, 87))	('SF3B1', 'Gene', '23451', (66, 71))	('GNA11', 'Gene', (135, 140))	('SF3B1', 'Gene', (19, 24))
46105	26991400	The majority of uveal melanomas have one of two mutually exclusive activating mutations in the very homologous genes encoding Galpha subunits, GNAQ (Galphaq) and GNA11 (Galpha11) (19-21).	('uveal melanomas', 'Disease', (16, 31))	('Galpha', 'Gene', (169, 175))	('Galpha11', 'Gene', (169, 177))	('Galphaq', 'Gene', (149, 156))	('mutations', 'Var', (78, 87))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('Galpha', 'Gene', '8802', (169, 175))	('GNA11', 'Gene', (162, 167))	('Galpha', 'Gene', (126, 132))	('uveal melanomas', 'Disease', 'MESH:C536494', (16, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('Galpha', 'Gene', (149, 155))	('Galphaq', 'Gene', '2776;2767', (149, 156))	('activating', 'PosReg', (67, 77))	('GNAQ', 'Gene', '2776', (143, 147))	('Galpha', 'Gene', '8802', (126, 132))	('GNAQ', 'Gene', (143, 147))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('Galpha', 'Gene', '8802', (149, 155))	('Galpha11', 'Gene', '2767', (169, 177))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('GNA11', 'Gene', '2767', (162, 167))
46106	26991400	Interestingly, the GNAQ mutation is more frequently found in benign blue nevi, while the GNA11 mutation is frequent in malignant uveal melanoma.	('found', 'Reg', (52, 57))	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('malignant uveal melanoma', 'Disease', 'MESH:C536494', (119, 143))	('GNAQ', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('benign blue nevi', 'Disease', (61, 77))	('malignant uveal melanoma', 'Disease', (119, 143))	('uveal melanoma', 'Phenotype', 'HP:0007716', (129, 143))	('GNA11', 'Gene', '2767', (89, 94))	('GNA11', 'Gene', (89, 94))	('mutation', 'Var', (24, 32))	('GNAQ', 'Gene', '2776', (19, 23))	('blue nevi', 'Phenotype', 'HP:0100814', (68, 77))
46107	26991400	showed that the GNAQ/11 mutations activate YAP, a major effector of the Hippo tumor suppressor pathway, and YAP mediates the oncogenic properties of GNAQ/GNA11 mutations.	('YAP', 'Gene', '10413', (108, 111))	('GNAQ', 'Gene', (149, 153))	('activate', 'PosReg', (34, 42))	('YAP', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('YAP', 'Gene', '10413', (43, 46))	('GNAQ', 'Gene', (16, 20))	('GNA11', 'Gene', (154, 159))	('GNAQ', 'Gene', '2776', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'biological_process', 'GO:0051726', ('78', '94'))	('mutations', 'Var', (24, 33))	('GNA11', 'Gene', '2767', (154, 159))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('78', '94'))	('GNAQ', 'Gene', '2776', (16, 20))	('tumor', 'Disease', (78, 83))	('YAP', 'Gene', (43, 46))
46108	26991400	first described inactivating somatic mutations in BAP1 gene (BRCA1-associated protein 1), on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('inactivating', 'Var', (16, 28))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('mutations', 'Var', (37, 46))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('BRCA1-associated protein 1', 'Gene', '8314', (61, 87))	('BAP1', 'Gene', (50, 54))	('BRCA1-associated protein 1', 'Gene', (61, 87))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
46109	26991400	One tumor had a germ line frame-shift mutation representing a susceptibility allele.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('frame-shift mutation', 'Var', (26, 46))	('tumor', 'Disease', 'MESH:D009369', (4, 9))
46112	26991400	Subsequently, more germline mutations of BAP1 have been described in uveal melanoma patients suggesting that BAP1 screening can identify people with predisposition to uveal melanoma.	('described', 'Reg', (56, 65))	('patients', 'Species', '9606', (84, 92))	('uveal melanoma', 'Disease', (69, 83))	('uveal melanoma', 'Disease', 'MESH:C536494', (69, 83))	('BAP1', 'Gene', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (167, 181))	('uveal melanoma', 'Disease', 'MESH:C536494', (167, 181))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('uveal melanoma', 'Disease', (167, 181))	('people', 'Species', '9606', (137, 143))	('germline', 'Var', (19, 27))
46113	26991400	These reports of mutation screens in patients with uveal melanoma suggest younger patients may harbor a germline BAP1 mutation.	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (82, 90))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mutation', 'Var', (118, 126))	('BAP1', 'Gene', (113, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
46117	26991400	Uveal melanoma is among a small group of cancers associated with SF3B1 mutations.	('melanoma', 'Disease', 'MESH:D008545', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('associated', 'Reg', (49, 59))	('SF3B1', 'Gene', (65, 70))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('mutations', 'Var', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('SF3B1', 'Gene', '23451', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('melanoma', 'Disease', (6, 14))	('cancers', 'Disease', (41, 48))
46118	26991400	These mutations define a genetic subset of uveal melanoma that have been reported by Harbour et al.	('uveal melanoma', 'Disease', 'MESH:C536494', (43, 57))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('uveal melanoma', 'Disease', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('mutations', 'Var', (6, 15))
46119	26991400	SF3B1 mutations are observed in codon 65 and mostly in tumors without loss of all or part of chromosome 3.	('SF3B1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SF3B1', 'Gene', '23451', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('mutations', 'Var', (6, 15))
46122	26991400	EIF1AX mutations are infrequent in monosomy 3 uveal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('uveal melanomas', 'Disease', 'MESH:C536494', (46, 61))	('uveal melanomas', 'Phenotype', 'HP:0007716', (46, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanomas', 'Disease', (46, 61))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
46126	26991400	Molecular prognostic testing for genetic mutations, chromosomal abnormalities, and gene expression profiling, as discussed above, are becoming more common in uveal melanoma and have led to the identification and enrollment of high risk patients in adjuvant therapy trials.	('common', 'Reg', (148, 154))	('genetic mutations', 'Var', (33, 50))	('patients', 'Species', '9606', (236, 244))	('chromosomal abnormalities', 'Disease', (52, 77))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (52, 77))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('uveal melanoma', 'Disease', 'MESH:C536494', (158, 172))	('uveal melanoma', 'Phenotype', 'HP:0007716', (158, 172))	('uveal melanoma', 'Disease', (158, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('led to', 'Reg', (182, 188))
46128	26991400	GNAQ and GNA11 mutations activate pathways that may provide a rationale for the use of a MEK or Akt inhibitor, while HDAC inhibitors may be the choice for treating BAP1-mutated uveal melanoma.	('GNA11', 'Gene', (9, 14))	('MEK', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('activate', 'PosReg', (25, 33))	('GNAQ', 'Gene', '2776', (0, 4))	('MEK', 'Gene', '5609', (89, 92))	('mutations', 'Var', (15, 24))	('pathways', 'Pathway', (34, 42))	('uveal melanoma', 'Disease', 'MESH:C536494', (177, 191))	('uveal melanoma', 'Phenotype', 'HP:0007716', (177, 191))	('GNAQ', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (177, 191))	('Akt', 'Gene', '207', (96, 99))	('Akt', 'Gene', (96, 99))	('GNA11', 'Gene', '2767', (9, 14))
46129	26991400	The identification of downstream effectors of GNAQ/11 mutations, like the components of the Hippo pathway, gives us an alternative to targeting the MAPK pathway, which, to date, has been disappointing.	('GNAQ', 'Gene', (46, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('148', '152'))	('MAPK pathway', 'Pathway', (148, 160))	('mutations', 'Var', (54, 63))	('GNAQ', 'Gene', '2776', (46, 50))
46139	26991400	Mice treated with crizotinib showed a significant reduction in the development of metastasis as compared to untreated control mice.	('mice', 'Species', '10090', (126, 130))	('reduction', 'NegReg', (50, 59))	('crizotinib', 'Var', (18, 28))	('Mice', 'Species', '10090', (0, 4))	('development of metastasis', 'CPA', (67, 92))	('crizotinib', 'Chemical', 'MESH:D000077547', (18, 28))
46140	26991400	Thus, inhibition of MET may prevent uveal melanoma metastasis and crizotinib could represent a potential adjuvant therapy strategy for patients with primary uveal melanoma at risk for distant disease.	('patients', 'Species', '9606', (135, 143))	('uveal melanoma metastasis', 'Disease', (36, 61))	('uveal melanoma metastasis', 'Disease', 'MESH:C536494', (36, 61))	('primary uveal melanoma', 'Disease', (149, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('primary uveal melanoma', 'Disease', 'MESH:C536494', (149, 171))	('MET', 'Gene', (20, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('prevent', 'NegReg', (28, 35))	('inhibition', 'Var', (6, 16))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('crizotinib', 'Chemical', 'MESH:D000077547', (66, 76))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
46169	28283736	ALM and mucosal melanoma have distinct genetic characteristics, such as less common BRAF and RAS mutations and a higher frequency of KIT mutations (10-20% for ALM, 15-20% for mucosal), compared to cutaneous melanomas (2%) and a lower somatic mutational burden than that for SSM.	('mutations', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('ALM', 'Phenotype', 'HP:0012060', (0, 3))	('mucosal melanoma', 'Disease', 'MESH:D008545', (8, 24))	('SSM', 'cellular_component', 'GO:1990843', ('274', '277'))	('RAS', 'Gene', (93, 96))	('mucosal melanoma', 'Disease', (8, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (197, 216))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (197, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (197, 215))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('SSM', 'Phenotype', 'HP:0012057', (274, 277))	('cutaneous melanomas', 'Disease', (197, 216))	('mutations', 'Var', (137, 146))	('KIT', 'Gene', (133, 136))	('KIT', 'molecular_function', 'GO:0005020', ('133', '136'))	('ALM', 'Phenotype', 'HP:0012060', (159, 162))
46171	28283736	This agent was generated by grafting the variable region sequences of a mouse antihuman PD-1 antibody onto a human IgG4-k isotype framework containing a stabilizing S228P mutation of the Fc region.	('PD-1', 'Gene', '5133', (88, 92))	('S228P', 'Var', (165, 170))	('human', 'Species', '9606', (109, 114))	('IgG4', 'cellular_component', 'GO:0071735', ('115', '119'))	('S228P', 'Mutation', 'p.S228P', (165, 170))	('antibody', 'cellular_component', 'GO:0019815', ('93', '101'))	('mouse', 'Species', '10090', (72, 77))	('antibody', 'cellular_component', 'GO:0019814', ('93', '101'))	('antibody', 'molecular_function', 'GO:0003823', ('93', '101'))	('PD-1', 'Gene', (88, 92))	('antibody', 'cellular_component', 'GO:0042571', ('93', '101'))	('human', 'Species', '9606', (82, 87))
46175	28283736	In a randomized phase 3 study performed in patients with ipilimumab-naive melanoma (KEYNOTE-006), pembrolizumab at a dose of 10 mg/kg Q3W or Q2W significantly improved the PFS and overall survival (OS), compared with ipilimumab, reducing the risk of death or disease progression by 42% and the risk of death by 31-37%, respectively, as well as being associated with fewer occurrences of high-grade toxicity.	('ipilimumab', 'Chemical', 'MESH:D000074324', (217, 227))	('ipilimumab-naive melanoma', 'Disease', 'MESH:D008545', (57, 82))	('death or disease', 'Disease', (250, 266))	('improved', 'PosReg', (159, 167))	('toxicity', 'Disease', 'MESH:D064420', (398, 406))	('patients', 'Species', '9606', (43, 51))	('Q2W', 'Var', (141, 144))	('death or disease', 'Disease', 'MESH:D003643', (250, 266))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('overall survival', 'CPA', (180, 196))	('PFS', 'CPA', (172, 175))	('toxicity', 'Disease', (398, 406))	('ipilimumab', 'Chemical', 'MESH:D000074324', (57, 67))	('pembrolizumab', 'Var', (98, 111))	('pembrolizumab', 'Chemical', 'MESH:C582435', (98, 111))	('reducing', 'NegReg', (229, 237))	('ipilimumab-naive melanoma', 'Disease', (57, 82))
46333	33731665	The biological characteristics of MM differ significantly when compared to cutaneous melanoma: BRAF mutation is present in about 50% of skin melanomas, whereas it is rare in MM (less than 10% of cases).	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('skin melanomas', 'Disease', (136, 150))	('MM', 'Phenotype', 'HP:0002861', (34, 36))	('skin melanomas', 'Disease', 'MESH:D008545', (136, 150))	('BRAF', 'Gene', '673', (95, 99))	('mutation', 'Var', (100, 108))	('BRAF', 'Gene', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('MM', 'Phenotype', 'HP:0002861', (174, 176))
46334	33731665	c-KIT mutation reaches a frequency of 15% to 20%.	('c-KIT', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('c-KIT', 'Gene', '3815', (0, 5))
46339	33731665	The increased frequency of c-KIT mutations in MM prompted studies of tyrosine kinase inhibitors such as Imatinib and Dasatinib, but findings have been divergent and the response is short-lived.	('c-KIT', 'Gene', (27, 32))	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('mutations', 'Var', (33, 42))	('Imatinib', 'Chemical', 'MESH:D000068877', (104, 112))	('c-KIT', 'Gene', '3815', (27, 32))	('MM', 'Phenotype', 'HP:0002861', (46, 48))	('Dasatinib', 'Chemical', 'MESH:D000069439', (117, 126))
46350	33731665	This case is unique in that the patient also had a BRAF mutation, which offers another therapeutic possibility in the future if there is disease progression, with significant efficacy.	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('patient', 'Species', '9606', (32, 39))	('BRAF', 'Gene', '673', (51, 55))
46352	33731665	These limitations include the delayed BRAF mutation status report, the unavailability of video mediastinoscope, the unavailability of PD-L1 measurement at the time of this diagnosis, and lack of liquid biopsy for follow-up.	('PD-L1', 'Gene', (134, 139))	('BRAF', 'Gene', '673', (38, 42))	('mutation status', 'Var', (43, 58))	('BRAF', 'Gene', (38, 42))	('PD-L1', 'Gene', '29126', (134, 139))
46354	33731665	Within this group, primary lung melanoma is extremely rare and this is the only case reported with a positive BRAF mutation.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('BRAF', 'Gene', '673', (110, 114))	('lung melanoma', 'Disease', (27, 40))	('lung melanoma', 'Disease', 'MESH:D008545', (27, 40))	('mutation', 'Var', (115, 123))	('BRAF', 'Gene', (110, 114))
46363	29512776	The miR-367 level in tumor tissues was positively correlated with tumor thickness, tumor stage, lymph node involvement, distant metastasis and the patient survival rate.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (83, 88))	('miR-367', 'Var', (4, 11))	('patient survival rate', 'CPA', (147, 168))	('patient', 'Species', '9606', (147, 154))	('correlated', 'Reg', (50, 60))	('distant metastasis', 'CPA', (120, 138))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('lymph node involvement', 'CPA', (96, 118))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
46364	29512776	A high miR-367 level was observed to enhance the growth, migration and invasion of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('growth', 'CPA', (49, 55))	('miR-367 level', 'Var', (7, 20))	('migration', 'CPA', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('enhance', 'PosReg', (37, 44))	('melanoma', 'Disease', (83, 91))
46366	29512776	miR-367 markedly increased the growth and invasion of melanoma cells, whereas the cotransfection of PTEN vectors limited the promoting function of miR-367 in the proliferation and invasion of A375 cells.	('increased', 'PosReg', (17, 26))	('invasion', 'CPA', (180, 188))	('miR-367', 'Var', (0, 7))	('growth', 'CPA', (31, 37))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('proliferation', 'CPA', (162, 175))	('melanoma', 'Disease', (54, 62))	('A375', 'CellLine', 'CVCL:0132', (192, 196))	('limited', 'NegReg', (113, 120))
46374	29512776	Emerging evidences identified that abnormal miRNAs expression was associated with the initiation and procession of tumors.	('miRNAs', 'Protein', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('abnormal', 'Var', (35, 43))	('associated', 'Reg', (66, 76))	('tumors', 'Disease', (115, 121))	('initiation', 'CPA', (86, 96))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
46382	29512776	In contrast, miR-367 was found to be related with TNM stage of patients and suppress gastric cancer development via targeting Rab23.	('miR-367', 'Var', (13, 20))	('TNM', 'Gene', (50, 53))	('Rab23', 'Gene', (126, 131))	('suppress', 'NegReg', (76, 84))	('targeting', 'Reg', (116, 125))	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('Rab23', 'Gene', '51715', (126, 131))	('patients', 'Species', '9606', (63, 71))	('TNM', 'Gene', '10178', (50, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))
46407	29512776	The miR-367 level was negatively correlated with the PTEN level in melanoma tissues (Fig.	('miR-367', 'Var', (4, 11))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('PTEN level', 'MPA', (53, 63))	('negatively', 'NegReg', (22, 32))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))
46410	29512776	The correlation was not statistically significant between the miR-367 level and age, sex of patients with melanoma, but high expression of miR-367 was significantly correlated with tumor thickness, TNM stage, lymph node involvement and distant metastasis of malignant melanoma as shown in Table I.	('TNM', 'Gene', (198, 201))	('high', 'Var', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('malignant melanoma', 'Disease', (258, 276))	('patients', 'Species', '9606', (92, 100))	('miR-367', 'Gene', (139, 146))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('melanoma', 'Disease', (268, 276))	('distant metastasis', 'CPA', (236, 254))	('tumor', 'Disease', (181, 186))	('malignant melanoma', 'Phenotype', 'HP:0002861', (258, 276))	('malignant melanoma', 'Disease', 'MESH:D008545', (258, 276))	('lymph node involvement', 'CPA', (209, 231))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('TNM', 'Gene', '10178', (198, 201))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))	('correlated', 'Reg', (165, 175))
46414	29512776	Conversely, the miR-367 level was decreased in A375 cells after transfection with miR-367 inhibitor (Fig.	('miR-367 level', 'MPA', (16, 29))	('transfection', 'Var', (64, 76))	('A375', 'CellLine', 'CVCL:0132', (47, 51))	('decreased', 'NegReg', (34, 43))
46418	29512776	Western blot analysis was implemented to identify whether miR-367 could regulate PTEN expression in A375 cells or not.	('miR-367', 'Var', (58, 65))	('A375', 'CellLine', 'CVCL:0132', (100, 104))	('expression', 'MPA', (86, 96))	('PTEN', 'Gene', (81, 85))	('regulate', 'Reg', (72, 80))
46419	29512776	The results further identified that high level of miR-367 remarkably suppressed PTEN expression in A375 cells.	('A375', 'CellLine', 'CVCL:0132', (99, 103))	('suppressed', 'NegReg', (69, 79))	('miR-367', 'Var', (50, 57))	('PTEN', 'Protein', (80, 84))
46424	29512776	In addition, upregulation of miR-367 enhanced the growth, invasion and migration of A375 cells, however, PTEN vectors ameliorated the ability of growth, invasion, and migration of A375 cells transfected with miR-367 mimics.	('invasion', 'CPA', (153, 161))	('migration of A375 cells', 'CPA', (71, 94))	('growth', 'CPA', (145, 151))	('A375', 'CellLine', 'CVCL:0132', (180, 184))	('migration', 'CPA', (167, 176))	('growth', 'CPA', (50, 56))	('invasion', 'CPA', (58, 66))	('upregulation', 'PosReg', (13, 25))	('A375', 'CellLine', 'CVCL:0132', (84, 88))	('miR-367', 'Gene', (29, 36))	('enhanced', 'PosReg', (37, 45))	('vectors', 'Var', (110, 117))	('ameliorated', 'PosReg', (118, 129))
46426	29512776	Briefly, miR-367 was able to promote the proliferation, invasion and migration of A375 cells via targeting PTEN.	('invasion', 'CPA', (56, 64))	('promote', 'PosReg', (29, 36))	('A375', 'CellLine', 'CVCL:0132', (82, 86))	('proliferation', 'CPA', (41, 54))	('miR-367', 'Var', (9, 16))	('PTEN', 'Protein', (107, 111))	('migration', 'CPA', (69, 78))
46429	29512776	The result showed that the volume of tumor in miR-367 mimics group was significantly increased in comparison with miR-control group at 10, 15, 20 and 25 days after A375 cells injection (Fig.	('A375', 'CellLine', 'CVCL:0132', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('miR-367 mimics', 'Var', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('increased', 'PosReg', (85, 94))
46430	29512776	3D), and the weight of tumor in miR-367 mimics group was markedly larger than that in miR-control group at 25 days after A375 cells injection (Fig.	('larger', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('A375', 'CellLine', 'CVCL:0132', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('miR-367', 'Var', (32, 39))	('tumor', 'Disease', (23, 28))
46431	29512776	Therefore, it was identified strongly that forced expression of miR-367 markedly augmented the growth of xenograft tumors.	('xenograft tumors', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('xenograft tumors', 'Disease', 'MESH:D009369', (105, 121))	('miR-367', 'Var', (64, 71))	('augmented', 'PosReg', (81, 90))
46441	29512776	All of these results combined manifested that miR-367 promoted melanoma progression by, at least in part, regulating the PTEN expression.	('promoted', 'PosReg', (54, 62))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('expression', 'MPA', (126, 136))	('regulating', 'Reg', (106, 116))	('miR-367', 'Var', (46, 53))	('melanoma', 'Disease', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('PTEN', 'Protein', (121, 125))
46445	29512776	Thirdly, forced expression of miR-367 inhibited expression of PTEN and promoted the phosphorylation of AKT, whereas downregulation of miR-367 distinctly promoted the expression of PTEN and alleviated the phosphorylation of AKT.	('AKT', 'Gene', '207', (103, 106))	('alleviated', 'NegReg', (189, 199))	('promoted', 'PosReg', (153, 161))	('PTEN', 'Protein', (180, 184))	('AKT', 'Gene', '207', (223, 226))	('AKT', 'Gene', (223, 226))	('promoted', 'PosReg', (71, 79))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('expression', 'MPA', (48, 58))	('AKT', 'Gene', (103, 106))	('phosphorylation', 'biological_process', 'GO:0016310', ('204', '219'))	('inhibited', 'NegReg', (38, 47))	('miR-367', 'Gene', (134, 141))	('phosphorylation', 'MPA', (204, 219))	('expression', 'MPA', (166, 176))	('PTEN', 'Protein', (62, 66))	('phosphorylation', 'MPA', (84, 99))	('downregulation', 'Var', (116, 130))
46448	29512776	All results combined identified that miR-367 played a pro-tumor role in A375 cells via regulating PTEN expression.	('miR-367', 'Var', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('expression', 'MPA', (103, 113))	('PTEN', 'Protein', (98, 102))	('A375', 'CellLine', 'CVCL:0132', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('regulating', 'Reg', (87, 97))
46450	29512776	These results further confirmed miR-367 could regulate the phosphorylation of AKT level by targeting PTEN mRNA, and be involved in malignant behaviors of A375 cells via regulating PTEN/AKT pathway.	('regulate', 'Reg', (46, 54))	('involved', 'Reg', (119, 127))	('AKT', 'Gene', (185, 188))	('PTEN', 'Protein', (101, 105))	('A375', 'CellLine', 'CVCL:0132', (154, 158))	('targeting', 'Reg', (91, 100))	('malignant behaviors', 'CPA', (131, 150))	('AKT', 'Gene', '207', (78, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('phosphorylation', 'MPA', (59, 74))	('miR-367', 'Var', (32, 39))	('AKT', 'Gene', '207', (185, 188))	('AKT', 'Gene', (78, 81))	('regulating', 'Reg', (169, 179))
46453	29512776	miR-367 augments the proliferation and invasion of melanoma.	('proliferation', 'CPA', (21, 34))	('miR-367', 'Var', (0, 7))	('invasion', 'CPA', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('augments', 'PosReg', (8, 16))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
46472	33306121	In addition, with respect to the mutations of Fam20C gene lead to Raine syndrome, which is characterized by generalized osteosclerosis, periosteal bone formation, and a unique facial phenotype.	('Raine syndrome', 'Disease', 'MESH:C535282', (66, 80))	('osteosclerosis', 'Disease', 'MESH:D010026', (120, 134))	('osteosclerosis', 'Phenotype', 'HP:0011001', (120, 134))	('osteosclerosis', 'Disease', (120, 134))	('periosteal bone formation', 'Phenotype', 'HP:0031485', (136, 161))	('mutations', 'Var', (33, 42))	('lead to', 'Reg', (58, 65))	('Fam20C', 'Gene', '56975', (46, 52))	('bone formation', 'biological_process', 'GO:0001503', ('147', '161'))	('Raine syndrome', 'Disease', (66, 80))	('Fam20C', 'Gene', (46, 52))	('generalized osteosclerosis', 'Phenotype', 'HP:0005789', (108, 134))
46536	33306121	Consequently, a strong association of the Fam20C high expression with worse OS, FP (first progression), and PPS (post-progression survival) in female and male patients was found.	('PPS', 'Disease', (108, 111))	('Fam20C', 'Gene', (42, 48))	('PPS', 'Disease', 'MESH:C562509', (108, 111))	('worse OS', 'Disease', (70, 78))	('high expression', 'Var', (49, 64))	('patients', 'Species', '9606', (159, 167))	('Fam20C', 'Gene', '56975', (42, 48))
46568	33306121	Macrophages secrete a large number of chemokines such as CC-like chemokines CCL22 and CCL20, which induce Tregs to recruit to the tumor site, similarly DCs also induce Treg generation, and then promote the metastasis of cancer cells.	('promote', 'PosReg', (194, 201))	('Tregs', 'Chemical', '-', (106, 111))	('Treg', 'Chemical', '-', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Disease', (130, 135))	('CCL20', 'Gene', '6364', (86, 91))	('induce', 'Reg', (161, 167))	('CCL', 'molecular_function', 'GO:0044101', ('86', '89'))	('CCL', 'molecular_function', 'GO:0044101', ('76', '79'))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Treg', 'Chemical', '-', (168, 172))	('CCL20', 'Gene', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Disease', (220, 226))	('CCL22', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('DCs', 'Var', (152, 155))	('CCL22', 'Gene', '6367', (76, 81))	('Treg generation', 'CPA', (168, 183))
46578	33306121	Therefore, it is desirable to speculate that the expression of Fam20C may affect the survival of patients through the progression of tumor cells.	('Fam20C', 'Gene', '56975', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('survival', 'CPA', (85, 93))	('Fam20C', 'Gene', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('affect', 'Reg', (74, 80))	('expression', 'Var', (49, 59))	('patients', 'Species', '9606', (97, 105))
46588	33306121	Here, we present an integrated study on the Fam20C expression levels in pan-cancer, the association of Fam20C variations with prognosis among different cancers and the potential mechanisms underlying different clinicopathological features.	('Fam20C', 'Gene', (44, 50))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('Fam20C', 'Gene', '56975', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Fam20C', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('variations', 'Var', (110, 120))	('Fam20C', 'Gene', '56975', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('association', 'Interaction', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
46651	31731729	Infiltration of various immune cells, especially CD8+ T and natural killer (NK) cells, which are cytolytic effector cells, was significantly increased by IL18 expression.	('IL18', 'molecular_function', 'GO:0045515', ('154', '158'))	('increased', 'PosReg', (141, 150))	('IL18', 'Gene', (154, 158))	('Infiltration of', 'CPA', (0, 15))	('CD8', 'Gene', (49, 52))	('CD8', 'Gene', '925', (49, 52))	('expression', 'Var', (159, 169))	('IL18', 'Gene', '3606', (154, 158))
46666	31731729	Exogenous IL-18 directly enhances the migration and invasion of a melanoma cell line, B16F10, suggesting that IL-18 has critical roles in melanoma malignancy.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('Exogenous', 'Var', (0, 9))	('melanoma', 'Disease', (138, 146))	('IL-18', 'Gene', (10, 15))	('melanoma', 'Disease', (66, 74))	('B16F10', 'CellLine', 'CVCL:0159', (86, 92))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('IL-18', 'molecular_function', 'GO:0045515', ('110', '115'))	('melanoma malignancy', 'Disease', 'MESH:D008545', (138, 157))	('enhances', 'PosReg', (25, 33))	('IL-18', 'molecular_function', 'GO:0045515', ('10', '15'))	('invasion', 'CPA', (52, 60))	('melanoma malignancy', 'Disease', (138, 157))	('migration', 'CPA', (38, 47))
46695	31731729	IL18 expression was examined for each alteration status (deep deletion, shallow deletion, diploid, and gain) and plotted.	('shallow deletion', 'Var', (72, 88))	('gain', 'PosReg', (103, 107))	('deep deletion', 'Var', (57, 70))	('IL18', 'Gene', (0, 4))	('IL18', 'molecular_function', 'GO:0045515', ('0', '4'))	('IL18', 'Gene', '3606', (0, 4))
46711	31731729	As shown in Figure 2a-c, high IL18 expression was associated with longer survival in SKCM, SARC, and BRCA, leading to a good prognosis (Log-rank P < 0.05).	('expression', 'MPA', (35, 45))	('BRCA', 'Gene', '672', (101, 105))	('IL18', 'molecular_function', 'GO:0045515', ('30', '34'))	('high', 'Var', (25, 29))	('IL18', 'Gene', (30, 34))	('BRCA', 'Gene', (101, 105))	('longer', 'PosReg', (66, 72))	('SKCM', 'Disease', (85, 89))	('IL18', 'Gene', '3606', (30, 34))	('SARC', 'Disease', (91, 95))
46712	31731729	In contrast, poor prognosis in two types of cancer, LGG and PAAD, were correlated with high IL18 expression (Log-rank P < 0.05, Figure 2d,e).	('cor', 'Chemical', '-', (71, 74))	('IL18', 'Gene', (92, 96))	('cancer', 'Disease', (44, 50))	('PAAD', 'Disease', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('LGG', 'Disease', (52, 55))	('IL18', 'Gene', '3606', (92, 96))	('IL18', 'molecular_function', 'GO:0045515', ('92', '96'))	('high', 'Var', (87, 91))	('expression', 'MPA', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
46721	31731729	In the Tumor Melanoma Metastatic-Bhardwaj-44 dataset, patients with high IL18 expression (n = 16) had significantly higher overall survival than patients with lower IL18 expression (n = 28) (Figure 3c).	('patients', 'Species', '9606', (145, 153))	('Tumor Melanoma', 'Phenotype', 'HP:0002861', (7, 21))	('IL18', 'molecular_function', 'GO:0045515', ('73', '77'))	('IL18', 'Gene', '3606', (73, 77))	('Tumor', 'Phenotype', 'HP:0002664', (7, 12))	('high', 'Var', (68, 72))	('higher', 'PosReg', (116, 122))	('patients', 'Species', '9606', (54, 62))	('Melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('Tumor Melanoma', 'Disease', 'MESH:D008545', (7, 21))	('IL18', 'Gene', (165, 169))	('overall survival', 'MPA', (123, 139))	('Tumor Melanoma', 'Disease', (7, 21))	('IL18', 'molecular_function', 'GO:0045515', ('165', '169'))	('IL18', 'Gene', (73, 77))	('IL18', 'Gene', '3606', (165, 169))
46724	31731729	Five missense mutations were found in the IL18 coding region.	('missense mutations', 'Var', (5, 23))	('IL18', 'Gene', (42, 46))	('IL18', 'Gene', '3606', (42, 46))	('IL18', 'molecular_function', 'GO:0045515', ('42', '46'))
46726	31731729	In total, 4.69% of IL18 genes were altered, consisting of 1.38% mutations, 3.31% deep deletions, and 3.31% of mRNA high (Figure 3e).	('altered', 'Reg', (35, 42))	('IL18', 'Gene', (19, 23))	('IL18', 'Gene', '3606', (19, 23))	('IL18', 'molecular_function', 'GO:0045515', ('19', '23'))	('deep deletions', 'Var', (81, 95))	('mutations', 'Var', (64, 73))	('mRNA high', 'Var', (110, 119))
46728	31731729	Figure 3f shows that IL18 expression was significantly lower in the deep-deletion samples than the shallow deletion and diploid samples.	('expression', 'MPA', (26, 36))	('IL18', 'molecular_function', 'GO:0045515', ('21', '25'))	('IL18', 'Gene', (21, 25))	('lower', 'NegReg', (55, 60))	('IL18', 'Gene', '3606', (21, 25))	('deep-deletion', 'Var', (68, 81))
46730	31731729	These data implied deep deletion CNA status could partially contribute that lower expression of IL18 in melanoma.	('IL18', 'Gene', '3606', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('expression', 'MPA', (82, 92))	('deep deletion', 'Var', (19, 32))	('lower', 'NegReg', (76, 81))	('IL18', 'Gene', (96, 100))	('IL18', 'molecular_function', 'GO:0045515', ('96', '100'))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
46763	31731729	Additionally, gammadelta T cells could be a better prognostic indicator in cancer than CD8+ T cells and NK cells.	('gammadelta', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('CD8', 'Gene', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CD8', 'Gene', '925', (87, 90))
46764	31731729	Here, infiltration of anti-tumor effector cells, CD8+ T cells, NK cells, and gammadelta T cells was markedly increased by IL18 expression (Table 1, Supplementary Table S6 and S7).	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('S7', 'Gene', '6264', (175, 177))	('tumor', 'Disease', (27, 32))	('IL18', 'Gene', (122, 126))	('IL18', 'molecular_function', 'GO:0045515', ('122', '126'))	('gammadelta T cells', 'CPA', (77, 95))	('CD8', 'Gene', (49, 52))	('infiltration', 'CPA', (6, 18))	('CD8', 'Gene', '925', (49, 52))	('IL18', 'Gene', '3606', (122, 126))	('NK cells', 'CPA', (63, 71))	('increased', 'PosReg', (109, 118))	('expression', 'Var', (127, 137))
46788	31731729	In vitro studies show the direct effects of exogenous IL-18 on melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('IL-18', 'molecular_function', 'GO:0045515', ('54', '59'))	('exogenous', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
46789	31731729	Exogenous IL-18 increases cell migration in the melanoma cell line B16F10, and cell adhesion in both murine and human melanoma cell lines, implying that IL-18 enhances malignant properties in melanoma cell.	('cell adhesion', 'CPA', (79, 92))	('malignant properties in', 'CPA', (168, 191))	('enhances', 'PosReg', (159, 167))	('human', 'Species', '9606', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('cell migration', 'CPA', (26, 40))	('cell adhesion', 'biological_process', 'GO:0007155', ('79', '92'))	('murine', 'Species', '10090', (101, 107))	('increases', 'PosReg', (16, 25))	('IL-18', 'molecular_function', 'GO:0045515', ('153', '158'))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('IL-18', 'Gene', (10, 15))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('cell migration', 'biological_process', 'GO:0016477', ('26', '40'))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('B16F10', 'CellLine', 'CVCL:0159', (67, 73))	('melanoma', 'Disease', (192, 200))	('IL-18', 'Var', (153, 158))	('IL-18', 'molecular_function', 'GO:0045515', ('10', '15'))
46792	31731729	In addition to the direct effects of IL-18 on NK cells, the expression of UL16 binding protein 2, which is a ligand for the NK cell-activating receptor, on tumor cells is increased by exogenous IL-18, leading to the increased NK cell cytotoxicity.	('cytotoxicity', 'Disease', 'MESH:D064420', (234, 246))	('expression', 'MPA', (60, 70))	('NK cell-activating receptor', 'Gene', (124, 151))	('exogenous', 'Var', (184, 193))	('ligand', 'molecular_function', 'GO:0005488', ('109', '115'))	('NK cell-activating receptor', 'Gene', '9437', (124, 151))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('UL16 binding protein 2', 'Gene', (74, 96))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('IL-18', 'molecular_function', 'GO:0045515', ('37', '42'))	('cytotoxicity', 'Disease', (234, 246))	('IL-18', 'molecular_function', 'GO:0045515', ('194', '199'))	('tumor', 'Disease', (156, 161))	('UL16 binding protein 2', 'Gene', '80328', (74, 96))	('increased', 'PosReg', (171, 180))	('increased', 'PosReg', (216, 225))
46798	31731729	Also, overexpression of IL-18 in a mouse model of malignant melanoma has been shown to increase tumor cell apoptosis, inhibit tumor growth, reduce lung metastasis, and inhibit angiogenesis, implying that IL-18 shows systemically a significant anti-cancer effect in the body.	('apoptosis', 'biological_process', 'GO:0006915', ('107', '116'))	('IL-18', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('increase', 'PosReg', (87, 95))	('overexpression', 'Var', (6, 20))	('malignant melanoma', 'Phenotype', 'HP:0002861', (50, 68))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('angiogenesis', 'CPA', (176, 188))	('malignant melanoma', 'Disease', 'MESH:D008545', (50, 68))	('inhibit', 'NegReg', (118, 125))	('cancer', 'Disease', (248, 254))	('IL-18', 'molecular_function', 'GO:0045515', ('24', '29'))	('reduce', 'NegReg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung metastasis', 'CPA', (147, 162))	('angiogenesis', 'biological_process', 'GO:0001525', ('176', '188'))	('IL-18', 'molecular_function', 'GO:0045515', ('204', '209'))	('tumor', 'Disease', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', (126, 131))	('malignant melanoma', 'Disease', (50, 68))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('inhibit', 'NegReg', (168, 175))	('apoptosis', 'biological_process', 'GO:0097194', ('107', '116'))
46820	31731729	As such, this study provided the first clinical significance that IL18 expression could be a good prognostic factor in patients with SKCM via inducing immune cell infiltration; however, there are some limitations.	('IL18', 'molecular_function', 'GO:0045515', ('66', '70'))	('IL18', 'Gene', '3606', (66, 70))	('inducing', 'Reg', (142, 150))	('expression', 'Var', (71, 81))	('patients', 'Species', '9606', (119, 127))	('SKCM', 'Disease', (133, 137))	('immune cell infiltration', 'CPA', (151, 175))	('IL18', 'Gene', (66, 70))
46842	31394860	An abnormal expression of HLA Class I may influence cytotoxic T lymphocyte (CTL) as well as Natural Killer (NK) cell responses.	('abnormal', 'Var', (3, 11))	('HLA', 'Gene', '3123', (26, 29))	('HLA', 'Gene', (26, 29))	('influence', 'Reg', (42, 51))	('expression', 'MPA', (12, 22))
46925	31394860	Later, van Essen not only analyzed peptide-loading components but also some other regulators of expression, and (similarly) found significant associations between the presence of TAP1 and TAP2 and expression of HLA Class I, HLA Class II and B2M.	('TAP1', 'Gene', (179, 183))	('HLA', 'Gene', (211, 214))	('associations', 'Interaction', (142, 154))	('B2M', 'Gene', (241, 244))	('TAP1', 'Gene', '6890', (179, 183))	('TAP2', 'Gene', (188, 192))	('B2M', 'Gene', '567', (241, 244))	('TAP2', 'Gene', '6891', (188, 192))	('presence', 'Var', (167, 175))	('HLA', 'Gene', '3123', (224, 227))	('HLA', 'Gene', (224, 227))	('expression', 'MPA', (197, 207))	('HLA', 'Gene', '3123', (211, 214))
46956	31394860	While the first study on the relation between HLA type and prognosis showed an association between the presence of HLA-B40 and the development of metastases, the later study by Maat in 2006 did not reproduce this, but rather found an association between B44 and a worse survival.	('presence', 'Var', (103, 111))	('metastases', 'Disease', (146, 156))	('worse survival', 'CPA', (264, 278))	('HLA', 'Gene', (115, 118))	('HLA', 'Gene', (46, 49))	('HLA-B', 'Gene', (115, 120))	('association', 'Interaction', (79, 90))	('HLA-B', 'Gene', '3106', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('HLA', 'Gene', '3123', (115, 118))	('HLA', 'Gene', '3123', (46, 49))
46959	31394860	Almost all M3 tumors also show gain in chromosome 8q, while this aberration can also be present in Disomy 3 (D3) tumors.	('M3 tumors', 'Disease', 'MESH:D015473', (11, 20))	('tumors', 'Disease', (113, 119))	('chromosome', 'Var', (39, 49))	('M3 tumors', 'Disease', (11, 20))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('gain', 'PosReg', (31, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Disomy 3', 'Disease', (99, 107))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
46964	31394860	investigated putative associations between copy numbers of multiple chromosomes and HLA expression.	('HLA', 'Gene', (84, 87))	('expression', 'MPA', (88, 98))	('HLA', 'Gene', '3123', (84, 87))	('copy', 'Var', (43, 47))
46965	31394860	Half of the studied UM showed M3 according to Single Nucleotide Polymorphism (SNP) analysis, which was associated with death due to metastasis (Kaplan-Meier, p < 0.001).	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('associated with', 'Reg', (103, 118))	('Single Nucleotide Polymorphism', 'Var', (46, 76))	('UM', 'Phenotype', 'HP:0007716', (20, 22))
47020	31394860	Jumonji domain containing protein 2 (JARID2) knockdown resulted in elevated levels of CIITA mRNA upon IFNgamma stimulation, suggesting that JARID2 is an inhibitor of HLA Class II activation.	('JARID2', 'Gene', (140, 146))	('HLA', 'Gene', '3123', (166, 169))	('HLA', 'Gene', (166, 169))	('elevated', 'PosReg', (67, 75))	('JARID2', 'Gene', '3720', (37, 43))	('JARID2', 'Gene', '3720', (140, 146))	('CIITA', 'Gene', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('CIITA', 'Gene', '4261', (86, 91))	('JARID2', 'Gene', (37, 43))	('knockdown', 'Var', (45, 54))
47051	31394860	It would be interesting to see whether induction of IDO could serve as a potential mechanism to downregulate HLA Class I and lower the tumor cell's metastatic potential in UM.	('IDO', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('metastatic potential', 'CPA', (148, 168))	('HLA', 'Gene', '3123', (109, 112))	('IDO', 'molecular_function', 'GO:0033754', ('52', '55'))	('tumor', 'Disease', (135, 140))	('HLA', 'Gene', (109, 112))	('IDO', 'molecular_function', 'GO:0047719', ('52', '55'))	('downregulate', 'NegReg', (96, 108))	('IDO', 'Gene', '3620', (52, 55))	('lower', 'NegReg', (125, 130))	('induction', 'Var', (39, 48))	('UM', 'Phenotype', 'HP:0007716', (172, 174))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
47065	31394860	Several studies have been performed on the role of HLA in UM and all confirm that a high HLA Class I expression is associated with a bad prognosis, in contrast to the situation in many other malignancies.	('UM', 'Phenotype', 'HP:0007716', (58, 60))	('high', 'Var', (84, 88))	('HLA', 'Gene', '3123', (89, 92))	('HLA', 'Gene', (89, 92))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('HLA', 'Gene', '3123', (51, 54))	('expression', 'MPA', (101, 111))	('malignancies', 'Disease', (191, 203))	('HLA', 'Gene', (51, 54))
47068	31394860	Epigenetic modifications influence expression, and loss of expression of the ubiquitin protease BAP1 is associated with an increased expression of HLA Class I antigens.	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('loss of', 'NegReg', (51, 58))	('BAP1', 'Gene', (96, 100))	('HLA', 'Gene', '3123', (147, 150))	('expression', 'MPA', (35, 45))	('expression', 'MPA', (59, 69))	('HLA', 'Gene', (147, 150))	('influence', 'Reg', (25, 34))	('Epigenetic modifications', 'Var', (0, 24))	('ubiquitin', 'molecular_function', 'GO:0031386', ('77', '86'))	('BAP1', 'Gene', '8314', (96, 100))
47082	21343931	Depletion of ARMS inhibited migration, invasion, and metastatic potential of melanoma cells in vitro and in vivo.	('migration', 'CPA', (28, 37))	('invasion', 'CPA', (39, 47))	('ARMS', 'Gene', '57498', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('Depletion', 'Var', (0, 9))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('inhibited', 'NegReg', (18, 27))	('Depletion of ARMS', 'Phenotype', 'HP:0100558', (0, 17))	('ARMS', 'Gene', (13, 17))
47108	21343931	The specific sequence for paired RNA oligonucleotides contained nucleotides 4271-4289 for ARMS-RNAi-1 and 4840-4858 for ARMS-siRNA-2 in mouse ARMS (accession number: AK122478).	('ARMS', 'Gene', '57498', (90, 94))	('ARMS', 'Gene', (142, 146))	('oligonucleotides', 'Chemical', 'MESH:D009841', (37, 53))	('ARMS', 'Gene', '57498', (120, 124))	('ARMS', 'Gene', (90, 94))	('4840-4858', 'Var', (106, 115))	('RNAi', 'biological_process', 'GO:0016246', ('95', '99'))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))	('ARMS', 'Gene', '57498', (142, 146))	('ARMS', 'Gene', (120, 124))	('mouse', 'Species', '10090', (136, 141))
47177	21343931	Knockdown of ARMS also decreased invasion capacity of A2058 (mean+-s.d.	('Knockdown', 'Var', (0, 9))	('ARMS', 'Gene', '57498', (13, 17))	('invasion capacity', 'CPA', (33, 50))	('ARMS', 'Gene', (13, 17))	('decreased', 'NegReg', (23, 32))
47181	21343931	These results suggest that knockdown of ARMS significantly decreases the migratory and invasive potential of human A2058, A375, and murine B16-F10 melanoma cells.	('knockdown', 'Var', (27, 36))	('murine', 'Species', '10090', (132, 138))	('decreases', 'NegReg', (59, 68))	('ARMS', 'Gene', '57498', (40, 44))	('A375', 'CellLine', 'CVCL:0132', (122, 126))	('human', 'Species', '9606', (109, 114))	('invasive potential', 'CPA', (87, 105))	('ARMS', 'Gene', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('migratory', 'CPA', (73, 82))	('B16-F10', 'CellLine', 'CVCL:0159', (139, 146))
47184	21343931	Second, treatment of B16-F10 control cells with a MEK-specific inhibitor PD98059 resulted in a significant decrease in migratory and invasive ability similar to that in ARMS-RNAi cells (Figures 3F and G).	('PD98059', 'Chemical', 'MESH:C093973', (73, 80))	('B16-F10', 'CellLine', 'CVCL:0159', (21, 28))	('RNAi', 'biological_process', 'GO:0016246', ('174', '178'))	('PD98059', 'Var', (73, 80))	('ARMS', 'Gene', (169, 173))	('decrease', 'NegReg', (107, 115))	('men', 'Species', '9606', (13, 16))	('ARMS', 'Gene', '57498', (169, 173))
47185	21343931	Third, treatment of ARMS-RNAi cells with PD98059 further inhibited cell migration and invasion in comparison with vehicle-treated ARMS-RNAi cells (Figures 3F and G).	('ARMS', 'Gene', (20, 24))	('PD98059', 'Var', (41, 48))	('inhibited', 'NegReg', (57, 66))	('ARMS', 'Gene', '57498', (130, 134))	('men', 'Species', '9606', (12, 15))	('ARMS', 'Gene', '57498', (20, 24))	('RNAi', 'biological_process', 'GO:0016246', ('135', '139'))	('PD98059', 'Chemical', 'MESH:C093973', (41, 48))	('cell migration', 'CPA', (67, 81))	('ARMS', 'Gene', (130, 134))	('cell migration', 'biological_process', 'GO:0016477', ('67', '81'))	('RNAi', 'biological_process', 'GO:0016246', ('25', '29'))
47199	21343931	We provide evidence that ARMS-mediated migratory and invasive abilities depend on the activated MEK/ERK signalling pathway, because constitutively active MEK reverts the compromised migratory and invasive activities caused by ARMS depletion and MEK1 inhibitor PD98059 leads to decreased migratory and invasive potential in melanoma cells.	('PD98059', 'Var', (260, 267))	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('ARMS', 'Gene', (25, 29))	('PD98059', 'Chemical', 'MESH:C093973', (260, 267))	('melanoma', 'Disease', 'MESH:D008545', (323, 331))	('MEK1', 'Gene', (245, 249))	('MEK1', 'molecular_function', 'GO:0004708', ('245', '249'))	('ARMS', 'Gene', '57498', (25, 29))	('ARMS', 'Gene', '57498', (226, 230))	('ARMS', 'Gene', (226, 230))	('melanoma', 'Phenotype', 'HP:0002861', (323, 331))	('signalling pathway', 'biological_process', 'GO:0007165', ('104', '122'))	('ERK', 'Gene', '5594', (100, 103))	('ERK', 'Gene', (100, 103))	('decreased', 'NegReg', (277, 286))	('MEK1', 'Gene', '5604', (245, 249))	('melanoma', 'Disease', (323, 331))
47213	32756500	High co-expression of CD163 and LAG-3 was associated with poor clinicopathological indexes of melanoma and worse survival compared to the high expression of the single markers.	('High', 'Var', (0, 4))	('CD163', 'Gene', (22, 27))	('LAG-3', 'Gene', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))
47223	32756500	Colon cancer TAMs from both mouse model and human specimens express PD-1, and high levels of PD-1 have been shown to inhibit phagocytosis and tumor immunity.	('human', 'Species', '9606', (44, 49))	('PD-1', 'Gene', (68, 72))	('TAMs', 'Chemical', '-', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('mouse', 'Species', '10090', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (142, 147))	('Colon cancer', 'Disease', (0, 12))	('phagocytosis', 'biological_process', 'GO:0006909', ('125', '137'))	('phagocytosis', 'CPA', (125, 137))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('PD-1', 'Var', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('inhibit', 'NegReg', (117, 124))
47225	32756500	In the context of melanoma, it was reported that CD163-positive TAMs can suppress antitumor immunity in anti-PD-1-resistant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('suppress', 'NegReg', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Disease', (124, 132))	('CD163-positive', 'Var', (49, 63))	('PD-1-resistant melanoma', 'Disease', (109, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('PD-1-resistant melanoma', 'Disease', 'MESH:D010300', (109, 132))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('melanoma', 'Disease', (18, 26))	('TAMs', 'Chemical', '-', (64, 68))
47249	32756500	The mean OS was significantly poorer in patients with high expression of both CD163 and PD-1 (CD163highPD-1high) (57.57 months; 95% CI, 48.49-66.66 months) compared with non-CD163highPD-1high (71.16 months; 95% CI, 63.49-78.82 months) (p = 0.037, Figure 2A) (Table 3).	('poorer', 'NegReg', (30, 36))	('high expression', 'Var', (54, 69))	('CD163', 'Gene', (78, 83))	('patients', 'Species', '9606', (40, 48))	('CD163highPD-1high', 'Var', (94, 111))	('PD-1', 'Gene', (88, 92))
47250	32756500	Patients with either high expression of CD163 or PD-1 showed inferior mean OS (68.17 months; 95% CI, 57.36-78.98 months) than those with low expression of both CD163 and PD-1 (CD163 lowPD-1low) (70.94 months; 95% CI, 61.78-80.10 months) (p = 0.036, Figure 2B).	('inferior mean OS', 'Disease', (61, 77))	('PD-1', 'Gene', (49, 53))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (21, 36))	('inferior mean OS', 'Disease', 'MESH:C567932', (61, 77))	('CD163', 'Var', (40, 45))
47251	32756500	Patients with either high expression of CD163 or LAG-3 revealed inferior mean OS (70.35 months; 95% CI, 57.80-82.89 months) than those with low expression of both CD163 and LAG-3 (CD163lowLAG-3low) with a marginal statistical significance (68.53 months; 95% CI, 60.20-76.85 months) (p = 0.064).	('inferior mean OS', 'Disease', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (21, 36))	('inferior mean OS', 'Disease', 'MESH:C567932', (64, 80))	('LAG-3', 'Gene', (49, 54))	('CD163', 'Var', (40, 45))
47252	32756500	PFS was also significantly worse in patients with high expression of both CD163 and PD-1 (p = 0.031, Figure 2D).	('high expression', 'Var', (50, 65))	('worse', 'NegReg', (27, 32))	('patients', 'Species', '9606', (36, 44))	('PFS', 'MPA', (0, 3))	('PD-1', 'Gene', (84, 88))	('CD163', 'Gene', (74, 79))
47253	32756500	PFS was inferior in patients with either high expression of CD163 or LAG-3 than those with low expression of both CD163 and LAG-3 (CD163lowLAG-3low) (p = 0.044, Figure 2F).	('high expression', 'Var', (41, 56))	('PFS', 'CPA', (0, 3))	('patients', 'Species', '9606', (20, 28))	('CD163', 'Var', (60, 65))	('inferior', 'NegReg', (8, 16))	('LAG-3', 'Gene', (69, 74))
47257	32756500	First, CD163-positive TAMs could affect the tumor-infiltrating lymphocytes (TILs) in TME.	('affect', 'Reg', (33, 39))	('TIL', 'Gene', '7096', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TIL', 'Gene', (76, 79))	('CD163-positive', 'Var', (7, 21))	('tumor', 'Disease', (44, 49))	('TAMs', 'Chemical', '-', (22, 26))
47259	32756500	In colorectal cancers, high expression of CD163 on TAMs was found in TME, resulting in an increased number of CD4+ lymphocytes that contributed to up-regulate the PD-1 expression.	('colorectal cancers', 'Disease', 'MESH:D015179', (3, 21))	('up-regulate', 'PosReg', (147, 158))	('expression', 'MPA', (168, 178))	('TAMs', 'Chemical', '-', (51, 55))	('increased', 'PosReg', (90, 99))	('CD4', 'Gene', (110, 113))	('CD163', 'Var', (42, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancers', 'Disease', (3, 21))	('CD4', 'Gene', '920', (110, 113))	('PD-1', 'Gene', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
47264	32756500	In a study focused on melanoma, CD163-positive M2-TAMs could block the recruitment of antitumor CD8+ T cells.	('recruitment', 'MPA', (71, 82))	('tumor', 'Disease', (90, 95))	('CD8', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('CD163-positive', 'Var', (32, 46))	('M2-TAMs', 'Gene', (47, 54))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Disease', (22, 30))	('M2-TAMs', 'Chemical', '-', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('CD8', 'Gene', '925', (96, 99))	('block', 'NegReg', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
47266	32756500	In our previous study, high CD163 expression was associated with lower OS, suggesting the prognostic significance of CD163 expression in cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 155))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('lower OS', 'Disease', (65, 73))	('CD163', 'Gene', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('cutaneous melanoma', 'Disease', (137, 155))
47295	32756500	Concurrent high expression of both CD163 and PD-1 (CD163highPD-1high) or LAG-3 (CD163highLAG-3high) in melanoma were independent poor prognostic factors.	('LAG-3', 'Gene', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('PD-1', 'Gene', (45, 49))	('CD163highPD-1high', 'Var', (51, 68))	('high expression', 'PosReg', (11, 26))	('CD163highLAG-3high', 'Var', (80, 98))	('CD163', 'Gene', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
47302	32083130	BRAF mutations were more frequently identified in melanomas without chromic sun-induced damage (non-CSD), while RAS mutations were more likely observed in acral melanomas.	('acral melanomas', 'Disease', (155, 170))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('BRAF', 'Gene', '673', (0, 4))	('observed', 'Reg', (143, 151))	('CSD', 'Gene', '7045', (100, 103))	('melanomas', 'Disease', 'MESH:D008545', (161, 170))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (50, 59))	('acral melanoma', 'Phenotype', 'HP:0012060', (155, 169))	('melanomas', 'Disease', (161, 170))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('mutations', 'Var', (5, 14))	('acral melanomas', 'Disease', 'MESH:D008545', (155, 170))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('acral melanomas', 'Phenotype', 'HP:0012060', (155, 170))	('CSD', 'Gene', (100, 103))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('identified', 'Reg', (36, 46))
47304	32083130	BRAF, RAS, and NF1 mutations were significantly associated with lymph node metastasis or presence of ulceration, implying that these cancer driver genes were independent prognostic factors.	('RAS', 'Gene', (6, 9))	('NF1', 'Gene', (15, 18))	('associated', 'Reg', (48, 58))	('NF1', 'Gene', '4763', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('lymph node metastasis', 'CPA', (64, 85))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', (133, 139))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
47313	32083130	For example, while BRAF gene mutation is one of the most frequently mutated genes in European and American populations (above 40%), only about 25% of Asian patients harbored BRAF alterations.	('patients', 'Species', '9606', (156, 164))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (174, 178))	('alterations', 'Var', (179, 190))
47316	32083130	About 45% of melanomas have been attributed to germline mutation of predisposition gene CDKN2A, and 2-3% melanomas mutated in gene CDK4 in European and American populations.	('CDKN2A', 'Gene', (88, 94))	('CDK4', 'Gene', (131, 135))	('melanomas', 'Disease', (105, 114))	('CDK4', 'Gene', '1019', (131, 135))	('CDKN2A', 'Gene', '1029', (88, 94))	('melanomas', 'Disease', (13, 22))	('germline mutation', 'Var', (47, 64))	('mutated', 'Var', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('CDK', 'molecular_function', 'GO:0004693', ('131', '134'))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
47318	32083130	Oncogenomic studies indicate that somatic CNV of some genes is involved in melanoma progressions, such as mutated gene amplifications in CCND1, CDK4, and TERT, of which the CNV status also has been reported in Chinese melanomas.	('melanoma progressions', 'Disease', (75, 96))	('mutated gene amplifications', 'Var', (106, 133))	('CCND1', 'Gene', '595', (137, 142))	('TERT', 'Gene', (154, 158))	('involved', 'Reg', (63, 71))	('melanomas', 'Disease', 'MESH:D008545', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanomas', 'Phenotype', 'HP:0002861', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma progressions', 'Disease', 'MESH:D008545', (75, 96))	('CDK4', 'Gene', (144, 148))	('TERT', 'Gene', '7015', (154, 158))	('CCND1', 'Gene', (137, 142))	('CDK', 'molecular_function', 'GO:0004693', ('144', '147'))	('CDK4', 'Gene', '1019', (144, 148))	('melanomas', 'Disease', (218, 227))
47319	32083130	Accurate classification of the spectra of mutational changes in melanoma may facilitate the development of disease-associated biomarkers.	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('mutational changes', 'Var', (42, 60))	('melanoma', 'Disease', (64, 72))
47322	32083130	In melanoma, ERK activation is most commonly due to the mutations of BRAF, followed by RAS, NF1, and other genes.	('mutations', 'Var', (56, 65))	('due', 'Reg', (45, 48))	('ERK', 'Gene', '5594', (13, 16))	('ERK', 'molecular_function', 'GO:0004707', ('13', '16'))	('NF1', 'Gene', (92, 95))	('activation', 'PosReg', (17, 27))	('NF1', 'Gene', '4763', (92, 95))	('BRAF', 'Gene', '673', (69, 73))	('ERK', 'Gene', (13, 16))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('BRAF', 'Gene', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
47323	32083130	In the Triple-WT subtype, alterations in genes such as KIT, FDGFRA, KDR, GNAQ, and GNA11 play an important role in melanoma carcinogenesis.	('KIT', 'Gene', (55, 58))	('melanoma carcinogenesis', 'Disease', 'MESH:D063646', (115, 138))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('KIT', 'Gene', '3815', (55, 58))	('FDGFRA', 'Gene', (60, 66))	('KDR', 'Gene', '3791', (68, 71))	('alterations', 'Var', (26, 37))	('GNAQ', 'Gene', (73, 77))	('GNA11', 'Gene', (83, 88))	('melanoma carcinogenesis', 'Disease', (115, 138))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('GNA11', 'Gene', '2767', (83, 88))	('KDR', 'Gene', (68, 71))
47324	32083130	The mutated or amplified genes of KIT, FDGFRA, and KDR, encoding a receptor tyrosine kinase (RTK) of the cell membrane, may activate the downstream signaling pathways in both ERK and PI3K.	('mutated', 'Var', (4, 11))	('KDR', 'Gene', (51, 54))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('ERK', 'molecular_function', 'GO:0004707', ('175', '178'))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('downstream signaling pathways', 'Pathway', (137, 166))	('activate', 'PosReg', (124, 132))	('ERK', 'Gene', '5594', (175, 178))	('cell membrane', 'cellular_component', 'GO:0005886', ('105', '118'))	('KIT', 'Gene', '3815', (34, 37))	('KDR', 'Gene', '3791', (51, 54))	('ERK', 'Gene', (175, 178))	('KIT', 'Gene', (34, 37))	('FDGFRA', 'Gene', (39, 45))
47334	32083130	SNV (single nucleotide various), InDel, CNV, and gene fusion can be detected with the pipeline of this detection kit.	('CNV', 'Var', (40, 43))	('InDel', 'Var', (33, 38))	('gene fusion', 'Var', (49, 60))	('kit', 'Gene', (113, 116))	('kit', 'Gene', '3815', (113, 116))
47336	32083130	Germline mutations were defined as follows: mutations found in both tumor and control DNA and/or mutations with a relatively high mutant allele frequency (MAF > 20%) and unconfirmed as somatic mutation in COSMIC (Catalogue Of Somatic Mutations In Cancer) database.	('tumor', 'Disease', (68, 73))	('mutations', 'Var', (97, 106))	('Cancer', 'Phenotype', 'HP:0002664', (247, 253))	('MAF', 'Gene', '4094', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutations', 'Var', (44, 53))	('MAF', 'Gene', (155, 158))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutant', 'Var', (130, 136))
47342	32083130	The specimen with most mutations harbored a gene alteration (T230M) in the SEMA domain of the MET gene, which mutated only in this melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (23, 32))	('MET', 'Gene', (94, 97))	('T230M', 'Mutation', 'rs920551872', (61, 66))	('T230M', 'Var', (61, 66))
47346	32083130	The top gene variations were BRAF V600E (20.5%), NRAS Q61R (12.8%), RAD50 L580X (12.8%), TERT promoter (12.8%), and MSH6 T1085X (10.3%).	('BRAF', 'Gene', '673', (29, 33))	('NRAS', 'Gene', '4893', (49, 53))	('RAD50', 'Gene', (68, 73))	('MSH6', 'Gene', '2956', (116, 120))	('BRAF', 'Gene', (29, 33))	('Q61R', 'Mutation', 'rs11554290', (54, 58))	('T1085X', 'Mutation', 'p.T1085X', (121, 127))	('TERT', 'Gene', (89, 93))	('T1085X', 'Var', (121, 127))	('TERT', 'Gene', '7015', (89, 93))	('L580X', 'Mutation', 'p.L580X', (74, 79))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('L580X', 'Var', (74, 79))	('NRAS', 'Gene', (49, 53))	('MSH6', 'Gene', (116, 120))	('RAD', 'biological_process', 'GO:1990116', ('68', '71'))
47347	32083130	More mutations were observed in tumors from female patients (p < 0.001).	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
47353	32083130	RAS gene mutated in 7 melanomas (7/39, 17.9%, 4 primary lesions; 3 metastatic lesions) from 5 patients.	('RAS', 'Gene', (0, 3))	('patients', 'Species', '9606', (94, 102))	('melanomas', 'Disease', (22, 31))	('mutated', 'Var', (9, 16))	('melanomas', 'Disease', 'MESH:D008545', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))
47354	32083130	NF1 variants were observed in 4 samples (4/39, 10.3%, 3 primary lesions; 1 metastatic lesion) from 3 patients.	('patients', 'Species', '9606', (101, 109))	('variants', 'Var', (4, 12))	('NF1', 'Gene', (0, 3))	('observed', 'Reg', (18, 26))	('NF1', 'Gene', '4763', (0, 3))
47357	32083130	In our study, CCND1 (13/39, 33.3%), MYC (9/39, 23.1%), and TERT (8/39, 20.5%) were the most common genes with CNV amplifications.	('MYC', 'Gene', '4609', (36, 39))	('CCND1', 'Gene', '595', (14, 19))	('TERT', 'Gene', (59, 63))	('TERT', 'Gene', '7015', (59, 63))	('MYC', 'Gene', (36, 39))	('amplifications', 'Var', (114, 128))	('CCND1', 'Gene', (14, 19))
47359	32083130	More CNV amplifications were detected in the non-CSD melanomas compared with those in acral melanomas (Table 1, p=0.004).	('melanomas', 'Disease', (92, 101))	('melanomas', 'Disease', (53, 62))	('acral melanomas', 'Disease', (86, 101))	('acral melanomas', 'Phenotype', 'HP:0012060', (86, 101))	('CNV', 'Var', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('CSD', 'Gene', (49, 52))	('acral melanomas', 'Disease', 'MESH:D008545', (86, 101))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('melanomas', 'Disease', 'MESH:D008545', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('CSD', 'Gene', '7045', (49, 52))	('acral melanoma', 'Phenotype', 'HP:0012060', (86, 100))
47362	32083130	One sample classified in the RAS group with BRAF mutation was observed in acral melanoma (1/20, 5%).	('acral melanoma', 'Disease', 'MESH:D008545', (74, 88))	('BRAF', 'Gene', '673', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', (44, 48))	('mutation', 'Var', (49, 57))	('acral melanoma', 'Phenotype', 'HP:0012060', (74, 88))	('acral melanoma', 'Disease', (74, 88))
47364	32083130	All the 7 samples with RAS mutation were observed in acral melanoma (7/20, 35%).	('acral melanoma', 'Disease', (53, 67))	('acral melanoma', 'Phenotype', 'HP:0012060', (53, 67))	('mutation', 'Var', (27, 35))	('observed', 'Reg', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('RAS', 'Gene', (23, 26))	('acral melanoma', 'Disease', 'MESH:D008545', (53, 67))
47365	32083130	Patients with lymph node metastasis and/or ulceration had 6 RAS mutations, which was more than those without lymph node metastasis or ulceration (only one RAS mutation) (yellow dots in Figure 2).	('Patients', 'Species', '9606', (0, 8))	('RAS', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))
47366	32083130	All the NF1 mutations were observed in patients with ulceration (p=0.008, black dots in Figure 2).	('NF1', 'Gene', (8, 11))	('patients', 'Species', '9606', (39, 47))	('NF1', 'Gene', '4763', (8, 11))	('mutations', 'Var', (12, 21))	('observed', 'Reg', (27, 35))	('ulceration', 'Disease', (53, 63))
47367	32083130	No interaction was revealed between Triple-WT mutations with tumor location, lymph node metastasis, and ulceration (blue dots in Figure 2 except one without pathological information).	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
47369	32083130	Those mutations may be defined as a driver mutation in cancer tissues, which tend to be stable in metastases during the malignant process to maintain malignant phenotype as reported in literature.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('metastases', 'Disease', (98, 108))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (55, 61))
47372	32083130	Germline mutations in the gene CDKN2A have been found in about 40% melanoma families and CDK4 alterations in 2-3% families.	('Germline mutations', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('CDK4', 'Gene', (89, 93))	('found', 'Reg', (48, 53))	('CDKN2A', 'Gene', (31, 37))	('CDK', 'molecular_function', 'GO:0004693', ('89', '92'))	('CDK4', 'Gene', '1019', (89, 93))	('CDKN2A', 'Gene', '1029', (31, 37))
47377	32083130	A pathogenic gene alteration T230M was identified in the SEMA domain of the MET gene, which was reported in a sample of head and neck squamous cell carcinoma.	('alteration T230M', 'Var', (18, 34))	('neck', 'cellular_component', 'GO:0044326', ('129', '133'))	('pathogenic', 'Reg', (2, 12))	('head', 'Disease', (120, 124))	('T230M', 'Mutation', 'rs920551872', (29, 34))	('MET', 'Gene', (76, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (120, 157))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (129, 157))	('neck squamous cell carcinoma', 'Disease', (129, 157))	('T230M', 'Var', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
47378	32083130	Previous reports suggest that mutations in the SEMA domain could activate the MET signal, which will promote tumor progress and more gene alterations.	('promote', 'PosReg', (101, 108))	('gene alterations', 'MPA', (133, 149))	('activate', 'PosReg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MET signal', 'MPA', (78, 88))	('tumor', 'Disease', (109, 114))
47388	32083130	Within the Triple-WT group, KIT took the most frequent mutations and assumed to be an important oncogene like other studies.	('KIT', 'Gene', '3815', (28, 31))	('KIT', 'Gene', (28, 31))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mutations', 'Var', (55, 64))
47393	32083130	All of the melanomas in BRAF subtypes were observed in non-CSD cutaneous melanomas, which confirmed the conclusion of previous studies that highly prevalent of BRAF changes melanomas on skin intermittently exposure to ultraviolet (UV) irradiation, while BRAF mutations are rare on other skins including acral skin.	('melanomas', 'Disease', (173, 182))	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('CSD', 'Gene', (59, 62))	('changes', 'Var', (165, 172))	('BRAF', 'Gene', '673', (254, 258))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (254, 258))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (63, 82))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (63, 82))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('melanomas', 'Disease', (73, 82))	('CSD', 'Gene', '7045', (59, 62))	('melanomas', 'Disease', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cutaneous melanomas', 'Disease', (63, 82))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas on skin', 'Phenotype', 'HP:0002861', (173, 190))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('melanomas', 'Disease', 'MESH:D008545', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
47394	32083130	The frequency of BRAF mutations (61.1%) in non-CSD cutaneous melanomas was similar to those described in other publications as 55.2-66.7% in non-CSD.	('CSD', 'Gene', (47, 50))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (51, 70))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (51, 70))	('CSD', 'Gene', '7045', (47, 50))	('CSD', 'Gene', (145, 148))	('BRAF', 'Gene', '673', (17, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', (17, 21))	('cutaneous melanomas', 'Disease', (51, 70))	('mutations', 'Var', (22, 31))	('CSD', 'Gene', '7045', (145, 148))
47395	32083130	However, only one acral melanoma (5%) was observed in a non-V600E BRAF mutation, which was less than that (8.9-30%) in other cohorts.	('acral melanoma', 'Phenotype', 'HP:0012060', (18, 32))	('acral melanoma', 'Disease', (18, 32))	('non-V600E', 'Var', (56, 65))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('acral melanoma', 'Disease', 'MESH:D008545', (18, 32))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('BRAF', 'Gene', (66, 70))
47396	32083130	The less frequency of BRAF mutation may be associated with the arising sites of the acral melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('acral melanomas', 'Disease', 'MESH:D008545', (84, 99))	('acral melanoma', 'Phenotype', 'HP:0012060', (84, 98))	('BRAF', 'Gene', '673', (22, 26))	('acral melanomas', 'Disease', (84, 99))	('mutation', 'Var', (27, 35))	('BRAF', 'Gene', (22, 26))	('acral melanomas', 'Phenotype', 'HP:0012060', (84, 99))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
47397	32083130	All the acral melanomas in our study were situated on palms and soles, on which lower frequency of BRAF mutations was demonstrated than that on dorsal acral sites.	('mutations', 'Var', (104, 113))	('acral melanoma', 'Phenotype', 'HP:0012060', (8, 22))	('acral melanomas', 'Disease', (8, 23))	('acral melanomas', 'Phenotype', 'HP:0012060', (8, 23))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('acral melanomas', 'Disease', 'MESH:D008545', (8, 23))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
47398	32083130	It is worth noting that the significance of BRAF mutation in melanomas is still a controversial issue.	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutation', 'Var', (49, 57))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanomas', 'Disease', (61, 70))
47399	32083130	On the one hand, BRAF mutations were identified in about 80% benign naevi of various histological types, implying a critical role in the initiation of melanoma.	('naevi', 'Phenotype', 'HP:0003764', (68, 73))	('BRAF', 'Gene', '673', (17, 21))	('benign naevi', 'Disease', (61, 73))	('BRAF', 'Gene', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mutations', 'Var', (22, 31))	('initiation of melanoma', 'Disease', 'MESH:D008545', (137, 159))	('initiation of melanoma', 'Disease', (137, 159))
47400	32083130	On the other hand, BRAF mutations were found more common in melanomas with advanced stages like vertical growth phase, lymph node metastasis, or ulceration, suggesting that BRAF mutations correlated more with melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanomas', 'Disease', 'MESH:D008545', (60, 69))	('mutations', 'Var', (24, 33))	('melanomas', 'Disease', (60, 69))	('ulceration', 'Disease', (145, 155))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (173, 177))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('BRAF', 'Gene', '673', (19, 23))	('vertical growth phase', 'CPA', (96, 117))	('BRAF', 'Gene', (19, 23))	('lymph', 'Disease', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('correlated', 'Reg', (188, 198))	('mutations', 'Var', (178, 187))
47401	32083130	All BRAF variants in our study were identified in patients with lymph node metastasis, which support the later statement that BRAF is important in progression rather than initiation of the melanoma.	('initiation of the melanoma', 'Disease', 'MESH:D008545', (171, 197))	('initiation of the melanoma', 'Disease', (171, 197))	('patients', 'Species', '9606', (50, 58))	('lymph node', 'Disease', (64, 74))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', '673', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('variants', 'Var', (9, 17))	('identified', 'Reg', (36, 46))
47402	32083130	Unlike BRAF, all RAS mutations have been identified in acral melanomas.	('mutations', 'Var', (21, 30))	('identified', 'Reg', (41, 51))	('RAS', 'Gene', (17, 20))	('acral melanomas', 'Phenotype', 'HP:0012060', (55, 70))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', '673', (7, 11))	('acral melanomas', 'Disease', 'MESH:D008545', (55, 70))	('BRAF', 'Gene', (7, 11))	('acral melanoma', 'Phenotype', 'HP:0012060', (55, 69))	('acral melanomas', 'Disease', (55, 70))
47403	32083130	A relative low frequency of RAS mutations in non-CSD melanoma was reported in other Asian studies as well (2.0% in mainland China, and 5% in Taiwan island).	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('RAS', 'Gene', (28, 31))	('melanoma', 'Disease', (53, 61))	('CSD', 'Gene', (49, 52))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('mutations', 'Var', (32, 41))	('CSD', 'Gene', '7045', (49, 52))
47404	32083130	Meanwhile, a higher frequency (22%) of RAS mutations in non-CSD melanoma was reported in a study based on patients worldwide.	('CSD', 'Gene', '7045', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (106, 114))	('RAS', 'Gene', (39, 42))	('CSD', 'Gene', (60, 63))
47406	32083130	In the acral melanomas, RAS mutated more frequently in our cohort (35%) than 8.8-28% reported previously.	('mutated', 'Var', (28, 35))	('RAS', 'Gene', (24, 27))	('acral melanomas', 'Disease', 'MESH:D008545', (7, 22))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('acral melanoma', 'Phenotype', 'HP:0012060', (7, 21))	('acral melanomas', 'Phenotype', 'HP:0012060', (7, 22))	('acral melanomas', 'Disease', (7, 22))
47407	32083130	As mentioned above, the palms and soles sites of the melanoma may contribute to the higher frequency, as higher frequencies of NRAS mutations were found in melanomas on the palms and soles rather than on the dorsal acral sites.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanomas', 'Phenotype', 'HP:0002861', (156, 165))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('mutations', 'Var', (132, 141))	('melanoma', 'Disease', (53, 61))	('melanomas', 'Disease', 'MESH:D008545', (156, 165))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('NRAS', 'Gene', (127, 131))	('melanomas', 'Disease', (156, 165))	('NRAS', 'Gene', '4893', (127, 131))
47409	32083130	Based on the correlations between the driver gene (NF1, BRAF, and RAS) alterations and clinical characterizations (ulceration, lymph node metastasis), patients harboring more mutations were prone to poor prognosis.	('BRAF', 'Gene', '673', (56, 60))	('patients', 'Species', '9606', (151, 159))	('alterations', 'Var', (71, 82))	('mutations', 'Var', (175, 184))	('NF1', 'Gene', (51, 54))	('NF1', 'Gene', '4763', (51, 54))	('BRAF', 'Gene', (56, 60))
47412	31024839	Dabrafenib and Trametinib in BRAF Mutant Metastatic Conjunctival Melanoma Conjunctival melanoma is a rare primary ocular tumor.	('BRAF', 'Gene', '673', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('ocular tumor', 'Disease', (114, 126))	('Conjunctival Melanoma Conjunctival melanoma', 'Phenotype', 'HP:0007716', (52, 95))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('BRAF', 'Gene', (29, 33))	('Conjunctival Melanoma', 'Disease', (52, 73))	('Trametinib', 'Chemical', 'MESH:C560077', (15, 25))	('Conjunctival Melanoma', 'Disease', 'MESH:D003229', (52, 73))	('ocular tumor', 'Phenotype', 'HP:0100012', (114, 126))	('Conjunctival melanoma', 'Phenotype', 'HP:0007716', (74, 95))	('Mutant', 'Var', (34, 40))	('Conjunctival melanoma', 'Disease', 'MESH:D003229', (74, 95))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('Conjunctival melanoma', 'Disease', (74, 95))	('ocular tumor', 'Disease', 'MESH:D009369', (114, 126))
47413	31024839	Similarly to cutaneous melanoma, up to 50% of conjunctival melanomas harbor BRAF mutations.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('harbor', 'Reg', (69, 75))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (46, 68))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (46, 67))	('conjunctival melanomas', 'Disease', (46, 68))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('mutations', 'Var', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('cutaneous melanoma', 'Disease', (13, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (13, 31))
47415	31024839	Combined therapy with BRAF and MEK inhibitors is approved for BRAF mutant cutaneous metastatic melanomas.	('melanomas', 'Disease', (95, 104))	('MEK', 'Gene', (31, 34))	('BRAF', 'Gene', '673', (22, 26))	('MEK', 'Gene', '5609', (31, 34))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('cutaneous metastatic melanomas', 'Phenotype', 'HP:0012056', (74, 104))	('BRAF', 'Gene', (22, 26))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('mutant', 'Var', (67, 73))	('BRAF', 'Gene', '673', (62, 66))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('BRAF', 'Gene', (62, 66))
47416	31024839	Herein, we report a case of a 70-years old patient with a metastatic conjunctival melanoma harboring V600E BRAF mutation successfully treated with dabrafenib and trametinib.	('BRAF', 'Gene', (107, 111))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('patient', 'Species', '9606', (43, 50))	('conjunctival melanoma', 'Disease', (69, 90))	('V600E', 'Var', (101, 106))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (69, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('trametinib', 'Chemical', 'MESH:C560077', (162, 172))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (69, 90))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('BRAF', 'Gene', '673', (107, 111))
47423	31024839	Around 40-50% of cutaneous melanomas harbor BRAF mutations, that appear at an early stage of tumor development.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (17, 36))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (17, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (17, 35))	('BRAF', 'Gene', '673', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', (44, 48))	('cutaneous melanomas', 'Disease', (17, 36))	('tumor', 'Disease', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
47424	31024839	In fact, activating BRAF mutations have a pro-oncogenic effect.	('mutations', 'Var', (25, 34))	('BRAF', 'Gene', '673', (20, 24))	('activating', 'PosReg', (9, 19))	('BRAF', 'Gene', (20, 24))	('pro-oncogenic effect', 'CPA', (42, 62))
47425	31024839	The most common mutation is represented by the substitution of a valine with glutamic acid in the codon 600 (V600E), that increases the catalytic activity of B-raf.	('valine with glutamic acid in the codon 600', 'Mutation', 'rs113488022', (65, 107))	('B-raf', 'Gene', (158, 163))	('substitution', 'Var', (47, 59))	('B-raf', 'Gene', '673', (158, 163))	('catalytic activity', 'MPA', (136, 154))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('catalytic activity', 'molecular_function', 'GO:0003824', ('136', '154'))	('increases', 'PosReg', (122, 131))	('V600E', 'Var', (109, 114))
47426	31024839	Conjunctival melanoma has not been completely characterized at the level of genetics, however, BRAF mutations have been reported in up to 50%, with V600E as the most frequent one (around 80-90%), followed by V600K.	('mutations', 'Var', (100, 109))	('Conjunctival melanoma', 'Disease', (0, 21))	('V600E', 'Mutation', 'rs113488022', (148, 153))	('BRAF', 'Gene', '673', (95, 99))	('V600E', 'Var', (148, 153))	('V600K', 'Var', (208, 213))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('BRAF', 'Gene', (95, 99))	('V600K', 'Mutation', 'rs121913227', (208, 213))	('Conjunctival melanoma', 'Phenotype', 'HP:0007716', (0, 21))	('Conjunctival melanoma', 'Disease', 'MESH:D003229', (0, 21))	('reported', 'Reg', (120, 128))
47429	31024839	Herein, we present a case of a patient with metastatic conjunctival melanoma harboring BRAF V600E mutation who was effectively treated with dabrafenib and trametinib.	('V600E', 'Mutation', 'rs113488022', (92, 97))	('conjunctival melanoma', 'Disease', (55, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('dabrafenib', 'Chemical', 'MESH:C561627', (140, 150))	('patient', 'Species', '9606', (31, 38))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (55, 76))	('trametinib', 'Chemical', 'MESH:C560077', (155, 165))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (55, 76))	('V600E', 'Var', (92, 97))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
47437	31024839	Codon 600 was also analyzed through Idylla  BRAF mutation test.	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))	('mutation', 'Var', (49, 57))
47446	31024839	Other cases of BRAF mutant conjunctival melanoma experienced a disease control with BRAF inhibition therapy (Table 1).	('BRAF', 'Gene', '673', (15, 19))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (15, 19))	('BRAF', 'Gene', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('conjunctival melanoma', 'Disease', (27, 48))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (27, 48))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (27, 48))	('mutant', 'Var', (20, 26))
47448	31024839	Indeed, we hypothesized that the target combination therapy could be the best option also for this BRAF mutant conjunctival melanoma patient.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('patient', 'Species', '9606', (133, 140))	('mutant', 'Var', (104, 110))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (111, 132))	('conjunctival melanoma', 'Disease', (111, 132))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (111, 132))
47465	31024839	Dabrafenib is a highly selective inhibitor of mutated BRAF and trametinib inhibits MEK1 and MEK2.	('MEK2', 'Gene', '5605', (92, 96))	('MEK2', 'Gene', (92, 96))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('mutated', 'Var', (46, 53))	('MEK1', 'molecular_function', 'GO:0004708', ('83', '87'))	('MEK1', 'Gene', '5604', (83, 87))	('trametinib', 'Chemical', 'MESH:C560077', (63, 73))	('inhibits', 'NegReg', (74, 82))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('MEK1', 'Gene', (83, 87))	('MEK2', 'molecular_function', 'GO:0004708', ('92', '96'))
47466	31024839	The combination of BRAF and MEK inhibitors shows response rates up to 70% with an improved survival in metastatic cutaneous melanoma harboring BRAF mutations of the codon 600.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('mutations', 'Var', (148, 157))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('survival', 'MPA', (91, 99))	('cutaneous melanoma', 'Disease', (114, 132))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('MEK', 'Gene', (28, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (114, 132))	('MEK', 'Gene', '5609', (28, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('improved', 'PosReg', (82, 90))
47468	31024839	It has been shown that activating BRAF mutations are detectable in up to 50% of conjunctival melanomas, of which about 80% are V600E, 15-20% V600K.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('V600E', 'Var', (127, 132))	('V600K', 'Var', (141, 146))	('V600K', 'Mutation', 'rs121913227', (141, 146))	('BRAF', 'Gene', '673', (34, 38))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (80, 101))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('BRAF', 'Gene', (34, 38))	('conjunctival melanomas', 'Disease', (80, 102))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (80, 102))	('activating', 'PosReg', (23, 33))
47469	31024839	In vitro, Vemurafenib and Dabrafenib inhibit the growth of BRAF-mutated conjunctival melanoma cell lines; MEK inhibitors also promote apoptosis of cell lines from conjunctival melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('apoptosis', 'CPA', (134, 143))	('conjunctival melanoma', 'Disease', (72, 93))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (163, 184))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (163, 184))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (10, 21))	('inhibitors', 'Var', (110, 120))	('MEK', 'Gene', '5609', (106, 109))	('inhibit', 'NegReg', (37, 44))	('promote', 'PosReg', (126, 133))	('Dabrafenib', 'Chemical', 'MESH:C561627', (26, 36))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (72, 93))	('growth', 'MPA', (49, 55))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('conjunctival melanoma', 'Disease', (163, 184))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (72, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('MEK', 'Gene', (106, 109))
47476	31024839	A third patient with a BRAF mutant pre-treated metastatic conjunctival melanoma benefitted from Vemurafenib with a partial response for about 4 months.	('mutant', 'Var', (28, 34))	('BRAF', 'Gene', '673', (23, 27))	('conjunctival melanoma', 'Disease', (58, 79))	('BRAF', 'Gene', (23, 27))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (58, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('pre', 'molecular_function', 'GO:0003904', ('35', '38'))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (96, 107))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (58, 79))	('patient', 'Species', '9606', (8, 15))	('benefitted', 'PosReg', (80, 90))
47478	31024839	Another patient with pre-treated metastatic conjunctival melanoma expressing BRAF mutation developed a partial response for over 6 months of therapy with the BRAF inhibitor Dabrafenib.	('Dabrafenib', 'Chemical', 'MESH:C561627', (173, 183))	('conjunctival melanoma', 'Disease', (44, 65))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (44, 65))	('mutation', 'Var', (82, 90))	('BRAF', 'Gene', '673', (77, 81))	('pre', 'molecular_function', 'GO:0003904', ('21', '24'))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (44, 65))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', '673', (158, 162))	('patient', 'Species', '9606', (8, 15))	('BRAF', 'Gene', (158, 162))
47484	31024839	In advanced cutaneous melanoma, the combined inhibition of BRAF/MEK in case of BRAF mutation is effective.	('MEK', 'Gene', (64, 67))	('MEK', 'Gene', '5609', (64, 67))	('cutaneous melanoma', 'Disease', (12, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (12, 30))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (12, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
47510	20426858	The differential distribution of genetic alterations in BRAF, NRAS and KIT among melanoma subtypes according to anatomic sites and sun exposure strongly implicated different molecular pathways involved in tumorigenesis for each subtype (Antonescu et al, 2007).	('NRAS', 'Gene', '4893', (62, 66))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('implicated', 'Reg', (153, 163))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('BRAF', 'Gene', '673', (56, 60))	('KIT', 'Gene', (71, 74))	('genetic alterations', 'Var', (33, 52))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('NRAS', 'Gene', (62, 66))	('BRAF', 'Gene', (56, 60))
47511	20426858	KIT mutations were detected in 21% of mucosal melanomas, 11% of acral melanomas, and 16.7% of melanomas arising in chronically sun-damaged skin as indicated by the presence of solar elastosis (Antonescu et al, 2007).	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('mucosal melanomas', 'Disease', (38, 55))	('sun-damaged', 'Phenotype', 'HP:0000992', (127, 138))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('acral melanomas', 'Disease', 'MESH:D008545', (64, 79))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('detected', 'Reg', (19, 27))	('acral melanomas', 'Phenotype', 'HP:0012060', (64, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('acral melanomas', 'Disease', (64, 79))	('melanomas', 'Disease', (46, 55))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('solar elastosis', 'Disease', (176, 191))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanomas', 'Disease', (70, 79))	('melanomas', 'Disease', (94, 103))	('mucosal melanomas', 'Disease', 'MESH:D008545', (38, 55))	('solar elastosis', 'Disease', 'MESH:D005148', (176, 191))
47512	20426858	In another recent study, KIT mutations were identified in 23% of acral melanomas, 15.6% of mucosal melanomas, 1.7% of cutaneous melanomas, and none in choroidal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('acral melanomas', 'Disease', 'MESH:D008545', (65, 80))	('choroidal melanomas', 'Disease', (151, 170))	('acral melanomas', 'Phenotype', 'HP:0012060', (65, 80))	('choroidal melanoma', 'Phenotype', 'HP:0012054', (151, 169))	('mucosal melanomas', 'Disease', 'MESH:D008545', (91, 108))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (118, 137))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (118, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('choroidal melanomas', 'Phenotype', 'HP:0012054', (151, 170))	('KIT', 'Gene', (25, 28))	('mucosal melanomas', 'Disease', (91, 108))	('acral melanomas', 'Disease', (65, 80))	('mutations', 'Var', (29, 38))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('cutaneous melanomas', 'Disease', (118, 137))	('choroidal melanomas', 'Disease', 'MESH:D008545', (151, 170))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('identified', 'Reg', (44, 54))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
47557	20426858	Clinical parameters predicting poor survival outcome that were included in the multivariate analysis were as follows: age (> 50 years vs = 50 years), gender (female vs male), primary site (oral and genitoruinary vs the other mucosal melanomas), lymph node status (N0-1 vs N2-3), complete resectability (R0 vs R1 resection).	('mucosal melanomas', 'Disease', 'MESH:D008545', (225, 242))	('N0-1', 'Var', (264, 268))	('mucosal melanomas', 'Disease', (225, 242))	('melanomas', 'Phenotype', 'HP:0002861', (233, 242))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))
47590	20426858	A potential breakthrough in the management of mucosal melanoma has been recently suggested by the observation of relatively high incidence of KIT mutations in mucosal melanomas.	('KIT', 'molecular_function', 'GO:0005020', ('142', '145'))	('KIT', 'Gene', (142, 145))	('men', 'Species', '9606', (38, 41))	('mucosal melanomas', 'Disease', 'MESH:D008545', (159, 176))	('mutations', 'Var', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('mucosal melanoma', 'Disease', (46, 62))	('mucosal melanoma', 'Disease', 'MESH:D008545', (159, 175))	('mucosal melanomas', 'Disease', (159, 176))	('mucosal melanoma', 'Disease', 'MESH:D008545', (46, 62))
47592	20426858	Other reports also support the use of specific kinase inhibitors such as imatinib or dasatinib in melanoma patients with activating KIT mutation.	('imatinib', 'Chemical', 'MESH:D000068877', (73, 81))	('dasatinib', 'Chemical', 'MESH:D000069439', (85, 94))	('mutation', 'Var', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('KIT', 'molecular_function', 'GO:0005020', ('132', '135'))	('melanoma', 'Disease', (98, 106))	('activating KIT', 'Gene', (121, 135))	('patients', 'Species', '9606', (107, 115))
47593	20426858	Given the high incidence of KIT mutations in mucosal melanoma, we plan to conduct a phase II clinical trial with KIT targeting small molecule in this subset of patients.	('KIT', 'Gene', (28, 31))	('patients', 'Species', '9606', (160, 168))	('mucosal melanoma', 'Disease', (45, 61))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('KIT', 'molecular_function', 'GO:0005020', ('28', '31'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (45, 61))	('mutations', 'Var', (32, 41))
47707	29559799	The FHD is C-terminally located and contains deletions in its wing regions.	('FHD', 'Disease', (4, 7))	('deletions', 'Var', (45, 54))	('FHD', 'Disease', 'MESH:D052456', (4, 7))
47709	29559799	Mutations of its gene, FOXP1, located on chromosome 3p14.1, can result in the development of autism spectrum disorder, intellectual disability, speech and language deficits as well as motor development delay.	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (93, 117))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('FOXP1', 'Gene', '27086', (23, 28))	('speech and language deficits', 'Phenotype', 'HP:0000750', (144, 172))	('intellectual disability', 'Disease', (119, 142))	('Mutations', 'Var', (0, 9))	('development delay', 'Phenotype', 'HP:0001263', (190, 207))	('FOXP1', 'Gene', (23, 28))	('autism', 'Phenotype', 'HP:0000717', (93, 99))	('motor development delay', 'Phenotype', 'HP:0001270', (184, 207))	('intellectual disability', 'Phenotype', 'HP:0001249', (119, 142))	('language deficits', 'Disease', 'MESH:D007806', (155, 172))	('autism spectrum disorder', 'Disease', 'MESH:D000067877', (93, 117))	('language deficits', 'Disease', (155, 172))	('result in', 'Reg', (64, 73))	('speech', 'Disease', (144, 150))	('intellectual disability', 'Disease', 'MESH:D008607', (119, 142))	('motor development delay', 'CPA', (184, 207))	('autism spectrum disorder', 'Disease', (93, 117))
47719	29559799	FOXP1 overexpression also disrupts terminal B-cell differentiation in ABC-DLBCL cells by inhibiting major histocompatibility complex class II expression.	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('100', '132'))	('disrupts', 'NegReg', (26, 34))	('FOXP1', 'Gene', '27086', (0, 5))	('terminal B-cell differentiation', 'CPA', (35, 66))	('B-cell differentiation', 'biological_process', 'GO:0030183', ('44', '66'))	('overexpression', 'Var', (6, 20))	('inhibiting', 'NegReg', (89, 99))	('FOXP1', 'Gene', (0, 5))
47723	29559799	In one study, two ABC-DLBCL cell lines (TMD8 and HBL-1) underwent FOXP1 knockdown resulting in their apoptosis, while the FOXP1 knockdown in GC-DLBCL cell lines did not induce cell death.	('FOXP1', 'Gene', (66, 71))	('FOXP1', 'Gene', '27086', (122, 127))	('cell death', 'biological_process', 'GO:0008219', ('176', '186'))	('FOXP1', 'Gene', (122, 127))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('FOXP1', 'Gene', '27086', (66, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('HBL-1', 'Disease', 'MESH:C565162', (49, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'CPA', (101, 110))	('knockdown', 'Var', (72, 81))	('HBL-1', 'Disease', (49, 54))
47741	29559799	The mean number of FOXP1-positive cells was calculated in each case, and subsequently, the tumors were grouped into three categories: no FOXP1 expression in SCs (the mean number of positive SCs <1/HPF), low expression in SCs (the mean number of positive SCs >=1/HPF and <20/HPF), and high expression in SCs (the mean number of positive SCs >=20/HPF).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SCs', 'molecular_function', 'GO:0004776', ('221', '224'))	('SCs', 'molecular_function', 'GO:0004776', ('190', '193'))	('FOXP1', 'Gene', '27086', (137, 142))	('SCs', 'molecular_function', 'GO:0004776', ('254', '257'))	('FOXP1', 'Gene', (19, 24))	('SCs', 'molecular_function', 'GO:0004776', ('336', '339'))	('SCs', 'molecular_function', 'GO:0004776', ('303', '306'))	('SCs', 'molecular_function', 'GO:0004776', ('157', '160'))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('FOXP1', 'Gene', (137, 142))	('FOXP1', 'Gene', '27086', (19, 24))	('low', 'Var', (203, 206))
47764	29559799	It was demonstrated that the independent unfavorable prognostic factors that have a statistically significant effect on cutaneous melanoma patients' survival in the context of CSOS are Breslow thickness (p=0.01, HR=1.16, 95% CI=1.04-1.31) and high expression of FOXP1 in melanoma cells (p=0.03, HR=0.32, 95% CI=0.11-0.89; Table 3).	('patients', 'Species', '9606', (139, 147))	('high expression', 'Var', (243, 258))	('FOXP1', 'Gene', '27086', (262, 267))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Disease', (271, 279))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Disease', (130, 138))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('cutaneous melanoma', 'Disease', (120, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('FOXP1', 'Gene', (262, 267))
47769	29559799	On the other hand, the presence of FOXP1 in stromal compartment was connected with thin nonulcerated melanoma and no regional lymph node metastases.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('connected', 'Reg', (68, 77))	('FOXP1', 'Gene', '27086', (35, 40))	('presence', 'Var', (23, 31))	('metastases', 'Disease', (137, 147))	('FOXP1', 'Gene', (35, 40))
47772	29559799	Moreover, it was proven that overexpressed FOXP1 could be used as a biomarker of early HCC in liver cirrhosis associated with hepatitis B virus infection.	('hepatitis', 'Phenotype', 'HP:0012115', (126, 135))	('FOXP1', 'Gene', '27086', (43, 48))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (94, 109))	('hepatitis B virus infection', 'Disease', (126, 153))	('hepatitis B virus infection', 'Disease', 'MESH:D006509', (126, 153))	('liver cirrhosis', 'Disease', 'MESH:D008103', (94, 109))	('FOXP1', 'Gene', (43, 48))	('overexpressed', 'Var', (29, 42))	('hepatitis B virus infection', 'Phenotype', 'HP:0410369', (126, 153))	('associated', 'Reg', (110, 120))	('liver cirrhosis', 'Disease', (94, 109))
47773	29559799	This phenomenon was further investigated, and silencing of FOXP1 gene impaired the HCC cell growth ability in vitro, while knockdown of the gene decreased HCC cells' tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cell growth', 'biological_process', 'GO:0016049', ('87', '98'))	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('FOXP1', 'Gene', '27086', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('silencing', 'Var', (46, 55))	('HCC cell growth ability in vitro', 'CPA', (83, 115))	('tumor', 'Disease', (166, 171))	('FOXP1', 'Gene', (59, 64))	('decreased', 'NegReg', (145, 154))	('knockdown', 'Var', (123, 132))	('HCC', 'Phenotype', 'HP:0001402', (155, 158))	('impaired', 'NegReg', (70, 78))
47775	29559799	These results suggest that FOXP1 overexpression inhibits G1/S cycle arrest by promoting Rb phosphorylation via CDK4- and CDK6-independent pathway.	('CDK4', 'Gene', (111, 115))	('phosphorylation', 'MPA', (91, 106))	('CDK', 'molecular_function', 'GO:0004693', ('121', '124'))	('inhibits', 'NegReg', (48, 56))	('G1/S cycle arrest', 'CPA', (57, 74))	('CDK4', 'Gene', '1019', (111, 115))	('Rb', 'Chemical', 'MESH:D012413', (88, 90))	('FOXP1', 'Gene', '27086', (27, 32))	('CDK', 'molecular_function', 'GO:0004693', ('111', '114'))	('CDK6', 'Gene', '1021', (121, 125))	('promoting', 'PosReg', (78, 87))	('overexpression', 'Var', (33, 47))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('CDK6', 'Gene', (121, 125))	('FOXP1', 'Gene', (27, 32))
47816	30216655	Recent studies have reported that the genetic alteration of some lncRNAs conferred a selective growth advantage to the cancer cells in which it occurs, playing an important role in the initiation and progression of cancer (Schmitt and Chang, 2016; Yan et al., 2015).	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('growth advantage', 'CPA', (95, 111))	('genetic alteration', 'Var', (38, 56))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
47821	30216655	Therefore, comprehensive identification of genetically altered driver lncRNAs across distinct tumor types is not only urgently needed, but also may promote new diagnostic and therapeutic strategies for cancer (Yan et al., 2015).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('genetically', 'Var', (43, 54))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('promote', 'PosReg', (148, 155))
47823	30216655	Some passenger lncRNAs also show random or hitchhiking somatic mutations, which can confound the analysis of cancer drivers (Garraway and Lander, 2013; Marx, 2014; Pon and Marra, 2015).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hitchhiking', 'Var', (43, 54))	('Pon', 'Gene', (164, 167))	('cancer', 'Disease', (109, 115))	('Pon', 'Gene', '5444', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
47826	30216655	Interestingly, such genetically altered lncRNAs were found to be mutually exclusive with well-known cancer driver genes.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('genetically altered', 'Var', (20, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
47836	30216655	Next, we screened for PCGs/lncRNAs whose copy number significantly affected their expression levels using a one-tailed Wilcoxon signed rank test with P < 0.05.	('expression levels', 'MPA', (82, 99))	('PCGs', 'Chemical', 'MESH:D010400', (22, 26))	('affected', 'Reg', (67, 75))	('copy number', 'Var', (41, 52))
47837	30216655	On average, 231 lncRNAs and 1425 PCGs per cancer type were found to be altered (with amplifications or deletions) (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('altered', 'Reg', (71, 78))	('deletions', 'Var', (103, 112))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('PCGs', 'Chemical', 'MESH:D010400', (33, 37))
47860	30216655	In detail, for each cancer type, only copy number affected PCGs that were recorded in the known driver PCG category downloaded from Cancer Gene Census (CGC) (Futreal et al., 2004) were regarded as driver PCGs according to the following criteria: (i) the copy number alteration of drivers occurred in more than 2.5% of samples; (ii) the copy number alteration showed detectable RNA expression (RPKM > 0.3 in at least 30% of the samples); and (iii) the copy number alteration significantly affected RNA expression levels by one-tailed Wilcoxon signed rank test with P < 0.05.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('RNA', 'cellular_component', 'GO:0005562', ('497', '500'))	('PCG', 'Chemical', '-', (204, 207))	('PCGs', 'Chemical', 'MESH:D010400', (204, 208))	('PCGs', 'Chemical', 'MESH:D010400', (59, 63))	('copy number alteration', 'Var', (451, 473))	('Cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('affected', 'Reg', (488, 496))	('cancer', 'Disease', (20, 26))	('RNA expression levels', 'MPA', (497, 518))	('PCG', 'Chemical', '-', (59, 62))	('PCG', 'Chemical', '-', (103, 106))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('RNA expression', 'MPA', (377, 391))	('copy number alteration', 'Var', (336, 358))	('RNA', 'cellular_component', 'GO:0005562', ('377', '380'))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
47882	30216655	Patients were stratified based on continuous copy number alteration or expression above or below the median.	('expression', 'MPA', (71, 81))	('continuous copy number alteration', 'Var', (34, 67))	('Patients', 'Species', '9606', (0, 8))
47890	30216655	(ii) lncRNAs were amplified in corresponding cells at log2 ratio > 0 (i.e., A549 for LUAD and MCF-7 for BRCA).	('BRCA', 'Gene', '672', (104, 108))	('BRCA', 'Gene', (104, 108))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (94, 99))	('A549', 'Var', (76, 80))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
47891	30216655	Here, copy number alterations of lncRNAs in cell lines were obtained from the Cancer Cell Line Encyclopedia (Barretina et al., 2012) (https://portals.broadinstitute.org/ccle/home).	('Cancer Cell Line Encyclopedia', 'Disease', (78, 107))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (78, 107))	('copy number alterations', 'Var', (6, 29))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))
47905	30216655	Copy number alterations affected a large fraction of cancer genomes, activating oncogenes and inactivating tumor suppressors, and consequently contributed to tumorigenesis.	('inactivating', 'NegReg', (94, 106))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oncogenes', 'Protein', (80, 89))	('cancer', 'Disease', (53, 59))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('activating', 'PosReg', (69, 79))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('affected', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('contributed to', 'Reg', (143, 157))
47908	30216655	An average of 3080 lncRNAs (and 4038 PCGs) per cancer type showed copy number alterations.	('PCGs', 'Chemical', 'MESH:D010400', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('copy number alterations', 'Var', (66, 89))	('cancer', 'Disease', (47, 53))	('showed', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
47917	30216655	1D), implying that copy number alteration was a potent contributor to lncRNA dysregulation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('copy number alteration', 'Var', (19, 41))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
47918	30216655	For example, lncRNA RP11-745C15.2 was amplified in 39.1% of samples in GBM, resulting in an almost 50-fold increase in the expression compared to wild-type (Fig.	('RP11', 'Gene', '26121', (20, 24))	('expression', 'MPA', (123, 133))	('increase', 'PosReg', (107, 115))	('lncRNA', 'Var', (13, 19))	('RP11', 'Gene', (20, 24))
47947	30216655	Although CRISPRd identified functional lncRNAs in the liver cancer cell line Huh7.5OC, we only found two candidates identified in our results (amplification of lncRNA LINC00885 and AC084809.2 in HNSC and BRCA, respectively; P = 0.30, hypergeometric test), which may be a result of the tissue specificity of lncRNAs.	('LINC00885', 'Gene', '401109', (167, 176))	('LINC00885', 'Gene', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (204, 208))	('AC084809.2', 'Var', (181, 191))	('Huh7.5OC', 'CellLine', 'CVCL:7927', (77, 85))	('HNSC', 'Phenotype', 'HP:0012288', (195, 199))	('BRCA', 'Gene', '672', (204, 208))	('liver cancer', 'Phenotype', 'HP:0002896', (54, 66))	('liver cancer', 'Disease', 'MESH:D006528', (54, 66))	('BRCA', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', (54, 66))
47949	30216655	For example, deletion of lncRNA ANRIL and CDK4 constituted a mutually exclusive module associated with the hallmark 'Self Sufficiency in Growth Signals' in GBM (Fig.	('CDK4', 'Gene', '1019', (42, 46))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('lncRNA', 'Gene', (25, 31))	("hallmark 'Self Sufficiency", 'Disease', (107, 133))	('ANRIL', 'Gene', (32, 37))	('associated', 'Reg', (87, 97))	('deletion', 'Var', (13, 21))	('Sufficiency in Growth', 'Phenotype', 'HP:0001510', (122, 143))	("hallmark 'Self Sufficiency", 'Disease', 'MESH:D012652', (107, 133))	('ANRIL', 'Gene', '100048912', (32, 37))	('CDK4', 'Gene', (42, 46))
47954	30216655	The inactivation of NORAD was sufficient to produce a chromosomal instability phenotype (Lee et al., 2016).	('inactivation', 'Var', (4, 16))	('produce', 'Reg', (44, 51))	('chromosomal instability phenotype', 'MPA', (54, 87))	('NORAD', 'Gene', '647979', (20, 25))	('chromosomal instability', 'Phenotype', 'HP:0040012', (54, 77))	('NORAD', 'Gene', (20, 25))
47955	30216655	In LUSC, deletion of lncRNA MIR31HG was identified to form a mutually exclusive module affecting hallmark 'Genome Instability and Mutation' (Fig.	("Mutation'", 'MPA', (130, 139))	('deletion', 'Var', (9, 17))	("'Genome Instability", 'MPA', (106, 125))	('affecting', 'Reg', (87, 96))	('MIR31HG', 'Gene', (28, 35))	('MIR31HG', 'Gene', '554202', (28, 35))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
47962	30216655	Similarly, these lncRNAs and cancer driver PCGs were both significantly enriched in sensitive/ultra-sensitive regions, which exhibit depletion of common polymorphisms and strong enrichment in disease-causing mutations (Khurana et al., 2013) (P < 0.001, hypergeometric test) (Fig.	('PCGs', 'Chemical', 'MESH:D010400', (43, 47))	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('disease-causing', 'Reg', (192, 207))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
47980	30216655	For example, in GBM, amplification of RP11-745C15.2 and deletion of CDKN2B-AS1 were both associated with the hallmark pathway of 'ceramide biosynthetic process', which was reported to promote apoptosis in glioblastoma (Sordillo et al., 2016), whereas, in PRAD, deletion of lncRNA AC003102.3, RGMB-AS1, and DLG5-AS1 was all related to the hallmark pathway of 'Urogenital System Development', during which the dysfunction in cell lineage specification predisposed prostate epithelia to hyperplasia and cancer (Brechka et al., 2016).	('associated', 'Reg', (89, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('CDKN2B-AS1', 'Gene', '100048912', (68, 78))	('CDKN2B-AS1', 'Gene', (68, 78))	('RGMB-AS1', 'Gene', (292, 300))	('DLG5-AS1', 'Gene', '100128292;9231;5729', (306, 314))	('amplification', 'Var', (21, 34))	('promote', 'PosReg', (184, 191))	('deletion', 'Var', (56, 64))	('RGMB-AS1', 'Gene', '503569', (292, 300))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	("'Urogenital System", 'Phenotype', 'HP:0000119', (358, 376))	('DLG5-AS1', 'Gene', (306, 314))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('RP11', 'Gene', '26121', (38, 42))	('prostate epithelia to hyperplasia and cancer', 'Disease', 'MESH:D011470', (462, 506))	('ceramide biosynthetic process', 'biological_process', 'GO:0046513', ('130', '159'))	('Urogenital System Development', 'biological_process', 'GO:0001655', ('359', '388'))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	('RP11', 'Gene', (38, 42))	('glioblastoma', 'Disease', (205, 217))
47987	30216655	6E,F) and deregulation of CCNE1 expression led to genomic instability via mitotic delay (Caldon et al., 2013).	('mitotic delay', 'CPA', (74, 87))	('CCNE1', 'Gene', '898', (26, 31))	('deregulation', 'Var', (10, 22))	('CCNE1', 'Gene', (26, 31))	('genomic instability', 'CPA', (50, 69))	('led to', 'Reg', (43, 49))
47994	30216655	Specifically, in LGG, amplification of candidate driver lncRNA AC000123.4 conferred a poor prognosis to patients with glioma (P < 0.001 for DFS, log-rank test) (Fig.	('glioma', 'Disease', (118, 124))	('amplification', 'Var', (22, 35))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('AC000123.4', 'Gene', (63, 73))	('patients', 'Species', '9606', (104, 112))	('poor', 'NegReg', (86, 90))
47995	30216655	The median recurrence-free interval of AC000123.4 amplification patients was 39.6 months [95% confidence interval (CI) = 35.6-63.8], whereas that of AC000123.4 diploid patients was 68.9 months (95% CI = 44.5-100.9).	('amplification', 'Var', (50, 63))	('AC000123.4 amplification', 'Var', (39, 63))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (64, 72))
47996	30216655	Multivariate Cox proportional hazards models further showed that AC000123.4 amplification had a poor effect on DFS (hazard ratio (HR), 1.99, 95% CI = 1.38-2.88) (Table S7) independent of the patient's age, gender and pathologic stages.	('AC000123.4 amplification', 'Var', (65, 89))	('Cox', 'Gene', (13, 16))	('DFS', 'Disease', (111, 114))	('patient', 'Species', '9606', (191, 198))	('Cox', 'Gene', '1351', (13, 16))
47997	30216655	Moreover, its expression was significantly up-regulated in tumors with AC000123.4 amplification (P = 0.002, Student's t test) (Fig.	('tumors', 'Disease', (59, 65))	('expression', 'MPA', (14, 24))	('AC000123.4 amplification', 'Var', (71, 95))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('up-regulated', 'PosReg', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
47998	30216655	Likewise, we observed that up-expression of AC000123.4 in LGG was also significantly associated with decreased survival in patients (P < 0.001 for DFS, log-rank test) (Fig.	('AC000123.4', 'Var', (44, 54))	('survival', 'MPA', (111, 119))	('up-expression', 'PosReg', (27, 40))	('patients', 'Species', '9606', (123, 131))	('decreased', 'NegReg', (101, 110))
48001	30216655	Activated EGFR increased the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis (Larsen et al., 2011) and amplification of EGFR also indicated poor prognosis in glioma (Sun et al., 2014) (Fig.	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('tumor', 'Disease', (43, 48))	('angiogenesis', 'biological_process', 'GO:0001525', ('126', '138'))	('EGFR', 'molecular_function', 'GO:0005006', ('182', '186'))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('EGFR', 'molecular_function', 'GO:0005006', ('10', '14'))	('promote', 'PosReg', (118, 125))	('production', 'MPA', (29, 39))	('VEGF', 'Gene', '7422', (57, 61))	('angiogenesis', 'CPA', (126, 138))	('VEGF', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (182, 186))	('amplification', 'Var', (165, 178))	('glioma', 'Disease', (220, 226))
48002	30216655	Interestingly, in EGFR wild-type samples, amplification of AC000123.4 is associated with a worse prognosis (DFS: HR = 1.86, 95% CI = 1.26-2.76, P = 0.0018) (Fig.	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (18, 22))	('AC000123.4', 'Gene', (59, 69))	('amplification', 'Var', (42, 55))
48004	30216655	The median recurrence-free interval of AC000123.4 amplification patients without EGFR amplification was 42.9 months (95% CI = 38.90-74.8), whereas that of AC000123.4 diploid patients without EGFR amplification was 72.0 months (95% CI = 44.55-not reached), suggesting a complementary prognostic role of AC000123.4 to EGFR.	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('316', '320'))	('EGFR', 'molecular_function', 'GO:0005006', ('191', '195'))	('EGFR', 'Gene', '1956', (316, 320))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (316, 320))	('EGFR', 'Gene', (191, 195))	('patients', 'Species', '9606', (174, 182))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('AC000123.4 amplification', 'Var', (39, 63))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
48005	30216655	Our above observations indicated that these genetically altered lncRNAs may substantially contribute to tumorigenesis by inducing similar functional effects with known cancer driver PCGs in a mutually exclusive manner, suggesting their cancer-driving roles.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('inducing', 'Reg', (121, 129))	('genetically altered', 'Var', (44, 63))	('tumor', 'Disease', (104, 109))	('PCGs', 'Chemical', 'MESH:D010400', (182, 186))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('contribute', 'Reg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
48010	30216655	As a result, cell migration was significantly reduced by depletion of five of these lncRNAs in lung adenocarcinoma and breast cancer cell lines, as shown by a Transwell migration assay (P < 0.05, unpaired Student's test) (Fig.	('cell migration', 'CPA', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('Transwell migration assay', 'CPA', (159, 184))	('depletion', 'Var', (57, 66))	('breast cancer', 'Disease', (119, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('lung adenocarcinoma', 'Disease', (95, 114))	('reduced', 'NegReg', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('cell migration', 'biological_process', 'GO:0016477', ('13', '27'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
48020	30216655	For example, lncRNA FAL1 amplified in ovarian cancers could promote cell proliferation by recruiting the chromatin repressor protein BMI-1 and inhibiting the expression of CDKN1A (Hu et al., 2014).	('chromatin', 'cellular_component', 'GO:0000785', ('105', '114'))	('cell proliferation', 'CPA', (68, 86))	('ovarian cancers', 'Disease', (38, 53))	('BMI-1', 'Gene', (133, 138))	('ovarian cancers', 'Disease', 'MESH:D010051', (38, 53))	('recruiting', 'PosReg', (90, 100))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('amplified', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('expression', 'MPA', (158, 168))	('FAL1', 'Gene', (20, 24))	('ovarian cancers', 'Phenotype', 'HP:0100615', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('promote', 'PosReg', (60, 67))	('inhibiting', 'NegReg', (143, 153))	('FAL1', 'Gene', '100874054', (20, 24))	('CDKN1A', 'Gene', (172, 178))	('CDKN1A', 'Gene', '1026', (172, 178))	('BMI-1', 'Gene', '648', (133, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
48024	30216655	Recurrence is considered as one potential sign of positive selection among tumors (Dees et al., 2012; Fu et al., 2014); therefore, functional lncRNAs with recurrent genetic alterations are more likely to be driver lncRNAs, instead of non-driver cancer lncRNAs.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (75, 81))	('genetic alterations', 'Var', (165, 184))
48025	30216655	With the aim of identifying driver lncRNAs, our method considers lncRNAs that show recurrent copy number alteration, exhibit mutually exclusive patterns with known cancer drivers, and affect various cancer hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('copy number alteration', 'Var', (93, 115))	('affect', 'Reg', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer hallmarks', 'Disease', (199, 215))	('cancer hallmarks', 'Disease', 'MESH:D009369', (199, 215))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (199, 205))
48035	30216655	When damage of a driver gene is sufficient to disturb the activity of certain key pathways, other gene alterations with similar functional consequences will offer no further selective advantage on that clone; that is the selection pressure on these other alterations could be diminished or even nullified during tumor evolution (Ciriello et al., 2012; Remy et al., 2015).	('activity', 'MPA', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('disturb', 'Reg', (46, 53))	('key pathways', 'Pathway', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', (312, 317))	('damage', 'Var', (5, 11))
48046	30216655	For example, in the hallmark 'Evading Immune Detection', we found that GO term 'regulation of defense response to virus' was only affected by mutually exclusive modules in HNSC, which is consistent with the prevalence and the roles of human papillomavirus in directly inhibiting innate immune system for this cancer type (Bodily and Laimins, 2011; Maxwell et al., 2016).	('human papillomavirus', 'Species', '10566', (235, 255))	('affected', 'Reg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('inhibiting', 'NegReg', (268, 278))	('HNSC', 'Gene', (172, 176))	('modules', 'Var', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('HNSC', 'Phenotype', 'HP:0012288', (172, 176))	('regulation of defense response to virus', 'biological_process', 'GO:0050688', ('80', '119'))	('cancer', 'Disease', (309, 315))
48052	30216655	A previous study has demonstrated that PVT1 epigenetically repressed the expression of CDKN2A by binding to the EZH2 (Kong et al., 2015); therefore, amplification of PVT1 and deletion of CDKN2A could consistently trigger the expression abnormality of CDKN2A and in turn lead to genomic instability.	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('CDKN2A', 'Gene', (187, 193))	('CDKN2A', 'Gene', '1029', (87, 93))	('amplification', 'Var', (149, 162))	('deletion', 'Var', (175, 183))	('genomic', 'MPA', (278, 285))	('CDKN2A', 'Gene', '1029', (251, 257))	('PVT1', 'Gene', (166, 170))	('EZH2', 'Gene', '2146', (112, 116))	('PVT1', 'Gene', (39, 43))	('PVT1', 'Gene', '5820', (166, 170))	('EZH2', 'Gene', (112, 116))	('CDKN2A', 'Gene', '1029', (187, 193))	('PVT1', 'Gene', '5820', (39, 43))	('CDKN2A', 'Gene', (87, 93))	('lead to', 'Reg', (270, 277))	('trigger', 'Reg', (213, 220))	('expression abnormality', 'MPA', (225, 247))	('CDKN2A', 'Gene', (251, 257))
48055	30216655	Interestingly, CCNE1 suffered much more frequent CNA (24.6%) than CDKN2A (4.5%) in OV, whereas the opposite trend was observed in LUAD (5.8% and 19.0% for CCNE1 and CDKN2A, respectively), indicating that amplification of PVT1 may dysregulate different downstream genes, which in turn contribute to cancer development.	('PVT1', 'Gene', '5820', (221, 225))	('CCNE1', 'Gene', (15, 20))	('amplification', 'Var', (204, 217))	('contribute', 'Reg', (284, 294))	('dysregulate', 'Reg', (230, 241))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2A', 'Gene', (165, 171))	('cancer', 'Disease', (298, 304))	('OV', 'Phenotype', 'HP:0012887', (83, 85))	('CCNE1', 'Gene', '898', (155, 160))	('CCNE1', 'Gene', (155, 160))	('CDKN2A', 'Gene', '1029', (165, 171))	('PVT1', 'Gene', (221, 225))	('CCNE1', 'Gene', '898', (15, 20))	('CDKN2A', 'Gene', (66, 72))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
48058	30216655	These findings suggest that both of these lncRNAs and derived miRNAs contribute to tumorigenesis, although, for lncRNAs LINC00969, U47924.29 and LINC00669, we did not find evidence of oncogenic roles recorded in literature.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LINC00969', 'Gene', '440993', (120, 129))	('tumor', 'Disease', (83, 88))	('LINC00969', 'Gene', (120, 129))	('LINC00669', 'Gene', '647946', (145, 154))	('LINC00669', 'Gene', (145, 154))	('U47924.29', 'Var', (131, 140))	('contribute', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
48063	30216655	XXZ performed copy number analysis and pan-cancer analysis.	('cancer', 'Disease', (43, 49))	('copy number analysis', 'Var', (14, 34))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
48149	27128153	Racial and ethnic disparities in uveal melanoma incidence, as well as those intra-racial differences in incidence associated with differences in iris coloration, suggest a possible protective role of increased pigmentation.	('pigmentation', 'biological_process', 'GO:0043473', ('210', '222'))	('uveal melanoma', 'Disease', 'MESH:C536494', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('uveal melanoma', 'Phenotype', 'HP:0007716', (33, 47))	('uveal melanoma', 'Disease', (33, 47))	('differences', 'Var', (130, 141))	('men', 'Species', '9606', (213, 216))	('increased pigmentation', 'Phenotype', 'HP:0000953', (200, 222))
48203	27128153	This syndrome is the result of germline mutations in the BAP1 gene, a tumor suppressor gene found on chromosome 3.	('chromosome', 'cellular_component', 'GO:0005694', ('101', '111'))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('result', 'Reg', (21, 27))	('BAP1', 'Gene', '8314', (57, 61))	('germline mutations', 'Var', (31, 49))	('BAP1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
48208	27128153	Notably, BAP1 mutations can be either germline mutations, resulting in the familial cancer predisposition, or sporadic in the uveal melanoma tumor cells alone.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('familial cancer', 'Disease', 'MESH:D009369', (75, 90))	('resulting in', 'Reg', (58, 70))	('BAP1', 'Gene', '8314', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('uveal melanoma tumor', 'Disease', (126, 146))	('uveal melanoma', 'Phenotype', 'HP:0007716', (126, 140))	('uveal melanoma tumor', 'Disease', 'MESH:C536494', (126, 146))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('familial cancer', 'Disease', (75, 90))
48209	27128153	Either type of recessive BAP1 mutation is unmasked by a loss of chromosome 3.	('BAP1', 'Gene', '8314', (25, 29))	('mutation', 'Var', (30, 38))	('BAP1', 'Gene', (25, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))
48210	27128153	BAP1 mutations have been shown to relate to uveal melanoma metastatic potential and the classification of tumors as higher-risk, class 2 tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('BAP1', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('relate', 'Reg', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (5, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BAP1', 'Gene', '8314', (0, 4))	('uveal melanoma', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
48267	27841141	Mutations in this gene are found in 10-30 per cent of melanoma patients with a positive family history.	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (63, 71))	('found', 'Reg', (27, 32))
48297	27841141	In situ melanoma (LM): 5 mm peripheral margins Lesions <1 mm thick: 1 cm excision margins Lesions 1-2 mm thick: 1-2 cm excision margins Lesions 2.1-4 mm thick: 2-3 cm margins (2 cm preferred) Lesions thicker than 4 mm: 2-3 cm margins.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('situ melanoma', 'Disease', (3, 16))	('LM', 'Phenotype', 'HP:0012059', (18, 20))	('situ melanoma', 'Disease', 'MESH:D008545', (3, 16))	('Lesions', 'Var', (47, 54))
48312	27841141	The long-term results of the Multicentre Selective Lymphadenectomy Trial-I (MSLT-I) indicate that SLNB is associated with improved disease-free survival for patients with intermediate thickness (1.2-3.5 mm) and thick (>=3.5 mm) melanomas, but this has been questioned in a recent editorial in the British Medical Journal.	('melanomas', 'Phenotype', 'HP:0002861', (228, 237))	('patients', 'Species', '9606', (157, 165))	('melanomas', 'Disease', 'MESH:D008545', (228, 237))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('disease-free survival', 'CPA', (131, 152))	('melanomas', 'Disease', (228, 237))	('SLNB', 'Var', (98, 102))	('improved', 'PosReg', (122, 130))
48327	27841141	Of these, lactate dehydrogenase (LDH) and the c-kit mutation may be helpful.	('c-kit', 'Gene', '3815', (46, 51))	('mutation', 'Var', (52, 60))	('c-kit', 'Gene', (46, 51))
48340	27841141	About 50 per cent of melanomas show a mutation in the BRAF gene, with valine substituted for glutamate at codon 600, and this mutation is known as V600E or V600K.	('V600E', 'Var', (147, 152))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanomas', 'Disease', (21, 30))	('V600K', 'Var', (156, 161))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('V600K', 'Mutation', 'rs121913227', (156, 161))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('valine substituted for glutamate at codon 600', 'Mutation', 'rs113488022', (70, 115))
48356	27841141	not showing a BRAF mutation.	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', '673', (14, 18))	('mutation', 'Var', (19, 27))
48381	27841141	For metastatic disease, unfortunately only a tiny percentage of mucosal melanomas show a BRAF mutation; therefore it is usually not appropriate to use BRAF inhibitors, so chemotherapy in the form of biological agents has to depend on immunotherapy with ipilimumab or the newer agents such as pembrolizumab, although to date there has been no specific study of the latter agent's efficacy specifically in mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (64, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mucosal melanomas', 'Disease', (64, 81))	('mucosal melanomas', 'Disease', 'MESH:D008545', (64, 81))	('BRAF', 'Gene', '673', (151, 155))	('melanoma', 'Phenotype', 'HP:0002861', (412, 420))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (151, 155))	('mucosal melanoma', 'Disease', (404, 420))	('BRAF', 'Gene', (89, 93))	('mucosal melanoma', 'Disease', 'MESH:D008545', (404, 420))	('ipilimumab', 'Chemical', 'MESH:D000074324', (253, 263))	('mutation', 'Var', (94, 102))	('pembrolizumab', 'Chemical', 'MESH:C582435', (292, 305))
48384	30734280	Genetic variants in ELOVL2 and HSD17B12 predict melanoma-specific survival Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression.	('cellular bioenergetics', 'MPA', (106, 128))	('biosynthesis', 'biological_process', 'GO:0009058', ('139', '151'))	('ELOVL2', 'Gene', (20, 26))	('HSD17B12', 'Gene', '51144', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('involved', 'Reg', (206, 214))	('variants', 'Var', (8, 16))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('membrane', 'cellular_component', 'GO:0016020', ('130', '138'))	('ELOVL2', 'Gene', '54898', (20, 26))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('HSD17B12', 'Gene', (31, 39))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('membrane biosynthesis', 'MPA', (130, 151))	('intracellular', 'cellular_component', 'GO:0005622', ('156', '169'))	('Fatty acids', 'Chemical', 'MESH:D005227', (75, 86))
48385	30734280	In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS).	('CM', 'Disease', 'MESH:C562393', (219, 221))	('fatty-acid', 'Chemical', 'MESH:D005227', (139, 149))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('single-nucleotide polymorphisms', 'Var', (80, 111))	('CM', 'Phenotype', 'HP:0012056', (219, 221))	('cutaneous melanoma disease', 'Disease', (173, 199))	('cutaneous melanoma disease', 'Disease', 'MESH:C562393', (173, 199))	('fatty-acid synthesis', 'biological_process', 'GO:0006633', ('139', '159'))	('associations', 'Interaction', (50, 62))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (173, 191))
48387	30734280	By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval=0.51-0.84 and P=8.34x10-4) and 2.29 (1.55-3.39 and P=3.61x10-5), respectively.	('ELOVL2', 'Gene', (147, 153))	('rs11037684 A>G', 'Var', (181, 195))	('HSD17B12', 'Gene', '51144', (172, 180))	('CM', 'Disease', 'MESH:C562393', (211, 213))	('Cox', 'Gene', '1351', (83, 86))	('CM', 'Phenotype', 'HP:0012056', (211, 213))	('predicted', 'Reg', (201, 210))	('HSD17B12', 'Gene', (172, 180))	('rs3734398', 'Mutation', 'rs3734398', (154, 163))	('rs3734398 T>C', 'Var', (154, 167))	('Cox', 'Gene', (83, 86))	('rs11037684', 'Mutation', 'rs11037684', (181, 191))
48388	30734280	Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level.	('rs3734398', 'Var', (20, 29))	('mRNA expression level', 'MPA', (108, 129))	('increased', 'PosReg', (98, 107))	('rs3734398', 'Mutation', 'rs3734398', (20, 29))	('ELOVL2', 'Gene', (13, 19))
48397	30734280	Chemical inhibition or genetic knock-down of these key enzymes lead to a reduced proliferation and survival of cancer cells in xenograft tumor models.	('tumor', 'Disease', (137, 142))	('genetic knock-down', 'Var', (23, 41))	('reduced', 'NegReg', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('knock-down', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('proliferation', 'CPA', (81, 94))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
48398	30734280	Interestingly, one study found that inhibition of fatty acid desaturation also increased the chemosensitivity of cancer cells that had an induced apoptosis by the mitochondrial pathway, suggesting an important role of the fatty acid metabolism in cancer cell survival and drug resistance.	('inhibition', 'Var', (36, 46))	('mitochondrial pathway', 'Pathway', (163, 184))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', (113, 119))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('222', '243'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('fatty', 'MPA', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('drug resistance', 'Phenotype', 'HP:0020174', (272, 287))	('fatty acid', 'Chemical', 'MESH:D005227', (50, 60))	('apoptosis', 'CPA', (146, 155))	('fatty acid desaturation', 'biological_process', 'GO:0006636', ('50', '73'))	('chemosensitivity of', 'CPA', (93, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('fatty acid', 'Chemical', 'MESH:D005227', (222, 232))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('increased', 'PosReg', (79, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('drug resistance', 'biological_process', 'GO:0009315', ('272', '287'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('drug resistance', 'biological_process', 'GO:0042493', ('272', '287'))
48400	30734280	It has also been reported that alterations in the fatty acid synthesis in melanoma cells helped the cells evade apoptosis and sustain survival after ultraviolet A exposure.	('alterations', 'Var', (31, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('50', '70'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('sustain survival', 'CPA', (126, 142))	('evade', 'NegReg', (106, 111))	('melanoma', 'Disease', (74, 82))	('fatty acid', 'Chemical', 'MESH:D005227', (50, 60))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('fatty acid synthesis', 'MPA', (50, 70))
48401	30734280	Given the importance of fatty acid synthesis in cancer development and progression, we aimed to identify novel genetic variants in the fatty acid synthesis pathway genes in their association with survival of CM patients by using two published genome-wide association study (GWAS) datasets, which may provide a new clue to novel cancer therapies with interruption of the fatty acid metabolism.	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('135', '155'))	('patients', 'Species', '9606', (211, 219))	('fatty acid', 'Chemical', 'MESH:D005227', (135, 145))	('association', 'Interaction', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CM', 'Phenotype', 'HP:0012056', (208, 210))	('CM', 'Disease', 'MESH:C562393', (208, 210))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('24', '44'))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('fatty acid', 'Chemical', 'MESH:D005227', (370, 380))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('370', '391'))	('fatty acid', 'Chemical', 'MESH:D005227', (24, 34))	('variants', 'Var', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
48420	30734280	As a result, 1,042 SNPs were significantly associated with CMSS at P < 0.05 in an additive genetic model, of which 538 SNPs were still considered noteworthy after the multiple test correction by FPRP, which took into account of the fact that the vast majority of the SNPs under investigation were imputed with a LD approach.	('CM', 'Phenotype', 'HP:0012056', (59, 61))	('SNPs', 'Var', (19, 23))	('CM', 'Disease', 'MESH:C562393', (59, 61))	('associated', 'Reg', (43, 53))
48425	30734280	In consideration of P values, LD and predicted functions, we selected ELOVL2 rs3734398 (genotyped) and HSD17B12 rs11037684 (genotyped) as the independent tagSNPs for further analysis.	('HSD17B12', 'Gene', '51144', (103, 111))	('ELOVL2', 'Gene', (70, 76))	('rs3734398', 'Mutation', 'rs3734398', (77, 86))	('rs11037684', 'Mutation', 'rs11037684', (112, 122))	('rs11037684', 'Var', (112, 122))	('HSD17B12', 'Gene', (103, 111))	('rs3734398', 'Var', (77, 86))
48428	30734280	In the MDACC study, we observed a statistically significant protective effect of the ELOVL2 rs3734398 C allele (Ptrend = 0.027) but a risk effect of the HSD17B12 rs11037684 G allele (Ptrend = 0.007) on CM-specific survival.	('rs11037684', 'Mutation', 'rs11037684', (162, 172))	('rs11037684 G', 'Var', (162, 174))	('rs3734398', 'Mutation', 'rs3734398', (92, 101))	('CM', 'Disease', 'MESH:C562393', (202, 204))	('CM', 'Phenotype', 'HP:0012056', (202, 204))	('HSD17B12', 'Gene', '51144', (153, 161))	('ELOVL2', 'Gene', (85, 91))	('rs3734398 C', 'Var', (92, 103))	('HSD17B12', 'Gene', (153, 161))
48429	30734280	Similar results were observed for the ELOVL2 rs3734398 C allele in the NHS/HPFS dataset (Ptrend = 0.005) and the combined dataset of both MDACC and NHS/HPFS (Ptrend = 0.003).	('ELOVL2', 'Gene', (38, 44))	('rs3734398 C', 'Var', (45, 56))	('NHS/HPFS', 'Gene', (71, 79))	('rs3734398', 'Mutation', 'rs3734398', (45, 54))
48430	30734280	Similarly, the risk effect of the HSD17B12 rs11037684 G allele was observed in the NHS/HPFS dataset (Ptrend = 0.002) and the combined dataset of both MDACC and NHS/HPFS (Ptrend = 0.002) (Table 2).	('NHS/HPFS', 'Disease', (83, 91))	('HSD17B12', 'Gene', (34, 42))	('rs11037684', 'Mutation', 'rs11037684', (43, 53))	('rs11037684 G', 'Var', (43, 55))	('HSD17B12', 'Gene', '51144', (34, 42))
48431	30734280	To further visualize the HR effects, we used Kaplan-Meier survival curves for the associations between CMSS and risk genotypes of ELOVL2 rs3734398 and HSD17B12 rs11037684 in the combined dataset of both MDACC and NHS/HPFS (Figure 2a and 2b).	('CM', 'Disease', 'MESH:C562393', (103, 105))	('HSD17B12', 'Gene', (151, 159))	('CM', 'Phenotype', 'HP:0012056', (103, 105))	('rs11037684', 'Mutation', 'rs11037684', (160, 170))	('rs3734398', 'Mutation', 'rs3734398', (137, 146))	('ELOVL2', 'Gene', (130, 136))	('rs11037684', 'Var', (160, 170))	('rs3734398', 'Var', (137, 146))	('associations', 'Interaction', (82, 94))	('HSD17B12', 'Gene', '51144', (151, 159))
48434	30734280	In multivariate competing risks regression models, rs3734398 was a statistically significant predictor of CMSS, after accounting for the postdiagnosis mortality in both datasets (with subdistribution HR of 0.72 in the MDACC dataset and 0.53 in the NHS/HPFS dataset, respectively); similarly, rs11037684 was also a significant predictor in the MDACC dataset (subdistribution HR = 1.93 and P = 0.014) and NHS/HPFS dataset (subdistribution HR = 2.56 and P = 0.002).	('rs11037684', 'Var', (292, 302))	('CM', 'Phenotype', 'HP:0012056', (106, 108))	('rs3734398', 'Var', (51, 60))	('CM', 'Disease', 'MESH:C562393', (106, 108))	('rs3734398', 'Mutation', 'rs3734398', (51, 60))	('rs11037684', 'Mutation', 'rs11037684', (292, 302))
48435	30734280	In the subsequent meta-analyses, for both rs3734398 and rs11037684, the direction, magnitude, and significance of subdistribution HR of CMSS were consistent with the cause-specific HR (Table S5).	('rs11037684', 'Mutation', 'rs11037684', (56, 66))	('CM', 'Phenotype', 'HP:0012056', (136, 138))	('rs3734398', 'Var', (42, 51))	('rs11037684', 'Var', (56, 66))	('CM', 'Disease', 'MESH:C562393', (136, 138))	('rs3734398', 'Mutation', 'rs3734398', (42, 51))
48437	30734280	To better estimate the joint effect of the two tagSNPs on risk of death, we combined the risk genotypes (those associated with an increased death risk) of ELOVL2 rs3734398 TT and HSD17B12 rs11037684 AG+GG into one variable as a genetic score.	('rs11037684 AG+GG', 'Var', (188, 204))	('rs3734398 TT', 'Var', (162, 174))	('ELOVL2', 'Gene', (155, 161))	('HSD17B12', 'Gene', (179, 187))	('rs3734398', 'Mutation', 'rs3734398', (162, 171))	('rs11037684', 'Mutation', 'rs11037684', (188, 198))	('HSD17B12', 'Gene', '51144', (179, 187))
48448	30734280	Notably, the rs3734398 C allele was significantly correlated with mRNA expression levels of ELOVL2 in an additive models (P = 0.024, Figure 2d).	('mRNA expression levels', 'MPA', (66, 88))	('rs3734398', 'Mutation', 'rs3734398', (13, 22))	('correlated', 'Reg', (50, 60))	('rs3734398 C', 'Var', (13, 24))
48450	30734280	We found that rs3734398 C allele was associated with a significantly increased ELOVL2 mRNA expression level (P = 7.3 x 10-7) in an additive genetic model (Figure 2e), which is consistent with our initial findings.	('rs3734398 C', 'Var', (14, 25))	('rs3734398', 'Mutation', 'rs3734398', (14, 23))	('increased', 'PosReg', (69, 78))	('ELOVL2 mRNA expression level', 'MPA', (79, 107))
48451	30734280	However, there was no significant correlation between rs11037684 genotypes and HSD17B12 mRNA expression levels (P = 0.911, 0.988 and 0.547 for additive, dominant and recessive models, respectively) (Figure S5) in the 1000 Genomes Project nor in the GTEx.	('mRNA expression levels', 'MPA', (88, 110))	('HSD17B12', 'Gene', (79, 87))	('rs11037684', 'Var', (54, 64))	('rs11037684', 'Mutation', 'rs11037684', (54, 64))	('HSD17B12', 'Gene', '51144', (79, 87))
48452	30734280	Using experimental data from the ENCODE Project (Figure S6), we found the two SNPs (i.e., rs3734398 and rs11037684) to be located in a DNase I hypersensitive site, where the DNase hypersensitivity and histone modification H3K27 acetylation indicated some signals for active enhancer and promoter functions.	('promoter functions', 'MPA', (287, 305))	('rs3734398', 'Mutation', 'rs3734398', (90, 99))	('rs11037684', 'Var', (104, 114))	('histone modification', 'biological_process', 'GO:0016570', ('201', '221'))	('rs11037684', 'Mutation', 'rs11037684', (104, 114))	('DNase I', 'molecular_function', 'GO:0004530', ('135', '142'))	('rs3734398', 'Var', (90, 99))	('hypersensitivity', 'Disease', (180, 196))	('hypersensitivity', 'Disease', 'MESH:D004342', (180, 196))	('hypersensitivity', 'biological_process', 'GO:0002524', ('180', '196'))	('enhancer', 'PosReg', (274, 282))
48453	30734280	The evidence from the DNase cluster and transcription factor CHIP-seq data suggests that rs3734398 is located on the SPI1 motif and that rs11037684 is located on the RP58 motif as indicated by the position weight matrix.	('RP58', 'Gene', '10472', (166, 170))	('RP58', 'Gene', (166, 170))	('transcription', 'biological_process', 'GO:0006351', ('40', '53'))	('transcription factor', 'molecular_function', 'GO:0000981', ('40', '60'))	('rs3734398', 'Mutation', 'rs3734398', (89, 98))	('rs11037684', 'Mutation', 'rs11037684', (137, 147))	('rs3734398', 'Var', (89, 98))	('rs11037684', 'Var', (137, 147))
48454	30734280	In the present study, we found that genetic variants ELOVL2 rs3734398 and HSD17B12 rs11037684 were likely to independently or jointly modulate the survival of CM patients.	('rs3734398', 'Var', (60, 69))	('patients', 'Species', '9606', (162, 170))	('rs11037684', 'Mutation', 'rs11037684', (83, 93))	('survival', 'CPA', (147, 155))	('rs11037684', 'Var', (83, 93))	('CM', 'Disease', 'MESH:C562393', (159, 161))	('ELOVL2', 'Gene', (53, 59))	('rs3734398', 'Mutation', 'rs3734398', (60, 69))	('HSD17B12', 'Gene', '51144', (74, 82))	('modulate', 'Reg', (134, 142))	('CM', 'Phenotype', 'HP:0012056', (159, 161))	('HSD17B12', 'Gene', (74, 82))
48456	30734280	Moreover, the rs3734398 C allele was correlated with an increase in ELOVL2 mRNA expression level in lymphoblastoid cell lines derived from 373 European descendants from the 1000 Genomes Project.	('rs3734398 C', 'Var', (14, 25))	('ELOVL2 mRNA expression level', 'MPA', (68, 96))	('rs3734398', 'Mutation', 'rs3734398', (14, 23))	('increase', 'PosReg', (56, 64))
48458	30734280	A deregulated fatty acid synthesis can affect drug resistance and cancer risk, prognosis and recurrence.	('recurrence', 'CPA', (93, 103))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('deregulated', 'Var', (2, 13))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('14', '34'))	('drug resistance', 'biological_process', 'GO:0042493', ('46', '61'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('affect', 'Reg', (39, 45))	('fatty acid synthesis', 'MPA', (14, 34))	('drug resistance', 'CPA', (46, 61))	('drug resistance', 'Phenotype', 'HP:0020174', (46, 61))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('prognosis', 'CPA', (79, 88))	('cancer', 'Disease', (66, 72))	('drug resistance', 'biological_process', 'GO:0009315', ('46', '61'))
48460	30734280	Furthermore, blocking the fatty acid synthesis overcomes tumor regrowth and metastasis after withdrawal of the antiangiogenic therapy in breast and colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (148, 160))	('blocking', 'Var', (13, 21))	('overcomes', 'NegReg', (47, 56))	('breast and colon cancer', 'Disease', 'MESH:D001943', (137, 160))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('fatty acid', 'Chemical', 'MESH:D005227', (26, 36))	('fatty', 'Protein', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('26', '46'))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (57, 62))
48461	30734280	When restricted to hepatocellular carcinoma patients receiving surgery treatment, genetic variants of FASN could predict recurrence risk.	('FASN', 'Gene', (102, 106))	('recurrence', 'MPA', (121, 131))	('patients', 'Species', '9606', (44, 52))	('FASN', 'Gene', '2194', (102, 106))	('genetic variants', 'Var', (82, 98))	('predict', 'Reg', (113, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (19, 43))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (19, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('hepatocellular carcinoma', 'Disease', (19, 43))
48463	30734280	Consistently, CM patients with high expression levels of fatty-acid metabolic signature genes resulted in a significant decrease in survival rates of CM patients, supporting a role of the fatty acid metabolism in CM progression.	('CM', 'Phenotype', 'HP:0012056', (150, 152))	('CM', 'Disease', 'MESH:C562393', (14, 16))	('CM', 'Phenotype', 'HP:0012056', (213, 215))	('patients', 'Species', '9606', (153, 161))	('fatty-acid', 'Chemical', 'MESH:D005227', (57, 67))	('survival rates', 'CPA', (132, 146))	('decrease', 'NegReg', (120, 128))	('CM', 'Phenotype', 'HP:0012056', (14, 16))	('patients', 'Species', '9606', (17, 25))	('high expression levels', 'Var', (31, 53))	('CM', 'Disease', 'MESH:C562393', (150, 152))	('fatty acid', 'Chemical', 'MESH:D005227', (188, 198))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('188', '209'))	('CM', 'Disease', 'MESH:C562393', (213, 215))
48464	30734280	We report here some striking significant associations of CMSS with genetic variants in ELOVL2 and HSD17B12.	('associations', 'Interaction', (41, 53))	('HSD17B12', 'Gene', (98, 106))	('CM', 'Phenotype', 'HP:0012056', (57, 59))	('ELOVL2', 'Gene', (87, 93))	('CM', 'Disease', 'MESH:C562393', (57, 59))	('HSD17B12', 'Gene', '51144', (98, 106))	('genetic variants', 'Var', (67, 83))
48467	30734280	We believe that these results are likely biologically plausible, since the genotype-phenotype correlation demonstrates that ELOVL2 expression levels may be modulated by rs3734398 T>C change, although additional investigation is needed to unravel molecular mechanisms underlying the observed correlation.	('modulated', 'Reg', (156, 165))	('ELOVL2 expression levels', 'MPA', (124, 148))	('rs3734398', 'Mutation', 'rs3734398', (169, 178))	('rs3734398 T>C change', 'Var', (169, 189))
48470	30734280	Deletion of ELOVL2 in a mouse model leads to a decrease in Foxp3+ regulatory T cells, suggesting its potential role in the adaptive immunity.	('Foxp3', 'Gene', '20371', (59, 64))	('mouse', 'Species', '10090', (24, 29))	('Foxp3', 'Gene', (59, 64))	('decrease', 'NegReg', (47, 55))	('ELOVL2', 'Gene', (12, 18))	('Deletion', 'Var', (0, 8))
48471	30734280	Recently, ELOVL2 rs3734398 has been reported to be significantly associated with plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement, which provides evidence on personalized dietary recommendations for reducing cardiovascular disease risk based on the genotype of this SNP.	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (109, 129))	('rs3734398', 'Var', (17, 26))	('eicosapentaenoic', 'Chemical', 'MESH:D015118', (88, 104))	('cardiovascular disease', 'Disease', 'MESH:D002318', (246, 268))	('ELOVL2', 'Gene', (10, 16))	('associated', 'Reg', (65, 75))	('cardiovascular disease', 'Disease', (246, 268))	('rs3734398', 'Mutation', 'rs3734398', (17, 26))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (246, 268))
48473	30734280	In light of our results and in the consideration that PUFAs are involved in crucial biological functions and that rs3734398 may regulate ELOVL2 expression, it is possible that genetic variants in ELOVL2 may be utilized in managing CM progression and prognosis in the future precision medicine, once validated by additional studies.	('CM', 'Phenotype', 'HP:0012056', (231, 233))	('rs3734398', 'Mutation', 'rs3734398', (114, 123))	('expression', 'MPA', (144, 154))	('variants', 'Var', (184, 192))	('CM', 'Disease', 'MESH:C562393', (231, 233))	('ELOVL2', 'Gene', (137, 143))	('regulate', 'Reg', (128, 136))	('PUFAs', 'Chemical', 'None', (54, 59))	('ELOVL2', 'Gene', (196, 202))
48480	30734280	Furthermore, HSD17B12 variants were found to be significantly associated with risk of biochemical recurrence in patients with localized prostate cancer in one study and with less aggressive form of neuroblastoma in another study.	('HSD17B12', 'Gene', (13, 21))	('neuroblastoma', 'Disease', 'MESH:D009447', (198, 211))	('associated', 'Reg', (62, 72))	('neuroblastoma', 'Disease', (198, 211))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('patients', 'Species', '9606', (112, 120))	('localized prostate cancer', 'Disease', 'MESH:D011471', (126, 151))	('biochemical recurrence', 'Disease', (86, 108))	('HSD17B12', 'Gene', '51144', (13, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (198, 211))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('variants', 'Var', (22, 30))	('localized prostate cancer', 'Disease', (126, 151))
48481	30734280	A major strength of the present study is the comprehensive analysis of associations between SNPs in all genes involved in the fatty acid synthesis pathway and survival of CM as well as the use of two published GWAS datasets with a relative long median follow-up time and strict quality control procedures.	('CM', 'Phenotype', 'HP:0012056', (171, 173))	('SNPs', 'Var', (92, 96))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('126', '146'))	('fatty acid', 'Chemical', 'MESH:D005227', (126, 136))	('associations', 'Interaction', (71, 83))	('CM', 'Disease', 'MESH:C562393', (171, 173))
48485	30734280	CI confidence interval CM cutaneous melanoma CMSS cutaneous melanoma-specific survival ELOVL2 elongation of very long-chain fatty acids 2 FASN fatty acid synthase FPRP false positive report probability GWAS genome-wide association study HRadj adjusted hazards ratio HSD17B12 hydroxysteroid 17-beta dehydrogenase 12 LD linkage disequilibrium NHS/HPFS the Nurses' Health Study and Health Professionals Follow-up Study SNP single-nucleotide polymorphism An increased fatty acid synthesis provides metabolic substrates for energy storage, membrane building and signaling transduction, which has been strongly associated with cancer prognosis.	('fatty acid', 'Chemical', 'MESH:D005227', (124, 134))	('membrane building', 'MPA', (535, 552))	('transduction', 'biological_process', 'GO:0009293', ('567', '579'))	('cancer', 'Disease', (621, 627))	('HSD17B12', 'Gene', (266, 274))	('metabolic substrates for energy storage', 'MPA', (494, 533))	('fatty acid', 'Chemical', 'MESH:D005227', (464, 474))	('cancer', 'Phenotype', 'HP:0002664', (621, 627))	('fatty acid synthase', 'Gene', (143, 162))	('hydroxysteroid 17-beta dehydrogenase 12', 'Gene', '51144', (275, 314))	('FASN', 'Gene', (138, 142))	('single-nucleotide polymorphism', 'Var', (420, 450))	('false', 'biological_process', 'GO:0071877', ('168', '173'))	('signaling', 'biological_process', 'GO:0023052', ('557', '566'))	('increased', 'PosReg', (454, 463))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('CM', 'Phenotype', 'HP:0012056', (23, 25))	('HRadj', 'Disease', 'None', (237, 242))	('fatty acid synthesis', 'MPA', (464, 484))	('HSD17B12', 'Gene', '51144', (266, 274))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('CM', 'Phenotype', 'HP:0012056', (45, 47))	('fatty acid synthase', 'Gene', '2194', (143, 162))	('cancer', 'Disease', 'MESH:D009369', (621, 627))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('464', '484'))	('CM', 'Disease', 'MESH:C562393', (23, 25))	('storage', 'biological_process', 'GO:0051235', ('526', '533'))	('membrane', 'cellular_component', 'GO:0016020', ('535', '543'))	('fatty acid', 'Chemical', 'MESH:D005227', (143, 153))	('HRadj', 'Disease', (237, 242))	('CM', 'Disease', 'MESH:C562393', (45, 47))	('false', 'biological_process', 'GO:0071878', ('168', '173'))	('fatty acids', 'Chemical', 'MESH:D005227', (124, 135))	('hydroxysteroid 17-beta dehydrogenase 12', 'Gene', (275, 314))	('associated', 'Reg', (605, 615))	('cutaneous melanoma', 'Disease', (50, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('cutaneous melanoma', 'Disease', (26, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (26, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (26, 44))	('FASN', 'Gene', '2194', (138, 142))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))
48486	30734280	The authors analyzed associations between variants in genes in the fatty acid synthesis pathway and cutaneous melanoma-specific survival by using datasets from two published genome-wide association studies.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cutaneous melanoma', 'Disease', (100, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('fatty acid', 'Chemical', 'MESH:D005227', (67, 77))	('variants', 'Var', (42, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('fatty acid synthesis', 'biological_process', 'GO:0006633', ('67', '87'))	('associations', 'Interaction', (21, 33))
48487	30734280	They found that ELOVL2 rs3734398 and HSD17B12 rs11037684 were significantly associated with cutaneous melanoma-specific survival, suggesting their potential roles as prognostic factors for melanoma patients.	('HSD17B12', 'Gene', (37, 45))	('rs3734398', 'Var', (23, 32))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('patients', 'Species', '9606', (198, 206))	('rs3734398', 'Mutation', 'rs3734398', (23, 32))	('ELOVL2', 'Gene', (16, 22))	('rs11037684', 'Var', (46, 56))	('associated with', 'Reg', (76, 91))	('melanoma', 'Disease', (102, 110))	('rs11037684', 'Mutation', 'rs11037684', (46, 56))	('cutaneous melanoma', 'Disease', (92, 110))	('HSD17B12', 'Gene', '51144', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (92, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (92, 110))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
48488	30188888	Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology.	('mutations', 'Var', (27, 36))	('PTPRJ', 'Gene', '483617', (21, 26))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (266, 274))	('malignant melanoma', 'Phenotype', 'HP:0002861', (153, 171))	('malignant melanoma', 'Disease', 'MESH:D008545', (153, 171))	('malignant melanoma', 'Disease', (84, 102))	('PTPRJ', 'Gene', (21, 26))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('inactivating', 'Var', (8, 20))	('Canine', 'Species', '9615', (146, 152))	('melanoma', 'Phenotype', 'HP:0002861', (266, 274))	('melanoma', 'Disease', (266, 274))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('malignant melanoma', 'Phenotype', 'HP:0002861', (84, 102))	('malignant melanoma', 'Disease', 'MESH:D008545', (84, 102))	('malignant melanoma', 'Disease', (153, 171))	('human', 'Species', '9606', (260, 265))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('canine', 'Species', '9615', (77, 83))	('dogs', 'Species', '9615', (218, 222))
48500	30188888	Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 alongside mutational patterns sharing important similarities with human melanoma subtypes.	('TP53', 'Gene', (143, 147))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('melanoma subtypes', 'Disease', (220, 237))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RAS', 'Gene', (128, 131))	('MDM2', 'Gene', (133, 137))	('melanoma subtypes', 'Disease', 'MESH:D008545', (220, 237))	('canine', 'Species', '9615', (81, 87))	('human', 'Species', '9606', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('mutations', 'Var', (68, 77))	('human', 'Species', '9606', (214, 219))	('cancer', 'Disease', (107, 113))	('contain', 'Reg', (60, 67))
48501	30188888	We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('canine', 'Species', '9615', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('PTPRJ', 'Gene', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('mutated', 'Var', (65, 72))
48505	30188888	Discovery of frequent activating BRAF mutations in melanoma and treatment with selective inhibitors of this mutant kinase has led to dramatic responses in the setting of metastatic disease.	('BRAF', 'Gene', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutations', 'Var', (38, 47))	('melanoma', 'Disease', (51, 59))	('activating', 'PosReg', (22, 32))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
48507	30188888	Moreover, targeted treatment options in melanoma subtypes without activating BRAF mutations are limited.	('melanoma subtypes', 'Disease', 'MESH:D008545', (40, 57))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BRAF', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('melanoma subtypes', 'Disease', (40, 57))
48512	30188888	Human mucosal melanoma is an aggressive histological subtype that is predominantly BRAF, RAS, and NF1 wild type (Triple Wild Type or TWT) with occasional mutations in KIT or NRAS.	('Human', 'Species', '9606', (0, 5))	('mucosal melanoma', 'Disease', (6, 22))	('mucosal melanoma', 'Disease', 'MESH:D008545', (6, 22))	('KIT', 'molecular_function', 'GO:0005020', ('167', '170'))	('mutations', 'Var', (154, 163))	('NRAS', 'Gene', (174, 178))	('KIT', 'Gene', (167, 170))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
48516	30188888	It is predominantly BRAFwt with frequent copy number alterations of regions of canine chromosomes (CFA) 13, 17, 22, and 30, alongside frequent MYC amplifications and deletions of CDKN2A.	('canine', 'Species', '9615', (79, 85))	('copy number alterations', 'Var', (41, 64))	('CDKN2A', 'Gene', '100271861', (179, 185))	('MYC', 'MPA', (143, 146))	('CDKN2A', 'Gene', (179, 185))	('deletions', 'Var', (166, 175))
48518	30188888	It has been shown that CFA30 aberrations are characteristic of canine oral melanoma and complex copy number profiles on this chromosome homologous to the same profiles on human chromosome (HSA) 15 in human mucosal melanoma are suggestive of rearrangements that may drive this melanoma subtype.	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('chromosome', 'cellular_component', 'GO:0005694', ('177', '187'))	('oral melanoma', 'Disease', (70, 83))	('human', 'Species', '9606', (171, 176))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('mucosal melanoma', 'Disease', (206, 222))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('mucosal melanoma', 'Disease', 'MESH:D008545', (206, 222))	('melanoma subtype', 'Disease', (276, 292))	('aberrations', 'Var', (29, 40))	('melanoma subtype', 'Disease', 'MESH:D008545', (276, 292))	('oral melanoma', 'Disease', 'MESH:D008545', (70, 83))	('human', 'Species', '9606', (200, 205))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('CFA30', 'Gene', (23, 28))	('canine', 'Species', '9615', (63, 69))
48521	30188888	Here we report the identification of recurrent inactivating mutations in the candidate tumor suppressor gene PTPRJ in addition to frequent RAS mutations, and mutually-exclusive MDM2 and TP53 alterations.	('RAS', 'Protein', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('inactivating mutations', 'Var', (47, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('PTPRJ', 'Gene', (109, 114))	('mutations', 'Var', (143, 152))
48529	30188888	Despite the prevalence of C:G>T:A transitions, most occurred in CpG dinucleotides and were not enriched at dipyrimidines (median 22.5%).	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (64, 81))	('C:G>T:A', 'Var', (26, 33))	('occurred', 'Reg', (52, 60))	('dipyrimidines', 'Chemical', '-', (107, 120))
48530	30188888	We additionally looked for TERT promoter mutations, which have been reported in 71% of human cutaneous melanomas and are associated with UV damage, but no somatic mutations were found within one kilobase of the TERT transcription start site.	('mutations', 'Var', (41, 50))	('cutaneous melanoma', 'Disease', (93, 111))	('human', 'Species', '9606', (87, 92))	('associated', 'Reg', (121, 131))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (93, 112))	('UV damage', 'Disease', 'MESH:C563466', (137, 146))	('melanomas', 'Disease', (103, 112))	('TERT promoter', 'Gene', (27, 40))	('UV damage', 'Disease', (137, 146))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('transcription', 'biological_process', 'GO:0006351', ('216', '229'))
48531	30188888	The most common mutation overall was C:G>T:A in GCG trinucleotides (median 3.29%) followed by C>T in ACG (median 2.6%) and C>A in TCT (median 2.5%) (S2 Fig).	('GCG', 'Chemical', '-', (48, 51))	('C>A', 'Var', (123, 126))	('trinucleotides', 'Chemical', '-', (52, 66))	('C>T', 'Var', (94, 97))	('C:G>T:A', 'Var', (37, 44))	('ACG', 'Chemical', 'MESH:C023716', (101, 104))
48533	30188888	Tumors assessed by whole-genome analysis displayed an abundance of somatic structural variants (SVs) and copy number variants (CNVs), with a modest burden of SNVs in coding regions (Fig 1A and 1B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('copy number variants', 'Var', (105, 125))
48537	30188888	A number of mutations in orthologs of human cancer genes were present in a single tumor each.	('human', 'Species', '9606', (38, 43))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
48539	30188888	To determine the prevalence of mutations in a panel of genes whose orthologs are known to play a role in human melanomagenesis, as well as the PTPRJ gene mutated in two cases, we performed targeted Sanger sequencing of all protein-coding regions of BAP1, BRAF, CDK4, GNA11, GNAQ, KIT, KRAS, MDM2, MITF, NF1, NRAS, PTEN, PTPRJ, and TP53 in the expanded cohort.	('CDK4', 'Gene', (261, 265))	('MITF', 'Gene', (297, 301))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('CDK', 'molecular_function', 'GO:0004693', ('261', '264'))	('MDM2', 'Gene', (291, 295))	('TP53', 'Gene', (331, 335))	('human', 'Species', '9606', (105, 110))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('PTEN', 'Gene', (314, 318))	('KIT', 'Gene', (280, 283))	('mutations', 'Var', (31, 40))	('BAP1', 'Gene', (249, 253))	('NRAS', 'Gene', (308, 312))	('PTPRJ', 'Gene', (320, 325))	('KIT', 'molecular_function', 'GO:0005020', ('280', '283'))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('KRAS', 'Gene', (285, 289))	('BRAF', 'Gene', (255, 259))	('NF1', 'Gene', (303, 306))
48548	30188888	CFA30 SVs were also present in three tumors with alterations occurring within a region spanning 15-24 Mb (also encompassing a GISTIC region) in each case.	('alterations', 'Var', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
48549	30188888	Complex chromosomal rearrangements reminiscent of chromothripsis were observed in four tumors (ND09-345, ND10-370, ND10-361, and ND10-441), with chained or clustered breakpoints localized to a subset of chromosomes in regions that also contained copy-number oscillations (S3 Fig).	('ND10-370', 'Var', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ND10', 'cellular_component', 'GO:0016605', ('105', '109'))	('ND10-441', 'Var', (129, 137))	('ND10', 'cellular_component', 'GO:0016605', ('129', '133'))	('ND09-345', 'Var', (95, 103))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('ND10', 'cellular_component', 'GO:0016605', ('115', '119'))	('tumors', 'Disease', (87, 93))	('ND10-361', 'Var', (115, 123))	('observed', 'Reg', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
48550	30188888	Approximately 90% of human cutaneous melanomas are driven in part by BRAF, RAS, NF1, and KIT mutations that confer constitutive mitogenic signaling through the MAPK pathway.	('melanomas', 'Disease', (37, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('160', '164'))	('NF1', 'Gene', (80, 83))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('MAPK pathway', 'Pathway', (160, 172))	('KIT', 'Gene', (89, 92))	('RAS', 'Gene', (75, 78))	('BRAF', 'Gene', (69, 73))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))	('driven', 'Reg', (51, 57))	('mutations', 'Var', (93, 102))	('mitogenic signaling', 'MPA', (128, 147))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('cutaneous melanoma', 'Disease', (27, 45))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (27, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('human', 'Species', '9606', (21, 26))	('melanomas', 'Disease', 'MESH:D008545', (37, 46))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))
48554	30188888	NRAS codon 61 (Q61R/H/K) and KRAS codon 12 (G12C) mutations occurred each in four cases while a single case bore an HRAS Q61R mutation (nine total RAS mutations).	('Q61R', 'SUBSTITUTION', 'None', (15, 19))	('Q61R', 'Var', (15, 19))	('Q61R', 'Mutation', 'rs121913233', (121, 125))	('Q61R', 'Mutation', 'rs121913233', (15, 19))	('KRAS', 'Gene', (29, 33))	('occurred', 'Reg', (60, 68))	('G12C', 'Mutation', 'rs121913530', (44, 48))	('Q61R', 'SUBSTITUTION', 'None', (121, 125))	('Q61R', 'Var', (121, 125))
48555	30188888	KIT mutations were present in one cutaneous and two mucosal tumors (S3 and S4 Tables).	('mucosal tumors', 'Disease', (52, 66))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('present', 'Reg', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (4, 13))	('mucosal tumors', 'Disease', 'MESH:D052016', (52, 66))	('KIT', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
48556	30188888	In the cutaneous case, the mutation results in a glutamine (Q) to arginine (R) change in codon 396, notably a site of variation between canine and human orthologs, a change that is not predicted to be damaging by PROVEAN, and may constitute a germline SNP, but germline DNA was not available in this case.	('glutamine', 'Chemical', 'MESH:D005973', (49, 58))	('human', 'Species', '9606', (147, 152))	('results in', 'Reg', (36, 46))	('change', 'Reg', (79, 85))	('mutation', 'Var', (27, 35))	('canine', 'Species', '9615', (136, 142))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('arginine', 'Chemical', 'MESH:D001120', (66, 74))
48557	30188888	KIT mutations in the mucosal cases included an in-frame deletion of amino acids 560-562, a likely damaging mutation in a commonly mutated region of the human ortholog, as well as an aspartic acid (D) to valine (V) change in codon 815 corresponding to the most common hotspot D816V mutations occurring in the kinase domain of KIT in human cancers (S5 Fig).	('cancers', 'Disease', (338, 345))	('KIT', 'molecular_function', 'GO:0005020', ('325', '328'))	('D816V', 'Chemical', '-', (275, 280))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('aspartic acid', 'Chemical', 'MESH:D001224', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('human', 'Species', '9606', (152, 157))	('valine', 'Chemical', 'MESH:D014633', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (338, 345))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('human', 'Species', '9606', (332, 337))	('cancers', 'Disease', 'MESH:D009369', (338, 345))
48560	30188888	It has since been shown to be frequently involved in allelic loss or loss of heterozygosity (LOH) in human cancers and mouse models and to potentially play a role in oncogenesis in diverse cancer types, but somatic homozygous deletions or truncating mutations have yet to be described in cancer from any species and its tumor suppressor status remains controversial.	('cancers', 'Disease', (107, 114))	('oncogenesis', 'biological_process', 'GO:0007048', ('166', '177'))	('loss of heterozygosity', 'NegReg', (69, 91))	('cancer', 'Disease', (288, 294))	('allelic loss', 'Disease', (53, 65))	('play', 'Reg', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('mouse', 'Species', '10090', (119, 124))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('truncating mutations', 'Var', (239, 259))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('allelic loss', 'Disease', 'MESH:C566065', (53, 65))	('human', 'Species', '9606', (101, 106))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('320', '336'))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumor suppressor', 'biological_process', 'GO:0051726', ('320', '336'))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
48562	30188888	Sequencing of PTPRJ across all 37 tumors revealed nine mutations in seven cases (all mucosal), comprising 19% of all tumors and 23% of mucosal cases.	('PTPRJ', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
48565	30188888	Consistent with this finding, the PTPRJ frameshift in the ND10-166 tumor occurred at an allele ratio of 61% in DNA and 100% in RNA.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('ND10', 'cellular_component', 'GO:0016605', ('58', '62'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('frameshift', 'Var', (40, 50))	('RNA', 'cellular_component', 'GO:0005562', ('127', '130'))	('ND10-166', 'Gene', (58, 66))
48566	30188888	Finally, PTPRJ transcript was observed in RNAseq data from the two PTPRJ-mutant tumors profiled by WGS and RNAseq (270.21 Fragments Per Kilobase of transcript per Million mapped reads (FPKMs) in ND10-166 and 92.37 FPKMS in ND10-376) as shown in S7 Fig.	('PTPRJ-mutant', 'Gene', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ND10', 'cellular_component', 'GO:0016605', ('223', '227'))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('PTPRJ-mutant', 'Var', (67, 79))	('ND10', 'cellular_component', 'GO:0016605', ('195', '199'))
48567	30188888	ND10-376, containing two somatic PTPRJ mutations (a frameshift and a splice site mutation) and 92.37 FPKMs, bore the lowest transcript abundance among all seven profiled tumors.	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (39, 48))	('transcript abundance', 'MPA', (124, 144))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('PTPRJ', 'Gene', (33, 38))	('lowest', 'NegReg', (117, 123))	('ND10', 'cellular_component', 'GO:0016605', ('0', '4'))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))
48569	30188888	Inactivation of the p53 network is a critical step in tumorigenesis in nearly all cancers.	('p53', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('Inactivation', 'Var', (0, 12))
48570	30188888	Although TP53 mutations and MDM2 amplifications in human melanoma are less common, 16/37 (43%) of the cases in our cohort of canine melanoma bore focal amplifications of MDM2 or truncating TP53 mutations (Fig 1C).	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('MDM2', 'Gene', (170, 174))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('TP53', 'Gene', (189, 193))	('truncating', 'Var', (178, 188))	('mutations', 'Var', (194, 203))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('human', 'Species', '9606', (51, 56))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('canine', 'Species', '9615', (125, 131))
48575	30188888	We additionally discovered seven tumors with mutations in TP53 whose protein product shares 80% identity with its human ortholog (S9 Fig).	('mutations', 'Var', (45, 54))	('tumors', 'Disease', (33, 39))	('TP53', 'Gene', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('human', 'Species', '9606', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))
48576	30188888	Three of these mutations were truncating-a homozygous T90X in ND10-252, heterozygous K151fs in ND11-201, and a heterozygous Q306X in ND10-564 (Fig 2D and S4 Table).	('ND11-201', 'Gene', (95, 103))	('ND10', 'cellular_component', 'GO:0016605', ('133', '137'))	('ND10-252', 'Gene', (62, 70))	('Q306X', 'Mutation', 'p.Q306X', (124, 129))	('K151fs', 'Var', (85, 91))	('T90X', 'Var', (54, 58))	('Q306X', 'Var', (124, 129))	('ND10', 'cellular_component', 'GO:0016605', ('62', '66'))	('K151fs', 'Mutation', 'p.K151fsX', (85, 91))	('T90X', 'Mutation', 'p.T90X', (54, 58))
48577	30188888	Of the three missense mutations, R145C and R270H were predicted to be damaging.	('R270H', 'Var', (43, 48))	('R145C', 'Var', (33, 38))	('R145C', 'Mutation', 'rs1064795369', (33, 38))	('R270H', 'Mutation', 'rs55819519', (43, 48))
48578	30188888	R145C occurred in two tumors and R270H in a single tumor, with both mutations confirmed somatic through analysis of matched germline DNA.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('R270H', 'Mutation', 'rs55819519', (33, 38))	('tumor', 'Disease', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('R145C', 'Var', (0, 5))	('tumor', 'Disease', (22, 27))	('R145C', 'Mutation', 'rs1064795369', (0, 5))	('occurred', 'Reg', (6, 14))	('R270H', 'Var', (33, 38))	('tumors', 'Disease', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
48582	30188888	In keeping with findings in other cancers, no sequence mutations were present in MDM2 and MDM2 amplifications were mutually exclusive with TP53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MDM2', 'Gene', (81, 85))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('TP53', 'Gene', (139, 143))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('MDM2', 'Gene', (90, 94))	('mutations', 'Var', (144, 153))
48586	30188888	PI3K cascade P = 0.002, mTOR signaling P = 0.008, signaling by Rho GTPases P = 0.012, VEGF signaling P = 0.017, RAF activation P = 0.017, melanoma signaling P = 0.021, RAS signaling P = 0.031, and MEK activation P = 0.036) and, in many cases, intersections with MDM2 signaling.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('melanoma', 'Disease', (138, 146))	('PI3K', 'Var', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('PI3K cascade', 'biological_process', 'GO:0014065', ('0', '12'))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('VEGF', 'Gene', (86, 90))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('mTOR', 'Gene', '478232', (24, 28))	('VEGF signaling', 'biological_process', 'GO:0038084', ('86', '100'))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('signaling', 'biological_process', 'GO:0023052', ('267', '276'))	('mTOR', 'Gene', (24, 28))	('VEGF', 'Gene', '403802', (86, 90))
48602	30188888	Cutaneous sun-exposed melanoma is characterized both by high point mutation frequencies linked to UV damage and also only modest burdens of structural variation.	('Cutaneous sun-exposed melanoma', 'Phenotype', 'HP:0012056', (0, 30))	('UV damage', 'Disease', 'MESH:C563466', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('UV damage', 'Disease', (98, 107))	('point mutation', 'Var', (61, 75))
48608	30188888	Numerous studies have shown a clear positive correlation between mutation burden, abundance of neoantigens, and clinical benefit in human melanoma and other cancers.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('melanoma', 'Disease', (138, 146))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('mutation', 'Var', (65, 73))	('cancers', 'Disease', (157, 164))	('human', 'Species', '9606', (132, 137))	('clinical', 'Species', '191496', (112, 120))
48611	30188888	High point mutation burden in sun-exposed cutaneous melanoma is understood to result from UV-induced over-representation of C>T transitions occurring in dipyrimidines versus non-dipyrimidines.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('C>T transitions', 'Var', (124, 139))	('dipyrimidines', 'Chemical', '-', (178, 191))	('over-representation', 'PosReg', (101, 120))	('dipyrimidines', 'Var', (153, 166))	('dipyrimidines', 'Chemical', '-', (153, 166))	('cutaneous melanoma', 'Disease', (42, 60))
48614	30188888	These mutations correlate with age in human cancers and are due to spontaneous deamination of 5-methylcytosine.	('human', 'Species', '9606', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (94, 110))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
48615	30188888	Enrichment for these mutations in canine melanoma is not surprising given that the largest risk factor for cancer in humans and dogs is biological (not chronological) age and that the mean age of these dogs at the time of surgical resection was 13 years (range: 10-16).	('dogs', 'Species', '9615', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('dogs', 'Species', '9615', (128, 132))	('canine', 'Species', '9615', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('melanoma', 'Disease', (41, 49))	('humans', 'Species', '9606', (117, 123))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (21, 30))
48617	30188888	Commonly observed mutational patterns in human melanoma such as kataegis were not observed, although four tumors exhibited clustered or chained translocations suggestive of breakage-fusion-bridge events due to telomere crisis or of chromothripsis, in which one or a few chromosomes undergo punctuated shattering and reassembly events.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('telomere', 'cellular_component', 'GO:0000781', ('210', '218'))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('breakage-fusion-bridge', 'Var', (173, 195))	('telomere', 'cellular_component', 'GO:0005696', ('210', '218'))
48619	30188888	Notably, we show here that MDM2 and mutually exclusive TP53 alterations are common in canine melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('common', 'Reg', (76, 82))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('TP53', 'Gene', (55, 59))	('MDM2', 'Gene', (27, 31))	('alterations', 'Var', (60, 71))	('canine', 'Species', '9615', (86, 92))
48620	30188888	Similarly, inactivating p53 mutations have been found in human mucosal and acral melanoma, suggesting p53 pathway dysregulation may be crucial in non-UV induced melanoma development.	('inactivating', 'Var', (11, 23))	('mucosal', 'Disease', (63, 70))	('p53', 'Gene', (24, 27))	('acral melanoma', 'Disease', (75, 89))	('acral melanoma', 'Phenotype', 'HP:0012060', (75, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Disease', (161, 169))	('mutations', 'Var', (28, 37))	('acral melanoma', 'Disease', 'MESH:D008545', (75, 89))	('human', 'Species', '9606', (57, 62))
48621	30188888	Further, UV-induced TERT promoter mutations are common in human cutaneous melanoma, and, although they are rare in sun-shielded subtypes, these subtypes have been shown to bear enrichment for other types of mutation that drive TERT overexpression such as SVs and CNVs.	('CNVs', 'Disease', (263, 267))	('human', 'Species', '9606', (58, 63))	('TERT promoter', 'Gene', (20, 33))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('cutaneous melanoma', 'Disease', (64, 82))	('mutation', 'Var', (207, 215))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 82))	('mutations', 'Var', (34, 43))	('SVs', 'Disease', (255, 258))
48628	30188888	Intriguingly, mutually exclusive focal amplification of MDM2 or inactivating mutation in TP53 have been shown to be enriched in BRAF-, NRAS-, and NF1-wild-type human melanoma, although human TP53-mutant melanomas tend to also display higher mutation burden and presence of C>T transitions.	('inactivating mutation', 'Var', (64, 85))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('melanoma', 'Disease', (166, 174))	('TP53', 'Gene', (89, 93))	('human', 'Species', '9606', (185, 190))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('mutation burden', 'MPA', (241, 256))	('TP53-mutant', 'Var', (191, 202))	('melanomas', 'Disease', (203, 212))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('C>T transitions', 'CPA', (273, 288))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('higher', 'PosReg', (234, 240))	('melanoma', 'Disease', (203, 211))	('MDM2', 'Gene', (56, 60))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))	('human', 'Species', '9606', (160, 165))
48629	30188888	Taken together the high degree of structural complexity, the lack of TERT mutations (barring one putative translocation) or telomere-lengthening mechanisms, and the frequency of MDM2/TP53 mutations all suggest that chromosome instability plays a key role in canine melanomagenesis.	('MDM2/TP53', 'Gene', (178, 187))	('chromosome', 'cellular_component', 'GO:0005694', ('215', '225'))	('chromosome instability', 'Phenotype', 'HP:0040012', (215, 237))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('telomere', 'cellular_component', 'GO:0000781', ('124', '132'))	('canine', 'Species', '9615', (258, 264))	('mutations', 'Var', (188, 197))	('melanoma', 'Disease', (265, 273))	('telomere', 'cellular_component', 'GO:0005696', ('124', '132'))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))
48630	30188888	In the discovery cohort, putatively pathogenic somatic mutations in orthologs of human cancer genes were present in a single tumor each including ATF6, EPAS1, FAT2, FAT4, FOXA3, FOXO1, GAB2, HRAS, KIT, KRAS, MMP21, NRAS, PBX1, and XPO1 (S3 Table).	('cancer', 'Disease', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MMP', 'molecular_function', 'GO:0004235', ('208', '211'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('KIT', 'molecular_function', 'GO:0005020', ('197', '200'))	('tumor', 'Disease', (125, 130))	('pathogenic', 'Reg', (36, 46))	('human', 'Species', '9606', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
48632	30188888	Combined, these mutations most commonly impact proliferative and cell cycle/apoptosis pathways in patterns that display both key similarities and differences with human melanoma subtypes (Fig 3D).	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('impact', 'Reg', (40, 46))	('mutations', 'Var', (16, 25))	('human', 'Species', '9606', (163, 168))	('melanoma subtypes', 'Disease', (169, 186))	('cell cycle', 'biological_process', 'GO:0007049', ('65', '75'))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('melanoma subtypes', 'Disease', 'MESH:D008545', (169, 186))
48633	30188888	For example, despite an absence of BRAF and lower abundance of RAS and KIT mutations in canine versus human mucosal melanoma, these tumors display likely MAPK activating events in 35% of cases.	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('canine', 'Species', '9615', (88, 94))	('KIT', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('mucosal melanoma', 'Disease', (108, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('RAS', 'Protein', (63, 66))	('mucosal melanoma', 'Disease', 'MESH:D008545', (108, 124))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))	('mutations', 'Var', (75, 84))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('MAPK', 'MPA', (154, 158))	('human', 'Species', '9606', (102, 107))
48634	30188888	Further, canine mucosal melanoma displays a higher burden of cell cycle and apoptotic events (51%) than all subtypes from the Hayward comparator human melanoma cohort assessed here due largely to enrichment for mutually exclusive MDM2 and TP53 mutations in canine mucosal melanoma.	('canine', 'Species', '9615', (9, 15))	('melanoma cohort', 'Disease', (151, 166))	('cell cycle', 'biological_process', 'GO:0007049', ('61', '71'))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('mucosal melanoma', 'Disease', (264, 280))	('human', 'Species', '9606', (145, 150))	('MDM2', 'Gene', (230, 234))	('mucosal melanoma', 'Disease', 'MESH:D008545', (264, 280))	('mucosal melanoma', 'Disease', (16, 32))	('melanoma cohort', 'Disease', 'MESH:D008545', (151, 166))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('cell cycle', 'CPA', (61, 71))	('mutations', 'Var', (244, 253))	('canine', 'Species', '9615', (257, 263))	('TP53', 'Gene', (239, 243))	('mucosal melanoma', 'Disease', 'MESH:D008545', (16, 32))
48635	30188888	However, these mutations are common in human cutaneous melanoma (ranging from 36% of cases in the Hayward comparator cohort to 62% in the TCGA cutaneous melanoma study).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('cutaneous melanoma', 'Disease', (45, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (45, 63))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (45, 63))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mutations', 'Var', (15, 24))	('cutaneous melanoma', 'Disease', (143, 161))	('human', 'Species', '9606', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
48641	30188888	The majority of human cutaneous melanomas are driven in part by constitutive activation of the MAPK pathway through mutation of genes such as BRAF, NRAS, NF1, KIT, GNAQ, and GNA11, often in a mutually exclusive pattern.	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('mutation', 'Var', (116, 124))	('GNA11', 'Gene', (174, 179))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('BRAF', 'Gene', (142, 146))	('KIT', 'molecular_function', 'GO:0005020', ('159', '162'))	('cutaneous melanoma', 'Disease', (22, 40))	('GNAQ', 'Gene', (164, 168))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('MAPK pathway', 'Pathway', (95, 107))	('human', 'Species', '9606', (16, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (22, 40))	('KIT', 'Gene', (159, 162))	('NF1', 'Gene', (154, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('melanomas', 'Disease', 'MESH:D008545', (32, 41))	('NRAS', 'Gene', (148, 152))	('melanomas', 'Disease', (32, 41))	('activation', 'PosReg', (77, 87))
48642	30188888	The high frequency of these mutations has motivated the TCGA classification of these tumors according to MAPK mutation status: BRAF (~50% of cases), RAS (~30%), NF1 (~15%), and TWT (~10%).	('RAS', 'Disease', (149, 152))	('BRAF', 'Disease', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('NF1', 'Disease', (161, 164))	('TWT', 'Disease', (177, 180))	('MAPK', 'molecular_function', 'GO:0004707', ('105', '109'))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MAPK', 'Gene', (105, 109))	('mutations', 'Var', (28, 37))	('tumors', 'Disease', (85, 91))
48645	30188888	Correspondingly, it has been shown that BRAF mutations are exceedingly rare in predominantly oral canine malignant melanoma and, to date, few alterations in other MAPK members have been discovered.	('malignant melanoma', 'Disease', 'MESH:D008545', (105, 123))	('mutations', 'Var', (45, 54))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('BRAF', 'Gene', (40, 44))	('malignant melanoma', 'Disease', (105, 123))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('canine', 'Species', '9615', (98, 104))	('malignant melanoma', 'Phenotype', 'HP:0002861', (105, 123))
48646	30188888	In total, 35% of mucosal and 43% of all canine melanomas bear an alteration impacting the MAPK pathway (Figs 1C and 3D).	('MAPK pathway', 'Pathway', (90, 102))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('canine', 'Species', '9615', (40, 46))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('impacting', 'Reg', (76, 85))	('alteration', 'Var', (65, 75))	('melanomas', 'Disease', (47, 56))
48647	30188888	Here we show a complete absence of somatic BRAF mutations (SNVs, CNVs, or translocations encompassing the BRAF locus) in canine malignant melanoma in keeping with prior studies.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('canine', 'Species', '9615', (121, 127))	('BRAF', 'Gene', (43, 47))	('malignant melanoma', 'Phenotype', 'HP:0002861', (128, 146))	('absence', 'NegReg', (24, 31))	('translocations', 'Var', (74, 88))	('malignant melanoma', 'Disease', 'MESH:D008545', (128, 146))	('malignant melanoma', 'Disease', (128, 146))	('mutations', 'Var', (48, 57))
48649	30188888	In humans, of these family members, malignant melanomas predominantly bear NRAS mutations with only very rare KRAS and HRAS mutations.	('mutations', 'Var', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('malignant melanomas', 'Phenotype', 'HP:0002861', (36, 55))	('NRAS', 'Gene', (75, 79))	('malignant melanomas', 'Disease', 'MESH:D008545', (36, 55))	('humans', 'Species', '9606', (3, 9))	('malignant melanoma', 'Phenotype', 'HP:0002861', (36, 54))	('malignant melanomas', 'Disease', (36, 55))
48650	30188888	In our cohort, we found four NRAS codon 61 alterations (11%), four KRAS G12C mutations and one HRAS Q61R mutation.	('NRAS codon 61', 'Gene', (29, 42))	('G12C', 'Mutation', 'rs121913530', (72, 76))	('alterations', 'Var', (43, 54))	('Q61R', 'Mutation', 'rs121913233', (100, 104))	('KRAS G12C mutations', 'Var', (67, 86))
48651	30188888	Further, four of these RAS alterations (two NRAS, one KRAS, and one HRAS mutation) occur in mucosal tumors, a frequency of 13% in this subtype.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mucosal tumors', 'Disease', 'MESH:D052016', (92, 106))	('occur', 'Reg', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mucosal tumors', 'Disease', (92, 106))	('RAS', 'Gene', (23, 26))	('alterations', 'Var', (27, 38))
48652	30188888	However, in our cohort all three acral tumors and both cutaneous tumors had detectable RAS alterations (three KRAS and two NRAS mutations).	('cutaneous tumors', 'Disease', 'MESH:D009369', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cutaneous tumors', 'Disease', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('alterations', 'Reg', (91, 102))	('acral tumors', 'Disease', (33, 45))	('cutaneous tumors', 'Phenotype', 'HP:0008069', (55, 71))	('RAS', 'Protein', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('acral tumors', 'Disease', 'MESH:D009369', (33, 45))	('KRAS', 'Var', (110, 114))
48653	30188888	This unusual pattern of RAS mutation in canine melanoma may reflect important differences in biological, tissue, and species specificities of RAS family members.	('RAS', 'Gene', (24, 27))	('canine', 'Species', '9615', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('mutation', 'Var', (28, 36))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
48657	30188888	Early genetic studies of quantitative trait loci for mouse cancer susceptibility with homologous regions in human cancers pointed to recurrent PTPRJ deletions, LOH, and missense mutations in small cohorts of colorectal (49%), lung (50%), and breast (78%) carcinomas in addition to a correlation between PTPRJ LOH and colorectal cancer progression.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('PTPRJ', 'Gene', (143, 148))	('cancers', 'Disease', (114, 121))	('colorectal', 'Disease', (208, 218))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (328, 334))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('colorectal cancer', 'Disease', 'MESH:D015179', (317, 334))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('carcinomas', 'Disease', 'MESH:D002277', (255, 265))	('colorectal cancer', 'Disease', (317, 334))	('mouse', 'Species', '10090', (53, 58))	('colorectal', 'Disease', 'MESH:D015179', (208, 218))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('colorectal', 'Disease', (317, 327))	('deletions', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('colorectal cancer', 'Phenotype', 'HP:0003003', (317, 334))	('carcinomas', 'Disease', (255, 265))	('human', 'Species', '9606', (108, 113))	('cancer', 'Disease', (59, 65))	('colorectal', 'Disease', 'MESH:D015179', (317, 327))	('missense mutations', 'Var', (169, 187))	('cancer', 'Disease', (114, 120))
48658	30188888	Additional sequencing studies in larger cohorts have identified nonsynonymous SNPs in the extracellular fibronectin repeats associated with risk of developing thyroid, colorectal, head and neck squamous cell, and esophageal cancers.	('extracellular', 'cellular_component', 'GO:0005576', ('90', '103'))	('esophageal cancers', 'Disease', (213, 231))	('nonsynonymous SNPs', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('colorectal', 'Disease', 'MESH:D015179', (168, 178))	('esophageal cancers', 'Disease', 'MESH:D004938', (213, 231))	('thyroid', 'Disease', (159, 166))	('associated', 'Reg', (124, 134))	('extracellular fibronectin', 'Protein', (90, 115))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('colorectal', 'Disease', (168, 178))	('neck', 'cellular_component', 'GO:0044326', ('189', '193'))
48659	30188888	More recently, a subclonal K1017N missense mutation in the non-catalytic cytoplasmic domain of PTPRJ was identified in a primary breast tumor with significant enrichment in a brain metastases and patient-derived xenograft.	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('breast tumor', 'Phenotype', 'HP:0100013', (129, 141))	('K1017N', 'Mutation', 'p.K1017N', (27, 33))	('breast tumor', 'Disease', 'MESH:D001943', (129, 141))	('patient', 'Species', '9606', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('metastases', 'Disease', (181, 191))	('breast tumor', 'Disease', (129, 141))	('identified', 'Reg', (105, 115))	('PTPRJ', 'Gene', (95, 100))	('K1017N missense mutation', 'Var', (27, 51))
48661	30188888	However, Ptprj knockout mice have normal development with no cancer predisposition and thus inactivation of this gene does not appear to be sufficient to induce tumorigenesis.	('inactivation', 'Var', (92, 104))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('mice', 'Species', '10090', (24, 28))	('cancer', 'Disease', (61, 67))	('Ptprj', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (161, 166))	('Ptprj', 'Gene', '19271', (9, 14))
48662	30188888	Across all TCGA studies published to date (10,951 cases from 33 tumor types in the TCGA PanCancer Atlas accessed via cBioPortal), the frequency of somatic PTPRJ point mutations and/or deep deletions is low- 211/10,951 (1.9%, S12 Table).	('deep deletions', 'Var', (184, 198))	('tumor', 'Disease', (64, 69))	('PTPRJ', 'Gene', (155, 160))	('point mutations', 'Var', (161, 176))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
48663	30188888	Only 21 somatic PTRPJ mutations are present in the TCGA human cutaneous melanoma data set consisting of 363 cases (a single homozygous deletion, five truncating mutations, and fifteen missense mutations).	('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))	('truncating', 'MPA', (150, 160))	('human', 'Species', '9606', (56, 61))	('PTRPJ', 'Gene', (16, 21))	('mutations', 'Var', (22, 31))	('missense mutations', 'Var', (184, 202))
48664	30188888	However, a related receptor-type protein tyrosine phosphatase, PTPRD, is thought play a role in regulation of STAT3 signaling and has been frequently implicated as a tumor suppressor in human cancers through inactivating somatic mutation, focal deletion or methylation in glioma, melanoma, neuroblastoma, colorectal, liver, head and neck, and lung cancers.	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('lung cancers', 'Disease', 'MESH:D008175', (343, 355))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('PTPRD', 'Gene', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('cancers', 'Disease', (192, 199))	('lung cancers', 'Disease', (343, 355))	('glioma', 'Disease', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('colorectal', 'Disease', 'MESH:D015179', (305, 315))	('neck', 'cellular_component', 'GO:0044326', ('333', '337'))	('lung cancers', 'Phenotype', 'HP:0100526', (343, 355))	('STAT3', 'Gene', (110, 115))	('glioma', 'Disease', 'MESH:D005910', (272, 278))	('PTPRD', 'Gene', '5789', (63, 68))	('melanoma', 'Disease', 'MESH:D008545', (280, 288))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('regulation', 'MPA', (96, 106))	('phosphatase', 'molecular_function', 'GO:0016791', ('50', '61'))	('STAT3', 'Gene', '6774', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('neuroblastoma', 'Disease', (290, 303))	('glioma', 'Phenotype', 'HP:0009733', (272, 278))	('methylation', 'Var', (257, 268))	('tumor', 'Disease', (166, 171))	('focal deletion', 'Var', (239, 253))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('neuroblastoma', 'Phenotype', 'HP:0003006', (290, 303))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('neuroblastoma', 'Disease', 'MESH:D009447', (290, 303))	('inactivating somatic mutation', 'Var', (208, 237))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('melanoma', 'Disease', (280, 288))	('colorectal', 'Disease', (305, 315))	('liver', 'Disease', (317, 322))	('human', 'Species', '9606', (186, 191))	('methylation', 'biological_process', 'GO:0032259', ('257', '268'))
48665	30188888	In human cutaneous melanoma, PTPRD is deleted or truncated in 9-12% of cutaneous cases, but has not been determined to occur at high frequency in rare histological subtypes.	('cutaneous', 'Disease', (71, 80))	('deleted', 'Var', (38, 45))	('human', 'Species', '9606', (3, 8))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('truncated', 'Var', (49, 58))	('PTPRD', 'Gene', '5789', (29, 34))	('PTPRD', 'Gene', (29, 34))
48667	30188888	We have discovered seven cases (19%) of canine melanomas bearing somatic PTPRJ mutations.	('PTPRJ', 'Gene', (73, 78))	('canine', 'Species', '9615', (40, 46))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('mutations', 'Var', (79, 88))	('melanomas', 'Disease', (47, 56))
48669	30188888	Sequencing of PTPRJ across all 37 tumors revealed nine mutations in seven cases (seven mucosal and one uveal) comprising 19% of all tumors and 23% of mucosal cases.	('PTPRJ', 'Gene', (14, 19))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Disease', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
48671	30188888	Overall, the enrichment for PTPRJ truncating mutation in canine malignant melanoma bears intriguing implications both for a previously underappreciated role for this gene in human melanoma (e.g.	('PTPRJ', 'Gene', (28, 33))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('human', 'Species', '9606', (174, 179))	('malignant melanoma', 'Disease', 'MESH:D008545', (64, 82))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('malignant melanoma', 'Disease', (64, 82))	('canine', 'Species', '9615', (57, 63))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('truncating mutation', 'Var', (34, 53))	('malignant melanoma', 'Phenotype', 'HP:0002861', (64, 82))
48672	30188888	through as-yet understudied roles for hemizygous deletion and/or epigenetic modifications) and for the possibility of unique mechanisms of tumorigenesis across species.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('hemizygous deletion', 'Var', (38, 57))	('epigenetic modifications', 'Var', (65, 89))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))
48673	30188888	Through deep integrated genomic analysis combining WGS, LI-WGS, RNA sequencing, aCGH, SNP arrays, and targeted Sanger sequencing we have determined that canine melanoma is driven by frequent dysregulation of MAPK and cell cycle/apoptosis pathways and, in some cases as is seen in our WGS cohort of predominantly Cocker Spaniels, extensive chromosomal instability.	('cell cycle/apoptosis pathways', 'Pathway', (217, 246))	('cell cycle', 'biological_process', 'GO:0007049', ('217', '227'))	('canine', 'Species', '9615', (153, 159))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('chromosomal instability', 'Phenotype', 'HP:0040012', (339, 362))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('228', '237'))	('apoptosis', 'biological_process', 'GO:0006915', ('228', '237'))	('MAPK', 'molecular_function', 'GO:0004707', ('208', '212'))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))	('dysregulation', 'Var', (191, 204))
48737	29533867	In addition, the topography of MCC may not exactly be coded as skin (ICD-O topography codes C44.0-C44.9) but may include topographies that most likely reflect the skin as the origin including the lip (C00.0-C00.9), anus, not other specified (NOS) (C21.0), anal canal, anal sphincter (C21.1), connective, subcutaneous and other soft tissues: head, face or neck (C49.0), upper limb and shoulder (C49.1), lower limb and hip (C49.2), trunk, NOS (C49.6), vulva (C51.0-C51.9), female genital tract, NOS (C57.9), penis (C60.0-C60.9), scrotum (C63.2), overlapping lesion of the male genital organs (C63.8), male genital organs, NOS (C63.9), other and ill-defined sites at the head, face or neck, NOS (C76.0), pelvis, NOS (C76.3), upper limb, NOS (C76.4), lower limb, NOS (C76.5) and other ill-defined sites (back, flank, trunk, NOS; C76.7).	('C21', 'Gene', '79718', (248, 251))	('lower limb', 'Phenotype', 'HP:0006385', (402, 412))	('C76.3', 'Var', (714, 719))	('MCC', 'cellular_component', 'GO:0033597', ('31', '34'))	('C21', 'Gene', (284, 287))	('neck', 'cellular_component', 'GO:0044326', ('355', '359'))	('C21', 'Gene', '79718', (284, 287))	('trunk', 'cellular_component', 'GO:0043198', ('813', '818'))	('lower limb', 'Phenotype', 'HP:0006385', (747, 757))	('MCC', 'biological_process', 'GO:0120197', ('31', '34'))	('C21', 'Gene', (248, 251))	('neck', 'cellular_component', 'GO:0044326', ('682', '686'))	('trunk', 'cellular_component', 'GO:0043198', ('430', '435'))
48750	29533867	For the retrieval of coded Merkel cell carcinoma, it is essential that cancer registries used the second edition of ICD-O because the first edition contains only less specific codes like trabecular carcinoma (8190/3), small cell carcinoma of the skin (8002/3, 8041/3, 8043/3, 8044/3), undifferentiated carcinoma of the skin (8020/3), and anaplastic carcinoma of the skin (8021/3).	('carcinoma of the skin', 'Disease', 'MESH:D012878', (302, 323))	('carcinoma of the skin', 'Disease', 'MESH:D012878', (229, 250))	('Merkel cell carcinoma', 'Disease', (27, 48))	('undifferentiated carcinoma of the skin', 'Phenotype', 'HP:0030447', (285, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('anaplastic carcinoma of the skin', 'Phenotype', 'HP:0030447', (338, 370))	('cancer', 'Disease', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('trabecular carcinoma', 'Disease', (187, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (349, 358))	('trabecular carcinoma', 'Disease', 'MESH:D000236', (187, 207))	('carcinoma of the skin', 'Disease', (349, 370))	('8002/3', 'Var', (252, 258))	('carcinoma of the skin', 'Disease', (302, 323))	('carcinoma of the skin', 'Disease', (229, 250))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('small cell carcinoma of the skin', 'Phenotype', 'HP:0030447', (218, 250))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (218, 238))	('carcinoma of the skin', 'Disease', 'MESH:D012878', (349, 370))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (27, 48))	('8190/3', 'Var', (209, 215))
48876	26131861	In conclusion, patients with clinically proven metastasis presented with MIA serum levels that were significantly higher when compared to those obtained among patients without metastasis and healthy donors.	('MIA', 'Gene', (73, 76))	('patients', 'Species', '9606', (15, 23))	('MIA', 'Gene', '8190', (73, 76))	('donor', 'Species', '9606', (199, 204))	('metastasis', 'Var', (47, 57))	('patients', 'Species', '9606', (159, 167))	('higher', 'PosReg', (114, 120))
48878	30701024	Pan-cancer analysis of intratumor heterogeneity associated with patient prognosis using multidimensional measures Human cancers accumulate various mutations during development and consist of highly heterogeneous cell populations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (64, 71))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('cancers', 'Disease', (120, 127))	('Human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
48886	30701024	Cancer is indicated via dysregulated cell growth, proliferation, and cell cycle progression.	('dysregulated', 'Var', (24, 36))	('cell cycle progression', 'CPA', (69, 91))	('cell growth', 'CPA', (37, 48))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cell cycle', 'biological_process', 'GO:0007049', ('69', '79'))	('cell growth', 'biological_process', 'GO:0016049', ('37', '48'))
48887	30701024	Cancer cells often consist of heterogeneous populations with various mutations rather than composed of homogeneous populations.	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (69, 78))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
48888	30701024	Previous studies demonstrated that cancer develops from mutations in certain driver genes and eventually accumulates various genetic mutations through cell growth, leading to intratumor heterogeneity (ITH).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (180, 185))	('leading to', 'Reg', (164, 174))	('mutations', 'Var', (133, 142))	('cell growth', 'biological_process', 'GO:0016049', ('151', '162'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
48892	30701024	VAFs are able to estimate the fraction of tumor populations containing mutations in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (71, 80))	('VAF', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
48895	30701024	Moreover, mutant-allele tumor heterogeneity (MATH) scores represent the variance of VAFs, and the entropy-based mutation allele fraction (EMAF) represents uncertainty of somatic mutation patterns.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutant-allele', 'Var', (10, 23))	('VAF', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
48904	30701024	Since correlation coefficients were -0.44, 0.03, and 0.00, which were observed between m_Peaks vs. m_MATH, m_Peak vs. m_Count, and m_Count vs. m_MATH, respectively, we considered the parameters could be used as independent variables representing the characteristics of VAF distributions.	('VAF', 'Chemical', '-', (269, 272))	('m_Peak', 'Var', (107, 113))	('m_Peaks', 'Var', (87, 94))
48910	30701024	We drew histograms of VAFs assembled from all mutations in samples belonging to each cluster and created trunk-branch models of mutations in tumors (Figure 2A).	('trunk', 'cellular_component', 'GO:0043198', ('105', '110'))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('trunk-branch', 'Disease', (105, 117))	('trunk-branch', 'Disease', 'MESH:D016750', (105, 117))	('VAF', 'Chemical', '-', (22, 25))
48912	30701024	Since the VAF distributions showed that samples in cluster 1 had more MF mutations with higher VAF than lower VAF, while the samples in cluster 2 had more MF mutations with lower VAF than higher VAF, they were predicted to have accumulated clonal mutations in cluster 1 and subclonal mutations in cluster 2, respectively.	('VAF', 'Chemical', '-', (95, 98))	('VAF', 'Chemical', '-', (10, 13))	('VAF', 'Chemical', '-', (195, 198))	('VAF', 'Chemical', '-', (179, 182))	('lower', 'NegReg', (173, 178))	('VAF', 'Chemical', '-', (110, 113))	('mutations', 'Var', (73, 82))
48913	30701024	This observation was consistent with a recent study by McGranahan and colleagues, which indicated that, in some cancer types, including melanoma and lung cancer, mutations accumulated prior to carcinogenesis.	('mutations', 'Var', (162, 171))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('carcinogenesis', 'Disease', (193, 207))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (136, 160))
48916	30701024	This trend can be interpreted as MF mutations occurring in the early stages of cancer development and maintained through cancer progression, without further accumulating a large number of MF mutations among samples in cluster 3.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
48917	30701024	In cluster 4, expansion of some subclones with certain MF mutations might occur during cancer progression under strong positive selection.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
48918	30701024	In contrast, samples in cluster 5 had MF mutations that possibly occurred under neutral cancer evolution.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
48919	30701024	To evaluate the clusters' genetic characteristics, we calculated MF mutation frequencies of each gene for 16 cancer types and examined the 10 genes with the highest frequency of mutations in each cluster (Supplementary Figure 2).	('mutation', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
48920	30701024	In BRCA, the frequencies of MF mutation in PIK3CA in clusters 3, 4, and 5 (35.5%, 40.5%, and 32.5%, respectively), in which the m_Count was small, were relatively high.	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('mutation', 'Var', (31, 39))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))	('PIK3CA', 'Gene', (43, 49))
48921	30701024	Once mutations in PIK3CA occurred, without a striking increase in the number of other mutations, cells may remain genetically stable.	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))	('mutations', 'Var', (5, 14))
48923	30701024	This result suggests that liver cancer cells with mutations in the driver gene CTNNB1, which have been generated in the earlier stage of cancer development, occupied in the cancer cell population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CTNNB1', 'Gene', '1499', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('liver cancer', 'Disease', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CTNNB1', 'Gene', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (26, 38))	('liver cancer', 'Disease', 'MESH:D006528', (26, 38))
48926	30701024	In our study, the samples in cluster 2 was predicted to have the highest ITH level due to a large number of mutations with lower VAF.	('VAF', 'Chemical', '-', (129, 132))	('ITH level', 'MPA', (73, 82))	('lower', 'NegReg', (123, 128))	('mutations', 'Var', (108, 117))
48928	30701024	In melanoma, the frequency of C>T transitions decreases, and the frequency of T>G transversions increases among branch mutations compared to trunk mutations.	('T>G transversions', 'Var', (78, 95))	('increases', 'PosReg', (96, 105))	('C>T transitions', 'Var', (30, 45))	('trunk', 'cellular_component', 'GO:0043198', ('141', '146'))	('decreases', 'NegReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
48929	30701024	Therefore, most mutations in samples with fewer mutations were proposed to occur in later, rather than earlier, stages of cancer development.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
48933	30701024	As mentioned above, samples in clusters 1 and 2 supposedly accumulated a large number of MF mutations during cancer development.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (92, 101))
48952	30701024	This suggested more mutations are associated with worse prognosis in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
48953	30701024	Cancer cells occupied by a lower number of mutations occurring early in cancer development might be associated with worse prognosis in BLCA and UCEC.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BLCA', 'Disease', (135, 139))	('Cancer', 'Disease', (0, 6))	('UCEC', 'Disease', (144, 148))	('mutations', 'Var', (43, 52))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
48954	30701024	Thus, samples were associated with poor prognosis when fewer mutations occurred at carcinogenesis and survived during cancer development.	('cancer', 'Disease', (118, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinogenesis', 'Disease', (83, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
48955	30701024	Since frequencies of MF mutations in IDH1, which is one of the driver genes in LGG, were higher among samples in clusters 3, 4, and 5 (69.5%, 54.5%, and 59.5%, respectively), it was expected that other factors that increase the number of mutations from the early to mid-stage of cancer development may affect patient prognosis.	('affect', 'Reg', (302, 308))	('patient prognosis', 'CPA', (309, 326))	('IDH1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('patient', 'Species', '9606', (309, 316))	('higher', 'PosReg', (89, 95))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
48968	30701024	Previous studies have shown that melanoma is a highly malignant cancer and harbors various mutations in the early stages of cancer development.	('cancer', 'Disease', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
48970	30701024	Our results consistently showed that most samples have a large number of mutations accumulated prior to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))	('mutations', 'Var', (73, 82))
48971	30701024	Taking the mutation spectrum into consideration, most mutations in the samples with fewer mutations were considered to occur in the later rather than earlier stages of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
48973	30701024	From these results, we proposed the following hypothesis of the genetic evolution of melanoma: melanoma is generated by a large number of genetic mutations, including those in BRAF (clusters 1 and 2), and only those cells with certain mutations are selected under selective pressure.	('mutations', 'Var', (146, 155))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('generated by', 'Reg', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', '673', (176, 180))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (176, 180))
48978	30701024	Previous studies showed that high TMB in NSCLC was associated with worse prognosis.	('NSCLC', 'Disease', (41, 46))	('TMB', 'Chemical', '-', (34, 37))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('high TMB', 'Var', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
48979	30701024	In LUAD, the mutations partially attributable to smoking may gradually accumulate in cells during cancer progression, leading to more aggressive cancer cells.	('more', 'PosReg', (129, 133))	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('leading to', 'Reg', (118, 128))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('aggressive cancer', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('aggressive cancer', 'Disease', (134, 151))
48980	30701024	Conversely, in LUSC, once mutations are occupied in cancer cells under selective pressure (cluster 4), those samples were predicted to have a worse prognosis than cancer cells with a large number of clonal mutations (cluster 1).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('LUSC', 'Phenotype', 'HP:0030359', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
48985	30701024	In this study, we analyzed 16 cancer types using only single nucleotide substitutions in genes.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('single nucleotide substitutions', 'Var', (54, 85))
48991	30701024	The MF mutations of amino acid substitution may have an impact on protein structures and/or functions, suggesting their possible involvement in cancer development or progression.	('protein', 'Protein', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('involvement', 'Reg', (129, 140))	('cancer', 'Disease', (144, 150))	('functions', 'MPA', (92, 101))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('impact', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutations', 'Var', (7, 16))
49013	28688464	This association is plausible because levodopa is an intermediary product involved in melanin synthesis, and it has been shown to increase melanin and melanoma cell growth in plant and human cell studies, respectively.	('human', 'Species', '9606', (185, 190))	('melanin', 'Chemical', 'MESH:D008543', (139, 146))	('levodopa', 'Var', (38, 46))	('levodopa', 'Chemical', 'MESH:D007980', (38, 46))	('melanin', 'CPA', (139, 146))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('increase', 'PosReg', (130, 138))	('melanin', 'Chemical', 'MESH:D008543', (86, 93))	('melanin synthesis', 'biological_process', 'GO:0042438', ('86', '103'))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('cell growth', 'biological_process', 'GO:0016049', ('160', '171'))
49148	28688464	Certain genetic variations, including alpha-synuclein, parkin, and LRRK2 mutations, are also associated with development of PD and PD-associated dementia.	('dementia', 'Disease', (145, 153))	('alpha-synuclein', 'Gene', '6622', (38, 53))	('dementia', 'Disease', 'MESH:D003704', (145, 153))	('mutations', 'Var', (73, 82))	('PD', 'Disease', 'MESH:D010300', (131, 133))	('associated with', 'Reg', (93, 108))	('PD', 'Disease', 'MESH:D010300', (124, 126))	('dementia', 'Phenotype', 'HP:0000726', (145, 153))	('LRRK2', 'Gene', (67, 72))	('alpha-synuclein', 'Gene', (38, 53))	('LRRK2', 'Gene', '120892', (67, 72))
49193	31406562	It has, however, been shown that partial sampling of lesions can lead to inaccurate staging, additional surgical procedures and increased anxiety for patients.	('anxiety', 'Disease', (138, 145))	('anxiety', 'Phenotype', 'HP:0000739', (138, 145))	('lead', 'Reg', (65, 69))	('patients', 'Species', '9606', (150, 158))	('partial sampling', 'Var', (33, 49))	('anxiety', 'Disease', 'MESH:D001008', (138, 145))
49277	30412573	Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood.	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('oncogenesis', 'biological_process', 'GO:0007048', ('169', '180'))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
49278	30412573	Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer.	('mutated trinucleotides', 'Var', (51, 73))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('trinucleotides', 'Var', (59, 73))	('cancer', 'Disease', (197, 203))	('trinucleotides', 'Chemical', '-', (59, 73))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
49280	30412573	We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Cancer', 'Disease', (190, 196))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('Cancer', 'Disease', 'MESH:D009369', (190, 196))
49281	30412573	We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (145, 154))
49282	30412573	We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair.	('enzyme activity', 'molecular_function', 'GO:0003824', ('95', '110'))	('APOBEC', 'cellular_component', 'GO:0030895', ('88', '94'))	('mismatch repair', 'biological_process', 'GO:0006298', ('125', '140'))	('AID', 'Gene', '57379', (84, 87))	('AID', 'Gene', (84, 87))	('mutations', 'Var', (44, 53))	('activity', 'MPA', (102, 110))	('deficient', 'Var', (115, 124))	('mismatch repair', 'MPA', (125, 140))
49283	30412573	We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively.	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('mutations', 'Var', (206, 215))	('IDH1', 'Gene', '3417', (219, 223))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (254, 274))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (254, 274))	('brain cancers', 'Disease', 'MESH:D001932', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('KRAS', 'Gene', (228, 232))	('mutagenesis', 'biological_process', 'GO:0006280', ('166', '177'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (254, 273))	('IDH1', 'Gene', (219, 223))	('KRAS', 'Gene', '3845', (228, 232))	('brain cancers', 'Disease', (236, 249))	('lung adenocarcinomas', 'Disease', (254, 274))	('aging', 'biological_process', 'GO:0007568', ('140', '145'))
49286	30412573	Cancer develops when cells acquire somatic driver mutations that confer a growth advantage.	('mutations', 'Var', (50, 59))	('growth advantage', 'CPA', (74, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
49289	30412573	In other cases, the altered trinucleotide preferences arising from a signature would have increased the likelihood of the associated driver mutation arising.	('driver mutation', 'MPA', (133, 148))	('trinucleotide preferences', 'Var', (28, 53))	('altered', 'Reg', (20, 27))	('increased', 'PosReg', (90, 99))	('trinucleotide', 'Chemical', '-', (28, 41))
49292	30412573	We examine known and novel associations between driver mutations and mutational signatures arising from processes such as defective proofreading during DNA replication, AID/APOBEC enzyme-associated mutagenesis and deficient mismatch repair.	('APOBEC', 'cellular_component', 'GO:0030895', ('173', '179'))	('mutagenesis', 'biological_process', 'GO:0006280', ('198', '209'))	('AID', 'Gene', '57379', (169, 172))	('AID', 'Gene', (169, 172))	('proofreading', 'MPA', (132, 144))	('DNA replication', 'biological_process', 'GO:0006260', ('152', '167'))	('mismatch repair', 'biological_process', 'GO:0006298', ('224', '239'))	('deficient', 'Var', (214, 223))	('mutagenesis', 'Var', (198, 209))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('mismatch repair', 'MPA', (224, 239))	('defective', 'Var', (122, 131))
49295	30412573	Driver mutations typically affect certain cancer-associated genes by, for example, activating an oncogene or inactivating a tumour suppressor gene.	('mutations', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('activating', 'Reg', (83, 93))	('inactivating', 'NegReg', (109, 121))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('affect', 'Reg', (27, 33))	('tumour', 'Disease', (124, 130))	('oncogene', 'Protein', (97, 105))
49296	30412573	Research in recent years has led to the identification of hundreds of driver mutations in cancer-associated genes, but only a handful of driver mutations are sufficient for oncogenesis in a single cancer sample.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (197, 203))	('oncogenesis', 'biological_process', 'GO:0007048', ('173', '184'))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
49300	30412573	Mutational signatures are displayed according to six substitution types (C>A, C>G, C>T, T>A, T>C and T>G) in the context of all trinucleotide combinations, thus representing each of the 96 possible mutation frequencies.	('C>G', 'Var', (78, 81))	('T>C and T>G', 'Var', (93, 104))	('C>T', 'Var', (83, 86))	('T>A', 'Var', (88, 91))	('T>G', 'Var', (101, 104))	('trinucleotide', 'Chemical', '-', (128, 141))	('C>A', 'Var', (73, 76))
49304	30412573	A recent study suggested that approximately two-thirds of mutations in human cancers arise due to errors in DNA replication occurring over time.	('errors', 'Var', (98, 104))	('mutations', 'Var', (58, 67))	('DNA replication', 'biological_process', 'GO:0006260', ('108', '123'))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
49305	30412573	Even cancers that have a strong environmental component therefore still harbour mutations incurred by unavoidable DNA replication errors.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('mutations', 'Var', (80, 89))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('DNA replication', 'biological_process', 'GO:0006260', ('114', '129'))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('harbour', 'Reg', (72, 79))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
49306	30412573	We therefore undertook this study to determine the association between common driver mutations and distinct mutational processes in human cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (85, 94))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
49307	30412573	Many mutational processes operating in cellular DNA alter the frequencies of mutation accumulation at certain trinucleotide contexts, thus resulting in these definable mutational signatures.	('definable', 'MPA', (158, 167))	('mutation', 'Var', (77, 85))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('alter', 'Reg', (52, 57))	('trinucleotide', 'Chemical', '-', (110, 123))	('resulting in', 'Reg', (139, 151))	('mutational signatures', 'MPA', (168, 189))
49313	30412573	For example, Signature 1 exhibits clock-like properties, and the number of mutations in this signature correlates with age across a majority of cancer types.	('correlates', 'Reg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (75, 84))	('clock-like', 'MPA', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
49315	30412573	By investigating recurrence of mutations in known cancer driver genes (see Methods and S1 Fig), we selected 50 driver mutations for potential association with mutational signatures (S2 Table).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (118, 127))	('association', 'Interaction', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
49316	30412573	These mutations alter 21 different genes, with TP53 (n = 10), KRAS (n = 7), PIK3CA (n = 4) and PTEN (n = 4) harbouring at total of 50% of all of the driver mutations selected.	('alter', 'Reg', (16, 21))	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (62, 66))	('mutations', 'Var', (156, 165))	('PIK3CA', 'Gene', (76, 82))	('PTEN', 'Gene', (95, 99))	('TP53', 'Gene', '7157', (47, 51))	('PTEN', 'Gene', '5728', (95, 99))	('PIK3CA', 'Gene', '5290', (76, 82))	('TP53', 'Gene', (47, 51))	('mutations', 'Var', (6, 15))
49317	30412573	We next defined the landscape of somatic driver mutations across the cancer samples in our cohort (Fig 1).	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (69, 75))
49319	30412573	These mutations include BRAF p.V600E, which was also the most common driver mutation in our cohort (n = 287).	('p.V600E', 'Var', (29, 36))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('p.V600E', 'Mutation', 'rs113488022', (29, 36))
49320	30412573	The BRAF p.V600E mutation was most frequent in skin cutaneous melanoma and thyroid carcinoma, affecting 43% (n = 193) and 56% (n = 29) of samples respectively.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (47, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('skin cutaneous melanoma', 'Disease', (47, 70))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (75, 92))	('p.V600E', 'Var', (9, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (75, 92))	('BRAF', 'Gene', (4, 8))	('thyroid carcinoma', 'Disease', (75, 92))	('BRAF', 'Gene', '673', (4, 8))	('frequent', 'Reg', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
49321	30412573	Of the other frequent mutations, four mutations altered KRAS amino acid G12, primarily affecting colorectal, lung and pancreatic adenocarcinomas.	('colorectal', 'Disease', 'MESH:D015179', (97, 107))	('KRAS', 'Gene', (56, 60))	('colorectal', 'Disease', (97, 107))	('KRAS', 'Gene', '3845', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('affecting', 'Reg', (87, 96))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (118, 144))	('pancreatic adenocarcinomas', 'Disease', (118, 144))	('mutations', 'Var', (22, 31))	('lung', 'Disease', (109, 113))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (118, 144))
49322	30412573	PIK3CA (p.E545K and p.H1047R) and TP53 (p.R248Q and p.R273C) harboured two highly frequent mutations each, and IDH1 p.R132H was most frequent in brain lower grade glioma (57%, n = 116).	('glioma', 'Disease', (163, 169))	('glioma', 'Disease', 'MESH:D005910', (163, 169))	('IDH1', 'Gene', (111, 115))	('p.R132H', 'Mutation', 'rs121913500', (116, 123))	('glioma', 'Phenotype', 'HP:0009733', (163, 169))	('PIK3CA', 'Gene', '5290', (0, 6))	('p.R248Q', 'Mutation', 'rs11540652', (40, 47))	('p.R132H', 'Var', (116, 123))	('p.H1047R', 'Var', (20, 28))	('TP53', 'Gene', (34, 38))	('frequent', 'Reg', (133, 141))	('IDH1', 'Gene', '3417', (111, 115))	('p.E545K', 'Var', (8, 15))	('p.R273C', 'Var', (52, 59))	('p.R248Q', 'Var', (40, 47))	('PIK3CA', 'Gene', (0, 6))	('p.H1047R', 'Mutation', 'rs121913279', (20, 28))	('p.E545K', 'Mutation', 'rs104886003', (8, 15))	('TP53', 'Gene', '7157', (34, 38))	('p.R273C', 'Mutation', 'rs121913343', (52, 59))
49323	30412573	Taken together, we found these driver mutations to generally represent known frequencies in other cancer cohorts.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
49325	30412573	To exclude potentially spurious associations, we only examined associations in which >= 10 samples in a given cancer type harboured the driver mutation of interest, and >= 10 samples in that same cancer type harboured the signature of interest at a frequency of >= 20%.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (110, 116))	('harboured', 'Reg', (122, 131))	('mutation', 'Var', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
49327	30412573	These associations arose across 11 cancer types, affecting 9 mutational signatures and 18 driver mutations from 11 different genes (Table 2).	('arose', 'Reg', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutational', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('affecting', 'Reg', (49, 58))	('cancer', 'Disease', (35, 41))
49329	30412573	These negative associations arose between signature 1 and IDH1 p.R132H in brain lower grade glioma and glioblastoma multiforme (Table 2).	('IDH1', 'Gene', '3417', (58, 62))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (103, 126))	('negative', 'NegReg', (6, 14))	('glioma', 'Disease', (92, 98))	('p.R132H', 'Var', (63, 70))	('glioblastoma multiforme', 'Disease', (103, 126))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('p.R132H', 'Mutation', 'rs121913500', (63, 70))	('IDH1', 'Gene', (58, 62))	('glioblastoma', 'Phenotype', 'HP:0012174', (103, 115))
49333	30412573	To validate our methodology, we first investigated the six significant associations that we observed between driver mutations and signature 10 across uterine corpus endometrial carcinoma and colorectal adenocarcinoma (Table 2).	('endometrial carcinoma and colorectal adenocarcinoma', 'Disease', 'MESH:D016889', (165, 216))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (165, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('signature 10', 'Gene', (130, 142))	('mutations', 'Var', (116, 125))
49334	30412573	Signature 10 arises in cancers which harbour Polymerase Epsilon (POLE) exonuclease domain mutations.	('domain mutations', 'Var', (83, 99))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
49335	30412573	In our study, we found the POLE p.P286R (c.857C>G) mutation to be significantly associated with signature 10 in uterine corpus endometrial carcinoma (Table 2).	('c.857C>G', 'Mutation', 'c.857C>G', (41, 49))	('endometrial carcinoma', 'Disease', (127, 148))	('p.P286R (c.857C>G', 'Var', (32, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (127, 148))	('associated', 'Reg', (80, 90))	('p.P286R', 'Mutation', 'p.P286R', (32, 39))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (127, 148))
49336	30412573	The trinucleotide context of this mutation (C[C>G]T) is not frequently observed in signature 10 (Fig 3A), supporting existing literature that demonstrates the POLE p.P286R mutation to underlie many instances of the presence of signature 10 in cancer.	('p.P286R', 'Mutation', 'p.P286R', (164, 171))	('trinucleotide', 'Chemical', '-', (4, 17))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('p.P286R', 'Var', (164, 171))
49337	30412573	The remaining driver mutations that we found to be significantly associated with signature 10 (PIK3CA p.R88Q, PTEN p.R130Q, ARID1A p.R1989* and TP53 p.R213*) all occur in a T[C>T]G context (Table 2).	('TP53', 'Gene', '7157', (144, 148))	('p.R130Q', 'Var', (115, 122))	('TP53', 'Gene', (144, 148))	('PIK3CA', 'Gene', (95, 101))	('p.R130Q', 'Mutation', 'rs121909229', (115, 122))	('PTEN', 'Gene', '5728', (110, 114))	('p.R1989*', 'Var', (131, 139))	('PIK3CA', 'Gene', '5290', (95, 101))	('p.R213*', 'Var', (149, 156))	('p.R88Q', 'Var', (102, 108))	('p.R88Q', 'Mutation', 'rs121913287', (102, 108))	('p.R213*', 'Mutation', 'p.R213*', (149, 156))	('ARID1A', 'Gene', '8289', (124, 130))	('ARID1A', 'Gene', (124, 130))	('p.R1989*', 'SUBSTITUTION', 'None', (131, 139))	('PTEN', 'Gene', (110, 114))
49339	30412573	In fact, in colorectal cancer, TP53 p.R213* mutations have been suggested to arise in response to POLE exonuclease domain mutation, where DNA methylation at this CpG trinucleotide may further enhance the likelihood of mutation occurrence.	('colorectal cancer', 'Disease', (12, 29))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('TP53', 'Gene', '7157', (31, 35))	('DNA methylation', 'biological_process', 'GO:0006306', ('138', '153'))	('TP53', 'Gene', (31, 35))	('trinucleotide', 'Chemical', '-', (166, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('p.R213*', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('p.R213*', 'Mutation', 'p.R213*', (36, 43))
49341	30412573	We found that a striking 36% (n = 14) of the associations that we identified arose between driver mutations in PIK3CA and signatures 2 or 13 across six different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('associations', 'Interaction', (45, 57))	('cancer', 'Disease', (162, 168))	('arose', 'Reg', (77, 82))	('PIK3CA', 'Gene', (111, 117))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PIK3CA', 'Gene', '5290', (111, 117))
49343	30412573	APOBEC activity has been implicated in the generation of specific PIK3CA mutations at p.E542K (c.1624G>A) and p.E545K (c.1633G>A), and we identified associations with both mutations in our study.	('c.1633G>A', 'Var', (119, 128))	('c.1624G>A', 'Var', (95, 104))	('c.1633G>A', 'Mutation', 'rs104886003', (119, 128))	('PIK3CA', 'Gene', (66, 72))	('p.E545K (c.1633G>A', 'Var', (110, 128))	('c.1624G>A', 'Mutation', 'rs121913273', (95, 104))	('p.E542K (c.1624G>A', 'Var', (86, 104))	('p.E545K', 'Mutation', 'rs104886003', (110, 117))	('p.E542K', 'Mutation', 'rs121913273', (86, 93))	('PIK3CA', 'Gene', '5290', (66, 72))	('implicated', 'Reg', (25, 35))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))
49344	30412573	In fact, both of these mutations match the extended context of the [T/C]TC[A/G] motif which has been established for APOBEC3A binding in single-stranded DNA (ssDNA).	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('APOBEC3A', 'Gene', (117, 125))	('binding', 'Interaction', (126, 133))	('APOBEC3A', 'Gene', '200315', (117, 125))	('mutations', 'Var', (23, 32))	('APOBEC', 'cellular_component', 'GO:0030895', ('117', '123'))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))
49345	30412573	In addition to the PIK3CA mutations, we found signatures 2 and 13 to be associated with ERBB2 p.S310F (c.929C>T) mutation in bladder cancer, and signature 13 to be associated with PPP2R1A p.P179R (c.536C>G) mutation in uterine corpus endometrial carcinoma (Table 2).	('ERBB2', 'Gene', (88, 93))	('PIK3CA', 'Gene', '5290', (19, 25))	('endometrial carcinoma', 'Disease', (234, 255))	('associated', 'Reg', (72, 82))	('c.929C>T', 'Mutation', 'rs1057519816', (103, 111))	('ERBB2', 'Gene', '2064', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (234, 255))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('PIK3CA', 'Gene', (19, 25))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (234, 255))	('associated', 'Reg', (164, 174))	('p.S310F (c.929C>T) mutation', 'Var', (94, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('PPP2R1A', 'Gene', '5518', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('p.S310F', 'Mutation', 'rs1057519816', (94, 101))	('c.536C>G', 'Mutation', 'rs786205228', (197, 205))	('PPP2R1A', 'Gene', (180, 187))	('p.P179R', 'Mutation', 'rs786205228', (188, 195))	('p.P179R (c.536C>G', 'Var', (188, 205))
49346	30412573	The broader contexts of these mutations, T[C>T]C and C[C>G]C respectively, do not match well with the typical APOBEC3A/B mutational context.	('APOBEC3A/B', 'Gene', (110, 120))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (110, 120))	('T[C>T]C', 'Var', (41, 48))	('C[C>G]', 'Var', (53, 59))	('APOBEC', 'cellular_component', 'GO:0030895', ('110', '116'))
49347	30412573	Using ssDNA folding predictions (see Methods), we find that both of the cytosines mutated in the ERBB2 and PPP2R1A drivers are predicted to be located at stem-loops, and that these loops are greater than three bases in size (S4 Fig).	('PPP2R1A', 'Gene', (107, 114))	('PPP2R1A', 'Gene', '5518', (107, 114))	('mutated', 'Var', (82, 89))	('ERBB2', 'Gene', (97, 102))	('ERBB2', 'Gene', '2064', (97, 102))
49349	30412573	Confirmation of whether and how APOBEC3A/B binds and mutates these DNA sequences will need to be experimentally validated.	('mutates', 'Var', (53, 60))	('APOBEC3A/B', 'Gene', '100913187;200315;9582', (32, 42))	('APOBEC3A/B', 'Gene', (32, 42))	('APOBEC', 'cellular_component', 'GO:0030895', ('32', '38'))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('binds', 'Interaction', (43, 48))
49352	30412573	Among the remaining five mutations is BRAF p.V600E, which is significantly associated with signatures 6 and 26 in colorectal adenocarcinoma (Table 2).	('p.V600E', 'Mutation', 'rs113488022', (43, 50))	('BRAF', 'Gene', '673', (38, 42))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (114, 139))	('p.V600E', 'Var', (43, 50))	('BRAF', 'Gene', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('colorectal adenocarcinoma', 'Disease', (114, 139))	('associated', 'Reg', (75, 85))
49353	30412573	The mechanism underlying the association between BRAF p.V600E and mismatch repair deficiency has not yet been established to our knowledge.	('p.V600E', 'Var', (54, 61))	('mismatch repair', 'biological_process', 'GO:0006298', ('66', '81'))	('BRAF', 'Gene', '673', (49, 53))	('mismatch', 'MPA', (66, 74))	('BRAF', 'Gene', (49, 53))	('p.V600E', 'Mutation', 'rs113488022', (54, 61))
49354	30412573	It is possible that this association arises because acquisition of a BRAF p.V600E mutation predisposes otherwise normal cells to developing mismatch repair deficiency, though this hypothesis requires further investigation.	('p.V600E', 'Mutation', 'rs113488022', (74, 81))	('p.V600E', 'Var', (74, 81))	('developing mismatch repair deficiency', 'MPA', (129, 166))	('BRAF', 'Gene', '673', (69, 73))	('mismatch repair', 'biological_process', 'GO:0006298', ('140', '155'))	('BRAF', 'Gene', (69, 73))
49355	30412573	In support of this hypothesis, BRAF p.V600E mutations do occur much less commonly in hereditary nonpolyposis colorectal cancers -cancers which frequently arise due to germline mismatch repair defects.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mismatch repair', 'biological_process', 'GO:0006298', ('176', '191'))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('p.V600E', 'Var', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('BRAF', 'Gene', '673', (31, 35))	('hereditary nonpolyposis colorectal cancers -cancers', 'Disease', 'MESH:D003123', (85, 136))	('BRAF', 'Gene', (31, 35))
49356	30412573	Our results suggest that many driver mutations in cancers with mismatch repair deficiencies may arise independently from, or prior to, loss of mismatch repair.	('mismatch repair', 'biological_process', 'GO:0006298', ('63', '78'))	('deficiencies', 'Var', (79, 91))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('mismatch repair', 'Protein', (63, 78))	('mutations', 'Var', (37, 46))	('mismatch repair', 'biological_process', 'GO:0006298', ('143', '158'))	('arise', 'Reg', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
49359	30412573	These negative associations arose between the IDH1 p.R132H driver mutation and signature 1, occurring in brain lower grade glioma and in glioblastoma multiforme (Table 2).	('glioma', 'Phenotype', 'HP:0009733', (123, 129))	('glioma', 'Disease', 'MESH:D005910', (123, 129))	('IDH1', 'Gene', (46, 50))	('glioblastoma multiforme', 'Disease', (137, 160))	('p.R132H', 'Var', (51, 58))	('IDH1', 'Gene', '3417', (46, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('glioma', 'Disease', (123, 129))	('p.R132H', 'Mutation', 'rs121913500', (51, 58))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (137, 160))
49360	30412573	Demonstrating this negative association, we observed a significantly lower proportion of signature 1 mutations in IDH1 p.R132H mutant rather than wild-type brain lower grade glioma (P < 0.0001) and glioblastoma multiforme (P < 0.001; Fig 4A) by two-sided Mann Whitney U-Test.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('IDH1', 'Gene', (114, 118))	('glioblastoma multiforme', 'Disease', (198, 221))	('mutations', 'Var', (101, 110))	('p.R132H', 'Mutation', 'rs121913500', (119, 126))	('glioblastoma', 'Phenotype', 'HP:0012174', (198, 210))	('lower', 'NegReg', (69, 74))	('glioma', 'Disease', (174, 180))	('IDH1', 'Gene', '3417', (114, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (198, 221))	('p.R132H', 'Var', (119, 126))
49362	30412573	Consistent with our observed association, we found that patients with IDH1 p.R132H mutated tumours in our cohort were generally younger than patients with IDH1 p.R132H wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('patients', 'Species', '9606', (56, 64))	('IDH1', 'Gene', (155, 159))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('p.R132H', 'Mutation', 'rs121913500', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('p.R132H', 'Mutation', 'rs121913500', (160, 167))	('IDH1', 'Gene', '3417', (155, 159))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('tumours', 'Disease', (91, 98))	('IDH1', 'Gene', '3417', (70, 74))	('tumours', 'Disease', (178, 185))	('p.R132H', 'Var', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('patients', 'Species', '9606', (141, 149))	('IDH1', 'Gene', (70, 74))
49364	30412573	IDH1 mutations have been found to less commonly occur in older people with glioblastoma, and the results of our mutational signature analyses provide molecular support for this finding in glioblastoma multiforme and brain lower grade glioma.	('glioblastoma', 'Disease', (75, 87))	('people', 'Species', '9606', (63, 69))	('glioblastoma', 'Disease', (188, 200))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('glioma', 'Disease', 'MESH:D005910', (234, 240))	('glioblastoma', 'Disease', 'MESH:D005909', (75, 87))	('glioma', 'Phenotype', 'HP:0009733', (234, 240))	('mutations', 'Var', (5, 14))	('glioblastoma multiforme', 'Disease', (188, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (188, 211))	('IDH1', 'Gene', (0, 4))	('glioma', 'Disease', (234, 240))	('IDH1', 'Gene', '3417', (0, 4))
49365	30412573	While age would increase the likelihood of any mutation arising by chance alone, our results suggest that age might disproportionately favour the occurrence of mutations other than IDH1 p.R132H in these brain cancers, or that this mutation confers a greater selective advantage in younger people.	('brain cancers', 'Disease', (203, 216))	('p.R132H', 'Mutation', 'rs121913500', (186, 193))	('favour', 'PosReg', (135, 141))	('mutations', 'Var', (160, 169))	('brain cancers', 'Disease', 'MESH:D001932', (203, 216))	('people', 'Species', '9606', (289, 295))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('IDH1', 'Gene', (181, 185))	('p.R132H', 'Var', (186, 193))	('IDH1', 'Gene', '3417', (181, 185))
49368	30412573	KRAS p.G12D transition mutations are the most common KRAS somatic mutation arising in the lung adenocarcinomas of people who have never smoked.	('p.G12D transition', 'Var', (5, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (90, 110))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (90, 110))	('people', 'Species', '9606', (114, 120))	('KRAS', 'Gene', (53, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('p.G12D', 'Mutation', 'rs121913529', (5, 11))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (0, 4))	('lung adenocarcinomas', 'Disease', (90, 110))	('KRAS', 'Gene', '3845', (0, 4))
49372	30412573	It has been suggested that approximately two-thirds of mutations in cancer arise from DNA replication errors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('DNA replication', 'biological_process', 'GO:0006260', ('86', '101'))	('cancer', 'Disease', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('arise from', 'Reg', (75, 85))
49374	30412573	24 of the 36 associations (66%) arising across cancer types occur in cases where the trinucleotide context of the driver mutation frequently arises in the associated signature, implying a possibly direct causal relationship between defective DNA replication and occurrence of that driver mutation.	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('trinucleotide', 'Chemical', '-', (85, 98))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (121, 129))	('DNA replication', 'biological_process', 'GO:0006260', ('242', '257'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
49376	30412573	Similarly, it is possible that somatic events that are causal in generating a replication-associated mutational signature arise as a result of exogenous environmental mutagens (for example, APOBEC enzyme activity could be altered following viral infection).	('viral infection', 'Disease', 'MESH:D001102', (240, 255))	('viral infection', 'biological_process', 'GO:0016032', ('240', '255'))	('enzyme activity', 'molecular_function', 'GO:0003824', ('197', '212'))	('activity', 'MPA', (204, 212))	('mutational', 'Var', (101, 111))	('viral infection', 'Disease', (240, 255))	('APOBEC', 'cellular_component', 'GO:0030895', ('190', '196'))	('APOBEC', 'Gene', (190, 196))	('altered', 'Reg', (222, 229))
49378	30412573	We observed a significant association in our study between BRAF p.V600M (c.1798G>A) and signature 7 in skin cutaneous melanoma (Table 2).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('c.1798G>A', 'Mutation', 'rs121913378', (73, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 126))	('p.V600M', 'Mutation', 'rs121913378', (64, 71))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('skin cutaneous melanoma', 'Disease', (103, 126))	('p.V600M (c.1798G>A', 'Var', (64, 82))
49379	30412573	While the A[C>T]T trinucleotide context of the BRAF p.V600M mutation is infrequent (0.4%) within signature 7, C>T transition mutations within a pyrimidine dimer context do generally characterise this signature.	('p.V600M', 'Mutation', 'rs121913378', (52, 59))	('pyrimidine', 'Chemical', 'MESH:C030986', (144, 154))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('C>T', 'Var', (110, 113))	('trinucleotide', 'Chemical', '-', (18, 31))	('p.V600M', 'Var', (52, 59))
49380	30412573	Of note, BRAF p.V600E mutations more commonly arise than p.V600M mutations in melanomas.	('melanomas', 'Disease', (78, 87))	('p.V600E', 'Var', (14, 21))	('BRAF', 'Gene', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('p.V600M', 'Mutation', 'rs121913378', (57, 64))	('p.V600E', 'Mutation', 'rs113488022', (14, 21))	('arise', 'Reg', (46, 51))	('BRAF', 'Gene', '673', (9, 13))
49381	30412573	The BRAF p.V600E (c.1799T>A) mutation is not a characteristic C>T transition and various models have been proposed for how such mutations may result from exposure to UV radiation.	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('c.1799T>A', 'Mutation', 'rs113488022', (18, 27))	('p.V600E (c.1799T>A', 'Var', (9, 27))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))
49382	30412573	Interestingly, we did not find a significant association between signature 7 and BRAF p.V600E in our study (P = 0.7086, S3 Table).	('p.V600E', 'Var', (86, 93))	('BRAF', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (81, 85))	('p.V600E', 'Mutation', 'rs113488022', (86, 93))
49383	30412573	Melanomas arising on skin without chronic sun-induced damage often harbour BRAF p.V600E mutations, while those arising on skin with chronic sun-induced damage typically harbour other BRAF mutations.	('p.V600E', 'Mutation', 'rs113488022', (80, 87))	('p.V600E', 'Var', (80, 87))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('BRAF', 'Gene', '673', (75, 79))	('Melanomas', 'Disease', (0, 9))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (183, 187))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (183, 187))
49384	30412573	Additionally, BRAF p.V600E mutations are commonly found in tumours from non-sun-exposed tissues such as thyroid and colorectal cancers, demonstrating that this mutation can arise following mutagenic processes other than UV radiation exposure.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('p.V600E', 'Mutation', 'rs113488022', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancers', 'Disease', (116, 134))	('p.V600E', 'Var', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('thyroid', 'Disease', (104, 111))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('BRAF', 'Gene', '673', (14, 18))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('BRAF', 'Gene', (14, 18))	('colorectal cancers', 'Disease', 'MESH:D015179', (116, 134))	('thyroid', 'Disease', 'MESH:D013959', (104, 111))	('tumours', 'Disease', (59, 66))
49385	30412573	In some melanomas, and particularly those with a low contribution from signature 7, we suggest that BRAF p.V600E mutations may also arise independently from UV radiation-associated mutagenesis.	('p.V600E', 'Mutation', 'rs113488022', (105, 112))	('mutagenesis', 'biological_process', 'GO:0006280', ('181', '192'))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Disease', 'MESH:D008545', (8, 17))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('p.V600E', 'Var', (105, 112))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('melanomas', 'Disease', (8, 17))
49386	30412573	We note the possibility though, that some BRAF p.V600E mutations do arise as a result of mutagenesis following UV radiation exposure, and that this mutation could then confer a particularly strong selective advantage over other pyrimidine dimer-associated mutations, accounting for its observed recurrence in melanoma.	('BRAF', 'Gene', '673', (42, 46))	('melanoma', 'Disease', (309, 317))	('p.V600E', 'Mutation', 'rs113488022', (47, 54))	('melanoma', 'Disease', 'MESH:D008545', (309, 317))	('p.V600E', 'Var', (47, 54))	('mutagenesis', 'biological_process', 'GO:0006280', ('89', '100'))	('BRAF', 'Gene', (42, 46))	('pyrimidine', 'Chemical', 'MESH:C030986', (228, 238))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('advantage', 'PosReg', (207, 216))
49390	30412573	These associations provide new insights into how some cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into mutational processes and cancer development.	('mutations', 'Var', (83, 92))	('advantageous', 'PosReg', (70, 82))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
49395	30412573	To select which samples to include in regression analyses, we excluded any mutations that were annotated by MuTect as present in a 'panel of normals', and then kept only cancer samples that harboured >= 30 single nucleotide somatic variants in cancer types with >= 40 samples.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('single nucleotide somatic variants', 'Var', (206, 240))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
49398	30412573	We then applied Sigfit (version 1.2.0) R package to determine the proportion of mutations attributable to each of the 30 mutational signatures from the COSMIC 'Signatures of Mutational Processes in Human Cancer' database.	('mutations', 'Var', (80, 89))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))	('Cancer', 'Disease', (204, 210))	('Human', 'Species', '9606', (198, 203))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))
49399	30412573	We first selected only missense and stop-gain variants that were present in > 3.5% of samples in at least one cancer type (where TCGA-COAD and TCGA-READ were considered collectively as CRC).	('cancer', 'Disease', (110, 116))	('stop-gain', 'PosReg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('variants', 'Var', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('missense', 'Var', (23, 31))
49400	30412573	Next, we retained only mutations that altered genes listed in the COSMIC 'Cancer Gene Census' (Tier 1; retrieved 24 November 2017).	('mutations', 'Var', (23, 32))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))
49401	30412573	Using only the 7,815 samples described above, we then selected mutations that were present in > 10 samples in at least one cancer type, resulting in a list of 34 driver mutations.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (169, 178))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
49403	30412573	We then selected only mutations present in >= 5 samples within the IntOGen database, and > 10 samples from at least one cancer type from our TCGA cohort.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
49404	30412573	We merged these two lists of mutations and analysed each using the Cancer Genome Interpreter.	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (29, 38))	('Cancer', 'Disease', (67, 73))
49405	30412573	We removed any mutations that were not designated as being a tumour driver by the Cancer Genome Interpreter.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (15, 24))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('tumour', 'Disease', (61, 67))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
49408	30412573	The regression model used the following formula, where  represents the proportion of mutations attributed to a given mutational signature in a sample,  represents the probability that a given driver mutation is present or absent in that sample and beta values denote estimates from logistic regression:  The odds ratio was calculated by exponentiating the beta1 coefficient estimated from the logistic regression model.	('beta1', 'Gene', '10678', (356, 361))	('mutations', 'Var', (85, 94))	('beta1', 'Gene', (356, 361))
49412	30412573	For validation of a subset of our findings, we obtained single nucleotide somatic mutations for an independent cohort of 619 whole-exome sequenced colorectal cancers from a previously published study.	('single nucleotide somatic', 'Var', (56, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancers', 'Disease', 'MESH:D015179', (147, 165))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('colorectal cancers', 'Disease', (147, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
49413	30412573	DNA sequences +- 20 bp of the mutation site in ERBB2 p.S310F and PPP2R1A p.P179R were obtained from the UCSC genome browser.	('p.P179R', 'Var', (73, 80))	('PPP2R1A', 'Gene', (65, 72))	('ERBB2', 'Gene', (47, 52))	('p.P179R', 'Mutation', 'rs786205228', (73, 80))	('ERBB2', 'Gene', '2064', (47, 52))	('PPP2R1A', 'Gene', '5518', (65, 72))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('p.S310F', 'Mutation', 'rs1057519816', (53, 60))	('p.S310F', 'Var', (53, 60))
49417	25600636	The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients.	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (53, 57))	('patients', 'Species', '9606', (78, 86))
49418	25600636	The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts.	('higher', 'PosReg', (68, 74))	('patients', 'Species', '9606', (34, 42))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('mutational', 'Var', (4, 14))
49421	25600636	Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('cyclin', 'Gene', (208, 214))	('low', 'Var', (75, 78))	('signaling', 'biological_process', 'GO:0023052', ('215', '224'))	('cyclin', 'molecular_function', 'GO:0016538', ('208', '214'))	('cyclin', 'Gene', '5111', (208, 214))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
49423	25600636	The application of next-generation sequencing through whole-genome, whole-exome, and whole-transcriptome approaches revolutionized the resolution of cancer genome alterations, including nucleotide substitutions, small insertions and deletions, copy number alterations, chromosomal rearrangements, splice variants, regulation of gene expression, and viral or microbial interactions.	('cancer', 'Disease', (149, 155))	('interactions', 'Interaction', (368, 380))	('copy number alterations', 'Var', (244, 267))	('small insertions', 'Var', (212, 228))	('regulation', 'Reg', (314, 324))	('nucleotide substitutions', 'Var', (186, 210))	('chromosomal', 'Disease', (269, 280))	('splice variants', 'Var', (297, 312))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('314', '343'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
49425	25600636	Identification of activating point-mutations in BRAF kinase (B-Raf proto-oncogene, serine/threonine kinase, Gene ID: 673) has now established a personalized medicine option with kinase inhibitors of mutated BRAF.	('mutated', 'Var', (199, 206))	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('point-mutations', 'Var', (29, 44))	('activating', 'PosReg', (18, 28))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
49431	25600636	Moreover, we characterize several novel variants of known oncogenes like BRAF and relate molecular features of new potential drivers of melanoma to recurring features observed in other cancer tissues.	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('variants', 'Var', (40, 48))	('cancer', 'Disease', (185, 191))
49432	25600636	The comprehensive analysis provides a foundation for future functional and clinical assessment of susceptibility variants in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('variants', 'Var', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))
49436	25600636	The tool GISTIC, genomic identification of significant targets in cancer, identified 3 amplifications and 3 deletions concordantly by both SNP arrays and whole-genome sequencing; it identified 14 amplified and 13 deleted recurrent focal SCNAs detected by SNP arrays affecting 745 amplifications and 1224 deletions of genes with q-values (minimum false discovery rate at which the test may be called significant) below a threshold of 0.01 in 299 patients (Figure 1, Supplementary tables 2-5).	('focal SCNAs', 'Disease', (231, 242))	('patients', 'Species', '9606', (445, 453))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('false', 'biological_process', 'GO:0071877', ('346', '351'))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('false', 'biological_process', 'GO:0071878', ('346', '351'))	('q-values', 'Var', (328, 336))	('cancer', 'Disease', (66, 72))	('deletions', 'Var', (304, 313))
49447	25600636	The SKCM dataset with a mutation rate of 18 mutations per mega base pairs (Mbp) is about 10-fold richer than other TCGA tissues (e.g.	('Mbp', 'Gene', '4155', (75, 78))	('mutations', 'Var', (44, 53))	('Mbp', 'Gene', (75, 78))
49448	25600636	glioblastoma multiforme (GBM) has a rate of 1.8 mutations per Mbp in TCGA).	('Mbp', 'Gene', '4155', (62, 65))	('glioblastoma multiforme', 'Disease', (0, 23))	('glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('TCGA', 'Gene', (69, 73))	('mutations', 'Var', (48, 57))	('Mbp', 'Gene', (62, 65))
49450	25600636	To explore the biological impact of mutations we added a second set of filters to identify cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (36, 45))
49452	25600636	The multi-step filter analysis confirmed known cancer driver genes BRAF (Figure 3-4, Supplementary table 6), RAC1, NRAS, TP53 (tumor protein p53, Gene ID: 7157), CDKN2A (results in p16INK transcript), STK19 (serine/threonine kinase 19, Gene ID: 8859), PPP6C (protein phosphatase 6, catalytic subunit, Gene ID: 5537), PTEN, IDH1 (isocitrate dehydrogenase 1, Gene ID: 3417), NMS (neuromedin S, Gene ID: 129521), CDK4, and VEGFC (vascular endothelial growth factor C, Gene ID: 7424) with significantly enriched functional mutations that passed a q-value cut-off below 0.01.	('mutations', 'Var', (519, 528))	('protein', 'cellular_component', 'GO:0003675', ('259', '266'))	('PTEN', 'Gene', '5728', (317, 321))	('CDK4', 'Gene', (410, 414))	('TP53', 'Gene', '7157', (121, 125))	('serine/threonine kinase 19', 'Gene', '8859', (208, 234))	('vascular endothelial growth factor C', 'Gene', '7424', (427, 463))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('p53', 'Gene', '7157', (141, 144))	('CDKN2A', 'Gene', (162, 168))	('isocitrate dehydrogenase 1', 'Gene', (329, 355))	('cancer', 'Disease', (47, 53))	('PPP6C', 'Gene', (252, 257))	('isocitrate dehydrogenase 1', 'Gene', '3417', (329, 355))	('NMS', 'Disease', 'MESH:D009459', (373, 376))	('CDK4', 'Gene', '1019', (410, 414))	('VEGFC', 'Gene', (420, 425))	('phosphatase', 'molecular_function', 'GO:0016791', ('267', '278'))	('NMS', 'Disease', (373, 376))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('STK19', 'Gene', '8859', (201, 206))	('IDH1', 'Gene', (323, 327))	('p53', 'Gene', (141, 144))	('vascular endothelial growth factor C', 'Gene', (427, 463))	('CDKN2A', 'Gene', '1029', (162, 168))	('TP53', 'Gene', (121, 125))	('RAC1', 'Gene', (109, 113))	('VEGFC', 'Gene', '7424', (420, 425))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('neuromedin S', 'Gene', '129521', (378, 390))	('PPP6C', 'Gene', '5537', (252, 257))	('serine/threonine kinase 19', 'Gene', (208, 234))	('RAC1', 'Gene', '5879', (109, 113))	('BRAF', 'Gene', '673', (67, 71))	('PTEN', 'Gene', (317, 321))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (127, 132))	('STK19', 'Gene', (201, 206))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('427', '461'))	('BRAF', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (323, 327))	('neuromedin S', 'Gene', (378, 390))	('STK19', 'molecular_function', 'GO:0004686', ('201', '206'))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CDK', 'molecular_function', 'GO:0004693', ('410', '413'))
49455	25600636	Given the predominance of BRAF mutations in metastatic melanoma, we characterized the somatic mutation landscape of the BRAF gene in the SKCM dataset as well as in other TCGA cancer tissues.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('mutations', 'Var', (31, 40))	('BRAF', 'Gene', '673', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('BRAF', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (120, 124))	('BRAF', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
49456	25600636	The metastatic SKCM cohort of 276 patients with somatic controls contained 140 patients with non-silent mutations of BRAF and included 151 amino acid replacements affecting 18 unique residues (50% patient mutation frequency, p-value <1.00e-15, q-value <2.26e-12).	('mutations', 'Var', (104, 113))	('patient', 'Species', '9606', (34, 41))	('patient', 'Species', '9606', (79, 86))	('patients', 'Species', '9606', (34, 42))	('patients', 'Species', '9606', (79, 87))	('BRAF', 'Gene', '673', (117, 121))	('affecting', 'Reg', (163, 172))	('patient', 'Species', '9606', (197, 204))	('BRAF', 'Gene', (117, 121))
49457	25600636	The single most abundant protein-coding amino acid replacement observed in 119 of 276 samples is p.V600E, switching BRAF into a constitutively active protein kinase.	('p.V600E', 'Var', (97, 104))	('BRAF', 'Gene', '673', (116, 120))	('protein kinase', 'Gene', (150, 164))	('BRAF', 'Gene', (116, 120))	('protein kinase', 'Gene', '53859', (150, 164))	('constitutively active', 'MPA', (128, 149))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('p.V600E', 'Mutation', 'rs113488022', (97, 104))	('switching', 'Reg', (106, 115))
49458	25600636	Besides V600E there are additional non-silent polar replacements in the activator loop (p.D594N, p.L597Q, p.V600K, p.V600R, and p.K601E).	('p.V600K', 'Var', (106, 113))	('p.V600K', 'Mutation', 'rs121913227', (106, 113))	('V600E', 'Mutation', 'rs113488022', (8, 13))	('p.L597Q', 'Var', (97, 104))	('p.K601E', 'Mutation', 'rs121913364', (128, 135))	('p.L597Q', 'Mutation', 'rs121913366', (97, 104))	('V600E', 'Var', (8, 13))	('p.V600R', 'Mutation', 'rs121913227', (115, 122))	('p.K601E', 'Var', (128, 135))	('p.D594N', 'Var', (88, 95))	('p.D594N', 'Mutation', 'rs397516896', (88, 95))	('p.V600R', 'Var', (115, 122))
49459	25600636	Next, we investigated whether such unprecedented diversity of BRAF mutations is specific to melanoma or common to other cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('mutations', 'Var', (67, 76))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('cancers', 'Disease', (120, 127))	('melanoma', 'Disease', (92, 100))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))
49460	25600636	By calculating the relative frequency of mutations corrected for the cohort size, other BRAF-driven cancers were identified (Figure 3, Supplementary table 6).	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
49461	25600636	Thyroid cancer (THCA) stood out for containing frequent and recurrent somatic mutations of BRAF p.V600E with 249 of 350 cases (Figure 3, Supplementary table 6).	('Thyroid cancer', 'Disease', 'MESH:D013964', (0, 14))	('BRAF', 'Gene', '673', (91, 95))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (0, 14))	('BRAF', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('p.V600E', 'Mutation', 'rs113488022', (96, 103))	('Thyroid cancer', 'Disease', (0, 14))	('p.V600E', 'Var', (96, 103))
49462	25600636	In contrast, other significantly enriched datasets with BRAF mutations like colon adenocarcinoma (COAD), lung adenocarcinoma (LUAD), or SKCM showed mutations up to 37% in other conserved sections of the protein like the RAS-binding domain (RBD) (p.K183E, p.K205Q, p.E228V), the glycine-rich ATP binding site (p.G466E, p.S467L, p.G469A, p.G469E, p.G469R), or the protein surface connecting RBD and protein kinase (p.E695K) (Figure 4).	('ATP binding', 'molecular_function', 'GO:0005524', ('291', '302'))	('protein', 'cellular_component', 'GO:0003675', ('362', '369'))	('p.E228V', 'Var', (264, 271))	('BRAF', 'Gene', (56, 60))	('p.K205Q', 'Mutation', 'p.K205Q', (255, 262))	('BRAF', 'Gene', '673', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('ATP', 'Chemical', 'MESH:D000255', (291, 294))	('p.G469R', 'Var', (345, 352))	('p.S467L', 'Mutation', 'rs867748453', (318, 325))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (76, 96))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('lung adenocarcinoma', 'Disease', (105, 124))	('p.E695K', 'Mutation', 'p.E695K', (413, 420))	('p.G469A', 'Var', (327, 334))	('p.K183E', 'Mutation', 'p.K183E', (246, 253))	('p.G469E', 'Mutation', 'rs121913355', (336, 343))	('protein kinase', 'Gene', (397, 411))	('p.G469A', 'Mutation', 'rs121913355', (327, 334))	('mutations', 'Var', (148, 157))	('protein kinase', 'Gene', '53859', (397, 411))	('glycine', 'Chemical', 'MESH:D005998', (278, 285))	('p.E228V', 'Mutation', 'p.E228V', (264, 271))	('p.K183E', 'Var', (246, 253))	('binding', 'molecular_function', 'GO:0005488', ('224', '231'))	('mutations', 'Var', (61, 70))	('COAD', 'Disease', 'MESH:D029424', (98, 102))	('p.G466E', 'Var', (309, 316))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('p.G466E', 'Mutation', 'rs121913351', (309, 316))	('p.G469E', 'Var', (336, 343))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('colon adenocarcinoma', 'Disease', (76, 96))	('p.G469R', 'Mutation', 'rs121913357', (345, 352))	('protein', 'cellular_component', 'GO:0003675', ('397', '404'))	('p.S467L', 'Var', (318, 325))	('p.K205Q', 'Var', (255, 262))	('COAD', 'Disease', (98, 102))
49463	25600636	In order to identify potential melanoma drivers, we assessed functional relevance of significant somatic mutations from nucleotide signature, structure activity relationship, mutual exclusivity to known cancer drivers, and recurrence in other cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('mutations', 'Var', (105, 114))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
49465	25600636	Their signature of nucleotide replacement related to UV radiation deviated from the exome-wide median by more than 5%, indicative for positive selection of cancer genes (Supplementary information 2).	('nucleotide replacement', 'Var', (19, 41))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))
49468	25600636	In addition, the cyclin pathway, M1529, including mutually exclusive mutations of cyclin-dependent kinase CDK4, its inhibitor CDKN2A, proline-rich protein BstNI subfamily 1 PRB1, and tumor suppressor TP53 showed statistically significant perturbation with a q-value below 1.0e-6.	('CDK', 'molecular_function', 'GO:0004693', ('106', '109'))	('TP53', 'Gene', '7157', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cyclin', 'Gene', (17, 23))	('cyclin', 'Gene', (82, 88))	('cyclin', 'molecular_function', 'GO:0016538', ('17', '23'))	('CDK4', 'Gene', (106, 110))	('mutations', 'Var', (69, 78))	('RB1', 'Gene', '19645', (174, 177))	('CDKN2A', 'Gene', (126, 132))	('TP53', 'Gene', (200, 204))	('tumor', 'Disease', (183, 188))	('CDK4', 'Gene', '1019', (106, 110))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('183', '199'))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('perturbation', 'Reg', (238, 250))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cyclin', 'Gene', '5111', (17, 23))	('cyclin', 'Gene', '5111', (82, 88))	('CDKN2A', 'Gene', '1029', (126, 132))	('RB1', 'Gene', (174, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('183', '199'))	('cyclin', 'molecular_function', 'GO:0016538', ('82', '88'))
49471	25600636	TMEM216 is the melanoma gene with the most significant synonymous somatic mutations of the TCGA SKCM dataset.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('TMEM216', 'Gene', (0, 7))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutations', 'Var', (74, 83))	('TMEM216', 'Gene', '51259', (0, 7))
49474	25600636	The c.T138G replacement creates a mutation in the 3' exon splice site of TMEM216.	('TMEM216', 'Gene', (73, 80))	('TMEM216', 'Gene', '51259', (73, 80))	('c.T138G', 'Mutation', 'rs559230605', (4, 11))	('c.T138G replacement', 'Var', (4, 23))
49476	25600636	Integrated systems biology analysis including somatic copy number alterations as well as pathway enrichment of somatic mutations point towards main signaling axes in melanoma; Gs-protein and MAPK signaling are frequently dysregulated in SKCM.	('SKCM', 'Disease', (237, 241))	('dysregulated', 'Reg', (221, 233))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('MAPK signaling', 'biological_process', 'GO:0000165', ('191', '205'))	('Gs-protein', 'MPA', (176, 186))	('MAPK', 'molecular_function', 'GO:0004707', ('191', '195'))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('MAPK', 'Gene', '5594', (191, 195))	('signaling', 'biological_process', 'GO:0023052', ('148', '157'))	('MAPK', 'Gene', (191, 195))	('mutations', 'Var', (119, 128))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
49477	25600636	The genomic observation in SKCM of strong mutual exclusivity of NRAS to BRAF is consistent with NRAS mutations activating both effector cascades BRAF/MEK/ERK and PI3K/Akt.	('MEK', 'Gene', '5609', (150, 153))	('BRAF', 'Gene', (72, 76))	('mutations', 'Var', (101, 110))	('BRAF', 'Gene', (145, 149))	('Akt', 'Gene', '207', (167, 170))	('ERK', 'Gene', '5594', (154, 157))	('ERK', 'molecular_function', 'GO:0004707', ('154', '157'))	('activating', 'PosReg', (111, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('ERK', 'Gene', (154, 157))	('NRAS', 'Gene', (96, 100))	('MEK', 'Gene', (150, 153))	('Akt', 'Gene', (167, 170))	('BRAF', 'Gene', '673', (72, 76))	('BRAF', 'Gene', '673', (145, 149))
49478	25600636	The analysis identified somatic mutations and copy number alterations affecting the Gs-protein pathway in more than 80% of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('Gs-protein pathway', 'Pathway', (84, 102))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('affecting', 'Reg', (70, 79))	('copy number alterations', 'Var', (46, 69))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
49479	25600636	Included were activating somatic point mutations and copy number amplification of BRAF (50%, responsive to MAPK signaling pathway activator), mutation and deletion of NRAS (31%, responsive to MAPK signaling pathway activator), as well as mutation and deletion of GNAI2 (guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2, Gene ID: 2771) (2%, responsive to GTP activator).	('MAPK', 'Gene', (107, 111))	('protein', 'cellular_component', 'GO:0003675', ('297', '304'))	('MAPK', 'Gene', (192, 196))	('MAPK', 'Gene', '5594', (107, 111))	('NRAS', 'Gene', (167, 171))	('mutations', 'Var', (39, 48))	('signaling pathway', 'biological_process', 'GO:0007165', ('112', '129'))	('deletion', 'Var', (251, 259))	('deletion', 'Var', (155, 163))	('MAPK', 'Gene', '5594', (192, 196))	('mutation', 'Var', (238, 246))	('MAPK', 'molecular_function', 'GO:0004707', ('192', '196'))	('GNAI2', 'Gene', '2771', (263, 268))	('copy number', 'Var', (53, 64))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('278', '296'))	('protein', 'cellular_component', 'GO:0003675', ('308', '315'))	('activating', 'PosReg', (14, 24))	('GNAI2', 'Gene', (263, 268))	('mutation', 'Var', (142, 150))	('MAPK', 'molecular_function', 'GO:0004707', ('107', '111'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('192', '206'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('107', '121'))	('signaling pathway', 'biological_process', 'GO:0007165', ('197', '214'))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('GTP', 'Chemical', 'MESH:D006160', (393, 396))	('guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2', 'Gene', '2771', (270, 357))
49481	25600636	So far statistically significant mutation of GNAI2 in melanoma has not been reported.	('mutation', 'Var', (33, 41))	('GNAI2', 'Gene', (45, 50))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('GNAI2', 'Gene', '2771', (45, 50))
49482	25600636	In addition, CAMP, CREB3, CREB5, MAPK1, and RAF1 are mutated in the Gs-protein pathway in more than 10% of the tumors.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('CREB5', 'Gene', (26, 31))	('CREB3', 'Gene', (19, 24))	('RAF1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CREB3', 'Gene', '10488', (19, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('tumors', 'Disease', (111, 117))	('CAMP', 'Gene', (13, 17))	('MAPK1', 'Gene', '5594', (33, 38))	('mutated', 'Var', (53, 60))	('CAMP', 'Gene', '820', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Gs-protein pathway', 'Pathway', (68, 86))	('CREB5', 'Gene', '9586', (26, 31))	('MAPK1', 'Gene', (33, 38))
49483	25600636	Other mutations, genomic amplifications, or deletions that affect melanogenesis pathways included somatic copy number amplification in genes FZD6, GNAS, EP300, CREB3L2 and MITF.	('affect', 'Reg', (59, 65))	('melanogenesis pathways', 'Pathway', (66, 88))	('MITF', 'Gene', '4286', (172, 176))	('CREB3L2', 'Gene', '64764', (160, 167))	('deletions', 'Var', (44, 53))	('FZD6', 'Gene', '8323', (141, 145))	('GNAS', 'Gene', (147, 151))	('FZD6', 'Gene', (141, 145))	('CREB3L2', 'Gene', (160, 167))	('EP300', 'Gene', (153, 158))	('MITF', 'Gene', (172, 176))	('EP300', 'Gene', '2033', (153, 158))	('GNAS', 'Gene', '2778', (147, 151))
49487	25600636	The TCGA landmark study across many cancer types revealed that the universe of cancer mutations is much bigger than previously thought.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
49494	25600636	In addition to aneuploidy or focal SCNA events, significant enrichment of inactivating TP53 may contribute to other classes of structural variations, like breakage or fusions.	('TP53', 'Gene', '7157', (87, 91))	('fusions', 'Disease', (167, 174))	('aneuploidy', 'Disease', (15, 25))	('TP53', 'Gene', (87, 91))	('breakage', 'Disease', (155, 163))	('inactivating', 'Var', (74, 86))	('contribute', 'Reg', (96, 106))	('aneuploidy', 'Disease', 'MESH:D000782', (15, 25))
49497	25600636	The mutation c.T138G in the splice site joining exons 2 and 3 disrupts the recognition motif of splicing auxiliary factor U2AF1.	('c.T138G in', 'Var', (13, 23))	('recognition motif', 'MPA', (75, 92))	('c.T138G', 'Mutation', 'rs559230605', (13, 20))	('disrupts', 'NegReg', (62, 70))	('U2AF1', 'Gene', '7307', (122, 127))	('U2AF1', 'Gene', (122, 127))	('splicing', 'biological_process', 'GO:0045292', ('96', '104'))	('U2AF', 'cellular_component', 'GO:0089701', ('122', '126'))
49502	25600636	Somatic missense mutation of BRAF has been identified in roughly half of all malignant melanoma cases and at much lower frequency in all other cancers.	('BRAF', 'Gene', '673', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('malignant melanoma', 'Disease', 'MESH:D008545', (77, 95))	('BRAF', 'Gene', (29, 33))	('malignant melanoma', 'Disease', (77, 95))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('identified', 'Reg', (43, 53))	('missense mutation', 'Var', (8, 25))	('malignant melanoma', 'Phenotype', 'HP:0002861', (77, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
49506	25600636	Our detailed and targeted sampling of the mutational landscape of BRAF in TCGA melanoma as well as in all other tissues of TCGA by next-generation sequencing brought three main insights forward: a) BRAF is significantly increased at a copy-number level and constitutively activated by somatic mutations; b) The whole-exome data showed unprecedented diverse mutational events within BRAF (Figure 3) aside from p.V600E preserving mutual exclusivity to activating NRAS mutations; c) Other cancers have similar or even stronger BRAF signatures than melanoma.	('cancers', 'Phenotype', 'HP:0002664', (486, 493))	('BRAF', 'Gene', '673', (524, 528))	('BRAF', 'Gene', (382, 386))	('cancers', 'Disease', (486, 493))	('BRAF', 'Gene', (524, 528))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (545, 553))	('melanoma', 'Disease', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (486, 492))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('p.V600E', 'Mutation', 'rs113488022', (409, 416))	('p.V600E', 'Var', (409, 416))	('cancers', 'Disease', 'MESH:D009369', (486, 493))	('melanoma', 'Phenotype', 'HP:0002861', (545, 553))	('melanoma', 'Disease', (545, 553))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', '673', (382, 386))
49508	25600636	Lessons already learned from molecular studies of the BRAF pathway are relevant to almost all cancer tissues, which showed somatic missense mutations.	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('missense mutations', 'Var', (131, 149))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
49510	25600636	A single SNP test for c.1799T>A is not sufficient to capture the majority of mutational events of BRAF in its RBD or in the ATP binding site of its PK domain.	('c.1799T>A', 'Mutation', 'rs113488022', (22, 31))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('ATP binding', 'molecular_function', 'GO:0005524', ('124', '135'))	('ATP', 'Chemical', 'MESH:D000255', (124, 127))	('c.1799T>A', 'Var', (22, 31))
49512	25600636	On a positive note, the diagnostic value of c.1799T>A for BRAF diagnostics is widened to many other cancers besides SKCM that homogeneously show single p.V600E substitutions like THCA, COAD, GBM, KIRP, READ, and LGG.	('c.1799T>A', 'Var', (44, 53))	('p.V600E', 'Var', (152, 159))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('COAD', 'Disease', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('THCA', 'Disease', (179, 183))	('c.1799T>A', 'Mutation', 'rs113488022', (44, 53))	('READ', 'Disease', (202, 206))	('BRAF', 'Gene', '673', (58, 62))	('COAD', 'Disease', 'MESH:D029424', (185, 189))	('p.V600E', 'Mutation', 'rs113488022', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('BRAF', 'Gene', (58, 62))	('cancers', 'Disease', (100, 107))
49516	25600636	If driver mutations are observed in other cancer tissues as well, lessons learned on regulation of signaling cascades and drug resistance of cancer targets might be directly translatable.	('drug resistance', 'Phenotype', 'HP:0020174', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('drug resistance', 'biological_process', 'GO:0009315', ('122', '137'))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('drug resistance', 'biological_process', 'GO:0042493', ('122', '137'))	('mutations', 'Var', (10, 19))	('regulation of signaling', 'biological_process', 'GO:0023051', ('85', '108'))	('cancer', 'Disease', (141, 147))
49527	25600636	Critical components of the computational filters were i) TCGA data portal for cohort selection and CGHub for access of raw data; ii) MuTect 1.1.4 at default settings for preprocessing, alignment of reads in the tumor and normal sequencing data, and mutation calling; iii) MutSig 2.0, an algorithm for identification of mutation significance, for assessing the clustering of mutations in hotspots as well as conservation of the sites; and iv) InVEx 1.0.1, a permutation based Intron vs Exon algorithm for ascertaining positive selection of somatic mutation above the background level considering heterogeneity on a per-patient and per-gene level.	('patient', 'Species', '9606', (618, 625))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('mutations', 'Var', (374, 383))
49533	25600636	COSMIC_54.vcf is a database referenced to GrCh37 of somatically-acquired mutations found in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('human', 'Species', '9606', (92, 97))	('mutations', 'Var', (73, 82))
49537	25600636	Mutations were inferred from raw binary alignment wes.bam files and compared to benchmarks at the cancer genome analysis multi-pipeline Firehose, which performs analyses including quality control, local realignment, single nucleotide variations identification, insertion and deletion identification, as well as inter-chromosomal and large intra-chromosomal structural rearrangement detection and mutation rate calculation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('single nucleotide variations', 'Var', (216, 244))	('cancer', 'Disease', (98, 104))	('insertion', 'Var', (261, 270))	('deletion', 'Var', (275, 283))
49540	25600636	v) Deviation from the exome-wide median of the signature of nucleotide replacement can be indicative for positive selection of cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('Deviation', 'Var', (3, 12))	('nucleotide replacement', 'Var', (60, 82))
49559	30988467	The functional variants identified based on DACRE scores appeared associated significantly with extreme DNA methylation levels and known enhancer elements (Supplementary Note 4).	('DACRE', 'Chemical', '-', (44, 49))	('extreme DNA methylation levels', 'MPA', (96, 126))	('enhancer', 'PosReg', (137, 145))	('variants', 'Var', (15, 23))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))
49561	30988467	We first predicted functional status of each of the somatic missense SNVs in TCGA BRCA and SKCM samples, based on the functional impact scores calculated by a set of 8 widely used functional variant predictors.	('BRCA', 'Gene', (82, 86))	('TCGA', 'Gene', (77, 81))	('predicted', 'Reg', (9, 18))	('missense', 'Var', (60, 68))	('BRCA', 'Gene', '672', (82, 86))
49564	30988467	Given a set of autologous bulk whole exome (WES) and whole transcriptome sequencing (WTS) data, Texomer performs allele-specific, tumor-deconvoluted transformation of read counts observed at the germline single nucleotide polymorphisms (SNPs) and somatic single nucleotide variants (SNVs) sites.	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('single nucleotide variants', 'Var', (255, 281))
49567	30988467	The ploidy ratio between the tumor and the normal WES and the variant B allele frequency (BAF) at the i-th germline SNP site observed from the total (Ni) and allelic (yi) read counts, can be estimated from tumor purity in the DNA sample (alphaD), and the integer total (TCNi) and the allele-specific copy numbers (ASCNi) in the tumor sample, as described in equations (1) and (2), respectively,   TCNi equals the summation of the ASCNi of the variant and the wildtype alleles.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('BAF', 'Gene', '8815', (90, 93))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('BAF', 'Gene', (90, 93))	('DNA', 'cellular_component', 'GO:0005574', ('226', '229'))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('variant', 'Var', (443, 450))	('tumor', 'Disease', (328, 333))
49568	30988467	The BAF of the s-th somatic SNV is calculated using a different equation (3) because somatic SNVs exist only in the tumor cells:  where SMCNs is the somatic variant allelic copy number corresponding to the s-th somatic SNV in the tumor cells.	('tumor', 'Disease', (230, 235))	('SMCNs', 'Var', (136, 141))	('BAF', 'Gene', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (116, 121))	('BAF', 'Gene', '8815', (4, 7))
49580	30988467	It does so by removing dosage and, presumably, additive effects of copy number alterations, whereas DAE does not.	('dosage', 'MPA', (23, 29))	('copy number alterations', 'Var', (67, 90))	('DAE', 'Chemical', '-', (100, 103))	('removing', 'NegReg', (14, 22))
49586	33834191	Higher RBP4 expression was associated with better overall survival time in HCC patients, and we identified a deletion-mutation rate of 1.4% in RBP4.	('deletion-mutation', 'Var', (109, 126))	('RBP4', 'Gene', (143, 147))	('RBP4', 'Gene', '5950', (143, 147))	('HCC', 'Gene', '619501', (75, 78))	('RBP4', 'Gene', '5950', (7, 11))	('RBP4', 'Gene', (7, 11))	('patients', 'Species', '9606', (79, 87))	('expression', 'MPA', (12, 22))	('HCC', 'Gene', (75, 78))
49608	33834191	Studies have indicated that high serum RBP4 in HCC combined with metabolic syndrome patients were closely associated with poor prognosis.	('RBP4', 'Gene', '5950', (39, 43))	('HCC', 'Gene', (47, 50))	('associated', 'Reg', (106, 116))	('metabolic syndrome', 'Disease', (65, 83))	('patients', 'Species', '9606', (84, 92))	('HCC', 'Gene', '619501', (47, 50))	('metabolic syndrome', 'Disease', 'MESH:D024821', (65, 83))	('high', 'Var', (28, 32))	('RBP4', 'Gene', (39, 43))
49620	33834191	The online CBioPortal site (https://www.cbioportal.org/) and LinkedOmics were used to access data for RBP4 gene mutations, co-expressed genes, and mutations related to protein expression.	('mutations', 'Var', (112, 121))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('RBP4', 'Gene', '5950', (102, 106))	('RBP4', 'Gene', (102, 106))
49635	33834191	For DSS, high RBP4 expression was also associated with better outcomes (HR = 0.32, 95% CI: 0.2-0.51), (log rank P = 2.8e-07, Figure 2J).	('expression', 'MPA', (19, 29))	('RBP4', 'Gene', (14, 18))	('DSS', 'Chemical', '-', (4, 7))	('RBP4', 'Gene', '5950', (14, 18))	('high', 'Var', (9, 13))
49637	33834191	Deletion mutations accounted for 1.4% of total RBP4 mutations, and five proteins were changed because of RBP4 related somatic mutations (T41l, RBP4-GPC3, IGHG1-RBP4, AMBP-RBP4, and CLU-RBP4) (Figure 3A).	('RBP4', 'Gene', (143, 147))	('CLU', 'Gene', (181, 184))	('RBP4', 'Gene', (47, 51))	('RBP4', 'Gene', '5950', (171, 175))	('CLU', 'Gene', '1191', (181, 184))	('IGHG1', 'Gene', '3500', (154, 159))	('Deletion mutations', 'Var', (0, 18))	('T41l', 'Var', (137, 141))	('RBP4', 'Gene', '5950', (105, 109))	('RBP4', 'Gene', (171, 175))	('RBP4', 'Gene', '5950', (185, 189))	('IGHG1', 'Gene', (154, 159))	('GPC3', 'Gene', (148, 152))	('RBP4', 'Gene', '5950', (160, 164))	('RBP4', 'Gene', (105, 109))	('AMBP', 'Gene', '259', (166, 170))	('mutations', 'Var', (52, 61))	('RBP4', 'Gene', '5950', (143, 147))	('changed', 'Reg', (86, 93))	('GPC3', 'Gene', '2719', (148, 152))	('AMBP', 'Gene', (166, 170))	('proteins', 'Protein', (72, 80))	('RBP4', 'Gene', (185, 189))	('RBP4', 'Gene', (160, 164))	('RBP4', 'Gene', '5950', (47, 51))
49638	33834191	The different types of RBP4 mutations also affected RBP4 m RNA expression (F-value = 9.969, P<0.001, Figure 3B).	('affected', 'Reg', (43, 51))	('RBP4', 'Gene', '5950', (23, 27))	('RBP4', 'Gene', (52, 56))	('RBP4', 'Gene', '5950', (52, 56))	('RNA', 'cellular_component', 'GO:0005562', ('59', '62'))	('mutations', 'Var', (28, 37))	('RBP4', 'Gene', (23, 27))
49639	33834191	The RBP4 mutation types were also correlated with immune cell infiltration levels, especially for neutrophils with deep-deletion and arm-level gain types of mutations (Figure 3C).	('deep-deletion', 'Var', (115, 128))	('RBP4', 'Gene', '5950', (4, 8))	('RBP4', 'Gene', (4, 8))	('mutations', 'Var', (157, 166))	('arm-level', 'MPA', (133, 142))	('immune cell infiltration levels', 'MPA', (50, 81))	('gain', 'PosReg', (143, 147))
49641	33834191	Collectively, RBP4 expression and mutations were associated with immune cell infiltration characteristics.	('RBP4', 'Gene', (14, 18))	('associated', 'Reg', (49, 59))	('RBP4', 'Gene', '5950', (14, 18))	('mutations', 'Var', (34, 43))	('immune cell infiltration characteristics', 'CPA', (65, 105))
49672	33834191	We determined that RBP4 mutations were negatively correlated with immune cell infiltration, indicating that RBP4 expression is closely related to immune cell bioactivity in preclinical and clinical models.	('RBP4', 'Gene', (108, 112))	('mutations', 'Var', (24, 33))	('negatively', 'NegReg', (39, 49))	('RBP4', 'Gene', '5950', (108, 112))	('RBP4', 'Gene', '5950', (19, 23))	('RBP4', 'Gene', (19, 23))	('immune cell infiltration', 'CPA', (66, 90))
49684	30664638	We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa.	('human', 'Species', '9606', (76, 81))	('lip', 'Disease', (97, 100))	('lip', 'Disease', 'MESH:D002971', (97, 100))	('mutation', 'Var', (17, 25))
49693	30664638	While hundreds of genomes of cutaneous melanoma have now been sequenced, defining a landscape that is replete with UV-induced mutations and driver mutations in genes such as BRAF, the genomes of tumors that develop at mucosal sites have not been as well characterized.	('mutations', 'Var', (147, 156))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('BRAF', 'Gene', (174, 178))	('mutations', 'Var', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
49694	30664638	To date, only ~20 human mucosal cases have been sequenced, revealing a genomic landscape that is associated with a low single nucleotide mutation burden and no evidence of a UV signature, but numerous large-scale copy number changes and whole-chromosome gains and losses.	('losses', 'NegReg', (264, 270))	('human', 'Species', '9606', (18, 23))	('copy number changes', 'Var', (213, 232))	('chromosome', 'cellular_component', 'GO:0005694', ('243', '253'))	('gains', 'PosReg', (254, 259))
49695	30664638	It is also known that the profile of driver genes differs among human melanoma subtypes; for example, BRAF mutations, which are found in around 45% of cutaneous melanomas, are rarely found in mucosal melanoma.	('human', 'Species', '9606', (64, 69))	('mucosal melanoma', 'Disease', (192, 208))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (151, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (151, 169))	('mutations', 'Var', (107, 116))	('mucosal melanoma', 'Disease', 'MESH:D008545', (192, 208))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (151, 170))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('melanoma subtypes', 'Disease', (70, 87))	('cutaneous melanomas', 'Disease', (151, 170))	('BRAF', 'Gene', (102, 106))	('melanoma subtypes', 'Disease', 'MESH:D008545', (70, 87))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanomas', 'Phenotype', 'HP:0002861', (161, 170))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
49696	30664638	The abovementioned difference in mutation burden is significant since most of the effort towards developing new therapies for melanoma has shifted to immunotherapies, which have yielded impressive results in tumors with a high mutational load, but appear less effective in mucosal melanomas, which have fewer neo-antigens.	('mucosal melanomas', 'Disease', (273, 290))	('men', 'Species', '9606', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('mucosal melanomas', 'Disease', 'MESH:D008545', (273, 290))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('melanomas', 'Phenotype', 'HP:0002861', (281, 290))	('melanoma', 'Disease', (281, 289))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('melanoma', 'Disease', 'MESH:D008545', (281, 289))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('melanoma', 'Disease', (126, 134))	('mutational', 'Var', (227, 237))
49697	30664638	Similarly, small molecular drugs that target mutant oncoproteins such as BRAFV600E have been developed, but these agents are not suitable for most cases of the mucosal subtype.	('oncoproteins', 'Protein', (52, 64))	('BRAFV600E', 'Var', (73, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (73, 82))
49705	30664638	We find similarities in terms of mutant genes and pathways, suggesting evolutionarily conserved mechanisms of tumor development, but also striking differences between species that help inform on the biology of mucosal melanoma.	('mucosal melanoma', 'Disease', (210, 226))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('mucosal melanoma', 'Disease', 'MESH:D008545', (210, 226))	('mutant', 'Var', (33, 39))	('men', 'Species', '9606', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
49717	30664638	It was notable that most of the human mucosal, canine oral, and equine melanomas we sequenced had less than 5 mutations/Mb (Fig.	('melanomas', 'Disease', (71, 80))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('equine', 'Species', '9796', (64, 70))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('canine', 'Species', '9615', (47, 53))	('human', 'Species', '9606', (32, 37))	('mutations/Mb', 'Var', (110, 122))
49722	30664638	Notably, a low mutation burden combined with a slight enrichment of C>T mutations has been reported previously in a mucosal melanoma of the nasal cavity in a small sequencing study of 5 samples, suggesting a potential role for UV in the development of some mucosal cases from this site.	('mucosal melanoma', 'Disease', (116, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('men', 'Species', '9606', (244, 247))	('mucosal melanoma', 'Disease', 'MESH:D008545', (116, 132))	('C>T mutations', 'Var', (68, 81))	('men', 'Species', '9606', (60, 63))
49723	30664638	By pooling all mutations found within each species to identify additional signatures within each cohort, we also identified COSMIC signature 1 in the human and canine melanomas, which has previously been found in all cancer types and is known to be correlated with age (see Methods and Supplementary Table 1).	('human', 'Species', '9606', (150, 155))	('men', 'Species', '9606', (292, 295))	('canine', 'Species', '9615', (160, 166))	('mutations', 'Var', (15, 24))	('melanomas', 'Disease', 'MESH:D008545', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('melanomas', 'Disease', (167, 176))
49727	30664638	In the cutaneous melanomas, samples with a higher mutational load were generally from horses without the gray coat phenotype, suggesting a different path to melanoma development in these cases (Fig.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (7, 26))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (7, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (7, 25))	('cutaneous melanomas', 'Disease', (7, 26))	('men', 'Species', '9606', (173, 176))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('mutational', 'Var', (50, 60))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('horses', 'Species', '9796', (86, 92))
49729	30664638	Identifying driver mutations and altered pathways allows for the molecular classification of cancers, which can facilitate disease prognostication and management.	('cancers', 'Disease', (93, 100))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('men', 'Species', '9606', (157, 160))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
49730	30664638	A recent pan-melanoma study identified 12 significantly mutated genes in a cohort composed of superficial spreading, nodular, acral, and several mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (145, 162))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('acral', 'Disease', (126, 131))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mutated', 'Var', (56, 63))	('melanoma', 'Disease', (153, 161))	('nodular', 'Disease', (117, 124))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('superficial spreading', 'Disease', (94, 115))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('mucosal melanomas', 'Disease', (145, 162))
49732	30664638	In keeping with previous reports, human mucosal melanomas sequenced in our study carried mutations in genes including NRAS (20%; 4 cases with Q61R/K, 2 cases with G12C/V, 2 cases with G13D, 1 case with Y64N), GNAQ (2%; V121L), KIT (7%; 2 cases with L576P, 1 case with D419H and V654A), SF3B1 (20%; 6 cases with R625H/C, and 3 other cases), and TP53 (15%; 8 different mutations in 7 samples), but lacked alterations of several other genes including CDK4, RAC1, and PPP6C, whose respective mutation has been observed in cutaneous melanoma.	('human', 'Species', '9606', (34, 39))	('mucosal melanomas', 'Disease', (40, 57))	('G13D', 'Mutation', 'rs112445441', (184, 188))	('D419H', 'Mutation', 'p.D419H', (268, 273))	('TP53', 'Gene', '7157', (344, 348))	('V121L', 'Mutation', 'p.V121L', (219, 224))	('G12C/V', 'Var', (163, 169))	('mutations', 'Var', (89, 98))	('L576P', 'Mutation', 'rs121913513', (249, 254))	('RAC1', 'Gene', (454, 458))	('L576P', 'Var', (249, 254))	('G12C', 'Mutation', 'rs121913250', (163, 167))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('G13D', 'Var', (184, 188))	('CDK4', 'Gene', (448, 452))	('Y64N', 'Mutation', 'p.Y64N', (202, 206))	('R625H', 'Var', (311, 316))	('PPP6C', 'Gene', (464, 469))	('RAC1', 'Gene', '5879', (454, 458))	('D419H', 'Var', (268, 273))	('Q61R', 'Mutation', 'rs11554290', (142, 146))	('V654A', 'Var', (278, 283))	('Y64N', 'Var', (202, 206))	('KIT', 'molecular_function', 'GO:0005020', ('227', '230'))	('Q61R/K', 'Var', (142, 148))	('melanoma', 'Phenotype', 'HP:0002861', (528, 536))	('TP53', 'Gene', (344, 348))	('CDK4', 'Gene', '1019', (448, 452))	('lacked', 'NegReg', (396, 402))	('R625H', 'SUBSTITUTION', 'None', (311, 316))	('mucosal melanomas', 'Disease', 'MESH:D008545', (40, 57))	('NRAS', 'Gene', (118, 122))	('CDK', 'molecular_function', 'GO:0004693', ('448', '451'))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (518, 536))	('cutaneous melanoma', 'Disease', (518, 536))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (518, 536))	('V654A', 'Mutation', 'rs121913523', (278, 283))
49733	30664638	Also absent were mutations in POLE, PTCHD2/DISP3, and DMXL2, which were recently reported in a study of Asian patients with mucosal melanoma of the oral cavity, while 3 cases (7%) carried PTPRD mutations (P823S, T1246M, and V634fs), as reported in the same study (Supplementary Data 2).	('T1246M', 'Var', (212, 218))	('DMXL2', 'Gene', (54, 59))	('PTCHD2', 'Gene', '57540', (36, 42))	('DISP3', 'Gene', (43, 48))	('V634fs', 'Mutation', 'p.V634fsX', (224, 230))	('men', 'Species', '9606', (270, 273))	('DISP3', 'Gene', '57540', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('V634fs', 'Var', (224, 230))	('P823S', 'Mutation', 'rs61733192', (205, 210))	('PTPRD', 'Gene', (188, 193))	('mucosal melanoma', 'Disease', 'MESH:D008545', (124, 140))	('T1246M', 'Mutation', 'p.T1246M', (212, 218))	('P823S', 'Var', (205, 210))	('mucosal melanoma', 'Disease', (124, 140))	('carried', 'Reg', (180, 187))	('PTCHD2', 'Gene', (36, 42))	('patients', 'Species', '9606', (110, 118))	('POLE', 'Gene', (30, 34))
49735	30664638	Intriguingly, while NRAS mutations were the most common somatic change in sinonasal tumors, these tumors were devoid of TP53 mutations, which were common in tumors from other mucosal sites (Fig.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (74, 90))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NRAS', 'Gene', (20, 24))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
49736	30664638	Similarly, SF3B1 R625 mutations were rare in sinonasal tumors, with the majority found in vaginal, vulvar, or anal tumors, as reported previously.	('R625 mutations', 'Var', (17, 31))	('sinonasal tumors', 'Phenotype', 'HP:0030072', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('vaginal', 'Disease', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('found', 'Reg', (81, 86))	('tumors', 'Disease', (115, 121))	('SF3B1', 'Gene', (11, 16))	('vulvar', 'Disease', (99, 105))	('tumors', 'Disease', (55, 61))	('mutations', 'Var', (22, 31))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
49737	30664638	The same study reported co-mutation of NF1 and KIT, which we observed in only one case in our sample collection.	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('NF1', 'Gene', (39, 42))	('co-mutation', 'Var', (24, 35))	('NF1', 'Gene', '4763', (39, 42))	('KIT', 'Gene', (47, 50))
49746	30664638	Our analysis of canine oral melanomas, widely considered a model of human mucosal melanoma, revealed no KIT mutations, however, we identified NRAS (11%; 4 cases with Q61H/R/K, 3 cases with G12A/D), TP53 (8%; 5 different mutations in 5 cases), BRAF (3%; G457A, D582G), and KRAS mutations (5%; G12D/V, G13D) (Fig.	('mucosal melanoma', 'Disease', 'MESH:D008545', (74, 90))	('human', 'Species', '9606', (68, 73))	('mucosal melanoma', 'Disease', (74, 90))	('oral melanomas', 'Disease', 'MESH:D008545', (23, 37))	('Q61H', 'Mutation', 'rs121913255', (166, 170))	('NRAS', 'Disease', (142, 146))	('KRAS', 'Gene', '3845', (272, 276))	('TP53', 'Gene', '7157', (198, 202))	('G457A', 'Var', (253, 258))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('KIT', 'molecular_function', 'GO:0005020', ('104', '107'))	('KRAS', 'Gene', (272, 276))	('D582G', 'Var', (260, 265))	('G457A', 'Mutation', 'rs112431538', (253, 258))	('G12A', 'Mutation', 'rs876658274', (189, 193))	('G13D', 'Mutation', 'rs112445441', (300, 304))	('canine', 'Species', '9615', (16, 22))	('D582G', 'Mutation', 'p.D582G', (260, 265))	('G12A/D', 'Var', (189, 195))	('G12D', 'Mutation', 'rs121913529', (292, 296))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('G13D', 'Var', (300, 304))	('Q61H/R/K', 'Var', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('TP53', 'Gene', (198, 202))	('oral melanomas', 'Disease', (23, 37))
49748	30664638	Notably, the canine oral melanomas in our series also lacked SF3B1 and GNAQ mutations, and no mutations in POLE, PTPRD, or DMXL2 were found, suggesting that these canine cancers may not represent a faithful genetic model for the subset of human mucosal melanomas with mutations in these genes.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('canine', 'Species', '9615', (163, 169))	('cancers', 'Disease', (170, 177))	('GNAQ', 'Gene', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (253, 262))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('human', 'Species', '9606', (239, 244))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('oral melanomas', 'Disease', (20, 34))	('canine', 'Species', '9615', (13, 19))	('mutations', 'Var', (268, 277))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('oral melanomas', 'Disease', 'MESH:D008545', (20, 34))	('SF3B1', 'Gene', (61, 66))	('lacked', 'NegReg', (54, 60))	('mutations', 'Var', (76, 85))	('mucosal melanomas', 'Disease', 'MESH:D008545', (245, 262))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('mucosal melanomas', 'Disease', (245, 262))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
49749	30664638	Only one case carried a missense mutation in PTCHD2/DISP3 (Supplementary Data 2).	('PTCHD2', 'Gene', (45, 51))	('missense mutation', 'Var', (24, 41))	('men', 'Species', '9606', (65, 68))	('PTCHD2', 'Gene', '57540', (45, 51))	('DISP3', 'Gene', (52, 57))	('DISP3', 'Gene', '57540', (52, 57))
49750	30664638	Surprisingly, only two (3%) canine oral melanoma cases carried a truncating mutation in PTPRJ, which was recently suggested to be inactivated in as many as 23% of canine mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (170, 187))	('canine', 'Species', '9615', (163, 169))	('oral melanoma', 'Disease', (35, 48))	('melanomas', 'Phenotype', 'HP:0002861', (178, 187))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('oral melanoma', 'Disease', 'MESH:D008545', (35, 48))	('canine', 'Species', '9615', (28, 34))	('mucosal melanomas', 'Disease', (170, 187))	('truncating mutation', 'Var', (65, 84))	('PTPRJ', 'Gene', (88, 93))
49752	30664638	The most prominent driver genes were NRAS (14%; 3 cases with Q61R, 1 case with G12A) and TP53 (14%, or 4 cases with 6 mutations; H54Y and P27S, R33W, R125W, and R158W and a deletion, g.50612732_50612735del, affecting a splice acceptor site), while two cases had mutations in BRAF (7%; V594E, and both P321L and S56L in vulvar tumor HD0021a).	('V594E', 'Var', (285, 290))	('P27S', 'Var', (138, 142))	('R33W', 'Var', (144, 148))	('P321L', 'Mutation', 'p.P321L', (301, 306))	('R158W', 'Var', (161, 166))	('TP53', 'Gene', '7157', (89, 93))	('g.50612732_50612735del', 'Var', (183, 205))	('G12A', 'Mutation', 'rs876658274', (79, 83))	('H54Y', 'Mutation', 'p.H54Y', (129, 133))	('S56L', 'Mutation', 'p.S56L', (311, 315))	('vulvar tumor', 'Disease', 'MESH:D014846', (319, 331))	('R125W', 'Mutation', 'p.R125W', (150, 155))	('S56L', 'Var', (311, 315))	('P27S', 'Mutation', 'rs922736614', (138, 142))	('V594E', 'Mutation', 'p.V594E', (285, 290))	('R158W', 'Mutation', 'p.R158W', (161, 166))	('P321L', 'Var', (301, 306))	('g.50612732_50612735del', 'Mutation', 'g.50612732_50612735del', (183, 205))	('vulvar tumor', 'Phenotype', 'HP:0030416', (319, 331))	('TP53', 'Gene', (89, 93))	('vulvar tumor', 'Disease', (319, 331))	('Q61R', 'Var', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('Q61R', 'Mutation', 'rs11554290', (61, 65))	('H54Y', 'Var', (129, 133))	('R125W', 'Var', (150, 155))	('R33W', 'Mutation', 'p.R33W', (144, 148))	('affecting', 'Reg', (207, 216))
49753	30664638	Mutations were also observed in PTEN (R202*, Y41fs), KIT (S339F), and RB1 (inframe deletion p.N366_R374delinsK), with 14% of samples carrying a mutation in at least one of these genes (Fig.	('Y41fs', 'Var', (45, 50))	('Y41fs', 'Mutation', 'p.Y41fsX', (45, 50))	('RB1', 'Gene', (70, 73))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('S339F', 'Mutation', 'p.S339F', (58, 63))	('p.N366_R374delinsK', 'Mutation', 'p.366,374delinsK', (92, 110))	('S339F', 'Var', (58, 63))	('KIT', 'Gene', (53, 56))	('R202*', 'SUBSTITUTION', 'None', (38, 43))	('R202*', 'Var', (38, 43))	('p.N366_R374delinsK', 'Var', (92, 110))	('KIT', 'molecular_function', 'GO:0005020', ('53', '56'))
49754	30664638	Intriguingly, we also found C>T missense mutations in the KNSTRN gene, previously implicated in human cutaneous squamous cell carcinoma, in 1 cutaneous melanoma (L27F in HD0004a) and two mucosal-like samples with a high mutation rate and UV signature (L27F in HD0021a, and P28L in HD0032a).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 135))	('human', 'Species', '9606', (96, 101))	('cutaneous melanoma', 'Disease', (142, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (142, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (142, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('L27F', 'Mutation', 'p.L27F', (162, 166))	('P28', 'cellular_component', 'GO:0070744', ('273', '276'))	('KNSTRN', 'Gene', (58, 64))	('P28L', 'Var', (273, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('L27F', 'Var', (252, 256))	('P28L', 'Mutation', 'rs766760890', (273, 277))	('cutaneous squamous cell carcinoma', 'Disease', (102, 135))	('C>T missense mutations', 'Var', (28, 50))	('L27F', 'Mutation', 'p.L27F', (252, 256))
49755	30664638	In humans, a recurrent C>T UV signature-associated hotspot mutation at a nearby residue (S24F) was shown to disrupt chromatid cohesion.	('chromatid', 'cellular_component', 'GO:0005695', ('116', '125'))	('disrupt', 'NegReg', (108, 115))	('chromatid', 'cellular_component', 'GO:0005694', ('116', '125'))	('chromatid cohesion', 'CPA', (116, 134))	('humans', 'Species', '9606', (3, 9))	('S24F', 'Mutation', 'rs868438023', (89, 93))	('C>T', 'Var', (23, 26))
49760	30664638	With the exception of one NRAS Q61R mutation, these tumors lacked point or indel mutations in known melanoma driver genes (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Q61R', 'Mutation', 'rs11554290', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('point', 'Var', (66, 71))	('NRAS Q61R', 'Var', (26, 35))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('lacked', 'NegReg', (59, 65))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('indel mutations', 'Var', (75, 90))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
49765	30664638	Mutations in ATRX have been linked to alternative telomere lengthening in a range of tumor types.	('tumor', 'Disease', (85, 90))	('linked', 'Reg', (28, 34))	('ATRX', 'Gene', (13, 17))	('alternative telomere lengthening', 'MPA', (38, 70))	('ATRX', 'Gene', '546', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('telomere', 'cellular_component', 'GO:0000781', ('50', '58'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('telomere', 'cellular_component', 'GO:0005696', ('50', '58'))
49766	30664638	Notably, telomere dysregulation has been shown to play an important role in cutaneous melanoma through the identification of genes such as POT1 and mutations in the promoter of TERT.	('telomere', 'cellular_component', 'GO:0005696', ('9', '17'))	('mutations in', 'Var', (148, 160))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('POT1', 'Gene', '25913', (139, 143))	('cutaneous melanoma', 'Disease', (76, 94))	('TERT', 'Gene', '7015', (177, 181))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('POT1', 'Gene', (139, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('telomere', 'cellular_component', 'GO:0000781', ('9', '17'))	('TERT', 'Gene', (177, 181))
49767	30664638	Importantly, ATRX mutations were found to co-occur with TP53 mutations (4 of 5 cases; Fisher's exact test, P = 0.006).	('ATRX', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (56, 60))	('ATRX', 'Gene', '546', (13, 17))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (18, 27))
49768	30664638	The association of ATRX and TP53 mutations has been noted in other cancers, particularly gliomas, and has been associated with an altered differentiation status.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('TP53', 'Gene', '7157', (28, 32))	('noted', 'Reg', (52, 57))	('cancers', 'Disease', (67, 74))	('ATRX', 'Gene', '546', (19, 23))	('association', 'Interaction', (4, 15))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('TP53', 'Gene', (28, 32))	('associated', 'Reg', (111, 121))	('mutations', 'Var', (33, 42))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('gliomas', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gliomas', 'Disease', 'MESH:D005910', (89, 96))	('ATRX', 'Gene', (19, 23))
49769	30664638	We also observed a PTPRJ truncating mutation and two missense mutations, notable because of the aforementioned truncating PTPRJ mutations in canine oral melanomas (Fig.	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('mutations', 'Var', (128, 137))	('oral melanomas', 'Disease', 'MESH:D008545', (148, 162))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('men', 'Species', '9606', (101, 104))	('truncating', 'NegReg', (111, 121))	('PTPRJ', 'Gene', (122, 127))	('oral melanomas', 'Disease', (148, 162))	('canine', 'Species', '9615', (141, 147))
49770	30664638	Similarly, mutations in BRCA2 were also found in human and canine cases, but not equine cases.	('canine', 'Species', '9615', (59, 65))	('mutations', 'Var', (11, 20))	('human', 'Species', '9606', (49, 54))	('equine', 'Species', '9796', (81, 87))	('found', 'Reg', (40, 45))	('BRCA2', 'Gene', (24, 29))
49771	30664638	In addition to mutations in established melanoma genes described above, 2 canine cases were also found to harbor mutations (G9V and R13C) in the highly conserved N-terminal region of the EIF1AX protein (Fig.	('EIF1AX', 'Gene', (187, 193))	('R13C', 'Mutation', 'p.R13C', (132, 136))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('canine', 'Species', '9615', (74, 80))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('G9V', 'Mutation', 'p.G9V', (124, 127))	('G9V', 'Var', (124, 127))	('EIF1AX', 'Gene', '611715', (187, 193))
49773	30664638	Indeed, the same amino acid substitutions at conserved sites G9 and R13 have been found in multiple human tumors (COSM6908971, COSM5899335), along with several other recurrent mutations in the N-terminal region, which are predicted to be activating.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('COSM6908971', 'Var', (114, 125))	('R13', 'Gene', (68, 71))	('tumors', 'Disease', (106, 112))	('found', 'Reg', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('COSM5899335', 'Var', (127, 138))	('substitutions', 'Var', (28, 41))
49774	30664638	This conservation strongly suggests that the same mutations in the canine cases play a functional role in these cancers.	('mutations', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('canine', 'Species', '9615', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('play', 'Reg', (80, 84))
49777	30664638	In addition to NRAS and TP53, which were mutated in all 3 species as described above, PTEN was disrupted by nonsense or frameshift mutations in all species, suggesting a key role for PI3K signaling in the genesis of these melanomas.	('PI3K signaling', 'biological_process', 'GO:0014065', ('183', '197'))	('melanomas', 'Disease', (222, 231))	('PTEN', 'Gene', (86, 90))	('TP53', 'Gene', (24, 28))	('PTEN', 'Gene', '5728', (86, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('disrupted', 'NegReg', (95, 104))	('melanomas', 'Disease', 'MESH:D008545', (222, 231))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanomas', 'Phenotype', 'HP:0002861', (222, 231))	('frameshift mutations', 'Var', (120, 140))	('nonsense', 'Var', (108, 116))	('TP53', 'Gene', '7157', (24, 28))
49778	30664638	Mutations in RB1 and FAT3 were found only in canine and equine cases.	('FAT3', 'Gene', '476772', (21, 25))	('FAT3', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('RB1', 'Gene', (13, 16))	('canine', 'Species', '9615', (45, 51))	('equine', 'Species', '9796', (56, 62))
49780	30664638	Mutations in FAT4 were also seen across species, however, the FAT4 mutations in the equine samples only occurred in two samples from the vulva (HD0021a) and third eyelid (HD0032a), both of which had a high mutation rate and UV mutation signature.	('equine', 'Species', '9796', (84, 90))	('occurred', 'Reg', (104, 112))	('FAT4', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))
49786	30664638	We identified recurrent large and whole-chromosome gains and losses in human mucosal melanoma that mirrored the copy number landscape reported previously using array-based comparative genome hybridization (aCGH), including recurrent gains of 1q, 6p, 8q, 7, and loss of 6q and 10 (Fig.	('mucosal melanoma', 'Disease', 'MESH:D008545', (77, 93))	('gains', 'PosReg', (51, 56))	('loss', 'Var', (261, 265))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('losses', 'NegReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mucosal melanoma', 'Disease', (77, 93))	('gains', 'PosReg', (233, 238))	('human', 'Species', '9606', (71, 76))
49791	30664638	All samples with a copy number loss of chromosome 31 also had a copy number gain of chromosome 25, and the majority of these were perineal or preputial melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('copy number loss', 'Var', (19, 35))	('copy number gain', 'Var', (64, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('melanomas', 'Disease', (152, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))
49795	30664638	Several shared recurrent copy number alterations can be visualized, including a focal deletion on chromosome 15 (human and canine), amplification of the distal end of chromosome 8 (human and canine), partial deletion of 12q (human, canine and equine), and deletion of the distal end of chromosome 6 (human and equine).	('human', 'Species', '9606', (181, 186))	('amplification', 'Var', (132, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('canine', 'Species', '9615', (191, 197))	('human', 'Species', '9606', (300, 305))	('equine', 'Species', '9796', (243, 249))	('canine', 'Species', '9615', (232, 238))	('human', 'Species', '9606', (113, 118))	('deletion', 'Var', (256, 264))	('human', 'Species', '9606', (225, 230))	('canine', 'Species', '9615', (123, 129))	('partial deletion', 'Var', (200, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('chromosome', 'cellular_component', 'GO:0005694', ('286', '296'))	('equine', 'Species', '9796', (310, 316))	('deletion', 'Var', (86, 94))
49801	30664638	Equine chromosome 25, where PPP6C and NOTCH1 are located, is syntenic with the distal end of human chromosome 9, however, the recurrent copy number changes in these regions are in the opposite direction.	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('chromosome', 'cellular_component', 'GO:0005694', ('7', '17'))	('human', 'Species', '9606', (93, 98))	('Equine', 'Species', '9796', (0, 6))	('NOTCH1', 'Var', (38, 44))	('PPP6C', 'Var', (28, 33))
49803	30664638	Amplification of MYC has previously been associated with advanced cutaneous melanoma.	('MYC', 'Gene', (17, 20))	('Amplification', 'Var', (0, 13))	('cutaneous melanoma', 'Disease', (66, 84))	('associated', 'Reg', (41, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('MYC', 'Gene', '4609', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
49805	30664638	In this way, we identified several genes found in the Cancer Gene Census (CGC) catalog that were focally amplified or deleted in both human and canine mucosal melanoma (Table 1 and Fig.	('human', 'Species', '9606', (134, 139))	('mucosal melanoma', 'Disease', (151, 167))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('mucosal melanoma', 'Disease', 'MESH:D008545', (151, 167))	('canine', 'Species', '9615', (144, 150))	('deleted', 'Var', (118, 125))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
49806	30664638	The most significant deletion from the GISTIC 2.0 analysis of human mucosal melanoma was a deletion at 15q15.1 (adjusted P-value = 0.009) (Supplementary Data 5), a region with synteny to a significant deletion (STAC footprint-based P-value = 0.04) on canine chromosome 30 spanning positions 2-12 Mb (Supplementary Data 6).	('deletion', 'Var', (91, 99))	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('men', 'Species', '9606', (145, 148))	('human', 'Species', '9606', (62, 67))	('men', 'Species', '9606', (306, 309))	('chromosome', 'cellular_component', 'GO:0005694', ('258', '268'))	('mucosal melanoma', 'Disease', (68, 84))	('canine', 'Species', '9615', (251, 257))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
49809	30664638	previously identified a significant focal deletion at ~7.2-7.7 Mb (relative to CanFam3.1) on chromosome 30 in canine oral melanomas; this smaller region contains KNSTRN and BUB1B but not B2M.	('canine', 'Species', '9615', (110, 116))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('oral melanomas', 'Disease', (117, 131))	('oral melanomas', 'Disease', 'MESH:D008545', (117, 131))	('BUB1B', 'Gene', (173, 178))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('deletion', 'Var', (42, 50))	('KNSTRN', 'Protein', (162, 168))
49811	30664638	However, as noted above, missense mutations in KNSTRN were observed in 2 mucosal-like and 1 cutaneous equine sample.	('missense mutations', 'Var', (25, 43))	('KNSTRN', 'Gene', (47, 53))	('equine', 'Species', '9796', (102, 108))	('observed', 'Reg', (59, 67))
49814	30664638	SMO is a well-established oncogene in a range of cancers including medulloblastoma and its amplification in both human and canine mucosal cases suggests a functional role in tumorigenesis (Table 1).	('tumor', 'Disease', (174, 179))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('medulloblastoma', 'Disease', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('amplification', 'Var', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('canine', 'Species', '9615', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('medulloblastoma', 'Disease', 'MESH:D008527', (67, 82))	('medulloblastoma', 'Phenotype', 'HP:0002885', (67, 82))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (113, 118))	('SMO', 'Gene', (0, 3))
49816	30664638	The conserved partial deletion on human 12q, described above, maps to syntenic regions on equine chromosome 28 and canine chromosomes 10 and 15 that contain Cancer Gene Census genes BTG1, CHST11, and USP44.	('USP44', 'Gene', '475430', (200, 205))	('canine', 'Species', '9615', (115, 121))	('human', 'Species', '9606', (34, 39))	('CHST11', 'Gene', (188, 194))	('BTG1', 'Gene', (182, 186))	('partial deletion', 'Var', (14, 30))	('Cancer', 'Disease', (157, 163))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('USP', 'molecular_function', 'GO:0051748', ('200', '203'))	('Cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('BTG1', 'Gene', '100684605', (182, 186))	('equine', 'Species', '9796', (90, 96))	('CHST11', 'Gene', '481299', (188, 194))	('USP44', 'Gene', (200, 205))
49827	30664638	In addition to our analysis of somatic mutations, we also looked for pathogenic germline variants in established human melanoma susceptibility genes, including CDKN2A, BAP1, POT1 and TP53, and their orthologs in the canine and equine genomes.	('variants', 'Var', (89, 97))	('TP53', 'Gene', '7157', (183, 187))	('CDKN2A', 'Gene', (160, 166))	('BAP1', 'Gene', (168, 172))	('TP53', 'Gene', (183, 187))	('CDKN2A', 'Gene', '1029', (160, 166))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('POT1', 'Gene', (174, 178))	('POT1', 'Gene', '25913', (174, 178))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('equine', 'Species', '9796', (227, 233))	('canine', 'Species', '9615', (216, 222))	('human', 'Species', '9606', (113, 118))
49828	30664638	In the human cases we found one patient (with multiple germline samples sequenced, PD25652b/e/f) with a pathogenic complex TP53 mutation (11 bp deletion + 5 bp insertion; ClinVar ID: 12381) which is in keeping with a previous case report outlining the development of mucosal melanoma in a Li Fraumeni syndrome patient (Table 2).	('men', 'Species', '9606', (296, 299))	('pathogenic', 'Reg', (104, 114))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (289, 309))	('Li Fraumeni syndrome', 'Disease', (289, 309))	('mucosal melanoma', 'Disease', 'MESH:D008545', (267, 283))	('human', 'Species', '9606', (7, 12))	('11 bp deletion + 5 bp insertion;', 'Var', (138, 170))	('men', 'Species', '9606', (259, 262))	('TP53', 'Gene', '7157', (123, 127))	('mutation (11 bp deletion + 5 bp insertion', 'Var', (128, 169))	('patient', 'Species', '9606', (310, 317))	('patient', 'Species', '9606', (32, 39))	('mucosal melanoma', 'Disease', (267, 283))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('PD25652b/e/f', 'Var', (83, 95))	('TP53', 'Gene', (123, 127))
49829	30664638	No known pathogenic or risk factor variants (as described in the ClinVar database), or deleterious substitutions (defined by a SIFT score <= 0.05) were identified in CDKN2A or BAP1, while a single case (PD25655b) carried a POT1 Q539H variant which has not been reported previously in the ClinVar database but is present in dbSNP (rs973319258) and the gnomAD database with a population variant allele frequency (VAF) of 1.6 x 10-5.	('CDKN2A', 'Gene', (166, 172))	('SIFT', 'Disease', 'None', (127, 131))	('rs973319258', 'Mutation', 'rs973319258', (330, 341))	('CDKN2A', 'Gene', '1029', (166, 172))	('rs973319258', 'Var', (330, 341))	('Q539H', 'Mutation', 'rs973319258', (228, 233))	('SIFT', 'Disease', (127, 131))	('POT1', 'Gene', '25913', (223, 227))	('POT1', 'Gene', (223, 227))
49831	30664638	Extending our search for pathogenic variants, risk factor variants and deleterious substitutions to all genes, we identified patients with truncating loss-of-function mutations in BRCA1 (E23fs; ClinVar ID: 17662; PD26992b) and BRCA2 (L122fs; ClinVar ID: 51504; PD25663b) (Table 2), both of which are associated with predisposition to breast and ovarian cancer.	('E23fs;', 'Var', (187, 193))	('patients', 'Species', '9606', (125, 133))	('PD26992b', 'Var', (213, 221))	('L122fs;', 'Var', (234, 241))	('E23fs', 'Mutation', 'rs80357914', (187, 192))	('BRCA1', 'Gene', '672', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('ovarian cancer', 'Phenotype', 'HP:0100615', (345, 359))	('BRCA1', 'Gene', (180, 185))	('L122fs', 'Mutation', 'p.L122fsX', (234, 240))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (334, 359))	('loss-of-function', 'NegReg', (150, 166))	('BRCA2', 'Gene', (227, 232))
49832	30664638	The BRCA1 E23fs (p.Glu23Valfs) mutation, also known as 185delAG, is a founder mutation in Ashkenazi Jews.	('BRCA1', 'Gene', (4, 9))	('p.Glu23Val', 'Var', (17, 27))	('p.Glu23Val', 'SUBSTITUTION', 'None', (17, 27))	('E23fs', 'Mutation', 'rs80357914', (10, 15))	('BRCA1', 'Gene', '672', (4, 9))	('185delAG', 'Mutation', 'c.185delAG', (55, 63))
49836	30664638	MUTYH variants have not been linked to melanoma previously and although MUTYH is generally considered a recessive tumor suppressor gene it is known that individuals heterozygous for disruptive MUTYH alleles are at greater risk of developing a range of cancers.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('variants', 'Var', (6, 14))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancers', 'Disease', (252, 259))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('melanoma', 'Disease', (39, 47))	('tumor', 'Disease', (114, 119))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('MUTYH', 'Var', (193, 198))
49837	30664638	Finally, we noted a patient with a pathogenic CHEK2 mutation (p.S471F; also known as p.S428F; ClinVar ID: 5603) which has been linked to a range of cancers and is also thought to be an Ashkenazi founder allele.	('p.S471F;', 'Var', (62, 70))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('pathogenic', 'Reg', (35, 45))	('p.S471F', 'Mutation', 'rs137853011', (62, 69))	('cancers', 'Disease', (148, 155))	('CHEK2', 'Gene', '11200', (46, 51))	('p.S428F', 'Mutation', 'rs137853011', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('p.S428F', 'Var', (85, 92))	('CHEK2', 'Gene', (46, 51))	('patient', 'Species', '9606', (20, 27))	('linked to', 'Reg', (127, 136))
49838	30664638	Thus, we have observed an intriguing concentration of pathogenic germline alleles in this cohort with disruptive mutations found in TP53, POT1, BRCA1, BRCA2, MUTYH and CHEK2.	('POT1', 'Gene', (138, 142))	('CHEK2', 'Gene', '11200', (168, 173))	('BRCA1', 'Gene', (144, 149))	('CHEK2', 'Gene', (168, 173))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('pathogenic', 'Reg', (54, 64))	('mutations', 'Var', (113, 122))	('POT1', 'Gene', '25913', (138, 142))	('BRCA2', 'Gene', (151, 156))	('BRCA1', 'Gene', '672', (144, 149))
49839	30664638	None of the canine or equine cases in our study carried potentially pathogenic (SIFT score <= 0.05) germline mutations in the abovementioned genes, with the exception of 2 equine cases with MUTYH L241V mutations (SIFT score = 0.01), that developed melanoma on the prepuce (HD0024a) and ventral neck (HD0026a).	('melanoma', 'Disease', (248, 256))	('equine', 'Species', '9796', (22, 28))	('SIFT', 'Disease', (80, 84))	('canine', 'Species', '9615', (12, 18))	('L241V', 'Mutation', 'p.L241V', (196, 201))	('men', 'Species', '9606', (131, 134))	('neck', 'cellular_component', 'GO:0044326', ('294', '298'))	('SIFT', 'Disease', 'None', (213, 217))	('equine', 'Species', '9796', (172, 178))	('developed', 'PosReg', (238, 247))	('mutations', 'Var', (109, 118))	('SIFT', 'Disease', 'None', (80, 84))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('SIFT', 'Disease', (213, 217))
49840	30664638	We have also reported the presence of the gray phenotype, caused by a germline intronic duplication in STX17 that activates the MAPK pathway, and the 11 bp ASIP exon 2 deletion (Fig.	('MAPK', 'molecular_function', 'GO:0004707', ('128', '132'))	('MAPK pathway', 'Pathway', (128, 140))	('duplication', 'Var', (88, 99))	('activates', 'PosReg', (114, 123))	('ASIP', 'Gene', (156, 160))	('STX17', 'Gene', (103, 108))	('STX17', 'Gene', '100054797', (103, 108))	('ASIP', 'Gene', '100054335', (156, 160))	('caused by', 'Reg', (58, 67))
49842	30664638	These included activating mutations in the MAPK pathway (NRAS, BRAF, NF1, and KRAS) which could be targeted using drugs such as trametinib (Fig.	('NF1', 'Gene', '4763', (69, 72))	('KRAS', 'Gene', (78, 82))	('mutations', 'Var', (26, 35))	('activating', 'PosReg', (15, 25))	('MAPK pathway', 'Pathway', (43, 55))	('trametinib', 'Chemical', 'MESH:C560077', (128, 138))	('KRAS', 'Gene', '3845', (78, 82))	('NF1', 'Gene', (69, 72))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))
49843	30664638	In all species, we also observed mutations in the PI3K pathway including loss-of-function mutations in PTEN, potentially targetable using PI3K inhibitors.	('PTEN', 'Gene', (103, 107))	('PTEN', 'Gene', '5728', (103, 107))	('mutations', 'Var', (90, 99))	('loss-of-function', 'NegReg', (73, 89))	('mutations', 'Var', (33, 42))	('PI3K pathway', 'Pathway', (50, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('PI3K', 'molecular_function', 'GO:0016303', ('138', '142'))
49844	30664638	In human and canine samples, and two equine samples from mucosal-like sites with a UV mutation signature, we found somatic mutations in BRCA2, which might suggest that these tumors would respond to PARP inhibitors.	('equine', 'Species', '9796', (37, 43))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('human', 'Species', '9606', (3, 8))	('canine', 'Species', '9615', (13, 19))	('BRCA2', 'Gene', (136, 141))	('mutation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PARP', 'Gene', '1302', (198, 202))	('respond', 'Reg', (187, 194))	('PARP', 'Gene', (198, 202))	('mutations', 'Var', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
49846	30664638	Importantly, in human and canine mucosal cases we also found recurrent amplifications of SMO, which can be inhibited using several compounds, including Glasdegib, which has recently been approved by the  United States Food and Drug Administration.	('amplifications', 'Var', (71, 85))	('SMO', 'Gene', (89, 92))	('human', 'Species', '9606', (16, 21))	('canine', 'Species', '9615', (26, 32))
49847	30664638	Finally, we note the presence of somatic mutations in other genes for which small molecular inhibitors have been developed, such as ROS1.	('ROS1', 'Gene', (132, 136))	('ROS1', 'Gene', '6098', (132, 136))	('mutations', 'Var', (41, 50))
49850	30664638	We identified similarities and differences in the mutation profiles, both in terms of the mutated driver genes but also in terms of mutation number, which are likely to influence tumor behavior and response to treatments.	('influence', 'Reg', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('men', 'Species', '9606', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutation', 'Var', (50, 58))	('tumor', 'Disease', (179, 184))
49851	30664638	Further, we reveal divergent DNA copy number profiles, with human and canine mucosal melanomas showing substantial copy number gains and losses, while equine cases appeared to have comparatively fewer copy number changes.	('copy number', 'Var', (115, 126))	('mucosal melanomas', 'Disease', (77, 94))	('canine', 'Species', '9615', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (77, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('equine', 'Species', '9796', (151, 157))	('losses', 'NegReg', (137, 143))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('gains', 'PosReg', (127, 132))	('human', 'Species', '9606', (60, 65))
49853	30664638	Our cross-species analysis of human and canine melanomas is particularly important since canine patients are used as spontaneous models of human mucosal melanoma, and while we found many similarities, such as mutations in NRAS, TP53, and NF1, the genomes of canine melanomas lacked mutations in other key human mucosal melanoma drivers, such as SF3B1 and ATRX.	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('ATRX', 'Gene', (355, 359))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (319, 327))	('TP53', 'Gene', (228, 232))	('canine', 'Species', '9615', (258, 264))	('mucosal melanoma', 'Disease', 'MESH:D008545', (145, 161))	('ATRX', 'Gene', '546', (355, 359))	('melanomas', 'Disease', 'MESH:D008545', (265, 274))	('mucosal melanoma', 'Disease', 'MESH:D008545', (311, 327))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('canine', 'Species', '9615', (89, 95))	('melanomas', 'Disease', (265, 274))	('mucosal melanoma', 'Disease', (145, 161))	('NRAS', 'Gene', (222, 226))	('canine', 'Species', '9615', (40, 46))	('melanomas', 'Disease', 'MESH:D008545', (47, 56))	('TP53', 'Gene', '7157', (228, 232))	('patients', 'Species', '9606', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('mucosal melanoma driver', 'Disease', (311, 334))	('mutations', 'Var', (282, 291))	('melanomas', 'Disease', (47, 56))	('human', 'Species', '9606', (30, 35))	('melanomas', 'Phenotype', 'HP:0002861', (265, 274))	('NF1', 'Gene', '4763', (238, 241))	('mucosal melanoma driver', 'Disease', 'MESH:D008545', (311, 334))	('human', 'Species', '9606', (139, 144))	('mutations', 'Var', (209, 218))	('SF3B1', 'Gene', (345, 350))	('human', 'Species', '9606', (305, 310))	('NF1', 'Gene', (238, 241))
49877	30664638	The list of SNVs from MuTect were input into MAC (v1.2) to identify multi-nucleotide variants, such as UV-induced CC > TT substitutions.	('v1.2', 'Gene', '28817', (50, 54))	('MAC', 'cellular_component', 'GO:0005579', ('45', '48'))	('v1.2', 'Gene', (50, 54))	('UV-induced', 'Gene', (103, 113))	('MAC', 'cellular_component', 'GO:0097423', ('45', '48'))	('substitutions', 'Var', (122, 135))
49885	30664638	In human, dog, and horse samples, variants found in MECOM, KDM3B, and BAP1, respectively, were removed as they appeared to be artefactual calls due to alignment of contaminating cDNA reads.	('variants', 'Var', (34, 42))	('MECOM', 'Gene', '100057450', (52, 57))	('human', 'Species', '9606', (3, 8))	('men', 'Species', '9606', (156, 159))	('KDM3B', 'Gene', (59, 64))	('BAP1', 'Gene', (70, 74))	('horse', 'Species', '9796', (19, 24))	('dog', 'Species', '9615', (10, 13))	('MECOM', 'Gene', (52, 57))	('KDM3B', 'Gene', '100062288', (59, 64))
49887	30664638	Variants taken forward for principal component analysis (PCA) included high quality variants in the melanoma cohort (as described above) that were also found in 1KGP at a minor SNP allele frequency >= 0.05, that were not in linkage disequilibrium with another SNP (pairwise R2 < 0.02), and that did not have a missing rate >0.05.	('Variants', 'Var', (0, 8))	('melanoma cohort', 'Disease', (100, 115))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma cohort', 'Disease', 'MESH:D008545', (100, 115))	('variants', 'Var', (84, 92))
49916	30664638	In each species, we first identified whole chromosomes (canine and equine) and chromosome arms (human) with recurrent SCNAs by calculating the median frequency of copy number gains across chromosomes/arms using 1 Mb windows.	('copy', 'Var', (163, 167))	('canine', 'Species', '9615', (56, 62))	('recurrent SCNAs', 'Phenotype', 'HP:0100776', (108, 123))	('equine', 'Species', '9796', (67, 73))	('human', 'Species', '9606', (96, 101))	('SCNAs', 'Disease', (118, 123))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))
49930	30664638	The raw sequencing data are available for download from the European Genome-phenome Archive under study accession EGAS00001001115 (human), and from the European Nucleotide Archive under study accessions ERP013521 (canine) and ERP012934 (equine).	('ERP012934', 'Var', (226, 235))	('canine', 'Species', '9615', (214, 220))	('human', 'Species', '9606', (131, 136))	('equine', 'Species', '9796', (237, 243))	('ERP013521', 'Var', (203, 212))
49992	21559997	Female sex (HR 0.79, CI 0.73-0.86; P < 0.001) and Breslow depth <=1 mm (HR 0.84, CI 0.73-0.96; P = 0.01) both predicted a decreased risk of death from any cause.	('death', 'Disease', 'MESH:D003643', (140, 145))	('<=1', 'Var', (64, 67))	('death', 'Disease', (140, 145))	('Breslow depth', 'CPA', (50, 63))	('decreased', 'NegReg', (122, 131))
49996	21559997	A decreased risk of death from melanoma was noted for female sex (HR 0.80, CI 0.73-0.88; P < 0.001), Breslow depth <=1 mm (HR 0.83, CI 0.71-0.97; P = 0.023), no primary surgery (HR 0.86, CI 0.75-0.99; P = 0.035), unknown type of primary surgery (HR 0.68, CI 0.49-0.96; P = 0.028), and treatment during era II (HR 0.81, CI 0.70-0.93; P = 0.003).	('death', 'Disease', 'MESH:D003643', (20, 25))	('death', 'Disease', (20, 25))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('decreased', 'NegReg', (2, 11))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('Breslow depth', 'CPA', (101, 114))	('<=1', 'Var', (115, 118))
50012	21559997	However, when comparing the population at risk, namely those patients who ultimately developed nodal metastases in the wide excision group and those patients with sentinel node metastases in the comparison group, there was a clear benefit to LM/SNB in terms of MSS.	('nodal metastases', 'Disease', 'MESH:D009362', (95, 111))	('MSS', 'Gene', '64374', (261, 264))	('patients', 'Species', '9606', (149, 157))	('MSS', 'Gene', (261, 264))	('sentinel node metastases', 'Disease', 'MESH:D009362', (163, 187))	('LM', 'Chemical', 'MESH:C062625', (242, 244))	('patients', 'Species', '9606', (61, 69))	('nodal metastases', 'Disease', (95, 111))	('LM/SNB', 'Var', (242, 248))	('benefit', 'PosReg', (231, 238))	('sentinel node metastases', 'Disease', (163, 187))
50013	21559997	While we do not have data regarding the indications for lymphadenectomies in era 1 and era 2 patients, we have shown that those patients more likely to receive LM/SNB (i.e., those diagnosed and treated after 1999) demonstrated a survival advantage.	('LM', 'Chemical', 'MESH:C062625', (160, 162))	('LM/SNB', 'Var', (160, 166))	('survival advantage', 'CPA', (229, 247))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (93, 101))
50046	29990794	In addition, experimental studies have shown that folic acid - a synthetic form of folate that is found in fortified foods and supplements and that constitutes a large portion of total folate intake - results in nuclear DNA damage in the presence of ultraviolet A radiation in keratinocyte and melanoma cell lines of the skin.	('folic acid', 'Chemical', 'MESH:D005492', (50, 60))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('results in', 'Reg', (201, 211))	('folic acid', 'Var', (50, 60))	('folate', 'Chemical', 'MESH:D005492', (185, 191))	('folate', 'Chemical', 'MESH:D005492', (83, 89))	('melanoma', 'Disease', 'MESH:D008545', (294, 302))	('melanoma', 'Disease', (294, 302))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('men', 'Species', '9606', (133, 136))	('men', 'Species', '9606', (19, 22))	('nuclear DNA damage', 'MPA', (212, 230))
50055	29990794	Higher intake of several of these nutrients including vitamins B6 and B12, betaine, and methionine has been associated with a modest decreased risk of several cancers including those of the lung, breast, pancreas, kidney, and gastrointestinal tract.	('cancers', 'Disease', (159, 166))	('breast', 'Disease', (196, 202))	('pancreas', 'Disease', (204, 212))	('B12', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('methionine', 'Var', (88, 98))	('gastrointestinal tract', 'Disease', (226, 248))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (226, 248))	('betaine', 'Chemical', 'MESH:D001622', (75, 82))	('kidney', 'Disease', (214, 220))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('methionine', 'Chemical', 'MESH:D008715', (88, 98))	('decreased', 'NegReg', (133, 142))	('B12', 'Gene', '4709', (70, 73))
50241	30301603	In primary tumors, miR-200c suppresses invasion by inhibiting epithelial-to-mesenchymal transition (EMT) via Zeb1/Zeb2-E-cadherin axis.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Zeb2', 'Gene', (114, 118))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('62', '98'))	('Zeb2', 'Gene', '9839', (114, 118))	('primary tumors', 'Disease', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('invasion', 'CPA', (39, 47))	('E-cadherin', 'Gene', (119, 129))	('cadherin', 'molecular_function', 'GO:0008014', ('121', '129'))	('miR-200c', 'Var', (19, 27))	('primary tumors', 'Disease', 'MESH:D009369', (3, 17))	('suppresses', 'NegReg', (28, 38))	('inhibiting', 'NegReg', (51, 61))	('EMT', 'biological_process', 'GO:0001837', ('100', '103'))	('E-cadherin', 'Gene', '999', (119, 129))	('Zeb1', 'Gene', (109, 113))	('Zeb1', 'Gene', '6935', (109, 113))	('epithelial-to-mesenchymal transition', 'CPA', (62, 98))
50242	30301603	In contrast, miR-200c promotes tumor metastasis at the step of colonization at the distant site.	('promotes', 'PosReg', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor metastasis', 'Disease', 'MESH:D009362', (31, 47))	('tumor metastasis', 'Disease', (31, 47))	('miR-200c', 'Var', (13, 21))
50272	30301603	Mice received POL cells developed much more GFP-labeled macroscopic metastatic foci in the lungs than that of the OL cells, as evident by whole lung fluorescent imaging (Fig.	('macroscopic metastatic foci in the', 'CPA', (56, 90))	('POL', 'Var', (14, 17))	('GFP-labeled', 'MPA', (44, 55))	('Mice', 'Species', '10090', (0, 4))
50328	25628199	An association between deficient levels of vitamin D3 and various types of malignant neoplasms such as colon, breast, and skin cancer, has already been shown.	('colon', 'Disease', 'MESH:D015179', (103, 108))	('malignant neoplasms', 'Disease', 'MESH:D009369', (75, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deficient levels', 'Var', (23, 39))	('malignant neoplasms', 'Disease', (75, 94))	('skin cancer', 'Phenotype', 'HP:0008069', (122, 133))	('skin cancer', 'Disease', (122, 133))	('breast', 'Disease', (110, 116))	('neoplasms', 'Phenotype', 'HP:0002664', (85, 94))	('colon', 'Disease', (103, 108))
50336	25628199	Some sudies reported that polymorphisms of VDR genes are associated to the occurrence of various types of cancer, including melanoma, and that the presence of this polymorphism such as Fokl, Taql, and apa1, could be a biological marker of susceptibility to skin cancer.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('polymorphisms', 'Var', (26, 39))	('skin cancer', 'Phenotype', 'HP:0008069', (257, 268))	('apa1', 'Gene', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('apa1', 'Gene', '57862', (201, 205))	('skin cancer', 'Disease', (257, 268))	('VDR genes', 'Gene', (43, 52))	('types of cancer', 'Disease', (97, 112))	('presence', 'Var', (147, 155))	('associated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
50395	32481257	Cox proportional hazards regression model was used to evaluate risks of log (GR) on DFS and DSS after adjustment for covariates.	('DSS', 'Disease', (92, 95))	('DFS', 'Disease', (84, 87))	('DFS', 'Disease', 'None', (84, 87))	('GR', 'Chemical', '-', (77, 79))	('log', 'Var', (72, 75))	('DSS', 'Chemical', '-', (92, 95))
50420	32481257	Notably, log (GR) was an independent prognostic factor for DFS (HR: 2.909; 95% CI: 1.464-5.778; P = .002) and DSS (HR: 9.027; 95% CI: 1.995-40.834; P = .004) in the early-stage group (stage<=2A).	('GR', 'Chemical', '-', (14, 16))	('DSS', 'Chemical', '-', (110, 113))	('DFS', 'Disease', (59, 62))	('DSS', 'Disease', (110, 113))	('log', 'Var', (9, 12))	('DFS', 'Disease', 'None', (59, 62))
50465	27703647	Of these, irregular border has been shown to be the strongest predictor of malignancy.	('malignancy', 'Disease', (75, 85))	('irregular border', 'Var', (10, 26))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))
50567	31126321	Firstly, the T cell panel contains the following antibodies: pan-cytokeratin (AE1/AE3, Thermofisher scientific and C11, Cell Signalling Technology), anti-CD3 (D7A6E), and anti-CD8 (4B11, DAKO).	('CD8', 'Gene', '925', (176, 179))	('AE1', 'Gene', (78, 81))	('Signalling', 'biological_process', 'GO:0023052', ('125', '135'))	('C11', 'Gene', (115, 118))	('AE1', 'Gene', '6521', (78, 81))	('AE3', 'Gene', '6508', (82, 85))	('anti-CD3', 'Var', (149, 157))	('pan-cytokeratin', 'Protein', (61, 76))	('CD8', 'Gene', (176, 179))	('C11', 'Gene', '51728', (115, 118))	('AE3', 'Gene', (82, 85))
50568	31126321	Secondly, the myeloid panel contains the following antibodies: pan-cytokeratin (AE1/AE3, Novusbio and C11, Biolegend), anti-HLA-DR (TAL1B5, Thermo Fisher Scientific), anti-CD68 (D4B9C, Cell Signalling Technology), and anti-CD163 (10D6, Thermo Fisher Scientific).	('CD68', 'Gene', (172, 176))	('pan-cytokeratin', 'Protein', (63, 78))	('anti-HLA-DR', 'Var', (119, 130))	('AE3', 'Gene', '6508', (84, 87))	('CD163', 'Gene', '9332', (223, 228))	('CD68', 'Gene', '968', (172, 176))	('C11', 'Gene', '51728', (102, 105))	('C11', 'Gene', (102, 105))	('CD163', 'Gene', (223, 228))	('AE3', 'Gene', (84, 87))	('AE1', 'Gene', '6521', (80, 83))	('AE1', 'Gene', (80, 83))	('Signalling', 'biological_process', 'GO:0023052', ('190', '200'))
50569	31126321	Immunofluorescent detection was performed directly and indirectly with Alexa488, Alexa594, Alexa647, Alexa680, CF555, and CF633 using an in-house methodology.	('Alexa488', 'Var', (71, 79))	('Alexa594', 'Chemical', 'MESH:C417664', (81, 89))	('CF555', 'Chemical', '-', (111, 116))	('CF555', 'Var', (111, 116))	('CF633', 'Chemical', '-', (122, 127))	('CF633', 'Var', (122, 127))	('Alexa647', 'Var', (91, 99))	('Alexa680', 'Chemical', '-', (101, 109))	('Alexa488', 'Chemical', '-', (71, 79))	('Alexa647', 'Chemical', 'MESH:C569686', (91, 99))	('Alexa680', 'Var', (101, 109))
50571	31126321	Following heat-mediated antigen retrieval in 10 mmol/L citrate buffer solution (pH 6), overnight labeling was performed with anti-CD4 (EPR68551, Abcam), anti-FOXP3 (236A/E7), and CD20 (L26, Dako) respectively.	('FOXP3', 'Gene', (158, 163))	('CD20', 'Gene', '54474', (179, 183))	('CD4', 'Gene', '920', (130, 133))	('CD20', 'Gene', (179, 183))	('citrate', 'Chemical', 'MESH:D019343', (55, 62))	('FOXP3', 'Gene', '50943', (158, 163))	('236A/E7', 'Var', (165, 172))	('CD4', 'Gene', (130, 133))
50653	31126321	Similarly, the immune profiles of human cancers can be grouped into three major phenotypes, which are associated with response to PD1/PDL1 blockade: immune-inflamed, immune excluded, and immune desert.	('PDL1', 'Gene', '29126', (134, 138))	('human', 'Species', '9606', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('blockade', 'Var', (139, 147))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('PDL1', 'Gene', (134, 138))	('cancers', 'Disease', (40, 47))	('PD1', 'Gene', '5133', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PD1', 'Gene', (130, 133))
50659	31126321	3c with high CD8B expression), opposed to the immune-desert phenotype (left cluster in Fig.	('high', 'Var', (8, 12))	('expression', 'MPA', (18, 28))	('CD8B', 'Gene', '926', (13, 17))	('CD8B', 'Gene', (13, 17))
50677	31126321	We analyzed recently published RNA-seq data set from pre- and on-treatment tumor biopsies from seven melanoma patients treated with a BRAF inhibitors, MEK inhibitors, or a combination thereof.	('inhibitors', 'Var', (139, 149))	('MEK', 'Gene', (151, 154))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('patients', 'Species', '9606', (110, 118))	('BRAF', 'Gene', '673', (134, 138))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('MEK', 'Gene', '5609', (151, 154))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BRAF', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('pre', 'molecular_function', 'GO:0003904', ('53', '56'))	('tumor', 'Disease', (75, 80))
50694	31126321	For instance, epigenetic reprogramming of genes expressing T helper (TH)-1 chemokines like CXCL9 and CXCL11 might increase CD8+ T cell infiltration into the tumor bed.	('tumor', 'Disease', (157, 162))	('CD8', 'Gene', (123, 126))	('increase', 'PosReg', (114, 122))	('T helper (TH)-1', 'Gene', '51497', (59, 74))	('CXCL11', 'Gene', (101, 107))	('CXCL11', 'Gene', '6373', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CD8', 'Gene', '925', (123, 126))	('CXCL9', 'Gene', '4283', (91, 96))	('T helper (TH)-1', 'Gene', (59, 74))	('epigenetic reprogramming', 'Var', (14, 38))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CXCL9', 'Gene', (91, 96))
50730	26907172	Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells The metabolism of cancer cells is often reprogrammed by dysregulation of metabolic enzymes.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('metabolism', 'biological_process', 'GO:0008152', ('132', '142'))	('Transketolase-like 1', 'Gene', (0, 20))	('Transketolase-like 1', 'Gene', '8277', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('59', '78'))	('induces', 'Reg', (83, 90))	('melanoma', 'Disease', (113, 121))	('Warburg effect', 'MPA', (95, 109))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('associated', 'Reg', (43, 53))	('ectopic expression', 'Var', (21, 39))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
50733	26907172	In melanoma, defective promoter methylation results in the expression of genes and their products that can affect the tumor cell's phenotype including the modification of immune and functional characteristics.	('affect', 'Reg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('expression of', 'MPA', (59, 72))	('defective', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('results in', 'Reg', (44, 54))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('tumor', 'Disease', (118, 123))	('modification', 'Reg', (155, 167))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
50743	26907172	Our data provide evidence for an important role of TKTL1 in aerobic glycolysis and tumor promotion in melanoma that may result from defective promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('promoter methylation', 'MPA', (142, 162))	('TKTL1', 'Gene', (51, 56))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('aerobic glycolysis', 'MPA', (60, 78))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('defective', 'Var', (132, 141))	('glycolysis', 'biological_process', 'GO:0006096', ('68', '78'))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
50763	26907172	Although TKTL1 expression in conjunctival melanoma tumors has been reported, the mechanism by which expression becomes unregulated and the functional consequences of aberrant TKTL1 expression in melanoma remains unclear and these warrant further investigation.	('melanoma', 'Disease', (42, 50))	('conjunctival melanoma tumors', 'Disease', 'MESH:D003230', (29, 57))	('TKTL1', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('conjunctival melanoma tumors', 'Disease', (29, 57))	('expression', 'MPA', (100, 110))	('TKTL1', 'Gene', (9, 14))	('aberrant', 'Var', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('conjunctival melanoma tumors', 'Phenotype', 'HP:0007716', (29, 57))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
50764	26907172	Methylation defects are commonly observed in melanoma and this can result in the expression of gene products that are otherwise silenced at a transcriptional level in somatic tissues.	('observed', 'Reg', (33, 41))	('result in', 'Reg', (67, 76))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('expression of gene products', 'MPA', (81, 108))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('Methylation defects', 'Var', (0, 19))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
50768	26907172	Given that TKTL1 is also an X chromosome coded molecule (Xq28) that, like the CTAg, is generally repressed in somatic tissues, we sought to determine if DNA hypomethylation also induced aberrant expression of TKTL1 in melanoma and to assess its role in promoting the Warburg effect in melanoma cells.	('DNA', 'cellular_component', 'GO:0005574', ('153', '156'))	('TKTL1', 'Gene', (209, 214))	('expression', 'MPA', (195, 205))	('hypomethylation', 'Var', (157, 172))	('CTAg', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('induced', 'Reg', (178, 185))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('aberrant', 'Var', (186, 194))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('153', '172'))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('X chromosome', 'cellular_component', 'GO:0000805', ('28', '40'))	('CTAg', 'Gene', '1485', (78, 82))	('Warburg effect', 'Disease', (267, 281))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))
50769	26907172	We detected increased expression of TKTL1 in a subset of metastatic melanoma tumors and cell lines and found TKTL1 expression in melanoma tumors was associated with promoter hypomethylation.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma tumors', 'Disease', 'MESH:D008545', (68, 83))	('promoter hypomethylation', 'Var', (165, 189))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('increased', 'PosReg', (12, 21))	('associated', 'Reg', (149, 159))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (115, 125))	('melanoma tumors', 'Disease', (129, 144))	('melanoma tumors', 'Disease', (68, 83))	('expression', 'MPA', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('melanoma tumors', 'Disease', 'MESH:D008545', (129, 144))	('TKTL1', 'Gene', (36, 41))	('TKTL1', 'Gene', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
50772	26907172	Taken together, our data suggests that a subset of melanomas with defective methylation rely on TKTL1-dependent aerobic glycolysis and have enhanced tumorigenesis.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('enhanced', 'PosReg', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('TKTL1-dependent aerobic glycolysis', 'MPA', (96, 130))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glycolysis', 'biological_process', 'GO:0006096', ('120', '130'))	('methylation', 'Var', (76, 87))	('melanomas', 'Disease', (51, 60))	('defective methylation', 'Var', (66, 87))	('tumor', 'Disease', (149, 154))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('rely', 'Reg', (88, 92))
50783	26907172	We found that tumors expressing high TKTL1 levels were statistically significantly associated with the high-risk group (log-rank p value 0.0277), risk being reduced survival and risk of relapse.	('high', 'Var', (32, 36))	('survival', 'CPA', (165, 173))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('associated', 'Reg', (83, 93))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('TKTL1', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('reduced', 'NegReg', (157, 164))
50788	26907172	Expression of TKTL1 has been reported to be controlled by methylation and demethylation of TKTL1 has been previously reported in lung and head and neck cancers.	('demethylation', 'Var', (74, 87))	('TKTL1', 'Gene', (14, 19))	('reported', 'Reg', (117, 125))	('neck cancers', 'Disease', 'MESH:D006258', (147, 159))	('head and neck cancer', 'Phenotype', 'HP:0012288', (138, 158))	('neck', 'cellular_component', 'GO:0044326', ('147', '151'))	('methylation', 'Var', (58, 69))	('head and neck cancers', 'Phenotype', 'HP:0012288', (138, 159))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('demethylation', 'biological_process', 'GO:0070988', ('74', '87'))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung', 'Disease', (129, 133))	('TKTL1', 'Gene', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('neck cancers', 'Disease', (147, 159))
50794	26907172	We extended our studies to a publically available clinical melanoma patient dataset to determine whether deregulation of TKTL1 expression was linked to DNA hypomethylation.	('patient', 'Species', '9606', (68, 75))	('expression', 'MPA', (127, 137))	('linked', 'Reg', (142, 148))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('152', '171'))	('TKTL1', 'Gene', (121, 126))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('deregulation', 'Var', (105, 117))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
50795	26907172	We used an in silico approach to assess the methylation status of the promoter region on the TKTL1 gene in 385 metastatic melanoma tissues from the Skin Cutaneous Melanoma (SKCM) dataset of The Cancer Genome Atlas (TCGA) database (www.cbioportal.org) and estimated its association with TKTL1 mRNA expression.	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('methylation', 'Var', (44, 55))	('Cancer Genome Atlas', 'Disease', (194, 213))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (194, 213))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (148, 171))	('TKTL1', 'Gene', (93, 98))	('Melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('mRNA expression', 'MPA', (292, 307))	('association', 'Interaction', (269, 280))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('Skin Cutaneous Melanoma', 'Disease', (148, 171))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (153, 171))
50799	26907172	We found that methylation status at both the CpG sites was statistically inversely correlated with TKTL1 gene expression in melanoma samples (Table 1 and Additional file 2: Figure S2A&B).	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('correlated', 'Reg', (83, 93))	('TKTL1 gene', 'Gene', (99, 109))	('melanoma', 'Disease', (124, 132))	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('methylation', 'Var', (14, 25))	('expression', 'MPA', (110, 120))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('inversely', 'NegReg', (73, 82))
50801	26907172	These results confirm that DNA hypomethylation is associated with aberrant activation of TKTL1 expression in metastatic melanoma.	('TKTL1', 'Gene', (89, 94))	('hypomethylation', 'Var', (31, 46))	('activation', 'PosReg', (75, 85))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('27', '46'))	('DNA hypomethylation', 'Var', (27, 46))	('expression', 'MPA', (95, 105))
50802	26907172	The epigenetic reactivation of TKTL1 occurs simultaneously with DNA hypomethylation of CTAgs in head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (96, 116))	('epigenetic reactivation', 'Var', (4, 27))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('64', '83'))	('TKTL1', 'Gene', (31, 36))	('CTAg', 'Gene', '1485', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('neck cancer', 'Disease', 'MESH:D006258', (105, 116))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('neck cancer', 'Disease', (105, 116))	('neck', 'cellular_component', 'GO:0044326', ('105', '109'))	('CTAg', 'Gene', (87, 91))
50809	26907172	Upon knockdown with TKTL1 siRNA, TKT levels were affected by one of the siRNAs but only modestly by the other (Additional file 3: Figure S3).	('TKT', 'Gene', (20, 23))	('knockdown', 'Var', (5, 14))	('affected', 'Reg', (49, 57))	('TKT', 'Gene', '7086', (33, 36))	('TKT', 'Gene', (33, 36))	('TKT', 'Gene', '7086', (20, 23))
50814	26907172	Measurements were made on conditioned medium of LM-MEL-59 cells after treatment with TKTL1 or control siRNA for 72 h. Depletion of TKTL1 in these cells caused a substantial decrease in glucose consumption and associated reduction in lactate production (Fig.	('decrease', 'NegReg', (173, 181))	('Depletion', 'Var', (118, 127))	('glucose consumption', 'Disease', 'MESH:D014397', (185, 204))	('glucose consumption', 'Disease', (185, 204))	('TKTL1', 'Gene', (131, 136))	('reduction', 'NegReg', (220, 229))	('lactate', 'Chemical', 'MESH:D019344', (233, 240))	('LM-MEL-59', 'CellLine', 'CVCL:5998', (48, 57))	('lactate production', 'MPA', (233, 251))
50815	26907172	3e & f) while ectopic expression of TKTL1 in LM-MEL-44 conferred a more glycolytic phenotype (Fig.	('LM-MEL-44', 'Reg', (45, 54))	('more glycolytic', 'MPA', (67, 82))	('while ectopic', 'Var', (8, 21))	('LM-MEL-44', 'CellLine', 'CVCL:6040', (45, 54))
50819	26907172	TKTL1 knockdown in LM-MEL-59 led to an increase in the percentage of G0-G1 phase cells and a decrease in the percentage of S phase cell population compared to control transfected cells (Fig.	('TKTL1', 'Gene', (0, 5))	('LM-MEL-59', 'CellLine', 'CVCL:5998', (19, 28))	('S phase', 'biological_process', 'GO:0051320', ('123', '130'))	('G1 phase', 'biological_process', 'GO:0051318', ('72', '80'))	('G0-G1 phase cells', 'CPA', (69, 86))	('increase', 'PosReg', (39, 47))	('decrease', 'NegReg', (93, 101))	('knockdown', 'Var', (6, 15))
50822	26907172	Similarly, MTS assay demonstrated slightly enhanced proliferation in TKTL1 overexpressing cells compared to empty vector treated cells, although no significance was achieved (Additional file 5: Figure S5B).	('enhanced', 'PosReg', (43, 51))	('proliferation', 'CPA', (52, 65))	('overexpressing', 'Var', (75, 89))	('TKTL1', 'Gene', (69, 74))	('rat', 'Species', '10116', (28, 31))	('S5B', 'Gene', '5711', (201, 204))	('rat', 'Species', '10116', (59, 62))	('S5B', 'Gene', (201, 204))
50826	26907172	In tumors expressing high TKTL1, oxythiamine has been used to block proliferation effectively both in vitro and in vivo.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('proliferation', 'CPA', (68, 81))	('tumors', 'Disease', (3, 9))	('block', 'NegReg', (62, 67))	('rat', 'Species', '10116', (75, 78))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('high', 'Var', (21, 25))	('oxythiamine', 'Chemical', 'MESH:D010119', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('TKTL1', 'Gene', (26, 31))
50836	26907172	We found a significant association of hypomethylation with TKTL1 gene expression in melanoma patient samples.	('hypomethylation', 'Var', (38, 53))	('TKTL1', 'Gene', (59, 64))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('expression', 'MPA', (70, 80))	('patient', 'Species', '9606', (93, 100))
50838	26907172	Abnormal DNA methylation dysregulates gene expression in cancer and this has been associated with changes in phenotype and function.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('methylation', 'Var', (13, 24))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('gene expression', 'MPA', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('dysregulates', 'Reg', (25, 37))	('gene expression', 'biological_process', 'GO:0010467', ('38', '53'))	('Abnormal DNA', 'Var', (0, 12))
50840	26907172	Simultaneous reactivation of TKTL1 with CTAg such as the melanoma antigen family (MAGE-A) has been reported in lung and head and neck cancers.	('CTAg', 'Gene', (40, 44))	('reported', 'Reg', (99, 107))	('neck cancers', 'Disease', 'MESH:D006258', (129, 141))	('head and neck cancer', 'Phenotype', 'HP:0012288', (120, 140))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('neck', 'cellular_component', 'GO:0044326', ('129', '133'))	('head and neck cancers', 'Phenotype', 'HP:0012288', (120, 141))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('lung', 'Disease', (111, 115))	('melanoma', 'Disease', (57, 65))	('CTAg', 'Gene', '1485', (40, 44))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('reactivation', 'Var', (13, 25))	('TKTL1', 'Gene', (29, 34))	('neck cancers', 'Disease', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
50845	26907172	We speculate that in melanoma aberrant demethylation occurs as a common underlying mechanism that links transcriptional activation of TKTL1 and CTAgs that may cooperate to promote cancer progression by mechanisms such as Warburg effect, motility, proliferation and apoptosis.	('CTAg', 'Gene', '1485', (144, 148))	('proliferation', 'CPA', (247, 260))	('aberrant demethylation', 'Var', (30, 52))	('TKTL1', 'Gene', (134, 139))	('rat', 'Species', '10116', (254, 257))	('demethylation', 'Var', (39, 52))	('demethylation', 'biological_process', 'GO:0070988', ('39', '52'))	('activation', 'PosReg', (120, 130))	('CTAg', 'Gene', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('rat', 'Species', '10116', (164, 167))	('cancer', 'Disease', (180, 186))	('Warburg effect', 'Disease', (221, 235))	('motility', 'CPA', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('265', '274'))	('promote', 'PosReg', (172, 179))	('apoptosis', 'CPA', (265, 274))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('apoptosis', 'biological_process', 'GO:0006915', ('265', '274'))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
50846	26907172	Aberrant expression of CTAgs has previously been associated with poor outcomes in melanoma and other cancers.	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('CTAg', 'Gene', (23, 27))	('cancers', 'Disease', (101, 108))	('associated', 'Reg', (49, 59))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CTAg', 'Gene', '1485', (23, 27))
50847	26907172	This study may provide the clue, that increased antigen expression and TKTL1 expression are both a consequence of a phenotype that results from methylation changes, and it is this phenotype that associates pro-tumorigenic metabolic changes with bystander tumor antigen expression.	('expression', 'MPA', (77, 87))	('changes', 'Var', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('TKTL1', 'Gene', (71, 76))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('antigen expression', 'MPA', (48, 66))	('tumor', 'Disease', (210, 215))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('results from', 'Reg', (131, 143))	('methylation', 'MPA', (144, 155))	('tumor antigen', 'molecular_function', 'GO:0008222', ('255', '268'))	('increased', 'PosReg', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
50853	26907172	Activating mutations in the BRAF protein kinase are the most common genetic alterations in melanoma, found in around 40 % of tumors.	('BRAF', 'Gene', '673', (28, 32))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('Activating mutations', 'Var', (0, 20))	('rat', 'Species', '10116', (80, 83))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('BRAF', 'Gene', (28, 32))
50856	26907172	However, both cell lines used to investigate the role of TKTL1 in this study lack the activating mutations in BRAF, so BRAF mutations do not appear to be a prerequisite for TKTL1-driven aerobic glycolysis.	('mutations', 'Var', (97, 106))	('BRAF', 'Gene', '673', (119, 123))	('activating', 'MPA', (86, 96))	('BRAF', 'Gene', (119, 123))	('glycolysis', 'biological_process', 'GO:0006096', ('194', '204'))	('BRAF', 'Gene', '673', (110, 114))	('BRAF', 'Gene', (110, 114))
50861	26907172	In circumstances where glucose metabolism exceeds the capacity of a cell to assimilate or store glucose-derived carbon, cells with high levels of TKTL1 expression have a growth advantage when compared to those with low levels of TKTL1.	('glucose metabolism', 'Disease', (23, 41))	('growth advantage', 'CPA', (170, 186))	('TKTL1', 'Gene', (146, 151))	('glucose', 'Chemical', 'MESH:D005947', (23, 30))	('glucose metabolism', 'Disease', 'MESH:D044882', (23, 41))	('high levels', 'Var', (131, 142))	('glucose', 'Chemical', 'MESH:D005947', (96, 103))	('carbon', 'Chemical', 'MESH:D002244', (112, 118))	('glucose metabolism', 'biological_process', 'GO:0006006', ('23', '41'))
50863	26907172	Our finding that TKTL1 expression enhances proliferation is consistent with these findings.	('rat', 'Species', '10116', (50, 53))	('TKTL1', 'Gene', (17, 22))	('expression', 'Var', (23, 33))	('enhances', 'PosReg', (34, 42))	('proliferation', 'CPA', (43, 56))
50866	26907172	High levels of TKTL1 were also correlated with invasion and poor prognosis in urothelial, laryngeal squamous and colorectal cancer.	('colorectal cancer', 'Disease', (113, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('High levels', 'Var', (0, 11))	('urothelial', 'Disease', (78, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TKTL1', 'Gene', (15, 20))	('laryngeal squamous', 'Disease', (90, 108))	('correlated', 'Reg', (31, 41))
50872	26907172	Although our results suggest that TKTL1 could be a therapeutic target in melanoma, treatment with oxythiamine, a thiamine antagonist, was ineffective even though it was previously shown to decrease proliferation in tumors with high TKTL1 expression.	('melanoma', 'Disease', (73, 81))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('rat', 'Species', '10116', (205, 208))	('thiamine', 'Chemical', 'MESH:D013831', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('decrease', 'NegReg', (189, 197))	('proliferation', 'CPA', (198, 211))	('thiamine', 'Chemical', 'MESH:D013831', (113, 121))	('TKTL1', 'Gene', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('high', 'Var', (227, 231))	('tumors', 'Disease', (215, 221))	('oxythiamine', 'Chemical', 'MESH:D010119', (98, 109))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
50873	26907172	Similarly, earlier studies demonstrated that oxythiamine was not effective in most thyroid cancer cells expressing high TKTL1 and in vivo in normal rat tissues that expressed high TKTL1.	('high', 'Var', (115, 119))	('oxythiamine', 'Chemical', 'MESH:D010119', (45, 56))	('rat', 'Species', '10116', (148, 151))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rat', 'Species', '10116', (34, 37))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))	('TKTL1', 'Gene', (120, 125))
50877	26907172	Our data suggests that we cannot rule out the possibility that TKT acts in concert with TKTL1 as we observed that TKT is highly expressed in melanoma cell lines and knockdown of TKTL1 impacts TKT expression, if only modestly.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('TKT', 'Gene', '7086', (178, 181))	('impacts', 'Reg', (184, 191))	('TKT', 'Gene', '7086', (114, 117))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('TKT', 'Gene', (63, 66))	('TKT', 'Gene', (114, 117))	('expression', 'MPA', (196, 206))	('TKT', 'Gene', (192, 195))	('TKT', 'Gene', '7086', (88, 91))	('knockdown', 'Var', (165, 174))	('TKT', 'Gene', (88, 91))	('TKT', 'Gene', '7086', (192, 195))	('TKT', 'Gene', '7086', (63, 66))	('TKT', 'Gene', (178, 181))
50912	26907172	For transient siRNA transfection, cells at 30 % confluence were transfected using a control siRNA and two different Silencer select siRNAs targeting TKTL1 (s224894 and s15774) at 10nM final concentration (Ambion) with Lipofectamine RNAiMAX according to the manufacturer's protocol (Invitrogen).	('s15774', 'Var', (168, 174))	('rat', 'Species', '10116', (197, 200))	('Lipofectamine', 'Chemical', 'MESH:C086724', (218, 231))	('TKTL1', 'Gene', (149, 154))	('s224894', 'Var', (156, 163))
50952	21080806	An analysis of melanoma trends stratified by thickness, based on the Surveillance, Epidemiology and End Results (SEER) registry data from 1988 to 2006, showed that all four thickness categories (<=1, 1.01-2, 2.01-4 and >4 mm) increased in incidence over the 19-year study period.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma trends', 'Disease', 'MESH:D008545', (15, 30))	('melanoma trends', 'Disease', (15, 30))	('<=1', 'Var', (195, 198))	('increased', 'PosReg', (226, 235))
50966	21080806	In addition, burns from indoor tanning were fairly common among users and conferred a similar risk of malignant melanoma to that seen from sunburns.	('burns', 'Var', (13, 18))	('malignant melanoma', 'Disease', 'MESH:D008545', (102, 120))	('malignant melanoma', 'Disease', (102, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('malignant melanoma', 'Phenotype', 'HP:0002861', (102, 120))
50996	21080806	Further support for the divergent pathway hypothesis comes from evidence of differences in genome-wide alterations in DNA copy number and mutational status of BRAF and N-RAS genes in melanomas arising from different sites and with different levels of sun exposure.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('mutational', 'Var', (138, 148))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('BRAF', 'Gene', (159, 163))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('alterations', 'Reg', (103, 114))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('N-RAS', 'Gene', (168, 173))	('melanomas', 'Disease', (183, 192))	('N-RAS', 'Gene', '4893', (168, 173))	('BRAF', 'Gene', '673', (159, 163))
51005	21080806	Interestingly, melanomas on the trunk of the body present frequent mutations in BRAF, which is strongly associated with MC1R polymorphisms.	('BRAF', 'Gene', (80, 84))	('MC1R', 'Gene', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('melanomas', 'Disease', 'MESH:D008545', (15, 24))	('mutations', 'Var', (67, 76))	('associated', 'Reg', (104, 114))	('trunk', 'cellular_component', 'GO:0043198', ('32', '37'))	('BRAF', 'Gene', '673', (80, 84))	('MC1R', 'Gene', '4157', (120, 124))	('melanomas', 'Disease', (15, 24))
51075	21080806	Ethnic differences in the skin phenotype and aggregation of mutations in genes associated with risk for developing melanoma are influenced by the geographic location of an individual.	('melanoma', 'Disease', (115, 123))	('mutations', 'Var', (60, 69))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))
51161	21080806	Targeted therapies refer to treatments designed to inhibit biochemical pathways activated by mutations in tumors.	('biochemical pathways', 'Pathway', (59, 79))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mutations', 'Var', (93, 102))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('men', 'Species', '9606', (33, 36))	('inhibit', 'NegReg', (51, 58))
51166	21080806	The success of this targeted therapy appears to be transient as the melanomas from many of the patients who initially responded to PLX4032 later became resistant.	('PLX4032', 'Var', (131, 138))	('patients', 'Species', '9606', (95, 103))	('melanomas', 'Disease', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('melanomas', 'Disease', 'MESH:D008545', (68, 77))	('PLX4032', 'Chemical', 'MESH:D000077484', (131, 138))
51168	21080806	Point mutations in cKIT, a tyrosine growth factor receptor, result in activation of proliferative and prosurvival signaling pathways.	('cKIT', 'Gene', '3815', (19, 23))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('Point mutations', 'Var', (0, 15))	('activation', 'PosReg', (70, 80))	('cKIT', 'Gene', (19, 23))
51200	32397120	Indeed, many studies have reported that the distribution of TILs in melanoma patients leads to a better prognosis, thus, TILs are increasingly gaining attention for their implications in melanoma treatment and predicting prognosis.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('prognosis', 'MPA', (104, 113))	('patients', 'Species', '9606', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('better', 'PosReg', (97, 103))	('TILs', 'Var', (60, 64))
51201	32397120	However, since TILs includes not only effector cells having a strong anti-cancer effect but also immunosuppressive cells as a heterogenous group, a distribution of many immunosuppressive cells can rather inhibit the effector cell activities.	('effector cell activities', 'CPA', (216, 240))	('inhibit', 'NegReg', (204, 211))	('distribution', 'Var', (148, 160))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
51267	32397120	Similar to Figure 2a,c, also showed that overall survival rate of patients with high Ly75 expression (n = 35) was significantly higher compared with patients with lower expression (n = 9), as based on the Tumor Melanoma Metastatic-Bhardwaj-44 dataset.	('Ly75', 'Gene', (85, 89))	('patients', 'Species', '9606', (149, 157))	('Ly75', 'Gene', '4065', (85, 89))	('Tumor Melanoma', 'Disease', (205, 219))	('Melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('Tumor Melanoma', 'Phenotype', 'HP:0002861', (205, 219))	('expression', 'Var', (90, 100))	('Tumor', 'Phenotype', 'HP:0002664', (205, 210))	('high', 'Var', (80, 84))	('higher', 'PosReg', (128, 134))	('patients', 'Species', '9606', (66, 74))	('Tumor Melanoma', 'Disease', 'MESH:D008545', (205, 219))
51270	32397120	The mutation and alteration frequencies of the Ly75 gene were 0.45% and 0.32%, respectively (Figure 3d).	('Ly75', 'Gene', '4065', (47, 51))	('Ly75', 'Gene', (47, 51))	('alteration', 'Var', (17, 27))
51279	32397120	Therefore, in this study, the correlation between Ly75 expression levels and immune cell infiltration was investigated to determine the mechanisms related to increased patient survival by high Ly75 mRNA expression.	('high', 'Var', (188, 192))	('patient', 'Species', '9606', (168, 175))	('Ly75', 'Gene', (193, 197))	('Ly75', 'Gene', (50, 54))	('Ly75', 'Gene', '4065', (193, 197))	('Ly75', 'Gene', '4065', (50, 54))	('increased', 'PosReg', (158, 167))
51325	32397120	Additionally, an in vivo study has demonstrated that targeting Ly75 with antigen-coupled anti-Ly75 monoclonal antibodies leads to antigen uptake, phagocytosis, and subsequent antigen presentation to T cells.	('targeting', 'Var', (53, 62))	('antigen presentation', 'MPA', (175, 195))	('phagocytosis', 'CPA', (146, 158))	('Ly75', 'Gene', (63, 67))	('Ly75', 'Gene', '4065', (63, 67))	('phagocytosis', 'biological_process', 'GO:0006909', ('146', '158'))	('antigen presentation', 'biological_process', 'GO:0019882', ('175', '195'))	('uptake', 'biological_process', 'GO:0098657', ('138', '144'))	('Ly75', 'Gene', (94, 98))	('uptake', 'biological_process', 'GO:0098739', ('138', '144'))	('antigen', 'MPA', (130, 137))	('Ly75', 'Gene', '4065', (94, 98))
51330	32397120	Consequently, it was found that targeting Ly75 leads to effective antigen presentation, cytokine production, antigen-specific T cell stimulation, and T cell proliferation.	('antigen-specific T cell stimulation', 'CPA', (109, 144))	('targeting', 'Var', (32, 41))	('cytokine production', 'biological_process', 'GO:0001816', ('88', '107'))	('Ly75', 'Gene', (42, 46))	('T cell proliferation', 'CPA', (150, 170))	('antigen presentation', 'biological_process', 'GO:0019882', ('66', '86'))	('effective', 'PosReg', (56, 65))	('Ly75', 'Gene', '4065', (42, 46))	('antigen presentation', 'MPA', (66, 86))	('T cell proliferation', 'biological_process', 'GO:0042098', ('150', '170'))	('cytokine production', 'MPA', (88, 107))
51337	32397120	Abnormal methylation is evident in cancer development, and the hypermethylation of CpG islands is considered to play an important role in the progression of cancer by the inactivation of tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('187', '203'))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('hypermethylation', 'Var', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('187', '203'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('cancer', 'Disease', (157, 163))	('methylation', 'MPA', (9, 20))	('cancer', 'Disease', (35, 41))	('inactivation', 'NegReg', (171, 183))
51338	32397120	A cohort study on melanoma and lung cancer shows that low methylation is related to decreased tumor immunity and poor clinical responses to immunotherapy.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('low', 'NegReg', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('methylation', 'Var', (58, 69))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('decreased tumor', 'Disease', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('decreased tumor', 'Disease', 'MESH:D002303', (84, 99))
51340	32397120	Particularly, DNA methylation of immune cells in a tumor microenvironment was recently reported to be specifically associated with poor survival for patients with melanoma.	('DNA methylation', 'Var', (14, 29))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('DNA methylation', 'biological_process', 'GO:0006306', ('14', '29'))	('melanoma', 'Disease', (163, 171))	('tumor', 'Disease', (51, 56))	('associated', 'Reg', (115, 125))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
51388	30775140	A positive CDKN2A mutation status has been associated with a high number of affected family members, multiple primary melanomas, pancreatic cancer, and early age at melanoma onset.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('melanomas', 'Phenotype', 'HP:0002861', (118, 127))	('CDKN2A', 'Gene', (11, 17))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanomas', 'Disease', 'MESH:D008545', (118, 127))	('mutation', 'Var', (18, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('associated', 'Reg', (43, 53))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('melanoma', 'Disease', (165, 173))	('melanomas', 'Disease', (118, 127))	('CDKN2A', 'Gene', '1029', (11, 17))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
51389	30775140	Mutations in the other melanoma predisposition genes:CDK4, BAP1, TERT, POT1, ACD, TERF2IP, and MITF:are rare, overall contributing to explain a further 10% of familial clustering of melanoma.	('TERF2IP', 'Gene', '54386', (82, 89))	('POT1', 'Gene', '25913', (71, 75))	('CDK4', 'Gene', (53, 57))	('ACD', 'Gene', (77, 80))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('POT1', 'Gene', (71, 75))	('melanoma', 'Disease', (23, 31))	('MITF', 'Gene', '4286', (95, 99))	('CDK4', 'Gene', '1019', (53, 57))	('Mutations', 'Var', (0, 9))	('CDK', 'molecular_function', 'GO:0004693', ('53', '56'))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('MITF', 'Gene', (95, 99))	('TERT', 'Gene', (65, 69))	('contributing', 'Reg', (118, 130))	('TERT', 'Gene', '7015', (65, 69))	('familial clustering', 'Disease', (159, 178))	('ACD', 'Gene', '65057', (77, 80))	('BAP1', 'Gene', (59, 63))	('TERF2IP', 'Gene', (82, 89))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('BAP1', 'Gene', '51411', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
51401	30775140	Germline susceptibility has been associated with mutations in high-penetrance melanoma predisposition genes, CDKN2A (cyclin-dependent kinase 2A) and less frequently in CDK4 (cyclin-dependent kinase 4), BAP1 (breast cancer associated protein-1), TERT (telomerase reverse transcriptase), and POT1 (protection of telomeres 1), or with variants in intermediate-risk genes, MC1R (melanocortin 1 receptor) and MITF (microphthalmia-associated transcription factor).	('cyclin', 'molecular_function', 'GO:0016538', ('174', '180'))	('cyclin-dependent kinase 2A', 'Gene', (117, 143))	('TERT', 'Gene', '7015', (245, 249))	('microphthalmia-associated transcription factor', 'Gene', '4286', (410, 456))	('melanocortin 1 receptor', 'Gene', '4157', (375, 398))	('melanocortin 1 receptor', 'Gene', (375, 398))	('CDKN2A', 'Gene', '1029', (109, 115))	('MITF', 'Gene', '4286', (404, 408))	('cyclin-dependent kinase 4', 'Gene', (174, 199))	('transcriptase', 'molecular_function', 'GO:0003899', ('270', '283'))	('POT1', 'Gene', '25913', (290, 294))	('mutations', 'Var', (49, 58))	('cyclin', 'molecular_function', 'GO:0016538', ('117', '123'))	('CDK', 'molecular_function', 'GO:0004693', ('168', '171'))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('cyclin-dependent kinase 4', 'Gene', '1019', (174, 199))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('microphthalmia-associated transcription factor', 'Gene', (410, 456))	('breast cancer associated protein-1', 'Gene', '51411', (208, 242))	('MITF', 'Gene', (404, 408))	('transcription', 'biological_process', 'GO:0006351', ('436', '449'))	('cyclin-dependent kinase 2A', 'Gene', '1029', (117, 143))	('POT1', 'Gene', (290, 294))	('microphthalmia', 'Phenotype', 'HP:0000568', (410, 424))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('MC1R', 'Gene', '4157', (369, 373))	('CDK4', 'Gene', (168, 172))	('breast cancer associated protein-1', 'Gene', (208, 242))	('MC1R', 'Gene', (369, 373))	('variants', 'Var', (332, 340))	('breast cancer', 'Phenotype', 'HP:0003002', (208, 221))	('BAP1', 'Gene', (202, 206))	('transcriptase', 'molecular_function', 'GO:0003968', ('270', '283'))	('CDKN2A', 'Gene', (109, 115))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('transcriptase', 'molecular_function', 'GO:0034062', ('270', '283'))	('associated', 'Reg', (33, 43))	('BAP1', 'Gene', '51411', (202, 206))	('TERT', 'Gene', (245, 249))	('CDK4', 'Gene', '1019', (168, 172))	('transcription factor', 'molecular_function', 'GO:0000981', ('436', '456'))
51406	30775140	Penetrance relates to the lifetime risk for a mutation carrier of developing melanoma and reflects the overall contribution of a specific gene alteration to the risk of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('carrier', 'molecular_function', 'GO:0005215', ('55', '62'))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('mutation', 'Var', (46, 54))
51411	30775140	The CDKN2A gene is the major melanoma susceptibility gene with more than 60 germline mutations identified to date, the majority of which are missense mutations in the p16 transcript.	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('p16', 'Gene', (167, 170))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('missense mutations', 'Var', (141, 159))	('CDKN2A', 'Gene', '1029', (4, 10))	('p16', 'Gene', '1029', (167, 170))	('CDKN2A', 'Gene', (4, 10))
51413	30775140	The likelihood of detecting a CDKN2A mutation in melanoma families increases with the number of affected members (approximately 10% for 2-case melanoma families and 30%-40% for families with 3 or more cases of melanoma), with the presence within the family of relatives with multiple primary melanoma (MPM), pancreatic cancer, or early age at melanoma onset.	('melanoma', 'Disease', 'MESH:D008545', (292, 300))	('mutation', 'Var', (37, 45))	('CDKN2A', 'Gene', '1029', (30, 36))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('increases', 'PosReg', (67, 76))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('pancreatic cancer', 'Disease', (308, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('melanoma', 'Disease', 'MESH:D008545', (343, 351))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))	('melanoma', 'Disease', (292, 300))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (308, 325))	('detecting', 'Reg', (18, 27))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('CDKN2A', 'Gene', (30, 36))	('melanoma', 'Phenotype', 'HP:0002861', (343, 351))	('melanoma', 'Disease', (343, 351))	('pancreatic cancer', 'Disease', 'MESH:D010190', (308, 325))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
51414	30775140	In addition, CDKN2A mutations are also detected in individuals with MPM in the absence of a family history of melanoma in 8.3%, 15%, and 57% in United States, North America, and Greece, respectively.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('CDKN2A', 'Gene', (13, 19))	('MPM', 'Disease', (68, 71))	('detected', 'Reg', (39, 47))	('CDKN2A', 'Gene', '1029', (13, 19))	('mutations', 'Var', (20, 29))
51416	30775140	Annual surveillance for pancreatic cancer is therefore warranted in high-risk melanoma families with CDKN2A mutations.	('pancreatic cancer', 'Disease', (24, 41))	('pancreatic cancer', 'Disease', 'MESH:D010190', (24, 41))	('CDKN2A', 'Gene', (101, 107))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CDKN2A', 'Gene', '1029', (101, 107))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (24, 41))
51417	30775140	Besides pancreatic cancer, families with CDKN2A mutations have been reported to also have an increased risk of developing breast, lung, and other tobacco-related cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (8, 25))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('tobacco', 'Species', '4097', (146, 153))	('pancreatic cancer', 'Disease', 'MESH:D010190', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('CDKN2A', 'Gene', (41, 47))	('pancreatic cancer', 'Disease', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung', 'Disease', (130, 134))	('breast', 'Disease', (122, 128))	('CDKN2A', 'Gene', '1029', (41, 47))	('mutations', 'Var', (48, 57))
51418	30775140	Few melanoma kindreds worldwide have been found to carry mutations of the CDK4 oncogene, the second identified high-risk melanoma susceptibility gene, encoding one of the binding partners of p16.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('binding', 'molecular_function', 'GO:0005488', ('171', '178'))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('p16', 'Gene', '1029', (191, 194))	('CDK4', 'Gene', '1019', (74, 78))	('CDK4', 'Gene', (74, 78))	('mutations', 'Var', (57, 66))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('p16', 'Gene', (191, 194))	('melanoma', 'Disease', (4, 12))	('CDK', 'molecular_function', 'GO:0004693', ('74', '77'))
51420	30775140	When CDK4 is mutated, p16 cannot inhibit the CDK4 kinase activity resulting in increased phosphorylation of RB bound to E2F transcription factors with higher E2F release.	('phosphorylation', 'MPA', (89, 104))	('CDK4', 'Gene', (5, 9))	('bound', 'Interaction', (111, 116))	('higher', 'PosReg', (151, 157))	('kinase activity', 'molecular_function', 'GO:0016301', ('50', '65'))	('CDK', 'molecular_function', 'GO:0004693', ('5', '8'))	('mutated', 'Var', (13, 20))	('CDK4', 'Gene', '1019', (45, 49))	('transcription', 'biological_process', 'GO:0006351', ('124', '137'))	('RB', 'Gene', '5925', (108, 110))	('CDK4', 'Gene', '1019', (5, 9))	('CDK', 'molecular_function', 'GO:0004693', ('45', '48'))	('phosphorylation', 'biological_process', 'GO:0016310', ('89', '104'))	('p16', 'Gene', (22, 25))	('E2F release', 'MPA', (158, 169))	('increased', 'PosReg', (79, 88))	('p16', 'Gene', '1029', (22, 25))	('CDK4', 'Gene', (45, 49))	('RB', 'Phenotype', 'HP:0009919', (108, 110))
51421	30775140	All CDK4 pathogenetic mutations cluster in codon 24 of exon 2, a critical site for p16 binding.	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('p16', 'Gene', '1029', (83, 86))	('cluster', 'Reg', (32, 39))	('pathogenetic', 'Reg', (9, 21))	('mutations', 'Var', (22, 31))	('p16', 'Gene', (83, 86))	('CDK4', 'Gene', '1019', (4, 8))	('CDK4', 'Gene', (4, 8))	('CDK', 'molecular_function', 'GO:0004693', ('4', '7'))
51423	30775140	In families negative for mutations in known high-risk genes, the introduction of next-generation sequencing methodologies led to the identification of germline mutations in a small number of novel high-penetrance melanoma susceptibility genes involved in pathways other than those mediated by known melanoma risk factors.	('mutations', 'Var', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (299, 307))	('melanoma', 'Disease', (213, 221))	('melanoma', 'Disease', 'MESH:D008545', (299, 307))
51429	30775140	TERT mutations induce increased expression of telomerase, thus promoting telomere stabilization and acting on cell aging, turnover, and senescence.	('cell aging', 'biological_process', 'GO:0007569', ('110', '120'))	('promoting', 'PosReg', (63, 72))	('mutations', 'Var', (5, 14))	('TERT', 'Gene', (0, 4))	('telomere', 'cellular_component', 'GO:0000781', ('73', '81'))	('TERT', 'Gene', '7015', (0, 4))	('increased', 'PosReg', (22, 31))	('telomere stabilization', 'CPA', (73, 95))	('telomere', 'cellular_component', 'GO:0005696', ('73', '81'))	('expression', 'MPA', (32, 42))	('senescence', 'biological_process', 'GO:0010149', ('136', '146'))	('telomerase', 'Protein', (46, 56))	('acting', 'Reg', (100, 106))
51432	30775140	Mutations in the POT1 gene have been recently identified in a total of 12 CDKN2A-negative melanoma families.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('POT1', 'Gene', '25913', (17, 21))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('POT1', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
51435	30775140	Families carrying POT1, ACD, and TERF2IP mutations often present with MPM and early-onset melanoma.	('mutations', 'Var', (41, 50))	('POT1', 'Gene', (18, 22))	('melanoma', 'Disease', (90, 98))	('MPM', 'Disease', (70, 73))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('TERF2IP', 'Gene', (33, 40))	('ACD', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('ACD', 'Gene', '65057', (24, 27))	('POT1', 'Gene', '25913', (18, 22))	('present', 'Reg', (57, 64))	('TERF2IP', 'Gene', '54386', (33, 40))
51441	30775140	Specific MC1R variants (R142H, R151C, R160W, and D294H) resulting in a reduced receptor function with a switch from eumelanin to pheomelanin synthesis are classified as red hair color (RHC) or "R" variants and have been strongly associated with fair skin, freckling, UV radiation sensitivity, and inability to tan.	('freckling', 'Phenotype', 'HP:0001480', (256, 265))	('R160W', 'Mutation', 'rs1805008', (38, 43))	('red hair color', 'Disease', (169, 183))	('D294H', 'Mutation', 'rs1805009', (49, 54))	('R151C', 'Var', (31, 36))	('eumelanin', 'Chemical', 'MESH:C041877', (116, 125))	('red hair color', 'Disease', 'MESH:D003117', (169, 183))	('receptor function', 'MPA', (79, 96))	('R160W', 'Var', (38, 43))	('fair skin', 'Disease', (245, 254))	('reduced', 'NegReg', (71, 78))	('freckling', 'Disease', (256, 265))	('associated', 'Reg', (229, 239))	('R142H', 'Var', (24, 29))	('UV radiation sensitivity', 'Disease', (267, 291))	('D294H', 'Var', (49, 54))	('R151C', 'Mutation', 'rs1805007', (31, 36))	('fair skin', 'Phenotype', 'HP:0007513', (245, 254))	('inability to tan', 'Disease', (297, 313))	('red hair', 'Phenotype', 'HP:0002297', (169, 177))	('R142H', 'Mutation', 'rs11547464', (24, 29))	('MC1R', 'Gene', '4157', (9, 13))	('MC1R', 'Gene', (9, 13))	('synthesis', 'biological_process', 'GO:0009058', ('141', '150'))
51442	30775140	MC1R variants, mainly R alleles, have been associated with an increased risk of melanoma independently of phenotypic features.	('MC1R', 'Gene', '4157', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('MC1R', 'Gene', (0, 4))	('variants', 'Var', (5, 13))	('associated', 'Reg', (43, 53))
51445	30775140	In addition, inheritance of MC1R variants with CDKN2A mutations has been shown to increase penetrance of melanoma in families carrying CDKN2A mutations.	('CDKN2A', 'Gene', (135, 141))	('penetrance', 'MPA', (91, 101))	('CDKN2A', 'Gene', '1029', (135, 141))	('MC1R', 'Gene', '4157', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('MC1R', 'Gene', (28, 32))	('mutations', 'Var', (54, 63))	('CDKN2A', 'Gene', (47, 53))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('CDKN2A', 'Gene', '1029', (47, 53))	('increase', 'PosReg', (82, 90))	('variants', 'Var', (33, 41))
51446	30775140	Finally, carrying R variants has been associated with specific clinico-dermoscopic features of melanoma such as hypopigmentation, structureless areas, atypia, and vessels.	('variants', 'Var', (20, 28))	('atypia', 'Disease', (151, 157))	('associated', 'Reg', (38, 48))	('vessels', 'Disease', (163, 170))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('structureless areas', 'Disease', (130, 149))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('hypopigmentation', 'Phenotype', 'HP:0001010', (112, 128))	('hypopigmentation', 'Disease', 'MESH:D017496', (112, 128))	('hypopigmentation', 'Disease', (112, 128))
51448	30775140	A rare functional variant p.E318K in the MITF gene has been implicated in familial melanoma and in melanoma/renal cell carcinoma susceptibility.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('p.E318K', 'Var', (26, 33))	('familial melanoma', 'Disease', (74, 91))	('melanoma/renal cell carcinoma', 'Disease', 'MESH:C538614', (99, 128))	('implicated', 'Reg', (60, 70))	('p.E318K', 'Mutation', 'rs149617956', (26, 33))	('melanoma/renal cell carcinoma', 'Disease', (99, 128))	('MITF', 'Gene', (41, 45))	('MITF', 'Gene', '4286', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('familial melanoma', 'Disease', 'OMIM:155600', (74, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
51449	30775140	The p.E318K mutation alters MITF sumoylation, increasing the MITF transcriptional activity with upregulation of downstream genes.	('increasing', 'PosReg', (46, 56))	('sumoylation', 'MPA', (33, 44))	('p.E318K', 'Mutation', 'rs149617956', (4, 11))	('sumoylation', 'biological_process', 'GO:0016925', ('33', '44'))	('MITF', 'Gene', '4286', (61, 65))	('MITF', 'Gene', (61, 65))	('p.E318K', 'Var', (4, 11))	('MITF', 'Gene', (28, 32))	('MITF', 'Gene', '4286', (28, 32))	('upregulation', 'PosReg', (96, 108))
51450	30775140	Clinically, a high nevus count, development of MPM, onset of melanoma before the age of 40, and nonblue eye color are phenotypic characteristics that have been associated with the p.E318K mutation.	('p.E318K', 'Var', (180, 187))	('nevus', 'Phenotype', 'HP:0003764', (19, 24))	('p.E318K', 'Mutation', 'rs149617956', (180, 187))	('MPM', 'Disease', (47, 50))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('associated', 'Reg', (160, 170))
51453	30775140	Genetic testing of the CDKN2A gene has been available for a long time and can be offered to patients with familial melanoma and/or MPM who are likely to carry a CDKN2A mutation.	('MPM', 'Disease', (131, 134))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('CDKN2A', 'Gene', (23, 29))	('patients', 'Species', '9606', (92, 100))	('CDKN2A', 'Gene', '1029', (23, 29))	('mutation', 'Var', (168, 176))	('CDKN2A', 'Gene', (161, 167))	('familial melanoma', 'Disease', (106, 123))	('familial melanoma', 'Disease', 'OMIM:155600', (106, 123))	('CDKN2A', 'Gene', '1029', (161, 167))
51458	30775140	If a CDKN2A mutation is detected in a family, screening of other family members is recommended.	('CDKN2A', 'Gene', '1029', (5, 11))	('CDKN2A', 'Gene', (5, 11))	('mutation', 'Var', (12, 20))
51464	30775140	Carriers of a CDKN2A mutation are at high risk of developing multiple melanomas and, in some families, pancreatic cancer.	('CDKN2A', 'Gene', '1029', (14, 20))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('pancreatic cancer', 'Disease', (103, 120))	('pancreatic cancer', 'Disease', 'MESH:D010190', (103, 120))	('mutation', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('melanomas', 'Disease', (70, 79))	('developing', 'PosReg', (50, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (103, 120))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('CDKN2A', 'Gene', (14, 20))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
51465	30775140	The identification of a deleterious CDKN2A mutation suggests that carriers should be included in intensive skin surveillance programs with skin examination, also including scalp, oral and genital mucosa, performed every 6 months.	('mutation', 'Var', (43, 51))	('CDKN2A', 'Gene', '1029', (36, 42))	('CDKN2A', 'Gene', (36, 42))
51469	30775140	The recommendation of avoiding smoking in cancer prevention programs has been recently suggested for CDKN2A mutation carriers after the description of an increased prevalence of tobacco-associated cancers in CDKN2A-mutated families.	('CDKN2A', 'Gene', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('CDKN2A', 'Gene', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('CDKN2A', 'Gene', '1029', (208, 214))	('tobacco', 'Species', '4097', (178, 185))	('cancer', 'Disease', (197, 203))	('cancers', 'Disease', (197, 204))	('CDKN2A', 'Gene', '1029', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mutation', 'Var', (108, 116))
51548	32028647	Opposite Roles of BAP1 in Overall Survival of Uveal Melanoma and Cutaneous Melanoma Background: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM).	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('uveal melanoma', 'Disease', (194, 208))	('BAP1', 'Gene', (18, 22))	('uveal melanoma', 'Disease', 'MESH:C536494', (194, 208))	('Melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRCA1-Associated Protein 1', 'Gene', (96, 122))	('Melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', '8314', (124, 128))	('CM', 'Disease', 'MESH:C562393', (238, 240))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('Melanoma and Cutaneous Melanoma', 'Disease', 'MESH:D008545', (52, 83))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('BRCA1-Associated Protein 1', 'Gene', '8314', (96, 122))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('UM', 'Disease', 'MESH:C536494', (210, 212))	('BAP1', 'Gene', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('cutaneous melanoma', 'Disease', (218, 236))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (218, 236))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (218, 236))	('BAP1', 'Gene', '8314', (18, 22))	('predispose', 'Reg', (149, 159))	('mutations', 'Var', (139, 148))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (65, 83))
51552	32028647	Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS).	('mRNA levels', 'MPA', (59, 70))	('associated', 'Reg', (102, 112))	('overall survival', 'MPA', (118, 134))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('copy number variations', 'Var', (74, 96))	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (54, 58))
51555	32028647	Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients.	('patients', 'Species', '9606', (56, 64))	('BAP1', 'Gene', '8314', (18, 22))	('CM', 'Disease', 'MESH:C562393', (53, 55))	('BAP1', 'Gene', (18, 22))	('low', 'Var', (14, 17))	('patients', 'Species', '9606', (104, 112))
51556	32028647	Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (70, 79))	('BAP1', 'Gene', (106, 110))	('correlated', 'Reg', (90, 100))	('CM', 'Disease', 'MESH:C562393', (139, 141))	('UM', 'Disease', 'MESH:C536494', (132, 134))	('expression levels', 'MPA', (111, 128))	('BAP1', 'Gene', '8314', (106, 110))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
51558	32028647	High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients.	('BCL2', 'Gene', (82, 86))	('High', 'Var', (0, 4))	('CM', 'Disease', 'MESH:C562393', (24, 26))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('KIT', 'Gene', '3815', (92, 95))	('BAP1', 'Gene', '8314', (5, 9))	('KIT', 'molecular_function', 'GO:0005020', ('92', '95'))	('associated', 'Reg', (45, 55))	('BCL2', 'molecular_function', 'GO:0015283', ('82', '86'))	('CDK', 'molecular_function', 'GO:0004693', ('76', '79'))	('KIT', 'Gene', (92, 95))	('patients', 'Species', '9606', (168, 176))	('BAP1', 'Gene', (5, 9))	('BCL2', 'Gene', '596', (82, 86))	('CDK1', 'Gene', '983', (76, 80))	('over-expressed', 'PosReg', (61, 75))	('CDK1', 'Gene', (76, 80))
51560	32028647	Germline mutations in BAP1 (BRCA1-Associated Protein 1) are associated with multiple types of hereditary cancers, which is now classified as BAP1-TPDS (BAP1 Tumor Predisposition Syndrome).	('Germline mutations', 'Var', (0, 18))	('hereditary cancers', 'Disease', (94, 112))	('BAP1', 'Gene', '8314', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('BAP1', 'Gene', '8314', (152, 156))	('BRCA1-Associated Protein 1', 'Gene', (28, 54))	('BAP1', 'Gene', (141, 145))	('hereditary cancers', 'Disease', 'MESH:D009369', (94, 112))	('associated', 'Reg', (60, 70))	('BAP1', 'Gene', '8314', (22, 26))	('BRCA1-Associated Protein 1', 'Gene', '8314', (28, 54))	('BAP1', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('BAP1', 'Gene', (22, 26))	('Tumor', 'Phenotype', 'HP:0002664', (157, 162))
51562	32028647	The BAP1 germline mutations are generally deletions or loss-of-function mutations, thus BAP1 was defined as a tumor suppressor gene.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('BAP1', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('loss-of-function', 'NegReg', (55, 71))	('deletions', 'Var', (42, 51))	('BAP1', 'Gene', '8314', (88, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('BAP1', 'Gene', (88, 92))	('BAP1', 'Gene', '8314', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
51564	32028647	Somatic mutations in UM tumors are also common.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('UM', 'Disease', 'MESH:C536494', (21, 23))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (24, 30))	('Somatic mutations', 'Var', (0, 17))
51565	32028647	In an analysis of germline vs. somatic mutations in UM tumors, 8% of tumors were reported to have germline mutation while 43-45% of tumors had somatic mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('UM', 'Disease', 'MESH:C536494', (52, 54))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('germline mutation', 'Var', (98, 115))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
51569	32028647	Loss of BAP1 in uveal melanoma cells did not impact cell proliferation or tumorigenesis; rather, loss of BAP1 led to de-differentiation accompanied by increased stem-like biomarkers.	('increased', 'PosReg', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('loss', 'Var', (97, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('BAP1', 'Gene', '8314', (105, 109))	('BAP1', 'Gene', '8314', (8, 12))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('uveal melanoma', 'Disease', (16, 30))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('BAP1', 'Gene', (8, 12))	('de-differentiation', 'CPA', (117, 135))	('BAP1', 'Gene', (105, 109))
51570	32028647	In cutaneous melanoma cell lines, however, stable over-expression of BAP1 promoted cell growth while knockdown of BAP1 suppressed cell proliferation with concomitant decrease of survivin, an anti-apoptotic protein.	('cell proliferation', 'biological_process', 'GO:0008283', ('130', '148'))	('cell growth', 'CPA', (83, 94))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('BAP1', 'Gene', (114, 118))	('BAP1', 'Gene', '8314', (69, 73))	('suppressed', 'NegReg', (119, 129))	('protein', 'cellular_component', 'GO:0003675', ('206', '213'))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('survivin', 'Protein', (178, 186))	('over-expression', 'PosReg', (50, 65))	('cell proliferation', 'CPA', (130, 148))	('BAP1', 'Gene', (69, 73))	('cutaneous melanoma', 'Disease', (3, 21))	('promoted', 'PosReg', (74, 82))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('BAP1', 'Gene', '8314', (114, 118))	('decrease', 'NegReg', (166, 174))	('knockdown', 'Var', (101, 110))
51572	32028647	BAP1 mutations are associated with worse prognosis and survival in UM patients due to increased metastatic potentials.	('patients', 'Species', '9606', (70, 78))	('increased', 'PosReg', (86, 95))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('metastatic potentials', 'CPA', (96, 117))	('UM', 'Disease', 'MESH:C536494', (67, 69))	('BAP1', 'Gene', '8314', (0, 4))
51573	32028647	A meta-analysis of various cancer types with BAP1 mutations indicated that BAP1 mutations were also associated with worse outcomes in renal cell carcinoma but not in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('BAP1', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('BAP1', 'Gene', '8314', (45, 49))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (134, 154))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))	('BAP1', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('cancer', 'Disease', (172, 178))	('BAP1', 'Gene', '8314', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (50, 59))	('renal cell carcinoma', 'Disease', (134, 154))	('cancer', 'Disease', (27, 33))
51582	32028647	The TCGA CM and UM patient information were level 1 and 2 raw data; mRNA expression data were RSEM-normalized (RNA-Seq by Expectation Maximization); mutations (single nucleotide changes or small insertion/deletions) and copy number variations (CNVs) in each tumor were level 3 processed data.	('small insertion/deletions', 'Var', (189, 214))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('patient', 'Species', '9606', (19, 26))	('single nucleotide changes', 'Var', (160, 185))	('tumor', 'Disease', (258, 263))	('mRNA expression', 'MPA', (68, 83))	('CM', 'Disease', 'MESH:C562393', (9, 11))	('UM', 'Disease', 'MESH:C536494', (16, 18))	('tumor', 'Disease', 'MESH:D009369', (258, 263))
51583	32028647	Survival curves for mRNA expression levels of BAP1 or BAP1 copy number variation (CNV) were plotted using Kaplan-Meier method.	('BAP1', 'Gene', '8314', (46, 50))	('copy number variation', 'Var', (59, 80))	('BAP1', 'Gene', '8314', (54, 58))	('BAP1', 'Gene', (46, 50))	('BAP1', 'Gene', (54, 58))
51596	32028647	Among the 80 UM tumors, 13 tumors carried a BAP1 point mutation and 44 showed copy number variation (CNV = -1, all hemizygous deletion, defined as BAP1-CNV group).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('UM', 'Disease', 'MESH:C536494', (13, 15))	('BAP1', 'Gene', (147, 151))	('copy number variation', 'Var', (78, 99))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('point mutation', 'Var', (49, 63))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('BAP1', 'Gene', '8314', (44, 48))	('BAP1', 'Gene', '8314', (147, 151))	('tumors', 'Disease', (16, 22))	('BAP1', 'Gene', (44, 48))
51598	32028647	Hemizygous deletion may indicate monosomy 3, which was a driver cause for uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('monosomy 3', 'Disease', (33, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('Hemizygous deletion', 'Var', (0, 19))	('indicate', 'Reg', (24, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('uveal melanoma', 'Disease', (74, 88))
51607	32028647	Eleven tumors carried BAP1 point mutations, with four silent synonymous mutations and seven missense mutations with unknown significance (I643T, E30K, P629S, R417M, S143N (N = 2), L416F and R59W).	('L416F', 'Mutation', 'p.L416F', (180, 185))	('P629S', 'Var', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('E30K', 'Var', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('I643T', 'Mutation', 'rs376519545', (138, 143))	('R417M', 'Mutation', 'p.R417M', (158, 163))	('R417M', 'Var', (158, 163))	('tumors', 'Disease', (7, 13))	('R59W', 'Mutation', 'rs1404823823', (190, 194))	('BAP1', 'Gene', '8314', (22, 26))	('P629S', 'Mutation', 'p.P629S', (151, 156))	('E30K', 'Mutation', 'p.E30K', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('BAP1', 'Gene', (22, 26))	('L416F', 'Var', (180, 185))	('R59W', 'Var', (190, 194))	('I643T', 'Var', (138, 143))	('S143N', 'Mutation', 'p.S143N', (165, 170))
51608	32028647	It was not surprising that these mutations were not associated with overall survival in CM (HR = 0.58, p = 0.36).	('CM', 'Disease', 'MESH:C562393', (88, 90))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (33, 42))
51611	32028647	Compared to patients with no BAP1 copy number alteration (i.e., BAP1 diploids), patients with BAP1 amplification or deletion both showed significant better survival (Table 1, Figure 1f).	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (80, 88))	('BAP1', 'Gene', '8314', (94, 98))	('deletion', 'Var', (116, 124))	('BAP1', 'Gene', '8314', (29, 33))	('better', 'PosReg', (149, 155))	('amplification', 'Var', (99, 112))	('BAP1', 'Gene', '8314', (64, 68))	('survival', 'CPA', (156, 164))	('BAP1', 'Gene', (94, 98))	('BAP1', 'Gene', (29, 33))	('BAP1', 'Gene', (64, 68))
51612	32028647	BAP1 deletion indicated non-significant better survival (HR = 0.74, p = 0.116); and BAP1 amplification (correlated with high level of mRNA) indicated significant better survival (HR = 0.56, p = 0.005) (Table 1).	('survival', 'CPA', (169, 177))	('amplification', 'Var', (89, 102))	('deletion', 'Var', (5, 13))	('BAP1', 'Gene', (0, 4))	('survival', 'CPA', (47, 55))	('BAP1', 'Gene', '8314', (84, 88))	('better', 'PosReg', (162, 168))	('BAP1', 'Gene', (84, 88))	('BAP1', 'Gene', '8314', (0, 4))	('better', 'PosReg', (40, 46))
51613	32028647	BAP1 amplification-predicted better survival remained significant after adjusting to age of diagnosis (HR 0.59, p = 0.013), but the significance was lost after adjusting to stage of disease (HR = 0.68, p = 0.08) (Supplemental Table S2).	('amplification-predicted', 'Var', (5, 28))	('BAP1', 'Gene', '8314', (0, 4))	('BAP1', 'Gene', (0, 4))	('better', 'PosReg', (29, 35))
51614	32028647	BAP1 amplified tumors had slightly lower percentage (12/55 = 21.8 vs. 42/178 = 23.6%) of stage T1 and slightly higher percentage of stage T4 disease (14/55 = 25.5% vs. 39/178 = 21.9%) as compared to diploid tumors.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('BAP1', 'Gene', (0, 4))	('stage T4 disease', 'Disease', (132, 148))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('amplified', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lower', 'NegReg', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('higher', 'PosReg', (111, 117))	('tumors', 'Disease', (207, 213))	('diploid tumors', 'Disease', 'MESH:C548012', (199, 213))	('BAP1', 'Gene', '8314', (0, 4))	('diploid tumors', 'Disease', (199, 213))	('tumors', 'Disease', (15, 21))	('stage T1', 'Disease', (89, 97))
51639	32028647	Next, we asked whether specific mutations or CNVs were associated with high BAP1 expression in CM or low BAP1 expression in UM, each of which indicated worse overall survivals.	('high', 'Var', (71, 75))	('BAP1', 'Gene', '8314', (76, 80))	('BAP1', 'Gene', '8314', (105, 109))	('UM', 'Disease', 'MESH:C536494', (124, 126))	('BAP1', 'Gene', (76, 80))	('expression', 'MPA', (110, 120))	('CM', 'Disease', 'MESH:C562393', (95, 97))	('BAP1', 'Gene', (105, 109))	('expression', 'MPA', (81, 91))
51641	32028647	Enrichment analysis (embedded in cBioportal,) revealed that EIF1AX (unadjusted p = 0.0072) and SF3B1 (unadjusted p = 0.0072) mutations were exclusive with low expression of BAP1.	('mutations', 'Var', (125, 134))	('SF3B1', 'Gene', (95, 100))	('EIF1AX', 'Gene', '1964', (60, 66))	('BAP1', 'Gene', '8314', (173, 177))	('EIF1AX', 'Gene', (60, 66))	('SF3B1', 'Gene', '23451', (95, 100))	('BAP1', 'Gene', (173, 177))
51643	32028647	Exclusivity of SF3B1 and EIF1AX mutations with BAP1 was consistent with previous reports, and supported classification of UM in three sub-types by mutations in three genes: BAP1, SF3B1, and EIF1AX.	('mutations', 'Var', (147, 156))	('UM', 'Disease', 'MESH:C536494', (122, 124))	('SF3B1', 'Gene', '23451', (15, 20))	('SF3B1', 'Gene', (179, 184))	('EIF1AX', 'Gene', (190, 196))	('EIF1AX', 'Gene', '1964', (190, 196))	('BAP1', 'Gene', '8314', (173, 177))	('SF3B1', 'Gene', '23451', (179, 184))	('mutations', 'Var', (32, 41))	('BAP1', 'Gene', '8314', (47, 51))	('EIF1AX', 'Gene', (25, 31))	('BAP1', 'Gene', (173, 177))	('SF3B1', 'Gene', (15, 20))	('EIF1AX', 'Gene', '1964', (25, 31))	('BAP1', 'Gene', (47, 51))
51645	32028647	SF3B1 mRNA levels were not associated with overall survival (HR = 1.29, p = 0.66, bottom 30% vs. top 30%); but SF3B1 mutation alone or mutation plus amplification indicated better overall survival (Supplemental Figure S2).	('SF3B1', 'Gene', '23451', (111, 116))	('SF3B1', 'Gene', (0, 5))	('overall survival', 'MPA', (180, 196))	('SF3B1', 'Gene', (111, 116))	('SF3B1', 'Gene', '23451', (0, 5))	('better', 'PosReg', (173, 179))	('mutation', 'Var', (117, 125))	('mutation plus amplification', 'Var', (135, 162))
51646	32028647	This outcome was perhaps due to the presence of SF3B1 mutation/amplification exclusively in the BAP1-high group.	('mutation/amplification', 'Var', (54, 76))	('BAP1', 'Gene', (96, 100))	('SF3B1', 'Gene', (48, 53))	('SF3B1', 'Gene', '23451', (48, 53))	('BAP1', 'Gene', '8314', (96, 100))
51653	32028647	The worse outcome of BAP1-low patients (including hemizygous deletion of BAP1 and low BAP1 mRNA) was validated in UM patients, while a new discovery of low BAP1 mRNA indicating a better overall survival in CM patients was described.	('CM', 'Disease', 'MESH:C562393', (206, 208))	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (86, 90))	('BAP1', 'Gene', '8314', (156, 160))	('BAP1', 'Gene', (21, 25))	('deletion', 'Var', (61, 69))	('low', 'NegReg', (82, 85))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', (86, 90))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (209, 217))	('UM', 'Disease', 'MESH:C536494', (114, 116))	('patients', 'Species', '9606', (117, 125))	('BAP1', 'Gene', (156, 160))	('BAP1', 'Gene', '8314', (21, 25))
51654	32028647	Furthermore, low BAP1 mRNA seemed to indicate a significantly better survival for CM patients of older age (>50 years) but did not predict survival for younger patients.	('patients', 'Species', '9606', (160, 168))	('better', 'PosReg', (62, 68))	('patients', 'Species', '9606', (85, 93))	('low', 'Var', (13, 16))	('BAP1', 'Gene', '8314', (17, 21))	('BAP1', 'Gene', (17, 21))	('CM', 'Disease', 'MESH:C562393', (82, 84))	('survival', 'MPA', (69, 77))
51655	32028647	The age-differentiated BAP1 role in CM survival is different than that in UM where loss of BAP1 predicted worse outcome in patients of all ages.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (91, 95))	('loss', 'Var', (83, 87))	('patients', 'Species', '9606', (123, 131))	('BAP1', 'Gene', '8314', (23, 27))	('CM', 'Disease', 'MESH:C562393', (36, 38))	('BAP1', 'Gene', '8314', (91, 95))	('UM', 'Disease', 'MESH:C536494', (74, 76))
51658	32028647	These results are consistent with the cellular role of BAP1 in CM cell lines A375 and C918 where depletion of BAP1 expression led to an inhibition of cell growth but were different with the survival outcome in the same Kumar et al.	('BAP1', 'Gene', '8314', (110, 114))	('CM', 'Disease', 'MESH:C562393', (63, 65))	('BAP1', 'Gene', (55, 59))	('BAP1', 'Gene', (110, 114))	('inhibition', 'NegReg', (136, 146))	('cell growth', 'CPA', (150, 161))	('A375', 'CellLine', 'CVCL:0132;0.014568046475425634', (77, 81))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('136', '161'))	('depletion', 'Var', (97, 106))	('BAP1', 'Gene', '8314', (55, 59))
51663	32028647	It is also a mystery why BAP1 amplification was associated with better overall survival, even though BAP1 amplification was correlated with higher BAP1 mRNA levels.	('better', 'PosReg', (64, 70))	('BAP1', 'Gene', (147, 151))	('BAP1', 'Gene', (25, 29))	('BAP1', 'Gene', '8314', (101, 105))	('higher', 'PosReg', (140, 146))	('amplification', 'Var', (30, 43))	('overall survival', 'MPA', (71, 87))	('BAP1', 'Gene', (101, 105))	('BAP1', 'Gene', '8314', (147, 151))	('BAP1', 'Gene', '8314', (25, 29))
51666	32028647	Specifically, low BAP1 expression or loss of BAP1 in UM was exclusive to SF3B1 or EIF1AX mutations, while high BAP1 expression in CM was non-significantly exclusive to 9p21 deletion.	('SF3B1', 'Gene', '23451', (73, 78))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (45, 49))	('BAP1', 'Gene', '8314', (111, 115))	('UM', 'Disease', 'MESH:C536494', (53, 55))	('BAP1', 'Gene', (18, 22))	('BAP1', 'Gene', (111, 115))	('EIF1AX', 'Gene', '1964', (82, 88))	('loss', 'NegReg', (37, 41))	('EIF1AX', 'Gene', (82, 88))	('mutations', 'Var', (89, 98))	('low', 'NegReg', (14, 17))	('CM', 'Disease', 'MESH:C562393', (130, 132))	('SF3B1', 'Gene', (73, 78))	('to 9', 'Species', '1214577', (165, 169))	('BAP1', 'Gene', '8314', (45, 49))	('expression', 'MPA', (23, 33))
51669	32028647	Nevertheless, BAP1 expression levels were not associated with GNAQ and GNA11 mutation status in UM tumors, nor with NRAS or PTEN mutation status in CM tumor.	('PTEN', 'Gene', (124, 128))	('GNAQ', 'Gene', '2776', (62, 66))	('GNA11', 'Gene', (71, 76))	('mutation', 'Var', (77, 85))	('GNAQ', 'Gene', (62, 66))	('tumor', 'Disease', (99, 104))	('BAP1', 'Gene', '8314', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PTEN', 'Gene', '5728', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('NRAS', 'Gene', '4893', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('BAP1', 'Gene', (14, 18))	('GNA11', 'Gene', '2767', (71, 76))	('expression levels', 'MPA', (19, 36))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('UM', 'Disease', 'MESH:C536494', (96, 98))	('CM', 'Disease', 'MESH:C562393', (148, 150))	('tumor', 'Disease', (151, 156))	('NRAS', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
51671	32028647	When the BRAF mutation status was used for adjustment in the multivariate Cox model, low BAP1 mRNA levels were still significantly associated with a better OS (HR = 0.74, p = 0.026) while BRAF mutation status did not predict OS in either simple or multivariate Cox model.	('Cox', 'Gene', (74, 77))	('BAP1', 'Gene', (89, 93))	('BRAF', 'Gene', (9, 13))	('low', 'NegReg', (85, 88))	('BRAF', 'Gene', '673', (188, 192))	('Cox', 'Gene', '1351', (261, 264))	('BRAF', 'Gene', (188, 192))	('Cox', 'Gene', (261, 264))	('mutation', 'Var', (14, 22))	('Cox', 'Gene', '1351', (74, 77))	('BAP1', 'Gene', '8314', (89, 93))	('BRAF', 'Gene', '673', (9, 13))
51677	32028647	For example, BAP1-induced apoptosis in neuroblastoma cells is mediated via an interaction with the 14-3-3 protein; thus, the loss of the 14-3-3 protein may lead to loss of BAP1 function (at least partially), even when BAP1 mRNA and DNA are normally expressed.	('BAP1', 'Gene', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('loss', 'Var', (125, 129))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('BAP1', 'Gene', (172, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('DNA', 'cellular_component', 'GO:0005574', ('232', '235'))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('BAP1', 'Gene', '8314', (218, 222))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('14-3-3 protein', 'Protein', (137, 151))	('BAP1', 'Gene', '8314', (13, 17))	('BAP1', 'Gene', (218, 222))	('function', 'MPA', (177, 185))	('loss', 'NegReg', (164, 168))	('BAP1', 'Gene', '8314', (172, 176))
51679	32028647	However, it was reported that these additional structural variants were all associated with low BAP1 mRNA expression, therefore mRNA expression levels should not mis-classify these additional mutations.	('variants', 'Var', (58, 66))	('BAP1', 'Gene', (96, 100))	('low', 'NegReg', (92, 95))	('BAP1', 'Gene', '8314', (96, 100))
51686	32028647	Table S1: Mean BAP1 mRNA levels in UM and CM are correlated with copy number of BAP1 gene.	('CM', 'Disease', 'MESH:C562393', (42, 44))	('UM', 'Disease', 'MESH:C536494', (35, 37))	('BAP1', 'Gene', '8314', (80, 84))	('BAP1', 'Gene', '8314', (15, 19))	('BAP1', 'Gene', (80, 84))	('copy number', 'Var', (65, 76))	('BAP1', 'Gene', (15, 19))
51687	32028647	BAP1 amplification predicts better overall survival comparing to diploids.	('BAP1', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('better', 'PosReg', (28, 34))	('BAP1', 'Gene', '8314', (0, 4))	('overall survival', 'MPA', (35, 51))
51704	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('ligand', 'molecular_function', 'GO:0005488', ('79', '85'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mismatch-repair', 'biological_process', 'GO:0006298', ('113', '128'))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
51706	30072739	Somatic mutations in oncogenes and tumor suppressors represent the most classic biomarkers as they are the main direct drivers of cancer progression .	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (35, 40))	('oncogenes', 'Gene', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Somatic mutations', 'Var', (0, 17))
51709	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', (151, 157))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
51719	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))
51733	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('Cajal body', 'cellular_component', 'GO:0015030', ('185', '195'))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
51738	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('snoRNA', 'Gene', (19, 25))	('C/D', 'Var', (15, 18))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
51748	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('300.13 +- 4.21', 'Var', (112, 126))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
51830	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('snoRNA', 'cellular_component', 'GO:0005733', ('72', '78'))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('expression', 'MPA', (19, 29))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('snoRNA', 'Gene', '85390', (72, 78))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))
51831	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('snoRNA', 'Gene', (62, 68))	('shorter', 'NegReg', (91, 98))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('snoRNA', 'cellular_component', 'GO:0005733', ('62', '68'))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('sarcoma', 'Disease', (153, 160))	('SNORD145', 'Var', (47, 55))	('kidney clear cell carcinoma', 'Disease', (117, 144))	('sdRNAs', 'MPA', (35, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('survival times', 'CPA', (99, 113))	('snoRNA', 'Gene', '85390', (62, 68))
51832	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
51850	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
51861	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))	('splicing', 'biological_process', 'GO:0045292', ('77', '85'))
51888	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
51890	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('GSE33858', 'Var', (52, 60))	('EBI', 'Gene', '6907', (150, 153))	('MTAB', 'molecular_function', 'GO:0047152', ('74', '78'))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
51916	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('snoRNA', 'Gene', (197, 203))	('snoRNA', 'cellular_component', 'GO:0005733', ('197', '203'))	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', '85390', (197, 203))
51917	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
51920	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
51926	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'cellular_component', 'GO:0005733', ('50', '56'))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
51931	12778069	Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas Uveal melanoma is the most frequent primary intraocular tumour in Caucasian adults, having an annual incidence rate of 0.7 per 100 000 people (Prescher et al, 1996).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (65, 84))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (65, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Disease', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('uveal melanomas', 'Disease', 'MESH:C536494', (34, 49))	('cutaneous melanomas', 'Disease', (65, 84))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('uveal melanoma', 'Phenotype', 'HP:0007716', (34, 48))	('uveal melanomas', 'Phenotype', 'HP:0007716', (34, 49))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('uveal melanomas', 'Disease', (34, 49))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('intraocular tumour', 'Disease', (129, 147))	('mutations', 'Var', (21, 30))	('people', 'Species', '9606', (220, 226))	('intraocular tumour', 'Disease', 'MESH:D064090', (129, 147))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (85, 99))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('BRAF', 'Gene', '673', (11, 15))	('Absence', 'NegReg', (0, 7))	('BRAF', 'Gene', (11, 15))
51938	12778069	It has recently been reported that a large proportion of cutaneous melanoma tumours contain activating oncogenic mutations in the BRAF gene (Davies et al, 2002).	('BRAF', 'Gene', '673', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('BRAF', 'Gene', (130, 134))	('mutations', 'Var', (113, 122))	('cutaneous melanoma tumours', 'Disease', (57, 83))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanoma tumours', 'Disease', 'MESH:C562393', (57, 83))	('activating', 'PosReg', (92, 102))
51940	12778069	Genetic alterations to key components of this pathway are known to contribute to the development of many cancers (Pollock and Meltzer, 2002).	('Genetic alterations', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Pollock', 'Species', '8060', (114, 121))	('contribute', 'Reg', (67, 77))
51941	12778069	Activating RAS point mutations are known to be found in more than 30% of human tumours, predominantly pancreatic, colonic, and in up to 36% of cutaneous melanomas (Demunter et al, 2001).	('Activating', 'PosReg', (0, 10))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (143, 162))	('RAS', 'Gene', (11, 14))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('cutaneous melanomas', 'Disease', (143, 162))	('tumours', 'Disease', (79, 86))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (73, 78))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('colonic', 'Disease', (114, 121))	('pancreatic', 'Disease', (102, 112))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (143, 162))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('point mutations', 'Var', (15, 30))
51942	12778069	BRAF is a gene that is regulated by RAS binding, and was shown to have missense mutations in 66% of primary melanoma tumours, 59% of melanoma cell lines, and 80% of melanoma short-term cultures (Brose et al, 2002; Davies et al, 2002).	('missense mutations', 'Var', (71, 89))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma tumours', 'Disease', 'MESH:D008545', (108, 124))	('melanoma tumours', 'Disease', (108, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('BRAF', 'Gene', '673', (0, 4))	('binding', 'molecular_function', 'GO:0005488', ('40', '47'))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
51943	12778069	Mutations have also been detected in up to 82% of cutaneous melanocytic nevi (Pollock et al, 2003).	('Pollock', 'Species', '8060', (78, 85))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('cutaneous melanocytic nevi', 'Disease', (50, 76))	('Mutations', 'Var', (0, 9))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (60, 76))	('detected', 'Reg', (25, 33))
51945	12778069	This makes BRAF an interesting candidate gene to screen in uveal melanoma tumours because of BRAF mutation being a potential mechanism for the activation of this pathway, and the fact that BRAF mutations are not thought to be related to the effects of UV light (Davies et al, 2002).	('uveal melanoma tumours', 'Disease', (59, 81))	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (189, 193))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('mutation', 'Var', (98, 106))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('uveal melanoma tumours', 'Disease', 'MESH:C536494', (59, 81))	('activation', 'PosReg', (143, 153))	('BRAF', 'Gene', (189, 193))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('BRAF', 'Gene', '673', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
51946	12778069	BRAF mutations were predominantly found in two small regions of the kinase domain of the BRAF molecule.	('BRAF', 'Gene', (89, 93))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', '673', (0, 4))	('found', 'Reg', (34, 39))	('BRAF', 'Gene', (0, 4))
51947	12778069	The majority of the mutations were a single T A base substitution at nucleotide 1796 in exon 15 of the BRAF gene, and in some of the adjacent codons.	('mutations', 'Var', (20, 29))	('BRAF', 'Gene', (103, 107))	('BRAF', 'Gene', '673', (103, 107))
51955	12778069	As a positive control, the cutaneous melanoma cell-line SK-MEL-28 DNA was used, that was known to contain the exon 15 T1796A (V599E) mutation (Davies et al, 2002).	('SK-MEL-28', 'CellLine', 'CVCL:0526', (56, 65))	('cutaneous melanoma', 'Disease', (27, 45))	('V599E', 'Mutation', 'p.V599E', (126, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('T1796A (V599E', 'Var', (118, 131))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('T1796A', 'Mutation', 'c.1796T>A', (118, 124))
51957	12778069	Particular attention was given to the sequence around the two small regions of the kinase domain of the BRAF molecule located in exons 11 and 15 that contain all of the published mutations.	('BRAF', 'Gene', (104, 108))	('BRAF', 'Gene', '673', (104, 108))	('mutations', 'Var', (179, 188))
51958	12778069	The SK-MEL-28 cell-line exon 15 T1796A (V599E) mutation was detected by sequencing, and the same mutation was also detected in two-thirds of the skin melanoma tumours studied.	('V599E', 'Mutation', 'p.V599E', (40, 45))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('T1796A', 'Var', (32, 38))	('skin melanoma tumours', 'Disease', 'MESH:D012878', (145, 166))	('skin melanoma tumours', 'Disease', (145, 166))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (4, 13))	('T1796A', 'Mutation', 'c.1796T>A', (32, 38))
51959	12778069	This result was expected as Davies et al (2002) had shown that 66% of the malignant melanoma tumours screened had BRAF mutations, and predominantly the T1796A mutation.	('T1796A', 'Mutation', 'c.1796T>A', (152, 158))	('malignant melanoma tumours', 'Disease', (74, 100))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('T1796A', 'Var', (152, 158))	('malignant melanoma tumours', 'Disease', 'MESH:D008545', (74, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('mutations', 'Var', (119, 128))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
51964	12778069	All previously reported mutations have been concentrated to these two hotspot regions in the BRAF kinase domain, hence, mutations in different regions of the molecule are unlikely to be able to activate the oncogene in such a strong manner.	('BRAF', 'Gene', (93, 97))	('mutations', 'Var', (24, 33))	('BRAF', 'Gene', '673', (93, 97))	('mutations', 'Var', (120, 129))
51968	12778069	Epigenetic mechanisms of gene inactivation may play a more important role in this tumour.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('Epigenetic', 'Var', (0, 10))	('gene inactivation', 'Var', (25, 42))
51969	12778069	If the RAS/RAF pathway is activated in uveal melanoma, then it is unlikely to be because of activating mutations in RAS or B-RAF, but other members of this pathway have yet to be studied, including A-RAF, C-RAF (RAF1), and GAP1.	('RAF', 'Gene', (11, 14))	('B-RAF', 'Gene', '673', (123, 128))	('RAF1', 'Gene', (212, 216))	('RAF', 'Gene', '22882', (207, 210))	('RAF', 'Gene', '22882', (200, 203))	('mutations', 'Var', (103, 112))	('RAF', 'Gene', (200, 203))	('B-RAF', 'Gene', (123, 128))	('RAF', 'Gene', (207, 210))	('C-RAF', 'Gene', '5894', (205, 210))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('RAS', 'Gene', (116, 119))	('A-RAF', 'Gene', '369', (198, 203))	('RAF', 'Gene', '22882', (212, 215))	('uveal melanoma', 'Disease', 'MESH:C536494', (39, 53))	('RAF', 'Gene', '22882', (125, 128))	('activated', 'PosReg', (26, 35))	('uveal melanoma', 'Disease', (39, 53))	('RAF', 'Gene', (212, 215))	('RAF', 'Gene', '22882', (11, 14))	('C-RAF', 'Gene', (205, 210))	('RAF1', 'Gene', '5894', (212, 216))	('uveal melanoma', 'Phenotype', 'HP:0007716', (39, 53))	('RAF', 'Gene', (125, 128))	('A-RAF', 'Gene', (198, 203))
51973	29138479	Previous studies have provided evidence that YAP can contribute to the metastatic behavior of melanoma, since specific knockdown of YAP leads to reduced metastatic and invasive capacity in vitro.	('reduced', 'NegReg', (145, 152))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('YAP', 'Gene', (132, 135))	('knockdown', 'Var', (119, 128))
51997	29138479	Furthermore, it has been revealed that YAP plays an essential role in Gq/11-induced tumorigenesis and that YAP can be treated as a potential drug target for uveal melanoma (UM) accompanied by mutations in GNAQ or GNA11.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Gq/11', 'Chemical', '-', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('UM', 'Phenotype', 'HP:0007716', (173, 175))	('GNA11', 'Gene', (213, 218))	('accompanied', 'Reg', (177, 188))	('GNAQ', 'Gene', '2776', (205, 209))	('tumor', 'Disease', (84, 89))	('GNA11', 'Gene', '2767', (213, 218))	('uveal melanoma', 'Phenotype', 'HP:0007716', (157, 171))	('uveal melanoma', 'Disease', 'MESH:C536494', (157, 171))	('mutations', 'Var', (192, 201))	('GNAQ', 'Gene', (205, 209))	('uveal melanoma', 'Disease', (157, 171))
52004	29138479	To investigate the relationship between YAP and LRP1, we first knocked down YAP and LRP1 in the A375 cells and MUM-2B cells.	('MUM-2', 'Gene', (111, 116))	('A375', 'CellLine', 'CVCL:0132', (96, 100))	('YAP', 'Gene', (76, 79))	('knocked down', 'Var', (63, 75))	('UM', 'Phenotype', 'HP:0007716', (112, 114))	('LRP1', 'Gene', (84, 88))	('MUM-2', 'Gene', '9589', (111, 116))
52005	29138479	We found that knockdown of YAP resulted in an inhibition of cell proliferation in A375 cells and MUM-2B cells, as measured by an MTT-based assay (Figs 1a and 2a).	('YAP', 'Gene', (27, 30))	('MTT', 'Chemical', 'MESH:C070243', (129, 132))	('A375', 'CellLine', 'CVCL:0132', (82, 86))	('MUM-2', 'Gene', (97, 102))	('inhibition', 'NegReg', (46, 56))	('cell proliferation in A375 cells', 'CPA', (60, 92))	('knockdown', 'Var', (14, 23))	('UM', 'Phenotype', 'HP:0007716', (98, 100))	('MUM-2', 'Gene', '9589', (97, 102))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('46', '78'))
52006	29138479	Moreover, knockdown of YAP increased caspase-3/7 activity compared to the control (Figs 1c and 2c).	('activity', 'MPA', (49, 57))	('increased', 'PosReg', (27, 36))	('caspase-3', 'Gene', (37, 46))	('caspase-3', 'Gene', '836', (37, 46))	('YAP', 'Gene', (23, 26))	('knockdown', 'Var', (10, 19))
52007	29138479	As expected, knockdown of LRP1 also led to an increase in Caspase-3/7 activity (Figs 1d,e and 2d,e).	('Caspase-3', 'Gene', (58, 67))	('activity', 'MPA', (70, 78))	('increase', 'PosReg', (46, 54))	('Caspase-3', 'Gene', '836', (58, 67))	('LRP1', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
52019	29138479	We found that knocking YAP down led to a significantly increased caspase-3/7 activity, and such an effect could be partially reversed by simultaneous overexpression of LRP1 in A375 cells (Fig.	('LRP1', 'Gene', (168, 172))	('knocking', 'Var', (14, 22))	('caspase-3', 'Gene', '836', (65, 74))	('increased', 'PosReg', (55, 64))	('A375', 'CellLine', 'CVCL:0132', (176, 180))	('activity', 'MPA', (77, 85))	('YAP', 'Gene', (23, 26))	('caspase-3', 'Gene', (65, 74))
52021	29138479	Moreover, we revealed that the reduced cell proliferation and colony formation caused by knocking down YAP could also be partially reversed by simultaneous overexpression of LRP1, suggesting that the pro-tumorigenic function of YAP may rely on LRP1 (Fig.	('colony formation', 'CPA', (62, 78))	('formation', 'biological_process', 'GO:0009058', ('69', '78'))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('YAP', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cell proliferation', 'biological_process', 'GO:0008283', ('39', '57'))	('tumor', 'Disease', (204, 209))	('cell proliferation', 'CPA', (39, 57))	('knocking down', 'Var', (89, 102))
52023	29138479	To further investigate whether knockdown of YAP or LRP1 could inhibit melanoma growth in vivo, A375 and MUM-2B cells were transfected with GFP-sh/YAP-sh/YAP-sh + LRP1-FLAG to produce subcutaneous tumors in athymic nude mice (Fig.	('MUM-2', 'Gene', (104, 109))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (183, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('nude mice', 'Species', '10090', (214, 223))	('melanoma growth', 'Disease', (70, 85))	('GFP-sh/YAP-sh/YAP-sh', 'Var', (139, 159))	('subcutaneous tumors', 'Disease', (183, 202))	('melanoma growth', 'Disease', 'MESH:D008545', (70, 85))	('UM', 'Phenotype', 'HP:0007716', (105, 107))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('inhibit', 'NegReg', (62, 69))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (183, 202))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('A375', 'CellLine', 'CVCL:0132', (95, 99))	('knockdown', 'Var', (31, 40))	('MUM-2', 'Gene', '9589', (104, 109))
52046	29138479	Ultimately, we identified that knockdown of the LRP1 protein could inhibit proliferation and metastasis of melanoma cells, the same effect produced by transfecting the YAP-sh plasmid into melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('inhibit', 'NegReg', (67, 74))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('LRP1', 'Gene', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('protein', 'Protein', (53, 60))	('melanoma', 'Disease', (188, 196))	('knockdown', 'Var', (31, 40))
52052	29138479	A study has revealed that YAP can be a potential therapeutic strategy in uveal melanoma with mutated GNAQ and GNA11.	('GNA11', 'Gene', '2767', (110, 115))	('uveal melanoma', 'Disease', 'MESH:C536494', (73, 87))	('mutated', 'Var', (93, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (73, 87))	('uveal melanoma', 'Disease', (73, 87))	('GNAQ', 'Gene', '2776', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('GNA11', 'Gene', (110, 115))	('GNAQ', 'Gene', (101, 105))
52055	29138479	Therefore, LRP1 may be a potentially feasible protein to therapeutically target in the treatment of melanoma with mutated YAP.	('YAP', 'Gene', (122, 125))	('LRP1', 'Gene', (11, 15))	('mutated', 'Var', (114, 121))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
52071	29138479	The primary antibodies included anti-YAP (CST, Boston, MA, USA, #4912), anti-LRP1 (Epitomics, Burlingame, California, MA, USA, #2703) and anti-GAPDH (CST, #5714).	('GAPDH', 'Gene', (143, 148))	('anti-YAP', 'Var', (32, 40))	('anti-LRP1', 'Var', (72, 81))	('GAPDH', 'Gene', '2597', (143, 148))
52089	22267972	A pseudo-metastatic model of uveal melanoma to the liver was developed in NOD/SCID/IL2Rgamma null mice and the study of mda-9/syntenin expression in primary and metastatic lesions revealed higher mda-9/syntenin in metastases.	('mda-9/syntenin', 'Var', (196, 210))	('SCID', 'Gene', '19090', (78, 82))	('uveal melanoma to the liver', 'Disease', 'MESH:C536494', (29, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('IL2', 'molecular_function', 'GO:0005134', ('83', '86'))	('metastases', 'Disease', (214, 224))	('SCID', 'Gene', (78, 82))	('metastases', 'Disease', 'MESH:D009362', (214, 224))	('higher', 'PosReg', (189, 195))	('uveal melanoma to the liver', 'Disease', (29, 56))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('mice', 'Species', '10090', (98, 102))
52091	22267972	Moreover, silencing of SDCBP in mda-9/syntenin-high uveal melanoma cells inhibited the hepatocyte growth factor (HGF)-triggered invasion of matrigel membranes and inhibited the activation of FAK, AKT and Src.	('uveal melanoma', 'Disease', (52, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (52, 66))	('HGF', 'Gene', '3082', (113, 116))	('SDCBP', 'Gene', '6386', (23, 28))	('inhibited', 'NegReg', (163, 172))	('HGF', 'Gene', (113, 116))	('uveal melanoma', 'Phenotype', 'HP:0007716', (52, 66))	('AKT', 'Gene', (196, 199))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('87', '111'))	('inhibited', 'NegReg', (73, 82))	('FAK', 'molecular_function', 'GO:0004717', ('191', '194'))	('Src', 'Gene', (204, 207))	('FAK', 'Gene', (191, 194))	('SDCBP', 'Gene', (23, 28))	('AKT', 'Gene', '207', (196, 199))	('hepatocyte growth factor', 'Gene', '3082', (87, 111))	('Src', 'Gene', '6714', (204, 207))	('silencing', 'Var', (10, 19))	('FAK', 'Gene', '5747', (191, 194))	('invasion of matrigel', 'CPA', (128, 148))	('hepatocyte growth factor', 'Gene', (87, 111))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
52105	22267972	high-risk) tumors, was later reported by the same authors as the top class discriminating gene, the loss of which causes an increase in the rate of liver metastasis in a transgenic mouse model of ocular melanoma.	('increase', 'PosReg', (124, 132))	('loss', 'Var', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('liver metastasis', 'CPA', (148, 164))	('ocular melanoma', 'Phenotype', 'HP:0007716', (196, 211))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('ocular melanoma', 'Disease', 'MESH:D008545', (196, 211))	('mouse', 'Species', '10090', (181, 186))	('ocular melanoma', 'Disease', (196, 211))
52114	22267972	This possibility is also supported by the finding that mda-9/syntenin is involved in cell migration of uveal melanoma cells in culture and in invasiveness and activation of focal adhesion kinase (FAK), AKT and Src triggered by HGF.	('focal adhesion kinase', 'Gene', (173, 194))	('cell migration', 'CPA', (85, 99))	('FAK', 'Gene', '5747', (196, 199))	('HGF', 'Gene', (227, 230))	('focal adhesion', 'cellular_component', 'GO:0005925', ('173', '187'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('activation', 'PosReg', (159, 169))	('uveal melanoma', 'Disease', (103, 117))	('AKT', 'Gene', (202, 205))	('invasiveness', 'CPA', (142, 154))	('focal adhesion kinase', 'Gene', '5747', (173, 194))	('Src', 'Gene', (210, 213))	('FAK', 'molecular_function', 'GO:0004717', ('196', '199'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('mda-9/syntenin', 'Var', (55, 69))	('Src', 'Gene', '6714', (210, 213))	('FAK', 'Gene', (196, 199))	('cell migration', 'biological_process', 'GO:0016477', ('85', '99'))	('AKT', 'Gene', '207', (202, 205))	('HGF', 'Gene', '3082', (227, 230))
52136	22267972	Gel was then blotted to nitrocellulose membranes (Hybond-C Extra, Amersham GE Healthcare, Little Chalfont, UK) according to standard procedures and stained with antibodies to mda-9/syntenin, HDAC1, Actin (Sigma-Aldrich), anti-FAK(pY397), anti-Src (pY418) and anti-Src pan (Invitrogen), and anti-FAK (Cell Signaling), anti-phospho-AKT (Ser473), anti-AKT (pan), anti-phospho-MET (Tyr1234/1235) and anti-MET (L41G3) (Cell Signaling).	('HDAC1', 'Gene', (191, 196))	('FAK', 'Gene', (226, 229))	('Src', 'Gene', '6714', (264, 267))	('AKT', 'Gene', (330, 333))	('Tyr1234/1235', 'Var', (378, 390))	('FAK', 'molecular_function', 'GO:0004717', ('295', '298'))	('anti-MET (L41G3', 'Var', (396, 411))	('HDAC1', 'Gene', '3065', (191, 196))	('AKT', 'Gene', '207', (349, 352))	('FAK', 'Gene', '5747', (226, 229))	('anti-phospho-MET', 'Var', (360, 376))	('Src', 'Gene', (243, 246))	('FAK', 'Gene', (295, 298))	('Ser', 'cellular_component', 'GO:0005790', ('335', '338'))	('AKT', 'Gene', '207', (330, 333))	('Src', 'Gene', '6714', (243, 246))	('FAK', 'Gene', '5747', (295, 298))	('FAK', 'molecular_function', 'GO:0004717', ('226', '229'))	('Src', 'Gene', (264, 267))	('Signaling', 'biological_process', 'GO:0023052', ('419', '428'))	('Signaling', 'biological_process', 'GO:0023052', ('305', '314'))	('AKT', 'Gene', (349, 352))
52163	22267972	High SDCBP mRNA expression conferred a risk with Odds Ratio of 9.0 (p = 0.01, IC 95% 1.46-55.48) for recurrence, which was as strong as monosomy 3 (OR: 12.50, p = 0.01, IC 95% 1.31-119.33), in our cohort.	('SDCBP', 'Gene', (5, 10))	('mRNA', 'MPA', (11, 15))	('SDCBP', 'Gene', '6386', (5, 10))	('High', 'Var', (0, 4))
52169	22267972	Expression of SDCBP was significantly higher (p = 0.009) in class-2 (high risk) than in class-1 (low risk) cases (Fig.	('SDCBP', 'Gene', '6386', (14, 19))	('Expression', 'MPA', (0, 10))	('class-2', 'Var', (60, 67))	('higher', 'PosReg', (38, 44))	('SDCBP', 'Gene', (14, 19))
52186	22267972	Nine patients with high-mda-9/syntenin tumors developed metastatic progression, while among the fourteen patients of the mda-9/syntenin-low group only two developed metastasis.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('metastatic progression', 'CPA', (56, 78))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('high-mda-9/syntenin', 'Var', (19, 38))
52207	22267972	The 92.1 cell line, which expresses high levels of mda-9/syntenin and the HGF receptor c-MET (Figure 8A) invaded the matrigel membrane in response to MG63 conditioned medium or to recombinant HGF (Figure 8B).	('c-MET', 'Gene', (87, 92))	('HGF', 'Gene', '3082', (74, 77))	('HGF', 'Gene', (192, 195))	('mda-9/syntenin', 'Var', (51, 65))	('c-MET', 'Gene', '4233', (87, 92))	('HGF', 'Gene', '3082', (192, 195))	('membrane', 'cellular_component', 'GO:0016020', ('126', '134'))	('MG63', 'Chemical', '-', (150, 154))	('HGF', 'Gene', (74, 77))
52208	22267972	SDCBP silencing significantly inhibited invasion triggered by both stimuli (Figure 8C).	('SDCBP', 'Gene', '6386', (0, 5))	('invasion', 'CPA', (40, 48))	('inhibited', 'NegReg', (30, 39))	('SDCBP', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))
52214	22267972	Silencing the expression of SDCBP by siRNA strongly inhibited constitutive and HGF induced Fak phosphorylation (45 and 50% respectively) (Fig.	('SDCBP', 'Gene', '6386', (28, 33))	('Fak', 'Gene', (91, 94))	('constitutive', 'MPA', (62, 74))	('HGF', 'Gene', (79, 82))	('expression', 'MPA', (14, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('inhibited', 'NegReg', (52, 61))	('Fak', 'Gene', '5747', (91, 94))	('HGF', 'Gene', '3082', (79, 82))	('Silencing', 'Var', (0, 9))	('Fak', 'molecular_function', 'GO:0004717', ('91', '94'))	('SDCBP', 'Gene', (28, 33))
52215	22267972	In addition, mda-9/syntenin silencing also partially inhibited constitutive and/or HGF-promoted Src (15 and 30% respectively) and AKT phosphorylation (20%) in 92.1 cells (Fig.	('inhibited', 'NegReg', (53, 62))	('constitutive', 'MPA', (63, 75))	('Src', 'Gene', (96, 99))	('AKT', 'Gene', '207', (130, 133))	('Src', 'Gene', '6714', (96, 99))	('HGF', 'Gene', (83, 86))	('phosphorylation', 'biological_process', 'GO:0016310', ('134', '149'))	('silencing', 'Var', (28, 37))	('HGF', 'Gene', '3082', (83, 86))	('AKT', 'Gene', (130, 133))	('mda-9/syntenin', 'Gene', (13, 27))
52224	22267972	Our results provide the first evidence that mda-9/syntenin is expressed in human uveal melanoma and that high level of expression of mda-9/syntenin conferres a high risk of metastatic recurrence.	('mda-9/syntenin', 'Var', (133, 147))	('uveal melanoma', 'Disease', (81, 95))	('metastatic recurrence', 'CPA', (173, 194))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('human', 'Species', '9606', (75, 80))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
52227	22267972	The possible role of mda-9/syntenin expression and metastatic progression was demonstrated in cutaneous melanoma, where mda-9/syntenin, through interaction with c-Src/FAK, activates the p38 MAPK/NFkB pathway with subsequent induction of genes involved in migration and invasion.	('activates', 'PosReg', (172, 181))	('interaction', 'Interaction', (144, 155))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('migration', 'CPA', (255, 264))	('MAPK', 'molecular_function', 'GO:0004707', ('190', '194'))	('FAK', 'molecular_function', 'GO:0004717', ('167', '170'))	('induction', 'PosReg', (224, 233))	('cutaneous melanoma', 'Disease', (94, 112))	('FAK', 'Gene', '5747', (167, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('c-Src', 'Gene', (161, 166))	('FAK', 'Gene', (167, 170))	('genes', 'Gene', (237, 242))	('c-Src', 'Gene', '6714', (161, 166))	('p38 MAPK/NFkB pathway', 'Pathway', (186, 207))	('mda-9/syntenin', 'Var', (120, 134))
52228	22267972	In the present study, a correlation of high SDCBP gene expression with metastatic progression was suggested by the analysis of the gene expression profile of 29 primary uveal melanomas.	('uveal melanomas', 'Disease', 'MESH:C536494', (169, 184))	('high', 'Var', (39, 43))	('uveal melanoma', 'Phenotype', 'HP:0007716', (169, 183))	('uveal melanomas', 'Phenotype', 'HP:0007716', (169, 184))	('gene expression', 'biological_process', 'GO:0010467', ('131', '146'))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('SDCBP', 'Gene', (44, 49))	('uveal melanomas', 'Disease', (169, 184))	('SDCBP', 'Gene', '6386', (44, 49))	('metastatic progression', 'CPA', (71, 93))
52229	22267972	Indeed we found that high SDCBP expression conferred a significantly increased risk of metastatic recurrence (Odds ratio of 11.70 p<0,005) in our cohort.	('SDCBP', 'Gene', '6386', (26, 31))	('SDCBP', 'Gene', (26, 31))	('high', 'Var', (21, 25))	('metastatic recurrence', 'CPA', (87, 108))
52237	22267972	It is of note that a high level of mda-9/syntenin protein in primary tumors was significantly related to earlier metastatic progression although, further studies involving larger groups of patients are needed to confirm this possibility.	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('earlier metastatic progression although', 'CPA', (105, 144))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mda-9/syntenin', 'Var', (35, 49))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('primary tumors', 'Disease', (61, 75))	('patients', 'Species', '9606', (189, 197))	('related', 'Reg', (94, 101))
52241	22267972	Though the possible role of mda-9/syntenin in nuclear functions has yet to be determined in uveal melanoma, recent findings indicated that mda-9/syntenin colocalizes with the SOX-4 transcription factor in the nucleus and stabilizes its expression in different tumor cells.	('tumor', 'Disease', (260, 265))	('colocalizes', 'Interaction', (154, 165))	('SOX-4', 'Gene', '6659', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('transcription factor', 'molecular_function', 'GO:0000981', ('181', '201'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (92, 106))	('mda-9/syntenin', 'Var', (139, 153))	('uveal melanoma', 'Disease', (92, 106))	('uveal melanoma', 'Disease', 'MESH:C536494', (92, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('transcription', 'biological_process', 'GO:0006351', ('181', '194'))	('SOX-4', 'Gene', (175, 180))	('expression', 'MPA', (236, 246))	('nucleus', 'cellular_component', 'GO:0005634', ('209', '216'))
52247	22267972	This hypothesis would corroborate the finding of a worse prognosis for those patients expressing high levels of mda-9/syntenin in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('high levels', 'Var', (97, 108))	('patients', 'Species', '9606', (77, 85))	('mda-9/syntenin', 'Var', (112, 126))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
52248	22267972	However, incubation of human uveal melanoma cell lines with mouse liver extracts did not increase mda-9/syntenin expression (data not shown) suggesting that high mda-9/syntenin expressing cells are more prone to metastasize.	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('prone', 'PosReg', (203, 208))	('mouse', 'Species', '10090', (60, 65))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('human', 'Species', '9606', (23, 28))	('metastasize', 'CPA', (212, 223))	('high mda-9/syntenin expressing', 'Var', (157, 187))
52249	22267972	In addition, our present observation that silencing of SDCBP by siRNA inhibits migration and invasiveness of uveal melanoma cells, suggests that mda-9/syntenin is involved in the metastatic dissemination.	('silencing', 'Var', (42, 51))	('SDCBP', 'Gene', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('inhibits', 'NegReg', (70, 78))	('SDCBP', 'Gene', '6386', (55, 60))	('invasiveness of uveal melanoma', 'Disease', 'MESH:C536494', (93, 123))	('invasiveness of uveal melanoma', 'Disease', (93, 123))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))
52253	22267972	Regarding the molecular mechanisms involved, we found that inhibition of mda-9/syntenin expression reduces the activation of FAK, Src and AKT mediated by HGF, whereas its overexpression has opposite effects.	('activation', 'PosReg', (111, 121))	('HGF', 'Gene', (154, 157))	('AKT', 'Gene', (138, 141))	('HGF', 'Gene', '3082', (154, 157))	('Src', 'Gene', (130, 133))	('FAK', 'Gene', '5747', (125, 128))	('Src', 'Gene', '6714', (130, 133))	('mda-9/syntenin', 'Gene', (73, 87))	('FAK', 'molecular_function', 'GO:0004717', ('125', '128'))	('inhibition', 'Var', (59, 69))	('reduces', 'NegReg', (99, 106))	('FAK', 'Gene', (125, 128))	('AKT', 'Gene', '207', (138, 141))
52258	31317143	Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma Copper (Cu) is a tightly regulated micronutrient that functions as a structural or catalytic cofactor for specific proteins essential for a diverse array of biological processes.	('BRAF', 'Gene', '673', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('BRAF', 'Gene', (68, 72))	('ATOX1', 'Gene', '475', (17, 22))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('Copper', 'Chemical', 'MESH:D003300', (100, 106))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('ATOX1', 'Gene', (17, 22))	('mutation-positive', 'Var', (73, 90))	('MAPK signaling', 'biological_process', 'GO:0000165', ('39', '53'))	('Cu', 'Chemical', 'MESH:D003300', (108, 110))
52262	31317143	We previously found that Cu is required for BRAFV600E-driven MAPK signaling and melanomagenesis.	('MAPK signaling', 'biological_process', 'GO:0000165', ('61', '75'))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('P', 'Chemical', 'MESH:D010758', (63, 64))	('melanoma', 'Disease', (80, 88))	('BRAFV600E-driven', 'Var', (44, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('Cu', 'Chemical', 'MESH:D003300', (25, 27))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
52265	31317143	Taken together, these results suggest that targeting the Cu chaperone ATOX1 as a novel therapeutic angle in BRAFV600E-driven melanomas.	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('BRAFV600E-driven', 'Var', (108, 124))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('Cu', 'Chemical', 'MESH:D003300', (57, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (108, 117))	('melanomas', 'Disease', (125, 134))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))
52269	31317143	The importance of intact Cu homeostatic mechanisms to cell growth control is underscored by the various growth phenotypes associated with aberrant Cu excretion and absorption in Menkes and Wilson disease, respectively.	('Wilson disease', 'Disease', 'MESH:D006527', (189, 203))	('aberrant', 'Var', (138, 146))	('excretion', 'biological_process', 'GO:0007588', ('150', '159'))	('cell growth', 'biological_process', 'GO:0016049', ('54', '65'))	('Wilson disease', 'Disease', (189, 203))	('Wilson disease', 'Phenotype', 'HP:0032102', (189, 203))	('Menkes', 'Disease', (178, 184))	('Cu', 'Chemical', 'MESH:D003300', (147, 149))	('Cu', 'Chemical', 'MESH:D003300', (25, 27))
52280	31317143	Specifically, functional studies revealed that genetic knockdown of ATOX1 reduced the Cu-stimulated growth of NSCLC cell lines.	('Cu', 'Chemical', 'MESH:D003300', (86, 88))	('knockdown', 'Var', (55, 64))	('S', 'Chemical', 'MESH:D013455', (111, 112))	('NSCLC', 'Disease', (110, 115))	('ATOX1', 'Gene', (68, 73))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('reduced', 'NegReg', (74, 81))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
52287	31317143	Given that our previous work demonstrated that genetic ablation of CTR1 or treatment with Cu chelators reduced the growth BRAFV600E-driven melanoma by dampening MAPK pathway activation, we interrogated the importance of ATOX1 in BRAF mutation-positive melanoma.	('activation', 'MPA', (174, 184))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('P', 'Chemical', 'MESH:D010758', (163, 164))	('MAPK pathway', 'Pathway', (161, 173))	('growth', 'MPA', (115, 121))	('BRAF', 'Gene', '673', (229, 233))	('BRAF', 'Gene', (229, 233))	('genetic ablation', 'Var', (47, 63))	('CTR1', 'Gene', (67, 71))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('CTR1', 'Gene', '1317', (67, 71))	('reduced', 'NegReg', (103, 110))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('BRAFV600E', 'Mutation', 'rs113488022', (122, 131))	('dampening', 'NegReg', (151, 160))	('Cu', 'Chemical', 'MESH:D003300', (90, 92))	('BRAF', 'Gene', '673', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('BRAF', 'Gene', (122, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))
52288	31317143	Here we demonstrate that targeting ATOX1 is a novel vulnerability in BRAF mutation-positive melanoma by influencing oncogene addicted kinase signaling.	('influencing', 'Reg', (104, 115))	('oncogene addicted kinase signaling', 'MPA', (116, 150))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('mutation-positive', 'Reg', (74, 91))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('targeting', 'Var', (25, 34))	('BRAF', 'Gene', '673', (69, 73))	('ATOX1', 'Gene', (35, 40))	('BRAF', 'Gene', (69, 73))
52325	31317143	We choose to investigate A375 and WM88 as they harbor oncogenic mutations in the serine/threonine kinase BRAF, which is the most commonly mutated gene in cutaneous melanoma and underlies therapeutic targeting via the FDA-approved small molecule kinase inhibitors dabrafenib and vemurafenib.	('BRAF', 'Gene', '673', (105, 109))	('dabrafenib', 'Chemical', 'MESH:C561627', (263, 273))	('WM88', 'CellLine', 'CVCL:6805', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('BRAF', 'Gene', (105, 109))	('vemurafenib', 'Chemical', 'MESH:D000077484', (278, 289))	('mutations', 'Var', (64, 73))	('cutaneous melanoma', 'Disease', (154, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (154, 172))
52326	31317143	Targeted disruption of ATOX1 with two different sgRNAs significantly reduced the colony formation of A375 and WM88 cells when plated at low density when compared to control (Fig.	('Targeted disruption', 'Var', (0, 19))	('ATOX1', 'Gene', (23, 28))	('WM88', 'CellLine', 'CVCL:6805', (110, 114))	('colony formation of A375', 'CPA', (81, 105))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('reduced', 'NegReg', (69, 76))	('disruption', 'Var', (9, 19))
52328	31317143	In the context of melanoma, oncogenic BRAFV600E constitutively phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, hyperactivating the canonical Mitogen Activated Protein Kinase Pathway (MAPK) to promote uncontrolled melanocytes growth and caner initiation and progression.	('ERK2', 'Gene', (173, 177))	('P', 'Chemical', 'MESH:D010758', (250, 251))	('MAPK', 'molecular_function', 'GO:0004707', ('259', '263'))	('P', 'Chemical', 'MESH:D010758', (235, 236))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('MEK2', 'molecular_function', 'GO:0004708', ('105', '109'))	('MEK1', 'molecular_function', 'GO:0004708', ('96', '100'))	('ERK1', 'molecular_function', 'GO:0004707', ('164', '168'))	('progression', 'CPA', (333, 344))	('MEK1', 'Gene', '5604', (96, 100))	('ERK1', 'Gene', (164, 168))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('ERK1', 'Gene', '5595', (164, 168))	('activates', 'PosReg', (82, 91))	('ERK2', 'molecular_function', 'GO:0004707', ('173', '177'))	('promote', 'PosReg', (268, 275))	('MEK2', 'Gene', (105, 109))	('MEK2', 'Gene', '5605', (105, 109))	('BRAFV600E', 'Var', (38, 47))	('activate', 'PosReg', (151, 159))	('caner initiation', 'CPA', (312, 328))	('ERK2', 'Gene', '5594', (173, 177))	('P', 'Chemical', 'MESH:D010758', (261, 262))	('hyperactivating', 'PosReg', (187, 202))	('uncontrolled melanocytes growth', 'CPA', (276, 307))	('MEK1', 'Gene', (96, 100))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
52329	31317143	Thus, targeting either oncogenic BRAFV600E and the MEK1/2 kinases has proven to be a clinically effective strategy to prolong survival in metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('prolong', 'PosReg', (118, 125))	('MEK1', 'molecular_function', 'GO:0004708', ('51', '55'))	('BRAFV600E', 'Var', (33, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))	('survival', 'MPA', (126, 134))
52330	31317143	Our lab previously established Cu as an essential micronutrient for BRAFV600E-driven MAPK signaling, tumor growth of human melanoma cell lines, and melanomagenesis in a genetically engineered mouse model.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('mouse', 'Species', '10090', (192, 197))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('human', 'Species', '9606', (117, 122))	('melanoma', 'Disease', (148, 156))	('MAPK signaling', 'biological_process', 'GO:0000165', ('85', '99'))	('MAPK', 'molecular_function', 'GO:0004707', ('85', '89'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('BRAFV600E-driven', 'Var', (68, 84))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('Cu', 'Chemical', 'MESH:D003300', (31, 33))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
52331	31317143	Capitalizing on the dependence of oncogenic BRAFV600E for MEK1/2-mediated signaling for growth and survival, we investigated whether canonical MAPK pathway activation was altered in response to genetic knockout of ATOX1.	('activation', 'PosReg', (156, 166))	('MEK1', 'molecular_function', 'GO:0004708', ('58', '62'))	('P', 'Chemical', 'MESH:D010758', (145, 146))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('canonical MAPK pathway', 'Pathway', (133, 155))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('BRAFV600E', 'Var', (44, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
52334	31317143	These data suggest that canonical MAPK pathway activation is specifically diminished in the absence of ATOX1 and may contribute to the reduced growth of BRAF mutation-positive melanoma cells in the absence of ATOX1.	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('canonical MAPK pathway', 'Pathway', (24, 46))	('BRAF', 'Gene', (153, 157))	('diminished', 'NegReg', (74, 84))	('melanoma', 'Disease', (176, 184))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('activation', 'PosReg', (47, 57))	('mutation-positive', 'Var', (158, 175))	('reduced', 'NegReg', (135, 142))	('growth', 'MPA', (143, 149))	('BRAF', 'Gene', '673', (153, 157))	('P', 'Chemical', 'MESH:D010758', (36, 37))
52335	31317143	Cu is required for BRAFV600E-driven MEK1/2 kinase activity through a direct Cu-MEK1/2 interaction, but it remains to be determined whether well-established Cu transport systems participate in Cu loading of these protein kinases.	('MEK1', 'molecular_function', 'GO:0004708', ('36', '40'))	('Cu', 'Chemical', 'MESH:D003300', (156, 158))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('BRAFV600E-driven', 'Var', (19, 35))	('MEK1', 'molecular_function', 'GO:0004708', ('79', '83'))	('kinase activity', 'molecular_function', 'GO:0016301', ('43', '58'))	('MEK1/2 kinase', 'Enzyme', (36, 49))	('BRAFV600E', 'Mutation', 'rs113488022', (19, 28))	('activity', 'MPA', (50, 58))	('Cu', 'Chemical', 'MESH:D003300', (192, 194))	('transport', 'biological_process', 'GO:0006810', ('159', '168'))	('Cu', 'Chemical', 'MESH:D003300', (0, 2))	('Cu', 'Chemical', 'MESH:D003300', (76, 78))
52339	31317143	Thus, ATOX1 is required for BRAFV600E-mutant melanoma MAPK pathway activation indirectly of a supporting Cu binding of MEK1/2.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('Cu binding', 'molecular_function', 'GO:1903136', ('105', '115'))	('activation', 'PosReg', (67, 77))	('BRAFV600E-mutant', 'Var', (28, 44))	('Cu', 'Chemical', 'MESH:D003300', (105, 107))	('P', 'Chemical', 'MESH:D010758', (56, 57))	('MEK1', 'molecular_function', 'GO:0004708', ('119', '123'))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (28, 37))
52340	31317143	Previous studies have suggested that Cu-chelators used in the treatment of Wilson disease could be exploited in BRAFV600E-driven melanoma as a unique vulnerability by forestalling MAPK signaling.	('MAPK signaling', 'MPA', (180, 194))	('Wilson disease', 'Disease', (75, 89))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('Wilson disease', 'Phenotype', 'HP:0032102', (75, 89))	('P', 'Chemical', 'MESH:D010758', (182, 183))	('Cu', 'Chemical', 'MESH:D003300', (37, 39))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('BRAFV600E-driven', 'Var', (112, 128))	('MAPK', 'molecular_function', 'GO:0004707', ('180', '184'))	('Wilson disease', 'Disease', 'MESH:D006527', (75, 89))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))	('MAPK signaling', 'biological_process', 'GO:0000165', ('180', '194'))	('forestalling', 'NegReg', (167, 179))
52341	31317143	In agreement, we hypothesized that treatment with the small molecule inhibitor DCAC50, which was previously shown to inhibit ATOX1 and CCS by blocking Cu transfer between these chaperones and downstream interacting target proteins, would acutely inhibit ATOX1 and reduce the growth of melanoma cell lines dependent on BRAFV600E-mediated activation of the MAPK pathway.	('BRAFV600E-mediated', 'Var', (318, 336))	('inhibit', 'NegReg', (246, 253))	('ATOX1', 'MPA', (254, 259))	('CCS', 'molecular_function', 'GO:0052728', ('135', '138'))	('CCS', 'Gene', (135, 138))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('Cu', 'Chemical', 'MESH:D003300', (151, 153))	('DCAC50', 'Gene', (79, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('355', '359'))	('inhibit', 'NegReg', (117, 124))	('blocking', 'NegReg', (142, 150))	('DCAC50', 'Chemical', '-', (79, 85))	('Cu transfer between these chaperones', 'MPA', (151, 187))	('CCS', 'Gene', '9973', (135, 138))	('CCS', 'molecular_function', 'GO:0052727', ('135', '138'))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))	('CCS', 'molecular_function', 'GO:0034019', ('135', '138'))	('growth', 'CPA', (275, 281))	('MAPK pathway', 'Pathway', (355, 367))	('P', 'Chemical', 'MESH:D010758', (357, 358))	('BRAFV600E', 'Mutation', 'rs113488022', (318, 327))	('reduce', 'NegReg', (264, 270))
52343	31317143	Thus, inhibition of ATOX1 with concentrations of the small molecule inhibitor DCAC50 that are known to be selective and effective in reducing the proliferation of NSCLC are equally potent in dampening the growth of BRAF mutant melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('growth', 'MPA', (205, 211))	('melanoma', 'Disease', (227, 235))	('BRAF', 'Gene', (215, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))	('mutant', 'Var', (220, 226))	('dampening', 'NegReg', (191, 200))	('NSCLC', 'Disease', (163, 168))	('DCAC50', 'Gene', (78, 84))	('ATOX1', 'Gene', (20, 25))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('DCAC50', 'Chemical', '-', (78, 84))	('BRAF', 'Gene', '673', (215, 219))	('inhibition', 'NegReg', (6, 16))	('reducing', 'NegReg', (133, 141))
52344	31317143	To address whether DCAC50 mechanistically reduced BRAFV600E-driven melanoma cell line colony formation by solely targeting overexpressed ATOX1, A375 and WM88 melanoma cell lines stably expressing a control sgRNA or two different sgRNAs targeting ATOX1 were treated with increasing concentrations of DCAC50 and growth at low density was evaluated (Fig.	('reduced', 'NegReg', (42, 49))	('DCAC50', 'Chemical', '-', (299, 305))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('melanoma', 'Disease', (67, 75))	('WM88', 'CellLine', 'CVCL:6805', (153, 157))	('DCAC50', 'Chemical', '-', (19, 25))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('BRAFV600E-driven', 'Gene', (50, 66))	('BRAFV600E', 'Mutation', 'rs113488022', (50, 59))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('DCAC50', 'Var', (19, 25))
52346	31317143	Thus, inhibition of BRAFV600E-mutant melanoma cell growth by the small molecule DCAC50 is due in large part to targeting only one of its molecular targets, ATOX1.	('BRAFV600E', 'Mutation', 'rs113488022', (20, 29))	('DCAC50', 'Chemical', '-', (80, 86))	('BRAFV600E-mutant', 'Var', (20, 36))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('DCAC50', 'Gene', (80, 86))
52351	31317143	Since ATOX1 is not responsible for directly delivering Cu to MEK1/2 in cells, the mechanism by which DCAC50 reduced the growth of these cancer cells remained to be determined.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('reduced', 'NegReg', (108, 115))	('DCAC50', 'Chemical', '-', (101, 107))	('growth', 'MPA', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('MEK1', 'molecular_function', 'GO:0004708', ('61', '65'))	('cancer', 'Disease', (136, 142))	('DCAC50', 'Var', (101, 107))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('Cu', 'Chemical', 'MESH:D003300', (55, 57))
52361	31317143	One intriguing hypothesis is that transcription factor dysregulation in melanoma is causing high expression of ATOX1, which is predicted to be regulated by MTF1 and cMYC-MAX both of which have been implicated in melanoma initiation and progression.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('MTF1', 'Gene', (156, 160))	('high', 'PosReg', (92, 96))	('cMYC', 'Gene', '4609', (165, 169))	('transcription', 'biological_process', 'GO:0006351', ('34', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('MTF1', 'Gene', '4520', (156, 160))	('melanoma initiation', 'Disease', 'MESH:D008545', (212, 231))	('transcription factor', 'molecular_function', 'GO:0000981', ('34', '54'))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('dysregulation', 'Var', (55, 68))	('ATOX1', 'Gene', (111, 116))	('cMYC', 'Gene', (165, 169))	('expression', 'MPA', (97, 107))	('melanoma initiation', 'Disease', (212, 231))
52362	31317143	Cutaneous melanoma can be classified genetically based on the frequency of mutations in BRAF, RAS, NF1, and triple-WT established and these four subtypes provided a framework for clinical management of the disease.	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('S', 'Chemical', 'MESH:D013455', (96, 97))	('BRAF', 'Gene', (88, 92))	('RAS', 'Gene', (94, 97))	('BRAF', 'Gene', '673', (88, 92))	('NF1', 'Gene', (99, 102))	('NF1', 'Gene', '4763', (99, 102))	('mutations', 'Var', (75, 84))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
52363	31317143	While BRAFV600E-driven melanoma is the most prevalent alteration, ATOX1 overexpression was detected in all four genomic subtypes of cutaneous melanoma, suggesting a potential unifying mechanism for the observed upregulation and dependence across the cancer.	('BRAFV600E', 'Mutation', 'rs113488022', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('dependence across the cancer', 'Disease', (228, 256))	('cutaneous melanoma', 'Disease', (132, 150))	('melanoma', 'Disease', (23, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('ATOX1', 'Gene', (66, 71))	('dependence across the cancer', 'Disease', 'MESH:D009369', (228, 256))	('BRAFV600E-driven', 'Var', (6, 22))	('overexpression', 'PosReg', (72, 86))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
52365	31317143	Functionally, we established that ATOX1 is required for the growth of BRAF mutation-positive melanoma and its genetic deletion or pharmacologic inhibition is associated with a dampening of oncogenic MAPK pathway activation.	('oncogenic MAPK pathway', 'Pathway', (189, 211))	('dampening', 'NegReg', (176, 185))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('activation', 'PosReg', (212, 222))	('mutation-positive', 'Reg', (75, 92))	('BRAF', 'Gene', '673', (70, 74))	('P', 'Chemical', 'MESH:D010758', (201, 202))	('deletion', 'Var', (118, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('199', '203'))	('BRAF', 'Gene', (70, 74))
52369	31317143	CTR1 knockdown) or pharmacologically (ie.	('CTR1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('CTR1', 'Gene', '1317', (0, 4))
52375	31317143	have provided convincing evidence that loss of ATP7A function either by genetic deletion or pharmacologic inhibition with the gastric proton pump inhibitor omeprazole can reduce oncogenic RAS-mediated transformed cell growth due in large part to elevated ROS levels or block melanomagenesis potentially through tyrosinase degradation.	('ROS levels', 'MPA', (255, 265))	('block', 'NegReg', (269, 274))	('loss', 'Var', (39, 43))	('tyrosinase', 'Gene', (311, 321))	('reduce', 'NegReg', (171, 177))	('genetic deletion', 'Var', (72, 88))	('omeprazole', 'Chemical', 'MESH:D009853', (156, 166))	('degradation', 'biological_process', 'GO:0009056', ('322', '333'))	('tyrosinase', 'Gene', '7299', (311, 321))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('S', 'Chemical', 'MESH:D013455', (257, 258))	('proton pump', 'cellular_component', 'GO:0005889', ('134', '145'))	('elevated ROS levels', 'Phenotype', 'HP:0025464', (246, 265))	('ROS', 'Chemical', '-', (255, 258))	('oncogenic RAS-mediated transformed cell growth', 'CPA', (178, 224))	('elevated', 'PosReg', (246, 254))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('ATP7A', 'Gene', '538', (47, 52))	('ATP7A', 'Gene', (47, 52))	('cell growth', 'biological_process', 'GO:0016049', ('213', '224'))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))
52379	31317143	In conclusion, this study highlights the importance of exploring additional Cu homeostasis machinery in the context of cancer and more specifically, suggests that inhibiting ATOX1 with the small molecule DCAC50 may be a promising strategy for the treatment of BRAF mutation-positive cancer in combination with other MAPK pathway inhibitors.	('DCAC50', 'Gene', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('MAPK', 'molecular_function', 'GO:0004707', ('316', '320'))	('mutation-positive', 'Reg', (265, 282))	('homeostasis', 'biological_process', 'GO:0042592', ('79', '90'))	('cancer', 'Disease', (283, 289))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('DCAC50', 'Chemical', '-', (204, 210))	('BRAF', 'Gene', '673', (260, 264))	('inhibiting', 'Var', (163, 173))	('ATOX1', 'Gene', (174, 179))	('cancer', 'Disease', (119, 125))	('BRAF', 'Gene', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('P', 'Chemical', 'MESH:D010758', (318, 319))	('Cu', 'Chemical', 'MESH:D003300', (76, 78))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
52381	31317143	While aberrant Cu accumulation is associated with cancer initiation and progression, the Cu homeostasis machinery that contributes to cell intrinsic and extrinsic mechanisms necessary for tumorigenesis remains largely undefined.	('tumor', 'Disease', (188, 193))	('associated', 'Reg', (34, 44))	('cancer initiation', 'Disease', 'MESH:D009369', (50, 67))	('aberrant', 'Var', (6, 14))	('cancer initiation', 'Disease', (50, 67))	('Cu', 'Chemical', 'MESH:D003300', (15, 17))	('Cu', 'Chemical', 'MESH:D003300', (89, 91))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('accumulation', 'PosReg', (18, 30))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('homeostasis', 'biological_process', 'GO:0042592', ('92', '103'))
52382	31317143	We present here an analysis of Cu chaperone expression across human cancers that illuminated a novel dependence on ATOX1 for cancer cell growth in the context of BRAF mutation-positive melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cell growth', 'biological_process', 'GO:0016049', ('132', '143'))	('human', 'Species', '9606', (62, 67))	('mutation-positive', 'Var', (167, 184))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cancer', 'Disease', (68, 74))	('BRAF', 'Gene', '673', (162, 166))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('Cu', 'Chemical', 'MESH:D003300', (31, 33))	('melanoma', 'Disease', (185, 193))	('BRAF', 'Gene', (162, 166))
52412	23812018	Briefly, 4-mum tissue sections were dewaxed, washed, and incubated with antibodies against ERalpha (clone 6F11, Novocastra, Newcastle Upon Tyne/UK; dilution 1:35), ERbeta (clone EMR02, Leica Microsystems, Buffalo Grove, IL; dilution 1:100), Androgen Receptor (clone AR441, Dako, Carpinteria, CA; dilution 1:30), and pHH3 (Upstate Millipore, Temecula, CA; dilution 1:400) at room temperature for 15 minutes.	('clone AR441', 'Var', (260, 271))	('Androgen Receptor', 'Gene', '367', (241, 258))	('ERbeta', 'Gene', '2100', (164, 170))	('ERbeta', 'Gene', (164, 170))	('ERalpha', 'Gene', (91, 98))	('pHH3', 'Chemical', '-', (316, 320))	('Androgen Receptor', 'Gene', (241, 258))	('Leica Microsystems', 'Disease', 'None', (185, 203))	('Leica Microsystems', 'Disease', (185, 203))	('ERalpha', 'Gene', '2099', (91, 98))
52481	23812018	Mitotic rate has been found to be a prognostic factor in primary cutaneous melanoma.	('cutaneous melanoma', 'Disease', (65, 83))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('Mitotic', 'Var', (0, 7))
52507	24434078	Recent advances in gene sequencing have shown an increased prevalence of c-KIT mutation in mucosal melanoma, and a significantly lower expression of mutations in the BRAF and NRAS oncogenes compared with cutaneous melanoma.	('BRAF', 'Gene', (166, 170))	('NRAS', 'Gene', '4893', (175, 179))	('mutations', 'Var', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('cutaneous melanoma', 'Disease', (204, 222))	('c-KIT', 'Gene', (73, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (204, 222))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (204, 222))	('c-KIT', 'Gene', '3815', (73, 78))	('mutation', 'Var', (79, 87))	('NRAS', 'Gene', (175, 179))	('expression', 'MPA', (135, 145))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('mucosal melanoma', 'Disease', (91, 107))	('BRAF', 'Gene', '673', (166, 170))	('mucosal melanoma', 'Disease', 'MESH:D008545', (91, 107))	('lower', 'NegReg', (129, 134))
52599	29383127	Uncharacterized early passage cell lines that lacked BRAF, NRAS, or NF1 mutations had near zero mean Pearson correlation of copy number alterations per gene to tumors and also tended to have higher stromal scores.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (72, 81))	('higher', 'PosReg', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('NF1', 'Gene', (68, 71))	('zero', 'NegReg', (91, 95))	('NF1', 'Gene', '4763', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('NRAS', 'Gene', (59, 63))	('copy number alterations', 'MPA', (124, 147))	('tumors', 'Disease', (160, 166))	('NRAS', 'Gene', '4893', (59, 63))	('stromal scores', 'CPA', (198, 212))
52602	29383127	Avoiding cell lines with co-occurring mutually exclusive mutations and the fewest differentially mutated genes within a known distribution of genetic similarity to tumors by copy number alterations may optimize selection.	('copy number alterations', 'Var', (174, 197))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
52611	29383127	Significant genetic alterations can be applied as a basic metric before investigating cancer biology with cell lines including significant mutations of oncogenes or tumor suppressors, karyotype similarity, and DNA methylation.	('tumor', 'Disease', (165, 170))	('DNA methylation', 'biological_process', 'GO:0006306', ('210', '225'))	('DNA', 'cellular_component', 'GO:0005574', ('210', '213'))	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('oncogenes', 'Gene', (152, 161))	('cancer', 'Disease', (86, 92))
52620	29383127	To address this limitation, we focus on genomic data, particularly DNA mutations and DNA copy number alterations, from 470 cases included in The Cancer Genome Atlas Skin Cutaneous Melanoma (TCGA-SKCM) study and 60 melanoma cell lines profiled by CCLE.	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (170, 188))	('Cancer Genome Atlas Skin Cutaneous Melanoma', 'Disease', (145, 188))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('Melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('Cancer Genome Atlas Skin Cutaneous Melanoma', 'Disease', 'MESH:D012878', (145, 188))	('mutations', 'Var', (71, 80))	('DNA', 'Gene', (67, 70))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('CCLE', 'Chemical', '-', (246, 250))	('DNA', 'Gene', (85, 88))
52623	29383127	Cutaneous melanoma cell lines were evaluated by (1) the presence of significantly mutated genes defined by TCGA-SKCM, (2) the number of differentially mutated genes, (3) the co-occurrence of mutations in cell lines that were found to be mutually exclusive in TCGA-SKCM, and (4) the correlation of copy number alterations per gene in focally amplified and deleted regions identified by GISTIC 2.0 analysis.	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('copy number alterations', 'Var', (297, 320))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
52641	29383127	HS600T, HS834T, HS688AT, HS839T, HS934T, and HS940T are melanoma derived cell cultures made available by ATCC as uncharacterized early passage lines, and all are included in the cluster with the highest stromal score.	('HS600T', 'Var', (0, 6))	('HS934T', 'Var', (33, 39))	('HS934T', 'CellLine', 'CVCL:1031', (33, 39))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('HS834T', 'Var', (8, 14))	('melanoma', 'Disease', (56, 64))	('HS688AT', 'Var', (16, 23))	('HS940T', 'Var', (45, 51))	('HS940T', 'CellLine', 'CVCL:1038', (45, 51))	('HS839T', 'Var', (25, 31))	('HS834T', 'CellLine', 'CVCL:0938', (8, 14))
52647	29383127	HS695T, MDAMB435S, and WM983B are the top three cell lines by FGA with more than half of all copy number segments altered (Figure 3B).	('MDAMB435S', 'CellLine', 'CVCL:0622', (8, 17))	('HS695T', 'Var', (0, 6))	('MDAMB435S', 'Var', (8, 17))	('WM983B', 'Var', (23, 29))
52648	29383127	HS940T, HS688AT, HS839T, HS600T, HS934T, and HS895T have the lowest FGA of the melanoma cell lines.	('HS600T', 'Var', (25, 31))	('HS934T', 'Var', (33, 39))	('HS934T', 'CellLine', 'CVCL:1031', (33, 39))	('FGA', 'CPA', (68, 71))	('lowest', 'NegReg', (61, 67))	('HS895T', 'Var', (45, 51))	('HS688AT', 'Var', (8, 15))	('HS940T', 'Var', (0, 6))	('HS839T', 'Var', (17, 23))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('HS895T', 'CellLine', 'CVCL:0993', (45, 51))	('melanoma', 'Disease', (79, 87))	('HS940T', 'CellLine', 'CVCL:1038', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
52651	29383127	Sample Pearson correlation coefficients were calculated for the copy number alteration per gene between each cell line and each tumor sample to determine the distribution of similarity.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('copy', 'Var', (64, 68))	('tumor', 'Disease', (128, 133))
52653	29383127	HS939T (mean = 0.31 +- 0.13) and SH4 (mean = 0.31 +- 0.14) both had the highest mean Pearson r value with tumors of all the cell lines.	('HS939T', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('HS939T', 'CellLine', 'CVCL:1036', (0, 6))	('Pearson r value', 'MPA', (85, 100))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('SH4', 'Gene', (33, 36))	('SH4', 'Gene', '100125850', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
52654	29383127	Interestingly HS939T, an uncharacterized early passage melanoma cell line, had the highest mean Pearson r value, but other uncharacterized early passage lines including HS600T, HS688AT, HS839T, HS934T, and HS895T all had mean Pearson r values near zero.	('HS934T', 'Var', (194, 200))	('HS895T', 'CellLine', 'CVCL:0993', (206, 212))	('HS934T', 'CellLine', 'CVCL:1031', (194, 200))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('HS939T', 'CellLine', 'CVCL:1036', (14, 20))	('HS939T', 'Var', (14, 20))	('HS600T', 'Var', (169, 175))	('Pearson r value', 'MPA', (96, 111))	('HS895T', 'Var', (206, 212))	('HS688AT', 'Var', (177, 184))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('HS839T', 'Var', (186, 192))	('melanoma', 'Disease', (55, 63))
52658	29383127	HS939T and SH4 are also the top two cell lines by correlation to the tumor mean copy number per gene.	('HS939T', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HS939T', 'CellLine', 'CVCL:1036', (0, 6))	('tumor', 'Disease', (69, 74))	('SH4', 'Gene', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('SH4', 'Gene', '100125850', (11, 14))
52662	29383127	Melanoma tumor samples are a very heterogeneous in terms of copy number alterations with a large range of FGA from 0.02 to 0.98.	('Melanoma tumor', 'Disease', (0, 14))	('copy number alterations', 'Var', (60, 83))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Melanoma tumor', 'Disease', 'MESH:D008545', (0, 14))
52663	29383127	To narrow the comparison to regions of significance, Pearson r values were calculated between cell lines and tumors by copy number per gene for a subset of genes within the peak of significant focal amplifications and deletions in metastatic melanoma tumors from TCGA-SKCM (n = 367) by GISTIC 2.0 analysis provided by the Broad Institute Genomic Data Analysis Center Firehose.	('deletions', 'Var', (218, 227))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('tumors', 'Disease', (251, 257))	('melanoma tumors', 'Disease', (242, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('melanoma tumors', 'Disease', 'MESH:D008545', (242, 257))	('tumors', 'Disease', (109, 115))
52664	29383127	Correlation of copy number per gene within significant focal amplifications and deletions presents a more specific metric of similarity between cell lines and tumors as opposed to comparing correlation of CNAs across all genes.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('deletions', 'Var', (80, 89))
52665	29383127	The average difference in the mean Pearson r value across all melanoma cell lines was seventeen times higher for correlation between genes found within focal amplifications and deletions relative to the mean correlation coefficients for CNAs in all coding genes.	('melanoma', 'Disease', (62, 70))	('deletions', 'Var', (177, 186))	('Pearson r', 'MPA', (35, 44))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('higher', 'PosReg', (102, 108))	('correlation', 'MPA', (113, 124))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
52666	29383127	The mean Pearson r value was higher for comparison of focal amplifications and deletions than across all genes for all samples except CHL1, HMCB, A2058, and HS939T for which the mean Pearson r value decreased.	('higher', 'PosReg', (29, 35))	('HS939T', 'CellLine', 'CVCL:1036', (157, 163))	('CHL1', 'Gene', '10752', (134, 138))	('Pearson', 'MPA', (9, 16))	('A2058', 'Var', (146, 151))	('deletions', 'Var', (79, 88))	('CHL1', 'Gene', (134, 138))	('HS939T', 'Var', (157, 163))
52667	29383127	Hierarchical clustering of Pearson r values between each cell line and tumor pairwise comparison of CNAs in genes found in focal amplifications and deletions are shown in Figure 5B.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('deletions', 'Var', (148, 157))
52668	29383127	The uncharacterized early passage cell lines HS839T, HS600T, HS934T, HS895T, HS940T, and HS688AT as well as CHL1 and HMCB, two commonly derived cell lines with high SNP identity, form a cluster with poor correlation across all tumor samples.	('CHL1', 'Gene', (108, 112))	('HS940T', 'Var', (77, 83))	('tumor', 'Disease', (227, 232))	('HS934T', 'Var', (61, 67))	('HS934T', 'CellLine', 'CVCL:1031', (61, 67))	('HS600T', 'Var', (53, 59))	('HS940T', 'CellLine', 'CVCL:1038', (77, 83))	('CHL1', 'Gene', '10752', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('HS839T', 'Var', (45, 51))	('HS895T', 'Var', (69, 75))	('HS688AT', 'Var', (89, 96))	('HS895T', 'CellLine', 'CVCL:0993', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
52671	29383127	There were 31 genes that were mutated in significantly higher proportion of cell lines relative to the proportion of tumors (Bonferroni adjusted p-value <= 0.05 by Fisher's Exact Test) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mutated', 'Var', (30, 37))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))
52672	29383127	Eight of the fifteen significantly mutated genes identified in the original TCGA-SKCM study were also mutated in melanoma cell lines including BRAF, TP53, NF1, NRAS, PTEN, MAP2K1, IDH1, and RB1.	('BRAF', 'Gene', (143, 147))	('PTEN', 'Gene', '5728', (166, 170))	('RB1', 'Gene', (190, 193))	('BRAF', 'Gene', '673', (143, 147))	('TP53', 'Gene', (149, 153))	('mutated', 'Var', (102, 109))	('NF1', 'Gene', '4763', (155, 158))	('NRAS', 'Gene', (160, 164))	('MAP2K1', 'Gene', '5604', (172, 178))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('NF1', 'Gene', (155, 158))	('RB1', 'Gene', '5925', (190, 193))	('MAP2K1', 'Gene', (172, 178))	('IDH1', 'Gene', (180, 184))	('MAP2K', 'molecular_function', 'GO:0004708', ('172', '177'))	('TP53', 'Gene', '7157', (149, 153))	('IDH1', 'Gene', '3417', (180, 184))	('PTEN', 'Gene', (166, 170))	('NRAS', 'Gene', '4893', (160, 164))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))
52674	29383127	There were three pairs of genes that were mutated in a mutually exclusive pattern in tumor samples (n = 412): BRAF and NRAS mutations (Bonferroni adjusted p-value < 0.05), BRAF and NF1 mutations (Bonferroni adjusted p-value < 0.05), and NRAS and PTEN mutations (Bonferroni adjusted p-value < 0.05) (Table 2).	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (251, 260))	('NRAS', 'Gene', '4893', (237, 241))	('mutations', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('NRAS', 'Gene', (119, 123))	('PTEN', 'Gene', (246, 250))	('PTEN', 'Gene', '5728', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('NRAS', 'Gene', '4893', (119, 123))	('NF1', 'Gene', '4763', (181, 184))	('NF1', 'Gene', (181, 184))	('BRAF', 'Gene', '673', (172, 176))	('mutations', 'Var', (185, 194))	('BRAF', 'Gene', '673', (110, 114))	('BRAF', 'Gene', (110, 114))	('NRAS', 'Gene', (237, 241))	('BRAF', 'Gene', (172, 176))
52675	29383127	WM88, HS695T, and LOXIMVI cell lines have co-occurring BRAF and NF1 mutations.	('NF1', 'Gene', (64, 67))	('NF1', 'Gene', '4763', (64, 67))	('BRAF', 'Gene', '673', (55, 59))	('mutations', 'Var', (68, 77))	('BRAF', 'Gene', (55, 59))
52676	29383127	HS936T and SKMEL30 cell lines have co-occurring BRAF and NRAS mutations.	('NRAS', 'Gene', '4893', (57, 61))	('NRAS', 'Gene', (57, 61))	('HS936T', 'CellLine', 'CVCL:1033', (0, 6))	('SKMEL30', 'CellLine', 'CVCL:0039', (11, 18))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('mutations', 'Var', (62, 71))	('HS936T', 'Var', (0, 6))
52677	29383127	HS944T has co-occurring NRAS and PTEN mutations.	('NRAS', 'Gene', '4893', (24, 28))	('HS944T', 'Var', (0, 6))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('HS944T', 'CellLine', 'CVCL:1040', (0, 6))	('NRAS', 'Gene', (24, 28))
52678	29383127	The mean log2 normalized mutations per megabase between metastatic tumors (n = 189), primary tumors (n = 24), and cell lines (n = 53) were found to be significantly different in at least two groups (p <= 0.05 by one-way ANOVA) (Figure 6A).	('mutations', 'Var', (25, 34))	('primary tumors', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('primary tumors', 'Disease', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', (67, 73))
52679	29383127	Mean log2 normalized mutations per megabase were found to be significantly higher in cell lines than primary tumors (p < 0.05), not significantly different between cell lines and metastatic tumors (p = 0.99), and significantly higher in metastatic tumors than primary tumors (p < 0.05).	('primary tumors', 'Disease', 'MESH:D009369', (260, 274))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (248, 254))	('tumors', 'Disease', (190, 196))	('primary tumors', 'Disease', 'MESH:D009369', (101, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('higher', 'Reg', (227, 233))	('tumors than primary tumors', 'Disease', (248, 274))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', (109, 115))	('log2', 'Var', (5, 9))	('higher', 'PosReg', (75, 81))	('tumors', 'Disease', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutations', 'Var', (21, 30))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('primary tumors', 'Disease', (101, 115))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('tumors than primary tumors', 'Disease', 'MESH:D009369', (248, 274))
52680	29383127	Though the mutational load of primary tumors was found to be significantly different from metastatic tumors and cell lines, sequencing coverage information was only available for a small subset of primary tumors.	('mutational', 'Var', (11, 21))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (38, 44))	('primary tumors', 'Disease', 'MESH:D009369', (30, 44))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('primary tumors', 'Disease', (30, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('primary tumors', 'Disease', (197, 211))	('tumors', 'Disease', (101, 107))	('different', 'Reg', (75, 84))	('primary tumors', 'Disease', 'MESH:D009369', (197, 211))
52684	29383127	UV radiation induced mutation signature is a common genomic feature of skin cancers like melanoma and has been previously been defined by C> T transitions at dipyrimidine sites making up >= 60% of all mutations or CC>TT making up >=5% of all mutations.	('skin cancers', 'Phenotype', 'HP:0008069', (71, 83))	('mutations', 'Var', (201, 210))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('skin cancers', 'Disease', (71, 83))	('dipyrimidine', 'Chemical', '-', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('skin cancers', 'Disease', 'MESH:D012878', (71, 83))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('C> T transitions', 'Var', (138, 154))
52685	29383127	Of the filtered tumor samples, 65.3% (269/412) harbor a UV mutation signature.	('mutation signature', 'Var', (59, 77))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (16, 21))
52686	29383127	Of the cell lines with DNA sequencing data, 15.1% (8/53) harbor a UV mutation signature including CHL1, G361, SKMEL30, COLO792, WM88, IPC298, SKMEL5, and HS934T.	('SKMEL5', 'Var', (142, 148))	('WM88', 'Var', (128, 132))	('HS934T', 'Var', (154, 160))	('SKMEL5', 'CellLine', 'CVCL:0527', (142, 148))	('HS934T', 'CellLine', 'CVCL:1031', (154, 160))	('CHL1', 'Gene', (98, 102))	('SKMEL30', 'Var', (110, 117))	('G361', 'Var', (104, 108))	('IPC298', 'Var', (134, 140))	('SKMEL30', 'CellLine', 'CVCL:0039', (110, 117))	('COLO792', 'Var', (119, 126))	('CHL1', 'Gene', '10752', (98, 102))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))
52687	29383127	In this study, commercially available melanoma cell lines profiled by CCLE were compared to tumors profiled by TCGA-SKCM according to genomic features including the number of mutations per megabase, the presence of differentially mutated genes, the presence of mutually exclusive mutations, total copy number alterations in the form of FGA, and the correlation of copy number alterations per gene.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (280, 289))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (175, 184))	('copy number alterations', 'Var', (297, 320))	('CCLE', 'Chemical', '-', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('tumors', 'Disease', (92, 98))	('melanoma', 'Disease', (38, 46))
52694	29383127	One mechanism maintaining the proliferative and invasive phenotypes in cell culture is through SOX9 promoter methylation which leads to the proliferative phenotype by expression, and the overexpression of SOX9 promotes the invasive phenotype in a mouse model.	('SOX9', 'Gene', (95, 99))	('overexpression', 'PosReg', (187, 201))	('proliferative phenotype', 'MPA', (140, 163))	('SOX9', 'Gene', '20682', (205, 209))	('mouse', 'Species', '10090', (247, 252))	('methylation', 'Var', (109, 120))	('expression', 'MPA', (167, 177))	('leads to', 'Reg', (127, 135))	('promotes', 'PosReg', (210, 218))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('SOX9', 'Gene', (205, 209))	('SOX9', 'Gene', '20682', (95, 99))	('invasive phenotype', 'CPA', (223, 241))
52699	29383127	MEWO and COLO792 were the only two NF1 mutants, and both have much larger numbers of mutations per megabase relative to other cell lines.	('mutations', 'Var', (85, 94))	('NF1', 'Gene', (35, 38))	('NF1', 'Gene', '4763', (35, 38))
52703	29383127	In this study using the subset of TCGA-SKCM samples filtered by estimated tumor purity, BRAF and NRAS mutations were found to occur in a mutually exclusive pattern.	('NRAS', 'Gene', (97, 101))	('occur', 'Reg', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('BRAF', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (97, 101))	('BRAF', 'Gene', '673', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (74, 79))
52704	29383127	Additionally, BRAF and NF1 mutations as well as NRAS and PTEN mutations were found occur in a mutually exclusive pattern, but none of these gene pairs were mutually exclusive in cell lines.	('mutations', 'Var', (27, 36))	('NRAS', 'Gene', '4893', (48, 52))	('NF1', 'Gene', (23, 26))	('PTEN', 'Gene', (57, 61))	('NF1', 'Gene', '4763', (23, 26))	('BRAF', 'Gene', '673', (14, 18))	('PTEN', 'Gene', '5728', (57, 61))	('BRAF', 'Gene', (14, 18))	('NRAS', 'Gene', (48, 52))
52705	29383127	The occurrence of NRAS and PTEN mutations were previously found to occur rarely in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('NRAS', 'Gene', '4893', (18, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (83, 101))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (83, 101))	('mutations', 'Var', (32, 41))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('cutaneous melanoma', 'Disease', (83, 101))	('NRAS', 'Gene', (18, 22))
52706	29383127	NF1 mutations generally occur with wild type BRAF and NRAS.	('occur', 'Reg', (24, 29))	('NRAS', 'Gene', (54, 58))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('NRAS', 'Gene', '4893', (54, 58))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NF1', 'Gene', '4763', (0, 3))
52707	29383127	WM88, HS695T, SKMEL30, LOXIMVI, HS936T, and HS944T all harbor one of these mutually exclusive mutation pairs.	('harbor', 'Reg', (55, 61))	('HS944T', 'Var', (44, 50))	('HS936T', 'CellLine', 'CVCL:1033', (32, 38))	('HS944T', 'CellLine', 'CVCL:1040', (44, 50))	('SKMEL30', 'Var', (14, 21))	('HS936T', 'Var', (32, 38))	('SKMEL30', 'CellLine', 'CVCL:0039', (14, 21))	('HS695T', 'Var', (6, 12))
52710	29383127	MELJUSO harbors mutations in both NF1 and NRAS, but these were not found to be mutually exclusive in tumors.	('NRAS', 'Gene', '4893', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NRAS', 'Gene', (42, 46))	('mutations', 'Var', (16, 25))	('NF1', 'Gene', (34, 37))	('NF1', 'Gene', '4763', (34, 37))	('tumors', 'Disease', (101, 107))
52714	29383127	Tumors that lack mutations in BRAF, NRAS, and NF1 were defined in the TCGA-SKCM study as triple wild type.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NF1', 'Gene', (46, 49))	('NRAS', 'Gene', (36, 40))	('NF1', 'Gene', '4763', (46, 49))	('NRAS', 'Gene', '4893', (36, 40))	('BRAF', 'Gene', (30, 34))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('BRAF', 'Gene', '673', (30, 34))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (17, 26))
52715	29383127	The triple wild type melanoma cell lines compared in this study have poor correlation with tumors by copy number per gene with mean Pearson r values between 0.22 for HS940T and -0.14 for CHL1.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('CHL1', 'Gene', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('HS940T', 'CellLine', 'CVCL:1038', (166, 172))	('CHL1', 'Gene', '10752', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('HS940T', 'Var', (166, 172))
52716	29383127	Uncharacterized early passage lines made available by ATCC including HS839T, HS600T, HS934T, HS895T, HS940T, and HS688AT had different molecular characteristics relative to tumors and other cell lines.	('HS940T', 'Var', (101, 107))	('HS934T', 'Var', (85, 91))	('HS895T', 'CellLine', 'CVCL:0993', (93, 99))	('HS940T', 'CellLine', 'CVCL:1038', (101, 107))	('HS934T', 'CellLine', 'CVCL:1031', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('HS600T', 'Var', (77, 83))	('HS895T', 'Var', (93, 99))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('HS688AT', 'Var', (113, 120))	('HS839T', 'Var', (69, 75))
52718	29383127	CJM, HMCB, and CHL1 also lacked mutations in BRAF, NRAS, or NF1, but these cell lines had similar FGA and mutational burden relative to other melanoma cell lines as well as tumors.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('CHL1', 'Gene', (15, 19))	('NF1', 'Gene', '4763', (60, 63))	('NF1', 'Gene', (60, 63))	('lacked', 'NegReg', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutations', 'Var', (32, 41))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('tumors', 'Disease', (173, 179))	('NRAS', 'Gene', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('CHL1', 'Gene', '10752', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('NRAS', 'Gene', '4893', (51, 55))	('melanoma', 'Disease', (142, 150))
52719	29383127	However, these three cell lines also had very low mean correlation to tumors by copy number alterations in focally amplified and deleted genes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('copy number alterations', 'Var', (80, 103))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
52724	29383127	Though a UV mutation signature is common in melanoma and occurs in 65.3% (269/412) of TCGA-SKCM tumors, only 15.1% (8/53) cell lines harbor a UV signature.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('TCGA-SKCM tumors', 'Disease', 'MESH:D009369', (86, 102))	('mutation', 'Var', (12, 20))	('TCGA-SKCM tumors', 'Disease', (86, 102))
52726	29383127	Cell lines which harbor mutations of interest, the fewest differentially mutated genes, and the highest Pearson sample correlation with most tumors provides criteria to select cell lines with more genetic similarity to patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patient', 'Species', '9606', (219, 226))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
52731	29383127	The CCLE MAF file included only coding regions, excluded common polymorphisms, mutations with a variant allele frequency < 10%, and putative neutral variants.	('MAF', 'Gene', (9, 12))	('MAF', 'Gene', '4094', (9, 12))	('CCLE', 'Chemical', '-', (4, 8))	('mutations', 'Var', (79, 88))
52742	29383127	Finally, cell lines and tumors were compared by average copy number per gene for genes within the peak of significant focal amplifications and deletions found in metastatic tumors from TCGA-SKCM (n = 367) by GISTIC 2.0 analysis downloaded from the Broad Institute GDAC Firehose.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('deletions', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
52743	29383127	Differentially mutated genes were identified using Fisher's Exact Test implemented via maftools to compare the proportion of tumors relative to the proportion of cell lines that carry a mutation in a given gene with a minimum of five samples carrying the mutation.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('maf', 'Gene', '4094', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('maf', 'Gene', (87, 90))	('mutation', 'Var', (186, 194))
52752	29383127	Total mutations were counted for TCGA-SKCM and CCLE from their respective MAF files filtered by variant allelic fraction >= 0.1 and >= 14 reads including synonymous variants, insertions, deletions, and single nucleotide polymorphisms.	('CCLE', 'Chemical', '-', (47, 51))	('MAF', 'Gene', (74, 77))	('single nucleotide polymorphisms', 'Var', (202, 233))	('insertions', 'Var', (175, 185))	('MAF', 'Gene', '4094', (74, 77))	('deletions', 'Var', (187, 196))
52753	29383127	Total coverage-normalized mutations were calculated by dividing the sum of all coding region mutations from the MAF files divided by the sequencing coverage calculated for each of the TCGA-SKCM samples and CCLE samples.	('CCLE', 'Chemical', '-', (206, 210))	('mutations', 'Var', (93, 102))	('MAF', 'Gene', (112, 115))	('MAF', 'Gene', '4094', (112, 115))
52754	29383127	UV signature for TCGA-SKCM samples (n = 412) and CCLE samples (n = 53) was determined by extracting the flanking bases surrounding mutations from MAF files using the maftools and summing the number of C>T transition mutations flanked by either C or T; then dividing the sum by the total number of substitution mutations in the MAF file.	('mutations', 'Var', (131, 140))	('CCLE', 'Chemical', '-', (49, 53))	('maf', 'Gene', '4094', (166, 169))	('C>T', 'Var', (201, 204))	('MAF', 'Gene', '4094', (146, 149))	('maf', 'Gene', (166, 169))	('MAF', 'Gene', '4094', (327, 330))	('MAF', 'Gene', (146, 149))	('MAF', 'Gene', (327, 330))
52755	29383127	MAF files for TCGA-SKCM and CCLE were filtered by variant allelic fraction >= 0.1 and >= 8 reads including synonymous variants, insertions, deletions, and single nucleotide polymorphisms.	('single nucleotide polymorphisms', 'Var', (155, 186))	('MAF', 'Gene', (0, 3))	('MAF', 'Gene', '4094', (0, 3))	('deletions', 'Var', (140, 149))	('CCLE', 'Chemical', '-', (28, 32))	('insertions', 'Var', (128, 138))
52816	25310216	Acculturation among Hispanics has been linked to higher perceived benefits of exposure to ultraviolet radiation, less worry about skin damage, higher rates of sunbathing, higher rates of indoor tanning, and an increased risk of sunburns.	('sunburns', 'Disease', (228, 236))	('Acculturation', 'Var', (0, 13))	('higher', 'PosReg', (171, 177))	('skin damage', 'Disease', (130, 141))	('higher', 'PosReg', (143, 149))	('skin damage', 'Disease', 'MESH:D012871', (130, 141))	('higher', 'PosReg', (49, 55))
52885	24289268	This temporary permeability of the cell membrane caused by the electric pulses facilitates a potent localized effect and magnifies the drug cytotoxicity by several orders of magnitude.	('cytotoxicity', 'Disease', 'MESH:D064420', (140, 152))	('potent localized effect', 'MPA', (93, 116))	('cell membrane', 'cellular_component', 'GO:0005886', ('35', '48'))	('facilitates', 'PosReg', (79, 90))	('cytotoxicity', 'Disease', (140, 152))	('magnifies', 'PosReg', (121, 130))	('electric pulses', 'Var', (63, 78))
52905	30453881	Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples Because driver mutations provide selective advantage to the mutant clone, they tend to occur at a higher frequency in tumor samples compared to selectively neutral (passenger) mutations.	('tumor', 'Disease', (79, 84))	('frameshift mutations', 'Var', (55, 75))	('mutations', 'Var', (108, 117))	('advantage', 'PosReg', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mutant', 'Var', (153, 159))	('missense', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('nonsense', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
52909	30453881	By comparing the observed and predicted number of mutations in a gene, we have identified known cancer-associated genes as well as 111 novel cancer associated genes.	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (141, 147))
52914	30453881	Mutations providing a proliferative or survival advantage to the mutant clone (drivers) occur more frequently in tumor samples compared to selectively neutral (passenger) mutations.	('tumor', 'Disease', (113, 118))	('mutant', 'Var', (65, 71))	('proliferative', 'CPA', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('survival advantage', 'CPA', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
52919	30453881	The authors noted that about half of the identified driver mutations "occur in yet-to-be-discovered cancer genes".	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (59, 68))
52923	30453881	The excess of mutations unexplained by gene characteristics is due to the gene involvement in cancer development and can be used to identify cancer-associated genes.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('involvement', 'Reg', (79, 90))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
52927	30453881	In total there were 2,233,115 missense, 163,823 nonsense, and 85,272 frameshift (FS) mutations, including those resulted from nucleotide insertions as well as nucleotide deletions.	('missense', 'Var', (30, 38))	('nucleotide insertions', 'Var', (126, 147))	('frameshift', 'Reg', (69, 79))	('mutations', 'Var', (85, 94))	('FS', 'Disease', 'MESH:D018223', (81, 83))	('nonsense', 'Var', (48, 56))
52935	30453881	The mean chromatin accessibility across 10 lymphoblastic cell lines was computed for each gene and used as a predictor for density of missense, nonsense and FS mutations separately.	('chromatin accessibility', 'MPA', (9, 32))	('missense', 'Var', (134, 142))	('chromatin', 'cellular_component', 'GO:0000785', ('9', '18'))	('nonsense', 'Var', (144, 152))	('FS', 'Disease', 'MESH:D018223', (157, 159))
52940	30453881	Residual analysis was used to detect outliers - genes with a higher than expected number of missense, nonsense, or FS mutations.	('nonsense', 'Var', (102, 110))	('mutations', 'Var', (118, 127))	('missense', 'Var', (92, 100))	('FS', 'Disease', 'MESH:D018223', (115, 117))
52941	30453881	For each gene, residual Z-scores were computed separately for missense, nonsense and FS mutations.	('missense', 'Var', (62, 70))	('FS', 'Disease', 'MESH:D018223', (85, 87))	('nonsense', 'Var', (72, 80))
52944	30453881	For nonsense mutations, there was a linear relationship between the percentage of each nucleotide and the mutation density, as expected from the nucleotide composition of stop codons (TAA, TAG, and TGA).	('TGA', 'Gene', '6899', (198, 201))	('TGA', 'Gene', (198, 201))	('nonsense mutations', 'Var', (4, 22))
52946	30453881	For missense mutations, the peaks are driven by TP53 and KRAS.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('missense mutations', 'Var', (4, 22))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))
52947	30453881	We found that the density of missense mutations in olfactory receptors is twice that of other genes in the human genome: 107.5 +- 2.9 versus 49.4 +- 0.4 mutations per 1 kb.	('olfactory receptors', 'Gene', (51, 70))	('human', 'Species', '9606', (107, 112))	('missense mutations', 'Var', (29, 47))
52948	30453881	Densities of nonsense and FS mutations in olfactory genes are not elevated.	('nonsense', 'Var', (13, 21))	('FS', 'Disease', 'MESH:D018223', (26, 28))	('olfactory genes', 'Gene', (42, 57))
52950	30453881	Figure 3c shows the relationship between the mutation densities of missense, nonsense and FS mutations and the relative replication time.	('nonsense', 'Var', (77, 85))	('missense', 'Var', (67, 75))	('FS', 'Disease', 'MESH:D018223', (90, 92))
52958	30453881	Gene size was the most significant predictor followed by the nucleotide diversity (negative association) and the percentages of "A" and "C" nucleotides that were positively associated with the number of FS mutations in the gene.	('mutations', 'Var', (206, 215))	('FS', 'Disease', 'MESH:D018223', (203, 205))	('associated', 'Reg', (173, 183))
52961	30453881	We tested how well the pan-mutation model works for predicting missense, nonsense and FS mutations separately.	('nonsense', 'Var', (73, 81))	('FS', 'Disease', 'MESH:D018223', (86, 88))	('missense', 'Var', (63, 71))
52970	30453881	Five genes, ATM, LRP1B, CSMD3, FBXW, and SMAD4 have an excess of missense and nonsense mutations.	('ATM', 'Gene', (12, 15))	('CSMD3', 'Gene', (24, 29))	('FBXW', 'Gene', (31, 35))	('CSMD3', 'Gene', '114788', (24, 29))	('missense', 'Var', (65, 73))	('LRP1B', 'Gene', '53353', (17, 22))	('LRP1B', 'Gene', (17, 22))	('SMAD4', 'Gene', '4089', (41, 46))	('ATM', 'Gene', '472', (12, 15))	('SMAD4', 'Gene', (41, 46))	('nonsense mutations', 'Var', (78, 96))
52971	30453881	Three genes, COL11A1, SLC25A5, and PCLO show a significant excess of frameshift and missense mutations.	('frameshift', 'Var', (69, 79))	('COL11A1', 'Gene', (13, 20))	('PCLO', 'Gene', (35, 39))	('PCLO', 'Gene', '27445', (35, 39))	('COL11A1', 'Gene', '1301', (13, 20))	('SLC25A5', 'Gene', '292', (22, 29))	('SLC25A5', 'Gene', (22, 29))	('missense mutations', 'Var', (84, 102))
52972	30453881	Twelve genes: APC, AXIN1, TET2, ASXL1, ARID2, RB1, NF1, VHL, PBRM1, KMT2D, KMT2C, and ARID1A, show an excess of frameshift and nonsense mutations.	('VHL', 'Gene', (56, 59))	('KMT2C', 'Gene', (75, 80))	('RB1', 'Gene', (46, 49))	('ASXL1', 'Gene', (32, 37))	('AXIN1', 'Gene', '8312', (19, 24))	('TET2', 'Gene', '54790', (26, 30))	('KMT2C', 'Gene', '58508', (75, 80))	('APC', 'cellular_component', 'GO:0005680', ('14', '17'))	('VHL', 'Gene', '7428', (56, 59))	('ARID2', 'Gene', '196528', (39, 44))	('KMT2D', 'Gene', '8085', (68, 73))	('frameshift', 'Var', (112, 122))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('RB1', 'Gene', '5925', (46, 49))	('APC', 'Disease', (14, 17))	('NF1', 'Gene', '4763', (51, 54))	('PBRM1', 'Gene', '55193', (61, 66))	('ARID1A', 'Gene', (86, 92))	('ARID2', 'Gene', (39, 44))	('TET2', 'Gene', (26, 30))	('AXIN1', 'Gene', (19, 24))	('NF1', 'Gene', (51, 54))	('nonsense mutations', 'Var', (127, 145))	('PBRM1', 'Gene', (61, 66))	('ASXL1', 'Gene', '171023', (32, 37))	('ARID1A', 'Gene', '8289', (86, 92))	('KMT2D', 'Gene', (68, 73))
52974	30453881	The mean Z-score for known TSs was significantly higher for FS, missense, and nonsense mutations compared to Z-scores for all other genes.	('nonsense mutations', 'Var', (78, 96))	('Z-score', 'MPA', (9, 16))	('FS', 'Disease', 'MESH:D018223', (60, 62))	('higher', 'PosReg', (49, 55))	('missense', 'Var', (64, 72))
52975	30453881	A higher Z-score for missense mutations is expected because typically activating missense mutations in oncogenes drive tumorigenesis.. We found that gene characteristics can explain considerable proportion of inter genic variation in the number of somatic mutations: 88% for missense, 40% for nonsense, and 23% for frameshift mutations.	('nonsense', 'Var', (293, 301))	('frameshift mutations', 'Var', (315, 335))	('tumor', 'Disease', (119, 124))	('missense', 'Var', (275, 283))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
52978	30453881	If we assume that the unexplained variation in the number of mutations is due to an involvement of the gene in cancer development, the results show that FS most frequently associated with tumorigenesis followed by nonsense and missense mutations.	('tumor', 'Disease', (188, 193))	('FS', 'Disease', 'MESH:D018223', (153, 155))	('nonsense', 'Var', (214, 222))	('associated with', 'Reg', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('missense mutations', 'Var', (227, 245))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
52979	30453881	Each gene in the human genome acquires mutations on background level based on intrinsic mutability of the gene which depends on gene characteristics.	('human', 'Species', '9606', (17, 22))	('hic', 'Gene', '29969', (112, 115))	('hic', 'Gene', (112, 115))	('mutations', 'Var', (39, 48))
52985	30453881	We have identified 18 novel cancer-associated genes with an excess of missense mutations: MUC4, CSMD3, FLG, USH2A, DNAH8, FAT4, MUC17, MUC16, SYNE1, COL11A1, RP1, SI, SACS, SLC25A5, DMD, DST, XIRP2, and PKHD1L1.	('COL11A1', 'Gene', '1301', (149, 156))	('CSMD3', 'Gene', (96, 101))	('SYNE1', 'Gene', (142, 147))	('SI', 'Disease', 'None', (163, 165))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FLG', 'Gene', '2312', (103, 106))	('USH2A', 'Gene', '7399', (108, 113))	('FAT4', 'Gene', '79633', (122, 126))	('SLC25A5', 'Gene', (173, 180))	('SACS', 'Gene', '26278', (167, 171))	('SYNE1', 'Gene', '23345', (142, 147))	('COL11A1', 'Gene', (149, 156))	('missense mutations', 'Var', (70, 88))	('MUC16', 'Gene', '94025', (135, 140))	('DNAH8', 'Gene', (115, 120))	('XIRP2', 'Gene', '129446', (192, 197))	('SACS', 'Gene', (167, 171))	('MUC4', 'Gene', '4585', (90, 94))	('MUC17', 'Gene', (128, 133))	('MUC4', 'Gene', (90, 94))	('PKHD1L1', 'Gene', '93035', (203, 210))	('PKHD1L1', 'Gene', (203, 210))	('FAT4', 'Gene', (122, 126))	('MUC17', 'Gene', '140453', (128, 133))	('cancer', 'Disease', (28, 34))	('RP1', 'Gene', (158, 161))	('USH2A', 'Gene', (108, 113))	('CSMD3', 'Gene', '114788', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MUC16', 'Gene', (135, 140))	('DMD', 'Disease', 'MESH:D020388', (182, 185))	('DMD', 'Disease', (182, 185))	('XIRP2', 'Gene', (192, 197))	('SLC25A5', 'Gene', '292', (173, 180))	('FLG', 'Gene', (103, 106))	('RP1', 'Gene', '6101', (158, 161))	('DNAH8', 'Gene', '1769', (115, 120))
52987	30453881	A larger number of novel cancer-associated genes identified through the analyses of FS and nonsense mutilations compared to the analysis of missense mutations can be due to the fact that a large proportion of variation in number of mutation is due to gene involvement in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutation', 'Var', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('involvement', 'Reg', (256, 267))	('FS', 'Disease', 'MESH:D018223', (84, 86))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('nonsense mutilations', 'Phenotype', 'HP:0000742', (91, 111))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (271, 277))
52989	30453881	For example, the observed number of missense mutations in AKT1 oncogene is 113.	('AKT1', 'Gene', (58, 62))	('missense mutations', 'Var', (36, 54))	('AKT1', 'Gene', '207', (58, 62))
52991	30453881	If we exclude p.E17K, in the reminder of the AKT1 gene the observed number of mutations is lower than expected: 27 observed versus 70 expected.	('p.E17K', 'Var', (14, 20))	('AKT1', 'Gene', '207', (45, 49))	('p.E17K', 'Mutation', 'rs121434592', (14, 20))	('AKT1', 'Gene', (45, 49))
52992	30453881	Missense mutations in functional domains may be loss-of-function mutations and as a result are negatively selected in tumors.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Missense mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('loss-of-function', 'NegReg', (48, 64))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
52993	30453881	Because our modeling does not take into account the distribution of mutations within the coding region, it may miss cancer genes with a clustering of functional mutations but a similar number of observed and expected mutations.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('miss', 'NegReg', (111, 115))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
52994	30453881	Interestingly, many novel cancer-associated genes identified by the excess of missense mutations are large genes with repetitive functional domains: LRP1B, CSMD3, FLG, USH2A and others.	('missense mutations', 'Var', (78, 96))	('USH2A', 'Gene', '7399', (168, 173))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('LRP1B', 'Gene', '53353', (149, 154))	('FLG', 'Gene', (163, 166))	('FLG', 'Gene', '2312', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CSMD3', 'Gene', (156, 161))	('CSMD3', 'Gene', '114788', (156, 161))	('USH2A', 'Gene', (168, 173))	('LRP1B', 'Gene', (149, 154))
52995	30453881	For example, one of the frequent mutations in CSMD3 gene is G > A substitution.	('G > A substitution', 'Var', (60, 78))	('CSMD3', 'Gene', (46, 51))	('CSMD3', 'Gene', '114788', (46, 51))
52996	30453881	It leads to arginine (R) to glutamine (Q) substitution.	('leads to', 'Reg', (3, 11))	('arginine', 'Chemical', 'MESH:D001120', (12, 20))	('glutamine', 'Chemical', 'MESH:D005973', (28, 37))	('arginine', 'Var', (12, 20))
52997	30453881	We found that the number of silent mutations reported by COSMIC genome wide screens across all cancer types is the most significant predictor of missense mutations.	('missense mutations', 'Var', (145, 163))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
53005	30453881	Therefore, the total number of silent mutations per gene generated by whole genome (exome) mutational screens across different cancer types is a key predictor of somatic mutations and needs to be included in cancer gene prediction models including MutsigCV to increase the specificity of the results.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutational', 'Var', (91, 101))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
53006	30453881	We found that top predictors for missense, nonsense and FS mutations are different.	('nonsense and', 'Var', (43, 55))	('missense', 'Var', (33, 41))	('FS', 'Disease', 'MESH:D018223', (56, 58))
53008	30453881	We applied stepwise best subset multivariate model to predict missense, nonsense, and FS mutations using gene characteristics, and by comparison of the observed and expected number of mutations identified novel cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('FS', 'Disease', 'MESH:D018223', (86, 88))	('missense', 'Var', (62, 70))	('cancer', 'Disease', (211, 217))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('nonsense', 'Var', (72, 80))
53011	30453881	CCLE Cancer Cell Line Encyclopedia COSMIC Catalog of Somatic Mutations in Cancer FS Frameshift mutations LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma ND Nucleotide diversity OG Oncogene SKCM Skin cutaneous melanoma SNS Single nucleotide substitution TS Tumor suppressors Conception and design: IG, CA, OG.	('Skin cutaneous melanoma', 'Disease', (205, 228))	('Cancer Cell Line Encyclopedia', 'Disease', (5, 34))	('Cancer', 'Phenotype', 'HP:0002664', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (205, 228))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('Single nucleotide substitution', 'Var', (233, 263))	('Cancer', 'Disease', (5, 11))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('CCLE', 'Chemical', '-', (0, 4))	('Tumor', 'Phenotype', 'HP:0002664', (267, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (5, 11))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (5, 34))	('FS', 'Disease', 'MESH:D018223', (81, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('Lung adenocarcinoma', 'Disease', (110, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (210, 228))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))
53020	31169498	For instance, research showed that several drugs for the treatment of melanoma only targeted tumors that carried a specific mutation in the BRAF gene: the presence of this mutation in a patient is therefore associated with a higher chance of survival due to a positive drug response (Figure 1).	('presence', 'Var', (155, 163))	('higher', 'PosReg', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survival', 'MPA', (242, 250))	('melanoma only targeted tumors', 'Disease', 'MESH:D008545', (70, 99))	('BRAF', 'Gene', '673', (140, 144))	('melanoma only targeted tumors', 'Disease', (70, 99))	('mutation', 'Var', (172, 180))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('BRAF', 'Gene', (140, 144))	('mutation', 'Var', (124, 132))	('patient', 'Species', '9606', (186, 193))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
53021	31169498	Indeed, subsequent research has shown that the higher the mutational 'burden' in the melanoma, the better the response to treatment (; Figure 1).	('better', 'PosReg', (99, 105))	('higher', 'PosReg', (47, 53))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('response', 'MPA', (110, 118))	('mutational', 'Var', (58, 68))
53086	32894202	These include the tumor molecular features including T cell infiltrate, mutational load, gut microbiome, germline genetics, proteomic biomarkers and possibly ethnicity.	('tumor', 'Disease', (18, 23))	('mutational load', 'Var', (72, 87))	('gut microbiome', 'Species', '749906', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
53088	32894202	Two autoimmune germline variants as potential biomarkers of anti-CTLA4 or anti-PD1 immune checkpoint inhibitors (ICI) efficacy in melanoma were identified and suggests that underlying genetic susceptibility to autoimmunity may play an important role during ICI treatments.	('CTLA4', 'Gene', '1493', (65, 70))	('variants', 'Var', (24, 32))	('CTLA4', 'Gene', (65, 70))	('autoimmunity', 'Phenotype', 'HP:0002960', (210, 222))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('if', 'Gene', '17319', (149, 151))	('melanoma', 'Disease', (130, 138))
53089	32894202	rs1893217 in PTPN2, involved in cytokine signaling, has been associated with colitis, celiac disease, inflammatory bowel, rheumatoid arthritis and type 1 diabetes.	('diabetes', 'Disease', (154, 162))	('celiac disease', 'Disease', 'MESH:D002446', (86, 100))	('arthritis', 'Phenotype', 'HP:0001369', (133, 142))	('rs1893217', 'Var', (0, 9))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (122, 142))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (147, 162))	('rs1893217', 'Mutation', 'rs1893217', (0, 9))	('colitis', 'Disease', (77, 84))	('associated', 'Reg', (61, 71))	('rheumatoid arthritis', 'Disease', (122, 142))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('inflammatory bowel', 'Disease', (102, 120))	('colitis', 'Disease', 'MESH:D003092', (77, 84))	('celiac disease', 'Disease', (86, 100))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('PTPN2', 'Gene', (13, 18))	('celiac disease', 'Phenotype', 'HP:0002608', (86, 100))	('PTPN2', 'Gene', '5771', (13, 18))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (122, 142))	('inflammatory bowel', 'Disease', 'MESH:D015212', (102, 120))	('colitis', 'Phenotype', 'HP:0002583', (77, 84))
53090	32894202	Similarly, rs17388568 was mapped to important immune-related genes (IL-2, IL-21 and ADAD1) and associated with allergy, colitis and type 1 diabetes.	('rs17388568', 'Var', (11, 21))	('IL-2', 'molecular_function', 'GO:0005134', ('68', '72'))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (132, 147))	('IL-2', 'Gene', (74, 78))	('associated', 'Reg', (95, 105))	('ADAD1', 'Gene', '132612', (84, 89))	('colitis', 'Disease', (120, 127))	('ADAD1', 'Gene', (84, 89))	('colitis', 'Disease', 'MESH:D003092', (120, 127))	('diabetes', 'Disease', 'MESH:D003920', (139, 147))	('IL-2', 'Gene', '3558', (68, 72))	('allergy', 'Disease', 'MESH:D004342', (111, 118))	('IL-21', 'molecular_function', 'GO:0001531', ('74', '79'))	('IL-2', 'Gene', '3558', (74, 78))	('IL-21', 'Gene', (74, 79))	('rs17388568', 'Mutation', 'rs17388568', (11, 21))	('allergy', 'Disease', (111, 118))	('IL-21', 'Gene', '59067', (74, 79))	('allergy', 'Phenotype', 'HP:0012393', (111, 118))	('colitis', 'Phenotype', 'HP:0002583', (120, 127))	('diabetes', 'Disease', (139, 147))	('IL-2', 'Gene', (68, 72))
53098	32894202	However, epigenetic downregulation of cGAs and/or STING in some tumors may preclude the activation of IFN type I by radiation therapy (REF: PMID: 29367762).	('IFN', 'Gene', '3439', (102, 105))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('preclude', 'NegReg', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('epigenetic', 'Var', (9, 19))	('IFN', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cGAs', 'Protein', (38, 42))
53103	32894202	In the non-canonical pathway, CD38 catalyzes the conversion of NAD+ to ADPR and CD203a converts ADPR to AMP (PMID: 27209048).	('CD203a', 'Var', (80, 86))	('CD38', 'Gene', (30, 34))	('ADPR', 'Chemical', '-', (71, 75))	('ADPR', 'Chemical', '-', (96, 100))	('CD38', 'Gene', '952', (30, 34))	('NAD+', 'Chemical', 'MESH:D009243', (63, 67))	('ADPR', 'MPA', (96, 100))	('AMP', 'Chemical', 'MESH:D000249', (104, 107))
53104	32894202	Radiation-induced cell death is associated with release of ATP and NAD+ in the TME, but we found that radiation also induces the upregulation of CD38, CD203a and CD73 on cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('NAD+', 'Chemical', 'MESH:D009243', (67, 71))	('death', 'Disease', (23, 28))	('cancer', 'Disease', (170, 176))	('cell death', 'biological_process', 'GO:0008219', ('18', '28'))	('ATP', 'Gene', (59, 62))	('upregulation', 'PosReg', (129, 141))	('CD38', 'Gene', (145, 149))	('ATP', 'Gene', '51761', (59, 62))	('CD73', 'Gene', '4907', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CD73', 'Gene', (162, 166))	('CD38', 'Gene', '952', (145, 149))	('death', 'Disease', 'MESH:D003643', (23, 28))	('CD203a', 'Var', (151, 157))
53117	32894202	Correlation between increased CD8+ T cell IFN-gamma release and serum IgG binding was also demonstrated by a study in which female BALB/c mice were vaccinated with a combination of an autophagosome-enriched vaccine derived from 4T1 mammary carcinoma along with poly-I:C adjuvant where serum was screened for IgG binding to arrays of peptides containing known mutation sites in 4T1.	('mutation sites', 'Var', (359, 373))	('CD8', 'Gene', (30, 33))	('increased', 'PosReg', (20, 29))	('CD8', 'Gene', '925', (30, 33))	('carcinoma', 'Disease', (240, 249))	('carcinoma', 'Disease', 'MESH:D009369', (240, 249))	('mice', 'Species', '10090', (138, 142))	('autophagosome', 'cellular_component', 'GO:0005776', ('184', '197'))	('IgG binding', 'molecular_function', 'GO:0019864', ('308', '319'))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (232, 249))	('IgG binding', 'molecular_function', 'GO:0019864', ('70', '81'))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('poly-I', 'Chemical', 'MESH:D011069', (261, 267))	('4T1', 'Gene', (377, 380))
53153	32894202	BRAF mutation has been shown to downregulate HLA class I and tumor antigen expression on melanoma cells.	('downregulate', 'NegReg', (32, 44))	('HLA class I', 'Protein', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (5, 13))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (89, 97))	('tumor', 'Disease', (61, 66))	('tumor antigen', 'molecular_function', 'GO:0008222', ('61', '74'))
53171	32894202	Studies examining possible predictive biomarkers of response to immunotherapy have reported a higher density of preexisting cytotoxic T lymphocytes in tumor biopsies of patients who displayed a greater response to anti-PD-1/PD-L1 immunotherapy, and more significantly, an increased influx of T cells and PD-L1 macrophages early during treatment.	('increased', 'PosReg', (272, 281))	('influx', 'MPA', (282, 288))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('increased influx of T cells', 'Phenotype', 'HP:0100828', (272, 299))	('tumor', 'Disease', (151, 156))	('anti-PD-1/PD-L1', 'Var', (214, 229))	('if', 'Gene', '17319', (258, 260))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
53186	32894202	JAK1/2 mutations have also recently been identified as genetic markers of acquired resistance to immunotherapy in melanoma that is responsible for cell proliferation, differentiation, cell migration, and apoptosis.	('if', 'Gene', '17319', (156, 158))	('JAK1/2', 'Gene', '3716;3717', (0, 6))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', (114, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('147', '165'))	('cell migration', 'biological_process', 'GO:0016477', ('184', '198'))	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('JAK1/2', 'Gene', (0, 6))	('if', 'Gene', '17319', (168, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('JAK', 'molecular_function', 'GO:0004713', ('0', '3'))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('if', 'Gene', '17319', (46, 48))	('mutations', 'Var', (7, 16))
53212	32894202	A meta-analysis in patients with metastatic uveal melanoma treated with anti-PD-1/PD-L1s reported an ORR of only 3.6% and a median PFS of 2.6 months.	('patients', 'Species', '9606', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('anti-PD-1/PD-L1s', 'Var', (72, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('uveal melanoma', 'Disease', (44, 58))
53218	32894202	The vast majority (85-95%) of uveal melanoma is characterized by activating mutations in genes encoding the G-protein-alpha subunits GNAQ or GNA11, which lead to stimulation of the MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.	('GNA11', 'Gene', '2767', (141, 146))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mutations', 'Var', (76, 85))	('Akt', 'Gene', (227, 230))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('GNAQ', 'Gene', (133, 137))	('phosphatidylinositol 3-kinase', 'Gene', (190, 219))	('phosphatidylinositol 3-kinase', 'Gene', '5291', (190, 219))	('uveal melanoma', 'Disease', 'MESH:C536494', (30, 44))	('uveal melanoma', 'Phenotype', 'HP:0007716', (30, 44))	('uveal melanoma', 'Disease', (30, 44))	('stimulation', 'PosReg', (162, 173))	('Akt', 'Gene', '207', (227, 230))	('GNA11', 'Gene', (141, 146))	('GNAQ', 'Gene', '2776', (133, 137))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))
53219	32894202	Several other genetic alterations have been implicated in the development of uveal melanoma.	('genetic alterations', 'Var', (14, 33))	('implicated', 'Reg', (44, 54))	('uveal melanoma', 'Disease', 'MESH:C536494', (77, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (77, 91))	('uveal melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
53220	32894202	Inactivating mutations in BAP1, a tumor suppressor gene located on chromosome 3p, are found in approximately 47% of primary uveal melanoma and 84% of metastatic uveal melanoma cases, consistent with the association between BAP1 mutations and poor prognosis.	('BAP1', 'Gene', '8314', (223, 227))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('BAP1', 'Gene', (26, 30))	('tumor', 'Disease', (34, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('BAP1', 'Gene', (223, 227))	('Inactivating mutations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('found', 'Reg', (86, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('BAP1', 'Gene', '8314', (26, 30))
53221	32894202	Mutations in splicing factor 3B subunit 1 (SF3B1), involved in pre-messenger RNA splicing, while associated with more favorable prognostic features than BAP1 mutations, are also found in cases of delayed metastasis, with a median of 8.2 years.	('SF3B1', 'Gene', (43, 48))	('BAP1', 'Gene', (153, 157))	('RNA splicing', 'biological_process', 'GO:0008380', ('77', '89'))	('SF3B1', 'Gene', '23451', (43, 48))	('BAP1', 'Gene', '8314', (153, 157))	('splicing factor 3B subunit 1', 'Gene', '23451', (13, 41))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (178, 183))	('pre', 'molecular_function', 'GO:0003904', ('63', '66'))	('delayed metastasis', 'CPA', (196, 214))	('splicing factor 3B subunit 1', 'Gene', (13, 41))	('splicing', 'biological_process', 'GO:0045292', ('13', '21'))
53223	32894202	These mutations are mutually exclusive from BAP1 and SF3B1 and are associated with a longer disease-free survival and a more favorable prognosis Furthermore, metastatic UM are characterized by the low mutational burden observed in uveal melanoma may partly account for the limited success of immune checkpoint blockade.	('BAP1', 'Gene', (44, 48))	('SF3B1', 'Gene', '23451', (53, 58))	('metastatic', 'Disease', (158, 168))	('uveal melanoma', 'Disease', 'MESH:C536494', (231, 245))	('BAP1', 'Gene', '8314', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('uveal melanoma', 'Phenotype', 'HP:0007716', (231, 245))	('uveal melanoma', 'Disease', (231, 245))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', (53, 58))
53243	32894202	The most common acquired genetic change distinguishing precursor lesions, such as melanocytic nevi or melanoma in situ (MIS), from invasive melanomas is loss of the CDKN2A locus.	('invasive melanomas', 'Disease', 'MESH:D008545', (131, 149))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (82, 98))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('melanocytic nevi', 'Disease', (82, 98))	('loss', 'Var', (153, 157))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('CDKN2A', 'Gene', (165, 171))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('invasive melanomas', 'Disease', (131, 149))	('CDKN2A', 'Gene', '1029', (165, 171))
53245	32894202	The loss of p16INK4A promotes melanocyte motility and the invasive and metastatic capacity of melanoma cells through the transcriptional activation of BRN2, a transcription factor previously associated with melanocytic invasive programs during both development and disease was demonstrated.	('transcriptional', 'MPA', (121, 136))	('transcription factor', 'molecular_function', 'GO:0000981', ('159', '179'))	('BRN2', 'Gene', '5454', (151, 155))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('p16INK4A', 'Gene', '1029', (12, 20))	('melanocyte motility', 'CPA', (30, 49))	('melanoma', 'Disease', (94, 102))	('promotes', 'PosReg', (21, 29))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('BRN2', 'Gene', (151, 155))	('activation', 'PosReg', (137, 147))	('p16INK4A', 'Gene', (12, 20))	('loss', 'Var', (4, 8))
53246	32894202	Loss of p16INK4A promotes melanocyte motility and the invasive and metastatic capacity of melanoma cells through the transcriptional activation of BRN2, a transcription factor previously associated with melanocytic invasive programs during both development and disease.	('melanoma', 'Disease', (90, 98))	('BRN2', 'Gene', '5454', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('p16INK4A', 'Gene', '1029', (8, 16))	('melanocyte motility', 'CPA', (26, 45))	('promotes', 'PosReg', (17, 25))	('transcription factor', 'molecular_function', 'GO:0000981', ('155', '175'))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))	('activation', 'PosReg', (133, 143))	('BRN2', 'Gene', (147, 151))	('p16INK4A', 'Gene', (8, 16))	('Loss', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
53258	32894202	We hypothesize that truncating the intracellular domain of the TGF-beta receptor will abrogate immunosuppressive signalling through this pathway, which may augment immunotherapy effectiveness.	('abrogate', 'NegReg', (86, 94))	('TGF-beta', 'Gene', (63, 71))	('signalling', 'biological_process', 'GO:0023052', ('113', '123'))	('truncating', 'Var', (20, 30))	('TGF-beta', 'Gene', '7039', (63, 71))	('augment', 'NegReg', (156, 163))	('immunosuppressive signalling', 'MPA', (95, 123))	('immunotherapy effectiveness', 'CPA', (164, 191))	('intracellular', 'cellular_component', 'GO:0005622', ('35', '48'))
53264	32894202	Genetic modification of TIL with TGF-DNRII is feasible to generate, safe to administer and has demonstrated efficacy in malignant melanoma.. Loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) inhibits T cell infiltration into tumors and has been found to correlate with resistance to anti-PD-1 in melanoma patients.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Loss', 'Var', (141, 145))	('tumors', 'Disease', (247, 253))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('175', '205'))	('malignant melanoma', 'Phenotype', 'HP:0002861', (120, 138))	('phosphatase and tensin homolog', 'Gene', '5728', (175, 205))	('inhibits', 'NegReg', (213, 221))	('malignant melanoma', 'Disease', 'MESH:D008545', (120, 138))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', (153, 158))	('DNR', 'Chemical', '-', (37, 40))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (247, 252))	('PTEN', 'Gene', (207, 211))	('phosphatase', 'molecular_function', 'GO:0016791', ('175', '186'))	('if', 'Gene', '17319', (11, 13))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('patients', 'Species', '9606', (327, 335))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('malignant melanoma', 'Disease', (120, 138))	('PTEN', 'Gene', '5728', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))
53265	32894202	We recently demonstrated that loss of PTEN impedes trafficking of effector T cells to tumors, reduces the sensitivity of melanoma cells to T cell mediated killing, and correlates with inferior outcomes in patients treated with immune checkpoint blockade.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('sensitivity', 'MPA', (106, 117))	('melanoma', 'Disease', (121, 129))	('PTEN', 'Gene', '5728', (38, 42))	('patients', 'Species', '9606', (205, 213))	('impedes', 'NegReg', (43, 50))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('ecto', 'Gene', (69, 73))	('tumors', 'Disease', (86, 92))	('reduces', 'NegReg', (94, 101))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('ecto', 'Gene', '51592', (69, 73))	('trafficking', 'CPA', (51, 62))	('loss', 'Var', (30, 34))	('PTEN', 'Gene', (38, 42))
53270	32894202	Overexpression of glycolysis-related enzymes impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('glycolysis', 'biological_process', 'GO:0006096', ('18', '28'))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cell killing', 'biological_process', 'GO:0001906', ('56', '68'))	('impaired T', 'Disease', (45, 55))	('impaired T', 'Disease', 'MESH:D060825', (45, 55))	('enhanced T cell', 'Phenotype', 'HP:0100828', (118, 133))	('inhibition of glycolysis', 'biological_process', 'GO:0045820', ('93', '117'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('inhibition', 'Var', (93, 103))
53271	32894202	Inhibition of glycolysis enhanced efficacy of adoptive T-cell therapy (ACT) and increased glycolytic activity was detected in cell lines from melanoma patients non-responding to ACT.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('enhanced', 'PosReg', (25, 33))	('Inhibition of glycolysis', 'biological_process', 'GO:0045820', ('0', '24'))	('increased', 'PosReg', (80, 89))	('glycolytic', 'MPA', (90, 100))	('patients', 'Species', '9606', (151, 159))	('Inhibition', 'Var', (0, 10))	('adoptive T-cell therapy', 'CPA', (46, 69))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('glycolysis', 'Enzyme', (14, 24))	('melanoma', 'Disease', (142, 150))
53280	32894202	The analysis of ctDNA provides three parameters that may be correlated with clinical outcome: (1) the total quantity of ctDNA in the sample, (2) the molecular fingerprint of the ctDNA by mutation detection, and (3) the quantification of mutant copy numbers.	('if', 'Gene', '17319', (224, 226))	('mutation', 'Var', (187, 195))	('mutant copy numbers', 'Var', (237, 256))
53287	32894202	OS was worse in patients with TMB <= 23.1 Mut/Mb and either ctDNA increase/detectable or ctDNA increase of > 50% at first follow-up.	('TMB <= 23.1 Mut/Mb', 'Var', (30, 48))	('patients', 'Species', '9606', (16, 24))	('ctDNA', 'Disease', (60, 65))	('increase/detectable', 'PosReg', (66, 85))	('TMB', 'Chemical', '-', (30, 33))
53313	32894202	Overall, tumor types with higher median mutation burden tend to be more responsive to checkpoint inhibitors than tumors that harbor few mutations.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('more', 'PosReg', (67, 71))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('responsive to checkpoint inhibitors', 'MPA', (72, 107))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
53320	32894202	Beyond beta-catenin, gene deletions and loss-of-function mutations of the tumor suppressor phosphatase and tensin homolog (PTEN) have also been associated with poor T cell infiltration in the tumor microenvironment in metastatic melanoma.	('mutations', 'Var', (57, 66))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('91', '121'))	('tumor', 'Disease', (74, 79))	('PTEN', 'Gene', (123, 127))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('melanoma', 'Disease', (229, 237))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('PTEN', 'Gene', '5728', (123, 127))	('loss-of-function', 'NegReg', (40, 56))	('tumor', 'Disease', (192, 197))	('beta-catenin', 'Gene', (7, 19))	('beta-catenin', 'Gene', '1499', (7, 19))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('phosphatase', 'molecular_function', 'GO:0016791', ('91', '102'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('phosphatase and tensin homolog', 'Gene', '5728', (91, 121))
53321	32894202	Loss of PTEN, which leads to increased activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, has been associated with primary and secondary resistance to PD-1 blockade in melanoma.	('PD-1 blockade in melanoma', 'Disease', (168, 193))	('Akt', 'Gene', (94, 97))	('activation', 'PosReg', (39, 49))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('phosphatidylinositol 3-kinase', 'Gene', (57, 86))	('phosphatidylinositol 3-kinase', 'Gene', '5291', (57, 86))	('PD-1 blockade in melanoma', 'Disease', 'MESH:D010300', (168, 193))	('Akt', 'Gene', '207', (94, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('Loss', 'Var', (0, 4))	('associated', 'Reg', (116, 126))
53324	32894202	Two oncogenic events linked to poor T cell infiltration and secondary immunotherapy resistance are tumor cell-intrinsic beta-catenin pathway activation and PTEN loss-of-function mutation or deletion.	('tumor', 'Disease', (99, 104))	('beta-catenin', 'Gene', '1499', (120, 132))	('PTEN loss', 'Disease', 'MESH:D006223', (156, 165))	('deletion', 'Var', (190, 198))	('mutation', 'Var', (178, 186))	('PTEN loss', 'Disease', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('beta-catenin', 'Gene', (120, 132))	('activation', 'PosReg', (141, 151))
53331	32894202	In cancer, PD-1+Tim-3+ CD8+ T cells are dysfunctional/exhausted.	('PD-1+Tim-3+', 'Var', (11, 22))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('dysfunctional', 'Disease', 'MESH:D009461', (40, 53))	('cancer', 'Disease', (3, 9))	('dysfunctional', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
53339	32894202	They also support that dual blockade of PD-1 and TIM-3 reinvigorates effector T cell responses more potently than single blockade.	('reinvigorates', 'Reg', (55, 68))	('TIM-3', 'Gene', (49, 54))	('dual blockade', 'Var', (23, 36))	('ecto', 'Gene', (72, 76))	('ecto', 'Gene', '51592', (72, 76))	('PD-1', 'Gene', (40, 44))
53341	32894202	Anti-TIM-3 antibody indirectly enhanced a CD8+ T cell response during chemotherapy.	('enhanced', 'PosReg', (31, 39))	('antibody', 'cellular_component', 'GO:0042571', ('11', '19'))	('antibody', 'cellular_component', 'GO:0019815', ('11', '19'))	('CD8', 'Gene', (42, 45))	('antibody', 'cellular_component', 'GO:0019814', ('11', '19'))	('CD8', 'Gene', '925', (42, 45))	('antibody', 'molecular_function', 'GO:0003823', ('11', '19'))	('Anti-TIM-3', 'Var', (0, 10))
53365	32894202	Its dysregulation has been implicated in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('upregulation', 'PosReg', (86, 98))	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('dysregulation', 'Var', (4, 17))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('implicated', 'Reg', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
53374	32894202	The dose expansion phase of the trial will evaluate CAN04 as monotherapy as well as in combination with cisplatin/gemcitabine in NSCLC and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma.	('pancreatic ductal adenocarcinoma', 'Disease', (169, 201))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (169, 201))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (169, 201))	('paclitaxel', 'Chemical', 'MESH:D017239', (155, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('gemcitabine', 'Chemical', 'MESH:C056507', (114, 125))	('nab', 'Chemical', '-', (151, 154))	('NSCLC', 'Disease', (129, 134))	('gemcitabine', 'Chemical', 'MESH:C056507', (139, 150))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('CAN04', 'Chemical', '-', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('CAN04', 'Var', (52, 57))
53378	32894202	MIW815 (ADU-S100) has shown efficacy in combination with PD-1 checkpoint inhibitors and elicited near complete clearance of injected and non-injected tumors in mice.	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('clearance', 'CPA', (111, 120))	('MIW815', 'Chemical', '-', (0, 6))	('MIW815', 'Var', (0, 6))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
53379	32894202	In a phase 1b combination trial of intratumorally administered MIW815, a novel synthetic cyclic dinucleotide that activates the STING pathway, and spartalizumab, a humanized IgG4 monoclonal antibody that blocks the binding of PD-1 to PD-L1/2.	('antibody', 'molecular_function', 'GO:0003823', ('190', '198'))	('antibody', 'cellular_component', 'GO:0042571', ('190', '198'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('antibody', 'cellular_component', 'GO:0019815', ('190', '198'))	('spartalizumab', 'Chemical', '-', (147, 160))	('STING pathway', 'Pathway', (128, 141))	('binding', 'molecular_function', 'GO:0005488', ('215', '222'))	('MIW815', 'Chemical', '-', (63, 69))	('MIW815', 'Var', (63, 69))	('antibody', 'cellular_component', 'GO:0019814', ('190', '198'))	('tumor', 'Disease', (40, 45))	('binding', 'Interaction', (215, 222))	('activates', 'PosReg', (114, 123))	('human', 'Species', '9606', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PD-L1/2', 'Gene', '29126;80380', (234, 241))	('IgG4', 'cellular_component', 'GO:0071735', ('174', '178'))	('PD-L1/2', 'Gene', (234, 241))	('cyclic dinucleotide', 'Chemical', '-', (89, 108))
53386	32894202	CD8 frequency as detected by IHC increased in responding patients with high PD-L1 at baseline.	('high', 'Var', (71, 75))	('IHC', 'Gene', '11797', (29, 32))	('patients', 'Species', '9606', (57, 65))	('CD8', 'Gene', (0, 3))	('increased', 'PosReg', (33, 42))	('CD8', 'Gene', '925', (0, 3))	('IHC', 'Gene', (29, 32))	('PD-L1', 'Gene', (76, 81))
53387	32894202	The combination of MIW815 and spartalizumab demonstrated antitumor activity in PD-1-naive patients with TNBC and patients with anti PD-1-relapsed/refractory melanoma.	('TNBC', 'Disease', (104, 108))	('MIW815', 'Var', (19, 25))	('spartalizumab', 'Chemical', '-', (30, 43))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TNBC', 'Disease', 'None', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('MIW815', 'Chemical', '-', (19, 25))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', (61, 66))
53398	32894202	Targeted therapy with BRAF/MEK inhibitor combinations are also effective as adjuvant therapy, with an estimated three-year RFS rate of 58% observed with dabrafenib plus trametinib versus 39% with placebo (HR for relapse or death, 0.47; 95% CI 0.39-0.58; P < 0.001), and so represent a new standard of care for BRAF-positive patients.	('BRAF', 'Gene', (310, 314))	('BRAF', 'Gene', '673', (310, 314))	('dabrafenib', 'Chemical', 'MESH:C561627', (153, 163))	('patients', 'Species', '9606', (324, 332))	('MEK', 'Gene', (27, 30))	('RFS', 'Disease', (123, 126))	('MEK', 'Gene', '5609', (27, 30))	('BRAF', 'Gene', '673', (22, 26))	('RFS', 'Disease', 'MESH:D005198', (123, 126))	('combinations', 'Var', (41, 53))	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', (223, 228))	('BRAF', 'Gene', (22, 26))	('trametinib', 'Chemical', 'MESH:C560077', (169, 179))
53451	32894202	There is large variability in TMB within tumor types, ranging from just a few to thousands of mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TMB', 'Chemical', '-', (30, 33))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
53452	32894202	A high TMB load has been shown to be associated with better response rates to checkpoint inhibitors in melanoma, NSCLC, and urothelial carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('TMB', 'Chemical', '-', (7, 10))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('high', 'Var', (2, 6))	('response', 'MPA', (60, 68))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('TMB', 'Protein', (7, 10))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('NSCLC', 'Disease', (113, 118))	('melanoma', 'Disease', (103, 111))	('better', 'PosReg', (53, 59))	('urothelial carcinoma', 'Disease', (124, 144))
53455	32894202	For example, mutations in the isocitrate dehydrogenase (IDH)-1 and IDH2 genes may facilitate escape from immune surveillance in a subset of malignant gliomas.	('malignant gliomas', 'Disease', (140, 157))	('facilitate', 'PosReg', (82, 92))	('malignant gliomas', 'Disease', 'MESH:D005910', (140, 157))	('IDH2', 'Gene', (67, 71))	('gliomas', 'Phenotype', 'HP:0009733', (150, 157))	('IDH2', 'Gene', '3418', (67, 71))	('isocitrate dehydrogenase (IDH)-1', 'Gene', '3417', (30, 62))	('mutations', 'Var', (13, 22))	('escape', 'MPA', (93, 99))
53457	32894202	Treatment with IDH-C35, a selective mutant IDH-1 inhibitor, restored chemokine expression, promoted T-cell infiltration, and increased the efficacy of therapeutic peptide vaccination against IDH-mutated gliomas in mice.	('gliomas', 'Disease', 'MESH:D005910', (203, 210))	('promoted', 'PosReg', (91, 99))	('IDH-C35', 'Var', (15, 22))	('IDH-1', 'Gene', '15926', (43, 48))	('increased', 'PosReg', (125, 134))	('gliomas', 'Phenotype', 'HP:0009733', (203, 210))	('restored', 'PosReg', (60, 68))	('T-cell infiltration', 'CPA', (100, 119))	('IDH-1', 'Gene', (43, 48))	('mice', 'Species', '10090', (214, 218))	('gliomas', 'Disease', (203, 210))	('chemokine expression', 'MPA', (69, 89))
53467	32894202	In a cohort of 150 melanoma patients receiving anti-PD-1 antibodies whole plasma was analyzed at baseline, and on-treatment at 6-week and 6-month timepoints.	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('anti-PD-1', 'Var', (47, 56))	('patients', 'Species', '9606', (28, 36))
53516	24661650	Mice with melanomas treated with hypofractionated radiotherapy (32 Gy in 4 once weekly fractions) had superior survival, irradiated tumor control and fewer lung metastases than mice treated with conventionally fractionated radiotherapy (60 Gy in daily 30 fractions).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('32 Gy', 'Var', (64, 69))	('melanomas', 'Disease', (10, 19))	('lung metastases', 'Disease', 'MESH:D009362', (156, 171))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('superior', 'PosReg', (102, 110))	('lung metastases', 'Disease', (156, 171))	('tumor', 'Disease', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('Mice', 'Species', '10090', (0, 4))	('fewer', 'NegReg', (150, 155))	('mice', 'Species', '10090', (177, 181))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))
53555	24661650	In 2002, investigators at the University of Utah reported 10 patients with melanoma who underwent fractionated radiotherapy (45-52.5 Gy in conventional fractionation in 9 patients, or 36 Gy hypofractionated in 1 patient) and received varying doses of interferon alpha-2b concurrently, or within one month of radiotherapy.	('patient', 'Species', '9606', (61, 68))	('patient', 'Species', '9606', (171, 178))	('interferon alpha-2b', 'Gene', '3440', (251, 270))	('patients', 'Species', '9606', (61, 69))	('patient', 'Species', '9606', (212, 219))	('interferon alpha-2b', 'Gene', (251, 270))	('patients', 'Species', '9606', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('45-52.5 Gy', 'Var', (125, 135))
53628	24661650	Preclinical studies with non-melanoma cancer models have demonstrated that CTLA-4 blockade promotes the abscopal effect of radiotherapy.	('abscopal effect of radiotherapy', 'CPA', (104, 135))	('promotes', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('blockade', 'Var', (82, 90))	('CTLA-4', 'Gene', (75, 81))	('non-melanoma cancer', 'Disease', (25, 44))	('non-melanoma cancer', 'Disease', 'MESH:D008545', (25, 44))
53632	24661650	Fewer lung metastases were noted in animals treated with radiation and CTLA-4 blockade, and that this effect appeared dependent on CD8+ cells.	('blockade', 'Var', (78, 86))	('Fewer', 'NegReg', (0, 5))	('CTLA-4', 'Gene', (71, 77))	('CD8', 'Gene', '925', (131, 134))	('CD8', 'Gene', (131, 134))	('lung metastases', 'Disease', (6, 21))	('lung metastases', 'Disease', 'MESH:D009362', (6, 21))
53675	24661650	Preclinical evidence suggests that PD-1 blockade may interact with radiation to improve local tumor control, survival, in a variety of radiation dose and fractionation schema.	('blockade', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('schema', 'Disease', 'None', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('schema', 'Disease', (168, 174))	('PD-1', 'Gene', (35, 39))	('improve', 'PosReg', (80, 87))	('PD-1', 'Gene', '5133', (35, 39))	('survival', 'CPA', (109, 117))
53708	31322504	Genetic profiling has shown that the mutation rate of melanoma is the highest among all cancers.	('mutation', 'Var', (37, 45))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('melanoma', 'Disease', (54, 62))	('cancers', 'Disease', (88, 95))	('highest', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
53712	31322504	All four subtypes harbored NRAS and BRAF mutations, and the proliferative subtype was associated with poor survival.	('mutations', 'Var', (41, 50))	('NRAS', 'Gene', '4893', (27, 31))	('BRAF', 'Gene', (36, 40))	('harbored', 'Reg', (18, 26))	('NRAS', 'Gene', (27, 31))	('BRAF', 'Gene', '673', (36, 40))
53772	31322504	However, both DNA hypermethylation and hypomethylation have been reported in skin tumors exposed to ultraviolet radiation, indicating possible methylation heterogeneity.	('skin tumors', 'Disease', 'MESH:D012878', (77, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('skin tumors', 'Phenotype', 'HP:0008069', (77, 88))	('methylation', 'biological_process', 'GO:0032259', ('143', '154'))	('skin tumors', 'Disease', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('14', '34'))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('hypomethylation', 'Var', (39, 54))
53775	31322504	In a population study of cutaneous melanoma patients based on self-reported personal behavior in the sun, an independent inverse association was detected between the presence (versus absence) of solar elastosis (a histologic indicator of cutaneous sun damage) and disease-specific mortality (HR 0.40, 95% CI: 0.20-0.80).	('solar elastosis', 'Disease', (195, 210))	('cutaneous melanoma', 'Disease', (25, 43))	('patients', 'Species', '9606', (44, 52))	('presence', 'Var', (166, 174))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('sun damage', 'Phenotype', 'HP:0000992', (248, 258))	('solar elastosis', 'Disease', 'MESH:D005148', (195, 210))	('disease-specific mortality', 'CPA', (264, 290))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('inverse', 'NegReg', (121, 128))
53780	31322504	The proposed mechanisms include increased vitamin D, nitric oxide and melanin production, altered DNA damage-repair mechanisms and BRAF mutations.	('DNA', 'Gene', (98, 101))	('increased vitamin D', 'Phenotype', 'HP:0100512', (32, 51))	('vitamin D', 'Chemical', 'MESH:D014807', (42, 51))	('BRAF', 'Gene', (131, 135))	('altered', 'Reg', (90, 97))	('nitric oxide', 'Chemical', 'MESH:D009569', (53, 65))	('vitamin D', 'MPA', (42, 51))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('mutations', 'Var', (136, 145))	('increased', 'PosReg', (32, 41))	('BRAF', 'Gene', '673', (131, 135))
53781	31322504	Sun exposure is the primary source of vitamin D, and high vitamin D levels have been associated with reduced risks of cancer and overall mortality.	('high vitamin D', 'Phenotype', 'HP:0100512', (53, 67))	('vitamin D', 'Chemical', 'MESH:D014807', (38, 47))	('cancer', 'Disease', (118, 124))	('vitamin D', 'Chemical', 'MESH:D014807', (58, 67))	('high', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
53814	28919783	High gene expression of TLR7 and TLR8 in melanoma tumors is associated with high expression levels of functional markers of immune cells, which predicts longer overall survival of patients with melanoma.	('melanoma tumors', 'Disease', 'MESH:D008545', (41, 56))	('melanoma tumors', 'Disease', (41, 56))	('patients', 'Species', '9606', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('TLR7', 'Gene', (24, 28))	('TLR7', 'Gene', '51284', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('longer', 'PosReg', (153, 159))	('High gene', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TLR8', 'Gene', '51311', (33, 37))	('high expression levels of functional', 'MPA', (76, 112))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('gene expression', 'biological_process', 'GO:0010467', ('5', '20'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('TLR8', 'Gene', (33, 37))
53816	28919783	Aberrant regulation of TLRs in human skin could, in part, lead to chronic inflammation and contribute to melanoma tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('contribute', 'Reg', (91, 101))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('TLRs', 'Gene', (23, 27))	('lead to', 'Reg', (58, 65))	('inflammation', 'Disease', (74, 86))	('tumor', 'Disease', (114, 119))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('human', 'Species', '9606', (31, 36))	('Aberrant regulation', 'Var', (0, 19))	('inflammation', 'biological_process', 'GO:0006954', ('74', '86'))
53823	28919783	Although TLR7 agonists have been used to treat cancer patients, their ability to generate tumor-specific immunity and to kill tumor cells directly by activating innate immune responses remains controversial.	('TLR7', 'Gene', (9, 13))	('agonists', 'Var', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', (90, 95))	('TLR7', 'Gene', '51284', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('activating', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (126, 131))
53824	28919783	Moreover, it has been theorized that TLR7 agonists may provoke inflammation and promote tumorigenesis in some cancer types.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('TLR7', 'Gene', (37, 41))	('cancer', 'Disease', (110, 116))	('inflammation', 'biological_process', 'GO:0006954', ('63', '75'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('provoke', 'PosReg', (55, 62))	('promote', 'PosReg', (80, 87))	('TLR7', 'Gene', '51284', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('tumor', 'Disease', (88, 93))	('agonists', 'Var', (42, 50))	('inflammation', 'Disease', (63, 75))
53836	28919783	As shown in Figure 1A, our survival analysis indicated that high TLR7 expression levels predict longer overall survival times (HR =1.734, P=0.0002) for these patients.	('TLR7', 'Gene', '51284', (65, 69))	('overall survival times', 'CPA', (103, 125))	('high', 'Var', (60, 64))	('expression levels', 'MPA', (70, 87))	('longer', 'PosReg', (96, 102))	('TLR7', 'Gene', (65, 69))	('patients', 'Species', '9606', (158, 166))
53839	28919783	Despite the smaller patient cohort, our survival analysis with the GSE19234 database indicated that high levels of TLR7 expression also predict longer overall survival times (HR =2.492, P=0.023, Figure 1C).	('overall survival times', 'CPA', (151, 173))	('expression', 'MPA', (120, 130))	('TLR7', 'Gene', '51284', (115, 119))	('longer', 'PosReg', (144, 150))	('high levels', 'Var', (100, 111))	('patient', 'Species', '9606', (20, 27))	('TLR7', 'Gene', (115, 119))
53844	28919783	Next, we performed multivariate survival analysis and found that high TLR7 expression levels were significantly associated with better prognosis independent of other variables (Table 2).	('TLR7', 'Gene', '51284', (70, 74))	('high', 'Var', (65, 69))	('TLR7', 'Gene', (70, 74))	('expression levels', 'MPA', (75, 92))
53858	28919783	TLRs are important components of innate immunity in skin tissues and their dysregulation has been shown to contribute to the development of melanoma.	('dysregulation', 'Var', (75, 88))	('innate immunity', 'biological_process', 'GO:0045087', ('33', '48'))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('contribute', 'Reg', (107, 117))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TLRs', 'Gene', (0, 4))
53862	28919783	However, some studies also have reported that aberrant activation of TLR enhances inflammation and promoted tumorigenesis.	('TLR', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('promoted', 'PosReg', (99, 107))	('tumor', 'Disease', (108, 113))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('aberrant activation', 'Var', (46, 65))	('inflammation', 'Disease', (82, 94))	('inflammation', 'biological_process', 'GO:0006954', ('82', '94'))	('enhances', 'PosReg', (73, 81))
53874	28919783	TLR activation has been shown to promote DC maturation and the production of cytokines, potentially resulting in the activation of specific type of T-cell immunity, involving the recruitment of CD8+ T cells.	('CD8', 'Gene', (194, 197))	('CD8', 'Gene', '925', (194, 197))	('promote', 'PosReg', (33, 40))	('activation', 'Var', (4, 14))	('activation', 'PosReg', (117, 127))	('production of cytokines', 'MPA', (63, 86))	('TLR', 'Gene', (0, 3))	('DC maturation', 'CPA', (41, 54))
53890	24345920	BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition Recurrent "driver" mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically-relevant molecular subsets of melanoma, but >30% are "pan-negative" for these recurrent mutations.	('BRAF', 'Gene', '673', (0, 4))	('GNA11', 'Gene', (182, 187))	('NRAS', 'Gene', (161, 165))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('BRAF', 'Gene', (0, 4))	('MEK', 'Gene', '5609', (91, 94))	('KIT', 'molecular_function', 'GO:0005020', ('165', '168'))	('GNAQ', 'Gene', '2776', (172, 176))	('Melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('GNAQ', 'Gene', (172, 176))	('MEK', 'Gene', (91, 94))	('mutations', 'Var', (125, 134))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('Melanomas', 'Disease', 'MESH:D008545', (51, 60))	('GNA11', 'Gene', '2767', (182, 187))	('NRAS', 'Gene', '4893', (161, 165))	('Melanomas', 'Disease', (51, 60))	('KIT', 'Gene', (167, 170))	('BRAF', 'Gene', '673', (155, 159))	('BRAF', 'Gene', (155, 159))
53892	24345920	Using a targeted next-generation sequencing (NGS) assay (FoundationOne ) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a "pan-negative" melanoma.	('fusion', 'Var', (136, 142))	('PAPSS1', 'Gene', (124, 130))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('RNA', 'cellular_component', 'GO:0005562', ('86', '89'))	('PAPSS1', 'Gene', '9061', (124, 130))
53893	24345920	We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne , as well as melanoma RNA, whole genome and whole exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('melanoma', 'Disease', (45, 53))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('Cancer Genome Atlas', 'Disease', (161, 180))	('melanomas', 'Disease', (45, 54))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (161, 180))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('fusions', 'Var', (234, 241))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
53896	24345920	NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a "pan-negative" sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive.	('MEK', 'Gene', (164, 167))	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('MEK', 'Gene', '5609', (164, 167))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('TRIM24-BRAF', 'Var', (143, 154))	('melanomas', 'Disease', (35, 44))	('MAPK', 'molecular_function', 'GO:0004707', ('115', '119'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('115', '129'))	('MAPK signaling', 'MPA', (117, 131))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
53897	24345920	Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 "pan-negative" cases.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 43))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('skin cutaneous melanoma', 'Disease', (20, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('fusions', 'Var', (94, 101))
53898	24345920	BRAF fusions define a new molecular subset of melanoma, potentially comprising 4-8% of "pan-negative" cases.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('fusions', 'Var', (5, 12))	('BRAF', 'Gene', (0, 4))
53900	24345920	A 2.2 cm thick (Clark Level V), focally ulcerated, malignant melanoma from the left shoulder of a 27-year-old Caucasian female was screened for common melanoma driver mutations in BRAF, NRAS, KIT, GNAQ and GNA11 by the Vanderbilt melanoma SNaPshot assay and determined to be "pan-negative".	('NRAS', 'Gene', (186, 190))	('malignant melanoma', 'Phenotype', 'HP:0002861', (51, 69))	('mutations', 'Var', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('malignant melanoma', 'Disease', 'MESH:D008545', (51, 69))	('melanoma', 'Disease', (230, 238))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('GNA11', 'Gene', (206, 211))	('GNAQ', 'Gene', '2776', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('GNAQ', 'Gene', (197, 201))	('KIT', 'Gene', (192, 195))	('BRAF', 'Gene', (180, 184))	('KIT', 'molecular_function', 'GO:0005020', ('192', '195'))	('NRAS', 'Gene', '4893', (186, 190))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('malignant melanoma', 'Disease', (51, 69))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('GNA11', 'Gene', '2767', (206, 211))
53904	24345920	This test involves targeted NGS of 3,320 exons in 182 cancer-related genes and 37 introns in 14 genes recurrently rearranged in cancer and simultaneously detects single nucleotide variants, insertions, deletions, copy number changes, and select rearrangements (see Supplementary Methods).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('single nucleotide variants', 'Var', (162, 188))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('deletions', 'Var', (202, 211))	('cancer', 'Disease', (54, 60))	('rearrangements', 'Var', (245, 259))	('insertions', 'Var', (190, 200))	('detects', 'Reg', (154, 161))	('copy number changes', 'Var', (213, 232))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (128, 134))
53905	24345920	Subsequent targeted RNA sequencing of tumor cDNA identified a novel, in-frame fusion between exon 5 of the sulfurylase kinase PAPSS1 (3'-phosphoadenosine 5'-phosphosulfate synthetase-1) and exon 9 of BRAF generated by a t(4;7)(q24;q34) translocation (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('t(4;7)(q24;q34) translocation', 'Var', (220, 249))	('t(4;7)(q24;q34)', 'STRUCTURAL_ABNORMALITY', 'None', (220, 235))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PAPSS1', 'Gene', (126, 132))	('PAPSS1', 'Gene', '9061', (126, 132))
53906	24345920	To determine the effect of the PAPSS1-BRAF fusion on MAPK signaling in cells, we expressed cDNAs encoding FLAG-tagged WT BRAF, mutant BRAF (V600E), WT PAPSS1 or the fusion in 293H cells.	('mutant', 'Var', (127, 133))	('PAPSS1', 'Gene', (31, 37))	('PAPSS1', 'Gene', '9061', (31, 37))	('PAPSS1', 'Gene', '9061', (151, 157))	('293H', 'CellLine', 'CVCL:6643', (175, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('V600E', 'Mutation', 'rs113488022', (140, 145))	('BRAF', 'Gene', (134, 138))	('V600E', 'Var', (140, 145))	('PAPSS1', 'Gene', (151, 157))	('MAPK signaling', 'biological_process', 'GO:0000165', ('53', '67'))
53910	24345920	These data confirm that the PAPSS1-BRAF fusion activates the MAPK signaling cascade.	('fusion', 'Var', (40, 46))	('MAPK signaling', 'biological_process', 'GO:0000165', ('61', '75'))	('PAPSS1', 'Gene', '9061', (28, 34))	('activates', 'PosReg', (47, 56))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('signaling cascade', 'biological_process', 'GO:0007165', ('66', '83'))	('MAPK signaling cascade', 'Pathway', (61, 83))	('PAPSS1', 'Gene', (28, 34))
53911	24345920	Activation of MAPK signaling by BRAF V600E is sensitive to inhibition by both vemurafenib (a BRAF mutant-specific inhibitor) and trametinib (a MEK inhibitor).	('MEK', 'Gene', (143, 146))	('MAPK signaling', 'Pathway', (14, 28))	('MEK', 'Gene', '5609', (143, 146))	('trametinib', 'Chemical', 'MESH:C560077', (129, 139))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('MAPK', 'molecular_function', 'GO:0004707', ('14', '18'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('14', '28'))	('BRAF V600E', 'Var', (32, 42))	('Activation', 'PosReg', (0, 10))	('vemurafenib', 'Chemical', 'MESH:D000077484', (78, 89))
53912	24345920	To determine if signaling induced by the BRAF fusion was inhibited by these agents, we transfected 293H cells with the V600E or PAPSS1-BRAF cDNAs and treated them with vehicle control or increasing concentrations of vemurafenib or trametinib for 2 hours.	('signaling', 'biological_process', 'GO:0023052', ('16', '25'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (216, 227))	('trametinib', 'Chemical', 'MESH:C560077', (231, 241))	('293H', 'CellLine', 'CVCL:6643', (99, 103))	('PAPSS1', 'Gene', (128, 134))	('PAPSS1', 'Gene', '9061', (128, 134))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('V600E', 'Var', (119, 124))
53913	24345920	Immunoblotting studies with the corresponding lysates showed that BRAF V600E-induced MEK1/2 phosphorylation was effectively reduced by vemurafenib, but MEK1/2 phosphorylation induced by PAPSS1-BRAF was not.	('V600E-induced', 'Var', (71, 84))	('phosphorylation', 'biological_process', 'GO:0016310', ('159', '174'))	('phosphorylation', 'MPA', (92, 107))	('MEK1', 'molecular_function', 'GO:0004708', ('85', '89'))	('PAPSS1', 'Gene', (186, 192))	('reduced', 'NegReg', (124, 131))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('MEK1/2', 'Gene', '5604;5605', (152, 158))	('PAPSS1', 'Gene', '9061', (186, 192))	('MEK1/2', 'Gene', (152, 158))	('MEK1/2', 'Gene', '5604;5605', (85, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (135, 146))	('MEK1', 'molecular_function', 'GO:0004708', ('152', '156'))	('MEK1/2', 'Gene', (85, 91))	('BRAF', 'Gene', (66, 70))
53914	24345920	Trametinib, however, was effective at reducing ERK1/2 phosphorylation in both V600E- and PAPSS1-BRAF-expressing cells (Figure 2B).	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('V600E-', 'Var', (78, 84))	('reducing', 'NegReg', (38, 46))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('PAPSS1', 'Gene', (89, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('ERK1/2', 'Gene', '5595;5594', (47, 53))	('ERK1', 'molecular_function', 'GO:0004707', ('47', '51'))	('ERK1/2', 'Gene', (47, 53))	('PAPSS1', 'Gene', '9061', (89, 95))	('phosphorylation', 'MPA', (54, 69))
53915	24345920	These results suggest that downstream signaling induced by the PAPSS1-BRAF fusion could be abrogated by MEK but not mutant-specific BRAF inhibitors.	('PAPSS1', 'Gene', (63, 69))	('fusion', 'Var', (75, 81))	('PAPSS1', 'Gene', '9061', (63, 69))	('downstream signaling', 'MPA', (27, 47))	('MEK', 'Gene', (104, 107))	('abrogated', 'NegReg', (91, 100))	('MEK', 'Gene', '5609', (104, 107))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))
53917	24345920	Only 8 of 52 (15%) tumors harbored V600 changes, at least less than half the expected percent in unbiased cohorts, and 8 of 52 (15.4%) harbored non-V600 (D594, L597, K601, etc.)	('K601', 'Var', (166, 170))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('V600 changes', 'Var', (35, 47))	('L597', 'Var', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
53920	24345920	Similar to PAPSS1-BRAF, ectopic expression of TRIM24-BRAF led to activation of the MAPK pathway which was sensitive to MEK, but not BRAF, inhibition (Figure S3).	('PAPSS1', 'Gene', (11, 17))	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('PAPSS1', 'Gene', '9061', (11, 17))	('TRIM24-BRAF', 'Var', (46, 57))	('MAPK pathway', 'Pathway', (83, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('activation', 'PosReg', (65, 75))
53923	24345920	In two of 49 (4.1%) "pan-negative" cases, we identified sequence reads indicative of potential BRAF fusions, involving CDC27 and TAX1BP1 as 5' partners (Figure S4).	('fusions', 'Var', (100, 107))	('TAX1BP1', 'Gene', (129, 136))	('TAX1BP1', 'Gene', '8887', (129, 136))	('CDC27', 'Gene', '996', (119, 124))	('CDC27', 'Gene', (119, 124))
53924	24345920	Consistent with these findings, TCGA reverse phase protein array (RPPA) data comparing levels of phosphorylated MEK1/2 in the tumors harboring fusions versus those with BRAF, NRAS, KIT, GNAQ or GNA11 mutations revealed that the fusion cases harbor phosphorylated MEK1/2 levels similar to, or greater than, levels observed in BRAF or NRAS-mutant melanomas (Figure S5).	('GNA11', 'Gene', '2767', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('melanomas', 'Disease', 'MESH:D008545', (345, 354))	('MEK1', 'molecular_function', 'GO:0004708', ('263', '267'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('melanomas', 'Disease', (345, 354))	('NRAS', 'Gene', '4893', (333, 337))	('tumors', 'Disease', (126, 132))	('GNAQ', 'Gene', '2776', (186, 190))	('NRAS', 'Gene', (175, 179))	('GNAQ', 'Gene', (186, 190))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('KIT', 'molecular_function', 'GO:0005020', ('181', '184'))	('GNA11', 'Gene', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('melanomas', 'Phenotype', 'HP:0002861', (345, 354))	('MEK1/2', 'Gene', '5604;5605', (263, 269))	('MEK1/2', 'Gene', (263, 269))	('MEK1/2', 'Gene', '5604;5605', (112, 118))	('MEK1/2', 'Gene', (112, 118))	('MEK1', 'molecular_function', 'GO:0004708', ('112', '116'))	('NRAS', 'Gene', (333, 337))	('melanoma', 'Phenotype', 'HP:0002861', (345, 353))	('fusion', 'Var', (228, 234))	('NRAS', 'Gene', '4893', (175, 179))
53925	24345920	Collectively, these data suggest that BRAF fusions exist in 4-8% of "pan-negative" melanomas.	('fusions', 'Var', (43, 50))	('melanomas', 'Disease', (83, 92))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
53926	24345920	The classification and treatment of melanomas by known recurrent single-nucleotide driver mutation status in BRAF (V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209) and GNA11 (Q209) has changed standard treatment practice by enabling rationally guided treatment.	('GNA11', 'Gene', '2767', (194, 199))	('D816', 'Var', (171, 175))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('single-nucleotide', 'Var', (65, 82))	('NRAS', 'Gene', (122, 126))	('Q209', 'Var', (184, 188))	('melanomas', 'Disease', (36, 45))	('KIT', 'molecular_function', 'GO:0005020', ('142', '145'))	('BRAF', 'Gene', (109, 113))	('GNA11', 'Gene', (194, 199))	('GNAQ', 'Gene', '2776', (178, 182))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('Q61', 'Var', (136, 139))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('GNAQ', 'Gene', (178, 182))	('L576', 'Var', (159, 163))	('NRAS', 'Gene', '4893', (122, 126))	('V559', 'Var', (153, 157))	('K642', 'Var', (165, 169))
53927	24345920	However, in our experience at Vanderbilt, using an established SNaPshot-based assay in the clinic, approximately one-third of melanomas are still "pan-negative" for these mutations.	('melanomas', 'Disease', (126, 135))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('mutations', 'Var', (171, 180))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))
53928	24345920	We recently determined that approximately 8% of cases negative for these drivers harbor other activating mutations in BRAF exon 15 (D594E/G/H/N/V, L597R/S/Q/V and K601E/I/N) rather than the better-known V600E/K/M/R/D alterations, and we showed in a patient harboring a BRAF L597 mutation that tumor regression could be induced by a MEK inhibitor.	('patient', 'Species', '9606', (249, 256))	('D594E', 'Var', (132, 137))	('BRAF', 'Gene', (269, 273))	('MEK', 'Gene', (332, 335))	('V600E', 'Var', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('L597R', 'SUBSTITUTION', 'None', (147, 152))	('L597 mutation', 'Var', (274, 287))	('MEK', 'Gene', '5609', (332, 335))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('K601E', 'Var', (163, 168))	('L597R', 'Var', (147, 152))	('tumor', 'Disease', (293, 298))	('activating', 'PosReg', (94, 104))	('BRAF exon 15', 'Gene', (118, 130))	('K601E', 'SUBSTITUTION', 'None', (163, 168))	('D594E', 'SUBSTITUTION', 'None', (132, 137))
53929	24345920	Here, we have identified another subset of potentially clinically relevant "pan-negative" melanomas defined by BRAF fusions.	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('melanomas', 'Disease', 'MESH:D008545', (90, 99))	('fusions', 'Var', (116, 123))	('melanomas', 'Disease', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
53930	24345920	Specifically, we found two novel BRAF fusions (PAPSS1-BRAF and TRIM24-BRAF) in 2 of 24 (8%) "pan-negative" melanomas genotyped on an assay that examines that status of 182 cancer-related genes and 37 introns in 14 genes recurrently rearranged in cancer.	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('PAPSS1', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('TRIM24-BRAF', 'Var', (63, 74))	('melanomas', 'Disease', (107, 116))	('cancer', 'Disease', (172, 178))	('PAPSS1', 'Gene', '9061', (47, 53))
53932	24345920	Through mining TCGA skin cutaneous melanoma dataset, we also identified two potential BRAF fusions in another 49 "pan-negative" cases, indicating a frequency of 4.1% in an independent cohort.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 43))	('fusions', 'Var', (91, 98))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('skin cutaneous melanoma', 'Disease', (20, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('BRAF', 'Gene', (86, 90))
53936	24345920	Interestingly, a version of TRIM24-BRAF fusion was identified in the early 1990s in a cDNA library derived from a model of mouse hepatocellular carcinoma, but not identified in humans until now.	('humans', 'Species', '9606', (177, 183))	('mouse', 'Species', '10090', (123, 128))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (129, 153))	('TRIM24-BRAF', 'Var', (28, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('hepatocellular carcinoma', 'Disease', (129, 153))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (129, 153))
53938	24345920	Like PAPSS1-BRAF, we show that expression of TRIM24-BRAF leads to activation of the MAPK pathway which is sensitive to MEK inhibition (Figure S3).	('MEK', 'Gene', (119, 122))	('MEK', 'Gene', '5609', (119, 122))	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('MAPK pathway', 'Pathway', (84, 96))	('PAPSS1', 'Gene', (5, 11))	('TRIM24-BRAF', 'Var', (45, 56))	('PAPSS1', 'Gene', '9061', (5, 11))	('activation', 'PosReg', (66, 76))
53940	24345920	A BRAF rearrangement was identified previously by break-apart fluorescence in situ hybridization (FISH) in a single malignant melanoma in 2010, however, insufficient sample remained for follow-up analyses that might have identified the fusion partner and allowed for its characterization.	('malignant melanoma', 'Disease', 'MESH:D008545', (116, 134))	('malignant melanoma', 'Disease', (116, 134))	('rearrangement', 'Var', (7, 20))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('insufficient', 'Disease', 'MESH:D000309', (153, 165))	('malignant melanoma', 'Phenotype', 'HP:0002861', (116, 134))	('insufficient', 'Disease', (153, 165))
53943	24345920	Because PAPSS1-BRAF and TRIM24-BRAF are structured similarly to all other BRAF fusions (Figure 5), and because we show that both PAPSS1-BRAF and TRIM24-BRAF activate MAPK pathway signaling (Figure 2, Figure S3), we expect these melanoma BRAF fusions will also be transforming.	('MAPK pathway signaling', 'Pathway', (166, 188))	('melanoma BRAF fusions', 'Disease', 'MESH:D008545', (228, 249))	('PAPSS1', 'Gene', (8, 14))	('signaling', 'biological_process', 'GO:0023052', ('179', '188'))	('activate', 'PosReg', (157, 165))	('PAPSS1', 'Gene', '9061', (8, 14))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('TRIM24-BRAF', 'Var', (24, 35))	('melanoma BRAF fusions', 'Disease', (228, 249))	('PAPSS1', 'Gene', (129, 135))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('TRIM24-BRAF', 'Var', (145, 156))	('PAPSS1', 'Gene', '9061', (129, 135))
53946	24345920	Similarly, the recently-discovered BRAF V600E splice variants which induce vemurafenib resistance harbor N-terminal exons and mutant kinase domain exons, but RBD exons are spliced out, allowing for constitutive dimerization at the RKTR dimerization interface.	('BRAF', 'Gene', (35, 39))	('induce', 'PosReg', (68, 74))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('vemurafenib', 'MPA', (75, 86))	('vemurafenib', 'Chemical', 'MESH:D000077484', (75, 86))	('V600E', 'Var', (40, 45))	('mutant', 'Var', (126, 132))
53947	24345920	Recently, Sievert, et al., demonstrated that KIAA1549-BRAF fusion variants can homodimerize with one another; introduction of a dimer interface mutant (R509H) disrupts this interaction.	('R509H', 'Var', (152, 157))	('homodimerize', 'MPA', (79, 91))	('R509H', 'Mutation', 'p.R509H', (152, 157))	('KIAA1549', 'Gene', (45, 53))	('disrupts', 'NegReg', (159, 167))	('interaction', 'Interaction', (173, 184))	('KIAA1549', 'Gene', '57670', (45, 53))
53950	24345920	Subsequent analysis of 51 additional melanomas (24 of which were "pan-negative") revealed a second fusion, TRIM24-BRAF, that also activates MEK1/2 and ERK1/2.	('ERK1/2', 'Gene', (151, 157))	('melanomas', 'Disease', (37, 46))	('MEK1', 'molecular_function', 'GO:0004708', ('138', '142'))	('ERK1/2', 'Gene', '5595;5594', (151, 157))	('melanomas', 'Disease', 'MESH:D008545', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('MEK1/2', 'Gene', (140, 146))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('activates', 'PosReg', (130, 139))	('MEK1/2', 'Gene', '5604;5605', (140, 146))	('ERK1', 'molecular_function', 'GO:0004707', ('149', '153'))	('TRIM24-BRAF', 'Var', (107, 118))
53951	24345920	We also identified two candidate BRAF fusions in the TCGA skin cutaneous melanoma dataset.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 81))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (63, 81))	('skin cutaneous melanoma', 'Disease', (58, 81))	('fusions', 'Var', (38, 45))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
53952	24345920	Thus, BRAF fusions may occur in 4-8% of the "pan-negative" melanoma population.	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('fusions', 'Var', (11, 18))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
53954	24345920	Collectively, these biochemical and genetic data define an additional molecular subset of melanoma that should be routinely screened for in the clinic, and knowledge about BRAF fusions in melanoma may provide insight into the mechanism of responses to treatment with an expanding list of available kinase inhibitors.	('melanoma', 'Disease', (90, 98))	('fusions', 'Var', (177, 184))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('BRAF', 'Gene', (172, 176))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
53955	24345920	Through comprehensive molecular tumor profiling, we identified novel BRAF fusions in two of 24 melanoma patients lacking other known recurrent driver mutations in BRAF, NRAS, KIT, GNAQ, and GNA11.	('GNA11', 'Gene', (190, 195))	('BRAF', 'Gene', (163, 167))	('NRAS', 'Gene', (169, 173))	('GNA11', 'Gene', '2767', (190, 195))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('melanoma', 'Disease', (95, 103))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('GNAQ', 'Gene', '2776', (180, 184))	('NRAS', 'Gene', '4893', (169, 173))	('fusions', 'Var', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('KIT', 'molecular_function', 'GO:0005020', ('175', '178'))	('tumor', 'Disease', (32, 37))	('patients', 'Species', '9606', (104, 112))	('GNAQ', 'Gene', (180, 184))
53957	24345920	We also identified two candidate BRAF fusions in another 49 "pan-negative" cases in the TCGA skin cutaneous melanoma dataset.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('skin cutaneous melanoma', 'Disease', (93, 116))	('fusions', 'Var', (38, 45))
53958	24345920	Thus, BRAF fusions represent a new, potentially clinically relevant target in melanomas possibly treatable with kinase inhibitors.	('melanomas', 'Disease', (78, 87))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('BRAF', 'Gene', (6, 10))	('fusions', 'Var', (11, 18))
53978	33687443	Additionally, targeted therapies approved for the treatment of BRAF V600-altered melanoma include BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) and MEK inhibitors (trametinib, combimetinib, binimetinib).	('combimetinib', 'Chemical', '-', (185, 197))	('vemurafenib', 'Chemical', 'MESH:D000077484', (127, 138))	('men', 'Species', '9606', (55, 58))	('MEK', 'Gene', (157, 160))	('MEK', 'Gene', '5609', (157, 160))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('encorafenib', 'Chemical', 'MESH:C000601108', (140, 151))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('trametinib', 'Chemical', 'MESH:C560077', (173, 183))	('BRAF', 'Gene', '673', (63, 67))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('V600-altered', 'Var', (68, 80))	('BRAF', 'Gene', (63, 67))	('binimetinib', 'Chemical', 'MESH:C581313', (199, 210))	('dabrafenib', 'Chemical', 'MESH:C561627', (115, 125))
54032	33687443	Median (IQR) OS was 16.3 (3.5-28.8) months for patients with M1c disease and liver metastases vs 56.5 (10.8-62.2) months for those with M1c disease and no liver metastases (HR, 0.52; 95% CI, 0.33-0.82; P = .004).	('liver metastases', 'Disease', (155, 171))	('liver metastases', 'Disease', 'MESH:D009362', (77, 93))	('patients', 'Species', '9606', (47, 55))	('liver metastases', 'Disease', 'MESH:D009362', (155, 171))	('M1c disease', 'Var', (61, 72))	('liver metastases', 'Disease', (77, 93))
54060	33687443	Preclinical studies have shown that elevations in LDH promote immunosuppression by enhancing the recruitment of T-regulatory cells, inhibiting natural killer (NK) cells, and increasing myeloid-derived suppressor cell frequency.	('promote', 'PosReg', (54, 61))	('myeloid-derived suppressor cell frequency', 'CPA', (185, 226))	('immunosuppression', 'Disease', (62, 79))	('elevations', 'Var', (36, 46))	('recruitment', 'MPA', (97, 108))	('men', 'Species', '9606', (104, 107))	('LDH', 'Gene', (50, 53))	('enhancing', 'PosReg', (83, 92))	('increasing', 'PosReg', (174, 184))	('inhibiting', 'NegReg', (132, 142))
54064	33687443	In the current therapeutic landscape, BRAF/MEK inhibition represents an alternative therapeutic option in patients with BRAF V600-altered melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('MEK', 'Gene', '5609', (43, 46))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('BRAF', 'Gene', '673', (120, 124))	('V600-altered', 'Var', (125, 137))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (120, 124))	('patients', 'Species', '9606', (106, 114))	('BRAF', 'Gene', (38, 42))	('MEK', 'Gene', (43, 46))
54068	33687443	We found that patients with BRAF alterations had a shorter time to progression but similar OS as patients with BRAF WT tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('BRAF', 'Gene', '673', (28, 32))	('shorter', 'NegReg', (51, 58))	('BRAF WT tumors', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('alterations', 'Var', (33, 44))	('BRAF WT tumors', 'Disease', 'MESH:C536751', (111, 125))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (28, 32))	('patients', 'Species', '9606', (14, 22))	('BRAF', 'Gene', (111, 115))	('patients', 'Species', '9606', (97, 105))
54069	33687443	Importantly, BRAF variant status was no longer significantly associated in the multivariable setting.	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('variant', 'Var', (18, 25))
54070	33687443	Prospective studies evaluating the differential outcomes based on BRAF variant status are in progress.	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('variant', 'Var', (71, 78))
54078	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))
54081	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'))
54082	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))	('mesothelioma', 'Disease', 'MESH:D008654', (221, 233))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('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))
54083	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))
54084	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))
54087	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))
54088	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'))
54089	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))
54093	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))	('cancer', 'Disease', (101, 107))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (200, 206))
54094	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))
54095	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))	('mutation', 'Var', (6, 14))	('associated', 'Reg', (66, 76))	('BAP1', 'Gene', (132, 136))	('BAP1', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('loss', 'NegReg', (137, 141))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
54096	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))
54097	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))
54100	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))
54102	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))
54103	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))
54104	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))	('BAP1', 'Gene', (55, 59))	('primary tumours', 'Disease', 'MESH:D009369', (165, 180))	('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))
54107	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))
54108	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))
54109	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'))
54110	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))
54113	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))
54116	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))
54117	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))	('cutaneous melanoma', 'Disease', (112, 130))	('BAP1', 'Gene', (70, 74))	('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))
54118	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))
54119	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))
54125	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))	('BAP1', 'Gene', (149, 153))	('loss-of-function', 'NegReg', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('alleles', 'Var', (154, 161))
54126	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))	('SIFT', 'Disease', (172, 176))	('BAP1', 'Gene', (117, 121))	('variants', 'Var', (122, 130))
54127	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))
54128	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))
54131	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))
54134	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))
54135	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))	('melanocytic lesions', 'Disease', (31, 50))	('variants', 'Var', (120, 128))
54137	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))
54141	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))
54144	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))
54145	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))
54147	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))
54148	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))
54149	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))
54150	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))
54152	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))
54154	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))
54155	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.	('impair', 'NegReg', (144, 150))	('variants', 'Var', (25, 33))	('cancer', 'Disease', (183, 189))	('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))
54156	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))
54157	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))
54158	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))
54159	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))
54161	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))	('cancers', 'Disease', (393, 400))	('cancer', 'Disease', (393, 399))	('mutations', 'Var', (330, 339))	('variants', 'Var', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
54163	28062663	Overall, less than ~0.2% of melanoma cases had identifiable loss-of-function BAP1 variants.	('melanoma', 'Disease', (28, 36))	('variants', 'Var', (82, 90))	('BAP1', 'Gene', (77, 81))	('loss-of-function', 'NegReg', (60, 76))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
54164	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))	('meningiomas', 'Disease', 'MESH:D008577', (180, 191))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('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))	('mutation', 'Var', (151, 159))	('cancers', 'Disease', (109, 116))	('BCC', 'Disease', (196, 199))	('cancer', 'Disease', (109, 115))	('variant', 'Var', (78, 85))	('associated', 'Reg', (131, 141))	('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))
54165	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))
54166	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))
54167	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))
54168	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))
54169	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))
54170	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))
54171	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))
54173	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))
54174	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.	('germline', 'Var', (214, 222))	('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))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mesothelioma', 'Disease', (88, 100))	('mutated', 'Var', (172, 179))	('BAP1', 'Gene', (167, 171))
54175	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))
54176	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))
54179	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))
54188	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))
54189	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', (144, 148))	('alleles', 'Var', (42, 49))	('SIFT', 'Disease', 'None', (144, 148))	('loss-of-function', 'NegReg', (25, 41))
54190	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))
54191	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))
54200	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))
54219	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))	('cutaneous melanoma', 'Disease', (8, 26))	('BRAF', 'Gene', (134, 138))	('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'))
54220	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))
54269	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))
54323	31258724	PSME1, PSME2, and PSME3 were significantly enriched in several biological processes and pathways including cell adhesion, adherens junction organization, regulation of autophagy, cellular protein localization, the cell cycle, apoptosis, and the Wnt and NF-kappaB pathways.	('autophagy', 'CPA', (168, 177))	('adherens junction organization', 'biological_process', 'GO:0034332', ('122', '152'))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('cellular protein localization', 'biological_process', 'GO:0034613', ('179', '208'))	('NF-kappaB', 'Gene', (253, 262))	('apoptosis', 'CPA', (226, 235))	('cell adhesion', 'biological_process', 'GO:0007155', ('107', '120'))	('cellular', 'CPA', (179, 187))	('cell cycle', 'CPA', (214, 224))	('PSME1', 'Gene', (0, 5))	('NF-kappaB', 'Gene', '4790', (253, 262))	('cell cycle', 'biological_process', 'GO:0007049', ('214', '224'))	('adherens junction organization', 'CPA', (122, 152))	('cell adhesion', 'CPA', (107, 120))	('PSME3', 'Var', (18, 23))	('PSME2', 'Gene', (7, 12))	('PSME1', 'Gene', '5720', (0, 5))	('regulation of autophagy', 'biological_process', 'GO:0010506', ('154', '177'))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('PSME2', 'Gene', '5721', (7, 12))	('adherens junction', 'cellular_component', 'GO:0005912', ('122', '139'))
54333	31258724	In some cancers, overexpression of PSME3 was associated with poor OS.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('OS', 'Chemical', '-', (66, 68))	('overexpression', 'Var', (17, 31))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PSME3', 'Protein', (35, 40))	('poor OS', 'Disease', (61, 68))
54365	31258724	In the KEGG pathway, high expression of PSME1 was positively correlated with cell adhesion (Figure 8A), apoptosis (Figure 8 D, E), the cell cycle (Figure 8F), metastasis (Figure 8I) and the Wnt and NF-kappaB signaling pathways (Figure 8 B, C and G).	('NF-kappaB', 'Gene', (198, 207))	('metastasis', 'CPA', (159, 169))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('cell cycle', 'CPA', (135, 145))	('correlated', 'Reg', (61, 71))	('cell cycle', 'biological_process', 'GO:0007049', ('135', '145'))	('high expression', 'Var', (21, 36))	('cell adhesion', 'biological_process', 'GO:0007155', ('77', '90'))	('PSME1', 'Gene', (40, 45))	('PSME1', 'Gene', '5720', (40, 45))	('NF-kappaB', 'Gene', '4790', (198, 207))	('apoptosis', 'CPA', (104, 113))	('cell adhesion', 'CPA', (77, 90))	('apoptosis', 'biological_process', 'GO:0097194', ('104', '113'))	('KEGG pathway', 'Pathway', (7, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('104', '113'))
54378	31258724	Pathway-based analysis revealed that PSME1 is associated with KEGG and apoptosis pathways and that PSME2 and PSME3 are significantly enriched in the canonical and planar cell polarity Wnt signaling pathways, which have been associated with cancer.	('PSME3', 'Var', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('PSME2', 'Gene', (99, 104))	('PSME2', 'Gene', '5721', (99, 104))	('PSME1', 'Gene', (37, 42))	('PSME1', 'Gene', '5720', (37, 42))	('associated', 'Reg', (224, 234))	('cell polarity', 'biological_process', 'GO:0007163', ('170', '183'))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('signaling', 'biological_process', 'GO:0023052', ('188', '197'))	('associated', 'Reg', (46, 56))	('cancer', 'Disease', (240, 246))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('apoptosis pathways', 'Pathway', (71, 89))
54387	31258724	Similarly, PSME3 silencing attenuated the cell proliferation, migration and invasive abilities of endometrial cancer cells.	('endometrial cancer', 'Disease', 'MESH:D016889', (98, 116))	('migration', 'CPA', (62, 71))	('attenuated', 'NegReg', (27, 37))	('endometrial cancer', 'Phenotype', 'HP:0012114', (98, 116))	('cell proliferation', 'CPA', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('endometrial cancer', 'Disease', (98, 116))	('PSME3', 'Gene', (11, 16))	('silencing', 'Var', (17, 26))	('invasive abilities', 'CPA', (76, 94))
54391	31258724	Other studies indicate that mutations in the TP53 gene, which encodes the tumor suppressor protein p53, occur in various types of cancer, and that PSME3 negatively regulates p53, whereby the elimination of endogenous PSME3 in human cancer cells abrogates MDM2-mediated p53 degradation, increases the activity of p53, and enhances apoptosis.	('TP53', 'Gene', (45, 49))	('cancer', 'Disease', (232, 238))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('p53', 'Gene', (312, 315))	('degradation', 'biological_process', 'GO:0009056', ('273', '284'))	('p53', 'Gene', '7157', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('p53', 'Gene', '7157', (269, 272))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('MDM2', 'Gene', (255, 259))	('p53', 'Gene', (174, 177))	('apoptosis', 'CPA', (330, 339))	('TP53', 'Gene', '7157', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('p53', 'Gene', (269, 272))	('increases', 'PosReg', (286, 295))	('activity', 'MPA', (300, 308))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('MDM2', 'Gene', '4193', (255, 259))	('degradation', 'MPA', (273, 284))	('elimination', 'Var', (191, 202))	('p53', 'Gene', '7157', (99, 102))	('mutations', 'Var', (28, 37))	('human', 'Species', '9606', (226, 231))	('enhances', 'PosReg', (321, 329))	('abrogates', 'NegReg', (245, 254))	('cancer', 'Disease', (130, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('330', '339'))	('apoptosis', 'biological_process', 'GO:0006915', ('330', '339'))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('p53', 'Gene', (99, 102))	('p53', 'Gene', '7157', (312, 315))
54392	31258724	Notably, p53 mutations show a positive correlation with PSME3 expression in various cancer cell lines.	('PSME3', 'Gene', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (13, 22))
54405	31945090	Pan-cancer analysis of somatic mutations and epigenetic alterations in insulated neighbourhood boundaries Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation.	('mutations', 'Var', (31, 40))	('epigenetic alterations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('lead to', 'Reg', (195, 202))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('oncogene dysregulation', 'MPA', (203, 225))
54406	31945090	We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('genome alterations', 'Var', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('associations', 'Interaction', (64, 76))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
54407	31945090	Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('abnormal', 'Var', (65, 73))	('bindings', 'Interaction', (146, 154))	('CTCF', 'Gene', (141, 145))	('copy number', 'CPA', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('methylation', 'MPA', (74, 85))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))
54408	31945090	Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (200, 206))	('mutations', 'Var', (179, 188))
54409	31945090	Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('transversions', 'Var', (124, 137))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutated', 'Var', (13, 20))	('cancer', 'Disease', (66, 72))
54411	31945090	Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('copy number alterations', 'Var', (49, 72))	('cancer', 'Disease', (20, 26))	('active junctions', 'MPA', (94, 110))
54412	31945090	While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('methylation', 'biological_process', 'GO:0032259', ('172', '183'))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (139, 145))
54417	31945090	Hypermethylation of CTCF binding sites has been observed to lead to loss of insulation between topological domains and consequent aberrant gene activation in gliomas.	('insulation between topological domains', 'MPA', (76, 114))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('Hypermethylation', 'Var', (0, 16))	('gene', 'MPA', (139, 143))	('activation', 'PosReg', (144, 154))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('loss', 'NegReg', (68, 72))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))
54418	31945090	Microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent acute lymphoblastic leukemia proto-oncogenes have also been reported.	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (103, 125))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('lymphoblastic leukemia', 'Disease', (103, 125))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (97, 125))	('boundary sites', 'MPA', (34, 48))	('Microdeletions', 'Var', (0, 14))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (103, 125))
54419	31945090	The same study also identified an enrichment in boundary CTCF site mutations in the genomes of esophageal and liver carcinoma.	('esophageal', 'Disease', (95, 105))	('liver carcinoma', 'Disease', (110, 125))	('liver carcinoma', 'Disease', 'MESH:D006528', (110, 125))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('liver carcinoma', 'Phenotype', 'HP:0001402', (110, 125))
54420	31945090	Furthermore, genomic rearrangements with breakpoints within TADs can lead to breakage or fusion of TADs that might result in oncogene activation, as observed in prostate cancer, where chromosomal deletions lead to the establishment of new domain boundaries and the rearrangement of gene interactions.	('chromosomal deletions', 'Var', (184, 205))	('gene', 'Protein', (282, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('rearrangements', 'Var', (21, 35))	('breakage', 'Var', (77, 85))	('activation', 'PosReg', (134, 144))	('oncogene', 'MPA', (125, 133))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rearrangement', 'Reg', (265, 278))	('lead', 'Reg', (69, 73))	('breakpoints', 'Var', (41, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('interactions', 'Interaction', (287, 299))
54421	31945090	Hotspots of mutations within CTCF motifs have been independently observed in melanoma related to UV exposure, and in gastrointestinal cancers.	('CTCF motifs', 'Gene', (29, 40))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (117, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('observed', 'Reg', (65, 73))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (117, 140))	('gastrointestinal cancers', 'Disease', (117, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
54430	31945090	While mutations in CTCF binding sites have been reported to occur frequently in several cancers, the significance of these findings across the broad spectrum of cancer types has not yet been evaluated.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('binding', 'Interaction', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CTCF', 'Gene', (19, 23))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (6, 15))	('occur', 'Reg', (60, 65))
54431	31945090	Specifically, we selected 14 cancer types for which at least 200,000 mutations across all patients were reported:this threshold was imposed in order to ensure adequate statistics.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
54433	31945090	Fig 2, left subplot, shows the accumulation of mutations in esophageal adenocarcinoma (ESAD), one of the tumour types for which this phenomenon was more evident.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('ESAD', 'Phenotype', 'HP:0011459', (87, 91))	('ESAD', 'Disease', 'MESH:D004941', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (60, 85))	('esophageal adenocarcinoma', 'Disease', (60, 85))	('tumour', 'Disease', (105, 111))	('mutations', 'Var', (47, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (60, 85))	('ESAD', 'Disease', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
54441	31945090	Hence, it could be argued that the enrichment of mutations in active in-boundary motifs is due to the proximity of these motifs to promoters, rather than to a cancer specific mechanism.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (49, 58))
54444	31945090	In no cancer type did we observe an enrichment of mutations in promoters, supporting the hypothesis that the accumulation of mutations in active CTCF motifs is not due to the overlap of promoters, and hence, not due to the open state of the chromatin.	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (50, 59))	('chromatin', 'cellular_component', 'GO:0000785', ('241', '250'))	('CTCF motifs', 'Gene', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))
54446	31945090	We also tried to test if mutations tend to cluster on active enhancers, defined as the intersection of H3K4me1 and H3K27Ac histone modifications, but for such regions we found a very small intersection with active in-boundary CTCF motifs and it was not possible to perform a significative statistical test.	('H3K27Ac', 'Var', (115, 122))	('H3K4me1', 'Chemical', 'MESH:C024755', (103, 110))	('mutations', 'Var', (25, 34))
54448	31945090	Notably, in the list of oncogenes we find TGFB1, whose up-regulation has been recently associated with disruption of CTCF binding motif due to somatic mutations in the melanoma A375 cell line.	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))	('up-regulation', 'PosReg', (55, 68))	('TGFB1', 'Gene', (42, 47))	('A375', 'CellLine', 'CVCL:0132', (177, 181))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('mutations', 'Var', (151, 160))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
54452	31945090	Next, we investigated whether the somatic mutations in active in-boundary motifs preferentially belong to a certain class of mutations, which could point to a specific tumourigenic mechanism.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Disease', (168, 174))	('point', 'Reg', (148, 153))	('mutations', 'Var', (42, 51))	('belong', 'Reg', (96, 102))
54454	31945090	Table 3 reports the counts of transition and transversion mutations for active in-boundary and active off-boundary motifs for all considered cancers.	('transversion mutations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
54458	31945090	Assuming that similar results can be generalised to somatic alterations, this finding suggests that transversions on CTCF motifs might have a stronger effect than transitions, which could hint towards a positive selection of transversions rather than transitions in insulated neighborhood boundaries in tumour cells, as these alterations are more likely to disrupt boundaries than transitions.	('neighborhood boundaries in tumour', 'Disease', (276, 309))	('neighborhood boundaries in tumour', 'Disease', 'MESH:D009369', (276, 309))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('CTCF motifs', 'Gene', (117, 128))	('transversions', 'Var', (100, 113))
54460	31945090	We considered the five tumour types for which we have the highest number of mutations (see Table B in S1 File):and studied their mutation patterns.	('tumour', 'Disease', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))
54461	31945090	Esophageal Adenocarcinoma (ESAD), Liver Cancer (LIRI) and Breast Cancer (BRCA) were associated with the largest enrichment of in-boundary mutations in all 3 considered ChIA-PET experiments (see Table 2).	('Liver Cancer', 'Disease', 'MESH:D006528', (34, 46))	('Breast Cancer', 'Disease', 'MESH:D001943', (58, 71))	('Liver Cancer', 'Phenotype', 'HP:0002896', (34, 46))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast Cancer', 'Disease', (58, 71))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (0, 25))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Breast Cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESAD', 'Disease', (27, 31))	('BRCA', 'Disease', (73, 77))	('Liver Cancer', 'Disease', (34, 46))	('mutations', 'Var', (138, 147))	('ESAD', 'Disease', 'MESH:D004941', (27, 31))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('BRCA', 'Disease', 'MESH:D001943', (73, 77))	('Esophageal Adenocarcinoma', 'Disease', (0, 25))	('ESAD', 'Phenotype', 'HP:0011459', (27, 31))
54465	31945090	Point mutations in skin cancer (MELA) and skin adenocarcinoma (SKCA) are shown in Fig 5D and 5E.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('skin cancer', 'Phenotype', 'HP:0008069', (19, 30))	('skin cancer', 'Disease', (19, 30))	('SKCA', 'Disease', 'MESH:D000230', (63, 67))	('skin cancer', 'Disease', 'MESH:D012878', (19, 30))	('MELA', 'Phenotype', 'HP:0002861', (32, 36))	('skin adenocarcinoma', 'Disease', 'MESH:D000230', (42, 61))	('MELA', 'Disease', 'MESH:D008545', (32, 36))	('skin adenocarcinoma', 'Disease', (42, 61))	('Point mutations', 'Var', (0, 15))	('MELA', 'Disease', (32, 36))	('SKCA', 'Disease', (63, 67))
54466	31945090	These mutations are consistent with the observed enrichment of C T and CC TT mutations in ultraviolet exposure-driven melanoma tumours.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('CC TT', 'Gene', (71, 76))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('melanoma tumours', 'Disease', 'MESH:D008545', (118, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma tumours', 'Disease', (118, 134))	('mutations', 'Var', (77, 86))
54469	31945090	In our analysis we found that signature SBS26, which is associated with defective DNA mismatch repair, is particularly prominent in the active in-boundary motifs in Esophageal Adenocarcinoma (ESAD Fig 6), Liver Cancer (LIRI, Fig I in S1 File) and Breast Cancer (BRCA, Fig H in S1 File), although the exposure of the same signature is not relevant in the whole genome of the same tumors.	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('BRCA', 'Disease', 'MESH:D001943', (262, 266))	('Liver Cancer', 'Disease', (205, 217))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', (165, 190))	('ESAD', 'Phenotype', 'HP:0011459', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('tumors', 'Disease', (379, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('Liver Cancer', 'Disease', 'MESH:D006528', (205, 217))	('Breast Cancer', 'Disease', 'MESH:D001943', (247, 260))	('mismatch repair', 'biological_process', 'GO:0006298', ('86', '101'))	('BRCA', 'Phenotype', 'HP:0003002', (262, 266))	('Liver Cancer', 'Phenotype', 'HP:0002896', (205, 217))	('Breast Cancer', 'Disease', (247, 260))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (165, 190))	('Breast Cancer', 'Phenotype', 'HP:0003002', (247, 260))	('defective', 'Var', (72, 81))	('ESAD', 'Disease', (192, 196))	('SBS26', 'Var', (40, 45))	('BRCA', 'Disease', (262, 266))	('ESAD', 'Disease', 'MESH:D004941', (192, 196))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))
54470	31945090	For what it concerns Skin Sancer (MELA) and Skin Adenocarcinoma (SKCA) we found that within in-boundary motifs the signature SBS7b has the highest exposure and not signature SBS7a as in the whole genome (Figs J and K in S1 File).	('SKCA', 'Disease', 'MESH:D000230', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('SBS7b', 'Var', (125, 130))	('Skin Adenocarcinoma', 'Disease', (44, 63))	('MELA', 'Disease', (34, 38))	('exposure', 'MPA', (147, 155))	('MELA', 'Phenotype', 'HP:0002861', (34, 38))	('Skin Adenocarcinoma', 'Disease', 'MESH:D000230', (44, 63))	('SKCA', 'Disease', (65, 69))	('MELA', 'Disease', 'MESH:D008545', (34, 38))
54471	31945090	We also found a significant overlap of frequently mutated boundaries across tumour types in the same five tumour types (Melanoma, Esophageal Adenocarcinoma, Skin Adenocarcinoma, Liver Cancer and Breast Cancer) associated with the highest number of mutations, see Fig F in S1 File.	('mutations', 'Var', (248, 257))	('Melanoma', 'Disease', 'MESH:D008545', (120, 128))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Breast Cancer', 'Disease', (195, 208))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (130, 155))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))	('Breast Cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Melanoma', 'Disease', (120, 128))	('Skin Adenocarcinoma, Liver Cancer', 'Disease', 'MESH:D006528', (157, 190))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('Melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('Esophageal Adenocarcinoma', 'Disease', (130, 155))	('tumour', 'Disease', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('associated', 'Reg', (210, 220))	('Liver Cancer', 'Phenotype', 'HP:0002896', (178, 190))	('Breast Cancer', 'Disease', 'MESH:D001943', (195, 208))
54473	31945090	All pair-wise comparisons resulted in very significant p-values, confirming that mutations in boundaries do not happen by random chance, hinting to a concerted oncogenic mechanism to dysregulate key cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (199, 205))
54475	31945090	Increased methylation leading to disruption of CTCF binding patterns has also been observed in immortalized cell lines, suggesting that abnormal methylation of CTFC motifs might be a mechanism of cancer gene dysregulation.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('abnormal', 'Var', (136, 144))	('binding', 'molecular_function', 'GO:0005488', ('52', '59'))	('methylation', 'MPA', (145, 156))	('mechanism', 'Reg', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))
54480	31945090	In several cancer types we observed hypermethylation on in-boundary motifs.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypermethylation', 'Var', (36, 52))
54490	31945090	Copy number alterations (CNA) are a main tumorigenic driver in many cancer types.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (41, 46))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
54491	31945090	In the context of neighbourhood dysregulation, recent work has reported tandem duplications intersecting with a TAD that led to de novo 3D contact domain formation.	('neighbourhood dysregulation', 'Disease', (18, 45))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('neighbourhood dysregulation', 'Disease', 'MESH:D021081', (18, 45))	('3D contact domain formation', 'MPA', (136, 163))	('tandem duplications', 'Var', (72, 91))	('led to', 'Reg', (121, 127))
54492	31945090	The same work revealed that TAD boundary intersecting deletions are associated with IRS4 dysregulation (a gene often over-expressed in different cancer types) in sarcoma and squamous cancers.	('cancer', 'Disease', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (183, 189))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('squamous cancers', 'Disease', 'MESH:D018307', (174, 190))	('sarcoma', 'Disease', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('deletions', 'Var', (54, 63))	('IRS4', 'Gene', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('squamous cancers', 'Disease', (174, 190))
54493	31945090	Motivated by these findings, we investigate here whether copy number alterations may contribute to cancer phenotypes by disrupting topologically associated domain boundaries.	('disrupting', 'NegReg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('contribute', 'Reg', (85, 95))	('topologically associated domain boundaries', 'MPA', (131, 173))	('copy number alterations', 'Var', (57, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
54503	31945090	In recent work, principal component analysis (PCA) on CNA data was performed on various cancer types, and Ovarian, Lung and Breast (basal subtype) cancers were found to have a similar signature characterised by a higher degree of copy number alterations compared to other types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('copy number alterations', 'Var', (230, 253))	('Ovarian', 'Disease', (106, 113))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('Breast (basal subtype) cancers', 'Disease', 'MESH:D001943', (124, 154))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (147, 153))	('Lung', 'Disease', (115, 119))
54508	31945090	In for instance, the loss of one boundary enables a constitutive enhancer to interact aberrantly with PDGFRA, a prominent oncogene in glioma.	('loss', 'Var', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('PDGFRA', 'Gene', (102, 108))	('enhancer', 'PosReg', (65, 73))	('glioma', 'Disease', (134, 140))	('interact', 'Interaction', (77, 85))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
54510	31945090	In, mutations of one insulator region identified as a melanoma driver are associated with the upregulation of TGFB1, although another study on melanoma could not find evidence of gene expression enrichment.	('gene expression', 'biological_process', 'GO:0010467', ('179', '194'))	('upregulation', 'PosReg', (94, 106))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('TGFB1', 'Gene', (110, 115))	('mutations', 'Var', (4, 13))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
54511	31945090	Other studies have described gene expression changes in the proximity of mutation hotspots at CTCF binding sites in gastrointestinal cancer.	('binding', 'molecular_function', 'GO:0005488', ('99', '106'))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (116, 139))	('gastrointestinal cancer', 'Disease', (116, 139))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (116, 139))	('CTCF', 'Gene', (94, 98))	('changes', 'Reg', (45, 52))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gene expression', 'MPA', (29, 44))
54512	31945090	While each of these results individually suggests an important role for the dysregulation of some constitutive neighbourhoods in specific tumors, a conclusive pan-cancer analysis is not yet available.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('dysregulation', 'Var', (76, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
54514	31945090	Table 5 summarises our analysis: we find that somatic mutations, methylation, and copy number variations are significantly enriched in the neighbourhood boundaries in some specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('methylation', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('copy number variations', 'Var', (82, 104))	('cancer', 'Disease', (181, 187))
54517	31945090	We also observe a very significant overlap of frequently mutated active boundaries on these five cancers (Table G in S1 File), confirming that mutations in boundary do not happen at random.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutated', 'Var', (57, 64))
54518	31945090	A positive selection of transversions versus transitions seems to be prevalent in most cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('transversions', 'Var', (24, 37))
54521	31945090	Finally, we observe that copy number alterations significantly overlap with active junctions in four cancer types, namely in Breast Cancer (BRCA), Lung Adenocarcinoma (LUAD), Lung Squamous Carcinoma (LUSC) and Ovarian Cancer (OV), all of them cancers where important oncogenic CNA signatures have been identified.	('Squamous Carcinoma', 'Disease', 'MESH:D002294', (180, 198))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('LUSC', 'Phenotype', 'HP:0030359', (200, 204))	('Breast Cancer', 'Phenotype', 'HP:0003002', (125, 138))	('Squamous Carcinoma', 'Disease', (180, 198))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('Ovarian Cancer', 'Disease', (210, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('LUAD', 'Phenotype', 'HP:0030078', (168, 172))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (210, 224))	('copy number alterations', 'Var', (25, 48))	('overlap', 'Reg', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('OV', 'Disease', 'MESH:D010051', (226, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('BRCA', 'Disease', 'MESH:D001943', (140, 144))	('Lung Adenocarcinoma', 'Disease', (147, 166))	('Lung Adenocarcinoma', 'Disease', 'MESH:C538231', (147, 166))	('LUAD', 'Disease', (168, 172))	('Squamous Carcinoma', 'Phenotype', 'HP:0002860', (180, 198))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (210, 224))	('Breast Cancer', 'Disease', 'MESH:D001943', (125, 138))	('LUAD', 'Disease', 'MESH:C538231', (168, 172))	('cancer', 'Disease', (101, 107))	('OV', 'Phenotype', 'HP:0100615', (226, 228))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Disease', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (243, 250))	('Lung Squamous Carcinoma', 'Phenotype', 'HP:0030359', (175, 198))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))	('Breast Cancer', 'Disease', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
54537	29441208	Microvessel density (MVD) counting, as described by Weidner et al., allows, through the application of immunohistochemical stains, like von Willebrand factor (vWF), cluster of differentiation (CD) 31, CD34, and CD105, the quantification of the vasculature of the tumors.	('von Willebrand factor', 'Gene', '7450', (136, 157))	('von Willebrand factor', 'Gene', (136, 157))	('vWF', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('CD105', 'Var', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('CD34', 'Gene', '947', (201, 205))	('CD34', 'Gene', (201, 205))	('vWF', 'Gene', '7450', (159, 162))
54546	29441208	Subgroup analysis, on the basis of the antibody used, did not highlight any statistically significant difference regarding the pooled HR, while decreased heterogeneity was noted, in the CD34 arm (HR: 0.97, 95% CI: 0.88-1.06, Q test p = 0.39, I2 = 0%), but not in the respective CD31 group (HR: 3.49, 95% CI: 0.42-29.03, Q test p < 0.0001, I2 = 95%).	('antibody', 'molecular_function', 'GO:0003823', ('39', '47'))	('CD34', 'Var', (186, 190))	('CD31', 'Gene', '5175', (278, 282))	('heterogeneity', 'MPA', (154, 167))	('antibody', 'cellular_component', 'GO:0042571', ('39', '47'))	('antibody', 'cellular_component', 'GO:0019815', ('39', '47'))	('CD31', 'Gene', (278, 282))	('antibody', 'cellular_component', 'GO:0019814', ('39', '47'))
54547	29441208	Due to the high prevalence and mortality ratios of cutaneous melanoma, various prognostic factors have been investigated in the literature, including age, sex, tumor location, lymph node involvement, tumor thickness, ulceration, Clark level, tumor vascularity, lymphovascular invasion, microsatellites, mitotic rate, regression, tumor infiltrating lymphocytes, BRAF mutations, distant metastasis, and LDH.	('BRAF', 'Gene', (361, 365))	('BRAF', 'Gene', '673', (361, 365))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('regression', 'CPA', (317, 327))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('mutations', 'Var', (366, 375))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mitotic rate', 'CPA', (303, 315))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('distant metastasis', 'CPA', (377, 395))
54643	31182807	Otub1 deficiency in mice causes aberrant responses of CD8 T cells to IL-15, rendering naive CD8 T cells hyper-sensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions.	('Otub1', 'Gene', (0, 5))	('CD8', 'Gene', '925', (54, 57))	('CD8', 'Gene', (92, 95))	('responses', 'MPA', (41, 50))	('mice', 'Species', '10090', (20, 24))	('CD8', 'Gene', '925', (92, 95))	('deficiency', 'Var', (6, 16))	('T cells hyper', 'Phenotype', 'HP:0100828', (96, 109))	('enhanced', 'PosReg', (160, 168))	('IL-15', 'molecular_function', 'GO:0016170', ('69', '74'))	('CD8', 'Gene', (54, 57))
54645	31182807	Consistently, Otub1 deletion profoundly enhances anticancer immunity through unleashing the activity of CD8 T cells and NK cells.	('unleashing', 'NegReg', (77, 87))	('cancer', 'Disease', (53, 59))	('Otub1', 'Gene', (14, 19))	('enhances', 'PosReg', (40, 48))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('CD8', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('deletion', 'Var', (20, 28))	('activity', 'CPA', (92, 100))	('CD8', 'Gene', '925', (104, 107))
54653	31182807	IL-15 is a member of common gamma-chain (gammac) family cytokines that functions through the IL-15 receptor (IL-15R) complex, composed of IL-15Ralpha, IL-15Rbeta (also called IL-2Rbeta or CD122), and gammac (also called CD132).	('IL-15', 'molecular_function', 'GO:0016170', ('151', '156'))	('CD132', 'Gene', (220, 225))	('CD122', 'Gene', '16185', (188, 193))	('IL-15Rbeta', 'Gene', (151, 161))	('IL-15R', 'Gene', (109, 115))	('IL-15Rbeta', 'Gene', '16185', (151, 161))	('IL-15', 'molecular_function', 'GO:0016170', ('93', '98'))	('CD122', 'Gene', (188, 193))	('IL-2Rbeta', 'Gene', '16185', (175, 184))	('IL-15', 'molecular_function', 'GO:0016170', ('0', '5'))	('IL-2', 'molecular_function', 'GO:0005134', ('175', '179'))	('CD132', 'Gene', '16186', (220, 225))	('IL-15', 'molecular_function', 'GO:0016170', ('138', '143'))	('common gamma-chain', 'Gene', '16186', (21, 39))	('IL-15R', 'molecular_function', 'GO:0042010', ('109', '115'))	('IL-15Ralpha', 'Var', (138, 149))	('common gamma-chain', 'Gene', (21, 39))	('IL-2Rbeta', 'Gene', (175, 184))
54663	31182807	Although Otub1 was similarly expressed in CD4 and CD8 T cells (data not shown), Otub1 deficiency did not increase the frequency of CD4 effector/memory T cells (Fig.	('CD8', 'Gene', (50, 53))	('CD8', 'Gene', '925', (50, 53))	('CD4', 'Gene', (42, 45))	('memory T', 'Disease', 'MESH:D008569', (144, 152))	('memory', 'biological_process', 'GO:0007613', ('144', '150'))	('memory T', 'Disease', (144, 152))	('CD4', 'Gene', '12504', (42, 45))	('Otub1', 'Gene', (80, 85))	('CD4', 'Gene', (131, 134))	('deficiency', 'Var', (86, 96))	('CD4', 'Gene', '12504', (131, 134))
54664	31182807	The Otub1-TKO and wildtype (WT) mice had comparable frequencies of regulatory T cells (Treg cells), and the Otub1-deficient Treg cells were fully functional in suppressing naive CD4 T cells (Supplementary Fig.	('CD4', 'Gene', '12504', (178, 181))	('Otub1-TKO', 'Var', (4, 13))	('suppressing', 'NegReg', (160, 171))	('mice', 'Species', '10090', (32, 36))	('CD4', 'Gene', (178, 181))
54665	31182807	Mixed bone marrow adoptive transfer studies revealed that the Otub1-TKO CD8 T cells had increased frequencies of effector/memory-like population than WT CD8 T cells even in the same recipient mice (Supplementary Fig.	('CD8', 'Gene', (153, 156))	('mice', 'Species', '10090', (192, 196))	('memory', 'biological_process', 'GO:0007613', ('122', '128'))	('CD8', 'Gene', '925', (153, 156))	('Otub1-TKO', 'Var', (62, 71))	('increased', 'PosReg', (88, 97))	('effector/memory-like population', 'CPA', (113, 144))	('CD8', 'Gene', (72, 75))	('CD8', 'Gene', '925', (72, 75))
54669	31182807	In contrast, Otub1 deficiency had no effect on naive CD4 T cell activation (Fig.	('Otub1', 'Gene', (13, 18))	('deficiency', 'Var', (19, 29))	('T cell activation', 'biological_process', 'GO:0042110', ('57', '74'))	('CD4', 'Gene', (53, 56))	('CD4', 'Gene', '12504', (53, 56))
54671	31182807	The Otub1-TKO mice displayed markedly enhanced immune responses against LM-OVA infection, as demonstrated by reduced liver bacterial load and increased frequencies of antigen-specific CD8 effector T cells producing IFN-gamma (Fig.	('IFN-gamma', 'Gene', '15978', (215, 224))	('increased', 'PosReg', (142, 151))	('immune', 'MPA', (47, 53))	('Otub1-TKO', 'Var', (4, 13))	('enhanced', 'PosReg', (38, 46))	('mice', 'Species', '10090', (14, 18))	('liver bacterial load', 'MPA', (117, 137))	('reduced', 'NegReg', (109, 116))	('IFN-gamma', 'Gene', (215, 224))	('CD8', 'Gene', (184, 187))	('CD8', 'Gene', '925', (184, 187))
54676	31182807	Since Otub1 deficiency had selective effect on CD8 T cells (Fig.	('CD8', 'Gene', (47, 50))	('Otub1', 'Gene', (6, 11))	('deficiency', 'Var', (12, 22))	('CD8', 'Gene', '925', (47, 50))
54679	31182807	In the Il15ra+/+ recipients, Otub1-TKO CD8 T cells had much higher frequencies of memory-like T cells than WT CD8 T cells (Fig.	('CD8', 'Gene', (39, 42))	('Il15', 'molecular_function', 'GO:0016170', ('7', '11'))	('memory-like T cells', 'CPA', (82, 101))	('CD8', 'Gene', '925', (39, 42))	('higher', 'PosReg', (60, 66))	('CD8', 'Gene', (110, 113))	('Il15ra', 'Gene', '16169', (7, 13))	('memory', 'biological_process', 'GO:0007613', ('82', '88'))	('Otub1-TKO', 'Var', (29, 38))	('CD8', 'Gene', '925', (110, 113))	('Il15ra', 'Gene', (7, 13))
54681	31182807	We also examined the effect of Otub1 deficiency on IL-15-mediated CD8 T cell proliferation under lymphopenic conditions.	('CD8', 'Gene', (66, 69))	('Otub1', 'Gene', (31, 36))	('CD8', 'Gene', '925', (66, 69))	('T cell proliferation', 'biological_process', 'GO:0042098', ('70', '90'))	('deficiency', 'Var', (37, 47))	('IL-15', 'molecular_function', 'GO:0016170', ('51', '56'))
54685	31182807	However, the hyper-proliferation of the Otub1-TKO OT-I T cells was critically dependent on IL-15, since it was largely eliminated in the Il15ra-/- recipient mice (Fig.	('Otub1-TKO', 'Var', (40, 49))	('mice', 'Species', '10090', (157, 161))	('Il15ra', 'Gene', '16169', (137, 143))	('Il15ra', 'Gene', (137, 143))	('Il15', 'molecular_function', 'GO:0016170', ('137', '141'))	('IL-15', 'molecular_function', 'GO:0016170', ('91', '96'))
54687	31182807	Our finding that Otub1 deficiency promoted the activation of CD8 T cells by TCR-CD28 signals indicated that homeostatic exposure of CD8 T cells to IL-15 might prime them for activation by antigens.	('activation', 'MPA', (47, 57))	('deficiency', 'Var', (23, 33))	('CD28', 'Gene', '12487', (80, 84))	('IL-15', 'molecular_function', 'GO:0016170', ('147', '152'))	('TCR', 'cellular_component', 'GO:0042101', ('76', '79'))	('Otub1', 'Gene', (17, 22))	('CD8', 'Gene', (61, 64))	('TCR', 'Gene', (76, 79))	('CD8', 'Gene', '925', (61, 64))	('TCR', 'biological_process', 'GO:0006283', ('76', '79'))	('TCR', 'Gene', '328483', (76, 79))	('promoted', 'PosReg', (34, 42))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('CD28', 'Gene', (80, 84))
54689	31182807	Furthermore, in a T cell adoptive transfer experiment, Otub1-TKO OT-I CD8 T cells isolated from Il15ra+/+ recipients, but not Il15ra-/- recipients, displayed the hyper-activation phenotype (Fig.	('Il15', 'molecular_function', 'GO:0016170', ('126', '130'))	('Il15ra', 'Gene', '16169', (126, 132))	('Il15', 'molecular_function', 'GO:0016170', ('96', '100'))	('hyper-activation phenotype', 'MPA', (162, 188))	('Il15ra', 'Gene', '16169', (96, 102))	('Il15ra', 'Gene', (126, 132))	('CD8', 'Gene', (70, 73))	('Otub1-TKO', 'Var', (55, 64))	('CD8', 'Gene', '925', (70, 73))	('Il15ra', 'Gene', (96, 102))
54691	31182807	In Il15ra+/+ recipients, the Otub1-TKO OT-I T cells displayed a much stronger response to LM-OVA infection than the WT OT-I T cells, but this phenotype was not detected in the Il15ra-/- recipients (Fig.	('response to LM-OVA infection', 'MPA', (78, 106))	('Il15ra', 'Gene', (176, 182))	('Il15', 'molecular_function', 'GO:0016170', ('3', '7'))	('Il15ra', 'Gene', '16169', (3, 9))	('Il15', 'molecular_function', 'GO:0016170', ('176', '180'))	('Il15ra', 'Gene', (3, 9))	('stronger', 'PosReg', (69, 77))	('Il15ra', 'Gene', '16169', (176, 182))	('Otub1-TKO', 'Var', (29, 38))
54693	31182807	RNA sequencing revealed that the Otub1-TKO naive OT-I T cells had upregulated expression of a large number of genes under homeostatic conditions (Supplementary Fig.	('expression', 'MPA', (78, 88))	('upregulated', 'PosReg', (66, 77))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('Otub1-TKO', 'Var', (33, 42))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('expression', 'Species', '29278', (78, 88))
54696	31182807	Within the Il15ra+/+ recipient mice, the Otub1-TKO CD8 T cells displayed upregulated expression of almost all of the genes analyzed compared to the WT CD8 T cells (Fig.	('expression', 'MPA', (85, 95))	('Il15', 'molecular_function', 'GO:0016170', ('11', '15'))	('CD8', 'Gene', (151, 154))	('CD8', 'Gene', '925', (151, 154))	('Otub1-TKO', 'Var', (41, 50))	('CD8', 'Gene', (51, 54))	('mice', 'Species', '10090', (31, 35))	('Il15ra', 'Gene', '16169', (11, 17))	('CD8', 'Gene', '925', (51, 54))	('upregulated', 'PosReg', (73, 84))	('Il15ra', 'Gene', (11, 17))	('expression', 'Species', '29278', (85, 95))
54702	31182807	To study the function of Otub1 in NK cell regulation, we inducibly deleted Otub1 in adult mice using a tamoxifen-inducible Cre (CreER) system (Fig.	('Otub1', 'Gene', (75, 80))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('mice', 'Species', '10090', (90, 94))	('tamoxifen', 'Chemical', 'MESH:D013629', (103, 112))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('deleted', 'Var', (67, 74))
54704	31182807	Importantly, although the Otub1 deletion had no effect on total NK cell number in the spleen, it markedly increased the frquency of stage 4 mature NK cells (CD11bhiCD27lo) and concomitantly reduced stage 3 NK cells (CD11bhiCD27hi) (Fig.	('CD11b', 'Gene', (216, 221))	('stage 3 NK cells', 'CPA', (198, 214))	('frquency', 'CPA', (120, 128))	('deletion', 'Var', (32, 40))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('N', 'Chemical', 'MESH:D009584', (206, 207))	('reduced', 'NegReg', (190, 197))	('CD27', 'Gene', '939', (164, 168))	('CD27', 'Gene', '939', (223, 227))	('CD27', 'Gene', (164, 168))	('CD27', 'Gene', (223, 227))	('CD11b', 'Gene', '3684', (157, 162))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('increased', 'PosReg', (106, 115))	('CD11b', 'Gene', '3684', (216, 221))	('Otub1', 'Gene', (26, 31))	('CD11b', 'Gene', (157, 162))
54709	31182807	Otub1 deficiency did not affect STAT5 activation but strikingly enhanced activation of AKT (Fig.	('Otub1', 'Gene', (0, 5))	('STAT5', 'Gene', '20850', (32, 37))	('deficiency', 'Var', (6, 16))	('activation', 'MPA', (73, 83))	('STAT5', 'Gene', (32, 37))	('AKT', 'Pathway', (87, 90))	('enhanced', 'PosReg', (64, 72))
54710	31182807	AKT activation is mediated via its phosphorylation at threonine 308 (T308) and serine 473 (S473).	('T308', 'Var', (69, 73))	('phosphorylation', 'biological_process', 'GO:0016310', ('35', '50'))	('AKT', 'Pathway', (0, 3))	('phosphorylation', 'MPA', (35, 50))	('serine 473', 'MPA', (79, 89))	('phospho', 'Chemical', 'MESH:C033601', (35, 42))	('serine', 'Chemical', 'MESH:C047902', (79, 85))	('S473', 'Var', (91, 95))	('activation', 'PosReg', (4, 14))	('threonine', 'Chemical', 'MESH:C061951', (54, 63))
54712	31182807	The Otub1 deficiency enhanced IL-15-stimulated phosphorylation of AKT S473 as well as FOXO1 and FOXO3 (Fig.	('Otub1', 'Gene', (4, 9))	('IL-15', 'molecular_function', 'GO:0016170', ('30', '35'))	('FOXO3', 'Gene', '56484', (96, 101))	('enhanced', 'PosReg', (21, 29))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('IL-15-stimulated phosphorylation', 'MPA', (30, 62))	('phospho', 'Chemical', 'MESH:C033601', (47, 54))	('FOXO1', 'Gene', (86, 91))	('FOXO3', 'Gene', (96, 101))	('deficiency', 'Var', (10, 20))	('FOXO1', 'Gene', '56458', (86, 91))	('AKT S473', 'Protein', (66, 74))
54715	31182807	Otub1 deficiency only had a weak effect on IL-2- and IL-7-stimulated AKT phosphorylation (Supplementary Fig.	('Otub1', 'Gene', (0, 5))	('IL-2- and IL-7', 'Gene', '16183;16196', (43, 57))	('deficiency', 'Var', (6, 16))	('IL-7', 'molecular_function', 'GO:0005139', ('53', '57'))	('IL-2', 'molecular_function', 'GO:0005134', ('43', '47'))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('AKT phosphorylation', 'CPA', (69, 88))	('phospho', 'Chemical', 'MESH:C033601', (73, 80))
54718	31182807	Otub1 knockdown in 15R-KIT T cells strongly promoted IL-15-stimulated AKT phosphorylation (Fig.	('Otub1', 'Gene', (0, 5))	('promoted', 'PosReg', (44, 52))	('phospho', 'Chemical', 'MESH:C033601', (74, 81))	('IL-15', 'molecular_function', 'GO:0016170', ('53', '58'))	('AKT phosphorylation', 'Pathway', (70, 89))	('knockdown', 'Var', (6, 15))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))
54719	31182807	Furthermore, Otub1 deficiency in NK cells also profoundly enhanced IL-15-stimulated activation of AKT, but not activation of STAT5 (Fig.	('Otub1', 'Gene', (13, 18))	('deficiency', 'Var', (19, 29))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('enhanced', 'PosReg', (58, 66))	('STAT5', 'Gene', (125, 130))	('AKT', 'Pathway', (98, 101))	('IL-15', 'molecular_function', 'GO:0016170', ('67', '72'))	('activation', 'MPA', (84, 94))	('STAT5', 'Gene', '20850', (125, 130))
54722	31182807	1d-h), we examined the effect of Otub1 deletion on TCR signaling.	('TCR', 'Gene', (51, 54))	('TCR', 'Gene', '328483', (51, 54))	('deletion', 'Var', (39, 47))	('TCR', 'cellular_component', 'GO:0042101', ('51', '54'))	('signaling', 'biological_process', 'GO:0023052', ('55', '64'))	('Otub1', 'Gene', (33, 38))	('TCR', 'biological_process', 'GO:0006283', ('51', '54'))
54723	31182807	Otub1 deficiency did not influence the phosphorylation of the protein tyrosine kinase Zap70, the adaptor protein SLP76, and the MAP kinase ERK (Supplementary Fig.	('Otub1', 'Gene', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('phosphorylation', 'MPA', (39, 54))	('SLP76', 'Gene', (113, 118))	('SLP76', 'Gene', '16822', (113, 118))	('ERK', 'molecular_function', 'GO:0004707', ('139', '142'))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('ERK', 'Gene', (139, 142))	('deficiency', 'Var', (6, 16))	('phospho', 'Chemical', 'MESH:C033601', (39, 46))	('Zap70', 'Gene', (86, 91))	('ERK', 'Gene', '26413', (139, 142))	('MAP', 'molecular_function', 'GO:0004239', ('128', '131'))	('Zap70', 'Gene', '22637', (86, 91))	('tyrosine', 'Chemical', 'None', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
54724	31182807	However, Otub1 deficiency markedly enhanced TCR-CD28-stimulated activation of AKT and phosphorylation of several AKT downstream proteins, including the transcription factors Foxo1 and Foxo3 and the mTORC1 targets S6 kinase (S6K), ribosomal S6 protein, and 4E-BP1 (Fig.	('S6K', 'Gene', (224, 227))	('S6 kinase', 'Gene', '72508', (213, 222))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))	('phospho', 'Chemical', 'MESH:C033601', (86, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('86', '101'))	('Foxo1', 'Gene', (174, 179))	('mTORC1', 'cellular_component', 'GO:0031931', ('198', '204'))	('phosphorylation', 'MPA', (86, 101))	('CD28', 'Gene', (48, 52))	('Foxo1', 'Gene', '56458', (174, 179))	('Foxo3', 'Gene', '56484', (184, 189))	('Foxo3', 'Gene', (184, 189))	('mTORC1', 'Gene', (198, 204))	('protein', 'cellular_component', 'GO:0003675', ('243', '250'))	('activation', 'PosReg', (64, 74))	('mTORC1', 'Gene', '382056', (198, 204))	('CD28', 'Gene', '12487', (48, 52))	('S6K', 'Gene', '72508', (224, 227))	('E-BP1', 'Gene', '18033', (257, 262))	('E-BP1', 'Gene', (257, 262))	('TCR', 'cellular_component', 'GO:0042101', ('44', '47'))	('AKT', 'Pathway', (78, 81))	('enhanced', 'PosReg', (35, 43))	('TCR', 'biological_process', 'GO:0006283', ('44', '47'))	('TCR', 'Gene', (44, 47))	('deficiency', 'Var', (15, 25))	('Otub1', 'Gene', (9, 14))	('TCR', 'Gene', '328483', (44, 47))	('S6 kinase', 'Gene', (213, 222))
54725	31182807	On the other hand, the Otub1 deficiency did not affect TCR-CD28-stimulated AKT signaling in CD4 T cells (Supplementary Fig.	('CD4', 'Gene', '12504', (92, 95))	('TCR', 'Gene', '328483', (55, 58))	('TCR', 'cellular_component', 'GO:0042101', ('55', '58'))	('CD28', 'Gene', (59, 63))	('CD28', 'Gene', '12487', (59, 63))	('TCR', 'biological_process', 'GO:0006283', ('55', '58'))	('AKT signaling', 'biological_process', 'GO:0043491', ('75', '88'))	('CD4', 'Gene', (92, 95))	('deficiency', 'Var', (29, 39))	('Otub1', 'Gene', (23, 28))	('TCR', 'Gene', (55, 58))
54734	31182807	Antibody-mediated IL-15 neutralization in WT OT-I mice also inhibited Otub1 membrane localization in CD8 T cells (Fig.	('CD8', 'Gene', '925', (101, 104))	('IL-15', 'molecular_function', 'GO:0016170', ('18', '23'))	('membrane', 'cellular_component', 'GO:0016020', ('76', '84'))	('Otub1 membrane localization', 'MPA', (70, 97))	('inhibited', 'NegReg', (60, 69))	('neutralization', 'Var', (24, 38))	('mice', 'Species', '10090', (50, 54))	('localization', 'biological_process', 'GO:0051179', ('85', '97'))	('CD8', 'Gene', (101, 104))
54735	31182807	Once in the membrane, AKT is phosphorylated T308 and S473 by PDK1 and mTORC2, respectively.	('membrane', 'cellular_component', 'GO:0016020', ('12', '20'))	('mTORC2', 'Gene', '74343', (70, 76))	('PDK1', 'molecular_function', 'GO:0004740', ('61', '65'))	('AKT', 'Pathway', (22, 25))	('PDK1', 'Gene', '228026', (61, 65))	('phospho', 'Chemical', 'MESH:C033601', (29, 36))	('mTORC2', 'cellular_component', 'GO:0031932', ('70', '76'))	('PDK1', 'Gene', (61, 65))	('T308', 'Var', (44, 48))	('S473', 'Var', (53, 57))	('mTORC2', 'Gene', (70, 76))
54736	31182807	Otub1 knockdown had no obvious effect on the activity of AKT upstream regulators, PI3 kinase (PI3K) and PTEN (data not shown), which catalyze the forward and reverse PIP3 generation reactions, respectively.	('activity', 'MPA', (45, 53))	('Otub1', 'Gene', (0, 5))	('PI3 kinase', 'Gene', (82, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('94', '98'))	('PTEN', 'Gene', '19211', (104, 108))	('knockdown', 'Var', (6, 15))	('PI3 kinase', 'Gene', '18708', (82, 92))	('PTEN', 'Gene', (104, 108))
54738	31182807	Conversely, Otub1 overexpression inhibited AKT ubiquitination, which was efficient for K63-linked, but not K48-linked, polyubiquitin chains (Fig.	('polyubiquitin', 'molecular_function', 'GO:0005552', ('119', '132'))	('polyubiquitin', 'biological_process', 'GO:0000209', ('119', '132'))	('AKT', 'Pathway', (43, 46))	('overexpression', 'PosReg', (18, 32))	('K63-linked', 'Var', (87, 97))	('expression', 'Species', '29278', (22, 32))	('inhibited', 'NegReg', (33, 42))	('Otub1', 'Protein', (12, 17))
54740	31182807	We found that mutation of C91 only moderately inhibited the function of Otub1 (data not shown), but simultaneous mutations of D88 and C91 generated an Otub1 mutant, D88A/C91S, that was unable to inhibit AKT ubiquitination (Fig.	('C91S', 'Mutation', 'p.C91S', (170, 174))	('D88A', 'Var', (165, 169))	('Otub1', 'Gene', (151, 156))	('mutations', 'Var', (113, 122))	('C91', 'Gene', (134, 137))	('function', 'MPA', (60, 68))	('AKT', 'Pathway', (203, 206))	('D88A', 'SUBSTITUTION', 'None', (165, 169))	('inhibited', 'NegReg', (46, 55))	('D88', 'Gene', (126, 129))
54741	31182807	WT Otub1, but not D88A/C91S, was also able to suppress AKT activation in reconstituted Otub1-deficient CD8 T cells and Otub1-knockdown 15R-KIT cells (Supplementary Fig.	('D88A', 'SUBSTITUTION', 'None', (18, 22))	('suppress', 'NegReg', (46, 54))	('C91S', 'Mutation', 'p.C91S', (23, 27))	('D88A', 'Var', (18, 22))	('CD8', 'Gene', (103, 106))	('AKT', 'Pathway', (55, 58))	('CD8', 'Gene', '925', (103, 106))	('KIT', 'molecular_function', 'GO:0005020', ('139', '142'))
54743	31182807	We found that mutation of K14 also abolished AKT ubiquitination under basal and IL-15-stimulated conditions (Fig.	('ubiquitination', 'MPA', (49, 63))	('abolished', 'NegReg', (35, 44))	('K14', 'Gene', (26, 29))	('K14', 'Gene', '16664', (26, 29))	('mutation', 'Var', (14, 22))	('IL-15', 'molecular_function', 'GO:0016170', ('80', '85'))	('AKT', 'Pathway', (45, 48))
54744	31182807	Consistently, mutation of K14, but not K8, abolished AKT phosphorylation (Fig.	('AKT', 'Pathway', (53, 56))	('K14', 'Gene', '16664', (26, 29))	('K14', 'Gene', (26, 29))	('phospho', 'Chemical', 'MESH:C033601', (57, 64))	('mutation', 'Var', (14, 22))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('abolished', 'NegReg', (43, 52))
54748	31182807	Fusion of UbK63 to AKT K14R largely rescued its defect in IL-15-stimulated phosphorylation as well as in ubiquitination (Fig.	('IL-15', 'molecular_function', 'GO:0016170', ('58', '63'))	('Fusion', 'Var', (0, 6))	('phospho', 'Chemical', 'MESH:C033601', (75, 82))	('UbK63', 'Gene', (10, 15))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('AKT', 'Gene', (19, 22))	('K14R', 'Mutation', 'p.K14R', (23, 27))	('ubiquitination', 'MPA', (105, 119))
54750	31182807	While WT AKT and AKT K8R displayed strong PIP3-binding activity, the AKT K14R mutant was defective in PIP3 binding (Fig.	('AKT', 'Gene', (69, 72))	('PIP3 binding', 'molecular_function', 'GO:0005547', ('102', '114'))	('PIP3-binding', 'Protein', (42, 54))	('K14R', 'Mutation', 'p.K14R', (73, 77))	('defective', 'NegReg', (89, 98))	('K14R', 'Var', (73, 77))	('PIP3-binding', 'molecular_function', 'GO:0005547', ('42', '54'))	('PIP3', 'Protein', (102, 106))
54751	31182807	Moreover, Otub1 strongly inhibited the PIP3-binding activity of AKT WT and AKT K8R, but it did not affect the residual PIP3-binding activity of K14R (Fig.	('K14R', 'Mutation', 'p.K14R', (144, 148))	('PIP3-binding', 'molecular_function', 'GO:0005547', ('39', '51'))	('Otub1', 'Var', (10, 15))	('PIP3-binding activity', 'MPA', (39, 60))	('PIP3-binding', 'molecular_function', 'GO:0005547', ('119', '131'))	('inhibited', 'NegReg', (25, 34))
54752	31182807	Fusion of UbK63 to AKT K14R, which restored its ubiquitination (Fig.	('Fusion', 'Var', (0, 6))	('UbK63', 'Gene', (10, 15))	('ubiquitination', 'MPA', (48, 62))	('restored', 'PosReg', (35, 43))	('K14R', 'Mutation', 'p.K14R', (23, 27))
54762	31182807	Otub1 appeared to regulate glycolysis through controlling AKT, since a selective AKT inhibitor (AKTi) erased the ECAR differences between WT and Otub1-TKO CD8 T cells (Fig.	('erased', 'NegReg', (102, 108))	('ECAR differences', 'MPA', (113, 129))	('CD8', 'Gene', (155, 158))	('CD8', 'Gene', '925', (155, 158))	('glycolysis', 'biological_process', 'GO:0006096', ('27', '37'))	('Otub1-TKO', 'Var', (145, 154))
54770	31182807	Furthermore, the Otub1-TKO, but not WT, Pmel1 T cells responded to in vitro restimulation with the antigen gp100, for IFN-gamma production (Fig.	('Otub1-TKO', 'Var', (17, 26))	('IFN-gamma', 'Gene', (118, 127))	('Pmel', 'Gene', (40, 44))	('gp100', 'Gene', (107, 112))	('Pmel', 'Gene', '20431', (40, 44))	('gp100', 'Gene', '20431', (107, 112))	('IFN-gamma', 'Gene', '15978', (118, 127))
54777	31182807	Furthermore, the Otub1-TKO CD8 T cells expressed higher levels of Glut1 than WT CD8 T cells in tumor microenvironment (Fig.	('levels', 'MPA', (56, 62))	('CD8', 'Gene', '925', (80, 83))	('Glut1', 'Gene', (66, 71))	('Otub1-TKO', 'Var', (17, 26))	('CD8', 'Gene', (27, 30))	('CD8', 'Gene', '925', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Glut1', 'Gene', '20525', (66, 71))	('CD8', 'Gene', (80, 83))	('higher', 'PosReg', (49, 55))	('tumor', 'Disease', (95, 100))
54781	31182807	Compared to the WT Pmel1 CD8 T cells, the Otub1-TKO Pmel1 CD8 T cells were profoundly more effective in suppressing tumor growth and improving survival of the B16 tumor-bearing mice (Fig.	('survival', 'CPA', (143, 151))	('CD8', 'Gene', (58, 61))	('Otub1-TKO', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CD8', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Pmel', 'Gene', '20431', (52, 56))	('Pmel', 'Gene', '20431', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('suppressing', 'NegReg', (104, 115))	('Pmel', 'Gene', (52, 56))	('CD8', 'Gene', '925', (58, 61))	('Pmel', 'Gene', (19, 23))	('mice', 'Species', '10090', (177, 181))	('improving', 'PosReg', (133, 142))	('CD8', 'Gene', '925', (25, 28))	('tumor', 'Disease', (116, 121))
54782	31182807	We next employed the Otub1-iKO model, in which Otub1 was inducibly deleted in adult mice in different cell types and challenged with B16F10 tumor cells (Fig.	('Otub1', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('B16F10', 'CellLine', 'CVCL:0159', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deleted', 'Var', (67, 74))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', (140, 145))
54783	31182807	The Otub1-iKO mice had greatly reduced tumor burden compared to WT mice (Fig.	('reduced', 'NegReg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('Otub1-iKO', 'Var', (4, 13))	('tumor', 'Disease', (39, 44))	('mice', 'Species', '10090', (67, 71))
54785	31182807	Moreover, tumor-infiltrating CD8 T cells in the Otub1-iKO mice contained a significantly higher frequency of effector cells expressing IFN-gamma and Granzyme B (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Granzyme B', 'Gene', (149, 159))	('Granzyme B', 'Gene', '14939', (149, 159))	('tumor', 'Disease', (10, 15))	('CD8', 'Gene', '925', (29, 32))	('IFN-gamma', 'Gene', (135, 144))	('mice', 'Species', '10090', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('higher', 'PosReg', (89, 95))	('Otub1-iKO', 'Var', (48, 57))	('CD8', 'Gene', (29, 32))	('IFN-gamma', 'Gene', '15978', (135, 144))
54787	31182807	Antibody-mediated depletion of either CD8 T cells or NK cells impaired the potent anticancer immunity of Otub1-iKO mice, causing the increase of tumor burden to a level similar to or higher than that in WT mice (Fig.	('impaired', 'NegReg', (62, 70))	('N', 'Chemical', 'MESH:D009584', (53, 54))	('higher', 'PosReg', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('mice', 'Species', '10090', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Otub1-iKO', 'Var', (105, 114))	('tumor', 'Disease', (145, 150))	('CD8', 'Gene', (38, 41))	('increase', 'PosReg', (133, 141))	('CD8', 'Gene', '925', (38, 41))	('mice', 'Species', '10090', (115, 119))	('cancer', 'Disease', (86, 92))
54795	31182807	Despite the abundant expression of Otub1 in CD4 T cells, the Otub1 deficiency had no effect on the homeostasis of CD4 T cells.	('Otub1', 'Gene', (61, 66))	('expression', 'Species', '29278', (21, 31))	('homeostasis', 'MPA', (99, 110))	('CD4', 'Gene', (114, 117))	('CD4', 'Gene', '12504', (114, 117))	('Otub1', 'Gene', (35, 40))	('homeostasis', 'biological_process', 'GO:0042592', ('99', '110'))	('CD4', 'Gene', (44, 47))	('deficiency', 'Var', (67, 77))	('CD4', 'Gene', '12504', (44, 47))
54798	31182807	T cell-specific deletion of Otub1 rendered CD8 T cells hyper-responsive to bacterial infections in vivo and to activation by TCR-CD28 signals in vitro.	('activation', 'PosReg', (111, 121))	('CD28', 'Gene', (129, 133))	('TCR', 'cellular_component', 'GO:0042101', ('125', '128'))	('CD8', 'Gene', (43, 46))	('TCR', 'Gene', (125, 128))	('Otub1', 'Gene', (28, 33))	('CD8', 'Gene', '925', (43, 46))	('CD28', 'Gene', '12487', (129, 133))	('deletion', 'Var', (16, 24))	('hyper-responsive', 'PosReg', (55, 71))	('TCR', 'Gene', '328483', (125, 128))	('infections', 'Disease', 'MESH:D007239', (85, 95))	('TCR', 'biological_process', 'GO:0006283', ('125', '128'))	('bacterial infection', 'Phenotype', 'HP:0002718', (75, 94))	('infections', 'Disease', (85, 95))	('bacterial infections', 'Phenotype', 'HP:0002718', (75, 95))	('T cells hyper', 'Phenotype', 'HP:0100828', (47, 60))
54803	31182807	Otub1 deficiency sensitized CD8 T cells for activation by both TCR-CD28 stimuli and listeria infections and promoted generation of antigen-specific effector cells.	('Otub1', 'Gene', (0, 5))	('TCR', 'cellular_component', 'GO:0042101', ('63', '66'))	('sensitized', 'Reg', (17, 27))	('TCR', 'Gene', '328483', (63, 66))	('CD28', 'Gene', (67, 71))	('listeria infections', 'Disease', 'MESH:D008088', (84, 103))	('CD28', 'Gene', '12487', (67, 71))	('activation', 'PosReg', (44, 54))	('deficiency', 'Var', (6, 16))	('CD8', 'Gene', (28, 31))	('TCR', 'biological_process', 'GO:0006283', ('63', '66'))	('promoted', 'PosReg', (108, 116))	('CD8', 'Gene', '925', (28, 31))	('listeria infections', 'Disease', (84, 103))	('TCR', 'Gene', (63, 66))
54804	31182807	The crucial role of Otub1 in regulating CD8 T cell responses was also revealed by the development of vitiligo in Otub1-TKO Pmel1 mice, which was due to aberrant CD8 T cell activation by the melanocyte self-antigen gp100.	('Pmel', 'Gene', (123, 127))	('Otub1-TKO', 'Var', (113, 122))	('Pmel', 'Gene', '20431', (123, 127))	('gp100', 'Gene', (214, 219))	('CD8', 'Gene', (161, 164))	('CD8', 'Gene', '925', (40, 43))	('gp100', 'Gene', '20431', (214, 219))	('vitiligo', 'Disease', (101, 109))	('vitiligo', 'Phenotype', 'HP:0001045', (101, 109))	('T cell activation', 'biological_process', 'GO:0042110', ('165', '182'))	('CD8', 'Gene', '925', (161, 164))	('mice', 'Species', '10090', (129, 133))	('activation', 'PosReg', (172, 182))	('CD8', 'Gene', (40, 43))
54807	31182807	Inducible deletion of Otub1 in adult mice greatly promoted tumor rejection, associated with increased tumor-infiltration with various immune cells, including CD8 T cells, NK cells, as well as CD4 T cells and cDC1 cells.	('CD4', 'Gene', '12504', (192, 195))	('promoted', 'PosReg', (50, 58))	('tumor', 'Disease', (59, 64))	('CD8', 'Gene', (158, 161))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('CD8', 'Gene', '925', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('increased', 'PosReg', (92, 101))	('deletion', 'Var', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('Otub1', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mice', 'Species', '10090', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CD4', 'Gene', (192, 195))
54810	31182807	In an adoptive T cell therapy model, Otub1 deletion also profoundly enhanced the tumor-rejection activity of CD8 effector T cells, which was consistent with the role of Otub1 in regulating the metabolism and effector molecule expression of activated CD8 T cells.	('CD8', 'Gene', (250, 253))	('enhanced', 'PosReg', (68, 76))	('CD8', 'Gene', (109, 112))	('CD8', 'Gene', '925', (250, 253))	('expression', 'Species', '29278', (226, 236))	('CD8', 'Gene', '925', (109, 112))	('deletion', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('metabolism', 'biological_process', 'GO:0008152', ('193', '203'))	('Otub1', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
54812	31182807	A central step in AKT activation is its recruitment to the plasma membrane, where it is activated via S473 phosphorylation by mTORC2 and T308 phosphorylation by PDK1.	('phospho', 'Chemical', 'MESH:C033601', (107, 114))	('PDK1', 'molecular_function', 'GO:0004740', ('161', '165'))	('PDK1', 'Gene', '228026', (161, 165))	('plasma membrane', 'cellular_component', 'GO:0005886', ('59', '74'))	('activated', 'PosReg', (88, 97))	('PDK1', 'Gene', (161, 165))	('mTORC2', 'cellular_component', 'GO:0031932', ('126', '132'))	('mTORC2', 'Gene', (126, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('recruitment', 'MPA', (40, 51))	('T308 phosphorylation', 'Var', (137, 157))	('mTORC2', 'Gene', '74343', (126, 132))	('phosphorylation', 'biological_process', 'GO:0016310', ('107', '122'))	('S473', 'Var', (102, 106))	('AKT', 'Pathway', (18, 21))	('phospho', 'Chemical', 'MESH:C033601', (142, 149))
54823	31182807	The HEK293T, B16F10, MC38 were from ATCC, and B16-OVA was provided by Qing Yi (Cleveland Clinic).	('B16F10', 'CellLine', 'CVCL:0159', (13, 19))	('HEK293T', 'Var', (4, 11))	('B16F10', 'Var', (13, 19))	('HEK293T', 'CellLine', 'CVCL:0063', (4, 11))
54825	31182807	pMIGR1-HA-AKT was generated by inserting human AKT1 cDNA into the EcoRI and BglII sites of the retrovirus vector pMIGR1 downstream of an HA tag, and the AKT mutants (K8R, K14R, E17K) were created by site-directed mutagenesis.	('E17K', 'Var', (177, 181))	('K14R', 'Mutation', 'p.K14R', (171, 175))	('K14R', 'Var', (171, 175))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('human', 'Species', '9606', (41, 46))	('E17K', 'Mutation', 'rs121434592', (177, 181))	('mutagenesis', 'biological_process', 'GO:0006280', ('213', '224'))	('K8R', 'Var', (166, 169))	('pMIGR1', 'Gene', (113, 119))	('inserting', 'Reg', (31, 40))
54826	31182807	The pcDNA3 expression vectors for Flag-tagged Otub1 and Otub1 C91S mutant were provided by Dr. Danuek Durocher (Lunenfeld-Tanenbaum Research Institute), and Flag-Otub1 C91S/D88A mutant was generated by site-directed mutagenesis.	('C91S', 'SUBSTITUTION', 'None', (168, 172))	('mutagenesis', 'biological_process', 'GO:0006280', ('216', '227'))	('C91S', 'Var', (62, 66))	('C91S', 'Var', (168, 172))	('C91S', 'SUBSTITUTION', 'None', (62, 66))	('Otub1', 'Gene', (56, 61))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('expression vectors', 'Species', '29278', (11, 29))	('C91S', 'Mutation', 'p.C91S', (168, 172))	('D88A', 'Mutation', 'p.D88A', (173, 177))	('C91S', 'Mutation', 'p.C91S', (62, 66))
54827	31182807	pPRIChp-Otub1-HA and pPRIChp-Otub1C91S/D88A-HA were generated by inserting human Otub1 and Otub1 C91S/D88A into the pPRIChp-HA retroviral vector (provided by Dr. Patrick Martin, University of Nice Sophia Antipolis).	('D88A', 'Mutation', 'p.D88A', (39, 43))	('C91S', 'SUBSTITUTION', 'None', (97, 101))	('D88A', 'Mutation', 'p.D88A', (102, 106))	('C91S', 'Var', (97, 101))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('C91S', 'SUBSTITUTION', 'None', (34, 38))	('human', 'Species', '9606', (75, 80))	('C91S', 'Var', (34, 38))
54833	31182807	Functional grade anti-mouse (m) CD3epsilon (145-2C11) and anti-mCD28 (37.51) antibodies were from eBioscience.	('CD28', 'Gene', (64, 68))	('CD3epsilon', 'Gene', '12501', (32, 42))	('rad', 'Gene', (12, 15))	('eBioscience', 'Disease', 'None', (98, 109))	('CD28', 'Gene', '12487', (64, 68))	('rad', 'Gene', '56437', (12, 15))	('145-2C11', 'Var', (44, 52))	('mouse', 'Species', '10090', (22, 27))	('CD3epsilon', 'Gene', (32, 42))	('eBioscience', 'Disease', (98, 109))
54843	31182807	Glut1 (EPR3915) was from abcam.	('Glut1', 'Gene', (0, 5))	('EPR3915', 'Var', (7, 14))	('Glut1', 'Gene', '20525', (0, 5))
54922	33801689	BRAF Gene and Melanoma: Back to the Future As widely acknowledged, 40-50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E).	('BRAF', 'Gene', (121, 125))	('V600E', 'Mutation', 'rs113488022', (148, 153))	('Melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('Melanoma', 'Disease', 'MESH:D008545', (14, 22))	('V600E', 'Var', (148, 153))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('BRAF', 'Gene', '673', (0, 4))	('Melanoma', 'Disease', (14, 22))	('melanoma', 'Disease', (81, 89))	('activating', 'PosReg', (110, 120))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (121, 125))	('patients', 'Species', '9606', (90, 98))
54927	33801689	To date, two largely mutually exclusive groups of cutaneous melanomas can be categorised: those harbouring an activating BRAF mutation (mostly BRAF V600E), which represent 40-50% of all melanoma patients, and those harbouring other mutations than BRAF.	('BRAF', 'Gene', (121, 125))	('V600E', 'Mutation', 'rs113488022', (148, 153))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('cutaneous melanomas', 'Disease', (50, 69))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('V600E', 'Var', (148, 153))	('patients', 'Species', '9606', (195, 203))	('activating', 'PosReg', (110, 120))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('BRAF', 'Gene', '673', (247, 251))	('BRAF', 'Gene', (247, 251))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (50, 69))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (50, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('BRAF', 'Gene', '673', (121, 125))
54941	33801689	Mutations in the BRAF gene could cause an impaired protein function, depending on localization and type.	('BRAF', 'Gene', '673', (17, 21))	('protein function', 'MPA', (51, 67))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('localization', 'biological_process', 'GO:0051179', ('82', '94'))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))	('impaired', 'NegReg', (42, 50))
54942	33801689	Concerning cutaneous melanoma, the most frequent (65%) and relevant alterations in BRAF gene sequence are those affecting codon V600 (formerly named V599) in the exon 15.	('codon V600', 'Var', (122, 132))	('cutaneous melanoma', 'Disease', (11, 29))	('affecting', 'Reg', (112, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (11, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))
54944	33801689	Non-V600 mutations, which are less frequent than V600 ones, have been found in 11% of all cutaneous melanoma patients.	('patients', 'Species', '9606', (109, 117))	('cutaneous melanoma', 'Disease', (90, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('Non-V600 mutations', 'Var', (0, 18))	('found', 'Reg', (70, 75))
54945	33801689	BRAF mutations in cutaneous melanoma are most common on the trunk (affecting less frequently the head and neck), on skin without marked solar elastosis and in younger age, thus suggesting a physiopathology role for intermittent UV exposition in early life rather than chronic sun damage.	('cutaneous melanoma', 'Disease', (18, 36))	('elastosis', 'Disease', 'MESH:D005148', (142, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('mutations', 'Var', (5, 14))	('neck', 'cellular_component', 'GO:0044326', ('106', '110'))	('BRAF', 'Gene', '673', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('elastosis', 'Disease', (142, 151))	('sun damage', 'Phenotype', 'HP:0000992', (276, 286))	('early life rather than chronic sun damage', 'Phenotype', 'HP:0007396', (245, 286))	('trunk', 'cellular_component', 'GO:0043198', ('60', '65'))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
54946	33801689	A recent study using sequencing data showed a model of the propagation and selection of clones with different categories of BRAF mutations to establish their evolutionary trajectories.	('mutations', 'Var', (129, 138))	('BRAF', 'Gene', (124, 128))	('BRAF', 'Gene', '673', (124, 128))
54947	33801689	The phylogenetic trees of cutaneous melanoma samples with amplification of BRAF express a major dominant clone, with only rare intermediates that are persistent from the previous selective sweeps, consistent with a linear evolutionary process.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (75, 79))	('cutaneous melanoma', 'Disease', (26, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (26, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (26, 44))	('amplification', 'Var', (58, 71))
54948	33801689	However, it is still not clear whether melanoma with amplification of BRAF experiences iterative selective sweeps and, if so, what the underlying molecular basis of this process might be.	('amplification', 'Var', (53, 66))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
54949	33801689	Actually, clinicopathological characteristics and frequency are different for each kind of BRAF mutation, so we should consider them as different entities.	('BRAF', 'Gene', '673', (91, 95))	('mutation', 'Var', (96, 104))	('BRAF', 'Gene', (91, 95))
54950	33801689	BRAF V600E is, globally, the most frequent mutation observed in cutaneous melanoma patients, accounting for 70-88% of all known V600 BRAF mutations.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('BRAF', 'Gene', '673', (133, 137))	('patients', 'Species', '9606', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', (64, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 82))	('V600', 'Var', (128, 132))
54952	33801689	BRAF V600K is the second most common mutation (10-20% of all V600 BRAF mutations) in cutaneous melanoma and, as V600E mutation, it consists of an amino acid change, with a valine (V) replaced by a lysine (K).	('V600K', 'Mutation', 'rs121913227', (5, 10))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('V600K', 'Var', (5, 10))	('lysine', 'Chemical', 'MESH:D008239', (197, 203))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (71, 80))	('cutaneous melanoma', 'Disease', (85, 103))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (66, 70))	('valine', 'MPA', (172, 178))	('V600E', 'Var', (112, 117))	('valine', 'Chemical', 'MESH:D014633', (172, 178))	('BRAF', 'Gene', (66, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
54953	33801689	Other rarer codon V600 BRAF mutations, approximately 10% of all V600 mutations, are V600R (<5%), V600D (<5%), V600E2 (<1%), V600M (<1%) and V600G (<1%).	('V600', 'Var', (18, 22))	('V600E', 'Mutation', 'rs113488022', (110, 115))	('BRAF', 'Gene', '673', (23, 27))	('V600', 'Gene', (64, 68))	('V600M', 'Mutation', 'rs121913378', (124, 129))	('V600D', 'Var', (97, 102))	('V600E2', 'Var', (110, 116))	('V600R', 'Mutation', 'rs121913227', (84, 89))	('BRAF', 'Gene', (23, 27))	('V600D', 'Mutation', 'rs121913377', (97, 102))	('V600R', 'Var', (84, 89))	('V600M', 'Var', (124, 129))	('V600G', 'Mutation', 'rs113488022', (140, 145))	('V600G', 'Var', (140, 145))
54954	33801689	Cutaneous melanomas harbouring BRAF V600E and V600K mutations, even if similar from a molecular point of view, have distinct clinicopathological features (Table 1).	('Cutaneous melanomas', 'Disease', 'MESH:C562393', (0, 19))	('V600K', 'Var', (46, 51))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('V600K', 'Mutation', 'rs121913227', (46, 51))	('Cutaneous melanomas', 'Disease', (0, 19))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('BRAF', 'Gene', '673', (31, 35))	('Cutaneous melanomas', 'Phenotype', 'HP:0012056', (0, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('BRAF', 'Gene', (31, 35))
54955	33801689	In fact, BRAF V600K-mutant cutaneous melanomas are considered more aggressive than V600E ones, since they have shown less tumour regression and shorter progression-free survival during treatment with combined BRAF and MEK inhibitors, together with a shorter disease-free interval from diagnosis of primary melanoma to the occurrence of first distant metastasis.	('BRAF', 'Gene', (9, 13))	('V600K', 'Mutation', 'rs121913227', (14, 19))	('cutaneous melanomas', 'Disease', (27, 46))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('V600E', 'Mutation', 'rs113488022', (83, 88))	('V600K-mutant', 'Var', (14, 26))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('melanoma', 'Disease', 'MESH:D008545', (306, 314))	('tumour', 'Disease', (122, 128))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('MEK', 'Gene', '5609', (218, 221))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('progression-free survival', 'CPA', (152, 177))	('MEK', 'Gene', (218, 221))	('less', 'NegReg', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (306, 314))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (27, 46))	('melanoma', 'Disease', (306, 314))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (27, 46))	('shorter', 'NegReg', (144, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('BRAF', 'Gene', '673', (9, 13))
54956	33801689	Analysis of BRAF V600K-mutant cutaneous melanoma samples from the Cancer Genome Atlas highlighted, with respect to V600E, an upregulation of energy metabolism, emphasizing their clinical aggressiveness.	('aggressiveness', 'Disease', (187, 201))	('aggressiveness', 'Phenotype', 'HP:0000718', (187, 201))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('aggressiveness', 'Disease', 'MESH:D001523', (187, 201))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('V600E', 'Mutation', 'rs113488022', (115, 120))	('Cancer', 'Disease', (66, 72))	('cutaneous melanoma', 'Disease', (30, 48))	('metabolism', 'biological_process', 'GO:0008152', ('148', '158'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('upregulation', 'PosReg', (125, 137))	('V600E', 'Var', (115, 120))	('V600K-mutant', 'Var', (17, 29))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('energy metabolism', 'MPA', (141, 158))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('V600K', 'Mutation', 'rs121913227', (17, 22))
54957	33801689	On the other hand, an older age at diagnosis, a higher degree of cumulative sun-induced damage and a higher mutational burden have been described in V600K-mutant cutaneous melanoma with respect to V600E melanomas, explaining good response to immunotherapy.	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('V600K-mutant', 'Var', (149, 161))	('cutaneous melanoma', 'Disease', (162, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('V600E', 'Mutation', 'rs113488022', (197, 202))	('melanomas', 'Disease', (203, 212))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('V600K', 'Mutation', 'rs121913227', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))
54959	33801689	In fact, it must be stressed that there is a higher trend of BRAF V600-mutant melanoma, with respect to BRAF wild-type ones, to involve the brain and liver as a first site of metastasis, thus affecting negatively the prognosis of these patients.	('V600-mutant', 'Var', (66, 77))	('BRAF', 'Gene', '673', (61, 65))	('patients', 'Species', '9606', (236, 244))	('affecting', 'Reg', (192, 201))	('BRAF', 'Gene', (61, 65))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Disease', (78, 86))	('BRAF', 'Gene', '673', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('BRAF', 'Gene', (104, 108))
54961	33801689	Rare V600 BRAF mutations, such as V600R, V600D and V600M, have been associated with good response to BRAF inhibitors and acceptable OS compared to V600E/K-mutant melanoma patients.	('BRAF', 'Gene', (101, 105))	('V600D', 'Var', (41, 46))	('V600R', 'Var', (34, 39))	('V600E', 'Var', (147, 152))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('V600', 'Var', (5, 9))	('V600E', 'SUBSTITUTION', 'None', (147, 152))	('V600M', 'Var', (51, 56))	('patients', 'Species', '9606', (171, 179))	('V600M', 'Mutation', 'rs121913378', (51, 56))	('V600D', 'Mutation', 'rs121913377', (41, 46))	('V600R', 'Mutation', 'rs121913227', (34, 39))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', '673', (101, 105))
54962	33801689	BRAF non-V600 mutations, as stated before, are less frequent than V600 ones, and their prognostic and predictive role is, to date, still difficult to elucidate.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('non-V600 mutations', 'Var', (5, 23))
54963	33801689	L597, K601 and G469 mutations, also known as class II BRAF mutations, determine an increased kinase catalytic activity, different from monomeric V600-mutant protein, through constitutive dimerization.	('L597', 'Var', (0, 4))	('increased', 'PosReg', (83, 92))	('dimerization', 'MPA', (187, 199))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('kinase catalytic activity', 'MPA', (93, 118))	('G469 mutations', 'Var', (15, 29))	('protein', 'cellular_component', 'GO:0003675', ('157', '164'))	('K601', 'Var', (6, 10))	('catalytic activity', 'molecular_function', 'GO:0003824', ('100', '118'))
54964	33801689	Interestingly, they are located in different regions of the gene: L597 and K601 in the activation segment, whilst G469 in the glycine rich region of BRAF.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('G469', 'Var', (114, 118))	('L597', 'Var', (66, 70))	('K601', 'Var', (75, 79))	('glycine', 'Chemical', 'MESH:D005998', (126, 133))
54965	33801689	Even if these mutations do not confer sensitivity to BRAF inhibitors, they activate downstream target proteins, thus explaining sensitivity to MEK inhibitors.	('MEK', 'Gene', (143, 146))	('activate', 'PosReg', (75, 83))	('BRAF', 'Gene', '673', (53, 57))	('MEK', 'Gene', '5609', (143, 146))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (14, 23))
54966	33801689	Codon D594 and G596 mutations, also known as class III BRAF mutations, have been described as kinase-impairing alterations.	('Codon', 'Var', (0, 5))	('BRAF', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (55, 59))	('G596 mutations', 'Var', (15, 29))
54967	33801689	In fact, different from V600E mutations, which cause hyperactivation of downstream kinase pathways, kinase-impairing mutations cause a reduction in BRAF catalytic activity; these proteins are RAS dependent and have low or absent kinase activity.	('mutations', 'Var', (117, 126))	('reduction', 'NegReg', (135, 144))	('kinase activity', 'molecular_function', 'GO:0016301', ('229', '244'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('153', '171'))	('downstream kinase pathways', 'Pathway', (72, 98))	('kinase-impairing', 'Disease', (100, 116))	('BRAF', 'Gene', '673', (148, 152))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('BRAF', 'Gene', (148, 152))
54968	33801689	Codon D594 and G596 mutations are rare, < 4% of all melanoma patients, but have been associated with a good prognosis and a more prolonged OS than V600-mutant patients.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('patients', 'Species', '9606', (61, 69))	('G596', 'Var', (15, 19))	('Codon D594', 'Var', (0, 10))	('patients', 'Species', '9606', (159, 167))
54969	33801689	Oncogenic BRAF fusions are the result of genomic rearrangements which constitutively cause activation of BRAF kinase catalytic activity through the loss of the auto-inhibitory domain of the gene, being replaced by another gene in 5' position.	('BRAF', 'Gene', '673', (105, 109))	('loss', 'NegReg', (148, 152))	('fusions', 'Var', (15, 22))	('BRAF', 'Gene', (105, 109))	('activation', 'PosReg', (91, 101))	('auto-inhibitory domain', 'MPA', (160, 182))	('catalytic activity', 'molecular_function', 'GO:0003824', ('117', '135'))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('catalytic activity', 'MPA', (117, 135))
54970	33801689	BRAF fusions are estimated to occur in 3-6% of all melanoma patients, with a higher frequency in female gender, younger age and certain histopathologic subtypes such as spitzoid melanomas.	('patients', 'Species', '9606', (60, 68))	('fusions', 'Var', (5, 12))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (169, 187))	('melanoma', 'Disease', (178, 186))	('spitzoid melanomas', 'Disease', (169, 187))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('melanomas', 'Phenotype', 'HP:0002861', (178, 187))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
54971	33801689	The location of the breakpoints occurring in introns 7-10, thus preserving the kinase domain, and more than 40 partner genes have been identified, most of them being on the same chromosome of the BRAF gene; the moderate UV signature observed in tumour samples harbouring BRAF fusions suggests that they are not a consequence of UV exposure.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('tumour', 'Disease', (245, 251))	('fusions', 'Var', (276, 283))	('BRAF', 'Gene', '673', (196, 200))	('BRAF', 'Gene', (271, 275))	('BRAF', 'Gene', (196, 200))	('BRAF', 'Gene', '673', (271, 275))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('chromosome', 'cellular_component', 'GO:0005694', ('178', '188'))	('kinase domain', 'MPA', (79, 92))
54975	33801689	Indeed, it has been shown that in patients with advanced BRAF mutated melanoma undergoing treatment with TT, higher levels of plasma circulating tumour DNA (ctDNA) may predict disease progression earlier than imaging and/or clinical assessments.	('melanoma', 'Disease', (70, 78))	('tumour', 'Disease', (145, 151))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('BRAF', 'Gene', '673', (57, 61))	('higher', 'PosReg', (109, 115))	('BRAF', 'Gene', (57, 61))	('TT', 'Chemical', '-', (105, 107))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('patients', 'Species', '9606', (34, 42))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('mutated', 'Var', (62, 69))
54976	33801689	Immunohistochemistry (IHC) is a consistent option for detecting the BRAF exon 15 p.V600E mutation, since it is simple and low cost with rapid turnaround time (TAT) and high sensitivity and specificity.	('p.V600E', 'Mutation', 'rs113488022', (81, 88))	('p.V600E', 'Var', (81, 88))	('BRAF', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (68, 72))
54978	33801689	However, its main limitations are represented by the possibility of false-negative results due to heterogeneity or a low concentration of BRAF exon 15 p.V600E and the inability to identify BRAF exon 15 other variants, such as the V600 K one.	('V600 K', 'Var', (230, 236))	('BRAF', 'Gene', '673', (189, 193))	('false', 'biological_process', 'GO:0071878', ('68', '73'))	('BRAF', 'Gene', '673', (138, 142))	('false', 'biological_process', 'GO:0071877', ('68', '73'))	('p.V600E', 'Mutation', 'rs113488022', (151, 158))	('BRAF', 'Gene', (189, 193))	('V600 K', 'Mutation', 'rs121913227', (230, 236))	('BRAF', 'Gene', (138, 142))	('p.V600E', 'Var', (151, 158))
54979	33801689	Nevertheless, the antibody VE1 has a low limit of detection and allows for the detection of BRAF p.V600E mutated cells at the single-cell level.	('antibody', 'cellular_component', 'GO:0019814', ('18', '26'))	('BRAF', 'Gene', '673', (92, 96))	('antibody', 'molecular_function', 'GO:0003823', ('18', '26'))	('BRAF', 'Gene', (92, 96))	('antibody', 'cellular_component', 'GO:0042571', ('18', '26'))	('p.V600E mutated', 'Var', (97, 112))	('antibody', 'cellular_component', 'GO:0019815', ('18', '26'))	('p.V600E', 'Mutation', 'rs113488022', (97, 104))
54983	33801689	Sanger sequencing represents a valid option for melanoma patients, since, for point mutations and small variant detection, it is an easily available, reproducible and relatively low-cost approach.	('melanoma', 'Disease', (48, 56))	('point mutations', 'Var', (78, 93))	('patients', 'Species', '9606', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
54986	33801689	Conversely to IHC, which is unable to identify BRAF exon 15 non-V600 other mutations, pyrosequencing finds its applicability in precisely detecting BRAF non-V600E mutations.	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('non-V600E mutations', 'Var', (153, 172))	('V600E', 'Mutation', 'rs113488022', (157, 162))	('BRAF', 'Gene', '673', (148, 152))	('BRAF', 'Gene', (148, 152))
54987	33801689	Indeed, a higher rare BRAF mutations detection rate has been reported for pyrosequencing (92.9%) than the cobas  4800 BRAF V600 mutation test (50.0%) and IHC (21.4%), highlighting the utility of pyrosequencing in detecting rare BRAF mutations, which otherwise should be excluded from TT approaches.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', '673', (228, 232))	('BRAF', 'Gene', (118, 122))	('BRAF', 'Gene', (228, 232))	('BRAF', 'Gene', '673', (22, 26))	('TT', 'Chemical', '-', (284, 286))	('pyrosequencing', 'Var', (74, 88))	('BRAF', 'Gene', (22, 26))
54988	33801689	For detecting BRAF mutations in melanoma patients, the real-time PCR (RT-PCR) approach utilizes a set of primers: one for targeting BRAF mutations and another for identifying the wild-type sequence.	('BRAF', 'Gene', (132, 136))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('mutations', 'Var', (19, 28))	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (41, 49))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', '673', (132, 136))
54989	33801689	The previously mentioned cobas  4800 BRAF V600 mutation test or THxID-BRAF kit is the Food and Drug Administration (FDA) approved RT-PCR test for detecting BRAF exon 15 p.V600 in melanoma patients.	('THxID-BRAF', 'Disease', 'None', (64, 74))	('BRAF', 'Gene', (156, 160))	('BRAF', 'Gene', '673', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('kit', 'Gene', '3815', (75, 78))	('BRAF', 'Gene', (37, 41))	('THxID-BRAF', 'Disease', (64, 74))	('BRAF', 'Gene', '673', (70, 74))	('patients', 'Species', '9606', (188, 196))	('kit', 'Gene', (75, 78))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('p.V600', 'Var', (169, 175))	('melanoma', 'Disease', (179, 187))	('BRAF', 'Gene', '673', (156, 160))	('BRAF', 'Gene', (70, 74))
54990	33801689	When compared with Sanger sequencing, a 100% of success rate was reported for cobas  4800 BRAF V600 mutation, whereas a failure rate of 9.2% was reported for Sanger sequencing; when compared with several other techniques, such as Sanger sequencing, pyrosequencing and allele-specific PCR, the frequency of BRAF exon 15 p.V600 mutations was marginally higher for the other techniques than for the cobas  4800 BRAF V600 mutation test (35.7% vs. 34.0%, respectively).	('BRAF', 'Gene', (90, 94))	('BRAF', 'Gene', (306, 310))	('p.V600 mutations', 'Var', (319, 335))	('BRAF', 'Gene', '673', (408, 412))	('BRAF', 'Gene', '673', (90, 94))	('BRAF', 'Gene', (408, 412))	('BRAF', 'Gene', '673', (306, 310))
54992	33801689	Next-generation sequencing (NGS) is a technology with higher sensitivity but also with higher costs and longer TAT compared to allele-specific tests, whose application in melanoma patients should be limited to those cases displaying a negative result with allele-specific BRAF exon 15 V600E/K PCR.	('V600E', 'Var', (285, 290))	('V600E', 'SUBSTITUTION', 'None', (285, 290))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('BRAF', 'Gene', '673', (272, 276))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('BRAF', 'Gene', (272, 276))	('patients', 'Species', '9606', (180, 188))
54993	33801689	Indeed, as reported by Unamuno Bustos et al., about 85% of the entire cohort of the investigated melanomas presented at least one mutation, with 50% of cases harbouring a BRAF mutation.	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('BRAF', 'Gene', '673', (171, 175))	('melanomas', 'Disease', (97, 106))	('BRAF', 'Gene', (171, 175))	('mutation', 'Var', (176, 184))
54994	33801689	Moreover, NGS may also be valuable for identifying rare actionable mutations that are not usually detected by targeted methods, as recently reported in literature, where NGS was able to assess a rare variant of BRAF exon 15 V600E (c.1799_1800TG > AA) ignored by a RT-PCR approach.	('BRAF', 'Gene', '673', (211, 215))	('BRAF', 'Gene', (211, 215))	('V600E (c.1799_1800TG > AA', 'Var', (224, 249))	('c.1799_1800TG > AA', 'Mutation', 'rs113488022', (231, 249))	('V600E', 'Mutation', 'rs113488022', (224, 229))
54996	33801689	The FDA and the European Medicines Agency (EMA) approved three BRAF and MEK inhibitor combination TTs for patients with unresectable/metastatic BRAF mutated melanoma: dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib.	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('vemurafenib', 'Chemical', 'MESH:D000077484', (195, 206))	('mutated', 'Var', (149, 156))	('encorafenib', 'Chemical', 'MESH:C000601108', (228, 239))	('binimetinib', 'Chemical', 'MESH:C581313', (245, 256))	('BRAF', 'Gene', '673', (144, 148))	('dabrafenib', 'Chemical', 'MESH:C561627', (167, 177))	('TT', 'Chemical', '-', (98, 100))	('MEK', 'Gene', (72, 75))	('melanoma', 'Disease', (157, 165))	('BRAF', 'Gene', (144, 148))	('MEK', 'Gene', '5609', (72, 75))	('patients', 'Species', '9606', (106, 114))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('cobimetinib', 'Chemical', 'MESH:C574276', (212, 223))	('trametinib', 'Chemical', 'MESH:C560077', (183, 193))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (63, 67))
54999	33801689	The recent 5-year pooled analysis including 563 treatment- naive patients with BRAF V600E/K mutated, unresectable or metastatic melanoma were randomly assigned to receive either D + T or D plus placebo or vemurafenib (V).	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('V600E', 'Var', (84, 89))	('V600E', 'SUBSTITUTION', 'None', (84, 89))	('BRAF', 'Gene', '673', (79, 83))	('patients', 'Species', '9606', (65, 73))	('vemurafenib', 'Chemical', 'MESH:D000077484', (205, 216))	('BRAF', 'Gene', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
55006	33801689	Vemurafenib was the first BRAF inhibitor to be approved by the FDA for the treatment of advanced BRAF exon 15 V600E-mutant melanoma patients.	('V600E', 'Mutation', 'rs113488022', (110, 115))	('BRAF', 'Gene', '673', (26, 30))	('V600E-mutant', 'Var', (110, 122))	('BRAF', 'Gene', (26, 30))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('BRAF', 'Gene', '673', (97, 101))	('patients', 'Species', '9606', (132, 140))	('BRAF', 'Gene', (97, 101))
55016	33801689	The KEYNOTE-006 study, evaluating the efficacy of pembrolizumab in BRAF V600-mutant melanoma patients, reported a 5-year median OS of 32.7 months (95% CI 24.5-41.6).	('BRAF', 'Gene', '673', (67, 71))	('V600-mutant', 'Var', (72, 83))	('BRAF', 'Gene', (67, 71))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('pembrolizumab', 'Chemical', 'MESH:C582435', (50, 63))	('melanoma', 'Disease', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('patients', 'Species', '9606', (93, 101))
55021	33801689	As previous stated, the subgroup analyses showed a slightly better outcome for patients with BRAF mutation, who achieved a 5-year OS rate of 60% compared with 46% of patients without the BRAF mutation (Table 2).	('better', 'PosReg', (60, 66))	('BRAF', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('BRAF', 'Gene', '673', (187, 191))	('patients', 'Species', '9606', (79, 87))	('BRAF', 'Gene', '673', (93, 97))	('patients', 'Species', '9606', (166, 174))	('BRAF', 'Gene', (187, 191))
55023	33801689	Taking into account the efficacy results of combined TT in metastatic melanoma patients with BRAF mutation and the clinical need to improve the outcomes of adjuvant therapy in melanoma, studies have been carried out to establish whether TT in an adjuvant setting would improve outcomes in BRAFV600-mutant patients with resected stage III and IV melanoma.	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('TT', 'Chemical', '-', (53, 55))	('improve', 'PosReg', (269, 276))	('mutation', 'Var', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (345, 353))	('outcomes', 'MPA', (277, 285))	('stage III', 'Disease', (328, 337))	('BRAF', 'Gene', '673', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('BRAF', 'Gene', (93, 97))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('patients', 'Species', '9606', (305, 313))	('BRAF', 'Gene', '673', (289, 293))	('BRAF', 'Gene', (289, 293))	('melanoma', 'Phenotype', 'HP:0002861', (345, 353))	('melanoma', 'Disease', (345, 353))	('patients', 'Species', '9606', (79, 87))	('TT', 'Chemical', '-', (237, 239))
55028	33801689	The COMBI-AD Phase 3 trial, evaluating the combination of dabrafenib and trametinib in patients with stage AJCC 7th edition IIIA (limited to lymph-node metastasis of >1 mm), IIIB or IIIC cutaneous melanoma resulted in 53% lower risk of relapse than placebo, achieving significant improvement in the 5-year RFS rate (52% versus 36%).	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('improvement', 'PosReg', (280, 291))	('RFS', 'MPA', (306, 309))	('IIIC cutaneous melanoma', 'Disease', (182, 205))	('IIIB', 'Var', (174, 178))	('dabrafenib', 'Chemical', 'MESH:C561627', (58, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (187, 205))	('IIIC cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 205))	('trametinib', 'Chemical', 'MESH:C560077', (73, 83))	('lower', 'NegReg', (222, 227))	('patients', 'Species', '9606', (87, 95))
55042	33801689	Analogously, pembrolizumab for high-risk stage III melanoma resulted in significantly longer RFS than placebo, with no new toxic effects reported and no differences according to the BRAF status.	('RFS', 'MPA', (93, 96))	('longer', 'PosReg', (86, 92))	('BRAF', 'Gene', '673', (182, 186))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('BRAF', 'Gene', (182, 186))	('melanoma', 'Disease', (51, 59))	('pembrolizumab', 'Var', (13, 26))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
55043	33801689	The 3-year RFS rate was 63.7% for pembrolizumab versus 44.1% for placebo with a HR of 0.56 (95% CI, 0.47 to 0.68) (Table 3).	('pembrolizumab', 'Var', (34, 47))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('RFS', 'Disease', (11, 14))
55062	33801689	BRAF amplification and NRAS and MEK2 activating mutations are the most frequently observed in both preclinical and clinical settings.	('MEK2', 'molecular_function', 'GO:0004708', ('32', '36'))	('amplification', 'Var', (5, 18))	('NRAS', 'Gene', (23, 27))	('NRAS', 'Gene', '4893', (23, 27))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('activating', 'PosReg', (37, 47))	('MEK2', 'Gene', (32, 36))	('MEK2', 'Gene', '5605', (32, 36))
55065	33801689	Mutations in the ERK gene are rare in melanoma, meaning that enhanced activity of this kinase is strictly dependent on upstream signals.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('enhanced', 'PosReg', (61, 69))	('activity', 'MPA', (70, 78))	('ERK', 'molecular_function', 'GO:0004707', ('17', '20'))	('ERK', 'Gene', '5594', (17, 20))	('Mutations', 'Var', (0, 9))	('ERK', 'Gene', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
55069	33801689	To date, several ERK inhibitors are under investigation in Phase 1/2 clinical trials in advanced solid tumours: MK-8353, ulixertinib, ravoxertinib, LTT462 and LY3214996.	('solid tumours', 'Disease', 'MESH:D009369', (97, 110))	('solid tumours', 'Disease', (97, 110))	('MK-8353', 'Var', (112, 119))	('ulixertinib', 'Chemical', 'MESH:C000618314', (121, 132))	('ravoxertinib', 'Chemical', '-', (134, 146))	('ERK', 'molecular_function', 'GO:0004707', ('17', '20'))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('ERK', 'Gene', '5594', (17, 20))	('LY3214996', 'Var', (159, 168))	('LTT462', 'Chemical', '-', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('ERK', 'Gene', (17, 20))	('LTT462', 'Var', (148, 154))	('ravoxertinib', 'Var', (134, 146))
55071	33801689	On the other hand, MEK and ERK inhibitors have demonstrated synergistic activities in RAS-mutant tumours and, according to preliminary pharmacokinetic data, LY3214996 could be a good partner for MEK inhibitors in future clinical trials, in order to provide adequate tolerability.	('RAS-mutant', 'Gene', (86, 96))	('RAS-mutant', 'Var', (86, 96))	('MEK', 'Gene', '5609', (19, 22))	('tumours', 'Disease', (97, 104))	('MEK', 'Gene', (195, 198))	('MEK', 'Gene', '5609', (195, 198))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('MEK', 'Gene', (19, 22))	('ERK', 'Gene', '5594', (27, 30))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('LY3214996', 'Var', (157, 166))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('ERK', 'Gene', (27, 30))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
55077	33801689	Loss of phosphatase and tensin homolog (PTEN), which catalyses dephosphorylation of PIP3 in PIP2 thus inactivating the PI3K pathway, has been detected in no more than 30% of melanoma patients; intriguingly, loss of PTEN is never associated with NRAS mutations in melanoma, whilst it is frequent in BRAF-mutant ones.	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('NRAS', 'Gene', '4893', (245, 249))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('PIP2', 'Chemical', 'MESH:D019269', (92, 96))	('phosphatase and tensin homolog', 'Gene', '5728', (8, 38))	('NRAS', 'Gene', (245, 249))	('PTEN', 'Gene', (40, 44))	('dephosphorylation', 'biological_process', 'GO:0016311', ('63', '80'))	('BRAF', 'Gene', '673', (298, 302))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('PTEN', 'Gene', (215, 219))	('BRAF', 'Gene', (298, 302))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('phosphatase', 'molecular_function', 'GO:0016791', ('8', '19'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('8', '38'))	('patients', 'Species', '9606', (183, 191))	('PIP3', 'Chemical', '-', (84, 88))	('PI3K', 'molecular_function', 'GO:0016303', ('119', '123'))	('loss', 'Var', (207, 211))	('PTEN', 'Gene', '5728', (40, 44))	('PTEN', 'Gene', '5728', (215, 219))	('PI3K pathway', 'Pathway', (119, 131))	('mutations', 'Var', (250, 259))
55086	33801689	Cell cycle is an organized process aimed at cell division through duplication of genetic information, and its activity is aberrant in tumour cells, being a hallmark in human cancer.	('human', 'Species', '9606', (168, 173))	('cell division', 'biological_process', 'GO:0051301', ('44', '57'))	('activity', 'MPA', (110, 118))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('duplication', 'Var', (66, 77))	('cancer', 'Disease', (174, 180))	('Cell cycle', 'CPA', (0, 10))	('tumour', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
55089	33801689	Genetic aberrations of members of this pathway are frequent in melanoma, observed in up to 90% of both preclinical and clinical models.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('Genetic aberrations', 'Var', (0, 19))	('frequent', 'Reg', (51, 59))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
55095	33801689	Concerning BRAF-mutant melanoma, preclinical data showed the usefulness of CDK4/6 inhibitor LY2835219 in killing vemurafenib-resistant cells, being the right premise for the use of this class of anticancer drugs in such a clinical scenario.	('CDK4/6', 'Gene', '1019;1021', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('CDK4/6', 'Gene', (75, 81))	('melanoma', 'Disease', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('cancer', 'Disease', (199, 205))	('BRAF', 'Gene', '673', (11, 15))	('LY2835219', 'Var', (92, 101))	('vemurafenib', 'Chemical', 'MESH:D000077484', (113, 124))	('LY2835219', 'Chemical', 'MESH:C000590451', (92, 101))	('BRAF', 'Gene', (11, 15))
55096	33801689	Voruciclib (P1446A-05) has been tested in combination with vemurafenib in a Phase 1 trial (NCT01841463) with good tolerability and efficacy, also in treatment-naive patients; similar results were reported for ribociclib, a potent and selective CDK4/6 inhibitor, administered together with encorafenib in BRAF-mutant melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('patients', 'Species', '9606', (325, 333))	('BRAF', 'Gene', '673', (304, 308))	('vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('P1446A', 'Var', (12, 18))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('BRAF', 'Gene', (304, 308))	('CDK', 'molecular_function', 'GO:0004693', ('244', '247'))	('CDK4/6', 'Gene', '1019;1021', (244, 250))	('Voruciclib', 'Chemical', 'MESH:C000627065', (0, 10))	('encorafenib', 'Chemical', 'MESH:C000601108', (289, 300))	('patients', 'Species', '9606', (165, 173))	('P1446A', 'SUBSTITUTION', 'None', (12, 18))	('CDK4/6', 'Gene', (244, 250))
55100	33801689	Cutaneous melanoma genomes have the highest mutation load of any cancer, mainly attributable to UV radiation signature (C > T nucleotide transitions), resulting in several somatic nonsynonymous mutations which are quantitively measured as number per coding area, a measurement called tumour mutational burden (TMB).	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('mutation', 'Var', (44, 52))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('nonsynonymous mutations', 'Var', (180, 203))	('tumour', 'Disease', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('TMB', 'Chemical', '-', (310, 313))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('Cutaneous melanoma', 'Disease', (0, 18))
55103	33801689	In a cohort of metastatic melanoma patients treated with a first-line combination of anti-PD-1 and anti-CTLA-4, TMB was notably higher in responder than non-responder patients, and high TMB values were associated with a statistically significant survival benefit; another work analysed response to anti-PD-1 antibodies in melanoma patients with regard to TMB but failed to demonstrate an association between survival and mutational load.	('anti-PD-1', 'Var', (85, 94))	('TMB', 'Chemical', '-', (355, 358))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (322, 330))	('melanoma', 'Disease', (26, 34))	('patients', 'Species', '9606', (331, 339))	('high', 'Var', (181, 185))	('TMB', 'MPA', (112, 115))	('patients', 'Species', '9606', (35, 43))	('TMB', 'Chemical', '-', (186, 189))	('CTLA-4', 'Gene', '1493', (104, 110))	('CTLA-4', 'Gene', (104, 110))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('melanoma', 'Disease', (322, 330))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('TMB', 'Chemical', '-', (112, 115))	('patients', 'Species', '9606', (167, 175))	('survival benefit', 'CPA', (246, 262))	('higher', 'PosReg', (128, 134))
55104	33801689	BRAF V600-mutant patients treated with first-line anti-PD-1 and anti-CTLA-4 combination therapy reached better overall survival (5-years OS: 60% vs. 48%) than BRAF wild-type ones; however, BRAF-mutant melanoma specimens have shown lower TMB values compared with wild-type ones, suggesting that factors other than neoantigen load are responsible for the good results observed in this specific molecular subtype.	('melanoma', 'Disease', (201, 209))	('BRAF', 'Gene', '673', (189, 193))	('TMB', 'Chemical', '-', (237, 240))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('BRAF', 'Gene', (159, 163))	('CTLA-4', 'Gene', (69, 75))	('TMB values', 'MPA', (237, 247))	('BRAF', 'Gene', '673', (0, 4))	('CTLA-4', 'Gene', '1493', (69, 75))	('patients', 'Species', '9606', (17, 25))	('lower', 'NegReg', (231, 236))	('V600-mutant', 'Var', (5, 16))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('BRAF', 'Gene', '673', (159, 163))
55107	33801689	PARP inhibitors are currently used as maintenance therapy in high-grade serous ovarian cancer patients after platinum-based therapy, with better results obtained in patients harbouring germline or somatic mutations of genes involved in homologous recombination, which is the mechanism involved in double-strand break DNA repair.	('patients', 'Species', '9606', (94, 102))	('serous ovarian cancer', 'Disease', (72, 93))	('PARP', 'Gene', (0, 4))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('platinum', 'Chemical', 'MESH:D010984', (109, 117))	('mutations', 'Var', (205, 214))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('homologous recombination', 'biological_process', 'GO:0035825', ('236', '260'))	('DNA', 'cellular_component', 'GO:0005574', ('317', '320'))	('patients', 'Species', '9606', (165, 173))	('DNA repair', 'biological_process', 'GO:0006281', ('317', '327'))	('PARP', 'Gene', '142', (0, 4))
55110	33801689	Concerning melanoma, a study, which explored genetic alterations by NGS in more than 52,000 tumours of 21 different cancer lineages, found HR mutations in slightly less than 20% of melanoma specimens, with BAP1 (7.7%) and ATM (3.7%) being the most frequently mutated genes.	('BAP1', 'Gene', '8314', (206, 210))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))	('ATM', 'Gene', '472', (222, 225))	('Concerning melanoma', 'Disease', (0, 19))	('mutations', 'Var', (142, 151))	('BAP1', 'Gene', (206, 210))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('ATM', 'Gene', (222, 225))	('cancer', 'Disease', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumours', 'Disease', (92, 99))	('Concerning melanoma', 'Disease', 'MESH:D008545', (0, 19))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
55111	33801689	In another study, BRAF V600-mutant melanomas harboured fewer HR mutations than BRAF wild-type ones, suggesting a divergence in melanomagenesis between these genetic alterations.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('fewer', 'NegReg', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanomas', 'Disease', (35, 44))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', '673', (18, 22))	('mutations', 'Var', (64, 73))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('V600-mutant', 'Var', (23, 34))	('BRAF', 'Gene', (79, 83))	('BRAF', 'Gene', (18, 22))	('melanoma', 'Disease', (35, 43))
55113	33801689	However, HR mutated melanomas are now under the magnifying glass, with ongoing and future clinical trials using PARP inhibitors in this specific subgroup of patients (niraparib, NCT03925350; olaparib + pembrolizumab, NCT04633902).	('PARP', 'Gene', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('NCT04633902', 'Var', (217, 228))	('olaparib', 'Chemical', 'MESH:C531550', (191, 199))	('melanomas', 'Disease', (20, 29))	('patients', 'Species', '9606', (157, 165))	('PARP', 'Gene', '142', (112, 116))	('NCT03925350', 'Var', (178, 189))	('niraparib', 'Chemical', 'MESH:C545685', (167, 176))	('melanomas', 'Disease', 'MESH:D008545', (20, 29))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('pembrolizumab', 'Chemical', 'MESH:C582435', (202, 215))
55117	33801689	Focal DNA hypermethylation of tumour suppressor gene promoters, such as PTEN and CDKN2A, have been identified in up to 60% of sporadic melanomas, in some cases also with a prognostic correlation; however, many other genes have been found to be methylated in melanoma.	('hypermethylation', 'Var', (10, 26))	('sporadic melanomas', 'Disease', (126, 144))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('PTEN', 'Gene', '5728', (72, 76))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('tumour', 'Disease', (30, 36))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('6', '26'))	('melanoma', 'Disease', 'MESH:D008545', (258, 266))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('CDKN2A', 'Gene', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('sporadic melanomas', 'Disease', 'MESH:D008545', (126, 144))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('CDKN2A', 'Gene', '1029', (81, 87))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('melanoma', 'Disease', (258, 266))	('PTEN', 'Gene', (72, 76))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('identified', 'Reg', (99, 109))
55126	33801689	Indeed, an ongoing trial is investigating the HDACi vorinostat in resistant BRAF V600-mutant advanced melanoma patients (NCT02836548).	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('vorinostat', 'Chemical', 'MESH:D000077337', (52, 62))	('HDAC', 'Gene', (46, 50))	('HDAC', 'Gene', '9734', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('V600-mutant', 'Var', (81, 92))	('patients', 'Species', '9606', (111, 119))
55132	33801689	BRAF inhibition could enhance angiogenesis, and consequently melanoma progression, by stimulating cancer-associated macrophages to produce, with a paradoxically activation of the MAPK pathway, VEGF, which stimulates melanoma cell growth.	('angiogenesis', 'biological_process', 'GO:0001525', ('30', '42'))	('MAPK', 'Gene', (179, 183))	('inhibition', 'Var', (5, 15))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Disease', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('VEGF', 'Gene', '7422', (193, 197))	('BRAF', 'Gene', (0, 4))	('enhance', 'PosReg', (22, 29))	('cell growth', 'biological_process', 'GO:0016049', ('225', '236'))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('VEGF', 'Gene', (193, 197))	('MAPK', 'Gene', '4216', (179, 183))	('activation', 'PosReg', (161, 171))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('stimulates', 'PosReg', (205, 215))	('MAPK', 'molecular_function', 'GO:0004707', ('179', '183'))	('angiogenesis', 'CPA', (30, 42))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('stimulating', 'Reg', (86, 97))
55141	33801689	Tyrosine-kinase inhibitors targeting VEGFR, such as lenvatinib and cabozantinib, are currently being tested together with immunotherapy in stage III-IV melanoma (NCT01136967, NCT04091750, NCT03957551) (Table 4).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('VEGFR', 'Gene', (37, 42))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('NCT04091750', 'Var', (175, 186))	('NCT01136967', 'Var', (162, 173))	('NCT03957551', 'Var', (188, 199))	('VEGFR', 'Gene', '3791', (37, 42))	('lenvatinib', 'Chemical', 'MESH:C531958', (52, 62))	('cabozantinib', 'Chemical', 'MESH:C558660', (67, 79))
55142	33801689	BRAF mutational status fills a pivotal role in the management of both advanced and completely resected melanoma patients; thus, special attention should be addressed to the detection of BRAF mutations, with the aim of avoiding the risk and under-treatment of false-negative cases.	('false', 'biological_process', 'GO:0071878', ('259', '264'))	('BRAF', 'Gene', (186, 190))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('mutations', 'Var', (191, 200))	('false', 'biological_process', 'GO:0071877', ('259', '264'))	('patients', 'Species', '9606', (112, 120))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (186, 190))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
55165	31691901	The extent of the conjunctiva involved by PAM is the most important clinical risk factor for development of conjunctival melanoma; For example PAM that involves 4 and 12 clock hours of conjunctiva is 7 and 20 times more likely, respectively, to develop melanoma than lesions involving 1 clock hour.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('men', 'Species', '9606', (100, 103))	('melanoma than lesions', 'Disease', 'MESH:D008545', (253, 274))	('melanoma', 'Phenotype', 'HP:0002861', (253, 261))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (108, 129))	('conjunctival melanoma', 'Disease', (108, 129))	('PAM', 'Var', (143, 146))	('develop', 'PosReg', (245, 252))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (108, 129))	('melanoma than lesions', 'Disease', (253, 274))
55187	31691901	Larsen et al., in a retrospective review of 139 patients from Denmark, found that tumours with BRAF mutations were eight times more likely to metastasise than those without (32% versus 4%).	('mutations', 'Var', (100, 109))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('metastasise', 'CPA', (142, 153))	('BRAF', 'Gene', '673', (95, 99))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('BRAF', 'Gene', (95, 99))	('tumours', 'Disease', (82, 89))	('patients', 'Species', '9606', (48, 56))
55235	31691901	In particular, 23-50% will have BRAF mutations.	('BRAF', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('BRAF', 'Gene', '673', (32, 36))
55236	31691901	Conjunctival melanomas with BRAF mutations appear to be more likely to metastasise.	('Conjunctival melanomas', 'Disease', (0, 22))	('BRAF', 'Gene', '673', (28, 32))	('mutations', 'Var', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('metastasise', 'CPA', (71, 82))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('BRAF', 'Gene', (28, 32))	('Conjunctival melanoma', 'Phenotype', 'HP:0007716', (0, 21))	('Conjunctival melanomas', 'Disease', 'MESH:D003229', (0, 22))
55237	31691901	In cutaneous melanoma, activation of the mitogen-activated protein kinase (MAPK) pathway via somatic mutations in BRAF is present in 40-60% of cases.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('mutations', 'Var', (101, 110))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('activation', 'PosReg', (23, 33))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('cutaneous melanoma', 'Disease', (3, 21))
55238	31691901	BRAF mutations have been associated with worse prognosis in cutaneous melanoma, but immunotherapy with BRAF and MEK inhibitors has improved survival in non-resectable metastatic disease.	('MEK', 'Gene', (112, 115))	('MEK', 'Gene', '5609', (112, 115))	('non-resectable metastatic disease', 'Disease', (152, 185))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('improved', 'PosReg', (131, 139))	('cutaneous melanoma', 'Disease', (60, 78))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('BRAF', 'Gene', (103, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
55249	33652578	Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival.	('teneurins', 'Protein', (67, 76))	('expression', 'MPA', (77, 87))	('deregulation', 'Var', (51, 63))	('teneurins', 'Chemical', '-', (67, 76))	('mutations', 'Var', (8, 17))	('associated', 'Reg', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patient', 'Species', '9606', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('chromosomal alterations', 'Var', (19, 42))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Disease', (122, 127))
55274	33652578	This trans-homodimerization of teneurins has been reported to allow the correct matching between axons and their targets to occur, thus contributing to correct circuit-wiring in the nervous system.	('circuit-wiring', 'CPA', (160, 174))	('contributing to', 'Reg', (136, 151))	('trans-homodimerization', 'Var', (5, 27))	('matching', 'MPA', (80, 88))	('teneurins', 'Chemical', '-', (31, 40))
55275	33652578	Upon homodimerization, teneurins' intracellular domains are cleaved close to the plasma membrane and translocate into the nucleus, where they regulate gene expression via direct and indirect interactions with transcription factors.	('intracellular', 'cellular_component', 'GO:0005622', ('34', '47'))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('gene expression', 'MPA', (151, 166))	('teneurins', 'Chemical', '-', (23, 32))	('nucleus', 'cellular_component', 'GO:0005634', ('122', '129'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('81', '96'))	('interactions', 'Interaction', (191, 203))	('regulate', 'Reg', (142, 150))	('homodimerization', 'Var', (5, 21))	('transcription', 'biological_process', 'GO:0006351', ('209', '222'))
55280	33652578	The different teneurins' alternative variants interact with different ligands, mediating either teneurin homodimerization or heterodimerization with latrophilins, leading to the activation of different biological functions.	('biological functions', 'MPA', (202, 222))	('teneurin', 'Chemical', '-', (96, 104))	('teneurins', 'Gene', (14, 23))	('activation', 'PosReg', (178, 188))	('teneurin', 'Protein', (96, 104))	('mediating', 'Reg', (79, 88))	('teneurin', 'Chemical', '-', (14, 22))	('teneurins', 'Chemical', '-', (14, 23))	('variants', 'Var', (37, 45))	('heterodimerization', 'MPA', (125, 143))	('homodimerization', 'MPA', (105, 121))
55291	33652578	Recent data have demonstrated a role for TENM1 in the establishment of olfactory circuits; indeed, TENM1 deletion in mice affects their ability to detect odors and TENM1 mutations in humans are correlated with congenital anosmia.	('ability to detect odors', 'MPA', (136, 159))	('TENM1', 'Gene', (99, 104))	('deletion', 'Var', (105, 113))	('TENM1', 'Gene', (164, 169))	('congenital anosmia', 'Disease', (210, 228))	('humans', 'Species', '9606', (183, 189))	('mutations', 'Var', (170, 179))	('anosmia', 'Phenotype', 'HP:0000458', (221, 228))	('affects', 'Reg', (122, 129))	('mice', 'Species', '10090', (117, 121))	('rat', 'Species', '10116', (24, 27))	('correlated with', 'Reg', (194, 209))	('congenital anosmia', 'Disease', 'MESH:C535983', (210, 228))
55301	33652578	Indeed, in vivo studies in rodents have demonstrated that TCAP-1 administration impacts upon CRF-associated behavior, such as anxiety and depression, and increases glucose levels in rat brains.	('increases', 'PosReg', (154, 163))	('anxiety', 'Phenotype', 'HP:0000739', (126, 133))	('impacts', 'Reg', (80, 87))	('increases glucose levels', 'Phenotype', 'HP:0003074', (154, 178))	('depression', 'Disease', 'MESH:D000275', (138, 148))	('depression', 'Phenotype', 'HP:0000716', (138, 148))	('CRF-associated', 'Disease', (93, 107))	('rat', 'Species', '10116', (47, 50))	('depression', 'Disease', (138, 148))	('TCAP', 'Gene', (58, 62))	('rat', 'Species', '10116', (182, 185))	('glucose levels', 'MPA', (164, 178))	('TCAP', 'Gene', '8557', (58, 62))	('anxiety', 'Disease', 'MESH:D001007', (126, 133))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('anxiety', 'Disease', (126, 133))	('administration', 'Var', (65, 79))	('rat', 'Species', '10116', (73, 76))
55302	33652578	Besides congenital general anosmia, TENM1 deregulation has also been associated with several tumors.	('TENM1', 'Gene', (36, 41))	('deregulation', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('congenital general anosmia', 'Disease', 'MESH:C535983', (8, 34))	('congenital general anosmia', 'Disease', (8, 34))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('anosmia', 'Phenotype', 'HP:0000458', (27, 34))
55306	33652578	However, data on the association between TENM1 deregulation and tumor progression are scarce and confined to a few tumor types, such as thyroid carcinoma, pituitary tumor and glioblastoma.	('tumor', 'Disease', (115, 120))	('pituitary tumor', 'Disease', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('deregulation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (136, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (175, 187))	('thyroid carcinoma', 'Disease', (136, 153))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', (64, 69))	('TENM1', 'Gene', (41, 46))	('glioblastoma', 'Disease', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (136, 153))	('pituitary tumor', 'Disease', 'MESH:D010911', (155, 170))
55307	33652578	Further support for TENM1's functional contribution to carcinogenesis, TENM1 mutations and chromosomal alterations have occasionally been found in tumors of differing origins.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('rat', 'Species', '10116', (107, 110))	('mutations', 'Var', (77, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('TENM1', 'Gene', (71, 76))	('carcinogenesis', 'Disease', (55, 69))
55319	33652578	Moreover, miR-486 restoration in papillary thyroid carcinoma cells significantly inhibited tumor cell proliferation, migration and invasion in vitro, via ERK and protein kinase B (Akt) signaling pathways, as well as inhibiting epithelial-to-mesenchymal transition (EMT) regulation and tumor cell growth in vivo.	('papillary thyroid carcinoma', 'Disease', (33, 60))	('EMT', 'biological_process', 'GO:0001837', ('265', '268'))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (33, 60))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('227', '263'))	('regulation', 'biological_process', 'GO:0065007', ('270', '280'))	('ERK', 'Gene', (154, 157))	('rat', 'Species', '10116', (120, 123))	('tumor', 'Disease', (91, 96))	('miR-486', 'Gene', '619554', (10, 17))	('invasion', 'CPA', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('rat', 'Species', '10116', (23, 26))	('Akt', 'Gene', (180, 183))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('protein kinase B', 'Gene', '2185', (162, 178))	('rat', 'Species', '10116', (109, 112))	('Akt', 'Gene', '207', (180, 183))	('protein kinase B', 'Gene', (162, 178))	('restoration', 'Var', (18, 29))	('inhibited', 'NegReg', (81, 90))	('inhibiting', 'NegReg', (216, 226))	('ERK', 'molecular_function', 'GO:0004707', ('154', '157'))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('Akt) signaling', 'biological_process', 'GO:0043491', ('180', '194'))	('tumor', 'Disease', (285, 290))	('ERK', 'Gene', '5594', (154, 157))	('cell growth', 'biological_process', 'GO:0016049', ('291', '302'))	('miR-486', 'Gene', (10, 17))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (33, 60))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
55320	33652578	Recent data show that TENM1 is also up-regulated in a follicular variant of papillary thyroid cancer, and it is significantly more highly expressed and mutated in thyroid malignant nodules than in benign ones.	('expressed', 'MPA', (138, 147))	('papillary thyroid cancer', 'Disease', (76, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('mutated', 'Var', (152, 159))	('up-regulated', 'PosReg', (36, 48))	('more highly', 'PosReg', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TENM1', 'Gene', (22, 27))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (76, 100))	('follicular', 'Disease', (54, 64))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (76, 100))
55322	33652578	Another tumor in which TENM1 seems to play an oncogenic role is glioblastoma, where it promotes the cell proliferation, the cytoskeletal remodeling of tumor cells and the invasion of the surrounding environment, both in vitro and in vivo, via the Myc-dependent transcriptional up-regulation of ras homolog family member A (RhoA) and consequent rho-associated protein kinase (ROCK) activation.	('ras homolog family member A', 'Gene', '387', (294, 321))	('rho-associated', 'Enzyme', (344, 358))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TENM1', 'Var', (23, 28))	('ras homolog family member A', 'Gene', (294, 321))	('rat', 'Species', '10116', (112, 115))	('RhoA', 'Gene', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Myc', 'Gene', '4609', (247, 250))	('up-regulation', 'PosReg', (277, 290))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('RhoA', 'Gene', '387', (323, 327))	('tumor', 'Disease', (8, 13))	('activation', 'PosReg', (381, 391))	('glioblastoma', 'Disease', (64, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('100', '118'))	('protein', 'cellular_component', 'GO:0003675', ('359', '366'))	('Myc', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('regulation', 'biological_process', 'GO:0065007', ('280', '290'))	('tumor', 'Disease', (151, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cell proliferation', 'CPA', (100, 118))	('promotes', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
55323	33652578	Indeed, the absence of TENM1, achieved via gene deletion or down-regulation by small interfering RNA (siRNA), drastically reduces the invasive capacity of glioblastoma cells.	('absence', 'NegReg', (12, 19))	('reduces', 'NegReg', (122, 129))	('glioblastoma', 'Disease', (155, 167))	('down-regulation', 'NegReg', (60, 75))	('regulation', 'biological_process', 'GO:0065007', ('65', '75'))	('TENM1', 'Gene', (23, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('gene deletion', 'Var', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
55327	33652578	Moreover, TENM1 mRNA up-regulation in response to hypoxia increases cell migration capacity in glioblastoma cells, while the blockade of TENM1 expression results in reduces hypoxia-induced glioblastoma cell migration.	('hypoxia', 'Disease', (50, 57))	('glioblastoma', 'Disease', (189, 201))	('glioblastoma cell migration', 'Disease', 'MESH:D005909', (189, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('increases', 'PosReg', (58, 67))	('glioblastoma cell migration', 'Disease', (189, 216))	('cell migration', 'biological_process', 'GO:0016477', ('68', '82'))	('hypoxia', 'Disease', (173, 180))	('TENM1', 'Gene', (10, 15))	('regulation', 'biological_process', 'GO:0065007', ('24', '34'))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('response to hypoxia', 'biological_process', 'GO:0001666', ('38', '57'))	('mRNA', 'MPA', (16, 20))	('rat', 'Species', '10116', (210, 213))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('up-regulation', 'PosReg', (21, 34))	('glioblastoma', 'Disease', (95, 107))	('reduces', 'NegReg', (165, 172))	('rat', 'Species', '10116', (76, 79))	('TENM1', 'Gene', (137, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('cell migration', 'biological_process', 'GO:0016477', ('202', '216'))	('blockade', 'Var', (125, 133))
55334	33652578	Interestingly, a single-cell analysis of circulating tumor cells, performed on a lung cancer patient, highlighted the presence of an acquired TENM1 single nucleotide variation in circulating tumor cells, whose function has not been elucidated.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TENM1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('single nucleotide variation', 'Var', (148, 175))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
55344	33652578	It has been shown that the intracellular domain of TENM2, cleaved and released after TENM2 dimerization, translocate into the nucleus, where it represses Zic-1 mediated transcription, promoting cellular differentiation.	('nucleus', 'cellular_component', 'GO:0005634', ('126', '133'))	('represses', 'NegReg', (144, 153))	('TENM2', 'Gene', (85, 90))	('dimerization', 'Var', (91, 103))	('promoting', 'PosReg', (184, 193))	('TENM2', 'Gene', (51, 56))	('Zic-1', 'Gene', (154, 159))	('cellular differentiation', 'CPA', (194, 218))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('Zic-1', 'Gene', '7545', (154, 159))	('intracellular', 'cellular_component', 'GO:0005622', ('27', '40'))
55348	33652578	The possible tumor suppressor role of TENM2 is also suggested by the observation that hepatitis B virus-related insertional mutagenesis, leading to TENM2 gene disruption, is frequently associated with hepatocarcinogenesis.	('tumor', 'Disease', (13, 18))	('hepatitis B virus', 'Species', '10407', (86, 103))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (201, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('hepatitis', 'Phenotype', 'HP:0012115', (86, 95))	('TENM2', 'Gene', (148, 153))	('insertional mutagenesis', 'Var', (112, 135))	('associated with', 'Reg', (185, 200))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('hepatocarcinogenesis', 'Disease', (201, 221))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mutagenesis', 'biological_process', 'GO:0006280', ('124', '135'))	('gene disruption', 'Var', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hepatitis B virus-related', 'Disease', (86, 111))
55359	33652578	A conflicting trend can be observed in urothelial, endometrial, head and neck, renal, stomach and thyroid cancers, as well as in glioma and melanoma, in which low levels of TENM2 expression are correlated with better patients' overall survival.	('endometrial', 'Disease', (51, 62))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('low levels', 'Var', (159, 169))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal', 'Disease', (79, 84))	('better', 'PosReg', (210, 216))	('glioma', 'Disease', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('thyroid cancers', 'Disease', 'MESH:D013964', (98, 113))	('overall survival', 'CPA', (227, 243))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('patients', 'Species', '9606', (217, 225))	('stomach', 'Disease', (86, 93))	('urothelial', 'Disease', (39, 49))	('neck', 'cellular_component', 'GO:0044326', ('73', '77'))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('TENM2', 'Gene', (173, 178))	('thyroid cancers', 'Disease', (98, 113))
55362	33652578	Accordingly, an analysis of triple negative breast cancer (TNBC) patient samples has suggested that there is a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('patient metastatic-free survival time', 'CPA', (177, 214))	('breast cancer', 'Disease', (44, 57))	('high', 'Var', (143, 147))	('reduced', 'NegReg', (169, 176))	('TENM2', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patient', 'Species', '9606', (65, 72))	('patient', 'Species', '9606', (177, 184))	('expression', 'MPA', (154, 164))
55365	33652578	A possible link between TENM2 deregulation and the drug sensitivity of cancer cells has also been proposed, again with contradictory results.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TENM2', 'Gene', (24, 29))	('cancer', 'Disease', (71, 77))	('drug sensitivity', 'CPA', (51, 67))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('drug sensitivity', 'Phenotype', 'HP:0020174', (51, 67))	('deregulation', 'Var', (30, 42))
55373	33652578	Further evidence supporting a possible role for TENM2 deregulation in the tumor microenvironment comes from whole-genome single nucleotide polymorphism profiling, which compared the progressive passages of tumor-derived endothelial cells.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TENM2', 'Gene', (48, 53))	('tumor', 'Disease', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('deregulation', 'Var', (54, 66))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
55378	33652578	Proof of the importance of TENM3 in visual system circuit connectivity has been found in behavioral studies that show that TENM3 KO mice lack binocular vision.	('vision', 'Disease', 'MESH:D015354', (152, 158))	('vision', 'biological_process', 'GO:0007601', ('152', '158'))	('TENM3', 'Var', (123, 128))	('mice', 'Species', '10090', (132, 136))	('vision', 'Disease', (152, 158))	('lack', 'NegReg', (137, 141))
55393	33652578	Data from different tumor types has suggested that TENM3 may possibly contribute to cancer metastasization.	('cancer metastasization', 'Disease', (84, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TENM3', 'Var', (51, 56))	('contribute', 'Reg', (70, 80))	('tumor', 'Disease', (20, 25))	('cancer metastasization', 'Disease', 'MESH:D009362', (84, 106))
55396	33652578	Increased TENM3 copy numbers and expressions have also been found in glioblastoma patients with leptomeningeal dissemination, compared to patients who do not present this pattern of metastasization.	('TENM3', 'Gene', (10, 15))	('leptomeningeal dissemination', 'Disease', (96, 124))	('patients', 'Species', '9606', (82, 90))	('Increased', 'PosReg', (0, 9))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('expressions', 'MPA', (33, 44))	('patients', 'Species', '9606', (138, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('copy numbers', 'Var', (16, 28))
55397	33652578	The possible pro-metastatic role of TENM3 can also be hypothesized in lung tumors in which patients' circulating tumor cells display TENM3 mutations that are also maintained in metastasis, suggesting that these mutations are important for the migration process.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (91, 99))	('rat', 'Species', '10116', (246, 249))	('mutations', 'Var', (139, 148))	('lung tumors', 'Disease', 'MESH:D008175', (70, 81))	('TENM3', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lung tumors', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (70, 81))	('tumor', 'Disease', (75, 80))
55398	33652578	Interestingly, a gene-based query at the Human Protein Atlas displayed a correlation between worst survival and high TENM3 expression in most of the tumors analyzed, including endometrial, lung, ovarian, stomach, thyroid, urothelial cancer and glioma.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (123, 133))	('glioma', 'Disease', (244, 250))	('high', 'Var', (112, 116))	('stomach', 'Disease', (204, 211))	('Human', 'Species', '9606', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('thyroid', 'Disease', (213, 220))	('ovarian', 'Disease', (195, 202))	('endometrial', 'Disease', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('tumors', 'Disease', (149, 155))	('TENM3', 'Gene', (117, 122))	('lung', 'Disease', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('ovarian', 'Disease', 'MESH:D010049', (195, 202))	('urothelial cancer', 'Disease', 'MESH:D014523', (222, 239))	('urothelial cancer', 'Disease', (222, 239))
55405	33652578	Although no translocations have been reported for TENM3, a high frequency of TENM3 mutation has been found in skin cutaneous melanoma and pancreatic adenocarcinoma, suggesting that TENM3 may also play a role in carcinogenesis in these tumor types, and in others that have not yet been investigated.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('found', 'Reg', (101, 106))	('carcinogenesis', 'Disease', (211, 225))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (138, 163))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('play', 'Reg', (196, 200))	('mutation', 'Var', (83, 91))	('pancreatic adenocarcinoma', 'Disease', (138, 163))	('tumor', 'Disease', (235, 240))	('TENM3', 'Gene', (77, 82))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (138, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('skin cutaneous melanoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('role', 'Reg', (203, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))
55409	33652578	Interestingly, a specific TENM3-mutated epitope CD8+ T cell response was observed when peripheral blood mononuclear cells were re-stimulated.	('CD8', 'Gene', (48, 51))	('TENM3-mutated', 'Var', (26, 39))	('CD8', 'Gene', '925', (48, 51))
55417	33652578	The TENM4 protein bears a phenylalanine in the third residue of the fifth EGF repeat in the extracellular domain, and, in the intracellular domain, two SH3-binding domains and one nuclear localization sequence.	('phenylalanine in', 'Var', (26, 42))	('EGF', 'Gene', (74, 77))	('localization', 'biological_process', 'GO:0051179', ('188', '200'))	('EGF', 'Gene', '1950', (74, 77))	('TENM4', 'Gene', (4, 9))	('phenylalanine', 'Chemical', 'MESH:D010649', (26, 39))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('EGF', 'molecular_function', 'GO:0005154', ('74', '77'))	('SH3-binding', 'Protein', (152, 163))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('extracellular', 'cellular_component', 'GO:0005576', ('92', '105'))	('intracellular', 'cellular_component', 'GO:0005622', ('126', '139'))
55418	33652578	Lastly, TENM4 lacks the predicted furin cleavage sequence just outside the plasma membrane.	('furin', 'Gene', '5045', (34, 39))	('furin', 'Gene', (34, 39))	('lacks', 'NegReg', (14, 19))	('plasma membrane', 'cellular_component', 'GO:0005886', ('75', '90'))	('TENM4', 'Var', (8, 13))
55420	33652578	Indeed, TENM4 KO neuroblastoma cells of mouse origin display decreased neurite length and ability to generate filopodia-like protrusions through FAK, Cdc42 and Rac1, whereas TENM4 overexpression in neuroblastoma cells promotes protrusion formation.	('neuroblastoma', 'Disease', (17, 30))	('mouse', 'Species', '10090', (40, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('TENM4', 'Var', (174, 179))	('neuroblastoma', 'Disease', (198, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('Cdc42', 'Gene', '12540', (150, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (198, 211))	('neurite', 'cellular_component', 'GO:0043005', ('71', '78'))	('formation', 'biological_process', 'GO:0009058', ('238', '247'))	('neuroblastoma', 'Disease', 'MESH:D009447', (198, 211))	('TENM4 KO', 'Var', (8, 16))	('protrusion formation', 'CPA', (227, 247))	('decreased', 'NegReg', (61, 70))	('Cdc42', 'Gene', (150, 155))	('FAK', 'Protein', (145, 148))	('FAK', 'molecular_function', 'GO:0004717', ('145', '148'))	('Rac1', 'Gene', (160, 164))	('neurite length', 'CPA', (71, 85))	('rat', 'Species', '10116', (105, 108))	('Rac1', 'Gene', '19353', (160, 164))
55421	33652578	Here, its disruption limits the generation of normal oligodendrocyte processes, leading to lower axon myelination, which results in the essential tremor phenotype in mice.	('lower', 'NegReg', (91, 96))	('axon myelination', 'Disease', (97, 113))	('essential tremor', 'Phenotype', 'HP:0030186', (136, 152))	('axon', 'cellular_component', 'GO:0030424', ('97', '101'))	('rat', 'Species', '10116', (36, 39))	('results in', 'Reg', (121, 131))	('axon myelination', 'Disease', 'MESH:D003711', (97, 113))	('tremor', 'Disease', 'MESH:D014202', (146, 152))	('mice', 'Species', '10090', (166, 170))	('tremor', 'Phenotype', 'HP:0001337', (146, 152))	('myelination', 'biological_process', 'GO:0042552', ('102', '113'))	('disruption', 'Var', (10, 20))	('tremor', 'Disease', (146, 152))	('limits', 'NegReg', (21, 27))
55422	33652578	Moreover, a similar phenotype, which is related to TENM4 missense mutations, has been identified in humans, although contrasting results have been obtained in a study performed in the Canadian population.	('missense mutations', 'Var', (57, 75))	('TENM4', 'Gene', (51, 56))	('humans', 'Species', '9606', (100, 106))
55425	33652578	This suggests that TENM4 is down-regulated following the activation and proliferation of satellite cells, probably in response to NOTCH signaling, and that TENM4 has a pivotal role in suppressing myogenic differentiation.	('TENM4', 'Gene', (19, 24))	('down-regulated', 'NegReg', (28, 42))	('myogenic differentiation', 'CPA', (196, 220))	('rat', 'Species', '10116', (79, 82))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))	('TENM4', 'Var', (156, 161))	('suppressing', 'NegReg', (184, 195))
55430	33652578	Recently, a missense mutation of the gene has been found to co-segregate with schizophrenia, suggesting that TENM4 has a potential role in this pathology.	('schizophrenia', 'Phenotype', 'HP:0100753', (78, 91))	('schizophrenia', 'Disease', 'MESH:D012559', (78, 91))	('schizophrenia', 'Disease', (78, 91))	('missense mutation', 'Var', (12, 29))
55431	33652578	A TENM4 risk variant has also been associated with mood disorders, and with the early onset of bipolar disorders.	('bipolar disorders', 'Phenotype', 'HP:0007302', (95, 112))	('TENM4', 'Gene', (2, 7))	('associated', 'Reg', (35, 45))	('bipolar disorder', 'Phenotype', 'HP:0007302', (95, 111))	('mood disorders', 'Disease', (51, 65))	('bipolar disorders', 'Disease', (95, 112))	('variant', 'Var', (13, 20))	('bipolar disorders', 'Disease', 'MESH:D001714', (95, 112))	('mood disorders', 'Disease', 'MESH:D019964', (51, 65))
55439	33652578	Interestingly, in the breast cancer cell line MDA-MB-175, TENM4 is involved in a translocation that generates the TENM4-neureguilin-1 fusion gene, resulting in Upsilon-heregulin fusion protein production.	('TENM4-neureguilin-1', 'Var', (114, 133))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Upsilon-heregulin fusion protein production', 'MPA', (160, 203))	('MDA-MB-175', 'CellLine', 'CVCL:1400', (46, 56))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TENM4', 'Gene', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('rat', 'Species', '10116', (104, 107))
55450	33652578	Significantly lower amounts of TENM4 mRNA transcripts, compared to normal tissues, can also be observed in ovarian serous cystadenocarcinoma, in skin cutaneous melanoma and in testicular germ cell tumors (Figure 5).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lower', 'NegReg', (14, 19))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 168))	('TENM4', 'Var', (31, 36))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (107, 140))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('skin cutaneous melanoma', 'Disease', (145, 168))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('germ cell tumors', 'Phenotype', 'HP:0100728', (187, 203))	('ovarian serous cystadenocarcinoma', 'Disease', (107, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('tumors', 'Disease', (197, 203))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (107, 140))
55454	33652578	Indeed, TENM4 peptides have been identified in a proteomic study using human urine, and TENM4 was detected as one of the most abundant proteins in the secretome and in the exosomes derived from a neuroblastoma cell line.	('neuroblastoma', 'Phenotype', 'HP:0003006', (196, 209))	('TENM4', 'Var', (88, 93))	('neuroblastoma', 'Disease', 'MESH:D009447', (196, 209))	('neuroblastoma', 'Disease', (196, 209))	('human', 'Species', '9606', (71, 76))
55457	33652578	Current findings suggest that teneurins deregulation is associated with cancer cells proliferation, migration and invasion.	('rat', 'Species', '10116', (103, 106))	('migration', 'CPA', (100, 109))	('teneurins', 'Protein', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (56, 66))	('rat', 'Species', '10116', (92, 95))	('teneurins', 'Chemical', '-', (30, 39))	('deregulation', 'Var', (40, 52))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('invasion', 'CPA', (114, 122))	('cancer', 'Disease', (72, 78))
55463	33652578	However, it has to be noted that an oncogenic role for TENM2 cannot be excluded, since in TNBC, a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time has been demonstrated.	('TNBC', 'Disease', (90, 94))	('high', 'Var', (130, 134))	('patient', 'Species', '9606', (164, 171))	('reduced', 'NegReg', (156, 163))	('TENM2', 'Gene', (135, 140))	('rat', 'Species', '10116', (218, 221))	('expression', 'MPA', (141, 151))	('patient metastatic-free survival time', 'CPA', (164, 201))
55469	33652578	The data mining of publicly available data sets derived from large cohorts of oncologic patients provides interesting evidence about the presence of somatic mutations and chromosomal alterations (e.g., translocations, copy number variations, chromothripsis, and viral genome integration) leading to both teneurins' inactivation or overexpression in human tumors.	('viral genome integration', 'Var', (262, 286))	('inactivation', 'NegReg', (315, 327))	('rat', 'Species', '10116', (187, 190))	('human', 'Species', '9606', (349, 354))	('overexpression', 'PosReg', (331, 345))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('copy number variations', 'Var', (218, 240))	('teneurins', 'Chemical', '-', (304, 313))	('patients', 'Species', '9606', (88, 96))	('rat', 'Species', '10116', (280, 283))	('chromothripsis', 'Disease', (242, 256))	('tumors', 'Disease', (355, 361))	('tumors', 'Disease', 'MESH:D009369', (355, 361))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('chromothripsis', 'Disease', 'MESH:D000072837', (242, 256))	('teneurins', 'Protein', (304, 313))	('translocations', 'Var', (202, 216))	('viral genome integration', 'biological_process', 'GO:0044826', ('262', '286'))
55476	33652578	; Writing:Original Draft Preparation: G.P., R.R., M.A., F.R., G.B.	('M.A.', 'Var', (50, 54))	('F.R.', 'Var', (56, 60))	('rat', 'Species', '10116', (30, 33))
55480	32639949	Epigenomic and genomic analysis of transcriptome modulation in skin cutaneous melanoma Skin cutaneous melanoma (SKCM) is characterized by both epigenetic DNA methylation (MET) abnormalities and genomic copy number variations (CNVs).	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('abnormalities', 'Var', (176, 189))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (87, 110))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (63, 86))	('epigenetic DNA', 'Var', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('skin cutaneous melanoma', 'Disease', (63, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (92, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('154', '169'))	('Skin cutaneous melanoma', 'Disease', (87, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))
55484	32639949	In the iC3 subtype, which was associated with the most aggressive SKCM cases, FAM135B gene mutation frequencies were increased, while CD8A, GBP5, KIAA0040, and SAMHD1 expression were downregulated, suggesting that these genes play important roles in cancer development and immune responses.	('FAM135B', 'Gene', (78, 85))	('mutation', 'Var', (91, 99))	('KIAA0040', 'Gene', '9674', (146, 154))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('increased', 'PosReg', (117, 126))	('GBP5', 'Gene', '115362', (140, 144))	('SAMHD1', 'Gene', (160, 166))	('cancer', 'Disease', (250, 256))	('FAM135B', 'Gene', '51059', (78, 85))	('SAMHD1', 'Gene', '25939', (160, 166))	('KIAA0040', 'Gene', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('GBP5', 'Gene', (140, 144))	('CD8A', 'Gene', '925', (134, 138))	('downregulated', 'NegReg', (183, 196))	('CD8A', 'Gene', (134, 138))
55488	32639949	Genome alternations, like DNA mutations or copy number variations (CNVs), frequently take place during tumorigenesis and can promote cancer development.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('tumor', 'Disease', (103, 108))	('copy number variations', 'Var', (43, 65))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('promote', 'PosReg', (125, 132))
55489	32639949	In addition, DNA MET profiling studies indicate that epigenetic regulation influences biological and clinical aspects of cancer development.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('regulation', 'biological_process', 'GO:0065007', ('64', '74'))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('epigenetic regulation', 'Var', (53, 74))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('influences', 'Reg', (75, 85))
55516	32639949	Analysis of different mutation types among SKCM subtypes revealed a difference in frequencies of FAM135B mutation.	('FAM135B', 'Gene', (97, 104))	('mutation', 'Var', (105, 113))	('FAM135B', 'Gene', '51059', (97, 104))
55521	32639949	Our present findings suggest that FAM135B mutation might promote invasive behaviors in iC2-iC4 subtype tumors to some extent, but additional molecular biology experiments and protein-protein (PPI) analyses are needed to verify these results.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('promote', 'PosReg', (57, 64))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('FAM135B', 'Gene', (34, 41))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('mutation', 'Var', (42, 50))	('iC2', 'Gene', (87, 90))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('PPI', 'biological_process', 'GO:0060134', ('192', '195'))	('iC2', 'Gene', '1781', (87, 90))	('FAM135B', 'Gene', '51059', (34, 41))	('invasive behaviors', 'CPA', (65, 83))
55548	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))
55561	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))
55563	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))
55577	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))
55615	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))
55639	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.	('Nm23-H1', 'Gene', '4830', (44, 51))	('suppress', 'NegReg', (73, 81))	('RhoG-DI2', 'Gene', '397', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('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))
55640	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))
55663	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))
55664	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))
55700	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))
55706	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))
55708	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))
55713	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'))
55720	26936398	Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma The epigenetic modifier EZH2 is in the center of a repressive complex controlling differentiation of normal cells.	('EZH2', 'Gene', '2146', (238, 242))	('Copy Number Amplification', 'Var', (8, 33))	('EZH2', 'Gene', (75, 79))	('Hyperactivating', 'PosReg', (38, 53))	('DNA', 'MPA', (95, 98))	('Epigenetic', 'Var', (121, 131))	('Melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))	('DNA Methylation', 'biological_process', 'GO:0006306', ('95', '110'))	('Tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Melanoma', 'Disease', 'MESH:D008545', (205, 213))	('EZH2', 'Gene', (238, 242))	('Mutations', 'Var', (62, 71))	('Melanoma', 'Disease', (205, 213))	('EZH2', 'Gene', '2146', (75, 79))
55723	26936398	In view of this we have used an integrated systems biology approach to analyze 471 cases of skin cutaneous melanoma (SKCM) in The Cancer Genome Atlas (TCGA) for mutations and amplifications of EZH2.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('amplifications', 'Var', (175, 189))	('Cancer Genome Atlas', 'Disease', (130, 149))	('skin cutaneous melanoma', 'Disease', (92, 115))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (130, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (97, 115))	('mutations', 'Var', (161, 170))	('EZH2', 'Gene', (193, 197))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (92, 115))
55725	26936398	These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data.	('alterations', 'Var', (6, 17))	('downregulation', 'NegReg', (91, 105))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('DNA', 'Protein', (71, 74))	('hypermethylation', 'MPA', (51, 67))	('patient', 'Species', '9606', (131, 138))
55728	26936398	These results suggest that inhibiting of EZH2 is a promising therapeutic avenue for a substantial fraction of melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('inhibiting', 'Var', (27, 37))	('EZH2', 'Gene', (41, 45))	('patients', 'Species', '9606', (119, 127))
55732	26936398	In many types of cancers including lymphomas and leukemia, EZH2 is postulated to exert its oncogenic effects via aberrant histone and DNA methylation, causing silencing of tumor suppressor genes.	('tumor suppressor', 'Gene', '7248', (172, 188))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('DNA methylation', 'Protein', (134, 149))	('lymphomas and leukemia', 'Disease', 'MESH:D007938', (35, 57))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lymphomas', 'Phenotype', 'HP:0002665', (35, 44))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('tumor suppressor', 'Gene', (172, 188))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('172', '188'))	('DNA methylation', 'biological_process', 'GO:0006306', ('134', '149'))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('EZH2', 'Gene', (59, 63))	('silencing', 'MPA', (159, 168))	('histone', 'Protein', (122, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('172', '188'))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))	('aberrant', 'Var', (113, 121))
55733	26936398	Recent studies have identified reversible H3K27me3 levels in response to aberrant EZH2 activity in melanoma suggesting suitability for pharmacological targeting.	('activity', 'MPA', (87, 95))	('EZH2', 'Protein', (82, 86))	('aberrant', 'Var', (73, 81))	('H3K27me3', 'Protein', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))
55734	26936398	In particular our recent studies have shown that small molecule inhibitors of EZH2 could induce cell cycle arrest and apoptosis of melanoma cells harboring somatic mutations of EZH2.	('apoptosis', 'CPA', (118, 127))	('EZH2', 'Gene', (177, 181))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('induce', 'PosReg', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('small molecule inhibitors', 'Var', (49, 74))	('arrest', 'Disease', (107, 113))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('96', '113'))	('inhibitors', 'Var', (64, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('mutations', 'Var', (164, 173))	('EZH2', 'Gene', (78, 82))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))
55736	26936398	Methylation status and transcriptional activity of target genes is combined with the transcriptional response of cellular melanoma models of activating EZH2 mutations to treatment with an EZH2 inhibitor.	('activating', 'PosReg', (141, 151))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('mutations', 'Var', (157, 166))	('EZH2', 'Gene', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))
55743	26936398	Illumina HiSeq 2000 V2 RNA Sequencing by expectation-maximization normalized Log2 data was filtered for differential expression in patients with activating EZH2 mutations in two-tailed Z-tests and p-values below 0.05 in 458 and 12633 patients in TCGA SKCM and Pan-cancer, respectively.	('patients', 'Species', '9606', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('TCGA SKCM', 'Disease', (246, 255))	('activating', 'PosReg', (145, 155))	('EZH2', 'Gene', (156, 160))	('patients', 'Species', '9606', (234, 242))	('mutations', 'Var', (161, 170))	('RNA', 'cellular_component', 'GO:0005562', ('23', '26'))	('Pan-cancer', 'Disease', (260, 270))	('Pan-cancer', 'Disease', 'MESH:C537931', (260, 270))
55745	26936398	Methylation data was thresholded for differential methylation in patients with activating EZH2 mutations in two-tailed Z-tests and p-values below 0.05.	('activating', 'PosReg', (79, 89))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('patients', 'Species', '9606', (65, 73))	('mutations', 'Var', (95, 104))	('EZH2', 'Gene', (90, 94))
55748	26936398	Somatic mutations of selected PRC genes were called by multi-step filtering after cohort selection, mapping of human genome and patient specific somatic references, assessment of recurrence, evolutionary conversation, basal mutation rate based on frequency of mutations of introns vs exons, and structural analysis.	('mutations', 'Var', (260, 269))	('PRC', 'Gene', (30, 33))	('human', 'Species', '9606', (111, 116))	('patient', 'Species', '9606', (128, 135))
55749	26936398	TCGA patients showed recurring mutations TCGA-BF-A1PV-01 EZH2(Y641N), TCGA-D9-A1JW-06 EZH2(Y641F), and TCGA-EE-A3AF-06 EZH2(Y641N).	('TCGA-BF-A1PV-01', 'Gene', (41, 56))	('Y641N', 'Mutation', 'rs267601395', (62, 67))	('TCGA-EE-A3AF-06', 'Gene', (103, 118))	('patients', 'Species', '9606', (5, 13))	('Y641F', 'Mutation', 'rs267601394', (91, 96))	('Y641N', 'Mutation', 'rs267601395', (124, 129))	('Y641N', 'Var', (62, 67))	('Y641N', 'Var', (124, 129))	('TCGA-D9-A1JW-06', 'Gene', (70, 85))	('Y641F', 'Var', (91, 96))
55751	26936398	EZH2 wild type status Y641 of MELJD, ME1007, and KMJR138 cell lines was confirmed by sequenom or sanger sequencing, while IGR1 had in-frame point mutations EZH2(Y641N), MM386(Y641H) and C001(Y641S).	('MM386(Y641H', 'Var', (169, 180))	('Y641H', 'Mutation', 'rs267601395', (175, 180))	('IGR1', 'Gene', (122, 126))	('Y641S', 'Mutation', 'rs267601394', (191, 196))	('EZH2', 'Gene', (156, 160))	('Y641N', 'Mutation', 'rs267601395', (161, 166))	('Y641N', 'Var', (161, 166))	('C001', 'Gene', (186, 190))
55759	26936398	cDNA was amplified using the AB7900 real-time quantitative PCR (RT-qPCR) system (Life Technologies, Carlsbad, CA, USA) using Universal PCR Mastermix and Taqman probes (Life Technologies, Carlsbad, CA, USA) specific for CDKN1A [GeneBank:1026] (Hs00355782_m1) and normalized to levels of 18 s (Hs99999901_s1).	('Hs00355782_m1', 'Var', (243, 256))	('CDKN1A', 'Gene', '1026', (219, 225))	('CDKN1A', 'Gene', (219, 225))
55760	26936398	The proportion of mutations that affect the different domains of EZH2 is similar between the melanoma cohort and the Pan-cancer average (DMNT binding domain 42.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma cohort', 'Disease', 'MESH:D008545', (93, 108))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('Pan-cancer', 'Disease', (117, 127))	('melanoma cohort', 'Disease', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('EZH2', 'Gene', (65, 69))	('DMNT', 'Chemical', '-', (137, 141))	('Pan-cancer', 'Disease', 'MESH:C537931', (117, 127))	('mutations', 'Var', (18, 27))
55765	26936398	The replacement of the JAK2 phosphorylation target residue Y641 alters EZH2 conformation, increasing its tri-methylation activity and stabilizing the protein.	('EZH2', 'Gene', (71, 75))	('Y641', 'Var', (59, 63))	('alters', 'Reg', (64, 70))	('JAK2', 'Gene', (23, 27))	('JAK', 'molecular_function', 'GO:0004713', ('23', '26'))	('methylation', 'biological_process', 'GO:0032259', ('109', '120'))	('conformation', 'MPA', (76, 88))	('stabilizing', 'MPA', (134, 145))	('tri-methylation activity', 'MPA', (105, 129))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('protein', 'Protein', (150, 157))	('increasing', 'PosReg', (90, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('JAK2', 'Gene', '3717', (23, 27))
55766	26936398	Therefore it is expected that EZH2 Y641 mutants in melanoma cells exhibit increased H3K27me3 levels.	('EZH2', 'Gene', (30, 34))	('Y641 mutants', 'Var', (35, 47))	('H3K27me3 levels', 'MPA', (84, 99))	('increased', 'PosReg', (74, 83))	('mutants', 'Var', (40, 47))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
55767	26936398	High levels of activating mutations affecting the SET domain were also evident in other cancers such as Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC) including 2 Y641 mutations, uterine corpus endometrial carcinoma (UCEC), lung cancer (LUAD), colorectal cancer (COAD), stomach cancer (STAD), and acute myeloid leukemia (LAML).	('endometrial carcinoma', 'Disease', (202, 223))	('leukemia', 'Phenotype', 'HP:0001909', (319, 327))	('stomach cancer', 'Phenotype', 'HP:0012126', (278, 292))	('COAD', 'Disease', (271, 275))	('Lymphoid Neoplasm', 'Disease', (104, 121))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (311, 327))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('mutations', 'Var', (26, 35))	('activating', 'PosReg', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (252, 269))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('Neoplasm', 'Phenotype', 'HP:0002664', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (202, 223))	('cancers', 'Disease', (88, 95))	('Lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (136, 151))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('stomach cancer', 'Disease', (278, 292))	('acute myeloid leukemia', 'Disease', (305, 327))	('colorectal cancer', 'Disease', 'MESH:D015179', (252, 269))	('COAD', 'Disease', 'MESH:D029424', (271, 275))	('lung cancer', 'Disease', (232, 243))	('B-cell Lymphoma', 'Disease', (136, 151))	('colorectal cancer', 'Disease', (252, 269))	('2 Y641 mutations', 'Var', (169, 185))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (136, 151))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (305, 327))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (305, 327))	('stomach cancer', 'Disease', 'MESH:D013274', (278, 292))	('Lymphoid Neoplasm', 'Disease', 'MESH:D008223', (104, 121))
55773	26936398	The EZH2 locus is over-expressed at the level of somatic copy number alterations (5.0% significant SCNA gain with a q-value below 0.01), which is higher than the TCGA Pan-cancer average of 1.8% (Figure 3A, Supplementary Table 2).	('Pan-cancer', 'Disease', 'MESH:C537931', (167, 177))	('alterations', 'Var', (69, 80))	('gain', 'PosReg', (104, 108))	('EZH2', 'Gene', (4, 8))	('SCNA', 'CPA', (99, 103))	('copy number alterations', 'Var', (57, 80))	('Pan-cancer', 'Disease', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
55779	26936398	Further, the pattern of SCNAs in melanoma is tightly linked to its mutational signature and tumor samples of patients with EZH2 and BRAF mutations are significantly enriched in somatic copy number amplifications with p-values below 0.05 and q-values below 10e-05 in comparison to BRAF wild type status (Figure 3C).	('BRAF', 'Gene', (132, 136))	('BRAF', 'Gene', '673', (280, 284))	('EZH2', 'Gene', (123, 127))	('patients', 'Species', '9606', (109, 117))	('BRAF', 'Gene', (280, 284))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mutations', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('copy number amplifications', 'Var', (185, 211))	('tumor', 'Disease', (92, 97))	('BRAF', 'Gene', '673', (132, 136))
55785	26936398	In SKCM, about 1/5th of the patient cohort is affected by somatic mutations, somatic copy number amplification, or transcriptional upregulation of EZH2.	('mutations', 'Var', (66, 75))	('upregulation', 'PosReg', (131, 143))	('EZH2', 'Gene', (147, 151))	('affected by', 'Reg', (46, 57))	('patient', 'Species', '9606', (28, 35))	('transcriptional', 'Var', (115, 130))
55791	26936398	Following treatment of melanoma cells with EZH2 inhibitor GSK126, H3K27me3 levels are expected to be decreased leading to increased transcriptional levels of EZH2 target genes.	('EZH2', 'Gene', (43, 47))	('GSK126', 'Chemical', 'MESH:C577920', (58, 64))	('GSK', 'molecular_function', 'GO:0050321', ('58', '61'))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('decreased', 'NegReg', (101, 110))	('GSK126', 'Var', (58, 64))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('H3K27me3 levels', 'MPA', (66, 81))	('increased', 'PosReg', (122, 131))	('transcriptional levels of', 'MPA', (132, 157))
55793	26936398	Common to all tested melanoma cell lines was presence of H3K27me3 that could be reduced by the EZH2 inhibitor GSK126 (Figure 7A).	('H3K27me3', 'Var', (57, 65))	('GSK126', 'Chemical', 'MESH:C577920', (110, 116))	('GSK', 'molecular_function', 'GO:0050321', ('110', '113'))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
55794	26936398	GSK126 is a competitive inhibitor of EZH2's methyltransferase activity that does not degrade EZH2 protein.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('activity', 'MPA', (62, 70))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('GSK126', 'Var', (0, 6))	('methyltransferase', 'Enzyme', (44, 61))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('s methyltransferase activity', 'molecular_function', 'GO:0008172', ('42', '70'))
55798	26936398	The overlap of TCGA and drug response transcriptomes resulted in 98 responsive genes, of which 65 genes also showed DNA hypermethylation in TCGA tumors with high EZH2 activity (Figure 5B and C, Supplementary Table 3).	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (145, 151))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('116', '136'))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('hypermethylation', 'Var', (120, 136))
55808	26936398	We were able to identify three cellular melanoma models, IGR1, C001, and MM386, which recapitulate the Y641 point mutations.	('Y641 point', 'Var', (103, 113))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))
55810	26936398	The gene product of CDKN1A, p21, is absent in melanocytes but present in melanoma cells.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('CDKN1A', 'Gene', (20, 26))	('CDKN1A', 'Gene', '1026', (20, 26))	('p21', 'Var', (28, 31))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
55811	26936398	In stark contrast, melanoma cell lines with activating EZH2 mutations show absence of p21 (Figure 7B).	('activating', 'PosReg', (44, 54))	('absence', 'NegReg', (75, 82))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('EZH2', 'Gene', (55, 59))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('mutations', 'Var', (60, 69))	('p21', 'Protein', (86, 89))
55813	26936398	MM386 and IGR-1 cells showed a dose dependent upregulation of CDKN1A by RT-qPCR (Figure 7C), following treatment with GSK126, which is a competitive inhibitor of EZH2s methyltransferase activity .	('IGR-1', 'CellLine', 'CVCL:1303', (10, 15))	('s methyltransferase activity', 'molecular_function', 'GO:0008172', ('166', '194'))	('upregulation', 'PosReg', (46, 58))	('GSK126', 'Chemical', 'MESH:C577920', (118, 124))	('CDKN1A', 'Gene', (62, 68))	('GSK', 'molecular_function', 'GO:0050321', ('118', '121'))	('RT-qPCR', 'Var', (72, 79))	('CDKN1A', 'Gene', '1026', (62, 68))
55814	26936398	Taken together, the transcriptional reactivation of CDKN1A following EZH2 inhibition by GSK126 shows reversal of the transcriptional silencing observed with activating EZH2 mutations.	('GSK', 'molecular_function', 'GO:0050321', ('88', '91'))	('activating', 'PosReg', (157, 167))	('EZH2', 'Gene', (168, 172))	('inhibition', 'NegReg', (74, 84))	('CDKN1A', 'Gene', (52, 58))	('mutations', 'Var', (173, 182))	('CDKN1A', 'Gene', '1026', (52, 58))	('GSK126', 'Chemical', 'MESH:C577920', (88, 94))	('transcriptional', 'MPA', (117, 132))	('transcriptional', 'MPA', (20, 35))
55815	26936398	Overexpressed in many types of cancers, EZH2 is postulated to exert its oncogenic effects via aberrant methylation, causing silencing of tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('137', '153'))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor suppressor', 'biological_process', 'GO:0051726', ('137', '153'))	('methylation', 'biological_process', 'GO:0032259', ('103', '114'))	('silencing', 'MPA', (124, 133))	('tumor suppressor', 'Gene', (137, 153))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('tumor suppressor', 'Gene', '7248', (137, 153))	('methylation', 'Var', (103, 114))	('EZH2', 'Gene', (40, 44))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('aberrant methylation', 'Var', (94, 114))
55817	26936398	The mutational signature of EZH2 (5.04% of SKCM patients) (Figure 1A) is mutually exclusive to non-synonymous somatic mutations in DNMT3A [GeneBank:1788] (occurring in 2.88% of patients) or DNMT3B [GeneBank:1789] (4.68% of patients) with an odds-ratio of 3.8, but is not strictly mutually exclusive to DNMT1 [GeneBank:1786] mutations (6.47% of patients) (Figure 10).	('DNMT3B', 'Gene', '1789', (190, 196))	('DNMT1', 'Gene', '1786', (302, 307))	('DNMT3B', 'Gene', (190, 196))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (118, 127))	('EZH2', 'Gene', (28, 32))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (344, 352))	('patients', 'Species', '9606', (223, 231))	('DNMT3A', 'Gene', (131, 137))	('DNMT3A', 'Gene', '1788', (131, 137))	('DNMT1', 'Gene', (302, 307))
55818	26936398	EZH2-D142V in the DNMT binding domain and DNMT1-I531R co-occur as well as EZH2-C535W and DNMT1-R1466C.	('DNMT1', 'Gene', '1786', (89, 94))	('DNMT', 'Gene', (42, 46))	('I531R', 'Mutation', 'p.I531R', (48, 53))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('DNMT', 'Gene', '1786', (42, 46))	('C535W', 'SUBSTITUTION', 'None', (79, 84))	('D142V', 'Mutation', 'p.D142V', (5, 10))	('DNMT1', 'Gene', (42, 47))	('DNMT1', 'Gene', (89, 94))	('EZH2-D142V', 'Var', (0, 10))	('DNMT', 'Gene', '1786', (89, 93))	('C535W', 'Var', (79, 84))	('R1466C', 'Mutation', 'rs147984942', (95, 101))	('DNMT', 'Gene', '1786', (18, 22))	('DNMT', 'Gene', (89, 93))	('DNMT1', 'Gene', '1786', (42, 47))	('DNMT', 'Gene', (18, 22))
55820	26936398	The mutual exclusivity (reflected in all cancers including blood-derived cancer with high EZH2 alterations LAML, acute myeloid leukemia, and DBLC, Lymphoid Neoplasm Diffuse Large B-cell Lymphoma) points towards a potential mechanism of somatic mutations in PRC2 driving cancer through EZH2 or alternatively DNMT3A/B (Figure 9, Figure 10).	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('Lymphoma', 'Phenotype', 'HP:0002665', (186, 194))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (119, 135))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (113, 135))	('cancer', 'Disease', (41, 47))	('cancers', 'Disease', (41, 48))	('cancer', 'Disease', (73, 79))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (179, 194))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Lymphoid Neoplasm', 'Disease', 'MESH:D008223', (147, 164))	('Lymphoid Neoplasm', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('mutations', 'Var', (244, 253))	('PRC2', 'Gene', (257, 261))	('B-cell Lymphoma', 'Disease', (179, 194))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('DNMT3A/B (Figure 9, Figure 10', 'Gene', '1788', (307, 336))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (179, 194))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('acute myeloid leukemia', 'Disease', (113, 135))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('Neoplasm', 'Phenotype', 'HP:0002664', (156, 164))
55825	26936398	Pathological hyperactivity of EZH2 can arise from somatic amplification persisting at the transcriptional level or from somatic mutations but both events eventually result in a disruption of the epigenetic homeostasis.	('homeostasis', 'biological_process', 'GO:0042592', ('206', '217'))	('mutations', 'Var', (128, 137))	('epigenetic homeostasis', 'MPA', (195, 217))	('EZH2', 'Gene', (30, 34))	('disruption', 'Reg', (177, 187))	('result in', 'Reg', (165, 174))	('hyperactivity', 'Disease', 'MESH:D006948', (13, 26))	('hyperactivity', 'Disease', (13, 26))	('hyperactivity', 'Phenotype', 'HP:0000752', (13, 26))	('amplification', 'Var', (58, 71))
55827	26936398	Irrespectively of lengths of N-terminal domains, somatic mutations across different cancers hit a unique phosphorylation site in the center of the SET domain resulting in hyperactivation and increased tri-methylation activity.	('hit', 'Reg', (92, 95))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('methylation', 'biological_process', 'GO:0032259', ('205', '216'))	('cancers', 'Disease', (84, 91))	('phosphorylation site', 'MPA', (105, 125))	('increased', 'PosReg', (191, 200))	('hyperactivation', 'MPA', (171, 186))	('mutations', 'Var', (57, 66))	('tri-methylation activity', 'MPA', (201, 225))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))
55828	26936398	Patients with somatic copy number amplifications of EZH2 showed a similar functional impact: gene suppression was most pronounced in cases where SCNA events translated to significant upregulation of EZH2 transcripts.	('upregulation', 'PosReg', (183, 195))	('copy number amplifications', 'Var', (22, 48))	('EZH2', 'Gene', (199, 203))	('EZH2', 'Gene', (52, 56))	('SCNA', 'Disease', (145, 149))	('transcripts', 'MPA', (204, 215))	('Patients', 'Species', '9606', (0, 8))
55831	26936398	Our analysis identified a coincidence of BRAF activation with EZH2 amplification providing a mechanistic link for previous studies, which showed an association between BRAF mutations and DNA hypermethylation.	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('187', '207'))	('DNA', 'cellular_component', 'GO:0005574', ('187', '190'))	('BRAF', 'Gene', '673', (41, 45))	('mutations', 'Var', (173, 182))	('association', 'Interaction', (148, 159))	('BRAF', 'Gene', '673', (168, 172))	('BRAF', 'Gene', (41, 45))	('BRAF', 'Gene', (168, 172))
55832	26936398	Abnormal DNA methylation of CpG markers is a well-known epigenetic feature of cancer.	('CpG', 'Gene', (28, 31))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('Abnormal DNA methylation', 'Var', (0, 24))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
55833	26936398	Melanoma exhibits global hypomethylation within the bulk genome and local hypermethylation at specific tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('tumor suppressor', 'Gene', '7248', (103, 119))	('Melanoma', 'Disease', (0, 8))	('hypomethylation', 'MPA', (25, 40))	('hypermethylation', 'Var', (74, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('103', '119'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('103', '119'))	('tumor suppressor', 'Gene', (103, 119))
55838	26936398	Gene expression studies carried out on melanoma lines with known activating mutations of EZH2 before and after treatment with the GSK126 inhibitor were a valuable resource to identify genes linked to EZH2 activation in the TCGA data set and allowed for detailed study of their epigenetic DNA makeup in SKCM patients.	('SKCM', 'Disease', (302, 306))	('GSK', 'molecular_function', 'GO:0050321', ('130', '133'))	('mutations', 'Var', (76, 85))	('EZH2', 'Gene', (89, 93))	('activation', 'PosReg', (205, 215))	('activating', 'PosReg', (65, 75))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('DNA', 'cellular_component', 'GO:0005574', ('288', '291'))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('EZH2', 'Gene', (200, 204))	('GSK126', 'Chemical', 'MESH:C577920', (130, 136))	('patients', 'Species', '9606', (307, 315))
55839	26936398	In vitro studies of cancer cell lines recapitulating activating Y641 mutations show a more than three-fold increase of tri-methylation of H3K27me3, a histone mark connected with gene silencing.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Y641', 'Gene', (64, 68))	('mutations', 'Var', (69, 78))	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('increase', 'PosReg', (107, 115))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('H3K27me3', 'Protein', (138, 146))	('cancer', 'Disease', (20, 26))	('tri-methylation', 'MPA', (119, 134))	('gene silencing', 'biological_process', 'GO:0016458', ('178', '192'))
55844	26936398	It has been suggested that aberrant EZH2 activity in cancer maintains the cells in a stem like state, therefore EZH2 inhibitors may represent a strategy to induce differentiation and repress tumor growth.	('aberrant', 'Var', (27, 35))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('differentiation', 'CPA', (163, 178))	('repress tumor', 'Disease', 'MESH:D009369', (183, 196))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('repress tumor', 'Disease', (183, 196))	('induce', 'PosReg', (156, 162))	('EZH2', 'Protein', (36, 40))
55847	26936398	We were able to confirm transcriptional reactivation of the tumor suppressor CDKN1A in EZH2 Y641 mutated melanoma cells, using an EZH2 inhibitor.	('transcriptional', 'MPA', (24, 39))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('CDKN1A', 'Gene', (77, 83))	('mutated', 'Var', (97, 104))	('melanoma', 'Disease', (105, 113))	('tumor suppressor', 'Gene', (60, 76))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('60', '76'))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('CDKN1A', 'Gene', '1026', (77, 83))	('EZH2', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor suppressor', 'Gene', '7248', (60, 76))	('tumor suppressor', 'biological_process', 'GO:0051726', ('60', '76'))
55849	26936398	These findings are consistent with a previous report that demonstrated EZH2 depletion in melanoma lead to reactivation of p21 and inhibited the growth of xenografts in mice.	('EZH2', 'Gene', (71, 75))	('depletion', 'Var', (76, 85))	('growth of xenografts in mice', 'CPA', (144, 172))	('inhibited', 'NegReg', (130, 139))	('mice', 'Species', '10090', (168, 172))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('reactivation', 'MPA', (106, 118))	('melanoma', 'Disease', (89, 97))	('p21', 'Protein', (122, 125))
55850	26936398	Patients with activating EZH2 mutations, show hypermethylation and transcriptional silencing of the tumor suppressor CDKN1A resulting in absence of p21, the gene product of CDKN1A.	('silencing', 'NegReg', (83, 92))	('tumor suppressor', 'Gene', '7248', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('CDKN1A', 'Gene', '1026', (173, 179))	('EZH2', 'Gene', (25, 29))	('transcriptional', 'MPA', (67, 82))	('absence', 'NegReg', (137, 144))	('activating', 'PosReg', (14, 24))	('CDKN1A', 'Gene', (117, 123))	('hypermethylation', 'Var', (46, 62))	('mutations', 'Var', (30, 39))	('Patients', 'Species', '9606', (0, 8))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('CDKN1A', 'Gene', '1026', (117, 123))	('tumor suppressor', 'Gene', (100, 116))	('p21', 'MPA', (148, 151))	('CDKN1A', 'Gene', (173, 179))
55851	26936398	Inhibition of EZH2 by small molecule drugs reactivates CDKN1A and illustrates how epigenetic control by EZH2 can regulate the plasticity of melanoma.	('plasticity', 'CPA', (126, 136))	('regulate', 'Reg', (113, 121))	('reactivates', 'NegReg', (43, 54))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('Inhibition', 'Var', (0, 10))	('CDKN1A', 'Gene', (55, 61))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('CDKN1A', 'Gene', '1026', (55, 61))
55852	26936398	An unexpected finding was the repression of many genes associated with immune responses in patients with EZH2 dysregulation.	('patients', 'Species', '9606', (91, 99))	('repression', 'NegReg', (30, 40))	('genes', 'Gene', (49, 54))	('EZH2', 'Gene', (105, 109))	('dysregulation', 'Var', (110, 123))
55853	26936398	However, this is consistent with increasing appreciation that activated EZH2 is associated with decreased transcription of genes involved in antigen presentation in melanoma patients.	('transcription of genes', 'MPA', (106, 128))	('activated', 'Var', (62, 71))	('decreased', 'NegReg', (96, 105))	('patients', 'Species', '9606', (174, 182))	('EZH2', 'Gene', (72, 76))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('antigen presentation', 'biological_process', 'GO:0019882', ('141', '161'))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
55854	26936398	Recent data suggests that specific oncogenic signals can mediate cancer immune evasion and resistance to immunotherapies and specifically EZH2 can dampen the anti-tumor immune response via repression of MHC-II genes.	('mediate', 'Reg', (57, 64))	('resistance to immunotherapies', 'CPA', (91, 120))	('EZH2', 'Var', (138, 142))	('immune evasion', 'biological_process', 'GO:0051842', ('72', '86'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('repression', 'NegReg', (189, 199))	('immune evasion', 'biological_process', 'GO:0042783', ('72', '86'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('immune response', 'biological_process', 'GO:0006955', ('169', '184'))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MHC-II genes', 'Gene', (203, 215))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('dampen', 'NegReg', (147, 153))
55856	26936398	Modulation of immune potentiation via epigenetic signals may point toward new candidate targets for melanoma treatment.	('Modulation', 'Var', (0, 10))	('epigenetic signals', 'Var', (38, 56))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('immune potentiation', 'MPA', (14, 33))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
55859	26936398	In summary these studies indicate that dysregulation of EZH2 is a relatively common occurrence in patients with melanoma and that this has negative implications for patient survival.	('dysregulation', 'Var', (39, 52))	('patient', 'Species', '9606', (98, 105))	('patient', 'Species', '9606', (165, 172))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('EZH2', 'Gene', (56, 60))
55863	26936398	Repression of the EZH2 target genes appears to be largely due to both tri-methylation of H3K27 as well as methylation of DNA and this provides a basis for investigating combinations of both EZH2 and DNA methyltransferase inhibitors in patients with over expressed EZH2.	('tri-methylation', 'Var', (70, 85))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('over expressed', 'PosReg', (249, 263))	('patients', 'Species', '9606', (235, 243))	('methylation', 'Var', (106, 117))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('EZH2', 'Gene', (264, 268))	('H3K27', 'Protein', (89, 94))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('Repression', 'NegReg', (0, 10))	('methylation', 'biological_process', 'GO:0032259', ('106', '117'))
55865	26936398	Hyperactivation of EZH2 by somatic copy number amplification, activating somatic mutations, or transcriptional upregulation correlates with DNA methylation and epigenetic silencing of genes involved in tumor suppression and immune responses in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('upregulation', 'PosReg', (111, 123))	('tumor', 'Disease', (202, 207))	('activating', 'PosReg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('transcriptional', 'MPA', (95, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('140', '155'))	('Hyperactivation', 'PosReg', (0, 15))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('mutations', 'Var', (81, 90))	('epigenetic silencing', 'Var', (160, 180))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('EZH2', 'Gene', (19, 23))	('melanoma', 'Disease', (244, 252))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
55871	33576304	More intriguingly, CD155 expression had a significant interaction with immune function in several tumors by analyzing Tumor mutational burden and microsatellite in stability, immune score and stromal score.	('tumors', 'Disease', (98, 104))	('CD155', 'Gene', '5817', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('microsatellite', 'Var', (146, 160))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('CD155', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Tumor', 'Phenotype', 'HP:0002664', (118, 123))	('interaction', 'Reg', (54, 65))
55933	33576304	There is also evidence that CD155/CD226 interaction can attenuate the generation of CD8+ T cells by regulating NK T-cell differentiation.	('CD8', 'Gene', '925', (84, 87))	('attenuate', 'NegReg', (56, 65))	('CD226', 'Gene', '10666', (34, 39))	('CD155', 'Gene', '5817', (28, 33))	('interaction', 'Var', (40, 51))	('regulating', 'Reg', (100, 110))	('NK T-cell differentiation', 'CPA', (111, 136))	('CD155', 'Gene', (28, 33))	('CD8', 'Gene', (84, 87))	('NK T-cell differentiation', 'biological_process', 'GO:0001865', ('111', '136'))	('CD226', 'Gene', (34, 39))
55944	33576304	ACC Adrenocortical carcinoma BLCA Bladder Urothelial Carcinoma BRCA Breast invasive carcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CHOL Cholangio carcinoma COAD Colon adenocarcinoma DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma ESCA Esophageal carcinoma GBM Glioblastoma multiforme HNSC Head and Neck squamous cell carcinoma KICH Kidney Chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LAML Acute Myeloid Leukemia LGG Brain Lower Grade Glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma TME tumor microenvironment OS overall survival DSS Disease-specific survival LUSC Lung squamous cell carcinoma MESO Mesothelioma OV Ovarian serous cystadenocarcinoma PAAD Pancreatic adenocarcinoma PCPG Pheochromocytoma and Paraganglioma PRAD Prostate adenocarcinoma READ Rectum adenocarcinoma SARC Sarcoma SKCM Skin Cutaneous Melanoma STAD Stomach adenocarcinoma TGCT Testicular Germ Cell Tumors THCA Thyroid carcinoma THYM Thymoma UCEC Uterine Corpus Endometrial Carcinoma UCS Uterine Carcinosarcoma UVM Uveal Melanoma TMB Tumor mutational burden MSI microsatellite in stability DFI Disease-free interval PFI Progression-free interval	('Tumor', 'Phenotype', 'HP:0002664', (978, 983))	('carcinoma', 'Disease', 'MESH:D009369', (179, 188))	('carcinoma', 'Disease', (845, 854))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (394, 427))	('Kidney renal papillary cell carcinoma', 'Disease', (433, 470))	('KICH', 'Disease', (365, 369))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (990, 1007))	('tumor', 'Phenotype', 'HP:0002664', (593, 598))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('Sarcoma', 'Disease', (887, 894))	('Kidney Chromophobe', 'Disease', (370, 388))	('serous cystadenocarcinoma', 'Disease', (729, 754))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (1034, 1062))	('Breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('Paraganglioma', 'Phenotype', 'HP:0002668', (812, 825))	('carcinoma', 'Disease', (998, 1007))	('carcinoma', 'Disease', (776, 785))	('carcinoma', 'Disease', (579, 588))	('CHOL', 'Disease', 'None', (164, 168))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (68, 93))	('Urothelial Carcinoma', 'Disease', (42, 62))	('carcinoma', 'Disease', (554, 563))	('Acute Myeloid Leukemia', 'Disease', (476, 498))	('Neck squamous cell carcinoma', 'Disease', (336, 364))	('Melanoma', 'Disease', 'MESH:D008545', (915, 923))	('carcinoma', 'Disease', 'MESH:D009369', (461, 470))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (791, 825))	('Melanoma', 'Disease', (1100, 1108))	('carcinoma', 'Disease', 'MESH:D009369', (284, 293))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (760, 785))	('carcinoma', 'Disease', (179, 188))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (990, 1007))	('Cholangio carcinoma', 'Phenotype', 'HP:0030153', (169, 188))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (760, 785))	('Pancreatic adenocarcinoma', 'Disease', (760, 785))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (194, 214))	('Rectum adenocarcinoma', 'Disease', 'MESH:D012004', (860, 881))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (831, 854))	('CHOL', 'Disease', (164, 168))	('carcinoma', 'Disease', 'MESH:D009369', (872, 881))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', 'MESH:D009369', (418, 427))	('Melanoma', 'Phenotype', 'HP:0002861', (915, 923))	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (327, 364))	('squamous cell carcinoma', 'Disease', (108, 131))	('Cholangio carcinoma', 'Disease', (169, 188))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (671, 699))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Breast invasive carcinoma', 'Disease', (68, 93))	('Kidney Chromophobe', 'Disease', 'MESH:D000238', (370, 388))	('carcinoma', 'Disease', (461, 470))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (136, 163))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (569, 588))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (482, 498))	('carcinoma', 'Disease', (872, 881))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('Mesothelioma', 'Disease', (705, 717))	('Kidney renal clear cell carcinoma', 'Disease', (394, 427))	('Thymoma', 'Disease', (1013, 1020))	('Corpus Endometrial Carcinoma', 'Disease', (1034, 1062))	('ACC', 'Gene', '31', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (539, 563))	('Liver hepatocellular carcinoma', 'Disease', (533, 563))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (533, 563))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Rectum adenocarcinoma', 'Disease', (860, 881))	('tumor', 'Disease', (593, 598))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (336, 364))	('carcinoma', 'Disease', (418, 427))	('KICH', 'Disease', 'None', (365, 369))	('TME', 'Chemical', '-', (589, 592))	('Stomach adenocarcinoma', 'Disease', (929, 951))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('DSS', 'Gene', '5376', (636, 639))	('tumor', 'Disease', 'MESH:D009369', (593, 598))	('clear cell carcinoma KIRP Kidney', 'Phenotype', 'HP:0006770', (407, 439))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('Prostate adenocarcinoma', 'Disease', (831, 854))	('Lymphoma', 'Phenotype', 'HP:0002665', (259, 267))	('Skin Cutaneous Melanoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D009369', (942, 951))	('carcinoma', 'Disease', 'MESH:D009369', (355, 364))	('serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (729, 754))	('Thymoma', 'Disease', 'MESH:D013945', (1013, 1020))	('carcinoma', 'Disease', 'MESH:D009369', (690, 699))	('Leukemia', 'Phenotype', 'HP:0001909', (490, 498))	('carcinoma', 'Disease', 'MESH:D009369', (745, 754))	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('TMB', 'Chemical', '-', (1109, 1112))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (791, 807))	('Stomach adenocarcinoma', 'Disease', 'MESH:D000230', (929, 951))	('Carcinoma', 'Phenotype', 'HP:0030731', (1053, 1062))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('carcinoma', 'Disease', 'MESH:D009369', (19, 28))	('Glioma', 'Disease', (521, 527))	('MESO Mesothelioma', 'Phenotype', 'HP:0100001', (700, 717))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (341, 364))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (252, 267))	('Tumors', 'Disease', 'MESH:D009369', (978, 984))	('Cholangio carcinoma', 'Disease', 'MESH:D009369', (169, 188))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('Glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('Melanoma', 'Disease', 'MESH:D008545', (1100, 1108))	('Lung squamous cell carcinoma', 'Disease', (671, 699))	('Carcinosarcoma', 'Disease', (1075, 1089))	('carcinoma', 'Disease', (284, 293))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (721, 754))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (476, 498))	('DSS', 'Gene', (636, 639))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (900, 923))	('carcinoma', 'Disease', (942, 951))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (1075, 1089))	('PFI', 'molecular_function', 'GO:0034016', ('1195', '1198'))	('carcinoma', 'Disease', (745, 754))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (341, 364))	('Colon adenocarcinoma', 'Disease', (194, 214))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (1067, 1089))	('Neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (298, 321))	('carcinoma', 'Disease', 'MESH:D009369', (998, 1007))	('ACC', 'Gene', (0, 3))	('Tumors', 'Phenotype', 'HP:0002664', (978, 984))	('Thyroid carcinoma', 'Disease', (990, 1007))	('Melanoma', 'Phenotype', 'HP:0002861', (1100, 1108))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (968, 984))	('carcinoma', 'Disease', 'MESH:D009369', (554, 563))	('THCA', 'Chemical', '-', (985, 989))	('endocervical adenocarcinoma', 'Disease', (136, 163))	('Melanoma', 'Disease', (915, 923))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', 'MESH:D016403', (220, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (676, 699))	('carcinoma', 'Disease', (154, 163))	('Glioma', 'Phenotype', 'HP:0009733', (521, 527))	('carcinoma', 'Disease', 'MESH:D009369', (205, 214))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (905, 923))	('BRCA', 'Gene', (63, 67))	('Tumors', 'Disease', (978, 984))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (1041, 1062))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (273, 293))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (676, 699))	('Thymoma', 'Phenotype', 'HP:0100522', (1013, 1020))	('carcinoma', 'Disease', 'MESH:D009369', (122, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (887, 894))	('Glioblastoma multiforme', 'Disease', (298, 321))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (569, 588))	('mutational', 'Var', (1119, 1129))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (433, 470))	('carcinoma', 'Disease', 'MESH:D009369', (845, 854))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (42, 62))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (1094, 1108))	('Mesothelioma', 'Disease', 'MESH:D008654', (705, 717))	('COAD', 'Disease', (189, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', (355, 364))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (476, 498))	('carcinoma', 'Disease', (690, 699))	('carcinoma', 'Disease', (205, 214))	('carcinoma', 'Disease', (84, 93))	('Glioma', 'Disease', 'MESH:D005910', (521, 527))	('UCEC Uterine Corpus', 'Phenotype', 'HP:0000139', (1021, 1040))	('BRCA', 'Gene', '672', (63, 67))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (671, 699))	('Tumor', 'Phenotype', 'HP:0002664', (1113, 1118))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', (220, 267))	('carcinoma', 'Disease', 'MESH:D009369', (776, 785))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (440, 470))	('carcinoma', 'Disease', 'MESH:D009369', (579, 588))	('Lung adenocarcinoma', 'Disease', (569, 588))	('carcinoma', 'Disease', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Disease', (122, 131))	('Sarcoma', 'Disease', 'MESH:D012509', (887, 894))
55945	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))
55948	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))
55949	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', 'MESH:C536494', (9, 23))	('uveal melanoma', 'Disease', (9, 23))	('uveal melanoma', 'Phenotype', 'HP:0007716', (9, 23))	('mutations', 'Var', (53, 62))	('TAK733', 'Chemical', 'MESH:C558666', (113, 119))	('GNAQ', 'Gene', '2776', (39, 43))
55950	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))	('NRAS', 'Gene', (36, 40))	('GNA11', 'Gene', (57, 62))	('GNA11', 'Gene', '2767', (57, 62))	('NRAS', 'Gene', '4893', (36, 40))	('GNAQ', 'Gene', (48, 52))	('BRAF', 'Gene', (42, 46))	('TAK733', 'Chemical', 'MESH:C558666', (119, 125))
55951	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))
55952	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))	('increase', 'PosReg', (27, 35))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', (64, 68))	('GNAQ', 'Gene', '2776', (84, 88))	('NRAS', 'Gene', '4893', (64, 68))	('inhibition', 'NegReg', (4, 14))	('mutant', 'Var', (89, 95))	('MEK', 'Gene', (40, 43))
55953	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))	('inhibited', 'NegReg', (48, 57))	('TAK733', 'Var', (61, 67))	('TAK733', 'Chemical', 'MESH:C558666', (61, 67))	('Uptake', 'biological_process', 'GO:0098657', ('0', '6'))
55956	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))	('survival', 'CPA', (195, 203))	('drive', 'Reg', (143, 148))	('melanoma', 'Disease', (149, 157))	('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'))
55960	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'))
55961	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))
55965	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))	('NRAS', 'Gene', '4893', (345, 349))	('dependent', 'MPA', (190, 199))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('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))
55966	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))
55967	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))
55968	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))
55969	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))
55970	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))	('MEK', 'Gene', '5609', (119, 122))	('MEK-1', 'Gene', (119, 124))	('TAK733', 'Chemical', 'MESH:C558666', (0, 6))	('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))
55973	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))
55974	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))
55975	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))
55976	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))	('cutaneous melanoma', 'Disease', (29, 47))	('GNAQ', 'Gene', (98, 102))	('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))
55977	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))
55978	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))
55979	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.	('BRAF', 'Gene', (58, 62))	('higher', 'PosReg', (36, 42))	('mutant', 'Var', (63, 69))	('MEK', 'Gene', (190, 193))	('BRAF', 'Gene', '673', (58, 62))	('sensitivity', 'MPA', (43, 54))	('MEK', 'Gene', '5609', (190, 193))
55981	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))
55982	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))
55983	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))
55987	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))
55988	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))	('uveal melanoma', 'Disease', (22, 36))	('GNAQ', 'Gene', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('TAK733', 'Chemical', 'MESH:C558666', (66, 72))
55989	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))
55991	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))
55993	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))
55996	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'))
56000	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))
56003	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))
56005	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))	('MEK', 'Gene', (21, 24))	('mutant', 'Var', (121, 127))	('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))
56006	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))
56007	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))
56009	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))
56010	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))
56013	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))
56017	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))	('inhibitors', 'Var', (127, 137))	('block', 'NegReg', (221, 226))	('MAPK', 'molecular_function', 'GO:0004707', ('61', '65'))	('MAPK', 'molecular_function', 'GO:0004707', ('166', '170'))	('MAPK pathway', 'Pathway', (61, 73))
56019	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))
56020	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))
56021	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))
56022	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))
56024	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', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('uveal melanomas', 'Disease', 'MESH:C536494', (181, 196))
56030	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))	('BRAFV600E', 'Mutation', 'rs113488022', (97, 106))	('MEK', 'Gene', '5609', (59, 62))	('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))
56042	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))	('Ser217', 'Chemical', '-', (111, 117))	('MEK', 'Gene', '5609', (106, 109))	('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'))
56137	32577730	Skin phenotypes are determined by several different genes, including MC1R, ASIP, TYR, and TYRP, and different variants in these genes are also associated with increased risks of skin cancers.	('associated', 'Reg', (143, 153))	('skin cancers', 'Phenotype', 'HP:0008069', (178, 190))	('skin cancer', 'Phenotype', 'HP:0008069', (178, 189))	('MC1R', 'Gene', '4157', (69, 73))	('ASIP', 'Gene', '434', (75, 79))	('skin cancers', 'Disease', (178, 190))	('variants', 'Var', (110, 118))	('MC1R', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('TYRP', 'Gene', (90, 94))	('skin cancers', 'Disease', 'MESH:D012878', (178, 190))	('ASIP', 'Gene', (75, 79))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('TYRP', 'Gene', '7306', (90, 94))
56138	32577730	Although such low-penetrance susceptibility gene variants are relatively common in the normal population, germline mutations in high-penetrance melanoma susceptibility gene CDKN2A are rare in the normal population but are found in 5%-20% of familial and multiple primary melanoma patients.	('patients', 'Species', '9606', (280, 288))	('CDKN2A', 'Gene', (173, 179))	('variants', 'Var', (49, 57))	('CDKN2A', 'Gene', '1029', (173, 179))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Disease', (271, 279))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
56139	32577730	Carriers of mutations in CDKN2A have much elevated risk of melanoma and 70%-80% develop, often multiple primary, melanoma.	('CDKN2A', 'Gene', '1029', (25, 31))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('develop', 'PosReg', (80, 87))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('CDKN2A', 'Gene', (25, 31))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
56142	32577730	Increased melanoma susceptibility often has a more complex etiology, attributed to a combination of low-penetrance susceptibility gene variants, pigmentation traits, nevus phenotype, and UV-exposure patterns.	('pigmentation traits', 'Disease', 'MESH:D010859', (145, 164))	('pigmentation', 'biological_process', 'GO:0043473', ('145', '157'))	('variants', 'Var', (135, 143))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('pigmentation traits', 'Disease', (145, 164))	('melanoma', 'Disease', (10, 18))	('nevus', 'Phenotype', 'HP:0003764', (166, 171))
56168	31519199	We report here a high prevalence of SPINT1 genetic alterations in SKCM patients and their association with altered tumor immune microenvironment and poor patient survival.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patient', 'Species', '9606', (154, 161))	('patients', 'Species', '9606', (71, 79))	('tumor', 'Disease', (115, 120))	('genetic alterations', 'Var', (43, 62))	('patient', 'Species', '9606', (71, 78))	('SPINT1', 'Gene', (36, 42))	('SKCM', 'Disease', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
56169	31519199	The zebrafish model reveals that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor immune microenvironment crosstalk, accelerates the onset of SKCM and promotes metastatic invasion.	('oncogenic transformation', 'CPA', (64, 88))	('zebrafish', 'Species', '7955', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SKCM', 'Disease', (170, 174))	('promotes', 'PosReg', (179, 187))	('tumor', 'Disease', (104, 109))	('facilitates', 'PosReg', (52, 63))	('Spint1a', 'Gene', (33, 40))	('deficiency', 'Var', (41, 51))	('metastatic invasion', 'CPA', (188, 207))	('regulates', 'Reg', (90, 99))	('accelerates', 'PosReg', (145, 156))	('Spint1a', 'Gene', '406426', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
56170	31519199	Notably, Spint1a deficiency is required at both cell autonomous and non-autonomous levels to enhance invasiveness of SKCM.	('deficiency', 'Var', (17, 27))	('Spint1a', 'Gene', (9, 16))	('invasiveness of', 'CPA', (101, 116))	('enhance', 'PosReg', (93, 100))	('Spint1a', 'Gene', '406426', (9, 16))
56189	31519199	The close functional relationship between ST14 and SPINT1 was also observed in a zebrafish model of skin inflammation, carrying a hypomorphic mutation of spint1a.	('zebrafish', 'Species', '7955', (81, 90))	('spint1a', 'Gene', '406426', (154, 161))	('skin inflammation', 'Disease', (100, 117))	('skin inflammation', 'Phenotype', 'HP:0011123', (100, 117))	('skin inflammation', 'Disease', 'MESH:D007249', (100, 117))	('mutation', 'Var', (142, 150))	('spint1a', 'Gene', (154, 161))	('inflammation', 'biological_process', 'GO:0006954', ('105', '117'))
56190	31519199	Indeed epidermal hyperproliferation and neutrophil infiltration observed in mutant zebrafish larvae are both rescued by st14a gene knock-down, suggesting a novel role for the SPINT1-ST14 axis in regulating inflammation.	('st14a', 'Gene', (120, 125))	('epidermal hyperproliferation', 'CPA', (7, 35))	('zebrafish', 'Species', '7955', (83, 92))	('mutant', 'Var', (76, 82))	('st14a', 'Gene', '678603', (120, 125))	('knock-down', 'Var', (131, 141))	('inflammation', 'Disease', 'MESH:D007249', (206, 218))	('inflammation', 'Disease', (206, 218))	('neutrophil infiltration', 'CPA', (40, 63))	('inflammation', 'biological_process', 'GO:0006954', ('206', '218'))
56191	31519199	Given the unique advantages of the zebrafish model for tumor cell transplantation, thanks to the transparency of embryos and even adults that allows the tracking of donor cells and the strong correlation between alterations of Spint1a-St14a levels with tumor progression, the spint1a mutant zebrafish represents an attractive model to study the role of SPINT1 and chronic inflammation in SKCM.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('inflammation', 'Disease', (372, 384))	('Spint1a', 'Gene', (227, 234))	('zebrafish', 'Species', '7955', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('inflammation', 'biological_process', 'GO:0006954', ('372', '384'))	('St14a', 'Gene', '678603', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('spint1a', 'Gene', (276, 283))	('Spint1a', 'Gene', '406426', (227, 234))	('St14a', 'Gene', (235, 240))	('tumor', 'Disease', (253, 258))	('donor', 'Species', '9606', (165, 170))	('spint1a', 'Gene', '406426', (276, 283))	('mutant', 'Var', (284, 290))	('zebrafish', 'Species', '7955', (291, 300))	('inflammation', 'Disease', 'MESH:D007249', (372, 384))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', (55, 60))
56192	31519199	Our results show that genetic alterations of SPINT1 correlated with a poor prognosis of SKCM patients and provide evidence that SPINT1 expression positively correlated with tumor macrophage infiltration, but not neutrophils.	('correlated', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('correlated with', 'Reg', (157, 172))	('SPINT1', 'Gene', (45, 51))	('SKCM', 'Disease', (88, 92))	('genetic alterations', 'Var', (22, 41))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('expression', 'MPA', (135, 145))	('SPINT1', 'Gene', (128, 134))	('patients', 'Species', '9606', (93, 101))
56193	31519199	In line with these clinical data, we show that Spint1a deficiency enhances at both cell autonomous and non-autonomous levels cell dissemination of SKCM in zebrafish models by promoting tumor dedifferentiation and altered immune surveillance.	('tumor', 'Disease', (185, 190))	('enhances', 'PosReg', (66, 74))	('Spint1a', 'Gene', '406426', (47, 54))	('dedifferentiation', 'biological_process', 'GO:0043696', ('191', '208'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('zebrafish', 'Species', '7955', (155, 164))	('deficiency', 'Var', (55, 65))	('immune surveillance', 'CPA', (221, 240))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Spint1a', 'Gene', (47, 54))	('cell dissemination', 'CPA', (125, 143))	('altered', 'Reg', (213, 220))	('promoting', 'PosReg', (175, 184))
56198	31519199	The hi2217 line, which carries a hypomorphic spint1a mutant allele that promotes skin inflammation, and transparent roya9/a9; nacrew2/w2 (casper) of 4-8 month old were previously described.	('spint1a', 'Gene', (45, 52))	('spint1a', 'Gene', '406426', (45, 52))	('inflammation', 'biological_process', 'GO:0006954', ('86', '98'))	('promotes', 'PosReg', (72, 80))	('mutant', 'Var', (53, 59))	('skin inflammation', 'Disease', (81, 98))	('skin inflammation', 'Disease', 'MESH:D007249', (81, 98))	('skin inflammation', 'Phenotype', 'HP:0011123', (81, 98))
56212	31519199	Between 25 to 50 cells/embryo were then injected in the yolk sac of 60-90 Casper or spint1 mutants zebrafish larvae of 48 h post-fertilization (hpf) and after 5 days at 28  C, larvae were scored manually in blind samples for zebrafish melanoma cells dissemination by fluorescence microscopy.	('zebrafish melanoma cells dissemination', 'Disease', 'MESH:D008545', (225, 263))	('yolk', 'cellular_component', 'GO:0060417', ('56', '60'))	('fertilization', 'biological_process', 'GO:0009566', ('129', '142'))	('sac', 'cellular_component', 'GO:0035003', ('61', '64'))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('sac', 'biological_process', 'GO:0071173', ('61', '64'))	('zebrafish', 'Species', '7955', (225, 234))	('spint1', 'Gene', '6692', (84, 90))	('zebrafish melanoma cells dissemination', 'Disease', (225, 263))	('mutants', 'Var', (91, 98))	('spint1', 'Gene', (84, 90))	('zebrafish', 'Species', '7955', (99, 108))
56235	31519199	Notably, these genetic alterations of SPINT1 significantly correlated with poor SKCM patient prognosis (Fig.	('patient', 'Species', '9606', (85, 92))	('SPINT1', 'Gene', (38, 44))	('poor SKCM patient', 'Disease', (75, 92))	('genetic alterations', 'Var', (15, 34))	('correlated with', 'Reg', (59, 74))
56238	31519199	1d), analyzing the differentially expressed genes in SKCM samples of the TCGA cohort with missense mutations or copy-number alterations of SPINT1.	('lyz', 'Gene', (8, 11))	('missense mutations', 'Var', (90, 108))	('lyz', 'Gene', '677744', (8, 11))	('SPINT1', 'Gene', (139, 145))	('copy-number alterations', 'Var', (112, 135))
56239	31519199	The results showed that regulation of immune system, inflammatory response, cell cycle, cell adhesion, and extracellular matrix organization represent key pathways significantly affected in human SKCM with these SPINT1 genetic alterations.	('extracellular matrix organization', 'biological_process', 'GO:0030198', ('107', '140'))	('regulation', 'biological_process', 'GO:0065007', ('24', '34'))	('inflammatory response', 'biological_process', 'GO:0006954', ('53', '74'))	('extracellular matrix organization', 'CPA', (107, 140))	('SPINT1', 'Gene', (212, 218))	('affected', 'Reg', (178, 186))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('107', '127'))	('cell cycle', 'CPA', (76, 86))	('inflammatory response', 'CPA', (53, 74))	('cell adhesion', 'CPA', (88, 101))	('SKCM', 'Disease', (196, 200))	('human', 'Species', '9606', (190, 195))	('cell cycle', 'biological_process', 'GO:0007049', ('76', '86'))	('regulation', 'MPA', (24, 34))	('genetic alterations', 'Var', (219, 238))	('cell adhesion', 'biological_process', 'GO:0007155', ('88', '101'))
56240	31519199	Collectively, these results suggest that both high and low levels of SPINT1 result in an unbalanced crosstalk between tumor cells and their microenvironment promoting higher aggressiveness.	('unbalanced crosstalk', 'MPA', (89, 109))	('higher', 'PosReg', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('aggressiveness', 'Disease', (174, 188))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('low levels', 'Var', (55, 65))	('aggressiveness', 'Phenotype', 'HP:0000718', (174, 188))	('tumor', 'Disease', (118, 123))	('SPINT1', 'Gene', (69, 75))	('aggressiveness', 'Disease', 'MESH:D001523', (174, 188))	('result in', 'Reg', (76, 85))
56254	31519199	Given the strong correlation between alterations of SPINT1 levels with the progression of SKCM and the crosstalk with the tumor immune microenvironment, we crossed the zebrafish line kita:Gal4;HRAS-G12V, which expresses the human oncogene HRAS-G12V in melanocytes and spontaneously develops SKCM, with the zebrafish mutant line spint1ahi2217Tg/hi2217Tg, which presents chronic skin inflammation (Fig.	('skin inflammation', 'Phenotype', 'HP:0011123', (377, 394))	('spint1a', 'Gene', '406426', (328, 335))	('HRAS-G12V', 'Var', (239, 248))	('zebrafish', 'Species', '7955', (168, 177))	('kita', 'Gene', '30256', (183, 187))	('skin inflammation', 'Disease', 'MESH:D007249', (377, 394))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('G12V', 'Mutation', 'rs104894230', (198, 202))	('human', 'Species', '9606', (224, 229))	('zebrafish', 'Species', '7955', (306, 315))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('kita', 'Gene', (183, 187))	('inflammation', 'biological_process', 'GO:0006954', ('382', '394'))	('G12V', 'Mutation', 'rs104894230', (244, 248))	('skin inflammation', 'Disease', (377, 394))	('tumor', 'Disease', (122, 127))	('spint1a', 'Gene', (328, 335))
56256	31519199	The results showed that spint1a deficiency resulted in increased number of HRAS-G12V+ cells (Fig.	('HRAS-G12V+ cells', 'CPA', (75, 91))	('G12V', 'Mutation', 'rs104894230', (80, 84))	('spint1a', 'Gene', (24, 31))	('spint1a', 'Gene', '406426', (24, 31))	('increased', 'PosReg', (55, 64))	('deficiency', 'Var', (32, 42))
56257	31519199	To determine if the enhanced Spint1a deficiency-driven oncogenic transformation was also able to promote SKCM aggressiveness, SKCM development in spint1ahi2217Tg/hi2217Tg fish were compared with wild type (spint1a+/hi2217Tg) from the end of metamorphosis stage (between 28 and 30 dpf) to 120 dpf (adult stage) (Fig.	('Spint1a', 'Gene', '406426', (29, 36))	('spint1a', 'Gene', (206, 213))	('spint1a', 'Gene', '406426', (206, 213))	('deficiency-driven', 'Var', (37, 54))	('spint1a', 'Gene', (146, 153))	('dpf', 'Chemical', '-', (280, 283))	('SKCM aggressiveness', 'Disease', 'MESH:D001523', (105, 124))	('Spint1a', 'Gene', (29, 36))	('spint1a', 'Gene', '406426', (146, 153))	('SKCM aggressiveness', 'Disease', (105, 124))	('metamorphosis', 'biological_process', 'GO:0007552', ('241', '254'))	('aggressiveness', 'Phenotype', 'HP:0000718', (110, 124))	('promote', 'PosReg', (97, 104))	('dpf', 'Chemical', '-', (292, 295))
56261	31519199	The results showed that Spint1a deficiency in SKCM cells enhanced the dissemination of SKCM, assayed as the percentage of invaded larvae and the number of foci per larva, compared to control SKCM cells (Fig.	('Spint1a', 'Gene', (24, 31))	('dissemination of', 'CPA', (70, 86))	('Spint1a', 'Gene', '406426', (24, 31))	('enhanced', 'PosReg', (57, 65))	('deficiency', 'Var', (32, 42))
56269	31519199	Collectively, these results suggest that Spint1a deficiency enhances SKCM invasion by both cell autonomous and non-autonomous mechanisms.	('Spint1a', 'Gene', (41, 48))	('enhances', 'PosReg', (60, 68))	('SKCM invasion', 'CPA', (69, 82))	('deficiency', 'Var', (49, 59))	('Spint1a', 'Gene', '406426', (41, 48))
56286	31519199	Curiously, it was found that while il1b, lyz and mpx mRNA levels were not affected by Spint1a deficiency, those of mpeg1 were elevated in Spint1a-deficient SKCMs.	('Spint1a', 'Gene', (138, 145))	('lyz', 'Gene', '677744', (41, 44))	('il1', 'molecular_function', 'GO:0005149', ('35', '38'))	('lyz', 'Gene', (41, 44))	('mpeg1', 'Gene', '335407', (115, 120))	('Spint1a', 'Gene', '406426', (86, 93))	('Spint1a', 'Gene', '406426', (138, 145))	('mpeg1', 'Gene', (115, 120))	('il1b', 'Gene', '405770', (35, 39))	('elevated', 'PosReg', (126, 134))	('mpx', 'Gene', '337514', (49, 52))	('deficiency', 'Var', (94, 104))	('mpx', 'Gene', (49, 52))	('il1b', 'Gene', (35, 39))	('Spint1a', 'Gene', (86, 93))
56293	31519199	We found that Spint1a deficiency is required at both cell autonomous and non-autonomous levels to enhance cell dissemination of SKCM by promoting tumor dedifferentiation and altered immune surveillance.	('enhance', 'PosReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('immune surveillance', 'CPA', (182, 201))	('Spint1a', 'Gene', (14, 21))	('cell dissemination', 'CPA', (106, 124))	('tumor', 'Disease', (146, 151))	('Spint1a', 'Gene', '406426', (14, 21))	('dedifferentiation', 'biological_process', 'GO:0043696', ('152', '169'))	('promoting', 'PosReg', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('altered', 'Reg', (174, 181))	('deficiency', 'Var', (22, 32))
56294	31519199	These results may have important clinical impact, since genetic alterations of SPINT1 were found in 10% of SKCM patients and correlated with altered cell cycle, differentiation and innate and adaptive immune signaling pathways and, more importantly, with a poor prognosis.	('differentiation', 'CPA', (161, 176))	('SKCM', 'Disease', (107, 111))	('genetic alterations', 'Var', (56, 75))	('altered', 'Reg', (141, 148))	('cell cycle', 'biological_process', 'GO:0007049', ('149', '159'))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('found', 'Reg', (91, 96))	('patients', 'Species', '9606', (112, 120))	('cell cycle', 'CPA', (149, 159))	('SPINT1', 'Gene', (79, 85))
56300	31519199	Curiously, activated neutrophils in a condition of repeated wounding have been shown to interact with pre-neoplastic cells promoting their proliferation through the release of prostaglandin E2 and, more importantly, SKCM ulceration correlates with increased neutrophil infiltration and tumor cell proliferation, which are both associated with poor prognosis.	('promoting', 'PosReg', (123, 132))	('SKCM', 'Var', (216, 220))	('increased', 'PosReg', (248, 257))	('tumor', 'Disease', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('cell proliferation', 'biological_process', 'GO:0008283', ('292', '310'))	('neutrophil infiltration', 'CPA', (258, 281))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (176, 192))	('release', 'MPA', (165, 172))	('proliferation', 'CPA', (139, 152))	('pre', 'molecular_function', 'GO:0003904', ('102', '105'))	('tumor', 'Disease', 'MESH:D009369', (286, 291))
56303	31519199	Curiously, Spint1a deficiency seems to have a prominent role in oncogenic transformation accelerating SKCM onset in vivo.	('SKCM onset', 'Disease', (102, 112))	('Spint1a', 'Gene', '406426', (11, 18))	('deficiency', 'Var', (19, 29))	('Spint1a', 'Gene', (11, 18))
56304	31519199	However, the strong oncogenic activity of HRAS-G12V, which is even able to induce melanoma without the need of coadjuvating mutations in tumor suppressors, results in a similar tumor burden in wild type and Spint1a-deficient fish at later stages.	('oncogenic', 'CPA', (20, 29))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('Spint1a', 'Gene', (207, 214))	('melanoma', 'Disease', (82, 90))	('G12V', 'Mutation', 'rs104894230', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HRAS-G12V', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('Spint1a', 'Gene', '406426', (207, 214))	('tumor', 'Disease', (177, 182))	('induce', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
56306	31519199	Although SPINT1 is a serine protease inhibitor with several targets, including ST14 and HGFA, deregulation of the SPINT1/ST14 axis leads to spontaneous squamous cell carcinoma in mice and keratinocyte hyperproliferation in zebrafish preceded by skin inflammation in both models.	('mice', 'Species', '10090', (179, 183))	('zebrafish', 'Species', '7955', (223, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('deregulation', 'Var', (94, 106))	('skin inflammation', 'Disease', (245, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (152, 175))	('keratinocyte hyperproliferation', 'CPA', (188, 219))	('skin inflammation', 'Disease', 'MESH:D007249', (245, 262))	('leads to', 'Reg', (131, 139))	('squamous cell carcinoma', 'Disease', (152, 175))	('inflammation', 'biological_process', 'GO:0006954', ('250', '262'))	('skin inflammation', 'Phenotype', 'HP:0011123', (245, 262))	('SPINT1/ST14', 'Gene', (114, 125))
56307	31519199	In addition, intestine-specific Spint1 deletion in mice induces the activation of the master inflammation transcription factor NF-kappaB and accelerated intestinal tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('inflammation', 'Disease', (93, 105))	('intestinal tumor', 'Disease', 'MESH:D007414', (153, 169))	('mice', 'Species', '10090', (51, 55))	('Spint1', 'Gene', '20732', (32, 38))	('inflammation', 'Disease', 'MESH:D007249', (93, 105))	('intestinal tumor', 'Disease', (153, 169))	('deletion', 'Var', (39, 47))	('inflammation', 'biological_process', 'GO:0006954', ('93', '105'))	('transcription factor', 'molecular_function', 'GO:0000981', ('106', '126'))	('activation', 'PosReg', (68, 78))	('accelerated', 'PosReg', (141, 152))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('NF-kappaB', 'Protein', (127, 136))	('Spint1', 'Gene', (32, 38))	('formation', 'biological_process', 'GO:0009058', ('170', '179'))
56310	31519199	In addition, Spint1a deficiency in both cell types does not show enhanced invasiveness compared to Spint1a deficiency in either cell type.	('Spint1a', 'Gene', '406426', (99, 106))	('Spint1a', 'Gene', '406426', (13, 20))	('deficiency', 'Var', (21, 31))	('invasiveness', 'CPA', (74, 86))	('Spint1a', 'Gene', (99, 106))	('Spint1a', 'Gene', (13, 20))
56314	31519199	Similarly, loss of SPINT1 in human pancreatic cancer cells promotes ST14-dependent metastasis in nude mouse orthotopic xenograft models.	('SPINT1', 'Gene', (19, 25))	('loss', 'Var', (11, 15))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('pancreatic cancer', 'Disease', (35, 52))	('promotes', 'PosReg', (59, 67))	('ST14-dependent metastasis', 'CPA', (68, 93))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (29, 34))	('mouse', 'Species', '10090', (102, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))
56315	31519199	We observed that genetic alterations in SPINT1 transcript levels in SKCM patient samples negatively correlated with EMT markers and that Spint1a-deficient zebrafish SKCM showed reduced cdh1 mRNA levels.	('Spint1a', 'Gene', '406426', (137, 144))	('cdh1', 'Gene', (185, 189))	('zebrafish', 'Species', '7955', (155, 164))	('cdh1', 'Gene', '114424', (185, 189))	('EMT', 'biological_process', 'GO:0001837', ('116', '119'))	('reduced', 'NegReg', (177, 184))	('transcript levels', 'MPA', (47, 64))	('patient', 'Species', '9606', (73, 80))	('genetic alterations', 'Var', (17, 36))	('negatively', 'NegReg', (89, 99))	('Spint1a', 'Gene', (137, 144))	('SPINT1', 'Gene', (40, 46))
56317	31519199	Importantly, the presence of aberrant E-cadherin expression in primary and metastatic SKCM is associated with a poor overall patient survival.	('poor', 'NegReg', (112, 116))	('expression', 'MPA', (49, 59))	('patient', 'Species', '9606', (125, 132))	('aberrant', 'Var', (29, 37))	('cadherin', 'molecular_function', 'GO:0008014', ('40', '48'))	('primary', 'Disease', (63, 70))	('metastatic SKCM', 'Disease', (75, 90))	('E-cadherin', 'Protein', (38, 48))
56319	31519199	This model has revealed that Spint1a deficiency facilitates oncogenic transformation, regulates the tumor/immune microenvironment crosstalk and is associated to SKCM aggressiveness.	('Spint1a', 'Gene', '406426', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('associated', 'Reg', (147, 157))	('SKCM aggressiveness', 'Disease', (161, 180))	('aggressiveness', 'Phenotype', 'HP:0000718', (166, 180))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('facilitates', 'PosReg', (48, 59))	('Spint1a', 'Gene', (29, 36))	('regulates', 'Reg', (86, 95))	('deficiency', 'Var', (37, 47))	('oncogenic transformation', 'CPA', (60, 84))	('SKCM aggressiveness', 'Disease', 'MESH:D001523', (161, 180))
56320	31519199	In addition, Spint1a deficiency in either tumor or microenvironment compartment increases SKCM aggressiveness.	('tumor', 'Disease', (42, 47))	('Spint1a', 'Gene', '406426', (13, 20))	('increases SKCM aggressiveness', 'Disease', 'MESH:D001523', (80, 109))	('aggressiveness', 'Phenotype', 'HP:0000718', (95, 109))	('deficiency', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('increases SKCM aggressiveness', 'Disease', (80, 109))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Spint1a', 'Gene', (13, 20))
56321	31519199	The high prevalence of SPINT1 genetic alterations in SKCM patients and their association with a poor prognosis, point out to SPINT1 as a novel therapeutic target for the treatment of SKCM.	('patients', 'Species', '9606', (58, 66))	('SKCM', 'Disease', (53, 57))	('SPINT1', 'Gene', (23, 29))	('genetic alterations', 'Var', (30, 49))
56323	31519199	This work was supported by the Spanish Ministry of Science, Innovation and Universities (grants BIO2014-52655-R and BIO2017-84702-R to VM and PI13/0234 to MLC), all co-funded with Fondos Europeos de Desarrollo Regional/European Regional Development Funds), Fundacion Seneca-Murcia (grant 19400/PI/14 to MLC), the University of Murcia (postdoctoral contracts to DGM), and the European Union Seventh Framework Programme-Marie Curie COFUND (FP7/2007-2013) under UMU Incoming Mobility Programme ACTion (U-IMPACT) Grant Agreement 267143.	('Seneca-Murcia', 'Disease', (267, 280))	('Seneca-Murcia', 'Disease', 'None', (267, 280))	('BIO2017-84702-R', 'Var', (116, 131))
56335	23251803	We included any of the above histologies associated with topography codes for mucosal lip (C00.3-C00.8), tongue (C01.9-C02.9), salivary glands (C07.9-C08.9), floor of mouth (C04.0-C04.9), gums (C03.0-C03.9), other mouth (C05.0-C06.9), nasopharynx (C11.0-C11.9), tonsils (C09.0-C09.9), oropharynx (C10.0-C10.9), hypopharynx (C12.9-C13.9), other pharynx (C14.0-C14.8), nasal cavity (C30.0), middle ear (C30.1), paranasal sinuses (C31.0-C31.9), or larynx (C32.0-C32.9).	('C12.9-C13.9', 'CellLine', 'CVCL:F711', (324, 335))	('C12.9-C13.9', 'Var', (324, 335))	('C11.0-C11.9', 'Var', (248, 259))	('mucosal lip', 'Disease', 'MESH:D052016', (78, 89))	('C10.0-C10.9', 'Var', (297, 308))	('C30.0', 'Var', (381, 386))	('C31.0-C31.9', 'Var', (428, 439))	('C05.0-C06.9', 'Var', (221, 232))	('mucosal lip', 'Disease', (78, 89))	('C30.1', 'Var', (401, 406))	('C01.9-C02.9', 'CellLine', 'CVCL:F711', (113, 124))
56345	23251803	Studies have shown an association with mutations in the kit proto-oncogene, which encodes the protein c-kit and is not typically mutated in cutaneous melanoma.	('c-kit', 'Gene', '3815', (102, 107))	('mutations', 'Var', (39, 48))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('association', 'Interaction', (22, 33))	('kit proto-oncogene', 'Gene', (56, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (140, 158))	('c-kit', 'Gene', (102, 107))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
56348	27911979	Clinicopathological features and clinical outcomes associated with TP53 and BRAFNon-V600 mutations in cutaneous melanoma patients BRAFV600, NRAS, TP53 and BRAFNon-V600 are among the most common mutations detected in non-acral cutaneous melanoma (CM) patients.	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutations', 'Var', (89, 98))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('CM', 'Phenotype', 'HP:0012056', (246, 248))	('TP53', 'Gene', (146, 150))	('TP53', 'Gene', (67, 71))	('cutaneous melanoma', 'Disease', (226, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('NRAS', 'Gene', '4893', (140, 144))	('patients', 'Species', '9606', (250, 258))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (220, 244))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('CM', 'Disease', 'MESH:D009202', (246, 248))	('BRAF', 'Gene', '673', (155, 159))	('patients', 'Species', '9606', (121, 129))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('BRAF', 'Gene', (155, 159))	('TP53', 'Gene', '7157', (146, 150))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', (130, 134))	('TP53', 'Gene', '7157', (67, 71))	('NRAS', 'Gene', (140, 144))
56349	27911979	While several studies have identified clinical and pathologic features associated with BRAFV600 and NRAS mutations, limited data is available regarding the correlates and significance of TP53 and BRAFNon-V600 mutations.	('NRAS', 'Gene', '4893', (100, 104))	('TP53', 'Gene', '7157', (187, 191))	('BRAF', 'Gene', '673', (196, 200))	('TP53', 'Gene', (187, 191))	('mutations', 'Var', (105, 114))	('BRAF', 'Gene', (196, 200))	('BRAF', 'Gene', (87, 91))	('NRAS', 'Gene', (100, 104))	('BRAF', 'Gene', '673', (87, 91))
56351	27911979	The prevalence of BRAFV600, NRAS, TP53, and BRAFNon-V600 mutations were 43%, 21%, 19%, and 7%.	('BRAF', 'Gene', '673', (44, 48))	('NRAS', 'Gene', '4893', (28, 32))	('TP53', 'Gene', (34, 38))	('BRAF', 'Gene', (44, 48))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', '673', (18, 22))	('BRAF', 'Gene', (18, 22))	('NRAS', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (34, 38))
56352	27911979	The presence of a TP53 mutation was associated with older age (p=0.019), head and neck primary tumor site (p=0.0001), and longer overall survival (OS) from the diagnosis of stage IV disease on univariate (p=0.039) and multivariate (p=0.015) analyses.	('OS', 'Chemical', '-', (147, 149))	('longer', 'PosReg', (122, 128))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('neck', 'cellular_component', 'GO:0044326', ('82', '86'))	('primary tumor', 'Disease', (87, 100))	('TP53', 'Gene', (18, 22))	('primary tumor', 'Disease', 'MESH:D009369', (87, 100))	('overall survival', 'CPA', (129, 145))	('head and neck primary tumor', 'Phenotype', 'HP:0012288', (73, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('presence', 'Var', (4, 12))
56358	27911979	One of the most impactful discoveries in melanoma was the identification of missense mutations in the BRAF gene.	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('missense mutations', 'Var', (76, 94))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
56359	27911979	Approximately 95% of these mutations result in substitutions for valine at position 600 of the BRAF protein (BRAFV600), most commonly with glutamic acid (BRAFV600E).	('mutations', 'Var', (27, 36))	('valine', 'Chemical', 'MESH:D014633', (65, 71))	('glutamic acid', 'MPA', (139, 152))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('glutamic acid', 'Chemical', 'MESH:D018698', (139, 152))	('valine', 'Var', (65, 71))	('result in', 'Reg', (37, 46))	('BRAF', 'Gene', '673', (95, 99))	('BRAF', 'Gene', '673', (154, 158))	('BRAF', 'Gene', (95, 99))	('BRAF', 'Gene', (154, 158))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('substitutions', 'Var', (47, 60))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))
56360	27911979	These mutations markedly activate the RAS-RAF-MAPK signaling pathway.	('activate', 'PosReg', (25, 33))	('RAF', 'Gene', (42, 45))	('RAF', 'Gene', '22882', (42, 45))	('MAPK signaling', 'biological_process', 'GO:0000165', ('46', '60'))	('signaling pathway', 'biological_process', 'GO:0007165', ('51', '68'))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('mutations', 'Var', (6, 15))
56361	27911979	In addition to improving the understanding of the molecular pathogenesis of melanoma, this discovery led to the development of highly effective targeted therapies for patients with BRAFV600 mutations, including the mutant-selective BRAF inhibitors (BRAFi) vemurafenib and dabrafenib and the MEK inhibitors (MEKi) trametinib and cobimetinib.	('BRAF', 'Gene', '673', (232, 236))	('BRAF', 'Gene', (232, 236))	('MEK', 'Gene', '5609', (307, 310))	('vemurafenib', 'Chemical', 'MESH:D000077484', (256, 267))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('MEK', 'Gene', '5609', (291, 294))	('mutations', 'Var', (190, 199))	('MEK', 'Gene', (307, 310))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('cobimetinib', 'Chemical', 'MESH:C574276', (328, 339))	('MEK', 'Gene', (291, 294))	('trametinib', 'Chemical', 'MESH:C560077', (313, 323))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('BRAF', 'Gene', '673', (249, 253))	('melanoma', 'Disease', (76, 84))	('pathogenesis', 'biological_process', 'GO:0009405', ('60', '72'))	('BRAF', 'Gene', (249, 253))	('patients', 'Species', '9606', (167, 175))	('dabrafenib', 'Chemical', 'MESH:C561627', (272, 282))
56364	27911979	Previous studies have that interrogated the clinical and pathological features that correlate with BRAFV600 and NRAS mutations have identified a number of significant associations.	('mutations', 'Var', (117, 126))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('NRAS', 'Gene', (112, 116))	('NRAS', 'Gene', '4893', (112, 116))
56365	27911979	However, very little is known about features of melanomas that are associated with TP53 mutations, which correlate with poor clinical outcomes in head and neck cancer and hematologic malignancies.	('head and neck cancer', 'Disease', 'MESH:D006258', (146, 166))	('TP53', 'Gene', '7157', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('TP53', 'Gene', (83, 87))	('neck', 'cellular_component', 'GO:0044326', ('155', '159'))	('mutations', 'Var', (88, 97))	('melanomas', 'Disease', (48, 57))	('hematologic malignancies', 'Disease', 'MESH:D019337', (171, 195))	('head and neck cancer', 'Phenotype', 'HP:0012288', (146, 166))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('hematologic malignancies', 'Disease', (171, 195))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
56366	27911979	Preclinical studies support that BRAFNon-V600 mutations are a potential therapeutic target, and clinical trials are ongoing to determine the efficacy of trametinib (MEKi) in melanoma patients with these mutations (NCT02296112).	('BRAF', 'Gene', '673', (33, 37))	('NCT02296112', 'Var', (214, 225))	('BRAF', 'Gene', (33, 37))	('MEK', 'Gene', (165, 168))	('MEK', 'Gene', '5609', (165, 168))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('trametinib', 'Chemical', 'MESH:C560077', (153, 163))	('patients', 'Species', '9606', (183, 191))
56368	27911979	We have performed a retrospective analysis of a large single-institution cohort of advanced cutaneous melanoma patients with clinical NGS testing results, which encompassed regions of prevalent hotspot mutations in 50 genes.	('mutations', 'Var', (202, 211))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('cutaneous melanoma', 'Disease', (92, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (92, 110))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (92, 110))	('patients', 'Species', '9606', (111, 119))
56373	27911979	Among detected mutations in the panel, TP53 mutations were further classified based on physicochemical or functional consequences including truncating mutations, missense mutations, DNA-binding domain mutations and UV signature mutations.	('truncating', 'MPA', (140, 150))	('missense mutations', 'Var', (162, 180))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('DNA-binding', 'molecular_function', 'GO:0003677', ('182', '193'))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('TP53', 'Gene', (39, 43))
56374	27911979	DNA-binding domain mutations are mutations in codons 102 to 292 which induce inactivation of TP53 by eliminating DNA-binding contacts or altering structural stability of the core domain.	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('eliminating', 'NegReg', (101, 112))	('DNA-binding', 'molecular_function', 'GO:0003677', ('0', '11'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('113', '124'))	('core', 'cellular_component', 'GO:0019013', ('174', '178'))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (19, 28))	('DNA-binding contacts', 'MPA', (113, 133))	('inactivation', 'MPA', (77, 89))	('structural stability of the core domain', 'MPA', (146, 185))	('altering', 'Reg', (137, 145))
56375	27911979	Missense mutations are further stratified into high (>=75) and low risk (<75) by an evolutionary action score system (http://mammoth.bcm.tmc.edu/EAp53/) to predict highly deleterious TP53 functions which was validated in head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', (230, 258))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (221, 258))	('TP53', 'Gene', '7157', (183, 187))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (230, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('neck', 'cellular_component', 'GO:0044326', ('230', '234'))	('TP53', 'Gene', (183, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('mammoth', 'Species', '37349', (125, 132))	('functions', 'MPA', (188, 197))	('Missense mutations', 'Var', (0, 18))
56383	27911979	A BRAFV600 mutation was detected in 398 patients (43.0%), NRAS mutation in 195 (21.1%), TP53 mutation in 180 (19.4%), and BRAFNon-V600 mutation in 60 (6.5%) [Table 2].	('NRAS', 'Gene', '4893', (58, 62))	('detected', 'Reg', (24, 32))	('patients', 'Species', '9606', (40, 48))	('BRAF', 'Gene', '673', (2, 6))	('BRAF', 'Gene', '673', (122, 126))	('mutation', 'Var', (63, 71))	('BRAF', 'Gene', (122, 126))	('BRAF', 'Gene', (2, 6))	('TP53', 'Gene', '7157', (88, 92))	('NRAS', 'Gene', (58, 62))	('TP53', 'Gene', (88, 92))
56385	27911979	TP53 mutations were detected in 11.3% of melanomas with a BRAFV600 mutation, 19.4% of tumors with an NRAS mutation, and 28.9% of tumors without a BRAFV600 or NRAS mutation [Supplemental Table 6 and Supplemental Fig 1A].	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('detected', 'Reg', (20, 28))	('NRAS', 'Gene', '4893', (158, 162))	('TP53', 'Gene', '7157', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('mutation', 'Var', (67, 75))	('NRAS', 'Gene', '4893', (101, 105))	('tumors', 'Disease', (86, 92))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('melanomas', 'Disease', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NRAS', 'Gene', (158, 162))	('BRAF', 'Gene', '673', (146, 150))	('BRAF', 'Gene', (146, 150))	('NRAS', 'Gene', (101, 105))	('TP53', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('BRAF', 'Gene', '673', (58, 62))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('BRAF', 'Gene', (58, 62))
56386	27911979	A BRAFNon-V600 mutation was detected in 0.5% of melanomas with a BRAFV600 mutation, 4.1% of tumors with an NRAS mutation, and 14.9% of tumors without a BRAFV600 or NRAS mutation [Supplemental Table 7 and Supplemental Fig 1B].	('BRAF', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BRAF', 'Gene', '673', (2, 6))	('BRAF', 'Gene', (2, 6))	('tumors', 'Disease', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Disease', (92, 98))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('NRAS', 'Gene', '4893', (164, 168))	('mutation', 'Var', (112, 120))	('NRAS', 'Gene', '4893', (107, 111))	('melanomas', 'Disease', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('BRAF', 'Gene', '673', (65, 69))	('NRAS', 'Gene', (164, 168))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('BRAF', 'Gene', (65, 69))	('BRAF', 'Gene', '673', (152, 156))	('NRAS', 'Gene', (107, 111))
56387	27911979	TP53 mutations were present in 8.9% of tumors with a BRAFNon-V600 mutation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))
56388	27911979	Analysis of the full patient cohort showed that the presence of a TP53 mutation that was detectable by the clinical CMS50 panel was associated with increased age at diagnosis (median 58 versus 56 years, p=0.019) [Table 3].	('CM', 'Phenotype', 'HP:0012056', (116, 118))	('TP53', 'Gene', '7157', (66, 70))	('patient', 'Species', '9606', (21, 28))	('presence', 'Var', (52, 60))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('CM', 'Disease', 'MESH:D009202', (116, 118))
56389	27911979	TP53 mutations were also significantly associated with primary tumor site (p=0.0001), as they were more common in tumors of the head and neck (27.4%) than the trunk (15.9%) or extremity (14.7%).	('neck', 'cellular_component', 'GO:0044326', ('137', '141'))	('TP53', 'Gene', '7157', (0, 4))	('common', 'Reg', (104, 110))	('TP53', 'Gene', (0, 4))	('trunk', 'cellular_component', 'GO:0043198', ('159', '164'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('primary tumor', 'Disease', (55, 68))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (39, 49))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors of the head and neck', 'Phenotype', 'HP:0012288', (114, 141))
56390	27911979	TP53 mutations were not significantly associated with primary tumor thickness or ulceration status.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (5, 14))	('primary tumor', 'Disease', (54, 67))	('primary tumor', 'Disease', 'MESH:D009369', (54, 67))
56391	27911979	Among the 531 patients that had developed stage IV disease, there was no significant association between TP53 mutation status and M stage or serum LDH at the diagnosis of stage IV disease.	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (14, 22))	('serum LDH', 'MPA', (141, 150))
56392	27911979	Similar analyses were performed to assess the characteristics associated with TP53 mutations separately in melanomas with a concurrent BRAFV600 mutation, in melanomas with a concurrent NRAS mutation, and in melanomas without a BRAFV600 or NRAS mutation [Supplemental Table 6].	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('melanomas', 'Phenotype', 'HP:0002861', (207, 216))	('melanomas', 'Disease', (107, 116))	('NRAS', 'Gene', (185, 189))	('BRAF', 'Gene', '673', (135, 139))	('BRAF', 'Gene', (135, 139))	('NRAS', 'Gene', (239, 243))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('TP53', 'Gene', '7157', (78, 82))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('melanomas', 'Disease', 'MESH:D008545', (207, 216))	('mutation', 'Var', (144, 152))	('melanomas', 'Disease', 'MESH:D008545', (157, 166))	('melanomas', 'Disease', (207, 216))	('BRAF', 'Gene', '673', (227, 231))	('BRAF', 'Gene', (227, 231))	('NRAS', 'Gene', '4893', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mutations', 'Var', (83, 92))	('melanomas', 'Disease', (157, 166))	('NRAS', 'Gene', '4893', (239, 243))	('TP53', 'Gene', (78, 82))
56396	27911979	The prevalence of TP53 mutations detected by the CMS50 panel among these patients was 21.1%.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('CM', 'Disease', 'MESH:D009202', (49, 51))	('mutations', 'Var', (23, 32))	('CM', 'Phenotype', 'HP:0012056', (49, 51))	('patients', 'Species', '9606', (73, 81))
56397	27911979	Patients with a TP53 mutation had longer overall survival (OS) from the diagnosis of stage IV on univariate analysis (median 18.8 versus 15.3 months, p=0.039) [Fig.	('OS', 'Chemical', '-', (59, 61))	('longer', 'PosReg', (34, 40))	('mutation', 'Var', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', '7157', (16, 20))	('overall survival', 'MPA', (41, 57))	('TP53', 'Gene', (16, 20))
56398	27911979	OS from stage IV was very similar for patients with a BRAFV600 mutation with or without a TP53 mutation (median 17.5 versus 16.9 months, p=0.89) [Supplemental Fig.	('OS', 'Chemical', '-', (0, 2))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (90, 94))	('mutation', 'Var', (63, 71))	('TP53', 'Gene', (90, 94))	('patients', 'Species', '9606', (38, 46))
56399	27911979	In contrast, non-significant trends for longer OS with TP53 mutation were observed among patients with NRAS mutations (median 21.7 versus 13.0 months, p=0.07) and among patients without a BRAFV600 or NRAS mutation (median 19.3 versus 15.8 months, p=0.08) [Supplemental Fig.	('mutation', 'Var', (60, 68))	('NRAS', 'Gene', '4893', (103, 107))	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (108, 117))	('NRAS', 'Gene', (200, 204))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('BRAF', 'Gene', '673', (188, 192))	('BRAF', 'Gene', (188, 192))	('NRAS', 'Gene', '4893', (200, 204))	('patients', 'Species', '9606', (89, 97))	('NRAS', 'Gene', (103, 107))	('OS', 'Chemical', '-', (47, 49))
56402	27911979	A total of 146 patients with clinical NGS testing performed within 12 months of stage IV diagnosis were treated with frontline ipilimumab, including 35 patients with a TP53 mutation.	('ipilimumab', 'Chemical', 'MESH:D000074324', (127, 137))	('patients', 'Species', '9606', (15, 23))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('patients', 'Species', '9606', (152, 160))	('mutation', 'Var', (173, 181))
56403	27911979	No significant correlation was observed between TP53 mutation status and OS from the start of ipilimumab treatment in the full cohort (median 11.1 months for TP53 mutant versus 13.9 months for TP53 mutation not detected, p=0.46) [Fig.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', '7157', (193, 197))	('OS', 'Chemical', '-', (73, 75))	('TP53', 'Gene', (48, 52))	('mutant', 'Var', (163, 169))	('ipilimumab', 'Chemical', 'MESH:D000074324', (94, 104))	('TP53', 'Gene', (193, 197))
56404	27911979	There was also no significant association with OS from the start of ipilimumab by TP53 mutation among the cohorts defined by the concurrent BRAFV600 and NRAS mutation status [Supplemental Fig.	('TP53', 'Gene', (82, 86))	('NRAS', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (140, 144))	('NRAS', 'Gene', '4893', (153, 157))	('BRAF', 'Gene', (140, 144))	('TP53', 'Gene', '7157', (82, 86))	('mutation', 'Var', (87, 95))	('OS', 'Chemical', '-', (47, 49))	('ipilimumab', 'Chemical', 'MESH:D000074324', (68, 78))
56405	27911979	Among the patients with a BRAFV600 mutation, 64 patients in the cohort were treated with an FDA-approved BRAF inhibitor as first-line therapy for stage IV disease [Supplemental Table 8].	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', '673', (26, 30))	('BRAF', 'Gene', (105, 109))	('stage IV disease', 'Disease', (146, 162))	('BRAF', 'Gene', (26, 30))	('mutation', 'Var', (35, 43))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (48, 56))
56406	27911979	The objective response rate (ORR) did not differ significantly between the patients with (n=9, ORR 55.6%) and without a TP53 mutation (n=55, ORR 47.3%, p=0.7).	('mutation', 'Var', (125, 133))	('patients', 'Species', '9606', (75, 83))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
56408	27911979	The outcomes associated with TP53 mutations were further characterized by analyzing the nature of the observed mutations in the stage IV patients, as different types of mutations in TP53 may have different prognostic significance.	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('patients', 'Species', '9606', (137, 145))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
56409	27911979	Consistent with the strong association of non-acral cutaneous melanoma with UVR exposure, 58.2% of the detected TP53 mutations in the cohort were substitutions that are associated with UVR-related DNA damage.	('mutations', 'Var', (117, 126))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('DNA', 'cellular_component', 'GO:0005574', ('197', '200'))	('TP53', 'Gene', '7157', (112, 116))	('non-acral', 'Disease', (42, 51))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (46, 70))	('TP53', 'Gene', (112, 116))
56411	27911979	Patients with UVR-related (n=55, median OS 17.5 months) and non-UVR related TP53 mutations (n=31, median OS 24.0 months) had trends for improved OS from stage IV compared to patients without a detectable TP53 mutation (median OS 15.3 months), but these differences did not reach statistical significance (p=0.09 and p=0.11, respectively) [Supplemental Fig.	('TP53', 'Gene', '7157', (76, 80))	('OS', 'Chemical', '-', (145, 147))	('patients', 'Species', '9606', (174, 182))	('TP53', 'Gene', '7157', (204, 208))	('OS', 'Chemical', '-', (40, 42))	('TP53', 'Gene', (76, 80))	('OS', 'Chemical', '-', (105, 107))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (81, 90))	('TP53', 'Gene', (204, 208))	('OS', 'Chemical', '-', (226, 228))	('improved', 'PosReg', (136, 144))
56412	27911979	Most TP53 mutations were missense mutations (n=61, median OS 19.3 months), and patients with such mutations had improved OS compared to patients without TP53 mutations detected by the CMS50 panel (p=0.002).	('OS', 'Chemical', '-', (58, 60))	('OS', 'Chemical', '-', (121, 123))	('CM', 'Disease', 'MESH:D009202', (184, 186))	('TP53', 'Gene', '7157', (153, 157))	('missense mutations', 'Var', (25, 43))	('patients', 'Species', '9606', (136, 144))	('TP53', 'Gene', '7157', (5, 9))	('patients', 'Species', '9606', (79, 87))	('TP53', 'Gene', (5, 9))	('TP53', 'Gene', (153, 157))	('CM', 'Phenotype', 'HP:0012056', (184, 186))	('mutations', 'Var', (10, 19))	('improved', 'PosReg', (112, 120))
56413	27911979	In contract, the presence of a truncating mutation in TP53 was less common (n=21) and was not associated with a significant difference in survival from stage IV (median OS 12.9 months, p=0.93) [Supplemental Fig.	('OS', 'Chemical', '-', (169, 171))	('TP53', 'Gene', '7157', (54, 58))	('presence', 'Var', (17, 25))	('truncating mutation', 'Var', (31, 50))	('TP53', 'Gene', (54, 58))
56414	27911979	The majority (n=74; 84.1%) of the mutations detected in TP53 affected the DNA binding domain of the protein, and the presence of such mutations was associated with improved OS compared to patients without a mutation detected (median OS 18.6 months, p=0.05).	('OS', 'Chemical', '-', (233, 235))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('improved', 'PosReg', (164, 172))	('TP53', 'Gene', '7157', (56, 60))	('affected', 'Reg', (61, 69))	('DNA binding', 'molecular_function', 'GO:0003677', ('74', '85'))	('patients', 'Species', '9606', (188, 196))	('OS', 'Chemical', '-', (173, 175))	('TP53', 'Gene', (56, 60))	('DNA binding domain of the', 'MPA', (74, 99))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('mutations', 'Var', (134, 143))	('mutations', 'Var', (34, 43))
56415	27911979	Although mutations in other domains of TP53 were not significantly associated with survival from stage IV (p=0.39), there was very limited power for this analysis due to the small number of such patients in this cohort (n=11) [Supplemental Fig.	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (195, 203))	('associated', 'Reg', (67, 77))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
56416	27911979	Finally, categorization of the TP53 mutations into two groups based on evolutionary score showed that high risk evolutionary score (N=51) correlated significantly with OS from stage IV (median OS 21.7 months, p=0.04) but not low risk (N=10, median OS 19.3 months, p=0.16) [Supplemental Fig.	('OS from stage IV', 'Disease', (168, 184))	('TP53', 'Gene', '7157', (31, 35))	('OS', 'Chemical', '-', (248, 250))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('OS', 'Chemical', '-', (193, 195))	('OS', 'Chemical', '-', (168, 170))
56418	27911979	BRAFNon-V600 mutations were detected in 2 patients with BRAFV600 mutations (0.5%), 8 patients with NRAS mutations (4.1%), and 50 patients with neither BRAFV600 nor NRAS mutations (14.9%) [Supplemental Fig.	('NRAS', 'Gene', '4893', (164, 168))	('detected', 'Reg', (28, 36))	('patients', 'Species', '9606', (129, 137))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', '673', (151, 155))	('patients', 'Species', '9606', (85, 93))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', (99, 103))	('BRAF', 'Gene', (151, 155))	('NRAS', 'Gene', (164, 168))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (99, 103))	('patients', 'Species', '9606', (42, 50))	('mutations', 'Var', (65, 74))	('BRAF', 'Gene', (56, 60))
56434	27911979	Since BRAF K601 and L597 mutations are located in the activating kinase domain of BRAF, and a BRAF inhibitor demonstrated some antitumor activity in a patient with a BRAF L597 mutant melanoma, clinical outcomes of patients with BRAF K601 and L597 mutations and other BRAFNon-V600 mutations with BRAF inhibitor treatment.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('patients', 'Species', '9606', (214, 222))	('BRAF', 'Gene', '673', (295, 299))	('L597 mutations', 'Var', (20, 34))	('BRAF', 'Gene', (295, 299))	('tumor', 'Disease', (131, 136))	('K601', 'Var', (233, 237))	('BRAF', 'Gene', '673', (166, 170))	('BRAF', 'Gene', (166, 170))	('mutations', 'Var', (25, 34))	('L597 mutations', 'Var', (242, 256))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('patient', 'Species', '9606', (151, 158))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('BRAF', 'Gene', '673', (94, 98))	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (228, 232))	('BRAF', 'Gene', '673', (267, 271))	('patient', 'Species', '9606', (214, 221))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('BRAF', 'Gene', (228, 232))	('BRAF', 'Gene', (267, 271))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))
56435	27911979	There was no difference in PFS and OS between patients with BRAF K601 and L597 mutations and the other BRAFNon-V600 mutations [supplemental Figure 7C and D].	('patients', 'Species', '9606', (46, 54))	('OS', 'Chemical', '-', (35, 37))	('BRAF', 'Gene', (60, 64))	('L597 mutations', 'Var', (74, 88))	('BRAF', 'Gene', '673', (60, 64))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', (103, 107))
56436	27911979	No responses were observed among 3 patients with BRAFNon-V600 mutations (BRAF L597R, G466E, G469E) treated with trametinib (MEKi) monotherapy [Table 4].	('BRAF', 'Gene', '673', (73, 77))	('G466E', 'Mutation', 'rs121913351', (85, 90))	('G466E', 'Var', (85, 90))	('L597R', 'Mutation', 'rs121913366', (78, 83))	('G469E', 'Var', (92, 97))	('MEK', 'Gene', (124, 127))	('MEK', 'Gene', '5609', (124, 127))	('BRAF', 'Gene', '673', (49, 53))	('patients', 'Species', '9606', (35, 43))	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', (49, 53))	('G469E', 'Mutation', 'rs121913355', (92, 97))	('trametinib', 'Chemical', 'MESH:C560077', (112, 122))
56439	27911979	The presence of a TP53 mutation was associated with improved OS from stage IV (HR 0.62, 95% CI 0.42-0.91, p=0.015).	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('improved', 'PosReg', (52, 60))	('TP53', 'Gene', (18, 22))	('OS', 'Chemical', '-', (61, 63))	('presence', 'Var', (4, 12))
56440	27911979	A number of previous studies have described the clinical and pathologic features associated with BRAFV600 and NRAS mutations, which are the most common hotspot oncogenic mutations detected in cutaneous melanomas.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (192, 211))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('mutations', 'Var', (115, 124))	('cutaneous melanomas', 'Disease', (192, 211))	('NRAS', 'Gene', '4893', (110, 114))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('NRAS', 'Gene', (110, 114))	('BRAF', 'Gene', '673', (97, 101))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))	('BRAF', 'Gene', (97, 101))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (192, 211))
56441	27911979	While many other mutations have been identified in melanoma, the ability to assess their clinical associations has been limited by their relative scarcity.	('identified', 'Reg', (37, 47))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('mutations', 'Var', (17, 26))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
56443	27911979	This analysis focused on TP53 and BRAFNon-V600 mutations, as they are particularly common in cutaneous melanomas without BRAFV600 or NRAS mutations, and as preclinical data supports potential functional roles for both events in this disease.	('BRAF', 'Gene', (121, 125))	('TP53', 'Gene', (25, 29))	('common', 'Reg', (83, 89))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (93, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('NRAS', 'Gene', (133, 137))	('mutations', 'Var', (47, 56))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (93, 112))	('BRAF', 'Gene', '673', (34, 38))	('cutaneous melanomas', 'Disease', (93, 112))	('NRAS', 'Gene', '4893', (133, 137))	('BRAF', 'Gene', (34, 38))	('BRAF', 'Gene', '673', (121, 125))	('TP53', 'Gene', '7157', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
56445	27911979	Similar with the rate observed in the melanoma TCGA (15%), we identified TP53 mutations in 19% of the full cohort of cutaneous melanoma patients who had undergone molecular testing with the clinical CMS50 NGS panel.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('CM', 'Disease', 'MESH:D009202', (199, 201))	('TP53', 'Gene', '7157', (73, 77))	('cutaneous melanoma', 'Disease', (117, 135))	('CM', 'Phenotype', 'HP:0012056', (199, 201))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('patients', 'Species', '9606', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
56446	27911979	Compared to patients who did not have an alteration detected by this panel, TP53 mutations were associated with older age and increased head and neck primary tumor location.	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('primary tumor', 'Disease', 'MESH:D009369', (150, 163))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('neck', 'cellular_component', 'GO:0044326', ('145', '149'))	('primary tumor', 'Disease', (150, 163))	('increased', 'PosReg', (126, 135))	('head and neck primary tumor', 'Phenotype', 'HP:0012288', (136, 163))
56447	27911979	These clinical associations are consistent with the observed correlation between ultraviolet radiation (UVR)-induced DNA damage and TP53 mutations in cutaneous melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('mutations', 'Var', (137, 146))	('cutaneous melanoma', 'Disease', (150, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
56448	27911979	In this cohort, 58% of TP53 mutations were consistent with UV-induced DNA damage, which is again similar to the rate reported in the melanoma TCGA (45.3%).	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
56449	27911979	While preclinical studies have shown that TP53 mutations accelerate BRAFV600-driven melanomagenesis, we observed that TP53 mutations were associated with a significantly improved survival from the diagnosis of stage IV disease on univariate and multivariate analyses.	('accelerate', 'PosReg', (57, 67))	('TP53', 'Gene', '7157', (42, 46))	('BRAF', 'Gene', '673', (68, 72))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('TP53', 'Gene', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('improved', 'PosReg', (170, 178))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (68, 72))	('melanoma', 'Disease', (84, 92))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
56450	27911979	The observed association of improved outcomes in melanomas with TP53 mutations contrasts with associations with poor clinical outcomes in a number of other cancers, including breast cancer, head and neck cancer, and hematologic malignancies.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Disease', (175, 188))	('TP53', 'Gene', '7157', (64, 68))	('head and neck cancer', 'Disease', 'MESH:D006258', (190, 210))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('mutations', 'Var', (69, 78))	('outcomes', 'MPA', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('TP53', 'Gene', (64, 68))	('melanomas', 'Disease', (49, 58))	('hematologic malignancies', 'Disease', (216, 240))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('improved', 'PosReg', (28, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('neck', 'cellular_component', 'GO:0044326', ('199', '203'))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('hematologic malignancies', 'Disease', 'MESH:D019337', (216, 240))	('head and neck cancer', 'Phenotype', 'HP:0012288', (190, 210))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
56451	27911979	However, these results are consistent with a previous study that identified improved clinical outcomes in melanomas with overexpression of the P53 protein, which is usually associated with mutations in the TP53 gene.	('protein', 'Protein', (147, 154))	('P53', 'Gene', (207, 210))	('TP53', 'Gene', '7157', (206, 210))	('TP53', 'Gene', (206, 210))	('P53', 'Gene', '7157', (207, 210))	('melanomas', 'Disease', (106, 115))	('P53', 'Gene', (143, 146))	('improved', 'PosReg', (76, 84))	('P53', 'Gene', '7157', (143, 146))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('overexpression', 'PosReg', (121, 135))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('mutations', 'Var', (189, 198))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))
56452	27911979	Our analysis also showed that missense substitution mutations in TP53, mutations that affected the DNA binding domain of the P53 protein and high risk evolutionary score of TP53 mutations were associated with significant improvements in OS from stage IV, but truncating mutations, mutations affecting other domains and low risk evolutionary score were not.	('TP53', 'Gene', '7157', (65, 69))	('P53', 'Gene', (174, 177))	('missense substitution mutations', 'Var', (30, 61))	('TP53', 'Gene', (173, 177))	('DNA binding', 'molecular_function', 'GO:0003677', ('99', '110'))	('improvements', 'PosReg', (221, 233))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('mutations', 'Var', (71, 80))	('P53', 'Gene', '7157', (174, 177))	('OS', 'Chemical', '-', (237, 239))	('P53', 'Gene', (125, 128))	('TP53', 'Gene', (65, 69))	('P53', 'Gene', (66, 69))	('TP53', 'Gene', '7157', (173, 177))	('P53', 'Gene', '7157', (66, 69))	('P53', 'Gene', '7157', (125, 128))	('DNA', 'MPA', (99, 102))	('binding', 'Interaction', (103, 110))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('mutations', 'Var', (178, 187))
56453	27911979	While these findings may further help to interpret the results of TP53 molecular testing results, the analysis of truncating mutations, mutations affecting other domains and low risk evolutionary score were limited by the small number of patients with such alterations in this cohort.	('TP53', 'Gene', (66, 70))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', '7157', (66, 70))
56454	27911979	At this time it is unclear why TP53 mutations are associated with improved survival in stage IV melanoma patients.	('patients', 'Species', '9606', (105, 113))	('TP53', 'Gene', '7157', (31, 35))	('improved', 'PosReg', (66, 74))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('IV melanoma', 'Disease', (93, 104))	('survival', 'MPA', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('IV melanoma', 'Disease', 'MESH:D008545', (93, 104))
56455	27911979	The presence of a somatic mutation in TP53 was also associated with a trend for improved OS from initial diagnosis in the full melanoma TCGA cohort, as patients with a TP53 mutation (n=64) had a median OS of 170 months, while patients without a TP53 mutation (n=350) had a median OS of 114 months (p=0.44).	('OS', 'Chemical', '-', (202, 204))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('TP53', 'Gene', (245, 249))	('TP53', 'Gene', '7157', (245, 249))	('improved', 'PosReg', (80, 88))	('OS', 'Chemical', '-', (280, 282))	('patients', 'Species', '9606', (226, 234))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('OS', 'Chemical', '-', (89, 91))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('presence', 'Var', (4, 12))	('patients', 'Species', '9606', (152, 160))	('mutation', 'Var', (173, 181))
56456	27911979	Analysis limited to the TCGA patients with stage III or IV metastases also showed a trend for improved OS with a TP53 mutation (median OS Not reached versus 72.8 months, p=0.25).	('patients', 'Species', '9606', (29, 37))	('OS', 'Chemical', '-', (103, 105))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('OS', 'Chemical', '-', (135, 137))	('improved', 'PosReg', (94, 102))	('TP53', 'Gene', '7157', (113, 117))	('mutation', 'Var', (118, 126))	('TP53', 'Gene', (113, 117))	('metastases', 'Disease', (59, 69))
56458	27911979	Thus, studies of additional cohorts with appropriate power and annotation will need to be evaluated in the future to further assess the prognostic significance of TP53 mutations in melanoma.	('TP53', 'Gene', '7157', (163, 167))	('TP53', 'Gene', (163, 167))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))	('mutations', 'Var', (168, 177))
56460	27911979	Recent studies support that increased missense mutation burden correlates with improved survival in metastatic melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('missense mutation burden', 'Var', (38, 62))	('improved', 'PosReg', (79, 87))	('survival', 'MPA', (88, 96))	('patients', 'Species', '9606', (120, 128))
56461	27911979	As TP53 mutations are associated with increased mutation burden, including in the melanoma TCGA cohort (p<0.0001 by Mann-Whitney test), it is possible that the presence of this mutation signifies the likelihood of increased mutation burden, and therefore enhanced anti-tumor immune surveillance.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('TP53', 'Gene', '7157', (3, 7))	('mutation burden', 'MPA', (48, 63))	('TP53', 'Gene', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('enhanced', 'PosReg', (255, 263))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('mutations', 'Var', (8, 17))	('melanoma', 'Disease', (82, 90))	('tumor', 'Disease', (269, 274))	('increased', 'PosReg', (214, 223))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('increased', 'PosReg', (38, 47))	('mutation burden', 'MPA', (224, 239))
56462	27911979	While this is a reasonable hypothesis, we did not observe a significant association between the presence of a TP53 mutation and an improvement in overall survival with ipilimumab.	('presence', 'Var', (96, 104))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('mutation', 'Var', (115, 123))	('ipilimumab', 'Chemical', 'MESH:D000074324', (168, 178))
56466	27911979	BRAFNon-V600 mutations were extremely rare in cutaneous melanomas with a concurrent BRAFV600 mutation (0.5%), but they were more frequent in melanomas with an NRAS mutation (4%) and in melanomas with neither of those oncogenic driver mutations (15%).	('NRAS', 'Gene', '4893', (159, 163))	('mutation', 'Var', (164, 172))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', (185, 194))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('NRAS', 'Gene', (159, 163))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('melanomas', 'Disease', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('cutaneous melanomas', 'Disease', (46, 65))	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('melanomas', 'Disease', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('mutation', 'Var', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
56469	27911979	The failure of a selective BRAF inhibitor in BRAFNon-V600 mutant melanoma can be explained by preclinical data which showed activation of endogenous CRAF in BRAFnon-V600 mutant melanoma.	('mutant', 'Var', (58, 64))	('CRAF', 'molecular_function', 'GO:0004709', ('149', '153'))	('activation', 'PosReg', (124, 134))	('endogenous', 'MPA', (138, 148))	('BRAF', 'Gene', '673', (157, 161))	('BRAF', 'Gene', '673', (27, 31))	('melanoma', 'Disease', (177, 185))	('CRAF', 'Gene', (149, 153))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (157, 161))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('BRAF', 'Gene', (27, 31))	('CRAF', 'Gene', '5894', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
56470	27911979	In contrast to other BRAFNon-V600 mutations, BRAF K601 and L597 mutations are located in the activating domain of BRAF, and a clinical response to a BRAF inhibitor has previously been reported in one metastatic melanoma patient with a BRAF L597 mutation.	('BRAF', 'Gene', '673', (235, 239))	('BRAF', 'Gene', (149, 153))	('K601', 'Var', (50, 54))	('BRAF', 'Gene', '673', (149, 153))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('BRAF', 'Gene', (235, 239))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('BRAF', 'Gene', '673', (21, 25))	('patient', 'Species', '9606', (220, 227))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (21, 25))
56472	27911979	While there is evidence that MEK inhibitors may be an effective strategy for melanomas with BRAFNon-V600 mutations, and objective response to a selective MEK inhibitor was reported in BRAF L597S mutant melanoma, no responses were seen among 3 patients with BRAF L597R, G466E or G469E mutations in this cohort that were treated with trametinib.	('melanomas', 'Disease', (77, 86))	('BRAF', 'Gene', (184, 188))	('L597R', 'Mutation', 'rs121913366', (262, 267))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('MEK', 'Gene', '5609', (154, 157))	('MEK', 'Gene', '5609', (29, 32))	('L597S', 'Mutation', 'rs121913368', (189, 194))	('patients', 'Species', '9606', (243, 251))	('trametinib', 'Chemical', 'MESH:C560077', (332, 342))	('G469E', 'Mutation', 'rs121913355', (278, 283))	('G466E', 'Var', (269, 274))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('G469E', 'Var', (278, 283))	('MEK', 'Gene', (154, 157))	('MEK', 'Gene', (29, 32))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('BRAF', 'Gene', (257, 261))	('BRAF', 'Gene', '673', (257, 261))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('G466E', 'Mutation', 'rs121913351', (269, 274))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('BRAF', 'Gene', '673', (184, 188))
56481	27911979	Indeed, the residues in TP53 that are assessed for mutations in the CMS50 panel largely overlap with the mutations that were detected in the melanoma TCGA [Supplemental Fig.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('CM', 'Disease', 'MESH:D009202', (68, 70))	('melanoma', 'Disease', (141, 149))	('mutations', 'Var', (51, 60))	('CM', 'Phenotype', 'HP:0012056', (68, 70))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (24, 28))
56486	27911979	Our results suggest that in contrast to many other tumor types, TP53 mutations may correlate with a favorable prognosis in advanced cutaneous melanoma patients, at least for those who undergo molecular testing within 12 months of stage IV diagnosis.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (151, 159))	('cutaneous melanoma', 'Disease', (132, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
56488	26609109	Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression New strategies are needed to diagnose and target human melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('human', 'Species', '9606', (140, 145))	('Pyrimidine', 'Chemical', 'MESH:C030986', (34, 44))	('Pyrimidine Metabolism', 'MPA', (34, 55))	('Deregulates', 'Reg', (22, 33))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('Pyrimidine Metabolism', 'biological_process', 'GO:0006220', ('34', '55'))	('Malignant Progression', 'CPA', (69, 90))	('Pyrimidine Metabolism', 'biological_process', 'GO:0006206', ('34', '55'))	('DPYD', 'Gene', (17, 21))	('Promotes', 'PosReg', (60, 68))	('Pyrimidine Metabolism', 'biological_process', 'GO:0006213', ('34', '55'))	('Hypermutation', 'Var', (0, 13))	('DPYD', 'Gene', '1806', (17, 21))
56492	26609109	Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand binding sites as well as the interfaces of protein domains that mediated electron transfer.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('DPYD', 'Gene', '1806', (27, 31))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('ligand', 'molecular_function', 'GO:0005488', ('112', '118'))	('electron transfer', 'biological_process', 'GO:0006118', ('192', '209'))	('electron transfer', 'biological_process', 'GO:0022904', ('192', '209'))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('mutations', 'Var', (95, 104))	('DPYD', 'Gene', (27, 31))	('mediated', 'Reg', (183, 191))
56493	26609109	Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM.	('nucleic acid processing', 'MPA', (112, 135))	('DPYD', 'Gene', '1806', (21, 25))	('nucleotide synthesis', 'MPA', (86, 106))	('upregulation', 'PosReg', (46, 58))	('degradation', 'biological_process', 'GO:0009056', ('73', '84'))	('downregulated', 'NegReg', (179, 192))	('mutations', 'Var', (8, 17))	('nucleotide synthesis', 'biological_process', 'GO:0009165', ('86', '106'))	('pyrimidine', 'Chemical', 'MESH:C030986', (62, 72))	('DPYD', 'Gene', (21, 25))	('pyrimidine degradation', 'MPA', (62, 84))	('nucleic acid', 'cellular_component', 'GO:0005561', ('112', '124'))
56503	26609109	The approach identifies DPYD (dihydropyrimidine dehydrogenase, Gene ID: 1806) as a pivotal factor of pyrimidine metabolism and offers a comprehensive view on how a hypermutated metabolic gene deregulates pyrimidine and nucleic acid synthesis and promotes malignant progression of melanoma.	('DPYD', 'Gene', '1806', (24, 28))	('promotes', 'PosReg', (246, 254))	('hypermutated', 'Var', (164, 176))	('dihydropyrimidine dehydrogenase', 'Gene', (30, 61))	('pyrimidine', 'Chemical', 'MESH:C030986', (101, 111))	('synthesis', 'biological_process', 'GO:0009058', ('232', '241'))	('nucleic acid', 'cellular_component', 'GO:0005561', ('219', '231'))	('dihydropyrimidine dehydrogenase', 'Gene', '1806', (30, 61))	('melanoma', 'Disease', 'MESH:D008545', (280, 288))	('deregulates', 'NegReg', (192, 203))	('malignant progression', 'CPA', (255, 276))	('DPYD', 'Gene', (24, 28))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('101', '122'))	('melanoma', 'Phenotype', 'HP:0002861', (280, 288))	('melanoma', 'Disease', (280, 288))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('101', '122'))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('101', '122'))	('pyrimidine', 'Chemical', 'MESH:C030986', (204, 214))	('pyrimidine', 'Chemical', 'MESH:C030986', (37, 47))
56510	26609109	This patient shows multiple missense mutations in DPYD with nucleotide transitions according to canonical UVB signature, C>T and G>A.	('patient', 'Species', '9606', (5, 12))	('DPYD', 'Gene', (50, 54))	('G>A', 'Var', (129, 132))	('DPYD', 'Gene', '1806', (50, 54))	('missense mutations', 'Var', (28, 46))	('C>T', 'Var', (121, 124))
56516	26609109	Metabolic pathways include global metabolism (KEGG ID:01100), oxidative phosphorylation (ID:00190), pyrimidine metabolism (ID:00240), purine metabolism (ID:00230), glycosphingolipid biosynthesis (ID:00601), metabolism of cytochrome P450 (ID:00980), tyrosine metabolism (ID:00350), as well as glutathione metabolism (ID:00480) to be significantly enriched pathways with deregulated gene expression with p-values lower than 0.001.	('ID:00980', 'Var', (238, 246))	('pyrimidine', 'Chemical', 'MESH:C030986', (100, 110))	('ID:00350', 'Var', (270, 278))	('purine metabolism', 'biological_process', 'GO:0006144', ('134', '151'))	('purine', 'MPA', (134, 140))	('KEGG', 'Var', (46, 50))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('221', '236'))	('tyrosine', 'Enzyme', (249, 257))	('ID:00480', 'Var', (316, 324))	('purine metabolism', 'biological_process', 'GO:0006163', ('134', '151'))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('221', '236'))	('metabolism', 'biological_process', 'GO:0008152', ('207', '217'))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('100', '121'))	('gene expression', 'biological_process', 'GO:0010467', ('381', '396'))	('ID:00190', 'Var', (89, 97))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('100', '121'))	('ID:00240', 'Var', (123, 131))	('purine metabolism', 'biological_process', 'GO:0042278', ('134', '151'))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('100', '121'))	('glutathione metabolism', 'MPA', (292, 314))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('62', '87'))	('glutathione metabolism', 'biological_process', 'GO:0006749', ('292', '314'))	('oxidative', 'MPA', (62, 71))	('tyrosine metabolism', 'biological_process', 'GO:0006570', ('249', '268'))	('metabolism', 'biological_process', 'GO:0008152', ('34', '44'))	('purine', 'Chemical', 'MESH:C030985', (134, 140))	('glycosphingolipid biosynthesis', 'biological_process', 'GO:0006688', ('164', '194'))	('global metabolism', 'MPA', (27, 44))
56524	26609109	DPYD stands out for its highest mutation rate above 20% for all melanoma patients and significant enrichment of somatic mutations above background mutation rate with a q-value of 4.40E-06 (Table 2).	('DPYD', 'Gene', '1806', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (73, 81))	('DPYD', 'Gene', (0, 4))
56527	26609109	For example, PRIM2 has recurrent somatic mutations at residue E221, G334, P391, and is also significantly mutated in HNSC (p=0.00558; q=3.34E-06) or LUSC (p=0.000339; q=2.27E-04).	('G334', 'Var', (68, 72))	('HNSC', 'Disease', (117, 121))	('LUSC', 'Disease', (149, 153))	('PRIM2', 'Gene', (13, 18))	('PRIM2', 'Gene', '5558', (13, 18))	('P391', 'Var', (74, 78))
56528	26609109	Somatic DPYD mutations coincide with deleterious mutations of gatekeeper and caretaker genes TP53, BRCA1, FAT3, FAT4, PTPRD, and SPEN with p-values below 1.0E-06 and q-values below 1.0E-04 connecting to DNA maintenance and stability.	('DNA', 'cellular_component', 'GO:0005574', ('203', '206'))	('FAT3', 'Gene', (106, 110))	('mutations', 'Var', (49, 58))	('BRCA1', 'Gene', (99, 104))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('DPYD', 'Gene', (8, 12))	('DPYD', 'Gene', '1806', (8, 12))	('gatekeeper', 'Species', '111938', (62, 72))	('mutations', 'Var', (13, 22))	('PTPRD', 'Gene', (118, 123))
56530	26609109	There are in total 74 non-synonymous mutations in DPYD detected, including incidents where two or three residues of the same polypeptide chain are affected.	('DPYD', 'Gene', (50, 54))	('non-synonymous mutations', 'Var', (22, 46))	('DPYD', 'Gene', '1806', (50, 54))
56531	26609109	Examples of multiple mutations coinciding in DPYD are S204F and D949N in patient TCGA-EE-A2MI, or V396I, G851R, E937K in patient TCGA-FW-A3R5.	('S204F', 'Var', (54, 59))	('E937K', 'Var', (112, 117))	('E937K', 'Mutation', 'rs776236081', (112, 117))	('V396I', 'Var', (98, 103))	('S204F', 'Mutation', 'rs1451202946', (54, 59))	('D949N', 'Var', (64, 69))	('D949N', 'Mutation', 'rs867232786', (64, 69))	('G851R', 'Mutation', 'rs891349588', (105, 110))	('V396I', 'Mutation', 'p.V396I', (98, 103))	('patient', 'Species', '9606', (73, 80))	('G851R', 'Var', (105, 110))	('patient', 'Species', '9606', (121, 128))	('DPYD', 'Gene', (45, 49))	('DPYD', 'Gene', '1806', (45, 49))
56532	26609109	The nucleotide signature of somatic transitions of DPYD tracks with the validated mutational signature of melanoma identified across human cancers, and is governed by UVB-associated C>T/G>A transitions (Supplementary table 6) (Figure 1B).	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('C>T/G>A', 'Var', (182, 189))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('human', 'Species', '9606', (133, 138))	('melanoma', 'Disease', (106, 114))	('DPYD', 'Gene', (51, 55))	('DPYD', 'Gene', '1806', (51, 55))
56533	26609109	In order to decipher functional implications of somatic mutations of DPYD, we analyzed the domain distribution, polymorphism phenotyping v2 (PPH2) scores, solvent accessible surface, proximity to ligands, and mutational recurrence of all identified somatic mutations (Supplementary table 7).	('DPYD', 'Gene', (69, 73))	('PPH', 'molecular_function', 'GO:0033978', ('141', '144'))	('mutations', 'Var', (257, 266))	('PPH', 'molecular_function', 'GO:0004238', ('141', '144'))	('DPYD', 'Gene', '1806', (69, 73))	('PPH2', 'Chemical', '-', (141, 145))
56538	26609109	The somatic mutations affect 153 residues of 1025 in the TCGA Pan-cancer dataset (TCGA: 181 mutation affecting 153 unique residues; SKCM: 74 mutations affecting 60 unique residues).	('mutation', 'Var', (92, 100))	('mutations', 'Var', (12, 21))	('Pan-cancer', 'Disease', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Pan-cancer', 'Disease', 'MESH:C537931', (62, 72))	('affect', 'Reg', (22, 28))
56540	26609109	While the pyrimidine binding domain has the highest mutational count with 55 mutations in total, correction for domain length shows that domains II-IV, which bind metabolite substrates and cofactors, show enriched mutation frequency (37 mutations over 197 residues in FAD binding domain II domain; 33 mutations over 155 residues in NADPH binding domain III domain; 55 mutations over 323 residues in the FMN and pyrimidine binding domain IV).	('mutations over', 'Var', (368, 382))	('FAD', 'Chemical', 'MESH:D005182', (268, 271))	('FAD binding', 'molecular_function', 'GO:0071949', ('268', '279'))	('mutations over', 'Var', (301, 315))	('pyrimidine', 'Chemical', 'MESH:C030986', (411, 421))	('FMN', 'Chemical', 'MESH:D005486', (403, 406))	('pyrimidine binding', 'molecular_function', 'GO:0002061', ('411', '429'))	('pyrimidine', 'Chemical', 'MESH:C030986', (10, 20))	('mutations over', 'Var', (237, 251))	('pyrimidine binding', 'molecular_function', 'GO:0002061', ('10', '28'))	('NADPH binding', 'molecular_function', 'GO:0070402', ('332', '345'))	('NADPH', 'Chemical', 'MESH:D009249', (332, 337))
56542	26609109	Molecular dynamics simulations in combination with computation of solvent accessible surface revealed an accumulation of damaging, missense somatic mutations in the core of the protein (PPH2 scores > 0.95; making up 52% of somatic mutations; solvent accessible surface values of affected residues below 0.50).	('mutations', 'Var', (148, 157))	('core', 'cellular_component', 'GO:0019013', ('165', '169'))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('PPH2', 'Chemical', '-', (186, 190))	('missense', 'Var', (131, 139))	('PPH', 'molecular_function', 'GO:0033978', ('186', '189'))	('PPH', 'molecular_function', 'GO:0004238', ('186', '189'))
56545	26609109	Recurring somatic missense mutations D291N, V335M, and A437 frame the nucleotide binding site (Figure 4A).	('A437 frame', 'Var', (55, 65))	('D291N', 'Mutation', 'rs1327845774', (37, 42))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('70', '88'))	('D291N', 'Var', (37, 42))	('V335M', 'Mutation', 'rs72549306', (44, 49))	('V335M', 'Var', (44, 49))
56546	26609109	In addition, the NADPH binding domain houses mutations A323D/P/T, V362I, G366I/S/V, as well as V365 nonsense mutation.	('V365 nonsense', 'Var', (95, 108))	('A323D', 'SUBSTITUTION', 'None', (55, 60))	('G366I', 'SUBSTITUTION', 'None', (73, 78))	('NADPH', 'Chemical', 'MESH:D009249', (17, 22))	('G366I', 'Var', (73, 78))	('V362I', 'Var', (66, 71))	('NADPH binding', 'molecular_function', 'GO:0070402', ('17', '30'))	('A323D', 'Var', (55, 60))	('V362I', 'Mutation', 'rs752020412', (66, 71))
56547	26609109	Somatic mutations involved in the hydrogen bond network and within less than 3.5A to the FAD ligand are P197S, E218K, G224S/V, S260R, and S492L.	('G224S', 'SUBSTITUTION', 'None', (118, 123))	('P197S', 'Var', (104, 109))	('S260R', 'Var', (127, 132))	('S492L', 'Mutation', 'rs72549304', (138, 143))	('S260R', 'Mutation', 'rs751387129', (127, 132))	('E218K', 'Var', (111, 116))	('FAD', 'Chemical', 'MESH:D005182', (89, 92))	('hydrogen', 'Chemical', 'MESH:D006859', (34, 42))	('ligand', 'molecular_function', 'GO:0005488', ('93', '99'))	('P197S', 'Mutation', 'rs761222249', (104, 109))	('S492L', 'Var', (138, 143))	('E218K', 'Mutation', 'rs766320421', (111, 116))	('G224S', 'Var', (118, 123))
56550	26609109	Mutations D949N, D965N, A554V, and E615A line up between C-terminal 4Fe-4S domain V and pyrimidine binding domain IV.	('A554V', 'Mutation', 'rs747220001', (24, 29))	('D965N', 'Mutation', 'p.D965N', (17, 22))	('D965N', 'Var', (17, 22))	('A554V', 'Var', (24, 29))	('D949N', 'Var', (10, 15))	('D949N', 'Mutation', 'rs867232786', (10, 15))	('E615A', 'Mutation', 'p.E615A', (35, 40))	('pyrimidine binding', 'molecular_function', 'GO:0002061', ('88', '106'))	('E615A', 'Var', (35, 40))	('pyrimidine', 'Chemical', 'MESH:C030986', (88, 98))
56551	26609109	The pyrimidine substrate binding pocket is framed by recurrent somatic mutations T575I, E611K, N668K, and G795E (Figure 4B).	('G795E', 'Var', (106, 111))	('E611K', 'Var', (88, 93))	('G795E', 'Mutation', 'rs28897684', (106, 111))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))	('pyrimidine', 'Chemical', 'MESH:C030986', (4, 14))	('T575I', 'Var', (81, 86))	('N668K', 'Mutation', 'p.N668K', (95, 100))	('T575I', 'Mutation', 'rs4648085', (81, 86))	('N668K', 'Var', (95, 100))	('E611K', 'Mutation', 'rs775917455', (88, 93))
56552	26609109	A hotspot of recurring somatic mutations D96N (3x), S204F (3x), M115I (2x), G851R (2x), E828K (2x), and P545H/L/S is at the interface between domain I, II, and IV (Figure 3C,D).	('M115I', 'Var', (64, 69))	('G851R', 'Mutation', 'rs891349588', (76, 81))	('E828K', 'Mutation', 'rs200687447', (88, 93))	('D96N', 'Var', (41, 45))	('E828K', 'Var', (88, 93))	('M115I', 'Mutation', 'rs377169736', (64, 69))	('G851R', 'Var', (76, 81))	('S204F', 'Var', (52, 57))	('P545H', 'SUBSTITUTION', 'None', (104, 109))	('S204F', 'Mutation', 'rs1451202946', (52, 57))	('D96N', 'Mutation', 'rs1305220034', (41, 45))	('P545H', 'Var', (104, 109))
56553	26609109	S204F is a structural residue of FAD binding domain II, linking the three domains forming the large cleft of DPYD.	('FAD binding', 'molecular_function', 'GO:0071949', ('33', '44'))	('S204F', 'Var', (0, 5))	('FAD', 'Chemical', 'MESH:D005182', (33, 36))	('S204F', 'Mutation', 'rs1451202946', (0, 5))	('DPYD', 'Gene', (109, 113))	('DPYD', 'Gene', '1806', (109, 113))
56554	26609109	S204F is part of an alpha-helix which directly bridges to residues L95I and N120S, affected by somatic mutations.	('L95I', 'Var', (67, 71))	('S204F', 'Var', (0, 5))	('S204F', 'Mutation', 'rs1451202946', (0, 5))	('N120S', 'Var', (76, 81))	('L95I', 'Mutation', 'rs75570676', (67, 71))	('N120S', 'Mutation', 'rs771534236', (76, 81))
56555	26609109	Similarly, Q828 is an anchor at domain IV and spans a hydrogen bond network to domain I via D96N, S99L, and M115I, affected by somatic mutations.	('hydrogen', 'Chemical', 'MESH:D006859', (54, 62))	('S99L', 'Var', (98, 102))	('S99L', 'Mutation', 'rs774456004', (98, 102))	('D96N', 'Mutation', 'rs1305220034', (92, 96))	('M115I', 'Var', (108, 113))	('M115I', 'Mutation', 'rs377169736', (108, 113))	('Q828', 'Var', (11, 15))	('D96N', 'Var', (92, 96))
56559	26609109	DPYD is mutated in 11.5% of primary tumors, while in metastatic tumors somatic mutations are detected in 22.5% of all whole exome-sequenced samples (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('DPYD', 'Gene', '1806', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('primary tumors', 'Disease', (28, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutated', 'Var', (8, 15))	('primary tumors', 'Disease', 'MESH:D009369', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('DPYD', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
56560	26609109	Comparison of gene expression and mutational data of DPYD and other key pyrimidine enzymes in SKCM shows that enrichment of somatic mutations in metastatic tumors coincides with elevated expression levels (Figure 5).	('mutations', 'Var', (132, 141))	('elevated', 'PosReg', (178, 186))	('DPYD', 'Gene', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('expression levels', 'MPA', (187, 204))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('pyrimidine', 'Chemical', 'MESH:C030986', (72, 82))	('DPYD', 'Gene', '1806', (53, 57))	('tumors', 'Disease', (156, 162))
56563	26609109	In addition, the direction of expression change in melanoma progression (up or down from tumor to metastasis) is the same as the difference between DPYD mutation and wild-type (up or down from wild-type to mutation, respectively).	('DPYD', 'Gene', (148, 152))	('DPYD', 'Gene', '1806', (148, 152))	('change', 'Reg', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('mutation', 'Var', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
56564	26609109	The observed deregulated gene expression of pyrimidine enzymes:including DPYD itself:correlates with metastatic progression and is enhanced by somatic DPYD mutations (Figure 5B, C).	('pyrimidine', 'Chemical', 'MESH:C030986', (44, 54))	('DPYD', 'Gene', '1806', (73, 77))	('pyrimidine enzymes', 'Enzyme', (44, 62))	('gene expression', 'biological_process', 'GO:0010467', ('25', '40'))	('mutations', 'Var', (156, 165))	('metastatic progression', 'CPA', (101, 123))	('DPYD', 'Gene', '1806', (151, 155))	('DPYD', 'Gene', (151, 155))	('enhanced', 'PosReg', (131, 139))	('DPYD', 'Gene', (73, 77))	('deregulated gene expression', 'MPA', (13, 40))
56565	26609109	Almost all differentially expressed pyrimidine enzymes (with the exception of POLR3D), which show up- or downregulation between primary and metastatic tumors, show progressive increase or decrease with DPYD mutation, respectively (Supplementary table 8).	('pyrimidine enzymes', 'Enzyme', (36, 54))	('up-', 'PosReg', (98, 101))	('DPYD', 'Gene', '1806', (202, 206))	('pyrimidine', 'Chemical', 'MESH:C030986', (36, 46))	('increase', 'PosReg', (176, 184))	('POLR3D', 'Gene', '661', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('downregulation', 'NegReg', (105, 119))	('decrease', 'NegReg', (188, 196))	('POLR3D', 'Gene', (78, 84))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('DPYD', 'Gene', (202, 206))	('mutation', 'Var', (207, 215))
56574	26609109	At a pathway level, somatic mutations in SKCM patients are most frequently observed in enzymes DPYD, DPYS, ENTPD1, CANT1, and UPP2 of pyrimidine degradation, as well as degradation of pyrimidine nucleoside triphosphates (q-value below 0.03) (Figure 6B, Supplementary Table 5).	('patients', 'Species', '9606', (46, 54))	('CANT1', 'Gene', '124583', (115, 120))	('SKCM', 'Gene', (41, 45))	('degradation of pyrimidine nucleoside triphosphates', 'MPA', (169, 219))	('pyrimidine nucleoside triphosphates', 'Chemical', '-', (184, 219))	('UPP2', 'Gene', '151531', (126, 130))	('DPYD', 'Gene', '1806', (95, 99))	('pyrimidine degradation', 'MPA', (134, 156))	('ENTPD1', 'Gene', '953', (107, 113))	('degradation', 'biological_process', 'GO:0009056', ('169', '180'))	('pyrimidine', 'Chemical', 'MESH:C030986', (184, 194))	('UPP2', 'Gene', (126, 130))	('DPYS', 'Gene', (101, 105))	('mutations', 'Var', (28, 37))	('ENTPD1', 'Gene', (107, 113))	('DPYS', 'Gene', '1807', (101, 105))	('pyrimidine', 'Chemical', 'MESH:C030986', (134, 144))	('observed', 'Reg', (75, 83))	('DPYD', 'Gene', (95, 99))	('degradation', 'biological_process', 'GO:0009056', ('145', '156'))	('CANT1', 'Gene', (115, 120))
56575	26609109	Somatic mutations of DPYD significantly enhance the signature of pyrimidine nucleoside triphosphates and nucleic acid generating enzymes CMPK1, AK9, NME7, POLA1, POLD3, POLK, POLR3F, POLR3G, PRIM2, and TWISTNB (p-value < 0.05) (Figure 6C, Supplementary Table 8).	('TWISTNB', 'Gene', (202, 209))	('nucleic acid', 'cellular_component', 'GO:0005561', ('105', '117'))	('AK9', 'Gene', '221264', (144, 147))	('POLD3', 'Gene', '10714', (162, 167))	('CMPK1', 'Gene', '51727', (137, 142))	('signature', 'MPA', (52, 61))	('DPYD', 'Gene', '1806', (21, 25))	('PRIM2', 'Gene', '5558', (191, 196))	('mutations', 'Var', (8, 17))	('POLR3F', 'Gene', (175, 181))	('POLK', 'Gene', '51426', (169, 173))	('POLR3G', 'Gene', '10622', (183, 189))	('TWISTNB', 'Gene', '221830', (202, 209))	('pyrimidine nucleoside triphosphates', 'Chemical', '-', (65, 100))	('POLR3G', 'Gene', (183, 189))	('PRIM2', 'Gene', (191, 196))	('POLK', 'Gene', (169, 173))	('NME7', 'Gene', (149, 153))	('DPYD', 'Gene', (21, 25))	('CMPK1', 'Gene', (137, 142))	('AK9', 'Gene', (144, 147))	('POLA1', 'Gene', (155, 160))	('NME7', 'Gene', '29922', (149, 153))	('POLD3', 'Gene', (162, 167))	('enhance', 'PosReg', (40, 47))	('POLA1', 'Gene', '5422', (155, 160))	('POLR3F', 'Gene', '10621', (175, 181))
56576	26609109	In addition, DPYD mutated samples show significantly increased DPYD transcript levels (p-value < 0.05).	('DPYD', 'Gene', (63, 67))	('mutated', 'Var', (18, 25))	('DPYD', 'Gene', '1806', (63, 67))	('DPYD', 'Gene', (13, 17))	('increased', 'PosReg', (53, 62))	('DPYD', 'Gene', '1806', (13, 17))
56580	26609109	The mutational analysis identified more than 130 unique and novel recurrent somatic mutations in DPYD, including recurrent missense, nonsense and splice site mutations (Supplementary table 7).	('DPYD', 'Gene', (97, 101))	('DPYD', 'Gene', '1806', (97, 101))	('missense', 'Var', (123, 131))	('mutations', 'Var', (84, 93))
56581	26609109	In addition, we were able to confirm frequently recurring deleterious mutations S204F and G275 frame shift (Figure 4A,C).	('S204F', 'Mutation', 'rs1451202946', (80, 85))	('G275 frame shift', 'Var', (90, 106))	('S204F', 'Var', (80, 85))
56584	26609109	Structural analysis of cancer driver BRAF showed unprecedented events in the RAS binding domain interface and the ATP binding pocket aside from established p.V600E/K/R/D substitutions.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('ATP binding', 'molecular_function', 'GO:0005524', ('114', '125'))	('BRAF', 'Gene', '673', (37, 41))	('p.V600E', 'Var', (156, 163))	('p.V600E', 'SUBSTITUTION', 'None', (156, 163))	('BRAF', 'Gene', (37, 41))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
56586	26609109	Events with three-time recurrence are detected in each of the functional domains with p.D96N (Fe-S cluster I-II), p.S204F (FAD binding domain), p.A323T/P/D (NADPH binding domain), and p.P545S/L/H (Pyrimidine binding domain).	('NADPH', 'Chemical', 'MESH:D009249', (157, 162))	('p.A323T', 'SUBSTITUTION', 'None', (144, 151))	('Pyrimidine binding', 'molecular_function', 'GO:0002061', ('197', '215'))	('p.S204F', 'SUBSTITUTION', 'None', (114, 121))	('FAD', 'Chemical', 'MESH:D005182', (123, 126))	('NADPH binding', 'molecular_function', 'GO:0070402', ('157', '170'))	('p.A323T', 'Var', (144, 151))	('p.P545S', 'SUBSTITUTION', 'None', (184, 191))	('p.D96N', 'Var', (86, 92))	('Pyrimidine', 'Chemical', 'MESH:C030986', (197, 207))	('p.D96N', 'Mutation', 'rs1305220034', (86, 92))	('p.P545S', 'Var', (184, 191))	('FAD binding', 'molecular_function', 'GO:0071949', ('123', '134'))	('p.S204F', 'Var', (114, 121))
56587	26609109	There are distinct areas of interest with high density of somatic recurrence of mutations in DPYD (Figure 4).	('DPYD', 'Gene', '1806', (93, 97))	('DPYD', 'Gene', (93, 97))	('mutations', 'Var', (80, 89))
56588	26609109	Two NADPH binding loops between V335 and G366 positions the nucleotide and initiate the electron transfer.	('NADPH', 'Chemical', 'MESH:D009249', (4, 9))	('NADPH binding', 'molecular_function', 'GO:0070402', ('4', '17'))	('electron transfer', 'biological_process', 'GO:0006118', ('88', '105'))	('V335', 'Var', (32, 36))	('electron transfer', 'biological_process', 'GO:0022904', ('88', '105'))	('initiate', 'Reg', (75, 83))	('G366', 'Var', (41, 45))	('electron transfer', 'MPA', (88, 105))	('nucleotide', 'MPA', (60, 70))
56589	26609109	Somatic mutations V335M, A437M, D291N, V362I, and G366I/S/V closely frame the nucleotide binding site and are expected to have reduced NADPH binding, similarly to the reduced affinity of reported variant G366A (Figure 4A).	('nucleotide binding', 'molecular_function', 'GO:0000166', ('78', '96'))	('A437M', 'Mutation', 'p.A437M', (25, 30))	('reduced', 'NegReg', (127, 134))	('V362I', 'Mutation', 'rs752020412', (39, 44))	('V335M', 'Mutation', 'rs72549306', (18, 23))	('A437M', 'Var', (25, 30))	('V335M', 'Var', (18, 23))	('binding', 'Interaction', (141, 148))	('D291N', 'Mutation', 'rs1327845774', (32, 37))	('G366A', 'Mutation', 'rs189046984', (204, 209))	('D291N', 'Var', (32, 37))	('G366I', 'SUBSTITUTION', 'None', (50, 55))	('NADPH binding', 'molecular_function', 'GO:0070402', ('135', '148'))	('NADPH', 'Chemical', 'MESH:D009249', (135, 140))	('G366I', 'Var', (50, 55))	('V362I', 'Var', (39, 44))	('NADPH', 'MPA', (135, 140))
56590	26609109	Recurring somatic mutations T575I, E611K, N668K, and G795E in pyrimidine and FMN binding site affect hydrogen bond network of enzymatic effector domain IV (Figure 4B).	('N668K', 'Var', (42, 47))	('T575I', 'Mutation', 'rs4648085', (28, 33))	('FMN binding', 'molecular_function', 'GO:0010181', ('77', '88'))	('G795E', 'Mutation', 'rs28897684', (53, 58))	('hydrogen', 'Chemical', 'MESH:D006859', (101, 109))	('hydrogen bond network', 'MPA', (101, 122))	('affect', 'Reg', (94, 100))	('pyrimidine', 'Chemical', 'MESH:C030986', (62, 72))	('E611K', 'Mutation', 'rs775917455', (35, 40))	('FMN', 'Chemical', 'MESH:D005486', (77, 80))	('T575I', 'Var', (28, 33))	('E611K', 'Var', (35, 40))	('N668K', 'Mutation', 'p.N668K', (42, 47))	('G795E', 'Var', (53, 58))
56592	26609109	E828 is engaged in a tight hydrogen bonding network to D96, S99, and M115, which are also affected by somatic mutations (Figure 4C).	('S99', 'Var', (60, 63))	('M115', 'Var', (69, 73))	('hydrogen', 'Chemical', 'MESH:D006859', (27, 35))	('E828', 'Var', (0, 4))	('D96', 'Var', (55, 58))
56593	26609109	E828K has demonstrated higher DPYD activity, stressing the importance of this hydrogen bonding network.	('hydrogen', 'Chemical', 'MESH:D006859', (78, 86))	('E828K', 'Mutation', 'rs200687447', (0, 5))	('higher', 'PosReg', (23, 29))	('E828K', 'Var', (0, 5))	('DPYD', 'Gene', (30, 34))	('DPYD', 'Gene', '1806', (30, 34))
56594	26609109	Somatic mutations in highly recurring sites D96N, S204F, P545L/S/H is associated with high PPH2 values of 1.0 indicating possibly damaging outcome of DPYD function.	('PPH2', 'Chemical', '-', (91, 95))	('P545L', 'Var', (57, 62))	('PPH', 'molecular_function', 'GO:0033978', ('91', '94'))	('S204F', 'Var', (50, 55))	('S204F', 'Mutation', 'rs1451202946', (50, 55))	('PPH', 'molecular_function', 'GO:0004238', ('91', '94'))	('D96N', 'Mutation', 'rs1305220034', (44, 48))	('PPH2 values', 'MPA', (91, 102))	('P545L', 'SUBSTITUTION', 'None', (57, 62))	('D96N', 'Var', (44, 48))	('DPYD', 'Gene', (150, 154))	('DPYD', 'Gene', '1806', (150, 154))
56596	26609109	Overall, the functional analysis of somatic mutations shows strong agreement with a comparative in vitro analyses of DPYD variants that somatic mutations have reduced DPYD activity (Supplementary table 7).	('DPYD', 'Gene', (117, 121))	('variants', 'Var', (122, 130))	('reduced', 'NegReg', (159, 166))	('DPYD', 'Gene', '1806', (117, 121))	('DPYD', 'Gene', (167, 171))	('DPYD', 'Gene', '1806', (167, 171))	('mutations', 'Var', (144, 153))
56605	26609109	The ribonucleotide reductases RRM1 responds to DPYD alteration, is significantly upregulated in metastatic melanoma, and bridges bottlenecks between deoxyribo- and ribonucleotides (Supplementary table 8, Figure 6C-D).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('RRM1', 'Gene', '6240', (30, 34))	('melanoma', 'Disease', (107, 115))	('upregulated', 'PosReg', (81, 92))	('RRM1', 'Gene', (30, 34))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('alteration', 'Var', (52, 62))	('DPYD', 'Gene', (47, 51))	('DPYD', 'Gene', '1806', (47, 51))
56613	26609109	Remarkably, mutated DPYD was found to be overexpressed in metastatic cells promoting synthesis of DNA and RNA (Figure 5).	('synthesis', 'biological_process', 'GO:0009058', ('85', '94'))	('mutated', 'Var', (12, 19))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('promoting', 'PosReg', (75, 84))	('DPYD', 'Gene', (20, 24))	('DPYD', 'Gene', '1806', (20, 24))
56614	26609109	In addition, somatic DPYD alterations co-occurred with mutations of tumor suppressors and DNA caretakers in melanoma patients.	('tumor', 'Disease', (68, 73))	('DPYD', 'Gene', '1806', (21, 25))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('mutations', 'Var', (55, 64))	('co-occurred', 'Reg', (38, 49))	('alterations', 'Reg', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('DPYD', 'Gene', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
56615	26609109	Deregulated pyrimidine catabolism may not only be connected to nucleotide anabolism but also negatively affect DNA maintenance and stability.	('stability', 'CPA', (131, 140))	('DNA maintenance', 'CPA', (111, 126))	('affect', 'Reg', (104, 110))	('Deregulated', 'Var', (0, 11))	('pyrimidine catabolism', 'MPA', (12, 33))	('nucleotide anabolism', 'biological_process', 'GO:0009165', ('63', '83'))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('negatively', 'NegReg', (93, 103))	('catabolism', 'biological_process', 'GO:0009056', ('23', '33'))	('connected', 'Reg', (50, 59))	('pyrimidine', 'Chemical', 'MESH:C030986', (12, 22))
56631	26609109	Recurring missense mutations accumulate in ligand binding sites as well as at domain interface between Fe4S4 clusters, FAD and pyrimidine binding.	('ligand', 'molecular_function', 'GO:0005488', ('43', '49'))	('FAD', 'Chemical', 'MESH:D005182', (119, 122))	('pyrimidine', 'Chemical', 'MESH:C030986', (127, 137))	('missense mutations', 'Var', (10, 28))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('ligand', 'MPA', (43, 49))	('pyrimidine binding', 'molecular_function', 'GO:0002061', ('127', '145'))
56632	26609109	The transcriptional data shows that mutated DPYD selectively activates components of pyrimidine metabolism.	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('85', '106'))	('pyrimidine', 'Chemical', 'MESH:C030986', (85, 95))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('85', '106'))	('activates', 'PosReg', (61, 70))	('DPYD', 'Gene', (44, 48))	('mutated', 'Var', (36, 43))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('85', '106'))	('DPYD', 'Gene', '1806', (44, 48))	('components of pyrimidine metabolism', 'MPA', (71, 106))
56635	26609109	At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression.	('DPYD', 'Gene', (49, 53))	('cause', 'Reg', (54, 59))	('promote', 'PosReg', (98, 105))	('DPYD', 'Gene', '1806', (49, 53))	('gene expression', 'biological_process', 'GO:0010467', ('106', '121'))	('switch', 'Reg', (62, 68))	('mutations', 'Var', (36, 45))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('72', '93'))	('gene expression', 'MPA', (106, 121))	('pyrimidine', 'Chemical', 'MESH:C030986', (72, 82))	('pyrimidine', 'Chemical', 'MESH:C030986', (125, 135))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('72', '93'))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('72', '93'))	('pyrimidine metabolism', 'MPA', (72, 93))
56683	18442364	On tissue sections, identification of melanoma cells was achieved with an antibody against the microphthalmia transcription factor MITF, which produces a specific nuclear signal in melanocytes.	('microphthalmia', 'Disease', (95, 109))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('MITF', 'Gene', (131, 135))	('produces', 'Reg', (143, 151))	('antibody', 'cellular_component', 'GO:0042571', ('74', '82'))	('microphthalmia', 'Phenotype', 'HP:0000568', (95, 109))	('antibody', 'Var', (74, 82))	('melanoma', 'Disease', (38, 46))	('transcription factor', 'molecular_function', 'GO:0000981', ('110', '130'))	('antibody', 'cellular_component', 'GO:0019815', ('74', '82'))	('microphthalmia', 'Disease', 'MESH:D008850', (95, 109))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('antibody', 'cellular_component', 'GO:0019814', ('74', '82'))	('nuclear signal', 'MPA', (163, 177))	('antibody', 'molecular_function', 'GO:0003823', ('74', '82'))
56710	18442364	The murine models require a combination of gain of function and loss of function mutations in a proto-oncogene and tumor suppressor gene, respectively.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('115', '131'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('gain of function', 'PosReg', (43, 59))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (81, 90))	('murine', 'Species', '10090', (4, 10))	('tumor suppressor', 'biological_process', 'GO:0051726', ('115', '131'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('loss of function', 'NegReg', (64, 80))
56719	18442364	In our SAGE analysis, the RACK1 tag was more abundant in the library established from primary culture of metastatic melanoma cells than in the library from normal skin melanocytes.	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('RACK1', 'Var', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))
56780	18442364	Tissues were fixed either in 4% PFA (n = 38) or in Bouin fixative (n = 2) and embedded in paraffin Mouse monoclonal antibodies were anti-MITF (1:50) (Zymed, Clinisciences, Montrouge, France) and anti-RACK1 (1:150) (Transduction Laboratories, BD Biosciences, Le Pont de Claix, France).	('anti-RACK1', 'Var', (195, 205))	('PFA', 'Chemical', 'MESH:C003043', (32, 35))	('Transduction', 'biological_process', 'GO:0009293', ('215', '227'))	('paraffin', 'Chemical', 'MESH:D010232', (90, 98))	('anti-MITF (1:50', 'Var', (132, 147))	('Mouse', 'Species', '10090', (99, 104))
56797	28781649	Consequently, 12 (12/57) melanoma tissues exhibited LKB1 promoter methylation, while only 2 (2/50) benign lesions presented with LKB1 hypermethylation.	('promoter', 'MPA', (57, 65))	('methylation', 'biological_process', 'GO:0032259', ('66', '77'))	('LKB1', 'Gene', (52, 56))	('methylation', 'Var', (66, 77))	('LKB1', 'Gene', '6794', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('LKB1', 'Gene', (129, 133))	('melanoma', 'Disease', (25, 33))	('LKB1', 'Gene', '6794', (129, 133))
56798	28781649	The frequency of LKB1 promoter methylation in melanoma was significantly increased compared with the benign controls (P<0.05).	('increased', 'PosReg', (73, 82))	('LKB1', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('LKB1', 'Gene', '6794', (17, 21))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('promoter', 'MPA', (22, 30))
56799	28781649	Additional statistical analysis demonstrated that hypermethylation of the LKB1 gene was correlated with Breslow's thickness, presence of ulceration and American Joint Committee on Cancer stage (P<0.05).	('correlated', 'Reg', (88, 98))	('hypermethylation', 'Var', (50, 66))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer', 'Disease', (180, 186))	("Breslow's thickness", 'Disease', (104, 123))	('LKB1', 'Gene', (74, 78))	('Cancer', 'Disease', 'MESH:D009369', (180, 186))	('LKB1', 'Gene', '6794', (74, 78))
56800	28781649	Additionally, Kaplan-Meier analysis revealed that LKB1 hypermethylation was significantly associated with poorer survival (P<0.01).	('hypermethylation', 'Var', (55, 71))	('LKB1', 'Gene', '6794', (50, 54))	('poorer', 'NegReg', (106, 112))	('LKB1', 'Gene', (50, 54))
56809	28781649	Several studies have demonstrated that the loss of LKB1 promotes metastasis in a number of tumor cell types, including melanoma cells.	('LKB1', 'Gene', (51, 55))	('metastasis in', 'CPA', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('LKB1', 'Gene', '6794', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('promotes', 'PosReg', (56, 64))	('loss', 'Var', (43, 47))	('tumor', 'Disease', (91, 96))
56811	28781649	LKB1 mutations were detected in certain types of sporadic cancers, including lung adenocarcinoma and cervical carcinoma.	('detected', 'Reg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('lung adenocarcinoma and cervical carcinoma', 'Disease', 'MESH:D000077192', (77, 119))	('LKB1', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('mutations', 'Var', (5, 14))	('LKB1', 'Gene', '6794', (0, 4))	('sporadic cancers', 'Disease', 'MESH:D009369', (49, 65))	('sporadic cancers', 'Disease', (49, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
56812	28781649	However, only 10% of patients with cutaneous melanoma have reported to exhibit mutations in the LKB1 gene, which means that genetic mutation is not the major mechanism for LKB1 gene inactivation, and there may be other mechanisms that mediate the lack of LKB1 expression.	('LKB1', 'Gene', (96, 100))	('LKB1', 'Gene', (255, 259))	('cutaneous melanoma', 'Disease', (35, 53))	('LKB1', 'Gene', '6794', (96, 100))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (35, 53))	('LKB1', 'Gene', '6794', (255, 259))	('LKB1', 'Gene', (172, 176))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (35, 53))	('patients', 'Species', '9606', (21, 29))	('LKB1', 'Gene', '6794', (172, 176))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('mutations', 'Var', (79, 88))
56813	28781649	Epigenetic alteration of tumor suppressor genes by aberrant methylation in promoter CpG islands has been acknowledged as an important mechanism for inactivation of gene expression.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (25, 30))	('inactivation', 'NegReg', (148, 160))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('gene expression', 'biological_process', 'GO:0010467', ('164', '179'))	('aberrant methylation', 'Var', (51, 71))	('Epigenetic alteration', 'Var', (0, 21))
56814	28781649	Previously, several studies have identified that hypermethylation of the LKB1 promoter region may be detected in certain cancer cell lines and primary tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('hypermethylation', 'Var', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('LKB1', 'Gene', (73, 77))	('tumor', 'Disease', (151, 156))	('detected', 'Reg', (101, 109))	('LKB1', 'Gene', '6794', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
56816	28781649	Whether epigenetic alteration of the LKB1 gene leads to an inactivation of LKB1 and a lack of LKB1 expression in melanoma remains unclear.	('expression', 'MPA', (99, 109))	('LKB1', 'Gene', (75, 79))	('LKB1', 'Gene', '6794', (37, 41))	('epigenetic alteration', 'Var', (8, 29))	('LKB1', 'Gene', '6794', (75, 79))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('lack', 'NegReg', (86, 90))	('melanoma', 'Disease', (113, 121))	('LKB1', 'Gene', (94, 98))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('LKB1', 'Gene', '6794', (94, 98))	('LKB1', 'Gene', (37, 41))	('inactivation', 'MPA', (59, 71))
56817	28781649	The aim of the present study was to investigate the status of LKB1 promoter methylation in human cutaneous melanoma and to evaluate the associations between aberrant LKB1 promoter methylation with clinicopathological features and prognosis in patients with melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('aberrant', 'Var', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('patients', 'Species', '9606', (243, 251))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('LKB1', 'Gene', (62, 66))	('LKB1', 'Gene', '6794', (62, 66))	('cutaneous melanoma', 'Disease', (97, 115))	('LKB1', 'Gene', (166, 170))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (97, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (97, 115))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('LKB1', 'Gene', '6794', (166, 170))	('melanoma', 'Disease', (257, 265))	('human', 'Species', '9606', (91, 96))
56842	28781649	Multivariate analysis was performed using the Cox proportional hazard models with a confidence interval of 95% to examine whether LKB1 promoter methylation was an independent prognostic factor for 5-year overall survival rates (OS).	('LKB1', 'Gene', (130, 134))	('methylation', 'Var', (144, 155))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('LKB1', 'Gene', '6794', (130, 134))
56843	28781649	The Kruskal-Wallis test was used to compare LKB1 expression between melanoma and benign lesions, methylated melanoma and the unmethylated.	('LKB1', 'Gene', '6794', (44, 48))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('methylated', 'Var', (97, 107))	('LKB1', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
56845	28781649	It was identified that 12/57 cases exhibited methylation amplification in melanoma tissues, while 2/50 benign controls displayed LKB1 promoter methylation.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('methylation', 'biological_process', 'GO:0032259', ('143', '154'))	('methylation amplification', 'Var', (45, 70))	('melanoma', 'Disease', (74, 82))	('LKB1', 'Gene', (129, 133))	('LKB1', 'Gene', '6794', (129, 133))
56846	28781649	The frequency of LKB1 promoter methylation was significantly increased in melanoma tissues compared with benign skin controls (chi2=6.747, P<0.05; Table I).	('LKB1', 'Gene', (17, 21))	('LKB1', 'Gene', '6794', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('melanoma', 'Disease', (74, 82))	('increased', 'PosReg', (61, 70))	('methylation', 'Var', (31, 42))	('promoter', 'MPA', (22, 30))
56853	28781649	Notably, significant differences in LKB1 expression were observed between benign lesions with melanomas, and between LKB1 methylated melanomas and unmethylated melanoma (P<0.05, Kruskal-Wallis test; Fig.	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Disease', (160, 168))	('LKB1', 'Gene', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('LKB1', 'Gene', (36, 40))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('expression', 'MPA', (41, 51))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('differences', 'Reg', (21, 32))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('LKB1', 'Gene', '6794', (117, 121))	('LKB1', 'Gene', '6794', (36, 40))	('methylated', 'Var', (122, 132))	('melanomas', 'Disease', (133, 142))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanomas', 'Disease', (94, 103))
56856	28781649	Statistical analysis revealed that LKB1 promoter methylation was closely associated with tumor Breslow's thickness (P=0.021), the presence of ulceration (P=0.002) and AJCC stage (P=0.006).	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('LKB1', 'Gene', (35, 39))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('methylation', 'Var', (49, 60))	('AJCC', 'Disease', (167, 171))	('LKB1', 'Gene', '6794', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
56859	28781649	It was identified that patients with LKB1 methylation exhibited a significantly shorter overall 5-year OS duration compared with those with unmethylated LKB1 (P<0.05; Fig.	('LKB1', 'Gene', '6794', (37, 41))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (80, 87))	('LKB1', 'Gene', (153, 157))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('methylation', 'Var', (42, 53))	('LKB1', 'Gene', '6794', (153, 157))	('LKB1', 'Gene', (37, 41))
56864	28781649	A previous study demonstrated that the loss of LKB1 serves an important role in tumor initiation and progression.	('LKB1', 'Gene', '6794', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor initiation', 'Disease', 'MESH:D009369', (80, 96))	('loss', 'Var', (39, 43))	('tumor initiation', 'Disease', (80, 96))	('LKB1', 'Gene', (47, 51))
56865	28781649	At present, the loss of LKB1 in different human tumors is involved in a combination of three molecular mechanisms, including mutation, loss of heterozygosity (LOH) and epigenetic modification.	('LKB1', 'Gene', (24, 28))	('human', 'Species', '9606', (42, 47))	('tumors', 'Disease', (48, 54))	('epigenetic modification', 'Var', (168, 191))	('LKB1', 'Gene', '6794', (24, 28))	('involved', 'Reg', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('loss', 'NegReg', (16, 20))	('loss of heterozygosity', 'Var', (135, 157))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutation', 'Var', (125, 133))
56866	28781649	Although LKB1 gene mutation was hypothesized as the primary mechanism of LKBI inactivation in Peutz-Jeghers syndrome (PJS) or PJS-associated tumors, results from Avizienyte et al suggested that mutational inactivation of LKB1 is a rare event in the majority of sporadic tumor types.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('LKBI', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('LKB1', 'Gene', '6794', (9, 13))	('mutation', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('mutational inactivation', 'Var', (194, 217))	('LKB1', 'Gene', '6794', (221, 225))	('Peutz-Jeghers syndrome', 'Disease', (94, 116))	('PJS', 'Disease', 'MESH:D010580', (118, 121))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('LKB1', 'Gene', (9, 13))	('PJS', 'Disease', 'MESH:D010580', (126, 129))	('tumor', 'Disease', (270, 275))	('inactivation', 'NegReg', (78, 90))	('PJS', 'Disease', (118, 121))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('LKB1', 'Gene', (221, 225))	('PJS', 'Disease', (126, 129))
56868	28781649	Trojan et al confirmed that the 5'-CpG islands of the LKB1 promoter region were methylated when analyzing a large series of paraffin embedded colorectal cancer specimens.	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('paraffin', 'Chemical', 'MESH:D010232', (124, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('colorectal cancer', 'Disease', (142, 159))	('methylated', 'Var', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('LKB1', 'Gene', (54, 58))	('LKB1', 'Gene', '6794', (54, 58))
56869	28781649	Esteller et al also demonstrated LKB1 promoter methylation in primary colorectal cancer specimens and suggested that LKB1 promoter methylation may mediate the inactivation of LKB1.	('LKB1', 'Gene', (175, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('LKB1', 'Gene', '6794', (33, 37))	('LKB1', 'Gene', '6794', (175, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('methylation', 'Var', (47, 58))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('LKB1', 'Gene', (117, 121))	('colorectal cancer', 'Disease', (70, 87))	('LKB1', 'Gene', (33, 37))	('LKB1', 'Gene', '6794', (117, 121))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('methylation', 'Var', (131, 142))
56871	28781649	Of the 57 cases, 12 cases of melanoma tissues exhibited LKB1 promoter methylation, and the frequency of LKB1 promoter methylation in melanoma tissues was significantly increased compared with benign skin lesion tissues.	('increased', 'PosReg', (168, 177))	('skin lesion', 'Disease', 'MESH:D012871', (199, 210))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('skin lesion', 'Disease', (199, 210))	('LKB1', 'Gene', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('exhibited', 'Reg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('LKB1', 'Gene', (56, 60))	('melanoma', 'Disease', (133, 141))	('LKB1', 'Gene', '6794', (104, 108))	('methylation', 'Var', (70, 81))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('LKB1', 'Gene', '6794', (56, 60))	('promoter', 'MPA', (61, 69))
56873	28781649	It was demonstrated that LKB1 methylation status was significantly associated with Breslow's thickness (P<0.05), the presence of ulceration (P<0.01) and AJCC stage (P<0.01).	('LKB1', 'Gene', (25, 29))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('LKB1', 'Gene', '6794', (25, 29))	('associated', 'Reg', (67, 77))	("Breslow's thickness", 'Disease', (83, 102))	('methylation status', 'Var', (30, 48))	('AJCC stage', 'Disease', (153, 163))
56875	28781649	The average duration of 5-year OS in patients with LKB1 methylation was significantly shorter compared with patients without LKB1 methylation.	('LKB1', 'Gene', (51, 55))	('methylation', 'biological_process', 'GO:0032259', ('130', '141'))	('shorter', 'NegReg', (86, 93))	('patients', 'Species', '9606', (37, 45))	('LKB1', 'Gene', (125, 129))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('LKB1', 'Gene', '6794', (51, 55))	('LKB1', 'Gene', '6794', (125, 129))	('patients', 'Species', '9606', (108, 116))	('methylation', 'Var', (56, 67))
56879	28781649	It was also demonstrated that downregulated LKB1 expression may be associated with LKB1 methylation.	('LKB1', 'Gene', '6794', (44, 48))	('methylation', 'Var', (88, 99))	('downregulated', 'NegReg', (30, 43))	('LKB1', 'Gene', (83, 87))	('expression', 'MPA', (49, 59))	('LKB1', 'Gene', '6794', (83, 87))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('LKB1', 'Gene', (44, 48))
56880	28781649	The role of LKB1 mutations and LOH in cutaneous melanoma requires confirmation, and it is possible that LKB1 loss is caused by a combination of factors.	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('LKB1', 'Gene', (104, 108))	('loss', 'NegReg', (109, 113))	('LKB1', 'Gene', '6794', (104, 108))	('mutations', 'Var', (17, 26))	('LKB1', 'Gene', (12, 16))	('cutaneous melanoma', 'Disease', (38, 56))	('LKB1', 'Gene', '6794', (12, 16))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
56881	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))
56883	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))	('TRIO', 'Gene', '7204', (43, 47))	('Galphaq', 'Gene', '2776', (13, 20))	('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))
56888	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.	('FAK', 'Gene', (32, 35))	('Gaq', 'Gene', (0, 3))	('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))
56892	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))
56893	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))
56894	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))
56895	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))	('oncogenic state', 'Disease', (82, 97))	('tumor', 'Disease', (115, 120))	('Aberrant activity', 'Var', (0, 17))	('promotion', 'PosReg', (102, 111))	('GPCRs', 'Protein', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('G proteins', 'Protein', (21, 31))
56905	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'))
56907	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))	('gene amplification', 'Var', (37, 55))	('CYSLTR2', 'Gene', '57105', (152, 159))	('CYSLTR2', 'Gene', '57105', (75, 82))	('GNA11', 'Gene', '2767', (143, 148))	('GNAQ', 'Gene', '2776', (137, 141))	('Galphaq', 'Gene', '2776', (180, 187))	('GNA11', 'Gene', (143, 148))	('GNAQ', 'Gene', (59, 63))	('GNA11', 'Gene', (65, 70))	('CYSLTR2', 'Gene', (152, 159))	('CYSLTR2', 'Gene', (75, 82))	('mutations', 'Var', (24, 33))	('Galphaq', 'Gene', (180, 187))	('GNA11', 'Gene', '2767', (65, 70))	('GNAQ', 'Gene', '2776', (59, 63))
56920	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))
56923	30773340	In total 56% of UM patients have alterations in PTK2 resulting in gene amplification or mRNA upregulation (Fig.	('upregulation', 'PosReg', (93, 105))	('patients', 'Species', '9606', (19, 27))	('PTK2', 'Gene', '5747', (48, 52))	('mRNA', 'MPA', (88, 92))	('alterations', 'Var', (33, 44))	('gene amplification', 'MPA', (66, 84))	('PTK2', 'Gene', (48, 52))
56924	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))
56926	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'))
56928	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))	('BRAF', 'Gene', (39, 43))	('MEK', 'Gene', '5609', (31, 34))	('EC50', 'MPA', (86, 90))
56929	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))	('reduced', 'NegReg', (24, 31))	('cell viability in', 'CPA', (32, 49))	('PTK2', 'Gene', (19, 23))	('PTK2', 'Gene', '5747', (19, 23))	('GNAQ', 'Gene', (100, 104))	('knockdown', 'Var', (6, 15))
56930	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'))
56931	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))
56932	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'))
56936	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))
56939	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'))	('activation', 'MPA', (117, 127))	('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))
56944	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))
56948	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))
56956	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))	('FAK', 'molecular_function', 'GO:0004717', ('181', '184'))	('knockdown', 'Var', (168, 177))	('GNAQ', 'Gene', '2776', (188, 192))	('FAKi', 'Gene', (159, 163))	('CTGF', 'Gene', (81, 85))
56957	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))
56958	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))
56960	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))
56970	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))
56971	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))
56972	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))	('dissociation', 'MPA', (64, 76))	('mutation', 'Var', (12, 20))	('rescued', 'PosReg', (52, 59))	('MOB1', 'Gene', (39, 43))
56973	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))
56974	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))
56975	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'))	('expression', 'Var', (27, 37))	('diminished', 'NegReg', (108, 118))	('MOB1-Y26F', 'Var', (41, 50))	('Y26F', 'Mutation', 'p.Y26F', (46, 50))
56977	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))
56979	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))
56984	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'))
56986	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))
56992	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))
56994	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))
56997	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))
57003	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))
57004	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))
57009	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))
57011	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))
57014	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))
57015	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'))
57016	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'))	('disassembly', 'MPA', (140, 151))	('MST1', 'Gene', (229, 233))	('mutation', 'Var', (313, 321))	('Hippo pathway', 'Pathway', (199, 212))	('disruption', 'NegReg', (181, 191))	('FAK', 'Var', (91, 94))
57017	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))
57026	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))
57030	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))
57034	30773340	Second, we further selected the genes whose inactivation leads to better patient survival in UM, thus potential target of a therapy.	('inactivation', 'Var', (44, 56))	('patient', 'Species', '9606', (73, 80))	('patient survival', 'CPA', (73, 89))	('better', 'PosReg', (66, 72))
57036	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))
57037	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))
57058	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))
57087	30458180	Overexpression of the integrin beta 1 (ITGbeta1) subunit often defines the invading front of skin tumors, and hyperactivation of ITGbeta1 can drive melanoma metastasis.	('ITGbeta1', 'Gene', (39, 47))	('ITGbeta1', 'Gene', (129, 137))	('skin tumors', 'Phenotype', 'HP:0008069', (93, 104))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('hyperactivation', 'Var', (110, 125))	('skin tumors', 'Disease', (93, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('melanoma metastasis', 'Disease', (148, 167))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('integrin beta 1', 'Gene', '3688', (22, 37))	('melanoma metastasis', 'Disease', 'MESH:D009362', (148, 167))	('drive', 'PosReg', (142, 147))	('skin tumors', 'Disease', 'MESH:D012878', (93, 104))	('integrin beta 1', 'Gene', (22, 37))
57125	30458180	Time-lapse TIRF microscopy revealed rapid turnover of small adhesions at leading and trailing edges in control cells (Figure 1b, subpanels ii and iii), while larger, radially-distributed FAs induced by forced NME1 expression exhibited slow, centripetal turnover (subpanels iv-vi; video files, Supplementary Figure 1).	('Ti', 'Chemical', 'MESH:D014025', (0, 2))	('forced', 'Var', (202, 208))	('expression', 'Var', (214, 224))	('NME1', 'Gene', (209, 213))
57128	30458180	Forced NME1 expression strongly enhanced adhesion to full length FN and a 110kDa proteolytic fragment containing the integrin-binding domain (Figure 2a).	('NME1', 'Gene', (7, 11))	('adhesion', 'MPA', (41, 49))	('integrin-binding', 'molecular_function', 'GO:0005178', ('117', '133'))	('expression', 'Var', (12, 22))	('FN', 'Gene', '2335', (65, 67))	('enhanced', 'PosReg', (32, 40))
57130	30458180	Thus, NME1 expression enhances integrin-mediated adhesion of melanoma cells to FN.	('integrin-mediated adhesion', 'MPA', (31, 57))	('enhances', 'PosReg', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('FN', 'Gene', '2335', (79, 81))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('expression', 'Var', (11, 21))	('NME1', 'Gene', (6, 10))
57132	30458180	NME1 also inhibited activation of three intracellular effectors of integrin signaling, FAK, SRC and p130Cas (Figure 2d).	('activation', 'MPA', (20, 30))	('intracellular', 'cellular_component', 'GO:0005622', ('40', '53'))	('signaling', 'biological_process', 'GO:0023052', ('76', '85'))	('p130Cas', 'Gene', '9564', (100, 107))	('inhibited', 'NegReg', (10, 19))	('Cas', 'cellular_component', 'GO:0005650', ('104', '107'))	('NME1', 'Var', (0, 4))	('FAK', 'molecular_function', 'GO:0004717', ('87', '90'))	('p130Cas', 'Gene', (100, 107))
57136	30458180	NME1 failed to regulate expression of ITGbeta1 transcripts in WM793 and WM1158 cells, however, nor was ITGbeta1 mRNA affected by ablation of the NME1 locus in mouse embryo fibroblasts (MEFs) (Figure 3a).	('NME1', 'Gene', (145, 149))	('ablation', 'Var', (129, 137))	('mouse', 'Species', '10090', (159, 164))	('MEFs', 'CellLine', 'CVCL:9115', (185, 189))	('WM1158', 'CellLine', 'CVCL:6785', (72, 78))	('affected', 'Reg', (117, 125))
57139	30458180	NME1 expression induced ITGbeta3 promoter activity by approximately 8-fold (Figure 3b, left) in M14 cells, and to a significant extent in WM1158 cells (Figure 3b, right).	('ITGbeta3', 'Protein', (24, 32))	('WM1158', 'CellLine', 'CVCL:6785', (138, 144))	('expression', 'Var', (5, 15))	('NME1', 'Gene', (0, 4))
57143	30458180	Co-enrichment of NME1 with the H3K27Ac modification within the ITGbeta3 promoter region demonstrates NME1 induces ITGbeta3 transcription via its DNA-binding function.	('induces', 'PosReg', (106, 113))	('DNA-binding', 'Interaction', (145, 156))	('H3K27Ac', 'Chemical', 'MESH:C024755', (31, 38))	('transcription', 'MPA', (123, 136))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('ITGbeta3', 'Gene', (114, 122))	('NME1', 'Var', (101, 105))	('DNA-binding', 'molecular_function', 'GO:0003677', ('145', '156'))	('H3K27Ac', 'Var', (31, 38))	('transcription', 'biological_process', 'GO:0006351', ('123', '136'))
57151	30458180	Herein, NME1 expression was shown to induce expression of ITGbeta3 at the surface of melanoma cells, driven by direct enhancement of ITGB3 transcription.	('expression', 'MPA', (44, 54))	('ITGbeta3', 'Gene', (58, 66))	('enhancement', 'PosReg', (118, 129))	('ITGB3', 'Gene', (133, 138))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('NME1', 'Gene', (8, 12))	('expression', 'Var', (13, 23))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('transcription', 'MPA', (139, 152))	('induce', 'PosReg', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('ITGB3', 'Gene', '3690', (133, 138))
57153	30458180	Binding of NME1 was detected at multiple sites within the ITGB3 promoter, and was augmented by forced NME1 expression.	('ITGB3', 'Gene', '3690', (58, 63))	('NME1', 'Gene', (102, 106))	('ITGB3', 'Gene', (58, 63))	('expression', 'Var', (107, 117))	('Binding', 'Interaction', (0, 7))	('augmented', 'PosReg', (82, 91))
57156	30458180	Puralpha/Purbeta) and transcription-enhancing factors that bind double-stranded DNA (e.g.	('Puralpha', 'Gene', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('Purbeta', 'Gene', (9, 16))	('Puralpha', 'Gene', '5813', (0, 8))	('Purbeta', 'Gene', '5813', (9, 16))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('bind', 'Interaction', (59, 63))	('double-stranded DNA', 'Var', (64, 83))
57158	30458180	Such a model could address how NME1 can both induce (ITGB3) and repress (ITGB1) transcriptional activity, or downregulate both genes in other cell types , depending on proteins and signaling pathways operative within a given cellular context.	('ITGB3', 'Gene', (53, 58))	('downregulate', 'NegReg', (109, 121))	('induce', 'PosReg', (45, 51))	('ITGB3', 'Gene', '3690', (53, 58))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('transcriptional activity', 'MPA', (80, 104))	('repress', 'MPA', (64, 71))	('ITGB1', 'Gene', (73, 78))	('NME1', 'Var', (31, 35))	('ITGB1', 'Gene', '3688', (73, 78))
57167	30458180	They also suggest loss of NME1 in advanced melanoma  converts ITGbeta3 to a metastasis driver.	('loss', 'Var', (18, 22))	('ITGbeta3', 'Gene', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('NME1', 'Gene', (26, 30))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))
57181	31552171	The target lesion control rate at 1-year was significantly higher in the ICI+RT group than in the RT-alone group or ICI-alone group (94.1% vs. 57.1% vs. 25%; P < 0.05).	('target lesion control', 'CPA', (4, 25))	('ICI', 'Chemical', 'MESH:C481040', (116, 119))	('higher', 'PosReg', (59, 65))	('ICI', 'Chemical', 'MESH:C481040', (73, 76))	('ICI+RT', 'Var', (73, 79))
57238	31552171	A BRAF mutation was reported in half of the patients in whom no BRAF mutation was detected.	('BRAF', 'Gene', '673', (64, 68))	('patients', 'Species', '9606', (44, 52))	('BRAF', 'Gene', '673', (2, 6))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', (2, 6))	('mutation', 'Var', (7, 15))
57352	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
57362	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('mutation', 'Var', (26, 34))	('tumour', 'Disease', (144, 150))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
57398	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
57399	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (15, 24))	('TCGA', 'Disease', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
57400	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('SKCM', 'Disease', (58, 62))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('BLCA', 'Disease', (76, 80))
57411	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
57412	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('hypermethylation', 'Var', (56, 72))	('tumour', 'Disease', (15, 21))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
57413	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
57414	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
57415	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('10', '29'))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
57416	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', '123036', (12, 16))	('TC2N', 'Gene', (12, 16))
57425	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
57429	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
57430	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('BLCA', 'Disease', (88, 92))	('non-synonymous mutation', 'Var', (23, 46))	('pathogenic', 'Reg', (12, 22))	('SKCM', 'Disease', (70, 74))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
57431	33247676	Whether these genetic mutations are causative or a sequel of cancer processes needs to be investigated.	('genetic mutations', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
57432	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('DNA', 'cellular_component', 'GO:0005574', ('312', '315'))	('tumour', 'Disease', (161, 167))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('susceptibility', 'MPA', (257, 271))	('metabolic wiring', 'CPA', (194, 210))	('altered', 'Reg', (186, 193))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
57441	33291726	Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis Global autozygosity in the form of runs of homozygosity is associated with various diseases.	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Global Autozygosity', 'Var', (0, 19))	('associated', 'Reg', (146, 156))	('Cancer', 'Disease', (39, 45))	('Associated', 'Reg', (23, 33))
57443	33291726	Our analysis shows strong and consistent associations between heterozygosity ratios and various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('heterozygosity ratios', 'Var', (62, 83))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
57444	33291726	Further analysis reveals the heterozygosity ratio's potential connections to mutational signatures and cancer prognosis.	('heterozygosity', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('connections', 'Reg', (62, 73))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
57446	33291726	From 4057 cancer subjects and 1668 healthy controls, we found strong associations between global autozygosity and risk in ten different cancer types.	('global autozygosity', 'Var', (90, 109))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
57447	33291726	For example, the heterozygosity ratio was found to be significantly associated with breast invasive carcinoma in Blacks and with male skin cutaneous melanoma in Caucasians.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('associated', 'Reg', (68, 78))	('heterozygosity ratio', 'Var', (17, 37))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('male skin cutaneous melanoma', 'Disease', 'MESH:D018567', (129, 157))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (84, 109))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (84, 109))	('breast invasive carcinoma', 'Disease', (84, 109))	('male skin cutaneous melanoma', 'Disease', (129, 157))
57450	33291726	According to the GWAS catalog (May 2020), 4424 unique SNPs have been found to influence cancer risk with p < 10-5 significance.	('influence', 'Reg', (78, 87))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SNPs', 'Var', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
57466	33291726	By comparing The Cancer Genome Atlas (TCGA) SNP data and reference allele in the GRCh38 genome, we estimated that around 8% of the variants in the human reference genome may not represent the major allele of the population.	('human', 'Species', '9606', (147, 152))	('Cancer', 'Disease', (17, 23))	('variants', 'Var', (131, 139))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))
57507	33291726	Linear regression models were used to describe the association between mutational signatures and HRNonRef and ROH.	('ROH', 'Chemical', '-', (110, 113))	('HRNonRef', 'Disease', (97, 105))	('association', 'Interaction', (51, 62))	('mutational signatures', 'Var', (71, 92))	('ROH', 'Disease', (110, 113))
57509	33291726	Five of the seven significant HRNonRef associations were from the ovarian cancer dataset, and consisted of SBS9 , SBS18 , SBS5 , SBS7c , and SBS22 .	('HRNonRef', 'Gene', (30, 38))	('SBS5', 'Var', (122, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (66, 80))	('ovarian cancer', 'Disease', (66, 80))	('SBS22', 'Var', (141, 146))	('SBS18', 'Var', (114, 119))	('SBS7c', 'Var', (129, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (66, 80))	('SBS9', 'Var', (107, 111))	('associations', 'Reg', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
57510	33291726	SBS18's etiology is proposed to be damaged by reactive oxygen species; SBS5's etiology is currently unknown; SBS7c is related to ultraviolet light damage and is possibly the consequence of translesion DNA synthesis by enzymes with a propensity to insert T, and SBS22 is related to aristolochic acid exposure.	('related', 'Reg', (118, 125))	('aristolochic acid', 'Chemical', 'MESH:C000228', (281, 298))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (46, 69))	('DNA synthesis', 'biological_process', 'GO:0071897', ('201', '214'))	('SBS7c', 'Var', (109, 114))
57511	33291726	The other two significant associations with HRNonRef were SBS44 (related to DNA mismatch repair,  in female skin cutaneous melanoma and SBS36 (related to defective base excision repair,  in prostate adenocarcinoma.	('mismatch repair', 'biological_process', 'GO:0006298', ('80', '95'))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('SBS44', 'Var', (58, 63))	('male skin cutaneous melanoma', 'Disease', (103, 131))	('base excision repair', 'biological_process', 'GO:0006284', ('164', '184'))	('prostate adenocarcinoma', 'Disease', (190, 213))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('SBS36', 'Var', (136, 141))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('male skin cutaneous melanoma', 'Disease', 'MESH:D018567', (103, 131))
57513	33291726	The other three significant associations with ROH were SBS36 ( in prostate adenocarcinoma, SBS42 (related to haloalkanes exposure, ) in male lung squamous cell carcinoma, and SBS7b (related to ultraviolet light exposure,  in males in male lung squamous cell carcinoma.	('prostate adenocarcinoma', 'Disease', (66, 89))	('SBS36', 'Gene', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('SBS42', 'Gene', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('ROH', 'Chemical', '-', (46, 49))	('haloalkanes', 'Chemical', '-', (109, 120))	('ROH', 'Gene', (46, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (239, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('SBS7b', 'Var', (175, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))
57518	33291726	Global autozygosity as a risk factor for diseases such as schizophrenia and Alzheimer's have been established.	('schizophrenia', 'Phenotype', 'HP:0100753', (58, 71))	('Alzheimer', 'Disease', 'MESH:D000544', (76, 85))	('Global autozygosity', 'Var', (0, 19))	('Alzheimer', 'Disease', (76, 85))	('schizophrenia', 'Disease', (58, 71))	('schizophrenia', 'Disease', 'MESH:D012559', (58, 71))
57525	33291726	The literature has shown that a single SNP can increase cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('increase', 'PosReg', (47, 55))	('SNP', 'Var', (39, 42))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('single SNP', 'Var', (32, 42))
57528	33291726	For example, germline variants in RBFOX1 increased the incidence of SF3B1 somatic mutation eight-fold via functional alterations in RNA splicing, and 19p13.3 variants were associated with a four-fold increased likelihood of somatic mutations in PTEN.	('alterations', 'Reg', (117, 128))	('RBFOX1', 'Gene', (34, 40))	('increased', 'PosReg', (41, 50))	('SF3B1', 'Gene', (68, 73))	('mutation', 'Var', (82, 90))	('variants', 'Var', (158, 166))	('RNA splicing', 'MPA', (132, 144))	('RNA splicing', 'biological_process', 'GO:0008380', ('132', '144'))	('PTEN', 'Gene', (245, 249))	('PTEN', 'Gene', '5728', (245, 249))	('SF3B1', 'Gene', '23451', (68, 73))	('RBFOX1', 'Gene', '54715', (34, 40))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))
57547	33291726	The associations between mutational signatures and HRNonRef/ROH were found by linear regression (R glm function with family = Gaussian parameter).	('HRNonRef/ROH', 'Disease', (51, 63))	('mutational signatures', 'Var', (25, 46))	('ROH', 'Chemical', '-', (60, 63))	('associations', 'Interaction', (4, 16))
57552	33291726	More importantly, our study demonstrates the connections between global autozygosity and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('connections', 'Interaction', (45, 56))	('cancer', 'Disease', (89, 95))	('global autozygosity', 'Var', (65, 84))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
57555	33291726	Further evidence was identified by exploring the associations between global autozygosity, mutational signatures, and cancer prognosis.	('cancer', 'Disease', (118, 124))	('associations', 'Interaction', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational', 'Var', (91, 101))	('global autozygosity', 'Var', (70, 89))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
57559	33291726	This research was supported by the Cancer Center Support Grant P30CA118100 and R01ES030993-01A1 from the National Cancer Institute of USA.	('R01ES030993-01A1', 'Var', (79, 95))	('P30CA118100', 'Var', (63, 74))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('R01ES030993-01A1', 'CellLine', 'CVCL:D092', (79, 95))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))
57561	32517051	Most genetic aberrations in melanoma result in hyperactivation of the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways.	('melanoma', 'Disease', (28, 36))	('PI3K', 'molecular_function', 'GO:0016303', ('141', '145'))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('phosphoinositide 3-kinase', 'Gene', '5294', (114, 139))	('genetic aberrations', 'Var', (5, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('104', '108'))	('hyperactivation', 'PosReg', (47, 62))	('phosphoinositide 3-kinase', 'Gene', (114, 139))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
57564	32517051	In this review we consider the functional implications of aberrant mRNA translation in melanoma and other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('melanoma', 'Disease', (87, 95))	('translation', 'biological_process', 'GO:0006412', ('72', '83'))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('aberrant', 'Var', (58, 66))	('malignancies', 'Disease', (106, 118))	('mRNA translation', 'MPA', (67, 83))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
57568	32517051	Specific mutations in melanoma may be more predominant within particular pathological subtypes.	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('mutations', 'Var', (9, 18))	('melanoma', 'Disease', (22, 30))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))
57569	32517051	For instance, The Cancer Genome Atlas (TCGA) defined three genomic subtypes of cutaneous melanoma based on the mutation status of BRAF, NRAS, NF1, and a fourth subgroup termed triple wild-type.	('cutaneous melanoma', 'Disease', (79, 97))	('NF1', 'Gene', '4763', (142, 145))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('BRAF', 'Gene', (130, 134))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NRAS', 'Gene', (136, 140))	('mutation', 'Var', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Disease', (18, 24))	('NRAS', 'Gene', '4893', (136, 140))	('NF1', 'Gene', (142, 145))
57570	32517051	Acral and mucosal melanomas, on the other hand, harbor distinct mutations, namely in the gene encoding the c-KIT receptor tyrosine kinase (RTK), while uveal melanomas often present with mutations in GNAQ/11.	('GNAQ/11', 'Gene', (199, 206))	('uveal melanomas', 'Phenotype', 'HP:0007716', (151, 166))	('RTK', 'Gene', (139, 142))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('c-KIT', 'Gene', (107, 112))	('present', 'Reg', (173, 180))	('melanomas', 'Disease', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('mutations', 'Var', (64, 73))	('c-KIT', 'Gene', '3815', (107, 112))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('mucosal melanomas', 'Disease', (10, 27))	('melanomas', 'Disease', 'MESH:D008545', (157, 166))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('melanomas', 'Disease', (157, 166))	('mutations', 'Var', (186, 195))	('KIT', 'molecular_function', 'GO:0005020', ('109', '112'))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
57571	32517051	BRAF mutations are mostly caused by single nucleotide substitutions, of which approximately 90% occur at codon 600, where a valine residue is swapped with glutamic acid (BRAFV600E).	('valine', 'Chemical', 'MESH:D014633', (124, 130))	('glutamic acid', 'Chemical', 'MESH:D018698', (155, 168))	('BRAF', 'Disease', (0, 4))	('BRAFV600E', 'Mutation', 'rs113488022', (170, 179))	('mutations', 'Var', (5, 14))	('caused', 'Reg', (26, 32))	('single nucleotide substitutions', 'Var', (36, 67))
57572	32517051	This specific mutation results in the constitutive activation of the BRAF oncoprotein and sustained activation of the MEK/ERK pathway (Figure 1), while also conferring insensitivity to negative feedback regulation of the mitogen-activated protein kinase (MAPK) pathway.	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('MAPK', 'molecular_function', 'GO:0004707', ('255', '259'))	('MEK', 'Gene', (118, 121))	('mutation', 'Var', (14, 22))	('BRAF oncoprotein', 'Protein', (69, 85))	('ERK', 'Gene', '5594', (122, 125))	('regulation', 'biological_process', 'GO:0065007', ('203', '213'))	('ERK', 'Gene', (122, 125))	('activation', 'PosReg', (100, 110))	('MEK', 'Gene', '5609', (118, 121))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('activation', 'PosReg', (51, 61))
57573	32517051	BRAF mutations account for approximately 52% of cutaneous melanoma mutations, compared to only 6% in mucosal melanoma.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (67, 76))	('mucosal melanoma', 'Disease', (101, 117))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mucosal melanoma', 'Disease', 'MESH:D008545', (101, 117))
57574	32517051	While BRAF mutations are the most prevalent in cutaneous melanoma, NRAS mutations display more aggressive phenotypes with increased mitotic rate, thicker primary tumors, and poorer prognosis.	('mutations', 'Var', (72, 81))	('mutations', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('NRAS', 'Gene', (67, 71))	('BRAF', 'Gene', (6, 10))	('cutaneous melanoma', 'Disease', (47, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (47, 65))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('increased', 'PosReg', (122, 131))	('mitotic rate', 'CPA', (132, 144))	('NRAS', 'Gene', '4893', (67, 71))	('prevalent', 'Reg', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
57575	32517051	Mutations in NRAS account for approximately 28% of cutaneous melanoma, of which more than 80% harbor a glutamine-to-leucine substitution (NRASQ61L), thus compromising the intrinsic GTPase activity of NRAS and increasing its GTP-bound form.	('NRAS', 'Gene', '4893', (13, 17))	('NRAS', 'Gene', (200, 204))	('GTP', 'Chemical', 'MESH:D006160', (224, 227))	('Mutations', 'Var', (0, 9))	('glutamine', 'Chemical', 'MESH:D005973', (103, 112))	('leucine', 'Chemical', 'MESH:D007930', (116, 123))	('NRAS', 'Gene', '4893', (138, 142))	('increasing', 'PosReg', (209, 219))	('GTP-bound form', 'MPA', (224, 238))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('NRAS', 'Gene', (13, 17))	('intrinsic', 'MPA', (171, 180))	('cutaneous melanoma', 'Disease', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('GTP', 'Chemical', 'MESH:D006160', (181, 184))	('NRAS', 'Gene', '4893', (200, 204))	('compromising', 'NegReg', (154, 166))	('GTPase activity', 'molecular_function', 'GO:0003924', ('181', '196'))	('NRAS', 'Gene', (138, 142))
57578	32517051	Mutations in the tumor suppressor NF1 are observed in approximately 14% of cutaneous melanoma, of which 63% are characterized by a loss-of-function.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('NF1', 'Gene', (34, 37))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('NF1', 'Gene', '4763', (34, 37))	('observed', 'Reg', (42, 50))
57579	32517051	Tumors that are negative for BRAF, NRAS, and NF1 mutations are termed triple wild-type and include a wide array of altered genes that may play a role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mutations', 'Var', (49, 58))	('NRAS', 'Gene', (35, 39))	('NRAS', 'Gene', '4893', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('NF1', 'Gene', (45, 48))	('NF1', 'Gene', '4763', (45, 48))
57580	32517051	For instance, mutations in KIT, the gene encoding the c-KIT receptor, account for 22% of triple wild-type tumors.	('KIT', 'Gene', '3815', (56, 59))	('c-KIT', 'Gene', '3815', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('KIT', 'Gene', (56, 59))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('KIT', 'molecular_function', 'GO:0005020', ('56', '59'))	('KIT', 'Gene', '3815', (27, 30))	('c-KIT', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('KIT', 'Gene', (27, 30))	('account', 'Reg', (70, 77))	('mutations', 'Var', (14, 23))	('KIT', 'molecular_function', 'GO:0005020', ('27', '30'))
57581	32517051	Oncogenic alterations in KIT include translocations within exons 11 and 13 (L576P and K624E, respectively), thus resulting in constitutive activation of c-KIT and subsequent activation of the PI3K/AKT and MAPK pathways (Figure 1).	('activation', 'PosReg', (139, 149))	('MAPK', 'molecular_function', 'GO:0004707', ('205', '209'))	('L576P', 'Mutation', 'rs121913513', (76, 81))	('AKT', 'Gene', (197, 200))	('L576P', 'Var', (76, 81))	('PI3K', 'molecular_function', 'GO:0016303', ('192', '196'))	('KIT', 'Gene', '3815', (155, 158))	('MAPK pathways', 'Pathway', (205, 218))	('KIT', 'Gene', (25, 28))	('AKT', 'Gene', '207', (197, 200))	('c-KIT', 'Gene', (153, 158))	('K624E', 'Mutation', 'p.K624E', (86, 91))	('activation', 'PosReg', (174, 184))	('c-KIT', 'Gene', '3815', (153, 158))	('KIT', 'molecular_function', 'GO:0005020', ('155', '158'))	('K624E', 'Var', (86, 91))	('KIT', 'Gene', '3815', (25, 28))	('KIT', 'molecular_function', 'GO:0005020', ('25', '28'))	('KIT', 'Gene', (155, 158))
57582	32517051	Several therapies have been designed to target the most frequent mutations in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('cutaneous melanoma', 'Disease', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))	('mutations', 'Var', (65, 74))
57587	32517051	Furthermore, BRAF inhibition can paradoxically activate wild-type CRAF, and continued monotherapy with vemurafenib following the onset of resistance may further support tumor progression.	('wild-type', 'CPA', (56, 65))	('activate', 'PosReg', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('CRAF', 'Gene', (66, 70))	('CRAF', 'Gene', '5894', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('vemurafenib', 'Chemical', 'MESH:D000077484', (103, 114))	('tumor', 'Disease', (169, 174))	('CRAF', 'molecular_function', 'GO:0004709', ('66', '70'))	('inhibition', 'Var', (18, 28))	('BRAF', 'Protein', (13, 17))	('support', 'PosReg', (161, 168))
57590	32517051	Some of these include BRAF amplification, oncogenic NRAS mutations, and MEK1/2 mutations, in addition to a PAX3-mediated upregulation of MITF in approximately 80% of melanoma during early stages of resistance.	('NRAS', 'Gene', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1', 'molecular_function', 'GO:0004708', ('72', '76'))	('upregulation', 'PosReg', (121, 133))	('MEK1/2', 'Gene', (72, 78))	('MITF', 'Gene', (137, 141))	('MITF', 'Gene', '4286', (137, 141))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('NRAS', 'Gene', '4893', (52, 56))	('BRAF', 'Gene', (22, 26))	('mutations', 'Var', (57, 66))	('PAX3', 'Gene', (107, 111))	('PAX3', 'Gene', '5077', (107, 111))	('amplification', 'Var', (27, 40))	('mutations', 'Var', (79, 88))
57592	32517051	Loss of other tumor suppressors such as PTEN, TP53, or CDKN2A may also account for the increased aggressiveness of BRAF-mutated tumors.	('CDKN2A', 'Gene', '1029', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('TP53', 'Gene', '7157', (46, 50))	('Loss', 'NegReg', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('aggressiveness', 'Disease', (97, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (97, 111))	('PTEN', 'Gene', (40, 44))	('aggressiveness', 'Disease', 'MESH:D001523', (97, 111))	('tumor', 'Disease', (128, 133))	('CDKN2A', 'Gene', (55, 61))	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BRAF-mutated', 'Var', (115, 127))	('tumor', 'Disease', (14, 19))	('TP53', 'Gene', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
57593	32517051	For instance, co-occurrence of BRAFV600E and loss of PTEN manifest in approximately 20% of melanomas and show increased metastatic potential.	('melanomas', 'Disease', (91, 100))	('BRAFV600E', 'Var', (31, 40))	('BRAFV600E', 'Mutation', 'rs113488022', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('increased', 'PosReg', (110, 119))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('PTEN', 'Gene', (53, 57))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('loss', 'NegReg', (45, 49))	('metastatic potential', 'CPA', (120, 140))
57600	32517051	In a phase-II clinical trial conducted in 28 patients with melanoma harboring c-KIT mutations or amplifications, treatment with imatinib yielded a durable response rate of 16%, with responses lasting more than one year.	('c-KIT', 'Gene', '3815', (78, 83))	('imatinib', 'Chemical', 'MESH:D000068877', (128, 136))	('KIT', 'molecular_function', 'GO:0005020', ('80', '83'))	('melanoma', 'Disease', (59, 67))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('c-KIT', 'Gene', (78, 83))	('amplifications', 'Var', (97, 111))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
57601	32517051	More recently, ponatinib has been shown to exhibit greater potency than imatinib in inhibiting tumor growth in melanomas harboring KIT mutations, likely because of an increased ponatinib-KIT affinity.	('imatinib', 'Chemical', 'MESH:D000068877', (72, 80))	('KIT', 'Gene', (187, 190))	('ponatinib', 'Chemical', 'MESH:C545373', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ponatinib', 'Chemical', 'MESH:C545373', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('affinity', 'Interaction', (191, 199))	('KIT', 'Gene', (131, 134))	('mutations', 'Var', (135, 144))	('KIT', 'molecular_function', 'GO:0005020', ('131', '134'))	('KIT', 'Gene', '3815', (187, 190))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('KIT', 'molecular_function', 'GO:0005020', ('187', '190'))	('melanomas', 'Disease', (111, 120))	('tumor', 'Disease', (95, 100))	('KIT', 'Gene', '3815', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('inhibiting', 'NegReg', (84, 94))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
57603	32517051	Once again, mechanisms of resistance hamper the therapeutic benefits of RTK inhibitors, including amplification or overexpression of KIT, other simultaneous activating alterations in NRAS, and secondary mutations in the activation loop of c-KIT.	('NRAS', 'Gene', (183, 187))	('KIT', 'molecular_function', 'GO:0005020', ('241', '244'))	('activating', 'PosReg', (157, 167))	('NRAS', 'Gene', '4893', (183, 187))	('KIT', 'Gene', '3815', (133, 136))	('hamper', 'NegReg', (37, 43))	('amplification', 'Var', (98, 111))	('KIT', 'Gene', (133, 136))	('KIT', 'molecular_function', 'GO:0005020', ('133', '136'))	('KIT', 'Gene', '3815', (241, 244))	('c-KIT', 'Gene', '3815', (239, 244))	('c-KIT', 'Gene', (239, 244))	('mutations', 'Var', (203, 212))	('alterations', 'Var', (168, 179))	('overexpression', 'PosReg', (115, 129))	('KIT', 'Gene', (241, 244))
57604	32517051	Furthermore, the L576P mutation in KIT, represented in approximately 34% of KIT mutations, confers poor sensitivity to imatinib in GIST.	('KIT', 'Gene', '3815', (76, 79))	('L576P', 'Mutation', 'rs121913513', (17, 22))	('KIT', 'Gene', (76, 79))	('L576P', 'Var', (17, 22))	('poor', 'NegReg', (99, 103))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('sensitivity to imatinib', 'MPA', (104, 127))	('KIT', 'molecular_function', 'GO:0005020', ('35', '38'))	('KIT', 'Gene', '3815', (35, 38))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('GIST', 'Phenotype', 'HP:0100723', (131, 135))	('KIT', 'Gene', (35, 38))
57605	32517051	In the context of melanoma where the L576P is the most common KIT mutation, patients show increased sensitivity to dasatinib.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('patients', 'Species', '9606', (76, 84))	('increased', 'PosReg', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('KIT', 'molecular_function', 'GO:0005020', ('62', '65'))	('sensitivity to dasatinib', 'MPA', (100, 124))	('KIT', 'Gene', '3815', (62, 65))	('dasatinib', 'Chemical', 'MESH:D000069439', (115, 124))	('L576P', 'Mutation', 'rs121913513', (37, 42))	('L576P', 'Var', (37, 42))	('melanoma', 'Disease', (18, 26))	('KIT', 'Gene', (62, 65))
57606	32517051	Melanoma cells expressing dual activating mutations in KIT (e.g., L576P/T670I or A829P) while being resistant to imatinib, nilotinib, and dasatinib, did exhibit increased sensitivity to dual inhibition of the MAPK and PI3K pathways.	('MAPK', 'molecular_function', 'GO:0004707', ('209', '213'))	('sensitivity', 'MPA', (171, 182))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('KIT', 'Gene', '3815', (55, 58))	('Melanoma', 'Disease', (0, 8))	('L576P', 'Mutation', 'rs121913513', (66, 71))	('activating', 'PosReg', (31, 41))	('T670I', 'Mutation', 'rs121913516', (72, 77))	('L576P/T670I', 'Var', (66, 77))	('increased', 'PosReg', (161, 170))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('nilotinib', 'Chemical', 'MESH:C498826', (123, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (138, 147))	('imatinib', 'Chemical', 'MESH:D000068877', (113, 121))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('KIT', 'Gene', (55, 58))	('A829P', 'Var', (81, 86))	('A829P', 'Mutation', 'rs1057519713', (81, 86))	('PI3K', 'molecular_function', 'GO:0016303', ('218', '222'))
57612	32517051	Hypophosphorylated 4E-BPs sequester eIF4E from binding to eIF4G, thus preventing formation of the translation initiation complex, while phosphorylation of 4E-BPs by mTOR releases eIF4E and activates translation (Figure 1).	('preventing', 'NegReg', (70, 80))	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('eIF4', 'cellular_component', 'GO:0008304', ('179', '183'))	('activates', 'PosReg', (189, 198))	('translation', 'biological_process', 'GO:0006412', ('199', '210'))	('translation initiation', 'biological_process', 'GO:0006413', ('98', '120'))	('phosphorylation', 'Var', (136, 151))	('4E-BPs', 'Chemical', '-', (155, 161))	('eIF4', 'cellular_component', 'GO:0008304', ('58', '62'))	('eIF4G', 'Gene', (58, 63))	('translation initiation complex', 'cellular_component', 'GO:0070992', ('98', '128'))	('translation', 'MPA', (199, 210))	('mTOR', 'Gene', (165, 169))	('eIF4', 'cellular_component', 'GO:0008304', ('36', '40'))	('eIF4E', 'MPA', (179, 184))	('4E-BPs', 'Chemical', '-', (19, 25))	('eIF4G', 'Gene', '1981', (58, 63))	('binding', 'molecular_function', 'GO:0005488', ('47', '54'))	('formation of the translation initiation complex', 'MPA', (81, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('136', '151'))	('mTOR', 'Gene', '2475', (165, 169))	('binding', 'Interaction', (47, 54))
57615	32517051	Increased levels of eIF4E are associated with poor prognosis in many cancer types including breast, melanoma, prostate, gallbladder, colorectal adenocarcinoma, and hepatocellular carcinoma and correlate with advancing tumor grade in squamous cell carcinoma and esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('eIF4E', 'Var', (20, 25))	('breast', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (218, 223))	('prostate', 'Disease', (110, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('colorectal adenocarcinoma', 'Disease', (133, 158))	('squamous cell carcinoma', 'Disease', (233, 256))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('hepatocellular carcinoma', 'Disease', (164, 188))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (133, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('Increased', 'PosReg', (0, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Disease', (69, 75))	('gallbladder', 'Disease', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))	('cancer', 'Disease', (272, 278))	('eIF4', 'cellular_component', 'GO:0008304', ('20', '24'))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))
57619	32517051	Moreover, while upstream components of the MAPK and PI3K pathways often show a heterogeneous expression pattern in tumors, the expression of phospho-eIF4E and phospho-4E-BP are more diffuse within the tumor and are overexpressed in breast cancer.	('breast cancer', 'Disease', (232, 245))	('phospho-4E-BP', 'Chemical', '-', (159, 172))	('tumor', 'Disease', (115, 120))	('heterogeneous expression', 'MPA', (79, 103))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', (201, 206))	('MAPK', 'molecular_function', 'GO:0004707', ('43', '47'))	('phospho-4E-BP', 'Var', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Disease', (115, 121))	('overexpressed', 'PosReg', (215, 228))	('phospho-eIF4E', 'Var', (141, 154))	('eIF4', 'cellular_component', 'GO:0008304', ('149', '153'))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))
57633	32517051	This results in an unusual DFD-out, auto-inhibited conformation in which the phenylalanine residue flips into the ATP binding pocket hindering the accessibility of ATP.	('DFD', 'Chemical', 'MESH:C100107', (27, 30))	('DFD-out', 'Disease', (27, 34))	('ATP binding', 'molecular_function', 'GO:0005524', ('114', '125'))	('ATP', 'Chemical', 'MESH:D000255', (164, 167))	('accessibility of ATP', 'MPA', (147, 167))	('flips', 'PosReg', (99, 104))	('ATP', 'Chemical', 'MESH:D000255', (114, 117))	('phenylalanine', 'Chemical', 'MESH:D010649', (77, 90))	('phenylalanine residue', 'Var', (77, 98))	('hindering', 'NegReg', (133, 142))
57638	32517051	While the MNK2b isoform has been suggested to possess pro-tumorigenic activity, MNK2a is thought to have tumor suppressive effects through phosphorylation, activation, and nuclear translocation of p38, thus causing stress-induced cell death.	('p38', 'Gene', '5594', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('phosphorylation', 'MPA', (139, 154))	('MNK2a', 'Var', (80, 85))	('cell death', 'biological_process', 'GO:0008219', ('230', '240'))	('nuclear', 'MPA', (172, 179))	('activation', 'PosReg', (156, 166))	('p38', 'Gene', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('causing', 'Reg', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('phosphorylation', 'biological_process', 'GO:0016310', ('139', '154'))	('tumor', 'Disease', (105, 110))
57643	32517051	Interestingly, in nasopharyngeal carcinoma (NPC), astrocytoma, and epithelial ovarian cancer tissues, immunohistochemistry (IHC) was used to show expression of MNK1 or phospho-MNK1 in the nuclei, whereas phospho-eIF4E was more readily observed in the cytoplasm.	('phospho-MNK1', 'Var', (168, 180))	('NPC', 'cellular_component', 'GO:0005643', ('44', '47'))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('epithelial ovarian cancer', 'Disease', (67, 92))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (67, 92))	('NPC', 'Phenotype', 'HP:0100630', (44, 47))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (18, 42))	('eIF4', 'cellular_component', 'GO:0008304', ('212', '216'))	('astrocytoma', 'Disease', 'MESH:D001254', (50, 61))	('cytoplasm', 'cellular_component', 'GO:0005737', ('251', '260'))	('MNK1', 'Var', (160, 164))	('astrocytoma', 'Disease', (50, 61))	('carcinoma', 'Disease', (33, 42))	('astrocytoma', 'Phenotype', 'HP:0009592', (50, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('carcinoma', 'Disease', 'MESH:D009369', (33, 42))
57645	32517051	Importantly, high levels of MNK2 also correlated with poorer prognosis in NSCLC adenocarcinomas and stage III and IV patients.	('poorer', 'NegReg', (54, 60))	('high levels', 'Var', (13, 24))	('NSCLC adenocarcinomas', 'Disease', (74, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('NSCLC adenocarcinomas', 'Disease', 'MESH:D000230', (74, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('MNK2', 'Protein', (28, 32))	('patients', 'Species', '9606', (117, 125))
57653	32517051	PSF is associated with poor prognosis in ER+ breast cancer cells, and knockdown of PSF results in a marked reduction of proliferation and increased apoptosis in colon cancer cells.	('proliferation', 'CPA', (120, 133))	('PSF', 'Gene', (83, 86))	('knockdown', 'Var', (70, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('apoptosis', 'CPA', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('reduction', 'NegReg', (107, 116))	('increased', 'PosReg', (138, 147))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('PSF', 'Gene', '6421', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('PSF', 'Gene', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('colon cancer', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('PSF', 'Gene', '6421', (83, 86))
57659	32517051	Furic and colleagues showed that immortalized mouse embryonic fibroblasts (MEFs) harboring a non-phosphorylated eIF4E (eIF4ES209A/S209A) are resistant to Ras-induced transformation, and their translation of specific mRNAs is reduced when compared to Wild-Type (WT) MEFs.	('translation of specific mRNAs', 'MPA', (192, 221))	('MEFs', 'CellLine', 'CVCL:9115', (75, 79))	('resistant', 'CPA', (141, 150))	('S209A', 'Mutation', 'p.S209A', (124, 129))	('eIF4', 'cellular_component', 'GO:0008304', ('119', '123'))	('eIF4ES209A/S209A', 'Var', (119, 135))	('translation', 'biological_process', 'GO:0006412', ('192', '203'))	('reduced', 'NegReg', (225, 232))	('mouse', 'Species', '10090', (46, 51))	('eIF4E', 'Gene', (112, 117))	('eIF4', 'cellular_component', 'GO:0008304', ('112', '116'))	('S209A', 'Mutation', 'p.S209A', (130, 135))	('MEFs', 'CellLine', 'CVCL:9115', (265, 269))
57661	32517051	The authors also attributed the decreased expression of these proteins to the ability of the mutant mice to be resistant to PTEN loss-induced prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mice', 'Species', '10090', (100, 104))	('expression', 'MPA', (42, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('loss-induced prostate cancer', 'Disease', 'MESH:D011471', (129, 157))	('mutant', 'Var', (93, 99))	('decreased', 'NegReg', (32, 41))	('loss-induced prostate cancer', 'Disease', (129, 157))
57662	32517051	Subsequent studies showed that cells lacking phospho-eIF4E were unable to efficiently translate SNAI1 and MMP3 and resisted undergoing EMT.	('EMT', 'biological_process', 'GO:0001837', ('135', '138'))	('MMP3', 'molecular_function', 'GO:0004248', ('106', '110'))	('MMP3', 'Gene', (106, 110))	('phospho-eIF4E', 'Var', (45, 58))	('eIF4', 'cellular_component', 'GO:0008304', ('53', '57'))	('MMP3', 'Gene', '4314', (106, 110))	('unable', 'NegReg', (64, 70))	('SNAI1', 'Gene', '6615', (96, 101))	('SNAI1', 'Gene', (96, 101))
57663	32517051	Moreover, when MNK1/2 were knocked down in KIT-mutant acral melanoma cells, their ability to translate SNAI1 and CCNE1 was compromised and their invasive and metastatic properties reduced.	('acral melanoma', 'Disease', 'MESH:D008545', (54, 68))	('compromised', 'NegReg', (123, 134))	('KIT', 'Gene', '3815', (43, 46))	('knocked down', 'Var', (27, 39))	('MNK1/2', 'Gene', (15, 21))	('CCNE1', 'Gene', (113, 118))	('acral melanoma', 'Disease', (54, 68))	('reduced', 'NegReg', (180, 187))	('CCNE1', 'Gene', '898', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('KIT', 'Gene', (43, 46))	('KIT', 'molecular_function', 'GO:0005020', ('43', '46'))	('SNAI1', 'Gene', '6615', (103, 108))	('SNAI1', 'Gene', (103, 108))
57667	32517051	Pro-metastatic neutrophils isolated from eIF4ES209A/S209A-bearing mice also manifest a decreased protein expression of anti-apoptotic factors BCL2 and MCL1, implicating the role of phospho-eIF4E in creating an anti-tumor microenvironment.	('eIF4', 'cellular_component', 'GO:0008304', ('189', '193'))	('anti-apoptotic factors', 'MPA', (119, 141))	('eIF4ES209A/S209A-bearing', 'Var', (41, 65))	('S209A', 'Mutation', 'p.S209A', (52, 57))	('decreased', 'NegReg', (87, 96))	('eIF4', 'cellular_component', 'GO:0008304', ('41', '45'))	('S209A', 'Mutation', 'p.S209A', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (215, 220))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('BCL2', 'molecular_function', 'GO:0015283', ('142', '146'))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('BCL2', 'Gene', (142, 146))	('MCL1', 'Gene', (151, 155))	('protein expression', 'MPA', (97, 115))	('Pro-metastatic neutrophils', 'CPA', (0, 26))
57672	32517051	Antisense oligonucleotides have been utilized to decrease the intracellular levels of eIF4E.	('intracellular levels', 'MPA', (62, 82))	('intracellular', 'cellular_component', 'GO:0005622', ('62', '75'))	('decrease', 'NegReg', (49, 57))	('eIF4', 'cellular_component', 'GO:0008304', ('86', '90'))	('oligonucleotides', 'Chemical', 'MESH:D009841', (10, 26))	('Antisense', 'Var', (0, 9))	('eIF4E', 'Protein', (86, 91))
57673	32517051	One such antisense anti-cancer drug candidate, LY2275796, has been tested in melanoma, with no evidence of effectiveness.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('LY2275796', 'Chemical', 'MESH:C569652', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('LY2275796', 'Var', (47, 56))
57674	32517051	In the phase I clinical trial, LY2275796 was tested in multiple advanced cancers including melanoma, and while administration of LY2275796 at 1000 mg/kg was well-tolerated and was effective at decreasing overall eIF4E levels in tissues, no tumor response was observed.	('LY2275796', 'Chemical', 'MESH:C569652', (129, 138))	('cancers', 'Disease', (73, 80))	('decreasing', 'NegReg', (193, 203))	('tumor', 'Disease', (240, 245))	('eIF4E levels', 'MPA', (212, 224))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('eIF4', 'cellular_component', 'GO:0008304', ('212', '216'))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('LY2275796', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('LY2275796', 'Chemical', 'MESH:C569652', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
57676	32517051	Overexpression of miR-768-3p was associated with decreased eIF4E levels.	('miR-768-3p', 'Chemical', '-', (18, 28))	('eIF4', 'cellular_component', 'GO:0008304', ('59', '63'))	('eIF4E levels', 'MPA', (59, 71))	('decreased', 'NegReg', (49, 58))	('miR-768-3p', 'Var', (18, 28))
57677	32517051	The authors showed that the downregulation of miR-768-3p was due to the hyperactivation of the MAPK pathway, a hallmark frequently manifested in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('miR-768-3p', 'Var', (46, 56))	('hyperactivation', 'PosReg', (72, 87))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('miR-768-3p', 'Chemical', '-', (46, 56))	('downregulation', 'NegReg', (28, 42))	('MAPK pathway', 'Pathway', (95, 107))
57678	32517051	Targeted inhibitors against BRAFV600E and MEK using PLX4720 and U0126, respectively, decreased the expression of eIF4E through upregulation of miR-768-3p.	('eIF4', 'cellular_component', 'GO:0008304', ('113', '117'))	('expression', 'MPA', (99, 109))	('U0126', 'Chemical', 'MESH:C113580', (64, 69))	('decreased', 'NegReg', (85, 94))	('U0126', 'Var', (64, 69))	('MEK', 'Gene', (42, 45))	('miR-768-3p', 'Chemical', '-', (143, 153))	('MEK', 'Gene', '5609', (42, 45))	('miR-768-3p', 'MPA', (143, 153))	('upregulation', 'PosReg', (127, 139))	('eIF4E', 'Gene', (113, 118))	('PLX4720', 'Var', (52, 59))	('BRAFV600E', 'Mutation', 'rs113488022', (28, 37))
57679	32517051	While antisense oligonucleotides successfully decrease overall levels of eIF4E, their efficacy in the clinic remains in question.	('levels', 'MPA', (63, 69))	('eIF4E', 'Protein', (73, 78))	('oligonucleotides', 'Chemical', 'MESH:D009841', (16, 32))	('eIF4', 'cellular_component', 'GO:0008304', ('73', '77'))	('decrease', 'NegReg', (46, 54))	('antisense oligonucleotides', 'Var', (6, 32))
57688	32517051	Moreover, not only did 4EGI-1 prevent the association of eIF4E to eIF4G, it also enhanced the ability of 4E-BP to sequester eIF4E, thus reducing the amount of eIF4E available for mRNA translation.	('amount of eIF4E available for mRNA translation', 'MPA', (149, 195))	('sequester', 'MPA', (114, 123))	('prevent', 'NegReg', (30, 37))	('eIF4', 'cellular_component', 'GO:0008304', ('124', '128'))	('enhanced', 'PosReg', (81, 89))	('reducing', 'NegReg', (136, 144))	('eIF4G', 'Gene', (66, 71))	('translation', 'biological_process', 'GO:0006412', ('184', '195'))	('4EGI-1', 'Var', (23, 29))	('association', 'Interaction', (42, 53))	('eIF4E', 'Protein', (57, 62))	('eIF4G', 'Gene', '1981', (66, 71))	('eIF4', 'cellular_component', 'GO:0008304', ('66', '70'))	('4E-BP', 'Chemical', '-', (105, 110))	('eIF4', 'cellular_component', 'GO:0008304', ('57', '61'))	('ability', 'MPA', (94, 101))	('eIF4', 'cellular_component', 'GO:0008304', ('159', '163'))
57689	32517051	4EGI-1 demonstrated anti-neoplastic effects on melanoma cells both in vitro and in murine xenografts with a desirable toxicity profile.	('anti-neoplastic effects', 'CPA', (20, 43))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('toxicity', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('4EGI-1', 'Var', (0, 6))	('murine', 'Species', '10090', (83, 89))
57692	32517051	Upon further characterization, it was demonstrated that SBI-756 impaired eIF4F complex formation in melanoma cells and inhibited the growth of BRAF, NRAS, and NF1-mutant melanoma cell lines.	('growth', 'MPA', (133, 139))	('eIF4F', 'cellular_component', 'GO:0016281', ('73', '78'))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('NRAS', 'Gene', '4893', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('SBI-756', 'Chemical', 'MESH:C000607014', (56, 63))	('impaired', 'NegReg', (64, 72))	('formation', 'biological_process', 'GO:0009058', ('87', '96'))	('eIF4F', 'Gene', '1981', (73, 78))	('NF1', 'Gene', '4763', (159, 162))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('NRAS', 'Gene', (149, 153))	('melanoma', 'Disease', (170, 178))	('inhibited', 'NegReg', (119, 128))	('SBI-756', 'Var', (56, 63))	('eIF4F', 'Gene', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('NF1', 'Gene', (159, 162))
57695	32517051	Concomitant administration of PLX4720 and SBI-756 in melanoma xenograft models mitigated the formation of BRAF-inhibitor-resistant tumors.	('mitigated', 'NegReg', (79, 88))	('SBI-756', 'Gene', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('PLX4720', 'Var', (30, 37))	('melanoma', 'Disease', (53, 61))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('formation', 'MPA', (93, 102))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('SBI-756', 'Chemical', 'MESH:C000607014', (42, 49))
57696	32517051	One critical aspect, not covered by the aforementioned study, was to investigate the effects of SBI-756 on invasion and metastasis, as 4EGI-1 can inhibit migration and invasion in vitro.	('inhibit', 'NegReg', (146, 153))	('4EGI-1', 'Var', (135, 141))	('SBI-756', 'Chemical', 'MESH:C000607014', (96, 103))
57715	32517051	The flavagline eFT226 (Zotatifin) has shown efficacy in suppressing the translation of numerous oncogenes including FGFR1, FGFR2, and HER2.	('FGFR2', 'Gene', (123, 128))	('FGFR2', 'Gene', '2263', (123, 128))	('eFT226', 'Var', (15, 21))	('translation', 'biological_process', 'GO:0006412', ('72', '83'))	('FGFR', 'molecular_function', 'GO:0005007', ('116', '120'))	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('eFT226', 'Chemical', '-', (15, 21))	('flavagline', 'Chemical', '-', (4, 14))	('Zotatifin', 'Chemical', '-', (23, 32))	('HER2', 'Gene', (134, 138))	('translation', 'MPA', (72, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('123', '127'))	('HER2', 'Gene', '2064', (134, 138))	('oncogenes', 'Gene', (96, 105))	('suppressing', 'NegReg', (56, 67))
57716	32517051	Notably, eFT226 significantly suppressed tumor growth in xenograft models harboring amplifications in FGFR1/2 and HER2, and is currently in a phase I/II clinical trial against advanced solid tumor malignancies (NCT04092673).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('HER2', 'Gene', (114, 118))	('suppressed', 'NegReg', (30, 40))	('tumor', 'Disease', (41, 46))	('HER2', 'Gene', '2064', (114, 118))	('tumor malignancies', 'Disease', (191, 209))	('FGFR1/2', 'Gene', (102, 109))	('eFT226', 'Chemical', '-', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('FGFR1/2', 'Gene', '2260;2263', (102, 109))	('amplifications', 'Var', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('eFT226', 'Var', (9, 15))	('tumor malignancies', 'Disease', 'MESH:D009369', (191, 209))
57731	32517051	mTOR inhibition leads to decreased S6 kinase 1 activity, which results in an increase in pro-survival and proliferative signals through PI3K/Akt signaling.	('S6 kinase 1', 'Enzyme', (35, 46))	('proliferative signals', 'CPA', (106, 127))	('inhibition', 'Var', (5, 15))	('decreased', 'NegReg', (25, 34))	('PI3K', 'molecular_function', 'GO:0016303', ('136', '140'))	('Akt', 'Gene', (141, 144))	('increase', 'PosReg', (77, 85))	('Akt', 'Gene', '207', (141, 144))	('activity', 'MPA', (47, 55))	('mTOR', 'Gene', '2475', (0, 4))	('pro-survival', 'biological_process', 'GO:0043066', ('89', '101'))	('Akt signaling', 'biological_process', 'GO:0043491', ('141', '154'))	('mTOR', 'Gene', (0, 4))	('pro-survival', 'CPA', (89, 101))
57736	32517051	The most widely tested MNK1/2 inhibitors, CGP57380 and cercosporamide, showed promise in early studies but suffered from significant off-target effects.	('MNK1/2', 'Enzyme', (23, 29))	('CGP57380', 'Chemical', 'MESH:C466997', (42, 50))	('CGP57380', 'Var', (42, 50))	('cercosporamide', 'Chemical', 'MESH:C085452', (55, 69))
57737	32517051	In melanoma, MNK1/2 inhibitors were shown to attenuate growth of pulmonary metastases in murine syngeneic grafts.	('pulmonary metastases', 'Disease', 'MESH:D009362', (65, 85))	('pulmonary metastases', 'Disease', (65, 85))	('murine', 'Species', '10090', (89, 95))	('inhibitors', 'Var', (20, 30))	('attenuate', 'NegReg', (45, 54))	('MNK1/2', 'Gene', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
57739	32517051	Comparably, in an experimental model of metastasis, mice treated with SEL201, an ATP-competitive MNK1/2 inhibitor, formed significantly fewer lung metastases than vehicle-control treated mice.	('lung metastases', 'Disease', (142, 157))	('lung metastases', 'Disease', 'MESH:D009362', (142, 157))	('mice', 'Species', '10090', (52, 56))	('mice', 'Species', '10090', (187, 191))	('SEL201', 'Var', (70, 76))	('SEL201', 'Chemical', '-', (70, 76))	('fewer', 'NegReg', (136, 141))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))
57740	32517051	Our group has shown that MNK1/2 inhibition using SEL201 blocks the progression of metastatic KIT melanoma, concomitant with suppression of eIF4E phosphorylation.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('MNK1/2', 'Protein', (25, 31))	('inhibition', 'NegReg', (32, 42))	('eIF4E', 'Protein', (139, 144))	('KIT melanoma', 'Disease', (93, 105))	('suppression', 'NegReg', (124, 135))	('KIT', 'molecular_function', 'GO:0005020', ('93', '96'))	('phosphorylation', 'biological_process', 'GO:0016310', ('145', '160'))	('KIT melanoma', 'Disease', 'MESH:D008545', (93, 105))	('phosphorylation', 'MPA', (145, 160))	('blocks', 'NegReg', (56, 62))	('SEL201', 'Var', (49, 55))	('eIF4', 'cellular_component', 'GO:0008304', ('139', '143'))	('SEL201', 'Chemical', '-', (49, 55))
57741	32517051	We have also shown that use of SEL201 in models of breast cancer is associated with decreased outgrowth of ductal carcinoma in situ and hindered invasive disease progression.	('hindered', 'NegReg', (136, 144))	('invasive disease', 'Disease', 'MESH:D009361', (145, 161))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('decreased outgrowth of ductal carcinoma', 'Disease', 'MESH:D044584', (84, 123))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('invasive disease', 'Disease', (145, 161))	('SEL201', 'Chemical', '-', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('SEL201', 'Gene', (31, 37))	('use', 'Var', (24, 27))	('decreased outgrowth of ductal carcinoma', 'Disease', (84, 123))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (107, 131))	('breast cancer', 'Disease', (51, 64))
57745	32517051	MNK1/2 inhibition has also shown promise in suppressing the growth and increasing the response to conventional therapy in AML.	('increasing', 'PosReg', (71, 81))	('growth', 'MPA', (60, 66))	('suppressing', 'NegReg', (44, 55))	('response to conventional therapy', 'MPA', (86, 118))	('inhibition', 'Var', (7, 17))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('MNK1/2', 'Gene', (0, 6))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('AML', 'Disease', (122, 125))
57748	32517051	In these studies, however, MNK1/2 inhibition was achieved using the CGP57380, and due to its lack of specificity, these results need to be interpreted with caution.	('CGP57380', 'Chemical', 'MESH:C466997', (68, 76))	('inhibition', 'NegReg', (34, 44))	('CGP57380', 'Var', (68, 76))	('MNK1/2', 'MPA', (27, 33))
57752	32517051	BAY1143269 is a MNK1/2 inhibitor from Bayer that is currently in phase I clinical trials against advanced or metastatic solid tumors.	('BAY1143269', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('advanced', 'Disease', (97, 105))	('solid tumors', 'Disease', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('BAY1143269', 'Chemical', 'MESH:C000622122', (0, 10))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))
57755	32517051	MNK1/2 inhibition has been shown to elicit desirable, anti-tumor responses in immune cells.	('elicit', 'Reg', (36, 42))	('tumor', 'Disease', (59, 64))	('inhibition', 'Var', (7, 17))	('MNK1/2', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
57763	32517051	Studies have also demonstrated that inhibition of MNK1/2 kinase activity decreased the production of IL-17.	('inhibition', 'Var', (36, 46))	('decreased', 'NegReg', (73, 82))	('MNK1/2 kinase', 'Enzyme', (50, 63))	('IL-17', 'Gene', '3605', (101, 106))	('IL-17', 'molecular_function', 'GO:0030367', ('101', '106'))	('IL-17', 'Gene', (101, 106))	('activity', 'MPA', (64, 72))	('kinase activity', 'molecular_function', 'GO:0016301', ('57', '72'))
57770	32517051	Overexpression of eIF4E, or a constitutively active MNK1, have also been shown to increase the production of RFLAT-1, a transcriptional regulator of CCL5 in T-cells.	('CCL', 'molecular_function', 'GO:0044101', ('149', '152'))	('CCL5', 'Gene', (149, 153))	('RFLAT-1', 'Gene', '51621', (109, 116))	('eIF4E', 'Var', (18, 23))	('eIF4', 'cellular_component', 'GO:0008304', ('18', '22'))	('increase', 'PosReg', (82, 90))	('MNK1', 'Gene', (52, 56))	('CCL5', 'Gene', '6352', (149, 153))	('RFLAT-1', 'Gene', (109, 116))	('production', 'MPA', (95, 105))
57773	32517051	In another study, in the context of a T-cell specific PTEN-null lymphoma model, deletion of MNK1/2 resulted in delayed onset of lymphoma, with a complete abolishment of eIF4E phosphorylation.	('lymphoma', 'Disease', (64, 72))	('lymphoma', 'Disease', 'MESH:D008223', (64, 72))	('deletion', 'Var', (80, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('eIF4E', 'Protein', (169, 174))	('MNK1/2', 'Gene', (92, 98))	('phosphorylation', 'MPA', (175, 190))	('phosphorylation', 'biological_process', 'GO:0016310', ('175', '190'))	('abolishment', 'NegReg', (154, 165))	('lymphoma', 'Disease', (128, 136))	('lymphoma', 'Disease', 'MESH:D008223', (128, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('eIF4', 'cellular_component', 'GO:0008304', ('169', '173'))
57774	32517051	Collectively, these results suggest that inhibition of MNK1/2 promotes favorable anti-tumor conditions intrinsically, while promoting a strong anti-tumor microenvironment, and provides a clear rationale for the relevance and importance of developing MNK1/2 inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('promoting', 'PosReg', (124, 133))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (148, 153))	('promotes', 'PosReg', (62, 70))	('inhibition', 'Var', (41, 51))	('MNK1/2', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
57778	32517051	Recent efforts have been put into combining immunotherapy with BRAF and MEK inhibition to further prolong patient overall survival.	('patient', 'Species', '9606', (106, 113))	('MEK', 'Gene', (72, 75))	('prolong', 'PosReg', (98, 105))	('MEK', 'Gene', '5609', (72, 75))	('inhibition', 'Var', (76, 86))
57788	32517051	In an aggressive cell model of liver cancer expressing MYCTg;KRASG12D, treatment with eFT508 significantly decreased the translation of and, thereby, surface expression of PD-L1.	('liver cancer', 'Phenotype', 'HP:0002896', (31, 43))	('KRASG12D', 'Var', (61, 69))	('translation', 'biological_process', 'GO:0006412', ('121', '132'))	('liver cancer', 'Disease', 'MESH:D006528', (31, 43))	('MYCTg;KRASG12D', 'Var', (55, 69))	('decreased', 'NegReg', (107, 116))	('liver cancer', 'Disease', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('translation', 'MPA', (121, 132))	('surface expression', 'MPA', (150, 168))	('PD-L1', 'Protein', (172, 177))
57789	32517051	This decrease in surface PD-L1 expression was also recapitulated when MYCTg;KRASG12D were overexpressed in cells harboring non-phosphorylatable eIF4E (eIF4ES209A/S209A).	('S209A', 'Mutation', 'p.S209A', (162, 167))	('eIF4', 'cellular_component', 'GO:0008304', ('151', '155'))	('eIF4', 'cellular_component', 'GO:0008304', ('144', '148'))	('expression', 'MPA', (31, 41))	('S209A', 'Mutation', 'p.S209A', (156, 161))	('eIF4ES209A/S209A', 'Var', (151, 167))
57796	32273881	The capability of the immune system to recognize cancer-associated mutations depends on the presence of a particular set of alleles, which elicit an immune response to fight against cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('immune response', 'biological_process', 'GO:0006955', ('149', '164'))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mutations', 'Var', (67, 76))	('cancer', 'Disease', (182, 188))	('elicit', 'Reg', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
57810	32273881	Recent findings suggest that the altered expression of HLA molecules is associated with metastatic progression and poor prognosis in the tumor.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('expression', 'MPA', (41, 51))	('associated', 'Reg', (72, 82))	('HLA', 'Gene', '3123', (55, 58))	('metastatic progression', 'CPA', (88, 110))	('altered', 'Var', (33, 40))	('HLA', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
57811	32273881	The modification of surface molecules, lack of co-stimulatory molecules, production of immunosuppressive cytokines, and alterations in HLA molecules are some of the primary escape mechanisms used by tumor cells to evade the immune response, which can directly distress the survival of an individual.	('tumor', 'Disease', (199, 204))	('HLA', 'Gene', (135, 138))	('immune response', 'biological_process', 'GO:0006955', ('224', '239'))	('modification', 'Var', (4, 16))	('evade', 'NegReg', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('surface', 'Protein', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('alterations', 'Var', (120, 131))	('distress', 'Reg', (260, 268))	('HLA', 'Gene', '3123', (135, 138))
57848	32273881	Here, we categorized HLA superalleles into favorable and unfavorable groups based on the impact of their presence on the survival of patients, i.e., whether the presence of the superallele improves or deteriorates the survival rate.	('HLA', 'Gene', '3123', (21, 24))	('patients', 'Species', '9606', (133, 141))	('deteriorates', 'NegReg', (201, 213))	('HLA', 'Gene', (21, 24))	('improves', 'PosReg', (189, 197))	('presence', 'Var', (161, 169))	('survival rate', 'CPA', (218, 231))
57877	32273881	This is an unfavorable allele as its presence decreases the MOS of patients, as represented in Supplementary Table S3.	('presence', 'Var', (37, 45))	('decreases', 'NegReg', (46, 55))	('MOS of patients', 'CPA', (60, 75))	('patients', 'Species', '9606', (67, 75))
57916	32273881	Results (shown in Supplementary Figure S2) indicate that the presence of SU superalleles reduces the survival of melanoma samples.	('SU', 'Chemical', '-', (73, 75))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('presence', 'Var', (61, 69))	('reduces', 'NegReg', (89, 96))
57918	32273881	Both multivariate and univariate analysis revealed that age (>60), stage (III and IV), Breslow depth (>3 mm), and RS (>0) are associated with poor survival in melanoma patients, as represented in Supplementary Figure S3.	('poor', 'NegReg', (142, 146))	('melanoma', 'Disease', (159, 167))	('>3 mm', 'Var', (102, 107))	('Breslow depth', 'CPA', (87, 100))	('patients', 'Species', '9606', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
58059	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))
58068	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))
58117	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))
58149	28858076	Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma Approximately, 50% of all cutaneous melanomas harbor activating BRAF V600 mutations, among these 10-30% carry the V600K mutation.	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('V600E', 'Mutation', 'rs113488022', (54, 59))	('V600K', 'Var', (193, 198))	('cutaneous melanomas', 'Disease', (105, 124))	('BRAF', 'Gene', '673', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('BRAF', 'Gene', (36, 40))	('cutaneous melanoma', 'Disease', (60, 78))	('activating', 'PosReg', (132, 142))	('V600K', 'Mutation', 'rs121913227', (193, 198))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (105, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('V600K', 'Mutation', 'rs121913227', (41, 46))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (105, 124))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (105, 123))
58150	28858076	Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('V600E', 'SUBSTITUTION', 'None', (154, 159))	('patients', 'Species', '9606', (12, 20))	('tumors', 'Disease', (32, 38))	('metastases', 'Disease', 'MESH:D009362', (58, 68))	('relapse', 'CPA', (106, 113))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('V600K', 'Var', (26, 31))	('shorter', 'NegReg', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('patients', 'Species', '9606', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (160, 166))	('V600E', 'Var', (154, 159))	('metastases', 'Disease', (58, 68))	('V600K', 'Mutation', 'rs121913227', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
58152	28858076	Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann-Whitney U-test.	('V600K', 'Mutation', 'rs121913227', (50, 55))	('BRAF', 'Gene', (35, 39))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (56, 79))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('V600K', 'Var', (50, 55))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('skin cutaneous melanoma', 'Disease', (56, 79))	('Cancer Genome Atlas', 'Disease', (104, 123))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (104, 123))	('BRAF', 'Gene', '673', (35, 39))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))
58153	28858076	Our analyses showed that elements of energy-metabolism and protein-translation pathways were up-regulated and that pro-apoptotic pathways were down-regulated in V600K tumors compared to V600E tumors.	('pro-apoptotic pathways', 'Pathway', (115, 137))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('up-regulated', 'PosReg', (93, 105))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('down-regulated', 'NegReg', (143, 157))	('tumors', 'Disease', (167, 173))	('V600K', 'Mutation', 'rs121913227', (161, 166))	('V600E', 'Var', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('protein-translation', 'biological_process', 'GO:0006412', ('59', '78'))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('metabolism', 'biological_process', 'GO:0008152', ('44', '54'))	('protein-translation pathways', 'Pathway', (59, 87))	('V600E', 'SUBSTITUTION', 'None', (186, 191))	('V600K', 'Var', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
58154	28858076	We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant down-regulation of several KIT-targeting microRNAs (mir) including mir-222 in V600K tumors, suggesting KIT and mir-222 might key genomic contributors to observed clinical differences.	('V600E', 'Var', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('c-Kit', 'Gene', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('V600K', 'Var', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('mir-222', 'Gene', '407007', (256, 263))	('mir-222', 'Gene', (256, 263))	('V600E', 'SUBSTITUTION', 'None', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('KIT', 'molecular_function', 'GO:0005020', ('248', '251'))	('tumors', 'Disease', (109, 115))	('tumors', 'Disease', (229, 235))	('V600K', 'Mutation', 'rs121913227', (82, 87))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('KIT', 'molecular_function', 'GO:0005020', ('172', '175'))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('down-regulation', 'NegReg', (145, 160))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('V600K', 'Mutation', 'rs121913227', (223, 228))	('KIT gene', 'Gene', (32, 40))	('expressions', 'MPA', (41, 52))	('mir-222', 'Gene', '407007', (212, 219))	('mir-222', 'Gene', (212, 219))	('V600K', 'Var', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('higher', 'PosReg', (72, 78))	('c-Kit', 'Gene', '3815', (14, 19))	('tumors', 'Disease', (88, 94))	('regulation', 'biological_process', 'GO:0065007', ('150', '160'))
58156	28858076	We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy-metabolism, protein-translation and pro-survival signals compared to V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('V600E', 'Var', (207, 212))	('pro-survival', 'CPA', (174, 186))	('protein-translation', 'biological_process', 'GO:0006412', ('150', '169'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('V600E', 'SUBSTITUTION', 'None', (81, 86))	('V600K', 'Var', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('pro-survival', 'biological_process', 'GO:0043066', ('174', '186'))	('V600E', 'SUBSTITUTION', 'None', (207, 212))	('increased', 'PosReg', (121, 130))	('metabolism', 'biological_process', 'GO:0008152', ('138', '148'))	('aggressiveness', 'Phenotype', 'HP:0000718', (38, 52))	('energy-metabolism', 'MPA', (131, 148))	('protein-translation', 'MPA', (150, 169))	('V600K', 'SUBSTITUTION', 'None', (56, 61))	('V600E', 'Var', (81, 86))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))
58157	28858076	If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K positive melanomas.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('melanomas', 'Disease', 'MESH:D008545', (184, 193))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('BRAF', 'Gene', (164, 168))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('BRAF', 'Gene', '673', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('V600K', 'Mutation', 'rs121913227', (169, 174))	('V600K', 'Mutation', 'rs121913227', (37, 42))	('V600K positive', 'Var', (169, 183))	('tumors', 'Disease', (43, 49))	('melanomas', 'Disease', (184, 193))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
58158	28858076	Lastly, small sample size in V600K tumors is a major limitation of our study.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('V600K', 'Var', (29, 34))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('V600K', 'Mutation', 'rs121913227', (29, 34))
58160	28858076	Approximately, 40-60% of cutaneous melanomas harbor activating BRAF mutations.	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (25, 44))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (25, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('activating', 'Reg', (52, 62))	('cutaneous melanomas', 'Disease', (25, 44))	('BRAF', 'Gene', '673', (63, 67))	('mutations', 'Var', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('BRAF', 'Gene', (63, 67))
58161	28858076	The majority of the BRAF mutations constitute a substitution of the valine residue at position 600 by a glutamate (V600E) through mutation of a single nucleotide GTG to GAG.	('mutations', 'Var', (25, 34))	('V600E', 'Mutation', 'rs113488022', (115, 120))	('mutation', 'Var', (130, 138))	('V600E', 'Var', (115, 120))	('GTG', 'Gene', '2678', (162, 165))	('BRAF', 'Gene', '673', (20, 24))	('valine residue at position 600 by a glutamate', 'Mutation', 'rs113488022', (68, 113))	('BRAF', 'Gene', (20, 24))	('GTG', 'Gene', (162, 165))
58162	28858076	Another prevalent BRAF mutation at the same residue is V600K mutation in which the valine residue is replaced by a lysine through two nucleotide substitutions (GTG to AAG).	('valine', 'Chemical', 'MESH:D014633', (83, 89))	('V600K', 'Var', (55, 60))	('GTG', 'Gene', (160, 163))	('lysine', 'Chemical', 'MESH:D008239', (115, 121))	('AAG', 'Gene', (167, 170))	('V600K', 'Mutation', 'rs121913227', (55, 60))	('AAG', 'Gene', '4350', (167, 170))	('BRAF', 'Gene', '673', (18, 22))	('GTG', 'Gene', '2678', (160, 163))	('BRAF', 'Gene', (18, 22))
58163	28858076	V600K mutation occurs in 10 to 30% of all BRAF V600 melanomas.	('V600K', 'Mutation', 'rs121913227', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('BRAF V600 melanomas', 'Disease', (42, 61))	('V600K', 'Var', (0, 5))	('BRAF V600 melanomas', 'Disease', 'MESH:D008545', (42, 61))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
58164	28858076	Other less common BRAF mutations at V600 residue include V600R and V600D.	('V600', 'Var', (36, 40))	('V600R', 'Mutation', 'rs121913227', (57, 62))	('V600D', 'Var', (67, 72))	('BRAF', 'Gene', '673', (18, 22))	('V600R', 'Var', (57, 62))	('BRAF', 'Gene', (18, 22))	('V600D', 'Mutation', 'rs121913377', (67, 72))
58165	28858076	Patients with V600K and those with V600E mutation seem to have some distinctive clinical features.	('V600K', 'Mutation', 'rs121913227', (14, 19))	('V600E', 'Var', (35, 40))	('Patients', 'Species', '9606', (0, 8))	('V600K', 'Var', (14, 19))	('V600E', 'Mutation', 'rs113488022', (35, 40))
58166	28858076	Patients with V600K tumors appear to be older (over 50) males, and the tumors often occur in the head and neck area (prone to sun damage).	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('V600K', 'Mutation', 'rs121913227', (14, 19))	('neck', 'cellular_component', 'GO:0044326', ('106', '110'))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (71, 77))	('sun damage', 'Phenotype', 'HP:0000992', (126, 136))	('V600K', 'Var', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
58167	28858076	Pathologically, V600K tumors appear to be thicker and are more mitotically active than V600E tumors.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('V600E', 'Var', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('V600K', 'Var', (16, 21))	('V600E', 'SUBSTITUTION', 'None', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('V600K', 'Mutation', 'rs121913227', (16, 21))	('mitotically active', 'CPA', (63, 81))	('more', 'PosReg', (58, 62))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', (22, 28))
58168	28858076	Clinically, patients with V600K tumors have an increased risk for brain and lung metastases and are at a siginficantly increased risk of relapse and have a shorter time from diagnosis to metastasis than those with V600E tumors.	('patients', 'Species', '9606', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('metastasis', 'Disease', 'MESH:D009362', (187, 197))	('metastasis', 'Disease', (187, 197))	('metastases', 'Disease', (81, 91))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('V600K', 'Var', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('V600E', 'Var', (214, 219))	('tumors', 'Disease', (32, 38))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('V600K', 'Mutation', 'rs121913227', (26, 31))	('V600E', 'SUBSTITUTION', 'None', (214, 219))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
58169	28858076	Despite those differences, a large clinical trial showed that V600K tumors were sensitive to vemurafenib, a BRAF inhibitor, and that patients with V600K or V600E tumors, when treated with vemurafenib, had similar overall survival and progression-free survival outcomes.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('patients', 'Species', '9606', (133, 141))	('V600K', 'Mutation', 'rs121913227', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('V600K', 'Var', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('V600K', 'Mutation', 'rs121913227', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('V600E', 'Var', (156, 161))	('vemurafenib', 'Chemical', 'MESH:D000077484', (188, 199))	('tumors', 'Disease', (68, 74))	('vemurafenib', 'Chemical', 'MESH:D000077484', (93, 104))	('tumors', 'Disease', (162, 168))	('V600E', 'SUBSTITUTION', 'None', (156, 161))	('V600K', 'Var', (147, 152))
58170	28858076	Although the clinical and histopathological differences between V600K and V600E tumors are well documented, little is known about their genomic differences.	('V600K', 'Mutation', 'rs121913227', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('V600E', 'Var', (74, 79))	('V600E', 'SUBSTITUTION', 'None', (74, 79))	('V600K', 'Var', (64, 69))
58175	28858076	Although the number of V600K tumor samples available for our analyses was small, our results may provide useful clues for clinical management and targeted chemotherapeutical interventions for the two BRAF melanoma subtypes.	('BRAF melanoma', 'Disease', (200, 213))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('V600K', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('V600K', 'Mutation', 'rs121913227', (23, 28))	('BRAF melanoma', 'Disease', 'MESH:D008545', (200, 213))
58176	28858076	We carried out all differential expression analyses (protein, gene and microRNA) between V600E and V600K tumors in Matlab using the Mann-Whitney U test (two-sided).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('V600K', 'Mutation', 'rs121913227', (99, 104))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('V600K', 'Var', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('V600E', 'Var', (89, 94))
58178	28858076	TCGA provided RNA-seq data on ~24,000 genes for 124 BRAF V600E tumor samples and 17 V600K tumor samples.	('tumor', 'Disease', (63, 68))	('V600E', 'Mutation', 'rs113488022', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('V600E', 'Var', (57, 62))	('V600K', 'Mutation', 'rs121913227', (84, 89))	('BRAF', 'Gene', '673', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BRAF', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
58179	28858076	TCGA sequenced 1,046 micro-RNAs in 121 V600E and 17 V600K tumor samples.	('V600K', 'Var', (52, 57))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('V600K', 'Mutation', 'rs121913227', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
58180	28858076	TCGA profiled protein expression in up to 91 BRAF V600E tumors and 17 BRAF V600K tumors.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('protein', 'Protein', (14, 21))	('tumors', 'Disease', (56, 62))	('V600E', 'SUBSTITUTION', 'None', (50, 55))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('V600E', 'Var', (50, 55))	('BRAF', 'Gene', '673', (70, 74))	('V600K', 'Mutation', 'rs121913227', (75, 80))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('BRAF', 'Gene', (70, 74))
58187	28858076	Of the 124 subjects with V600E tumors and 17 with V600K tumors, TCGA had matched clinical data on 106 and 13, respectively.	('V600K', 'Mutation', 'rs121913227', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('V600E', 'Var', (25, 30))	('V600E', 'SUBSTITUTION', 'None', (25, 30))	('V600K', 'Var', (50, 55))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
58189	28858076	An apparent trend of shorter overall survival for patients with V600K tumors than for those with V600E tumors (Figure 1) was not statistically significant (hazard ratio=1.4, 95% confidence interval [0.62, 3.25], p=0.39), similar to other published findings.	('V600K', 'Mutation', 'rs121913227', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('shorter', 'NegReg', (21, 28))	('patients', 'Species', '9606', (50, 58))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('V600E', 'Var', (97, 102))	('overall survival', 'MPA', (29, 45))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('V600E', 'SUBSTITUTION', 'None', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('V600K', 'Var', (64, 69))
58190	28858076	Nonetheless, this tendency to shorter survival in V600K subjects is consistent with literature findings that V600K tumors tend to have less favorable outcomes than V600E tumors.	('V600K', 'Mutation', 'rs121913227', (50, 55))	('V600K', 'Mutation', 'rs121913227', (109, 114))	('V600E', 'Var', (164, 169))	('V600E', 'SUBSTITUTION', 'None', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('V600K', 'Var', (50, 55))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('V600K', 'Var', (109, 114))	('shorter', 'NegReg', (30, 37))	('tumors', 'Disease', (170, 176))	('survival', 'MPA', (38, 46))
58191	28858076	Among the ~24,000 genes with RNA-seq gene expression levels from TCGA, we found 1,675 differentially expressed with p<0.05 between BRAF subtypes; among these 593 were up-regulated and 1,082 were down-regulated in BRAF V600K tumors compared to V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('V600E', 'SUBSTITUTION', 'None', (243, 248))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('BRAF', 'Gene', (213, 217))	('BRAF', 'Gene', '673', (213, 217))	('V600K', 'Mutation', 'rs121913227', (218, 223))	('down-regulated', 'NegReg', (195, 209))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('BRAF', 'Gene', '673', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('V600E', 'Var', (243, 248))	('BRAF', 'Gene', (131, 135))	('V600K', 'Var', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('gene expression', 'biological_process', 'GO:0010467', ('37', '52'))	('up-regulated', 'PosReg', (167, 179))	('tumors', 'Disease', (249, 255))
58192	28858076	Gene ontology (GO) analysis applied to the top 250 (as ordered by p-values for differential expression) genes up-regulated in V600K tumors compared to V600E tumors showed that the up-regulated genes were over-represented in metabolic processes (Table 1A), consistent with up-regulation of proliferation signals in those tumors from protein expression analysis.	('V600K', 'Mutation', 'rs121913227', (126, 131))	('up-regulated', 'PosReg', (110, 122))	('tumors', 'Disease', 'MESH:D009369', (320, 326))	('Gene ontology', 'biological_process', 'GO:0003673', ('0', '13'))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('V600E', 'Var', (151, 156))	('up-regulated', 'PosReg', (180, 192))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('V600K', 'Var', (126, 131))	('protein', 'cellular_component', 'GO:0003675', ('332', '339'))	('tumors', 'Disease', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('V600E', 'SUBSTITUTION', 'None', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (320, 326))	('over-represented', 'PosReg', (204, 220))	('regulation', 'biological_process', 'GO:0065007', ('275', '285'))	('metabolic processes', 'CPA', (224, 243))	('tumors', 'Disease', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', (320, 326))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
58193	28858076	Among the top 250 genes down-regulated in V600K tumors compared to V600E tumors, GO analysis showed an over-representation in embryonic development pathways (Table 1B).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('over-representation', 'PosReg', (103, 122))	('down-regulated', 'NegReg', (24, 38))	('V600K', 'Mutation', 'rs121913227', (42, 47))	('tumors', 'Disease', (48, 54))	('embryonic development pathways', 'Pathway', (126, 156))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('V600E', 'Var', (67, 72))	('V600E', 'SUBSTITUTION', 'None', (67, 72))	('V600K', 'Var', (42, 47))
58194	28858076	Among the 103 proteins for which data were available for at least four V600K tumor samples, 14 were differentially expressed with p<0.05 between BRAF subtypes; among these 7 were up-regulated and 7 were down-regulated in BRAF V600K tumors compared to V600E tumors (Table 2, Supplementary Figure S1A and S1B).	('BRAF', 'Gene', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('BRAF', 'Gene', '673', (221, 225))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('BRAF', 'Gene', (221, 225))	('V600K', 'Mutation', 'rs121913227', (226, 231))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', (232, 237))	('up-regulated', 'PosReg', (179, 191))	('V600E', 'Var', (251, 256))	('down-regulated', 'NegReg', (203, 217))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('V600K', 'Var', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('V600E', 'SUBSTITUTION', 'None', (251, 256))	('tumors', 'Disease', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (77, 82))	('V600K', 'Mutation', 'rs121913227', (71, 76))	('BRAF', 'Gene', '673', (145, 149))
58195	28858076	Among the significantly down-regulated proteins in V600K tumors were Bak and caspase-7 (Figure 2).	('Bak', 'Protein', (69, 72))	('caspase-7', 'Gene', '840', (77, 86))	('V600K', 'Var', (51, 56))	('down-regulated', 'NegReg', (24, 38))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('V600K', 'Mutation', 'rs121913227', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('Bak', 'Chemical', '-', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('proteins', 'Protein', (39, 47))	('caspase-7', 'Gene', (77, 86))
58198	28858076	Another member of the pro-apoptotic family of proteins, Bid, was also down-regulated in V600K samples (Table 2).	('V600K', 'Var', (88, 93))	('down-regulated', 'NegReg', (70, 84))	('V600K', 'Mutation', 'rs121913227', (88, 93))	('Bid', 'Gene', '637', (56, 59))	('Bid', 'Gene', (56, 59))
58200	28858076	Taken together, these results suggest that the pro-apoptotic signaling pathways might be down-regulated to promote cell survival and growth in V600K tumors Among the proteins up-regulated in V600K tumors compared to V600E tumors, S6 (RPS6) and eEF2 are involved in mRNA translation and ribosomal biogenesis.	('up-regulated', 'PosReg', (175, 187))	('down-regulated', 'NegReg', (89, 103))	('V600E', 'SUBSTITUTION', 'None', (216, 221))	('pro-apoptotic signaling pathways', 'Pathway', (47, 79))	('V600K', 'Mutation', 'rs121913227', (143, 148))	('cell survival', 'CPA', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('RPS6', 'Gene', '6194', (234, 238))	('tumors', 'Disease', (222, 228))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('eEF2', 'Gene', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('V600K', 'Var', (191, 196))	('tumors', 'Disease', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('V600K', 'Var', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('RPS6', 'Gene', (234, 238))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('V600E', 'Var', (216, 221))	('growth', 'CPA', (133, 139))	('eEF2', 'Gene', '1938', (244, 248))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('translation', 'biological_process', 'GO:0006412', ('270', '281'))	('V600K', 'Mutation', 'rs121913227', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('promote', 'PosReg', (107, 114))
58203	28858076	Besides eEF2, eEF2K and phosphorylated 4E-BP1 (4E-BP1_pT37_T46) were up-regulated in V600K tumors compared to V600E tumors, although those changes in protein levels were not statistically significant (data not shown).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('4E-BP1', 'Gene', '1978', (47, 53))	('eEF2K', 'molecular_function', 'GO:0004686', ('14', '19'))	('eEF2', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('eEF2K', 'Gene', (14, 19))	('V600K', 'Mutation', 'rs121913227', (85, 90))	('eEF2', 'Gene', (14, 18))	('up-regulated', 'PosReg', (69, 81))	('4E-BP1', 'Gene', (39, 45))	('V600E', 'Var', (110, 115))	('4E-BP1', 'Gene', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('eEF2', 'Gene', '1938', (8, 12))	('V600K', 'Var', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('V600E', 'SUBSTITUTION', 'None', (110, 115))	('eEF2', 'Gene', '1938', (14, 18))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('eEF2K', 'Gene', '29904', (14, 19))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('4E-BP1', 'Gene', '1978', (39, 45))
58208	28858076	Tuberin (TSC2), also up-regulated in V600K tumors compared to V600E tumors (Figure 2), forms a complex with TSC1, and the complex serves to control various cellular functions as an important upstream hub for the mTOR pathway.	('TSC1', 'Gene', (108, 112))	('complex', 'Interaction', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('TSC1', 'Gene', '7248', (108, 112))	('V600K', 'Mutation', 'rs121913227', (37, 42))	('up-regulated', 'PosReg', (21, 33))	('V600E', 'Var', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('V600K', 'Var', (37, 42))	('Tuberin', 'Gene', (0, 7))	('Tuberin', 'Gene', '7249', (0, 7))	('TSC2', 'Gene', '7249', (9, 13))	('V600E', 'SUBSTITUTION', 'None', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('control', 'Reg', (140, 147))	('tumors', 'Disease', (43, 49))	('mTOR', 'Gene', (212, 216))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (68, 74))	('TSC2', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (212, 216))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
58209	28858076	Those results suggest that the mTOR pathway may be differentially affected between V600K and V600E tumors.	('V600K', 'Var', (83, 88))	('mTOR', 'Gene', (31, 35))	('V600E', 'Var', (93, 98))	('mTOR', 'Gene', '2475', (31, 35))	('V600K', 'Mutation', 'rs121913227', (83, 88))	('V600E', 'SUBSTITUTION', 'None', (93, 98))	('affected', 'Reg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
58210	28858076	Lastly, the phosphorylated mTOR protein (mTOR_pS2448) level was also elevated in V600K BRAF tumors compared to V600E BRAF tumors, although the elevation did not reach statistical significance (Figure 3).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('BRAF tumors', 'Disease', (87, 98))	('BRAF tumors', 'Disease', 'MESH:D009369', (87, 98))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('V600K', 'Var', (81, 86))	('BRAF tumors', 'Disease', 'MESH:D009369', (117, 128))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('mTOR', 'Gene', '2475', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('elevated', 'PosReg', (69, 77))	('V600K', 'Mutation', 'rs121913227', (81, 86))	('BRAF tumors', 'Disease', (117, 128))	('mTOR', 'Gene', '2475', (27, 31))	('V600E', 'Mutation', 'rs113488022', (111, 116))
58211	28858076	The other proteins that were up-regulated in V600K tumors compared to V600E tumors include TFRC and PCNA.	('TFRC', 'Gene', (91, 95))	('V600K', 'Var', (45, 50))	('V600E', 'Var', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('V600E', 'SUBSTITUTION', 'None', (70, 75))	('V600K', 'Mutation', 'rs121913227', (45, 50))	('PCNA', 'Gene', (100, 104))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', (51, 57))	('up-regulated', 'PosReg', (29, 41))	('TFRC', 'Gene', '7037', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PCNA', 'molecular_function', 'GO:0003892', ('100', '104'))	('PCNA', 'Gene', '5111', (100, 104))
58214	28858076	It is not clear why those two proteins were up-regulated in V600K tumors compared to V600E tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('V600E', 'SUBSTITUTION', 'None', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('V600K', 'Var', (60, 65))	('up-regulated', 'PosReg', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('V600E', 'Var', (85, 90))	('V600K', 'Mutation', 'rs121913227', (60, 65))
58215	28858076	Finally, c-Kit, a receptor tyrosine kinase that plays a multifunctional role in melanogenesis, cell growth, migration and survival, was also up-regulated in V600K tumors.	('c-Kit', 'Gene', (9, 14))	('up-regulated', 'PosReg', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cell growth', 'biological_process', 'GO:0016049', ('95', '106'))	('tumors', 'Disease', (163, 169))	('V600K', 'Var', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('V600K', 'Mutation', 'rs121913227', (157, 162))	('c-Kit', 'Gene', '3815', (9, 14))
58216	28858076	Among the 1,046 microRNAs analyzed by TCGA, 106 were differentially expressed with p<0.05 between V600E and V600K SKCM tumors; among these 29 were up-regulated and 77 were down-regulated in V600K tumors compared to V600E tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('V600E', 'Var', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors', 'Disease', (119, 125))	('V600K', 'Var', (190, 195))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('V600K', 'Mutation', 'rs121913227', (108, 113))	('tumors', 'Disease', (221, 227))	('V600E', 'SUBSTITUTION', 'None', (215, 220))	('up-regulated', 'PosReg', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('SKCM tumors', 'Disease', (114, 125))	('SKCM tumors', 'Disease', 'MESH:D009369', (114, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (196, 202))	('down-regulated', 'NegReg', (172, 186))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('V600E', 'Var', (98, 103))	('V600E', 'Mutation', 'rs113488022', (215, 220))	('V600K', 'Var', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('V600K', 'Mutation', 'rs121913227', (190, 195))	('V600E', 'SUBSTITUTION', 'None', (98, 103))
58217	28858076	Interestingly, several of the most significantly down-regulated microRNAs (Table 3) in V600K tumors compared to V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('V600K', 'Mutation', 'rs121913227', (87, 92))	('microRNAs', 'MPA', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('down-regulated', 'NegReg', (49, 63))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('V600E', 'Var', (112, 117))	('V600E', 'SUBSTITUTION', 'None', (112, 117))	('V600K', 'Var', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
58218	28858076	Several of them, such as mir-222 (Figure 4), mir-34b/c, mir-19b-2, and mir-148a, are either known or predicted to target the KIT gene (see below) (Supplementary Figure S2).	('target', 'Reg', (114, 120))	('mir-19b', 'Gene', (56, 63))	('mir-148a', 'Var', (71, 79))	('KIT gene', 'Gene', (125, 133))	('mir-19b', 'Gene', '406980', (56, 63))	('mir-34b', 'Gene', (45, 52))	('mir-222', 'Gene', '407007', (25, 32))	('mir-222', 'Gene', (25, 32))	('KIT', 'molecular_function', 'GO:0005020', ('125', '128'))	('mir-34b', 'Gene', '407041', (45, 52))
58219	28858076	Up-regulated miRNAs in V600K tumors compared to V600E tumors include mir-330 and let7g, both of which appear to have antiproliferative effects.	('mir-330', 'Gene', '442902', (69, 76))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('V600E', 'Var', (48, 53))	('V600E', 'SUBSTITUTION', 'None', (48, 53))	('V600K', 'Var', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mir-330', 'Gene', (69, 76))	('Up-regulated', 'PosReg', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('V600K', 'Mutation', 'rs121913227', (23, 28))	('tumors', 'Disease', (29, 35))	('let7g', 'Gene', '406890', (81, 86))	('antiproliferative effects', 'CPA', (117, 142))	('tumors', 'Disease', (54, 60))	('let7g', 'Gene', (81, 86))
58220	28858076	Our gene expression analysis suggested the up-regulation of metabolic processes and down-regulation of embryonic development pathways in V600K tumors compared to V600E tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (168, 174))	('V600K', 'Var', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('metabolic processes', 'CPA', (60, 79))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('embryonic development pathways', 'Pathway', (103, 133))	('gene expression', 'biological_process', 'GO:0010467', ('4', '19'))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('V600E', 'Var', (162, 167))	('down-regulation', 'NegReg', (84, 99))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('V600K', 'Mutation', 'rs121913227', (137, 142))	('V600E', 'SUBSTITUTION', 'None', (162, 167))	('up-regulation', 'PosReg', (43, 56))	('down-regulation of embryonic development', 'biological_process', 'GO:0045992', ('84', '124'))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
58221	28858076	Our protein expression analysis suggested that pro-apoptotic pathways were down-regulated, possibly contributing to enhanced cell survival and growth in V600K tumors compared to V600E tumors.	('enhanced', 'PosReg', (116, 124))	('V600E', 'Var', (178, 183))	('growth', 'CPA', (143, 149))	('V600E', 'SUBSTITUTION', 'None', (178, 183))	('V600K', 'Var', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cell survival', 'CPA', (125, 138))	('pro-apoptotic pathways', 'Pathway', (47, 69))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('V600K', 'Mutation', 'rs121913227', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('down-regulated', 'NegReg', (75, 89))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
58223	28858076	Perhaps the most striking feature to emerge from our differential expression analyses was the fact that c-Kit was significantly up-regulated in V600K tumors while several micro-RNAs known or predicted to target KIT were significantly down-regulated.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('V600K', 'Mutation', 'rs121913227', (144, 149))	('up-regulated', 'PosReg', (128, 140))	('KIT', 'molecular_function', 'GO:0005020', ('211', '214'))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('c-Kit', 'Gene', (104, 109))	('V600K', 'Var', (144, 149))	('c-Kit', 'Gene', '3815', (104, 109))
58224	28858076	Both KIT gene expression and protein expression were up-regulated in V600K tumors compared to V600E tumors (p=0.03) (Figure 5).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('V600K', 'Mutation', 'rs121913227', (69, 74))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('KIT gene', 'Gene', (5, 13))	('V600E', 'Var', (94, 99))	('up-regulated', 'PosReg', (53, 65))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('KIT', 'molecular_function', 'GO:0005020', ('5', '8'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('V600K', 'Var', (69, 74))	('tumors', 'Disease', (100, 106))	('V600E', 'SUBSTITUTION', 'None', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('expression', 'MPA', (14, 24))	('protein expression', 'MPA', (29, 47))
58226	28858076	The coordinated up-regulation of c-Kit protein level and KIT gene expression and concomitantly down-regulation of several KIT-targeting microRNAs suggested to us that the c-Kit signaling pathway is possibly an important feature distinguishing between V600E and V600K BRAF tumors.	('Kit signaling pathway', 'biological_process', 'GO:0038109', ('173', '194'))	('V600K', 'Mutation', 'rs121913227', (261, 266))	('c-Kit', 'Gene', '3815', (171, 176))	('down-regulation', 'NegReg', (95, 110))	('expression', 'MPA', (66, 76))	('BRAF tumors', 'Disease', (267, 278))	('V600E', 'Mutation', 'rs113488022', (251, 256))	('KIT', 'molecular_function', 'GO:0005020', ('57', '60'))	('c-Kit', 'Gene', (171, 176))	('up-regulation', 'PosReg', (16, 29))	('KIT', 'molecular_function', 'GO:0005020', ('122', '125'))	('V600K', 'Var', (261, 266))	('c-Kit', 'Gene', '3815', (33, 38))	('BRAF tumors', 'Disease', 'MESH:D009369', (267, 278))	('V600E', 'Var', (251, 256))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('c-Kit', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('regulation', 'biological_process', 'GO:0065007', ('19', '29'))	('KIT gene', 'Gene', (57, 65))	('gene expression', 'biological_process', 'GO:0010467', ('61', '76'))
58228	28858076	In the TCGA data, mir-222 expression was negatively correlated with that of KIT in all 450 SKCM samples (Spearman rho = -0.27, p= 7.0E-09) and 14 V600K samples (Spearman rho =-0.32, p=0.26) (Figure 6).	('expression', 'MPA', (26, 36))	('negatively', 'NegReg', (41, 51))	('V600K', 'Var', (146, 151))	('V600K', 'Mutation', 'rs121913227', (146, 151))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('mir-222', 'Gene', '407007', (18, 25))	('mir-222', 'Gene', (18, 25))
58238	28858076	Those results suggest a link between down-regulation of mir-222 and the over-representation of metabolism genes among genes whose expression is up-regulated in V600K tumors, although the exact relationship between the two is unclear.	('up-regulated', 'PosReg', (144, 156))	('expression', 'MPA', (130, 140))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('metabolism', 'biological_process', 'GO:0008152', ('95', '105'))	('down-regulation', 'NegReg', (37, 52))	('metabolism genes', 'Gene', (95, 111))	('V600K', 'Var', (160, 165))	('regulation', 'biological_process', 'GO:0065007', ('42', '52'))	('mir-222', 'Gene', '407007', (56, 63))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('V600K', 'Mutation', 'rs121913227', (160, 165))	('mir-222', 'Gene', (56, 63))	('over-representation', 'PosReg', (72, 91))
58239	28858076	TCGA had previously identified 18 significantly mutated genes in melanoma; three (GNA11, KIT, and PTEN) showed proportionally higher number of mutations in V600K tumors than in V600E tumors (Table 4A).	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('GNA11', 'Gene', '2767', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Disease', (183, 189))	('V600E', 'SUBSTITUTION', 'None', (177, 182))	('PTEN', 'Gene', (98, 102))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('V600K', 'Mutation', 'rs121913227', (156, 161))	('mutations', 'Var', (143, 152))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('GNA11', 'Gene', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('PTEN', 'Gene', '5728', (98, 102))	('V600K', 'Var', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('V600E', 'Var', (177, 182))	('tumors', 'Disease', (162, 168))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))
58240	28858076	A closer examination of the mutations in each of the three genes did not find a pattern of association between the mutations and c-Kit expression among the 13 V600K tumors (Table 4B).	('c-Kit', 'Gene', (129, 134))	('V600K', 'Var', (159, 164))	('c-Kit', 'Gene', '3815', (129, 134))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('V600K', 'Mutation', 'rs121913227', (159, 164))	('expression', 'MPA', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
58241	28858076	In fact, the three V600K tumors with the highest c-Kit expression were all wild-type for the three genes (highlighted in Table 4B).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('V600K', 'Var', (19, 24))	('expression', 'MPA', (55, 65))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('c-Kit', 'Gene', (49, 54))	('V600K', 'Mutation', 'rs121913227', (19, 24))	('c-Kit', 'Gene', '3815', (49, 54))
58242	28858076	We saw no evident association between the elevated expression of c-Kit and any copy number changes in the KIT gene (Table 4B).	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('c-Kit', 'Gene', (65, 70))	('c-Kit', 'Gene', '3815', (65, 70))	('expression', 'MPA', (51, 61))	('copy number changes', 'Var', (79, 98))	('elevated', 'PosReg', (42, 50))	('KIT', 'Gene', (106, 109))
58243	28858076	No differential methylation in KIT promoter was found between V600K and V600E tumors (data not shown).	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('V600E', 'Var', (72, 77))	('V600E', 'SUBSTITUTION', 'None', (72, 77))	('V600K', 'Mutation', 'rs121913227', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('KIT', 'molecular_function', 'GO:0005020', ('31', '34'))	('V600K', 'Var', (62, 67))
58244	28858076	In conclusion, our analyses of multiple genomic data suggest that both c-Kit protein and KIT gene expression levels were significantly higher in V600K tumors than in V600E tumors.	('V600K', 'Var', (145, 150))	('c-Kit', 'Gene', (71, 76))	('V600E', 'Var', (166, 171))	('KIT gene expression levels', 'MPA', (89, 115))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('tumors', 'Disease', (151, 157))	('V600E', 'SUBSTITUTION', 'None', (166, 171))	('KIT', 'molecular_function', 'GO:0005020', ('89', '92'))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('V600K', 'Mutation', 'rs121913227', (145, 150))	('c-Kit', 'Gene', '3815', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('higher', 'PosReg', (135, 141))
58245	28858076	Concurrently, mir-222 expression was significantly down-regulated in V600K tumors compared to V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('V600K', 'Var', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('V600K', 'Mutation', 'rs121913227', (69, 74))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('V600E', 'Var', (94, 99))	('V600E', 'SUBSTITUTION', 'None', (94, 99))	('down-regulated', 'NegReg', (51, 65))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mir-222', 'Gene', '407007', (14, 21))	('mir-222', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('expression', 'MPA', (22, 32))
58246	28858076	We also found that those differential changes concomitantly correlated with increased proliferation and pro-survival signals/pathways in V600K tumors compared to V600E tumors, providing a plausible link between the observed clinical phenotypes and genomics between the two subtype BRAF tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('subtype BRAF tumors', 'Disease', (273, 292))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', (286, 292))	('subtype BRAF tumors', 'Disease', 'MESH:C535673', (273, 292))	('pro-survival', 'biological_process', 'GO:0043066', ('104', '116'))	('pro-survival signals/pathways', 'Pathway', (104, 133))	('V600K', 'Var', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('increased', 'PosReg', (76, 85))	('tumors', 'Disease', (143, 149))	('proliferation', 'CPA', (86, 99))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('V600E', 'Var', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('V600K', 'Mutation', 'rs121913227', (137, 142))	('V600E', 'SUBSTITUTION', 'None', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
58247	28858076	An increasing number of studies have demonstrated that BRAF V600K and V600E tumors are not identical.	('V600E', 'Var', (70, 75))	('V600K', 'Mutation', 'rs121913227', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('V600E', 'SUBSTITUTION', 'None', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', (55, 59))
58248	28858076	V600K tumors are more aggressive in that patients with those tumors have a significantly higher risk for relapse and a shorter time from diagnosis to metastasis compared to V600E tumors.	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('V600K', 'Var', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('V600E', 'Var', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', (61, 67))	('relapse', 'CPA', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', (6, 12))	('patients', 'Species', '9606', (41, 49))	('metastasis', 'Disease', (150, 160))	('V600E', 'SUBSTITUTION', 'None', (173, 178))	('V600K', 'Mutation', 'rs121913227', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Disease', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('metastasis', 'Disease', 'MESH:D009362', (150, 160))
58249	28858076	Structurally, both V600E and V600K mutations are located in the activation segment helix 1 inside the kinase domain and are predicted to perturb the structure of the helix, thus, promoting dimerization of the protein.	('perturb', 'Reg', (137, 144))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('V600K', 'Var', (29, 34))	('protein', 'Protein', (209, 216))	('V600E', 'Var', (19, 24))	('V600K', 'Mutation', 'rs121913227', (29, 34))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('promoting', 'PosReg', (179, 188))	('structure of the helix', 'MPA', (149, 171))	('dimerization', 'MPA', (189, 201))
58251	28858076	Our computational analysis of multiple genomic data from TCGA suggested that V600K tumors had higher c-Kit protein and KIT gene expression levels than V600E tumors.	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('gene expression', 'biological_process', 'GO:0010467', ('123', '138'))	('higher', 'PosReg', (94, 100))	('c-Kit', 'Gene', (101, 106))	('V600K', 'Mutation', 'rs121913227', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('V600E', 'Var', (151, 156))	('KIT gene expression levels', 'MPA', (119, 145))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('KIT', 'molecular_function', 'GO:0005020', ('119', '122'))	('tumors', 'Disease', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('V600E', 'SUBSTITUTION', 'None', (151, 156))	('V600K', 'Var', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', (83, 89))	('c-Kit', 'Gene', '3815', (101, 106))
58252	28858076	We also found evidence of down-regulation of pro-apoptotic proteins and up-regulation of metabolism in V600K tumors compared to V600E tumors.	('tumors', 'Disease', (134, 140))	('V600K', 'Var', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('regulation of metabolism', 'biological_process', 'GO:0019222', ('75', '99'))	('up-regulation', 'PosReg', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('V600K', 'Mutation', 'rs121913227', (103, 108))	('down-regulation', 'NegReg', (26, 41))	('pro-apoptotic proteins', 'Protein', (45, 67))	('V600E', 'Var', (128, 133))	('metabolism', 'MPA', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('V600E', 'SUBSTITUTION', 'None', (128, 133))	('tumors', 'Disease', (109, 115))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
58253	28858076	Proteins involved in mRNA translation and ribosomal biogenesis were also up-regulated in V600K tumors compared to V600E tumors, suggesting that the mTOR pathway may be further activated in V600K tumors.	('tumors', 'Disease', (120, 126))	('V600K', 'Mutation', 'rs121913227', (189, 194))	('mTOR', 'Gene', '2475', (148, 152))	('V600E', 'SUBSTITUTION', 'None', (114, 119))	('V600K', 'Var', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ribosomal biogenesis', 'MPA', (42, 62))	('tumors', 'Disease', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('translation', 'biological_process', 'GO:0006412', ('26', '37'))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mRNA translation', 'MPA', (21, 37))	('Proteins', 'Protein', (0, 8))	('V600K', 'Mutation', 'rs121913227', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('up-regulated', 'PosReg', (73, 85))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mTOR', 'Gene', (148, 152))	('V600E', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
58254	28858076	Several proteins involved in DNA repair such as ATM, CHEK2, and PCNA, also had higher expression in V600K tumors compared to V600E tumors (Supplementary Figure S1A).	('DNA repair', 'biological_process', 'GO:0006281', ('29', '39'))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('ATM', 'Gene', '472', (48, 51))	('tumors', 'Disease', (106, 112))	('CHEK2', 'Gene', '11200', (53, 58))	('higher', 'PosReg', (79, 85))	('PCNA', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('V600E', 'Var', (125, 130))	('V600K', 'Mutation', 'rs121913227', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('PCNA', 'molecular_function', 'GO:0003892', ('64', '68'))	('ATM', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('proteins', 'Protein', (8, 16))	('PCNA', 'Gene', '5111', (64, 68))	('expression', 'MPA', (86, 96))	('V600E', 'SUBSTITUTION', 'None', (125, 130))	('tumors', 'Disease', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('V600K', 'Var', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('CHEK2', 'Gene', (53, 58))
58258	28858076	What caused the upregulation c-Kit and KIT expression in V600K tumors is unclear.	('c-Kit', 'Gene', '3815', (29, 34))	('KIT', 'molecular_function', 'GO:0005020', ('39', '42'))	('upregulation', 'PosReg', (16, 28))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('KIT', 'Protein', (39, 42))	('tumors', 'Disease', (63, 69))	('V600K', 'Var', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('V600K', 'Mutation', 'rs121913227', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('expression', 'MPA', (43, 53))	('c-Kit', 'Gene', (29, 34))
58260	28858076	However, MITF gene expression did not differ between V600K and V600E tumors (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MITF', 'Gene', '4286', (9, 13))	('V600E', 'Var', (63, 68))	('MITF', 'Gene', (9, 13))	('V600K', 'Var', (53, 58))	('V600E', 'SUBSTITUTION', 'None', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('V600K', 'Mutation', 'rs121913227', (53, 58))
58261	28858076	We found that mir-222 expression was significantly down-regulated in V600K tumors compared to V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('V600K', 'Var', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('V600K', 'Mutation', 'rs121913227', (69, 74))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('V600E', 'Var', (94, 99))	('V600E', 'SUBSTITUTION', 'None', (94, 99))	('down-regulated', 'NegReg', (51, 65))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mir-222', 'Gene', '407007', (14, 21))	('mir-222', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('expression', 'MPA', (22, 32))
58264	28858076	If so, what caused the down-regulation of mir-222 in V600K tumors?	('V600K', 'Var', (53, 58))	('down-regulation', 'NegReg', (23, 38))	('mir-222', 'Gene', '407007', (42, 49))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('regulation', 'biological_process', 'GO:0065007', ('28', '38'))	('mir-222', 'Gene', (42, 49))	('V600K', 'Mutation', 'rs121913227', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
58265	28858076	No differential methylation changes (TCGA methylation450 data, not shown) between V600K and V600E tumors were found in the promoter of human mir-222 gene.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('human', 'Species', '9606', (135, 140))	('V600K', 'Var', (82, 87))	('methylation', 'MPA', (16, 27))	('mir-222', 'Gene', '407007', (141, 148))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('V600E', 'Var', (92, 97))	('V600E', 'SUBSTITUTION', 'None', (92, 97))	('mir-222', 'Gene', (141, 148))	('V600K', 'Mutation', 'rs121913227', (82, 87))
58268	28858076	PLZF (ZBTB16) expression was not differential between V600K and V600E subtypes, however (data not shown).	('PLZF', 'Gene', (0, 4))	('ZBTB16', 'Gene', (6, 12))	('expression', 'MPA', (14, 24))	('V600K', 'Var', (54, 59))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('PLZF', 'Gene', '7704', (0, 4))	('ZBTB16', 'Gene', '7704', (6, 12))	('V600K', 'Mutation', 'rs121913227', (54, 59))	('V600E', 'Var', (64, 69))
58270	28858076	Although FOSL2 and RUNX3 were significantly down-regulated in V600K tumors compared to V600E tumors, whether either of the two played a role in the differential regulation of mir-222 expression is unclear.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('V600E', 'Var', (87, 92))	('V600K', 'Mutation', 'rs121913227', (62, 67))	('RUNX3', 'Gene', '864', (19, 24))	('FOSL2', 'Gene', (9, 14))	('FOSL2', 'Gene', '2355', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('V600E', 'SUBSTITUTION', 'None', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('V600K', 'Var', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('regulation', 'biological_process', 'GO:0065007', ('161', '171'))	('mir-222', 'Gene', '407007', (175, 182))	('RUNX3', 'Gene', (19, 24))	('mir-222', 'Gene', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (93, 99))	('down-regulated', 'NegReg', (44, 58))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (93, 99))
58271	28858076	Hypoxia has been shown to down-regulate mir-222 expression, raising the question whether hypoxia in V600K tumors is more severe than in V600E tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('hypoxia', 'Disease', (89, 96))	('tumors', 'Disease', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('V600E', 'SUBSTITUTION', 'None', (136, 141))	('hypoxia', 'Disease', 'MESH:D000860', (89, 96))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (48, 58))	('V600K', 'Mutation', 'rs121913227', (100, 105))	('tumors', 'Disease', (142, 148))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('mir-222', 'Gene', '407007', (40, 47))	('mir-222', 'Gene', (40, 47))	('Hypoxia', 'Disease', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('V600K', 'Var', (100, 105))	('down-regulate', 'NegReg', (26, 39))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('V600E', 'Var', (136, 141))
58274	28858076	We believe that enhanced growth and pro-survival signals in V600K tumors compared to V600E tumors may be in part responsible for the observed clinical aggressiveness of V600K tumors.	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (175, 181))	('V600K', 'Var', (169, 174))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('growth', 'CPA', (25, 31))	('V600E', 'Var', (85, 90))	('V600K', 'Mutation', 'rs121913227', (60, 65))	('enhanced', 'PosReg', (16, 24))	('pro-survival', 'biological_process', 'GO:0043066', ('36', '48'))	('V600K', 'SUBSTITUTION', 'None', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('V600K', 'SUBSTITUTION', 'None', (169, 174))	('V600K', 'Mutation', 'rs121913227', (169, 174))	('aggressiveness', 'Phenotype', 'HP:0000718', (151, 165))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('V600E', 'SUBSTITUTION', 'None', (85, 90))	('tumors', 'Disease', (66, 72))	('V600K', 'Var', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
58275	28858076	Lastly, our observations/conclusions were built on a small number of V600K tumors (13-19) vs a more substantial number of V600E tumors (91-124).	('V600K', 'Var', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('V600K', 'Mutation', 'rs121913227', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('V600E', 'Var', (122, 127))	('V600E', 'SUBSTITUTION', 'None', (122, 127))
58276	28858076	The sample sizes for some of the differentially expressed proteins identified in V600K tumors were smaller (4-13).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('V600K', 'Var', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('V600K', 'Mutation', 'rs121913227', (81, 86))
58277	28858076	Small sample size in V600K tumors is a major limitation of our study.	('V600K', 'Var', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('V600K', 'Mutation', 'rs121913227', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))
58278	28858076	Furthermore, underlying differences between V600E and V600K tumors are likely complex; c-Kit/mir-222 are likely not the only players.	('mir-222', 'Gene', (93, 100))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('mir-222', 'Gene', '407007', (93, 100))	('V600K', 'Var', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('c-Kit', 'Gene', (87, 92))	('c-Kit', 'Gene', '3815', (87, 92))	('V600K', 'Mutation', 'rs121913227', (54, 59))	('V600E', 'Var', (44, 49))	('tumors', 'Disease', (60, 66))
58279	33431815	Ultraviolet radiation drives mutations in a subset of mucosal melanomas Although identified as the key environmental driver of common cutaneous melanoma, the role of ultraviolet radiation (UVR)-induced DNA damage in mucosal melanoma is poorly defined.	('mucosal melanomas', 'Disease', 'MESH:D008545', (54, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('DNA', 'cellular_component', 'GO:0005574', ('202', '205'))	('cutaneous melanoma', 'Disease', (134, 152))	('mutations', 'Var', (29, 38))	('mucosal melanoma', 'Disease', 'MESH:D008545', (216, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('mucosal melanomas', 'Disease', (54, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('mucosal melanoma', 'Disease', 'MESH:D008545', (54, 70))	('mucosal melanoma', 'Disease', (216, 232))
58282	33431815	Mucosal melanomas are not thought to be UV radiation (UVR)-driven, yet some present UVR-related mutations.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('mutations', 'Var', (96, 105))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
58283	33431815	Here the authors show that some mucosal melanomas, especially conjunctival, present mutations characteristic of UVR exposure, yet share structural variants typical of other mucosal melanomas.	('mucosal melanomas', 'Disease', (32, 49))	('mucosal melanomas', 'Disease', 'MESH:D008545', (173, 190))	('conjunctival', 'Disease', (62, 74))	('mucosal melanomas', 'Disease', 'MESH:D008545', (32, 49))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('mutations', 'Var', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (181, 190))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('present', 'Reg', (76, 83))	('mucosal melanomas', 'Disease', (173, 190))
58286	33431815	For example, KIT and SF3B1 mutations are more common in mucosal melanomas, whereas BRAF and NRAS mutations are more common in common cutaneous melanomas.	('mutations', 'Var', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('common', 'Reg', (46, 52))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('SF3B1', 'Gene', '23451', (21, 26))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('KIT', 'Gene', '3815', (13, 16))	('NRAS', 'Gene', '4893', (92, 96))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (133, 152))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (133, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('BRAF', 'Gene', '673', (83, 87))	('mucosal melanomas', 'Disease', 'MESH:D008545', (56, 73))	('BRAF', 'Gene', (83, 87))	('cutaneous melanomas', 'Disease', (133, 152))	('NRAS', 'Gene', (92, 96))	('SF3B1', 'Gene', (21, 26))	('mucosal melanomas', 'Disease', (56, 73))	('KIT', 'Gene', (13, 16))
58296	33431815	Mutational signature analysis on our WGS data revealed a predominance of COSMIC SBS7v2 in nine of the conjunctival melanomas, whereas one conjunctival melanoma and the other eight mucosal melanomas were dominated by the SBS1v2 (age-related), SBS5v2 (ubiquitous), and SBS3v2 (BRCA1, BRCA2, and PALB2-associated) (Fig.	('BRCA1', 'Gene', '672', (275, 280))	('conjunctival melanomas', 'Disease', (102, 124))	('BRCA2', 'Gene', '675', (282, 287))	('BRCA1', 'Gene', (275, 280))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (138, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mucosal melanomas', 'Disease', (180, 197))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (138, 159))	('PALB2', 'Gene', (293, 298))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('PALB2', 'Gene', '79728', (293, 298))	('conjunctival melanoma', 'Disease', (138, 159))	('SBS7v2', 'Var', (80, 86))	('BRCA2', 'Gene', (282, 287))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (102, 124))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (102, 123))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (102, 123))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mucosal melanomas', 'Disease', 'MESH:D008545', (180, 197))
58298	33431815	Compared to their non-SBS7v2 counterparts, the SBS7v2 mucosal melanomas presented higher proportions of C-to-T transitions at dipyrimidines (mean 84.7% versus 29.0%; P < 0.0001; Fig.	('SBS7v2', 'Var', (47, 53))	('dipyrimidines', 'Chemical', '-', (126, 139))	('mucosal melanomas', 'Disease', 'MESH:D008545', (54, 71))	('higher', 'PosReg', (82, 88))	('mucosal melanomas', 'Disease', (54, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('C-to-T transitions at dipyrimidines', 'MPA', (104, 139))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
58299	33431815	Similarly, compared to their non-SBS7v2 counterparts, the SBS7v2 cutaneous melanomas presented higher proportions of C-to-T transitions at dipyrimidines (median 82.34% versus 36.09%; P < 0.0001; Fig.	('SBS7v2', 'Var', (58, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (65, 84))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (65, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('higher', 'PosReg', (95, 101))	('cutaneous melanomas', 'Disease', (65, 84))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('dipyrimidines', 'Chemical', '-', (139, 152))	('C-to-T transitions at dipyrimidines', 'MPA', (117, 152))
58305	33431815	Previous studies have reported increased numbers of structural variants and indels in mucosal melanomas compared to common cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (123, 142))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (123, 142))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('cutaneous melanomas', 'Disease', (123, 142))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('mucosal melanomas', 'Disease', (86, 103))	('mucosal melanomas', 'Disease', 'MESH:D008545', (86, 103))	('indels', 'Var', (76, 82))	('structural variants', 'Var', (52, 71))
58307	33431815	Consistent with previous studies, the mucosal melanomas presented more structural variants and indels than common cutaneous melanomas (Fig.	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (114, 133))	('indels', 'Var', (95, 101))	('mucosal melanomas', 'Disease', (38, 55))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (114, 133))	('structural variants', 'Var', (71, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('cutaneous melanomas', 'Disease', (114, 133))	('mucosal melanomas', 'Disease', 'MESH:D008545', (38, 55))
58308	33431815	Critically, we observed no significant differences between the SBS7v2-dominant and the non-SBS7v2 cohorts (Fig.	('SBS7v2-dominant', 'Var', (63, 78))	('Critically', 'Disease', (0, 10))	('Critically', 'Disease', 'MESH:D016638', (0, 10))
58309	33431815	This was recapitulated in the validation cohort, where we again observed no significant difference in chromosomal structural variants or number of indels between the SBS7v2-dominant and non-SBS7v2 mucosal melanomas (Supplementary Fig.	('mucosal melanomas', 'Disease', (197, 214))	('melanomas', 'Phenotype', 'HP:0002861', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('mucosal melanomas', 'Disease', 'MESH:D008545', (197, 214))	('SBS7v2-dominant', 'Var', (166, 181))
58312	33431815	Note, however, that SBS7v2 also dominated the genomes of MuM10, MuM11, and MuM18, which were from the tarsal conjunctiva which is considered to be more sun-protected, and SBS7v2 dominated the genome of MuM15, which was a large lesion spanning the sun-protected fornix and the sun-exposed caruncle (Supplementary Table 1).	('SBS7v2', 'Var', (20, 26))	('MuM1', 'Gene', '84939', (57, 61))	('MuM1', 'Gene', (64, 68))	('MuM1', 'Gene', '84939', (75, 79))	('MuM1', 'Gene', (57, 61))	('MuM1', 'Gene', '84939', (202, 206))	('MuM1', 'Gene', (75, 79))	('MuM1', 'Gene', (202, 206))	('SBS7v2', 'Var', (171, 177))	('MuM1', 'Gene', '84939', (64, 68))
58319	33431815	BRAF mutations are generally associated with common cutaneous melanoma, but only weakly associated with mucosal melanoma.	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('mucosal melanoma', 'Disease', (104, 120))	('mutations', 'Var', (5, 14))	('mucosal melanoma', 'Disease', 'MESH:D008545', (104, 120))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('associated', 'Reg', (29, 39))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
58320	33431815	We observed that six of the nine UVR mucosal melanomas carried BRAF mutations, whereas only one of the nine non-UVR mucosal melanomas had a BRAF mutation (Fig.	('melanomas', 'Phenotype', 'HP:0002861', (124, 133))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('mucosal melanomas', 'Disease', (116, 133))	('mucosal melanomas', 'Disease', 'MESH:D008545', (37, 54))	('BRAF', 'Gene', '673', (140, 144))	('mucosal melanomas', 'Disease', 'MESH:D008545', (116, 133))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))	('BRAF', 'Gene', (140, 144))	('BRAF', 'Gene', '673', (63, 67))	('mutations', 'Var', (68, 77))	('BRAF', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('mucosal melanomas', 'Disease', (37, 54))
58321	33431815	Notably, eight of the nine UVR-exposed mucosal melanomas and all 51 UVR-exposed cutaneous melanomas carried mutations in  one to eleven known melanoma genes, with the remaining mucosal melanoma (MuM10) carrying a frame-shift mutation in the melanocyte gene TYRP1 (Fig.	('melanoma', 'Disease', (90, 98))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (80, 99))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (80, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))	('mucosal melanoma', 'Disease', 'MESH:D008545', (177, 193))	('MuM1', 'Gene', (195, 199))	('MuM1', 'Gene', '84939', (195, 199))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('cutaneous melanomas', 'Disease', (80, 99))	('mucosal melanoma', 'Disease', (177, 193))	('TYRP1', 'Gene', '7306', (257, 262))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('mucosal melanoma', 'Disease', 'MESH:D008545', (39, 55))	('TYRP1', 'Gene', (257, 262))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('carried', 'Reg', (100, 107))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('mutations', 'Var', (108, 117))	('mucosal melanomas', 'Disease', 'MESH:D008545', (39, 56))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('frame-shift mutation', 'Var', (213, 233))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('mucosal melanomas', 'Disease', (39, 56))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
58322	33431815	Thus, FGFR2/4, ERBB4, NF1, CDKN2A, NFKBIE, SALL4, TERT, GRIN2A, and TP53 mutations were restricted to UVR-exposed melanomas (Fig.	('NF1', 'Gene', '4763', (22, 25))	('CDKN2A', 'Gene', (27, 33))	('ERBB4', 'Gene', '2066', (15, 20))	('TP53', 'Gene', (68, 72))	('FGFR2/4', 'Gene', (6, 13))	('NF1', 'Gene', (22, 25))	('ERBB4', 'Gene', (15, 20))	('SALL4', 'Gene', '57167', (43, 48))	('FGFR2/4', 'Gene', '2263;2264', (6, 13))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('6', '10'))	('melanomas', 'Disease', (114, 123))	('TERT', 'Gene', (50, 54))	('CDKN2A', 'Gene', '1029', (27, 33))	('GRIN2A', 'Gene', '2903', (56, 62))	('TERT', 'Gene', '7015', (50, 54))	('SALL4', 'Gene', (43, 48))	('NFKBIE', 'Gene', '4794', (35, 41))	('TP53', 'Gene', '7157', (68, 72))	('NFKBIE', 'Gene', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('GRIN2A', 'Gene', (56, 62))	('mutations', 'Var', (73, 82))
58323	33431815	Conversely, the non-UVR-exposed mucosal and cutaneous melanomas carried mutations in only two (1 sample), one (5 samples), or none (6 samples) of the melanoma genes (Fig.	('mutations', 'Var', (72, 81))	('cutaneous melanomas', 'Disease', (44, 63))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (44, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (44, 63))
58324	33431815	Additionally, 31 (52%) UVR-exposed melanomas had TERT and/or TERT promoter mutations, but only one (8%) non-UVR-exposed melanoma had a mutation in this gene (Fig.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('TERT', 'Gene', (61, 65))	('TERT', 'Gene', '7015', (61, 65))	('melanomas', 'Disease', (35, 44))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('TERT', 'Gene', (49, 53))	('mutations', 'Var', (75, 84))	('TERT', 'Gene', '7015', (49, 53))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
58325	33431815	These data show remarkable enrichment for the same driver oncogene mutations in UVR-exposed cutaneous melanoma and UVR-exposed mucosal melanoma.	('mucosal melanoma', 'Disease', (127, 143))	('mucosal melanoma', 'Disease', 'MESH:D008545', (127, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('mutations', 'Var', (67, 76))	('cutaneous melanoma', 'Disease', (92, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (92, 110))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (92, 110))
58326	33431815	We previously reported that mutations in a ten-gene panel (LRP1B, GPR98, XIRP2, PKHD1L1, USH2A, DNAH9, PCDH15, DNAH10, TP53, PCDHAC1) were a surrogate of UVR exposure.	('DNAH9', 'Gene', (96, 101))	('XIRP2', 'Gene', (73, 78))	('PCDH15', 'Gene', (103, 109))	('USH2A', 'Gene', (89, 94))	('PKHD1L1', 'Gene', '93035', (80, 87))	('TP53', 'Gene', '7157', (119, 123))	('PKHD1L1', 'Gene', (80, 87))	('GPR98', 'Gene', (66, 71))	('DNAH9', 'Gene', '1770', (96, 101))	('LRP1B', 'Gene', (59, 64))	('PCDH15', 'Gene', '65217', (103, 109))	('DNAH10', 'Gene', (111, 117))	('PCDHAC1', 'Gene', '56135', (125, 132))	('USH2A', 'Gene', '7399', (89, 94))	('GPR98', 'Gene', '84059', (66, 71))	('XIRP2', 'Gene', '129446', (73, 78))	('TP53', 'Gene', (119, 123))	('LRP1B', 'Gene', '53353', (59, 64))	('mutations', 'Var', (28, 37))	('DNAH10', 'Gene', '196385', (111, 117))	('PCDHAC1', 'Gene', (125, 132))
58329	33431815	2e), including all nine UVR mucosal melanomas, eight of which carried mutations in two or more of these genes (Fig.	('UVR', 'Disease', (24, 27))	('mutations', 'Var', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mucosal melanomas', 'Disease', (28, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('mucosal melanomas', 'Disease', 'MESH:D008545', (28, 45))
58333	33431815	Our analysis revealed particularly striking similarities between UVR-exposed mucosal melanomas and UVR-driven common cutaneous melanomas, as both presented high mutation burdens and abundant mutations that activate the BRAF-ERK pathway.	('mucosal melanomas', 'Disease', (77, 94))	('ERK', 'Gene', (224, 227))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (117, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('activate', 'PosReg', (206, 214))	('mutations', 'Var', (191, 200))	('cutaneous melanomas', 'Disease', (117, 136))	('mucosal melanomas', 'Disease', 'MESH:D008545', (77, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', (219, 223))	('BRAF', 'Gene', '673', (219, 223))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('ERK', 'Gene', '5594', (224, 227))	('ERK', 'molecular_function', 'GO:0004707', ('224', '227'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (117, 136))
58334	33431815	Notably, BRAF mutations are rare in mucosal melanoma compared to common cutaneous melanoma, so BRAF mutation testing is not recommended or reimbursed in some jurisdictions.	('mucosal melanoma', 'Disease', 'MESH:D008545', (36, 52))	('cutaneous melanoma', 'Disease', (72, 90))	('BRAF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('BRAF', 'Gene', '673', (95, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('BRAF', 'Gene', (95, 99))	('mucosal melanoma', 'Disease', (36, 52))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
58335	33431815	However, we show that UVR-driven mucosal melanomas harbor high frequency BRAF mutations, so could benefit from BRAF and MEK targeted therapies.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('BRAF', 'Gene', '673', (73, 77))	('MEK', 'Gene', (120, 123))	('mucosal melanomas', 'Disease', 'MESH:D008545', (33, 50))	('MEK', 'Gene', '5609', (120, 123))	('mutations', 'Var', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (73, 77))	('benefit', 'PosReg', (98, 105))	('mucosal melanomas', 'Disease', (33, 50))	('BRAF', 'Gene', (111, 115))
58341	33431815	Despite the similarities in mutation burden and oncogene pathway activation, we note that chromosomal structural variations did not distinguish UVR from non-UVR mucosal melanomas, but did distinguish mucosal from common cutaneous melanoma.	('mucosal melanomas', 'Disease', (161, 178))	('cutaneous melanoma', 'Disease', (220, 238))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (220, 238))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (220, 238))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('mucosal', 'Disease', (200, 207))	('mucosal melanomas', 'Disease', 'MESH:D008545', (161, 178))	('distinguish', 'Reg', (188, 199))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('variations', 'Var', (113, 123))
58343	33431815	Together, these data show us that mucosal melanomas do not belong to a homogeneous group of diseases and suggest that tumors arising from mucosal melanocytes are subject to a common tumorigenic process resulting in the accumulation of structural genome variations, to which are added UVR-driven processes in a subset of cases.	('variations', 'Var', (253, 263))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (182, 187))	('accumulation', 'PosReg', (219, 231))	('mucosal melanomas', 'Disease', (34, 51))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('mucosal melanomas', 'Disease', 'MESH:D008545', (34, 51))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (118, 123))	('structural genome variations', 'Var', (235, 263))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
58344	33431815	This aligns with recent reports that SF3B1 R625 mutations are recurrently present in vulvo-vaginal and anorectal melanomas but not in other mucosal locations.	('anorectal melanomas', 'Disease', 'MESH:D008545', (103, 122))	('SF3B1', 'Gene', '23451', (37, 42))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('vulvo-vaginal', 'Disease', (85, 98))	('R625 mutations', 'Var', (43, 57))	('SF3B1', 'Gene', (37, 42))	('mutations', 'Var', (48, 57))	('anorectal melanomas', 'Disease', (103, 122))	('present', 'Reg', (74, 81))
58346	33431815	The UVR-driven mucosal melanomas tend to arise on sun-exposed sites such as the conjunctiva and lips, but sun exposure per se does not identify this subset of mucosal melanomas, as highlighted by the presence of non-SBS7v2 tumors at potentially sun-exposed sites and SBS7v2 tumors at more sun-protected sites.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Disease', (223, 229))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('lip', 'Disease', 'MESH:D008047', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('non-SBS7v2', 'Var', (212, 222))	('tumors', 'Disease', (274, 280))	('mucosal melanomas', 'Disease', 'MESH:D008545', (159, 176))	('mucosal melanomas', 'Disease', 'MESH:D008545', (15, 32))	('lip', 'Disease', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('melanomas', 'Phenotype', 'HP:0002861', (167, 176))	('mucosal melanomas', 'Disease', (159, 176))	('SBS7v2', 'Gene', (267, 273))	('mucosal melanomas', 'Disease', (15, 32))
58347	33431815	Whilst imprecision in site reporting may play a role in this, one possibility is that mucosal cells in sun-exposed sites may accumulate UVR-induced mutations and expand into large clones of mutant cells, extending into sun-protected areas where such cells could further develop into a melanoma.	('mutations', 'Var', (148, 157))	('accumulate', 'PosReg', (125, 135))	('mutant', 'Var', (190, 196))	('UVR-induced', 'Gene', (136, 147))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))
58348	33431815	Conversely, the presence of non-SBS7v2 tumors at potentially sun-exposed sites is consistent with our previously report that in a UVR/BRAFV600E-driven mouse melanoma model, a small number of tumors developed without evidence of UVR-associated DNA damage.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('BRAFV600E', 'Mutation', 'rs113488022', (134, 143))	('mouse', 'Species', '10090', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', (39, 45))	('non-SBS7v2', 'Var', (28, 38))
58369	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))
58371	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))
58372	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))
58373	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))
58374	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'))
58378	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))
58384	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))	('patients', 'Species', '9606', (379, 387))	('interleukin-2', 'Gene', '3558', (241, 254))	('mucosal melanoma', 'Disease', 'MESH:D008545', (318, 334))	('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))	('mucosal melanoma', 'Disease', (318, 334))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('vemurafenib', 'Chemical', 'MESH:D000077484', (167, 178))	('mutation', 'Var', (36, 44))
58385	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))
58386	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))	('CKIT', 'Gene', '3815', (0, 4))	('L576P', 'Mutation', 'rs121913513', (149, 154))	('K642E', 'Var', (159, 164))	('CKIT', 'Gene', '3815', (126, 130))	('patients', 'Species', '9606', (65, 73))	('K642E', 'Mutation', 'rs121913512', (159, 164))	('L576P', 'Var', (149, 154))	('c-KIT', 'Gene', (216, 221))	('CKIT', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
58390	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))	('GNA11', 'Gene', (32, 37))	('uveal melanoma', 'Disease', (86, 100))	('GNAQ', 'Gene', (23, 27))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))
58391	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))
58392	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))
58393	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))
58394	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))
58401	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))	('patient', 'Species', '9606', (30, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (131, 145))	('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))
58407	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))
58408	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))
58409	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))	('uveal melanoma', 'Disease', 'MESH:C536494', (225, 239))	('patient', 'Species', '9606', (24, 31))	('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))
58415	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))
58417	25030020	To our knowledge, this is the first case report to demonstrate mucosal melanoma harboring a GNAQ mutation.	('GNAQ', 'Gene', (92, 96))	('mucosal melanoma', 'Disease', (63, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mucosal melanoma', 'Disease', 'MESH:D008545', (63, 79))	('mutation', 'Var', (97, 105))	('GNAQ', 'Gene', '2776', (92, 96))
58436	22833605	Briefly, extensive laboratory data and animal experiments (on DNA mutations and repair, immune function, cell integrity, cell cycle regulation, and other critical biological functions) documented a role for ultraviolet A in skin carcinogenesis   and that the body's repair and removal of damaged DNA was less effective when the damage was caused by ultraviolet A rather than by ultraviolet B.	('mutations', 'Var', (66, 75))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (224, 243))	('men', 'Species', '9606', (189, 192))	('men', 'Species', '9606', (52, 55))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('121', '142'))	('skin carcinogenesis', 'Disease', (224, 243))	('DNA', 'cellular_component', 'GO:0005574', ('296', '299'))
58437	22833605	Experiments in human volunteers showed that exposure to ultraviolet A and ultraviolet B can weaken the immune system through mechanisms that interact and overlap, increasing vulnerability to cancer as well as to other diseases.	('cancer', 'Disease', (191, 197))	('weaken', 'NegReg', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('human', 'Species', '9606', (15, 20))	('weaken the immune system', 'Phenotype', 'HP:0002721', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('immune system', 'CPA', (103, 116))	('ultraviolet B', 'Var', (74, 87))	('increasing', 'PosReg', (163, 173))	('men', 'Species', '9606', (6, 9))
58544	26541511	the BRAF mutational status, the presence of brain metastases, the lactate dehydrogenase (LDH) level prior to receiving ipilimumab [<2-fold upper level norm (ULN) vs. >=2x ULN], the number of ipilimumab doses (<4 vs. 4), and the absolute lymphocyte count (ALC) (<1000/microl vs. >=1000/microl) before the first (week 1), the second (week 4) and the third dose (week 7) of ipilimumab.	('mutational', 'Var', (9, 19))	('ipilimumab', 'Chemical', 'MESH:D000074324', (191, 201))	('BRAF', 'Gene', (4, 8))	('brain metastases', 'Disease', 'MESH:D009362', (44, 60))	('BRAF', 'Gene', '673', (4, 8))	('brain metastases', 'Disease', (44, 60))	('ipilimumab', 'Chemical', 'MESH:D000074324', (119, 129))	('ipilimumab', 'Chemical', 'MESH:D000074324', (371, 381))
58576	26541511	BRAF mutational status, the ALC before the first and the third dose of ipilimumab in patients with cutaneous melanoma were not associated with OS.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('patients', 'Species', '9606', (85, 93))	('BRAF', 'Gene', '673', (0, 4))	('mutational', 'Var', (5, 15))	('ipilimumab', 'Chemical', 'MESH:D000074324', (71, 81))	('cutaneous melanoma', 'Disease', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('BRAF', 'Gene', (0, 4))	('OS', 'Chemical', '-', (143, 145))
58578	26541511	patients with less than 4 doses were at higher risk of death; hazard ratio 4.3, 95 % CI 2.3-8.0), an ALC >=1000/microl before the second dose of ipilimumab (week 4) (e.g.	('ipilimumab', 'Chemical', 'MESH:D000074324', (145, 155))	('patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (55, 60))	('death', 'Disease', (55, 60))	('ALC', 'Var', (101, 104))
58579	26541511	patients with ALC <1000/microl were at higher risk of death; hazard ratio 2.0; 95 % CI 1.1-3.8), and the absence of brain metastases (e.g.	('death', 'Disease', 'MESH:D003643', (54, 59))	('death', 'Disease', (54, 59))	('ALC <1000/microl', 'Var', (14, 30))	('patients', 'Species', '9606', (0, 8))	('brain metastases', 'Disease', 'MESH:D009362', (116, 132))	('brain metastases', 'Disease', (116, 132))
58629	32226509	A Functional Synonymous Variant in PDGFRA Is Associated with Better Survival in Acral Melanoma Purpose: Polymorphisms of genes in the platelet-derived growth factor (PDGF) signaling pathway have been found to predict cutaneous melanoma (CM) survival, but their clinical effects in acral melanoma (AM) patients have not been explored.	('Variant', 'Var', (24, 31))	('patients', 'Species', '9606', (301, 309))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('134', '164'))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('predict', 'Reg', (209, 216))	('PDGF', 'molecular_function', 'GO:0005161', ('166', '170'))	('Acral Melanoma', 'Phenotype', 'HP:0012060', (80, 94))	('acral melanoma', 'Disease', 'MESH:D008545', (281, 295))	('CM', 'Phenotype', 'HP:0012056', (237, 239))	('acral melanoma', 'Phenotype', 'HP:0012060', (281, 295))	('Polymorphisms', 'Var', (104, 117))	('AM', 'Phenotype', 'HP:0012060', (297, 299))	('PDGFRA', 'Gene', (35, 41))	('PDGFRA', 'Gene', '5156', (35, 41))	('Acral Melanoma', 'Disease', 'MESH:D008545', (80, 94))	('cutaneous melanoma', 'Disease', (217, 235))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (217, 235))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (217, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('CM', 'Disease', 'MESH:D009202', (237, 239))	('Melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('Acral Melanoma', 'Disease', (80, 94))	('acral melanoma', 'Disease', (281, 295))	('signaling pathway', 'biological_process', 'GO:0007165', ('172', '189'))
58630	32226509	The aim of this study was to characterize the functional effect of the tag single-nucleotide polymorphism (SNP) rs2228230:C>T and assess its association with clinical outcomes in AM patients.	('AM', 'Phenotype', 'HP:0012060', (179, 181))	('association', 'Interaction', (141, 152))	('rs2228230:C>T', 'DBSNP_MENTION', 'None', (112, 125))	('patients', 'Species', '9606', (182, 190))	('rs2228230:C>T', 'Var', (112, 125))
58632	32226509	PDGF receptor alpha (PDGFRA) expression vectors with the rs2228230:C or rs2228230:T allele were constructed to evaluate the expression and signaling activity of PDGFRA.	('expression vectors', 'Species', '29278', (29, 47))	('PDGFRA', 'Gene', (21, 27))	('rs2228230', 'Mutation', 'rs2228230', (57, 66))	('rs2228230:T', 'Var', (72, 83))	('expression', 'Species', '29278', (124, 134))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('rs2228230', 'Mutation', 'rs2228230', (72, 81))	('expression', 'Species', '29278', (29, 39))	('PDGF', 'molecular_function', 'GO:0005161', ('0', '4'))	('rs2228230:C', 'Var', (57, 68))
58635	32226509	Results: In silico analyses indicated that the rs2228230:T allele increases the minimum free energy and reduces synonymous codon usage.	('minimum free energy', 'MPA', (80, 99))	('synonymous codon usage', 'MPA', (112, 134))	('rs2228230', 'Mutation', 'rs2228230', (47, 56))	('increases', 'PosReg', (66, 75))	('reduces', 'NegReg', (104, 111))	('rs2228230', 'Var', (47, 56))
58636	32226509	The rs2228230:T allele decreased the expression of PDGFRA by reducing the stability of its mRNA and protein as well as the signaling activity of the MAPK and PI3K/AKT pathways.	('reducing', 'NegReg', (61, 69))	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('rs2228230:T', 'Var', (4, 15))	('rs2228230', 'Mutation', 'rs2228230', (4, 13))	('AKT', 'Gene', (163, 166))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('PDGFRA', 'Gene', (51, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('149', '153'))	('signaling activity', 'MPA', (123, 141))	('expression', 'Species', '29278', (37, 47))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('expression', 'MPA', (37, 47))	('decreased', 'NegReg', (23, 32))	('AKT', 'Gene', '207', (163, 166))
58637	32226509	PDGFRA mRNA and protein expression was significantly reduced in AM tissues with the rs2228230:T allele.	('expression', 'Species', '29278', (24, 34))	('PDGFRA', 'Gene', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('reduced', 'NegReg', (53, 60))	('rs2228230:T', 'Var', (84, 95))	('AM', 'Phenotype', 'HP:0012060', (64, 66))	('rs2228230', 'Mutation', 'rs2228230', (84, 93))
58638	32226509	The progression-free survival and overall survival of AM patients with the rs2228230:T allele were significantly longer than those of patients with the CC genotype.	('progression-free survival', 'CPA', (4, 29))	('rs2228230', 'Mutation', 'rs2228230', (75, 84))	('longer', 'PosReg', (113, 119))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (134, 142))	('AM', 'Phenotype', 'HP:0012060', (54, 56))	('rs2228230:T', 'Var', (75, 86))	('overall survival', 'CPA', (34, 50))
58639	32226509	Conclusion: Our study indicated that rs2228230:T can reduce the expression of PDGFRA and downstream signaling activity and is associated with better survival in AM patients.	('reduce', 'NegReg', (53, 59))	('rs2228230', 'Mutation', 'rs2228230', (37, 46))	('rs2228230:T', 'Var', (37, 48))	('AM', 'Phenotype', 'HP:0012060', (161, 163))	('expression', 'MPA', (64, 74))	('downstream signaling activity', 'MPA', (89, 118))	('patients', 'Species', '9606', (164, 172))	('better', 'PosReg', (142, 148))	('PDGFRA', 'Protein', (78, 84))	('survival', 'CPA', (149, 157))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('expression', 'Species', '29278', (64, 74))
58640	32226509	PDGFRA plays a role in tumor progression, and mutations in PDGFRA have been associated with idiopathic hypereosinophilic syndrome, gastrointestinal stromal tumors, and several other cancers.	('gastrointestinal stromal tumors', 'Disease', (131, 162))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (156, 161))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('idiopathic hypereosinophilic syndrome', 'Disease', 'MESH:D017681', (92, 129))	('idiopathic hypereosinophilic syndrome', 'Disease', (92, 129))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('PDGFRA', 'Gene', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('associated', 'Reg', (76, 86))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (131, 162))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (131, 162))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('hypereosinophilic syndrome', 'Phenotype', 'HP:0032061', (103, 129))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
58641	32226509	We and others have demonstrated that mutations, increased copy numbers, and overexpression of PDGFRA occur in melanoma patients, and that functional mutations of PDGFRA increase MAPK and PI3K/AKT pathway activation, which can be inhibited by several tyrosine kinase inhibitors such as imatinib, crenolanib, and sunitinib.	('imatinib', 'Chemical', 'MESH:D000068877', (285, 293))	('AKT', 'Gene', '207', (192, 195))	('PDGFRA', 'Gene', (94, 100))	('overexpression', 'PosReg', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('copy', 'MPA', (58, 62))	('mutations', 'Var', (149, 158))	('PDGFRA', 'Gene', (162, 168))	('AKT', 'Gene', (192, 195))	('increased', 'PosReg', (48, 57))	('activation', 'PosReg', (204, 214))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('178', '182'))	('patients', 'Species', '9606', (119, 127))	('crenolanib', 'Chemical', 'MESH:C577197', (295, 305))	('PI3K', 'molecular_function', 'GO:0016303', ('187', '191'))	('increase', 'PosReg', (169, 177))	('expression', 'Species', '29278', (80, 90))	('sunitinib', 'Chemical', 'MESH:D000077210', (311, 320))
58642	32226509	Besides functional mutations, polymorphisms can also influence susceptibility to disease and response to anticancer drug treatment.	('influence', 'Reg', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('polymorphisms', 'Var', (30, 43))	('cancer', 'Disease', (109, 115))	('susceptibility', 'MPA', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
58643	32226509	A genome-wide association study (GWAS) in Australian and European populations found that the single-nucleotide polymorphism (SNP) rs3219090 within PARP1 is a melanoma susceptibility locus, and subsequent studies demonstrated that the rs3219090 risk allele is correlated with higher expression levels of PARP1 mRNA but longer melanoma-specific survival.	('PARP1', 'Gene', (147, 152))	('rs3219090', 'Mutation', 'rs3219090', (130, 139))	('rs3219090', 'Var', (130, 139))	('expression', 'Species', '29278', (282, 292))	('rs3219090', 'Mutation', 'rs3219090', (234, 243))	('melanoma', 'Phenotype', 'HP:0002861', (325, 333))	('melanoma', 'Disease', (325, 333))	('expression levels', 'MPA', (282, 299))	('PARP1', 'Gene', (303, 308))	('rs3219090', 'Var', (234, 243))	('melanoma', 'Disease', 'MESH:D008545', (325, 333))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('single-nucleotide', 'Var', (93, 110))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('higher', 'PosReg', (275, 281))	('melanoma', 'Disease', (158, 166))	('longer', 'PosReg', (318, 324))
58645	32226509	The genetic variants of members of the PDGF signaling pathway have been demonstrated to predict cutaneous melanoma (CM) survival in patients in the United States.	('CM', 'Phenotype', 'HP:0012056', (116, 118))	('signaling pathway', 'biological_process', 'GO:0007165', ('44', '61'))	('cutaneous melanoma', 'Disease', (96, 114))	('PDGF signaling', 'Gene', (39, 53))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('genetic variants', 'Var', (4, 20))	('predict', 'Reg', (88, 95))	('PDGF', 'molecular_function', 'GO:0005161', ('39', '43'))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('patients', 'Species', '9606', (132, 140))	('CM', 'Disease', 'MESH:D009202', (116, 118))
58647	32226509	However, the clinical relevance of PDGFRA polymorphisms in AM patients has not been explored yet.	('PDGFRA', 'Gene', (35, 41))	('polymorphisms', 'Var', (42, 55))	('patients', 'Species', '9606', (62, 70))	('AM', 'Phenotype', 'HP:0012060', (59, 61))
58648	32226509	rs2228230:C>T is the most common and only tag SNP located within the coding sequence of PDGFRA (Figure S1).	('rs2228230:C>T', 'Var', (0, 13))	('PDGFRA', 'Gene', (88, 94))	('rs2228230:C>T', 'DBSNP_MENTION', 'None', (0, 13))
58650	32226509	The minor T allele of rs2228230 in infants was reported to be associated with a reduced risk of obstructive heart defects after alcohol exposure during the periconceptional period.	('rs2228230', 'Mutation', 'rs2228230', (22, 31))	('heart defects', 'Phenotype', 'HP:0030680', (108, 121))	('reduced', 'NegReg', (80, 87))	('infants', 'Species', '9606', (35, 42))	('rs2228230', 'Var', (22, 31))	('obstructive heart defects', 'Disease', 'MESH:D006331', (96, 121))	('alcohol', 'Chemical', 'MESH:D000438', (128, 135))	('obstructive heart defects', 'Disease', (96, 121))
58651	32226509	Meanwhile, the genotype of rs2228230 was found to be significantly associated with corneal astigmatism according to a meta-analysis of five GWASs of 8,513 Asian individuals.	('rs2228230', 'Var', (27, 36))	('corneal astigmatism', 'Phenotype', 'HP:0025612', (83, 102))	('rs2228230', 'Mutation', 'rs2228230', (27, 36))	('astigmatism', 'Phenotype', 'HP:0000483', (91, 102))	('corneal astigmatism', 'Disease', 'MESH:D001251', (83, 102))	('associated', 'Reg', (67, 77))	('corneal astigmatism', 'Disease', (83, 102))
58652	32226509	The rs2228230:T allele has also been demonstrated to be associated with worse disease-free survival in renal cell carcinoma in a Spanish population.	('renal cell carcinoma', 'Disease', (103, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('rs2228230:T', 'Var', (4, 15))	('rs2228230', 'Mutation', 'rs2228230', (4, 13))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('worse', 'NegReg', (72, 77))	('disease-free survival', 'CPA', (78, 99))
58653	32226509	Therefore, in this study, we investigated the functional effect of rs2228230 through in silico and in vitro studies as well as the association of the rs2228230 genotype with PDGFRA expression and clinical outcomes of AM patients in two independent cohorts.	('PDGFRA', 'Gene', (174, 180))	('rs2228230', 'Mutation', 'rs2228230', (150, 159))	('AM', 'Phenotype', 'HP:0012060', (217, 219))	('rs2228230', 'Mutation', 'rs2228230', (67, 76))	('patients', 'Species', '9606', (220, 228))	('rs2228230', 'Var', (67, 76))	('rs2228230', 'Var', (150, 159))	('expression', 'Species', '29278', (181, 191))
58676	32226509	At 48 h after transfection, cells were starved overnight and exposed to 1 microg/mL MG132 (APExBIO) for 6 h to inhibit protein degradation, and protein was extracted for western blotting.	('inhibit', 'NegReg', (111, 118))	('protein degradation', 'biological_process', 'GO:0030163', ('119', '138'))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('MG132', 'Var', (84, 89))	('protein degradation', 'MPA', (119, 138))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('MG132', 'Chemical', 'MESH:C072553', (84, 89))
58680	32226509	To identify the rs2228230 genotype in the TCGA Skin Cutaneous Melanoma (SKCM) dataset, level 2 TCGA SKCM genotype data were extracted from NCI Genomic Data Commons Data Portal (GDC Legacy Archive) with a Birdseed confidence threshold of <0.05.	('CM', 'Disease', 'MESH:D009202', (102, 104))	('rs2228230', 'Mutation', 'rs2228230', (16, 25))	('Melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('CM', 'Phenotype', 'HP:0012056', (102, 104))	('Skin Cutaneous Melanoma', 'Disease', (47, 70))	('rs2228230', 'Var', (16, 25))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (47, 70))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('CM', 'Disease', 'MESH:D009202', (74, 76))	('CM', 'Phenotype', 'HP:0012056', (74, 76))
58682	32226509	The effect of rs2228230:C>T on the mRNA structures and thermodynamics of PDGFRA were predicted using the RNAfold Web Server.	('rs2228230:C>T', 'Var', (14, 27))	('PDGFRA', 'Gene', (73, 79))	('rs2228230:C>T', 'DBSNP_MENTION', 'None', (14, 27))
58685	32226509	To clarify the association of rs2223230 genotype with PDGFRA expression, we conducted a series of in silico and in vitro analyses.	('expression', 'Species', '29278', (61, 71))	('rs2223230', 'Var', (30, 39))	('PDGFRA', 'Gene', (54, 60))	('rs2223230', 'Mutation', 'rs2223230', (30, 39))
58686	32226509	First, the mRNA secondary structure of full-length PDGFRA was predicted using the RNAfold WebServer, which showed that the mRNA secondary structure of PDGFRA with the rs2228230:C allele (Figure 1A) differed from that with the rs2228230:T allele (Figure 1B).	('rs2228230:C', 'Var', (167, 178))	('rs2228230', 'Mutation', 'rs2228230', (167, 176))	('rs2228230', 'Mutation', 'rs2228230', (226, 235))	('PDGFRA', 'Gene', (151, 157))	('mRNA secondary structure', 'MPA', (123, 147))	('differed', 'Reg', (198, 206))
58687	32226509	The minimum free energy (MFE) values of PDGFRA with the rs2228230:C allele and rs2228230:T allele were predicted to be -1392.95 kcal/mol and -1478.56 kcal/mol, respectively, indicating that the stability of PDGFRA mRNA with the rs2228230:T allele was lower than that with the rs2228230:C allele.	('MFE', 'Chemical', '-', (25, 28))	('rs2228230', 'Var', (79, 88))	('lower', 'NegReg', (251, 256))	('rs2228230', 'Mutation', 'rs2228230', (79, 88))	('rs2228230:C', 'Var', (56, 67))	('rs2228230', 'Mutation', 'rs2228230', (56, 65))	('rs2228230', 'Var', (228, 237))	('stability', 'MPA', (194, 203))	('rs2228230', 'Mutation', 'rs2228230', (276, 285))	('rs2228230', 'Mutation', 'rs2228230', (228, 237))
58688	32226509	Second, we extracted the codon usage values and calculated the RSCU values to verify if the rs2228230:T allele could alter the codon usage of valine.	('valine', 'Chemical', 'MESH:D014633', (142, 148))	('codon usage of valine', 'MPA', (127, 148))	('RSCU', 'Chemical', '-', (63, 67))	('rs2228230:T', 'Var', (92, 103))	('alter', 'Reg', (117, 122))	('rs2228230', 'Mutation', 'rs2228230', (92, 101))
58689	32226509	We found that the RSCU value of GTC (rs2228230:C) is higher than that of GTT (rs2228230:T) at both the genome (Figure 1C) and PDGFRA gene level (Figure 1D).	('rs2228230', 'Mutation', 'rs2228230', (37, 46))	('higher', 'PosReg', (53, 59))	('rs2228230:', 'Var', (37, 47))	('RSCU', 'MPA', (18, 22))	('RSCU', 'Chemical', '-', (18, 22))	('rs2228230', 'Mutation', 'rs2228230', (78, 87))
58691	32226509	These in silico analyses indicated that the rs2228230:T allele might reduce PDGFRA expression through decreased mRNA stability and lower codon usage.	('rs2228230', 'Mutation', 'rs2228230', (44, 53))	('PDGFRA', 'Gene', (76, 82))	('expression', 'Species', '29278', (83, 93))	('codon usage', 'MPA', (137, 148))	('rs2228230:T', 'Var', (44, 55))	('expression', 'MPA', (83, 93))	('lower', 'NegReg', (131, 136))	('reduce', 'NegReg', (69, 75))	('mRNA stability', 'MPA', (112, 126))	('decreased', 'NegReg', (102, 111))
58692	32226509	To validate this hypothesis, we constructed PDGFRA expression vectors with the rs2228230:C allele or rs2228230:T allele containing a FLAG tag sequence and transfected them into HEK293 cells.	('expression vectors', 'Species', '29278', (51, 69))	('rs2228230:T', 'Var', (101, 112))	('rs2228230:C', 'Var', (79, 90))	('rs2228230', 'Mutation', 'rs2228230', (79, 88))	('rs2228230', 'Mutation', 'rs2228230', (101, 110))
58694	32226509	qRT-PCR showed that the relative expression level of PDGFRA mRNA was 1.75-fold lower in cells transfected with the rs2228230:T allele than in cells transfected with the rs2228230:C allele (P < 0.001; Figure 1E).	('lower', 'NegReg', (79, 84))	('expression level', 'MPA', (33, 49))	('expression', 'Species', '29278', (33, 43))	('PDGFRA', 'Gene', (53, 59))	('rs2228230:T', 'Var', (115, 126))	('rs2228230', 'Mutation', 'rs2228230', (115, 124))	('rs2228230', 'Mutation', 'rs2228230', (169, 178))
58695	32226509	Protein expression of PDGFRA was further examined by western blotting after 48 h of transfection, and the results were consistent with those of qRT-PCR; the expression level of PDGFRA was four-fold lower in cells with the rs2228230:T allele (P < 0.001; Figure 1F).	('expression', 'Species', '29278', (157, 167))	('rs2228230', 'Mutation', 'rs2228230', (222, 231))	('expression', 'Species', '29278', (8, 18))	('PDGFRA', 'Gene', (177, 183))	('expression level', 'MPA', (157, 173))	('rs2228230:T', 'Var', (222, 233))	('lower', 'NegReg', (198, 203))
58696	32226509	These results conclusively demonstrated that the genotype of rs2228230 affected the expression of PDGFRA at both the mRNA and protein level.	('affected', 'Reg', (71, 79))	('expression', 'Species', '29278', (84, 94))	('rs2228230', 'Var', (61, 70))	('expression', 'MPA', (84, 94))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('rs2228230', 'Mutation', 'rs2228230', (61, 70))	('PDGFRA', 'Gene', (98, 104))
58697	32226509	We further investigated whether post-transcriptional or post-translational mechanisms were involved in the reduced expression of PDGFRA with the rs2228230:T allele.	('PDGFRA', 'Gene', (129, 135))	('rs2228230:T', 'Var', (145, 156))	('reduced', 'NegReg', (107, 114))	('expression', 'Species', '29278', (115, 125))	('expression', 'MPA', (115, 125))	('rs2228230', 'Mutation', 'rs2228230', (145, 154))
58698	32226509	As shown in Figure 2A, the mRNA decay rate of PDGFRA was significantly higher in cells with the rs2228230:T allele than in cells with the rs2228230:C allele (P < 0.001), indicating that PDGFRA mRNA stability was reduced by the rs2228230:T allele.	('rs2228230:T', 'Var', (227, 238))	('higher', 'PosReg', (71, 77))	('mRNA decay', 'biological_process', 'GO:0006402', ('27', '37'))	('rs2228230:T', 'Var', (96, 107))	('rs2228230', 'Mutation', 'rs2228230', (96, 105))	('rs2228230', 'Mutation', 'rs2228230', (227, 236))	('rs2228230', 'Mutation', 'rs2228230', (138, 147))	('mRNA decay rate', 'MPA', (27, 42))	('mRNA stability', 'MPA', (193, 207))	('reduced', 'NegReg', (212, 219))
58699	32226509	Cells transfected with the rs2228230:C allele or rs2228230:T allele of PDGFRA were treated with the protein synthesis inhibitor CHX for various durations.	('rs2228230:T', 'Var', (49, 60))	('rs2228230:C', 'Var', (27, 38))	('protein synthesis', 'biological_process', 'GO:0006412', ('100', '117'))	('rs2228230', 'Mutation', 'rs2228230', (27, 36))	('PDGFRA', 'Gene', (71, 77))	('rs2228230', 'Mutation', 'rs2228230', (49, 58))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('CHX', 'Chemical', 'MESH:D003513', (128, 131))
58700	32226509	PDGFRA levels decreased with increasing CHX exposure time, and the degradation rate of PDGFRA in cells with the rs2228230:T allele was significantly faster than that in cells with the rs2228230:C allele, indicating that the rs2228230:T allele increased proteolytic degradation (P < 0.001; Figure 2B-D).	('decreased', 'NegReg', (14, 23))	('rs2228230:T', 'Var', (224, 235))	('rs2228230', 'Mutation', 'rs2228230', (224, 233))	('degradation', 'biological_process', 'GO:0009056', ('265', '276'))	('PDGFRA', 'Gene', (87, 93))	('degradation', 'MPA', (67, 78))	('PDGFRA', 'MPA', (0, 6))	('faster', 'PosReg', (149, 155))	('CHX', 'Chemical', 'MESH:D003513', (40, 43))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('rs2228230:T', 'Var', (112, 123))	('increased', 'PosReg', (243, 252))	('rs2228230', 'Mutation', 'rs2228230', (184, 193))	('proteolytic degradation', 'MPA', (253, 276))	('rs2228230', 'Mutation', 'rs2228230', (112, 121))
58701	32226509	MG132 is a proteasome inhibitor that can block the activity of the 20S proteasome and the proteolytic activity of the 26S proteasome complex.	('26S proteasome', 'cellular_component', 'GO:0000502', ('118', '132'))	('MG132', 'Var', (0, 5))	('activity', 'MPA', (51, 59))	('proteasome', 'molecular_function', 'GO:0004299', ('71', '81'))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('block', 'NegReg', (41, 46))	('26S proteasome', 'cellular_component', 'GO:0000504', ('118', '132'))	('proteolytic activity', 'MPA', (90, 110))	('26S proteasome', 'cellular_component', 'GO:0005837', ('118', '132'))	('20S proteasome', 'cellular_component', 'GO:0005839', ('67', '81'))	('proteasome', 'molecular_function', 'GO:0004299', ('122', '132'))	('proteasome complex', 'cellular_component', 'GO:0000502', ('122', '140'))	('20S', 'Protein', (67, 70))	('proteasome', 'molecular_function', 'GO:0004299', ('11', '21'))	('proteasome', 'cellular_component', 'GO:0000502', ('11', '21'))
58702	32226509	After proteolytic degradation was inhibited, cells with the rs2228230:T allele showed a 43% decrease in PDGFRA translation compared to cells with the rs2228230:C allele (P < 0.001; Figure 2E, F), indicating that the rs2228230:T allele also decreased the protein synthesis rate of PDGFRA.	('rs2228230:T', 'Var', (216, 227))	('rs2228230', 'Mutation', 'rs2228230', (150, 159))	('protein synthesis', 'biological_process', 'GO:0006412', ('254', '271'))	('decrease', 'NegReg', (92, 100))	('decreased', 'NegReg', (240, 249))	('PDGFRA', 'Gene', (104, 110))	('rs2228230', 'Mutation', 'rs2228230', (216, 225))	('rs2228230', 'Mutation', 'rs2228230', (60, 69))	('translation', 'biological_process', 'GO:0006412', ('111', '122'))	('protein synthesis rate', 'MPA', (254, 276))	('protein', 'cellular_component', 'GO:0003675', ('254', '261'))	('degradation', 'biological_process', 'GO:0009056', ('18', '29'))	('rs2228230:T', 'Var', (60, 71))	('translation', 'MPA', (111, 122))
58703	32226509	Hence, the rs2228230 genotype impacts the mRNA and protein stability of PDGFRA.	('rs2228230', 'Var', (11, 20))	('PDGFRA', 'Gene', (72, 78))	('impacts', 'Reg', (30, 37))	('rs2228230', 'Mutation', 'rs2228230', (11, 20))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
58704	32226509	As the above investigations demonstrated that the genotype of rs2228230 could influence PDGFRA expression, we hypothesized that it might also affect PDGFRA function.	('rs2228230', 'Var', (62, 71))	('influence', 'Reg', (78, 87))	('affect', 'Reg', (142, 148))	('rs2228230', 'Mutation', 'rs2228230', (62, 71))	('expression', 'Species', '29278', (95, 105))	('PDGFRA', 'Gene', (88, 94))	('function', 'MPA', (156, 164))	('expression', 'MPA', (95, 105))
58706	32226509	The basic expression and phosphorylation levels of all molecules were similar after serum starvation (Figure 2G, H); after serum stimulation, the expression levels of total and phosphorylated PDGFRA, phospho-AKT, and phospho-ERK were significantly decreased in cells with the rs2228230:T allele compared to those with the rs2228230:C allele, while the expression levels of total AKT and ERK were not different in the two groups.	('ERK', 'molecular_function', 'GO:0004707', ('225', '228'))	('AKT', 'Gene', '207', (379, 382))	('AKT', 'Gene', '207', (208, 211))	('ERK', 'molecular_function', 'GO:0004707', ('387', '390'))	('phosphorylation', 'biological_process', 'GO:0016310', ('25', '40'))	('decreased', 'NegReg', (248, 257))	('expression levels', 'MPA', (146, 163))	('AKT', 'Gene', (379, 382))	('rs2228230:T', 'Var', (276, 287))	('AKT', 'Gene', (208, 211))	('expression', 'Species', '29278', (10, 20))	('expression', 'Species', '29278', (146, 156))	('expression', 'Species', '29278', (352, 362))	('rs2228230', 'Mutation', 'rs2228230', (276, 285))	('rs2228230', 'Mutation', 'rs2228230', (322, 331))	('PDGFRA', 'Protein', (192, 198))
58707	32226509	Thus, the genotype of rs2228230 could influence the signaling activity of PDGFRA.	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('rs2228230', 'Mutation', 'rs2228230', (22, 31))	('influence', 'Reg', (38, 47))	('rs2228230', 'Var', (22, 31))	('signaling activity', 'MPA', (52, 70))	('PDGFRA', 'Gene', (74, 80))
58708	32226509	The association of the rs2228230 genotype with expression of PDGFRA in AM was validated in FFPE samples, as no commercial AM cell lines were available.	('rs2228230', 'Mutation', 'rs2228230', (23, 32))	('expression', 'Species', '29278', (47, 57))	('association', 'Interaction', (4, 15))	('PDGFRA', 'Gene', (61, 67))	('AM', 'Phenotype', 'HP:0012060', (71, 73))	('AM', 'Phenotype', 'HP:0012060', (122, 124))	('rs2228230', 'Var', (23, 32))	('expression', 'MPA', (47, 57))
58710	32226509	The mean expression level of PDGFRA mRNA in the CC group was 27.101 (range: 0.000-97.353), while the mean value was 5.068 (range: 0.000-59.542) in the CT+TT group (P < 0.001; Figure 3B, C), demonstrating that the PDGFRA mRNA expression level was significantly reduced in melanoma tissues with the rs2228230:T genotype.	('expression', 'Species', '29278', (9, 19))	('rs2228230:T', 'Var', (297, 308))	('reduced', 'NegReg', (260, 267))	('expression', 'MPA', (9, 19))	('melanoma', 'Disease', (271, 279))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('expression', 'Species', '29278', (225, 235))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('rs2228230', 'Mutation', 'rs2228230', (297, 306))	('CT+TT', 'Chemical', '-', (151, 156))
58711	32226509	The association of rs2228230 with PDGFRA protein expression was analyzed by immunohistochemical (IHC) staining in 82 AM tissues.	('AM', 'Phenotype', 'HP:0012060', (117, 119))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('expression', 'Species', '29278', (49, 59))	('rs2228230', 'Var', (19, 28))	('rs2228230', 'Mutation', 'rs2228230', (19, 28))	('PDGFRA', 'Gene', (34, 40))
58712	32226509	The positive rate of PDGFRA in patients with the rs2228230:T allele (25.5%, 12/47) was significantly lower than in patients with the CC genotype (54.3%, 19/35; P = 0.008).	('PDGFRA', 'Gene', (21, 27))	('patients', 'Species', '9606', (115, 123))	('rs2228230:T', 'Var', (49, 60))	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (31, 39))	('rs2228230', 'Mutation', 'rs2228230', (49, 58))
58714	32226509	These data indicated that the rs2228230:T allele was associated with decreased expression of PDGFRA at both the mRNA and protein level in AM.	('expression', 'Species', '29278', (79, 89))	('rs2228230', 'Mutation', 'rs2228230', (30, 39))	('expression', 'MPA', (79, 89))	('decreased', 'NegReg', (69, 78))	('PDGFRA', 'Gene', (93, 99))	('AM', 'Phenotype', 'HP:0012060', (138, 140))	('rs2228230:T', 'Var', (30, 41))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
58717	32226509	The distribution of rs2228230 was in concordance with the Hardy-Weinberg equilibrium in both cohorts, and the minor allele frequency of rs2228230 was as expected in Asians according to the NCBI database of genetic variation dbSNP (Table S2).	('rs2228230', 'Var', (136, 145))	('rs2228230', 'Mutation', 'rs2228230', (136, 145))	('rs2228230', 'Var', (20, 29))	('rs2228230', 'Mutation', 'rs2228230', (20, 29))
58718	32226509	The correlation of the PDGFRA rs2228230 genotype with clinical characteristics of AM was analyzed, and no factor was found to be significantly correlated in either cohort (Table S3).	('PDGFRA', 'Gene', (23, 29))	('rs2228230', 'Var', (30, 39))	('rs2228230', 'Mutation', 'rs2228230', (30, 39))	('AM', 'Phenotype', 'HP:0012060', (82, 84))
58719	32226509	In the discovery cohort, Kaplan-Meier survival analysis revealed that both progression-free survival (PFS; P = 0.022; Figure 4A) and OS (P = 0.037; Figure 4B) of AM patients with the rs2228230:T allele were significantly longer compared to those of patients with the CC genotype.	('patients', 'Species', '9606', (249, 257))	('rs2228230:T', 'Var', (183, 194))	('AM', 'Phenotype', 'HP:0012060', (162, 164))	('patients', 'Species', '9606', (165, 173))	('rs2228230', 'Mutation', 'rs2228230', (183, 192))	('longer', 'PosReg', (221, 227))	('OS', 'Chemical', '-', (133, 135))	('progression-free survival', 'CPA', (75, 100))
58722	32226509	The association of the rs2228230 genotype with prognosis was further analyzed in the combined cohort, and the protective effect of the rs2228230:T allele remained significant (Figure 4E, F); AM patients with the rs2228230:T allele had longer PFS (HR: 0.656; 95% CI: 0.540-0.798; P < 0.001) and OS (HR: 0.586; 95% CI: 0.436-0.788; P < 0.001) compared to patients with the CC genotype.	('longer', 'PosReg', (235, 241))	('rs2228230', 'Mutation', 'rs2228230', (23, 32))	('patients', 'Species', '9606', (194, 202))	('rs2228230', 'Mutation', 'rs2228230', (212, 221))	('patients', 'Species', '9606', (353, 361))	('PFS', 'CPA', (242, 245))	('AM', 'Phenotype', 'HP:0012060', (191, 193))	('OS', 'Chemical', '-', (294, 296))	('rs2228230', 'Mutation', 'rs2228230', (135, 144))	('rs2228230:T', 'Var', (212, 223))
58725	32226509	Both Kaplan-Meier survival analysis (Figure 5A, B) and univariate Cox analysis (Table S6) showed that the genotype of rs2228230 was not related to PFS or OS in CM.	('related', 'Reg', (136, 143))	('rs2228230', 'Var', (118, 127))	('CM', 'Disease', 'MESH:D009202', (160, 162))	('OS', 'Chemical', '-', (154, 156))	('rs2228230', 'Mutation', 'rs2228230', (118, 127))	('PFS', 'Disease', (147, 150))	('CM', 'Phenotype', 'HP:0012056', (160, 162))
58726	32226509	The association of the rs2228230 genotype with prognosis and PDGFRA expression was also analyzed in the TCGA SKCM dataset, in which most of the patients were Caucasian.	('rs2228230', 'Mutation', 'rs2228230', (23, 32))	('expression', 'Species', '29278', (68, 78))	('CM', 'Disease', 'MESH:D009202', (111, 113))	('patients', 'Species', '9606', (144, 152))	('PDGFRA', 'Gene', (61, 67))	('CM', 'Phenotype', 'HP:0012056', (111, 113))	('rs2228230', 'Var', (23, 32))
58727	32226509	As in our CM cohort, the genotype of rs2228230 was not related to PFS or OS (Figure 5C, D).	('rs2228230', 'Mutation', 'rs2228230', (37, 46))	('PFS', 'Disease', (66, 69))	('CM', 'Disease', 'MESH:D009202', (10, 12))	('OS', 'Chemical', '-', (73, 75))	('CM', 'Phenotype', 'HP:0012056', (10, 12))	('rs2228230', 'Var', (37, 46))
58729	32226509	These results demonstrated that the effect of rs2228230 on PDGFRA expression and survival in CM differed according to original site.	('survival', 'CPA', (81, 89))	('expression', 'Species', '29278', (66, 76))	('rs2228230', 'Var', (46, 55))	('PDGFRA', 'Gene', (59, 65))	('expression', 'MPA', (66, 76))	('CM', 'Disease', 'MESH:D009202', (93, 95))	('CM', 'Phenotype', 'HP:0012056', (93, 95))	('rs2228230', 'Mutation', 'rs2228230', (46, 55))
58735	32226509	Our in silico and in vitro studies performed to clarify the effect of the rs2228230 genotype on PDGFRA expression demonstrated that the mRNA and protein expression decreased in cells transfected with the rs2228230:T allele.	('expression', 'Species', '29278', (103, 113))	('decreased', 'NegReg', (164, 173))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('rs2228230:T', 'Var', (204, 215))	('expression', 'Species', '29278', (153, 163))	('rs2228230', 'Mutation', 'rs2228230', (204, 213))	('rs2228230', 'Mutation', 'rs2228230', (74, 83))
58736	32226509	mRNA secondary structure analysis revealed that the rs2228230:T allele changed the structure of PDGFRA and increased the MFE.	('MFE', 'MPA', (121, 124))	('PDGFRA', 'Gene', (96, 102))	('rs2228230:T', 'Var', (52, 63))	('increased', 'PosReg', (107, 116))	('structure', 'MPA', (83, 92))	('MFE', 'Chemical', '-', (121, 124))	('changed', 'Reg', (71, 78))	('rs2228230', 'Mutation', 'rs2228230', (52, 61))
58738	32226509	After RNA synthesis was inhibited by ActD, PDGFRA mRNA decayed faster in cells with the rs2228230:T allele than in cells with the rs2228230:C allele.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('rs2228230', 'Mutation', 'rs2228230', (130, 139))	('decayed', 'NegReg', (55, 62))	('PDGFRA', 'Gene', (43, 49))	('RNA synthesis', 'biological_process', 'GO:0032774', ('6', '19'))	('RNA synthesis', 'MPA', (6, 19))	('rs2228230:T', 'Var', (88, 99))	('rs2228230', 'Mutation', 'rs2228230', (88, 97))
58739	32226509	The genetic code is degenerate, but synonymous codons are not used equally; the codon usage bias might alter the rate of translation elongation and therefore affect protein conformation and expression.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('translation elongation', 'biological_process', 'GO:0006414', ('121', '143'))	('expression', 'MPA', (190, 200))	('translation elongation', 'MPA', (121, 143))	('codon usage bias', 'Var', (80, 96))	('protein conformation', 'MPA', (165, 185))	('expression', 'Species', '29278', (190, 200))	('alter', 'Reg', (103, 108))	('affect', 'Reg', (158, 164))	('rate', 'MPA', (113, 117))
58740	32226509	According to the codon usage values of four valine codons at the genome and PDGFRA gene level, we confirmed that codon usage was biased toward the major allele C, indicating that the translation elongation of PDGFRA would be slower in cells with the rs2228230:T allele.	('rs2228230', 'Mutation', 'rs2228230', (250, 259))	('slower', 'NegReg', (225, 231))	('translation elongation', 'biological_process', 'GO:0006414', ('183', '205'))	('valine', 'Chemical', 'MESH:D014633', (44, 50))	('rs2228230:T', 'Var', (250, 261))	('translation elongation', 'MPA', (183, 205))	('PDGFRA', 'Gene', (209, 215))
58741	32226509	The subsequent experiment demonstrated that after proteolytic degradation was inhibited, the cells with the rs2228230:T allele showed a decreased rate of PDGFRA protein synthesis.	('PDGFRA protein synthesis', 'MPA', (154, 178))	('degradation', 'biological_process', 'GO:0009056', ('62', '73'))	('rs2228230:T', 'Var', (108, 119))	('protein synthesis', 'biological_process', 'GO:0006412', ('161', '178'))	('rs2228230', 'Mutation', 'rs2228230', (108, 117))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('decreased', 'NegReg', (136, 145))
58742	32226509	Furthermore, the degradation rate of PDGFRA was significantly faster in cells with the rs2228230:T allele after protein synthesis was inhibited, indicating that the rs2228230:T allele also increased proteolytic degradation.	('proteolytic degradation', 'MPA', (199, 222))	('degradation', 'biological_process', 'GO:0009056', ('211', '222'))	('faster', 'PosReg', (62, 68))	('degradation rate', 'MPA', (17, 33))	('rs2228230', 'Mutation', 'rs2228230', (165, 174))	('rs2228230:T', 'Var', (87, 98))	('inhibited', 'NegReg', (134, 143))	('rs2228230', 'Mutation', 'rs2228230', (87, 96))	('PDGFRA', 'Gene', (37, 43))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('degradation', 'biological_process', 'GO:0009056', ('17', '28'))	('protein synthesis', 'biological_process', 'GO:0006412', ('112', '129'))	('rs2228230:T', 'Var', (165, 176))	('increased', 'PosReg', (189, 198))
58743	32226509	Thus, the rs2228230 genotype could affect PDGFRA expression by regulating mRNA stability, protein synthesis, and degradation rates.	('protein synthesis', 'MPA', (90, 107))	('affect', 'Reg', (35, 41))	('PDGFRA', 'Gene', (42, 48))	('mRNA stability', 'MPA', (74, 88))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('rs2228230', 'Mutation', 'rs2228230', (10, 19))	('expression', 'Species', '29278', (49, 59))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('expression', 'MPA', (49, 59))	('degradation rates', 'MPA', (113, 130))	('regulating', 'Reg', (63, 73))	('protein synthesis', 'biological_process', 'GO:0006412', ('90', '107'))	('rs2228230', 'Var', (10, 19))
58744	32226509	Furthermore, rs2228230:T not only reduced PDGFRA expression but also decreased the activation of the MAPK and PI3K/AKT pathways.	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('AKT', 'Gene', '207', (115, 118))	('reduced', 'NegReg', (34, 41))	('rs2228230', 'Mutation', 'rs2228230', (13, 22))	('expression', 'Species', '29278', (49, 59))	('PI3K', 'molecular_function', 'GO:0016303', ('110', '114'))	('decreased', 'NegReg', (69, 78))	('rs2228230', 'Var', (13, 22))	('expression', 'MPA', (49, 59))	('AKT', 'Gene', (115, 118))	('PDGFRA', 'Protein', (42, 48))
58745	32226509	Other molecular mechanisms by which sSNPs within coding sequences can affect protein expression and function have been reported.	('affect', 'Reg', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('function', 'MPA', (100, 108))	('sSNPs', 'Var', (36, 41))	('expression', 'Species', '29278', (85, 95))	('protein expression', 'MPA', (77, 95))
58746	32226509	Compared to the major allele, the minor T allele of rs2228230 reduces a serine- and arginine-rich splicing factor 2 (SRSF2)-binding site and increases a serine- and arginine-rich splicing factor 6 (SRSF6)-binding site.	('reduces', 'NegReg', (62, 69))	('rs2228230', 'Var', (52, 61))	('binding', 'molecular_function', 'GO:0005488', ('205', '212'))	('increases', 'PosReg', (141, 150))	('splicing', 'biological_process', 'GO:0045292', ('98', '106'))	('rs2228230', 'Mutation', 'rs2228230', (52, 61))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('SRSF6', 'Chemical', '-', (198, 203))	('splicing', 'biological_process', 'GO:0045292', ('179', '187'))	('serine', 'Chemical', 'MESH:D012694', (153, 159))	('binding', 'molecular_function', 'GO:0005488', ('124', '131'))
58747	32226509	Both SRSF2 and SRSF6 are arginine-rich proteins; however, SRSF2 is located only in the nucleus, whereas SRSF6 can shuttle between the nucleus and cytoplasm, indicating that besides altering mRNA stability, rs2228230 might also affect mRNA splicing.	('affect', 'Reg', (227, 233))	('mRNA splicing', 'biological_process', 'GO:0000374', ('234', '247'))	('rs2228230', 'Var', (206, 215))	('altering', 'Reg', (181, 189))	('SRSF6', 'Chemical', '-', (104, 109))	('mRNA splicing', 'biological_process', 'GO:0000373', ('234', '247'))	('mRNA splicing', 'biological_process', 'GO:0006371', ('234', '247'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('234', '247'))	('nucleus', 'cellular_component', 'GO:0005634', ('87', '94'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('146', '155'))	('SRSF6', 'Chemical', '-', (15, 20))	('rs2228230', 'Mutation', 'rs2228230', (206, 215))	('mRNA splicing', 'MPA', (234, 247))	('mRNA splicing', 'biological_process', 'GO:0000394', ('234', '247'))	('mRNA stability', 'MPA', (190, 204))	('mRNA splicing', 'biological_process', 'GO:0000372', ('234', '247'))	('nucleus', 'cellular_component', 'GO:0005634', ('134', '141'))
58748	32226509	For example, the minor allele of rs10065172 reduces the binding capacity to miR-196 and therefore dysregulates the expression of IRGM in Crohn's disease.	('rs10065172', 'Var', (33, 43))	("Crohn's disease", 'Disease', 'MESH:D003424', (137, 152))	("Crohn's disease", 'Phenotype', 'HP:0100280', (137, 152))	("Crohn's disease", 'Disease', (137, 152))	('expression', 'Species', '29278', (115, 125))	('expression', 'MPA', (115, 125))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('dysregulates', 'Reg', (98, 110))	('miR-196', 'Protein', (76, 83))	('reduces', 'NegReg', (44, 51))	('rs10065172', 'Mutation', 'rs10065172', (33, 43))	('IRGM', 'Gene', (129, 133))
58749	32226509	It has been demonstrated that the sSNP T2562G within CFTR alters the local translation speed and therefore changes CFTR stability and function by introducing a low-abundance tRNA in a bronchial epithelial tissue-specific manner.	('changes', 'Reg', (107, 114))	('tRNA', 'MPA', (174, 178))	('CFTR', 'MPA', (115, 119))	('function', 'MPA', (134, 142))	('alters', 'Reg', (58, 64))	('T2562G', 'Mutation', 'rs1042077', (39, 45))	('tRNA', 'molecular_function', 'GO:0030533', ('174', '178'))	('local translation speed', 'MPA', (69, 92))	('CFTR', 'Gene', (53, 57))	('sSNP', 'Var', (34, 38))	('introducing', 'Reg', (146, 157))	('translation', 'biological_process', 'GO:0006412', ('75', '86'))	('T2562G', 'Var', (39, 45))	('stability', 'MPA', (120, 129))
58750	32226509	Moreover, sSNPs might influence the protein folding process and result in misfolded protein and decreased expression thereof.	('expression thereof', 'MPA', (106, 124))	('expression', 'Species', '29278', (106, 116))	('decreased', 'NegReg', (96, 105))	('influence', 'Reg', (22, 31))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('sSNPs', 'Var', (10, 15))	('protein folding', 'biological_process', 'GO:0006457', ('36', '51'))	('protein folding', 'MPA', (36, 51))	('misfolded protein', 'MPA', (74, 91))
58751	32226509	In this study, we found that the minor allele T of rs2228230 was associated with reduced mRNA and protein expression of PDGFRA in AM samples, and the following study in two independent cohorts demonstrated that AM patients with the rs2228230:T allele had longer PFS and OS compared to patients with the CC genotype, indicating that it may be used as a predictor of improved outcome.	('rs2228230', 'Mutation', 'rs2228230', (232, 241))	('patients', 'Species', '9606', (214, 222))	('expression', 'Species', '29278', (106, 116))	('rs2228230', 'Var', (51, 60))	('longer', 'PosReg', (255, 261))	('rs2228230:T', 'Var', (232, 243))	('rs2228230', 'Mutation', 'rs2228230', (51, 60))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('patients', 'Species', '9606', (285, 293))	('OS', 'Chemical', '-', (270, 272))	('reduced', 'NegReg', (81, 88))	('AM', 'Phenotype', 'HP:0012060', (130, 132))	('AM', 'Phenotype', 'HP:0012060', (211, 213))	('PDGFRA', 'Gene', (120, 126))
58753	32226509	These results indicated that the prognostic value of rs2228230:T varies based on original site, which might be because UV radiation-induced genetic aberration is more extensive in CM, and other molecular variations could affect PDGFRA expression and signaling activation.	('expression', 'MPA', (235, 245))	('signaling', 'MPA', (250, 259))	('signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('PDGFRA', 'Protein', (228, 234))	('affect', 'Reg', (221, 227))	('CM', 'Disease', 'MESH:D009202', (180, 182))	('CM', 'Phenotype', 'HP:0012056', (180, 182))	('rs2228230', 'Var', (53, 62))	('variations', 'Var', (204, 214))	('expression', 'Species', '29278', (235, 245))	('rs2228230', 'Mutation', 'rs2228230', (53, 62))
58756	32226509	In conclusion, our study showed that the minor T allele of rs2228230 can reduce the expression and function of PDGFRA by altering the stability and synthesis of its mRNA and protein, and that it is associated with better survival in AM patients.	('AM', 'Phenotype', 'HP:0012060', (233, 235))	('synthesis of', 'MPA', (148, 160))	('function', 'MPA', (99, 107))	('PDGFRA', 'Gene', (111, 117))	('patients', 'Species', '9606', (236, 244))	('rs2228230', 'Mutation', 'rs2228230', (59, 68))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('rs2228230', 'Var', (59, 68))	('altering', 'Reg', (121, 129))	('expression', 'Species', '29278', (84, 94))	('expression', 'MPA', (84, 94))	('synthesis', 'biological_process', 'GO:0009058', ('148', '157'))	('reduce', 'NegReg', (73, 79))	('better', 'PosReg', (214, 220))	('stability', 'MPA', (134, 143))
58773	33552470	Metastasis from melanoma causing bowel perforation is rare and presents as an acute abdomen.	('Metastasis', 'Var', (0, 10))	('bowel perforation', 'Disease', (33, 50))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('acute abdomen', 'Disease', (78, 91))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('bowel perforation', 'Phenotype', 'HP:0031368', (33, 50))
58834	32860274	Increasing evidences revealed that aberration of epigenetic regulation was critical for the regulation of gene and noncoding RNA expression, thus affecting the pathogenesis and progression of cancers, including SKCM.	('pathogenesis', 'biological_process', 'GO:0009405', ('160', '172'))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('SKCM', 'Disease', (211, 215))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('cancers', 'Disease', (192, 199))	('aberration', 'Var', (35, 45))	('affecting', 'Reg', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
58865	32860274	And the result suggested that the overall survival of SKCM patients with high CBX5 level was better compared with low/medium CBX5 level (Figure 4E, P = .0092), while the overall survival of SKCM patients with high CBX7 level was worse compared with low/medium CBX7 level (Figure 4G, P = .039).	('CBX5', 'Gene', '23468', (78, 82))	('CBX7', 'Gene', (214, 218))	('CBX5', 'Gene', (78, 82))	('high', 'Var', (73, 77))	('SKCM', 'Disease', (54, 58))	('survival', 'CPA', (42, 50))	('CBX7', 'Gene', (260, 264))	('patients', 'Species', '9606', (195, 203))	('CBX5', 'Gene', '23468', (125, 129))	('patients', 'Species', '9606', (59, 67))	('CBX7', 'Gene', '23492', (214, 218))	('better', 'PosReg', (93, 99))	('CBX5', 'Gene', (125, 129))	('CBX7', 'Gene', '23492', (260, 264))
58870	32860274	Genetic alteration of CBX family in SKCM were consist of Missense mutation and nonsense mutation (Figure 5).	('nonsense mutation', 'Var', (79, 96))	('Missense mutation', 'Var', (57, 74))	('CBX', 'Gene', (22, 25))	('CBX', 'Gene', '10951', (22, 25))
58904	32860274	26  Abnormal splicing process could result in tumor genesis and progression, including SKCM.	('SKCM', 'Disease', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('progression', 'CPA', (64, 75))	('tumor', 'Disease', (46, 51))	('result in', 'Reg', (36, 45))	('Abnormal splicing process', 'Var', (4, 29))	('splicing', 'biological_process', 'GO:0045292', ('13', '21'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
58907	32860274	Our study also revealed that the expression of CBX family was associated with the abundance of certain immune cells and somatic copy number alterations of CBX family could certainly inhibit the immune cell infiltrations in SKCM.	('SKCM', 'Disease', (223, 227))	('immune cell infiltrations', 'CPA', (194, 219))	('CBX', 'Gene', '10951', (47, 50))	('CBX', 'Gene', '10951', (155, 158))	('copy number alterations', 'Var', (128, 151))	('CBX', 'Gene', (47, 50))	('inhibit', 'NegReg', (182, 189))	('alterations', 'Var', (140, 151))	('CBX', 'Gene', (155, 158))
58914	32860274	33 ,  34  PLK1 alteration could facilitate cancerous transformation and promote cancer development.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('PLK1', 'Gene', '5347', (10, 14))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancerous transformation', 'Disease', 'MESH:D009369', (43, 67))	('promote', 'PosReg', (72, 79))	('facilitate', 'PosReg', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancerous transformation', 'Disease', (43, 67))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PLK1', 'Gene', (10, 14))	('alteration', 'Var', (15, 25))	('cancer', 'Disease', (80, 86))
58918	28607807	We examined whether VDR expression in excised melanoma tissues is associated with VDR gene (VDR) polymorphisms.	('VDR', 'Gene', '7421', (82, 85))	('VDR', 'Gene', '7421', (20, 23))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('associated', 'Reg', (66, 76))	('VDR', 'Gene', (92, 95))	('VDR', 'Gene', (82, 85))	('VDR', 'Gene', (20, 23))	('polymorphisms', 'Var', (97, 110))	('VDR', 'Gene', '7421', (92, 95))
58923	28607807	: Stage I melanomas, Breslow thickness of <1.00 mm, level II Clark invasion, Aa heterozygous genotype, and AaTT combined genotype were more frequent in melanomas with high vs. low VDR expression.	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('I melanomas', 'Disease', (8, 19))	('VDR', 'Gene', (180, 183))	('melanomas', 'Disease', (10, 19))	('high', 'Var', (167, 171))	('I melanomas', 'Disease', 'MESH:D008545', (8, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('VDR', 'Gene', '7421', (180, 183))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('melanomas', 'Disease', (152, 161))	('melanomas', 'Disease', 'MESH:D008545', (10, 19))
58925	28607807	Combined genotype AATT was more frequent in melanomas lacking VDR expression (odds ratio=14.5; P=0.025).	('melanomas', 'Disease', (44, 53))	('VDR', 'Gene', '7421', (62, 65))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('AATT', 'Var', (18, 22))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('VDR', 'Gene', (62, 65))	('lacking', 'NegReg', (54, 61))
58927	28607807	: We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells.	('polymorphisms', 'Var', (26, 39))	('VDR', 'Gene', (22, 25))	('VDR', 'Gene', '7421', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('VDR', 'Gene', '7421', (22, 25))	('affect', 'Reg', (44, 50))	('VDR', 'Gene', (51, 54))
58953	28607807	Genetic variants of VDR may modulate its actions, with FokI, BsmI, ApaI, and TaqI being the most studied single-nucleotide polymorphisms (SNPs).	('actions', 'MPA', (41, 48))	('VDR', 'Gene', '7421', (20, 23))	('variants', 'Var', (8, 16))	('VDR', 'Gene', (20, 23))	('modulate', 'Reg', (28, 36))
58954	28607807	VDR-FokI polymorphism is a functional SNP that extends lengths of the receptor protein from 424 to 427 amino acid residues.	('polymorphism', 'Var', (9, 21))	('VDR', 'Gene', '7421', (0, 3))	('VDR', 'Gene', (0, 3))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))
58955	28607807	BsmI, ApaI, and TaqI polymorphisms are located in the 3' terminal region of the VDR gene and do not affect protein sequence of the VDR receptor.	('VDR', 'Gene', (131, 134))	('affect', 'Reg', (100, 106))	('VDR', 'Gene', (80, 83))	('VDR', 'Gene', '7421', (131, 134))	('polymorphisms', 'Var', (21, 34))	('VDR', 'Gene', '7421', (80, 83))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
59004	28607807	A higher frequency of Clark II invasion (38.9% vs. 15.8%, OR=3.39, CI=1.13-10.2, P=0.025) was observed in high- than low-VDR-expression group.	('high-', 'Var', (106, 111))	('VDR', 'Gene', '7421', (121, 124))	('Clark II invasion', 'CPA', (22, 39))	('VDR', 'Gene', (121, 124))
59014	28607807	EachVDR polymorphism of FokI, BsmI, ApaI, and TaqI was in HWE.	('VDR', 'Gene', (4, 7))	('polymorphism', 'Var', (8, 20))	('VDR', 'Gene', '7421', (4, 7))
59016	28607807	Table S1  to  Table S3  in the supplementary materials, available with the full text of this article at www.cancerbiomed.org), heterozygous Aa genotype was more frequent in melanomas with high than low VDR expression (61.1% vs. 36.8%, OR=2.69, CI=1.05-6.90, P=0.037).	('melanomas', 'Disease', (173, 182))	('high', 'Var', (188, 192))	('VDR', 'Gene', '7421', (202, 205))	('melanomas', 'Disease', 'MESH:D008545', (173, 182))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('frequent', 'Reg', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('men', 'Species', '9606', (37, 40))	('VDR', 'Gene', (202, 205))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
59019	28607807	In comparing the >20% vs. <=20% VDR-expression-positive groups, combined genotype AaTT (OR=3.89, CI= 0.96-15.8, P=0.046) was more frequent in the former than in the latter group.	('VDR', 'Gene', '7421', (32, 35))	('AaTT', 'Var', (82, 86))	('VDR', 'Gene', (32, 35))
59034	28607807	Consistent with studies performed by other authors on a Polish cohort, we observed that stage I melanomas were more frequent in tumors with high than with low VDR expression.	('I melanomas', 'Disease', 'MESH:D008545', (94, 105))	('VDR', 'Gene', '7421', (159, 162))	('high', 'Var', (140, 144))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('VDR', 'Gene', (159, 162))	('I melanomas', 'Disease', (94, 105))
59041	28607807	At variance, in Polish patients studied by Brozyna and colleagues cytoplasmic VDR immunostaining was higher in group of brisk TIL-positive vs. that of absent and non-brisk TIL melanomas (P=0.01), and VDR expression was lower in melanomas with ulceration.	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('higher', 'PosReg', (101, 107))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('VDR', 'Gene', (200, 203))	('patients', 'Species', '9606', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (228, 237))	('lower', 'NegReg', (219, 224))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('VDR', 'Gene', (78, 81))	('melanomas', 'Disease', 'MESH:D008545', (228, 237))	('TIL melanomas', 'Disease', 'MESH:D008545', (172, 185))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanomas', 'Disease', (176, 185))	('VDR', 'Gene', '7421', (200, 203))	('brisk TIL-positive', 'Var', (120, 138))	('TIL melanomas', 'Disease', (172, 185))	('VDR', 'Gene', '7421', (78, 81))	('melanomas', 'Disease', (228, 237))
59042	28607807	We noted a tendency for higher frequency of superficial spreading (P=0.063) in melanomas with high than low VDR expression.	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('VDR', 'Gene', (108, 111))	('superficial spreading', 'CPA', (44, 65))	('melanomas', 'Disease', (79, 88))	('VDR', 'Gene', '7421', (108, 111))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('high', 'Var', (94, 98))
59045	28607807	Melanomas with a thickness below 1.00 mm were more frequently observed in cases with high than low VDR expression, whereas those with thickness of over or equal to 1.01 mm were more frequent in melanomas with low VDR expression.	('VDR', 'Gene', '7421', (213, 216))	('low', 'NegReg', (95, 98))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('Melanomas', 'Disease', (0, 9))	('VDR', 'Gene', (99, 102))	('high', 'Var', (85, 89))	('melanomas', 'Disease', 'MESH:D008545', (194, 203))	('VDR', 'Gene', (213, 216))	('VDR', 'Gene', '7421', (99, 102))	('melanomas', 'Disease', (194, 203))
59046	28607807	Clark level II (none of the studied melanomas presented a Clark I) was detected more frequently in melanomas with high than low VDR expression (P=0.025).	('melanomas', 'Disease', (99, 108))	('VDR', 'Gene', (128, 131))	('high', 'Var', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('VDR', 'Gene', '7421', (128, 131))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('melanomas', 'Disease', (36, 45))
59049	28607807	To our knowledge, our study was the first to investigate the relationship between VDR expression of human melanoma cells in excised tissues of patients and VDR polymorphisms.	('VDR', 'Gene', '7421', (82, 85))	('VDR', 'Gene', (156, 159))	('human', 'Species', '9606', (100, 105))	('patients', 'Species', '9606', (143, 151))	('VDR', 'Gene', '7421', (156, 159))	('VDR', 'Gene', (82, 85))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('polymorphisms', 'Var', (160, 173))
59052	28607807	The heterozygous genotype Aa was identified in 61.1% of melanomas with high VDR expression vs. 36.8% of melanomas with low VDR expression (OR=2.69, P=0.037).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('VDR', 'Gene', (76, 79))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('high', 'Var', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('VDR', 'Gene', (123, 126))	('VDR', 'Gene', '7421', (76, 79))	('melanomas', 'Disease', (56, 65))	('melanomas', 'Disease', (104, 113))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('VDR', 'Gene', '7421', (123, 126))
59057	28607807	A meta-analysis study indicated that VDR-ApaI polymorphism of the European population features an association with overall skin cancer risk (Aa vs. AA, OR=1.27, CI=1.05-1.53; Aa+aa vs. AA, OR=1.23, CI=1.04-1.47).	('association', 'Interaction', (98, 109))	('skin cancer', 'Phenotype', 'HP:0008069', (123, 134))	('skin cancer', 'Disease', (123, 134))	('VDR', 'Gene', (37, 40))	('skin cancer', 'Disease', 'MESH:D012878', (123, 134))	('polymorphism', 'Var', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('VDR', 'Gene', '7421', (37, 40))
59060	28607807	The AaTT combined genotype was more frequent in melanomas with high than low VDR expression.	('frequent', 'Reg', (36, 44))	('VDR', 'Gene', (77, 80))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanomas', 'Disease', (48, 57))	('high', 'Var', (63, 67))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('VDR', 'Gene', '7421', (77, 80))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
59068	28607807	Regulation of VDR abundance is an important modulation mechanism of cellular responsiveness to 1alpha, 25-dihydroxyvitamin D. Mechanisms underlying regulation of VDR abundance include alterations in transcription rate of VDR gene and/or stability of VDR mRNA and epigenetic changes.	('1alpha, 25-dihydroxyvitamin D', 'Chemical', 'MESH:C097949', (95, 124))	('epigenetic changes', 'Var', (263, 281))	('VDR', 'Gene', (162, 165))	('VDR', 'Gene', (221, 224))	('alterations', 'Reg', (184, 195))	('VDR', 'Gene', (250, 253))	('VDR', 'Gene', '7421', (14, 17))	('transcription rate', 'MPA', (199, 217))	('regulation', 'biological_process', 'GO:0065007', ('148', '158'))	('VDR', 'Gene', '7421', (162, 165))	('VDR', 'Gene', '7421', (221, 224))	('stability', 'CPA', (237, 246))	('VDR', 'Gene', '7421', (250, 253))	('transcription', 'biological_process', 'GO:0006351', ('199', '212'))	('VDR', 'Gene', (14, 17))
59081	28607807	Deletion of VDR notably results in an increased susceptibility to tumorigenesis and also reduces ability of keratinocytes to clear UVB-induced DNA mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('VDR', 'Gene', (12, 15))	('tumor', 'Disease', (66, 71))	('susceptibility', 'Reg', (48, 62))	('VDR', 'Gene', '7421', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('reduces', 'NegReg', (89, 96))	('increased', 'PosReg', (38, 47))	('Deletion', 'Var', (0, 8))
59117	32265897	Based on the identified literature, IFI30, GBP1, and GBP4 suppress mouse primary T cell activation in vitro and mouse innate immune response in vivo while IFI30 and GBP1 appear to increase cell proliferation in a glioma cell line and two breast cancer cell lines but diminish cell proliferation in a colon cancer cell line.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('diminish', 'NegReg', (267, 275))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('breast cancer', 'Disease', (238, 251))	('T cell activation', 'biological_process', 'GO:0042110', ('81', '98'))	('IFI30', 'Var', (155, 160))	('suppress', 'NegReg', (58, 66))	('cell proliferation', 'biological_process', 'GO:0008283', ('276', '294'))	('colon cancer', 'Disease', (300, 312))	('increase', 'PosReg', (180, 188))	('IFI30', 'Var', (36, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('189', '207'))	('GBP1', 'Var', (165, 169))	('mouse innate immune response', 'CPA', (112, 140))	('cell proliferation', 'CPA', (189, 207))	('mouse primary T cell activation', 'CPA', (67, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (300, 312))	('mouse', 'Species', '10090', (67, 72))	('glioma', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('GBP4', 'Gene', (53, 57))	('innate immune response', 'biological_process', 'GO:0045087', ('118', '140'))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('GBP1', 'Gene', (43, 47))	('colon cancer', 'Disease', 'MESH:D015179', (300, 312))	('mouse', 'Species', '10090', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
59118	32265897	Intriguingly, however, IFI30 RNA expression is associated with better patient survival in breast cancer and diffuse large B cell lymphomas (DLBCL) while GPB1 RNA is associated with better patient survival in melanoma but poorer prognosis in human glioblastoma.	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('human', 'Species', '9606', (241, 246))	('B cell lymphomas', 'Disease', (122, 138))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (122, 138))	('IFI30 RNA expression', 'Var', (23, 43))	('patient', 'Species', '9606', (70, 77))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (122, 137))	('large B cell', 'Phenotype', 'HP:0005404', (116, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (247, 259))	('B cell lymphomas', 'Disease', 'MESH:D016393', (122, 138))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lymphomas', 'Phenotype', 'HP:0002665', (129, 138))	('glioblastoma', 'Disease', (247, 259))	('patient', 'Species', '9606', (188, 195))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (247, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('RNA', 'cellular_component', 'GO:0005562', ('158', '161'))	('GPB1 RNA', 'Var', (153, 161))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('better', 'PosReg', (63, 69))
59138	32265897	Ten thousand two hundred fifty-five genes (40% of total genes) had an average FPKM > 1 and differential expression between tumors and normal controls (False Discovery Rate (FDR) < 0.05 in ANOVA).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('expression', 'MPA', (104, 114))	('differential', 'Reg', (91, 103))	('FPKM', 'Var', (78, 82))
59154	32265897	In IFNgamma positive tumors, IFI30, GBP1, and GBP4 were significantly upregulated (p < 0.0001) at 2.7-, 4.2-, and 6.2-fold, respectively (Figure 3A) while only IFI30 and GBP1 were upregulated (p < 0.05) at 1.4- and 1.2-fold, respectively in IFNgamma negative tumors compared to their matched normal controls (Figure 3B).	('IFNgamma', 'Gene', '3458', (241, 249))	('IFI30', 'Var', (29, 34))	('GBP4', 'Gene', (46, 50))	('GBP1', 'Gene', (36, 40))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('upregulated', 'PosReg', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('IFNgamma', 'Gene', (3, 11))	('IFNgamma', 'Gene', (241, 249))	('IFNgamma', 'Gene', '3458', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
59155	32265897	Notably, the abundance of IFI30, GBP1 and GBP4 was substantially higher in IFNgamma positive tumors (362, 51, 25 FPKM, respectively) than in IFNgamma negative tumors (207, 18, 7 FPKM, respectively) (Table S9).	('positive', 'Var', (84, 92))	('IFNgamma', 'Gene', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IFI30', 'Gene', (26, 31))	('IFNgamma', 'Gene', '3458', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('IFNgamma', 'Gene', (75, 83))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (159, 165))	('GBP1', 'Gene', (33, 37))	('IFNgamma', 'Gene', '3458', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('GBP4', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', (93, 99))	('higher', 'PosReg', (65, 71))	('abundance', 'MPA', (13, 22))
59171	32265897	In contrast, there were no differences (p > 0.05) in expression of the above 9 immune cell specific genes in normal tissues from patients with IFNgamma positive vs. negative CRC (Figure 4B).	('patients', 'Species', '9606', (129, 137))	('IFNgamma', 'Gene', '3458', (143, 151))	('IFNgamma', 'Gene', (143, 151))	('positive', 'Var', (152, 160))
59181	32265897	To further define the dosage impact of IFNgamma on the expression of six ICPs and three ICPRGs, we generated six IFNgamma expression level gradients 1 IFNgamma: FPKM > 5 (4 CRCs); IFNgamma: FPKM = 4.9-2 (20 CRCs); IFNgamma: FPKM = 1.99-1(44 CRCs); IFNgamma: FPKM = 0.99-0.5 (73 CRCs); IFNgamma: FPKM = 0.49-0.01 (467 CRC); and IFNgamma: FPKM < 0.009 (107 CRCs) in 716 CRCs (Indivumed [79 CRCs] and TCGA [637 CRCs]) (Figure 5A) and examined the impact of the levels on expression of the ICPs and ICPRGs examined in our more limited cohort.	('IFNgamma', 'Gene', '3458', (327, 335))	('IFNgamma', 'Gene', '3458', (285, 293))	('IFNgamma', 'Gene', (327, 335))	('IFNgamma', 'Gene', (180, 188))	('FPKM = 0.49-0.01', 'Var', (295, 311))	('IFNgamma', 'Gene', '3458', (180, 188))	('IFNgamma', 'Gene', (113, 121))	('IFNgamma', 'Gene', '3458', (214, 222))	('FPKM < 0.009', 'Var', (337, 349))	('IFNgamma', 'Gene', (39, 47))	('IFNgamma', 'Gene', (214, 222))	('IFNgamma', 'Gene', '3458', (113, 121))	('IFNgamma', 'Gene', '3458', (39, 47))	('IFNgamma', 'Gene', '3458', (151, 159))	('IFNgamma', 'Gene', (151, 159))	('IFNgamma', 'Gene', (248, 256))	('IFNgamma', 'Gene', (285, 293))	('IFNgamma', 'Gene', '3458', (248, 256))
59213	32265897	In fact, GBP1 and GBP4 were associated with a favorable prognosis in 4 types of cancer (CRC, SKCM, BC, and STC) according to the Pathology Atlas analysis.	('SKCM', 'Disease', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GBP1', 'Var', (9, 13))	('GBP4', 'Var', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
59214	32265897	These data are consistent with the evidence [KEYNOTE-001 trial/pembrolizumab (anti-PDL1) treatment] that high expression of PDL1, a classical immune suppressive check point molecule was associated with better survival among pembrolizumab-treated NSCLC and melanoma patients.	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('PDL1', 'Gene', '29126', (83, 87))	('better', 'PosReg', (202, 208))	('PDL1', 'Gene', '29126', (124, 128))	('NSCLC', 'Disease', (246, 251))	('melanoma', 'Disease', (256, 264))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('patients', 'Species', '9606', (265, 273))	('PDL1', 'Gene', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('survival', 'MPA', (209, 217))	('PDL1', 'Gene', (124, 128))	('pembrolizumab', 'Chemical', 'MESH:C582435', (224, 237))	('pembrolizumab', 'Chemical', 'MESH:C582435', (63, 76))	('high expression', 'Var', (105, 120))
59222	23694694	Lack of SF3B1 R625 mutations in cutaneous melanoma Melanoma is a deadly disease affecting people worldwide.	('melanoma', 'Disease', (42, 50))	('Lack', 'NegReg', (0, 4))	('SF3B1', 'Gene', '23451', (8, 13))	('people', 'Species', '9606', (90, 96))	('Melanoma', 'Disease', 'MESH:D008545', (51, 59))	('Melanoma', 'Disease', (51, 59))	('deadly disease', 'Disease', (65, 79))	('deadly disease', 'Disease', 'MESH:D004194', (65, 79))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('R625', 'Var', (14, 18))	('SF3B1', 'Gene', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
59224	23694694	Hotspot mutations in SF3B1 were recently reported in uveal melanoma.	('reported', 'Reg', (41, 49))	('SF3B1', 'Gene', (21, 26))	('mutations', 'Var', (8, 17))	('uveal melanoma', 'Disease', (53, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (53, 67))	('uveal melanoma', 'Phenotype', 'HP:0007716', (53, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('SF3B1', 'Gene', '23451', (21, 26))
59229	23694694	High numbers of BRAF and NRAS mutations were identified with frequencies varying according to melanoma subtype.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma subtype', 'Disease', (94, 110))	('melanoma subtype', 'Disease', 'MESH:D008545', (94, 110))	('mutations', 'Var', (30, 39))	('NRAS', 'Gene', (25, 29))	('NRAS', 'Gene', '4893', (25, 29))
59231	23694694	We conclude that recurrent mutations in codon 625 of SF3B1 as reported in uveal melanoma are not present in most types of cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('mutations in codon 625', 'Var', (27, 49))	('SF3B1', 'Gene', '23451', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('uveal melanoma', 'Disease', (74, 88))	('SF3B1', 'Gene', (53, 58))
59237	23694694	Activating driver mutations in genes such as NRAS and BRAF were identified in cutaneous melanoma.	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('NRAS', 'Gene', (45, 49))	('cutaneous melanoma', 'Disease', (78, 96))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (78, 96))	('NRAS', 'Gene', '4893', (45, 49))	('mutations', 'Var', (18, 27))
59241	23694694	However there is some overlap in tumor biology as ~80% of blue nevi, which are benign melanocytic tumors of the skin, also harbor GNAQ or GNA11 mutations, and BAP1 mutations can be found in both cutaneous nevi and cutaneous melanoma.	('nevi', 'Phenotype', 'HP:0003764', (63, 67))	('BAP1', 'Gene', '8314', (159, 163))	('nevi', 'Phenotype', 'HP:0003764', (205, 209))	('cutaneous melanoma', 'Disease', (214, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (214, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (214, 232))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('blue nevi', 'Disease', (58, 67))	('GNA11', 'Gene', (138, 143))	('tumor', 'Disease', (33, 38))	('BAP1', 'Gene', (159, 163))	('GNAQ', 'Gene', '2776', (130, 134))	('blue nevi', 'Phenotype', 'HP:0100814', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('GNAQ', 'Gene', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('harbor', 'Reg', (123, 129))	('cutaneous nevi', 'Disease', (195, 209))	('benign melanocytic tumors of the skin', 'Disease', (79, 116))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors of the skin', 'Phenotype', 'HP:0008069', (98, 116))	('benign melanocytic tumors of the skin', 'Disease', 'MESH:D012878', (79, 116))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('GNA11', 'Gene', '2767', (138, 143))	('melanocytic tumors of the skin', 'Phenotype', 'HP:0002861', (86, 116))
59244	23694694	SF3B1 mutations had been previously detected in myeloid malignancies such as CLL (chronic lymphoid leukemia) and MDS (myelodysplastic syndrome) and also reported in breast cancer.	('myeloid malignancies', 'Disease', (48, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('detected', 'Reg', (36, 44))	('MDS', 'Disease', 'MESH:D009190', (113, 116))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('SF3B1', 'Gene', (0, 5))	('chronic lymphoid leukemia', 'Disease', 'MESH:D007945', (82, 107))	('breast cancer', 'Disease', (165, 178))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (90, 107))	('myelodysplastic syndrome', 'Disease', (118, 142))	('MDS', 'Disease', (113, 116))	('CLL', 'Disease', (77, 80))	('reported', 'Reg', (153, 161))	('mutations', 'Var', (6, 15))	('SF3B1', 'Gene', '23451', (0, 5))	('chronic lymphoid leukemia', 'Disease', (82, 107))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (118, 142))	('CLL', 'Disease', 'MESH:D015451', (77, 80))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (118, 142))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (82, 107))	('myeloid malignancies', 'Disease', 'MESH:D009369', (48, 68))
59245	23694694	SF3B1 is a splice factor, with mutations expected to result in altered pre mRNA splicing.	('mutations', 'Var', (31, 40))	('SF3B1', 'Gene', (0, 5))	('altered', 'Reg', (63, 70))	('pre mRNA splicing', 'MPA', (71, 88))	('SF3B1', 'Gene', '23451', (0, 5))	('pre mRNA splicing', 'biological_process', 'GO:0000398', ('71', '88'))	('pre', 'molecular_function', 'GO:0003904', ('71', '74'))
59246	23694694	The goal of our study was to analyze if SF3B1 mutations not only play a role in uveal, but also in cutaneous melanoma.	('SF3B1', 'Gene', (40, 45))	('mutations', 'Var', (46, 55))	('role', 'Reg', (72, 76))	('SF3B1', 'Gene', '23451', (40, 45))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('uveal', 'Disease', (80, 85))	('cutaneous melanoma', 'Disease', (99, 117))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('play', 'Reg', (65, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
59255	23694694	BRAF Exon 15 and NRAS Exon 1 and 2 were analyzed for presence of mutations by Sanger sequencing (Table 1).	('NRAS', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', '4893', (17, 21))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (65, 74))
59256	23694694	We identified 36 BRAF mutations (35 p.V600E, 1 p.V600K) and 19 NRAS mutations (11 p.Q61K, 3 p.Q61L, 5 p.Q61R).	('NRAS', 'Gene', '4893', (63, 67))	('p.V600K', 'Mutation', 'rs121913227', (47, 54))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('p.Q61R', 'Mutation', 'rs11554290', (102, 108))	('p.Q61L', 'Mutation', 'rs11554290', (92, 98))	('BRAF', 'Gene', '673', (17, 21))	('p.Q61R', 'Var', (102, 108))	('p.V600E', 'Var', (36, 43))	('p.Q61K', 'Var', (82, 88))	('p.Q61L', 'Var', (92, 98))	('BRAF', 'Gene', (17, 21))	('p.Q61K', 'Mutation', 'rs121913254', (82, 88))	('p.V600K', 'Var', (47, 54))	('NRAS', 'Gene', (63, 67))
59258	23694694	Prevalence of BRAF and NRAS mutations varied by histologic subtype; ALM - 33% BRAF, 13% NRAS, NM - 42% BRAF, 25% NRAS, and SSM - 60% BRAF, 23% NRAS mutations.	('NRAS', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (103, 107))	('NRAS', 'Gene', '4893', (23, 27))	('BRAF', 'Gene', (103, 107))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (78, 82))	('NRAS', 'Gene', (88, 92))	('BRAF', 'Gene', (133, 137))	('NRAS', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('NRAS', 'Gene', (23, 27))	('SSM', 'cellular_component', 'GO:1990843', ('123', '126'))	('ALM', 'Phenotype', 'HP:0012060', (68, 71))	('NRAS', 'Gene', '4893', (113, 117))	('SSM', 'Phenotype', 'HP:0012057', (123, 126))	('mutations', 'Var', (28, 37))	('NRAS', 'Gene', '4893', (88, 92))	('NRAS', 'Gene', '4893', (143, 147))	('NM', 'Phenotype', 'HP:0012058', (94, 96))
59263	23694694	The distribution of activating oncogene mutations in BRAF and NRAS in our cohort is comparable to those reported elsewhere.	('BRAF', 'Gene', '673', (53, 57))	('activating', 'PosReg', (20, 30))	('NRAS', 'Gene', '4893', (62, 66))	('BRAF', 'Gene', (53, 57))	('mutations', 'Var', (40, 49))	('NRAS', 'Gene', (62, 66))
59264	23694694	Overall 65% of melanoma had a BRAF or NRAS mutation in a mutually exclusive pattern.	('NRAS', 'Gene', '4893', (38, 42))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('mutation', 'Var', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('NRAS', 'Gene', (38, 42))
59265	23694694	Of the three melanoma subtypes analyzed in considerable numbers (SSM, NM, ALM), percentages of BRAF and NRAS mutations combined were highest in SSM reaching 82%, lower in NM with 67% and lowest in ALM with 46%.	('NRAS', 'Gene', '4893', (104, 108))	('highest', 'Reg', (133, 140))	('SSM', 'Phenotype', 'HP:0012057', (144, 147))	('ALM', 'Phenotype', 'HP:0012060', (74, 77))	('SSM', 'Phenotype', 'HP:0012057', (65, 68))	('ALM', 'Phenotype', 'HP:0012060', (197, 200))	('BRAF', 'Gene', '673', (95, 99))	('SSM', 'cellular_component', 'GO:1990843', ('144', '147'))	('NM', 'Phenotype', 'HP:0012058', (171, 173))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('BRAF', 'Gene', (95, 99))	('SSM', 'Disease', (144, 147))	('SSM', 'cellular_component', 'GO:1990843', ('65', '68'))	('mutations', 'Var', (109, 118))	('NRAS', 'Gene', (104, 108))	('melanoma subtype', 'Disease', (13, 29))	('NM', 'Phenotype', 'HP:0012058', (70, 72))	('melanoma subtype', 'Disease', 'MESH:D008545', (13, 29))
59268	23694694	However p.N505H (c.1513A > C) is listed as a "variant of unknown origin" in a gastrointestinal stromal tumor in the COSMIC database.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (78, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p.N505H (c.1513A > C', 'Var', (8, 28))	('gastrointestinal stromal tumor', 'Disease', (78, 108))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (78, 108))	('p.N505H', 'Mutation', 'p.N505H', (8, 15))	('c.1513A > C', 'Mutation', 'c.1513A>C', (17, 28))
59269	23694694	The cutaneous ALM sample lacked mutations in BRAF or NRAS which could support a potential relevance, as typically KIT mutations are found to be mutually exclusive with BRAF and NRAS mutations.	('mutations', 'Var', (118, 127))	('NRAS', 'Gene', (177, 181))	('NRAS', 'Gene', (53, 57))	('mutations', 'Var', (32, 41))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', '673', (168, 172))	('NRAS', 'Gene', '4893', (177, 181))	('NRAS', 'Gene', '4893', (53, 57))	('BRAF', 'Gene', (168, 172))	('KIT', 'molecular_function', 'GO:0005020', ('114', '117'))	('ALM', 'Phenotype', 'HP:0012060', (14, 17))
59271	23694694	We obtained high quality sequencing results allowing analysis of exon 14 and in particular codon 625 of SF3B1 in 81 samples and found no mutations.	('SF3B1', 'Gene', (104, 109))	('SF3B1', 'Gene', '23451', (104, 109))	('codon 625', 'Var', (91, 100))
59273	23694694	In uveal melanomas, mutations were primarily found in tumors with a favorable prognosis.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('uveal melanomas', 'Disease', (3, 18))	('uveal melanomas', 'Phenotype', 'HP:0007716', (3, 18))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('uveal melanomas', 'Disease', 'MESH:C536494', (3, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('found', 'Reg', (45, 50))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', (54, 60))
59274	23694694	Future studies could analyze if SF3B1 mutations occur in benign cutaneous melanocytic tumors (nevi) or potentially in sites other than in codon 603-641 of exon 14 of SF3B1.	('SF3B1', 'Gene', '23451', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('occur', 'Reg', (48, 53))	('benign cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (57, 92))	('SF3B1', 'Gene', '23451', (32, 37))	('benign cutaneous melanocytic tumors', 'Disease', (57, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('SF3B1', 'Gene', (166, 171))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))
59277	23694694	In contrast, genetic alterations in uveal melanoma such as GNAQ and GNA11 mutations were also found in selected cases of cutaneous melanoma and are frequently found in blue nevi (benign cutaneous melanocytic tumors).	('uveal melanoma', 'Disease', 'MESH:C536494', (36, 50))	('GNA11', 'Gene', '2767', (68, 73))	('uveal melanoma', 'Disease', (36, 50))	('GNAQ', 'Gene', '2776', (59, 63))	('uveal melanoma', 'Phenotype', 'HP:0007716', (36, 50))	('GNAQ', 'Gene', (59, 63))	('nevi', 'Phenotype', 'HP:0003764', (173, 177))	('found', 'Reg', (159, 164))	('blue nevi', 'Disease', (168, 177))	('GNA11', 'Gene', (68, 73))	('benign cutaneous melanocytic tumors', 'Disease', (179, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('found', 'Reg', (94, 99))	('blue nevi', 'Phenotype', 'HP:0100814', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('cutaneous melanoma', 'Disease', (121, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (121, 139))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (121, 139))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('benign cutaneous melanocytic tumors', 'Disease', 'MESH:D009508', (179, 214))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
59278	23694694	BAP1 inactivating mutations are found in cutaneous nevi and melanoma, although considerably less frequently than in uveal melanoma.	('cutaneous nevi', 'Disease', (41, 55))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('BAP1', 'Gene', (0, 4))	('found', 'Reg', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (116, 130))	('uveal melanoma', 'Disease', (116, 130))	('uveal melanoma', 'Disease', 'MESH:C536494', (116, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('BAP1', 'Gene', '8314', (0, 4))	('inactivating mutations', 'Var', (5, 27))
59279	23694694	Our current study would signify that SF3B1 mutations, occurring in almost 20% of uveal melanoma, do not play a major role in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (125, 143))	('SF3B1', 'Gene', '23451', (37, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (125, 143))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (125, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('uveal melanoma', 'Disease', 'MESH:C536494', (81, 95))	('mutations', 'Var', (43, 52))	('uveal melanoma', 'Phenotype', 'HP:0007716', (81, 95))	('uveal melanoma', 'Disease', (81, 95))	('SF3B1', 'Gene', (37, 42))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
59313	33498755	After maturation, DCs upregulate their antigen presentation machinery and co-stimulatory molecules, such as CD40, CD80 or CD86, becoming potent T-cell activators.	('CD86', 'Gene', '942', (122, 126))	('CD40', 'Var', (108, 112))	('antigen presentation machinery', 'MPA', (39, 69))	('CD80', 'Gene', '941', (114, 118))	('antigen presentation', 'biological_process', 'GO:0019882', ('39', '59'))	('upregulate', 'PosReg', (22, 32))	('CD86', 'Gene', (122, 126))	('DC', 'Gene', '13179', (18, 20))	('CD80', 'Gene', (114, 118))
59327	33498755	Murine cDC1s express CD11c, MHC-II, CD103, CD8alpha, XCR1, CLEC9A and DNGR1 and are developmentally dependent on IRF8, ID2, and BATF3.	('XCR1', 'Gene', (53, 57))	('CD103', 'Gene', (36, 41))	('CD8alpha', 'Gene', (43, 51))	('IRF8', 'Gene', (113, 117))	('IRF8', 'Gene', '15900', (113, 117))	('MHC-II', 'Gene', (28, 34))	('ID2', 'Gene', (119, 122))	('CD11c', 'Var', (21, 26))	('BATF3', 'Gene', (128, 133))	('den', 'Chemical', 'MESH:D004052', (105, 108))	('Murine', 'Species', '10090', (0, 6))	('ID2', 'Gene', '15902', (119, 122))	('BATF3', 'Gene', '381319', (128, 133))	('CD8alpha', 'Gene', '12525', (43, 51))	('MHC-II', 'Gene', '111364', (28, 34))	('DC', 'Gene', '13179', (8, 10))
59328	33498755	Human cDC1s express CD11c, HLA-DR, XCR1, CLEC9A, DNGR1, and CD141.	('Human', 'Species', '9606', (0, 5))	('DNGR1', 'Gene', (49, 54))	('CD141', 'Gene', (60, 65))	('CD141', 'Gene', '7056', (60, 65))	('CD11c', 'Var', (20, 25))	('DC', 'Gene', '13179', (7, 9))
59336	33498755	A substantial fraction of intratumoral CD103+ cDC1s does not migrate to the lymph nodes, but still plays a crucial role in cancer immunity.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('CD103+', 'Var', (39, 45))	('plays', 'Reg', (99, 104))	('DC', 'Gene', '13179', (47, 49))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
59337	33498755	demonstrated that, in mouse models, non-migrating CD103+ cDC1s mediate their effects directly in the TME by producing distinct chemokines.	('DC', 'Gene', '13179', (58, 60))	('mouse', 'Species', '10090', (22, 27))	('producing', 'Reg', (108, 117))	('CD103+', 'Var', (50, 56))
59343	33498755	Murine cDC2s express CD11c, MHC-II, CD11b and CD172a, whereas human cDC2s are characterized by the expression of CD11c, HLA-DR, CD1c, CD1a and CD172a.	('CD1a', 'Gene', '909', (134, 138))	('cDC2', 'Gene', (7, 11))	('cDC2', 'Gene', '983', (7, 11))	('CD1c', 'Gene', '911', (128, 132))	('human', 'Species', '9606', (62, 67))	('CD172a', 'Gene', (143, 149))	('CD11c', 'Var', (113, 118))	('MHC-II', 'Gene', '111364', (28, 34))	('MHC-II', 'Gene', (28, 34))	('CD11c', 'Var', (21, 26))	('CD1c', 'Gene', (128, 132))	('CD1a', 'Gene', (134, 138))	('Murine', 'Species', '10090', (0, 6))	('cDC2', 'Gene', (68, 72))	('CD172a', 'Gene', (46, 52))	('cDC2', 'Gene', '983', (68, 72))	('CD11b', 'Gene', (36, 41))	('CD11b', 'Gene', '16409', (36, 41))
59358	33498755	Therefore, the presence of pDCs in the TME of these tumors is associated with a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('presence', 'Var', (15, 23))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('DC', 'Gene', '13179', (28, 30))
59362	33498755	Murine moDCs express CD11c, MHC-II, CD11b, Ly6C, CD14, CD64, CD206, CD209 and CCR2, while human moDC additionally express CD1c and CD1a (Table 1).	('human', 'Species', '9606', (90, 95))	('CD1c', 'Gene', '911', (122, 126))	('Ly6C', 'Gene', '17067', (43, 47))	('MHC-II', 'Gene', '111364', (28, 34))	('CD64', 'Gene', (55, 59))	('DC', 'Gene', '13179', (98, 100))	('CD1a', 'Gene', (131, 135))	('CD209', 'Gene', (68, 73))	('Ly6C', 'Gene', (43, 47))	('DC', 'Gene', '13179', (9, 11))	('CD1c', 'Gene', (122, 126))	('CD14', 'Gene', (49, 53))	('CD11c', 'Var', (21, 26))	('CD206', 'Gene', '17533', (61, 66))	('CD11b', 'Gene', '16409', (36, 41))	('CD14', 'Gene', '12475', (49, 53))	('CCR2', 'Gene', (78, 82))	('CD209', 'Gene', '170786', (68, 73))	('MHC-II', 'Gene', (28, 34))	('CCR', 'molecular_function', 'GO:0043880', ('78', '81'))	('CD1a', 'Gene', '909', (131, 135))	('Murine', 'Species', '10090', (0, 6))	('CD64', 'Gene', '14129', (55, 59))	('CD206', 'Gene', (61, 66))	('CD11b', 'Gene', (36, 41))	('CCR2', 'Gene', '12772', (78, 82))
59377	33498755	The importance of these chemokines has been demonstrated in mouse models in which the absence of CXCL9 and CXCL10 prevents CD8+ T-cell recall within the tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CD8', 'Gene', (123, 126))	('CXCL10', 'Var', (107, 113))	('CD8', 'Gene', '925', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('absence', 'Var', (86, 93))	('prevents', 'NegReg', (114, 122))	('mouse', 'Species', '10090', (60, 65))
59383	33498755	TME may also affect the function and stimulation of DCs.	('TME', 'Var', (0, 3))	('DC', 'Gene', '13179', (52, 54))	('function', 'MPA', (24, 32))	('stimulation', 'MPA', (37, 48))	('affect', 'Reg', (13, 19))
59390	33498755	Indeed, in mouse mammary tumors, IL-10 production by macrophages can suppress IL-12 expression by CD103+ cDC1s resulting in activation of tumor-specific CD8+ T cells.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('activation', 'PosReg', (124, 134))	('CD8', 'Gene', '925', (153, 156))	('tumor', 'Disease', (138, 143))	('tumors', 'Disease', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('IL-10 production', 'biological_process', 'GO:0032613', ('33', '49'))	('DC', 'Gene', '13179', (106, 108))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('IL-10', 'molecular_function', 'GO:0005141', ('33', '38'))	('CD8', 'Gene', (153, 156))	('tumor', 'Disease', (25, 30))	('CD103+', 'Var', (98, 104))	('IL-12', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('suppress', 'NegReg', (69, 77))	('mouse', 'Species', '10090', (11, 16))	('IL-12', 'molecular_function', 'GO:0005143', ('78', '83'))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))
59419	33498755	Genetic and cellular ablation of NK cells has provided evidence that these cells are essential in regulating DC accumulation within the tumor through the production of FLT3L.	('DC', 'Gene', '13179', (109, 111))	('den', 'Chemical', 'MESH:D004052', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('FLT3L', 'Gene', (168, 173))	('ablation', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
59443	33498755	Broz and colleagues were among the first to demonstrate the importance of CD103+ cDC1 in stimulating tumor-specific CD8+ T cell responses within the TME.	('CD8', 'Gene', (116, 119))	('stimulating', 'PosReg', (89, 100))	('DC', 'Gene', '13179', (82, 84))	('CD103+', 'Var', (74, 80))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CD8', 'Gene', '925', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
59450	33498755	The authors also demonstrated that TLR3 engagement is able to induce IFN-lambda production from tumor-associated cDC1s, thus proposing TLR3 activation as a potential therapeutic strategy.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('induce', 'PosReg', (62, 68))	('TLR3', 'Gene', (35, 39))	('tumor', 'Disease', (96, 101))	('engagement', 'Var', (40, 50))	('DC', 'Gene', '13179', (114, 116))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('IFN-lambda production', 'MPA', (69, 90))
59469	33498755	Human CD141+ DCs express high levels of TLR3, and treatment with TLR3 agonists, such as polyinosinic-polycytidylic acid (Poly I:C) and its derivates Poly-ICLC (Hiltonol) and poly-IC12U (Ampligen), have been shown to efficiently activate DCs by inducing cross-presentation, pro-inflammatory cytokines, Th1 cell immunity, NK cells and cytotoxic CD8+ T cell responses.	('Human', 'Species', '9606', (0, 5))	('cross-presentation', 'MPA', (253, 271))	('activate', 'PosReg', (228, 236))	('polyinosinic-polycytidylic', 'Var', (88, 114))	('NK cells', 'CPA', (320, 328))	('CD8', 'Gene', (343, 346))	('cross-presentation', 'biological_process', 'GO:0002479', ('253', '271'))	('CD141', 'Gene', (6, 11))	('-IC12U', 'Chemical', '-', (178, 184))	('Poly-ICLC', 'Var', (149, 158))	('cross-presentation', 'biological_process', 'GO:0002480', ('253', '271'))	('Poly I:C', 'Chemical', 'MESH:D011070', (121, 129))	('Hiltonol', 'Chemical', 'MESH:C019531', (160, 168))	('poly-IC12U', 'Var', (174, 184))	('CD141', 'Gene', '7056', (6, 11))	('DC', 'Gene', '13179', (237, 239))	('pro-inflammatory cytokines', 'MPA', (273, 299))	('inducing', 'PosReg', (244, 252))	('CD8', 'Gene', '925', (343, 346))	('DC', 'Gene', '13179', (13, 15))	('Th1 cell immunity', 'CPA', (301, 318))	('polyinosinic-polycytidylic acid', 'Chemical', 'MESH:D011070', (88, 119))	('Ampligen', 'Chemical', 'MESH:C047490', (186, 194))	('cross-presentation', 'biological_process', 'GO:0042590', ('253', '271'))
59475	33498755	The interaction between CD40 and CD40L may also increase cross-presentation by DCs.	('interaction', 'Interaction', (4, 15))	('CD40L', 'Gene', '959', (33, 38))	('cross-presentation', 'biological_process', 'GO:0002480', ('57', '75'))	('DC', 'Gene', '13179', (79, 81))	('cross-presentation', 'biological_process', 'GO:0042590', ('57', '75'))	('CD40L', 'Gene', (33, 38))	('CD40', 'Var', (24, 28))	('cross-presentation', 'MPA', (57, 75))	('cross-presentation', 'biological_process', 'GO:0002479', ('57', '75'))	('increase', 'PosReg', (48, 56))
59485	33498755	The addition of anti-CD40 antibody to FLT3L, radiotherapy and Poly-ICLC has been shown to induce regression of poorly T cell-infiltrated tumors refractory to PD-1/PD-L1 therapy in four syngeneic mouse models: colon adenocarcinoma, melanoma and two triple-negative mammary cancers of melanoma.	('antibody', 'cellular_component', 'GO:0019815', ('26', '34'))	('tumors', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('antibody', 'cellular_component', 'GO:0019814', ('26', '34'))	('anti-CD40', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mouse', 'Species', '10090', (195, 200))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (209, 229))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('antibody', 'molecular_function', 'GO:0003823', ('26', '34'))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('FLT3L', 'Gene', (38, 43))	('antibody', 'cellular_component', 'GO:0042571', ('26', '34'))	('cancers', 'Disease', 'MESH:D009369', (272, 279))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('colon adenocarcinoma', 'Disease', (209, 229))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
59487	33498755	These very encouraging results were followed by a Phase I clinical trial initiated on December 1th, 2020 to evaluate the safety of in situ immunomodulation with recombinant CDX-301, radiotherapy, anti-CD40 mAb and Poly-ICLC in patients with unresectable and metastatic breast cancer (NCT04616248).	('breast cancer', 'Disease', 'MESH:D001943', (269, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('anti-CD40', 'Var', (196, 205))	('breast cancer', 'Disease', (269, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (269, 282))	('unresectable', 'Disease', (241, 253))	('patients', 'Species', '9606', (227, 235))
59495	33498755	Radiation therapy causes cell death in highly replicating cancer cells by creating breaks in the DNA double-strand.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('death', 'Disease', 'MESH:D003643', (30, 35))	('death', 'Disease', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cell death', 'biological_process', 'GO:0008219', ('25', '35'))	('DNA double-strand', 'Protein', (97, 114))	('breaks', 'Var', (83, 89))
59506	33498755	Cryoablation induces tumor cell death by necrosis and osmosis.	('necrosis', 'biological_process', 'GO:0008219', ('41', '49'))	('death', 'Disease', (32, 37))	('necrosis', 'biological_process', 'GO:0070265', ('41', '49'))	('tumor', 'Disease', (21, 26))	('necrosis', 'biological_process', 'GO:0019835', ('41', '49'))	('necrosis', 'biological_process', 'GO:0008220', ('41', '49'))	('necrosis', 'biological_process', 'GO:0001906', ('41', '49'))	('necrosis and osmosis', 'Disease', 'MESH:D009336', (41, 61))	('cell death', 'biological_process', 'GO:0008219', ('27', '37'))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('death', 'Disease', 'MESH:D003643', (32, 37))	('Cryoablation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
59510	33498755	In liver tumors, cryoablation in more than 20% of the tissue causes a systemic inflammatory response due to the release of IL-6, IL-10 and TNFalpha.	('inflammatory response', 'biological_process', 'GO:0006954', ('79', '100'))	('systemic inflammatory response', 'MPA', (70, 100))	('IL-10', 'molecular_function', 'GO:0005141', ('129', '134'))	('causes', 'Reg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('liver tumors', 'Disease', 'MESH:D008113', (3, 15))	('release', 'MPA', (112, 119))	('IL-6', 'Gene', (123, 127))	('cryoablation', 'Var', (17, 29))	('liver tumors', 'Phenotype', 'HP:0002896', (3, 15))	('IL-6', 'Gene', '3569', (123, 127))	('liver tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('IL-6', 'molecular_function', 'GO:0005138', ('123', '127'))	('TNFalpha', 'Gene', (139, 147))	('TNFalpha', 'Gene', '7124', (139, 147))
59512	33498755	The preclinical study by den Brok showed that cryoablation leads to maturation of DCs, which resulted in a tumor-specific immune response that protected half of the mice from a new infusion of tumor cells.	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (107, 112))	('DC', 'Gene', '13179', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cryoablation', 'Var', (46, 58))	('immune response', 'biological_process', 'GO:0006955', ('122', '137'))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('den', 'Chemical', 'MESH:D004052', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (193, 198))	('resulted in', 'Reg', (93, 104))
59524	33498755	Notably, deletion of PD-L1 in DCs, but not in macrophages, significantly reduced tumor growth and led to enhanced antitumor CD8+ T-cell responses.	('DC', 'Gene', '13179', (30, 32))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('deletion', 'Var', (9, 17))	('reduced', 'NegReg', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CD8', 'Gene', (124, 127))	('tumor', 'Disease', (118, 123))	('PD-L1', 'Gene', (21, 26))	('CD8', 'Gene', '925', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('enhanced', 'PosReg', (105, 113))	('tumor', 'Disease', (81, 86))
59529	33498755	These recent findings suggest that ICB therapy is effective not only by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses, and that blocking the PD-1 pathway early with immune checkpoint inhibitors, at the time of priming and expansion of memory T cells, could be critical for enhancing antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('blocking', 'Var', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('PD-1 pathway', 'Pathway', (264, 276))	('triggering', 'Reg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('tumor', 'Disease', (225, 230))	('memory', 'biological_process', 'GO:0007613', ('358', '364'))	('tumor', 'Disease', (410, 415))	('enhancing', 'PosReg', (396, 405))	('DC', 'Gene', '13179', (152, 154))
59575	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('TGCACGA', 'Gene', (65, 72))	('MIR-184', 'Gene', (55, 62))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
59622	31970154	As shown in Figure 2D, more than one-fifth of all HNSC samples harbored PGRMC1 amplification, and consistently, HNSC samples harboring PGRMC1 amplification exhibited higher mRNA expression than those that exhibit diploid PGRMC1.	('higher', 'PosReg', (166, 172))	('HNSC', 'Phenotype', 'HP:0012288', (50, 54))	('PGRMC1', 'Gene', (72, 78))	('PGRMC1', 'Gene', '10857', (135, 141))	('HNSC', 'Disease', (50, 54))	('PGRMC1', 'Gene', '10857', (221, 227))	('HNSC', 'Disease', 'MESH:C535575', (50, 54))	('HNSC', 'Phenotype', 'HP:0012288', (112, 116))	('PGRMC1', 'Gene', '10857', (72, 78))	('PGRMC1', 'Gene', (135, 141))	('HNSC', 'Disease', 'MESH:C535575', (112, 116))	('amplification', 'Var', (142, 155))	('amplification', 'Var', (79, 92))	('PGRMC1', 'Gene', (221, 227))	('HNSC', 'Disease', (112, 116))	('mRNA expression', 'MPA', (173, 188))
59624	31970154	In summary, a positive correlation between PGRMC1 copy number amplification and mRNA over-expression was found among HNSC samples, and its over-expression is an adverse prognostic factor for HNSC patients.	('HNSC', 'Phenotype', 'HP:0012288', (117, 121))	('mRNA', 'MPA', (80, 84))	('PGRMC1', 'Gene', (43, 49))	('HNSC', 'Phenotype', 'HP:0012288', (191, 195))	('HNSC', 'Disease', (117, 121))	('HNSC', 'Disease', 'MESH:C535575', (117, 121))	('HNSC', 'Disease', (191, 195))	('positive', 'Reg', (14, 22))	('HNSC', 'Disease', 'MESH:C535575', (191, 195))	('patients', 'Species', '9606', (196, 204))	('copy number amplification', 'Var', (50, 75))	('over-expression', 'PosReg', (139, 154))	('PGRMC1', 'Gene', '10857', (43, 49))	('over-expression', 'PosReg', (85, 100))
59641	31970154	Remarkably, as shown in Figure 7B, the genomic alterations rate of PIK3CA in the PGRMC1 high-expression sub-group is 1.5-fold higher than the samples of low-expression sub-group, which reached nearly 45% of the total samples for HNSC cohort.	('PIK3CA', 'Gene', '5290', (67, 73))	('PGRMC1', 'Gene', (81, 87))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('PGRMC1', 'Gene', '10857', (81, 87))	('higher', 'PosReg', (126, 132))	('high-expression', 'Var', (88, 103))	('HNSC', 'Disease', (229, 233))	('HNSC', 'Disease', 'MESH:C535575', (229, 233))	('PIK3CA', 'Gene', (67, 73))	('genomic alterations', 'MPA', (39, 58))
59643	31970154	As many studies reported that HNSC with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSC progression (Qiu et al.,; Lui et al.,), these data revealed the positive correlation between PGRMC1 over-expression and PIK3CA genomic alterations, known for its association of cancer progression and metastasis, which provided further support for the oncogenic role of PGRMC1 and the potential interaction with PIK3CA.	('HNSC', 'Disease', (30, 34))	('PGRMC1', 'Gene', (441, 447))	('PIK3CA', 'Gene', (483, 489))	('HNSC', 'Phenotype', 'HP:0012288', (30, 34))	('PGRMC1', 'Gene', (265, 271))	('mutation', 'Var', (51, 59))	('HNSC', 'Disease', 'MESH:C535575', (30, 34))	('over-expression', 'PosReg', (272, 287))	('cancer', 'Disease', (349, 355))	('PIK3CA', 'Gene', '5290', (292, 298))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('HNSC', 'Disease', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('PGRMC1', 'Gene', '10857', (441, 447))	('PIK3CA', 'Gene', '5290', (483, 489))	('HNSC', 'Phenotype', 'HP:0012288', (167, 171))	('HNSC', 'Disease', 'MESH:C535575', (167, 171))	('PGRMC1', 'Gene', '10857', (265, 271))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('PIK3CA', 'Gene', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (349, 355))
59649	31970154	Remarkably, the tumors harboring PGRMC1 high-expression showed the more abundant counts of somatic mutations and the fraction of genomic copy number alterations compared with PGRMC1 low-expression tumors (Figure 8C).	('PGRMC1', 'Gene', '10857', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('PGRMC1', 'Gene', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('PGRMC1', 'Gene', '10857', (175, 181))	('high-expression', 'Var', (40, 55))	('tumors', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (16, 22))	('PGRMC1', 'Gene', (33, 39))
59653	31970154	In this present study, we assessed the prognostic impact of aberrant PGRMC1 expression in head and neck cancer and other cancers to identify patients who may benefit from anti-cancer therapy targeting PGRMC1 and also investigated the oncogenic mechanism of PGRMC1 over-expression in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('PGRMC1', 'Gene', (257, 263))	('PGRMC1', 'Gene', (201, 207))	('cancer', 'Disease', (104, 110))	('patients', 'Species', '9606', (141, 149))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('head and neck cancer', 'Phenotype', 'HP:0012288', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGRMC1', 'Gene', '10857', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('neck', 'cellular_component', 'GO:0044326', ('99', '103'))	('cancer', 'Disease', (283, 289))	('PGRMC1', 'Gene', '10857', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('head and neck cancer', 'Disease', 'MESH:D006258', (90, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('PGRMC1', 'Gene', '10857', (201, 207))	('aberrant', 'Var', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('PGRMC1', 'Gene', (69, 75))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (121, 127))
59654	31970154	Considering the amplification is one of the major genetic mechanisms that could increase the gene expression of oncogenes (Savelyeva and Schwab,; Lockwood et al.,; Zhang et al.,), it suggested that the copy number amplification of PGRMC1 could serve as a potential genetic driver for its over-expression.	('PGRMC1', 'Gene', '10857', (231, 237))	('PGRMC1', 'Gene', (231, 237))	('increase', 'PosReg', (80, 88))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('over-expression', 'PosReg', (288, 303))	('gene expression', 'MPA', (93, 108))	('copy number amplification', 'Var', (202, 227))
59655	31970154	Our data revealed, previously undescribed, the oncogenic and prognosis value of PGRMC1 over-expression and copy number amplification in the head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (140, 160))	('copy number amplification', 'Var', (107, 132))	('neck', 'cellular_component', 'GO:0044326', ('149', '153'))	('over-expression', 'PosReg', (87, 102))	('head and neck cancer', 'Disease', 'MESH:D006258', (140, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('PGRMC1', 'Gene', (80, 86))	('PGRMC1', 'Gene', '10857', (80, 86))
59656	31970154	It is convinced that the status of PGRMC1 copy number amplification and over-expression will probably influence response to head and neck cancer treatment strategy.	('copy number amplification', 'Var', (42, 67))	('influence', 'Reg', (102, 111))	('over-expression', 'MPA', (72, 87))	('head and neck cancer', 'Phenotype', 'HP:0012288', (124, 144))	('neck', 'cellular_component', 'GO:0044326', ('133', '137'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PGRMC1', 'Gene', (35, 41))	('PGRMC1', 'Gene', '10857', (35, 41))	('head and neck cancer', 'Disease', 'MESH:D006258', (124, 144))
59669	28059929	Multivariate analysis showed improved HPFS for PHP versus Y90 (P = 0.004), PHP versus CE (P = 0.02) but not for CE versus Y90.	('Y90', 'Chemical', 'MESH:C000615496', (122, 125))	('Y90', 'Chemical', 'MESH:C000615496', (58, 61))	('PHP', 'Var', (47, 50))	('HPFS', 'MPA', (38, 42))	('improved', 'PosReg', (29, 37))	('PHP', 'Var', (75, 78))
59673	28059929	Only PHP treatment versus Y90 and lower tumor burden had improved OS on multivariate analysis (P = 0.03, 0.03, respectively).	('PHP', 'Var', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('improved', 'PosReg', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Y90', 'Chemical', 'MESH:C000615496', (26, 29))
59674	28059929	HPFS and PFS were significantly prolonged in patients treated with PHP versus CE or Y90.	('prolonged', 'PosReg', (32, 41))	('HPFS', 'CPA', (0, 4))	('PHP', 'Var', (67, 70))	('patients', 'Species', '9606', (45, 53))	('Y90', 'Chemical', 'MESH:C000615496', (84, 87))	('PFS', 'CPA', (9, 12))
59692	28059929	We performed a retrospective study to evaluate the outcomes of hepatic progression-free survival (HPFS), progression-free survival (PFS), and overall survival (OS) in highly selected patients with hepatic recurrence treated with Y90, PHP, or CE.	('hepatic', 'Disease', (197, 204))	('PHP', 'Gene', (234, 237))	('hepatic', 'MPA', (63, 70))	('Y90', 'Chemical', 'MESH:C000615496', (229, 232))	('Y90', 'Var', (229, 232))	('patients', 'Species', '9606', (183, 191))
59693	28059929	After obtaining Institutional Review Board approval, a single institution retrospective review of all patients treated with Y90, PHP, or CE for unresectable hepatic metastases secondary to uveal or cutaneous melanoma from 2008 to 2014 was conducted.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('patients', 'Species', '9606', (102, 110))	('cutaneous melanoma', 'Disease', (198, 216))	('hepatic metastases', 'Disease', (157, 175))	('Y90', 'Var', (124, 127))	('Y90', 'Chemical', 'MESH:C000615496', (124, 127))	('uveal or cutaneous melanoma', 'Phenotype', 'HP:0007716', (189, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (198, 216))	('hepatic metastases', 'Disease', 'MESH:D009362', (157, 175))
59705	28059929	Y90 radioembolization of hepatic tumors has been proven to be a safe method of radiation delivery which minimizes the risk of systemic toxicity.	('Y90', 'Chemical', 'MESH:C000615496', (0, 3))	('hepatic tumors', 'Disease', 'MESH:D056486', (25, 39))	('Y90', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('hepatic tumors', 'Disease', (25, 39))	('toxicity', 'Disease', 'MESH:D064420', (135, 143))	('toxicity', 'Disease', (135, 143))
59727	28059929	There was a difference in the location of the primary tumor, with a majority of patients undergoing Y90 having uveal melanoma, whereas cutaneous melanoma was more common in the other treatment groups (Fisher's exact test; P = 0.002) (Table 1).	('uveal melanoma', 'Phenotype', 'HP:0007716', (111, 125))	('uveal melanoma', 'Disease', 'MESH:C536494', (111, 125))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('patients', 'Species', '9606', (80, 88))	('cutaneous melanoma', 'Disease', (135, 153))	('uveal melanoma', 'Disease', (111, 125))	('Y90', 'Chemical', 'MESH:C000615496', (100, 103))	('Y90', 'Var', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
59729	28059929	MVA showed significantly improved HPFS for PHP versus Y90 (hazard ratio [HR], 0.11, 95% confidence interval [CI], 0.03, 0.49; P = 0.004), PHP versus CE (HR, 0.31, 95% CI, 0.12, 0.81; P = 0.02) but not for CE versus Y90 (HR, 0.36, 95% CI, 0.089, 1.51; P = 0.17).	('improved', 'PosReg', (25, 33))	('HPFS', 'MPA', (34, 38))	('PHP', 'Var', (138, 141))	('Y90', 'Chemical', 'MESH:C000615496', (215, 218))	('Y90', 'Chemical', 'MESH:C000615496', (54, 57))	('PHP', 'Var', (43, 46))
59732	28059929	There was a significant difference in median PFS: Y90 54 days; PHP 245 days, and CE 52 days; Log-rank test, P = 0.03 (Fig.	('PHP 245', 'Var', (63, 70))	('Y90', 'Chemical', 'MESH:C000615496', (50, 53))	('CE 52', 'Var', (81, 86))	('Y90 54 days', 'Var', (50, 61))
59733	28059929	MVA showed improved PFS for PHP versus Y90 (HR, 0.17, 95% CI, 0.04, 0.63; P = 0.008), PHP versus CE (HR, 0.37, 95% CI, 0.14, 0.94; P = 0.04) but not for CE versus Y90 (HR, 0.46, 95% CI, 0.13, 1.65; P = 0.23).	('PFS', 'MPA', (20, 23))	('PHP', 'Var', (86, 89))	('improved', 'PosReg', (11, 19))	('PHP', 'Var', (28, 31))	('Y90', 'Chemical', 'MESH:C000615496', (163, 166))	('Y90', 'Chemical', 'MESH:C000615496', (39, 42))
59735	28059929	Median OS from time of treatment was longest for PHP at 608 days versus Y90 295 days or CE 265 days.	('Y90', 'Var', (72, 75))	('PHP', 'Var', (49, 52))	('Y90', 'Chemical', 'MESH:C000615496', (72, 75))
59742	28059929	The application of Y90 in the treatment of metastatic melanoma, although less well studied than its use for colorectal cancer and hepatocellular carcinoma, has been reported in the literature as safe and efficacious.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Disease', (54, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('colorectal cancer', 'Disease', (108, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('Y90', 'Chemical', 'MESH:C000615496', (19, 22))	('Y90', 'Var', (19, 22))	('hepatocellular carcinoma', 'Disease', (130, 154))
59762	28059929	There was a difference, however, seen in HPFS and PFS and in OS for patients undergoing PHP compared with Y90 and these findings are important for discussing treatment options with patients and prompting additional studies to confirm these results.	('PFS', 'CPA', (50, 53))	('Y90', 'Chemical', 'MESH:C000615496', (106, 109))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (181, 189))	('HPFS', 'Disease', (41, 45))	('PHP', 'Var', (88, 91))
59880	32474365	Distinguishing Tumor and Stromal Sources of MicroRNAs Linked to Metastasis in Cutaneous Melanoma MicroRNA (miRNA) dysregulation in cancer causes changes in gene expression programs regulating tumor progression and metastasis.	('cancer', 'Disease', (131, 137))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('gene expression programs', 'MPA', (156, 180))	('Metastasis in Cutaneous Melanoma', 'Disease', (64, 96))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene expression', 'biological_process', 'GO:0010467', ('156', '171'))	('Metastasis in Cutaneous Melanoma', 'Disease', 'MESH:D009362', (64, 96))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('changes', 'Reg', (145, 152))	('Tumor', 'Phenotype', 'HP:0002664', (15, 20))	('dysregulation', 'Var', (114, 127))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
59899	32474365	These changes in gene expression can promote phenotypes that contribute to cancer progression, metastasis, and resistance to therapy.	('gene expression', 'biological_process', 'GO:0010467', ('17', '32'))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('promote', 'PosReg', (37, 44))	('cancer', 'Disease', (75, 81))	('changes', 'Var', (6, 13))	('resistance', 'CPA', (111, 121))	('metastasis', 'CPA', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
59900	32474365	Defining miRNA associated with metastasis in melanoma could provide insights into the genes and pathways that drive metastatic progression, and potentially lead to the discovery of new therapeutic targets or biomarkers.	('metastasis', 'Disease', (31, 41))	('miRNA', 'Var', (9, 14))	('associated', 'Reg', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
59926	32474365	Acquired expression of C19MC has been reported in other cancers, but this constitutes a novel finding in melanoma.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('C19MC', 'Var', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
60022	32474365	Melanocytes and keratinocytes are known to interact, and changes in these interactions have been linked to melanoma tumorigenesis and metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma tumorigenesis', 'Disease', (107, 129))	('changes', 'Var', (57, 64))	('linked', 'Reg', (97, 103))	('metastasis', 'CPA', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (107, 129))	('interactions', 'Interaction', (74, 86))
60034	32474365	Apart from stromal-enriched miRNA, dysregulation of large miRNA gene clusters may be a hallmark of the melanoma miRNA landscape.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('miRNA gene clusters', 'Gene', (58, 77))	('dysregulation', 'Var', (35, 48))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
60036	32474365	However, our identification of C19MC activation in melanoma is novel.	('C19MC', 'Var', (31, 36))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
60037	32474365	Aberrant C19MC expression has been reported in several cancers, and these miRNA have immune-modulatory effects potentially relevant to melanoma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('Aberrant', 'Var', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('reported', 'Reg', (35, 43))	('C19MC', 'Protein', (9, 14))	('melanoma', 'Disease', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
60038	32474365	However, little is known about how C19MC expression is acquired, or the functional consequence this has in tumors.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('C19MC', 'Var', (35, 40))
60043	14612910	Role of MC1R variants in uveal melanoma Uveal melanoma although rare is the most common primary intraocular malignancy in adults with an incidence of six per million per year (Parkin et al, 1992).	('variants', 'Var', (13, 21))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('intraocular malignancy', 'Disease', 'MESH:C563596', (96, 118))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('MC1R', 'Gene', '4157', (8, 12))	('intraocular malignancy', 'Disease', (96, 118))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('MC1R', 'Gene', (8, 12))
60056	14612910	Several point mutations in MC1R affecting function have been identified, for example, V60L, R151C, R160W, D294H, some of which have been reported to be over-represented in individuals with fair hair and skin (Valverde et al, 1995; Flanagan et al, 2000; Box et al, 2001a,2001b).	('affecting', 'Reg', (32, 41))	('R160W', 'Mutation', 'rs1805008', (99, 104))	('R151C', 'Var', (92, 97))	('R160W', 'Var', (99, 104))	('MC1R', 'Gene', '4157', (27, 31))	('MC1R', 'Gene', (27, 31))	('D294H', 'Mutation', 'rs1805009', (106, 111))	('function', 'MPA', (42, 50))	('V60L', 'Var', (86, 90))	('fair hair', 'Phenotype', 'HP:0002286', (189, 198))	('R151C', 'Mutation', 'rs1805007', (92, 97))	('D294H', 'Var', (106, 111))	('V60L', 'Mutation', 'rs1805005', (86, 90))
60057	14612910	In addition to acting as determinates of pigmentation, some variants may confer an increased risk of cutaneous melanoma (Valverde et al, 1996; Healy et al, 1999; Palmer et al, 2000).	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('pigmentation', 'biological_process', 'GO:0043473', ('41', '53'))	('variants', 'Var', (60, 68))
60059	14612910	We have assessed the risk of uveal melanoma associated with germline MC1R variants through sequence analysis of 350 patients and a series of 133 population controls.	('MC1R', 'Gene', '4157', (69, 73))	('patients', 'Species', '9606', (116, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('MC1R', 'Gene', (69, 73))	('variants', 'Var', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
60080	14612910	Eight variants were detected - V60L, D84E, V92M, R151C, I155T, R160W, R163Q, D294H - among the patients and controls studied (Table 1  ).	('R163Q', 'Mutation', 'rs885479', (70, 75))	('D294H', 'Mutation', 'rs1805009', (77, 82))	('patients', 'Species', '9606', (95, 103))	('R160W', 'Mutation', 'rs1805008', (63, 68))	('D84E', 'Var', (37, 41))	('R151C', 'Mutation', 'rs1805007', (49, 54))	('I155T', 'Var', (56, 61))	('R160W', 'Var', (63, 68))	('V60L', 'Var', (31, 35))	('V92M', 'Var', (43, 47))	('R163Q', 'Var', (70, 75))	('I155T', 'Mutation', 'rs1110400', (56, 61))	('R151C', 'Var', (49, 54))	('D84E', 'Mutation', 'rs1805006', (37, 41))	('D294H -', 'Var', (77, 84))	('V92M', 'Mutation', 'rs2228479', (43, 47))	('V60L', 'Mutation', 'rs1805005', (31, 35))
60081	14612910	The frequencies of combinations of MC1R variants did not differ from expected observed allele frequencies (data not shown).	('variants', 'Var', (40, 48))	('MC1R', 'Gene', '4157', (35, 39))	('MC1R', 'Gene', (35, 39))
60082	14612910	Hence, the MC1R variants can be considered as independent variants and consequently were analysed as such.	('MC1R', 'Gene', (11, 15))	('variants', 'Var', (16, 24))	('MC1R', 'Gene', '4157', (11, 15))
60083	14612910	The frequencies of the MC1R variants that have been reported in 190 UK population controls - D84E (3.5%), V92M (17.3%) and D294H (6.8%) (Ichii-Jones et al, 1998) - are not statically different from that observed in the cases and controls in our study.	('MC1R', 'Gene', (23, 27))	('D294H', 'Var', (123, 128))	('D84E', 'Var', (93, 97))	('Ichii', 'Species', '99806', (137, 142))	('D294H', 'Mutation', 'rs1805009', (123, 128))	('D84E', 'Mutation', 'rs1805006', (93, 97))	('V92M', 'Var', (106, 110))	('MC1R', 'Gene', '4157', (23, 27))	('V92M', 'Mutation', 'rs2228479', (106, 110))
60084	14612910	In addition, the frequencies of the V60L, D84E, R151C, R160W and D294H variants are not statistically different from the frequencies previously documented in the 738 individuals of Northern European ancestry reported by Vajdic et al (2003) (23.2, 2.8, 20.6, 15.6 and 6.0%, respectively).	('R151C', 'Mutation', 'rs1805007', (48, 53))	('D294H', 'Var', (65, 70))	('V60L', 'Mutation', 'rs1805005', (36, 40))	('D84E', 'Mutation', 'rs1805006', (42, 46))	('R160W', 'Mutation', 'rs1805008', (55, 60))	('D294H', 'Mutation', 'rs1805009', (65, 70))	('V60L', 'Var', (36, 40))	('R151C', 'Var', (48, 53))	('R160W', 'Var', (55, 60))	('D84E', 'Var', (42, 46))
60086	14612910	The relationship between these three phenotypes and MC1R variation is detailed in Table 2  .	('variation', 'Var', (57, 66))	('MC1R', 'Gene', '4157', (52, 56))	('MC1R', 'Gene', (52, 56))
60087	14612910	No significant association was seen between possession of one or more MC1R variants and eye colour (P=0.46).	('MC1R', 'Gene', '4157', (70, 74))	('MC1R', 'Gene', (70, 74))	('variants', 'Var', (75, 83))	('eye colour', 'Disease', (88, 98))
60088	14612910	Similarly, no significant relationship was seen between skin type and possession of a MC1R variant (P=0.29) or naevus count (P=0.45).	('MC1R', 'Gene', (86, 90))	('naevus', 'Phenotype', 'HP:0003764', (111, 117))	('MC1R', 'Gene', '4157', (86, 90))	('variant', 'Var', (91, 98))
60089	14612910	There was, however, an association between MC1R status and hair colour with an over-representation of variants in individuals with light or red hair (P=0.03).	('association', 'Interaction', (23, 34))	('over-representation', 'PosReg', (79, 98))	('variants', 'Var', (102, 110))	('MC1R', 'Gene', (43, 47))	('red hair', 'Disease', (140, 148))	('MC1R', 'Gene', '4157', (43, 47))	('red hair', 'Phenotype', 'HP:0002297', (140, 148))	('red hair', 'Disease', 'MESH:C567091', (140, 148))
60090	14612910	The frequency of each of the MC1R variants in the 350 patients was not statistically different from that observed in the controls.	('patients', 'Species', '9606', (54, 62))	('MC1R', 'Gene', (29, 33))	('variants', 'Var', (34, 42))	('MC1R', 'Gene', '4157', (29, 33))
60091	14612910	Of the 350 patients studied, 129 (36.9%) had no MC1R variants, 154 (44.0%) had one MC1R variant and 67 (19.1%) possessed two or more variants.	('MC1R', 'Gene', '4157', (83, 87))	('MC1R', 'Gene', '4157', (48, 52))	('MC1R', 'Gene', (48, 52))	('MC1R', 'Gene', (83, 87))	('patients', 'Species', '9606', (11, 19))	('variants', 'Var', (53, 61))
60092	14612910	The mean ages at diagnosis in noncarriers and carriers of one and two or more of MC1R variants in our study were not significantly different - 57.9, s.d.	('MC1R', 'Gene', '4157', (81, 85))	('MC1R', 'Gene', (81, 85))	('variants', 'Var', (86, 94))
60093	14612910	Two research groups have previously reported on the relationship between MC1R variants and risk of uveal melanoma - Metzelaar-Blok et al (2001) based on analysis of 162 patients and Vajdic et al (2003) based on analysis of 62 patients.	('patients', 'Species', '9606', (169, 177))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('MC1R', 'Gene', '4157', (73, 77))	('MC1R', 'Gene', (73, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (99, 113))	('uveal melanoma', 'Disease', 'MESH:C536494', (99, 113))	('patients', 'Species', '9606', (226, 234))	('uveal melanoma', 'Disease', (99, 113))	('variants', 'Var', (78, 86))
60094	14612910	Also shown are pooled estimates of the risk of uveal melanoma based on all studies for individual variants and one, two or more and any MC1R variant.	('MC1R', 'Gene', '4157', (136, 140))	('MC1R', 'Gene', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('variant', 'Var', (141, 148))	('variants', 'Var', (98, 106))
60096	14612910	We performed this study to determine whether germline MC1R variants confer an increased risk of uveal melanoma.	('uveal melanoma', 'Disease', (96, 110))	('variants', 'Var', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('MC1R', 'Gene', '4157', (54, 58))	('MC1R', 'Gene', (54, 58))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
60098	14612910	The frequency of MC1R variants detected in patients in our study was not significantly different from the frequencies in the general population, and were very similar to estimates obtained in unselected North-European populations.	('patients', 'Species', '9606', (43, 51))	('MC1R', 'Gene', '4157', (17, 21))	('variants', 'Var', (22, 30))	('MC1R', 'Gene', (17, 21))
60099	14612910	Furthermore, we found that the age at diagnosis of uveal melanoma in carriers of MC1R variants was not significantly different from noncarriers.	('uveal melanoma', 'Phenotype', 'HP:0007716', (51, 65))	('uveal melanoma', 'Disease', (51, 65))	('MC1R', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('variants', 'Var', (86, 94))	('MC1R', 'Gene', '4157', (81, 85))	('carriers', 'Reg', (69, 77))	('uveal melanoma', 'Disease', 'MESH:C536494', (51, 65))
60100	14612910	These findings imply that MC1R variants are unlikely to confer an increased risk of uveal melanoma.	('MC1R', 'Gene', (26, 30))	('variants', 'Var', (31, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (84, 98))	('uveal melanoma', 'Disease', (84, 98))	('uveal melanoma', 'Disease', 'MESH:C536494', (84, 98))	('MC1R', 'Gene', '4157', (26, 30))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
60101	14612910	The main strengths of our study are the large number of patients in our sample and correlation of MC1R variants with age at diagnosis, a factor that has not previously been investigated.	('patients', 'Species', '9606', (56, 64))	('variants', 'Var', (103, 111))	('correlation', 'Interaction', (83, 94))	('MC1R', 'Gene', '4157', (98, 102))	('MC1R', 'Gene', (98, 102))
60102	14612910	In our study, we detected eight MC1R variants: V60L, D84E V92M, R151C, I155T, R160H, R163Q and D294H.	('R151C', 'Mutation', 'rs1805007', (64, 69))	('R160H', 'Var', (78, 83))	('R163Q', 'Var', (85, 90))	('V92M', 'SUBSTITUTION', 'None', (58, 62))	('V60L', 'Mutation', 'rs1805005', (47, 51))	('D294H', 'Mutation', 'rs1805009', (95, 100))	('R151C', 'Var', (64, 69))	('D84E', 'Var', (53, 57))	('MC1R', 'Gene', '4157', (32, 36))	('D294H', 'Var', (95, 100))	('D84E', 'SUBSTITUTION', 'None', (53, 57))	('R160H', 'Mutation', 'p.R160H', (78, 83))	('R163Q', 'Mutation', 'rs885479', (85, 90))	('V60L', 'Var', (47, 51))	('MC1R', 'Gene', (32, 36))	('I155T', 'Var', (71, 76))	('I155T', 'Mutation', 'rs1110400', (71, 76))	('V92M', 'Var', (58, 62))
60103	14612910	Previous studies have demonstrated a relationship between MC1R variants and hair and skin type, notably a strong association between the R151C, R160Q and R294H variants, with fair skin and red hair (Valverde et al, 1995; Palmer et al, 2000; Bastiaens et al, 2001).	('red hair', 'Disease', (189, 197))	('red hair', 'Phenotype', 'HP:0002297', (189, 197))	('R151C', 'Mutation', 'rs1805007', (137, 142))	('red hair', 'Disease', 'MESH:C567091', (189, 197))	('MC1R', 'Gene', '4157', (58, 62))	('R160Q', 'Var', (144, 149))	('R160Q', 'Mutation', 'rs780813746', (144, 149))	('R294H', 'Var', (154, 159))	('MC1R', 'Gene', (58, 62))	('R151C', 'Var', (137, 142))	('fair skin', 'Phenotype', 'HP:0007513', (175, 184))	('fair skin', 'Disease', (175, 184))	('R294H', 'Mutation', 'p.R294H', (154, 159))
60104	14612910	Collectively, the MC1R variants we detected were over-represented in the patients with light skin and red or fair hair, in keeping with these previous observations.	('light skin', 'Phenotype', 'HP:0001010', (87, 97))	('fair hair', 'Phenotype', 'HP:0002286', (109, 118))	('over-represented', 'PosReg', (49, 65))	('MC1R', 'Gene', '4157', (18, 22))	('MC1R', 'Gene', (18, 22))	('variants', 'Var', (23, 31))	('patients', 'Species', '9606', (73, 81))
60106	14612910	Most, but not all, previous studies have shown that MC1R variants are associated with an increased risk of both cutaneous melanoma (Valverde et al, 1996; Palmer et al, 2000) and nonmelanoma skin cancers (Box et al, 2001a,2001b).	('nonmelanoma skin cancers', 'Disease', (178, 202))	('skin cancers', 'Phenotype', 'HP:0008069', (190, 202))	('nonmelanoma skin cancers', 'Disease', 'MESH:D012878', (178, 202))	('MC1R', 'Gene', '4157', (52, 56))	('MC1R', 'Gene', (52, 56))	('cutaneous melanoma', 'Disease', (112, 130))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('variants', 'Var', (57, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
60107	14612910	This suggests that certain MC1R variants can exert an effect on melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway (Palmer et al, 2000; Van der Velden et al, 2001).	('MC1R', 'Gene', '4157', (27, 31))	('MC1R', 'Gene', (27, 31))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('variants', 'Var', (32, 40))	('effect', 'Reg', (54, 60))	('fair skin', 'Phenotype', 'HP:0007513', (130, 139))
60108	14612910	Our data support the findings of Metzelaar-Blok et al (2001) and the recent study reported by Vajdic et al (2003), who found no relationship between variation in MC1R and risk of uveal melanoma.	('uveal melanoma', 'Disease', 'MESH:C536494', (179, 193))	('MC1R', 'Gene', '4157', (162, 166))	('MC1R', 'Gene', (162, 166))	('variation', 'Var', (149, 158))	('uveal melanoma', 'Phenotype', 'HP:0007716', (179, 193))	('uveal melanoma', 'Disease', (179, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
60109	14612910	Moreover, pooling data from all three studies provide no evidence that variants confer an increased risk of uveal melanoma.	('variants', 'Var', (71, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (108, 122))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('uveal melanoma', 'Disease', (108, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
60116	14612910	Moreover, differences in the relative importance of aetiological factors between the two tumour types are reflected at the molecular level - activating mutations of BRAF are almost universal in cutaneous melanomas but not in uveal tumours (Davies et al, 2002; Cohen et al, 2003; Edmunds et al, 2003).	('mutations', 'Var', (152, 161))	('cutaneous melanomas', 'Disease', (194, 213))	('melanomas', 'Phenotype', 'HP:0002861', (204, 213))	('BRAF', 'Gene', '673', (165, 169))	('activating', 'PosReg', (141, 151))	('BRAF', 'Gene', (165, 169))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('uveal tumours', 'Disease', 'MESH:D014604', (225, 238))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('uveal tumours', 'Disease', (225, 238))	('tumour', 'Disease', (231, 237))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (194, 213))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (194, 213))
60130	31333775	To the best of our knowledge, the relationship between aberrant expression of EMP2 and melanoma have not been previously reported.	('si', 'Chemical', 'MESH:D012825', (70, 72))	('melanoma', 'Disease', (87, 95))	('aberrant expression', 'Var', (55, 74))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('EMP2', 'Gene', '2013', (78, 82))	('EMP2', 'Gene', (78, 82))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
60140	31333775	Further, studies have indicated that the knockdown of EMP2 does not significantly interfere A375 melanoma cell proliferation.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('EMP2', 'Gene', '2013', (54, 58))	('A375', 'CellLine', 'CVCL:0132', (92, 96))	('EMP2', 'Gene', (54, 58))	('knockdown', 'Var', (41, 50))	('cell proliferation', 'biological_process', 'GO:0008283', ('106', '124'))
60204	31333775	In addition, the expression of EMP2 was much higher with MHY1485 co-treatment, indicating that the suppression of autophagic process was indeed upregulated EMP2 in A375 cells.	('A375', 'CellLine', 'CVCL:0132', (164, 168))	('upregulated', 'PosReg', (144, 155))	('expression', 'MPA', (17, 27))	('MHY1485', 'Var', (57, 64))	('EMP2', 'Gene', '2013', (31, 35))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('autophagic process', 'CPA', (114, 132))	('EMP2', 'Gene', (31, 35))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('EMP2', 'Gene', '2013', (156, 160))	('MHY1485', 'Chemical', 'MESH:C577756', (57, 64))	('EMP2', 'Gene', (156, 160))	('higher', 'PosReg', (45, 51))
60206	31333775	Taken together, we concluded the degradation of EMP2 in A375 is regulated by the autophagic process, especially the autolysosome.	('degradation', 'biological_process', 'GO:0009056', ('33', '44'))	('EMP2', 'Gene', '2013', (48, 52))	('autolysosome', 'CPA', (116, 128))	('degradation', 'MPA', (33, 44))	('EMP2', 'Gene', (48, 52))	('A375', 'CellLine', 'CVCL:0132', (56, 60))	('autolysosome', 'cellular_component', 'GO:0044754', ('116', '128'))	('autophagic process', 'CPA', (81, 99))	('A375', 'Var', (56, 60))
60254	31019223	DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs.	('double strand breakage', 'Var', (4, 26))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('anaemia', 'Phenotype', 'HP:0001903', (84, 91))	('Fanconi anaemia', 'Disease', (76, 91))	('Fanconi anaemia', 'Phenotype', 'HP:0001994', (76, 91))	('DNA repair', 'biological_process', 'GO:0006281', ('92', '102'))	('DNA damage response', 'biological_process', 'GO:0006974', ('40', '59'))	('Fanconi anaemia', 'Disease', 'MESH:D005199', (76, 91))	('triggers', 'Reg', (27, 35))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('expression', 'MPA', (135, 145))	('metastasising OMMs', 'Disease', (153, 171))	('elevated', 'PosReg', (126, 134))	('OMM', 'Chemical', '-', (167, 170))	('DNA damage response network', 'Pathway', (40, 67))
60272	31019223	Putative activating mutations in Kit have been described in 7-16% of human mucosal melanomas and in 12% of canine OMM, and mutations in NRAS have been reported in 3.9% of canine OMMs and in 10-22% of human mucosal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (214, 223))	('mucosal melanomas', 'Disease', (206, 223))	('Kit', 'Gene', (33, 36))	('human', 'Species', '9606', (200, 205))	('OMM', 'Chemical', '-', (178, 181))	('OMM', 'Chemical', '-', (114, 117))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('mucosal melanomas', 'Disease', 'MESH:D008545', (75, 92))	('NRAS', 'Gene', (136, 140))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('mucosal melanomas', 'Disease', (75, 92))	('human', 'Species', '9606', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('mutations', 'Var', (20, 29))	('NRAS', 'Gene', '403872', (136, 140))	('canine', 'Species', '9615', (171, 177))	('activating', 'PosReg', (9, 19))	('mucosal melanomas', 'Disease', 'MESH:D008545', (206, 223))	('canine', 'Species', '9615', (107, 113))	('mutations', 'Var', (123, 132))
60273	31019223	Around 50% of human cutaneous melanomas have an activating BRAF mutation, but BRAF mutations occur in only 4-9.5% of human mucosal melanomas, and have not been found in canine OMMs.	('cutaneous melanomas', 'Disease', (20, 39))	('BRAF', 'Gene', '673', (78, 82))	('activating', 'MPA', (48, 58))	('BRAF', 'Gene', (78, 82))	('canine', 'Species', '9615', (169, 175))	('melanomas', 'Phenotype', 'HP:0002861', (30, 39))	('mucosal melanomas', 'Disease', 'MESH:D008545', (123, 140))	('melanomas', 'Phenotype', 'HP:0002861', (131, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (20, 38))	('mutation', 'Var', (64, 72))	('human', 'Species', '9606', (117, 122))	('human', 'Species', '9606', (14, 19))	('mucosal melanomas', 'Disease', (123, 140))	('OMM', 'Chemical', '-', (176, 179))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (20, 39))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (20, 39))
60274	31019223	The metastatic cascade comprises a series of steps, which are believed to be at least partially mediated by the acquisition of metastasis-associated genetic and/or epigenetic alterations additional to those that drive tumour development.	('tumour', 'Disease', (218, 224))	('metastasis-associated', 'Disease', (127, 148))	('epigenetic alterations', 'Var', (164, 186))	('genetic', 'Var', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('tumour', 'Disease', 'MESH:D009369', (218, 224))
60275	31019223	These somatic changes may affect gene expression, and metastasis-associated gene expression signatures have been identified for many human tumours.	('gene expression', 'MPA', (33, 48))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('gene expression', 'biological_process', 'GO:0010467', ('76', '91'))	('affect', 'Reg', (26, 32))	('tumours', 'Disease', (139, 146))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('changes', 'Var', (14, 21))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('human', 'Species', '9606', (133, 138))
60313	31019223	For SLC25A51 and SNORA76 there was a negative correlation between the gene expression values measured by microarray and RT-qPCR, and for SLC25A51 there was a difference between the 'direction' of NM: M differential expression as assessed by microarray and RT-qPCR, respectively (Table 4).	('difference', 'Reg', (158, 168))	('SNORA76', 'Var', (17, 24))	('SLC25A51', 'Gene', (4, 12))	('gene expression', 'MPA', (70, 85))	('SLC25A51', 'Gene', '100686420', (137, 145))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('SLC25A51', 'Gene', (137, 145))	('SLC25A51', 'Gene', '100686420', (4, 12))	('negative', 'NegReg', (37, 45))
60324	31019223	Molecular genetic and epigenetic 'events' that promote canine OMM metastasis may be both predictive indicators of canine OMM metastasis and the focus for therapeutics intended to prevent metastasis.	('canine', 'Species', '9615', (55, 61))	('canine', 'Species', '9615', (114, 120))	('OMM', 'Chemical', '-', (121, 124))	('promote', 'PosReg', (47, 54))	('canine OMM', 'Disease', (55, 65))	("epigenetic 'events", 'Var', (22, 40))	('OMM', 'Chemical', '-', (62, 65))
60328	31019223	An understanding of the mechanisms by which changes in gene expression mediate OMM metastasis is afforded by functional annotation enrichment analysis.	('OMM', 'Chemical', '-', (79, 82))	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('changes', 'Var', (44, 51))	('OMM', 'Disease', (79, 82))	('mediate', 'Reg', (71, 78))
60329	31019223	Disruption of the balance between phosphorylation and dephosphorylation is associated with carcinogenesis, and protein phosphatases have been recognised as tumour suppressors.	('phosphorylation', 'MPA', (34, 49))	('balance', 'MPA', (18, 25))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('tumour', 'Disease', (156, 162))	('carcinogenesis', 'Disease', (91, 105))	('dephosphorylation', 'biological_process', 'GO:0016311', ('54', '71'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('dephosphorylation', 'MPA', (54, 71))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('associated', 'Reg', (75, 85))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))	('Disruption', 'Var', (0, 10))
60330	31019223	Aberrant expression of protein phosphatase inhibitors has been reported in a wide variety of human cancers.	('protein phosphatase inhibitors', 'Protein', (23, 53))	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('phosphatase', 'molecular_function', 'GO:0016791', ('31', '42'))	('cancers', 'Disease', (99, 106))	('expression', 'MPA', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
60332	31019223	PPP1R37, GPATCH2 (also known as PPP1R30), CASC5 (or PPP1R55) and CSRNP2 (or PPP1R72) encode proteins recognised as inhibitory regulatory subunits of phosphoprotein phosphatase 1 (PPP1), a protein serine-threonine phosphatase that regulates several members of the Transforming growth factor beta signalling pathway, which promotes invasion and metastasis in advanced stages of cancer.	('signalling pathway', 'biological_process', 'GO:0007165', ('295', '313'))	('cancer', 'Disease', (376, 382))	('Transforming growth factor beta', 'molecular_function', 'GO:0005160', ('263', '294'))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('promotes', 'PosReg', (321, 329))	('GPATCH2', 'Gene', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('Transforming growth factor beta signalling pathway', 'Pathway', (263, 313))	('PPP1R37', 'Gene', '484452', (0, 7))	('CSRNP2', 'Gene', '486541', (65, 71))	('regulates', 'Reg', (230, 239))	('PPP1R37', 'Gene', (0, 7))	('phosphatase', 'molecular_function', 'GO:0016791', ('213', '224'))	('phosphatase', 'molecular_function', 'GO:0016791', ('164', '175'))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('PPP1R55', 'Var', (52, 59))	('CSRNP2', 'Gene', (65, 71))	('invasion', 'CPA', (330, 338))	('CASC5', 'Gene', (42, 47))	('GPATCH2', 'Gene', '488594', (9, 16))
60333	31019223	Inhibition of PPP1 by the regulatory subunit PPP1R1A in Ewing sarcoma has been shown to promote tumour growth and metastasis.	('PPP1', 'Gene', (14, 18))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (56, 69))	('PPP1R1A', 'Gene', (45, 52))	('promote', 'PosReg', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour growth', 'Disease', (96, 109))	('Ewing sarcoma', 'Disease', (56, 69))	('Inhibition', 'Var', (0, 10))	('tumour growth', 'Disease', 'MESH:D006130', (96, 109))	('PPP1R1A', 'Gene', '100855706', (45, 52))
60350	31019223	Deregulation of the expression of genes involved in cholesterol homeostasis pathways has been associated with cancer development and progression.	('cancer', 'Disease', (110, 116))	('expression', 'MPA', (20, 30))	('Deregulation', 'Var', (0, 12))	('progression', 'CPA', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (94, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cholesterol homeostasis', 'biological_process', 'GO:0042632', ('52', '75'))
60371	31019223	Deregulated APOBEC3A expression in cancer is believed to induce double strand breaks in genomic DNA activating DNA damage response pathways.	('double', 'MPA', (64, 70))	('DNA damage response pathways', 'Pathway', (111, 139))	('Deregulated', 'Var', (0, 11))	('APOBEC3A', 'Gene', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('APOBEC', 'cellular_component', 'GO:0030895', ('12', '18'))	('induce', 'Reg', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('DNA damage response', 'biological_process', 'GO:0006974', ('111', '130'))	('cancer', 'Disease', (35, 41))
60372	31019223	The repair of such breaks triggers the formation of single stranded DNAs which are substrates for APOBEC3A-mediated hypermutation, such that 5'-(C/T)TTA APOBEC3A mutation signatures occur in clusters (on one DNA strand) in multiple human cancers.	('APOBEC', 'cellular_component', 'GO:0030895', ('98', '104'))	('cancers', 'Disease', (238, 245))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	("5'-(C/T)TTA", 'Var', (141, 152))	('APOBEC3A', 'Gene', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('APOBEC', 'cellular_component', 'GO:0030895', ('153', '159'))	('formation', 'biological_process', 'GO:0009058', ('39', '48'))	('human', 'Species', '9606', (232, 237))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('mutation', 'Var', (162, 170))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))
60373	31019223	APOBEC3A-mediated mutagenesis occurs at different stages in different cancers, and is thought to drive tumour evolution, including promoting metastasis.	('metastasis', 'CPA', (141, 151))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('mutagenesis', 'biological_process', 'GO:0006280', ('18', '29'))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutagenesis', 'Var', (18, 29))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('promoting', 'PosReg', (131, 140))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('APOBEC3A-mediated', 'Gene', (0, 17))	('drive', 'Reg', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('tumour', 'Disease', (103, 109))
60377	31019223	Silencing of RPL29 suppressed the proliferation of human pancreatic tumour cells and enhanced apoptosis suggesting an involvement in cell proliferation.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('involvement', 'Reg', (118, 129))	('cell proliferation', 'biological_process', 'GO:0008283', ('133', '151'))	('suppressed', 'NegReg', (19, 29))	('enhanced', 'PosReg', (85, 93))	('RPL29', 'Gene', (13, 18))	('pancreatic tumour', 'Disease', 'MESH:D010190', (57, 74))	('pancreatic tumour', 'Disease', (57, 74))	('human', 'Species', '9606', (51, 56))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))	('Silencing', 'Var', (0, 9))	('apoptosis', 'CPA', (94, 103))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (57, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))
60378	31019223	However, RPL29 silencing had no effect on the viability of human metastatic melanoma cells.	('melanoma', 'Disease', (76, 84))	('human', 'Species', '9606', (59, 64))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('silencing', 'Var', (15, 24))	('RPL29', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
60383	31019223	Small molecule inhibitors of CXCR4 were shown to be effective at disrupting the liver metastasis of uveal melanoma cells in mice, and migration of human cutaneous melanoma cells in vitro.	('uveal melanoma', 'Phenotype', 'HP:0007716', (100, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('CXCR4', 'molecular_function', 'GO:0038147', ('29', '34'))	('human', 'Species', '9606', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('uveal melanoma', 'Disease', (100, 114))	('cutaneous melanoma', 'Disease', (153, 171))	('mice', 'Species', '10090', (124, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (153, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('liver metastasis', 'Disease', 'MESH:D009362', (80, 96))	('migration', 'CPA', (134, 143))	('liver metastasis', 'Disease', (80, 96))	('disrupting', 'NegReg', (65, 75))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('inhibitors', 'Var', (15, 25))
60385	31019223	Intriguingly, it has been postulated that APOBEC3A-mediated hypermutation could generate new tumour-specific antigens thereby enhancing the efficacy of immune stimulation therapies.	('tumour', 'Disease', (93, 99))	('enhancing', 'PosReg', (126, 135))	('hypermutation', 'Var', (60, 73))	('APOBEC3A-mediated', 'Gene', (42, 59))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('immune stimulation therapies', 'CPA', (152, 180))
60396	31019223	Several of the differences in gene expression observed between primary canine OMMs that metastasised and OMMs that did not metastasise in this study have previously been associated with human cutaneous melanoma metastasis.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('cutaneous melanoma metastasis', 'Disease', (192, 221))	('gene expression', 'MPA', (30, 45))	('canine', 'Species', '9615', (71, 77))	('cutaneous melanoma metastasis', 'Disease', 'MESH:D009362', (192, 221))	('OMM', 'Chemical', '-', (105, 108))	('human', 'Species', '9606', (186, 191))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('differences', 'Var', (15, 26))	('OMM', 'Chemical', '-', (78, 81))	('associated', 'Reg', (170, 180))	('gene expression', 'biological_process', 'GO:0010467', ('30', '45'))
60433	18794428	At a median follow-up of 57 months, 10-year rates of DFS and MSS for SN - versus SN + patients were 96+-1.1% versus 54+-9.6% (p<0.0001) and 98+-0.9% versus 83+-7.7% (p<0.0001), respectively.	('DFS', 'Disease', (53, 56))	('MSS', 'Gene', (61, 64))	('SN -', 'Var', (69, 73))	('MSS', 'Gene', '64374', (61, 64))	('patients', 'Species', '9606', (86, 94))
60491	18794428	Patients with micrometastasis in the tumor-positive SN trended towards decreased 10-year MSS when compared to patients with only ITC in the tumor-positive node (77+-12% and 86+-13%, respectively; p=0.64).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MSS', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (37, 42))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('MSS', 'Gene', '64374', (89, 92))	('decreased', 'NegReg', (71, 80))	('micrometastasis', 'Var', (14, 29))	('tumor', 'Disease', (140, 145))
60553	33003444	To this aim, 306 formalin-fixed and paraffin-embedded (FFPE) tissues from primary CM diagnosed in different geographical areas were submitted to B-RAF proto-oncogene serine/threonine kinase (BRAF) and N-RAS proto-oncogene GTPase (NRAS) mutational status detection and mRNA and miRNA profiling by qPCR.	('NRAS', 'Gene', '4893', (230, 234))	('N-RAS proto-oncogene GTPase', 'Gene', (201, 228))	('BRAF', 'Gene', (191, 195))	('CM', 'Phenotype', 'HP:0012056', (82, 84))	('B-RAF proto-oncogene serine/threonine kinase', 'Gene', '673', (145, 189))	('N-RAS proto-oncogene GTPase', 'Gene', '4893', (201, 228))	('B-RAF proto-oncogene serine/threonine kinase', 'Gene', (145, 189))	('paraffin', 'Chemical', 'MESH:D010232', (36, 44))	('formalin', 'Chemical', 'MESH:D005557', (17, 25))	('mutational', 'Var', (236, 246))	('NRAS', 'Gene', (230, 234))	('BRAF', 'Gene', '673', (191, 195))
60555	33003444	Furthermore, four microRNAs, namely miR-150-5p, miR-155-5p, miR-204-5p, and miR-211-5p, were included in the profiling.	('miR-155', 'Gene', '406947', (48, 55))	('miR-211', 'Gene', (76, 83))	('miR-204-5p', 'Chemical', '-', (60, 70))	('miR-211', 'Gene', '406993', (76, 83))	('miR-150-5p', 'Var', (36, 46))	('miR-204-5p', 'Var', (60, 70))	('miR-155', 'Gene', (48, 55))	('miR-150-5p', 'Chemical', '-', (36, 46))
60557	33003444	In detail, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p.	('miR-155', 'Gene', (113, 120))	('miR-211', 'Gene', '406993', (129, 136))	('patients', 'Species', '9606', (57, 65))	('miR-211', 'Gene', (129, 136))	('miR-150-5p', 'Chemical', '-', (101, 111))	('miR-204-5p', 'Chemical', '-', (21, 31))	('miR-155', 'Gene', '406947', (113, 120))	('miR-204-5p', 'Var', (21, 31))	('TYRP1', 'Gene', '7306', (11, 16))	('TYRP1', 'Gene', (11, 16))
60564	33003444	At the genomic level, three subtypes have been identified: the BRAF subtype, the most common one, characterized by V600 amino acid residue mutations and the RAS subtype identified by the presence of RAS hot-spot mutations (N-, K-, H-RAS).	('V600 amino acid residue mutations', 'Var', (115, 148))	('H-RAS', 'Gene', (231, 236))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('H-RAS', 'Gene', '3265', (231, 236))
60565	33003444	The most frequent RAS mutations involve the N-RAS, especially the Q61 amino acid residue.	('RAS', 'Disease', (18, 21))	('Q61', 'Var', (66, 69))	('N-RAS', 'Gene', (44, 49))	('mutations', 'Var', (22, 31))	('N-RAS', 'Gene', '4893', (44, 49))
60567	33003444	The third group was defined by NF1 mutations, which downregulate the RAS function through GTPase activity.	('NF1', 'Gene', '4763', (31, 34))	('activity', 'MPA', (97, 105))	('RAS', 'Protein', (69, 72))	('NF1', 'Gene', (31, 34))	('GTPase activity', 'molecular_function', 'GO:0003924', ('90', '105'))	('downregulate', 'NegReg', (52, 64))	('GTPase', 'Protein', (90, 96))	('mutations', 'Var', (35, 44))
60576	33003444	In detail, miR-150-5p was linked with the tumor-infiltrated lymphocytes (TILSs) and with the proto-oncogene MYB, which plays a role in the regulation of hematopoiesis and tumorigenesis.	('miR-150-5p', 'Var', (11, 21))	('hematopoiesis', 'Disease', 'MESH:C536227', (153, 166))	('tumor', 'Disease', (42, 47))	('MYB', 'Gene', (108, 111))	('MYB', 'Gene', '4602', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('hematopoiesis', 'Disease', (153, 166))	('regulation of hematopoiesis', 'biological_process', 'GO:1903706', ('139', '166'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('miR-150-5p', 'Chemical', '-', (11, 21))
60578	33003444	Consequently, miR-150-5p and miR-155-5p are physiologically involved in immunological processes.	('miR-155', 'Gene', (29, 36))	('miR-150-5p', 'Chemical', '-', (14, 24))	('miR-150-5p', 'Var', (14, 24))	('miR-155', 'Gene', '406947', (29, 36))	('involved', 'Reg', (60, 68))
60579	33003444	The other two microRNAs, miR-204-5p and miR-211-5p, belong to the same family of miRNA (miR204/211 family) and act as tumor suppressors.	('miR204', 'Gene', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('miR204', 'Gene', '406987', (88, 94))	('miR-211', 'Gene', '406993', (40, 47))	('miR-211', 'Gene', (40, 47))	('tumor', 'Disease', (118, 123))	('miR-204-5p', 'Chemical', '-', (25, 35))	('miR-204-5p', 'Var', (25, 35))
60594	33003444	The resulting 288 of the 306 specimens were analyzed for BRAF and NRAS mutations: 96 (33.3%) patients were BRAF mutated (V600E or V600K), while 62 (21.5%) patients had mutations in the NRAS gene (Q61R, Q61K, Q61L, or Q61H).	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('Q61K', 'Mutation', 'rs121913254', (202, 206))	('patients', 'Species', '9606', (155, 163))	('NRAS', 'Gene', (185, 189))	('patients', 'Species', '9606', (93, 101))	('men', 'Species', '9606', (34, 37))	('NRAS', 'Gene', (66, 70))	('Q61L', 'Mutation', 'rs11554290', (208, 212))	('V600E', 'Mutation', 'rs113488022', (121, 126))	('V600K', 'Mutation', 'rs121913227', (130, 135))	('Q61H', 'Var', (217, 221))	('Q61L', 'Var', (208, 212))	('Q61R', 'Var', (196, 200))	('Q61R', 'Mutation', 'rs11554290', (196, 200))	('BRAF', 'Gene', '673', (107, 111))	('NRAS', 'Gene', '4893', (185, 189))	('BRAF', 'Gene', (107, 111))	('V600E', 'Var', (121, 126))	('NRAS', 'Gene', '4893', (66, 70))	('Q61K', 'Var', (202, 206))	('V600K', 'Var', (130, 135))	('Q61H', 'Mutation', 'rs121913255', (217, 221))
60595	33003444	Associations of the mutational status with patients' CM features are listed in Table 3.	('patients', 'Species', '9606', (43, 51))	('mutational', 'Var', (20, 30))	('Associations', 'Interaction', (0, 12))	('CM', 'Phenotype', 'HP:0012056', (53, 55))
60596	33003444	BRAF mutations were more frequent in men (p = 0.04), in CM located on the trunk (p = 0.02) and in younger patients (p = 0.0001).	('mutations', 'Var', (5, 14))	('CM', 'Phenotype', 'HP:0012056', (56, 58))	('BRAF', 'Gene', '673', (0, 4))	('men', 'Species', '9606', (37, 40))	('patients', 'Species', '9606', (106, 114))	('BRAF', 'Gene', (0, 4))	('trunk', 'cellular_component', 'GO:0043198', ('74', '79'))
60603	33003444	Anatomical site (p = 0.011) and lymph node involvement (p = 0.049) had a statistically significant influence on the detected BRAF and NRAS mutation rate (overall regression p = 0.04- post estimation by Pearson chi2 goodness-of-fit test p = 0.3).	('mutation', 'Var', (139, 147))	('influence', 'Reg', (99, 108))	('men', 'Species', '9606', (50, 53))	('NRAS', 'Gene', '4893', (134, 138))	('BRAF', 'Gene', '673', (125, 129))	('NRAS', 'Gene', (134, 138))	('BRAF', 'Gene', (125, 129))
60606	33003444	For NRAS mutations, the regression results were not statistically significant (p =0.5).	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('NRAS', 'Gene', '4893', (4, 8))
60612	33003444	Higher expression levels of miR-150-5p and miR-155-5p were recorded in patients living in TS in comparison to those living in BZ and I/IL (p < 0.0001 for both, Figure 1b,c).	('miR-150-5p', 'Var', (28, 38))	('expression levels', 'MPA', (7, 24))	('miR-155', 'Gene', (43, 50))	('patients', 'Species', '9606', (71, 79))	('BZ', 'Chemical', '-', (126, 128))	('Higher', 'PosReg', (0, 6))	('miR-155', 'Gene', '406947', (43, 50))	('miR-150-5p', 'Chemical', '-', (28, 38))
60613	33003444	On the other hand, miR-204-5p (Figure 1d) was less expressed in patients living in TS than in those residing in BZ (p < 0.0001) and I/IL (p = 0.002).	('less', 'NegReg', (46, 50))	('patients', 'Species', '9606', (64, 72))	('miR-204-5p', 'Var', (19, 29))	('miR-204-5p', 'Chemical', '-', (19, 29))	('BZ', 'Chemical', '-', (112, 114))
60615	33003444	As shown in Figure 2a,b,d, the expression of miR-150-5p (p < 0.0001, r = -0.3), miR-155-5p (p = 0.001, r = -0.2), and miR-211-5p (p = 0.006, r = -0.2) decreased in patients living at high altitude, while miR-204-5p expression was positively correlated with altitude of residence (p < 0.0001, r = 0.3) (Figure.	('miR-204-5p', 'Chemical', '-', (204, 214))	('miR-204-5p', 'Var', (204, 214))	('miR-150-5p', 'Chemical', '-', (45, 55))	('miR-211', 'Gene', '406993', (118, 125))	('miR-211', 'Gene', (118, 125))	('decreased', 'NegReg', (151, 160))	('miR-150-5p', 'Gene', (45, 55))	('miR-155', 'Gene', '406947', (80, 87))	('expression', 'MPA', (31, 41))	('patients', 'Species', '9606', (164, 172))	('miR-155', 'Gene', (80, 87))
60624	33003444	Furthermore, miR-150-5p showed a significantly higher expression in CM in the upper limbs compared to those in the lower limbs (p = 0.02) (Figure S3).	('expression', 'MPA', (54, 64))	('CM', 'Phenotype', 'HP:0012056', (68, 70))	('higher', 'PosReg', (47, 53))	('lower limbs', 'Phenotype', 'HP:0006385', (115, 126))	('miR-150-5p', 'Var', (13, 23))	('miR-150-5p', 'Chemical', '-', (13, 23))
60625	33003444	In our cohort, CD2, PDL1, miR-150-5p, miR-155-5p, and miR-204-5p expression was significantly linked to CM stage, namely their expression decreases as stage progresses (p < 0.0001, p = 0.002, p = 0.0001, p = 0.01, and p = 0.02, respectively; Figure 3a-e).	('miR-155', 'Gene', '406947', (38, 45))	('decreases', 'NegReg', (138, 147))	('PDL1', 'Gene', '29126', (20, 24))	('expression', 'MPA', (127, 137))	('linked', 'Reg', (94, 100))	('CM stage', 'Disease', (104, 112))	('miR-204-5p', 'Chemical', '-', (54, 64))	('miR-155', 'Gene', (38, 45))	('CM', 'Phenotype', 'HP:0012056', (104, 106))	('PDL1', 'Gene', (20, 24))	('CD2', 'Gene', (15, 18))	('miR-204-5p', 'Var', (54, 64))	('miR-150-5p', 'Chemical', '-', (26, 36))	('miR-150-5p', 'Var', (26, 36))	('CD2', 'Gene', '914', (15, 18))
60628	33003444	Similar results were obtained for miR-150-5p and miR-155-5p (Figure S4) (p = 0.0004 and p = 0.001, respectively).	('miR-155', 'Gene', (49, 56))	('miR-150-5p', 'Chemical', '-', (34, 44))	('miR-150-5p', 'Var', (34, 44))	('miR-155', 'Gene', '406947', (49, 56))
60630	33003444	Similar results were found for miR-150-5p and miR-204-5p, which were inversely correlated with CM thickness (p = 0.0001 and p = 0.0004, respectively; Figure 4c,d).	('miR-150-5p', 'Var', (31, 41))	('CM', 'Phenotype', 'HP:0012056', (95, 97))	('miR-150-5p', 'Chemical', '-', (31, 41))	('miR-204-5p', 'Chemical', '-', (46, 56))	('miR-204-5p', 'Var', (46, 56))	('CM thickness', 'Disease', (95, 107))
60631	33003444	Regarding ulceration, expression levels of TRPM1, MITF, and miR-204-5p in our cohort were higher in non-ulcerated than ulcerated CMs (p = 0.006, p = 0.03, and p = 0.001, respectively).	('MITF', 'Gene', '4286', (50, 54))	('MITF', 'Gene', (50, 54))	('CM', 'Phenotype', 'HP:0012056', (129, 131))	('TRPM1', 'Gene', (43, 48))	('miR-204-5p', 'Chemical', '-', (60, 70))	('miR-204-5p', 'Var', (60, 70))	('expression levels', 'MPA', (22, 39))	('non-ulcerated', 'Disease', (100, 113))	('higher', 'PosReg', (90, 96))	('TRPM1', 'Gene', '4308', (43, 48))
60633	33003444	Considering both BRAF and NRAS mutations, the expression of miR-150-5p was higher in BRAF-mutated CM than in NRAS-mutated CM (p = 0.0001) (Figure S5).	('CM', 'Phenotype', 'HP:0012056', (122, 124))	('CM', 'Phenotype', 'HP:0012056', (98, 100))	('NRAS', 'Gene', (109, 113))	('higher', 'PosReg', (75, 81))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('NRAS', 'Gene', '4893', (109, 113))	('NRAS', 'Gene', (26, 30))	('BRAF', 'Gene', (17, 21))	('miR-150-5p', 'Chemical', '-', (60, 70))	('miR-150-5p', 'Var', (60, 70))	('NRAS', 'Gene', '4893', (26, 30))	('expression', 'MPA', (46, 56))
60641	33003444	A similar result was found for miR-150-5p, miR-155-5p, and miR-211-5p, with higher expression levels associated with longer survival (in univariate analysis) as shown in Figure 6d,e,f (p = 0.0001, p = 0.004, and p = 0.02, respectively).	('miR-150-5p', 'Var', (31, 41))	('miR-211', 'Gene', '406993', (59, 66))	('miR-150-5p', 'Chemical', '-', (31, 41))	('expression levels', 'MPA', (83, 100))	('miR-155', 'Gene', (43, 50))	('longer', 'PosReg', (117, 123))	('miR-155', 'Gene', '406947', (43, 50))	('higher', 'PosReg', (76, 82))	('miR-211', 'Gene', (59, 66))
60647	33003444	The expression levels of miR-150-5p, miR-155-5p, and miR-211-5p were significantly higher in patients living in Trieste (TS), which is a city located by the sea, compared to the geographic areas of South Tyrol (BZ) and Innsbruck/IL (I/IL), which are characterized by higher altitudes of residence (in our dataset, the mean altitude of the South Tyrol region is 884 m a.s.l.	('miR-150-5p', 'Var', (25, 35))	('expression levels', 'MPA', (4, 21))	('sea', 'Gene', (157, 160))	('patients', 'Species', '9606', (93, 101))	('miR-155', 'Gene', (37, 44))	('BZ', 'Chemical', '-', (211, 213))	('sea', 'Gene', '6395', (157, 160))	('miR-211', 'Gene', '406993', (53, 60))	('miR-211', 'Gene', (53, 60))	('miR-155', 'Gene', '406947', (37, 44))	('higher', 'PosReg', (83, 89))	('miR-150-5p', 'Chemical', '-', (25, 35))
60648	33003444	The opposite trend was found for miR-204-5p and TYRP1, which were significantly highly expressed in CM of patients living in South Tyrol.	('miR-204-5p', 'Chemical', '-', (33, 43))	('miR-204-5p', 'Var', (33, 43))	('CM', 'Phenotype', 'HP:0012056', (100, 102))	('patients', 'Species', '9606', (106, 114))	('TYRP1', 'Gene', (48, 53))	('TYRP1', 'Gene', '7306', (48, 53))
60649	33003444	Actually, miR-150-5p, miR-155-5p, and miR-211-5p expression decreases as altitude increases; conversely, miR-204-5p and TYRP1 were significantly higher in patients living at altitudes of or above 750 m a.s.l.	('miR-211', 'Gene', (38, 45))	('miR-211', 'Gene', '406993', (38, 45))	('miR-204-5p', 'Chemical', '-', (105, 115))	('miR-150-5p', 'Chemical', '-', (10, 20))	('miR-204-5p', 'Var', (105, 115))	('patients', 'Species', '9606', (155, 163))	('miR-155', 'Gene', '406947', (22, 29))	('TYRP1', 'Gene', (120, 125))	('TYRP1', 'Gene', '7306', (120, 125))	('higher', 'PosReg', (145, 151))	('miR-155', 'Gene', (22, 29))
60656	33003444	Furthermore, in vitro studies have shown that miR-150-5p is downregulated by hypoxia in pancreatic cell lines.	('hypoxia', 'Disease', (77, 84))	('miR-150-5p', 'Chemical', '-', (46, 56))	('miR-150-5p', 'Var', (46, 56))	('downregulated', 'NegReg', (60, 73))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
60663	33003444	In line with this finding, three suppressor miRNAs analyzed in this study (namely miR-150-5p, miR-155-5p, and miR-211-5p) were more expressed in residents at low altitude level.	('miR-211', 'Gene', '406993', (110, 117))	('miR-211', 'Gene', (110, 117))	('miR-155', 'Gene', '406947', (94, 101))	('miR-155', 'Gene', (94, 101))	('miR-150-5p', 'Var', (82, 92))	('miR-150-5p', 'Chemical', '-', (82, 92))
60670	33003444	In particular, miR-150-5p and miR-155-5p were found to be inversely associated with Breslow's depth, stage, and lymph node involvement.	('miR-155', 'Gene', (30, 37))	("Breslow's depth", 'Disease', (84, 99))	('miR-150-5p', 'Var', (15, 25))	('stage', 'CPA', (101, 106))	('miR-150-5p', 'Chemical', '-', (15, 25))	('lymph node involvement', 'CPA', (112, 134))	('miR-155', 'Gene', '406947', (30, 37))	('men', 'Species', '9606', (130, 133))
60672	33003444	In line with us, Tembe and colleagues associated miR-150-5p with longer survivors and inversely associated to melanoma stage (mainly III and IV).	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('miR-150-5p', 'Var', (49, 59))	('miR-150-5p', 'Chemical', '-', (49, 59))	('associated', 'Reg', (96, 106))
60673	33003444	Our findings seem to be confirmed by the more recent overexpression of miR-150-5p, which was found to inhibit the proliferation, migration, and invasion of melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('migration', 'CPA', (129, 138))	('miR-150-5p', 'Var', (71, 81))	('proliferation', 'CPA', (114, 127))	('inhibit', 'NegReg', (102, 109))	('miR-150-5p', 'Chemical', '-', (71, 81))
60678	33003444	The other two miRNAs studied here, namely miR-204-5p and miR-211-5p, belong to the same family (microRNA mir204/211 family) and they are encoded by the TRPM3 and TRPM1 gene, respectively.	('mir204', 'Gene', '406987', (105, 111))	('TRPM3', 'Gene', '80036', (152, 157))	('TRPM1', 'Gene', '4308', (162, 167))	('mir204', 'Gene', (105, 111))	('TRPM3', 'Gene', (152, 157))	('miR-211', 'Gene', '406993', (57, 64))	('miR-204-5p', 'Var', (42, 52))	('miR-204-5p', 'Chemical', '-', (42, 52))	('miR-211', 'Gene', (57, 64))	('TRPM1', 'Gene', (162, 167))
60679	33003444	In our cohort, miR-204-5p was inversely associated with melanoma ulceration, stage, and depth.	('miR-204-5p', 'Chemical', '-', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('stage', 'Disease', (77, 82))	('miR-204-5p', 'Var', (15, 25))	('melanoma ulceration', 'Disease', (56, 75))	('melanoma ulceration', 'Disease', 'MESH:D014456', (56, 75))	('inversely', 'NegReg', (30, 39))	('associated', 'Reg', (40, 50))
60680	33003444	Similar results were highlighted by Galasso and co-workers on the association of miR-204-5p with important clinical parameters, such as Breslow's depth.	('miR-204-5p', 'Var', (81, 91))	('association', 'Interaction', (66, 77))	("Breslow's depth", 'Disease', (136, 151))	('miR-204-5p', 'Chemical', '-', (81, 91))
60686	33003444	In our cohort, similarly to miR-211-5p, MITF expression was also associated to longer melanoma-specific survival, findings that are supported by Mazar and colleagues.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('miR-211', 'Gene', '406993', (28, 35))	('MITF', 'Gene', (40, 44))	('miR-211', 'Gene', (28, 35))	('melanoma', 'Disease', (86, 94))	('MITF', 'Gene', '4286', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('longer', 'PosReg', (79, 85))	('expression', 'Var', (45, 55))
60694	33003444	Contrary to previous studies, in our cohort, BRAFV600 mutations were more frequently detected in men.	('men', 'Species', '9606', (97, 100))	('mutations', 'Var', (54, 63))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (45, 49))	('detected', 'Reg', (85, 93))
60695	33003444	This result is likely due to our selection criteria as CMs of male patients were analyzed from the trunk, which has already been reported as a preferential anatomical site associated with BRAF mutation.	('trunk', 'cellular_component', 'GO:0043198', ('99', '104'))	('patients', 'Species', '9606', (67, 75))	('BRAF', 'Gene', '673', (188, 192))	('BRAF', 'Gene', (188, 192))	('CM', 'Phenotype', 'HP:0012056', (55, 57))	('mutation', 'Var', (193, 201))
60698	33003444	NRAS mutations were frequently recorded in CMs located on the lower limbs (7.7%, n = 22 of 287) in our dataset, in agreement with others.	('CM', 'Phenotype', 'HP:0012056', (43, 45))	('mutations', 'Var', (5, 14))	('CMs', 'Disease', (43, 46))	('NRAS', 'Gene', (0, 4))	('recorded', 'Reg', (31, 39))	('NRAS', 'Gene', '4893', (0, 4))	('lower limbs', 'Phenotype', 'HP:0006385', (62, 73))	('men', 'Species', '9606', (120, 123))
60716	33003444	Chromogenic detection was performed using Diaminobenzidine chromogen (DAB) for BRAFV600E, while for NRASQ61R using the UltraView Universal Alkaline Phosphatase Red Detection Kit (Ventana Medical System, Tucson, AZ 85755, USA).	('BRAFV600E', 'Var', (79, 88))	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('Kit', 'Gene', '3815', (174, 177))	('Diaminobenzidine', 'Chemical', '-', (42, 58))	('DAB', 'Chemical', '-', (70, 73))	('Phosphatase', 'molecular_function', 'GO:0016791', ('148', '159'))	('Kit', 'Gene', (174, 177))
60720	33003444	Tissue sections with equivocal staining were checked through digital droplet PCR (ddPCR) to confirm the presence or the absence of BRAF/NRAS mutations.	('BRAF', 'Gene', (131, 135))	('mutations', 'Var', (141, 150))	('absence', 'NegReg', (120, 127))	('NRAS', 'Gene', (136, 140))	('NRAS', 'Gene', '4893', (136, 140))	('BRAF', 'Gene', '673', (131, 135))
60721	33003444	BRAF and NRAS mutations were detected by digital droplet PCR (Biorad, Hercules, CA 94547, USA; Cat.	('Cat', 'molecular_function', 'GO:0004096', ('95', '98'))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
60729	33003444	D7440), together with 210 nM of TaqMan probe (IDT, Coralville, IA 52241, USA), 320 nM of reverse and forward primers (IDT, Coralville, IA 52241, USA), Rox100, and made up to a final volume of 21 muL with sterile water.	('muL', 'Gene', (195, 198))	('muL', 'Gene', '4591', (195, 198))	('D7440', 'Var', (0, 5))	('water', 'Chemical', 'MESH:D014867', (212, 217))
60740	33003444	A statistical model to predict the probability of BRAF mutations for individual patients was developed, including age at diagnosis, sex, geographical area of residence, altitude of residence, Breslow's depth, the presence of ulceration, and the lymph node involvement at diagnosis as independent variables.	('BRAF', 'Gene', (50, 54))	('patients', 'Species', '9606', (80, 88))	('mutations', 'Var', (55, 64))	('men', 'Species', '9606', (263, 266))	('BRAF', 'Gene', '673', (50, 54))
60743	33003444	Namely, TYRP1 and miR-204-5p were highly expressed in patients living at higher altitudes, unlike miR-150-5p, miR-155-5p, and miR-211-5p.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('miR-155', 'Gene', '406947', (110, 117))	('TYRP1', 'Gene', '7306', (8, 13))	('patients', 'Species', '9606', (54, 62))	('TYRP1', 'Gene', (8, 13))	('miR-150-5p', 'Chemical', '-', (98, 108))	('miR-155', 'Gene', (110, 117))	('miR-211', 'Gene', '406993', (126, 133))	('miR-211', 'Gene', (126, 133))
60769	31650817	Magnetic resonance imaging (MRI) showed hyperintensity of the medial rectus on T1-weighted imaging and hypointensity on T2-weighted imaging (Figure 2) compatible with melanoma metastases.	('melanoma metastases', 'Disease', (167, 186))	('hyperintensity', 'MPA', (40, 54))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma metastases', 'Disease', 'MESH:D009362', (167, 186))	('hypointensity', 'Var', (103, 116))
60773	31650817	Next-generation sequencing identified a somatic mutation in the GNA11 gene.	('GNA11', 'Gene', '2767', (64, 69))	('GNA11', 'Gene', (64, 69))	('mutation', 'Var', (48, 56))
60774	31650817	A sensitizing BRAF mutation was not found in this tumor.	('mutation', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('BRAF', 'Gene', '673', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('BRAF', 'Gene', (14, 18))	('tumor', 'Disease', (50, 55))
60941	24163809	More numerous CD138+ cells were present in areas of regression in tumors with high pT, especially in ulcerated ones, but the data lacks statistical significance (Figures 8(a) and 8(b)).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pT', 'Chemical', 'MESH:D010984', (83, 85))	('CD138', 'Gene', (14, 19))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('high pT', 'Var', (78, 85))	('CD138', 'Gene', '6382', (14, 19))
61007	22558444	It seems reasonable that the increased risk associated with European ethnicity should be attributed to lighter skin pigmentation.	('European ethnicity', 'Var', (60, 78))	('skin pigmentation', 'Disease', (111, 128))	('skin pigmentation', 'Phenotype', 'HP:0000953', (111, 128))	('skin pigmentation', 'Disease', 'MESH:D010859', (111, 128))	('pigmentation', 'biological_process', 'GO:0043473', ('116', '128'))
61026	22558444	On the basis of the American Joint Committee on Cancer T-category criteria and Breslow thickness, the case group tumors were categorized, by diameter, as follows: <=1.0 mm (T1); 1.01-2.00 mm (T2); 2.01-4.00 mm (T3); and >4.0 mm (T4).	('1.01-2.00 mm', 'Var', (178, 190))	('<=1.0 mm', 'Var', (163, 171))	('tumors', 'Disease', (113, 119))	('2.01-4.00 mm', 'Var', (197, 209))	('>4.0 mm', 'Var', (220, 227))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Cancer', 'Disease', 'MESH:D009369', (48, 54))	('Cancer', 'Disease', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
61043	22558444	Risk factors such as eye color (blue, green, or light brown), hair color (blond, red, or light brown), density of childhood freckling, skin phototype, and history of pigmented lesion removal were associated with an overall increase in melanoma risk.	('increase', 'PosReg', (223, 231))	('blond', 'Var', (74, 79))	('pigmented lesion removal', 'Disease', 'MESH:D010859', (166, 190))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Disease', (235, 243))	('blue', 'Var', (32, 36))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('pigmented lesion removal', 'Disease', (166, 190))	('freckling', 'Phenotype', 'HP:0001480', (124, 133))
61069	22558444	Multiple episodes of sunburn can damage the genetic material, causing mutations that accumulate throughout life and promote the process of skin carcinogenesis.	('mutations', 'Var', (70, 79))	('causing', 'Reg', (62, 69))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (139, 158))	('sunburn', 'Disease', (21, 28))	('genetic', 'Protein', (44, 51))	('promote', 'PosReg', (116, 123))	('sunburn', 'Disease', 'MESH:D013471', (21, 28))	('damage', 'Reg', (33, 39))	('skin carcinogenesis', 'Disease', (139, 158))
61070	22558444	Recent studies indicate that increased sensitivity to sun exposure is also associated with polymorphisms and mutations in genes involved in skin pigmentation.	('skin pigmentation', 'Disease', (140, 157))	('skin pigmentation', 'Disease', 'MESH:D010859', (140, 157))	('polymorphisms', 'Var', (91, 104))	('sensitivity to sun', 'Phenotype', 'HP:0000992', (39, 57))	('pigmentation', 'biological_process', 'GO:0043473', ('145', '157'))	('mutations', 'Var', (109, 118))	('associated', 'Reg', (75, 85))	('skin pigmentation', 'Phenotype', 'HP:0000953', (140, 157))
61092	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('signaling', 'biological_process', 'GO:0023052', ('300', '309'))	('signaling pathway', 'biological_process', 'GO:0007165', ('75', '92'))	('IFNgamma', 'Gene', (107, 115))
61151	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('RNA', 'cellular_component', 'GO:0005562', ('12', '15'))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
61157	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Pt16', 'Var', (58, 62))	('Treg', 'Chemical', '-', (12, 16))	('Pt25', 'Var', (49, 53))	('patients', 'Species', '9606', (163, 171))	('Treg', 'Chemical', '-', (120, 124))
61172	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('cell death', 'biological_process', 'GO:0008219', ('193', '203'))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('activating', 'PosReg', (262, 272))	('angiogenesis', 'biological_process', 'GO:0001525', ('248', '260'))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('evading', 'Var', (155, 162))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('death', 'Disease', (198, 203))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('invasion', 'CPA', (273, 281))	('inducing', 'PosReg', (239, 247))	('replicative immortality', 'CPA', (214, 237))	('metabolism', 'biological_process', 'GO:0008152', ('322', '332'))	('sustaining', 'PosReg', (119, 129))	('death', 'Disease', 'MESH:D003643', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('immune destruction', 'CPA', (346, 364))	('enabling', 'PosReg', (205, 213))	('proliferative signaling', 'MPA', (130, 153))
61186	32341527	Identified melanoma genetic risk variants include rare, highly penetrant mutations in genes such as CDKN2A and POT1, as well as more common variants (e.g., lower-penetrance variants in MC1R).	('POT1', 'Gene', (111, 115))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('MC1R', 'Gene', '4157', (185, 189))	('POT1', 'Gene', '25913', (111, 115))	('lower-penetrance', 'NegReg', (156, 172))	('MC1R', 'Gene', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('CDKN2A', 'Gene', (100, 106))	('variants', 'Var', (173, 181))	('variants', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (100, 106))	('melanoma', 'Disease', (11, 19))
61189	32341527	This meta-analysis of cutaneous melanoma susceptibility is more than three times the effective sample size of previous cutaneous melanoma GWAS, providing unprecedented power to identify cutaneous melanoma susceptibility variants and enhanced distinction of independent variants in known cutaneous melanoma susceptibility regions.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('variants', 'Var', (220, 228))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('cutaneous melanoma', 'Disease', (186, 204))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (186, 204))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (186, 204))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('cutaneous melanoma', 'Disease', (22, 40))	('cutaneous melanoma', 'Disease', (287, 305))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (287, 305))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (287, 305))	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (119, 142))	('cutaneous melanoma GWAS', 'Disease', (119, 142))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (22, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
61190	32341527	We report here 68 independent cutaneous melanoma associated variants across 54 loci that confirm the importance of key functional pathways and highlight previously unknown cutaneous melanoma etiologic routes (Tables 1-2).	('cutaneous melanoma', 'Disease', (172, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (172, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (172, 190))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('cutaneous melanoma', 'Disease', (30, 48))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('variants', 'Var', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))
61202	32341527	In addition to the 54 lead variants, 14 independent variants with linkage disequilibrium (LD) r2EUR < 0.05 with lead variants at or near 6 loci (TERT, AGR3, CDKN2A, OCA2, MC1R, and TP53) were identified (Supplementary Table 3).	('OCA2', 'Gene', '4948', (165, 169))	('TP53', 'Gene', (181, 185))	('MC1R', 'Gene', (171, 175))	('AGR3', 'Gene', (151, 155))	('variants', 'Var', (117, 125))	('CDKN2A', 'Gene', (157, 163))	('OCA2', 'Gene', (165, 169))	('CDKN2A', 'Gene', '1029', (157, 163))	('TP53', 'Gene', '7157', (181, 185))	('TERT', 'Gene', (145, 149))	('MC1R', 'Gene', '4157', (171, 175))	('TERT', 'Gene', '7015', (145, 149))	('AGR3', 'Gene', '155465', (151, 155))
61203	32341527	Conditional and joint analysis of summary data identified a further 9 variants at or near SLC45A2, IRF4, AGR3, CCND1, GPRC5A, FTO, and MC1R; however, these additional variants were not carried forward, having either Pmeta > 5 x 10-8 in the single variant analysis or excess heterogeneity (I2 > 31%) and Pmeta_r < 5 x 10-8 (Supplementary Table 4).	('CCND1', 'Gene', (111, 116))	('SLC45A2', 'Gene', (90, 97))	('FTO', 'Gene', '79068', (126, 129))	('CCND1', 'Gene', '595', (111, 116))	('variants', 'Var', (70, 78))	('MC1R', 'Gene', '4157', (135, 139))	('SLC45A2', 'Gene', '51151', (90, 97))	('AGR3', 'Gene', '155465', (105, 109))	('FTO', 'Gene', (126, 129))	('GPRC5A', 'Gene', '9052', (118, 124))	('GPRC5A', 'Gene', (118, 124))	('AGR3', 'Gene', (105, 109))	('MC1R', 'Gene', (135, 139))	('IRF4', 'Gene', '3662', (99, 103))	('IRF4', 'Gene', (99, 103))
61209	32341527	The total cutaneous melanoma meta-analysis also confirms the previously reported IRF4 and MITF associations, as well as 6 regions previously identified only by combining nevus count and cutaneous melanoma GWAS data (Table 2; Supplementary Note).	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (186, 209))	('cutaneous melanoma GWAS', 'Disease', (186, 209))	('MITF', 'Gene', '4286', (90, 94))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (186, 204))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (186, 204))	('IRF4', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('associations', 'Var', (95, 107))	('IRF4', 'Gene', '3662', (81, 85))	('cutaneous melanoma', 'Disease', (10, 28))	('MITF', 'Gene', (90, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (10, 28))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (10, 28))
61213	32341527	We performed separate GWAS by sex, age at cutaneous melanoma diagnosis (<=40, 40-60, >=60 years) and major cutaneous melanoma subtypes (superficial spreading (SS), lentigo maligna (LM), nodular melanoma (NM), and acral lentiginous (AL)) to identify variants associated with select subgroups (Supplementary Table 8).	('nodular melanoma', 'Disease', 'MESH:D008545', (186, 202))	('lentigo maligna', 'Disease', (164, 179))	('variants', 'Var', (249, 257))	('lentigo maligna', 'Disease', 'MESH:D018327', (164, 179))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('superficial spreading', 'Disease', (136, 157))	('nodular melanoma', 'Disease', (186, 202))	('cutaneous melanoma', 'Disease', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('acral lentiginous', 'Disease', (213, 230))	('nodular melanoma', 'Phenotype', 'HP:0012058', (186, 202))	('cutaneous melanoma', 'Disease', (42, 60))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('acral lentiginous', 'Disease', 'MESH:D007911', (213, 230))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('lentigo maligna', 'Phenotype', 'HP:0012059', (164, 179))
61214	32341527	We also performed polygenic risk score (PRS) analyses based on the lead independent genome-wide significant SNPs for nevus count (10 variants; Online Methods) and hair color (276 variants; Online Methods) to explore further whether either trait's association with cutaneous melanoma differs across phenotypic subtypes (significance threshold = 0.05/28; Online Methods).	('cutaneous melanoma', 'Disease', (264, 282))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (264, 282))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (264, 282))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('nevus', 'Phenotype', 'HP:0003764', (117, 122))	('variants', 'Var', (133, 141))
61219	32341527	To investigate possible biological pathways underlying cutaneous melanoma signals, variants independently associated with cutaneous melanoma in the total meta-analysis were evaluated in GWAS of telomere length, tanning response, pigmentation and nevus count (Online Methods, Table 1 and 2, Supplementary Tables 5,7-8).	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('pigmentation', 'biological_process', 'GO:0043473', ('229', '241'))	('variants', 'Var', (83, 91))	('associated', 'Reg', (106, 116))	('cutaneous melanoma', 'Disease', (55, 73))	('nevus', 'Phenotype', 'HP:0003764', (246, 251))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (55, 73))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (55, 73))	('telomere', 'cellular_component', 'GO:0000781', ('194', '202'))	('pigmentation', 'Disease', (229, 241))	('pigmentation', 'Disease', 'MESH:D010859', (229, 241))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('telomere', 'cellular_component', 'GO:0005696', ('194', '202'))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))
61221	32341527	Several new loci, including rs12473635 near DTNB and rs78378222 near TP53, are associated with nevus count, reinforcing the role of nevi in cutaneous melanoma susceptibility.	('associated', 'Reg', (79, 89))	('cutaneous melanoma', 'Disease', (140, 158))	('DTNB', 'Gene', '1838', (44, 48))	('TP53', 'Gene', '7157', (69, 73))	('rs12473635', 'Var', (28, 38))	('TP53', 'Gene', (69, 73))	('DTNB', 'Gene', (44, 48))	('nevi', 'Phenotype', 'HP:0003764', (132, 136))	('rs78378222', 'Mutation', 'rs78378222', (53, 63))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('nevus', 'Phenotype', 'HP:0003764', (95, 100))	('rs12473635', 'Mutation', 'rs12473635', (28, 38))	('nevus count', 'Disease', (95, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (140, 158))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (140, 158))	('rs78378222', 'Var', (53, 63))
61222	32341527	Furthermore, four novel loci have previously been associated with telomere length (rs3950296/TERC, rs4731207/POT1, rs2967383/MPHOSPH6, and rs143190905/RTEL1) (Table 2, Supplementary Table 5) providing additional support for the role of telomere maintenance in cutaneous melanoma susceptibility following earlier findings that genetic determinants of telomere length are generally associated with melanoma risk.	('rs3950296', 'Var', (83, 92))	('POT1', 'Gene', '25913', (109, 113))	('MPHOSPH6', 'Gene', '10200', (125, 133))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('melanoma', 'Disease', (270, 278))	('rs143190905', 'DBSNP_MENTION', 'None', (139, 150))	('RTEL1', 'Gene', (151, 156))	('associated', 'Reg', (380, 390))	('telomere', 'Disease', (66, 74))	('TERC', 'Gene', '7012', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (396, 404))	('melanoma', 'Disease', (396, 404))	('rs2967383', 'DBSNP_MENTION', 'None', (115, 124))	('POT1', 'Gene', (109, 113))	('rs4731207', 'Var', (99, 108))	('MPHOSPH6', 'Gene', (125, 133))	('telomere', 'cellular_component', 'GO:0000781', ('236', '244'))	('cutaneous melanoma', 'Disease', (260, 278))	('TERC', 'Gene', (93, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (260, 278))	('rs3950296', 'DBSNP_MENTION', 'None', (83, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (260, 278))	('telomere', 'cellular_component', 'GO:0005696', ('236', '244'))	('rs2967383', 'Var', (115, 124))	('telomere', 'cellular_component', 'GO:0000781', ('66', '74'))	('melanoma', 'Disease', 'MESH:D008545', (270, 278))	('RTEL1', 'Gene', '51750', (151, 156))	('telomere', 'cellular_component', 'GO:0000781', ('350', '358'))	('telomere', 'cellular_component', 'GO:0005696', ('66', '74'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('236', '256'))	('telomere', 'cellular_component', 'GO:0005696', ('350', '358'))	('melanoma', 'Disease', 'MESH:D008545', (396, 404))	('rs4731207', 'DBSNP_MENTION', 'None', (99, 108))	('rs143190905', 'Var', (139, 150))	('associated', 'Reg', (50, 60))
61231	32341527	This analysis built on a previous melanocyte TWAS that analyzed data from a prior cutaneous melanoma GWAS meta-analysis and identified significant novel associations between cutaneous melanoma and imputed gene expression of five genes at four loci.	('imputed gene expression', 'Var', (197, 220))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (82, 105))	('gene expression', 'biological_process', 'GO:0010467', ('205', '220'))	('cutaneous melanoma', 'Disease', (174, 192))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma GWAS', 'Disease', (82, 105))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))
61233	32341527	To empirically identify the target tissues for cutaneous melanoma risk variants, we used partitioned LD score regression to determine the proportion of total cutaneous melanoma GWAS meta-analysis heritability that could be captured by genes expressed in melanocytes and in 50 GTEx tissue types.	('variants', 'Var', (71, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (158, 176))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (158, 181))	('cutaneous melanoma', 'Disease', (47, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('cutaneous melanoma GWAS', 'Disease', (158, 181))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (47, 65))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (158, 176))
61241	32341527	We identified 68 independent cutaneous melanoma -associated variants across 54 loci.	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('variants', 'Var', (60, 68))
61247	32341527	Interestingly, we found little evidence for difference in cutaneous melanoma locus effect estimates by contributing GWAS (Supplementary Figure 2) or differences in effect size and allele frequency by geographic regions (Supplementary Figure 3), beyond minor variation in pigmentation genes (e.g., rs6059655 near ASIP and rs1805007 near MC1R).	('pigmentation', 'Disease', 'MESH:D010859', (271, 283))	('MC1R', 'Gene', (336, 340))	('pigmentation', 'Disease', (271, 283))	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('rs6059655', 'Var', (297, 306))	('rs1805007', 'Var', (321, 330))	('ASIP', 'Gene', '434', (312, 316))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('pigmentation', 'biological_process', 'GO:0043473', ('271', '283'))	('rs6059655', 'Mutation', 'rs6059655', (297, 306))	('ASIP', 'Gene', (312, 316))	('rs1805007', 'Mutation', 'rs1805007', (321, 330))	('MC1R', 'Gene', '4157', (336, 340))
61256	32341527	Interestingly, following these expanded pleiotropic analyses, many loci were associated with neither nevus count or hair color, indicating that many risk variants act outside of these classic cutaneous melanoma risk phenotypes (Tables 1-2).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (192, 210))	('nevus', 'Phenotype', 'HP:0003764', (101, 106))	('variants', 'Var', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('cutaneous melanoma', 'Disease', (192, 210))
61258	32341527	It is important to note that confirmation of the genes we have identified are causal for cutaneous melanoma, and the biological understanding of how variants at these loci influence cutaneous melanoma, remains to be functionally established.	('cutaneous melanoma', 'Disease', (182, 200))	('causal', 'Reg', (78, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('variants', 'Var', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('influence', 'Reg', (172, 181))	('cutaneous melanoma', 'Disease', (89, 107))
61262	32341527	For example, we identified an association between multiple independent variants at the TP53 locus, rs78378222 and rs1641548, and cutaneous melanoma further reinforcing the potential importance of DNA repair and genome integrity for cutaneous melanoma susceptibility (see Supplementary Note).	('rs78378222', 'Var', (99, 109))	('rs78378222', 'Mutation', 'rs78378222', (99, 109))	('TP53', 'Gene', '7157', (87, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 147))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('DNA repair', 'biological_process', 'GO:0006281', ('196', '206'))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('TP53', 'Gene', (87, 91))	('DNA', 'cellular_component', 'GO:0005574', ('196', '199'))	('cutaneous melanoma', 'Disease', (232, 250))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (232, 250))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 250))	('cutaneous melanoma', 'Disease', (129, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (129, 147))	('rs1641548', 'Var', (114, 123))	('rs1641548', 'Mutation', 'rs1641548', (114, 123))
61263	32341527	Rare germline mutations in TP53 lead to Li-Fraumeni syndrome which is associated with early onset of cancer, including cutaneous melanoma.	('lead to', 'Reg', (32, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (119, 137))	('TP53', 'Gene', (27, 31))	('TP53', 'Gene', '7157', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('germline mutations', 'Var', (5, 23))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (40, 60))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Li-Fraumeni syndrome', 'Disease', (40, 60))	('cutaneous melanoma', 'Disease', (119, 137))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
61264	32341527	Notably, one of the common sequence variants we found to be associated with cutaneous melanoma has previously been shown to alter TP53 mRNA levels by disruption of TP53 polyadenylation.	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cutaneous melanoma', 'Disease', (76, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('disruption', 'NegReg', (150, 160))	('TP53', 'Gene', '7157', (130, 134))	('variants', 'Var', (36, 44))	('polyadenylation', 'MPA', (169, 184))	('alter', 'Reg', (124, 129))	('TP53', 'Gene', (130, 134))	('associated', 'Reg', (60, 70))
61265	32341527	TP53 responds to cellular stresses to regulate target gene expression resulting in DNA repair, cell cycle arrest, apoptosis, and cellular senescence; variation resulting in loss of normal TP53 function could result in clonal expansion of cells that carry accumulated mutations, which may explain the association with both cutaneous melanoma and nevus count.	('variation', 'Var', (150, 159))	('nevus', 'Disease', (345, 350))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('loss', 'NegReg', (173, 177))	('arrest', 'Disease', 'MESH:D006323', (106, 112))	('TP53', 'Gene', '7157', (0, 4))	('DNA repair', 'biological_process', 'GO:0006281', ('83', '93'))	('melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('cellular senescence', 'biological_process', 'GO:0090398', ('129', '148'))	('cutaneous melanoma', 'Disease', (322, 340))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('TP53', 'Gene', '7157', (188, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (322, 340))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (322, 340))	('mutations', 'Var', (267, 276))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (95, 112))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('95', '112'))	('nevus', 'Phenotype', 'HP:0003764', (345, 350))	('TP53', 'Gene', (0, 4))	('arrest', 'Disease', (106, 112))	('function', 'MPA', (193, 201))	('TP53', 'Gene', (188, 192))
61267	32341527	Additional previously-identified GWAS loci are located near CCND1 (rs4354713), ATM (rs1801516), and PARP1 (rs2695237), all genes with established roles in telomere maintenance, DNA repair, and regulation of senescence.	('ATM', 'Gene', '472', (79, 82))	('DNA repair', 'biological_process', 'GO:0006281', ('177', '187'))	('senescence', 'biological_process', 'GO:0010149', ('207', '217'))	('PARP1', 'Gene', (100, 105))	('rs1801516', 'Mutation', 'rs1801516', (84, 93))	('CCND1', 'Gene', (60, 65))	('rs2695237', 'Mutation', 'rs2695237', (107, 116))	('telomere maintenance', 'biological_process', 'GO:0000723', ('155', '175'))	('ATM', 'Gene', (79, 82))	('rs2695237', 'Var', (107, 116))	('PARP1', 'Gene', '142', (100, 105))	('rs4354713', 'Mutation', 'rs4354713', (67, 76))	('telomere', 'cellular_component', 'GO:0000781', ('155', '163'))	('telomere', 'cellular_component', 'GO:0005696', ('155', '163'))	('rs1801516', 'Var', (84, 93))	('regulation', 'biological_process', 'GO:0065007', ('193', '203'))	('rs4354713', 'Var', (67, 76))	('DNA', 'cellular_component', 'GO:0005574', ('177', '180'))	('CCND1', 'Gene', '595', (60, 65))
61268	32341527	The well-established role of immunity in melanoma biology has fueled a search for an association between variation within the HLA region and melanoma risk.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('variation', 'Var', (105, 114))	('melanoma', 'Disease', (141, 149))	('HLA', 'Gene', '3119', (126, 129))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('HLA', 'Gene', (126, 129))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
61270	32341527	Here, we report identification of a genome-wide significant association between cutaneous melanoma susceptibility and rs28986343 at the HLA locus (see Supplementary Note).	('HLA', 'Gene', '3119', (136, 139))	('cutaneous melanoma', 'Disease', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('HLA', 'Gene', (136, 139))	('rs28986343', 'Var', (118, 128))	('rs28986343', 'Mutation', 'rs28986343', (118, 128))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
61271	32341527	This additional evidence for a role for immunity adds to previous and current TWAS and colocalization analyses suggesting association between rs408825 and expression of the innate immunity gene MX2.	('association', 'Interaction', (122, 133))	('MX2', 'Gene', (194, 197))	('expression', 'MPA', (155, 165))	('MX2', 'Gene', '4600', (194, 197))	('innate immunity', 'biological_process', 'GO:0045087', ('173', '188'))	('rs408825', 'Mutation', 'rs408825', (142, 150))	('rs408825', 'Var', (142, 150))
61272	32341527	Additionally, many risk alleles for the autoimmune melanocyte-related disorder vitiligo are protective for cutaneous melanoma with the lead SNPs either identical (rs1126809/TYR; rs6059655/ASIP), or in strong LD with cutaneous melanoma lead SNPs (rs251464 near PPARGC1B for vitiligo, rs32578 for melanoma, LD r2EUR = 0.73; rs72928038 near BACH2 for vitiligo, rs6908626 for melanoma, r2EUR = 0.95; rs1129038 near OCA2 for vitiligo, rs12913832 for melanoma, r2EUR = 0.99).	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('OCA2', 'Gene', '4948', (411, 415))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (216, 234))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (216, 234))	('rs72928038', 'Var', (322, 332))	('rs32578', 'Var', (283, 290))	('melanoma', 'Phenotype', 'HP:0002861', (445, 453))	('melanoma', 'Disease', (445, 453))	('rs12913832', 'Var', (430, 440))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('disorder vitiligo', 'Disease', (70, 87))	('melanoma', 'Disease', (295, 303))	('cutaneous melanoma lead SNPs', 'Disease', 'MESH:C562393', (216, 244))	('vitiligo', 'Phenotype', 'HP:0001045', (273, 281))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('rs6908626', 'Mutation', 'rs6908626', (358, 367))	('rs1126809', 'DBSNP_MENTION', 'None', (163, 172))	('melanoma', 'Disease', (372, 380))	('melanoma', 'Phenotype', 'HP:0002861', (372, 380))	('rs6908626', 'Var', (358, 367))	('rs251464', 'Mutation', 'rs251464', (246, 254))	('rs251464', 'Var', (246, 254))	('cutaneous melanoma lead SNPs', 'Disease', (216, 244))	('BACH2', 'Gene', (338, 343))	('disorder vitiligo', 'Disease', 'MESH:D014820', (70, 87))	('PPARGC1B', 'Gene', (260, 268))	('rs6059655', 'Mutation', 'rs6059655', (178, 187))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('vitiligo', 'Phenotype', 'HP:0001045', (79, 87))	('melanoma', 'Disease', (117, 125))	('cutaneous melanoma', 'Disease', (107, 125))	('melanoma', 'Disease', 'MESH:D008545', (445, 453))	('BACH2', 'Gene', '60468', (338, 343))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('rs32578', 'Mutation', 'rs32578', (283, 290))	('rs72928038', 'Mutation', 'rs72928038', (322, 332))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('vitiligo', 'Phenotype', 'HP:0001045', (348, 356))	('vitiligo', 'Phenotype', 'HP:0001045', (420, 428))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('rs1126809', 'Var', (163, 172))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('rs12913832', 'Mutation', 'rs12913832', (430, 440))	('melanoma', 'Disease', 'MESH:D008545', (372, 380))	('ASIP', 'Gene', '434', (188, 192))	('rs1129038', 'Mutation', 'rs1129038', (396, 405))	('OCA2', 'Gene', (411, 415))	('ASIP', 'Gene', (188, 192))	('PPARGC1B', 'Gene', '133522', (260, 268))
61275	32341527	The cutaneous melanoma meta-analysis identified a locus near FOXD3, while the pleiotropic cutaneous melanoma+Nevus analysis and TWAS locus identified a novel locus significantly associated with allelic expression of NOTCH2 in melanocytes (Supplementary Note).	('NOTCH2', 'Gene', (216, 222))	('FOXD3', 'Gene', (61, 66))	('associated', 'Reg', (178, 188))	('cutaneous melanoma', 'Disease', (90, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('Nevus', 'Phenotype', 'HP:0003764', (109, 114))	('allelic expression', 'Var', (194, 212))	('NOTCH2', 'Gene', '4853', (216, 222))	('FOXD3', 'Gene', '27022', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('cutaneous melanoma', 'Disease', (4, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (4, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 22))
61278	32341527	Whole-genome and targeted sequencing studies of melanoma-prone families led to the identification of a functional intermediate-penetrance missense mutation of MITF associated with both melanoma and nevus count (MITF p.E318K), a variant that was rediscovered by this population-based meta-analysis (rs149617956, P = 5.17 x 10-25, OR = 0.38).	('MITF', 'Gene', (211, 215))	('melanoma', 'Disease', (48, 56))	('MITF', 'Gene', (159, 163))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('MITF', 'Gene', '4286', (159, 163))	('rs149617956', 'Mutation', 'rs149617956', (298, 309))	('MITF', 'Gene', '4286', (211, 215))	('associated', 'Reg', (164, 174))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('missense mutation', 'Var', (138, 155))	('nevus', 'Phenotype', 'HP:0003764', (198, 203))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('p.E318K', 'Var', (216, 223))	('nevus count', 'Disease', (198, 209))	('melanoma', 'Disease', (185, 193))	('p.E318K', 'Mutation', 'rs149617956', (216, 223))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
61283	32341527	Germline mutations in this gene are associated with a variety of tumors including gastric, breast, and potentially colorectal cancer.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('breast', 'Disease', (91, 97))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('associated', 'Reg', (36, 46))	('colorectal cancer', 'Disease', (115, 132))	('gastric', 'Disease', (82, 89))
61301	32341527	Three of our 68 reported variants have a MAF less than 0.01: rs149617956 with MAF = 0.002, rs79356439 with MAF = 0.008 and rs3212371 with MAF = 0.003.	('rs3212371', 'Mutation', 'rs3212371', (123, 132))	('rs79356439', 'Mutation', 'rs79356439', (91, 101))	('rs149617956', 'Var', (61, 72))	('rs3212371', 'Var', (123, 132))	('rs79356439', 'Var', (91, 101))	('rs149617956', 'Mutation', 'rs149617956', (61, 72))
61311	32341527	For each subject in our study, we calculated two polygenic scores (PRS), using 276 genetic variants associated with pigmentation and 10 genetic variants associated with nevus count.	('pigmentation', 'Disease', (116, 128))	('nevus', 'Phenotype', 'HP:0003764', (169, 174))	('associated', 'Reg', (100, 110))	('variants', 'Var', (91, 99))	('pigmentation', 'Disease', 'MESH:D010859', (116, 128))	('pigmentation', 'biological_process', 'GO:0043473', ('116', '128'))
61323	32341527	Cutaneous melanoma heritability enrichment for SNPs around tissue-specific genes was assessed by stratified LD score regression as described previously  and implemented in the LDSC program v1.0.0 (https://github.com/bulik/ldsc).	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('SNPs', 'Var', (47, 51))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
61325	32341527	We performed colocalization analyses of cutaneous melanoma GWAS signals with eQTL signals from our melanocyte and 48 GTEx (v7) tissue eQTL datasets (note that 2 tissue types that were included for LDSC using expression data were not included here as well as in TWAS analyses due to lack of eQTL data from GTEx), using eQTL and GWAS CAusal Variants Identification in Associated Regions (eCAVIAR, v2.0, http://genetics.cs.ucla.edu/caviar/, https://github.com/fhormoz/caviar).	('Variants', 'Var', (339, 347))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (40, 63))	('cutaneous melanoma GWAS', 'Disease', (40, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (40, 58))
61328	32341527	To avoid reporting spurious effects, we applied a conservative criterion and only reported variants displaying LD r2 > 0.9 with the cutaneous melanoma GWAS lead SNP and eQTL P-value below a Bonferroni-corrected cutoff of each dataset (0.05/number of eGenes tested for each tissue dataset).	('cutaneous melanoma GWAS', 'Disease', 'MESH:C562393', (132, 155))	('cutaneous melanoma GWAS', 'Disease', (132, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('variants', 'Var', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
61340	26012346	We detected global DNA hypomethylation in leukocytes of melanoma and breast cancer patients compared with healthy controls (p < 0.001).	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))	('global DNA hypomethylation', 'Var', (12, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('19', '38'))	('patients', 'Species', '9606', (83, 91))	('detected', 'Reg', (3, 11))
61344	26012346	Not surprisingly, a growing number of human diseases are associated with alterations in DNA methylation.	('human', 'Species', '9606', (38, 43))	('alterations', 'Var', (73, 84))	('DNA methylation', 'Protein', (88, 103))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('DNA methylation', 'biological_process', 'GO:0006306', ('88', '103'))	('human diseases', 'Disease', (38, 52))
61345	26012346	Deregulation of epigenetic modification in tumor DNA such as hypermethylation of CpG islands at gene promoters and global reduction of 5-methylcytosine (5mC) levels has been observed in almost every cancer type.	('epigenetic modification', 'Var', (16, 39))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('5mC', 'Chemical', 'MESH:D044503', (153, 156))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (135, 151))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('reduction', 'NegReg', (122, 131))	('hypermethylation', 'Var', (61, 77))	('cancer', 'Disease', (199, 205))	('tumor', 'Disease', (43, 48))
61346	26012346	Although DNA methylation profiles are often tissue- and cell-specific, recent data indicate that epigenetic traits in white blood cells are phenotypic markers of genomic instability and promising candidate risk markers for solid tumors even after adjusting for known cancer risk factors.	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('solid tumors', 'Disease', (223, 235))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('epigenetic traits', 'Var', (97, 114))	('solid tumors', 'Disease', 'MESH:D009369', (223, 235))
61349	26012346	Moreover, the rates of incidence of some epigenetically influenced diseases, such as cancer, differ among ethnic groups, due to different environmental exposures, lifestyles and genetic or epigenetic variants.	('men', 'Species', '9606', (145, 148))	('differ', 'Reg', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('epigenetic variants', 'Var', (189, 208))
61351	26012346	In addition, genetic ancestry is associated with breast cancer risk in US Latinas and Mexican women, where higher European ancestry was associated with increased risk and higher Native American ancestry was associated with decreased risk of breast cancer.	('women', 'Species', '9606', (94, 99))	('genetic ancestry', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('associated', 'Reg', (33, 43))	('breast cancer', 'Disease', (241, 254))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))
61377	26012346	In order to test for association of genes involved in DNA methylation with global DNA methylation, we genotyped SNPs in MTHFR (C677T rs1801131), DNMT3A (rs4665777), DNMT3B (rs406193) and BRCA1 (rs16942, rs1799950, rs176092, rs8176193) in all breast cancer cases and controls with methylation level data.	('rs1801131', 'DBSNP_MENTION', 'None', (133, 142))	('MTHFR', 'Gene', (120, 125))	('DNA methylation', 'biological_process', 'GO:0006306', ('82', '97'))	('BRCA1', 'Gene', '672', (187, 192))	('BRCA1', 'Gene', (187, 192))	('rs4665777', 'Var', (153, 162))	('C677T', 'SUBSTITUTION', 'None', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('rs8176193', 'Mutation', 'rs8176193', (224, 233))	('rs16942', 'Mutation', 'rs16942', (194, 201))	('rs4665777', 'Mutation', 'rs4665777', (153, 162))	('rs176092', 'Mutation', 'rs176092', (214, 222))	('rs176092', 'Var', (214, 222))	('DNA methylation', 'biological_process', 'GO:0006306', ('54', '69'))	('rs1799950', 'Var', (203, 212))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('rs1799950', 'Mutation', 'rs1799950', (203, 212))	('DNMT3A', 'Gene', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('rs8176193', 'Var', (224, 233))	('rs1801131', 'Var', (133, 142))	('DNMT3B', 'Gene', (165, 171))	('DNMT3B', 'Gene', '1789', (165, 171))	('MTHFR', 'Gene', '4524', (120, 125))	('breast cancer', 'Disease', (242, 255))	('rs406193', 'Mutation', 'rs406193', (173, 181))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))	('rs16942', 'Var', (194, 201))	('C677T', 'Var', (127, 132))	('rs406193', 'Var', (173, 181))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('methylation', 'biological_process', 'GO:0032259', ('280', '291'))	('DNMT3A', 'Gene', '1788', (145, 151))
61387	26012346	We did not detect an association between genetic variants directly or indirectly involved in epigenetic processes such as C677T in MTHFR, rs4665777 in DNMT3A, rs406193 in DNMT3B, rs16942, rs1799950, rs8176092, rs8176193in BRCA1, and global DNA methylation levels in the breast cancer study (p > 0.05 for all, Additional file 6: Table S3).	('rs4665777', 'Mutation', 'rs4665777', (138, 147))	('rs8176092', 'Mutation', 'rs8176092', (199, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('rs16942', 'Mutation', 'rs16942', (179, 186))	('rs406193', 'Mutation', 'rs406193', (159, 167))	('breast cancer', 'Disease', 'MESH:D001943', (270, 283))	('breast cancer', 'Disease', (270, 283))	('rs8176193', 'Mutation', 'rs8176193', (210, 219))	('global DNA methylation levels', 'MPA', (233, 262))	('rs1799950', 'Var', (188, 197))	('rs406193', 'Var', (159, 167))	('C677T', 'Var', (122, 127))	('rs8176092', 'Var', (199, 208))	('rs1799950', 'Mutation', 'rs1799950', (188, 197))	('MTHFR', 'Gene', '4524', (131, 136))	('DNMT3A', 'Gene', '1788', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('DNMT3B', 'Gene', (171, 177))	('DNMT3B', 'Gene', '1789', (171, 177))	('BRCA1', 'Gene', '672', (222, 227))	('C677T', 'SUBSTITUTION', 'None', (122, 127))	('rs16942', 'Var', (179, 186))	('rs8176193in', 'Var', (210, 221))	('BRCA1', 'Gene', (222, 227))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('MTHFR', 'Gene', (131, 136))	('DNA methylation', 'biological_process', 'GO:0006306', ('240', '255'))	('DNMT3A', 'Gene', (151, 157))	('rs4665777', 'Var', (138, 147))
61399	26012346	We have uncovered evidence of global DNA hypomethylation in leukocytes of cancer patients and of a negative correlation between African genetic individual ancestry and leucocyte methylation among sporadic cancer patients from an admixed population.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('negative', 'NegReg', (99, 107))	('sporadic cancer', 'Disease', (196, 211))	('hypomethylation', 'Var', (41, 56))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('sporadic cancer', 'Disease', 'MESH:D009369', (196, 211))	('methylation', 'biological_process', 'GO:0032259', ('178', '189'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('37', '56'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
61400	26012346	Genomic DNA hypomethylation is believed to have an important impact on tumor biology through the generation of chromosomal instability, reactivation of transposable elements, and loss of imprinting.	('impact', 'Reg', (61, 67))	('chromosomal instability', 'MPA', (111, 134))	('chromosomal instability', 'Phenotype', 'HP:0040012', (111, 134))	('DNA hypomethylation', 'Var', (8, 27))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('loss', 'NegReg', (179, 183))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('reactivation', 'MPA', (136, 148))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('8', '27'))	('tumor', 'Disease', (71, 76))	('men', 'Species', '9606', (168, 171))
61401	26012346	Thus, an association between genomic hypomethylation and cancer was expected.	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('genomic', 'Var', (29, 36))
61402	26012346	Epimutations and global DNA hypomethylation, associated with increased cancer risk could be detected in peripheral blood, instead of the affected tissue.	('Epimutations', 'Var', (0, 12))	('global DNA hypomethylation', 'Var', (17, 43))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('cancer', 'Disease', (71, 77))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('24', '43'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
61417	26012346	identified DNA methylation differences that distinguish three major human ethnic groups (Caucasian-American, African-American and Han Chinese-American) and CpG methylation quantitative trait loci associated with natural human variation, contributing to the diverse phenotypic characteristics of human populations.	('human', 'Species', '9606', (295, 300))	('human', 'Species', '9606', (68, 73))	('differences', 'Var', (27, 38))	('human', 'Species', '9606', (220, 225))	('DNA', 'Gene', (11, 14))	('methylation', 'biological_process', 'GO:0032259', ('160', '171'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('methylation differences', 'Var', (15, 38))
61422	26012346	Thus, the prevalence of epigenetic alterations may provide a basis for understanding the unequal cancer burden of disease early onset, aggressiveness, and poor outcomes experienced by individuals of different ethnicities.	('aggressiveness', 'Phenotype', 'HP:0000718', (135, 149))	('cancer', 'Disease', (97, 103))	('aggressiveness', 'Disease', 'MESH:D001523', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('epigenetic alterations', 'Var', (24, 46))	('aggressiveness', 'Disease', (135, 149))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
61425	32855206	A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('immune signaling networks', 'Pathway', (61, 86))	('cancer', 'Disease', (37, 43))	('signaling', 'biological_process', 'GO:0023052', ('68', '77'))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rewire', 'Reg', (54, 60))
61426	32855206	Here we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('alter', 'Reg', (88, 93))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (44, 53))	('immune', 'MPA', (94, 100))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Disease', (114, 120))
61447	32855206	For an immune pathway i in cancer type j, the score is defined as following:  Where  is the number of mutated immune genes in pathway i;  is the total number of genes in pathway i;  is the number of patients of cancer j that with gene mutations in pathway i; and  is the total number of patients sequenced in cancer j.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('patients', 'Species', '9606', (287, 295))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('gene mutations', 'Var', (230, 244))	('cancer', 'Disease', (309, 315))
61475	32855206	Recombinant MAGE-A3 protein combined with immunostimulant AS02B or AS15, has been administered to patients with early metastatic melanoma.	('MAGE-A3', 'Gene', (12, 19))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Disease', (129, 137))	('AS02B', 'Var', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('MAGE-A3', 'Gene', '4102', (12, 19))
61485	32855206	It has been suggested that the mutations in immune pathways could impact tumor-immune interactions.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('immune pathways', 'Pathway', (44, 59))	('impact', 'Reg', (66, 72))
61490	32855206	We found that the cancer types that are likely to respond well to immunotherapy had higher proportion of immune-related gene mutations, such as skin cutaneous melanoma (SKCM) and kidney cancer (Figure S2C).	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 167))	('mutations', 'Var', (125, 134))	('kidney cancer', 'Disease', 'MESH:D007680', (179, 192))	('skin cutaneous melanoma', 'Disease', (144, 167))	('kidney cancer', 'Phenotype', 'HP:0009726', (179, 192))	('immune-related gene', 'Gene', (105, 124))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('kidney cancer', 'Disease', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
61495	32855206	The top-1 gene (PLXNA4) ranked by mutation frequency was mutated in approximately 19% of lung cancer patients.	('patients', 'Species', '9606', (101, 109))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('PLXNA4', 'Gene', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('top-1', 'Gene', '7150', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('top-1', 'Gene', (4, 9))	('mutated', 'Var', (57, 64))	('PLXNA4', 'Gene', '91584', (16, 22))
61497	32855206	We further found that the expression of PLXNA4 was correlated with the patients' survival in LUSC (Figure S2E, p=0.017).	('PLXNA4', 'Gene', '91584', (40, 46))	('expression', 'Var', (26, 36))	('patients', 'Species', '9606', (71, 79))	('PLXNA4', 'Gene', (40, 46))	('correlated', 'Reg', (51, 61))
61498	32855206	These results suggest that the mutations in cytokine receptors pathway might play critical roles in cancer and the proposed PMB index could help prioritizing key mutations in cancer pathways.	('cancer', 'Disease', (100, 106))	('mutations', 'Var', (31, 40))	('play', 'Reg', (77, 81))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('PMB', 'Chemical', '-', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cytokine receptors pathway', 'Pathway', (44, 70))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
61504	32855206	These results indicate that these genes could play a role in promoting tumor growth.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('genes', 'Var', (34, 39))	('promoting', 'PosReg', (61, 70))	('tumor', 'Disease', (71, 76))
61518	32855206	Given the importance of the proposed immune-related scores in predicting immune response, we next determined whether cancer mutations in immunity candidate driver regions were significantly correlated with these scores (Table S3).	('correlated', 'Reg', (190, 200))	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('immune response', 'biological_process', 'GO:0006955', ('73', '88'))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
61520	32855206	Specifically, mutations in seven genes (UBXN1, LTBP2, STAT1, NGFR, NRAS, MET and LTBP4) were significantly correlated with all of three types of immune-related scores.	('correlated', 'Reg', (107, 117))	('NGFR', 'Gene', (61, 65))	('MET', 'Gene', '79811', (73, 76))	('LTBP4', 'Gene', '8425', (81, 86))	('LTBP4', 'Gene', (81, 86))	('LTBP2', 'Gene', (47, 52))	('NRAS', 'Gene', (67, 71))	('NGFR', 'Gene', '4804', (61, 65))	('STAT1', 'Gene', '6772', (54, 59))	('LTBP2', 'Gene', '4053', (47, 52))	('MET', 'Gene', (73, 76))	('NRAS', 'Gene', '4893', (67, 71))	('UBXN1', 'Gene', (40, 45))	('STAT1', 'Gene', (54, 59))	('mutations', 'Var', (14, 23))	('UBXN1', 'Gene', '51035', (40, 45))
61523	32855206	Moreover, we also identified mutations of STAT1 significantly correlated with these scores, which was consistent with previous observation that STAT1 played an important role in the innate immune response.	('STAT1', 'Gene', (144, 149))	('STAT1', 'Gene', '6772', (144, 149))	('STAT1', 'Gene', (42, 47))	('STAT1', 'Gene', '6772', (42, 47))	('mutations', 'Var', (29, 38))	('innate immune response', 'biological_process', 'GO:0045087', ('182', '204'))	('correlated', 'Reg', (62, 72))
61526	32855206	We first identified the protein regions whose mutations were significantly correlated with the abundance of six tumor-infiltrating immune cells (TIIC) subsets (B cells, CD4 T cells, CD8 T cells, macrophages, neutrophils, and dendritic cells).	('mutations', 'Var', (46, 55))	('CD4', 'Gene', (169, 172))	('CD8', 'Gene', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CD8', 'Gene', '925', (182, 185))	('correlated', 'Reg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD4', 'Gene', '920', (169, 172))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('tumor', 'Disease', (112, 117))
61532	32855206	For example, patients with LTBP4 mutations exhibited significantly higher abundance of CD8 T cells and neutrophils (Figure 4E).	('higher', 'PosReg', (67, 73))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (33, 42))	('LTBP4', 'Gene', '8425', (27, 32))	('LTBP4', 'Gene', (27, 32))	('CD8', 'Gene', (87, 90))	('CD8', 'Gene', '925', (87, 90))
61534	32855206	Moreover, we found that not only the genomic variants in LTBP4 were correlated with immune cell abundance, but patients with copy number alterations also exhibited significantly different abundance (Figure S5C).	('different', 'Reg', (178, 187))	('correlated', 'Reg', (68, 78))	('LTBP4', 'Gene', (57, 62))	('copy number alterations', 'Var', (125, 148))	('LTBP4', 'Gene', '8425', (57, 62))	('genomic variants', 'Var', (37, 53))	('abundance', 'MPA', (188, 197))	('immune cell abundance', 'MPA', (84, 105))	('patients', 'Species', '9606', (111, 119))
61535	32855206	These results suggest that the genomic alterations might contribute to immunotherapy response through affecting the immune cell infiltration in cancer.	('genomic alterations', 'Var', (31, 50))	('affecting', 'Reg', (102, 111))	('contribute', 'Reg', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Disease', (144, 150))	('immunotherapy response', 'CPA', (71, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
61538	32855206	Approximately 25% of the mutations in PIK3CA and HRAS could generate neoantigens (Figure 5B).	('mutations', 'Var', (25, 34))	('neoantigens', 'MPA', (69, 80))	('HRAS', 'Gene', (49, 53))	('generate', 'Reg', (60, 68))	('PIK3CA', 'Gene', (38, 44))	('PIK3CA', 'Gene', '5290', (38, 44))	('HRAS', 'Gene', '3265', (49, 53))
61539	32855206	Next, we focused on mutations in PIK3CA and EGFR that give rise to neoantigens.	('PIK3CA', 'Gene', '5290', (33, 39))	('neoantigens', 'MPA', (67, 78))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('PIK3CA', 'Gene', (33, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))	('mutations', 'Var', (20, 29))	('give rise to', 'Reg', (54, 66))
61541	32855206	For example, we identified 46 missense mutations that could generate neoantigens in PIK3CA.	('PIK3CA', 'Gene', '5290', (84, 90))	('neoantigens', 'MPA', (69, 80))	('missense mutations', 'Var', (30, 48))	('generate', 'Reg', (60, 68))	('PIK3CA', 'Gene', (84, 90))
61542	32855206	Moreover, we identified a mutation cluster (including R38C/H, E81K, R88Q, R93W, K111E and R115L) in PIK3CA (Figure 5E).	('K111E', 'Mutation', 'rs1057519933', (80, 85))	('R115L', 'Mutation', 'rs200018596', (90, 95))	('R88Q', 'Mutation', 'rs121913287', (68, 72))	('E81K', 'Mutation', 'rs1057519929', (62, 66))	('R38C', 'SUBSTITUTION', 'None', (54, 58))	('R38C', 'Var', (54, 58))	('R115L', 'Var', (90, 95))	('PIK3CA', 'Gene', (100, 106))	('E81K', 'Var', (62, 66))	('R88Q', 'Var', (68, 72))	('R93W', 'Var', (74, 78))	('K111E', 'Var', (80, 85))	('PIK3CA', 'Gene', '5290', (100, 106))	('R93W', 'Mutation', 'p.R93W', (74, 78))
61543	32855206	For EGFR, we identified 17 mutations that could generate neoantigens.	('mutations', 'Var', (27, 36))	('neoantigens', 'MPA', (57, 68))	('EGFR', 'Gene', (4, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('generate', 'Reg', (48, 56))	('EGFR', 'Gene', '1956', (4, 8))
61544	32855206	We also found seven mutations formed a cluster in 3D (including R108K, R252/P/C/H and A189V/D, Figure 5E).	('R108K', 'Var', (64, 69))	('R252/P/C/H', 'Mutation', 'rs751667358', (71, 81))	('R252/P/C/H', 'Var', (71, 81))	('A189V', 'Var', (86, 91))	('R108K', 'Mutation', 'rs1057519828', (64, 69))	('A189V', 'SUBSTITUTION', 'None', (86, 91))
61545	32855206	We hypothesize that functional mutations which cause a conformational change in the protein may be more likely to be recognized by MHC molecules for immune pruning, but if these mutations subsequently suppress inflammatory signaling it may allow for proliferation of tumor cells with activating mutations.	('mutations', 'Var', (31, 40))	('signaling', 'biological_process', 'GO:0023052', ('223', '232'))	('suppress', 'NegReg', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('allow', 'Reg', (240, 245))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('conformational change', 'MPA', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('mutations', 'Var', (178, 187))	('inflammatory signaling', 'MPA', (210, 232))
61560	32855206	These mutations were distributed in various types of cancer.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('distributed', 'Reg', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (6, 15))
61561	32855206	We identified six mutations in PIK3R1 (encoding p85alpha) that reduced binding of HLAs (Figure 7B) and some mutations clustered in a possibly functional spot (Figure 7C).	('p85alpha', 'Gene', '5295', (48, 56))	('mutations', 'Var', (108, 117))	('reduced', 'NegReg', (63, 70))	('PIK3R1', 'Gene', '5295', (31, 37))	('HLAs', 'Protein', (82, 86))	('PIK3R1', 'Gene', (31, 37))	('p85alpha', 'Gene', (48, 56))	('binding', 'Interaction', (71, 78))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))	('mutations', 'Var', (18, 27))
61562	32855206	Consistently, we identified two mutations (N564D and K567E) that increased growth of cancer cell lines (Figure 7D).	('increased', 'PosReg', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('N564D', 'Mutation', 'rs1057519841', (43, 48))	('K567E', 'Var', (53, 58))	('cancer', 'Disease', (85, 91))	('K567E', 'Mutation', 'rs946866092', (53, 58))	('N564D', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
61563	32855206	These results suggest that our network-based method helps identify cancer functional mutations by their change in binding affinity to HLAs.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('binding', 'molecular_function', 'GO:0005488', ('114', '121'))	('change', 'Reg', (104, 110))	('HLAs', 'Protein', (134, 138))	('mutations', 'Var', (85, 94))	('binding', 'Interaction', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
61579	32855206	For example, up-regulation of BIRC5 is correlated with CNV amplification; and down-regulation of CCL14 is correlated with CNV deletion across cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('regulation', 'biological_process', 'GO:0065007', ('83', '93'))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BIRC5', 'Gene', '332', (30, 35))	('regulation', 'biological_process', 'GO:0065007', ('16', '26'))	('BIRC5', 'Gene', (30, 35))	('down-regulation', 'NegReg', (78, 93))	('CCL14', 'Gene', '6358', (97, 102))	('CCL', 'molecular_function', 'GO:0044101', ('97', '100'))	('amplification', 'Var', (59, 72))	('up-regulation', 'PosReg', (13, 26))	('CNV deletion', 'Var', (122, 134))	('CCL14', 'Gene', (97, 102))	('cancer', 'Disease', (142, 148))
61580	32855206	Moreover, eQTLs analysis revealed a hotspot locus that modulates the expression of DEFB1 (Figure S10A-D), which might function through perturbation of CTCF binding.	('CTCF', 'Gene', (151, 155))	('S10A', 'SUBSTITUTION', 'None', (97, 101))	('perturbation', 'Var', (135, 147))	('CTCF', 'Gene', '10664', (151, 155))	('S10A', 'Var', (97, 101))	('expression', 'MPA', (69, 79))	('modulates', 'Reg', (55, 64))	('DEFB1', 'Gene', '1672', (83, 88))	('binding', 'molecular_function', 'GO:0005488', ('156', '163'))	('binding', 'Interaction', (156, 163))	('DEFB1', 'Gene', (83, 88))
61613	32158881	It is hypothesized that these melanocytes are predisposed to malignant transformation due to mutations of the NF1 gene.	('NF1', 'Gene', (110, 113))	('mutations', 'Var', (93, 102))	('NF1', 'Gene', '4763', (110, 113))	('due', 'Reg', (86, 89))	('malignant transformation', 'CPA', (61, 85))
61614	32158881	Since there are established links between the NF1 gene mutation and other neural crest-derived tumors such as malignant peripheral nerve sheath tumors, phaeochromocytoma and giant congenital melanocytic nevi, its association with malignant melanoma is deemed possible.	('tumors', 'Disease', (144, 150))	('NF1', 'Gene', '4763', (46, 49))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (191, 207))	('congenital melanocytic nevi', 'Phenotype', 'HP:0100814', (180, 207))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('giant congenital melanocytic nevi', 'Phenotype', 'HP:0005600', (174, 207))	('tumors', 'Disease', (95, 101))	('malignant melanoma', 'Phenotype', 'HP:0002861', (230, 248))	('phaeochromocytoma and giant congenital melanocytic nevi', 'Disease', 'MESH:D009508', (152, 207))	('NF1', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('malignant melanoma', 'Disease', 'MESH:D008545', (230, 248))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (110, 150))	('nevi', 'Phenotype', 'HP:0003764', (203, 207))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('malignant peripheral nerve sheath tumors', 'Disease', (110, 150))	('mutation', 'Var', (55, 63))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D009442', (110, 150))	('malignant melanoma', 'Disease', (230, 248))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
61659	21863025	Overexpression of CR-1 can lead to in vitro transformation of human mammary epithelial cells and can promote mammary tumourigenesis in transgenic mice.	('promote', 'PosReg', (101, 108))	('transgenic mice', 'Species', '10090', (135, 150))	('human', 'Species', '9606', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('CR-1', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('in vitro transformation', 'CPA', (35, 58))	('lead to', 'Reg', (27, 34))	('tumour', 'Disease', (117, 123))
61662	21863025	Indeed, it has been observed that treatment with antisense oligonucleotides directed against CR-1 results in a significant inhibition of the in vitro and in vivo growth of human carcinoma cells of different histological origin, in which CR-1 can function as autocrine or paracrine growth factor.	('carcinoma', 'Disease', (178, 187))	('antisense oligonucleotides', 'Var', (49, 75))	('human', 'Species', '9606', (172, 177))	('growth', 'CPA', (162, 168))	('inhibition', 'NegReg', (123, 133))	('CR-1', 'Gene', (93, 97))	('carcinoma', 'Disease', 'MESH:D002277', (178, 187))	('oligonucleotides', 'Chemical', 'MESH:D009841', (59, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
61690	21863025	Levels of phospho and total Smad-2 and c-Src were measured following treatment with recombinant CR-1 (100 ng ml-1) and/or Nodal (400 ng ml-1).	('100', 'Var', (102, 105))	('c-Src', 'Gene', (39, 44))	('Smad-2', 'Gene', (28, 34))	('c-Src', 'Gene', '6714', (39, 44))
61719	21863025	We observed a significant reduction in the levels of CR-1 mRNA in CON 242 and COPA 159 transfected with the anti-CR-1 siRNA as compared with untreated cells and cells treated with a negative control siRNA (Figure 5A).	('COPA', 'Gene', '1314', (78, 82))	('CR-1 mRNA', 'MPA', (53, 62))	('COPA', 'Gene', (78, 82))	('levels', 'MPA', (43, 49))	('reduction', 'NegReg', (26, 35))	('anti-CR-1', 'Var', (108, 117))
61720	21863025	In agreement with these findings, transfection of COPA 159 and CON 242 cell lines with anti-CR-1 siRNAs produced a significant reduction of CR-1 protein expression after 48 h of treatment, as assessed by flow cytometry (data not shown).	('CR-1 protein', 'Protein', (140, 152))	('COPA', 'Gene', '1314', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('anti-CR-1', 'Var', (87, 96))	('reduction', 'NegReg', (127, 136))	('COPA', 'Gene', (50, 54))
61722	21863025	Treatment of CON 242 with anti-CR-1 siRNAs resulted in a marked reduction of phospho-Src, whereas it produced a slight reduction of phosho-Smad-2 (Figure 5B).	('Src', 'Gene', (85, 88))	('Src', 'Gene', '6714', (85, 88))	('anti-CR-1', 'Var', (26, 35))	('phosho-Smad-2', 'MPA', (132, 145))	('reduction', 'NegReg', (64, 73))	('reduction', 'NegReg', (119, 128))
61724	21863025	However, silencing of CR-1 in this latter cell line produced slight effects on the activation of c-Src and Smad-2 (Figure 5B).	('c-Src', 'Gene', (97, 102))	('CR-1', 'Gene', (22, 26))	('Smad-2', 'Gene', (107, 113))	('silencing', 'Var', (9, 18))	('c-Src', 'Gene', '6714', (97, 102))	('activation', 'MPA', (83, 93))
61725	21863025	We next investigated whether the silencing of endogenous CR-1 affects the proliferation and invasive ability of melanoma cells that express high levels of CR-1.	('CR-1', 'Gene', (57, 61))	('melanoma cell', 'Disease', 'MESH:D008545', (112, 125))	('silencing', 'Var', (33, 42))	('invasive ability', 'CPA', (92, 108))	('affects', 'Reg', (62, 69))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('proliferation', 'CPA', (74, 87))	('melanoma cell', 'Disease', (112, 125))
61726	21863025	In CON 242 and COPA 159 cells, a significant reduction on cell growth was observed following transfection with anti-CR-1 siRNA (Figure 6A).	('COPA', 'Gene', (15, 19))	('cell growth', 'CPA', (58, 69))	('COPA', 'Gene', '1314', (15, 19))	('anti-CR-1', 'Gene', (111, 120))	('cell growth', 'biological_process', 'GO:0016049', ('58', '69'))	('transfection', 'Var', (93, 105))	('reduction', 'NegReg', (45, 54))
61727	21863025	In addition, a time-dependent inhibition of the invasive ability of melanoma cells was observed after silencing of endogenous CR-1 mRNA (Figure 6B).	('melanoma cell', 'Disease', (68, 81))	('melanoma cell', 'Disease', 'MESH:D008545', (68, 81))	('endogenous', 'MPA', (115, 125))	('CR-1', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('inhibition', 'NegReg', (30, 40))	('silencing', 'Var', (102, 111))
61739	21863025	Our paper is also the first to formally demonstrate that CR-1 can function as an autocrine and/or paracrine growth factor in melanoma cells, in which CR-1 is able to activate both Nodal and Src signalling.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('signalling', 'biological_process', 'GO:0023052', ('194', '204'))	('melanoma cell', 'Disease', (125, 138))	('Src', 'Gene', '6714', (190, 193))	('melanoma cell', 'Disease', 'MESH:D008545', (125, 138))	('activate', 'PosReg', (166, 174))	('Src', 'Gene', (190, 193))	('CR-1', 'Var', (150, 154))
61747	21863025	In this regard, our findings suggest that expression of CR-1 might significantly enhance the metastatic potential of melanoma cells through the activation of the Nodal/ALK/Smad pathway.	('melanoma cell', 'Disease', (117, 130))	('ALK', 'Gene', (168, 171))	('activation', 'PosReg', (144, 154))	('melanoma cell', 'Disease', 'MESH:D008545', (117, 130))	('expression', 'Var', (42, 52))	('CR-1', 'Gene', (56, 60))	('ALK', 'Gene', '238', (168, 171))	('enhance', 'PosReg', (81, 88))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
61748	21863025	Although treatment with recombinant CR-1 and Nodal only slightly enhanced the activation of Smad-2 in melanoma cells, blockade of ALK activation with a specific inhibitor was able to significantly reduce the ability of CR-1 to stimulate melanoma cell invasion, suggesting that Nodal/Smad-2 signalling has an important role in CR-1-induced invasiveness.	('melanoma cell', 'Disease', 'MESH:D008545', (102, 115))	('reduce', 'NegReg', (197, 203))	('melanoma cell', 'Disease', (237, 250))	('activation', 'MPA', (78, 88))	('ALK', 'Gene', (130, 133))	('signalling', 'biological_process', 'GO:0023052', ('290', '300'))	('melanoma cell', 'Disease', 'MESH:D008545', (237, 250))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma cell', 'Disease', (102, 115))	('stimulate', 'PosReg', (227, 236))	('Smad-2', 'Gene', (92, 98))	('blockade', 'Var', (118, 126))	('ALK', 'Gene', '238', (130, 133))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))
61761	21863025	Saracatinib but not SB-431542 also inhibited the basal invasion of serum-starved melanoma cells, suggesting that in these growth conditions c-Src signalling is driving the invasion of melanoma cells.	('melanoma cell', 'Disease', 'MESH:D008545', (81, 94))	('Saracatinib', 'Chemical', 'MESH:C515233', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma cell', 'Disease', (184, 197))	('signalling', 'biological_process', 'GO:0023052', ('146', '156'))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('c-Src', 'Gene', (140, 145))	('melanoma cell', 'Disease', 'MESH:D008545', (184, 197))	('inhibited', 'NegReg', (35, 44))	('c-Src', 'Gene', '6714', (140, 145))	('Saracatinib', 'Var', (0, 11))	('melanoma cell', 'Disease', (81, 94))	('SB-431542', 'Chemical', 'MESH:C459179', (20, 29))	('basal invasion of', 'CPA', (49, 66))
61863	29524010	Genetic variations in ESR1 (ERalpha) were found to impact melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('ERalpha', 'Gene', (28, 35))	('ESR1', 'Gene', '2099', (22, 26))	('ERalpha', 'Gene', '2099', (28, 35))	('ESR1', 'Gene', (22, 26))	('Genetic variations', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('impact', 'Reg', (51, 57))	('melanoma', 'Disease', (58, 66))
61873	29313974	However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR-related genes) in CM-specific survival (CMSS).	('CM', 'Phenotype', 'HP:0012056', (158, 160))	('CM-specific', 'Disease', (158, 169))	('CM', 'Phenotype', 'HP:0012056', (180, 182))	('variants', 'Var', (57, 65))	('steroid hormone', 'Chemical', 'MESH:D013256', (75, 90))
61874	29313974	Here, we performed a pathway-based analysis to evaluate genetic variants of 191 SHR-related genes in 858 CMSS patients using a dataset from a genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS.	('CM', 'Phenotype', 'HP:0012056', (105, 107))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (202, 226))	('CMSS', 'Disease', (105, 109))	('Texas MD Anderson Cancer', 'Disease', (202, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('SHR-related genes', 'Gene', (80, 97))	('variants', 'Var', (64, 72))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (306, 314))
61875	29313974	Using multivariate Cox proportional hazards regression analysis, we identified three independent SNPs (RORA rs782917 G>A, RORA rs17204952 C>T and DNMT1 rs7253062 G>A) as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25-2.09), 1.60 (1.20-2.13) and 1.52 (1.20-1.94), respectively.	('CMSS', 'Disease', (184, 188))	('Cox', 'Gene', (19, 22))	('RORA', 'Gene', '6095', (103, 107))	('DNMT1', 'Gene', '1786', (146, 151))	('rs7253062 G>A', 'Var', (152, 165))	('rs782917', 'Mutation', 'rs782917', (108, 116))	('RORA', 'Gene', (122, 126))	('RORA', 'Gene', '6095', (122, 126))	('rs17204952', 'Mutation', 'rs17204952', (127, 137))	('rs7253062', 'Mutation', 'rs7253062', (152, 161))	('CM', 'Phenotype', 'HP:0012056', (184, 186))	('Cox', 'Gene', '1351', (19, 22))	('RORA', 'Gene', (103, 107))	('DNMT1', 'Gene', (146, 151))
61877	29313974	Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies.	('DNMT1', 'Gene', (55, 60))	('genetic variants', 'Var', (26, 42))	('CMSS', 'Disease', (93, 97))	('RORA', 'Gene', (46, 50))	('DNMT1', 'Gene', '1786', (55, 60))	('RORA', 'Gene', '6095', (46, 50))	('CM', 'Phenotype', 'HP:0012056', (93, 95))
61894	29313974	Thus, identification of genetic variants in steroid hormone receptor genes through hypothesis-based gene-set analysis, may reveal biomarkers that predict survival of CM patients, leading to novel cancer hormone therapies.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('patients', 'Species', '9606', (169, 177))	('steroid hormone', 'Chemical', 'MESH:D013256', (44, 59))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('genetic variants', 'Var', (24, 40))	('cancer', 'Disease', (196, 202))	('CM', 'Phenotype', 'HP:0012056', (166, 168))
61918	29313974	After Cox regression analysis with adjustment for age and sex, eight SNPs remained significantly associated with CMSS at P < 0.05, including seven SNPs (rs78293, rs782925, rs782915, rs782918, rs782917, rs17204952, and rs782919) in RORA, and one SNP (rs7253062) in DNMT1.	('rs782917', 'Var', (192, 200))	('Cox', 'Gene', '1351', (6, 9))	('rs78293', 'Var', (153, 160))	('rs782918', 'Mutation', 'rs782918', (182, 190))	('men', 'Species', '9606', (41, 44))	('rs17204952', 'Var', (202, 212))	('DNMT1', 'Gene', '1786', (264, 269))	('rs7253062', 'Mutation', 'rs7253062', (250, 259))	('Cox', 'Gene', (6, 9))	('rs78293', 'Mutation', 'rs78293', (153, 160))	('rs7253062', 'Var', (250, 259))	('rs782919', 'Mutation', 'rs782919', (218, 226))	('RORA', 'Gene', (231, 235))	('rs782925', 'Var', (162, 170))	('rs782919', 'Var', (218, 226))	('DNMT1', 'Gene', (264, 269))	('rs782917', 'Mutation', 'rs782917', (192, 200))	('CMSS', 'Disease', (113, 117))	('rs782915', 'Var', (172, 180))	('RORA', 'Gene', '6095', (231, 235))	('rs782915', 'Mutation', 'rs782915', (172, 180))	('rs782918', 'Var', (182, 190))	('rs782925', 'Mutation', 'rs782925', (162, 170))	('rs17204952', 'Mutation', 'rs17204952', (202, 212))	('CM', 'Phenotype', 'HP:0012056', (113, 115))
61919	29313974	We further conducted a stepwise Cox regression analysis of selected clinical variables from the MDACC dataset plus the eight validated SNPs to identify SNPs as independent predictors of CMSS.	('SNPs', 'Var', (152, 156))	('CMSS', 'Disease', (186, 190))	('CM', 'Phenotype', 'HP:0012056', (186, 188))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))
61920	29313974	Three SNPs (i.e., RORA rs782917, RORA rs17204952 and DNMT1 rs7253062) remained significant in the final model (Table 2).	('RORA', 'Gene', (18, 22))	('rs782917', 'Mutation', 'rs782917', (23, 31))	('RORA', 'Gene', '6095', (18, 22))	('rs782917', 'Var', (23, 31))	('RORA', 'Gene', (33, 37))	('DNMT1', 'Gene', (53, 58))	('rs7253062', 'Var', (59, 68))	('rs7253062', 'Mutation', 'rs7253062', (59, 68))	('DNMT1', 'Gene', '1786', (53, 58))	('RORA', 'Gene', '6095', (33, 37))	('rs17204952', 'Mutation', 'rs17204952', (38, 48))
61921	29313974	We then performed the LD analysis of RORA rs782917 and RORA rs17204952 and found that they were not in LD (r2 = 0).	('RORA', 'Gene', '6095', (55, 59))	('RORA', 'Gene', (37, 41))	('rs17204952', 'Mutation', 'rs17204952', (60, 70))	('rs17204952', 'Var', (60, 70))	('rs782917', 'Mutation', 'rs782917', (42, 50))	('RORA', 'Gene', '6095', (37, 41))	('rs782917', 'Var', (42, 50))	('RORA', 'Gene', (55, 59))
61922	29313974	Functional prediction indicated that RORA rs782917, RORA rs17204952 and DNMT1 rs7253062 were putatively functional (Table 1), and these three SNPs were then subject to further analysis.	('RORA', 'Gene', (52, 56))	('DNMT1', 'Gene', (72, 77))	('rs7253062', 'Mutation', 'rs7253062', (78, 87))	('rs7253062', 'Var', (78, 87))	('DNMT1', 'Gene', '1786', (72, 77))	('RORA', 'Gene', '6095', (52, 56))	('RORA', 'Gene', (37, 41))	('rs17204952', 'Mutation', 'rs17204952', (57, 67))	('rs17204952', 'Var', (57, 67))	('rs782917', 'Mutation', 'rs782917', (42, 50))	('RORA', 'Gene', '6095', (37, 41))	('rs782917', 'Var', (42, 50))
61923	29313974	For visual presentation, all genotyped and imputed SNPs in RORA and DNMT1 with an expansion of 100 kilobases in the flanking regions of the gene are shown in a regional association plot, in which these three independent SNPs are each labeled in purple (Supplementary Figure 3).	('expansion', 'Var', (82, 91))	('men', 'Species', '9606', (259, 262))	('RORA', 'Gene', (59, 63))	('DNMT1', 'Gene', (68, 73))	('DNMT1', 'Gene', '1786', (68, 73))	('RORA', 'Gene', '6095', (59, 63))
61924	29313974	As shown in Table 3, we found that under an additive genetic model, RORA rs782917 A, RORA rs17204952 T and DNMT1 rs7253062 A variant alleles were associated with an increased death risk of CM, with a variant-allele attributed HR of 1.61 (95% CI = 1.17-2.21, P = 0.003), 1.56 (95% CI = 1.09-2.24, P = 0.015) and 1.44 (95% CI = 1.06-1.96, P = 0.019) in the MDACC study and 1.63 (95% CI = 1.06-2.52, P = 0.027), 1.67 (95% CI = 1.05-2.66, P = 0.030) and 1.67 (95% CI = 1.13-2.48, P = 0.010) in the Harvard study, as well as 1.62 (95% CI =1.25-2.09, P = 2.24E-04), 1.60 (95% CI =1.20-2.13, P = 1.17E-03) and 1.52 (95% CI =1.20-1.94, P = 6.47E-04) in a meta-analysis of the two datasets (Table 1).	('variant', 'Var', (125, 132))	('rs17204952', 'Mutation', 'rs17204952', (90, 100))	('DNMT1', 'Gene', '1786', (107, 112))	('1.44', 'Var', (311, 315))	('rs7253062', 'Mutation', 'rs7253062', (113, 122))	('RORA', 'Gene', (68, 72))	('6.47E', 'CellLine', 'CVCL:L675', (632, 637))	('CM', 'Phenotype', 'HP:0012056', (189, 191))	('RORA', 'Gene', (85, 89))	('RORA', 'Gene', '6095', (68, 72))	('rs782917', 'Mutation', 'rs782917', (73, 81))	('RORA', 'Gene', '6095', (85, 89))	('DNMT1', 'Gene', (107, 112))
61925	29313974	We further combined the risk genotypes of rs782917 GA+AA, rs17204952 CT+TT and rs7253062 GA+AA into a genetic score to assess the joint effect of these three independent SNPs on CMSS.	('rs17204952 CT+TT', 'Var', (58, 74))	('rs7253062 GA+AA', 'Var', (79, 94))	('CM', 'Phenotype', 'HP:0012056', (178, 180))	('rs7253062', 'Mutation', 'rs7253062', (79, 88))	('rs782917', 'Mutation', 'rs782917', (42, 50))	('rs782917', 'Var', (42, 50))	('rs17204952', 'Mutation', 'rs17204952', (58, 68))
61934	29313974	In the eQTL analysis to evaluate correlations between SNPs and mRNA expression levels of their corresponding gene in lymphoblastoid cell lines derived from 373 European descendants from the 1000 Genomes Project, we found that RORA rs17204952 genotypes were correlated with decreased mRNA expression levels of RORA in a recessive model (P = 0.015, Supplementary Figure 5 A-C).	('mRNA expression levels', 'MPA', (283, 305))	('RORA', 'Gene', '6095', (309, 313))	('rs17204952', 'Mutation', 'rs17204952', (231, 241))	('rs17204952', 'Var', (231, 241))	('RORA', 'Gene', (226, 230))	('RORA', 'Gene', '6095', (226, 230))	('decreased', 'NegReg', (273, 282))	('RORA', 'Gene', (309, 313))	('men', 'Species', '9606', (353, 356))
61935	29313974	However, there was no significant correlation between rs782917 genotypes and RORA mRNA expression levels, nor between rs7253062 genotypes and DNMT1 mRNA expression levels.	('rs7253062', 'Var', (118, 127))	('DNMT1', 'Gene', (142, 147))	('rs782917', 'Mutation', 'rs782917', (54, 62))	('DNMT1', 'Gene', '1786', (142, 147))	('rs782917', 'Var', (54, 62))	('RORA', 'Gene', (77, 81))	('RORA', 'Gene', '6095', (77, 81))	('rs7253062', 'Mutation', 'rs7253062', (118, 127))
61936	29313974	We have also queried the eQTL results (V7 release) in normal skin tissues from the sun-exposed lower leg and unexposed suprapubic from the GTEx Portal (http://www.gtexportal.org/home/), and found rs7253062 was correlated with the mRNA of expression DNMT1 with nominal P = 0.012 in normal skin tissues from sun-exposed lower leg (Supplementary Table 5).	('DNMT1', 'Gene', (249, 254))	('DNMT1', 'Gene', '1786', (249, 254))	('lower leg', 'Phenotype', 'HP:0006385', (318, 327))	('rs7253062', 'Mutation', 'rs7253062', (196, 205))	('rs7253062', 'Var', (196, 205))	('lower leg', 'Phenotype', 'HP:0006385', (95, 104))	('men', 'Species', '9606', (335, 338))
61937	29313974	In the present study, we identified three significant SNPs (RORA rs782917 G>A, RORA rs17204952 C>T and DNMT1 rs7253062 G>A) as potential predictors of CMSS, which highlights the critical roles of these two genes, each encoding a member of steroid hormone receptors and their related regulators (RORA and DNMT1).	('RORA', 'Gene', '6095', (79, 83))	('rs7253062 G>A', 'Var', (109, 122))	('DNMT1', 'Gene', '1786', (103, 108))	('steroid hormone', 'Chemical', 'MESH:D013256', (239, 254))	('RORA', 'Gene', '6095', (295, 299))	('rs17204952', 'Mutation', 'rs17204952', (84, 94))	('rs7253062', 'Mutation', 'rs7253062', (109, 118))	('DNMT1', 'Gene', (304, 309))	('CM', 'Phenotype', 'HP:0012056', (151, 153))	('RORA', 'Gene', (60, 64))	('rs782917', 'Mutation', 'rs782917', (65, 73))	('DNMT1', 'Gene', '1786', (304, 309))	('RORA', 'Gene', '6095', (60, 64))	('RORA', 'Gene', (295, 299))	('CMSS', 'Disease', (151, 155))	('DNMT1', 'Gene', (103, 108))	('rs17204952 C>T', 'Var', (84, 98))	('RORA', 'Gene', (79, 83))
61938	29313974	Moreover, the RORA rs17204952 T allele was correlated with decreased mRNA expression levels of RORA in lymphoblastoid cell lines derived from 373 European descendants from the 1000 Genomes Project, rs782917 and rs17204952 may affect gene transcriptional regulation as histone modification enrichment region enhancer through assisting in the combination of transformation factor binding site and DNA enzymes, DNMT1 rs7253062 was correlated with the expression of DNMT1 mRNA in normal skin tissues from sun-exposed lower leg, and may play a role in gene transcription regulation.	('combination', 'Interaction', (341, 352))	('lower leg', 'Phenotype', 'HP:0006385', (513, 522))	('regulation', 'biological_process', 'GO:0065007', ('254', '264'))	('binding', 'molecular_function', 'GO:0005488', ('378', '385'))	('rs17204952', 'Var', (211, 221))	('play', 'Reg', (532, 536))	('transcription', 'biological_process', 'GO:0006351', ('552', '565'))	('rs17204952', 'Mutation', 'rs17204952', (19, 29))	('role', 'Reg', (539, 543))	('gene transcriptional regulation', 'MPA', (233, 264))	('RORA', 'Gene', '6095', (95, 99))	('DNMT1', 'Gene', '1786', (408, 413))	('assisting', 'PosReg', (324, 333))	('RORA', 'Gene', '6095', (14, 18))	('rs782917', 'Mutation', 'rs782917', (198, 206))	('enhancer', 'PosReg', (307, 315))	('DNMT1', 'Gene', '1786', (462, 467))	('rs17204952', 'Var', (19, 29))	('men', 'Species', '9606', (295, 298))	('rs7253062', 'Mutation', 'rs7253062', (414, 423))	('affect', 'Reg', (226, 232))	('rs782917', 'Var', (198, 206))	('histone', 'MPA', (268, 275))	('histone modification', 'biological_process', 'GO:0016570', ('268', '288'))	('DNMT1', 'Gene', (408, 413))	('mRNA expression levels', 'MPA', (69, 91))	('rs7253062', 'Var', (414, 423))	('DNMT1', 'Gene', (462, 467))	('decreased', 'NegReg', (59, 68))	('rs17204952', 'Mutation', 'rs17204952', (211, 221))	('regulation', 'biological_process', 'GO:0065007', ('566', '576'))	('RORA', 'Gene', (95, 99))	('DNA', 'cellular_component', 'GO:0005574', ('395', '398'))	('RORA', 'Gene', (14, 18))
61959	29313974	The deletion or reduction of DNMT1 leads to substantial genome-wide hypomethylation and chromosomal instability in human tumors.	('chromosomal', 'MPA', (88, 99))	('genome-wide hypomethylation', 'MPA', (56, 83))	('DNMT1', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('reduction', 'NegReg', (16, 25))	('DNMT1', 'Gene', '1786', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('deletion', 'Var', (4, 12))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
61960	29313974	Recent studies have identified associations between DNMT1 dysregulation, melanomagenesis, and melanocyte malignant transformation.	('DNMT1', 'Gene', (52, 57))	('melanoma', 'Disease', (73, 81))	('DNMT1', 'Gene', '1786', (52, 57))	('associations', 'Interaction', (31, 43))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanocyte malignant transformation', 'CPA', (94, 129))	('dysregulation', 'Var', (58, 71))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
61961	29313974	In addition, DNMT1 silencing is associated with reductions in the mesenchymal properties and invasive potential of melanoma cells.	('mesenchymal properties', 'CPA', (66, 88))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('silencing', 'Var', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('DNMT1', 'Gene', (13, 18))	('reductions', 'NegReg', (48, 58))	('DNMT1', 'Gene', '1786', (13, 18))
61963	29313974	Previous studies have showed that changes in DNA methylation of cancer related genes can be an elementary process accounting for tumorigenesis.	('men', 'Species', '9606', (98, 101))	('changes in DNA methylation', 'biological_process', 'GO:0044728', ('34', '60'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('DNA', 'MPA', (45, 48))	('changes', 'Var', (34, 41))	('tumor', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
61964	29313974	The polymorphisms of the DNMT1 gene rs2228611 contributes to favorable prognosis in gastric cancer.	('rs2228611', 'Mutation', 'rs2228611', (36, 45))	('DNMT1', 'Gene', '1786', (25, 30))	('gastric cancer', 'Disease', (84, 98))	('rs2228611', 'Var', (36, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('DNMT1', 'Gene', (25, 30))
61965	29313974	The DNMT1 rs2228611 and rs759920 SNPs are associated with an increased risk of ovarian cancer development.	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('associated', 'Reg', (42, 52))	('rs759920', 'Var', (24, 32))	('rs2228611', 'Mutation', 'rs2228611', (10, 19))	('men', 'Species', '9606', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('DNMT1', 'Gene', (4, 9))	('rs2228611', 'Var', (10, 19))	('rs759920', 'Mutation', 'rs759920', (24, 32))	('ovarian cancer', 'Disease', (79, 93))	('DNMT1', 'Gene', '1786', (4, 9))
61972	29313974	Here, the authors identified three independent SHR-related genes SNPs (RORA rs782917 G>A, RORA rs17204952 C>T and DNMT1 rs7253062 G>A) as potential predictors of cutaneous melanoma-specific survival.	('rs7253062 G>A', 'Var', (120, 133))	('DNMT1', 'Gene', (114, 119))	('RORA', 'Gene', (90, 94))	('cutaneous melanoma', 'Disease', (162, 180))	('RORA', 'Gene', '6095', (90, 94))	('rs7253062', 'Mutation', 'rs7253062', (120, 129))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (162, 180))	('DNMT1', 'Gene', '1786', (114, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('RORA', 'Gene', (71, 75))	('rs17204952', 'Mutation', 'rs17204952', (95, 105))	('RORA', 'Gene', '6095', (71, 75))	('rs782917', 'Mutation', 'rs782917', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('SHR-related genes', 'Gene', (47, 64))
62037	29757889	As depicted in Figure 2C (left graph), TIL lines such as TIL#3102 and #3103 expanded more CD3- (grey bar), most likely NK cells, when the propagation was executed with anti-4-1BB alone.	('#3103', 'Var', (70, 75))	('4-1BB', 'Gene', '3604', (173, 178))	('CD3', 'Gene', (90, 93))	('expanded', 'PosReg', (76, 84))	('TIL#3102', 'Var', (57, 65))	('CD3', 'Gene', '12501', (90, 93))	('4-1BB', 'Gene', (173, 178))
62038	29757889	On the other hand, the combination with OKT3 gave rise to a more uniform CD3+ T-cell product (Figure 2C, left graph).	('CD3', 'Gene', (73, 76))	('more', 'PosReg', (60, 64))	('CD3', 'Gene', '12501', (73, 76))	('combination', 'Var', (23, 34))
62053	29757889	Thus, providing the 3 signals attributed to T-cell activation lead to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma.	('uveal melanoma', 'Disease', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('T-cell activation', 'biological_process', 'GO:0042110', ('44', '61'))	('tumor', 'Disease', (116, 121))	('expansion', 'Var', (70, 79))	('uveal melanoma', 'Phenotype', 'HP:0007716', (151, 165))	('uveal melanoma', 'Disease', 'MESH:C536494', (151, 165))
62068	29757889	NK cells can also be stimulated through targeting the 4-1BB axis, which is what was observed when 4-1BB was targeted alone.	('targeting', 'Var', (40, 49))	('4-1BB', 'Gene', (54, 59))	('4-1BB', 'Gene', '3604', (98, 103))	('4-1BB', 'Gene', '3604', (54, 59))	('NK cells', 'CPA', (0, 8))	('stimulated', 'PosReg', (21, 31))	('4-1BB', 'Gene', (98, 103))
62140	32508531	8b) and statistical results suggested that higher expression levels (tail 80 samples) of CXCL9, CXCL10, CXCL13, CCL4, CCL5 were related to more patients of lower Breslow depth (0-1.5 mm, 51.2%), BRAF mutation (60%) and lower Clark levels (I-III 45% and IV-V, 55%), reduced T4 stage (T4, 25%).	('reduced', 'NegReg', (265, 272))	('lower', 'NegReg', (219, 224))	('CCL5', 'Gene', (118, 122))	('CCL', 'molecular_function', 'GO:0044101', ('118', '121'))	('lower', 'NegReg', (156, 161))	('CXCL13', 'Gene', '10563', (104, 110))	('T4 stage', 'CPA', (273, 281))	('CXCL10', 'Gene', '3627', (96, 102))	('mutation', 'Var', (200, 208))	('reduced T4', 'Phenotype', 'HP:0000821', (265, 275))	('CXCL13', 'Gene', (104, 110))	('higher', 'PosReg', (43, 49))	('CCL4', 'Gene', '6351', (112, 116))	('expression levels', 'MPA', (50, 67))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('CXCL10', 'Gene', (96, 102))	('CXCL9', 'Gene', (89, 94))	('Clark levels', 'MPA', (225, 237))	('CCL5', 'Gene', '6352', (118, 122))	('CCL', 'molecular_function', 'GO:0044101', ('112', '115'))	('patients', 'Species', '9606', (144, 152))	('Breslow depth', 'CPA', (162, 175))	('CCL4', 'Gene', (112, 116))	('CXCL9', 'Gene', '4283', (89, 94))
62143	32508531	As a result, there were nearly 6% (CXCL9), 5% (CXCL10), 3% (CXCL13), 4% (CCL4), 5% (CCL5), 3% (NMU), 4% (GAL) of SKCM samples had genetic alteration.	('CXCL13', 'Gene', '10563', (60, 66))	('CCL4', 'Gene', (73, 77))	('CXCL9', 'Gene', '4283', (35, 40))	('genetic alteration', 'Var', (130, 148))	('CXCL10', 'Gene', '3627', (47, 53))	('CXCL10', 'Gene', (47, 53))	('CCL', 'molecular_function', 'GO:0044101', ('73', '76'))	('GAL', 'Gene', (105, 108))	('CXCL9', 'Gene', (35, 40))	('GAL', 'Gene', '51083', (105, 108))	('CCL5', 'Gene', (84, 88))	('SKCM', 'Chemical', '-', (113, 117))	('CXCL13', 'Gene', (60, 66))	('CCL4', 'Gene', '6351', (73, 77))	('NMU', 'Gene', '10874', (95, 98))	('CCL', 'molecular_function', 'GO:0044101', ('84', '87'))	('NMU', 'Gene', (95, 98))	('CCL5', 'Gene', '6352', (84, 88))
62145	32508531	While genetic change in GAL and NMU were mainly related to amplification.	('GAL', 'Gene', (24, 27))	('GAL', 'Gene', '51083', (24, 27))	('NMU', 'Gene', '10874', (32, 35))	('amplification', 'Var', (59, 72))	('NMU', 'Gene', (32, 35))	('genetic change', 'Var', (6, 20))
62289	22825502	In laboratory studies, selenium compounds have been shown to induce immunotoxicity, genotoxicity and oxidative stress at doses as low as those found in our study, and to affect Akt enzymatic activity  and p53 expression, mechanisms which have been implicated in melanoma etiopathogenesis , although neither of these effects clearly confirms a specific activity of selenium in inducing melanoma onset or progression.	('toxicity', 'Disease', (74, 82))	('expression', 'MPA', (209, 219))	('melanoma onset', 'Disease', 'MESH:D008545', (385, 399))	('toxicity', 'Disease', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))	('melanoma', 'Disease', 'MESH:D008545', (385, 393))	('melanoma', 'Disease', (262, 270))	('selenium', 'Chemical', 'MESH:D012643', (23, 31))	('selenium', 'Var', (23, 31))	('p53', 'Gene', '7157', (205, 208))	('oxidative stress', 'Phenotype', 'HP:0025464', (101, 117))	('selenium', 'Chemical', 'MESH:D012643', (364, 372))	('progression', 'CPA', (403, 414))	('melanoma onset', 'Disease', (385, 399))	('p53', 'Gene', (205, 208))	('affect', 'Reg', (170, 176))	('Akt', 'Gene', (177, 180))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('induce', 'Reg', (61, 67))	('melanoma', 'Disease', (385, 393))	('Akt', 'Gene', '207', (177, 180))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('melanoma', 'Phenotype', 'HP:0002861', (385, 393))	('inducing', 'Reg', (376, 384))	('toxicity', 'Disease', 'MESH:D064420', (88, 96))
62291	22825502	Selenium has also been shown to be carcinogenic in some studies, but none of these investigations included animal or in vitro models of cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('carcinogenic', 'Disease', 'MESH:D063646', (35, 47))	('carcinogenic', 'Disease', (35, 47))	('cutaneous melanoma', 'Disease', (136, 154))	('Selenium', 'Var', (0, 8))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))
62461	28966807	Genetic studies in Gorlin syndrome (or nevoid basal cell carcinoma syndrome), an inherited condition with increased risk of developing BCC, identified germline mutations in the Hedgehog (Hh) signalling pathway.	('BCC', 'Phenotype', 'HP:0002671', (135, 138))	('Gorlin syndrome', 'Disease', (19, 34))	('basal cell carcinoma syndrome', 'Disease', 'MESH:D002280', (46, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (46, 66))	('Hh) signalling pathway', 'biological_process', 'GO:0007224', ('187', '209'))	('germline mutations', 'Var', (151, 169))	('Gorlin syndrome', 'Disease', 'MESH:D001478', (19, 34))	('basal cell carcinoma syndrome', 'Disease', (46, 75))
62464	28966807	BCC carcinogenesis is characterized by aberrant activation of the Hh pathway, resulting from either genetic inactivation of PTCH or activating mutations in SMO.	('SMO', 'Gene', '6608', (156, 159))	('BCC carcinogenesis', 'Disease', 'MESH:D063646', (0, 18))	('Hh pathway', 'Pathway', (66, 76))	('genetic inactivation', 'Var', (100, 120))	('SMO', 'Gene', (156, 159))	('activation', 'PosReg', (48, 58))	('PTCH', 'Gene', '5727', (124, 128))	('BCC', 'Phenotype', 'HP:0002671', (0, 3))	('BCC carcinogenesis', 'Disease', (0, 18))	('PTCH', 'Gene', (124, 128))	('activating', 'PosReg', (132, 142))
62566	28966807	This melanoma sub-group presents a variable molecular profile, with KIT and NRAS gene mutations, with an initially more radial, intraepidermal (in-situ) growth pattern.	('mutations', 'Var', (86, 95))	('NRAS', 'Gene', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('NRAS', 'Gene', '4893', (76, 80))	('growth pattern', 'biological_process', 'GO:0040007', ('153', '167'))	('growth pattern', 'biological_process', 'GO:0007150', ('153', '167'))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('KIT', 'Gene', (68, 71))
62570	28966807	If left undiagnosed and un-treated, lentigo-maligna and superficial spreading melanoma variants progress over a variable time-period (years) from in situ-stages, to frank, invasive tumours, switching to a vertical growth phase, with the risk of loco-regional (lymphatic) or systemic (hematogenous) dissemination.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('superficial spreading melanoma', 'Phenotype', 'HP:0012057', (56, 86))	('variants', 'Var', (87, 95))	('superficial spreading', 'Disease', (56, 77))	('progress', 'PosReg', (96, 104))	('lentigo-maligna', 'Disease', (36, 51))	('invasive tumours', 'Disease', (172, 188))	('lentigo-maligna', 'Disease', 'MESH:D018327', (36, 51))	('melanoma', 'Disease', (78, 86))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('systemic', 'CPA', (274, 282))	('invasive tumours', 'Disease', 'MESH:D009361', (172, 188))
62788	23533572	The final concentration of the gel reagents used were the following: acrylamide-bisacrylamide 3-0.08%, 125 mM Tris-HCl pH 8.8, 0.1% SDS (w/v), 0.1% ammonium persulphate (w/v), 0.07% TEMED (v/v) in the stacking gel and 600 mM Tris-HCl pH 6.8, 0.078% SDS (w/v), 0.045% ammonium persulphate (w/v), 0.047% TEMED (v/v) in the resolving gradient gel.	('0.078%', 'Var', (242, 248))	('SDS', 'Chemical', 'MESH:D012967', (249, 252))	('0.047%', 'Var', (295, 301))	('acrylamide-bisacrylamide', 'Chemical', '-', (69, 93))	('0.045%', 'Var', (260, 266))	('SDS', 'Chemical', 'MESH:D012967', (132, 135))
62827	23533572	Regarding the experiments involving the use of animals, the experimental procedures were performed as described in the protocol deposited according to Decreto Legislativo 116/92 at the review board of Universita Cattolica del Sacro Cuore, Roma, approved with the identification number A39B.	('Reg', 'Gene', (0, 3))	('Roma', 'Disease', 'None', (239, 243))	('Roma', 'Disease', (239, 243))	('A39B', 'SUBSTITUTION', 'None', (285, 289))	('Reg', 'Gene', '5967', (0, 3))	('A39B', 'Var', (285, 289))
62870	23533572	4B, C and D, alpha2MG was reproducibly down-regulated in both human and mice melanoma vs healthy controls, while two lipoproteins (Apo E and Apo A1) were reproducibly up-regulated, in both human and mice melanoma vs healthy controls.	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('mice', 'Species', '10090', (199, 203))	('melanoma', 'Disease', (204, 212))	('human', 'Species', '9606', (189, 194))	('human', 'Species', '9606', (62, 67))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('alpha2MG', 'Var', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('mice', 'Species', '10090', (72, 76))	('Apo', 'Gene', (141, 144))	('up-regulated', 'PosReg', (167, 179))	('down-regulated', 'NegReg', (39, 53))
62896	23533572	One of the most significantly modified proteins, down-regulated in melanoma, was identified as alpha2MG, a potent protease inhibitor able to modulate several cellular processes, including cell adhesion, proliferation, migration and invasion, key processes involved in cancer progression -.	('cell adhesion', 'CPA', (188, 201))	('cancer', 'Disease', (268, 274))	('modulate', 'Reg', (141, 149))	('proliferation', 'CPA', (203, 216))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('invasion', 'CPA', (232, 240))	('melanoma', 'Disease', (67, 75))	('down-regulated', 'NegReg', (49, 63))	('alpha2MG', 'Var', (95, 103))	('migration', 'CPA', (218, 227))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cell adhesion', 'biological_process', 'GO:0007155', ('188', '201'))	('proteins', 'Protein', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (268, 274))
62903	23533572	The involvement of alpha2MG in aggressiveness of human cancer cells was hypothesized by in vitro studies, but the results of the present study represent the first in vivo evidence from a murine melanoma model confirmed in human patients, suggesting alpha2MG, Apo E and Apo A1 as novel potential serum predictors in cutaneous melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (325, 333))	('melanoma', 'Disease', (325, 333))	('Apo E', 'Gene', (259, 264))	('human', 'Species', '9606', (49, 54))	('patients', 'Species', '9606', (228, 236))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('cutaneous melanoma', 'Disease', (315, 333))	('human', 'Species', '9606', (222, 227))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (315, 333))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (315, 333))	('cancer', 'Disease', (55, 61))	('murine', 'Species', '10090', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('melanoma', 'Disease', 'MESH:D008545', (325, 333))	('alpha2MG', 'Var', (249, 257))	('aggressiveness', 'Disease', (31, 45))	('patients', 'Species', '9606', (334, 342))	('aggressiveness', 'Phenotype', 'HP:0000718', (31, 45))	('aggressiveness', 'Disease', 'MESH:D001523', (31, 45))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('Apo A1', 'Gene', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
62977	29464914	The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status.	('positive', 'Var', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
62982	29464914	In analyses leading to the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) melanoma staging system, the presence of ulceration was shown to be an independent adverse predictor of survival in stages I-III melanoma and thus was incorporated into the AJCC staging system 2.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('presence', 'Var', (126, 134))	('melanoma', 'Disease', (226, 234))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
62984	29464914	Meanwhile, associations between the presence of microscopic satellitosis (MS) and disease-free survival (DFS)/recurrence-free survival (RFS) have been consistently significant in several studies.	('disease-free', 'Disease', (82, 94))	('associations', 'Interaction', (11, 23))	('presence', 'Var', (36, 44))	('satellitosis', 'Disease', (60, 72))	('significant', 'Reg', (164, 175))	('satellitosis', 'Disease', 'None', (60, 72))
62987	29464914	Therefore, the purpose of this study was to evaluate the importance of ulceration width and other important pathological measurements such as LVI, MS, PNI, and mitotic rate in terms of SLN positivity, RFS, and MSS for patients with cutaneous melanoma in the SLN era.	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('patients', 'Species', '9606', (218, 226))	('positivity', 'Var', (189, 199))	('cutaneous melanoma', 'Disease', (232, 250))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (232, 250))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 250))
62989	29464914	In our institution, in general, all the patients with invasive melanoma with AJCC 7th edition stages T1b and above, as well as at least T1a (i.e., tumor with Breslow thickness <1 mm without mitotic rate or ulceration, but was transected at the base), are offered SLN biopsy in addition to wide local excision of the lesion.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('invasive melanoma', 'Disease', (54, 71))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('invasive melanoma', 'Disease', 'MESH:D008545', (54, 71))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('T1b', 'Var', (101, 104))
63032	29464914	The presence of LVI was the second strongest independent predictor for SLN positivity after thicker tumor thickness, but it did not independently predict RFS or MSS when adjusting for other factors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('SLN', 'MPA', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('positivity', 'Var', (75, 85))
63034	29464914	The sensitivity of detection of lymphatic invasion can be increased using immunohistochemistry, ranging from 16 to 33% with D2-40 (podoplanin) 12, 13, 14, 16, and ranging from 37 to 43% with dual staining for D2-40 and S-100 17, or D2-40 and MITF 16, which makes it easier to distinguish melanoma cells from hematopoietic cells within lymphatic vessels.	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('D2-40', 'Var', (124, 129))	('melanoma cells', 'Disease', 'MESH:D008545', (288, 302))	('lymphatic invasion', 'CPA', (32, 50))	('melanoma cells', 'Disease', (288, 302))
63045	25407517	A Primary Melanoma and its Asynchronous Metastasis Highlight the Role of BRAF, CDKN2A, and TERT Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remain unclear.	('CDKN2A', 'Gene', '1029', (79, 85))	('TERT', 'Gene', (148, 152))	('TERT', 'Gene', '7015', (148, 152))	('BRAF', 'Gene', (73, 77))	('Melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('CDKN2A', 'Gene', (136, 142))	('Primary Melanoma', 'Disease', (2, 18))	('contribute', 'Reg', (153, 163))	('TERT', 'Gene', (91, 95))	('TERT', 'Gene', '7015', (91, 95))	('CDKN2A', 'Gene', '1029', (136, 142))	('CDKN2A', 'Gene', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('BRAF', 'Gene', '673', (130, 134))	('Alterations', 'Var', (96, 107))	('BRAF', 'Gene', (130, 134))	('BRAF', 'Gene', '673', (73, 77))	('Primary Melanoma', 'Disease', 'MESH:D008545', (2, 18))
63048	25407517	Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('CDKN2A', 'Gene', (152, 158))	('cancer genome atlas', 'Disease', (56, 75))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('mutation', 'Var', (139, 147))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('CDKN2A', 'Gene', '1029', (152, 158))	('BRAF', 'Gene', '673', (134, 138))	('loss', 'NegReg', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('BRAF', 'Gene', (134, 138))	('melanomas', 'Disease', (93, 102))	('cancer genome atlas', 'Disease', 'MESH:D009369', (56, 75))
63051	25407517	In the TCGA melanoma cohort, there was a non-significant trend towards poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss.	('BRAF', 'Gene', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma cohort', 'Disease', 'MESH:D008545', (12, 27))	('mutation', 'Var', (151, 159))	('cutaneous melanoma', 'Disease', (101, 119))	('melanoma cohort', 'Disease', (12, 27))	('CDKN2A', 'Gene', (164, 170))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('patients', 'Species', '9606', (120, 128))	('CDKN2A', 'Gene', '1029', (164, 170))	('BRAF', 'Gene', '673', (146, 150))	('loss', 'NegReg', (171, 175))
63052	25407517	BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma.	('CDKN2A', 'Gene', '1029', (18, 24))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('BRAF', 'Gene', '673', (0, 4))	('TERT', 'Gene', (49, 53))	('BRAF', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (49, 53))	('loss', 'NegReg', (25, 29))	('CDKN2A', 'Gene', (18, 24))	('mutation', 'Var', (5, 13))
63056	25407517	Activating mutations in BRAF occur in approximately one-half of malignant melanomas and less frequently in benign and atypical Spitzoid tumors (2-28%).	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('Activating mutations', 'Var', (0, 20))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('Spitzoid tumors', 'Disease', (127, 142))	('malignant melanomas', 'Phenotype', 'HP:0002861', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('malignant melanomas', 'Disease', 'MESH:D008545', (64, 83))	('Spitzoid tumors', 'Disease', 'MESH:D009369', (127, 142))	('malignant melanomas', 'Disease', (64, 83))
63057	25407517	A subset of Spitzoid melanocytic tumors, those with loss of BAP1 expression, more commonly have activating BRAF mutations.	('BRAF', 'Gene', (107, 111))	('loss', 'NegReg', (52, 56))	('activating', 'PosReg', (96, 106))	('Spitzoid melanocytic tumors', 'Disease', (12, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (112, 121))	('BAP1', 'Gene', '8314', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('Spitzoid melanocytic tumors', 'Disease', 'MESH:D009508', (12, 39))	('BRAF', 'Gene', '673', (107, 111))	('BAP1', 'Gene', (60, 64))
63058	25407517	Studies of cutaneous melanomas and nevi have demonstrated that activating mutations in BRAF occur as one of the earliest events in melanoma development; however, they are not sufficient for full transformation.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (11, 30))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('cutaneous melanomas', 'Disease', (11, 30))	('nevi', 'Phenotype', 'HP:0003764', (35, 39))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('melanoma', 'Disease', (21, 29))	('BRAF', 'Gene', (87, 91))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('activating mutations', 'Var', (63, 83))	('BRAF', 'Gene', '673', (87, 91))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (11, 30))
63059	25407517	A germinal melanoma with initiating oncogenic mutations, like an activating BRAF mutation, must acquire additional mutations prior to becoming fully transformed.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('mutations', 'Var', (46, 55))	('mutation', 'Var', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
63060	25407517	Mutation of tumor suppressors, including CDKN2A, PTEN, TP53 and BAP1, frequently represent potent secondary genetic changes that promote further tumorigenesis.	('PTEN', 'Gene', '5728', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('promote', 'PosReg', (129, 136))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('BAP1', 'Gene', '8314', (64, 68))	('CDKN2A', 'Gene', (41, 47))	('tumor', 'Disease', (12, 17))	('CDKN2A', 'Gene', '1029', (41, 47))	('PTEN', 'Gene', (49, 53))	('BAP1', 'Gene', (64, 68))
63061	25407517	Loss, mutation, or methylation of the CDKN2A locus occurs in most melanomas.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('methylation', 'Var', (19, 30))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('mutation', 'Var', (6, 14))	('Loss', 'NegReg', (0, 4))	('melanomas', 'Disease', (66, 75))	('CDKN2A', 'Gene', (38, 44))	('CDKN2A', 'Gene', '1029', (38, 44))
63062	25407517	Specifically, germline mutations in CDKN2A remain the most widely recognized cause of inherited melanoma susceptibility, and loss of the 9p21 locus, containing the CDKN2A allele, has been associated with poor prognosis in both cutaneous melanoma and atypical Spitz tumors.	('CDKN2A', 'Gene', (36, 42))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('CDKN2A', 'Gene', '1029', (164, 170))	('Spitz tumors', 'Disease', (259, 271))	('loss', 'Var', (125, 129))	('CDKN2A', 'Gene', '1029', (36, 42))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('germline mutations', 'Var', (14, 32))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('melanoma', 'Disease', (237, 245))	('cutaneous melanoma', 'Disease', (227, 245))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (227, 245))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (227, 245))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('Spitz tumors', 'Disease', 'MESH:D018332', (259, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('CDKN2A', 'Gene', (164, 170))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
63064	25407517	Thus, the aberrant activation of telomerase is another molecular alteration frequently found during the development of melanoma.	('aberrant', 'Var', (10, 18))	('activation', 'PosReg', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('telomerase', 'Protein', (33, 43))
63066	25407517	More recently, activating mutations in the core promoter of TERT, the catalytic subunit of telomerase, have been found in ~40-70% of melanomas and are independently associated with poor prognosis.	('melanomas', 'Disease', (133, 142))	('TERT', 'Gene', '7015', (60, 64))	('associated', 'Reg', (165, 175))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('mutations', 'Var', (26, 35))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('activating', 'PosReg', (15, 25))	('core', 'cellular_component', 'GO:0019013', ('43', '47'))	('TERT', 'Gene', (60, 64))
63083	25407517	We utilized the clinical information (time of diagnosis, time of death, tumor stage, gender, age), data on somatic mutations in BRAF (V600E or K601E) and copy number changes.	('K601E', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('BRAF', 'Gene', '673', (128, 132))	('V600E', 'Var', (134, 139))	('K601E', 'Mutation', 'rs121913364', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('BRAF', 'Gene', (128, 132))
63088	25407517	Among these groups, we studied the effect of CDKN2A deletion among the patients concomitantly bearing (or not bearing) a BRAF mutation using a significance of alpha= 0.0083 after employing the Bonferroni correction for multiple comparisons.	('BRAF', 'Gene', (121, 125))	('patients', 'Species', '9606', (71, 79))	('mutation', 'Var', (126, 134))	('CDKN2A', 'Gene', (45, 51))	('BRAF', 'Gene', '673', (121, 125))	('deletion', 'Var', (52, 60))	('CDKN2A', 'Gene', '1029', (45, 51))
63106	25407517	Sanger sequencing confirmed the presence of a mutation (c.1799T>A, p.600V>E) in the metastasis.	('c.1799T>A', 'Mutation', 'rs113488022', (56, 65))	('c.1799T>A', 'Var', (56, 65))	('p.600V>E', 'Mutation', 'rs113488022', (67, 75))	('p.600V>E', 'Var', (67, 75))
63107	25407517	The concordance of the BRAF mutation of the primary and metastatic lesion is consistent with that of another recent study.	('mutation', 'Var', (28, 36))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (23, 27))
63110	25407517	A subset of atypical Spitz tumors characterized by BRAF mutations and loss of BAP1 expression has been described.	('Spitz tumors', 'Disease', 'MESH:D018332', (21, 33))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (56, 65))	('loss', 'NegReg', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Spitz tumors', 'Disease', (21, 33))	('BRAF', 'Gene', '673', (51, 55))	('BAP1', 'Gene', '8314', (78, 82))	('expression', 'MPA', (83, 93))	('BRAF', 'Gene', (51, 55))	('BAP1', 'Gene', (78, 82))
63112	25407517	Both the primary melanoma and the metastatic lesion demonstrated strong nuclear staining by the BAP1 antibody throughout the lesions (data not shown), suggesting that homozygous loss or truncating mutations of BAP1 were absent in both lesions and did not contribute to the pathogenesis of this tumor.	('tumor', 'Disease', (294, 299))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('BAP1', 'Gene', (210, 214))	('BAP1', 'Gene', (96, 100))	('primary melanoma', 'Disease', (9, 25))	('primary melanoma', 'Disease', 'MESH:D008545', (9, 25))	('BAP1', 'Gene', '8314', (210, 214))	('pathogenesis', 'biological_process', 'GO:0009405', ('273', '285'))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('BAP1', 'Gene', '8314', (96, 100))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))	('truncating mutations', 'Var', (186, 206))
63117	25407517	Highly recurrent mutations of nucleotide 1,295,228 and 1,295,250 on chromosome 5 generate binding sites for ETS transcription factors in sporadic melanomas.	('melanomas', 'Disease', 'MESH:D008545', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('binding', 'Interaction', (90, 97))	('ETS transcription factors', 'Gene', (108, 133))	('melanomas', 'Disease', (146, 155))	('transcription', 'biological_process', 'GO:0006351', ('112', '125'))	('mutations', 'Var', (17, 26))
63118	25407517	While both sites were wild type in the primary melanoma, the metastatic melanoma demonstrated a C228T mutation by Sanger sequencing (Figure 4A).	('C228T', 'Var', (96, 101))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('metastatic', 'Disease', (61, 71))	('primary melanoma', 'Disease', 'MESH:D008545', (39, 55))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('primary melanoma', 'Disease', (39, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('C228T', 'Mutation', 'c.228C>T', (96, 101))
63119	25407517	Due to the limitations of tissue availability and Sanger sequencing, we cannot definitively exclude the presence of the TERT promoter mutations in a small proportion of the cells of the primary lesion.	('TERT', 'Gene', (120, 124))	('TERT', 'Gene', '7015', (120, 124))	('mutations', 'Var', (134, 143))
63126	25407517	Loss of CDKN2A has been associated with poor prognosis in cutaneous melanoma.	('CDKN2A', 'Gene', (8, 14))	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('CDKN2A', 'Gene', '1029', (8, 14))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('Loss', 'Var', (0, 4))
63127	25407517	While BRAF mutations predict poor prognosis in patients with metastatic disease, the effects of BRAF mutations on early stage disease is not clear.	('mutations', 'Var', (11, 20))	('metastatic disease', 'Disease', (61, 79))	('patients', 'Species', '9606', (47, 55))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('BRAF', 'Gene', (6, 10))
63128	25407517	Using TCGA survival cohorts, we have analyzed CDKN2A deletion and BRAF mutation in relationship to age, stage and gender.	('CDKN2A', 'Gene', (46, 52))	('deletion', 'Var', (53, 61))	('CDKN2A', 'Gene', '1029', (46, 52))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))
63129	25407517	Consistent with the literature, there was an association between younger age and BRAF mutations.	('mutations', 'Var', (86, 95))	('BRAF', 'Gene', (81, 85))	('BRAF', 'Gene', '673', (81, 85))
63130	25407517	The median age of patients carrying a BRAF mutation was 47 years compared to 58 years for those without mutations (Wilcoxon test p=2.98e-06).	('mutation', 'Var', (43, 51))	('BRAF', 'Gene', (38, 42))	('patients', 'Species', '9606', (18, 26))	('BRAF', 'Gene', '673', (38, 42))
63132	25407517	In contrast to existing data suggesting that BRAF mutation was associated with worse disease-free survival, we found that the presence of BRAF mutation correlated with better survival without reaching significance (HR=0.73, p=0.11, N=204).	('BRAF', 'Gene', '673', (138, 142))	('better', 'PosReg', (168, 174))	('mutation', 'Var', (143, 151))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (138, 142))	('mutation', 'Var', (50, 58))
63133	25407517	Existing studies suggest that CDKN2A locus loss predicts poor survival, but it is not clear how this effect relates to other genetic events such as an activating BRAF mutation and to the tumor stage.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('poor', 'NegReg', (57, 61))	('CDKN2A', 'Gene', (30, 36))	('mutation', 'Var', (167, 175))	('activating', 'PosReg', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CDKN2A', 'Gene', '1029', (30, 36))	('tumor', 'Disease', (187, 192))	('loss', 'NegReg', (43, 47))	('BRAF', 'Gene', '673', (162, 166))	('BRAF', 'Gene', (162, 166))
63134	25407517	In our dataset, CDKN2A locus deletion alone did not predict a worse prognosis, even though it trended in this direction (HR=1.25, p=0.26, N=231).	('deletion', 'Var', (29, 37))	('CDKN2A', 'Gene', '1029', (16, 22))	('CDKN2A', 'Gene', (16, 22))
63135	25407517	Among stage I cutaneous melanoma patients bearing BRAF mutations, the concomitant loss of CDKN2A did not significantly predict poor survival but also trended in this direction (HR=7.02, p=0.026, N=18).	('CDKN2A', 'Gene', '1029', (90, 96))	('BRAF', 'Gene', (50, 54))	('cutaneous melanoma', 'Disease', (14, 32))	('patients', 'Species', '9606', (33, 41))	('mutations', 'Var', (55, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (14, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (14, 32))	('loss', 'NegReg', (82, 86))	('CDKN2A', 'Gene', (90, 96))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('BRAF', 'Gene', '673', (50, 54))
63136	25407517	Similarly, in early stage cutaneous melanoma (stages I and II), the concomitant presence of BRAF mutation and loss of CDKN2A trended towards poor survival without reaching significance (HR=3.32, p=0.032, N=46) (Figure 5).	('CDKN2A', 'Gene', (118, 124))	('loss', 'NegReg', (110, 114))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (26, 44))	('BRAF', 'Gene', '673', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('CDKN2A', 'Gene', '1029', (118, 124))	('BRAF', 'Gene', (92, 96))	('cutaneous melanoma', 'Disease', (26, 44))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (26, 44))	('mutation', 'Var', (97, 105))	('poor', 'NegReg', (141, 145))
63137	25407517	CDKN2A deletion plus BRAF mutation did not predict poor survival among stage III and IV patients where it actually trended towards better survival (HR=0.60, p=0.31, N=32).	('CDKN2A', 'Gene', '1029', (0, 6))	('mutation', 'Var', (26, 34))	('patients', 'Species', '9606', (88, 96))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('stage III', 'Disease', (71, 80))	('better', 'PosReg', (131, 137))	('deletion', 'Var', (7, 15))	('CDKN2A', 'Gene', (0, 6))
63138	25407517	Thus, in the TCGA dataset, the loss of CDKN2A did not significantly affect survival regardless of BRAF mutation status.	('CDKN2A', 'Gene', (39, 45))	('loss', 'Var', (31, 35))	('CDKN2A', 'Gene', '1029', (39, 45))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('affect', 'Reg', (68, 74))
63140	25407517	We found that this patient's stage I melanoma harbored a mutation in BRAF and a loss of CDKN2A.	('mutation', 'Var', (57, 65))	('CDKN2A', 'Gene', (88, 94))	('patient', 'Species', '9606', (19, 26))	('CDKN2A', 'Gene', '1029', (88, 94))	('loss', 'NegReg', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('BRAF', 'Gene', '673', (69, 73))	('harbored', 'Reg', (46, 54))	('BRAF', 'Gene', (69, 73))
63143	25407517	However, using copy number variation data from the TCGA, we found that the loss of CDKN2A did not predict poor prognosis in cutaneous melanoma.	('CDKN2A', 'Gene', '1029', (83, 89))	('cutaneous melanoma', 'Disease', (124, 142))	('CDKN2A', 'Gene', (83, 89))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (124, 142))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('loss', 'Var', (75, 79))
63145	25407517	We do note that the loss of CDKN2A did trend towards poor prognosis, especially in the presence of an activating BRAF mutation.	('BRAF', 'Gene', '673', (113, 117))	('loss', 'Var', (20, 24))	('activating', 'PosReg', (102, 112))	('BRAF', 'Gene', (113, 117))	('CDKN2A', 'Gene', (28, 34))	('mutation', 'Var', (118, 126))	('CDKN2A', 'Gene', '1029', (28, 34))
63147	25407517	In contrast, BRAF mutation status and CDKN2A allele status are routinely assessed in pathology laboratories.	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('CDKN2A', 'Gene', (38, 44))	('mutation', 'Var', (18, 26))	('CDKN2A', 'Gene', '1029', (38, 44))
63148	25407517	Thus, determining the precise effects of activating BRAF mutations and CDKN2A loss on survival may reveal important prognostic factors in early stage cutaneous melanoma.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('CDKN2A', 'Gene', (71, 77))	('activating', 'PosReg', (41, 51))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('CDKN2A', 'Gene', '1029', (71, 77))	('mutations', 'Var', (57, 66))	('loss', 'NegReg', (78, 82))	('BRAF', 'Gene', '673', (52, 56))	('cutaneous melanoma', 'Disease', (150, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('BRAF', 'Gene', (52, 56))
63150	25407517	Because TERT promoter mutations are found more frequently in sun-exposed sites and show mutations that could be consistent with UV-induced cytidine-to-thymidine transitions, it has been suggested that these mutations might occur early in the development of cutaneous melanoma.	('cutaneous melanoma', 'Disease', (257, 275))	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('thymidine', 'Chemical', 'MESH:D013936', (151, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (257, 275))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (257, 275))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('mutations', 'Var', (22, 31))	('cytidine', 'Chemical', 'MESH:D003562', (139, 147))
63152	25407517	However, as C228T mutations are also frequently found in UV-protected internal malignancies, it is possible that the melanoma acquired its TERT promoter mutation after metastasizing.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('TERT', 'Gene', '7015', (139, 143))	('C228T', 'Mutation', 'c.228C>T', (12, 17))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('C228T', 'Var', (12, 17))	('malignancies', 'Disease', (79, 91))	('TERT', 'Gene', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
63153	25407517	Alternatively, the C228T mutant cells could have been present as a small subset of the primary lesion, which was not detected by Sanger sequencing, but then became the dominant cell type by the time the melanoma was metastatic.	('C228T', 'Mutation', 'c.228C>T', (19, 24))	('C228T', 'Var', (19, 24))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
63154	25407517	In either case, because both a BRAF mutation and loss of CDKN2A were present in the majority of the primary lesion by immunohistochemistry and FISH, respectively, it is likely that these changes preceded any TERT promoter activating mutation.	('TERT', 'Gene', (208, 212))	('TERT', 'Gene', '7015', (208, 212))	('loss', 'NegReg', (49, 53))	('CDKN2A', 'Gene', (57, 63))	('CDKN2A', 'Gene', '1029', (57, 63))	('BRAF', 'Gene', '673', (31, 35))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
63155	25407517	In addition to the identification of recurrent mutations in the TERT promoter in sporadic melanomas, recent studies have identified mutations in the POT1 telomere binding protein in families with inherited cutaneous melanoma.	('identified', 'Reg', (121, 131))	('protein', 'cellular_component', 'GO:0003675', ('171', '178'))	('telomere', 'cellular_component', 'GO:0005696', ('154', '162'))	('POT1', 'Gene', '25913', (149, 153))	('melanomas', 'Disease', 'MESH:D008545', (90, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (206, 224))	('telomere binding', 'biological_process', 'GO:0007003', ('154', '170'))	('melanomas', 'Disease', (90, 99))	('telomere binding', 'molecular_function', 'GO:0042162', ('154', '170'))	('POT1', 'Gene', (149, 153))	('inherited cutaneous melanoma', 'Disease', 'MESH:C562393', (196, 224))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('inherited cutaneous melanoma', 'Disease', (196, 224))	('mutations', 'Var', (132, 141))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('telomere', 'cellular_component', 'GO:0000781', ('154', '162'))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
63156	25407517	These mutations in POT1 appear to be loss-of-function mutants that impair telomere capping, which are also associated with increased telomere length.	('increased', 'PosReg', (123, 132))	('telomere', 'cellular_component', 'GO:0005696', ('133', '141'))	('POT1', 'Gene', '25913', (19, 23))	('telomere', 'cellular_component', 'GO:0000781', ('133', '141'))	('POT1', 'Gene', (19, 23))	('increased telomere length', 'Phenotype', 'HP:0031413', (123, 148))	('telomere', 'cellular_component', 'GO:0000781', ('74', '82'))	('telomere capping', 'MPA', (74, 90))	('telomere capping', 'biological_process', 'GO:0016233', ('74', '90'))	('impair', 'NegReg', (67, 73))	('telomere', 'cellular_component', 'GO:0005696', ('74', '82'))	('mutations', 'Var', (6, 15))
63157	25407517	Separate epidemiologic studies have suggested that increased telomere length might be a risk factor for the development of nevi and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('nevi', 'Disease', (123, 127))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('telomere length', 'Var', (61, 76))	('increased', 'PosReg', (51, 60))	('telomere', 'cellular_component', 'GO:0000781', ('61', '69'))	('nevi', 'Phenotype', 'HP:0003764', (123, 127))	('increased telomere length', 'Phenotype', 'HP:0031413', (51, 76))	('telomere', 'cellular_component', 'GO:0005696', ('61', '69'))
63161	25407517	Finally, heterogeneous or increased telomere length might simply be a marker of telomere uncapping, which would be the primary driver of genomic instability and aneuploidy.	('telomere', 'MPA', (36, 44))	('telomere', 'cellular_component', 'GO:0000781', ('36', '44'))	('telomere', 'cellular_component', 'GO:0000781', ('80', '88'))	('increased telomere length', 'Phenotype', 'HP:0031413', (26, 51))	('telomere', 'cellular_component', 'GO:0005696', ('36', '44'))	('aneuploidy', 'Disease', 'MESH:D000782', (161, 171))	('telomere', 'cellular_component', 'GO:0005696', ('80', '88'))	('telomere uncapping', 'CPA', (80, 98))	('increased', 'PosReg', (26, 35))	('heterogeneous', 'Var', (9, 22))	('aneuploidy', 'Disease', (161, 171))
63167	25407517	Analysis of the recurrent patterns of copy number changes indicates that these frequent events represent potent drivers selected during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('copy', 'Var', (38, 42))
63168	25407517	Through the analysis of large genomic datasets, it will be important to determine how the different copy number changes interact with each other and with other genetic events to influence tumor behavior and clinical outcome.	('tumor', 'Disease', (188, 193))	('changes', 'Var', (112, 119))	('interact', 'Reg', (120, 128))	('influence', 'Reg', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('copy number changes', 'Var', (100, 119))
63171	25407517	In the early stages of tumorigenesis, telomere dysfunction, which usually occurs in the absences of telomerase, in combination with other genetic changes drives genomic instability, aneuploidization, and the development of cancerous cellular clones.	('development', 'CPA', (208, 219))	('genomic', 'MPA', (161, 168))	('telomere', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('telomere', 'cellular_component', 'GO:0005696', ('38', '46'))	('cancerous', 'Disease', 'MESH:D009369', (223, 232))	('aneuploidization', 'Var', (182, 198))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('drives', 'Reg', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('cancerous', 'Disease', (223, 232))	('telomere', 'cellular_component', 'GO:0000781', ('38', '46'))
63172	25407517	Late in tumor development, the reactivation of telomerase re-establishes telomere protection and promotes the growth of the aneuploid tumor.	('re-establishes', 'PosReg', (58, 72))	('telomerase', 'Protein', (47, 57))	('telomere', 'MPA', (73, 81))	('telomere', 'cellular_component', 'GO:0005696', ('73', '81'))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('telomere', 'cellular_component', 'GO:0000781', ('73', '81'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('aneuploid tumor', 'Disease', 'MESH:D000782', (124, 139))	('promotes', 'PosReg', (97, 105))	('tumor', 'Disease', (8, 13))	('aneuploid tumor', 'Disease', (124, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('reactivation', 'Var', (31, 43))	('growth', 'MPA', (110, 116))	('tumor', 'Disease', (134, 139))
63176	25407517	Subsequently, the upregulation of telomerase expression through mutations of the TERT promoter then stabilized the telomeres of the metastatic lesion resulting in less DNA damage at telomeres in the metastatic lesion.	('telomerase', 'Protein', (34, 44))	('less', 'NegReg', (163, 167))	('upregulation', 'PosReg', (18, 30))	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (81, 85))	('mutations', 'Var', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('DNA damage', 'MPA', (168, 178))
63177	25407517	In this model, the C228T TERT promoter mutation was acquired after aneuploidization to stabilize the genome of the metastatic melanoma.	('C228T', 'Mutation', 'c.228C>T', (19, 24))	('TERT', 'Gene', (25, 29))	('C228T', 'Var', (19, 24))	('TERT', 'Gene', '7015', (25, 29))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))
63192	31722735	Molecular biomarkers associated with a higher risk of metastasis are monosomy 3 or genomic alterations of BAP-1.	('genomic alterations', 'Var', (83, 102))	('monosomy 3', 'Var', (69, 79))	('BAP-1', 'Gene', '8314', (106, 111))	('BAP-1', 'Gene', (106, 111))
63217	31722735	Mutations and inactivations of MBD4 which were previously linked to a hypermutator profile with high sensitivity to PD-1 inhibition were not investigated in any case.	('PD-1', 'Gene', (116, 120))	('inactivations', 'Var', (14, 27))	('PD-1', 'Gene', '9825', (116, 120))	('Mutations', 'Var', (0, 9))	('MBD4', 'Gene', '8930', (31, 35))	('MBD4', 'Gene', (31, 35))
63283	25646071	We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma.	('cadmium', 'Chemical', 'MESH:D002104', (38, 45))	('epigenetic changes', 'Var', (54, 72))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('cell transformation', 'CPA', (77, 96))
63284	25646071	DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma.	('expression', 'MPA', (30, 40))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('rat', 'Species', '10116', (80, 83))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cadmium', 'Chemical', 'MESH:D002104', (128, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('methylation', 'Var', (4, 15))	('reduced', 'NegReg', (22, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
63304	25646071	Liver is the first organ to be reached and there cadmium activates MT production.	('cadmium', 'Chemical', 'MESH:D002104', (49, 56))	('activates', 'PosReg', (57, 66))	('cadmium', 'Var', (49, 56))	('MT production', 'MPA', (67, 80))
63320	25646071	Foulkes showed that, in rat jejunum, cadmium uptake was depressed by high concentrations of polyvalent cations, including Pb, Ni, Cr3+, Sr, and Mg .	('cadmium', 'Chemical', 'MESH:D002104', (37, 44))	('depressed', 'NegReg', (56, 65))	('rat', 'Species', '10116', (81, 84))	('uptake', 'biological_process', 'GO:0098739', ('45', '51'))	('cadmium uptake', 'MPA', (37, 51))	('Pb', 'Chemical', 'MESH:D007854', (122, 124))	('Sr', 'Chemical', 'MESH:D013324', (136, 138))	('uptake', 'biological_process', 'GO:0098657', ('45', '51'))	('Mg', 'Chemical', 'MESH:D008274', (144, 146))	('Cr3+', 'Var', (130, 134))	('rat', 'Species', '10116', (24, 27))
63367	25646071	Early signs of glomerular damage provoked by cadmium are increased excretion of albumin and transferrin.	('glomerular damage', 'Disease', (15, 32))	('cadmium', 'Chemical', 'MESH:D002104', (45, 52))	('glomerular damage', 'Disease', 'MESH:D007674', (15, 32))	('excretion', 'biological_process', 'GO:0007588', ('67', '76'))	('excretion of albumin', 'MPA', (67, 87))	('increased', 'PosReg', (57, 66))	('transferrin', 'Gene', '7018', (92, 103))	('transferrin', 'Gene', (92, 103))	('cadmium', 'Var', (45, 52))
63369	25646071	Glomerular filtration rate (GFR) decreases slowly but progressively and it's possible that cadmium accelerates the normal age-related decline in kidney function.	('Glomerular filtration', 'biological_process', 'GO:0003094', ('0', '21'))	('rat', 'Species', '10116', (15, 18))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (22, 25))	('kidney function', 'MPA', (145, 160))	('cadmium', 'Var', (91, 98))	('Glomerular filtration rate', 'MPA', (0, 26))	('cadmium', 'Chemical', 'MESH:D002104', (91, 98))
63384	25646071	When animals are pregnant, cadmium crosses the placenta inducing malformations in the newborns.	('cadmium', 'Chemical', 'MESH:D002104', (27, 34))	('cadmium', 'Var', (27, 34))	('malformations', 'Disease', 'MESH:D000014', (65, 78))	('malformations', 'Disease', (65, 78))	('inducing', 'Reg', (56, 64))
63399	25646071	Recent studies have indicated that cadmium, even at non-toxic concentrations, can induce inflammatory changes in the airways and in the vascular bed, and that these effects might be mediated by its ability to induce CXCL1 and CXCL2 chemokines.	('induce', 'Reg', (209, 215))	('cadmium', 'Var', (35, 42))	('CXCL2', 'Gene', (226, 231))	('induce', 'Reg', (82, 88))	('CXCL1', 'Gene', '2919', (216, 221))	('cadmium', 'Chemical', 'MESH:D002104', (35, 42))	('CXCL2', 'Gene', '2920', (226, 231))	('CXCL1', 'Gene', (216, 221))	('rat', 'Species', '10116', (69, 72))	('inflammatory changes', 'CPA', (89, 109))
63401	25646071	Further studies will be needed to ascertain whether cadmium can directly potentiate the activation of receptors of the innate immune system, including the Toll-like receptors and Nod-like receptors, leading to the induction of proinflammatory cytokines.	('activation', 'PosReg', (88, 98))	('cadmium', 'Var', (52, 59))	('cadmium', 'Chemical', 'MESH:D002104', (52, 59))	('induction', 'Reg', (214, 223))	('potentiate', 'PosReg', (73, 83))	('proinflammatory cytokines', 'MPA', (227, 252))
63408	25646071	Cadmium can activate oncogenes or genes associated with cell proliferation, such as c-myc, c-jun or c-fos, both in vivo and in vitro and it can also induce up-regulation of signal pathways resulting in increased mitogenesis, such as, for example, the AP-1 and MAP kinase pathways.	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('activate', 'PosReg', (12, 20))	('c-fos', 'Gene', (100, 105))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('AP-1', 'Gene', '2353', (251, 255))	('genes', 'Gene', (34, 39))	('MAP', 'molecular_function', 'GO:0004239', ('260', '263'))	('cell proliferation', 'CPA', (56, 74))	('c-myc', 'Gene', (84, 89))	('signal pathways', 'Pathway', (173, 188))	('c-jun', 'Gene', '3725', (91, 96))	('c-jun', 'Gene', (91, 96))	('increased', 'PosReg', (202, 211))	('Cadmium', 'Var', (0, 7))	('up-regulation', 'PosReg', (156, 169))	('AP-1', 'Gene', (251, 255))	('rat', 'Species', '10116', (68, 71))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('MAP kinase pathways', 'Pathway', (260, 279))	('AP-1', 'cellular_component', 'GO:0005907', ('251', '255'))	('c-fos', 'Gene', '2353', (100, 105))	('mitogenesis', 'MPA', (212, 223))	('oncogenes', 'Gene', (21, 30))	('c-myc', 'Gene', '4609', (84, 89))
63409	25646071	A direct action of cadmium on the expression of E-cadherin, a transmembrane Ca(II)-binding glycoprotein, has not been demonstrated yet, but the few available data indicate that cadmium may disrupt E- cadherin-dependent cell communication and promote cell division.	('transmembrane', 'cellular_component', 'GO:0016021', ('62', '75'))	('rat', 'Species', '10116', (125, 128))	('cell division', 'biological_process', 'GO:0051301', ('250', '263'))	('disrupt', 'NegReg', (189, 196))	('cadherin', 'molecular_function', 'GO:0008014', ('200', '208'))	('cell division', 'CPA', (250, 263))	('cadherin', 'molecular_function', 'GO:0008014', ('50', '58'))	('cadmium', 'Var', (177, 184))	('cell communication', 'biological_process', 'GO:0007154', ('219', '237'))	('binding', 'molecular_function', 'GO:0005488', ('83', '90'))	('E- cadherin', 'Gene', '999', (197, 208))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('E- cadherin', 'Gene', (197, 208))	('cadmium', 'Chemical', 'MESH:D002104', (177, 184))	('cadmium', 'Chemical', 'MESH:D002104', (19, 26))	('transmembrane', 'cellular_component', 'GO:0044214', ('62', '75'))	('promote', 'PosReg', (242, 249))
63416	25646071	But, nevertheless, the IARC (International Agency for Research on Cancer) classified cadmium as a group I carcinogen by virtue of its effect in inducing renal cancer.	('renal cancer', 'Disease', 'MESH:D007680', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('IARC', 'Disease', 'None', (23, 27))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cadmium', 'Var', (85, 92))	('IARC', 'Disease', (23, 27))	('renal cancer', 'Disease', (153, 165))	('cadmium', 'Chemical', 'MESH:D002104', (85, 92))	('inducing', 'PosReg', (144, 152))	('renal cancer', 'Phenotype', 'HP:0009726', (153, 165))
63420	25646071	Alterations in DNA mismatch repair genes have also been described.	('mismatch repair', 'biological_process', 'GO:0006298', ('19', '34'))	('Alterations', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('rat', 'Species', '10116', (4, 7))	('DNA mismatch repair genes', 'Gene', (15, 40))
63421	25646071	Moreover, cadmium was shown to interfere with the transcriptional machinery by substituting for zinc in some transcriptional factors .	('transcriptional', 'MPA', (50, 65))	('cadmium', 'Chemical', 'MESH:D002104', (10, 17))	('interfere', 'NegReg', (31, 40))	('substituting', 'Var', (79, 91))
63422	25646071	Epidemiological studies have provided further evidence that in addition to lung cancer, other cancers can be induced by cadmium.	('lung cancer', 'Disease', (75, 86))	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('induced', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('cadmium', 'Chemical', 'MESH:D002104', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))	('cadmium', 'Var', (120, 127))
63426	25646071	However cadmium can induce perturbations of genome stability through several indirect mechanisms, such as the production of reactive oxygen species (ROS), the disturbance of cellular signalling processes, DNA repair, mitotic cycle regulation, induction of apoptosis as well as epigenetic alterations, which may act together and lead to carcinogenesis.	('mitotic cycle regulation', 'CPA', (217, 241))	('rat', 'Species', '10116', (292, 295))	('DNA repair', 'CPA', (205, 215))	('cellular signalling processes', 'CPA', (174, 203))	('carcinogenesis', 'Disease', (336, 350))	('DNA repair', 'biological_process', 'GO:0006281', ('205', '215'))	('genome stability', 'CPA', (44, 60))	('cadmium', 'Chemical', 'MESH:D002104', (8, 15))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('disturbance', 'Reg', (159, 170))	('signalling', 'biological_process', 'GO:0023052', ('183', '193'))	('carcinogenesis', 'Disease', 'MESH:D063646', (336, 350))	('lead to', 'Reg', (328, 335))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('243', '265'))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (124, 147))	('apoptosis', 'CPA', (256, 265))	('epigenetic alterations', 'Var', (277, 299))	('regulation', 'biological_process', 'GO:0065007', ('231', '241'))
63437	25646071	Decreased antioxidant activities induce apoptosis and overproduction of ROS leads to inhibition of apoptosis.	('antioxidant activities', 'MPA', (10, 32))	('apoptosis', 'CPA', (40, 49))	('overproduction', 'Var', (54, 68))	('Decreased', 'NegReg', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('40', '49'))	('apoptosis', 'biological_process', 'GO:0006915', ('40', '49'))	('apoptosis', 'CPA', (99, 108))	('inhibition', 'NegReg', (85, 95))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('85', '108'))	('ROS', 'Gene', (72, 75))
63442	25646071	Recently, it has been shown that cadmium is able to induce apoptosis in naive alveolar epithelial cells, likely by a mechanism of oxidative stress.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('oxidative stress', 'Phenotype', 'HP:0025464', (130, 146))	('cadmium', 'Var', (33, 40))	('apoptosis', 'CPA', (59, 68))	('cadmium', 'Chemical', 'MESH:D002104', (33, 40))
63443	25646071	Indeed, cadmium may also affect antioxidative proteins, such as catalase and glutathione reductase, which have a crucial role in ROS elimination and induce, thereby, a reduction in cellular antioxidants and release of ROS by mitochondria.	('release of ROS by mitochondria', 'MPA', (207, 237))	('cellular antioxidants', 'MPA', (181, 202))	('ROS', 'Chemical', 'MESH:D017382', (218, 221))	('cadmium', 'Var', (8, 15))	('mitochondria', 'cellular_component', 'GO:0005739', ('225', '237'))	('antioxidative proteins', 'Enzyme', (32, 54))	('glutathione reductase', 'Gene', (77, 98))	('catalase', 'Gene', '847', (64, 72))	('glutathione reductase', 'Gene', '2936', (77, 98))	('cadmium', 'Chemical', 'MESH:D002104', (8, 15))	('catalase', 'Gene', (64, 72))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('reduction', 'NegReg', (168, 177))	('affect', 'Reg', (25, 31))
63444	25646071	Cadmium is believed to impair not only the repair of DNA damage caused by oxidative stress but also the repair of DNA double-strand breaks and DNA interstrand crosslinks.	('impair', 'NegReg', (23, 29))	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('Cadmium', 'Var', (0, 7))	('repair', 'MPA', (43, 49))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
63445	25646071	It is noteworthy that cadmium has been shown to act as a tumour "progressor" in mouse models of sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (96, 104))	('tumour', 'Disease', (57, 63))	('sarcomas', 'Disease', (96, 104))	('mouse', 'Species', '10090', (80, 85))	('cadmium', 'Var', (22, 29))	('cadmium', 'Chemical', 'MESH:D002104', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('sarcomas', 'Disease', 'MESH:D012509', (96, 104))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
63449	25646071	Cadmium exposure has been associated with tumors of the lung, testes, injection site, prostate, hematopoietic system, pancreas, adrenals, liver, kidney and pituitary and several of these sites concur with potential target sites of cadmium carcinogenesis in humans.	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('tumors of the lung', 'Disease', (42, 60))	('Cadmium', 'Var', (0, 7))	('pancreas', 'Disease', 'MESH:D010190', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('carcinogenesis', 'Disease', (239, 253))	('pancreas', 'Disease', (118, 126))	('cadmium', 'Chemical', 'MESH:D002104', (231, 238))	('humans', 'Species', '9606', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))	('Cadmium', 'Chemical', 'MESH:D002104', (0, 7))	('tumors of the lung', 'Disease', 'MESH:D008175', (42, 60))
63454	25646071	Instead, epigenetic events appear to be involved in the starting phase of heavy metal carcinogenesis by "writing" and "erasing" epigenetic signals at the promoter regions of several cancerous genes.	('carcinogenesis', 'Disease', (86, 100))	('epigenetic events', 'Var', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancerous', 'Disease', 'MESH:D009369', (182, 191))	('erasing', 'NegReg', (119, 126))	('metal', 'Chemical', 'MESH:D008670', (80, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('cancerous', 'Disease', (182, 191))	('involved', 'Reg', (40, 48))
63455	25646071	Epigenetic alterations regulate key events in cellular homeostasis, including transcriptional and translational regulation of gene expression.	('Epigenetic alterations', 'Var', (0, 22))	('regulate', 'Reg', (23, 31))	('rat', 'Species', '10116', (15, 18))	('cellular homeostasis', 'biological_process', 'GO:0019725', ('46', '66'))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('112', '141'))	('transcriptional', 'MPA', (78, 93))	('cellular homeostasis', 'MPA', (46, 66))	('translational regulation', 'MPA', (98, 122))
63456	25646071	The most well studied epigenetic alterations are DNA methylation, the covalent, post-translational modification of histones, and non-coding small RNAs (miRNAs).	('post-translational modification', 'MPA', (80, 111))	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('histones', 'Protein', (115, 123))	('rat', 'Species', '10116', (37, 40))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('covalent', 'MPA', (70, 78))	('non-coding small RNAs', 'Var', (129, 150))	('post-translational modification', 'biological_process', 'GO:0043687', ('80', '111'))	('DNA methylation', 'Var', (49, 64))	('methylation', 'Var', (53, 64))
63461	25646071	The carcinogenic potential of cadmium through epigenetic changes includes silencing of DNA repair and tumor-suppressor genes.	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('DNA repair', 'biological_process', 'GO:0006281', ('87', '97'))	('epigenetic changes', 'Var', (46, 64))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('DNA repair', 'Protein', (87, 97))	('silencing', 'NegReg', (74, 83))	('carcinogenic', 'Disease', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('cadmium', 'Chemical', 'MESH:D002104', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
63468	25646071	These data are of concern, since genome-wide methylation loss from LINE-1 promoter sites, which are normally heavily methylated at CpG sites, is considered as a frequent epigenetic change in malignancies and may play a role in carcinogenesis.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('LINE-1', 'Gene', (67, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (227, 241))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('methylation', 'Var', (45, 56))	('play', 'Reg', (212, 216))	('loss', 'NegReg', (57, 61))	('carcinogenesis', 'Disease', (227, 241))	('role', 'Reg', (219, 223))	('malignancies', 'Disease', (191, 203))
63470	25646071	The association between urinary cadmium and decreased LINE-1 methylation was stronger among carriers of the rare alleles of DNMT1 rs10854076 and rs2228611, indicating that cadmium effects can vary according to DNMT1 polymorphisms.	('cadmium', 'Chemical', 'MESH:D002104', (172, 179))	('DNMT1', 'Gene', (124, 129))	('stronger', 'PosReg', (77, 85))	('DNMT1', 'Gene', '1786', (124, 129))	('DNMT1', 'Gene', '1786', (210, 215))	('rs10854076', 'Var', (130, 140))	('rs10854076', 'Mutation', 'rs10854076', (130, 140))	('cadmium', 'Chemical', 'MESH:D002104', (32, 39))	('LINE-1', 'Gene', (54, 60))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('decreased', 'NegReg', (44, 53))	('rs2228611', 'Mutation', 'rs2228611', (145, 154))	('rs2228611', 'Var', (145, 154))	('DNMT1', 'Gene', (210, 215))
63474	25646071	Agglomerative DNA hypermethylation has been observed in different kinds of human tumors in association with a reduction in plasticity-associated gene transcription of consecutive genes.	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('reduction', 'NegReg', (110, 119))	('hypermethylation', 'Var', (18, 34))	('rat', 'Species', '10116', (7, 10))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('14', '34'))	('plasticity-associated gene transcription', 'MPA', (123, 163))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('human', 'Species', '9606', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
63477	25646071	Moreover, four key genes related to DNA repair, hMSH2, ERCC1, XRCC1, and hOGG1, were hypermethylated at the promoter and suppressed at the mRNA and protein levels in cadmium-transformed cells compared to controls.	('hOGG1', 'Gene', (73, 78))	('hMSH', 'molecular_function', 'GO:0018775', ('48', '52'))	('XRCC1', 'Gene', '7515', (62, 67))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('ERCC1', 'Gene', (55, 60))	('hypermethylated', 'Var', (85, 100))	('hOGG1', 'Gene', '4968', (73, 78))	('cadmium', 'Chemical', 'MESH:D002104', (166, 173))	('hMSH2', 'Gene', '4436', (48, 53))	('XRCC1', 'Gene', (62, 67))	('suppressed', 'NegReg', (121, 131))	('ERCC1', 'Gene', '2067', (55, 60))	('hMSH2', 'Gene', (48, 53))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA repair', 'biological_process', 'GO:0006281', ('36', '46'))
63479	25646071	Hypermethylation and repression of DNA repair genes, therefore, appear to be an early signature for cadmium-induced cancer and may also constitute part of the mechanism by which the toxicant induces tumorigenesis.	('tumor', 'Disease', (199, 204))	('cancer', 'Disease', (116, 122))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cadmium', 'Chemical', 'MESH:D002104', (100, 107))	('DNA repair genes', 'Gene', (35, 51))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('repression', 'NegReg', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('induces', 'Reg', (191, 198))
63481	25646071	A study using human prostate cells was in line with these results by showing that a 10-week exposure to cadmium led to malignant transformation in association with DNA hypermethylation at the global level, overexpression of DNMT3b and increased DNMT activity, promoter hypermethylation and decreased expression of the tumor suppressor genes RASSF1A and p16INK4A.	('decreased', 'NegReg', (290, 299))	('tumor suppressor', 'Gene', (318, 334))	('increased', 'PosReg', (235, 244))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('cadmium', 'Chemical', 'MESH:D002104', (104, 111))	('DNMT', 'Gene', '1786', (224, 228))	('tumor suppressor', 'Gene', '7248', (318, 334))	('promoter', 'MPA', (260, 268))	('DNMT', 'Gene', (224, 228))	('DNMT3b', 'Gene', '1789', (224, 230))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('164', '184'))	('human', 'Species', '9606', (14, 19))	('expression', 'MPA', (300, 310))	('DNMT3b', 'Gene', (224, 230))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('318', '334'))	('malignant transformation', 'CPA', (119, 143))	('RASSF1A', 'Gene', '11186', (341, 348))	('DNMT', 'Gene', '1786', (245, 249))	('p16INK4A', 'Gene', (353, 361))	('tumor suppressor', 'biological_process', 'GO:0051726', ('318', '334'))	('DNMT', 'Gene', (245, 249))	('DNA hypermethylation', 'Var', (164, 184))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('RASSF1A', 'Gene', (341, 348))	('p16INK4A', 'Gene', '1029', (353, 361))	('overexpression', 'PosReg', (206, 220))
63487	25646071	Recently, a causal association was demonstrated between caspase 8 promoter hypermethylation, pathological changes in the liver of rats and mice exposed to cadmium, and loss of the apoptotic pathway.	('loss', 'NegReg', (168, 172))	('promoter hypermethylation', 'Var', (66, 91))	('caspase 8', 'Protein', (56, 65))	('rats', 'Species', '10116', (130, 134))	('apoptotic pathway', 'Pathway', (180, 197))	('cadmium', 'Chemical', 'MESH:D002104', (155, 162))	('rat', 'Species', '10116', (130, 133))	('mice', 'Species', '10090', (139, 143))	('rat', 'Species', '10116', (42, 45))
63489	25646071	In addition, caspase 8 promoter was aberrantly methylated in all liver tissues from patients with hepatic cell carcinoma (HCC) while it was unmethylated in all the normal liver tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatic cell carcinoma', 'Disease', (98, 120))	('aberrantly methylated', 'Var', (36, 57))	('patients', 'Species', '9606', (84, 92))	('caspase', 'Protein', (13, 20))	('hepatic cell carcinoma', 'Disease', 'MESH:D006528', (98, 120))	('hepatic cell carcinoma', 'Phenotype', 'HP:0001402', (98, 120))
63490	25646071	Moreover, it has been shown that the hypermethylation of caspase 8 promoter is a common feature of relapsed glioblastoma multiforme.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (108, 131))	('hypermethylation', 'Var', (37, 53))	('caspase 8', 'Gene', (57, 66))	('glioblastoma multiforme', 'Disease', (108, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
63500	25646071	Further studies are recommended to explore whether cadmium can alter gene expression by inducing histone changes at a global or gene-specific level.	('cadmium', 'Var', (51, 58))	('histone changes', 'MPA', (97, 112))	('cadmium', 'Chemical', 'MESH:D002104', (51, 58))	('gene expression', 'biological_process', 'GO:0010467', ('69', '84'))	('gene expression', 'MPA', (69, 84))	('inducing', 'Reg', (88, 96))	('men', 'Species', '9606', (25, 28))
63503	25646071	Aberrant expression of miRNAs has been associated with several human disease states, including cancer, cardiovascular disease, and genetic disorders.	('Aberrant expression', 'Var', (0, 19))	('cardiovascular disease', 'Disease', (103, 125))	('miRNAs', 'Protein', (23, 29))	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('genetic disorders', 'Disease', (131, 148))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (103, 125))	('cancer', 'Disease', (95, 101))	('genetic disorders', 'Disease', 'MESH:D030342', (131, 148))	('associated', 'Reg', (39, 49))	('cardiovascular disease', 'Disease', 'MESH:D002318', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
63511	25646071	Focal adhesion (hsa04510) and the MAPK signaling pathway (hsa04010) were the two top pathways in the analysis of enrichment in KEGG pathways of the downregulated miRNAs targets.	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('hsa04010', 'Var', (58, 66))	('MAPK', 'Gene', '5595;5594;5595', (34, 38))	('hsa04510', 'Var', (16, 24))	('MAPK', 'Gene', (34, 38))	('MAPK signaling', 'biological_process', 'GO:0000165', ('34', '48'))	('Focal adhesion', 'cellular_component', 'GO:0005925', ('0', '14'))	('signaling pathway', 'biological_process', 'GO:0007165', ('39', '56'))	('men', 'Species', '9606', (119, 122))
63521	25646071	showed that cadmium reduced the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in human bronchial epithelial cells through upregulation of miR-101 and miR-144.	('CFTR', 'Gene', '1080', (103, 107))	('reduced', 'NegReg', (20, 27))	('cystic fibrosis transmembrane conductance regulator', 'molecular_function', 'GO:0005260', ('50', '101'))	('miR-101', 'Chemical', '-', (169, 176))	('upregulation', 'PosReg', (153, 165))	('miR-144', 'Gene', (181, 188))	('transmembrane', 'cellular_component', 'GO:0044214', ('66', '79'))	('miR-101', 'Var', (169, 176))	('CFTR', 'Gene', (103, 107))	('miR-144', 'Gene', '406936', (181, 188))	('cadmium', 'Chemical', 'MESH:D002104', (12, 19))	('transmembrane', 'cellular_component', 'GO:0016021', ('66', '79'))	('cystic fibrosis transmembrane conductance regulator', 'Gene', '1080', (50, 101))	('expression', 'MPA', (32, 42))	('human', 'Species', '9606', (112, 117))
63522	25646071	Notably, miR-101 might promote inflammation by downregulating the expression of MAPK phosphatase-1 (MKP-1).	('MKP-1', 'Gene', (100, 105))	('inflammation', 'Disease', (31, 43))	('phosphatase', 'molecular_function', 'GO:0016791', ('85', '96'))	('promote', 'PosReg', (23, 30))	('miR-101', 'Chemical', '-', (9, 16))	('MKP-1', 'Gene', '1843', (100, 105))	('MAPK phosphatase-1', 'Gene', '1843', (80, 98))	('MAPK', 'molecular_function', 'GO:0004707', ('80', '84'))	('expression', 'MPA', (66, 76))	('inflammation', 'biological_process', 'GO:0006954', ('31', '43'))	('miR-101', 'Var', (9, 16))	('downregulating', 'NegReg', (47, 61))	('MAPK phosphatase-1', 'Gene', (80, 98))	('inflammation', 'Disease', 'MESH:D007249', (31, 43))
63541	25646071	For example, a tendency towards disease progression is associated with MT overexpression in primary melanoma.	('MT overexpression', 'Var', (71, 88))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))
63551	25646071	Interestingly, however, VM-forming tumour cells showed increased survival following cadmium exposure relative to other subpopulations in 3D cultures or cells cultured in 2D.	('increased', 'PosReg', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('cadmium', 'Var', (84, 91))	('survival', 'CPA', (65, 73))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('cadmium', 'Chemical', 'MESH:D002104', (84, 91))	('tumour', 'Disease', (35, 41))
63566	25646071	Similarly, we could document that short-term cadmium exposure had a critical impact on the behavior of melanoma cells through epigenetic modifications of p16INK4A and caspase 8, resulting in their altered expression and in aberrant cell proliferation and apoptosis.	('cell proliferation', 'biological_process', 'GO:0008283', ('232', '250'))	('p16INK4A', 'Gene', (154, 162))	('p16INK4A', 'Gene', '1029', (154, 162))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (223, 250))	('cell proliferation', 'CPA', (232, 250))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))	('epigenetic modifications', 'Var', (126, 150))	('altered', 'Reg', (197, 204))	('rat', 'Species', '10116', (244, 247))	('apoptosis', 'biological_process', 'GO:0097194', ('255', '264'))	('men', 'Species', '9606', (24, 27))	('apoptosis', 'biological_process', 'GO:0006915', ('255', '264'))	('expression', 'MPA', (205, 215))	('caspase 8', 'Gene', (167, 176))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('cadmium', 'Chemical', 'MESH:D002104', (45, 52))	('impact', 'Reg', (77, 83))	('apoptosis', 'CPA', (255, 264))
63568	25646071	In skin melanoma the extrinsic pathway of apoptosis was affected and caspase 8 hypermethylation and inactivation was indicated as the main pathogenic mechanism.	('caspase 8', 'Protein', (69, 78))	('extrinsic pathway of apoptosis', 'Pathway', (21, 51))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('hypermethylation', 'Var', (79, 95))	('skin melanoma', 'Disease', 'MESH:D008545', (3, 16))	('skin melanoma', 'Disease', (3, 16))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('affected', 'Reg', (56, 64))	('inactivation', 'MPA', (100, 112))
63569	25646071	In uveal melanoma, instead, p16INK4A aberrant methylation and silencing was called as the determinant cause.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('p16INK4A', 'Gene', '1029', (28, 36))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('aberrant methylation', 'Var', (37, 57))	('silencing', 'MPA', (62, 71))	('p16INK4A', 'Gene', (28, 36))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
63572	25646071	Our results show that cadmium-treated uveal melanoma cell lines have >80% methylated clones (i.e., severe hypermethylation and complete methylation) in the p16 INK4A promoter versus >60% unmethylated clones (i.e., severe hypomethylation and complete unmethylation) in the same gene region of the corresponding untreated cells.	('uveal melanoma', 'Disease', (38, 52))	('p16 INK4A', 'Gene', (156, 165))	('severe hypermethylation', 'Var', (99, 122))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('p16 INK4A', 'Gene', '1029', (156, 165))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('cadmium', 'Chemical', 'MESH:D002104', (22, 29))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))	('methylation', 'MPA', (136, 147))	('methylated', 'Var', (74, 84))
63574	25646071	Integrative analysis of DNA methylation and RNA expression data revealed a positive association between DNA methylation and transcript expression of p16INK4A and caspase 8 either before or after treatment with cadmium.	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('cadmium', 'Chemical', 'MESH:D002104', (210, 217))	('caspase 8', 'Gene', (162, 171))	('positive', 'PosReg', (75, 83))	('p16INK4A', 'Gene', '1029', (149, 157))	('transcript expression', 'MPA', (124, 145))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('rat', 'Species', '10116', (5, 8))	('men', 'Species', '9606', (200, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('methylation', 'Var', (108, 119))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('DNA methylation', 'biological_process', 'GO:0006306', ('104', '119'))	('p16INK4A', 'Gene', (149, 157))
63578	25646071	The silencing of p16INK4A and caspase 8 by cadmium in melanoma cells is of particular importance in light of the negligible role played by constitutional epimutations of CDKN2A (p16INK4A and p14ARF) genes in melanoma families, whereby it was concluded that it is unlikely that they play a role in susceptibility to the disease in families without CDKN2A mutations.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('p16INK4A', 'Gene', (17, 25))	('silencing', 'NegReg', (4, 13))	('cadmium', 'Chemical', 'MESH:D002104', (43, 50))	('p16INK4A', 'Gene', '1029', (17, 25))	('CDKN2A', 'Gene', (170, 176))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('CDKN2A', 'Gene', '1029', (170, 176))	('p14ARF', 'Gene', '1029', (191, 197))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('CDKN2A', 'Gene', (347, 353))	('caspase', 'Enzyme', (30, 37))	('epimutations', 'Var', (154, 166))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('p16INK4A', 'Gene', (178, 186))	('p16INK4A', 'Gene', '1029', (178, 186))	('CDKN2A', 'Gene', '1029', (347, 353))	('p14ARF', 'Gene', (191, 197))
63581	25646071	These data confirm the ones presented in this study, and highlight a crucial role of the environment in inducing epigenetic changes in a key gene in melanoma development, such as p16INK4A, in absence of inherited mutations.	('men', 'Species', '9606', (165, 168))	('men', 'Species', '9606', (96, 99))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('epigenetic changes', 'Var', (113, 131))	('inducing', 'Reg', (104, 112))	('p16INK4A', 'Gene', (179, 187))	('p16INK4A', 'Gene', '1029', (179, 187))
63583	25646071	Notably, p16INK4A methylation well correlated with increased melanoma thickness and marginally with increased Clark level.	('p16INK4A', 'Gene', '1029', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('methylation', 'Var', (18, 29))	('increased melanoma thickness', 'Disease', 'MESH:D008545', (51, 79))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('increased melanoma thickness', 'Disease', (51, 79))	('p16INK4A', 'Gene', (9, 17))
63588	25646071	Several studies have demonstrated that expression of caspase 8 may be controlled by epigenetic modifications, which differ according to the type of cancer cells.	('cancer', 'Disease', (148, 154))	('caspase', 'Protein', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('controlled', 'Reg', (70, 80))	('expression', 'MPA', (39, 49))	('rat', 'Species', '10116', (28, 31))	('epigenetic modifications', 'Var', (84, 108))
63589	25646071	However, although an association between aberrant DNA methylation of caspase 8 and carcinogenesis has been demonstrated in several studies, the functional relevance of this epigenetic trait in melanomagenesis has not yet been fully understood.	('rat', 'Species', '10116', (114, 117))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('DNA', 'cellular_component', 'GO:0005574', ('50', '53'))	('melanoma', 'Disease', (193, 201))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('50', '65'))	('caspase', 'Protein', (69, 76))	('aberrant DNA methylation', 'Var', (41, 65))	('carcinogenesis', 'Disease', (83, 97))
63590	25646071	Our findings, showing for the first time that caspase 8 expression is impaired by DNA hypermethylation following cadmium treatment in cutaneous melanoma cell lines, highlight the potential relevance of such a mechanism in the context of this tumor and extend earlier in vitro and in vivo observations linking exposure to cadmium with decreased expression of caspase 8 in tumours different from melanoma.	('tumour', 'Phenotype', 'HP:0002664', (371, 377))	('expression', 'MPA', (344, 354))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('tumor', 'Disease', (242, 247))	('melanoma', 'Disease', (144, 152))	('cutaneous melanoma', 'Disease', (134, 152))	('cadmium', 'Chemical', 'MESH:D002104', (113, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('82', '102'))	('melanoma', 'Disease', 'MESH:D008545', (394, 402))	('hypermethylation', 'Var', (86, 102))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('expression', 'MPA', (56, 66))	('caspase', 'Protein', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumours', 'Disease', (371, 378))	('melanoma', 'Phenotype', 'HP:0002861', (394, 402))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('melanoma', 'Disease', (394, 402))	('men', 'Species', '9606', (126, 129))	('tumours', 'Phenotype', 'HP:0002664', (371, 378))	('tumours', 'Disease', 'MESH:D009369', (371, 378))	('cadmium', 'Chemical', 'MESH:D002104', (321, 328))	('impaired', 'NegReg', (70, 78))
63592	25646071	Based on evidence that both the programmed re-expression of caspase 8 by demethylation and caspase 8 gene transfer can sensitize tumour cell lines for drug-induced apoptosis, it is possible to hypothesize that this pollutant may prevent drug-induced apoptosis and interfere with therapeutic strategies targeting cutaneous melanoma.	('caspase', 'Gene', (91, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (312, 330))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (312, 330))	('apoptosis', 'biological_process', 'GO:0097194', ('250', '259'))	('rat', 'Species', '10116', (293, 296))	('prevent', 'NegReg', (229, 236))	('apoptosis', 'biological_process', 'GO:0006915', ('250', '259'))	('drug-induced apoptosis', 'CPA', (237, 259))	('gene transfer', 'Var', (101, 114))	('demethylation', 'biological_process', 'GO:0070988', ('73', '86'))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('caspase 8', 'Gene', (60, 69))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (322, 330))	('tumour', 'Disease', (129, 135))	('sensitize', 'Reg', (119, 128))	('interfere', 'NegReg', (264, 273))	('demethylation', 'Var', (73, 86))	('cutaneous melanoma', 'Disease', (312, 330))
63593	25646071	Therefore, these findings may be of interest because they: i) highlight the crucial role of acute cadmium exposure in silencing key genes involved in the control of cell cycle and apoptosis in melanoma; ii) discriminate between cutaneous and uveal melanoma on the basis of the genes epigenetically modified by cadmium; iii) indicate cadmium pollution as one of the potential causes of inactivation of p16INK4A, a previously recognized biomarker of malignant melanoma; iv) show for the first time the significance of caspase 8 methylation and silencing in cutaneous melanoma and the role of cadmium in this effect.	('melanoma', 'Disease', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (565, 573))	('melanoma', 'Disease', (565, 573))	('uveal melanoma', 'Disease', 'MESH:C536494', (242, 256))	('cell cycle', 'biological_process', 'GO:0007049', ('165', '175'))	('uveal melanoma', 'Disease', (242, 256))	('cutaneous melanoma', 'Disease', (555, 573))	('melanoma', 'Disease', 'MESH:D008545', (458, 466))	('cadmium', 'Chemical', 'MESH:D002104', (98, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (555, 573))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (555, 573))	('cadmium', 'Chemical', 'MESH:D002104', (590, 597))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (242, 256))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('caspase', 'Protein', (516, 523))	('silencing', 'MPA', (542, 551))	('cadmium', 'Chemical', 'MESH:D002104', (333, 340))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('malignant melanoma', 'Disease', (448, 466))	('melanoma', 'Disease', 'MESH:D008545', (565, 573))	('melanoma', 'Phenotype', 'HP:0002861', (458, 466))	('melanoma', 'Disease', (458, 466))	('methylation', 'Var', (526, 537))	('cadmium', 'Chemical', 'MESH:D002104', (310, 317))	('methylation', 'biological_process', 'GO:0032259', ('526', '537'))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('p16INK4A', 'Gene', (401, 409))	('p16INK4A', 'Gene', '1029', (401, 409))	('malignant melanoma', 'Phenotype', 'HP:0002861', (448, 466))	('malignant melanoma', 'Disease', 'MESH:D008545', (448, 466))
63594	25646071	In conclusion, our data suggest that aberrant DNA methylation of p16INK4A and caspase 8 gene promoters is associated with single-phenotype defects in melanoma cells after acute exposure to low non cytotoxic doses of cadmium.	('DNA methylation', 'MPA', (46, 61))	('cadmium', 'Chemical', 'MESH:D002104', (216, 223))	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('associated', 'Reg', (106, 116))	('caspase 8', 'Gene', (78, 87))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('p16INK4A', 'Gene', (65, 73))	('melanoma', 'Disease', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('DNA methylation', 'biological_process', 'GO:0006306', ('46', '61'))	('aberrant', 'Var', (37, 45))	('p16INK4A', 'Gene', '1029', (65, 73))
63595	25646071	Further studies are warranted to address the role of epigenetic mechanisms induced by environmental pollutants in worsening the melanoma progression.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('epigenetic', 'Var', (53, 63))	('worsening', 'PosReg', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
63600	25646071	Relying on available evidence, cadmium apparently has little direct genotoxic activity and acts apparently through various indirect mechanisms, including ROS generation, DNA repair inhibition, impairment of the cellular antioxidant defence system, interference with signal transduction, and possibly the disruption of cell-cell adhesion with the consequent initiation of cancer.	('DNA repair', 'biological_process', 'GO:0006281', ('170', '180'))	('inhibition', 'NegReg', (181, 191))	('cadmium', 'Var', (31, 38))	('DNA repair', 'MPA', (170, 180))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('318', '336'))	('ROS generation', 'MPA', (154, 168))	('impairment', 'NegReg', (193, 203))	('interference', 'NegReg', (248, 260))	('signal transduction', 'biological_process', 'GO:0007165', ('266', '285'))	('men', 'Species', '9606', (199, 202))	('cadmium', 'Chemical', 'MESH:D002104', (31, 38))	('signal transduction', 'MPA', (266, 285))	('ROS generation', 'biological_process', 'GO:1903409', ('154', '168'))	('initiation of cancer', 'Disease', 'MESH:D009369', (357, 377))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('rat', 'Species', '10116', (162, 165))	('initiation of cancer', 'Disease', (357, 377))	('cellular antioxidant defence system', 'MPA', (211, 246))
63604	25646071	Moreover, they highlight the role of epigenetics in melanoma progression following exposure to cadmium.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('cadmium', 'Chemical', 'MESH:D002104', (95, 102))	('epigenetics', 'Var', (37, 48))
63605	25646071	It is speculated that in cutaneous melanoma cadmium affects the extrinsic apoptotic pathway, that is prevalent in this kind of tumor, through methylation and inactivation of caspase 8, while in uveal melanoma the metal alters the cell cycle through methylation and silencing of p16INK4A.	('cutaneous melanoma', 'Disease', (25, 43))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (25, 43))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('alters', 'Reg', (219, 225))	('uveal melanoma', 'Disease', (194, 208))	('uveal melanoma', 'Disease', 'MESH:C536494', (194, 208))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('metal', 'Chemical', 'MESH:D008670', (213, 218))	('uveal melanoma', 'Phenotype', 'HP:0007716', (194, 208))	('p16INK4A', 'Gene', (278, 286))	('affects', 'Reg', (52, 59))	('silencing', 'NegReg', (265, 274))	('p16INK4A', 'Gene', '1029', (278, 286))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('cell cycle', 'CPA', (230, 240))	('extrinsic apoptotic pathway', 'Pathway', (64, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('230', '240'))	('caspase 8', 'Protein', (174, 183))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('methylation', 'biological_process', 'GO:0032259', ('249', '260'))	('inactivation', 'NegReg', (158, 170))	('methylation', 'Var', (249, 260))	('extrinsic apoptotic pathway', 'biological_process', 'GO:0097191', ('64', '91'))	('tumor', 'Disease', (127, 132))	('methylation', 'MPA', (142, 153))	('cadmium', 'Chemical', 'MESH:D002104', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
63606	25646071	It's possible that in a near future well characterized epigenetic modifications will aid in the molecular diagnosis and treatment of a variety of cancers and other disorders induced by cadmium.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cadmium', 'Chemical', 'MESH:D002104', (185, 192))	('men', 'Species', '9606', (125, 128))	('induced', 'Reg', (174, 181))	('epigenetic modifications', 'Var', (55, 79))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('aid', 'Reg', (85, 88))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
63621	29487896	Our data demonstrate that, via the oncogenic combinations of mutant proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B (BrafV600E) or mutant Kirsten rat sarcoma viral oncogene homolog (KrasG12D) expression combined with conditional loss of the tumor suppressor phosphatase and tensin homolog (Pten), melanoma cell expansion emerges near the bulge, the anatomical residence of MCSCs in anagen, soon after induced telogen to anagen transition.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('melanoma', 'Phenotype', 'HP:0002861', (320, 328))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('281', '311'))	('melanoma', 'Disease', (320, 328))	('rat', 'Species', '10116', (16, 19))	('sarcoma', 'Disease', (173, 180))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '114486', (93, 138))	('Pten', 'Gene', '50557', (313, 317))	('phosphatase', 'molecular_function', 'GO:0016791', ('281', '292'))	('loss', 'NegReg', (252, 256))	('Pten', 'Gene', (313, 317))	('tumor suppressor', 'biological_process', 'GO:0051726', ('264', '280'))	('proto-oncogene B-Raf', 'Gene', '109880', (68, 88))	('tumor', 'Disease', (264, 269))	('cell expansion', 'biological_process', 'GO:0016049', ('329', '343'))	('sarcoma', 'Phenotype', 'HP:0100242', (173, 180))	('BrafV600E', 'Mutation', 'rs113488022', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('melanoma', 'Disease', 'MESH:D008545', (320, 328))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('anagen', 'biological_process', 'GO:0042640', ('405', '411'))	('proto-oncogene B-Raf', 'Gene', (68, 88))	('mutant', 'Var', (61, 67))	('telogen', 'biological_process', 'GO:0042639', ('432', '439'))	('sarcoma', 'Disease', (106, 113))	('rat', 'Species', '10116', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('anagen', 'biological_process', 'GO:0042640', ('443', '449'))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (93, 138))	('MCSC', 'Gene', '227731', (396, 400))	('MCSC', 'Gene', (396, 400))	('sarcoma', 'Disease', 'MESH:D012509', (173, 180))	('mutant', 'Var', (154, 160))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('264', '280'))
63656	32036455	Instead, more than 80% harbour mutations in the guanine nucleotide binding protein Q polypeptide (GNAQ) and alpha-11 (GNA11) genes (Onken et al.	('alpha-11', 'Gene', (108, 116))	('GNA11', 'Gene', (118, 123))	('mutations', 'Var', (31, 40))	('alpha-11', 'Gene', '8248', (108, 116))	('GNA11', 'Gene', '2767', (118, 123))	('GNAQ', 'Gene', (98, 102))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('GNAQ', 'Gene', '2776', (98, 102))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('56', '74'))
63695	28614138	Acute Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy During Vemurafenib and Pembrolizumab Treatment for Metastatic Melanoma To describe a case of a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy (AEPVM) during vemurafenib and pembrolizumab treatment for metastatic melanoma.	('vitelliform maculopathy', 'Phenotype', 'HP:0007677', (261, 284))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (75, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (199, 217))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (199, 217))	('melanoma', 'Disease', 'MESH:D008545', (355, 363))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (91, 104))	('Melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('Vitelliform Maculopathy', 'Phenotype', 'HP:0007677', (44, 67))	('vitelliform maculopathy', 'Disease', (261, 284))	('Metastatic Melanoma', 'Disease', (119, 138))	('Metastatic Melanoma', 'Disease', 'MESH:D008545', (119, 138))	('mutation-positive', 'Var', (181, 198))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('BRAF', 'Gene', (176, 180))	('melanoma', 'Disease', (355, 363))	('pembrolizumab', 'Chemical', 'MESH:C582435', (316, 329))	('melanoma', 'Phenotype', 'HP:0002861', (355, 363))	('vemurafenib', 'Chemical', 'MESH:D000077484', (300, 311))	('Exudative Paraneoplastic Polymorphous Vitelliform Maculopathy', 'Disease', 'MESH:D008268', (6, 67))	('patient', 'Species', '9606', (163, 170))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('cutaneous melanoma', 'Disease', (199, 217))	('vitelliform maculopathy', 'Disease', 'MESH:D008268', (261, 284))	('BRAF', 'Gene', '673', (176, 180))
63707	28614138	Personalized cancer therapy that targets pathways disrupted by specific gene mutations is one of the recent triumphs of medicine and has significantly extended the survival of patients with metastatic cutaneous melanoma.	('patients', 'Species', '9606', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('cutaneous melanoma', 'Disease', (201, 219))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('extended', 'PosReg', (151, 159))	('mutations', 'Var', (77, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (201, 219))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (201, 219))
63711	28614138	In recent years, MEK inhibitors have been implicated in myriad ophthalmic sequelae such as neurosensory retinal detachment, vascular injury, anterior uveitis, visual field defects, and others.	('MEK', 'Gene', (17, 20))	('neurosensory retinal detachment', 'Disease', 'MESH:D012163', (91, 122))	('anterior uveitis', 'Phenotype', 'HP:0012122', (141, 157))	('anterior uveitis', 'Disease', 'MESH:D014606', (141, 157))	('anterior uveitis', 'Disease', (141, 157))	('visual field defects', 'Disease', 'MESH:D005128', (159, 179))	('vascular injury', 'Disease', (124, 139))	('MEK', 'Gene', '5609', (17, 20))	('vascular injury', 'Disease', 'MESH:D057772', (124, 139))	('inhibitors', 'Var', (21, 31))	('visual field defects', 'Phenotype', 'HP:0001123', (159, 179))	('retinal detachment', 'Phenotype', 'HP:0000541', (104, 122))	('uveitis', 'Phenotype', 'HP:0000554', (150, 157))	('implicated', 'Reg', (42, 52))	('visual field defects', 'Disease', (159, 179))	('neurosensory retinal detachment', 'Disease', (91, 122))
63772	31661138	It has recently been reported that human mucosal and dog oral melanoma bear more similar genetic alterations, such as copy number variations (CNVs), single nucleotide variations (SNVs) and mutations or deletions than human cutaneous melanoma.	('copy', 'Var', (118, 122))	('melanoma', 'Disease', (62, 70))	('oral melanoma', 'Disease', 'MESH:D008545', (57, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (223, 241))	('human', 'Species', '9606', (217, 222))	('human', 'Species', '9606', (35, 40))	('dog', 'Species', '9615', (53, 56))	('oral melanoma', 'Disease', (57, 70))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('single nucleotide variations', 'Var', (149, 177))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('mutations', 'Var', (189, 198))	('melanoma', 'Disease', (233, 241))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
63776	31661138	Several genetic mutations or loss of function events observed in human melanoma have also been identified in dog oral melanoma, such as BRAFV600E, NRAS (Q61) mutation, loss function of phosphatase and tensin homolog (PTEN) and c-KIT mutation and/or overexpression.	('human', 'Species', '9606', (65, 70))	('phosphatase', 'molecular_function', 'GO:0016791', ('185', '196'))	('phosphatase and tensin homolog', 'Gene', '403832', (185, 215))	('dog', 'Species', '9615', (109, 112))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('overexpression', 'PosReg', (249, 263))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('185', '215'))	('c-KIT', 'Gene', (227, 232))	('loss function', 'NegReg', (168, 181))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('mutation', 'Var', (233, 241))	('NRAS', 'Gene', '403872', (147, 151))	('BRAFV600E', 'Var', (136, 145))	('oral melanoma', 'Disease', (113, 126))	('KIT', 'molecular_function', 'GO:0005020', ('229', '232'))	('PTEN', 'Gene', (217, 221))	('oral melanoma', 'Disease', 'MESH:D008545', (113, 126))	('PTEN', 'Gene', '403832', (217, 221))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('mutation', 'Var', (158, 166))	('c-KIT', 'Gene', '403811', (227, 232))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('NRAS', 'Gene', (147, 151))
63778	31661138	Some aberrant genes promote cancer progression, while simultaneously inhibiting normal cellular process, whereas other deregulated genes occur as passenger alterations.	('normal cellular process', 'CPA', (80, 103))	('cellular process', 'cellular_component', 'GO:0042995', ('87', '103'))	('aberrant genes', 'Var', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cellular process', 'biological_process', 'GO:0009987', ('87', '103'))	('promote', 'PosReg', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('inhibiting', 'NegReg', (69, 79))	('cancer', 'Disease', (28, 34))
63803	31661138	We downloaded 3 RNA-seq datasets from the GEO database: GSE71747 for the human melanoma tissue, GSE88741 for the human melanoma cell line and GSE29155 for human prostate cancer.	('RNA', 'cellular_component', 'GO:0005562', ('16', '19'))	('GSE29155', 'CellLine', 'CVCL:6F81', (142, 150))	('GSE71747', 'Var', (56, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('human', 'Species', '9606', (155, 160))	('human', 'Species', '9606', (73, 78))	('prostate cancer', 'Disease', (161, 176))	('melanoma', 'Disease', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('GSE88741', 'Var', (96, 104))	('GSE29155', 'Var', (142, 150))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('human', 'Species', '9606', (113, 118))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
63809	31661138	Primer sequences of the TaqMan Gene Expression assays are available in the following IDs: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH; Cf04419463), collagen type VII alpha 1 chain (COL7A1; Cf02690281), AKT serine/threonine kinase 3 (AKT3; Cf02704523), ERBB receptor feedback inhibitor 1 (ERRFI1; Cf02653684), inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB; Cf02695869), nerve growth factor (NGF; Cf02697134), epidermal growth factor receptor (EGFR; CF02626541), matrix metalloproteinase 9 (MMP9; CF02621845) and interleukin (IL)6 (Cf02624282).	('ERBB receptor feedback inhibitor 1', 'Gene', (256, 290))	('Cf02624282', 'Var', (551, 561))	('COL7A1', 'Gene', '403467', (185, 191))	('epidermal growth factor receptor', 'Gene', (429, 461))	('NGF', 'Gene', '403402', (411, 414))	('ERRFI1', 'Gene', (292, 298))	('nerve growth factor', 'Gene', '403402', (390, 409))	('Gene Expression', 'biological_process', 'GO:0010467', ('31', '46'))	('GAPDH', 'Gene', (132, 137))	('collagen', 'molecular_function', 'GO:0005202', ('152', '160'))	('EGFR', 'molecular_function', 'GO:0005006', ('463', '467'))	('nerve growth factor', 'Gene', (390, 409))	('ERRFI1', 'Gene', '489636', (292, 298))	('IKBKB', 'Gene', (370, 375))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('429', '452'))	('MMP9', 'molecular_function', 'GO:0004229', ('510', '514'))	('EGFR', 'Gene', '404306', (463, 467))	('AKT3', 'Gene', (237, 241))	('EGFR', 'Gene', (463, 467))	('MMP9', 'Gene', '403885', (510, 514))	('IL)6', 'molecular_function', 'GO:0005138', ('545', '549'))	('NGF', 'Gene', (411, 414))	('AKT serine/threonine kinase 3', 'Gene', '442964', (206, 235))	('inhibitor of nuclear factor kappa B kinase subunit beta', 'Gene', '482839', (313, 368))	('Glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '403755', (90, 130))	('IKBKB', 'Gene', '482839', (370, 375))	('IKBKB', 'molecular_function', 'GO:0008384', ('370', '375'))	('epidermal growth factor receptor', 'Gene', '404306', (429, 461))	('COL7A1', 'Gene', (185, 191))	('MMP9', 'Gene', (510, 514))	('CF02621845', 'Var', (516, 526))	('matrix metalloproteinase 9', 'Gene', '403885', (482, 508))	('AKT3', 'Gene', '442964', (237, 241))	('matrix metalloproteinase 9', 'Gene', (482, 508))	('GAPDH', 'Gene', '403755', (132, 137))	('ERBB receptor feedback inhibitor 1', 'Gene', '489636', (256, 290))	('AKT serine/threonine kinase 3', 'Gene', (206, 235))	('Glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (90, 130))
63825	31661138	Cytokine-cytokine receptor interaction (CFA04060), focal adhesion (CFA04510) and ECM-receptor interaction (CFA04512) were the top 3 pathways.	('CFA04060', 'Var', (40, 48))	('CFA04510', 'Chemical', '-', (67, 75))	('ECM-receptor interaction', 'CPA', (81, 105))	('focal adhesion', 'cellular_component', 'GO:0005925', ('51', '65'))	('focal adhesion', 'CPA', (51, 65))	('CFA04512', 'Chemical', '-', (107, 115))	('CFA04060', 'Chemical', '-', (40, 48))	('Cytokine-cytokine receptor interaction', 'MPA', (0, 38))
63851	31661138	In a study on human squamous cell carcinomas of the head and neck and esophagus, KRT13 was found to be epigenetically silenced, while the chromosomal location of the S100A8 gene was found to be frequently altered or deleted and downregulated.	('silenced', 'NegReg', (118, 126))	('S100A8', 'Gene', (166, 172))	('neck', 'cellular_component', 'GO:0044326', ('61', '65'))	('KRT13', 'Gene', (81, 86))	('S100A8', 'Gene', '6279', (166, 172))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (20, 44))	('squamous cell carcinomas', 'Disease', (20, 44))	('deleted', 'Var', (216, 223))	('human', 'Species', '9606', (14, 19))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (20, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('downregulated', 'NegReg', (228, 241))
63857	31661138	Loss of alleles or abnormalities in HSA1 (human chromosome 1) in human malignant melanoma was previously reported.	('human', 'Species', '9606', (65, 70))	('HSA1', 'Gene', '81050', (36, 40))	('human', 'Species', '9606', (42, 47))	('HSA1', 'Gene', (36, 40))	('abnormalities', 'Var', (19, 32))	('Loss', 'NegReg', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('malignant melanoma', 'Phenotype', 'HP:0002861', (71, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('48', '58'))	('malignant melanoma', 'Disease', 'MESH:D008545', (71, 89))	('malignant melanoma', 'Disease', (71, 89))
63908	31661138	17H03926, 15H14872, 25292180 and 22780283).	('22780283', 'Var', (33, 41))	('17H03926', 'Chemical', '-', (0, 8))	('15H14872', 'Chemical', '-', (10, 18))	('25292180', 'Var', (20, 28))
63919	30981094	Acral and mucosal melanomas are more frequently characterized by DNA structural changes and mutation signatures of unknown etiology.	('mutation', 'Var', (92, 100))	('mucosal melanomas', 'Disease', (10, 27))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (10, 27))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))
63920	30981094	Although cutaneous melanoma is characterized by defects in BRAF, CDKN2A, NRAS, and TP53, acral melanoma is associated with genetic mutations of BRAF, NRAS, KIT, MAP2K2, and NF1, and mucosal melanoma is associated with mutations of SF3B1 .	('MAP2K2', 'Gene', (161, 167))	('NF1', 'Gene', '4763', (173, 176))	('KIT', 'Gene', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('BRAF', 'Gene', '673', (144, 148))	('acral melanoma', 'Disease', (89, 103))	('BRAF', 'Gene', (144, 148))	('SF3B1', 'Gene', (231, 236))	('NRAS', 'Gene', '4893', (150, 154))	('NRAS', 'Gene', (73, 77))	('defects', 'NegReg', (48, 55))	('NF1', 'Gene', (173, 176))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('TP53', 'Gene', (83, 87))	('CDKN2A', 'Gene', (65, 71))	('MAP2K2', 'Gene', '5605', (161, 167))	('MAP2K', 'molecular_function', 'GO:0004708', ('161', '166'))	('mucosal melanoma', 'Disease', (182, 198))	('SF3B1', 'Gene', '23451', (231, 236))	('acral melanoma', 'Disease', 'MESH:D008545', (89, 103))	('associated', 'Reg', (107, 117))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('NRAS', 'Gene', (150, 154))	('acral melanoma', 'Phenotype', 'HP:0012060', (89, 103))	('TP53', 'Gene', '7157', (83, 87))	('CDKN2A', 'Gene', '1029', (65, 71))	('mutations', 'Var', (131, 140))	('NRAS', 'Gene', '4893', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('mutations', 'Var', (218, 227))	('associated', 'Reg', (202, 212))	('KIT', 'molecular_function', 'GO:0005020', ('156', '159'))	('cutaneous melanoma', 'Disease', (9, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))
63942	28668274	Impact of Time Between Diagnosis and SLNB on Outcomes in Cutaneous Melanoma Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response.	('allowing', 'Reg', (245, 253))	('affect', 'Reg', (140, 146))	('Melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('Cutaneous Melanoma', 'Disease', (57, 75))	('SLN', 'Gene', (129, 132))	('SLN', 'Gene', '6588', (37, 40))	('metastases', 'Disease', 'MESH:D009362', (214, 224))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('melanoma', 'Disease', (277, 285))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('delay', 'Var', (92, 97))	('SLN', 'Gene', '6588', (129, 132))	('outcomes', 'MPA', (147, 155))	('metastases', 'Disease', (214, 224))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('immune response', 'biological_process', 'GO:0006955', ('286', '301'))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (57, 75))	('growth', 'CPA', (186, 192))	('allowing', 'PosReg', (177, 185))	('melanoma', 'Disease', 'MESH:D008545', (277, 285))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('SLN', 'Gene', (37, 40))
64021	28668274	Nodal positivity in both groups is associated with reduced DFS and MSS.	('MSS', 'CPA', (67, 70))	('reduced', 'NegReg', (51, 58))	('Nodal positivity', 'Var', (0, 16))	('MSS', 'Chemical', '-', (67, 70))	('DFS', 'Disease', (59, 62))
64057	33257317	Some genetic mutations linked to worse prognosis, including BAP1 itself.	('mutations', 'Var', (13, 22))	('BAP1', 'Gene', '8314', (60, 64))	('BAP1', 'Gene', (60, 64))
64058	33257317	Moreover, UM familial predisposition syndrome is marked by BAP1 germline mutations, which in turn is associated with other cancers, including cutaneous melanoma, malignant mesothelioma and renal cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('germline', 'Var', (64, 72))	('cutaneous melanoma', 'Disease', (142, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (142, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (142, 160))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('BAP1', 'Gene', '8314', (59, 63))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (162, 184))	('UM familial predisposition syndrome', 'Disease', (10, 45))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('associated', 'Reg', (101, 111))	('malignant mesothelioma', 'Disease', (162, 184))	('BAP1', 'Gene', (59, 63))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (162, 184))	('renal cell carcinoma', 'Disease', (189, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))
64094	33257317	After adjusting for sex, race, age at diagnosis of UM, site of UM, stage at diagnosis of UM, size at diagnosis of UM, and undergoing cancer-directed surgery for UM, multivariate Cox models showed a better overall survival for females, but worse outcomes for black patients, ciliary body UM, larger or more advanced UM (table 6).	('ciliary', 'Var', (274, 281))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('age', 'Gene', (31, 34))	('cancer', 'Disease', (133, 139))	('age', 'Gene', (69, 72))	('better', 'PosReg', (198, 204))	('patients', 'Species', '9606', (264, 272))	('age', 'Gene', '5973', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('age', 'Gene', '5973', (31, 34))
64105	33257317	Germline pathogenic variants in several cancer genes have been reported in patients with UM.	('variants', 'Var', (20, 28))	('reported', 'Reg', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
64109	33257317	CHEK2 mutations predispose to papillary thyroid, prostate and breast cancers.	('CHEK2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('predispose', 'Reg', (16, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('papillary thyroid', 'Disease', (30, 47))	('prostate', 'Disease', (49, 57))	('CHEK2', 'Gene', '11200', (0, 5))	('mutations', 'Var', (6, 15))
64110	33257317	PALB2 mutations show an association with breast, ovarian and pancreatic cancers.	('ovarian and pancreatic cancers', 'Disease', 'MESH:D010195', (49, 79))	('breast', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PALB2', 'Gene', '79728', (0, 5))	('PALB2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('association', 'Reg', (24, 35))	('mutations', 'Var', (6, 15))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (61, 79))
64111	33257317	Mutations of SMARCE1 results in spinal meningiomas and its high expression associate with poor prognosis of breast cancer.	('spinal meningiomas', 'Disease', (32, 50))	('expression', 'MPA', (64, 74))	('meningiomas', 'Phenotype', 'HP:0002858', (39, 50))	('spinal meningiomas', 'Disease', 'MESH:D008577', (32, 50))	('SMARCE1', 'Gene', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SMARCE1', 'Gene', '6605', (13, 20))	('Mutations', 'Var', (0, 9))	('spinal meningiomas', 'Phenotype', 'HP:0100010', (32, 50))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('results in', 'Reg', (21, 31))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
64148	29402264	The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each).	('DMFS', 'Chemical', '-', (47, 51))	('SL', 'Disease', 'MESH:C564794', (225, 227))	('DMFS', 'Var', (47, 51))	('RFS', 'Disease', (39, 42))
64167	29402264	Analysis of survival rates by molecular substage resulted in Class 1A RFS, DMFS and MSS of 91%, 96% and 100%, respectively, compared to Class 2B rates of 43%, 51% and 70%, respectively (P < 0.001; Fig.	('DMFS', 'Disease', (75, 79))	('DMFS', 'Chemical', '-', (75, 79))	('MSS', 'Chemical', '-', (84, 87))	('RFS', 'Var', (70, 73))
64179	29402264	In univariate Cox regression analysis, Breslow thickness, mitotic rate, ulceration, positive SLN, and molecular Class 2 were all significant predictors of recurrence and distant metastasis.	('positive', 'Var', (84, 92))	('distant metastasis', 'CPA', (170, 188))	('SL', 'Disease', 'MESH:C564794', (93, 95))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('Breslow thickness', 'CPA', (39, 56))	('ulceration', 'Disease', (72, 82))	('mitotic rate', 'CPA', (58, 70))	('recurrence', 'CPA', (155, 165))
64180	29402264	In multivariate analysis, molecular Class 2, Breslow thickness, and positive SLN were independent predictors of RFS and DMFS (Table 3).	('positive', 'Var', (68, 76))	('DMFS', 'Disease', (120, 124))	('RFS', 'Disease', (112, 115))	('SL', 'Disease', 'MESH:C564794', (77, 79))	('DMFS', 'Chemical', '-', (120, 124))
64184	29402264	For SLN-positive/Class 1, the RFS, DMFS and MSS rates were 61%, 74% and 93%, respectively, while in SLN-positive/Class 2 patients' rates were 37%, 44% and 63%, respectively.	('SL', 'Disease', 'MESH:C564794', (4, 6))	('MSS', 'Disease', (44, 47))	('SL', 'Disease', 'MESH:C564794', (100, 102))	('MSS', 'Chemical', '-', (44, 47))	('DMFS', 'Var', (35, 39))	('DMFS', 'Chemical', '-', (35, 39))	('patients', 'Species', '9606', (121, 129))
64225	24625986	Although BNIP3-shRNA increased mitochondrial mass and baseline levels of reactive oxygen species production, which are features associated with aggressive cancer cell behavior, it also prevented cell migration and completely abolished the ability to form a tubular-like network on matrigel, a hallmark of vasculogenic mimicry (VM).	('reactive oxygen species', 'Chemical', 'MESH:D017382', (73, 96))	('increased', 'PosReg', (21, 30))	('BNIP3-shRNA', 'Var', (9, 20))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('mitochondrial mass', 'MPA', (31, 49))	('prevented', 'NegReg', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('cell migration', 'biological_process', 'GO:0016477', ('195', '209'))	('aggressive cancer', 'Disease', 'MESH:D009369', (144, 161))	('increased mitochondrial mass', 'Phenotype', 'HP:0040014', (21, 49))	('abolished', 'NegReg', (225, 234))	('cell migration', 'CPA', (195, 209))	('aggressive cancer', 'Disease', (144, 161))
64226	24625986	We found that this attenuated aggressive behavior of these melanoma cells was underscored by severe changes in cell morphology and remodeling of the actin cytoskeleton associated with loss of BNIP3.	('aggressive behavior', 'biological_process', 'GO:0002118', ('30', '49'))	('aggressive behavior', 'CPA', (30, 49))	('aggressive behavior', 'Phenotype', 'HP:0000718', (30, 49))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('149', '167'))	('BNIP3', 'Gene', (192, 197))	('loss', 'Var', (184, 188))	('changes', 'Reg', (100, 107))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('attenuated', 'NegReg', (19, 29))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('cell morphology', 'CPA', (111, 126))
64228	24625986	Moreover, loss of BNIP3 resulted in re-organization of focal adhesion sites associated with increased levels of phosphorylated focal adhesion kinase.	('loss', 'Var', (10, 14))	('focal adhesion', 'cellular_component', 'GO:0005925', ('127', '141'))	('focal adhesion kinase', 'Gene', (127, 148))	('BNIP3', 'Gene', (18, 23))	('increased', 'PosReg', (92, 101))	('focal adhesion kinase', 'Gene', '14083', (127, 148))	('re-organization', 'CPA', (36, 51))	('focal adhesion', 'cellular_component', 'GO:0005925', ('55', '69'))	('focal adhesion sites', 'CPA', (55, 75))
64229	24625986	Remarkably, BNIP3 silencing led to a drop of the protein levels of the integrin-associated protein CD47 and its downstream signaling effectors Rac1 and Cdc42.	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('protein levels of', 'MPA', (49, 66))	('silencing', 'Var', (18, 27))	('Cdc42', 'Gene', (152, 157))	('integrin-associated protein', 'Gene', '16423', (71, 98))	('integrin-associated protein', 'Gene', (71, 98))	('Rac1', 'Gene', '19353', (143, 147))	('Rac1', 'Gene', (143, 147))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('Cdc42', 'Gene', '12540', (152, 157))	('drop', 'NegReg', (37, 41))	('CD47', 'MPA', (99, 103))	('BNIP3', 'Gene', (12, 17))
64248	24625986	Since BNIP3 is an atypical BH3-only protein with a contextual role in cancer cell death, we first tested the effects of BNIP3 knockdown (KD) on melanoma survival and long-term clonogenic growth.	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('BNIP3', 'Gene', (120, 125))	('tested', 'Reg', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('cell death', 'biological_process', 'GO:0008219', ('77', '87'))	('knockdown', 'Var', (126, 135))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
64250	24625986	Notably, BNIP3 KD almost completely abrogated melanoma's long-term clonogenic growth (Figure 1c, Supplementary Figure S1B), underscoring its essential pro-survival role.	('pro-survival', 'biological_process', 'GO:0043066', ('151', '163'))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('long-term clonogenic growth', 'CPA', (57, 84))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('abrogated', 'NegReg', (36, 45))	('BNIP3 KD', 'Var', (9, 17))
64254	24625986	In addition, immunocytochemistry with anti-TOMM20 antibody (Figure 2e), revealed a dense and disorganized mitochondrial network in BNIP3 knocked down cells.	('mitochondrial network', 'CPA', (106, 127))	('antibody', 'cellular_component', 'GO:0019815', ('50', '58'))	('TOMM20', 'Gene', (43, 49))	('knocked down', 'Var', (137, 149))	('antibody', 'cellular_component', 'GO:0019814', ('50', '58'))	('antibody', 'molecular_function', 'GO:0003823', ('50', '58'))	('TOMM20', 'Gene', '67952', (43, 49))	('antibody', 'cellular_component', 'GO:0042571', ('50', '58'))	('BNIP3', 'Gene', (131, 136))
64259	24625986	Since BNIP3 silencing increased the levels of intracellular ROS, we next analyzed the migratory ability of BNIP3-shRNA transduced cells by monitoring wound healing closure as a function of time (during 0-18 h).	('wound healing', 'biological_process', 'GO:0042060', ('150', '163'))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('BNIP3', 'Gene', (6, 11))	('N', 'Chemical', 'MESH:D009584', (108, 109))	('intracellular', 'cellular_component', 'GO:0005622', ('46', '59'))	('silencing', 'Var', (12, 21))	('increased', 'PosReg', (22, 31))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))	('levels of intracellular ROS', 'MPA', (36, 63))
64261	24625986	The addition of the antioxidant N-acetylcysteine (NAC) reduced the migration of control melanoma cells and it further aggravated the effect of BNIP3 KD (Supplementary Figure S2B) in line with previous reports indicating that ROS promote cell migration.	('NAC', 'cellular_component', 'GO:0005854', ('50', '53'))	('cell migration', 'CPA', (237, 251))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('reduced', 'NegReg', (55, 62))	('melanoma', 'Disease', (88, 96))	('NAC', 'Chemical', 'MESH:D000111', (50, 53))	('aggravated', 'PosReg', (118, 128))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('cell migration', 'biological_process', 'GO:0016477', ('237', '251'))	('migration', 'CPA', (67, 76))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (32, 48))	('BNIP3 KD', 'Var', (143, 151))
64262	24625986	Since loss of BNIP3 increased baseline ROS production (Figure 2b) over controls, these results also indicate that the reduced migratory capacity of the untreated BNIP3 silenced melanoma cells relies on mechanisms that are ROS independent.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('increased', 'PosReg', (20, 29))	('loss', 'Var', (6, 10))	('reduced', 'NegReg', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('BNIP3', 'Gene', (14, 19))	('migratory capacity', 'CPA', (126, 144))	('baseline ROS production', 'MPA', (30, 53))	('melanoma', 'Disease', (177, 185))	('increased baseline ROS production', 'Phenotype', 'HP:0025464', (20, 53))	('BNIP3', 'Gene', (162, 167))	('ROS', 'Chemical', 'MESH:D017382', (222, 225))
64265	24625986	In contrast, BNIP3 KD completely abrogated the ability of melanoma cells to form capillary structures (Figure 3b, Supplementary Figure S2C).	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('abrogated', 'NegReg', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))	('BNIP3 KD', 'Var', (13, 21))
64267	24625986	12 h), BNIP3 KD had minimal impact on melanoma viability as measured by PI exclusion (Figure 1b).	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BNIP3 KD', 'Var', (7, 15))	('melanoma viability', 'Disease', 'MESH:D008545', (38, 56))	('melanoma viability', 'Disease', (38, 56))
64269	24625986	Light microscopy analysis of BNIP3-silenced melanoma cells, revealed that loss of BNIP3 in melanoma cells had a striking effect on cellular morphology.	('effect', 'Reg', (121, 127))	('BNIP3', 'Gene', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('cellular morphology', 'CPA', (131, 150))	('loss', 'Var', (74, 78))
64270	24625986	BNIP3-shRNA expressing B16-F10 melanoma cells displayed a flat shape and an increased cell and nuclear size as compared with control cells (Figure 4a, quantified in Figures 4b and c).	('B16-F10', 'CellLine', 'CVCL:0159', (23, 30))	('increased', 'PosReg', (76, 85))	('flat shape', 'CPA', (58, 68))	('B16-F10', 'Var', (23, 30))	('BNIP3-shRNA', 'Gene', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (1, 2))
64274	24625986	B16-F10 cells expressing BNIP3-shRNA displayed a reduced number of lamellipodia (arrows Figure 4e) and filopodia (arrows Figure 4f).	('filopodia', 'CPA', (103, 112))	('reduced', 'NegReg', (49, 56))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('B16-F10', 'CellLine', 'CVCL:0159', (0, 7))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('BNIP3-shRNA', 'Var', (25, 36))
64277	24625986	Remarkably, this BNIP3-mediated cytoskeletal phenotype was not mimicked by silencing the essential autophagy gene Atg5 (Supplementary Figure S3C,D) in melanoma cells, thus indicating that defects in the core autophagy machinery are not sufficient to explain the dramatic changes in the cytoskeletal architecture caused by loss of BNIP3 expression.	('Atg5', 'Gene', '11793', (114, 118))	('autophagy', 'biological_process', 'GO:0016236', ('99', '108'))	('core', 'cellular_component', 'GO:0019013', ('203', '207'))	('autophagy', 'biological_process', 'GO:0016236', ('208', '217'))	('autophagy', 'biological_process', 'GO:0006914', ('99', '108'))	('autophagy', 'biological_process', 'GO:0006914', ('208', '217'))	('changes', 'Reg', (271, 278))	('loss', 'Var', (322, 326))	('melanoma', 'Disease', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('Atg5', 'Gene', (114, 118))	('BNIP3', 'Gene', (330, 335))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
64278	24625986	Given the major function played by BNIP3 in the maintenance of the actin cytoskeleton and cell migration, we then assessed the impact of loss of BNIP3 on FAs.	('cell migration', 'biological_process', 'GO:0016477', ('90', '104'))	('FAs', 'Chemical', 'MESH:C038178', (154, 157))	('cell migration', 'CPA', (90, 104))	('BNIP3', 'Gene', (35, 40))	('BNIP3', 'Gene', (145, 150))	('loss', 'Var', (137, 141))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('67', '85'))
64289	24625986	Moreover, BNIP3 silencing also affected the activation status of Rac1 and Cdc42 as measured by p21-activated kinase (PAK)-based pull-down assays, since PAK is a direct Cdc42 and Rac1 effector that associates only with their GTP-bound forms (Figure 6b).	('Cdc42', 'Gene', '12540', (74, 79))	('affected', 'Reg', (31, 39))	('BNIP3', 'Gene', (10, 15))	('activation', 'MPA', (44, 54))	('Cdc42', 'Gene', (74, 79))	('GTP', 'Chemical', 'MESH:D006160', (224, 227))	('silencing', 'Var', (16, 25))	('Rac1', 'Gene', '19353', (178, 182))	('Cdc42', 'Gene', '12540', (168, 173))	('Rac1', 'Gene', (65, 69))	('Rac1', 'Gene', '19353', (65, 69))	('Rac1', 'Gene', (178, 182))	('Cdc42', 'Gene', (168, 173))
64292	24625986	Counteracting either Rac1 activity with Ehop-016 or Cdc42 activity with ML141, two small molecule inhibitors specific for these Rho GTPase members, reduced the production of lamellipodia (Ehop-016) or filopodia (ML141) protrusions in B16-F10 cells (Supplementary Figures S4A and B), thus confirming their inhibitory effects.	('Ehop-016', 'Chemical', '-', (40, 48))	('ML141', 'Chemical', '-', (212, 217))	('Ehop-016', 'Chemical', '-', (188, 196))	('Cdc42', 'Gene', (52, 57))	('filopodia', 'CPA', (201, 210))	('reduced', 'NegReg', (148, 155))	('ML141', 'Chemical', '-', (72, 77))	('Rac1', 'Gene', '19353', (21, 25))	('Rac1', 'Gene', (21, 25))	('GTP', 'Chemical', 'MESH:D006160', (132, 135))	('B16-F10', 'CellLine', 'CVCL:0159', (234, 241))	('lamellipodia', 'CPA', (174, 186))	('ML141', 'Var', (212, 217))	('Ehop-016', 'Var', (188, 196))	('Cdc42', 'Gene', '12540', (52, 57))
64294	24625986	Thus, a reduced expression/activity of these cytoskeleton effectors in BNIP3 knocked down cells could contribute, at least in part, to the inhibitory effects of BNIP3 on melanoma cell migration and VM.	('knocked down', 'Var', (77, 89))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('45', '57'))	('melanoma cell migration', 'Disease', 'MESH:D008545', (170, 193))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('BNIP3', 'Gene', (71, 76))	('melanoma cell migration', 'Disease', (170, 193))	('cell migration', 'biological_process', 'GO:0016477', ('179', '193'))	('reduced', 'NegReg', (8, 15))	('expression/activity', 'MPA', (16, 35))
64299	24625986	Along with CD47, BNIP3 KD reduced the protein levels of the adherens junction protein VE-cadherin and the tight junction protein ZO-1 (Figure 7c), as also evidenced by the reduction in ZO-1 foci in BNIP3-silenced cells by immunocytochemistry (Figure 7d).	('tight junction protein ZO-1', 'Gene', (106, 133))	('BNIP3 KD', 'Var', (17, 25))	('ZO-1', 'Gene', (129, 133))	('protein levels', 'MPA', (38, 52))	('ZO-1', 'Gene', '21872', (129, 133))	('adherens junction', 'cellular_component', 'GO:0005912', ('60', '77'))	('VE-cadherin', 'Gene', '12562', (86, 97))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('tight junction protein ZO-1', 'Gene', '21872', (106, 133))	('reduced', 'NegReg', (26, 33))	('ZO-1', 'Gene', '21872', (185, 189))	('tight junction', 'cellular_component', 'GO:0070160', ('106', '120'))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('ZO-1', 'Gene', (185, 189))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('reduction', 'NegReg', (172, 181))	('VE-cadherin', 'Gene', (86, 97))
64301	24625986	The addition of the inhibitor of the proteasome MG132 to BNIP3-shRNA cells led to a reestablishment in CD47 protein levels (Figure 7e), suggesting that increased proteasomal degradation of CD47 occurs in BNIP3-silenced cells.	('N', 'Chemical', 'MESH:D009584', (205, 206))	('MG132', 'Chemical', 'MESH:C072553', (48, 53))	('MG132', 'Var', (48, 53))	('proteasomal degradation', 'MPA', (162, 185))	('proteasome', 'molecular_function', 'GO:0004299', ('37', '47'))	('CD47 protein levels', 'MPA', (103, 122))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('proteasome', 'cellular_component', 'GO:0000502', ('37', '47'))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('degradation', 'biological_process', 'GO:0009056', ('174', '185'))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
64302	24625986	Moreover, blockage of V-ATPase-driven endosomal/lysosomal acidification by Bafilomycin A1, also rescued CD47 levels in BNIP3-knocked down cells (Figure 7e), thus implying that while basal CD47 turnover in melanoma cells is relatively slow, loss of BNIP3 might also stimulates the lysosomal degradation of CD47.	('V-ATPase', 'Gene', (22, 30))	('acidification', 'biological_process', 'GO:0045851', ('58', '71'))	('rescued CD47 levels', 'MPA', (96, 115))	('loss', 'Var', (240, 244))	('Bafilomycin', 'Chemical', '-', (75, 86))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('V-ATPase', 'cellular_component', 'GO:0008245', ('22', '30'))	('V-ATPase', 'Gene', '242341', (22, 30))	('degradation', 'biological_process', 'GO:0009056', ('290', '301'))	('BNIP3', 'Gene', (248, 253))	('stimulates', 'PosReg', (265, 275))	('V-ATPase', 'cellular_component', 'GO:0000219', ('22', '30'))	('lysosomal degradation', 'MPA', (280, 301))
64308	24625986	In this study, we show for the first time that altering baseline BNIP3 expression in melanoma cells causes aberrations in the actin cytoskeletal organization, thereby impairing hallmarks of aggressive tumors, like migration and VM.	('aggressive tumors', 'Disease', 'MESH:D001523', (190, 207))	('altering', 'Var', (47, 55))	('BNIP3', 'Gene', (65, 70))	('aggressive tumors', 'Disease', (190, 207))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('impairing', 'NegReg', (167, 176))	('melanoma', 'Disease', (85, 93))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('actin cytoskeletal organization', 'MPA', (126, 157))
64309	24625986	First, we show that BNIP3 in melanoma helps controlling redox status compatible with cell viability, most likely by removing the excess of ROS-producing mitochondria, since silencing BNIP3 expression provokes an increase in the amount of ROS and doubles mitochondrial mass.	('excess', 'MPA', (129, 135))	('mitochondrial mass', 'MPA', (254, 272))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('doubles', 'PosReg', (246, 253))	('amount of ROS', 'MPA', (228, 241))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('silencing', 'Var', (173, 182))	('ROS', 'Chemical', 'MESH:D017382', (238, 241))	('mitochondria', 'cellular_component', 'GO:0005739', ('153', '165'))	('increase', 'PosReg', (212, 220))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))	('BNIP3', 'Gene', (183, 188))
64314	24625986	They rather suggest that loss of BNIP3 affects migration and abolishes VM by modulating additional mechanisms, which may counterbalance the effects of increased ROS signaling on these processes, as discussed below.	('BNIP3', 'Gene', (33, 38))	('loss', 'Var', (25, 29))	('ROS', 'Chemical', 'MESH:D017382', (161, 164))	('abolishes', 'NegReg', (61, 70))	('increased ROS signaling', 'Phenotype', 'HP:0025464', (151, 174))	('affects', 'Reg', (39, 46))	('migration', 'CPA', (47, 56))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('modulating', 'Reg', (77, 87))
64315	24625986	Second, we show that loss of BNIP3 causes profound morphological alterations of melanoma cells coupled with striking changes in the dynamic organization of the actin filaments, required to form lamellipodia and filopodia, driving cell migration.	('loss', 'Var', (21, 25))	('cell migration', 'CPA', (230, 244))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('driving', 'PosReg', (222, 229))	('changes', 'Reg', (117, 124))	('cell migration', 'biological_process', 'GO:0016477', ('230', '244'))	('dynamic organization of the actin filaments', 'MPA', (132, 175))	('BNIP3', 'Gene', (29, 34))
64317	24625986	BNIP3 silencing reduced CD47 protein levels, whereas a physiologically relevant increase in BNIP3 protein levels, induced by hypoxia, augmented CD47 protein levels in melanoma cells.	('hypoxia', 'Disease', (125, 132))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('BNIP3', 'Gene', (92, 97))	('CD47 protein levels', 'MPA', (144, 163))	('increase', 'PosReg', (80, 88))	('BNIP3', 'Gene', (0, 5))	('reduced', 'NegReg', (16, 23))	('CD47 protein levels', 'MPA', (24, 43))	('protein levels', 'MPA', (98, 112))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('hypoxia', 'Disease', 'MESH:D000860', (125, 132))	('silencing', 'Var', (6, 15))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('augmented', 'PosReg', (134, 143))
64320	24625986	Here we show that BNIP3 silencing alters CD47-modulated intracellular complexes regulating cytoskeletal dynamics, like Cdc42 and Rac1, members of the Rho-GTPases orchestrating cell spreading and movements.	('Rac1', 'Gene', '19353', (129, 133))	('alters', 'Reg', (34, 40))	('Rac1', 'Gene', (129, 133))	('intracellular', 'cellular_component', 'GO:0005622', ('56', '69'))	('Cdc42', 'Gene', '12540', (119, 124))	('BNIP3', 'Gene', (18, 23))	('CD47-modulated', 'Gene', (41, 55))	('Cdc42', 'Gene', (119, 124))	('silencing', 'Var', (24, 33))	('GTP', 'Chemical', 'MESH:D006160', (154, 157))
64321	24625986	In line with this, adhesion and cell spreading on vitronectin substratum of C32 melanoma were stimulated by CD47 expression.	('stimulated', 'PosReg', (94, 104))	('cell spreading', 'CPA', (32, 46))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('CD47', 'Gene', (108, 112))	('C32 melanoma', 'Disease', (76, 88))	('expression', 'Var', (113, 123))	('C32 melanoma', 'Disease', 'MESH:D008545', (76, 88))	('vitronectin', 'Gene', '22370', (50, 61))	('vitronectin', 'Gene', (50, 61))
64324	24625986	On the other hand, the persistence of bundles of actin stress fibers and elevated integrin-P-FAK complexes in BNIP3-shRNA expressing cells suggest that disturbing BNIP3 function unbalances the spatio-temporal dynamics of multiple Rho GTPase family members, resulting in a unique actin cytoskeletal phenotype.	('actin cytoskeletal phenotype', 'MPA', (279, 307))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('GTP', 'Chemical', 'MESH:D006160', (234, 237))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('function', 'Var', (169, 177))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('disturbing', 'Var', (152, 162))	('FAK', 'Gene', '14083', (93, 96))	('BNIP3', 'Gene', (163, 168))	('FAK', 'Gene', (93, 96))	('FAK', 'molecular_function', 'GO:0004717', ('93', '96'))
64327	24625986	Irrespective of the complex crosstalk between Rho GTPase family members, which requires further studies, the loss of clonogenic survival and abolishment of VM phenotype caused by loss of BNIP3 in melanoma cells, indicate that rather than affecting a particular mode of motility, BNIP3 modulates essential processes supporting cancer cell survival and spreading.	('GTP', 'Chemical', 'MESH:D006160', (50, 53))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('modulates', 'Reg', (285, 294))	('cancer', 'Disease', (326, 332))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('BNIP3', 'Gene', (187, 192))	('loss', 'Var', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
64340	24625986	Moreover, since CD47 is one of the few well-established 'don't-eat-me' signals that may enable cancer cells to escape phagocytosis by innate immune cells, our study implicates that loss of BNIP3 by reducing CD47 levels may enhance engulfment of melanoma cells and possibly reduce its evasion from phagocytic immunosurvelliance, an outstanding facet of this study that is currently under investigation in our laboratory.	('reduce', 'NegReg', (273, 279))	('engulfment', 'CPA', (231, 241))	('CD47', 'MPA', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('cancer', 'Disease', (95, 101))	('evasion', 'MPA', (284, 291))	('BNIP3', 'Gene', (189, 194))	('enhance', 'PosReg', (223, 230))	('phagocytosis', 'biological_process', 'GO:0006909', ('118', '130'))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('reducing', 'NegReg', (198, 206))	('loss', 'Var', (181, 185))
64354	24625986	Three shRNAs targeted against the murine mRNA coding for the proteins Atg5 (NM_053069; NM_053069; NM_053069) and BNIP3 (NM_009760; NM_009760; NM_009760) and for the human BNIP3 (NM_004052.2-800s1c1; NM_004052.2-226s1c1; NM_004052.2-184s1c1) were used.	('N', 'Chemical', 'MESH:D009584', (172, 173))	('Atg5', 'Gene', (70, 74))	('N', 'Chemical', 'MESH:D009584', (220, 221))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('N', 'Chemical', 'MESH:D009584', (76, 77))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('NM_053069', 'Var', (98, 107))	('NM_053069; NM_053069; NM_053069', 'Var', (76, 107))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (114, 115))	('NM_004052.2-226s1c1; NM_004052.2-184s1c1', 'Var', (199, 239))	('human', 'Species', '9606', (165, 170))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('murine', 'Species', '10090', (34, 40))	('N', 'Chemical', 'MESH:D009584', (199, 200))	('NM_004052.2-184s1c1', 'Var', (220, 239))	('NM_004052.2-800s1c1', 'Var', (178, 197))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('NM_009760; NM_009760; NM_009760', 'Var', (120, 151))	('Atg5', 'Gene', '11793', (70, 74))
64392	21623751	For site-specific analyses, melanomas were categorized as occurring on the head and neck (ICD-09 and ICD-10 codes: 1720-1724, C43 0-C43 4), trunk (codes 1725, C43 5), upper limb (codes 1726, C43 6), lower limb (codes 1727, C43 7) or unspecified site (codes 1728-1729, and C 43 8-C 43 9).	('ICD', 'Disease', 'OMIM:252500', (90, 93))	('codes 1727', 'Var', (211, 221))	('ICD', 'Disease', (90, 93))	('unspecified', 'Species', '32644', (233, 244))	('ICD', 'Disease', 'OMIM:252500', (101, 104))	('codes 1728-1729', 'Var', (251, 266))	('ICD', 'Disease', (101, 104))	('melanomas', 'Disease', (28, 37))	('C43', 'Var', (126, 129))	('lower limb', 'Phenotype', 'HP:0006385', (199, 209))	('neck', 'cellular_component', 'GO:0044326', ('84', '88'))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('codes 1726', 'Var', (179, 189))	('C43', 'Var', (159, 162))	('codes 1725', 'Var', (147, 157))	('trunk', 'cellular_component', 'GO:0043198', ('140', '145'))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))
64413	21623751	At the same time, changes in clothing fashions have also resulted in increases in sun exposure on previously littleexposed body sites like the trunk and limbs, and such exposure is specifically associated with melanoma at these sites.	('changes', 'Var', (18, 25))	('increases', 'PosReg', (69, 78))	('trunk', 'cellular_component', 'GO:0043198', ('143', '148'))	('sun exposure', 'MPA', (82, 94))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('associated with', 'Reg', (194, 209))
64437	33178596	Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis The worldwide incidence of skin cutaneous melanoma (SKCM) is increasing at a more rapid rate than other tumors.	('RNA', 'cellular_component', 'GO:0005562', ('9', '12'))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 175))	('Skin Cutaneous Melanoma Prognosis', 'Disease', 'MESH:C562393', (91, 124))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('Melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('skin cutaneous melanoma', 'Disease', (152, 175))	('Skin Cutaneous Melanoma Prognosis', 'Disease', (91, 124))	('tumors', 'Disease', (229, 235))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('RNA-Binding', 'molecular_function', 'GO:0003723', ('52', '63'))	('as', 'Gene', '112935892', (73, 75))	('Mutations', 'Var', (39, 48))	('as', 'Gene', '112935892', (191, 193))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('RNA Splicing', 'biological_process', 'GO:0008380', ('9', '21'))	('SKCM', 'Chemical', '-', (177, 181))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (96, 114))
64438	33178596	Aberrant alternative splicing (AS) is found to be common in cancer; however, how this process contributes to cancer prognosis still remains largely unknown.	('Aberrant alternative splicing', 'Var', (0, 29))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('AS', 'Gene', '112935892', (31, 33))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (60, 66))	('splicing', 'biological_process', 'GO:0045292', ('21', '29'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
64439	33178596	Mutations in RNA-binding proteins (RBPs) may trigger great changes in the splicing process.	('splicing', 'biological_process', 'GO:0045292', ('74', '82'))	('splicing process', 'MPA', (74, 90))	('RNA-binding', 'molecular_function', 'GO:0003723', ('13', '24'))	('RBP', 'Gene', (35, 38))	('changes', 'Reg', (59, 66))	('Mutations', 'Var', (0, 9))	('RBP', 'Gene', '57794', (35, 38))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('trigger', 'Reg', (45, 52))
64440	33178596	In this study, we comprehensively analyzed DNA and RNA sequencing data and clinical information of SKCM patients, together with widespread changes in splicing patterns induced by RBP mutations.	('SKCM', 'Chemical', '-', (99, 103))	('changes', 'Reg', (139, 146))	('mutations', 'Var', (183, 192))	('RBP', 'Gene', (179, 182))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('splicing patterns', 'MPA', (150, 167))	('RBP', 'Gene', '57794', (179, 182))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('RNA', 'cellular_component', 'GO:0005562', ('51', '54'))	('SKCM', 'Disease', (99, 103))	('patients', 'Species', '9606', (104, 112))
64441	33178596	We screened mRNA expression-related and prognosis-related mutations in RBPs and investigated the potential affections of RBP mutations on splicing patterns.	('mutations', 'Var', (58, 67))	('splicing', 'biological_process', 'GO:0045292', ('138', '146'))	('RBP', 'Gene', (121, 124))	('RBP', 'Gene', '57794', (121, 124))	('RBP', 'Gene', (71, 74))	('RBP', 'Gene', '57794', (71, 74))
64442	33178596	Mutations in 853 RBPs were demonstrated to be correlated with splicing aberrations (p < 0.01).	('RBP', 'Gene', (17, 20))	('splicing', 'biological_process', 'GO:0045292', ('62', '70'))	('RBP', 'Gene', '57794', (17, 20))	('correlated', 'Reg', (46, 56))	('Mutations', 'Var', (0, 9))	('splicing aberrations', 'MPA', (62, 82))
64443	33178596	Functional enrichment analysis revealed that these alternative splicing events (ASEs) may participate in tumor progress by regulating the modification process, cell-cycle checkpoint, metabolic pathways, MAPK signaling, PI3K-Akt signaling, and other important pathways in cancer.	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('160', '181'))	('modification process', 'MPA', (138, 158))	('cell-cycle checkpoint', 'CPA', (160, 181))	('MAPK signaling', 'biological_process', 'GO:0000165', ('203', '217'))	('cancer', 'Disease', (271, 277))	('alternative splicing', 'Var', (51, 71))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('Akt signaling', 'biological_process', 'GO:0043491', ('224', '237'))	('tumor', 'Disease', (105, 110))	('MAPK signaling', 'Pathway', (203, 217))	('regulating', 'Reg', (123, 133))	('metabolic pathways', 'Pathway', (183, 201))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('Akt', 'Gene', (224, 227))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('splicing', 'biological_process', 'GO:0045292', ('63', '71'))	('AS', 'Gene', '112935892', (80, 82))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Akt', 'Gene', '207', (224, 227))	('PI3K', 'molecular_function', 'GO:0016303', ('219', '223'))	('participate', 'Reg', (90, 101))
64444	33178596	We also constructed a prediction model based on overall survival-related AS events (OS-ASEs) affected by RBP mutations, which exhibited a good predict efficiency with the area under the curve of 0.989.	('RBP', 'Gene', '57794', (105, 108))	('as', 'Gene', '112935892', (40, 42))	('AS', 'Gene', '112935892', (73, 75))	('AS', 'Gene', '112935892', (87, 89))	('mutations', 'Var', (109, 118))	('RBP', 'Gene', (105, 108))
64445	33178596	Our work highlights the importance of RBP mutations in splicing alterations and provides effective biomarkers for prediction of prognosis of SKCM.	('SKCM', 'Disease', (141, 145))	('SKCM', 'Chemical', '-', (141, 145))	('RBP', 'Gene', (38, 41))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('RBP', 'Gene', '57794', (38, 41))	('splicing alterations', 'MPA', (55, 75))	('mutations', 'Var', (42, 51))
64449	33178596	Both genetic and epigenetic alterations that interfere with normal cell physiological function are the fundamental reason of tumorigenesis.	('as', 'Gene', '112935892', (117, 119))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('epigenetic alterations', 'Var', (17, 39))
64453	33178596	AS aberrations may lead to transcriptome variations in some cancer-related genes and in turn impact tumor progression as well as therapy resistance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lead to', 'Reg', (19, 26))	('AS', 'Gene', '112935892', (0, 2))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('as', 'Gene', '112935892', (118, 120))	('therapy resistance', 'CPA', (129, 147))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('transcriptome', 'MPA', (27, 40))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('as', 'Gene', '112935892', (126, 128))	('aberrations', 'Var', (3, 14))	('impact', 'Reg', (93, 99))
64457	33178596	Importantly, AS is regulated by a number of RNA-binding proteins (RBPs), mutations of which may trigger widespread splicing aberrations in downstream spliced genes.	('AS', 'Gene', '112935892', (13, 15))	('RBP', 'Gene', (66, 69))	('RBP', 'Gene', '57794', (66, 69))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('splicing', 'biological_process', 'GO:0045292', ('115', '123'))	('trigger', 'Reg', (96, 103))	('widespread splicing aberrations', 'MPA', (104, 135))	('mutations', 'Var', (73, 82))	('RNA-binding', 'molecular_function', 'GO:0003723', ('44', '55'))
64459	33178596	It is now clear that either mutations or expression changes in RBPs along with corresponding AS aberrations potentially have great value in exploring tumorigenesis and progression.	('expression', 'MPA', (41, 51))	('RBP', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('RBP', 'Gene', '57794', (63, 66))	('AS', 'Gene', '112935892', (93, 95))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('mutations', 'Var', (28, 37))
64460	33178596	Mutations or expression changes in splicing regulatory factors have been described as oncogenic drivers and would contribute to affecting oncogenic processes.	('splicing regulatory factors', 'Gene', (35, 62))	('as', 'Gene', '112935892', (83, 85))	('expression', 'MPA', (13, 23))	('oncogenic processes', 'CPA', (138, 157))	('Mutations', 'Var', (0, 9))	('splicing', 'biological_process', 'GO:0045292', ('35', '43'))	('affecting', 'Reg', (128, 137))
64461	33178596	However, recent studies focused on SKCM have several limitations: they only investigate one or a few genes, they lack effective biomarker identification, they are only reliable to a specific patient specimen, and there is no comprehensive investigation on how splicing regulatory factor aberrations contribute to SKCM development.	('SKCM', 'Chemical', '-', (313, 317))	('patient', 'Species', '9606', (191, 198))	('SKCM', 'Disease', (313, 317))	('splicing', 'biological_process', 'GO:0045292', ('260', '268'))	('aberrations', 'Var', (287, 298))	('SKCM', 'Chemical', '-', (35, 39))	('contribute', 'Reg', (299, 309))	('investigate', 'Reg', (76, 87))
64462	33178596	There still exists a demand of systematic investigation on how mutations or expression patterns of RBPs along with related AS changes contribute to SKCM survival outcomes.	('mutations', 'Var', (63, 72))	('RBP', 'Gene', (99, 102))	('AS', 'Gene', '112935892', (123, 125))	('RBP', 'Gene', '57794', (99, 102))	('SKCM survival', 'Disease', (148, 161))	('SKCM', 'Chemical', '-', (148, 152))	('contribute', 'Reg', (134, 144))
64463	33178596	Here, we systematically investigated the DNA and RNA sequencing data as well as clinical information of SKCM samples obtained from the Cancer Genome Atlas (TCGA) dataset, combined with ASE information from TCGA SpliceSeq data, so as to comprehensively describe the complex network of alterations in RBPs and their global effects in ASEs.	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('AS', 'Gene', '112935892', (332, 334))	('AS', 'Gene', '112935892', (185, 187))	('as', 'Gene', '112935892', (69, 71))	('SKCM', 'Chemical', '-', (104, 108))	('RNA', 'cellular_component', 'GO:0005562', ('49', '52'))	('as', 'Gene', '112935892', (152, 154))	('RBP', 'Gene', (299, 302))	('RBP', 'Gene', '57794', (299, 302))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('alterations', 'Var', (284, 295))	('as', 'Gene', '112935892', (77, 79))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))	('as', 'Gene', '112935892', (165, 167))	('as', 'Gene', '112935892', (230, 232))
64474	33178596	Samples with both RBP mutation data and AS information were selected in the study.	('AS', 'Gene', '112935892', (40, 42))	('RBP', 'Gene', '57794', (18, 21))	('mutation', 'Var', (22, 30))	('RBP', 'Gene', (18, 21))
64477	33178596	The Upset plot was constructed with the "UpSetR" package in R. Differential expression was analyzed between samples with or without RBP mutations.	('as', 'Gene', '112935892', (16, 18))	('mutations', 'Var', (136, 145))	('RBP', 'Gene', (132, 135))	('RBP', 'Gene', '57794', (132, 135))	('as', 'Gene', '112935892', (88, 90))
64478	33178596	The Wilcoxon-Mann-Whitney test was applied for estimating the correlations between RBP mutations and mRNA expression alterations, and RBPs were considered differentially expressed if p-value < 0.05.	('RBP', 'Gene', (134, 137))	('RBP', 'Gene', '57794', (134, 137))	('mRNA expression alterations', 'MPA', (101, 128))	('RBP', 'Gene', (83, 86))	('as', 'Gene', '112935892', (32, 34))	('RBP', 'Gene', '57794', (83, 86))	('mutations', 'Var', (87, 96))
64479	33178596	The association between RBPs with mRNA expression-related mutations and PSI value of ASEs was evaluated using Pearson correlation analysis; outcomes with  Cor >0.5 and p < 0.05 were regarded as significant correlation.	('mutations', 'Var', (58, 67))	('AS', 'Gene', '112935892', (85, 87))	('as', 'Gene', '112935892', (4, 6))	('mRNA expression-related', 'Gene', (34, 57))	('as', 'Gene', '112935892', (191, 193))	('RBP', 'Gene', (24, 27))	('as', 'Gene', '112935892', (91, 93))	('RBP', 'Gene', '57794', (24, 27))
64480	33178596	The bubble plots were visualized using "ggplot2" package in R. The association between RBP mutations and prognosis of SKCM were investigated using Kaplan-Meier survival estimate analysis.	('SKCM', 'Disease', (118, 122))	('as', 'Gene', '112935892', (67, 69))	('SKCM', 'Chemical', '-', (118, 122))	('mutations', 'Var', (91, 100))	('RBP', 'Gene', (87, 90))	('RBP', 'Gene', '57794', (87, 90))
64496	33178596	We first systematically investigated the splicing process alterations induced by RBP mutations.	('RBP', 'Gene', (81, 84))	('mutations', 'Var', (85, 94))	('RBP', 'Gene', '57794', (81, 84))	('splicing', 'biological_process', 'GO:0045292', ('41', '49'))
64498	33178596	The mutant situations of 1,350 known and predicted RBPs were studied in 467 SKCM samples, 452 of which were found to carry mutations in RBPs.	('RBP', 'Gene', (136, 139))	('SKCM', 'Chemical', '-', (76, 80))	('RBP', 'Gene', (51, 54))	('RBP', 'Gene', '57794', (136, 139))	('RBP', 'Gene', '57794', (51, 54))	('mutations', 'Var', (123, 132))
64501	33178596	As a result, mutations in 853 RBPs were found to be obviously correlated with 19748 different ASEs (Supplementary Table 2), including 1,655 AAs in 1,334 genes, 1,478 ADs in 1,161 genes, 3,681 APs in 2,280 genes, 3,665 ATs in 2,206 genes, 7,802 ESs in 4,178 genes, 85 MEs in 84 genes, and 1,382 RIs in 1,042 genes (Figures 2B,C).	('As', 'Gene', '112935892', (141, 143))	('RBP', 'Gene', '57794', (30, 33))	('AD', 'Disease', 'MESH:D000544', (166, 168))	('AD', 'Disease', (166, 168))	('AS', 'Gene', '112935892', (94, 96))	('mutations', 'Var', (13, 22))	('As', 'Gene', '112935892', (0, 2))	('RBP', 'Gene', (30, 33))
64503	33178596	The above results indicated that RBP mutations were significantly correlated with extensive AS alterations in SKCM.	('RBP', 'Gene', '57794', (33, 36))	('correlated', 'Reg', (66, 76))	('SKCM', 'Chemical', '-', (110, 114))	('mutations', 'Var', (37, 46))	('SKCM', 'Disease', (110, 114))	('AS', 'Gene', '112935892', (92, 94))	('RBP', 'Gene', (33, 36))
64504	33178596	We also investigated whether the aberrant splicing process driven by RBP mutations occurred as a consequence of mRNA expression alterations of RBPs.	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('RBP', 'Gene', (143, 146))	('RBP', 'Gene', (69, 72))	('RBP', 'Gene', '57794', (143, 146))	('splicing', 'MPA', (42, 50))	('RBP', 'Gene', '57794', (69, 72))	('as', 'Gene', '112935892', (92, 94))	('mutations', 'Var', (73, 82))
64505	33178596	To screen out mutations in RBPs that altered the mRNA expression level, we combined DNA and RNA sequencing data downloaded from TCGA and analyzed.	('mRNA expression level', 'MPA', (49, 70))	('altered', 'Reg', (37, 44))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('RBP', 'Gene', (27, 30))	('RBP', 'Gene', '57794', (27, 30))	('RNA', 'cellular_component', 'GO:0005562', ('92', '95'))	('mutations', 'Var', (14, 23))
64506	33178596	As a result, a total of 91 RBPs exhibited a significant differential expression between wild and mutant genotypes (Supplementary Table 3).	('RBP', 'Gene', (27, 30))	('RBP', 'Gene', '57794', (27, 30))	('mutant', 'Var', (97, 103))	('expression', 'MPA', (69, 79))	('differential', 'Reg', (56, 68))	('As', 'Gene', '112935892', (0, 2))
64507	33178596	In more details, RBPs with upregulated and downregulated mRNA expression levels in mutant samples compared to wild type were exhibited, respectively (Figure 3A).	('downregulated', 'NegReg', (43, 56))	('RBP', 'Gene', (17, 20))	('mutant', 'Var', (83, 89))	('RBP', 'Gene', '57794', (17, 20))	('mRNA expression levels', 'MPA', (57, 79))	('upregulated', 'PosReg', (27, 38))
64509	33178596	Then, we excavated the splicing alterations that may occur as a consequence of expression-associated RBP mutations described above.	('as', 'Gene', '112935892', (59, 61))	('as', 'Gene', '112935892', (90, 92))	('mutations', 'Var', (105, 114))	('RBP', 'Gene', (101, 104))	('splicing', 'biological_process', 'GO:0045292', ('23', '31'))	('RBP', 'Gene', '57794', (101, 104))
64516	33178596	The expression-associated RBP mutations discovered in this study and their affecting ASEs provide new information about RBP mutations with a potential role in physiological function regulation of SKCM.	('SKCM', 'Chemical', '-', (196, 200))	('AS', 'Gene', '112935892', (85, 87))	('RBP', 'Gene', (120, 123))	('regulation', 'biological_process', 'GO:0065007', ('182', '192'))	('RBP', 'Gene', '57794', (120, 123))	('as', 'Gene', '112935892', (15, 17))	('mutations', 'Var', (30, 39))	('RBP', 'Gene', (26, 29))	('RBP', 'Gene', '57794', (26, 29))
64517	33178596	To further define whether mutations in RBPs could influence the survival outcomes of SKCM patients, the DNA sequencing data of 1,350 RBPs and clinical information of 177 SKCM patients with RBP mutations were combined and analyzed.	('SKCM', 'Chemical', '-', (85, 89))	('RBP', 'Gene', '57794', (39, 42))	('RBP', 'Gene', '57794', (133, 136))	('RBP', 'Gene', (189, 192))	('RBP', 'Gene', '57794', (189, 192))	('mutations', 'Var', (26, 35))	('SKCM', 'Chemical', '-', (170, 174))	('patients', 'Species', '9606', (175, 183))	('DNA', 'cellular_component', 'GO:0005574', ('104', '107'))	('patients', 'Species', '9606', (90, 98))	('influence', 'Reg', (50, 59))	('RBP', 'Gene', (133, 136))	('RBP', 'Gene', (39, 42))
64518	33178596	By taking the Kaplan-Meier test, 43 RBPs were demonstrated to carry prognosis-associated mutations (p < 0.05) (Supplementary Table 5).	('RBP', 'Gene', (36, 39))	('as', 'Gene', '112935892', (78, 80))	('RBP', 'Gene', '57794', (36, 39))	('mutations', 'Var', (89, 98))
64520	33178596	Among the 43 significant RBPs, mutations in 5 RBPs were regarded as high-risk factors (green dots), and for the rest of the 38 RBPs, the mutant type showed a lower-risk grade (yellow dots) (Figure 4B).	('RBP', 'Gene', (127, 130))	('mutations', 'Var', (31, 40))	('RBP', 'Gene', (25, 28))	('as', 'Gene', '112935892', (65, 67))	('RBP', 'Gene', '57794', (127, 130))	('RBP', 'Gene', '57794', (25, 28))	('RBP', 'Gene', (46, 49))	('RBP', 'Gene', '57794', (46, 49))
64521	33178596	In summary, mutations in the above 43 RBPs were found to have a significant correlation with the overall survival of SKCM patients, which indicated a promising efficiency of RBP mutations in prognosis prediction.	('correlation', 'Reg', (76, 87))	('RBP', 'Gene', (174, 177))	('RBP', 'Gene', '57794', (174, 177))	('mutations', 'Var', (12, 21))	('SKCM', 'Chemical', '-', (117, 121))	('RBP', 'Gene', (38, 41))	('patients', 'Species', '9606', (122, 130))	('RBP', 'Gene', '57794', (38, 41))	('mutations', 'Var', (178, 187))	('SKCM', 'Disease', (117, 121))
64523	33178596	There were 19,748 ASEs in 7,776 parent genes that showed a close correlation with RBP mutations (Supplementary Table 2, p < 0.01).	('mutations', 'Var', (86, 95))	('RBP', 'Gene', (82, 85))	('AS', 'Gene', '112935892', (18, 20))	('RBP', 'Gene', '57794', (82, 85))
64533	33178596	Univariable COX regression analysis was then performed to investigate all the overall survival-related ASEs (OS-ASEs) affected by RBP mutations (Supplementary Table 6).	('RBP', 'Gene', (130, 133))	('RBP', 'Gene', '57794', (130, 133))	('AS', 'Gene', '112935892', (103, 105))	('as', 'Gene', '112935892', (37, 39))	('mutations', 'Var', (134, 143))	('AS', 'Gene', '112935892', (112, 114))
64534	33178596	According to the volcano plot, a total of 919 OS-ASEs in 757 parent genes were identified as prognosis-associated ASEs (p < 0.05) (Figure 6A), which included 75 AAs in 74 genes, 86 ADs in 80 genes, 212 APs in 163 genes, 176 ATs in 122 genes, 320 ESs in 301 genes, 2 MEs in 2 genes, and 48 RIs in 47 genes (Figures 6B,C).	('ATs', 'Var', (224, 227))	('as', 'Gene', '112935892', (103, 105))	('as', 'Gene', '112935892', (90, 92))	('As', 'Gene', '112935892', (162, 164))	('AS', 'Gene', '112935892', (49, 51))	('AS', 'Gene', '112935892', (114, 116))	('AD', 'Disease', 'MESH:D000544', (181, 183))	('AD', 'Disease', (181, 183))
64539	33178596	LASSO regression analysis and multivariate Cox regression analysis were then performed to construct a prognostic model based on all types of OS-ASEs that are influenced by RBP mutations, among which 10 OS-ASEs were selected as candidate predict factors (Figures 8A,B).	('AS', 'Gene', '112935892', (144, 146))	('mutations', 'Var', (176, 185))	('as', 'Gene', '112935892', (224, 226))	('RBP', 'Gene', (172, 175))	('RBP', 'Gene', '57794', (172, 175))	('AS', 'Gene', '112935892', (205, 207))	('influenced', 'Reg', (158, 168))	('as', 'Gene', '112935892', (120, 122))	('AS', 'Gene', '112935892', (1, 3))
64545	33178596	We also constructed a prediction model based on RBP mutations to determine the prognosis value of RBPs themselves instead of their affections on ASEs (Supplementary Figure 4).	('mutations', 'Var', (52, 61))	('RBP', 'Gene', (98, 101))	('RBP', 'Gene', '57794', (98, 101))	('RBP', 'Gene', (48, 51))	('RBP', 'Gene', '57794', (48, 51))	('as', 'Gene', '112935892', (40, 42))	('AS', 'Gene', '112935892', (145, 147))
64546	33178596	Mutations in 13 RBPs were selected in this model (Supplementary Figures 4A,B; Supplementary Table 7), and the AUC value under the ROC curve was 0.527 (Supplementary Figure 4C).	('Mutations', 'Var', (0, 9))	('RBP', 'Gene', '57794', (16, 19))	('as', 'Gene', '112935892', (141, 143))	('RBP', 'Gene', (16, 19))
64547	33178596	This result indicated that mutations in RBPs affect SKCM progression and outcome mostly through regulating downstream ASEs instead of themselves.	('mutations', 'Var', (27, 36))	('affect', 'Reg', (45, 51))	('SKCM', 'Chemical', '-', (52, 56))	('regulating', 'Reg', (96, 106))	('AS', 'Gene', '112935892', (118, 120))	('RBP', 'Gene', (40, 43))	('SKCM', 'Disease', (52, 56))	('RBP', 'Gene', '57794', (40, 43))
64556	33178596	Candidates including S100B, ki-67, metallothioneins (MTs), and lactate dehydrogenase (LDH) were repeatedly demonstrated to associate with poor clinical outcomes of SKCM patients.	('SKCM', 'Chemical', '-', (164, 168))	('patients', 'Species', '9606', (169, 177))	('S100B', 'Gene', '6285', (21, 26))	('ki-67', 'Var', (28, 33))	('S100B', 'Gene', (21, 26))	('as', 'Gene', '112935892', (81, 83))	('SKCM', 'Disease', (164, 168))	('as', 'Gene', '112935892', (123, 125))
64557	33178596	Genetic biomarkers such as specific mutations in BRAF and NRAS were also considered to have prognostic implication in SKCM.	('NRAS', 'Gene', '4893', (58, 62))	('as', 'Gene', '112935892', (24, 26))	('SKCM', 'Disease', (118, 122))	('mutations', 'Var', (36, 45))	('SKCM', 'Chemical', '-', (118, 122))	('BRAF', 'Gene', '673', (49, 53))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (49, 53))
64562	33178596	Currently, an increasing number of evidences have been proposed to regard the alternative splicing as an effective indicator of carcinogenic processes.	('alternative splicing', 'Var', (78, 98))	('carcinogenic', 'Disease', 'MESH:D063646', (128, 140))	('as', 'Gene', '112935892', (19, 21))	('carcinogenic', 'Disease', (128, 140))	('as', 'Gene', '112935892', (99, 101))	('splicing', 'biological_process', 'GO:0045292', ('90', '98'))
64567	33178596	ASEs were mostly regulated by a series of RBPs, whose mutations may contribute to many of AS alterations observed in cancer.	('AS', 'Gene', '112935892', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (54, 63))	('RBP', 'Gene', (42, 45))	('AS', 'Gene', '112935892', (90, 92))	('contribute', 'Reg', (68, 78))	('RBP', 'Gene', '57794', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
64568	33178596	In the past few years, increasing researches have revealed the significant role of RBP mutations in prognosis prediction in multiple cancer types, while their role in SKCM prognosis has not been discussed yet.	('as', 'Gene', '112935892', (28, 30))	('SKCM', 'Chemical', '-', (167, 171))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('as', 'Gene', '112935892', (183, 185))	('as', 'Gene', '112935892', (8, 10))	('RBP', 'Gene', (83, 86))	('cancer', 'Disease', (133, 139))	('RBP', 'Gene', '57794', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (87, 96))
64569	33178596	To determine the underlying mechanism, we deeply investigated the potential regulatory associations between RBP mutations and ASEs, so as to provide insight into the phenotype changes of ASEs in SKCM and contribute to precision treatment.	('as', 'Gene', '112935892', (87, 89))	('as', 'Gene', '112935892', (135, 137))	('mutations', 'Var', (112, 121))	('RBP', 'Gene', (108, 111))	('RBP', 'Gene', '57794', (108, 111))	('AS', 'Gene', '112935892', (187, 189))	('SKCM', 'Disease', (195, 199))	('SKCM', 'Chemical', '-', (195, 199))	('AS', 'Gene', '112935892', (126, 128))
64571	33178596	We then systematically investigated RBP mutations that correlated with mRNA expression, overall survival, and ASEs, as well as the overall situation, interaction network, and enriched pathways of related spliced genes.	('correlated', 'Reg', (55, 65))	('as', 'Gene', '112935892', (124, 126))	('mRNA expression', 'MPA', (71, 86))	('AS', 'Gene', '112935892', (110, 112))	('mutations', 'Var', (40, 49))	('as', 'Gene', '112935892', (116, 118))	('RBP', 'Gene', (36, 39))	('RBP', 'Gene', '57794', (36, 39))
64573	33178596	In our study, 19,748 ASEs were identified to associate with RBP mutations.	('as', 'Gene', '112935892', (45, 47))	('AS', 'Gene', '112935892', (21, 23))	('mutations', 'Var', (64, 73))	('RBP', 'Gene', (60, 63))	('RBP', 'Gene', '57794', (60, 63))
64577	33178596	The final prediction model based on all types of ASEs consists of 10 spliced events, including MTMR14-63114-ES, BATF2-16723-AP, ME1-76870-ES, URI1-48867-ES, ITGB1BP1-52620-ES, DNM2-47584-AA, EXOC6-12541-AP, OSCP1-1775-AP, ING2-71271-AP, and ZNF83-51481-AT.	('ING2', 'Gene', (222, 226))	('OSCP1', 'Gene', (207, 212))	('BATF2', 'Gene', '116071', (112, 117))	('MTMR14', 'Gene', (95, 101))	('DNM2', 'Gene', '1785', (176, 180))	('BATF2', 'Gene', (112, 117))	('EXOC6', 'Gene', '54536', (191, 196))	('ING2', 'Gene', '3622', (222, 226))	('as', 'Gene', '112935892', (28, 30))	('MTMR14', 'Gene', '64419', (95, 101))	('ITGB1BP1', 'Gene', '9270', (157, 165))	('URI1', 'Gene', '8725', (142, 146))	('DNM2', 'Gene', (176, 180))	('ZNF83', 'Gene', (241, 246))	('URI1', 'Gene', (142, 146))	('OSCP1', 'Gene', '127700', (207, 212))	('ZNF83', 'Gene', '55769', (241, 246))	('AS', 'Gene', '112935892', (49, 51))	('EXOC6', 'Gene', (191, 196))	('ME1-76870-ES', 'Var', (128, 140))	('ITGB1BP1', 'Gene', (157, 165))
64580	33178596	According to our research, we revealed a novel network between RBPs and alternative splicing changes in SKCM that provide sufficient resources of information to understand the molecular mechanism of, and potentially reverse, the tumorigenesis and survival outcomes.	('alternative splicing changes', 'Var', (72, 100))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('SKCM', 'Chemical', '-', (104, 108))	('RBP', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('splicing', 'biological_process', 'GO:0045292', ('84', '92'))	('tumor', 'Disease', (229, 234))	('RBP', 'Gene', '57794', (63, 66))	('SKCM', 'Gene', (104, 108))
64581	33178596	One core implication of our research for SKCM prognostic and clinical studies is to expand the functional effects of genetic and epigenetic alterations into changes included in the AS process of genes involved in tumor-related pathways.	('tumor', 'Disease', (213, 218))	('SKCM', 'Chemical', '-', (41, 45))	('AS', 'Gene', '112935892', (181, 183))	('epigenetic alterations', 'Var', (129, 151))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('core', 'cellular_component', 'GO:0019013', ('4', '8'))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
64583	33178596	Besides, given the high prevalence of splicing defects in tumor, several small molecule modulators targeting RNA processing have been explored and exhibited promising therapeutic effects in tumor treatment.	('splicing', 'Var', (38, 46))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('splicing', 'biological_process', 'GO:0045292', ('38', '46'))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('RNA', 'cellular_component', 'GO:0005562', ('109', '112'))	('RNA processing', 'biological_process', 'GO:0006396', ('109', '123'))
64585	33178596	Certainly, more researches concerning the molecular mechanism of significant RBP mutations on AS regulation are needed in the future.	('RBP', 'Gene', '57794', (77, 80))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('AS', 'Gene', '112935892', (94, 96))	('mutations', 'Var', (81, 90))	('RBP', 'Gene', (77, 80))
64587	33178596	In conclusion, our research described a comprehensive landscape of aberrant alternative splicing and its regulation in SKCM.	('aberrant alternative splicing', 'Var', (67, 96))	('SKCM', 'Disease', (119, 123))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('SKCM', 'Chemical', '-', (119, 123))	('regulation', 'biological_process', 'GO:0065007', ('105', '115'))
64610	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))
64611	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))	('loss', 'NegReg', (241, 245))	('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))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (88, 113))	('gaining 8q', 'Var', (131, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (62, 76))	('uveal melanoma', 'Disease', 'MESH:C536494', (62, 76))
64612	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))
64614	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'))
64617	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))
64619	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))
64620	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))
64624	31109147	GNAQ and GNA11 mutations promote YAP activation and its nuclear localisation.	('GNA11', 'Gene', (9, 14))	('GNAQ', 'Gene', '2776', (0, 4))	('activation', 'PosReg', (37, 47))	('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))
64627	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))	('uveal melanoma', 'Disease', 'MESH:C536494', (100, 114))	('p.Leu129Gln', 'Var', (200, 211))	('CYSLTR2', 'Gene', '57105', (181, 188))	('p.Leu129Gln', 'Mutation', 'p.L129Q', (200, 211))	('uveal melanoma', 'Disease', (100, 114))	('CYSLTR2', 'Gene', (181, 188))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('patients', 'Species', '9606', (86, 94))
64628	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))	('PLCB4', 'Gene', '5332', (79, 84))	('GNAQ', 'Gene', '2776', (63, 67))	('GNA11', 'Gene', (69, 74))	('activate', 'PosReg', (141, 149))	('PLCB4', 'Gene', (79, 84))	('GNAQ', 'Gene', (63, 67))	('GNA11', 'Gene', '2767', (69, 74))
64629	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))	('CYSLTR2', 'Gene', (44, 51))	('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))
64631	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))
64633	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))
64634	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))
64637	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'))
64641	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))
64643	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))
64644	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))
64645	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))
64647	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'))
64648	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'))
64649	31109147	SF3B1 mutation has been found in about 15% to 19% of UM cases.	('UM', 'Phenotype', 'HP:0007716', (53, 55))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('mutation', 'Var', (6, 14))
64650	31109147	Interestingly, mutation in SF3B1 gene is mutually exclusive of BAP1 mutations and is usually associated with disomy of chromosome 3.	('mutation', 'Var', (15, 23))	('disomy of chromosome 3', 'Disease', (109, 131))	('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))
64653	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', 'Var', (39, 47))
64657	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))
64659	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))
64660	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))
64661	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))
64662	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))
64663	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))
64671	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))
64680	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))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('PRAME', 'Gene', '23532', (57, 62))	('uveal melanoma', 'Disease', 'MESH:C536494', (20, 34))	('tumours', 'Disease', (196, 203))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('PRAME', 'Gene', (57, 62))	('uveal melanoma', 'Phenotype', 'HP:0007716', (20, 34))	('uveal melanoma', 'Disease', (20, 34))	('SF3B1', 'Gene', (112, 117))
64681	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))
64685	31109147	In the onset/progression of different cancers, including UM, many chromosome aberrations and point mutations may occur.	('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))	('chromosome', 'Var', (66, 76))	('occur', 'Reg', (113, 118))
64689	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))
64701	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))	('103Pd', 'Var', (157, 162))	('106Ru', 'Var', (112, 117))	('ruthenium-106', 'Chemical', 'MESH:C000615522', (97, 110))	('iodine-125', 'Chemical', 'MESH:C000614960', (120, 130))	('palladium-103', 'Chemical', 'MESH:C000615531', (142, 155))
64736	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.	('patients', 'Species', '9606', (155, 163))	('survival', 'CPA', (61, 69))	('IHP', 'Var', (117, 120))	('patients', 'Species', '9606', (95, 103))
64758	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))
64761	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))
64772	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))
64777	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))
64783	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))
64789	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))
64808	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))
64844	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))
64848	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))
64878	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))
64907	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))
64910	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))
64924	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))
64949	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))	('antibodies', 'Var', (22, 32))	('anti-PD-1 antibodies', 'Var', (12, 32))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
64954	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))
64955	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))	('BRAF', 'Gene', '673', (137, 141))	('trametinib', 'Chemical', 'MESH:C560077', (185, 195))	('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))
64963	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))	('BRAF', 'Gene', '673', (151, 155))	('BRAF', 'Gene', (68, 72))	('trametinib', 'Chemical', 'MESH:C560077', (199, 209))	('MEK', 'Gene', '5609', (185, 188))	('BRAF', 'Gene', (151, 155))	('V600E', 'SUBSTITUTION', 'None', (73, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (230, 243))
64968	31947592	In phase 1 of the KEYNOTE-022 trial (NCT02130466), 15 BRAF-V600E/K-mutant patients were enrolled for triplet therapy.	('V600E', 'SUBSTITUTION', 'None', (59, 64))	('BRAF', 'Gene', '673', (54, 58))	('BRAF', 'Gene', (54, 58))	('patients', 'Species', '9606', (74, 82))	('V600E', 'Var', (59, 64))
65009	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))
65024	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))
65029	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))
65030	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))	('pembrolizumab', 'Chemical', 'MESH:C582435', (36, 49))	('longer', 'PosReg', (84, 90))	('recurrence-free survival', 'CPA', (91, 115))
65034	31947592	Anti-PD-1 antibodies such as nivolumab and pembrolizumab, achieved higher recurrence-free survival rates with lower toxicity.	('toxicity', 'Disease', 'MESH:D064420', (116, 124))	('nivolumab', 'Chemical', 'MESH:D000077594', (29, 38))	('toxicity', 'Disease', (116, 124))	('higher', 'PosReg', (67, 73))	('recurrence-free survival', 'CPA', (74, 98))	('pembrolizumab', 'Chemical', 'MESH:C582435', (43, 56))	('Anti-PD-1', 'Var', (0, 9))
65046	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))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('brain metastases', 'Disease', (182, 198))	('OS', 'Chemical', '-', (161, 163))	('melanoma', 'Disease', (111, 119))	('pembrolizumab', 'Chemical', 'MESH:C582435', (277, 290))	('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))	('brain metastases', 'Disease', 'MESH:D009362', (182, 198))	('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))	('ipilimumab', 'Chemical', 'MESH:D000074324', (241, 251))
65061	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))
65062	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))
65064	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))
65071	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))
65091	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))
65093	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))
65108	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))
65109	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))
65111	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))
65133	27746730	Some of key features of each type of tumor and individual patient's cancer including a specific pattern of DNA mutations, deletion, amplification, gene rearrangements, translocation, microsatellite instability, and epigenetic alterations have been revealed, but not fully understood.	('mutations', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('gene rearrangements', 'Var', (147, 166))	('amplification', 'Var', (132, 145))	('translocation', 'Var', (168, 181))	('patient', 'Species', '9606', (58, 65))	('microsatellite instability', 'Var', (183, 209))	('DNA', 'Gene', (107, 110))	('deletion', 'Var', (122, 130))	('tumor', 'Disease', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Disease', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))
65138	27746730	Initially, system-level approaches have revealed a number of genetic and epigenetic alterations that contribute to oncogenesis, progression and metastasis of cancer cells.	('contribute', 'Reg', (101, 111))	('epigenetic alterations', 'Var', (73, 95))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('oncogenesis', 'biological_process', 'GO:0007048', ('115', '126'))	('genetic', 'Var', (61, 68))	('metastasis of cancer', 'Disease', (144, 164))	('progression', 'CPA', (128, 139))	('oncogenesis', 'CPA', (115, 126))	('metastasis of cancer', 'Disease', 'MESH:D009362', (144, 164))
65149	27746730	For instance, Imatinib for the Abelson kinase (ABL), Lapatinib for epidermal growth factor receptor (EGFR) and ERBB2 transmembrane protein kinases, and novel inhibitors such as Vemurafenib to mutated BRAFV 600E protein kinase.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('67', '90'))	('transmembrane', 'cellular_component', 'GO:0016021', ('117', '130'))	('Lapatinib', 'Chemical', 'MESH:D000077341', (53, 62))	('ABL', 'Gene', '25', (47, 50))	('ERBB2', 'Gene', (111, 116))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (177, 188))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('transmembrane', 'cellular_component', 'GO:0044214', ('117', '130'))	('epidermal growth factor receptor', 'Gene', (67, 99))	('BRAFV', 'Gene', (200, 205))	('Abelson kinase', 'Gene', '25', (31, 45))	('ABL', 'Gene', (47, 50))	('Abelson kinase', 'Gene', (31, 45))	('ERBB2', 'Gene', '2064', (111, 116))	('epidermal growth factor receptor', 'Gene', '1956', (67, 99))	('Imatinib', 'Chemical', 'MESH:D000068877', (14, 22))	('mutated', 'Var', (192, 199))	('BRAFV 600E', 'Mutation', 'rs113488022', (200, 210))	('EGFR', 'Gene', (101, 105))	('protein kinase', 'Enzyme', (211, 225))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))
65176	27746730	CBioPortal has been cited in hundreds studies to describing mutational patterns of most common oncogene and tumor suppressor, insertion, deletion, and amplification that drive specific tumor-type, and prognosis in patients and entire cohort.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('patients', 'Species', '9606', (214, 222))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('deletion', 'Var', (137, 145))	('oncogene', 'Gene', (95, 103))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('amplification', 'Var', (151, 164))
65177	27746730	The user needs to follow up four-steps in the cBioPortal web interface and click on specific bottom to select: (1) a cancer study of interest, for example, skin cutaneous melanomas studies; (2) one or more genomic profiles, for example, mutations and copy number alterations; (3) a patient case set, for example, all complete TCGA patients with mutation, copy number, and mRNA data; and (4) a gene of interest using HUGO gene symbols or gene sets or pathways of interest.	('skin cutaneous melanomas', 'Disease', 'MESH:C562393', (156, 180))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (161, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (161, 179))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('skin cutaneous melanomas', 'Disease', (156, 180))	('patient', 'Species', '9606', (282, 289))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('cancer', 'Disease', (117, 123))	('copy number', 'Var', (355, 366))	('patient', 'Species', '9606', (331, 338))	('mutation', 'Var', (345, 353))	('patients', 'Species', '9606', (331, 339))
65186	27746730	BRAF missense mutation occurred in 51% of population.	('missense mutation', 'Var', (5, 22))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
65187	27746730	Interesting, one third of patients displayed both amplification and mutation in BRAF gene (columns in red and green).	('mutation', 'Var', (68, 76))	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', '673', (80, 84))	('patients', 'Species', '9606', (26, 34))
65190	27746730	A plot shows the correlation between BRAF mRNA expression and the putative copy-number alterations (gain or amplification; Figure 1D).	('copy-number alterations', 'Var', (75, 98))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', '673', (37, 41))
65191	27746730	The Kaplan-Meier overall survival curve (Figure 1E) indicates that the cases with BRAF mutation had higher overall survival than the cases without BRAF alterations (Logrank Test p = 0.0373).	('overall survival', 'MPA', (107, 123))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('higher', 'PosReg', (100, 106))	('mutation', 'Var', (87, 95))
65192	27746730	Figure 1F shows hot spot mutations across BRAF protein amino sequence and highlight frequently observed missense V600D/E/K/R mutations.	('BRAF', 'Gene', (42, 46))	('missense', 'Var', (104, 112))	('V600D', 'SUBSTITUTION', 'None', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('V600D', 'Var', (113, 118))	('BRAF', 'Gene', '673', (42, 46))
65206	27746730	Many other studies using different types of cell lines have confirmed literature results linking some specific gene mutations to EGFR, ERBB2, MET, PDGFR, ALK, and BRAF gene with the NCI-60 cell line sensitivity to kinase inhibitors.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('ALK', 'Gene', (154, 157))	('EGFR', 'Gene', '1956', (129, 133))	('MET', 'Gene', (142, 145))	('mutations', 'Var', (116, 125))	('ALK', 'Gene', '238', (154, 157))	('ERBB2', 'Gene', '2064', (135, 140))	('PDGFR', 'Gene', (147, 152))	('EGFR', 'Gene', (129, 133))	('PDGFR', 'Gene', '5159', (147, 152))	('ERBB2', 'Gene', (135, 140))	('NCI-60', 'CellLine', 'CVCL:A592', (182, 188))
65208	27746730	The authors identified, as expected, that the checkpoint genes TP53, ATM (ATM serine/threonine kinase), ATR (ATR serine/threonine kinase), MLH1 (mutL homolog 1), MSH3 (mutL homolog 3), and APC (adenomatous polyposis coli) were frequently mutated in these cell lines.	('ATM', 'Gene', (74, 77))	('ATM', 'Gene', '472', (69, 72))	('mutL homolog 1', 'Gene', '4292', (145, 159))	('TP53', 'Gene', '7157', (63, 67))	('mutL homolog 1', 'Gene', (145, 159))	('ATR', 'Gene', (109, 112))	('APC', 'Disease', 'MESH:D011125', (189, 192))	('APC', 'Disease', (189, 192))	('ATR', 'Gene', '545', (104, 107))	('MSH3', 'Gene', (162, 166))	('MLH1', 'Gene', (139, 143))	('MSH3', 'Gene', '4437', (162, 166))	('APC', 'cellular_component', 'GO:0005680', ('189', '192'))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (194, 220))	('ATM', 'Gene', '472', (74, 77))	('ATM', 'Gene', (69, 72))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (194, 220))	('adenomatous polyposis coli', 'Disease', (194, 220))	('MLH1', 'Gene', '4292', (139, 143))	('mutL homolog 3', 'Gene', '27030', (168, 182))	('TP53', 'Gene', (63, 67))	('ATR', 'Gene', '545', (109, 112))	('mutated', 'Var', (238, 245))	('mutL homolog 3', 'Gene', (168, 182))	('ATR', 'Gene', (104, 107))
65215	27746730	To illustrate CellMiner applicability we show in Figure 3 results of correlations of mutated BRAF gene expression and Vemurafenib drug activity against NCI-60 cell lines (Figure 3).	('correlations', 'Interaction', (69, 81))	('BRAF', 'Gene', (93, 97))	('gene expression', 'biological_process', 'GO:0010467', ('98', '113'))	('NCI-60', 'CellLine', 'CVCL:A592', (152, 158))	('mutated', 'Var', (85, 92))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (118, 129))	('BRAF', 'Gene', '673', (93, 97))
65217	27746730	Next, we used the toll "pattern comparison" to discovery similar drugs to target mutated BRAF (Figure 4).	('BRAF', 'Gene', (89, 93))	('mutated', 'Var', (81, 88))	('BRAF', 'Gene', '673', (89, 93))
65227	27746730	However, colon cancer patients with BRAFV 600E do not respond to these drugs.	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('BRAFV 600E', 'Mutation', 'rs113488022', (36, 46))	('patients', 'Species', '9606', (22, 30))	('colon cancer', 'Disease', (9, 21))	('BRAFV 600E', 'Var', (36, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
65233	27746730	Moreover, users can identify if the presence wild-type or mutated p53 gene expression influences drug cell death activity.	('p53', 'Gene', '7157', (66, 69))	('cell death', 'biological_process', 'GO:0008219', ('102', '112'))	('influences', 'Reg', (86, 96))	('drug cell death activity', 'CPA', (97, 121))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('mutated', 'Var', (58, 65))	('p53', 'Gene', (66, 69))
65234	27746730	We exemplified the use of this tool using mutated BRAF and Vemurafenib to discover that Dabrafenib has same molecular target (Figure 4).	('BRAF', 'Gene', (50, 54))	('mutated', 'Var', (42, 49))	('Dabrafenib', 'Chemical', 'MESH:C561627', (88, 98))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (59, 70))	('BRAF', 'Gene', '673', (50, 54))
65244	27746730	Cancer cells resistant to many cytotoxic compounds have been linked to widespread occurrence of deleted or down-regulated gene of the extrinsic signaling pathways, such as TNF family members and up-regulation or amplification of BCL2 protein family members of the intrinsic mitochondria pathways.	('protein', 'cellular_component', 'GO:0003675', ('234', '241'))	('TNF family members', 'Gene', (172, 190))	('gene', 'Gene', (122, 126))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('mitochondria', 'cellular_component', 'GO:0005739', ('274', '286'))	('intrinsic mitochondria pathways', 'Pathway', (264, 295))	('BCL2', 'Gene', '596', (229, 233))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('amplification', 'Var', (212, 225))	('regulation', 'biological_process', 'GO:0065007', ('198', '208'))	('down-regulated', 'NegReg', (107, 121))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('extrinsic signaling pathways', 'Pathway', (134, 162))	('BCL2', 'Gene', (229, 233))	('BCL2', 'molecular_function', 'GO:0015283', ('229', '233'))	('up-regulation', 'PosReg', (195, 208))
65245	27746730	In fact, a recent study using CMAP showed that LY294002, a PI3K inhibitor, and gossypol and AT-101, MCL1 or other anti-apoptotic BCL-2 family member inhibitors, were capable of reversing the prednisolone-resistance of MLL-rearranged Acute Lymphoblastic Leukemia (ALL) in infants.	('MLL', 'Gene', (218, 221))	('Acute Lymphoblastic Leukemia', 'Disease', 'MESH:D054198', (233, 261))	('LY294002', 'Chemical', 'MESH:C085911', (47, 55))	('CMAP', 'Gene', (30, 34))	('MCL1', 'Gene', '4170', (100, 104))	('Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006721', (233, 261))	('ALL', 'Phenotype', 'HP:0006721', (263, 266))	('prednisolone', 'Chemical', 'MESH:D011239', (191, 203))	('AT-101', 'Chemical', 'MESH:C028178', (92, 98))	('reversing', 'NegReg', (177, 186))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))	('gossypol', 'Chemical', 'MESH:D006072', (79, 87))	('prednisolone-resistance', 'MPA', (191, 214))	('Leukemia', 'Phenotype', 'HP:0001909', (253, 261))	('infants', 'Species', '9606', (271, 278))	('CMAP', 'Gene', '8530', (30, 34))	('LY294002', 'Var', (47, 55))	('BCL-2', 'molecular_function', 'GO:0015283', ('129', '134'))	('MCL1', 'Gene', (100, 104))	('Acute Lymphoblastic Leukemia', 'Disease', (233, 261))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (239, 261))	('MLL', 'Gene', '4297', (218, 221))
65251	27746730	We collected and analyzed the global mRNA expression levels of MDA-MB-361-pLKO (control) and MDA-MB-IBC-I expressing shRNA against DCD (treatment) using Affymetrix U133 Plus 2.0 chip.	('MDA-MB-361', 'CellLine', 'CVCL:0620', (63, 73))	('DCD', 'Gene', (131, 134))	('DCD', 'Gene', '117159', (131, 134))	('MDA-MB-IBC-I', 'Var', (93, 105))	('MDA-MB', 'CellLine', 'CVCL:0062', (63, 69))	('MDA-MB', 'CellLine', 'CVCL:0062', (93, 99))
65252	27746730	CMAP identified connectivity with a similar set of genes (signature) generally elicited in cellular response to the drugs Sirolimus (p = 0.0002), LY-294002 (p = 0.0004), and Wortmannin (p = 0.0011) (Figure 5).	('LY-294002', 'Var', (146, 155))	('Sirolimus', 'Chemical', 'MESH:D020123', (122, 131))	('Wortmannin', 'Chemical', 'MESH:D000077191', (174, 184))	('Sirolimus', 'MPA', (122, 131))	('elicited', 'Reg', (79, 87))	('cellular response to', 'MPA', (91, 111))	('CMAP', 'Gene', (0, 4))	('CMAP', 'Gene', '8530', (0, 4))
65265	27746730	The tumor's molecular signature varies widely in several human malignancies and spectrum of gene mutations that may have potential as predictive biomarkers continues to grow.	('tumor', 'Disease', (4, 9))	('mutations', 'Var', (97, 106))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('malignancies', 'Disease', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('human', 'Species', '9606', (57, 62))
65266	27746730	Recently, COSMIC Web portal updates on 2 million mutated variants in over 1 million tumor samples in the cancer genome examined.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (84, 89))	('mutated variants', 'Var', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('variants', 'Var', (57, 65))
65267	27746730	We know that a very small number of rare mutations substantially contribute to oncogenesis and cancer progression.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('oncogenesis', 'CPA', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('contribute', 'Reg', (65, 75))	('oncogenesis', 'biological_process', 'GO:0007048', ('79', '90'))
65268	27746730	For instance, cutaneous skin melanoma cells bearing BRAFV 600E mutation that respond positively to Vemurafenib, the first BRAF kinase inhibitor approved to treat metastatic melanoma, progress to resistant cells.	('Vemurafenib', 'Chemical', 'MESH:D000077484', (99, 110))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('BRAF', 'Gene', '673', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanoma', 'Disease', (173, 181))	('cutaneous skin melanoma', 'Disease', 'MESH:C562393', (14, 37))	('mutation', 'Var', (63, 71))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('127', '143'))	('BRAF', 'Gene', '673', (52, 56))	('progress', 'PosReg', (183, 191))	('BRAFV 600E', 'Mutation', 'rs113488022', (52, 62))	('cutaneous skin melanoma', 'Disease', (14, 37))	('cutaneous skin melanoma', 'Phenotype', 'HP:0012056', (14, 37))	('BRAF', 'Gene', (52, 56))
65269	27746730	The resistant cells display activation of parallel signaling pathways, such as ERK signaling, through KRAS and BRAFV 600E amplification and mutations in the MAP2K1 and MAP2K2 genes.	('ERK', 'Gene', (79, 82))	('BRAFV 600E', 'Gene', (111, 121))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('amplification', 'Var', (122, 135))	('ERK', 'molecular_function', 'GO:0004707', ('79', '82'))	('activation', 'PosReg', (28, 38))	('MAP2K1', 'Gene', '5604', (157, 163))	('MAP2K2', 'Gene', (168, 174))	('mutations', 'Var', (140, 149))	('MAP2K2', 'Gene', '5605', (168, 174))	('KRAS', 'Gene', (102, 106))	('MAP2K', 'molecular_function', 'GO:0004708', ('157', '162'))	('ERK', 'Gene', '2048', (79, 82))	('BRAFV 600E', 'Mutation', 'rs113488022', (111, 121))	('KRAS', 'Gene', '3845', (102, 106))	('MAP2K1', 'Gene', (157, 163))	('MAP2K', 'molecular_function', 'GO:0004708', ('168', '173'))
65272	27746730	It is interesting that not only genetic mutation and amplification of these driver oncogenes, but also changes in cellular environment increase dependency in Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades.	('dependency', 'MPA', (144, 154))	('PTEN', 'Gene', (183, 187))	('ERK', 'Gene', '2048', (170, 173))	('increase', 'PosReg', (135, 143))	('genetic mutation', 'Var', (32, 48))	('Akt', 'Gene', '207', (188, 191))	('amplification', 'Var', (53, 66))	('PTEN', 'Gene', '5728', (183, 187))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('ERK', 'Gene', (170, 173))	('Raf', 'Gene', '22882', (162, 165))	('MEK', 'Gene', (166, 169))	('PI3K', 'molecular_function', 'GO:0016303', ('178', '182'))	('MEK', 'Gene', '5609', (166, 169))	('changes', 'Reg', (103, 110))	('Akt', 'Gene', (188, 191))	('Raf', 'Gene', (162, 165))
65293	27746730	For instance, NRAS mutations were found in 3 PDXs, MAP2K1 (MEK1) mutations in 2, BRAF amplification in 4, and aberrant PTEN in 7.	('NRAS', 'Gene', '4893', (14, 18))	('MAP2K1', 'Gene', (51, 57))	('MAP2K', 'molecular_function', 'GO:0004708', ('51', '56'))	('MEK1', 'Gene', '5604', (59, 63))	('BRAF', 'Gene', '673', (81, 85))	('mutations', 'Var', (19, 28))	('MEK1', 'molecular_function', 'GO:0004708', ('59', '63'))	('BRAF', 'Gene', (81, 85))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('found', 'Reg', (34, 39))	('MEK1', 'Gene', (59, 63))	('MAP2K1', 'Gene', '5604', (51, 57))	('NRAS', 'Gene', (14, 18))	('mutations', 'Var', (65, 74))
65301	27746730	It is known that loss of PTEN induces senescence via a mechanism that requires p53.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('senescence', 'MPA', (38, 48))	('induces', 'Reg', (30, 37))	('senescence', 'biological_process', 'GO:0010149', ('38', '48'))	('PTEN', 'Gene', '5728', (25, 29))	('PTEN', 'Gene', (25, 29))	('loss', 'Var', (17, 21))
65318	32075964	Predicting clinical benefit of immunotherapy by antigenic or functional mutations affecting tumour immunogenicity Neoantigen burden is regarded as a fundamental determinant of response to immunotherapy.	('mutations', 'Var', (72, 81))	('clinical', 'Species', '191496', (11, 19))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour immunogenicity', 'Disease', (92, 113))	('tumour immunogenicity', 'Disease', 'MESH:D009369', (92, 113))
65321	32075964	Our results suggest that the clinical benefit of immunotherapy can be determined by neoantigens that induce immunity and functional mutations that facilitate immune evasion.	('facilitate', 'PosReg', (147, 157))	('immune evasion', 'biological_process', 'GO:0051842', ('158', '172'))	('immune evasion', 'MPA', (158, 172))	('mutations', 'Var', (132, 141))	('clinical', 'Species', '191496', (29, 37))	('immune evasion', 'biological_process', 'GO:0042783', ('158', '172'))
65325	32075964	In particular, checkpoint blockade therapies, such as anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab and pembrolizumab), are able to reverse tumour-induced immunosuppression and induce durable clinical responses.	('anti-CTLA-4', 'Var', (54, 65))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('pembrolizumab', 'Chemical', 'MESH:C582435', (108, 121))	('anti-PD-1', 'Var', (83, 92))	('ipilimumab', 'Chemical', 'MESH:D000074324', (67, 77))	('tumour', 'Disease', (144, 150))	('clinical', 'Species', '191496', (196, 204))	('nivolumab', 'Chemical', 'MESH:D000077594', (94, 103))
65330	32075964	Tumour heterogeneity, copy number alteration, aneuploidy, and genetic alteration of specific genes or pathways have been identified as resistance markers.	('pathways', 'Pathway', (102, 110))	('aneuploidy', 'Disease', (46, 56))	('genetic alteration', 'Var', (62, 80))	('copy number alteration', 'Var', (22, 44))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('aneuploidy', 'Disease', 'MESH:D000782', (46, 56))
65332	32075964	Especially, tumours loaded with neoantigens should carry a large number of functional mutations due to high mutation rates.	('mutations', 'Var', (86, 95))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))
65348	32075964	If some of protein-changing mutations perturb immune reaction, tumours carrying these mutations will not be responsive to immunotherapy despite high neoantigen load.	('tumours', 'Disease', (63, 70))	('perturb', 'Reg', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('protein', 'cellular_component', 'GO:0003675', ('11', '18'))	('mutations', 'Var', (28, 37))	('immune reaction', 'CPA', (46, 61))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
65358	32075964	We next wanted to evaluate the clinical utility of combining these two approaches on the basis of the melanoma samples in Roh cohort and lung cancer samples in SMC cohort that came with information on therapeutic response to checkpoint inhibitor and known resistance parameters such as copy number alteration (gain or loss) and tumour heterogeneity.	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('SMC', 'cellular_component', 'GO:0016029', ('160', '163'))	('copy number alteration', 'Var', (286, 308))	('lung cancer', 'Disease', (137, 148))	('tumour', 'Disease', 'MESH:D009369', (328, 334))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('gain or loss', 'Disease', 'MESH:D015430', (310, 322))	('tumour', 'Disease', (328, 334))	('gain or loss', 'Disease', (310, 322))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('clinical', 'Species', '191496', (31, 39))
65365	32075964	For each tumour type, we trained random forest on the samples showing the immune evasion signatures by using as features the genes that harbour deleterious or damaging mutations in > 5% of all samples.	('immune evasion', 'MPA', (74, 88))	('tumour type', 'Disease', (9, 20))	('tumour type', 'Disease', 'MESH:D009369', (9, 20))	('immune evasion', 'biological_process', 'GO:0042783', ('74', '88'))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('immune evasion', 'biological_process', 'GO:0051842', ('74', '88'))	('mutations', 'Var', (168, 177))
65375	32075964	In contrast to mutations that promote immune evasion, such somatic variations that increase immune reaction will be eliminated by negative selection during tumour evolution.	('increase', 'PosReg', (83, 91))	('immune evasion', 'biological_process', 'GO:0051842', ('38', '52'))	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('variations', 'Var', (67, 77))	('immune reaction', 'MPA', (92, 107))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('immune evasion', 'biological_process', 'GO:0042783', ('38', '52'))
65377	32075964	For example, a genetic polymorphism in the CTLA-4 gene was reported to alter the CTLA-4-driven regulation of T cell activation in the context of autoimmune disease.	('CTLA-4-driven regulation of T cell activation', 'MPA', (81, 126))	('autoimmune disease', 'Disease', 'MESH:D001327', (145, 163))	('alter', 'Reg', (71, 76))	('autoimmune disease', 'Phenotype', 'HP:0002960', (145, 163))	('regulation of T cell activation', 'biological_process', 'GO:0050863', ('95', '126'))	('genetic polymorphism', 'Var', (15, 35))	('CTLA-4', 'Gene', (43, 49))	('autoimmune disease', 'Disease', (145, 163))
65382	32075964	Our results indicate that a large fraction of variation in the clinical benefit of immunotherapy can be explained by contrasting effects of antigenic versus functional mutations on tumour immunogenicity.	('clinical', 'Species', '191496', (63, 71))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('tumour immunogenicity', 'Disease', 'MESH:D009369', (181, 202))	('mutations', 'Var', (168, 177))	('tumour immunogenicity', 'Disease', (181, 202))
65383	32075964	This approach offers practical advantage as well because calling single nucleotide variants is straightforward and less technically challenging than determining other parameters such as copy number alterations and tumour heterogeneity.	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('single nucleotide variants', 'Var', (65, 91))	('tumour', 'Disease', (214, 220))
65398	32075964	The BAM files produced after these processes were subjected to MuTect (https://software.broadinstitute.org/cancer/cga/mutect) version 1.1.4 for the calling of single nucleotide variants (SNVs), and small insertions and deletions (indels).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('single nucleotide variants', 'Var', (159, 185))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
65400	32075964	CNVkit, a copy number detection tool specific for whole-exome and short-read sequencing platforms, was used to detect copy number alterations between matched normal and tumour samples.	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('copy number alterations', 'Var', (118, 141))	('tumour', 'Disease', (169, 175))
65401	32075964	Somatic mutation calls for samples in three independent melanoma cohorts with anti-CTLA-4, namely, Van allen et al.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('anti-CTLA-4', 'Var', (78, 89))	('melanoma', 'Disease', (56, 64))	('anti-CTLA-4', 'Gene', (78, 89))
65411	32075964	The skin cutaneous melanoma samples from TCGA were divided into two groups based on whether the number of neoantigens or mutations was higher or lower than the median level.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 27))	('mutations', 'Var', (121, 130))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('skin cutaneous melanoma', 'Disease', (4, 27))	('lower', 'NegReg', (145, 150))
65430	24302811	For example, gene-expression profiling was used to predict clinical outcomes in pediatric patients with acute myeloid leukemia and to find genes whose aberrant expression leads to a poor prognosis.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (104, 126))	('gene-expression', 'biological_process', 'GO:0010467', ('13', '28'))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('aberrant expression', 'Var', (151, 170))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (110, 126))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (104, 126))	('patients', 'Species', '9606', (90, 98))	('acute myeloid leukemia', 'Disease', (104, 126))
65466	24302811	At the end of LOOCV trials, a set of male-specific genes that were selected at least 75% of the time in the entire LOOCV were 1882_g_at (MECOM: MDS1 and EVI1 complex locus), 37902_at (CRYZ: crystallin, zeta (quinone reductase)), 38789_at (TKT: transketolase (Wernicke-Korsakoff syndrome)), 39105_at (VASP: vasodilator-stimulated phosphoprotein), 40844_at (CTR9: Ctr9, Paf1/RNA polymerase II complex component, homolog (S. cerevisiae)), 36981_at (SRP9: signal recognition particle 9 kDa), 36338_at (LUZP1: leucine zipper protein 1), 31870_at (CD37: CD37 antigen), 1624_at (RAP1GDS1: RAP1, GTP-GDP dissociation stimulator 1), and 39142_at (NUDT21: cleavage and polyadenylation specific factor 5, 25 kDa).	('MDS1', 'Gene', (144, 148))	('CR', 'Chemical', '-', (184, 186))	('SRP', 'cellular_component', 'GO:0005786', ('446', '449'))	('Ctr9', 'Gene', (362, 366))	('36338_at', 'Var', (488, 496))	('transketolase', 'Gene', (244, 257))	('36981_at', 'Var', (436, 444))	('GDS', 'molecular_function', 'GO:0005085', ('576', '579'))	('31870_at', 'Var', (532, 540))	('RAP1', 'Gene', '855505', (582, 586))	('RAP1', 'Gene', '855505', (572, 576))	('Ctr9', 'Gene', '854020', (362, 366))	('39142_at', 'Var', (628, 636))	('RNA polymerase II complex', 'cellular_component', 'GO:0005665', ('373', '398'))	('Wernicke-Korsakoff syndrome', 'Disease', 'MESH:D020915', (259, 286))	('RAP1', 'Gene', (582, 586))	('protein', 'cellular_component', 'GO:0003675', ('520', '527'))	('RAP1', 'Gene', (572, 576))	('CTR9', 'Gene', '854020', (356, 360))	('transketolase', 'Gene', '7086', (244, 257))	('CTR9', 'Gene', (356, 360))	('S. cerevisiae', 'Species', '4932', (419, 432))	('Wernicke-Korsakoff syndrome', 'Disease', (259, 286))	('signal recognition particle', 'cellular_component', 'GO:0048500', ('452', '479'))	('MDS1', 'Gene', '855170', (144, 148))
65468	24302811	Among them 38789_at (TKT: Transketolase) and 36338_at (EST) were also included in the thirty-five genes associated with prognosis of pediatric AML identified by Yagi et al..	('38789_at', 'Var', (11, 19))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('Transketolase', 'Gene', (26, 39))	('36338_at', 'Var', (45, 53))	('Transketolase', 'Gene', '7086', (26, 39))	('AML', 'Disease', (143, 146))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
65469	24302811	Similarly, nine top-ranked genes for classifying female patients into R/CR were 40601_at (TM2D1: TM2 domain containing 1), 36330_at (CCBL1: cysteine conjugate beta- lyase; cytoplasmic (glutamine transaminase K, kynurenine aminotransferase)), 40586_at (EEF1E1: eukaryotic translation elongation factor 1 epsilon 1), 36648_at (CRSP9: cofactor required for Sp1 transcriptional activation, subunit 9, 33 kDa), 32351_at (GPR20: G protein-coupled receptor 20), 1718_at (ARPC2: actin-related protein 2/3 complex, subunit 2, 34 kDa), 38622_at (MTG1: mitochondrial GTPase 1 homolog (S. cerevisiae)), 36496_at (IMPA2: inositol(myo)-1(or 4)-monophosphatase 2), and 38337_at (ZNF193: zinc finger protein 193).	('patients', 'Species', '9606', (56, 64))	('36496_at', 'Var', (591, 599))	('CRSP9', 'Gene', (325, 330))	('GPR20', 'Gene', (416, 421))	('protein', 'cellular_component', 'GO:0003675', ('684', '691'))	('CCBL1', 'Gene', (133, 138))	('CR', 'Chemical', '-', (72, 74))	('glutamine transaminase K', 'Gene', (185, 209))	('G protein-coupled receptor 20', 'Gene', '2843', (423, 452))	('S. cerevisiae', 'Species', '4932', (574, 587))	('protein', 'cellular_component', 'GO:0003675', ('425', '432'))	('mitochondrial GTPase 1 homolog', 'Gene', '92170', (542, 572))	('CR', 'Chemical', '-', (325, 327))	('CCBL1', 'Gene', '883', (133, 138))	('G protein-coupled receptor 20', 'Gene', (423, 452))	('EEF1E1', 'Gene', (252, 258))	('38622_at', 'Var', (526, 534))	('TM2D1', 'Gene', (90, 95))	('mitochondrial GTPase 1 homolog', 'Gene', (542, 572))	('CRSP9', 'Gene', '9443', (325, 330))	('actin-related protein 2/3 complex, subunit 2, 34 kDa', 'Gene', '10109;10097', (471, 523))	('ARPC2', 'Gene', (464, 469))	('translation elongation', 'biological_process', 'GO:0006414', ('271', '293'))	('glutamine transaminase K', 'Gene', '883', (185, 209))	('ARPC2', 'Gene', '10109', (464, 469))	('MTG1', 'Gene', '92170', (536, 540))	('inositol(myo)-1(or 4)-monophosphatase 2', 'Gene', '856418', (608, 647))	('EEF1E1', 'Gene', '9521', (252, 258))	('eukaryotic translation elongation factor 1 epsilon 1', 'Gene', '9521', (260, 312))	('GPR20', 'Gene', '2843', (416, 421))	('38337_at', 'Var', (654, 662))	('protein', 'cellular_component', 'GO:0003675', ('485', '492'))	('MTG1', 'Gene', (536, 540))	('TM2D1', 'Gene', '83941', (90, 95))
65471	24302811	Data with male-specific genes showed higher prediction accuracy (71.9%) to classify male patients than the accuracy (43.8%) to classify male patients from data with female-specific genes.	('genes', 'Var', (24, 29))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (141, 149))	('higher', 'PosReg', (37, 43))
65472	24302811	Similarly, data with female-specific genes showed higher prediction accuracy (76.2%) to classify female patients than the accuracy (61.9%) to classify female patients from data with male-specific genes.	('patients', 'Species', '9606', (158, 166))	('genes', 'Var', (37, 42))	('higher', 'PosReg', (50, 56))	('patients', 'Species', '9606', (104, 112))
65481	24302811	They were 41209_at (LPL: lipoprotein lipase), 41755_at (COBLL1: COBL-like 1), 39878_at (PCDH9: protocadherin 9), 38211_at (ZBTB20: zinc finger and BTB domain containing 20), 39488_at (PCDH9: protocadherin 9), 36886_f_at (KIR2DL3: killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail, 3), 32140_at (SORL1: sortilin-related receptor, L(DLR class) A repeats-containing), 33535_at (P2RX1: purinergic receptor P2X, ligand-gated ion channel, 1), 39967_at (LDOC1: leucine zipper, downregulated in cancer 1), 32842_at (BCL7A: B-cell CLL/lymphoma 7A), and 36899_at (SATB1: special AT-rich sequence binding protein 1 (binds to nuclear matrix/scaffold-associating DNA's)).	('special AT-rich sequence binding protein 1 (binds to nuclear matrix/scaffold-associating DNA', 'Gene', '6304', (588, 680))	('lipoprotein lipase', 'Gene', (25, 43))	('33535_at', 'Var', (392, 400))	('COBL-like 1', 'Gene', '22837', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (514, 520))	('SATB1', 'Gene', (581, 586))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('242', '256'))	('BCL7A', 'Gene', '605', (535, 540))	('SORL1', 'Gene', (322, 327))	('LPL', 'Gene', '4023', (20, 23))	('BTB domain', 'molecular_function', 'GO:0031208', ('147', '157'))	('LPL', 'Gene', (20, 23))	('ZBTB20', 'Gene', (123, 129))	('COBL-like 1', 'Gene', (64, 75))	('COBLL1', 'Gene', '22837', (56, 62))	('COBLL1', 'Gene', (56, 62))	('SATB1', 'Gene', '6304', (581, 586))	('lipoprotein lipase', 'Gene', '4023', (25, 43))	('PCDH9', 'Gene', (184, 189))	('nuclear matrix', 'cellular_component', 'GO:0016363', ('641', '655'))	('PCDH9', 'Gene', (88, 93))	('LDOC1', 'Gene', '23641', (474, 479))	('DNA', 'cellular_component', 'GO:0005574', ('677', '680'))	('SORL1', 'Gene', '6653', (322, 327))	('cancer', 'Disease', (514, 520))	('ligand', 'molecular_function', 'GO:0005488', ('434', '440'))	('PCDH9', 'Gene', '5101', (184, 189))	('39967_at', 'Var', (464, 472))	('ZBTB20', 'Gene', '26137', (123, 129))	('B-cell CLL/lymphoma 7A', 'Gene', (542, 564))	('PCDH9', 'Gene', '5101', (88, 93))	('BCL7A', 'Gene', (535, 540))	('LDOC1', 'Gene', (474, 479))	('protocadherin 9', 'Gene', (191, 206))	('36899_at', 'Var', (571, 579))	('protocadherin 9', 'Gene', (95, 110))	('32140_at', 'Var', (312, 320))	('cancer', 'Phenotype', 'HP:0002664', (514, 520))	('lymphoma', 'Phenotype', 'HP:0002665', (553, 561))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (542, 561))	('protocadherin 9', 'Gene', '5101', (191, 206))	('protocadherin 9', 'Gene', '5101', (95, 110))	('protein', 'cellular_component', 'GO:0003675', ('621', '628'))	('B-cell CLL/lymphoma 7A', 'Gene', '605', (542, 564))	('binding', 'molecular_function', 'GO:0005488', ('613', '620'))	('32842_at', 'Var', (525, 533))
65483	24302811	They were 33745_at (PHKG2: phosphorylase kinase, gamma 2 (testis)), 38152_at (LOH11CR2A: loss of heterozygosity, 11, chromosomal region 2, gene A), 34142_at (PDE8A: phosphodiesterase 8A), 39593_at (FGL2: fibrinogen-like 2), and 217_at (KLK2: kallikrein 2, prostatic).	('fibrinogen', 'molecular_function', 'GO:0008001', ('204', '214'))	('PDE', 'molecular_function', 'GO:0004114', ('158', '161'))	('33745_at', 'Var', (10, 18))	('kallikrein', 'molecular_function', 'GO:0003807', ('242', '252'))	('kallikrein', 'molecular_function', 'GO:0004293', ('242', '252'))	('39593_at', 'Var', (188, 196))	('38152_at', 'Var', (68, 76))	('LOH11CR2A: loss of heterozygosity, 11, chromosomal region 2', 'Gene', '4013', (78, 137))	('chromosomal region', 'cellular_component', 'GO:0098687', ('117', '135'))	('phosphodiesterase', 'molecular_function', 'GO:0008081', ('165', '182'))	('fibrinogen', 'cellular_component', 'GO:0005577', ('204', '214'))	('34142_at', 'Var', (148, 156))
65491	24302811	The probes are from tumor tissue and from reference tissue that are differentially labeled by the incorporation of cyanine 3 (Cy3) and cyanine 5 (Cy5), respectively.	('Cy5', 'Chemical', '-', (146, 149))	('cyanine 5', 'Chemical', '-', (135, 144))	('cyanine 3', 'Chemical', '-', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('incorporation', 'Var', (98, 111))	('cyanine 5', 'Var', (135, 144))	('Cy3', 'Chemical', '-', (126, 129))	('tumor', 'Disease', (20, 25))
65503	24302811	The following ten male-specific genes were selected at least 75% of the time during 20 trials of 10-fold CV: A_23_P128263 (PRB1: proline-rich protein BstNI subfamily 1), A_23_P83838 (CA8: carbonic anhydrase VIII), A_24_P212990 (MGC70863: similar to RPL23AP7 protein), A_23_P333650 (RAD9B: RAD9 homolog B (S. cerevisiae)), A_32_P125251 (N/A), A_23_P108835 (YPEL5: yippee-like 5 (Drosophila)), A_32_P150856 (LOC407835: mitogen-activated protein kinase kinase 2 pseudogene), A_23_P11936 (UBXN11: UBX domain protein 11), A_24_P169976 (N/A), and A_32_P3998 (ZNF600: zinc finger protein 600).	('A_32_P125251', 'Var', (322, 334))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('protein', 'cellular_component', 'GO:0003675', ('258', '265'))	('RAD', 'biological_process', 'GO:1990116', ('289', '292'))	('A_24_P169976', 'Var', (517, 529))	('A_23_P11936', 'Var', (472, 483))	('protein', 'cellular_component', 'GO:0003675', ('573', '580'))	('Drosophila', 'Species', '7227', (378, 388))	('A_32_P3998', 'Var', (541, 551))	('PRB1', 'Gene', '856649', (123, 127))	('protein', 'cellular_component', 'GO:0003675', ('504', '511'))	('RAD', 'biological_process', 'GO:1990116', ('282', '285'))	('S. cerevisiae', 'Species', '4932', (305, 318))	('protein', 'cellular_component', 'GO:0003675', ('435', '442'))	('A_23_P333650', 'Var', (268, 280))	('A_23_P108835', 'Var', (342, 354))	('A_24_P212990', 'Var', (214, 226))	('PRB1', 'Gene', (123, 127))
65504	24302811	For female patients, the following eight female-specific genes were selected from 20 trials of 10-fold CV: A_23_P69497 (CLEC3B: C-type lectin domain family 3, member B), A_24_P118884 (N/A), A_23_P152420 (KIAA0182), A_24_P265177 (PHC3: polyhomeotic-like 3 (Drosophila)), A_23_P251421 (CDCA7: Cell division cycle associated 7), A_23_P211738 (UBP1: upstream binding protein 1 (LBP-1a)), A_23_P47377 (HSD17B12: hydroxysteroid (17-beta) dehydrogenase 12), and A_32_P113646 (CDNA FLJ45341 fis, clone BRHIP3009672).	('CLEC3B', 'Gene', (120, 126))	('A_23_P47377', 'Var', (384, 395))	('A_23_P251421', 'Var', (270, 282))	('binding', 'molecular_function', 'GO:0005488', ('355', '362'))	('CLEC3B', 'Gene', '7123', (120, 126))	('KIAA0182', 'Gene', '23199', (204, 212))	('lectin', 'molecular_function', 'GO:0005530', ('135', '141'))	('A_23_P211738', 'Var', (326, 338))	('Drosophila', 'Species', '7227', (256, 266))	('A_24_P265177', 'Var', (215, 227))	('KIAA0182', 'Gene', (204, 212))	('UBP', 'molecular_function', 'GO:0004843', ('340', '343'))	('protein', 'cellular_component', 'GO:0003675', ('363', '370'))	('Cell division cycle', 'biological_process', 'GO:0007049', ('291', '310'))	('patients', 'Species', '9606', (11, 19))	('C-type lectin domain family 3, member B', 'Gene', '7123', (128, 167))
65524	33503876	Comprehensive Review on the Clinical Relevance of Long Non-Coding RNAs in Cutaneous Melanoma Cutaneous melanoma is considered a rare tumor, although it is one of the most common cancers in young adults and its incidence has risen in the last decades.	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Cutaneous melanoma', 'Disease', (93, 111))	('Cutaneous Melanoma', 'Disease', (74, 92))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (74, 92))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cancers', 'Disease', (178, 185))	('tumor', 'Disease', (133, 138))	('Long Non-Coding RNAs', 'Var', (50, 70))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
65531	33503876	Approximately 5-10% occur in a familial context, associated with mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene or, less frequently, in alteration of other genes like breast cancer 1-associated protein (BAP1), telomerase reverse transcriptase (TERT) or protection of telomeres 1 (POT1).	('telomerase reverse transcriptase', 'Gene', (226, 258))	('CDKN2A', 'Gene', (115, 121))	('associated', 'Reg', (49, 59))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('POT1', 'Gene', (296, 300))	('breast cancer', 'Disease', (183, 196))	('telomerase reverse transcriptase', 'Gene', '7015', (226, 258))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('CDKN2A', 'Gene', '1029', (115, 121))	('TERT', 'Gene', (260, 264))	('TERT', 'Gene', '7015', (260, 264))	('mutation', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('transcriptase', 'molecular_function', 'GO:0003968', ('245', '258'))	('transcriptase', 'molecular_function', 'GO:0034062', ('245', '258'))	('BAP1', 'Gene', '8314', (219, 223))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (77, 113))	('POT1', 'Gene', '25913', (296, 300))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('77', '110'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (77, 113))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('94', '110'))	('BAP1', 'Gene', (219, 223))	('transcriptase', 'molecular_function', 'GO:0003899', ('245', '258'))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
65532	33503876	However, most of them are sporadic with the highest prevalence of somatic mutations among cancers and the major risk factor is exposure to the ultraviolet radiation (UVR) of the sun, which causes formation of pyrimidine dimers, photoproducts, oxidative stress and inflammation.	('cancers', 'Disease', (90, 97))	('oxidative stress', 'Phenotype', 'HP:0025464', (243, 259))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('pyrimidine', 'Chemical', 'MESH:C030986', (209, 219))	('formation', 'biological_process', 'GO:0009058', ('196', '205'))	('mutations', 'Var', (74, 83))	('inflammation', 'biological_process', 'GO:0006954', ('264', '276'))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('pyrimidine dimers', 'MPA', (209, 226))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('inflammation', 'Disease', 'MESH:D007249', (264, 276))	('inflammation', 'Disease', (264, 276))
65534	33503876	In particular, NRAS mutations represent 10-25% of cases, and mutation in the exon 15, codon 600, of the proto-oncogene BRAF (BRAF V600) accounts for 50% of the alterations, constituting a negative prognostic factor.	('BRAF', 'Gene', '673', (119, 123))	('NRAS', 'Gene', (15, 19))	('mutation in', 'Var', (61, 72))	('BRAF', 'Gene', (119, 123))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', (125, 129))	('BRAF', 'Gene', '673', (125, 129))	('mutations', 'Var', (20, 29))
65547	33503876	Considering the huge percentage of melanomas associated to BRAFV600E mutation, several studies focused their attention on the correlated lncRNAs.	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('melanomas', 'Disease', (35, 44))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('BRAFV600E', 'Var', (59, 68))
65552	33503876	BANCR silencing impairs MAPK signaling pathway, inhibiting tumor growth and migration.	('MAPK signaling pathway', 'Pathway', (24, 46))	('MAPK', 'molecular_function', 'GO:0004707', ('24', '28'))	('tumor', 'Disease', (59, 64))	('signaling pathway', 'biological_process', 'GO:0007165', ('29', '46'))	('inhibiting', 'NegReg', (48, 58))	('MAPK signaling', 'biological_process', 'GO:0000165', ('24', '38'))	('BANCR', 'Gene', '100885775', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('silencing', 'Var', (6, 15))	('BANCR', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('impairs', 'NegReg', (16, 23))
65553	33503876	BANCR knockdown, indeed, is able to inhibit melanoma cell migration by upregulating the chemokine CXCL11, and to impair melanoma cell proliferation by modulating ERK1/2 and JNK (MAPK pathway).	('ERK1/2', 'Gene', (162, 168))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('BANCR', 'Gene', '100885775', (0, 5))	('ERK1/2', 'Gene', '5595;5594', (162, 168))	('ERK1', 'molecular_function', 'GO:0004707', ('162', '166'))	('BANCR', 'Gene', (0, 5))	('JNK', 'Gene', (173, 176))	('JNK', 'Gene', '5599', (173, 176))	('CXCL11', 'Gene', (98, 104))	('CXCL11', 'Gene', '6373', (98, 104))	('cell migration', 'biological_process', 'GO:0016477', ('53', '67'))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('inhibit', 'NegReg', (36, 43))	('melanoma', 'Disease', (44, 52))	('cell proliferation', 'biological_process', 'GO:0008283', ('129', '147'))	('modulating', 'Reg', (151, 161))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('MAPK', 'molecular_function', 'GO:0004707', ('178', '182'))	('upregulating', 'PosReg', (71, 83))	('impair', 'NegReg', (113, 119))	('JNK', 'molecular_function', 'GO:0004705', ('173', '176'))	('knockdown', 'Var', (6, 15))
65556	33503876	Similarly, a close correlation between BRAFV600E-mutated samples and RMEL3 lncRNA was described by Goedert and colleagues.	('BRAFV600E-mutated', 'Var', (39, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('RMEL3 lncRNA', 'Disease', (69, 81))
65557	33503876	RMEL3 knockdown in BRAF-mutated cell lines results in a significant impairment of cell growth and survival.	('BRAF', 'Gene', '673', (19, 23))	('RMEL3', 'Gene', (0, 5))	('BRAF', 'Gene', (19, 23))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('knockdown', 'Var', (6, 15))	('impairment', 'NegReg', (68, 78))
65558	33503876	Moreover, RMEL3 silencing leads to deregulation of proteins involved in MAPK and PI3K pathways (decreased b-Raf and p-AKT levels and increased tumor suppressor PTEN levels), as well as of cell cycle and apoptosis regulators (decreased p-RB and cyclin-B1 levels and increased p-21 and p-27 levels).	('cell cycle', 'biological_process', 'GO:0007049', ('188', '198'))	('p-RB', 'Gene', (235, 239))	('p-RB', 'Gene', '5925', (235, 239))	('cyclin-B1', 'Gene', '891', (244, 253))	('AKT', 'Gene', (118, 121))	('tumor suppressor', 'Gene', (143, 159))	('silencing', 'Var', (16, 25))	('p-27', 'Gene', (284, 288))	('deregulation', 'MPA', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('PI3K pathways', 'Pathway', (81, 94))	('proteins', 'Protein', (51, 59))	('p-21', 'Gene', (275, 279))	('MAPK', 'Pathway', (72, 76))	('decreased', 'NegReg', (96, 105))	('p-27', 'Gene', '3429', (284, 288))	('cyclin-B1', 'Gene', (244, 253))	('b-Raf', 'Gene', '673', (106, 111))	('cyclin', 'molecular_function', 'GO:0016538', ('244', '250'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('tumor suppressor', 'Gene', '7248', (143, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('MAPK', 'molecular_function', 'GO:0004707', ('72', '76'))	('AKT', 'Gene', '207', (118, 121))	('increased', 'PosReg', (265, 274))	('p-21', 'Gene', '1026', (275, 279))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('RMEL3', 'Gene', (10, 15))	('PTEN', 'Gene', (160, 164))	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('b-Raf', 'Gene', (106, 111))	('PTEN', 'Gene', '5728', (160, 164))	('decreased', 'NegReg', (225, 234))	('increased', 'PosReg', (133, 142))
65559	33503876	Finally, BRAFV600E melanoma cells treated with BRAF or MEK inhibitors significantly decreased RMEL3 expression levels, suggesting RMEL3 as a downstream effector of ERK signaling and as a promising candidate for pharmacological target.	('RMEL3', 'Protein', (94, 99))	('BRAF', 'Gene', (9, 13))	('ERK', 'molecular_function', 'GO:0004707', ('164', '167'))	('expression levels', 'MPA', (100, 117))	('BRAF', 'Gene', (47, 51))	('melanoma', 'Disease', (19, 27))	('BRAF', 'Gene', '673', (47, 51))	('MEK', 'Gene', (55, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('ERK', 'Gene', '5594', (164, 167))	('MEK', 'Gene', '5609', (55, 58))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('inhibitors', 'Var', (59, 69))	('ERK', 'Gene', (164, 167))	('decreased', 'NegReg', (84, 93))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('BRAF', 'Gene', '673', (9, 13))
65561	33503876	ZEB1 antisense RNA 1 (ZEB1-AS) is a recent lncRNA whose expression levels have been associate not only to BRAF mutation, but also to RAS mutations in metastatic melanoma samples according to TCGA data.	('expression levels', 'MPA', (56, 73))	('BRAF', 'Gene', '673', (106, 110))	('ZEB1', 'Gene', (22, 26))	('associate', 'Reg', (84, 93))	('ZEB1', 'Gene', '6935', (0, 4))	('ZEB1', 'Gene', '6935', (22, 26))	('BRAF', 'Gene', (106, 110))	('antisense RNA', 'molecular_function', 'GO:0009388', ('5', '18'))	('ZEB1', 'Gene', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('mutation', 'Var', (111, 119))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('RNA', 'cellular_component', 'GO:0005562', ('15', '18'))
65575	33503876	Since lncRNA signatures may be affected by driver gene mutations (as suggested in Section 2), in silico devices may be implemented considering the mutational state of patients to describe lncRNA prediction signatures suitable to specific subsets of patients.	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (167, 175))	('affected', 'Reg', (31, 39))	('lncRNA signatures', 'MPA', (6, 23))
65582	33503876	miR-129-5p sequestration by TUG1 leads to the over-expression of astrocyte-elevated gene-1 (AEG-1), a protein involved in the PI3K/AKT pathway, the WNT signaling pathway and chemo-resistance to cisplatin and 5-fluorouracil.	('AKT', 'Gene', '207', (131, 134))	('TUG1', 'Gene', '55000', (28, 32))	('sequestration', 'Var', (11, 24))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (208, 222))	('astrocyte-elevated gene-1', 'Gene', '92140', (65, 90))	('AKT', 'Gene', (131, 134))	('astrocyte-elevated gene-1', 'Gene', (65, 90))	('TUG1', 'Gene', (28, 32))	('AEG-1', 'Gene', '92140', (92, 97))	('over-expression', 'PosReg', (46, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('WNT signaling pathway', 'biological_process', 'GO:0016055', ('148', '169'))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('miR-129-5p', 'Gene', '100302178', (0, 10))	('AEG-1', 'Gene', (92, 97))	('miR-129-5p', 'Gene', (0, 10))
65583	33503876	The cytoplasmic intergenic lncRNA MIRAT (MAPK inhibitor resistance-associated transcript), instead, has been described as significantly over-expressed in melanoma cells, carrying NRAS or BRAF mutations, resistant to small molecule inhibitors of the MAPK cascade.	('MAPK cascade', 'biological_process', 'GO:0000165', ('249', '261'))	('MAPK', 'molecular_function', 'GO:0004707', ('249', '253'))	('BRAF', 'Gene', '673', (187, 191))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('melanoma', 'Disease', (154, 162))	('NRAS', 'Gene', (179, 183))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('mutations', 'Var', (192, 201))	('over-expressed', 'PosReg', (136, 150))	('NRAS', 'Gene', '4893', (179, 183))	('BRAF', 'Gene', (187, 191))
65596	33503876	While several studies have revealed that the MEG3 function is mediated, at least in part, by the activation of the p53/MDM2 axis, its function in melanoma as ceRNA for miR-499-5p and miR-21 has been recently demonstrated by regulating CYLD and E-cadherin expressions, respectively.	('CYLD', 'Gene', '1540', (235, 239))	('p53', 'Gene', (115, 118))	('miR-499-5p', 'Var', (168, 178))	('E-cadherin', 'Gene', (244, 254))	('E-cadherin', 'Gene', '999', (244, 254))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('MEG3', 'Gene', (45, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('246', '254'))	('miR-21', 'Gene', '406991', (183, 189))	('activation', 'PosReg', (97, 107))	('MDM2', 'Gene', (119, 123))	('MEG3', 'Gene', '55384', (45, 49))	('CYLD', 'Gene', (235, 239))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('MDM2', 'Gene', '4193', (119, 123))	('p53', 'Gene', '7157', (115, 118))	('miR-21', 'Gene', (183, 189))	('regulating', 'Reg', (224, 234))
65615	33503876	Consistently, ANRIL silencing activates the expression of INK4a and INK4b, thus significantly reducing the tumorigenesis of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('INK4b', 'Gene', '1030', (68, 73))	('melanoma', 'Disease', (124, 132))	('expression', 'MPA', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('silencing', 'Var', (20, 29))	('INK4a', 'Gene', '1029', (58, 63))	('ANRIL', 'Gene', '100048912', (14, 19))	('INK4a', 'Gene', (58, 63))	('activates', 'PosReg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('reducing', 'NegReg', (94, 102))	('ANRIL', 'Gene', (14, 19))	('INK4b', 'Gene', (68, 73))
65621	33503876	Accordingly, FALEC silencing produces growth inhibition and cell cycle arrest and enhances apoptosis, suggesting its role as oncogenic lncRNA.	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('FALEC', 'Gene', '100874054', (13, 18))	('apoptosis', 'CPA', (91, 100))	('silencing', 'Var', (19, 28))	('enhances', 'PosReg', (82, 90))	('FALEC', 'Gene', (13, 18))	('arrest', 'Disease', 'MESH:D006323', (71, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('arrest', 'Disease', (71, 77))	('growth inhibition', 'CPA', (38, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('60', '77'))
65625	33503876	Consistently, stable short hairpin-mediated knockdown of NORAD lncRNA inhibits ER stress and thus interferes with the migration and the invasion of melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('migration and', 'CPA', (118, 131))	('melanoma', 'Disease', (148, 156))	('inhibits', 'NegReg', (70, 78))	('knockdown', 'Var', (44, 53))	('interferes', 'NegReg', (98, 108))	('ER stress', 'MPA', (79, 88))	('NORAD', 'Gene', (57, 62))
65628	33503876	Hence, interfering with MAP3K2 activation by modulating FOXD3-AS1 could revert proliferation, invasion and migration of melanoma cells.	('proliferation', 'CPA', (79, 92))	('interfering', 'NegReg', (7, 18))	('modulating', 'Var', (45, 55))	('MAP3K2', 'Gene', (24, 30))	('FOXD3', 'Gene', '27022', (56, 61))	('MAP3K', 'molecular_function', 'GO:0004709', ('24', '29'))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('FOXD3', 'Gene', (56, 61))	('AS1', 'Gene', (62, 65))	('AS1', 'Gene', '5729', (62, 65))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('MAP3K2', 'Gene', '10746', (24, 30))	('revert', 'NegReg', (72, 78))
65639	33503876	Finally, HOTAIR can act also as ceRNA for miR-152-3p, which in turn regulates the MET mRNA, inducing the activation of the downstream PI3K/AKT/mTOR-signaling pathway.	('HOTAIR', 'Gene', (9, 15))	('MET', 'Gene', (82, 85))	('AKT', 'Gene', '207', (139, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('134', '138'))	('HOTAIR', 'Gene', '100124700', (9, 15))	('activation', 'PosReg', (105, 115))	('regulates', 'MPA', (68, 77))	('inducing', 'PosReg', (92, 100))	('AKT', 'Gene', (139, 142))	('mTOR', 'Gene', '2475', (143, 147))	('signaling pathway', 'biological_process', 'GO:0007165', ('148', '165'))	('mTOR', 'Gene', (143, 147))	('miR-152-3p', 'Var', (42, 52))	('MET', 'Gene', '79811', (82, 85))
65643	33503876	Interestingly, serial liquid biopsies from stage I-IIIA of melanoma patients revealed significantly higher levels of LINC01638 in those who exhibited local recurrence than in patients without recurrence, suggesting its involvement in the recurrence process, although the mechanisms by which it occurs still need to be elucidated.	('levels', 'MPA', (107, 113))	('LINC01638', 'Chemical', '-', (117, 126))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (175, 183))	('higher', 'PosReg', (100, 106))	('involvement', 'Reg', (219, 230))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('LINC01638', 'Var', (117, 126))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
65652	33503876	In vitro studies revealed that PVT1 knockdown inhibits proliferation, induces cell cycle arrest at the G0/G1 phase and enhances the apoptotic events in melanoma cell lines.	('arrest', 'Disease', (89, 95))	('PVT1', 'Gene', '5820', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('proliferation', 'CPA', (55, 68))	('induces', 'Reg', (70, 77))	('G1 phase', 'biological_process', 'GO:0051318', ('106', '114'))	('inhibits', 'NegReg', (46, 54))	('knockdown', 'Var', (36, 45))	('enhances', 'PosReg', (119, 127))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (78, 95))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('78', '95'))	('PVT1', 'Gene', (31, 35))	('arrest', 'Disease', 'MESH:D006323', (89, 95))	('apoptotic events', 'CPA', (132, 148))
65671	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))
65675	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))
65676	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'))
65677	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'))	('melanoma', 'Disease', (163, 171))	('KIT', 'Gene', (207, 210))	('NRAS', 'Gene', (198, 202))	('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))
65678	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))
65692	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))	('stage IV disease', 'Disease', (21, 37))	('M1a', 'Var', (54, 57))	('M1b', 'Var', (65, 68))	('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))
65701	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))
65703	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).	('NRAS', 'Gene', (66, 70))	('Q61K', 'Var', (80, 84))	('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))
65704	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))
65707	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))
65709	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))
65711	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))
65715	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))
65716	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))
65719	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))	('STK19', 'molecular_function', 'GO:0004686', ('110', '115'))	('V173M', 'Mutation', 'rs876660754', (130, 135))	('STK19', 'Gene', '8859', (110, 115))	('A27P', 'Mutation', 'rs730882000', (104, 108))	('RAC1', 'Gene', (99, 103))	('A27P', 'Var', (104, 108))	('P1171L', 'Mutation', 'p.P1171L', (91, 97))	('patients', 'Species', '9606', (10, 18))
65721	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))
65722	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))
65723	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', '673', (189, 193))	('BRAF', 'Gene', (189, 193))	('patients', 'Species', '9606', (170, 178))	('BRAF', 'Gene', (219, 223))	('G469A', 'Mutation', 'rs121913355', (236, 241))	('BRAF', 'Gene', '673', (219, 223))	('patients', 'Species', '9606', (10, 18))	('GNAQ', 'Gene', '2776', (357, 361))	('melanoma', 'Disease', (59, 67))	('patient', 'Species', '9606', (268, 275))	('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))
65724	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))
65725	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))
65739	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))
65744	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))
65746	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))
65747	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))	('NF1', 'Gene', (133, 136))	('NRAS', 'Gene', (256, 260))	('age', 'Gene', '5973', (318, 321))	('BRAF', 'Gene', (251, 255))	('NF1', 'Gene', '4763', (133, 136))	('melanoma', 'Disease', (271, 279))	('NRAS', 'Gene', '4893', (256, 260))	('BRAF', 'Gene', '673', (251, 255))	('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))
65755	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))
65756	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))
65763	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))
65765	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))
65766	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))
65768	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))
65770	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))
65772	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))
65775	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))	('NRAS', 'Gene', (111, 115))	('variants', 'Var', (130, 138))	('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))
65782	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))
65785	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'))
65786	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))	('GNAQ', 'Gene', '2776', (48, 52))	('BRAF', 'Gene', '673', (26, 30))	('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))
65787	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))
65789	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))
65793	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))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('mutations', 'Var', (119, 128))	('melanoma', 'Disease', (179, 187))
65814	31645905	Biomarkers have been developed to predict patients' responsivity to immunotherapy treatments, such as genome-wide mutational load, PD-L1 protein expression in infiltrating immune cells, the number of cytotoxic T cells in a tumor microenvironment, or MSI status.	('men', 'Species', '9606', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('men', 'Species', '9606', (87, 90))	('PD-L1', 'Gene', '29126', (131, 136))	('MSI', 'Gene', '5928', (250, 253))	('MSI', 'Gene', (250, 253))	('mutational load', 'Var', (114, 129))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('patients', 'Species', '9606', (42, 50))	('protein', 'Protein', (137, 144))	('PD-L1', 'Gene', (131, 136))
65854	31645905	In head and neck squamous cell carcinoma (HNSC, P = 0.0044, adjusted) and skin cutaneous melanoma (SKCM, P = 0.0044, adjusted), patients with T3/4 had significantly lower immune response than those with T1/2, while kidney renal clear cell carcinoma (KIRC, P = 0.0044, adjusted) showed the opposite trend.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (215, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('KIRC', 'Disease', (250, 254))	('SKCM', 'Disease', 'MESH:C562393', (99, 103))	('kidney renal clear cell carcinoma', 'Disease', (215, 248))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('immune response', 'biological_process', 'GO:0006955', ('171', '186'))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KIRC', 'Disease', 'MESH:D002292', (250, 254))	('immune response', 'MPA', (171, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (12, 40))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('T3/4', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('lower', 'NegReg', (165, 170))	('lower immune response', 'Phenotype', 'HP:0002721', (165, 186))	('SKCM', 'Disease', (99, 103))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
65872	31645905	It appears that the hypermutated (HM) colon adenocarcinoma (COAD) patients had the significantly highest immune response among the three different molecular subtypes (CIN, GS, HM) (P = 1.04 x 10-06, Figure 8C).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('immune response', 'biological_process', 'GO:0006955', ('105', '120'))	('immune response', 'MPA', (105, 120))	('hypermutated', 'Var', (20, 32))	('COAD', 'Disease', 'MESH:D015179', (60, 64))	('HM) colon adenocarcinoma', 'Disease', 'MESH:D015179', (34, 58))	('COAD', 'Disease', (60, 64))	('CIN', 'Phenotype', 'HP:0040012', (167, 170))	('highest', 'PosReg', (97, 104))	('patients', 'Species', '9606', (66, 74))
65889	31645905	Our results further demonstrated that the hypermutated (HM) subtype in colon adenocarcinoma (COAD) had a significantly higher immune response than either the chromosomal instability (CIN) or genome stable (GS) subtypes, making such patients potential candidates for immunotherapeutic treatments.	('COAD', 'Disease', 'MESH:D015179', (93, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (158, 181))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('patients', 'Species', '9606', (232, 240))	('immune', 'MPA', (126, 132))	('men', 'Species', '9606', (289, 292))	('immune response', 'biological_process', 'GO:0006955', ('126', '141'))	('colon adenocarcinoma', 'Disease', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (119, 125))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (71, 91))	('COAD', 'Disease', (93, 97))	('hypermutated', 'Var', (42, 54))
65916	31645905	For the same reason, the molecular subtypes investigated in detail in this study included: Basal/Her2/LumA/LumB in breast invasive carcinoma (BRCA) patients, CIN/GS/HM-indel/HM-SNV or /EBV in gastrointestinal cancer patients, IDH mutation status in glioma patients, and POLE/MSI/CN_Low/CN_High in uterine corpus endometrial carcinoma (UCEC) patients.	('patients', 'Species', '9606', (341, 349))	('IDH', 'Gene', '3417', (226, 229))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 215))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (115, 140))	('gastrointestinal cancer', 'Disease', (192, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (192, 215))	('CIN', 'Phenotype', 'HP:0040012', (158, 161))	('patients', 'Species', '9606', (148, 156))	('LumA', 'Gene', '79188', (102, 106))	('breast invasive carcinoma (BRCA', 'Gene', (115, 146))	('glioma', 'Disease', (249, 255))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (115, 147))	('MSI', 'Gene', (275, 278))	('MSI', 'Gene', '5928', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('patients', 'Species', '9606', (216, 224))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('LumA', 'Gene', (102, 106))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Her2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (256, 264))	('CIN/GS/HM-indel/HM-SNV', 'Var', (158, 180))	('Her2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
65919	31645905	The Normal subtype in breast invasive carcinoma (BRCA) and IDH mutant group in glioblastoma multiforme (GBM) typically had a small number of patients, and as such were excluded from downstream analyses.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (79, 102))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (22, 54))	('IDH', 'Gene', (59, 62))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (22, 47))	('mutant', 'Var', (63, 69))	('GBM', 'Disease', (104, 107))	('IDH', 'Gene', '3417', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('GBM', 'Disease', 'MESH:D005909', (104, 107))	('breast invasive carcinoma (BRCA', 'Gene', (22, 53))	('glioblastoma multiforme', 'Disease', (79, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
65923	31645905	CIN Chromosomal instability GS genome stable HM hypermutated MSI microsatellite instability EBV Epstein-Barr virus SNV single-nucleotide variant HPV human papillomavirus	('single-nucleotide variant', 'Var', (119, 144))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (96, 114))	('HPV', 'Species', '10566', (145, 148))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('human papillomavirus', 'Species', '10566', (149, 169))	('Epstein-Barr virus', 'Disease', (96, 114))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
65928	29391527	High SMARCA4 expression was associated with poor prognosis in many types of tumors, including liver hepatocellular carcinoma (LIHC), and kidney renal clear cell carcinoma (KIRC).	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (137, 170))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('LIHC', 'Disease', 'None', (126, 130))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 124))	('liver hepatocellular carcinoma', 'Disease', (94, 124))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('LIHC', 'Disease', (126, 130))	('SMARCA4', 'Gene', (5, 12))	('SMARCA4', 'Gene', '6597', (5, 12))	('kidney renal clear cell carcinoma', 'Disease', (137, 170))
65929	29391527	In contrast, high SMARCA2 expression was associated with good prognosis.	('high', 'Var', (13, 17))	('SMARCA2', 'Gene', '6595', (18, 25))	('SMARCA2', 'Gene', (18, 25))	('expression', 'MPA', (26, 36))
65939	29391527	The mechanisms by which loss-of-function mutations in SWI/SNF complex subunits trigger tumor formation or affect tumor cell behavior is still a highly debated issue.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('loss-of-function', 'NegReg', (24, 40))	('formation', 'biological_process', 'GO:0009058', ('93', '102'))	('trigger', 'PosReg', (79, 86))	('tumor', 'Disease', (87, 92))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('54', '69'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SWI/SNF', 'Gene', (54, 61))	('affect', 'Reg', (106, 112))
65940	29391527	Several data point to the pathological effects of aberrant residual SWI/SNF complexes as the cause of the potential selective advantage of SWI/SNF mutant cancer cells.	('mutant', 'Var', (147, 153))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('SWI/SNF complexes', 'Protein', (68, 85))	('SWI/SNF', 'Gene', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('aberrant', 'Var', (50, 58))
65943	29391527	In addition, SMARCA4 has been found to be silenced or mutated in a number of cancer cell lines.	('SMARCA4', 'Gene', (13, 20))	('SMARCA4', 'Gene', '6597', (13, 20))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutated', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
65944	29391527	Brg1 homozygous knockout mice die early during development; however, heterozygote mice or conditional inactivation of Brg1 in some adult tissues display increased tumor formation.	('Brg1', 'Gene', '20586', (0, 4))	('mice', 'Species', '10090', (82, 86))	('Brg1', 'Gene', (118, 122))	('mice', 'Species', '10090', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('formation', 'biological_process', 'GO:0009058', ('169', '178'))	('Brg1', 'Gene', '20586', (118, 122))	('conditional inactivation', 'Var', (90, 114))	('tumor', 'Disease', (163, 168))	('Brg1', 'Gene', (0, 4))
65947	29391527	Furthermore, heterozygote and homozygote Brm mutants treated with carcinogens display increased tumor development.	('mutants', 'Var', (45, 52))	('increased', 'PosReg', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('Brm', 'Gene', (41, 44))	('carcinogens', 'Disease', 'MESH:D063646', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('carcinogens', 'Disease', (66, 77))
65953	29391527	A meta-analysis of prognosis data indicated that tumors with high SMARCA4 expression are mostly associated with poor prognosis, while tumors with high SMARCA2 expression are mostly associated with good prognosis.	('expression', 'MPA', (74, 84))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('SMARCA4', 'Gene', (66, 73))	('SMARCA4', 'Gene', '6597', (66, 73))	('high', 'Var', (61, 65))	('SMARCA2', 'Gene', (151, 158))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('SMARCA2', 'Gene', '6595', (151, 158))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
65967	29391527	We next investigated whether SMARCA4 overexpression occurs predominantly in tumors harboring SMARCA4 mutations as a possible consequence of a putative negative autoregulation.	('SMARCA4', 'Gene', '6597', (29, 36))	('overexpression', 'PosReg', (37, 51))	('negative', 'NegReg', (151, 159))	('mutations', 'Var', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('SMARCA4', 'Gene', (93, 100))	('autoregulation', 'MPA', (160, 174))	('SMARCA4', 'Gene', '6597', (93, 100))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('SMARCA4', 'Gene', (29, 36))
65968	29391527	Using data on SMARCA4 mutations in 18 types of tumors obtained from TCGA through cBioPortal, we found SMARCA4 to be mutated in either none or up to 8.5% of the samples, depending on the tumor type.	('SMARCA4', 'Gene', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SMARCA4', 'Gene', (14, 21))	('SMARCA4', 'Gene', '6597', (102, 109))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('SMARCA4', 'Gene', '6597', (14, 21))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutated', 'Var', (116, 123))	('tumor', 'Disease', (47, 52))
65969	29391527	SMARCA4 mutated tumors displayed similar level of accumulation of SMARCA4 mRNA as tumors harboring non-mutated SMARCA4 (Supplementary Fig.	('SMARCA4', 'Gene', (0, 7))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('SMARCA4', 'Gene', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mutated', 'Var', (8, 15))	('SMARCA4', 'Gene', '6597', (66, 73))	('SMARCA4', 'Gene', '6597', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SMARCA4', 'Gene', (111, 118))	('SMARCA4', 'Gene', '6597', (111, 118))	('accumulation', 'PosReg', (50, 62))	('tumors', 'Disease', (16, 22))
65971	29391527	Taken together, these data demonstrate that SMARCA4 expression is upregulated and SMARCA2 is downregulated in most types of tumors irrespectively of the presence of mutations in the gene.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SMARCA2', 'Gene', (82, 89))	('SMARCA2', 'Gene', '6595', (82, 89))	('upregulated', 'PosReg', (66, 77))	('expression', 'MPA', (52, 62))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('downregulated', 'NegReg', (93, 106))	('mutations', 'Var', (165, 174))	('SMARCA4', 'Gene', (44, 51))	('SMARCA4', 'Gene', '6597', (44, 51))
65975	29391527	High expression of SMARCA4 was significantly associated (COX P <= 0.01) with a poor prognosis in breast and ovarian cancer, lung adenocarcinoma, liposarcoma and uveal melanoma datasets (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (161, 175))	('uveal melanoma', 'Disease', (161, 175))	('liposarcoma', 'Disease', 'MESH:D008080', (145, 156))	('High', 'Var', (0, 4))	('SMARCA4', 'Gene', (19, 26))	('lung adenocarcinoma', 'Disease', (124, 143))	('liposarcoma', 'Phenotype', 'HP:0012034', (145, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (97, 122))	('uveal melanoma', 'Disease', 'MESH:C536494', (161, 175))	('associated', 'Reg', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('liposarcoma', 'Disease', (145, 156))	('SMARCA4', 'Gene', '6597', (19, 26))
65976	29391527	In contrast, high expression of SMARCA2 was associated to good prognosis in breast and ovarian cancer, lung adenocarcinoma, and liposarcoma datasets (Fig.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (76, 101))	('liposarcoma', 'Phenotype', 'HP:0012034', (128, 139))	('high', 'Var', (13, 17))	('liposarcoma', 'Disease', 'MESH:D008080', (128, 139))	('lung adenocarcinoma', 'Disease', (103, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SMARCA2', 'Gene', (32, 39))	('SMARCA2', 'Gene', '6595', (32, 39))	('liposarcoma', 'Disease', (128, 139))
65977	29391527	In fact, high expression of SMARCA2 was associated with poor prognosis only in colon carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (79, 94))	('colon carcinoma', 'Disease', (79, 94))	('SMARCA2', 'Gene', (28, 35))	('SMARCA2', 'Gene', '6595', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('high', 'Var', (9, 13))
65985	29391527	Analysis of these plots indicates that high expression of SMARCA4 is associated with poor prognosis in LIHC, BLCA, SKCM and KIRC (Fig.	('SMARCA4', 'Gene', (58, 65))	('BLCA', 'Disease', (109, 113))	('LIHC', 'Disease', 'None', (103, 107))	('high expression', 'Var', (39, 54))	('SKCM', 'Disease', (115, 119))	('SMARCA4', 'Gene', '6597', (58, 65))	('KIRC', 'Disease', (124, 128))	('LIHC', 'Disease', (103, 107))
65986	29391527	In clear contrast, high expression of SMARCA2 is associated with good prognosis in LIHC and KIRC (Fig.	('LIHC', 'Disease', 'None', (83, 87))	('high expression', 'Var', (19, 34))	('KIRC', 'Disease', (92, 96))	('SMARCA2', 'Gene', (38, 45))	('SMARCA2', 'Gene', '6595', (38, 45))	('LIHC', 'Disease', (83, 87))
65987	29391527	Taken together, these data suggest that in most of the cohorts analyzed, high expression of SMARCA4 is associated with poor prognosis, while high expression of SMARCA2 is associated with good prognosis.	('SMARCA2', 'Gene', (160, 167))	('SMARCA2', 'Gene', '6595', (160, 167))	('SMARCA4', 'Gene', '6597', (92, 99))	('high', 'Var', (73, 77))	('SMARCA4', 'Gene', (92, 99))
65990	29391527	Consistently with the prognosis results, LIHC tumors with high levels of SMARCA4 expression (upper decile) presented a significant increased proportion of advanced stages, and poorly differentiated histology with respect to the rest of the LIHC tumors analyzed (Table 1).	('high levels', 'Var', (58, 69))	('LIHC tumors', 'Disease', 'MESH:D009369', (240, 251))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('LIHC tumors', 'Disease', (41, 52))	('increased', 'PosReg', (131, 140))	('LIHC tumors', 'Disease', 'MESH:D009369', (41, 52))	('LIHC tumors', 'Disease', (240, 251))	('advanced stages', 'CPA', (155, 170))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('SMARCA4', 'Gene', (73, 80))	('SMARCA4', 'Gene', '6597', (73, 80))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('expression', 'MPA', (81, 91))
65991	29391527	In contrast, tumors with high levels of SMARCA2 transcript (upper decile) presented increased proportion of well-differentiated tumors (Table 1).	('SMARCA2', 'Gene', (40, 47))	('SMARCA2', 'Gene', '6595', (40, 47))	('high levels', 'Var', (25, 36))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
65993	29391527	Similarly, in KIRC tumors, high expression of SMARCA4 is associated with increased undifferentiated histological grade (Fig.	('increased', 'PosReg', (73, 82))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('high expression', 'Var', (27, 42))	('SMARCA4', 'Gene', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('SMARCA4', 'Gene', '6597', (46, 53))
65995	29391527	In addition, in KIRC tumors, high expression of SMARCA4 was strongly associated with the presence of metastasis (high proportion of N1, P = 0.035, and M1, P = 0.0009) (Table 2).	('high', 'Var', (29, 33))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', (21, 27))	('metastasis', 'CPA', (101, 111))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('SMARCA4', 'Gene', (48, 55))	('SMARCA4', 'Gene', '6597', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
66019	29391527	5j; Supplementary Figs S3d and S4b), and often presented E2F (P = 1.05x10-26), MYC (P = 3.9x10-16) and ELK1 (P = 1.2 x 10-11) binding sites, suggesting a reduced proliferation of these tumor cells.	('tumor', 'Disease', (185, 190))	('ELK1', 'Gene', (103, 107))	('E2F', 'Protein', (57, 60))	('MYC', 'Gene', (79, 82))	('ELK1', 'Gene', '2002', (103, 107))	('S3d', 'Var', (23, 26))	('S4b', 'Var', (31, 34))	('binding', 'Interaction', (126, 133))	('proliferation', 'CPA', (162, 175))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('MYC', 'Gene', '4609', (79, 82))	('reduced', 'NegReg', (154, 161))	('binding', 'molecular_function', 'GO:0005488', ('126', '133'))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
66027	29391527	In contrast, genes positively coexpressed with SMARCA2 and negatively coexpressed with SMARCA4 (Supplementary Table S7) were enriched in liver metabolism functions, such as lipid metabolism (ACADL, ACSL1, LIPG), amino acid metabolism (TAT, BCKDHB, PAH, IDH1), xenobiotic detoxification (CYP3A4, CYP4V2, CYP8B1), and blood coagulation (F8, F11) categories.	('xenobiotic detoxification', 'Disease', 'MESH:C565043', (260, 285))	('BCKDHB', 'Gene', (240, 246))	('TAT', 'Disease', 'None', (235, 238))	('SMARCA2', 'Gene', (47, 54))	('SMARCA2', 'Gene', '6595', (47, 54))	('ACADL', 'Gene', (191, 196))	('ACADL', 'Gene', '33', (191, 196))	('LIPG', 'Gene', (205, 209))	('CYP3A4', 'Var', (287, 293))	('CYP4V2', 'Gene', (295, 301))	('lipid metabolism', 'MPA', (173, 189))	('metabolism', 'biological_process', 'GO:0008152', ('223', '233'))	('PAH', 'molecular_function', 'GO:0033972', ('248', '251'))	('IDH1', 'Gene', (253, 257))	('liver metabolism functions', 'MPA', (137, 163))	('SMARCA4', 'Gene', (87, 94))	('PAH', 'Gene', (248, 251))	('CYP8B1', 'Gene', '1582', (303, 309))	('blood coagulation', 'Disease', 'MESH:D001778', (316, 333))	('amino acid metabolism', 'MPA', (212, 233))	('detoxification', 'biological_process', 'GO:0098754', ('271', '285'))	('BCKDHB', 'Gene', '594', (240, 246))	('TAT', 'Disease', (235, 238))	('ACSL1', 'Gene', '2180', (198, 203))	('IDH1', 'Gene', '3417', (253, 257))	('metabolism', 'biological_process', 'GO:0008152', ('143', '153'))	('CYP8B1', 'molecular_function', 'GO:0033779', ('303', '309'))	('LIPG', 'Gene', '9388', (205, 209))	('lipid metabolism', 'biological_process', 'GO:0006629', ('173', '189'))	('ACSL1', 'Gene', (198, 203))	('CYP8B1', 'Gene', (303, 309))	('xenobiotic detoxification', 'Disease', (260, 285))	('CYP3A4', 'molecular_function', 'GO:0033780', ('287', '293'))	('SMARCA4', 'Gene', '6597', (87, 94))	('blood coagulation', 'Disease', (316, 333))	('PAH', 'Gene', '5053', (248, 251))	('blood coagulation', 'biological_process', 'GO:0007596', ('316', '333'))	('lipid', 'Chemical', 'MESH:D008055', (173, 178))	('CYP4V2', 'Gene', '285440', (295, 301))
66061	29391527	A role of SWI/SNF complexes as tumor suppressors is widely accepted, mostly based on the fact that genes encoding SWI/SNF subunits are mutated in a wide-ranging proportion of tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutated', 'Var', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
66062	29391527	Thus, SMARCA4 is frequently mutated (more than 90% of the cases) in ovarian small cell carcinoma of the hypercalcemic type.	('SMARCA4', 'Gene', (6, 13))	('mutated', 'Var', (28, 35))	('SMARCA4', 'Gene', '6597', (6, 13))	('ovarian small cell carcinoma of the hypercalcemic type', 'Disease', 'MESH:D018288', (68, 122))	('ovarian small', 'Phenotype', 'HP:0008724', (68, 81))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (76, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
66063	29391527	However, several studies and inspection of the TCGA data indicate that, in most of the tumor types SMARCA4 mutations vary between 0% and 15% of the cases.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
66070	29391527	Furthermore, we find that high levels of SMARCA4 expression are associated with an advanced tumor stage and histological grade in LIHC, and with increased metastasis in KIRC.	('associated', 'Reg', (64, 74))	('metastasis', 'CPA', (155, 165))	('high', 'Var', (26, 30))	('SMARCA4', 'Gene', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('increased', 'PosReg', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SMARCA4', 'Gene', '6597', (41, 48))	('LIHC', 'Disease', (130, 134))	('LIHC', 'Disease', 'None', (130, 134))	('tumor', 'Disease', (92, 97))	('histological grade', 'CPA', (108, 126))
66071	29391527	Taken together, these data suggest that, at least for several types of cancers, high expression of SMARCA4 confers a selective advantage to tumor cells.	('SMARCA4', 'Gene', (99, 106))	('SMARCA4', 'Gene', '6597', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('high expression', 'Var', (80, 95))	('tumor', 'Disease', (140, 145))
66085	29391527	Consistently, Kaufmann et al., recently showed that knockdown of SMARCA4 impairs proliferation and decreases cyclin B and cyclin E expression in hepatocellular carcinoma cell lines.	('decreases', 'NegReg', (99, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('cyclin', 'molecular_function', 'GO:0016538', ('109', '115'))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('SMARCA4', 'Gene', (65, 72))	('SMARCA4', 'Gene', '6597', (65, 72))	('impairs', 'NegReg', (73, 80))	('proliferation', 'CPA', (81, 94))	('knockdown', 'Var', (52, 61))	('cyclin', 'molecular_function', 'GO:0016538', ('122', '128'))
66091	29391527	Interestingly, RhoA signaling activation was reported upon SMARCA4 re-expression in SMARCA4-deficient human adrenal adenocarcinoma SW13 cells.	('SMARCA4-deficient human adrenal adenocarcinoma', 'Disease', 'MESH:D000310', (84, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('re-expression', 'Var', (67, 80))	('SMARCA4', 'Gene', (59, 66))	('RhoA', 'Gene', (15, 19))	('activation', 'PosReg', (30, 40))	('SMARCA4-deficient human adrenal adenocarcinoma', 'Disease', (84, 130))	('SMARCA4', 'Gene', '6597', (59, 66))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('RhoA', 'Gene', '387', (15, 19))	('SW13', 'CellLine', 'CVCL:0542', (131, 135))	('SMARCA4', 'Gene', (84, 91))	('adrenal adenocarcinoma', 'Phenotype', 'HP:0006744', (108, 130))	('SMARCA4', 'Gene', '6597', (84, 91))
66094	29391527	In addition, high levels of SMARCA2 expression were associated with a low tumor stage and well-differentiated tumors in LIHC and KIRC.	('low tumor', 'Disease', 'MESH:D009800', (70, 79))	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('low tumor', 'Disease', (70, 79))	('LIHC', 'Disease', (120, 124))	('SMARCA2', 'Gene', (28, 35))	('tumors', 'Disease', (110, 116))	('SMARCA2', 'Gene', '6595', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('LIHC', 'Disease', 'None', (120, 124))	('expression', 'MPA', (36, 46))
66221	31169496	Cox regression analyses were conducted to establish a four-DNA methylation signature that was significantly associated with the overall survival (OS) of patients with CM, and that was validated in an independent cohort.	('Cox', 'Gene', '9377', (0, 3))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('overall survival', 'MPA', (128, 144))	('patients', 'Species', '9606', (153, 161))	('Cox', 'Gene', (0, 3))	('OS', 'Chemical', '-', (146, 148))	('associated with', 'Reg', (108, 123))	('methylation', 'Var', (63, 74))	('CM', 'Disease', 'MESH:D009202', (167, 169))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))
66234	31169496	Aberrant DNA methylation is an epigenetic hallmark of cancer and actively contributes to cancer development and progression by inactivating tumor suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('inactivating', 'NegReg', (127, 139))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Disease', (89, 95))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('contributes', 'Reg', (74, 85))	('Aberrant', 'Var', (0, 8))	('hallmark of cancer', 'Disease', 'MESH:D009369', (42, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('men', 'Species', '9606', (103, 106))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hallmark of cancer', 'Disease', (42, 60))	('tumor', 'Disease', (140, 145))
66235	31169496	Some characteristics of methylation markers render them particularly attractive for development of clinically applicable biomarkers, including high stability in biologic samples, limited susceptibility to tumor environmental factors, and ease of detection.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('men', 'Species', '9606', (91, 94))	('methylation', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('men', 'Species', '9606', (218, 221))
66236	31169496	A growing number of studies have demonstrated that aberrant DNA methylation plays important roles in tumorigenesis and progression, and DNA methylation has great potential to act as a biomarker for predicting the prognosis of patients with a variety of malignancies.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('DNA methylation', 'biological_process', 'GO:0006306', ('60', '75'))	('malignancies', 'Disease', (253, 265))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('aberrant', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('progression', 'CPA', (119, 130))	('tumor', 'Disease', (101, 106))	('patients', 'Species', '9606', (226, 234))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('DNA', 'Protein', (60, 63))	('malignancies', 'Disease', 'MESH:D009369', (253, 265))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
66237	31169496	For instance, GATA4 is epigenetically silenced in gastrointestinal cancers and lung cancer; OPCML promoter methylation has been identified as a biomarker for predicting ovarian cancer prognosis; PCDH19 methylation is associated with poor hepatocellular carcinoma prognosis and Sigalotti et al.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (50, 74))	('PCDH19', 'Gene', (195, 201))	('lung cancer', 'Disease', (79, 90))	('hepatocellular carcinoma', 'Disease', (238, 262))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (169, 183))	('GATA4', 'Gene', '2626', (14, 19))	('gastrointestinal cancers', 'Disease', (50, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('PCDH19', 'Gene', '57526', (195, 201))	('methylation', 'biological_process', 'GO:0032259', ('202', '213'))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('ovarian cancer', 'Disease', (169, 183))	('OPCML', 'Gene', (92, 97))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (238, 262))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('methylation', 'Var', (202, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (169, 183))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('GATA4', 'Gene', (14, 19))	('associated', 'Reg', (217, 227))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (238, 262))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('OPCML', 'Gene', '4978', (92, 97))
66254	31169496	By subjecting the DNA methylation level data in the training cohort to univariate Cox proportional hazard regression analysis, a total of 4454 DNA methylation sites that significantly (p<0.001) correlated with the OS of patients with CM were identified as candidate markers.	('DNA', 'cellular_component', 'GO:0005574', ('143', '146'))	('Cox', 'Gene', (82, 85))	('correlated', 'Reg', (194, 204))	('DNA methylation', 'biological_process', 'GO:0006306', ('143', '158'))	('CM', 'Disease', 'MESH:D009202', (234, 236))	('OS', 'Chemical', '-', (214, 216))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('patients', 'Species', '9606', (220, 228))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('Cox', 'Gene', '9377', (82, 85))	('sites', 'Var', (159, 164))
66255	31169496	Subsequently, these candidate markers were used to perform multivariate Cox stepwise regression analyses, and a hazard ratio model consisting of four methylation sites (cg06778853, cg24670442, cg18456782, cg26263675) was selected as the optimum prognostic model for predicting OS.	('cg06778853', 'Var', (169, 179))	('cg06778853', 'Chemical', '-', (169, 179))	('Cox', 'Gene', '9377', (72, 75))	('cg24670442', 'Var', (181, 191))	('cg18456782', 'Chemical', '-', (193, 203))	('cg26263675', 'Chemical', '-', (205, 215))	('Cox', 'Gene', (72, 75))	('cg18456782', 'Var', (193, 203))	('cg24670442', 'Chemical', '-', (181, 191))	('OS', 'Chemical', '-', (277, 279))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('cg26263675', 'Var', (205, 215))
66256	31169496	The risk score formula based on the DNA methylation level and regression coefficients of four methylation sites was created as follows: Risk score = -1.912 x beta value of cg06778853 +4.262 x beta value of cg24670442 +1.229 x beta value of cg18456782 - 2.108 x beta value of cg26263675.	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('cg18456782', 'Chemical', '-', (240, 250))	('cg06778853', 'Chemical', '-', (172, 182))	('cg24670442 +1.229', 'Var', (206, 223))	('cg18456782 -', 'Var', (240, 252))	('cg26263675', 'Chemical', '-', (275, 285))	('cg26263675', 'Var', (275, 285))	('cg06778853 +4.262', 'Var', (172, 189))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('cg24670442', 'Chemical', '-', (206, 216))
66257	31169496	Among these methylation sites, cg24670442 and cg18456782 had positive coefficients, indicating a correlation between higher DNA methylation level and shorter OS, while higher levels of DNA methylation in cg06778853 and cg26263675 sites correlated with longer OS.	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('cg06778853', 'Var', (204, 214))	('cg24670442', 'Chemical', '-', (31, 41))	('DNA methylation level', 'MPA', (124, 145))	('cg06778853', 'Chemical', '-', (204, 214))	('higher', 'PosReg', (117, 123))	('cg26263675', 'Chemical', '-', (219, 229))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('shorter OS', 'Disease', (150, 160))	('OS', 'Chemical', '-', (158, 160))	('cg24670442', 'Var', (31, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('185', '200'))	('OS', 'Chemical', '-', (259, 261))	('DNA methylation', 'biological_process', 'GO:0006306', ('124', '139'))	('cg18456782', 'Var', (46, 56))	('cg26263675', 'Var', (219, 229))	('longer OS', 'Disease', (252, 261))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('cg18456782', 'Chemical', '-', (46, 56))
66261	31169496	Patients exhibiting long-term survival tended to have lower methylation levels of cg24670442, cg18456782 and higher methylation levels of the other two methylation sites, consistent with the results of multivariate Cox regression analysis.	('methylation levels', 'MPA', (116, 134))	('methylation levels', 'MPA', (60, 78))	('cg18456782', 'Chemical', '-', (94, 104))	('Cox', 'Gene', (215, 218))	('higher', 'PosReg', (109, 115))	('cg18456782', 'Var', (94, 104))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('Cox', 'Gene', '9377', (215, 218))	('Patients', 'Species', '9606', (0, 8))	('cg24670442', 'Var', (82, 92))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('cg24670442', 'Chemical', '-', (82, 92))	('lower', 'NegReg', (54, 59))
66265	31169496	According to the results of Cox regression analysis, the four-DNA methylation signature were significantly associated with the OS of patients using the risk scores as a continuous variable in both the training and validation cohorts (training cohort: p=1.73E-7, HR: 2.72, 95% CI of HR: 1.91-3.88; validation cohort: p=3.19E-6, HR: 3.58, 95% CI of HR: 2.04-6.29).	('Cox', 'Gene', '9377', (28, 31))	('associated', 'Reg', (107, 117))	('patients', 'Species', '9606', (133, 141))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('methylation', 'Var', (66, 77))	('Cox', 'Gene', (28, 31))	('DNA methylation', 'biological_process', 'GO:0006306', ('62', '77'))	('OS', 'Chemical', '-', (127, 129))
66293	31169496	The presence of MGMT promoter methylation is an independent variable associated with longer OS, and the methylation of PTEN has been reported as an independent negative prognostic factor in terms of OS.	('OS', 'Chemical', '-', (199, 201))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('associated', 'Reg', (69, 79))	('MGMT', 'Gene', (16, 20))	('PTEN', 'Gene', (119, 123))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))	('methylation', 'Var', (104, 115))	('longer OS', 'Disease', (85, 94))	('MGMT', 'Gene', '4255', (16, 20))	('PTEN', 'Gene', '5728', (119, 123))	('OS', 'Chemical', '-', (92, 94))	('presence', 'Var', (4, 12))	('MGMT', 'molecular_function', 'GO:0003908', ('16', '20'))
66307	31169496	In fact, cg24670442, one of the four-DNA methylation signatures, corresponding to GBP5 gene, was significantly negatively correlated with PD-1, PD-L1, PD-L2, CTLA-4 (p<0.001, and r = -0.681,-0.405, -0.436,-0.171, respectively), and patients with long-term survival exhibiting lower methylation levels and higher expression level.	('PD-L2', 'Gene', '80380', (151, 156))	('GBP5', 'Gene', '115362', (82, 86))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cg24670442', 'Chemical', '-', (9, 19))	('higher', 'PosReg', (305, 311))	('patients', 'Species', '9606', (232, 240))	('negatively', 'NegReg', (111, 121))	('methylation', 'biological_process', 'GO:0032259', ('282', '293'))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('PD-1', 'Gene', (138, 142))	('methylation levels', 'MPA', (282, 300))	('GBP5', 'Gene', (82, 86))	('PD-1', 'Gene', '5133', (138, 142))	('lower', 'NegReg', (276, 281))	('expression level', 'MPA', (312, 328))	('cg24670442', 'Var', (9, 19))	('PD-L2', 'Gene', (151, 156))
66310	31169496	Collectively, these results imply that our four-DNA methylation signature, although developed to accurately stratify patients in terms of prognosis, may also play a role in ICB immunotherapy.	('ICB', 'Chemical', '-', (173, 176))	('ICB', 'Disease', (173, 176))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('play', 'Reg', (158, 162))	('patients', 'Species', '9606', (117, 125))	('methylation', 'Var', (52, 63))	('DNA methylation', 'biological_process', 'GO:0006306', ('48', '63'))	('role', 'Reg', (165, 169))
66313	31169496	For instance, hypermethylated estrogen receptor alpha (ER-alpha) is a significant factor in melanoma progression; methylation-dependent SOX9 expression mediates invasion in human melanoma cells and is a negative prognostic factor in advanced melanoma, and MGMT gene promoter methylation in metastatic CM is associated with longer survival.	('ER-alpha', 'Gene', '2099', (55, 63))	('SOX9', 'Gene', '6662', (136, 140))	('mediates', 'Reg', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('MGMT', 'Gene', '4255', (256, 260))	('longer', 'PosReg', (323, 329))	('methylation-dependent', 'Var', (114, 135))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('negative', 'NegReg', (203, 211))	('estrogen receptor alpha', 'Gene', (30, 53))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('human', 'Species', '9606', (173, 178))	('MGMT', 'molecular_function', 'GO:0003908', ('256', '260'))	('CM', 'Disease', 'MESH:D009202', (301, 303))	('MGMT', 'Gene', (256, 260))	('melanoma', 'Disease', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('methylation', 'biological_process', 'GO:0032259', ('275', '286'))	('SOX9', 'Gene', (136, 140))	('estrogen receptor alpha', 'Gene', '2099', (30, 53))	('ER-alpha', 'Gene', (55, 63))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))
66315	31169496	Based on a TCGA dataset that included 461 CM samples, the current study identified a prognostic DNA methylation signature with potential clinical applicability, validated it in an independent cohort, and investigated its high reproducibility and utility in various clinical groups.	('CM', 'Disease', 'MESH:D009202', (42, 44))	('DNA', 'Gene', (96, 99))	('methylation', 'Var', (100, 111))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('DNA methylation', 'biological_process', 'GO:0006306', ('96', '111'))
66330	31169496	Intriguingly, the correlation analyses and the observed predictive performance suggested that our four-DNA methylation signature was significantly correlated with the ICB immunotherapy-related signature.	('DNA methylation', 'biological_process', 'GO:0006306', ('103', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('ICB', 'Chemical', '-', (167, 170))	('methylation', 'Var', (107, 118))	('correlated', 'Reg', (147, 157))
66333	31169496	Furthermore, epigenetic changes have been shown to alter gene expression, and epigenetic inactivation of tumor suppressor genes has been implicated in tumorigenesis of various malignancies, including CM.	('gene expression', 'MPA', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('epigenetic changes', 'Var', (13, 31))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('malignancies', 'Disease', 'MESH:D009369', (176, 188))	('CM', 'Disease', 'MESH:D009202', (200, 202))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('implicated', 'Reg', (137, 147))	('gene expression', 'biological_process', 'GO:0010467', ('57', '72'))	('alter', 'Reg', (51, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('malignancies', 'Disease', (176, 188))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('epigenetic inactivation', 'Var', (78, 101))
66336	31169496	For our four-DNA methylation sites, researchers have revealed that their corresponding genes may be crucial in immunity and cancer development, including CM.	('CM', 'Disease', 'MESH:D009202', (154, 156))	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('cancer', 'Disease', (124, 130))	('men', 'Species', '9606', (138, 141))	('methylation', 'Var', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DNA methylation', 'biological_process', 'GO:0006306', ('13', '28'))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
66340	31169496	RAB37, as a tumor suppressor gene, promotes M1-like macrophage infiltration and suppresses tumor growth, and it was frequently down-regulated due to promoter hypermethylation in metastatic lung cancer, can serve as a potential predictive biomarker.	('M1-like macrophage infiltration', 'CPA', (44, 75))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (91, 96))	('down-regulated', 'NegReg', (127, 141))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('promotes', 'PosReg', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('12', '28'))	('lung cancer', 'Disease', (189, 200))	('RAB37', 'Gene', '326624', (0, 5))	('suppresses', 'NegReg', (80, 90))	('promoter hypermethylation', 'Var', (149, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('12', '28'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('RAB37', 'Gene', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))
66341	31169496	RAB37-mediated SFRP1 secretion suppresses cancer stemness, and dysregulated RAB37-SFRP1 pathway confers cancer stemness via the activation of Wnt signaling.	('cancer stemness', 'Disease', (104, 119))	('RAB37', 'Gene', '326624', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('SFRP1', 'Gene', '6422', (82, 87))	('SFRP1', 'Gene', (15, 20))	('confers', 'PosReg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer stemness', 'Disease', 'MESH:D009369', (42, 57))	('Wnt signaling', 'Pathway', (142, 155))	('RAB37', 'Gene', '326624', (0, 5))	('RAB37', 'Gene', (76, 81))	('activation', 'PosReg', (128, 138))	('SFRP1', 'Gene', '6422', (15, 20))	('secretion', 'biological_process', 'GO:0046903', ('21', '30'))	('cancer stemness', 'Disease', 'MESH:D009369', (104, 119))	('suppresses', 'NegReg', (31, 41))	('cancer stemness', 'Disease', (42, 57))	('SFRP1', 'Gene', (82, 87))	('dysregulated', 'Var', (63, 75))	('RAB37', 'Gene', (0, 5))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))
66342	31169496	OCA2 is involved in the melanin biosynthetic process and mammalian pigmentation, and the DNA variant in intron of OCA2 (rs4778138) has been found associated with CM risk.	('OCA2', 'Gene', (114, 118))	('OCA2', 'Gene', '4948', (0, 4))	('pigmentation', 'biological_process', 'GO:0043473', ('67', '79'))	('men', 'Species', '9606', (70, 73))	('mammalian', 'Species', '9606', (57, 66))	('OCA2', 'Gene', (0, 4))	('OCA2', 'Gene', '4948', (114, 118))	('CM', 'Disease', 'MESH:D009202', (162, 164))	('rs4778138', 'Mutation', 'rs4778138', (120, 129))	('associated', 'Reg', (146, 156))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('melanin', 'Chemical', 'MESH:D008543', (24, 31))	('rs4778138', 'Var', (120, 129))	('melanin biosynthetic process', 'biological_process', 'GO:0042438', ('24', '52'))
66343	31169496	The hypomethylation levels of cg18456782 (OCA2) was associated with lower expression of OCA2 and a lower risk.	('expression', 'MPA', (74, 84))	('lower', 'NegReg', (68, 73))	('OCA2', 'Gene', '4948', (42, 46))	('OCA2', 'Gene', (88, 92))	('OCA2', 'Gene', (42, 46))	('cg18456782', 'Chemical', '-', (30, 40))	('OCA2', 'Gene', '4948', (88, 92))	('cg18456782', 'Var', (30, 40))
66350	31169496	Therefore, the current study provides new insight that a combination of epigenetic biomarkers could help to improve risk-stratification and prediction of survival in patients with melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('epigenetic', 'Var', (72, 82))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('patients', 'Species', '9606', (166, 174))
66351	31169496	In conclusion, we identified and verified a four-DNA methylation signature that was significantly associated with the OS of patients in TCGA and an independent cohort.	('DNA methylation', 'biological_process', 'GO:0006306', ('49', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('OS', 'Chemical', '-', (118, 120))	('associated', 'Reg', (98, 108))	('patients', 'Species', '9606', (124, 132))	('methylation', 'Var', (53, 64))
66352	31169496	The four-DNA methylation signature was not only independent of clinical factors including patient sex, age, stage, tumor location, and Breslow thickness, but also exhibited superior ability in predicting OS compared with known biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('methylation', 'Var', (13, 24))	('OS', 'Chemical', '-', (204, 206))	('tumor', 'Disease', (115, 120))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('predicting', 'Reg', (193, 203))	('patient', 'Species', '9606', (90, 97))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
66354	31169496	Furthermore, the four-DNA methylation signature was significantly correlated with the ICB immunotherapy-related signature.	('methylation', 'Var', (26, 37))	('correlated', 'Reg', (66, 76))	('ICB', 'Disease', (86, 89))	('DNA methylation', 'biological_process', 'GO:0006306', ('22', '37'))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('ICB', 'Chemical', '-', (86, 89))
66355	31169496	Therefore, though these exploratory findings are warranted to validate the potential role of this prognostic signature in clinical application and the functional characterization in CM development, these four-DNA methylation sites, or some of them, may participate in the progress of the cancer, and have great potential implications for both risk-stratification, adjuvant management and measures of response to ICB immunotherapy of patients with CM.	('sites', 'Var', (225, 230))	('CM', 'Disease', 'MESH:D009202', (447, 449))	('participate in', 'Reg', (253, 267))	('CM', 'Disease', 'MESH:D009202', (182, 184))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('men', 'Species', '9606', (379, 382))	('DNA methylation', 'biological_process', 'GO:0006306', ('209', '224'))	('methylation sites', 'Var', (213, 230))	('implications', 'Reg', (321, 333))	('cancer', 'Disease', (288, 294))	('ICB', 'Chemical', '-', (412, 415))	('patients', 'Species', '9606', (433, 441))	('men', 'Species', '9606', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('DNA', 'cellular_component', 'GO:0005574', ('209', '212'))
66385	31169496	"The univariate Cox proportional hazard analysis was first conducted in the training cohort to identify methylation markers significantly (P < 0.001) associated with patient survival."	('Cox', 'Gene', '9377', (16, 19))	('patient', 'Species', '9606', (166, 173))	('patient survival', 'CPA', (166, 182))	('methylation', 'Var', (104, 115))	('Cox', 'Gene', (16, 19))	('associated with', 'Reg', (150, 165))
66399	31169496	2) The DNA variant in intron of OCA2 has been found to have a protective effect in melanoma GWAS (rs4778138, beta = -0.18, PMID: 26237428).	('melanoma GWAS', 'Disease', (83, 96))	('OCA2', 'Gene', (32, 36))	('rs4778138', 'Mutation', 'rs4778138', (98, 107))	('melanoma GWAS', 'Disease', 'MESH:D008545', (83, 96))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('OCA2', 'Gene', '4948', (32, 36))	('variant', 'Var', (11, 18))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
66400	31169496	The authors state that cg18456782 (OCA2) marker "had positive coefficients, indicating a correlation between higher DNA methylation level and shorter overall survival".	('OCA2', 'Gene', (35, 39))	('DNA methylation level', 'MPA', (116, 137))	('higher', 'PosReg', (109, 115))	('shorter', 'NegReg', (142, 149))	('OCA2', 'Gene', '4948', (35, 39))	('cg18456782', 'Chemical', '-', (23, 33))	('overall', 'MPA', (150, 157))	('cg18456782', 'Var', (23, 33))
66402	31169496	This is consistent with the presented data and suggests that while in GWAS the OCA2 variant has been found having a protective function, survival and expression data suggests a risk pattern for OCA2 gene.	('OCA2', 'Gene', '4948', (79, 83))	('variant', 'Var', (84, 91))	('OCA2', 'Gene', (194, 198))	('OCA2', 'Gene', '4948', (194, 198))	('OCA2', 'Gene', (79, 83))
66409	31169496	In the Discussion section: "Furthermore, epigenetic changes have been shown to alter gene expression, and epigenetic inactivation of tumor suppressor genes has been implicated in tumorigenesis of various malignancies, including CM (41).	('malignancies', 'Disease', (204, 216))	('epigenetic inactivation', 'Var', (106, 129))	('gene expression', 'MPA', (85, 100))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('epigenetic changes', 'Var', (41, 59))	('alter', 'Reg', (79, 84))	('CM', 'Disease', 'MESH:D009202', (228, 230))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (133, 138))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('implicated', 'Reg', (165, 175))	('tumor', 'Disease', (179, 184))
66424	31169496	But as an alternative, Benjamini and Hochberg False Discovery Rate correction was performed, and the results indicated all of our four methylation sites were also significantly (P < 0.001) associated with patient survival.	('methylation', 'Var', (135, 146))	('associated with', 'Reg', (189, 204))	('patient survival', 'CPA', (205, 221))	('patient', 'Species', '9606', (205, 212))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
66438	31169496	In the Results section: "Patients exhibiting long-term survival tended to have lower methylation levels of cg24670442, cg18456782 and higher methylation levels of the other two methylation sites, consistent with the results of multivariate Cox regression analysis.	('cg24670442', 'Chemical', '-', (107, 117))	('Cox', 'Gene', '9377', (240, 243))	('methylation levels', 'MPA', (85, 103))	('higher', 'PosReg', (134, 140))	('lower', 'NegReg', (79, 84))	('Cox', 'Gene', (240, 243))	('Patients', 'Species', '9606', (25, 33))	('methylation levels', 'MPA', (141, 159))	('cg24670442', 'Var', (107, 117))	('cg18456782', 'Chemical', '-', (119, 129))	('cg18456782', 'Var', (119, 129))
66445	31169496	In the Discussion section: "OCA2 is involved in the melanin biosynthetic process and mammalian pigmentation (Crawford et al., 2017), and the DNA variant in intron of OCA2 (rs4778138) has been found associated with CM risk (Law et al., 2015).	('rs4778138', 'Mutation', 'rs4778138', (172, 181))	('melanin', 'Chemical', 'MESH:D008543', (52, 59))	('OCA2', 'Gene', (166, 170))	('men', 'Species', '9606', (98, 101))	('rs4778138', 'Var', (172, 181))	('OCA2', 'Gene', '4948', (28, 32))	('OCA2', 'Gene', '4948', (166, 170))	('associated', 'Reg', (198, 208))	('mammalian', 'Species', '9606', (85, 94))	('CM', 'Disease', 'MESH:D009202', (214, 216))	('OCA2', 'Gene', (28, 32))
66451	22289720	Epigenetic Biomarkers in Skin Cancer Epigenetic aberrations have been associated with cutaneous melanoma tumorigenesis and progression including dysregulated DNA gene promoter region methylation, histone modification, and microRNA.	('histone modification', 'MPA', (196, 216))	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('Epigenetic aberrations', 'Var', (37, 59))	('Skin Cancer', 'Disease', 'MESH:D012878', (25, 36))	('cutaneous melanoma', 'Disease', (86, 104))	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (86, 104))	('associated', 'Reg', (70, 80))	('tumor', 'Disease', (105, 110))	('DNA gene promoter', 'Gene', (158, 175))	('histone modification', 'biological_process', 'GO:0016570', ('196', '216'))	('dysregulated', 'Var', (145, 157))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('microRNA', 'Var', (222, 230))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('Skin Cancer', 'Disease', (25, 36))	('Skin Cancer', 'Phenotype', 'HP:0008069', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))
66452	22289720	Epigenetic (methylation) biomarkers can be detected in tissue and in blood as circulating DNA in melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('melanoma', 'Disease', (97, 105))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('Epigenetic', 'Var', (0, 10))	('patients', 'Species', '9606', (106, 114))
66454	22289720	Important progress has been made in epigenetic melanoma biomarker development and verification of clinical utility, and this review discusses some of the key current developments and existing challenges.	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('epigenetic', 'Var', (36, 46))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
66465	22289720	Methylation events of promoter regions have been strongly implicated in cutaneous melanoma progression.	('cutaneous melanoma', 'Disease', (72, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('Methylation events', 'Var', (0, 18))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('implicated', 'Reg', (58, 68))
66467	22289720	Epigenetic inactivation of multiple TRGs has been implicated in the establishment of malignancy and throughout stages of melanoma progression and metastasis.	('malignancy', 'Disease', (85, 95))	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('implicated', 'Reg', (50, 60))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))	('TRGs', 'Gene', (36, 40))	('Epigenetic inactivation', 'Var', (0, 23))
66472	22289720	Other limitations of SBM include incomplete bisulfite conversion and differential PCR efficiency for methylated versus unmethylated sequences.	('bisulfite conversion', 'MPA', (44, 64))	('methylated', 'Var', (101, 111))	('bisulfite', 'Chemical', 'MESH:C042345', (44, 53))
66478	22289720	Aberrantly methylated melanoma TRGs can serve as BMs for early diagnosis of cancer, evaluation of cancer progression, and as prognostic indicators in melanoma patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('melanoma', 'Disease', (22, 30))	('cancer', 'Disease', (98, 104))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('Aberrantly methylated', 'Var', (0, 21))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('patients', 'Species', '9606', (159, 167))
66479	22289720	Our group identified and verified the inactivation of RAS association domain family protein 1A (RASSF1A), a tumor suppressor gene, in melanoma.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('RASSF1A', 'Gene', (96, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('inactivation', 'Var', (38, 50))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('tumor', 'Disease', (108, 113))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('RASSF1A', 'Gene', '11186', (96, 103))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('RAS association domain family protein 1A', 'Gene', (54, 94))	('RAS association domain family protein 1A', 'Gene', '11186', (54, 94))
66482	22289720	Separately, RASSF1A methylation has also been reported in approximately 50% of Merkel cell carcinoma (MCC) cases in a study of 83 tumors.	('tumors', 'Disease', (130, 136))	('RASSF1A', 'Gene', '11186', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('MCC', 'cellular_component', 'GO:0033597', ('102', '105'))	('RASSF1A', 'Gene', (12, 19))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (79, 100))	('methylation', 'Var', (20, 31))	('reported', 'Reg', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('MCC', 'biological_process', 'GO:0120197', ('102', '105'))	('Merkel cell carcinoma', 'Disease', (79, 100))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
66484	22289720	MINT loci are hypermethylated CpG sites located in non-coding DNA regions that have been reported in gastrointestinal cancer and correlated with hypermethylation of TRGs with a defined CIMP.	('gastrointestinal cancer', 'Disease', (101, 124))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (101, 124))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('TRGs', 'Protein', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('hypermethylation', 'Var', (145, 161))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (101, 124))	('CIMP', 'Chemical', '-', (185, 189))
66486	22289720	Moreover, there was a significant association between the methylation status of MINT17 and MINT31 and TRGs, supporting the existence of a CIMP that is associated with advancing clinical stage in melanoma patients and suggests a worse prognosis in patients with hypermethylation of these genes.	('TRGs', 'Gene', (102, 106))	('methylation status', 'Var', (58, 76))	('hypermethylation', 'Var', (261, 277))	('MINT3', 'Gene', (91, 96))	('MINT3', 'Gene', '9546', (91, 96))	('patients', 'Species', '9606', (204, 212))	('CIMP', 'Chemical', '-', (138, 142))	('MINT1', 'Gene', '320', (80, 85))	('associated', 'Reg', (151, 161))	('patients', 'Species', '9606', (247, 255))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('MINT1', 'Gene', (80, 85))
66490	22289720	The CTC BMs were significantly associated with the presence of methylated cf-CNA and the presence of both was an indicator of poor OS under biochemotherapy (BC).	('CTC BMs', 'Disease', (4, 11))	('OS', 'Chemical', '-', (131, 133))	('associated', 'Reg', (31, 41))	('methylated', 'Var', (63, 73))	('cf-CNA', 'Gene', (74, 80))	('presence', 'Var', (51, 59))
66493	22289720	In a study of stage IV melanoma patients undergoing BC with tamoxifen, serum estrogen receptor alpha (ER-alpha) methylation was an unfavorable prognostic factor and a negative predictor of overall and progression-free survival in patients treated with BC (Figure 3).	('negative', 'NegReg', (167, 175))	('patients', 'Species', '9606', (32, 40))	('ER-alpha', 'Gene', (102, 110))	('estrogen receptor alpha', 'Gene', (77, 100))	('estrogen receptor alpha', 'Gene', '2099', (77, 100))	('IV melanoma', 'Disease', (20, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (60, 69))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('methylation', 'Var', (112, 123))	('patients', 'Species', '9606', (230, 238))	('IV melanoma', 'Disease', 'MESH:D008545', (20, 31))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('ER-alpha', 'Gene', '2099', (102, 110))
66494	22289720	Global DNA hypomethylation can lead to chromosomal instability, activation of endogenous retroviral elements, and reactivation of genes with oncogenic activity, such as cancer testis genes, for example, the MAGE (melanoma antigen) family.	('Global DNA', 'Var', (0, 10))	('melanoma antigen', 'Gene', '51152', (213, 229))	('reactivation', 'MPA', (114, 126))	('cancer', 'Disease', (169, 175))	('cancer testis', 'Phenotype', 'HP:0010788', (169, 182))	('chromosomal', 'MPA', (39, 50))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('7', '26'))	('genes', 'Gene', (130, 135))	('MAGE', 'Gene', '51152', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('MAGE', 'Gene', (207, 211))	('lead to', 'Reg', (31, 38))	('activation', 'PosReg', (64, 74))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('chromosomal instability', 'Phenotype', 'HP:0040012', (39, 62))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('melanoma antigen', 'Gene', (213, 229))
66495	22289720	In malignant melanoma, aberrant expression of MAGE genes occurs secondary to promoter hypomethylation.	('malignant melanoma', 'Phenotype', 'HP:0002861', (3, 21))	('MAGE', 'Gene', '51152', (46, 50))	('malignant melanoma', 'Disease', 'MESH:D008545', (3, 21))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('malignant melanoma', 'Disease', (3, 21))	('promoter hypomethylation', 'Var', (77, 101))	('MAGE', 'Gene', (46, 50))	('expression', 'MPA', (32, 42))
66496	22289720	In patients with Stage IIIC cutaneous melanoma, Sigalotti et al., identified LINE-1 methylation as a molecular marker of prognosis with patients demonstrating LINE-1 hypomethylation having a significantly better OS compared to those with hypermethylated LINE-1 sequences.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('patients', 'Species', '9606', (136, 144))	('LINE-1', 'Gene', (159, 165))	('hypomethylation', 'Var', (166, 181))	('patients', 'Species', '9606', (3, 11))	('better', 'PosReg', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('OS', 'Chemical', '-', (212, 214))	('cutaneous melanoma', 'Disease', (28, 46))
66499	22289720	demonstrated that DNMT3A and DNMT3B protein expression are significantly correlated with increasing AJCC stage and that high expression of DNMT3B by immunohistochemistry (IHC) staining was significantly correlated with worse OS in AJCC stage III melanoma patients by multivariate analysis (p=0.004).	('DNMT3B', 'Gene', (29, 35))	('DNMT3B', 'Gene', '1789', (29, 35))	('worse OS', 'Disease', (219, 227))	('II melanoma', 'Disease', 'MESH:D008545', (243, 254))	('DNMT3B', 'Gene', (139, 145))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('high', 'Var', (120, 124))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('patients', 'Species', '9606', (255, 263))	('correlated with', 'Reg', (203, 218))	('OS', 'Chemical', '-', (225, 227))	('AJCC stage', 'Disease', (100, 110))	('DNMT3A', 'Gene', (18, 24))	('II melanoma', 'Disease', (243, 254))	('DNMT3A', 'Gene', '1788', (18, 24))	('DNMT3B', 'Gene', '1789', (139, 145))
66510	22289720	Overall, these epigenetic changes in melanoma can serve as potential BMs for prognosis and prediction.	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('epigenetic changes', 'Var', (15, 33))	('melanoma', 'Disease', (37, 45))
66511	22289720	Epigenomics in melanoma offer new potential BMs for tumor and blood while at the same time offering potential targets for therapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('tumor', 'Disease', (52, 57))	('Epigenomics', 'Var', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
66512	22289720	miRNA are considered an epigenomic mechanism that can have normal regulatory function but also can have negative influence when dysregulated, particularly in cancer progression as in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('regulatory function', 'MPA', (66, 85))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('negative', 'NegReg', (104, 112))	('miRNA', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
66516	22289720	Deregulated miRNA expression may serve as diagnostic or prognostic BM in cutaneous melanoma (see Table 1 for a list of recent miRNA melanoma studies).	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('Deregulated', 'Var', (0, 11))	('cutaneous melanoma', 'Disease', (73, 91))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('miRNA', 'Protein', (12, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
66542	22289720	Histone changes have been primarily linked to the ability for malignant melanoma to escape the senescent phenotype that characterizes benign nevi and normal tissue.	('changes', 'Var', (8, 15))	('senescent', 'CPA', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('Histone', 'Protein', (0, 7))	('malignant melanoma', 'Phenotype', 'HP:0002861', (62, 80))	('nevi', 'Phenotype', 'HP:0003764', (141, 145))	('malignant melanoma', 'Disease', 'MESH:D008545', (62, 80))	('malignant melanoma', 'Disease', (62, 80))	('linked', 'Reg', (36, 42))
66546	22289720	They also reported that 5-year survival in patients with high EZH2 expression was 48%, compared with 71% (p = .032) among the cases with low EZH2 expression, suggesting prognostic BM potential.	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (43, 51))	('EZH2', 'Gene', '2146', (62, 66))	('EZH2', 'Gene', '2146', (141, 145))	('EZH2', 'Gene', (62, 66))	('EZH2', 'Gene', (141, 145))
66554	22289720	These represent challenges yet to be resolved in the effort to establish epigenetic histone BMs in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('epigenetic', 'Var', (73, 83))	('melanoma', 'Disease', (99, 107))
66560	22289720	Other rarer forms of skin cancer, such as CTCL and its variants have studies that confirmed repression of BCL7a, PTPRG, TP73, and FAS through methylation.	('BCL7a', 'Gene', '605', (106, 111))	('BCL7a', 'Gene', (106, 111))	('CTCL', 'Gene', (42, 46))	('variants', 'Var', (55, 63))	('repression', 'NegReg', (92, 102))	('CTCL', 'Gene', '64061', (42, 46))	('skin cancer', 'Phenotype', 'HP:0008069', (21, 32))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('PTPRG', 'Gene', (113, 118))	('skin cancer', 'Disease', (21, 32))	('CTCL', 'Phenotype', 'HP:0012192', (42, 46))	('skin cancer', 'Disease', 'MESH:D012878', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('methylation', 'Var', (142, 153))	('TP73', 'Gene', '7161', (120, 124))	('TP73', 'Gene', (120, 124))	('PTPRG', 'Gene', '5793', (113, 118))
66561	22289720	MCC demonstrated p14ARK (encoding tumor suppressor p14) methylation in 42% of 19 tumor samples.	('MCC', 'biological_process', 'GO:0120197', ('0', '3'))	('p14', 'Gene', (17, 20))	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('p14', 'Gene', (51, 54))	('p14', 'Gene', '1029', (17, 20))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('p14', 'Gene', '1029', (51, 54))	('MCC', 'cellular_component', 'GO:0033597', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('methylation', 'Var', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (81, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))
66563	22289720	The development of epigenetic BMs for the diagnosis and prognosis of cutaneous melanoma continues to be promising, yet challenging.	('cutaneous melanoma', 'Disease', (69, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('epigenetic', 'Var', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))
66624	33663112	Therefore, we considered whether these was the reason that our identified genes controlled the overall survival of patients with SKCM and investigated the relationship between clinical features and patient survival.	('patients', 'Species', '9606', (115, 123))	('genes', 'Var', (74, 79))	('patient', 'Species', '9606', (198, 205))	('SKCM', 'Disease', (129, 133))	('patient', 'Species', '9606', (115, 122))	('controlled', 'Reg', (80, 90))
66629	33663112	Moreover, we evaluated the connection between risk score and each clinicopathological characteristic, revealing that patients in T0-2 stage or those with metastatic melanoma were significantly associated with lower risk scores (Fig.	('risk scores', 'MPA', (215, 226))	('lower', 'NegReg', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('T0-2', 'Var', (129, 133))	('patients', 'Species', '9606', (117, 125))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
66667	32855975	Antiganglioside antibodies anti-GM1 and -GD1a were positively correlated, while anti-GM3, -GD1b, and -GT1b were negatively associated with the inflammatory markers, interleukin 8 (IL-8), and C reactive protein (CRP).	('C reactive protein', 'Gene', (191, 209))	('anti-GM3', 'Var', (80, 88))	('CRP', 'Gene', (211, 214))	('correlated', 'Interaction', (62, 72))	('CRP', 'Gene', '1401', (211, 214))	('C reactive protein', 'Gene', '1401', (191, 209))	('inflammatory markers', 'MPA', (143, 163))	('associated', 'Interaction', (123, 133))	('IL-8', 'molecular_function', 'GO:0005153', ('180', '184'))	('negatively', 'NegReg', (112, 122))	('Antiganglioside', 'Protein', (0, 15))	('anti-GM1', 'Var', (27, 35))	('interleukin 8', 'Gene', (165, 178))	('IL-8', 'Gene', '3576', (180, 184))	('protein', 'cellular_component', 'GO:0003675', ('202', '209'))	('interleukin 8', 'Gene', '3576', (165, 178))	('IL-8', 'Gene', (180, 184))
66674	32855975	A series of studies performed in in vivo experimental models and in vitro in murine and human cancer cells have shown that monoclonal antiganglioside antibodies have antitumor potential.	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('murine', 'Species', '10090', (77, 83))	('monoclonal', 'Var', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('antitumor potential', 'CPA', (166, 185))
66677	32855975	Proteomic studies showed that antiganglioside antibodies could induce changes like the disruption of signalling systems (P38-MAPK, PARP, JNK1/2/3, METc, ERK1/2, P13K/AKT, and FAK), modulation of the level, and function of transcription factors (P53, SP1, MYCN, and HSF1), regulating the balance between apoptosis-inducing and apoptosis-suppressing factors (cysteine-aspartyl-proteases, Bax, Bcl-2).	('MYCN', 'Gene', '4613', (255, 259))	('ERK1/2', 'Gene', (153, 159))	('P13K', 'SUBSTITUTION', 'None', (161, 165))	('changes', 'Reg', (70, 77))	('AKT', 'Gene', (166, 169))	('PARP', 'Gene', '1302', (131, 135))	('JNK1/2/3', 'Gene', '5599;5601;5602', (137, 145))	('ERK1/2', 'Gene', '5595;5594', (153, 159))	('MAPK', 'molecular_function', 'GO:0004707', ('125', '129'))	('P53', 'Gene', (245, 248))	('apoptosis', 'biological_process', 'GO:0097194', ('326', '335'))	('apoptosis', 'biological_process', 'GO:0006915', ('326', '335'))	('P38-MAPK', 'Gene', (121, 129))	('JNK', 'molecular_function', 'GO:0004705', ('137', '140'))	('signalling', 'biological_process', 'GO:0023052', ('101', '111'))	('HSF1', 'Gene', (265, 269))	('HSF1', 'Gene', '3297', (265, 269))	('PARP', 'Gene', (131, 135))	('Bcl-2', 'Gene', (391, 396))	('apoptosis', 'biological_process', 'GO:0006915', ('303', '312'))	('apoptosis', 'biological_process', 'GO:0097194', ('303', '312'))	('P13K', 'Var', (161, 165))	('MYCN', 'Gene', (255, 259))	('AKT', 'Gene', '207', (166, 169))	('P53', 'Gene', '7157', (245, 248))	('FAK', 'Gene', (175, 178))	('FAK', 'molecular_function', 'GO:0004717', ('175', '178'))	('transcription', 'biological_process', 'GO:0006351', ('222', '235'))	('Bcl-2', 'Gene', '596', (391, 396))	('antiganglioside', 'Var', (30, 45))	('antibodies', 'Var', (46, 56))	('ERK1', 'molecular_function', 'GO:0004707', ('153', '157'))	('Bax', 'Gene', (386, 389))	('function', 'MPA', (210, 218))	('P38-MAPK', 'Gene', '5594', (121, 129))	('FAK', 'Gene', '5747', (175, 178))	('Bax', 'Gene', '581', (386, 389))	('disruption', 'MPA', (87, 97))	('JNK1/2/3', 'Gene', (137, 145))	('signalling systems', 'MPA', (101, 119))	('Bcl-2', 'molecular_function', 'GO:0015283', ('391', '396'))
66694	32855975	These data support the role of anti-GD1a in the early diagnosis of localized prostate disease.	('localized prostate disease', 'Disease', 'MESH:D011469', (67, 93))	('localized prostate disease', 'Disease', (67, 93))	('anti-GD1a', 'Var', (31, 40))
66697	32855975	Anti-GD1b, -GT1b, and -GQ1b (IgM type) influence the progression of melanoma, soft tissue sarcomas, Ehrlich subcutaneous solid tumors, Ehrlich carcinomas accompanied by ascites, and gastric cancer.	('carcinomas', 'Disease', (143, 153))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('ascites', 'Disease', (169, 176))	('gastric cancer', 'Disease', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('influence', 'Reg', (39, 48))	('tumors', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinomas', 'Disease', 'MESH:D009369', (143, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('ascites', 'Disease', 'MESH:D001201', (169, 176))	('Anti-GD1b', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (78, 97))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (78, 98))	('ascites', 'Phenotype', 'HP:0001541', (169, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('sarcomas', 'Disease', 'MESH:D012509', (90, 98))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcomas', 'Phenotype', 'HP:0100242', (90, 98))	('sarcomas', 'Disease', (90, 98))
66709	30956779	Inhibitors against CTLA-4, PD-1, and PD-L1 proteins are in clinical use and have been responsible for long-lasting responses in different types of cancer.	('CTLA-4', 'Gene', '1493', (19, 25))	('PD-L1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('PD-1', 'Gene', (27, 31))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('proteins', 'Protein', (43, 51))	('CTLA-4', 'Gene', (19, 25))	('cancer', 'Disease', (147, 153))
66755	30956779	Specifically, SKCM_1 denotes the SKCM patients (n = 258) in the cluster with apparently higher immune gene expression signature, whereas SKCM_2 denotes the SKCM patients (n = 177) in the other cluster with an apparently lower immune gene expression signature.	('higher', 'PosReg', (88, 94))	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('gene expression', 'biological_process', 'GO:0010467', ('233', '248'))	('SKCM', 'Disease', (33, 37))	('patients', 'Species', '9606', (161, 169))	('SKCM_1', 'Var', (14, 20))	('patients', 'Species', '9606', (38, 46))	('immune gene expression signature', 'MPA', (95, 127))
66792	30956779	Although it is beyond the scope of the current study, in the future we plan to perform a thorough interrogation on the relationship between this global immune gene signature and oncogenic pathways, copy number alterations, mutational load, and established clinicopathological characteristics, such as tumor metastasis, grade, and stage.	('tumor metastasis', 'Disease', 'MESH:D009362', (301, 317))	('mutational load', 'Var', (223, 238))	('grade', 'CPA', (319, 324))	('tumor metastasis', 'Disease', (301, 317))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('copy number alterations', 'Var', (198, 221))
66803	30956779	POLE was commonly mutated in endometrial and colorectal cancer, while MSI tumors frequently occurred in endometrial, stomach, and colon cancer.	('endometrial', 'Disease', (104, 115))	('MSI tumors', 'Disease', 'MESH:D009369', (70, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('stomach', 'Disease', (117, 124))	('mutated', 'Var', (18, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colorectal cancer', 'Disease', (45, 62))	('endometrial', 'Disease', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MSI tumors', 'Disease', (70, 80))	('occurred', 'Reg', (92, 100))	('colon cancer', 'Disease', (130, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
66860	31557882	In hepatocellular carcinoma (HCC), the high expression of STK26 was associated with large tumor size, microvascular invasion, intrahepatic metastasis, and TNM grading of patients with advanced HCC, which was independent prognostic factor of the overall survival rate (P = 0.004) and time to recurrence (P = 0.001) of patients after hepatectomy.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('HCC', 'Disease', 'MESH:D006528', (29, 32))	('TNM', 'Gene', '10178', (155, 158))	('STK26', 'Gene', (58, 63))	('TNM', 'Gene', (155, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('HCC', 'Disease', 'MESH:D006528', (193, 196))	('STK', 'molecular_function', 'GO:0050359', ('58', '61'))	('high', 'Var', (39, 43))	('tumor', 'Disease', (90, 95))	('intrahepatic metastasis', 'Disease', 'MESH:D009362', (126, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('patients', 'Species', '9606', (170, 178))	('microvascular invasion', 'CPA', (102, 124))	('HCC', 'Disease', (29, 32))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('STK26', 'Gene', '51765', (58, 63))	('intrahepatic metastasis', 'Disease', (126, 149))	('hepatocellular carcinoma', 'Disease', (3, 27))	('HCC', 'Disease', (193, 196))	('associated', 'Reg', (68, 78))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (317, 325))
66861	31557882	In addition, the inhibition of STK26 suppressed autophagy and the tumorigenicity of glioblastoma cells, while its therapeutic targeting enhanced the antitumor effects of radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('enhanced', 'PosReg', (136, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('autophagy', 'CPA', (48, 57))	('tumor', 'Disease', (66, 71))	('autophagy', 'biological_process', 'GO:0016236', ('48', '57'))	('inhibition', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('STK', 'molecular_function', 'GO:0050359', ('31', '34'))	('STK26', 'Gene', (31, 36))	('autophagy', 'biological_process', 'GO:0006914', ('48', '57'))	('STK26', 'Gene', '51765', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('glioblastoma', 'Disease', (84, 96))	('suppressed', 'NegReg', (37, 47))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
66862	31557882	In breast cancer, in vitro experiments showed that knocking out STK26 led to an enhanced vascular invasion of breast cancer cells.	('STK26', 'Gene', (64, 69))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('STK', 'molecular_function', 'GO:0050359', ('64', '67'))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('vascular invasion of breast cancer', 'Disease', 'MESH:D001943', (89, 123))	('STK26', 'Gene', '51765', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('vascular invasion of breast cancer', 'Disease', (89, 123))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('enhanced', 'PosReg', (80, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('knocking out', 'Var', (51, 63))
66870	31557882	found that seven pediatric B-cell precursor acute lymphoblastic leukemia with dup (1q) revealed non-synonymous somatic single nucleotide variants in KCNT2 by sequencing the breakpoint regions and all exons on 1q.	('KCNT2', 'Gene', '343450', (149, 154))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (50, 72))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (50, 72))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (44, 72))	('KCNT2', 'Gene', (149, 154))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('single nucleotide variants', 'Var', (119, 145))	('lymphoblastic leukemia', 'Disease', (50, 72))
66879	31557882	Interestingly, it was found that knockdown of CASP12 diminished trans-resveratrol-mediated apoptosis in hNC cells.	('diminished', 'NegReg', (53, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('trans-resveratrol', 'Chemical', 'MESH:C059514', (64, 81))	('knockdown', 'Var', (33, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('CASP12', 'Gene', (46, 52))	('trans-resveratrol-mediated apoptosis', 'MPA', (64, 100))	('CASP12', 'Gene', '100506742', (46, 52))
66887	27536319	Gene Coexpression Analyses Differentiate Networks Associated with Diverse Cancers Harboring TP53 Missense or Null Mutations In a variety of solid cancers, missense mutations in the well-established TP53 tumor suppressor gene may lead to the presence of a partially-functioning protein molecule, whereas mutations affecting the protein encoding reading frame, often referred to as null mutations, result in the absence of p53 protein.	('tumor suppressor', 'biological_process', 'GO:0051726', ('203', '219'))	('tumor', 'Disease', (203, 208))	('lead to', 'Reg', (229, 236))	('p53', 'Gene', '7157', (421, 424))	('protein', 'cellular_component', 'GO:0003675', ('277', '284'))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('TP53', 'Gene', (92, 96))	('partially-functioning', 'MPA', (255, 276))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancers', 'Disease', 'MESH:D009369', (74, 81))	('protein', 'cellular_component', 'GO:0003675', ('425', '432'))	('p53', 'Gene', (421, 424))	('TP53', 'Gene', '7157', (198, 202))	('solid cancers', 'Disease', 'MESH:D009369', (140, 153))	('protein', 'Protein', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('solid cancers', 'Disease', (140, 153))	('protein', 'cellular_component', 'GO:0003675', ('327', '334'))	('missense mutations', 'Var', (155, 173))	('TP53', 'Gene', '7157', (92, 96))	('presence', 'MPA', (241, 249))	('Cancers', 'Disease', (74, 81))	('Cancers', 'Phenotype', 'HP:0002664', (74, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('203', '219'))	('TP53', 'Gene', (198, 202))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
66888	27536319	Both types of mutations have been observed in the same cancer type.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('observed', 'Reg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (55, 61))
66889	27536319	As the resulting tumor biology may be quite different between these two groups, we used RNA-sequencing data from The Cancer Genome Atlas (TCGA) from four different cancers with poor prognosis, namely ovarian, breast, lung and skin cancers, to compare the patterns of coexpression of genes in tumors grouped according to their TP53 missense or null mutation status.	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('lung', 'Disease', (217, 221))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (117, 136))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('TP53', 'Gene', '7157', (326, 330))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Disease', (292, 298))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('Cancer Genome Atlas', 'Disease', (117, 136))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('RNA', 'cellular_component', 'GO:0005562', ('88', '91'))	('breast', 'Disease', (209, 215))	('tumor', 'Disease', (17, 22))	('skin cancers', 'Phenotype', 'HP:0008069', (226, 238))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('null mutation status', 'Var', (343, 363))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('ovarian', 'Disease', (200, 207))	('cancers', 'Disease', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('TP53', 'Gene', (326, 330))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('tumor', 'Disease', (292, 297))	('skin cancers', 'Disease', (226, 238))	('skin cancers', 'Disease', 'MESH:D012878', (226, 238))	('missense', 'Var', (331, 339))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
66890	27536319	For each cancer, our analysis identified a set of genes showing differential coexpression patterns between the TP53 missense- and null mutation-carrying groups that was robust to the choice of the tuning parameter in WGCNA.	('cancer', 'Disease', (9, 15))	('TP53', 'Gene', '7157', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TP53', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('missense-', 'Var', (116, 125))
66891	27536319	After comparing these sets of genes across the four cancers, one gene (KIR3DL2) consistently showed differential coexpression patterns between the null and missense groups.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('DL2', 'molecular_function', 'GO:0033904', ('75', '78'))	('coexpression patterns', 'MPA', (113, 134))	('KIR3DL2', 'Gene', '3812', (71, 78))	('differential', 'Reg', (100, 112))	('missense', 'Var', (156, 164))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('KIR3DL2', 'Gene', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
66894	27536319	It is well-established that mutations of the TP53 gene, which renders loss of function of encoded p53 tumor suppressor protein, is the most frequent somatic genetic anomaly observed in human cancers (Muller and Vousden,).	('human', 'Species', '9606', (185, 190))	('TP53', 'Gene', (45, 49))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('p53', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('cancers', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('TP53', 'Gene', '7157', (45, 49))	('genetic anomaly', 'Disease', 'MESH:D030342', (157, 172))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('tumor', 'Disease', (102, 107))	('mutations', 'Var', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('loss of function', 'NegReg', (70, 86))	('genetic anomaly', 'Disease', (157, 172))	('p53', 'Gene', '7157', (98, 101))
66896	27536319	The TP53 mutation frequency varies across cancer types, with high-grade serous ovarian carcinomas exhibiting the highest frequency at 96% (Bell et al.,; Cerami et al.,; Gao et al.,), suggesting that TP53 mutations are critical drivers for the development of this subtype of ovarian cancer (Ahmed et al.,).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ovarian cancer', 'Disease', 'MESH:D010051', (274, 288))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (72, 97))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('TP53', 'Gene', '7157', (199, 203))	('TP53', 'Gene', (4, 8))	('ovarian cancer', 'Disease', (274, 288))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('ovarian cancer', 'Phenotype', 'HP:0100615', (274, 288))	('mutations', 'Var', (204, 213))	('serous ovarian carcinomas', 'Disease', (72, 97))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (79, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (72, 97))	('cancer', 'Disease', (282, 288))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('men', 'Species', '9606', (250, 253))	('cancer', 'Disease', (42, 48))
66899	27536319	As a consequence of acquiring somatic TP53 mutations, tumor cells are thus able to evade apoptosis and senescence, and progress to more malignant phenotypes.	('progress', 'PosReg', (119, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('TP53', 'Gene', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('senescence', 'biological_process', 'GO:0010149', ('103', '113'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (43, 52))	('senescence', 'CPA', (103, 113))	('tumor', 'Disease', (54, 59))	('evade apoptosis', 'CPA', (83, 98))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('TP53', 'Gene', '7157', (38, 42))
66900	27536319	However, unlike other established tumor suppressor genes, such as RB1, which are most commonly inactivated by frame-shift or nonsense mutations, TP53 often encodes mutant proteins as a consequence of missense mutations with a single base-pair change in the coding sequence.	('mutant', 'Var', (164, 170))	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('encodes', 'Reg', (156, 163))	('RB1', 'Gene', '5925', (66, 69))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('missense mutations', 'Var', (200, 218))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('proteins', 'Protein', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RB1', 'Gene', (66, 69))
66901	27536319	The mutant p53 protein, having a prolonged half-life relative to the normal isoform, is able to accumulate in tumor cells, and thus is readily detectable by immunohistochemistry.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('mutant', 'Var', (4, 10))	('accumulate', 'PosReg', (96, 106))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('protein', 'Protein', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
66902	27536319	The functional consequences of mutant p53 protein are the subject of intense research (reviewed in Brosh and Rotter,; Freed-Pastor and Prives,; Muller and Vousden,), which has shown, using various cell line models, that mutant p53 protein can bind and inactivate p53-related proteins.	('mutant', 'Var', (31, 37))	('inactivate', 'NegReg', (252, 262))	('p53', 'Gene', (227, 230))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('mutant', 'Var', (220, 226))	('p53', 'Gene', '7157', (227, 230))	('p53', 'Gene', (263, 266))	('bind', 'Interaction', (243, 247))	('p53', 'Gene', '7157', (263, 266))	('protein', 'cellular_component', 'GO:0003675', ('231', '238'))	('protein', 'Protein', (231, 238))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
66903	27536319	Moreover, it has been shown that some mutant p53 proteins have acquired new oncogenic functions through interactions with other transcription factors.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('oncogenic functions', 'CPA', (76, 95))	('proteins', 'Protein', (49, 57))	('p53', 'Gene', '7157', (45, 48))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('interactions', 'Interaction', (104, 116))
66904	27536319	The consequences of a missense mutation are in stark contrast to frame-shift, nonsense and splice-site mutations in TP53 that have also been observed in a significant fraction of human tumors.	('TP53', 'Gene', (116, 120))	('human', 'Species', '9606', (179, 184))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('missense mutation', 'Var', (22, 39))	('TP53', 'Gene', '7157', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
66905	27536319	This latter set of variants is collectively referred to as p53-null mutations, as they affect the reading frame, resulting in the absence of an encoded protein.	('p53', 'Gene', (59, 62))	('absence', 'NegReg', (130, 137))	('p53', 'Gene', '7157', (59, 62))	('affect', 'Reg', (87, 93))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('protein', 'Protein', (152, 159))	('reading frame', 'MPA', (98, 111))	('variants', 'Var', (19, 27))
66906	27536319	Both types of mutations have been detected in the same cancer type, where missense mutations are more commonly observed than the other types.	('detected', 'Reg', (34, 42))	('observed', 'Reg', (111, 119))	('missense mutations', 'Var', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (55, 61))
66907	27536319	In high-grade serous ovarian carcinomas, we and others have shown that among TP53 mutation-positive tumor samples, between 60 and 70% harbor TP53 missense mutations, and the remaining 30-40% harbor p53-null mutations (Ahmed et al.,; Cancer Genome Atlas Research,; Wojnarowicz et al.,).	('missense mutations', 'Var', (146, 164))	('tumor', 'Disease', (100, 105))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TP53', 'Gene', (141, 145))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (21, 39))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('TP53', 'Gene', (77, 81))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (14, 39))	('p53', 'Gene', '7157', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TP53', 'Gene', '7157', (141, 145))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (233, 252))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('p53', 'Gene', (198, 201))	('TP53', 'Gene', '7157', (77, 81))	('serous ovarian carcinomas', 'Disease', (14, 39))	('mutation-positive', 'Var', (82, 99))	('Cancer Genome Atlas', 'Disease', (233, 252))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (14, 39))
66908	27536319	Past attempts to correlate TP53 mutation status with various clinical parameters, such as overall outcome or response to therapy, has often resulted in conflicting results.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
66909	27536319	This is in large part due to an overly superficial examination of the mutations, i.e., by limiting mutation analyses to those exons that encode the DNA binding domain, or by inferring mutation status by immunohistochemistry, which detects tumor cells harboring stable mutant p53 protein but does not readily distinguish those harboring p53 null variants from wild-type variants.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('DNA binding', 'molecular_function', 'GO:0003677', ('148', '159'))	('p53', 'Gene', '7157', (275, 278))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('protein', 'Protein', (279, 286))	('mutant', 'Var', (268, 274))	('p53', 'Gene', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('p53', 'Gene', '7157', (336, 339))	('tumor', 'Disease', (239, 244))	('protein', 'cellular_component', 'GO:0003675', ('279', '286'))	('p53', 'Gene', (336, 339))
66910	27536319	However, evidence is emerging that the type of TP53 mutation is associated with differences in clinical outcome.	('associated', 'Reg', (64, 74))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))
66911	27536319	Older studies also did not consider the biological consequences resulting from the nature of the somatic TP53 mutation, which would distinguish cancer cases with TP53 missense mutations from those with null mutations.	('missense mutations', 'Var', (167, 185))	('TP53', 'Gene', '7157', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('TP53', 'Gene', (162, 166))	('cancer', 'Disease', (144, 150))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
66912	27536319	For example, our group has shown that the subgroup of high-grade serous ovarian carcinomas expressing mutant p53 protein exhibited significantly prolonged overall disease-free survival as compared with carcinomas harboring p53 null mutations (Wojnarowicz et al.,).	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('carcinomas', 'Disease', 'MESH:D002277', (202, 212))	('serous ovarian carcinomas', 'Disease', (65, 90))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('p53', 'Gene', '7157', (223, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('p53', 'Gene', '7157', (109, 112))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (65, 90))	('carcinomas', 'Disease', (202, 212))	('p53', 'Gene', (223, 226))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (72, 90))	('p53', 'Gene', (109, 112))	('disease-free survival', 'CPA', (163, 184))	('mutant', 'Var', (102, 108))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (65, 90))	('carcinomas', 'Disease', (80, 90))	('protein', 'Protein', (113, 120))	('prolonged', 'PosReg', (145, 154))
66913	27536319	Our results were consistent with earlier reports associating high-grade serous ovarian carcinomas harboring p53 null mutations with poorer overall outcome (Kobel et al.,) or distant metastasis (Sood et al.,).	('null mutations', 'Var', (112, 126))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('serous ovarian carcinomas', 'Disease', (72, 97))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (79, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('distant metastasis', 'CPA', (174, 192))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (72, 97))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (72, 97))
66914	27536319	In contrast, a recent study using a subset of the gene expression data from TCGA set for high grade serous ovarian cancers, has provided some evidence that patients with gain-of function p53 mutant proteins are characterized by a greater likelihood of platinum treatment resistance and distance metastasis (Kang et al.,).	('patients', 'Species', '9606', (156, 164))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('greater', 'PosReg', (230, 237))	('p53', 'Gene', (187, 190))	('distance metastasis', 'CPA', (286, 305))	('serous ovarian cancers', 'Disease', (100, 122))	('p53', 'Gene', '7157', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('gain-of function', 'PosReg', (170, 186))	('proteins', 'Protein', (198, 206))	('mutant', 'Var', (191, 197))	('platinum treatment resistance', 'CPA', (252, 281))	('men', 'Species', '9606', (266, 269))	('platinum', 'Chemical', 'MESH:D010984', (252, 260))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (100, 122))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('ovarian cancers', 'Phenotype', 'HP:0100615', (107, 122))
66915	27536319	Thus TP53 mutations may exert different effects on tumor progression and possible chemoresistance in the development of ovarian cancer.	('men', 'Species', '9606', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('tumor', 'Disease', (51, 56))	('ovarian cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('chemoresistance', 'CPA', (82, 97))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('effects', 'Reg', (40, 47))	('mutations', 'Var', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
66916	27536319	This notion is supported in part by our observation of significant genomic copy number differences of specific chromosomal regions in a comparative analysis of high grade serous ovarian cancer harboring p53 missense with those harboring p53 null mutations (Wojnarowicz et al.,).	('p53', 'Gene', '7157', (237, 240))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('p53', 'Gene', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('missense', 'Var', (207, 215))	('serous ovarian cancer', 'Disease', (171, 192))	('p53', 'Gene', (237, 240))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (171, 192))	('p53', 'Gene', '7157', (203, 206))
66919	27536319	We focused our analysis only on samples with TP53 mutations and compared profiles parsed according to the major consequences of TP53 mutation.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('TP53', 'Gene', '7157', (45, 49))
66921	27536319	Therefore, we hypothesized that differences in gene regulation in the context of TP53 missense or null tumors might be better captured by an alternative analysis based on changes in gene coexpression patterns.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('regulation', 'biological_process', 'GO:0065007', ('52', '62'))	('missense', 'Var', (86, 94))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
66923	27536319	These cancer types were selected because they exhibit a high frequency of somatic TP53 mutations and RNA-sequencing data were available from TCGA.	('TP53', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('TP53', 'Gene', '7157', (82, 86))	('cancer', 'Disease', (6, 12))	('mutations', 'Var', (87, 96))	('RNA', 'cellular_component', 'GO:0005562', ('101', '104'))
66930	27536319	The somatic TP53 mutation status has been reported for most of the cancer types, and this information was obtained from the Open-Access Validated Somatic Mutation Data available from the TCGA portal.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('mutation', 'Var', (17, 25))	('TP53', 'Gene', '7157', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TP53', 'Gene', (12, 16))
66932	27536319	The mutations were classified into two groups, either null or missense mutations, based on a review of the somatic mutations reported for each cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('missense mutations', 'Var', (62, 80))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
66933	27536319	The p53 null group contained frame-shift, nonsense and splice-site mutations, as a consequence of intragenic nucleotide insertions or deletions and/or single base-pair substitutions, which are expected to affect protein encoding reading frames and have been associated with unstable transcripts and lack of protein (Wojnarowicz et al.,).	('nucleotide insertions', 'Var', (109, 130))	('p53', 'Gene', '7157', (4, 7))	('frame-shift', 'Var', (29, 40))	('deletions', 'Var', (134, 143))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('lack', 'NegReg', (299, 303))	('affect', 'Reg', (205, 211))	('unstable transcripts', 'MPA', (274, 294))	('protein', 'Protein', (307, 314))	('protein encoding reading frames', 'MPA', (212, 243))	('protein', 'cellular_component', 'GO:0003675', ('307', '314'))	('p53', 'Gene', (4, 7))
66934	27536319	Most of the remaining mutations were expected to be p53-expressing missense isoforms which would largely exhibit stable gene and protein expression (Wojnarowicz et al.,), and these were assigned to our p53-missense group.	('p53', 'Gene', (202, 205))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('mutations', 'Var', (22, 31))	('p53', 'Gene', '7157', (202, 205))
66935	27536319	Only samples with known TP53 mutations were used in our analyses (Table 1).	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))
66938	27536319	We have defined a statistic for gene g, g = 1, ...G, that captures the difference in the coexpression patterns between null and missense tumors by:  The motivation for this statistic is represented schematically in Figure 1.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('missense', 'Var', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
66939	27536319	Since the distribution of this statistic is unknown, and will depend partially on the level of expression of gene g as well as its variability and correlation, we estimated statistical significance, separately for each cancer type, by performing 1000 permutations of the null and missense labels across tumors within the same cancer type, and recalculating the Sg statistics for each gene.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (326, 332))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Disease', (219, 225))	('missense', 'Var', (280, 288))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
66943	27536319	The lower bound for beta followed the suggestion by the WGCNA authors, based on the function "pickSoftThreshold" (the minimum suggested value from separate analyses of null- and missense-carrying tumors).	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('missense-carrying', 'Var', (178, 195))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
66945	27536319	We also defined an "optimal" soft threshold when both the coexpression overlap matrices for missense and null tumors reached at least an R2 of 0.90 when assessing fit to expectation derived from a scale-free topology (see also Supplemental Methods).	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('missense', 'Var', (92, 100))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('men', 'Species', '9606', (233, 236))
66951	27536319	The number of samples harboring somatic TP53 mutations available for our study ranged from 59 for SKCM to 260 for LUAD (Table 1).	('TP53', 'Gene', '7157', (40, 44))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', (40, 44))
66952	27536319	OV had the largest number of samples where missense variants were found, at 62% of all TP53 mutation-positive cases.	('TP53', 'Gene', '7157', (87, 91))	('OV', 'Phenotype', 'HP:0100615', (0, 2))	('TP53', 'Gene', (87, 91))	('missense variants', 'Var', (43, 60))	('mutation-positive', 'Reg', (92, 109))
66953	27536319	However, the distribution of each of the two categories of TP53 mutations for each type of cancer was similar, ranging from 46 to 62% for the number of cases harboring missense variants (Table 1).	('TP53', 'Gene', (59, 63))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('missense variants', 'Var', (168, 185))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TP53', 'Gene', '7157', (59, 63))
66954	27536319	Although immunohistochemistry staining for p53 protein would further distinguish null and missense mutated samples, in the absence of such data, our method of classification shows good separation of gene expression distributions for each cancer type (Figure 2).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('missense', 'Var', (90, 98))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', (43, 46))	('gene expression', 'biological_process', 'GO:0010467', ('199', '214'))
66955	27536319	We had previously found interesting differences in chromosome copy number in several genomic intervals when comparing groups with different TP53 mutation types in high grade serous ovarian cancer samples, and in that work we also found that the TP53 mutation types showed association with overall/progression free survival (Wojnarowicz et al.,).	('mutation', 'Var', (250, 258))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (174, 195))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('TP53', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('overall/progression free survival', 'CPA', (289, 322))	('TP53', 'Gene', '7157', (245, 249))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('TP53', 'Gene', (245, 249))	('association', 'Reg', (272, 283))	('TP53', 'Gene', '7157', (140, 144))	('serous ovarian cancer', 'Disease', (174, 195))
66957	27536319	Figure 3 shows that although over 300 genes were identified with p < 0.05 in each of the analyses with soft thresholds between 3 and 6 (range 327-378 genes), there is a core set of 176 genes that consistently display significantly distinct relationships (or network connectivity) in the tumor groups parsed according to TP53 missense or null mutation type.	('null mutation', 'Var', (337, 350))	('distinct', 'Reg', (231, 239))	('TP53', 'Gene', '7157', (320, 324))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('core', 'cellular_component', 'GO:0019013', ('169', '173'))	('TP53', 'Gene', (320, 324))	('relationships', 'Interaction', (240, 253))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('missense', 'Var', (325, 333))
66963	27536319	We then examined the overlap between the genes identified in our analyses of each cancer type to search for pathways that might indicate some communalities in the differential coexpression networks based on TP53 mutation type.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (207, 211))	('mutation', 'Var', (212, 220))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('TP53', 'Gene', (207, 211))
66967	27536319	It should be noted that power was lowest for the analysis of SKCM since there were only 59 cancer samples harboring TP53 mutations that were available for our analyses, in contrast to the larger data sets available for each of the other cancer types which ranged from 80 to 260 samples (Table 1).	('TP53', 'Gene', (116, 120))	('mutations', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TP53', 'Gene', '7157', (116, 120))	('cancer', 'Disease', (237, 243))
66971	27536319	Using our optimal soft threshold for each cancer, the empirical p-values testing for differences in coexpression at KIR3DL2 were 0.02 for OV, 0.03 for BRCA, 0.002 for LUAD, and 0.05 for SKCM.	('BRCA', 'Gene', '672', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA', 'Phenotype', 'HP:0003002', (151, 155))	('BRCA', 'Gene', (151, 155))	('0.05', 'Var', (177, 181))	('KIR3DL2', 'Gene', (116, 123))	('OV', 'Phenotype', 'HP:0100615', (138, 140))	('0.002', 'Var', (157, 162))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('DL2', 'molecular_function', 'GO:0033904', ('120', '123'))	('0.03', 'Var', (142, 146))	('KIR3DL2', 'Gene', '3812', (116, 123))	('LUAD', 'Disease', (167, 171))
66972	27536319	For OV and LUAD, tumors with missense mutations in TP53 tended to show stronger coexpression between KIR3DL2 and other genes, whereas the tumors with null mutations in TP53 showed stronger coexpression in BRCA and SKCM.	('tumors', 'Disease', (17, 23))	('KIR3DL2', 'Gene', '3812', (101, 108))	('BRCA', 'Gene', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('DL2', 'molecular_function', 'GO:0033904', ('105', '108'))	('missense mutations', 'Var', (29, 47))	('coexpression', 'MPA', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('stronger', 'PosReg', (71, 79))	('BRCA', 'Phenotype', 'HP:0003002', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('KIR3DL2', 'Gene', (101, 108))	('TP53', 'Gene', '7157', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('TP53', 'Gene', (168, 172))	('BRCA', 'Gene', '672', (205, 209))	('tumors', 'Disease', (138, 144))	('OV', 'Phenotype', 'HP:0100615', (4, 6))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
66975	27536319	For OV and LUAD this was the maximum of the range of the overlap measure found in the tumors with null mutations (0.04), whereas we defined the expected range from tumors with missense mutations for BRCA (maximum 0.13) and SKCM (maximum 0.17).	('BRCA', 'Phenotype', 'HP:0003002', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (103, 112))	('BRCA', 'Gene', '672', (199, 203))	('tumors', 'Disease', (164, 170))	('BRCA', 'Gene', (199, 203))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('OV', 'Phenotype', 'HP:0100615', (4, 6))	('missense mutations', 'Var', (176, 194))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
66978	27536319	Evidently, the missense-null differences in overlap measure vary substantially across cancers, even though many of the same partner genes are highlighted in more than one cancer.	('overlap', 'MPA', (44, 51))	('missense-null', 'Var', (15, 28))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (86, 92))
66981	27536319	In contrast, when we examined these 164 genes for evidence of changes in the mean levels of expression between the missense and null mutation-carrying tumors, no particular patterns are detectable.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('missense', 'Var', (115, 123))	('levels of expression', 'MPA', (82, 102))
66990	27536319	However, different analytic perspectives can often lead to new insights especially when combined with additional molecular genetic information such as the nature of TP53 mutation.	('lead to', 'Reg', (51, 58))	('TP53', 'Gene', '7157', (165, 169))	('TP53', 'Gene', (165, 169))	('mutation', 'Var', (170, 178))
66991	27536319	Here, we have proposed a test statistic that highlights differential coexpression between two groups defined by the presence of TP53 missense and null mutations, and hence finding genes that show very different patterns of the overlap measures (built on the weighted correlations) and connectivity.	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('missense', 'Var', (133, 141))	('coexpression', 'Interaction', (69, 81))	('null mutations', 'Var', (146, 160))
66997	27536319	In our study, although quite a bit is known about differences in gene expression between wild type and mutant p53 (e.g., O'Farrell et al.,), no previous exploration has been undertaken of differences in expression in cancer cells expressing mutant p53 proteins vs. no protein.	('p53', 'Gene', (110, 113))	('mutant', 'Var', (241, 247))	('p53', 'Gene', (248, 251))	('p53', 'Gene', '7157', (248, 251))	('mutant', 'Var', (103, 109))	('p53', 'Gene', '7157', (110, 113))	('protein', 'cellular_component', 'GO:0003675', ('268', '275'))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('proteins', 'Protein', (252, 260))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
67000	27536319	We then transformed the z-values to p-values, and applied significance thresholds in line with Table 1 assuming a uniform distribution (i.e., p <= 350/14,800 for OV, p <= 930/14800 for BRCA, p <= 1200/14,800 for SKCM, p <= 370/14,800 for LUAD).	('BRCA', 'Phenotype', 'HP:0003002', (185, 189))	('BRCA', 'Gene', '672', (185, 189))	('BRCA', 'Gene', (185, 189))	('p <= 930/14800', 'Var', (166, 180))	('OV', 'Phenotype', 'HP:0100615', (162, 164))
67003	27536319	KIR3DL2 shows evidence of very different coexpression patterns between tumors carrying TP53 null and missense mutations.	('missense mutations', 'Var', (101, 119))	('DL2', 'molecular_function', 'GO:0033904', ('4', '7'))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('KIR3DL2', 'Gene', (0, 7))	('coexpression', 'MPA', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('null', 'Var', (92, 96))	('tumors', 'Disease', (71, 77))	('KIR3DL2', 'Gene', '3812', (0, 7))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
67012	27536319	However, there is evidence in cancer cell model systems that mutant p53 can modulate the expression of immunoregulatory genes (reviewed in Menendez et al.,).	('modulate', 'Reg', (76, 84))	('expression', 'MPA', (89, 99))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('immunoregulatory genes', 'Gene', (103, 125))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
67013	27536319	Further research associating the major immune-phenotypes observed in solid tumors with TP53 mutation type rather than status alone might clarify the role of mutant p53 isoforms in tumor cell microenvironment.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('TP53', 'Gene', '7157', (87, 91))	('men', 'Species', '9606', (203, 206))	('mutation', 'Var', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('TP53', 'Gene', (87, 91))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('solid tumors', 'Disease', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p53', 'Gene', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (75, 80))	('p53', 'Gene', '7157', (164, 167))
67020	27536319	Considering patterns of coexpression in tumors carrying either missense or null mutations in TP53 is a fruitful strategy that leads to a set of genes showing evidence for differential coexpression and enriched for many immune system pathways.	('null mutations', 'Var', (75, 89))	('missense', 'Var', (63, 71))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
67026	26790922	At a median follow-up of 5 years, findings from our previously published randomised trial of narrow (1 cm) versus wide (3 cm) excision margins in patients with thick cutaneous melanomas showed that narrow margins were associated with an increased frequency of locoregional relapse, but no significant difference in overall survival was apparent.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('narrow margins', 'Var', (198, 212))	('thick cutaneous melanomas', 'Disease', (160, 185))	('thick cutaneous melanomas', 'Disease', 'MESH:C562393', (160, 185))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (166, 185))	('locoregional relapse', 'CPA', (260, 280))	('patients', 'Species', '9606', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
67032	26790922	Although a higher number of deaths overall occurred in the 1 cm group compared with the 3 cm group (253 vs 241), the difference was not significant (unadjusted HR 1 14 [95% CI 0 96-1 36]; p=0 14).	('1 cm', 'Var', (59, 63))	('death', 'Disease', 'MESH:D003643', (28, 33))	('death', 'Disease', (28, 33))
67052	26790922	We showed a negative association between narrow margins and locoregional relapse-free survival (defined as local recurrence, in-transit metastases, and regional lymph node metastases); ie, a 1 cm margin was associated with a significantly greater risk of locoregional recurrence than the 3 cm margin (multivariable adjusted HR 1 34 [95% CI 1 06-1 71]; p=0 02).	('locoregional recurrence', 'Disease', (255, 278))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('1 cm', 'Var', (191, 195))	('metastases', 'Disease', (136, 146))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('metastases', 'Disease', (172, 182))
67098	26790922	For three participants (two in the 1 cm margin group, one in the 3 cm group), melanoma was present at the time of death but this was not the cause of death.	('death', 'Disease', 'MESH:D003643', (150, 155))	('death', 'Disease', (150, 155))	('1 cm', 'Var', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('participants', 'Species', '9606', (10, 22))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))
67103	26790922	194 deaths attributed to melanoma occurred in the 1 cm margin group compared with 165 in the 3 cm margin group (unadjusted HR 1 24 [95% CI 1 01-1 53]; p=0 041; figure 2).	('death', 'Disease', 'MESH:D003643', (4, 9))	('death', 'Disease', (4, 9))	('1 cm margin', 'Var', (50, 61))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))
67109	26790922	When the effect of competing deaths due to other causes was taken in account, the cumulative incidence of death from melanoma was higher in the 1 cm margin group than in the 3 cm margin group (figure 4; point estimates of cumulative incidence at 8 8 years were 47 9% [95% CI 42 8-53 2] in the 1 cm margin group, 38 1% [33 3-43 4] in the 3 cm group).	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('death', 'Disease', (29, 34))	('death', 'Disease', 'MESH:D003643', (29, 34))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('1 cm', 'Var', (144, 148))	('melanoma', 'Disease', (117, 125))
67111	26790922	No differences between the two margin widths were noted regarding the cumulative incidence of death due to other causes (figure 4; point estimates of cumulative incidence at 8 8 years were 14 5% [95% CI 10 1-20 6] in the 1 cm margin group, 18 2% [13 6-24 0] in the 3 cm group).	('death', 'Disease', 'MESH:D003643', (94, 99))	('death', 'Disease', (94, 99))	('1 cm', 'Var', (221, 225))
67117	26790922	At a median follow-up of 8 8 years (106 months) the risk of death from melanoma was significantly higher in the narrow (1 cm) margin group than in the wider (3 cm) margin group.	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('narrow (1 cm) margin', 'Var', (112, 132))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))
67119	26790922	The estimated risk of death from any cause was higher in the 1 cm margin group than in the 3 cm margin group, although this difference was not significant.	('death', 'Disease', (22, 27))	('1 cm margin', 'Var', (61, 72))	('death', 'Disease', 'MESH:D003643', (22, 27))
67122	26790922	Findings from our previous report of this trial with a median follow-up of 5 years showed that, in patients with high-risk melanoma, a 1 cm excision margin was associated with a significant increase in locoregional relapse compared with a 3 cm excision margin.	('increase', 'PosReg', (190, 198))	('1 cm', 'Var', (135, 139))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('patients', 'Species', '9606', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('locoregional relapse', 'CPA', (202, 222))
67137	26790922	The absence of a proven survival benefit in these nodal studies is at odds with the probable biological hypothesis for an effect on survival shown in this study:ie, that removal of microsatellites around the primary tumour affects the development of metastatic disease.	('microsatellites', 'Var', (181, 196))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('development of metastatic disease', 'CPA', (235, 268))	('tumour', 'Disease', 'MESH:D009369', (216, 222))	('removal', 'Var', (170, 177))	('affects', 'Reg', (223, 230))	('tumour', 'Disease', (216, 222))
67175	21081927	Cell surface staining for FXYD5, TSPAN8, CD9, CD53, CD63, CD81, CD82, CD151, RELN and intracellular staining for BCL11A, CAPG, renalase and ID3 were carried out according to a procedure detailed in Supplementary Materials and Methods.	('CD63', 'Gene', '967', (52, 56))	('BCL11A', 'Gene', (113, 119))	('RELN', 'Gene', '5649', (77, 81))	('renalase', 'Gene', (127, 135))	('intracellular', 'cellular_component', 'GO:0005622', ('86', '99'))	('renalase', 'Gene', '55328', (127, 135))	('ID3', 'Gene', '3399', (140, 143))	('CD82', 'Gene', '3732', (64, 68))	('CD63', 'Gene', (52, 56))	('CD53', 'Gene', '963', (46, 50))	('CD82', 'Gene', (64, 68))	('BCL11A', 'Gene', '53335', (113, 119))	('ID3', 'Gene', (140, 143))	('RELN', 'Gene', (77, 81))	('CD81', 'Var', (58, 62))	('CD53', 'Gene', (46, 50))
67207	21081927	Melanoma cells were surface stained for TSPAN8, RELN and FXYD5 or intracellularly stained for renalase, CAPG, BCL11A and ID3.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('ID3', 'Gene', (121, 124))	('BCL11A', 'Gene', '53335', (110, 116))	('Melanoma', 'Disease', (0, 8))	('RELN', 'Gene', (48, 52))	('BCL11A', 'Gene', (110, 116))	('RELN', 'Gene', '5649', (48, 52))	('TSPAN8', 'Var', (40, 46))	('ID3', 'Gene', '3399', (121, 124))	('renalase', 'Gene', (94, 102))	('renalase', 'Gene', '55328', (94, 102))
67211	21081927	These cell lines and clones, widely used as a metastasis melanoma model, were classified into two groups: (a) PNA-moderate or -negative cells with low or no invasive potential: M4Be, T1C11, M3Ge, M3Da and M1Do; and (b) PNA-positive cells with a high invasive potential: TW12 and T1P26.	('rat', 'Species', '10116', (118, 121))	('metastasis melanoma', 'Disease', 'MESH:D009362', (46, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('M3Ge', 'Var', (190, 194))	('T1C11', 'Var', (183, 188))	('M4Be', 'Var', (177, 181))	('metastasis melanoma', 'Disease', (46, 65))	('M1Do', 'Var', (205, 209))	('M3Da', 'Var', (196, 200))	('M1', 'CellLine', 'CVCL:J159', (205, 207))
67246	21081927	More importantly, the functional role of TSPAN8 was demonstrated by silencing endogenous TSPAN8 with siRNA, which reduces invasive outgrowth from tumour spheroids within matrigel, without impact on the cell proliferation and survival.	('tumour spheroids', 'Disease', 'MESH:C000598645', (146, 162))	('tumour spheroids', 'Disease', (146, 162))	('reduces', 'NegReg', (114, 121))	('rat', 'Species', '10116', (214, 217))	('TSPAN8', 'Gene', (89, 95))	('cell proliferation', 'biological_process', 'GO:0008283', ('202', '220'))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('silencing', 'Var', (68, 77))	('rat', 'Species', '10116', (59, 62))
67268	21081927	It is thought that TSPAN8 contributes to the cell motility of metastatic carcinoma cell lines, mostly through its association with alpha6beta4 and CD151 following PMA treatment, whereas association with alpha3beta1 and alpha6beta1 promotes haematogenic spread of tumour cells.	('tumour', 'Disease', (263, 269))	('alpha6beta4', 'Var', (131, 142))	('carcinoma', 'Disease', (73, 82))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('TSPAN8', 'Gene', (19, 25))	('PMA', 'Chemical', '-', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cell motility', 'biological_process', 'GO:0048870', ('45', '58'))	('association', 'Interaction', (114, 125))	('cell motility', 'CPA', (45, 58))	('tumour', 'Phenotype', 'HP:0002664', (263, 269))	('tumour', 'Disease', 'MESH:D009369', (263, 269))	('association', 'Interaction', (186, 197))	('contributes', 'Reg', (26, 37))	('CD151', 'Gene', (147, 152))	('promotes', 'PosReg', (231, 239))
67269	21081927	An interesting finding in this study is that siRNA TSPAN8 knockdown reduced the invasive outgrowth of melanoma spheroids embedded in matrigel.	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('reduced', 'NegReg', (68, 75))	('knockdown', 'Var', (58, 67))
67270	21081927	It seems unlikely that this was caused by a decrease in cell survival or growth rate, as TSPAN8 silencing did not affect viability or proliferation.	('rat', 'Species', '10116', (80, 83))	('TSPAN8', 'Gene', (89, 95))	('rat', 'Species', '10116', (141, 144))	('silencing', 'Var', (96, 105))
67271	21081927	Our observations are in line with previous studies showing that ectopic TSPAN8 expression in low-metastatic carcinoma cells did not confer any advantage for cell proliferation but led to a high metastatic potential.	('rat', 'Species', '10116', (169, 172))	('carcinoma', 'Disease', 'MESH:D002277', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('ectopic', 'Var', (64, 71))	('led to', 'Reg', (180, 186))	('cell proliferation', 'biological_process', 'GO:0008283', ('157', '175'))	('carcinoma', 'Disease', (108, 117))	('TSPAN8', 'Gene', (72, 78))
67272	21081927	Three-dimensional models of melanoma culture represent a technical approach that adequately reflects the clinical melanoma tumour stage: cell lines derived from VGP, but not RGP, melanoma lesions invade 3D matrices.	('melanoma', 'Disease', (28, 36))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma tumour', 'Disease', (114, 129))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('VGP', 'Var', (161, 164))	('melanoma lesions', 'Disease', 'MESH:D008545', (179, 195))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma lesions', 'Disease', (179, 195))	('melanoma tumour', 'Disease', 'MESH:D008545', (114, 129))	('melanoma', 'Disease', (179, 187))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (114, 122))
67274	21081927	Although TSPAN8 silencing reduced the invasive outgrowth of melanoma cells embedded in matrigel, it did not impair their ability to close an artificial gap created over a confluent monolayer, even when cells were grown on plates coated with collagen-IV (the main basement membrane component), collagen-I (the most abundant component of the dermis) or a recontituted basement membrane: matrigel.	('collagen', 'molecular_function', 'GO:0005202', ('293', '301'))	('collagen', 'molecular_function', 'GO:0005202', ('241', '249'))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('basement membrane', 'cellular_component', 'GO:0005604', ('263', '280'))	('reduced', 'NegReg', (26, 33))	('invasive outgrowth', 'CPA', (38, 56))	('silencing', 'Var', (16, 25))	('basement membrane', 'cellular_component', 'GO:0005604', ('366', '383'))	('TSPAN8', 'Gene', (9, 15))
67279	21081927	If the present in vitro findings have any physiological relevance, it is thus conceivable that TSPAN8 expression might give melanoma cells the ability to cross the cutaneous basement membrane, an early event leading to dermal invasion and progression to metastatic disease.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('leading to', 'Reg', (208, 218))	('basement membrane', 'cellular_component', 'GO:0005604', ('174', '191'))	('ability', 'MPA', (143, 150))	('TSPAN8', 'Gene', (95, 101))	('metastatic disease', 'CPA', (254, 272))	('expression', 'Var', (102, 112))	('dermal invasion', 'CPA', (219, 234))
67293	31123404	These include tumor mutation burden (TMB) or tumor mutation load, neoantigen burden, DNA mismatch repair deficiency, and high microsatellite instability.	('TMB', 'Chemical', '-', (37, 40))	('neoantigen burden', 'MPA', (66, 83))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('high microsatellite instability', 'MPA', (121, 152))	('mismatch repair', 'biological_process', 'GO:0006298', ('89', '104'))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('deficiency', 'Var', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
67320	31123404	Here, we followed the F1CDx approach to calculate the TMB for our panel, defining the cutoff values as TMB-high (>=20 mutations/Mb), TMB-medium (<20 mutations/Mb >=10 mutations/Mb) and TMB-low (<10 mutations/Mb).	('TMB', 'Chemical', '-', (133, 136))	('mutations/Mb', 'Var', (118, 130))	('TMB', 'Chemical', '-', (185, 188))	('TMB', 'Chemical', '-', (103, 106))	('TMB', 'Chemical', '-', (54, 57))	('F1CDx', 'Chemical', '-', (22, 27))	('<20 mutations/Mb', 'Var', (145, 161))
67323	31123404	We calculated the proportion of patient samples from 15 different cancers with mutations in each gene.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('patient', 'Species', '9606', (32, 39))	('mutations', 'Var', (79, 88))
67343	31123404	Some well-established cancer-associated genes, such as PI3KCA and TP53, were frequently mutated in most cancer types.	('PI3', 'Gene', (55, 58))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (22, 28))	('PI3', 'Gene', '5266', (55, 58))	('mutated', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
67350	31123404	TP53, EGFR, PIC3CA and KRAS were often mutated in TMB-low samples in LUAD.	('TP53', 'Gene', '7157', (0, 4))	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', (6, 10))	('PIC3CA', 'Gene', (12, 18))	('mutated', 'Var', (39, 46))	('KRAS', 'Gene', (23, 27))	('PIC', 'cellular_component', 'GO:0019035', ('12', '15'))	('PIC', 'cellular_component', 'GO:0097550', ('12', '15'))	('TMB', 'Chemical', '-', (50, 53))	('KRAS', 'Gene', '3845', (23, 27))	('EGFR', 'Gene', '1956', (6, 10))
67355	31123404	MUC16 (coding length, 43524 bp) encodes a transmembrane glycoprotein with a molecular weight of 2000 kDa, meaning that it also has a high risk of mutation TMB is defined as the number of somatic coding mutations per million bases.	('MUC16', 'Gene', '94025', (0, 5))	('TMB', 'Chemical', '-', (155, 158))	('transmembrane', 'cellular_component', 'GO:0044214', ('42', '55'))	('transmembrane', 'cellular_component', 'GO:0016021', ('42', '55'))	('MUC16', 'Gene', (0, 5))	('mutation', 'Var', (146, 154))
67358	31123404	However, the relationship of those hotspot mutations with TMB are still not well-understood.	('TMB', 'Chemical', '-', (58, 61))	('TMB', 'Disease', (58, 61))	('mutations', 'Var', (43, 52))
67360	31123404	Firstly, we defined hotspot mutations as highly frequent mutations found in at least ten samples in the complete set of cancer WES data (Figure S2).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
67361	31123404	Next, we focused on those hotspot mutations which occurred in at least three samples in one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
67362	31123404	Finally, a total of 150 unique mutations were investigated for their association to TMB level (327 cancer type-specific mutations).	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TMB level', 'Disease', (84, 93))	('cancer', 'Disease', (99, 105))	('association', 'Interaction', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TMB', 'Chemical', '-', (84, 87))
67363	31123404	For these mutations, we calculated the P-value using a Mann-Whitney U-test and the fold-change by the median TMB value in mutation-positive samples (samples containing the mutation) and mutation-negative samples (samples without the mutation), as listed in Figure S3.	('mutation', 'Var', (172, 180))	('mutation-positive', 'Reg', (122, 139))	('TMB', 'Chemical', '-', (109, 112))	('mutations', 'Var', (10, 19))
67364	31123404	Figure 3A shows that most of these hotspot mutations were associated with high TMB (101/327) and only a small number of mutations were associated with low TMB (5/327).	('mutations', 'Var', (43, 52))	('high TMB', 'Disease', (74, 82))	('TMB', 'Chemical', '-', (155, 158))	('TMB', 'Chemical', '-', (79, 82))
67365	31123404	We found that some hotspot mutations occurred in only one cancer type.	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))
67366	31123404	For example, the mutations P.S71L in OR2A5, P.G362E in CNTNAP2, P.F17F in BCL2L12 and P.T554I in SLC27A5 only occurred in SKCM and were associated with high TMB, with an adjusted-log10 (P-value)>1.3 and log2 (fold-change)>1.	('associated', 'Reg', (136, 146))	('CNTNAP2', 'Gene', (55, 62))	('BCL2L12', 'Gene', (74, 81))	('TMB', 'Chemical', '-', (157, 160))	('BCL2L12', 'Gene', '83596', (74, 81))	('F17F', 'Mutation', 'rs267605591', (66, 70))	('SLC27A5', 'Gene', '10998', (97, 104))	('T554I', 'Mutation', 'rs868246582', (88, 93))	('S71L', 'Mutation', 'rs149614119', (29, 33))	('P.G362E', 'Var', (44, 51))	('SLC27A5', 'Gene', (97, 104))	('OR2A5', 'Gene', (37, 42))	('OR2A5', 'Gene', '393046', (37, 42))	('CNTNAP2', 'Gene', '26047', (55, 62))	('P.F17F', 'Var', (64, 70))	('G362E', 'Mutation', 'p.G362E', (46, 51))	('BCL2', 'molecular_function', 'GO:0015283', ('74', '78'))	('high TMB', 'Disease', (152, 160))	('P.S71L', 'Var', (27, 33))	('P.T554I', 'Var', (86, 93))
67367	31123404	However, other hotspot mutations occurred in at least two cancer types.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('occurred', 'Reg', (33, 41))	('mutations', 'Var', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
67368	31123404	For example, the mutation KRAS:P.G12V appeared in BRCA, COAD, LUAD, OV, PAAD, STAD and UCEC, but only in OV was this mutation was positively related to low TMB, with a -log10 (P-value) of 2.29 and log2 (fold-change) of -2.26.	('COAD', 'Disease', 'MESH:D029424', (56, 60))	('P.G12V', 'Var', (31, 37))	('low TMB', 'MPA', (152, 159))	('G12V', 'Mutation', 'rs121913529', (33, 37))	('COAD', 'Disease', (56, 60))	('BRCA', 'Gene', '672', (50, 54))	('TMB', 'Chemical', '-', (156, 159))	('KRAS', 'Gene', (26, 30))	('BRCA', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (26, 30))
67369	31123404	As shown in Figure 3A-B, only in LUAD were the mutations P.E746_A750del and P.L858R in EGFR significantly associated with low TMB (adjusted P-value <0.00006 and log2 (fold-change) of 4.28).	('L858R', 'Mutation', 'rs121434568', (78, 83))	('EGFR', 'Gene', '1956', (87, 91))	('TMB', 'Chemical', '-', (126, 129))	('A750del', 'Mutation', 'c.750delA', (64, 71))	('EGFR', 'molecular_function', 'GO:0005006', ('87', '91'))	('EGFR', 'Gene', (87, 91))	('low', 'NegReg', (122, 125))	('P.L858R', 'Var', (76, 83))	('P.E746_A750del', 'Var', (57, 71))	('TMB', 'MPA', (126, 129))
67370	31123404	In other words, samples with these two hotspot mutations were usually TMB-low in LUAD and would be targetable by first-generation tyrosine kinase inhibitors.	('LUAD', 'Disease', (81, 85))	('mutations', 'Var', (47, 56))	('TMB', 'Chemical', '-', (70, 73))
67371	31123404	Most colorectal patients with the BRAF P.V600E mutation were TMB-high, with a P-value of 8.21E-19 (fold-change: 31.9 vs 3.4).	('TMB', 'Chemical', '-', (61, 64))	('colorectal', 'Disease', 'MESH:D015179', (5, 15))	('patients', 'Species', '9606', (16, 24))	('colorectal', 'Disease', (5, 15))	('BRAF', 'Gene', '673', (34, 38))	('P.V600E', 'Var', (39, 46))	('BRAF', 'Gene', (34, 38))	('V600E', 'Mutation', 'rs113488022', (41, 46))
67372	31123404	However, the BRAF V600E mutation was associated with TMB-low in LUAD patients with P-value 0.015 (fold change: 1.9 vs 5.9).	('V600E', 'Var', (18, 23))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('patients', 'Species', '9606', (69, 77))	('TMB', 'Chemical', '-', (53, 56))	('TMB-low', 'Disease', (53, 60))
67373	31123404	In summary, our results indicated that some hotspot mutations were strongly associated with TMB level, either low or high.	('associated', 'Reg', (76, 86))	('TMB', 'Chemical', '-', (92, 95))	('mutations', 'Var', (52, 61))	('TMB level', 'Disease', (92, 101))
67377	31123404	TMB estimated from simulated F1CDx and MSK-IMPACT panels showed a high correlation to TMB estimated from WES, with R2 correlation values of 0.95 and 0.94, respectively, for total mutations (Figure 4A and B).	('TMB', 'Chemical', '-', (86, 89))	('TMB', 'Chemical', '-', (0, 3))	('MSK', 'Gene', '150094', (39, 42))	('F1CDx', 'Chemical', '-', (29, 34))	('MSK', 'Gene', (39, 42))	('mutations', 'Var', (179, 188))
67389	31123404	Besides, we found that randomly selected gene sets had little difference between F1CDx, MSK-IMPACT and F1CDX+MSK in almost all cancer types.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('F1CDX+MSK', 'Gene', '150094', (103, 112))	('F1CDx', 'Var', (81, 86))	('MSK', 'Gene', '150094', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('MSK', 'Gene', (88, 91))	('MSK', 'Gene', '150094', (109, 112))	('MSK', 'Gene', (109, 112))	('cancer', 'Disease', (127, 133))	('F1CDX+MSK', 'Gene', (103, 112))	('F1CDx', 'Chemical', '-', (81, 86))
67414	29349077	Mutations in the RAS genes are associated with around 30% of all human tumors.	('human', 'Species', '9606', (65, 70))	('RAS', 'Gene', (17, 20))	('associated', 'Reg', (31, 41))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
67416	29349077	For example, mutations in KRAS are common in lung, colon, and pancreatic cancers, those in NRAS predominate in melanoma, and HRAS mutations are commonly seen in bladder, head and neck, and skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (62, 80))	('HRAS', 'Gene', '3265', (125, 129))	('neck', 'cellular_component', 'GO:0044326', ('179', '183'))	('HRAS', 'Gene', (125, 129))	('NRAS', 'Gene', (91, 95))	('pancreatic cancers', 'Disease', (62, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('skin cancers', 'Phenotype', 'HP:0008069', (189, 201))	('colon', 'Disease', (51, 56))	('pancreatic cancers', 'Disease', 'MESH:D010190', (62, 80))	('KRAS', 'Gene', '3845', (26, 30))	('lung', 'Disease', (45, 49))	('common', 'Reg', (35, 41))	('skin cancers', 'Disease', (189, 201))	('seen', 'Reg', (153, 157))	('bladder', 'Disease', (161, 168))	('KRAS', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (91, 95))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('skin cancers', 'Disease', 'MESH:D012878', (189, 201))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (130, 139))
67417	29349077	Alterations in multiple signaling pathways that regulate cell proliferation and survival contribute to the tumorigenesis and progression of this disease.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('Alterations', 'Var', (0, 11))	('contribute', 'Reg', (89, 99))	('cell proliferation', 'biological_process', 'GO:0008283', ('57', '75'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
67418	29349077	Cutaneous melanoma frequently harbors activating mutations in NRAS (around 20%) or the RAS-regulated kinase BRAF (around 37%), suggesting that the RAS-RAF-MAPK pathway may be critical in the pathogenesis of cutaneous melanoma.	('NRAS', 'Gene', (62, 66))	('NRAS', 'Gene', '4893', (62, 66))	('mutations', 'Var', (49, 58))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('activating', 'PosReg', (38, 48))	('cutaneous melanoma', 'Disease', (207, 225))	('pathogenesis', 'biological_process', 'GO:0009405', ('191', '203'))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('BRAF', 'Gene', '673', (108, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (207, 225))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (207, 225))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('155', '159'))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('BRAF', 'Gene', (108, 112))	('Cutaneous melanoma', 'Disease', (0, 18))
67420	29349077	Currently, there has been remarkable progress in understanding melanoma pathogenesis, and numerous studies have now shown the correlation of BRAF and NRAS mutation status with clinical outcome and immune and targeted therapy strategies in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('BRAF', 'Gene', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('NRAS', 'Gene', (150, 154))	('mutation', 'Var', (155, 163))	('pathogenesis', 'biological_process', 'GO:0009405', ('72', '84'))	('BRAF', 'Gene', '673', (141, 145))	('NRAS', 'Gene', '4893', (150, 154))	('melanoma', 'Disease', (63, 71))
67455	29349077	Univariate Cox regression survival analysis showed that high HRAS mRNA expression was a risk factor for worse patient survival (HR: 1.532, 95% CI: 1.163~2.017, p = 0.002 for overall survival).	('HRAS', 'Gene', (61, 65))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('HRAS', 'Gene', '3265', (61, 65))	('patient', 'Species', '9606', (110, 117))	('high', 'Var', (56, 60))
67461	29349077	Compared to wild-type RAS isoforms, mutational RAS isoforms mRNA expressions were significantly higher, respectively (p = 0.005 for KRAS, p < 0.001 for NRAS, and p = 0.030 for HRAS) (Table 4).	('KRAS', 'Gene', (132, 136))	('NRAS', 'Gene', (152, 156))	('KRAS', 'Gene', '3845', (132, 136))	('HRAS', 'Gene', '3265', (176, 180))	('NRAS', 'Gene', '4893', (152, 156))	('HRAS', 'Gene', (176, 180))	('mutational', 'Var', (36, 46))	('higher', 'PosReg', (96, 102))	('mRNA expressions', 'MPA', (60, 76))
67463	29349077	For the group with BRAF mutation, NRAS mRNA expression was significantly lower than BRAF wild-type group (p = 0.015) (Table 4).	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (19, 23))	('BRAF', 'Gene', (84, 88))	('lower', 'NegReg', (73, 78))	('NRAS', 'Gene', (34, 38))	('mutation', 'Var', (24, 32))	('NRAS', 'Gene', '4893', (34, 38))
67471	29349077	The enriched pathways of the genes positively correlated with HRAS included oxidative phosphorylation (hsa00190, p = 4.73E - 21), Huntington's disease (hsa05016, p = 1.78E - 19), Parkinson's disease (hsa05012, p = 1.42E - 16), Alzheimer's disease (hsa05010, p = 2.70E - 15), and ribosome (hsa03010, p = 4.11E - 6) (Figure 4(a)).	('hsa05010', 'Var', (248, 256))	("Parkinson's disease", 'Disease', 'MESH:D010300', (179, 198))	('HRAS', 'Gene', '3265', (62, 66))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (227, 246))	('oxidative phosphorylation', 'MPA', (76, 101))	('hsa00190', 'Var', (103, 111))	("Huntington's disease", 'Disease', 'MESH:D006816', (130, 150))	("Huntington's disease", 'Disease', (130, 150))	('HRAS', 'Gene', (62, 66))	('hsa05016', 'Var', (152, 160))	("Alzheimer's disease", 'Disease', (227, 246))	("Parkinson's disease", 'Disease', (179, 198))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('76', '101'))	('ribosome', 'cellular_component', 'GO:0005840', ('279', '287'))	('hsa03010', 'Var', (289, 297))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (227, 246))
67472	29349077	And the enriched pathways of the genes negatively correlated with HRAS included ubiquitin-mediated proteolysis (hsa04120, p = 5.32E - 10), RNA degradation (hsa03018, p = 7.29E - 8), MAPK signaling pathway (hsa04010, p = 0.003), Wnt signaling pathway (hsa04310, p = 0.006), and RIG-I-like receptor signaling pathway (hsa04622, p = 0.007) (Figure 4(b)).	('proteolysis', 'biological_process', 'GO:0006508', ('99', '110'))	('hsa04310', 'Var', (251, 259))	('RIG-I-like receptor signaling pathway', 'Pathway', (277, 314))	('ubiquitin', 'molecular_function', 'GO:0031386', ('80', '89'))	('MAPK', 'molecular_function', 'GO:0004707', ('182', '186'))	('Wnt signaling pathway', 'Pathway', (228, 249))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('228', '249'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('182', '196'))	('HRAS', 'Gene', '3265', (66, 70))	('signaling pathway', 'biological_process', 'GO:0007165', ('187', '204'))	('RNA', 'cellular_component', 'GO:0005562', ('139', '142'))	('RNA degradation', 'biological_process', 'GO:0006401', ('139', '154'))	('HRAS', 'Gene', (66, 70))	('negatively', 'NegReg', (39, 49))	('hsa04010', 'Var', (206, 214))	('hsa04622', 'Var', (316, 324))	('hsa04120', 'Var', (112, 120))	('ubiquitin-mediated proteolysis', 'MPA', (80, 110))	('hsa03018', 'Var', (156, 164))	('RNA degradation', 'MPA', (139, 154))	('signaling pathway', 'biological_process', 'GO:0007165', ('297', '314'))	('MAPK signaling pathway', 'Pathway', (182, 204))
67476	29349077	We found that these genes were enriched in the following pathways (p < 0.05): chronic myeloid leukemia (hsa05220, p = 0.004), prostate cancer (hsa05215, p = 0.007), regulation of actin cytoskeleton (hsa04810, p = 0.011), acute myeloid leukemia (hsa05221, p = 0.014), cell cycle (hsa04110, p = 0.024), spliceosome (hsa03040, p = 0.024), pancreatic cancer (hsa05212, p = 0.025), MAPK signaling pathway (hsa04010, p = 0.029), and TGF-beta signaling pathway (hsa04350, p = 0.041) (Table 5).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (336, 353))	('myeloid leukemia', 'Disease', 'MESH:D007951', (86, 102))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('hsa04010', 'Var', (401, 409))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (78, 102))	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (221, 243))	('MAPK signaling', 'biological_process', 'GO:0000165', ('377', '391'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('436', '453'))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (221, 243))	('hsa03040', 'Var', (314, 322))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('TGF-beta signaling pathway', 'Pathway', (427, 453))	('leukemia', 'Phenotype', 'HP:0001909', (235, 243))	('pancreatic cancer', 'Disease', 'MESH:D010190', (336, 353))	('MAPK signaling pathway', 'Pathway', (377, 399))	('cell cycle', 'biological_process', 'GO:0007049', ('267', '277'))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('myeloid leukemia', 'Disease', 'MESH:D007951', (227, 243))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (227, 243))	('MAPK', 'molecular_function', 'GO:0004707', ('377', '381'))	('pancreatic cancer', 'Disease', (336, 353))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('spliceosome', 'cellular_component', 'GO:0005681', ('301', '312'))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('382', '399'))	('myeloid leukemia', 'Disease', (86, 102))	('prostate cancer', 'Disease', (126, 141))	('hsa05212', 'Var', (355, 363))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('179', '197'))	('acute myeloid leukemia', 'Disease', (221, 243))
67502	29349077	With regard to NRAS, the most common oncogenic change (>80% of all NRAS mutations) is a point mutation leading to the substitution of leucine by glutamine at amino acid 61, with mutations at amino acids 12 and 13 occurring less frequently.	('substitution', 'Var', (118, 130))	('mutations', 'Var', (72, 81))	('leucine by glutamine at amino acid 61', 'Mutation', 'rs11554290', (134, 171))	('NRAS', 'Gene', (15, 19))	('NRAS', 'Gene', (67, 71))	('NRAS', 'Gene', '4893', (15, 19))	('NRAS', 'Gene', '4893', (67, 71))
67503	29349077	Amino acid 61 mutations also account for the majority of HRAS mutations in melanoma, whereas most KRAS mutations are at amino acid 12.	('KRAS', 'Gene', '3845', (98, 102))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('HRAS', 'Gene', '3265', (57, 61))	('melanoma', 'Disease', (75, 83))	('KRAS', 'Gene', (98, 102))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('HRAS', 'Gene', (57, 61))	('Amino acid 61 mutations', 'Var', (0, 23))	('mutations', 'Var', (62, 71))
67504	29349077	Although it is not clear why NRAS mutations are more frequent in melanoma compared to HRAS or KRAS mutations, there is evidence that NRAS is overexpressed in melanocytes relative to other RAS isoforms.	('KRAS', 'Gene', (94, 98))	('HRAS', 'Gene', '3265', (86, 90))	('frequent', 'Reg', (53, 61))	('NRAS', 'Gene', (29, 33))	('NRAS', 'Gene', (133, 137))	('HRAS', 'Gene', (86, 90))	('KRAS', 'Gene', '3845', (94, 98))	('NRAS', 'Gene', '4893', (29, 33))	('NRAS', 'Gene', '4893', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('mutations', 'Var', (34, 43))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
67506	29349077	However, the status of the wide-type RAS allele may also play a role in tumors carrying mutant RAS genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('play', 'Reg', (57, 61))	('RAS genes', 'Gene', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutant', 'Var', (88, 94))
67514	23130279	Of course, different biological conditions can arise in those rare instances in which a cutaneous melanoma develops on skin where the ability to repair the photo-induced damage is altered genetically as xeroderma pigmentosum, with a reported incidence of melanoma approximately 2000 times greater, or in case of genetic or acquired immunodeficiency, that is, cases of immune impairment in organ transplant recipients or in patients affected by Hodgkin's lymphoma.	('immune impairment', 'Phenotype', 'HP:0002721', (368, 385))	('immunodeficiency', 'Phenotype', 'HP:0002721', (332, 348))	('lymphoma', 'Phenotype', 'HP:0002665', (454, 462))	("Hodgkin's lymphoma", 'Disease', (444, 462))	('altered', 'Var', (180, 187))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (203, 224))	('patients', 'Species', '9606', (423, 431))	('immunodeficiency', 'Disease', (332, 348))	('xeroderma pigmentosum', 'Disease', (203, 224))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (444, 462))	('cutaneous melanoma', 'Disease', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('melanoma', 'Disease', (255, 263))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (444, 462))	('immunodeficiency', 'Disease', 'MESH:D007153', (332, 348))
67565	23130279	Some mutations, early events in melanocytic tumors, in BRAF (melanocytic nevi), NRAS (congenital nevi), HRAS (Spitz nevi), and GNAQ (blue nevi) can all cause activation of the mitogen-activated protein kinase (MAPK) signaling pathway in the initiation of melanocytic tumors.	('melanocytic tumors', 'Disease', 'MESH:D009508', (255, 273))	('NRAS', 'Gene', '4893', (80, 84))	('BRAF', 'Gene', '673', (55, 59))	('melanocytic tumors', 'Disease', 'MESH:D009508', (32, 50))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('BRAF', 'Gene', (55, 59))	('melanocytic tumors', 'Disease', (32, 50))	('initiation of melanocytic tumors', 'Disease', 'MESH:D009508', (241, 273))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('MAPK', 'molecular_function', 'GO:0004707', ('210', '214'))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('210', '225'))	('nevi', 'Phenotype', 'HP:0003764', (116, 120))	('HRAS', 'Gene', '3265', (104, 108))	('NRAS', 'Gene', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('nevi', 'Phenotype', 'HP:0003764', (138, 142))	('HRAS', 'Gene', (104, 108))	('mutations', 'Var', (5, 14))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('activation', 'PosReg', (158, 168))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('GNAQ', 'Gene', '2776', (127, 131))	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('initiation of melanocytic tumors', 'Disease', (241, 273))	('GNAQ', 'Gene', (127, 131))	('signaling pathway', 'biological_process', 'GO:0007165', ('216', '233'))	('blue nevi', 'Phenotype', 'HP:0100814', (133, 142))
67582	31689494	The observation that 50 % of all cutaneous melanomas harbor activating mutations in the serine-threonine kinase BRAF led to the clinical development of BRAF inhibitors and then the BRAF-MEK inhibitor combinations.	('activating', 'PosReg', (60, 70))	('BRAF', 'Gene', (152, 156))	('cutaneous melanomas', 'Disease', (33, 52))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('BRAF', 'Gene', (181, 185))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', '673', (181, 185))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('serine', 'Chemical', 'MESH:D012694', (88, 94))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (33, 52))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (33, 52))	('MEK', 'Gene', (186, 189))	('BRAF', 'Gene', '673', (152, 156))	('MEK', 'Gene', '5609', (186, 189))
67583	31689494	The BRAF-MEK inhibitor combination can deliver durable responses in patients whose melanomas harbor BRAF mutations and is associated with a 5-year survival rate of ~33 %.	('melanomas harbor BRAF', 'Disease', 'MESH:C537062', (83, 104))	('melanomas harbor BRAF', 'Disease', (83, 104))	('patients', 'Species', '9606', (68, 76))	('BRAF', 'Gene', '673', (100, 104))	('mutations', 'Var', (105, 114))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('MEK', 'Gene', (9, 12))	('BRAF', 'Gene', (100, 104))	('MEK', 'Gene', '5609', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))
67589	31689494	Melanomas that develop on acral skin sites are distinct from cutaneous melanomas in having lower mutational burdens and different oncogenic drivers, including lower frequencies of BRAF mutations (10-23 %), variable KIT mutation rates (3-29 %), amplification of CCND1 and CDK4 and deletion/mutations in CDK2NA, PTEN, NF1 and hTERT (Table 1).	('KIT', 'Gene', '3815', (215, 218))	('PTEN', 'Gene', '5728', (310, 314))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('NF1', 'Gene', (316, 319))	('hTERT', 'Gene', '7015', (324, 329))	('CDK', 'molecular_function', 'GO:0004693', ('302', '305'))	('CDK2NA', 'Gene', '1017', (302, 308))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (61, 80))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (61, 80))	('CDK4', 'Gene', (271, 275))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('BRAF', 'Gene', '673', (180, 184))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAF', 'Gene', (180, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('CCND1', 'Gene', '595', (261, 266))	('lower', 'NegReg', (159, 164))	('KIT', 'Gene', (215, 218))	('CDK', 'molecular_function', 'GO:0004693', ('271', '274'))	('hTERT', 'Gene', (324, 329))	('CDK4', 'Gene', '1019', (271, 275))	('CDK2NA', 'Gene', (302, 308))	('cutaneous melanomas', 'Disease', (61, 80))	('CCND1', 'Gene', (261, 266))	('deletion/mutations', 'Var', (280, 298))	('PTEN', 'Gene', (310, 314))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('mutations', 'Var', (185, 194))	('amplification', 'Var', (244, 257))	('NF1', 'Gene', '4763', (316, 319))	('KIT', 'molecular_function', 'GO:0005020', ('215', '218'))
67607	31689494	Acral melanoma shows a higher number of structural chromosomal changes and a lower number of point mutations than non-acral melanoma, furthering this hypothesis.	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('acral melanoma', 'Phenotype', 'HP:0012060', (118, 132))	('Acral melanoma', 'Disease', (0, 14))	('acral melanoma', 'Disease', (118, 132))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Acral melanoma', 'Disease', 'MESH:D008545', (0, 14))	('Acral melanoma', 'Phenotype', 'HP:0012060', (0, 14))	('acral melanoma', 'Disease', 'MESH:D008545', (118, 132))	('structural chromosomal changes', 'Var', (40, 70))
67608	31689494	However, one study showed that a small number of subungual acral melanomas (8.6 %) had significant numbers of UV-associated mutations, suggesting at least a partial relationship to sun exposure.	('UV-associated', 'Gene', (110, 123))	('acral melanomas', 'Phenotype', 'HP:0012060', (59, 74))	('acral melanomas', 'Disease', (59, 74))	('acral melanoma', 'Phenotype', 'HP:0012060', (59, 73))	('mutations', 'Var', (124, 133))	('acral melanomas', 'Disease', 'MESH:D008545', (59, 74))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))
67609	31689494	Genomically, a significant proportion of acral melanoma falls into the triple wild type category, with only 38-55 % of tumors having mutations in BRAF, NRAS, or NF1.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('BRAF', 'Gene', (146, 150))	('NRAS', 'Gene', (152, 156))	('tumors', 'Disease', (119, 125))	('acral melanoma falls', 'Disease', (41, 61))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('BRAF', 'Gene', '673', (146, 150))	('NRAS', 'Gene', '4893', (152, 156))	('falls', 'Phenotype', 'HP:0002527', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('acral melanoma', 'Phenotype', 'HP:0012060', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutations', 'Var', (133, 142))	('NF1', 'Gene', (161, 164))	('NF1', 'Gene', '4763', (161, 164))	('acral melanoma falls', 'Disease', 'MESH:D002303', (41, 61))
67632	31689494	One defining characteristic of the vast majority of melanomas is constitutive activation of the mitogen activated protein kinase (MAPK) signaling pathway, which most frequently results from mutations in components of the signaling pathway.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('results from', 'Reg', (177, 189))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('mutations', 'Var', (190, 199))	('signaling pathway', 'biological_process', 'GO:0007165', ('221', '238'))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('melanomas', 'Disease', (52, 61))	('activation', 'PosReg', (78, 88))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('130', '145'))
67634	31689494	Acquisition of BRAF mutations, which are most common at position 600 (V600E, V600 K, V600D and V600R) leads to the stabilization of the kinase in the active state, and stimulation of the MAPK pathway.	('stabilization', 'MPA', (115, 128))	('BRAF', 'Gene', '673', (15, 19))	('V600R', 'Var', (95, 100))	('V600D', 'Mutation', 'rs121913377', (85, 90))	('V600E', 'Var', (70, 75))	('BRAF', 'Gene', (15, 19))	('MAPK pathway', 'Pathway', (187, 199))	('stimulation', 'PosReg', (168, 179))	('V600 K', 'Mutation', 'rs121913227', (77, 83))	('V600R', 'Mutation', 'rs121913227', (95, 100))	('V600 K', 'Var', (77, 83))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('V600D', 'Var', (85, 90))	('MAPK', 'molecular_function', 'GO:0004707', ('187', '191'))
67636	31689494	These mutations which in melanoma most frequently occur in the GTP binding site at Glutamine 61, result in inactivation of the intrinsic GTPase activity without turning itself off so that the RAS protein remains in the "On" position.	('GTPase', 'Enzyme', (137, 143))	('GTP', 'Chemical', 'MESH:D006160', (137, 140))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))	('GTP binding', 'molecular_function', 'GO:0005525', ('63', '74'))	('inactivation', 'NegReg', (107, 119))	('Glutamine', 'Chemical', 'MESH:D005973', (83, 92))	('GTP', 'Chemical', 'MESH:D006160', (63, 66))	('GTPase activity', 'molecular_function', 'GO:0003924', ('137', '152'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('activity', 'MPA', (144, 152))	('mutations', 'Var', (6, 15))
67637	31689494	Other mutations associated with constitutive MAPK activation in melanoma include inactivating mutations in the tumor suppressor NF1, leading to a similar loss of control over RAS/MAPK signaling, and activating mutations in Rac1 which activates the MAPK pathway through transactivation of PAK1.	('MAPK', 'molecular_function', 'GO:0004707', ('248', '252'))	('PAK1', 'Gene', (288, 292))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('MAPK activation', 'biological_process', 'GO:0000187', ('45', '60'))	('control over RAS/MAPK signaling', 'MPA', (162, 193))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('MAPK pathway', 'Pathway', (248, 260))	('PAK1', 'Gene', '5058', (288, 292))	('transactivation', 'biological_process', 'GO:2000144', ('269', '284'))	('activation', 'PosReg', (50, 60))	('Rac1', 'Gene', '5879', (223, 227))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('inactivating mutations', 'Var', (81, 103))	('loss', 'NegReg', (154, 158))	('activates', 'PosReg', (234, 243))	('MAPK', 'molecular_function', 'GO:0004707', ('45', '49'))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', (111, 116))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('MAPK signaling', 'biological_process', 'GO:0000165', ('179', '193'))	('MAPK', 'molecular_function', 'GO:0004707', ('179', '183'))	('NF1', 'Gene', '4763', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('MAPK', 'Gene', (45, 49))	('Rac1', 'Gene', (223, 227))	('transactivation', 'PosReg', (269, 284))	('activating mutations', 'Var', (199, 219))	('NF1', 'Gene', (128, 131))
67640	31689494	These studies showed that while the commonly mutated cutaneous melanoma driver genes, BRAF and NRAS, were also sometimes mutated in acral melanoma, mutation rates were much lower.	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('acral melanoma', 'Phenotype', 'HP:0012060', (132, 146))	('acral melanoma', 'Disease', (132, 146))	('mutated', 'Var', (121, 128))	('NRAS', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (86, 90))	('cutaneous melanoma', 'Disease', (53, 71))	('acral melanoma', 'Disease', 'MESH:D008545', (132, 146))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (53, 71))	('NRAS', 'Gene', '4893', (95, 99))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('BRAF', 'Gene', (86, 90))
67641	31689494	Mutated positions were similar to those observed in cutaneous: BRAF V600 and NRAS G12, G13, and Q61.	('G13', 'Var', (87, 90))	('NRAS', 'Gene', (77, 81))	('NRAS', 'Gene', '4893', (77, 81))	('Q61', 'Var', (96, 99))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))
67644	31689494	A recent genetic/transcriptomic study of 34 acral melanomas identified NRAS mutations in 12 % of the patients, compared to 15-20 % typically seen in cutaneous melanoma.	('patients', 'Species', '9606', (101, 109))	('acral melanomas', 'Disease', 'MESH:D008545', (44, 59))	('mutations', 'Var', (76, 85))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('cutaneous melanoma', 'Disease', (149, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('NRAS', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('acral melanoma', 'Phenotype', 'HP:0012060', (44, 58))	('NRAS', 'Gene', '4893', (71, 75))	('acral melanomas', 'Disease', (44, 59))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (149, 167))	('acral melanomas', 'Phenotype', 'HP:0012060', (44, 59))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
67646	31689494	The frequency of BRAF mutations in the same cohort was 18 % with 4 of these being V600E mutations, one G466E mutation and one V600 K mutation.	('V600E', 'Mutation', 'rs113488022', (82, 87))	('BRAF', 'Gene', '673', (17, 21))	('G466E', 'Var', (103, 108))	('G466E', 'Mutation', 'rs121913351', (103, 108))	('V600 K', 'Mutation', 'rs121913227', (126, 132))	('BRAF', 'Gene', (17, 21))	('V600E', 'Var', (82, 87))	('mutations', 'Var', (22, 31))
67647	31689494	Homozygous loss of NF1, was also identified in 9 % of acral melanoma samples.	('acral melanoma', 'Disease', 'MESH:D008545', (54, 68))	('NF1', 'Gene', (19, 22))	('acral melanoma', 'Disease', (54, 68))	('NF1', 'Gene', '4763', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('Homozygous loss', 'Var', (0, 15))
67648	31689494	Other rare mutations in genes that could also potentially activate the MAPK pathway were identified, including those in EGFR, KRAS, PREX2 and ERBB3.	('KRAS', 'Gene', '3845', (126, 130))	('mutations', 'Var', (11, 20))	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('PREX2', 'Gene', '80243', (132, 137))	('activate', 'PosReg', (58, 66))	('PREX2', 'Gene', (132, 137))	('ERBB3', 'Gene', '2065', (142, 147))	('MAPK', 'molecular_function', 'GO:0004707', ('71', '75'))	('ERBB3', 'Gene', (142, 147))	('MAPK pathway', 'Pathway', (71, 83))	('EGFR', 'Gene', '1956', (120, 124))	('KRAS', 'Gene', (126, 130))	('EGFR', 'Gene', (120, 124))
67649	31689494	The relatively high abundance of MAPK pathway activating mutations in acral melanoma was supported by immunohistochemical (IHC) studies that examined specific pathway mediators.	('acral melanoma', 'Phenotype', 'HP:0012060', (70, 84))	('MAPK', 'molecular_function', 'GO:0004707', ('33', '37'))	('MAPK pathway', 'Pathway', (33, 45))	('mutations', 'Var', (57, 66))	('acral melanoma', 'Disease', 'MESH:D008545', (70, 84))	('activating', 'PosReg', (46, 56))	('acral melanoma', 'Disease', (70, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
67650	31689494	In a recent acral melanoma sequencing study from Britain, BRAF and NRAS mutations were identified in 11 % and 12 % of the tested tumors respectively, and 25 % of tested acral melanoma samples were positive for phosphorylated ERK (pERK).	('ERK', 'Gene', '5594', (225, 228))	('tumors', 'Disease', (129, 135))	('acral melanoma', 'Disease', (169, 183))	('phosphorylated', 'MPA', (210, 224))	('NRAS', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('acral melanoma', 'Disease', 'MESH:D008545', (12, 26))	('mutations', 'Var', (72, 81))	('ERK', 'Gene', '5594', (231, 234))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('acral melanoma', 'Phenotype', 'HP:0012060', (12, 26))	('ERK', 'Gene', (225, 228))	('acral melanoma', 'Disease', 'MESH:D008545', (169, 183))	('ERK', 'molecular_function', 'GO:0004707', ('225', '228'))	('acral melanoma', 'Phenotype', 'HP:0012060', (169, 183))	('ERK', 'Gene', (231, 234))	('identified', 'Reg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NRAS', 'Gene', '4893', (67, 71))	('positive', 'Reg', (197, 205))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('acral melanoma', 'Disease', (12, 26))	('BRAF', 'Gene', '673', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('BRAF', 'Gene', (58, 62))
67651	31689494	Interestingly, these two mutations were mutually exclusive, and 67 % of samples with high expression levels of pERK had either BRAF or NRAS mutation.	('NRAS', 'Gene', (135, 139))	('BRAF', 'Gene', '673', (127, 131))	('ERK', 'Gene', '5594', (112, 115))	('expression levels', 'MPA', (90, 107))	('mutation', 'Var', (140, 148))	('NRAS', 'Gene', '4893', (135, 139))	('BRAF', 'Gene', (127, 131))	('ERK', 'Gene', (112, 115))
67652	31689494	A recent small-scale analysis of 17 primary acral melanomas from a Spanish cohort identified NRAS mutations in 17 % of samples, and no BRAF mutations.	('BRAF', 'Gene', '673', (135, 139))	('acral melanomas', 'Disease', 'MESH:D008545', (44, 59))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('BRAF', 'Gene', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('NRAS', 'Gene', '4893', (93, 97))	('mutations', 'Var', (98, 107))	('acral melanoma', 'Phenotype', 'HP:0012060', (44, 58))	('acral melanomas', 'Phenotype', 'HP:0012060', (44, 59))	('acral melanomas', 'Disease', (44, 59))	('NRAS', 'Gene', (93, 97))
67653	31689494	This work additionally identified copy number gains in other RAS-associated genes including CCND1, TERT, and NRAS, indicating that RAS pathway activation occurred in 87.5 % of samples.	('copy number gains', 'Var', (34, 51))	('TERT', 'Gene', (99, 103))	('NRAS', 'Gene', (109, 113))	('CCND1', 'Gene', (92, 97))	('TERT', 'Gene', '7015', (99, 103))	('NRAS', 'Gene', '4893', (109, 113))	('CCND1', 'Gene', '595', (92, 97))
67656	31689494	In this particular cohort, BRAF/NRAS mutations were less common, with one patient harboring an NRAS Q61R mutation and 3 samples harboring BRAF V600E mutations.	('patient', 'Species', '9606', (74, 81))	('NRAS', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (138, 142))	('NRAS', 'Gene', '4893', (32, 36))	('NRAS', 'Gene', (95, 99))	('V600E mutations', 'Var', (143, 158))	('BRAF', 'Gene', '673', (27, 31))	('Q61R', 'Var', (100, 104))	('V600E', 'Mutation', 'rs113488022', (143, 148))	('BRAF', 'Gene', (27, 31))	('Q61R', 'Mutation', 'rs11554290', (100, 104))	('BRAF', 'Gene', (138, 142))	('NRAS', 'Gene', '4893', (95, 99))
67657	31689494	Despite the low occurrence rate of these mutations, the MAPK pathway was found to be active (by pERK staining) in 79 % of the samples.	('mutations', 'Var', (41, 50))	('ERK', 'Gene', (97, 100))	('MAPK pathway', 'Pathway', (56, 68))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('ERK', 'Gene', '5594', (97, 100))
67660	31689494	In a Taiwanese study, 7 % of samples harbored mutations in the MEK1 gene, in addition to the presence of BRAF and NRAS mutations.	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (46, 55))	('NRAS', 'Gene', (114, 118))	('BRAF', 'Gene', (105, 109))	('MEK1', 'Gene', '5604', (63, 67))	('NRAS', 'Gene', '4893', (114, 118))	('MEK1', 'molecular_function', 'GO:0004708', ('63', '67'))	('MEK1', 'Gene', (63, 67))
67661	31689494	A study of 88 acral melanoma cases from Korea reported BRAF mutation rates to be 34 %, NRAS mutation rates to be 22 %, GNAQ to be 17 %, NF1 to be 17 % and KIT to be 11 %.	('acral melanoma', 'Phenotype', 'HP:0012060', (14, 28))	('mutation', 'Var', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('NRAS', 'Gene', '4893', (87, 91))	('KIT', 'molecular_function', 'GO:0005020', ('155', '158'))	('GNAQ', 'Gene', (119, 123))	('BRAF', 'Gene', (55, 59))	('acral melanoma', 'Disease', 'MESH:D008545', (14, 28))	('NF1', 'Gene', (136, 139))	('KIT', 'Gene', '3815', (155, 158))	('BRAF', 'Gene', '673', (55, 59))	('acral melanoma', 'Disease', (14, 28))	('NF1', 'Gene', '4763', (136, 139))	('GNAQ', 'Gene', '2776', (119, 123))	('NRAS', 'Gene', (87, 91))	('KIT', 'Gene', (155, 158))
67664	31689494	Across different studies, BRAF has been found to be mutated in ~20 % of acral tumors and NRAS in ~10 %.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('NRAS', 'Gene', '4893', (89, 93))	('BRAF', 'Gene', '673', (26, 30))	('mutated', 'Var', (52, 59))	('acral tumors', 'Disease', 'MESH:C536316', (72, 84))	('acral tumors', 'Disease', (72, 84))	('BRAF', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NRAS', 'Gene', (89, 93))
67667	31689494	Overall mutation rates are lower in acral melanomas than in sun-exposed cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (72, 91))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (72, 91))	('acral melanoma', 'Phenotype', 'HP:0012060', (36, 50))	('acral melanomas', 'Phenotype', 'HP:0012060', (36, 51))	('lower', 'NegReg', (27, 32))	('acral melanomas', 'Disease', (36, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('cutaneous melanomas', 'Disease', (72, 91))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('mutation', 'Var', (8, 16))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('acral melanomas', 'Disease', 'MESH:D008545', (36, 51))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
67672	31689494	Activation of AKT signaling is thought to be important during early melanoma development, where PTEN loss or silencing may allow nascent melanoma cells to escape oncogene-induced senescence following the acquisition of a BRAF mutation.	('BRAF', 'Gene', (221, 225))	('PTEN loss', 'Disease', 'MESH:D006223', (96, 105))	('AKT signaling', 'biological_process', 'GO:0043491', ('14', '27'))	('AKT', 'Gene', (14, 17))	('mutation', 'Var', (226, 234))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('PTEN loss', 'Disease', (96, 105))	('melanoma', 'Disease', (68, 76))	('silencing', 'NegReg', (109, 118))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('melanoma', 'Disease', (137, 145))	('escape', 'CPA', (155, 161))	('BRAF', 'Gene', '673', (221, 225))	('senescence', 'biological_process', 'GO:0010149', ('179', '189'))	('AKT', 'Gene', '207', (14, 17))
67675	31689494	Activating mutations in AKT and PIK3CA occur infrequently in cutaneous melanoma.	('PIK3CA', 'Gene', '5290', (32, 38))	('AKT', 'Gene', (24, 27))	('Activating mutations', 'Var', (0, 20))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('AKT', 'Gene', '207', (24, 27))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('cutaneous melanoma', 'Disease', (61, 79))	('PIK3CA', 'Gene', (32, 38))
67678	31689494	A mutational analysis of a cohort of Swedish patients with acral melanoma revealed a small subset of patients with mutations in PTEN.	('patients', 'Species', '9606', (101, 109))	('acral melanoma', 'Phenotype', 'HP:0012060', (59, 73))	('mutations', 'Var', (115, 124))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('acral melanoma', 'Disease', 'MESH:D008545', (59, 73))	('patients', 'Species', '9606', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('acral melanoma', 'Disease', (59, 73))
67681	31689494	An IHC analysis of acral melanoma revealed increased S727 phosphorylation of STAT3 in more invasive acral melanoma samples compared to less advanced in situ acral melanoma samples.	('acral melanoma', 'Disease', 'MESH:D008545', (157, 171))	('acral melanoma', 'Disease', 'MESH:D008545', (100, 114))	('acral melanoma', 'Phenotype', 'HP:0012060', (157, 171))	('acral melanoma', 'Disease', 'MESH:D008545', (19, 33))	('S727', 'Var', (53, 57))	('acral melanoma', 'Phenotype', 'HP:0012060', (100, 114))	('acral melanoma', 'Phenotype', 'HP:0012060', (19, 33))	('increased', 'PosReg', (43, 52))	('STAT3', 'Gene', (77, 82))	('invasive acral melanoma', 'Disease', (91, 114))	('STAT3', 'Gene', '6774', (77, 82))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('acral melanoma', 'Disease', (19, 33))	('situ acral melanoma', 'Disease', 'MESH:D002278', (152, 171))	('situ acral melanoma', 'Disease', (152, 171))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('invasive acral melanoma', 'Disease', 'MESH:D008545', (91, 114))
67682	31689494	The evidence to date suggests that although acral melanomas have fewer UV-signature mutations and different mutational profiles, they may rely upon similar signaling pathways as cutaneous melanomas.	('cutaneous melanomas', 'Disease', 'MESH:C562393', (178, 197))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (178, 196))	('acral melanomas', 'Disease', 'MESH:D008545', (44, 59))	('cutaneous melanomas', 'Disease', (178, 197))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('UV-signature', 'Gene', (71, 83))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('rely', 'Reg', (138, 142))	('mutations', 'Var', (84, 93))	('acral melanoma', 'Phenotype', 'HP:0012060', (44, 58))	('acral melanomas', 'Phenotype', 'HP:0012060', (44, 59))	('acral melanomas', 'Disease', (44, 59))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('fewer', 'NegReg', (65, 70))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (178, 197))
67684	31689494	In addition to point mutations and small insertions, large chromosomal rearrangements and copy number variations also drive melanoma formation and progression.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('large chromosomal rearrangements', 'Var', (53, 85))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('progression', 'CPA', (147, 158))	('copy number variations', 'Var', (90, 112))	('drive', 'Reg', (118, 123))
67685	31689494	Early studies, using array comparative genomic hybridization, looked at the patterns of DNA copy number aberration across 102 primary melanomas (including those associated with chronic sun damage, as well as 28 acral melanomas).	('copy number aberration', 'Var', (92, 114))	('acral melanomas', 'Disease', 'MESH:D008545', (211, 226))	('melanomas', 'Disease', (134, 143))	('acral melanoma', 'Phenotype', 'HP:0012060', (211, 225))	('acral melanomas', 'Phenotype', 'HP:0012060', (211, 226))	('acral melanomas', 'Disease', (211, 226))	('melanomas', 'Disease', (217, 226))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('melanomas', 'Disease', 'MESH:D008545', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanomas', 'Phenotype', 'HP:0002861', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('DNA', 'Gene', (88, 91))	('sun damage', 'Phenotype', 'HP:0000992', (185, 195))	('melanomas', 'Disease', 'MESH:D008545', (217, 226))	('melanomas', 'Phenotype', 'HP:0002861', (217, 226))
67687	31689494	Subsequent investigation revealed that oncogenic KIT mutations were found in 3 out of 7 samples with genomic amplification and that 36 % of acral melanoma samples had either mutations or copy number gains in KIT.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('KIT', 'Gene', '3815', (208, 211))	('acral melanoma', 'Disease', 'MESH:D008545', (140, 154))	('KIT', 'Gene', (208, 211))	('mutations', 'Var', (53, 62))	('found', 'Reg', (68, 73))	('acral melanoma', 'Disease', (140, 154))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('acral melanoma', 'Phenotype', 'HP:0012060', (140, 154))	('KIT', 'Gene', '3815', (49, 52))	('copy number gains', 'Var', (187, 204))	('mutations', 'Var', (174, 183))	('KIT', 'molecular_function', 'GO:0005020', ('208', '211'))	('KIT', 'Gene', (49, 52))
67689	31689494	A number of other common copy number alterations have been identified in acral melanomas.	('acral melanoma', 'Phenotype', 'HP:0012060', (73, 87))	('identified', 'Reg', (59, 69))	('acral melanomas', 'Phenotype', 'HP:0012060', (73, 88))	('acral melanomas', 'Disease', (73, 88))	('copy number alterations', 'Var', (25, 48))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('acral melanomas', 'Disease', 'MESH:D008545', (73, 88))
67691	31689494	Interestingly, these common copy number changes in cell cycle genes were seen more often in acral tumors lacking BRAF or NRAS mutations.	('acral tumors lacking BRAF', 'Disease', 'MESH:D001259', (92, 117))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NRAS', 'Gene', '4893', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cell cycle', 'biological_process', 'GO:0007049', ('51', '61'))	('acral tumors lacking BRAF', 'Disease', (92, 117))	('cell cycle genes', 'Gene', (51, 67))	('NRAS', 'Gene', (121, 125))	('copy number changes', 'Var', (28, 47))
67699	31689494	Overall, acral melanomas exhibit a higher frequency of copy number alterations covering a higher proportion of the genome compared to cutaneous melanomas.	('acral melanoma', 'Phenotype', 'HP:0012060', (9, 23))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('acral melanomas', 'Phenotype', 'HP:0012060', (9, 24))	('acral melanomas', 'Disease', (9, 24))	('copy number alterations', 'Var', (55, 78))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('cutaneous melanomas', 'Disease', (134, 153))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (134, 153))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (134, 153))	('acral melanomas', 'Disease', 'MESH:D008545', (9, 24))
67700	31689494	Whole genome studies have identified several breakage-fusion-bridge events and chromothripsis, a phenomenon that up to thousands of clusters of chromosomal rearrangement occur in a single event in confined genomics region.	('chromothripsis', 'Disease', 'MESH:D000072837', (79, 93))	('chromothripsis', 'Disease', (79, 93))	('breakage-fusion-bridge', 'Var', (45, 67))
67717	31689494	There is however some suggestion that the likelihood of immunotherapy response is linked to tumor neoantigen load, and that increased mutational burden may be predictive of response.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutational burden', 'Var', (134, 151))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('linked', 'Reg', (82, 88))
67723	31689494	It was found that a higher density of CD3 + TIL was associated with male gender, thinner Breslow thickness, negative lymph node, earlier disease stage, and p16 nuclear protein expression (> 10 % stained by IHC).	('CD3 +', 'Var', (38, 43))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('p16', 'Gene', '1029', (156, 159))	('p16', 'Gene', (156, 159))
67759	31689494	The discovery of activating BRAF mutations in the majority of cutaneous melanomas led to the development of BRAF-specific inhibitors, including vemurafenib, dabrafenib and encorafenib.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (62, 81))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (62, 81))	('BRAF', 'Gene', '673', (28, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('activating', 'PosReg', (17, 27))	('cutaneous melanomas', 'Disease', (62, 81))	('mutations', 'Var', (33, 42))	('encorafenib', 'Chemical', 'MESH:C000601108', (172, 183))	('dabrafenib', 'Chemical', 'MESH:C561627', (157, 167))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (28, 32))	('vemurafenib', 'Chemical', 'MESH:D000077484', (144, 155))	('BRAF', 'Gene', (108, 112))
67760	31689494	In preclinical models, inhibition of BRAF led to growth arrest, apoptosis induction, and the regression of melanoma xenografts.	('apoptosis induction', 'CPA', (64, 83))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('BRAF', 'Gene', '673', (37, 41))	('inhibition', 'Var', (23, 33))	('growth arrest', 'Phenotype', 'HP:0001510', (49, 62))	('BRAF', 'Gene', (37, 41))	('arrest', 'Disease', (56, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('64', '73'))	('regression', 'CPA', (93, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('64', '73'))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
67767	31689494	The observation that acral melanomas frequently harbor mutations and amplifications in the CDK4/CCND1 axis has suggested the possibility of using CDK4/6 inhibitors, which are already FDA-approved for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in women who no longer benefit from endocrine therapy.	('hormone receptor', 'Gene', (217, 233))	('CDK', 'molecular_function', 'GO:0004693', ('91', '94'))	('acral melanoma', 'Phenotype', 'HP:0012060', (21, 35))	('CDK4/6', 'Gene', '1019;1021', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('CDK4', 'Gene', (146, 150))	('CCND1', 'Gene', '595', (96, 101))	('CDK4', 'Gene', (91, 95))	('CCND1', 'Gene', (96, 101))	('HER2', 'Gene', '2064', (244, 248))	('CDK4', 'Gene', '1019', (146, 150))	('mutations', 'Var', (55, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('hormone receptor', 'Gene', '3164', (217, 233))	('acral melanomas', 'Disease', 'MESH:D008545', (21, 36))	('CDK4', 'Gene', '1019', (91, 95))	('amplifications', 'Var', (69, 83))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('acral melanomas', 'Phenotype', 'HP:0012060', (21, 36))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))	('CDK4/6', 'Gene', (146, 152))	('breast cancer', 'Disease', (281, 294))	('women', 'Species', '9606', (298, 303))	('CDK', 'molecular_function', 'GO:0004693', ('146', '149'))	('HER2', 'Gene', (244, 248))	('acral melanomas', 'Disease', (21, 36))
67768	31689494	A recent phase II trial applied palbociclib, a CDK4/6 inhibitor, in advanced acral melanoma patients with CDK pathway gene aberration (CDK4 or/and CCND1 amplification or/and CDKN2A loss).	('CCND1', 'Gene', '595', (147, 152))	('CDK', 'molecular_function', 'GO:0004693', ('106', '109'))	('acral melanoma', 'Phenotype', 'HP:0012060', (77, 91))	('CDK4', 'Gene', '1019', (135, 139))	('CDK4/6', 'Gene', (47, 53))	('CDK4', 'Gene', '1019', (47, 51))	('CCND1', 'Gene', (147, 152))	('CDK', 'molecular_function', 'GO:0004693', ('135', '138'))	('patients', 'Species', '9606', (92, 100))	('CDK4/6', 'Gene', '1019;1021', (47, 53))	('CDK', 'molecular_function', 'GO:0004693', ('47', '50'))	('amplification', 'Var', (153, 166))	('CDKN2A', 'Gene', (174, 180))	('acral melanoma', 'Disease', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('CDK pathway', 'Gene', (106, 117))	('CDK4', 'Gene', (135, 139))	('CDK4', 'Gene', (47, 51))	('CDKN2A', 'Gene', '1029', (174, 180))	('loss', 'NegReg', (181, 185))	('acral melanoma', 'Disease', 'MESH:D008545', (77, 91))
67771	31689494	The enrichment of KIT mutations in acral melanoma relative to other subtypes led to several clinical trials of targeted inhibition of this molecular.	('acral melanoma', 'Disease', (35, 49))	('KIT', 'Gene', (18, 21))	('acral melanoma', 'Disease', 'MESH:D008545', (35, 49))	('mutations', 'Var', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('acral melanoma', 'Phenotype', 'HP:0012060', (35, 49))	('KIT', 'Gene', '3815', (18, 21))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))
67774	31689494	Imatinib has been shown to induce apoptosis in melanoma cells with activating KIT mutations, and small molecular inhibitors like imatinib, nilotinib, and dasatinib that inhibit KIT and other tyrosine kinases, have been tested in trials of KIT-mutant or KIT-amplified melanoma.	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('KIT', 'Gene', '3815', (239, 242))	('induce', 'PosReg', (27, 33))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('KIT', 'molecular_function', 'GO:0005020', ('177', '180'))	('KIT', 'molecular_function', 'GO:0005020', ('239', '242'))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('KIT', 'Gene', '3815', (253, 256))	('KIT', 'Gene', (177, 180))	('KIT', 'Gene', '3815', (78, 81))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('nilotinib', 'Chemical', 'MESH:C498826', (139, 148))	('KIT', 'molecular_function', 'GO:0005020', ('78', '81'))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('imatinib', 'Chemical', 'MESH:D000068877', (129, 137))	('apoptosis', 'CPA', (34, 43))	('KIT', 'Gene', (239, 242))	('activating', 'PosReg', (67, 77))	('KIT', 'Gene', '3815', (177, 180))	('dasatinib', 'Chemical', 'MESH:D000069439', (154, 163))	('KIT', 'molecular_function', 'GO:0005020', ('253', '256'))	('mutations', 'Var', (82, 91))	('KIT', 'Gene', (253, 256))	('KIT', 'Gene', (78, 81))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))
67777	31689494	Ten of the 11 responding patients had exon 11 mutations, four of which with an L576 P mutation.	('L576 P', 'Var', (79, 85))	('L576 P', 'Mutation', 'rs121913513', (79, 85))	('exon', 'Var', (38, 42))	('patients', 'Species', '9606', (25, 33))
67784	31689494	Although there are some signs from clinical studies that BRAF and MEK-inhibitors may be effective in acral melanoma, the majority of acral melanomas lack BRAF mutations and are not good candidates for that specific type of targeted therapy.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('acral melanoma', 'Disease', 'MESH:D008545', (133, 147))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('BRAF', 'Gene', '673', (57, 61))	('acral melanoma', 'Phenotype', 'HP:0012060', (101, 115))	('acral melanomas lack BRAF', 'Disease', (133, 158))	('mutations', 'Var', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('acral melanoma', 'Disease', (101, 115))	('MEK', 'Gene', (66, 69))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', '673', (154, 158))	('MEK', 'Gene', '5609', (66, 69))	('acral melanoma', 'Phenotype', 'HP:0012060', (133, 147))	('acral melanomas lack BRAF', 'Disease', 'MESH:D008545', (133, 158))	('BRAF', 'Gene', (154, 158))	('acral melanomas', 'Phenotype', 'HP:0012060', (133, 148))	('acral melanoma', 'Disease', 'MESH:D008545', (101, 115))
67785	31689494	Mutations in KIT are also found in only a minority of acral melanomas, and clinical results so far have been modest.	('acral melanomas', 'Disease', 'MESH:D008545', (54, 69))	('KIT', 'molecular_function', 'GO:0005020', ('13', '16'))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('acral melanoma', 'Phenotype', 'HP:0012060', (54, 68))	('acral melanomas', 'Disease', (54, 69))	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))	('KIT', 'Gene', '3815', (13, 16))	('acral melanomas', 'Phenotype', 'HP:0012060', (54, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('KIT', 'Gene', (13, 16))
67789	31689494	These differences may be a consequence of the lower mutational frequency and therefore a lower neoantigen burden present in acral melanoma.	('acral melanoma', 'Disease', (124, 138))	('lower', 'NegReg', (89, 94))	('acral melanoma', 'Phenotype', 'HP:0012060', (124, 138))	('mutational', 'Var', (52, 62))	('neoantigen burden', 'MPA', (95, 112))	('lower', 'NegReg', (46, 51))	('acral melanoma', 'Disease', 'MESH:D008545', (124, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))
67796	31689494	Unfortunately, these models are driven by the most common mutations found in cutaneous melanoma.	('mutations', 'Var', (58, 67))	('cutaneous melanoma', 'Disease', (77, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
67819	28114321	That is, they showed that the deregulation of the LEDA, FZD6, and ENPP2 genes predicts metastatic death (p-value < 10-4).	('metastatic death', 'CPA', (87, 103))	('LEDA', 'Gene', (50, 54))	('ENPP2', 'Gene', '5168', (66, 71))	('FZD6', 'Gene', '8323', (56, 60))	('predicts', 'Reg', (78, 86))	('FZD6', 'Gene', (56, 60))	('ENPP2', 'Gene', (66, 71))	('deregulation', 'Var', (30, 42))
67867	28114321	In general, defects in interferon signaling results in dysfunction of the immune system.	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('defects', 'Var', (12, 19))	('interferon', 'Gene', '3439', (23, 33))	('dysfunction', 'MPA', (55, 66))	('results in', 'Reg', (44, 54))	('interferon', 'Gene', (23, 33))
67884	28114321	One reason underlying the difficulty in assessing the survival rate of melanoma is the relatively high heterogeneity of genetic mutations, which results in subpopulations (clones) that are resistant to therapy.	('mutations', 'Var', (128, 137))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('results in', 'Reg', (145, 155))
67888	28114321	Future work in this direction can leverage available techniques for 1) clonal decomposition based on genetic mutations, and 2) deconvolution of gene expression profiles into signatures that are specific to a cell-type or tumor clone.	('gene expression', 'biological_process', 'GO:0010467', ('144', '159'))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
67895	31591149	Analysis of The Cancer Genome Atlas (TCGA) cutaneous melanoma dataset showed that high GILT mRNA expression was associated with improved overall survival.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('improved', 'PosReg', (128, 136))	('mRNA', 'Protein', (92, 96))	('overall survival', 'MPA', (137, 153))	('cutaneous melanoma', 'Disease', (43, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (43, 61))	('high GILT', 'Var', (82, 91))
67905	31591149	CD8 T cell killing of MHC class I-expressing tumor cells is a highly effective mechanism of tumor destruction, and as such, loss of MHC class I or components of the MHC class I pathway in tumor cells are mechanisms of immune evasion and resistance to immune checkpoint blockade.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('CD8', 'Gene', '925', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cell killing', 'biological_process', 'GO:0001906', ('6', '18'))	('loss', 'Var', (124, 128))	('MHC', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('MHC', 'Gene', (165, 168))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MHC', 'Gene', (132, 135))	('CD8', 'Gene', (0, 3))	('MHC', 'Gene', '3107', (22, 25))	('immune evasion', 'biological_process', 'GO:0042783', ('218', '232'))	('immune evasion', 'biological_process', 'GO:0051842', ('218', '232'))	('MHC', 'Gene', '3107', (165, 168))	('MHC', 'Gene', '3107', (132, 135))	('tumor', 'Disease', (92, 97))	('immune evasion', 'MPA', (218, 232))
67922	31591149	Subsequently, high GILT expression was found to be associated with improved survival in breast cancer.	('survival', 'MPA', (76, 84))	('high', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('improved', 'PosReg', (67, 75))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
67927	31591149	Tumor subtype classifications - mutant Braf (146 samples), mutant NF1 (27 samples), mutant Ras (91 samples) and Triple wild-type (44 samples) were obtained from.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutant', 'Var', (59, 65))	('Braf', 'Gene', (39, 43))	('mutant', 'Var', (84, 90))	('Braf', 'Gene', '673', (39, 43))	('mutant', 'Var', (32, 38))	('NF1', 'Gene', (66, 69))	('NF1', 'Gene', '4763', (66, 69))
67929	31591149	These samples were similarly sub-classified as mutant BRAF (6 samples), mutant NF1 (5 samples), mutant RAS (6 samples) and triple wild-type (19 samples).	('BRAF', 'Gene', (54, 58))	('mutant', 'Var', (72, 78))	('BRAF', 'Gene', '673', (54, 58))	('NF1', 'Gene', (79, 82))	('mutant', 'Var', (47, 53))	('NF1', 'Gene', '4763', (79, 82))
67952	31591149	Melanoma cell lines and HEK293T cells were verified by short tandem repeat analysis by the University of Arizona Genetics Core prior to and at the conclusion of experiments.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('short tandem repeat analysis', 'Var', (55, 83))	('HEK293T', 'CellLine', 'CVCL:0063', (24, 31))
67984	31591149	There was a similar trend of improved survival with high GILT expression in the Braf mutant subtype, the most common subtype of melanoma, although this association was not significant after adjusting for multiple comparisons [Supplemental Fig.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('Braf', 'Gene', (80, 84))	('Braf', 'Gene', '673', (80, 84))	('high GILT expression', 'Var', (52, 72))	('improved', 'PosReg', (29, 37))	('mutant', 'Var', (85, 91))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
67987	31591149	Together these data support an association of high GILT expression with improved overall survival in melanoma.	('high', 'Var', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('improved', 'PosReg', (72, 80))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('overall survival', 'MPA', (81, 97))
68023	31591149	We also found that GILT and MHC class II staining were increased in APCs of halo nevi compared to nevi and that GILT expression was increased in keratinocytes of halo nevi compared to nevi (Supplemental Fig.	('halo', 'cellular_component', 'GO:1990038', ('76', '80'))	('MHC', 'Gene', (28, 31))	('APC', 'Gene', (68, 71))	('APC', 'Gene', '324', (68, 71))	('MHC', 'Gene', '3107', (28, 31))	('expression', 'MPA', (117, 127))	('increased', 'PosReg', (55, 64))	('nevi', 'Phenotype', 'HP:0003764', (184, 188))	('increased', 'PosReg', (132, 141))	('GILT', 'Gene', (112, 116))	('nevi', 'Phenotype', 'HP:0003764', (167, 171))	('nevi', 'Phenotype', 'HP:0003764', (98, 102))	('rat', 'Species', '10116', (147, 150))	('GILT', 'CPA', (19, 23))	('halo', 'cellular_component', 'GO:1990038', ('162', '166'))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('halo nevi', 'Var', (162, 171))
68026	31591149	We have focused on the expression of GILT and MHC class II in melanocytes in impacting clinical outcome, given the variation of GILT expression in melanocytes in melanoma specimens in contrast to uniform expression of GILT in APCs in melanoma specimens.	('clinical outcome', 'MPA', (87, 103))	('GILT', 'Gene', (128, 132))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('impacting', 'Reg', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('APC', 'Gene', (226, 229))	('MHC', 'Gene', (46, 49))	('MHC', 'Gene', '3107', (46, 49))	('variation', 'Var', (115, 124))	('APC', 'Gene', '324', (226, 229))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))
68034	31591149	High activity and consistency scores in the antigen processing and presentation, MHC class II, and interferon gamma signaling pathways were each associated with improved overall survival in melanoma with each logrank showing adj p value < 0.01 (Fig.	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('44', '79'))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('High', 'Var', (0, 4))	('melanoma', 'Disease', (190, 198))	('overall survival', 'MPA', (170, 186))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('interferon gamma', 'molecular_function', 'GO:0005133', ('99', '115'))	('MHC', 'Gene', (81, 84))	('interferon gamma', 'Gene', '3458', (99, 115))	('improved', 'PosReg', (161, 169))	('MHC', 'Gene', '3107', (81, 84))	('antigen', 'Protein', (44, 51))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('interferon gamma', 'Gene', (99, 115))
68048	31591149	We demonstrate an association of high GILT expression with improved overall survival in melanoma.	('high', 'Var', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('improved', 'PosReg', (59, 67))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('GILT', 'Protein', (38, 42))	('overall survival', 'MPA', (68, 84))	('rat', 'Species', '10116', (10, 13))
68053	31591149	GILT expression as a biomarker of improved cancer survival is further supported by a similar association of high GILT expression in diffuse large B cell lymphoma and breast cancer with improved survival.	('improved', 'PosReg', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('improved', 'PosReg', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('lymphoma and breast cancer', 'Disease', 'MESH:D001943', (153, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (43, 49))	('GILT', 'Gene', (113, 117))	('large B cell', 'Phenotype', 'HP:0005404', (140, 152))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('high', 'Var', (108, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (146, 161))
68054	31591149	We anticipate that level of GILT expression in melanoma cells is primarily determined by the cytokines and immune cells in the tumor microenvironment, as only a minority of specimens (3 in the TCGA cutaneous melanoma and 1 in the acral melanoma datasets) were found to have non-synonymous mutations in GILT corresponding with low GILT expression.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('cutaneous melanoma', 'Disease', (198, 216))	('acral melanoma', 'Disease', (230, 244))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (198, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('GILT', 'Gene', (302, 306))	('low', 'NegReg', (326, 329))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('non-synonymous mutations', 'Var', (274, 298))	('GILT expression', 'MPA', (330, 345))	('acral melanoma', 'Disease', 'MESH:D008545', (230, 244))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('acral melanoma', 'Phenotype', 'HP:0012060', (230, 244))	('melanoma', 'Disease', (236, 244))	('tumor', 'Disease', (127, 132))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
68055	31591149	We propose three, non-mutually exclusive, models to explain the association of high GILT expression and an active and intact MHC class II pathway with improved survival in melanoma.	('improved', 'PosReg', (151, 159))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('MHC', 'Gene', (125, 128))	('survival', 'MPA', (160, 168))	('GILT', 'Protein', (84, 88))	('MHC', 'Gene', '3107', (125, 128))	('high', 'Var', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
68062	31591149	This hypothesis is supported by the variation in GILT and MHC class II protein expression in melanoma cells in tumor specimens, the induction of GILT expression along with MHC class II in melanoma cells, and the variation in MHC class II pathway activity and consistency scores being associated with survival (Fig.	('GILT', 'Gene', (49, 53))	('MHC', 'Gene', '3107', (58, 61))	('variation', 'Var', (212, 221))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('GILT', 'Gene', (145, 149))	('protein', 'Protein', (71, 78))	('MHC', 'Gene', '3107', (225, 228))	('activity', 'MPA', (246, 254))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('associated', 'Reg', (284, 294))	('MHC', 'Gene', (172, 175))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('tumor', 'Disease', (111, 116))	('MHC', 'Gene', (58, 61))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('MHC', 'Gene', '3107', (172, 175))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('MHC', 'Gene', (225, 228))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))
68067	31591149	While MHC class II expression on melanoma cells is anticipated to result in an improved anti-tumor immune response and improved prognosis, some earlier studies paradoxically identified that MHC class II expression on melanoma cells was associated with poor prognosis.	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('MHC', 'Gene', '3107', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('improved', 'PosReg', (79, 87))	('MHC', 'Gene', (190, 193))	('melanoma', 'Disease', (33, 41))	('expression', 'Var', (19, 29))	('tumor', 'Disease', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('immune response', 'biological_process', 'GO:0006955', ('99', '114'))	('MHC', 'Gene', '3107', (190, 193))	('MHC', 'Gene', (6, 9))	('melanoma', 'Disease', (217, 225))
68068	31591149	This inconsistency could be explained by dysfunction of the MHC class II pathway, despite expression of MHC class II itself.	('dysfunction', 'Var', (41, 52))	('MHC', 'Gene', '3107', (104, 107))	('MHC', 'Gene', (60, 63))	('MHC', 'Gene', '3107', (60, 63))	('MHC', 'Gene', (104, 107))
68085	31591149	Variation in the MHC class II pathway consistency scores, that is associated with survival, argues for further investigation to demonstrate a causal role for GILT and the MHC class II pathway in melanoma survival.	('MHC', 'Gene', '3107', (17, 20))	('melanoma', 'Disease', (195, 203))	('rat', 'Species', '10116', (135, 138))	('MHC', 'Gene', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('MHC', 'Gene', (171, 174))	('Variation', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('MHC', 'Gene', '3107', (171, 174))
68102	31591149	A375 melanoma cells have high levels of constitutive ERK1/2 phosphorylation, likely due to an activating BRAF mutation.	('phosphorylation', 'MPA', (60, 75))	('BRAF', 'Gene', '673', (105, 109))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('BRAF', 'Gene', (105, 109))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('ERK1/2', 'Gene', (53, 59))	('constitutive', 'MPA', (40, 52))	('mutation', 'Var', (110, 118))	('activating', 'PosReg', (94, 104))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('ERK1', 'molecular_function', 'GO:0004707', ('53', '57'))
68114	29235570	TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma.	('TP53', 'Gene', '7157', (0, 4))	('cutaneous melanoma', 'Disease', (27, 45))	('TP53', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 141))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('p53', 'Gene', (80, 83))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('p53', 'Gene', '7157', (80, 83))	('cutaneous melanoma', 'Disease', (123, 141))
68116	29235570	A panel of three p53WT (A375, WM35 and C8161) and three p53MUT (WM164, WM35-R and CHL-1) melanoma cell lines were used.	('C8161', 'Var', (39, 44))	('p53', 'Gene', (56, 59))	('CHL-1) melanoma', 'Disease', 'MESH:D006689', (82, 97))	('A375', 'CellLine', 'CVCL:0132', (24, 28))	('WM164', 'Var', (64, 69))	('p53', 'Gene', '7157', (56, 59))	('A375', 'Var', (24, 28))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
68118	29235570	GSK2830371, at doses (<=10 muM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner.	('p53', 'Gene', (299, 302))	('p53', 'Gene', '7157', (299, 302))	('muM', 'Gene', '56925', (27, 30))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('potentiated', 'PosReg', (130, 141))	('p53', 'Gene', (236, 239))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('muM', 'Gene', (27, 30))	('cell killing', 'biological_process', 'GO:0001906', ('179', '191'))	('p53', 'Gene', '7157', (236, 239))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GSK2830371', 'Var', (0, 10))	('MDM2', 'Gene', (203, 207))	('p53', 'Gene', '7157', (222, 225))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('p53', 'Gene', (222, 225))	('inhibitors', 'Var', (208, 218))
68119	29235570	The siRNA-mediated knockdown of p53 provided further evidence to support the p53 dependence.	('knockdown', 'Var', (19, 28))	('p53', 'Gene', (32, 35))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('p53', 'Gene', '7157', (32, 35))
68120	29235570	GSK2830371 increased p53 stabilisation through Ser15 phosphorylation and consequent Lys382 acetylation, and decreased ubiquitination and proteasome-dependent degradation when it was combined with MDM2 inhibitors.	('proteasome', 'cellular_component', 'GO:0000502', ('137', '147'))	('Ser15', 'Chemical', '-', (47, 52))	('degradation', 'biological_process', 'GO:0009056', ('158', '169'))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('stabilisation', 'MPA', (25, 38))	('p53', 'Gene', '7157', (21, 24))	('proteasome-dependent degradation', 'MPA', (137, 169))	('increased', 'PosReg', (11, 20))	('Lys382 acetylation', 'MPA', (84, 102))	('Ser15 phosphorylation', 'MPA', (47, 68))	('GSK2830371', 'Var', (0, 10))	('ubiquitination', 'MPA', (118, 132))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('p53', 'Gene', (21, 24))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('Lys382', 'Chemical', '-', (84, 90))	('proteasome', 'molecular_function', 'GO:0004299', ('137', '147'))	('decreased', 'NegReg', (108, 117))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))
68122	29235570	GSK2830371 enhanced the induction of p53 transcriptional target genes, cell cycle arrest and apoptosis.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('induction', 'MPA', (24, 33))	('enhanced', 'PosReg', (11, 19))	('apoptosis', 'CPA', (93, 102))	('GSK2830371', 'Var', (0, 10))	('p53', 'Gene', (37, 40))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('p53', 'Gene', '7157', (37, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (71, 88))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('71', '88'))	('cell cycle arrest', 'CPA', (71, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))
68123	29235570	GSK2830371, a WIP1 inhibitor, at doses with no growth-inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('increasing', 'PosReg', (160, 170))	('inhibitors', 'Var', (146, 156))	('phosphorylation', 'biological_process', 'GO:0016310', ('171', '186'))	('p53', 'Gene', '7157', (269, 272))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('acetylation', 'MPA', (188, 199))	('potentiated', 'PosReg', (81, 92))	('p53', 'Gene', '7157', (221, 224))	('cutaneous melanoma', 'Disease', (228, 246))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (228, 246))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (228, 246))	('growth-inhibitory', 'MPA', (97, 114))	('p53', 'Gene', (269, 272))	('p53', 'Gene', (221, 224))	('GSK2830371', 'Var', (0, 10))	('cytotoxic activity', 'CPA', (119, 137))	('WIP1', 'Gene', '8493', (14, 18))	('stabilisation', 'MPA', (204, 217))	('WIP1', 'Gene', (14, 18))	('phosphorylation', 'MPA', (171, 186))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('MDM2', 'Gene', (141, 145))
68130	29235570	Mutation of TP53 results in loss of wild-type (WT) p53 tumour suppressor function and can also have dominant oncogenic functions (gain-of-function mutations) that are entirely independent of WT p53, causing cancer cell development, survival and proliferation.	('tumour', 'Disease', (55, 61))	('p53', 'Gene', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('p53', 'Gene', '7157', (51, 54))	('survival', 'CPA', (232, 240))	('cancer', 'Disease', (207, 213))	('Mutation', 'Var', (0, 8))	('TP53', 'Gene', '7157', (12, 16))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('proliferation', 'CPA', (245, 258))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', (12, 16))	('causing', 'PosReg', (199, 206))	('cell development', 'biological_process', 'GO:0048468', ('214', '230'))	('loss', 'NegReg', (28, 32))
68131	29235570	However, melanomas have p53 mutations only in a minority of cases (~20%).	('p53', 'Gene', '7157', (24, 27))	('p53', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanomas', 'Phenotype', 'HP:0002861', (9, 18))	('melanomas', 'Disease', 'MESH:D008545', (9, 18))	('melanomas', 'Disease', (9, 18))	('mutations', 'Var', (28, 37))
68132	29235570	Furthermore, p53 mutations and loss of CKDN2A appear to be mutually exclusive, possibly reflecting p53 dependence.	('loss', 'NegReg', (31, 35))	('CKDN2A', 'Gene', (39, 45))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('mutations', 'Var', (17, 26))	('p53', 'Gene', '7157', (13, 16))
68133	29235570	Therefore, a therapeutic strategy to rescue and reactivate p53 function can be envisioned in melanomas that retain WT p53.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('p53', 'Gene', (59, 62))	('reactivate', 'Var', (48, 58))	('p53', 'Gene', '7157', (59, 62))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('p53', 'Gene', (118, 121))	('p53', 'Gene', '7157', (118, 121))	('melanomas', 'Disease', (93, 102))
68137	29235570	The RG7388 (Idasanutlin), an orally available second-generation MDM2-p53 binding antagonist, efficiently suppressed tumour growth in vivo; clinical trials of RG7388 are currently ongoing to investigate the clinical efficacy of MDM2 inhibitors in relapsed multiple myeloma (NCT02633059), relapsed or refractory acute myeloid leukaemia (NCT02670044, NCT02545283) and relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma (NCT02624986).	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('follicular lymphoma', 'Disease', 'MESH:D008224', (388, 407))	('multiple myeloma', 'Disease', (255, 271))	('tumour', 'Disease', (116, 122))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (316, 333))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (425, 440))	('follicular lymphoma', 'Disease', (388, 407))	('lymphoma', 'Phenotype', 'HP:0002665', (399, 407))	('p53 binding', 'molecular_function', 'GO:0002039', ('69', '80'))	('myeloid leukaemia', 'Disease', (316, 333))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (310, 333))	('multiple myeloma', 'Phenotype', 'HP:0006775', (255, 271))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (425, 440))	('p53', 'Gene', '7157', (69, 72))	('NCT02633059', 'Var', (273, 284))	('NCT02670044', 'Var', (335, 346))	('myeloid leukaemia', 'Disease', 'MESH:D007938', (316, 333))	('multiple myeloma', 'Disease', 'MESH:D009101', (255, 271))	('p53', 'Gene', (69, 72))	('B-cell lymphoma', 'Disease', (425, 440))	('lymphoma', 'Phenotype', 'HP:0002665', (432, 440))	('NCT02624986', 'Var', (442, 453))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
68140	29235570	GSK2830371 allosterically inhibits the enzymatic activity of WIP1 protein and also enhances ubiquitin-mediated degradation of WIP1.	('inhibits', 'NegReg', (26, 34))	('WIP1', 'Gene', (61, 65))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('WIP1', 'Gene', (126, 130))	('ubiquitin-mediated degradation', 'MPA', (92, 122))	('ubiquitin', 'molecular_function', 'GO:0031386', ('92', '101'))	('WIP1', 'Gene', '8493', (61, 65))	('WIP1', 'Gene', '8493', (126, 130))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('enzymatic activity', 'MPA', (39, 57))	('GSK2830371', 'Var', (0, 10))	('enhances', 'PosReg', (83, 91))	('degradation', 'biological_process', 'GO:0009056', ('111', '122'))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
68141	29235570	Preclinical studies have shown that GSK2830371 can enhance p53-mediated tumour suppression by MDM2 inhibitors, nutlin-3, nutlin-3a and RG7388 or by chemotherapy.	('MDM2', 'Gene', (94, 98))	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('inhibitors', 'NegReg', (99, 109))	('GSK2830371', 'Chemical', 'MESH:C587624', (36, 46))	('nutlin-3', 'Chemical', 'MESH:C482205', (111, 119))	('GSK2830371', 'Var', (36, 46))	('GSK', 'molecular_function', 'GO:0050321', ('36', '39'))	('enhance', 'PosReg', (51, 58))	('nutlin-3', 'Chemical', 'MESH:C482205', (121, 129))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
68147	29235570	Melanoma cells were seeded in 96-well plates 24 h before 72 h of treatment with nutlin-3 RG7388, HDM201, GSK2830371 or combinations.	('GSK2830371', 'Chemical', 'MESH:C587624', (105, 115))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('GSK2830371', 'Var', (105, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('GSK', 'molecular_function', 'GO:0050321', ('105', '108'))	('Melanoma', 'Disease', (0, 8))	('nutlin-3', 'Chemical', 'MESH:C482205', (80, 88))	('HDM201', 'Gene', (97, 103))	('RG7388', 'Var', (89, 95))
68149	29235570	Melanoma cell lines were seeded in 6-well plates and left for 24 h before treatment with MDM2 inhibitors for 72 h, combined with or without WIPi.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('MDM2', 'Gene', (89, 93))	('inhibitors', 'Var', (94, 104))
68155	29235570	The WM35 was transfected with plasmid cDNA constructs encoding either wild-type or mutated p53 (S15A or S15D) using Lipofectamine 2000 (Thermo Fisher Scientific, Cramlington, UK) and incubated for 18 h to allow protein expression before collecting lysates for immunoblotting.	('S15A', 'SUBSTITUTION', 'None', (96, 100))	('mutated', 'Var', (83, 90))	('S15D', 'Mutation', 'p.S15D', (104, 108))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (116, 134))	('protein', 'cellular_component', 'GO:0003675', ('211', '218'))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('S15A', 'Var', (96, 100))
68158	29235570	A total of 2 mug of anti-p53 (sc-126, Santa Cruz Biotechnology), anti-Ub (sc-8017, Santa Cruz Biotechnology) or normal IgG (sc-2025, Santa Cruz Biotechnology) was incubated with lysates.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('Ub', 'Chemical', '-', (70, 72))	('mug', 'molecular_function', 'GO:0043739', ('13', '16'))	('sc-8017', 'Var', (74, 81))
68170	29235570	Growth inhibition measured by SRB assay showed that GSK2830371 at concentrations of <=10 muM had no or minimal growth-inhibitory effect on p53WT (A375, WM35, C8161) and p53MUT (WM164, WM35-R, CHL-1) melanoma cells (Figure 1B).	('muM', 'Gene', '56925', (89, 92))	('muM', 'Gene', (89, 92))	('GSK', 'molecular_function', 'GO:0050321', ('52', '55'))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('SRB', 'Gene', (30, 33))	('A375', 'CellLine', 'CVCL:0132', (146, 150))	('GSK2830371', 'Chemical', 'MESH:C587624', (52, 62))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('CHL-1) melanoma', 'Disease', 'MESH:D006689', (192, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('GSK2830371', 'Var', (52, 62))	('SRB', 'Gene', '10575', (30, 33))	('growth-inhibitory', 'MPA', (111, 128))	('minimal', 'NegReg', (103, 110))
68171	29235570	Immunoblotting of WM35 cells treated by MDM2 inhibitor (either 5 muM nutlin-3 or 1 muM RG7388), combining with different concentrations of GSK2830371 (Figure 1C), illustrated that WIP1 protein decreased gradually with increased dosages of GSK2830371.	('WIP1', 'Gene', '8493', (180, 184))	('GSK2830371', 'Chemical', 'MESH:C587624', (239, 249))	('nutlin-3', 'Chemical', 'MESH:C482205', (69, 77))	('muM', 'Gene', '56925', (65, 68))	('muM', 'Gene', '56925', (83, 86))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('GSK2830371', 'Var', (239, 249))	('GSK', 'molecular_function', 'GO:0050321', ('139', '142'))	('muM', 'Gene', (65, 68))	('WIP1', 'Gene', (180, 184))	('muM', 'Gene', (83, 86))	('GSK2830371', 'Chemical', 'MESH:C587624', (139, 149))	('decreased', 'NegReg', (193, 202))	('GSK', 'molecular_function', 'GO:0050321', ('239', '242'))
68174	29235570	The transcriptional targets of p53, MDM2 and p21 increased modestly after combination treatment with GSK2830371.	('MDM2', 'Gene', (36, 40))	('p53', 'Gene', (31, 34))	('GSK2830371', 'Var', (101, 111))	('p53', 'Gene', '7157', (31, 34))	('p21', 'Gene', (45, 48))	('GSK2830371', 'Chemical', 'MESH:C587624', (101, 111))	('p21', 'Gene', '1026', (45, 48))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('transcriptional targets', 'MPA', (4, 27))	('combination', 'Interaction', (74, 85))
68177	29235570	A GSK2830371 concentration of 2.5 muM displayed the best potentiation when combined with either MDM2 inhibitor and was therefore used for subsequent experiments to evaluate the role of WIP1 in p53 network responses.	('muM', 'Gene', '56925', (34, 37))	('WIP1', 'Gene', (185, 189))	('GSK2830371', 'Var', (2, 12))	('p53', 'Gene', (193, 196))	('muM', 'Gene', (34, 37))	('potentiation', 'MPA', (57, 69))	('GSK', 'molecular_function', 'GO:0050321', ('2', '5'))	('p53', 'Gene', '7157', (193, 196))	('WIP1', 'Gene', '8493', (185, 189))	('GSK2830371', 'Chemical', 'MESH:C587624', (2, 12))
68180	29235570	Significantly increased phospho-p53 (Ser15) was found after combination treatment with either nutlin-3 or RG7388 and GSK2830371 (Supplementary Figure S1C).	('increased', 'PosReg', (14, 23))	('GSK', 'molecular_function', 'GO:0050321', ('117', '120'))	('RG7388', 'Gene', (106, 112))	('nutlin-3', 'Chemical', 'MESH:C482205', (94, 102))	('combination', 'Interaction', (60, 71))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('GSK2830371', 'Chemical', 'MESH:C587624', (117, 127))	('GSK2830371', 'Var', (117, 127))	('Ser', 'cellular_component', 'GO:0005790', ('37', '40'))	('Ser15', 'Chemical', '-', (37, 42))
68181	29235570	Growth inhibition and clonogenic survival following treatment with MDM2 inhibitor (either nutlin-3, RG7388 or HDM201) with or without GSK2830371 (2.5 muM) combination was evaluated for a panel of p53WT (A375, WM35 and C8161) and p53MUT (WM164, WM35-R, CHL-1) melanoma cell lines (Figures 2 and 3 and Supplementary Figure S2).	('Growth inhibition', 'CPA', (0, 17))	('muM', 'Gene', (150, 153))	('GSK2830371', 'Chemical', 'MESH:C587624', (134, 144))	('nutlin-3', 'Chemical', 'MESH:C482205', (90, 98))	('A375', 'CellLine', 'CVCL:0132', (203, 207))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('CHL-1) melanoma', 'Disease', 'MESH:D006689', (252, 267))	('p53', 'Gene', (229, 232))	('p53', 'Gene', '7157', (229, 232))	('GSK', 'molecular_function', 'GO:0050321', ('134', '137'))	('WM164', 'Var', (237, 242))	('clonogenic survival', 'CPA', (22, 41))	('muM', 'Gene', '56925', (150, 153))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (196, 199))
68182	29235570	GSK2830371 enhanced the growth-inhibitory effects of MDM2 inhibitors in p53WT rather than p53MUT melanoma cells, showing that potentiation by GSK2830371 worked in a p53-dependent manner (Figure 2A and Supplementary Figure S2A).	('GSK2830371', 'Var', (142, 152))	('p53', 'Gene', (165, 168))	('p53', 'Gene', (90, 93))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Disease', (97, 105))	('p53', 'Gene', '7157', (165, 168))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('MDM2', 'Gene', (53, 57))	('p53', 'Gene', '7157', (90, 93))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('enhanced', 'PosReg', (11, 19))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GSK2830371', 'Var', (0, 10))	('GSK2830371', 'Chemical', 'MESH:C587624', (142, 152))	('growth-inhibitory effects', 'MPA', (24, 49))	('GSK', 'molecular_function', 'GO:0050321', ('142', '145'))
68183	29235570	GSK2830371 significantly decreased the GI50 for nutlin-3, RG7388 or HDM201 compared with the GI50 for nutlin-3 or RG7388 alone in p53WT melanoma cells (Figure 2B and Supplementary Figure S2B).	('nutlin-3', 'Chemical', 'MESH:C482205', (48, 56))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('nutlin-3', 'Chemical', 'MESH:C482205', (102, 110))	('decreased', 'NegReg', (25, 34))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GI50', 'MPA', (39, 43))	('GSK2830371', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('p53', 'Gene', (130, 133))	('melanoma', 'Disease', (136, 144))	('HDM201', 'Var', (68, 74))	('p53', 'Gene', '7157', (130, 133))	('RG7388', 'Var', (58, 64))
68184	29235570	A clonogenic assay was performed to see whether GSK2830371 can enhance the cytotoxic activity of MDM2 inhibitors.	('GSK', 'molecular_function', 'GO:0050321', ('48', '51'))	('cytotoxic activity', 'CPA', (75, 93))	('enhance', 'PosReg', (63, 70))	('GSK2830371', 'Chemical', 'MESH:C587624', (48, 58))	('GSK2830371', 'Var', (48, 58))	('MDM2', 'Gene', (97, 101))
68185	29235570	The GSK2830371 further inhibited colony formation when it was added to either MDM2 inhibitor in p53WT melanoma cells (Figure 3A and Supplementary Figure S2C).	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('inhibited', 'NegReg', (23, 32))	('colony formation', 'CPA', (33, 49))	('GSK2830371', 'Chemical', 'MESH:C587624', (4, 14))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('formation', 'biological_process', 'GO:0009058', ('40', '49'))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('GSK', 'molecular_function', 'GO:0050321', ('4', '7'))	('GSK2830371', 'Var', (4, 14))
68186	29235570	GSK2830371 significantly decreased the LC50 for nutlin-3, RG7388 or HDM201 compared with the LC50 for MDM2 inhibitor alone for A375 or C8161 cells (P<0.05) and with a similar trend for WM35 (Figure 3B and Supplementary Figure S2D).	('nutlin-3', 'Chemical', 'MESH:C482205', (48, 56))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('decreased', 'NegReg', (25, 34))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GSK2830371', 'Var', (0, 10))	('LC50', 'MPA', (39, 43))	('HDM201', 'Var', (68, 74))	('A375', 'CellLine', 'CVCL:0132', (127, 131))	('RG7388', 'Var', (58, 64))
68188	29235570	The potentiation by GSK2830371 in clonogenic assays was limited to p53WT and was not seen with p53MUT melanoma cells (Figure 3C).	('GSK2830371', 'Chemical', 'MESH:C587624', (20, 30))	('clonogenic assays', 'CPA', (34, 51))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('GSK2830371', 'Var', (20, 30))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('GSK', 'molecular_function', 'GO:0050321', ('20', '23'))
68190	29235570	Therefore, it was hypothesised that inhibition of WIP1 protein by GSK2830371 could enhance the stabilisation of p53 through increasing acetylation and decreasing ubiquitin-mediated degradation.	('ubiquitin', 'molecular_function', 'GO:0031386', ('162', '171'))	('WIP1', 'Gene', '8493', (50, 54))	('acetylation', 'MPA', (135, 146))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('stabilisation', 'MPA', (95, 108))	('enhance', 'PosReg', (83, 90))	('GSK2830371', 'Chemical', 'MESH:C587624', (66, 76))	('p53', 'Gene', (112, 115))	('degradation', 'biological_process', 'GO:0009056', ('181', '192'))	('decreasing', 'NegReg', (151, 161))	('WIP1', 'Gene', (50, 54))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('GSK2830371', 'Var', (66, 76))	('p53', 'Gene', '7157', (112, 115))	('increasing', 'PosReg', (124, 134))	('ubiquitin-mediated degradation', 'MPA', (162, 192))
68194	29235570	Furthermore, this increase was associated with higher levels of phosphorylation (Ser15) and acetylation (Lys382) of p53, and higher expressions of MDM2 and p21.	('Ser15', 'Chemical', '-', (81, 86))	('Ser', 'cellular_component', 'GO:0005790', ('81', '84'))	('phosphorylation', 'MPA', (64, 79))	('Ser15', 'Var', (81, 86))	('Lys382', 'Chemical', '-', (105, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('64', '79'))	('acetylation', 'MPA', (92, 103))	('p21', 'Gene', '1026', (156, 159))	('Lys382', 'Var', (105, 111))	('higher', 'PosReg', (47, 53))	('MDM2', 'Gene', (147, 151))	('p21', 'Gene', (156, 159))	('p53', 'Gene', '7157', (116, 119))	('expressions', 'MPA', (132, 143))	('higher', 'PosReg', (125, 131))	('p53', 'Gene', (116, 119))
68195	29235570	To examine whether the phosphorylation of p53 (Ser15) is a key residue for subsequent C-terminal acetylation of p53, WM35 cells were transfected with different p53 mutant plasmid constructs, including WT, S15A and S15D mutations (Figure 4B).	('p53', 'Gene', (42, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('23', '38'))	('S15A', 'SUBSTITUTION', 'None', (205, 209))	('p53', 'Gene', '7157', (42, 45))	('S15D mutations', 'Var', (214, 228))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('S15D', 'Mutation', 'p.S15D', (214, 218))	('p53', 'Gene', (112, 115))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('p53', 'Gene', '7157', (112, 115))	('S15A', 'Var', (205, 209))	('Ser15', 'Chemical', '-', (47, 52))
68198	29235570	Acetyl-p53 (Lys382) was detected in the cells after p53 (WT) and the S15D phosphomimetic mutant transfection but not when ser15 was mutated to the non-phosphorylatable alanine, indicating that Ser15 and its phosphorylation is an essential and sufficient residue for p53 acetylation.	('Lys382', 'Var', (12, 18))	('alanine', 'Chemical', 'MESH:D000409', (168, 175))	('Lys382', 'Chemical', '-', (12, 18))	('S15D', 'Mutation', 'p.S15D', (69, 73))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('p53', 'Gene', '7157', (7, 10))	('Ser', 'cellular_component', 'GO:0005790', ('193', '196'))	('p53', 'Gene', (266, 269))	('p53', 'Gene', '7157', (266, 269))	('phosphorylation', 'biological_process', 'GO:0016310', ('207', '222'))	('ser15', 'Chemical', '-', (122, 127))	('Ser15', 'Chemical', '-', (193, 198))	('S15D', 'Var', (69, 73))	('p53', 'Gene', (7, 10))
68199	29235570	To evaluate whether WIP1 inhibition by GSK2830371 stabilises p53 by slowing down its degradation, cycloheximide (CHX) was used to block de novo protein synthesis (Figure 4C).	('GSK2830371', 'Var', (39, 49))	('WIP1', 'Gene', (20, 24))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('degradation', 'biological_process', 'GO:0009056', ('85', '96'))	('CHX', 'Chemical', 'MESH:D003513', (113, 116))	('slowing down', 'NegReg', (68, 80))	('degradation', 'MPA', (85, 96))	('WIP1', 'Gene', '8493', (20, 24))	('protein synthesis', 'biological_process', 'GO:0006412', ('144', '161'))	('cycloheximide', 'Chemical', 'MESH:D003513', (98, 111))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('GSK', 'molecular_function', 'GO:0050321', ('39', '42'))	('GSK2830371', 'Chemical', 'MESH:C587624', (39, 49))
68202	29235570	During the 4 h CHX treatment, GSK2830371 slowed down p53 degradation, evidenced by significantly higher levels of p53 protein with concurrent GSK2830371 treatment than without GSK2830371 treatment (P=0.02) (Figure 4D and E).	('GSK2830371', 'Var', (142, 152))	('higher', 'PosReg', (97, 103))	('GSK2830371', 'Chemical', 'MESH:C587624', (30, 40))	('CHX', 'Chemical', 'MESH:D003513', (15, 18))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('slowed down', 'NegReg', (41, 52))	('GSK2830371', 'Var', (30, 40))	('p53', 'Gene', (53, 56))	('GSK2830371', 'Chemical', 'MESH:C587624', (176, 186))	('p53', 'Gene', '7157', (53, 56))	('GSK', 'molecular_function', 'GO:0050321', ('176', '179'))	('GSK2830371', 'Chemical', 'MESH:C587624', (142, 152))	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('degradation', 'biological_process', 'GO:0009056', ('57', '68'))	('GSK', 'molecular_function', 'GO:0050321', ('142', '145'))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
68203	29235570	To test whether the degradation is proteasome dependent, A375 cells were treated with RG7388+-WIP1i and MG132 for 6 h. The MG132 completely prevented the degradation of p53 and masked any difference in stabilisation of p53 by RG7388+-WIP1i (Figure 4F).	('WIP1', 'Gene', (234, 238))	('p53', 'Gene', (169, 172))	('stabilisation', 'MPA', (202, 215))	('MG132', 'Var', (123, 128))	('degradation', 'MPA', (154, 165))	('A375', 'CellLine', 'CVCL:0132', (57, 61))	('proteasome', 'molecular_function', 'GO:0004299', ('35', '45'))	('MG132', 'Chemical', 'MESH:C072553', (123, 128))	('prevented', 'NegReg', (140, 149))	('degradation', 'biological_process', 'GO:0009056', ('154', '165'))	('proteasome', 'cellular_component', 'GO:0000502', ('35', '45'))	('degradation', 'biological_process', 'GO:0009056', ('20', '31'))	('WIP1', 'Gene', '8493', (94, 98))	('p53', 'Gene', '7157', (219, 222))	('p53', 'Gene', '7157', (169, 172))	('WIP1', 'Gene', (94, 98))	('WIP1', 'Gene', '8493', (234, 238))	('MG132', 'Chemical', 'MESH:C072553', (104, 109))	('p53', 'Gene', (219, 222))
68204	29235570	Co-immunoprecipitation showed GSK2830371 treatment decreased Ub-p53 by pulling down either p53 or ubiqutin (Figure 4G).	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('GSK2830371', 'Chemical', 'MESH:C587624', (30, 40))	('GSK2830371', 'Var', (30, 40))	('decreased', 'NegReg', (51, 60))	('Ub', 'Chemical', '-', (61, 63))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('pulling down', 'NegReg', (71, 83))	('ubiqutin', 'MPA', (98, 106))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
68207	29235570	The KU55933 also decreased the growth-inhibitory effects of MDM2 inhibitors on A375 cells (Supplementary Figure S4).	('KU55933', 'Chemical', 'MESH:C495818', (4, 11))	('MDM2', 'Gene', (60, 64))	('decreased', 'NegReg', (17, 26))	('growth-inhibitory', 'CPA', (31, 48))	('A375', 'CellLine', 'CVCL:0132', (79, 83))	('inhibitors', 'Var', (65, 75))	('KU55933', 'Var', (4, 11))
68209	29235570	Sanger sequencing revealed that WM35-R has a homozygous TP53 point mutation (1001G>T) resulting in a Gly334Val amino acid substitution in the p53 protein (Supplementary Figure S5), which is the hinge between beta-strand (residues 326-333) and alpha-helix (residues 335-354) regions in the oligomerisation domain.	('Gly334Val', 'SUBSTITUTION', 'None', (101, 110))	('1001G>T', 'Var', (77, 84))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('TP53', 'Gene', '7157', (56, 60))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('TP53', 'Gene', (56, 60))	('Gly334Val', 'Var', (101, 110))	('1001G>T', 'Mutation', 'c.1001G>T', (77, 84))
68211	29235570	Compared with MDM2 inhibitors alone, the combination of MDM2 inhibitor and GSK2830371 increased p53 phosphorylation (Ser15), acetylation (Lys382) and stabilisation in WM35 but did not increase p53 acetylation (Lys382) and stabilisation in WM35-R (Supplementary Figure S6A).	('acetylation', 'MPA', (125, 136))	('GSK', 'molecular_function', 'GO:0050321', ('75', '78'))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('increased', 'PosReg', (86, 95))	('GSK2830371', 'Chemical', 'MESH:C587624', (75, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('100', '115'))	('p53', 'Gene', (193, 196))	('Ser15', 'Chemical', '-', (117, 122))	('p53', 'Gene', '7157', (193, 196))	('stabilisation', 'MPA', (150, 163))	('Lys382', 'Var', (210, 216))	('Ser', 'cellular_component', 'GO:0005790', ('117', '120'))	('Lys382', 'Chemical', '-', (210, 216))	('Lys382', 'Var', (138, 144))	('Lys382', 'Chemical', '-', (138, 144))
68213	29235570	Interestingly, the mutant p53 in WM35-R cells was still subject to some degradation; however, after 4 -h of CHX treatment, GSK2830371 decreased the wt-p53 degradation in WM35 more than the mut-p53 in WM35-R (Supplementary Figure S6B).	('decreased', 'NegReg', (134, 143))	('CHX', 'Chemical', 'MESH:D003513', (108, 111))	('GSK2830371', 'Chemical', 'MESH:C587624', (123, 133))	('p53', 'Gene', (193, 196))	('p53', 'Gene', '7157', (151, 154))	('degradation', 'biological_process', 'GO:0009056', ('72', '83'))	('GSK2830371', 'Var', (123, 133))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (193, 196))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (151, 154))	('degradation', 'biological_process', 'GO:0009056', ('155', '166'))	('GSK', 'molecular_function', 'GO:0050321', ('123', '126'))
68214	29235570	To test the hypothesis that GSK2830371 enhances the transcriptional activity of p53 in cutaneous melanoma cells treated by MDM2 inhibitors, mRNA expression of candidate genes related to cell cycle arrest and apoptosis were evaluated by quantitative real-time PCR (qRT-PCR).	('GSK', 'molecular_function', 'GO:0050321', ('28', '31'))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('cutaneous melanoma', 'Disease', (87, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (87, 105))	('enhances', 'PosReg', (39, 47))	('p53', 'Gene', (80, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (87, 105))	('transcriptional activity', 'MPA', (52, 76))	('GSK2830371', 'Chemical', 'MESH:C587624', (28, 38))	('p53', 'Gene', '7157', (80, 83))	('GSK2830371', 'Var', (28, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('186', '203'))	('apoptosis', 'biological_process', 'GO:0097194', ('208', '217'))	('apoptosis', 'biological_process', 'GO:0006915', ('208', '217'))
68215	29235570	The p53WT cells (A375, C8161, WM35) and one p53MUT cell line, WM35-R, were treated with either 1 muM nutlin-3 or 0.2 muM RG7388, combined with or without GSK2830371 (2.5 muM) for 6 h. Overall, nutlin-3 or RG7388 induced expression of candidate genes and GSK2830371 potentiated the induced genes in p53WT cells rather than WM35-R.	('nutlin-3', 'Chemical', 'MESH:C482205', (193, 201))	('muM', 'Gene', '56925', (170, 173))	('GSK', 'molecular_function', 'GO:0050321', ('254', '257'))	('A375', 'CellLine', 'CVCL:0132', (17, 21))	('muM', 'Gene', (170, 173))	('potentiated', 'PosReg', (265, 276))	('GSK2830371', 'Chemical', 'MESH:C587624', (154, 164))	('muM', 'Gene', '56925', (97, 100))	('GSK2830371', 'Var', (254, 264))	('muM', 'Gene', (97, 100))	('GSK2830371', 'Chemical', 'MESH:C587624', (254, 264))	('p53', 'Gene', '7157', (44, 47))	('GSK', 'molecular_function', 'GO:0050321', ('154', '157'))	('p53', 'Gene', '7157', (298, 301))	('p53', 'Gene', '7157', (4, 7))	('expression', 'MPA', (220, 230))	('muM', 'Gene', '56925', (117, 120))	('nutlin-3', 'Chemical', 'MESH:C482205', (101, 109))	('p53', 'Gene', (44, 47))	('muM', 'Gene', (117, 120))	('p53', 'Gene', (298, 301))	('p53', 'Gene', (4, 7))
68216	29235570	The fold changes of mRNA in response to MDM2 inhibitors with or without WIP1i were less in WM35 than A375 and C8161 (Figure 5 and Supplementary Figure S7).	('A375', 'Var', (101, 105))	('WIP1', 'Gene', (72, 76))	('MDM2 inhibitors', 'Gene', (40, 55))	('A375', 'CellLine', 'CVCL:0132', (101, 105))	('less', 'NegReg', (83, 87))	('mRNA', 'MPA', (20, 24))	('response', 'MPA', (28, 36))	('WIP1', 'Gene', '8493', (72, 76))	('C8161', 'Var', (110, 115))
68218	29235570	However, the effects of GSK2830371 on transcript levels were modest, consistent with GSK2830371 alone having no or minimal growth-inhibitory effect in SRB and clonogenic assays (Figures 1B and 3C and D) and with the lack of obvious changes in p21 and MDM2 proteins in immunoblotting (Figure 1C and Supplementary Figure S1).	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('SRB', 'Gene', '10575', (151, 154))	('SRB', 'Gene', (151, 154))	('GSK2830371', 'Chemical', 'MESH:C587624', (24, 34))	('GSK2830371', 'Chemical', 'MESH:C587624', (85, 95))	('GSK2830371', 'Var', (85, 95))	('GSK', 'molecular_function', 'GO:0050321', ('85', '88'))	('p21', 'Gene', '1026', (243, 246))	('clonogenic assays', 'CPA', (159, 176))	('p21', 'Gene', (243, 246))
68222	29235570	GSK2830371 also showed the same trend for enhancing the effect of nutlin-3 on the expression of these genes, but the fold changes were mostly not statistically significant (P>0.05).	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('expression', 'MPA', (82, 92))	('nutlin-3', 'Chemical', 'MESH:C482205', (66, 74))	('enhancing', 'PosReg', (42, 51))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('GSK2830371', 'Var', (0, 10))
68224	29235570	GSK2830371 appeared to increase the effect of nutlin-3 treatment in WM35 on the expression of pro-apoptotic genes, although some of these trends were not statistically significant (P>0.05).	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('nutlin-3', 'Chemical', 'MESH:C482205', (46, 54))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('increase', 'PosReg', (23, 31))	('GSK2830371', 'Var', (0, 10))	('expression', 'MPA', (80, 90))
68226	29235570	Given that GSK2830371 potentiated the growth inhibition and clonogenic reduction by MDM2 inhibitors, FACS analysis was carried out to investigate changes in cell cycle distribution.	('MDM2', 'Gene', (84, 88))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('GSK', 'molecular_function', 'GO:0050321', ('11', '14'))	('potentiated', 'PosReg', (22, 33))	('inhibitors', 'Var', (89, 99))	('clonogenic reduction', 'CPA', (60, 80))	('GSK2830371', 'Chemical', 'MESH:C587624', (11, 21))	('GSK2830371', 'Var', (11, 21))	('growth inhibition', 'CPA', (38, 55))
68229	29235570	In all the cell lines, 2.5 muM GSK2830371 alone did not affect the cell cycle distribution through 72 h of treatment (Figure 6 and Supplementary Figures S9 and S10) In general, RG7388 (0.2 muM) or HDM201 (0.2 muM) treatment of p53WT cells (A375, WM35, C8161) decreased the proportion of cells in S phase that was accompanied by G1-phase increases, with or without G2-phase increases.	('p53', 'Gene', (227, 230))	('muM', 'Gene', (209, 212))	('muM', 'Gene', '56925', (27, 30))	('G1-phase', 'biological_process', 'GO:0051318', ('328', '336'))	('cell cycle', 'biological_process', 'GO:0007049', ('67', '77'))	('increases', 'PosReg', (337, 346))	('muM', 'Gene', (27, 30))	('Supplementary Figures S9', 'Disease', (131, 155))	('A375', 'CellLine', 'CVCL:0132', (240, 244))	('G1-phase', 'CPA', (328, 336))	('RG7388', 'Var', (177, 183))	('decreased', 'NegReg', (259, 268))	('S phase', 'biological_process', 'GO:0051320', ('296', '303'))	('GSK', 'molecular_function', 'GO:0050321', ('31', '34'))	('G2-phase', 'biological_process', 'GO:0051319', ('364', '372'))	('C8161', 'Var', (252, 257))	('muM', 'Gene', '56925', (189, 192))	('p53', 'Gene', '7157', (227, 230))	('Supplementary Figures S9', 'Disease', 'MESH:D017034', (131, 155))	('muM', 'Gene', (189, 192))	('GSK2830371', 'Chemical', 'MESH:C587624', (31, 41))	('muM', 'Gene', '56925', (209, 212))
68230	29235570	Treatment with GSK2830371 further enhanced the changes in cell cycle distribution markedly when it was combined with MDM2 inhibitors.	('enhanced', 'PosReg', (34, 42))	('cell cycle', 'biological_process', 'GO:0007049', ('58', '68'))	('GSK', 'molecular_function', 'GO:0050321', ('15', '18'))	('changes', 'Reg', (47, 54))	('cell', 'MPA', (58, 62))	('GSK2830371', 'Chemical', 'MESH:C587624', (15, 25))	('GSK2830371', 'Var', (15, 25))
68233	29235570	Cell cycle distribution was not affected in TP53 mutant WM35-R cells regardless of the treatment conditions, demonstrating that the changes in cell cycle distribution observed are p53 dependent.	('mutant', 'Var', (49, 55))	('p53', 'Gene', '7157', (180, 183))	('p53', 'Gene', (180, 183))	('TP53', 'Gene', '7157', (44, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('143', '153'))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('TP53', 'Gene', (44, 48))
68236	29235570	The potentiation of growth inhibition by GSK2830371 on RG7388 or HDM201 was suppressed by the p53 knockdown (Figure 7).	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('knockdown', 'Var', (98, 107))	('GSK', 'molecular_function', 'GO:0050321', ('41', '44'))	('GSK2830371', 'Chemical', 'MESH:C587624', (41, 51))	('suppressed', 'NegReg', (76, 86))	('GSK2830371', 'Var', (41, 51))	('growth inhibition', 'CPA', (20, 37))
68237	29235570	In the current study, we demonstrated that doses of the GSK2830371, WIP1 inhibitor, with no growth-inhibitory activity nevertheless potentiated the growth inhibition and cell killing of wild-type p53 cutaneous melanoma cells by MDM2 inhibitors, nutlin-3, RG7388 and HDM201.	('growth inhibition', 'CPA', (148, 165))	('potentiated', 'PosReg', (132, 143))	('cell killing', 'CPA', (170, 182))	('WIP1', 'Gene', '8493', (68, 72))	('cell killing', 'biological_process', 'GO:0001906', ('170', '182'))	('MDM2', 'Gene', (228, 232))	('p53', 'Gene', (196, 199))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('cutaneous melanoma', 'Disease', (200, 218))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (200, 218))	('nutlin-3', 'Chemical', 'MESH:C482205', (245, 253))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (200, 218))	('GSK2830371', 'Chemical', 'MESH:C587624', (56, 66))	('HDM201', 'Var', (266, 272))	('WIP1', 'Gene', (68, 72))	('p53', 'Gene', '7157', (196, 199))	('GSK2830371', 'Var', (56, 66))	('GSK', 'molecular_function', 'GO:0050321', ('56', '59'))
68242	29235570	Although p53 expression has generally been associated with the levels of transcriptional target genes responsible for cell cycle arrest and apoptosis, apoptosis has been reported only to proceed in certain conditions, such as achieving a transcriptional threshold by p53 reactivation or suppression of its negative regulators.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('118', '135'))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('suppression', 'NegReg', (287, 298))	('p53', 'Gene', (9, 12))	('transcriptional threshold', 'MPA', (238, 263))	('levels of', 'MPA', (63, 72))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (267, 270))	('p53', 'Gene', '7157', (267, 270))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('associated', 'Reg', (43, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('reactivation', 'Var', (271, 283))
68244	29235570	In the current study, inhibition of WIP1, a negative regulator of p53, potentiated the activation of p53 in all three p53WT melanoma cell lines through post-translation modification, but only enhanced apoptosis in A375 cells and did not shift cell cycle arrest to apoptosis in the cells not primed for apoptosis (WM35 and C8161 in the current study).	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('enhanced', 'PosReg', (192, 200))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('translation', 'biological_process', 'GO:0006412', ('157', '168'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('243', '260'))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('p53', 'Gene', '7157', (118, 121))	('apoptosis', 'CPA', (201, 210))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('potentiated', 'PosReg', (71, 82))	('p53', 'Gene', (118, 121))	('post-translation modification', 'Var', (152, 181))	('p53', 'Gene', '7157', (101, 104))	('A375', 'CellLine', 'CVCL:0132', (214, 218))	('apoptosis', 'biological_process', 'GO:0097194', ('302', '311'))	('inhibition', 'Var', (22, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('302', '311'))	('activation', 'PosReg', (87, 97))	('WIP1', 'Gene', '8493', (36, 40))	('p53', 'Gene', '7157', (66, 69))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (243, 260))	('p53', 'Gene', (101, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('201', '210'))	('WIP1', 'Gene', (36, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('201', '210'))	('p53', 'Gene', (66, 69))
68245	29235570	Post-translational modification of p53 has critical effects on its stability and function.	('p53', 'Gene', (35, 38))	('function', 'MPA', (81, 89))	('p53', 'Gene', '7157', (35, 38))	('Post-translational modification', 'Var', (0, 31))	('effects', 'Reg', (52, 59))	('Post-translational modification', 'biological_process', 'GO:0043687', ('0', '31'))	('stability', 'MPA', (67, 76))
68248	29235570	Therefore, p53 acetylation increases its stability by inhibiting MDM2-mediated ubiquitination of p53 and can stimulate its sequence-specific DNA binding activity.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('MDM2-mediated ubiquitination', 'MPA', (65, 93))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('p53', 'Gene', (97, 100))	('stimulate', 'PosReg', (109, 118))	('increases', 'PosReg', (27, 36))	('stability', 'MPA', (41, 50))	('p53', 'Gene', '7157', (97, 100))	('acetylation', 'Var', (15, 26))	('sequence-specific', 'MPA', (123, 140))	('sequence-specific DNA binding', 'molecular_function', 'GO:0043565', ('123', '152'))	('inhibiting', 'NegReg', (54, 64))
68249	29235570	The WIP1 phosphatase and ATM kinase work antagonistically on the same p53-related substrates, ATM (Ser1981), MDM2 (Ser395) and p53 (Ser15), to maintain a fine balance of these proteins in order to regulate the function and stability of p53.	('regulate', 'Reg', (197, 205))	('Ser1981', 'Var', (99, 106))	('WIP1', 'Gene', (4, 8))	('Ser', 'cellular_component', 'GO:0005790', ('99', '102'))	('ATM', 'Gene', '472', (94, 97))	('ATM', 'Gene', (25, 28))	('phosphatase', 'molecular_function', 'GO:0016791', ('9', '20'))	('Ser1981', 'Chemical', '-', (99, 106))	('p53', 'Gene', '7157', (127, 130))	('Ser', 'cellular_component', 'GO:0005790', ('115', '118'))	('p53', 'Gene', '7157', (236, 239))	('ATM', 'Gene', (94, 97))	('p53', 'Gene', (127, 130))	('Ser', 'cellular_component', 'GO:0005790', ('132', '135'))	('stability', 'MPA', (223, 232))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (236, 239))	('Ser15', 'Chemical', '-', (132, 137))	('ATM', 'Gene', '472', (25, 28))	('p53', 'Gene', (70, 73))	('function', 'MPA', (210, 218))	('Ser395', 'Chemical', '-', (115, 121))	('WIP1', 'Gene', '8493', (4, 8))
68250	29235570	For example, autophosphorylation of ATM (Ser1981) after irradiation has been shown to stabilise ATM at DNA damage sites and phosphorylate p53 (Ser15).	('ATM', 'Gene', '472', (96, 99))	('p53', 'Gene', (138, 141))	('ATM', 'Gene', (36, 39))	('Ser1981', 'Chemical', '-', (41, 48))	('Ser15', 'Chemical', '-', (143, 148))	('Ser', 'cellular_component', 'GO:0005790', ('41', '44'))	('p53', 'Gene', '7157', (138, 141))	('Ser15', 'Var', (143, 148))	('ATM', 'Gene', '472', (36, 39))	('Ser1981', 'Var', (41, 48))	('phosphorylate', 'MPA', (124, 137))	('ATM', 'Gene', (96, 99))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('Ser', 'cellular_component', 'GO:0005790', ('143', '146'))
68251	29235570	Ser1981 of ATM is also a substrate of WIP1 phosphatase and WIP1 inhibition by GSK2830371 can increase phospho-ATM (Ser1981) in a non-genotoxic manner.	('Ser', 'cellular_component', 'GO:0005790', ('115', '118'))	('WIP1', 'Gene', (59, 63))	('GSK2830371', 'Chemical', 'MESH:C587624', (78, 88))	('Ser1981', 'Chemical', '-', (0, 7))	('WIP1', 'Gene', (38, 42))	('increase', 'PosReg', (93, 101))	('ATM', 'Gene', '472', (110, 113))	('phosphatase', 'molecular_function', 'GO:0016791', ('43', '54'))	('Ser1981', 'Chemical', '-', (115, 122))	('GSK2830371', 'Var', (78, 88))	('WIP1', 'Gene', '8493', (59, 63))	('ATM', 'Gene', (11, 14))	('inhibition', 'NegReg', (64, 74))	('WIP1', 'Gene', '8493', (38, 42))	('GSK', 'molecular_function', 'GO:0050321', ('78', '81'))	('ATM', 'Gene', (110, 113))	('ATM', 'Gene', '472', (11, 14))	('Ser', 'cellular_component', 'GO:0005790', ('0', '3'))
68254	29235570	Therefore, GSK2830371 is an effective non-genotoxic way of increasing activation of the ATM-mediated network by inhibition of WIP1 to maintain the phosphorylated state of key proteins.	('WIP1', 'Gene', (126, 130))	('GSK', 'molecular_function', 'GO:0050321', ('11', '14'))	('ATM', 'Gene', (88, 91))	('increasing activation', 'PosReg', (59, 80))	('inhibition', 'NegReg', (112, 122))	('WIP1', 'Gene', '8493', (126, 130))	('GSK2830371', 'Chemical', 'MESH:C587624', (11, 21))	('GSK2830371', 'Var', (11, 21))	('ATM', 'Gene', '472', (88, 91))	('phosphorylated state of key proteins', 'MPA', (147, 183))
68256	29235570	GSK2830371 as a single agent selectively inhibits the growth of MCF-7 and MX-1 cells, PPM1D amplified breast cancer cells and a subset of p53WT haematological cancer cell lines.	('p53', 'Gene', (138, 141))	('MX-1', 'CellLine', 'CVCL:4774', (74, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('amplified', 'PosReg', (92, 101))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('cancer', 'Disease', (159, 165))	('PPM1D', 'Gene', '8493', (86, 91))	('breast cancer', 'Disease', (102, 115))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('MCF-7', 'CellLine', 'CVCL:0031', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (109, 115))	('GSK2830371', 'Var', (0, 10))	('growth', 'CPA', (54, 60))	('PPM1D', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('inhibits', 'NegReg', (41, 49))	('haematological cancer', 'Phenotype', 'HP:0004377', (144, 165))	('p53', 'Gene', '7157', (138, 141))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))
68257	29235570	In one previous report using cells with different PPM1D gene alterations (gain-of-function mutations, amplification or copy number gain), all cells except MCF-7 cell were resistant to GSK2830371 (GI50>10 muM) as a single agent treatment.	('gain-of-function', 'PosReg', (74, 90))	('PPM1D', 'Gene', (50, 55))	('MCF-7', 'CellLine', 'CVCL:0031', (155, 160))	('GSK', 'molecular_function', 'GO:0050321', ('184', '187'))	('alterations', 'Var', (61, 72))	('PPM1D', 'Gene', '8493', (50, 55))	('muM', 'Gene', '56925', (204, 207))	('GSK2830371', 'Chemical', 'MESH:C587624', (184, 194))	('muM', 'Gene', (204, 207))
68258	29235570	Consistent with this report, GSK2830371 alone had no obvious growth-inhibitory activity (GI50>10 muM) in all of the melanoma cell lines we investigated in the current study (Figure 1A).	('GSK', 'molecular_function', 'GO:0050321', ('29', '32'))	('GSK2830371', 'Var', (29, 39))	('muM', 'Gene', '56925', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('growth-inhibitory activity', 'MPA', (61, 87))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('muM', 'Gene', (97, 100))	('GSK2830371', 'Chemical', 'MESH:C587624', (29, 39))
68259	29235570	Actually, modest phosphorylation of p53 (Ser15) following treatment with single agent GSK2830371 was detected by immunoblotting (Figure 4A) and RPPA (Supplementary Figure S1B) that resulted in a statistically significant but small increase in transcript level of some genes (Figure 6) and slight induction of p21 protein (Figures 1C and 4A).	('p21', 'Gene', '1026', (309, 312))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Ser', 'cellular_component', 'GO:0005790', ('41', '44'))	('increase', 'PosReg', (231, 239))	('p21', 'Gene', (309, 312))	('phosphorylation', 'MPA', (17, 32))	('p53', 'Gene', (36, 39))	('induction', 'PosReg', (296, 305))	('p53', 'Gene', '7157', (36, 39))	('GSK2830371', 'Chemical', 'MESH:C587624', (86, 96))	('Ser15', 'Chemical', '-', (41, 46))	('GSK', 'molecular_function', 'GO:0050321', ('86', '89'))	('transcript level', 'MPA', (243, 259))	('GSK2830371', 'Var', (86, 96))	('protein', 'cellular_component', 'GO:0003675', ('313', '320'))
68261	29235570	Previous studies with genotoxic modalities such as ionising or UV irradiation indicated a model in which resultant phosphorylation of p53 on Ser15 recruits histone acetyl transferases (HATs) to acetylate lysine residues in the p53 C-terminal domain.	('p53', 'Gene', (227, 230))	('p53', 'Gene', '7157', (134, 137))	('lysine', 'Chemical', 'MESH:D008239', (204, 210))	('phosphorylation', 'Var', (115, 130))	('p53', 'Gene', '7157', (227, 230))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('Ser15', 'Chemical', '-', (141, 146))	('Ser', 'cellular_component', 'GO:0005790', ('141', '144'))	('acetylate lysine residues', 'MPA', (194, 219))	('p53', 'Gene', (134, 137))
68263	29235570	Consistent with a recent report using nutlin-3a and GSK2830371, our results showed that enhanced phosphorylation (Ser15) and acetylation (Lys382) of p53 were found after non-genotoxic nutlin-3 and GSK2830371 treatment.	('acetylation', 'MPA', (125, 136))	('p53', 'Gene', (149, 152))	('GSK', 'molecular_function', 'GO:0050321', ('197', '200'))	('nutlin-3', 'Chemical', 'MESH:C482205', (38, 46))	('GSK2830371', 'Var', (197, 207))	('GSK', 'molecular_function', 'GO:0050321', ('52', '55'))	('p53', 'Gene', '7157', (149, 152))	('nutlin-3', 'Chemical', 'MESH:C482205', (184, 192))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('GSK2830371', 'Chemical', 'MESH:C587624', (52, 62))	('Ser15', 'Chemical', '-', (114, 119))	('Ser', 'cellular_component', 'GO:0005790', ('114', '117'))	('enhanced', 'PosReg', (88, 96))	('GSK2830371', 'Chemical', 'MESH:C587624', (197, 207))	('Lys382', 'Chemical', '-', (138, 144))
68264	29235570	In addition, we transfected p53 (Ser15) mutants to prove the Ser15 is the essential and sufficient residue for p53 acetylation.	('p53', 'Gene', (28, 31))	('Ser', 'cellular_component', 'GO:0005790', ('61', '64'))	('Ser', 'cellular_component', 'GO:0005790', ('33', '36'))	('p53', 'Gene', '7157', (28, 31))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('mutants', 'Var', (40, 47))	('Ser15', 'Chemical', '-', (33, 38))	('Ser15', 'Chemical', '-', (61, 66))
68267	29235570	The MG132 reversed the change in p53 expression, indicating that GSK2830371 decreased the proteasomal degradation of p53.	('MG132', 'Chemical', 'MESH:C072553', (4, 9))	('degradation', 'biological_process', 'GO:0009056', ('102', '113'))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('GSK', 'molecular_function', 'GO:0050321', ('65', '68'))	('decreased', 'NegReg', (76, 85))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('GSK2830371', 'Chemical', 'MESH:C587624', (65, 75))	('GSK2830371', 'Var', (65, 75))
68268	29235570	Both the p53 acetylation leading to inhibition of its ubiquitination by MDM2 and WIP1 inhibition by siRNA leading to decrease in p53 ubiquitination are consistent with our finding that WIP1 inhibition by GSK2830371 stabilised p53 as a result of the decreased MDM2-mediated ubiquitination shown by co-immunoprecipitation.	('GSK', 'molecular_function', 'GO:0050321', ('204', '207'))	('inhibition', 'NegReg', (190, 200))	('p53', 'Gene', '7157', (9, 12))	('WIP1', 'Gene', '8493', (185, 189))	('p53', 'Gene', (129, 132))	('decrease', 'NegReg', (117, 125))	('inhibition', 'NegReg', (86, 96))	('WIP1', 'Gene', (185, 189))	('p53', 'Gene', (9, 12))	('WIP1', 'Gene', '8493', (81, 85))	('acetylation', 'MPA', (13, 24))	('WIP1', 'Gene', (81, 85))	('inhibition', 'NegReg', (36, 46))	('ubiquitination', 'MPA', (54, 68))	('GSK2830371', 'Var', (204, 214))	('p53', 'Gene', '7157', (226, 229))	('p53', 'Gene', (226, 229))	('decreased', 'NegReg', (249, 258))	('p53', 'Gene', '7157', (129, 132))	('GSK2830371', 'Chemical', 'MESH:C587624', (204, 214))
68269	29235570	When the cells were treated by the lower concentrations of MDM2 inhibitors, the MDM2 was only partially inhibited by MDM2 inhibitors, hence p53 acetylation then played a critical role in p53 stability by antagonising ubiquitiylation (Figure 4).	('p53', 'Gene', (187, 190))	('inhibitors', 'Var', (122, 132))	('p53', 'Gene', '7157', (187, 190))	('antagonising', 'NegReg', (204, 216))	('ubiquitiylation', 'MPA', (217, 232))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
68270	29235570	GSK2830371 potentiated MDM2 inhibitors to amplify the expression of p53 transcriptionally targeted genes that are responsible for cell cycle arrest and apoptosis in p53WT melanoma cells, but the degree of potentiation was cell line dependent.	('expression', 'MPA', (54, 64))	('p53', 'Gene', (165, 168))	('p53', 'Gene', '7157', (165, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('amplify', 'PosReg', (42, 49))	('GSK2830371', 'Chemical', 'MESH:C587624', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('GSK2830371', 'Var', (0, 10))	('melanoma', 'Disease', (171, 179))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('130', '147'))
68271	29235570	Greater potentiation by GSK2830371 was found with A375 and C8161 cells than for WM35 by qRT-PCR, immunoblotting, growth inhibition and clonogenic assay.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('GSK2830371', 'Chemical', 'MESH:C587624', (24, 34))	('GSK2830371', 'Var', (24, 34))	('A375', 'CellLine', 'CVCL:0132', (50, 54))	('potentiation', 'MPA', (8, 20))
68274	29235570	The results of the current study indicate that the responsiveness of melanoma cell lines to MDM2 inhibitors and WIP1i depends to a large part on the fold differences between the basal and maximal relative transcript levels of downstream p53 transcriptional target genes, and is also likely to be modulated by the downstream status of pro-survival and anti-apoptotic pathways (Supplementary Figure S8).	('p53', 'Gene', '7157', (237, 240))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('pro-survival', 'biological_process', 'GO:0043066', ('334', '346'))	('MDM2', 'Gene', (92, 96))	('WIP1', 'Gene', (112, 116))	('WIP1', 'Gene', '8493', (112, 116))	('p53', 'Gene', (237, 240))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('inhibitors', 'Var', (97, 107))
68338	28403068	Among Caucasian melanoma patients, male gender (OR 1.5; CI = 1.5-1.6), northern plains (OR 1.2; CI = 1.1-1.2), tumor depth >0.76 mm (OR 2.1; CI = 2.0-2.2), regional (OR 3.0; CI = 2.8-3.2), distant disease (OR 4.7; CI = 4.0-5.4), NM (OR 1.5; CI = 1.5-1.6), LM (OR 1.7; CI = 1.6-1.8), and AL (OR 1.9; CI = 1.7-2.1) were all independently associated with increased mortality, P < 0.001.	('AL', 'Chemical', '-', (287, 289))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('distant', 'Disease', (189, 196))	('LM', 'Phenotype', 'HP:0012059', (256, 258))	('associated', 'Reg', (336, 346))	('NM', 'Phenotype', 'HP:0012058', (229, 231))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('>0.76', 'Var', (123, 128))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('increased', 'PosReg', (352, 361))	('tumor', 'Disease', (111, 116))	('melanoma', 'Disease', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('patients', 'Species', '9606', (25, 33))
68359	28403068	In the current study, regional and distant disease, as well as tumor depth >1.51 mm were also associated with increased mortality for both Caucasian and AAs, which is consistent with prior reports.	('tumor', 'Disease', (63, 68))	('regional', 'CPA', (22, 30))	('>1.51', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('AAs', 'Disease', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
68369	28403068	Low socioeconomic status has been strongly associated with later stages at melanoma presentation and lower survival rates than higher socioeconomic groups.	('survival', 'MPA', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('lower', 'NegReg', (101, 106))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('Low socioeconomic status', 'Var', (0, 24))
68371	28403068	In a separate report by Chang et al, lower socioeconomic status was strongly associated with lower 5-year survival among early (83.2% vs 90.9%, P < 0.05) and late-stage melanoma patients (30.0% vs 45.5%, P > 0.05).	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('late-stage melanoma', 'Disease', (158, 177))	('patients', 'Species', '9606', (178, 186))	('late-stage melanoma', 'Disease', 'MESH:D008545', (158, 177))	('lower', 'NegReg', (93, 98))	('5-year survival', 'MPA', (99, 114))	('lower socioeconomic status', 'Var', (37, 63))
68403	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
68407	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('protein degradation', 'biological_process', 'GO:0030163', ('65', '84'))	('expression', 'MPA', (134, 144))	('levels', 'MPA', (118, 124))	('protein degradation', 'MPA', (65, 84))	('contribute', 'Reg', (91, 101))	('elevated', 'PosReg', (109, 117))	('AURKA', 'Gene', '6790', (128, 133))	('activation', 'PosReg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))
68409	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
68410	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('161', '179'))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (129, 134))	('AURKA', 'Gene', '6790', (12, 17))	('AURKA', 'Gene', (12, 17))	('AURKA', 'Gene', (129, 134))	('AKIs suppresses cancer', 'Disease', (138, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
68429	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('overexpression', 'PosReg', (34, 48))	('AURKA', 'Gene', '6790', (75, 80))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
68430	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('regulation', 'biological_process', 'GO:0065007', ('111', '121'))	('AURKA', 'Gene', '6790', (30, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('gene amplification', 'Var', (67, 85))	('AURKA', 'Gene', (30, 35))
68457	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (111, 116))	('AURKA', 'Gene', '6790', (86, 91))	('stabilize', 'PosReg', (101, 110))	('PUM2', 'Gene', (20, 24))	('autophosphorylation', 'MPA', (44, 63))	('cdh', 'Protein', (164, 167))	('AURKA', 'Gene', (111, 116))	('AURKA', 'Gene', (86, 91))	('stimulate', 'PosReg', (34, 43))	('autoactivation', 'MPA', (68, 82))	('expression', 'MPA', (125, 135))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
68460	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
68468	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (25, 30))	('AURKA', 'Gene', '6790', (142, 147))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', '6790', (50, 55))	('Ser', 'cellular_component', 'GO:0005790', ('122', '125'))	('Ser', 'cellular_component', 'GO:0005790', ('59', '62'))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))
68476	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('spindle assembly', 'biological_process', 'GO:0051225', ('155', '171'))	('IKK2', 'molecular_function', 'GO:0008384', ('28', '32'))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('AURKA', 'Gene', (124, 129))	('AURKA', 'Gene', (19, 24))	('mitotic progression', 'CPA', (176, 195))	('IKK2', 'Gene', '3551', (28, 32))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('bipolar spindle assembly', 'CPA', (147, 171))	('spindle', 'cellular_component', 'GO:0005819', ('155', '162'))
68482	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('degradation', 'biological_process', 'GO:0009056', ('113', '124'))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('proteasome', 'molecular_function', 'GO:0004299', ('93', '103'))	('proteasome', 'cellular_component', 'GO:0000502', ('93', '103'))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
68493	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
68500	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('spindle', 'cellular_component', 'GO:0005819', ('15', '22'))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
68502	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser', 'cellular_component', 'GO:0005790', ('88', '91'))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('TPX2', 'Gene', '22974', (20, 24))
68512	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('facilitates', 'PosReg', (84, 95))	('Ser', 'cellular_component', 'GO:0005790', ('58', '61'))	('promotion', 'PosReg', (111, 120))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('AURKA', 'Gene', '6790', (24, 29))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Var', (66, 72))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('Ser184', 'Chemical', '-', (77, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('Thr148', 'Chemical', '-', (66, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('Ser184', 'Var', (77, 83))	('pancreatic cancer', 'Disease', (151, 168))
68521	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('Ser162', 'Chemical', '-', (36, 42))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('tumor', 'Disease', (156, 161))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('Ser162', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('glycolysis', 'biological_process', 'GO:0006096', ('114', '124'))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))	('glycolysis', 'MPA', (114, 124))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('Ser', 'cellular_component', 'GO:0005790', ('36', '39'))	('Phosphorylation', 'MPA', (0, 15))	('LDHB', 'Gene', (19, 23))	('biosynthesis', 'biological_process', 'GO:0009058', ('129', '141'))	('LDHB', 'Gene', '3945', (19, 23))
68522	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('AURKA', 'Gene', (105, 110))
68525	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('enhanced', 'PosReg', (56, 64))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
68529	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('AURKA', 'Gene', '6790', (0, 5))	('AURKA', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('120', '123'))	('activity', 'MPA', (29, 37))	('localization', 'biological_process', 'GO:0051179', ('51', '63'))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('Ser283', 'Chemical', '-', (120, 126))	('subcellular localization', 'MPA', (39, 63))	('LIMK2', 'Gene', (111, 116))	('Ser283', 'Var', (120, 126))	('regulates', 'Reg', (6, 15))	('LIMK2', 'Gene', (16, 21))	('Thr494', 'Var', (128, 134))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('Thr505', 'Chemical', '-', (139, 145))	('kinase activity', 'molecular_function', 'GO:0016301', ('22', '37'))
68530	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('cell migration', 'biological_process', 'GO:0016477', ('92', '106'))	('anchorage-independent growth', 'CPA', (111, 139))	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('RalA', 'Gene', '5898', (68, 72))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('enhances', 'PosReg', (83, 91))	('AURKA', 'Gene', '6790', (42, 47))	('cell migration', 'CPA', (92, 106))	('RalA', 'Gene', '5898', (17, 21))	('phosphorylation', 'Var', (49, 64))
68531	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('Thr267', 'Chemical', '-', (71, 77))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('ALDH1A1', 'Gene', '216', (107, 114))	('ALDH1A1', 'Gene', (0, 7))	('enhancing', 'PosReg', (134, 143))	('regulates', 'Reg', (97, 106))	('Thr493', 'Var', (90, 96))	('ALDH1A1', 'Gene', '216', (0, 7))	('Thr493', 'Chemical', '-', (90, 96))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', (107, 114))	('EMT', 'biological_process', 'GO:0001837', ('187', '190'))	('protein stability', 'MPA', (115, 132))	('ALDH', 'molecular_function', 'GO:0004030', ('107', '111'))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
68534	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('phosphorylation', 'biological_process', 'GO:0016310', ('24', '39'))	('Ser', 'cellular_component', 'GO:0005790', ('9', '12'))	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', '6790', (43, 48))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
68536	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('Ser', 'cellular_component', 'GO:0005790', ('40', '43'))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
68539	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('137', '154'))	('RASSF1A', 'Gene', '11186', (19, 26))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('arrest', 'Disease', (148, 154))	('Ser203', 'Chemical', '-', (39, 45))	('RASSF1A', 'Gene', (19, 26))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('Thr202', 'Chemical', '-', (50, 56))	('microtubules', 'Protein', (105, 117))	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (80, 87))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('RASSF1A', 'Gene', (80, 87))	('AURKA', 'Gene', '6790', (30, 35))	('M-phase', 'biological_process', 'GO:0000279', ('129', '136'))	('induce', 'Reg', (122, 128))	('ability', 'MPA', (69, 76))	('AURKA', 'Gene', (30, 35))
68543	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('AMPK', 'molecular_function', 'GO:0047322', ('102', '106'))	('Phosphorylation', 'Var', (0, 15))	('AMPK', 'molecular_function', 'GO:0050405', ('65', '69'))	('facilitating', 'PosReg', (129, 141))	('signaling pathway', 'biological_process', 'GO:0007165', ('107', '124'))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('AMPK', 'molecular_function', 'GO:0050405', ('102', '106'))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('NSCLC', 'Disease', (170, 175))	('AMPK', 'molecular_function', 'GO:0004691', ('65', '69'))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))	('AMPK', 'molecular_function', 'GO:0004691', ('102', '106'))	('AMPK', 'molecular_function', 'GO:0047322', ('65', '69'))
68550	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('51', '62'))	('transcriptional activity', 'MPA', (76, 100))	('Ser365', 'Var', (39, 45))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('AURKA', 'Gene', (30, 35))
68553	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))	('androgen degradation', 'biological_process', 'GO:0006710', ('58', '78'))
68555	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('AURKA', 'Gene', '6790', (19, 24))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('KCTD12', 'Gene', (83, 89))	('Ser', 'cellular_component', 'GO:0005790', ('28', '31'))	('cancer', 'Disease', (55, 61))
68565	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('BPR1K0609S1', 'Var', (161, 172))	('AURKA', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
68567	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('somnolence', 'Disease', (102, 112))	('toxicity', 'Disease', (25, 33))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('MLN8237', 'Var', (62, 69))	('neutropenia', 'Disease', (89, 100))
68568	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
68569	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
68570	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cell proliferation', 'CPA', (34, 52))	('senescence', 'CPA', (160, 170))	('MLN8237', 'Var', (0, 7))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('inducing', 'PosReg', (75, 83))	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('mitosis', 'biological_process', 'GO:0000278', ('66', '73'))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('cancer', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('accelerating', 'PosReg', (121, 133))	('senescence', 'biological_process', 'GO:0010149', ('160', '170'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'biological_process', 'GO:0016236', ('106', '115'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('84', '101'))	('autophagy', 'CPA', (106, 115))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('autophagy', 'biological_process', 'GO:0006914', ('106', '115'))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('arrest', 'Disease', (95, 101))
68571	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('EMT process', 'CPA', (4, 15))	('MLN8237 treatment', 'Var', (35, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))	('EMT', 'biological_process', 'GO:0001837', ('4', '7'))
68572	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
68573	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('degradation', 'biological_process', 'GO:0009056', ('67', '78'))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
68574	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('formation', 'biological_process', 'GO:0009058', ('52', '61'))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
68575	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
68576	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
68580	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
68581	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
68582	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
68583	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('benefit', 'PosReg', (132, 139))	('N-myc', 'Gene', (86, 91))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
68584	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
68585	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
68586	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
68587	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
68588	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
68589	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
68591	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
68593	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('35', '52'))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('affecting', 'Reg', (56, 65))	('NF-kB pathway', 'Pathway', (70, 83))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
68594	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('decreases', 'NegReg', (13, 22))	('tumor', 'Disease', (68, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('leiomyosarcoma', 'Disease', (97, 111))
68597	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('drug', 'MPA', (104, 108))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'biological_process', 'GO:0009315', ('104', '119'))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('drug resistance', 'biological_process', 'GO:0042493', ('104', '119'))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
68598	33451333	AT9283 exhibits strong activity against several kinases.	('kinases', 'Pathway', (48, 55))	('activity', 'MPA', (23, 31))	('AT9283', 'Var', (0, 6))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
68599	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('tumor', 'Disease', (60, 65))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))	('BCR-ABL', 'Gene', (138, 145))
68602	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
68605	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('apoptosis', 'CPA', (106, 115))	('MK-0457', 'Var', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('cell cycle progression', 'CPA', (71, 93))	('cell cycle', 'biological_process', 'GO:0007049', ('71', '81'))	('accumulation', 'PosReg', (16, 28))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))
68607	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
68609	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', (57, 64))	('BCR-ABL', 'Gene', '25', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
68610	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
68611	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('apoptosis', 'CPA', (43, 52))	('suppresses', 'NegReg', (71, 81))	('PHA-739358', 'Var', (0, 10))	('autophagy', 'biological_process', 'GO:0016236', ('57', '66'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('24', '41'))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('arrest', 'Disease', (35, 41))	('autophagy', 'biological_process', 'GO:0006914', ('57', '66'))	('EMT process', 'CPA', (86, 97))	('induces', 'Reg', (16, 23))	('autophagy', 'CPA', (57, 66))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))
68612	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
68613	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
68614	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
68615	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('AS703569', 'Var', (30, 38))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
68616	33451333	AURKA inhibitors have been shown to have great potential for enhancing the efficacy of multiple established therapeutic agents in both preclinical and clinical studies.	('AURKA', 'Gene', (0, 5))	('efficacy', 'MPA', (75, 83))	('inhibitors', 'Var', (6, 16))	('AURKA', 'Gene', '6790', (0, 5))	('enhancing', 'PosReg', (61, 70))
68623	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
68626	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
68630	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('Myc', 'Gene', '17869', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
68633	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('MLN8237', 'Var', (24, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('autophagy', 'biological_process', 'GO:0016236', ('129', '138'))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('increase', 'PosReg', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('autophagy', 'biological_process', 'GO:0006914', ('129', '138'))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('metastases', 'Disease', (142, 152))	('LC3B', 'Gene', '81631', (165, 169))	('Akt', 'Gene', '207', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
68634	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
68637	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
68638	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('sensitization', 'biological_process', 'GO:0046960', ('101', '114'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('MLN8054', 'Var', (25, 32))
68639	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
68644	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('hTERT', 'Gene', (126, 131))	('lymphoma', 'Disease', (78, 86))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('cell killing', 'biological_process', 'GO:0001906', ('87', '99'))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('microRNA levels', 'MPA', (137, 152))	('reductions', 'NegReg', (105, 115))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
68648	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('EGFR', 'Gene', '1956', (0, 4))
68652	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
68653	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
68656	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('senescence', 'CPA', (127, 137))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))	('senescence', 'biological_process', 'GO:0010149', ('127', '137'))
68657	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('G1 phase', 'biological_process', 'GO:0051318', ('126', '134'))	('apoptosis', 'biological_process', 'GO:0097194', ('192', '201'))	('mitochondrial apoptosis', 'CPA', (178, 201))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('p53', 'Gene', (160, 163))	('AML', 'Disease', (205, 208))	('activated', 'PosReg', (68, 77))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('apoptosis', 'biological_process', 'GO:0006915', ('192', '201'))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
68660	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('antibody', 'molecular_function', 'GO:0003823', ('96', '104'))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('antibody', 'cellular_component', 'GO:0042571', ('96', '104'))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('antibody', 'cellular_component', 'GO:0019815', ('96', '104'))	('p53', 'Gene', (188, 191))	('protein', 'cellular_component', 'GO:0003675', ('192', '199'))	('increases', 'PosReg', (38, 47))	('reduction', 'NegReg', (128, 137))	('PHLDA1', 'Gene', (177, 183))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))	('antibody', 'cellular_component', 'GO:0019814', ('96', '104'))
68661	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('antibody', 'cellular_component', 'GO:0042571', ('55', '63'))	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('antibody', 'cellular_component', 'GO:0019815', ('55', '63'))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('antibody', 'molecular_function', 'GO:0003823', ('55', '63'))	('antibody', 'cellular_component', 'GO:0019814', ('55', '63'))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
68662	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('antibody', 'cellular_component', 'GO:0042571', ('27', '35'))	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('75', '84'))	('antibody', 'cellular_component', 'GO:0019815', ('27', '35'))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('antibody', 'cellular_component', 'GO:0019814', ('27', '35'))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('antibody', 'molecular_function', 'GO:0003823', ('27', '35'))	('tumor', 'Disease', (88, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('75', '84'))	('senescence', 'biological_process', 'GO:0010149', ('127', '137'))
68680	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
68689	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('kinase activity', 'molecular_function', 'GO:0016301', ('166', '181'))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
68693	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('p53', 'Gene', (75, 78))	('increased', 'PosReg', (92, 101))	('mutation', 'Var', (79, 87))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
68713	31839882	Consistent with that study were previous publications showing that high expression of immune gene signatures was associated with favorable prognosis in breast and colorectal cancer.	('high', 'Var', (67, 71))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (152, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('immune gene signatures', 'Gene', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
68738	31839882	CTNNB1 gene mutation has been shown to be associated with low immune response.	('CTNNB1', 'Gene', '1499', (0, 6))	('low immune response', 'CPA', (58, 77))	('low immune response', 'Phenotype', 'HP:0002721', (58, 77))	('CTNNB1', 'Gene', (0, 6))	('immune response', 'biological_process', 'GO:0006955', ('62', '77'))	('mutation', 'Var', (12, 20))
68739	31839882	On the other hand, patients with POLE gene mutations had higher immune activity and were associated with favorable prognosis compared with patients without POLE mutations.	('patients', 'Species', '9606', (19, 27))	('immune activity', 'MPA', (64, 79))	('higher', 'PosReg', (57, 63))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (43, 52))	('POLE gene', 'Gene', (33, 42))
68776	31839882	MHC class I molecules, including HLA-A, -B, and -C, present peptides from inside the cell to T lymphocytes, while MHC class II molecules (HLA-DP, -DM, -DO, -DQ, and -DR) present antigens from outside the cell.	('peptides', 'MPA', (60, 68))	('HLA-DP', 'Var', (138, 144))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (33, 50))
68822	28652266	Among ncRNAs, long ncRNAs (lncRNAs) that are >200 bases long have been reported to interact with DNA-binding proteins, such as chromatin-modifying complexes and transcription factors, and regulate gene expression through epigenetic alterations in the nucleus or to function as a molecular sponge in the cytoplasm.	('nucleus', 'cellular_component', 'GO:0005634', ('251', '258'))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('gene expression', 'MPA', (197, 212))	('cytoplasm', 'cellular_component', 'GO:0005737', ('303', '312'))	('epigenetic alterations', 'Var', (221, 243))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('interact', 'Interaction', (83, 91))	('rat', 'Species', '10116', (236, 239))	('regulate', 'Reg', (188, 196))	('gene expression', 'biological_process', 'GO:0010467', ('197', '212'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('97', '108'))	('chromatin', 'cellular_component', 'GO:0000785', ('127', '136'))
68833	28652266	The expression of both JHDM1D and JHDM1D-AS1 was decreased by deletion of common 5' promoter regions of JHDM1D and JHDM1D-AS1 using guide RNA (gRNA)-mediated genome editing (Fig.	('JHDM1D', 'Gene', '80853', (23, 29))	('JHDM1D', 'Gene', '80853', (34, 40))	('JHDM1D', 'Gene', (104, 110))	('JHDM1D', 'Gene', (115, 121))	('JHDM1D-AS1', 'Gene', '100134229', (115, 125))	('expression', 'MPA', (4, 14))	('JHDM1D', 'Gene', '80853', (104, 110))	('JHDM1D-AS1', 'Gene', (34, 44))	('decreased', 'NegReg', (49, 58))	('JHDM1D', 'Gene', '80853', (115, 121))	('JHDM1D-AS1', 'Gene', '100134229', (34, 44))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('JHDM1D', 'Gene', (23, 29))	('deletion', 'Var', (62, 70))	('JHDM1D', 'Gene', (34, 40))	('JHDM1D-AS1', 'Gene', (115, 125))
68859	28652266	To investigate whether silencing of JHDM1D-AS1 small interfering RNAs (siRNAs) influences cancer cell growth in vitro and tumor growth in vivo, we knocked down JHDM1D-AS1 using siRNA (Fig.	('influences', 'Reg', (79, 89))	('JHDM1D-AS1', 'Gene', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('knocked down', 'Var', (147, 159))	('JHDM1D-AS1', 'Gene', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('JHDM1D-AS1', 'Gene', '100134229', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('JHDM1D-AS1', 'Gene', '100134229', (160, 170))	('cancer', 'Disease', (90, 96))	('tumor', 'Disease', (122, 127))
68861	28652266	4C) conditions in PANC-1 and AsPC-1 cells in vitro, inhibition of JHDM1D-AS1 significantly decreased the tumor growth of PANC-1 cells in vivo (Fig.	('PANC-1', 'Gene', (121, 127))	('AsPC-1', 'CellLine', 'CVCL:0152', (29, 35))	('JHDM1D-AS1', 'Gene', '100134229', (66, 76))	('PANC-1', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibition', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PANC-1', 'Gene', '104066', (121, 127))	('JHDM1D-AS1', 'Gene', (66, 76))	('PANC-1', 'Gene', '104066', (18, 24))	('tumor', 'Disease', (105, 110))	('decreased', 'NegReg', (91, 100))
68897	28652266	A xenograft study revealed that JHDM1D-AS1 overexpression indeed increased tumor growth in vivo, accompanied by elevated blood vessel formation and macrophage infiltration.	('increased', 'PosReg', (65, 74))	('JHDM1D-AS1', 'Gene', (32, 42))	('blood vessel formation', 'CPA', (121, 143))	('rat', 'Species', '10116', (165, 168))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('elevated', 'PosReg', (112, 120))	('macrophage infiltration', 'CPA', (148, 171))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('JHDM1D-AS1', 'Gene', '100134229', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('overexpression', 'Var', (43, 57))	('tumor', 'Disease', (75, 80))
68914	28652266	Based on these results, we suggest that inhibition of the nutrient starvation-responsive lncRNA JHDM1D-AS1 can be a potential therapeutic approach for cancer in the future.	('inhibition', 'Var', (40, 50))	('JHDM1D-AS1', 'Gene', '100134229', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('JHDM1D-AS1', 'Gene', (96, 106))
68932	28652266	Prewashed magnetic Dynabeads (Life Technologies, MA) were incubated with anti-H3K27ac antibody (Millipore, MA) or anti-SREBP2 antibody (Cayman, MI) in ChIP dilution buffer (20 mM Tris-HCl [pH 8.0], 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, protease inhibitor cocktail [Roche, Basel, Switzerland]) for 6 h by wheel rotating at 4 C. Subsequently, sonicated cross-linked nuclear lysates were added and incubated overnight at 4 C by wheel rotating.	('SREBP2', 'Gene', (119, 125))	('antibody', 'cellular_component', 'GO:0019815', ('126', '134'))	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019814', ('126', '134'))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('anti-H3K27ac', 'Var', (73, 85))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('antibody', 'molecular_function', 'GO:0003823', ('126', '134'))	('Triton X-100', 'Chemical', 'MESH:D017830', (225, 237))	('NaCl', 'Chemical', 'MESH:D012965', (205, 209))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))	('Tris-HCl', 'Chemical', '-', (179, 187))	('SREBP2', 'Gene', '6721', (119, 125))	('antibody', 'cellular_component', 'GO:0042571', ('126', '134'))
68962	31320640	To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (157, 166))	('mucosal melanoma', 'Disease', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('mucosal melanoma', 'Disease', 'MESH:D008545', (46, 62))
68963	31320640	Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TERT', 'Gene', (137, 141))	('CDK', 'molecular_function', 'GO:0004693', ('143', '146'))	('structural rearrangements', 'Var', (101, 126))	('TERT', 'Gene', '7015', (137, 141))	('Tumors', 'Disease', (0, 6))	('CDK4', 'Gene', (143, 147))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CDK4', 'Gene', '1019', (143, 147))	('MDM2', 'Gene', '4193', (152, 156))	('MDM2', 'Gene', (152, 156))
68965	31320640	SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas.	('SF3B1', 'Gene', (0, 5))	('implicate', 'Reg', (99, 108))	('CTNNB1', 'Gene', (82, 88))	('mucosal melanomas', 'Disease', (165, 182))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('SF3B1', 'Gene', '23451', (0, 5))	('mucosal melanomas', 'Disease', 'MESH:D008545', (165, 182))	('melanomas', 'Phenotype', 'HP:0002861', (173, 182))	('anorectal melanomas', 'Disease', 'MESH:D008545', (58, 77))	('signaling', 'biological_process', 'GO:0023052', ('124', '133'))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('mutations', 'Var', (89, 98))	('CTNNB1', 'Gene', '1499', (82, 88))	('anorectal melanomas', 'Disease', (58, 77))	('female genital', 'Disease', (39, 53))	('mutations', 'Var', (6, 15))
68966	31320640	TERT aberrations and ATRX mutations are associated with alterations in telomere length.	('telomere', 'cellular_component', 'GO:0005696', ('71', '79'))	('alterations', 'Reg', (56, 67))	('ATRX', 'Gene', (21, 25))	('TERT', 'Gene', (0, 4))	('mutations', 'Var', (26, 35))	('TERT', 'Gene', '7015', (0, 4))	('ATRX', 'Gene', '546', (21, 25))	('telomere length', 'MPA', (71, 86))	('telomere', 'cellular_component', 'GO:0000781', ('71', '79'))
68976	31320640	Compared to cutaneous melanoma they are typically detected at a more advanced stage, lack dominant MAP kinase-activating mutations, and respond to immunotherapy less frequently.	('lack', 'NegReg', (85, 89))	('MAP', 'molecular_function', 'GO:0004239', ('99', '102'))	('mutations', 'Var', (121, 130))	('cutaneous melanoma', 'Disease', (12, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (12, 30))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (12, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))
68977	31320640	Alterations to SF3B1, KIT, and NF1 are relatively common compared to cutaneous melanomas, while mutations to BRAF and NRAS are less frequent in mucosal melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('Alterations', 'Var', (0, 11))	('NF1', 'Gene', (31, 34))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('NRAS', 'Gene', '4893', (118, 122))	('SF3B1', 'Gene', (15, 20))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (69, 88))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (69, 88))	('common', 'Reg', (50, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('mucosal melanomas', 'Disease', 'MESH:D008545', (144, 161))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('SF3B1', 'Gene', '23451', (15, 20))	('mucosal melanomas', 'Disease', (144, 161))	('NRAS', 'Gene', (118, 122))	('KIT', 'Gene', (22, 25))	('KIT', 'molecular_function', 'GO:0005020', ('22', '25'))	('cutaneous melanomas', 'Disease', (69, 88))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('NF1', 'Gene', '4763', (31, 34))
68978	31320640	Similar to some cutaneous melanomas, BRAF fusions occur in mucosal melanoma, although they are rare.	('mucosal melanoma', 'Disease', (59, 75))	('BRAF', 'Gene', '673', (37, 41))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('BRAF', 'Gene', (37, 41))	('mucosal melanoma', 'Disease', 'MESH:D008545', (59, 75))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (16, 35))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (16, 35))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('fusions', 'Var', (42, 49))	('cutaneous melanomas', 'Disease', (16, 35))
68979	31320640	Tumors carrying such fusions are somewhat sensitive to anti-MEK targeted therapy, but long-term disease control is rarely achieved.	('MEK', 'Gene', '5609', (60, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('fusions', 'Var', (21, 28))	('MEK', 'Gene', (60, 63))
68991	31320640	In keeping with our previous report for this tumor type, all mucosal melanomas showed a low single-nucleotide variant (SNV) and insertion/deletion (indel) mutation burden, with an average of 2.7 mutations per Mb (range 0.54-7.1) (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('mucosal melanomas', 'Disease', (61, 78))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mucosal melanomas', 'Disease', 'MESH:D008545', (61, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('insertion/deletion', 'Var', (128, 146))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
68999	31320640	Signature 3 has been associated with BRCA1, BRCA2, and/or PALB2 mutations.	('associated', 'Reg', (21, 31))	('PALB2', 'Gene', '79728', (58, 63))	('BRCA2', 'Gene', (44, 49))	('mutations', 'Var', (64, 73))	('PALB2', 'Gene', (58, 63))	('BRCA1', 'Gene', '672', (37, 42))	('BRCA2', 'Gene', '675', (44, 49))	('BRCA1', 'Gene', (37, 42))
69000	31320640	However, no pathogenic germline variants or biallelic loss of somatic mutations in BRCA1, BRCA2, or PALB2 was identified in the samples with >50% contribution of the signature 3-like signature.	('mutations', 'Var', (70, 79))	('BRCA2', 'Gene', (90, 95))	('BRCA1', 'Gene', '672', (83, 88))	('loss', 'NegReg', (54, 58))	('BRCA1', 'Gene', (83, 88))	('BRCA2', 'Gene', '675', (90, 95))	('PALB2', 'Gene', '79728', (100, 105))	('PALB2', 'Gene', (100, 105))
69008	31320640	RS4 and RS6 are characterized by clustered SV breakpoints, with RS4 having a high number of inter-chromosomal translocations and RS6 having clustered inversions, duplications, and deletions.	('RS4', 'Gene', (64, 67))	('clustered SV', 'Disease', 'MESH:D003027', (33, 45))	('clustered SV', 'Disease', (33, 45))	('duplications', 'Var', (162, 174))	('deletions', 'Var', (180, 189))
69010	31320640	Twenty-eight tumors were characterized by high overall SV counts, clustered breakpoints, a dominance of signatures RS4 and RS6, and a high number of kataegis loci (localized regions of substitution hypermutation) (Group 1).	('SV counts', 'MPA', (55, 64))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('RS6', 'Var', (123, 126))	('RS4', 'Var', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
69013	31320640	Although there were some tumors that showed patterns similar to chromothripsis (clustered breakpoints, oscillation of copy number, and retention of heterozygosity) and breakage-fusion-bridge (BFB) (loss of telomeric regions and a high number of inversions), most events were too complex to confidently assign to one particular type of mutational mechanism.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('breakage-fusion-bridge', 'Var', (168, 190))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('retention', 'biological_process', 'GO:0051235', ('135', '144'))	('loss', 'NegReg', (198, 202))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('telomeric regions', 'Protein', (206, 223))	('chromothripsis', 'Disease', (64, 78))
69017	31320640	Most of the samples with chromosome 5p-12q translocations were oral mucosal melanomas (7 oral, 1 anorectal), of East Asian ancestry (7 East Asian, 1 European), had amplifications of CDK4 or MDM2 (7/8) on chromosome 12 and TERT or SKP2 (4/8) on chromosome 5 and were, on average, younger at tumor diagnosis when compared with the overall cohort (P = 0.006, mean age 42 vs 58).	('MDM2', 'Gene', '4193', (190, 194))	('TERT', 'Gene', (222, 226))	('TERT', 'Gene', '7015', (222, 226))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('CDK4', 'Gene', '1019', (182, 186))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (63, 85))	('amplifications', 'Var', (164, 178))	('oral mucosal melanomas', 'Disease', (63, 85))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('SKP2', 'Gene', (230, 234))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('MDM2', 'Gene', (190, 194))	('chromosome 5p-12q translocations', 'Var', (25, 57))	('SKP2', 'Gene', '6502', (230, 234))	('chromosome', 'cellular_component', 'GO:0005694', ('204', '214'))	('chromosome', 'cellular_component', 'GO:0005694', ('244', '254'))	('CDK', 'molecular_function', 'GO:0004693', ('182', '185'))	('CDK4', 'Gene', (182, 186))
69018	31320640	The trinucleotide context of SNVs that fell within kataegis loci displayed characteristics of mutational signatures 2 and 13 which are associated with APOBEC deamination (Supplementary Fig.	('APOBEC deamination', 'Disease', (151, 169))	('trinucleotide', 'Chemical', '-', (4, 17))	('mutational signatures', 'Var', (94, 115))	('associated with', 'Reg', (135, 150))	('APOBEC', 'cellular_component', 'GO:0030895', ('151', '157'))
69019	31320640	Supplementary Data 3 lists all coding SNVs/indels in the mucosal melanomas subjected to WGS.	('mucosal melanomas', 'Disease', (57, 74))	('mucosal melanomas', 'Disease', 'MESH:D008545', (57, 74))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanomas', 'Phenotype', 'HP:0002861', (65, 74))	('SNVs/indels', 'Var', (38, 49))
69022	31320640	The BRAF mutations were diverse (Fig.	('mutations', 'Var', (9, 18))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
69023	31320640	NRAS mutations were targeted to hotspots on codon 61, which is the dominant hotspot in cutaneous melanoma, and codon 12, a hotspot less commonly mutated in cutaneous melanoma (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('cutaneous melanoma', 'Disease', (87, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (87, 105))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (87, 105))	('mutations', 'Var', (5, 14))	('cutaneous melanoma', 'Disease', (156, 174))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (156, 174))	('NRAS', 'Gene', (0, 4))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (156, 174))	('NRAS', 'Gene', '4893', (0, 4))
69024	31320640	NRAS mutations were mostly found in samples from recurrent/metastatic sites (two primary, eight recurrent/metastatic, two unknown, Fisher's exact, P = 0.032).	('found', 'Reg', (27, 32))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
69025	31320640	Interestingly, there was little overlap between tumors with MAPK pathway mutations and SF3B1-mutated tumors, suggesting that the latter mutations may result in MAPK activation.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('MAPK activation', 'biological_process', 'GO:0000187', ('160', '175'))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('MAPK', 'molecular_function', 'GO:0004707', ('160', '164'))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('SF3B1', 'Gene', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SF3B1', 'Gene', '23451', (87, 92))	('MAPK', 'Gene', (160, 164))	('MAPK', 'molecular_function', 'GO:0004707', ('60', '64'))	('activation', 'PosReg', (165, 175))	('mutations', 'Var', (73, 82))	('tumors', 'Disease', (101, 107))
69026	31320640	All SF3B1 mutations targeted the 625 codon hotspot (Fig.	('targeted', 'Reg', (20, 28))	('SF3B1', 'Gene', (4, 9))	('SF3B1', 'Gene', '23451', (4, 9))	('625 codon hotspot', 'MPA', (33, 50))	('mutations', 'Var', (10, 19))
69028	31320640	SF3B1 mutations were also mostly in mucosal melanomas of European ancestry (7/8) and all were from primary tumor samples.	('mucosal melanomas', 'Disease', (36, 53))	('SF3B1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mucosal melanomas', 'Disease', 'MESH:D008545', (36, 53))	('SF3B1', 'Gene', '23451', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mutations', 'Var', (6, 15))
69029	31320640	BRAF mutations were rare in the nasal cavity, with no codon 600 mutations and only one G-loop mutation identified (G469A).	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('G469A', 'Mutation', 'rs121913355', (115, 120))	('mutations', 'Var', (5, 14))
69030	31320640	The six tumors with >50% UV signature had no statistically significant difference in driver genes mutations, but lacked mutations in TP53, SPRED1, SF3B1.	('lacked', 'NegReg', (113, 119))	('SF3B1', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutations', 'Var', (98, 107))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('SPRED1', 'Gene', '161742', (139, 145))	('SF3B1', 'Gene', '23451', (147, 152))	('SPRED1', 'Gene', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))
69034	31320640	Once again, SF3B1 mutations were also predominant (5/6) in tumors from anogenital regions.	('SF3B1', 'Gene', (12, 17))	('predominant', 'Reg', (38, 49))	('SF3B1', 'Gene', '23451', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (18, 27))
69038	31320640	Two samples were from Australia (an anorectal melanoma with p.L31_I35del and a mucosal melanoma arising in the lacrimal sac with p.S33C) and two were from China (a nasal melanoma with p.T41A and an oral melanoma carrying both p.P44A and p.S45P mutations on the same haplotype).	('p.T41A', 'Mutation', 'rs121913412', (184, 190))	('nasal melanoma', 'Disease', 'MESH:D008545', (164, 178))	('p.P44A', 'Mutation', 'rs1418681944', (226, 232))	('p.S33C', 'Mutation', 'rs121913400', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('mucosal melanoma', 'Disease', 'MESH:D008545', (79, 95))	('p.P44A', 'Var', (226, 232))	('anorectal melanoma', 'Disease', (36, 54))	('mucosal melanoma', 'Disease', (79, 95))	('oral melanoma', 'Disease', (198, 211))	('sac', 'biological_process', 'GO:0071173', ('120', '123'))	('sac', 'cellular_component', 'GO:0035003', ('120', '123'))	('p.L31_I35del', 'Mutation', 'p.31,35delI', (60, 72))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('nasal melanoma', 'Disease', (164, 178))	('oral melanoma', 'Disease', 'MESH:D008545', (198, 211))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('p.S33C', 'Var', (129, 135))	('p.S45P', 'Mutation', 'rs121913407', (237, 243))	('p.L31_I35del', 'Var', (60, 72))	('p.S45P', 'Var', (237, 243))	('anorectal melanoma', 'Disease', 'MESH:D008545', (36, 54))
69039	31320640	Two samples in the WES validation cohort also had CTNNB1 mutations.	('CTNNB1', 'Gene', (50, 56))	('mutations', 'Var', (57, 66))	('CTNNB1', 'Gene', '1499', (50, 56))
69040	31320640	All of these mutations occurred at documented hotspots in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('occurred', 'Reg', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (66, 72))
69041	31320640	Additionally, in single WGS samples, we noted hotspot activating mutations in the oncogenes MAP2K1, GNAQ, and KRAS as well as unambiguous loss-of-function (LoF) mutations in the tumor suppressor genes CDKN2A (nonsense), BAP1 (frameshift), MEN1 (nonsense), and NF2 (frameshift).	('GNAQ', 'Gene', '2776', (100, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('178', '194'))	('loss-of-function', 'NegReg', (138, 154))	('GNAQ', 'Gene', (100, 104))	('MEN1', 'Gene', (239, 243))	('BAP1', 'Gene', '8314', (220, 224))	('tumor', 'Disease', (178, 183))	('NF2', 'Gene', '4771', (260, 263))	('CDKN2A', 'Gene', (201, 207))	('MAP2K1', 'Gene', '5604', (92, 98))	('tumor suppressor', 'biological_process', 'GO:0051726', ('178', '194'))	('MAP2K1', 'Gene', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('NF2', 'Gene', (260, 263))	('activating', 'PosReg', (54, 64))	('CDKN2A', 'Gene', '1029', (201, 207))	('MAP2K', 'molecular_function', 'GO:0004708', ('92', '97'))	('KRAS', 'Gene', '3845', (110, 114))	('BAP1', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('KRAS', 'Gene', (110, 114))	('nonsense', 'Var', (245, 253))	('mutations', 'Var', (161, 170))	('MEN1', 'Gene', '4221', (239, 243))	('mutations', 'Var', (65, 74))
69044	31320640	4c, d), and copy loss of NF1, PTEN, CDKN2A, ATM, and ARID1B (Fig.	('CDKN2A', 'Gene', (36, 42))	('ATM', 'Gene', (44, 47))	('CDKN2A', 'Gene', '1029', (36, 42))	('ARID1B', 'Gene', (53, 59))	('ATM', 'Gene', '472', (44, 47))	('NF1', 'Gene', (25, 28))	('copy loss', 'Var', (12, 21))	('PTEN', 'Gene', (30, 34))	('NF1', 'Gene', '4763', (25, 28))	('PTEN', 'Gene', '5728', (30, 34))	('ARID1B', 'Gene', '57492', (53, 59))
69046	31320640	We observed homozygous deletion of SPRED1 in two tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('deletion', 'Var', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('SPRED1', 'Gene', '161742', (35, 41))	('SPRED1', 'Gene', (35, 41))
69054	31320640	We related tumor TL to primary tumor site and mutations in key genes affecting telomere biology (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('mutations', 'Var', (46, 55))	('telomere', 'cellular_component', 'GO:0000781', ('79', '87'))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (31, 36))	('telomere', 'cellular_component', 'GO:0005696', ('79', '87'))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
69056	31320640	In contrast, ATRX mutations were less frequent (4/67 inactivating SNVs and 3/67 SVs; one with both SNV and SV) and were associated with increased TL (P = 0.0025; Supplementary Fig.	('ATRX', 'Gene', (13, 17))	('inactivating', 'NegReg', (53, 65))	('ATRX', 'Gene', '546', (13, 17))	('increased', 'PosReg', (136, 145))	('mutations', 'Var', (18, 27))
69060	31320640	Activating TERT mutations and loss of function ATRX mutations were mutually exclusive, as has also been observed in gliomas.	('ATRX', 'Gene', (47, 51))	('mutations', 'Var', (52, 61))	('Activating', 'PosReg', (0, 10))	('ATRX', 'Gene', '546', (47, 51))	('TERT', 'Gene', (11, 15))	('gliomas', 'Disease', (116, 123))	('TERT', 'Gene', '7015', (11, 15))	('gliomas', 'Disease', 'MESH:D005910', (116, 123))	('gliomas', 'Phenotype', 'HP:0009733', (116, 123))
69061	31320640	For 4/6 ATRX-mutated samples, TP53 SNV mutations also occurred.	('TP53', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (8, 12))	('mutations', 'Var', (39, 48))	('occurred', 'Reg', (54, 62))	('ATRX', 'Gene', (8, 12))	('TP53', 'Gene', '7157', (30, 34))
69062	31320640	In addition, in the WES cohort, all three LoF ATRX mutations also co-occurred with TP53 mutations.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (51, 60))	('ATRX', 'Gene', '546', (46, 50))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('ATRX', 'Gene', (46, 50))	('LoF', 'NegReg', (42, 45))
69063	31320640	When TL was assessed against putative mucosal cancer drivers identified in this study, a strong correlation with KIT activating mutations and telomere shortening was observed (P = 0.0018, Supplementary Fig 7f).	('telomere', 'cellular_component', 'GO:0005696', ('142', '150'))	('mutations', 'Var', (128, 137))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('activating', 'PosReg', (117, 127))	('mucosal cancer', 'Disease', 'MESH:D009062', (38, 52))	('KIT', 'Gene', (113, 116))	('mucosal cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('telomere', 'cellular_component', 'GO:0000781', ('142', '150'))	('telomere shortening', 'Phenotype', 'HP:0031413', (142, 161))	('telomere', 'MPA', (142, 150))
69065	31320640	Mucosal melanomas carried an average of four (range 0-15) established and putative driver gene aberrations (of all types) (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('Mucosal melanomas', 'Disease', (0, 17))	('aberrations', 'Var', (95, 106))	('Mucosal melanomas', 'Disease', 'MESH:D008545', (0, 17))
69066	31320640	Overall, all but one tumor (66/67) had at least one well-established driver gene mutation (Fig.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mutation', 'Var', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
69069	31320640	When comparing any aberration with respect to primary and recurrent/metastatic sample types, SF3B1 (Fisher's exact, P = 0.0057) and SPRED1 (Fisher's exact, P = 0.02) mutations were mostly present in primary samples and NRAS aberrations were predominantly in recurrent/metastatic tumors.	('NRAS', 'Gene', '4893', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('SPRED1', 'Gene', '161742', (132, 138))	('mutations', 'Var', (166, 175))	('SF3B1', 'Gene', (93, 98))	('tumors', 'Disease', (279, 285))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('NRAS', 'Gene', (219, 223))	('SPRED1', 'Gene', (132, 138))	('SF3B1', 'Gene', '23451', (93, 98))
69070	31320640	The inhibitors with the highest levels of evidence included three patients with BRAF V600E where FDA guidelines indicate use of BRAF and/or MEK inhibitors and seven samples with KIT mutations.	('MEK', 'Gene', (140, 143))	('BRAF', 'Gene', (80, 84))	('KIT', 'molecular_function', 'GO:0005020', ('178', '181'))	('MEK', 'Gene', '5609', (140, 143))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('patients', 'Species', '9606', (66, 74))	('BRAF', 'Gene', '673', (128, 132))	('V600E', 'Var', (85, 90))	('BRAF', 'Gene', '673', (80, 84))	('BRAF', 'Gene', (128, 132))
69071	31320640	Notably, a large proportion of the cohort (47/67, 70%) harbored mutations potentially responsive to CDK4/6 inhibitors, although the evidence for such treatments is in the lower confidence categories of case reports and early trials.	('CDK4/6', 'Gene', (100, 106))	('CDK', 'molecular_function', 'GO:0004693', ('100', '103'))	('mutations', 'Var', (64, 73))	('CDK4/6', 'Gene', '1019;1021', (100, 106))
69072	31320640	The driver mutations identified as responsive to CDK4/6 inhibitors include CDK4 and CCND1 amplifications, as well as CDKN2A deletions.	('CDKN2A', 'Gene', '1029', (117, 123))	('CDK', 'molecular_function', 'GO:0004693', ('75', '78'))	('CCND1', 'Gene', (84, 89))	('CDK', 'molecular_function', 'GO:0004693', ('49', '52'))	('CDK4', 'Gene', (75, 79))	('amplifications', 'Var', (90, 104))	('CCND1', 'Gene', '595', (84, 89))	('CDK4', 'Gene', '1019', (75, 79))	('CDK4/6', 'Gene', '1019;1021', (49, 55))	('CDKN2A', 'Gene', (117, 123))	('CDK4', 'Gene', (49, 53))	('deletions', 'Var', (124, 133))	('CDK4/6', 'Gene', (49, 55))	('CDK4', 'Gene', '1019', (49, 53))
69073	31320640	In addition, although not identified as a significantly mutated driver, a number of samples also had CDK6 amplifications (9/67, 13%) that indicates potential sensitivity to CDK4/6 inhibitors.	('amplifications', 'Var', (106, 120))	('CDK4/6', 'Gene', (173, 179))	('CDK', 'molecular_function', 'GO:0004693', ('101', '104'))	('CDK4/6', 'Gene', '1019;1021', (173, 179))	('CDK', 'molecular_function', 'GO:0004693', ('173', '176'))	('CDK6', 'Gene', (101, 105))	('CDK6', 'Gene', '1021', (101, 105))
69074	31320640	The analysis also identified a MITF amplification, NF1 mutation, and a mutation in MAP2K1 (encoding MEK1) that may confer resistance to MEK/MAPK inhibitors.	('MEK1', 'molecular_function', 'GO:0004708', ('100', '104'))	('MEK', 'Gene', (100, 103))	('mutation', 'Var', (71, 79))	('MEK', 'Gene', (136, 139))	('MAP2K1', 'Gene', (83, 89))	('MEK', 'Gene', '5609', (136, 139))	('NF1', 'Gene', '4763', (51, 54))	('MAP2K', 'molecular_function', 'GO:0004708', ('83', '88'))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('MEK1', 'Gene', '5604', (100, 104))	('MEK', 'Gene', '5609', (100, 103))	('MEK1', 'Gene', (100, 104))	('mutation', 'Var', (55, 63))	('NF1', 'Gene', (51, 54))	('MITF', 'Gene', '4286', (31, 35))	('MITF', 'Gene', (31, 35))	('MAP2K1', 'Gene', '5604', (83, 89))
69077	31320640	Additionally, the frequency of specific driver mutations varies with primary melanoma site.	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('mutations', 'Var', (47, 56))
69078	31320640	For example, SF3B1 hotspot mutations are common in anorectal and vulvovaginal melanomas but are rare in mucosal melanomas from other sites and BRAF mutations are less common in the nasal cavity.	('mutations', 'Var', (27, 36))	('anorectal', 'Disease', (51, 60))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (65, 87))	('SF3B1', 'Gene', (13, 18))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (65, 87))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('SF3B1', 'Gene', '23451', (13, 18))	('mucosal melanomas', 'Disease', (104, 121))	('vulvovaginal melanomas', 'Disease', (65, 87))	('mucosal melanomas', 'Disease', 'MESH:D008545', (104, 121))
69082	31320640	Interestingly, in contrast to prior reports, mutations resulting from UVR exposure were identified in some melanomas from facial mucosal sites while confirmed to be absent from lower body mucosal sites.	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('mutations', 'Var', (45, 54))	('identified', 'Reg', (88, 98))	('melanomas', 'Disease', (107, 116))
69084	31320640	Nevertheless, when compared with cutaneous melanomas, the UVR-related mutation load of sinonasal and oral mucosal melanomas is low.	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (101, 123))	('cutaneous melanomas', 'Disease', (33, 52))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (33, 52))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('low', 'NegReg', (127, 130))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (33, 52))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('UVR-related', 'Gene', (58, 69))	('sinonasal', 'Disease', (87, 96))	('oral mucosal melanomas', 'Disease', (101, 123))	('mutation', 'Var', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
69085	31320640	However, the evidence of UVR-related mutagenesis in mucosal melanomas of the facial area implicates reflected or attenuated UVR exposure as a carcinogen even in these relatively sun-shielded sites.	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutagenesis', 'biological_process', 'GO:0006280', ('37', '48'))	('mucosal melanomas', 'Disease', (52, 69))	('mutagenesis', 'Var', (37, 48))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mucosal melanomas', 'Disease', 'MESH:D008545', (52, 69))	('attenuated', 'NegReg', (113, 123))
69089	31320640	The dominant, non-UVR-related mutagenic processes included the clock-like (age-related) mutational processes of signature 1 (spontaneous deamination of 5-methylcytosine), an endogenous process that is active in the vast majority of cancers.	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('cancers', 'Disease', (232, 239))	('mutational', 'Var', (88, 98))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (152, 168))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))
69090	31320640	Significantly higher proportions of signature 1-related mutations were present in the mucosal melanomas of lower than upper body sites.	('mutations', 'Var', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('signature 1-related', 'Gene', (36, 55))	('mucosal melanomas', 'Disease', (86, 103))	('mucosal melanomas', 'Disease', 'MESH:D008545', (86, 103))
69098	31320640	However, while NF1 and SPRED1 mutations typically co-occur in cutaneous melanoma, in our study of mucosal melanomas, most SPRED1 aberrations identified in WGS samples (11/13) occurred in NF1 wild-type samples, with only two SVs in SPRED1 co-occurring with NF1 mutations.	('SPRED1', 'Gene', '161742', (122, 128))	('SPRED1', 'Gene', (23, 29))	('NF1', 'Gene', '4763', (15, 18))	('cutaneous melanoma', 'Disease', (62, 80))	('NF1', 'Gene', '4763', (187, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (62, 80))	('SPRED1', 'Gene', (122, 128))	('NF1', 'Gene', (15, 18))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (62, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (98, 115))	('occurred', 'Reg', (175, 183))	('SPRED1', 'Gene', '161742', (231, 237))	('NF1', 'Gene', (187, 190))	('mucosal melanomas', 'Disease', (98, 115))	('NF1', 'Gene', '4763', (256, 259))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('mutations', 'Var', (30, 39))	('SPRED1', 'Gene', (231, 237))	('SPRED1', 'Gene', '161742', (23, 29))	('NF1', 'Gene', (256, 259))	('aberrations', 'Var', (129, 140))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
69099	31320640	As previously reported, we found a substantial proportion of mucosal melanomas had aberrations of the MAPK pathway, including frequent mutations in NRAS, BRAF, NF1, and KIT.	('NRAS', 'Gene', (148, 152))	('mucosal melanomas', 'Disease', (61, 78))	('KIT', 'Gene', (169, 172))	('NF1', 'Gene', (160, 163))	('NRAS', 'Gene', '4893', (148, 152))	('NF1', 'Gene', '4763', (160, 163))	('mutations', 'Var', (135, 144))	('BRAF', 'Gene', '673', (154, 158))	('mucosal melanomas', 'Disease', 'MESH:D008545', (61, 78))	('MAPK', 'molecular_function', 'GO:0004707', ('102', '106'))	('BRAF', 'Gene', (154, 158))	('MAPK pathway', 'Pathway', (102, 114))	('KIT', 'molecular_function', 'GO:0005020', ('169', '172'))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))
69100	31320640	Mutations were also identified in several other known cancer driver genes, including CTNNB1, implicating the previously unappreciated role of WNT signaling in the genesis of mucosal melanomas.	('CTNNB1', 'Gene', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mucosal melanomas', 'Disease', (174, 191))	('cancer', 'Disease', (54, 60))	('CTNNB1', 'Gene', '1499', (85, 91))	('mucosal melanomas', 'Disease', 'MESH:D008545', (174, 191))	('Mutations', 'Var', (0, 9))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
69101	31320640	Since activation of the Wnt/beta-catenin pathway has also been demonstrated to cause T cell exclusion, CTNNB1 mutations may also contribute to the relatively poorer responses to immunotherapy observed in some advanced stage mucosal melanoma patients Hotspot mutations were also identified in the oncogenes MAP2K1 and KRAS, which together with a BRAF fusion, further highlight the reliance on MAPK pathway activation in this tumor type.	('MAPK', 'molecular_function', 'GO:0004707', ('392', '396'))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('cause', 'Reg', (79, 84))	('mucosal melanoma', 'Disease', 'MESH:D008545', (224, 240))	('tumor', 'Disease', (424, 429))	('CTNNB1', 'Gene', '1499', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (424, 429))	('mucosal melanoma', 'Disease', (224, 240))	('MAP2K1', 'Gene', '5604', (306, 312))	('MAP2K', 'molecular_function', 'GO:0004708', ('306', '311'))	('mutations', 'Var', (110, 119))	('MAP2K1', 'Gene', (306, 312))	('tumor', 'Phenotype', 'HP:0002664', (424, 429))	('KRAS', 'Gene', '3845', (317, 321))	('CTNNB1', 'Gene', (103, 109))	('patients', 'Species', '9606', (241, 249))	('BRAF', 'Gene', '673', (345, 349))	('beta-catenin', 'Gene', (28, 40))	('BRAF', 'Gene', (345, 349))	('KRAS', 'Gene', (317, 321))	('beta-catenin', 'Gene', '1499', (28, 40))	('T cell', 'CPA', (85, 91))	('activation', 'PosReg', (6, 16))
69106	31320640	In addition, we identified a number of tumors with regions of amplified loci on multiple chromosomes linked by high numbers of translocations.	('tumors', 'Disease', (39, 45))	('amplified loci', 'Var', (62, 76))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
69107	31320640	We have previously observed similar patterns in ovarian cancer, and these patterns are characteristic of double minute chromosomes or neochromosomes.	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('double minute chromosomes', 'Var', (105, 130))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('ovarian cancer', 'Disease', (48, 62))
69108	31320640	A number of mucosal melanomas in our cohort showed a pattern of translocations involving 12p amplifications which is similar to that of neochromosomes in liposarcomas.	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('liposarcomas', 'Disease', (154, 166))	('mucosal melanomas', 'Disease', 'MESH:D008545', (12, 29))	('liposarcomas', 'Phenotype', 'HP:0012034', (154, 166))	('liposarcomas', 'Disease', 'MESH:D008080', (154, 166))	('translocations', 'Var', (64, 78))	('melanomas', 'Phenotype', 'HP:0002861', (20, 29))	('mucosal melanomas', 'Disease', (12, 29))
69109	31320640	Localized structural rearrangement events targeted a number of regions, including 5p, 11p, and 12p, with a common consequence of these complex events being amplification of oncogenes such as TERT, MDM2, CCND1, CDK4.	('MDM2', 'Gene', '4193', (197, 201))	('amplification', 'Var', (156, 169))	('CCND1', 'Gene', '595', (203, 208))	('MDM2', 'Gene', (197, 201))	('CDK4', 'Gene', (210, 214))	('TERT', 'Gene', (191, 195))	('CCND1', 'Gene', (203, 208))	('TERT', 'Gene', '7015', (191, 195))	('CDK4', 'Gene', '1019', (210, 214))	('CDK', 'molecular_function', 'GO:0004693', ('210', '213'))
69110	31320640	Therefore, amplification of oncogenes or other cancer genes conferring a growth advantage may be an important mechanism driving mucosal melanoma.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mucosal melanoma', 'Disease', (128, 144))	('mucosal melanoma', 'Disease', 'MESH:D008545', (128, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('oncogenes', 'Gene', (28, 37))	('amplification', 'Var', (11, 24))
69111	31320640	All but one of the eight tumors in this study with translocations between 5p and 12p, usually resulting in amplifications of MDM2/CDK4 and TERT, were oral mucosal melanomas and of East Asian ancestry.	('translocations', 'Var', (51, 65))	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('amplifications', 'MPA', (107, 121))	('TERT', 'Gene', '7015', (139, 143))	('resulting', 'Reg', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('tumors', 'Disease', (25, 31))	('oral mucosal melanomas', 'Disease', (150, 172))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('CDK', 'molecular_function', 'GO:0004693', ('130', '133'))	('CDK4', 'Gene', (130, 134))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (150, 172))	('CDK4', 'Gene', '1019', (130, 134))	('MDM2', 'Gene', '4193', (125, 129))	('MDM2', 'Gene', (125, 129))	('TERT', 'Gene', (139, 143))
69112	31320640	Interestingly, oral mucosal melanomas carrying such translocations occurred at significantly younger age than those without translocations.	('translocations', 'Var', (52, 66))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (15, 37))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('oral mucosal melanomas', 'Disease', (15, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
69114	31320640	This notion is supported by Lyu et al., who recently reported amplifications of 12q14 and 5p15 in ~50% of oral mucosal melanomas, and 6/19 tumors had amplification of both regions.	('oral mucosal melanomas', 'Disease', (106, 128))	('12q14', 'Gene', (80, 85))	('p15', 'Gene', '1030', (91, 94))	('amplifications', 'Var', (62, 76))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('oral mucosal melanomas', 'Disease', 'MESH:D013280', (106, 128))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('p15', 'Gene', (91, 94))
69115	31320640	One potential consequence of genomic instability in mucosal melanomas is an effect on telomere maintenance and length.	('telomere', 'cellular_component', 'GO:0000781', ('86', '94'))	('effect', 'Reg', (76, 82))	('telomere maintenance', 'CPA', (86, 106))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('telomere', 'cellular_component', 'GO:0005696', ('86', '94'))	('mucosal melanomas', 'Disease', (52, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('mucosal melanomas', 'Disease', 'MESH:D008545', (52, 69))	('genomic instability', 'Var', (29, 48))	('length', 'MPA', (111, 117))	('telomere maintenance', 'biological_process', 'GO:0000723', ('86', '106'))
69116	31320640	A key event in cellular immortality is the presence of a telomere maintenance mechanism to escape cellular crisis, potentially occurring through activation of telomerase (TERT) or through alternative lengthening of telomeres (ALT), resulting from ATRX inactivation.	('activation', 'PosReg', (145, 155))	('telomere', 'cellular_component', 'GO:0000781', ('57', '65'))	('inactivation', 'Var', (252, 264))	('ATRX', 'Gene', (247, 251))	('telomere', 'cellular_component', 'GO:0005696', ('57', '65'))	('TERT', 'Gene', (171, 175))	('ATRX', 'Gene', '546', (247, 251))	('TERT', 'Gene', '7015', (171, 175))	('cellular crisis', 'MPA', (98, 113))	('telomere', 'MPA', (57, 65))	('cellular immortality', 'CPA', (15, 35))	('ALT', 'molecular_function', 'GO:0004021', ('226', '229'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('57', '77'))
69117	31320640	We identified mutually exclusive loss of function ATRX mutations and putatively activating TERT promoter mutations and amplifications, suggesting that both maintenance mechanisms are important in distinct subsets of mucosal melanoma.	('ATRX', 'Gene', '546', (50, 54))	('TERT', 'Gene', (91, 95))	('mutations', 'Var', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('mucosal melanoma', 'Disease', 'MESH:D008545', (216, 232))	('TERT', 'Gene', '7015', (91, 95))	('activating', 'PosReg', (80, 90))	('ATRX', 'Gene', (50, 54))	('mucosal melanoma', 'Disease', (216, 232))
69121	31320640	have very recently shown that such inhibitors are effective in treating patient derived xenografts of mucosal melanomas carrying CDK4 aberrations, thus providing experimental support for this notion.	('mucosal melanomas', 'Disease', (102, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('CDK4', 'Gene', (129, 133))	('mucosal melanomas', 'Disease', 'MESH:D008545', (102, 119))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('patient', 'Species', '9606', (72, 79))	('CDK4', 'Gene', '1019', (129, 133))	('aberrations', 'Var', (134, 145))
69122	31320640	Immunotherapies are standard of care for metastatic cutaneous melanoma patients; however, mucosal melanoma patients treated with PD-1 antibodies respond half as often as cutaneous melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('patients', 'Species', '9606', (107, 115))	('cutaneous melanoma', 'Disease', (52, 70))	('antibodies', 'Var', (134, 144))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('patients', 'Species', '9606', (71, 79))	('mucosal melanoma', 'Disease', (90, 106))	('cutaneous melanoma', 'Disease', (170, 188))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (170, 188))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (170, 188))	('mucosal melanoma', 'Disease', 'MESH:D008545', (90, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('patients', 'Species', '9606', (189, 197))	('PD-1', 'Gene', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
69124	31320640	Our data also suggest that activation of the beta-catenin pathway (through mutations in CTNNB1) may be a contributing factor.	('beta-catenin', 'Gene', '1499', (45, 57))	('CTNNB1', 'Gene', '1499', (88, 94))	('mutations', 'Var', (75, 84))	('activation', 'PosReg', (27, 37))	('beta-catenin', 'Gene', (45, 57))	('CTNNB1', 'Gene', (88, 94))
69154	31320640	In-house scripts were used to take output from MAC, rerun variant effect prediction on MNVs, and fix VCF entries.	('VCF entries', 'Disease', (101, 112))	('MAC', 'cellular_component', 'GO:0097423', ('47', '50'))	('effect', 'Reg', (66, 72))	('VCF entries', 'Disease', 'MESH:D004062', (101, 112))	('variant', 'Var', (58, 65))	('MAC', 'cellular_component', 'GO:0005579', ('47', '50'))
69164	31320640	For genes recurrently affected by rearrangement breakage sites, COSMIC cancer genes that were rearranged in at least four patients were included.	('rearrangement breakage sites', 'Var', (34, 62))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
69173	31320640	References to BRAF inhibitor resistance was removed in samples that did not contain a BRAF mutation.	('mutation', 'Var', (91, 99))	('BRAF', 'Gene', '673', (86, 90))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', (86, 90))
69179	28147343	The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types For many years, defects in the ribosome have been associated to cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RPL5', 'Gene', '6125', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ribosome', 'cellular_component', 'GO:0005840', ('128', '136'))	('associated', 'Reg', (147, 157))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('haploinsufficient tumor', 'Disease', (37, 60))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('4', '21'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('defects', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (161, 167))	('RPL5', 'Gene', (27, 31))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (37, 60))
69180	28147343	Recently, somatic mutations and deletions affecting ribosomal protein genes were identified in a few leukemias and solid tumor types.	('deletions', 'Var', (32, 41))	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('leukemias', 'Disease', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('ribosomal protein genes', 'Gene', (52, 75))	('leukemias', 'Disease', 'MESH:D007938', (101, 110))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('52', '69'))	('identified', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
69183	28147343	RPL5 was located at a significant peak of heterozygous deletion or mutated in 11% of glioblastoma, 28% of melanoma and 34% of breast cancer samples.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('glioblastoma', 'Disease', (85, 97))	('breast cancer', 'Disease', (126, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('mutated', 'Var', (67, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
69184	28147343	Moreover, patients with low RPL5 expression displayed worse overall survival in glioblastoma and in one breast cancer cohort.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('one breast', 'Phenotype', 'HP:0012813', (100, 110))	('RPL5', 'Protein', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('overall survival', 'MPA', (60, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (10, 18))	('low', 'Var', (24, 27))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('worse', 'NegReg', (54, 59))
69187	28147343	In conclusion, RPL5 heterozygous inactivation occurs at high incidence (11-34%) in multiple tumor types, currently representing the most common somatic ribosomal protein defect in cancer, and we demonstrate a tumor suppressor role for RPL5 in breast cancer.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('protein defect in cancer', 'Disease', 'MESH:D009369', (162, 186))	('protein defect in cancer', 'Disease', (162, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumor', 'Disease', (209, 214))	('a tumor', 'Disease', 'MESH:D009369', (207, 214))	('RPL5', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('152', '169'))	('breast cancer', 'Disease', (243, 256))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('209', '225'))	('a tumor', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('RPL5', 'Gene', (235, 239))	('heterozygous inactivation', 'Var', (20, 45))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor suppressor', 'biological_process', 'GO:0051726', ('209', '225'))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
69188	28147343	Cancers contain a variety of genomic lesions including mutations, translocations, copy number alterations and epigenetic changes that can result in altered protein functions.	('copy number alterations', 'Var', (82, 105))	('translocations', 'Var', (66, 80))	('Cancers', 'Disease', (0, 7))	('mutations', 'Var', (55, 64))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('protein functions', 'MPA', (156, 173))	('altered', 'Reg', (148, 155))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('result', 'Reg', (138, 144))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))	('epigenetic changes', 'Var', (110, 128))
69192	28147343	Somatic mutations and deletions affecting ribosomal protein genes occur in up to 20% of acute T-cell leukemia (T-ALL) cases, with the most frequent defects affecting RPL10 (also known as uL16; 7.9% of pediatric T-ALL cases) and RPL22 (eL22; 10%) and with rare defects in RPL5 (uL18) and RPL11 (uL5).	('RPL22', 'Gene', (228, 233))	('deletions', 'Var', (22, 31))	('ribosomal protein genes', 'Gene', (42, 65))	('RPL22', 'Gene', '6146', (228, 233))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('42', '59'))	('RPL11', 'Gene', '6135', (287, 292))	('RPL10', 'Gene', (166, 171))	('RPL10', 'Gene', '6134', (166, 171))	('acute T-cell leukemia', 'Disease', 'MESH:D054218', (88, 109))	('affecting', 'Reg', (156, 165))	('RPL5', 'Gene', (271, 275))	('RPL11', 'Gene', (287, 292))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute T-cell leukemia', 'Disease', (88, 109))	('protein', 'cellular_component', 'GO:0003675', ('52', '59'))
69194	28147343	The Cancer Genome Atlas (TCGA) pan-cancer analyses identified RPL5 and RPL22 as significantly mutated in glioblastoma multiforme (GBM, 2.8%) and uterine corpus endometrial carcinoma (UCEC, 10.9%) respectively, and inactivating RPL22 mutations have also been described in colorectal and gastric cancer.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('RPL22', 'Gene', '6146', (71, 76))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RPL22', 'Gene', (71, 76))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('RPL5', 'Gene', (62, 66))	('RPL22', 'Gene', '6146', (227, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('inactivating', 'Var', (214, 226))	('RPL22', 'Gene', (227, 232))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (271, 300))	('corpus endometrial carcinoma', 'Disease', (153, 181))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (153, 181))	('glioblastoma multiforme', 'Disease', (105, 128))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (105, 128))	('Cancer Genome Atlas', 'Disease', (4, 23))	('mutations', 'Var', (233, 242))	('cancer', 'Disease', (35, 41))
69196	28147343	Mutations reported for RPL10 in T-ALL are all missense mutations, with a strong mutational hotspot at residue arginine 98 (R98S), indicating an oncogenic role for these mutations.	('R98S', 'Mutation', 'p.R98S', (123, 127))	('Mutations', 'Var', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('RPL10', 'Gene', '6134', (23, 28))	('RPL10', 'Gene', (23, 28))
69197	28147343	In contrast, all other somatic defects that have been identified so far in ribosomal protein genes are heterozygous and many of them are clearly inactivating mutations or deletions, suggesting roles as haploinsufficient tumor suppressors for these proteins in cancer.	('ribosomal protein', 'Gene', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('inactivating', 'NegReg', (145, 157))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('75', '92'))	('deletions', 'Var', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (202, 225))	('cancer', 'Disease', (260, 266))	('haploinsufficient tumor', 'Disease', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
69198	28147343	Congenital heterozygous inactivating mutations and deletions affecting RPL5, RPL11 and RPS15 have also been described in Diamond Blackfan Anemia (DBA), a congenital syndrome belonging to a family of human disorders, ribosomopathies, caused by impaired ribosome biogenesis and function.	('Anemia', 'Disease', (138, 144))	('ribosomopathies', 'Disease', 'None', (216, 231))	('ribosomopathies', 'Disease', (216, 231))	('RPS15', 'Gene', '6209', (87, 92))	('Anemia', 'Disease', 'MESH:D000740', (138, 144))	('human', 'Species', '9606', (199, 204))	('RPS15', 'Gene', (87, 92))	('described', 'Reg', (108, 117))	('RPL5', 'Gene', (71, 75))	('ribosome', 'cellular_component', 'GO:0005840', ('252', '260'))	('congenital syndrome belonging', 'Disease', 'MESH:D000013', (154, 183))	('ribosome biogenesis', 'biological_process', 'GO:0042254', ('252', '271'))	('deletions', 'Var', (51, 60))	('RPL11', 'Gene', (77, 82))	('RPL11', 'Gene', '6135', (77, 82))	('congenital syndrome belonging', 'Disease', (154, 183))	('Anemia', 'Phenotype', 'HP:0001903', (138, 144))
69201	28147343	Besides the identification of somatic ribosome defects in cancer and the elevated cancer risks of ribosomopathy patients, the link between ribosome defects and cancer is supported by the observation that heterozygous inactivation of certain ribosomal protein genes induces tumor development in zebrafish.	('ribosome defects', 'Disease', 'MESH:D005128', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (82, 88))	('ribosome', 'cellular_component', 'GO:0005840', ('38', '46'))	('tumor', 'Disease', (273, 278))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))	('elevated cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ribosome defects', 'Disease', (139, 155))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('ribosomal protein', 'Gene', (241, 258))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('ribosomopathy', 'Disease', 'None', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ribosomopathy', 'Disease', (98, 111))	('zebrafish', 'Species', '7955', (294, 303))	('elevated cancer', 'Disease', 'MESH:D009369', (73, 88))	('ribosome', 'cellular_component', 'GO:0005840', ('139', '147'))	('heterozygous inactivation', 'Var', (204, 229))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ribosome defects', 'Disease', 'MESH:D005128', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('induces', 'PosReg', (265, 272))	('patients', 'Species', '9606', (112, 120))	('ribosome defects', 'Disease', (38, 54))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('241', '258'))	('cancer', 'Disease', (58, 64))
69202	28147343	Moreover, Rpl11 and Rpl22 haploinsufficiency accelerates mouse lymphoma development and loss of one copy of Rpl5 or Rps24 (eS24) has been linked to development of rare soft tissue sarcomas in mice.	('Rpl22', 'Gene', '19934', (20, 25))	('linked', 'Reg', (138, 144))	('Rpl11', 'Gene', '67025', (10, 15))	('Rpl11', 'Gene', (10, 15))	('haploinsufficiency', 'Disease', 'MESH:D058495', (26, 44))	('eS24', 'Gene', '103943', (123, 127))	('eS24', 'Gene', (123, 127))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('haploinsufficiency', 'Disease', (26, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcomas', 'Disease', (180, 188))	('Rpl5', 'Gene', (108, 112))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('mice', 'Species', '10090', (192, 196))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (168, 188))	('Rps24', 'Gene', (116, 121))	('accelerates', 'PosReg', (45, 56))	('Rpl22', 'Gene', (20, 25))	('Rps24', 'Gene', '20088', (116, 121))	('lymphoma', 'Disease', (63, 71))	('loss', 'Var', (88, 92))	('lymphoma', 'Disease', 'MESH:D008223', (63, 71))	('Rpl5', 'Gene', '100503670', (108, 112))	('mouse', 'Species', '10090', (57, 62))
69208	28147343	RPL22 inactivation was reported to indirectly activate c-MYC expression, via an NF-kB - Lin28B - Let7 miRNA axis.	('inactivation', 'Var', (6, 18))	('c-MYC', 'Gene', (55, 60))	('RPL22', 'Gene', (0, 5))	('Lin28B', 'Gene', '389421', (88, 94))	('activate', 'PosReg', (46, 54))	('c-MYC', 'Gene', '4609', (55, 60))	('RPL22', 'Gene', '6146', (0, 5))	('Lin28B', 'Gene', (88, 94))
69212	28147343	We analyzed mutations from 4 926 tumors and copy number changes from 7 322 tumors across 16 different tumor types for the 81 genes encoding ribosomal proteins.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (75, 80))
69215	28147343	Whereas somatic mutations in RPL5 had been described in 3% of GBM samples, we found that RPL5 heterozygous inactivation currently represents the most common somatic ribosome defect in human cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('RPL5', 'Gene', (29, 33))	('ribosome', 'cellular_component', 'GO:0005840', ('165', '173'))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('heterozygous', 'Var', (94, 106))	('RPL5', 'Gene', (89, 93))	('human', 'Species', '9606', (184, 189))
69218	28147343	Overall, the frequency of such defects in individual ribosomal protein genes was below 3% in all cancer types (Supplementary Table 2).	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('defects', 'Var', (31, 38))	('cancer', 'Disease', (97, 103))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('53', '70'))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ribosomal protein', 'Protein', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
69219	28147343	However, mutational frequency represents only one criterium to discriminate functional cancer drivers.	('mutational', 'Var', (9, 19))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
69223	28147343	RPSA was identified in Stomach Adenocarcinoma (STAD) because of a significant cluster of mutations (q-value: 0.004; OncodriveCLUST ) (Figure 1A-1B; Supplementary Figure 1).	('RPSA', 'Gene', (0, 4))	('RPSA', 'Gene', '3921', (0, 4))	('Stomach Adenocarcinoma', 'Disease', (23, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (89, 98))	('Stomach Adenocarcinoma', 'Disease', 'MESH:D013274', (23, 45))
69224	28147343	RPS5 and RPS20 show an accumulation of high functional impact mutations, in STAD and UCEC respectively (q-values: 0.026 and 0.042; Oncodrive FM).	('mutations', 'Var', (62, 71))	('RPS5', 'Gene', '6193', (0, 4))	('RPS5', 'Gene', (0, 4))	('RPS20', 'Gene', (9, 14))	('RPS20', 'Gene', '6224', (9, 14))
69225	28147343	Accumulation of high functional impact mutations was also found for RPL5 in GBM (q-value: 0.0002) and SKCM (q-value: 0.004) and for RPL11 in SKCM (q-value: 0.0007).	('RPL11', 'Gene', '6135', (132, 137))	('RPL11', 'Gene', (132, 137))	('RPL5', 'Var', (68, 72))	('mutations', 'Var', (39, 48))
69226	28147343	Some of these mutations were clearly inactivating frameshift, nonsense or splice site mutations (Figure 1B), indicative of a tumor suppressor function.	('inactivating', 'NegReg', (37, 49))	('nonsense or splice site', 'Var', (62, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('frameshift', 'Var', (50, 60))	('a tumor', 'Disease', 'MESH:D009369', (123, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('125', '141'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('125', '141'))	('a tumor', 'Disease', (123, 130))	('mutations', 'Var', (14, 23))
69228	28147343	Because these defects often encompass many genes, we increased the specificity of our screening for driver events by applying additional filtering criteria: i) that the ribosomal protein gene was included in the region of the deletion (or amplification) that is predicted to contain the cancer driving target gene; ii) that the same region does not include other known cancer genes; iii) that the ribosomal protein gene was also affected by mutations, in addition to the significant copy number change.	('ribosomal protein gene', 'Gene', (397, 419))	('cancer', 'Disease', (369, 375))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('397', '414'))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('mutations', 'Var', (441, 450))	('affected', 'Reg', (429, 437))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('protein', 'cellular_component', 'GO:0003675', ('407', '414'))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('169', '186'))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
69237	28147343	However, a closer analysis showed that the known cancer genes are more than 7 Mbp away from RPL5 and also in this tumor type RPL5 was located in a pronounced deletion peak (Figure 2C).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (114, 119))	('RPL5', 'Var', (125, 129))	('Mbp', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Mbp', 'Gene', '4155', (78, 81))	('cancer', 'Disease', (49, 55))
69238	28147343	RPL5 deletions were associated with 29-38% lower average RPL5 mRNA expression levels in GBM (p = 0.016), SKCM (p = 2.36e-04) and BRCA (p = 2.2e-16) (Figure 2D).	('BRCA', 'Gene', '672', (129, 133))	('RPL5', 'Gene', (0, 4))	('BRCA', 'Gene', (129, 133))	('RPL5 mRNA expression levels', 'MPA', (57, 84))	('deletions', 'Var', (5, 14))	('lower', 'NegReg', (43, 48))
69240	28147343	RPL5, the most commonly altered ribosomal protein we detected, was significantly mutated and deleted in GBM (11%) and SKCM (28%) and significantly deleted in BRCA (34%).	('BRCA', 'Gene', (158, 162))	('altered', 'Reg', (24, 31))	('deleted', 'Var', (93, 100))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('32', '49'))	('ribosomal', 'Protein', (32, 41))	('RPL5', 'Gene', (0, 4))	('BRCA', 'Gene', '672', (158, 162))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
69246	28147343	Because RPL5 has been functionally linked to TP53 and c-MYC, we tested for an association between RPL5 defects and defects in c-MYC, TP53, or the negative TP53 regulators MDM4 and MDM2 (Figure 4 and Supplementary Figure 4).	('MDM2', 'Gene', '4193', (180, 184))	('MDM4', 'Gene', '4194', (171, 175))	('MDM4', 'Gene', (171, 175))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (155, 159))	('c-MYC', 'Gene', '4609', (126, 131))	('defects', 'Var', (103, 110))	('c-MYC', 'Gene', '4609', (54, 59))	('defects', 'Var', (115, 122))	('TP53', 'Gene', '7157', (45, 49))	('TP53', 'Gene', (155, 159))	('tested', 'Reg', (64, 70))	('RPL5', 'Gene', (98, 102))	('c-MYC', 'Gene', (54, 59))	('TP53', 'Gene', '7157', (133, 137))	('c-MYC', 'Gene', (126, 131))	('TP53', 'Gene', (133, 137))	('MDM2', 'Gene', (180, 184))
69247	28147343	In BRCA, significant co-occurrence of RPL5 defects and TP53 pathway inactivation by TP53 inactivation or by mutation/amplification of MDM2 or MDM4 was detected.	('RPL5 defects', 'Gene', (38, 50))	('BRCA', 'Gene', (3, 7))	('inactivation', 'Var', (89, 101))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('BRCA', 'Gene', '672', (3, 7))	('MDM4', 'Gene', '4194', (142, 146))	('MDM2', 'Gene', '4193', (134, 138))	('MDM4', 'Gene', (142, 146))	('MDM2', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (84, 88))	('inactivation', 'NegReg', (68, 80))	('mutation/amplification', 'Var', (108, 130))
69253	28147343	It represents a candidate tumor suppressor, based on its heterozygous inactivating mutations and focal deletions and based on the correlation of lower RPL5 expression with worse survival.	('RPL5', 'Protein', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('deletions', 'Var', (103, 112))	('lower', 'NegReg', (145, 150))	('expression', 'MPA', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))
69256	28147343	Triple negative breast cancer cell lines MCF7 (TP53 WT, RPL5 WT) and MDA-MB-231 (TP53 homozygous R280K missense mutation, RPL5 WT) were transduced with lentiviral vectors allowing inducible RPL5 protein knockdown of 30-50% (Figure 5A, Supplementary Figure 6, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('breast cancer', 'Disease', (16, 29))	('protein', 'cellular_component', 'GO:0003675', ('195', '202'))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (278, 288))	('TP53', 'Gene', (47, 51))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('MCF7', 'CellLine', 'CVCL:0031', (259, 263))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('TP53', 'Gene', '7157', (47, 51))	('MCF7', 'CellLine', 'CVCL:0031', (41, 45))	('R280K', 'Mutation', 'rs121912660', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('TP53', 'Gene', '7157', (81, 85))	('knockdown', 'Var', (203, 212))	('TP53', 'Gene', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
69260	28147343	In both subcutaneous breast cancer models, RPL5 knockdown significantly increased the tumor weight when sacrificing the animals (Figure 6A, MCF7 p = 0.009 and MDA-MB-231 p = 0.044).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('tumor', 'Disease', (86, 91))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (159, 169))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('RPL5', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('MCF7', 'CellLine', 'CVCL:0031', (140, 144))	('knockdown', 'Var', (48, 57))
69265	28147343	In addition, the shRPL5 induced mouse tumors showed reduced phosphorylation of CDK1/CDC2 at tyrosine 15, a dephosphoryation that is required for cell cycle progression from G2 to mitosis (Figure 6C, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('phosphorylation', 'MPA', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('CDK', 'molecular_function', 'GO:0004693', ('79', '82'))	('tumors', 'Disease', (38, 44))	('reduced', 'NegReg', (52, 59))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('mitosis', 'biological_process', 'GO:0000278', ('179', '186'))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('shRPL5', 'Var', (17, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (92, 100))	('mouse', 'Species', '10090', (32, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (218, 228))	('CDK1/CDC2', 'Gene', (79, 88))	('mitosis', 'Disease', (179, 186))	('MCF7', 'CellLine', 'CVCL:0031', (199, 203))	('mitosis', 'Disease', 'None', (179, 186))
69266	28147343	These results are consistent with the enhanced proliferation associated with RPL5 knockdown in the cell culture experiments and the increased tumor weights in vivo.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('enhanced', 'PosReg', (38, 46))	('tumor', 'Disease', (142, 147))	('RPL5', 'Gene', (77, 81))	('knockdown', 'Var', (82, 91))	('increased', 'PosReg', (132, 141))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
69267	28147343	Changes in TP53, MDM2 and c-MYC protein levels upon RPL5 knockdown were assessed by immunoblotting, in vitro and in vivo (Figure 5C, Figure 6D-6E and Supplementary Figure 8).	('RPL5', 'Gene', (52, 56))	('c-MYC', 'Gene', '4609', (26, 31))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('MDM2', 'Gene', '4193', (17, 21))	('knockdown', 'Var', (57, 66))	('MDM2', 'Gene', (17, 21))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('c-MYC', 'Gene', (26, 31))	('Changes', 'Reg', (0, 7))
69269	28147343	MDM2 expression did not differ in vivo and it was upregulated in vitro only for MDA-MB-231.	('upregulated', 'PosReg', (50, 61))	('expression', 'MPA', (5, 15))	('MDA-MB-231', 'Var', (80, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))
69272	28147343	We aimed to identify novel ribosomal protein genes which are significantly targeted by genetic alterations and represent potential causative cancer genes.	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('genetic alterations', 'Var', (87, 106))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ribosomal protein genes', 'Gene', (27, 50))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('27', '44'))	('cancer', 'Disease', (141, 147))
69275	28147343	RPL22 was found to be significantly mutated in UCEC, according to a TCGA pan-cancer analysis.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('UCEC', 'Disease', (47, 51))	('RPL22', 'Gene', (0, 5))	('mutated', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('RPL22', 'Gene', '6146', (0, 5))
69276	28147343	However, most RPL22 mutations detected in TCGA UCEC are potentially caused by misalignment of reads to homologous regions in the genome.	('caused by', 'Reg', (68, 77))	('RPL22', 'Gene', '6146', (14, 19))	('mutations', 'Var', (20, 29))	('RPL22', 'Gene', (14, 19))
69278	28147343	RPS15 and RPL10 mutations have been reported in CLL and T-ALL, which are not represented in the TCGA dataset analyzed here.	('T-ALL', 'Disease', (56, 61))	('RPL10', 'Gene', '6134', (10, 15))	('CLL', 'Disease', (48, 51))	('mutations', 'Var', (16, 25))	('RPL10', 'Gene', (10, 15))	('reported', 'Reg', (36, 44))	('RPS15', 'Gene', '6209', (0, 5))	('RPS15', 'Gene', (0, 5))
69281	28147343	Other mechanisms such as methylation, regulation by microRNAs or long non-coding RNAs might further cause ribosomal protein dysregulation in cancer.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('protein dysregulation', 'Disease', 'MESH:D021081', (116, 137))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('microRNAs', 'Var', (52, 61))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('106', '123'))	('protein dysregulation', 'Disease', (116, 137))	('methylation', 'Var', (25, 36))	('long non-coding RNAs', 'Var', (65, 85))	('cause', 'Reg', (100, 105))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
69288	28147343	RPS5 and RPS20 show accumulation of high functional impact mutations, some of which may disrupt RNA interactions.	('RPS5', 'Gene', (0, 4))	('RNA', 'cellular_component', 'GO:0005562', ('96', '99'))	('RPS5', 'Gene', '6193', (0, 4))	('mutations', 'Var', (59, 68))	('disrupt', 'NegReg', (88, 95))	('RPS20', 'Gene', (9, 14))	('RNA interactions', 'Interaction', (96, 112))	('RPS20', 'Gene', '6224', (9, 14))
69289	28147343	Most interestingly, both RPL11 and RPL5 present inactivating mutations and emerge as candidate cancer drivers in the same cancer type (SKCM).	('inactivating mutations', 'Var', (48, 70))	('RPL11', 'Gene', '6135', (25, 30))	('RPL5', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (122, 128))	('RPL11', 'Gene', (25, 30))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
69293	28147343	The observation of heterozygous inactivating RPL5 mutations and deletions across multiple tumor types suggested a role as haploinsufficient tumor suppressor gene.	('mutations', 'Var', (50, 59))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (122, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deletions', 'Var', (64, 73))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('haploinsufficient tumor', 'Disease', (122, 145))	('tumor suppressor', 'biological_process', 'GO:0051726', ('140', '156'))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('140', '156'))	('RPL5', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (140, 145))
69294	28147343	It is interesting to note that the Rabadan group integrated TCGA data with known causative genes in cancer predisposing Mendelian diseases, such as DBA, and that they also pick up RPL5 as candidate tumor suppressor in GBM in their analyses.	('DBA', 'Disease', (148, 151))	('cancer', 'Disease', (100, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('198', '214'))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Mendelian diseases', 'Disease', (120, 138))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('198', '214'))	('TCGA', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Mendelian diseases', 'Disease', 'MESH:D030342', (120, 138))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('RPL5', 'Var', (180, 184))
69295	28147343	In the current study, we show that the incidence of RPL5 alterations in GBM is much higher than previously assumed and that heterozygous RPL5 inactivation occurs at high incidence in GBM, SKCM and BRCA.	('alterations', 'Var', (57, 68))	('RPL5', 'Gene', (52, 56))	('BRCA', 'Gene', (197, 201))	('BRCA', 'Gene', '672', (197, 201))
69296	28147343	As such, RPL5 inactivation currently represents the most common somatic ribosome defect in cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('RPL5 inactivation', 'Var', (9, 26))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ribosome', 'cellular_component', 'GO:0005840', ('72', '80'))
69298	28147343	In this context, LUAD, KIRC, STAD and PRAD also show inactivating mutations or deletions in RPL5 (Supplementary Figure 9), suggesting that RPL5 may also act as a tumor suppressor in these tumor types.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('a tumor', 'Disease', 'MESH:D009369', (160, 167))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('162', '178'))	('tumor', 'Disease', (162, 167))	('deletions', 'Var', (79, 88))	('a tumor', 'Disease', (160, 167))	('inactivating mutations', 'Var', (53, 75))	('RPL5', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor suppressor', 'biological_process', 'GO:0051726', ('162', '178'))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
69299	28147343	In addition, RPL5 shows inactivating mutations in 2% of T-ALL samples and we showed that RPL5 is part of a minimal deleted region that is heterozygously deleted in 20-40% of advanced multiple myeloma cases (Supplementary Figure 10).	('inactivating mutations', 'Var', (24, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (183, 199))	('multiple myeloma', 'Disease', 'MESH:D009101', (183, 199))	('multiple myeloma', 'Disease', (183, 199))	('RPL5', 'Gene', (13, 17))	('RPL5', 'Gene', (89, 93))
69301	28147343	Knockdown of RPL5 by ~50% in both TP53 WT MCF7 and TP53 mutant MDA-MB-231 breast cancer lines accelerated the tumor growth in vivo.	('TP53', 'Gene', '7157', (51, 55))	('MCF7', 'CellLine', 'CVCL:0031', (42, 46))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', (51, 55))	('mutant', 'Var', (56, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('accelerated', 'PosReg', (94, 105))	('TP53', 'Gene', '7157', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
69303	28147343	The MDA-MB-231 cell line did not show significant proliferation changes in vitro upon RPL5 knockdown, although a significant increase in tumor growth was observed in vivo.	('RPL5', 'Gene', (86, 90))	('tumor', 'Disease', (137, 142))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (4, 14))	('increase', 'PosReg', (125, 133))	('knockdown', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
69308	28147343	Loss of RPL5 in human primary lung fibroblasts does not induce cell cycle arrest by checkpoint activation but suppresses cell cycle progression by reducing translation rates, including translation of some cyclins.	('suppresses', 'NegReg', (110, 120))	('reducing', 'NegReg', (147, 155))	('cell cycle progression', 'CPA', (121, 143))	('RPL5', 'Gene', (8, 12))	('cell cycle', 'biological_process', 'GO:0007049', ('121', '131'))	('translation', 'biological_process', 'GO:0006412', ('185', '196'))	('translation rates', 'MPA', (156, 173))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('63', '80'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('human', 'Species', '9606', (16, 21))	('cyclins', 'Protein', (205, 212))	('Loss', 'Var', (0, 4))	('translation', 'MPA', (185, 196))	('translation', 'biological_process', 'GO:0006412', ('156', '167'))
69316	28147343	Moreover, we observed increased in vivo tumor volumes upon RPL5 knockdown, both in the TP53 wild type MCF7 and in the TP53 mutant MDA-MB-231 line and no consistent changes were observed in TP53 and MDM2 protein expression upon knock-down of RPL5 in these breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('TP53', 'Gene', (189, 193))	('breast cancer', 'Disease', (255, 268))	('increased', 'PosReg', (22, 31))	('TP53', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))	('TP53', 'Gene', '7157', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('TP53', 'Gene', '7157', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('TP53', 'Gene', '7157', (118, 122))	('tumor', 'Disease', (40, 45))	('MDM2', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('MCF7', 'CellLine', 'CVCL:0031', (102, 106))	('mutant', 'Var', (123, 129))	('MDM2', 'Gene', '4193', (198, 202))
69317	28147343	These results suggest that the RPL5 knockdown phenotype is likely TP53-independent.	('TP53', 'Gene', (66, 70))	('RPL5', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('TP53', 'Gene', '7157', (66, 70))
69320	28147343	c-MYC protein was upregulated in both breast cancer cell lines with RPL5 knockdown in vitro and in MDA-MB-231 tumors in vivo but downregulated in MCF7 tumors.	('downregulated', 'NegReg', (129, 142))	('protein', 'cellular_component', 'GO:0003675', ('6', '13'))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('tumors', 'Disease', (151, 157))	('c-MYC', 'Gene', '4609', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast cancer', 'Disease', (38, 51))	('tumors', 'Disease', (110, 116))	('c-MYC', 'Gene', (0, 5))	('knockdown', 'Var', (73, 82))	('MCF7 tumors', 'Disease', (146, 157))	('MCF7 tumors', 'Disease', 'MESH:D009369', (146, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('RPL5', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('upregulated', 'PosReg', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
69322	28147343	However, c-MYC upregulation does not fully explain the proliferation and tumor growth advantage conferred by RPL5 knockdown since it also occurs in MCF7 tumors despite c-MYC downregulation.	('c-MYC', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MCF7 tumors', 'Disease', 'MESH:D009369', (148, 159))	('RPL5', 'Gene', (109, 113))	('knockdown', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('c-MYC', 'Gene', (9, 14))	('downregulation', 'NegReg', (174, 188))	('tumor', 'Disease', (153, 158))	('c-MYC', 'Gene', '4609', (168, 173))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('c-MYC', 'Gene', '4609', (9, 14))	('MCF7 tumors', 'Disease', (148, 159))
69326	28147343	These results may suggest that alterations targeting the TP53 pathway or c-MYC may co-operate with RPL5 in tumorigenesis, and/or that RPL5 inactivation may facilitate acquisition of these lesions.	('alterations', 'Var', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('c-MYC', 'Gene', '4609', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('c-MYC', 'Gene', (73, 78))	('facilitate', 'PosReg', (156, 166))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('acquisition', 'MPA', (167, 178))	('RPL5 inactivation', 'Var', (134, 151))
69327	28147343	In summary, we provide the first comprehensive analysis of defects in coding regions of ribosomal proteins across several cancer types using the TCGA platform.	('ribosomal proteins', 'Protein', (88, 106))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('coding regions', 'MPA', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('defects', 'Var', (59, 66))
69334	28147343	A gene was considered as significantly mutated in a cancer type if presenting a significantly high frequency of mutations (MutSig2.0), or a significant mutational clustering in a particular region (OncodriveCLUST), or a significant accumulation of mutations with predicted high impact on protein function (OncodriveFM).	('protein function', 'MPA', (288, 304))	('mutations', 'Var', (248, 257))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutational', 'Var', (152, 162))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('protein', 'cellular_component', 'GO:0003675', ('288', '295'))
69335	28147343	Mechismo was used to predict the functional impact of residue changes on protein and RNA interactions and TransFIC was used to estimate the functional impact of mutations.	('residue changes', 'Var', (54, 69))	('protein', 'Protein', (73, 80))	('Mechismo', 'Chemical', '-', (0, 8))	('RNA', 'cellular_component', 'GO:0005562', ('85', '88'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
69336	28147343	For a gene to be considered significantly deleted (or amplified) in a tumor entity, the following criteria had to be met: i) presence in a significant peak of deletion (or amplification) according to Gistic2.0; ii) presence in the 'wide peak' region predicted by Gistic2.0 that most likely harbors the target genes of the deletion (or amplification); iii) absence of other known cancer genes from Cancer Gene Census in the same 'wide peak'; iv) presence of mutations in at least 2% of samples; v) at least 5 samples in the tumor entity in which the gene is deleted (or amplified).	('cancer', 'Disease', (379, 385))	('Cancer', 'Disease', 'MESH:D009369', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (523, 528))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('tumor', 'Disease', (70, 75))	('a tumor', 'Disease', 'MESH:D009369', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Disease', (523, 528))	('deleted', 'Var', (557, 564))	('a tumor', 'Disease', (68, 75))	('Cancer', 'Disease', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
69340	28147343	The interaction between RPL5 inactivating mutations and deletions and TP53 inactivating mutations and deletions and with MDM2, MDM4 and c-MYC non inactivating mutations and amplifications was tested in BRCA, GBM and SKCM.	('BRCA', 'Gene', (202, 206))	('deletions', 'Var', (102, 111))	('TP53', 'Gene', '7157', (70, 74))	('c-MYC', 'Gene', '4609', (136, 141))	('TP53', 'Gene', (70, 74))	('deletions', 'Var', (56, 65))	('MDM4', 'Gene', '4194', (127, 131))	('c-MYC', 'Gene', (136, 141))	('RPL5', 'Gene', (24, 28))	('MDM2', 'Gene', '4193', (121, 125))	('BRCA', 'Gene', '672', (202, 206))	('MDM2', 'Gene', (121, 125))	('MDM4', 'Gene', (127, 131))
69358	28147343	For experimental work, a one-tailed T-test was used to determine whether RPL5 knockdown increased breast cancer tumor weights and two-tailed paired Student's t-tests when comparing breast cancer cells in various assays.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (98, 117))	('knockdown', 'Var', (78, 87))	('breast cancer', 'Disease', (181, 194))	('breast cancer tumor', 'Disease', 'MESH:D001943', (98, 117))	('increased', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('breast cancer tumor', 'Disease', (98, 117))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RPL5', 'Gene', (73, 77))
69410	15488140	Exceptions included AIM-1, CXCL-1 (GRO-alpha), D2S448 and MAGEA1 which are all significantly more expressed by tumors other than melanomas.	('AIM-1', 'Gene', '202', (20, 25))	('D2S448', 'Var', (47, 53))	('melanomas', 'Disease', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('melanomas', 'Disease', 'MESH:D008545', (129, 138))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('CXCL-1', 'Gene', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('GRO-alpha', 'Gene', (35, 44))	('MAGEA1', 'Gene', (58, 64))	('CXCL-1', 'Gene', '2919', (27, 33))	('AIM-1', 'Gene', (20, 25))	('GRO-alpha', 'Gene', '2919', (35, 44))	('MAGEA1', 'Gene', '4100', (58, 64))
69417	15488140	This finding may have important repercussions in the design of antigen-specific immunization protocols and at the same time may complicate the interpretation of tumor antigen loss variant analysis by broadening loss of expression to antigens other than those targeted by a given therapy.	('variant', 'Var', (180, 187))	('expression', 'MPA', (219, 229))	('loss', 'NegReg', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('complicate', 'NegReg', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor antigen', 'molecular_function', 'GO:0008222', ('161', '174'))	('loss', 'NegReg', (175, 179))	('tumor', 'Disease', (161, 166))
69471	15488140	Test and reference RNA were labeled with Cy5 (red) and Cy3 (green) and co-hybridized to a costum-made17.5 K cDNA micro-array .	('Cy3', 'Var', (55, 58))	('Cy5', 'Var', (41, 44))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('Cy5', 'Chemical', 'MESH:C085321', (41, 44))	('Cy3', 'Chemical', '-', (55, 58))
69475	26915072	Mean frequencies of circulating gammadelta T cells before and after melanoma removal were very similar and comparable to healthy subjects, but patients who progressed to stage III or IV showed a significantly decreased frequency of circulating Vgamma9Vdelta2 T cells.	('melanoma removal', 'Disease', 'MESH:D008545', (68, 84))	('melanoma removal', 'Disease', (68, 84))	('Vgamma9Vdelta2', 'Var', (244, 258))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('patients', 'Species', '9606', (143, 151))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (244, 260))	('decreased', 'NegReg', (209, 218))
69477	26915072	Highly suggestive of progressive differentiation toward a cytotoxic phenotype, Vgamma9Vdelta2T cells from patients at follow up had increased cytotoxic potential and limited cytokine production capability, while the opposite pattern was detected in Vgamma9Vdelta2T cells from patients before melanoma removal.	('patients', 'Species', '9606', (276, 284))	('cytokine production', 'biological_process', 'GO:0001816', ('174', '193'))	('Vgamma9Vdelta2T', 'Var', (79, 94))	('cytotoxic potential', 'CPA', (142, 161))	('Vgamma9Vdelta2T', 'CellLine', 'CVCL:M092', (79, 94))	('increased', 'PosReg', (132, 141))	('limited', 'NegReg', (166, 173))	('cytokine production capability', 'MPA', (174, 204))	('melanoma removal', 'Disease', 'MESH:D008545', (292, 308))	('melanoma removal', 'Disease', (292, 308))	('patients', 'Species', '9606', (106, 114))	('Vgamma9Vdelta2T', 'CellLine', 'CVCL:M092', (249, 264))	('melanoma', 'Phenotype', 'HP:0002861', (292, 300))
69488	26915072	In a recent study, we have demonstrated that gammadelta T lymphocytes are well represented amongst TILs in cutaneous melanomas, produce the pro-inflammatory cytokines TNF-alpha and IFN-gamma and exert a strong cytotoxic activity against melanoma cells in vitro.	('melanoma', 'Disease', (237, 245))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('gammadelta', 'Var', (45, 55))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (107, 126))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (107, 126))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('IFN-gamma', 'Gene', '3458', (181, 190))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))	('cutaneous melanomas', 'Disease', (107, 126))	('TNF-alpha', 'Gene', '7124', (167, 176))	('cytotoxic activity', 'CPA', (210, 228))	('TNF-alpha', 'Gene', (167, 176))	('IFN-gamma', 'Gene', (181, 190))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('melanoma', 'Disease', (117, 125))
69489	26915072	Strongly suggestive of their anti-tumor role, percentages of Vgamma9Vdelta2 T cells, but not total gammadelta or Vdelta1 T cells, correlate with early stage of melanoma and absence of metastasis.	('tumor', 'Disease', (34, 39))	('metastasis', 'CPA', (184, 194))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('Vgamma9Vdelta2', 'Var', (61, 75))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (61, 77))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
69490	26915072	In this study, we have investigated the diagnostic and prognostic potential of a Vgamma9Vdelta2 T-cell-based blood analysis on the grounds, that it may provide a useful biomarker of the patient's anti-tumor immune response.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('immune response', 'biological_process', 'GO:0006955', ('207', '222'))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (81, 97))	('Vgamma9Vdelta2', 'Var', (81, 95))	('tumor', 'Disease', (201, 206))	('patient', 'Species', '9606', (186, 193))
69491	26915072	To this aim, we have evaluated circulating Vgamma9Vdelta2 T lymphocytes in terms of frequency, effector functions and relationship with clinical stage and evolution, in subjects before and after removal of melanoma, and compared them with healthy controls.	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (43, 59))	('Vgamma9Vdelta2', 'Var', (43, 57))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
69507	26915072	The fluorochrome-conjugated monoclonal antibodies (mAbs) used to characterized the entire population were the following: anti-CD45, anti-CD3, anti-CD14, anti-CD19, anti-pan gammadelta TCR, anti-Vdelta1, anti-Vdelta2, anti-CD27 and anti-CD45RA, all purchased from BD Biosciences (Mountain View, CA).	('TCR', 'biological_process', 'GO:0006283', ('184', '187'))	('CD45', 'Gene', '5788', (236, 240))	('CD14', 'Gene', (147, 151))	('CD27', 'Gene', '939', (222, 226))	('CD45', 'Gene', '5788', (126, 130))	('CD27', 'Gene', (222, 226))	('CD14', 'Gene', '929', (147, 151))	('CD45', 'Gene', (236, 240))	('anti-CD3', 'Var', (132, 140))	('TCR', 'cellular_component', 'GO:0042101', ('184', '187'))	('CD19', 'Gene', (158, 162))	('CD45', 'Gene', (126, 130))	('CD19', 'Gene', '930', (158, 162))
69514	26915072	Then PBMC were stained with anti-TCR Vdelta2 and anti-CD3 mAbs for 15 min at 4 C. Samples were fixed, permeabilized according to manufacturer's instructions and incubated with anti-IFN-gamma (25723.11, BD Biosciences, Mountain View, CA), anti-perforin (deltaG9, Vinci-Biochem, Firenze, Italy) or anti-Granzyme B (GB11, BD Biosciences) mAbs or isotype-matched control mAbs, for 30 min at 4 C. After washing, the expression of surface CD107a/b and intracellular IFN-gamma, perforin or Granzyme B was analyzed upon gating on the Vdelta2+ T cell population.	('intracellular', 'cellular_component', 'GO:0005622', ('446', '459'))	('Granzyme B', 'Gene', '3002', (301, 311))	('Granzyme B', 'Gene', '3002', (483, 493))	('IFN-gamma', 'Gene', '3458', (460, 469))	('CD107a', 'Gene', (433, 439))	('Granzyme B', 'Gene', (301, 311))	('CD107a', 'Gene', '3916', (433, 439))	('deltaG9', 'Var', (253, 260))	('TCR', 'cellular_component', 'GO:0042101', ('33', '36'))	('Granzyme B', 'Gene', (483, 493))	('deltaG9', 'DELETION', 'None', (253, 260))	('IFN-gamma', 'Gene', '3458', (181, 190))	('IFN-gamma', 'Gene', (181, 190))	('IFN-gamma', 'Gene', (460, 469))	('TCR', 'biological_process', 'GO:0006283', ('33', '36'))
69519	26915072	The phenotype and the functional responses of Vgamma9Vdelta2 T cells were analyzed before and at follow-up after melanoma removal and compared to those observed in healthy subjects.	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (46, 62))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('Vgamma9Vdelta2', 'Var', (46, 60))	('melanoma removal', 'Disease', 'MESH:D008545', (113, 129))	('melanoma removal', 'Disease', (113, 129))
69522	26915072	As shown in Fig 2A, the majority of circulating Vgamma9Vdelta2 T lymphocytes in patients at follow up after melanoma removal expressed the TEMRA phenotype, while the other three subsets were poorly represented.	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (48, 64))	('Vgamma9Vdelta2', 'Var', (48, 62))	('patients', 'Species', '9606', (80, 88))	('expressed', 'Reg', (125, 134))	('melanoma removal', 'Disease', 'MESH:D008545', (108, 124))	('melanoma removal', 'Disease', (108, 124))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
69525	26915072	The phenotypic modifications of Vgamma9Vdelta2 T cells in subjects at follow up after melanoma removal were paralleled by modifications in their functional responses in vitro.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (32, 48))	('Vgamma9Vdelta2', 'Var', (32, 46))	('melanoma removal', 'Disease', 'MESH:D008545', (86, 102))	('melanoma removal', 'Disease', (86, 102))	('modifications', 'Reg', (122, 135))
69527	26915072	Conversely, the cytotoxic capability of Vgamma9Vdelta2 T cells (measured by the CD107 mobilization assay after Iomomycin/PMA or Zoledronate stimulation) consistently increased in patients after melanoma removal, and differences to values in patients before melanoma removal attained statistical significance.	('melanoma removal', 'Disease', (194, 210))	('Iomomycin', 'Chemical', '-', (111, 120))	('PMA', 'Chemical', '-', (121, 124))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (40, 56))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma removal', 'Disease', 'MESH:D008545', (257, 273))	('melanoma removal', 'Disease', (257, 273))	('increased', 'PosReg', (166, 175))	('Zoledronate', 'Chemical', 'MESH:D000077211', (128, 139))	('Vgamma9Vdelta2', 'Var', (40, 54))	('patients', 'Species', '9606', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('cytotoxic capability', 'CPA', (16, 36))	('patients', 'Species', '9606', (241, 249))	('melanoma removal', 'Disease', 'MESH:D008545', (194, 210))
69531	26915072	Progression was invariably associated to substantial declines in Vgamma9Vdelta2 T cell numbers: as shown in Fig 4, patients who progressed to stage III or IV showed a decreased frequency of circulating Vgamma9Vdelta2 T cells at 36-months follow-up compared to values at diagnosis (4.55% to 1.81%).	('patients', 'Species', '9606', (115, 123))	('declines', 'Disease', 'MESH:D060825', (53, 61))	('Vgamma9Vdelta2', 'Var', (202, 216))	('declines', 'Disease', (53, 61))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (202, 218))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (65, 81))	('decreased', 'NegReg', (167, 176))
69535	26915072	We observed no statistically significant associations between the percentage of circulating Vgamma9Vdelta2 T cells before melanoma removal and stage, RFS and OS (data not shown).	('melanoma removal', 'Disease', 'MESH:D008545', (122, 138))	('melanoma removal', 'Disease', (122, 138))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (92, 108))	('stage', 'Disease', (143, 148))	('Vgamma9Vdelta2 T', 'Var', (92, 108))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('RFS', 'Disease', (150, 153))
69537	26915072	Previously, we reported that the presence of Vgamma9Vdelta2 T cells among tumor-infiltrating lymphocytes was positively correlated with earlier tumor stages (0, I and II).	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('correlated', 'Reg', (120, 130))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (45, 61))	('Vgamma9Vdelta2 T', 'Var', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
69540	26915072	Two recent surveys have reviewed the available published studies on the in vivo activation and adoptive transfer of ex vivo- expanded gammadelta T cells in cancer patients, providing evidence that Vgamma9Vdelta2 T cell-based immunotherapy improves overall survival and, in view of its low toxicity grade, provides a proof of principle for its utilization as adjuvant to conventional therapies for resistant/refractory patients care.	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (197, 213))	('patients', 'Species', '9606', (163, 171))	('overall survival', 'CPA', (248, 264))	('cancer', 'Disease', (156, 162))	('improves', 'PosReg', (239, 247))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Vgamma9Vdelta2', 'Var', (197, 211))	('toxicity', 'Disease', 'MESH:D064420', (289, 297))	('patients', 'Species', '9606', (418, 426))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('toxicity', 'Disease', (289, 297))
69543	26915072	However, Vgamma9Vdelta2 T cells had increased proliferative and cytokine-producing capability after melanoma removal, in comparison with the same subjects before surgical intervention or with control donors.	('proliferative and', 'CPA', (46, 63))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (9, 25))	('Vgamma9Vdelta2', 'Var', (9, 23))	('melanoma removal', 'Disease', 'MESH:D008545', (100, 116))	('melanoma removal', 'Disease', (100, 116))	('increased', 'PosReg', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))
69548	26915072	One possibility might be that changes in Vgamma9Vdelta2 T cell numbers and functions might be age- and sex-related and not a consequence of tumor growth.	('Vgamma9Vdelta2', 'Var', (41, 55))	('changes', 'Var', (30, 37))	('functions', 'CPA', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (41, 57))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
69549	26915072	Accordingly, Vgamma9Vdelta2 T cells change characteristically with age, gradually decreasing beyond 30 years of age and drop more strikingly in men than in women.	('men', 'Species', '9606', (144, 147))	('women', 'Species', '9606', (156, 161))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (13, 29))	('decreasing', 'NegReg', (82, 92))	('Vgamma9Vdelta2', 'Var', (13, 27))	('men', 'Species', '9606', (158, 161))
69553	26915072	Highly suggestive of progressive differentiation toward a cytotoxic phenotype, Vgamma9Vdelta2 T cells from patients at follow-up had increased cytotoxic potential and limited cytokine production capability.	('limited', 'NegReg', (167, 174))	('patients', 'Species', '9606', (107, 115))	('cytokine production', 'MPA', (175, 194))	('increased', 'PosReg', (133, 142))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (79, 95))	('cytotoxic potential', 'CPA', (143, 162))	('Vgamma9Vdelta2', 'Var', (79, 93))	('cytokine production', 'biological_process', 'GO:0001816', ('175', '194'))
69554	26915072	Whether or not this predominant Vgamma9Vdelta2 TEMRA phenotypic and functional status is associated with clinically relevant melanoma features is actually unknown.	('associated', 'Reg', (89, 99))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (32, 48))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('Vgamma9Vdelta2', 'Var', (32, 46))
69556	26915072	However, recent studies in patients with chronic lymphatic leukemia have demonstrated that elevated numbers of circulating Vgamma9Vdelta2 T cells with dominant TEM and TEMRA phenotypes are a negative prognosticator, which is reminiscent of data previously reported in conventional CD4+ and CD8+ cells; in these patients, TEMRA CD8+ cells displayed the phenotypic hallmarks of functional exhaustion, further supporting the concept that long-lasting tumor-induced chronic activation may lead to the undesired accumulation of cells unable to exert effective antitumor activity.	('CD8', 'Gene', '925', (327, 330))	('CD8', 'Gene', (290, 293))	('TEMRA', 'Var', (321, 326))	('tumor', 'Disease', (448, 453))	('tumor', 'Disease', (559, 564))	('tumor', 'Disease', 'MESH:D009369', (448, 453))	('tumor', 'Disease', 'MESH:D009369', (559, 564))	('lymphatic leukemia', 'Phenotype', 'HP:0005526', (49, 67))	('patients', 'Species', '9606', (27, 35))	('elevated numbers of circulating Vgamma9Vdelta2 T', 'Phenotype', 'HP:0002851', (91, 139))	('CD8', 'Gene', (327, 330))	('CD4', 'Gene', '920', (281, 284))	('CD8', 'Gene', '925', (290, 293))	('chronic lymphatic leukemia', 'Disease', (41, 67))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (448, 453))	('tumor', 'Phenotype', 'HP:0002664', (559, 564))	('CD4', 'Gene', (281, 284))	('chronic lymphatic leukemia', 'Disease', 'MESH:D015451', (41, 67))	('TEM', 'cellular_component', 'GO:0097197', ('160', '163'))	('chronic lymphatic leukemia', 'Phenotype', 'HP:0005550', (41, 67))	('patients', 'Species', '9606', (311, 319))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (123, 139))
69557	26915072	Indeed, several in vitro and in vivo data indicate that chronic Vgamma9Vdelta2 T cell activation may induce functional exhaustion or anergy.	('T cell activation', 'biological_process', 'GO:0042110', ('79', '96'))	('anergy', 'CPA', (133, 139))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (64, 80))	('Vgamma9Vdelta2', 'Var', (64, 78))	('activation', 'PosReg', (86, 96))	('functional exhaustion', 'CPA', (108, 129))
69561	26915072	We further determined prognostic significance of tumor-infiltrating Vgamma9Vdelta2T cells for the prediction of cancer development during the follow-up period in a cohort of 74 previously studies melanoma patients, and we show here that the presence of Vgamma9Vdelta2 T cells among tumor-infiltrating lymphocytes was positively correlated with RFS and OS of melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (358, 366))	('melanoma', 'Disease', (358, 366))	('patients', 'Species', '9606', (205, 213))	('OS of melanoma', 'Disease', 'MESH:C567932', (352, 366))	('cancer', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (282, 287))	('correlated', 'Reg', (328, 338))	('OS of melanoma', 'Disease', (352, 366))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('Vgamma9Vdelta2T', 'CellLine', 'CVCL:M092', (68, 83))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (358, 366))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (49, 54))	('Vgamma9Vdelta2 T', 'CellLine', 'CVCL:M092', (253, 269))	('patients', 'Species', '9606', (367, 375))	('RFS', 'Disease', (344, 347))	('men', 'Species', '9606', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Vgamma9Vdelta2 T cells', 'Var', (253, 275))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))
69572	31434983	Additionally, an analysis of the correlation network reconstructed using TCGA-SKCM emphasized KMO and KYNU with high variability among BRAF wild-type compared with V600E, which underscored their role in distinct CD4+ T-cell behavior in tumour immunity.	('CD4', 'Gene', (212, 215))	('tumour', 'Disease', 'MESH:D009369', (236, 242))	('BRAF', 'Gene', '673', (135, 139))	('V600E', 'Var', (164, 169))	('KYNU', 'Gene', '8942', (102, 106))	('tumour', 'Disease', (236, 242))	('BRAF', 'Gene', (135, 139))	('CD4', 'Gene', '920', (212, 215))	('CM', 'Disease', 'MESH:D009202', (80, 82))	('V600E', 'Mutation', 'rs113488022', (164, 169))	('KMO', 'Gene', (94, 97))	('KYNU', 'Gene', (102, 106))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('KMO', 'Gene', '8564', (94, 97))
69577	31434983	Although the utilization of immune checkpoint inhibitors (ICIs) such as antibodies against CTLA4 and PD-1/PD-L1 has revolutionized the treatment of melanoma in advanced stages, only a subset of patients shows long-lasting responses to this treatment.	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('patients', 'Species', '9606', (194, 202))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('PD-L1', 'Gene', (106, 111))	('PD-1', 'Gene', (101, 105))	('antibodies', 'Var', (72, 82))	('CTLA4', 'Gene', '1493', (91, 96))	('PD-1', 'Gene', '5133', (101, 105))	('PD-L1', 'Gene', '29126', (106, 111))	('CTLA4', 'Gene', (91, 96))
69591	31434983	The deregulation of the KP causes an alteration of the balance between KYNA and QUIN, as defined in many neurological and inflammatory disorders.	('deregulation', 'Var', (4, 16))	('QUIN', 'Chemical', '-', (80, 84))	('KYNA', 'Chemical', 'MESH:D007736', (71, 75))	('alteration', 'Reg', (37, 47))	('inflammatory disorders', 'Disease', (122, 144))	('inflammatory disorders', 'Disease', 'MESH:D015212', (122, 144))
69594	31434983	TRP depletion leads to reduced proliferation and increased apoptosis of T-cells.	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('increased', 'PosReg', (49, 58))	('depletion', 'Var', (4, 13))	('TRP', 'Gene', (0, 3))	('apoptosis', 'CPA', (59, 68))	('reduced', 'NegReg', (23, 30))	('TRP', 'Chemical', 'MESH:D014364', (0, 3))
69603	31434983	In this respect, based on the identified correlations, we characterized the production of KYN, 3-HK, and KYNA in vitro using melanoma-derived BRAF wild type (wt) and BRAF V600E mutant cell lines cultured with primary CD4+ CD25- T-cells.	('BRAF', 'Gene', '673', (142, 146))	('BRAF', 'Gene', (166, 170))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('CD4', 'Gene', (217, 220))	('CD25', 'Gene', (222, 226))	('KYN', 'Chemical', 'MESH:D007737', (105, 108))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('KYNA', 'Chemical', 'MESH:D007736', (105, 109))	('CD4', 'Gene', '920', (217, 220))	('V600E', 'Mutation', 'rs113488022', (171, 176))	('KYN', 'Chemical', 'MESH:D007737', (90, 93))	('CD25', 'Gene', '3559', (222, 226))	('V600E', 'Var', (171, 176))	('BRAF', 'Gene', '673', (166, 170))	('3-HK', 'Chemical', 'MESH:C005045', (95, 99))	('BRAF', 'Gene', (142, 146))
69626	31434983	Interestingly, CD4+ T-cells were more proliferative in a BRAF wt cell line compared with V600E cell lines in the presence of the IDO1 blockade (Supplementary Fig.	('IDO', 'molecular_function', 'GO:0033754', ('129', '132'))	('BRAF', 'Gene', '673', (57, 61))	('IDO1', 'Gene', '3620', (129, 133))	('blockade', 'Var', (134, 142))	('BRAF', 'Gene', (57, 61))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('IDO', 'molecular_function', 'GO:0047719', ('129', '132'))	('CD4', 'Gene', (15, 18))	('CD4', 'Gene', '920', (15, 18))	('IDO1', 'Gene', (129, 133))	('more', 'PosReg', (33, 37))	('proliferative', 'CPA', (38, 51))
69629	31434983	In the closer look, we noticed CD4+ T-cells were less proliferative in the presence of BRAF wt MCLs compared with V600E MCLs (Fig.	('MCL', 'Disease', 'MESH:C535516', (95, 98))	('MCL', 'Disease', 'MESH:C535516', (120, 123))	('CD4', 'Gene', (31, 34))	('proliferative', 'CPA', (54, 67))	('CD4', 'Gene', '920', (31, 34))	('MCL', 'Disease', (95, 98))	('V600E', 'Var', (114, 119))	('MCL', 'Disease', (120, 123))	('BRAF', 'Gene', (87, 91))	('less', 'NegReg', (49, 53))	('BRAF', 'Gene', '673', (87, 91))	('V600E', 'Mutation', 'rs113488022', (114, 119))
69634	31434983	On the other hand, KYNA production was higher in V600 wt MCLs (BE) co-cultured with CD4+ T-cells compared with V600E cell lines (A375, SK-MEL-28, and DFB).	('MCL', 'Disease', 'MESH:C535516', (57, 60))	('higher', 'PosReg', (39, 45))	('KYNA', 'Chemical', 'MESH:D007736', (19, 23))	('KYNA production', 'MPA', (19, 34))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (135, 143))	('MCL', 'Disease', (57, 60))	('CD4', 'Gene', (84, 87))	('A375', 'CellLine', 'CVCL:0132', (129, 133))	('V600', 'Var', (49, 53))	('CD4', 'Gene', '920', (84, 87))	('V600E', 'Mutation', 'rs113488022', (111, 116))
69640	31434983	The proliferation of CD4+ T-cell and IFNgamma production measured on day five and reveals that the presence of KYNA can revoke the CD4+ T-cell proliferation and IFNgamma production (Fig.	('revoke', 'PosReg', (120, 126))	('KYNA', 'Chemical', 'MESH:D007736', (111, 115))	('CD4', 'Gene', (21, 24))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('136', '156'))	('CD4', 'Gene', '920', (21, 24))	('IFNgamma', 'Gene', (37, 45))	('IFNgamma', 'Gene', '3458', (37, 45))	('IFNgamma', 'Gene', (161, 169))	('CD4', 'Gene', (131, 134))	('CD4', 'Gene', '920', (131, 134))	('IFNgamma', 'Gene', '3458', (161, 169))	('KYNA', 'Gene', (111, 115))	('presence', 'Var', (99, 107))
69654	31434983	Furthermore, KYNA production in BRAF wt was higher than BRAF V600E MCLs (Fig.	('BRAF', 'Gene', '673', (32, 36))	('MCL', 'Disease', (67, 70))	('BRAF', 'Gene', (32, 36))	('higher', 'PosReg', (44, 50))	('BRAF', 'Gene', '673', (56, 60))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('KYNA', 'Chemical', 'MESH:D007736', (13, 17))	('KYNA production', 'MPA', (13, 28))	('V600E', 'Var', (61, 66))	('MCL', 'Disease', 'MESH:C535516', (67, 70))	('BRAF', 'Gene', (56, 60))
69665	31434983	Comparing the structure of these networks revealed interesting structural dissimilarities between BRAF V600E and BRAF wt networks.	('BRAF', 'Gene', '673', (113, 117))	('V600E', 'Var', (103, 108))	('BRAF', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (98, 102))	('BRAF', 'Gene', (98, 102))	('V600E', 'Mutation', 'rs113488022', (103, 108))
69669	31434983	The median degree value of 20 in the BRAF wt network decreased to 14.5 in the BRAF V600E network.	('V600E', 'Var', (83, 88))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (78, 82))	('BRAF', 'Gene', (37, 41))	('V600E', 'Mutation', 'rs113488022', (83, 88))
69670	31434983	The magnitude of the average clustering coefficient went down from 0.73 for the BRAF wt network to 0.62 in the BRAF V600E network, indicating greater clustering tendency of the BRAF wt network.	('BRAF', 'Gene', (80, 84))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('V600E', 'Mutation', 'rs113488022', (116, 121))	('BRAF', 'Gene', '673', (80, 84))	('BRAF', 'Gene', '673', (111, 115))	('V600E', 'Var', (116, 121))	('BRAF', 'Gene', (111, 115))
69673	31434983	The topological profile of KYNU and KMO in BRAFV600E-network changed utterly.	('KMO', 'Gene', '8564', (36, 39))	('KYNU', 'Gene', '8942', (27, 31))	('BRAFV600E-network', 'Var', (43, 60))	('changed', 'Reg', (61, 68))	('KMO', 'Gene', (36, 39))	('KYNU', 'Gene', (27, 31))
69675	31434983	Interestingly, the EdgeBetweenness of CD86-KYNU increased from almost the bottom-ranked EdgeBetweenness (411) in BRAF wt to top-ranked (6) in BRAF V600E (Table S6) which suggests that perturbing (removing) these two nodes can have a considerable effect on the BRAF V600E network.	('increased', 'PosReg', (48, 57))	('BRAF', 'Gene', '673', (113, 117))	('KYNU', 'Gene', '8942', (43, 47))	('BRAF', 'Gene', (113, 117))	('CD86', 'Gene', '942', (38, 42))	('BRAF', 'Gene', '673', (260, 264))	('KYNU', 'Gene', (43, 47))	('CD86', 'Gene', (38, 42))	('BRAF', 'Gene', (260, 264))	('perturbing', 'Var', (184, 194))	('BRAF', 'Gene', '673', (142, 146))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('V600E', 'Mutation', 'rs113488022', (265, 270))	('BRAF', 'Gene', (142, 146))
69683	31434983	These findings not only support the immunomodulatory potential of the kynurenine pathway in the tumour microenvironment but also display KMO and KYNU alteration in the kynurenine pathway that regulates the immune function of CD4+ T-cells.	('KMO', 'Gene', (137, 140))	('KYNU', 'Gene', (145, 149))	('alteration', 'Var', (150, 160))	('KMO', 'Gene', '8564', (137, 140))	('regulates', 'Reg', (192, 201))	('kynurenine', 'Enzyme', (168, 178))	('kynurenine', 'Chemical', 'MESH:D007737', (168, 178))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('CD4', 'Gene', (225, 228))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('kynurenine', 'Chemical', 'MESH:D007737', (70, 80))	('immune', 'MPA', (206, 212))	('CD4', 'Gene', '920', (225, 228))	('KYNU', 'Gene', '8942', (145, 149))	('tumour', 'Disease', (96, 102))
69690	31434983	Recent studies with a combination of INCB024360 and the PD-1 blockade (pembrolizumab) in patients with advanced melanoma did not show any significant improvement compared with the single PD-1 blockade, which supports the clinical relevance of our studies and indicates that IDO1 inhibition alone will not enhance the effect of immune checkpoint blockade.	('PD-1 blockade', 'Disease', (56, 69))	('IDO', 'molecular_function', 'GO:0033754', ('274', '277'))	('INCB024360', 'Var', (37, 47))	('PD-1 blockade', 'Disease', 'MESH:D010300', (56, 69))	('IDO1', 'Gene', '3620', (274, 278))	('PD-1 blockade', 'Disease', (187, 200))	('pembrolizumab', 'Chemical', 'MESH:C582435', (71, 84))	('PD-1 blockade', 'Disease', 'MESH:D010300', (187, 200))	('patients', 'Species', '9606', (89, 97))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('IDO', 'molecular_function', 'GO:0047719', ('274', '277'))	('IDO1', 'Gene', (274, 278))
69693	31434983	5e) and opens up the possibility that disrupting the metabolism of kynurenines may be used to design novel and more effective treatment strategies.	('disrupting', 'Var', (38, 48))	('metabolism', 'biological_process', 'GO:0008152', ('53', '63'))	('kynurenines', 'Chemical', 'MESH:D007737', (67, 78))	('metabolism', 'MPA', (53, 63))
69787	33593392	Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers.	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TRK', 'Gene', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('190', '206'))	('cancers', 'Disease', (224, 231))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor suppressor', 'biological_process', 'GO:0051726', ('190', '206'))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('colorectal cancer', 'Disease', (80, 97))	('TRK', 'Gene', '4914', (66, 69))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('tumor', 'Disease', (190, 195))	('methylations', 'Var', (45, 57))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('TRK', 'Gene', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TRK', 'Gene', '4914', (142, 145))
69792	33593392	The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression.	('expression', 'MPA', (171, 181))	('gene expression', 'biological_process', 'GO:0010467', ('166', '181'))	('CRC', 'Disease', (98, 101))	('methylated', 'Var', (84, 94))	('TRK', 'Gene', (45, 48))	('TRK', 'Gene', '4914', (45, 48))
69793	33593392	We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC.	('cg11525479', 'Var', (92, 102))	('cg11525479', 'Chemical', '-', (92, 102))	('NTRK3', 'Gene', '4916', (50, 55))	('CRC', 'Disease', (143, 146))	('NTRK3', 'Gene', (50, 55))	('cg27034819', 'Chemical', '-', (77, 87))	('cg27034819', 'Var', (77, 87))	('predicted', 'Reg', (113, 122))
69796	33593392	Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('pancreatic cancer', 'Disease', (87, 104))	('predicted', 'Reg', (41, 50))	('NTRK3', 'Gene', '4916', (9, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('glioblastoma and stomach adenocarcinoma', 'Disease', 'MESH:D005909', (106, 145))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('methylation', 'Var', (24, 35))	('NTRK3', 'Gene', (9, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))
69797	33593392	This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CRC', 'Disease', (146, 149))	('NTRK3', 'Gene', '4916', (45, 50))	('NTRK3', 'Gene', (45, 50))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('methylation', 'Var', (51, 62))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
69801	33593392	Among them, the aberrant methylation in gene promoters is prevalent across multiple cancers, which can lead to the inactivation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('131', '147'))	('aberrant methylation', 'Var', (16, 36))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('inactivation', 'NegReg', (115, 127))	('multiple cancers', 'Disease', (75, 91))	('methylation', 'Var', (25, 36))	('lead', 'Reg', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('131', '147'))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('multiple cancers', 'Disease', 'MESH:D009369', (75, 91))
69803	33593392	The aberrations of NTRKs gene function were widely known to play an oncogenic role in multiple cancers.	('multiple cancers', 'Disease', (86, 102))	('aberrations', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('play', 'Reg', (60, 64))	('multiple cancers', 'Disease', 'MESH:D009369', (86, 102))	('TRK', 'Gene', (20, 23))	('TRK', 'Gene', '4914', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
69804	33593392	Among them, NTRKs gene fusion was the best-characterized aberration, which promotes tumorigenesis through the constitutive activation of downstream cell growth and proliferative pathways.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('fusion', 'Var', (23, 29))	('cell growth', 'biological_process', 'GO:0016049', ('148', '159'))	('promotes', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TRK', 'Gene', (13, 16))	('TRK', 'Gene', '4914', (13, 16))	('tumor', 'Disease', (84, 89))	('activation', 'PosReg', (123, 133))	('downstream cell', 'Pathway', (137, 152))
69806	33593392	Similar to gene fusion, the aberrant expression of NTRKs gene is a critical event in cancers.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('aberrant', 'Var', (28, 36))	('cancers', 'Disease', (85, 92))	('TRK', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TRK', 'Gene', '4914', (52, 55))
69809	33593392	Based on this, inhibition of NTRK2-encoded TRKB was shown to induce antitumor effects and cellular apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('induce', 'PosReg', (61, 67))	('tumor', 'Disease', (72, 77))	('NTRK2', 'Gene', '4915', (29, 34))	('TRKB', 'Gene', '4915', (43, 47))	('TRKB', 'Gene', (43, 47))	('cellular apoptosis', 'CPA', (90, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('inhibition', 'Var', (15, 25))	('NTRK2', 'Gene', (29, 34))
69812	33593392	A hypermethylated NTRKs gene promoter is associated with suppressed expression in multiple cancers, such as CRC, neuroblastoma, glioma, ovarian cancer and prostate cancer.	('multiple cancers', 'Disease', 'MESH:D009369', (82, 98))	('expression', 'MPA', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('neuroblastoma', 'Phenotype', 'HP:0003006', (113, 126))	('hypermethylated', 'Var', (2, 17))	('TRK', 'Gene', (19, 22))	('neuroblastoma, glioma, ovarian cancer', 'Disease', 'MESH:D009447', (113, 150))	('multiple cancers', 'Disease', (82, 98))	('TRK', 'Gene', '4914', (19, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', (155, 170))	('CRC', 'Disease', (108, 111))	('suppressed', 'NegReg', (57, 67))
69827	33593392	The primers and probe designed to target cg27034819 and cg11525479 were illustrated in Fig.	('cg11525479', 'Var', (56, 66))	('cg11525479', 'Chemical', '-', (56, 66))	('cg27034819', 'Var', (41, 51))	('cg27034819', 'Chemical', '-', (41, 51))
69831	33593392	The assessment of KRAS and BRAF mutation was performed in the Molecular Diagnostic Laboratory of the Sixth Affiliated Hospital of Sun Yat-sen University, as previously described.	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
69834	33593392	The characteristics of CRC cases with and without NTRK3 promoter hypermethylation were compared using the Wilcoxon rank-sum tests or Chi-square tests.	('NTRK3', 'Gene', '4916', (50, 55))	('NTRK3', 'Gene', (50, 55))	('CRC', 'Disease', (23, 26))	('promoter hypermethylation', 'Var', (56, 81))
69835	33593392	In addition, Cox proportional hazards analyses were used to obtain HRs and corresponding 95% confidence intervals (CI) for the association between NTRK3 promoter hypermethylation and DFS.	('association', 'Interaction', (127, 138))	('NTRK3', 'Gene', (147, 152))	('promoter hypermethylation', 'Var', (153, 178))	('NTRK3', 'Gene', '4916', (147, 152))	('DFS', 'Disease', (183, 186))
69836	33593392	The comparison between NTRK3 hypermethylation and known prognostic factors was assessed using likelihood ratio (LR) and Akaike information criterion (AIC) in competing models including or not including NTRK3 hypermethylation.	('NTRK3', 'Gene', '4916', (23, 28))	('NTRK3', 'Gene', (202, 207))	('AIC', 'Disease', 'MESH:D058540', (150, 153))	('hypermethylation', 'Var', (29, 45))	('NTRK3', 'Gene', (23, 28))	('NTRK3', 'Gene', '4916', (202, 207))	('AIC', 'Disease', (150, 153))
69839	33593392	In TCGA dataset, the normalized beta value of cg27034819 and cg11525479 (adjacent to cg27034819), targeting the downstream region of the promoter region in NTRK3, was extracted from 450K microarray and its association with survival outcome was analyzed.	('cg27034819', 'Chemical', '-', (85, 95))	('cg11525479', 'Chemical', '-', (61, 71))	('cg11525479', 'Var', (61, 71))	('NTRK3', 'Gene', '4916', (156, 161))	('cg27034819', 'Chemical', '-', (46, 56))	('NTRK3', 'Gene', (156, 161))	('cg27034819', 'Var', (46, 56))
69845	33593392	In the Cox proportional hazards analyses of 450K microarray probes targeting genomic loci within NTRKs gene, we found that the methylation of most CpG sites targeted by these probes was associated with poor survival outcomes in CRC (Fig.	('methylation', 'MPA', (127, 138))	('survival outcomes', 'CPA', (207, 224))	('TRK', 'Gene', (98, 101))	('TRK', 'Gene', '4914', (98, 101))	('probes', 'Var', (175, 181))	('poor', 'NegReg', (202, 206))	('associated with', 'Reg', (186, 201))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))
69846	33593392	Among them, the methylation of cg27034819 was top-ranked for predicting CRC death.	('CRC death', 'Disease', (72, 81))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('cg27034819', 'Chemical', '-', (31, 41))	('cg27034819', 'Var', (31, 41))	('predicting', 'Reg', (61, 71))	('CRC death', 'Disease', 'MESH:D015179', (72, 81))	('methylation', 'Var', (16, 27))
69847	33593392	Of note, we found the probe cg11525479 was very close to cg27034819 in their targeting loci (Fig.	('cg11525479', 'Var', (28, 38))	('cg11525479', 'Chemical', '-', (28, 38))	('cg27034819', 'Chemical', '-', (57, 67))	('cg27034819', 'Var', (57, 67))
69848	33593392	2e), and the methylation of cg11525479 also had a predictive value for CRC death that was superior to most probes.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('CRC death', 'Disease', 'MESH:D015179', (71, 80))	('cg11525479', 'Var', (28, 38))	('cg11525479', 'Chemical', '-', (28, 38))	('CRC death', 'Disease', (71, 80))
69849	33593392	These results suggested that the specific region within NTRK3 promoter targeted by cg27034819 and cg11525479 could be used to stratify the death risk of CRC.	('death', 'Disease', (139, 144))	('cg11525479', 'Var', (98, 108))	('cg11525479', 'Chemical', '-', (98, 108))	('CRC', 'Disease', (153, 156))	('NTRK3', 'Gene', (56, 61))	('cg27034819', 'Chemical', '-', (83, 93))	('cg27034819', 'Var', (83, 93))	('death', 'Disease', 'MESH:D003643', (139, 144))	('NTRK3', 'Gene', '4916', (56, 61))
69853	33593392	NTRK3 promoter hypermethylation was observed in 26 of 229 patients (11.35%), and it was more frequent in patients with MSI (P = 0.015; Table 1).	('NTRK3', 'Gene', (0, 5))	('patients', 'Species', '9606', (105, 113))	('MSI', 'Disease', (119, 122))	('NTRK3', 'Gene', '4916', (0, 5))	('hypermethylation', 'Var', (15, 31))	('patients', 'Species', '9606', (58, 66))
69854	33593392	Moreover, NTRK3 promoter hypermethylation was associated with KRAS mutation (P = 0.001; Table 1).	('KRAS', 'Gene', (62, 66))	('NTRK3', 'Gene', (10, 15))	('KRAS', 'Gene', '3845', (62, 66))	('promoter hypermethylation', 'Var', (16, 41))	('NTRK3', 'Gene', '4916', (10, 15))	('associated', 'Reg', (46, 56))
69856	33593392	In the Kaplan-Meier curve, significantly worse DFS outcomes were observed in patients with NTRK3 promoter hypermethylation compared to those with NTRK3 promoter hypomethylation (P = 0.012; Fig.	('NTRK3', 'Gene', '4916', (146, 151))	('promoter hypermethylation', 'Var', (97, 122))	('NTRK3', 'Gene', (146, 151))	('worse', 'NegReg', (41, 46))	('NTRK3', 'Gene', '4916', (91, 96))	('patients', 'Species', '9606', (77, 85))	('NTRK3', 'Gene', (91, 96))
69857	33593392	The prognostic value of NTRK3 promoter methylation status was further confirmed by univariate Cox proportional hazards (P = 0.014, HR 2.194, 95% CI [1.169, 4.117]; Table 2).	('NTRK3', 'Gene', '4916', (24, 29))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('NTRK3', 'Gene', (24, 29))	('methylation status', 'Var', (39, 57))
69858	33593392	Next, in the light of multivariate analysis, NTRK3 promoter hypermethylation was still a prognostic factor adjusted by age, TNM stage, and BRAF mutation (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]; Table 2).	('BRAF', 'Gene', (139, 143))	('promoter', 'MPA', (51, 59))	('TNM', 'Gene', '10178', (124, 127))	('NTRK3', 'Gene', (45, 50))	('mutation', 'Var', (144, 152))	('TNM', 'Gene', (124, 127))	('BRAF', 'Gene', '673', (139, 143))	('NTRK3', 'Gene', '4916', (45, 50))
69861	33593392	A nomogram for predicting 3-year and 5-year DFS outcome was generated using the variables from the multivariate Cox model, including NTRK3 methylation, age at diagnosis, TNM stage, and BRAF mutation (Fig.	('mutation', 'Var', (190, 198))	('TNM', 'Gene', (170, 173))	('NTRK3', 'Gene', '4916', (133, 138))	('methylation', 'biological_process', 'GO:0032259', ('139', '150'))	('BRAF', 'Gene', '673', (185, 189))	('TNM', 'Gene', '10178', (170, 173))	('NTRK3', 'Gene', (133, 138))	('BRAF', 'Gene', (185, 189))	('methylation', 'Var', (139, 150))
69862	33593392	The model 1 had a lower AIC and a higher LR compared with the model 2 (AIC: 597.73 vs 600.69; LR: 6.91 vs 5.95, P = 0.005; Table 3), indicating that NTRK3 hypermethylation alone is better in predicting prognosis than rough TNM staging alone.	('hypermethylation', 'Var', (155, 171))	('NTRK3', 'Gene', '4916', (149, 154))	('TNM', 'Gene', '10178', (223, 226))	('AIC', 'Disease', 'MESH:D058540', (71, 74))	('lower', 'NegReg', (18, 23))	('AIC', 'Disease', (24, 27))	('NTRK3', 'Gene', (149, 154))	('TNM', 'Gene', (223, 226))	('AIC', 'Disease', (71, 74))	('AIC', 'Disease', 'MESH:D058540', (24, 27))
69863	33593392	In the comparison between model 2 and 3, after NTRK3 hypermethylation was added to TNM stage, a lower AIC and a higher LR were observed (AIC: 600.69 vs 592.41; LR: 5.95 vs 16.23, P = 0.002; Table 3).	('AIC', 'Disease', (102, 105))	('higher', 'PosReg', (112, 118))	('AIC', 'Disease', (137, 140))	('lower', 'NegReg', (96, 101))	('TNM', 'Gene', '10178', (83, 86))	('NTRK3', 'Gene', '4916', (47, 52))	('AIC', 'Disease', 'MESH:D058540', (102, 105))	('AIC', 'Disease', 'MESH:D058540', (137, 140))	('added', 'Reg', (74, 79))	('hypermethylation', 'Var', (53, 69))	('NTRK3', 'Gene', (47, 52))	('TNM', 'Gene', (83, 86))
69864	33593392	These results suggest NTRK3 hypermethylation could increase prognostic values of TNM staging.	('increase', 'PosReg', (51, 59))	('hypermethylation', 'Var', (28, 44))	('TNM', 'Gene', (81, 84))	('NTRK3', 'Gene', '4916', (22, 27))	('TNM', 'Gene', '10178', (81, 84))	('NTRK3', 'Gene', (22, 27))	('prognostic', 'CPA', (60, 70))
69866	33593392	As expected, after NTRK3 hypermethylation was included, model 5 had a lower AIC and a higher LR in comparison to model 4 (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032; Table 3).	('AIC', 'Disease', 'MESH:D058540', (76, 79))	('hypermethylation', 'Var', (25, 41))	('NTRK3', 'Gene', '4916', (19, 24))	('AIC', 'Disease', (122, 125))	('lower', 'NegReg', (70, 75))	('AIC', 'Disease', 'MESH:D058540', (122, 125))	('AIC', 'Disease', (76, 79))	('NTRK3', 'Gene', (19, 24))
69867	33593392	Thus, the model recommended by AJCC may get increased discriminatory ability in predicting prognosis with NTRK3 hypermethylation.	('NTRK3', 'Gene', '4916', (106, 111))	('NTRK3', 'Gene', (106, 111))	('hypermethylation', 'Var', (112, 128))
69868	33593392	Both the methylation of cg27034819 and cg11525479 were analyzed on their associations with survival outcome in 23 tumors using TCGA methylation profiles generated by 450K microarray.	('cg11525479', 'Var', (39, 49))	('cg11525479', 'Chemical', '-', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cg27034819', 'Chemical', '-', (24, 34))	('cg27034819', 'Var', (24, 34))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
69869	33593392	Overall, similar to the conflicting findings from in vitro and in vivo studies on NTRKs gene, the association of their methylations with survival outcome varied in different tumors.	('association', 'Interaction', (98, 109))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('methylations', 'Var', (119, 131))	('tumors', 'Disease', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('TRK', 'Gene', (83, 86))	('TRK', 'Gene', '4914', (83, 86))
69870	33593392	The hypermethylation of cg27034819 was significantly associated with worse survival outcome in colon adenocarcinoma (COAD; P = 0.008, HR 1.91, 95% CI [1.18, 3.09]), rectum adenocarcinoma (READ; P 0.006, HR 3.73, 95% CI [1.37, 10.15]), kidney chromophobe (KICH; P = 0.005, HR 7.36, 95% CI [1.83, 29.581], and pancreatic adenocarcinoma (PAAD; P = 0.001, HR 1.96, 95% CI [1.30, 2.96]) cohorts.	('carcinoma', 'Disease', (106, 115))	('carcinoma', 'Disease', 'MESH:D009369', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (308, 333))	('cg27034819', 'Chemical', '-', (24, 34))	('carcinoma', 'Disease', 'MESH:D009369', (106, 115))	('carcinoma', 'Disease', (324, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cg27034819', 'Gene', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('kidney chromophobe', 'Disease', (235, 253))	('carcinoma', 'Disease', (177, 186))	('hypermethylation', 'Var', (4, 20))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (308, 333))	('carcinoma', 'Disease', 'MESH:D009369', (324, 333))	('kidney chromophobe', 'Disease', 'MESH:D000238', (235, 253))	('pancreatic adenocarcinoma', 'Disease', (308, 333))
69872	33593392	In cg11525479 methylation analysis, a similar predictive value for worse survival were found in COAD, READ, and PAAD, and a similar predictive value for better survival were found in GBM, SKCM and STAD (Fig.	('COAD', 'Disease', (96, 100))	('GBM', 'Disease', (183, 186))	('SKCM', 'Disease', (188, 192))	('methylation', 'Var', (14, 25))	('cg11525479', 'Chemical', '-', (3, 13))	('READ', 'Disease', (102, 106))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))	('cg11525479', 'Gene', (3, 13))
69873	33593392	These results suggested a robust prognostic value of the methylation of the specific promoter region targeted by cg27034819 and cg11525479 in multiple tumors.	('cg27034819', 'Chemical', '-', (113, 123))	('cg27034819', 'Var', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('methylation of the specific promoter region', 'MPA', (57, 100))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('cg11525479', 'Var', (128, 138))	('cg11525479', 'Chemical', '-', (128, 138))
69874	33593392	In this study, we found the NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed expression of NTRK2 and NTRK3.	('expression', 'MPA', (150, 160))	('NTRK3', 'Gene', (174, 179))	('methylated', 'Var', (68, 78))	('TRK', 'Gene', (29, 32))	('TRK', 'Gene', '4914', (29, 32))	('NTRK2', 'Gene', (164, 169))	('TRK', 'Gene', (175, 178))	('CRC', 'Disease', (82, 85))	('TRK', 'Gene', '4914', (175, 178))	('TRK', 'Gene', (165, 168))	('NTRK3', 'Gene', '4916', (174, 179))	('TRK', 'Gene', '4914', (165, 168))	('suppressed', 'NegReg', (139, 149))	('NTRK2', 'Gene', '4915', (164, 169))
69875	33593392	Through a screen of probes targeting NTRKs gene, we identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that was the most promising prognostic marker for CRC.	('cg27034819', 'Chemical', '-', (126, 136))	('cg27034819', 'Var', (126, 136))	('TRK', 'Gene', (38, 41))	('CRC', 'Disease', (202, 205))	('TRK', 'Gene', (100, 103))	('TRK', 'Gene', '4914', (38, 41))	('TRK', 'Gene', '4914', (100, 103))	('NTRK3', 'Gene', '4916', (99, 104))	('cg11525479', 'Var', (141, 151))	('cg11525479', 'Chemical', '-', (141, 151))	('NTRK3', 'Gene', (99, 104))
69876	33593392	We developed a QMSP assay to determine the methylation of this region that could be easily applied in clinical assay and validate its predictive value for survival outcome in a cohort of 229 CRC patients and 23 TCGA cohorts including a colon cancer cohort, a rectal cancer cohort and 21 cohorts of other tumor types.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('rectal cancer', 'Phenotype', 'HP:0100743', (259, 272))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('methylation', 'Var', (43, 54))	('cancer', 'Disease', (266, 272))	('CRC', 'Disease', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('colon cancer', 'Disease', 'MESH:D015179', (236, 248))	('colon cancer', 'Phenotype', 'HP:0003003', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('colon cancer', 'Disease', (236, 248))	('tumor', 'Disease', (304, 309))	('QMSP', 'Chemical', '-', (15, 19))
69877	33593392	Using NTRK3 promoter methylation, age, TNM stage, and BRAF mutation, a novel nomogram predicting DFS outcome was developed and validated with a good prognostic performance.	('NTRK3', 'Gene', (6, 11))	('methylation', 'biological_process', 'GO:0032259', ('21', '32'))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('TNM', 'Gene', (39, 42))	('NTRK3', 'Gene', '4916', (6, 11))	('mutation', 'Var', (59, 67))	('TNM', 'Gene', '10178', (39, 42))
69882	33593392	These results indicated that NTRK2 and NTRK3 may play a more important role of tumor suppressor in CRC, and methylation silencing of NTRK2 and NTRK3 would contribute more to CRC tumorigenesis.	('NTRK2', 'Gene', (133, 138))	('NTRK3', 'Gene', '4916', (39, 44))	('CRC', 'Disease', (99, 102))	('NTRK3', 'Gene', (39, 44))	('NTRK3', 'Gene', '4916', (143, 148))	('contribute', 'Reg', (155, 165))	('NTRK2', 'Gene', (29, 34))	('NTRK3', 'Gene', (143, 148))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('methylation silencing', 'Var', (108, 129))	('tumor', 'Disease', (79, 84))	('NTRK2', 'Gene', '4915', (133, 138))	('CRC', 'Disease', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('NTRK2', 'Gene', '4915', (29, 34))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
69886	33593392	The robustness of this assay includes the finding that the probe cg11525479 that was very close to cg27034819 also had a prognostic value superior to most probes.	('cg11525479', 'Var', (65, 75))	('cg11525479', 'Chemical', '-', (65, 75))	('cg27034819', 'Var', (99, 109))	('cg27034819', 'Chemical', '-', (99, 109))
69888	33593392	Using this assay in our CRC cohort, we found that NTRK3 promoter hypermethylation was associated with worse DFS validation.	('promoter hypermethylation', 'Var', (56, 81))	('associated', 'Reg', (86, 96))	('NTRK3', 'Gene', '4916', (50, 55))	('DFS', 'Disease', (108, 111))	('NTRK3', 'Gene', (50, 55))
69889	33593392	Furthermore, we revealed that NTRK3 promoter hypermethylation is highly associated with MSI and KRAS mutation that is known as response biomarkers for cancer treatment and have conflicting predictive value for survival.	('MSI', 'Disease', (88, 91))	('NTRK3', 'Gene', (30, 35))	('KRAS', 'Gene', '3845', (96, 100))	('promoter hypermethylation', 'Var', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (72, 82))	('NTRK3', 'Gene', '4916', (30, 35))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('KRAS', 'Gene', (96, 100))
69893	33593392	First, NTRK3 methylation status is better than rough TNM stage (I, II, III) in predicting prognosis in CRC.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation', 'Var', (13, 24))	('TNM', 'Gene', (53, 56))	('NTRK3', 'Gene', (7, 12))	('TNM', 'Gene', '10178', (53, 56))	('NTRK3', 'Gene', '4916', (7, 12))	('CRC', 'Disease', (103, 106))
69894	33593392	Then, the addition of NTRK3 promoter methylation status in TNM stage and the AJCC models was shown to improve the predictive performance for DFS in CRC patients.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('TNM', 'Gene', '10178', (59, 62))	('improve', 'PosReg', (102, 109))	('CRC', 'Disease', (148, 151))	('NTRK3', 'Gene', '4916', (22, 27))	('methylation status', 'Var', (37, 55))	('DFS', 'Disease', (141, 144))	('TNM', 'Gene', (59, 62))	('NTRK3', 'Gene', (22, 27))	('patients', 'Species', '9606', (152, 160))
69898	33593392	In our analyses, NTRK3 hypermethylation was associated with worse survival in some tumors, such as CRC, kidney chromophobe, and pancreatic adenocarcinoma, but it is related to a better outcome in other tumors, including glioblastoma multiforme, skin Cutaneous Melanoma, and stomach adenocarcinoma.	('Melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('NTRK3', 'Gene', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('pancreatic adenocarcinoma', 'Disease', (128, 153))	('CRC', 'Disease', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('glioblastoma', 'Phenotype', 'HP:0012174', (220, 232))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('skin Cutaneous Melanoma', 'Disease', (245, 268))	('hypermethylation', 'Var', (23, 39))	('glioblastoma multiforme', 'Disease', (220, 243))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (274, 296))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (220, 243))	('worse', 'NegReg', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (250, 268))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('stomach adenocarcinoma', 'Disease', (274, 296))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (128, 153))	('kidney chromophobe', 'Disease', 'MESH:D000238', (104, 122))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (128, 153))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('kidney chromophobe', 'Disease', (104, 122))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', (83, 89))	('skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (245, 268))	('NTRK3', 'Gene', '4916', (17, 22))
69903	33593392	We found NTRKs gene was commonly suppressed by promoter methylation in CRC compared to normal mucosa.	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('TRK', 'Gene', (10, 13))	('TRK', 'Gene', '4914', (10, 13))	('promoter methylation', 'Var', (47, 67))	('suppressed', 'NegReg', (33, 43))
69904	33593392	We identified the cg27034819-cg11525479 region within NTRK3 promoter as the most promising predictive marker for survival outcome, and it was validated in our CRC cohort and 23 TCGA cohorts including a colon cancer cohort, a rectal cancer cohort and 21 cohorts of other tumor types.	('cg11525479', 'Chemical', '-', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', (232, 238))	('NTRK3', 'Gene', '4916', (54, 59))	('cg27034819', 'Chemical', '-', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('cg27034819-cg11525479', 'Var', (18, 39))	('NTRK3', 'Gene', (54, 59))	('colon cancer', 'Disease', (202, 214))	('tumor', 'Disease', (270, 275))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
69906	33593392	In addition, we observed a performance improvement of currently used prognostic models after the introduction of NTRK3 promoter methylation.	('performance', 'MPA', (27, 38))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('NTRK3', 'Gene', '4916', (113, 118))	('improvement', 'PosReg', (39, 50))	('methylation', 'Var', (128, 139))	('NTRK3', 'Gene', (113, 118))
69911	23550303	Recent findings indicate that germline BAP1 mutations cause a novel cancer syndrome, characterized, at least in the affected families studied so far, by the onset at an early age of benign melanocytic skin tumours with mutated BAP1, and later in life by a high incidence of mesothelioma, uveal melanoma, cutaneous melanoma and possibly additional cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mesothelioma', 'Disease', 'MESH:D008654', (274, 286))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('mutated', 'Var', (219, 226))	('cancers', 'Disease', 'MESH:D009369', (347, 354))	('uveal melanoma', 'Disease', 'MESH:C536494', (288, 302))	('uveal melanoma', 'Disease', (288, 302))	('benign melanocytic skin tumours', 'Disease', (182, 213))	('BAP1', 'Gene', (39, 43))	('cause', 'Reg', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('early age of benign melanocytic skin', 'Phenotype', 'HP:0007396', (169, 205))	('cancers', 'Phenotype', 'HP:0002664', (347, 354))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('cancers', 'Disease', (347, 354))	('germline', 'Var', (30, 38))	('benign melanocytic skin tumours', 'Disease', 'MESH:D012878', (182, 213))	('melanoma', 'Phenotype', 'HP:0002861', (314, 322))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('BAP1', 'Gene', (227, 231))	('mutations', 'Var', (44, 53))	('cancer syndrome', 'Disease', (68, 83))	('cutaneous melanoma', 'Disease', (304, 322))	('mesothelioma', 'Disease', (274, 286))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (304, 322))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (304, 322))
69918	23550303	Chromosome microarray and genetic linkage analyses on the L and W families implicated chromosome region 3p21, a locus frequently altered in both UVM and mesotheliomas.	('UVM', 'Disease', (145, 148))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('chromosome region 3p21', 'Var', (86, 108))	('mesotheliomas', 'Disease', 'MESH:D008654', (153, 166))	('chromosome region', 'cellular_component', 'GO:0098687', ('86', '103'))	('mesotheliomas', 'Disease', (153, 166))
69919	23550303	Sequencing this region of chromosome 3 led to the identification of BAP1 as the gene mutated and associated with high rates of mesothelioma in the L and W families (experiments are in progress to address whether BAP1 also causes the high incidence of mesothelioma in Cappadocia).	('mesothelioma in Cappadocia', 'Disease', (251, 277))	('mesothelioma', 'Disease', (127, 139))	('mesothelioma', 'Disease', (251, 263))	('BAP1', 'Var', (212, 216))	('chromosome', 'cellular_component', 'GO:0005694', ('26', '36'))	('mesothelioma', 'Disease', 'MESH:D008654', (127, 139))	('mesothelioma in Cappadocia', 'Disease', 'MESH:D008654', (251, 277))	('mesothelioma', 'Disease', 'MESH:D008654', (251, 263))	('associated', 'Reg', (97, 107))	('BAP1', 'Gene', (68, 72))	('causes', 'Reg', (222, 228))
69920	23550303	BAP1 is a member of the ubiquitin C-terminal hydrolases (UCH) subfamily of deubiquitylating enzymes (DUBs) and was mutated in each family member who had developed mesothelioma, UVM and other cancers.	('BAP1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Disease', (191, 198))	('mutated', 'Var', (115, 122))	('mesothelioma', 'Disease', (163, 175))	('UVM', 'Disease', (177, 180))	('developed', 'PosReg', (153, 162))	('ubiquitin C', 'Gene', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mesothelioma', 'Disease', 'MESH:D008654', (163, 175))	('ubiquitin', 'molecular_function', 'GO:0031386', ('24', '33'))	('ubiquitin C', 'Gene', '7316', (24, 35))
69921	23550303	None of these tumour types was detected in family members who did not carry BAP1 mutations.	('tumour', 'Disease', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('tumour', 'Disease', 'MESH:D009369', (14, 20))
69922	23550303	Moreover, among several cases of sporadic mesotheliomas, we found that 2/26 patients had germline BAP1 mutations and importantly we found that both of these patients had been previously diagnosed with UVM.	('BAP1', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (76, 84))	('sporadic mesotheliomas', 'Phenotype', 'HP:0100001', (33, 55))	('sporadic mesotheliomas', 'Disease', (33, 55))	('patients', 'Species', '9606', (157, 165))	('sporadic mesotheliomas', 'Disease', 'MESH:D008654', (33, 55))	('sporadic mesothelioma', 'Phenotype', 'HP:0100001', (33, 54))
69924	23550303	On the basis of these findings, we have proposed that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma and UVM.	('cause', 'Reg', (78, 83))	('cancer syndrome', 'Disease', (90, 105))	('UVM', 'Disease', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BAP1', 'Gene', (63, 67))	('mesothelioma', 'Disease', 'MESH:D008654', (123, 135))	('mutations', 'Var', (68, 77))	('cancer syndrome', 'Disease', 'MESH:D009369', (90, 105))	('germline', 'Var', (54, 62))	('mesothelioma', 'Disease', (123, 135))
69925	23550303	In this Progress article, we discuss this potential inherited cancer syndrome, the possible mechanisms through which mutations in BAP1 might lead to tumour development and the clinical implications raised by detection of germline BAP1 mutations.	('mutations', 'Var', (117, 126))	('BAP1', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('lead to', 'Reg', (141, 148))	('cancer syndrome', 'Disease', 'MESH:D009369', (62, 77))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('cancer syndrome', 'Disease', (62, 77))	('tumour', 'Disease', (149, 155))
69926	23550303	reported that germline BAP1 mutations caused benign atypical melanocytic tumours.	('BAP1', 'Gene', (23, 27))	('melanocytic tumours', 'Disease', 'MESH:D009508', (61, 80))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('melanocytic tumours', 'Disease', (61, 80))	('mutations', 'Var', (28, 37))	('caused', 'Reg', (38, 44))
69929	23550303	They studied 32 sporadic ASTs and found that 9 had loss of BAP1 expression and 8 of these had concomitant BRAF mutations.	('mutations', 'Var', (111, 120))	('expression', 'MPA', (64, 74))	('BAP1', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('loss', 'NegReg', (51, 55))
69930	23550303	Only 1 of 23 ASTs that expressed BAP1 had a BRAF mutation (P< 0.0001) .	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))	('BAP1', 'Gene', (33, 37))	('mutation', 'Var', (49, 57))
69931	23550303	BRAF mutations are common in melanocytic nevi (80%) and in cutaneous melanoma (65%) but are rare in ASTs.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cutaneous melanoma', 'Disease', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (29, 45))	('common', 'Reg', (19, 25))	('melanocytic', 'Disease', (29, 40))	('BRAF', 'Gene', (0, 4))	('melanocytic', 'Disease', 'MESH:D009508', (29, 40))	('nevi', 'Phenotype', 'HP:0003764', (41, 45))
69932	23550303	noted the same type of skin tumours arising in families with germline BAP1 mutations and referred to them as nevoid melanoma-like melanocytic proliferations (NEMMPs).	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('skin tumours', 'Disease', 'MESH:D012878', (23, 35))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('skin tumours', 'Disease', (23, 35))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('BAP1', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('melanoma-like melanocytic proliferations', 'Disease', 'MESH:D059545', (116, 156))	('melanoma-like melanocytic proliferations', 'Disease', (116, 156))
69936	23550303	We found that all the melanocytic tumors in these BAP1 mutant patients had the same histological and molecular characteristics.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('melanocytic tumors', 'Disease', 'MESH:D009508', (22, 40))	('mutant', 'Var', (55, 61))	('patients', 'Species', '9606', (62, 70))	('BAP1', 'Gene', (50, 54))	('melanocytic tumors', 'Disease', (22, 40))
69937	23550303	In our review of the skin tumours in patients with mutant BAP1 we found that these are nevus-like lesions usually formed by a conventional junctional, compound or dermal nevus composed of small melanocytes expressing BAP1.	('patients', 'Species', '9606', (37, 45))	('nevus', 'Phenotype', 'HP:0003764', (170, 175))	('BAP1', 'Gene', (58, 62))	('mutant', 'Var', (51, 57))	('skin tumours', 'Disease', 'MESH:D012878', (21, 33))	('skin tumours', 'Disease', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('nevus', 'Phenotype', 'HP:0003764', (87, 92))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
69938	23550303	Next to these conventional nevus cells there is a dermal lesion formed by large epithelioid BAP1 negative and most frequently BRAF mutated melanocytes with virtually no mitotic activity.	('mutated', 'Var', (131, 138))	('dermal lesion', 'Disease', (50, 63))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('nevus', 'Phenotype', 'HP:0003764', (27, 32))	('dermal lesion', 'Disease', 'MESH:D016136', (50, 63))
69940	23550303	Acknowledging that these lesions are characteristic of, although possibly not unique to, BAP1 mutation carriers, we proposed naming them melanocytic BAP1-mutated atypical intradermal tumours (MBAITs).	('melanocytic', 'Disease', 'MESH:D009508', (137, 148))	('melanocytic', 'Disease', (137, 148))	('BAP1', 'Gene', (89, 93))	('intradermal tumours', 'Disease', 'MESH:D018330', (171, 190))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('intradermal tumours', 'Disease', (171, 190))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('mutation', 'Var', (94, 102))
69944	23550303	reported inactivating mutations of BAP1 in 26 of 31 aggressive (class 2) UVMs, among which a germline mutation was found in 1 of 26 patients.	('inactivating mutations', 'Var', (9, 31))	('patients', 'Species', '9606', (132, 140))	('BAP1', 'Gene', (35, 39))
69947	23550303	In this family, there were 7 BAP1 mutation carriers (5 tested and two inferred) and only one was cancer free at age 55; the other six had developed UVM (2 cases), cutaneous melanoma, mesothelioma, meningioma, lung and other types of carcinoma.	('lung', 'Disease', (209, 213))	('carcinoma', 'Disease', (233, 242))	('meningioma', 'Disease', 'MESH:D008577', (197, 207))	('cancer', 'Disease', (97, 103))	('mutation', 'Var', (34, 42))	('mesothelioma', 'Disease', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('mesothelioma', 'Disease', 'MESH:D008654', (183, 195))	('cutaneous melanoma', 'Disease', (163, 181))	('developed', 'PosReg', (138, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (163, 181))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (163, 181))	('BAP1', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('meningioma', 'Disease', (197, 207))	('meningioma', 'Phenotype', 'HP:0002858', (197, 207))	('UVM', 'Disease', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
69951	23550303	Also, they found that 2 of 7 probands from families with UVM-cutaneous melanoma carried germline BAP1 mutations, compared to 1 of 193 probands from families with a history of cutaneous melanoma and no UVMs (p=0.003).	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('UVM-cutaneous melanoma', 'Disease', 'MESH:C562393', (57, 79))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('BAP1', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('UVM-cutaneous melanoma', 'Disease', (57, 79))	('cutaneous melanoma', 'Disease', (175, 193))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (175, 193))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))
69952	23550303	reported that 2 of 66 (3%) patients with UVM unselected for family history carried germline BAP1 mutations.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (27, 35))	('BAP1', 'Gene', (92, 96))
69953	23550303	Additional tumour types, including renal, breast and lung carcinomas were also found among BAP1 mutation carriers.	('BAP1', 'Gene', (91, 95))	('carriers', 'Reg', (105, 113))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('mutation', 'Var', (96, 104))	('renal', 'Disease', (35, 40))	('tumour', 'Disease', 'MESH:D009369', (11, 17))	('found', 'Reg', (79, 84))	('breast and lung carcinomas', 'Disease', 'MESH:D001943', (42, 68))	('tumour', 'Disease', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
69954	23550303	Very recently, BAP1 mutations have been reported in sporadic renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (61, 76))	('sporadic renal carcinoma', 'Disease', (52, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('sporadic renal carcinoma', 'Disease', 'MESH:C538614', (52, 76))	('reported', 'Reg', (40, 48))	('BAP1', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
69955	23550303	Moreover, a novel inactivating germline splice mutation was reported in a family with UVM and cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cutaneous melanoma', 'Disease', (94, 112))	('UVM', 'Disease', (86, 89))	('inactivating germline splice mutation', 'Var', (18, 55))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))
69957	23550303	To date, 53 of 76 BAP1 germline mutation carriers have developed malignancies; 13 of these 53 developed two or more cancers.	('germline mutation', 'Var', (23, 40))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('BAP1', 'Gene', (18, 22))	('developed', 'PosReg', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('malignancies', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
69960	23550303	In the BAP1 mutation families, there is an exceptionally high incidence of malignancy overall (69.74% cancer incidence among 76 mutation carriers).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BAP1', 'Gene', (7, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('mutation', 'Var', (12, 20))	('malignancy', 'Disease', (75, 85))
69962	23550303	All of the mutation carriers unaffected by cancer are younger than 55 years old and may develop malignancies later in life.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('cancer', 'Disease', (43, 49))	('malignancies', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (11, 19))	('develop', 'PosReg', (88, 95))
69963	23550303	However, the relatively high frequency in the general population of the carcinomas that develop in BAP1 mutation carriers does not allow us yet to distinguish with certainty if the association with carcinomas is causal.	('BAP1', 'Gene', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinomas', 'Disease', (72, 82))	('mutation', 'Var', (104, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (198, 208))	('carcinomas', 'Disease', (198, 208))	('carcinomas', 'Disease', 'MESH:D002277', (198, 208))
69964	23550303	It should also be noted that population-based studies have shown that mutation carriers in the general population may have a lower risk than suggested by estimates obtained from families with multiple tumours, as for example observed for CDKN2A mutations.	('CDKN2A', 'Gene', (238, 244))	('multiple tumours', 'Disease', (192, 208))	('CDKN2A', 'Gene', '1029', (238, 244))	('mutations', 'Var', (245, 254))	('multiple tumours', 'Disease', 'MESH:D009369', (192, 208))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (70, 78))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
69965	23550303	Therefore, large population based studies will be required to validate the association of germline BAP1 mutations with the exceptionally high incidence of malignancies detected in the BAP1 mutant families.	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('mutant', 'Var', (189, 195))	('malignancies', 'Disease', 'MESH:D009369', (155, 167))	('BAP1', 'Gene', (184, 188))	('malignancies', 'Disease', (155, 167))	('association', 'Interaction', (75, 86))
69967	23550303	However, the Li-Fraumeni syndrome, caused by inherited mutations of the TP53 tumour suppressor gene, is an autosomal dominant cancer syndrome characteristically associated with the development of multiple tumour types .	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('caused by', 'Reg', (35, 44))	('Li-Fraumeni syndrome', 'Disease', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('multiple tumour', 'Disease', (196, 211))	('tumour', 'Disease', (205, 211))	('mutations', 'Var', (55, 64))	('TP53', 'Gene', '7157', (72, 76))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('autosomal dominant cancer syndrome', 'Disease', 'MESH:D009386', (107, 141))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('TP53', 'Gene', (72, 76))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (13, 33))	('autosomal dominant cancer syndrome', 'Disease', (107, 141))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('multiple tumour', 'Disease', 'MESH:D009369', (196, 211))
69972	23550303	Protein ubiquitylation was initially seen as a mechanism to label proteins for degradation; however, this notion has evolved as we have come to understand that ubiquitylation and DUBs regulate various cellular processes, including DNA repair, gene transcription, cell membrane trafficking, cell cycle progression, stress response, cell communication, differentiation and apoptosis, and that they have a role in cancer development.	('transcription', 'biological_process', 'GO:0006351', ('248', '261'))	('apoptosis', 'CPA', (371, 380))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('stress response', 'CPA', (314, 329))	('cell membrane trafficking', 'CPA', (263, 288))	('cell communication', 'biological_process', 'GO:0007154', ('331', '349'))	('differentiation', 'CPA', (351, 366))	('role', 'Reg', (403, 407))	('cell cycle progression', 'CPA', (290, 312))	('DNA repair', 'MPA', (231, 241))	('cell cycle', 'biological_process', 'GO:0007049', ('290', '300'))	('DNA', 'cellular_component', 'GO:0005574', ('231', '234'))	('cell membrane', 'cellular_component', 'GO:0005886', ('263', '276'))	('apoptosis', 'biological_process', 'GO:0097194', ('371', '380'))	('Protein ubiquitylation', 'biological_process', 'GO:0016567', ('0', '22'))	('cancer', 'Disease', (411, 417))	('apoptosis', 'biological_process', 'GO:0006915', ('371', '380'))	('degradation', 'biological_process', 'GO:0009056', ('79', '90'))	('regulate', 'Reg', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('ubiquitylation', 'Var', (160, 174))	('cell communication', 'CPA', (331, 349))	('cellular processes', 'CPA', (201, 219))	('DNA repair', 'biological_process', 'GO:0006281', ('231', '241'))	('gene transcription', 'CPA', (243, 261))
69979	23550303	Indeed, inhibition of BAP1 by short hairpin RNAs (shRNAs) impaired the DDR and caused HeLa cells to become hypersensitive to ionizing radiation resulting in S-phase retardation, a phenotype similar to BRCA1 deficiency.	('hypersensitive', 'Disease', (107, 121))	('HeLa', 'CellLine', 'CVCL:0030', (86, 90))	('hypersensitive to ionizing radiation', 'Phenotype', 'HP:0011133', (107, 143))	('hypersensitive', 'Disease', 'MESH:D004342', (107, 121))	('DDR', 'MPA', (71, 74))	('BRCA1 deficiency', 'Disease', 'OMIM:604370', (201, 217))	('S-phase', 'biological_process', 'GO:0051320', ('157', '164'))	('inhibition', 'Var', (8, 18))	('retardation', 'Disease', (165, 176))	('retardation', 'Disease', 'MESH:D008607', (165, 176))	('impaired', 'NegReg', (58, 66))	('BAP1', 'Gene', (22, 26))	('BRCA1 deficiency', 'Disease', (201, 217))
69983	23550303	Accordingly, NCI-H226 cells expressing exogenous wild-type BAP1 grew poorly in cell culture and when injected into athymic nude mice, they formed tumours that were about 10-15-fold smaller than those obtained with cells infected with vector alone or expressing BAP1 mutants lacking deubiquitylating activity (C91A substitution) or the second nuclear localization signal, NLS2, that is required for the nuclear compartmentalization of BAP1.	('lacking', 'NegReg', (274, 281))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('deubiquitylating activity', 'MPA', (282, 307))	('C91A', 'SUBSTITUTION', 'None', (309, 313))	('localization', 'biological_process', 'GO:0051179', ('350', '362'))	('BAP1', 'Gene', (261, 265))	('mutants', 'Var', (266, 273))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('NCI-H226', 'CellLine', 'CVCL:1544', (13, 21))	('nude mice', 'Species', '10090', (123, 132))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('C91A', 'Var', (309, 313))
69987	23550303	HCF1 is ubiquitylated on lysine residues, preferentially through K48-linked and K63-linked chains.	('HCF1', 'Gene', (0, 4))	('K63-linked chains', 'Var', (80, 97))	('preferentially', 'PosReg', (42, 56))	('K48-linked', 'Var', (65, 75))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
69998	23550303	PRC2 might also be important in tumours that have mutant BAP1.	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutant', 'Var', (50, 56))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('BAP1', 'Gene', (57, 61))
70000	23550303	proposed inhibiting PRC2 as a possible therapeutic strategy for treating mesothelioma.	('mesothelioma', 'Disease', 'MESH:D008654', (73, 85))	('mesothelioma', 'Disease', (73, 85))	('inhibiting', 'Var', (9, 19))	('PRC2', 'Gene', (20, 24))
70010	23550303	In the tumours that develop in BAP1 mutant carriers, BAP1 expression is either absent because of loss of heterozygosity (LOH), resulting in biallelic inactivation, or the BAP1 protein is localized in the cytoplasm where it may retain DUB activity, with as yet unknown possible effects on the cellular 'ubiquitinome'.	('biallelic', 'MPA', (140, 149))	('heterozygosity', 'MPA', (105, 119))	('absent', 'NegReg', (79, 85))	('expression', 'MPA', (58, 68))	('activity', 'MPA', (238, 246))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('tumours', 'Disease', 'MESH:D009369', (7, 14))	('BAP1', 'Gene', (31, 35))	('cytoplasm', 'cellular_component', 'GO:0005737', ('204', '213'))	('mutant', 'Var', (36, 42))	('tumours', 'Disease', (7, 14))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('BAP1', 'Gene', (53, 57))
70011	23550303	Because germline BAP1 mutations are associated with mesotheliomas, UVMs and cutaneous melanomas, there should be some common pathways controlled by BAP1 that are of particular importance to the development of these malignancies.	('UVMs', 'Disease', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mesotheliomas', 'Disease', 'MESH:D008654', (52, 65))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('mesotheliomas', 'Disease', (52, 65))	('malignancies', 'Disease', (215, 227))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (76, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (76, 95))	('cutaneous melanomas', 'Disease', (76, 95))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (36, 46))	('malignancies', 'Disease', 'MESH:D009369', (215, 227))	('BAP1', 'Gene', (17, 21))
70012	23550303	The finding that somatic BAP1 mutations are common in these cancers supports this interpretation.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('BAP1', 'Gene', (25, 29))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('common', 'Reg', (44, 50))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
70013	23550303	Somatic BAP1 mutations were found in 84% of metastasizing UVM biopsies and in 22% and 23% of sporadic US mesothelioma biopsies.	('mesothelioma', 'Disease', 'MESH:D008654', (105, 117))	('found', 'Reg', (28, 33))	('mesothelioma', 'Disease', (105, 117))	('BAP1', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('metastasizing UVM', 'Disease', (44, 61))
70014	23550303	found somatic inactivating BAP1 mutations in 61% of Japanese mesothelioma biopsies.	('mesothelioma', 'Disease', 'MESH:D008654', (61, 73))	('BAP1', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('mesothelioma', 'Disease', (61, 73))
70015	23550303	Studies in mice revealed that Bap1 deletion is lethal during embryogenesis.	('embryogenesis', 'biological_process', 'GO:0009790', ('61', '74'))	('Bap1', 'Gene', (30, 34))	('embryogenesis', 'biological_process', 'GO:0009793', ('61', '74'))	('mice', 'Species', '10090', (11, 15))	('deletion', 'Var', (35, 43))	('embryogenesis', 'biological_process', 'GO:0009792', ('61', '74'))	('Bap1', 'Gene', '104416', (30, 34))
70019	23550303	We are presently testing the hypothesis that germline Bap1 mutations increase the susceptibility to mineral fibre-induced and UV light-induced carcinogenesis; this may explain the absence of mesothelioma and melanoma in mice that were not exposed to these carcinogens.	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('mice', 'Species', '10090', (220, 224))	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (191, 216))	('Bap1', 'Gene', '104416', (54, 58))	('carcinogenesis', 'Disease', (143, 157))	('mutations', 'Var', (59, 68))	('Bap1', 'Gene', (54, 58))	('susceptibility', 'MPA', (82, 96))
70023	23550303	In such an environment, an impaired DDR caused by BAP1 deletion, might be expected to favour the accumulation of genetic damage that eventually gives rise to a malignant clone.	('favour', 'PosReg', (86, 92))	('genetic damage', 'Disease', 'MESH:D030342', (113, 127))	('gives rise to', 'Reg', (144, 157))	('genetic damage', 'Disease', (113, 127))	('DDR', 'MPA', (36, 39))	('malignant clone', 'CPA', (160, 175))	('deletion', 'Var', (55, 63))	('BAP1', 'Gene', (50, 54))	('accumulation', 'MPA', (97, 109))
70025	23550303	Moreover, we found very minimal and Wiesner et al, found no evidence of exposure to asbestos or erionite among the patients who developed mesothelioma in the families with BAP1 mutations, findings that do not support gene-environment interaction in causing mesothelioma, at least in these families.	('patients', 'Species', '9606', (115, 123))	('mesothelioma', 'Disease', (257, 269))	('asbestos', 'Disease', (84, 92))	('BAP1', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('mesothelioma', 'Disease', (138, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (257, 269))	('asbestos', 'Disease', 'MESH:D001195', (84, 92))	('erionite', 'Chemical', 'MESH:C083174', (96, 104))	('mesothelioma', 'Disease', 'MESH:D008654', (138, 150))
70029	23550303	Because BAP1 mutation carriers represent only a fraction of patients who develop UVM (3-4%), the overall association of UVM with UV light exposure should be re-evaluated in BAP1 mutations positive versus BAP1 mutation negative patients.	('mutation', 'Var', (13, 21))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (8, 12))	('BAP1', 'Gene', (173, 177))	('patients', 'Species', '9606', (227, 235))
70032	23550303	We anticipate that as more studies uncover the precise mechanisms by which BAP1 mutations cause mesothelioma and melanomas, specific preventive and therapeutic approaches for these malignancies will be developed (Box 1).	('mesothelioma and melanoma', 'Disease', 'MESH:D008654', (96, 121))	('melanomas', 'Disease', (113, 122))	('BAP1', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('malignancies', 'Disease', 'MESH:D009369', (181, 193))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('malignancies', 'Disease', (181, 193))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('cause', 'Reg', (90, 95))
70033	23550303	It is worth noting that a recent paper showed that histone deacetylase inhibitors (HDACIs) impair the in vitro and in vivo growth of UVM metastatic tumours with BAP1 inactivating mutations.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('BAP1', 'Gene', (161, 165))	('inactivating mutations', 'Var', (166, 188))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('growth', 'CPA', (123, 129))	('impair', 'NegReg', (91, 97))	('UVM', 'Disease', (133, 136))
70034	23550303	The apparent ability of BAP1 mutations to cause multiple tumour types and the high tumour phenotype penetrance (Table 1) suggests that this gene has a major role in influencing cancer cell growth.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cell growth', 'biological_process', 'GO:0016049', ('184', '195'))	('BAP1', 'Gene', (24, 28))	('multiple tumour', 'Disease', 'MESH:D009369', (48, 63))	('mutations', 'Var', (29, 38))	('cause', 'Reg', (42, 47))	('high tumour', 'Disease', (78, 89))	('high tumour', 'Disease', 'MESH:D009369', (78, 89))	('multiple tumour', 'Disease', (48, 63))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
70042	23550303	Wiesner et al noted that in BAP1 mutation carriers benign melanocytic tumors develop during the second decade of life and their number increases with age, a finding confirmed in the BAP1 mutant families we are studying.	('mutation', 'Var', (33, 41))	('melanocytic tumors', 'Disease', 'MESH:D009508', (58, 76))	('BAP1', 'Gene', (28, 32))	('increases', 'PosReg', (135, 144))	('melanocytic tumors', 'Disease', (58, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
70043	23550303	The occurrence of cutaneous melanoma in some BAP1 mutation carriers, including one that appeared to originate from these melanoctytic tumors, suggests that occasionally these benign tumors may undergo malignant transformation.	('melanoctytic tumors', 'Disease', (121, 140))	('melanoctytic tumors', 'Disease', 'MESH:D009369', (121, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('mutation', 'Var', (50, 58))
70044	23550303	This finding may account, at least in part, for the overall high risk of cutaneous melanoma detected among BAP1 germline mutation carriers (Table 1).	('cutaneous melanoma', 'Disease', (73, 91))	('germline mutation', 'Var', (112, 129))	('BAP1', 'Gene', (107, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
70047	23550303	Suspected MBAITs could be removed and tested to identify patients with BAP1 mutations.	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))
70051	23550303	Thus, the detection of families with inherited mutations of BAP1 offers opportunities for early cancer detection and more effective therapeutic approaches.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('BAP1', 'Gene', (60, 64))
70055	33335896	We found that CEP inhibited human primary cutaneous melanoma cells viability and proliferation in 24 h in vitro, and topical application or intra-tumoral injection of CEP decreased the growth of cutaneous melanoma in mice within 4 weeks.	('tumor', 'Disease', (146, 151))	('CEP', 'Chemical', 'MESH:C006947', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('inhibited', 'NegReg', (18, 27))	('cutaneous melanoma', 'Disease', (195, 213))	('proliferation in 24 h', 'CPA', (81, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (195, 213))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (195, 213))	('CEP', 'Chemical', 'MESH:C006947', (14, 17))	('CEP', 'Var', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mice', 'Species', '10090', (217, 221))	('CEP', 'molecular_function', 'GO:0047849', ('14', '17'))	('growth', 'MPA', (185, 191))	('cutaneous melanoma', 'Disease', (42, 60))	('topical', 'molecular_function', 'GO:0003809', ('117', '124'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('decreased', 'NegReg', (171, 180))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('human', 'Species', '9606', (28, 33))	('CEP', 'molecular_function', 'GO:0047849', ('167', '170'))
70075	33335896	Aberrant regulation of cathepsin B expression correlates with the invasive and metastatic phenotype of cancer.	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (35, 45))	('Aberrant regulation', 'Var', (0, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cathepsin B', 'Gene', (23, 34))
70082	33335896	In recent studies, it was identified that CEP may potently induce apoptosis in murine leukemia cell lines, adenosquamous carcinoma cell lines, and OSCC cell lines.	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (107, 130))	('adenosquamous carcinoma', 'Disease', (107, 130))	('CEP', 'Var', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('CEP', 'molecular_function', 'GO:0047849', ('42', '45'))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('murine', 'Species', '10090', (79, 85))	('induce', 'PosReg', (59, 65))	('leukemia', 'Disease', (86, 94))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('leukemia', 'Disease', 'MESH:D007938', (86, 94))	('apoptosis', 'CPA', (66, 75))	('CEP', 'Chemical', 'MESH:C006947', (42, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))
70083	33335896	It has been reported that CEP not only exerts antitumor effects by improving the immune activity of the host, but also can increase the effects of chemotherapeutic agents, such as anticancer agents of adriamycin and doxorubicin.	('cancer', 'Disease', (184, 190))	('adriamycin', 'Chemical', 'MESH:D004317', (201, 211))	('effects', 'MPA', (136, 143))	('CEP', 'Chemical', 'MESH:C006947', (26, 29))	('improving', 'PosReg', (67, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CEP', 'Var', (26, 29))	('increase', 'PosReg', (123, 131))	('immune activity', 'CPA', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('CEP', 'molecular_function', 'GO:0047849', ('26', '29'))	('tumor', 'Disease', (50, 55))
70137	33335896	Melanoma cells incubated with 200 ug/L cathepsin B for 24 h, the total apoptotic value of melanoma cells was decreased from 3.82 +- 0.12 to 3.45 +- 0.09% (P = 0.03) (Figure 2A).	('decreased', 'NegReg', (109, 118))	('melanoma', 'Disease', (90, 98))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('cathepsin', 'Var', (39, 48))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('apoptotic value', 'CPA', (71, 86))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
70138	33335896	Melanoma cells incubated with 200 ug/L cathepsin B for 24 h, the cellular activity was increased 12.7 +- 1.59% comparing with the control (P = 0.015) (Figure 2B).	('increased', 'PosReg', (87, 96))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('200 ug/L', 'Var', (30, 38))	('Melanoma', 'Disease', (0, 8))	('cathepsin', 'Gene', (39, 48))	('cellular activity', 'CPA', (65, 82))
70139	33335896	Primary cutaneous melanoma cells incubated with cathepsin B for 24 h, the cell apoptosis rate was increased in a dose-dependent manner.	('cell apoptosis rate', 'CPA', (74, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('cathepsin', 'Var', (48, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('increased', 'PosReg', (98, 107))	('Primary cutaneous melanoma', 'Disease', (0, 26))	('Primary cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
70145	33335896	Incubated with 10 mg/L CEP for 24 h, the expression of cathepsin B was decreased by 32.12 +- 7.92% in melanocytes and 10.48 +- 1.23% in melanoma cells.	('expression', 'MPA', (41, 51))	('cathepsin B', 'Gene', (55, 66))	('CEP', 'Var', (23, 26))	('CEP', 'Chemical', 'MESH:C006947', (23, 26))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('CEP', 'molecular_function', 'GO:0047849', ('23', '26'))	('melanoma', 'Disease', (136, 144))	('decreased', 'NegReg', (71, 80))
70151	33335896	Incubation of melanoma cells with different concentrations of CEP for 24 h decreased the expression of autophagy-related proteins LC3-I and LC3-II in a dose-dependent manner, with LC3II/I values varying as 0.975 +- 0.096 (0 mg/L CEP), 0.600 +- 0.082 (5 mg/L CEP, P > 0.05), 0.427 +- 0.046 (10 mg/L CEP, P < 0.05), 0.405 +- 0.086 (20 mg/L CEP, P < 0.05) (Figure 4E), respectively.	('CEP', 'molecular_function', 'GO:0047849', ('62', '65'))	('LC3', 'Gene', '84557', (140, 143))	('0.405 +- 0.086', 'Var', (314, 328))	('autophagy', 'biological_process', 'GO:0016236', ('103', '112'))	('CEP', 'Chemical', 'MESH:C006947', (62, 65))	('CEP', 'molecular_function', 'GO:0047849', ('338', '341'))	('LC3', 'Gene', '84557', (130, 133))	('expression', 'MPA', (89, 99))	('CEP', 'Chemical', 'MESH:C006947', (229, 232))	('CEP', 'molecular_function', 'GO:0047849', ('229', '232'))	('CEP', 'molecular_function', 'GO:0047849', ('298', '301'))	('LC3', 'Gene', (180, 183))	('autophagy', 'biological_process', 'GO:0006914', ('103', '112'))	('CEP', 'Chemical', 'MESH:C006947', (338, 341))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanoma', 'Disease', (14, 22))	('LC3', 'Gene', (140, 143))	('CEP', 'Chemical', 'MESH:C006947', (298, 301))	('CEP', 'molecular_function', 'GO:0047849', ('258', '261'))	('CEP', 'Chemical', 'MESH:C006947', (258, 261))	('LC3', 'Gene', (130, 133))	('0.427 +- 0.046', 'Var', (274, 288))	('0.600 +- 0.082', 'Var', (235, 249))	('LC3', 'Gene', '84557', (180, 183))	('autophagy-related', 'CPA', (103, 120))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('decreased', 'NegReg', (75, 84))
70153	33335896	After intra-tumoral injecting of CEP (20 mg/kg), the tumor volume was decreased as 214.36 +- 12.46 mm3 (P = 0.069) at 14-day, 255.25 +- 7.85 mm3 (P = 0.042) at 21-day and 318.69 +- 12.98 mm3 (P = 0.031)at 28-day comparing with the control in the same period as 245.22 + 10.63, 293.27 + 9.61, and 397.86 +- 15.57 mm3.	('CEP', 'molecular_function', 'GO:0047849', ('33', '36'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('decreased', 'NegReg', (70, 79))	('CEP', 'Var', (33, 36))	('CEP', 'Chemical', 'MESH:C006947', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (12, 17))
70169	33335896	In addition, others have found that CEP significantly increased the expression of p21Waf1 protein and decreased the expression of cyclins A and D proteins to exert the antitumor effect of ovarian cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('expression', 'MPA', (116, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('expression', 'MPA', (68, 78))	('CEP', 'Chemical', 'MESH:C006947', (36, 39))	('tumor', 'Disease', (172, 177))	('protein', 'Protein', (90, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (188, 202))	('CEP', 'molecular_function', 'GO:0047849', ('36', '39'))	('cyclins A and D', 'Gene', '890', (130, 145))	('increased', 'PosReg', (54, 63))	('ovarian cancer', 'Disease', (188, 202))	('p21Waf1', 'Var', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('decreased', 'NegReg', (102, 111))
70170	33335896	But CEP has been poorly studied in cutaneous melanoma, and in our study, it not only downregulates cathepsin B levels but also possesses novel antitumor mechanisms and inhibits primary cutaneous melanoma activity and metastasis by either topical application or intra-tumoral injection in mice.	('inhibits', 'NegReg', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('downregulates', 'NegReg', (85, 98))	('CEP', 'molecular_function', 'GO:0047849', ('4', '7'))	('tumor', 'Disease', (147, 152))	('topical', 'molecular_function', 'GO:0003809', ('238', '245'))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('cathepsin B levels', 'MPA', (99, 117))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('mice', 'Species', '10090', (288, 292))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('CEP', 'Chemical', 'MESH:C006947', (4, 7))	('cutaneous melanoma', 'Disease', (185, 203))	('CEP', 'Var', (4, 7))	('metastasis', 'CPA', (217, 227))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (185, 203))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (185, 203))	('cutaneous melanoma', 'Disease', (35, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (35, 53))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (35, 53))	('tumor', 'Disease', (267, 272))
70174	33335896	Modulation of autophagy is now being explored as a therapeutic option in melanoma treatment.	('autophagy', 'CPA', (14, 23))	('melanoma', 'Disease', (73, 81))	('Modulation', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('autophagy', 'biological_process', 'GO:0006914', ('14', '23'))	('autophagy', 'biological_process', 'GO:0016236', ('14', '23'))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
70175	33335896	It has been found that the "BRAF-TFEB-autophagy-lysosome" axis represents a key regulatory pathway in BRAF mutant melanoma, leading to tumor progression, metastasis, and resistance to BRAF-targeted therapy in melanoma.	('BRAF', 'Gene', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('BRAF-TFEB', 'Gene', (28, 37))	('autophagy', 'biological_process', 'GO:0016236', ('37', '46'))	('resistance', 'CPA', (170, 180))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('lysosome', 'cellular_component', 'GO:0005764', ('47', '55'))	('BRAF', 'Gene', '673', (102, 106))	('BRAF', 'Gene', (102, 106))	('autophagy', 'biological_process', 'GO:0006914', ('37', '46'))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('BRAF-TFEB', 'Gene', '673;7942', (28, 37))	('tumor', 'Disease', (135, 140))	('metastasis', 'CPA', (154, 164))	('BRAF', 'Gene', '673', (28, 32))	('BRAF', 'Gene', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('melanoma', 'Disease', (114, 122))	('leading to', 'Reg', (124, 134))	('mutant', 'Var', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('BRAF', 'Gene', '673', (184, 188))
70181	33335896	identified that cepharanthine could induce autophagy, apoptosis and cell cycle arrest in cancer cells.	('apoptosis', 'CPA', (54, 63))	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('autophagy', 'biological_process', 'GO:0006914', ('43', '52'))	('cepharanthine', 'Chemical', 'MESH:C006947', (16, 29))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('arrest', 'Disease', (79, 85))	('cepharanthine', 'Var', (16, 29))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('68', '85'))	('cancer', 'Disease', (89, 95))	('apoptosis', 'biological_process', 'GO:0097194', ('54', '63'))	('apoptosis', 'biological_process', 'GO:0006915', ('54', '63'))	('autophagy', 'CPA', (43, 52))	('autophagy', 'biological_process', 'GO:0016236', ('43', '52'))	('induce', 'PosReg', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
70184	33335896	This demonstrates that CEP can inhibit the growth of primary cutaneous melanoma by inhibiting autophagy and cathepsin B.	('growth', 'MPA', (43, 49))	('autophagy', 'biological_process', 'GO:0016236', ('94', '103'))	('cathepsin', 'CPA', (108, 117))	('autophagy', 'CPA', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('autophagy', 'biological_process', 'GO:0006914', ('94', '103'))	('CEP', 'Var', (23, 26))	('CEP', 'Chemical', 'MESH:C006947', (23, 26))	('inhibiting', 'NegReg', (83, 93))	('inhibit', 'NegReg', (31, 38))	('CEP', 'molecular_function', 'GO:0047849', ('23', '26'))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))
70185	33335896	We found not only that cathepsin B and autophagy-related protein expression were decreased by CEP, but also that p53, p21Cip1p, and p16Inka expression were simultaneously increased in human melanoma cells.	('p21Cip1p', 'Gene', '1026', (118, 126))	('p16', 'Gene', '1029', (132, 135))	('p21Cip1p', 'Gene', (118, 126))	('autophagy', 'biological_process', 'GO:0016236', ('39', '48'))	('human', 'Species', '9606', (184, 189))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('p53', 'Gene', (113, 116))	('increased', 'PosReg', (171, 180))	('CEP', 'Var', (94, 97))	('decreased', 'NegReg', (81, 90))	('CEP', 'Chemical', 'MESH:C006947', (94, 97))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('CEP', 'molecular_function', 'GO:0047849', ('94', '97'))	('autophagy', 'biological_process', 'GO:0006914', ('39', '48'))	('autophagy-related protein', 'Protein', (39, 64))	('cathepsin B', 'Protein', (23, 34))	('expression', 'MPA', (140, 150))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('p53', 'Gene', '7157', (113, 116))	('p16', 'Gene', (132, 135))
70187	33335896	Previous studies have shown that mutations in P53, P21, CDKN2A, A CDK4, CDKN2A, p16 (INK4A), p14, MC1R, and DNA repair genes predispose to melanoma.	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('mutations', 'Var', (33, 42))	('P21', 'Gene', '1026', (51, 54))	('p14', 'Gene', (93, 96))	('INK4A', 'Gene', (85, 90))	('P53', 'Gene', (46, 49))	('P21', 'Gene', (51, 54))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('DNA repair', 'biological_process', 'GO:0006281', ('108', '118'))	('CDKN2A', 'Gene', (56, 62))	('CDK4', 'Gene', (66, 70))	('CDKN2A', 'Gene', (72, 78))	('P53', 'Gene', '7157', (46, 49))	('CDK', 'molecular_function', 'GO:0004693', ('66', '69'))	('MC1R', 'Gene', '4157', (98, 102))	('p16', 'Gene', (80, 83))	('CDKN2A', 'Gene', '1029', (72, 78))	('CDKN2A', 'Gene', '1029', (56, 62))	('MC1R', 'Gene', (98, 102))	('CDK4', 'Gene', '1019', (66, 70))	('predispose', 'Reg', (125, 135))	('p16', 'Gene', '1029', (80, 83))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('p14', 'Gene', '1029', (93, 96))	('INK4A', 'Gene', '1029', (85, 90))
70188	33335896	Previous studies have revealed that CEP could inhibit ABCC10 (also known as MRP7) which is a broad-specificity transporter of xenobiotics, including many antitumor drugs (taxanes, epothilone B, vinca alkaloids, cytarabine, tamoxifen) and accepted as one of the most important of drug efflux transporters overexpressed on the membrane of cancer cells majorly cause the multi-drug resistance to cancer chemotherapy.	('tamoxifen', 'Chemical', 'MESH:D013629', (223, 232))	('vinca alkaloids', 'Chemical', 'MESH:D014748', (194, 209))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (393, 399))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cause', 'Reg', (358, 363))	('inhibit', 'NegReg', (46, 53))	('efflux', 'biological_process', 'GO:0140115', ('284', '290'))	('cytarabine', 'Chemical', 'MESH:D003561', (211, 221))	('drug resistance', 'biological_process', 'GO:0009315', ('374', '389'))	('drug resistance', 'Phenotype', 'HP:0020174', (374, 389))	('drug resistance', 'biological_process', 'GO:0042493', ('374', '389'))	('CEP', 'Var', (36, 39))	('CEP', 'Chemical', 'MESH:C006947', (36, 39))	('efflux', 'biological_process', 'GO:0140352', ('284', '290'))	('epothilone B', 'Chemical', 'MESH:C093788', (180, 192))	('taxanes', 'Chemical', 'MESH:D043823', (171, 178))	('MRP7', 'Gene', '89845', (76, 80))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (393, 399))	('MRP7', 'Gene', (76, 80))	('tumor', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('CEP', 'molecular_function', 'GO:0047849', ('36', '39'))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('ABCC10', 'Gene', (54, 60))	('membrane', 'cellular_component', 'GO:0016020', ('325', '333'))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('ABCC10', 'Gene', '89845', (54, 60))
70190	33335896	revealed that CEP could potently enhance the sensitivity to cytotoxic agents such as doxorubicin in K562 leukemia cells, not only via a reversal of ABCB1- mediated multi-drug resistance (MDR) but also increasing the accumulation of doxorubicin in nuclei.	('doxorubicin', 'Chemical', 'MESH:D004317', (232, 243))	('drug resistance', 'biological_process', 'GO:0009315', ('170', '185'))	('K562', 'CellLine', 'CVCL:0004', (100, 104))	('drug resistance', 'biological_process', 'GO:0042493', ('170', '185'))	('multi-drug resistance', 'MPA', (164, 185))	('drug resistance', 'Phenotype', 'HP:0020174', (170, 185))	('CEP', 'Chemical', 'MESH:C006947', (14, 17))	('CEP', 'Var', (14, 17))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('MDR', 'molecular_function', 'GO:0004745', ('187', '190'))	('CEP', 'molecular_function', 'GO:0047849', ('14', '17'))	('accumulation of doxorubicin in', 'MPA', (216, 246))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('ABCB1', 'Gene', (148, 153))	('ABCB1', 'Gene', '5243', (148, 153))	('increasing', 'PosReg', (201, 211))	('sensitivity to cytotoxic agents', 'MPA', (45, 76))	('leukemia', 'Disease', 'MESH:D007938', (105, 113))	('enhance', 'PosReg', (33, 40))	('leukemia', 'Disease', (105, 113))
70194	33335896	In this study, we demonstrated the effects of CEP as a novel tumor-regional therapy for cutaneous melanoma basing on the finding that CEP could inhibit the growth of human primary cutaneous melanoma cells by altering the expression of cathepsin B, tumor suppressor genes, and autophagy-related proteins.	('autophagy', 'biological_process', 'GO:0006914', ('276', '285'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('inhibit', 'NegReg', (144, 151))	('CEP', 'molecular_function', 'GO:0047849', ('134', '137'))	('CEP', 'molecular_function', 'GO:0047849', ('46', '49'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('248', '264'))	('tumor', 'Disease', (248, 253))	('CEP', 'Chemical', 'MESH:C006947', (46, 49))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('cutaneous melanoma', 'Disease', (180, 198))	('tumor suppressor', 'Gene', '7248', (248, 264))	('human', 'Species', '9606', (166, 171))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (180, 198))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (180, 198))	('CEP', 'Var', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('CEP', 'Chemical', 'MESH:C006947', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor suppressor', 'biological_process', 'GO:0051726', ('248', '264'))	('expression', 'MPA', (221, 231))	('altering', 'Reg', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cathepsin B', 'Protein', (235, 246))	('tumor', 'Disease', (61, 66))	('autophagy', 'biological_process', 'GO:0016236', ('276', '285'))	('cutaneous melanoma', 'Disease', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('growth', 'CPA', (156, 162))	('tumor suppressor', 'Gene', (248, 264))	('autophagy-related', 'CPA', (276, 293))
70211	28737763	Approximately two-thirds of these melanomas harbor BRAF mutations, and are most often classified histologically as superficial spreading and nodular melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mutations', 'Var', (56, 65))	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('nodular melanomas', 'Disease', (141, 158))	('nodular melanomas', 'Phenotype', 'HP:0012058', (141, 158))	('superficial spreading', 'Disease', (115, 136))	('melanomas', 'Disease', (34, 43))	('BRAF', 'Gene', '673', (51, 55))	('melanomas', 'Disease', (149, 158))	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('BRAF', 'Gene', (51, 55))	('nodular melanomas', 'Disease', 'MESH:D020518', (141, 158))
70214	28737763	This subtype is also often associated with intratumoral lymphoid aggregates and is more likely to be associated with mutations in tumor-suppressor genes when compared to the mixed desmoplastic type, which is more likely to be associated with BRAF and NRAS activating oncogenic driver mutations.	('intratumoral lymphoid aggregates', 'Disease', (43, 75))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (117, 126))	('BRAF', 'Gene', '673', (242, 246))	('tumor-suppressor', 'Gene', '7248', (130, 146))	('BRAF', 'Gene', (242, 246))	('associated', 'Reg', (27, 37))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('intratumoral lymphoid aggregates', 'Disease', 'MESH:D008223', (43, 75))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('tumor-suppressor', 'Gene', (130, 146))	('NRAS', 'Gene', (251, 255))	('associated', 'Reg', (101, 111))	('NRAS', 'Gene', '4893', (251, 255))
70262	28737763	Adaptive PD-L1 expression in the pretreatment melanoma microenvironment has been associated with an improved prognosis, and is also predictive of response to anti-PD-1/PD-L1 therapies in melanoma and other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('expression', 'Var', (15, 25))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('improved', 'PosReg', (100, 108))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Disease', (46, 54))	('tumor', 'Disease', (206, 211))	('PD-L1', 'Gene', '29126', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('PD-L1', 'Gene', (168, 173))	('PD-1', 'Gene', (163, 167))	('PD-1', 'Gene', '5133', (163, 167))	('prognosis', 'MPA', (109, 118))	('PD-L1', 'Gene', '29126', (168, 173))	('PD-L1', 'Gene', (9, 14))
70264	28737763	Many of the more recent studies reporting response rates to anti-PD-1/PD-L1 for patients with melanoma variants did not study PD-L1 expression.	('PD-L1', 'Gene', '29126', (70, 75))	('patients', 'Species', '9606', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('variants', 'Var', (103, 111))	('PD-1', 'Gene', (65, 69))	('PD-L1', 'Gene', (126, 131))	('PD-1', 'Gene', '5133', (65, 69))	('PD-L1', 'Gene', '29126', (126, 131))	('PD-L1', 'Gene', (70, 75))
70275	28737763	The association between PD-L1 expression and TILs is also in keeping with a prior observation that the presence of TILs is associated with improved outcomes in acral melanoma and a lower risk of metastasis in mucosal melanoma, and that patients with PD-L1(+) mucosal melanoma experience a significantly longer recurrence-free survival.	('mucosal melanoma', 'Disease', 'MESH:D008545', (209, 225))	('PD-L1', 'Gene', (24, 29))	('TILs', 'Gene', (115, 119))	('PD-L1', 'Gene', '29126', (24, 29))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('mucosal melanoma', 'Disease', (209, 225))	('presence', 'Var', (103, 111))	('patients', 'Species', '9606', (236, 244))	('acral melanoma', 'Disease', (160, 174))	('metastasis', 'CPA', (195, 205))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('longer', 'PosReg', (303, 309))	('acral melanoma', 'Disease', 'MESH:D008545', (160, 174))	('mucosal melanoma', 'Disease', 'MESH:D008545', (259, 275))	('PD-L1', 'Gene', (250, 255))	('lower', 'NegReg', (181, 186))	('acral melanoma', 'Phenotype', 'HP:0012060', (160, 174))	('improved', 'PosReg', (139, 147))	('PD-L1', 'Gene', '29126', (250, 255))	('mucosal melanoma', 'Disease', (259, 275))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('recurrence-free survival', 'CPA', (310, 334))
70282	28737763	PD-L1 expression has previously been associated with an epithelial to mesenchymal transition (EMT) in other tumor types, though the relationship between PD-L1, EMT, and the presence of a cytotoxic T-cell infiltrate was not assessed.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('associated with', 'Reg', (37, 52))	('PD-L1', 'Gene', (153, 158))	('EMT', 'biological_process', 'GO:0001837', ('94', '97'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('56', '92'))	('PD-L1', 'Gene', '29126', (153, 158))	('tumor', 'Disease', (108, 113))	('PD-L1', 'Gene', (0, 5))	('EMT', 'biological_process', 'GO:0001837', ('160', '163'))	('PD-L1', 'Gene', '29126', (0, 5))	('expression', 'Var', (6, 16))	('epithelial to mesenchymal transition', 'CPA', (56, 92))
70284	28737763	Features beyond PD-L1 expression such as mutational burden have also been proposed as biomarkers of response to anti-PD-1.	('PD-L1', 'Gene', (16, 21))	('mutational burden', 'Var', (41, 58))	('PD-L1', 'Gene', '29126', (16, 21))	('PD-1', 'Gene', (117, 121))	('PD-1', 'Gene', '5133', (117, 121))
70288	28737763	Thus, mutational burden also generally parallels the reported ORRs for melanoma subtypes, though perhaps not as closely as PD-L1 expression.	('melanoma subtypes', 'Disease', 'MESH:D008545', (71, 88))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mutational burden', 'Var', (6, 23))	('PD-L1', 'Gene', (123, 128))	('melanoma subtypes', 'Disease', (71, 88))	('PD-L1', 'Gene', '29126', (123, 128))
70290	28737763	A recent study showed that mutational burden was a contributing factor to general prognosis for patients with melanoma, but its relative contribution was less than PD-1/PD-L1 axis molecule expression.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('PD-L1', 'Gene', (169, 174))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('contributing', 'Reg', (51, 63))	('PD-L1', 'Gene', '29126', (169, 174))	('PD-1', 'Gene', (164, 168))	('PD-1', 'Gene', '5133', (164, 168))	('patients', 'Species', '9606', (96, 104))	('mutational burden', 'Var', (27, 44))
70292	28737763	The relationship of these alterations to PD-L1 expression or specific melanoma subtypes has yet to be defined.	('PD-L1', 'Gene', '29126', (41, 46))	('melanoma subtypes', 'Disease', (70, 87))	('alterations', 'Var', (26, 37))	('melanoma subtypes', 'Disease', 'MESH:D008545', (70, 87))	('PD-L1', 'Gene', (41, 46))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
70312	28737763	These features, when combined with other characteristics of the tumor microenvironment, such as high mutational load and the presence of lymphoid aggregates, provide a possible explanation for the observed high response rates to anti-PD-1 monotherapy in these patients.	('tumor', 'Disease', (64, 69))	('PD-1', 'Gene', (234, 238))	('PD-1', 'Gene', '5133', (234, 238))	('patients', 'Species', '9606', (260, 268))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutational load', 'Var', (101, 116))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
70334	31316083	nSREBP1 activates the transcription of DNFA genes, in concert with other transcription factors such as LXR, USF1, NFY1 and SP1, and co-activators including MED15 and CREBBP.	('nSREBP1', 'Var', (0, 7))	('CREBBP', 'Gene', (166, 172))	('DNFA', 'Chemical', '-', (39, 43))	('DNFA genes', 'Gene', (39, 49))	('activates', 'PosReg', (8, 17))	('CREBBP', 'Gene', '1387', (166, 172))	('USF1', 'Gene', '7391', (108, 112))	('transcription', 'biological_process', 'GO:0006351', ('73', '86'))	('MED15', 'Gene', '51586', (156, 161))	('MED15', 'Gene', (156, 161))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('transcription', 'MPA', (22, 35))	('USF1', 'Gene', (108, 112))
70377	31316083	Melanomas are transformed from benign, melanocytic nevi, with proliferation of melanocytes commonly triggered by BRAFV600E-activating mutation.	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('proliferation', 'CPA', (62, 75))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('triggered', 'Reg', (100, 109))	('Melanomas', 'Disease', (0, 9))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (39, 55))	('BRAFV600E-activating mutation', 'Var', (113, 142))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('BRAFV600E', 'Mutation', 'rs113488022', (113, 122))
70383	31316083	BRAF and NRAS mutations, while being well-known risk factors and drivers of cancer onset, have limited prognostic significance for overall survival of melanoma patients.	('patients', 'Species', '9606', (160, 168))	('NRAS', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('BRAF', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))
70397	31316083	SREBF2 depletion exerts potent effects on the expression of the DNCS genes HMGCS1 and HMGCR in HT-144 and A375 cells (Supplementary Fig.	('effects', 'Reg', (31, 38))	('SREBF2', 'Gene', (0, 6))	('HMGCR', 'Gene', (86, 91))	('HMGCS1', 'Gene', '3157', (75, 81))	('DNCS', 'Chemical', '-', (64, 68))	('depletion', 'Var', (7, 16))	('SREBF2', 'Gene', '6721', (0, 6))	('HMGCS1', 'Gene', (75, 81))	('HMGCR', 'Gene', '3156', (86, 91))	('expression', 'MPA', (46, 56))	('A375', 'CellLine', 'CVCL:0132', (106, 110))	('HT-144', 'CellLine', 'CVCL:0318', (95, 101))
70402	31316083	SREBF1 depletion by siRNA blocked DNFA gene activation on days 3 and 5, whereas DNFA enzyme protein (Fig.	('SREBF1', 'Gene', (0, 6))	('blocked', 'NegReg', (26, 33))	('SREBF1', 'Gene', '6720', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('DNFA', 'Chemical', '-', (34, 38))	('depletion', 'Var', (7, 16))	('DNFA', 'Chemical', '-', (80, 84))	('DNFA gene', 'Gene', (34, 43))	('activation', 'MPA', (44, 54))
70404	31316083	Consistently, we observed higher expression of DNFA genes after overexpressing nSREBP1a than nSREBP1c.	('DNFA', 'Chemical', '-', (47, 51))	('higher', 'PosReg', (26, 32))	('DNFA genes', 'Gene', (47, 57))	('expression', 'MPA', (33, 43))	('nSREBP1a', 'Var', (79, 87))
70406	31316083	To characterize the transcriptome changes after SREBF1 depletion, we carried out RNA-Seq analysis after SREBF1 depletion with pooled siRNAs and individual ASOs in HT-144 cells, followed by PCA on RNA-Seq data.	('ASOs', 'Chemical', 'MESH:D016376', (155, 159))	('SREBF1', 'Gene', (104, 110))	('RNA', 'cellular_component', 'GO:0005562', ('196', '199'))	('SREBF1', 'Gene', '6720', (104, 110))	('SREBF1', 'Gene', '6720', (48, 54))	('HT-144', 'CellLine', 'CVCL:0318', (163, 169))	('depletion', 'Var', (111, 120))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))	('SREBF1', 'Gene', (48, 54))
70418	31316083	Using gene-set enrichment analyses (GSEA) with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO) terms on DEGs, we determined that the downregulated genes after SREBF1 depletion are primarily involved in fatty acid biosynthesis and lipid metabolism (Fig.	('depletion', 'Var', (197, 206))	('genes', 'MPA', (178, 183))	('SREBF1', 'Gene', (190, 196))	('downregulated', 'NegReg', (164, 177))	('fatty acid biosynthesis', 'biological_process', 'GO:0006633', ('233', '256'))	('GSEA', 'Chemical', '-', (36, 40))	('lipid', 'Chemical', 'MESH:D008055', (261, 266))	('gene ontology', 'biological_process', 'GO:0003673', ('107', '120'))	('fatty acid', 'Chemical', 'MESH:D005227', (233, 243))	('lipid metabolism', 'biological_process', 'GO:0006629', ('261', '277'))	('SREBF1', 'Gene', '6720', (190, 196))
70419	31316083	Cellular inflammatory response pathways are significantly enriched in upregulated genes after SREBF1 depletion (Fig.	('inflammatory response', 'biological_process', 'GO:0006954', ('9', '30'))	('SREBF1', 'Gene', (94, 100))	('Cellular inflammatory response pathways', 'Pathway', (0, 39))	('upregulated', 'PosReg', (70, 81))	('depletion', 'Var', (101, 110))	('SREBF1', 'Gene', '6720', (94, 100))
70429	31316083	To elucidate the molecular mechanism of SREBP1-governed DNFA gene activation in melanoma cells, we used a chromatin immunoprecipitation (ChIP)-qPCR assay to detect occupancy of SREBP1, RNA polymerase II (RNAP II), and H3K36me3 - a histone marker associated with transcription elongation on DNFA genes.	('H3K36me3', 'Var', (218, 226))	('DNFA', 'Chemical', '-', (290, 294))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('RNA', 'cellular_component', 'GO:0005562', ('185', '188'))	('DNFA', 'Chemical', '-', (56, 60))	('transcription', 'biological_process', 'GO:0006351', ('262', '275'))
70431	31316083	9e-g) suggest that removal of SREBP1 at DNFA promoters inhibits transcription activity and mRNA production.	('DNFA', 'Chemical', '-', (40, 44))	('inhibits', 'NegReg', (55, 63))	('transcription activity', 'MPA', (64, 86))	('transcription', 'biological_process', 'GO:0006351', ('64', '77'))	('removal', 'Var', (19, 26))	('mRNA production', 'MPA', (91, 106))	('SREBP1', 'Gene', (30, 36))
70450	31316083	Using cell viability assay, we found that HT-144 and HT-144BR displayed similar sensitivities to ASO-4 treatment, as did LOXIMVI and LOXIMVIBR (Fig.	('HT-144BR', 'CellLine', 'CVCL:8779', (53, 61))	('HT-144', 'Var', (42, 48))	('LOXIMVI', 'Chemical', '-', (133, 140))	('LOXIMVIBR', 'Chemical', '-', (133, 142))	('HT-144', 'CellLine', 'CVCL:0318', (42, 48))	('HT-144', 'CellLine', 'CVCL:0318', (53, 59))	('LOXIMVI', 'Chemical', '-', (121, 128))	('HT-144BR', 'Var', (53, 61))	('ASO-4', 'Chemical', '-', (97, 102))
70452	31316083	To confirm that DNFA enzyme inhibition is the crucial driver for reduced cell viability, we then used small molecule inhibitors of FASN and SCD enzymes, which reportedly decreased tumor growth in preclinical studies.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('DNFA', 'Chemical', '-', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('inhibitors', 'Var', (117, 127))	('decreased', 'NegReg', (170, 179))
70471	31316083	14a-h), a cell line with reported MEK/ERK reactivation associated with vemurafenib treatment, vemurafenib exerts little induction of DNFA gene expression nor dose-dependent induction of PPARGC1A.	('PPARGC1A', 'Gene', (186, 194))	('vemurafenib', 'Var', (94, 105))	('expression', 'MPA', (143, 153))	('nor', 'NegReg', (154, 157))	('MEK', 'Gene', (34, 37))	('vemurafenib', 'Chemical', 'MESH:D000077484', (94, 105))	('MEK', 'Gene', '5609', (34, 37))	('DNFA', 'Chemical', '-', (133, 137))	('ERK', 'molecular_function', 'GO:0004707', ('38', '41'))	('DNFA gene', 'Gene', (133, 142))	('PPARGC1A', 'Gene', '10891', (186, 194))	('vemurafenib', 'Chemical', 'MESH:D000077484', (71, 82))	('gene expression', 'biological_process', 'GO:0010467', ('138', '153'))	('ERK', 'Gene', '5594', (38, 41))	('ERK', 'Gene', (38, 41))
70474	31316083	We saw evidence of a dose-response relationship between ERKi and induction of DNFA gene expression, where treatment of SCH772984 at 1 muM achieved stronger induction of DNFA gene expression (Supplementary Fig.	('ERK', 'Gene', '5594', (56, 59))	('muM', 'Gene', '56925', (134, 137))	('SCH772984', 'Var', (119, 128))	('DNFA', 'Chemical', '-', (78, 82))	('expression', 'MPA', (179, 189))	('DNFA gene', 'Gene', (169, 178))	('ERK', 'Gene', (56, 59))	('muM', 'Gene', (134, 137))	('gene expression', 'biological_process', 'GO:0010467', ('174', '189'))	('SCH772984', 'Chemical', 'MESH:C587178', (119, 128))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('DNFA', 'Chemical', '-', (169, 173))	('induction', 'MPA', (156, 165))
70475	31316083	Our overall interpretation is that BRAF/MEK/ERK pathway inhibition upregulates DNFA gene expression, possibly through AKT activation, which then contributes to vemurafenib tolerance in melanoma cells.	('BRAF', 'Gene', (35, 39))	('AKT', 'Gene', (118, 121))	('ERK', 'Gene', (44, 47))	('DNFA', 'Chemical', '-', (79, 83))	('MEK', 'Gene', (40, 43))	('expression', 'MPA', (89, 99))	('contributes to', 'Reg', (145, 159))	('vemurafenib', 'Chemical', 'MESH:D000077484', (160, 171))	('inhibition', 'Var', (56, 66))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('AKT', 'Gene', '207', (118, 121))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('MEK', 'Gene', '5609', (40, 43))	('upregulates', 'PosReg', (67, 78))	('ERK', 'Gene', '5594', (44, 47))	('tolerance', 'MPA', (172, 181))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('BRAF', 'Gene', '673', (35, 39))	('melanoma', 'Disease', (185, 193))	('DNFA gene', 'Gene', (79, 88))
70483	31316083	14a-g), while noting that, consistent with our findings above for A375, vemurafenib treatment alone yielded little induction of DNFA gene expression in A375 compared to HT-144, and the antagonistic effect was correspondingly lower.	('A375', 'Var', (152, 156))	('DNFA gene', 'Gene', (128, 137))	('A375', 'CellLine', 'CVCL:0132', (66, 70))	('vemurafenib', 'Chemical', 'MESH:D000077484', (72, 83))	('expression', 'MPA', (138, 148))	('A375', 'CellLine', 'CVCL:0132', (152, 156))	('HT-144', 'CellLine', 'CVCL:0318', (169, 175))	('DNFA', 'Chemical', '-', (128, 132))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))
70485	31316083	Cancers frequently exhibit reprogrammed metabolic traits such as elevated DNFA that act to sustain active proliferation and cell survival under adverse conditions, and support the process of tumorigenesis and metastasis, as well as resistance to targeted therapies.	('elevated', 'Var', (65, 73))	('DNFA', 'Chemical', '-', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cell survival', 'CPA', (124, 137))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('active proliferation', 'CPA', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('DNFA', 'Gene', (74, 78))	('metastasis', 'CPA', (209, 219))
70489	31316083	Moreover, increased DNFA pathway expression appears to be intrinsic to malignant cancer cell types independently of onco-drivers, including constitutively active BRAF mutants.	('malignant cancer', 'Disease', 'MESH:D009369', (71, 87))	('malignant cancer', 'Disease', (71, 87))	('DNFA pathway', 'Pathway', (20, 32))	('DNFA', 'Chemical', '-', (20, 24))	('expression', 'MPA', (33, 43))	('BRAF', 'Gene', '673', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutants', 'Var', (167, 174))	('increased', 'PosReg', (10, 19))	('BRAF', 'Gene', (162, 166))
70500	31316083	Therefore, inhibition of multiple DNFA enzymes could be of therapeutic benefit due to a potent cumulative effect on lipogenesis, as observed with SREBP1 mRNA-inhibiting ASOs and DNFA enzyme-targeting cocktails.	('lipogenesis', 'biological_process', 'GO:0008610', ('116', '127'))	('lipogenesis', 'MPA', (116, 127))	('ASOs', 'Chemical', 'MESH:D016376', (169, 173))	('DNFA', 'Chemical', '-', (178, 182))	('DNFA', 'Chemical', '-', (34, 38))	('inhibition', 'Var', (11, 21))
70505	31316083	Because vemurafenib sometimes fails to inhibit MEK/ERK (key targets downstream of BRAF), current clinical regimens combine inhibitors of both BRAF and MEK and/or ERK for treating metastatic melanomas.	('MEK', 'Gene', (151, 154))	('MEK', 'Gene', '5609', (47, 50))	('melanomas', 'Phenotype', 'HP:0002861', (190, 199))	('BRAF', 'Gene', '673', (142, 146))	('BRAF', 'Gene', (142, 146))	('MEK', 'Gene', (47, 50))	('ERK', 'Gene', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('ERK', 'Gene', (162, 165))	('vemurafenib', 'Chemical', 'MESH:D000077484', (8, 19))	('melanomas', 'Disease', 'MESH:D008545', (190, 199))	('ERK', 'molecular_function', 'GO:0004707', ('51', '54'))	('melanomas', 'Disease', (190, 199))	('ERK', 'molecular_function', 'GO:0004707', ('162', '165'))	('BRAF', 'Gene', '673', (82, 86))	('MEK', 'Gene', '5609', (151, 154))	('BRAF', 'Gene', (82, 86))	('inhibitors', 'Var', (123, 133))	('ERK', 'Gene', '5594', (51, 54))	('ERK', 'Gene', '5594', (162, 165))
70506	31316083	However, even when combined inhibition is achieved, resistance arises via genetic alterations that upregulate the PI3K/AKT pathway.	('PI3K', 'molecular_function', 'GO:0016303', ('114', '118'))	('AKT', 'Gene', '207', (119, 122))	('upregulate', 'PosReg', (99, 109))	('alterations', 'Var', (82, 93))	('AKT', 'Gene', (119, 122))
70519	31316083	The BRAF inhibitor vemurafenib (S1267) and ERK inhibitor SCH772984 (S7101) were purchased from Selleck Chemicals.	('ERK', 'molecular_function', 'GO:0004707', ('43', '46'))	('SCH772984', 'Chemical', 'MESH:C587178', (57, 66))	('ERK', 'Gene', '5594', (43, 46))	('ERK', 'Gene', (43, 46))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('vemurafenib', 'Chemical', 'MESH:D000077484', (19, 30))	('S7101', 'Var', (68, 73))	('S1267', 'Var', (32, 37))
70529	31316083	The human-specific siRNAs targeting SREBF1 (6720), SREBF2 (6721), MED15 (51586) and CREBBP (1387) were pre-designed ON-TARGETplus SMARTpool siRNA reagents from Dharmacon.	('SREBF1', 'Gene', '6720', (36, 42))	('human', 'Species', '9606', (4, 9))	('SREBF2', 'Gene', (51, 57))	('MED15', 'Gene', (66, 71))	('MED15', 'Gene', '51586', (66, 71))	('CREBBP', 'Gene', '1387', (84, 90))	('pre', 'molecular_function', 'GO:0003904', ('103', '106'))	('SREBF1', 'Gene', (36, 42))	('6720', 'Var', (44, 48))	('6721', 'Var', (59, 63))	('SREBF2', 'Gene', '6721', (51, 57))	('CREBBP', 'Gene', (84, 90))
70597	22268848	Mutations in oncogenes and tumor suppressors that are common in other cancers are conspicuously absent in uveal melanoma.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (27, 32))	('absent', 'NegReg', (96, 102))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('cancers', 'Disease', (70, 77))	('oncogenes', 'Protein', (13, 22))
70599	22268848	Mutations in the Gq alpha subunits, encoded by GNAQ and GNA11, appear to be early or perhaps initiating events that require further mutations for malignant transformation.	('GNAQ', 'Gene', (47, 51))	('Mutations', 'Var', (0, 9))	('GNAQ', 'Gene', '2776', (47, 51))	('GNA11', 'Gene', (56, 61))	('GNA11', 'Gene', '2767', (56, 61))
70600	22268848	On the other hand, mutations in the BRCA1-associated protein-1 (BAP1) appear to occur later and demarcate a molecular brink beyond which metastasis becomes highly likely.	('BRCA1-associated protein-1', 'Gene', (36, 62))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('mutations', 'Var', (19, 28))	('BRCA1-associated protein-1', 'Gene', '8314', (36, 62))	('metastasis', 'CPA', (137, 147))	('BAP1', 'Gene', (64, 68))
70601	22268848	BAP1 mutations can also occur in the germline, leading to a distinctive cancer predisposition syndrome.	('BAP1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('leading to', 'Reg', (47, 57))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
70616	22268848	1p loss is one of the few chromosomal abnormalities that provides prognostic information that is independent of chromosome 3 status, with its presence portending decreased disease-free survival.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (26, 51))	('decreased', 'NegReg', (162, 171))	('disease-free survival', 'CPA', (172, 193))	('1p loss', 'Var', (0, 7))	('chromosomal abnormalities', 'Disease', (26, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('112', '122'))
70619	22268848	This relative mutual exclusivity of 6p gain and monosomy 3 may represent alternative evolutionary pathways that are available during tumor progression, the former being less likely to eventuate in metastasis than the latter.	('monosomy 3', 'Var', (48, 58))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
70626	22268848	These findings suggest that inactivation of CDKN2A may play a role in UM progression.	('UM', 'Phenotype', 'HP:0007716', (70, 72))	('CDKN2A', 'Gene', (44, 50))	('inactivation', 'Var', (28, 40))	('CDKN2A', 'Gene', '1029', (44, 50))	('play', 'Reg', (55, 59))
70627	22268848	However, germline CDKN2A mutations are very rare in patients with UM.	('CDKN2A', 'Gene', '1029', (18, 24))	('mutations', 'Var', (25, 34))	('UM', 'Phenotype', 'HP:0007716', (66, 68))	('CDKN2A', 'Gene', (18, 24))	('patients', 'Species', '9606', (52, 60))
70631	22268848	These mutations occurred almost exclusively in metastasizing tumors that had also lost the other copy of chromosome 3, consistent with the 'two-hit' model for recessive cancer genes.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('occurred', 'Reg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('recessive cancer', 'Disease', 'MESH:D009369', (159, 175))	('recessive cancer', 'Disease', (159, 175))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (6, 15))
70632	22268848	BAP1 mutations had previously been identified in a small number of breast and lung cancer cell lines and more recently in malignant pleural mesotheliomas, cutaneous melanoma, and possibly other cancers such as meningioma.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('identified', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Disease', (194, 201))	('meningioma', 'Disease', (210, 220))	('meningioma', 'Phenotype', 'HP:0002858', (210, 220))	('BAP1', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('meningioma', 'Disease', 'MESH:D008577', (210, 220))	('cutaneous melanoma', 'Disease', (155, 173))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (155, 173))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (155, 173))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('mutations', 'Var', (5, 14))	('malignant pleural mesotheliomas', 'Disease', 'MESH:C562839', (122, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('malignant pleural mesotheliomas', 'Disease', (122, 153))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('pleural mesotheliomas', 'Phenotype', 'HP:0100002', (132, 153))	('breast and lung cancer', 'Disease', 'MESH:D001943', (67, 89))
70636	22268848	While the relative importance of these various interactions remains unclear, a crucial role for BAP1's deubiquinating activity is strongly suggested by several lines of evidence: (i) the requirement for this activity for tumor suppression in cell culture experiments and (ii) most missense mutations directly target the deubiquitinating catalytic domain.	('deubiquinating activity', 'MPA', (103, 126))	('missense mutations', 'Var', (281, 299))	('deubiquitinating catalytic domain', 'MPA', (320, 353))	('BAP1', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('target', 'Reg', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
70649	22268848	However, in a much larger study of 75 primary UMs, LOH of the PTEN locus was found in 76% of tumors, and actual mutations within the PTEN coding region were found in 11% of tumors.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('UM', 'Phenotype', 'HP:0007716', (46, 48))	('LOH', 'Var', (51, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PTEN', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('PTEN', 'Gene', '5728', (133, 137))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
70650	22268848	PTEN inactivation was also found to be associated with increased aneuploidy and decreased survival in UM.	('aneuploidy', 'Disease', (65, 75))	('increased', 'PosReg', (55, 64))	('decreased', 'NegReg', (80, 89))	('aneuploidy', 'Disease', 'MESH:D000782', (65, 75))	('survival in UM', 'CPA', (90, 104))	('inactivation', 'Var', (5, 17))	('PTEN', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (102, 104))	('PTEN', 'Gene', '5728', (0, 4))
70653	22268848	Interestingly, however, BRAF mutations may occur in up to 47% of iris melanomas, which are more anterior and more strongly linked to ultraviolet light exposure than the more common posterior UMs of the ciliary body and choroid.	('iris melanomas', 'Disease', 'MESH:D007499', (65, 79))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('mutations', 'Var', (29, 38))	('UM', 'Phenotype', 'HP:0007716', (191, 193))	('BRAF', 'Gene', '673', (24, 28))	('BRAF', 'Gene', (24, 28))	('iris melanomas', 'Disease', (65, 79))	('iris melanomas', 'Phenotype', 'HP:0011524', (65, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('linked', 'Reg', (123, 129))
70655	22268848	This curious absence of MAPK pathway mutations persisted until the recent discovery of mutations in GNAQ, which encodes the Galphaq subunit, in almost half of UMs.	('MAPK', 'molecular_function', 'GO:0004707', ('24', '28'))	('GNAQ', 'Gene', '2776', (100, 104))	('UM', 'Phenotype', 'HP:0007716', (159, 161))	('Galphaq', 'Gene', (124, 131))	('Galphaq', 'Gene', '2776', (124, 131))	('GNAQ', 'Gene', (100, 104))	('mutations', 'Var', (87, 96))	('MAPK', 'Pathway', (24, 28))
70656	22268848	Mutant GNAQ was shown to activate the MAPK pathway, although it may have also important effects on other pathways such as the phosphatidylinositol-calcium second messenger system.	('effects', 'Reg', (88, 95))	('activate', 'PosReg', (25, 33))	('phosphatidylinositol-calcium', 'Chemical', '-', (126, 154))	('GNAQ', 'Gene', '2776', (7, 11))	('GNAQ', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('MAPK pathway', 'Pathway', (38, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('38', '42'))
70657	22268848	Attention was drawn to this gene as a result of a forward genetic screen in mice that identified hypermorphic mutations in Gnaq or its paralog Gna11, which act through the melanocyte lineage factor Ednrb, as a cause of increased numbers of intradermal melanocytes.	('Gnaq', 'Gene', '14682', (123, 127))	('mutations', 'Var', (110, 119))	('Gnaq', 'Gene', (123, 127))	('Gna11', 'Gene', '14672', (143, 148))	('mice', 'Species', '10090', (76, 80))	('Gna11', 'Gene', (143, 148))	('increased', 'PosReg', (219, 228))
70658	22268848	A subsequent study found that 83% of UMs contained mutations in either GNAQ or GNA11 affecting either Q209 or R183 in a mutually exclusive pattern.	('mutations', 'Var', (51, 60))	('GNAQ', 'Gene', (71, 75))	('UM', 'Phenotype', 'HP:0007716', (37, 39))	('Q209', 'MPA', (102, 106))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('R183', 'Var', (110, 114))	('GNAQ', 'Gene', '2776', (71, 75))
70659	22268848	These mutations lead to constitutive activation of the Galphaq and Galpha11 subunits by abrogating their intrinsic GTPase activity required to return them to an inactive state.	('GTPase activity', 'molecular_function', 'GO:0003924', ('115', '130'))	('abrogating', 'NegReg', (88, 98))	('activation', 'PosReg', (37, 47))	('Galpha11', 'Gene', (67, 75))	('Galphaq', 'Gene', (55, 62))	('intrinsic', 'MPA', (105, 114))	('Galphaq', 'Gene', '2776', (55, 62))	('Galpha11', 'Gene', '2767', (67, 75))	('GTPase', 'Protein', (115, 121))	('mutations', 'Var', (6, 15))
70660	22268848	GNAQ/11 mutations are found in benign uveal nevi and in the vast majority of UMs regardless of cytogenetic status, GEP class, or BAP1 status.	('GNAQ', 'Gene', '2776', (0, 4))	('benign uveal', 'Disease', 'MESH:D014603', (31, 43))	('mutations', 'Var', (8, 17))	('found', 'Reg', (22, 27))	('UM', 'Phenotype', 'HP:0007716', (77, 79))	('nevi', 'Phenotype', 'HP:0003764', (44, 48))	('GNAQ', 'Gene', (0, 4))	('benign uveal', 'Disease', (31, 43))
70661	22268848	Further, these mutations are not sufficient for full malignant transformation to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('mutations', 'Var', (15, 24))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
70662	22268848	This would seem to place GNAQ/11 mutations as early or perhaps initiating events in UM progression.	('GNAQ', 'Gene', '2776', (25, 29))	('GNAQ', 'Gene', (25, 29))	('UM', 'Phenotype', 'HP:0007716', (84, 86))	('mutations', 'Var', (33, 42))
70663	22268848	On the other hand, BAP1 mutations are seen almost exclusively in metastasizing class 2 tumors with monosomy 3, suggesting that this mutation occurs relatively late in the primary tumor and may represent a rate-limiting step in metastasis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('primary tumor', 'Disease', 'MESH:D009369', (171, 184))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('BAP1', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('primary tumor', 'Disease', (171, 184))
70664	22268848	Either BAP1 mutation or loss of chromosome 3 can occur first, but both events appear to be necessary for the tumor to acquire the metastasizing class 2 phenotype.	('BAP1', 'Gene', (7, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutation', 'Var', (12, 20))	('tumor', 'Disease', (109, 114))
70667	22268848	Monosomy 3, the most common change in UM, is also seen in cutaneous melanoma, although at a lower frequency.	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('UM', 'Phenotype', 'HP:0007716', (38, 40))	('Monosomy 3', 'Var', (0, 10))
70668	22268848	Likewise, loss on 9p and 10, which are very common in cutaneous melanoma, are also seen in UM, albeit not as often.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('loss on 9p', 'Var', (10, 20))	('UM', 'Phenotype', 'HP:0007716', (91, 93))	('cutaneous melanoma', 'Disease', (54, 72))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (54, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (54, 72))
70669	22268848	Activating mutations in BRAF and NRAS are common in some types of cutaneous melanoma, but are distinctively rare in UM.	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('NRAS', 'Gene', (33, 37))	('Activating mutations', 'Var', (0, 20))	('NRAS', 'Gene', '4893', (33, 37))	('BRAF', 'Gene', (24, 28))	('BRAF', 'Gene', '673', (24, 28))	('UM', 'Phenotype', 'HP:0007716', (116, 118))	('common', 'Reg', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
70671	22268848	BAP1 mutations, which are strongly linked to metastasis in UM, also occur in cutaneous melanoma, but it is unclear whether these mutations play the same role in the latter as they do in the former.	('occur', 'Reg', (68, 73))	('BAP1', 'Gene', (0, 4))	('UM', 'Phenotype', 'HP:0007716', (59, 61))	('mutations', 'Var', (5, 14))	('cutaneous melanoma', 'Disease', (77, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
70673	22268848	A few studies have suggested a link between UM and breast cancer, possibly as a consequence of germline BRCA2 mutations.	('BRCA2', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BRCA2', 'Gene', '675', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('breast cancer', 'Disease', (51, 64))
70674	22268848	In one study, constitutional DNA samples were analyzed for BRCA2 mutations in 62 patients with UM who were selected primarily on the basis of a family history of breast cancer or UM harbored; three (4.8%) patients harbored BRCA2 sequence variants that were judged to be potentially deleterious.	('UM', 'Phenotype', 'HP:0007716', (179, 181))	('BRCA2', 'Gene', '675', (59, 64))	('patients', 'Species', '9606', (205, 213))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('BRCA2', 'Gene', '675', (223, 228))	('variants', 'Var', (238, 246))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('BRCA2', 'Gene', (59, 64))	('breast cancer', 'Disease', (162, 175))	('BRCA2', 'Gene', (223, 228))	('mutations', 'Var', (65, 74))
70675	22268848	An Israeli study identified 4/143 (2.8%) patients with UM who carried a germline 6174delT BRCA2 mutation.	('BRCA2', 'Gene', (90, 95))	('UM', 'Phenotype', 'HP:0007716', (55, 57))	('BRCA2', 'Gene', '675', (90, 95))	('6174delT', 'Var', (81, 89))	('patients', 'Species', '9606', (41, 49))	('6174delT', 'Mutation', 'rs786204278', (81, 89))
70676	22268848	An Australian study found germline BRCA2 mutations in 2/71 (2.8%) patients with UM, but neither of these patients had a positive family history, thus leaving open the possibility that these were silent polymorphisms.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (105, 113))	('BRCA2', 'Gene', '675', (35, 40))	('UM', 'Phenotype', 'HP:0007716', (80, 82))	('patients', 'Species', '9606', (66, 74))	('BRCA2', 'Gene', (35, 40))
70677	22268848	Given the rarity of familial UM in the literature, we were surprised to find that one of the patients with UM in our original study carried a germline BAP1 mutation that was reduced to homozygosity in the tumor by loss of the other copy of chromosome 3.	('UM', 'Phenotype', 'HP:0007716', (107, 109))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('BAP1', 'Gene', (151, 155))	('UM', 'Phenotype', 'HP:0007716', (29, 31))	('loss', 'NegReg', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('chromosome', 'cellular_component', 'GO:0005694', ('240', '250'))	('patients', 'Species', '9606', (93, 101))	('mutation', 'Var', (156, 164))
70678	22268848	We have identified another family from our ocular oncology center in which UM and cutaneous melanoma occurred in multiple family member in association with a germline BAP1 mutation (author's unpublished data).	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('occurred', 'Reg', (101, 109))	('germline', 'Var', (158, 166))	('mutation', 'Var', (172, 180))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('ocular oncology', 'Phenotype', 'HP:0100012', (43, 58))	('oncology', 'Phenotype', 'HP:0002664', (50, 58))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('BAP1', 'Gene', (167, 171))
70682	22268848	In support of this idea, a cutaneous melanocytic tumor associated with germline BAP1 mutation also harbored mutant BRAF, and only the portion of the tumor that had lost the other copy of BAP1 progressed to melanoma.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('BRAF', 'Gene', '673', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('BRAF', 'Gene', (115, 119))	('harbored', 'Reg', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('associated', 'Reg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (49, 54))	('mutation', 'Var', (85, 93))	('mutant', 'Var', (108, 114))	('cutaneous melanocytic tumor', 'Disease', (27, 54))	('cutaneous melanocytic tumor', 'Disease', 'MESH:D009508', (27, 54))	('tumor', 'Disease', (149, 154))	('BAP1', 'Gene', (80, 84))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))
70683	22268848	Similarly, our reported case of UM associated with a germline BAP1 mutation harbored a GNAQ mutation and had lost the other copy of chromosome 3.	('mutation', 'Var', (67, 75))	('GNAQ', 'Gene', '2776', (87, 91))	('BAP1', 'Gene', (62, 66))	('other copy of chromosome 3', 'MPA', (118, 144))	('UM', 'Phenotype', 'HP:0007716', (32, 34))	('harbored', 'Reg', (76, 84))	('GNAQ', 'Gene', (87, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('lost', 'NegReg', (109, 113))
70685	22268848	The discovery of GNAQ/11 and BAP1 mutations in UM provides an unprecedented opportunity for targeted therapy of metastatic disease.	('metastatic disease', 'Disease', (112, 130))	('GNAQ', 'Gene', (17, 21))	('UM', 'Phenotype', 'HP:0007716', (47, 49))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('GNAQ', 'Gene', '2776', (17, 21))
70686	22268848	For GNAQ/11 mutations, the therapeutic goal is to inhibit oncogenic downstream signaling resulting from these mutations.	('GNAQ', 'Gene', '2776', (4, 8))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (12, 21))	('inhibit', 'NegReg', (50, 57))	('GNAQ', 'Gene', (4, 8))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('oncogenic downstream signaling', 'MPA', (58, 88))
70687	22268848	Direct inhibition of mutant Galphaq or Galpha11 may prove difficult, however, because these mutations abrogate the intrinsic GTPase activity that would normally allow these proteins to return to their GDP-bound, inactive state.	('mutant', 'Var', (21, 27))	('GTPase activity', 'molecular_function', 'GO:0003924', ('125', '140'))	('activity', 'MPA', (132, 140))	('Galphaq', 'Gene', (28, 35))	('Galphaq', 'Gene', '2776', (28, 35))	('Galpha11', 'Gene', (39, 47))	('mutations', 'Var', (92, 101))	('GDP', 'Chemical', 'MESH:D006153', (201, 204))	('abrogate', 'NegReg', (102, 110))	('Galpha11', 'Gene', '2767', (39, 47))	('GTPase', 'Protein', (125, 131))
70688	22268848	An alternative strategy is to inhibit downstream signaling molecules that are activated by GNAQ/11 mutations.	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('inhibit', 'NegReg', (30, 37))	('GNAQ', 'Gene', (91, 95))	('mutations', 'Var', (99, 108))	('GNAQ', 'Gene', '2776', (91, 95))
70689	22268848	One such target is MEK, a key component of the MAPK mitogenic pathway that is activated by GNAQ/11 mutations.	('MEK', 'Gene', '5609', (19, 22))	('activated', 'PosReg', (78, 87))	('GNAQ', 'Gene', (91, 95))	('MAPK', 'molecular_function', 'GO:0004707', ('47', '51'))	('mutations', 'Var', (99, 108))	('MEK', 'Gene', (19, 22))	('GNAQ', 'Gene', '2776', (91, 95))
70697	22268848	Activating mutations in GNAQ/11 appear to represent a very early or initiating event, whereas inactivating mutations in BAP1 appear to demarcate a threshold in tumor progression beyond which metastasis and death await.	('GNAQ', 'Gene', '2776', (24, 28))	('demarcate', 'Reg', (135, 144))	('Activating mutations', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inactivating mutations', 'Var', (94, 116))	('GNAQ', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('BAP1', 'Gene', (120, 124))
70698	22268848	The opportunities for targeted therapy afforded by the discovery of GNAQ/11 and BAP1 mutations are being explored.	('GNAQ', 'Gene', (68, 72))	('mutations', 'Var', (85, 94))	('GNAQ', 'Gene', '2776', (68, 72))	('BAP1', 'Gene', (80, 84))
70740	33194572	FNAC was performed by a professional cytopathologist at the cancer center, as follows: inquiring about the medical history; determining the location, size, and characteristics of the mass; disinfecting skin; spreading disinfection towels; fixing the mass with the index and middle fingers, puncturing the needle into the mass, using negative pressure for aspiration, and withdrawing the needle after obtaining sufficient specimen.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('FNAC', 'Chemical', '-', (0, 4))	('aspiration', 'Phenotype', 'HP:0002835', (355, 365))	('cancer', 'Disease', (60, 66))	('puncturing', 'Var', (290, 300))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('men', 'Species', '9606', (426, 429))
70746	33194572	For patients with FNAC positivity, a sentinel lymph node biopsy was performed after the complete resection of the lesions.	('FNAC', 'Gene', (18, 22))	('patients', 'Species', '9606', (4, 12))	('positivity', 'Var', (23, 33))	('FNAC', 'Chemical', '-', (18, 22))
70850	33194572	However, FNAC on both primary and lymph node sites increases the risk of adversely affecting the prognosis for Chinese patients with acral and cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (143, 161))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 161))	('FNAC', 'Chemical', '-', (9, 13))	('patients', 'Species', '9606', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('affecting', 'Reg', (83, 92))	('FNAC', 'Var', (9, 13))	('cutaneous melanoma', 'Disease', (143, 161))	('acral', 'Disease', (133, 138))
70854	33549124	Gender-specific associations between polymorphisms of the circadian gene RORA and cutaneous melanoma susceptibility Melanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide.	('polymorphisms', 'Var', (37, 50))	('Melanoma', 'Disease', 'MESH:D008545', (116, 124))	('Melanoma', 'Disease', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('RORA', 'Gene', '6095', (73, 77))	('skin cancers', 'Disease', 'MESH:D012878', (145, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('Melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('skin cancers', 'Phenotype', 'HP:0008069', (145, 157))	('skin cancers', 'Disease', (145, 157))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('RORA', 'Gene', (73, 77))
70856	33549124	Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('Genetic variability', 'Var', (0, 19))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('risk', 'Reg', (94, 98))
70858	33549124	Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients.	('single nucleotide polymorphisms', 'Var', (48, 79))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('influence', 'Reg', (134, 143))	('melanoma', 'Disease', (211, 219))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('patients', 'Species', '9606', (220, 228))	('cutaneous melanoma', 'Disease', (174, 192))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))
70868	33549124	Overall, we cannot ascertain that circadian pathway genetic variation is involved in melanoma susceptibility or prognosis.	('genetic variation', 'Var', (52, 69))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('involved', 'Reg', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
70869	33549124	Nevertheless, we identified an interesting relationship between melanoma susceptibility and RORA polymorphisms acting in sex-specific manner and which is worth further future investigation.	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('RORA', 'Gene', (92, 96))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('polymorphisms', 'Var', (97, 110))
70872	33549124	In general, the predisposition to melanoma follows a polygenic model where in addition to the high penetrance genes with familial aggregation, as CDKN2A mutations, many low/medium penetrance genes are recognized with a risk-modifying role in the general population.	('CDKN2A', 'Gene', (146, 152))	('familial aggregation', 'Disease', 'MESH:D001791', (121, 141))	('CDKN2A', 'Gene', '1029', (146, 152))	('mutations', 'Var', (153, 162))	('familial aggregation', 'Disease', (121, 141))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
70876	33549124	An increasing number of epidemiological studies associates chronodisruption with the risk of developing various type of cancers, including melanoma, leading the International Agency for Research on Cancer (IARC) to classify Shifwork (with night shifts, which involves circadian disruption) as a potential carcinogenic for humans (Group 2A).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (198, 204))	('carcinogenic', 'Disease', 'MESH:D063646', (305, 317))	('carcinogenic', 'Disease', (305, 317))	('humans', 'Species', '9606', (322, 328))	('AR', 'Gene', '367', (207, 209))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Cancer', 'Disease', (198, 204))	('Shifwork', 'Var', (224, 232))
70879	33549124	Only one study addressed the issue on genetic variability of the promoter region of the NPAS2 clock gene and melanoma risk, and found a significant association with a polymorphic GGC repeat.	('polymorphic', 'Var', (167, 178))	('GGC', 'Gene', (179, 182))	('GGC', 'Gene', '79017', (179, 182))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('NPAS2', 'Gene', '4862', (88, 93))	('NPAS2', 'Gene', (88, 93))
70880	33549124	Another study examined the association of polymorphisms of steroid hormone receptors and melanoma prognosis, and found significant associations between cutaneous melanoma-specific survival and two SNPs on the clock gene RORA, whose putative protein encodes a ligand-activated transcription factor.	('transcription factor', 'molecular_function', 'GO:0000981', ('276', '296'))	('cutaneous melanoma', 'Disease', (152, 170))	('associations', 'Interaction', (131, 143))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (152, 170))	('polymorphisms', 'Var', (42, 55))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (152, 170))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('SNPs', 'Var', (197, 201))	('transcription', 'biological_process', 'GO:0006351', ('276', '289'))	('association', 'Interaction', (27, 38))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('steroid', 'Chemical', 'MESH:D013256', (59, 66))	('protein', 'cellular_component', 'GO:0003675', ('241', '248'))	('RORA', 'Gene', (220, 224))	('ligand', 'molecular_function', 'GO:0005488', ('259', '265'))
70882	33549124	In the present article, we focused our attention on the role of single nucleotide polymorphisms (SNPs) of the components of the circadian system on melanoma biology.	('single nucleotide polymorphisms', 'Var', (64, 95))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))
70892	33549124	We selected either Tag SNPs, interrogating The Genome Variation Server of the University of Washington (http://gvs.gs.washington.edu/GVS/) and the TagSNP tool of the US National Institute of Environmental Health Sciences (https://snpinfo.niehs.nih.gov/snpinfo/snptag.html), or variants already known to be associated with cancer susceptibility or prognosis, that had a minor allele frequency > 5%.	('variants', 'Var', (277, 285))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('cancer', 'Disease', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('men', 'Species', '9606', (198, 201))
70905	33549124	A total of 14 preselected SNPs in 7 circadian clock genes were successfully genotyped, and no departures from Hardy-Weinberg equilibrium were observed neither among the controls nor among the patients, as summarized in Additional file 1: Table S1.	('SNPs', 'Var', (26, 30))	('circadian', 'Gene', (36, 45))	('patients', 'Species', '9606', (192, 200))
70908	33549124	After adjusting for multiple testing, we identified two SNPs on RORA locus significantly associated with melanoma susceptibility.	('associated', 'Reg', (89, 99))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('RORA', 'Gene', (64, 68))	('SNPs', 'Var', (56, 60))
70909	33549124	rs339972 C allele and rs10519097 T allele were associated with a decreased melanoma risk (OR 0.76; 95% CI 0.63-0.91; P = 0.003 and OR 0.77; 95% CI 0.61-0.97; P = 0.026, respectively).	('rs10519097 T', 'Var', (22, 34))	('rs339972', 'Mutation', 'rs339972', (0, 8))	('rs10519097', 'Mutation', 'rs10519097', (22, 32))	('decreased melanoma', 'Disease', 'MESH:D008545', (65, 83))	('decreased melanoma', 'Disease', (65, 83))	('rs339972 C', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))
70912	33549124	Interestingly, the RORA rs339972 C allele was associated with a decreased melanoma susceptibility only in the female subgroup (OR 0.67; 95% CI 0.51-0.88; P = 0.003) while RORA rs10519097 T allele was associated with a decreased predisposition to develop melanoma only in the male subgroup (OR 0.62; 95% CI 0.44-0.87; P = 0.005).	('rs10519097', 'Mutation', 'rs10519097', (176, 186))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('rs339972', 'Mutation', 'rs339972', (24, 32))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('RORA rs339972 C', 'Var', (19, 34))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('develop', 'PosReg', (246, 253))	('melanoma', 'Disease', (254, 262))	('decreased melanoma', 'Disease', 'MESH:D008545', (64, 82))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('decreased melanoma', 'Disease', (64, 82))
70913	33549124	A further subgroup analysis was carried out dividing the female dataset by age at diagnosis (> 50 years old vs < 50 years old) to discriminate if menopausal or premenopausal status could interact with RORA variants and melanoma associations.	('variants', 'Var', (206, 214))	('RORA', 'Gene', (201, 205))	('men', 'Species', '9606', (163, 166))	('premenopausal status', 'Phenotype', 'HP:0008209', (160, 180))	('men', 'Species', '9606', (146, 149))	('associations', 'Interaction', (228, 240))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('interact', 'Reg', (187, 195))	('melanoma', 'Disease', (219, 227))
70915	33549124	A significant result (P = 0.000015) was found for RORA rs339972 in pancreas, while no significant eQTLs were identified for RORA SNP rs10519097.	('rs10519097', 'Mutation', 'rs10519097', (133, 143))	('pancreas', 'MPA', (67, 75))	('RORA rs339972', 'Var', (50, 63))	('rs339972', 'Mutation', 'rs339972', (55, 63))
70922	33549124	In particular, subgroup analysis revealed that rs339972 was statistically significant with respect to the association with melanoma susceptibility in females, while rs10519097 in males.	('rs339972', 'Mutation', 'rs339972', (47, 55))	('association', 'Interaction', (106, 117))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('rs10519097', 'Mutation', 'rs10519097', (165, 175))	('rs10519097', 'Var', (165, 175))	('rs339972', 'Var', (47, 55))
70932	33549124	Both RORA studied variants, rs10519097 and rs33997, are located within introns (first and second respectively) of RORA transcript 1, referred to as RORA1, while they are upstream to transcripts 2-4, RORA2-4.	('rs33997', 'Mutation', 'rs33997', (43, 50))	('rs10519097', 'Mutation', 'rs10519097', (28, 38))	('rs10519097', 'Var', (28, 38))	('rs33997', 'Var', (43, 50))
70936	33549124	Recently, two variants in the RORA locus were found to be associated with melanoma prognosis, rs782917 and rs17204952 as well as rs7253062 in DNMT1, a steroid hormone receptor as well.	('rs782917', 'Var', (94, 102))	('DNMT1', 'Gene', (142, 147))	('DNMT1', 'Gene', '1786', (142, 147))	('rs7253062', 'Mutation', 'rs7253062', (129, 138))	('associated', 'Reg', (58, 68))	('steroid', 'Chemical', 'MESH:D013256', (151, 158))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('RORA', 'Gene', (30, 34))	('rs782917', 'Mutation', 'rs782917', (94, 102))	('rs17204952', 'Mutation', 'rs17204952', (107, 117))	('rs17204952', 'Var', (107, 117))	('rs7253062', 'Var', (129, 138))
70937	33549124	Combined analysis of risk genotypes of the three variants revealed a decreased cutaneous melanoma specific survival in a dose-response manner.	('cutaneous melanoma', 'Disease', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('variants', 'Var', (49, 57))	('decreased', 'NegReg', (69, 78))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))
70938	33549124	The authors performed a pathway-based analysis to evaluate genetic variants of 191 steroid hormone-related genes.	('steroid hormone-related genes', 'Gene', (83, 112))	('steroid', 'Chemical', 'MESH:D013256', (83, 90))	('variants', 'Var', (67, 75))
70948	33549124	In particular, the analyzed RORA polymorphisms have different effect on melanoma susceptibility whereas rs339972 minor allele has a protective effect on premenopausal women while rs10519097 minor allele has a protective effect exclusively in men.	('rs339972 minor', 'Var', (104, 118))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('men', 'Species', '9606', (169, 172))	('rs339972', 'Mutation', 'rs339972', (104, 112))	('men', 'Species', '9606', (156, 159))	('rs10519097', 'Var', (179, 189))	('women', 'Species', '9606', (167, 172))	('men', 'Species', '9606', (242, 245))	('rs10519097', 'Mutation', 'rs10519097', (179, 189))
70951	33549124	In our previous meta-analysis, rs339972 was statistically significant with respect to the association with cancer in general while rs10519097 with breast cancer risk.	('rs339972', 'Var', (31, 39))	('rs10519097', 'Var', (131, 141))	('rs339972', 'Mutation', 'rs339972', (31, 39))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', (147, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (107, 113))	('rs10519097', 'Mutation', 'rs10519097', (131, 141))
70952	33549124	In our previous case-control studies we found rs339972 to be associated with both gastric cancer and sarcoma susceptibility.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('sarcoma', 'Disease', 'MESH:D012509', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sarcoma', 'Disease', (101, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('rs339972', 'Var', (46, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('rs339972', 'Mutation', 'rs339972', (46, 54))	('gastric cancer', 'Disease', (82, 96))	('associated', 'Reg', (61, 71))
70953	33549124	Noticeably, in our previous meta-analysis subgroups meta-analysis employing two datasets (4587 subjects) showed that the association of rs10519097 with breast cancer was significant with an intermediate level of evidence (summary OR: 0.85, CI: 0.75-0.96, P = 0.008).	('association', 'Interaction', (121, 132))	('rs10519097', 'Var', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('rs10519097', 'Mutation', 'rs10519097', (136, 146))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))
70955	33549124	A significant result (P = 0.000015) was found for RORA rs339972 in pancreas, nevertheless a GWAS revealed no significant associations with pancreatic cancer risk (OR: 0.92, CI: 0.85-1.00, P = 0.04).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('rs339972', 'Mutation', 'rs339972', (55, 63))	('pancreatic cancer', 'Disease', (139, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('RORA rs339972', 'Var', (50, 63))	('pancreas', 'Disease', (67, 75))
70956	33549124	To the best of our knowledge, this is one of the few pioneering analyses investigating the relationship between cutaneous melanoma susceptibility or prognosis and circadian gene variants.	('variants', 'Var', (178, 186))	('cutaneous melanoma', 'Disease', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))
70960	33549124	Overall, we cannot conclude in favour of the hypothesis that variability of the circadian clock genes may affect melanoma susceptibility or prognosis, but we did find an interesting relationship between melanoma biology and RORA gene variants, which we believe is worth further investigation.	('variants', 'Var', (234, 242))	('RORA', 'Gene', (224, 228))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('affect', 'Reg', (106, 112))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
71004	31519915	Increased IL-10+ B cell numbers in tumor tissues can also be accompanied by increased numbers of CD4+CD25+/highCD127low/- and Foxp3+ Tregs, which are independently associated with tumor progression or reduced patient survival.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reduced', 'NegReg', (201, 208))	('patient survival', 'CPA', (209, 225))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('increased', 'PosReg', (76, 85))	('CD25', 'Gene', '3559', (101, 105))	('tumor', 'Disease', (35, 40))	('IL-10', 'molecular_function', 'GO:0005141', ('10', '15'))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('associated', 'Reg', (164, 174))	('Increased', 'PosReg', (0, 9))	('CD4', 'Gene', '920', (97, 100))	('Foxp3', 'Gene', (126, 131))	('patient', 'Species', '9606', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD4', 'Gene', (97, 100))	('tumor', 'Disease', (180, 185))	('CD25', 'Gene', (101, 105))	('IL-10+ B', 'Var', (10, 18))	('Foxp3', 'Gene', '50943', (126, 131))
71066	31519915	Finally, high expression (above median) of our TIPB signature was correlated with longer overall survival in the TCGA cohort (Fig.	('longer', 'PosReg', (82, 88))	('TIPB', 'Gene', (47, 51))	('overall survival', 'MPA', (89, 105))	('TIPB', 'Chemical', '-', (47, 51))	('high', 'Var', (9, 13))
71077	31519915	There, MCM-induced B cells significantly increased the effect (NF-kB promoter activity) of PD-1 blockade on PD-1-expressing Jurkat T cells (two-sided t-test, BH adjusted p 0.02-0.06, see Methods, Fig.	('increased', 'PosReg', (41, 50))	('PD-1', 'Gene', (91, 95))	('blockade', 'Var', (96, 104))	('BH', 'Chemical', '-', (158, 160))	('MCM', 'Chemical', '-', (7, 10))	('Jurkat T', 'CellLine', 'CVCL:0065', (124, 132))
71078	31519915	Additionally, MCM increased B cell viability (Supplementary Fig.	('B cell viability', 'CPA', (28, 44))	('MCM', 'Var', (14, 17))	('increased', 'PosReg', (18, 27))	('MCM', 'Chemical', '-', (14, 17))
71114	31519915	In human melanoma, even small variations within the release of tumor antigens/neoantigens, extrinsic or environmental factors, the secretion and consumption of cytokines and chemokines, distinct genetic subtypes as well as therapeutic agents can tip this balance.	('variations', 'Var', (30, 40))	('tumor', 'Disease', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('human', 'Species', '9606', (3, 8))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('secretion', 'biological_process', 'GO:0046903', ('131', '140'))	('tip', 'Reg', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('release', 'MPA', (52, 59))
71193	31519915	Each section was subjected to six successive rounds of Ab staining, each consisting of protein blocking with 20% normal goat serum (Dako) in PBS, incubation with primary Abs, biotinylated anti-mouse/rabbit secondary antibodies and Streptavidin-HRP (Dako, 50003), followed by TSA visualization with fluorophores Opal 520, Opal 540, Opal 570, Opal 620, Opal 650, and Opal 690 (PerkinElmer) diluted in 1X Plus Amplification Diluent (PerkinElmer), Ab-TSA complex-stripping in heated citrate buffer (pH 6.0) and/or Tris-EDTA buffer (pH 9) for 30 min and fixation with 7.5% neutralized formaldehyde.	('TSA', 'Chemical', '-', (447, 450))	('Ab-TSA', 'Chemical', '-', (444, 450))	('formaldehyde', 'Chemical', 'MESH:D005557', (580, 592))	('goat', 'Species', '9925', (120, 124))	('mouse', 'Species', '10090', (193, 198))	('TSA', 'molecular_function', 'GO:0033984', ('275', '278'))	('citrate', 'Chemical', 'MESH:D019343', (479, 486))	('TSA', 'Chemical', '-', (275, 278))	('rabbit', 'Species', '9986', (199, 205))	('TSA', 'molecular_function', 'GO:0033984', ('447', '450'))	('Opal 690', 'Var', (365, 373))	('Opal 520', 'Var', (311, 319))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('Tris-EDTA', 'Chemical', '-', (510, 519))
71211	31519915	Clinical study and patient materials: J.G., M.M.G., F.R., P.P., W.F.P., S.N.W.	('patient', 'Species', '9606', (19, 26))	('F.R.', 'Var', (52, 56))	('W.F.P.', 'Var', (64, 70))	('P.P.', 'Var', (58, 62))	('M.M.G.', 'Var', (44, 50))
71212	31519915	RNA-seq data were deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession numbers E-MTAB-7472 (induction experiment) and E-MTAB-7473 (anti-CD20 study).	('TAB', 'Chemical', '-', (125, 128))	('CD20', 'Gene', (179, 183))	('CD20', 'Gene', '931', (179, 183))	('E-MTAB-7472', 'Var', (122, 133))	('TAB', 'Chemical', '-', (164, 167))	('MTAB', 'molecular_function', 'GO:0047152', ('163', '167'))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('MTAB', 'molecular_function', 'GO:0047152', ('124', '128'))
71216	24926260	Here we describe a 42-year-old man with concurrent BRAF E586K and NRAS Q81K driver mutations.	('NRAS', 'Gene', (66, 70))	('NRAS', 'Gene', '4893', (66, 70))	('E586K', 'Mutation', 'rs121913340', (56, 61))	('man', 'Species', '9606', (31, 34))	('BRAF', 'Gene', '673', (51, 55))	('Q81K', 'Mutation', 'p.Q81K', (71, 75))	('BRAF', 'Gene', (51, 55))	('E586K', 'Var', (56, 61))
71217	24926260	To our knowledge, this is the first description of these driver mutations occurring simultaneously in primary cutaneous melanoma.	('cutaneous melanoma', 'Disease', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mutations', 'Var', (64, 73))
71221	24926260	Many different melanoma driver mutations have been identified, with approximately 50-60% being mutated BRAF and 15-20% mutated NRAS Interestingly, the V600E and Q16R mutations account for roughly 90% of BRAF and NRAS mutations, respectively.	('V600E', 'Var', (151, 156))	('Q16R', 'Mutation', 'p.Q16R', (161, 165))	('melanoma', 'Disease', (15, 23))	('BRAF', 'Gene', '673', (103, 107))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', '673', (203, 207))	('NRAS', 'Gene', (127, 131))	('NRAS', 'Gene', (212, 216))	('BRAF', 'Gene', (203, 207))	('Q16R', 'Var', (161, 165))	('NRAS', 'Gene', '4893', (127, 131))	('mutations', 'Var', (217, 226))	('NRAS', 'Gene', '4893', (212, 216))	('BRAF', 'Gene', (103, 107))	('V600E', 'Mutation', 'rs113488022', (151, 156))
71222	24926260	Less common driver mutations include other BRAF and NRAS mutations as well as mutations in other genes such as c-Kit (2-6%), CTNNB1 (2-3%), GNA11 (2%), GNAQ (1%), and MEK1 (2-6%).	('NRAS', 'Gene', (52, 56))	('MEK1', 'molecular_function', 'GO:0004708', ('167', '171'))	('MEK1', 'Gene', '5604', (167, 171))	('BRAF', 'Gene', '673', (43, 47))	('NRAS', 'Gene', '4893', (52, 56))	('GNA11', 'Gene', (140, 145))	('BRAF', 'Gene', (43, 47))	('MEK1', 'Gene', (167, 171))	('GNAQ', 'Gene', '2776', (152, 156))	('mutations', 'Var', (57, 66))	('GNA11', 'Gene', '2767', (140, 145))	('CTNNB1', 'Gene', (125, 131))	('c-Kit', 'Gene', (111, 116))	('c-Kit', 'Gene', '3815', (111, 116))	('GNAQ', 'Gene', (152, 156))	('CTNNB1', 'Gene', '1499', (125, 131))
71223	24926260	In general, melanomas with concurrent driver mutations are rare; Goel et al.	('mutations', 'Var', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('melanomas', 'Disease', (12, 21))
71225	24926260	The activating BRAF E586K mutation, causing constitutive enzyme heterodimerization and activation, is rare in melanomas.	('BRAF', 'Gene', '673', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('BRAF', 'Gene', (15, 19))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('E586K', 'Mutation', 'rs121913340', (20, 25))	('activating', 'PosReg', (4, 14))	('heterodimerization', 'MPA', (64, 82))	('activation', 'MPA', (87, 97))	('melanomas', 'Disease', (110, 119))	('E586K', 'Var', (20, 25))
71226	24926260	Similarly, the NRAS Q81K mutation accounts for a small percentage of melanoma NRAS driver mutations.	('mutations', 'Var', (90, 99))	('NRAS', 'Gene', (15, 19))	('NRAS', 'Gene', (78, 82))	('NRAS', 'Gene', '4893', (15, 19))	('NRAS', 'Gene', '4893', (78, 82))	('melanoma NRAS', 'Disease', (69, 82))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma NRAS', 'Disease', 'MESH:D008545', (69, 82))	('Q81K', 'Mutation', 'p.Q81K', (20, 24))
71230	24926260	Dual S100 and Mart-1 IHC positivity is typical of melanomas (fig.	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('Mart-1', 'Gene', '2315', (14, 20))	('Mart-1', 'Gene', (14, 20))	('Dual', 'Var', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanomas', 'Disease', (50, 59))
71234	24926260	A sequencing analysis of the BRAF exons 11 and 15 and the NRAS exons 2 and 3 revealed concurrent BRAF E586K and NRAS Q16R driver mutations.	('BRAF', 'Gene', '673', (29, 33))	('NRAS', 'Gene', '4893', (58, 62))	('E586K', 'Mutation', 'rs121913340', (102, 107))	('BRAF', 'Gene', (29, 33))	('NRAS', 'Gene', (112, 116))	('E586K', 'Var', (102, 107))	('Q16R', 'Mutation', 'p.Q16R', (117, 121))	('NRAS', 'Gene', '4893', (112, 116))	('BRAF', 'Gene', '673', (97, 101))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (97, 101))
71236	24926260	NRAS mutations in melanoma commonly compromise the ability of the enzyme to hydrolyze guanosine triphosphate, allowing the enzyme to be constitutively active and activate downstream signaling proteins such as RAS and BRAF.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('hydrolyze guanosine triphosphate', 'MPA', (76, 108))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('compromise', 'NegReg', (36, 46))	('RAS', 'Protein', (209, 212))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (86, 108))	('NRAS', 'Gene', '4893', (0, 4))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (217, 221))	('activate', 'PosReg', (162, 170))	('NRAS', 'Gene', (0, 4))	('ability', 'MPA', (51, 58))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('BRAF', 'Gene', (217, 221))	('melanoma', 'Disease', (18, 26))
71238	24926260	Additionally, RAS also activates the phosphatidylinositol 3-kinase/PTEN/Akt pathway, leading to apoptosis inhibition and malignant cell survival.	('Akt', 'Gene', (72, 75))	('malignant cell survival', 'CPA', (121, 144))	('activates', 'PosReg', (23, 32))	('PTEN', 'Gene', (67, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('PTEN', 'Gene', '5728', (67, 71))	('apoptosis inhibition', 'CPA', (96, 116))	('Akt', 'Gene', '207', (72, 75))	('RAS', 'Var', (14, 17))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
71239	24926260	Concurrent NRAS and BRAF activating driver mutations are not expected to be common events, as they lie on the same molecular signal transduction pathway, and once one activating driver mutation occurs there would be little selective pressure for a second mutation to occur.	('mole', 'Phenotype', 'HP:0003764', (115, 119))	('signal transduction', 'biological_process', 'GO:0007165', ('125', '144'))	('NRAS', 'Gene', '4893', (11, 15))	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', (20, 24))	('NRAS', 'Gene', (11, 15))
71240	24926260	To our knowledge, concurrent BRAF E586K and NRAS Q81K driver mutations have not been previously identified in melanomas.	('BRAF', 'Gene', '673', (29, 33))	('Q81K', 'Mutation', 'p.Q81K', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('BRAF', 'Gene', (29, 33))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('E586K', 'Mutation', 'rs121913340', (34, 39))	('NRAS', 'Gene', (44, 48))	('E586K', 'Var', (34, 39))	('melanomas', 'Disease', (110, 119))	('NRAS', 'Gene', '4893', (44, 48))
71241	24926260	The clinical treatment of this rare combination of concurrent driver mutations in this case may be difficult, as it is unknown whether the BRAF E586K mutation responds to BRAF inhibitors.	('BRAF', 'Gene', (139, 143))	('BRAF', 'Gene', '673', (171, 175))	('E586K', 'Mutation', 'rs121913340', (144, 149))	('E586K', 'Var', (144, 149))	('BRAF', 'Gene', (171, 175))	('BRAF', 'Gene', '673', (139, 143))
71242	24926260	Additionally, there is in vitro evidence that NRAS mutations may confer resistance to BRAF inhibitors.	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', (46, 50))	('NRAS', 'Gene', '4893', (46, 50))	('BRAF', 'Gene', '673', (86, 90))	('resistance', 'MPA', (72, 82))	('BRAF', 'Gene', (86, 90))
71257	26504364	IL-8 overexpression increases CXCR1 and CXCR2 expression on tumor cells, endothelial cells, and immune related cells (neutrophils and macrophages) resident in tumor tissue.	('CXCR2', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('CXCR1', 'Gene', '3577', (30, 35))	('CXCR2', 'Gene', '3579', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IL-8', 'Gene', (0, 4))	('CXCR1', 'Gene', (30, 35))	('overexpression', 'Var', (5, 19))	('IL-8', 'molecular_function', 'GO:0005153', ('0', '4'))	('increases', 'PosReg', (20, 29))
71266	26504364	Briefly, anti-25-OH vitamin D3 antibodies detect the presence of 25-OH vitamin D3 indicated by peroxidase activity, measured as substrate OD at 450 nm.	('25-OH vitamin D3', 'Chemical', '-', (14, 30))	('25-OH vitamin D3', 'Chemical', '-', (65, 81))	('peroxidase activity', 'MPA', (95, 114))	('peroxidase activity', 'molecular_function', 'GO:0004601', ('95', '114'))	('25-OH', 'Var', (65, 70))
71275	26504364	In the light of the presented results, we can draw a preliminary biomarker pattern for enhanced risk of developing the metastasis stage in melanoma for patients that have vitamin D deficiency, doubled by an increased circulatory IL-8 and LDH.	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (171, 191))	('vitamin D', 'Gene', (171, 180))	('deficiency', 'Var', (181, 191))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('increased', 'PosReg', (207, 216))	('metastasis stage', 'CPA', (119, 135))	('IL-8 and LDH', 'Gene', '3576', (229, 241))	('IL-8', 'molecular_function', 'GO:0005153', ('229', '233'))
71331	33169786	The depletion of MPEG1 could impact cell mitosis, disturb centrosome duplication, as well as induce chromosome misalignment and mis-segregation in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', (147, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (147, 171))	('mitosis', 'biological_process', 'GO:0000278', ('41', '48'))	('centrosome', 'MPA', (58, 68))	('MPEG1', 'Gene', '219972', (17, 22))	('MPEG1', 'Gene', (17, 22))	('mis-segregation', 'CPA', (128, 143))	('depletion', 'Var', (4, 13))	('disturb', 'Reg', (50, 57))	('induce', 'Reg', (93, 99))	('cell mitosis', 'CPA', (36, 48))	('centrosome', 'cellular_component', 'GO:0005813', ('58', '68'))	('chromosome misalignment', 'CPA', (100, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('impact', 'Reg', (29, 35))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('centrosome duplication', 'biological_process', 'GO:0051298', ('58', '80'))
71355	31227503	HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance.	('HDAC', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (127, 141))	('uveal melanoma', 'Phenotype', 'HP:0007716', (74, 88))	('HDAC', 'Gene', '9734', (0, 4))	('uveal melanoma', 'Disease', 'MESH:C536494', (127, 141))	('inhibition', 'Var', (5, 15))	('enhances', 'PosReg', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('MEK', 'Gene', (49, 52))	('MEK', 'Gene', '5609', (49, 52))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('uveal melanoma', 'Disease', 'MESH:C536494', (74, 88))	('uveal melanoma', 'Phenotype', 'HP:0007716', (127, 141))	('uveal melanoma', 'Disease', (74, 88))	('MEK', 'Gene', (109, 112))	('MEK', 'Gene', '5609', (109, 112))
71368	31227503	These mutations (most commonly at Q209L/P) disable the intrinsic GTPase activity, leading to constitutive activation.	('intrinsic', 'MPA', (55, 64))	('GTPase activity', 'molecular_function', 'GO:0003924', ('65', '80'))	('activity', 'MPA', (72, 80))	('GTP', 'Chemical', 'MESH:D006160', (65, 68))	('Q209L', 'SUBSTITUTION', 'None', (34, 39))	('Q209L', 'Var', (34, 39))	('constitutive activation', 'MPA', (93, 116))	('disable', 'NegReg', (43, 50))	('GTPase', 'Protein', (65, 71))
71370	31227503	Protein kinase C (PKC) is activated by these second messengers in GNAQ/GNA11 mutant melanomas.	('melanomas', 'Disease', (84, 93))	('PKC', 'Disease', 'MESH:C537180', (18, 21))	('GNA11', 'Gene', (71, 76))	('GNAQ', 'Gene', '2776', (66, 70))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('GNA11', 'Gene', '2767', (71, 76))	('activated', 'PosReg', (26, 35))	('PKC', 'molecular_function', 'GO:0004697', ('18', '21'))	('PKC', 'Disease', (18, 21))	('GNAQ', 'Gene', (66, 70))	('mutant', 'Var', (77, 83))
71380	31227503	Silencing of GNAQ/GNA11 in uveal melanoma cells led to decreased nuclear accumulation of YAP, with further studies showing that the YAP inhibitor verteporfin abrogates GNAQ/GNA11 driven tumor growth in an orthotopic uveal melanoma ocular xenograft model.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('GNAQ', 'Gene', (13, 17))	('YAP', 'Gene', '10413', (89, 92))	('tumor', 'Disease', (186, 191))	('Silencing', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (18, 23))	('GNA11', 'Gene', (173, 178))	('uveal melanoma', 'Disease', (27, 41))	('uveal melanoma', 'Disease', 'MESH:C536494', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('uveal melanoma ocular xenograft', 'Disease', (216, 247))	('YAP', 'Gene', (132, 135))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('uveal melanoma', 'Disease', 'MESH:C536494', (216, 230))	('uveal melanoma', 'Phenotype', 'HP:0007716', (27, 41))	('nuclear accumulation', 'MPA', (65, 85))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('decreased', 'NegReg', (55, 64))	('uveal melanoma ocular xenograft', 'Disease', 'MESH:C536494', (216, 247))	('GNA11', 'Gene', (18, 23))	('YAP', 'Gene', (89, 92))	('uveal melanoma', 'Phenotype', 'HP:0007716', (216, 230))	('YAP', 'Gene', '10413', (132, 135))	('GNA11', 'Gene', '2767', (173, 178))	('GNAQ', 'Gene', '2776', (168, 172))	('GNAQ', 'Gene', (168, 172))	('abrogates', 'NegReg', (158, 167))	('GNAQ', 'Gene', '2776', (13, 17))	('verteporfin', 'Chemical', 'MESH:D000077362', (146, 157))
71414	31227503	Media was changed for another 12h prior to the drug(s) treatment with MEKi (10nM), HDACi (10nM) or both for 72h.	('10nM', 'Var', (76, 80))	('HDAC', 'Gene', '9734', (83, 87))	('HDAC', 'Gene', (83, 87))	('10nM', 'Var', (90, 94))
71424	31227503	Eight week old female CBySmn.CB17-Prdkc scid/j mice (Stock No: 001803 - Jax) were subcutaneously injected with 1.0 x106 92.1 or MP41 uveal melanoma cells per mouse.	('mouse', 'Species', '10090', (158, 163))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('MP41', 'Var', (128, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (133, 147))	('uveal melanoma', 'Disease', (133, 147))	('mice', 'Species', '10090', (47, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (133, 147))
71426	31227503	Eight week old female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (Stock No: 005557 - Jackson Laboratory) were injected with 2.0 x105 MP41 uveal melanoma cells per mouse into the tail vein i.	('Il2', 'molecular_function', 'GO:0005134', ('39', '42'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (128, 142))	('uveal melanoma', 'Disease', 'MESH:C536494', (128, 142))	('uveal melanoma', 'Disease', (128, 142))	('mouse', 'Species', '10090', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('Il2rgtm1Wjl/SzJ', 'Var', (39, 54))
71434	31227503	We began by characterizing the MEK inhibitor response of a panel of GNAQ/GNA11 mutant uveal melanoma cell lines that were derived from primary and metastatic lesions (92.1, Mel270, MP41: primary, OMM1 and MM28: metastatic).	('GNA11', 'Gene', (73, 78))	('uveal melanoma', 'Phenotype', 'HP:0007716', (86, 100))	('uveal melanoma', 'Disease', 'MESH:C536494', (86, 100))	('MP41', 'Var', (181, 185))	('GNA11', 'Gene', '2767', (73, 78))	('uveal melanoma', 'Disease', (86, 100))	('GNAQ', 'Gene', (68, 72))	('mutant', 'Var', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('GNAQ', 'Gene', '2776', (68, 72))
71439	31227503	The ABPP studies demonstrated that MEK inhibition increased the ATP uptake of 128 proteins and 98 proteins in the 92.1 and Mel270 cells, respectively (Figure 1F).	('inhibition', 'Var', (39, 49))	('uptake', 'biological_process', 'GO:0098657', ('68', '74'))	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('ABPP', 'Gene', (4, 8))	('increased', 'PosReg', (50, 59))	('ABPP', 'Gene', '351', (4, 8))	('ATP uptake of 128 proteins', 'MPA', (64, 90))	('MEK', 'Enzyme', (35, 38))	('uptake', 'biological_process', 'GO:0098739', ('68', '74'))
71446	31227503	Although there was some evidence that the PI3Ki also suppressed the outgrowth of MEK inhibitor treated uveal melanoma cells in colony formation assays, the effects were incomplete and tumor cells were still able to evade therapy (Figure 2E,F).	('PI3Ki', 'Var', (42, 47))	('colony formation assays', 'CPA', (127, 150))	('uveal melanoma', 'Disease', (103, 117))	('uveal melanoma', 'Disease', 'MESH:C536494', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('uveal melanoma', 'Phenotype', 'HP:0007716', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('formation', 'biological_process', 'GO:0009058', ('134', '143'))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('tumor', 'Disease', (184, 189))	('outgrowth', 'CPA', (68, 77))	('MEK inhibitor', 'Gene', (81, 94))	('suppressed', 'NegReg', (53, 63))
71448	31227503	These findings were confirmed by RTK arrays, with MEKi being found to increase the phosphorylation of multiple RTKs including IGF-1R (in the 92.1 cells), as well as ROR1 and ROR2 (in both the 92.1 and Mel270 cell lines) (Figures 3B).	('RTK', 'Gene', '5979', (33, 36))	('increase', 'PosReg', (70, 78))	('RTK', 'Gene', (111, 114))	('ROR2', 'Gene', '4920', (174, 178))	('ROR2', 'Gene', (174, 178))	('ROR1', 'Gene', (165, 169))	('ROR1', 'Gene', '4919', (165, 169))	('phosphorylation', 'MPA', (83, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('IGF-1R', 'Gene', (126, 132))	('IGF-1R', 'Gene', '3480', (126, 132))	('RTK', 'Gene', (33, 36))	('RTK', 'Gene', '5979', (111, 114))	('MEKi', 'Var', (50, 54))
71449	31227503	q-RT-PCR and Western Blot analyses demonstrated increases in IGF-1R, ROR1 and ROR2 mRNA and protein expression following MEKi (Figure 3C,D).	('increases', 'PosReg', (48, 57))	('IGF-1R', 'Gene', '3480', (61, 67))	('ROR1', 'Gene', '4919', (69, 73))	('IGF-1R', 'Gene', (61, 67))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('MEKi', 'Var', (121, 125))	('ROR1', 'Gene', (69, 73))	('ROR2', 'Gene', (78, 82))	('ROR2', 'Gene', '4920', (78, 82))
71452	31227503	Silencing of ROR1/2 (Figure 3F) in the 92.1 cells inhibited the increases in AKT phosphorylation observed following MEKi treatment (Figure 3G).	('AKT', 'Gene', '207', (77, 80))	('ROR1/2', 'Gene', '4919;4920', (13, 19))	('ROR1/2', 'Gene', (13, 19))	('AKT', 'Gene', (77, 80))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (50, 59))
71453	31227503	Silencing of IGF-1R in combination with the MEKi was found to increase cell death and decrease the numbers of 92.1 cells, but not Mel270 cells, a result consistent with the increased IGF-1R signaling seen only in the 92.1 cell line (Figure 3F,H,I).	('IGF-1R', 'Gene', '3480', (183, 189))	('cell death', 'CPA', (71, 81))	('signaling', 'biological_process', 'GO:0023052', ('190', '199'))	('IGF-1R', 'Gene', (183, 189))	('increased IGF-1R', 'Phenotype', 'HP:0030269', (173, 189))	('cell death', 'biological_process', 'GO:0008219', ('71', '81'))	('IGF-1R', 'Gene', '3480', (13, 19))	('decrease', 'NegReg', (86, 94))	('IGF-1R', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('increase', 'PosReg', (62, 70))
71454	31227503	In contrast, silencing of ROR1/2 enhanced the effects of MEKi in terms of decreased cell survival and apoptosis induction in both of the cell lines evaluated (Figures 3F,H,I).	('apoptosis induction', 'CPA', (102, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('ROR1/2', 'Gene', '4919;4920', (26, 32))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('silencing', 'Var', (13, 22))	('cell survival', 'CPA', (84, 97))	('decreased', 'NegReg', (74, 83))	('enhanced', 'PosReg', (33, 41))	('ROR1/2', 'Gene', (26, 32))
71462	31227503	Additionally, siRNA knockdown of YAP (Figure 4I) increased the level of MEKi -induced apoptosis in multiple uveal melanoma cell lines (Figure 4J).	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('MEKi -induced apoptosis', 'MPA', (72, 95))	('uveal melanoma', 'Phenotype', 'HP:0007716', (108, 122))	('multiple uveal melanoma', 'Disease', (99, 122))	('multiple uveal melanoma', 'Disease', 'MESH:C536494', (99, 122))	('increased', 'PosReg', (49, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('YAP', 'Gene', '10413', (33, 36))	('YAP', 'Gene', (33, 36))	('knockdown', 'Var', (20, 29))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
71473	31227503	Among these, several drugs were identified with some activity against one or more uveal melanoma cell lines including PI3K inhibitors (GSK2126458, idelalisib), two kinesin inhibitors (Ispinesib, SB743921), CDK inhibitors (dinaciclib), H3K27 histone demethylase (GSK-J4), and mTOR (Sapanisertib) (Figure 6B).	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('dinaciclib', 'Chemical', 'MESH:C553669', (222, 232))	('CDK', 'Enzyme', (206, 209))	('H3K27 histone', 'Protein', (235, 248))	('GSK', 'molecular_function', 'GO:0050321', ('262', '265'))	('GSK2126458', 'Chemical', 'MESH:C561454', (135, 145))	('Sapanisertib', 'Chemical', 'MESH:C572449', (281, 293))	('GSK2126458', 'Var', (135, 145))	('uveal melanoma', 'Disease', 'MESH:C536494', (82, 96))	('uveal melanoma', 'Disease', (82, 96))	('GSK', 'molecular_function', 'GO:0050321', ('135', '138'))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('uveal melanoma', 'Phenotype', 'HP:0007716', (82, 96))	('mTOR', 'Gene', (275, 279))	('PI3K', 'Gene', (118, 122))	('CDK', 'molecular_function', 'GO:0004693', ('206', '209'))	('idelalisib', 'Chemical', 'MESH:C552946', (147, 157))	('kinesin', 'molecular_function', 'GO:0003777', ('164', '171'))	('mTOR', 'Gene', '2475', (275, 279))
71479	31227503	It was found that co-treatment of multiple uveal melanoma cell lines, including 92.1, MP41, Mel270 and MM28 with the MEKi-HDACi (trametinib-panobinostat) combination was associated with significantly (P<0.05) higher levels of apoptosis compared to either single agent (Figure 6F).	('panobinostat', 'Chemical', 'MESH:D000077767', (140, 152))	('trametinib', 'Chemical', 'MESH:C560077', (129, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('multiple uveal melanoma', 'Disease', (34, 57))	('apoptosis', 'MPA', (226, 235))	('multiple uveal melanoma', 'Disease', 'MESH:C536494', (34, 57))	('MP41', 'Var', (86, 90))	('higher', 'PosReg', (209, 215))	('uveal melanoma', 'Phenotype', 'HP:0007716', (43, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('HDAC', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('HDAC', 'Gene', '9734', (122, 126))
71489	31227503	Although single-agent MEKi was more effective against MP41 uveal melanoma cells than 92.1 cells, its effects in both models were relatively short lived and the tumors re-initiated growth.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('uveal melanoma', 'Phenotype', 'HP:0007716', (59, 73))	('uveal melanoma', 'Disease', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('MP41', 'Var', (54, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (59, 73))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
71502	31227503	Uveal melanomas typically harbor activating mutations in the small G-proteins GNAQ and GNA11 which are not kinases and therefore not easily tractable to drug development.	('GNAQ', 'Gene', '2776', (78, 82))	('GNAQ', 'Gene', (78, 82))	('small G-protein', 'Gene', (61, 76))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('Uveal melanoma', 'Disease', 'MESH:C536494', (0, 14))	('melanomas', 'Disease', (6, 15))	('small G-protein', 'Gene', '5880', (61, 76))	('Uveal melanoma', 'Phenotype', 'HP:0007716', (0, 14))	('Uveal melanoma', 'Disease', (0, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('mutations', 'Var', (44, 53))	('activating', 'PosReg', (33, 43))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('GNA11', 'Gene', '2767', (87, 92))	('GNA11', 'Gene', (87, 92))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))
71513	31227503	Inhibition of RAF and MEK is known to trigger a rapid transcriptional reprogramming that is associated with increased RTK expression.	('expression', 'MPA', (122, 132))	('RAF', 'Gene', (14, 17))	('RAF', 'Gene', '22882', (14, 17))	('RTK', 'Gene', (118, 121))	('increased', 'PosReg', (108, 117))	('Inhibition', 'Var', (0, 10))	('RTK', 'Gene', '5979', (118, 121))	('MEK', 'Gene', (22, 25))
71515	31227503	Similar findings have been also reported in many other cancers including BRAF and NRAS-mutant melanoma; where BRAF and MEK inhibition frequently leads to a relief of feedback inhibition and increased signaling through multiple RTKs including IGF-1R, EGFR, ERBB3, EphA2 and c-MET.	('MEK', 'Gene', (119, 122))	('BRAF', 'Gene', '673', (73, 77))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('RTK', 'Gene', (227, 230))	('inhibition', 'Var', (123, 133))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('NRAS', 'Gene', (82, 86))	('RTK', 'Gene', '5979', (227, 230))	('BRAF', 'Gene', '673', (110, 114))	('signaling', 'MPA', (200, 209))	('BRAF', 'Gene', (110, 114))	('EGFR', 'Gene', (250, 254))	('ERBB3', 'Gene', (256, 261))	('EGFR', 'molecular_function', 'GO:0005006', ('250', '254'))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('feedback inhibition', 'MPA', (166, 185))	('cancers', 'Disease', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('melanoma', 'Disease', (94, 102))	('EphA2', 'Gene', (263, 268))	('EGFR', 'Gene', '1956', (250, 254))	('EphA2', 'Gene', '1969', (263, 268))	('NRAS', 'Gene', '4893', (82, 86))	('ERBB3', 'Gene', '2065', (256, 261))	('c-MET', 'Gene', '4233', (273, 278))	('IGF-1R', 'Gene', (242, 248))	('IGF-1R', 'Gene', '3480', (242, 248))	('increased', 'PosReg', (190, 199))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('c-MET', 'Gene', (273, 278))	('BRAF', 'Gene', (73, 77))	('relief', 'PosReg', (156, 162))
71517	31227503	To investigate whether this also occurred in GNAQ-mutant uveal melanoma cell lines, we performed RTK arrays and identified increased IGF1-R and ROR1/2 activity following MEK inhibition.	('increased', 'PosReg', (123, 132))	('RTK', 'Gene', (97, 100))	('ROR1/2', 'Gene', (144, 150))	('ROR1/2', 'Gene', '4919;4920', (144, 150))	('inhibition', 'Var', (174, 184))	('increased IGF1', 'Phenotype', 'HP:0030269', (123, 137))	('uveal melanoma', 'Disease', 'MESH:C536494', (57, 71))	('IGF1-R', 'Gene', '3480', (133, 139))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('uveal melanoma', 'Disease', (57, 71))	('GNAQ', 'Gene', (45, 49))	('IGF1-R', 'Gene', (133, 139))	('RTK', 'Gene', '5979', (97, 100))	('activity', 'MPA', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('MEK', 'Gene', (170, 173))	('GNAQ', 'Gene', '2776', (45, 49))
71522	31227503	In GNAQ/GNA11 mutant uveal melanoma cells, YAP is activated by the guanine nucleotide exchange factor Trio leading to YAP activation via Rho and Rac.	('uveal melanoma', 'Disease', (21, 35))	('GNA11', 'Gene', (8, 13))	('Rho', 'Protein', (137, 140))	('YAP', 'Gene', '10413', (43, 46))	('Trio', 'Gene', (102, 106))	('YAP', 'Gene', (118, 121))	('activation', 'PosReg', (122, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (21, 35))	('Rac', 'Gene', '207', (145, 148))	('YAP', 'Gene', '10413', (118, 121))	('GNAQ', 'Gene', '2776', (3, 7))	('Trio', 'Gene', '7204', (102, 106))	('GNA11', 'Gene', '2767', (8, 13))	('GNAQ', 'Gene', (3, 7))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('YAP', 'Gene', (43, 46))	('Rac', 'Gene', (145, 148))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (67, 85))	('mutant', 'Var', (14, 20))	('uveal melanoma', 'Disease', 'MESH:C536494', (21, 35))
71527	31227503	YAP signaling is known to be activated through GPCRs, with our RNA-seq studies identifying a whole series of candidate receptors that were upregulated following MEK inhibition.	('upregulated', 'PosReg', (139, 150))	('YAP', 'Gene', (0, 3))	('MEK', 'Gene', (161, 164))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('GPCR', 'Gene', (47, 51))	('YAP', 'Gene', '10413', (0, 3))	('inhibition', 'Var', (165, 175))	('signaling', 'biological_process', 'GO:0023052', ('4', '13'))	('GPCR', 'Gene', '1909', (47, 51))
71531	31227503	There is also evidence from cutaneous melanoma that EDNRB antagonists reduce melanoma growth in vitro and in in vivo xenograft models.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('EDNRB', 'Gene', (52, 57))	('reduce', 'NegReg', (70, 76))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('antagonists', 'Var', (58, 69))	('cutaneous melanoma', 'Disease', (28, 46))
71533	31227503	Further evidence suggests that autocrine Endothelin-1 might also regulate melanoma heterogeneity following BRAF inhibition and could mediate the switch to an Axl-high/MITF-low (drug resistant) phenotype.	('BRAF', 'Gene', (107, 111))	('inhibition', 'Var', (112, 122))	('MITF', 'Gene', (167, 171))	('MITF', 'Gene', '4286', (167, 171))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('regulate', 'Reg', (65, 73))	('Endothelin-1', 'Gene', (41, 53))	('BRAF', 'Gene', '673', (107, 111))	('Endothelin-1', 'Gene', '1906', (41, 53))
71534	31227503	We here demonstrate that uveal melanoma cells released ET-3 in response to MEK inhibition and that the resulting increase in EDNRB signaling activates YAP signaling, leading to increased cell survival.	('EDNRB signaling', 'MPA', (125, 140))	('uveal melanoma', 'Disease', (25, 39))	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('activates', 'PosReg', (141, 150))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('ET-3', 'Gene', (55, 59))	('inhibition', 'Var', (79, 89))	('increased', 'PosReg', (177, 186))	('ET-3', 'Gene', '1908', (55, 59))	('cell survival', 'CPA', (187, 200))	('increase', 'PosReg', (113, 121))	('YAP', 'Gene', '10413', (151, 154))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('MEK', 'Gene', (75, 78))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))	('YAP', 'Gene', (151, 154))
71535	31227503	Although it is likely that EDNRB plays a role in the increased YAP signaling observed following MEK inhibition, it is unlikely to be only GCPR involved, and it is possible that different uveal melanomas may have unique GPCR dependencies.	('uveal melanomas', 'Disease', 'MESH:C536494', (187, 202))	('YAP', 'Gene', (63, 66))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('GPCR', 'Gene', '1909', (219, 223))	('MEK', 'Gene', (96, 99))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('EDNRB', 'Gene', (27, 32))	('uveal melanoma', 'Phenotype', 'HP:0007716', (187, 201))	('inhibition', 'Var', (100, 110))	('increased', 'PosReg', (53, 62))	('GPCR', 'Gene', (219, 223))	('YAP', 'Gene', '10413', (63, 66))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('uveal melanomas', 'Disease', (187, 202))	('uveal melanomas', 'Phenotype', 'HP:0007716', (187, 202))
71536	31227503	One potential strategy to target multiple G-proteins (and GPCRs) simultaneously could be through allosteric inhibitors of GDP/GTP exchange with recent studies demonstrating that GTP exchange inhibitors such as the depsipeptide FR900359 have activity against GNAQ-mutant uveal melanoma cell lines.	('activity', 'MPA', (241, 249))	('GDP', 'Chemical', 'MESH:D006153', (122, 125))	('GTP', 'Chemical', 'MESH:D006160', (178, 181))	('GTP', 'Chemical', 'MESH:D006160', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('GNAQ', 'Gene', '2776', (258, 262))	('GPCR', 'Gene', '1909', (58, 62))	('GTP', 'MPA', (178, 181))	('GNAQ', 'Gene', (258, 262))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('uveal melanoma', 'Disease', (270, 284))	('GPCR', 'Gene', (58, 62))	('FR900359', 'Var', (227, 235))
71537	31227503	The increased GPCR expression noted following MEK inhibition might be expected to increase the adhesion of uveal melanoma cells to the extracellular matrix, potentially decreasing their metastatic potential.	('expression', 'MPA', (19, 29))	('uveal melanoma', 'Disease', 'MESH:C536494', (107, 121))	('uveal melanoma', 'Phenotype', 'HP:0007716', (107, 121))	('uveal melanoma', 'Disease', (107, 121))	('inhibition', 'Var', (50, 60))	('GPCR', 'Gene', '1909', (14, 18))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('135', '155'))	('metastatic potential', 'CPA', (186, 206))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('adhesion', 'CPA', (95, 103))	('increase', 'PosReg', (82, 90))	('MEK', 'Gene', (46, 49))	('GPCR', 'Gene', (14, 18))	('increased', 'PosReg', (4, 13))	('decreasing', 'NegReg', (169, 179))
71542	31227503	In cutaneous melanoma there is also evidence that HDAC inhibition can restore sensitivity to BRAF inhibition following the onset of resistance.	('BRAF', 'Gene', (93, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('HDAC', 'Gene', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('restore', 'PosReg', (70, 77))	('HDAC', 'Gene', '9734', (50, 54))	('inhibition', 'Var', (55, 65))	('BRAF', 'Gene', '673', (93, 97))	('cutaneous melanoma', 'Disease', (3, 21))
71561	27716417	A focused analysis of tumors from six tissues reveals that rare patient-specific gene CNAs often have stronger effects on signature genes than frequent gene CNAs.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('patient', 'Species', '9606', (64, 71))	('stronger effects', 'PosReg', (102, 118))	('CNAs', 'Var', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (22, 28))	('signature genes', 'MPA', (122, 137))
71562	27716417	Although only a relatively small fraction of all mutations in any given cancer cell contributes to tumorigenesis, it is emerging that many more genes than previously thought determine clinically relevant endpoints such as proliferation rates, metastatic potential, or drug resistance.	('tumor', 'Disease', (99, 104))	('determine', 'Reg', (174, 183))	('mutations', 'Var', (49, 58))	('drug resistance', 'biological_process', 'GO:0009315', ('268', '283'))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('drug resistance', 'biological_process', 'GO:0042493', ('268', '283'))	('drug resistance', 'CPA', (268, 283))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('metastatic potential', 'CPA', (243, 263))	('drug resistance', 'Phenotype', 'HP:0020174', (268, 283))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('proliferation rates', 'CPA', (222, 241))	('cancer', 'Disease', (72, 78))
71565	27716417	mutations that are more frequent than expected by chance in a specific cohort) are more likely to have tumor-related effects, individual cancer risks are most likely not fully explained by frequent mutations alone.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
71566	27716417	Rare mutations could act in combination with frequent mutations or they may, entirely independent from frequent mutations, establish a significant risk for the patient on their own.	('patient', 'Species', '9606', (160, 167))	('establish', 'Reg', (123, 132))	('mutations', 'Var', (5, 14))
71567	27716417	Quantifying the risks associated with rare mutations has been complicated by the following reasons: (1) by definition, only a few patients carry these mutations, which reduces the probability of observing them in clinical studies, (2) even if they are observed, it is often difficult to quantify cancer risks statistically by comparing carriers with non-carriers due to insufficient statistical power, (3) complex interactions with other mutations (epistasis) may hide effects when analyzing single mutations in isolation, and (4) rare mutations of individual genes may have weak effects, but the co-occurrence of a sufficient number of such mutations in the same cell could significantly increase cancer risks.	('insufficient', 'Disease', 'MESH:D000309', (370, 382))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (698, 704))	('insufficient', 'Disease', (370, 382))	('cancer', 'Disease', (698, 704))	('increase', 'PosReg', (689, 697))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('interactions', 'Interaction', (414, 426))	('cancer', 'Disease', 'MESH:D009369', (698, 704))	('cancer', 'Disease', (296, 302))	('mutations', 'Var', (151, 160))	('mutations', 'Var', (642, 651))
71569	27716417	Apart from SNVs, DNA copy number alterations (CNAs) and chromosomal instability are a hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('chromosomal instability', 'Phenotype', 'HP:0040012', (56, 79))	('cancer', 'Disease', (98, 104))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('chromosomal instability', 'CPA', (56, 79))	('DNA copy number alterations', 'Var', (17, 44))
71570	27716417	Further, CNA-affected genes with altered expression levels are more likely to be involved in tumorigenesis than affected genes with unchanged expression levels.	('expression levels', 'MPA', (41, 58))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('involved', 'Reg', (81, 89))	('tumor', 'Disease', (93, 98))	('CNA-affected', 'Disease', (9, 21))	('altered', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
71572	27716417	All these methods (and many others) have greatly contributed to the identification of potential CNA tumor driver mutations and a better understanding of tumorigenesis, but none of these methods allows us to quantify the impact of rare gene CNAs.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
71575	27716417	Recently, another study proposed a network-based method that enables the identification of rare mutations involved in the perturbation of pathways and protein complexes involved in tumorigenesis.	('tumor', 'Disease', (181, 186))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('mutations', 'Var', (96, 105))
71637	27716417	We confirm that an increased HAX1 copy number contributes to an increased HAX1 expression level with downstream effects on the expression of TSEN15 (Additional file 3: Table S2).	('HAX1', 'Gene', (29, 33))	('TSEN15', 'Gene', '116461', (141, 147))	('HAX1', 'Gene', '10456', (74, 78))	('expression', 'MPA', (127, 137))	('HAX1', 'Gene', (74, 78))	('copy number', 'Var', (34, 45))	('TSEN15', 'Gene', (141, 147))	('increased', 'PosReg', (19, 28))	('increased', 'PosReg', (64, 73))	('HAX1', 'Gene', '10456', (29, 33))	('effects', 'Reg', (112, 119))	('expression level', 'MPA', (79, 95))
71639	27716417	Our impact analysis further predicts TSEN15 as a downstream target of two other high-impact gene deletions of PLXNB2 and CHAC1 that both strongly impact on the expression of TSEN15.	('expression', 'MPA', (160, 170))	('PLXNB2', 'Gene', '23654', (110, 116))	('impact', 'Reg', (146, 152))	('TSEN15', 'Gene', (174, 180))	('TSEN15', 'Gene', '116461', (37, 43))	('CHAC1', 'Gene', '79094', (121, 126))	('TSEN15', 'Gene', '116461', (174, 180))	('CHAC1', 'Gene', (121, 126))	('PLXNB2', 'Gene', (110, 116))	('TSEN15', 'Gene', (37, 43))	('deletions', 'Var', (97, 106))
71644	27716417	The amplification of the oncogene EGFR on chromosome 7 is involved in GBM etiology.	('EGFR', 'Gene', (34, 38))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('involved', 'Reg', (58, 66))	('GBM', 'Disease', (70, 73))	('amplification', 'Var', (4, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('EGFR', 'Gene', '1956', (34, 38))
71649	27716417	For example, amplifications of the tumor suppressor genes WAC in GBM (97 tumors with amplifications vs 218 tumors with normal gene copy number, Fig.	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('WAC', 'Gene', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('GBM', 'Gene', (65, 68))	('amplifications', 'Var', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('amplifications', 'Var', (13, 27))	('tumors', 'Disease', (107, 113))	('tumor', 'Disease', (73, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
71650	27716417	4 a, chromosome 10, p-arm) and CDH1 in OV (61 tumors with amplifications vs 174 tumors with normal gene copy number, Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('5', '15'))	('CDH1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('amplifications', 'Var', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CDH1', 'Gene', '999', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
71652	27716417	We revealed considerable variation between patients with respect to how many and to what extent gene CNAs affect survival signature genes.	('gene CNAs', 'Var', (96, 105))	('patients', 'Species', '9606', (43, 51))	('CNAs', 'Var', (101, 105))	('survival', 'MPA', (113, 121))	('affect', 'Reg', (106, 112))
71658	27716417	In conclusion, the patient-specific expression pattern of survival signature genes can substantially be driven by individual rare gene CNAs, which is consistent with recent findings that patient-specific mutation patterns impact on survival.	('patient', 'Species', '9606', (19, 26))	('driven', 'Reg', (104, 110))	('impact', 'Reg', (222, 228))	('CNAs', 'Var', (135, 139))	('patient', 'Species', '9606', (187, 194))	('expression', 'MPA', (36, 46))
71661	27716417	Second, we considered single-gene tests to determine if patients with a specific gene CNA had significant differences in survival compared to patients without this gene CNA.	('patients', 'Species', '9606', (56, 64))	('survival', 'MPA', (121, 129))	('differences', 'Reg', (106, 117))	('patients', 'Species', '9606', (142, 150))	('CNA', 'Var', (86, 89))
71664	27716417	A first hypothesis was that rare high-impact mutations occur later in the tumor etiology and affect different endpoints than frequent gene CNAs.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('affect', 'Reg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))
71688	27716417	Based on the score derivation, negative scores are expected to be associated with shorter patient survival than positive scores.	('patient survival', 'CPA', (90, 106))	('patient', 'Species', '9606', (90, 97))	('negative', 'Var', (31, 39))	('shorter', 'NegReg', (82, 89))
71703	27716417	The contributions of patient-specific rare and frequent gene CNAs tend to be rather tumor type-specific.	('gene CNAs', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))
71704	27716417	Thus, although the number of cellular endpoints that have to be altered is limited, the space of possible mutational patterns affecting the aggressiveness of a tumor (and ultimately patient survival) is practically unlimited.	('aggressiveness', 'Disease', 'MESH:D001523', (140, 154))	('aggressiveness', 'Disease', (140, 154))	('affecting', 'Reg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('patient', 'Species', '9606', (182, 189))	('aggressiveness', 'Phenotype', 'HP:0000718', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutational', 'Var', (106, 116))	('tumor', 'Disease', (160, 165))
71710	27716417	In addition, the importance of rare and frequent gene CNAs to distinguish between short and long patient survival was also highly tumor type-specific.	('gene CNAs', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patient', 'Species', '9606', (97, 104))	('tumor', 'Disease', (130, 135))
71711	27716417	Further, we found many survival impact genes that are well-established cancer genes in one tissue to be also mutated (with a large predicted impact) in other tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (71, 77))	('mutated', 'Var', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('survival impact genes', 'Gene', (23, 44))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
71718	27716417	Third, the impact scoring (which integrates both models) was predictive for survival in four out of five independent clinical cohorts that were not used for any of the previous analyses, revealing the tumor type-specific contributions of rare and frequent gene CNAs for the separation into long- and short-lived patients.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('patients', 'Species', '9606', (312, 320))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('gene CNAs', 'Var', (256, 265))	('tumor', 'Disease', (201, 206))
71730	27716417	We have demonstrated this potential for the recurrent duplication of chromosome 7 in glioblastomas, suggesting additional driver genes apart from the known role of EGFR.	('EGFR', 'Gene', (164, 168))	('glioblastomas', 'Phenotype', 'HP:0012174', (85, 98))	('duplication', 'Var', (54, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (85, 98))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('glioblastomas', 'Disease', (85, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('EGFR', 'Gene', '1956', (164, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('164', '168'))
71731	27716417	Since copy number changes play a role in many other diseases or genetic disorders (e.g.	('genetic disorders', 'Disease', (64, 81))	('play', 'Reg', (26, 30))	('role', 'Reg', (33, 37))	('copy number changes', 'Var', (6, 25))	('genetic disorders', 'Disease', 'MESH:D030342', (64, 81))
71779	27716417	The q values of the selected high-impact genes were less than 0.006 for all TCGA cohorts (q value cutoffs: AML < 0.0053, GBM < 0.0048, HNSC < 0.0058, LUAD < 0.0056, OV < 0.0046, and SKCM < 0.0049).	('OV < 0.0046', 'Var', (165, 176))	('HNSC < 0.0058', 'Var', (135, 148))	('AML', 'Disease', 'MESH:D015470', (107, 110))	('AML', 'Disease', (107, 110))
71810	27716417	AML Acute myeloid leukemia BRCA Breast invasive carcinoma CCLE Cancer cell line encyclopedia CCTN Cancer cell transcriptional network CLCGP Clinical lung cancer genome project CNA Copy number alteration CNV Copy number variation COAD Colon adenocarcinoma GBM Glioblastoma multiforme HNSC Head and neck squamous cell carcinoma lasso Least absolute shrinkage and selection operator LINCS Library of Integrated Network-based Cellular Signatures LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma OV Ovarian serous cystadenocarcinoma RF Random forest RSF Random survival forest SKCM Skin cutaneous melanoma SNV Single nucleotide variation STAD Stomach adenocarcinoma TCGA The cancer genome atlas THCA Thyroid carcinoma	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (648, 670))	('adenocarcinoma', 'Disease', (452, 466))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (587, 610))	('lung cancer', 'Disease', (149, 160))	('adenocarcinoma', 'Disease', 'MESH:D000230', (240, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (452, 466))	('adenocarcinoma', 'Disease', (656, 670))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (504, 537))	('RSF', 'Chemical', '-', (555, 558))	('Glioblastoma', 'Phenotype', 'HP:0012174', (259, 271))	('BRCA', 'Gene', (27, 31))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (297, 325))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (234, 254))	('cancer', 'Phenotype', 'HP:0002664', (680, 686))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (504, 537))	('neck', 'cellular_component', 'GO:0044326', ('297', '301'))	('Cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (32, 57))	('carcinoma', 'Disease', (528, 537))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (705, 722))	('adenocarcinoma', 'Disease', (523, 537))	('Cancer', 'Disease', 'MESH:D009369', (63, 69))	('carcinoma', 'Disease', (661, 670))	('BRCA', 'Gene', '672', (27, 31))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('carcinoma', 'Disease', 'MESH:D002277', (528, 537))	('adenocarcinoma', 'Disease', 'MESH:D000230', (523, 537))	('squamous cell carcinoma', 'Disease', (477, 500))	('Cancer', 'Disease', (98, 104))	('carcinoma', 'Disease', 'MESH:D002277', (661, 670))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (447, 466))	('adenocarcinoma', 'Disease', 'MESH:D000230', (656, 670))	('Breast invasive carcinoma', 'Disease', (32, 57))	('carcinoma', 'Disease', 'MESH:D002277', (713, 722))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('Skin cutaneous melanoma', 'Disease', (587, 610))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (477, 500))	('carcinoma', 'Disease', 'MESH:D002277', (491, 500))	('carcinoma', 'Disease', 'MESH:D002277', (316, 325))	('COAD', 'Disease', 'MESH:D029424', (229, 233))	('cancer', 'Disease', 'MESH:D009369', (680, 686))	('carcinoma', 'Disease', 'MESH:D002277', (457, 466))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (477, 500))	('carcinoma', 'Disease', (48, 57))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Disease', (713, 722))	('Acute myeloid leukemia', 'Disease', (4, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (491, 500))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('Colon adenocarcinoma', 'Disease', (234, 254))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (4, 26))	('carcinoma', 'Disease', (491, 500))	('carcinoma', 'Disease', (316, 325))	('neck squamous cell carcinoma', 'Disease', (297, 325))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (457, 466))	('carcinoma', 'Disease', (457, 466))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (32, 57))	('CCLE', 'Chemical', '-', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (602, 610))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (259, 282))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (302, 325))	('Stomach adenocarcinoma', 'Disease', (648, 670))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Disease', (245, 254))	('COAD', 'Disease', (229, 233))	('AML', 'Disease', (0, 3))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (4, 26))	('Ovarian serous cystadenocarcinoma', 'Disease', (504, 537))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (592, 610))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cancer', 'Disease', (680, 686))	('carcinoma', 'Disease', 'MESH:D002277', (245, 254))	('cancer', 'Disease', (154, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (10, 26))	('adenocarcinoma', 'Disease', (240, 254))	('Single nucleotide variation', 'Var', (615, 642))	('Glioblastoma multiforme', 'Disease', (259, 282))
71828	22545195	Any single alteration alone or in combination with other alterations could therefore potentially serve as useful prognostic indicator(s) and/or target(s) for cancer therapy.	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('alteration', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
71831	22545195	It is generally believed that "malignancy results from genetic changes that uncouple the normal balance between multiplication and differentiation".	('malignancy', 'Disease', (31, 41))	('changes', 'Var', (63, 70))	('malignancy', 'Disease', 'MESH:D009369', (31, 41))
71838	22545195	However, MITF expression has been associated with both poor prognosis as well as better prognosis of melanoma, depending on the stage of the tumor.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('expression', 'Var', (14, 24))	('MITF', 'Gene', '4286', (9, 13))	('MITF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('tumor', 'Disease', (141, 146))
71842	22545195	A high percentage of metastatic tumors and a subset of primary melanomas have been found to harbor amplification of the MITF gene.	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('MITF', 'Gene', '4286', (120, 124))	('MITF', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('melanomas', 'Disease', (63, 72))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('amplification', 'Var', (99, 112))	('tumors', 'Disease', (32, 38))	('primary melanoma', 'Disease', 'MESH:D008545', (55, 71))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('primary melanoma', 'Disease', (55, 71))
71843	22545195	Such amplification and consequent higher levels of MITF protein expression in metastatic melanoma was reported to be associated with a decrease in five-year survival of patients with metastatic disease.	('expression', 'MPA', (64, 74))	('patients', 'Species', '9606', (169, 177))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('amplification', 'Var', (5, 18))	('higher', 'PosReg', (34, 40))	('MITF', 'Gene', (51, 55))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('MITF', 'Gene', '4286', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('decrease', 'NegReg', (135, 143))	('levels', 'MPA', (41, 47))
71847	22545195	Polymorphisms in the MC1R gene are known to be associated with the diversity of human pigmentation.	('MC1R', 'Gene', '4157', (21, 25))	('MC1R', 'Gene', (21, 25))	('Polymorphisms', 'Var', (0, 13))	('pigmentation', 'Disease', 'MESH:D010859', (86, 98))	('pigmentation', 'biological_process', 'GO:0043473', ('86', '98'))	('pigmentation', 'Disease', (86, 98))	('human', 'Species', '9606', (80, 85))	('associated', 'Reg', (47, 57))
71848	22545195	Melanoma risk is associated in the individuals with the pale skin pigment and individuals with selected MC1R gene variants have an increased risk for melanoma development that is independent of skin type and hair color.	('MC1R', 'Gene', '4157', (104, 108))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('pale skin pigment', 'Phenotype', 'HP:0007513', (56, 73))	('Melanoma', 'Disease', (0, 8))	('MC1R', 'Gene', (104, 108))	('variants', 'Var', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('skin type and hair color', 'Disease', 'MESH:D012871', (194, 218))
71849	22545195	However, to our knowledge, the prognostic value of MC1R variants or their expression levels in primary cutaneous melanoma has not been examined.	('MC1R', 'Gene', '4157', (51, 55))	('cutaneous melanoma', 'Disease', (103, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('MC1R', 'Gene', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('variants', 'Var', (56, 64))
71883	22545195	Ectopic expression of MAP2 in metastatic melanoma cells lines leads to microtubule stabilization, cell cycle arrest in G2-M phase and growth inhibition of metastatic melanoma cells in vitro.	('MAP', 'molecular_function', 'GO:0004239', ('22', '25'))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('98', '115'))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('growth inhibition', 'CPA', (134, 151))	('Ectopic expression', 'Var', (0, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('cell cycle arrest in G2-M phase', 'CPA', (98, 129))	('microtubule', 'cellular_component', 'GO:0005874', ('71', '82'))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('microtubule stabilization', 'MPA', (71, 96))	('melanoma', 'Disease', (41, 49))	('M phase', 'biological_process', 'GO:0000279', ('122', '129'))	('MAP2', 'Gene', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('MAP2', 'Gene', '4133', (22, 26))	('microtubule stabilization', 'biological_process', 'GO:0007026', ('71', '96'))
71892	22545195	In the process of identification of the genomic events associated with the acquisition of metastatic potential, Kim et al., reported amplification of NEDD9.	('NEDD9', 'Gene', (150, 155))	('NEDD9', 'Gene', '4739', (150, 155))	('amplification', 'Var', (133, 146))
71913	21541354	miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice.	('miR-34a', 'Var', (0, 7))	('SCID', 'Disease', (102, 106))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('SCID', 'Disease', 'MESH:D053632', (102, 106))	('miR-185', 'Var', (12, 19))	('mice', 'Species', '10090', (111, 115))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('inhibit', 'NegReg', (42, 49))
71923	21541354	In some cases, cancer is facilitated by the loss of certain miRNAs, such as miR-15/16 cluster in chronic lymphocytic leukemia, miR-34a in uveal melanoma and miR-31 in mesothelioma.	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (97, 125))	('loss', 'NegReg', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('chronic lymphocytic leukemia', 'Disease', (97, 125))	('uveal melanoma', 'Disease', (138, 152))	('uveal melanoma', 'Disease', 'MESH:C536494', (138, 152))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (97, 125))	('facilitated', 'PosReg', (25, 36))	('mesothelioma', 'Disease', (167, 179))	('miR-31', 'Gene', (157, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (138, 152))	('cancer', 'Disease', (15, 21))	('mesothelioma', 'Disease', 'MESH:D008654', (167, 179))	('miR-15/16', 'Gene', (76, 85))	('miR-34a', 'Var', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('miR-31', 'Gene', '407035', (157, 163))
71924	21541354	The loss of these miRNAs enhances invasiveness, migration and proliferation of cancer cells.	('migration', 'CPA', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('enhances', 'PosReg', (25, 33))	('cancer', 'Disease', (79, 85))	('invasiveness', 'CPA', (34, 46))	('loss', 'Var', (4, 8))
71929	21541354	Few inhibitory miRNAs were identified in melanoma, including miR-34a (uveal melanoma), miR-193b, let-7a, and miR-211, while miR-182 and miR-221/222 were shown to stimulate metastatic potential of melanoma cells.	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('miR-221', 'Gene', '407006', (136, 143))	('miR-193b', 'Gene', (87, 95))	('miR-211', 'Gene', '406993', (109, 116))	('miR-34a', 'Var', (61, 68))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('miR-182', 'Gene', (124, 131))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('miR-193b', 'Gene', '574455', (87, 95))	('miR-182', 'Gene', '406958', (124, 131))	('stimulate', 'PosReg', (162, 171))	('miR-211', 'Gene', (109, 116))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('let-7a', 'Var', (97, 103))	('miR-221', 'Gene', (136, 143))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))
71947	21541354	We focused mainly on HAGlow miRNAs, which are presumably tumor-suppressive and could provide the basis for novel lines of therapy for melanoma.	('HAGlow', 'Var', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('tumor', 'Disease', (57, 62))
71950	21541354	Twenty nine of the miRNAs were predicted to target all four processes, with only 12 having been reported to experimentally exert a suppressive effect in any cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('miRNAs', 'Var', (19, 25))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))
71952	21541354	Three miRNAs were within expression range (miR-34a, miR-185 and miR-204, Figure 2C) and two which were silenced (miR-31 and miR-184, Figure 2B) in the HAG cells.	('miR-204', 'Gene', '406987', (64, 71))	('miR-184', 'Gene', '406960', (124, 131))	('miR-204', 'Gene', (64, 71))	('miR-184', 'Gene', (124, 131))	('miR-185', 'Var', (52, 59))	('miR-31', 'Gene', '407035', (113, 119))	('miR-34a', 'Var', (43, 50))	('miR-31', 'Gene', (113, 119))
71954	21541354	Different roles of miR-17, miR-31 and miR-34a in cancer have been reported before, although never in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('miR-34a', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('miR-31', 'Gene', (27, 33))	('cutaneous melanoma', 'Disease', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('miR-17', 'Gene', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('miR-31', 'Gene', '407035', (27, 33))	('miR-17', 'Gene', '406952', (19, 25))	('cancer', 'Disease', (49, 55))
71955	21541354	In contrast, there is scarce evidence on the roles of miRNAs -184, -185 and -204 in cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('miRNAs -184', 'Var', (54, 65))	('cancer', 'Disease', (84, 90))
71966	21541354	Remarkably, a substantial and consistent inhibition in net proliferation was conferred by miR-31, miR-34a, miR-184 and miR-185 as compared to the control cell (Figure 4B).	('miR-184', 'Gene', '406960', (107, 114))	('miR-184', 'Gene', (107, 114))	('miR-31', 'Gene', (90, 96))	('miR-185', 'Var', (119, 126))	('miR-34a', 'Var', (98, 105))	('net proliferation', 'CPA', (55, 72))	('miR-31', 'Gene', '407035', (90, 96))	('inhibition', 'NegReg', (41, 51))
71970	21541354	Tube formation activity was substantially inhibited by miR-34a and miR-185, and more mildly by miR-31 and miR-184, but not by miR-204, as compared to control (Figure 5, A-F).	('miR-204', 'Gene', '406987', (126, 133))	('Tube formation activity', 'CPA', (0, 23))	('miR-31', 'Gene', '407035', (95, 101))	('miR-34a', 'Var', (55, 62))	('Tube formation', 'biological_process', 'GO:0035148', ('0', '14'))	('miR-185', 'Var', (67, 74))	('miR-204', 'Gene', (126, 133))	('inhibited', 'NegReg', (42, 51))	('miR-31', 'Gene', (95, 101))	('miR-184', 'Gene', '406960', (106, 113))	('miR-184', 'Gene', (106, 113))
71981	21541354	The effect of the Suppressive miRNAs, miR-34a and miR-185 on tumor growth was measured following subcutaneous injection of 3x105 HAG transductants.	('miR-34a', 'Var', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('miR-185', 'Var', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
71982	21541354	Importantly, a statistically significant inhibition in tumor growth was observed in both miR-34a and miR-185 transducatnts, as compared to control tumors (Figure 7A).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('miR-185 transducatnts', 'Var', (101, 122))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('miR-34a', 'Var', (89, 96))	('inhibition', 'NegReg', (41, 51))
71983	21541354	Concurring with these results, ex-vivo weighing of tumor explants upon termination of the experiments confirmed that the average tumor mass of both miR-34a and miR-185 transducatnts was lower than Mock-transduced tumors (Figure 7B).	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('miR-34a', 'Var', (148, 155))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-185', 'Var', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('lower', 'NegReg', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
71995	21541354	In the present work we focused on a group of either well characterized miRNAs known to have a role in other malignancies (miR-17, miR-31 and miR-34a), and on a second group of relatively unstudied miRNAs with regard to their role in malignant processes (miR-184, miR-185, miR-204).	('miR-184', 'Gene', '406960', (254, 261))	('miR-184', 'Gene', (254, 261))	('miR-31', 'Gene', '407035', (130, 136))	('miR-34a', 'Var', (141, 148))	('miR-204', 'Gene', '406987', (272, 279))	('malignancies', 'Disease', 'MESH:D009369', (108, 120))	('miR-17', 'Gene', (122, 128))	('miR-185', 'Var', (263, 270))	('miR-31', 'Gene', (130, 136))	('miR-204', 'Gene', (272, 279))	('malignancies', 'Disease', (108, 120))	('miR-17', 'Gene', '406952', (122, 128))
71998	21541354	miR-34a was consistently reported as a suppressive miRNA in many malignancies.	('suppressive', 'NegReg', (39, 50))	('miR-34a', 'Var', (0, 7))	('malignancies', 'Disease', (65, 77))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))
71999	21541354	Our results concur with the suggested inhibitory role for miR-34a and miR-31.	('miR-31', 'Gene', '407035', (70, 76))	('miR-34a', 'Var', (58, 65))	('miR-31', 'Gene', (70, 76))
72001	21541354	Since c-Met has been reported to participate in tubulogenesis processes through the c-Met/HGF system, it is tempting to speculate that the mechanism by which miR-34a inhibits tube formation is via this gene.	('c-Met', 'Gene', '4233', (6, 11))	('tubulogenesis', 'biological_process', 'GO:0048754', ('48', '61'))	('c-Met', 'Gene', (6, 11))	('inhibits', 'NegReg', (166, 174))	('HGF', 'Gene', (90, 93))	('c-Met', 'Gene', (84, 89))	('c-Met', 'Gene', '4233', (84, 89))	('HGF', 'Gene', '3082', (90, 93))	('tube formation', 'biological_process', 'GO:0035148', ('175', '189'))	('miR-34a', 'Var', (158, 165))	('tube formation', 'CPA', (175, 189))
72003	21541354	In agreement with these reports, ectopic expression of miR-17-5p in the PAG cells enhanced proliferation rate (Figure 6B).	('enhanced', 'PosReg', (82, 90))	('ectopic expression', 'Var', (33, 51))	('miR-17-5p', 'Gene', '406952', (55, 64))	('miR-17-5p', 'Gene', (55, 64))	('PAG', 'Chemical', '-', (72, 75))	('proliferation rate', 'CPA', (91, 109))
72004	21541354	In contrast, very little is known about miR-184, miR-185 and miR-204 in cancer.	('miR-204', 'Gene', '406987', (61, 68))	('miR-185', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('miR-204', 'Gene', (61, 68))	('miR-184', 'Gene', '406960', (40, 47))	('miR-184', 'Gene', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
72016	21541354	Recent publications showed the possibility of targeting experimental melanoma metastases using nanoparticles carrying miR-34a or a synthetic miRNA agonist.	('melanoma metastases', 'Disease', (69, 88))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma metastases', 'Disease', 'MESH:D009362', (69, 88))	('miR-34a', 'Var', (118, 125))
72042	25048604	Association between BRAFV600E and NRASQ61R Mutations and Clinicopathologic Characteristics, Risk Factors and Clinical Outcome of Primary Invasive Cutaneous Melanoma Previous studies suggest that solar UV exposure in early life is predictive of cutaneous melanoma risk in adulthood, whereas the relation of BRAF mutation with sun exposure and disease prognosis has been less certain.	('BRAFV600E', 'Mutation', 'rs113488022', (20, 29))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('BRAF', 'Gene', '673', (306, 310))	('BRAF', 'Gene', (306, 310))	('Primary Invasive Cutaneous Melanoma', 'Disease', (129, 164))	('Mutations', 'Var', (43, 52))	('cutaneous melanoma', 'Disease', (244, 262))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (244, 262))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (244, 262))	('Melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('BRAF', 'Gene', '673', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('BRAF', 'Gene', (20, 24))	('Primary Invasive Cutaneous Melanoma', 'Disease', 'MESH:C562393', (129, 164))	('NRASQ61R', 'Gene', (34, 42))
72043	25048604	We investigated the associations between BRAFV600E and NRASQ61R mutations and known risk factors, clinicopathologic characteristics and clinical outcomes of melanoma in a case series of primary invasive cutaneous melanoma from the Nurses' Health Study (NHS).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (203, 221))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (203, 221))	('NRASQ61R', 'Var', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('BRAFV600E', 'Gene', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('cutaneous melanoma', 'Disease', (203, 221))
72045	25048604	Logistic regression analyses were performed to detect the associations of mutations with melanoma risk factors, and Kaplan-Meier method was used to examine associations between mutations and survival.	('associations', 'Interaction', (58, 70))	('mutations', 'Var', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
72047	25048604	Patients with BRAFV600E mutations tended to have shorter melanoma-specific survival when compared to patients wild-type at both loci (median survival time 110 months vs. 159 months) (P=0.03).	('patients', 'Species', '9606', (101, 109))	('BRAFV600E mutations', 'Var', (14, 33))	('shorter', 'NegReg', (49, 56))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('Patients', 'Species', '9606', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('BRAFV600E', 'Mutation', 'rs113488022', (14, 23))
72049	25048604	BRAFV600E mutation may be associated with an unfavorable prognosis among melanoma patients.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('patients', 'Species', '9606', (82, 90))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
72055	25048604	BRAF mutations have been reported to occur in more than 60% of cultured melanoma cell lines and 50% of primary human melanomas, with a majority in or around codon 600 in exon 15 (V600E).	('V600E', 'Var', (179, 184))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('melanomas', 'Disease', 'MESH:D008545', (117, 126))	('melanoma', 'Disease', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('human', 'Species', '9606', (111, 116))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', (117, 126))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))	('melanoma', 'Disease', (117, 125))
72056	25048604	NRAS mutations have been reported to occur in 15% of human melanomas, mainly in codon 61 in exon 2 (Q61R).	('melanomas', 'Disease', (59, 68))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('human', 'Species', '9606', (53, 58))	('NRAS', 'Gene', (0, 4))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('Q61R', 'Mutation', 'rs11554290', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('NRAS', 'Gene', '4893', (0, 4))
72057	25048604	Although BRAF and NRAS mutations were rarely found to occur in the same melanomas, both mutations have been shown to activate the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway and thus may play important roles in cancer initiation and progression.	('play', 'Reg', (207, 211))	('cancer initiation', 'Disease', 'MESH:D009369', (231, 248))	('BRAF', 'Gene', (9, 13))	('MAPK', 'Gene', '5594', (180, 184))	('mutations', 'Var', (88, 97))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('ERK', 'molecular_function', 'GO:0004707', ('142', '145'))	('activate', 'PosReg', (117, 125))	('NRAS', 'Gene', (18, 22))	('RAF', 'Gene', (10, 13))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('MEK', 'Gene', '5609', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('RAF', 'Gene', '22882', (134, 137))	('ERK', 'Gene', '5594', (142, 145))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('roles', 'Reg', (222, 227))	('melanomas', 'Disease', (72, 81))	('MEK', 'Gene', (138, 141))	('RAF', 'Gene', (134, 137))	('ERK', 'Gene', (142, 145))	('NRAS', 'Gene', '4893', (18, 22))	('cancer initiation', 'Disease', (231, 248))	('MAPK', 'Gene', (180, 184))	('MAPK', 'molecular_function', 'GO:0004707', ('180', '184'))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('RAF', 'Gene', '22882', (10, 13))	('BRAF', 'Gene', '673', (9, 13))
72058	25048604	Furthermore, since the discovery of activating BRAF mutation in cutaneous melanoma, it has become a favored target for drug design, and several previous studies have tried to correlate BRAF as well as NRAS mutations with constitutional and clinical features of melanoma.	('NRAS', 'Gene', (201, 205))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (64, 82))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('NRAS', 'Gene', '4893', (201, 205))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('melanoma', 'Disease', (74, 82))	('BRAF', 'Gene', '673', (185, 189))	('mutation', 'Var', (52, 60))	('cutaneous melanoma', 'Disease', (64, 82))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('BRAF', 'Gene', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('activating', 'PosReg', (36, 46))	('melanoma', 'Disease', (261, 269))
72069	25048604	Eligible tumors (n=151) were sent to laboratory for BRAFV600E and NRASQ61R genotyping, and 127 tumors were successfully genotyped for both mutations.	('BRAFV600E', 'Var', (52, 61))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('BRAFV600E', 'Mutation', 'rs113488022', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumors', 'Disease', (95, 101))
72077	25048604	Pyrosequencing of the BRAF and NRAS mutations was performed using the Qiagen PyroMark Q24 platform (Qiagen, Strauss, Germany).	('NRAS', 'Gene', '4893', (31, 35))	('BRAF', 'Gene', '673', (22, 26))	('mutations', 'Var', (36, 45))	('BRAF', 'Gene', (22, 26))	('NRAS', 'Gene', (31, 35))
72078	25048604	Based on the pyrosequencing results, each of the 127 tumors was assigned one of the following genotype: BRAFV600E mutation, 31 patients (24.4%); NRASQ61R mutation, 31 patients (24.4%); and wild-type at both loci, 72 patients (56.7%).	('BRAFV600E', 'Mutation', 'rs113488022', (104, 113))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (216, 224))	('patients', 'Species', '9606', (127, 135))	('BRAFV600E', 'Gene', (104, 113))	('NRASQ61R mutation', 'Var', (145, 162))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
72079	25048604	Among tumors with mutations, 7 tumors (5.5%) had mutations at both loci.	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (18, 27))
72081	25048604	Associations of melanoma clinicopathlogic characteristics, risk factors and clinical outcome with mutations were evaluated using the 3 major genotypes (BRAFV600E mutation, NRASQ61R mutation, and wild-type at both loci).	('BRAFV600E', 'Mutation', 'rs113488022', (152, 161))	('NRASQ61R mutation', 'Var', (172, 189))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('BRAFV600E mutation', 'Var', (152, 170))	('melanoma', 'Disease', (16, 24))
72092	25048604	Tumors harboring BRAFV600E mutation were more likely to occur on the trunk whereas tumors harboring NRASQ61R mutation were more likely to occur on the lower extremity (Figure 1).	('lower extremity', 'Phenotype', 'HP:0006385', (151, 166))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('trunk', 'cellular_component', 'GO:0043198', ('69', '74'))	('BRAFV600E', 'Var', (17, 26))	('BRAFV600E', 'Mutation', 'rs113488022', (17, 26))
72096	25048604	Melanoma patients residing in states with higher UV index at 15 years of age also appeared to have higher ORs for harboring BRAFV600E mutation, though the estimates were not statistically significant.	('patients', 'Species', '9606', (9, 17))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('BRAFV600E', 'Var', (124, 133))	('BRAFV600E', 'Mutation', 'rs113488022', (124, 133))	('Melanoma', 'Disease', (0, 8))	('ORs', 'MPA', (106, 109))
72098	25048604	The median survival time was 110 months (range, 4-366 months) for melanoma patients with BRAFV600E mutation, 128 months (range, 13-365 months) for patients with NRASQ61R mutation, and 159 months (range, 11-379 months) for patients with wild-type at both loci.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (147, 155))	('NRASQ61R', 'Var', (161, 169))	('BRAFV600E', 'Var', (89, 98))	('BRAFV600E', 'Mutation', 'rs113488022', (89, 98))
72099	25048604	In particular, the difference between MSS of melanoma patients with BRAFV600E mutation and patients with wild-type also reached statistical significance (P=0.03, log-rank test).	('BRAFV600E', 'Var', (68, 77))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
72100	25048604	Seven tumors were found to harbor both BRAFV600E and NRASQ61R mutations (Supplemental Table S1).	('men', 'Species', '9606', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('NRASQ61R', 'Var', (53, 61))	('BRAFV600E', 'Var', (39, 48))
72102	25048604	Other features of the both mutated tumors were not distinct from those of the other 3 genotypes.	('mutated', 'Var', (27, 34))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))
72104	25048604	In the present study, we provide a comprehensive analysis on the association between BRAFV600E and NRASQ61R mutations and clinicopathologic characteristics, conventional risk factors, and clinical outcome of primary cutaneous melanomas in a case series from the NHS.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (216, 235))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (216, 234))	('primary cutaneous melanomas', 'Disease', 'MESH:C562393', (208, 235))	('association', 'Interaction', (65, 76))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('NRASQ61R', 'Gene', (99, 107))	('BRAFV600E', 'Var', (85, 94))	('BRAFV600E', 'Mutation', 'rs113488022', (85, 94))	('primary cutaneous melanomas', 'Disease', (208, 235))
72106	25048604	Furthermore, patients with BRAFV600E mutated melanomas appeared to experience shorter survival as compared to patient with wild-type at both loci, suggesting an unfavorable prognosis associated with the mutation.	('survival', 'MPA', (86, 94))	('patient', 'Species', '9606', (13, 20))	('BRAFV600E', 'Var', (27, 36))	('patients', 'Species', '9606', (13, 21))	('BRAFV600E', 'Mutation', 'rs113488022', (27, 36))	('melanomas', 'Disease', (45, 54))	('patient', 'Species', '9606', (110, 117))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('shorter', 'NegReg', (78, 85))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
72109	25048604	Another study also found the fraction of alleles carrying BRAFV600E substitution was variable but strongly associated with sun exposure.	('associated', 'Reg', (107, 117))	('BRAFV600E', 'Var', (58, 67))	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('sun exposure', 'Disease', (123, 135))
72110	25048604	However, older subjects after accumulating sun exposure sufficient to produce chronic sun-induced damage in the surrounding skin also exhibit lower BRAF mutation frequencies, arguing against a simple positive link between UV exposure and BRAF mutation.	('BRAF', 'Gene', '673', (238, 242))	('BRAF', 'Gene', (238, 242))	('lower', 'NegReg', (142, 147))	('BRAF', 'Gene', '673', (148, 152))	('mutation', 'Var', (153, 161))	('BRAF', 'Gene', (148, 152))
72111	25048604	Alternatively, there is evidence showing that BRAF mutations are more likely to develop in tumors located on skin subject to intermittent sun exposure, whereas NRAS mutations are more commonly found in tumors on skin with continuous sun exposure.	('tumors', 'Disease', (91, 97))	('BRAF', 'Gene', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('BRAF', 'Gene', '673', (46, 50))	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('NRAS', 'Gene', '4893', (160, 164))	('develop', 'PosReg', (80, 87))	('tumors located on skin', 'Phenotype', 'HP:0008069', (91, 113))	('tumors on skin', 'Phenotype', 'HP:0008069', (202, 216))
72112	25048604	In line with the previous evidence, our data also suggest that melanomas harboring BRAFV600E mutations tended to distribute more commonly on skin subject to intermittent sun exposure (trunk), and melanomas harboring NRASQ61R mutations tended to distribute more commonly on skin with continuous sun exposure (lower extremity).	('melanomas', 'Disease', 'MESH:D008545', (196, 205))	('BRAFV600E', 'Mutation', 'rs113488022', (83, 92))	('mutations', 'Var', (93, 102))	('lower extremity', 'Phenotype', 'HP:0006385', (308, 323))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Disease', (196, 205))	('BRAFV600E', 'Gene', (83, 92))	('melanomas', 'Disease', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('trunk', 'cellular_component', 'GO:0043198', ('184', '189'))	('melanomas', 'Phenotype', 'HP:0002861', (196, 205))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
72116	25048604	It has been suggested that error-prone replication of UV-induced DNA damage could underlie the acquisition of BRAF mutations in melanocytic tumors.	('mutations', 'Var', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('BRAF', 'Gene', '673', (110, 114))	('melanocytic tumors', 'Disease', 'MESH:D009508', (128, 146))	('melanocytic tumors', 'Disease', (128, 146))	('BRAF', 'Gene', (110, 114))
72118	25048604	We found a similar overall prevalence rate of somatic NRAS mutation (24.4%, 31/127) and a lower rate of overall BRAF mutation (24.4%, 31/127) as compared with previous studies.	('NRAS', 'Gene', (54, 58))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('NRAS', 'Gene', '4893', (54, 58))	('mutation', 'Var', (59, 67))
72121	25048604	For example, a previous study found 3 patients with both BRAF and NRAS mutations among 233 primary melanomas.	('NRAS', 'Gene', (66, 70))	('primary melanomas', 'Disease', 'MESH:D008545', (91, 108))	('NRAS', 'Gene', '4893', (66, 70))	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('mutations', 'Var', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('primary melanomas', 'Disease', (91, 108))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('patients', 'Species', '9606', (38, 46))
72122	25048604	Several reasons may help explain the lower prevalence of BRAF mutation and relatively high prevalence of both mutations in the present study.	('mutation', 'Var', (62, 70))	('BRAF', 'Gene', (57, 61))	('BRAF', 'Gene', '673', (57, 61))
72123	25048604	First, we focused on the most common BRAF mutation in or around codon 600 in exon 15 (V600E), and may miss a few other BRAF mutations (e.g., V600K).	('BRAF', 'Gene', '673', (37, 41))	('V600K', 'Var', (141, 146))	('BRAF', 'Gene', '673', (119, 123))	('V600E', 'Var', (86, 91))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (119, 123))	('V600K', 'Mutation', 'rs121913227', (141, 146))	('V600E', 'Mutation', 'rs113488022', (86, 91))
72124	25048604	However, BRAFV600E mutation accounts for more than 80% of all BRAF mutations.	('BRAF', 'Gene', (9, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (9, 18))	('mutations', 'Var', (67, 76))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (9, 13))
72126	25048604	The NRAS mutation is generally found to be less common than BRAF mutation in cutaneous melanoma, and individuals with NRAS mutations are characterized by older age at diagnosis.	('mutation', 'Var', (9, 17))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (77, 95))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('NRAS', 'Gene', (118, 122))	('NRAS', 'Gene', '4893', (118, 122))	('cutaneous melanoma', 'Disease', (77, 95))	('NRAS', 'Gene', (4, 8))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (77, 95))	('NRAS', 'Gene', '4893', (4, 8))
72127	25048604	Similarly, our melanoma patients with NRASQ61R mutations also had an older median age at diagnosis, though the difference between groups was not statistically significant.	('NRASQ61R', 'Gene', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('older', 'PosReg', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (24, 32))
72130	25048604	Previous reports on the associations between BRAF and NRAS mutations and survival of melanoma patients have been inconsistent.	('patients', 'Species', '9606', (94, 102))	('associations', 'Interaction', (24, 36))	('NRAS', 'Gene', (54, 58))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('NRAS', 'Gene', '4893', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutations', 'Var', (59, 68))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))
72131	25048604	A previous study reported shorter survival associated with BRAF mutation among patients with metastatic melanomas, and another study also reported poor prognosis associated with NRAS mutation among patients with primary melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('metastatic melanomas', 'Disease', 'MESH:D008545', (93, 113))	('NRAS', 'Gene', '4893', (178, 182))	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('mutation', 'Var', (64, 72))	('melanomas', 'Phenotype', 'HP:0002861', (220, 229))	('patients', 'Species', '9606', (198, 206))	('primary melanomas', 'Disease', 'MESH:D008545', (212, 229))	('shorter', 'NegReg', (26, 33))	('metastatic melanomas', 'Disease', (93, 113))	('survival', 'MPA', (34, 42))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('patients', 'Species', '9606', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('primary melanomas', 'Disease', (212, 229))	('NRAS', 'Gene', (178, 182))
72132	25048604	In the present study, patients with BRAFV600E mutated melanomas appeared to experience shorter melanoma-specific survival when compared to melanoma wild-type at both loci (P=0.03).	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', (95, 103))	('patients', 'Species', '9606', (22, 30))	('melanoma', 'Disease', (54, 62))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('shorter', 'NegReg', (87, 94))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('BRAFV600E', 'Var', (36, 45))	('BRAFV600E', 'Mutation', 'rs113488022', (36, 45))	('melanomas', 'Disease', (54, 63))
72133	25048604	BRAF mutation has become a favored target for drug design since its discovery in cutaneous melanoma, and recent clinical studies have identified several drugs which may improve survival among melanoma patients with BRAF mutated tumors.	('BRAF', 'Gene', (215, 219))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('BRAF', 'Gene', '673', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('BRAF', 'Gene', (0, 4))	('mutated', 'Var', (220, 227))	('survival', 'MPA', (177, 185))	('tumors', 'Disease', (228, 234))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('patients', 'Species', '9606', (201, 209))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('improve', 'PosReg', (169, 176))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('cutaneous melanoma', 'Disease', (81, 99))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))	('mutation', 'Var', (5, 13))	('BRAF', 'Gene', '673', (215, 219))
72134	25048604	The unfavorable prognosis of patients with BRAF mutated melanomas suggests that drug development targeting the mutated BRAF locus would be necessary to improve the survival of melanoma patients among this subgroup.	('patients', 'Species', '9606', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('melanoma', 'Disease', (56, 64))	('mutated', 'Var', (111, 118))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', '673', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('BRAF', 'Gene', (43, 47))	('BRAF', 'Gene', (119, 123))	('melanomas', 'Disease', (56, 65))	('patients', 'Species', '9606', (185, 193))	('men', 'Species', '9606', (92, 95))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
72139	25048604	Finally, a few less common mutations (e.g., BRAFV600K) were not examined in the study, and we did not validate the results of pyrosequencing by other technologies and therefore may lead to potential mutation misclassification.	('BRAFV600K', 'Var', (44, 53))	('lead to', 'Reg', (181, 188))	('BRAFV600K', 'Mutation', 'rs121913227', (44, 53))
72140	25048604	However, previous studies have demonstrated that pyrosequencing is an efficient method for detecting point mutations in BRAF and NRAS with excellent concordance to PCR/single-stand conformation polymorphism analysis and conventional DNA sequencing of identical samples.	('DNA', 'cellular_component', 'GO:0005574', ('233', '236'))	('NRAS', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (120, 124))	('NRAS', 'Gene', '4893', (129, 133))	('BRAF', 'Gene', (120, 124))	('point mutations', 'Var', (101, 116))
72141	25048604	In conclusion, our data provide evidence that the risk of developing BRAFV600E mutation in primary cutaneous melanoma is associated with residence in locations with high UV index in mid life, patient with BRAFV600E mutated melanomas tended to have shorter survival time after diagnosis when compared to patients wild-type at both loci (BRAFV600E and NRASQ61R).	('patients', 'Species', '9606', (303, 311))	('patient', 'Species', '9606', (192, 199))	('BRAFV600E', 'Mutation', 'rs113488022', (69, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('survival time', 'CPA', (256, 269))	('melanomas', 'Phenotype', 'HP:0002861', (223, 232))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Disease', (223, 232))	('shorter', 'NegReg', (248, 255))	('BRAFV600E', 'Gene', (69, 78))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('cutaneous melanoma', 'Disease', (99, 117))	('BRAFV600E', 'Var', (205, 214))	('BRAFV600E', 'Mutation', 'rs113488022', (205, 214))	('patient', 'Species', '9606', (303, 310))	('BRAFV600E', 'Mutation', 'rs113488022', (336, 345))	('melanomas', 'Disease', 'MESH:D008545', (223, 232))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
72165	24228023	Moreover, T lymphocytes isolated from skin are in part IL-17+, confirming that there is a clear intercellular communication between immune T cells and non-immune keratinocyte cells and that any deregulation in the information circulation can trigger skin disease.	('skin disease', 'Disease', (250, 262))	('trigger', 'Reg', (242, 249))	('skin disease', 'Phenotype', 'HP:0000951', (250, 262))	('deregulation', 'Var', (194, 206))	('intercellular communication', 'MPA', (96, 123))	('IL-17', 'molecular_function', 'GO:0030367', ('55', '60'))	('skin disease', 'Disease', 'MESH:D012871', (250, 262))
72210	24228023	The authors found that in vitro MO-MDSCs expressing high levels of CCR5 attracted increased numbers of Tregs, maintaining immune-suppressions.	('CCR', 'molecular_function', 'GO:0043880', ('67', '70'))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('high levels', 'Var', (52, 63))	('Tregs', 'CPA', (103, 108))	('Treg', 'Chemical', '-', (103, 107))	('CCR5', 'Gene', '1234', (67, 71))	('increased', 'PosReg', (82, 91))	('immune-suppressions', 'MPA', (122, 141))	('CCR5', 'Gene', (67, 71))
72217	24228023	The authors point out that CD28 in FOXP3+ Tregs induces complete functioning and moreover, the established role of CD28 can be exploited in skin tumorigenesis.	('CD28', 'Var', (27, 31))	('skin tumor', 'Phenotype', 'HP:0008069', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('induces', 'PosReg', (48, 55))	('skin tumor', 'Disease', (140, 150))	('Treg', 'Chemical', '-', (42, 46))	('skin tumor', 'Disease', 'MESH:D012878', (140, 150))	('complete functioning', 'MPA', (56, 76))	('Th', 'Chemical', 'MESH:D013910', (0, 2))
72233	24228023	Production of cytokines with pro-tumor inflammatory function molecules was decreased in mice with IL-17R-/- genotype.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('IL-17R-/- genotype', 'Var', (98, 116))	('IL-17R', 'molecular_function', 'GO:0030368', ('98', '104'))	('tumor', 'Disease', (33, 38))	('mice', 'Species', '10090', (88, 92))	('decreased', 'NegReg', (75, 84))
72259	24228023	Most peritumoral inflammatory cells have an activated phenotype, HLA-DR+, CD25+, CD45RO + and so on.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('CD25', 'Gene', '3559', (74, 78))	('tumor', 'Disease', (9, 14))	('CD45RO +', 'Var', (81, 89))	('CD25', 'Gene', (74, 78))
72276	24228023	Using imiquimod, the effector response via CD3+/CD4+ T lymphocytes is increased, along with a slight increase in NK cells and Tc CD3+/CD8+.	('effector response', 'CPA', (21, 38))	('CD3+/CD4+ T', 'Var', (43, 54))	('increased', 'PosReg', (70, 79))	('CD8', 'Gene', (134, 137))	('NK cells', 'CPA', (113, 121))	('CD8', 'Gene', '925', (134, 137))	('increase', 'PosReg', (101, 109))	('Tc', 'Chemical', 'MESH:D013667', (126, 128))
72284	24228023	Shedding ICAM-1 in the environment can trap T lymphocytes and hinder an eventual tumor cell-T interaction (adapted from).	('ICAM-1', 'Gene', '3383', (9, 15))	('hinder', 'NegReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ICAM-1', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Shedding', 'Var', (0, 8))	('tumor', 'Disease', (81, 86))
72302	24228023	This irradiation generates mutations in p53 gene (thymidine dimmers) which result in the uncontrolled proliferation of keratinocytes.	('mutations', 'Var', (27, 36))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('p53', 'Gene', (40, 43))	('result in', 'Reg', (75, 84))	('thymidine', 'Chemical', 'MESH:D013936', (50, 59))	('p53', 'Gene', '7157', (40, 43))	('uncontrolled proliferation', 'CPA', (89, 115))
72310	24228023	CD4+ T lymphocytes infiltrate SCC tumors and could play a role in tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (66, 71))	('CD4+', 'Var', (0, 4))	('SCC tumors', 'Disease', 'MESH:D009369', (30, 40))	('play', 'Reg', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('SCC tumors', 'Disease', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
72327	24228023	The Th1 cytokine pattern is predominant and tumor infiltrate comprise both CD8+ T cells (anti-tumor effectors) and CD4+ T cells (pro-tumor cells).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Th1', 'Gene', (4, 7))	('CD8', 'Gene', '925', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Th', 'Chemical', 'MESH:D013910', (4, 6))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CD4+ T', 'Var', (115, 121))	('tumor', 'Disease', (133, 138))	('Th1', 'Gene', '51497', (4, 7))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('CD8', 'Gene', (75, 78))	('tumor', 'Disease', (44, 49))
72342	24228023	The disturbances in cytokines balance exhaust the T cell benefic populations by releasing their TCR repertoire or by a sustained inhibition mediated by CTLA4.	('TCR', 'cellular_component', 'GO:0042101', ('96', '99'))	('TCR', 'biological_process', 'GO:0006283', ('96', '99'))	('TCR', 'Gene', '6962', (96, 99))	('CTLA4', 'Gene', '1493', (152, 157))	('releasing', 'PosReg', (80, 89))	('disturbances', 'Var', (4, 16))	('CTLA4', 'Gene', (152, 157))	('inhibition', 'NegReg', (129, 139))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('TCR', 'Gene', (96, 99))
72348	24228023	In fact, the MF variant is a malignancy of resident effector memory T cells, while the SS variant is a central memory T lymphocytes malignancy.	('variant', 'Var', (16, 23))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('malignancy', 'Disease', 'MESH:D009369', (29, 39))	('central memory T', 'Disease', (103, 119))	('central memory T', 'Disease', 'MESH:D008569', (103, 119))	('memory', 'biological_process', 'GO:0007613', ('61', '67'))	('malignancy', 'Disease', (29, 39))	('memory', 'biological_process', 'GO:0007613', ('111', '117'))	('malignancy', 'Disease', (132, 142))
72389	24228023	This effect can be the result of the immune distortion and immune-induced alterations that can contribute to cancer pathogenesis.	('contribute', 'Reg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('immune distortion', 'Var', (37, 54))	('pathogenesis', 'biological_process', 'GO:0009405', ('116', '128'))	('cancer', 'Disease', (109, 115))	('alterations', 'Var', (74, 85))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
72405	24228023	Blocking of the Stat3 signaling pathway in melanoma cell can lead to an increased expression of multiple chemo-attractants, the main effect of which is the increase of migration of lymphocytes, NK cells, neutrophils and macrophages to tumor sites.	('migration', 'CPA', (168, 177))	('increased', 'PosReg', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('expression', 'MPA', (82, 92))	('Blocking', 'Var', (0, 8))	('Stat3 signaling pathway', 'Pathway', (16, 39))	('increase', 'PosReg', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('signaling pathway', 'biological_process', 'GO:0007165', ('22', '39'))	('melanoma', 'Disease', (43, 51))	('tumor', 'Disease', (235, 240))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))
72425	24228023	Moreover, an imbalance in cathepsins - cystatins can be involved in hindering immune cell effector functions and facilitating tumor cell invasion.	('hindering', 'NegReg', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('imbalance', 'Var', (13, 22))	('cathepsins - cystatins', 'Protein', (26, 48))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('immune cell effector functions', 'CPA', (78, 108))	('imbalance', 'Phenotype', 'HP:0002172', (13, 22))	('tumor', 'Disease', (126, 131))
72450	24228023	In a recent melanoma mouse model, total ablation of CD4 was more successful than deleting Tregs in the generation of anti-tumoral memory CD8 T cells.	('tumoral memory', 'Disease', 'MESH:D008569', (122, 136))	('ablation', 'Var', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('mouse', 'Species', '10090', (21, 26))	('CD4', 'Gene', (52, 55))	('CD8', 'Gene', (137, 140))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('CD8', 'Gene', '925', (137, 140))	('tumoral memory', 'Disease', (122, 136))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Treg', 'Chemical', '-', (90, 94))	('memory', 'biological_process', 'GO:0007613', ('130', '136'))
72456	24228023	In TILs, FOXP3+ CD4+ T began to express PD-1+ and accounted for more than half of T CD4+ cells.	('PD-1', 'Gene', '5133', (40, 44))	('TIL', 'Gene', '21897', (3, 6))	('FOXP3+', 'Var', (9, 15))	('TIL', 'Gene', (3, 6))	('PD-1', 'Gene', (40, 44))
72472	24228023	Mice with a mutation in the p19(ARF) gene (a type that is sen-sitive to skin carcinogenesis) and control mice were used for detecting differences in their plasma proteome that can indicate tumorigenesis.	('p19', 'Gene', '83430', (28, 31))	('tumor', 'Disease', (189, 194))	('indicate', 'Reg', (180, 188))	('p19', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('ARF', 'Disease', (32, 35))	('skin carcinogenesis', 'Disease', (72, 91))	('p19', 'cellular_component', 'GO:0070743', ('28', '31'))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('Mice', 'Species', '10090', (0, 4))	('mutation', 'Var', (12, 20))	('mice', 'Species', '10090', (105, 109))	('ARF', 'Disease', 'MESH:D058186', (32, 35))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (72, 91))
72488	24228023	Increased topoisomerase IIalpha and reduced p21waf1 and p27kip1 in BCC were found differently expressed in comparison to SCC.	('BCC', 'Phenotype', 'HP:0002671', (67, 70))	('topoisomerase', 'molecular_function', 'GO:0003917', ('10', '23'))	('topoisomerase', 'molecular_function', 'GO:0003918', ('10', '23'))	('topoisomerase IIalpha', 'Enzyme', (10, 31))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('p27kip1', 'Gene', '1027', (56, 63))	('Increased', 'PosReg', (0, 9))	('reduced', 'NegReg', (36, 43))	('SCC', 'Gene', '6317', (121, 124))	('p21waf1', 'Var', (44, 51))	('p27kip1', 'Gene', (56, 63))
72574	30637789	A closer examination of this article reveals that it is on nevus-associated loci and melanoma and suggests that gene IRF4 is more likely to be associated with melanoma with a younger age.	('melanoma', 'Disease', (159, 167))	('associated', 'Reg', (143, 153))	('IRF4', 'Gene', '3662', (117, 121))	('IRF4', 'Gene', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('nevus', 'Phenotype', 'HP:0003764', (59, 64))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('gene', 'Var', (112, 116))
72595	30637789	SF3B1 mutations at codon 625 occur in cutaneous melanoma although with a low frequency.	('SF3B1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('SF3B1', 'Gene', '23451', (0, 5))	('occur', 'Reg', (29, 34))	('cutaneous melanoma', 'Disease', (38, 56))	('mutations', 'Var', (6, 15))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
72599	30637789	CASP9 has a critical cancer-related function and may be related to the epigenetic deregulation of the mitochondria-independent apoptosis in recurrent GBM.	('recurrent GBM', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('epigenetic deregulation', 'Var', (71, 94))	('CASP9', 'Gene', '842', (0, 5))	('mitochondria', 'cellular_component', 'GO:0005739', ('102', '114'))	('mitochondria-independent apoptosis', 'MPA', (102, 136))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('CASP9', 'Gene', (0, 5))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('related', 'Reg', (56, 63))
72601	30637789	CUZD1 is mapped at chromosome 10q26.13, and the loss of 10q is common in the development and progression of GBM, which suggests a potential association between CUZD1 and GBM.	('loss of', 'Var', (48, 55))	('CUZD1', 'Gene', (0, 5))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('CUZD1', 'Gene', '50624', (0, 5))	('CUZD1', 'Gene', '50624', (160, 165))	('CUZD1', 'Gene', (160, 165))
72602	30637789	A decreasing expression of ABCC1 is associated with the mechanism by which FK506 sensitizes GBM cells.	('FK506', 'Var', (75, 80))	('decreasing', 'NegReg', (2, 12))	('expression', 'MPA', (13, 23))	('FK506', 'Chemical', 'MESH:D016559', (75, 80))	('sensitizes', 'Reg', (81, 91))	('ABCC1', 'Gene', (27, 32))	('ABCC1', 'Gene', '4363', (27, 32))	('GBM cells', 'CPA', (92, 101))
72613	28794454	While tumor ECM is continuously submitted to intense remodeling, dysregulation of its integrity crucially contributes to the severity of disease progression.	('contributes', 'Reg', (106, 117))	('dysregulation', 'Var', (65, 78))	('integrity', 'MPA', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
72626	28794454	Breast cancer constitutes a blatant example for which alterations in ECM architecture have long-term been known as a prominent risk factor, with both low lumican expression and more aligned collagen fibers correlating with poor outcome in this pathology.	('more', 'PosReg', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('low', 'NegReg', (150, 153))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('lumican', 'Protein', (154, 161))	('collagen', 'molecular_function', 'GO:0005202', ('190', '198'))	('alterations', 'Var', (54, 65))	('Breast cancer', 'Disease', (0, 13))
72634	28794454	In both allograft and xenograft melanoma models, TAX2 peptide impacts tumor growth while sharply altering tumor-associated vascularization and decreasing intratumoral blood flow.	('xenograft melanoma', 'Disease', (22, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (70, 75))	('TAX2', 'Gene', (49, 53))	('TAX2', 'Chemical', '-', (49, 53))	('altering', 'Reg', (97, 105))	('decreasing', 'NegReg', (143, 153))	('tumor', 'Disease', (159, 164))	('xenograft melanoma', 'Disease', 'MESH:D008545', (22, 40))	('impacts', 'Reg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('peptide', 'Var', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (106, 111))
72635	28794454	In addition, TAX2 treatment also dramatically inhibits lung metastases dissemination and growth following invasive B16F10 melanoma cells tail vein inoculation.	('TAX2', 'Chemical', '-', (13, 17))	('lung metastases dissemination', 'Disease', 'MESH:D009362', (55, 84))	('B16F10', 'CellLine', 'CVCL:0159', (115, 121))	('lung metastases dissemination', 'Disease', (55, 84))	('inhibits', 'NegReg', (46, 54))	('treatment', 'Var', (18, 27))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('growth', 'CPA', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('TAX2', 'Gene', (13, 17))
72638	28794454	Data obtained further indicate that such lumican-related structural changes are likely to sharply modulate tumor stromal reaction as well as response to matrix-targeting therapeutic strategies, as demonstrated considering TAX2 peptide treatment.	('TAX2', 'Chemical', '-', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('changes', 'Var', (68, 75))	('modulate', 'Reg', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
72645	28794454	Interestingly, alterations in LUM gene sequence are found in about 5% of clinical samples in TCGA dataset as well as across 3 independent studies (Fig.	('clinical samples', 'Species', '191496', (73, 89))	('LUM gene', 'Gene', (30, 38))	('alterations', 'Var', (15, 26))
72648	28794454	A decrease in both overall and disease-free survival of TCGA patients is observed when mutations in LUM gene sequence are reported (Fig.	('LUM gene', 'Gene', (100, 108))	('decrease', 'NegReg', (2, 10))	('patients', 'Species', '9606', (61, 69))	('TCGA', 'Disease', (56, 60))	('mutations', 'Var', (87, 96))
72649	28794454	Altogether, this first round of data arising from multiple databases analyses undoubtedly establishes a relationship between altered lumican expression and poor clinical outcome in human melanoma.	('human', 'Species', '9606', (181, 186))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('lumican', 'Protein', (133, 140))	('altered', 'Var', (125, 132))	('expression', 'MPA', (141, 151))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('clinical', 'Species', '191496', (161, 169))
72660	28794454	Interestingly, TAX2 peptide induces a 40% reduction in tumor burden from lumican-deficient mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('peptide', 'Var', (20, 27))	('tumor', 'Disease', (55, 60))	('TAX2', 'Gene', (15, 19))	('TAX2', 'Chemical', '-', (15, 19))	('reduction', 'NegReg', (42, 51))
72670	28794454	Indeed, TAX2-mediated TSP-1:CD47 antagonization led to a two-fold increase in CD3+ T cell infiltration in treated tumors from both WT and Lum -/- mice (Fig.	('increase', 'PosReg', (66, 74))	('antagonization', 'Var', (33, 47))	('CD3', 'Gene', '12501', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CD47', 'Gene', '16423', (28, 32))	('Lum', 'Gene', '17022', (138, 141))	('CD47', 'Gene', (28, 32))	('mice', 'Species', '10090', (146, 150))	('tumors', 'Disease', (114, 120))	('Lum', 'Gene', (138, 141))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('TAX2', 'Chemical', '-', (8, 12))	('TSP-1', 'Gene', '21825', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TSP-1', 'Gene', (22, 27))	('CD3', 'Gene', (78, 81))	('TSP-1', 'molecular_function', 'GO:0004277', ('22', '27'))
72671	28794454	Interestingly, we also noticed a 75% decrease in basal levels of tumor-infiltrating T cells under lumican deficiency.	('decrease', 'NegReg', (37, 45))	('tumor', 'Disease', (65, 70))	('lumican', 'Protein', (98, 105))	('deficiency', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
72701	28794454	A comprehensive and large-scale mining of public microarray databases was first performed in this study, thus unambiguously demonstrating a correlation between altered lumican expression and poor outcome in human melanoma.	('expression', 'MPA', (176, 186))	('lumican', 'Protein', (168, 175))	('altered', 'Var', (160, 167))	('human', 'Species', '9606', (207, 212))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))
72707	28794454	A thorough screening of multiple melanoma clinical datasets further highlighted that both alterations in LUM gene sequence as well as lower mRNA expression are associated with decreased patient survival (Fig.	('alterations', 'Var', (90, 101))	('lower', 'NegReg', (134, 139))	('clinical', 'Species', '191496', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('mRNA expression', 'MPA', (140, 155))	('LUM gene', 'Gene', (105, 113))	('decreased', 'NegReg', (176, 185))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('patient survival', 'CPA', (186, 202))	('patient', 'Species', '9606', (186, 193))
72717	28794454	Our data clearly indicate that lumican deficiency is associated with fast-growing melanoma allografts (Fig.	('deficiency', 'Var', (39, 49))	('melanoma allografts', 'Disease', (82, 101))	('melanoma allografts', 'Disease', 'MESH:D008545', (82, 101))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('associated', 'Reg', (53, 63))	('fast-growing', 'CPA', (69, 81))	('lumican', 'Protein', (31, 38))
72733	28794454	ECM re-organization and modifications in collagen structure, especially at tumor invasion front, are now well recognized to promote metastatic dissemination along aligned fibers.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('collagen', 'molecular_function', 'GO:0005202', ('41', '49'))	('metastatic dissemination along aligned fibers', 'CPA', (132, 177))	('promote', 'PosReg', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('modifications', 'Var', (24, 37))	('tumor', 'Disease', (75, 80))
72737	28794454	As way of example, collagen linearization has been shown to promote redistribution of beta1-integrin away from the plasma membrane of mammary tumor cells, which is consistent with the above-mentioned acquisition of an invasive phenotype in 3D models.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('collagen', 'molecular_function', 'GO:0005202', ('19', '27'))	('plasma membrane', 'cellular_component', 'GO:0005886', ('115', '130'))	('beta1-integrin', 'Protein', (86, 100))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('redistribution', 'MPA', (68, 82))	('collagen linearization', 'Var', (19, 41))
72738	28794454	In view of these results, it cannot be ruled out that modifications in collagen network architecture may affect subcellular distribution of a wider range of cell receptors, hence sharply modifying communications that establish at the cell/matrix interface as well as tumor response to ECM-targeted strategies.	('collagen', 'molecular_function', 'GO:0005202', ('71', '79'))	('cell receptors', 'Protein', (157, 171))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('communications', 'MPA', (197, 211))	('modifying', 'Reg', (187, 196))	('modifications', 'Var', (54, 67))	('affect', 'Reg', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('collagen network', 'cellular_component', 'GO:0098645', ('71', '87'))	('subcellular distribution', 'MPA', (112, 136))	('tumor', 'Disease', (267, 272))
72739	28794454	As well, disorganization of tumor collagen network may also affect soluble factors and matricellular proteins intratumoral distribution.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('soluble', 'cellular_component', 'GO:0005625', ('67', '74'))	('disorganization', 'Var', (9, 24))	('tumor', 'Disease', (115, 120))	('collagen', 'molecular_function', 'GO:0005202', ('34', '42'))	('soluble factors', 'Protein', (67, 82))	('affect', 'Reg', (60, 66))	('matricellular proteins', 'Protein', (87, 109))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('collagen network', 'cellular_component', 'GO:0098645', ('34', '50'))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
72751	28794454	Disruption of TSP-1:CD47 interaction under TAX2 treatment indeed promotes accumulation of infiltrating CD3+ T cells within melanoma tumors implanted in WT mice (Fig.	('CD47', 'Gene', '16423', (20, 24))	('TSP-1', 'molecular_function', 'GO:0004277', ('14', '19'))	('melanoma tumors', 'Disease', 'MESH:D008545', (123, 138))	('CD47', 'Gene', (20, 24))	('interaction', 'Interaction', (25, 36))	('TSP-1', 'Gene', (14, 19))	('TSP-1', 'Gene', '21825', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('CD3', 'Gene', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma tumors', 'Disease', (123, 138))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mice', 'Species', '10090', (155, 159))	('TAX2', 'Chemical', '-', (43, 47))	('CD3', 'Gene', '12501', (103, 106))	('accumulation', 'PosReg', (74, 86))	('Disruption', 'Var', (0, 10))
72761	28794454	Therefore, ongoing studies are now aimed at further deciphering the pathway involved, as well as to investigate a putative role for lumican in fostering tumor response to immunotherapeutic approaches such as immune checkpoint inhibitors anti-PD-1 and anti-CTLA-4.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('fostering', 'PosReg', (143, 152))	('CTLA-4', 'Gene', '12477', (256, 262))	('anti-PD-1', 'Var', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('CTLA-4', 'Gene', (256, 262))
72772	28794454	Lum -/- mouse line was generated by targeted mutation and fixed to the C57BL/6J genetic background (B6.129S-Lum tm1Chak/J).	('Lum', 'Gene', '17022', (0, 3))	('Lum', 'Gene', '17022', (108, 111))	('Lum', 'Gene', (0, 3))	('mutation', 'Var', (45, 53))	('Chak', 'Gene', '58800', (115, 119))	('Chak', 'Gene', (115, 119))	('Lum', 'Gene', (108, 111))	('mouse', 'Species', '10090', (8, 13))
72811	28794454	Gabor filtering was performed using omega direction values of 45  + 225 , 90 + 270 , 135 + 315  and 0  + 180  so as to detect and highlight collagen fiber edges.	('0  + 180', 'Var', (100, 108))	('135 + 315', 'Var', (85, 94))	('90 + 270', 'Var', (74, 82))	('Gabor', 'Chemical', '-', (0, 5))	('collagen', 'molecular_function', 'GO:0005202', ('140', '148'))
72834	22096570	Defects in primary cilium assembly and function are associated with profound developmental disorders including Bardet Biedl Syndrome, Alstrom Syndrome, and polycystic kidney disease.	('developmental disorders', 'Disease', 'MESH:D002658', (77, 100))	('Bardet Biedl Syndrome', 'Disease', (111, 132))	('primary cilium', 'Protein', (11, 25))	('kidney disease', 'Phenotype', 'HP:0000112', (167, 181))	('Bardet Biedl Syndrome', 'Disease', 'MESH:D020788', (111, 132))	('primary cilium', 'cellular_component', 'GO:0005929', ('11', '25'))	('Defects', 'Var', (0, 7))	('associated', 'Reg', (52, 62))	('primary cilium', 'cellular_component', 'GO:0097731', ('11', '25'))	('cilium assembly', 'biological_process', 'GO:0060271', ('19', '34'))	('polycystic kidney disease', 'Disease', (156, 181))	('developmental disorders', 'Disease', (77, 100))	('Alstrom Syndrome', 'Disease', 'MESH:D056769', (134, 150))	('polycystic kidney', 'Phenotype', 'HP:0000113', (156, 173))	('Alstrom Syndrome', 'Disease', (134, 150))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (156, 181))	('function', 'MPA', (39, 47))
72840	22096570	Interestingly however, pancreatic ductal adenocarcinoma and cutaneous melanoma have similar genetics, both exhibiting increased incidence in kindreds bearing heritable p16Ink4a and other mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('pancreatic ductal adenocarcinoma', 'Disease', (23, 55))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (23, 55))	('mutations', 'Var', (187, 196))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (23, 55))	('p16Ink4a', 'Gene', '1029', (168, 176))	('cutaneous melanoma', 'Disease', (60, 78))	('p16Ink4a', 'Gene', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (60, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (60, 78))
72841	22096570	Moreover, melanoma and pancreatic ductal adenocarcinoma are frequently driven by activating mutations in components of the Ras signaling pathway and we have shown that excessive Ras signaling can actively suppress cilium assembly in pancreatic ductal adenocarcinoma cells.	('pancreatic ductal adenocarcinoma', 'Disease', (233, 265))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (23, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('cilium', 'cellular_component', 'GO:0005929', ('214', '220'))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (233, 265))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('suppress', 'NegReg', (205, 213))	('mutations', 'Var', (92, 101))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (23, 55))	('cilium assembly', 'MPA', (214, 229))	('signaling', 'biological_process', 'GO:0023052', ('182', '191'))	('Ras signaling', 'MPA', (178, 191))	('cilium assembly', 'biological_process', 'GO:0060271', ('214', '229'))	('pancreatic ductal adenocarcinoma', 'Disease', (23, 55))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (233, 265))	('signaling pathway', 'biological_process', 'GO:0007165', ('127', '144'))	('melanoma', 'Disease', (10, 18))
72878	22096570	While biallelic deletion of genes required for the assembly and function of primary cilia dysregulates pathways important in cancer development and can modify the tumorigenic potency of hedgehog pathway mutations, the relationship between the primary cilium and the development of cancers not bearing hedgehog mutations is unclear.	('modify', 'Reg', (152, 158))	('pathways', 'Pathway', (103, 111))	('tumor', 'Disease', (163, 168))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancers', 'Disease', (281, 288))	('primary cilium', 'cellular_component', 'GO:0005929', ('243', '257'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('hedgehog pathway', 'Pathway', (186, 202))	('primary cilium', 'cellular_component', 'GO:0097731', ('243', '257'))	('cancer', 'Disease', (125, 131))	('biallelic deletion', 'Var', (6, 24))	('dysregulates', 'Reg', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('mutations', 'Var', (203, 212))	('cancer', 'Disease', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
72880	22096570	While pancreatic carcinoma and cutaneous melanoma are of highly divergent embryologic origin, both are most frequently associated with mutations inducing constitutive Ras pathway activation and both are associated with frequent loss of function mutations or epigenetic silencing of the p16 tumor suppressor.	('inducing', 'Reg', (145, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('tumor', 'Disease', (290, 295))	('cutaneous melanoma', 'Disease', (31, 49))	('mutations', 'Var', (245, 254))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('mutations', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('290', '306'))	('constitutive Ras pathway', 'Pathway', (154, 178))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (6, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('290', '306'))	('epigenetic silencing', 'Var', (258, 278))	('p16', 'Gene', (286, 289))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('pancreatic carcinoma', 'Disease', (6, 26))	('p16', 'Gene', '1029', (286, 289))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('activation', 'PosReg', (179, 189))	('loss of function', 'NegReg', (228, 244))
72886	22096570	Immunostaining was performed as described, with acetylated tubulin (Sigma), detyrosinated tubulin (Covance), gamma tubulin (Sigma), CP100 (gift from B.Dynlacht), Sox 10 (Santa Cruz Biotechnology), and Ki67 (AbCam) antibodies used at 1:2000, 1:500, 1:200, 1:200, 1:200, and 1:200, respectively.	('CP100', 'Var', (132, 137))	('Sox 10', 'Gene', (162, 168))	('gamma tubulin', 'Protein', (109, 122))	('Sox 10', 'Gene', '6663', (162, 168))	('Ki67', 'Chemical', '-', (201, 205))
72930	20944647	That study also reported a high prevalence of germline CDKN2A mutations among patients with multiple primary melanomas.	('CDKN2A', 'Gene', '1029', (55, 61))	('primary melanomas', 'Disease', (101, 118))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('patients', 'Species', '9606', (78, 86))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('primary melanomas', 'Disease', 'MESH:D008545', (101, 118))	('CDKN2A', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))
72932	20944647	That study also reported similar findings to ours; in particular, that patients with high nevus counts were almost 3-fold more likely than those with low nevus counts to develop multiple primaries.	('nevus', 'Phenotype', 'HP:0003764', (90, 95))	('patients', 'Species', '9606', (71, 79))	('high', 'Var', (85, 89))	('nevus', 'Phenotype', 'HP:0003764', (154, 159))	('develop', 'PosReg', (170, 177))
72934	20944647	Similar to the Scottish group, the GEM investigators found a strong and statistically significant 4-fold increased relative risk of multiple primary melanoma associated with the mutations in CDKN2A..	('CDKN2A', 'Gene', (191, 197))	('primary melanoma', 'Disease', (141, 157))	('associated', 'Reg', (158, 168))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('CDKN2A', 'Gene', '1029', (191, 197))	('mutations', 'Var', (178, 187))	('primary melanoma', 'Disease', 'MESH:D008545', (141, 157))
72943	20944647	Supplementary analyses showed significant differences in age and tumor characteristics between those QFMP participants who were followed up with those who were not, and thus the cumulative risk of developing a second melanoma in this cohort was higher (13% at 10 years) than has been reported previously in the Queensland population (6.4%).	('higher', 'PosReg', (245, 251))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('tumor', 'Disease', (65, 70))	('QFMP', 'Var', (101, 105))	('participants', 'Species', '9606', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('differences', 'Reg', (42, 53))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('melanoma', 'Disease', (217, 225))
72961	20944647	Skin color, self- assessed on unexposed sites such as the inner upper arm, was recorded in two categories (dark/medium, fair), eye color in three categories (blue/gray, green/hazel, brown), and early adult hair color in six categories (fair/blonde, light brown, light red/ginger, dark red/auburn, dark brown, black).	('adult hair color', 'Disease', (200, 216))	('light red/ginger', 'Var', (262, 278))	('adult hair color', 'Phenotype', 'HP:0002286', (200, 216))	('adult hair color', 'Disease', 'MESH:D003117', (200, 216))	('dark', 'Disease', (280, 284))	('red/ginger', 'Species', '230707', (268, 278))
73008	26462471	Categories were made for SLN tumor burden as follows: <0.1 (sub-micrometastases), 0.1-1.0, and >1.0 mm.	('metastases', 'Disease', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('SLN tumor', 'Disease', 'MESH:D009369', (25, 34))	('SLN tumor', 'Disease', (25, 34))	('0.1-1.0', 'Var', (82, 89))
73023	26462471	Moreover, in pT1 tumors (Breslow thickness <=1.00 mm) with known mitotic index (n = 139), we have not found any metastases to SLNs in cases with MI < 1/mm2 (0/40); for 46 tumors with MI = 1/mm2, we detected four SLNs+ (8.7 %); and for 53 tumors with MI > 1/mm2, we found metastases in three SLNs (6 %) (Fig.	('pT1', 'Gene', (13, 16))	('mm2', 'Gene', '10687', (257, 260))	('tumors', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumors', 'Disease', (238, 244))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('metastases', 'Disease', 'MESH:D009362', (271, 281))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mm2', 'Gene', '10687', (152, 155))	('mm2', 'Gene', (257, 260))	('metastases', 'Disease', (112, 122))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('metastases', 'Disease', (271, 281))	('tumors', 'Disease', (171, 177))	('MI <', 'Var', (145, 149))	('mm2', 'Gene', '10687', (190, 193))	('mm2', 'Gene', (152, 155))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('pT1', 'Gene', '58492', (13, 16))	('mm2', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
73036	26462471	However, we have also demonstrated the independent negative value of high mitotic index of the primary tumor in this group of patients (which correlates with the tumor Breslow thickness).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumor', 'Disease', 'MESH:D009369', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (162, 167))	('negative', 'NegReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('patients', 'Species', '9606', (126, 134))	('high', 'Var', (69, 73))	('primary tumor', 'Disease', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
73043	26462471	Our results indicate also the heterogeneity of patients undergoing CLND due to positive SLN, which is strictly related to tumor load.	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('positive', 'Var', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('CLND', 'Disease', (67, 71))	('tumor', 'Disease', (122, 127))	('SLN', 'Gene', (88, 91))
73050	26462471	According to our analysis, the positivity of NSLN is related to a 50 % higher chance of death after 8 years as compared to patients with metastases limited to SLN only.	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('death', 'Disease', (88, 93))	('NSLN', 'Disease', (45, 49))	('patients', 'Species', '9606', (123, 131))	('positivity', 'Var', (31, 41))	('metastases', 'Disease', (137, 147))	('death', 'Disease', 'MESH:D003643', (88, 93))
73091	26141681	Anatomical site was coded using the International Classification of Diseases (ICD) 10 (four digit) as follows: C430 (lip), C431 (eyelid), C432 (ear), C433 (other and unspecified parts of face), and C434 (scalp and neck) were located on 'Head and Neck'; C435 corresponded to 'Trunk'; C436 to 'Upper Limb'; C437 to 'Lower Limb'; C438 (other specified sites of skin) and C439 (site unspecified) to 'Other' sites.	('C431', 'CellLine', 'CVCL:0037', (123, 127))	('scalp', 'Disease', 'MESH:C538225', (204, 209))	('scalp', 'Disease', (204, 209))	('C431', 'Var', (123, 127))	('C433', 'Var', (150, 154))	('Trunk', 'cellular_component', 'GO:0043198', ('275', '280'))	('C434', 'Var', (198, 202))	('unspecified', 'Species', '32644', (379, 390))	('ICD', 'Disease', 'OMIM:252500', (78, 81))	('parts of face', 'Phenotype', 'HP:0005323', (178, 191))	('C430', 'Var', (111, 115))	('ICD', 'Disease', (78, 81))	('unspecified', 'Species', '32644', (166, 177))	('C432', 'Var', (138, 142))	('neck', 'cellular_component', 'GO:0044326', ('214', '218'))
73155	32716505	Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants.	('mutations', 'Var', (70, 79))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
73156	32716505	Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown.	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cutaneous melanoma', 'Disease', (84, 102))	('mutations', 'Var', (22, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))
73159	32716505	Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes.	('CDKN2A', 'Gene', '1029', (121, 127))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('p.G101W', 'Mutation', 'rs104894094', (128, 135))	('p.G101W', 'Var', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('CDKN2A', 'Gene', (121, 127))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))
73160	32716505	This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.	('mutations', 'Var', (190, 199))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('arise from', 'Reg', (97, 107))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
73164	32716505	Within melanoma-dense families, high-penetrance segregating mutations have been found in CDKN2A, CDK4, BAP1, MITF, TERT, POT1, ACD, and TERF2IP.	('POT1', 'Gene', (121, 125))	('BAP1', 'Gene', '8314', (103, 107))	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('ACD', 'Gene', (127, 130))	('CDK', 'molecular_function', 'GO:0004693', ('97', '100'))	('MITF', 'Gene', '4286', (109, 113))	('BAP1', 'Gene', (103, 107))	('CDKN2A', 'Gene', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('TERT', 'Gene', (115, 119))	('TERT', 'Gene', '7015', (115, 119))	('CDK4', 'Gene', (97, 101))	('MITF', 'Gene', (109, 113))	('ACD', 'Gene', '65057', (127, 130))	('CDKN2A', 'Gene', '1029', (89, 95))	('POT1', 'Gene', '25913', (121, 125))	('CDK4', 'Gene', '1019', (97, 101))	('TERF2IP', 'Gene', (136, 143))	('mutations', 'Var', (60, 69))	('TERF2IP', 'Gene', '54386', (136, 143))
73165	32716505	However, these rare high-penetrance mutations underpin melanoma development in only approximately 50% of densely affected families.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('underpin', 'Reg', (46, 54))	('mutations', 'Var', (36, 45))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
73168	32716505	In addition to rare high-penetrance mutations, genome-wide association studies (GWASs) have identified many loci harboring common genetic variants with a low to moderate impact on melanoma risk.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('variants', 'Var', (138, 146))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))
73174	32716505	For example, if the familial clustering is due solely to an unidentified high-penetrance variant, the PRS would be expected to be lower than in sporadic cases and more similar to the melanoma-free population.	('lower', 'NegReg', (130, 135))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma-free', 'Disease', 'MESH:D008569', (183, 196))	('PRS', 'Chemical', '-', (102, 105))	('variant', 'Var', (89, 96))	('PRS', 'MPA', (102, 105))	('melanoma-free', 'Disease', (183, 196))
73175	32716505	In contrast, if the clustering is due to the low penetrance variants in the PRS, the PRS would be expected to be higher than in the sporadic cases.	('PRS', 'Gene', (76, 79))	('PRS', 'Chemical', '-', (85, 88))	('low', 'NegReg', (45, 48))	('variants', 'Var', (60, 68))	('PRS', 'Chemical', '-', (76, 79))
73176	32716505	Finally, it is possible that having a high polygenic load may increase the penetrance from a melanoma risk mutation.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('high polygenic load', 'Var', (38, 57))	('mutation', 'Var', (107, 115))	('penetrance', 'MPA', (75, 85))	('increase', 'PosReg', (62, 70))
73178	32716505	That is, family members had a higher polygenic risk for bipolar disorders than healthy controls, suggesting that it may, in part, explain their familial aggregation.	('bipolar disorders', 'Disease', 'MESH:D001714', (56, 73))	('bipolar disorders', 'Disease', (56, 73))	('polygenic', 'Var', (37, 46))	('bipolar disorders', 'Phenotype', 'HP:0007302', (56, 73))	('bipolar disorder', 'Phenotype', 'HP:0007302', (56, 72))
73179	32716505	A recent study reported significantly lower melanoma PRS scores in families carrying high-penetrance mutations compared to those families without such a mutation.	('high-penetrance mutations', 'Var', (85, 110))	('melanoma PRS', 'Disease', 'MESH:C535274', (44, 56))	('lower', 'NegReg', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma PRS', 'Disease', (44, 56))
73190	32716505	In one family for whom three individuals with melanoma were available for sequencing, we identified a pathogenic founder CDKN2A variant, p.G101W.	('CDKN2A', 'Gene', '1029', (121, 127))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('p.G101W', 'Var', (137, 144))	('melanoma', 'Disease', (46, 54))	('p.G101W', 'Mutation', 'rs104894094', (137, 144))	('CDKN2A', 'Gene', (121, 127))
73191	32716505	This variant, first described in 1994, is one of the most frequently reported deleterious founder missense variants reported in CDKN2A and results in impaired binding of p16 to CDK4.	('CDKN2A', 'Gene', '1029', (128, 134))	('missense variants', 'Var', (98, 115))	('CDK4', 'Gene', (177, 181))	('binding', 'Interaction', (159, 166))	('CDK4', 'Gene', '1019', (177, 181))	('p16', 'Gene', '1029', (170, 173))	('binding', 'molecular_function', 'GO:0005488', ('159', '166'))	('CDK', 'molecular_function', 'GO:0004693', ('177', '180'))	('impaired', 'NegReg', (150, 158))	('CDKN2A', 'Gene', (128, 134))	('p16', 'Gene', (170, 173))
73195	32716505	In terms of genetic architecture, melanoma has a number of common variants with a relatively large odds ratio (OR) for a complex trait (Supplementary Material, Table S4).	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('variants', 'Var', (66, 74))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))
73196	32716505	However, our results were not driven by GWAS variants of large effect, with the mean of affected family members' PRS higher than that of unrelated controls in the absence of genetic variants from the MC1R or CDKN2A GWAS loci (data not shown).	('CDKN2A', 'Gene', (208, 214))	('CDKN2A', 'Gene', '1029', (208, 214))	('variants', 'Var', (182, 190))	('PRS', 'Chemical', '-', (113, 116))	('MC1R', 'Gene', '4157', (200, 204))	('MC1R', 'Gene', (200, 204))	('higher', 'PosReg', (117, 123))
73200	32716505	The vast majority of melanoma families in the QFMP were pre-screened for known high-penetrance melanoma mutations in CDKN2A and CDK4.	('CDK4', 'Gene', '1019', (128, 132))	('mutations', 'Var', (104, 113))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('CDK', 'molecular_function', 'GO:0004693', ('128', '131'))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Disease', (21, 29))	('CDKN2A', 'Gene', (117, 123))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('CDK4', 'Gene', (128, 132))	('CDKN2A', 'Gene', '1029', (117, 123))
73202	32716505	similar to the distribution of PRS in healthy controls) might be more likely to harbor a (novel) high-penetrance mutation, and indeed recent work has shown that melanoma families with a high-penetrance mutation may have lower polygenic risk for melanoma compared to families without.	('mutation', 'Var', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('polygenic risk', 'MPA', (226, 240))	('mutation', 'Var', (202, 210))	('lower', 'NegReg', (220, 225))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('PRS', 'Chemical', '-', (31, 34))	('high-penetrance mutation', 'Var', (186, 210))
73203	32716505	Sequencing of 21 families selected from those with low mean-family PRS (that is, the average PRS across genotyped, affected, family members was more similar to healthy controls) identified a single family carrying a previously undetected high-penetrance deleterious CDKN2A mutation, p.G101W.	('PRS', 'Chemical', '-', (93, 96))	('PRS', 'Chemical', '-', (67, 70))	('CDKN2A', 'Gene', (266, 272))	('CDKN2A', 'Gene', '1029', (266, 272))	('p.G101W', 'Mutation', 'rs104894094', (283, 290))	('p.G101W', 'Var', (283, 290))
73205	32716505	S3) and (iv) since our PRS only indexed a minority of the genetic variation in melanoma risk, these families may be carrying a large number of common low-penetrance risk variants, which are not in our current PRS.	('PRS', 'Chemical', '-', (23, 26))	('variants', 'Var', (170, 178))	('PRS', 'Chemical', '-', (209, 212))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
73215	32716505	This work provides further evidence that cutaneous melanoma, like other common complex disorders, can arise from multiple pathways including rare high-penetrance mutations as well as via a combination of large numbers of alleles of small effect.	('arise from', 'Reg', (102, 112))	('cutaneous melanoma', 'Disease', (41, 59))	('mutations', 'Var', (162, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (41, 59))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (41, 59))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
73241	32716505	To explore the impact of MC1R (chromosome 16q) and CDKN2A (chromosome 9p) regions, which have common variants with relatively large effect sizes for a GWAS, on the PRS, we also generated SNP lists excluding all SNPs from 85 megabase (mb) to the end of chromosome 16 (328 variants) and 18-25 mb of chromosome 9 (505 variants).	('CDKN2A', 'Gene', '1029', (51, 57))	('MC1R', 'Gene', '4157', (25, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('31', '41'))	('chromosome', 'cellular_component', 'GO:0005694', ('252', '262'))	('MC1R', 'Gene', (25, 29))	('PRS', 'Chemical', '-', (164, 167))	('variants', 'Var', (101, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('297', '307'))	('CDKN2A', 'Gene', (51, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
73260	32716505	Mark M. Iles acknowledges funding support from Cancer Research UK (c588/a19167) and the NIH (ca083115).	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('c588/a19167', 'Var', (67, 78))	('Cancer', 'Disease', (47, 53))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))
73262	32716505	Support for specific cohorts is reported below:  Queensland Familial Melanoma Project and Brisbane Adolescent Twins Study  Sample and data collection was supported by funding from the NHMRC (200071, 241944, 339462, 380385, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496675, 496739, 552485, 552498, APP1049894), the Melanoma Research Alliance, the National Institute of Health's National Cancer Institute (CA88363, CA83115, CA122838, CA87969, CA055075, CA100264, CA133996 and CA49449) and the Australian Cancer Councils of New South Wales, Victoria and Queensland.	('Familial Melanoma', 'Disease', (60, 77))	('Melanoma', 'Phenotype', 'HP:0002861', (344, 352))	('Melanoma', 'Disease', 'MESH:D008545', (69, 77))	('Familial Melanoma', 'Disease', 'MESH:C562393', (60, 77))	('Cancer', 'Disease', (532, 538))	('Melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('Cancer', 'Phenotype', 'HP:0002664', (532, 538))	('Melanoma', 'Disease', 'MESH:D008545', (344, 352))	('Melanoma', 'Disease', (69, 77))	('CA88363', 'Var', (434, 441))	('CA87969', 'Var', (462, 469))	('Cancer', 'Disease', (416, 422))	('Cancer', 'Disease', 'MESH:D009369', (532, 538))	('Melanoma', 'Disease', (344, 352))	('Cancer', 'Phenotype', 'HP:0002664', (416, 422))	('Cancer', 'Disease', 'MESH:D009369', (416, 422))	('CA133996', 'Var', (491, 499))	('CA49449', 'Var', (504, 511))
73299	31359351	This fact was reflected in the study findings, as the combination of SLNB and 31-GEP testing led to significantly improved prognostication when compared with either modality alone.	('SLNB', 'Gene', (69, 73))	('prognostication', 'MPA', (123, 138))	('improved', 'PosReg', (114, 122))	('GEP', 'Gene', '2896', (81, 84))	('GEP', 'Gene', (81, 84))	('combination', 'Var', (54, 65))
73358	28104840	Among these cancer hallmarks is immune evasion, which is accomplished by neoantigen editing, defects in antigen presentation and inhibition of tumor infiltration, and/or cytotoxic activities of immune cells.	('defects', 'Var', (93, 100))	('neoantigen editing', 'Var', (73, 91))	('tumor', 'Disease', (143, 148))	('antigen presentation', 'MPA', (104, 124))	('cancer hallmarks', 'Disease', (12, 28))	('cancer hallmarks', 'Disease', 'MESH:D009369', (12, 28))	('immune evasion', 'biological_process', 'GO:0042783', ('32', '46'))	('cytotoxic activities', 'CPA', (170, 190))	('inhibition', 'NegReg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('immune evasion', 'biological_process', 'GO:0051842', ('32', '46'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('antigen presentation', 'biological_process', 'GO:0019882', ('104', '124'))	('immune evasion', 'Disease', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
73360	28104840	Understanding how SCNAs and mutation load affect tumor evolution, and through what mechanisms, is a key objective in cancer research.	('affect', 'Reg', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation load', 'Var', (28, 41))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
73364	28104840	First, we found that, for most tumors, there was a positive correlation between SCNA levels and the total number of mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SCNA levels', 'MPA', (80, 91))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (116, 125))
73365	28104840	Second, tumors harboring activating oncogenic mutations in the receptor tyrosine kinase-RAS-phosphatidylinositol 3-kinase pathway showed fewer SCNAs, a finding at odds with the hypothesis of oncogene-driven genomic instability.	('receptor tyrosine kinase', 'Gene', (63, 87))	('mutations', 'Var', (46, 55))	('receptor tyrosine kinase', 'Gene', '5979', (63, 87))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (92, 121))	('activating', 'PosReg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('phosphatidylinositol 3-kinase', 'Gene', (92, 121))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('fewer', 'NegReg', (137, 142))	('SCNAs', 'Disease', (143, 148))
73369	28104840	The combination of the tumor SCNA score and the tumor mutational load was a better predictor of survival after immunotherapy than either biomarker alone.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutational', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
73374	28104840	A high load of tumor neoantigens (reflecting a high level of point mutations) promotes the detection of tumors by the immune system, limiting immune evasion.	('point mutations', 'Var', (61, 76))	('detection', 'MPA', (91, 100))	('promotes', 'PosReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('immune evasion', 'biological_process', 'GO:0042783', ('142', '156'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (104, 109))	('immune evasion', 'biological_process', 'GO:0051842', ('142', '156'))	('tumors', 'Disease', (104, 110))	('limiting', 'NegReg', (133, 141))	('tumor', 'Disease', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('immune evasion', 'MPA', (142, 156))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
73384	28104840	Antibody-mediated inactivation of inhibitory molecules, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), has produced durable responses in a subset (20 to 30%) of patients with advanced tumors.	('cytotoxic T lymphocyte-associated protein 4', 'Gene', (64, 107))	('ligand', 'molecular_function', 'GO:0005488', ('138', '144'))	('patients', 'Species', '9606', (214, 222))	('CTLA-4', 'Gene', '1493', (109, 115))	('cytotoxic T lymphocyte-associated protein 4', 'Gene', '1493', (64, 107))	('tumors', 'Disease', (237, 243))	('inactivation', 'Var', (18, 30))	('programmed death-ligand 1', 'Gene', (121, 146))	('PD-L1', 'Gene', '29126', (148, 153))	('programmed death-ligand 1', 'Gene', '29126', (121, 146))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('responses', 'MPA', (177, 186))	('CTLA-4', 'Gene', (109, 115))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PD-L1', 'Gene', (148, 153))
73388	28104840	Cytolytic immune infiltrates have also been shown to correlate with the total number of mutations in certain human tumor types, although the mechanisms controlling immune infiltration are not well understood.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
73390	28104840	We have uncovered unanticipated relationships of SCNA levels with mutation number, with classes of cancer drivers, and with cell proliferation and immune infiltration signatures.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('relationships', 'Interaction', (32, 45))	('SCNA levels', 'MPA', (49, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('cancer', 'Disease', (99, 105))	('mutation', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
73396	28104840	In contrast with a previous report showing that SCNAs are more abundant in tumors with a low mutation burden, we found a positive correlation between the number (n) of mutations and SCNA level (Fig.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SCNA level', 'MPA', (182, 192))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (168, 177))
73399	28104840	The distribution of the number of mutations in these tumor types is bimodal, with most of the samples bearing ~100 exonic mutations on average and the remaining samples having a ~10-fold higher number of mutations (hypermutated; fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('exonic mutations', 'Var', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
73400	28104840	The negative correlation between mutations and SCNAs in CRC and UCEC tumors was dependent on the presence of these hypermutated samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CRC', 'Disease', (56, 59))	('CRC', 'Phenotype', 'HP:0030731', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
73401	28104840	Thus, within individual cancer types, the number of mutations tends to positively correlate with the SCNA level.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('SCNA level', 'Disease', (101, 111))
73402	28104840	Next, we separated mutations in driver genes, that is, tumor suppressor genes (TSGs) or oncogenes (OGs), as predicted by TUSON Explorer, and mutations in passenger genes, that is, genes not predicted to be cancer drivers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('oncogenes', 'Gene', (88, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('55', '71'))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
73405	28104840	To investigate how alterations in different classes of cancer drivers relate to aneuploidy, we analyzed the correlations between SCNA levels and mutations in sets of TSGs and OGs acting in 14 different cancer pathways (table S2B).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aneuploidy', 'Disease', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('aneuploidy', 'Disease', 'MESH:D000782', (80, 90))	('TSGs', 'Gene', (166, 170))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('acting', 'Reg', (179, 185))	('SCNA levels', 'MPA', (129, 140))	('cancer', 'Disease', (55, 61))
73406	28104840	Mutations in only one pathway showed a negative correlation with SCNAs: the receptor tyrosine kinase (RTK) pathway, which also includes phosphatidylinositol 3-kinase (PI3K) and RAS pathway genes (Fig.	('RTK', 'Gene', '5979', (102, 105))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (136, 165))	('receptor tyrosine kinase', 'Gene', (76, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('receptor tyrosine kinase', 'Gene', '5979', (76, 100))	('Mutations', 'Var', (0, 9))	('phosphatidylinositol 3-kinase', 'Gene', (136, 165))	('RTK', 'Gene', (102, 105))	('RAS pathway', 'Pathway', (177, 188))
73413	28104840	The level of pS345Chk1, a physical marker of S phase, was also increased in high aneuploidy tumors (fig.	('increased', 'PosReg', (63, 72))	('high aneuploidy tumors', 'Disease', (76, 98))	('pS345Chk1', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('high aneuploidy tumors', 'Disease', 'MESH:D000782', (76, 98))	('S phase', 'biological_process', 'GO:0051320', ('45', '52'))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
73452	28104840	In CRC, lung adenocarcinoma (LUAD), and UCEC, tumors with high mutation burden showed an increased immune signature score, consistent with previous observations (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutation burden', 'Var', (63, 78))	('lung adenocarcinoma', 'Disease', (8, 27))	('increased', 'PosReg', (89, 98))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('immune signature score', 'MPA', (99, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (8, 27))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('tumors', 'Disease', (46, 52))	('CRC', 'Disease', (3, 6))	('CRC', 'Phenotype', 'HP:0030731', (3, 6))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
73453	28104840	In contrast, in all cancer types except gliomas, tumor samples with high arm/chromosome SCNA levels showed a significant decrease in the immune signature score (~50% difference on average) (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high', 'Var', (68, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('77', '87'))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('immune signature score', 'MPA', (137, 159))	('cancer', 'Disease', (20, 26))	('decrease', 'NegReg', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
73455	28104840	Compared to mutation number, the level of SCNAs showed a stronger correlation with the cytotoxic immune signature in most of the tumor types examined, even in those where mutation number positively correlated with the SCNA level (Fig.	('cytotoxic immune signature', 'MPA', (87, 113))	('SCNA level', 'MPA', (218, 228))	('correlation', 'Interaction', (66, 77))	('correlated', 'Reg', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('mutation number', 'Var', (171, 186))
73463	28104840	We used least absolute shrinkage and selection operator (lasso) to determine the contribution of SCNA level, the total number of point mutations, TP53 mutations, patient age, patient gender, and tumor stage to both signatures.	('tumor', 'Disease', (195, 200))	('TP53', 'Gene', '7157', (146, 150))	('patient', 'Species', '9606', (175, 182))	('TP53', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('patient', 'Species', '9606', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mutations', 'Var', (151, 160))
73466	28104840	6A), as were mutations in TP53, a negative regulator of cell cycle entry.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('TP53', 'Gene', '7157', (26, 30))
73470	28104840	The total number of mutations was selected by lasso in three tumor types (CRC, LUAD, and UCEC) (Fig.	('tumor', 'Disease', (61, 66))	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CRC', 'Phenotype', 'HP:0030731', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (20, 29))
73475	28104840	First, we assessed tumor SCNA levels and mutational load in patients who did or did not achieve long-term survival after treatment.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mutational', 'Var', (41, 51))
73480	28104840	Next, we examined survival after stratifying the patients into two equal groups (that is, upper and lower 50%) based on either the tumor SCNA level or mutational load.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutational load', 'Var', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (49, 57))
73482	28104840	A higher number of tumor mutations correlated with better survival (HR = 0.68, P = 0.079; Fig.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('survival', 'CPA', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('better', 'PosReg', (51, 57))	('tumor', 'Disease', (19, 24))
73489	28104840	In this data set, a higher number of tumor mutations predicted better survival (HR = 0.61, P = 0.039; table S6C and fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (43, 52))	('better', 'PosReg', (63, 69))	('survival', 'CPA', (70, 78))
73490	28104840	The correlation of both high mutation number and low SCNA level with better survival may be due to the role of an antitumor immune response in predicting a better outcome even in the absence of immunotherapy, an observation that has been previously described.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('high mutation number', 'Var', (24, 44))	('SCNA level', 'MPA', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('immune response', 'biological_process', 'GO:0006955', ('124', '139'))	('tumor', 'Disease', (118, 123))	('better', 'PosReg', (69, 75))
73493	28104840	Overall, these data indicate that tumor SCNA levels and mutational load can be used together to predict patients' survival after immunotherapy.	('mutational', 'Var', (56, 66))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
73497	28104840	We uncovered relationships between the level of SCNAs and mutations in driver genes acting in specific cancer pathways that deepen our understanding of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
73498	28104840	Unexpectedly, the level of SCNAs negatively correlated with mutations in driver genes involved in the RTK pathway, such as EGFR, PIK3CA, KRAS, and BRAF.	('EGFR', 'Gene', (123, 127))	('PIK3CA', 'Gene', (129, 135))	('RTK', 'Gene', '5979', (102, 105))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('PIK3CA', 'Gene', '5290', (129, 135))	('BRAF', 'Gene', (147, 151))	('negatively', 'NegReg', (33, 43))	('BRAF', 'Gene', '673', (147, 151))	('KRAS', 'Gene', (137, 141))	('RTK', 'Gene', (102, 105))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', '3845', (137, 141))
73500	28104840	Our analysis suggests that mutated OGs (which may behave differently in vivo than in an experimental overexpression setting) may not represent a significant source of genomic instability and SCNAs in human tumors.	('mutated', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (206, 212))	('human', 'Species', '9606', (200, 205))	('OGs', 'Protein', (35, 38))
73507	28104840	Because the number of mutations predicts patients' survival independently of the SCNA level, combining the SCNA level with the number of mutations results in a further improvement of survival prediction.	('patients', 'Species', '9606', (41, 49))	('survival', 'MPA', (183, 191))	('mutations', 'Var', (22, 31))	('improvement', 'PosReg', (168, 179))
73509	28104840	Thus, one hypothesis is that protein imbalance may impair a tumor signal needed for cytotoxic immune cell infiltration.	('imbalance', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('imbalance', 'Phenotype', 'HP:0002172', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('impair', 'NegReg', (51, 57))	('protein', 'Protein', (29, 36))	('tumor', 'Disease', (60, 65))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))
73511	28104840	An alternative, speculative hypothesis involves the relative concentration of neoantigen peptides in high versus low aneuploidy tumors.	('aneuploidy tumors', 'Disease', 'MESH:D000782', (117, 134))	('aneuploidy tumors', 'Disease', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (101, 105))
73515	28104840	These hypotheses also predict that the role of aneuploidy in promoting cancer immune escape is dependent on the presence of neoantigens, thus mutations.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('aneuploidy', 'Disease', 'MESH:D000782', (47, 57))	('cancer', 'Disease', (71, 77))	('aneuploidy', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('promoting', 'PosReg', (61, 70))
73518	28104840	Information on both point mutations and copy number changes can simultaneously be derived from sequencing performed on patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patient', 'Species', '9606', (119, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('copy number changes', 'Var', (40, 59))	('point mutations', 'Var', (20, 35))
73523	28104840	To determine SCNA calls, i.e., the presence or absence of amplifications or deletions, we considered different noise thresholds in different tumor types based on tumor purity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (141, 146))	('deletions', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
73537	28104840	For the focal SCNAs (deletions or amplifications involving a region smaller than 50% of a chromosome arm), we applied GISTIC2 to the segmentation file (from all tumor samples) of the copy number data, after excluding the arm-level (and chromosome-level) copy number changes.	('chromosome', 'cellular_component', 'GO:0005694', ('236', '246'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('deletions', 'Var', (21, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('90', '100'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('segmentation', 'biological_process', 'GO:0035282', ('133', '145'))	('tumor', 'Disease', (161, 166))
73538	28104840	The focal SCNA events (amplification and deletion) resulting from GISTIC2 analysis are listed in table S1, B and C. To distinguish between arm and chromosome events, among the arm-level SCNA events, all cases where both arms of a chromosome had the same copy number change (in value and sign) were considered as chromosome SCNA events, while all the others were considered as arm SCNA events (table S1D).	('S1, B and C', 'Gene', '5707', (103, 114))	('copy number', 'Var', (254, 265))	('chromosome', 'cellular_component', 'GO:0005694', ('230', '240'))	('chromosome', 'cellular_component', 'GO:0005694', ('312', '322'))	('chromosome SCNA', 'Disease', (312, 327))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))
73539	28104840	We first determined in each tumor sample whether each arm, chromosome or focal region (focal events listed in table S1, B and C) was amplified, highly amplified, deleted, or highly deleted.	('tumor', 'Disease', (28, 33))	('S1, B and C', 'Gene', '5707', (116, 127))	('deleted', 'Var', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
73545	28104840	For each TSG or OG, we defined a tumor sample as mutated in that predicted driver gene if the tumor contained at least one mutation predicted to be functionally relevant.	('mutated', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (33, 38))
73546	28104840	Specifically, for each OG, recurrent mutations were defined as all the missense mutations recurring in the same position (same amino-acid residue) with a frequency of 20% among all missense mutations (in the OG) or a frequency of 5% and a minimum total absolute number of 10 mutations among all tumor samples.	('missense mutations', 'Var', (71, 89))	('missense mutations', 'Var', (181, 199))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))
73547	28104840	S1A, for CRC, UCEC, STAD, and other tumor types, the distribution of the number of mutations across samples is bimodal, highlighting the presence of a subset of hypermutated tumors.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (174, 180))	('CRC', 'Disease', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('CRC', 'Phenotype', 'HP:0030731', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
73568	28104840	For each of these genomic regions, the frequency of amplification and deletion across samples within each tumor type was determined.	('deletion', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
73570	28104840	Both Pearson and Spearman correlation between the net frequencies of copy number changes at the focal-level versus arm-level across the 807 genomic regions are reported for each tumor type in table S5D.	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('copy number', 'Var', (69, 80))
73607	28104840	Multivariable Cox proportional hazard model was applied considering the combination of low SCNA level (bottom 50%) and immunotherapy treatment and combination of high N of mutations and immunotherapy treatment as predictors, in addition to other covariates to control for differences between the three data sets (table S6D).	('Cox', 'Gene', (14, 17))	('mutations', 'Var', (172, 181))	('SCNA level', 'MPA', (91, 101))	('Cox', 'Gene', '1351', (14, 17))
73610	22275984	Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('death', 'Disease', (211, 216))	('high-Breslow thickness', 'Var', (37, 59))	('nodal disease', 'Disease', 'MESH:D013611', (112, 125))	('primary tumours', 'Disease', 'MESH:D009369', (14, 29))	('Patients', 'Species', '9606', (0, 8))	('primary tumours', 'Disease', (14, 29))	('nodal disease', 'Disease', (112, 125))	('developing metastasis', 'CPA', (158, 179))	('death', 'Disease', 'MESH:D003643', (211, 216))
73632	22275984	Overall survival Disease-free interval Distant metastasis-free interval Safety and toxicity Quality of life (QoL) Identification of markers of angiogenesis in peripheral blood and tumour tissue Patients with histological confirmation of completely resected American Joint Commission on Cancer (AJCC) stage IIB (T3bN0M0 and T4aN0M0), IIC (T4bN0M0) and III (TxN1-3M0) cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (376, 384))	('Patients', 'Species', '9606', (194, 202))	('Cancer', 'Disease', 'MESH:D009369', (286, 292))	('angiogenesis', 'biological_process', 'GO:0001525', ('143', '155'))	('toxicity', 'Disease', 'MESH:D064420', (83, 91))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('toxicity', 'Disease', (83, 91))	('T3bN0M0', 'Var', (311, 318))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))	('T4aN0M0', 'Var', (323, 330))	('Cancer', 'Disease', (286, 292))	('cutaneous melanoma', 'Disease', (366, 384))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (366, 384))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (366, 384))	('tumour', 'Disease', (180, 186))
73699	31533822	The investigation dataset, represented by RNA-seq and miRNA qPCR array data, originated from three primary tumour samples of melanoma patients (entitled P2PM, P4PM, P6PM) and two control samples: one matched normal skin P4NS and a healthy melanocyte cell line NHEM (see Additional file 4: Table S3).	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('miR', 'Gene', '220972', (54, 57))	('melanoma', 'Disease', (125, 133))	('miR', 'Gene', (54, 57))	('P2PM', 'Var', (153, 157))	('P6PM', 'Var', (165, 169))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('P4PM', 'Var', (159, 163))	('patients', 'Species', '9606', (134, 142))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('RNA', 'cellular_component', 'GO:0005562', ('42', '45'))	('tumour', 'Disease', (107, 113))
73769	31533822	For the three primary melanoma samples from the investigation set, the calculated RS was the highest for P6PM (RS = 1.92).	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('highest', 'Reg', (93, 100))	('P6PM', 'Var', (105, 109))
73784	31533822	The weights of miRNA component MIC20 were positively correlated with the weights of RIC2, RIC25 and RIC27 (correlation of 0.69, 0.86 and 0.64 accordingly) and were positively linked with survival (LHR = - 1.32, p-value = 1.2e-4).	('MIC20', 'Var', (31, 36))	('survival', 'CPA', (187, 195))	('RIC', 'Gene', '53827', (100, 103))	('RIC', 'Gene', (84, 87))	('RIC', 'Gene', '53827', (90, 93))	('correlated', 'Interaction', (53, 63))	('linked with', 'Reg', (175, 186))	('RIC', 'Gene', (100, 103))	('LHR', 'molecular_function', 'GO:0004964', ('197', '200'))	('RIC', 'Gene', '53827', (84, 87))	('RIC', 'Gene', (90, 93))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
73799	31533822	MiRNAs of MIC25 were significantly enriched in four cytogenetic locations: chr1q24.3, chr5q32, chr17p13.1 and chr21q21.1 (adj.p-values of 5.0e-6, 2.6e-3, 4.1e-02 and 9.7e-5, respectively).	('chr5q32', 'Var', (86, 93))	('MIC25', 'Gene', (10, 15))	('chr21q21.1', 'Var', (110, 120))	('MIC25', 'Gene', '84303', (10, 15))	('chr1q24.3', 'Var', (75, 84))	('chr17p13.1', 'Var', (95, 105))
73800	31533822	In the clinical samples of investigation cohort, the highest amount of stromal and endothelial cells was observed in P2PM and P4NS samples (Fig.	('P2PM', 'Var', (117, 121))	('P4NS', 'Var', (126, 130))	('clinical samples', 'Species', '191496', (7, 23))
73817	31533822	In the investigated samples, the highest weight was observed for the most aggressive tumour P6PM and the lowest value for normal skin P4NS.	('aggressive tumour', 'Disease', (74, 91))	('P6PM', 'Var', (92, 96))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('aggressive tumour', 'Disease', 'MESH:D001523', (74, 91))
73851	31533822	Deregulation of miRNAs in this locus has recently been shown to predict lung cancer patient outcome.	('Deregulation', 'Var', (0, 12))	('lung cancer', 'Disease', (72, 83))	('predict', 'Reg', (64, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('patient', 'Species', '9606', (84, 91))
73889	28198461	Germline mutations in BAP1 also predispose to cutaneous melanoma, but the mutations are relatively more important in rare cancers (uveal melanoma and mesothelioma) constituting a novel cancer syndrome.	('Germline mutations', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('cancer syndrome', 'Disease', (185, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (131, 145))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('BAP1', 'Gene', '8314', (22, 26))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))	('predispose', 'Reg', (32, 42))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('BAP1', 'Gene', (22, 26))	('mutations', 'Var', (74, 83))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (131, 162))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer syndrome', 'Disease', 'MESH:D009369', (185, 200))
73891	28198461	In the case of melanoma, it would be pertinent to assess familial clusters, with sites which are manifested in CDKN2A and BAP1 mutation carriers, or whether the risks could be extended to as yet unknown cancer sites.	('BAP1', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('mutation', 'Var', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('CDKN2A', 'Gene', (111, 117))	('BAP1', 'Gene', '8314', (122, 126))	('CDKN2A', 'Gene', '1029', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
73928	28198461	As to the genetic architecture of melanoma, high-risk CDKN2A mutations contribute to about 30% of melanomas in families of three or more affected individuals.	('melanomas', 'Disease', (98, 107))	('contribute', 'Reg', (71, 81))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('CDKN2A', 'Gene', (54, 60))	('mutations', 'Var', (61, 70))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('CDKN2A', 'Gene', '1029', (54, 60))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
73929	28198461	According to a recent Swedish study, CDKN2A positive families accounted for 11.5% (31/269) of all families, and these presented with a median of 6 melanomas compared to 2 in mutation negative families.	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('melanomas', 'Disease', (147, 156))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanomas', 'Disease', 'MESH:D008545', (147, 156))	('melanomas', 'Phenotype', 'HP:0002861', (147, 156))	('positive', 'Var', (44, 52))
73930	28198461	We show here that families of 3 or more diagnosed melanomas accounted for less than 8% of familial melanoma, which together with the above data suggest that CDKN2A mutations are likely to be, at most, a minor contributor to the present findings on discordant cancers.	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('familial melanoma', 'Disease', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('cancers', 'Disease', (259, 266))	('familial melanoma', 'Disease', 'OMIM:155600', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('CDKN2A', 'Gene', (157, 163))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Disease', (50, 59))	('CDKN2A', 'Gene', '1029', (157, 163))	('mutations', 'Var', (164, 173))
73944	28198461	Nervous system and thyroid cancers also showed independent support for being true associations, both may also manifest CDKN2A mutations or deletions.	('thyroid cancers', 'Disease', 'MESH:D013964', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Nervous system', 'Disease', (0, 14))	('CDKN2A', 'Gene', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('CDKN2A', 'Gene', '1029', (119, 125))	('mutations', 'Var', (126, 135))	('thyroid cancers', 'Disease', (19, 34))	('deletions', 'Var', (139, 148))
73948	28198461	It is known that ocular and cutaneous melanomas share familial risks and BAP1 and possibly also BRCA2 mutations may be involved.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('BAP1', 'Gene', '8314', (73, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (28, 47))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (28, 47))	('BRCA2', 'Gene', '675', (96, 101))	('BAP1', 'Gene', (73, 77))	('cutaneous melanomas', 'Disease', (28, 47))	('mutations', 'Var', (102, 111))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('ocular', 'Disease', (17, 23))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('BRCA2', 'Gene', (96, 101))
73977	24959217	Molecular alterations in clinical stage III cutaneous melanoma: Correlation with clinicopathological features and patient outcome The aim of the present study was to evaluate the frequency and type of oncogenic v-raf murine sarcoma viral oncogene homolog B1 (BRAF)/neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in cutaneous melanoma with clinically detected nodal metastases (stage IIIB and C) in relation to clinicopathological features and outcome.	('cutaneous melanoma', 'Disease', (334, 352))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (334, 352))	('clinical', 'Species', '191496', (358, 366))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (334, 352))	('neuroblastoma', 'Phenotype', 'HP:0003006', (265, 278))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (211, 257))	('melanoma', 'Disease', 'MESH:D008545', (344, 352))	('nodal metastases', 'Disease', (378, 394))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('cutaneous melanoma', 'Disease', (44, 62))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 62))	('melanoma', 'Phenotype', 'HP:0002861', (344, 352))	('melanoma', 'Disease', (344, 352))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (211, 257))	('clinical', 'Species', '191496', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('mutations', 'Var', (321, 330))	('nodal metastases', 'Disease', 'MESH:D009362', (378, 394))	('patient', 'Species', '9606', (114, 121))	('neuroblastoma RAS viral (v-ras) oncogene homolog', 'Gene', '4893', (265, 313))
73978	24959217	The clinicopathological data of 250 patients following therapeutic lymphadenectomy (LND) between 1995 and 2010, as well as BRAF/NRAS mutational status in corresponding nodal metastases, were analyzed.	('nodal metastases', 'Disease', (168, 184))	('patients', 'Species', '9606', (36, 44))	('nodal metastases', 'Disease', 'MESH:D009362', (168, 184))	('BRAF/NRAS', 'Gene', (123, 132))	('mutational', 'Var', (133, 143))
73979	24959217	BRAF mutations were detected in 154 (62%) cases (141 p.V600E, nine p.V600K and four others) and mutually exclusive NRAS mutations were detected in 42 (17%) cases.	('detected', 'Reg', (20, 28))	('p.V600E', 'Var', (53, 60))	('mutations', 'Var', (5, 14))	('p.V600K', 'Var', (67, 74))	('p.V600K', 'Mutation', 'rs121913227', (67, 74))	('p.V600E', 'Mutation', 'rs113488022', (53, 60))
73980	24959217	The presence of a BRAF mutation was found to correlate with patients of a younger age.	('patients', 'Species', '9606', (60, 68))	('BRAF', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))
73993	24959217	This genetic background is commonly achieved via oncogenic mutations in the following two genes: v-raf murine sarcoma viral oncogene homolog B1 (BRAF); or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS).	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (97, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (155, 168))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (97, 143))	('mutations', 'Var', (59, 68))	('neuroblastoma RAS viral (v-ras) oncogene homolog', 'Gene', '4893', (155, 203))
73994	24959217	The reported frequency of BRAF mutations varies between 40 and 70% in cutaneous melanoma and these are most frequently detected in tumors occurring in skin that is not chronically damaged by the sun.	('mutations', 'Var', (31, 40))	('cutaneous melanoma', 'Disease', (70, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 88))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('BRAF', 'Gene', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors occurring in skin', 'Phenotype', 'HP:0008069', (131, 155))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
73995	24959217	To date, >50 distinct mutations in BRAF have been identified, however, ~90% of BRAF mutants in melanoma are single-base transitions (T>A) at position 1,799, leading to the substitution of glutamic acid for valine at codon 600 of the BRAF protein (p.V600E), which leads to a 500-fold increase in its kinase activity.	('kinase activity', 'MPA', (299, 314))	('glutamic acid for valine at codon 600', 'Mutation', 'rs113488022', (188, 225))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('kinase activity', 'molecular_function', 'GO:0016301', ('299', '314'))	('melanoma', 'Disease', (95, 103))	('increase', 'PosReg', (283, 291))	('p.V600E', 'Mutation', 'rs113488022', (247, 254))	('mutants', 'Var', (84, 91))	('glutamic', 'Protein', (188, 196))	('p.V600E', 'Var', (247, 254))	('BRAF', 'Gene', (79, 83))	('substitution', 'Var', (172, 184))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))
73996	24959217	The second most common mutation is p.V600K (16-20% of all BRAF mutations), followed by p.V600D/p.V600R.	('p.V600K', 'Var', (35, 42))	('p.V600D/p.V600R', 'Var', (87, 102))	('p.V600D', 'Mutation', 'rs121913377', (87, 94))	('p.V600K', 'Mutation', 'rs121913227', (35, 42))	('common', 'Reg', (16, 22))	('p.V600R', 'Mutation', 'rs121913227', (95, 102))
73997	24959217	Mutated BRAF is important for melanogenesis, however, BRAF p.V600E is not sufficient for the malignant transformation of melanocytes and is an early oncogenic event also found at a high frequency in benign nevi.	('nevi', 'Phenotype', 'HP:0003764', (206, 210))	('malignant transformation of melanocytes', 'Phenotype', 'HP:0002861', (93, 132))	('BRAF', 'Gene', (54, 58))	('p.V600E', 'Mutation', 'rs113488022', (59, 66))	('benign nevi', 'Disease', (199, 210))	('p.V600E', 'Var', (59, 66))
73998	24959217	NRAS mutations are present in 15-30% of melanomas of the skin, with codon 61 most commonly altered.	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('melanomas of the skin', 'Disease', (40, 61))	('NRAS', 'Gene', (0, 4))	('melanomas of the skin', 'Disease', 'MESH:D008545', (40, 61))
73999	24959217	Although it has been demonstrated in experimental models that a mutation in NRAS is capable of inducing melanoma in Cdkn2a-deficient mice, NRAS mutations occur in the congenital nevi at a similar frequency to melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('mice', 'Species', '10090', (133, 137))	('NRAS', 'Gene', (76, 80))	('mutation', 'Var', (64, 72))	('NRAS', 'Gene', (139, 143))	('Cdkn2a', 'Gene', '12578', (116, 122))	('Cdkn2a', 'Gene', (116, 122))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('inducing', 'Reg', (95, 103))	('melanoma', 'Disease', (209, 217))	('nevi', 'Phenotype', 'HP:0003764', (178, 182))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
74000	24959217	Mutations of the two oncogenes (BRAF and NRAS) have a well established and powerful predictive role as validated targets in recently developed molecular targeted therapy for melanoma.	('BRAF', 'Gene', (32, 36))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (41, 45))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))
74001	24959217	BRAF inhibitors, such as vemurafenib and dabrafenib, demonstrate clinical benefit in melanomas harboring the BRAF p.V600E mutation and MEK inhibitors act in the presence of BRAF and NRAS mutations.	('melanomas', 'Disease', (85, 94))	('vemurafenib', 'Chemical', 'MESH:D000077484', (25, 36))	('BRAF', 'Gene', (109, 113))	('p.V600E', 'Var', (114, 121))	('BRAF', 'Gene', (173, 177))	('MEK', 'Gene', '5609', (135, 138))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('MEK', 'Gene', (135, 138))	('dabrafenib', 'Chemical', 'MESH:C561627', (41, 51))	('p.V600E', 'Mutation', 'rs113488022', (114, 121))	('NRAS', 'Gene', (182, 186))	('clinical', 'Species', '191496', (65, 73))
74002	24959217	One study has indicated that the presence of a BRAF mutation markedly correlates with inferior survival in a metastatic setting, however, this finding was not paralleled by differences in disease-free survival (DFS) from the time of the primary melanoma diagnosis.	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('BRAF', 'Gene', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('presence', 'Var', (33, 41))	('mutation', 'Var', (52, 60))	('inferior', 'NegReg', (86, 94))
74003	24959217	An additional study has also implied that the presence of NRAS mutations has a negative influence on survival in stage IV melanoma patients.	('mutations', 'Var', (63, 72))	('IV melanoma', 'Disease', (119, 130))	('patients', 'Species', '9606', (131, 139))	('survival', 'MPA', (101, 109))	('negative', 'NegReg', (79, 87))	('presence', 'Var', (46, 54))	('IV melanoma', 'Disease', 'MESH:D008545', (119, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('NRAS', 'Gene', (58, 62))
74005	24959217	The aim of the current study was to determine the BRAF and NRAS mutational status of nodal metastases in a large homogeneous group of cutaneous melanoma patients (BRAF inhibitor-naive patients with clinically detected regional nodal metastases), and to correlate those results with the clinical data and patient survival.	('nodal metastases', 'Disease', (85, 101))	('BRAF', 'Gene', (50, 54))	('patient', 'Species', '9606', (304, 311))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (184, 192))	('clinical', 'Species', '191496', (286, 294))	('nodal metastases', 'Disease', 'MESH:D009362', (85, 101))	('nodal metastases', 'Disease', (227, 243))	('clinical', 'Species', '191496', (198, 206))	('patient', 'Species', '9606', (153, 160))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('NRAS', 'Gene', (59, 63))	('nodal metastases', 'Disease', 'MESH:D009362', (227, 243))	('cutaneous melanoma', 'Disease', (134, 152))	('mutational', 'Var', (64, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (134, 152))	('patient', 'Species', '9606', (184, 191))
74025	24959217	The following clinical, pathological and molecular parameters were tested as potential factors affecting patient survival: Gender, age (<=40, >40-60 and >60 years), primary tumor Breslow thickness (<=1.00, 1.01-2.00, 2.01-4.00 and >4.00 mm), presence of ulceration of the primary lesion, primary tumor level of invasion (II/III vs. IV/V), localization of LND (inguinal vs. axillary), number of lymph nodes with metastases (1, 2-3 or >=4), presence of extracapsular invasion in the involved lymph nodes, BRAF status [BRAF-mutated vs. wild-type (WT); and p.V600E mutation vs. other BRAF mutations and vs. wild-type] and NRAS status (NRAS-mutated vs. WT).	('patient', 'Species', '9606', (105, 112))	('BRAF', 'Disease', (503, 507))	('p.V600E', 'Var', (553, 560))	('clinical', 'Species', '191496', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('localization', 'biological_process', 'GO:0051179', ('339', '351'))	('tumor', 'Disease', (296, 301))	('BRAF-', 'Gene', '673', (516, 521))	('tumor', 'Disease', 'MESH:D009369', (296, 301))	('BRAF-', 'Gene', (516, 521))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('metastases', 'Disease', (411, 421))	('p.V600E', 'Mutation', 'rs113488022', (553, 560))	('metastases', 'Disease', 'MESH:D009362', (411, 421))
74026	24959217	BRAF mutations were detected in 154 of 250 (61.6%) melanoma nodal metastases and were predominantly p.V600E mutations (Table II).	('p.V600E', 'Var', (100, 107))	('detected', 'Reg', (20, 28))	('melanoma nodal metastases', 'Disease', (51, 76))	('mutations', 'Var', (5, 14))	('p.V600E', 'Mutation', 'rs113488022', (100, 107))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma nodal metastases', 'Disease', 'MESH:D009362', (51, 76))
74030	24959217	Among the clinicopathological features (Table I), the presence of BRAF mutations was found to correlate with a younger age of patients (median age, 52 years for BRAF-mutated and 60 years for BRAF-WT; P<0.01).	('BRAF-', 'Gene', (161, 166))	('presence', 'Var', (54, 62))	('BRAF-', 'Gene', '673', (191, 196))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (126, 134))	('BRAF', 'Gene', (66, 70))	('BRAF-', 'Gene', '673', (161, 166))	('BRAF-', 'Gene', (191, 196))
74033	24959217	No correlation was identified between BRAF mutational status and OS (calculated from the date of the LND and primary tumor excision) and the prognosis did not differ between BRAF-mutated (P=0.73) and BRAF-WT (P=0.87) melanomas, however, a trend for an improved OS was identified for non-V600E mutants (Fig.	('BRAF-', 'Gene', '673', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('BRAF-', 'Gene', (174, 179))	('melanomas', 'Disease', (217, 226))	('V600E', 'Mutation', 'rs113488022', (287, 292))	('BRAF-', 'Gene', '673', (200, 205))	('BRAF-', 'Gene', (200, 205))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanomas', 'Phenotype', 'HP:0002861', (217, 226))	('non-V600E', 'Var', (283, 292))	('melanomas', 'Disease', 'MESH:D008545', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improved', 'PosReg', (252, 260))
74040	24959217	The present study has expanded the detailed molecular analysis of clinical stage III melanoma by the characterization of BRAF and NRAS mutations in a homogeneous group of patients with regional nodal macrometastases.	('BRAF', 'Gene', (121, 125))	('III melanoma', 'Disease', (81, 93))	('III melanoma', 'Disease', 'MESH:D008545', (81, 93))	('clinical', 'Species', '191496', (66, 74))	('metastases', 'Disease', (205, 215))	('mutations', 'Var', (135, 144))	('patients', 'Species', '9606', (171, 179))	('metastases', 'Disease', 'MESH:D009362', (205, 215))	('NRAS', 'Gene', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))
74041	24959217	The distribution of BRAF and NRAS mutations in this cohort was similar to that in previously reported studies (particularly consistent with stage IV melanoma) with mutually exclusive BRAF-mutants found in 62% and NRAS-mutants in 17% of cases.	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('stage', 'Disease', (140, 145))	('NRAS', 'Gene', (29, 33))	('IV melanoma', 'Disease', (146, 157))	('BRAF-', 'Gene', '673', (183, 188))	('BRAF-', 'Gene', (183, 188))	('BRAF', 'Gene', (20, 24))	('mutations', 'Var', (34, 43))	('IV melanoma', 'Disease', 'MESH:D008545', (146, 157))
74042	24959217	The results of the current study confirmed former clinical associations with tumor mutational status, but also differed from the observations in stage IV melanoma concerning the role of BRAF or NRAS mutations as a prognostic marker following complete surgical resection of the metastatic regional lymph nodes.	('BRAF', 'Gene', (186, 190))	('NRAS', 'Gene', (194, 198))	('IV melanoma', 'Disease', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('clinical', 'Species', '191496', (50, 58))	('IV melanoma', 'Disease', 'MESH:D008545', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (199, 208))	('tumor', 'Disease', (77, 82))
74043	24959217	The patients' age at diagnosis of stage III melanoma was significantly lower in tumors with BRAF mutations in contrast to patients with NRAS mutations, who were on average older.	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('BRAF', 'Gene', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (4, 12))	('III melanoma', 'Disease', (40, 52))	('III melanoma', 'Disease', 'MESH:D008545', (40, 52))	('lower', 'NegReg', (71, 76))
74045	24959217	Several studies have reported no influence of BRAF or NRAS mutations on patient survival from the time of diagnosis in earlier stages of the disease.	('patient', 'Species', '9606', (72, 79))	('BRAF', 'Gene', (46, 50))	('NRAS', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))
74046	24959217	The only exception is the study by Moreau et al, which approached BRAF mutational analysis in a heterogenous group of 105 stage III cutaneous melanoma patients and showed a negative prognostic value of BRAF mutations.	('patients', 'Species', '9606', (151, 159))	('cutaneous melanoma', 'Disease', (132, 150))	('mutational', 'Var', (71, 81))	('mutations', 'Var', (207, 216))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('negative', 'NegReg', (173, 181))
74048	24959217	The present study showed no difference in patient survival from the primary tumor diagnosis and date of the LND, based on BRAF or NRAS mutational status.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutational status', 'Var', (135, 152))	('BRAF', 'Gene', (122, 126))	('patient', 'Species', '9606', (42, 49))	('NRAS', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
74052	24959217	It appears counter-intuitive that positive BRAF status may be associated with a negative prognosis, if the presence of BRAF mutations in melanoma closely correlates with a younger age of patients, a well-documented positive prognostic factor in stage I-III melanoma.	('III melanoma', 'Disease', (253, 265))	('III melanoma', 'Disease', 'MESH:D008545', (253, 265))	('patients', 'Species', '9606', (187, 195))	('mutations', 'Var', (124, 133))	('BRAF', 'Gene', (119, 123))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))
74053	24959217	For non-V600E BRAF-mutants, a trend was identified in the current study for a further improved prognosis, which may be associated with a different molecular pathogenesis of this subgroup.	('pathogenesis', 'biological_process', 'GO:0009405', ('157', '169'))	('prognosis', 'MPA', (95, 104))	('V600E', 'Mutation', 'rs113488022', (8, 13))	('non-V600E', 'Var', (4, 13))	('BRAF-', 'Gene', '673', (14, 19))	('improved', 'PosReg', (86, 94))	('BRAF-', 'Gene', (14, 19))
74056	24959217	The BRAF and NRAS genotype distribution in the nodal metastases of cutaneous melanomas is identical to that observed in stage IV melanoma, with BRAF p.V600E as the most frequent mutation harbored by melanoma cell metastases in lymph nodes.	('p.V600E', 'Var', (149, 156))	('nodal metastases', 'Disease', 'MESH:D009362', (47, 63))	('melanoma cell metastases', 'Disease', 'MESH:D009362', (199, 223))	('IV melanoma', 'Disease', (126, 137))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('IV melanoma', 'Disease', 'MESH:D008545', (126, 137))	('melanoma cell metastases', 'Disease', (199, 223))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('BRAF', 'Gene', (144, 148))	('metastases of cutaneous melanomas', 'Disease', 'MESH:D009362', (53, 86))	('metastases of cutaneous melanomas', 'Disease', (53, 86))	('p.V600E', 'Mutation', 'rs113488022', (149, 156))	('nodal metastases', 'Disease', (47, 63))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
74057	24959217	It cannot be confirmed that the BRAF and NRAS mutations are associated with a more aggressive course of disease, as has been observed in a series of patients with distant metastases.	('patients', 'Species', '9606', (149, 157))	('mutations', 'Var', (46, 55))	('BRAF', 'Gene', (32, 36))	('metastases', 'Disease', (171, 181))	('NRAS', 'Gene', (41, 45))	('metastases', 'Disease', 'MESH:D009362', (171, 181))	('associated', 'Reg', (60, 70))
74066	32530570	We show that higher UVMSE scores could be a useful predictor of better immunotherapy outcome, especially in patients with low/intermediate TMB, likely due to increased hydrophobicity (and hence immunogenicity) of neopeptides.	('hydrophobicity', 'MPA', (168, 182))	('better', 'PosReg', (64, 70))	('MSE', 'Gene', (22, 25))	('low/intermediate TMB', 'Var', (122, 142))	('MSE', 'Gene', '101180900', (22, 25))	('patients', 'Species', '9606', (108, 116))	('TMB', 'Chemical', '-', (139, 142))	('immunotherapy outcome', 'CPA', (71, 92))	('increased', 'PosReg', (158, 167))
74069	32530570	not significant NGS next-generation sequencing OS overall survival PD partial disease PD-1 programmed cell death 1 PD-L1 programmed death ligand 1 PFS progression-free survival PR partial response RECIST response evaluation criteria in solid tumors ROC receiver operating characteristic SD stable disease SKCM skin cutaneous melanoma TCGA The Cancer Genome Atlas TMB tumor mutation burden UV ultraviolet UVMSE UV mutational signature enrichment VCF variant call format Cells in the human body naturally present antigens, which are short peptide fragments derived from intracellular and extracellular sources, on their surfaces in major histocompatibility complex (MHC) proteins.	('programmed cell death 1', 'Gene', '5133', (91, 114))	('men', 'Species', '9606', (440, 443))	('melanoma', 'Phenotype', 'HP:0002861', (325, 333))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (310, 333))	('tumor', 'Disease', (242, 247))	('skin cutaneous melanoma', 'Disease', (310, 333))	('men', 'Species', '9606', (549, 552))	('intracellular', 'cellular_component', 'GO:0005622', ('568', '581'))	('programmed cell death', 'biological_process', 'GO:0012501', ('91', '112'))	('MSE', 'Gene', '101180900', (406, 409))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('Cancer', 'Phenotype', 'HP:0002664', (343, 349))	('extracellular', 'cellular_component', 'GO:0005576', ('586', '599'))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('630', '662'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (315, 333))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', (367, 372))	('Cancer', 'Disease', (343, 349))	('MSE', 'Gene', (406, 409))	('stable disease', 'Disease', (290, 304))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('SD', 'Disease', 'MESH:D029461', (287, 289))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('tumors', 'Disease', (242, 248))	('human', 'Species', '9606', (482, 487))	('VCF', 'Gene', (445, 448))	('PD-L1', 'Gene', (115, 120))	('ligand', 'molecular_function', 'GO:0005488', ('138', '144'))	('TMB', 'Chemical', '-', (363, 366))	('variant', 'Var', (449, 456))	('Cancer', 'Disease', 'MESH:D009369', (343, 349))	('PD-L1', 'Gene', '29126', (115, 120))	('PD-1', 'Gene', (86, 90))	('stable disease', 'Disease', 'MESH:D060050', (290, 304))	('PD-1', 'Gene', '5133', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('programmed cell death 1', 'Gene', (91, 114))
74070	32530570	In contrast, cancer cells should be recognized and attacked by cytotoxic T cells because malignant cells harbor mutations that manifest as altered peptide neoantigens marking them as nonself.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (112, 121))	('peptide neoantigens', 'MPA', (147, 166))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('altered', 'Reg', (139, 146))	('cancer', 'Disease', (13, 19))
74076	32530570	Other factors that correlate, albeit imperfectly, with a propensity to PD-1/PD-L1 inhibitor responsiveness include PD-L1 overexpression [8, 12, 13] and Apolipoprotein B mRNA Editing Enzyme, Catalytic Polypeptide-like (APOBEC) mutational activity [15].	('APOBEC', 'Gene', (218, 224))	('mutational', 'Var', (226, 236))	('PD-1', 'Gene', '5133', (71, 75))	('Apolipoprotein', 'molecular_function', 'GO:0005319', ('152', '166'))	('APOBEC', 'cellular_component', 'GO:0030895', ('218', '224'))	('PD-L1', 'Gene', (76, 81))	('Apolipoprotein B mRNA Editing', 'Protein', (152, 181))	('PD-L1', 'Gene', '29126', (115, 120))	('PD-L1', 'Gene', '29126', (76, 81))	('overexpression', 'PosReg', (121, 135))	('Apolipoprotein', 'molecular_function', 'GO:0005320', ('152', '166'))	('mRNA Editing', 'biological_process', 'GO:0016556', ('169', '181'))	('PD-1', 'Gene', (71, 75))	('PD-L1', 'Gene', (115, 120))
74077	32530570	Most mutations in melanomas are caused by exposure to ultraviolet (UV) light [16] through the action of free radicals formed by high-energy UV rays disrupting covalent double bonds in pyrimidine DNA bases [16].	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('free radicals', 'Chemical', 'MESH:D005609', (104, 117))	('caused by', 'Reg', (32, 41))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', (18, 27))	('pyrimidine', 'Chemical', 'MESH:C030986', (184, 194))	('covalent double bonds', 'MPA', (159, 180))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('DNA', 'cellular_component', 'GO:0005574', ('195', '198'))	('disrupting', 'NegReg', (148, 158))
74079	32530570	However, some residual dipyrimidine mutations remain uncorrected, leading to increased brittleness in the DNA helix and improper replication and transcription.	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('increased brittleness', 'Phenotype', 'HP:0002659', (77, 98))	('replication', 'CPA', (129, 140))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('dipyrimidine mutations', 'Var', (23, 45))	('transcription', 'MPA', (145, 158))	('increased', 'PosReg', (77, 86))	('dipyrimidine', 'Chemical', '-', (23, 35))	('brittleness in the DNA helix', 'CPA', (87, 115))
74080	32530570	Dipyrimidines composed of linked cytosines are usually mispaired with two adenines during DNA replication, resulting in the characteristic CC TT mutations commonly associated with UV light [17].	('CC TT', 'Gene', (139, 144))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('associated', 'Reg', (164, 174))	('mutations', 'Var', (145, 154))	('adenines', 'Chemical', 'MESH:D000225', (74, 82))	('cytosines', 'Chemical', 'MESH:D003596', (33, 42))	('DNA replication', 'biological_process', 'GO:0006260', ('90', '105'))	('Dipyrimidines', 'Chemical', '-', (0, 13))
74081	32530570	Lower energy UVA radiation tends to cause G T mutations by free radicals oxidizing guanine, creating a new 7,8-dihydro-8-oxoguanine species that can pair with adenine, which then causes the guanine's replacement with a thymine in a succeeding DNA replication cycle [16].	('mutations', 'Var', (46, 55))	('guanine', 'Chemical', 'MESH:D006147', (124, 131))	('adenine', 'Chemical', 'MESH:D000225', (159, 166))	('guanine', 'Chemical', 'MESH:D006147', (83, 90))	('thymine', 'MPA', (219, 226))	('men', 'Species', '9606', (207, 210))	('causes', 'Reg', (179, 185))	('thymine', 'Chemical', 'MESH:D013941', (219, 226))	('7,8-dihydro-8-oxoguanine', 'Chemical', 'MESH:C453560', (107, 131))	('DNA replication', 'biological_process', 'GO:0006260', ('243', '258'))	('guanine', 'Chemical', 'MESH:D006147', (190, 197))	('DNA', 'cellular_component', 'GO:0005574', ('243', '246'))	('free radicals', 'Chemical', 'MESH:D005609', (59, 72))	('replacement', 'MPA', (200, 211))
74082	32530570	We also show a positive correlation between response to immunotherapy and level of UV mutations in 151 patients seen at the University of California San Diego Moores Cancer Center.	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (86, 95))	('California San Diego Moores Cancer', 'Disease', 'MESH:C536670', (138, 172))	('patients', 'Species', '9606', (103, 111))	('California San Diego Moores Cancer', 'Disease', (138, 172))
74086	32530570	The hydrophobicity of the dipeptides was multiplied before and after mutagenesis by the probability of observing the codons corresponding to the dipeptide on the human coding genome (derived from the Kazusa's codon usage database [24]) and the probability of UV mutagenesis on the stretch [21].	('mutagenesis', 'Var', (69, 80))	('mutagenesis', 'Var', (262, 273))	('dipeptides', 'Chemical', 'MESH:D004151', (26, 36))	('dipeptide', 'Chemical', 'MESH:D004151', (145, 154))	('human', 'Species', '9606', (162, 167))	('mutagenesis', 'biological_process', 'GO:0006280', ('69', '80'))	('mutagenesis', 'biological_process', 'GO:0006280', ('262', '273'))	('dipeptide', 'Chemical', 'MESH:D004151', (26, 35))
74089	32530570	The substitution alone results in an increase in hydrophobicity of +3.6 AU, but this value must be further weighted by the probability of the mutation occurring in the specific 6-nucleotide stretch.	('hydrophobicity', 'MPA', (49, 63))	('6-nucleotide', 'Chemical', '-', (177, 189))	('AU', 'Chemical', '-', (72, 74))	('increase', 'PosReg', (37, 45))	('substitution', 'Var', (4, 16))
74090	32530570	Analogous calculations were performed for all possible nucleotide substitutions (three unique nucleotides per position) at all definable, mutable positions (2nd, 3rd, 4th, and 5th positions) in all 6-nucleotide stretches (n = 4096) resulting in a total of 49 152 possible singly mutated stretches, whose relative hydrophobicity changes were summed together to estimate the genome-wide hydrophobicity change for each round of mutagenesis.	('6-nucleotide', 'Chemical', '-', (198, 210))	('substitutions', 'Var', (66, 79))	('singly mutated', 'MPA', (272, 286))	('mutagenesis', 'biological_process', 'GO:0006280', ('425', '436'))	('stretches', 'Var', (287, 296))
74093	32530570	Molecular profiles, obtained by next-generation sequencing (NGS) of human tumors, consisting of mutations such as substitutions or small insertions/deletions and mRNA expression data, were downloaded from the community resource project The Cancer Genome Atlas (TCGA), using the Broad GDAC Firehose website (https://gdac.broadinstitute.org:standardized data run release 2016_01_28).	('human', 'Species', '9606', (68, 73))	('substitutions', 'Var', (114, 127))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('Cancer', 'Disease', (240, 246))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Cancer', 'Disease', 'MESH:D009369', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
74100	32530570	From 9166 samples in the TCGA database (33 distinct tumor types), we selected 3543 tumors without (a) POLE and POLD1 mutations, (b) mismatch repair gene loss, underexpression, or mutations, (c) and microsatellite instability-high alterations because these alterations are already known to influence immunotherapy response [12, 26, 27].	('POLD1', 'Gene', '5424', (111, 116))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mismatch repair', 'biological_process', 'GO:0006298', ('132', '147'))	('mismatch', 'Gene', (132, 140))	('microsatellite instability', 'Disease', 'MESH:D053842', (198, 224))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('microsatellite instability', 'Disease', (198, 224))	('POLD1', 'Gene', (111, 116))	('mutations', 'Var', (117, 126))	('immunotherapy response', 'CPA', (299, 321))	('loss', 'NegReg', (153, 157))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (179, 188))	('tumors', 'Disease', (83, 89))	('influence', 'Reg', (289, 298))
74101	32530570	Using the mutation description available for these tumors, we then performed two types of analysis: (a) In the first analysis, for each tumor, the differences in total hydrophobicity (i.e., the sum of the hydrophobicity of all amino acids) of each transcript's full-length peptide product (after versus before mutagenesis) were considered; and (b) for the second analysis, for each tumor, mutated transcripts were used to generate all possible 8- to 10-mer neoantigens encompassing a mutation (since MHC I presents 8-10 amino acid peptides); the differences in total hydrophobicity of the neoantigens after versus before mutagenesis were considered.	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (382, 387))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutation', 'Var', (484, 492))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mutagenesis', 'biological_process', 'GO:0006280', ('310', '321'))	('mutagenesis', 'biological_process', 'GO:0006280', ('621', '632'))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
74115	32530570	The UVMSE score quantifies how frequently mutations described in the defined UV signature 7 occur at a specific sequence context compared to analogous single nucleotide substitutions in other contexts.	('MSE', 'Gene', (6, 9))	('mutations', 'Var', (42, 51))	('UV signature 7', 'Gene', (77, 91))	('MSE', 'Gene', '101180900', (6, 9))
74116	32530570	Its enrichment can be calculated as follows:  MutTCC TTC is the amount of TCC TTC and GGA GAA reverse complement mutations counted in a 41-nucleotide stretch on the human genome (GrCh37.75) centered around a detected single nucleotide substitution from the VCF file.	('men', 'Species', '9606', (10, 13))	('human', 'Species', '9606', (165, 170))	('TCC', 'cellular_component', 'GO:0005579', ('74', '77'))	('men', 'Species', '9606', (108, 111))	('GAA', 'Gene', '2548', (90, 93))	('mutations', 'Var', (113, 122))	('GAA', 'Gene', (90, 93))
74119	32530570	The weighted enrichment value for each of the 192 described mutations in the signature was then summed together to yield the UVMSE score for a particular sample.	('mutations', 'Var', (60, 69))	('MSE', 'Gene', (127, 130))	('MSE', 'Gene', '101180900', (127, 130))	('men', 'Species', '9606', (19, 22))
74120	32530570	Patients were divided into two groups of interest: (a) patients presenting a tumor with a high load of UV mutations ('UV high'); and (b) patients presenting a tumor with a low load of UV mutations ('UV low').	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Disease', (159, 164))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
74124	32530570	Best response observed, progression-free survival (PFS) and overall survival (OS) in months, and TMB and patient demographics were compared between patients presenting a high UVMSE score (>= 0.7917) versus patients presenting a low UVMSE score.	('patients', 'Species', '9606', (148, 156))	('patient', 'Species', '9606', (105, 112))	('MSE', 'Gene', '101180900', (177, 180))	('MSE', 'Gene', (177, 180))	('patient', 'Species', '9606', (206, 213))	('TMB', 'Chemical', '-', (97, 100))	('patients', 'Species', '9606', (206, 214))	('MSE', 'Gene', '101180900', (234, 237))	('patient', 'Species', '9606', (148, 155))	('MSE', 'Gene', (234, 237))	('high', 'Var', (170, 174))
74125	32530570	Statistical significance for the in silico modeling results was assessed using a Wilcoxon signed-rank test (nonparametric paired test) for the comparison of change in total hydrophobicity before and after UV mutagenesis in 6-nucleotide stretches.	('mutagenesis', 'Var', (208, 219))	('6-nucleotide', 'Chemical', '-', (223, 235))	('mutagenesis', 'biological_process', 'GO:0006280', ('208', '219'))	('total hydrophobicity', 'MPA', (167, 187))
74133	32530570	After one cycle of UV mutagenesis when considering all 4096 possible stretches (P < 0.0001), the median hydrophobicity increased by 1.6 x 10-7 AU, and the average hydrophobicity increased by 5.8 x 10-6 AU (Tables 1 and S1).	('mutagenesis', 'biological_process', 'GO:0006280', ('22', '33'))	('hydrophobicity', 'MPA', (163, 177))	('AU', 'Chemical', '-', (143, 145))	('AU', 'Chemical', '-', (202, 204))	('mutagenesis', 'Var', (22, 33))	('increased', 'PosReg', (119, 128))	('increased', 'PosReg', (178, 187))
74143	32530570	In our cohort of 151 patients, the mean UVMSE for patients with a melanoma diagnosis, which we used as a proxy for high UV exposure status due to the most common etiology of melanoma being excessive UV exposure [16], was significantly higher at 0.8043 (95% CI: 0.7887-0.8199) compared to nonmelanoma patients who had an average UVMSE of 0.7827 (95% CI: 0.7737-0.7918; P = 0.0029; calculated on the genomic real estate in the Foundation Medicine panel; Fig.	('nonmelanoma', 'Disease', (288, 299))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('patients', 'Species', '9606', (21, 29))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('MSE', 'Gene', '101180900', (42, 45))	('patients', 'Species', '9606', (300, 308))	('0.8043', 'Var', (245, 251))	('MSE', 'Gene', (42, 45))	('nonmelanoma', 'Disease', 'None', (288, 299))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('higher', 'PosReg', (235, 241))	('patients', 'Species', '9606', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('MSE', 'Gene', '101180900', (330, 333))	('MSE', 'Gene', (330, 333))
74144	32530570	In a univariate model based on our 151 patients in the UCSD Moores Cancer Center Cohort, the factors associated with high UV signature included Caucasian ethnicity, tumor type being melanoma, and TMB high (all P < 0.003; Table 2).	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TMB', 'Chemical', '-', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('patients', 'Species', '9606', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))	('melanoma', 'Disease', (182, 190))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('high', 'Var', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('UCSD Moores Cancer', 'Disease', 'MESH:D009369', (55, 73))	('UCSD Moores Cancer', 'Disease', (55, 73))	('tumor', 'Disease', (165, 170))
74150	32530570	Table S8 shows that tumor type melanoma, TMB high, UV high, and immunotherapies other than single-agent checkpoint inhibitors were significantly associated with better response rates as well as longer PFS and OS (all P < 0.01; univariate analysis).	('TMB', 'Chemical', '-', (41, 44))	('better', 'PosReg', (161, 167))	('UV high', 'Var', (51, 58))	('tumor type melanoma', 'Disease', (20, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('response rates', 'CPA', (168, 182))	('TMB high', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PFS', 'CPA', (201, 204))	('tumor type melanoma', 'Disease', 'MESH:D008545', (20, 39))
74153	32530570	Results were similar in that UV high versus UV low was associated with response in univariate but not multivariate analysis when only nonmelanoma or only melanoma patients were analyzed (Tables S2 and S3).	('nonmelanoma', 'Disease', 'None', (134, 145))	('patients', 'Species', '9606', (163, 171))	('nonmelanoma', 'Disease', (134, 145))	('response', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', (137, 145))	('UV high', 'Var', (29, 36))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))
74167	32530570	Interestingly, other factors such as PD-L1 amplification may also predict immunotherapy response [35].	('predict', 'Reg', (66, 73))	('PD-L1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('PD-L1', 'Gene', '29126', (37, 42))	('immunotherapy response', 'CPA', (74, 96))
74169	32530570	We show that the mutational landscape caused by UV light, as quantified by the UVMSE, is positively correlated with increased hydrophobicity of exome protein products in both in silico simulation and pan-cancer TCGA data.	('cancer', 'Disease', (204, 210))	('hydrophobicity of exome protein products', 'MPA', (126, 166))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('MSE', 'Gene', '101180900', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('MSE', 'Gene', (81, 84))	('increased', 'PosReg', (116, 125))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('mutational', 'Var', (17, 27))
74172	32530570	The fact that the number of UV mutations is associated with an increase in putative neoantigen hydrophobicity is a possible explanation for why melanomas tend to respond well to checkpoint blockade immunotherapy [40].	('increase', 'PosReg', (63, 71))	('mutations', 'Var', (31, 40))	('melanomas', 'Disease', (144, 153))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanomas', 'Phenotype', 'HP:0002861', (144, 153))	('putative neoantigen hydrophobicity', 'MPA', (75, 109))	('melanomas', 'Disease', 'MESH:D008545', (144, 153))
74185	32530570	The correlation of UV exposure with better immunotherapy outcome appears to be more important in cases with low/intermediate TMB (versus high TMB), perhaps because, in the latter, the large number of mutations already permits immune recognition once T cells are reactivated after checkpoint blockade therapy.	('low/intermediate', 'Var', (108, 124))	('mutations', 'Var', (200, 209))	('TMB', 'Chemical', '-', (142, 145))	('immune', 'MPA', (226, 232))	('TMB', 'Chemical', '-', (125, 128))
74208	21552679	However, there are reports of associations between development of AMS and changes in chromosomes 9p21 and 1p36.	('AMS', 'Disease', (66, 69))	('changes', 'Var', (74, 81))	('chromosomes', 'Gene', (85, 96))	('AMS', 'Disease', 'MESH:C535557', (66, 69))	('p36', 'Gene', (107, 110))	('associations', 'Interaction', (30, 42))	('p36', 'Gene', '302', (107, 110))
74209	21552679	It was demonstrated that the presence of dysplastic nevi increases the risk of melanoma in patients with germline mutations in CDKN2A, the main genomic locus of melanoma susceptibility.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (41, 56))	('patients', 'Species', '9606', (91, 99))	('nevi', 'Phenotype', 'HP:0003764', (52, 56))	('mutations', 'Var', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('increases', 'PosReg', (57, 66))	('CDKN2A', 'Gene', (127, 133))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('dysplastic nevi', 'Disease', (41, 56))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (79, 87))	('CDKN2A', 'Gene', '1029', (127, 133))	('dysplastic nevi', 'Disease', 'MESH:D004416', (41, 56))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
74211	21552679	The presence of a susceptibility gene for the development of dysplastic nevi was also observed on chromosome 7q21.3 in patients with the p16 gene mutation in four families with familial melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('mutation', 'Var', (146, 154))	('dysplastic nevi', 'Disease', (61, 76))	('p16', 'Gene', (137, 140))	('chromosome', 'cellular_component', 'GO:0005694', ('98', '108'))	('patients', 'Species', '9606', (119, 127))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('familial melanoma', 'Disease', (177, 194))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (61, 76))	('dysplastic nevi', 'Disease', 'MESH:D004416', (61, 76))	('milia', 'Phenotype', 'HP:0001056', (179, 184))	('familial melanoma', 'Disease', 'OMIM:155600', (177, 194))	('p16', 'Gene', '1029', (137, 140))
74213	21552679	Moreover, melanocytic lesions of rapid growth or development are more likely to have mutations in this gene when compared to lesions without a history of changes in their clinical aspects.	('melanocytic lesions of rapid growth', 'Disease', (10, 45))	('mutations', 'Var', (85, 94))	('melanocytic lesions of rapid growth', 'Disease', 'MESH:D006130', (10, 45))
74214	21552679	Other genetic changes described in dysplastic nevi include microsatellite instability, loss of heterozygosity (LOH) and increased activity of the telomerase enzyme.	('dysplastic nevi', 'Phenotype', 'HP:0001062', (35, 50))	('dysplastic nevi', 'Disease', 'MESH:D004416', (35, 50))	('loss', 'Var', (87, 91))	('nevi', 'Phenotype', 'HP:0003764', (46, 50))	('telomerase enzyme', 'Enzyme', (146, 163))	('dysplastic nevi', 'Disease', (35, 50))	('increased', 'PosReg', (120, 129))	('microsatellite instability', 'MPA', (59, 85))	('activity', 'MPA', (130, 138))
74383	30522515	proposed that abnormal B-cell function and the use of immunosuppressive agents might lead to lymphoma by direct mutagenesis or by disturbing immune surveillance; other factors include age, underlying genetic factors, environmental triggers.	('lymphoma', 'Disease', 'MESH:D008223', (93, 101))	('lead to', 'Reg', (85, 92))	('B-cell function', 'CPA', (23, 38))	('mutagenesis', 'biological_process', 'GO:0006280', ('112', '123'))	('abnormal', 'Var', (14, 22))	('abnormal B-', 'Phenotype', 'HP:0002846', (14, 25))	('lymphoma', 'Disease', (93, 101))	('immune surveillance', 'MPA', (141, 160))	('disturbing', 'NegReg', (130, 140))	('mutagenesis', 'Var', (112, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))
74396	32966289	Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('hypomelanotic melanoma', 'Disease', (53, 75))	('OCA2', 'Species', '1933259', (107, 111))	('melanin', 'Chemical', 'MESH:D008543', (209, 216))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('hypomelanotic melanoma', 'Disease', 'MESH:D008545', (132, 154))	('albinism', 'Phenotype', 'HP:0001022', (21, 29))	('hypomelanotic melanoma', 'Disease', 'MESH:D008545', (53, 75))	('OCA2', 'Gene', (107, 111))	('hypomelanotic melanoma', 'Disease', (132, 154))	('variants', 'Var', (112, 120))
74397	32966289	This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls.	('TYRP1', 'Gene', (86, 91))	('OCA2', 'Gene', (162, 166))	('variants', 'Var', (150, 158))	('amelanotic/hypomelanotic melanoma', 'Disease', (187, 220))	('OCA2', 'Gene', (80, 84))	('SLC45A2', 'Gene', (93, 100))	('OCA2', 'Species', '1933259', (162, 166))	('OCA2', 'Species', '1933259', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('pigmented melanoma', 'Disease', (222, 240))	('SLC24A5', 'Gene', '570312', (102, 109))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (187, 220))	('TYR', 'Gene', (75, 78))	('albinism', 'Phenotype', 'HP:0001022', (59, 67))	('SLC24A5', 'Gene', (102, 109))	('pigmented melanoma', 'Disease', 'MESH:D008545', (222, 240))
74400	32966289	Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088).	('pigmented melanoma', 'Disease', (103, 121))	('variants', 'Var', (17, 25))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (58, 91))	('pigmented melanoma', 'Disease', 'MESH:D008545', (103, 121))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('TYR/OCA1', 'Gene', (29, 37))	('OCA1', 'Species', '1933259', (33, 37))	('amelanotic/hypomelanotic melanoma', 'Disease', (58, 91))	('common', 'Reg', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
74401	32966289	The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X2 P = 0.007).	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('melanoma', 'Disease', (152, 160))	('OCA2', 'Species', '1933259', (4, 8))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (127, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('amelanotic/hypomelanotic melanoma', 'Disease', (127, 160))	('OCA2', 'Gene', (4, 8))	('p.V443I', 'Var', (28, 35))	('p.V443I', 'Mutation', 'rs121918166', (28, 35))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
74402	32966289	No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls.	('OCA2', 'Gene', (90, 94))	('pigmented melanoma', 'Disease', 'MESH:D008545', (137, 155))	('OCA2', 'Species', '1933259', (90, 94))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (3, 36))	('skin darkening', 'Phenotype', 'HP:0000953', (62, 76))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('rs7174027', 'Mutation', 'rs7174027', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('pigmented melanoma', 'Disease', (137, 155))	('amelanotic/hypomelanotic melanoma', 'Disease', (3, 36))	('rs7174027', 'Var', (106, 115))
74403	32966289	Variants in TYR and OCA2 may play a role in amelanotic/hypomelanotic melanoma susceptibility.	('OCA2', 'Species', '1933259', (20, 24))	('Variants', 'Var', (0, 8))	('play', 'Reg', (29, 33))	('role', 'Reg', (36, 40))	('amelanotic/hypomelanotic melanoma', 'Disease', (44, 77))	('TYR', 'Gene', (12, 15))	('OCA2', 'Gene', (20, 24))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (44, 77))
74404	32966289	We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.	('loss of tumor pigmentation', 'Disease', 'MESH:D010859', (79, 105))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Atlas Skin Cutaneous Melanoma', 'Disease', (300, 329))	('mutation', 'Var', (162, 170))	('loss of tumor pigmentation', 'Disease', (79, 105))	('amelanotic/hypomelanotic melanoma', 'Disease', (186, 219))	('Atlas Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (300, 329))	('Cancer', 'Disease', 'MESH:D009369', (286, 292))	('Cancer', 'Phenotype', 'HP:0002664', (286, 292))	('loss of function', 'NegReg', (24, 40))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('Cancer', 'Disease', (286, 292))	('pigmentation', 'biological_process', 'GO:0043473', ('93', '105'))	('hypomelanotic melanoma vs pigmented melanoma', 'Disease', (197, 241))	('OCA2', 'Species', '1933259', (178, 182))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (311, 329))	('TYR/OCA2', 'Gene', (174, 182))	('Melanoma', 'Phenotype', 'HP:0002861', (321, 329))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (186, 219))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('hypomelanotic melanoma vs pigmented melanoma', 'Disease', 'MESH:D008545', (197, 241))
74412	32966289	Other albinism classes are: OCA2 caused by deletion or loss of activity of the melanosomal P-protein (OCA2 gene); OCA3 attributable to mutations in TYRP1; OCA4 due to loss of SLC45A2; and OCA5 which is linked to chromosome 4q24, with the responsible gene yet to be characterized.	('OCA2', 'Disease', (28, 32))	('OCA4', 'Species', '1933259', (155, 159))	('OCA2', 'Species', '1933259', (102, 106))	('OCA3', 'Species', '1933259', (114, 118))	('TYRP1', 'Gene', (148, 153))	('activity', 'MPA', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('loss of', 'NegReg', (55, 62))	('mutations', 'Var', (135, 144))	('OCA3', 'Disease', (114, 118))	('OCA2 gene', 'Gene', (102, 111))	('OCA2', 'Species', '1933259', (28, 32))	('P-protein', 'molecular_function', 'GO:0004375', ('91', '100'))	('OCA4', 'Disease', (155, 159))	('loss', 'NegReg', (167, 171))	('albinism', 'Phenotype', 'HP:0001022', (6, 14))	('OCA5', 'Species', '1933259', (188, 192))	('chromosome', 'cellular_component', 'GO:0005694', ('212', '222'))	('deletion', 'Var', (43, 51))	('SLC45A2', 'Enzyme', (175, 182))
74413	32966289	More recently OCA6 and OCA7 have been identified with mutations in SLC24A5 and the LRMDA genes respectively.	('LRMDA', 'Gene', (83, 88))	('mutations', 'Var', (54, 63))	('SLC24A5', 'Gene', '570312', (67, 74))	('SLC24A5', 'Gene', (67, 74))
74415	32966289	Common variants in several of these genes are associated with normal as well as pathological variation in human pigmentation.	('human', 'Species', '9606', (106, 111))	('variants', 'Var', (7, 15))	('pigmentation', 'biological_process', 'GO:0043473', ('112', '124'))	('associated', 'Reg', (46, 56))	('pigmentation', 'Disease', 'MESH:D010859', (112, 124))	('pigmentation', 'Disease', (112, 124))
74416	32966289	An important example is OCA2 [MIM 611409], where protein coding or regulatory variants alter the expression or function of the P-protein, which assists trafficking and processing of the TYR protein.	('P-protein', 'molecular_function', 'GO:0004375', ('127', '136'))	('expression', 'MPA', (97, 107))	('OCA2', 'Species', '1933259', (24, 28))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('TYR', 'Protein', (186, 189))	('P-protein', 'Protein', (127, 136))	('function', 'MPA', (111, 119))	('trafficking', 'MPA', (152, 163))	('processing', 'MPA', (168, 178))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('alter', 'Reg', (87, 92))	('variants', 'Var', (78, 86))	('assists', 'PosReg', (144, 151))
74417	32966289	Deletion of the region encompassing the OCA2 gene on chromosome 15, as observed in Prader-Willi and Angelman syndromes, is associated with hypopigmentation of the skin, hair, and eyes, and extra copies of this chromosomal region result in generalized hyperpigmentation of the skin.	('associated with', 'Reg', (123, 138))	('pigmentation', 'Disease', (256, 268))	('hypopigmentation', 'Disease', 'MESH:D017496', (139, 155))	('result in', 'Reg', (229, 238))	('hypopigmentation', 'Phenotype', 'HP:0001010', (139, 155))	('generalized hyperpigmentation', 'Phenotype', 'HP:0007440', (239, 268))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('OCA2', 'Gene', (40, 44))	('hyperpigmentation of the skin', 'Phenotype', 'HP:0000953', (251, 280))	('Prader-Willi and Angelman syndromes', 'Disease', 'MESH:D011218', (83, 118))	('chromosomal region', 'cellular_component', 'GO:0098687', ('210', '228'))	('hypopigmentation', 'Disease', (139, 155))	('OCA2', 'Species', '1933259', (40, 44))	('pigmentation', 'Disease', 'MESH:D010859', (256, 268))	('extra copies', 'Var', (189, 201))	('pigmentation', 'Disease', 'MESH:D010859', (143, 155))	('pigmentation', 'Disease', (143, 155))	('Deletion', 'Var', (0, 8))
74418	32966289	The greatest contributor to normal variation in eye color is a common intronic single nucleotide polymorphism, rs12913832 in OCA2, that also affects skin color, but has a disproportionately small magnitude of effect on melanoma risk.	('skin', 'MPA', (149, 153))	('OCA2', 'Species', '1933259', (125, 129))	('rs12913832', 'Var', (111, 121))	('affects', 'Reg', (141, 148))	('rs12913832', 'Mutation', 'rs12913832', (111, 121))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('OCA2', 'Gene', (125, 129))
74421	32966289	We have previously shown the common MC1R and TYR variants associated with fair skin occur at increased frequency in AHM.	('TYR', 'Gene', (45, 48))	('variants', 'Var', (49, 57))	('fair skin', 'Phenotype', 'HP:0007513', (74, 83))	('fair skin', 'Disease', (74, 83))	('MC1R', 'Gene', '4157', (36, 40))	('AHM', 'Disease', (116, 119))	('MC1R', 'Gene', (36, 40))
74422	32966289	Therefore, it is reasonable to hypothesize that rarer albinism-associated variants should also be more frequent in AHM cases as compared to pigmented melanoma (PM).	('pigmented melanoma', 'Disease', 'MESH:D008545', (140, 158))	('albinism', 'Phenotype', 'HP:0001022', (54, 62))	('AHM', 'Disease', (115, 118))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('pigmented melanoma', 'Disease', (140, 158))	('variants', 'Var', (74, 82))	('frequent', 'Reg', (103, 111))
74424	32966289	This study aimed to compare the rates of rare alleles in albinism genes in patients with AHM, PM only, or with no melanoma history and found differences in rates of TYR/OCA1 and OCA2 variants.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Disease', (114, 122))	('OCA2', 'Species', '1933259', (178, 182))	('albinism', 'Phenotype', 'HP:0001022', (57, 65))	('patients', 'Species', '9606', (75, 83))	('variants', 'Var', (183, 191))	('AHM', 'Disease', (89, 92))	('OCA1', 'Species', '1933259', (169, 173))	('OCA2', 'Gene', (178, 182))	('albinism genes', 'Gene', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('TYR/OCA1', 'Var', (165, 173))
74429	32966289	A separate Excel file containing ANNOVAR annotated variants of these 10 genes is also provided (S4 File), and specific in silico analysis of TYR and OCA2 variants of unknown significance are shown in S5 File.	('OCA2', 'Gene', (149, 153))	('variants', 'Var', (154, 162))	('TYR', 'Gene', (141, 144))	('variants', 'Var', (51, 59))	('OCA2', 'Species', '1933259', (149, 153))
74438	32966289	In our dataset, PolyPhen2 (HVAR) and MutationTaster provided the most consistent correlation with known naevi and melanoma-related genes.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('PolyPhen2', 'Var', (16, 25))	('naevi', 'Phenotype', 'HP:0003764', (104, 109))	('MutationTaster', 'Var', (37, 51))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
74443	32966289	A total of 20 coding region variants (S1 Table, gnomAD minor allele frequency (MAF)) were seen for the TYR gene with the two common alleles p.S192Y (36.4%) and p.R402Q (27.3%) having been previously reported in this dataset.	('p.R402Q', 'Var', (160, 167))	('TYR', 'Gene', (103, 106))	('p.S192Y', 'Mutation', 'rs1042602', (140, 147))	('p.R402Q', 'Mutation', 'rs1126809', (160, 167))	('p.S192Y', 'Var', (140, 147))
74444	32966289	In addition to these common variants, there were 18 rare coding variants with <1% frequency in gnomAD or MGRB control collection, 13 of which have been previously reported to cause OCA1 (Albinism database http://www.ifpcs.org/albinism/index.html).	('OCA1', 'Species', '1933259', (181, 185))	('cause', 'Reg', (175, 180))	('albinism', 'Phenotype', 'HP:0001022', (226, 234))	('OCA1', 'Disease', (181, 185))	('variants', 'Var', (64, 72))	('Albinism', 'Phenotype', 'HP:0001022', (187, 195))
74445	32966289	Three of these TYR rare variants (p.A23T, p.T373K and p.P460L) were found in the AHM population in comparison to six (p.R217Q, p.V275F, p.R299H, p.N371T, p.T373K, p.P460L) in the larger PM group.	('p.T373K', 'Var', (154, 161))	('p.P460L', 'Var', (54, 61))	('p.R299H', 'Mutation', 'rs61754375', (136, 143))	('p.R299H', 'Var', (136, 143))	('p.V275F', 'Var', (127, 134))	('p.N371T', 'Var', (145, 152))	('p.T373K', 'Mutation', 'rs61754388', (42, 49))	('p.V275F', 'Mutation', 'rs104894314', (127, 134))	('p.A23T', 'Var', (34, 40))	('p.T373K', 'Var', (42, 49))	('p.P460L', 'Mutation', 'p.P460L', (163, 170))	('p.N371T', 'Mutation', 'rs61754387', (145, 152))	('p.P460L', 'Var', (163, 170))	('p.P460L', 'Mutation', 'p.P460L', (54, 61))	('p.R217Q', 'Mutation', 'rs61754365', (118, 125))	('p.R217Q', 'Var', (118, 125))	('p.T373K', 'Mutation', 'rs61754388', (154, 161))	('p.A23T', 'Mutation', 'rs1373014646', (34, 40))
74446	32966289	In considering the frequency of individual rare TYR variants in different subtypes of melanoma, the p.A23T variant showed the largest difference, occurring at a higher frequency in AHM vs PM (X2 unadjusted P = 0.008).	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('p.A23T', 'Mutation', 'rs1373014646', (100, 106))	('higher', 'PosReg', (161, 167))	('p.A23T', 'Var', (100, 106))	('AHM', 'Disease', (181, 184))
74447	32966289	The p.A23T and p.T373K variants were more common in AHM cases as compared to controls (X2 unadjusted P = 0.006 and X2 P = 0.02 respectively).	('AHM', 'Disease', (52, 55))	('p.A23T', 'Mutation', 'rs1373014646', (4, 10))	('p.A23T', 'Var', (4, 10))	('p.T373K', 'Mutation', 'rs61754388', (15, 22))	('p.T373K', 'Var', (15, 22))
74448	32966289	There were 18 coding variants in OCA2 (S1 Table, gnomAD MAF), two of which, p.R305W (5.05%) and p.R419Q (6.5%), have been described previously as being common, with a third variant p.V443I at 1.09% in MGRB controls (Table 1 and S1 Table).	('OCA2', 'Gene', (33, 37))	('p.R305W', 'Var', (76, 83))	('p.R305W', 'Mutation', 'p.R305W', (76, 83))	('p.R419Q', 'Var', (96, 103))	('OCA2', 'Species', '1933259', (33, 37))	('p.R419Q', 'Mutation', 'rs1800407', (96, 103))	('p.V443I', 'Var', (181, 188))	('p.V443I', 'Mutation', 'rs121918166', (181, 188))
74449	32966289	Seven of the remaining 15 rare variants (<1%) have been reported as causative for OCA2 albinism (excluding p.R266W which has been reported as common in African populations) and seven were in silico predicted to be deleterious.	('causative', 'Reg', (68, 77))	('variants', 'Var', (31, 39))	('p.R266W', 'Mutation', 'p.R266W', (107, 114))	('OCA2', 'Species', '1933259', (82, 86))	('OCA2 albinism', 'Disease', (82, 95))	('albinism', 'Phenotype', 'HP:0001022', (87, 95))
74450	32966289	None of these rare alleles were seen in the AHM group, but there were six seen each once in the PM group (p.A55fs, p.P211L, p.I370T, p.N489D, p.F685fs, p.L734R).	('p.F685fs', 'Var', (142, 150))	('p.P211L', 'Var', (115, 122))	('p.A55fs', 'Mutation', 'p.A55fsX', (106, 113))	('p.L734R', 'Mutation', 'rs768934658', (152, 159))	('p.A55fs', 'Var', (106, 113))	('p.L734R', 'Var', (152, 159))	('p.F685fs', 'Mutation', 'p.F685fsX', (142, 150))	('p.N489D', 'Var', (133, 140))	('p.N489D', 'Mutation', 'rs121918170', (133, 140))	('p.I370T', 'Var', (124, 131))	('p.P211L', 'Mutation', 'rs774134420', (115, 122))	('p.I370T', 'Mutation', 'rs34731820', (124, 131))
74452	32966289	However, analyzing each variant separately revealed that the p.V443I variant occurred at higher frequency in AHM cases (4.44%) compared to PM cases (1.57%), BNMS controls (0.84%), or the MGRB (1.09%) (combined control comparison X2 P = 0.01), with comparison of "any melanoma" nominally significant (X2 P = 0.04).	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('p.V443I', 'Mutation', 'rs121918166', (61, 68))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('p.V443I', 'Var', (61, 68))	('AHM', 'Disease', (109, 112))
74453	32966289	Combining the TYR and OCA2 rare alleles (excluding p.V443I due to MAF >1% in MGRB controls) together for statistical analysis (Table 1), there was a higher frequency in AHM than in PM cases (4.67% vs 2.71%), but this did not achieve statistical significance.	('AHM', 'Disease', (169, 172))	('OCA2', 'Gene', (22, 26))	('p.V443I', 'Mutation', 'rs121918166', (51, 58))	('p.V443I', 'Var', (51, 58))	('OCA2', 'Species', '1933259', (22, 26))
74454	32966289	However, compared to combined controls (3.13% BNMS/2.04% MGRB), there was a highly significant greater occurrence of TYR+OCA2 deleterious alleles in total melanoma cases (SMMAT P = 0.008), but not AHM (SMMAT P = 0.90), nor in comparison between AHM and PM (SMMAT P = 0.095).	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('OCA2', 'Species', '1933259', (121, 125))	('TYR+OCA2', 'Var', (117, 125))	('melanoma', 'Disease', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('greater', 'PosReg', (95, 102))
74455	32966289	There were no rare variants in TYRP1 (OCA3), SLC45A2 (OCA4), SLC24A5 (OCA6) or LRMDA (OCA7) in our AHM population.	('SLC45A2', 'Gene', (45, 52))	('TYRP1', 'Gene', (31, 36))	('OCA3', 'Species', '1933259', (38, 42))	('SLC24A5', 'Gene', '570312', (61, 68))	('SLC24A5', 'Gene', (61, 68))	('OCA4', 'Species', '1933259', (54, 58))	('variants', 'Var', (19, 27))
74456	32966289	There was also no rare variants for SLC24A5 (OCA6) in the melanoma samples, and no significant difference in frequencies between cases and controls for the four TYRP1, five SLC45A2 and one LRMDA rare alleles that were observed in the study.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('SLC24A5', 'Gene', '570312', (36, 43))	('SLC24A5', 'Gene', (36, 43))	('variants', 'Var', (23, 31))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
74457	32966289	The odds ratios (OR) were then evaluated for TYR rare variant frequencies and the OCA2 p.V443I allele frequency.	('TYR rare', 'Var', (45, 53))	('OCA2', 'Gene', (82, 86))	('OCA2', 'Species', '1933259', (82, 86))	('p.V443I', 'Mutation', 'rs121918166', (87, 94))	('p.V443I', 'Var', (87, 94))
74459	32966289	Upon comparing AHM cases to BNMS controls, higher OR for both TYR at 14.52 (95%CI 2.87-31.58) and OCA2 p.V443I at 5.17 (95%CI 1.80-14.85) were obtained.	('p.V443I', 'Var', (103, 110))	('AHM', 'Disease', (15, 18))	('TYR', 'Var', (62, 65))	('p.V443I', 'Mutation', 'rs121918166', (103, 110))	('OCA2', 'Species', '1933259', (98, 102))
74460	32966289	In each of these analyses, the combined rare variants of TYR were of higher penetrance than OCA2 p.V443I alone.	('p.V443I', 'Mutation', 'rs121918166', (97, 104))	('variants', 'Var', (45, 53))	('OCA2', 'Species', '1933259', (92, 96))	('TYR', 'Gene', (57, 60))	('higher', 'PosReg', (69, 75))
74462	32966289	These small numbers resulted in very high OR but with broad confidence intervals, and a larger data set will be required to confirm the apparent synergistic penetrance of combined genotypes at TYR and OCA2 p.V443I.	('OCA2', 'Gene', (201, 205))	('p.V443I', 'Mutation', 'rs121918166', (206, 213))	('p.V443I', 'Var', (206, 213))	('OCA2', 'Species', '1933259', (201, 205))
74464	32966289	Notably, the most significantly associated SNP for blue eye color, rs12913832*G/A (intron 86 of HERC2) (Fig 1), was not statistically associated with AHM (Tables 3 and 4).	('rs12913832', 'Mutation', 'rs12913832', (67, 77))	('rs12913832*G/A', 'Var', (67, 81))	('blue eye', 'Phenotype', 'HP:0000635', (51, 59))	('AHM', 'Disease', (150, 153))	('HERC2', 'Gene', (96, 101))	('HERC2', 'Gene', '8924', (96, 101))
74465	32966289	The three-SNP haplotype (rs7495174, rs4778241, rs4778138) of the first intron of OCA2, predictive of eye color, was expanded to allow a larger region to be analyzed.	('rs4778241', 'Var', (36, 45))	('rs7495174', 'Var', (25, 34))	('rs7495174', 'Mutation', 'rs7495174', (25, 34))	('rs4778241', 'Mutation', 'rs4778241', (36, 45))	('OCA2', 'Gene', (81, 85))	('rs4778138', 'Var', (47, 56))	('rs4778138', 'Mutation', 'rs4778138', (47, 56))	('OCA2', 'Species', '1933259', (81, 85))
74467	32966289	Most significantly, the rs7174027*A SNP flanking the OCA2 gene promoter region/transcription start site was absent in AHM patients, compared to a frequency of 7.1% in the PM group (X2 unadjusted P = 0.0005) and 9.43% frequency in the BNMS control group (X2 unadjusted P = 8x10-5).	('rs7174027*A', 'Var', (24, 35))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('AHM', 'Disease', (118, 121))	('absent', 'NegReg', (108, 114))	('OCA2', 'Gene', (53, 57))	('patients', 'Species', '9606', (122, 130))	('OCA2', 'Species', '1933259', (53, 57))	('rs7174027', 'Mutation', 'rs7174027', (24, 33))
74468	32966289	Three other SNPs, rs1470608*T, rs4778138*G and rs7495174*G, also showed a significant difference in comparing the AHM to the PM case group or BNMS controls.	('rs4778138', 'Mutation', 'rs4778138', (31, 40))	('rs1470608*T', 'Var', (18, 29))	('rs7495174*G', 'Var', (47, 58))	('rs4778138*G', 'Var', (31, 42))	('rs1470608', 'Mutation', 'rs1470608', (18, 27))	('rs7495174', 'Mutation', 'rs7495174', (47, 56))
74469	32966289	Rs4778138*G and rs7495174*G have previously been associated with blue eye color.	('Rs4778138', 'Mutation', 'Rs4778138', (0, 9))	('associated', 'Reg', (49, 59))	('rs7495174*G', 'Var', (16, 27))	('Rs4778138*G', 'Var', (0, 11))	('blue eye', 'Phenotype', 'HP:0000635', (65, 73))	('rs7495174', 'Mutation', 'rs7495174', (16, 25))	('blue eye color', 'Disease', (65, 79))
74470	32966289	Following the significant OCA2 haplotype findings above, we analyzed the interaction of HERC2/OCA2 rs12913832*G/A and rs7174027*G/A SNPs in blue eye color, sun sensitivity and AHM (Table 4, Fig 1).	('HERC2', 'Gene', (88, 93))	('interaction', 'Interaction', (73, 84))	('rs12913832*G/A', 'Var', (99, 113))	('rs7174027', 'Mutation', 'rs7174027', (118, 127))	('HERC2', 'Gene', '8924', (88, 93))	('OCA2', 'Species', '1933259', (94, 98))	('blue eye', 'Phenotype', 'HP:0000635', (140, 148))	('rs12913832', 'Mutation', 'rs12913832', (99, 109))	('blue eye color', 'Disease', (140, 154))	('sun sensitivity', 'Phenotype', 'HP:0000992', (156, 171))	('rs7174027*G/A', 'Var', (118, 131))	('SNPs in blue eye color', 'Phenotype', 'HP:0000592', (132, 154))	('OCA2', 'Species', '1933259', (26, 30))
74471	32966289	The HERC2 rs12913832*A allele was further confirmed to be significantly associated with blue eye color (P<2.2x10-16; OR 25.32 (18.16-35.92)).	('blue eye color', 'Disease', (88, 102))	('associated', 'Reg', (72, 82))	('HERC2', 'Gene', (4, 9))	('HERC2', 'Gene', '8924', (4, 9))	('rs12913832*A', 'Var', (10, 22))	('rs12913832', 'Mutation', 'rs12913832', (10, 20))	('blue eye', 'Phenotype', 'HP:0000635', (88, 96))
74472	32966289	The rs7174027*A allele was most significantly associated with AHM (P = 0.0002; OR 19.67 (2.76.16-2495.52)) and to a lesser degree with blue eye color (P = 0.0047; OR 2.17 (1.33-3.54)).	('rs7174027*A', 'Var', (4, 15))	('blue eye color', 'Disease', (135, 149))	('associated', 'Reg', (46, 56))	('AHM', 'Disease', (62, 65))	('rs7174027', 'Mutation', 'rs7174027', (4, 13))	('blue eye', 'Phenotype', 'HP:0000635', (135, 143))
74473	32966289	Both SNPs were significantly associated with sun sensitivity, rs12913832*A (P = 0.0018) and rs7174027*A (P = 0.0036) and with Fitzpatrick skin type I (OR 1.29 (1.03-1.61) and 1.60 (1.13-2.29) respectively).	('sun sensitivity', 'Phenotype', 'HP:0000992', (45, 60))	('rs7174027', 'Mutation', 'rs7174027', (92, 101))	('rs12913832', 'Mutation', 'rs12913832', (62, 72))	('associated', 'Reg', (29, 39))	('sun sensitivity', 'Disease', (45, 60))	('rs7174027*A', 'Var', (92, 103))	('Fitzpatrick skin type I', 'Disease', (126, 149))	('rs12913832*A', 'Var', (62, 74))
74476	32966289	Data from 10,389 adult cancers from the Cancer Genome Atlas (TCGA) dataset were first used to compare the common and rare MC1R variant allele frequencies in PM and AHM samples in the 470 SKCM (Skin Cutaneous Melanoma) collection.	('MC1R', 'Gene', '4157', (122, 126))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('MC1R', 'Gene', (122, 126))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer', 'Disease', (40, 46))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (193, 216))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancers', 'Disease', (23, 30))	('variant', 'Var', (127, 134))	('Melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Skin Cutaneous Melanoma', 'Disease', (193, 216))
74478	32966289	Although there were no R/R genotypes seen in the AHM samples they all carried either an r or R variant and no WT/WT, compared with a frequency of 19.7% of PM and 37.9% in other cancers.	('carried', 'Reg', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('variant', 'Var', (95, 102))	('cancers', 'Disease', (177, 184))	('r or R variant', 'Var', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
74479	32966289	Thus the SKCM AHM samples are consistent with having a higher frequency of MC1R variants compared to PM.	('MC1R', 'Gene', '4157', (75, 79))	('MC1R', 'Gene', (75, 79))	('variants', 'Var', (80, 88))
74480	32966289	The 7 AHM did not carry any deleterious germline deleterious or albinism alleles, nor the OCA2 p.V443I polymorphism.	('OCA2', 'Gene', (90, 94))	('albinism', 'Phenotype', 'HP:0001022', (64, 72))	('OCA2', 'Species', '1933259', (90, 94))	('albinism', 'CPA', (64, 72))	('p.V443I', 'Var', (95, 102))	('p.V443I', 'Mutation', 'rs121918166', (95, 102))
74481	32966289	However, upon examination of the sequencing data matched AHM tumor for somatic mutations or copy number variation (CNV) changes, four of the albinism genes were found to have deleterious mutations present in one or more samples (Table 5).	('copy number variation', 'Var', (92, 113))	('AHM tumor', 'Disease', (57, 66))	('albinism genes', 'Gene', (141, 155))	('AHM tumor', 'Disease', 'MESH:D009369', (57, 66))	('changes', 'Var', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('albinism', 'Phenotype', 'HP:0001022', (141, 149))
74482	32966289	The TYR gene had moderate to severe missense amino acid mutations in two AHM samples (p.P70S and p.M96_F98del), with a third sample having a CNV loss within the OCA2 gene.	('OCA2', 'Species', '1933259', (161, 165))	('p.M96_F98del', 'Mutation', 'p.96,98delF', (97, 109))	('loss', 'NegReg', (145, 149))	('OCA2', 'Gene', (161, 165))	('p.P70S', 'Var', (86, 92))	('p.M96_F98del', 'Var', (97, 109))	('p.P70S', 'Mutation', 'rs372689330', (86, 92))	('TYR', 'Gene', (4, 7))	('missense amino acid mutations', 'Var', (36, 65))
74483	32966289	In considering only the TYR point mutation/deletion, this represents 28.6% of the AHM compared with 3.0% of PM and 3.7% of other tumor samples (P = 0.021 and 0.026 respectively).	('TYR point mutation/deletion', 'Var', (24, 51))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('AHM', 'Disease', (82, 85))	('tumor', 'Disease', (129, 134))
74485	32966289	These results clearly demonstrate that rare albinism-associated variants in TYR, and the OCA2 p.V443I variant, are more frequent in individuals with melanoma as compared to controls.	('OCA2', 'Species', '1933259', (89, 93))	('albinism-associated', 'Disease', (44, 63))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('albinism', 'Phenotype', 'HP:0001022', (44, 52))	('melanoma', 'Disease', (149, 157))	('TYR', 'Gene', (76, 79))	('frequent', 'Reg', (120, 128))	('OCA2', 'Gene', (89, 93))	('p.V443I', 'Mutation', 'rs121918166', (94, 101))	('p.V443I', 'Var', (94, 101))
74486	32966289	This is in keeping with the recent report, by Goldstein and colleagues that familial melanoma cases in the USA had an increased burden of rare germline variants in TYR and OCA2, and sporadic melanoma cases an increased frequency of mutations in TYR.	('sporadic melanoma', 'Disease', (182, 199))	('familial melanoma', 'Disease', (76, 93))	('OCA2', 'Species', '1933259', (172, 176))	('familial melanoma', 'Disease', 'MESH:C562393', (76, 93))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('TYR', 'Gene', (245, 248))	('sporadic melanoma', 'Disease', 'MESH:D008545', (182, 199))	('mutations', 'Var', (232, 241))	('variants', 'Var', (152, 160))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('OCA2', 'Gene', (172, 176))	('TYR', 'Gene', (164, 167))
74487	32966289	In particular, the TYR stopgain p.R402* mutation (rs62645917) co-segregated with melanoma in five familial cases and has a population frequency of ~3x10-5.	('p.R402*', 'Mutation', 'p.R402*', (32, 39))	('rs62645917', 'Mutation', 'rs62645917', (50, 60))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('TYR', 'Gene', (19, 22))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('p.R402*', 'Var', (32, 39))
74488	32966289	In the present collection, rare variant burden tests showed that familial and population-based cutaneous melanoma patients tended to have higher frequencies of rare germline variants in albinism genes including TYR and OCA2.	('albinism', 'Phenotype', 'HP:0001022', (186, 194))	('OCA2', 'Species', '1933259', (219, 223))	('TYR', 'Var', (211, 214))	('albinism', 'Gene', (186, 194))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('OCA2', 'Gene', (219, 223))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))	('patients', 'Species', '9606', (114, 122))
74489	32966289	Of further significance, our study demonstrated that rare variants of TYR and the OCA2 p.V443I allele were even more frequent in individuals with AHM as compared to those with PM.	('AHM', 'Disease', (146, 149))	('TYR', 'Gene', (70, 73))	('OCA2', 'Gene', (82, 86))	('OCA2', 'Species', '1933259', (82, 86))	('frequent', 'Reg', (117, 125))	('p.V443I', 'Mutation', 'rs121918166', (87, 94))	('p.V443I', 'Var', (87, 94))
74492	32966289	In another example demonstrating skin lightening in a Japanese study, the OCA2 p.A481T polymorphism was strongly associated with melanin index, correlating with lighter skin color (P = 6.18x10-8), and is an albinism allele recognized by Lasseaux et al.	('melanin index', 'MPA', (129, 142))	('OCA2', 'Gene', (74, 78))	('skin lightening', 'Phenotype', 'HP:0001010', (33, 48))	('melanin', 'Chemical', 'MESH:D008543', (129, 136))	('lighter skin color', 'MPA', (161, 179))	('p.A481T', 'Var', (79, 86))	('OCA2', 'Species', '1933259', (74, 78))	('p.A481T', 'Mutation', 'rs74653330', (79, 86))	('albinism', 'Phenotype', 'HP:0001022', (207, 215))	('associated', 'Reg', (113, 123))
74493	32966289	As lighter skin color is recognized as a risk factor for melanoma this would provide a plausible explanation for the raised frequency of TYR and OCA2 p.V443I albinism/deleterious gene allele carriers in melanoma cases.	('p.V443I', 'Mutation', 'rs121918166', (150, 157))	('p.V443I', 'Var', (150, 157))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('OCA2', 'Species', '1933259', (145, 149))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('albinism', 'Phenotype', 'HP:0001022', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('OCA2', 'Gene', (145, 149))
74495	32966289	The OCA2 p.V443I was not reported upon by Goldstein et al., as it occurred at greater frequency than 0.1% in their collection which was selected as the cut off frequency in this earlier study, however the OCA2 p.C777Y and p.Y342C alleles are reported on here (seen only in controls, see S1 Table).	('OCA2', 'Gene', (205, 209))	('OCA2', 'Species', '1933259', (4, 8))	('p.V443I', 'Mutation', 'rs121918166', (9, 16))	('p.C777Y', 'Var', (210, 217))	('p.Y342C', 'Mutation', 'rs142931246', (222, 229))	('OCA2', 'Species', '1933259', (205, 209))	('p.Y342C', 'Var', (222, 229))	('p.C777Y', 'Mutation', 'rs776814755', (210, 217))
74496	32966289	Although melanoma in albinism patients is rare, it is almost invariably presents as amelanotic melanoma as seen in TYR-mutated OCA1 patients.	('amelanotic melanoma', 'Disease', (84, 103))	('OCA1', 'Species', '1933259', (127, 131))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('TYR-mutated', 'Var', (115, 126))	('melanoma', 'Disease', (95, 103))	('OCA1', 'Gene', (127, 131))	('amelanotic melanoma', 'Disease', 'MESH:D018328', (84, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('patients', 'Species', '9606', (30, 38))	('albinism', 'Phenotype', 'HP:0001022', (21, 29))	('presents', 'Reg', (72, 80))	('patients', 'Species', '9606', (132, 140))
74497	32966289	Deleterious variants in TYR/OCA1 were more common in AHM melanoma cases than in PM cases and the same was true for the OCA2 hypomorphic allele p.V443I.	('TYR/OCA1', 'Gene', (24, 32))	('OCA1', 'Species', '1933259', (28, 32))	('AHM melanoma', 'Disease', (53, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('common', 'Reg', (43, 49))	('p.V443I', 'Var', (143, 150))	('variants', 'Var', (12, 20))	('p.V443I', 'Mutation', 'rs121918166', (143, 150))	('AHM melanoma', 'Disease', 'MESH:D008545', (53, 65))	('OCA2', 'Species', '1933259', (119, 123))
74501	32966289	As such, we postulate that a loss of melanin in melanoma tumor tissue in AHM may occur due to loss of heterozygosity (LOH) or somatic mutation of the functional copy of the TYR or OCA2 genes, with the remaining deleterious albinism allele(s) leading to a deficiency in melanogenesis or the observed lack of pigment.	('OCA2', 'Gene', (180, 184))	('deficiency in melanogenesis', 'Disease', (255, 282))	('TYR', 'Gene', (173, 176))	('loss', 'NegReg', (94, 98))	('OCA2', 'Species', '1933259', (180, 184))	('mutation', 'Var', (134, 142))	('melanin', 'Chemical', 'MESH:D008543', (37, 44))	('loss', 'NegReg', (29, 33))	('albinism', 'Phenotype', 'HP:0001022', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('deficiency in melanogenesis', 'Disease', 'MESH:D007153', (255, 282))	('melanoma tumor', 'Disease', (48, 62))	('melanoma tumor', 'Disease', 'MESH:D008545', (48, 62))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
74502	32966289	Examination of seven AHM samples from the TCGA SKCM collection did not reveal any deleterious of albinism alleles in the germline of these patients, as such whether this genetic loss of function mechanism actually occurs in AHM melanoma tissue remains to be experimentally confirmed.	('AHM melanoma', 'Disease', 'MESH:D008545', (224, 236))	('patients', 'Species', '9606', (139, 147))	('loss of function', 'NegReg', (178, 194))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('albinism', 'Phenotype', 'HP:0001022', (97, 105))	('genetic', 'Var', (170, 177))	('AHM melanoma', 'Disease', (224, 236))
74503	32966289	However, data supportive of this hypothesis is that the matched tumor tissues revealed that somatic mutations or CNV changes were present in albinism genes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('albinism genes', 'Gene', (141, 155))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('changes', 'Var', (117, 124))	('albinism', 'Phenotype', 'HP:0001022', (141, 149))
74504	32966289	Moreover, the rate of TYR somatic mutation was found to be significantly higher in AHM compared with PM or other cancers.	('TYR somatic mutation', 'Var', (22, 42))	('higher', 'Reg', (73, 79))	('AHM', 'Disease', (83, 86))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
74505	32966289	Chromosomal deletion and LOH is a common event in melanoma pathogenesis, so it seems plausible that in some tumors, hypopigmentation could arise in heterozygote carriers of albinism variants due to LOH.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pathogenesis', 'biological_process', 'GO:0009405', ('59', '71'))	('albinism', 'Phenotype', 'HP:0001022', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('variants', 'Var', (182, 190))	('hypopigmentation', 'Disease', 'MESH:D017496', (116, 132))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('hypopigmentation', 'Phenotype', 'HP:0001010', (116, 132))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('albinism', 'Disease', (173, 181))	('hypopigmentation', 'Disease', (116, 132))	('arise', 'Reg', (139, 144))
74506	32966289	Common noncoding polymorphisms in the HERC2/OCA2 locus have previously been associated with melanoma, with both HERC2 rs12913832 and OCA2 intron haplotype region SNPs associated with eye color and melanoma.	('HERC2', 'Gene', (112, 117))	('associated with', 'Reg', (167, 182))	('OCA2', 'Species', '1933259', (133, 137))	('rs12913832', 'Mutation', 'rs12913832', (118, 128))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('OCA2', 'Gene', (133, 137))	('melanoma', 'Disease', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('associated', 'Reg', (76, 86))	('HERC2', 'Gene', '8924', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Disease', (92, 100))	('OCA2', 'Species', '1933259', (44, 48))	('HERC2', 'Gene', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('HERC2', 'Gene', '8924', (38, 43))	('eye color', 'Disease', (183, 192))	('rs12913832', 'Var', (118, 128))
74507	32966289	The nonsynonymous p.V443I hypomorphic allele was first reported in two melanoma cases, then identified in an OCA2 albinism/familial melanoma family as a compound heterozygote with the deleterious p.L734R allele.	('p.V443I', 'Var', (18, 25))	('p.L734R', 'Var', (196, 203))	('melanoma', 'Disease', (132, 140))	('familial melanoma', 'Disease', 'MESH:C562393', (123, 140))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('albinism', 'Phenotype', 'HP:0001022', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('OCA2', 'Species', '1933259', (109, 113))	('p.V443I', 'Mutation', 'rs121918166', (18, 25))	('p.L734R', 'Mutation', 'rs768934658', (196, 203))	('familial melanoma', 'Disease', (123, 140))
74509	32966289	In a recent report of a multi-gene panel screening of Dutch non-CDKN2A/CDK4 melanoma families, 9 rare pathogenic variants of OCA2 were found.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('CDKN2A', 'Gene', (64, 70))	('OCA2', 'Species', '1933259', (125, 129))	('CDKN2A', 'Gene', '1029', (64, 70))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))	('variants', 'Var', (113, 121))	('OCA2', 'Gene', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
74510	32966289	The p.V443I and p.N489D alleles were detected at double the frequency of Dutch GoNL reference database controls (1.8% and 0.71%) similar to the frequency of these alleles in all melanoma cases reported here (1.81% and 0.09%, S1 Table).	('p.N489D', 'Var', (16, 23))	('p.N489D', 'Mutation', 'rs121918170', (16, 23))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('p.V443I', 'Mutation', 'rs121918166', (4, 11))	('p.V443I', 'Var', (4, 11))
74512	32966289	Notably, a p.V443I homozygous Dutch patient was reported as having 3 primary melanomas, as was another individual who was biallelic for OCA2.	('melanomas', 'Disease', (77, 86))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('p.V443I', 'Mutation', 'rs121918166', (11, 18))	('p.V443I', 'Var', (11, 18))	('OCA2', 'Species', '1933259', (136, 140))	('patient', 'Species', '9606', (36, 43))
74513	32966289	In another recent study of Australian and Danish melanoma families, the OCA2 p.V443I frequency was increased in cases (6 carriers in 107 cases, crude allele frequency 2.8%) and the OCA2 p.N489D was detected in three cases from one pedigree (1.4%).	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('OCA2', 'Species', '1933259', (181, 185))	('p.N489D', 'Var', (186, 193))	('p.V443I', 'Mutation', 'rs121918166', (77, 84))	('p.V443I', 'Var', (77, 84))	('p.N489D', 'Mutation', 'rs121918170', (186, 193))	('OCA2', 'Species', '1933259', (72, 76))	('increased', 'PosReg', (99, 108))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('OCA2', 'Gene', (72, 76))
74514	32966289	This is comparable to our data, where 7 of 106 (3.3%) of multiple primary melanoma cases had a report of an affected first degree relative and p.N489D was present in one multiple primary melanoma patient and five (BNMS and MGRB) controls.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('patient', 'Species', '9606', (196, 203))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('p.N489D', 'Var', (143, 150))	('melanoma', 'Disease', (74, 82))	('p.N489D', 'Mutation', 'rs121918170', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))
74517	32966289	The rs7174027*A allele was absent in all 45 AHM samples analyzed, but present in 7.1% of pigmented cases and 9.43% of BNMS controls, giving the highest P-value in comparing SNPs between AHM and PM (0.0005) and any BNMS cases vs controls (8x10-5).	('rs7174027*A', 'Var', (4, 15))	('pigmented', 'Disease', (89, 98))	('SNPs', 'MPA', (173, 177))	('rs7174027', 'Mutation', 'rs7174027', (4, 13))	('pigmented', 'Disease', 'MESH:D010859', (89, 98))
74518	32966289	The intronic haplotype tagged by rs7174027 acts independently of the most highly associated SNP for eye color, rs12913832, in its effects on AHM.	('AHM', 'Disease', (141, 144))	('rs7174027', 'Mutation', 'rs7174027', (33, 42))	('effects', 'Reg', (130, 137))	('rs12913832', 'Var', (111, 121))	('rs7174027', 'Var', (33, 42))	('rs12913832', 'Mutation', 'rs12913832', (111, 121))
74519	32966289	It was reported earlier that the three-SNP haplotype based on rs7495174*A/G, rs4778241*C/A, and rs4778138*A/G (termed blue-eye associated haplotype 1, BEH1) was a recessive modifier associated with lighter pigmentary phenotypes.	('rs4778138', 'Mutation', 'rs4778138', (96, 105))	('rs7495174', 'Mutation', 'rs7495174', (62, 71))	('rs4778241', 'Mutation', 'rs4778241', (77, 86))	('rs7495174*A/G', 'Var', (62, 75))	('rs4778138*A/G', 'Var', (96, 109))	('rs4778241*C/A', 'Var', (77, 90))	('blue-eye', 'Phenotype', 'HP:0000635', (118, 126))
74520	32966289	This OCA2 haplotype block, including rs7174027, could potentially lead to a reduction in expression of OCA2 levels so as to functionally contribute to the hypopigmented phenotype in the AHM cohort, although direct experimental testing has not yet found any evidence for this.	('reduction', 'NegReg', (76, 85))	('expression', 'MPA', (89, 99))	('OCA2', 'Gene', (5, 9))	('OCA2', 'Species', '1933259', (103, 107))	('hypopigmented', 'Disease', (155, 168))	('rs7174027', 'Mutation', 'rs7174027', (37, 46))	('OCA2', 'Species', '1933259', (5, 9))	('contribute', 'Reg', (137, 147))	('hypopigmented', 'Disease', 'MESH:D017496', (155, 168))	('OCA2', 'Gene', (103, 107))	('rs7174027', 'Var', (37, 46))
74521	32966289	However, in support of a transcriptional model for intron 1 regulating OCA2 expression, a melanocyte-specific eQTL analysis of human primary melanocyte cultures reported that the rs4778138*A/G SNP (in the BEH1 haplotype block, Table 4) significantly affected expression (P = 8.72x10-8 and slope of rank normalized expression of 0.62), where individuals homozygous for the A allele had lower expression than the G homozygotes.	('affected', 'Reg', (250, 258))	('human', 'Species', '9606', (127, 132))	('expression', 'MPA', (391, 401))	('OCA2', 'Gene', (71, 75))	('rs4778138*A/G', 'Var', (179, 192))	('rs4778138', 'Mutation', 'rs4778138', (179, 188))	('OCA2', 'Species', '1933259', (71, 75))	('lower', 'NegReg', (385, 390))	('expression', 'MPA', (259, 269))
74522	32966289	The rs4778138*G SNP has previously been identified as the protective allele for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('rs4778138*G', 'Var', (4, 15))	('rs4778138', 'Mutation', 'rs4778138', (4, 13))
74523	32966289	Our study makes a significant contribution to the literature in expanding the understanding of how albinism genes influence risk for both amelanotic and pigmented melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('influence', 'Reg', (114, 123))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('pigmented melanomas', 'Disease', (153, 172))	('albinism', 'Phenotype', 'HP:0001022', (99, 107))	('amelanotic', 'Disease', (138, 148))	('pigmented melanomas', 'Disease', 'MESH:D008545', (153, 172))	('albinism', 'Gene', (99, 107))	('genes', 'Var', (108, 113))
74528	32966289	Individuals with darker hair may still be heterozygous carriers of deleterious TYR and OCA2 p.V443I albinism genes that will have effects on melanogenesis in the skin and so increase the risk of these hypopigmented melanomas.	('TYR', 'Gene', (79, 82))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanogenesis', 'MPA', (141, 154))	('p.V443I', 'Mutation', 'rs121918166', (92, 99))	('p.V443I', 'Var', (92, 99))	('OCA2', 'Species', '1933259', (87, 91))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('hypopigmented melanomas', 'Disease', 'MESH:D008545', (201, 224))	('effects', 'Reg', (130, 137))	('increase', 'PosReg', (174, 182))	('hypopigmented melanomas', 'Disease', (201, 224))	('albinism', 'Phenotype', 'HP:0001022', (100, 108))	('OCA2', 'Gene', (87, 91))
74529	32966289	Individuals carrying OCA deleterious gene variants have an increased risk of CM development, which might be more likely to present as AHM, due to a second hit to the gene during tumor development.	('tumor', 'Disease', (178, 183))	('variants', 'Var', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('OCA', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
74532	32966289	Most significantly, the rs7174027*A SNP in the first intron of the OCA2 gene, which may influence the promoter activity of this region, was absent in AHM patients.	('rs7174027*A', 'Var', (24, 35))	('influence', 'Reg', (88, 97))	('OCA2', 'Gene', (67, 71))	('promoter activity', 'MPA', (102, 119))	('patients', 'Species', '9606', (154, 162))	('AHM', 'Disease', (150, 153))	('OCA2', 'Species', '1933259', (67, 71))	('rs7174027', 'Mutation', 'rs7174027', (24, 33))
74533	32966289	This OCA2 haplotype may lead to a change in expression of OCA2 levels, functionally contributing to the hypopigmented tissue in the AHM cohort.	('change', 'Reg', (34, 40))	('expression', 'MPA', (44, 54))	('OCA2', 'Gene', (5, 9))	('OCA2', 'Species', '1933259', (58, 62))	('hypopigmented', 'Disease', (104, 117))	('haplotype', 'Var', (10, 19))	('OCA2', 'Species', '1933259', (5, 9))	('hypopigmented', 'Disease', 'MESH:D017496', (104, 117))	('contributing', 'Reg', (84, 96))	('OCA2', 'Gene', (58, 62))
74534	32966289	21 Apr 2020  PONE-D-20-07313 Albinism variants in individuals with amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants and their somatic mutation in AHM tumor tissue PLOS ONE Dear Dr. Sturm, Thank you for submitting your manuscript to PLOS ONE.	('AHM tumor', 'Disease', 'MESH:D009369', (176, 185))	('Albinism', 'Phenotype', 'HP:0001022', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('OCA2', 'Species', '1933259', (132, 136))	('amelanotic/hypomelanotic melanoma', 'Disease', (67, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('PONE-D-20-07313', 'Chemical', '-', (13, 28))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (67, 100))	('AHM tumor', 'Disease', (176, 185))	('variants', 'Var', (137, 145))
74538	32966289	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In the research article entitled "Albinism variants in individuals with amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants and their somatic mutation in AHM tumor tissue", the authors use whole exome sequencing to look for rare variants (<1% MAF) in albinism-associated genes in a small group of patients who had amelanotic or hypomelanotic melanoma.	('amelanotic/hypomelanotic melanoma', 'Disease', (162, 195))	('AHM tumor', 'Disease', 'MESH:D009369', (271, 280))	('patients', 'Species', '9606', (414, 422))	('TYR', 'Gene', (219, 222))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('albinism', 'Phenotype', 'HP:0001022', (368, 376))	('melanoma', 'Phenotype', 'HP:0002861', (459, 467))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('OCA2', 'Species', '1933259', (227, 231))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (162, 195))	('variants', 'Var', (232, 240))	('amelanotic or hypomelanotic melanoma', 'Disease', 'MESH:D018328', (431, 467))	('amelanotic or hypomelanotic melanoma', 'Disease', (431, 467))	('Albinism', 'Phenotype', 'HP:0001022', (124, 132))	('variants', 'Var', (133, 141))	('OCA2', 'Gene', (227, 231))	('AHM tumor', 'Disease', (271, 280))	('albinism-associated genes', 'Gene', (368, 393))
74539	32966289	They show that rare variants in TYR (OCA1) are more common in AHM than PM patients.	('variants', 'Var', (20, 28))	('TYR (OCA1', 'Gene', (32, 41))	('patients', 'Species', '9606', (74, 82))	('OCA1', 'Species', '1933259', (37, 41))	('AHM', 'Disease', (62, 65))	('common', 'Reg', (52, 58))
74540	32966289	No rare variants were found in OCA2,3,4,6,7 in the AHM patients but they did find higher incidence of a variant (p.V443I) in OCA2 that is below <1% in gnomAD but not in their own control group.	('p.V443I', 'Mutation', 'rs121918166', (113, 120))	('OCA2', 'Species', '1933259', (31, 35))	('OCA2', 'Species', '1933259', (125, 129))	('p.V443I', 'Var', (113, 120))	('patients', 'Species', '9606', (55, 63))	('OCA2', 'Gene', (125, 129))
74541	32966289	They then analyzed blue eye color-associated polymorphisms at OCA2/HERC2 and found a significant difference in rs7174027*A (associated with darker eye color) between AHM (not detected) and PM (also controls).	('blue eye', 'Phenotype', 'HP:0000635', (19, 27))	('rs7174027', 'Mutation', 'rs7174027', (111, 120))	('OCA2', 'Species', '1933259', (62, 66))	('HERC2', 'Gene', (67, 72))	('rs7174027*A', 'Var', (111, 122))	('HERC2', 'Gene', '8924', (67, 72))
74542	32966289	Lastly, the authors suggest that AHM could occur due to LOH or somatic mutation of the functional copy of TYR or OCA2.	('OCA2', 'Gene', (113, 117))	('OCA2', 'Species', '1933259', (113, 117))	('AHM', 'Disease', (33, 36))	('LOH', 'Var', (56, 59))	('TYR', 'Gene', (106, 109))
74543	32966289	The authors support this model using TCGA melanomas which found higher incidence of mutations or CNV in albinism genes in amelanotic melanomas (n=7) compared to pigmented melanomas (n=431).	('amelanotic melanomas', 'Disease', (122, 142))	('melanomas', 'Disease', (171, 180))	('pigmented melanomas', 'Disease', 'MESH:D008545', (161, 180))	('albinism genes', 'Gene', (104, 118))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('albinism', 'Phenotype', 'HP:0001022', (104, 112))	('melanomas', 'Disease', 'MESH:D008545', (42, 51))	('melanomas', 'Disease', (42, 51))	('amelanotic melanomas', 'Disease', 'MESH:D018328', (122, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('CNV', 'Var', (97, 100))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('mutations', 'Var', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('pigmented melanomas', 'Disease', (161, 180))	('melanomas', 'Disease', (133, 142))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
74549	32966289	Reviewer #2: A manuscript by Rayner and co-authors entitled "Albinism variants in individuals with amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants and their somatic mutation in AHM tumor tissue" may potentially be of interest to PLOS One readers, but the way the authors presented their research and organized the data in the manuscript is very difficult to follow and understand.	('OCA2', 'Species', '1933259', (164, 168))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('AHM tumor', 'Disease', (208, 217))	('amelanotic/hypomelanotic melanoma', 'Disease', (99, 132))	('AHM tumor', 'Disease', 'MESH:D009369', (208, 217))	('Albinism', 'Phenotype', 'HP:0001022', (61, 69))	('OCA2', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('variants', 'Var', (169, 177))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (99, 132))
74550	32966289	In the RESULTS, Analysis of albinism gene alleles in PM and AHM cases section the authors write: Three of these TYR rare variants 202 (p.A23T, p.T373K and p.P460L) were found in the AHM population in comparison to six 203 (p.R217Q, p.V275F, p.R299H, p.N371T, p.T373K, p.P460L) in the larger PM group.	('p.T373K', 'Mutation', 'rs61754388', (259, 266))	('p.V275F', 'Var', (232, 239))	('p.V275F', 'Mutation', 'rs104894314', (232, 239))	('found', 'Reg', (169, 174))	('p.T373K', 'Var', (143, 150))	('p.R299H', 'Mutation', 'rs61754375', (241, 248))	('p.A23T', 'Var', (135, 141))	('p.R299H', 'Var', (241, 248))	('p.R217Q', 'Var', (223, 230))	('p.N371T', 'Var', (250, 257))	('p.N371T', 'Mutation', 'rs61754387', (250, 257))	('p.T373K', 'Mutation', 'rs61754388', (143, 150))	('p.T373K', 'Var', (259, 266))	('p.P460L', 'Mutation', 'p.P460L', (155, 162))	('p.A23T', 'Mutation', 'rs1373014646', (135, 141))	('p.P460L', 'Var', (155, 162))	('p.P460L', 'Mutation', 'p.P460L', (268, 275))	('p.P460L', 'Var', (268, 275))	('p.R217Q', 'Mutation', 'rs61754365', (223, 230))	('albinism', 'Phenotype', 'HP:0001022', (28, 36))
74553	32966289	New Title: Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants Authors: Jenna E. Rayner, David L. Duffy, Darren J. Smit, Kasturee Jagirdar, Katie J. Lee, Brian De'Ambrosis, B.	("De'Ambrosis", 'Disease', 'MESH:C537981', (229, 240))	('variants', 'Var', (41, 49))	("De'Ambrosis", 'Disease', (229, 240))	('albinism', 'Phenotype', 'HP:0001022', (32, 40))	('OCA2', 'Gene', (118, 122))	('amelanotic/hypomelanotic melanoma', 'Disease', (53, 86))	('OCA2', 'Species', '1933259', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('variants', 'Var', (123, 131))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (53, 86))
74554	32966289	In the results section we have modified these sentences, "In considering the frequency of individual rare TYR variants in different subtypes of melanoma, the p.A23T variant showed the largest difference, occurring at a higher frequency in AHM vs PM (X2 unadjusted P=0.008)."	('p.A23T', 'Mutation', 'rs1373014646', (158, 164))	('p.A23T', 'Var', (158, 164))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
74555	32966289	"The p.A23T and p.T373K variants were more common in AHM cases as compared to controls (X2 unadjusted P=0.006 and X2 P=0.02 respectively)."	('p.A23T', 'Var', (5, 11))	('common', 'Reg', (43, 49))	('AHM', 'Disease', (53, 56))	('p.T373K', 'Mutation', 'rs61754388', (16, 23))	('p.A23T', 'Mutation', 'rs1373014646', (5, 11))	('p.T373K', 'Var', (16, 23))
74556	32966289	"However, analyzing each variant separately revealed that the p.V443I variant occurred at higher frequency in AHM cases (4.44%) compared to PM cases (1.57%), BNMS controls (0.84%), or the MGRB (1.09%) (combined control comparison X2 P=.01), with comparison of any case nominally significant (X2 unadjusted P=0.04)."	('p.V443I', 'Var', (62, 69))	('p.V443I', 'Mutation', 'rs121918166', (62, 69))	('AHM', 'Disease', (110, 113))
74557	32966289	"Most significantly, the rs7174027*A SNP flanking the OCA2 gene promoter region/transcription start site was absent in AHM patients, compared to a frequency of 7.1% in the PM group (X2 unadjusted P=0.0005) and 9.43% frequency in the BNMS control group (X2 unadjusted P=8x10-5)."	('rs7174027*A', 'Var', (25, 36))	('OCA2', 'Gene', (54, 58))	('patients', 'Species', '9606', (123, 131))	('AHM', 'Disease', (119, 122))	('OCA2', 'Species', '1933259', (54, 58))	('absent', 'NegReg', (109, 115))	('rs7174027', 'Mutation', 'rs7174027', (25, 34))
74560	32966289	Review Comments to the Author Reviewer #1: In the research article entitled "Albinism variants in individuals with amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants and their somatic mutation in AHM tumor tissue", the authors use whole exome sequencing to look for rare variants (<1% MAF) in albinism-associated genes in a small group of patients who had amelanotic or hypomelanotic melanoma.	('albinism', 'Phenotype', 'HP:0001022', (321, 329))	('amelanotic/hypomelanotic melanoma', 'Disease', (115, 148))	('variants', 'Var', (185, 193))	('OCA2', 'Species', '1933259', (180, 184))	('Albinism', 'Phenotype', 'HP:0001022', (77, 85))	('variants', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('patients', 'Species', '9606', (367, 375))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('amelanotic or hypomelanotic melanoma', 'Disease', 'MESH:D018328', (384, 420))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (115, 148))	('amelanotic or hypomelanotic melanoma', 'Disease', (384, 420))	('AHM tumor', 'Disease', 'MESH:D009369', (224, 233))	('AHM tumor', 'Disease', (224, 233))	('melanoma', 'Phenotype', 'HP:0002861', (412, 420))
74567	32966289	We have changed the title to, "Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants" Small clarifications / fixes Lines 221 to 223: Here the authors start with 18 variants and remove the two high frequency gnomAD variants which would leave 16 variants but the next sentence talks about the 15 rare variants.	('albinism', 'Phenotype', 'HP:0001022', (52, 60))	('OCA2', 'Species', '1933259', (138, 142))	('amelanotic/hypomelanotic melanoma', 'Disease', (73, 106))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (73, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('gnomAD', 'Gene', (274, 280))	('variants', 'Var', (143, 151))
74568	32966289	This now reads, "There were 18 coding variants in OCA2 (Table S1, gnomAD MAF), two of which, p.R305W (5.05%) and p.R419Q (6.5%), have been described previously as being common [10], with a third variant p.V443I at 1.09% in MGRB controls (Table 1 and S1).	('p.R419Q', 'Var', (113, 120))	('p.R305W', 'Var', (93, 100))	('OCA2', 'Gene', (50, 54))	('p.R305W', 'Mutation', 'p.R305W', (93, 100))	('p.R419Q', 'Mutation', 'rs1800407', (113, 120))	('OCA2', 'Species', '1933259', (50, 54))	('p.V443I', 'Mutation', 'rs121918166', (203, 210))	('p.V443I', 'Var', (203, 210))
74571	32966289	Notably the OCA2 V443I allele is slightly above this cut off and was analysed separately (see comment and revision in response to reviewer 1).	('V443I', 'Mutation', 'rs121918166', (17, 22))	('V443I', 'Var', (17, 22))	('OCA2', 'Species', '1933259', (12, 16))	('OCA2', 'Gene', (12, 16))
74573	32966289	27 Jul 2020  PONE-D-20-07313R1 Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 PLOS ONE Dear Dr. Sturm, Thank you for submitting your manuscript to PLOS ONE.	('albinism', 'Phenotype', 'HP:0001022', (52, 60))	('OCA2', 'Species', '1933259', (138, 142))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (73, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('TYR', 'Var', (130, 133))	('PONE-D-20-07313', 'Chemical', '-', (13, 28))	('variants', 'Var', (61, 69))	('amelanotic/hypomelanotic melanoma', 'Disease', (73, 106))
74574	32966289	A substantial number of missense variants of uncertain significance (in TYR and OCA2) were included in the analyses; however, their deleteriousness was not sufficiently documented/proven.	('OCA2', 'Gene', (80, 84))	('missense variants', 'Var', (24, 41))	('OCA2', 'Species', '1933259', (80, 84))	('TYR', 'Gene', (72, 75))
74583	32966289	c) Similar to what has been mentioned above in regard to Table 1: In the columns named "Controls" and "Melanoma Cases", "(MAF%)" is not Minor Allele Frequency for values shown in rows "Total number of TYR (or OCA2; or TYR and OCA2) alleles (MAF<1% s) observed in each subgroup."	('OCA2', 'Species', '1933259', (209, 213))	('TYR', 'Var', (218, 221))	('Melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('OCA2', 'Gene', (226, 230))	('Melanoma', 'Disease', 'MESH:D008545', (103, 111))	('Melanoma', 'Disease', (103, 111))	('OCA2', 'Species', '1933259', (226, 230))
74585	32966289	Title: Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants Authors: Jenna E. Rayner, David L. Duffy, Darren J. Smit, Kasturee Jagirdar, Katie J. Lee, Brian De'Ambrosis, B.	('OCA2', 'Gene', (114, 118))	("De'Ambrosis", 'Disease', (225, 236))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (49, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('OCA2', 'Species', '1933259', (114, 118))	('albinism', 'Phenotype', 'HP:0001022', (28, 36))	('variants', 'Var', (37, 45))	('amelanotic/hypomelanotic melanoma', 'Disease', (49, 82))	('variants', 'Var', (119, 127))	("De'Ambrosis", 'Disease', 'MESH:C537981', (225, 236))
74588	32966289	The TYR p.A23T variant the reviewer highlights was found only once, notably in the AHM group (Table S1).	('AHM', 'Disease', (83, 86))	('TYR p.A23T', 'Var', (4, 14))	('p.A23T', 'Mutation', 'rs1373014646', (8, 14))
74589	32966289	rs1373014646*G/A p.A23T e once in the AHM group, but also present in gnomAD rs1160771486*A/G p.M179V e once in the MGRB control group, but also present in gnomAD rs61754368*GT p.K243fs e once in the MGRB control group alone rs200854796*C/T p.R298W e once in the BNMS melanoma group in total, but not in PM or AHM subgroups, also in present in gnomAD rs543973275*TT p.T489fs e once in the BNMS melanoma group in total alone, but not in PM or AHM subgroups  There was one example where the variant had other evidence besides that designated using "e" rs200471520*G/A p.G154E e,g once in the MGRB control group, but also present in gnomAD I will list which variants were designated as deleterious only based on "e" for OCA2.	('rs200854796', 'Mutation', 'rs200854796', (224, 235))	('p.G154E', 'Mutation', 'rs200471520', (565, 572))	('rs1160771486', 'Mutation', 'rs1160771486', (76, 88))	('BNMS melanoma', 'Disease', (262, 275))	('rs543973275', 'Mutation', 'rs543973275', (350, 361))	('rs1373014646', 'Mutation', 'rs1373014646', (0, 12))	('rs1373014646*', 'Var', (0, 13))	('BNMS melanoma', 'Disease', (388, 401))	('p.T489fs', 'Mutation', 'p.T489fsX', (365, 373))	('p.M179V', 'Mutation', 'rs1160771486', (93, 100))	('rs200854796', 'Var', (224, 235))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('BNMS melanoma', 'Disease', 'MESH:D008545', (262, 275))	('rs200471520', 'Mutation', 'rs200471520', (549, 560))	('p.A23T', 'Mutation', 'rs1373014646', (17, 23))	('p.R298W', 'Mutation', 'rs200854796', (240, 247))	('rs61754368', 'Mutation', 'rs61754368', (162, 172))	('melanoma', 'Phenotype', 'HP:0002861', (393, 401))	('BNMS melanoma', 'Disease', 'MESH:D008545', (388, 401))	('p.K243fs', 'Mutation', 'p.K243fsX', (176, 184))	('OCA2', 'Species', '1933259', (716, 720))
74591	32966289	Although the TYR p.A23T mutation has not been clinically described as a deleterious allele, by homology to the TYRP1 protein p.A24T variant, which has been clinically associated with OCA3, we are confident that this will be a hypopigmenting allele of TYR.	('p.A24T', 'Mutation', 'rs61758405', (125, 131))	('p.A23T', 'Var', (17, 23))	('OCA3', 'Disease', (183, 187))	('OCA3', 'Species', '1933259', (183, 187))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('associated', 'Reg', (167, 177))	('p.A23T', 'Mutation', 'rs1373014646', (17, 23))
74592	32966289	To simplify the in silico presentation we have now included the analysis of all the alleles indicated as "e" for TYR and OCA2 listed in Table S1 into a separate Excel file (Supplementary File 5; S5_File.xlsx).	('OCA2', 'Species', '1933259', (121, 125))	('OCA2', 'Gene', (121, 125))	('TYR', 'Var', (113, 116))
74594	32966289	The text on page 5 now reads,  "A separate Excel file containing ANNOVAR annotated variants (53) of these 10 genes is also provided (Supplementary File 4), and specific in silico analysis of TYR and OCA2 variants of unknown significance are shown in Supplementary File 5."	('variants', 'Var', (204, 212))	('TYR', 'Gene', (191, 194))	('OCA2', 'Species', '1933259', (199, 203))	('OCA2', 'Gene', (199, 203))
74595	32966289	ANNOVAR annotated variants of unknow significance for TYR and OCA2 genes.	('TYR', 'Gene', (54, 57))	('OCA2', 'Gene', (62, 66))	('variants', 'Var', (18, 26))	('OCA2', 'Species', '1933259', (62, 66))
74596	32966289	The TYR and OCA2 gene variants listed in Table S1 as deleterious by in silico analysis using Polyphen2 [30] or MutationTaster [32].	('OCA2', 'Species', '1933259', (12, 16))	('variants', 'Var', (22, 30))	('TYR', 'Gene', (4, 7))	('OCA2', 'Gene', (12, 16))
74597	32966289	At the time when considering which in silico prediction tools were best to choose from we looked at nine common MC1R gene variants that we have previously performed detailed cellular and biochemical functional analysis viz., Beaumont KA, Shekar SN, Newton RA, James MR, Stow JL, Duffy DL, Sturm RA.	('variants', 'Var', (122, 130))	('RA', 'Disease', 'MESH:D001172', (295, 297))	('RA', 'Disease', 'MESH:D001172', (256, 258))	('MC1R', 'Gene', '4157', (112, 116))	('MC1R', 'Gene', (112, 116))
74598	32966289	Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles.	('MC1R', 'Gene', (77, 81))	('negative', 'NegReg', (28, 36))	('variant', 'Var', (82, 89))	('activity', 'MPA', (37, 45))	('MC1R', 'Gene', '4157', (77, 81))
74600	32966289	Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk.	('red hair', 'Disease', (87, 95))	('cell surface expression', 'MPA', (8, 31))	('red hair', 'Phenotype', 'HP:0002297', (87, 95))	('variant', 'Var', (46, 53))	('MC1R', 'Gene', (41, 45))	('human', 'Species', '9606', (35, 40))	('skin cancer', 'Phenotype', 'HP:0008069', (100, 111))	('cell surface', 'cellular_component', 'GO:0009986', ('8', '20'))	('skin cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Altered', 'Reg', (0, 7))	('skin cancer', 'Disease', 'MESH:D012878', (100, 111))	('associated', 'Reg', (71, 81))	('MC1R', 'Gene', '4157', (41, 45))
74604	32966289	In comparing the functional and in silico analysis with our own pipeline analysis, we made the interpretation that the Polyphen2 and MutationTaster programs were the most consistent in the case of what we already knew about the genetic effects of MC1R variants in humans.	('variants', 'Var', (252, 260))	('MC1R', 'Gene', (247, 251))	('humans', 'Species', '9606', (264, 270))	('MC1R', 'Gene', '4157', (247, 251))
74605	32966289	In the results section we have modified these sentences: "In considering the frequency of individual rare TYR variants in different subtypes of melanoma, the p.A23T variant showed the largest difference, occurring at a higher frequency in AHM vs PM (X2 unadjusted P=0.008)."	('p.A23T', 'Mutation', 'rs1373014646', (158, 164))	('p.A23T', 'Var', (158, 164))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
74606	32966289	"However, analyzing each variant separately revealed that the p.V443I variant occurred at higher frequency in AHM cases (4.44%) compared to PM cases (1.57%), BNMS controls (0.84%), or the MGRB (1.09%) (combined control comparison X2 P=.01), with comparison of any case nominally significant (X2 P=0.04)."	('p.V443I', 'Var', (62, 69))	('p.V443I', 'Mutation', 'rs121918166', (62, 69))	('AHM', 'Disease', (110, 113))
74607	32966289	Table 1, no change for statistical correction  Table 2, no change Table 3, this text has been added to the footnote, "e Bonferroni corrected (two phenotypes x 6 variants) critical P=0.004 equivalent to a table wide  =0.05" Table 4, no change Table 5, no change for statistical correction Table S1, "u Bonferroni corrected (three phenotypes x 30 variants) critical P=0.0005 equivalent to a table wide  =0.05" Table S2,  "l Bonferroni corrected (three phenotypes x 33 variants) critical P=0.0005 equivalent to a table wide  =0.05" Table S3,  "f Bonferroni corrected (three phenotypes x 49 variants) critical P=0.00003 equivalent to a table wide  =0.05" As the OCA2 p.V443I allele is a previously published variant in the literature we do not consider it appropriate to perform a correction seeing this is a preplanned sub analysis.	('OCA2', 'Species', '1933259', (658, 662))	('p.V443I', 'Mutation', 'rs121918166', (663, 670))	('p.V443I', 'Var', (663, 670))	('OCA2', 'Gene', (658, 662))
74609	32966289	We have changed the sentence to read, "We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P= 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection."	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (349, 367))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Atlas Skin Cutaneous Melanoma', 'Disease', (338, 367))	('mutation', 'Var', (201, 209))	('TYR/OCA2', 'Var', (213, 221))	('Cancer', 'Disease', 'MESH:D009369', (324, 330))	('amelanotic/hypomelanotic melanoma', 'Disease', (225, 258))	('Atlas Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (338, 367))	('Melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('loss of tumor pigmentation', 'Disease', 'MESH:D010859', (118, 144))	('loss of function', 'NegReg', (63, 79))	('loss of tumor pigmentation', 'Disease', (118, 144))	('Cancer', 'Phenotype', 'HP:0002664', (324, 330))	('hypomelanotic melanoma vs pigmented melanoma', 'Disease', (236, 280))	('OCA2', 'Species', '1933259', (217, 221))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (225, 258))	('Cancer', 'Disease', (324, 330))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('hypomelanotic melanoma vs pigmented melanoma', 'Disease', 'MESH:D008545', (236, 280))
74610	32966289	The TYR pP50S is a deleterious mutation in Ensembl and the rs number is now given as a footnote in Table 5,  "c rs372689330" 4.	('Ensembl', 'Gene', (43, 50))	('rs372689330', 'Mutation', 'rs372689330', (112, 123))	('TYR pP50S', 'Var', (4, 13))
74615	32966289	The major conclusions from the paper come from the data presented as TYR/OCA1 and OCA2/OCA2 in Table S1 which then feeds into Table 1 which will appear in the printed manuscript.	('TYR/OCA1', 'Var', (69, 77))	('OCA2', 'Species', '1933259', (87, 91))	('OCA1', 'Species', '1933259', (73, 77))	('OCA2', 'Species', '1933259', (82, 86))	('OCA2/OCA2', 'Var', (82, 91))
74617	32966289	19 Aug 2020  Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants PONE-D-20-07313R2 Dear Dr. Sturm, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('amelanotic/hypomelanotic melanoma', 'Disease', (55, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (55, 88))	('variants', 'Var', (125, 133))	('PONE-D-20-07313', 'Chemical', '-', (134, 149))	('albinism', 'Phenotype', 'HP:0001022', (34, 42))	('variants', 'Var', (43, 51))	('OCA2', 'Species', '1933259', (120, 124))
74618	32966289	26 Aug 2020  PONE-D-20-07313R2  Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: increased carriage of TYR and OCA2 variants  Dear Dr. Sturm: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('variants', 'Var', (144, 152))	('albinism', 'Phenotype', 'HP:0001022', (53, 61))	('variants', 'Var', (62, 70))	('amelanotic/hypomelanotic melanoma', 'Disease', (74, 107))	('PONE-D-20-07313', 'Chemical', '-', (13, 28))	('OCA2', 'Species', '1933259', (139, 143))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('amelanotic/hypomelanotic melanoma', 'Disease', 'MESH:D018328', (74, 107))
74620	31991588	However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies.	('lower', 'NegReg', (63, 68))	('higher', 'PosReg', (136, 142))	('clinical', 'Species', '191496', (9, 17))	('PD-1', 'Gene', (158, 162))	('clinical response', 'CPA', (9, 26))	('anti-CTLA-4 antibodies', 'Var', (36, 58))	('antibodies', 'Var', (48, 58))	('immunotherapy-related adverse events', 'Disease', (88, 124))	('PD-1', 'Gene', '6622', (158, 162))
74622	31991588	To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment.	('therapeutic responses', 'CPA', (198, 219))	('CD80', 'Gene', '941', (146, 150))	('anti-CTLA-4 antibodies', 'Var', (161, 183))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('interaction', 'Interaction', (108, 119))	('CD86', 'Gene', '942', (155, 159))	('CD80', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('CD86', 'Gene', (155, 159))	('tumor', 'Disease', (277, 282))	('depletion', 'NegReg', (238, 247))	('antibodies', 'Var', (173, 183))
74623	31991588	Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP).	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('reduced', 'NegReg', (79, 86))	('enhanced', 'PosReg', (96, 104))	('phagocytosis', 'biological_process', 'GO:0006909', ('151', '163'))	('antibody', 'cellular_component', 'GO:0042571', ('105', '113'))	('ADCC', 'biological_process', 'GO:0001788', ('165', '169'))	('irAE', 'MPA', (87, 91))	('antibodies', 'Var', (63, 73))	('cytotoxicity', 'Disease', (138, 150))	('antibody', 'cellular_component', 'GO:0019815', ('105', '113'))	('antibody', 'cellular_component', 'GO:0019814', ('105', '113'))	('anti-CTLA-4', 'Gene', (51, 62))	('anti-CTLA-4 antibodies', 'Var', (51, 73))	('antibody', 'molecular_function', 'GO:0003823', ('105', '113'))
74628	31991588	Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (14, 43))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (14, 43))	('anti-CTLA-4', 'Var', (92, 103))	('NSCLC', 'Disease', (45, 50))	('non-small cell lung carcinoma', 'Disease', (14, 43))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (18, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
74629	31991588	Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg.	('NSCLC', 'Disease', (56, 61))	('anti-CTLA-4', 'Gene', (109, 120))	('anti-CTLA-4 antibodies', 'Var', (109, 131))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('human', 'Species', '9606', (50, 55))	('antibodies', 'Var', (121, 131))	('Treg', 'Chemical', '-', (168, 172))	('tumor', 'Disease', (160, 165))	('deplete', 'NegReg', (147, 154))
74630	31991588	Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (66, 95))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (66, 95))	('anti-CTLA-4', 'Gene', (139, 150))	('non-small cell lung carcinoma', 'Disease', (66, 95))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (70, 95))	('anti-CTLA-4', 'Var', (139, 150))
74631	31991588	Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('anti-CTLA-4', 'Var', (82, 93))	('cancers', 'Disease', (71, 78))	('anti-CTLA-4', 'Gene', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
74633	31991588	As the first immune checkpoint explored for cancer immunotherapy, CTLA-4 was validated as an immunotherapeutic target after FDA approval of Ipilimumab for human use, either as monotherapy for melanoma, or as part of combination therapy with the anti-PD-1 antibody, Nivolumab, in melanoma, renal cancer, and colorectal cancer with microsatellite instability.	('cancer', 'Disease', (318, 324))	('colorectal cancer', 'Phenotype', 'HP:0003003', (307, 324))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (140, 150))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('antibody', 'cellular_component', 'GO:0019815', ('255', '263'))	('PD-1', 'Gene', (250, 254))	('microsatellite instability', 'Var', (330, 356))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('renal cancer', 'Disease', (289, 301))	('renal cancer', 'Phenotype', 'HP:0009726', (289, 301))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))	('antibody', 'cellular_component', 'GO:0019814', ('255', '263'))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('colorectal cancer', 'Disease', 'MESH:D015179', (307, 324))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('renal cancer', 'Disease', 'MESH:D007680', (289, 301))	('colorectal cancer', 'Disease', (307, 324))	('PD-1', 'Gene', '6622', (250, 254))	('Nivolumab', 'Chemical', 'MESH:D000077594', (265, 274))	('antibody', 'molecular_function', 'GO:0003823', ('255', '263'))	('cancer', 'Disease', (44, 50))	('human', 'Species', '9606', (155, 160))	('antibody', 'cellular_component', 'GO:0042571', ('255', '263'))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
74637	31991588	An important development in cancer immunotherapy is a re-evaluation of the mechanism by which anti-CTLA-4 antibodies induce tumor rejection.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', (124, 129))	('induce', 'PosReg', (117, 123))	('anti-CTLA-4', 'Var', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('anti-CTLA-4', 'Gene', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
74639	31991588	Second, several groups, including ours, have reported that the therapeutic effect of anti-CTLA-4 antibodies requires ADCC activity that selectively depletes regulatory T cells in the tumor microenvironment.	('ADCC', 'biological_process', 'GO:0001788', ('117', '121'))	('depletes', 'NegReg', (148, 156))	('antibodies', 'Var', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('anti-CTLA-4', 'Gene', (85, 96))	('anti-CTLA-4 antibodies', 'Var', (85, 107))	('tumor', 'Disease', (183, 188))	('regulatory T cells', 'MPA', (157, 175))	('ADCC', 'Protein', (117, 121))
74640	31991588	These two lines of fundamental studies have inspired the development of the next generation of anti-CTLA-4 antibodies with enhanced ADCC activity or preferential activation in the tumor microenvironment.	('enhanced', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('anti-CTLA-4', 'Gene', (95, 106))	('ADCC', 'biological_process', 'GO:0001788', ('132', '136'))	('tumor', 'Disease', (180, 185))	('activity', 'MPA', (137, 145))	('ADCC', 'Protein', (132, 136))	('anti-CTLA-4', 'Var', (95, 106))
74671	31991588	Cells were stained with fluorochrome-conjugated monoclonal antibodies against mouse CD8 (Cat# 100748, Biolegend, Cat# 45-0081-82, eBioscience), mouse CD4 (Cat# 100453, Biolegend, Cat# 100531, Biolegend), mouse CD45 (Cat# 103151, Biolegend, Cat# 47-0451-82, eBioscience), mouse Foxp3 (Cat# 48-5773-82, Thermo Fisher Scientific, Cat# 17-5773-82, eBioscience), human CTLA-4 (Cat# 369604, Biolegend), and Mouse IgG2a, kappa Isotype Ctrl CTLA-4 (Cat# 400214, Biolegend).	('mouse', 'Species', '10090', (144, 149))	('mouse', 'Species', '10090', (271, 276))	('Cat', 'molecular_function', 'GO:0004096', ('179', '182'))	('Cat', 'molecular_function', 'GO:0004096', ('89', '92'))	('mouse', 'Species', '10090', (78, 83))	('Mouse', 'Species', '10090', (401, 406))	('Cat', 'Var', (216, 219))	('mouse', 'Species', '10090', (204, 209))	('human', 'Species', '9606', (358, 363))	('Cat# 369604', 'Var', (372, 383))	('Cat', 'molecular_function', 'GO:0004096', ('113', '116'))	('Cat', 'molecular_function', 'GO:0004096', ('155', '158'))	('Cat', 'molecular_function', 'GO:0004096', ('441', '444'))	('Cat', 'molecular_function', 'GO:0004096', ('327', '330'))	('CD8', 'Gene', '925', (84, 87))	('Cat', 'molecular_function', 'GO:0004096', ('284', '287'))	('Cat', 'molecular_function', 'GO:0004096', ('240', '243'))	('CD45', 'Gene', '19264', (210, 214))	('Cat', 'molecular_function', 'GO:0004096', ('216', '219'))	('IgG2a', 'Gene', '668478', (407, 412))	('IgG2a', 'cellular_component', 'GO:0071735', ('407', '412'))	('IgG2a', 'Gene', (407, 412))	('Cat', 'molecular_function', 'GO:0004096', ('372', '375'))	('CD45', 'Gene', (210, 214))	('CD8', 'Gene', (84, 87))
74677	31991588	We used the following formula to estimate the total ranking number for each cancer type: where the RANKADCC represents the "ADCC Features" partitioning, that was the mean value of 3 ranking numbers based on the estimated cell fraction of Treg cells, FCGR3A gene expression, and FCGR3A SNP rate for V158F.	('FCGR3A', 'Gene', '2214', (250, 256))	('Treg', 'Chemical', '-', (238, 242))	('ADCC', 'biological_process', 'GO:0001788', ('123', '127'))	('FCGR3A', 'Gene', '2214', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FCGR3A', 'Gene', (250, 256))	('V158F', 'Mutation', 'rs396991', (298, 303))	('V158F', 'Var', (298, 303))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FCGR3A', 'Gene', (278, 284))
74684	31991588	We and others have previously reported that anti-CTLA-4 antibodies, including Ipilimumab selectively depleted Treg in the mouse tumor microenvironment but not in the spleen.	('Treg', 'CPA', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('anti-CTLA-4', 'Gene', (44, 55))	('Treg', 'Chemical', '-', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (78, 88))	('antibodies', 'Var', (56, 66))	('tumor', 'Disease', (128, 133))	('depleted', 'NegReg', (101, 109))	('mouse', 'Species', '10090', (122, 127))
74685	31991588	More recently, we reported that pH-sensitive anti-CTLA-4 antibodies are more effective in ADCC and tumor rejection, which raise the issue as to whether increasing ADCC activity jeopardizes the selectivity of the antibodies.	('tumor', 'Disease', (99, 104))	('antibodies', 'Var', (57, 67))	('ADCC', 'biological_process', 'GO:0001788', ('90', '94'))	('ADCC', 'Disease', (90, 94))	('ADCC', 'biological_process', 'GO:0001788', ('163', '167'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('anti-CTLA-4', 'Gene', (45, 56))
74733	31991588	The increased mutation rates lead to an expanded pool of potential neo-tumor antigens that also correlate with responsiveness to Ipilimumab (Supplementary Materials Figure S2A).	('Ipilimumab', 'Chemical', 'MESH:D000074324', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutation', 'Var', (14, 22))	('tumor', 'Disease', (71, 76))
74759	31991588	Since this population also expressed the highest levels of CTLA-4 (Figure 6c), it is liely that ADCC-competent anti-CTLA-4 would be highly selective for activated Treg in NSCLC.	('ADCC', 'biological_process', 'GO:0001788', ('96', '100'))	('anti-CTLA-4', 'Var', (111, 122))	('NSCLC', 'Disease', (171, 176))	('Treg', 'Chemical', '-', (163, 167))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
74769	31991588	In addition, in a mouse model with the human FcR system, it was demonstrated that binding to FCGRIIIA is critical for optimal ADCC of Treg and tumor rejection by anti-CTLA-4 antibodies.	('binding', 'molecular_function', 'GO:0005488', ('82', '89'))	('ADCC', 'biological_process', 'GO:0001788', ('126', '130'))	('tumor', 'Disease', (143, 148))	('mouse', 'Species', '10090', (18, 23))	('Treg', 'Chemical', '-', (134, 138))	('Treg', 'CPA', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('anti-CTLA-4', 'Var', (162, 173))	('human', 'Species', '9606', (39, 44))	('binding', 'Interaction', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('anti-CTLA-4', 'Gene', (162, 173))
74781	31991588	Therefore, it is likely multiple cancer types may well respond to anti-CTLA-4 therapy if appropriate antibodies are employed.	('anti-CTLA-4', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('multiple cancer', 'Disease', 'MESH:D009369', (24, 39))	('multiple cancer', 'Disease', (24, 39))
74784	31991588	Our re-analysis of scRNAseq data of tumor-infiltrating T cells in NSCLC patients suggests that selective Treg depletion is achievable with anti-CTLA-4 antibodies.	('Treg', 'Chemical', '-', (105, 109))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('depletion', 'NegReg', (110, 119))	('tumor', 'Disease', (36, 41))	('anti-CTLA-4', 'Var', (139, 150))	('patients', 'Species', '9606', (72, 80))
74785	31991588	While the high ranking suggests NSCLC as a prime candidate for new anti-CTLA-4 antibodies, it is worth considering the fact that multiple randomized trials have failed to show significant improvement in survival of patients receiving Ipilimumab in combination with chemotherapy.	('patients', 'Species', '9606', (215, 223))	('anti-CTLA-4', 'Gene', (67, 78))	('NSCLC', 'Disease', (32, 37))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (234, 244))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('anti-CTLA-4', 'Var', (67, 78))
74788	31991588	Therefore, a new generation of anti-CTLA-4 antibodies must show higher anti-tumor activity in order to achieve better outcomes.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('anti-CTLA-4', 'Var', (31, 42))	('tumor', 'Disease', (76, 81))	('anti-CTLA-4', 'Gene', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
74791	31991588	In this context, we recently showed that increasing pH sensitivity of anti-CTLA-4 antibodies improves both therapeutic effect and safety when compared directly with Ipilimumab.	('therapeutic effect', 'CPA', (107, 125))	('safety', 'CPA', (130, 136))	('antibodies', 'Var', (82, 92))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (165, 175))	('anti-CTLA-4', 'Gene', (70, 81))	('anti-CTLA-4 antibodies', 'Var', (70, 92))	('improves', 'PosReg', (93, 101))
74792	31991588	Since Treg has been implicated in pathogenesis and prognosis of multiple cancer types, it is anticipated that anti-CTLA-4 antibodies that effectively and selectively deplete Treg in tumor microenvironment would have a broad impact in cancer immunotherapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pathogenesis', 'biological_process', 'GO:0009405', ('34', '46'))	('multiple cancer', 'Disease', (64, 79))	('tumor', 'Disease', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('antibodies', 'Var', (122, 132))	('deplete', 'NegReg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Treg', 'Chemical', '-', (174, 178))	('multiple cancer', 'Disease', 'MESH:D009369', (64, 79))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Treg', 'Chemical', '-', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Disease', (234, 240))	('Treg', 'Protein', (174, 178))	('anti-CTLA-4', 'Gene', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
74793	31991588	In summary, our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('anti-CTLA-4', 'Gene', (138, 149))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (65, 94))	('non-small cell lung carcinoma', 'Disease', (65, 94))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (69, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('anti-CTLA-4', 'Var', (138, 149))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (65, 94))
74801	31991588	TCGA The Cancer Genome Atlas  GSEA Gene-set Enrichment Analysis  ADCC Antibody Dependent Cell-mediated Cytotoxicity/phagocytosis  ADCP Antibody Dependent Cell-mediated Phagocytosis  NSCLC Non Small Cell Lung Cancer  TMB Tumor Mutation Burden	('Cancer Genome Atlas', 'Disease', (9, 28))	('Cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('phagocytosis', 'biological_process', 'GO:0006909', ('116', '128'))	('NSCLC', 'Disease', (182, 187))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (9, 28))	('TMB', 'Chemical', '-', (216, 219))	('Tumor', 'Phenotype', 'HP:0002664', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('Mutation', 'Var', (226, 234))	('Phagocytosis', 'biological_process', 'GO:0006909', ('168', '180'))	('Cytotoxicity', 'Disease', (103, 115))	('Non Small Cell Lung Cancer  TMB Tumor', 'Disease', (188, 225))	('ADCC', 'biological_process', 'GO:0001788', ('65', '69'))	('Lung Cancer', 'Phenotype', 'HP:0100526', (203, 214))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (192, 214))	('GSEA', 'Chemical', '-', (30, 34))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))
74813	30191256	Approved targeted therapies for MAPK pathway dysregulation by BRAF mutation, which is implicated approximately half of melanomas, include BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) and MEK inhibitors (trametinib, cobimetinib, and binimetinib).	('binimetinib', 'Chemical', 'MESH:C581313', (246, 257))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('dabrafenib', 'Chemical', 'MESH:C561627', (168, 178))	('encorafenib', 'Chemical', 'None', (184, 195))	('mutation', 'Var', (67, 75))	('MAPK pathway', 'Pathway', (32, 44))	('dysregulation', 'Reg', (45, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('MEK', 'Gene', '5609', (201, 204))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('vemurafenib', 'Chemical', 'MESH:C551177', (155, 166))	('MEK', 'Gene', (201, 204))	('trametinib', 'Chemical', 'MESH:C560077', (217, 227))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('melanomas', 'Disease', 'MESH:D008545', (119, 128))	('melanomas', 'Disease', (119, 128))	('cobimetinib', 'Chemical', 'MESH:C574276', (229, 240))
74819	30191256	Combined PD-1 and CTLA-4 blockade in the CheckMate 067 and 069 RCTs demonstrated improved PFS and OS compared to ipilimumab.	('improved', 'PosReg', (81, 89))	('CTLA-4', 'Gene', (18, 24))	('blockade', 'Var', (25, 33))	('CTLA-4', 'Gene', '1493', (18, 24))	('PFS', 'CPA', (90, 93))	('PD-1', 'Gene', (9, 13))
74820	30191256	Targeted agents including small molecules that specifically inhibit downstream effectors of the MAPK pathway, such as mutated BRAF (e.g.	('inhibit', 'NegReg', (60, 67))	('mutated', 'Var', (118, 125))	('MAPK', 'molecular_function', 'GO:0004707', ('96', '100'))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', (126, 130))	('MAPK pathway', 'Pathway', (96, 108))
74879	30191256	In our analyses, stage 4 patients treated with ICB were younger, more recently diagnosed, privately insured, treated at academic facilities, had fewer co-morbidities, and were treated with radiotherapy, and less likely to receive targeted therapy, as compared to patients who did not receive immunotherapy.	('less', 'NegReg', (207, 211))	('patients', 'Species', '9606', (263, 271))	('ICB', 'Var', (47, 50))	('targeted therapy', 'CPA', (230, 246))	('patients', 'Species', '9606', (25, 33))
74892	30191256	Additionally, in the era of precision oncology where various cancer types are increasingly characterized and categorized by molecular alterations, a key limitation of the NCDB is its lack of molecular data - in particular, BRAF mutational status in melanoma patients.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (249, 257))	('cancer', 'Disease', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('melanoma', 'Disease', (249, 257))	('oncology', 'Phenotype', 'HP:0002664', (38, 46))	('BRAF', 'Gene', '673', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutational status', 'Var', (228, 245))	('patients', 'Species', '9606', (258, 266))	('BRAF', 'Gene', (223, 227))
74899	33786423	We identify pathogenic germline variants associated with increased TMB (GVITMB).	('TMB', 'Disease', (67, 70))	('GVITMB', 'Chemical', '-', (72, 78))	('variants', 'Var', (32, 40))	('TMB', 'Chemical', '-', (67, 70))	('increased', 'PosReg', (57, 66))	('TMB', 'Chemical', '-', (75, 78))
74901	33786423	GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant.	('variant', 'Var', (183, 190))	('GVITMB', 'Chemical', '-', (0, 6))	('variant', 'Var', (107, 114))	('dysfunction', 'MPA', (70, 81))	('gene', 'Gene', (89, 93))
74904	33786423	GVITMB were found in 7 genes and 38 gene sets GVITMB influence the somatic mutation and gene expression profiles of tumors GVITMB predict immune checkpoint inhibitory efficacy in SKCM Genetics; Genomics; Cancer The explosion of massively parallel sequencing data has helped to identify rare germline variants that cause or contribute to disease.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('GVITMB', 'Chemical', '-', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))	('disease', 'Disease', (337, 344))	('variants', 'Var', (300, 308))	('GVITMB', 'Chemical', '-', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('GVITMB', 'Chemical', '-', (46, 52))	('Cancer', 'Disease', (204, 210))	('cause', 'Reg', (314, 319))	('Cancer', 'Disease', 'MESH:D009369', (204, 210))	('contribute', 'Reg', (323, 333))
74905	33786423	In oncology, it is well-established that patients with germline variants in genes mutated in certain genetic syndromes, such as Lynch syndrome, Li-Fraumeni syndrome, von Hippel-Lindau syndrome, and Fanconi anemia, are at much higher risk of acquiring cancer.	('Li-Fraumeni syndrome', 'Disease', (144, 164))	('von Hippel-Lindau syndrome', 'Disease', (166, 192))	('Fanconi anemia', 'Disease', (198, 212))	('Lynch syndrome', 'Disease', (128, 142))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (166, 192))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (198, 212))	('anemia', 'Phenotype', 'HP:0001903', (206, 212))	('germline variants', 'Var', (55, 72))	('Lynch syndrome', 'Disease', 'MESH:D003123', (128, 142))	('patients', 'Species', '9606', (41, 49))	('oncology', 'Phenotype', 'HP:0002664', (3, 11))	('Fanconi anemia', 'Disease', 'MESH:D005199', (198, 212))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (144, 164))	('cancer', 'Disease', (251, 257))
74907	33786423	For example, patients with Lynch syndrome have pathogenic germline variants in mismatch repair genes, such as MSH2, MSH6, PMS2, and MLH1, and their tumors exhibit higher levels of microsatellite instability.	('PMS2', 'Gene', '5395', (122, 126))	('patients', 'Species', '9606', (13, 21))	('MSH2', 'Gene', (110, 114))	('MLH1', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MSH2', 'Gene', '4436', (110, 114))	('MLH1', 'Gene', '4292', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('higher', 'PosReg', (163, 169))	('MSH6', 'Gene', (116, 120))	('Lynch syndrome', 'Disease', (27, 41))	('germline variants', 'Var', (58, 75))	('PMS2', 'Gene', (122, 126))	('MSH6', 'Gene', '2956', (116, 120))	('mismatch repair', 'biological_process', 'GO:0006298', ('79', '94'))	('microsatellite instability', 'MPA', (180, 206))	('tumors', 'Disease', (148, 154))	('Lynch syndrome', 'Disease', 'MESH:D003123', (27, 41))	('pathogenic', 'Reg', (47, 57))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
74909	33786423	We have reported that germline variants affect tumor progression across a large spectrum of cancers through the analysis of common germline variants with a minor allele frequency greater than 5% in the general population.	('variants', 'Var', (31, 39))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancers', 'Disease', (92, 99))	('affect', 'Reg', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (47, 52))
74910	33786423	In this study, we analyze rare pathogenic germline variants to identify germline variants associated with increased tumor mutational burden (GVITMB) to test whether these germline variants increase the likelihood of a patient responding to immune checkpoint inhibitors.	('patient', 'Species', '9606', (218, 225))	('GVITMB', 'Chemical', '-', (141, 147))	('variants', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('responding to immune checkpoint inhibitors', 'MPA', (226, 268))	('increase', 'PosReg', (189, 197))
74911	33786423	After identifying the set of pathogenic germline variants predictive of tumor mutational burden (TMB), we demonstrate that they predict responsiveness to immune checkpoint inhibitors in a cohort of 140 patients with skin cutaneous melanoma.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (216, 239))	('variants', 'Var', (49, 57))	('predict', 'Reg', (128, 135))	('tumor', 'Disease', (72, 77))	('skin cutaneous melanoma', 'Disease', (216, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('TMB', 'Chemical', '-', (97, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (221, 239))	('patients', 'Species', '9606', (202, 210))	('responsiveness to immune checkpoint inhibitors', 'MPA', (136, 182))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
74912	33786423	had previously described 435 rare pathogenic germline variants that were found in the patients in The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', (102, 108))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pathogenic', 'Reg', (34, 44))	('variants', 'Var', (54, 62))	('patients', 'Species', '9606', (86, 94))
74913	33786423	Briefly, all somatic variants were scored based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines developed for rare variants in cancer and variants known to be pathogenic in ClinVar and curated databases were labeled as pathogenic.	('variants', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ACMG-AMP', 'Chemical', '-', (150, 158))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('variants', 'Var', (190, 198))
74914	33786423	The majority of these pathogenic germline variants were predicted to functionally perturb known tumor suppressor genes or oncogenes.	('perturb', 'NegReg', (82, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('variants', 'Var', (42, 50))	('pathogenic', 'Reg', (22, 32))	('tumor', 'Disease', (96, 101))	('oncogenes', 'Gene', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))
74916	33786423	We set a modest threshold requiring at least five patients in the cancer cohort to have a pathogenic germline variant in a given gene.	('pathogenic', 'Reg', (90, 100))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('variant', 'Var', (110, 117))
74917	33786423	We utilized four approaches to identify germline variants associated with increased TMB.	('TMB', 'Chemical', '-', (84, 87))	('TMB', 'Disease', (84, 87))	('variants', 'Var', (49, 57))
74922	33786423	Overall TMB, nonsynonymous TMB, and clonal nonsynonymous TMB have previously been reported to be associated with favorable response in patients treated with immune checkpoint inhibitors.	('patients', 'Species', '9606', (135, 143))	('TMB', 'Chemical', '-', (27, 30))	('TMB', 'Disease', (8, 11))	('nonsynonymous', 'Var', (13, 26))	('TMB', 'Chemical', '-', (8, 11))	('TMB', 'Chemical', '-', (57, 60))
74930	33786423	We identified significant associations of pathogenic germline variants in gene sets and TMB in Colon Adenocarcinoma (COAD), Skin Cutaneous Melanoma (SKCM), and Uterine Corpus Endometrial Carcinoma (UCEC) (Figure 4B, Table 2, list of perturbed genes in Table S1).	('Carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (175, 196))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (124, 147))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (129, 147))	('TMB in Colon Adenocarcinoma', 'Disease', (88, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('Corpus Endometrial Carcinoma', 'Disease', (168, 196))	('Skin Cutaneous Melanoma', 'Disease', (124, 147))	('germline variants', 'Var', (53, 70))	('gene sets', 'Gene', (74, 83))	('pathogenic', 'Reg', (42, 52))	('TMB in Colon Adenocarcinoma', 'Disease', 'MESH:D003110', (88, 115))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (168, 196))
74931	33786423	Last, we identified pathogenic germline variants associated with TMB using a pan-cancer approach in which the pathogenic germline variants were grouped by gene set (Figure 4C, Table 3, list of perturbed genes in Table S2).	('pan', 'Gene', '51816', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('TMB', 'Chemical', '-', (65, 68))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('pan', 'Gene', (77, 80))	('variants', 'Var', (40, 48))	('TMB', 'Disease', (65, 68))
74932	33786423	Several of the gene sets were related to Wnt signaling, and the pathogenic germline variants in APC greatly contributed to these associations, as described in our analysis of individual genes.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('Wnt signaling', 'MPA', (41, 54))	('related', 'Reg', (30, 37))	('contributed', 'Reg', (108, 119))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('APC', 'cellular_component', 'GO:0005680', ('96', '99'))	('APC', 'Disease', (96, 99))	('variants', 'Var', (84, 92))	('associations', 'Interaction', (129, 141))
74938	33786423	Patients with GVITMB in the mismatch repair gene PMS2 were much more likely to exhibit somatic mutations in PMS2 than patients without the GVITMB in PMS2 (beta = 3.05, p value = 5.86E-5, adjusted p value=4.1E-4).	('PMS2', 'Gene', (49, 53))	('GVITMB', 'Var', (14, 20))	('exhibit', 'Reg', (79, 86))	('GVITMB', 'Chemical', '-', (14, 20))	('PMS2', 'Gene', (108, 112))	('GVITMB', 'Chemical', '-', (139, 145))	('Patients', 'Species', '9606', (0, 8))	('PMS2', 'Gene', (149, 153))	('PMS2', 'Gene', '5395', (49, 53))	('PMS2', 'Gene', '5395', (108, 112))	('mutations', 'Var', (95, 104))	('PMS2', 'Gene', '5395', (149, 153))	('patients', 'Species', '9606', (118, 126))	('mismatch repair', 'biological_process', 'GO:0006298', ('28', '43'))
74939	33786423	We found that GVITMB in ERCC3 or TP53 were associated with an increased incidence of somatic mutations in gene sets that include ERCC3 or TP53, respectively (Table S3).	('ERCC3', 'Gene', (129, 134))	('ERCC3', 'Gene', '2071', (24, 29))	('TP53', 'Gene', '7157', (138, 142))	('GVITMB', 'Var', (14, 20))	('GVITMB', 'Chemical', '-', (14, 20))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (138, 142))	('ERCC3', 'Gene', (24, 29))	('ERCC3', 'Gene', '2071', (129, 134))	('TP53', 'Gene', (33, 37))
74940	33786423	In addition, patients with SKCM with GVITMB in the disease gene set (a compilation of genes associated with human diseases) were more likely to acquire somatic mutations in other genes of the same gene set (beta=20.2, p value = 4.12E-6, adjusted p value=1.73E-4).	('mutations', 'Var', (160, 169))	('patients', 'Species', '9606', (13, 21))	('GVITMB', 'Var', (37, 43))	('human', 'Species', '9606', (108, 113))	('GVITMB', 'Chemical', '-', (37, 43))	('acquire', 'PosReg', (144, 151))
74945	33786423	Patients with pathogenic germline variants in the disease gene set exhibited prolonged progression-free survival (p = 0.0245, hazard ratio [HR] = 0.662) (Figures 5A and 5B) and were more likely to show a response to immune checkpoint inhibitors based on Response evaluation criteria in solid tumors (RECIST) criteria (p = 0.0393, odds = 1.781, ordering of categories was progressive disease, stable disease, partial response, and then complete response) (Figure 5C).	('solid tumors', 'Disease', 'MESH:D009369', (286, 298))	('germline variants', 'Var', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('response', 'MPA', (204, 212))	('progression-free survival', 'CPA', (87, 112))	('solid tumors', 'Disease', (286, 298))	('Patients', 'Species', '9606', (0, 8))	('progressive disease', 'Disease', (371, 390))	('prolonged', 'PosReg', (77, 86))
74946	33786423	Although patients with pathogenic germline variants had a higher median number of overall mutations, nonsynonymous mutations, and clonal nonsynonymous mutations, this difference was not statistically significant (Table S4, top three rows).	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (90, 99))	('higher', 'PosReg', (58, 64))
74947	33786423	We were better powered to detect such an association by pooling all pathogenic germline variants found in the genes of the gene sets that we found to be associated with elevated TMB in SKCM the TCGA dataset (Figures 5D and Table 2).	('TMB', 'Chemical', '-', (178, 181))	('elevated', 'PosReg', (169, 177))	('associated', 'Reg', (153, 163))	('TMB', 'MPA', (178, 181))	('variants', 'Var', (88, 96))
74948	33786423	When tested, we found that patients with pathogenic germline variants in these genes exhibited favorable outcome and were less likely to progress (Figure 5E, p = 0.0349, HR = 0.688).	('progress', 'CPA', (137, 145))	('germline variants', 'Var', (52, 69))	('less', 'NegReg', (122, 126))	('patients', 'Species', '9606', (27, 35))	('pathogenic', 'Reg', (41, 51))
74949	33786423	Similarly, patients with pathogenic germline variants in these genes were more likely to exhibit a response to immune checkpoint inhibitors based on RECIST criteria (Figure 5F, p = 0.0341, odds = 1.842).	('response to immune checkpoint inhibitors', 'MPA', (99, 139))	('pathogenic', 'Reg', (25, 35))	('germline variants', 'Var', (36, 53))	('patients', 'Species', '9606', (11, 19))
74950	33786423	Turning to TMB, we found that the median number of total mutations, nonsynonymous mutations, and clonal nonsynonymous mutations was greater in patients with pathogenic germline variants in genes in our gene set than patients without these pathogenic germline variants, although these differences were also not statistically significant (Table S4, lower three rows).	('TMB', 'Chemical', '-', (11, 14))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (216, 224))	('greater', 'PosReg', (132, 139))	('variants', 'Var', (177, 185))
74952	33786423	Although patients with pathogenic germline variants are often screened more aggressively for cancer, clinical guidelines for these patients have only changed in a few circumstances.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('germline', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('pathogenic', 'Reg', (23, 33))
74953	33786423	We had previously identified common germline variants associated with differences in patient outcome across a multitude of cancers, suggesting that germline variation contributes not only to cancer risk but also to tumor progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patient', 'Species', '9606', (85, 92))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('contributes', 'Reg', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('variants', 'Var', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancer', 'Disease', (123, 129))	('cancers', 'Disease', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (215, 220))	('associated', 'Reg', (54, 64))
74955	33786423	Some of these associations were expected and confirmed existing hypotheses (e.g., mutations in known DNA repair genes such as MSH6 and PMS2), whereas other associations (e.g., mutations in SLC25A16) are more surprising and can motivate future hypotheses.	('mutations', 'Var', (176, 185))	('MSH6', 'Gene', '2956', (126, 130))	('PMS2', 'Gene', '5395', (135, 139))	('SLC25A16', 'Gene', (189, 197))	('SLC25A16', 'Gene', '8034', (189, 197))	('mutations', 'Var', (82, 91))	('PMS2', 'Gene', (135, 139))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('DNA repair', 'Gene', (101, 111))	('DNA repair', 'biological_process', 'GO:0006281', ('101', '111'))	('MSH6', 'Gene', (126, 130))
74956	33786423	Our findings suggest that these pathogenic germline variants remain relevant after a patient has been diagnosed with cancer and may contribute to the molecular differences in tumors collected from patients with and without pathogenic germline variants.	('tumors', 'Disease', (175, 181))	('patient', 'Species', '9606', (85, 92))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('patients', 'Species', '9606', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('variants', 'Var', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patient', 'Species', '9606', (197, 204))
74957	33786423	After identifying the set of pathogenic germline variants associated with TMB in skin cutaneous melanoma, we showed that patients with these pathogenic germline variants exhibit prolonged progression-free survival and increased responsiveness to immune checkpoint inhibitors.	('skin cutaneous melanoma', 'Disease', (81, 104))	('variants', 'Var', (161, 169))	('prolonged', 'PosReg', (178, 187))	('variants', 'Var', (49, 57))	('responsiveness to', 'MPA', (228, 245))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (86, 104))	('increased', 'PosReg', (218, 227))	('TMB', 'Disease', (74, 77))	('TMB', 'Chemical', '-', (74, 77))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('progression-free survival', 'CPA', (188, 213))	('patients', 'Species', '9606', (121, 129))
74959	33786423	In this study, we identify pathogenic germline variants associated with TMB as a proxy for immune checkpoint inhibitory efficacy, although determining the extent to which TMB is predictive of immune checkpoint inhibitor efficacy across all cancers is still an active area of research.	('TMB', 'Chemical', '-', (171, 174))	('TMB', 'Disease', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('germline', 'Var', (38, 46))	('TMB', 'Chemical', '-', (72, 75))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('pathogenic', 'Reg', (27, 37))
74962	33786423	Tumors with pathogenic germline variants in the nucleotide excision repair gene ERCC3 were associated with elevated TMB in our study.	('ERCC3', 'Gene', (80, 85))	('germline', 'Var', (23, 31))	('TMB', 'Chemical', '-', (116, 119))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('ERCC3', 'Gene', '2071', (80, 85))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TMB', 'Disease', (116, 119))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('48', '74'))	('elevated', 'PosReg', (107, 115))
74963	33786423	Although a previous study showed that somatic mutations in the nucleotide base excision repair gene ERCC2 likely contributes to increased TMB, no previous study has demonstrated an association between nucleotide excision repair gene perturbation and immune checkpoint inhibitor efficacy.	('TMB', 'Disease', (138, 141))	('mutations', 'Var', (46, 55))	('base excision repair', 'biological_process', 'GO:0006284', ('74', '94'))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('201', '227'))	('TMB', 'Chemical', '-', (138, 141))	('increased', 'PosReg', (128, 137))	('ERCC2', 'Gene', (100, 105))	('ERCC2', 'Gene', '2068', (100, 105))
74965	33786423	We found patients with pathogenic germline variants in APC, which binds to beta-catenin and leads to its degradation, and genes involved with beta-catenin degradation to be associated with elevated somatic mutation burden.	('beta-catenin', 'Gene', '1499', (75, 87))	('patients', 'Species', '9606', (9, 17))	('binds', 'Interaction', (66, 71))	('beta-catenin', 'Gene', (142, 154))	('beta-catenin', 'Gene', '1499', (142, 154))	('APC', 'Disease', 'MESH:D011125', (55, 58))	('degradation', 'MPA', (105, 116))	('degradation', 'biological_process', 'GO:0009056', ('105', '116'))	('degradation', 'biological_process', 'GO:0009056', ('155', '166'))	('beta-catenin', 'Gene', (75, 87))	('APC', 'Disease', (55, 58))	('elevated', 'PosReg', (189, 197))	('leads to', 'Reg', (92, 100))	('APC', 'cellular_component', 'GO:0005680', ('55', '58'))	('germline variants', 'Var', (34, 51))
74966	33786423	Aberrations to the Wnt signaling pathway are linked to the formation of many cancers.	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('linked', 'Reg', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('19', '40'))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Aberrations', 'Var', (0, 11))	('Wnt signaling pathway', 'Pathway', (19, 40))
74968	33786423	Further work is necessary to predict whether pathogenic germline variants in APC and genes involved with beta-catenin degradation will be associated with increased or decreased response to immunotherapy, as the elevated TMB would be expected to increase efficacy, whereas the elevated beta-catenin signaling would be expected to decrease efficacy.	('APC', 'cellular_component', 'GO:0005680', ('77', '80'))	('APC', 'Disease', (77, 80))	('beta-catenin', 'Gene', (285, 297))	('elevated', 'PosReg', (211, 219))	('TMB', 'Chemical', '-', (220, 223))	('response', 'MPA', (177, 185))	('increase', 'PosReg', (245, 253))	('germline variants', 'Var', (56, 73))	('beta-catenin', 'Gene', (105, 117))	('TMB', 'MPA', (220, 223))	('signaling', 'biological_process', 'GO:0023052', ('298', '307'))	('beta-catenin', 'Gene', '1499', (285, 297))	('degradation', 'biological_process', 'GO:0009056', ('118', '129'))	('APC', 'Disease', 'MESH:D011125', (77, 80))	('beta-catenin', 'Gene', '1499', (105, 117))	('efficacy', 'MPA', (254, 262))	('efficacy', 'MPA', (338, 346))	('decreased', 'NegReg', (167, 176))
74969	33786423	Tumors from patients with pathogenic germline variants in SLC25A13 exhibited elevated somatic mutation burden.	('patients', 'Species', '9606', (12, 20))	('SLC25A13', 'Gene', '10165', (58, 66))	('germline variants', 'Var', (37, 54))	('elevated', 'PosReg', (77, 85))	('Tumors', 'Disease', (0, 6))	('somatic mutation burden', 'CPA', (86, 109))	('SLC25A13', 'Gene', (58, 66))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
74970	33786423	Pathogenic germline variants in this gene are associated with the urea cycle disorder type II citrullinemia and neonatal intrahepatic cholestasis.	('cholestasis', 'Phenotype', 'HP:0001396', (134, 145))	('urea cycle disorder type II citrullinemia', 'Disease', 'MESH:D056806', (66, 107))	('neonatal intrahepatic cholestasis', 'Disease', (112, 145))	('urea cycle disorder', 'Phenotype', 'HP:0000816', (66, 85))	('intrahepatic cholestasis', 'Phenotype', 'HP:0001406', (121, 145))	('germline', 'Var', (11, 19))	('associated', 'Reg', (46, 56))	('urea cycle disorder type II citrullinemia', 'Disease', (66, 107))	('neonatal intrahepatic cholestasis', 'Disease', 'MESH:D002780', (112, 145))	('urea cycle', 'biological_process', 'GO:0000050', ('66', '76'))
74971	33786423	have previously shown that tumors exhibiting urea cycle dysfunction generate nitrogen metabolites, resulting in DNA damage and ultimately better response to immune checkpoint blockade.	('response', 'MPA', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('nitrogen metabolites', 'MPA', (77, 97))	('nitrogen', 'Chemical', 'MESH:D009584', (77, 85))	('DNA damage', 'MPA', (112, 122))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('urea cycle', 'biological_process', 'GO:0000050', ('45', '55'))	('better', 'PosReg', (138, 144))	('urea', 'Chemical', 'MESH:D014508', (45, 49))	('dysfunction', 'Var', (56, 67))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('urea cycle', 'Enzyme', (45, 55))
74975	33786423	As the pathogenic germline mutations in FANCL associated with TMB are predicted to be loss-of-function mutations, we hypothesize that they lower the efficacy of interstrand crosslink repair, affecting TMB.	('affecting', 'Reg', (191, 200))	('FANCL', 'Gene', '55120', (40, 45))	('efficacy', 'MPA', (149, 157))	('TMB', 'Chemical', '-', (62, 65))	('TMB', 'Disease', (201, 204))	('loss-of-function', 'NegReg', (86, 102))	('germline', 'Var', (18, 26))	('TMB', 'Chemical', '-', (201, 204))	('lower', 'NegReg', (139, 144))	('FANCL', 'Gene', (40, 45))	('TMB', 'Disease', (62, 65))	('pathogenic', 'Reg', (7, 17))
74976	33786423	High TMB has been associated with response to checkpoint blockade in several malignancies.	('High', 'Var', (0, 4))	('malignancies', 'Disease', (77, 89))	('associated', 'Reg', (18, 28))	('TMB', 'Chemical', '-', (5, 8))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
74982	33786423	In this study, we have shown that pathogenic germline variants inform TMB and that these sets of pathogenic germline variants can be used to predict immune checkpoint inhibitor efficacy in patients with skin cutaneous melanoma.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (203, 226))	('TMB', 'CPA', (70, 73))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('skin cutaneous melanoma', 'Disease', (203, 226))	('TMB', 'Chemical', '-', (70, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (208, 226))	('variants', 'Var', (54, 62))	('patients', 'Species', '9606', (189, 197))
74984	33786423	In this study, we used the TCGA data to identify pathogenic germline variants that are associated with increased tumor mutation burden (GVITMB).	('tumor', 'Disease', (113, 118))	('increased', 'PosReg', (103, 112))	('variants', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('GVITMB', 'Chemical', '-', (136, 142))
74986	33786423	For the association analysis, we collapse the pathogenic variants in genes and gene set with the assumption that all pathogenic germline variants contribute toward increased TMB.	('variants', 'Var', (137, 145))	('TMB', 'Disease', (174, 177))	('variants', 'Var', (57, 65))	('TMB', 'Chemical', '-', (174, 177))	('increased', 'PosReg', (164, 173))
75019	26075084	Other recognized risk factors include Caucasian ethnicity, preexisting choroidal nevi, and genetic factors such as specific chromosomal abnormalities and GNAQ/11 mutations.	('GNAQ', 'Gene', '2776', (154, 158))	('mutations', 'Var', (162, 171))	('GNAQ', 'Gene', (154, 158))	('choroidal nevi', 'Phenotype', 'HP:0025314', (71, 85))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('specific chromosomal', 'Disease', (115, 135))
75022	26075084	It has been known for many years that ultraviolet exposure, coupled with specific skin pigment gene polymorphisms, is a prominent factor in the development of cutaneous melanoma.	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (90, 93))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('cutaneous melanoma', 'Disease', (159, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('polymorphisms', 'Var', (100, 113))
75024	26075084	For example, the oncogenic V600E bRAF mutation, expressed in the majority of patients with cutaneous melanoma, is thought to be the result of solar ultraviolet exposure and is absent from melanomas occurring in body locations that are naturally protected from ultraviolet radiation.	('bRAF', 'Gene', '673', (33, 37))	('V600E', 'Var', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanomas', 'Disease', (188, 197))	('patients', 'Species', '9606', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('cutaneous melanoma', 'Disease', (91, 109))	('V600E', 'Mutation', 'rs113488022', (27, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('bRAF', 'Gene', (33, 37))
75025	26075084	Genetic analysis of V600E bRAF expression in patients with UM has uncovered a relationship between the frequency of this mutation and the ocular location of the melanoma.	('bRAF', 'Gene', '673', (26, 30))	('UM', 'Phenotype', 'HP:0007716', (59, 61))	('bRAF', 'Gene', (26, 30))	('ocular location', 'Disease', (138, 153))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('patients', 'Species', '9606', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('V600E', 'Var', (20, 25))
75026	26075084	V600E mutations have been detected in patients with anterior UM, such as those of the iris, consistent with ultraviolet exposure; however, most UM cases arise in the posterior uveal tract and V600E mutation rates here are negligible.	('UM', 'Phenotype', 'HP:0007716', (144, 146))	('UM', 'Phenotype', 'HP:0007716', (61, 63))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('patients', 'Species', '9606', (38, 46))	('V600E', 'Var', (192, 197))	('V600E', 'Var', (0, 5))
75040	26075084	This study described the development of an ocular tumor in one animal following blue light exposure (434-475 nm) coupled with the administration of an antiapoptotic agent.	('434-475 nm', 'Var', (101, 111))	('men', 'Species', '9606', (32, 35))	('ocular tumor', 'Disease', 'MESH:D009369', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ocular tumor', 'Disease', (43, 55))	('ocular tumor', 'Phenotype', 'HP:0100012', (43, 55))
75074	32793865	Pooled data identified a significantly higher all-cause mortality in the punch biopsy group (risk ratio [RR], 1.520; P=.02).	('mortality', 'Disease', (56, 65))	('punch biopsy', 'Var', (73, 85))	('higher', 'PosReg', (39, 45))	('mortality', 'Disease', 'MESH:D003643', (56, 65))
75075	32793865	A higher, but nonsignificant, rate of melanoma-specific mortality (RR, 1.96; P=.22) and melanoma recurrence (RR, 1.20; P=.186) was also found for the punch biopsy group.	('mortality', 'Disease', (56, 65))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('punch biopsy', 'Var', (150, 162))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('mortality', 'Disease', 'MESH:D003643', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))
75125	32793865	The result of pooling the studies that track melanoma-specific mortality found a higher but nonsignificant rate of death among those in the punch incision group (RR, 1.96; P=.15).	('punch incision', 'Var', (140, 154))	('mortality', 'Disease', 'MESH:D003643', (63, 72))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('mortality', 'Disease', (63, 72))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
75144	31929526	Loss of Yap in T cells results in enhanced T-cell activation, differentiation, and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors.	('differentiation', 'CPA', (62, 77))	('enhanced', 'PosReg', (34, 42))	('improved', 'PosReg', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('T-cell activation', 'biological_process', 'GO:0042110', ('43', '60'))	('function', 'CPA', (83, 91))	('Yap', 'Gene', (8, 11))	('T-cell activation', 'CPA', (43, 60))	('infiltrate', 'CPA', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('repress tumors', 'Disease', 'MESH:D009369', (171, 185))	('enhanced T-cell activation', 'Phenotype', 'HP:0005419', (34, 60))	('Loss', 'Var', (0, 4))	('repress tumors', 'Disease', (171, 185))
75145	31929526	Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T-cell responses in the tumor microenvironment and as a negative regulator of T-cell tumor infiltration and patient survival in diverse human cancers.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('T-cell tumor infiltration', 'Disease', 'MESH:D018270', (195, 220))	('tumor', 'Disease', (28, 33))	('Yap', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('T-cell tumor infiltration', 'Disease', (195, 220))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (202, 207))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('deletion', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('human', 'Species', '9606', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('tumor', 'Disease', (141, 146))	('patient', 'Species', '9606', (225, 232))
75157	31929526	Yap controls signals that mediate cell death and survival, proliferation, and cell fate determination, while dysregulated Yap activity contributes to disease, most notably cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cell death', 'biological_process', 'GO:0008219', ('34', '44'))	('cell fate determination', 'CPA', (78, 101))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('dysregulated', 'Var', (109, 121))	('cancer', 'Disease', (172, 178))	('cell fate determination', 'biological_process', 'GO:0001709', ('78', '101'))	('contributes', 'Reg', (135, 146))
75160	31929526	Furthermore, an immune-cell-intrinsic role for Yap in CD4+ T cells has also been described, with Yap potentiating transforming growth factor beta (TGFbeta) signaling responses that direct Treg function.	('potentiating', 'PosReg', (101, 113))	('Yap', 'Var', (97, 100))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('114', '145'))	('TGFbeta', 'Gene', '21802', (147, 154))	('TGFbeta', 'Gene', (147, 154))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))
75172	31929526	To gain insight into the roles of Yap in T cells, we generated a mouse model in which Yap deletion and enhanced yellow fluorescent protein (EYFP) expression are induced under the control of the CD4 promoter (Yap-locus of X-over P1 [loxP]/loxP; lox-stop-lox [LSL]-EYFP; CD4-Cre, herein referred to as Yap-conditional knockout [cKO]).	('deletion', 'Var', (90, 98))	('mouse', 'Species', '10090', (65, 70))	('Yap', 'Gene', (86, 89))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('enhanced', 'PosReg', (103, 111))
75173	31929526	Yap expression was efficiently reduced in both CD4+ and CD8+ T cells in Yap-cKO mice, which was expected given the activity of this Cre model at the CD4+CD8+ double-positive (DP) stage of T-cell development (S1A and S1B Fig), and cells were also efficiently marked by EYFP expression (S1C and S1D Fig).	('CD8', 'Gene', (153, 156))	('reduced', 'NegReg', (31, 38))	('CD8', 'Gene', '925', (153, 156))	('T-cell development', 'biological_process', 'GO:0030217', ('188', '206'))	('Yap expression', 'Gene', (0, 14))	('Yap-cKO', 'Var', (72, 79))	('mice', 'Species', '10090', (80, 84))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))
75178	31929526	CD44 and CD25 in CD4+ and CD8+ T cells exhibited significantly higher expression under all stimulation conditions tested, with CD69 being significantly up-regulated only after stimulation with intermediate anti-CD3 concentrations (0.25 and 0.5 mug/mL for CD8+ T cells, and 0.125 mug/mL for CD4+ T cells).	('CD25', 'Gene', '16184', (9, 13))	('mug', 'molecular_function', 'GO:0043739', ('244', '247'))	('CD69', 'Gene', (127, 131))	('CD8', 'Gene', '925', (26, 29))	('mug', 'molecular_function', 'GO:0043739', ('279', '282'))	('0.125 mug/mL', 'Var', (273, 285))	('CD8', 'Gene', (255, 258))	('up-regulated', 'PosReg', (152, 164))	('CD8', 'Gene', '925', (255, 258))	('expression', 'MPA', (70, 80))	('CD44', 'Gene', '12505', (0, 4))	('CD44', 'Gene', (0, 4))	('CD3', 'Gene', (211, 214))	('higher', 'PosReg', (63, 69))	('CD25', 'Gene', (9, 13))	('CD8', 'Gene', (26, 29))	('CD3', 'Gene', '12501', (211, 214))
75180	31929526	These data indicate that Yap plays an inhibitory role in T-cell activation and that loss of Yap enhances the sensitivity of CD4+ and CD8+ T cells to T cell receptor (TCR) signaling.	('CD8', 'Gene', (133, 136))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('CD8', 'Gene', '925', (133, 136))	('TCR', 'biological_process', 'GO:0006283', ('166', '169'))	('TCR', 'cellular_component', 'GO:0042101', ('166', '169'))	('T cell receptor', 'Gene', (149, 164))	('enhances', 'PosReg', (96, 104))	('T-cell activation', 'biological_process', 'GO:0042110', ('57', '74'))	('T cell receptor', 'Gene', '328483', (149, 164))	('loss', 'Var', (84, 88))	('sensitivity', 'MPA', (109, 120))	('Yap', 'Gene', (92, 95))
75199	31929526	There were significantly more Yap-cKO thymocytes in the post-positive-selection stage (TCRbeta+CD69+) compared to WT mice (approximately 1% increase in total cells).	('mice', 'Species', '10090', (117, 121))	('TCRbeta', 'Gene', (87, 94))	('Yap-cKO', 'Var', (30, 37))	('TCRbeta', 'Gene', '21473', (87, 94))
75208	31929526	Our analysis showed no increase in Nur77 expression in Yap-cKO mice compared to WT (Fig 3F), suggesting that Yap-cKO thymocytes do not receive prolonged TCR signaling relative to WT cells.	('Nur77', 'Gene', '15370', (35, 40))	('TCR', 'cellular_component', 'GO:0042101', ('153', '156'))	('Yap-cKO', 'Var', (109, 116))	('mice', 'Species', '10090', (63, 67))	('Nur77', 'Gene', (35, 40))	('TCR', 'biological_process', 'GO:0006283', ('153', '156'))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))
75211	31929526	We observed similar reduced growth of subcutaneous LLC tumors in Yap-cKO mice (Fig 4C and 4D), suggesting a general role for Yap in antitumor T-cell responses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduced', 'NegReg', (20, 27))	('LLC tumors', 'Disease', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('LLC', 'cellular_component', 'GO:0038045', ('51', '54'))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (55, 60))	('growth', 'MPA', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Yap-cKO', 'Var', (65, 72))	('LLC tumors', 'Disease', 'MESH:D009369', (51, 61))	('tumor', 'Disease', (136, 141))	('subcutaneous', 'Disease', (38, 50))
75213	31929526	Immunofluorescence microscopy analysis revealed that tumors that developed in Yap-cKO mice were significantly more infiltrated with CD8+ T cells at both the tumor center and tumor edge compared to WT mice (Fig 4E).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (174, 179))	('Yap-cKO', 'Var', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('more infiltrated', 'PosReg', (110, 126))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('mice', 'Species', '10090', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('tumors', 'Disease', (53, 59))
75214	31929526	Flow cytometry analysis revealed more Yap-cKO CD4+ and CD8+ T cells infiltrating tumors compared to WT counterparts (Fig 4F and 4H).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('Yap-cKO', 'Var', (38, 45))	('CD8', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD8', 'Gene', '925', (55, 58))	('4H', 'Chemical', 'MESH:D006859', (128, 130))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
75218	31929526	Absolute numbers of tdTomato+ (WT) and EYFP+ (Yap-cKO) CD8+ T cells were then measured in tumors after 15 days.	('EYFP+', 'Var', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))
75219	31929526	Yap-cKO CD8+ T cells showed a significantly enhanced capacity to infiltrate tumors (Fig 4J), with nearly 30% of all CD8+ tumor-infiltrating T cells being EYFP+ Yap-cKO T cells compared to almost undetectable numbers of tdTomato+ WT T cells (Fig 4K).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CD8', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (121, 126))	('tdTomato+ WT T', 'Disease', (219, 233))	('tdTomato+ WT T', 'Disease', 'MESH:C536751', (219, 233))	('tumors', 'Disease', (76, 82))	('CD8', 'Gene', '925', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CD8', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CD8', 'Gene', '925', (8, 11))	('enhanced', 'PosReg', (44, 52))	('EYFP+', 'Var', (154, 159))
75220	31929526	These data are the first to conclusively show that Yap-cKO CD8+ T cells have intrinsically enhanced tumor infiltration capacity.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor infiltration', 'Disease', 'MESH:D017254', (100, 118))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('tumor infiltration', 'Disease', (100, 118))	('Yap-cKO', 'Var', (51, 58))	('enhanced', 'PosReg', (91, 99))
75223	31929526	A large number of genes were differentially expressed in CD4+ and CD8+ TILs isolated from Yap-cKO mice compared to WT mice (Fig 5A and 5B and S2A and S2B Fig).	('CD4+', 'Var', (57, 61))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('mice', 'Species', '10090', (118, 122))	('differentially', 'Reg', (29, 43))	('mice', 'Species', '10090', (98, 102))
75224	31929526	These data are consistent with Yap function being coordinated with T-cell activation and suggest that the enhanced antitumor responses observed in Yap-cKO T cells are mediated by changes in cellular responses to local tumor signals, including TCR signaling and the cytokine milieu.	('tumor', 'Disease', (119, 124))	('TCR', 'cellular_component', 'GO:0042101', ('243', '246'))	('enhanced', 'PosReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Yap-cKO', 'Var', (147, 154))	('TCR', 'biological_process', 'GO:0006283', ('243', '246'))	('TCR signaling', 'MPA', (243, 256))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('changes', 'Reg', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('T-cell activation', 'biological_process', 'GO:0042110', ('67', '84'))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
75227	31929526	Subset-defining transcription factors and cytokines associated with each of the major CD4+ T-cell phenotypes were all up-regulated in Yap KO CD4+ TILs (S3G and S3H Fig), suggesting that Yap deletion leads to enhanced naive CD4+ T-cell differentiation, consistent with our in vitro observations.	('deletion', 'Var', (190, 198))	('up-regulated', 'PosReg', (118, 130))	('S3H', 'Chemical', 'MESH:C042345', (160, 163))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('228', '250'))	('naive CD4+ T-cell differentiation', 'CPA', (217, 250))	('transcription', 'biological_process', 'GO:0006351', ('16', '29'))	('Yap', 'Gene', (186, 189))	('enhanced', 'PosReg', (208, 216))
75228	31929526	Using unique up-regulated genes after differentiation to each of the major T helper subsets, our data showed that Yap-cKO CD4+ TILs are more skewed towards a Th2 and Treg phenotype compared to WT CD4+ TILs (S4A-S4D Fig), consistent with prior studies showing that the B16F10 tumor microenvironment enhances these fates.	('Th2', 'Gene', '15111', (158, 161))	('CD4+', 'Var', (122, 126))	('B16F10', 'CellLine', 'CVCL:0159', (268, 274))	('up-regulated', 'PosReg', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('Yap-cKO CD4+', 'Var', (114, 126))	('Th2', 'Gene', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
75230	31929526	An unbiased analysis of transcription factor binding motifs in upstream regulatory regions of the genes altered in Yap-cKO CD4+ and CD8+ TILs revealed the TEAD transcription factor motif as the most significantly enriched in both cell populations (S5A and S5B Fig), suggesting that Yap-regulated TEAD activity contributes to transcriptional regulation of these genes.	('transcription factor', 'molecular_function', 'GO:0000981', ('160', '180'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('24', '52'))	('regulation', 'biological_process', 'GO:0065007', ('341', '351'))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('transcriptional regulation', 'MPA', (325, 351))	('TEA', 'Chemical', 'MESH:C488288', (296, 299))	('CD8', 'Gene', (132, 135))	('TEA', 'Chemical', 'MESH:C488288', (155, 158))	('CD8', 'Gene', '925', (132, 135))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))	('CD4+', 'Var', (123, 127))
75231	31929526	Comparison of gene expression changes identified in CD4+ and CD8+ Yap-cKO TILs with clinical data from TCGA showed significant correlation of gene signatures with T-cell infiltration across a variety of human cancers (Fig 5I).	('gene', 'MPA', (142, 146))	('human', 'Species', '9606', (203, 208))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('CD4+', 'Var', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('gene expression', 'biological_process', 'GO:0010467', ('14', '29'))	('cancers', 'Disease', (209, 216))	('T-cell infiltration', 'CPA', (163, 182))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
75233	31929526	Genes altered in Yap-cKO TILs were also significantly associated with patient survival across several cancers (Fig 4J), as seen most significantly in LUAD for both CD4+ and CD8+ Yap-cKO gene signatures (Fig 4K and 4L).	('CD8', 'Gene', '925', (173, 176))	('LUAD', 'Disease', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CD4+', 'Var', (164, 168))	('Yap-cKO', 'Gene', (178, 185))	('Yap-cKO', 'Gene', (17, 24))	('patient', 'Species', '9606', (70, 77))	('patient survival', 'CPA', (70, 86))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('CD8', 'Gene', (173, 176))	('cancers', 'Disease', (102, 109))	('associated with', 'Reg', (54, 69))
75236	31929526	We found that disrupting Yap activity leads to enhanced T-cell activation, augmented differentiation, and increased tumor infiltration.	('tumor infiltration', 'Disease', (116, 134))	('T-cell activation', 'CPA', (56, 73))	('enhanced', 'PosReg', (47, 55))	('T-cell activation', 'biological_process', 'GO:0042110', ('56', '73'))	('disrupting', 'Var', (14, 24))	('enhanced T-cell activation', 'Phenotype', 'HP:0005419', (47, 73))	('tumor infiltration', 'Disease', 'MESH:D017254', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('differentiation', 'CPA', (85, 100))	('increased', 'PosReg', (106, 115))	('augmented', 'PosReg', (75, 84))
75238	31929526	Experimental data indicated that CD4+ and CD8+ T cells from Yap-cKO mice were more sensitive to TCR signaling compared to WT cells.	('mice', 'Species', '10090', (68, 72))	('TCR', 'cellular_component', 'GO:0042101', ('96', '99'))	('Yap-cKO', 'Var', (60, 67))	('TCR', 'biological_process', 'GO:0006283', ('96', '99'))	('CD8', 'Gene', (42, 45))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('CD8', 'Gene', '925', (42, 45))	('sensitive to TCR signaling', 'MPA', (83, 109))
75242	31929526	RNA-seq analysis of Yap-cKO versus WT TILs revealed that CD3, CD28, CD80, and CD86 receptor molecules, kinases, phosphatases, and scaffold proteins are all up-regulated with Yap deletion, offering a mechanism for enhanced activation of CD4+ and CD8+ T cells.	('CD80', 'Gene', (68, 72))	('CD8', 'Gene', (68, 71))	('Yap', 'Gene', (174, 177))	('enhanced activation', 'PosReg', (213, 232))	('CD8', 'Gene', '925', (245, 248))	('CD86', 'Gene', '12524', (78, 82))	('CD8', 'Gene', '925', (78, 81))	('up-regulated', 'PosReg', (156, 168))	('CD3', 'Gene', (57, 60))	('CD86', 'Gene', (78, 82))	('CD8', 'Gene', '925', (68, 71))	('CD80', 'Gene', '12519', (68, 72))	('deletion', 'Var', (178, 186))	('CD28', 'Gene', (62, 66))	('CD8', 'Gene', (245, 248))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('CD8', 'Gene', (78, 81))	('CD3', 'Gene', '12501', (57, 60))	('CD28', 'Gene', '12487', (62, 66))	('kinases', 'MPA', (103, 110))
75245	31929526	We observed a slight increase in total number of TCRbeta+CD69+ thymocytes in Yap-cKO mice compared to WT mice.	('mice', 'Species', '10090', (85, 89))	('Yap-cKO', 'Var', (77, 84))	('increase', 'PosReg', (21, 29))	('TCRbeta', 'Gene', '21473', (49, 56))	('mice', 'Species', '10090', (105, 109))	('TCRbeta', 'Gene', (49, 56))
75251	31929526	Interestingly, neither Yap deletion nor verteporfin treatment significantly impacted T-cell proliferation.	('Yap', 'Gene', (23, 26))	('T-cell proliferation', 'CPA', (85, 105))	('verteporfin', 'Chemical', 'MESH:C098350', (40, 51))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('85', '105'))	('deletion', 'Var', (27, 35))	('impacted', 'Reg', (76, 84))
75265	31929526	The significant correlation of CD8+ and CD4+ Yap-cKO gene signatures with tumor T-cell infiltration in TCGA data suggest that Yap represses CD8+ and CD4+ T-cell migration and tumor infiltration in human cancers.	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (31, 34))	('tumor', 'Disease', (74, 79))	('T-cell migration', 'biological_process', 'GO:0072678', ('154', '170'))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Yap', 'Var', (126, 129))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('represses', 'NegReg', (130, 139))	('tumor', 'Disease', (175, 180))	('tumor infiltration', 'Disease', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CD8', 'Gene', '925', (140, 143))	('CD8', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('human', 'Species', '9606', (197, 202))	('tumor infiltration', 'Disease', 'MESH:D017254', (175, 193))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancers', 'Disease', (203, 210))
75268	31929526	Collectively, our data show that Yap is an important immunosuppressor and suggest that inhibition of Yap activity in T cells could have important clinical implications in T-cell therapies against cancer and other diseases.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('activity', 'MPA', (105, 113))	('cancer', 'Disease', (196, 202))	('inhibition', 'Var', (87, 97))	('Yap', 'Protein', (101, 104))
75287	31929526	Plates were coated with anti-CD3 antibody (Biolegend) at concentrations of 0, 0.125, 0.25, 0.5, and 1 mug/ml at 4 C overnight and were washed twice with PBS before incubation.	('CD3', 'Gene', '12501', (29, 32))	('0.125', 'Var', (78, 83))	('antibody', 'cellular_component', 'GO:0019815', ('33', '41'))	('antibody', 'cellular_component', 'GO:0019814', ('33', '41'))	('antibody', 'molecular_function', 'GO:0003823', ('33', '41'))	('0.5', 'Var', (91, 94))	('0.25', 'Var', (85, 89))	('mug', 'molecular_function', 'GO:0043739', ('102', '105'))	('CD3', 'Gene', (29, 32))	('antibody', 'cellular_component', 'GO:0042571', ('33', '41'))
75289	31929526	On days 1 and 3, cells were stained with dead cell dye as well as antibodies recognizing the lineage and activation markers CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 PerCP-Cy5.5 (Biolegend), CD69 PE (Biolegend), CD44 BV650 (Biolegend), and CD25 APC (Biolegend).	('CD44', 'Gene', (208, 212))	('CD8', 'Gene', (158, 161))	('CD25', 'Gene', (236, 240))	('APC', 'Disease', 'MESH:D011125', (241, 244))	('CD8', 'Gene', '925', (158, 161))	('CD44', 'Gene', '12505', (208, 212))	('CD25', 'Gene', '16184', (236, 240))	('CD69 PE', 'Var', (187, 194))	('CD3', 'Gene', (124, 127))	('APC', 'Disease', (241, 244))	('CD3', 'Gene', '12501', (124, 127))	('CD4 BUV395', 'Var', (141, 151))	('APC', 'cellular_component', 'GO:0005680', ('241', '244'))
75297	31929526	Cells were stained with the LIVE/DEAD fixable near-IR dead cell stain kit (Invitrogen); antibodies for surface markers CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 APCFire750 (Biolegend), and CD25 BV510 (Biolegend); antibodies for intracellular cytokines IFNgamma APC (Biolegend) and IL-17 PerCP-Cy5.5 (Biolegend); or antibodies for transcription factors GATA3 PECy7 (Biolegend) and Foxp3 PE (BD), as described earlier.	('IL-17', 'Gene', '16171', (277, 282))	('CD8', 'Gene', '925', (153, 156))	('Foxp3', 'Gene', (376, 381))	('IL-17', 'molecular_function', 'GO:0030367', ('277', '282'))	('IL-17', 'Gene', (277, 282))	('GATA3', 'Gene', '14462', (348, 353))	('APC', 'Disease', 'MESH:D011125', (157, 160))	('APC', 'Disease', (157, 160))	('CD25', 'Gene', '16184', (185, 189))	('CD25', 'Gene', (185, 189))	('IFNgamma', 'Gene', '15978', (248, 256))	('APC', 'cellular_component', 'GO:0005680', ('257', '260'))	('intracellular', 'cellular_component', 'GO:0005622', ('224', '237'))	('CD8', 'Gene', (153, 156))	('CD3', 'Gene', (119, 122))	('GATA3', 'Gene', (348, 353))	('APC', 'Disease', 'MESH:D011125', (257, 260))	('Foxp3', 'Gene', '20371', (376, 381))	('APC', 'Disease', (257, 260))	('transcription', 'biological_process', 'GO:0006351', ('326', '339'))	('IFNgamma', 'Gene', (248, 256))	('CD3', 'Gene', '12501', (119, 122))	('CD4 BUV395', 'Var', (136, 146))
75300	31929526	Cells were stained with dead cell dye and antibodies for the following surface markers: CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 PerCP-Cy5.5 (Biolegend), TCRbeta BV510 (Biolegend), CCR7 PECy7 (Biolegend), H-2Kb PE (Biolegend), CD69 BV421 (Biolegend), CD45R/B220 APCFire750 (Biolegend), CD25 APCFire750 (Biolegend), GL3 APCFire750 (Biolegend), and NK1.1 APCFire750 (Biolegend).	('CD25', 'Gene', '16184', (283, 287))	('CD25', 'Gene', (283, 287))	('APC', 'Disease', 'MESH:D011125', (350, 353))	('CD45R', 'Gene', (248, 253))	('APC', 'Disease', 'MESH:D011125', (316, 319))	('CD45R', 'Gene', '19264', (248, 253))	('APC', 'Disease', (350, 353))	('TCRbeta', 'Gene', '21473', (151, 158))	('APC', 'Disease', (316, 319))	('CD8', 'Gene', (122, 125))	('CD3', 'Gene', (88, 91))	('CCR', 'molecular_function', 'GO:0043880', ('178', '181'))	('APC', 'Disease', 'MESH:D011125', (259, 262))	('CD69 BV421', 'Var', (224, 234))	('APC', 'Disease', (259, 262))	('APC', 'Disease', 'MESH:D011125', (288, 291))	('CD3', 'Gene', '12501', (88, 91))	('CD4 BUV395', 'Var', (105, 115))	('APC', 'Disease', (288, 291))	('CCR7', 'Gene', (178, 182))	('CD8', 'Gene', '925', (122, 125))	('H-2Kb PE', 'Chemical', 'MESH:C032876', (202, 210))	('CCR7', 'Gene', '12775', (178, 182))	('TCRbeta', 'Gene', (151, 158))
75303	31929526	Cells were treated with ACK red blood cell lysis buffer (Gibco), and tumor single-cell suspensions were prepared for staining and analysis by flow cytometry, using DAPI (Biolegend) and antibodies for CD45 BV510 (Biolegend), CD3 BUV737 (BD), CD4 BUV395 (BD), and CD8 PerCP-Cy5.5 (Biolegend).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CD45 BV510', 'Var', (200, 210))	('tumor', 'Disease', (69, 74))	('lysis', 'biological_process', 'GO:0019835', ('43', '48'))	('CD3', 'Gene', (224, 227))	('CD8', 'Gene', (262, 265))	('CD4 BUV395', 'Var', (241, 251))	('CD3', 'Gene', '12501', (224, 227))	('ACK', 'Gene', (24, 27))	('CD8', 'Gene', '925', (262, 265))	('ACK', 'Gene', '107482', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
75307	31929526	On day 15 of tumor growth, tumors were harvested and stained for flow cytometric analysis with dead cell dye, DAPI (Biolegend), and antibodies recognizing CD45 BV510 (Biolegend), CD3 BUV737 (BD), CD4 APC (Biolegend), and CD8 PerCP-Cy5.5 (Biolegend).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (13, 18))	('CD8', 'Gene', '925', (221, 224))	('APC', 'Disease', (200, 203))	('CD45 BV510', 'Var', (155, 165))	('tumor', 'Disease', (27, 32))	('CD3', 'Gene', (179, 182))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('CD3', 'Gene', '12501', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('APC', 'cellular_component', 'GO:0005680', ('200', '203'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('APC', 'Disease', 'MESH:D011125', (200, 203))	('CD8', 'Gene', (221, 224))
75311	31929526	Taqman primers (Life Tech) for mouse Gapdh (4352339E), Yap (Mm01143263_m1), or TEAD1-4 (Mm00493507_m1, Mm00449004_m1, Mm00449013_m1, Mm01189836_m1) were mixed with cDNA and Taqman Universal Master Mix II (Life Tech), and ddCT values were calculated relative to unstimulated controls.	('Mm01189836_m1', 'Var', (133, 146))	('4352339E', 'Var', (44, 52))	('Mm00449004_m1', 'Var', (103, 116))	('mouse', 'Species', '10090', (31, 36))	('Gapdh', 'Gene', '14433', (37, 42))	('Mm00493507_m1', 'Var', (88, 101))	('Gapdh', 'Gene', (37, 42))	('TEAD1-4', 'Gene', (79, 86))	('Mm00449013_m1', 'Var', (118, 131))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (79, 86))	('Mm01143263_m1', 'Var', (60, 73))	('4352339E', 'Chemical', 'MESH:D017962', (44, 52))
75314	31929526	Tumors cells were subsequently stained with DAPI and antibodies recognizing CD45 V500 (Biolegend), CD3 PE (Biolegend), CD4 APC (Biolegend), CD8 PerCP-Cy5.5 (Biolegend), and CD4+ and CD8+ TILs were sorted from each tumor using a BD FACSAria instrument.	('CD3', 'Gene', (99, 102))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('APC', 'cellular_component', 'GO:0005680', ('123', '126'))	('CD3', 'Gene', '12501', (99, 102))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', (182, 185))	('CD8', 'Gene', '925', (140, 143))	('CD8', 'Gene', '925', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('CD45 V500', 'Var', (76, 85))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (214, 219))
75319	31929526	Differentially expressed genes (DEGs) between Yap-cKO versus WT CD4+ and CD8+ cells were defined as log2(FC) > 1 (up) or log2(FC) < -1 (down) and FDR < 0.05.	('CD8', 'Gene', '925', (73, 76))	('Yap-cKO', 'Var', (46, 53))	('DEGs', 'Chemical', 'MESH:C062694', (32, 36))	('CD8', 'Gene', (73, 76))	('Differentially', 'Reg', (0, 14))	('Di', 'Chemical', 'MESH:C076868', (0, 2))
75325	31929526	Red signifies that an average survival probability is higher for patients with high activity of Yap-regulated signature, whereas dark blue signifies that an average survival probability is higher for patients with low Yap activity.	('patients', 'Species', '9606', (200, 208))	('higher', 'PosReg', (54, 60))	('activity', 'MPA', (84, 92))	('high', 'Var', (79, 83))	('patients', 'Species', '9606', (65, 73))	('survival', 'MPA', (30, 38))
75345	31929526	OT1 TCR and B16-Ova tumor); 2) knocking down Yap in peripheral T cells from WT mice by an shRNA approach; or 3) introducing Yap (i.e.	('introducing', 'Reg', (112, 123))	('Ova tumor', 'Phenotype', 'HP:0100615', (16, 25))	('knocking down', 'Var', (31, 44))	('TCR', 'cellular_component', 'GO:0042101', ('4', '7'))	('mice', 'Species', '10090', (79, 83))	('Yap', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('TCR', 'biological_process', 'GO:0006283', ('4', '7'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
75349	31929526	-The authors state that phenotype of "Yap-cKO CD4+ TILs are more skewed towards a Th2 and Treg phenotype compared to WT CD4+ TILs".	('CD4+', 'Var', (46, 50))	('Th2', 'Gene', '15111', (82, 85))	('Th2', 'Gene', (82, 85))
75358	27442652	Case report of a Li-Fraumeni syndrome-like phenotype with a de novo mutation in CHEK2 Supplemental Digital Content is available in the text Cases of multiple tumors are rarely reported in China.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('mutation', 'Var', (68, 76))	('multiple tumors', 'Disease', (149, 164))	('multiple tumors', 'Disease', 'MESH:D009369', (149, 164))	('CHEK2', 'Gene', (80, 85))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (17, 37))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('Li-Fraumeni syndrome', 'Disease', (17, 37))
75362	27442652	A novel deleterious germline mutation (chr22:29091846, G->A, p.H371Y) was identified in CHEK2, a Li-Fraumeni syndrome causal gene.	('p.H371Y', 'Var', (61, 68))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (97, 117))	('CHEK2', 'Gene', (88, 93))	('Li-Fraumeni syndrome', 'Disease', (97, 117))	('p.H371Y', 'Mutation', 'rs531398630', (61, 68))	('CHEK2', 'Gene', '11200', (88, 93))
75374	27442652	Sequencing the DNA of several families with LFS showed an autosomal dominant inheritance of the mutated TP53 gene.	('mutated', 'Var', (96, 103))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))
75375	27442652	Meanwhile, the frequency of new (de novo) TP53 mutations is estimated to be at least 7% and may be as high as 20%.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
75378	27442652	After that, although the possibility of CHEK2's contribution to LFS and Li-Fraumeni syndrome-like (LFS-L) has been inferred by many researchers, there was no evidence indicating CHEK2 is a major gene involved in LFS and LFS-L. To date, 4 mutations in CHEK2 have been reported to be associated with LFS or LFS-L: c.1100delC frameshift mutation, c.470T>C nonsynonymous mutation, c.1422delT frameshift deletion, and c.983T>C nonsynonymous mutation, which confirms the relationship between CHEK2 and LFS.	('c.1422delT frameshift deletion', 'Var', (377, 407))	('CHEK2', 'Gene', (251, 256))	('LFS-L', 'Disease', (305, 310))	('nonsynonymous', 'MPA', (353, 366))	('Li-Fraumeni syndrome', 'Disease', (72, 92))	('c.1100delC frameshift mutation', 'Var', (312, 342))	('c.1100delC', 'Mutation', 'rs555607708', (312, 322))	('c.1422delT', 'Mutation', 'rs587780174', (377, 387))	('CHEK2', 'Gene', '11200', (251, 256))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (72, 92))	('CHEK2', 'Gene', (178, 183))	('c.983T>C', 'Var', (413, 421))	('CHEK2', 'Gene', (486, 491))	('CHEK2', 'Gene', '11200', (178, 183))	('c.470T>C', 'Mutation', 'rs17879961', (344, 352))	('c.470T>C', 'Var', (344, 352))	('associated', 'Reg', (282, 292))	('CHEK2', 'Gene', '11200', (486, 491))	('CHEK2', 'Gene', (40, 45))	('LFS', 'Disease', (298, 301))	('CHEK2', 'Gene', '11200', (40, 45))	('c.983T>C', 'Mutation', 'rs1487204500', (413, 421))
75379	27442652	De novo original causal mutations in TP53 have been revealed.	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (24, 33))	('TP53', 'Gene', '7157', (37, 41))
75380	27442652	However, a causal mutation in CHEK2 has not been reported in patients with LFS-L. Spontaneous germline mutation, which occurs due to an error in copying genetic material or an error in cell division, is estimated to occur at 1.18 x 10-8 per position and 1.5 in the exonic region of the human genome, on average.	('patients', 'Species', '9606', (61, 69))	('human', 'Species', '9606', (286, 291))	('cell division', 'biological_process', 'GO:0051301', ('185', '198'))	('CHEK2', 'Gene', '11200', (30, 35))	('error', 'Var', (136, 141))	('CHEK2', 'Gene', (30, 35))
75412	27442652	We eventually detected 511, 1341, and 3247 somatic single nucleotide variants (SNVs) for the thyroid tumor, lung tumor, and skin tumors, respectively, and the mutation spectrum can be observed in Supplementary Fig.	('lung tumor', 'Disease', (108, 118))	('single nucleotide variants', 'Var', (51, 77))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('skin tumors', 'Disease', (124, 135))	('thyroid tumor', 'Disease', (93, 106))	('lung tumor', 'Phenotype', 'HP:0100526', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('thyroid tumor', 'Disease', 'MESH:D013959', (93, 106))	('skin tumors', 'Disease', 'MESH:D012878', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('thyroid tumor', 'Phenotype', 'HP:0100031', (93, 106))	('skin tumor', 'Phenotype', 'HP:0008069', (124, 134))	('skin tumors', 'Phenotype', 'HP:0008069', (124, 135))	('lung tumor', 'Disease', 'MESH:D008175', (108, 118))
75423	27442652	The T:A->G:C was the highest mutated type in the spectrum of thyroid tumor SNVs, while the C:G->T:A was the maximum type in the mutation spectrum of both skin and lung tumors (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('thyroid tumor', 'Disease', 'MESH:D013959', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('thyroid tumor', 'Phenotype', 'HP:0100031', (61, 74))	('C:G->T:A', 'Var', (91, 99))	('skin and lung tumors', 'Disease', 'MESH:D012878', (154, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('lung tumor', 'Phenotype', 'HP:0100526', (163, 173))	('T:A->G:C', 'Var', (4, 12))	('thyroid tumor', 'Disease', (61, 74))	('lung tumors', 'Phenotype', 'HP:0100526', (163, 174))
75427	27442652	We then focused on the germline mutations in cancer-related functional genes (Supplementary Table S5) and found a novel deleterious heterozygous nonsynonymous mutation (chr22:29091846, G->A, p.H371Y) in CHEK2, which is not recorded in the 1000 genome database and dbSNP137.	('chr22:29091846', 'Var', (169, 183))	('CHEK2', 'Gene', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('p.H371Y', 'Mutation', 'rs531398630', (191, 198))	('p.H371Y', 'Var', (191, 198))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('dbSNP137', 'Chemical', '-', (264, 272))	('cancer', 'Disease', (45, 51))	('CHEK2', 'Gene', '11200', (203, 208))
75428	27442652	Interestingly, a nonsynonymous 2-bp mutation located nearby was also related to multiple cancers in the clivar database.	('multiple cancers', 'Disease', (80, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('multiple cancers', 'Disease', 'MESH:D009369', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('related', 'Reg', (69, 76))	('nonsynonymous 2-bp mutation', 'Var', (17, 44))
75429	27442652	Previous publications showed that LFS and LFS-L can be ascribed mostly to TP53 and CHEK2 mutations.	('CHEK2', 'Gene', '11200', (83, 88))	('LFS', 'Disease', (34, 37))	('CHEK2', 'Gene', (83, 88))	('LFS-L', 'Disease', (42, 47))	('TP53', 'Gene', '7157', (74, 78))	('mutations', 'Var', (89, 98))	('TP53', 'Gene', (74, 78))
75431	27442652	The mutation in our case was discovered for the first time, and the sorting tolerant from intolerant predicts that this amino acid substitution may have damaging effects on the protein function of CHEK2.	('protein function', 'MPA', (177, 193))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('amino acid substitution', 'Var', (120, 143))	('CHEK2', 'Gene', (197, 202))	('CHEK2', 'Gene', '11200', (197, 202))
75433	27442652	To confirm the originality of the identified mutation in CHEK2, we performed Sanger sequencing on this locus for the patient and her 2 sisters, whose genomic DNA we obtained.	('DNA', 'cellular_component', 'GO:0005574', ('158', '161'))	('mutation', 'Var', (45, 53))	('CHEK2', 'Gene', '11200', (57, 62))	('patient', 'Species', '9606', (117, 124))	('CHEK2', 'Gene', (57, 62))
75434	27442652	The genotype results validated the heterozygous G->A mutation in the patient and showed that both of her 2 healthy sisters were homozygous G. Moreover, 3 nearby mutations were also genotyped by the Sanger method to determine a parental origin.	('G->A mutation', 'Var', (48, 61))	('mutation', 'Var', (53, 61))	('patient', 'Species', '9606', (69, 76))
75435	27442652	To our surprise, the phased haplotype results demonstrated that the deleterious nonsynonymous G->A mutations in the studied patients originated from DNM rather than inherited mutations (Fig.	('originated from', 'Reg', (133, 148))	('mutations', 'Var', (99, 108))	('DNM', 'Gene', '1759', (149, 152))	('DNM', 'Gene', (149, 152))	('G->A', 'Gene', (94, 98))	('patients', 'Species', '9606', (124, 132))
75436	27442652	Thus, our result revealed that the DNM (p.H371Y) in CHEK2 was the pathogenic mutation in our patients.	('CHEK2', 'Gene', '11200', (52, 57))	('CHEK2', 'Gene', (52, 57))	('p.H371Y', 'Mutation', 'rs531398630', (40, 47))	('DNM', 'Gene', (35, 38))	('DNM', 'Gene', '1759', (35, 38))	('p.H371Y', 'Var', (40, 47))	('patients', 'Species', '9606', (93, 101))
75439	27442652	We have found a new mutation in CHEK2, which sorting tolerant from intolerant suggests to be damaging, and we confirmed the mutation to be de novo, rather than inherited, using the haplotype inferences from the surrounding mutations from samples of family members.	('CHEK2', 'Gene', '11200', (32, 37))	('mutation', 'Var', (20, 28))	('CHEK2', 'Gene', (32, 37))
75441	27442652	The c.1100delC variant in CHEK2 was reported to be a major LFS susceptibility mutation in the United States but not in Dutch populations.	('c.1100delC', 'Var', (4, 14))	('LFS', 'Disease', (59, 62))	('CHEK2', 'Gene', '11200', (26, 31))	('CHEK2', 'Gene', (26, 31))	('c.1100delC', 'Mutation', 'rs555607708', (4, 14))
75442	27442652	The c.983T>C was found to cause the Dutch mutation but was not found in patients from the USA or Finland.	('cause', 'Reg', (26, 31))	('c.983T>C', 'Var', (4, 12))	('c.983T>C', 'Mutation', 'rs1487204500', (4, 12))	('Dutch mutation', 'Disease', (36, 50))	('patients', 'Species', '9606', (72, 80))
75443	27442652	Additionally, a germline mutation in chr22:29091848 has been reported to be associated with hereditary cancer-predisposing syndrome, which, to a certain extent, demonstrated that the mutation we found is indeed associated with cancer-related diseases.	('chr22:29091848', 'Gene', (37, 51))	('germline', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (211, 221))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('associated', 'Reg', (76, 86))	('hereditary cancer', 'Disease', 'MESH:D009369', (92, 109))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('hereditary cancer', 'Disease', (92, 109))
75445	27442652	In our case, each tumor tissue had somatic mutations reported in TCGA, from which we hypothesize that although the mutation in CHEK2 is the pathogenic mutation in the patients with LFS or LFS-L, finally either the tumor is more associated with the accumulation of somatic mutations in a particular organization or the mutation in CHEK2 induces chromosomal instability and somatic mutation accumulation.	('chromosomal instability', 'CPA', (344, 367))	('CHEK2', 'Gene', (127, 132))	('CHEK2', 'Gene', '11200', (127, 132))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('induces', 'Reg', (336, 343))	('CHEK2', 'Gene', '11200', (330, 335))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('CHEK2', 'Gene', (330, 335))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('somatic mutation', 'CPA', (372, 388))	('tumor', 'Disease', (214, 219))	('chromosomal instability', 'Phenotype', 'HP:0040012', (344, 367))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mutation', 'Var', (115, 123))	('mutation', 'Var', (318, 326))
75454	31931413	Further, using both a bioinformatics analysis and experimental approaches, we demonstrated that m6A downregulated the expression of the positive p53 regulator, PRDM2, through the YTHDF2-promoted decay of PRDM2 mRNAs.	('m6A', 'Var', (96, 99))	('PRDM2', 'Gene', (160, 165))	('rat', 'Species', '10116', (85, 88))	('YTHDF2', 'Gene', '51441', (179, 185))	('mRNAs', 'MPA', (210, 215))	('downregulated', 'NegReg', (100, 113))	('decay', 'MPA', (195, 200))	('YTHDF2', 'Gene', (179, 185))	('expression', 'MPA', (118, 128))	('PRDM2', 'Gene', (204, 209))
75455	31931413	We showed that m6A upregulated the expression of the negative p53 regulator, YY1 and MDM2 through YTHDF1-stimulated translation of YY1 and MDM2 mRNA.	('upregulated', 'PosReg', (19, 30))	('YY1', 'Var', (131, 134))	('YY1', 'Gene', (77, 80))	('MDM2', 'Gene', (85, 89))	('expression', 'MPA', (35, 45))	('translation', 'biological_process', 'GO:0006412', ('116', '127'))	('translation', 'MPA', (116, 127))	('YTHDF1', 'Gene', '54915', (98, 104))	('YTHDF1', 'Gene', (98, 104))	('MDM2', 'Var', (139, 143))
75456	31931413	Taken together, our study revealed the novel role of m6A in mediating arsenite-induced human keratinocyte transformation by suppressing p53 activation.	('activation', 'MPA', (140, 150))	('p53', 'Protein', (136, 139))	('human', 'Species', '9606', (87, 92))	('suppressing', 'NegReg', (124, 135))	('rat', 'Species', '10116', (95, 98))	('m6A', 'Var', (53, 56))	('human keratinocyte', 'Disease', (87, 105))	('arsenite', 'Chemical', 'MESH:C015001', (70, 78))
75458	31931413	Increased m6A attenuates p53 activation in arsenite-transformed human keratinocytes.	('m6A', 'Var', (10, 13))	('human', 'Species', '9606', (64, 69))	('activation', 'PosReg', (29, 39))	('rat', 'Species', '10116', (72, 75))	('arsenite', 'Chemical', 'MESH:C015001', (43, 51))	('attenuates', 'NegReg', (14, 24))	('p53', 'Protein', (25, 28))
75462	31931413	A recent study from our group has demonstrated that N6-methyladenosine (m6A), one of the most abundant and reversible post-transcriptional modifications in eukaryotic RNA, mediates the proliferation and apoptosis of arsenite-transformed human bronchial epithelial cells .	('proliferation', 'CPA', (185, 198))	('mediates', 'Reg', (172, 180))	('human', 'Species', '9606', (237, 242))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('rat', 'Species', '10116', (192, 195))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (52, 70))	('apoptosis', 'CPA', (203, 212))	('arsenite', 'Chemical', 'MESH:C015001', (216, 224))	('rat', 'Species', '10116', (41, 44))	('N6-methyladenosine', 'Var', (52, 70))	('RNA', 'cellular_component', 'GO:0005562', ('167', '170'))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))
75464	31931413	This is further supported by the results from the studies showing that m6A is associated with arsenite-induced oxidative stress , which is the major cause of its carcinogenicity.	('arsenite-induced', 'MPA', (94, 110))	('associated', 'Reg', (78, 88))	('arsenite', 'Chemical', 'MESH:C015001', (94, 102))	('m6A', 'Var', (71, 74))	('carcinogenic', 'Disease', 'MESH:D063646', (162, 174))	('carcinogenic', 'Disease', (162, 174))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))
75465	31931413	Increased m6A promoted the proliferation of human keratinocytes that are exposed to low levels of arsenite, possibly through the inhibition of oxidative stress .	('human', 'Species', '9606', (44, 49))	('m6A', 'Var', (10, 13))	('rat', 'Species', '10116', (52, 55))	('oxidative stress', 'Phenotype', 'HP:0025464', (143, 159))	('proliferation', 'CPA', (27, 40))	('arsenite', 'Chemical', 'MESH:C015001', (98, 106))	('rat', 'Species', '10116', (34, 37))	('promoted', 'PosReg', (14, 22))
75469	31931413	It has been shown that m6A is also involved in the mutations of the tumor suppressor p53 and regulation of the expression of the genes in the p53 pathway in human cells .	('tumor', 'Disease', (68, 73))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('mutations', 'Var', (51, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('68', '84'))	('involved', 'Reg', (35, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('68', '84'))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('p53', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('human', 'Species', '9606', (157, 162))
75470	31931413	In myeloid leukemia patients, the genetic alterations of m6A regulatory genes are associated with p53 gene mutation .	('m6A regulatory genes', 'Gene', (57, 77))	('associated', 'Reg', (82, 92))	('rat', 'Species', '10116', (46, 49))	('myeloid leukemia', 'Disease', 'MESH:D007951', (3, 19))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (3, 19))	('leukemia', 'Phenotype', 'HP:0001909', (11, 19))	('p53 gene', 'Gene', (98, 106))	('patients', 'Species', '9606', (20, 28))	('genetic alterations', 'Var', (34, 53))	('mutation', 'Var', (107, 115))	('myeloid leukemia', 'Disease', (3, 19))
75475	31931413	We found that m6A mediated arsenite-induced cell transformation by suppressing p53 activation rather than regulating p53 gene expression.	('rat', 'Species', '10116', (94, 97))	('m6A', 'Var', (14, 17))	('arsenite', 'Chemical', 'MESH:C015001', (27, 35))	('activation', 'MPA', (83, 93))	('p53', 'Protein', (79, 82))	('cell transformation', 'CPA', (44, 63))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('suppressing', 'NegReg', (67, 78))
75477	31931413	Our study provides the first evidence that m6A modification plays a pivotal role in arsenite-induced inactivation of p53, shedding light on a new mechanism by which RNA epigenetics mediates arsenite carcinogenicity.	('arsenite', 'Chemical', 'MESH:C015001', (84, 92))	('arsenite', 'Chemical', 'MESH:C015001', (190, 198))	('p53', 'Gene', (117, 120))	('inactivation', 'MPA', (101, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (199, 211))	('carcinogenic', 'Disease', (199, 211))	('RNA', 'cellular_component', 'GO:0005562', ('165', '168'))	('epigenetics', 'Var', (169, 180))	('mediates', 'Reg', (181, 189))
75496	31931413	Antibodies against METTL3, METTL14, WTAP, KIAA1429, FTO, YTDHF1, p53 acetyl-lys382, and PRDM2 were from Abcam (Cambridge, UK).	('YTDHF1', 'Gene', (57, 63))	('METTL3', 'Gene', (19, 25))	('METTL14', 'Gene', '57721', (27, 34))	('METTL14', 'Gene', (27, 34))	('WTAP', 'Gene', '9589', (36, 40))	('FTO', 'Gene', '79068', (52, 55))	('KIAA1429', 'Gene', (42, 50))	('KIAA1429', 'Gene', '25962', (42, 50))	('p53', 'Var', (65, 68))	('WTAP', 'Gene', (36, 40))	('METTL3', 'Gene', '56339', (19, 25))	('lys382', 'Chemical', '-', (76, 82))	('PRDM2', 'Gene', (88, 93))	('FTO', 'Gene', (52, 55))
75498	31931413	Antibodies against p53 phospho-ser15, phospho-ser46, phospho-ser392, MDM2, and YY1 were from Absin Bioscience Inc. (Shanghai, China).	('phospho-ser392', 'Var', (53, 67))	('phospho-ser46', 'Var', (38, 51))	('ser', 'cellular_component', 'GO:0005790', ('61', '64'))	('ser', 'cellular_component', 'GO:0005790', ('31', '34'))	('ser392', 'Chemical', '-', (61, 67))	('p53 phospho-ser15', 'Var', (19, 36))	('ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('ser46', 'Chemical', '-', (46, 51))	('ser15', 'Chemical', '-', (31, 36))
75522	31931413	The data of the gene expression in the cells and animals that were exposed to arsenic were obtained from GEO database (GSE47047, GSE97303, GSE103873, GSE2187, GSE33520, GSE36684, and GSE21193).	('GSE36684', 'Var', (169, 177))	('GSE33520', 'Var', (159, 167))	('GSE21193', 'Var', (183, 191))	('GSE97303', 'Var', (129, 137))	('GSE103873', 'Var', (139, 148))	('GSE2187', 'Var', (150, 157))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('GSE2187', 'Chemical', '-', (150, 157))	('GSE47047', 'Var', (119, 127))	('arsenic', 'Chemical', 'MESH:D001151', (78, 85))
75538	31931413	Thus, it is possible that m6A level in the cells may be altered by the aberrant expressions of m6A methyltransferases, demethylases, and readers induced by arsenite resulting in keratinocyte transformation.	('rat', 'Species', '10116', (180, 183))	('m6A level', 'MPA', (26, 35))	('demethylase', 'Gene', (119, 130))	('altered', 'Reg', (56, 63))	('demethylase', 'Gene', '8932', (119, 130))	('m6A', 'Gene', (95, 98))	('keratinocyte transformation', 'CPA', (178, 205))	('arsenite', 'Chemical', 'MESH:C015001', (156, 164))	('aberrant', 'Var', (71, 79))
75539	31931413	To further determine the effects of m6A methylation on arsenite-induced transformation, we examined the viability, migration, and apoptosis of HaCaT-T cells under the downregulation of m6A by knocking down METTL3 using siRNAs (Fig.	('rat', 'Species', '10116', (118, 121))	('METTL3', 'Gene', '56339', (206, 212))	('HaCaT-T', 'CellLine', 'CVCL:0038', (143, 150))	('METTL3', 'Gene', (206, 212))	('arsenite', 'Chemical', 'MESH:C015001', (55, 63))	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('knocking', 'Var', (192, 200))
75540	31931413	We initially validated knockdown of METTL3 and the reduction of m6A in HaCaT-T cells.	('m6A', 'MPA', (64, 67))	('HaCaT-T', 'CellLine', 'CVCL:0038', (71, 78))	('reduction', 'NegReg', (51, 60))	('knockdown', 'Var', (23, 32))	('METTL3', 'Gene', '56339', (36, 42))	('METTL3', 'Gene', (36, 42))
75541	31931413	2a and 2b, knockdown of METTL3 significantly reduced its mRNA and protein levels in HaCaT cells and HaCaT-T cells (Fig.	('reduced', 'NegReg', (45, 52))	('METTL3', 'Gene', (24, 30))	('HaCaT cells', 'CellLine', 'CVCL:0038', (84, 95))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))	('HaCaT-T', 'CellLine', 'CVCL:0038', (100, 107))	('knockdown', 'Var', (11, 20))	('METTL3', 'Gene', '56339', (24, 30))
75543	31931413	However, the m6A level in HaCaT cells was not altered by the knockdown of the methyltransferase (Fig.	('knockdown', 'Var', (61, 70))	('HaCaT cells', 'CellLine', 'CVCL:0038', (26, 37))	('m6A level', 'MPA', (13, 22))
75544	31931413	The results showed that METTL3 knockdown specifically reduced the level of METTL3 and m6A in HaCaT-T cells.	('METTL3', 'Gene', (75, 81))	('m6A', 'MPA', (86, 89))	('METTL3', 'Gene', (24, 30))	('level', 'MPA', (66, 71))	('reduced', 'NegReg', (54, 61))	('HaCaT-T', 'CellLine', 'CVCL:0038', (93, 100))	('METTL3', 'Gene', '56339', (75, 81))	('knockdown', 'Var', (31, 40))	('METTL3', 'Gene', '56339', (24, 30))
75547	31931413	Next, we examined if METTL3 knockdown facilitated cell death through apoptosis induced by the cellular exposure to10 muM arsenite for 24 h (Fig.	('cell death', 'CPA', (50, 60))	('METTL3', 'Gene', '56339', (21, 27))	('cell death', 'biological_process', 'GO:0008219', ('50', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('METTL3', 'Gene', (21, 27))	('facilitated', 'PosReg', (38, 49))	('apoptosis', 'CPA', (69, 78))	('knockdown', 'Var', (28, 37))	('arsenite', 'Chemical', 'MESH:C015001', (121, 129))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
75548	31931413	Indeed, we found that METTL3 knockdown resulted in a higher apoptosis rate in HaCaT-T cells than HaCaT-T cells and the siControl (Fig.	('higher', 'PosReg', (53, 59))	('rat', 'Species', '10116', (70, 73))	('knockdown', 'Var', (29, 38))	('HaCaT-T', 'CellLine', 'CVCL:0038', (78, 85))	('apoptosis rate', 'CPA', (60, 74))	('HaCaT-T', 'CellLine', 'CVCL:0038', (97, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('60', '69'))	('apoptosis', 'biological_process', 'GO:0006915', ('60', '69'))	('METTL3', 'Gene', '56339', (22, 28))	('METTL3', 'Gene', (22, 28))
75551	31931413	The results revealed that HaCaT-T cell migration was significantly inhibited by METTL3 knockdown compared with the control cells (Fig.	('T cell migration', 'biological_process', 'GO:0072678', ('32', '48'))	('inhibited', 'NegReg', (67, 76))	('HaCaT-T', 'CellLine', 'CVCL:0038', (26, 33))	('HaCaT-T cell migration', 'CPA', (26, 48))	('METTL3', 'Gene', '56339', (80, 86))	('METTL3', 'Gene', (80, 86))	('rat', 'Species', '10116', (42, 45))	('knockdown', 'Var', (87, 96))
75554	31931413	Since m6A is associated with p53 function , we further hypothesize that m6A mediates arsenite-induced transformation by regulating the expression and activation of p53.	('regulating', 'Reg', (120, 130))	('m6A', 'Var', (72, 75))	('activation', 'PosReg', (150, 160))	('expression', 'MPA', (135, 145))	('arsenite', 'Chemical', 'MESH:C015001', (85, 93))	('p53', 'Gene', (164, 167))
75555	31931413	To test this possibility, we initially determined if the mutations of p53 can be involved in arsenite-induced keratinocyte transformation, we sequenced a segment in the p53 encoding region of HaCaT and HaCaT-T cells (exons 5-9, commonly mutated regions in cancers ) (Fig.	('p53', 'Gene', (70, 73))	('cancers', 'Disease', 'MESH:D009369', (256, 263))	('involved', 'Reg', (81, 89))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('cancers', 'Disease', (256, 263))	('HaCaT-T', 'CellLine', 'CVCL:0038', (202, 209))	('HaCaT', 'CellLine', 'CVCL:0038', (192, 197))	('mutations', 'Var', (57, 66))	('rat', 'Species', '10116', (112, 115))	('HaCaT', 'CellLine', 'CVCL:0038', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('arsenite', 'Chemical', 'MESH:C015001', (93, 101))
75557	31931413	The results are consistent with those from our bioinformatics analysis of the TCGA database showing that p53 mutations did not affect the survival of SKCM patients (Supplementary Fig.	('SKCM', 'Disease', (150, 154))	('p53', 'Gene', (105, 108))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (155, 163))
75558	31931413	This further suggests that p53 mutations were not involved in m6A-mediated HaCaT transformation induced by arsenite.	('mutations', 'Var', (31, 40))	('HaCaT', 'CellLine', 'CVCL:0038', (75, 80))	('HaCaT transformation', 'MPA', (75, 95))	('arsenite', 'Chemical', 'MESH:C015001', (107, 115))	('p53', 'Gene', (27, 30))
75559	31931413	To further determine if m6A can affect the expression level of p53, we examined the expression of p53 in HaCaT and HaCaT-T cells with METTL3 knockdown (Fig.	('HaCaT-T', 'CellLine', 'CVCL:0038', (115, 122))	('knockdown', 'Var', (141, 150))	('METTL3', 'Gene', (134, 140))	('HaCaT', 'CellLine', 'CVCL:0038', (115, 120))	('HaCaT', 'CellLine', 'CVCL:0038', (105, 110))	('affect', 'Reg', (32, 38))	('expression', 'MPA', (43, 53))	('METTL3', 'Gene', '56339', (134, 140))
75560	31931413	We found that the mRNA level of p53 in these cells was not significantly altered by the METTL3 knockdown.	('knockdown', 'Var', (95, 104))	('METTL3', 'Gene', '56339', (88, 94))	('METTL3', 'Gene', (88, 94))
75565	31931413	We found that p53 activity was significantly decreased in HaCaT-T cells, and this was reversed by knockdown of METTL3 in HaCaT-T cells (Fig.	('p53', 'Protein', (14, 17))	('activity', 'MPA', (18, 26))	('METTL3', 'Gene', '56339', (111, 117))	('knockdown', 'Var', (98, 107))	('decreased', 'NegReg', (45, 54))	('METTL3', 'Gene', (111, 117))	('HaCaT-T', 'CellLine', 'CVCL:0038', (58, 65))	('HaCaT-T', 'CellLine', 'CVCL:0038', (121, 128))
75569	31931413	The suppression of the gene expression in HaCaT-T cells was relieved by knockdown of METTL3 (Fig.	('METTL3', 'Gene', (85, 91))	('METTL3', 'Gene', '56339', (85, 91))	('gene expression', 'biological_process', 'GO:0010467', ('23', '38'))	('HaCaT-T', 'CellLine', 'CVCL:0038', (42, 49))	('knockdown', 'Var', (72, 81))
75573	31931413	All these results suggest that m6A mediated arsenite-induced keratinocyte transformation by reducing the transcriptional activity of p53.	('reducing', 'NegReg', (92, 100))	('arsenite-induced', 'Disease', (44, 60))	('rat', 'Species', '10116', (63, 66))	('arsenite', 'Chemical', 'MESH:C015001', (44, 52))	('p53', 'Protein', (133, 136))	('transcriptional activity', 'MPA', (105, 129))	('m6A', 'Var', (31, 34))
75574	31931413	We found that in HaCaT-T cells, p53 nuclear localization was significantly reduced along with an increased amount of cytoplasmic staining of p53, and this was significantly reversed by knockdown of METTL3 in HaCaT-T cells (Fig.	('increased', 'PosReg', (97, 106))	('HaCaT-T', 'CellLine', 'CVCL:0038', (208, 215))	('p53', 'Protein', (32, 35))	('HaCaT-T', 'CellLine', 'CVCL:0038', (17, 24))	('cytoplasmic staining', 'MPA', (117, 137))	('reduced', 'NegReg', (75, 82))	('nuclear localization', 'MPA', (36, 56))	('knockdown', 'Var', (185, 194))	('localization', 'biological_process', 'GO:0051179', ('44', '56'))	('METTL3', 'Gene', '56339', (198, 204))	('METTL3', 'Gene', (198, 204))
75579	31931413	Further, we found that knockdown of METTL3 significantly increased the phosphorylation at Ser392 and acetylation at Lys382 in HaCaT-T cells (Fig.	('phosphorylation', 'MPA', (71, 86))	('Ser392', 'Protein', (90, 96))	('acetylation', 'MPA', (101, 112))	('Lys382', 'Chemical', '-', (116, 122))	('knockdown', 'Var', (23, 32))	('HaCaT-T', 'CellLine', 'CVCL:0038', (126, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('71', '86'))	('METTL3', 'Gene', '56339', (36, 42))	('increased', 'PosReg', (57, 66))	('Ser392', 'Chemical', '-', (90, 96))	('Ser', 'cellular_component', 'GO:0005790', ('90', '93'))	('METTL3', 'Gene', (36, 42))
75581	31931413	The results suggest that m6A mediated arsenite-induced human keratinocyte transformation by suppressing p53 activation rather than affecting p53 gene expression.	('suppressing', 'NegReg', (92, 103))	('human', 'Species', '9606', (55, 60))	('human keratinocyte transformation', 'CPA', (55, 88))	('rat', 'Species', '10116', (119, 122))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('activation', 'MPA', (108, 118))	('arsenite', 'Chemical', 'MESH:C015001', (38, 46))	('rat', 'Species', '10116', (63, 66))	('p53', 'Protein', (104, 107))	('m6A', 'Var', (25, 28))
75584	31931413	Our experimental results further demonstrated that the mRNA and protein levels of PRDM2 that upregulates p53 activation  were decreased in HaCaT-T cells compared to HaCaT cells (Fig.	('decreased', 'NegReg', (126, 135))	('upregulates', 'PosReg', (93, 104))	('PRDM2', 'Gene', (82, 87))	('HaCaT-T', 'CellLine', 'CVCL:0038', (139, 146))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('rat', 'Species', '10116', (40, 43))	('activation', 'PosReg', (109, 119))	('p53', 'Gene', (105, 108))	('HaCaT-T', 'Var', (139, 146))	('HaCaT cells', 'CellLine', 'CVCL:0038', (165, 176))
75590	31931413	All of these results indicate that the p53 activation regulators affected by m6A were involved in arsenite-induced transformation of human keratinocytes.	('arsenite-induced', 'MPA', (98, 114))	('activation', 'PosReg', (43, 53))	('arsenite', 'Chemical', 'MESH:C015001', (98, 106))	('m6A', 'Var', (77, 80))	('p53', 'Gene', (39, 42))	('involved', 'Reg', (86, 94))	('human', 'Species', '9606', (133, 138))	('rat', 'Species', '10116', (141, 144))
75592	31931413	6a) suggesting that m6A stimulated the expression of the p53 activation regulators in the patient tissue.	('patient', 'Species', '9606', (90, 97))	('stimulated', 'PosReg', (24, 34))	('p53', 'Gene', (57, 60))	('expression', 'MPA', (39, 49))	('m6A', 'Var', (20, 23))
75594	31931413	We found that knockdown of METTL3 by METTL3 siRNA (siMETTL3) in HaCaT-T cells partially relieved the inhibition of the p53 positive regulator, PRDM2, but decreased the level of the overexpression of the p53 suppressor, MDM2 and YY1 in the cells (Fig 5c-5f).	('decreased', 'NegReg', (154, 163))	('METTL3', 'Gene', '56339', (27, 33))	('HaCaT-T', 'CellLine', 'CVCL:0038', (64, 71))	('relieved', 'NegReg', (88, 96))	('METTL3', 'Gene', (27, 33))	('PRDM2', 'Gene', (143, 148))	('overexpression', 'MPA', (181, 195))	('inhibition', 'MPA', (101, 111))	('METTL3', 'Gene', '56339', (53, 59))	('knockdown', 'Var', (14, 23))	('METTL3', 'Gene', (37, 43))	('METTL3', 'Gene', '56339', (37, 43))	('METTL3', 'Gene', (53, 59))
75595	31931413	6b), we then determined the m6A level in p53 mRNA in HaCaT and HaCaT-T cells using MeRIP.	('HaCaT', 'CellLine', 'CVCL:0038', (53, 58))	('HaCaT', 'CellLine', 'CVCL:0038', (63, 68))	('m6A level', 'MPA', (28, 37))	('p53', 'Var', (41, 44))	('HaCaT-T', 'CellLine', 'CVCL:0038', (63, 70))
75600	31931413	We found that knockdown of YTHDF1 that promotes translation of m6A-methylated transcripts decreased both the mRNA and protein levels of MDM2 and YY1 (Fig.	('promotes', 'PosReg', (39, 47))	('YTHDF1', 'Gene', '54915', (27, 33))	('decreased', 'NegReg', (90, 99))	('knockdown', 'Var', (14, 23))	('translation', 'MPA', (48, 59))	('translation', 'biological_process', 'GO:0006412', ('48', '59'))	('YTHDF1', 'Gene', (27, 33))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
75603	31931413	Taken together, both our bioinformatics analysis and experimental results revealed that m6A resulted in p53 inactivation by modulating p53 activation regulators in arsenite-transformed human keratinocytes.	('p53', 'Gene', (104, 107))	('human', 'Species', '9606', (185, 190))	('rat', 'Species', '10116', (193, 196))	('inactivation', 'NegReg', (108, 120))	('m6A', 'Var', (88, 91))	('modulating', 'Reg', (124, 134))	('arsenite', 'Chemical', 'MESH:C015001', (164, 172))	('p53 activation regulators', 'MPA', (135, 160))
75610	31931413	Consequently, this increases p53 nuclear export and decreases p53 phosphorylation and acetylation at Ser392 and Ser382, respectively, leading to p53 inactivation and keratinocyte transformation (Fig.	('Ser382', 'Var', (112, 118))	('Ser', 'cellular_component', 'GO:0005790', ('101', '104'))	('keratinocyte transformation', 'CPA', (166, 193))	('decreases', 'NegReg', (52, 61))	('p53', 'Gene', (145, 148))	('p53', 'Protein', (29, 32))	('Ser392', 'Chemical', '-', (101, 107))	('nuclear export', 'MPA', (33, 47))	('phosphorylation', 'MPA', (66, 81))	('increases', 'PosReg', (19, 28))	('Ser', 'cellular_component', 'GO:0005790', ('112', '115'))	('rat', 'Species', '10116', (168, 171))	('inactivation', 'NegReg', (149, 161))	('Ser382', 'Chemical', '-', (112, 118))	('p53', 'Protein', (62, 65))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('nuclear export', 'biological_process', 'GO:0051168', ('33', '47'))	('acetylation', 'MPA', (86, 97))
75611	31931413	Among several proteins that have been identified in the m6A "writer" complex, including METTL3, METTL14, WTAP, and KIAA1429 , METTL3 is the one that plays a key role in generating m6A.	('rat', 'Species', '10116', (173, 176))	('METTL3', 'Gene', (126, 132))	('m6A', 'Var', (180, 183))	('METTL14', 'Gene', '57721', (96, 103))	('METTL14', 'Gene', (96, 103))	('KIAA1429', 'Gene', '25962', (115, 123))	('METTL3', 'Gene', (88, 94))	('METTL3', 'Gene', '56339', (88, 94))	('WTAP', 'Gene', '9589', (105, 109))	('WTAP', 'Gene', (105, 109))	('m6A writer complex', 'cellular_component', 'GO:0036396', ('56', '74'))	('KIAA1429', 'Gene', (115, 123))	('METTL3', 'Gene', '56339', (126, 132))
75612	31931413	This is because genetic depletion of METTL3 in plants, yeast, and mammalian cells results in nearly complete loss of m6A in polyadenylated RNA .	('mammalian', 'Species', '9606', (66, 75))	('RNA', 'cellular_component', 'GO:0005562', ('139', '142'))	('yeast', 'Species', '4932', (55, 60))	('loss', 'NegReg', (109, 113))	('m6A', 'MPA', (117, 120))	('genetic depletion', 'Var', (16, 33))	('METTL3', 'Gene', '56339', (37, 43))	('METTL3', 'Gene', (37, 43))
75618	31931413	Therefore, we decided to knockdown METTL3 in our experiments.	('METTL3', 'Gene', (35, 41))	('METTL3', 'Gene', '56339', (35, 41))	('knockdown', 'Var', (25, 34))
75619	31931413	Interestingly, we did not observe a significant change in m6A level in HaCaT cells with knockdown of METTL3.	('METTL3', 'Gene', (101, 107))	('HaCaT cells', 'CellLine', 'CVCL:0038', (71, 82))	('knockdown', 'Var', (88, 97))	('m6A level', 'MPA', (58, 67))	('METTL3', 'Gene', '56339', (101, 107))
75623	31931413	Our results showed that knockdown of METTL3 decreased the m6A level in HaCaT cells from 0.275% to 0.255%.	('HaCaT cells', 'CellLine', 'CVCL:0038', (71, 82))	('m6A level', 'MPA', (58, 67))	('METTL3', 'Gene', '56339', (37, 43))	('METTL3', 'Gene', (37, 43))	('knockdown', 'Var', (24, 33))	('decreased', 'NegReg', (44, 53))
75624	31931413	Previous studies have focused on the mechanisms underlying arsenite carcinogenesis through aberrant gene expression and mutations, as well as altered functions of proteins.	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('altered', 'Reg', (142, 149))	('proteins', 'Protein', (163, 171))	('carcinogenesis', 'Disease', (68, 82))	('aberrant gene', 'Var', (91, 104))	('arsenite', 'Chemical', 'MESH:C015001', (59, 67))	('mutations', 'Var', (120, 129))	('functions', 'MPA', (150, 159))
75626	31931413	A recent study from our group has provided the first evidence that m6A is involved in arsenite-induced cell transformation .	('m6A', 'Var', (67, 70))	('involved', 'Reg', (74, 82))	('arsenite', 'Chemical', 'MESH:C015001', (86, 94))	('arsenite-induced', 'Disease', (86, 102))
75627	31931413	In this study, we further demonstrated that m6A mediated arsenite-induced cell transformation by inhibiting p53 activation rather than by altering p53 expression (Fig.	('inhibiting', 'NegReg', (97, 107))	('arsenite', 'Chemical', 'MESH:C015001', (57, 65))	('m6A', 'Var', (44, 47))	('rat', 'Species', '10116', (33, 36))	('rat', 'Species', '10116', (123, 126))	('activation', 'MPA', (112, 122))	('cell transformation', 'CPA', (74, 93))	('p53', 'Protein', (108, 111))
75629	31931413	Thus, we only detected the effects of transient siRNA transfection on the transformation of HaCaT cells using cell viability assay, wound-healing assay, and cell apoptosis, which only require short period of time (24 h).	('HaCaT cells', 'CellLine', 'CVCL:0038', (92, 103))	('siRNA', 'Gene', (48, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('wound-healing', 'biological_process', 'GO:0042060', ('132', '145'))	('transfection', 'Var', (54, 66))
75633	31931413	There has been a controversy regarding whether chronic arsenite exposure can lead to carcinogenesis by inducing p53 mutations based on population-based studies .	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('lead', 'Reg', (77, 81))	('inducing', 'Reg', (103, 111))	('carcinogenesis', 'Disease', (85, 99))	('mutations', 'Var', (116, 125))	('p53', 'Gene', (112, 115))	('arsenite', 'Chemical', 'MESH:C015001', (55, 63))
75634	31931413	This is because the results from the population-based studies are usually affected by a variety of confounding factors, which can introduce the bias to the results of p53 mutational studies, especially those from the human population that was chronically exposed to low doses of arsenite.	('affected', 'Reg', (74, 82))	('human', 'Species', '9606', (217, 222))	('mutational', 'Var', (171, 181))	('arsenite', 'Chemical', 'MESH:C015001', (279, 287))	('p53', 'Gene', (167, 170))
75637	31931413	The results are consistent with a report showing that no p53 mutations in exons 5-8 are detected in rats that are exposed to the metabolite of arsenite, dimethylarsinic acid  Thus, our results suggest that it is unlikely that p53 mutations and aberrant expression were involved in arsenite-induced human keratinocytes transformation that was mediated by m6A.	('human', 'Species', '9606', (298, 303))	('rat', 'Species', '10116', (306, 309))	('expression', 'MPA', (253, 263))	('arsenite', 'Chemical', 'MESH:C015001', (143, 151))	('rats', 'Species', '10116', (100, 104))	('dimethylarsinic acid', 'Chemical', 'MESH:D002101', (153, 173))	('arsenite', 'Chemical', 'MESH:C015001', (281, 289))	('mutations', 'Var', (230, 239))	('involved', 'Reg', (269, 277))	('p53', 'Gene', (226, 229))	('rat', 'Species', '10116', (100, 103))
75640	31931413	Furthermore, it has been found that microRNA, miR-410, -548ac, and -548a-3p, and p53 regulators, HMGB1 and MDM2 can also be involved in the suppression of p53 activation induced by arsenite in cellular transformation and carcinogenesis .	('activation', 'PosReg', (159, 169))	('p53', 'Gene', (155, 158))	('miR-410', 'Var', (46, 53))	('carcinogenesis', 'Disease', (221, 235))	('cellular transformation', 'CPA', (193, 216))	('arsenite', 'Chemical', 'MESH:C015001', (181, 189))	('HMGB1', 'Gene', (97, 102))	('suppression', 'NegReg', (140, 151))	('HMGB1', 'Gene', '3146', (97, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))
75641	31931413	However, our results cannot exclude a possibility that m6A transcripts in p53 may facilitate the selection of a mutated codon in the other encoding regions of the protein through m6A in TP53 codon RNA transcripts that promote the selection of m6A-R273H pre-mRNA for splicing producing the mutant protein in cancer cells .	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('splicing', 'biological_process', 'GO:0045292', ('266', '274'))	('pre', 'molecular_function', 'GO:0003904', ('253', '256'))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('protein', 'cellular_component', 'GO:0003675', ('296', '303'))	('TP53', 'Gene', '7157', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('m6A-R273H', 'Var', (243, 252))	('TP53', 'Gene', (186, 190))	('RNA', 'cellular_component', 'GO:0005562', ('197', '200'))	('R273H', 'Mutation', 'rs28934576', (247, 252))
75642	31931413	Thus, our study revealed the m6A-mediated mechanism underlying arsenite-induced human keratinocyte transformation, shedding light on the complex mechanisms by which arsenite induces alterations of p53 activation in cell transformation and carcinogenesis.	('activation', 'PosReg', (201, 211))	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('rat', 'Species', '10116', (186, 189))	('carcinogenesis', 'Disease', (239, 253))	('rat', 'Species', '10116', (88, 91))	('p53', 'Gene', (197, 200))	('cell transformation', 'CPA', (215, 234))	('human', 'Species', '9606', (80, 85))	('arsenite', 'Chemical', 'MESH:C015001', (165, 173))	('arsenite', 'Chemical', 'MESH:C015001', (63, 71))	('alterations', 'Var', (182, 193))
75649	31931413	Our bioinformatics analysis of p53 mutation and expression, its target genes, and regulators in SKCM further indicated that p53 inactivation played a crucial role in the development of skin cancer.	('p53', 'Gene', (31, 34))	('p53', 'Gene', (124, 127))	('skin cancer', 'Disease', (185, 196))	('inactivation', 'NegReg', (128, 140))	('skin cancer', 'Phenotype', 'HP:0008069', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutation', 'Var', (35, 43))	('skin cancer', 'Disease', 'MESH:D012878', (185, 196))
75650	31931413	Our bioinformatics analysis of the co-expression of both m6A methyltransferases and p53 regulators in SKCM tissue also indicated a correlation between m6A and p53 in skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (166, 177))	('p53', 'Gene', (159, 162))	('skin cancer', 'Phenotype', 'HP:0008069', (166, 177))	('m6A', 'Var', (151, 154))	('correlation', 'Interaction', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('skin cancer', 'Disease', (166, 177))
75653	31931413	This is further supported by our recent findings showing that m6A is associated with oxidative stress in arsenite-driven hormesis , and arsenite-induced oxidative stress increases the levels of m6A .	('arsenite', 'Chemical', 'MESH:C015001', (105, 113))	('levels', 'MPA', (184, 190))	('arsenite-driven hormesis', 'MPA', (105, 129))	('increases', 'PosReg', (170, 179))	('associated', 'Reg', (69, 79))	('oxidative stress', 'Phenotype', 'HP:0025464', (85, 101))	('arsenite', 'Chemical', 'MESH:C015001', (136, 144))	('oxidative stress', 'MPA', (85, 101))	('m6A', 'MPA', (194, 197))	('m6A', 'Var', (62, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (153, 169))
75765	31388313	MicroRNA-3662 targets ZEB1 and attenuates the invasion of the highly aggressive melanoma cell line A375 Cutaneous melanoma is the most aggressive form of skin cancer.	('skin cancer', 'Disease', (154, 165))	('A375', 'CellLine', 'CVCL:0132', (99, 103))	('skin cancer', 'Phenotype', 'HP:0008069', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('Cutaneous melanoma', 'Disease', (104, 122))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ZEB1', 'Gene', (22, 26))	('skin cancer', 'Disease', 'MESH:D012878', (154, 165))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('invasion', 'CPA', (46, 54))	('melanoma', 'Disease', (114, 122))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('MicroRNA-3662', 'Var', (0, 13))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('attenuates', 'NegReg', (31, 41))	('ZEB1', 'Gene', '21417', (22, 26))
75768	31388313	miR-3662, a microRNA is a potential tumor suppressor targeting zinc finger E-box binding homeobox 1 (ZEB1), which functions as a key regulator of the epithelial-mesenchymal transition (EMT) process.	('ZEB1', 'Gene', (101, 105))	('E-box binding', 'molecular_function', 'GO:0070888', ('75', '88'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('EMT', 'biological_process', 'GO:0001837', ('185', '188'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('miR-3662', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('miR-3662', 'Chemical', '-', (0, 8))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('150', '183'))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('epithelial-mesenchymal', 'CPA', (150, 172))
75772	31388313	Using virtual screening of the miRDB database, miR-3662 was shown to target the 3' untranslated region (UTR) of the ZEB1 gene.	('miR-3662', 'Chemical', '-', (47, 55))	('ZEB1', 'Gene', (116, 120))	('miR-3662', 'Var', (47, 55))
75773	31388313	Expression of miR-3662 via a lentivirus vector significantly decreased protein levels of ZEB1 and inhibited the growth of A375 cells in vitro and in vivo.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('A375', 'CellLine', 'CVCL:0132', (122, 126))	('miR-3662', 'Var', (14, 22))	('inhibited', 'NegReg', (98, 107))	('ZEB1', 'Protein', (89, 93))	('protein levels', 'MPA', (71, 85))	('Expression', 'Species', '29278', (0, 10))	('miR-3662', 'Chemical', '-', (14, 22))	('decreased', 'NegReg', (61, 70))	('growth of A375 cells', 'CPA', (112, 132))
75774	31388313	The reduction in ZEB1 expression induced by miR-3662 resulted in EMT inhibition in A375 cells and decreased the relative expression of metastasis genes.	('EMT', 'CPA', (65, 68))	('miR-3662', 'Chemical', '-', (44, 52))	('reduction', 'NegReg', (4, 13))	('expression', 'Species', '29278', (121, 131))	('relative expression of', 'MPA', (112, 134))	('A375', 'CellLine', 'CVCL:0132', (83, 87))	('expression', 'Species', '29278', (22, 32))	('inhibition', 'NegReg', (69, 79))	('ZEB1', 'Gene', (17, 21))	('EMT', 'biological_process', 'GO:0001837', ('65', '68'))	('miR-3662', 'Var', (44, 52))	('decreased', 'NegReg', (98, 107))	('expression', 'MPA', (22, 32))
75779	31388313	When exposed to risk factors, such as ultraviolet radiation (UV), mutations can accumulate within the cell genome of melanocytes, leading to their transformation to cutaneous melanoma.	('mutations', 'Var', (66, 75))	('cutaneous melanoma', 'Disease', (165, 183))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (165, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('transformation', 'Reg', (147, 161))
75786	31388313	As such, ZEB1 is a promising potential therapeutic target, the inhibition of which may attenuate the proliferation or metastasis of cancer cells.	('metastasis of cancer', 'Disease', (118, 138))	('metastasis of cancer', 'Disease', 'MESH:D009362', (118, 138))	('attenuate', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('inhibition', 'Var', (63, 73))
75790	31388313	This work aimed to identify a miRNA targeting ZEB1, miR-3662, and further examine the effects of this miRNA on the proliferation and invasive growth of A375, a highly aggressive melanoma cell line used to mimic the spread of cutaneous melanoma.	('invasive growth', 'biological_process', 'GO:0036267', ('133', '148'))	('invasive growth', 'biological_process', 'GO:0044412', ('133', '148'))	('invasive growth', 'biological_process', 'GO:0051831', ('133', '148'))	('invasive growth', 'biological_process', 'GO:0044409', ('133', '148'))	('miR-3662', 'Var', (52, 60))	('aggressive melanoma', 'Disease', 'MESH:D008545', (167, 186))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('invasive growth', 'biological_process', 'GO:0007125', ('133', '148'))	('A375', 'CellLine', 'CVCL:0132', (152, 156))	('aggressive melanoma', 'Disease', (167, 186))	('cutaneous melanoma', 'Disease', (225, 243))	('invasive growth', 'biological_process', 'GO:0001404', ('133', '148'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (225, 243))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (225, 243))	('miR-3662', 'Chemical', '-', (52, 60))	('invasive growth', 'CPA', (133, 148))
75794	31388313	Expression vectors with full length ZEB1 genes or ZEB1 gene cDNA sequences with mutated miR-3662 binding sites were purchased from Vigene Corporation (Jinan, China).	('binding', 'molecular_function', 'GO:0005488', ('97', '104'))	('ZEB1 gene', 'Gene', (50, 59))	('Expression vectors', 'Species', '29278', (0, 18))	('miR-3662', 'Chemical', '-', (88, 96))	('mutated', 'Var', (80, 87))	('ZEB1 genes', 'Gene', (36, 46))	('miR-3662', 'Gene', (88, 96))
75804	31388313	A375 cells transfected with miR-3662, miR-3662+ ZEB1Mut or miR-3662+ inhibitor or control miRNA were harvested 48 h following transfection and total protein samples extracted for Western blot experiments.	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('miR-3662', 'Var', (28, 36))	('miR-3662+', 'Var', (38, 47))	('miR-3662', 'Chemical', '-', (59, 67))	('miR-3662', 'Chemical', '-', (38, 46))	('miR-3662', 'Chemical', '-', (28, 36))
75812	31388313	A375 cells stably infected with miR-3662, miR-3662+ ZEB1Mut, or control miRNA or OCM-1A cells stably transfected with ZEB1 vector or empty vector were mixed with biological-medical gel (Cai-Hong-Yi-Xue-She-Bei, Kunming, China) and injected into the muscle tissue in the legs of nude mice.	('miR-3662', 'Chemical', '-', (32, 40))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('OCM-1', 'Species', '83984', (81, 86))	('miR-3662', 'Var', (32, 40))	('miR-3662+', 'Var', (42, 51))	('miR-3662', 'Chemical', '-', (42, 50))	('nude mice', 'Species', '10090', (278, 287))
75822	31388313	Analysis of the expression of miR-3662 in both tumor and non-tumor tissues revealed a higher level of miR-3662 expression in non-tumor specimens than that in tumor specimens (Figure 1C).	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('non-tumor', 'Disease', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('expression', 'MPA', (111, 121))	('non-tumor', 'Disease', 'MESH:D009369', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-3662', 'Var', (102, 110))	('miR-3662', 'Chemical', '-', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (158, 163))	('expression', 'Species', '29278', (111, 121))	('miR-3662', 'Chemical', '-', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('non-tumor', 'Disease', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('expression', 'Species', '29278', (16, 26))	('non-tumor', 'Disease', 'MESH:D009369', (57, 66))
75823	31388313	Additionally, a higher level of miR-3662 expression was detected in the less aggressive stages of melanoma (Clark I or Clark II) compared to the more aggressive stages of melanoma (such as Clark IV or Clark V) (Figure 1D).	('miR-3662', 'Chemical', '-', (32, 40))	('expression', 'Species', '29278', (41, 51))	('expression', 'MPA', (41, 51))	('miR-3662', 'Var', (32, 40))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))
75825	31388313	To understand the role of ZEB1 in proliferation or metastasis of melanoma, MTT and transwell experiments were performed to reveal that the knockdown of ZEB1 inhibited the proliferation, in vitro invasion and migration of A375 cells (Figures S2-S4), demonstrating a role for ZEB1 in the function of melanoma cells.	('MTT', 'Chemical', 'MESH:C070243', (75, 78))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (51, 73))	('ZEB1', 'Gene', (152, 156))	('inhibited', 'NegReg', (157, 166))	('knockdown', 'Var', (139, 148))	('metastasis of melanoma', 'Disease', (51, 73))	('invasion', 'CPA', (195, 203))	('migration', 'CPA', (208, 217))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('melanoma', 'Disease', (298, 306))	('A375', 'CellLine', 'CVCL:0132', (221, 225))	('melanoma', 'Disease', 'MESH:D008545', (298, 306))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('proliferation', 'CPA', (171, 184))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
75827	31388313	The transfection of miR-3662, but not control miRNA, resulted in a significant decrease in the protein levels of ZEB1 in A375 cells (Figure 3B and C).	('ZEB1', 'Protein', (113, 117))	('A375', 'CellLine', 'CVCL:0132', (121, 125))	('decrease', 'NegReg', (79, 87))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('miR-3662', 'Chemical', '-', (20, 28))	('protein levels', 'MPA', (95, 109))	('miR-3662', 'Var', (20, 28))
75828	31388313	Moreover, transfection of miR-3662's inhibitor or mutated ZEB1 was sufficient to restore the expression of ZEB1 within these cells.	('restore', 'PosReg', (81, 88))	('miR-3662', 'Chemical', '-', (26, 34))	('expression', 'Species', '29278', (93, 103))	('mutated', 'Var', (50, 57))	('expression', 'MPA', (93, 103))	('ZEB1', 'Gene', (58, 62))	('ZEB1', 'Gene', (107, 111))
75830	31388313	Western blot analysis revealed that the decrease in ZEB1 levels resulting from miRNA-3662 expression were able to be restored with the over-expression of the mutated ZEB1 (Figure S6).	('expression', 'Species', '29278', (140, 150))	('decrease', 'NegReg', (40, 48))	('ZEB1', 'Gene', (166, 170))	('miRNA-3662 expression', 'Var', (79, 100))	('expression', 'Species', '29278', (90, 100))	('ZEB1 levels', 'MPA', (52, 63))	('over-expression', 'PosReg', (135, 150))	('mutated', 'Var', (158, 165))
75831	31388313	Taken together, these data suggest that miR-3662 acts to repress the expression of ZEB1 protein by directly targeting the ZEB1 mRNA's 3' UTR in A375 cells.	('A375', 'CellLine', 'CVCL:0132', (144, 148))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('ZEB1 protein', 'Gene', (83, 95))	('miR-3662', 'Chemical', '-', (40, 48))	('expression', 'Species', '29278', (69, 79))	('repress', 'NegReg', (57, 64))	('expression', 'MPA', (69, 79))	('miR-3662', 'Var', (40, 48))	('targeting', 'Reg', (108, 117))
75832	31388313	To investigate whether miR-3662 impacts on the invasive growth of A375 cells, the expression of EMT and invasion related factors was examined by qPCR and Western blot assays.	('expression', 'Species', '29278', (82, 92))	('impacts', 'Reg', (32, 39))	('miR-3662', 'Chemical', '-', (23, 31))	('A375', 'CellLine', 'CVCL:0132', (66, 70))	('invasive growth', 'biological_process', 'GO:0007125', ('47', '62'))	('miR-3662', 'Var', (23, 31))	('invasive growth', 'biological_process', 'GO:0044412', ('47', '62'))	('EMT', 'biological_process', 'GO:0001837', ('96', '99'))	('invasive growth', 'biological_process', 'GO:0001404', ('47', '62'))	('invasive growth', 'biological_process', 'GO:0036267', ('47', '62'))	('invasive growth', 'biological_process', 'GO:0051831', ('47', '62'))	('invasive growth', 'biological_process', 'GO:0044409', ('47', '62'))
75834	31388313	Conversely, transfection of an inhibitor of miR-3662 or ZEB1Mut decreased the observed inhibitory effect of miR-3662 on the EMT process in A375 cells (Figure 4).	('miR-3662', 'Chemical', '-', (44, 52))	('inhibitory effect', 'MPA', (87, 104))	('miR-3662', 'Var', (108, 116))	('EMT', 'biological_process', 'GO:0001837', ('124', '127'))	('EMT process in A375 cells', 'CPA', (124, 149))	('miR-3662', 'Chemical', '-', (108, 116))	('A375', 'CellLine', 'CVCL:0132', (139, 143))	('decreased', 'NegReg', (64, 73))
75835	31388313	These results suggest that miR-3662 acts to inhibit the EMT process of A375 cells by targeting ZEB1.	('miR-3662', 'Var', (27, 35))	('targeting', 'Reg', (85, 94))	('inhibit', 'NegReg', (44, 51))	('EMT process of A375 cells', 'CPA', (56, 81))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('miR-3662', 'Chemical', '-', (27, 35))	('ZEB1', 'Gene', (95, 99))	('A375', 'CellLine', 'CVCL:0132', (71, 75))
75836	31388313	qPCR analysis of the effect of miR-3662 on the expression of invasive growth-related genes in A375 cells, demonstrated that miR-3662 expression resulted in the inhibition of mmp3 and mmp9, two matrix metalloproteinases that mediate the degradation of extracellular matrix (ECM) during the invasive growth of cancer cells (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('invasive growth', 'biological_process', 'GO:0001404', ('289', '304'))	('invasive growth', 'biological_process', 'GO:0044409', ('61', '76'))	('inhibition', 'NegReg', (160, 170))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('251', '271'))	('invasive growth', 'biological_process', 'GO:0044412', ('289', '304'))	('invasive growth', 'biological_process', 'GO:0051831', ('289', '304'))	('expression', 'Species', '29278', (133, 143))	('invasive growth', 'biological_process', 'GO:0001404', ('61', '76'))	('invasive growth', 'biological_process', 'GO:0044412', ('61', '76'))	('invasive growth', 'biological_process', 'GO:0051831', ('61', '76'))	('mmp3', 'molecular_function', 'GO:0004248', ('174', '178'))	('miR-3662', 'Chemical', '-', (31, 39))	('mmp9', 'Gene', (183, 187))	('degradation', 'biological_process', 'GO:0009056', ('236', '247'))	('invasive growth', 'biological_process', 'GO:0007125', ('289', '304'))	('miR-3662', 'Var', (124, 132))	('cancer', 'Disease', (308, 314))	('invasive growth', 'biological_process', 'GO:0036267', ('289', '304'))	('mmp9', 'molecular_function', 'GO:0004229', ('183', '187'))	('invasive growth', 'biological_process', 'GO:0007125', ('61', '76'))	('miR-3662', 'Chemical', '-', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('invasive growth', 'biological_process', 'GO:0036267', ('61', '76'))	('A375', 'CellLine', 'CVCL:0132', (94, 98))	('expression', 'Species', '29278', (47, 57))	('mmp3', 'Gene', (174, 178))	('invasive growth', 'biological_process', 'GO:0044409', ('289', '304'))
75837	31388313	Furthermore, miR-3662 was also observed to increase the expression of timp1 (tissue inhibitor of metalloproteinase 1), an inhibitor of matrix metalloproteinases in tissues (Figure 5).	('metalloproteinase 1', 'molecular_function', 'GO:0051405', ('97', '116'))	('miR-3662', 'Chemical', '-', (13, 21))	('expression', 'Species', '29278', (56, 66))	('timp1', 'Gene', (70, 75))	('expression', 'MPA', (56, 66))	('increase', 'PosReg', (43, 51))	('miR-3662', 'Var', (13, 21))
75843	31388313	In these animals the transfection of miR-3662 gave rise to a decrease in the subcutaneous growth of A375 cells, supporting the role of miR-3662 as an inhibitor of tumor progression.	('miR-3662', 'Chemical', '-', (135, 143))	('decrease', 'NegReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miR-3662', 'Chemical', '-', (37, 45))	('A375', 'CellLine', 'CVCL:0132', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('transfection', 'Var', (21, 33))	('subcutaneous growth of A375 cells', 'CPA', (77, 110))	('miR-3662', 'Var', (37, 45))	('tumor', 'Disease', (163, 168))
75844	31388313	Indeed, transfection of ZEB1,Mut which is unresponsive to the miRNA, almost blocked the effects of miR-3662 on A375 subcutaneous cell growth (Figure 7).	('effects', 'MPA', (88, 95))	('miR-3662', 'Var', (99, 107))	('blocked', 'NegReg', (76, 83))	('A375 subcutaneous cell growth', 'CPA', (111, 140))	('miR-3662', 'Chemical', '-', (99, 107))	('A375', 'CellLine', 'CVCL:0132', (111, 115))	('cell growth', 'biological_process', 'GO:0016049', ('129', '140'))	('ZEB1', 'Gene', (24, 28))	('transfection', 'Var', (8, 20))
75845	31388313	Analysis of subcutaneous tumors from the murine models demonstrated reductions in tumor volumes (Figure 7B) and tumor weights (Figure 7C) with the expression of miR-3662, supporting its role in decreasing the tumorigenic potential of ZEB1.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('miR-3662', 'Chemical', '-', (161, 169))	('tumor', 'Disease', (82, 87))	('decreasing', 'NegReg', (194, 204))	('tumor', 'Disease', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('reductions', 'NegReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (112, 117))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (12, 31))	('expression', 'Species', '29278', (147, 157))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (12, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('murine', 'Species', '10090', (41, 47))	('miR-3662', 'Var', (161, 169))
75846	31388313	Additionally, the growth inhibition rates calculated of tumor volume (Figure 7D) or tumor weight (Figure 7E), show a reduction in growth with ZEB1 inhibition by miR-3662.	('reduction', 'NegReg', (117, 126))	('ZEB1', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('growth', 'MPA', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (56, 61))	('miR-3662', 'Chemical', '-', (161, 169))	('tumor', 'Disease', (84, 89))	('inhibition', 'NegReg', (147, 157))	('growth', 'MPA', (18, 24))	('miR-3662', 'Var', (161, 169))
75850	31388313	These data demonstrate that miR-3662 acts to inhibit the subcutaneous growth tumor cells in vivo by targeting ZEB1.	('miR-3662', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('targeting', 'Reg', (100, 109))	('miR-3662', 'Chemical', '-', (28, 36))	('inhibit', 'NegReg', (45, 52))	('tumor', 'Disease', (77, 82))	('ZEB1', 'Gene', (110, 114))
75853	31388313	The transfection of miR-3662 in these cells, inhibited their invasive capacity in murine muscle tissue (Figure 8); whereas transfection of ZEB1Mut in these cells almost blocked the effect of miR-3662 on A375 cells' invasive growth (Figure 8).	('miR-3662', 'Chemical', '-', (191, 199))	('invasive capacity in murine muscle tissue', 'CPA', (61, 102))	('A375', 'CellLine', 'CVCL:0132', (203, 207))	('invasive growth', 'biological_process', 'GO:0007125', ('215', '230'))	('transfection', 'Var', (4, 16))	('invasive growth', 'biological_process', 'GO:0001404', ('215', '230'))	('murine', 'Species', '10090', (82, 88))	('miR-3662', 'Chemical', '-', (20, 28))	('invasive growth', 'biological_process', 'GO:0044412', ('215', '230'))	('invasive growth', 'biological_process', 'GO:0036267', ('215', '230'))	('inhibited', 'NegReg', (45, 54))	('invasive growth', 'biological_process', 'GO:0051831', ('215', '230'))	('invasive growth', 'biological_process', 'GO:0044409', ('215', '230'))	('miR-3662', 'Var', (20, 28))
75865	31388313	The identification of miR-3662 as potentially targeting ZEB1 through the 3'-UTR of this transcript was determined via an online database (miRDB.org).	('miR-3662', 'Chemical', '-', (22, 30))	('targeting', 'Reg', (46, 55))	('ZEB1', 'Gene', (56, 60))	('miR-3662', 'Var', (22, 30))
75866	31388313	miR-3662 is a novel tumor suppressor with only 5 reports.	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('miR-3662', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('miR-3662', 'Chemical', '-', (0, 8))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
75867	31388313	Among them, Chen et al (2018) suggested that miR-3662 suppresses hepatocellular carcinoma growth through inhibition of the HIF-1alpha-mediated Warburg effect.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('hepatocellular carcinoma', 'Disease', (65, 89))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (65, 89))	('miR-3662', 'Var', (45, 53))	('HIF-1alpha-mediated', 'Protein', (123, 142))	('inhibition', 'NegReg', (105, 115))	('suppresses', 'NegReg', (54, 64))	('miR-3662', 'Chemical', '-', (45, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))
75868	31388313	Therefore, targeting the ZEB1 gene by miR-3662 is a promising approach to attenuate the invasive growth of melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('invasive growth', 'biological_process', 'GO:0007125', ('88', '103'))	('miR-3662', 'Var', (38, 46))	('melanoma', 'Disease', (107, 115))	('invasive growth', 'biological_process', 'GO:0001404', ('88', '103'))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('invasive growth', 'biological_process', 'GO:0044412', ('88', '103'))	('invasive growth', 'biological_process', 'GO:0036267', ('88', '103'))	('invasive growth', 'biological_process', 'GO:0051831', ('88', '103'))	('invasive growth', 'biological_process', 'GO:0044409', ('88', '103'))	('miR-3662', 'Chemical', '-', (38, 46))	('ZEB1', 'Gene', (25, 29))	('attenuate', 'NegReg', (74, 83))
75869	31388313	Here we confirmed the expression of miR-3662 in tumorigenic cell lines by qPCR and Western blot assays, indicating a potential role for this miRNA in these cells.	('miR-3662', 'Chemical', '-', (36, 44))	('tumor', 'Disease', (48, 53))	('miR-3662', 'Var', (36, 44))	('expression', 'Species', '29278', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
75871	31388313	Consequently, transfection of miR-3662 was assumed to be an efficient strategy to decrease ZEB1 expression.	('expression', 'Species', '29278', (96, 106))	('decrease', 'NegReg', (82, 90))	('expression', 'MPA', (96, 106))	('miR-3662', 'Chemical', '-', (30, 38))	('ZEB1', 'Gene', (91, 95))	('miR-3662', 'Var', (30, 38))
75872	31388313	Indeed, transfection of miR-3662 inhibited the EMT process of A375 cells, decreased invasion-related gene expression, and inhibited the invasive growth of A375 cells in nude mice by decreasing the expression of ZEB1.	('ZEB1', 'Protein', (211, 215))	('EMT', 'biological_process', 'GO:0001837', ('47', '50'))	('nude mice', 'Species', '10090', (169, 178))	('A375', 'CellLine', 'CVCL:0132', (155, 159))	('invasive growth', 'biological_process', 'GO:0007125', ('136', '151'))	('expression', 'Species', '29278', (197, 207))	('invasive growth of A375 cells', 'CPA', (136, 165))	('invasive growth', 'biological_process', 'GO:0036267', ('136', '151'))	('miR-3662', 'Var', (24, 32))	('inhibited', 'NegReg', (122, 131))	('invasion-related gene', 'Gene', (84, 105))	('miR-3662', 'Chemical', '-', (24, 32))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	('inhibited', 'NegReg', (33, 42))	('invasive growth', 'biological_process', 'GO:0044409', ('136', '151'))	('invasive growth', 'biological_process', 'GO:0001404', ('136', '151'))	('expression', 'MPA', (197, 207))	('invasive growth', 'biological_process', 'GO:0044412', ('136', '151'))	('expression', 'Species', '29278', (106, 116))	('invasive growth', 'biological_process', 'GO:0051831', ('136', '151'))	('A375', 'CellLine', 'CVCL:0132', (62, 66))	('decreasing', 'NegReg', (182, 192))	('EMT process of A375 cells', 'CPA', (47, 72))	('decreased', 'NegReg', (74, 83))
75873	31388313	The BRAF mutation is widely used as an indicator or risk-related factor for melanoma's malignant progress.	('mutation', 'Var', (9, 17))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
75879	31388313	In the present work, transfection of miR-3662 inhibited the EMT process and the expression of matrix metalloproteinases, MMP3 or MMP9.	('EMT process', 'CPA', (60, 71))	('miR-3662', 'Chemical', '-', (37, 45))	('matrix metalloproteinases', 'Protein', (94, 119))	('expression', 'Species', '29278', (80, 90))	('miR-3662', 'Var', (37, 45))	('MMP3', 'Gene', (121, 125))	('expression', 'MPA', (80, 90))	('MMP9', 'Gene', (129, 133))	('MMP9', 'molecular_function', 'GO:0004229', ('129', '133'))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('MMP3', 'molecular_function', 'GO:0004248', ('121', '125'))	('inhibited', 'NegReg', (46, 55))
75880	31388313	These results reveal a potential mechanism of action for miR-3662 in inhibiting A375 cell invasion.	('miR-3662', 'Var', (57, 65))	('inhibiting', 'NegReg', (69, 79))	('miR-3662', 'Chemical', '-', (57, 65))	('A375', 'CellLine', 'CVCL:0132', (80, 84))
75882	31388313	Richard et al (2013), Pal et al (2016) and Caramel et al (2013) demonstrated that a high level of ZEB1 expression in epithelial cells is related to BRAF mutation in melanoma.	('Pal', 'molecular_function', 'GO:0004598', ('22', '25'))	('expression', 'Species', '29278', (103, 113))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))	('related', 'Reg', (137, 144))	('ZEB1', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('mutation', 'Var', (153, 161))	('BRAF', 'Gene', (148, 152))
75886	31388313	The inhibitory activation of miR-3662 has been observed on A375 cells in muscle, where it is related to the decreased EMT process and reduced MMP activity.	('MMP activity', 'CPA', (142, 154))	('A375', 'CellLine', 'CVCL:0132', (59, 63))	('EMT', 'biological_process', 'GO:0001837', ('118', '121'))	('MMP', 'molecular_function', 'GO:0004235', ('142', '145'))	('decreased', 'NegReg', (108, 117))	('miR-3662', 'Var', (29, 37))	('EMT process', 'CPA', (118, 129))	('reduced', 'NegReg', (134, 141))	('decreased EMT', 'Phenotype', 'HP:0032198', (108, 121))	('miR-3662', 'Chemical', '-', (29, 37))
75887	31388313	The tumor model utilized in this study mimics the invasion of melanoma in skin/muscle and highlights the potential application of miR-3662 in attenuating melanoma cells invasive growth.	('tumor', 'Disease', (4, 9))	('miR-3662', 'Chemical', '-', (130, 138))	('invasive growth', 'CPA', (169, 184))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('invasive growth', 'biological_process', 'GO:0044409', ('169', '184'))	('attenuating', 'NegReg', (142, 153))	('invasive growth', 'biological_process', 'GO:0001404', ('169', '184'))	('invasive growth', 'biological_process', 'GO:0044412', ('169', '184'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('invasive growth', 'biological_process', 'GO:0051831', ('169', '184'))	('melanoma', 'Disease', (62, 70))	('invasive growth', 'biological_process', 'GO:0007125', ('169', '184'))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('invasive growth', 'biological_process', 'GO:0036267', ('169', '184'))	('miR-3662', 'Var', (130, 138))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
75889	31388313	In this work, our results demonstrated that miR-3662 inhibited the invasion of A375 cells by targeting ZEB1, and offers a potential therapeutic target and treatment via lentiviral delivery.	('miR-3662', 'Chemical', '-', (44, 52))	('inhibited', 'NegReg', (53, 62))	('A375', 'CellLine', 'CVCL:0132', (79, 83))	('ZEB1', 'Protein', (103, 107))	('miR-3662', 'Var', (44, 52))	('targeting', 'Reg', (93, 102))	('invasion of A375 cells', 'CPA', (67, 89))
75891	31388313	The present work demonstrated that ZEB1 is targeted by miR-3662.	('miR-3662', 'Var', (55, 63))	('miR-3662', 'Chemical', '-', (55, 63))	('ZEB1', 'Gene', (35, 39))
75892	31388313	The stable overexpression of miR-3662 in A375, a highly aggressive melanoma cell line, through lentiviral transfection, decreased ZEB1's expression and inhibited the invasion of A375 cells in the muscle tissue of nude mice.	('decreased', 'NegReg', (120, 129))	('A375', 'CellLine', 'CVCL:0132', (41, 45))	('expression', 'MPA', (137, 147))	('expression', 'Species', '29278', (137, 147))	('aggressive melanoma', 'Disease', (56, 75))	('A375', 'CellLine', 'CVCL:0132', (178, 182))	('expression', 'Species', '29278', (15, 25))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('ZEB1', 'Gene', (130, 134))	('miR-3662', 'Var', (29, 37))	('invasion of A375 cells in the muscle tissue', 'CPA', (166, 209))	('nude mice', 'Species', '10090', (213, 222))	('overexpression', 'PosReg', (11, 25))	('inhibited', 'NegReg', (152, 161))	('aggressive melanoma', 'Disease', 'MESH:D008545', (56, 75))	('miR-3662', 'Chemical', '-', (29, 37))
75893	29125844	Significant associations between driver gene mutations and DNA methylation alterations across many cancer types Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer.	('hallmark of cancer', 'Disease', (216, 234))	('DNA methylation', 'biological_process', 'GO:0006306', ('59', '74'))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('hallmark of cancer', 'Disease', 'MESH:D009369', (216, 234))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('aberrant methylation patterns', 'MPA', (183, 212))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cause', 'Reg', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
75895	29125844	We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types.	('CpG island hypermethylation', 'Var', (114, 141))	('associated', 'Reg', (46, 56))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('aberrant hypomethylation', 'Var', (86, 110))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
75896	29125844	Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes.	('uterine', 'Disease', (97, 104))	('mutation-methylation', 'Var', (22, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('thyroid cancer', 'Disease', (113, 127))	('distinguish', 'Reg', (73, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (113, 127))
75897	29125844	The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways.	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('NADPH oxidation', 'biological_process', 'GO:0070995', ('163', '178'))	('methylation differences', 'Var', (36, 59))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', (190, 196))	('differences', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('thyroid cancer', 'Disease', (72, 86))	('mutation-associated', 'Reg', (16, 35))	('JAK-STAT signaling', 'MPA', (143, 161))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('JAK', 'molecular_function', 'GO:0004713', ('143', '146'))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('linked', 'Reg', (101, 107))	('NADPH', 'Chemical', 'MESH:D009249', (163, 168))
75899	29125844	Mutations that alter the function of driver genes by changing DNA nucleotides have been recognized as key players in cancer progression.	('DNA nucleotides', 'MPA', (62, 77))	('function', 'MPA', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
75900	29125844	However, recent evidence has shown that DNA methylation, which can control gene expression, is also highly dysregulated in cancer and contributes to carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gene expression', 'MPA', (75, 90))	('methylation', 'Var', (44, 55))	('carcinogenesis', 'Disease', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('cancer', 'Disease', (123, 129))	('contributes to', 'Reg', (134, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))
75901	29125844	Whether methylation alterations correspond to mutated driver genes in cancer remains unclear.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (70, 76))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('methylation', 'Var', (8, 19))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
75902	29125844	In this study, we analyzed 4,302 tumors from 18 cancer types and demonstrated that driver gene mutations are inherently connected with the aberrant DNA methylation landscape in cancer.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('DNA methylation', 'biological_process', 'GO:0006306', ('148', '163'))	('tumors', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (33, 39))
75903	29125844	We showed that driver gene-associated methylation patterns can classify heterogeneous tumors within a cancer type into homogeneous subtypes and have the potential to influence genes that contribute to tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('methylation patterns', 'Var', (38, 58))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('genes', 'Gene', (176, 181))	('influence', 'Reg', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
75904	29125844	This finding could help us better understand the fundamental connection between driver gene mutations and DNA methylation alterations in cancer, and to further improve cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))
75905	29125844	DNA methylation (DNAm) is highly dysregulated in cancers from many organs, displaying aberrant CpG island (CGI) hypermethylation and long-range blocks of hypomethylation.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hypermethylation', 'Var', (112, 128))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
75912	29125844	Because tumors of the same molecular subtype often harbor both dysregulated DNAm at particular locations in the genome and mutations in driver genes, we decided to investigate the connection between somatic mutations and specific aberrant DNAm patterns.	('dysregulated', 'Var', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
75914	29125844	For example, mutations in SETD2, the H3K36me3 writer, lead to ectopic H3K36me3, coinciding with DNA hypermethylation in renal cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lead', 'Reg', (54, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('SETD2', 'Gene', '29072', (26, 31))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (120, 141))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (120, 141))	('SETD2', 'Gene', (26, 31))	('ectopic H3K36me3', 'MPA', (62, 78))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('mutations', 'Var', (13, 22))	('renal cell carcinomas', 'Disease', (120, 141))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('96', '116'))
75915	29125844	For example, in glioblastoma, mutated IDH1 produces abnormal 2-hydroxyglutarate.	('IDH1', 'Gene', '3417', (38, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('2-hydroxyglutarate', 'MPA', (61, 79))	('mutated', 'Var', (30, 37))	('abnormal 2-hydroxyglutarate', 'Phenotype', 'HP:0012401', (52, 79))	('IDH1', 'Gene', (38, 42))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (61, 79))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
75918	29125844	Finally, the KRAS G13D mutation upregulates another transcriptional repressor, ZNF304, to establish a CIMP-intermediate pattern in colorectal cancer.	('ZNF304', 'Gene', (79, 85))	('mutation', 'Var', (23, 31))	('upregulates', 'PosReg', (32, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('G13D', 'Mutation', 'rs112445441', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('KRAS', 'Gene', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('CIMP', 'Chemical', '-', (102, 106))	('ZNF304', 'Gene', '57343', (79, 85))	('colorectal cancer', 'Disease', (131, 148))	('KRAS', 'Gene', '3845', (13, 17))
75920	29125844	In head and neck squamous cell carcinomas (HNSCs), for instance, an atypical CIMP subtype was recently identified in association with CASP8 mutations, which are not known to have a functional link to the epigenome.	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (3, 41))	('CASP8', 'Gene', (134, 139))	('CASP8', 'Gene', '841', (134, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('HNSC', 'Phenotype', 'HP:0012288', (43, 47))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (12, 41))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('CIMP', 'Chemical', '-', (77, 81))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (17, 41))	('association', 'Reg', (117, 128))	('neck squamous cell carcinomas', 'Disease', (12, 41))	('mutations', 'Var', (140, 149))	('HNSCs', 'Phenotype', 'HP:0012288', (43, 48))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
75921	29125844	And in gastric cancer, PIK3CA mutations co-occur with CIMP, which is thought to be caused by Epstein-Barr virus (EBV) infection.	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('PIK3CA', 'Gene', (23, 29))	('CIMP', 'Chemical', '-', (54, 58))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (93, 127))	('PIK3CA', 'Gene', '5290', (23, 29))	('gastric cancer', 'Disease', (7, 21))	('mutations', 'Var', (30, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CIMP', 'Disease', (54, 58))
75922	29125844	In this type of cancer, TP53 mutations are largely mutually exclusive with PIK3CA mutations.	('PIK3CA', 'Gene', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('PIK3CA', 'Gene', '5290', (75, 81))	('TP53', 'Gene', (24, 28))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', '7157', (24, 28))
75923	29125844	Thus, we would also expect TP53 mutations to be associated with non-CIMP tumors.	('TP53', 'Gene', '7157', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TP53', 'Gene', (27, 31))	('associated', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CIMP', 'Chemical', '-', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (73, 79))
75924	29125844	Based on these findings, we hypothesized that tumor genomic and epigenetic landscapes are stable and interdependent, and that specific driver mutations are associated with specific DNAm patterns.	('mutations', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('associated', 'Reg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
75925	29125844	Thus, in this study, we systematically evaluated mutation-methylation associations across 4,302 tumors from 18 cancer types, along with 727 normal tissue samples from The Cancer Genome Atlas (TCGA).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Cancer Genome Atlas', 'Disease', (171, 190))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (171, 190))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('mutation-methylation', 'Var', (49, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
75926	29125844	By investigating DNAm alterations associated with mutated driver genes on both a genome-wide scale and a site-specific scale, we were able to show that (i) mutated driver genes are tightly associated with DNAm variation in cancer; (ii) some driver gene associations are present across cancer types; for example, TP53 mutations predominantly correspond to hypomethylation across cancer types; (iii) other associations are cancer type-specific; and (iv) these associations can be used to classify tumors into molecular subtypes and gain insight into functional alterations.	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('tumors', 'Disease', 'MESH:D009369', (495, 501))	('cancer', 'Disease', (223, 229))	('mutations', 'Var', (317, 326))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('cancer', 'Disease', (285, 291))	('TP53', 'Gene', (312, 316))	('tumors', 'Phenotype', 'HP:0002664', (495, 501))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (378, 384))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('tumors', 'Disease', (495, 501))	('hypomethylation', 'Var', (355, 370))	('TP53', 'Gene', '7157', (312, 316))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
75927	29125844	Together, these results establish that driver mutations and DNAm alterations are tightly coupled in tumor cells, and that this coupling may affect important regulatory networks related to oncogenesis.	('regulatory networks', 'MPA', (157, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (100, 105))	('oncogenesis', 'biological_process', 'GO:0007048', ('188', '199'))	('affect', 'Reg', (140, 146))	('DNAm', 'MPA', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
75930	29125844	For each cancer type, a driver gene was considered to be associated with a PC if samples in which the gene was mutated (any synonymous/non-synonymous mutation reported in TCGA level 2 exome-sequencing data) were unevenly distributed toward the positive or negative extremes of that PC (q<0.05; two-sided Wilcoxon rank-sum test).	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutated', 'Var', (111, 118))
75935	29125844	For each cancer type, the full list of driver genes associated with methylation PCs can be found in S1 Table, and the full list of MutSigCV-reported driver genes can be found in S2 Table.	('cancer', 'Disease', (9, 15))	('methylation', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
75937	29125844	Thus, the frequent driver gene-PC associations in almost every cancer type suggest a tight connection between driver gene mutations and DNA methylation alterations in cancer.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('cancer', 'Disease', (167, 173))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (63, 69))
75941	29125844	In total, 14 of 18 cancer types harbored significant associations between driver gene mutations and the top five methylation PCs at CGIs, 14 of 18 at SSs, and 15 of 18 in open sea regions.	('mutations', 'Var', (86, 95))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('SSs', 'Chemical', '-', (150, 153))	('driver gene', 'Gene', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
75943	29125844	Some researchers have recently proposed that aberrant DNAm in cancer is driven by cell proliferation and developed a DNAm-based mitotic index (derived from the average methylation level across 385 CpG sites).	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('aberrant', 'Var', (45, 53))	('cell proliferation', 'CPA', (82, 100))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
75945	29125844	However, after removing probes correlated with the DNAm-based mitotic index (p<0.05; Pearson correlation), methylation PC-driver gene associations remained for 11 cancer types (S3 Fig), indicating that mutation-methylation associations cannot be totally explained by the DNAm-based mitotic index.	('methylation', 'biological_process', 'GO:0032259', ('211', '222'))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation', 'Var', (107, 118))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
75947	29125844	We next asked whether driver gene-associated methylation alterations correspond to genome-wide methylation patterns characteristic of cancer: i.e., widespread CGI hypermethylation and huge hypomethylated blocks, primarily in open sea regions.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('hypermethylation', 'Var', (163, 179))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('alterations', 'Var', (57, 68))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
75948	29125844	A high HyperZ index indicates that aberrant hypermethylation exists in many CGIs for a given sample, whereas a high HypoZ index indicates that extensive open sea hypomethylation is present.	('open sea hypomethylation', 'Disease', 'MESH:D009041', (153, 177))	('aberrant', 'Var', (35, 43))	('open sea hypomethylation', 'Disease', (153, 177))
75950	29125844	For example, a high HyperZ index was associated with BRAF in COAD and IDH1 in glioblastoma (GBM); both genes are linked to CIMP in cancer.	('cancer', 'Disease', (131, 137))	('high', 'Var', (15, 19))	('glioblastoma', 'Disease', (78, 90))	('COAD', 'Disease', (61, 65))	('BRAF', 'Gene', '673', (53, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('BRAF', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('IDH1', 'Gene', '3417', (70, 74))	('COAD', 'Disease', 'MESH:D029424', (61, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('CIMP', 'Chemical', '-', (123, 127))	('associated', 'Reg', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('linked', 'Reg', (113, 119))	('IDH1', 'Gene', (70, 74))
75952	29125844	The associations we detected in most cancer types underscore the relationship between driver gene mutations and the genome-wide methylation alterations commonly observed in cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (37, 43))	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
75954	29125844	Next, we investigated whether the connection between driver gene mutations and methylation alterations was methylation site-specific in each cancer type.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('methylation', 'MPA', (79, 90))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (65, 74))
75955	29125844	To do so, we calculated the associations between every driver gene and every methylation array probe for all 18 cancer types, testing whether the presence of mutations in a driver gene was associated with high or low methylation levels at a given probe site (q<0.05; Wilcoxon rank-sum test).	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylation levels', 'MPA', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('low', 'NegReg', (213, 216))	('methylation', 'biological_process', 'GO:0032259', ('217', '228'))	('mutations', 'Var', (158, 167))
75957	29125844	An example of the chromosomal distribution of driver gene-associated methylation probes present in kidney renal clear cell carcinoma (KIRC) is shown in S4A Fig.	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 132))	('methylation', 'Var', (69, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('kidney renal clear cell carcinoma', 'Disease', (99, 132))
75958	29125844	A heat map illustrates mutations in these 14 genes in KIRC (S4B Fig), showing some co-occurrence between SETD2 mutations and PBRM1 mutations, and between BAP1 mutations and PBRM1 mutations, whereas SETD2 mutations and BAP1 mutations are almost mutually exclusive.	('PBRM1', 'Gene', (173, 178))	('mutations', 'Var', (111, 120))	('mutations', 'Var', (131, 140))	('SETD2', 'Gene', '29072', (105, 110))	('PBRM1', 'Gene', '55193', (173, 178))	('SETD2', 'Gene', (198, 203))	('BAP1', 'Gene', (154, 158))	('mutations', 'Var', (159, 168))	('SETD2', 'Gene', (105, 110))	('PBRM1', 'Gene', '55193', (125, 130))	('BAP1', 'Gene', '8314', (218, 222))	('co-occurrence', 'Interaction', (83, 96))	('mutations', 'Var', (179, 188))	('PBRM1', 'Gene', (125, 130))	('BAP1', 'Gene', (218, 222))	('BAP1', 'Gene', '8314', (154, 158))	('SETD2', 'Gene', '29072', (198, 203))
75962	29125844	By definition, positive associations indicate higher methylation levels among tumor samples in the presence of driver gene mutations, whereas negative associations indicate lower methylation levels.	('methylation', 'MPA', (179, 190))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('driver gene', 'Gene', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('methylation levels', 'MPA', (53, 71))	('lower', 'NegReg', (173, 178))	('tumor', 'Disease', (78, 83))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('mutations', 'Var', (123, 132))
75969	29125844	Genomic distribution analysis on RNF43-associated probes revealed that positively associated probes were enriched in gene promoters, whereas negatively associated probes were enriched in gene bodies, suggesting that they may have different functional impacts (S5 Fig).	('RNF43', 'Gene', '54894', (33, 38))	('probes', 'Var', (93, 99))	('RNF43', 'Gene', (33, 38))
75970	29125844	In short, a few driver genes were linked to genome-wide patterns of CGI hypermethylation and open sea hypomethylation in particular cancer types, whereas many more driver genes were linked to a few probe sites aberrantly methylated in cancer (S2 Table).	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('open sea hypomethylation in particular cancer', 'Disease', 'MESH:D009369', (93, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hypermethylation', 'Var', (72, 88))	('open sea hypomethylation in particular cancer', 'Disease', (93, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('linked', 'Reg', (34, 40))
75976	29125844	These genes were selected because they were associated with extensive methylation alterations (more than 1,000 probe associations per driver gene) in at least two cancer types.	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation alterations', 'Var', (70, 93))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
75978	29125844	This suggests a tight connection between TP53 mutations and open sea hypomethylation across multiple cancer types.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('open sea hypomethylation across multiple cancer', 'Disease', (60, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('open sea hypomethylation across multiple cancer', 'Disease', 'MESH:D009369', (60, 107))
75981	29125844	By contrast, IDH1 strongly favored positive associations in two cancer types, GBM and SKCM, consistent with reports that mutated IDH1 downregulates TET-dependent demethylation, resulting in aberrant CGI hypermethylation.	('SKCM', 'Disease', (86, 90))	('IDH1', 'Gene', (129, 133))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('downregulates', 'NegReg', (134, 147))	('CGI hypermethylation', 'MPA', (199, 219))	('TET-dependent demethylation', 'MPA', (148, 175))	('cancer', 'Disease', (64, 70))	('mutated', 'Var', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('IDH1', 'Gene', (13, 17))	('demethylation', 'biological_process', 'GO:0070988', ('162', '175'))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', '3417', (13, 17))	('TET', 'Chemical', 'MESH:C010349', (148, 151))	('GBM', 'Disease', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
75991	29125844	For each cancer type, we then identified genes whose expression levels were correlated with TP53-associated probes (q<0.05; Spearman correlation) in gene promoters or bodies exhibiting aberrant methylation changes (magnitude of median difference in beta values between TP53-mutated tumors and normal samples >0.1).	('cancer', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('TP53', 'Gene', '7157', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', (269, 273))	('TP53', 'Gene', '7157', (92, 96))	('expression', 'MPA', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation changes', 'Var', (194, 213))
75995	29125844	The enriched pathways/gene sets remained largely the same when repeating the analysis restricted to genes corresponding to TP53-negatively associated probes, whereas no enriched pathways/gene sets were found for genes corresponding to TP53-positively associated probes.	('probes', 'Var', (150, 156))	('TP53', 'Gene', '7157', (235, 239))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (235, 239))	('TP53', 'Gene', (123, 127))
76000	29125844	And in UCEC, mutations in TP53 were nearly mutually exclusive with PTEN and CTNNB1 mutations, which co-occurred in many tumor samples.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (83, 92))	('CTNNB1', 'Gene', '1499', (76, 82))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PTEN', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CTNNB1', 'Gene', (76, 82))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (67, 71))	('tumor', 'Disease', (120, 125))
76001	29125844	For both cancer types, we performed hierarchical clustering on the union of the 500 methylation probes most significantly associated with mutations in each of the top three genes (Fig 4).	('associated', 'Reg', (122, 132))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (138, 147))
76003	29125844	SS and open sea regions); BRAF mutants displayed hypomethylation in open sea and some SS regions, whereas NRAS and HRAS mutants displayed methylation levels similar to normal samples in open sea and SS regions, with little hypermethylation.	('mutants', 'Var', (31, 38))	('BRAF', 'Gene', '673', (26, 30))	('HRAS', 'Gene', '3265', (115, 119))	('BRAF', 'Gene', (26, 30))	('methylation', 'biological_process', 'GO:0032259', ('138', '149'))	('NRAS', 'Gene', (106, 110))	('HRAS', 'Gene', (115, 119))	('hypomethylation', 'MPA', (49, 64))	('methylation levels', 'MPA', (138, 156))	('NRAS', 'Gene', '4893', (106, 110))
76007	29125844	Two methylation subtypes were also identified in UCEC, this time corresponding to TP53 vs. PTEN mutations, consistent with the serous vs. endometrioid histological subtypes of UCEC, respectively (Fig 4B).	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('UCEC', 'Disease', (49, 53))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('mutations', 'Var', (96, 105))
76009	29125844	Most UCEC samples with mutations in both PTEN and CTNNB1 displayed greater levels of open sea hypomethylation than samples with PTEN mutations alone, a finding which has not been previously reported.	('CTNNB1', 'Gene', (50, 56))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('CTNNB1', 'Gene', '1499', (50, 56))	('mutations', 'Var', (23, 32))	('greater', 'PosReg', (67, 74))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (85, 109))	('open sea hypomethylation', 'Disease', (85, 109))
76013	29125844	We focused on CpG sites in promoter regions and gene bodies in NRAS and HRAS mutants (the NRAS-HRAS group) vs. BRAF mutants (the BRAF group).	('NRAS', 'Gene', '4893', (63, 67))	('NRAS', 'Gene', (90, 94))	('HRAS', 'Gene', (95, 99))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('HRAS', 'Gene', '3265', (72, 76))	('NRAS', 'Gene', '4893', (90, 94))	('NRAS-HRAS group', 'Gene', '4893', (90, 105))	('HRAS', 'Gene', (72, 76))	('mutants', 'Var', (77, 84))	('NRAS-HRAS group', 'Gene', (90, 105))	('HRAS', 'Gene', '3265', (95, 99))	('BRAF', 'Gene', '673', (111, 115))	('NRAS', 'Gene', (63, 67))	('BRAF', 'Gene', (111, 115))
76024	29125844	We did not find a substantial proportion of differentially methylated genes implicated in tumor progression among the top differentially expressed genes (defined by median difference in expression between NRAS-HRAS mutants and normal samples).	('NRAS-HRAS', 'Gene', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutants', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
76025	29125844	However, when we considered the top 17 differentially expressed, highly transcribed genes (median expression level in mutants > 10 log2 RSEM; median difference > 1 log2 RSEM; highlighted in S6 Table in bold), 6 out of 17 were implicated in tumorigenesis.	('tumor', 'Disease', (240, 245))	('mutants', 'Var', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('expression level', 'MPA', (98, 114))	('implicated', 'Reg', (226, 236))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
76030	29125844	This result demonstrates that methylation changes are indeed associated with differential gene expression between BRAF-mutated and NRAS- and HRAS-mutated samples in THCA.	('gene expression', 'biological_process', 'GO:0010467', ('90', '105'))	('methylation changes', 'Var', (30, 49))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('HRAS', 'Gene', '3265', (141, 145))	('THCA', 'Phenotype', 'HP:0002890', (165, 169))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('HRAS', 'Gene', (141, 145))	('NRAS-', 'Gene', '4893', (131, 136))	('differential gene expression', 'MPA', (77, 105))	('NRAS-', 'Gene', (131, 136))	('associated', 'Reg', (61, 71))
76031	29125844	In this study, we demonstrated that driver gene mutations are tightly tied to the DNAm landscape in multiple types of cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
76032	29125844	In each cancer type, a few driver genes dominate the site-specific associations, and some potentially contribute to CGI hypermethylation and extensive hypomethylation, i.e., the hallmarks of cancer.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (8, 14))	('contribute', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('extensive hypomethylation', 'MPA', (141, 166))	('hypermethylation', 'Var', (120, 136))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CGI', 'MPA', (116, 119))
76034	29125844	Several driver genes that displayed primarily positive or negative associations with methylation probes in this study have been previously linked to CGI hypermethylation or open sea hypomethylation, respectively.	('methylation', 'Var', (85, 96))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (173, 197))	('open sea hypomethylation', 'Disease', (173, 197))	('linked', 'Reg', (139, 145))	('CGI', 'Disease', (149, 152))	('negative', 'NegReg', (58, 66))	('associations', 'Interaction', (67, 79))
76037	29125844	In addition to these examples, we identified novel driver genes that may contribute to CGI hypermethylation, such as BAP1 in KIRC, or to open sea hypomethylation, such as CTNNB1 in LIHC.	('contribute', 'Reg', (73, 83))	('CTNNB1', 'Gene', (171, 177))	('BAP1', 'Gene', '8314', (117, 121))	('CGI', 'MPA', (87, 90))	('BAP1', 'Gene', (117, 121))	('hypermethylation', 'Var', (91, 107))	('CTNNB1', 'Gene', '1499', (171, 177))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (137, 161))	('open sea hypomethylation', 'Disease', (137, 161))
76038	29125844	By illuminating the driver genes associated with widespread DNAm alterations, as well as driver genes associated with more limited DNAm alterations, our comprehensive analysis provides a detailed mutation-methylation map for many types of cancer.	('alterations', 'Var', (65, 76))	('methylation', 'biological_process', 'GO:0032259', ('205', '216'))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
76039	29125844	Several mutated driver genes displayed consistent and widespread positive or negative associations across cancers, corresponding to extensive DNAm alterations.	('associations', 'Interaction', (86, 98))	('negative', 'NegReg', (77, 85))	('mutated', 'Var', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('positive', 'PosReg', (65, 73))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
76041	29125844	For example, mutations in IDH1 and SETD2 directly affect the epigenetic landscape by inhibiting TET-dependent demethylation and disturbing DNA methyltransferase targeting, respectively.	('epigenetic landscape', 'MPA', (61, 81))	('demethylation', 'biological_process', 'GO:0070988', ('110', '123'))	('inhibiting', 'NegReg', (85, 95))	('DNA methyltransferase targeting', 'MPA', (139, 170))	('disturbing', 'Reg', (128, 138))	('IDH1', 'Gene', (26, 30))	('TET', 'Chemical', 'MESH:C010349', (96, 99))	('affect', 'Reg', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('SETD2', 'Gene', '29072', (35, 40))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (26, 30))	('SETD2', 'Gene', (35, 40))	('TET-dependent demethylation', 'MPA', (96, 123))
76042	29125844	BRAF mutations, by contrast, displayed inconsistent methylation patterns between cancer types in this study.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
76043	29125844	In COAD, BRAF-mutated samples mutations displayed widespread CGI hypermethylation.	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('COAD', 'Disease', (3, 7))	('mutations', 'Var', (30, 39))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('CGI hypermethylation', 'MPA', (61, 81))
76045	29125844	However, in THCA, BRAF-mutated samples (260/266 of which harbored the V600E mutation) largely displayed hypomethylation.	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('V600E', 'Var', (70, 75))	('displayed', 'Reg', (94, 103))	('BRAF', 'Gene', '673', (18, 22))	('hypomethylation', 'MPA', (104, 119))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (18, 22))
76046	29125844	Although no mechanistic explanation for this observation is yet available, it is possible that the mutation does not upregulate MAFG in THCA.	('THCA', 'Phenotype', 'HP:0002890', (136, 140))	('THCA', 'Disease', (136, 140))	('MAFG', 'Gene', (128, 132))	('mutation', 'Var', (99, 107))	('MAFG', 'Gene', '4097', (128, 132))
76048	29125844	Several mechanisms have been documented to support the consistent hypomethylation we observed in association with TP53 mutations, across cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('association', 'Interaction', (97, 108))	('cancer', 'Disease', (137, 143))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
76049	29125844	For example, in hepatocellular carcinoma, loss-of-function mutations in TP53 allow pre-malignant cells to bypass senescence induced by global hypomethylation, which could explain the connection between TP53 mutations and hypomethylation.	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (72, 76))	('senescence', 'biological_process', 'GO:0010149', ('113', '123'))	('pre', 'molecular_function', 'GO:0003904', ('83', '86'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('TP53', 'Gene', (72, 76))	('hepatocellular carcinoma', 'Disease', (16, 40))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('TP53', 'Gene', '7157', (202, 206))
76050	29125844	In this study, we found that hypomethylated sites associated with TP53 mutation are shared across cancer types and correspond to upregulated E2F-targets and genes involved in cell cycle regulation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hypomethylated sites', 'Var', (29, 49))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('175', '196'))	('TP53', 'Gene', '7157', (66, 70))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('upregulated', 'PosReg', (129, 140))	('E2F-targets', 'MPA', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
76052	29125844	Moreover, CpG methylation regulates E2F activity by preventing E2F family members from binding target promoters, supporting the correlation between TP53-associated hypomethylation at E2F targets and their upregulation.	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('regulates', 'Reg', (26, 35))	('preventing', 'NegReg', (52, 62))	('upregulation', 'PosReg', (205, 217))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('binding', 'Interaction', (87, 94))	('E2F', 'Protein', (63, 66))	('methylation', 'Var', (14, 25))	('activity', 'MPA', (40, 48))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
76053	29125844	Upregulated E2F activity may promote cell proliferation, consistent with the association between TP53 mutations and a high expression-based mitotic index in 9 cancer types found in this study (S3 Table).	('cancer', 'Disease', (159, 165))	('promote', 'PosReg', (29, 36))	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('E2F', 'Protein', (12, 15))	('activity', 'MPA', (16, 24))	('Upregulated', 'PosReg', (0, 11))	('cell proliferation', 'CPA', (37, 55))
76054	29125844	Therefore, the hypomethylation at E2F targets could regulate E2F activity or could simply represent the footprint of upregulated E2F activity due to TP53 loss, yielding the association between TP53 mutations and DNAm changes at E2F targets.	('TP53', 'Gene', '7157', (193, 197))	('E2F activity', 'MPA', (61, 73))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (198, 207))	('association', 'Interaction', (173, 184))	('TP53', 'Gene', (193, 197))	('TP53', 'Gene', (149, 153))	('loss', 'NegReg', (154, 158))	('regulate', 'Reg', (52, 60))
76056	29125844	Future research is needed to elucidate the role of hypomethylation in TP53-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TP53', 'Gene', '7157', (70, 74))	('hypomethylation', 'Var', (51, 66))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
76057	29125844	However, the DNAm landscape can be affected by mutations in epigenetic modifying enzymes such as SETD2, the H3K36me3 writer.	('H3K36me3 writer', 'Var', (108, 123))	('mutations', 'Var', (47, 56))	('affected', 'Reg', (35, 43))	('SETD2', 'Gene', '29072', (97, 102))	('DNAm landscape', 'MPA', (13, 27))	('SETD2', 'Gene', (97, 102))
76059	29125844	This is evidenced by the recent finding that BRAF V600E and KRAS G13D mutations in COAD upregulate the transcription factors MAFG and ZNF304, respectively, resulting in targeted promoter CGI hypermethylation near MAFG and ZNF304 binding sites.	('G13D', 'Mutation', 'rs112445441', (65, 69))	('ZNF304', 'Gene', (222, 228))	('KRAS', 'Gene', (60, 64))	('ZNF304', 'Gene', (134, 140))	('BRAF', 'Gene', (45, 49))	('MAFG', 'Gene', '4097', (213, 217))	('BRAF', 'Gene', '673', (45, 49))	('COAD', 'Disease', 'MESH:D029424', (83, 87))	('MAFG', 'Gene', '4097', (125, 129))	('mutations', 'Var', (70, 79))	('V600E', 'Mutation', 'rs113488022', (50, 55))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('ZNF304', 'Gene', '57343', (222, 228))	('upregulate', 'PosReg', (88, 98))	('ZNF304', 'Gene', '57343', (134, 140))	('COAD', 'Disease', (83, 87))	('promoter CGI hypermethylation', 'MPA', (178, 207))	('MAFG', 'Gene', (213, 217))	('MAFG', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (60, 64))	('binding', 'molecular_function', 'GO:0005488', ('229', '236'))
76060	29125844	The TP53-associated hypomethylation at E2F targets found in this study may also be explained in this way.	('hypomethylation', 'Var', (20, 35))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
76062	29125844	Conversely, changes in DNAm can cause mutations in cancer.	('DNAm', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cause', 'Reg', (32, 37))	('changes', 'Var', (12, 19))
76065	29125844	The associations observed may simply reflect the presence of specific DNAm patterns in the same tumor subtypes in which particular driver gene mutations are enriched or depleted.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
76066	29125844	In the previously mentioned example, DNA hypomethylation triggers TP53-mediated senescence, and hepatocellular carcinoma emerges when senescence is bypassed due to later TP53 loss.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('triggers', 'Reg', (57, 65))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))	('DNA hypomethylation', 'Var', (37, 56))	('loss', 'NegReg', (175, 179))	('senescence', 'biological_process', 'GO:0010149', ('80', '90'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('37', '56'))	('senescence', 'biological_process', 'GO:0010149', ('134', '144'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
76067	29125844	In this manner, positive selection for both the gene level and the DNAm level alterations could mechanistically link two non-causal events during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('alterations', 'Var', (78, 89))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
76068	29125844	Because mutation-methylation patterns may reflect important oncogenic characteristics, using these patterns to separate tumors into molecular subtypes could potentially aid treatment selection.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('aid', 'Reg', (169, 172))	('mutation-methylation patterns', 'Var', (8, 37))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
76070	29125844	Likewise, the two UCEC subtypes characterized by PTEN and TP53 mutations corresponded to the endometrioid-like and serous-like subtypes identified in TCGA analysis, respectively (Fig 4B).	('mutations', 'Var', (63, 72))	('PTEN', 'Gene', '5728', (49, 53))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('endometrioid-like', 'Disease', (93, 110))	('PTEN', 'Gene', (49, 53))
76071	29125844	Moreover, TCGA classification indicated that the endometrioid-like subtype could be further subdivided into a microsatellite instability subtype (with a low frequency of CTNNB1 mutations) and a low-copy-number subtype (with a high frequency of CTNNB1 mutations).	('CTNNB1', 'Gene', '1499', (244, 250))	('microsatellite instability', 'MPA', (110, 136))	('mutations', 'Var', (177, 186))	('CTNNB1', 'Gene', '1499', (170, 176))	('endometrioid-like', 'Disease', (49, 66))	('CTNNB1', 'Gene', (244, 250))	('CTNNB1', 'Gene', (170, 176))
76072	29125844	Consistent with this finding, in our study tumors with co-occurring PTEN and CTNNB1 mutations displayed more hypomethylation (corresponding to the low-copy-number subtype) than tumors with PTEN mutations alone.	('hypomethylation', 'MPA', (109, 124))	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CTNNB1', 'Gene', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('PTEN', 'Gene', (68, 72))	('mutations', 'Var', (84, 93))	('CTNNB1', 'Gene', '1499', (77, 83))	('PTEN', 'Gene', '5728', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
76074	29125844	The mutual exclusivity of the NRAS, HRAS, and BRAF mutations in THCA tumors has been interpreted to mean that these mutations must have interchangeable effects on MAPK signaling activation, the main cancer-driving event in papillary thyroid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('mutations', 'Var', (51, 60))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (223, 250))	('HRAS', 'Gene', '3265', (36, 40))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (223, 251))	('activation', 'PosReg', (178, 188))	('cancer', 'Disease', (199, 205))	('HRAS', 'Gene', (36, 40))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('NRAS', 'Gene', '4893', (30, 34))	('THCA', 'Disease', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (69, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (233, 250))	('THCA', 'Phenotype', 'HP:0002890', (64, 68))	('papillary thyroid carcinomas', 'Disease', (223, 251))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (223, 251))	('MAPK', 'MPA', (163, 167))	('MAPK signaling', 'biological_process', 'GO:0000165', ('163', '177'))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (233, 251))	('MAPK', 'molecular_function', 'GO:0004707', ('163', '167'))	('NRAS', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
76075	29125844	Our analysis, however, highlights substantial differences in DNAm between BRAF-mutated vs. NRAS- and HRAS-mutated THCA tumors; moreover, the differences in DNAm appear to profoundly shape gene expression profiles, which may contribute to thyroid tumorigenesis.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('HRAS', 'Gene', '3265', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('HRAS', 'Gene', (101, 105))	('gene expression', 'biological_process', 'GO:0010467', ('188', '203'))	('thyroid tumor', 'Disease', 'MESH:D013959', (238, 251))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('shape', 'Reg', (182, 187))	('differences', 'Var', (141, 152))	('tumors', 'Disease', (119, 125))	('thyroid tumor', 'Disease', (238, 251))	('gene expression profiles', 'MPA', (188, 212))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('NRAS-', 'Gene', '4893', (91, 96))	('contribute', 'Reg', (224, 234))	('THCA', 'Phenotype', 'HP:0002890', (114, 118))	('NRAS-', 'Gene', (91, 96))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('thyroid tumor', 'Phenotype', 'HP:0100031', (238, 251))
76076	29125844	In this study, differential DNAm in six JAK and STAT family genes were found to correlate with their upregulation in BRAF-mutated tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('upregulation', 'PosReg', (101, 113))	('JAK', 'Gene', (40, 43))	('differential DNAm', 'Var', (15, 32))	('STAT family genes', 'Gene', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BRAF', 'Gene', '673', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('JAK', 'molecular_function', 'GO:0004713', ('40', '43'))	('BRAF', 'Gene', (117, 121))
76080	29125844	Paired with the aggressiveness of BRAF vs. RAS mutation-positive thyroid tumors, our results support a connection between BRAF mutations, JAK-STAT signaling upregulation (including STAT3 activation), and THCA metastasis, suggesting the role of STAT3 and other JAK-STAT family genes in oncogenesis in THCA.	('THCA', 'Disease', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('JAK', 'molecular_function', 'GO:0004713', ('138', '141'))	('THCA', 'Phenotype', 'HP:0002890', (300, 304))	('STAT3', 'Gene', (181, 186))	('THCA', 'Phenotype', 'HP:0002890', (204, 208))	('JAK-STAT signaling', 'MPA', (138, 156))	('STAT3', 'Gene', (244, 249))	('STAT3', 'Gene', '6774', (181, 186))	('upregulation', 'PosReg', (157, 169))	('STAT3', 'Gene', '6774', (244, 249))	('thyroid tumors', 'Disease', 'MESH:D013959', (65, 79))	('mutations', 'Var', (127, 136))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('aggressiveness', 'Disease', (16, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (16, 30))	('JAK', 'molecular_function', 'GO:0004713', ('260', '263'))	('thyroid tumor', 'Phenotype', 'HP:0100031', (65, 78))	('aggressiveness', 'Disease', 'MESH:D001523', (16, 30))	('oncogenesis', 'biological_process', 'GO:0007048', ('285', '296'))	('BRAF', 'Gene', '673', (122, 126))	('thyroid tumors', 'Disease', (65, 79))	('BRAF', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
76082	29125844	These differences in the molecular processes linked to different driver gene mutations may contribute to distinct pathways of tumorigenesis, yielding different prognoses and clinical phenotypes.	('contribute', 'Reg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
76083	29125844	For example, although the majority of BRAF-mutated samples carried the V600E mutation (25 out of 34 BRAF-mutated tumors carried BRAF V600E in COAD, 167/195 in SKCM, and 260/266 in THCA), this group also included a few non-V600E mutations.	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('BRAF', 'Gene', '673', (128, 132))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('BRAF', 'Gene', '673', (38, 42))	('COAD', 'Disease', (142, 146))	('BRAF', 'Gene', '673', (100, 104))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', (100, 104))	('THCA', 'Phenotype', 'HP:0002890', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BRAF', 'Gene', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
76084	29125844	However, combinatorial effects of driver gene mutations on methylation could exist, as several driver gene mutations typically co-occur in a given tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('mutations', 'Var', (107, 116))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
76085	29125844	Although MutSigCV is one of the most reliable driver gene-detection tools available, limitations associated with the detection algorithm:paired with limitations imposed by the number of tumor samples available in TCGA:may have led us to miss methylation-altering mutations that occurred in unknown driver genes.	('methylation', 'biological_process', 'GO:0032259', ('242', '253'))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mutations', 'Var', (263, 272))	('tumor', 'Disease', (186, 191))	('methylation-altering', 'MPA', (242, 262))
76091	29125844	In addition, in the future, further analysis of methylation and expression data may identify driver gene mutation-induced methylation alterations that dysregulate genes/pathways that promote tumor growth.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutation-induced', 'Reg', (105, 121))	('dysregulate', 'Reg', (151, 162))	('methylation alterations', 'Var', (122, 145))	('genes/pathways', 'Pathway', (163, 177))	('tumor', 'Disease', (191, 196))	('alterations', 'Var', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('promote', 'PosReg', (183, 190))
76093	29125844	Demethylating agents such as 5-aza-2'-deoxycytidine, for example, have been used to reactivate epigenetically silenced tumor suppressor genes and also to decrease overexpression of oncogenes.	('tumor', 'Disease', (119, 124))	('overexpression', 'MPA', (163, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('119', '135'))	('reactivate epigenetically silenced', 'Var', (84, 118))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (29, 51))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('119', '135'))	('decrease', 'NegReg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('oncogenes', 'Protein', (181, 190))
76094	29125844	By contrast, the methyl donor S-adenosylmethionine has been shown to downregulate the oncogenes c-MYC and HRAS, inhibiting cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('c-MYC', 'Gene', (96, 101))	('HRAS', 'Gene', (106, 110))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (30, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('downregulate', 'NegReg', (69, 81))	('HRAS', 'Gene', '3265', (106, 110))	('c-MYC', 'Gene', '4609', (96, 101))	('donor', 'Species', '9606', (24, 29))	('S-adenosylmethionine', 'Var', (30, 50))	('cell growth', 'biological_process', 'GO:0016049', ('130', '141'))	('inhibiting', 'NegReg', (112, 122))
76095	29125844	In summary, in light of the connection between driver gene mutations and DNA methylation shown here, it will be important to further study how coordinated genomic and epigenomic alterations result in the hallmarks of cancer.	('result in', 'Reg', (190, 199))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (59, 68))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
76103	29125844	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms (SNPs), and (iv) probes with missing rates >=90% across all samples for a given cancer type.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('probes', 'Var', (135, 141))
76116	29125844	A driver gene was classified as either mutated (any mutations) or not mutated (no mutations) for each tumor sample.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
76117	29125844	Finally, we performed the same association test for every driver gene and the HyperZ and HypoZ indices, to identify driver genes potentially associated with genome-wide CGI hypermethylation and open sea hypomethylation.	('hypermethylation', 'Var', (173, 189))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (194, 218))	('associated', 'Reg', (141, 151))	('open sea hypomethylation', 'Disease', (194, 218))
76120	29125844	First, we visually identified two THCA molecular subtypes based on driver gene mutations and DNA methylation patterns (Fig 4A): (i) BRAF-mutated tumors (the BRAF group) and (ii) NRAS- and HRAS-mutated tumors (the NRAS-HRAS group).	('HRAS', 'Gene', (188, 192))	('NRAS-HRAS group', 'Gene', '4893', (213, 228))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (79, 88))	('DNA methylation', 'biological_process', 'GO:0006306', ('93', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('NRAS-', 'Gene', (213, 218))	('NRAS-', 'Gene', '4893', (213, 218))	('BRAF', 'Gene', '673', (157, 161))	('HRAS', 'Gene', '3265', (218, 222))	('BRAF', 'Gene', (157, 161))	('HRAS', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('NRAS-', 'Gene', '4893', (178, 183))	('NRAS-', 'Gene', (178, 183))	('NRAS-HRAS group', 'Gene', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('HRAS', 'Gene', '3265', (188, 192))	('tumors', 'Disease', (201, 207))
76121	29125844	The search was restricted to genes whose aberrant expression levels coincided with hyper- or hypomethylated probes associated with BRAF, HRAS, and NRAS mutations (see section below).	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('mutations', 'Var', (152, 161))	('expression levels', 'MPA', (50, 67))	('NRAS', 'Gene', (147, 151))	('HRAS', 'Gene', '3265', (137, 141))	('NRAS', 'Gene', '4893', (147, 151))	('HRAS', 'Gene', (137, 141))
76122	29125844	We sought genes whose aberrant expression was correlated with aberrant methylation in the presence of BRAF, HRAS, or NRAS mutations.	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', '3265', (108, 112))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (117, 121))	('HRAS', 'Gene', (108, 112))	('aberrant', 'Var', (62, 70))	('BRAF', 'Gene', (102, 106))	('methylation', 'MPA', (71, 82))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('mutations', 'Var', (122, 131))
76124	29125844	Third, we integrated the results from the first and second steps to identify aberrantly methylated probes whose methylation levels were significantly correlated with the expression levels of their corresponding genes for each group of BRAF-, HRAS-, and NRAS- mutated samples.	('BRAF', 'Gene', '673', (235, 239))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('methylation levels', 'MPA', (112, 130))	('BRAF', 'Gene', (235, 239))	('HRAS', 'Gene', '3265', (242, 246))	('expression levels', 'MPA', (170, 187))	('NRAS-', 'Gene', '4893', (253, 258))	('HRAS', 'Gene', (242, 246))	('correlated', 'Reg', (150, 160))	('NRAS-', 'Gene', (253, 258))	('aberrantly methylated probes', 'Var', (77, 105))
76125	29125844	For example, when we looked for genes that were upregulated in BRAF-mutated samples but exhibited no change or were downregulated in HRAS- and NRAS-mutated samples, we restricted the search to genes that were hyper- (or hypo-) methylated in BRAF-mutated samples but exhibited no change or were hypo- (or hyper-) methylated in HRAS- and NRAS-mutated samples in the third step.	('HRAS', 'Gene', (133, 137))	('NRAS-', 'Gene', '4893', (143, 148))	('hypo-', 'Var', (220, 225))	('NRAS-', 'Gene', (143, 148))	('hyper-', 'Var', (209, 215))	('HRAS', 'Gene', '3265', (133, 137))	('BRAF', 'Gene', '673', (241, 245))	('BRAF', 'Gene', '673', (63, 67))	('HRAS', 'Gene', '3265', (326, 330))	('upregulated', 'PosReg', (48, 59))	('BRAF', 'Gene', (241, 245))	('BRAF', 'Gene', (63, 67))	('HRAS', 'Gene', (326, 330))	('NRAS-', 'Gene', (336, 341))	('NRAS-', 'Gene', '4893', (336, 341))
76129	33668131	Oncogene-induced epigenetic silencing plays an important role in negative regulation of immunostimulatory antiviral responses in the cancer cells.	('Oncogene-induced', 'Var', (0, 16))	('negative', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('cancer', 'Disease', (133, 139))	('immunostimulatory antiviral responses', 'MPA', (88, 125))	('epigenetic silencing', 'Var', (17, 37))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
76137	33668131	Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.	('epigenetic modifiers', 'Var', (59, 79))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
76141	33668131	We begin by focusing on the cancer-cell per se, analyzing how oncogene-induced modifications serve to optimize the intracellular environment towards OV replication.	('modifications', 'Var', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('intracellular', 'cellular_component', 'GO:0005622', ('115', '128'))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
76145	33668131	In this context, we also discuss the reversal of this form of epigenetic silencing, which may elicit tumor immunogenicity through the expression of endogenous retroelements, thus generating a "viral mimicry" state, emulating the immune-stimulatory potential of OVs.	('rat', 'Species', '10116', (183, 186))	('epigenetic silencing', 'Var', (62, 82))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mimicry" state', 'Phenotype', 'HP:0011468', (199, 213))	('elicit', 'Reg', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
76153	33668131	Oncogene-induced perturbations to antiviral responses are prominent molecular mechanisms by which the cancer-cell milieu becomes optimized towards OV replication.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('perturbations', 'Var', (17, 30))	('antiviral responses', 'MPA', (34, 53))
76154	33668131	Oncogenic mutations in RAS, a GTP-activated molecular switch, ensue exposure to genotoxic agents, and are estimated to occur in 16-30% of all human cancers, with highest incidence in pancreatic (90%) and colon (50%) cancers; and considerable portions of melanoma and lung adenocarcinoma.	('colon', 'Disease', 'MESH:D003110', (204, 209))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('lung adenocarcinoma', 'Disease', (267, 286))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('RAS', 'Gene', (23, 26))	('melanoma', 'Disease', (254, 262))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('human', 'Species', '9606', (142, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (267, 286))	('pancreatic', 'Disease', 'MESH:D010195', (183, 193))	('occur', 'Reg', (119, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (267, 286))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('GTP', 'Chemical', 'MESH:D006160', (30, 33))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('pancreatic', 'Disease', (183, 193))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colon', 'Disease', (204, 209))	('mutations', 'Var', (10, 19))
76155	33668131	Activated RAS (either because of oncogenic mutations or following stimulation of upstream growth receptors) stimulates downstream signaling pathways mediated by phosphatidylinositol 3 (OH)-kinase (PI3K), RAL guanine nucleotide dissociation stimulator (RALGDS) family members, and members of the RAF family, which activate the RAF/MEK/ERK pathway.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (208, 226))	('PI3K', 'molecular_function', 'GO:0016303', ('197', '201'))	('downstream signaling pathways', 'Pathway', (119, 148))	('activate', 'PosReg', (313, 321))	('RAF/MEK/ERK pathway', 'Pathway', (326, 345))	('mutations', 'Var', (43, 52))	('ERK', 'molecular_function', 'GO:0004707', ('334', '337'))	('stimulates', 'PosReg', (108, 118))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))
76167	33668131	Thus, while IRF2 expression is downregulated in many different tumor types suggesting potential tumor suppressor roles, other studies proposed pro-tumorigenic functions for IRF2, including via antagonism of IRF1 functions.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (147, 152))	('antagonism', 'Var', (193, 203))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', (96, 101))	('IRF2', 'Gene', (12, 16))	('downregulated', 'NegReg', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('IRF2', 'Gene', '16363', (173, 177))	('IRF2', 'Gene', '16363', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('IRF2', 'Gene', (173, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
76170	33668131	In accord with the enhanced protein synthesis requirements of cancer cells, PKR has been identified as a tumor suppressor in different malignancy settings; inducing apoptosis upon its activation.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('105', '121'))	('malignancy', 'Disease', 'MESH:D009369', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('inducing', 'PosReg', (156, 164))	('apoptosis', 'CPA', (165, 174))	('PKR', 'Var', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('malignancy', 'Disease', (135, 145))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('protein synthesis', 'biological_process', 'GO:0006412', ('28', '45'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('105', '121'))	('tumor', 'Disease', (105, 110))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
76174	33668131	In accord with PKR being an ISG, mutant IAV lacking NS1 replicate only in interferon-deficient systems and perturbation of expression of MK2 or MK3 reduces IAV titers, and enhances PKR activation and eIF2alpha phosphorylation by the dsRNA mimic polyI:C. In accord with RAF/MEK/ERK-mediated licensing of cells towards IAV infection, IAV shows a strong tropism towards cells expressing active RAF both in vitro and in vivo.	('C', 'Chemical', 'MESH:D002244', (251, 252))	('infection', 'Disease', 'MESH:D007239', (321, 330))	('IAV', 'Species', '11320', (40, 43))	('PKR', 'Enzyme', (181, 184))	('tropism', 'biological_process', 'GO:0009606', ('351', '358'))	('IAV titers', 'MPA', (156, 166))	('mutant', 'Var', (33, 39))	('MK3', 'Gene', '7867', (144, 147))	('MK2', 'Gene', (137, 140))	('IAV', 'Species', '11320', (317, 320))	('MK3', 'Gene', (144, 147))	('IAV', 'Species', '11320', (332, 335))	('NS1', 'Gene', '10625', (52, 55))	('eIF2', 'cellular_component', 'GO:0005850', ('200', '204'))	('IAV', 'Species', '11320', (156, 159))	('activation', 'MPA', (185, 195))	('infection', 'Disease', (321, 330))	('phosphorylation', 'biological_process', 'GO:0016310', ('210', '225'))	('MK2', 'Gene', '9261', (137, 140))	('phosphorylation', 'MPA', (210, 225))	('ERK', 'molecular_function', 'GO:0004707', ('277', '280'))	('reduces', 'NegReg', (148, 155))	('eIF2alpha', 'Gene', (200, 209))	('enhances', 'PosReg', (172, 180))	('eIF2alpha', 'Gene', '83939', (200, 209))	('NS1', 'Gene', (52, 55))	('polyI', 'Chemical', 'MESH:D011069', (245, 250))
76176	33668131	The centrality of PKR inhibition by the RAS/RAF/MEK/ERK signaling axis in determining susceptibility of cancer cells to OVs is further exemplified by: (i) the requirements of herpes simplex virus 1 (HSV1) Deltagamma(1)34.5 mutants for MEK-mediated PKR inhibition, (ii) the oncotropism of VAI mutant adenovirus towards cells in which RAS inactivates PKR, and (iii) the selectivity of the mammalian reovirus towards RAS-transformed cells, which was initially identified as dependent on PKR inactivation.	('PKR', 'Enzyme', (349, 352))	('mutant', 'Var', (292, 298))	('ERK', 'molecular_function', 'GO:0004707', ('52', '55'))	('adenovirus', 'Species', '10508', (299, 309))	('inactivates', 'NegReg', (337, 348))	('HSV1', 'Species', '10298', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('herpes simplex virus 1', 'Species', '10298', (175, 197))	('reovirus', 'Species', '10891', (397, 405))	('mammalian', 'Species', '9606', (387, 396))	('herpes simplex', 'Phenotype', 'HP:0012302', (175, 189))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))
76184	33668131	Interestingly, inactivation of the tumor suppressor phosphatase and tensin homologue (PTEN), which among its well-documented malignancy-promoting activities accelerates tumorigenesis induced by KRAS, results in increased phosphorylation of Ser97 in IRF3, in the negative regulation of IRF-mediated IFN induction upon viral challenge, and in increased viral (VSV) replication.	('PTEN', 'Gene', (86, 90))	('Ser97', 'Chemical', '-', (240, 245))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('regulation', 'biological_process', 'GO:0065007', ('271', '281'))	('negative regulation', 'NegReg', (262, 281))	('IRF3', 'Gene', (249, 253))	('Ser97', 'Protein', (240, 245))	('VSV', 'Species', '11276', (358, 361))	('phosphorylation', 'biological_process', 'GO:0016310', ('221', '236'))	('PTEN', 'Gene', '5728', (86, 90))	('tumor', 'Disease', (35, 40))	('malignancy', 'Disease', (125, 135))	('increased', 'PosReg', (211, 220))	('phosphatase', 'molecular_function', 'GO:0016791', ('52', '63'))	('tumor', 'Disease', (169, 174))	('IRF3', 'Gene', '3661', (249, 253))	('phosphorylation', 'MPA', (221, 236))	('rat', 'Species', '10116', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('accelerates', 'PosReg', (157, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('increased', 'PosReg', (341, 350))	('phosphatase and tensin homologue', 'Gene', 'None', (52, 84))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('Ser', 'cellular_component', 'GO:0005790', ('240', '243'))	('inactivation', 'Var', (15, 27))
76188	33668131	For example, oncogenic KRAS stimulates anabolic metabolism to maintain pancreatic tumors through activation of MAPK and MYC pathways and the ensuing increased expression of genes which regulate sterol biosynthesis, pyrimidine metabolism and glycosylation.	('glycosylation', 'biological_process', 'GO:0070085', ('241', '254'))	('increased', 'PosReg', (149, 158))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('sterol', 'Chemical', 'MESH:D013261', (194, 200))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (71, 88))	('MAPK', 'Pathway', (111, 115))	('expression', 'MPA', (159, 169))	('pyrimidine metabolism', 'biological_process', 'GO:0006220', ('215', '236'))	('sterol biosynthesis', 'biological_process', 'GO:0016126', ('194', '213'))	('MYC', 'Gene', (120, 123))	('anabolic metabolism', 'MPA', (39, 58))	('pyrimidine metabolism', 'biological_process', 'GO:0006213', ('215', '236'))	('activation', 'PosReg', (97, 107))	('pyrimidine metabolism', 'biological_process', 'GO:0006206', ('215', '236'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('pancreatic tumors', 'Disease', 'MESH:D010190', (71, 88))	('oncogenic KRAS', 'Var', (13, 27))	('pancreatic tumors', 'Disease', (71, 88))	('pyrimidine', 'Chemical', 'MESH:C030986', (215, 225))	('metabolism', 'biological_process', 'GO:0008152', ('48', '58'))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('stimulates', 'PosReg', (28, 38))	('MYC', 'Gene', '4609', (120, 123))	('KRAS', 'Var', (23, 27))
76193	33668131	The similitude of the metabolic requirements of KRAS-transformed tumors and viruses is further exemplified by the effects of inhibitors of dihydroorotate dehydrogenase (DHODH), which perturb de novo pyrimidine biosynthesis, selectively inhibit the growth of KRAS mutant cell lines and exhibit broad-range antiviral activity against RNA viruses.	('perturb', 'NegReg', (183, 190))	('tumors', 'Disease', (65, 71))	('KRAS', 'Gene', (258, 262))	('inhibit', 'NegReg', (236, 243))	('dihydroorotate dehydrogenase', 'Gene', '1723', (139, 167))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('DHODH', 'Gene', (169, 174))	('inhibitors', 'Var', (125, 135))	('RNA viruses', 'Disease', (332, 343))	('de novo pyrimidine biosynthesis', 'MPA', (191, 222))	('pyrimidine', 'Chemical', 'MESH:C030986', (199, 209))	('DHODH', 'Gene', '1723', (169, 174))	('growth', 'MPA', (248, 254))	('dihydroorotate dehydrogenase', 'Gene', (139, 167))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RNA', 'cellular_component', 'GO:0005562', ('332', '335'))	('antiviral activity', 'MPA', (305, 323))	('biosynthesis', 'biological_process', 'GO:0009058', ('210', '222'))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
76197	33668131	Tumor immunoediting is commonly divided into three phases (the "three E's"): (i) elimination, where cancer cells are destroyed by immunosurveillance mechanisms; (ii) equilibrium, where cells surviving the initial immune onslaught undergo consecutive rounds of functional, epigenetic and genetic changes.	('genetic', 'Var', (287, 294))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('epigenetic', 'Var', (272, 282))
76200	33668131	This occurs through multiple mechanisms including: inactivating mutations, epigenetic silencing or sequestration of components of cell death pathways induced by immune cells, overexpression of decoy receptors (reviewed in), or interference with the cancer-cell apoptotic machineries.	('cell', 'CPA', (130, 134))	('decoy receptors', 'Protein', (193, 208))	('sequestration', 'MPA', (99, 112))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('inactivating mutations', 'Var', (51, 73))	('overexpression', 'PosReg', (175, 189))	('cancer', 'Disease', (249, 255))	('cell death', 'biological_process', 'GO:0008219', ('130', '140'))	('epigenetic silencing', 'Var', (75, 95))	('rat', 'Species', '10116', (106, 109))	('interference', 'NegReg', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
76204	33668131	This occurs via a broad range of processes including inactivating mutations or epigenetic silencing of MHC-I per se or of co-factors required for its expression; inhibition of signaling pathways that promote MHC-I expression; or activation of pathways that inhibit MHC-I expression).	('inhibition', 'NegReg', (162, 172))	('C', 'Chemical', 'MESH:D002244', (210, 211))	('epigenetic silencing', 'Var', (79, 99))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('inactivating mutations', 'Var', (53, 75))	('C', 'Chemical', 'MESH:D002244', (267, 268))	('signaling pathways', 'Pathway', (176, 194))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('MHC-I', 'Gene', (103, 108))	('expression', 'MPA', (214, 224))	('promote', 'PosReg', (200, 207))	('pathways', 'Pathway', (243, 251))
76205	33668131	Additionally, cancer cells also decrease expression of pro-inflammatory cytokines, such as in the epigenetic silencing of IFN-gamma or IFN-kappa in cervical cancer and Human Papillomavirus Type 16 (HPV-16)-positive cells, respectively; or the reduced expression of pro-inflammatory cytokines in non-small cell lung cancers (NSCLC).	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('NSCLC', 'Disease', 'MESH:D002289', (324, 329))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (299, 322))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'MPA', (41, 51))	('NSCLC', 'Disease', (324, 329))	('lung cancer', 'Phenotype', 'HP:0100526', (310, 321))	('IFN-kappa', 'Gene', (135, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (324, 329))	('lung cancers', 'Disease', 'MESH:D008175', (310, 322))	('HPV-16', 'Species', '333760', (198, 204))	('decrease expression of pro-inflammatory cytokines', 'Phenotype', 'HP:0012648', (32, 81))	('Human Papillomavirus Type 16', 'Species', '333760', (168, 196))	('cancers', 'Phenotype', 'HP:0002664', (315, 322))	('cancer', 'Disease', (315, 321))	('lung cancers', 'Disease', (310, 322))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('IFN-gamma', 'Gene', '3458', (122, 131))	('IFN-gamma', 'Gene', (122, 131))	('decrease', 'NegReg', (32, 40))	('epigenetic silencing', 'Var', (98, 118))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (295, 322))	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lung cancers', 'Phenotype', 'HP:0100526', (310, 322))	('expression', 'MPA', (251, 261))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('reduced', 'NegReg', (243, 250))	('IFN-kappa', 'Gene', '56832', (135, 144))
76213	33668131	In light of the multiple steps involved in the induction, signal transduction and cellular response to IFNs, cancer-induced defects to IFN signaling occur through a plethora of molecular mechanisms including: (i) perturbations to the expression of the IFN receptor; e.g., the ubiquitination and downregulation of the type I IFN receptor (IFNAR1) following inflammatory signaling, nutrient deprivation or hypoxia (all conditions prevalent in the TME).	('hypoxia', 'Disease', (404, 411))	('hypoxia', 'Disease', 'MESH:D000860', (404, 411))	('IFNAR1', 'Gene', (338, 344))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('signal transduction', 'biological_process', 'GO:0007165', ('58', '77'))	('downregulation', 'NegReg', (295, 309))	('cancer', 'Disease', (109, 115))	('IFNAR1', 'Gene', '3454', (338, 344))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('perturbations', 'Var', (213, 226))	('plethora', 'Phenotype', 'HP:0001050', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ubiquitination', 'MPA', (276, 290))	('signaling', 'biological_process', 'GO:0023052', ('369', '378'))
76214	33668131	Such down regulation, which was observed in melanoma and colorectal cancer, is associated with increased metastatic propensity and with the generation of an immune-privileged TME; (ii) perturbations to JAK/STAT1 signaling including epigenetic silencing and inactivating mutations in JAK1.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('JAK1', 'Gene', '3716', (283, 287))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('JAK', 'molecular_function', 'GO:0004713', ('202', '205'))	('down regulation', 'NegReg', (5, 20))	('rat', 'Species', '10116', (144, 147))	('colorectal cancer', 'Disease', (57, 74))	('inactivating mutations', 'Var', (257, 279))	('STAT1', 'Gene', (206, 211))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('JAK1', 'Gene', (283, 287))	('perturbations', 'Var', (185, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('regulation', 'biological_process', 'GO:0065007', ('10', '20'))	('signaling', 'biological_process', 'GO:0023052', ('212', '221'))	('JAK', 'molecular_function', 'GO:0004713', ('283', '286'))	('metastatic propensity', 'CPA', (105, 126))	('STAT1', 'Gene', '6772', (206, 211))	('increased', 'PosReg', (95, 104))	('epigenetic silencing', 'Var', (232, 252))
76215	33668131	In this context, whole-exome and RNA sequencing, and reverse-phase protein array data from different the Cancer Genome Atlas (TCGA) datasets (skin cutaneous melanoma, breast invasive carcinoma, lung adenocarcinoma, and colorectal adenocarcinoma) revealed alterations in JAK1 or JAK2 in 5-12 % of the samples, with dependence on cancer type; (iii) crosstalk of JAK/STAT1 signaling with pro-tumorigenic signaling pathways; such as the inhibition of IFN-induced expression of inflammatory genes following STAT3 activation.	('JAK1', 'Gene', (270, 274))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('JAK', 'molecular_function', 'GO:0004713', ('360', '363'))	('JAK2', 'Gene', '3717', (278, 282))	('cancer', 'Disease', (328, 334))	('JAK', 'molecular_function', 'GO:0004713', ('278', '281'))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('inflammatory genes', 'Gene', (473, 491))	('signaling', 'biological_process', 'GO:0023052', ('401', '410'))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('lung adenocarcinoma', 'Disease', (194, 213))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('JAK2', 'Gene', (278, 282))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (167, 192))	('inhibition', 'NegReg', (433, 443))	('alterations', 'Var', (255, 266))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))	('Cancer', 'Disease', (105, 111))	('STAT1', 'Gene', (364, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('colorectal adenocarcinoma', 'Disease', (219, 244))	('rat', 'Species', '10116', (259, 262))	('JAK1', 'Gene', '3716', (270, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', (389, 394))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('signaling', 'biological_process', 'GO:0023052', ('370', '379'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (194, 213))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('IFN-induced expression of', 'MPA', (447, 472))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('STAT1', 'Gene', '6772', (364, 369))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (147, 165))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('STAT3', 'Gene', (502, 507))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (194, 213))	('crosstalk', 'Reg', (347, 356))	('skin cutaneous melanoma, breast invasive carcinoma', 'Disease', 'MESH:D001943', (142, 192))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (219, 244))	('STAT3', 'Gene', '6774', (502, 507))	('JAK', 'molecular_function', 'GO:0004713', ('270', '273'))
76219	33668131	A major additional source of stimuli are mutations, which are recognized as tumor-associated antigens and play a prominent immunostimulatory role.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
76220	33668131	Thus, DNA fragments generated as a result of genomic instability or upon therapeutic induction of double-stranded DNA breaks, activate cGAS/IFN-mediated responses, serving thus as a source of immunostimulatory cytokines.	('cGAS', 'Gene', (135, 139))	('activate', 'PosReg', (126, 134))	('double-stranded DNA breaks', 'Var', (98, 124))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('cGAS', 'Gene', '115004', (135, 139))	('rat', 'Species', '10116', (24, 27))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
76222	33668131	These scenarios support the notion that PRR-mediated activation of type I-IFN responses occurs throughout tumorigenesis, and may force the cancer cell to hamper such responses in order to escape the anti-proliferative and the immune-stimulatory effects of IFN signaling.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('PRR-mediated', 'Var', (40, 52))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('activation', 'PosReg', (53, 63))	('rat', 'Species', '10116', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PRR', 'molecular_function', 'GO:0038187', ('40', '43'))	('anti-proliferative', 'CPA', (199, 217))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('type I-IFN responses', 'MPA', (67, 87))	('hamper', 'NegReg', (154, 160))	('escape', 'NegReg', (188, 194))	('tumor', 'Disease', (106, 111))	('cancer', 'Disease', (139, 145))
76227	33668131	Similarly, truncation in the beta2-microglobulin gene resulting in defects in MHC-I-mediated antigen presentation and loss-of-function mutations to JAK1 or JAK2, implying defects to the transduction of antiviral IFN signals; mediate resistance to PD-1 blockade in melanoma.	('PD-1 blockade in melanoma', 'Disease', 'MESH:D010300', (247, 272))	('beta2-microglobulin', 'Gene', '567', (29, 48))	('mutations', 'Var', (135, 144))	('JAK', 'molecular_function', 'GO:0004713', ('148', '151'))	('beta2-microglobulin', 'Gene', (29, 48))	('JAK', 'molecular_function', 'GO:0004713', ('156', '159'))	('JAK2', 'Gene', '3717', (156, 160))	('JAK1', 'Gene', (148, 152))	('antigen presentation', 'biological_process', 'GO:0019882', ('93', '113'))	('defects', 'NegReg', (67, 74))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('transduction', 'MPA', (186, 198))	('defects', 'NegReg', (171, 178))	('loss-of-function', 'NegReg', (118, 134))	('truncation', 'Var', (11, 21))	('JAK2', 'Gene', (156, 160))	('transduction', 'biological_process', 'GO:0009293', ('186', '198'))	('PD-1 blockade in melanoma', 'Disease', (247, 272))	('MHC-I-mediated antigen presentation', 'MPA', (78, 113))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('JAK1', 'Gene', '3716', (148, 152))
76233	33668131	A connection between tumorigenic features of cancer cells, epigenetic silencing and defects in antiviral responses is already observed upon spontaneous immortalization of fibroblasts which results in epigenetic silencing of ISGs.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (21, 26))	('epigenetic silencing', 'Var', (59, 79))	('ISGs', 'Gene', (224, 228))	('antiviral responses', 'MPA', (95, 114))	('epigenetic silencing', 'Var', (200, 220))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancer', 'Disease', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
76235	33668131	Similarly, the promoter of IFN-gamma was shown to be methylated in cervical cancer.	('IFN-gamma', 'Gene', '3458', (27, 36))	('IFN-gamma', 'Gene', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('methylated', 'Var', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
76246	33668131	Indeed, we explored the complete absence of IFN signaling in LNCaP prostate cancer cells, which also present oncogenic KRAS mutation, to select an oncolytic mutant of the epizootic hemorrhagic disease virus (EHDV), an orbivirus (arbovirus of the Reoviridae family) that naturally targets ruminants, and that we named EHDV-Tel Aviv University (EHDV-TAU).	('hemorrhagic disease', 'Phenotype', 'HP:0001928', (181, 200))	('EHDV', 'Species', '40054', (317, 321))	('mutant', 'Var', (157, 163))	('EHDV', 'Species', '40054', (208, 212))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('LNCaP prostate cancer', 'Disease', (61, 82))	('epizootic hemorrhagic disease virus', 'Species', '40054', (171, 206))	('KRAS', 'Gene', (119, 123))	('EHDV', 'Species', '40054', (343, 347))	('mutation', 'Var', (124, 132))	('LNCaP prostate cancer', 'Disease', 'MESH:D011471', (61, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))
76249	33668131	Moreover, in the latter case, treatment with inhibitors of epigenetic silencing restored PRR expression and viral induction of IFN responses in the B16F10 cells; exemplifying the role of epigenetic silencing of IFN/ISGs in the cancer cell, as a mechanism for OV selectivity.	('PRR expression', 'MPA', (89, 103))	('IFN responses', 'MPA', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('B16F10', 'CellLine', 'CVCL:0159', (148, 154))	('epigenetic silencing', 'Var', (187, 207))	('restored', 'PosReg', (80, 88))	('PRR', 'molecular_function', 'GO:0038187', ('89', '92'))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
76260	33668131	Given the potential immunogenicity of endogenous retroelements and their epigenetic suppression, reactivation of these elements by epigenetic modifiers in cancer cells may results in the abovementioned viral mimicry, leading to an anti-cancerous state.	('viral mimicry', 'CPA', (202, 215))	('cancerous', 'Disease', 'MESH:D009369', (236, 245))	('reactivation', 'Var', (97, 109))	('epigenetic', 'Var', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (236, 242))	('cancerous', 'Disease', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('leading to', 'Reg', (217, 227))	('results in', 'Reg', (172, 182))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
76266	33668131	One of the many targets of E2F is the Dnmt1 gene.	('Dnmt1', 'Gene', (38, 43))	('E2F', 'Var', (27, 30))	('Dnmt1', 'Gene', '1786', (38, 43))
76268	33668131	Thus, mitogenic signals suppress ERVs expression via DNA methylation, mediated by the CDK4/6-Cyclin D-Rb-DNMT1 axis, and inhibition of this axis results in ERVs activation followed by enhanced anti-tumor immunity.	('Rb', 'Phenotype', 'HP:0009919', (102, 104))	('inhibition', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('DNA methylation', 'biological_process', 'GO:0006306', ('53', '68'))	('enhanced', 'PosReg', (184, 192))	('activation', 'PosReg', (161, 171))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('suppress', 'NegReg', (24, 32))	('DNA methylation', 'MPA', (53, 68))	('expression', 'MPA', (38, 48))	('CDK', 'molecular_function', 'GO:0004693', ('86', '89'))	('tumor', 'Disease', (198, 203))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('Cyclin', 'molecular_function', 'GO:0016538', ('93', '99'))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('ERVs', 'Protein', (33, 37))	('Rb', 'Gene', '5925', (102, 104))	('ERVs', 'CPA', (156, 160))
76272	33668131	Similar to what is observed in OV-infected cells, reversal of DNA methylation-mediated epigenetic silencing of hERVs stimulates anti-tumor immunity through viral mimicry.	('hERVs', 'Gene', (111, 116))	('infected', 'Disease', 'MESH:D007239', (34, 42))	('reversal', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('infected', 'Disease', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('hERVs', 'Species', '206037', (111, 116))	('epigenetic silencing', 'Var', (87, 107))	('DNA methylation', 'biological_process', 'GO:0006306', ('62', '77'))	('stimulates', 'PosReg', (117, 127))	('tumor', 'Disease', (133, 138))	('methylation-mediated', 'Var', (66, 86))
76288	30028904	The disease is caused by a tri-nucleotide repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene in DM type 1 (DM1), or a tetra-nucleotide repeat expansion in the zinc finger 9 (ZNF9) gene in DM type 2 (DM2).	('tetra-nucleotide repeat expansion', 'Var', (139, 172))	('DMPK', 'Gene', (103, 107))	('DM1', 'Gene', '1760', (128, 131))	('caused by', 'Reg', (15, 24))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('tri-nucleotide', 'Chemical', 'MESH:D009711', (27, 41))	('ZNF9', 'Gene', '7555', (195, 199))	('tetra', 'Species', '42554', (139, 144))	('tri-nucleotide repeat expansion', 'Var', (27, 58))	('DM2', 'Gene', '7555', (220, 223))	('dystrophia myotonica-protein kinase', 'Gene', (66, 101))	('dystrophia myotonica-protein kinase', 'Gene', '1760', (66, 101))	('ZNF9', 'Gene', (195, 199))	('DM1', 'Gene', (128, 131))	('DM2', 'Gene', (220, 223))	('DMPK', 'Gene', '1760', (103, 107))
76289	30028904	The size of the nucleotide repeat expansion in DM1, but not DM2, is modestly correlated with disease severity and age at onset; congenital DM is the most severe form of the disease.	('nucleotide repeat expansion', 'Var', (16, 43))	('DM2', 'Gene', '7555', (60, 63))	('DM2', 'Gene', (60, 63))	('DM1', 'Gene', (47, 50))	('congenital DM', 'Disease', (128, 141))	('DM1', 'Gene', '1760', (47, 50))
76338	30028904	Perhaps the most appealing hypothesis is that DM alternative splicing abnormality may alter the expression of oncogene or tumor suppressor genes.	('splicing', 'biological_process', 'GO:0045292', ('61', '69'))	('oncogene', 'Gene', (110, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('122', '138'))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('122', '138'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('alter', 'Reg', (86, 91))	('DM alternative splicing abnormality', 'Var', (46, 81))	('tumor', 'Disease', (122, 127))
76362	28910167	Therefore, depending on tumour type and/or microenvironment, AMPs may positively or negatively impact the development of cancers.	('cancers', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('impact', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('negatively', 'NegReg', (84, 94))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('AMPs', 'Chemical', '-', (61, 65))	('AMPs', 'Var', (61, 65))
76363	28910167	Despite studies in a wide range of cancers, the expression profile of AMPs in uveal melanoma, the most common primary ocular tumour in adults, has not previously been investigated, and the effects of AMPs on behaviour of these cells are unknown.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('AMPs', 'Var', (70, 74))	('AMPs', 'Chemical', '-', (70, 74))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('uveal melanoma', 'Disease', (78, 92))	('AMPs', 'Chemical', '-', (200, 204))	('behaviour', 'biological_process', 'GO:0007610', ('208', '217'))	('ocular tumour', 'Disease', (118, 131))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('ocular tumour', 'Disease', 'MESH:D005134', (118, 131))	('ocular tumour', 'Phenotype', 'HP:0100012', (118, 131))
76370	28910167	The detailed mechanisms underlying vasculogenic mimicry formation are still being elucidated, but it is associated with cancer cells with altered extracellular matrix gene expression that proliferate, migrate and organize into patent channels in response to angiogenesis promoting factors and the tumor microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('angiogenesis', 'biological_process', 'GO:0001525', ('258', '270'))	('altered', 'Var', (138, 145))	('migrate', 'CPA', (201, 208))	('cancer', 'Disease', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('formation', 'biological_process', 'GO:0009058', ('56', '65'))	('proliferate', 'CPA', (188, 199))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('146', '166'))	('tumor', 'Disease', (297, 302))	('gene expression', 'biological_process', 'GO:0010467', ('167', '182'))
76371	28910167	In addition to stimulating migration of some tumour cells, AMPs such as LL-37, PR39 and alpha defensins, can promote blood vessel development and interfere with tumor-associated angiogenesis.	('LL-37', 'Gene', (72, 77))	('AMPs', 'Chemical', '-', (59, 63))	('promote', 'PosReg', (109, 116))	('PR39', 'Var', (79, 83))	('angiogenesis', 'biological_process', 'GO:0001525', ('178', '190'))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('blood vessel development', 'biological_process', 'GO:0001568', ('117', '141'))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('interfere', 'NegReg', (146, 155))	('LL-37', 'Gene', '820', (72, 77))	('blood vessel development', 'CPA', (117, 141))	('alpha defensins', 'Protein', (88, 103))	('tumor', 'Disease', (161, 166))	('tumour', 'Disease', (45, 51))
76418	28910167	Increased expression of endogenous LL-37 has been implicated in the development or progression of several cancers including breast, ovarian and lung, where it can stimulate proliferation, enhance metastatic capacity, and transactivate the epidermal growth factor receptor (EGFR).	('epidermal growth factor receptor', 'Gene', '1956', (239, 271))	('metastatic capacity', 'CPA', (196, 215))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('enhance', 'PosReg', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('EGFR', 'Gene', (273, 277))	('lung', 'Disease', (144, 148))	('implicated', 'Reg', (50, 60))	('proliferation', 'CPA', (173, 186))	('LL-37', 'Gene', '820', (35, 40))	('LL-37', 'Gene', (35, 40))	('breast, ovarian', 'Disease', 'MESH:D010051', (124, 139))	('transactivate', 'Var', (221, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('273', '277'))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('EGFR', 'Gene', '1956', (273, 277))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('239', '262'))	('stimulate', 'PosReg', (163, 172))	('epidermal growth factor receptor', 'Gene', (239, 271))
76436	28910167	Given that AMPs can modulate behaviors such as migration, proliferation and vessel formation in melanoma and breast cancer, we hypothesized that AMPs may influence vasculogenic mimicry.	('breast cancer', 'Disease', (109, 122))	('proliferation', 'CPA', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('AMPs', 'Chemical', '-', (11, 15))	('vasculogenic mimicry', 'CPA', (164, 184))	('influence', 'Reg', (154, 163))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('AMPs', 'Var', (145, 149))	('migration', 'CPA', (47, 56))	('AMPs', 'Chemical', '-', (145, 149))	('vessel formation', 'CPA', (76, 92))	('modulate', 'Reg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
76447	28910167	In summary our data show expression of AMPs in uveal melanoma and cutaneous melanoma cells lines.	('cutaneous melanoma', 'Disease', (66, 84))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (66, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (66, 84))	('AMPs', 'Var', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('uveal melanoma', 'Disease', 'MESH:C536494', (47, 61))	('uveal melanoma', 'Disease', (47, 61))	('AMPs', 'Chemical', '-', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
76450	28910167	Further, the AMPs LL-37 and HNP-1 do not significantly influence melanoma cell migration or vasculogenic mimicry.	('influence', 'Reg', (55, 64))	('LL-37', 'Gene', (18, 23))	('vasculogenic mimicry', 'CPA', (92, 112))	('cell migration', 'biological_process', 'GO:0016477', ('74', '88'))	('LL-37', 'Gene', '820', (18, 23))	('HNP-1', 'Gene', '574045', (28, 33))	('AMPs', 'Chemical', '-', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma cell migration', 'Disease', 'MESH:D008545', (65, 88))	('AMPs', 'Var', (13, 17))	('HNP-1', 'Gene', (28, 33))	('melanoma cell migration', 'Disease', (65, 88))
76451	28910167	Based on our current observations, we cannot confirm that AMPs have a significant role in the pathogenesis and progression of melanomas, but certainly they do not appear to influence major tumour characteristics associated with tumour progression in the cell lines analyzed.	('AMPs', 'Var', (58, 62))	('influence', 'Reg', (173, 182))	('tumour', 'Disease', (228, 234))	('melanomas', 'Disease', (126, 135))	('AMPs', 'Chemical', '-', (58, 62))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('pathogenesis', 'biological_process', 'GO:0009405', ('94', '106'))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('tumour', 'Disease', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (228, 234))
76466	25593912	Early events in the development of melanocytic tumors are often hotspot mutations in genes involved in the MAPK pathway, which is one of the most important pathways involved in melanocytic tumor development (Figure 1).	('mutations', 'Var', (72, 81))	('melanocytic tumor', 'Disease', 'MESH:D009508', (35, 52))	('hot', 'Gene', '137872', (64, 67))	('melanocytic tumor', 'Disease', 'MESH:D009508', (177, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('MAPK', 'Gene', '5594', (107, 111))	('melanocytic tumors', 'Disease', 'MESH:D009508', (35, 53))	('hot', 'Gene', (64, 67))	('MAPK', 'Gene', (107, 111))	('melanocytic tumors', 'Disease', (35, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MAPK', 'molecular_function', 'GO:0004707', ('107', '111'))	('melanocytic tumor', 'Disease', (177, 194))
76467	25593912	Important oncogenes in this pathway are BRAF (7q34), NRAS (1p13), HRAS (11p15), GNAQ (9p21), GNA11 (19p13), and KIT (4q12).	('BRAF', 'Gene', '673', (40, 44))	('BRAF', 'Gene', (40, 44))	('9p21', 'Var', (86, 90))	('HRAS', 'Gene', (66, 70))	('NRAS', 'Gene', (53, 57))	('GNAQ', 'Gene', '2776', (80, 84))	('KIT', 'molecular_function', 'GO:0005020', ('112', '115'))	('NRAS', 'Gene', '4893', (53, 57))	('GNA11', 'Gene', '2767', (93, 98))	('GNA11', 'Gene', (93, 98))	('GNAQ', 'Gene', (80, 84))	('HRAS', 'Gene', '3265', (66, 70))
76468	25593912	Mutations in these genes are mostly mutually exclusive, by themselves do not cause malignant progression, stay present with malignant progression, and activate the MAPK pathway.	('MAPK', 'Gene', '5594', (164, 168))	('activate', 'PosReg', (151, 159))	('MAPK', 'Gene', (164, 168))	('Mutations', 'Var', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('164', '168'))
76469	25593912	Different subtypes of benign and malignant melanocytic tumors are characterized by different mutations in these genes of the MAPK pathway.	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MAPK', 'Gene', '5594', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('MAPK', 'Gene', (125, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('125', '129'))	('malignant melanocytic tumors', 'Disease', (33, 61))	('malignant melanocytic tumors', 'Disease', 'MESH:D018198', (33, 61))	('malignant melanocytic tumors', 'Phenotype', 'HP:0002861', (33, 61))
76470	25593912	In common nevi for instance, BRAF and NRAS mutations are present in 60-87.5% and 20%, respectively.	('NRAS', 'Gene', '4893', (38, 42))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('mutations', 'Var', (43, 52))	('NRAS', 'Gene', (38, 42))	('nevi', 'Phenotype', 'HP:0003764', (10, 14))
76471	25593912	In large congenital nevi upto 80%, NRAS mutations are reported.	('large congenital', 'Phenotype', 'HP:0004488', (3, 19))	('nevi', 'Phenotype', 'HP:0003764', (20, 24))	('large congenital nevi', 'Disease', (3, 24))	('NRAS', 'Gene', (35, 39))	('NRAS', 'Gene', '4893', (35, 39))	('mutations', 'Var', (40, 49))
76472	25593912	In blue nevi, mainly GNAQ (83%) and GNA11 (7%) mutations are found, and in Spitz nevi, HRAS mutations are reported in 20-29%.	('blue nevi', 'Phenotype', 'HP:0100814', (3, 12))	('GNAQ', 'Gene', '2776', (21, 25))	('HRAS', 'Gene', '3265', (87, 91))	('GNA11', 'Gene', '2767', (36, 41))	('HRAS', 'Gene', (87, 91))	('GNA11', 'Gene', (36, 41))	('mutations', 'Var', (47, 56))	('GNAQ', 'Gene', (21, 25))	('nevi', 'Phenotype', 'HP:0003764', (8, 12))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))
76482	25593912	Several studies have reported the presence of HRAS mutations in spitzoid tumors with benign behavior, and absence in clear-cut spitzoid melanomas.	('spitzoid tumors', 'Disease', (64, 79))	('mutations', 'Var', (51, 60))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (127, 145))	('spitzoid melanomas', 'Disease', (127, 145))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('HRAS', 'Gene', '3265', (46, 50))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('HRAS', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('spitzoid tumors', 'Disease', 'MESH:D009369', (64, 79))
76483	25593912	There is only one recent paper mentioning the occurrence of HRAS mutations in upto 10% (2/20 cases examined) of primary cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (120, 139))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (120, 139))	('cutaneous melanomas', 'Disease', (120, 139))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('HRAS', 'Gene', '3265', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('HRAS', 'Gene', (60, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('mutations', 'Var', (65, 74))
76494	25593912	Subsequently, it was found that these spitzoid-looking MBAITs, besides a BAP1 mutation, also contained a BRAF mutation.	('BAP1', 'Gene', '8314', (73, 77))	('BRAF', 'Gene', '673', (105, 109))	('mutation', 'Var', (78, 86))	('BRAF', 'Gene', (105, 109))	('BAP1', 'Gene', (73, 77))	('mutation', 'Var', (110, 118))	('spitzoid', 'Chemical', '-', (38, 46))
76498	25593912	In 8/9 cases (89%), a BRAFV600E mutation was found, and in 5/9 cases (55%), a somatic BAP1 mutation was present.	('BRAFV600E', 'Mutation', 'rs113488022', (22, 31))	('BAP1', 'Gene', (86, 90))	('BAP1', 'Gene', '8314', (86, 90))	('BRAFV600E', 'Var', (22, 31))
76503	25593912	In 11 cases BAP1 mutation analysis was performed with in 10 cases a loss of function mutation of BAP1, and in the remaining single case with wild-type BAP1, BAP1 protein expression was lost on the immunohistochemical level.	('loss of function', 'NegReg', (68, 84))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('BAP1', 'Gene', '8314', (97, 101))	('BAP1', 'Gene', (151, 155))	('BAP1', 'Gene', (157, 161))	('mutation', 'Var', (85, 93))	('BAP1', 'Gene', '8314', (12, 16))	('BAP1', 'Gene', (97, 101))	('BAP1', 'Gene', '8314', (157, 161))	('BAP1', 'Gene', (12, 16))	('BAP1', 'Gene', '8314', (151, 155))	('expression', 'MPA', (170, 180))
76512	25593912	Most of the MBAIT cases reported thus far do not seem to be tested for the presence of NRAS mutations, so the number of NRAS-mutated cases may be larger, and the genetic make-up of these BAP1-associated melanocytic lesions could be broader than currently thought.	('NRAS', 'Gene', '4893', (87, 91))	('BAP1', 'Gene', '8314', (187, 191))	('mutations', 'Var', (92, 101))	('NRAS', 'Gene', (120, 124))	('BAP1', 'Gene', (187, 191))	('NRAS', 'Gene', '4893', (120, 124))	('melanocytic lesions', 'Disease', (203, 222))	('NRAS', 'Gene', (87, 91))	('melanocytic lesions', 'Disease', 'MESH:D009508', (203, 222))
76515	25593912	The difference in outcome between the uveal lesions and the skin lesions with a BAP1 mutation may be related to the presence of different oncogenic driver mutations in uveal lesions, which harbor GNAQ or GNA11 mutations instead of BRAF or NRAS mutations.	('GNA11', 'Gene', (204, 209))	('GNAQ', 'Gene', '2776', (196, 200))	('BRAF', 'Gene', (231, 235))	('BRAF', 'Gene', '673', (231, 235))	('GNA11', 'Gene', '2767', (204, 209))	('skin lesions', 'Disease', (60, 72))	('uveal lesions', 'Disease', (168, 181))	('NRAS', 'Gene', (239, 243))	('GNAQ', 'Gene', (196, 200))	('mutation', 'Var', (85, 93))	('uveal lesions', 'Disease', (38, 51))	('uveal lesions', 'Disease', 'MESH:D014603', (38, 51))	('BAP1', 'Gene', '8314', (80, 84))	('uveal lesions', 'Disease', 'MESH:D014603', (168, 181))	('NRAS', 'Gene', '4893', (239, 243))	('skin lesions', 'Disease', 'MESH:D012871', (60, 72))	('BAP1', 'Gene', (80, 84))
76516	25593912	The suggested progression-promoting effect of mutated BAP1 is in line with the tumor suppressive function of intact BAP1 as a deubiquitylase required for efficient assembly of the homologous recombination (HR) factors BRCA1 and RAD51 after DNA double-strand breaks (DSBs).	('BAP1', 'Gene', (116, 120))	('progression-promoting', 'CPA', (14, 35))	('deubiquitylase', 'molecular_function', 'GO:0004843', ('126', '140'))	('tumor', 'Disease', (79, 84))	('mutated', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))	('BAP1', 'Gene', '8314', (54, 58))	('homologous recombination', 'biological_process', 'GO:0035825', ('180', '204'))	('RAD', 'biological_process', 'GO:1990116', ('228', '231'))	('BRCA1', 'Gene', '672', (218, 223))	('RAD51', 'Gene', (228, 233))	('BAP1', 'Gene', '8314', (116, 120))	('RAD51', 'Gene', '5888', (228, 233))	('BAP1', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('BRCA1', 'Gene', (218, 223))
76518	25593912	Defective HR and increased sensitivity to radiation due to BAP1 deficiency may, therefore, lead to genomic instability, a hallmark of cancer.	('increased', 'PosReg', (17, 26))	('lead to', 'Reg', (91, 98))	('hallmark of cancer', 'Disease', 'MESH:D009369', (122, 140))	('deficiency', 'Var', (64, 74))	('BAP1', 'Gene', (59, 63))	('Defective', 'NegReg', (0, 9))	('sensitivity', 'MPA', (27, 38))	('increased sensitivity to radiation', 'Phenotype', 'HP:0011133', (17, 51))	('genomic instability', 'CPA', (99, 118))	('hallmark of cancer', 'Disease', (122, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('BAP1', 'Gene', '8314', (59, 63))
76522	25593912	These two examined functions of BAP1 could explain tumor progression due to altered BAP1 expression.	('expression', 'MPA', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('BAP1', 'Gene', '8314', (32, 36))	('tumor', 'Disease', (51, 56))	('BAP1', 'Gene', '8314', (84, 88))	('altered', 'Var', (76, 83))	('BAP1', 'Gene', (32, 36))	('BAP1', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
76528	25593912	Mutation analysis of the BAP1 gene is difficult, since it is a complex gene and mutations can be present along all of the 17 exons of the gene.	('BAP1', 'Gene', '8314', (25, 29))	('BAP1', 'Gene', (25, 29))	('mutations', 'Var', (80, 89))
76529	25593912	A low tumor percentage due to the small size of a lesion or small size of the spitzoid component, or the presence of a lot of TILs, can all hamper BAP1 mutation analysis in this setting.	('BAP1', 'Gene', (147, 151))	('low tumor', 'Disease', 'MESH:D009800', (2, 11))	('low tumor', 'Disease', (2, 11))	('spitzoid', 'Chemical', '-', (78, 86))	('BAP1', 'Gene', '8314', (147, 151))	('hamper', 'NegReg', (140, 146))	('mutation', 'Var', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
76530	25593912	The third group of spitzoid lesions, those with kinase fusions has only recently been described.	('spitzoid lesions', 'Disease', (19, 35))	('spitzoid lesions', 'Disease', 'MESH:D051437', (19, 35))	('kinase fusions', 'Var', (48, 62))
76531	25593912	described the presence of alterations in ROS1, NTRK1, ALK, BRAF, and RET in, respectively, 17%, 16%, 10%, 5%, and 3% of spitzoid tumors.	('ALK', 'Gene', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('spitzoid tumors', 'Disease', 'MESH:D009369', (120, 135))	('RET', 'Gene', '5979', (69, 72))	('spitzoid tumors', 'Disease', (120, 135))	('ROS1', 'Gene', (41, 45))	('NTRK1', 'Gene', '4914', (47, 52))	('alterations', 'Var', (26, 37))	('ROS1', 'Gene', '6098', (41, 45))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('RET', 'Gene', (69, 72))	('ALK', 'Gene', '238', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NTRK1', 'Gene', (47, 52))
76536	25593912	FISH for copy number alterations did not meet the criteria for melanoma diagnosis in any case.	('copy number alterations', 'Var', (9, 32))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Disease', (63, 71))
76542	25593912	Another way of ALK activation is by gain-of-function point mutations, but these are less frequent than ALK rearrangements.	('gain-of-function', 'PosReg', (36, 52))	('ALK', 'Gene', (15, 18))	('ALK', 'Gene', '238', (103, 106))	('activation', 'PosReg', (19, 29))	('ALK', 'Gene', '238', (15, 18))	('ALK', 'Gene', (103, 106))	('point mutations', 'Var', (53, 68))
76546	25593912	ALK rearrangements leading to TPM3-ALK fusion have also been reported in anaplastic large cell lymphoma and papillary thyroid carcinoma, and result in a constitutive tyrosinase kinase activity, in this way causing tumor development.	('causing', 'Reg', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('TPM3', 'Gene', (30, 34))	('ALK', 'Gene', '238', (35, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (95, 103))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (73, 103))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (118, 135))	('ALK', 'Gene', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('cell lymphoma', 'Phenotype', 'HP:0012191', (90, 103))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (108, 135))	('tumor', 'Disease', (214, 219))	('lymphoma', 'Disease', (95, 103))	('papillary thyroid carcinoma', 'Disease', (108, 135))	('fusion', 'Var', (39, 45))	('ALK', 'Gene', '238', (0, 3))	('tyrosinase', 'Gene', (166, 176))	('lymphoma', 'Disease', 'MESH:D008223', (95, 103))	('TPM3', 'Gene', '7170', (30, 34))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (108, 135))	('rearrangements', 'Var', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('kinase activity', 'molecular_function', 'GO:0016301', ('177', '192'))	('ALK', 'Gene', (0, 3))	('tyrosinase', 'Gene', '7299', (166, 176))
76552	25593912	Both NRAS and BRAF mutations have been detected in CMN in a mutually exclusive pattern, and there is a genotype-phenotype correlation between the size of CMN and type of mutation.	('CMN', 'Phenotype', 'HP:0100814', (154, 157))	('NRAS', 'Gene', (5, 9))	('CMN', 'Phenotype', 'HP:0100814', (51, 54))	('mutations', 'Var', (19, 28))	('NRAS', 'Gene', '4893', (5, 9))	('BRAF', 'Gene', '673', (14, 18))	('detected', 'Reg', (39, 47))	('BRAF', 'Gene', (14, 18))
76553	25593912	Especially, large and giant CMN harbor somatic NRAS mutations ( >75%) in contrast to medium-sized CMN that are less frequently NRAS mutated and especially small CMN and acquired melanocytic nevi that frequently carry BRAFV600E mutations (up to 80% in acquired nevi).	('mutations', 'Var', (52, 61))	('CMN', 'Phenotype', 'HP:0100814', (161, 164))	('BRAFV600E', 'Var', (217, 226))	('CMN', 'Phenotype', 'HP:0100814', (28, 31))	('NRAS', 'Gene', (47, 51))	('nevi', 'Phenotype', 'HP:0003764', (190, 194))	('NRAS', 'Gene', (127, 131))	('NRAS', 'Gene', '4893', (47, 51))	('NRAS', 'Gene', '4893', (127, 131))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (178, 194))	('nevi', 'Phenotype', 'HP:0003764', (260, 264))	('BRAFV600E', 'Mutation', 'rs113488022', (217, 226))	('CMN', 'Phenotype', 'HP:0100814', (98, 101))
76556	25593912	showed that large and giant CMN contain NRASQ61 mutations (Q61R or Q61K) in up to 94.7% of cases.	('NRAS', 'Gene', (40, 44))	('Q61K', 'Mutation', 'rs121913254', (67, 71))	('Q61K', 'Var', (67, 71))	('CMN', 'Phenotype', 'HP:0100814', (28, 31))	('Q61R', 'Var', (59, 63))	('NRAS', 'Gene', '4893', (40, 44))	('Q61R', 'Mutation', 'rs11554290', (59, 63))
76557	25593912	In addition, using whole-exome sequencing, they found no other coding mutations in five large/giant CMN implying that at present NRAS mutations are the sole recurrent mutation in these lesions.	('NRAS', 'Gene', '4893', (129, 133))	('NRAS', 'Gene', (129, 133))	('mutations', 'Var', (134, 143))	('CMN', 'Phenotype', 'HP:0100814', (100, 103))
76558	25593912	Somatic NRAS mutations, therefore, seem to be sufficient to drive melanocytic proliferations in utero.	('melanocytic proliferations', 'Disease', 'MESH:D059545', (66, 92))	('melanocytic proliferations', 'Disease', (66, 92))	('NRAS', 'Gene', (8, 12))	('drive', 'PosReg', (60, 65))	('NRAS', 'Gene', '4893', (8, 12))	('mutations', 'Var', (13, 22))
76559	25593912	In addition, identical NRASQ61 mutations were recently demonstrated in multiple CMN samples from the same patient.	('mutations', 'Var', (31, 40))	('NRAS', 'Gene', (23, 27))	('patient', 'Species', '9606', (106, 113))	('CMN', 'Phenotype', 'HP:0100814', (80, 83))	('NRAS', 'Gene', '4893', (23, 27))
76560	25593912	This finding suggests that multiple CMN are clonal proliferations caused by a single, postzygotic NRAS mutation in a neuro-ectodermal precursor cell rather than de novo proliferations arising from different mutations.	('NRAS', 'Gene', '4893', (98, 102))	('NRAS', 'Gene', (98, 102))	('CMN', 'Phenotype', 'HP:0100814', (36, 39))	('mutation', 'Var', (103, 111))	('caused by', 'Reg', (66, 75))
76562	25593912	The osteocartilageneous structures of the face are neuro-ectodermal in origin and can be affected by mutations in components of the RAS/RAF/MEK/ERK pathway in patients with germline RASopathies who have characteristic facial features.	('RAF', 'Gene', '22882', (136, 139))	('MEK', 'Gene', (140, 143))	('RASopathies', 'Disease', (182, 193))	('mutations', 'Var', (101, 110))	('RASopathies', 'Disease', 'None', (182, 193))	('characteristic facial features', 'Phenotype', 'HP:0001999', (203, 233))	('ERK', 'molecular_function', 'GO:0004707', ('144', '147'))	('MEK', 'Gene', '5609', (140, 143))	('osteocartilageneous structures of', 'CPA', (4, 37))	('ERK', 'Gene', '5594', (144, 147))	('affected by', 'Reg', (89, 100))	('patients', 'Species', '9606', (159, 167))	('osteocartilageneous structures', 'Phenotype', 'HP:0030431', (4, 34))	('RAF', 'Gene', (136, 139))	('ERK', 'Gene', (144, 147))
76563	25593912	hypothesized that the occurrence of a postzygotic, somatic NRAS mutation in early neuro-ectodermal precursors might be responsible for the characteristic facial features in patients with CMN as well.	('mutation', 'Var', (64, 72))	('CMN', 'Disease', (187, 190))	('patients', 'Species', '9606', (173, 181))	('facial', 'Disease', (154, 160))	('responsible', 'Reg', (119, 130))	('CMN', 'Phenotype', 'HP:0100814', (187, 190))	('NRAS', 'Gene', (59, 63))	('characteristic facial features', 'Phenotype', 'HP:0001999', (139, 169))	('NRAS', 'Gene', '4893', (59, 63))
76569	25593912	Recently, it was shown that postzygotic, somatic NRAS mutations contribute to the pathogenesis of NCM.	('NRAS', 'Gene', '4893', (49, 53))	('pathogenesis', 'biological_process', 'GO:0009405', ('82', '94'))	('mutations', 'Var', (54, 63))	('contribute', 'Reg', (64, 74))	('NCM', 'Disease', (98, 101))	('NRAS', 'Gene', (49, 53))
76570	25593912	Identical, somatic NRASQ61 mutations were detected in multiple CMN as well as in the CNS melanocytic tumor in the same NCM patients.	('mutations', 'Var', (27, 36))	('melanocytic tumor', 'Disease', (89, 106))	('CMN', 'Disease', (63, 66))	('NRAS', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (123, 131))	('NRAS', 'Gene', '4893', (19, 23))	('CMN', 'Phenotype', 'HP:0100814', (63, 66))	('melanocytic tumor', 'Disease', 'MESH:D009508', (89, 106))	('detected', 'Reg', (42, 50))
76571	25593912	also detected a somatic NRASQ61 mutation in three non-melanocytic CNS tumors occurring in patients with CMN (including choroid plexus papilloma, neurocristic hamartoma, and meningioma).	('NRAS', 'Gene', '4893', (24, 28))	('non-melanocytic CNS tumors', 'Disease', 'MESH:D009508', (50, 76))	('papilloma', 'Phenotype', 'HP:0012740', (134, 143))	('neurocristic hamartoma', 'Disease', (145, 167))	('meningioma', 'Disease', 'MESH:D008577', (173, 183))	('non-melanocytic CNS tumors', 'Disease', (50, 76))	('neurocristic hamartoma', 'Disease', 'MESH:D006222', (145, 167))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('choroid plexus papilloma', 'Phenotype', 'HP:0200022', (119, 143))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NRAS', 'Gene', (24, 28))	('mutation', 'Var', (32, 40))	('choroid plexus papilloma', 'Disease', (119, 143))	('CMN', 'Phenotype', 'HP:0100814', (104, 107))	('patients', 'Species', '9606', (90, 98))	('meningioma', 'Disease', (173, 183))	('choroid plexus papilloma', 'Disease', 'MESH:D020288', (119, 143))	('meningioma', 'Phenotype', 'HP:0002858', (173, 183))	('hamartoma', 'Phenotype', 'HP:0010566', (158, 167))
76572	25593912	The presence of identical, somatic NRASQ61 mutations in both CMN and in CNS melanocytic (and non-melanocytic) neoplasms in the same patients suggests that these mutations occur in the developing neuro-ectoderm early during embryogenesis.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('CMN', 'Phenotype', 'HP:0100814', (61, 64))	('NRAS', 'Gene', (35, 39))	('embryogenesis', 'biological_process', 'GO:0009792', ('223', '236'))	('CNS melanocytic (and non-melanocytic) neoplasms', 'Disease', 'MESH:D009508', (72, 119))	('NRAS', 'Gene', '4893', (35, 39))	('embryogenesis', 'biological_process', 'GO:0009790', ('223', '236'))	('mutations', 'Var', (43, 52))	('embryogenesis', 'biological_process', 'GO:0009793', ('223', '236'))	('patients', 'Species', '9606', (132, 140))
76574	25593912	For instance, postzygotic, somatic RAS mutations (HRAS, KRAS) were recently shown to be present in distinct lesions of the keratinocytic epidermal nevus syndrome, a mosaic RASopathy characterized by the presence of epidermal nevi in association with extra-cutaneous abnormalities (CNS, ocular, skeletal, cardiovascular, and genitourinary system).	('cutaneous abnormalities', 'Phenotype', 'HP:0000951', (256, 279))	('ocular', 'Disease', (286, 292))	('keratinocytic epidermal nevus syndrome', 'Disease', (123, 161))	('epidermal nevus', 'Phenotype', 'HP:0010816', (137, 152))	('extra-cutaneous abnormalities', 'Disease', 'MESH:D010145', (250, 279))	('HRAS', 'Gene', '3265', (50, 54))	('mutations', 'Var', (39, 48))	('HRAS', 'Gene', (50, 54))	('RASopathy', 'Disease', 'None', (172, 181))	('nevi', 'Phenotype', 'HP:0003764', (225, 229))	('KRAS', 'Gene', '3845', (56, 60))	('RASopathy', 'Disease', (172, 181))	('keratinocytic epidermal nevus syndrome', 'Disease', 'MESH:C580062', (123, 161))	('KRAS', 'Gene', (56, 60))	('skeletal', 'Disease', (294, 302))	('genitourinary system', 'Phenotype', 'HP:0000119', (324, 344))	('nevus', 'Phenotype', 'HP:0003764', (147, 152))	('extra-cutaneous abnormalities', 'Disease', (250, 279))	('epidermal nevi', 'Phenotype', 'HP:0010816', (215, 229))
76576	25593912	A mouse model has demonstrated a role for postzygotic, early embryonic NRAS mutations in the pathogenesis of NCM.	('mutations', 'Var', (76, 85))	('pathogenesis', 'biological_process', 'GO:0009405', ('93', '105'))	('embryonic NRAS', 'Disease', (61, 75))	('NCM', 'Disease', (109, 112))	('embryonic NRAS', 'Disease', 'MESH:D009373', (61, 75))	('mouse', 'Species', '10090', (2, 7))
76578	25593912	NRAS mutations are a therapeutic target for treatment with MEK inhibitors.	('MEK', 'Gene', (59, 62))	('MEK', 'Gene', '5609', (59, 62))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
76583	25593912	In part of these cases, molecular analysis of genes in the MAPK pathway and CDKN2A mutation analysis can be useful in the differential diagnosis.	('CDKN2A', 'Gene', '1029', (76, 82))	('MAPK', 'Gene', '5594', (59, 63))	('MAPK', 'Gene', (59, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('mutation', 'Var', (83, 91))	('CDKN2A', 'Gene', (76, 82))
76588	25593912	While most cutaneous melanomas harbor a BRAF or NRAS mutation (see Table 1), CCS in approximately 75% have a t(12;22)(a13;q12) or less commonly a t(2;22)(q34;q12) translocation leading to the EWSR1/ATF1 or EWSR1/CREB1 fusion transcripts.	('BRAF', 'Gene', '673', (40, 44))	('NRAS', 'Gene', '4893', (48, 52))	('mutation', 'Var', (53, 61))	('EWSR1', 'Gene', (206, 211))	('BRAF', 'Gene', (40, 44))	('cutaneous melanomas', 'Disease', (11, 30))	('CCS', 'molecular_function', 'GO:0052728', ('77', '80'))	('ATF1', 'Gene', (198, 202))	('CREB1', 'Gene', (212, 217))	('t(2;22)(q34;q12) translocation', 'Var', (146, 176))	('EWSR1', 'Gene', '2130', (192, 197))	('fusion', 'Reg', (218, 224))	('t(2;22)(q34;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (146, 162))	('CREB1', 'Gene', '1385', (212, 217))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('ATF1', 'Gene', '466', (198, 202))	('NRAS', 'Gene', (48, 52))	('CCS', 'molecular_function', 'GO:0052727', ('77', '80'))	('EWSR1', 'Gene', '2130', (206, 211))	('EWSR1', 'Gene', (192, 197))	('t(12;22)(a13;q12', 'Var', (109, 125))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (11, 30))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (11, 30))	('CCS', 'molecular_function', 'GO:0034019', ('77', '80'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))
76590	25593912	They found the translocation in 78.6% of the CCSs but in none of the melanomas, whereas BRAF and NRAS mutations were present in, respectively, 51.6 and 12.9% of the melanomas and not in any of the CCSs.	('NRAS', 'Gene', (97, 101))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('CCSs', 'Disease', (45, 49))	('melanomas', 'Disease', (165, 174))	('BRAF', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (97, 101))	('BRAF', 'Gene', '673', (88, 92))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanomas', 'Disease', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('translocation', 'Var', (15, 28))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))
76593	25593912	Recently, we described two cases in which mutation analysis lead to the correct diagnosis of (dedifferentiated) metastatic melanoma.	('lead to', 'Reg', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mutation analysis', 'Var', (42, 59))	('melanoma', 'Disease', (123, 131))
76604	25593912	If the first melanoma was not a cutaneous melanoma, the problem can often be solved by mutation analysis since different types of melanomas have mutations in different genes of the MAPK pathway as mentioned in Table 1.	('melanoma', 'Disease', (42, 50))	('MAPK', 'Gene', '5594', (181, 185))	('mutations', 'Var', (145, 154))	('cutaneous melanoma', 'Disease', (32, 50))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (32, 50))	('melanomas', 'Disease', (130, 139))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('MAPK', 'molecular_function', 'GO:0004707', ('181', '185'))	('MAPK', 'Gene', (181, 185))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
76605	25593912	If the primary melanoma was a cutaneous melanoma, mutation analysis of NRAS and BRAF can be of help, but since these mutations are hotspot mutations, it is of limited use.	('BRAF', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('hot', 'Gene', (131, 134))	('hot', 'Gene', '137872', (131, 134))	('NRAS', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('NRAS', 'Gene', '4893', (71, 75))	('primary melanoma', 'Disease', 'MESH:D008545', (7, 23))	('primary melanoma', 'Disease', (7, 23))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('BRAF', 'Gene', '673', (80, 84))	('cutaneous melanoma', 'Disease', (30, 48))	('mutation', 'Var', (50, 58))
76607	25593912	CDKN2A mutation analysis can sometimes be helpful as we have published before, and is illustrated by the case above, to differentiate between a new primary and a melanoma metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma metastasis', 'Disease', (162, 181))	('mutation', 'Var', (7, 15))	('CDKN2A', 'Gene', (0, 6))	('melanoma metastasis', 'Disease', 'MESH:D009362', (162, 181))	('CDKN2A', 'Gene', '1029', (0, 6))
76608	25593912	The advantage of using CDKN2A mutations for clonality is that CDKN2A mutations are unique mutations instead of hot spot mutations.	('mutations', 'Var', (69, 78))	('hot', 'Gene', (111, 114))	('CDKN2A', 'Gene', (23, 29))	('CDKN2A', 'Gene', (62, 68))	('CDKN2A', 'Gene', '1029', (23, 29))	('hot', 'Gene', '137872', (111, 114))	('CDKN2A', 'Gene', '1029', (62, 68))
76610	25593912	Metastatic melanoma treatment got a great impulse after the discovery that the (hot spot) mutations in genes involved in the MAPK pathway in melanoma, as well as in GNAQ and GNA11, which proved targetable on the protein level by specific inhibitors.	('GNAQ', 'Gene', '2776', (165, 169))	('mutations', 'Var', (90, 99))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('MAPK', 'Gene', '5594', (125, 129))	('GNA11', 'Gene', (174, 179))	('GNAQ', 'Gene', (165, 169))	('MAPK', 'molecular_function', 'GO:0004707', ('125', '129'))	('Metastatic melanoma', 'Disease', 'MESH:D008545', (0, 19))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('hot', 'Gene', (80, 83))	('GNA11', 'Gene', '2767', (174, 179))	('hot', 'Gene', '137872', (80, 83))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('MAPK', 'Gene', (125, 129))	('Metastatic melanoma', 'Disease', (0, 19))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanoma', 'Disease', (11, 19))
76611	25593912	GNAQ and GNA11 mutations are mainly present in uveal and primary brain melanomas, and combinations of MEK inhibitors with either PI3K or mTOR inhibitors have shown efficacy in GNAQ- and GNA11-mutant melanomas.	('MEK', 'Gene', '5609', (102, 105))	('GNA11', 'Gene', '2767', (186, 191))	('combinations', 'Interaction', (86, 98))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('mTOR', 'Gene', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('GNA11', 'Gene', '2767', (9, 14))	('MEK', 'Gene', (102, 105))	('brain melanomas', 'Disease', (65, 80))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('mTOR', 'Gene', '2475', (137, 141))	('melanomas', 'Disease', 'MESH:D008545', (199, 208))	('GNA11', 'Gene', (186, 191))	('melanomas', 'Disease', (199, 208))	('GNAQ', 'Gene', '2776', (176, 180))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('GNAQ', 'Gene', (176, 180))	('GNA11', 'Gene', (9, 14))	('melanomas', 'Disease', (71, 80))	('GNAQ', 'Gene', '2776', (0, 4))	('GNAQ', 'Gene', (0, 4))	('brain melanomas', 'Disease', 'MESH:D008545', (65, 80))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))
76614	25593912	An overview of the most frequent mutations in the distinct melanoma subtypes and their frequencies, as well as the different therapeutic options, are depicted in Table 1.	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('mutations', 'Var', (33, 42))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
76623	25593912	of 7.5-29% in the BRAF and NRAS mutation status of the metastatic melanoma when compared to the primary.	('NRAS', 'Gene', '4893', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('BRAF', 'Gene', (18, 22))	('BRAF', 'Gene', '673', (18, 22))	('NRAS', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
76631	25593912	We can agree with this especially in selected cases, when the primary location is likely to be associated with a BRAF mutation and when no mutation in other targetable genes (like NRAS or KIT) have been identified.	('BRAF', 'Gene', '673', (113, 117))	('NRAS', 'Gene', (180, 184))	('BRAF', 'Gene', (113, 117))	('KIT', 'molecular_function', 'GO:0005020', ('188', '191'))	('NRAS', 'Gene', '4893', (180, 184))	('mutation', 'Var', (118, 126))	('associated', 'Reg', (95, 105))
76633	25593912	The most frequent BRAF mutation is a mononucleotide point mutation in codon 600 (CTG) of exon 15, c.1799T >A (p.(Val600Glu)), in which the valine (V) of codon 600 is replaced by glutamine (E).	('valine', 'Chemical', 'MESH:D014633', (139, 145))	('mononucleotide', 'Chemical', '-', (37, 51))	('p.(Val600Glu)', 'Mutation', 'rs113488022', (110, 123))	('CTG', 'Chemical', '-', (81, 84))	('c.1799T >A', 'Var', (98, 108))	('c.1799T >A', 'Mutation', 'rs113488022', (98, 108))	('BRAF', 'Gene', '673', (18, 22))	('glutamine', 'Chemical', 'MESH:D005973', (178, 187))	('BRAF', 'Gene', (18, 22))
76635	25593912	In a recent study in which 1112 primary and metastatic melanomas from different locations were analyzed for BRAF mutations (774 skin melanomas, 111 acral melanomas, 26 mucosal melanomas, 23 uveal melanomas, 1 leptomeningeal melanoma, and 177 metastases), 44.9% of the cases harbored a BRAF mutation: in 75.4% of the cases, mutations were BRAFV600E either deriving from the c.1799T >A or from a c.1799 1800delinsAA mutation.	('melanomas', 'Disease', 'MESH:D008545', (196, 205))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('metastases', 'Disease', (242, 252))	('acral melanomas', 'Disease', (148, 163))	('melanomas', 'Disease', (196, 205))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('mutations', 'Var', (113, 122))	('BRAF', 'Gene', '673', (285, 289))	('skin melanomas', 'Disease', (128, 142))	('melanomas', 'Disease', 'MESH:D008545', (154, 163))	('BRAF', 'Gene', (285, 289))	('uveal melanomas', 'Disease', (190, 205))	('skin melanomas', 'Disease', 'MESH:D008545', (128, 142))	('uveal melanomas', 'Phenotype', 'HP:0007716', (190, 205))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('melanomas', 'Disease', (154, 163))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('c.1799 1800delinsAA', 'Mutation', 'c.17991800delinsAA', (394, 413))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanomas', 'Disease', (176, 185))	('BRAF', 'Gene', '673', (108, 112))	('leptomeningeal melanoma', 'Disease', (209, 232))	('melanomas', 'Disease', (55, 64))	('BRAF', 'Gene', (338, 342))	('BRAF', 'Gene', '673', (338, 342))	('melanomas', 'Phenotype', 'HP:0002861', (196, 205))	('BRAF', 'Gene', (108, 112))	('mutations', 'Var', (323, 332))	('c.1799 1800delinsAA', 'Var', (394, 413))	('BRAFV600E', 'Mutation', 'rs113488022', (338, 347))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('mucosal melanomas', 'Disease', 'MESH:D008545', (168, 185))	('acral melanomas', 'Disease', 'MESH:D008545', (148, 163))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('melanomas', 'Disease', (133, 142))	('acral melanomas', 'Phenotype', 'HP:0012060', (148, 163))	('melanomas', 'Disease', 'MESH:D008545', (55, 64))	('mucosal melanomas', 'Disease', (168, 185))	('uveal melanomas', 'Disease', 'MESH:C536494', (190, 205))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('metastases', 'Disease', 'MESH:D009362', (242, 252))	('c.1799T >A', 'Var', (373, 383))	('c.1799T >A', 'Mutation', 'rs113488022', (373, 383))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (209, 232))
76637	25593912	BRAF exon 11 mutations were also observed in a low percentage (0.4%).	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('BRAF', 'Gene', '673', (0, 4))
76638	25593912	There are several studies that have reported that all melanomas with BRAF codon 600 mutations are sensitive to BRAF inhibitors, such as vemurafenib (Zelboraf , Roche Molecular Systems Inc.) and dabrafenib (GSK2118436).	('dabrafenib', 'Chemical', 'MESH:C561627', (194, 204))	('GSK', 'molecular_function', 'GO:0050321', ('206', '209'))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('codon', 'Var', (74, 79))	('Zelboraf', 'Chemical', 'MESH:D000077484', (149, 157))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mutations', 'Var', (84, 93))	('BRAF', 'Gene', (111, 115))	('vemurafenib', 'Chemical', 'MESH:D000077484', (136, 147))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', '673', (111, 115))	('melanomas', 'Disease', (54, 63))	('BRAF', 'Gene', (69, 73))	('GSK2118436', 'Chemical', 'MESH:C561627', (206, 216))
76640	25593912	A test must be able to detect BRAF mutations that have been reported to be insensitive to BRAF-inhibitor treatment, like the kinase-dead mutation BRAFD594.	('BRAF', 'Gene', (90, 94))	('BRAF', 'Gene', (146, 150))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('BRAF', 'Gene', '673', (90, 94))	('BRAF', 'Gene', '673', (146, 150))	('mutations', 'Var', (35, 44))
76644	30630828	Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFi+/-MEKi.	('V600E', 'Mutation', 'rs113488022', (110, 115))	('V600K', 'Mutation', 'rs121913227', (182, 187))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('MEK', 'Gene', (228, 231))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('V600K', 'Var', (120, 125))	('V600E', 'Var', (110, 115))	('V600K', 'Var', (78, 83))	('BRAF', 'Gene', '673', (220, 224))	('V600E', 'Mutation', 'rs113488022', (68, 73))	('BRAF', 'Gene', (220, 224))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('V600K', 'Var', (182, 187))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('V600E', 'Var', (68, 73))	('V600K', 'Mutation', 'rs121913227', (120, 125))	('BRAF', 'Gene', '673', (105, 109))	('melanomas', 'Disease', (126, 135))	('BRAF', 'Gene', (105, 109))	('MEK', 'Gene', '5609', (228, 231))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('V600K', 'Mutation', 'rs121913227', (78, 83))	('melanoma', 'Disease', (96, 104))
76647	30630828	Baseline tissue and clinical outcome with BRAFi+/-MEKi were studied in 93 patients (78 V600E, 15 V600K).	('BRAF', 'Gene', '673', (42, 46))	('V600K', 'Var', (97, 102))	('V600E', 'Var', (87, 92))	('patients', 'Species', '9606', (74, 82))	('V600K', 'Mutation', 'rs121913227', (97, 102))	('BRAF', 'Gene', (42, 46))	('V600E', 'Mutation', 'rs113488022', (87, 92))	('MEK', 'Gene', (50, 53))	('MEK', 'Gene', '5609', (50, 53))
76648	30630828	V600K patients had numerically less tumour regression (median -31% vs -52%, p=0.154) and shorter progression-free survival (PFS, median 5.7 vs 7.1 months, p=0.15) compared with V600E.	('less', 'NegReg', (31, 35))	('V600K', 'Mutation', 'rs121913227', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('V600E', 'Mutation', 'rs113488022', (177, 182))	('progression-free survival', 'CPA', (97, 122))	('patients', 'Species', '9606', (6, 14))	('V600K', 'Var', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('shorter', 'NegReg', (89, 96))
76649	30630828	V600K melanomas had lower expression of the ERK pathway feedback regulator DUSP6, confirmed with TCGA data (116 V600E, 17 V600K).	('expression', 'MPA', (26, 36))	('V600K', 'Mutation', 'rs121913227', (0, 5))	('lower', 'NegReg', (20, 25))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('ERK', 'Gene', '5594', (44, 47))	('melanomas', 'Disease', (6, 15))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('ERK', 'Gene', (44, 47))	('DUSP6', 'Gene', (75, 80))	('DUSP6', 'Gene', '1848', (75, 80))	('V600K', 'Var', (122, 127))	('V600K', 'Var', (0, 5))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('V600K', 'Mutation', 'rs121913227', (122, 127))
76650	30630828	Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E.	('expression', 'MPA', (40, 50))	('V600K', 'Mutation', 'rs121913227', (24, 29))	('ERK', 'Gene', '5594', (54, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('ERK', 'molecular_function', 'GO:0004707', ('54', '57'))	('lower', 'NegReg', (34, 39))	('expression', 'MPA', (69, 79))	('ERK', 'Gene', (54, 57))	('PI3K-AKT genes', 'Gene', (83, 97))	('higher', 'PosReg', (62, 68))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('V600K', 'Var', (24, 29))
76651	30630828	Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumour suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (74, 83))	('tumour', 'Disease', (98, 104))	('V600K', 'Var', (39, 44))	('PIK3R1', 'Gene', '5295', (87, 93))	('PIK3R1', 'Gene', (87, 93))	('V600K', 'Mutation', 'rs121913227', (39, 44))
76652	30630828	In patients treated with anti-PD-1, V600K (n=19) had superior outcomes than V600E (n=84), including response rate (53% vs 29%, p=0.059), PFS (median 19 vs 2.7 months, p=0.049) and overall survival (20.4 vs 11.7 months, p=0.081).	('V600K', 'Mutation', 'rs121913227', (36, 41))	('V600E', 'Mutation', 'rs113488022', (76, 81))	('PFS', 'MPA', (137, 140))	('anti-PD-1', 'Gene', (25, 34))	('V600K', 'Var', (36, 41))	('overall survival', 'CPA', (180, 196))	('patients', 'Species', '9606', (3, 11))	('response', 'CPA', (100, 108))
76653	30630828	BRAF V600K melanomas appear to benefit less from BRAFi+/-MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways.	('ERK', 'Gene', (110, 113))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('MEK', 'Gene', '5609', (57, 60))	('V600E', 'Var', (67, 72))	('less', 'NegReg', (39, 43))	('V600E', 'Mutation', 'rs113488022', (67, 72))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('BRAF', 'Gene', '673', (0, 4))	('melanomas', 'Disease', (11, 20))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (0, 4))	('V600K', 'Mutation', 'rs121913227', (5, 10))	('ERK', 'Gene', '5594', (110, 113))	('BRAF', 'Gene', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('MEK', 'Gene', (57, 60))
76655	30630828	The identification of BRAF driver mutations in melanoma has led to the development of specific inhibitors targeting the extracellular-signal-regulated kinase (ERK) pathway, which have high response rates and improve survival in patients with BRAF-mutant advanced melanoma and those at high risk of recurrence.	('improve', 'PosReg', (208, 215))	('melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('melanoma', 'Disease', (263, 271))	('ERK', 'Gene', '5594', (159, 162))	('ERK', 'molecular_function', 'GO:0004707', ('159', '162'))	('survival', 'MPA', (216, 224))	('patients', 'Species', '9606', (228, 236))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('extracellular-signal-regulated kinase', 'Gene', (120, 157))	('ERK', 'Gene', (159, 162))	('BRAF', 'Gene', '673', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (263, 271))	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (242, 246))	('BRAF', 'Gene', (242, 246))	('extracellular-signal-regulated kinase', 'Gene', '5594', (120, 157))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('mutations', 'Var', (34, 43))	('extracellular', 'cellular_component', 'GO:0005576', ('120', '133'))
76656	30630828	BRAF mutations are present in approximately 40% of cutaneous melanomas and the majority occur at codon 600 (90%).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (51, 70))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (51, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('BRAF', 'Gene', '673', (0, 4))	('cutaneous melanomas', 'Disease', (51, 70))	('BRAF', 'Gene', (0, 4))
76657	30630828	Among these, 70-80% are V600E (codon GTG>GAG), 20-30% are V600K (GTG>AAG), and rarer mutations including V600R (GTG>AGG), V600D (GTG>GAT), V600E2 (GTG>GAA), V600G (GTG>GGG), V600M (GTG>ATG), V600A (GTG>GCG) and V600L (GTG>TTG) .	('V600E', 'Var', (24, 29))	('GAT', 'Gene', (133, 136))	('AAG', 'Gene', '4350', (69, 72))	('V600L', 'Var', (211, 216))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('V600G', 'Var', (157, 162))	('V600L', 'Mutation', 'p.V600L', (211, 216))	('V600K', 'Mutation', 'rs121913227', (58, 63))	('V600G', 'Mutation', 'p.V600G', (157, 162))	('GAA', 'Gene', (151, 154))	('GCG', 'Gene', '2641', (202, 205))	('AAG', 'Gene', (69, 72))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('V600R', 'Mutation', 'p.V600R', (105, 110))	('V600A', 'Var', (191, 196))	('V600M', 'Mutation', 'p.V600M', (174, 179))	('codon GTG>GAG', 'Mutation', 'rs113488022', (31, 44))	('GCG', 'Gene', (202, 205))	('GAA', 'Gene', '2548', (151, 154))	('V600M', 'Var', (174, 179))	('V600D', 'Var', (122, 127))	('V600R', 'Var', (105, 110))	('GAT', 'Gene', '10249', (133, 136))	('V600K', 'Var', (58, 63))	('V600D', 'Mutation', 'p.V600D', (122, 127))	('V600A', 'Mutation', 'p.V600A', (191, 196))
76658	30630828	Previous studies have shown that V600E and V600K BRAF-mutant metastatic melanoma have distinct clinicopathologic features, suggesting different etiology.	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('V600E', 'Var', (33, 38))	('V600K', 'Var', (43, 48))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))	('V600K', 'Mutation', 'rs121913227', (43, 48))
76659	30630828	V600K melanomas occur more frequently in older people, in the head and neck region, and are associated with chronic sun damage.	('V600K', 'Mutation', 'rs121913227', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('people', 'Species', '9606', (47, 53))	('V600K', 'Var', (0, 5))	('sun damage', 'Phenotype', 'HP:0000992', (116, 126))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('associated', 'Reg', (92, 102))	('neck', 'cellular_component', 'GO:0044326', ('71', '75'))
76660	30630828	Furthermore, even though individual phase III targeted therapy trials have not performed a direct comparison between V600E and V600K-mutant melanomas, in three separate trials V600K melanomas had numerically lower response rate and shorter median progression-free survival with BRAFi compared to V600E melanomas, and two pooled analyses of BRAFi+/-MEKi showed shorter progression-free survival in multivariate analysis.	('V600E', 'Mutation', 'rs113488022', (117, 122))	('melanomas', 'Phenotype', 'HP:0002861', (302, 311))	('V600K', 'Var', (176, 181))	('V600K', 'Mutation', 'rs121913227', (127, 132))	('melanomas', 'Disease', (140, 149))	('MEK', 'Gene', (348, 351))	('BRAF', 'Gene', '673', (278, 282))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('BRAF', 'Gene', (278, 282))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('progression-free survival', 'CPA', (368, 393))	('BRAF', 'Gene', (340, 344))	('BRAF', 'Gene', '673', (340, 344))	('melanomas', 'Phenotype', 'HP:0002861', (140, 149))	('shorter', 'NegReg', (232, 239))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('lower', 'NegReg', (208, 213))	('V600E', 'Mutation', 'rs113488022', (296, 301))	('progression-free survival', 'CPA', (247, 272))	('response', 'MPA', (214, 222))	('melanomas', 'Disease', 'MESH:D008545', (302, 311))	('shorter', 'NegReg', (360, 367))	('V600K', 'Mutation', 'rs121913227', (176, 181))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanomas', 'Disease', (302, 311))	('melanomas', 'Disease', 'MESH:D008545', (182, 191))	('melanomas', 'Disease', (182, 191))	('MEK', 'Gene', '5609', (348, 351))	('melanomas', 'Disease', 'MESH:D008545', (140, 149))
76662	30630828	In this study, we sought to identify potential mechanisms for these apparent clinicopathologic differences, by comparing gene expression and mutational profiles of V600E and V600K melanomas from patients treated with BRAFi+/-MEKi, validated on the Skin Cutaneous Melanoma TCGA (The Cancer Genome Atlas) dataset.	('V600K', 'Mutation', 'rs121913227', (174, 179))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (253, 271))	('Cutaneous Melanoma', 'Disease', 'MESH:C562393', (253, 271))	('V600E', 'Mutation', 'rs113488022', (164, 169))	('BRAF', 'Gene', (217, 221))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('patients', 'Species', '9606', (195, 203))	('Melanoma', 'Phenotype', 'HP:0002861', (263, 271))	('V600K', 'Var', (174, 179))	('MEK', 'Gene', '5609', (225, 228))	('Cutaneous Melanoma', 'Disease', (253, 271))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('V600E', 'Var', (164, 169))	('MEK', 'Gene', (225, 228))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('BRAF', 'Gene', '673', (217, 221))	('Cancer', 'Phenotype', 'HP:0002664', (282, 288))	('melanomas', 'Disease', (180, 189))
76664	30630828	Consecutive patients with V600E/K BRAF-mutant metastatic melanoma enrolled on clinical trials of BRAF+/-MEK inhibitors at two Melanoma Institute Australia treatment facilities (The Poche Centre, North Sydney and Westmead Hospital - ethical approval from the Sydney Local Health District Human Research Ethics Committee, Protocol Number X15-0454 and HREC/11/RPAH/444) between July/2009 and July/2013 were included (BRAFi+/-MEKi cohort).	('BRAF', 'Gene', (414, 418))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('V600E', 'SUBSTITUTION', 'None', (26, 31))	('patients', 'Species', '9606', (12, 20))	('Melanoma', 'Disease', 'MESH:D008545', (126, 134))	('N', 'Chemical', 'MESH:D009584', (329, 330))	('BRAF', 'Gene', (97, 101))	('BRAF', 'Gene', '673', (414, 418))	('Melanoma', 'Disease', (126, 134))	('MEK', 'Gene', '5609', (422, 425))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('MEK', 'Gene', '5609', (104, 107))	('Melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('MEK', 'Gene', (422, 425))	('MEK', 'Gene', (104, 107))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))	('V600E', 'Var', (26, 31))	('Human', 'Species', '9606', (287, 292))	('BRAF', 'Gene', '673', (97, 101))
76668	30630828	An independent cohort of V600E/K BRAF-mutant metastatic melanoma patients treated with anti-PD-1 immunotherapy (pembrolizumab or nivolumab) were examined to explore response to anti-PD-1 immunotherapy by genotype (Immunotherapy cohort).	('BRAF', 'Gene', '673', (33, 37))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('BRAF', 'Gene', (33, 37))	('V600E', 'Var', (25, 30))	('V600E', 'SUBSTITUTION', 'None', (25, 30))	('pembrolizumab', 'Disease', (112, 125))	('pembrolizumab', 'Disease', 'None', (112, 125))	('patients', 'Species', '9606', (65, 73))
76676	30630828	A pan-cancer 88-gene Next-generation sequencing (NGS) panel to detect DNA coding mutations was performed on all 93 samples as has been previously described.	('DNA coding', 'Gene', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (81, 90))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('cancer', 'Disease', (6, 12))
76679	30630828	The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) RNA sequencing (RNAseq) and whole exome sequencing (WES) datasets for BRAF V600E (N=116) and V600K (n=17) samples were downloaded on 6th of February 2017 using R package TCGAbiolinks from the GDC portal.	('BRAF', 'Gene', (132, 136))	('V600K', 'Var', (155, 160))	('SKCM', 'Disease', (56, 60))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('N', 'Chemical', 'MESH:D009584', (144, 145))	('skin cutaneous melanoma', 'Disease', (31, 54))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('V600K', 'Mutation', 'rs121913227', (155, 160))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('V600E', 'Mutation', 'rs113488022', (137, 142))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('SKCM', 'Disease', 'MESH:C562393', (56, 60))	('BRAF', 'Gene', '673', (132, 136))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))	('V600E', 'Var', (137, 142))
76682	30630828	Sample with more than 2000 mutations were filtered out and a Mann-Whitney test was performed between V600E and V600K samples.	('V600K', 'Var', (111, 116))	('V600K', 'Mutation', 'rs121913227', (111, 116))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('V600E', 'Var', (101, 106))
76684	30630828	On both the NanoString platform and the TCGA data, a differential expression analysis was performed between the V600E and V600K cohorts and a gene was defined as differentially expressed when its FDR-adjusted p-value was less than 0.05.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('V600K', 'Var', (122, 127))	('V600E', 'Var', (112, 117))	('V600K', 'Mutation', 'rs121913227', (122, 127))
76686	30630828	On both the TCGA and the NGS datasets, the Mann-Whitney U test was performed to compare the mutational load between V600E and V600K samples.	('V600K', 'Mutation', 'rs121913227', (126, 131))	('V600E', 'Mutation', 'rs113488022', (116, 121))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('V600K', 'Var', (126, 131))	('V600E', 'Var', (116, 121))
76689	30630828	Ninety-three consecutive patients with V600E (n=78) or V600K (n=15) BRAF-mutant metastatic melanoma treated with BRAFi+/-MEKi on clinical trials at two Melanoma Institute Australia treatment facilities (The Poche Centre, North Sydney and Westmead Hospital) were examined (Table 1).	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('V600E', 'Var', (39, 44))	('V600K', 'Mutation', 'rs121913227', (55, 60))	('Melanoma', 'Disease', (152, 160))	('Melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('V600K', 'Var', (55, 60))	('BRAF', 'Gene', '673', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('BRAF', 'Gene', (68, 72))	('patients', 'Species', '9606', (25, 33))	('MEK', 'Gene', '5609', (121, 124))	('N', 'Chemical', 'MESH:D009584', (221, 222))	('BRAF', 'Gene', '673', (113, 117))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('BRAF', 'Gene', (113, 117))	('MEK', 'Gene', (121, 124))	('Melanoma', 'Disease', 'MESH:D008545', (152, 160))
76691	30630828	Although not statistically different, likely due to small sample size for the V600K group, the median age was numerically higher in V600K compared to V600E melanoma patients (med 58 versus 56.5 years-old).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('higher', 'PosReg', (122, 128))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('V600K', 'Var', (132, 137))	('V600E', 'Mutation', 'rs113488022', (150, 155))	('patients', 'Species', '9606', (165, 173))	('V600K', 'Mutation', 'rs121913227', (132, 137))	('V600K', 'Mutation', 'rs121913227', (78, 83))
76693	30630828	Only 20% of the V600E patients were treated with combination BRAF+MEK inhibitors, while 33% of the V600K patients were treated with combination therapy.	('V600K', 'Mutation', 'rs121913227', (99, 104))	('patients', 'Species', '9606', (105, 113))	('BRAF', 'Gene', '673', (61, 65))	('V600E', 'Mutation', 'rs113488022', (16, 21))	('patients', 'Species', '9606', (22, 30))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))	('BRAF', 'Gene', (61, 65))	('V600E', 'Var', (16, 21))
76694	30630828	Few direct comparisons of response rates and survival between V600E and V600K melanomas have been performed previously, however phase III clinical trials and two pooled analyses suggest that V600K melanomas may have a lower response rate and shorter progression-free survival with BRAFi+/-MEKi compared to V600E melanomas, and yet have similar overall survival.	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (312, 321))	('shorter', 'NegReg', (242, 249))	('response', 'MPA', (224, 232))	('lower', 'NegReg', (218, 223))	('V600E', 'Mutation', 'rs113488022', (306, 311))	('melanomas', 'Disease', (312, 321))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('V600K', 'Var', (191, 196))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('MEK', 'Gene', '5609', (289, 292))	('progression-free survival', 'CPA', (250, 275))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanomas', 'Phenotype', 'HP:0002861', (312, 321))	('MEK', 'Gene', (289, 292))	('melanomas', 'Disease', (78, 87))	('BRAF', 'Gene', '673', (281, 285))	('V600K', 'Mutation', 'rs121913227', (72, 77))	('melanomas', 'Disease', 'MESH:D008545', (197, 206))	('BRAF', 'Gene', (281, 285))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('V600K', 'Mutation', 'rs121913227', (191, 196))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('melanomas', 'Disease', (197, 206))
76695	30630828	In this study which included a small number of V600K melanomas, despite the fact more patients with V600K melanoma were treated with combination BRAF+MEK inhibitors, patients with V600K melanoma had a numerically lower median degree of response to therapy (-31% vs -52%, p=0.15) and a lower rate of complete response (0% vs 10%) (Figure 1.A).	('melanomas', 'Disease', (53, 62))	('V600K', 'Mutation', 'rs121913227', (47, 52))	('BRAF', 'Gene', (145, 149))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('V600K', 'Mutation', 'rs121913227', (180, 185))	('patients', 'Species', '9606', (86, 94))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('V600K', 'Mutation', 'rs121913227', (100, 105))	('V600K', 'Var', (47, 52))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('V600K', 'Var', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('V600K', 'Var', (100, 105))	('MEK', 'Gene', '5609', (150, 153))	('melanoma', 'Disease', (186, 194))	('lower', 'NegReg', (213, 218))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (106, 114))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('MEK', 'Gene', (150, 153))	('patients', 'Species', '9606', (166, 174))	('BRAF', 'Gene', '673', (145, 149))
76696	30630828	While not statistically significant, V600K patients also had a median 5.7 months progression-free survival and no patient remained progression-free beyond 9 months, while median progression-free survival was 7.1 months in V600E patients and approximately 20% remained progression-free at 5 years (Figure 1.B).	('patient', 'Species', '9606', (43, 50))	('patients', 'Species', '9606', (43, 51))	('V600K', 'Var', (37, 42))	('patients', 'Species', '9606', (228, 236))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('V600K', 'Mutation', 'rs121913227', (37, 42))	('V600E', 'Var', (222, 227))	('patient', 'Species', '9606', (114, 121))	('patient', 'Species', '9606', (228, 235))
76697	30630828	To investigate potential mechanisms for these clinicopathologic differences, including a possible smaller benefit with BRAFi+/-MEKi in V600K melanomas, we sought to identify differences in gene expression between both groups.	('smaller', 'NegReg', (98, 105))	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('V600K', 'Var', (135, 140))	('MEK', 'Gene', (127, 130))	('MEK', 'Gene', '5609', (127, 130))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('V600K', 'Mutation', 'rs121913227', (135, 140))	('melanomas', 'Disease', (141, 150))	('gene expression', 'biological_process', 'GO:0010467', ('189', '204'))
76698	30630828	Nanostring data revealed that expression of DUSP6 (Dual Specificity Phosphatase 6), a transcriptional target of the ERK pathway involved in feedback regulation and reflective of ERK activation, was the most significant differentiated gene, with lower expression in V600K melanoma (p=0.024, Figure 2.A).	('V600K', 'Var', (265, 270))	('ERK', 'Gene', (116, 119))	('ERK', 'Gene', (178, 181))	('DUSP6', 'Gene', '1848', (44, 49))	('Dual Specificity Phosphatase 6', 'Gene', '1848', (51, 81))	('DUSP6', 'Gene', (44, 49))	('Dual Specificity Phosphatase 6', 'Gene', (51, 81))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('V600K', 'Mutation', 'rs121913227', (265, 270))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('Phosphatase', 'molecular_function', 'GO:0016791', ('68', '79'))	('lower', 'NegReg', (245, 250))	('expression', 'MPA', (251, 261))	('ERK', 'molecular_function', 'GO:0004707', ('178', '181'))	('ERK', 'Gene', '5594', (116, 119))	('ERK', 'Gene', '5594', (178, 181))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Disease', (271, 279))	('ERK', 'molecular_function', 'GO:0004707', ('116', '119'))
76699	30630828	This was confirmed using RNA sequencing data from the TCGA, including V600E (n=116) and V600K (n=17) tumors (n=133, p=0.003; Figure 2.B).	('V600E', 'Var', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('V600K', 'Var', (88, 93))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('V600K', 'Mutation', 'rs121913227', (88, 93))	('tumors', 'Disease', (101, 107))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
76700	30630828	Moreover, besides DUSP6, other genes related to transcriptional output of MEK/ERK pathway including ETV4, DUSP4 and SPRY2 were within the top 30 differentially expressed genes, with higher expression in V600E melanomas, while PIK3CB expression was higher in V600K melanomas (Supplementary table 1).	('expression', 'MPA', (233, 243))	('higher', 'PosReg', (182, 188))	('melanomas', 'Disease', 'MESH:D008545', (209, 218))	('DUSP4', 'Gene', (106, 111))	('V600E', 'Mutation', 'rs113488022', (203, 208))	('melanomas', 'Disease', 'MESH:D008545', (264, 273))	('V600K', 'Mutation', 'rs121913227', (258, 263))	('DUSP6', 'Gene', '1848', (18, 23))	('melanomas', 'Disease', (209, 218))	('ERK', 'molecular_function', 'GO:0004707', ('78', '81'))	('ETV4', 'Gene', (100, 104))	('melanomas', 'Disease', (264, 273))	('DUSP6', 'Gene', (18, 23))	('MEK', 'Gene', '5609', (74, 77))	('V600E', 'Var', (203, 208))	('PIK3CB', 'Gene', (226, 232))	('PIK3CB', 'Gene', '5291', (226, 232))	('ERK', 'Gene', '5594', (78, 81))	('ETV4', 'Gene', '2118', (100, 104))	('melanomas', 'Phenotype', 'HP:0002861', (209, 218))	('V600K', 'Var', (258, 263))	('melanomas', 'Phenotype', 'HP:0002861', (264, 273))	('SPRY2', 'Gene', '10253', (116, 121))	('MEK', 'Gene', (74, 77))	('DUSP4', 'Gene', '1846', (106, 111))	('SPRY2', 'Gene', (116, 121))	('expression', 'MPA', (189, 199))	('ERK', 'Gene', (78, 81))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('higher', 'PosReg', (248, 254))
76702	30630828	Interestingly, the expression of ERK pathway genes was lower in V600K melanomas (p=0.0003), while the expression of PI3K-AKT pathway genes, was significantly higher in V600K melanoma compared to V600E (p=0.005) (Supplementary Figure 1).	('V600K', 'Mutation', 'rs121913227', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('higher', 'PosReg', (158, 164))	('V600E', 'Mutation', 'rs113488022', (195, 200))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))	('V600K', 'Var', (168, 173))	('PI3K', 'molecular_function', 'GO:0016303', ('116', '120'))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('expression', 'MPA', (19, 29))	('ERK', 'Gene', '5594', (33, 36))	('V600K', 'Var', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('PI3K-AKT pathway', 'Pathway', (116, 132))	('ERK', 'Gene', (33, 36))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('expression', 'MPA', (102, 112))	('V600K', 'Mutation', 'rs121913227', (168, 173))	('lower', 'NegReg', (55, 60))	('melanomas', 'Disease', (70, 79))	('ERK', 'molecular_function', 'GO:0004707', ('33', '36'))
76703	30630828	These data support the hypothesis that V600K melanomas are less dependent on the ERK pathway and more dependent on alternative pathways, specifically the PI3K-AKT pathway.	('dependent', 'Reg', (102, 111))	('ERK', 'Gene', '5594', (81, 84))	('PI3K-AKT pathway', 'Pathway', (154, 170))	('ERK', 'Gene', (81, 84))	('ERK', 'molecular_function', 'GO:0004707', ('81', '84'))	('PI3K', 'molecular_function', 'GO:0016303', ('154', '158'))	('V600K', 'Var', (39, 44))	('melanomas', 'Disease', (45, 54))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('V600K', 'Mutation', 'rs121913227', (39, 44))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
76704	30630828	In an attempt to explore whether mutational data may explain differences in both pathway expression and the clinical phenotype of V600E and V600K melanoma, targeted NGS data of genomic DNA were examined.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('melanoma', 'Disease', (146, 154))	('V600K', 'Mutation', 'rs121913227', (140, 145))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('V600E', 'Mutation', 'rs113488022', (130, 135))	('V600K', 'Var', (140, 145))	('V600E', 'Var', (130, 135))
76705	30630828	As expected given the clinical phenotype, V600K melanomas had a numerically but insignificantly higher mutational load in our BRAFi+/-MEKi cohort using the 88-gene panel (p=0.1375) (Figure 3.A), however, whole exome sequencing data from the TCGA cohort revealed a significantly higher mutational load in V600K melanomas (p=0.0003) (Figure 3.B).	('melanomas', 'Phenotype', 'HP:0002861', (310, 319))	('MEK', 'Gene', '5609', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('MEK', 'Gene', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('V600K', 'Mutation', 'rs121913227', (304, 309))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('melanomas', 'Disease', 'MESH:D008545', (310, 319))	('V600K', 'Mutation', 'rs121913227', (42, 47))	('melanomas', 'Disease', (48, 57))	('melanomas', 'Disease', (310, 319))	('mutational load', 'MPA', (285, 300))	('mutational load', 'MPA', (103, 118))	('V600K', 'Var', (304, 309))	('higher', 'PosReg', (278, 284))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('higher', 'PosReg', (96, 102))	('V600K', 'Var', (42, 47))
76706	30630828	The genes that were more frequently mutated in V600K melanoma on NGS fitted mainly into three groups: PI3K-AKT pathway genes (PIK3R1), tumor suppressor genes (SMARCA4, NF2, RB1, FBXW7, TP53 and APC) and proto-oncogenes (KIT, RET and KRAS) (Supplementary Figure 2 and Supplementary table 2).	('V600K', 'Mutation', 'rs121913227', (47, 52))	('KIT', 'molecular_function', 'GO:0005020', ('220', '223'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('RB1', 'Gene', (173, 176))	('SMARCA4', 'Gene', (159, 166))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('135', '151'))	('PIK3R1', 'Gene', '5295', (126, 132))	('RET', 'Gene', (225, 228))	('KRAS', 'Gene', '3845', (233, 237))	('FBXW7', 'Gene', '55294', (178, 183))	('V600K', 'Var', (47, 52))	('KIT', 'Gene', '3815', (220, 223))	('RB1', 'Gene', '5925', (173, 176))	('KRAS', 'Gene', (233, 237))	('APC', 'Gene', '324', (194, 197))	('TP53', 'Gene', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('tumor', 'Disease', (135, 140))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('SMARCA4', 'Gene', '6597', (159, 166))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('135', '151'))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('PIK3R1', 'Gene', (126, 132))	('APC', 'cellular_component', 'GO:0005680', ('194', '197'))	('NF2', 'Gene', '4771', (168, 171))	('RET', 'Gene', '5979', (225, 228))	('FBXW7', 'Gene', (178, 183))	('APC', 'Gene', (194, 197))	('KIT', 'Gene', (220, 223))	('PI3K', 'molecular_function', 'GO:0016303', ('102', '106'))	('TP53', 'Gene', '7157', (185, 189))	('NF2', 'Gene', (168, 171))
76707	30630828	Given prior associations with mutational load, immune expression and immunotherapy response, we then looked at the expression of immune genes, by checking iPRES signature in V600E versus V600K mutant melanoma in the TCGA dataset, but no significant difference was detected between these two genotypes (Supplementary Figure 4).	('V600E', 'Var', (174, 179))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('V600K', 'Var', (187, 192))	('melanoma', 'Disease', (200, 208))	('V600K', 'Mutation', 'rs121913227', (187, 192))	('V600E', 'Mutation', 'rs113488022', (174, 179))
76708	30630828	We further explored whether there was a subset of V600E melanomas that behave like V600K melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', (89, 98))	('V600E', 'Var', (50, 55))	('V600E', 'Mutation', 'rs113488022', (50, 55))	('V600K', 'Mutation', 'rs121913227', (83, 88))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', (56, 65))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
76709	30630828	Analyses of DUSP6 expression, mutational load, age and response to therapy did not identify a clear subset of V600E melanomas behaving like V600K melanoma, that is, having lower DUSP6 expression, with higher mutation burden, in older patients with less response to BRAFi+/-MEKi (Supplementary Figure 5).	('V600E', 'Mutation', 'rs113488022', (110, 115))	('melanomas', 'Disease', (116, 125))	('lower', 'NegReg', (172, 177))	('DUSP6', 'Gene', '1848', (12, 17))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('expression', 'MPA', (184, 194))	('DUSP6', 'Gene', '1848', (178, 183))	('V600K', 'Mutation', 'rs121913227', (140, 145))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('V600E', 'Var', (110, 115))	('DUSP6', 'Gene', (12, 17))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('patients', 'Species', '9606', (234, 242))	('DUSP6', 'Gene', (178, 183))	('MEK', 'Gene', '5609', (273, 276))	('BRAF', 'Gene', (265, 269))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('MEK', 'Gene', (273, 276))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('BRAF', 'Gene', '673', (265, 269))
76710	30630828	Finally, based on the higher mutational load seen in V600K melanomas, we hypothesized that they should respond better to immunotherapy than V600E melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('higher', 'PosReg', (22, 28))	('mutational load', 'MPA', (29, 44))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('melanomas', 'Disease', (59, 68))	('V600K', 'Var', (53, 58))	('V600E', 'Mutation', 'rs113488022', (140, 145))	('V600K', 'Mutation', 'rs121913227', (53, 58))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
76711	30630828	We examined an independent cohort of 103 BRAF V600E/K patients treated with anti-PD-1 immunotherapy (V600E, n=84; V600K, n=19) (Table 2).	('V600E', 'Mutation', 'rs113488022', (101, 106))	('V600E', 'Mutation', 'rs113488022', (46, 51))	('V600K', 'Var', (114, 119))	('patients', 'Species', '9606', (54, 62))	('V600E', 'Var', (101, 106))	('V600E', 'Var', (46, 51))	('V600E', 'SUBSTITUTION', 'None', (46, 51))	('BRAF', 'Gene', '673', (41, 45))	('V600K', 'Mutation', 'rs121913227', (114, 119))	('V600E', 'SUBSTITUTION', 'None', (101, 106))	('BRAF', 'Gene', (41, 45))
76712	30630828	Patients with V600K were significantly older than those with V600E melanoma (61.5 vs 50 year-old, p=0.0358) and were more often male (84% vs 51%, p=0.01) (Table 2).	('V600K', 'Mutation', 'rs121913227', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('V600E', 'Mutation', 'rs113488022', (61, 66))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('Patients', 'Species', '9606', (0, 8))	('V600K', 'Var', (14, 19))
76714	30630828	With a median 31.7 months follow-up, there was a trend toward a higher response rate to immunotherapy in patients with V600K compared to V600E melanomas (53% vs 29%, P=0.059) (Figure 4.A).	('patients', 'Species', '9606', (105, 113))	('V600K', 'Mutation', 'rs121913227', (119, 124))	('higher', 'PosReg', (64, 70))	('melanomas', 'Disease', (143, 152))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('V600K', 'Var', (119, 124))	('V600E', 'Mutation', 'rs113488022', (137, 142))	('melanomas', 'Disease', 'MESH:D008545', (143, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('V600E', 'Var', (137, 142))
76715	30630828	Moreover, progression-free survival was longer in V600K melanoma patients (median 19 vs 2.7 months, p=0.049) (Figure 4.B), while the prolonged overall survival for V600K did not reach statistical significance (20.4 vs 11.7 months, p=0.081) (Figure 4.C).	('V600K', 'Mutation', 'rs121913227', (50, 55))	('progression-free survival', 'CPA', (10, 35))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('V600K', 'Mutation', 'rs121913227', (164, 169))	('melanoma', 'Disease', (56, 64))	('longer', 'PosReg', (40, 46))	('V600K', 'Var', (50, 55))	('patients', 'Species', '9606', (65, 73))
76716	30630828	This study demonstrates that V600E and V600K BRAF-mutant melanomas are biologically distinct subtypes of melanoma, not only having different clinical phenotypes, but also different molecular features and differing responses to systemic therapies.	('V600E', 'Mutation', 'rs113488022', (29, 34))	('melanomas', 'Disease', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('melanoma', 'Disease', (57, 65))	('V600K', 'Var', (39, 44))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('V600E', 'Var', (29, 34))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('V600K', 'Mutation', 'rs121913227', (39, 44))
76717	30630828	V600K melanomas, most frequent in older patients with chronic sun damage, have less activation of the ERK pathway than V600E melanomas, potentially explaining their relative resistance to BRAFi+/-MEKi, but in contrast, they have a higher mutational load and respond better to immunotherapy.	('sun damage', 'Phenotype', 'HP:0000992', (62, 72))	('higher', 'PosReg', (231, 237))	('MEK', 'Gene', '5609', (196, 199))	('V600K', 'Var', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('MEK', 'Gene', (196, 199))	('BRAF', 'Gene', '673', (188, 192))	('ERK', 'molecular_function', 'GO:0004707', ('102', '105'))	('BRAF', 'Gene', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('less', 'NegReg', (79, 83))	('mutational load', 'MPA', (238, 253))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('ERK', 'Gene', '5594', (102, 105))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('V600K', 'Mutation', 'rs121913227', (0, 5))	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('patients', 'Species', '9606', (40, 48))	('melanomas', 'Disease', (6, 15))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('melanomas', 'Disease', (125, 134))	('ERK', 'Gene', (102, 105))
76719	30630828	BRAF V600 mutations induce RAS-independent activation of the ERK pathway, with consequent dysregulation of ERK signaling (high expression and activation of ERK), driving cell proliferation and survival.	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (156, 159))	('activation', 'PosReg', (43, 53))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('ERK', 'Gene', (61, 64))	('dysregulation', 'MPA', (90, 103))	('ERK', 'Gene', (107, 110))	('driving', 'PosReg', (162, 169))	('V600 mutations', 'Var', (5, 19))	('survival', 'CPA', (193, 201))	('ERK', 'molecular_function', 'GO:0004707', ('156', '159'))	('ERK', 'Gene', '5594', (156, 159))	('activation', 'PosReg', (142, 152))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('ERK', 'Gene', '5594', (61, 64))	('ERK', 'molecular_function', 'GO:0004707', ('107', '110'))	('cell proliferation', 'biological_process', 'GO:0008283', ('170', '188'))	('cell proliferation', 'CPA', (170, 188))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
76721	30630828	In this study we demonstrated in pre-treatment biopsies from melanoma patients that the negative feedback regulator of the ERK pathway, DUSP6, is expressed higher in V600E melanomas compared to V600K.	('V600E', 'Var', (166, 171))	('melanomas', 'Disease', (172, 181))	('ERK', 'Gene', (123, 126))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('patients', 'Species', '9606', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('ERK', 'molecular_function', 'GO:0004707', ('123', '126'))	('V600K', 'Mutation', 'rs121913227', (194, 199))	('DUSP6', 'Gene', '1848', (136, 141))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('higher', 'PosReg', (156, 162))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('DUSP6', 'Gene', (136, 141))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('V600E', 'Mutation', 'rs113488022', (166, 171))	('melanoma', 'Disease', (172, 180))	('pre', 'molecular_function', 'GO:0003904', ('33', '36'))	('ERK', 'Gene', '5594', (123, 126))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))
76722	30630828	This relative increase in ERK pathway activation, confirmed using gene set expression analysis from the TCGA dataset, is consistent with cell line data demonstrating higher fold BRAF-kinase activity in V600E mutant cell lines compared to V600K.	('BRAF', 'Gene', '673', (178, 182))	('ERK', 'Gene', '5594', (26, 29))	('V600E', 'Var', (202, 207))	('kinase activity', 'molecular_function', 'GO:0016301', ('183', '198'))	('ERK', 'Gene', (26, 29))	('V600E', 'Mutation', 'rs113488022', (202, 207))	('BRAF', 'Gene', (178, 182))	('activation', 'PosReg', (38, 48))	('V600K', 'Mutation', 'rs121913227', (238, 243))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('increase', 'PosReg', (14, 22))
76723	30630828	Furthermore, we demonstrated that an alternative proliferation and survival pathway, the PI3K-AKT pathway, is more activated in V600K melanoma.	('PI3K', 'molecular_function', 'GO:0016303', ('89', '93'))	('V600K', 'Var', (128, 133))	('PI3K-AKT pathway', 'Pathway', (89, 105))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('V600K', 'Mutation', 'rs121913227', (128, 133))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('activated', 'PosReg', (115, 124))
76724	30630828	Together these data suggest differential activity of pathway signaling in V600E and V600K melanomas, potentially explaining the relative resistance of V600K melanoma to BRAFi+/-MEKi despite similar potency for inhibition with dabrafenib (IC50 0.65 V600E and 0.5 V600K, respectively).	('melanoma', 'Disease', (90, 98))	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('V600K', 'Mutation', 'rs121913227', (151, 156))	('V600K', 'Mutation', 'rs121913227', (84, 89))	('V600E', 'Mutation', 'rs113488022', (74, 79))	('melanomas', 'Disease', 'MESH:D008545', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('MEK', 'Gene', '5609', (177, 180))	('melanoma', 'Disease', (157, 165))	('melanomas', 'Disease', (90, 99))	('V600E', 'Mutation', 'rs113488022', (248, 253))	('V600K', 'Var', (151, 156))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('signaling', 'biological_process', 'GO:0023052', ('61', '70'))	('V600K', 'Var', (84, 89))	('MEK', 'Gene', (177, 180))	('V600E', 'Var', (74, 79))	('melanomas', 'Phenotype', 'HP:0002861', (90, 99))	('pathway signaling', 'Pathway', (53, 70))	('V600K', 'Mutation', 'rs121913227', (262, 267))	('dabrafenib', 'Chemical', 'MESH:C561627', (226, 236))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('activity', 'MPA', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
76725	30630828	This possible disadvantage of V600K melanoma with BRAFi+/-MEKi may be seen in the clinic, with this data set as well as clinical trials suggesting that V600K patients have lower response rate and shorter progression-free survival compared to V600E patients.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('BRAF', 'Gene', (50, 54))	('shorter', 'NegReg', (196, 203))	('melanoma', 'Disease', (36, 44))	('MEK', 'Gene', (58, 61))	('V600K', 'Var', (152, 157))	('V600E', 'Mutation', 'rs113488022', (242, 247))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('MEK', 'Gene', '5609', (58, 61))	('lower', 'NegReg', (172, 177))	('V600K', 'Mutation', 'rs121913227', (152, 157))	('response', 'MPA', (178, 186))	('progression-free survival', 'CPA', (204, 229))	('V600K', 'Var', (30, 35))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (248, 256))	('BRAF', 'Gene', '673', (50, 54))	('V600K', 'Mutation', 'rs121913227', (30, 35))
76727	30630828	While V600 BRAF-mutant melanomas typically occur in younger patients whose tumors arise on skin without chronic sun-induced damage, these associations are driven by the V600E genotype, which is the most frequent (70-80% BRAF-mutant melanomas).	('tumors arise on skin', 'Phenotype', 'HP:0008069', (75, 95))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('BRAF', 'Gene', '673', (220, 224))	('melanomas', 'Disease', 'MESH:D008545', (232, 241))	('BRAF', 'Gene', (220, 224))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('melanomas', 'Disease', (232, 241))	('V600E', 'Mutation', 'rs113488022', (169, 174))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('V600', 'Var', (6, 10))	('tumors', 'Disease', (75, 81))	('melanomas', 'Disease', (23, 32))	('melanomas', 'Phenotype', 'HP:0002861', (232, 241))	('V600E', 'Var', (169, 174))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
76728	30630828	In contrast, V600K melanomas (20-30%) typically occur in older patients, on the head and neck, and in chronic sun damaged skin.	('V600K', 'Mutation', 'rs121913227', (13, 18))	('sun damage', 'Phenotype', 'HP:0000992', (110, 120))	('melanomas', 'Disease', 'MESH:D008545', (19, 28))	('occur', 'Reg', (48, 53))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('sun damaged skin', 'Phenotype', 'HP:0000992', (110, 126))	('patients', 'Species', '9606', (63, 71))	('V600K', 'Var', (13, 18))	('neck', 'cellular_component', 'GO:0044326', ('89', '93'))	('melanomas', 'Disease', (19, 28))
76729	30630828	Consistent with these clinicopathologic differences, our data demonstrate a higher mutational load in V600K melanomas, and that several groups of genes, notably tumor suppressor genes and proto-oncogenes, are more frequently mutated in this genotype.	('melanomas', 'Disease', 'MESH:D008545', (108, 117))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('161', '177'))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mutational load', 'MPA', (83, 98))	('V600K', 'Var', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('melanomas', 'Disease', (108, 117))	('higher', 'PosReg', (76, 82))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('tumor', 'Disease', (161, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('161', '177'))	('V600K', 'Mutation', 'rs121913227', (102, 107))
76732	30630828	Despite the large number of melanoma tissue samples, a limitation of this study is the size of the V600K cohort, which diminished the power to analyze associations between the molecular findings and clinical outcomes.	('melanoma', 'Disease', (28, 36))	('associations', 'Interaction', (151, 163))	('V600K', 'Mutation', 'rs121913227', (99, 104))	('diminished', 'NegReg', (119, 129))	('V600K', 'Var', (99, 104))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
76733	30630828	We did not see a difference in the expression of immune markers in TCGA cohort either, as differently from our BRAFi+/-MEKi cohort where we have macro-dissected the tumors, TCGA analyzed the highest tumor content areas, and may have missed the tumor-stroma interface.	('MEK', 'Gene', (119, 122))	('tumor-stroma', 'Disease', (244, 256))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor-stroma', 'Disease', 'MESH:D009369', (244, 256))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (199, 204))	('highest', 'PosReg', (191, 198))	('tumors', 'Disease', (165, 171))	('TCGA', 'Var', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', (165, 170))	('MEK', 'Gene', '5609', (119, 122))	('tumor', 'Disease', (244, 249))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
76735	30630828	Prospective samples from stage III and IV patients have been collected in order to further characterize immune signatures and correlate these with response to immunotherapy in the adjuvant and metastatic settings, and the respective mutant BRAF genotype.	('mutant', 'Var', (233, 239))	('BRAF', 'Gene', (240, 244))	('BRAF', 'Gene', '673', (240, 244))	('patients', 'Species', '9606', (42, 50))
76738	30630828	Our data, along with the published BRAF+/-MEKi clinical trials, suggest that V600K melanomas may be best served with adjuvant immunotherapy.	('BRAF', 'Gene', (35, 39))	('MEK', 'Gene', (42, 45))	('MEK', 'Gene', '5609', (42, 45))	('melanomas', 'Disease', (83, 92))	('V600K', 'Var', (77, 82))	('BRAF', 'Gene', '673', (35, 39))	('melanomas', 'Disease', 'MESH:D008545', (83, 92))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))	('V600K', 'Mutation', 'rs121913227', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
76739	30630828	In addition to exploring clinical trial data in the metastatic setting, data from the adjuvant clinical trials should also be explored by BRAF mutation genotype.	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('mutation', 'Var', (143, 151))
76740	30630828	If our results are validated, the best treatment for patients with BRAF mutant melanoma may well differ based on V600E and V600K genotypes.	('melanoma', 'Disease', (79, 87))	('BRAF', 'Gene', '673', (67, 71))	('patients', 'Species', '9606', (53, 61))	('mutant', 'Var', (72, 78))	('V600K', 'Mutation', 'rs121913227', (123, 128))	('BRAF', 'Gene', (67, 71))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('V600E', 'Var', (113, 118))	('V600K', 'Var', (123, 128))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
76741	30630828	The differences in gene expression and mutational load between V600E and V600K BRAF-mutant melanomas provide translational data that explain clinically meaningful differences in response to BRAFi+/-MEKi and immunotherapy, and provide further rationale for the selection of one therapy over the other.	('V600E', 'Var', (63, 68))	('melanomas', 'Disease', (91, 100))	('BRAF', 'Gene', (190, 194))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('V600K', 'Var', (73, 78))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))	('BRAF', 'Gene', '673', (79, 83))	('differences', 'Reg', (4, 15))	('V600K', 'Mutation', 'rs121913227', (73, 78))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('BRAF', 'Gene', (79, 83))	('MEK', 'Gene', (198, 201))	('MEK', 'Gene', '5609', (198, 201))	('BRAF', 'Gene', '673', (190, 194))
76743	30630828	This study demonstrates that V600E and V600K BRAF-mutant melanomas are biologically distinct subtypes, not only having different clinical phenotypes, but also different molecular features and differing responses to systemic therapies.	('V600E', 'Mutation', 'rs113488022', (29, 34))	('melanomas', 'Disease', (57, 66))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('V600K', 'Var', (39, 44))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (45, 49))	('V600E', 'Var', (29, 34))	('V600K', 'Mutation', 'rs121913227', (39, 44))
76744	30630828	V600K melanomas, most frequent in older patients with chronic sun damage, have less activation of the ERK pathway than V600E melanomas, what might explain their potential lower benefit with BRAFi -/+ MEKi inhibitors, but in contrast, they have a higher mutational load and respond better to immunotherapy.	('sun damage', 'Phenotype', 'HP:0000992', (62, 72))	('higher', 'PosReg', (246, 252))	('V600K', 'Var', (0, 5))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (125, 134))	('BRAF', 'Gene', '673', (190, 194))	('BRAF', 'Gene', (190, 194))	('ERK', 'molecular_function', 'GO:0004707', ('102', '105'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('less', 'NegReg', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('ERK', 'Gene', '5594', (102, 105))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('MEK', 'Gene', '5609', (200, 203))	('V600K', 'Mutation', 'rs121913227', (0, 5))	('melanomas', 'Disease', 'MESH:D008545', (125, 134))	('mutational load', 'MPA', (253, 268))	('patients', 'Species', '9606', (40, 48))	('melanomas', 'Disease', (6, 15))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('melanomas', 'Disease', (125, 134))	('ERK', 'Gene', (102, 105))	('MEK', 'Gene', (200, 203))
76745	30630828	The differences in gene expression and mutational load between V600E and V600K BRAF-mutant melanomas provide mechanistic data that translate to clinically significant differences in response to BRAFi -/+ MEKi inhibitors and immunotherapy.	('V600E', 'Var', (63, 68))	('BRAF', 'Gene', '673', (194, 198))	('melanomas', 'Disease', (91, 100))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('BRAF', 'Gene', (194, 198))	('V600K', 'Var', (73, 78))	('differences', 'Reg', (167, 178))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))	('BRAF', 'Gene', '673', (79, 83))	('differences', 'Reg', (4, 15))	('MEK', 'Gene', (204, 207))	('V600K', 'Mutation', 'rs121913227', (73, 78))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('BRAF', 'Gene', (79, 83))	('response', 'MPA', (182, 190))	('MEK', 'Gene', '5609', (204, 207))
76753	29028110	Since the early 1990s, a major advance in the management of patients with cutaneous melanoma has involved the technique of lymphatic mapping and sentinel lymph node (SLN) biopsy; this is now routinely used as a staging procedure for patients with T1b, T2, T3, and T4 (according to the eighth edition of the American Joint Committee on Cancer [AJCC] Cancer Staging Manual) primary cutaneous melanomas and clinically negative regional lymph nodes in most melanoma treatment centers throughout the world.	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('Cancer', 'Disease', 'MESH:D009369', (349, 355))	('melanoma', 'Phenotype', 'HP:0002861', (390, 398))	('melanoma', 'Disease', (390, 398))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (380, 399))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (380, 399))	('melanoma', 'Phenotype', 'HP:0002861', (453, 461))	('melanoma', 'Disease', (453, 461))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (380, 398))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (380, 398))	('patients', 'Species', '9606', (60, 68))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cutaneous melanomas', 'Disease', (380, 399))	('melanoma', 'Disease', 'MESH:D008545', (390, 398))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('Cancer', 'Disease', (335, 341))	('melanoma', 'Disease', (84, 92))	('Cancer', 'Phenotype', 'HP:0002664', (349, 355))	('patients', 'Species', '9606', (233, 241))	('melanoma', 'Disease', 'MESH:D008545', (453, 461))	('Cancer', 'Disease', (349, 355))	('melanomas', 'Phenotype', 'HP:0002861', (390, 399))	('T1b', 'Var', (247, 250))	('Cancer', 'Disease', 'MESH:D009369', (335, 341))	('cutaneous melanoma', 'Disease', (74, 92))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 92))
76757	29028110	Two major new classes of effective systemic therapeutic agents are now in widespread clinical use: immunotherapies (eg, checkpoint inhibitors against cytotoxic T lymphocyte antigen 4 [CTLA-4] and/or programmed death 1 [PD-1]), which enhance the natural host antitumor immune response; and molecularly targeted antitumor therapies (eg, B-Raf proto-oncogene, serine/threonine kinase [BRAF] inhibitors alone or in combination with mitogen-activated protein kinase-kinase [MEK] inhibitors for the approximately 40%-50% of patients with BRAF V600-mutant melanoma).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('mitogen-activated protein kinase-kinase', 'Gene', (428, 467))	('BRAF', 'Gene', (382, 386))	('PD-1', 'Gene', (219, 223))	('BRAF', 'Gene', '673', (532, 536))	('PD-1', 'Gene', '5133', (219, 223))	('tumor', 'Disease', (314, 319))	('programmed death 1', 'Gene', (199, 217))	('BRAF', 'Gene', '673', (382, 386))	('BRAF', 'Gene', (532, 536))	('lymphocyte antigen', 'molecular_function', 'GO:0005557', ('162', '180'))	('melanoma', 'Phenotype', 'HP:0002861', (549, 557))	('CTLA-4', 'Gene', '1493', (184, 190))	('melanoma', 'Disease', (549, 557))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('CTLA-4', 'Gene', (184, 190))	('protein', 'cellular_component', 'GO:0003675', ('446', '453'))	('immune response', 'biological_process', 'GO:0006955', ('268', '283'))	('patients', 'Species', '9606', (518, 526))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', (262, 267))	('cytotoxic T lymphocyte antigen 4', 'Gene', '1493', (150, 182))	('V600-mutant', 'Var', (537, 548))	('mitogen-activated protein kinase-kinase', 'Gene', '5609', (428, 467))	('melanoma', 'Disease', 'MESH:D008545', (549, 557))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('MEK', 'Gene', '5609', (469, 472))	('cytotoxic T lymphocyte antigen 4', 'Gene', (150, 182))	('MEK', 'Gene', (469, 472))	('programmed death 1', 'Gene', '5133', (199, 217))
76782	29028110	Microsatellites should not be included in the measurement of tumor thickness.	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Microsatellites', 'Var', (0, 15))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
76796	29028110	For these survival curves, patients with T1 melanomas were included if they had clinical (c) or pathological (p) T1 N0 melanomas, but patients with T2 through T4 melanomas were included only if they had pN0 melanoma (ie, no tumor-containing SLNs and no evidence of microsatellites, satellites, or in-transit metastases at diagnosis or after initial treatment).	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('patients', 'Species', '9606', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanomas', 'Disease', (162, 171))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanomas', 'Disease', (44, 53))	('pN0', 'Var', (203, 206))	('patients', 'Species', '9606', (27, 35))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('T1 melanomas', 'Disease', 'MESH:D008545', (41, 53))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('tumor', 'Disease', (224, 229))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('T1 melanomas', 'Disease', (41, 53))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('melanomas', 'Disease', 'MESH:D008545', (119, 128))	('metastases', 'Disease', 'MESH:D009362', (308, 318))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('melanomas', 'Disease', (119, 128))	('metastases', 'Disease', (308, 318))
76801	29028110	MSS for all T subcategories were notably higher than those reported in the seventh edition, in which the 10-year MSS rates were 93% and 39% for patients with T1a N0 and T4b N0 melanomas, respectively, or in the sixth edition.	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('MSS', 'MPA', (113, 116))	('T4b N0', 'Var', (169, 175))	('patients', 'Species', '9606', (144, 152))	('melanomas', 'Disease', (176, 185))	('higher', 'PosReg', (41, 47))	('T1a N0', 'Var', (158, 164))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
76813	29028110	In the eighth edition, as in the seventh edition, the absence or presence of ulceration is designated "a" or "b," respectively, in each T subcategory (eg, T2a and T2b correspond to nonulcerated and ulcerated T2 melanomas, respectively) (Table 2).	('ulcerated T2 melanomas', 'Disease', (198, 220))	('T2b', 'Var', (163, 166))	('melanomas', 'Phenotype', 'HP:0002861', (211, 220))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('ulcerated T2 melanomas', 'Disease', 'MESH:D014456', (198, 220))	('nonulcerated', 'Disease', (181, 193))	('T2a', 'Var', (155, 158))
76819	29028110	For example, the 5-year and 10-year MSS rates are 93% and 88%, respectively, for patients with T2bpN0 primary cutaneous melanomas and 94% and 88%, respectively, for those with T3apN0 primary cutaneous melanomas.	('T2bpN0', 'Var', (95, 101))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (110, 129))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (110, 129))	('patients', 'Species', '9606', (81, 89))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (191, 210))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (191, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (191, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('cutaneous melanomas', 'Disease', (110, 129))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('cutaneous melanomas', 'Disease', (191, 210))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))
76827	29028110	Although it is not included in the T1 subcategory criteria, mitotic activity in T1 melanomas also has been associated with an increased risk of SLN metastasis.	('mitotic activity', 'Var', (60, 76))	('SLN', 'Disease', (144, 147))	('T1 melanomas', 'Disease', (80, 92))	('T1 melanomas', 'Disease', 'MESH:D008545', (80, 92))	('associated with', 'Reg', (107, 122))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanomas', 'Phenotype', 'HP:0002861', (83, 92))
76828	29028110	The N category documents metastatic disease both in regional lymph nodes and in non-nodal locoregional sites (ie, microsatellites, satellites, and in-transit metastases).	('metastases', 'Disease', 'MESH:D009362', (158, 168))	('metastases', 'Disease', (158, 168))	('microsatellites', 'Var', (114, 129))	('metastatic disease', 'Disease', (25, 43))
76835	29028110	If microsatellites, satellites, or in-transit metastases are present, then patients are assigned to an N "c" subcategory according to the number of tumor-involved regional nodes, regardless of whether they are clinically occult or clinically detected: N1c, N2c or N3c if 0, 1 or >=2 regional nodes contain tumor, respectively (Table 3).	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('N3c', 'Var', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('metastases', 'Disease', (46, 56))	('N2c', 'Var', (257, 260))	('tumor', 'Disease', (148, 153))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', (306, 311))	('N1c', 'Var', (252, 255))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('microsatellites', 'Var', (3, 18))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
76841	29028110	The presence and absence of microsatellite, satellite, or intransit metastases, regardless of the number of such lesions, are components of the N category in the eighth edition (Table 3).	('metastases', 'Disease', (68, 78))	('microsatellite', 'Var', (28, 42))	('satellite', 'CPA', (44, 53))	('metastases', 'Disease', 'MESH:D009362', (68, 78))
76844	29028110	Microsatellites have classically been defined as microscopic cutaneous and/or subcutaneous metastases found adjacent or deep to a primary melanoma on pathological examination (see discussion below).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('metastases', 'Disease', (91, 101))	('primary melanoma', 'Disease', (130, 146))	('primary melanoma', 'Disease', 'MESH:D008545', (130, 146))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('Microsatellites', 'Var', (0, 15))
76849	29028110	Microsatellites, satellites, and in-transit metastases have been shown to portend a relatively poor prognosis.	('satellites', 'CPA', (17, 27))	('metastases', 'Disease', 'MESH:D009362', (44, 54))	('Microsatellites', 'Var', (0, 15))	('metastases', 'Disease', (44, 54))
76855	29028110	Although occasionally seen in the primary melanoma diagnostic biopsy specimen, microsatellites, when present, are more commonly identified in the wide excision specimen.	('primary melanoma', 'Disease', (34, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('primary melanoma', 'Disease', 'MESH:D008545', (34, 50))	('microsatellites', 'Var', (79, 94))
76882	29028110	As in the seventh edition, patients with clinical T1b N0 melanoma are included in clinical stage IB.	('T1b N0', 'Var', (50, 56))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('patients', 'Species', '9606', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))
76883	29028110	In contrast, patients with pathological T1b N0 melanoma are included in pathological stage IA (and not stage IB as in the seventh edition) (Table 6).	('patients', 'Species', '9606', (13, 21))	('T1b N0', 'Var', (40, 46))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
76884	29028110	This stage grouping reflects the better survival of patients who have T1b melanoma with pathologically negative nodes because, if SLN biopsy was performed, it only includes those with a tumor-negative SLN (ie, T1b pN1 patients would be stage III), compared with a group of patients with T1b melanoma who were only clinically staged.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('SLN', 'Var', (201, 204))	('patients', 'Species', '9606', (273, 281))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('T1b pN1', 'Var', (210, 217))	('tumor', 'Disease', (186, 191))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('patients', 'Species', '9606', (52, 60))
76885	29028110	The 5-year and 10-year MSS rates were 97% and 93%, respectively, for patients with clinical T1b N0 melanoma, compared with 99% and 96%, respectively, for those with pathological T1b N0 melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('T1b N0', 'Var', (92, 98))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('patients', 'Species', '9606', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('melanoma', 'Disease', (185, 193))
76887	29028110	3), the Melanoma Expert Panel hypothesized that more accurate prognostic estimates could be obtained by including both T-category factors, tumor thickness and ulceration status, along with the number of tumor-involved lymph nodes and whether they were detected clinically or were clinically occult (ie, positive SLN), and the presence of microsatellite, satellite, and/or in-transit metastases (ie, 9 N categories) (Table 3).	('satellite', 'CPA', (354, 363))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('metastases', 'Disease', (383, 393))	('Melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('microsatellite', 'Var', (338, 352))	('Melanoma', 'Disease', 'MESH:D008545', (8, 16))	('tumor', 'Disease', (139, 144))	('metastases', 'Disease', 'MESH:D009362', (383, 393))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('Melanoma', 'Disease', (8, 16))
76890	29028110	The 5-year MSS rate according to stage III subgroups ranges from 93% in patients with stage IIIA disease (1-3 clinically occult, tumor-involved SLNs [N1a or N2a] and T1a, T1b, or T2a primaries) to 32% for those with stage IIID disease (patients with a thick and ulcerated primary [T4b] and either >=4 tumor-involved regional nodes [N3a or N3b] or >=2 tumor-involved nodes and evidence of microsatellite, satellite, or in-transit metastases [N3c]) (Fig.	('satellite', 'CPA', (404, 413))	('metastases', 'Disease', 'MESH:D009362', (429, 439))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('IIID disease', 'Disease', 'MESH:C566892', (222, 234))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', (351, 356))	('IIID disease', 'Disease', (222, 234))	('N3b]', 'Var', (339, 343))	('patients', 'Species', '9606', (236, 244))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('metastases', 'Disease', (429, 439))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('microsatellite', 'Var', (388, 402))	('patients', 'Species', '9606', (72, 80))
76943	29028110	This work was supported in part by the National Institutes of Health Specialized Program of Research Excellence (SPORE) Melanoma Grant P50 CA93459 (to The University of Texas MD Anderson Cancer Center); the National Institutes of Health/National Cancer Institute through The University of Texas MD Anderson Cancer Center Support Grant P30CA016672; a Melanoma Research Alliance Team Science Award; the generous philanthropic contributions to The University of Texas MD Anderson Melanoma Moon Shots Program; the Robert and Lynne Grossman Family Foundation; the Michael and Patricia Booker Melanoma Research Endowment; and the National Health and Medical Research Council of Australia, Melanoma Institute Australia, and the Medical Foundation of The University of Sydney.	('Melanoma', 'Disease', 'MESH:D008545', (350, 358))	('Melanoma', 'Disease', 'MESH:D008545', (587, 595))	('Melanoma', 'Disease', 'MESH:D008545', (120, 128))	('Cancer', 'Disease', 'MESH:D009369', (246, 252))	('Melanoma', 'Disease', 'MESH:D008545', (477, 485))	('Melanoma', 'Disease', 'MESH:D008545', (683, 691))	('Cancer', 'Disease', (307, 313))	('Cancer', 'Disease', (187, 193))	('P30CA016672', 'Var', (335, 346))	('Melanoma', 'Disease', (120, 128))	('Melanoma Institute Australia', 'Disease', (683, 711))	('Melanoma', 'Disease', (350, 358))	('Melanoma', 'Disease', (587, 595))	('Patricia Booker Melanoma', 'Disease', 'MESH:D008545', (571, 595))	('Melanoma', 'Disease', (477, 485))	('Melanoma', 'Disease', (683, 691))	('Texas MD Anderson Cancer', 'Disease', (169, 193))	('Texas MD Anderson Melanoma Moon', 'Disease', (459, 490))	('Texas MD Anderson Cancer', 'Disease', (289, 313))	('Melanoma', 'Phenotype', 'HP:0002861', (587, 595))	('Cancer', 'Disease', 'MESH:D009369', (307, 313))	('Melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('Cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Melanoma', 'Phenotype', 'HP:0002861', (350, 358))	('Cancer', 'Disease', 'MESH:D009369', (187, 193))	('Melanoma', 'Phenotype', 'HP:0002861', (683, 691))	('Patricia Booker Melanoma', 'Disease', (571, 595))	('Melanoma Institute Australia', 'Disease', 'MESH:D008545', (683, 711))	('Melanoma', 'Phenotype', 'HP:0002861', (477, 485))	('Cancer', 'Disease', (246, 252))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (169, 193))	('Texas MD Anderson Cancer', 'Disease', 'MESH:C535460', (289, 313))	('Texas MD Anderson Melanoma Moon', 'Disease', 'MESH:C535460', (459, 490))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))
76958	28207831	In conclusion, the meta-analysis of the data in these articles provides strong evidence that the methylation status of the RASSF1A gene promoter was strongly related to melanoma susceptibility.	('RASSF1A', 'Gene', (123, 130))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('RASSF1A', 'Gene', '11186', (123, 130))	('methylation status', 'Var', (97, 115))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('related to', 'Reg', (158, 168))
76983	28207831	This study used a subject and text word strategy, as follows: 'melanoma or melanotic cancer or black cancer', 'RASSF1A or Ras association domain family 1 A or RASSF1', 'methylation or hyper-methylation or epigenetic'.	('RASSF1', 'Gene', (111, 117))	('RASSF1', 'Gene', (159, 165))	('hyper-methylation', 'Var', (184, 201))	('melanoma or melanotic cancer', 'Disease', (63, 91))	("epigenetic'", 'Var', (205, 216))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('methylation', 'biological_process', 'GO:0032259', ('190', '201'))	('black cancer', 'Disease', 'MESH:D009369', (95, 107))	('Ras association domain family 1 A', 'Gene', (122, 155))	('black cancer', 'Disease', (95, 107))	("'methylation", 'Var', (168, 180))	('methylation', 'biological_process', 'GO:0032259', ('169', '180'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RASSF1A', 'Gene', '11186', (111, 118))	('Ras association domain family 1 A', 'Gene', '11186', (122, 155))	('RASSF1', 'Gene', '11186', (111, 117))	('RASSF1', 'Gene', '11186', (159, 165))	('RASSF1A', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('melanoma or melanotic cancer', 'Disease', 'MESH:C563985', (63, 91))	('melanotic cancer', 'Phenotype', 'HP:0002861', (75, 91))
76987	28207831	The strength of the relationship between RASSF1A gene promoter methylation and the risk of melanoma was measured by the pooled odds ratios (ORs) with a 95% confidence interval (CI).	('RASSF1A', 'Gene', (41, 48))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('RASSF1A', 'Gene', '11186', (41, 48))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('methylation', 'Var', (63, 74))
76994	28207831	According to the meta-analysis, we found that the frequency of RASSF1A gene promoter methylation in melanoma was: OR = 12.67, 95% CI: 6.16~26.05, z = 6.90, P<0.0001 by a fixed effects model and OR = 9.25, 95% CI: 4.37~19.54, z = 5.82, P<0.0001 by a random effects model without evidence of heterogeneity (tau2 = 0.00; H = 1 [1; 1.55]; I2 = 0% [0%; 58.6%], P = 0.5158).	('methylation', 'Var', (85, 96))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('RASSF1A', 'Gene', (63, 70))	('RASSF1A', 'Gene', '11186', (63, 70))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
76995	28207831	This shows a statistically significant increase in the likelihood of RASSF1A gene promoter methylation in melanoma compared with the controls (Fig 2A).	('methylation', 'Var', (91, 102))	('RASSF1A', 'Gene', (69, 76))	('increase', 'PosReg', (39, 47))	('RASSF1A', 'Gene', '11186', (69, 76))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('promoter', 'MPA', (82, 90))	('melanoma', 'Disease', (106, 114))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))
76996	28207831	As we have inferred, the different methods used to assess methylation (both MSP and QMSP) also revealed a significant association between RASSF1A gene methylation and melanoma (OR = 14.75, 3.34 by a fixed effects model, respectively) (Fig 2C), as association was also shown with the use of different primers (Fig 2D).	('RASSF1A', 'Gene', (138, 145))	('methylation', 'Var', (151, 162))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('RASSF1A', 'Gene', '11186', (138, 145))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('methylation', 'biological_process', 'GO:0032259', ('151', '162'))
76998	28207831	According to previous studies and assembly-Mar.2006 (NCBI 36/hg18), we analyzed 11 different probes located in the RASSF1A gene promoter region (cg24859722, cg13872831, cg00777121, cg04743654, cg12966367, cg08047457, cg25747192, cg21554552, cg27569446, cg25486143, cg06172942), which contain the transcription start site (chr3:50353240) of the RASSF1A gene and the CpG island A (chr3: 50352808-50353544) of RASSF1 gene.	('cg08047457', 'Var', (205, 215))	('cg21554552', 'Var', (229, 239))	('RASSF1A', 'Gene', '11186', (344, 351))	('RASSF1A', 'Gene', '11186', (115, 122))	('cg00777121', 'Var', (169, 179))	('RASSF1A', 'Gene', (115, 122))	('RASSF1A', 'Gene', (344, 351))	('cg27569446', 'Var', (241, 251))	('RASSF1', 'Gene', '11186', (115, 121))	('cg25747192', 'Var', (217, 227))	('RASSF1', 'Gene', (115, 121))	('cg25486143', 'Var', (253, 263))	('cg04743654', 'Var', (181, 191))	('RASSF1', 'Gene', '11186', (344, 350))	('RASSF1', 'Gene', '11186', (407, 413))	('transcription', 'biological_process', 'GO:0006351', ('296', '309'))	('RASSF1', 'Gene', (344, 350))	('cg12966367', 'Var', (193, 203))	('RASSF1', 'Gene', (407, 413))	('cg06172942', 'Var', (265, 275))
77020	28207831	We found that RASSF1A gene promoter methylation was closely related to melanoma susceptibility.	('related', 'Reg', (60, 67))	('RASSF1A', 'Gene', (14, 21))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('RASSF1A', 'Gene', '11186', (14, 21))	('methylation', 'Var', (36, 47))
77024	28207831	Ultimately, we found no relationship between RASSF1A gene promoter methylation and melanoma prognosis, and no significant difference between RASSF1A gene promoter and the clinical-pathological features of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('RASSF1A', 'Gene', (45, 52))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('RASSF1A', 'Gene', (141, 148))	('RASSF1A', 'Gene', '11186', (45, 52))	('RASSF1A', 'Gene', '11186', (141, 148))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('methylation', 'Var', (67, 78))
77027	28207831	In conclusion, this meta-analysis of article data provides strong evidence that the methylation status of the RASSF1A gene promoter was strongly related to melanoma susceptibility.	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('related to', 'Reg', (145, 155))	('RASSF1A', 'Gene', (110, 117))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('methylation status', 'Var', (84, 102))	('RASSF1A', 'Gene', '11186', (110, 117))
77029	28207831	However, we found no significant difference between RASSF1A gene promoter methylation and the prognosis or between RASSF1A promoter methylation and the clinical-pathological features of melanoma.	('RASSF1A', 'Gene', '11186', (115, 122))	('methylation', 'Var', (74, 85))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('RASSF1A', 'Gene', (52, 59))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('RASSF1A', 'Gene', (115, 122))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('RASSF1A', 'Gene', '11186', (52, 59))
77057	31199813	identified a single-nucleotide polymorphism (SNP) (rs17702471) in GPC6/GPC5 that was associated with an increased risk of invasive epithelial ovarian carcinoma.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (142, 159))	('rs17702471', 'Mutation', 'rs17702471', (51, 61))	('GPC6', 'Gene', '10082', (66, 70))	('invasive epithelial ovarian carcinoma', 'Disease', 'MESH:D000077216', (122, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('GPC5', 'Gene', '2262', (71, 75))	('invasive epithelial ovarian carcinoma', 'Disease', (122, 159))	('GPC5', 'Gene', (71, 75))	('GPC6', 'Gene', (66, 70))	('associated', 'Reg', (85, 95))	('rs17702471', 'Var', (51, 61))
77142	15310399	Lifestyle, sun exposure, fair skin, light eye color, poor ability to tan, Northern European or Celtic ethnicity, family history of melanoma, benign nevi, various major histocompatibility complex alleles, and mutations in the p16 gene have been reported as risk factors for cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('fair skin', 'Phenotype', 'HP:0007513', (25, 34))	('melanoma', 'Disease', (131, 139))	('nevi', 'Phenotype', 'HP:0003764', (148, 152))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('p16', 'Gene', '1029', (225, 228))	('light eye color', 'Phenotype', 'HP:0007730', (36, 51))	('mutations', 'Var', (208, 217))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('major histocompatibility complex', 'biological_process', 'GO:0046776', ('162', '194'))	('cutaneous melanoma', 'Disease', (273, 291))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (273, 291))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (273, 291))	('p16', 'Gene', (225, 228))
77228	15310399	The countries of ancestry reported was also consistent with the relative high frequency of C282Y, the major allele associated with hemochromatosis, in Alabama hemochromatosis probands compared to controls.	('C282Y', 'Var', (91, 96))	('Alabama hemochromatosis', 'Disease', 'MESH:D006432', (151, 174))	('Alabama hemochromatosis', 'Disease', (151, 174))	('associated', 'Reg', (115, 125))	('hemochromatosis', 'Disease', (131, 146))	('hemochromatosis', 'Disease', (159, 174))	('hemochromatosis', 'Disease', 'MESH:D006432', (131, 146))	('C282Y', 'Mutation', 'p.C282Y', (91, 96))	('hemochromatosis', 'Disease', 'MESH:D006432', (159, 174))
77248	32276436	Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive.	('Germline mutations', 'Var', (0, 18))	('hereditary melanoma', 'Disease', (100, 119))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('associated with', 'Reg', (72, 87))	('hereditary melanoma', 'Disease', 'MESH:D008545', (100, 119))
77251	32276436	In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations.	('variants', 'Var', (41, 49))	('protein', 'cellular_component', 'GO:0003675', ('77', '84'))	('function', 'MPA', (99, 107))	('ARHGEF40', 'Gene', (32, 40))	('altered', 'Reg', (69, 76))	('CDH23', 'Gene', '64072', (22, 27))	('protein structure', 'MPA', (77, 94))	('ARHGEF40', 'Gene', '55701', (32, 40))	('CDH23', 'Gene', (22, 27))
77262	32276436	Furthermore, hereditary melanoma has been associated with germline mutations in high-risk melanoma susceptibility genes (CDKN2A, CDK4, TERT, POT1), polymorphisms in intermediate-risk melanoma susceptibility genes (BAP1, ACD, TERF2IP, MC1R and MITF), and germline missense substitutions in MITF.	('melanoma', 'Disease', (90, 98))	('TERT', 'Gene', '7015', (135, 139))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('BAP1', 'Gene', '8314', (214, 218))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('CDKN2A', 'Gene', (121, 127))	('POT1', 'Gene', '25913', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('CDK4', 'Gene', (129, 133))	('ACD', 'Gene', (220, 223))	('hereditary melanoma', 'Disease', (13, 32))	('BAP1', 'Gene', (214, 218))	('POT1', 'Gene', (141, 145))	('CDKN2A', 'Gene', '1029', (121, 127))	('MC1R', 'Gene', '4157', (234, 238))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('MITF', 'Gene', '4286', (243, 247))	('MC1R', 'Gene', (234, 238))	('CDK', 'molecular_function', 'GO:0004693', ('129', '132'))	('CDK4', 'Gene', '1019', (129, 133))	('polymorphisms', 'Var', (148, 161))	('hereditary melanoma', 'Disease', 'MESH:D008545', (13, 32))	('MITF', 'Gene', '4286', (289, 293))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('TERF2IP', 'Gene', (225, 232))	('associated', 'Reg', (42, 52))	('MITF', 'Gene', (243, 247))	('mutations', 'Var', (67, 76))	('ACD', 'Gene', '65057', (220, 223))	('TERF2IP', 'Gene', '54386', (225, 232))	('MITF', 'Gene', (289, 293))	('TERT', 'Gene', (135, 139))
77263	32276436	Germline mutations in CDKN2A are present in ~20-40% of multiple primary melanomas (MPM) cases.	('Germline mutations', 'Var', (0, 18))	('melanomas', 'Disease', 'MESH:D008545', (72, 81))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('melanomas', 'Disease', (72, 81))	('present', 'Reg', (33, 40))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))
77267	32276436	In this work, we employed whole exome sequencing (WES) to identify novel susceptibility genes for hereditary melanoma in patients with MPM, who were negative for germline mutations in the genes CDKN2A, CDK4, and MITF (p.E318K).	('CDKN2A', 'Gene', (194, 200))	('CDK', 'molecular_function', 'GO:0004693', ('202', '205'))	('p.E318K', 'SUBSTITUTION', 'None', (218, 225))	('CDKN2A', 'Gene', '1029', (194, 200))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('p.E318K', 'Var', (218, 225))	('MITF', 'Gene', '4286', (212, 216))	('MITF', 'Gene', (212, 216))	('hereditary melanoma', 'Disease', (98, 117))	('hereditary melanoma', 'Disease', 'MESH:D008545', (98, 117))	('CDK4', 'Gene', (202, 206))	('CDK4', 'Gene', '1019', (202, 206))	('patients', 'Species', '9606', (121, 129))
77278	32276436	The patients had been diagnosed with MPM and previously screened for melanoma susceptibility genes CDKN2A, CDK4, and MITF (p.E318K) germline mutations.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('CDK4', 'Gene', '1019', (107, 111))	('CDKN2A', 'Gene', (99, 105))	('MPM', 'Disease', (37, 40))	('p.E318K', 'Var', (123, 130))	('CDKN2A', 'Gene', '1029', (99, 105))	('CDK4', 'Gene', (107, 111))	('p.E318K', 'SUBSTITUTION', 'None', (123, 130))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))	('patients', 'Species', '9606', (4, 12))	('MITF', 'Gene', '4286', (117, 121))	('MITF', 'Gene', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
77285	32276436	In order to understand the possible molecular consequences of the identified CDH23, ARHGEF40, and BRD9 mutations in the absence of structural data for each of the corresponding protein variants, structural models were generated using the SWISS-MODEL online server (protocol detailed in Supplementary Materials).	('mutations', 'Var', (103, 112))	('CDH23', 'Gene', (77, 82))	('CDH23', 'Gene', '64072', (77, 82))	('ARHGEF40', 'Gene', (84, 92))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('BRD9', 'Gene', '65980', (98, 102))	('BRD9', 'Gene', (98, 102))	('ARHGEF40', 'Gene', '55701', (84, 92))
77295	32276436	To determine the frequency of CDH23, ARHGEF40, BRD9, NRAS, and BRAF mutations in SKCM samples, data recently re-annotated from TCGA at GDC  and cBioPortal was employed.	('CDH23', 'Gene', (30, 35))	('NRAS', 'Gene', (53, 57))	('ARHGEF40', 'Gene', (37, 45))	('BRD9', 'Gene', '65980', (47, 51))	('BRD9', 'Gene', (47, 51))	('CDH23', 'Gene', '64072', (30, 35))	('NRAS', 'Gene', '4893', (53, 57))	('BRAF', 'Gene', '673', (63, 67))	('mutations', 'Var', (68, 77))	('ARHGEF40', 'Gene', '55701', (37, 45))	('BRAF', 'Gene', (63, 67))
77298	32276436	In order to evaluate cumulative effects of the multiple variants in a genomic region identified in our analysis (NTN4, MTCL1, FNDC1, CAND2, ITIH3, RPL32, and RNF213), we conducted the following region-based aggregation tests: the burden test, which indicated if a region has a large proportion of causal variants with effects in the same direction; the sequence kernel association test (SKAT), which is more powerful in the presence of both risk-increasing and risk-decreasing variants or if there are many non-causal variants; and the omnibus test SKAT-O, which adaptively combines the SKAT and burden test statistics.	('MTCL1', 'Gene', (119, 124))	('ITIH3', 'Gene', '3699', (140, 145))	('RNF213', 'Gene', (158, 164))	('RPL32', 'Gene', '6161', (147, 152))	('NTN4', 'Gene', '59277', (113, 117))	('FNDC1', 'Gene', '84624', (126, 131))	('RPL32', 'Gene', (147, 152))	('CAND2', 'Gene', '23066', (133, 138))	('RNF213', 'Gene', '57674', (158, 164))	('ITIH3', 'Gene', (140, 145))	('MTCL1', 'Gene', '23255', (119, 124))	('variants', 'Var', (304, 312))	('CAND2', 'Gene', (133, 138))	('FNDC1', 'Gene', (126, 131))	('NTN4', 'Gene', (113, 117))
77299	32276436	As per the filtering steps detailed in Figure 1A, 14,048 high-quality variants remained from WES data of eight patients with multiple primary melanomas (MPM), which were negative for all the susceptibility genes for melanoma (CDKN2A, CDK4, MITF, BAP1) and telomere maintenance complex genes such as Telomerase Reverse Transcriptase (TERT), Protection of Telomeres 1 (POT1), Shelterin Complex Subunit and Telomerase Recruitment Factor (ACD) and Telomeric repeat-binding factor 2-interacting protein 1 (TERF2IP).	('Transcriptase', 'molecular_function', 'GO:0034062', ('318', '331'))	('TERF2IP', 'Gene', '54386', (501, 508))	('TERT', 'Gene', (333, 337))	('TERT', 'Gene', '7015', (333, 337))	('CDKN2A', 'Gene', (226, 232))	('CDK4', 'Gene', (234, 238))	('MITF', 'Gene', (240, 244))	('BAP1', 'Gene', '8314', (246, 250))	('Shelterin Complex', 'cellular_component', 'GO:0070187', ('374', '391'))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('Protection of Telomeres 1', 'Gene', '25913', (340, 365))	('melanoma', 'Disease', (142, 150))	('Protection of Telomeres 1', 'Gene', (340, 365))	('ACD', 'Gene', (435, 438))	('Transcriptase', 'molecular_function', 'GO:0003899', ('318', '331'))	('CDKN2A', 'Gene', '1029', (226, 232))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('CDK4', 'Gene', '1019', (234, 238))	('telomere', 'cellular_component', 'GO:0000781', ('256', '264'))	('BAP1', 'Gene', (246, 250))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('Telomerase Reverse Transcriptase', 'Gene', (299, 331))	('telomere', 'cellular_component', 'GO:0005696', ('256', '264'))	('POT1', 'Gene', '25913', (367, 371))	('CDK', 'molecular_function', 'GO:0004693', ('234', '237'))	('melanomas', 'Disease', (142, 151))	('Telomerase Reverse Transcriptase', 'Gene', '7015', (299, 331))	('Telomeric repeat-binding', 'molecular_function', 'GO:0042162', ('444', '468'))	('telomere maintenance', 'biological_process', 'GO:0000723', ('256', '276'))	('Telomeric repeat-binding factor 2-interacting protein 1', 'Gene', '54386', (444, 499))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('Transcriptase', 'molecular_function', 'GO:0003968', ('318', '331'))	('ACD', 'Gene', '65057', (435, 438))	('POT1', 'Gene', (367, 371))	('variants', 'Var', (70, 78))	('protein', 'cellular_component', 'GO:0003675', ('490', '497'))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('MITF', 'Gene', '4286', (240, 244))	('melanoma', 'Disease', (216, 224))	('TERF2IP', 'Gene', (501, 508))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('patients', 'Species', '9606', (111, 119))
77300	32276436	In order to evaluate the pathogenicity of these 13 variants in MPM, we screened 18 additional MPM patients, and 37 patients with criteria for familial melanoma, 51 being negative and 4 positive for CDKN2A mutations (frequencies in Table 1).	('patients', 'Species', '9606', (115, 123))	('familial melanoma', 'Disease', (142, 159))	('CDKN2A', 'Gene', (198, 204))	('CDKN2A', 'Gene', '1029', (198, 204))	('mutations', 'Var', (205, 214))	('familial melanoma', 'Disease', 'MESH:C562393', (142, 159))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('MPM', 'Disease', (94, 97))
77301	32276436	Interestingly, when we screened these variants in the 37 indexes with familial melanoma a low variant frequency was observed, being absent in nearly half the cases (Table 1).	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('familial melanoma', 'Disease', 'MESH:C562393', (70, 87))	('familial melanoma', 'Disease', (70, 87))	('variants', 'Var', (38, 46))
77302	32276436	As shown in Table 1, most of the variants were polymorphisms (10 of 13), presenting a frequency >1% and <5%, with the exception for MAP2K3 gene variant, which was a common variant with a frequency of 92%.	('variants', 'Var', (33, 41))	('MAP2K3', 'Gene', '5606', (132, 138))	('variant', 'Var', (144, 151))	('MAP2K', 'molecular_function', 'GO:0004708', ('132', '137'))	('MAP2K3', 'Gene', (132, 138))
77303	32276436	Furthermore, the BMX and CFAP47 variants were found in homozygosity in a healthy control, thus being excluded, as familial melanoma susceptibility is consistent with autosomal dominant inheritance.	('CFAP47', 'Gene', '286464', (25, 31))	('BMX', 'Gene', (17, 20))	('familial melanoma', 'Disease', (114, 131))	('familial melanoma', 'Disease', 'MESH:C562393', (114, 131))	('BMX', 'Gene', '660', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('variants', 'Var', (32, 40))	('CFAP47', 'Gene', (25, 31))
77304	32276436	Importantly, we identified 3 rare variants in the CDH23, ARHGEF40 and BRD9 genes (0-0.7% frequency in healthy controls, Table 1) and confirmed their rarity using ExAC (0.007002, 0.001894 and 0.000464, respectively) and gnomAD (not found, 0.00186 and 0.000404, respectively).	('CDH23', 'Gene', (50, 55))	('0.001894', 'Var', (178, 186))	('BRD9', 'Gene', (70, 74))	('CDH23', 'Gene', '64072', (50, 55))	('ARHGEF40', 'Gene', (57, 65))	('0.007002', 'Var', (168, 176))	('ARHGEF40', 'Gene', '55701', (57, 65))	('BRD9', 'Gene', '65980', (70, 74))
77305	32276436	In order to evaluate if these rare variants could synergize and increase melanoma susceptibility, we performed a region-based aggregation test analysis with all variants identified.	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('increase melanoma', 'Disease', 'MESH:D008545', (64, 81))	('increase melanoma', 'Disease', (64, 81))	('variants', 'Var', (35, 43))
77306	32276436	We found a statistically significant cumulative effect of NTN4, MTCL1, FNDC1, CAND2, ITIH3, RPL32 and RNF213 variants in the MPM group, compared to the healthy control group (Table 2).	('MTCL1', 'Gene', (64, 69))	('variants', 'Var', (109, 117))	('FNDC1', 'Gene', '84624', (71, 76))	('ITIH3', 'Gene', '3699', (85, 90))	('RNF213', 'Gene', (102, 108))	('CAND2', 'Gene', '23066', (78, 83))	('NTN4', 'Gene', (58, 62))	('MTCL1', 'Gene', '23255', (64, 69))	('RPL32', 'Gene', '6161', (92, 97))	('significant', 'Reg', (25, 36))	('FNDC1', 'Gene', (71, 76))	('ITIH3', 'Gene', (85, 90))	('RNF213', 'Gene', '57674', (102, 108))	('NTN4', 'Gene', '59277', (58, 62))	('CAND2', 'Gene', (78, 83))	('RPL32', 'Gene', (92, 97))
77308	32276436	We investigated in silico the possible molecular consequences of the identified CDH23, ARHGEF40 and BRD9 mutations by generating structural models, which were not obtained for BRD9.	('BRD9', 'Gene', (100, 104))	('ARHGEF40', 'Gene', (87, 95))	('BRD9', 'Gene', '65980', (176, 180))	('CDH23', 'Gene', '64072', (80, 85))	('BRD9', 'Gene', (176, 180))	('ARHGEF40', 'Gene', '55701', (87, 95))	('mutations', 'Var', (105, 114))	('BRD9', 'Gene', '65980', (100, 104))	('CDH23', 'Gene', (80, 85))
77311	32276436	Structural models of CDH23 EC4 (Table S3) were aligned in Pymol with the template yielding the highest score (PDB ID 5SZO), corresponding to EC repeats 1-4 of protocadherin gammaB7 (PCDHgammaB7; yellow ribbons in Figure S1, top and middle panels).	('protocadherin gammaB7', 'Gene', (159, 180))	('CDH23', 'Gene', '64072', (21, 26))	('CDH23', 'Gene', (21, 26))	('PCDHgammaB7', 'Gene', (182, 193))	('EC repeats 1-4', 'Var', (141, 155))	('PCDHgammaB7', 'Gene', '56099', (182, 193))	('protocadherin gammaB7', 'Gene', '56099', (159, 180))
77312	32276436	Zooming-in on the Ala366Thr substitution (Figure S1, bottom panel), the mutated residue seems unlikely to affect protein folding, stability or aggregation, being located at the protein surface and replacing an uncharged side chain with a polar one.	('Ala366Thr', 'Chemical', '-', (18, 27))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('replacing', 'Reg', (197, 206))	('protein folding', 'biological_process', 'GO:0006457', ('113', '128'))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('Ala366Thr substitution', 'Var', (18, 40))	('uncharged side chain', 'MPA', (210, 230))	('affect', 'Reg', (106, 112))	('stability', 'MPA', (130, 139))
77313	32276436	Therefore, such a pathogenic substitution could affect either the CDH23 homodimer assembly, or its interaction with other proteins.	('affect', 'Reg', (48, 54))	('CDH23', 'Gene', '64072', (66, 71))	('pathogenic', 'Reg', (18, 28))	('substitution', 'Var', (29, 41))	('homodimer assembly', 'MPA', (72, 90))	('CDH23', 'Gene', (66, 71))	('interaction', 'Interaction', (99, 110))
77316	32276436	It is thus envisaged that the CDH23 p.Ala366Thr variant acquires an otherwise absent mannosylation site.	('mannosylation', 'biological_process', 'GO:0097502', ('85', '98'))	('CDH23', 'Gene', (30, 35))	('p.Ala366Thr', 'SUBSTITUTION', 'None', (36, 47))	('p.Ala366Thr', 'Var', (36, 47))	('mannosylation site', 'MPA', (85, 103))	('CDH23', 'Gene', '64072', (30, 35))	('absent', 'NegReg', (78, 84))
77319	32276436	The Arg834Cys substitution resulting from the herein identified pathogenic ARHGEF40 mutation is located in the central region containing the spectrin repeats.	('mutation', 'Var', (84, 92))	('Arg834Cys', 'Chemical', '-', (4, 13))	('spectrin', 'cellular_component', 'GO:0008091', ('141', '149'))	('ARHGEF40', 'Gene', (75, 83))	('pathogenic', 'Reg', (64, 74))	('Arg834Cys', 'Var', (4, 13))	('ARHGEF40', 'Gene', '55701', (75, 83))
77320	32276436	Accordingly, the best models were generated against repeats 14-16 of beta2-spectrin (Table S3, Figure S2), revealing that the substituted Arg834 is located in a disordered link between two alpha-helices, with its side chain within H-bonding distance (2.6-3.4 A) with Glu858 (Figure S2; blue) or Gln851 (Figure S2; green) side chains.	('Arg834', 'Var', (138, 144))	('spectrin', 'cellular_component', 'GO:0008091', ('75', '83'))	('Gln851', 'Chemical', '-', (295, 301))	('Gln851', 'Var', (295, 301))	('Glu858', 'Chemical', '-', (267, 273))	('Arg834', 'Chemical', '-', (138, 144))
77321	32276436	Substitution by a cysteine residue will likely result in the loss of these H-bonds, disturbing the conformation of this motif within the Solo central domain and eventually causing protein misfolding and/or aggregation.	('Substitution', 'Var', (0, 12))	('cysteine', 'Chemical', 'MESH:D003545', (18, 26))	('causing', 'Reg', (172, 179))	('H-bonds', 'Protein', (75, 82))	('Solo', 'Gene', '55701', (137, 141))	('loss', 'NegReg', (61, 65))	('disturbing', 'NegReg', (84, 94))	('protein', 'Protein', (180, 187))	('Solo', 'Gene', (137, 141))	('conformation', 'MPA', (99, 111))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
77322	32276436	We found that the novel identified variants and polymorphisms (Table 2) seemed to influence melanoma development.	('influence', 'Reg', (82, 91))	('variants', 'Var', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))
77323	32276436	Particularly, we found that three rare variants in CDH23, ARHGEF40 and BRD9, respectively, could be pathogenic on their own.	('CDH23', 'Gene', '64072', (51, 56))	('ARHGEF40', 'Gene', '55701', (58, 66))	('BRD9', 'Gene', '65980', (71, 75))	('BRD9', 'Gene', (71, 75))	('CDH23', 'Gene', (51, 56))	('pathogenic', 'Reg', (100, 110))	('variants', 'Var', (39, 47))	('ARHGEF40', 'Gene', (58, 66))
77325	32276436	As expected, BRAF and NRAS mutations were highly frequent (54% and 29%, respectively; Figure 2A).	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (13, 17))	('NRAS', 'Gene', (22, 26))	('BRAF', 'Gene', (13, 17))	('NRAS', 'Gene', '4893', (22, 26))
77326	32276436	CDH23 was also highly mutated (17%), missense and truncations being the predominant types of mutations.	('CDH23', 'Gene', (0, 5))	('CDH23', 'Gene', '64072', (0, 5))	('missense', 'Var', (37, 45))
77327	32276436	Many missense CDH23 mutations were of unknown significance, demonstrating the importance of studying this gene and its alterations.	('missense', 'Var', (5, 13))	('CDH23', 'Gene', '64072', (14, 19))	('mutations', 'Var', (20, 29))	('CDH23', 'Gene', (14, 19))
77328	32276436	ARHGEF40 and BRD9 were mutated in 18 of 448 melanoma patients (4%; Figure 2B).	('ARHGEF40', 'Gene', '55701', (0, 8))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('BRD9', 'Gene', '65980', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('mutated', 'Var', (23, 30))	('BRD9', 'Gene', (13, 17))	('ARHGEF40', 'Gene', (0, 8))
77329	32276436	Since NRAS and BRAF mutations are mutually exclusive and CDH23 mutations were detected simultaneously either with NRAS or BRAF mutations, we evaluated the prognostic value of these mutations.	('mutations', 'Var', (63, 72))	('BRAF', 'Gene', '673', (15, 19))	('CDH23', 'Gene', (57, 62))	('BRAF', 'Gene', (15, 19))	('NRAS', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (122, 126))	('CDH23', 'Gene', '64072', (57, 62))	('NRAS', 'Gene', '4893', (114, 118))	('BRAF', 'Gene', (122, 126))	('NRAS', 'Gene', (6, 10))	('NRAS', 'Gene', '4893', (6, 10))
77330	32276436	BRAF mutated samples had a significantly higher disease-specific survival (p = 0.036), as already described.	('disease-specific survival', 'CPA', (48, 73))	('BRAF', 'Gene', '673', (0, 4))	('higher', 'PosReg', (41, 47))	('mutated', 'Var', (5, 12))	('BRAF', 'Gene', (0, 4))
77331	32276436	Furthermore, data from patients with mutated CDH23 revealed a lower disease-specific survival (p = 0.047).	('disease-specific survival', 'CPA', (68, 93))	('patients', 'Species', '9606', (23, 31))	('lower', 'NegReg', (62, 67))	('CDH23', 'Gene', (45, 50))	('mutated', 'Var', (37, 44))	('CDH23', 'Gene', '64072', (45, 50))
77332	32276436	Contrarily, ARHGEF40 and BRD9 mutations did not reach a statistically significant prognostic value due to the small sample size of mutated cases (Figure 2C).	('ARHGEF40', 'Gene', (12, 20))	('mutations', 'Var', (30, 39))	('ARHGEF40', 'Gene', '55701', (12, 20))	('BRD9', 'Gene', '65980', (25, 29))	('BRD9', 'Gene', (25, 29))
77333	32276436	Nevertheless, melanoma is characteristically a high mutational burden tumour type, and since gene length and mutation frequency are usually correlated, it is plausible that CDH23 mutations do not constitute a proper marker of prognostic value and its high mutation frequency derives from large size of this gene (>419,000 bases).	('melanoma', 'Disease', (14, 22))	('CDH23', 'Gene', (173, 178))	('CDH23', 'Gene', '64072', (173, 178))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (179, 188))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
77338	32276436	Altogether, these results suggested that CDH23, ARHGEF40, and BRD9 genes could be also important for sporadic melanoma and consequently, a mutation in these genes could be pivotal in this disease.	('CDH23', 'Gene', '64072', (41, 46))	('ARHGEF40', 'Gene', (48, 56))	('BRD9', 'Gene', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('mutation', 'Var', (139, 147))	('ARHGEF40', 'Gene', '55701', (48, 56))	('sporadic melanoma', 'Disease', (101, 118))	('CDH23', 'Gene', (41, 46))	('sporadic melanoma', 'Disease', 'MESH:D008545', (101, 118))	('BRD9', 'Gene', '65980', (62, 66))
77345	32276436	In the present study, we aimed to identify novel rare genetic variants responsible for hereditary melanoma susceptibility.	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('variants', 'Var', (62, 70))	('hereditary melanoma', 'Disease', (87, 106))	('hereditary melanoma', 'Disease', 'MESH:D008545', (87, 106))
77346	32276436	Eight patients, with true features of hereditary melanoma such as MPM and high number of nevi which were negative for germline mutations in CDKN2A, CDK4, and MITF (p.E318K) genes were selected for WES.	('nevi', 'Phenotype', 'HP:0003764', (89, 93))	('CDK4', 'Gene', '1019', (148, 152))	('CDK', 'molecular_function', 'GO:0004693', ('148', '151'))	('CDKN2A', 'Gene', (140, 146))	('p.E318K', 'SUBSTITUTION', 'None', (164, 171))	('p.E318K', 'Var', (164, 171))	('MITF', 'Gene', '4286', (158, 162))	('MITF', 'Gene', (158, 162))	('CDKN2A', 'Gene', '1029', (140, 146))	('hereditary melanoma', 'Disease', 'MESH:D008545', (38, 57))	('patients', 'Species', '9606', (6, 14))	('high number of nevi', 'Phenotype', 'HP:0001054', (74, 93))	('MPM', 'Disease', (66, 69))	('hereditary melanoma', 'Disease', (38, 57))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('CDK4', 'Gene', (148, 152))
77347	32276436	Interestingly, additional MPM and familial melanoma patients positive for CDKN2A or MITF (p.E318K) mutations did not harbour any of the suggestive variants identified in this study, supporting their probable relevant impact on MPM development.	('familial melanoma', 'Disease', 'MESH:C562393', (34, 51))	('MITF', 'Gene', (84, 88))	('positive', 'Reg', (61, 69))	('MITF', 'Gene', '4286', (84, 88))	('MPM', 'Disease', (26, 29))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('CDKN2A', 'Gene', (74, 80))	('CDKN2A', 'Gene', '1029', (74, 80))	('mutations', 'Var', (99, 108))	('impact', 'Reg', (217, 223))	('p.E318K', 'SUBSTITUTION', 'None', (90, 97))	('familial melanoma', 'Disease', (34, 51))	('p.E318K', 'Var', (90, 97))	('MPM', 'Disease', (227, 230))	('patients', 'Species', '9606', (52, 60))
77348	32276436	Even though most variants identified in the MPM cases were polymorphisms, variants in the CDH23, ARHGEF40, and BRD9 genes were rare in the databases employed, even among the healthy controls of the Portuguese population.	('BRD9', 'Gene', '65980', (111, 115))	('variants', 'Var', (17, 25))	('CDH23', 'Gene', '64072', (90, 95))	('ARHGEF40', 'Gene', (97, 105))	('BRD9', 'Gene', (111, 115))	('ARHGEF40', 'Gene', '55701', (97, 105))	('CDH23', 'Gene', (90, 95))
77355	32276436	Throughout our study, neither mutations on CDH23, ARHGEF40, and BRD9 nor expression of ARHGEF40 and BRD9 affected the overall survival of the patients.	('BRD9', 'Gene', (100, 104))	('ARHGEF40', 'Gene', (87, 95))	('CDH23', 'Gene', (43, 48))	('affected', 'Reg', (105, 113))	('BRD9', 'Gene', '65980', (64, 68))	('CDH23', 'Gene', '64072', (43, 48))	('ARHGEF40', 'Gene', (50, 58))	('ARHGEF40', 'Gene', '55701', (87, 95))	('mutations', 'Var', (30, 39))	('BRD9', 'Gene', (64, 68))	('BRD9', 'Gene', '65980', (100, 104))	('ARHGEF40', 'Gene', '55701', (50, 58))	('patients', 'Species', '9606', (142, 150))
77357	32276436	Hence, the three variants identified in the present study may play an important role in melanoma susceptibility.	('melanoma', 'Disease', (88, 96))	('variants', 'Var', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))
77366	32276436	Moreover, BRD9 inhibition has been shown to result in decreased cell proliferation, G1-arrest, and apoptosis in rhabdoid tumour cell lines and synovial sarcoma.	('rhabdoid tumour', 'Disease', (112, 127))	('cell proliferation', 'CPA', (64, 82))	('synovial sarcoma', 'Disease', (143, 159))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('cell proliferation', 'biological_process', 'GO:0008283', ('64', '82'))	('apoptosis', 'CPA', (99, 108))	('rhabdoid tumour', 'Disease', 'MESH:D018335', (112, 127))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('decreased', 'NegReg', (54, 63))	('G1-arrest', 'Disease', 'MESH:D006323', (84, 93))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (143, 159))	('synovial sarcoma', 'Disease', 'MESH:D013584', (143, 159))	('BRD9', 'Gene', '65980', (10, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('inhibition', 'Var', (15, 25))	('G1-arrest', 'Disease', (84, 93))	('BRD9', 'Gene', (10, 14))
77369	32276436	Solo misfolding/aggregation may compromise the organization of F-actin and keratin fibres, and the localization of plakoglobin to cell-to-cell adhesion sites, the latter being particularly relevant in terms of tumorigenesis, since plakoglobin has been proposed to act as a tumour and metastasis suppressor.	('cell adhesion', 'biological_process', 'GO:0007155', ('138', '151'))	('compromise', 'NegReg', (32, 42))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumour', 'Disease', (273, 279))	('misfolding/aggregation', 'Var', (5, 27))	('tumor', 'Disease', (210, 215))	('Solo', 'Gene', '55701', (0, 4))	('F-actin', 'Protein', (63, 70))	('F-actin', 'cellular_component', 'GO:0031941', ('63', '70'))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('Solo', 'Gene', (0, 4))	('localization', 'biological_process', 'GO:0051179', ('99', '111'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('keratin fibres', 'Protein', (75, 89))	('organization', 'MPA', (47, 59))
77371	32276436	Interestingly, according to our Gene Ontology data, ARHGEF40 is particularly associated with skin and epidermal development, indicating that an ARHGEF40 mutation could have a relevant impact on melanoma.	('ARHGEF40', 'Gene', '55701', (144, 152))	('ARHGEF40', 'Gene', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('Gene Ontology', 'biological_process', 'GO:0003673', ('32', '45'))	('ARHGEF40', 'Gene', '55701', (52, 60))	('associated', 'Reg', (77, 87))	('ARHGEF40', 'Gene', (144, 152))	('impact', 'Reg', (184, 190))	('mutation', 'Var', (153, 161))	('skin', 'Disease', (93, 97))
77373	32276436	GEFs have also been associated with initiation and promotion of melanoma and basal cell carcinoma.	('promotion', 'PosReg', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('melanoma and basal cell carcinoma', 'Disease', 'MESH:D002280', (64, 97))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (77, 97))	('GEFs', 'Var', (0, 4))
77375	32276436	Additionally, ARHGEF40 might regulate its protein activity through alternative splicing and, according to our Human Splicing Finder tool results, the identified variant in this gene allowed the creation of an ESS site that blocks exon recognition.	('ARHGEF40', 'Gene', (14, 22))	('splicing', 'biological_process', 'GO:0045292', ('79', '87'))	('exon recognition', 'MPA', (230, 246))	('protein', 'Protein', (42, 49))	('blocks', 'NegReg', (223, 229))	('ARHGEF40', 'Gene', '55701', (14, 22))	('Human', 'Species', '9606', (110, 115))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('variant', 'Var', (161, 168))	('Splicing', 'biological_process', 'GO:0045292', ('116', '124'))	('regulate', 'Reg', (29, 37))
77381	32276436	Furthermore, despite being reported that mutations in CDH23 are commonly observed in hearing impairment conditions, they have also been associated with pituitary adenomas.	('associated', 'Reg', (136, 146))	('mutations', 'Var', (41, 50))	('CDH23', 'Gene', (54, 59))	('hearing', 'biological_process', 'GO:0007605', ('85', '92'))	('hearing impairment', 'Phenotype', 'HP:0000365', (85, 103))	('hearing impairment conditions', 'Disease', 'MESH:D006311', (85, 114))	('pituitary adenomas', 'Disease', 'MESH:D010911', (152, 170))	('CDH23', 'Gene', '64072', (54, 59))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (152, 170))	('hearing impairment conditions', 'Disease', (85, 114))	('pituitary adenomas', 'Disease', (152, 170))	('observed', 'Reg', (73, 81))
77383	32276436	Besides, as CDH23 seems to regulate ERK and MAPK cascades, known melanoma-signalling pathways, mutations in this gene might play a role in MPM development by modulating the activity of these molecules.	('CDH23', 'Gene', (12, 17))	('ERK', 'Gene', '5594', (36, 39))	('modulating', 'Reg', (158, 168))	('ERK', 'molecular_function', 'GO:0004707', ('36', '39'))	('MPM', 'Disease', (139, 142))	('role', 'Reg', (131, 135))	('ERK', 'Gene', (36, 39))	('CDH23', 'Gene', '64072', (12, 17))	('regulate', 'Reg', (27, 35))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('signalling', 'biological_process', 'GO:0023052', ('74', '84'))	('activity', 'MPA', (173, 181))	('mutations', 'Var', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('MAPK cascades', 'Pathway', (44, 57))	('melanoma', 'Disease', (65, 73))	('play', 'Reg', (124, 128))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
77386	32276436	The particular mutation herein identified introduces a possible site for mannosylation absent in wildtype CDH23, which is supported by the mounting evidence that aberrant patterns of cadherin glycosylation are linked to carcinogenesis and metastasis.	('cadherin', 'Gene', '999;1000', (183, 191))	('mutation', 'Var', (15, 23))	('cadherin', 'Gene', (183, 191))	('linked to', 'Reg', (210, 219))	('CDH23', 'Gene', (106, 111))	('CDH23', 'Gene', '64072', (106, 111))	('metastasis', 'CPA', (239, 249))	('mannosylation', 'biological_process', 'GO:0097502', ('73', '86'))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('cadherin', 'molecular_function', 'GO:0008014', ('183', '191'))	('mannosylation', 'MPA', (73, 86))	('carcinogenesis', 'Disease', (220, 234))	('glycosylation', 'biological_process', 'GO:0070085', ('192', '205'))
77388	32276436	Besides the role of E-cadherin in metastasis and invasion, CDH1 mutations were found in familial gastric cancer and lobular breast cancer.	('lobular breast cancer', 'Disease', (116, 137))	('familial gastric cancer', 'Disease', 'MESH:D013274', (88, 111))	('lobular breast cancer', 'Disease', 'MESH:D001943', (116, 137))	('CDH1', 'Gene', '999', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (116, 137))	('E-cadherin', 'Gene', (20, 30))	('E-cadherin', 'Gene', '999', (20, 30))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('found', 'Reg', (79, 84))	('familial gastric cancer', 'Disease', (88, 111))	('cadherin', 'molecular_function', 'GO:0008014', ('22', '30'))	('CDH1', 'Gene', (59, 63))
77390	32276436	Overall, this data supports the hypothesis for the pathogenicity of this rare CDH23 variant, as it could play a similar role to that of CDH1 in gastric cancer.	('CDH23', 'Gene', (78, 83))	('CDH1', 'Gene', '999', (136, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('play', 'Reg', (105, 109))	('variant', 'Var', (84, 91))	('CDH23', 'Gene', '64072', (78, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('gastric cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CDH1', 'Gene', (136, 140))
77392	32276436	Since BRAF and NRAS mutations are usually mutually exclusive and clinical resistance to therapy involving these genes being a common issue in melanoma, finding new targets for treatment is crucial.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('NRAS', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('BRAF', 'Gene', '673', (6, 10))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', (6, 10))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', (142, 150))
77393	32276436	Since CDH23 mutations may coexist with BRAF or NRAS mutations, in future studies it would be interesting to analyse if the presence of CDH23 mutations could alter overall survival in BRAF or NRAS mutated melanoma patients, as it may lower patient overall survival and account for BRAF and NRAS resistance.	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('CDH23', 'Gene', (6, 11))	('NRAS', 'Gene', '4893', (47, 51))	('patients', 'Species', '9606', (213, 221))	('patient', 'Species', '9606', (239, 246))	('BRAF', 'Gene', '673', (39, 43))	('NRAS', 'Gene', (191, 195))	('patient', 'Species', '9606', (213, 220))	('CDH23', 'Gene', '64072', (135, 140))	('BRAF', 'Gene', (39, 43))	('lower', 'NegReg', (233, 238))	('CDH23', 'Gene', '64072', (6, 11))	('overall survival', 'MPA', (163, 179))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('mutations', 'Var', (141, 150))	('melanoma', 'Disease', (204, 212))	('NRAS', 'Gene', '4893', (289, 293))	('alter', 'Reg', (157, 162))	('NRAS', 'Gene', (47, 51))	('presence', 'Var', (123, 131))	('overall survival', 'CPA', (247, 263))	('BRAF', 'Gene', '673', (280, 284))	('BRAF', 'Gene', (280, 284))	('mutations', 'Var', (12, 21))	('NRAS', 'Gene', '4893', (191, 195))	('BRAF', 'Gene', '673', (183, 187))	('CDH23', 'Gene', (135, 140))	('NRAS', 'Gene', (289, 293))	('BRAF', 'Gene', (183, 187))
77394	32276436	In summary, we have identified three novel mutations in CDH23, ARHGEF40, and BRD9 genes, which could confer cutaneous melanoma susceptibility.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('cutaneous melanoma', 'Disease', (108, 126))	('ARHGEF40', 'Gene', '55701', (63, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (108, 126))	('BRD9', 'Gene', '65980', (77, 81))	('mutations', 'Var', (43, 52))	('confer', 'Reg', (101, 107))	('CDH23', 'Gene', (56, 61))	('BRD9', 'Gene', (77, 81))	('CDH23', 'Gene', '64072', (56, 61))	('ARHGEF40', 'Gene', (63, 71))
77396	32276436	Nevertheless, the polymorphic variants identified showed a statistically significant cumulative effect on melanoma, demonstrating that they could contribute to increased MPM susceptibility in a polygenic manner.	('variants', 'Var', (30, 38))	('MPM', 'Disease', (170, 173))	('increased', 'PosReg', (160, 169))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))
77398	32276436	The following are available online at , Figure S1: Structural models of CDH23 p.Ala266Thr pathogenic variant, Figure S2: Structural models of ARHGEF40 (Solo) p.Arg834Cys pathogenic variant, Figure S3: Analysis of the frequency of mutation in additional datasets, Table S1: Selected variants after bioinformatics analysis and subsequent Sanger validation, Table S2: Variant impact prediction by in silico tools, Table S3: Structural models of CDH23 and ARHGEF40 obtained by homology modelling using the SWISS-MODEL server, Table S4: Primer list employed for variant validation, Table S5: Patient clinicopathological data.	('p.Arg834Cys', 'Var', (158, 169))	('ARHGEF40', 'Gene', (142, 150))	('CDH23', 'Gene', '64072', (72, 77))	('Solo', 'Gene', (152, 156))	('variant', 'Var', (101, 108))	('ARHGEF40', 'Gene', '55701', (452, 460))	('p.Ala266Thr', 'Var', (78, 89))	('ARHGEF40', 'Gene', '55701', (142, 150))	('p.Arg834Cys', 'SUBSTITUTION', 'None', (158, 169))	('CDH23', 'Gene', '64072', (442, 447))	('ARHGEF40', 'Gene', (452, 460))	('CDH23', 'Gene', (72, 77))	('p.Ala266Thr', 'SUBSTITUTION', 'None', (78, 89))	('Patient', 'Species', '9606', (587, 594))	('Solo', 'Gene', '55701', (152, 156))	('CDH23', 'Gene', (442, 447))
77474	31020815	Excess body weight is associated with hyperinsulinemia, insulin resistance, and high insulin-like growth factor-1 levels, which lead to tumor growth via stimulation of angiogenesis and inhibition of apoptosis.	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('85', '111'))	('insulin', 'Gene', (85, 92))	('insulin', 'Gene', '3630', (43, 50))	('Excess body weight', 'Phenotype', 'HP:0004324', (0, 18))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (38, 54))	('Excess body', 'Var', (0, 11))	('angiogenesis', 'CPA', (168, 180))	('tumor', 'Disease', (136, 141))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (38, 54))	('stimulation of angiogenesis', 'biological_process', 'GO:0045766', ('153', '180'))	('insulin', 'Gene', '3630', (56, 63))	('insulin', 'Gene', (43, 50))	('insulin', 'molecular_function', 'GO:0016088', ('56', '63'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('insulin', 'Gene', '3630', (85, 92))	('inhibition', 'NegReg', (185, 195))	('lead to', 'Reg', (128, 135))	('insulin resistance', 'Phenotype', 'HP:0000855', (56, 74))	('inhibition of apoptosis', 'biological_process', 'GO:0043066', ('185', '208'))	('hyperinsulinemia', 'Disease', (38, 54))	('apoptosis', 'CPA', (199, 208))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('stimulation', 'PosReg', (153, 164))	('insulin', 'Gene', (56, 63))
77483	29151970	Cox proportional hazards regression analysis identified Ki67 expression and CLN status as independent prognostic factors in OMM patients.	('OMM', 'Chemical', '-', (124, 127))	('Ki67 expression', 'Var', (56, 71))	('OMM', 'Disease', (124, 127))	('Ki67', 'Chemical', '-', (56, 60))	('patients', 'Species', '9606', (128, 136))	('CLN status', 'Var', (76, 86))	('CLN', 'Chemical', '-', (76, 79))
77486	29151970	Conclusions: Ki67 expression may be a useful pathological predictor of survival of OMM patients without distant metastases.	('Ki67', 'Var', (13, 17))	('OMM', 'Chemical', '-', (83, 86))	('Ki67', 'Chemical', '-', (13, 17))	('metastases', 'Disease', (112, 122))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('OMM', 'Disease', (83, 86))	('patients', 'Species', '9606', (87, 95))
77496	29151970	The level of Ki67 expression has been used as a prognostic determination index in a number of human cancers , especially in breast carcinoma and cervical cancer.	('Ki67', 'Var', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Ki67', 'Chemical', '-', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast carcinoma and cervical cancer', 'Disease', 'MESH:D001943', (124, 160))	('human', 'Species', '9606', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('breast carcinoma', 'Phenotype', 'HP:0003002', (124, 140))	('cancers', 'Disease', (100, 107))
77498	29151970	Recently, some studies aimed to clarify whether Ki67 could act as a prognostic index in some subtypes of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('Ki67', 'Chemical', '-', (48, 52))	('Ki67', 'Var', (48, 52))
77543	29151970	Multivariate analysis confirmed that the presence of positive CLNs was an independent negative prognostic factor for OMM (HR, 1.717; 95% CI, 1.146-2.572; P = 0.009; Table 1).	('OMM', 'Chemical', '-', (117, 120))	('CLN', 'Chemical', '-', (62, 65))	('positive CLNs', 'Var', (53, 66))	('negative', 'NegReg', (86, 94))	('OMM', 'Disease', (117, 120))
77546	29151970	Kaplan-Meier survival curves showed that cases with high Ki67 expression had significantly poorer OS compared with low Ki67 expression cases (P <0.001).	('high Ki67 expression', 'Var', (52, 72))	('OS', 'Chemical', '-', (98, 100))	('poorer', 'NegReg', (91, 97))	('Ki67', 'Chemical', '-', (57, 61))	('Ki67', 'Chemical', '-', (119, 123))
77547	29151970	Multivariate analysis using the Cox regression hazard model confirmed that Ki67 expression was an independent prognostic factor for poor OS (HR, 1.474; 95% CI, 1.268-1.713; P < 0.001; Table 1) among patients with OMM.	('Ki67', 'Chemical', '-', (75, 79))	('Ki67 expression', 'Var', (75, 90))	('poor OS', 'Disease', (132, 139))	('OMM', 'Chemical', '-', (213, 216))	('patients', 'Species', '9606', (199, 207))	('OS', 'Chemical', '-', (137, 139))
77552	29151970	As shown, Ki67 expression was not significantly associated with other characteristics including gender, age, primary site, ECOG PS score, tumor size and CLN status.	('CLN', 'Chemical', '-', (153, 156))	('tumor', 'Disease', (138, 143))	('Ki67', 'Var', (10, 14))	('Ki67', 'Chemical', '-', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
77558	29151970	5, the expression of Ki67 in recurrent OMM was significantly higher than that in primary OMM (P = 0.03).	('Ki67', 'Var', (21, 25))	('higher', 'PosReg', (61, 67))	('Ki67', 'Chemical', '-', (21, 25))	('recurrent OMM', 'Disease', (29, 42))	('expression', 'MPA', (7, 17))	('OMM', 'Chemical', '-', (39, 42))	('OMM', 'Chemical', '-', (89, 92))
77560	29151970	The results showed that OMM patients with higher Ki67 scores (3-5) showed poor survival time in comparison to those with lower Ki67 scores (0-2) (Log-rank = 57.867, P < 0.001, Fig.	('OMM', 'Chemical', '-', (24, 27))	('Ki67', 'Chemical', '-', (127, 131))	('survival time', 'CPA', (79, 92))	('poor', 'NegReg', (74, 78))	('Ki67', 'Chemical', '-', (49, 53))	('OMM', 'Disease', (24, 27))	('patients', 'Species', '9606', (28, 36))	('Ki67 scores', 'Var', (49, 60))
77561	29151970	The present results revealed that CLN status and Ki67 expression score were independent prognostic factors of OMM (Table 1).	('OMM', 'Chemical', '-', (110, 113))	('Ki67', 'Chemical', '-', (49, 53))	('CLN status', 'Var', (34, 44))	('CLN', 'Chemical', '-', (34, 37))	('OMM', 'Disease', (110, 113))
77563	29151970	Patients with higher Ki67 expression score (3-5) showed significantly poorer OS compared to those with lower score (0-2) in both CLN-negative ((Log-rank = 47.635, P < 0.001, Fig.	('Ki67', 'Var', (21, 25))	('CLN', 'Chemical', '-', (129, 132))	('Ki67', 'Chemical', '-', (21, 25))	('poorer', 'NegReg', (70, 76))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (77, 79))
77581	29151970	The presence of Ki67 protein is an indicator of proliferative activity and is detected in the nucleus of cells during late G1, S, G2, and M phases, thus staining most cells in the cell cycle.	('Ki67', 'Var', (16, 20))	('nucleus', 'cellular_component', 'GO:0005634', ('94', '101'))	('staining', 'Reg', (153, 161))	('cell cycle', 'biological_process', 'GO:0007049', ('180', '190'))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('protein', 'Protein', (21, 28))	('Ki67', 'Chemical', '-', (16, 20))
77582	29151970	A series of studies have indicated that Ki67 could be used as a predictive and prognostic marker in a number of cancers including prostate cancer, gastrointestinal stromal tumors, clear-cell renal cell cancer, epithelial ovarian cancer and non-small-cell lung cancer.	('non-small-cell lung cancer', 'Disease', (240, 266))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (240, 266))	('prostate cancer', 'Disease', (130, 145))	('clear-cell renal cell cancer', 'Disease', 'MESH:C538614', (180, 208))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Ki67', 'Var', (40, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('Ki67', 'Chemical', '-', (40, 44))	('gastrointestinal stromal tumors', 'Disease', (147, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('cancers', 'Disease', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('clear-cell renal cell cancer', 'Disease', (180, 208))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('epithelial ovarian cancer', 'Disease', (210, 235))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (147, 178))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (147, 178))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (210, 235))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))
77583	29151970	In a meta-analysis of 64,196 breast cancer patients, authors concluded that Ki67 has an independent poor prognostic value in terms of OS.	('patients', 'Species', '9606', (43, 51))	('Ki67', 'Var', (76, 80))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('Ki67', 'Chemical', '-', (76, 80))	('OS', 'Chemical', '-', (134, 136))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
77591	29151970	It has been suggested that the level of Ki67 expression could be used as a decision-making tool during chemotherapy treatment of breast cancer.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('Ki67', 'Var', (40, 44))	('Ki67', 'Chemical', '-', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
77598	29151970	Our results identified that Ki67 expression was an adverse prognostic marker for OS time among patients with OMM and could act as an independent prognostic factor for OMMs, which may be developed as a useful histological parameter of prognostic significance of OMM without distant metastases in the future.	('adverse', 'NegReg', (51, 58))	('OMM', 'Chemical', '-', (261, 264))	('Ki67 expression', 'Var', (28, 43))	('patients', 'Species', '9606', (95, 103))	('OS time', 'Disease', (81, 88))	('metastases', 'Disease', (281, 291))	('Ki67', 'Chemical', '-', (28, 32))	('OMM', 'Chemical', '-', (109, 112))	('OS', 'Chemical', '-', (81, 83))	('OMM', 'Chemical', '-', (167, 170))	('metastases', 'Disease', 'MESH:D009362', (281, 291))
77607	29151970	Researchers observed tumors with overexpression of Ki67 (more than 10%) were thicker than those with low Ki67 expression.	('overexpression', 'PosReg', (33, 47))	('thicker', 'PosReg', (77, 84))	('Ki67', 'Chemical', '-', (51, 55))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('Ki67', 'Var', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Ki67', 'Chemical', '-', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
77613	29151970	Similar characteristics of Ki67 expression were seen in a number of other cancers.	('Ki67', 'Var', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('Ki67', 'Chemical', '-', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
77621	29151970	In summary, the present study demonstrates that Ki67 could act as an important molecular biological indicator for predicting the prognosis of distant metastases-free OMM patients.	('patients', 'Species', '9606', (170, 178))	('metastases-free OMM', 'Disease', (150, 169))	('metastases-free OMM', 'Disease', 'MESH:D009362', (150, 169))	('Ki67', 'Chemical', '-', (48, 52))	('Ki67', 'Var', (48, 52))
77622	29151970	Further, Ki67 is a potential candidate for pathological grading and staging of OMM in the future.	('OMM', 'Chemical', '-', (79, 82))	('Ki67', 'Var', (9, 13))	('OMM', 'Disease', (79, 82))	('Ki67', 'Chemical', '-', (9, 13))
77671	30583691	In a research conducted by Burger et al., (2012) on 168 patients, LNR was considered an independent prognostic factor for survival, and LNR was divided into three categories based on the study by Rossi et al., (2008) According to the results, the mortality rate was four times higher in the patients with the LNR of >0.25 compared to the subjects with the LNR of <0.1.	('patients', 'Species', '9606', (56, 64))	('LNR of >0.25', 'Var', (309, 321))	('higher', 'PosReg', (277, 283))	('patients', 'Species', '9606', (291, 299))	('mortality', 'MPA', (247, 256))
77675	30590044	Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators.	('tumor', 'Disease', (192, 197))	('Signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cytotoxicity', 'Disease', (143, 155))	('Mutations', 'Var', (0, 9))	('Hypoxic Signaling in Cancer', 'Disease', 'MESH:C566796', (95, 122))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('Innate Immunity Pathway', 'Pathway', (16, 39))	('Hypoxic Signaling in Cancer', 'Disease', (95, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('Innate Immunity', 'biological_process', 'GO:0045087', ('16', '31'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
77677	30590044	We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types.	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('changes', 'Reg', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('overall survival', 'MPA', (144, 160))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (180, 186))	('complement genes', 'Gene', (55, 71))
77678	30590044	Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('colorectal cancer', 'Disease', (168, 185))	('hypoxia', 'Disease', (157, 164))	('crosstalk', 'Reg', (124, 133))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
77679	30590044	The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55.	('mutations', 'Var', (131, 140))	('complement', 'Gene', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increased', 'PosReg', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('hypoxia', 'Disease', 'MESH:D000860', (233, 240))	('hypoxic tumor', 'Disease', 'MESH:D009369', (146, 159))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cytotoxicity', 'Disease', (203, 215))	('hypoxia', 'Disease', (233, 240))	('hypoxic signaling', 'MPA', (69, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('signaling', 'biological_process', 'GO:0023052', ('77', '86'))	('CD55', 'Gene', (284, 288))	('hypoxic tumor', 'Disease', (146, 159))
77681	30590044	Mutations in the complement system are prevalent across cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('prevalent', 'Reg', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Mutations', 'Var', (0, 9))	('complement system', 'Gene', (17, 34))
77682	30590044	find that colorectal cancers with complement component mutations are associated with increased hypoxic signaling and poor overall survival outcomes.	('increased hypoxic', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('colorectal cancers', 'Disease', 'MESH:D015179', (10, 28))	('mutations', 'Var', (55, 64))	('colorectal cancers', 'Disease', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('increased hypoxic', 'Disease', 'MESH:D000860', (85, 102))
77684	30590044	Since uncontrolled activation of the complement system is associated with cell lysis/cytotoxicity and can result in normal tissue toxicity, the pathway is tightly controlled by membrane-bound regulators such as CD35 (complement receptor type 1), CD46 (membrane cofactor protein), CD55 (complement decay accelerating factor), and CD59 (protectin).	('toxicity', 'Disease', (130, 138))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('result', 'Reg', (106, 112))	('membrane', 'cellular_component', 'GO:0016020', ('252', '260'))	('membrane', 'cellular_component', 'GO:0016020', ('177', '185'))	('toxicity', 'Disease', (89, 97))	('CD46', 'Gene', (246, 250))	('complement receptor type 1', 'Gene', '1378', (217, 243))	('CD35', 'Gene', '1378', (211, 215))	('protein', 'cellular_component', 'GO:0003675', ('270', '277'))	('complement decay accelerating factor', 'Gene', (286, 322))	('lysis', 'biological_process', 'GO:0019835', ('79', '84'))	('complement decay accelerating factor', 'Gene', '1604', (286, 322))	('CD46', 'Gene', '4179', (246, 250))	('CD55', 'Var', (280, 284))	('membrane cofactor protein', 'Gene', '4179', (252, 277))	('CD35', 'Gene', (211, 215))	('complement receptor type 1', 'Gene', (217, 243))	('membrane cofactor protein', 'Gene', (252, 277))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('cytotoxicity', 'Disease', (85, 97))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
77689	30590044	The existence of complement mutations across cancer types could provide additional evidence to support a role for complement in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('complement', 'Gene', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (28, 37))
77691	30590044	As the complement system is a complex set of over 50 proteins converging on functional networks, interrogation of mutations across cancer types and within the whole pathway is likely to yield the most insights about the relevance of any potential alterations.	('cancer', 'Disease', (131, 137))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
77693	30590044	Exome sequencing efforts, including TCGA datasets, have also recently proved useful in finding patient-specific tumor-derived antigens (neoantigens) arising as a consequence of tumor-specific mutations.	('mutations', 'Var', (192, 201))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (177, 182))
77696	30590044	Our analysis of pathways expressed in patients with complement mutations associated with poor prognostic outcomes reveals crosstalk between the complement system and hypoxia.	('mutations', 'Var', (63, 72))	('crosstalk', 'Reg', (122, 131))	('associated', 'Reg', (73, 83))	('patients', 'Species', '9606', (38, 46))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('hypoxia', 'Disease', (166, 173))
77705	30590044	Importantly, those tumors with dysregulated complement through either protein or genetic alterations are associated with the worse prognostic outcome, highlighting the clinical relevance of these findings.	('dysregulated', 'Var', (31, 43))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('complement', 'Protein', (44, 54))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('genetic alterations', 'Var', (81, 100))	('clinical', 'Species', '191496', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('rat', 'Species', '10116', (93, 96))
77706	30590044	Using TCGA, we found that mutations and copy number alterations (CNAs) in complement system genes occurred in all tumor types queried (Figure 1A).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('mutations', 'Var', (26, 35))	('complement system genes', 'Gene', (74, 97))	('occurred', 'Reg', (98, 106))	('copy number alterations', 'Var', (40, 63))
77710	30590044	Furthermore, methylation changes of 40 complement genes are also significantly correlated with mRNA expression changes (correlation coefficients ranging from :0.5562 to 0.3180), suggesting that methylation and CNA could alter complement pathway activation through mechanisms independent of alterations in protein structure.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation', 'Var', (194, 205))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('rat', 'Species', '10116', (294, 297))	('mRNA', 'MPA', (95, 99))	('activation', 'MPA', (245, 255))	('protein', 'cellular_component', 'GO:0003675', ('305', '312'))	('alter', 'Reg', (220, 225))	('complement pathway', 'Pathway', (226, 244))
77712	30590044	KS test analysis revealed that mutations in complement system genes, as a group, occurred at a rate above background in 8 of the cancers analyzed (Figure 1B; Table S1C).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('rat', 'Species', '10116', (95, 98))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('complement system genes', 'Gene', (44, 67))	('occurred', 'Reg', (81, 89))	('KS', 'Chemical', '-', (0, 2))
77713	30590044	A pan-cancer meta-analysis of the KS test results maintained significance even without melanoma, which had an individually high rate of complement mutations (Figure 1C; Table S1C).	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('KS', 'Chemical', '-', (34, 36))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('rat', 'Species', '10116', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
77716	30590044	Interestingly, we found that, across a number of cancer types, several complement mutations scored as significant (Figure 1D; Table S1D).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (82, 91))	('significant', 'Reg', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
77717	30590044	Given the rising interest in the role of T cell-mediated responses mounted to tumor-derived antigens, we asked whether any of the mutations predicted to be drivers by MutSig2CV analysis could also give rise to neoantigens with sufficiently strong predicted binding affinities (<500 nM) by NetMHCpan.	('binding', 'molecular_function', 'GO:0005488', ('257', '264'))	('binding', 'Interaction', (257, 264))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('give rise', 'Reg', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NetMHCpan', 'Chemical', '-', (289, 298))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', (78, 83))	('neoantigens', 'MPA', (210, 221))
77718	30590044	To assess the relevance of the predicted binding affinities for complement mutation-derived neoantigens in comparison with frequently mutated cancer drivers, we analyzed an equivalent number of peptides derived from mutations in three driver genes in colorectal cancer as assessed by MutSig2CV (APC, TP53, and ARID1A).	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('APC', 'Disease', 'MESH:D011125', (295, 298))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('TP53', 'Gene', '7157', (300, 304))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('APC', 'Disease', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('APC', 'cellular_component', 'GO:0005680', ('295', '298'))	('TP53', 'Gene', (300, 304))	('ARID1A', 'Gene', '8289', (310, 316))	('colorectal cancer', 'Disease', (251, 268))	('ARID1A', 'Gene', (310, 316))	('mutations', 'Var', (216, 225))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (251, 268))	('cancer', 'Disease', (142, 148))
77721	30590044	Given the prevalence of complement mutation-derived neoantigens with high binding affinities, we asked whether any of the complement mutations predicted to be drivers would also be expected to result in changes in immune infiltrates.	('rat', 'Species', '10116', (227, 230))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))	('immune infiltrates', 'MPA', (214, 232))	('mutations', 'Var', (133, 142))	('changes', 'Reg', (203, 210))	('binding', 'Interaction', (74, 81))
77722	30590044	Interestingly, several of these mutations were associated with significant increased cytolytic activity, CD8+ T cells, and cytotoxic lymphocyte infiltration (Figures S1C-S1I).	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('cytolytic activity', 'CPA', (85, 103))	('rat', 'Species', '10116', (150, 153))	('cytotoxic lymphocyte infiltration', 'CPA', (123, 156))	('mutations', 'Var', (32, 41))	('increased', 'PosReg', (75, 84))
77725	30590044	This analysis confirmed that complement mutations occur at a global level, with 79.7% of datasets analyzed (including 34 different cancer types) containing at least one complement network and several datasets containing more than one mutated complement network (Figure 2A; Table S2A).	('cancer', 'Disease', (131, 137))	('containing', 'Reg', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
77726	30590044	These data support the hypothesis that mutations in complement genes may be cooperative in nature, with genes working within functional networks.	('rat', 'Species', '10116', (81, 84))	('complement genes', 'Gene', (52, 68))	('mutations', 'Var', (39, 48))
77727	30590044	We hypothesized that grouping mutations into subsets based on known gene function, and then performing downstream analysis, could provide information about the functional relevance of these mutations and their possible cooperation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mutations', 'Var', (190, 199))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('mutations', 'Var', (30, 39))	('rat', 'Species', '10116', (224, 227))	('cancer', 'Disease', (234, 240))
77729	30590044	Interestingly, when performing these analyses, we found that several groups of mutations and CNAs were associated with changes in overall survival outcome across different cancer types (Figures 2B-2G; Tables S2C-S2N).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('changes', 'Reg', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('overall survival', 'MPA', (130, 146))	('cancer', 'Disease', (172, 178))	('CNAs', 'Gene', (93, 97))	('mutations', 'Var', (79, 88))
77730	30590044	The association between component mutations in colorectal cancer and poor overall survival outcome is noteworthy (Figures 2B and2C).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('mutations', 'Var', (34, 43))
77731	30590044	In addition, there is a strong association between poor overall survival and amplifications in components in skin cutaneous melanoma (SKCM) and deletions in regulators in LGG (Figures 2D-2G).	('skin cutaneous melanoma', 'Disease', (109, 132))	('amplifications', 'Var', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('overall survival', 'MPA', (56, 72))	('deletions', 'Var', (144, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('LGG', 'Gene', (171, 174))	('poor', 'NegReg', (51, 55))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (109, 132))
77734	30590044	Similarly to what we had observed from our multivariate analysis, we found that multiple complement gene mutations and CNA were significantly associated with poor overall survival outcomes (e.g., mutations in components in COADREAD, p value = 0.00273).	('poor', 'NegReg', (158, 162))	('complement gene', 'Gene', (89, 104))	('mutations', 'Var', (105, 114))	('associated', 'Reg', (142, 152))	('COADREAD', 'Disease', 'None', (223, 231))	('CNA', 'Gene', (119, 122))	('COADREAD', 'Disease', (223, 231))	('mutations', 'Var', (196, 205))
77737	30590044	These analyses showed significant correlations with overall survival for certain groups of genes (e.g., protease and receptor mutations, q < 0.05), as well as for individual genes (e.g., mutations and deletions in C1QA, p < 0.05), even when performing stage, age, and cancer-type corrections (Tables S2O-S2T).	('C1QA', 'Gene', (214, 218))	('cancer-type', 'Disease', 'MESH:D009369', (268, 279))	('C1QA', 'Gene', '712', (214, 218))	('deletions', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer-type', 'Disease', (268, 279))	('mutations', 'Var', (187, 196))	('mutations', 'Var', (126, 135))	('correlations', 'Reg', (34, 46))
77738	30590044	Overall, these analyses demonstrate that certain complement mutations and CNAs (either analyzed at the individual gene level or in gene subsets) are associated with changes in overall survival, both in specific cancer types as well as when analyzed at the pan-cancer level.	('CNAs', 'Gene', (74, 78))	('overall survival', 'MPA', (176, 192))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (211, 217))	('complement', 'Gene', (49, 59))	('cancer', 'Disease', (260, 266))	('changes', 'Reg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('rat', 'Species', '10116', (31, 34))
77743	30590044	Overall, hypoxia gene sets as a whole were enriched in patients with complement mutations (p value = 0.0005, GSEA-squared), with two of the four additional hypoxia signatures nominally enriched (p < 0.05) in these two groups of patients (Figures S2C and S2D; Tables S3A, S3D, and S3E).	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', (9, 16))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (228, 236))	('GSEA', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (55, 63))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
77745	30590044	We then refined the analysis by asking whether hypoxia signatures were also enriched specifically in patients with component mutations in colorectal cancer, where a strong association between these mutations and poor overall survival had been observed.	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (101, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
77746	30590044	Overall, hypoxia signatures as a whole were enriched in patients with component mutations (p value = 0.0008, GSEA-squared) with four of five signatures being nominally enriched (p < 0.05) (Figures 3B-3E; Tables S3B-S3E and S3G-S3I).	('patients', 'Species', '9606', (56, 64))	('hypoxia', 'Disease', (9, 16))	('mutations', 'Var', (80, 89))	('GSEA', 'Chemical', '-', (109, 113))	('S3G-S3I', 'Var', (223, 230))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
77748	30590044	To assess the specificity of the association between hypoxia and complement mutations in colorectal cancer, we asked whether component mutations were also associated with hypoxia signatures in SKCM, another cancer type where this group of mutations was associated with poor outcome.	('hypoxia', 'Disease', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('cancer', 'Disease', (207, 213))	('SKCM', 'Disease', (193, 197))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('associated', 'Reg', (155, 165))	('mutations', 'Var', (135, 144))	('colorectal cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('hypoxia', 'Disease', (171, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
77749	30590044	Interestingly, no significant association was found between component mutations in SKCM and hypoxia signatures in this group (Figure S2G; Table S3J).	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('SKCM', 'Gene', (83, 87))	('mutations', 'Var', (70, 79))	('hypoxia', 'Disease', (92, 99))
77750	30590044	To extend these analyses, we also asked whether hypoxia signatures would be enriched in patients with mutations in a different group of complement genes, the regulators, also associated with poor overall survival in LGG, and once again observed no significant association (Figure S2H; Table S3K).	('LGG', 'Disease', (216, 219))	('poor', 'NegReg', (191, 195))	('associated with', 'Reg', (175, 190))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (102, 111))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('hypoxia', 'Disease', (48, 55))
77751	30590044	These data suggest certain specificity in the association between component mutations and hypoxia in colorectal cancer, and therefore we decided to focus on colorectal cancer for our subsequent experiments.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('mutations', 'Var', (76, 85))	('colorectal cancer', 'Disease', (157, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('association', 'Interaction', (46, 57))	('hypoxia', 'Disease', (90, 97))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
77752	30590044	Furthermore, these data suggest that colorectal cancer patients with component mutations have tumors associated with high expression of hypoxia signatures, and therefore may have more hypoxic tumors, providing one potential explanation for the poor overall survival observed in this patient population.	('hypoxia', 'Disease', (136, 143))	('tumors', 'Disease', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('hypoxic tumors', 'Disease', (184, 198))	('mutations', 'Var', (79, 88))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (283, 290))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('colorectal cancer', 'Disease', (37, 54))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('hypoxic tumors', 'Disease', 'MESH:D009369', (184, 198))
77756	30590044	Notably, the murine colorectal cancer cells tested, CT26, have a mutation in central complement component C3 (pV254I).	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('complement component C3', 'Disease', (85, 108))	('complement component C3', 'Disease', 'MESH:C565169', (85, 108))	('colorectal cancer', 'Disease', (20, 37))	('CT26', 'CellLine', 'CVCL:7254', (52, 56))	('murine', 'Species', '10090', (13, 19))	('mutation', 'Var', (65, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('pV254I', 'Gene', (110, 116))
77757	30590044	The human colorectal cancer cells tested, HCT116 also harbor a C3 mutation, but in this case the C3 mutation is silent, and therefore should not alter amino acid sequence.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))	('colorectal cancer', 'Disease', (10, 27))	('mutation', 'Var', (66, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
77759	30590044	On one hand, complement component mutations are highly associated with hypoxia signatures and therefore hypoxia-induced gene expression changes.	('hypoxia', 'Disease', (71, 78))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))	('associated', 'Reg', (55, 65))	('complement component', 'Gene', (13, 33))	('expression', 'MPA', (125, 135))	('gene expression', 'biological_process', 'GO:0010467', ('120', '135'))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('mutations', 'Var', (34, 43))
77760	30590044	On the other, we note that hypoxia itself can also regulate the terminal consequence of complement system activation by making cancer cells (including those with complement component mutations) more resistant to CMC.	('resistant', 'CPA', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (183, 192))	('CMC', 'Chemical', '-', (212, 215))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('hypoxia', 'Disease', (27, 34))	('cancer', 'Disease', (127, 133))
77765	30590044	We asked whether increased mRNA levels of either of these regulators was associated with a hypoxia signature (same as was used in Figure 3A) and found that there was a positive and significant correlation between CD55 mRNA expression and the hypoxia signature tested in colorectal cancer TCGA patient samples (Figure 4B).	('hypoxia', 'Disease', (242, 249))	('increased', 'PosReg', (17, 26))	('hypoxia', 'Disease', 'MESH:D000860', (242, 249))	('colorectal cancer', 'Disease', (270, 287))	('hypoxia', 'Disease', (91, 98))	('CD55', 'Var', (213, 217))	('patient', 'Species', '9606', (293, 300))	('colorectal cancer', 'Disease', 'MESH:D015179', (270, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('colorectal cancer', 'Phenotype', 'HP:0003003', (270, 287))	('mRNA levels', 'MPA', (27, 38))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
77770	30590044	Notably, CD55 mRNA expression in colorectal cancer correlates with poor patient prognosis (Figure 4C).	('CD55 mRNA', 'Var', (9, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('patient', 'Species', '9606', (72, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('colorectal cancer', 'Disease', (33, 50))
77776	30590044	These data suggested that both HIF1alpha and HIF2alpha contribute to the regulation of CD55 under hypoxic conditions (Figures S3G and S3H).	('hypoxic conditions', 'Disease', 'MESH:D009135', (98, 116))	('regulation', 'MPA', (73, 83))	('CD55', 'Gene', (87, 91))	('hypoxic conditions', 'Disease', (98, 116))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))	('S3H', 'Var', (134, 137))
77777	30590044	Since the greatest decrease in CD55 expression was observed following depletion of the dimerization HIFa partner, HIF1beta, these data indicate that the hypoxia-inducible expression of CD55 is likely dependent on both HIF1alpha and HIF2alpha (since loss of HIF1beta leads to loss of HIF1alpha- and HIF2alpha-dependent transcriptional activation).	('decrease', 'NegReg', (19, 27))	('CD55', 'Gene', (185, 189))	('HIF1beta', 'Gene', '405', (114, 122))	('HIF1beta', 'Gene', '405', (257, 265))	('CD55', 'Gene', (31, 35))	('loss', 'Var', (249, 253))	('hypoxia', 'Disease', 'MESH:D000860', (153, 160))	('hypoxia', 'Disease', (153, 160))	('HIF1beta', 'Gene', (257, 265))	('expression', 'MPA', (36, 46))	('HIF1beta', 'Gene', (114, 122))
77788	30590044	Pathway-level mutational analysis revealed that complement pathway mutations are widespread across many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('complement pathway', 'Pathway', (48, 66))	('mutations', 'Var', (67, 76))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
77789	30590044	Additionally, KS test analysis revealed that mutations in complement genes, as a group, occur at a rate above background in a number of the cancers analyzed.	('mutations', 'Var', (45, 54))	('rat', 'Species', '10116', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('occur', 'Reg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('KS', 'Chemical', '-', (14, 16))	('complement genes', 'Gene', (58, 74))
77791	30590044	This is due to the fact that specific groups of mutations in these cancer types could still be clinically significant if not analyzed as a block.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('clinical', 'Species', '191496', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (48, 57))
77792	30590044	Indeed, analysis of immune infiltration differences between patients with and without CD55 mutations (one of the mutations giving rise to neoantigens) correlates with altered immune infiltrates including increased cytotoxic T cell responses.	('cytotoxic T cell responses', 'CPA', (214, 240))	('patients', 'Species', '9606', (60, 68))	('increased', 'PosReg', (204, 213))	('CD55', 'Gene', (86, 90))	('rat', 'Species', '10116', (33, 36))	('mutations', 'Var', (91, 100))	('rat', 'Species', '10116', (188, 191))	('altered', 'Reg', (167, 174))
77796	30590044	A closer look at the CD55 mutations identified in colorectal cancer suggests that these mutations occur across different short consensus repeat (SCR) domains, suggesting that they are likely to be loss of function.	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('CD55', 'Gene', (21, 25))	('short consensus repeat', 'Disease', 'MESH:D000647', (121, 143))	('short consensus repeat', 'Disease', (121, 143))	('mutations', 'Var', (26, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
77797	30590044	However, to our knowledge, none of the CD55 mutations we report here overlap with variants identified in other diseases such as Cromer Inab phenotype (lack of all Cromer complex blood group antigens) or even those variants that have been associated with lung cancer or gastric cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('gastric cancer', 'Disease', (269, 283))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('lung cancer', 'Disease', (254, 265))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (44, 53))	('variants', 'Var', (214, 222))	('associated', 'Reg', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('CD55', 'Gene', (39, 43))
77798	30590044	Interestingly, showed that missense mutation L205F (present in a colon adenocarcinoma patient) results in 50% reduced CD55 function compared to wild-type CD55.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (65, 85))	('reduced', 'NegReg', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('L205F', 'Mutation', 'p.L205F', (45, 50))	('patient', 'Species', '9606', (86, 93))	('CD55', 'Protein', (118, 122))	('L205F', 'Var', (45, 50))	('colon adenocarcinoma', 'Disease', (65, 85))
77799	30590044	We note, however, that CD55 mutations are not associated with changes in overall survival in colorectal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('CD55', 'Gene', (23, 27))	('colorectal cancer', 'Disease', (93, 110))	('mutations', 'Var', (28, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('patients', 'Species', '9606', (111, 119))
77800	30590044	In contrast, we report that high CD55 mRNA expression is significantly associated with decreased disease-free survival in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('decreased', 'NegReg', (87, 96))	('colorectal cancer', 'Disease', (122, 139))	('CD55', 'Protein', (33, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('disease-free survival', 'CPA', (97, 118))	('high', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
77819	30590044	However, while apoptosis programs may also be triggered in hypoxic tumors (especially in a p53 wild-type tumor), it is common for tumors to evade such apoptosis through mechanisms including p53 mutations.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0006915', ('151', '160'))	('apoptosis', 'biological_process', 'GO:0097194', ('15', '24'))	('apoptosis', 'biological_process', 'GO:0006915', ('15', '24'))	('hypoxic tumors', 'Disease', (59, 73))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('p53', 'Gene', '7157', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (105, 110))	('apoptosis programs', 'CPA', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p53', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', (130, 136))	('mutations', 'Var', (194, 203))	('p53', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('hypoxic tumors', 'Disease', 'MESH:D009369', (59, 73))	('evade', 'NegReg', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
77853	30590044	To determine the enrichment of complement mutations in each TCGA cancer, a modified Kolmogorov-Smirnov (KS) test using the method of GSEA (kt.test2; https://github.com/franapoli/signed-ks-test) was performed on "mutation ranks."	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('GSEA', 'Chemical', '-', (133, 137))	('cancer', 'Disease', (65, 71))	('mutations', 'Var', (42, 51))	('KS', 'Chemical', '-', (104, 106))
77874	30590044	The list of variants predicted as "cancer drivers" by Mutsig2CV was used for neoantigen prediction (following removal of synonymous mutations), Genes, mutations, neoantigens and predicted binding affinities (IC50) are shown in Tables S1E-S1I).	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (12, 20))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
77875	30590044	The term neoantigen refers to tumor specific DNA alterations that give rise to novel peptide sequences, usually entirely absent from the normal human genome.	('alterations', 'Var', (49, 60))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('rat', 'Species', '10116', (53, 56))	('give rise to', 'Reg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
77876	30590044	The list of variants and the list of HLA alleles was fed into the NetMHCpan (v3) via topiary tool (https://github.com/openvax/topiary) to calculate predicted binding affinities of predicted true neoantigens.	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('variants', 'Var', (12, 20))	('NetMHCpan', 'Chemical', '-', (66, 75))	('binding', 'Interaction', (158, 165))
77900	30590044	An additional covariate of mutational load which is the sum of all non-silent mutations in a cancer sample was used (variable: corrected.for.load.wal.pval; Tables S2C, S2E, S2G, S2I, S2K, and S2M) to control for genomic instability and as a proxy for MSI.	('S2K', 'Var', (183, 186))	('S2M', 'Var', (192, 195))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MSI', 'Disease', 'None', (251, 254))	('MSI', 'Disease', (251, 254))	('S2I', 'Var', (178, 181))	('S2M', 'Mutation', 'p.S2M', (192, 195))	('S2E', 'Var', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('S2G', 'Var', (173, 176))
77901	30590044	These data represent Benjamani Hochberg corrected Log q-values of the model including age, stage, gender, and in the cases of COADREAD, ESCA, STAD and UCEC also mutational load correction.	('COADREAD', 'Disease', 'None', (126, 134))	('ESCA', 'Disease', (136, 140))	('COADREAD', 'Disease', (126, 134))	('mutational load correction', 'Var', (161, 187))
77907	30590044	Complement mutations occur at a significantly higher rate than background mutations Complement component mutations are associated with poor overall survival Tumors with complement component mutations harbor increased hypoxic signaling Hypoxic colorectal cancer cells are resistant to complement-mediated cytotoxicity	('Hypoxic colorectal cancer', 'Disease', (235, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('complement component', 'Gene', (169, 189))	('cytotoxicity', 'Disease', (304, 316))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('mutations', 'Var', (190, 199))	('Hypoxic colorectal cancer', 'Disease', 'MESH:D015179', (235, 260))	('increased hypoxic', 'Disease', 'MESH:D000860', (207, 224))	('Tumors', 'Disease', (157, 163))	('Tumors', 'Disease', 'MESH:D009369', (157, 163))	('Tumors', 'Phenotype', 'HP:0002664', (157, 163))	('rat', 'Species', '10116', (53, 56))	('increased hypoxic', 'Disease', (207, 224))	('cytotoxicity', 'Disease', 'MESH:D064420', (304, 316))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('Tumor', 'Phenotype', 'HP:0002664', (157, 162))
77923	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))
77930	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
77931	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
77965	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', (61, 64))	('cancer', 'Disease', (113, 119))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
77994	32199022	Consequently, AS is a vital process, and any changes to the splicing pattern is strongly related to protein functions, which in turn impacts numerous physiological functions of the human body, like hematopoiesis, brain development, and muscular activity.	('human', 'Species', '9606', (181, 186))	('brain development', 'biological_process', 'GO:0007420', ('213', '230'))	('hematopoiesis', 'Disease', 'MESH:C536227', (198, 211))	('splicing', 'biological_process', 'GO:0045292', ('60', '68'))	('protein', 'Protein', (100, 107))	('hematopoiesis', 'biological_process', 'GO:0030097', ('198', '211'))	('related', 'Reg', (89, 96))	('impacts', 'Reg', (133, 140))	('hematopoiesis', 'Disease', (198, 211))	('muscular activity', 'CPA', (236, 253))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('changes', 'Var', (45, 52))	('brain development', 'CPA', (213, 230))
78000	32199022	According to genomic classification, SKCM could be divided into 4 subtypes: BRAF hotspot mutants subtype (52%, mainly BRAF V600E, V600K, and V600R mutations), RAS hotspot mutants subtype (28%, mainly RAS Q61R, Q61K, Q61L, Q61H, G12R/D/A, and G13R/D mutations), NF1 any mutants subtype (14%, NF1 any mutations) and triple wild-type subtype (6%, lack of hot-spot BRAF, N/H/K-RAS, or NF1 mutations).	('NF1', 'Gene', '4763', (261, 264))	('G12R', 'SUBSTITUTION', 'None', (228, 232))	('G12R', 'Var', (228, 232))	('NF1', 'Gene', (381, 384))	('NF1', 'Gene', (261, 264))	('V600R mutations', 'Var', (141, 156))	('Q61R', 'Mutation', 'rs121913240', (204, 208))	('NF1', 'Gene', '4763', (291, 294))	('V600E', 'Mutation', 'rs113488022', (123, 128))	('G13R', 'Var', (242, 246))	('mutants', 'Var', (89, 96))	('Q61L', 'Var', (216, 220))	('V600K', 'Mutation', 'rs121913227', (130, 135))	('RAS', 'Disease', (159, 162))	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', (118, 122))	('NF1', 'Gene', (291, 294))	('G13R', 'SUBSTITUTION', 'None', (242, 246))	('Q61L', 'Mutation', 'rs121913240', (216, 220))	('Q61K', 'Mutation', 'rs121913238', (210, 214))	('V600E', 'Var', (123, 128))	('BRAF', 'Gene', (76, 80))	('Q61H', 'Mutation', 'rs1418502863', (222, 226))	('BRAF', 'Gene', (361, 365))	('BRAF', 'Gene', '673', (361, 365))	('V600R', 'Mutation', 'rs121913227', (141, 146))	('BRAF', 'Gene', '673', (76, 80))	('K-RAS', 'Gene', (371, 376))	('K-RAS', 'Gene', '3845', (371, 376))	('V600K', 'Var', (130, 135))	('Q61K', 'Var', (210, 214))	('NF1', 'Gene', '4763', (381, 384))	('Q61H', 'Var', (222, 226))
78027	32199022	Their associations at the transcriptome level are presented in Figure 8A, which shows 2 genes with negative correlation, among which TFR2 mutation might result in abnormality in the cell cycle, while RALGPS1 was found to be associated with lung cancer as well as acute lymphoblastic leukemia.	('abnormality', 'MPA', (163, 174))	('associated', 'Reg', (224, 234))	('mutation', 'Var', (138, 146))	('lung cancer', 'Disease', 'MESH:D008175', (240, 251))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (269, 291))	('TFR2', 'Gene', (133, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (240, 251))	('leukemia', 'Phenotype', 'HP:0001909', (283, 291))	('cell cycle', 'CPA', (182, 192))	('result in', 'Reg', (153, 162))	('TFR2', 'Gene', '7036', (133, 137))	('RALGPS1', 'Gene', (200, 207))	('RALGPS1', 'Gene', '9649', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('acute lymphoblastic leukemia', 'Disease', (263, 291))	('abnormality in the cell cycle', 'Phenotype', 'HP:0011018', (163, 192))	('lung cancer', 'Disease', (240, 251))	('cell cycle', 'biological_process', 'GO:0007049', ('182', '192'))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (263, 291))
78042	32199022	AS has a key great part to play in regulating gene expression; as a result, any abnormality in splicing may be related to various human diseases.	('splicing', 'MPA', (95, 103))	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('related', 'Reg', (111, 118))	('abnormality', 'Var', (80, 91))	('splicing', 'biological_process', 'GO:0045292', ('95', '103'))	('human', 'Species', '9606', (130, 135))
78043	32199022	Specifically, abnormalities in AS have been frequently detected in different cancers, exemplified by p53 and PTEN, BRCA1 and PRMT2 in breast cancer, TIMP1 and CD44 in colon cancer, together with Bcl-xL and CD44 in lung cancer.	('abnormalities', 'Var', (14, 27))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('BRCA1', 'Gene', '672', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('PTEN', 'Gene', '5728', (109, 113))	('BRCA1', 'Gene', (115, 120))	('lung cancer', 'Disease', (214, 225))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('TIMP1', 'Gene', (149, 154))	('breast cancer', 'Disease', (134, 147))	('PRMT2', 'Gene', '3275', (125, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('CD44', 'Gene', '960', (206, 210))	('CD44', 'Gene', (206, 210))	('CD44', 'Gene', '960', (159, 163))	('CD44', 'Gene', (159, 163))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('TIMP1', 'Gene', '7076', (149, 154))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PRMT2', 'Gene', (125, 130))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('p53', 'Gene', '7157', (101, 104))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('detected', 'Reg', (55, 63))	('Bcl-xL', 'Gene', (195, 201))	('PTEN', 'Gene', (109, 113))	('p53', 'Gene', (101, 104))	('colon cancer', 'Disease', (167, 179))	('Bcl-xL', 'Gene', '598', (195, 201))
78045	32199022	It has been reported in the literature that aberrant JMJD6 splicing level boosts the carcinogenesis of melanoma by regulating the PAK1 AS.	('boosts', 'PosReg', (74, 80))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('PAK1', 'Gene', '5058', (130, 134))	('JMJD6', 'Gene', (53, 58))	('JMJD6', 'Gene', '23210', (53, 58))	('PAK1', 'Gene', (130, 134))	('splicing', 'biological_process', 'GO:0045292', ('59', '67'))	('carcinogenesis of', 'CPA', (85, 102))	('regulating', 'Reg', (115, 125))	('aberrant', 'Var', (44, 52))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
78056	32199022	MCF2L is widely studied in the field of inflammatory diseases, and variants of MCF2L could aggravate osteoarthritis immune response.	('inflammatory diseases', 'Disease', 'MESH:D007249', (40, 61))	('MCF2L', 'Gene', (0, 5))	('MCF2L', 'Gene', '23263', (0, 5))	('osteoarthritis', 'Phenotype', 'HP:0002758', (101, 115))	('osteoarthritis', 'Disease', (101, 115))	('inflammatory diseases', 'Disease', (40, 61))	('MCF2L', 'Gene', (79, 84))	('MCF2L', 'Gene', '23263', (79, 84))	('osteoarthritis', 'Disease', 'MESH:D010003', (101, 115))	('variants', 'Var', (67, 75))	('aggravate', 'PosReg', (91, 100))	('immune response', 'biological_process', 'GO:0006955', ('116', '131'))
78061	32199022	RalA has been reported to be widely activated in human SKCM cell lines and shRNA-mediated knockdown of RalA could inhibit SKCM cell line growth .	('SKCM cell line growth', 'CPA', (122, 143))	('inhibit', 'NegReg', (114, 121))	('knockdown', 'Var', (90, 99))	('human', 'Species', '9606', (49, 54))	('RalA', 'Gene', (103, 107))
78065	20231618	Presence of Tumor-Infiltrating Lymphocytes and a Dominant Nodule Within Primary Melanoma Are Prognostic Factors for Relapse-Free Survival of Patients With Thick (T4) Primary Melanoma Pathologic Analysis of the E1690 and E1694 Intergroup Trials Lymphocytic infiltration of primary cutaneous melanoma has been demonstrated to be of prognostic significance.	('primary cutaneous melanoma', 'Disease', (272, 298))	('E1690', 'Var', (210, 215))	('Patients', 'Species', '9606', (141, 149))	('E1694', 'Var', (220, 225))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (280, 298))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('Lymphocytic infiltration', 'Disease', (244, 268))	('Melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Dominant Nodule Within Primary Melanoma', 'Disease', (49, 88))	('Primary Melanoma', 'Disease', 'MESH:D008545', (72, 88))	('Primary Melanoma', 'Disease', (166, 182))	('Tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Primary Melanoma', 'Disease', 'MESH:D008545', (166, 182))	('Lymphocytic infiltration', 'Disease', 'MESH:D017254', (244, 268))	('Dominant Nodule Within Primary Melanoma', 'Disease', 'MESH:D001929', (49, 88))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (272, 298))	('Melanoma', 'Phenotype', 'HP:0002861', (174, 182))
78067	20231618	In multivariate analysis, there was significant correlation of the presence of TILs and improved survival.	('TIL', 'Gene', '7096', (79, 82))	('presence', 'Var', (67, 75))	('survival', 'CPA', (97, 105))	('TIL', 'Gene', (79, 82))	('improved', 'PosReg', (88, 96))
78085	20231618	Eligibility criteria for intergroup trials E1694 and E1690 included patients with primary cutaneous melanoma thicker than 4 mm in the absence of regional node metastases (American Joint Committee on Cancer stage II B disease) or the presence of regional lymph node involvement (American Joint Committee on Cancer stage III disease) at diagnosis or at subsequent recurrence.	('metastases', 'Disease', (159, 169))	('Cancer', 'Disease', 'MESH:D009369', (306, 312))	('primary cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('E1690', 'Var', (53, 58))	('Cancer', 'Disease', (199, 205))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('Cancer', 'Phenotype', 'HP:0002664', (199, 205))	('patients', 'Species', '9606', (68, 76))	('Cancer', 'Disease', 'MESH:D009369', (199, 205))	('primary cutaneous melanoma', 'Disease', (82, 108))	('Cancer', 'Phenotype', 'HP:0002664', (306, 312))	('Cancer', 'Disease', (306, 312))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('E1694', 'Var', (43, 48))
78089	20231618	Pathology slides of the primary tumor were available from 14 patients in the E1690 trial and 342 patients in the E1694 trial.	('primary tumor', 'Disease', (24, 37))	('primary tumor', 'Disease', 'MESH:D009369', (24, 37))	('patients', 'Species', '9606', (61, 69))	('E1690', 'Var', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('patients', 'Species', '9606', (97, 105))
78107	20231618	For the study, 293 patients were evaluated (12 from E1690 and 281 from E1694).	('E1694', 'Var', (71, 76))	('E1690', 'Var', (52, 57))	('patients', 'Species', '9606', (19, 27))
78109	20231618	Of the patients, 144 received high-dose interferon and 149 patients were assigned observation (E1690) or vaccination (E1694) with GMK (Progenics, Tarrytown, NY).	('GMK', 'Gene', (130, 133))	('patients', 'Species', '9606', (59, 67))	('E1694', 'Var', (118, 123))	('GMK', 'Gene', '2987', (130, 133))	('patients', 'Species', '9606', (7, 15))
78118	20231618	The presence of a DN had a significantly adverse effect on RFS when analysis was stratified by TIL pattern (P =.038).	('RFS', 'MPA', (59, 62))	('TIL', 'Gene', (95, 98))	('DN', 'Chemical', '-', (18, 20))	('RFS', 'Chemical', '-', (59, 62))	('presence', 'Var', (4, 12))	('TIL', 'Gene', '7096', (95, 98))	('adverse', 'NegReg', (41, 48))
78119	20231618	The presence of a DN had an adverse effect on OS (P = .089) and RFS (P = .051) when stratified according to lymph node involvement.	('RFS', 'Chemical', '-', (64, 67))	('DN', 'Chemical', '-', (18, 20))	('RFS', 'CPA', (64, 67))	('OS', 'Chemical', '-', (46, 48))	('presence', 'Var', (4, 12))
78126	20231618	The 5-year OS rates were 0.72 (95% CI, 0.58-0.86) in patients with brisk TILs, 0.54 (95% CI, 0.46-0.62) in patients with nonbrisk TILs, and 0.54 (95% CI, 0.44-0.64) in patients with no TILs.	('OS', 'Chemical', '-', (11, 13))	('TIL', 'Gene', '7096', (130, 133))	('patients', 'Species', '9606', (53, 61))	('TIL', 'Gene', '7096', (185, 188))	('nonbrisk', 'Var', (121, 129))	('TIL', 'Gene', '7096', (73, 76))	('TIL', 'Gene', (130, 133))	('patients', 'Species', '9606', (168, 176))	('TIL', 'Gene', (185, 188))	('TIL', 'Gene', (73, 76))	('patients', 'Species', '9606', (107, 115))
78132	20231618	In the Cox model, TIL status grouped according to brisk vs absent/nonbrisk was significantly associated with OS (P = .033) and RFS (P = .055), while adjusting for Breslow thickness, node involvement, and ulceration.	('TIL', 'Gene', '7096', (18, 21))	('RFS', 'Disease', (127, 130))	('RFS', 'Chemical', '-', (127, 130))	('associated', 'Reg', (93, 103))	('TIL', 'Gene', (18, 21))	('OS', 'Chemical', '-', (109, 111))	('brisk', 'Var', (50, 55))
78164	20231618	Although the presence of brisk or nonbrisk TILs in the primary tumor was a significant prognostic factor in multivariate analysis (adjusting for other risk factors), TILs did not achieve significance in univariate analysis.	('TIL', 'Gene', (43, 46))	('brisk', 'Var', (25, 30))	('primary tumor', 'Disease', (55, 68))	('TIL', 'Gene', '7096', (166, 169))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TIL', 'Gene', '7096', (43, 46))	('TIL', 'Gene', (166, 169))
78176	32855398	Current methods for reconstructing evolution from bulk sequencing data rely on computational approaches to identify sets of mutations that are present in a similar proportion of cells within the tumour.	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('mutations', 'Var', (124, 133))	('tumour', 'Disease', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
78177	32855398	For each set of mutations, the fraction of cancer cells (cancer cell fraction, CCF) carrying them may be estimated from their allele frequencies by adjusting for purity and copy number.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (57, 63))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cell fraction', 'cellular_component', 'GO:0000267', ('64', '77'))
78178	32855398	As neoplastic cells proliferate, some of their daughter cells can acquire mutations that convey a selective advantage, allowing them to become precursors for new tumour cell lineages.	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Disease', (162, 168))	('mutations', 'Var', (74, 83))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
78182	32855398	Throughout this study, we refer to mutations (and mutation clusters) observed in all tumour cells within a sample as 'clonal', those found in a subset of tumour cells as 'subclonal' and those found clonally in all samples from the same patient as 'truncal'.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', (154, 160))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('patient', 'Species', '9606', (236, 243))	('mutations', 'Var', (35, 44))
78184	32855398	In this paper we extend the definition of ITH to 'intra-patient tumour heterogeneity', using it to refer to the observation of variants within a tumour that are non-truncal, including variants that may be clonal within some individual samples.	('variants', 'Var', (127, 135))	('tumour', 'Disease', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('variants', 'Var', (184, 192))	('patient', 'Species', '9606', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
78185	32855398	The mutational load of melanoma is one of the highest among all malignancies and, as somatic mutations provide an insight into a cancer's initiation and evolution, genome sequencing studies can provide valuable insights into the progression of the disease.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('malignancies', 'Disease', (64, 76))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('mutational', 'Var', (4, 14))
78186	32855398	Using targeted panel sequencing of 263 cancer driver genes across 12 primary melanomas matched with regional metastases, Shain and colleagues demonstrated that whilst some primary melanomas and matching regional metastases have pathogenic mutations in just one branch of the phylogenetic tree, there were no driver mutations exclusive to metastases (i.e., not shared with the primaries).	('metastases', 'Disease', 'MESH:D009362', (212, 222))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('metastases', 'Disease', (338, 348))	('melanomas', 'Disease', (77, 86))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('metastases', 'Disease', 'MESH:D009362', (338, 348))	('mutations', 'Var', (239, 248))	('metastases', 'Disease', (109, 119))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('melanomas', 'Disease', (180, 189))	('metastases', 'Disease', 'MESH:D009362', (109, 119))	('metastases', 'Disease', (212, 222))
78187	32855398	By further showing that most somatic alterations (point mutations and copy number changes) were shared, the authors concluded that primary melanomas and melanoma metastases tend to select for the same set of pathogenic mutations.	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanomas', 'Disease', (139, 148))	('melanoma metastases', 'Disease', (153, 172))	('mutations', 'Var', (219, 228))	('melanoma metastases', 'Disease', 'MESH:D009362', (153, 172))
78189	32855398	Although many private mutations were subclonal, this study found polyclonal seeding (defined as a sample harbouring subclonal mutations from 2 or more clonal lineages each of which is also found in another tumour site, thus representing multiple seeding events by two or more genotypically distinct cells) to be a rare event.	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('mutations', 'Var', (22, 31))	('mutations', 'Var', (126, 135))	('polyclonal', 'Disease', (65, 75))	('tumour', 'Disease', (206, 212))
78190	32855398	A picture has therefore emerged whereby the majority of mutations in melanoma metastases are truncal and shared by all progeny.	('melanoma metastases', 'Disease', (69, 88))	('mutations', 'Var', (56, 65))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma metastases', 'Disease', 'MESH:D009362', (69, 88))
78191	32855398	Leading up to the formation of a primary melanoma, a stepwise model of progression has been proposed, which includes selection for particular advantageous molecular alterations (including copy number aberrations), facilitating the sequential transition through successive stages.	('formation', 'biological_process', 'GO:0009058', ('18', '27'))	('copy number aberrations', 'Var', (188, 211))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
78193	32855398	Multi-site sequencing studies in melanoma have thus far been based on a small number of single nucleotide variants (SNVs) falling in coding exons, with gene panels focussed on SNVs in known cancer genes.	('falling', 'NegReg', (122, 129))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('single nucleotide variants', 'Var', (88, 114))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('falling', 'Phenotype', 'HP:0002527', (122, 129))
78194	32855398	The VAF can also be affected by contributions from alleles in stroma and infiltrating immune cells, as well as the presence of both the mutated and wildtype alleles in the tumour.	('VAF', 'CPA', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('affected', 'Reg', (20, 28))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('mutated', 'Var', (136, 143))
78195	32855398	Importantly, changes to the copy number of a locus may also alter the VAF dramatically and, if not accounted for, will result in inaccurate clonal frequency estimates, giving a misleading picture of the clonal structure of a tumour.	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('alter', 'Reg', (60, 65))	('tumour', 'Disease', (225, 231))	('result', 'Reg', (119, 125))	('changes', 'Var', (13, 20))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('copy number', 'Var', (28, 39))	('clonal', 'MPA', (140, 146))	('VAF', 'MPA', (70, 73))
78199	32855398	Using multi-sample clonality analyses across 13 whole-genome sequenced metastases from this patient, as well as multi-site analyses of whole-exome sequenced metastases from a further 7 patients, we identify clusters of co-occurring truncal, clonal and subclonal mutations across multiple samples, and uncover the chronological order of genomic alterations.	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('patient', 'Species', '9606', (92, 99))	('truncal', 'Disease', (232, 239))	('metastases', 'Disease', (71, 81))	('patient', 'Species', '9606', (185, 192))	('patients', 'Species', '9606', (185, 193))	('metastases', 'Disease', 'MESH:D009362', (71, 81))	('mutations', 'Var', (262, 271))	('metastases', 'Disease', (157, 167))
78218	32855398	We detected 1993 putative somatic indels, of which 10 were frameshifts and common to all metastases (see 'Data availability' section).	('frameshifts', 'Var', (59, 70))	('metastases', 'Disease', (89, 99))	('metastases', 'Disease', 'MESH:D009362', (89, 99))
78219	32855398	All 13 metastases carried an activating missense BRAFV600R mutation (c.1798_1799delGTinAG), as well as mutations in the melanoma driver genes PTENA43T and MAP2K1G128S (the latter has not been previously reported in the COSMIC database), and a splice-site variant in ARID2, all of which were truncal across all metastases.	('activating', 'PosReg', (29, 39))	('mutations', 'Var', (103, 112))	('metastases', 'Disease', (310, 320))	('metastases', 'Disease', 'MESH:D009362', (7, 17))	('MAP2K1', 'Gene', (155, 161))	('MAP2K', 'molecular_function', 'GO:0004708', ('155', '160'))	('ARID2', 'Gene', '196528', (266, 271))	('BRAFV600R', 'Gene', (49, 58))	('c.1798_1799delGT', 'Var', (69, 85))	('c.1798_1799delGT', 'DELETION', 'None', (69, 85))	('metastases', 'Disease', 'MESH:D009362', (310, 320))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('ARID2', 'Gene', (266, 271))	('metastases', 'Disease', (7, 17))	('PTENA43T', 'Gene', (142, 150))	('MAP2K1', 'Gene', '5604', (155, 161))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
78223	32855398	Using this approach, we found that >90% of all somatic variants in the metastases were metastatic-truncal, with only one additional cluster which represents at least 1% of the SNVs (N =1651, 1.35%).	('metastatic-truncal', 'Disease', (87, 105))	('metastases', 'Disease', (71, 81))	('variants', 'Var', (55, 63))	('metastases', 'Disease', 'MESH:D009362', (71, 81))
78224	32855398	The large metastatic-truncal cluster was dominated by C > T transitions at dipyrimidines (characteristic of UV-induced mutational damage) and was shared across all metastases, implying that ITH was absent (Fig.	('metastases', 'Disease', 'MESH:D009362', (164, 174))	('C > T transitions', 'Var', (54, 71))	('metastases', 'Disease', (164, 174))	('dipyrimidines', 'Chemical', '-', (75, 88))
78225	32855398	None of these variants were in established cancer driver genes listed in the Catalogue of Somatic Mutations In Cancer (COSMIC).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('variants', 'Var', (14, 22))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))
78235	32855398	In addition to the main clonal cluster, we further identified that the two primary tumour samples harboured the same subclone represented by 37 SNVs (at CCF 0.25 95% CI 0.22-0.37 and 0.29 95% CI 0.18-0.34 for samples PD38258u and PD38258v, respectively).	('PD38258u', 'Var', (217, 225))	('PD38258u', 'Chemical', '-', (217, 225))	('primary tumour', 'Disease', (75, 89))	('PD38258v', 'Var', (230, 238))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('primary tumour', 'Disease', 'MESH:D009369', (75, 89))	('PD38258v', 'Chemical', '-', (230, 238))
78241	32855398	We identified an average of 598 (range of 108-2088) non-synonymous coding variants (including missense, nonsense and splice-region mutations), and 7 (range 2-15) frameshift variants per patient, both totalled across all samples within each patient (see 'Data availability' section).	('variants', 'Var', (74, 82))	('patient', 'Species', '9606', (240, 247))	('patient', 'Species', '9606', (186, 193))	('frameshift', 'Reg', (162, 172))
78244	32855398	All 7 patients had metastases harbouring an activating BRAFV600E driver mutation and, in accordance with previous reports, all melanoma drivers were represented on the trunks (rather than the branches) of the phylogenetic trees (except for a previously unreported TP53R141C mutation in patient MultiSite_WES_Patient1) (Fig.	('activating', 'PosReg', (44, 54))	('TP53', 'Gene', '7157', (264, 268))	('TP53', 'Gene', (264, 268))	('BRAFV600E', 'Var', (55, 64))	('patient', 'Species', '9606', (6, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('metastases', 'Disease', (19, 29))	('patients', 'Species', '9606', (6, 14))	('patient', 'Species', '9606', (286, 293))	('melanoma', 'Disease', (127, 135))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('metastases', 'Disease', 'MESH:D009362', (19, 29))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))
78257	32855398	This guanine nucleotide exchange factor has previously been shown to be upregulated in a cell line model of melanoma brain metastasis (cerebrotropic A375Br cells vs. parental A375P cells) and silencing of PLEKHA5 expression decreased in-vitro potential of these cells to cross the blood-brain barrier.	('silencing', 'Var', (192, 201))	('A375Br', 'CellLine', 'CVCL:0132', (149, 155))	('PLEKHA5', 'Gene', '54477', (205, 212))	('decreased', 'NegReg', (224, 233))	('in-vitro potential', 'CPA', (234, 252))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (5, 23))	('melanoma brain metastasis', 'Disease', (108, 133))	('upregulated', 'PosReg', (72, 83))	('guanine nucleotide exchange factor', 'MPA', (5, 39))	('A375P', 'CellLine', 'CVCL:6233', (175, 180))	('melanoma brain metastasis', 'Disease', 'MESH:D009362', (108, 133))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('PLEKHA5', 'Gene', (205, 212))
78259	32855398	This is consistent with recent analyses implicating the upregulation of oxidative phosphorylation in patient-matched brain vs. extracranial metastases, as well as further functional studies demonstrating that inhibition of this pathway resulted in increased survival in both implantation xenografts and spontaneous murine models of melanoma brain metastases.	('oxidative phosphorylation', 'MPA', (72, 97))	('upregulation', 'PosReg', (56, 68))	('metastases', 'Disease', 'MESH:D009362', (347, 357))	('increased', 'PosReg', (248, 257))	('survival', 'CPA', (258, 266))	('inhibition', 'Var', (209, 219))	('murine', 'Species', '10090', (315, 321))	('metastases', 'Disease', (140, 150))	('melanoma brain metastases', 'Disease', 'MESH:D009362', (332, 357))	('melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('upregulation of oxidative phosphorylation', 'biological_process', 'GO:1903862', ('56', '97'))	('melanoma brain metastases', 'Disease', (332, 357))	('patient', 'Species', '9606', (101, 108))	('metastases', 'Disease', 'MESH:D009362', (140, 150))	('metastases', 'Disease', (347, 357))
78266	32855398	In our study, analyses of clonal structure from multi-site whole-genome sequenced melanoma metastases provided a powerful method to detect mutation clusters and a unique insight into clonal evolution.	('melanoma metastases', 'Disease', (82, 101))	('mutation clusters', 'Var', (139, 156))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma metastases', 'Disease', 'MESH:D009362', (82, 101))
78267	32855398	In agreement with previous literature, we identified a single cluster of truncal variants ubiquitously represented across all metastases and representing >90% of all somatic SNVs.	('metastases', 'Disease', (126, 136))	('truncal variants', 'Var', (73, 89))	('metastases', 'Disease', 'MESH:D009362', (126, 136))
78268	32855398	Initial analyses therefore showed that ITH appeared to be absent and that metastases were derived from a single parental clone harbouring the majority of genetic alterations.	('genetic alterations', 'Var', (154, 173))	('metastases', 'Disease', (74, 84))	('metastases', 'Disease', 'MESH:D009362', (74, 84))
78275	32855398	In a previous single-patient WGS study analysing a primary acral melanoma and its concurrent ipsilateral inguinal lymph node, a wide spectrum of SNVs and copy number alterations were found to be shared between the primary and metastatic tumour, however, the phylogenetic architecture could not be fully reconstructed.	('copy number alterations', 'Var', (154, 177))	('acral melanoma', 'Phenotype', 'HP:0012060', (59, 73))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('patient', 'Species', '9606', (21, 28))	('acral melanoma', 'Disease', 'MESH:D008545', (59, 73))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Disease', (237, 243))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('acral melanoma', 'Disease', (59, 73))
78277	32855398	A recent detailed multi-regional clonality analysis in uveal melanomas has also found multiple driver mutations in the branches of the phylogenetic trees, suggesting that these melanomas also continue to evolve as they progress from primary to metastatic disease.	('melanomas', 'Phenotype', 'HP:0002861', (177, 186))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('uveal melanomas', 'Disease', 'MESH:C536494', (55, 70))	('melanomas', 'Disease', 'MESH:D008545', (177, 186))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('uveal melanomas', 'Disease', (55, 70))	('mutations', 'Var', (102, 111))	('primary', 'Disease', (233, 240))	('uveal melanomas', 'Phenotype', 'HP:0007716', (55, 70))	('metastatic disease', 'Disease', (244, 262))	('melanomas', 'Disease', (177, 186))	('melanomas', 'Disease', (61, 70))
78280	32855398	This contrasts with recent reports in prostate cancer, where branching generally occurred throughout the tumours' evolutionary trajectories, and with studies of various other tumour types reporting the frequent occurrence of subclonal driver mutations, but is concordant with previous studies of melanoma.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('melanoma', 'Disease', (296, 304))	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('melanoma', 'Disease', 'MESH:D008545', (296, 304))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumour', 'Disease', (105, 111))	('tumours', 'Disease', (105, 112))	('mutations', 'Var', (242, 251))	('prostate cancer', 'Disease', (38, 53))	('tumour', 'Disease', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))
78286	32855398	This is consistent with lung cancer analyses, where subclonal lineages acquired mutations that lacked the tobacco-smoking signature and were replaced with mutations associated with APOBEC cytidine deaminase activity.	('lacked', 'NegReg', (95, 101))	('mutations', 'Var', (80, 89))	('APOBEC', 'cellular_component', 'GO:0030895', ('181', '187'))	('tobacco', 'Species', '4097', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('cytidine deaminase activity', 'molecular_function', 'GO:0004126', ('188', '215'))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
78318	32855398	The validation experiment was enriched to cover all 2247 metastatic non-truncal variant positions, 652 manually selected metastatic truncal variant positions (identified as either cancer driver mutations or with loss-of-function mutations from the truncal cluster).	('loss-of-function', 'NegReg', (212, 228))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (229, 238))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
78323	32855398	DNA was extracted from the two tumour blocks from the same chest wall primary and variants supported by at least 2 alternate bases were called in the primary (samples PD38258u and PD38258v).	('PD38258v', 'Chemical', '-', (180, 188))	('PD38258u', 'Var', (167, 175))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('PD38258u', 'Chemical', '-', (167, 175))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))	('PD38258v', 'Var', (180, 188))
78342	32855398	The CCF represents the fraction of tumour cells carrying a mutation, and accounts for differences in tumour purity and copy number.	('tumour', 'Disease', (101, 107))	('tumour purity', 'Disease', (101, 114))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('mutation', 'Var', (59, 67))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour purity', 'Disease', 'MESH:D009369', (101, 114))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Disease', (35, 41))
78363	30254376	Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma.	('BRAF', 'Gene', (190, 194))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('Drug resistance', 'Phenotype', 'HP:0020174', (108, 123))	('mutated', 'Var', (91, 98))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('BRAF', 'Gene', '673', (86, 90))	('drug resistance', 'biological_process', 'GO:0009315', ('67', '82'))	('drug resistance', 'Phenotype', 'HP:0020174', (67, 82))	('Drug resistance', 'biological_process', 'GO:0009315', ('108', '123'))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('drug resistance', 'biological_process', 'GO:0042493', ('67', '82'))	('Drug resistance', 'biological_process', 'GO:0042493', ('108', '123'))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BRAF', 'Gene', (86, 90))	('BRAF', 'Gene', '673', (190, 194))
78369	30254376	Kinase inhibitors (KIs) of the MAPK pathway were developed following the discovery that BRAF mutations occurring in nearly 50% of patients are major oncogenic drivers of melanoma proliferation and survival.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('mutations', 'Var', (93, 102))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('31', '35'))	('melanoma proliferation', 'Disease', (170, 192))	('melanoma proliferation', 'Disease', 'MESH:D008545', (170, 192))	('patients', 'Species', '9606', (130, 138))
78378	30254376	These transcriptome changes involve both cell intrinsic and cell extrinsic mechanisms, and reset the interaction of melanoma cells with cells of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('reset', 'Reg', (91, 96))	('interaction', 'Interaction', (101, 112))	('tumor', 'Disease', (149, 154))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('changes', 'Var', (20, 27))	('involve', 'Reg', (28, 35))
78381	30254376	In this context we started to assess deregulation of miRNA expression as a major non-genomic alteration at the basis of de novo drug resistance in melanoma.	('drug resistance', 'biological_process', 'GO:0009315', ('128', '143'))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('drug resistance', 'biological_process', 'GO:0042493', ('128', '143'))	('drug resistance', 'Phenotype', 'HP:0020174', (128, 143))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('deregulation', 'Var', (37, 49))
78392	30254376	BRAF-V600 mutations were evaluated through Sanger method from genomic DNA extracted from M14 and WM266 melanoma cells.	('WM266', 'Chemical', '-', (97, 102))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
78423	30254376	Two human BRAF-mutated cell lines bearing different mutations (M14/V600E; WM266/V600D) were exposed to increasing drug concentrations (from 50 nM to 2 muM every two weeks for a total period of 2 months) (Fig.	('human', 'Species', '9606', (4, 9))	('WM266', 'Chemical', '-', (74, 79))	('V600E', 'Mutation', 'rs113488022', (67, 72))	('BRAF', 'Gene', '673', (10, 14))	('BRAF', 'Gene', (10, 14))	('V600D', 'Mutation', 'rs121913377', (80, 85))	('M14/V600E', 'Var', (63, 72))
78424	30254376	BRAF mutational status in these two melanoma cell lines was confirmed by direct sequencing (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('BRAF', 'Gene', '673', (0, 4))	('mutational', 'Var', (5, 15))	('BRAF', 'Gene', (0, 4))
78431	30254376	1e, every dot represents cell populations at a given drug dose), confirmed that changes of the entire miRNome expression (n = 800 miRNAs) are able to distinguish different drug sensitivity states.	('changes', 'Var', (80, 87))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('drug sensitivity', 'Phenotype', 'HP:0020174', (172, 188))
78464	30254376	Indeed miR-204-5p enforced expression in M14S melanoma cells reduced Bcl-2 expression levels both at RNA and protein levels (Fig.	('M14S', 'SUBSTITUTION', 'None', (41, 45))	('miR-204', 'Gene', '406987', (7, 14))	('Bcl-2', 'Gene', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('Bcl-2', 'Gene', '596', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('M14S', 'Var', (41, 45))	('miR-204', 'Gene', (7, 14))	('Bcl-2', 'molecular_function', 'GO:0015283', ('69', '74'))	('reduced', 'NegReg', (61, 68))	('RNA', 'cellular_component', 'GO:0005562', ('101', '104'))
78474	30254376	Interestingly, modulation of autophagy has been postulated to be a potential mechanism of adaptive resistance to MAPKi in sensitive and resistant BRAF-mutated melanoma cells.	('melanoma', 'Disease', (159, 167))	('BRAF', 'Gene', (146, 150))	('autophagy', 'biological_process', 'GO:0016236', ('29', '38'))	('modulation', 'Var', (15, 25))	('autophagy', 'biological_process', 'GO:0006914', ('29', '38'))	('autophagy', 'CPA', (29, 38))	('BRAF', 'Gene', '673', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
78477	30254376	Therefore, we decided to validate this prediction through qRT-PCR following UPMIRNAs enforced expression in M14S melanoma cells.	('M14S', 'SUBSTITUTION', 'None', (108, 112))	('UPMIRNAs', 'PosReg', (76, 84))	('M14S', 'Var', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))
78480	30254376	Hence, we assessed TIMP2 expression levels upon miR-4443 overexpression in M14S melanoma cells.	('miR-4443', 'Gene', '100616407', (48, 56))	('overexpression', 'PosReg', (57, 71))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('TIMP2', 'Gene', '7077', (19, 24))	('miR-4443', 'Gene', (48, 56))	('M14S', 'Var', (75, 79))	('TIMP2', 'Gene', (19, 24))	('M14S', 'SUBSTITUTION', 'None', (75, 79))
78486	30254376	All the combinations tested were able to strongly reduce M14R melanoma cell colony formation as compared to single treatments: miR-204-5p + miR199b-5p, amiR-4443 + amiR-4488, miR-204-5p + amiR-4443, miR-204-5p + amiR-4488, miR-199b-5p + amiR-4443 and miR-199b-5p + amiR-4488 (Fig.	('miR', 'Gene', '220972', (140, 143))	('miR-204', 'Gene', (127, 134))	('miR', 'Gene', (251, 254))	('miR-199b', 'Gene', '406978', (223, 231))	('miR-204', 'Gene', (199, 206))	('miR', 'Gene', (189, 192))	('miR-4488', 'Gene', (213, 221))	('miR-204', 'Gene', (175, 182))	('miR', 'Gene', (165, 168))	('miR-4488', 'Gene', (165, 173))	('miR-199b', 'Gene', '406978', (251, 259))	('miR-4488', 'Gene', (266, 274))	('miR-4443', 'Gene', '100616407', (189, 197))	('miR', 'Gene', (266, 269))	('miR-4488', 'Gene', '100616470', (165, 173))	('miR-4488', 'Gene', '100616470', (213, 221))	('miR', 'Gene', (140, 143))	('formation', 'biological_process', 'GO:0009058', ('83', '92'))	('miR-4488', 'Gene', '100616470', (266, 274))	('miR-4443', 'Gene', (189, 197))	('M14R', 'Mutation', 'p.M14R', (57, 61))	('miR', 'Gene', '220972', (238, 241))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', '220972', (213, 216))	('miR-204', 'Gene', '406987', (127, 134))	('miR-204', 'Gene', '406987', (175, 182))	('miR-204', 'Gene', '406987', (199, 206))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', '220972', (175, 178))	('miR', 'Gene', '220972', (199, 202))	('miR', 'Gene', '220972', (266, 269))	('combinations', 'Var', (8, 20))	('miR', 'Gene', '220972', (223, 226))	('miR', 'Gene', (238, 241))	('miR-199b', 'Gene', (223, 231))	('miR-4443', 'Gene', '100616407', (238, 246))	('miR', 'Gene', (153, 156))	('reduce', 'NegReg', (50, 56))	('miR', 'Gene', (213, 216))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('miR-4443', 'Gene', '100616407', (153, 161))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', (127, 130))	('miR', 'Gene', (175, 178))	('miR', 'Gene', '220972', (251, 254))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (199, 202))	('miR', 'Gene', (223, 226))	('miR-199b', 'Gene', (251, 259))	('miR-4443', 'Gene', (238, 246))	('miR-4443', 'Gene', (153, 161))
78487	30254376	These findings were confirmed in two additional melanoma cell lines rendered resistant to a BRAFi, namely WM266R and A375R (Supplementary Fig.	('melanoma', 'Disease', (48, 56))	('A375R', 'Mutation', 'p.A375R', (117, 122))	('WM266R', 'Var', (106, 112))	('BRAF', 'Gene', '673', (92, 96))	('WM266R', 'Chemical', '-', (106, 112))	('BRAF', 'Gene', (92, 96))	('A375R', 'Var', (117, 122))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
78489	30254376	Others have previously reported that double-drug-resistant melanoma cell lines are more difficult to growth inhibit.	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('double-drug-resistant', 'Var', (37, 58))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
78490	30254376	Indeed, we observed no growth inhibition effect on A375DR when the four miRNAs were targeted individually (Supplementary Fig.	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))	('A375DR', 'Var', (51, 57))
78500	30254376	Of note, also in this case upregulation of cytokine genes was more pronounced in WM266 BRAFi-resistant cells.	('cytokine genes', 'Gene', (43, 57))	('upregulation', 'PosReg', (27, 39))	('WM266', 'Var', (81, 86))	('WM266 BRAFi', 'CellLine', 'CVCL:2765', (81, 92))
78508	30254376	Accordingly, tubes formed by cord-like structures in HUVEC co-cultured with WM266R cells were strongly enhanced as compared to HUVEC co-cultured with parental WM266S cells (Fig.	('WM266', 'Chemical', '-', (159, 164))	('WM266', 'Chemical', '-', (76, 81))	('tubes formed by cord-like structures', 'CPA', (13, 49))	('WM266R cells', 'Var', (76, 88))	('WM266R', 'Chemical', '-', (76, 82))	('enhanced', 'PosReg', (103, 111))
78510	30254376	S5C, confirmed that tube formation induced by CM from WM266R melanoma cells was as efficient as recombinant VEGF and was significantly inhibited by the addition of either drug.	('tube formation', 'CPA', (20, 34))	('VEGF', 'Gene', (108, 112))	('WM266R', 'Chemical', '-', (54, 60))	('VEGF', 'Gene', '7422', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('tube formation', 'biological_process', 'GO:0035148', ('20', '34'))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('inhibited', 'NegReg', (135, 144))	('WM266R', 'Var', (54, 60))
78511	30254376	In order to find a correlation between miRNAs deregulation and VEGF increased production, we focused our attention on members of miR-199 family since they were reported to control VEGF expression.	('VEGF', 'Gene', (63, 67))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('VEGF', 'Gene', (180, 184))	('expression', 'MPA', (185, 195))	('VEGF', 'Gene', '7422', (63, 67))	('deregulation', 'Var', (46, 58))	('VEGF', 'Gene', '7422', (180, 184))
78553	30254376	Secondly, deregulated miRNA collectively control a growing number of signaling pathways which affect both cell intrinsic growth behaviors such as resistance to apoptosis and autophagy, as well as drivers of the interactions of melanoma cells with the tumor microenvironment through the increased secretion of a large set of proinflammatory and pro-angiogenic factors.	('tumor', 'Disease', (251, 256))	('cell intrinsic growth behaviors', 'CPA', (106, 137))	('affect', 'Reg', (94, 100))	('autophagy', 'biological_process', 'GO:0016236', ('174', '183'))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('autophagy', 'CPA', (174, 183))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('deregulated', 'Var', (10, 21))	('autophagy', 'biological_process', 'GO:0006914', ('174', '183'))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('secretion', 'biological_process', 'GO:0046903', ('296', '305'))	('signaling pathways', 'Pathway', (69, 87))	('miR', 'Gene', '220972', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('resistance to apoptosis', 'CPA', (146, 169))	('increased', 'PosReg', (286, 295))	('secretion', 'MPA', (296, 305))	('control', 'Reg', (41, 48))	('interactions', 'Interaction', (211, 223))	('miR', 'Gene', (22, 25))
78571	30254376	BRAF inhibitors increase melanoma cell contractility, induce changes in cell shape by rewiring their cytoskeleton and activating the YAP/TAZ mechanotransduction pathway.	('cytoskeleton', 'cellular_component', 'GO:0005856', ('101', '113'))	('rewiring', 'Reg', (86, 94))	('cell shape', 'CPA', (72, 82))	('TAZ', 'Gene', (137, 140))	('changes', 'Reg', (61, 68))	('TAZ', 'Gene', '6901', (137, 140))	('inhibitors', 'Var', (5, 15))	('YAP', 'Gene', '10413', (133, 136))	('increase', 'PosReg', (16, 24))	('cytoskeleton', 'CPA', (101, 113))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (25, 33))	('activating', 'PosReg', (118, 128))	('YAP', 'Gene', (133, 136))
78574	30254376	Likewise, it will be important to further dissect if miRNA deregulation is contributing to modify the reciprocal interaction of melanoma cells with other cells of the tumour microenvironment such as CAFs, macrophages, NK cells and cells of the adaptive immune system.	('miR', 'Gene', '220972', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('miR', 'Gene', (53, 56))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('deregulation', 'Var', (59, 71))	('tumour', 'Disease', (167, 173))	('modify', 'Reg', (91, 97))	('reciprocal interaction', 'MPA', (102, 124))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
78576	30254376	Reverting the expression of deregulated miRNAs by either enforcing expression of DOWNMIRNAs or inhibiting expression of UPMIRNAs was able consistently to impair in concert with BRAF and MEK inhibitors the emergence of drug resistance in vitro in short term as well as in long-term clonogenic assays.	('impair', 'NegReg', (154, 160))	('drug resistance', 'Phenotype', 'HP:0020174', (218, 233))	('inhibiting', 'NegReg', (95, 105))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('DOWNMIRNAs', 'Var', (81, 91))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('drug resistance', 'biological_process', 'GO:0009315', ('218', '233'))	('drug resistance', 'biological_process', 'GO:0042493', ('218', '233'))	('expression', 'MPA', (67, 77))	('emergence', 'MPA', (205, 214))	('MEK', 'Gene', (186, 189))	('MEK', 'Gene', '5609', (186, 189))
78578	30254376	The most likely explanation is that double drug-resistant melanoma cells activate, in order to survive, a plethora of parallel oncogenic pathways, which require in order to be rewired their simultaneous inhibition by a combined set of pleiotropic inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('oncogenic pathways', 'Pathway', (127, 145))	('double drug-resistant', 'Var', (36, 57))	('activate', 'PosReg', (73, 81))	('plethora', 'Phenotype', 'HP:0001050', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
78584	31398831	Atypical BRAF and NRAS Mutations in Mucosal Melanoma Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas.	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('BRAF', 'Gene', (9, 13))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (160, 179))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (160, 178))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (160, 179))	('melanomas', 'Disease', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))	('NRAS', 'Gene', (18, 22))	('Mucosal Melanoma', 'Disease', (36, 52))	('cutaneous melanomas', 'Disease', (160, 179))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('Mutations', 'Var', (23, 32))	('melanomas', 'Disease', (103, 112))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('NRAS', 'Gene', '4893', (18, 22))	('Primary mucosal melanomas', 'Disease', (53, 78))	('melanomas', 'Disease', (69, 78))	('Primary mucosal melanomas', 'Disease', 'MESH:D008545', (53, 78))	('Melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('Mucosal Melanoma', 'Disease', 'MESH:D008545', (36, 52))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('BRAF', 'Gene', '673', (9, 13))
78586	31398831	Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations.	('tumors', 'Disease', (335, 341))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('NRAS', 'Gene', (225, 229))	('mutations', 'Var', (231, 240))	('neuroblastoma RAS viral', 'Disease', 'MESH:D009447', (183, 206))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (126, 171))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('v-raf murine sarcoma viral oncogene homolog B', 'Gene', (126, 171))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('tumors', 'Disease', 'MESH:D009369', (335, 341))	('neuroblastoma', 'Phenotype', 'HP:0003006', (183, 196))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (316, 324))	('melanoma', 'Disease', (93, 101))	('cutaneous melanoma', 'Disease', (306, 324))	('neuroblastoma RAS viral', 'Disease', (183, 206))	('BRAF', 'Gene', (173, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (306, 324))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (306, 324))	('melanoma', 'Disease', (252, 260))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('mucosal melanoma', 'Disease', 'MESH:D008545', (244, 260))	('MAPK', 'molecular_function', 'GO:0004707', ('46', '50'))	('tumors', 'Phenotype', 'HP:0002664', (335, 341))	('mucosal melanoma', 'Disease', (244, 260))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))
78587	31398831	We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas.	('mutations', 'Var', (63, 72))	('cutaneous melanomas', 'Disease', (119, 138))	('mucosal melanoma', 'Disease', (90, 106))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('mucosal melanoma', 'Disease', 'MESH:D008545', (90, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('different', 'Reg', (77, 86))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (119, 138))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (119, 138))	('NRAS', 'Gene', (58, 62))	('BRAF', 'Gene', (49, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
78588	31398831	Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('mutations', 'Var', (142, 151))	('mucosal melanoma', 'Disease', (51, 67))	('lung cancer', 'Disease', (113, 124))	('cancers', 'Disease', (97, 104))	('mucosal melanoma', 'Disease', (155, 171))	('linked', 'Reg', (181, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mucosal melanoma', 'Disease', 'MESH:D008545', (51, 67))	('mucosal melanoma', 'Disease', 'MESH:D008545', (155, 171))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
78589	31398831	We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.	('mutations', 'Var', (45, 54))	('mucosal melanomas', 'Disease', (64, 81))	('NRAS', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('mucosal melanomas', 'Disease', 'MESH:D008545', (64, 81))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('protein activities', 'MPA', (109, 127))	('effects', 'Reg', (98, 105))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('BRAF', 'Gene', (31, 35))
78598	31398831	Indeed, nearly half of cutaneous melanomas harbor activating BRAF V600E/K mutations, and therefore, can be treated with BRAF kinase inhibitors in combination with an MEK inhibitor.	('cutaneous melanomas', 'Disease', (23, 42))	('V600E', 'Var', (66, 71))	('V600E', 'SUBSTITUTION', 'None', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('BRAF', 'Gene', (61, 65))	('MEK', 'Gene', (166, 169))	('MEK', 'Gene', '5609', (166, 169))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (23, 42))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (23, 41))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (23, 42))	('activating', 'PosReg', (50, 60))
78599	31398831	However, BRAF V600E/K mutations are less common in mucosal melanoma, rendering them less amenable to BRAF/MEK inhibitor therapies.	('mucosal melanoma', 'Disease', (51, 67))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (9, 13))	('V600E', 'SUBSTITUTION', 'None', (14, 19))	('MEK', 'Gene', (106, 109))	('MEK', 'Gene', '5609', (106, 109))	('mucosal melanoma', 'Disease', 'MESH:D008545', (51, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
78600	31398831	Targeted therapy against v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) activating mutations, seen in around 10-22% of mucosal melanomas, has been tested in clinical trials but results have been underwhelming.	('mutations', 'Var', (104, 113))	('mucosal melanomas', 'Disease', (140, 157))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('sarcoma viral', 'Disease', 'MESH:D001102', (56, 69))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('KIT', 'molecular_function', 'GO:0005020', ('88', '91'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (140, 157))	('KIT', 'Gene', (88, 91))	('activating', 'PosReg', (93, 103))	('sarcoma viral', 'Disease', (56, 69))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))
78602	31398831	Despite the clinical benefit achieved with KIT inhibition in select patients with melanoma harboring KIT mutations, most patients ultimately experience disease progression.	('experience', 'Reg', (141, 151))	('KIT', 'Gene', (101, 104))	('inhibition', 'NegReg', (47, 57))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('patients', 'Species', '9606', (68, 76))	('KIT', 'Gene', (43, 46))	('KIT', 'molecular_function', 'GO:0005020', ('101', '104'))	('mutations', 'Var', (105, 114))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('KIT', 'molecular_function', 'GO:0005020', ('43', '46'))	('patients', 'Species', '9606', (121, 129))
78605	31398831	The combination of anti-PD1 with anti-CTLA4 seems to have greater efficacy than either agent alone, but the efficacy of the combined immunotherapies is still lower in mucosal than cutaneous melanomas.	('anti-PD1', 'Var', (19, 27))	('CTLA4', 'Gene', '1493', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('lower', 'NegReg', (158, 163))	('melanomas', 'Phenotype', 'HP:0002861', (190, 199))	('mucosal than cutaneous melanomas', 'Disease', 'MESH:C562393', (167, 199))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (180, 198))	('mucosal than cutaneous melanomas', 'Disease', (167, 199))	('CTLA4', 'Gene', (38, 43))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (180, 199))	('combination', 'Interaction', (4, 15))
78608	31398831	Indeed, mucosal melanomas seem to present recurrent mutations in BRAF, CTNNB1, DMXL2, GNAQ, GNA11, KIT, NF1, RAS, SF3B1, and SPRED1, among others.	('GNAQ', 'Gene', '2776', (86, 90))	('melanomas', 'Phenotype', 'HP:0002861', (16, 25))	('KIT', 'Gene', (99, 102))	('SF3B1', 'Gene', (114, 119))	('RAS', 'Gene', (109, 112))	('KIT', 'molecular_function', 'GO:0005020', ('99', '102'))	('GNAQ', 'Gene', (86, 90))	('GNA11', 'Gene', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('CTNNB1', 'Gene', '1499', (71, 77))	('DMXL2', 'Gene', '23312', (79, 84))	('SF3B1', 'Gene', '23451', (114, 119))	('SPRED1', 'Gene', '161742', (125, 131))	('DMXL2', 'Gene', (79, 84))	('NF1', 'Gene', '4763', (104, 107))	('CTNNB1', 'Gene', (71, 77))	('mutations', 'Var', (52, 61))	('mucosal melanomas', 'Disease', 'MESH:D008545', (8, 25))	('GNA11', 'Gene', '2767', (92, 97))	('SPRED1', 'Gene', (125, 131))	('BRAF', 'Gene', (65, 69))	('mucosal melanomas', 'Disease', (8, 25))	('NF1', 'Gene', (104, 107))
78609	31398831	Here, seeking to further characterize the molecular pathogenesis of mucosal melanoma, we explored NRAS and BRAF mutations in mucosal melanoma and compared them to the mutation profiles in cutaneous melanoma and other tumors with mutations in NRAS and BRAF.	('BRAF', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('pathogenesis', 'biological_process', 'GO:0009405', ('52', '64'))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('mucosal melanoma', 'Disease', (125, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', (98, 102))	('mucosal melanoma', 'Disease', (68, 84))	('mucosal melanoma', 'Disease', 'MESH:D008545', (125, 141))	('cutaneous melanoma', 'Disease', (188, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (188, 206))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
78610	31398831	We discovered that there is very limited data comparing the type of NRAS and BRAF mutations in mucosal and cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (107, 126))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (107, 126))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('NRAS', 'Gene', (68, 72))	('BRAF', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('cutaneous melanomas', 'Disease', (107, 126))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))
78611	31398831	However, we were able to show that in addition to being less frequent, NRAF and BRAF mutations are different in mucosal melanoma compared to cutaneous melanomas, with mucosal melanoma mutations being strikingly closer to the type of mutations found in cancers such as lung cancers, raising fundamental questions about their etiology.	('mutations', 'Var', (184, 193))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('cancers', 'Disease', (273, 280))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('RAF', 'Gene', (81, 84))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('mucosal melanoma', 'Disease', 'MESH:D008545', (167, 183))	('mucosal melanoma', 'Disease', 'MESH:D008545', (112, 128))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (141, 160))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (141, 160))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('RAF', 'Gene', '22882', (72, 75))	('mucosal melanoma', 'Disease', (167, 183))	('mucosal melanoma', 'Disease', (112, 128))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', (252, 259))	('RAF', 'Gene', (72, 75))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('cutaneous melanomas', 'Disease', (141, 160))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('lung cancers', 'Disease', 'MESH:D008175', (268, 280))	('lung cancers', 'Disease', (268, 280))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('RAF', 'Gene', '22882', (81, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('lung cancers', 'Phenotype', 'HP:0100526', (268, 280))
78621	31398831	Whilst the MAPK pathway is activated, in melanocytes, by growth factors such as SCF (Stem Cell Factor), EGF (Epidermal Growth Factor), FGF (Fibroblast Growth Factor), or HGF (Hepatocyte Growth Factor), this pathway is very often constitutively activated in melanoma due to the presence of activating mutations of NRAS and BRAF, and inactivating mutations of the GAP NF1.	('Stem Cell Factor', 'molecular_function', 'GO:0005173', ('85', '101'))	('HGF', 'Gene', '3082', (170, 173))	('SCF', 'Gene', '4254', (80, 83))	('EGF', 'molecular_function', 'GO:0005154', ('104', '107'))	('NF1', 'Gene', (366, 369))	('melanoma', 'Disease', 'MESH:D008545', (257, 265))	('Epidermal Growth Factor', 'Gene', (109, 132))	('HGF', 'Gene', (170, 173))	('NF1', 'Gene', '4763', (366, 369))	('Hepatocyte Growth Factor', 'molecular_function', 'GO:0005171', ('175', '199'))	('SCF', 'Gene', (80, 83))	('MAPK pathway', 'Pathway', (11, 23))	('Hepatocyte Growth Factor', 'Gene', '3082', (175, 199))	('Epidermal Growth Factor', 'Gene', '1950', (109, 132))	('Fibroblast Growth Factor', 'molecular_function', 'GO:0005104', ('140', '164'))	('EGF', 'Gene', '1950', (104, 107))	('MAPK', 'molecular_function', 'GO:0004707', ('11', '15'))	('BRAF', 'Gene', (322, 326))	('Stem Cell Factor', 'Gene', '4254', (85, 101))	('Stem Cell Factor', 'Gene', (85, 101))	('inactivating mutations', 'Var', (332, 354))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanoma', 'Disease', (257, 265))	('Hepatocyte Growth Factor', 'Gene', (175, 199))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('109', '132'))	('EGF', 'Gene', (104, 107))	('activating', 'PosReg', (289, 299))	('activated', 'PosReg', (244, 253))	('SCF', 'molecular_function', 'GO:0005173', ('80', '83'))	('NRAS', 'Gene', (313, 317))
78622	31398831	Mutations in NRAS, BRAF, and to a lesser extent NF1, are mutually exclusive because their oncogenic activity is linked to stimulation of the MAPK pathway.	('NF1', 'Gene', '4763', (48, 51))	('oncogenic activity', 'CPA', (90, 108))	('stimulation', 'PosReg', (122, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('MAPK pathway', 'Pathway', (141, 153))	('BRAF', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('NF1', 'Gene', (48, 51))
78624	31398831	An intriguing observation from the early days of RAS research is that different types of cancer appear to be coupled to a mutation of a particular RAS isoform.	('mutation', 'Var', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('coupled', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
78625	31398831	For example, KRAS, which is the most frequently mutated isoform in cancer, is mutated in pancreatic, colorectal, and lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('colorectal', 'Disease', (101, 111))	('pancreatic', 'Disease', 'MESH:D010195', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('pancreatic', 'Disease', (89, 99))	('mutated', 'Var', (78, 85))	('KRAS', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung adenocarcinoma', 'Disease', (117, 136))
78626	31398831	In contrast, NRAS mutations are mainly found in melanoma, hematopoietic, and lymphoid tissue malignancies, and to a lesser extend thyroid tumors.	('melanoma', 'Disease', (48, 56))	('thyroid tumors', 'Disease', (130, 144))	('thyroid tumors', 'Disease', 'MESH:D013959', (130, 144))	('found', 'Reg', (39, 44))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('NRAS', 'Gene', (13, 17))	('hematopoietic', 'Disease', (58, 71))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (77, 105))	('extend thyroid', 'Phenotype', 'HP:0008249', (123, 137))	('lymphoid tissue malignancies', 'Disease', (77, 105))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('mutations', 'Var', (18, 27))
78627	31398831	HRAS mutations are rare but found mainly in head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('HRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('mutations', 'Var', (5, 14))	('found', 'Reg', (28, 33))	('neck', 'cellular_component', 'GO:0044326', ('53', '57'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('HRAS', 'Gene', '3265', (0, 4))	('neck squamous cell carcinoma', 'Disease', (53, 81))
78628	31398831	KRAS mutations occur mainly at codon 12 (83%), whereas NRAS tumors mainly harbor mutations at codon 61 (63%).	('NRAS tumors', 'Disease', 'MESH:D009369', (55, 66))	('NRAS tumors', 'Disease', (55, 66))	('mutations', 'Var', (5, 14))	('KRAS', 'Disease', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
78629	31398831	HRAS displays an approximately 40%/30%/30% split between mutations at codons 61, 12, and 13, respectively.	('mutations', 'Var', (57, 66))	('HRAS', 'Gene', (0, 4))	('HRAS', 'Gene', '3265', (0, 4))
78630	31398831	To better understand the molecular pathogenesis of mucosal melanoma we compiled NRAS mutations in 1387 mucosal melanoma from 36 publications and added the data from 67 mucosal melanomas from our own research center (Table S1).	('NRAS', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('mucosal melanoma', 'Disease', (51, 67))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('mucosal melanoma', 'Disease', (103, 119))	('mucosal melanomas', 'Disease', (168, 185))	('pathogenesis', 'biological_process', 'GO:0009405', ('35', '47'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (168, 184))	('mucosal melanoma', 'Disease', 'MESH:D008545', (51, 67))	('mutations', 'Var', (85, 94))	('mucosal melanoma', 'Disease', 'MESH:D008545', (103, 119))	('mucosal melanomas', 'Disease', 'MESH:D008545', (168, 185))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
78633	31398831	The data showed that NRAS mutations were present in 12% (179/1454) of mucosal melanoma, and 54% (96/179) were located on Q61, 31% (56/179) on G12, and 15% (27/179) on G13 (Figure 2).	('mucosal melanoma', 'Disease', (70, 86))	('mutations', 'Var', (26, 35))	('NRAS', 'Gene', (21, 25))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mucosal melanoma', 'Disease', 'MESH:D008545', (70, 86))
78634	31398831	We compared those data with NRAS mutations in cutaneous melanomas, hematopoietic and lymphoid tissue malignancies, and thyroid cancers from The Catalog of Somatic Mutations in Cancer (cancer.sanger.ac.uk).	('cancer', 'Disease', (184, 190))	('lymphoid tissue malignancies', 'Disease', (85, 113))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (33, 42))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('thyroid cancers', 'Disease', (119, 134))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (85, 113))	('cutaneous melanomas', 'Disease', (46, 65))	('thyroid cancers', 'Disease', 'MESH:D013964', (119, 134))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('NRAS', 'Gene', (28, 32))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
78635	31398831	We found that NRAS exhibits distinctive codon mutations and amino acid substitutions in melanoma compared to hematopoietic and lymphoid tissue malignancies and thyroid cancers, as could be expected.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('lymphoid tissue malignancies', 'Disease', (127, 155))	('melanoma', 'Disease', (88, 96))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (127, 155))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('amino acid substitutions', 'Var', (60, 84))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('thyroid cancers', 'Disease', (160, 175))	('NRAS', 'Gene', (14, 18))	('thyroid cancers', 'Disease', 'MESH:D013964', (160, 175))
78636	31398831	Thyroid cancers showed almost exclusively Q61 mutations (97%), and hematopoietic tumors were strongly associated with mutations at G12 (49%) and G13 (24%) (Figure 2).	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('associated', 'Reg', (102, 112))	('Thyroid cancers', 'Disease', (0, 15))	('G13', 'Var', (145, 148))	('Thyroid cancers', 'Disease', 'MESH:D013964', (0, 15))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (67, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hematopoietic tumors', 'Disease', (67, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations at G12', 'Var', (118, 134))	('Q61 mutations', 'Var', (42, 55))
78637	31398831	Surprisingly however, the comparison also showed a noticeable difference between cutaneous and mucosal melanomas regarding the location of NRAS mutations.	('mucosal melanomas', 'Disease', (95, 112))	('NRAS', 'Gene', (139, 143))	('mucosal melanomas', 'Disease', 'MESH:D008545', (95, 112))	('mutations', 'Var', (144, 153))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
78638	31398831	Although the most frequent types of NRAS mutations are located in codon 61 for both cutaneous melanoma (88%) and mucosal melanoma (54%), mutations at codons 12 and 13 occurred more frequently in mucosal melanomas (46%) than cutaneous melanomas (12%).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mucosal melanoma', 'Disease', 'MESH:D008545', (113, 129))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (224, 243))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (224, 243))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (224, 242))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (224, 242))	('mucosal melanomas', 'Disease', 'MESH:D008545', (195, 212))	('mucosal melanoma', 'Disease', (113, 129))	('mutations', 'Var', (41, 50))	('mucosal melanomas', 'Disease', (195, 212))	('cutaneous melanoma', 'Disease', (84, 102))	('cutaneous melanomas', 'Disease', (224, 243))	('occurred', 'Reg', (167, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (84, 102))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('melanomas', 'Phenotype', 'HP:0002861', (234, 243))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('NRAS', 'Gene', (36, 40))	('mucosal melanoma', 'Disease', 'MESH:D008545', (195, 211))	('mutations', 'Var', (137, 146))
78639	31398831	In all malignancies, the most commonly observed NRAS codon 61 mutations are the Q61R (CAA/CGA) and Q61K (CAA/AAA) changes (Figure 2).	('NRAS codon 61', 'Gene', (48, 61))	('CGA', 'Gene', (90, 93))	('malignancies', 'Disease', 'MESH:D009369', (7, 19))	('Q61K', 'Var', (99, 103))	('Q61K', 'Mutation', 'rs121913254', (99, 103))	('malignancies', 'Disease', (7, 19))	('Q61R', 'Mutation', 'rs3742712', (80, 84))	('CGA', 'Gene', '1113', (90, 93))	('Q61R', 'Var', (80, 84))
78640	31398831	Mutations at codon 13 were mainly G13R (GGT/GCT) and G13D (GGT/GAT), but with a prevalence of G13R in cutaneous melanoma, and of G13D in mucosal melanoma and hematopoietic malignancies.	('GAT', 'Gene', (63, 66))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('mucosal melanoma', 'Disease', 'MESH:D008545', (137, 153))	('G13D', 'Var', (129, 133))	('G13R', 'Var', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Disease', (102, 120))	('G13R', 'Mutation', 'rs121434595', (94, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('mucosal melanoma', 'Disease', (137, 153))	('GGT', 'Disease', (59, 62))	('GGT', 'Disease', 'MESH:C536836', (59, 62))	('hematopoietic malignancies', 'Disease', (158, 184))	('G13R', 'Mutation', 'rs121434595', (34, 38))	('G13D', 'Mutation', 'rs112445441', (53, 57))	('GGT', 'Disease', (40, 43))	('GGT', 'Disease', 'MESH:C536836', (40, 43))	('GAT', 'Gene', '10249', (63, 66))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (158, 184))	('G13D', 'Mutation', 'rs112445441', (129, 133))
78641	31398831	(Figure 2) Alterations of codon 12 were predominantly G12D in cutaneous melanomas and hematopoietic malignancies, and a combination of G12A and G12D in mucosal melanomas (Figure 2).	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('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))	('G12D', 'Var', (144, 148))	('G12D', 'Mutation', 'rs121913529', (144, 148))	('mucosal melanomas', 'Disease', 'MESH:D008545', (152, 169))	('hematopoietic malignancies', 'Disease', (86, 112))	('G12D', 'Var', (54, 58))	('cutaneous melanomas', 'Disease', (62, 81))	('G12D', 'Mutation', 'rs121913529', (54, 58))	('mucosal melanomas', 'Disease', (152, 169))	('G12A', 'Var', (135, 139))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('codon 12', 'Gene', (26, 34))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (86, 112))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('G12A', 'Mutation', 'rs121913237', (135, 139))
78643	31398831	Hematopoietic tumors presented mainly CG   TA mutations, thyroid cancers TA   CG mutations, and cutaneous melanomas CG   AT and TA   CG, whereas mucosal melanomas presented the different substitutions more uniformly (Figure 3).	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (96, 115))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (96, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('mutations', 'Var', (81, 90))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('AT', 'Disease', 'None', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (46, 55))	('cutaneous melanomas', 'Disease', (96, 115))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('thyroid cancers', 'Disease', 'MESH:D013964', (57, 72))	('mucosal melanomas', 'Disease', 'MESH:D008545', (145, 162))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('mucosal melanomas', 'Disease', (145, 162))	('Hematopoietic tumors', 'Disease', 'MESH:D019337', (0, 20))	('Hematopoietic tumors', 'Disease', (0, 20))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('thyroid cancers', 'Disease', (57, 72))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
78645	31398831	Although NRAS mutations in cutaneous melanoma do not present the typical UV signature, Q61 mutations have previously been linked to UV.	('cutaneous melanoma', 'Disease', (27, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (27, 45))	('Q61', 'Gene', (87, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (27, 45))	('NRAS', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('mutations', 'Var', (91, 100))	('linked', 'Reg', (122, 128))	('mutations', 'Var', (14, 23))
78648	31398831	A mutagenic effect of UV irradiation could be demonstrated after UV irradiation of a cloned human NRAS proto-oncogene in vitro and subsequent transfection, leading to the codon 61 Q61R (CAA/CGA) and Q61K (CAA/AAA) changes that are identical to those found in cutaneous melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (269, 277))	('CGA', 'Gene', '1113', (190, 193))	('cutaneous melanoma', 'Disease', (259, 277))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (259, 277))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (259, 277))	('CGA', 'Gene', (190, 193))	('Q61K', 'Mutation', 'rs121913254', (199, 203))	('Q61R', 'Mutation', 'rs3742712', (180, 184))	('Q61K', 'Var', (199, 203))	('human', 'Species', '9606', (92, 97))	('Q61R', 'Var', (180, 184))
78650	31398831	Finally, UV-induced skin tumors in a C3H mouse contained mutations preferentially in the NRAS oncogene and frequently opposite or adjacent to dipyrimidine sites.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mouse', 'Species', '10090', (41, 46))	('skin tumors', 'Disease', 'MESH:D012878', (20, 31))	('preferentially', 'PosReg', (67, 81))	('mutations', 'Var', (57, 66))	('dipyrimidine', 'Chemical', '-', (142, 154))	('NRAS oncogene', 'Gene', (89, 102))	('skin tumors', 'Phenotype', 'HP:0008069', (20, 31))	('skin tumors', 'Disease', (20, 31))
78651	31398831	NRAS mutations on Q61 found in cutaneous melanoma are hence consistent with known mechanisms for UV induction.	('mutations on Q61', 'Var', (5, 21))	('cutaneous melanoma', 'Disease', (31, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))
78653	31398831	With its higher frequency of mutations at G12 and G13, causes of mucosal melanoma could have been the same as hematopoietic malignancies.	('hematopoietic malignancies', 'Disease', (110, 136))	('mucosal melanoma', 'Disease', (65, 81))	('mucosal melanoma', 'Disease', 'MESH:D008545', (65, 81))	('G13', 'Var', (50, 53))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (110, 136))	('mutations at G12', 'Var', (29, 45))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
78654	31398831	This is interesting because mutations in hematopoietic malignancies are not associated with a specific mutagen, but rather due to a combination of proliferation-dependent mutation incorporation, spontaneous deamination of cytosine, and defects in repair processes.	('hematopoietic malignancies', 'Disease', (41, 67))	('mutation', 'Var', (171, 179))	('repair processes', 'CPA', (247, 263))	('due to', 'Reg', (123, 129))	('defects', 'NegReg', (236, 243))	('cytosine', 'Chemical', 'MESH:D003596', (222, 230))	('deamination of cytosine', 'MPA', (207, 230))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (41, 67))	('mutations', 'Var', (28, 37))
78655	31398831	These data suggest that mutations in NRAS in mucosal melanomas are neither UV-induced nor spontaneous, but may be due to genotoxic agents, which remain to be identified.	('NRAS', 'Gene', (37, 41))	('mucosal melanomas', 'Disease', (45, 62))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('mucosal melanomas', 'Disease', 'MESH:D008545', (45, 62))	('mutations', 'Var', (24, 33))	('due', 'Reg', (114, 117))
78656	31398831	BRAF mutations are present in approximately 8% of human tumors, but with huge variation in frequency depending on the malignancy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('malignancy', 'Disease', 'MESH:D009369', (118, 128))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('BRAF', 'Gene', (0, 4))	('malignancy', 'Disease', (118, 128))	('human', 'Species', '9606', (50, 55))
78657	31398831	BRAF is commonly mutated in melanomas (50%), papillary thyroid cancers (45%), hairy cell leukemias (100%), and idiopathic disorder Langerhans cell histiocytosis (50-60%), and less frequently in colorectal cancers (10%), lung adenocarcinomas (10%), and hematopoietic and lymphoid tissue malignancies (8%).	('melanomas', 'Disease', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('BRAF', 'Gene', (0, 4))	('histiocytosis', 'Phenotype', 'HP:0100727', (147, 160))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (220, 240))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (45, 70))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (270, 298))	('hairy cell leukemias', 'Disease', 'MESH:D007943', (78, 98))	('idiopathic disorder Langerhans cell histiocytosis', 'Disease', 'MESH:C538636', (111, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (220, 239))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('papillary thyroid cancers', 'Disease', (45, 70))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (45, 70))	('colorectal cancers', 'Disease', (194, 212))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (220, 240))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung adenocarcinomas', 'Disease', (220, 240))	('lymphoid tissue malignancies', 'Disease', (270, 298))	('mutated', 'Var', (17, 24))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('disorder Langerhans cell histiocytosis', 'Phenotype', 'HP:0031871', (122, 160))	('hematopoietic', 'Disease', (252, 265))	('leukemias', 'Phenotype', 'HP:0001909', (89, 98))	('colorectal cancers', 'Disease', 'MESH:D015179', (194, 212))	('idiopathic disorder Langerhans cell histiocytosis', 'Disease', (111, 160))	('hairy cell leukemias', 'Disease', (78, 98))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))
78658	31398831	BRAF missense mutations in tumors encompass 115 of the 766 BRAF amino acids, but most of the mutations occur in the activation loop (A-loop) near V600, or in the GSGSFG phosphate-binding loop (P-loop) at residues 464-469.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('missense mutations', 'Var', (5, 23))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('mutations', 'Var', (93, 102))	('phosphate', 'Chemical', 'MESH:D010710', (169, 178))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('BRAF', 'Gene', (0, 4))	('V600', 'Var', (146, 150))
78659	31398831	The most frequent mutation is a substitution T to A in exon 15, resulting in an amino acid change in the activation segment of BRAF at codon 600 from valine (V) to glutamic acid (E).	('substitution', 'Var', (32, 44))	('activation segment', 'MPA', (105, 123))	('BRAF at', 'Gene', (127, 134))	('valine', 'Chemical', 'MESH:D014633', (150, 156))	('amino acid change', 'MPA', (80, 97))	('glutamic acid', 'Chemical', 'MESH:D018698', (164, 177))
78660	31398831	To gain insight into the molecular pathogenesis of mucosal melanoma, we compiled BRAF mutations in 1312 mucosal melanoma from 33 publications and added the data from 27 mucosal melanomas from our own research center (Table S2).	('mutations', 'Var', (86, 95))	('mucosal melanoma', 'Disease', (51, 67))	('mucosal melanomas', 'Disease', 'MESH:D008545', (169, 186))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanomas', 'Phenotype', 'HP:0002861', (177, 186))	('mucosal melanoma', 'Disease', (104, 120))	('pathogenesis', 'biological_process', 'GO:0009405', ('35', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('mucosal melanoma', 'Disease', 'MESH:D008545', (51, 67))	('mucosal melanoma', 'Disease', 'MESH:D008545', (104, 120))	('BRAF', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mucosal melanoma', 'Disease', 'MESH:D008545', (169, 185))	('mucosal melanomas', 'Disease', (169, 186))
78661	31398831	The data showed that BRAF mutations were present in 8% (107/1339) of mucosal melanoma, 63% (67/107) were located on the V600 codon, and 37% (40/107) on another codon (Figure 4).	('mucosal melanoma', 'Disease', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('V600', 'Var', (120, 124))	('mutations', 'Var', (26, 35))	('mucosal melanoma', 'Disease', 'MESH:D008545', (69, 85))
78662	31398831	We compared those data with BRAF mutations in cutaneous melanomas, hematopoietic and lymphoid tissue malignancies, thyroid cancers, and lung adenocarcinoma from The Catalog of Somatic Mutations in Cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lymphoid tissue malignancies', 'Disease', (85, 113))	('mutations', 'Var', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (46, 65))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (46, 65))	('lung adenocarcinoma', 'Disease', (136, 155))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('thyroid cancers', 'Disease', 'MESH:D013964', (115, 130))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (85, 113))	('BRAF', 'Gene', (28, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('cutaneous melanomas', 'Disease', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('thyroid cancers', 'Disease', (115, 130))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
78663	31398831	The comparison shows that not only are BRAF mutations less frequent in mucosal melanoma, but there is also a noticeable difference regarding the location of BRAF mutations between both melanoma subtypes.	('mucosal melanoma', 'Disease', 'MESH:D008545', (71, 87))	('melanoma subtypes', 'Disease', (185, 202))	('melanoma subtypes', 'Disease', 'MESH:D008545', (185, 202))	('mutations', 'Var', (44, 53))	('mucosal melanoma', 'Disease', (71, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
78664	31398831	We found that whereas cutaneous melanomas present a vast majority of V600 mutation (more than 90%), like hematopoietic and lymphoid tissue malignancies and thyroid cancers, mucosal melanomas are characterized by a high prevalence of non-V600 mutations (37%), as in lung adenocarcinomas (48%; 259/543) (Figure 4).	('mucosal melanomas', 'Disease', 'MESH:D008545', (173, 190))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('melanomas', 'Phenotype', 'HP:0002861', (181, 190))	('thyroid cancers', 'Disease', 'MESH:D013964', (156, 171))	('mucosal melanomas', 'Disease', (173, 190))	('lymphoid tissue malignancies', 'Disease', (123, 151))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (22, 41))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (265, 285))	('non-V600 mutations', 'Var', (233, 251))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (265, 284))	('thyroid cancers', 'Disease', (156, 171))	('cutaneous melanomas', 'Disease', (22, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (265, 285))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('V600 mutation', 'Var', (69, 82))	('lung adenocarcinomas', 'Disease', (265, 285))	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (123, 151))
78665	31398831	In all malignancies, V600E is the most commonly observed BRAF codon 600 mutation (at least 89%), followed in melanomas by V600K (9%) and V600R (1-2%) (Figure 4).	('V600E', 'Var', (21, 26))	('V600R', 'Var', (137, 142))	('BRAF codon 600', 'Gene', (57, 71))	('melanomas', 'Disease', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (7, 19))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanomas', 'Disease', 'MESH:D008545', (109, 118))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('V600R', 'Mutation', 'rs121913227', (137, 142))	('V600K', 'Var', (122, 127))	('malignancies', 'Disease', (7, 19))	('V600E', 'Mutation', 'rs113488022', (21, 26))	('V600K', 'Mutation', 'rs121913227', (122, 127))
78666	31398831	We then compared the non-V600 mutations focusing on point mutations representing more than 2% of non-V600 alterations in the different malignancies.	('point mutations', 'Var', (52, 67))	('malignancies', 'Disease', (135, 147))	('malignancies', 'Disease', 'MESH:D009369', (135, 147))
78667	31398831	Looking at the location of the mutated codon, we noticed that mucosal melanomas showed mutations on D594 (40%), G469 (24%), and K601 (16%), which is similar to the mutation spectrum in hematopoietic and lymphoid tissue malignancies (40%, 22%, and 18%, respectively), but different from the one in cutaneous melanoma, which presents mutations on K601 (30%), L597 (24%), D594 (17%), and G469 (15%) (Figure 4).	('lymphoid tissue malignancies', 'Disease', 'MESH:D008223', (203, 231))	('K601', 'Var', (345, 349))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('D594', 'Var', (100, 104))	('G469', 'Var', (112, 116))	('cutaneous melanoma', 'Disease', (297, 315))	('lymphoid tissue malignancies', 'Disease', (203, 231))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (297, 315))	('mucosal melanomas', 'Disease', (62, 79))	('G469', 'Var', (385, 389))	('D594', 'Var', (369, 373))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (297, 315))	('mucosal melanomas', 'Disease', 'MESH:D008545', (62, 79))	('K601', 'Var', (128, 132))	('mutations', 'Var', (87, 96))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (307, 315))
78669	31398831	In thyroid cancers, non-V600 mutations are almost exclusively K601E (91%) mutations.	('thyroid cancers', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('K601E', 'Var', (62, 67))	('thyroid cancers', 'Disease', 'MESH:D013964', (3, 18))	('non-V600 mutations', 'Var', (20, 38))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('K601E', 'Mutation', 'rs121913364', (62, 67))
78670	31398831	In cutaneous melanomas, apart from the prevalence of the K601E (30%) mutation, a wide range of non-V600 mutations is presented.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (3, 22))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (3, 22))	('cutaneous melanomas', 'Disease', (3, 22))	('K601E', 'Mutation', 'rs121913364', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('K601E', 'Var', (57, 62))
78671	31398831	This is different from the mucosal melanomas, which show a prevalence of D594G (33%), G469A (19%), and K601E (19%), similar to the mutation spectrum in lung adenocarcinomas (19%, 34%, and 13%, respectively).	('G469A', 'Mutation', 'rs121913355', (86, 91))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('K601E', 'Var', (103, 108))	('lung adenocarcinomas', 'Disease', (152, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('D594G', 'Mutation', 'rs121913338', (73, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (152, 172))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (152, 172))	('mucosal melanomas', 'Disease', (27, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('mucosal melanomas', 'Disease', 'MESH:D008545', (27, 44))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('D594G', 'Var', (73, 78))	('K601E', 'Mutation', 'rs121913364', (103, 108))	('G469A', 'Var', (86, 91))
78672	31398831	By contrast, hematopoietic tumors present D594G (27%), G469A (25%), D594N (20%), and K601N (17%) (Figure 4).	('D594G', 'Mutation', 'rs121913338', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('D594N', 'Var', (68, 73))	('G469A', 'Mutation', 'rs121913355', (55, 60))	('hematopoietic tumors', 'Disease', (13, 33))	('D594G', 'Var', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('K601N', 'Var', (85, 90))	('K601N', 'Mutation', 'rs121913365', (85, 90))	('G469A', 'Disease', (55, 60))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (13, 33))	('D594N', 'Mutation', 'rs397516896', (68, 73))
78673	31398831	Therefore, the BRAF mutation spectrum in mucosal melanomas is different from the spectrum seen in cutaneous melanomas (UV-induced) or in hematopoietic malignancies (spontaneous), but is closely related to the mutation spectrum seen in lung cancers where mutations are often associated to the genotoxic effects of cigarette smoking.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('lung cancers', 'Phenotype', 'HP:0100526', (235, 247))	('mutation', 'Var', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('hematopoietic malignancies', 'Disease', (137, 163))	('cutaneous melanomas', 'Disease', (98, 117))	('BRAF', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanomas', 'Phenotype', 'HP:0002861', (108, 117))	('mucosal melanomas', 'Disease', (41, 58))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (137, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (98, 117))	('lung cancers', 'Disease', 'MESH:D008175', (235, 247))	('lung cancers', 'Disease', (235, 247))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (98, 117))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
78674	31398831	Similarly to NRAS, BRAF mutations suggest the existence of genotoxic agents in mucosal melanoma, which remain to be identified.	('BRAF', 'Gene', (19, 23))	('mucosal melanoma', 'Disease', (79, 95))	('mucosal melanoma', 'Disease', 'MESH:D008545', (79, 95))	('mutations', 'Var', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
78678	31398831	Indeed, the specific NRAS and BRAF mutants found in mucosal melanoma could be linked to their particular effects on protein activity during mucosal melanocyte transformation, adding an additional layer of complexity.	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('mutants', 'Var', (35, 42))	('mucosal melanoma', 'Disease', (52, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('BRAF', 'Gene', (30, 34))	('NRAS', 'Gene', (21, 25))	('effects', 'Reg', (105, 112))	('mucosal melanoma', 'Disease', 'MESH:D008545', (52, 68))	('protein activity', 'MPA', (116, 132))
78680	31398831	In colorectal and lung cancers, KRAS G12V mutations have been associated with a worse prognosis than KRAS G12D mutations, raising the possibility that particular amino acid substitutions might dictate specific transforming characteristics of oncogenic RAS alleles.	('dictate', 'Reg', (193, 200))	('KRAS G12V mutations', 'Var', (32, 51))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('G12V', 'Mutation', 'rs121913529', (37, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('G12D', 'Mutation', 'rs121913529', (106, 110))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (3, 30))	('lung cancers', 'Phenotype', 'HP:0100526', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('transforming characteristics', 'CPA', (210, 238))
78681	31398831	Moreover, the Q61L, Q61V, and Q61K mutant variants transform NIH 3T3 cells nearly 300-fold and 1000-fold more efficiently than the Q61G and Q61E mutants, respectively.	('Q61L', 'Mutation', 'rs121913240', (14, 18))	('Q61G', 'Mutation', 'p.Q61G', (131, 135))	('Q61K', 'Var', (30, 34))	('NIH 3T3', 'CellLine', 'CVCL:0594', (61, 68))	('Q61E', 'Mutation', 'rs121913238', (140, 144))	('Q61K', 'Mutation', 'rs121913254', (30, 34))	('Q61V', 'Mutation', 'p.Q61V', (20, 24))	('transform', 'Reg', (51, 60))	('Q61V', 'Var', (20, 24))	('Q61L', 'Var', (14, 18))
78682	31398831	In agreement with this hypothesis, it was reported that, in the p16INK4a-deficient mouse melanoma model, the frequency of metastatic melanoma initiation by NRAS Q61R was increased more than 20-fold, compared with NRAS G12D.	('p16INK4a', 'Gene', (64, 72))	('Q61R', 'Mutation', 'rs3742712', (161, 165))	('mouse', 'Species', '10090', (83, 88))	('increased', 'PosReg', (170, 179))	('G12D', 'Mutation', 'rs121913529', (218, 222))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('p16INK4a', 'Gene', '12578', (64, 72))	('melanoma initiation', 'Disease', 'MESH:D008545', (133, 152))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanoma initiation', 'Disease', (133, 152))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('NRAS Q61R', 'Var', (156, 165))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
78683	31398831	The mechanistic basis for the enhanced oncogenic activities of NRAS Q61 mutants in melanoma remains to be clearly established.	('mutants', 'Var', (72, 79))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('enhanced', 'PosReg', (30, 38))	('oncogenic activities', 'CPA', (39, 59))	('NRAS Q61', 'Gene', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))
78684	31398831	Nonetheless, there is evidence that the Q61 mutants, through a malfunction of the allosteric switch, have a very strong oncogenic effect in tumors where the RAF-MEK-ERK pathway is primarily involved in promoting transformation.	('RAF', 'Gene', (157, 160))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Q61', 'Var', (40, 43))	('MEK', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (161, 164))	('oncogenic effect', 'CPA', (120, 136))	('ERK', 'molecular_function', 'GO:0004707', ('165', '168'))	('allosteric switch', 'MPA', (82, 99))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ERK', 'Gene', '5594', (165, 168))	('ERK', 'Gene', (165, 168))	('RAF', 'Gene', '22882', (157, 160))
78686	31398831	In contrast, the prevalence of G12 and G13 NRAS mutants in mucosal melanoma raises the intriguing possibility that the RAF-MEK-ERK pathway could have a lesser role in the transformation of mucosal melanocytes.	('mucosal melanoma', 'Disease', (59, 75))	('MEK', 'Gene', (123, 126))	('MEK', 'Gene', '5609', (123, 126))	('G13 NRAS', 'Var', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mucosal melanoma', 'Disease', 'MESH:D008545', (59, 75))	('ERK', 'Gene', '5594', (127, 130))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('ERK', 'Gene', (127, 130))	('G12', 'Var', (31, 34))	('RAF', 'Gene', '22882', (119, 122))	('RAF', 'Gene', (119, 122))
78687	31398831	In a mouse lung tumorigenesis comparing Q61L/R to G12V/D mutants, it was shown that Q61L/R is more potent than G12V/D at activating KRAS (assessed by KRAS-GTP) and driving the MAPK pathway.	('G12V', 'Mutation', 'rs121913529', (111, 115))	('KRAS-GTP', 'Gene', '16653', (150, 158))	('Q61L', 'SUBSTITUTION', 'None', (84, 88))	('MAPK pathway', 'Pathway', (176, 188))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('G12V', 'Mutation', 'rs121913529', (50, 54))	('Q61L', 'SUBSTITUTION', 'None', (40, 44))	('Q61L', 'Var', (40, 44))	('activating', 'PosReg', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Q61L', 'Var', (84, 88))	('KRAS-GTP', 'Gene', (150, 158))	('tumor', 'Disease', (16, 21))	('KRAS', 'Pathway', (132, 136))	('mouse', 'Species', '10090', (5, 10))	('MAPK', 'molecular_function', 'GO:0004707', ('176', '180'))
78688	31398831	Q61L/R mutations were the only KRAS oncogenes that induced detectable p16 expression in primary lung fibroblasts and resulted in more potent growth arrest than G12V/D mutations.	('expression', 'MPA', (74, 84))	('G12V', 'Mutation', 'rs121913529', (160, 164))	('p16', 'Gene', '1029', (70, 73))	('growth arrest', 'Phenotype', 'HP:0001510', (141, 154))	('growth arrest', 'CPA', (141, 154))	('Q61L', 'SUBSTITUTION', 'None', (0, 4))	('Q61L', 'Var', (0, 4))	('induced', 'Reg', (51, 58))	('p16', 'Gene', (70, 73))
78689	31398831	However, Q61L/R mutations were rarely detected in lung tumors developing after the administration of urethane, raising the interesting prospect that the more potent Q61L/R mutations were selected against in favor of the weaker G12V/D mutations, which may evade a growth-arrest response.	('lung tumors', 'Disease', (50, 61))	('Q61L', 'SUBSTITUTION', 'None', (9, 13))	('lung tumors', 'Phenotype', 'HP:0100526', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Q61L', 'Var', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('urethane', 'Chemical', 'MESH:D014520', (101, 109))	('G12V/D', 'Var', (227, 233))	('Q61L', 'SUBSTITUTION', 'None', (165, 169))	('lung tumors', 'Disease', 'MESH:D008175', (50, 61))	('Q61L', 'Var', (165, 169))	('G12V', 'Mutation', 'rs121913529', (227, 231))
78690	31398831	A similar mechanism could explain the prevalence of weaker G12/G13 mutations in mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (80, 97))	('G12/G13', 'Var', (59, 66))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('mucosal melanomas', 'Disease', (80, 97))
78691	31398831	Although most studies on the role of BRAF in melanoma have focused on the BRAF V600E mutation, several other mutations in the BRAF gene have been identified, and the biochemistry of the various altered BRAF proteins has been shown to vary substantially.	('V600E', 'Var', (79, 84))	('BRAF', 'Gene', (74, 78))	('V600E', 'Mutation', 'rs113488022', (79, 84))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
78692	31398831	This is interesting because, although BRAF mutations are rare in mucosal melanoma, they are characterized by a higher prevalence of non-V600 mutations than in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('mucosal melanoma', 'Disease', (65, 81))	('cutaneous melanoma', 'Disease', (159, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('mucosal melanoma', 'Disease', 'MESH:D008545', (65, 81))	('mutations', 'Var', (43, 52))	('non-V600 mutations', 'Var', (132, 150))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
78693	31398831	Many of these mutants show a lower BRAF kinase activity toward MEK in vitro than that of the V600E mutant, explaining why these mutants are often classified as "low activity" or "impaired activity" mutants (for example, G469A and D594G are found frequently in mucosal melanomas).	('melanomas', 'Phenotype', 'HP:0002861', (268, 277))	('G469A', 'Mutation', 'rs121913355', (220, 225))	('G469A', 'Var', (220, 225))	('mucosal melanomas', 'Disease', (260, 277))	('D594G', 'Var', (230, 235))	('MEK', 'Gene', (63, 66))	('MEK', 'Gene', '5609', (63, 66))	('kinase activity', 'molecular_function', 'GO:0016301', ('40', '55'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (260, 277))	('V600E', 'Mutation', 'rs113488022', (93, 98))	('D594G', 'Mutation', 'rs121913338', (230, 235))	('lower', 'NegReg', (29, 34))	('BRAF kinase activity', 'MPA', (35, 55))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))
78694	31398831	However, in vivo, these mutants are able to promote MEK phosphorylation in a CRAF-dependent manner by directly binding to and activating CRAF.	('CRAF', 'Gene', '5894', (77, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('promote', 'PosReg', (44, 51))	('mutants', 'Var', (24, 31))	('CRAF', 'molecular_function', 'GO:0004709', ('77', '81'))	('CRAF', 'molecular_function', 'GO:0004709', ('137', '141'))	('binding', 'Interaction', (111, 118))	('MEK', 'Gene', (52, 55))	('binding', 'molecular_function', 'GO:0005488', ('111', '118'))	('MEK', 'Gene', '5609', (52, 55))	('CRAF', 'Gene', (77, 81))	('CRAF', 'Gene', (137, 141))	('CRAF', 'Gene', '5894', (137, 141))	('activating', 'PosReg', (126, 136))
78695	31398831	In a genetically engineered mouse model, conditional melanocyte-specific expression of either BRAF D594A or KRAS G12D was insufficient to induce nevi or melanomas.	('D594A', 'Mutation', 'rs121913338', (99, 104))	('KRAS G12D', 'Var', (108, 117))	('BRAF D594A', 'Var', (94, 104))	('mouse', 'Species', '10090', (28, 33))	('insufficient', 'Disease', 'MESH:D000309', (122, 134))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('melanomas', 'Disease', 'MESH:D008545', (153, 162))	('insufficient', 'Disease', (122, 134))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('nevi', 'Phenotype', 'HP:0003764', (145, 149))	('G12D', 'Mutation', 'rs121913529', (113, 117))	('nevi', 'CPA', (145, 149))	('induce', 'PosReg', (138, 144))	('melanomas', 'Disease', (153, 162))
78696	31398831	However, co-expression of both mutant proteins promoted cellular dimerization of the catalytically inert BRAF D594A with the catalytically competent CRAF, inducing melanoma.	('CRAF', 'molecular_function', 'GO:0004709', ('149', '153'))	('inducing', 'Reg', (155, 163))	('cellular dimerization', 'MPA', (56, 77))	('promoted', 'PosReg', (47, 55))	('D594A', 'Mutation', 'rs121913338', (110, 115))	('D594A', 'Var', (110, 115))	('CRAF', 'Gene', (149, 153))	('CRAF', 'Gene', '5894', (149, 153))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('melanoma', 'Disease', (164, 172))
78698	31398831	These data strongly indicate that kinase-impaired BRAF mutations are oncogenic drivers, but require activated RAS and CRAF to activate downstream signaling.	('BRAF', 'Gene', (50, 54))	('CRAF', 'molecular_function', 'GO:0004709', ('118', '122'))	('mutations', 'Var', (55, 64))	('signaling', 'biological_process', 'GO:0023052', ('146', '155'))	('CRAF', 'Gene', (118, 122))	('CRAF', 'Gene', '5894', (118, 122))
78699	31398831	However, so far, only one mucosal melanoma carrying both mutants (BRAF D594E + NRAS G13R) has been described.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('BRAF D594E + NRAS G13R', 'Var', (66, 88))	('D594E', 'Mutation', 'rs121913337', (71, 76))	('mucosal melanoma', 'Disease', (26, 42))	('mucosal melanoma', 'Disease', 'MESH:D008545', (26, 42))	('G13R', 'Mutation', 'rs121434595', (84, 88))
78701	31398831	Alterations of upstream effectors of RAS, such as NF1 or SPRED1, in mucosal melanomas could play this role, but there is currently not enough extensive genomic data on mucosal melanoma to confirm this hypothesis.	('mucosal melanomas', 'Disease', (68, 85))	('SPRED1', 'Gene', '161742', (57, 63))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('NF1', 'Gene', (50, 53))	('Alterations', 'Var', (0, 11))	('mucosal melanoma', 'Disease', (168, 184))	('mucosal melanomas', 'Disease', 'MESH:D008545', (68, 85))	('NF1', 'Gene', '4763', (50, 53))	('mucosal melanoma', 'Disease', 'MESH:D008545', (168, 184))	('SPRED1', 'Gene', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
78702	31398831	Beyond the BRAF dimerization-induced activation through activated RAS, cell-based studies also showed that certain oncogenic BRAF mutants, such as L597V or G466E, promote spontaneous BRAF dimerization and activation by forming homodimers in the absence of RAS-GTP.	('L597V', 'Mutation', 'rs121913369', (147, 152))	('BRAF dimerization', 'MPA', (183, 200))	('L597V', 'Var', (147, 152))	('mutants', 'Var', (130, 137))	('homodimers', 'Interaction', (227, 237))	('RAS-GTP', 'Chemical', '-', (256, 263))	('activation', 'MPA', (205, 215))	('G466E', 'Var', (156, 161))	('promote', 'PosReg', (163, 170))	('BRAF', 'Gene', (125, 129))	('G466E', 'Mutation', 'rs121913351', (156, 161))
78703	31398831	Because the impaired activity mutants are frequently found in mucosal melanomas, their homodimerization or heterodimerization with CRAF should play a major role in the transformation of mucosal melanocytes.	('impaired', 'NegReg', (12, 20))	('CRAF', 'Gene', (131, 135))	('homodimerization', 'MPA', (87, 103))	('play', 'Reg', (143, 147))	('CRAF', 'molecular_function', 'GO:0004709', ('131', '135'))	('mucosal melanomas', 'Disease', (62, 79))	('mutants', 'Var', (30, 37))	('CRAF', 'Gene', '5894', (131, 135))	('heterodimerization', 'MPA', (107, 125))	('activity', 'MPA', (21, 29))	('mucosal melanomas', 'Disease', 'MESH:D008545', (62, 79))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
78704	31398831	In addition to driving the MAPK pathway, it was also shown that the BRAF impaired activity D594A mutant can promote aneuploidy.	('aneuploidy', 'Disease', 'MESH:D000782', (116, 126))	('aneuploidy', 'Disease', (116, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('BRAF impaired activity', 'Gene', (68, 90))	('promote', 'PosReg', (108, 115))	('D594A', 'Mutation', 'rs121913338', (91, 96))	('D594A', 'Var', (91, 96))	('MAPK pathway', 'Pathway', (27, 39))
78707	31398831	Therefore, the BRAF D594A mutant not only drives aneuploidy in a MEK-ERK independent manner, but also activates MEK-ERK to overcome the growth-inhibitory effect of aneuploidy, and hence, facilitates the emergence of aneuploid cells with a growth advantage.	('MEK', 'Gene', (112, 115))	('BRAF D594A', 'Var', (15, 25))	('facilitates', 'PosReg', (187, 198))	('activates', 'PosReg', (102, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (49, 59))	('ERK', 'Gene', (116, 119))	('aneuploid cells with', 'CPA', (216, 236))	('ERK', 'molecular_function', 'GO:0004707', ('69', '72'))	('D594A', 'Mutation', 'rs121913338', (20, 25))	('aneuploidy', 'Disease', (49, 59))	('aneuploidy', 'Disease', 'MESH:D000782', (164, 174))	('MEK', 'Gene', '5609', (65, 68))	('ERK', 'Gene', '5594', (69, 72))	('MEK', 'Gene', '5609', (112, 115))	('growth-inhibitory effect', 'MPA', (136, 160))	('drives', 'PosReg', (42, 48))	('MEK', 'Gene', (65, 68))	('overcome', 'MPA', (123, 131))	('ERK', 'Gene', '5594', (116, 119))	('ERK', 'molecular_function', 'GO:0004707', ('116', '119'))	('ERK', 'Gene', (69, 72))	('aneuploidy', 'Disease', (164, 174))
78708	31398831	These results provide a link between impaired activity BRAF mutants and chromosomal instability, which could play a role in the development of mucosal melanomas.	('mucosal melanomas', 'Disease', (143, 160))	('chromosomal instability', 'Phenotype', 'HP:0040012', (72, 95))	('activity', 'MPA', (46, 54))	('mucosal melanomas', 'Disease', 'MESH:D008545', (143, 160))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mutants', 'Var', (60, 67))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('BRAF', 'Gene', (55, 59))	('chromosomal instability', 'CPA', (72, 95))
78710	31398831	Many variants have been described in the context of mucosal melanoma, but besides KIT mutations, there is still no clear consensus on the most frequent driver mutations.	('mutations', 'Var', (86, 95))	('mucosal melanoma', 'Disease', (52, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (52, 68))
78711	31398831	We catalogued alterations of the NRAS and BRAF genes in mucosal melanoma and showed that they represent a significant portion of mutations (20%) in these tumors.	('alterations', 'Var', (14, 25))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('NRAS', 'Gene', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('mucosal melanoma', 'Disease', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('BRAF', 'Gene', (42, 46))	('mucosal melanoma', 'Disease', 'MESH:D008545', (56, 72))
78712	31398831	We also demonstrated that mutations in NRAS and BRAF in mucosal melanoma are different from the ones found in cutaneous melanoma, suggesting the existence of genotoxic agents in mucosal melanoma that remain to be identified.	('mucosal melanoma', 'Disease', (178, 194))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('mucosal melanoma', 'Disease', 'MESH:D008545', (178, 194))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('NRAS', 'Gene', (39, 43))	('cutaneous melanoma', 'Disease', (110, 128))	('mutations', 'Var', (26, 35))	('mucosal melanoma', 'Disease', (56, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (110, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('BRAF', 'Gene', (48, 52))	('mucosal melanoma', 'Disease', 'MESH:D008545', (56, 72))
78716	31398831	Moreover, the BRAF mutation spectrum in mucosal melanoma is closely related to the mutation spectrum seen in lung cancers where mutations are often associated with the genotoxic effects of cigarette smoking.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('mutation', 'Var', (19, 27))	('mucosal melanoma', 'Disease', (40, 56))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancers', 'Disease', (109, 121))	('BRAF', 'Gene', (14, 18))	('mucosal melanoma', 'Disease', 'MESH:D008545', (40, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
78718	31398831	The peculiar NRAS and BRAF mutation spectra in mucosal melanomas could also be linked to different oncogenic potencies as well as distinct cell-specific functional consequences.	('mucosal melanomas', 'Disease', (47, 64))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('linked', 'Reg', (79, 85))	('mucosal melanomas', 'Disease', 'MESH:D008545', (47, 64))	('mutation', 'Var', (27, 35))	('BRAF', 'Gene', (22, 26))	('NRAS', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
78719	31398831	It is thus possible that the prevalence of specific NRAS mutations is related, in some measure, to the activation of other RAS effector pathways to complement RAF activation for mucosal melanoma development.	('NRAS', 'Gene', (52, 56))	('mucosal melanoma', 'Disease', (178, 194))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('RAF', 'Gene', (159, 162))	('mucosal melanoma', 'Disease', 'MESH:D008545', (178, 194))	('RAF', 'Gene', '22882', (159, 162))	('RAS effector pathways', 'Pathway', (123, 144))	('mutations', 'Var', (57, 66))	('activation', 'PosReg', (103, 113))
78720	31398831	In accordance with this hypothesis, it is interesting to note that, in two studies of genital nevi, the BRAF V600E mutation was found in 76% (26/34) and the NRAS Q61K in 3% (1/34) of nevi and no G12/G13 NRAS or non-V600E BRAF mutations were detected; this is in clear contrast to the mutations found in genital melanomas.	('nevi', 'Phenotype', 'HP:0003764', (183, 187))	('NRAS Q61K', 'Var', (157, 166))	('found', 'Reg', (128, 133))	('V600E', 'Mutation', 'rs113488022', (215, 220))	('nevi', 'Phenotype', 'HP:0003764', (94, 98))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('Q61K', 'Mutation', 'rs121913254', (162, 166))	('melanomas', 'Phenotype', 'HP:0002861', (311, 320))	('melanoma', 'Phenotype', 'HP:0002861', (311, 319))	('BRAF', 'Gene', (104, 108))	('genital melanomas', 'Disease', (303, 320))	('genital melanomas', 'Disease', 'MESH:D008545', (303, 320))	('V600E', 'Var', (109, 114))
78721	31398831	The presence of NRAS and BRAF mutations in mucosal melanomas raises the question of their therapeutic potential for this particularly deadly form of melanoma, which has not yet fully benefited from genomics-era advances in precision oncology.	('mucosal melanomas', 'Disease', (43, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma', 'Disease', (149, 157))	('mucosal melanomas', 'Disease', 'MESH:D008545', (43, 60))	('NRAS', 'Gene', (16, 20))	('oncology', 'Phenotype', 'HP:0002664', (233, 241))	('mutations', 'Var', (30, 39))	('BRAF', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
78722	31398831	Although the first generation of BRAF inhibitors aimed at the V600E mutant are not suitable for treating the atypical BRAF mutations, second-generation BRAF inhibitors and CRAF inhibitors could be used.	('CRAF', 'Gene', (172, 176))	('V600E', 'Var', (62, 67))	('CRAF', 'Gene', '5894', (172, 176))	('V600E', 'Mutation', 'rs113488022', (62, 67))	('CRAF', 'molecular_function', 'GO:0004709', ('172', '176'))
78723	31398831	In melanoma cells harboring the low-activity BRAF mutations (D594G or G469E), targeting CRAF with either sorafenib or small interfering RNAs decreases ERK phosphorylation and induces apoptosis.	('induces', 'Reg', (175, 182))	('decreases', 'NegReg', (141, 150))	('apoptosis', 'CPA', (183, 192))	('melanoma', 'Disease', (3, 11))	('D594G', 'Mutation', 'rs121913338', (61, 66))	('ERK', 'molecular_function', 'GO:0004707', ('151', '154'))	('decreases ERK', 'Phenotype', 'HP:0000654', (141, 154))	('D594G', 'Var', (61, 66))	('ERK', 'Gene', '5594', (151, 154))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('small interfering', 'Var', (118, 135))	('G469E', 'Mutation', 'rs121913355', (70, 75))	('phosphorylation', 'MPA', (155, 170))	('sorafenib', 'Chemical', 'MESH:D000077157', (105, 114))	('CRAF', 'Gene', (88, 92))	('ERK', 'Gene', (151, 154))	('CRAF', 'molecular_function', 'GO:0004709', ('88', '92'))	('G469E', 'Var', (70, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('155', '170'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('CRAF', 'Gene', '5894', (88, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('183', '192'))	('apoptosis', 'biological_process', 'GO:0006915', ('183', '192'))
78724	31398831	The type IIa BRAF inhibitor PLX7904 and its optimized analogue PLX8394 have been shown to inhibit signaling driven by V600 and non-V600 mutants in lung adenocarcinomas, where 48% of BRAF mutant tumors have non-V600 mutations.	('inhibit', 'NegReg', (90, 97))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (147, 167))	('IIa BRAF', 'Gene', (9, 17))	('V600', 'Var', (118, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('mutant', 'Var', (187, 193))	('signaling', 'MPA', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('IIa BRAF', 'Gene', '673', (9, 17))	('PLX7904', 'Var', (28, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumors', 'Disease', (194, 200))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (147, 167))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('lung adenocarcinomas', 'Disease', (147, 167))	('non-V600 mutants', 'Var', (127, 143))
78726	31398831	Moreover, rare activating mutations of ARAF have been identified in melanoma associated with an NRAS mutation, reinforcing the potential role of ARAF in NRAS-induced melanoma.	('ARAF', 'Gene', '369', (145, 149))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('ARAF', 'Gene', (145, 149))	('ARAF', 'Gene', '369', (39, 43))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('ARAF', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('activating', 'PosReg', (15, 25))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('NRAS', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))
78727	31398831	Finally, mucosal melanomas mutated on BRAF and NRAS may also be sensitive to MEK inhibitors as well as MEK inhibitor-based combinations.	('mutated', 'Var', (27, 34))	('mucosal melanomas', 'Disease', 'MESH:D008545', (9, 26))	('sensitive', 'Reg', (64, 73))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('MEK', 'Gene', (103, 106))	('NRAS', 'Gene', (47, 51))	('MEK', 'Gene', '5609', (103, 106))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('BRAF', 'Gene', (38, 42))	('mucosal melanomas', 'Disease', (9, 26))	('MEK', 'Gene', (77, 80))	('MEK', 'Gene', '5609', (77, 80))
78729	31398831	In summary, the findings of the present study refine our understanding of the role of BRAF and NRAS mutations in mucosal melanomas and could pave the way for therapeutic intervention.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mutations', 'Var', (100, 109))	('mucosal melanomas', 'Disease', (113, 130))	('melanomas', 'Phenotype', 'HP:0002861', (121, 130))	('mucosal melanomas', 'Disease', 'MESH:D008545', (113, 130))	('NRAS', 'Gene', (95, 99))	('BRAF', 'Gene', (86, 90))
78730	31398831	The clarification of the contribution of the atypical NRAS and BRAF mutations to mucosal melanoma pathogenesis will however require the development of suitable cellular and animal models for this melanoma subtype.	('melanoma subtype', 'Disease', 'MESH:D008545', (196, 212))	('mucosal melanoma', 'Disease', (81, 97))	('pathogenesis', 'biological_process', 'GO:0009405', ('98', '110'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (81, 97))	('NRAS', 'Gene', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mutations', 'Var', (68, 77))	('BRAF', 'Gene', (63, 67))	('melanoma subtype', 'Disease', (196, 212))
78731	31398831	The following are available online at , Table S1: NRAS mutations in mucosal melanoma, Table S2: BRAF mutations in mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (68, 84))	('mutations', 'Var', (101, 110))	('mutations', 'Var', (55, 64))	('NRAS', 'Gene', (50, 54))	('mucosal melanoma', 'Disease', (114, 130))	('mucosal melanoma', 'Disease', 'MESH:D008545', (114, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mucosal melanoma', 'Disease', (68, 84))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
78735	33256110	In tumors, RAGE activation is fueled by numerous ligands, S100B and HMGB1 being the most notable, but the role of many other ligands is not well understood and should not be underappreciated.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('HMGB1', 'Gene', (68, 73))	('HMGB1', 'Gene', '3146', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('S100B', 'Var', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
78746	33256110	Melanomagenesis is the result of genetic and epigenetic modifications, as well as alterations in signaling pathways controlling key cellular functions.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('epigenetic modifications', 'Var', (45, 69))	('Melanoma', 'Disease', (0, 8))	('age', 'Gene', (7, 10))	('signaling', 'biological_process', 'GO:0023052', ('97', '106'))	('alterations', 'Reg', (82, 93))	('signaling pathways', 'Pathway', (97, 115))	('age', 'Gene', '5973', (7, 10))
78787	33256110	PD1L1 is a cell surface transmembrane protein expressed by tumor cells and can also occur in a soluble form as result of alternate splicing or proteolysis.	('transmembrane', 'cellular_component', 'GO:0044214', ('24', '37'))	('transmembrane', 'cellular_component', 'GO:0016021', ('24', '37'))	('tumor', 'Disease', (59, 64))	('cell surface', 'cellular_component', 'GO:0009986', ('11', '23'))	('PD1L1', 'Gene', (0, 5))	('splicing', 'biological_process', 'GO:0045292', ('131', '139'))	('proteolysis', 'biological_process', 'GO:0006508', ('143', '154'))	('soluble', 'cellular_component', 'GO:0005625', ('95', '102'))	('PD1L1', 'Gene', '29126', (0, 5))	('alternate splicing', 'Var', (121, 139))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
78795	33256110	Inside cells, S100B interacts with the transcription factor p53 and inhibits its transcriptional activity, resulting in the increased survival of melanoma cells by decreasing p53-dependent apoptosis.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('increased', 'PosReg', (124, 133))	('survival', 'CPA', (134, 142))	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('p53', 'Gene', '7157', (175, 178))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('transcription factor', 'molecular_function', 'GO:0000981', ('39', '59'))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('p53', 'Gene', (60, 63))	('interacts', 'Interaction', (20, 29))	('decreasing', 'NegReg', (164, 174))	('transcriptional activity', 'MPA', (81, 105))	('p53', 'Gene', '7157', (60, 63))	('p53', 'Gene', (175, 178))	('inhibits', 'NegReg', (68, 76))	('S100B', 'Var', (14, 19))
78796	33256110	When secreted by tumors, S100B can be used as a prognostic biomarker, higher levels of S100B being predictive of poorer outcome.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (17, 23))	('higher', 'PosReg', (70, 76))	('S100B', 'Var', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
78807	33256110	Vemurafenib, dabrafenib, and encorafenib inhibit the mutant forms of the BRAF kinase, where valine in position 600 is replaced by an aspartic acid (V600E) or a lysine residue (V600K).	('V600E', 'Mutation', 'rs113488022', (148, 153))	('V600K', 'Var', (176, 181))	('encorafenib', 'Chemical', 'MESH:C000601108', (29, 40))	('V600E', 'Var', (148, 153))	('lysine', 'Chemical', 'MESH:D008239', (160, 166))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('V600K', 'Mutation', 'rs121913227', (176, 181))	('BRAF kinase', 'Enzyme', (73, 84))	('dabrafenib', 'Chemical', 'MESH:C561627', (13, 23))	('inhibit', 'NegReg', (41, 48))	('valine in position 600 is replaced by an aspartic acid', 'Mutation', 'rs121913377', (92, 146))
78808	33256110	These mutations are frequently observed in melanoma tumors, with BRAF V600E mutants being present in up to 60% of melanoma tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('melanoma tumors', 'Disease', (114, 129))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('BRAF V600E', 'Var', (65, 75))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('melanoma tumors', 'Disease', 'MESH:D008545', (114, 129))	('melanoma tumors', 'Disease', (43, 58))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('observed', 'Reg', (31, 39))	('melanoma tumors', 'Disease', 'MESH:D008545', (43, 58))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
78841	33256110	S100B has been described as the "lineage marker" of malignant melanoma.	('age', 'Gene', (37, 40))	('malignant melanoma', 'Phenotype', 'HP:0002861', (52, 70))	('age', 'Gene', '5973', (37, 40))	('malignant melanoma', 'Disease', 'MESH:D008545', (52, 70))	('S100B', 'Var', (0, 5))	('malignant melanoma', 'Disease', (52, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
78853	33256110	S100B can directly reduce p53 activity by binding to the C-terminal oligomerization domain of p53, thereby preventing p53 oligomerization and activation.	('preventing', 'NegReg', (107, 117))	('reduce', 'NegReg', (19, 25))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (118, 121))	('binding', 'Interaction', (42, 49))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (118, 121))	('S100B', 'Var', (0, 5))	('oligomerization', 'MPA', (122, 137))	('p53', 'Gene', '7157', (26, 29))	('activation', 'MPA', (142, 152))	('binding', 'molecular_function', 'GO:0005488', ('42', '49'))	('activity', 'MPA', (30, 38))
78854	33256110	In vitro data also showed that S100B can inhibit the phosphorylation and regulation of p53 by protein kinase C. In addition, S100B was shown to reduce the tumor-suppressive activities of p53 by down-regulating the expression of p53 downstream effector genes.	('S100B', 'Var', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('p53', 'Gene', (187, 190))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('reduce', 'NegReg', (144, 150))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('tumor', 'Disease', (155, 160))	('down-regulating', 'NegReg', (194, 209))	('p53', 'Gene', '7157', (187, 190))	('regulation', 'biological_process', 'GO:0065007', ('73', '83'))	('expression', 'MPA', (214, 224))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
78868	33256110	In many cancers, S100A4 has been shown to stimulate tumor proliferation and metastasis.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancers', 'Disease', (8, 15))	('tumor', 'Disease', (52, 57))	('S100A4', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('stimulate', 'PosReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
78869	33256110	S100A4 is a ligand of RAGE and has been shown to stimulate metastasis in various cancer models, including melanoma, through its interaction with RAGE.	('metastasis', 'CPA', (59, 69))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('ligand', 'molecular_function', 'GO:0005488', ('12', '18'))	('cancer', 'Disease', (81, 87))	('interaction', 'Interaction', (128, 139))	('S100A4', 'Var', (0, 6))	('stimulate', 'PosReg', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('melanoma', 'Disease', (106, 114))
78872	33256110	In a follow-up study, these authors showed that the S100A4/RAGE signaling altered endothelial cell integrity by decreasing tight junction proteins (occludin) and adherence junction protein (E-cadherin).	('E-cadherin', 'Gene', (190, 200))	('E-cadherin', 'Gene', '999', (190, 200))	('tight junction', 'cellular_component', 'GO:0070160', ('123', '137'))	('occludin', 'Gene', '100506658', (148, 156))	('decreasing', 'NegReg', (112, 122))	('S100A4/RAGE', 'Var', (52, 63))	('occludin', 'Gene', (148, 156))	('cadherin', 'molecular_function', 'GO:0008014', ('192', '200'))	('adherence junction protein', 'MPA', (162, 188))	('altered', 'Reg', (74, 81))	('endothelial cell integrity', 'CPA', (82, 108))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('signaling', 'biological_process', 'GO:0023052', ('64', '73'))	('tight junction proteins', 'MPA', (123, 146))
78874	33256110	All these in vitro data were supported by studies using a mouse model of metastatic melanoma, where mice injected with S100A4 or RAGE overexpressing A375 cells showed higher tumor incidence and mortality than mice injected with the control non-transfected A375.	('tumor', 'Disease', (174, 179))	('higher', 'PosReg', (167, 173))	('mice', 'Species', '10090', (209, 213))	('mouse', 'Species', '10090', (58, 63))	('mice', 'Species', '10090', (100, 104))	('mortality', 'Disease', (194, 203))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('S100A4', 'Var', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('A375', 'CellLine', 'CVCL:0132', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mortality', 'Disease', 'MESH:D003643', (194, 203))	('A375', 'CellLine', 'CVCL:0132', (256, 260))
78875	33256110	Additionally, we previously demonstrated that S100A4 levels were significantly higher in RAGE overexpressing WM115 tumors, which were subcutaneously implanted in mice, than in control tumors generated from non-transfected WM115 cells.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('WM115', 'Var', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Disease', (115, 121))	('S100A4 levels', 'MPA', (46, 59))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('mice', 'Species', '10090', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('WM115', 'CellLine', 'CVCL:0040', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('WM115', 'CellLine', 'CVCL:0040', (109, 114))	('higher', 'PosReg', (79, 85))
78878	33256110	S100A6 is overexpressed in Spitz nevi, melanocytic nevi, and melanomas; in fact, tissue analysis of melanoma patients revealed that most melanomas showed positive staining for S100A6.	('patients', 'Species', '9606', (109, 117))	('melanomas', 'Disease', 'MESH:D008545', (137, 146))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('S100A6', 'Var', (176, 182))	('melanomas', 'Disease', (137, 146))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (39, 55))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('nevi', 'Phenotype', 'HP:0003764', (51, 55))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanomas', 'Disease', 'MESH:D008545', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('nevi', 'Phenotype', 'HP:0003764', (33, 37))	('melanoma', 'Disease', (137, 145))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('melanomas', 'Disease', (61, 70))
78888	33256110	In a mouse model of metastatic melanoma, it was shown that uteroglobulin knock-out mice, which naturally overexpress S100A8/A9 in their lungs, developed more metastases in this organ than their wild-type littermates.	('mouse', 'Species', '10090', (5, 10))	('mice', 'Species', '10090', (83, 87))	('metastases', 'Disease', (158, 168))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('S100A8/A9', 'Var', (117, 126))	('overexpress', 'PosReg', (105, 116))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
78889	33256110	This study suggested that S100A8/A9 had the ability to attract melanoma cells to the lungs through the activation of RAGE.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('S100A8/A9', 'Var', (26, 35))	('attract', 'CPA', (55, 62))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
78890	33256110	In a more recent study, the role of S100A8/A9 as a lung attractant for melanoma metastases was confirmed.	('S100A8/A9', 'Var', (36, 45))	('melanoma metastases', 'Disease', 'MESH:D009362', (71, 90))	('attractant', 'molecular_function', 'GO:0042056', ('56', '66'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma metastases', 'Disease', (71, 90))
78892	33256110	S100A8/A9 has also been proposed to be a prognostic marker for metastasis, as well as a predictor of survival and determinant of therapeutic response in melanoma patients.	('patients', 'Species', '9606', (162, 170))	('metastasis', 'CPA', (63, 73))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('S100A8/A9', 'Var', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))
78893	33256110	When the expressions of S100A8/A9 proteins were analyzed in melanocytic nevi, primary melanomas, and metastases, higher expression was found in metastases compared to primary melanoma tumors, suggesting that S100A8/A9 is a tumor microenvironment-associated protein that is key to the process of metastasis in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('protein', 'cellular_component', 'GO:0003675', ('257', '264'))	('S100A8/A9', 'Var', (208, 217))	('metastases', 'Disease', (101, 111))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('metastases', 'Disease', 'MESH:D009362', (144, 154))	('melanoma', 'Disease', (309, 317))	('melanoma tumors', 'Disease', 'MESH:D008545', (175, 190))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('expression', 'MPA', (120, 130))	('tumor', 'Disease', (184, 189))	('melanoma tumors', 'Disease', (175, 190))	('metastases', 'Disease', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (223, 228))	('melanoma', 'Disease', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (60, 76))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('melanoma', 'Disease', 'MESH:D008545', (309, 317))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('melanomas', 'Disease', (86, 95))	('metastases', 'Disease', 'MESH:D009362', (101, 111))
78896	33256110	S100A8/A9/RAGE, S100A8/A9-ALCAM, and S100A8/A9/MCAM axes mediate malignant melanoma progression through the activity of nuclear factor kappa beta (NF-kappaB) and production of reactive oxygen species (ROS).	('ALCAM', 'Gene', (26, 31))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (176, 199))	('mediate', 'Reg', (57, 64))	('activity', 'MPA', (108, 116))	('S100A8/A9/RAGE', 'Var', (0, 14))	('malignant melanoma', 'Phenotype', 'HP:0002861', (65, 83))	('NF-kappaB', 'Gene', '4790', (147, 156))	('MCAM', 'Gene', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('MCAM', 'Gene', '4162', (47, 51))	('malignant melanoma', 'Disease', 'MESH:D008545', (65, 83))	('ROS', 'Chemical', 'MESH:D017382', (201, 204))	('ALCAM', 'Gene', '214', (26, 31))	('NF-kappaB', 'Gene', (147, 156))	('malignant melanoma', 'Disease', (65, 83))
78921	33256110	reported that disruption of the HMGB1/RAGE axis hampered melanoma tumor growth and reduced the synthesis of inflammatory cytokines.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('synthesis', 'biological_process', 'GO:0009058', ('95', '104'))	('HMGB1', 'Gene', '3146', (32, 37))	('melanoma tumor', 'Disease', (57, 71))	('hampered', 'NegReg', (48, 56))	('reduced', 'NegReg', (83, 90))	('melanoma tumor', 'Disease', 'MESH:D008545', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('synthesis of inflammatory cytokines', 'MPA', (95, 130))	('disruption', 'Var', (14, 24))	('HMGB1', 'Gene', (32, 37))
78925	33256110	Importantly, silencing RAGE in these melanocytes resulted in a decreased secretion of HMGB1 as well as decreased resistance to apoptosis, strongly suggesting that the HMGB1/RAGE axis contributes to the early stages of melanoma development.	('HMGB1', 'Gene', (167, 172))	('RAGE', 'Gene', (23, 27))	('HMGB1', 'Gene', '3146', (167, 172))	('decreased', 'NegReg', (63, 72))	('age', 'Gene', (210, 213))	('decreased', 'NegReg', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('secretion', 'biological_process', 'GO:0046903', ('73', '82'))	('secretion', 'MPA', (73, 82))	('HMGB1', 'Gene', (86, 91))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('HMGB1', 'Gene', '3146', (86, 91))	('resistance to apoptosis', 'MPA', (113, 136))	('age', 'Gene', '5973', (210, 213))	('apoptosis', 'biological_process', 'GO:0097194', ('127', '136'))	('apoptosis', 'biological_process', 'GO:0006915', ('127', '136'))	('silencing', 'Var', (13, 22))
78943	33256110	Another member of the Rho family, RhoA, together with Cdc42, has also been shown to initiate metastasis as a result of the activation of RAGE by S100A4.	('metastasis', 'CPA', (93, 103))	('Cdc42', 'Gene', '998', (54, 59))	('RAGE', 'MPA', (137, 141))	('activation', 'PosReg', (123, 133))	('RhoA', 'Gene', '387', (34, 38))	('S100A4', 'Var', (145, 151))	('Cdc42', 'Gene', (54, 59))	('RhoA', 'Gene', (34, 38))
78955	33256110	In another study, inhibition of the HMGB1/RAGE axis suppressed the ERK/p90 ribosomal S6 kinase (p90RSK)/CREB signaling pathway, resulting in the apoptosis in HGC-27 cells.	('HMGB1', 'Gene', (36, 41))	('ERK', 'molecular_function', 'GO:0004707', ('67', '70'))	('HMGB1', 'Gene', '3146', (36, 41))	('ERK/p90 ribosomal S6 kinase', 'Gene', '6195;5594', (67, 94))	('signaling pathway', 'biological_process', 'GO:0007165', ('109', '126'))	('CREB', 'Gene', (104, 108))	('HGC-27', 'CellLine', 'CVCL:1279', (158, 164))	('p90RSK', 'Gene', (96, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('suppressed', 'NegReg', (52, 62))	('CREB', 'Gene', '1385', (104, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('inhibition', 'Var', (18, 28))	('ERK/p90 ribosomal S6 kinase', 'Gene', (67, 94))	('p90RSK', 'Gene', '6195', (96, 102))	('apoptosis', 'CPA', (145, 154))
78986	29572294	We find that such mutations (i) are more prominent in proteins that can exist in the on and off state, (ii) reflect the identity of a tumor of origin, and (iii) often localize within interfaces which mediate interactions with other proteins or ligands.	('localize', 'Reg', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('proteins', 'Protein', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('interactions', 'Interaction', (208, 220))	('tumor', 'Disease', (134, 139))	('mutations', 'Var', (18, 27))
78987	29572294	Following, we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (152, 161))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('human', 'Species', '9606', (50, 55))
78988	29572294	Jointly, these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes.	('switching', 'Reg', (113, 122))	('functions', 'MPA', (123, 132))	('disruption', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('protein interactions', 'Protein', (69, 89))	('cancer', 'Disease', (136, 142))	('dysregulation', 'Var', (52, 65))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
78991	29572294	Analysis of different cancer genomics datasets has further underscored a high degree of heterogeneity in the mutation frequency and spectrum among different cancer types (Garraway & Lander, 2013; Lawrence et al, 2013) and uncovered a long tail of low-frequency driver mutations (Garraway & Lander, 2013).	('driver', 'Var', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('long tail', 'Phenotype', 'HP:0002831', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
78994	29572294	Large-scale cancer genome initiatives, specifically The Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov/) and International Cancer Genome Consortium (International Cancer Genome et al, 2010; ICGC, http://icgc.org/), have increased statistical power in the analyses of cancer mutations and have driven the development of innovative approaches for the study of patient data (Dees et al, 2012; Hofree et al, 2013; Kandoth et al, 2013; Lawrence et al, 2013, 2014; Chen et al, 2014; Sanchez-Garcia et al, 2014).	('Sanchez-Garcia', 'Disease', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('patient', 'Species', '9606', (367, 374))	('Cancer', 'Disease', (172, 178))	('Cancer', 'Disease', (132, 138))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (56, 75))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('statistical', 'MPA', (239, 250))	('Sanchez-Garcia', 'Disease', 'MESH:C536767', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer Genome Atlas', 'Disease', (56, 75))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (276, 282))	('mutations', 'Var', (283, 292))	('Cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (229, 238))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))
78997	29572294	Many of the individual cancer mutations are not well studied in terms of how they influence the properties of proteins (Cancer Genome Atlas Research et al, 2013).	('influence', 'Reg', (82, 91))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('properties of proteins', 'MPA', (96, 118))	('Cancer Genome Atlas', 'Disease', (120, 139))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (120, 139))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
78999	29572294	In this study, we applied the tool to 40 cancer types with the TCGA or ICGC sequencing data and identified 180 hotspot mutation residues in 160 genes that had a likely functional impact.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))	('mutation residues', 'Var', (119, 136))
79000	29572294	These mutations alone had the power to cluster tumors based on the cell type of origin, and many of the hotspots were found within proteins, for example, enzymes, that are known to exist in the active and inactive states.	('cluster tumors', 'Disease', 'MESH:D003027', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cluster tumors', 'Disease', (39, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (6, 15))
79004	29572294	We mapped protein interfaces in these and based on the presence of mutation clusters within the mapped interfaces, we were able to identify 87 proteins in which cancer mutations were likely to affect protein interactions.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutation', 'Var', (67, 75))	('affect', 'Reg', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('protein', 'Protein', (200, 207))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (168, 177))
79007	29572294	Overall, characterization of the recurrent functional mutations suggests that a disruption and dysregulation of protein interactions could be an important molecular mechanism for switching functions of cancer proteins.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('interactions', 'Interaction', (120, 132))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('dysregulation', 'MPA', (95, 108))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('cancer', 'Disease', (202, 208))	('protein', 'Protein', (112, 119))
79008	29572294	Collectively, the data encompassed 40 different cancer types from 22 tissues, with the sequencing information from ~10,000 tumor samples, including ~1,300,000 mutations within coding sequences (see Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (159, 168))	('000 tumor', 'Disease', 'MESH:D009369', (119, 128))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('000 tumor', 'Disease', (119, 128))
79010	29572294	The tool identifies and characterizes individual hotspot protein residues that accumulate mutations at a significantly higher rate than their surrounding protein sequence (Figs 1 and EV1).	('mutations', 'Var', (90, 99))	('EV1', 'Gene', (183, 186))	('EV1', 'Gene', '11322', (183, 186))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))
79013	29572294	Simulations of randomly re-assigned mutations within titin, that is, a gene with the highest overall mutation burden, did not report any hotspot residues (1,000 repetitions).	('titin', 'Gene', (53, 58))	('titin', 'Gene', '7273', (53, 58))	('mutations', 'Var', (36, 45))
79014	29572294	Using the approach introduced here, we applied the DominoEffect tool to the pan-cancer data and identified both known instances of hotspot driver mutations as well as residues that were as yet not annotated as such.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', (80, 86))
79015	29572294	In total, we identified 180 hotspots within 160 genes (Dataset EV1) for which the reported mutations were categorized as deleterious by the PolyPhen-2.	('mutations', 'Var', (91, 100))	('EV1', 'Gene', '11322', (63, 66))	('EV1', 'Gene', (63, 66))
79018	29572294	Of note, on average, 88% of tumor allele changes assigned as hotspot mutations were reported as heterozygotic in the TCGA dataset.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
79021	29572294	Independently of the hotspot analysis, we additionally searched for cancer mutation clusters in known and modeled protein interaction interfaces (Fig 1).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (75, 83))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))
79022	29572294	Strikingly, 36% (3,679/10,118) of the analyzed cancer genomes had at least one of the 180 hotspot residues mutated (Fig 2A).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
79023	29572294	For a comparison, the same size randomly selected gene set that contained any of the protein positions with five or more pan-cancer mutations was on average mutated in 14% of the patients (P < 6 x 10-12, distance from the observed distribution of 1,000 random values).	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (125, 131))	('mutated', 'Var', (157, 164))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
79024	29572294	The major contributors to the highly prevalent mutations were the well-studied oncogenes KRAS, BRAF, IDH1, PIK3CA, NRAS, SF3B1, CTNNB1, and PTEN: More than one-quarter (i.e., 27%) of all patients had a hotspot mutation in at least one of these genes.	('NRAS', 'Gene', (115, 119))	('PIK3CA', 'Gene', (107, 113))	('SF3B1', 'Gene', (121, 126))	('PTEN', 'Gene', (140, 144))	('patients', 'Species', '9606', (187, 195))	('CTNNB1', 'Gene', '1499', (128, 134))	('BRAF', 'Gene', '673', (95, 99))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (89, 93))	('IDH1', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (140, 144))	('SF3B1', 'Gene', '23451', (121, 126))	('NRAS', 'Gene', '4893', (115, 119))	('PIK3CA', 'Gene', '5290', (107, 113))	('KRAS', 'Gene', (89, 93))	('CTNNB1', 'Gene', (128, 134))	('IDH1', 'Gene', '3417', (101, 105))	('hotspot', 'PosReg', (202, 209))
79029	29572294	The obtained extensive set of known and candidate cancer-associated genes with hotspot mutations provides an opportunity to define gene and protein characteristics associated with such residues.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (87, 96))
79031	29572294	Among the most prominent examples of cancer drivers with hotspot residues are kinases and Ras proteins where the hotspot mutations frequently act by switching the proteins to a constantly active state.	('residues', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', (37, 43))	('proteins', 'MPA', (163, 171))	('Ras', 'Protein', (90, 93))	('switching', 'Reg', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
79035	29572294	Moreover, the fraction of enzymes was even two times higher among the here-identified genes with hotspot residues than among the genes in the Cancer Gene Census that were involved in translocations (P < 0.0003).	('higher', 'PosReg', (53, 59))	('residues', 'Var', (105, 113))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('enzymes', 'MPA', (26, 33))	('Cancer', 'Disease', (142, 148))	('fraction', 'MPA', (14, 22))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))
79038	29572294	In accordance with these observations, protein domains that were most frequently encoded by the genes with hotspot residues were kinase and Ras domains, Fig 2C and Dataset EV4; adjusted P-values for the overrepresentation were < 6 x 10-9 and < 0.008, respectively, Fisher's test, when compared to the background set of non-cancer proteins).	('non-cancer proteins', 'Disease', (319, 338))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('non-cancer proteins', 'Disease', 'MESH:D009369', (319, 338))	('residues', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))
79044	29572294	Overall, this shows that many of the genes with hotspot residues relate to cancer-associated processes and that jointly more than a third of them encode proteins that are known to exist in an active and inactive state.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('residues', 'Var', (56, 64))	('encode', 'Reg', (146, 152))	('cancer', 'Disease', (75, 81))	('proteins', 'Protein', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('relate', 'Reg', (65, 71))
79046	29572294	We found that domains which were targets of hotspot mutations in two or more proteins were often associated with enzymatic activities, or with binding to proteins, nucleic acids, or lipids (Fig 2E and Dataset EV1).	('proteins', 'Protein', (154, 162))	('mutations', 'Var', (52, 61))	('binding', 'Interaction', (143, 150))	('lipids', 'Chemical', 'MESH:D008055', (182, 188))	('enzymatic activities', 'MPA', (113, 133))	('EV1', 'Gene', '11322', (209, 212))	('binding', 'molecular_function', 'GO:0005488', ('143', '150'))	('EV1', 'Gene', (209, 212))	('associated', 'Reg', (97, 107))
79050	29572294	A hotspot residue within this protein mapped to the KH domain that has a role in nucleic acid recognition and is also a target of a hotspot mutation in the known cancer driver FUBP1.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('FUBP1', 'Gene', '8880', (176, 181))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('FUBP1', 'Gene', (176, 181))	('nucleic acid', 'cellular_component', 'GO:0005561', ('81', '93'))	('role', 'Reg', (73, 77))
79052	29572294	As a following step, we analyzed the PDB structures of proteins with the identified hotspot mutations (Berman et al, 2000; www.rcsb.org).	('PDB', 'Gene', (37, 40))	('PDB', 'Gene', '5131', (37, 40))	('mutations', 'Var', (92, 101))
79053	29572294	When structural data were available, we aligned the segments with hotspot mutations onto the corresponding PDB sequences (see Materials and Methods).	('mutations', 'Var', (74, 83))	('PDB', 'Gene', '5131', (107, 110))	('PDB', 'Gene', (107, 110))
79058	29572294	The observed hotspot mutations in CARM1 and METTL4 could thus have an effect on the interactions between the CARM1 proteins that together form a complex, or on the METTL4 binding to its interactor protein METTL3.	('binding', 'molecular_function', 'GO:0005488', ('171', '178'))	('effect', 'Reg', (70, 76))	('METTL4', 'Gene', (44, 50))	('interactions', 'Interaction', (84, 96))	('METTL4', 'Gene', '64863', (44, 50))	('CARM1', 'Gene', (109, 114))	('METTL3', 'Gene', (205, 211))	('binding', 'Interaction', (171, 178))	('CARM1', 'Gene', '10498', (34, 39))	('proteins', 'Protein', (115, 123))	('METTL3', 'Gene', '56339', (205, 211))	('CARM1', 'Gene', (34, 39))	('complex', 'Interaction', (145, 152))	('have', 'Reg', (62, 66))	('mutations', 'Var', (21, 30))	('METTL4', 'Gene', (164, 170))	('METTL4', 'Gene', '64863', (164, 170))	('CARM1', 'Gene', '10498', (109, 114))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))
79060	29572294	Finally, hotspot residues in the PBX2 and MAX proteins mapped to their conserved DNA interfaces, suggesting abolished or altered transcriptional regulation.	('PBX2', 'Gene', (33, 37))	('transcriptional regulation', 'MPA', (129, 155))	('altered', 'Reg', (121, 128))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('regulation', 'biological_process', 'GO:0065007', ('145', '155'))	('residues', 'Var', (17, 25))	('PBX2', 'Gene', '5089', (33, 37))
79061	29572294	In the case of the PTEN (Papa et al, 2014), FBXW7 (Welcker & Clurman, 2008) and SMAD4 (Miyaki & Kuroki, 2003) genes, as well as several other tumor suppressors (de Vries et al, 2002; Hanel et al, 2013), a frequent mechanism of inactivation is through point mutations that reoccur at the defined residues and act dominantly on the molecular level.	('FBXW7', 'Gene', '55294', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FBXW7', 'Gene', (44, 49))	('mechanism', 'NegReg', (214, 223))	('tumor', 'Disease', (142, 147))	('PTEN', 'Gene', (19, 23))	('SMAD4', 'Gene', '4089', (80, 85))	('PTEN', 'Gene', '5728', (19, 23))	('is through', 'Var', (240, 250))	('Papa', 'Gene', '5069', (25, 29))	('and', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Papa', 'Gene', (25, 29))	('SMAD4', 'Gene', (80, 85))
79062	29572294	In the cancer genomics studies, mutational clustering is often used as a signature that is associated with oncogenes (Davoli et al, 2013; Vogelstein et al, 2013).	('mutational', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
79064	29572294	In order to categorize hotspot mutations that could function by inactivating tumor suppressors, we analyzed which of the here-identified genes were categorized as tumor suppressors in the Cancer Gene Census, or were predicted to be suppressors based on mutation signatures in an independent study (Davoli et al, 2013).	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('inactivating', 'NegReg', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Cancer', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
79065	29572294	In addition, to further expand the set of tumor suppressor candidates, we assessed the frequency of deleterious mutations within the here-defined set of hotspot genes using the mutation data from the above-described TCGA and ICGC datasets.	('tumor', 'Disease', (42, 47))	('tumor suppressor', 'biological_process', 'GO:0051726', ('42', '58'))	('mutations', 'Var', (112, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('42', '58'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
79066	29572294	Using a conservative threshold that required an overrepresentation of deleterious over neutral changes within a protein, we found that 15 genes with a hotspot mutation also exhibited mutation patterns typical of tumor suppressors (Dataset EV5).	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mutation', 'Var', (159, 167))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))
79071	29572294	Furthermore, to gain additional insights into the distribution of functional effects of hotspot mutations, we classified genes in which hotspot residues were mutated in 10 or more tumor samples into the following three categories: (i) instances where mutations occurred within a tumor suppressor and were likely inactivating, (ii) instances where mutations affected protein binding properties and were likely activating, and (iii) all other instances (Fig 3B and Dataset EV6).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor suppressor', 'biological_process', 'GO:0051726', ('279', '295'))	('mutations', 'Var', (251, 260))	('activating', 'MPA', (409, 419))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('protein', 'cellular_component', 'GO:0003675', ('366', '373'))	('protein binding', 'molecular_function', 'GO:0005515', ('366', '381'))	('inactivating', 'NegReg', (312, 324))	('tumor', 'Disease', (279, 284))	('affected', 'Reg', (357, 365))	('tumor', 'Disease', (180, 185))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('279', '295'))	('protein', 'Protein', (366, 373))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))	('mutations', 'Var', (347, 356))
79072	29572294	These more frequently mutated instances encompassed in total 53 genes and included the experimentally characterized hotspots within the PTEN, FBXW7, SMAD4, EP300, and CREBBP tumor suppressors.	('tumor', 'Disease', (174, 179))	('EP300', 'Gene', (156, 161))	('EP300', 'Gene', '2033', (156, 161))	('SMAD4', 'Gene', (149, 154))	('CREBBP', 'Gene', (167, 173))	('encompassed', 'Reg', (40, 51))	('mutated', 'Var', (22, 29))	('CREBBP', 'Gene', '1387', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('FBXW7', 'Gene', '55294', (142, 147))	('FBXW7', 'Gene', (142, 147))	('SMAD4', 'Gene', '4089', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PTEN', 'Gene', (136, 140))	('PTEN', 'Gene', '5728', (136, 140))
79073	29572294	In the set of proteins with more frequently mutated and better-characterized hotspots, 32% (i.e.,17 of 53) were tumor suppressor, 51% (i.e., 27 of 53) represented instances where hotspot mutations were likely to affect protein binding properties, and 17% (i.e., 9 of 53) were proteins in which the impacts of hotspot mutations could not be readily classified.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('protein binding', 'molecular_function', 'GO:0005515', ('219', '234'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutated', 'Var', (44, 51))	('mutations', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('affect', 'Reg', (212, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('protein', 'cellular_component', 'GO:0003675', ('219', '226'))	('protein', 'Protein', (219, 226))
79076	29572294	Using a complementary approach, we compared the presence of iPfam domains (Wang et al, 2012; Finn et al, 2014), that is, Pfam domains that can mediate protein-protein interactions, in the protein sets that we established above: (i) proteins that contain hotspot mutations, (ii) other proteins encoded by the Cancer Gene Census (described above), and (iii) all other human proteins.	('Finn', 'Species', '1754191', (93, 97))	('Cancer', 'Disease', (308, 314))	('Cancer', 'Phenotype', 'HP:0002664', (308, 314))	('protein', 'cellular_component', 'GO:0003675', ('159', '166'))	('protein', 'cellular_component', 'GO:0003675', ('188', '195'))	('Cancer', 'Disease', 'MESH:D009369', (308, 314))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('mutations', 'Var', (262, 271))	('human', 'Species', '9606', (366, 371))
79082	29572294	Individually, 20 (i.e., 19%) of these 106 proteins had interaction neighborhoods strongly enriched in the known cancer drivers (adjusted P < 0.05, Dataset EV7), and these clusters often included other proteins with hotspot mutations (Dataset EV7).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('interaction', 'Interaction', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (223, 232))	('included', 'Reg', (186, 194))
79085	29572294	Additionally, 27 interaction pairs in which one partner was a candidate with a hotspot mutation and the other partner was a Cancer Gene Census protein were also supported with a PDB structure or a homology-based structural model that indicated a stable interaction between the proteins (see Materials and Methods).	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('PDB', 'Gene', '5131', (178, 181))	('Cancer', 'Disease', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('interaction', 'Interaction', (253, 264))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (87, 95))	('PDB', 'Gene', (178, 181))
79087	29572294	The hotspot mutation in this gene was originally reported in the TCGA study of bladder cancer (Cancer Genome Atlas Research, 2014a), but its impact has as yet not been characterized.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('Cancer Genome Atlas', 'Disease', (95, 114))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('mutation', 'Var', (12, 20))	('bladder cancer', 'Disease', (79, 93))
79088	29572294	The observation that a number of the candidates with hotspot mutations were physically associated with each other or with known cancer drivers suggests their possible connections to interaction networks relevant in disease development.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('interaction', 'Interaction', (182, 193))	('connections', 'Interaction', (167, 178))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Interaction', (87, 97))	('cancer', 'Disease', (128, 134))
79091	29572294	We found that 35 out of 180 hotspot residues were largely associated with one tumor type, that is, more than 75% of the mutations on these 35 positions were reported in a single tumor type (Dataset EV8).	('tumor', 'Disease', (178, 183))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
79094	29572294	For instance, for 89 hotspot positions, a single tumor type never contributed to 50% or more of the mutations (Dataset EV8).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
79095	29572294	Next, we performed a hierarchical clustering of the analyzed tumor types, based on the percentage of patients that had a mutation in each of the identified hotspots.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
79096	29572294	Patterns of hotspot mutations could also point to the shared and cell-type-specific pathways in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('point', 'Reg', (41, 46))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (20, 29))
79103	29572294	Blood tumors were largely defined by the scarcity of point mutations, and skin cutaneous melanoma and thyroid cancer were clustered together based on a high frequency of the BRAF hotspot mutation.	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BRAF', 'Gene', '673', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BRAF', 'Gene', (174, 178))	('thyroid cancer', 'Disease', (102, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('mutation', 'Var', (187, 195))	('Blood tumors', 'Phenotype', 'HP:0004377', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
79105	29572294	Overall, this analysis showed a strong power of hotspot mutations to reflect the identity of a tumor of origin.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
79107	29572294	Proteins in which the mutation clusters were identified with the most significant P-values were cancer drivers for which it was previously shown that mutations in their interfaces can lead to disease development by disrupting interactions with regulatory proteins (PIK3CA and PPP2R1A) or by preventing GTP hydrolysis (KRAS, HRAS, and GNAS); Dataset EV9, 87 proteins in total.	('mutation', 'Var', (22, 30))	('GNAS', 'Gene', '2778', (334, 338))	('interactions', 'Interaction', (226, 238))	('HRAS', 'Gene', '3265', (324, 328))	('preventing', 'NegReg', (291, 301))	('HRAS', 'Gene', (324, 328))	('cancer', 'Disease', (96, 102))	('disrupting', 'NegReg', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PIK3CA', 'Gene', (265, 271))	('GTP hydrolysis', 'biological_process', 'GO:0006184', ('302', '316'))	('KRAS', 'Gene', '3845', (318, 322))	('mutations', 'Var', (150, 159))	('PPP2R1A', 'Gene', '5518', (276, 283))	('disease', 'Disease', (192, 199))	('KRAS', 'Gene', (318, 322))	('GTP', 'Chemical', 'MESH:D006160', (302, 305))	('PPP2R1A', 'Gene', (276, 283))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('lead to', 'Reg', (184, 191))	('GTP hydrolysis', 'MPA', (302, 316))	('GNAS', 'Gene', (334, 338))	('PIK3CA', 'Gene', '5290', (265, 271))
79113	29572294	Of interest, both CUL1 and CUL4B had a mutation cluster at one of the interface contacts with the regulator protein CAND1 (Fig 6C).	('CUL4B', 'Gene', '8450', (27, 32))	('mutation', 'Var', (39, 47))	('CUL1', 'Gene', (18, 22))	('CAND1', 'Gene', (116, 121))	('CAND1', 'Gene', '55832', (116, 121))	('CUL1', 'Gene', '8454', (18, 22))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('CUL4B', 'Gene', (27, 32))
79114	29572294	In addition, we used annotations of protein complexes from the ConsensusPathDB (Kamburov et al, 2013) and found a number of protein complexes relevant in cancer that would be affected through these mutations (Dataset EV10).	('EV1', 'Gene', (217, 220))	('EV1', 'Gene', '11322', (217, 220))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('affected', 'Reg', (175, 183))	('protein', 'Protein', (124, 131))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))
79116	29572294	Of relevance, mutations in the GNB1 protein interface were recently shown to promote cellular growth and transformation, as well as kinase inhibitor resistance (Yoda et al, 2015).	('GNB1', 'Gene', '2782', (31, 35))	('promote', 'PosReg', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('cellular growth', 'CPA', (85, 100))	('cellular growth', 'biological_process', 'GO:0016049', ('85', '100'))	('GNB1', 'Gene', (31, 35))	('transformation', 'CPA', (105, 119))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('132', '148'))	('protein', 'Protein', (36, 43))	('kinase inhibitor resistance', 'MPA', (132, 159))	('mutations', 'Var', (14, 23))
79119	29572294	In addition to finding mutation clusters within protein-protein interfaces, the analysis identified a mutation cluster at the interface of the PAX5 transcription factor with DNA, as well as a number of contacts with small ligands, most commonly ATP and GTP.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('PAX5', 'Gene', '5079', (143, 147))	('mutation', 'Var', (102, 110))	('PAX5', 'Gene', (143, 147))	('transcription factor', 'molecular_function', 'GO:0000981', ('148', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('GTP', 'Chemical', 'MESH:D006160', (253, 256))	('ATP', 'Chemical', 'MESH:D000255', (245, 248))	('transcription', 'biological_process', 'GO:0006351', ('148', '161'))
79120	29572294	PAX5 is a known tumor suppressor with a highly conserved DNA-binding motif (Garvie et al, 2001) that is often involved in leukemia development, however, most frequently through translocations.	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('PAX5', 'Gene', (0, 4))	('translocations', 'Var', (177, 191))	('PAX5', 'Gene', '5079', (0, 4))	('involved', 'Reg', (110, 118))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('57', '68'))
79121	29572294	Overall, mutation clusters in structural interfaces were able to highlight additional cancer-relevant proteins and protein regions, which can mediate a switch in protein activity and function.	('mutation', 'Var', (9, 17))	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (170, 178))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
79124	29572294	Here, based on the sequencing data for more than 10,000 cancer genomes, we composed a set of most common hotspot mutations with a likely functional effect and characterized these using available structural and interaction data, as well as protein sequence features and residue annotations.	('000 cancer', 'Disease', 'MESH:D009369', (52, 62))	('000 cancer', 'Disease', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (113, 122))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
79128	29572294	Mechanistically, these mutations tend to disrupt the original protein function, exemplified by the disrupted substrate binding in CREBBP and EP300, or to prevent the activation of a tumor suppressor, exemplified by mutations within the SMAD4 interface or CHEK2 activation loop (Dataset EV5).	('CREBBP', 'Gene', (130, 136))	('disrupted', 'NegReg', (99, 108))	('EP300', 'Gene', (141, 146))	('activation', 'MPA', (166, 176))	('substrate', 'MPA', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('protein', 'Protein', (62, 69))	('SMAD4', 'Gene', (236, 241))	('mutations', 'Var', (215, 224))	('mutations', 'Var', (23, 32))	('CREBBP', 'Gene', '1387', (130, 136))	('disrupt', 'NegReg', (41, 48))	('prevent', 'NegReg', (154, 161))	('CHEK2', 'Gene', (255, 260))	('SMAD4', 'Gene', '4089', (236, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('182', '198'))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('CHEK2', 'Gene', '11200', (255, 260))	('original', 'MPA', (53, 61))	('tumor', 'Disease', (182, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('182', '198'))	('EP300', 'Gene', '2033', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
79129	29572294	Alternatively, these mutations can interfere with the oncogene regulation, exemplified by the PIK3R1 interface to PIK3CA.	('PIK3CA', 'Gene', '5290', (114, 120))	('regulation', 'biological_process', 'GO:0065007', ('63', '73'))	('oncogene regulation', 'MPA', (54, 73))	('interfere', 'Reg', (35, 44))	('PIK3R1', 'Gene', '5295', (94, 100))	('PIK3R1', 'Gene', (94, 100))	('PIK3CA', 'Gene', (114, 120))	('mutations', 'Var', (21, 30))
79132	29572294	As more cancer genomes get sequenced, we expect that the list of genes with hotspot mutations will expand.	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
79136	29572294	Cancer classification based on molecular data, which include point mutations, copy number variations, and mRNA and protein expression, has proven to be able to recapitulate pathological subtypes and suggest finer subclasses within tumor types (Hoadley et al, 2014).	('point mutations', 'Var', (61, 76))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('copy number variations', 'Var', (78, 100))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (231, 236))	('mRNA', 'MPA', (106, 110))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
79137	29572294	Remarkably, here we observed that clustering of tumor types based on a small number of functional hotspot mutations was able to largely mimic the behavior of much more complex molecular datasets.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
79142	29572294	Of relevance, many (i.e., 45) of the proteins with hotspot mutations are classified as druggable (Dataset EV12).	('EV1', 'Gene', (106, 109))	('EV1', 'Gene', '11322', (106, 109))	('mutations', 'Var', (59, 68))
79146	29572294	In this way, we detect a number of additional interaction interfaces that are significantly affected by cancer mutations.	('mutations', 'Var', (111, 120))	('affected', 'Reg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('interaction', 'Interaction', (46, 57))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
79150	29572294	Eventually, a larger catalog of cancer-associated mutations further characterized in vitro and in model organisms would be invaluable for understanding different routes of disease emergence and for identifying therapeutic opportunities.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
79153	29572294	In this study, we used the package on the Pan-cancer data, but with more permissive thresholds, it can also be used for finding hotspot mutations relevant for individual tumor types.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
79162	29572294	Jointly, the analyzed TCGA and ICGC mutation datasets covered 40 different tumor types which spanned 23 tissues of origin.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TCGA', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ICGC', 'Gene', (31, 35))	('tumor', 'Disease', (75, 80))	('mutation', 'Var', (36, 44))
79164	29572294	A major source of false positives in the set of the identified hotspot mutations is due to common variants that, incorrectly, were not detected in the paired healthy tissue from the same patient.	('false', 'biological_process', 'GO:0071877', ('18', '23'))	('mutations', 'Var', (71, 80))	('false', 'biological_process', 'GO:0071878', ('18', '23'))	('patient', 'Species', '9606', (187, 194))	('variants', 'Var', (98, 106))
79167	29572294	Based on this catalogue, we classified the genes with the identified hotspot mutations as known or candidate cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
79168	29572294	Next, through the Ensembl BioMart service (Kinsella et al, 2011), we retrieved predictions for all human genes that are homologous to those with hotspot mutations, and assessed which of these were in the cancer Gene Census or had a hotspot mutation themselves.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutations', 'Var', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (99, 104))
79169	29572294	We composed two other sets of genes to which we compared those with hotspot mutations: (i) all other genes in the Cancer Gene Census, that is, excluding those with hotspots and paralogs of genes with hotspot mutations (based on the Ensembl homology assignments) and (ii) all other protein coding genes in the UniProtKB reference set of human proteins (release 2016_06, July 2016), that is, excluding all Cancer Gene Census genes or genes with hotspot mutations.	('Cancer', 'Phenotype', 'HP:0002664', (404, 410))	('mutations', 'Var', (76, 85))	('Cancer', 'Disease', (404, 410))	('Cancer', 'Disease', 'MESH:D009369', (404, 410))	('mutations', 'Var', (208, 217))	('protein', 'cellular_component', 'GO:0003675', ('281', '288'))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (336, 341))
79174	29572294	For all proteins with hotspot mutations, for which X-ray structural data were available, we obtained a representative PDB structure.	('mutations', 'Var', (30, 39))	('PDB', 'Gene', (118, 121))	('PDB', 'Gene', '5131', (118, 121))
79181	29572294	Genes with a high number of the reported deleterious changes (at least 25) and large contribution of these changes to the overall mutation load (the ratio of deleterious over synonymous changes was higher than 0.7) were considered as tumor suppressor candidates.	('changes', 'Var', (53, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('234', '250'))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor suppressor', 'biological_process', 'GO:0051726', ('234', '250'))
79182	29572294	To address whether a mechanism of action for any of the mutations was interference with the activation of tumor suppressors through phosphorylation, we obtained positions of phosphosites in these proteins using the PhosphoSitePlus resource (Hornbeck et al, 2012).	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('phosphorylation', 'biological_process', 'GO:0016310', ('132', '147'))	('tumor', 'Disease', (106, 111))
79183	29572294	To compare a fraction of domains that mediate protein interactions among the previously composed sets of genes (genes with hotspot mutations, other genes in the Cancer Gene Census and background human proteins), we obtained domain annotations from the iPfam 1.0 (June 2013) and used chi-squared test in R. Further, we used a Functional Annotation service from the ConsensusPathDB-human database compendium (Kamburov et al, 2013).	('human', 'Species', '9606', (195, 200))	('mutations', 'Var', (131, 140))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Disease', (161, 167))	('Cancer', 'Disease', 'MESH:D009369', (161, 167))	('human', 'Species', '9606', (380, 385))
79190	29572294	For each of the identified hotspot mutations, we looked at the individual tumor types and calculated a fraction of patients which had this residue mutated.	('patients', 'Species', '9606', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (35, 44))
79191	29572294	We next drew a heatmap plot where the clustering of tissue types was defined with the pvclust results and where, for the clarity, we reduced the number of the visualized hotspots by including only those mutated in one-third or more of the patients in at least one tumor type.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('mutated', 'Var', (203, 210))	('tumor', 'Disease', (264, 269))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
79198	29572294	For the required mutation data, we provided the amino acid changes reported in the above-described TCGA and ICGC datasets, and we specified intrinsically disordered protein regions by using the IUPred tool (Dosztanyi et al, 2005; version 1.0) with the settings for short disorder and a residue disorder prediction threshold of 0.5.	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('short disorder', 'Disease', 'MESH:C537327', (265, 279))	('disordered protein', 'Disease', 'MESH:D001796', (154, 172))	('mutation', 'Var', (17, 25))	('short disorder', 'Disease', (265, 279))	('disordered protein', 'Disease', (154, 172))
79201	29572294	Using as thresholds CNV values > 1 and mRNA z-scores > 2, we looked at the percentages of patients in each tumor type that had the "hotspot genes" amplified and/or overexpressed.	('amplified', 'Var', (147, 156))	('overexpressed', 'PosReg', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (90, 98))
79224	32799825	In the tumor microenvironment, S1P exhibits multiple functions: (a) it increases the survival of macrophages; (b) it serves as the "come-and-get-me" signal of dead cells, attracting and enhancing macrophage migration by combining with S1PR1; (c) it stimulates the polarization of TAM/M2 macrophages by activating S1PR1/2/4.	('polarization', 'CPA', (264, 276))	('S1PR1/2/4', 'Gene', (313, 322))	('S1P', 'Chemical', 'MESH:C060506', (313, 316))	('activating', 'PosReg', (302, 312))	('survival of macrophages', 'CPA', (85, 108))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('stimulates', 'PosReg', (249, 259))	('S1PR1', 'Gene', '1901', (235, 240))	('S1PR1', 'Gene', (235, 240))	('S1PR1', 'Gene', '1901', (313, 318))	('S1P', 'Chemical', 'MESH:C060506', (31, 34))	('S1PR1/2/4', 'Gene', '1901;9294;8698', (313, 322))	('S1PR1', 'Gene', (313, 318))	('macrophage migration', 'biological_process', 'GO:1905517', ('194', '214'))	('combining', 'Interaction', (220, 229))	('increases', 'PosReg', (71, 80))	('enhancing', 'PosReg', (186, 195))	('macrophage migration', 'CPA', (196, 216))	('S1P', 'Var', (31, 34))	('tumor', 'Disease', (7, 12))	('S1P', 'Chemical', 'MESH:C060506', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
79263	32799825	Two probes (204642_at and 239401_at) matching S1PR1 were detected.	('S1PR1', 'Gene', '1901', (46, 51))	('S1PR1', 'Gene', (46, 51))	('204642_at', 'Var', (12, 21))	('239401_at', 'Var', (26, 35))
79264	32799825	Notably, in three breast cancer cohorts (GSE1456-GPL96, GSE7378, and GSE12276), low S1PR1 expression was significantly associated with a poorer prognosis breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('low', 'NegReg', (80, 83))	('S1PR1', 'Gene', '1901', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('GSE12276', 'Var', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancer', 'Disease', (18, 31))	('S1PR1', 'Gene', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('expression', 'MPA', (90, 100))	('GSE1456-GPL96', 'Var', (41, 54))
79268	32799825	In addition, low S1PR1 expression was also related to poor prognosis in two cohorts of patients with lung cancer (GSE31210 and GSE8894), as determined using two probes (204642_at and 239401_at) (Fig.	('S1PR1', 'Gene', (17, 22))	('low', 'NegReg', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('poor', 'NegReg', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('204642_at', 'Var', (169, 178))	('239401_at', 'Var', (183, 192))	('S1PR1', 'Gene', '1901', (17, 22))	('patients', 'Species', '9606', (87, 95))	('lung cancer', 'Disease', (101, 112))	('expression', 'MPA', (23, 33))
79269	32799825	Kaplan-Meier plotter database also showed that low expression of S1PR1 was an independent risk factor for poor prognosis of lung cancer (overall survival, HR = 0.7, P = 6.9e-08; recurrence-free survival, HR = 0.71, P = 0.00035), but not related to post-progression survival in lung cancer (HR = 0.82, P = 0.14) (Fig.	('low expression', 'Var', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('lung cancer', 'Disease', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('S1PR1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('lung cancer', 'Disease', (124, 135))	('S1PR1', 'Gene', '1901', (65, 70))
79281	32799825	Taken together, high expression of S1PR1 could be considered a good prognostic indictor for breast and lung cancers depending on the clinical characteristics.	('S1PR1', 'Gene', '1901', (35, 40))	('high', 'Var', (16, 20))	('S1PR1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancers', 'Phenotype', 'HP:0100526', (103, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast and lung cancers', 'Disease', 'MESH:D001943', (92, 115))
79295	32799825	cBioPortal database was used to determine the types and frequencies of S1PR1 alterations in BRCA, LUAD, and LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('S1PR1', 'Gene', '1901', (71, 76))	('BRCA', 'Phenotype', 'HP:0003002', (92, 96))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (92, 96))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('BRCA', 'Gene', (92, 96))	('S1PR1', 'Gene', (71, 76))
79297	32799825	S1PR1 was altered in 6% of patients with LUAD and 2.3% of patients with LUSC, including mRNA missense mutations, truncating mutations, amplifications, and deletions (Fig.	('LUAD', 'Disease', (41, 45))	('altered', 'Reg', (10, 17))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('S1PR1', 'Gene', '1901', (0, 5))	('patients', 'Species', '9606', (27, 35))	('amplifications', 'Var', (135, 149))	('missense mutations', 'Var', (93, 111))	('deletions', 'Var', (155, 164))	('truncating', 'MPA', (113, 123))	('patients', 'Species', '9606', (58, 66))	('S1PR1', 'Gene', (0, 5))
79299	32799825	These results suggest that mutations in S1PR1 are associated with prognosis in LUAD.	('mutations', 'Var', (27, 36))	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('S1PR1', 'Gene', '1901', (40, 45))	('S1PR1', 'Gene', (40, 45))	('associated', 'Reg', (50, 60))
79321	32799825	This further confirms that S1PR1 is significantly related to immune infiltrating cells in lung and breast cancer, suggesting that high levels of S1PR1 could induce immune activity in the lung and breast cancer microenvironment.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('S1PR1', 'Gene', '1901', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (99, 112))	('S1PR1', 'Gene', (27, 32))	('S1PR1', 'Gene', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('induce', 'PosReg', (157, 163))	('breast cancer', 'Disease', (196, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('high levels', 'Var', (130, 141))	('immune activity', 'CPA', (164, 179))	('S1PR1', 'Gene', '1901', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
79325	32799825	Prognostic data from Kaplan-Meier plotter showed that low levels of S1PR1 are significantly related to poor prognosis in breast cancer and lung cancer.	('S1PR1', 'Gene', (68, 73))	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('S1PR1', 'Gene', '1901', (68, 73))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('low levels', 'Var', (54, 64))
79335	32799825	These studies support our findings that high expression of S1PR1 is beneficial for tumor survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high expression', 'Var', (40, 55))	('S1PR1', 'Gene', (59, 64))	('tumor', 'Disease', (83, 88))	('S1PR1', 'Gene', '1901', (59, 64))	('beneficial', 'PosReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
79344	32799825	As shown in recently reports, endothelial loss of S1PR1 led to a reduction in CD45+ cells, macrophages, and DCs, which influences tumor growth and metastasis.	('influences', 'Reg', (119, 129))	('loss', 'Var', (42, 46))	('CD45', 'Gene', '5788', (78, 82))	('DCs', 'MPA', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('S1PR1', 'Gene', '1901', (50, 55))	('CD45', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('S1PR1', 'Gene', (50, 55))	('tumor', 'Disease', (130, 135))	('reduction', 'NegReg', (65, 74))	('metastasis', 'CPA', (147, 157))
79345	32799825	In addition, S1P is involved in enhancing endocytosis and migration of mature dendritic cells through S1PR3, an event that may increase the immune response to cancer cells.	('cancer', 'Disease', (159, 165))	('enhancing', 'PosReg', (32, 41))	('endocytosis', 'MPA', (42, 53))	('S1PR3', 'Gene', '1903', (102, 107))	('S1PR3', 'Gene', (102, 107))	('immune response', 'biological_process', 'GO:0006955', ('140', '155'))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('increase', 'PosReg', (127, 135))	('S1P', 'Chemical', 'MESH:C060506', (13, 16))	('S1P', 'Chemical', 'MESH:C060506', (102, 105))	('S1P', 'Var', (13, 16))	('endocytosis', 'biological_process', 'GO:0006897', ('42', '53'))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('migration', 'CPA', (58, 67))
79354	32799825	This shows that S1PR1 defects promote the occurrence of VM, and the knockout of S1PR1 in breast cancer cells increases the number of VMs.	('S1PR1', 'Gene', '1901', (80, 85))	('promote', 'PosReg', (30, 37))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('S1PR1', 'Gene', '1901', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('knockout', 'Var', (68, 76))	('defects', 'Var', (22, 29))	('S1PR1', 'Gene', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('S1PR1', 'Gene', (16, 21))	('increases', 'PosReg', (109, 118))	('VMs', 'Disease', (133, 136))
79355	32799825	More importantly, tumor cells with low S1PR1 expression receive nutrition through VM, and accelerate tumor growth in animal models.	('tumor', 'Disease', (18, 23))	('S1PR1', 'Gene', '1901', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('accelerate', 'PosReg', (90, 100))	('S1PR1', 'Gene', (39, 44))	('low', 'Var', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
79372	33724703	The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas.	('KIT', 'Gene', (69, 72))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('mucosal melanoma', 'Disease', (31, 47))	('cutaneous melanomas', 'Disease', (127, 146))	('NF1', 'Gene', (84, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (127, 145))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('mucosal melanoma', 'Disease', 'MESH:D008545', (31, 47))	('NF1', 'Gene', '4763', (84, 87))	('SF3B1', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (127, 146))	('KIT', 'Gene', '3815', (69, 72))	('SF3B1', 'Gene', '23451', (56, 61))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (127, 146))	('mutations', 'Var', (18, 27))
79388	33724703	Previous characterizations of melanoma subtypes have demonstrated lower mutational burden in acral/mucosal melanoma with a mean of 2.64 mutations per megabase compared with a mean of 101 observed in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (199, 217))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (199, 217))	('lower', 'NegReg', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('mutations', 'Var', (136, 145))	('mucosal melanoma', 'Disease', (99, 115))	('mutational burden', 'MPA', (72, 89))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Disease', (30, 38))	('melanoma', 'Disease', (209, 217))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('cutaneous melanoma', 'Disease', (199, 217))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))
79391	33724703	Previous genetic analyses have uncovered increases in KIT mutations in mucosal melanoma.	('mutations', 'Var', (58, 67))	('mucosal melanoma', 'Disease', 'MESH:D008545', (71, 87))	('KIT', 'Gene', '3815', (54, 57))	('increases', 'PosReg', (41, 50))	('KIT', 'Gene', (54, 57))	('mucosal melanoma', 'Disease', (71, 87))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('KIT', 'molecular_function', 'GO:0005020', ('54', '57'))
79392	33724703	These studies have also demonstrated the presence of NF1, SF3B1, and NRAS mutations in mucosal melanoma.	('NRAS', 'Gene', '4893', (69, 73))	('presence', 'Reg', (41, 49))	('NF1', 'Gene', (53, 56))	('mucosal melanoma', 'Disease', (87, 103))	('SF3B1', 'Gene', (58, 63))	('mutations', 'Var', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('NF1', 'Gene', '4763', (53, 56))	('SF3B1', 'Gene', '23451', (58, 63))	('mucosal melanoma', 'Disease', 'MESH:D008545', (87, 103))	('NRAS', 'Gene', (69, 73))
79397	33724703	21 ,  22 ,  23 ,  24  OncoPanel is a cancer genomic assay to detect somatic mutations, copy number variations, and structural variants in tumor DNA extracted from fresh, frozen, or formalin-fixed paraffin-embedded samples.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (138, 143))	('cancer', 'Disease', (37, 43))	('structural variants', 'Var', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('formalin', 'Chemical', 'MESH:D005557', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('DNA', 'cellular_component', 'GO:0005574', ('144', '147'))	('copy number variations', 'Var', (87, 109))	('paraffin', 'Chemical', 'MESH:D010232', (196, 204))
79400	33724703	The OncoPanel assay provides reports on single-nucleotide variants, copy number variants, structural variants, tumor mutation burden (TMB), and select mutational signatures (e.g., UV exposure, smoking).	('TMB', 'Chemical', '-', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('single-nucleotide variants', 'Var', (40, 66))	('tumor', 'Disease', (111, 116))	('variants', 'Var', (80, 88))	('copy number variants', 'Var', (68, 88))
79442	33724703	Three patients with KIT mutations received imatinib as a later line of therapy without documented responses to therapy (2 patients progressed and one patient had to stop due to toxicity from the therapy).	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('toxicity', 'Disease', (177, 185))	('patient', 'Species', '9606', (150, 157))	('patient', 'Species', '9606', (122, 129))	('patient', 'Species', '9606', (6, 13))	('imatinib', 'Chemical', 'MESH:D000068877', (43, 51))	('patients', 'Species', '9606', (122, 130))	('KIT', 'Gene', '3815', (20, 23))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (24, 33))	('KIT', 'Gene', (20, 23))	('toxicity', 'Disease', 'MESH:D064420', (177, 185))
79443	33724703	The most frequent mutations seen in mucosal melanomas were in SF3B1 (27%), KIT (18%), and NF1 (17%).	('mucosal melanomas', 'Disease', (36, 53))	('mutations', 'Var', (18, 27))	('NF1', 'Gene', '4763', (90, 93))	('KIT', 'Gene', '3815', (75, 78))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('KIT', 'molecular_function', 'GO:0005020', ('75', '78'))	('KIT', 'Gene', (75, 78))	('mucosal melanomas', 'Disease', 'MESH:D008545', (36, 53))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('SF3B1', 'Gene', (62, 67))	('SF3B1', 'Gene', '23451', (62, 67))	('NF1', 'Gene', (90, 93))
79444	33724703	Three genes were enriched for mutations among mucosal melanomas in contrast to cutaneous melanomas: SF3B1 (27% vs. 2%), KIT (18% vs. 3%), and ATRX (9% vs. 1%).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (79, 98))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (79, 98))	('KIT', 'molecular_function', 'GO:0005020', ('120', '123'))	('cutaneous melanomas', 'Disease', (79, 98))	('ATRX', 'Gene', '546', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('SF3B1', 'Gene', (100, 105))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('KIT', 'Gene', '3815', (120, 123))	('mutations', 'Var', (30, 39))	('ATRX', 'Gene', (142, 146))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('mucosal melanomas', 'Disease', (46, 63))	('SF3B1', 'Gene', '23451', (100, 105))	('KIT', 'Gene', (120, 123))	('mucosal melanomas', 'Disease', 'MESH:D008545', (46, 63))
79445	33724703	These mutations have been observed previously in mucosal melanoma, particularly KIT and SF3B1 mutations.	('KIT', 'Gene', '3815', (80, 83))	('SF3B1', 'Gene', '23451', (88, 93))	('mutations', 'Var', (94, 103))	('KIT', 'molecular_function', 'GO:0005020', ('80', '83'))	('KIT', 'Gene', (80, 83))	('mucosal melanoma', 'Disease', (49, 65))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('mucosal melanoma', 'Disease', 'MESH:D008545', (49, 65))	('observed', 'Reg', (26, 34))	('SF3B1', 'Gene', (88, 93))
79447	33724703	A broad array of KIT mutations and amplifications were observed, similar to what has been seen in the past in melanoma 27  Mutations observed included activating mutations in the tyrosine kinase domain (D816 V) on exon 8and mutations in exon 11 and 13 (W557R, L576P, K642E).	('K642E', 'Var', (267, 272))	('L576P', 'Var', (260, 265))	('D816 V', 'Mutation', 'rs121913507', (203, 209))	('melanoma', 'Disease', (110, 118))	('K642E', 'Mutation', 'rs121913512', (267, 272))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('W557R', 'Var', (253, 258))	('KIT', 'Gene', '3815', (17, 20))	('KIT', 'molecular_function', 'GO:0005020', ('17', '20'))	('KIT', 'Gene', (17, 20))	('L576P', 'Mutation', 'rs121913513', (260, 265))	('W557R', 'Mutation', 'rs121913235', (253, 258))	('D816 V', 'Gene', (203, 209))
79449	33724703	A higher percentage of SF3B1 mutations was observed in patients with melanoma of anal/rectal origin when compared with patients with vulvovaginal or nasopharynx melanoma.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('mutations', 'Var', (29, 38))	('patients', 'Species', '9606', (119, 127))	('SF3B1', 'Gene', '23451', (23, 28))	('patients', 'Species', '9606', (55, 63))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))	('SF3B1', 'Gene', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
79450	33724703	Patients with vulvovaginal melanoma had higher percentages of TP53 mutations, which frequently correlated with ATRX mutations.	('ATRX', 'Gene', '546', (111, 115))	('TP53', 'Gene', '7157', (62, 66))	('vulvovaginal melanoma', 'Disease', (14, 35))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('Patients', 'Species', '9606', (0, 8))	('ATRX', 'Gene', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (14, 35))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (14, 35))
79451	33724703	In addition, a higher percentage of MYC mutations was observed in patients with sinus/nasopharynx melanoma when compared with patients with vulvovaginal melanomas (Figure 3B-D).	('MYC', 'Gene', '4609', (36, 39))	('melanomas', 'Phenotype', 'HP:0002861', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('vulvovaginal melanomas', 'Disease', (140, 162))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('mutations', 'Var', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('vulvovaginal melanomas', 'Disease', 'MESH:D014848', (140, 162))	('melanoma', 'Disease', (98, 106))	('MYC', 'Gene', (36, 39))	('patients', 'Species', '9606', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('vulvovaginal melanomas', 'Phenotype', 'HP:0030418', (140, 162))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (140, 161))	('patients', 'Species', '9606', (66, 74))
79452	33724703	The average mutational burden/megabase for mucosal melanomas was 6.23 (95% CI: 3.63-10.89) and did not correlate with response (Figure 4A).	('mucosal melanomas', 'Disease', (43, 60))	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('mucosal melanomas', 'Disease', 'MESH:D008545', (43, 60))	('mutational', 'Var', (12, 22))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
79453	33724703	Patients whose mucosal melanomas harbored a KIT mutation had one of the strongest associations with a favorable DCB, although it did not meet our threshold for statistical significance (71% vs. 28%, adjusted p-value 0.16).	('KIT', 'molecular_function', 'GO:0005020', ('44', '47'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (15, 32))	('KIT', 'Gene', '3815', (44, 47))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('DCB', 'Disease', (112, 115))	('KIT', 'Gene', (44, 47))	('mutation', 'Var', (48, 56))	('associations', 'Interaction', (82, 94))	('mucosal melanomas', 'Disease', (15, 32))	('DCB', 'Chemical', '-', (112, 115))
79454	33724703	ATM variants also had an association with a favorable DCB that similarly did not meet statistical significance.	('favorable DCB', 'Disease', (44, 57))	('variants', 'Var', (4, 12))	('association', 'Interaction', (25, 36))	('ATM', 'Gene', (0, 3))	('DCB', 'Chemical', '-', (54, 57))	('ATM', 'Gene', '472', (0, 3))
79455	33724703	(Figure 4B) In regards to the two complete responses observed, one patient had none of the main mutations observed and the second had an SF3B1 mutation.	('SF3B1', 'Gene', (137, 142))	('patient', 'Species', '9606', (67, 74))	('mutation', 'Var', (143, 151))	('SF3B1', 'Gene', '23451', (137, 142))
79461	33724703	These mutations are activating mutations that lead to increased c-kit signaling, thereby causing tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('c-kit', 'Gene', '3815', (64, 69))	('c-kit', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('increased', 'PosReg', (54, 63))	('tumor', 'Disease', (97, 102))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('causing', 'Reg', (89, 96))	('mutations', 'Var', (6, 15))
79465	33724703	Our study supports this approach by suggesting that patients with KIT mutations might be more likely to benefit from immunotherapy, although this did not reach statistical significance.	('KIT', 'Gene', (66, 69))	('mutations', 'Var', (70, 79))	('benefit', 'PosReg', (104, 111))	('immunotherapy', 'CPA', (117, 130))	('KIT', 'molecular_function', 'GO:0005020', ('66', '69'))	('KIT', 'Gene', '3815', (66, 69))	('patients', 'Species', '9606', (52, 60))
79467	33724703	ATM variants also trended toward a benefit to immunotherapy within our cohort.	('benefit', 'PosReg', (35, 42))	('variants', 'Var', (4, 12))	('ATM', 'Gene', (0, 3))	('immunotherapy', 'CPA', (46, 59))	('ATM', 'Gene', '472', (0, 3))
79469	33724703	While not associated with response to ICB, several mutations are associated with different primary sites of mucosal melanoma.	('mutations', 'Var', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('mucosal melanoma', 'Disease', (108, 124))	('associated', 'Reg', (65, 75))	('mucosal melanoma', 'Disease', 'MESH:D008545', (108, 124))
79470	33724703	Splicing Factor 3b subunit 1 (SF3B1) encodes for one component of a complex involved in splicing mRNA, and mutation of SF3B1 has been observed to lead to alternate splicing.	('SF3B1', 'Gene', (30, 35))	('SF3B1', 'Gene', (119, 124))	('Splicing', 'biological_process', 'GO:0045292', ('0', '8'))	('SF3B1', 'Gene', '23451', (30, 35))	('Splicing Factor 3b subunit 1', 'Gene', '23451', (0, 28))	('alternate splicing', 'MPA', (154, 172))	('SF3B1', 'Gene', '23451', (119, 124))	('splicing', 'biological_process', 'GO:0045292', ('164', '172'))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('Splicing Factor 3b subunit 1', 'Gene', (0, 28))	('lead to', 'Reg', (146, 153))	('mutation', 'Var', (107, 115))
79471	33724703	35  The differences in splicing when SF3B1 is mutated may lead to varying gene expression and may vary based upon the tissue of origin since splices occur after transcription.	('splicing', 'MPA', (23, 31))	('SF3B1', 'Gene', '23451', (37, 42))	('transcription', 'biological_process', 'GO:0006351', ('161', '174'))	('gene expression', 'MPA', (74, 89))	('mutated', 'Var', (46, 53))	('lead to', 'Reg', (58, 65))	('splicing', 'biological_process', 'GO:0045292', ('23', '31'))	('SF3B1', 'Gene', (37, 42))	('gene expression', 'biological_process', 'GO:0010467', ('74', '89'))
79472	33724703	36 ,  37  Another cancer with high rates of SF3B1 mutations is uveal melanoma, which is relatively unresponsive to ICB.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('SF3B1', 'Gene', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (63, 77))	('mutations', 'Var', (50, 59))	('SF3B1', 'Gene', '23451', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('melanoma', 'Disease', (69, 77))
79473	33724703	38 ,  39  In uveal melanoma, SF3B1 mutations are associated with low-grade disease and a favorable prognosis, whereas their role in mucosal melanoma is not clear to date.	('SF3B1', 'Gene', '23451', (29, 34))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('associated', 'Reg', (49, 59))	('mucosal melanoma', 'Disease', (132, 148))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('low-grade disease', 'Disease', (65, 82))	('mucosal melanoma', 'Disease', 'MESH:D008545', (132, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('SF3B1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
79474	33724703	In this cohort patients with vulvovaginal melanoma had higher percentages of TP53 mutations, which frequently correlated with ATRX mutations.	('patients', 'Species', '9606', (15, 23))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (29, 50))	('ATRX', 'Gene', (126, 130))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (29, 50))	('mutations', 'Var', (82, 91))	('vulvovaginal melanoma', 'Disease', (29, 50))	('ATRX', 'Gene', '546', (126, 130))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
79475	33724703	Mutations in the ATRX gene, which is involved in chromatin remodeling, have been observed in mucosal melanomas previously.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('ATRX', 'Gene', (17, 21))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('ATRX', 'Gene', '546', (17, 21))	('observed', 'Reg', (81, 89))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('49', '69'))	('Mutations', 'Var', (0, 9))	('mucosal melanomas', 'Disease', (93, 110))	('chromatin', 'cellular_component', 'GO:0000785', ('49', '58'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (93, 110))
79476	33724703	13  Prior studies also found that mutations in ATRX frequently co-occur with TP53 mutations and are mutually exclusive to SF3B1 mutations.	('ATRX', 'Gene', (47, 51))	('SF3B1', 'Gene', (122, 127))	('ATRX', 'Gene', '546', (47, 51))	('SF3B1', 'Gene', '23451', (122, 127))	('co-occur', 'Reg', (63, 71))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('mutations', 'Var', (34, 43))
79477	33724703	As newer agents targeting splicing and chromatin remodeling are developed, the clinical patterns of mutations in mucosal melanoma may help guide trial selection.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('mutations', 'Var', (100, 109))	('mucosal melanoma', 'Disease', 'MESH:D008545', (113, 129))	('chromatin', 'cellular_component', 'GO:0000785', ('39', '48'))	('splicing', 'biological_process', 'GO:0045292', ('26', '34'))	('mucosal melanoma', 'Disease', (113, 129))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('39', '59'))
79493	31304984	TMX knockdown altered mitochondrial organization, enhanced bioenergetics, and elevated mitochondrial- and NOX4-derived ROS.	('mito', 'Species', '262676', (87, 91))	('NOX4', 'Gene', (106, 110))	('altered', 'Reg', (14, 21))	('mitochondrial organization', 'MPA', (22, 48))	('TMX', 'Gene', '81542', (0, 3))	('elevated', 'PosReg', (78, 86))	('NOX4', 'Gene', '50507', (106, 110))	('bioenergetics', 'MPA', (59, 72))	('mito', 'Species', '262676', (22, 26))	('enhanced', 'PosReg', (50, 58))	('knockdown', 'Var', (4, 13))	('TMX', 'Gene', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))
79547	31304984	To this end, WM3734 carries the BRAF V600E mutation while the Mel Juso line is BRAF wild type (WT).	('BRAF', 'Gene', '673', (32, 36))	('BRAF', 'Gene', (32, 36))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('V600E', 'Var', (37, 42))	('BRAF', 'Gene', '673', (79, 83))	('WM3734', 'CellLine', 'CVCL:6800', (13, 19))	('BRAF', 'Gene', (79, 83))
79548	31304984	Later in the study, we expand the cell line panel to include 1205Lu, due to their highly aggressive behavior in animal xenografts, and WM1366, due to their NFAT1-negative status (see Appendix Table S1 for additional information on the melanoma cell lines used in this study).	('WM1366', 'CellLine', 'CVCL:6789', (135, 141))	('aggressive behavior', 'biological_process', 'GO:0002118', ('89', '108'))	('melanoma cell lines', 'Disease', 'MESH:D008545', (235, 254))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('1205Lu', 'Var', (61, 67))	('aggressive behavior', 'Phenotype', 'HP:0000718', (89, 108))	('WM1366', 'Var', (135, 141))	('melanoma cell lines', 'Disease', (235, 254))
79552	31304984	Similar observations apply to Mel Juso (Fig 2F-H), WM1366 (Fig EV2J and K), WM983B (Fig EV2L and M), and WM164 (Fig EV2N and O), examined for their different genetic backgrounds (Appendix Table S1).	('EV2', 'Gene', (88, 91))	('WM1366', 'CellLine', 'CVCL:6789', (51, 57))	('EV2', 'Gene', '147138', (116, 119))	('EV2', 'Gene', (116, 119))	('EV2', 'Gene', '147138', (63, 66))	('EV2', 'Gene', (63, 66))	('WM983B', 'Var', (76, 82))	('EV2', 'Gene', '147138', (88, 91))
79556	31304984	The data shown in Figs 3A-E and EV3A-C display no overt effects of TMX silencing on SOCE in melanoma cells.	('melanoma cell', 'Disease', 'MESH:D008545', (92, 105))	('EV3', 'Chemical', '-', (32, 35))	('TMX', 'Gene', (67, 70))	('SOCE', 'biological_process', 'GO:0002115', ('84', '88'))	('silencing', 'Var', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma cell', 'Disease', (92, 105))	('TMX', 'Gene', '81542', (67, 70))
79557	31304984	These results suggested that alterations in TMX expression control NFAT1 translocation through an alternative molecular mechanism.	('NFAT1', 'Gene', (67, 72))	('alterations', 'Var', (29, 40))	('translocation', 'MPA', (73, 86))	('TMX', 'Gene', (44, 47))	('TMX', 'Gene', '81542', (44, 47))
79561	31304984	Our data show a significant increase in cellular H2O2 levels in the TMX1 (red)- and TMX3 (orange)-silenced WM3734 and Mel Juso melanoma cells (Fig 3F-H).	('cellular H2O2 levels', 'MPA', (40, 60))	('TMX1', 'Gene', (68, 72))	('melanoma cell', 'Disease', (127, 140))	('WM3734', 'CellLine', 'CVCL:6800', (107, 113))	('TMX3', 'Gene', (84, 88))	('melanoma cell', 'Disease', 'MESH:D008545', (127, 140))	('-silenced', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('increase', 'PosReg', (28, 36))	('H2O2', 'Chemical', 'MESH:D006861', (49, 53))
79563	31304984	Figure EV3D and E shows that cellular pH is not altered following TMX silencing.	('silencing', 'Var', (70, 79))	('TMX', 'Gene', (66, 69))	('TMX', 'Gene', '81542', (66, 69))	('EV3', 'Chemical', '-', (7, 10))
79564	31304984	In addition, TMX1 silencing caused a moderate, but significant, increase in H2O2 levels in the NFAT1-negative WM1366 cells, with no effect on the cellular pH (Fig EV3F and G).	('silencing', 'Var', (18, 27))	('WM1366', 'CellLine', 'CVCL:6789', (110, 116))	('TMX1', 'Gene', (13, 17))	('H2O2', 'Chemical', 'MESH:D006861', (76, 80))	('increase', 'PosReg', (64, 72))	('EV3F', 'Chemical', '-', (163, 167))	('H2O2 levels', 'MPA', (76, 87))
79571	31304984	We next examined the mechanism behind the inhibition of NFAT1 translocation following TMX knockdown.	('TMX', 'Gene', (86, 89))	('knockdown', 'Var', (90, 99))	('TMX', 'Gene', '81542', (86, 89))	('translocation', 'MPA', (62, 75))	('NFAT1', 'Gene', (56, 61))	('inhibition', 'NegReg', (42, 52))
79572	31304984	Accordingly, we asked if the increased oxidative environment within the cytosol caused by altered TMX expression could be responsible for NFAT1 inhibition.	('cytosol', 'cellular_component', 'GO:0005829', ('72', '79'))	('increased oxidative environment', 'Phenotype', 'HP:0025464', (29, 60))	('altered', 'Var', (90, 97))	('TMX', 'Gene', '81542', (98, 101))	('increased', 'PosReg', (29, 38))	('TMX', 'Gene', (98, 101))	('oxidative environment', 'MPA', (39, 60))
79574	31304984	Figure 4A demonstrates that H2O2 inhibits NFAT1 translocation in a concentration-dependent manner.	('inhibits', 'NegReg', (33, 41))	('NFAT1', 'Gene', (42, 47))	('H2O2', 'Chemical', 'MESH:D006861', (28, 32))	('H2O2', 'Var', (28, 32))
79585	31304984	Using an alternative commercially available calcineurin activity assay, we confirmed that TMX knockdown inhibits calcineurin in melanoma cells (Fig EV3N).	('calcineurin activity', 'molecular_function', 'GO:0033192', ('44', '64'))	('knockdown', 'Var', (94, 103))	('EV3', 'Chemical', '-', (148, 151))	('calcineurin', 'molecular_function', 'GO:0004723', ('113', '124'))	('TMX', 'Gene', (90, 93))	('inhibits', 'NegReg', (104, 112))	('calcineurin', 'MPA', (113, 124))	('melanoma cell', 'Disease', (128, 141))	('calcineurin', 'molecular_function', 'GO:0004722', ('113', '124'))	('TMX', 'Gene', '81542', (90, 93))	('melanoma cell', 'Disease', 'MESH:D008545', (128, 141))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
79598	31304984	To first explore the role of mitochondria in ROS production, we expressed HyPer in the mitochondrial matrix of WM3734 and Mel Juso melanoma cells and observed that TMX silencing led to an increase in resting mitochondrial H2O2 levels (Fig 5A-C).	('mito', 'Species', '262676', (87, 91))	('silencing', 'Var', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('TMX', 'Gene', '81542', (164, 167))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('mitochondria', 'cellular_component', 'GO:0005739', ('29', '41'))	('melanoma cell', 'Disease', (131, 144))	('mito', 'Species', '262676', (29, 33))	('led', 'Gene', '399668', (178, 181))	('resting mitochondrial H2O2 levels', 'MPA', (200, 233))	('mito', 'Species', '262676', (208, 212))	('melanoma cell', 'Disease', 'MESH:D008545', (131, 144))	('increase', 'PosReg', (188, 196))	('H2O2', 'Chemical', 'MESH:D006861', (222, 226))	('mitochondrial matrix', 'cellular_component', 'GO:0005759', ('87', '107'))	('WM3734', 'CellLine', 'CVCL:6800', (111, 117))	('led', 'Gene', (178, 181))	('TMX', 'Gene', (164, 167))
79606	31304984	Figure EV4K shows that inhibition of the mitochondrial Ca2+ uptake only partially reversed the TMX silencing-induced mitochondrial H2O2 production.	('mitochondrial Ca2+ uptake', 'MPA', (41, 66))	('mitochondrial H2O2 production', 'MPA', (117, 146))	('TMX', 'Gene', '81542', (95, 98))	('mito', 'Species', '262676', (117, 121))	('H2O2', 'Chemical', 'MESH:D006861', (131, 135))	('Ca2+', 'Chemical', 'MESH:D000069285', (55, 59))	('TMX', 'Gene', (95, 98))	('silencing-induced', 'Var', (99, 116))	('uptake', 'biological_process', 'GO:0098657', ('60', '66'))	('mito', 'Species', '262676', (41, 45))	('uptake', 'biological_process', 'GO:0098739', ('60', '66'))
79608	31304984	Figure EV4L demonstrates no overt effects of this antioxidant on the TMX1 silencing-induced mitochondrial Ca2+ elevation.	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('EV4L', 'Chemical', '-', (7, 11))	('mitochondrial Ca2+ elevation', 'MPA', (92, 120))	('silencing-induced', 'Var', (74, 91))	('TMX1', 'Gene', (69, 73))	('Ca2+ elevation', 'Phenotype', 'HP:0003072', (106, 120))	('mito', 'Species', '262676', (92, 96))
79609	31304984	Based on these findings, we next asked if TMX1 silencing might affect the mitochondrial Ca2+ signaling machinery.	('affect', 'Reg', (63, 69))	('signaling', 'biological_process', 'GO:0023052', ('93', '102'))	('mito', 'Species', '262676', (74, 78))	('TMX1', 'Gene', (42, 46))	('silencing', 'Var', (47, 56))	('Ca2+', 'Chemical', 'MESH:D000069285', (88, 92))	('mitochondrial Ca2+ signaling machinery', 'Pathway', (74, 112))
79615	31304984	Moreover, by calculating the area occupied by mitochondria within the plasma membrane periphery, we observed a significant increase in mitochondria in the vicinity of the PM in the TMX1 knockdown WM3734 cells (see Figs 5I and J, and 9A-E for details).	('knockdown', 'Var', (186, 195))	('mito', 'Species', '262676', (135, 139))	('mito', 'Species', '262676', (46, 50))	('TMX1', 'Gene', (181, 185))	('plasma membrane', 'cellular_component', 'GO:0005886', ('70', '85'))	('mitochondria', 'cellular_component', 'GO:0005739', ('135', '147'))	('increase', 'PosReg', (123, 131))	('mitochondria', 'cellular_component', 'GO:0005739', ('46', '58'))	('WM3734', 'CellLine', 'CVCL:6800', (196, 202))	('mitochondria', 'MPA', (135, 147))
79623	31304984	This increase is mitigated if NOX4 expression is silenced or if protein function is suppressed with the NOX4 inhibitor GKT137831 (Fig 5O and P); pH changes do not contribute as shown with the control sensor SypHer (Fig EV4Q).	('GKT137831', 'Chemical', 'MESH:C576694', (119, 128))	('NOX4', 'Gene', (30, 34))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('NOX4', 'Gene', (104, 108))	('GKT137831', 'Var', (119, 128))	('NOX4', 'Gene', '50507', (30, 34))	('EV4Q', 'Chemical', '-', (219, 223))	('NOX4', 'Gene', '50507', (104, 108))	('protein', 'Protein', (64, 71))	('suppressed', 'NegReg', (84, 94))
79624	31304984	Summarizing, our data suggest two sources for elevated ROS upon TMX1 knockdown: first, the mitochondria through elevated Ca2+ and altered morphology, positioning, and architecture; and second, the ER via enhanced NOX4 activity.	('mitochondria', 'MPA', (91, 103))	('elevated', 'PosReg', (46, 54))	('TMX1', 'Gene', (64, 68))	('NOX4', 'Gene', (213, 217))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('mitochondria', 'cellular_component', 'GO:0005739', ('91', '103'))	('Ca2+', 'MPA', (121, 125))	('elevated', 'PosReg', (112, 120))	('Ca2+', 'Chemical', 'MESH:D000069285', (121, 125))	('activity', 'MPA', (218, 226))	('mito', 'Species', '262676', (91, 95))	('altered', 'Reg', (130, 137))	('enhanced', 'PosReg', (204, 212))	('NOX4', 'Gene', '50507', (213, 217))	('knockdown', 'Var', (69, 78))	('ROS', 'MPA', (55, 58))
79627	31304984	Consistent with these data, long-term knockdown of TMX1 using two different shRNAs in two different melanoma cell lines showed a comparable inhibition in proliferation (Fig 6B).	('proliferation', 'CPA', (154, 167))	('TMX1', 'Gene', (51, 55))	('melanoma cell lines', 'Disease', (100, 119))	('inhibition', 'NegReg', (140, 150))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('knockdown', 'Var', (38, 47))	('melanoma cell lines', 'Disease', 'MESH:D008545', (100, 119))
79629	31304984	Figure 6C shows that NFAT1 silencing reduces the proliferation of the two melanoma cell lines tested.	('silencing', 'Var', (27, 36))	('reduces', 'NegReg', (37, 44))	('melanoma cell lines', 'Disease', 'MESH:D008545', (74, 93))	('NFAT1', 'Gene', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma cell lines', 'Disease', (74, 93))
79632	31304984	To investigate the role of ROS in the TMX silencing-induced inhibition of melanoma cell proliferation, we treated the knockdown cells with NAC and mitochondria-targeted mTEMPO.	('TMX', 'Gene', (38, 41))	('NAC', 'Gene', (139, 142))	('NAC', 'Gene', '7504', (139, 142))	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('NAC', 'cellular_component', 'GO:0005854', ('139', '142'))	('TMX', 'Gene', '81542', (38, 41))	('cell proliferation', 'biological_process', 'GO:0008283', ('83', '101'))	('melanoma cell', 'Disease', (74, 87))	('mitochondria', 'cellular_component', 'GO:0005739', ('147', '159'))	('mito', 'Species', '262676', (147, 151))	('melanoma cell', 'Disease', 'MESH:D008545', (74, 87))	('silencing-induced', 'Var', (42, 59))
79633	31304984	The results presented in Fig 6D show that antioxidants reverse the "negative" effect of TMX silencing on melanoma cell growth and thus support the central role of ROS in the TMX-mediated control of melanoma behavior.	('melanoma cell growth', 'Disease', 'MESH:D008545', (105, 125))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('TMX', 'Gene', '81542', (174, 177))	('TMX', 'Gene', '81542', (88, 91))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('silencing', 'Var', (92, 101))	('cell growth', 'biological_process', 'GO:0016049', ('112', '123'))	('melanoma cell growth', 'Disease', (105, 125))	('ROS', 'Chemical', 'MESH:D017382', (163, 166))	('TMX', 'Gene', (88, 91))	('TMX', 'Gene', (174, 177))	('melanoma behavior', 'Disease', 'MESH:D008545', (198, 215))	('melanoma behavior', 'Disease', (198, 215))
79635	31304984	Figure 6E shows that silencing of TMX1 or TMX3 reduces melanoma cell migration potential.	('reduces', 'NegReg', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma cell', 'Disease', (55, 68))	('TMX1', 'Gene', (34, 38))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('melanoma cell', 'Disease', 'MESH:D008545', (55, 68))	('TMX3', 'Gene', (42, 46))	('silencing', 'Var', (21, 30))
79636	31304984	Similar as for the proliferation data, antioxidant treatment abrogated the "negative" effects of TMX silencing on melanoma's migration potential (Fig 6F).	("melanoma's migration", 'Disease', 'MESH:D008545', (114, 134))	('TMX', 'Gene', (97, 100))	('silencing', 'Var', (101, 110))	('abrogated', 'NegReg', (61, 70))	('TMX', 'Gene', '81542', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	("melanoma's migration", 'Disease', (114, 134))
79638	31304984	To compare the role of TMX oxidoreductases in NFAT1-positive and NFAT1-negative melanoma cells, we silenced TMX1 and TMX3 in WM1366 cells and evaluated cell proliferation and migration as performed in WM3734 and Mel Juso.	('WM1366', 'CellLine', 'CVCL:6789', (125, 131))	('silenced', 'Var', (99, 107))	('TMX', 'Gene', (117, 120))	('TMX', 'Gene', '81542', (23, 26))	('melanoma cell', 'Disease', (80, 93))	('TMX', 'Gene', (108, 111))	('WM3734', 'CellLine', 'CVCL:6800', (201, 207))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma cell', 'Disease', 'MESH:D008545', (80, 93))	('TMX', 'Gene', (23, 26))	('TMX', 'Gene', '81542', (108, 111))	('TMX', 'Gene', '81542', (117, 120))	('migration', 'CPA', (175, 184))	('cell proliferation', 'biological_process', 'GO:0008283', ('152', '170'))	('cell proliferation', 'CPA', (152, 170))
79641	31304984	The inhibitory effect of TMX silencing on cell migration was less evident in the WM1366 cells (Fig EV5C), supporting the functional importance of NFAT1 in melanoma cell aggressive behavior.	('melanoma cell aggressive behavior', 'Disease', (155, 188))	('cell migration', 'CPA', (42, 56))	('aggressive behavior', 'Phenotype', 'HP:0000718', (169, 188))	('cell migration', 'biological_process', 'GO:0016477', ('42', '56'))	('melanoma cell aggressive behavior', 'Disease', 'MESH:D001523', (155, 188))	('silencing', 'Var', (29, 38))	('TMX', 'Gene', '81542', (25, 28))	('WM1366', 'CellLine', 'CVCL:6789', (81, 87))	('aggressive behavior', 'biological_process', 'GO:0002118', ('169', '188'))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('TMX', 'Gene', (25, 28))
79645	31304984	Confirmation of TMX1 knockdown in the tumor samples is shown in Fig EV5D.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('TMX1', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('knockdown', 'Var', (21, 30))
79646	31304984	In the first three weeks following s.c. injection, we observed a decrease in tumor growth in the TMX1 knockdown groups, which corresponded with the effects seen in vitro (Fig 6I and J).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('knockdown', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('decrease', 'NegReg', (65, 73))	('TMX1', 'Gene', (97, 101))	('tumor', 'Disease', (77, 82))
79648	31304984	Figure EV5E and F shows that phosphorylated AKT (Ser473) is upregulated in many tumors lacking TMX1 vs. control, but not in TMX1-silenced cells grown under standard 2D culture conditions.	('Ser', 'cellular_component', 'GO:0005790', ('49', '52'))	('upregulated', 'PosReg', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('AKT', 'Gene', '207', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('phosphorylated', 'MPA', (29, 43))	('lacking', 'NegReg', (87, 94))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('AKT', 'Gene', (44, 47))	('Ser473', 'Var', (49, 55))	('Ser473', 'Chemical', '-', (49, 55))
79650	31304984	Other long-term adaptive mechanisms upon TMX silencing could be changes in metabolism and energy handling.	('silencing', 'Var', (45, 54))	('changes', 'Reg', (64, 71))	('energy handling', 'MPA', (90, 105))	('TMX', 'Gene', '81542', (41, 44))	('metabolism', 'MPA', (75, 85))	('TMX', 'Gene', (41, 44))	('metabolism', 'biological_process', 'GO:0008152', ('75', '85'))
79658	31304984	In univariate models, again the discretized state of TMX3 (hazard ratio (HR) 3.09, 95% confidence interval (CI) 1.41-6.77, P < 0.005), but also the NFAT1 expression (HR 1.02, 95% CI 1.01-1.04, P < 0.05), showed a significant negative impact on patient survival rates (Appendix Table S2).	('discretized', 'Var', (32, 43))	('patient', 'Species', '9606', (244, 251))	('TMX3', 'Gene', (53, 57))	('patient survival rates', 'CPA', (244, 266))	('NFAT1', 'Gene', (148, 153))	('negative', 'NegReg', (225, 233))	('expression', 'MPA', (154, 164))
79665	31304984	This approach indicated that in the BRAF V600E group, more patients had high NFAT1 (n_high = 26 vs. n_low = 22) compared with the WT group (n_high = 15 vs. n_low = 34, Fisher's exact test, P = 0.024).	('NFAT1', 'Gene', (77, 82))	('BRAF', 'Gene', (36, 40))	('V600E', 'Var', (41, 46))	('patients', 'Species', '9606', (59, 67))	('BRAF', 'Gene', '673', (36, 40))	('V600E', 'Mutation', 'rs113488022', (41, 46))
79666	31304984	As shown in Fig 7B, neither TMX1 nor TMX3 showed systematic changes in their expression levels when the BRAF WT and BRAF V600E cohorts were compared.	('V600E', 'Var', (121, 126))	('changes', 'Reg', (60, 67))	('BRAF', 'Gene', '673', (116, 120))	('BRAF', 'Gene', (116, 120))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('expression levels', 'MPA', (77, 94))	('V600E', 'Mutation', 'rs113488022', (121, 126))
79668	31304984	We found that the survival probability is significantly reduced (log-rank test P = 0.0022) in the patients with high NFAT1 when compared with the patients with low NFAT1 (Fig 7C).	('reduced', 'NegReg', (56, 63))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))	('NFAT1', 'Gene', (117, 122))	('survival', 'CPA', (18, 26))	('patients', 'Species', '9606', (146, 154))
79669	31304984	We performed the same analysis in the BRAF V600E patient group and found that in this case, NFAT1 status was not as relevant (Fig 7D).	('V600E', 'Mutation', 'rs113488022', (43, 48))	('patient', 'Species', '9606', (49, 56))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (43, 48))
79670	31304984	In addition, downregulation of BRAF in the WM3734 cells did not significantly affect the TMX1 silencing-induced inhibition of NFAT1 nuclear translocation (Fig EV5O and P).	('silencing-induced', 'Var', (94, 111))	('TMX1', 'Gene', (89, 93))	('NFAT1', 'Gene', (126, 131))	('inhibition', 'NegReg', (112, 122))	('WM3734', 'CellLine', 'CVCL:6800', (43, 49))	('downregulation', 'NegReg', (13, 27))	('nuclear translocation', 'MPA', (132, 153))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
79671	31304984	Moreover, the qPCR-based correlational analysis of the BRAF status and NFAT1, TMX1, and TMX3 expression in the panel of cell lines used in this study (Fig EV5Q-S) showed a similar relationship as for the melanoma patients, i.e., increased NFAT1 in the BRAF V600E cells and unchanged TMX1 and TMX3 (compare to Fig 7B).	('NFAT1', 'Gene', (239, 244))	('TMX3', 'MPA', (292, 296))	('V600E', 'Var', (257, 262))	('melanoma', 'Disease', (204, 212))	('BRAF', 'Gene', '673', (252, 256))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('BRAF', 'Gene', (252, 256))	('increased', 'PosReg', (229, 238))	('patients', 'Species', '9606', (213, 221))	('BRAF', 'Gene', '673', (55, 59))	('V600E', 'Mutation', 'rs113488022', (257, 262))	('BRAF', 'Gene', (55, 59))	('TMX1', 'MPA', (283, 287))
79673	31304984	Nevertheless, within this signaling network, our data clearly showed that the TMX-ROS-NFAT1 signaling axis is functionally relevant in both BRAF WT and BRAF V600E melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (163, 172))	('BRAF', 'Gene', (152, 156))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('V600E', 'SUBSTITUTION', 'None', (157, 162))	('TMX', 'Gene', '81542', (78, 81))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('BRAF', 'Gene', '673', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('BRAF', 'Gene', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('melanomas', 'Disease', (163, 172))	('TMX', 'Gene', (78, 81))	('V600E', 'Var', (157, 162))	('BRAF', 'Gene', '673', (152, 156))
79675	31304984	For this purpose, we used differential gene expression datasets from two independent NFAT1 knockdown studies in melanoma cell lines (for details, see Shoshan et al, 2016; Aibar et al, 2017).	('melanoma cell lines', 'Disease', 'MESH:D008545', (112, 131))	('NFAT1', 'Gene', (85, 90))	('knockdown', 'Var', (91, 100))	('gene expression', 'biological_process', 'GO:0010467', ('39', '54'))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma cell lines', 'Disease', (112, 131))
79677	31304984	As shown in Fig 7F and Appendix Table S5, more than by chance of the genes suppressed following NFAT1 silencing are assigned to the standard terms "Mitochondrion-localized" (GO:0005739 mitochondrion) and "Redox-related" (GO:0016491 oxidoreductase activity, and GO:0016209 antioxidant activity).	('suppressed', 'NegReg', (75, 85))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('268', '288'))	('mitochondrion', 'cellular_component', 'GO:0005739', ('183', '196'))	('oxidoreductase activity', 'molecular_function', 'GO:0016491', ('228', '251'))	('Mitochondrion', 'cellular_component', 'GO:0005739', ('147', '160'))	('NFAT1', 'Gene', (96, 101))	('silencing', 'Var', (102, 111))	('mito', 'Species', '262676', (185, 189))
79691	31304984	We first investigated the link between TMX and NFAT1, with its signaling relevance; then, we examined how TMX-driven ER-mitochondria changes affect mitochondrial Ca2+ signaling and ROS production, and finally, we studied the functional relevance of TMX and NFAT1 for melanoma biology and patient outcome.	('patient', 'Species', '9606', (288, 295))	('ROS production', 'MPA', (181, 195))	('affect', 'Reg', (141, 147))	('mito', 'Species', '262676', (148, 152))	('changes', 'Var', (133, 140))	('Ca2+', 'Chemical', 'MESH:D000069285', (162, 166))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('TMX', 'Gene', '81542', (249, 252))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('TMX', 'Gene', '81542', (106, 109))	('TMX', 'Gene', (39, 42))	('mitochondria', 'cellular_component', 'GO:0005739', ('120', '132'))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('mito', 'Species', '262676', (120, 124))	('TMX', 'Gene', '81542', (39, 42))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('TMX', 'Gene', (249, 252))	('mitochondrial Ca2+ signaling', 'MPA', (148, 176))	('TMX', 'Gene', (106, 109))
79695	31304984	In melanoma, for example, it was reported that targeting NFAT signaling enhanced melanoma cell death in oncogenic BRAF V600E cells (Flockhart et al, 2009; Perotti et al, 2012).	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('cell death', 'biological_process', 'GO:0008219', ('90', '100'))	('targeting', 'Var', (47, 56))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('enhanced', 'PosReg', (72, 80))	('V600E', 'Mutation', 'rs113488022', (119, 124))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma cell death', 'Disease', (81, 100))	('melanoma', 'Disease', (3, 11))	('NFAT', 'Protein', (57, 61))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma cell death', 'Disease', 'MESH:D008545', (81, 100))
79696	31304984	Accordingly, we examined the link between the BRAF mutational status and the TMX-ROS-NFAT1 signaling axis in melanoma cell lines and patient databases.	('BRAF', 'Gene', (46, 50))	('mutational', 'Var', (51, 61))	('BRAF', 'Gene', '673', (46, 50))	('examined', 'Reg', (16, 24))	('patient', 'Species', '9606', (133, 140))	('melanoma cell lines', 'Disease', 'MESH:D008545', (109, 128))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('TMX', 'Gene', (77, 80))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('melanoma cell lines', 'Disease', (109, 128))	('TMX', 'Gene', '81542', (77, 80))
79697	31304984	Our findings suggested that TMX-NFAT1 signaling is functionally relevant not only in BRAF WT but also in BRAF V600E melanomas and can contribute to melanoma aggressive behavior, in particular in BRAF WT patients.	('contribute to', 'Reg', (134, 147))	('TMX', 'Gene', '81542', (28, 31))	('aggressive behavior', 'Phenotype', 'HP:0000718', (157, 176))	('melanoma aggressive behavior', 'Disease', (148, 176))	('V600E', 'Var', (110, 115))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('patients', 'Species', '9606', (203, 211))	('signaling', 'biological_process', 'GO:0023052', ('38', '47'))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('V600E', 'SUBSTITUTION', 'None', (110, 115))	('BRAF', 'Gene', '673', (105, 109))	('TMX', 'Gene', (28, 31))	('melanoma aggressive behavior', 'Disease', 'MESH:D001523', (148, 176))	('BRAF', 'Gene', (105, 109))	('aggressive behavior', 'biological_process', 'GO:0002118', ('157', '176'))
79698	31304984	Silencing of TMX1 or TMX3 (to interfere with ER-mitochondria contacts) inhibited NFAT1 translocation in melanoma cells, and these results are in line with previous findings by another group (Sharma et al, 2013), which prompted us to originally hypothesize that TMX1 and TMX3 might affect cytosolic Ca2+ signaling to regulate NFAT1 (Crabtree & Olson, 2002).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('mito', 'Species', '262676', (48, 52))	('Ca2+', 'Chemical', 'MESH:D000069285', (298, 302))	('melanoma cell', 'Disease', (104, 117))	('inhibited', 'NegReg', (71, 80))	('TMX1', 'Gene', (13, 17))	('NFAT1', 'Gene', (325, 330))	('cytosolic Ca2+ signaling', 'MPA', (288, 312))	('signaling', 'biological_process', 'GO:0023052', ('303', '312'))	('affect', 'Reg', (281, 287))	('mitochondria', 'cellular_component', 'GO:0005739', ('48', '60'))	('NFAT1 translocation', 'MPA', (81, 100))	('melanoma cell', 'Disease', 'MESH:D008545', (104, 117))	('Silencing', 'Var', (0, 9))
79699	31304984	However, TMX knockdown showed no overt changes in SOCE, so this mechanism could not explain NFAT1 inhibition.	('SOCE', 'biological_process', 'GO:0002115', ('50', '54'))	('TMX', 'Gene', (9, 12))	('knockdown', 'Var', (13, 22))	('TMX', 'Gene', '81542', (9, 12))	('SOCE', 'MPA', (50, 54))
79704	31304984	This is in line with our observations from silencing TMX1, which caused intracellular mitochondrial repositioning that may expose mitochondria to Ca2+ hotspots close to the plasma membrane and thus cause elevated mitochondrial Ca2+ levels and increased ROS production.	('TMX1', 'Gene', (53, 57))	('mito', 'Species', '262676', (86, 90))	('elevated', 'PosReg', (204, 212))	('Ca2+', 'Chemical', 'MESH:D000069285', (227, 231))	('mitochondria', 'cellular_component', 'GO:0005739', ('130', '142'))	('mitochondrial Ca2+ levels', 'MPA', (213, 238))	('silencing', 'Var', (43, 52))	('Ca2+', 'Chemical', 'MESH:D000069285', (146, 150))	('mito', 'Species', '262676', (213, 217))	('increased', 'PosReg', (243, 252))	('increased ROS production', 'Phenotype', 'HP:0025464', (243, 267))	('mito', 'Species', '262676', (130, 134))	('plasma membrane', 'cellular_component', 'GO:0005886', ('173', '188'))	('ROS production', 'MPA', (253, 267))	('intracellular', 'cellular_component', 'GO:0005622', ('72', '85'))	('ROS', 'Chemical', 'MESH:D017382', (253, 256))
79707	31304984	Changes in mitochondrial morphology and dynamics could, independently of Ca2+, also explain the observed elevation in mitochondrial ROS following TMX knockdown and the increased cellular oxidative stress (Willems et al, 2015).	('dynamics', 'MPA', (40, 48))	('increased', 'PosReg', (168, 177))	('mito', 'Species', '262676', (11, 15))	('elevation', 'PosReg', (105, 114))	('Ca2+', 'Chemical', 'MESH:D000069285', (73, 77))	('mitochondrial ROS', 'Protein', (118, 135))	('TMX', 'Gene', (146, 149))	('knockdown', 'Var', (150, 159))	('mito', 'Species', '262676', (118, 122))	('cellular oxidative stress', 'MPA', (178, 203))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('TMX', 'Gene', '81542', (146, 149))	('oxidative stress', 'Phenotype', 'HP:0025464', (187, 203))	('mitochondrial', 'MPA', (11, 24))
79709	31304984	ER stress was not observed, but our data showed that NOX4, which is upregulated in melanoma (Yamaura et al, 2009; Meitzler et al, 2017), is also a key player in ROS production following TMX knockdown.	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('upregulated', 'PosReg', (68, 79))	('knockdown', 'Var', (190, 199))	('ROS', 'Chemical', 'MESH:D017382', (161, 164))	('NOX4', 'Gene', '50507', (53, 57))	('TMX', 'Gene', (186, 189))	('ROS production', 'MPA', (161, 175))	('NOX4', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('TMX', 'Gene', '81542', (186, 189))
79712	31304984	Our data also revealed that TMX silencing-induced H2O2 inhibits NFAT1 translocation via the oxidation of calcineurin, a concept previously explored but not in melanoma (Wang et al, 1996; Reiter et al, 1999).	('melanoma', 'Disease', (159, 167))	('TMX', 'Gene', (28, 31))	('H2O2', 'Gene', (50, 54))	('led', 'Gene', '399668', (19, 22))	('inhibits', 'NegReg', (55, 63))	('silencing-induced', 'Var', (32, 49))	('H2O2', 'Chemical', 'MESH:D006861', (50, 54))	('calcineurin', 'molecular_function', 'GO:0004723', ('105', '116'))	('TMX', 'Gene', '81542', (28, 31))	('led', 'Gene', (19, 22))	('oxidation', 'MPA', (92, 101))	('NFAT1 translocation', 'MPA', (64, 83))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('calcineurin', 'molecular_function', 'GO:0004722', ('105', '116'))
79714	31304984	Given the broad importance of calcineurin, in particular in cancer, these findings identified one of the mechanisms linking TMX knockdown with reduced NFAT1 translocation.	('NFAT1 translocation', 'MPA', (151, 170))	('calcineurin', 'molecular_function', 'GO:0004723', ('30', '41'))	('TMX', 'Gene', (124, 127))	('knockdown', 'Var', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('TMX', 'Gene', '81542', (124, 127))	('calcineurin', 'molecular_function', 'GO:0004722', ('30', '41'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('reduced', 'NegReg', (143, 150))
79715	31304984	Thus, our results suggest that TMX knockdown drives ROS production (from mitochondria and NOX4), with inhibitory consequences on calcineurin/NFAT1 signaling.	('NOX4', 'Gene', '50507', (90, 94))	('knockdown', 'Var', (35, 44))	('mito', 'Species', '262676', (73, 77))	('TMX', 'Gene', (31, 34))	('calcineurin', 'molecular_function', 'GO:0004722', ('129', '140'))	('ROS production', 'MPA', (52, 66))	('TMX', 'Gene', '81542', (31, 34))	('NOX4', 'Gene', (90, 94))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('calcineurin', 'molecular_function', 'GO:0004723', ('129', '140'))	('mitochondria', 'cellular_component', 'GO:0005739', ('73', '85'))	('signaling', 'biological_process', 'GO:0023052', ('147', '156'))	('calcineurin/NFAT1', 'MPA', (129, 146))
79716	31304984	Based on our data, which show that the basal and the SOCE-induced calcineurin and NFAT1 activity are suppressed following TMX silencing, it is likely that the redox regulation of NFAT1 is dominant over its Ca2+-driven activation.	('regulation', 'biological_process', 'GO:0065007', ('165', '175'))	('NFAT1', 'Enzyme', (82, 87))	('Ca2+', 'Chemical', 'MESH:D000069285', (206, 210))	('TMX', 'Gene', '81542', (122, 125))	('calcineurin', 'molecular_function', 'GO:0004723', ('66', '77'))	('activity', 'MPA', (88, 96))	('SOCE', 'biological_process', 'GO:0002115', ('53', '57'))	('calcineurin', 'Enzyme', (66, 77))	('silencing', 'Var', (126, 135))	('calcineurin', 'molecular_function', 'GO:0004722', ('66', '77'))	('TMX', 'Gene', (122, 125))	('suppressed', 'NegReg', (101, 111))
79723	31304984	The importance of NFAT1 within this constellation was further supported by the less aggressive behavior of the NFAT1-negative WM1366 cells, in which TMX silencing had less dramatic effects on melanoma pathobiology when compared with the NFAT1-positive melanoma cells.	('effects', 'Reg', (181, 188))	('TMX', 'Gene', (149, 152))	('silencing', 'Var', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('WM1366', 'CellLine', 'CVCL:6789', (126, 132))	('TMX', 'Gene', '81542', (149, 152))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('melanoma cell', 'Disease', (252, 265))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('aggressive behavior', 'Phenotype', 'HP:0000718', (84, 103))	('melanoma cell', 'Disease', 'MESH:D008545', (252, 265))	('aggressive behavior', 'biological_process', 'GO:0002118', ('84', '103'))
79728	31304984	Together, our data and TCGA analyses suggest the combined TMX/NFAT1 high expression is indicative of aggressive disease and is of importance to regulate oxidative stress.	('CGA', 'Gene', (24, 27))	('aggressive disease', 'Disease', (101, 119))	('high', 'PosReg', (68, 72))	('TMX', 'Gene', '81542', (58, 61))	('combined', 'Var', (49, 57))	('CGA', 'Gene', '1113', (24, 27))	('oxidative stress', 'Phenotype', 'HP:0025464', (153, 169))	('TMX', 'Gene', (58, 61))	('aggressive disease', 'Disease', 'MESH:D001523', (101, 119))
79730	31304984	Given that antioxidants can promote melanoma metastatic spread (Le Gal et al, 2015; Piskounova et al, 2015) and that inhibition of antioxidant enzymes can lead to specific elimination of cancer cells (Stafford et al, 2018), our findings highlight the importance of better understanding redox-based processes in cancer and the possibility of using TMX-ROS-NFAT1 signaling for clinical purposes.	('elimination', 'NegReg', (172, 183))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('TMX', 'Gene', (347, 350))	('cancer', 'Disease', (187, 193))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('ROS', 'Chemical', 'MESH:D017382', (351, 354))	('promote', 'PosReg', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('inhibition', 'Var', (117, 127))	('TMX', 'Gene', '81542', (347, 350))	('signaling', 'biological_process', 'GO:0023052', ('361', '370'))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
79744	31304984	The shRNAs were transduced into WM3734, 1205Lu, and WM1366 with a lentiviral vector (pLKO.1), which was also used as control, and cells were selected with puromycin (2 mug/ml).	('mug', 'molecular_function', 'GO:0043739', ('168', '171'))	('puromycin', 'Chemical', 'MESH:D011691', (155, 164))	('1205Lu', 'Var', (40, 46))	('WM3734', 'CellLine', 'CVCL:6800', (32, 38))	('WM3734', 'Var', (32, 38))	('WM1366', 'CellLine', 'CVCL:6789', (52, 58))
79750	31304984	Mitochondrial and cytosolic Ca2+ imaging were performed using the FRET (fluorescence resonance energy transfer) sensors 4mt-D3cpV or D3cpV (excitation 420 and 505 nm; emission filters 483 +- 16 nm and 542 +- 14 nm) in Ringer's buffer containing 0.25 mM Ca2+ or 1 mM Ca2+.	('4mt-D3cpV', 'Var', (120, 129))	('D3cpV', 'Var', (133, 138))	('Ca2+', 'Chemical', 'MESH:D000069285', (28, 32))	('Ca2+', 'Chemical', 'MESH:D000069285', (266, 270))	('D3cpV', 'Chemical', '-', (124, 129))	('Ca2+', 'Chemical', 'MESH:D000069285', (253, 257))	('D3cpV', 'Chemical', '-', (133, 138))
79778	31304984	Cell monolayers from control and TMX1 knockdown HeLa and 1205Lu cells were fixed and processed as previously described (Raturi et al, 2016).	('HeLa', 'CellLine', 'CVCL:0030', (48, 52))	('knockdown', 'Var', (38, 47))	('TMX1', 'Gene', (33, 37))
79799	31304984	The full Aibar et al and Shoshan et al datasets are available at NCBI GEO under accessions GSM2027644 and GSM2027645 and GSM2644430 and GSM2644431.	('GSM2027644', 'Chemical', '-', (91, 101))	('GSM2027645', 'Chemical', '-', (106, 116))	('GSM2027645', 'Var', (106, 116))	('GSM2644431', 'Var', (136, 146))	('GSM2644430', 'Chemical', '-', (121, 131))	('GSM2027644', 'Var', (91, 101))	('GSM2644430', 'Var', (121, 131))	('GSM2644431', 'Chemical', '-', (136, 146))
79804	31304984	When relevant, the patients were partitioned into three cohorts given their BRAF genotype: wild type (BRAF WT), existence of mutation V600E (BRAF V600E), and other mutations.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('BRAF', 'Gene', (141, 145))	('patients', 'Species', '9606', (19, 27))	('BRAF', 'Gene', '673', (102, 106))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('BRAF', 'Gene', (102, 106))	('V600E', 'Var', (134, 139))	('BRAF', 'Gene', '673', (141, 145))	('V600E', 'Mutation', 'rs113488022', (146, 151))
79809	28399795	We systematically evaluated batch effects on somatic sequence variations in pan-cancer TCGA data, revealing 999 somatic variants that were batch-biased with statistical significance (P < 0.00001, Fisher's exact test, false discovery rate <= 0.0027).	('variants', 'Var', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('false', 'biological_process', 'GO:0071877', ('217', '222'))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('false', 'biological_process', 'GO:0071878', ('217', '222'))	('cancer', 'Disease', (80, 86))
79810	28399795	Furthermore, some batch-biased variants occur in known cancer genes, potentially causing misinterpretation of mutation profiles.	('variants', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('causing', 'Reg', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
79811	28399795	The Cancer Genome Atlas (TCGA) is a comprehensive database that includes multi-layered genome profiles collected from more than 30 cancer types, including genomic mutations, mRNA and miRNA, DNA copy number, DNA methylation and protein expression profiles.	('cancer', 'Disease', (131, 137))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('mutations', 'Var', (163, 172))	('DNA', 'cellular_component', 'GO:0005574', ('207', '210'))	('DNA methylation', 'biological_process', 'GO:0006306', ('207', '222'))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mRNA', 'MPA', (174, 178))	('Cancer Genome Atlas', 'Disease', (4, 23))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('DNA', 'cellular_component', 'GO:0005574', ('190', '193'))
79816	28399795	), we identified 999 batch-biased variants from pan-cancer data.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('variants', 'Var', (34, 42))	('cancer', 'Disease', (52, 58))
79829	28399795	Of the 999 batch-biased variants, 240 (24%) variants occurred recurrently across different cancer types, indicating that batch biases were not related to cancer types (Fig.	('variants', 'Var', (24, 32))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('occurred', 'Reg', (53, 61))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
79830	28399795	These recurrent batch biases were identified particularly in KIRC, LUAD, and UCEC with the plate IDs 0886 (n = 237), 0928 (n = 233) and A10C (n = 38), respectively (Fig.	('0928', 'Var', (117, 121))	('A10C', 'Mutation', 'rs766956186', (136, 140))	('A10C', 'Var', (136, 140))
79831	28399795	We also analysed the mutation frequencies at the gene level, revealing 14 genes with recurrent batch-biased mutations: SLPI, OVGP1, HEBP1, IL32, KCTD6, SSX9, DCDC2, FAM104A, IKZF4, EEF1B2, EMG1, HPGDS, MOCS2, and APIP (Fig.	('APIP', 'Gene', (213, 217))	('APIP', 'Gene', '51074', (213, 217))	('SSX9', 'Gene', '280660', (152, 156))	('FAM104A', 'Gene', (165, 172))	('EEF1B2', 'Gene', '1933', (181, 187))	('DCDC2', 'Gene', (158, 163))	('EEF1B2', 'Gene', (181, 187))	('IKZF4', 'Gene', (174, 179))	('HPGDS', 'Gene', '27306', (195, 200))	('HEBP1', 'Gene', (132, 137))	('IL32', 'Gene', (139, 143))	('EMG1', 'Gene', '10436', (189, 193))	('EMG1', 'Gene', (189, 193))	('FAM104A', 'Gene', '84923', (165, 172))	('IKZF4', 'Gene', '64375', (174, 179))	('DCDC2', 'Gene', '51473', (158, 163))	('MOCS2', 'Gene', '4338', (202, 207))	('KCTD6', 'Gene', '200845', (145, 150))	('SLPI', 'Gene', (119, 123))	('SSX9', 'Gene', (152, 156))	('mutations', 'Var', (108, 117))	('SLPI', 'Gene', '6590', (119, 123))	('OVGP1', 'Gene', '5016', (125, 130))	('KCTD6', 'Gene', (145, 150))	('MOCS2', 'Gene', (202, 207))	('OVGP1', 'Gene', (125, 130))	('IL32', 'Gene', '9235', (139, 143))	('HEBP1', 'Gene', '50865', (132, 137))	('HPGDS', 'Gene', (195, 200))
79832	28399795	Of the substitution mutations, the batch-biased variants had frequent T > A/A > T mutations (56.75%), whereas the unbiased variants had frequent C > T/G > A mutations (50.57%), revealing a large difference in mutation spectrum between the biased and the unbiased variants (Fig.	('A/A > T', 'Gene', '5265', (74, 81))	('A/A > T', 'Gene', (74, 81))	('C > T/G > A', 'Var', (145, 156))
79834	28399795	5, the batch-biased but not the unbiased T > A/A > T variants had a clear consensus sequence of the dinucleotide 'AG' with upstream long T polymers and the dinucleotide 'TT' in the following downstream sequence (Fig.	('A/A > T', 'Gene', '5265', (45, 52))	('variants', 'Var', (53, 61))	('A/A > T', 'Gene', (45, 52))
79836	28399795	The presence of batch-biased variants in cancer-driver genes could induce serious errors in data interpretation.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('errors', 'Reg', (82, 88))	('variants', 'Var', (29, 37))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
79840	28399795	Moreover, these genes had relatively high mutation rates in the pan-cancer data (KMT2D, 14.41%; ARID1A, 9.04%; NAV3, 8.52%), which might be overestimated due to the erroneous batch-biased variant calls, although this remains to be validated (Fig.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ARID1A', 'Gene', '8289', (96, 102))	('KMT2D', 'Gene', (81, 86))	('ARID1A', 'Gene', (96, 102))	('NAV3', 'Gene', (111, 115))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('KMT2D', 'Gene', '8085', (81, 86))	('mutation', 'Var', (42, 50))	('NAV3', 'Gene', '89795', (111, 115))	('cancer', 'Disease', (68, 74))
79845	28399795	Moreover, the 'G after A' problem is further enhanced by the polypyrimidine tract that precedes the acceptor AG.	('polypyrimidine', 'Chemical', '-', (61, 75))	('polypyrimidine tract', 'Var', (61, 81))	('enhanced', 'PosReg', (45, 53))	("'G after A", 'Disease', (14, 24))
79847	28399795	This result implies that batch-biased variants might occur even at cancer genes, emphasising those batch-biased variants should be considered carefully in mutation data analysis.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))	('variants', 'Var', (38, 46))
79848	28399795	BRC Biospecimen Core Resource BRCA Breast invasive carcinoma COAD Colon adenocarcinoma GCC Genome Characterization Center GSC Genome Sequencing Center KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Lower grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma MAF Mutation annotation format PRAD Prostate adenocarcinoma SKCM Skin cutaneous melanoma SMG Significantly mutated gene SNP Single-nucleotide polymorphism STAD Stomach adenocarcinoma STAD Stomach adenocarcinoma TCGA The Cancer Genome Atlas THCA Thyroid carcinoma TSS Tissue Source Sites UCEC Uterine corpus endometrial carcinoma	('endometrial carcinoma', 'Disease', (624, 645))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (35, 60))	('carcinoma', 'Disease', 'MESH:D002277', (77, 86))	('carcinoma', 'Disease', (51, 60))	('carcinoma', 'Disease', (636, 645))	('Stomach adenocarcinoma', 'Disease', (505, 527))	('melanoma', 'Phenotype', 'HP:0002861', (397, 405))	('SMG', 'Gene', '23034', (406, 409))	('carcinoma', 'Disease', 'MESH:D002277', (367, 376))	('glioma', 'Disease', (249, 255))	('adenocarcinoma', 'Disease', (513, 527))	('adenocarcinoma', 'Disease', (362, 376))	('GSC', 'Gene', (122, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (297, 316))	('carcinoma', 'Disease', (307, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinoma', 'Disease', (77, 86))	('carcinoma', 'Disease', (490, 499))	('Cancer Genome Atlas', 'Disease', (537, 556))	('Skin cutaneous melanoma', 'Disease', (382, 405))	('Colon adenocarcinoma', 'Disease', (66, 86))	('adenocarcinoma', 'Disease', (302, 316))	('Single-nucleotide polymorphism', 'Var', (441, 471))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (35, 60))	('carcinoma', 'Disease', (367, 376))	('Kidney renal papillary cell carcinoma', 'Disease', (195, 232))	('carcinoma', 'Disease', 'MESH:D002277', (490, 499))	('adenocarcinoma', 'Disease', 'MESH:D000230', (485, 499))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (195, 232))	('carcinoma', 'Disease', 'MESH:D002277', (282, 291))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (477, 499))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (624, 645))	('BRCA', 'Gene', (30, 34))	('Breast invasive carcinoma', 'Disease', (35, 60))	('Stomach adenocarcinoma', 'Disease', (477, 499))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('adenocarcinoma', 'Disease', 'MESH:D000230', (513, 527))	('COAD', 'Disease', (61, 65))	('adenocarcinoma', 'Disease', 'MESH:D000230', (362, 376))	('carcinoma', 'Disease', (282, 291))	('adenocarcinoma', 'Disease', (72, 86))	('carcinoma', 'Disease', 'MESH:D002277', (570, 579))	('Cancer', 'Phenotype', 'HP:0002664', (537, 543))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (156, 189))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (353, 376))	('adenocarcinoma', 'Disease', 'MESH:D000230', (72, 86))	('adenocarcinoma', 'Disease', 'MESH:D000230', (302, 316))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (604, 623))	('BRCA', 'Gene', '672', (30, 34))	('carcinoma', 'Disease', (223, 232))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (387, 405))	('carcinoma', 'Disease', (570, 579))	('carcinoma', 'Disease', 'MESH:D002277', (518, 527))	('carcinoma', 'Disease', 'MESH:D002277', (223, 232))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (382, 405))	('carcinoma', 'Disease', 'MESH:D002277', (180, 189))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (562, 579))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (66, 86))	('Prostate adenocarcinoma', 'Disease', (353, 376))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (267, 291))	('Liver hepatocellular carcinoma', 'Disease', (261, 291))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (261, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Disease', (518, 527))	('GSC', 'Gene', '145258', (122, 125))	('COAD', 'Disease', 'MESH:D029424', (61, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (624, 645))	('Kidney renal clear cell carcinoma', 'Disease', (156, 189))	('carcinoma', 'Disease', 'MESH:D002277', (51, 60))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (537, 556))	('carcinoma', 'Disease', 'MESH:D002277', (636, 645))	('GSC', 'cellular_component', 'GO:0032593', ('122', '125'))	('carcinoma', 'Disease', (180, 189))	('THCA', 'Phenotype', 'HP:0002890', (557, 561))	('SMG', 'Gene', (406, 409))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (505, 527))	('adenocarcinoma', 'Disease', (485, 499))	('carcinoma', 'Disease', 'MESH:D002277', (307, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
79857	33925915	Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time.	('melanomas', 'Disease', (105, 114))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('exacerbate', 'PosReg', (31, 41))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('age', 'Gene', '5973', (88, 91))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('acquire', 'PosReg', (126, 133))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('mutant', 'Var', (98, 104))	('Cutaneous melanoma', 'Disease', (0, 18))	('age', 'Gene', (88, 91))
79867	33925915	Several combinations involving immune checkpoint inhibition (ICI), targeted therapy through mutant-BRAF inhibition, intratumoral application of immunomodulators, oncolytic viruses, and anti-angiogenic approaches are being trialed to prime the anti-tumor response, enhance the sensitivity of CM cells to therapeutic interventions, and overcome therapy resistance of mutant cancer cells.	('cancer', 'Disease', (372, 378))	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('prime', 'PosReg', (233, 238))	('tumor', 'Disease', (121, 126))	('BRAF', 'Gene', (99, 103))	('enhance', 'PosReg', (264, 271))	('BRAF', 'Gene', '673', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('CM', 'Phenotype', 'HP:0012056', (291, 293))	('inhibition', 'Var', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('sensitivity', 'MPA', (276, 287))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
79889	33925915	Mono-pembrolizumab in the management of naive as well as pretreated patients resulted in sustained ORR of 30 to 40%.	('age', 'Gene', '5973', (29, 32))	('Mono-pembrolizumab', 'Chemical', '-', (0, 18))	('patients', 'Species', '9606', (68, 76))	('age', 'Gene', (29, 32))	('Mono-pembrolizumab', 'Var', (0, 18))
79923	33925915	In advanced melanoma, the most common druggable mutations are found in the MAPK/ERK pathway (Figure 1b).	('ERK', 'Gene', '5594', (80, 83))	('common', 'Reg', (31, 37))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', (12, 20))	('ERK', 'Gene', (80, 83))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('mutations', 'Var', (48, 57))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))
79925	33925915	MAPK/ERK pathway mutations enhance proliferation, survival, and spread of melanoma cells, and thus, patients carrying the mutation are eligible for treatment with BRAF and MEK inhibitors.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('MEK', 'Gene', (172, 175))	('ERK', 'Gene', '5594', (5, 8))	('proliferation', 'CPA', (35, 48))	('MEK', 'Gene', '5609', (172, 175))	('enhance', 'PosReg', (27, 34))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('ERK', 'molecular_function', 'GO:0004707', ('5', '8'))	('ERK', 'Gene', (5, 8))	('patients', 'Species', '9606', (100, 108))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('mutations', 'Var', (17, 26))	('survival', 'CPA', (50, 58))
79935	33925915	While triple therapy combinations were prone to a higher incidence of AEs, these studies were the first to indicate that BRAFi/MEKi/anti-PD1/PDL1 combinations have the potential to increase the frequency of long-lasting antitumor responses in BRAF v600-mutant melanoma patients.	('BRAF', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('MEK', 'Gene', (127, 130))	('BRAF', 'Gene', '673', (243, 247))	('MEK', 'Gene', '5609', (127, 130))	('BRAF', 'Gene', (243, 247))	('tumor', 'Disease', (224, 229))	('v600-mutant', 'Var', (248, 259))	('PDL1', 'Gene', '29126', (141, 145))	('melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('melanoma', 'Disease', (260, 268))	('melanoma', 'Disease', 'MESH:D008545', (260, 268))	('BRAF', 'Gene', '673', (121, 125))	('PDL1', 'Gene', (141, 145))	('patients', 'Species', '9606', (269, 277))	('increase', 'PosReg', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
79943	33925915	Deletion of RL1 and US12, encoding for ICP34.5 and ICP47 in T-VEC blocks the ability of the virus to hijack the replication machinery of normal cells by making it susceptible to the anti-viral cell response through protein kinase R (PKR) activation.	('US12', 'Gene', (20, 24))	('hijack', 'MPA', (101, 107))	('protein kinase R', 'Gene', (215, 231))	('ICP47', 'Var', (51, 56))	('replication', 'MPA', (112, 123))	('Deletion', 'Var', (0, 8))	('PKR', 'Gene', (233, 236))	('making', 'Reg', (153, 159))	('blocks', 'NegReg', (66, 72))	('susceptible', 'MPA', (163, 174))	('PKR', 'Gene', '5610', (233, 236))	('RL1', 'Gene', (12, 15))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('protein kinase R', 'Gene', '5610', (215, 231))	('ability', 'MPA', (77, 84))
79945	33925915	Moreover, it was found that insertion of US11 and GM-CSF improved oncolytic effect and augmented immune response leading to systemic activation of CD8+ TIL.	('augmented', 'PosReg', (87, 96))	('CD8', 'Gene', (147, 150))	('US11', 'Gene', (41, 45))	('TIL', 'Gene', '7096', (152, 155))	('CD8', 'Gene', '925', (147, 150))	('insertion', 'Var', (28, 37))	('oncolytic effect', 'CPA', (66, 82))	('immune response', 'biological_process', 'GO:0006955', ('97', '112'))	('improved', 'PosReg', (57, 65))	('systemic activation', 'MPA', (124, 143))	('TIL', 'Gene', (152, 155))	('immune response', 'CPA', (97, 112))
79950	33925915	Recently, final analysis of the OPTiM phase III trials comparing T-VEC versus GM-CSF treatment in 436 patients with unresectable stage III-IV melanoma, T-VEC was shown to improve long-term efficacy and was well tolerated with median OS for T-VEC treatment of 23.3 months and ORR of 31.5%.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('patients', 'Species', '9606', (102, 110))	('improve', 'PosReg', (171, 178))	('age', 'Gene', '5973', (131, 134))	('age', 'Gene', (131, 134))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('T-VEC', 'Var', (152, 157))	('melanoma', 'Disease', (142, 150))
79958	33925915	In a pre-clinical study, MAPK inhibition was shown to enhance T-VEC replication in murine and human melanoma cell lines.	('T-VEC replication', 'MPA', (62, 79))	('inhibition', 'Var', (30, 40))	('MAPK', 'Protein', (25, 29))	('human', 'Species', '9606', (94, 99))	('MAPK', 'molecular_function', 'GO:0004707', ('25', '29'))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('enhance', 'PosReg', (54, 61))	('melanoma', 'Disease', (100, 108))	('pre', 'molecular_function', 'GO:0003904', ('5', '8'))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('murine', 'Species', '10090', (83, 89))
79969	33925915	Moreover, it has been detected that cyclic dinucleotides may represent immune adjuvants by activating STING, in turn stimulating a pro-inflammatory immune response.	('immune response', 'biological_process', 'GO:0006955', ('148', '163'))	('pro-inflammatory immune response', 'MPA', (131, 163))	('cyclic dinucleotides', 'Var', (36, 56))	('stimulating', 'PosReg', (117, 128))	('STING', 'MPA', (102, 107))	('activating', 'PosReg', (91, 101))	('cyclic dinucleotides', 'Chemical', '-', (36, 56))
79976	33925915	Disruption of pro- and anti-angiogenic balance in tumor angiogenesis can lead to unorganized and permeable vessels lacking proper barrier function.	('angiogenesis', 'biological_process', 'GO:0001525', ('56', '68'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('lead to', 'Reg', (73, 80))	('lacking', 'NegReg', (115, 122))	('tumor', 'Disease', (50, 55))	('Disruption', 'Var', (0, 10))
79987	33925915	Moreover, recently a landmark phase III randomized clinical study in which patients with unresectable hepatocellular carcinoma were treated with a PD-L1 inhibitor (atezolizumab) and a VEGF inhibitor (bevacizumab) combination found a significantly improved overall and progression-free survival when compared to a group treated with the standard of care protein kinase inhibitor, sorafenib.	('PD-L1', 'Gene', '29126', (147, 152))	('overall', 'CPA', (256, 263))	('combination', 'Var', (213, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('atezolizumab', 'Chemical', 'MESH:C000594389', (164, 176))	('patients', 'Species', '9606', (75, 83))	('sorafenib', 'Chemical', 'MESH:D000077157', (379, 388))	('progression-free survival', 'CPA', (268, 293))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (102, 126))	('PD-L1', 'Gene', (147, 152))	('protein', 'cellular_component', 'GO:0003675', ('353', '360'))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (102, 126))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('361', '377'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (200, 211))	('improved', 'PosReg', (247, 255))	('hepatocellular carcinoma', 'Disease', (102, 126))
79992	33925915	A phase I trial in advanced melanoma patients has shown VEGF-A blockade with ipilimumab administration to be safe with increased CD8 T cell and macrophage infiltration in tumor biopsies as well as improved survival with a median of 25.1 months.	('melanoma', 'Disease', (28, 36))	('CD8', 'Gene', (129, 132))	('CD8', 'Gene', '925', (129, 132))	('patients', 'Species', '9606', (37, 45))	('survival', 'CPA', (206, 214))	('age', 'Gene', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('VEGF-A', 'Gene', '7422', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('improved', 'PosReg', (197, 205))	('VEGF-A', 'Gene', (56, 62))	('ipilimumab', 'Chemical', 'MESH:D000074324', (77, 87))	('blockade', 'Var', (63, 71))	('age', 'Gene', '5973', (151, 154))	('tumor', 'Disease', (171, 176))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('increased', 'PosReg', (119, 128))
79993	33925915	Two phase II studies evaluating ipilimumab monotherapy vs. ipilimumab/bevacizumab in unresectable stage III/IV melanoma and atezolizumab/bevacizumab in patients with locally advanced and metastatic cutaneous and mucosal melanoma are currently ongoing and recruiting (NCT01950390/NCT04091217).	('mucosal melanoma', 'Disease', (212, 228))	('ipilimumab', 'Chemical', 'MESH:D000074324', (59, 69))	('melanoma and atezolizumab', 'Disease', 'MESH:D008545', (111, 136))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('mucosal melanoma', 'Disease', 'MESH:D008545', (212, 228))	('age', 'Gene', (100, 103))	('ipilimumab', 'Chemical', 'MESH:D000074324', (32, 42))	('bevacizumab', 'Chemical', 'MESH:D000068258', (137, 148))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('NCT01950390/NCT04091217', 'Var', (267, 290))	('age', 'Gene', '5973', (100, 103))	('patients', 'Species', '9606', (152, 160))	('bevacizumab', 'Chemical', 'MESH:D000068258', (70, 81))
80159	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))
80162	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))	('BRAF', 'Gene', '673', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('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))
80262	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))
80264	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'))
80274	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))
80275	26712692	However, BRAF was not mutated in any of the UM tumors (n=22); (BRAF mutation frequency; CM vs. UM metastases, P<0.0001).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('CM', 'Phenotype', 'HP:0012056', (88, 90))	('BRAF', 'Gene', (9, 13))	('mutation', 'Var', (68, 76))	('metastases', 'Disease', (98, 108))	('UM', 'Phenotype', 'HP:0007716', (44, 46))	('UM', 'Phenotype', 'HP:0007716', (95, 97))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('BRAF', 'Gene', '673', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (9, 13))
80276	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))
80292	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))
80293	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))
80304	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))
80317	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))	('ocular melanoma', 'Disease', 'MESH:D008545', (94, 109))	('CM', 'Disease', 'MESH:D009202', (163, 165))	('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))
80320	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))
80326	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))
80327	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))
80329	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))
80334	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'))
80350	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.	('melanoma proliferation', 'Disease', (195, 217))	('NRAS', 'Gene', (108, 112))	('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))
80352	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))
80354	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))
80356	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))	('effect', 'Reg', (211, 217))	('survivin levels', 'MPA', (221, 236))
80366	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'))
80369	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))
80371	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))
80372	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'))	('MG132', 'Chemical', 'MESH:C072553', (107, 112))	('CHX', 'Chemical', 'MESH:D003513', (113, 116))	('diminished', 'NegReg', (28, 38))	('resting levels of survivin', 'MPA', (39, 65))	('depletion', 'Var', (11, 20))
80378	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))	('proliferation', 'CPA', (125, 138))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('survivin', 'Protein', (112, 120))	('increase', 'PosReg', (100, 108))
80379	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))
80389	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))
80391	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))
80394	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))
80482	22576141	In our hospital-based case-control study including 305 melanoma patients and 370 healthy controls single nucleotide polymorphisms in the genes CYP27B1 (rs4646536), CYP24A1 (rs927650), VDBP (rs1155563, rs7041), and VDR (rs757343, rs731236, rs2107301, rs7975232) were analyzed for their association with melanoma risk and prognosis.	('rs927650', 'Var', (173, 181))	('rs927650', 'Mutation', 'rs927650', (173, 181))	('VDBP', 'Gene', (184, 188))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('rs2107301', 'Mutation', 'rs2107301', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('rs1155563', 'Mutation', 'rs1155563', (190, 199))	('rs757343', 'Mutation', 'rs757343', (219, 227))	('VDBP', 'Gene', '2638', (184, 188))	('CYP27B1', 'Gene', (143, 150))	('CYP24A1', 'Gene', (164, 171))	('rs7041', 'Mutation', 'rs7041', (201, 207))	('rs731236', 'Mutation', 'rs731236', (229, 237))	('rs7975232', 'Var', (250, 259))	('rs2107301', 'Var', (239, 248))	('VDR', 'Gene', (214, 217))	('rs7975232', 'Mutation', 'rs7975232', (250, 259))	('rs731236', 'Var', (229, 237))	('rs4646536', 'Var', (152, 161))	('rs1155563', 'Var', (190, 199))	('CYP24A1', 'Gene', '1591', (164, 171))	('rs4646536', 'Mutation', 'rs4646536', (152, 161))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('patients', 'Species', '9606', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('rs7041', 'Var', (201, 207))	('CYP27B1', 'Gene', '1594', (143, 150))	('rs757343', 'Var', (219, 227))	('VDR', 'Gene', '7421', (214, 217))
80483	22576141	Except VDR rs731236 and VDR rs2107301, the other six polymorphisms have not been analyzed regarding melanoma before.	('rs731236', 'Var', (11, 19))	('rs731236', 'Mutation', 'rs731236', (11, 19))	('VDR', 'Gene', '7421', (24, 27))	('rs2107301', 'Var', (28, 37))	('VDR', 'Gene', '7421', (7, 10))	('rs2107301', 'Mutation', 'rs2107301', (28, 37))	('VDR', 'Gene', (7, 10))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('VDR', 'Gene', (24, 27))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
80495	22576141	Single nucleotide polymorphisms (SNP) associated with melanoma susceptibility or the course of disease have been described as molecular risk factors in genes involved in the regulation of skin pigmentation, such as the melanocortin-1 receptor gene, in DNA repair, such as the xeroderma pigmentosum group C gene, in the detoxification of oxidative stress metabolites, such as the glutathione S-transferase gene, in the regulation of the immune system, such as the interleukin-10 gene, or in the production of proteins of the steroid and thyroid hormone superfamily, including the peroxisome proliferator-activated receptor genes.	('skin pigmentation', 'Disease', 'MESH:D010859', (188, 205))	('pigmentation', 'biological_process', 'GO:0043473', ('193', '205'))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('DNA repair', 'biological_process', 'GO:0006281', ('252', '262'))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (276, 297))	('interleukin-10', 'Gene', '3586', (463, 477))	('DNA', 'cellular_component', 'GO:0005574', ('252', '255'))	('associated', 'Reg', (38, 48))	('xeroderma pigmentosum', 'Disease', (276, 297))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('peroxisome', 'cellular_component', 'GO:0005777', ('579', '589'))	('regulation', 'biological_process', 'GO:0065007', ('174', '184'))	('detoxification', 'biological_process', 'GO:0098754', ('319', '333'))	('oxidative stress', 'Phenotype', 'HP:0025464', (337, 353))	('glutathione S-transferase', 'Gene', '373156', (379, 404))	('skin pigmentation', 'Phenotype', 'HP:0000953', (188, 205))	('skin pigmentation', 'Disease', (188, 205))	('regulation', 'biological_process', 'GO:0065007', ('418', '428'))	('melanocortin-1 receptor', 'Gene', (219, 242))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanocortin-1 receptor', 'Gene', '4157', (219, 242))	('interleukin-10', 'Gene', (463, 477))	('glutathione S-transferase', 'Gene', (379, 404))
80502	22576141	In general 1,25(OH)2D3, the hormonal derivative of vitamin D3 and the ligand of the VDR, exhibits anti-proliferative and pro-differentiation effects in VDR-expressing cell types.	('pro-differentiation effects', 'CPA', (121, 148))	('ligand', 'molecular_function', 'GO:0005488', ('70', '76'))	('VDR', 'Gene', (152, 155))	('anti-proliferative', 'CPA', (98, 116))	('VDR', 'Gene', (84, 87))	('1,25(OH)2D3', 'Var', (11, 22))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (11, 22))	('vitamin D3', 'Chemical', 'MESH:D002762', (51, 61))	('VDR', 'Gene', '7421', (152, 155))	('VDR', 'Gene', '7421', (84, 87))
80503	22576141	It has been shown that melanocytes as well as melanoma cells express VDR and that 1,25(OH)2D3 has an anti-proliferative effect on melanocytes as well as melanoma cells in vitro.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('VDR', 'Gene', '7421', (69, 72))	('1,25(OH)2D3', 'Var', (82, 93))	('melanoma', 'Disease', (153, 161))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (82, 93))	('VDR', 'Gene', (69, 72))	('anti-proliferative effect', 'CPA', (101, 126))
80505	22576141	The analysis of polymorphisms in genes of the vitamin D metabolism concerning their association with melanoma as well as other types of cancer is a current research topic.	('association', 'Interaction', (84, 95))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('46', '66'))	('polymorphisms', 'Var', (16, 29))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Disease', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('vitamin D', 'Chemical', 'MESH:D014807', (46, 55))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
80506	22576141	assessed the association of a novel adenine-guanine substitution 1,012 bp upstream of the exon 1a transcription start site (A-1012G) in the VDR gene with melanoma risk and prognosis in 171 melanoma patients and 80 healthy controls.	('association', 'Interaction', (13, 24))	('A-1012G', 'Mutation', 'rs4516035', (124, 131))	('A-1012G', 'Var', (124, 131))	('patients', 'Species', '9606', (198, 206))	('VDR', 'Gene', (140, 143))	('adenine-guanine', 'Chemical', '-', (36, 51))	('VDR', 'Gene', '7421', (140, 143))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
80508	22576141	reported a correlation of the VDR SNP BsmI (rs1544410) with an increased melanoma risk as well as a strong association with an increased Breslow tumor thickness.	('rs1544410', 'Mutation', 'rs1544410', (44, 53))	('melanoma', 'Disease', (73, 81))	('rs1544410', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('VDR', 'Gene', '7421', (30, 33))	('VDR', 'Gene', (30, 33))	('tumor', 'Disease', (145, 150))	('Breslow', 'Disease', (137, 144))	('increased', 'PosReg', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
80509	22576141	In another study, the Taq I (rs731236) and the Fok I (rs2228570) SNPs of the VDR gene were analyzed for their melanoma risk association.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('rs731236', 'Mutation', 'rs731236', (29, 37))	('rs2228570', 'Mutation', 'rs2228570', (54, 63))	('VDR', 'Gene', (77, 80))	('rs731236', 'Var', (29, 37))	('rs2228570', 'Var', (54, 63))	('VDR', 'Gene', '7421', (77, 80))
80515	22576141	Information about SNPs in other vitamin D metabolism-related genes that might contribute to skin cancer or other types of internal cancers is scarce.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('skin cancer', 'Disease', (92, 103))	('skin cancer', 'Disease', 'MESH:D012878', (92, 103))	('internal cancers', 'Disease', (122, 138))	('contribute', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('internal cancers', 'Disease', 'MESH:D009369', (122, 138))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('vitamin D', 'Chemical', 'MESH:D014807', (32, 41))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('32', '52'))	('SNPs', 'Var', (18, 22))	('skin cancer', 'Phenotype', 'HP:0008069', (92, 103))
80516	22576141	analyzed the SNPs rs7041 and rs4588 in the VDBP gene for their association with basal cell carcinoma (BCC).	('VDBP', 'Gene', (43, 47))	('rs4588', 'Mutation', 'rs4588', (29, 35))	('basal cell carcinoma', 'Disease', (80, 100))	('SNPs', 'Var', (13, 17))	('association', 'Interaction', (63, 74))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (80, 100))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (80, 100))	('rs4588', 'Var', (29, 35))	('BCC', 'Phenotype', 'HP:0002671', (102, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('rs7041', 'Mutation', 'rs7041', (18, 24))	('VDBP', 'Gene', '2638', (43, 47))
80517	22576141	Only the AT variant of rs7041 was associated with an increased BCC risk in younger patients after age stratification.	('rs7041', 'Mutation', 'rs7041', (23, 29))	('patients', 'Species', '9606', (83, 91))	('BCC', 'Disease', (63, 66))	('rs7041', 'Var', (23, 29))	('BCC', 'Phenotype', 'HP:0002671', (63, 66))
80518	22576141	The minor allele of the CYP24A1 gene SNP rs927650 has been reported to be associated with a decreased risk of disease recurrence/regression in prostate cancer patients.	('prostate cancer', 'Disease', 'MESH:D011471', (143, 158))	('rs927650', 'Mutation', 'rs927650', (41, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (143, 158))	('CYP24A1', 'Gene', '1591', (24, 31))	('disease recurrence/regression', 'CPA', (110, 139))	('rs927650', 'Var', (41, 49))	('prostate cancer', 'Disease', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('decreased', 'NegReg', (92, 101))	('patients', 'Species', '9606', (159, 167))	('CYP24A1', 'Gene', (24, 31))
80519	22576141	The CYP27B1 single nucleotide polymorphism rs4646536 was not associated with the susceptibility for developing colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (111, 123))	('rs4646536', 'Var', (43, 52))	('rs4646536', 'Mutation', 'rs4646536', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colon cancer', 'Disease', (111, 123))	('CYP27B1', 'Gene', '1594', (4, 11))	('colon cancer', 'Phenotype', 'HP:0003003', (111, 123))	('CYP27B1', 'Gene', (4, 11))
80520	22576141	In our present hospital-based case-control study, we tested eight vitamin D metabolism-related polymorphisms focusing on the VDBP gene (rs1155563 and rs7041) and the genes coding for CYP27B1 and CYP24A1 (rs4646536 and rs927650) for their association with melanoma risk and melanoma prognosis.	('CYP24A1', 'Gene', '1591', (195, 202))	('rs7041', 'Var', (150, 156))	('rs1155563', 'Mutation', 'rs1155563', (136, 145))	('rs4646536', 'Var', (204, 213))	('rs4646536', 'Mutation', 'rs4646536', (204, 213))	('tested', 'Reg', (53, 59))	('CYP27B1', 'Gene', (183, 190))	('vitamin D', 'Chemical', 'MESH:D014807', (66, 75))	('rs927650', 'Var', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (273, 281))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('rs927650', 'Mutation', 'rs927650', (218, 226))	('rs1155563', 'Var', (136, 145))	('VDBP', 'Gene', (125, 129))	('CYP27B1', 'Gene', '1594', (183, 190))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('66', '86'))	('CYP24A1', 'Gene', (195, 202))	('rs7041', 'Mutation', 'rs7041', (150, 156))	('melanoma', 'Phenotype', 'HP:0002861', (273, 281))	('melanoma', 'Disease', (273, 281))	('VDBP', 'Gene', '2638', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('association', 'Interaction', (238, 249))	('melanoma', 'Disease', (255, 263))
80521	22576141	In addition, four SNPs in the VDR gene (rs2107301, rs7975232, rs757343, and rs731236) were assessed in our 305 melanoma patients and 370 healthy controls study group.	('rs2107301', 'Mutation', 'rs2107301', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('rs7975232', 'Mutation', 'rs7975232', (51, 60))	('rs757343', 'Mutation', 'rs757343', (62, 70))	('rs731236', 'Var', (76, 84))	('rs757343', 'Var', (62, 70))	('VDR', 'Gene', (30, 33))	('rs2107301', 'Var', (40, 49))	('patients', 'Species', '9606', (120, 128))	('rs731236', 'Mutation', 'rs731236', (76, 84))	('VDR', 'Gene', '7421', (30, 33))	('rs7975232', 'Var', (51, 60))
80525	22576141	The following SNPs were analyzed with pre-designed genotyping assays: rs731236 (VDR), rs7975232 (VDR), rs2107301 (VDR), rs757343 (VDR), rs4646536 (CYP27B1), rs927650 (CYP24A1), rs7041 (VDBP) (assay numbers C_2404008_10, C_28977635_10, C_16174096_10, C_2404009_20, C_25623453_10, C_7595497_10, C_3133594_30, respectively).	('rs927650', 'Mutation', 'rs927650', (157, 165))	('VDR', 'Gene', (114, 117))	('C_16174096_10', 'Var', (235, 248))	('VDBP', 'Gene', (185, 189))	('C_3133594_30', 'Var', (293, 305))	('VDR', 'Gene', (130, 133))	('pre', 'molecular_function', 'GO:0003904', ('38', '41'))	('CYP24A1', 'Gene', (167, 174))	('C_28977635_10', 'Var', (220, 233))	('rs7975232', 'Var', (86, 95))	('VDR', 'Gene', (97, 100))	('C_2404009_20', 'Var', (250, 262))	('rs7975232', 'Mutation', 'rs7975232', (86, 95))	('VDBP', 'Gene', '2638', (185, 189))	('C_7595497_10', 'Var', (279, 291))	('CYP27B1', 'Gene', '1594', (147, 154))	('rs757343', 'Var', (120, 128))	('VDR', 'Gene', '7421', (114, 117))	('rs2107301', 'Mutation', 'rs2107301', (103, 112))	('CYP24A1', 'Gene', '1591', (167, 174))	('rs7041', 'Mutation', 'rs7041', (177, 183))	('C_25623453_10', 'Var', (264, 277))	('VDR', 'Gene', '7421', (130, 133))	('VDR', 'Gene', (80, 83))	('C_2404008_10', 'Var', (206, 218))	('VDR', 'Gene', '7421', (97, 100))	('rs731236', 'Mutation', 'rs731236', (70, 78))	('rs2107301', 'Var', (103, 112))	('rs757343', 'Mutation', 'rs757343', (120, 128))	('rs4646536', 'Var', (136, 145))	('rs731236', 'Var', (70, 78))	('rs927650', 'Var', (157, 165))	('rs7041', 'Var', (177, 183))	('rs4646536', 'Mutation', 'rs4646536', (136, 145))	('VDR', 'Gene', '7421', (80, 83))	('CYP27B1', 'Gene', (147, 154))
80529	22576141	For these, the estimated power was 36 % (rs2107301), 48 % (rs7041), and 47 % (rs757343).	('rs2107301', 'Var', (41, 50))	('rs7041', 'Var', (59, 65))	('rs2107301', 'Mutation', 'rs2107301', (41, 50))	('rs757343', 'Var', (78, 86))	('rs7041', 'Mutation', 'rs7041', (59, 65))	('rs757343', 'Mutation', 'rs757343', (78, 86))
80539	22576141	The SNPs rs4646536 and rs927650 in CYP27B1 and CYP24A1, respectively, are both located in intron regions as is the rs1155563 VDBP SNP.	('rs927650', 'Var', (23, 31))	('rs1155563', 'Mutation', 'rs1155563', (115, 124))	('rs4646536', 'Mutation', 'rs4646536', (9, 18))	('VDBP', 'Gene', '2638', (125, 129))	('CYP27B1', 'Gene', '1594', (35, 42))	('VDBP', 'Gene', (125, 129))	('rs927650', 'Mutation', 'rs927650', (23, 31))	('CYP24A1', 'Gene', '1591', (47, 54))	('rs4646536', 'Var', (9, 18))	('CYP27B1', 'Gene', (35, 42))	('CYP24A1', 'Gene', (47, 54))
80541	22576141	Three of the VDR SNPs are located in intron regions: rs757343, rs2107301, and rs7975232.	('VDR', 'Gene', '7421', (13, 16))	('rs757343', 'Var', (53, 61))	('rs7975232', 'Var', (78, 87))	('rs2107301', 'Mutation', 'rs2107301', (63, 72))	('rs7975232', 'Mutation', 'rs7975232', (78, 87))	('VDR', 'Gene', (13, 16))	('rs2107301', 'Var', (63, 72))	('rs757343', 'Mutation', 'rs757343', (53, 61))
80542	22576141	The synonymous VDR SNP rs731236 is located in exon 9.	('rs731236', 'Mutation', 'rs731236', (23, 31))	('VDR', 'Gene', '7421', (15, 18))	('rs731236', 'Var', (23, 31))	('VDR', 'Gene', (15, 18))
80543	22576141	The genotype frequencies of the polymorphisms rs731236, rs7975232, rs7041, rs4646536, rs927650, rs1155563 conformed to the Hardy-Weinberg equilibrium (HWE).	('rs7041', 'Mutation', 'rs7041', (67, 73))	('rs1155563', 'Mutation', 'rs1155563', (96, 105))	('rs731236', 'Mutation', 'rs731236', (46, 54))	('rs4646536', 'Var', (75, 84))	('rs4646536', 'Mutation', 'rs4646536', (75, 84))	('rs7975232', 'Mutation', 'rs7975232', (56, 65))	('rs1155563', 'Var', (96, 105))	('rs731236', 'Var', (46, 54))	('rs7041', 'Var', (67, 73))	('rs927650', 'Mutation', 'rs927650', (86, 94))	('rs7975232', 'Var', (56, 65))	('rs927650', 'Var', (86, 94))
80544	22576141	The SNPs rs2107301 and rs757343 showed a small deviance from HWE, however, could be incorporated into the further analysis as we performed several control steps.	('rs757343', 'Mutation', 'rs757343', (23, 31))	('rs2107301', 'Mutation', 'rs2107301', (9, 18))	('rs757343', 'Var', (23, 31))	('rs2107301', 'Var', (9, 18))
80546	22576141	With the dominant model, the CYP27B1 rs4646536 as well as the VDR rs757343 and rs 2107301 SNPs exhibited the lowest p values of 0.42, 0.65, and 0.56, respectively, corresponding to ORs of 1.19, 1.12, and 1.22.	('rs757343', 'Var', (66, 74))	('rs4646536', 'Mutation', 'rs4646536', (37, 46))	('VDR', 'Gene', '7421', (62, 65))	('rs757343', 'Mutation', 'rs757343', (66, 74))	('CYP27B1', 'Gene', (29, 36))	('VDR', 'Gene', (62, 65))	('rs 2107301', 'Var', (79, 89))	('CYP27B1', 'Gene', '1594', (29, 36))
80547	22576141	With the additive model, the lowest p values were found for the VDBP SNPs rs1155563 and rs7041 as well as for the VDR rs2107301 and again for the CYP27B1 rs4646536 corresponding to 0.16 (OR: 0.80), 0.44 (OR: 0.89), 0.50 (OR: 0.90), and 0.58 (OR: 1.09), respectively.	('VDR', 'Gene', (114, 117))	('rs2107301', 'Var', (118, 127))	('rs4646536', 'Var', (154, 163))	('CYP27B1', 'Gene', (146, 153))	('rs7041', 'Var', (88, 94))	('rs1155563', 'Mutation', 'rs1155563', (74, 83))	('VDR', 'Gene', '7421', (114, 117))	('rs4646536', 'Mutation', 'rs4646536', (154, 163))	('CYP27B1', 'Gene', '1594', (146, 153))	('VDBP', 'Gene', '2638', (64, 68))	('rs1155563', 'Var', (74, 83))	('rs7041', 'Mutation', 'rs7041', (88, 94))	('rs2107301', 'Mutation', 'rs2107301', (118, 127))	('VDBP', 'Gene', (64, 68))
80551	22576141	With the dominant model, the p values ranged from 0.15 (OR: 0.53) for the VDBP rs1155563 SNP to 0.93 (OR: -0.02) for the CYP27B1 rs4646536 SNP.	('VDBP', 'Gene', (74, 78))	('rs4646536', 'Mutation', 'rs4646536', (129, 138))	('CYP27B1', 'Gene', (121, 128))	('rs1155563 SNP', 'Var', (79, 92))	('rs4646536 SNP', 'Var', (129, 142))	('CYP27B1', 'Gene', '1594', (121, 128))	('rs1155563', 'Mutation', 'rs1155563', (79, 88))	('VDBP', 'Gene', '2638', (74, 78))
80552	22576141	With the additive model, the lowest p values were observed for the VDBP SNPs rs7041 and rs1155563 as well as for the VDR SNPs rs2107301, rs757343, and rs731236 corresponding to 0.14 (OR: 0.22), 0.17 (OR: 0.22), 0.15 (OR: 0.22), 0.41 (OR: -0.19), and 0.43 (OR: 0.12), respectively.	('VDR', 'Gene', (117, 120))	('rs7041', 'Mutation', 'rs7041', (77, 83))	('VDBP', 'Gene', '2638', (67, 71))	('rs2107301', 'Mutation', 'rs2107301', (126, 135))	('rs731236', 'Mutation', 'rs731236', (151, 159))	('rs1155563', 'Mutation', 'rs1155563', (88, 97))	('VDR', 'Gene', '7421', (117, 120))	('rs757343', 'Var', (137, 145))	('rs7041', 'Var', (77, 83))	('rs2107301', 'Var', (126, 135))	('rs1155563', 'Var', (88, 97))	('rs731236', 'Var', (151, 159))	('rs757343', 'Mutation', 'rs757343', (137, 145))	('VDBP', 'Gene', (67, 71))
80562	22576141	For melanoma cells as well as melanocytes, an anti-proliferative effect of 1,25(OH)2D3 in vitro has been shown.	('anti-proliferative effect', 'MPA', (46, 71))	('1,25(OH)2D3', 'Var', (75, 86))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (75, 86))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))
80565	22576141	In this present hospital-based case-control study, we analyzed putative associations of 8 SNPs in vitamin D metabolism-related genes with melanoma risk as well as melanoma prognosis in a study group of 305 melanoma patients and 375 controls.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('patients', 'Species', '9606', (215, 223))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('98', '118'))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('associations', 'Interaction', (72, 84))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('vitamin D', 'Chemical', 'MESH:D014807', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('SNPs', 'Var', (90, 94))
80566	22576141	Most of the studies examining associations between skin cancer and polymorphisms in the vitamin D metabolism analyzed polymorphisms in the VDR gene.	('VDR', 'Gene', (139, 142))	('skin cancer', 'Disease', 'MESH:D012878', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('88', '108'))	('associations', 'Interaction', (30, 42))	('vitamin D', 'Chemical', 'MESH:D014807', (88, 97))	('skin cancer', 'Disease', (51, 62))	('VDR', 'Gene', '7421', (139, 142))	('polymorphisms', 'Var', (118, 131))	('polymorphisms', 'Var', (67, 80))
80567	22576141	Studies about polymorphisms in other genes contributing to the vitamin D status and their possible associations to skin cancer risk are rare.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('vitamin D', 'Chemical', 'MESH:D014807', (63, 72))	('skin cancer', 'Disease', 'MESH:D012878', (115, 126))	('skin cancer', 'Phenotype', 'HP:0008069', (115, 126))	('polymorphisms', 'Var', (14, 27))	('associations', 'Interaction', (99, 111))	('skin cancer', 'Disease', (115, 126))
80568	22576141	To our knowledge, only the rs7041 polymorphism in VDBP gene was reported to be associated with an increased BCC risk.	('BCC', 'Phenotype', 'HP:0002671', (108, 111))	('rs7041 polymorphism', 'Var', (27, 46))	('associated', 'Reg', (79, 89))	('rs7041', 'Mutation', 'rs7041', (27, 33))	('VDBP', 'Gene', '2638', (50, 54))	('BCC', 'Disease', (108, 111))	('VDBP', 'Gene', (50, 54))
80569	22576141	Polymorphisms in the other vitamin D metabolism-related genes may also be relevant concerning cancer susceptibility.	('vitamin D', 'Chemical', 'MESH:D014807', (27, 36))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('27', '47'))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
80570	22576141	Polymorphisms in the vitamin D metabolism-related genes CYP24A1 and CYP27B1 were reported to be associated with colon as well as prostate cancer risk, respectively.	('vitamin D', 'Chemical', 'MESH:D014807', (21, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (129, 144))	('CYP24A1', 'Gene', (56, 63))	('CYP27B1', 'Gene', '1594', (68, 75))	('CYP24A1', 'Gene', '1591', (56, 63))	('associated', 'Reg', (96, 106))	('Polymorphisms', 'Var', (0, 13))	('vitamin D metabolism', 'biological_process', 'GO:0042359', ('21', '41'))	('prostate cancer', 'Disease', (129, 144))	('colon', 'Disease', 'MESH:D015179', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CYP27B1', 'Gene', (68, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (129, 144))	('colon', 'Disease', (112, 117))
80571	22576141	We analyzed the rs4646536 SNP in the CYP27B1 gene.	('rs4646536 SNP', 'Var', (16, 29))	('CYP27B1', 'Gene', '1594', (37, 44))	('CYP27B1', 'Gene', (37, 44))	('rs4646536', 'Mutation', 'rs4646536', (16, 25))
80572	22576141	This gene seems relevant for carcinogenesis as other polymorphisms in this gene were found to be associated with prostate cancer and colon cancer.	('carcinogenesis', 'Disease', (29, 43))	('colon cancer', 'Phenotype', 'HP:0003003', (133, 145))	('colon cancer', 'Disease', 'MESH:D015179', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('prostate cancer', 'Disease', (113, 128))	('colon cancer', 'Disease', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('associated', 'Reg', (97, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))	('polymorphisms', 'Var', (53, 66))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
80573	22576141	The rs4646536 polymorphism has rarely been analyzed with respect to cancer susceptibility before.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs4646536', 'Var', (4, 13))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('rs4646536', 'Mutation', 'rs4646536', (4, 13))	('cancer', 'Disease', (68, 74))
80577	22576141	Moreover, associations of SNPs in the CYP24A1 gene with prostate cancer prognosis have been reported.	('CYP24A1', 'Gene', '1591', (38, 45))	('associations', 'Interaction', (10, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('SNPs', 'Var', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('CYP24A1', 'Gene', (38, 45))	('prostate cancer', 'Disease', (56, 71))
80578	22576141	The polymorphism rs927650 that is analyzed in our present study, as well as another polymorphism (rs2762939) in the CYP24A1 gene were significantly associated with prostate cancer prognosis.	('prostate cancer', 'Phenotype', 'HP:0012125', (164, 179))	('rs927650', 'Mutation', 'rs927650', (17, 25))	('rs2762939', 'Var', (98, 107))	('prostate cancer', 'Disease', (164, 179))	('rs927650', 'Var', (17, 25))	('rs2762939', 'Mutation', 'rs2762939', (98, 107))	('associated with', 'Reg', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CYP24A1', 'Gene', (116, 123))	('prostate cancer', 'Disease', 'MESH:D011471', (164, 179))	('CYP24A1', 'Gene', '1591', (116, 123))
80580	22576141	We also analyzed two SNPs in the VDBP gene, rs1155563 and rs7041.	('rs7041', 'Var', (58, 64))	('rs1155563', 'Var', (44, 53))	('rs7041', 'Mutation', 'rs7041', (58, 64))	('rs1155563', 'Mutation', 'rs1155563', (44, 53))	('VDBP', 'Gene', '2638', (33, 37))	('VDBP', 'Gene', (33, 37))
80584	22576141	The GC1S and GC1F haplotypes were associated with higher levels of VDBP and serum 25(OH)D concentration as well as higher affinity of VDBP to vitamin D metabolites compared with the GC2 haplotype.	('VDBP', 'Gene', '2638', (134, 138))	('higher', 'PosReg', (50, 56))	('vitamin D', 'Chemical', 'MESH:D014807', (142, 151))	('VDBP', 'Gene', '2638', (67, 71))	('GC1S', 'Gene', (4, 8))	('VDBP', 'Gene', (134, 138))	('GC2', 'Gene', '83733', (182, 185))	('levels', 'MPA', (57, 63))	('VDBP', 'Gene', (67, 71))	('25(OH)D', 'Chemical', '-', (82, 89))	('GC1F', 'Gene', (13, 17))	('higher', 'PosReg', (115, 121))	('affinity', 'Interaction', (122, 130))	('haplotypes', 'Var', (18, 28))	('GC2', 'Gene', (182, 185))
80585	22576141	In genome wide association studies of circulating vitamin D levels, the rs7041 and rs1155563 polymorphisms were found to be associated with another common VDBP SNP, rs 2282679.	('rs7041', 'Var', (72, 78))	('rs1155563', 'Var', (83, 92))	('associated', 'Reg', (124, 134))	('VDBP', 'Gene', '2638', (155, 159))	('vitamin D', 'Chemical', 'MESH:D014807', (50, 59))	('rs7041', 'Mutation', 'rs7041', (72, 78))	('VDBP', 'Gene', (155, 159))	('rs1155563', 'Mutation', 'rs1155563', (83, 92))
80586	22576141	These three common VDBP variants, with the rs2282679 prevailing, conferred an association signal with 25(OH)D levels in metaanalyses.	('rs2282679', 'Var', (43, 52))	('25(OH)D', 'Chemical', '-', (102, 109))	('rs2282679', 'Mutation', 'rs2282679', (43, 52))	('VDBP', 'Gene', '2638', (19, 23))	('VDBP', 'Gene', (19, 23))	('association', 'Interaction', (78, 89))
80590	22576141	Neither the rs7041 nor the rs1155563 have ever been analyzed for their association with melanoma so far.	('rs7041', 'Mutation', 'rs7041', (12, 18))	('rs1155563', 'Mutation', 'rs1155563', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('rs1155563', 'Var', (27, 36))	('rs7041', 'Var', (12, 18))
80591	22576141	Polymorphisms in the VDR gene have been analyzed for their associations with prostate cancer, breast cancer, colorectal adenomas and also for their association with melanomas.	('VDR', 'Gene', '7421', (21, 24))	('associations', 'Interaction', (59, 71))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('colorectal adenomas', 'Disease', 'MESH:D015179', (109, 128))	('Polymorphisms', 'Var', (0, 13))	('association', 'Interaction', (148, 159))	('colorectal adenomas', 'Disease', (109, 128))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('breast cancer', 'Disease', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('VDR', 'Gene', (21, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('melanomas', 'Disease', (165, 174))	('prostate cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
80593	22576141	The two VDR SNPs analyzed in this study, rs7975232, and rs757343, have not been investigated for their association with melanoma yet.	('VDR', 'Gene', (8, 11))	('rs7975232', 'Mutation', 'rs7975232', (41, 50))	('VDR', 'Gene', '7421', (8, 11))	('rs757343', 'Mutation', 'rs757343', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('rs7975232', 'Var', (41, 50))	('rs757343', 'Var', (56, 64))
80594	22576141	The VDR SNPs rs731236 and rs2107301 have been analyzed with respect to melanoma before.	('VDR', 'Gene', '7421', (4, 7))	('rs2107301', 'Mutation', 'rs2107301', (26, 35))	('rs731236', 'Mutation', 'rs731236', (13, 21))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('rs2107301', 'Var', (26, 35))	('VDR', 'Gene', (4, 7))	('rs731236', 'Var', (13, 21))
80595	22576141	Two studies identified a decreased melanoma risk in association with rs731236, but most studies could not find an association of rs731236 with melanoma risk or prognosis.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('rs731236', 'Var', (69, 77))	('rs731236', 'Mutation', 'rs731236', (129, 137))	('decreased', 'NegReg', (25, 34))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('rs731236', 'Mutation', 'rs731236', (69, 77))	('melanoma', 'Disease', (35, 43))
80602	22576141	As pointed out, the vitamin D system-associated polymorphisms may predispose also to other malignancies.	('predispose', 'Reg', (66, 76))	('malignancies', 'Disease', (91, 103))	('polymorphisms', 'Var', (48, 61))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('vitamin D', 'Chemical', 'MESH:D014807', (20, 29))
80603	22576141	Further, we are confident that our study population is representative as we already identified DNA repair gene SNPs and interleukin 10 promoter polymorphisms as independent molecular melanoma risk factors with this study population.	('interleukin 10', 'Gene', (120, 134))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('DNA repair', 'biological_process', 'GO:0006281', ('95', '105'))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('polymorphisms', 'Var', (144, 157))	('interleukin 10', 'Gene', '3586', (120, 134))	('DNA', 'cellular_component', 'GO:0005574', ('95', '98'))
80640	32495158	The CAL-54 cell line conforms with copy number amplifications (CNAs) in several key kidney cancer genes.	('kidney cancer', 'Disease', (84, 97))	('kidney cancer', 'Disease', 'MESH:D007680', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('copy number amplifications', 'Var', (35, 61))	('CAL-54', 'CellLine', 'CVCL:1111', (4, 10))
80673	32495158	The more comprehensive gene set (gs-ifng-m14004) had the highest enrichment score (ES) in SKCM tissues (ES = 0.825, FDR, q value 0.0; FWER p value 0.0) (Fig.	('SKCM', 'Disease', (90, 94))	('ES', 'Chemical', '-', (104, 106))	('ES', 'Chemical', '-', (83, 85))	('gs-ifng-m14004', 'Var', (33, 47))
80686	32495158	In SKCM with low PD-L1-mRNA tissue levels, patient survival was significantly shorter than in those with high-level PD-L1-mRNA levels (OS: HR 1.984; p < 0.0001 and DFS: HR 1.436; p = 0.0046).	('patient', 'Species', '9606', (43, 50))	('low', 'Var', (13, 16))	('PD-L1-mRNA', 'MPA', (17, 27))	('shorter', 'NegReg', (78, 85))	('patient survival', 'CPA', (43, 59))
80699	32495158	In IFN-gamma-responsive tumors such as melanoma and ccRCC, patients with high PD-L1-mRNA tissue levels had longer OS and DFS than those with low PD-L1-mRNA levels.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('DFS', 'CPA', (121, 124))	('PD-L1-mRNA', 'MPA', (78, 88))	('RCC', 'Disease', (54, 57))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('longer', 'PosReg', (107, 113))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))
80711	32495158	Conversely, tandem amplification of PD-L1/PD-L2 and JAK2, causing enhanced IFN-gamma signaling, was associated with high responsiveness towards immune checkpoint blockade in Hodgkin's lymphoma.	('responsiveness', 'MPA', (121, 135))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (174, 192))	('JAK2', 'Gene', (52, 56))	("Hodgkin's lymphoma", 'Disease', (174, 192))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (174, 192))	('enhanced', 'PosReg', (66, 74))	('PD-L2', 'Gene', (42, 47))	('PD-L2', 'Gene', '80380', (42, 47))	('tandem amplification', 'Var', (12, 32))	('JAK', 'molecular_function', 'GO:0004713', ('52', '55'))	('IFN-gamma signaling', 'MPA', (75, 94))
80714	32495158	In melanoma, a high PD-L1 protein score was associated with shorter survival.	('high', 'Var', (15, 19))	('PD-L1 protein', 'Protein', (20, 33))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('survival', 'MPA', (68, 76))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('shorter', 'NegReg', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
80715	32495158	In particular, a high PD-L1 score, considering PD-L1 in cancer cells or macrophages, predicted both worse outcome and, in a mouse model, the knockout of PD-L1 or of IFN-gamma signaling by STAT1-knockdown in tumor cells prolonged survival.	('PD-L1', 'Gene', (153, 158))	('prolonged', 'PosReg', (219, 228))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mouse', 'Species', '10090', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('survival', 'CPA', (229, 237))	('knockout', 'Var', (141, 149))
80716	32495158	Furthermore, in RCC, a high PD-L1 protein score was predictive of poor outcome in patients who received anti-angiogenic TKI treatment with sunitinib or pazopanib (COMPARZ trial).	('PD-L1', 'Protein', (28, 33))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('high', 'Var', (23, 27))	('RCC', 'Disease', (16, 19))	('patients', 'Species', '9606', (82, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (152, 161))	('sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))
80744	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))
80745	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))
80813	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))
80827	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))	('uveal melanoma', 'Disease', 'MESH:C536494', (355, 369))	('ipilimumab', 'Chemical', 'MESH:D000074324', (51, 61))	('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))	('ipilimumab', 'Chemical', 'MESH:D000074324', (185, 195))
80919	29507279	For the evaluation of the independent factors that predicted recurrence in our study, with the Cox regression (Table 3), the most stable prediction model included the following variables: histological type, TIL, positive SLN, a Breslow score higher than 2 mm.	('positive SLN', 'Var', (212, 224))	('Cox', 'Gene', (95, 98))	('Cox', 'Gene', '1351', (95, 98))	('Breslow', 'MPA', (228, 235))
80932	29507279	conducted a study on 1,693 melanoma patients with stage I-II and showed that regression was associated with a significant lower risk of disease progression (9.5% regressed melanomas developed metastatic disease versus 23.4% non-regressed melanomas, p<0.001) and with a better DFS and OS.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('melanomas', 'Phenotype', 'HP:0002861', (238, 247))	('melanomas', 'Disease', (172, 181))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('lower', 'NegReg', (122, 127))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('patients', 'Species', '9606', (36, 44))	('developed', 'PosReg', (182, 191))	('regressed', 'Var', (162, 171))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('melanomas', 'Disease', 'MESH:D008545', (238, 247))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('OS', 'Chemical', '-', (284, 286))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanomas', 'Disease', (238, 247))	('melanoma', 'Disease', (172, 180))	('metastatic disease', 'CPA', (192, 210))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))
80939	29507279	Multivariate analysis revealed that regression was not an independent prognostic factor for the outcome of patients with melanoma; just Breslow index >2 mm, positive SLN, and mild TIL were statistically linked to the survival of melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('Breslow index', 'MPA', (136, 149))	('melanoma', 'Disease', (121, 129))	('patients', 'Species', '9606', (238, 246))	('patients', 'Species', '9606', (107, 115))	('melanoma', 'Phenotype', 'HP:0002861', (229, 237))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('melanoma', 'Disease', (229, 237))	('positive', 'Var', (157, 165))	('>2 mm', 'Var', (150, 155))	('melanoma', 'Disease', 'MESH:D008545', (229, 237))	('mild TIL', 'Var', (175, 183))	('linked to', 'Reg', (203, 212))
80952	24068125	Metastasis was found in 28.6% of invasive melanomas and nodular melanoma, Clark IV/ V, Breslow > 1 mm, mitotic index >= 6 and ulcerated lesions were more likely to metastasize.	('ulcerated lesions', 'Disease', (126, 143))	('nodular melanoma', 'Disease', 'MESH:D020518', (56, 72))	('invasive melanomas', 'Disease', (33, 51))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('Metastasis', 'Disease', 'MESH:D009362', (0, 10))	('Metastasis', 'Disease', (0, 10))	('ulcerated lesions', 'Disease', 'MESH:D014456', (126, 143))	('nodular melanoma', 'Disease', (56, 72))	('invasive melanomas', 'Disease', 'MESH:D008545', (33, 51))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('nodular melanoma', 'Phenotype', 'HP:0012058', (56, 72))	('mitotic index >= 6', 'Var', (103, 121))	('metastasize', 'CPA', (164, 175))	('invasive melanomas and nodular melanoma', 'Disease', 'MESH:D008545', (33, 72))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
80969	24068125	This is of major concern given that approximately 20% of tumor patients presenting Breslow 1-4 mm have sentinel lymph node metastases, with this value increasing to 34% among patients with an index of over 4mm.	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('sentinel lymph node metastases', 'Disease', (103, 133))	('sentinel lymph node metastases', 'Disease', 'MESH:D009362', (103, 133))	('Breslow 1-4 mm', 'Var', (83, 97))
81014	23054107	Preclinical studies and phases I and II clinical trials have provided evidence that [99mTc]tilmanocept fulfills many of the desired characteristics of the ideal radiotracer for SLN identification.	('tilmanocept', 'Chemical', '-', (91, 102))	('[99mTc]', 'Var', (84, 91))	('tilmanocept', 'Gene', (91, 102))	('S', 'Chemical', 'MESH:D013455', (177, 178))
81064	23054107	Among the 154 melanoma patients who were injected with both [99mTc]tilmanocept and blue dye, there were a total of 45 tumor-containing nodes in 34 patients (22.1 % SLN positivity rate).	('melanoma', 'Disease', (14, 22))	('tilmanocept', 'Chemical', '-', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('S', 'Chemical', 'MESH:D013455', (164, 165))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Disease', (118, 123))	('[99mTc]', 'Var', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
81068	23054107	Thus, [99mTc]tilmanocept exhibited a higher detection rate for melanoma-containing SLNs than blue dye.	('[99mTc]', 'Var', (6, 13))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('detection', 'MPA', (44, 53))	('higher', 'PosReg', (37, 43))	('tilmanocept', 'Chemical', '-', (13, 24))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('S', 'Chemical', 'MESH:D013455', (83, 84))	('melanoma', 'Disease', (63, 71))
81080	23054107	These results led to the conduct of two phase III nonrandomized trials evaluating [99mTc]tilmanocept in patients with melanoma or breast cancer undergoing clinically indicated SLN biopsy with either isosulfan blue or Patent Blue V dye.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('melanoma', 'Disease', (118, 126))	('breast cancer', 'Disease', (130, 143))	('S', 'Chemical', 'MESH:D013455', (176, 177))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('isosulfan blue', 'Chemical', 'MESH:C025484', (199, 213))	('patients', 'Species', '9606', (104, 112))	('tilmanocept', 'Chemical', '-', (89, 100))	('[99mTc', 'Var', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
81083	23054107	This result established with a high degree of statistical probability that [99mTc]tilmanocept is in fact concordant with vital blue dye above the prespecified 90 % concordance level.	('[99mTc]', 'Var', (75, 82))	('tilmanocept', 'Chemical', '-', (82, 93))	('concordant', 'MPA', (105, 115))
81092	23054107	The rigorous data obtained in these two phase III trials strongly support [99mTc]tilmanocept as a safe and effective agent for lymphatic mapping and intraoperative identification of melanoma SLNs.	('melanoma SLNs', 'Disease', (182, 195))	('melanoma SLNs', 'Disease', 'MESH:D008545', (182, 195))	('tilmanocept', 'Chemical', '-', (81, 92))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('[99mTc]', 'Var', (74, 81))
81094	29650805	NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance.	('drug resistance', 'biological_process', 'GO:0042493', ('126', '141'))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('drug resistance', 'Phenotype', 'HP:0020174', (126, 141))	('melanoma', 'Disease', (12, 20))	('NRAS-mutant', 'Var', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (12, 20))	('drug resistance', 'biological_process', 'GO:0009315', ('126', '141'))	('drug resistance', 'MPA', (126, 141))
81098	29650805	Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.	('melanomas', 'Disease', 'MESH:D008545', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('MEK', 'Protein', (42, 45))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('melanomas', 'Disease', (117, 126))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Disease', (201, 206))	('co-targeting', 'Var', (29, 41))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('BET', 'Chemical', '-', (50, 53))
81101	29650805	Additionally, development of secondary NRAS mutations is a frequent mechanism for acquired resistance to BRAF inhibitors (Nazarian et al, 2010; Van Allen et al, 2014).	('BRAF', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', (39, 43))
81104	29650805	Here, we focused on identifying novel approaches targeting "non-oncogene addictions", which have the potential to induce cell death of NRAS Mut melanoma when combined with inhibitors of RAS effectors, and explored the efficacy of this strategy in targeted and immune checkpoint inhibitor-resistant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (298, 306))	('RA', 'Disease', 'MESH:D001172', (186, 188))	('rat', 'Species', '10116', (237, 240))	('RA', 'Disease', 'MESH:D001172', (136, 138))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('melanoma', 'Disease', (298, 306))	('cell death', 'CPA', (121, 131))	('induce', 'PosReg', (114, 120))	('melanoma', 'Disease', (144, 152))	('Mut', 'Var', (140, 143))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))
81105	29650805	Melanoma, like other cancers, is driven by genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (55, 77))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('rat', 'Species', '10116', (70, 73))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanoma', 'Disease', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))
81106	29650805	Epigenetic mechanisms implicated in melanomagenesis include altered gene expression via promoter hypo- or hypermethylation, histone modification, chromatin remodeling, and expression of non-coding RNAs (Sarkar et al, 2015).	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('146', '166'))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('chromatin', 'cellular_component', 'GO:0000785', ('146', '155'))	('gene expression', 'MPA', (68, 83))	('histone', 'MPA', (124, 131))	('histone modification', 'biological_process', 'GO:0016570', ('124', '144'))	('promoter hypo-', 'Var', (88, 102))	('gene expression', 'biological_process', 'GO:0010467', ('68', '83'))	('altered', 'Reg', (60, 67))	('hypermethylation', 'Var', (106, 122))
81107	29650805	For example, hypermethylation of the CDKN2A tumor suppressor promoter occurs in ~ 20% of primary melanomas and is associated with reduced patient survival (Straume et al, 2002).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('44', '60'))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('CDKN2A', 'Gene', (37, 43))	('patient survival', 'CPA', (138, 154))	('CDKN2A', 'Gene', '1029', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('melanomas', 'Disease', (97, 106))	('reduced', 'NegReg', (130, 137))	('patient', 'Species', '9606', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('hypermethylation', 'Var', (13, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('44', '60'))	('tumor', 'Disease', (44, 49))
81108	29650805	Oncogenic pathways, like mutant NRAS, can modulate and interact with the cancer epigenome; hence, epigenetic factors could constitute therapeutic targets for NRAS Mut tumors (Besaratinia & Tommasi, 2014).	('cancer', 'Disease', (73, 79))	('mutant', 'Var', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('NRAS Mut tumors', 'Disease', (158, 173))	('NRAS Mut tumors', 'Disease', 'MESH:C565390', (158, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('interact', 'Reg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('rat', 'Species', '10116', (179, 182))	('modulate', 'Reg', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
81109	29650805	For example, RAS/MAPK signaling promotes expression of the chromatin remodeler EZH2, which mediates chromatin compaction via histone H3K27 methylation, thereby repressing expression of its target genes (Fujii et al, 2011; Hou et al, 2012).	('expression', 'MPA', (171, 181))	('histone H3K27 methylation', 'biological_process', 'GO:0070734', ('125', '150'))	('expression', 'MPA', (41, 51))	('chromatin', 'cellular_component', 'GO:0000785', ('100', '109'))	('MAPK', 'molecular_function', 'GO:0004707', ('17', '21'))	('EZH2', 'Gene', (79, 83))	('repressing', 'PosReg', (160, 170))	('EZH2', 'Gene', '2146', (79, 83))	('MAPK signaling', 'biological_process', 'GO:0000165', ('17', '31'))	('RA', 'Disease', 'MESH:D001172', (13, 15))	('chromatin', 'cellular_component', 'GO:0000785', ('59', '68'))	('promotes', 'PosReg', (32, 40))	('methylation', 'Var', (139, 150))	('histone', 'Protein', (125, 132))
81113	29650805	Bromodomains are known to bind acetylated lysine residues in the N-terminal tail of histones and non-histone proteins, serving as scaffolds facilitating gene transcription and regulating many cellular processes including DNA replication and cell cycle progression (Shi & Vakoc, 2014).	('acetylated lysine residues', 'Var', (31, 57))	('cell cycle progression', 'CPA', (241, 263))	('DNA replication', 'biological_process', 'GO:0006260', ('221', '236'))	('gene transcription', 'MPA', (153, 171))	('bind', 'Interaction', (26, 30))	('transcription', 'biological_process', 'GO:0006351', ('158', '171'))	('cell cycle', 'biological_process', 'GO:0007049', ('241', '251'))	('regulating', 'Reg', (176, 186))	('facilitating', 'PosReg', (140, 152))	('DNA replication', 'CPA', (221, 236))	('lysine', 'Chemical', 'MESH:D008239', (42, 48))	('DNA', 'cellular_component', 'GO:0005574', ('221', '224'))
81114	29650805	Several small molecule inhibitors of BET proteins (BETi) have been developed as potential anti-cancer agents, and some are currently undergoing clinical investigation in various tumor types including melanoma (NCT02259114, NCT02369029, NCT01987362, NCT02683395, NCT01587703; Brand et al, 2015).	('BET', 'Chemical', '-', (37, 40))	('NCT01587703', 'Var', (262, 273))	('BETi', 'Chemical', '-', (51, 55))	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('melanoma', 'Disease', (200, 208))	('NCT02683395', 'Var', (249, 260))	('cancer', 'Disease', (95, 101))	('NCT02259114', 'Var', (210, 221))	('NCT02369029', 'Var', (223, 234))	('BET', 'Chemical', '-', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('NCT01987362', 'Var', (236, 247))
81117	29650805	To identify therapeutic vulnerabilities in NRAS-mutant melanoma, we explored different potential targets for expression in the TCGA skin cutaneous melanoma dataset (SKCM, Provisional 2017; http://www.cbioportal.org) (Cerami et al, 2012; Gao et al, 2013).	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (137, 155))	('NRAS-mutant', 'Var', (43, 54))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 155))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('skin cutaneous melanoma', 'Disease', (132, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
81118	29650805	This analysis revealed that high BRD4 mRNA expression was associated with poor patient survival (P = 0.001; Fig 1A) and disease-free survival (P = 0.0008; Fig EV1) in NRAS-mutant melanoma patients, but not in other genetic cohorts (Appendix Fig S1).	('NRAS-mutant', 'Gene', (167, 178))	('disease-free survival', 'CPA', (120, 141))	('BRD4', 'Gene', (33, 37))	('EV1', 'Gene', (159, 162))	('patient', 'Species', '9606', (188, 195))	('poor', 'NegReg', (74, 78))	('patient survival', 'CPA', (79, 95))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('mRNA expression', 'MPA', (38, 53))	('patients', 'Species', '9606', (188, 196))	('BRD4', 'Gene', '23476', (33, 37))	('patient', 'Species', '9606', (79, 86))	('high', 'Var', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('EV1', 'Gene', '11322', (159, 162))
81120	29650805	To determine the effect of BRD4 blockade, we silenced BRD4 in NRAS-mutant melanoma cells (Appendix Fig S2).	('BRD4', 'Gene', (54, 58))	('silenced', 'Var', (45, 53))	('NRAS-mutant', 'Gene', (62, 73))	('NRAS-mutant', 'Var', (62, 73))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('BRD4', 'Gene', (27, 31))	('BRD4', 'Gene', '23476', (54, 58))	('BRD4', 'Gene', '23476', (27, 31))
81123	29650805	We next evaluated the effect of JQ-1 (a prototype BET inhibitor) on cell viability and determined the half-maximal inhibitory concentration (IC50) of JQ-1 in NRAS-mutant melanoma cells intrinsically resistant to MAPK inhibitors as well as non-transformed cells (Fig 2A and Appendix Table S1).	('NRAS-mutant', 'Gene', (158, 169))	('NRAS-mutant', 'Var', (158, 169))	('JQ-1', 'Gene', (150, 154))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('rat', 'Species', '10116', (133, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('212', '216'))	('BET', 'Chemical', '-', (50, 53))
81124	29650805	JQ-1 decreased the viability of NRAS-mutant melanoma cells; moreover, sensitivity to JQ-1 inversely correlated with BRD4 protein levels (Pearson's correlation coefficient = -0.759, P = 0.018; Figs 2A-C and EV2) but not with BRD2 or BRD3 levels (Fig 2D-H).	('JQ-1', 'Gene', (85, 89))	('BRD2', 'Gene', '6046', (224, 228))	('BRD2', 'Gene', (224, 228))	('viability', 'MPA', (19, 28))	('EV2', 'Gene', '147138', (206, 209))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('EV2', 'Gene', (206, 209))	('melanoma', 'Disease', (44, 52))	('BRD4', 'Gene', (116, 120))	('BRD3', 'Gene', '8019', (232, 236))	('BRD3', 'Gene', (232, 236))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('BRD4', 'Gene', '23476', (116, 120))	('decreased', 'NegReg', (5, 14))	('NRAS-mutant', 'Gene', (32, 43))	('NRAS-mutant', 'Var', (32, 43))
81126	29650805	We selected inhibitors of MEK (PD0325901; PD901), CDK4/6 (PD0332991; PD991), and PI3K (BKM120) (Fig EV2).	('PI3K', 'molecular_function', 'GO:0016303', ('81', '85'))	('PI3K', 'Var', (81, 85))	('MEK', 'Enzyme', (26, 29))	('CDK4/6', 'Gene', (50, 56))	('CDK', 'molecular_function', 'GO:0004693', ('50', '53'))	('PD991', 'Chemical', '-', (69, 74))	('EV2', 'Gene', '147138', (100, 103))	('PD0332991; PD991', 'Var', (58, 74))	('EV2', 'Gene', (100, 103))	('PD0325901; PD901', 'Var', (31, 47))	('PD901', 'Chemical', '-', (42, 47))	('BKM120', 'Chemical', 'MESH:C571178', (87, 93))	('CDK4/6', 'Gene', '1019;1021', (50, 56))	('PD0325901', 'Chemical', 'MESH:C506614', (31, 40))
81131	29650805	While BET or MEK inhibitors predominantly induced cytostatic effects as single agents, the combination of both compounds triggered significant apoptosis selectively in NRAS-mutant melanoma cells without affecting non-transformed cells (Fig EV3D).	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('NRAS-mutant', 'Gene', (168, 179))	('cytostatic effects', 'MPA', (50, 68))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('BET', 'Chemical', '-', (6, 9))	('NRAS-mutant', 'Var', (168, 179))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))
81133	29650805	Combining trametinib with the clinically relevant BETi OTX-015 more potently induced cell death compared to single agents (Appendix Fig S3), further supporting the notion that the combination of BET and MEK inhibitors elicit cytotoxic effects in NRAS-mutant melanoma.	('melanoma', 'Disease', 'MESH:D008545', (258, 266))	('induced', 'Reg', (77, 84))	('cell death', 'CPA', (85, 95))	('cytotoxic effects', 'CPA', (225, 242))	('BET', 'Chemical', '-', (195, 198))	('OTX-015', 'Chemical', 'MESH:C000605331', (55, 62))	('BETi', 'Chemical', '-', (50, 54))	('trametinib', 'Chemical', 'MESH:C560077', (10, 20))	('NRAS-mutant', 'Gene', (246, 257))	('NRAS-mutant', 'Var', (246, 257))	('cell death', 'biological_process', 'GO:0008219', ('85', '95'))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('melanoma', 'Disease', (258, 266))	('BET', 'Chemical', '-', (50, 53))
81134	29650805	In similar experiments, we found that although combining JQ-1 with the CDK4/6 inhibitor, PD991, appeared to be effective in NRAS-mutant melanoma (Fig EV2, and Appendix Fig S4A and B), this combination significantly inhibited the proliferation of non-transformed cells (Appendix Fig S4B).	('EV2', 'Gene', '147138', (150, 153))	('EV2', 'Gene', (150, 153))	('inhibited', 'NegReg', (215, 224))	('PD991', 'Chemical', '-', (89, 94))	('rat', 'Species', '10116', (236, 239))	('CDK4/6', 'Gene', (71, 77))	('NRAS-mutant', 'Gene', (124, 135))	('NRAS-mutant', 'Var', (124, 135))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('CDK4/6', 'Gene', '1019;1021', (71, 77))	('melanoma', 'Disease', (136, 144))	('proliferation of non-transformed cells', 'CPA', (229, 267))	('CDK', 'molecular_function', 'GO:0004693', ('71', '74'))
81138	29650805	We next evaluated the efficacy of BET and MEK inhibitors in 3D collagen-embedded NRAS-mutant melanoma spheroids, as these more closely resemble the behavior of human melanoma in vivo (Smalley et al, 2007, 2008).	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('BET', 'Chemical', '-', (34, 37))	('human', 'Species', '9606', (160, 165))	('collagen', 'molecular_function', 'GO:0005202', ('63', '71'))	('NRAS-mutant', 'Gene', (81, 92))	('NRAS-mutant', 'Var', (81, 92))
81139	29650805	Combined treatment with JQ1 or OTX-015 plus PD901 triggered substantial cell death of NRAS-mutant melanoma spheroids, compared to vehicle or single agent treatments (Fig 3A and B).	('OTX-015', 'Chemical', 'MESH:C000605331', (31, 38))	('PD901', 'Chemical', '-', (44, 49))	('NRAS-mutant', 'Gene', (86, 97))	('NRAS-mutant', 'Var', (86, 97))	('cell death', 'CPA', (72, 82))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('cell death', 'biological_process', 'GO:0008219', ('72', '82'))
81141	29650805	Treatment of M93-047 NRAS-mutant xenografts with vehicle, BETi (JQ-1 or OTX-015), MEKi (PD901), or BETi plus MEKi, demonstrated that BETi/MEKi combinations led to sustained tumor growth inhibition compared to single agents (Fig 3C and D, and Appendix Table S2).	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('combinations', 'Var', (143, 155))	('BETi', 'Chemical', '-', (58, 62))	('OTX-015', 'Chemical', 'MESH:C000605331', (72, 79))	('PD901', 'Chemical', '-', (88, 93))	('NRAS-mutant', 'Gene', (21, 32))	('NRAS-mutant', 'Var', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('rat', 'Species', '10116', (122, 125))	('BETi', 'Chemical', '-', (133, 137))	('BETi', 'Chemical', '-', (99, 103))
81142	29650805	Of note, whereas BETi alone did not prevent tumor growth (Fig 3C and D), the MEKi PD901 decreased tumor growth rate, but this effect was not sustained and tumors resumed growth after 2 weeks of treatment.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD901', 'Chemical', '-', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('decreased', 'NegReg', (88, 97))	('tumor', 'Disease', (98, 103))	('BETi', 'Chemical', '-', (17, 21))	('tumor', 'Disease', (44, 49))	('PD901', 'Gene', (82, 87))	('MEKi', 'Var', (77, 81))
81144	29650805	To better understand the mechanism whereby MEK and BET inhibitors cooperate to inhibit the growth of NRAS-mutant melanoma, we performed RNA-sequencing and proteomic analysis of cells treated with single-agent JQ-1, PD901, or the combination of both drugs.	('inhibit', 'NegReg', (79, 86))	('rat', 'Species', '10116', (71, 74))	('PD901', 'Chemical', '-', (215, 220))	('growth', 'MPA', (91, 97))	('BET', 'Chemical', '-', (51, 54))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('RNA', 'cellular_component', 'GO:0005562', ('136', '139'))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('NRAS-mutant', 'Gene', (101, 112))	('NRAS-mutant', 'Var', (101, 112))
81145	29650805	Differential expression analysis showed that the combination of JQ-1 and PD901 affected 7,909 genes (FDR < 5%) compared to vehicle-treated cells (Fig 4A).	('PD901', 'Chemical', '-', (73, 78))	('combination', 'Var', (49, 60))	('affected', 'Reg', (79, 87))	('PD901', 'Gene', (73, 78))	('JQ-1', 'Var', (64, 68))
81150	29650805	Genes that were synergistically downregulated in response to JQ1/PD901 combination treatment were independently validated by qRT-PCR in two NRAS-mutant patient-derived cell lines (Fig 4C, Appendix Fig S6A and B, and Appendix Table S3), including genes that regulate cell division, DNA replication, and apoptosis (Fig 4C, and Appendix Fig S6A and B).	('apoptosis', 'biological_process', 'GO:0006915', ('302', '311'))	('downregulated', 'NegReg', (32, 45))	('NRAS-mutant', 'Gene', (140, 151))	('NRAS-mutant', 'Var', (140, 151))	('DNA replication', 'biological_process', 'GO:0006260', ('281', '296'))	('DNA', 'cellular_component', 'GO:0005574', ('281', '284'))	('cell division', 'biological_process', 'GO:0051301', ('266', '279'))	('JQ1/PD901', 'Gene', (61, 70))	('PD901', 'Chemical', '-', (65, 70))	('patient', 'Species', '9606', (152, 159))	('apoptosis', 'biological_process', 'GO:0097194', ('302', '311'))
81156	29650805	RPPA analysis also revealed that co-targeting BET and MEK upregulates the pro-apoptotic factor Bim and triggers caspase-7 cleavage (> 1.5-fold; Fig 4D).	('caspase-7', 'Gene', (112, 121))	('caspase-7', 'Gene', '840', (112, 121))	('BET', 'Gene', (46, 49))	('upregulates', 'PosReg', (58, 69))	('triggers', 'Reg', (103, 111))	('BET', 'Chemical', '-', (46, 49))	('MEK', 'Gene', (54, 57))	('co-targeting', 'Var', (33, 45))
81157	29650805	We selected candidates that were found to be markedly and consistently affected by the combination treatment at the mRNA and protein level in all the cell lines evaluated by the two different BET inhibitors for further validation by immunoblotting in a panel of NRAS-mutant cell lines (Fig 4E and Appendix Fig S6E).	('BET', 'Chemical', '-', (192, 195))	('affected', 'Reg', (71, 79))	('NRAS-mutant', 'Gene', (262, 273))	('NRAS-mutant', 'Var', (262, 273))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))
81158	29650805	Activation of the effector caspase-7 was observed in all NRAS-mutant melanoma cell lines following co-inhibition of BET and MEK.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('BET', 'Chemical', '-', (116, 119))	('Activation', 'PosReg', (0, 10))	('caspase-7', 'Gene', (27, 36))	('caspase-7', 'Gene', '840', (27, 36))	('NRAS-mutant', 'Gene', (57, 68))	('NRAS-mutant', 'Var', (57, 68))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
81160	29650805	We noted that TCF19 is expressed in NRAS-mutant melanoma cells and in melanocytes, albeit at lower levels (Fig 5A).	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('TCF19', 'Gene', (14, 19))	('NRAS-mutant', 'Gene', (36, 47))	('NRAS-mutant', 'Var', (36, 47))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('TCF19', 'Gene', '6941', (14, 19))
81161	29650805	Additionally, TCF19 levels positively correlated with BRD4 protein levels and sensitivity to BETi in NRAS-mutant melanoma cells (r = -0.740, P = 0.023; Figs 2A and B, and 5A and B).	('sensitivity', 'MPA', (78, 89))	('BRD4', 'Gene', (54, 58))	('BETi', 'Chemical', '-', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('TCF19', 'Gene', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('BRD4', 'Gene', '23476', (54, 58))	('NRAS-mutant', 'Gene', (101, 112))	('NRAS-mutant', 'Var', (101, 112))	('correlated', 'Reg', (38, 48))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))	('TCF19', 'Gene', '6941', (14, 19))
81162	29650805	We next explored the biological effects of blocking TCF19 in NRAS-mutant cells, as the role of this PHD-type zinc finger-containing domain transcription factor has not been previously investigated in melanoma.	('TCF19', 'Gene', '6941', (52, 57))	('transcription factor', 'molecular_function', 'GO:0000981', ('139', '159'))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('melanoma', 'Disease', (200, 208))	('PHD', 'molecular_function', 'GO:0050175', ('100', '103'))	('blocking', 'NegReg', (43, 51))	('TCF19', 'Gene', (52, 57))	('NRAS-mutant', 'Gene', (61, 72))	('NRAS-mutant', 'Var', (61, 72))
81163	29650805	Depletion of TCF19 with two different shRNA constructs led to an increase of cells in G2/M followed by apoptosis of NRAS-mutant melanoma cells (Fig 5C-E and Appendix Fig S7).	('increase', 'PosReg', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('cells in G2/M', 'CPA', (77, 90))	('NRAS-mutant', 'Var', (116, 127))	('NRAS-mutant', 'Gene', (116, 127))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('TCF19', 'Gene', (13, 18))	('TCF19', 'Gene', '6941', (13, 18))	('apoptosis', 'CPA', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
81167	29650805	Taken together, these results indicate that the combination of BETi/MEKi perturbs the cell cycle machinery and activates apoptotic signaling in NRAS-mutant melanoma cells in part by synergistically downregulating the PHD-type zinc finger domain containing transcription factor TCF19.	('activates', 'PosReg', (111, 120))	('NRAS-mutant', 'Gene', (144, 155))	('NRAS-mutant', 'Var', (144, 155))	('PHD', 'molecular_function', 'GO:0050175', ('217', '220'))	('BETi', 'Chemical', '-', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('TCF19', 'Gene', (277, 282))	('transcription factor', 'molecular_function', 'GO:0000981', ('256', '276'))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('perturbs', 'NegReg', (73, 81))	('transcription', 'biological_process', 'GO:0006351', ('256', '269'))	('downregulating', 'NegReg', (198, 212))	('apoptotic signaling', 'CPA', (121, 140))	('TCF19', 'Gene', '6941', (277, 282))	('cell cycle machinery', 'CPA', (86, 106))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('cell cycle', 'biological_process', 'GO:0007049', ('86', '96'))
81170	29650805	Mutations in NRAS confer both intrinsic and acquired resistance to BRAF and MEK inhibitors (Poulikakos et al, 2011; Boussemart et al, 2016; Fiskus & Mitsiades, 2016).	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (67, 71))
81177	29650805	The BRAFi-resistant tumor, WM3936-1, was derived from a BRAFV600E mutant patient who developed a subcutaneous lesion harboring de novo NRAS (Q61K) and PI3KCA (H1047Y) mutations after 9 months of treatment with the BRAFi dabrafenib (Krepler et al, 2016).	('H1047Y', 'SUBSTITUTION', 'None', (159, 165))	('BRAF', 'Gene', '673', (214, 218))	('NRAS', 'Gene', (135, 139))	('BRAFV600E', 'Mutation', 'rs113488022', (56, 65))	('mutant', 'Var', (66, 72))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', (214, 218))	('H1047Y', 'Var', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('subcutaneous lesion', 'Phenotype', 'HP:0001482', (97, 116))	('patient', 'Species', '9606', (73, 80))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('dabrafenib', 'Chemical', 'MESH:C561627', (220, 230))	('Q61K', 'Mutation', 'rs121913254', (141, 145))	('tumor', 'Disease', (20, 25))	('BRAF', 'Gene', (56, 60))
81183	29650805	In contrast, co-targeting BET and MEK led to a striking reduction in tumor volume, improved animal survival, and decreased expression of TCF19 (Fig 6E and F, and Appendix Fig S9F).	('BET', 'Chemical', '-', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('co-targeting', 'Var', (13, 25))	('improved', 'PosReg', (83, 91))	('expression', 'MPA', (123, 133))	('tumor', 'Disease', (69, 74))	('MEK', 'Var', (34, 37))	('TCF19', 'Gene', (137, 142))	('TCF19', 'Gene', '6941', (137, 142))	('reduction', 'NegReg', (56, 65))	('decreased', 'NegReg', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('animal survival', 'CPA', (92, 107))
81184	29650805	Since TCF19 levels were associated with sensitivity to BET inhibitors (Fig 5B) and patient's survival (Fig 5E), we examined the expression of TCF19 in serial biopsies (pre-treatment, on-treatment, and progression) derived from patients treated with various targeted (BRAFi/MEKi) and/or immunotherapies (e.g., anti-CTLA, anti-PD1, anti-PDL1, IL-2; Appendix Table S5).	('IL-2', 'molecular_function', 'GO:0005134', ('341', '345'))	('associated', 'Reg', (24, 34))	('PDL1', 'Gene', '29126', (335, 339))	('IL-2', 'Gene', '3558', (341, 345))	('anti-CTLA', 'Var', (309, 318))	('TCF19', 'Gene', '6941', (142, 147))	('BET', 'Chemical', '-', (55, 58))	('pre', 'molecular_function', 'GO:0003904', ('168', '171'))	('TCF19', 'Gene', (142, 147))	('TCF19', 'Gene', '6941', (6, 11))	('patients', 'Species', '9606', (227, 235))	('BRAF', 'Gene', '673', (267, 271))	('BRAF', 'Gene', (267, 271))	('TCF19', 'Gene', (6, 11))	('IL-2', 'Gene', (341, 345))	('PDL1', 'Gene', (335, 339))	('patient', 'Species', '9606', (227, 234))	('anti-PD1', 'Var', (320, 328))	('patient', 'Species', '9606', (83, 90))
81187	29650805	Indeed, the combination of OTX-015/PD901 induced substantial apoptosis of short-term cultures derived from immunotherapy-resistant patients (Appendix Table S6), along with inhibition of TCF19 and activation of apoptotic markers (Fig 6H and Appendix Fig S9G).	('patients', 'Species', '9606', (131, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('PD901', 'Chemical', '-', (35, 40))	('apoptosis', 'CPA', (61, 70))	('OTX-015/PD901', 'Var', (27, 40))	('OTX-015', 'Chemical', 'MESH:C000605331', (27, 34))	('TCF19', 'Gene', '6941', (186, 191))	('combination', 'Var', (12, 23))	('apoptotic', 'CPA', (210, 219))	('OTX-015/PD901', 'Gene', (27, 40))	('activation', 'PosReg', (196, 206))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('TCF19', 'Gene', (186, 191))	('inhibition', 'NegReg', (172, 182))
81188	29650805	Altogether our data demonstrate that co-targeting BET and MEK elicits potent anti-tumor effects in highly drug-resistant NRAS-mutant melanoma models and support the premise that BETi/MEKi combinations may be a valuable salvage strategy for MAPK and immune checkpoint inhibitor-resistant tumors (Fig 7).	('BETi', 'Chemical', '-', (178, 182))	('NRAS-mutant', 'Gene', (121, 132))	('NRAS-mutant', 'Var', (121, 132))	('tumor', 'Disease', (82, 87))	('co-targeting', 'Var', (37, 49))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('rat', 'Species', '10116', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('rat', 'Species', '10116', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('MAPK', 'molecular_function', 'GO:0004707', ('240', '244'))	('BET', 'Chemical', '-', (178, 181))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))	('BET', 'Chemical', '-', (50, 53))
81189	29650805	Epigenetic readers, such as BET family proteins, play a key role by binding to chromatin and regulating the transcription of oncogenes and tumor suppressors.	('chromatin', 'Protein', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('binding', 'Interaction', (68, 75))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('transcription', 'biological_process', 'GO:0006351', ('108', '121'))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Epigenetic', 'Var', (0, 10))	('BET', 'Chemical', '-', (28, 31))	('binding', 'molecular_function', 'GO:0005488', ('68', '75'))	('transcription', 'MPA', (108, 121))	('regulating', 'Reg', (93, 103))	('oncogenes', 'Gene', (125, 134))
81195	29650805	We found that genetic silencing of BRD4 or pharmacological inhibition of BET/BRD proteins has mainly cytostatic effects in NRAS-mutant melanoma cells in vitro and minimal effects in vivo.	('cytostatic effects', 'MPA', (101, 119))	('NRAS-mutant', 'Gene', (123, 134))	('NRAS-mutant', 'Var', (123, 134))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('BRD4', 'Gene', '23476', (35, 39))	('BET/BRD', 'Gene', (73, 80))	('BET', 'Chemical', '-', (73, 76))	('proteins', 'Protein', (81, 89))	('genetic silencing', 'Var', (14, 31))	('BRD4', 'Gene', (35, 39))
81196	29650805	However, BETi/MEKi combinations elicit robust anti-tumor effects in NRAS-mutant melanoma.	('NRAS-mutant', 'Var', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('tumor', 'Disease', (51, 56))	('BETi', 'Chemical', '-', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('NRAS-mutant', 'Gene', (68, 79))
81197	29650805	Co-targeting BET and MEK lead to synergistic downregulation of multiple genes that stall the initiation of DNA replication and G2/M cell cycle checkpoint.	('BET', 'Chemical', '-', (13, 16))	('MEK', 'Gene', (21, 24))	('DNA replication', 'biological_process', 'GO:0006260', ('107', '122'))	('Co-targeting', 'Var', (0, 12))	('downregulation', 'NegReg', (45, 59))	('BET', 'Gene', (13, 16))	('DNA', 'cellular_component', 'GO:0005574', ('107', '110'))	('cell cycle checkpoint', 'biological_process', 'GO:0000075', ('132', '153'))
81198	29650805	Our results are consistent with studies in malignant peripheral nerve sheath tumors (MPNST), where a set of 25 genes were similarly downregulated by BETi/MEKi (De Raedt et al, 2014).	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('malignant peripheral nerve sheath tumors', 'Disease', (43, 83))	('BETi/MEKi', 'Var', (149, 158))	('BETi', 'Chemical', '-', (149, 153))	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (43, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('downregulated', 'NegReg', (132, 145))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (43, 83))
81209	29650805	Additionally, combined BET/MEK inhibition synergistically downregulated TCF19 triggering death of therapy-resistant tumor cells.	('BET', 'Chemical', '-', (23, 26))	('TCF19', 'Gene', '6941', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('downregulated', 'NegReg', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibition', 'Var', (31, 41))	('TCF19', 'Gene', (72, 77))	('tumor', 'Disease', (116, 121))
81231	29650805	Small molecule inhibitors were purchased from Selleckchem (Houston, TX; PD0325901 (S1036), PD033991 (S1579), BKM-120 (S2247), or MedChemExpress (Monmouth Junction, NJ; OTX-015 (HY-15743).	('PD0325901', 'Chemical', 'MESH:C506614', (72, 81))	('S1579', 'Var', (101, 106))	('OTX-015', 'Chemical', 'MESH:C000605331', (168, 175))	('S1036', 'Var', (83, 88))	('S2247', 'Var', (118, 123))
81235	29650805	mRNA expression of BRD4, BRD3, and BRD2 for NRAS (n = 98), BRAF (n = 188), NF1 (n = 47) mutant, and WT/WT/WT (n = 170) melanoma samples were downloaded and stratified into two groups (BRD-low or BRD-high) according to the median tissue mRNA expression levels.	('BRD4', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('NF1', 'Gene', (75, 78))	('NRAS', 'Gene', (44, 48))	('NF1', 'Gene', '4763', (75, 78))	('mRNA expression', 'MPA', (0, 15))	('melanoma', 'Disease', (119, 127))	('BRD3', 'Gene', (25, 29))	('BRD2', 'Gene', (35, 39))	('mutant', 'Var', (88, 94))	('BRAF', 'Gene', (59, 63))	('BRD4', 'Gene', '23476', (19, 23))	('BRD2', 'Gene', '6046', (35, 39))	('BRD3', 'Gene', '8019', (25, 29))	('BRAF', 'Gene', '673', (59, 63))	('rat', 'Species', '10116', (158, 161))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))
81294	29650805	The Wistar Institute: https://www.wistar.org  MRF: https://www.melanoma.org  MRA: https://www.curemelanoma.org   https://www.inspire.com/groups/melanoma-exchange/  ACS: https://www.cancer.org/cancer/melanoma-skin-cancer.html  The V Foundation for Cancer Research: https://www.jimmyv.org   http://Clinicaltrials.org  While treatment of melanoma has been transformed by new targeted and immunotherapies, thus far there are no approved targeted therapies for nearly 30% of melanomas harboring NRAS mutations.	('melanoma-exchange', 'Disease', 'MESH:D008545', (144, 161))	('mutations', 'Var', (495, 504))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('melanoma', 'Disease', (144, 152))	('curemelanoma', 'Disease', (94, 106))	('melanoma', 'Phenotype', 'HP:0002861', (335, 343))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('melanoma', 'Disease', (335, 343))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Disease', (63, 71))	('melanomas', 'Disease', 'MESH:D008545', (470, 479))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ACS', 'molecular_function', 'GO:0043884', ('164', '167'))	('MRF', 'Gene', '745', (46, 49))	('melanomas', 'Disease', (470, 479))	('Cancer', 'Phenotype', 'HP:0002664', (247, 253))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('cancer', 'Disease', (213, 219))	('RA', 'Disease', 'MESH:D001172', (491, 493))	('melanoma', 'Disease', 'MESH:D008545', (470, 478))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Cancer', 'Disease', (247, 253))	('RA', 'Disease', 'MESH:D001172', (78, 80))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('melanomas', 'Phenotype', 'HP:0002861', (470, 479))	('ACS', 'molecular_function', 'GO:0003987', ('164', '167'))	('melanoma', 'Disease', 'MESH:D008545', (335, 343))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('cancer', 'Disease', (181, 187))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('curemelanoma', 'Disease', 'None', (94, 106))	('MRF', 'Gene', (46, 49))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('melanoma-exchange', 'Disease', (144, 161))	('Cancer', 'Disease', 'MESH:D009369', (247, 253))	('melanoma-skin-cancer', 'Disease', 'MESH:D012878', (199, 219))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('melanoma-skin-cancer', 'Disease', (199, 219))	('melanoma', 'Disease', (470, 478))
81297	29650805	Furthermore, high levels of BRD4 are associated with poor outcome in NRASMut melanoma patients.	('high levels', 'Var', (13, 24))	('BRD4', 'Gene', '23476', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('BRD4', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('NRASMut', 'Disease', (69, 76))	('patients', 'Species', '9606', (86, 94))
81298	29650805	We demonstrate that co-targeting BET and MEK synergistically restrains tumor growth and prolongs the survival of NRASMut tumor-bearing mice with no overt toxicity.	('toxicity', 'Disease', 'MESH:D064420', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('toxicity', 'Disease', (154, 162))	('co-targeting', 'Var', (20, 32))	('MEK', 'Gene', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (121, 126))	('restrains', 'NegReg', (61, 70))	('prolongs', 'PosReg', (88, 96))	('rat', 'Species', '10116', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('BET', 'Gene', (33, 36))	('mice', 'Species', '10090', (135, 139))	('survival', 'CPA', (101, 109))	('tumor', 'Disease', (71, 76))	('BET', 'Chemical', '-', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
81299	29650805	Transcriptomic analysis revealed that co-treatment with BET and MEK inhibitors mitigated a transcriptional signature associated with innate resistance to immune checkpoint and targeted inhibitors.	('mitigated', 'NegReg', (79, 88))	('MEK', 'Gene', (64, 67))	('transcriptional signature', 'MPA', (91, 116))	('inhibitors', 'Var', (68, 78))	('BET', 'Chemical', '-', (56, 59))
81300	29650805	Accordingly, BETi/MEKi combinations inhibited the growth of anti-PD1- and BRAFi/MEKi-resistant tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('growth', 'MPA', (50, 56))	('inhibited', 'NegReg', (36, 45))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BETi', 'Chemical', '-', (13, 17))	('tumors', 'Disease', (95, 101))	('combinations', 'Var', (23, 35))
81302	29650805	We further discovered that co-targeting BET and MEK downregulates TCF19 and that this transcription factor is required for melanoma cell survival.	('transcription factor', 'molecular_function', 'GO:0000981', ('86', '106'))	('BET', 'Chemical', '-', (40, 43))	('TCF19', 'Gene', '6941', (66, 71))	('transcription', 'biological_process', 'GO:0006351', ('86', '99'))	('co-targeting', 'Var', (27, 39))	('BET', 'Gene', (40, 43))	('MEK', 'Gene', (48, 51))	('downregulates', 'NegReg', (52, 65))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Disease', (123, 131))	('TCF19', 'Gene', (66, 71))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))
81305	28497782	RAF proteins exert both specific and compensatory functions during tumour progression of NRAS-driven melanoma NRAS and its effector BRAF are frequently mutated in melanoma.	('RAF', 'Gene', '387609', (133, 136))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('RAF', 'Gene', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('mutated', 'Var', (152, 159))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', (163, 171))	('tumour', 'Disease', (67, 73))	('RAF', 'Gene', '387609', (0, 3))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('NRAS', 'Gene', '18176', (89, 93))	('NRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (110, 114))	('NRAS', 'Gene', '18176', (110, 114))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('RAF', 'Gene', (133, 136))
81307	28497782	Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance.	('Raf', 'Gene', '387609', (36, 39))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('mouse', 'Species', '10090', (62, 67))	('tumour', 'Disease', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('ablation', 'Var', (24, 32))	('Raf', 'Gene', (36, 39))	('benign tumours to malignant tumour', 'Disease', 'MESH:C535700', (160, 194))	('benign tumours to malignant tumour', 'Disease', (160, 194))
81311	28497782	The melanoma-driver mutations in NRAS and BRAF are mutually exclusive but the contribution of RAF signalling downstream of NRAS remains to be clarified.	('melanoma-driver', 'Disease', (4, 19))	('NRAS', 'Gene', (33, 37))	('signalling', 'biological_process', 'GO:0023052', ('98', '108'))	('melanoma-driver', 'Disease', 'MESH:D008545', (4, 19))	('BRAF', 'Gene', (42, 46))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('mutations', 'Var', (20, 29))
81314	28497782	Activation of the RAS/RAF/MEK/ERK signalling pathway is found in the vast majority of melanomas and often occurs through mutations of either NRAS or BRAF (15-20% and 40-50% cutaneous melanomas, respectively).	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('mutations', 'Var', (121, 130))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (173, 192))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (173, 192))	('MEK', 'Gene', '17242', (26, 29))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (173, 191))	('BRAF', 'Gene', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('Activation', 'PosReg', (0, 10))	('ERK', 'molecular_function', 'GO:0004707', ('30', '33'))	('melanomas', 'Disease', (183, 192))	('signalling pathway', 'biological_process', 'GO:0007165', ('34', '52'))	('cutaneous melanomas', 'Disease', (173, 192))	('MEK', 'Gene', (26, 29))	('NRAS', 'Gene', (141, 145))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanomas', 'Disease', (86, 95))
81315	28497782	These driver mutations represent a very early event found in benign melanocytic lesions, called nevi, and are maintained throughout all stages of invasive and metastatic melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('benign melanocytic lesions', 'Disease', (61, 87))	('benign melanocytic lesions', 'Phenotype', 'HP:0000995', (61, 87))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('nevi', 'Disease', (96, 100))	('benign melanocytic lesions', 'Disease', 'MESH:D009508', (61, 87))	('mutations', 'Var', (13, 22))	('nevi', 'Phenotype', 'HP:0003764', (96, 100))
81318	28497782	In addition, such compounds cannot be used to treat half of melanoma patients, especially those harbouring NRAS mutations, since BRAF inhibitors paradoxically activate the MAPK/ERK pathway in BRAF wild-type cells.	('ERK', 'molecular_function', 'GO:0004707', ('177', '180'))	('MAPK', 'molecular_function', 'GO:0004707', ('172', '176'))	('BRAF', 'Gene', (129, 133))	('inhibitors', 'Var', (134, 144))	('activate', 'PosReg', (159, 167))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutations', 'Var', (112, 121))	('melanoma', 'Disease', (60, 68))	('patients', 'Species', '9606', (69, 77))	('MAPK/ERK pathway', 'Pathway', (172, 188))	('NRAS', 'Gene', (107, 111))
81319	28497782	Indeed, BRAFV600E and NRAS mutations, although mutually exclusive, are not strictly equivalent and the contribution of RAF signalling downstream of NRAS remained to be clarified.	('BRAFV600E', 'Var', (8, 17))	('BRAFV600E', 'Mutation', 'rs113488022', (8, 17))	('signalling', 'biological_process', 'GO:0023052', ('123', '133'))	('NRAS', 'Gene', (22, 26))
81320	28497782	Despite much attention being focused on BRAF mutant melanoma, NRAS was the first melanoma oncogene to be identified, and mutations in NRAS, KRAS and HRAS are present in about 20, 2 and 1% of all melanomas, respectively.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('mutant', 'Var', (45, 51))	('melanoma', 'Disease', (52, 60))	('mutations', 'Var', (121, 130))	('melanomas', 'Disease', (195, 204))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('HRAS', 'Gene', (149, 153))	('melanoma', 'Disease', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('NRAS', 'Gene', (134, 138))	('melanomas', 'Disease', 'MESH:D008545', (195, 204))	('melanoma', 'Disease', (195, 203))	('KRAS', 'Gene', (140, 144))
81326	28497782	However, paradoxical activation of the MAPK/ERK pathway by BRAF inhibitors is observed in NRAS-mutated melanoma and results from the recruitment of inhibited BRAF at the membrane where it acts as a scaffold to enhance CRAF activity.	('CRAF activity', 'CPA', (218, 231))	('NRAS-mutated', 'Disease', (90, 102))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('MAPK/ERK pathway', 'Pathway', (39, 55))	('enhance', 'PosReg', (210, 217))	('inhibitors', 'Var', (64, 74))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('BRAF', 'Gene', (59, 63))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('membrane', 'cellular_component', 'GO:0016020', ('170', '178'))	('activation', 'PosReg', (21, 31))	('inhibited', 'NegReg', (148, 157))	('melanoma', 'Disease', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('CRAF', 'molecular_function', 'GO:0004709', ('218', '222'))	('BRAF', 'Protein', (158, 162))
81335	28497782	In contrast, concomitant ablation of both BRAF and CRAF resulted in a complete blockage of tumour growth.	('tumour growth', 'Disease', 'MESH:D006130', (91, 104))	('CRAF', 'molecular_function', 'GO:0004709', ('51', '55'))	('ablation', 'Var', (25, 33))	('blockage', 'NegReg', (79, 87))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('tumour growth', 'Disease', (91, 104))
81339	28497782	Constitutive expression of an activated form of human NRAS (NRASQ61K) in the melanocytic lineage results in spontaneous cutaneous melanoma development, a process that is accelerated on an Ink4a-deficient background.	('NRASQ61K', 'Var', (60, 68))	('results in', 'Reg', (97, 107))	('human', 'Species', '9606', (48, 53))	('NRAS', 'Gene', (54, 58))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))
81343	28497782	In agreement with previous reports, Tyr::NRASQ61K/o;Ink4a+/- control mice, when compared to wild-type mice, rapidly started to develop a highly hyperpigmented phenotype within the first week, which was remarkable on dorsal skin after depilation at 6 months (Fig.	('develop', 'PosReg', (127, 134))	('mice', 'Species', '10090', (102, 106))	('hyperpigmented phenotype', 'Phenotype', 'HP:0000953', (144, 168))	('Tyr', 'Chemical', 'MESH:D014443', (36, 39))	('mice', 'Species', '10090', (69, 73))	(':NRASQ61K/o', 'Var', (40, 51))
81346	28497782	Importantly, staining for beta-galactosidase activity on dorsal skin from newborn (P0.5) animals indicated that NRASQ61K did not affect the normal development of the melanocytic lineage before birth (Supplementary Fig.	('NRASQ61K', 'Var', (112, 120))	('beta-galactosidase', 'Gene', (26, 44))	('beta-galactosidase', 'Gene', '12091', (26, 44))	('affect', 'Reg', (129, 135))	('beta-galactosidase activity', 'molecular_function', 'GO:0004565', ('26', '53'))
81349	28497782	Deletion of both BRAF and CRAF upon Cre expression in melanocytic cells induced a complete reversion of the hyperpigmented phenotype since double KO mice were indistinguishable from wild-type mice with a normal light skin (Fig.	('mice', 'Species', '10090', (192, 196))	('hyperpigmented phenotype', 'Phenotype', 'HP:0000953', (108, 132))	('light skin', 'Phenotype', 'HP:0001010', (211, 221))	('CRAF', 'molecular_function', 'GO:0004709', ('26', '30'))	('BRAF', 'Gene', (17, 21))	('mice', 'Species', '10090', (149, 153))	('CRAF', 'Gene', (26, 30))	('Deletion', 'Var', (0, 8))
81357	28497782	In contrast, BRAF deletion resulted in a pigmentation pattern similar to that of double KO or wild-type mice.	('pigmentation pattern', 'MPA', (41, 61))	('mice', 'Species', '10090', (104, 108))	('BRAF', 'Gene', (13, 17))	('resulted in', 'Reg', (27, 38))	('pigmentation', 'biological_process', 'GO:0043473', ('41', '53'))	('deletion', 'Var', (18, 26))
81366	28497782	In all, 53.5% of Tyr::NRASQ61K/o;Ink4a+/- control mice (31 out of 58) developed melanoma with an average latency of 10.8+-2.7 months (Fig.	(':NRASQ61K/o', 'Var', (21, 32))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('developed', 'PosReg', (70, 79))	('mice', 'Species', '10090', (50, 54))	('Tyr', 'Chemical', 'MESH:D014443', (17, 20))
81367	28497782	No tumour was observed in BRAF KO and BRAF/CRAF KO mice, in agreement with the lack of hyperpigmented phenotype upon early BRAF deletion, thereby confirming the requirement of BRAF for tumour initiation.	('tumour initiation', 'Disease', (185, 202))	('mice', 'Species', '10090', (51, 55))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('BRAF', 'Gene', (123, 127))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('hyperpigmented phenotype', 'Phenotype', 'HP:0000953', (87, 111))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('tumour', 'Disease', (3, 9))	('CRAF', 'molecular_function', 'GO:0004709', ('43', '47'))	('tumour initiation', 'Disease', 'MESH:D009369', (185, 202))	('tumour', 'Disease', (185, 191))	('deletion', 'Var', (128, 136))
81369	28497782	The lower incidence and longer latency compared to control mice could be either in favour of a role for CRAF in tumour growth or due to the mild effect of its early deletion on hyperpigmentation and nevi appearance as described above.	('nevi', 'CPA', (199, 203))	('tumour growth', 'Disease', 'MESH:D006130', (112, 125))	('mice', 'Species', '10090', (59, 63))	('hyperpigmentation', 'Disease', 'MESH:D017495', (177, 194))	('hyperpigmentation', 'Disease', (177, 194))	('CRAF', 'molecular_function', 'GO:0004709', ('104', '108'))	('deletion', 'Var', (165, 173))	('nevi', 'Phenotype', 'HP:0003764', (199, 203))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour growth', 'Disease', (112, 125))
81381	28497782	Cell cycle analyses revealed that BRAF and CRAF double KO cells accumulated into G0/G1 phase resulting in a fewer proportion of cells in S-phase compared to dimethylsulphoxide (DMSO)-treated samples (Fig.	('G1 phase', 'biological_process', 'GO:0051318', ('84', '92'))	('DMSO', 'Chemical', 'MESH:D004121', (177, 181))	('fewer', 'NegReg', (108, 113))	('dimethylsulphoxide', 'Chemical', 'MESH:D004121', (157, 175))	('CRAF', 'molecular_function', 'GO:0004709', ('43', '47'))	('double KO', 'Var', (48, 57))	('accumulated', 'PosReg', (64, 75))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('S-phase', 'biological_process', 'GO:0051320', ('137', '144'))
81382	28497782	Taken together, these results demonstrated that the RAF/MAPK pathway is absolutely required for NRASQ61K-driven tumour growth in melanoma.	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('tumour growth in melanoma', 'Disease', (112, 137))	('NRASQ61K-driven', 'Var', (96, 111))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('tumour growth in melanoma', 'Disease', 'MESH:D008545', (112, 137))
81386	28497782	CRAF depletion reproducibly induced a very weak effect on tumour growth and a mild slowdown of cell proliferation (Fig.	('cell proliferation', 'CPA', (95, 113))	('depletion', 'Var', (5, 14))	('CRAF', 'molecular_function', 'GO:0004709', ('0', '4'))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour growth', 'Disease', (58, 71))	('slowdown', 'NegReg', (83, 91))	('tumour growth', 'Disease', 'MESH:D006130', (58, 71))
81401	28497782	Our observations in the mouse model being in apparent discrepancy with these conclusions, we re-investigated the respective functions of BRAF and CRAF by using RNA interference experiments in three human melanoma cell lines harbouring NRAS mutations: WM1361 (NRASQ61K), WM852 (NRASQ61R) and Sbcl2 (NRASQ61K).	('CRAF', 'molecular_function', 'GO:0004709', ('146', '150'))	('mouse', 'Species', '10090', (24, 29))	('Sbcl2', 'Chemical', '-', (291, 296))	('RNA interference', 'biological_process', 'GO:0016246', ('160', '176'))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('RNA', 'cellular_component', 'GO:0005562', ('160', '163'))	('melanoma', 'Disease', (204, 212))	('NRASQ61K', 'Var', (298, 306))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('WM852 (NRASQ61R', 'Var', (270, 285))	('human', 'Species', '9606', (198, 203))	('WM1361 (NRASQ61K', 'Var', (251, 267))	('WM1361', 'CellLine', 'CVCL:6788', (251, 257))
81403	28497782	Taken together, these results indicated that when CRAF is knocked down in NRAS-mutated human melanoma cell lines, BRAF is able to compensate to maintain MAPK activation and proliferation.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('MAPK activation', 'biological_process', 'GO:0000187', ('153', '168'))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('human', 'Species', '9606', (87, 92))	('knocked', 'Var', (58, 65))	('activation', 'PosReg', (158, 168))	('proliferation', 'CPA', (173, 186))	('MAPK', 'molecular_function', 'GO:0004707', ('153', '157'))	('CRAF', 'molecular_function', 'GO:0004709', ('50', '54'))	('MAPK', 'Protein', (153, 157))
81405	28497782	Therefore, the compensatory effects of RAF kinases is a conserved mechanism between human and murine NRAS-driven melanoma, since neither CRAF, nor BRAF loss alone is sufficient to block melanoma cell proliferation in both species.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma', 'Disease', (186, 194))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('melanoma', 'Disease', 'MESH:D008545', (186, 194))	('CRAF', 'molecular_function', 'GO:0004709', ('137', '141'))	('block melanoma', 'Disease', 'MESH:D008545', (180, 194))	('loss', 'Var', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('BRAF', 'Gene', (147, 151))	('melanoma', 'Disease', (113, 121))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('human', 'Species', '9606', (84, 89))	('block melanoma', 'Disease', (180, 194))	('murine', 'Species', '10090', (94, 100))
81415	28497782	In a clinical perspective, it is widely acknowledged that paradoxical ERK activation by RAF inhibitors in non-BRAF-mutated cancer cells mostly relies on BRAF and CRAF dimerization.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inhibitors', 'Var', (92, 102))	('ERK', 'Enzyme', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('activation', 'PosReg', (74, 84))	('cancer', 'Disease', (123, 129))	('RAF', 'Gene', (88, 91))	('ERK', 'molecular_function', 'GO:0004707', ('70', '73'))	('CRAF', 'molecular_function', 'GO:0004709', ('162', '166'))
81419	28497782	Aberrant RAS activation plays causal role in human cancer with an estimated 30% of human tumours harbouring somatic oncogenic mutations mainly in KRAS, but also in NRAS and HRAS.	('NRAS', 'Disease', (164, 168))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('human', 'Species', '9606', (83, 88))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('human', 'Species', '9606', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (126, 135))	('KRAS', 'Disease', (146, 150))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
81420	28497782	NRAS mutations occur in ~20% of human cutaneous melanomas, while HRAS and KRAS mutations are rare in this disease.	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('cutaneous melanomas', 'Disease', (38, 57))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('human', 'Species', '9606', (32, 37))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (38, 57))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (38, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))
81424	28497782	Likewise, once melanoma have developed, tamoxifen-induced deletion of both kinases completely blocked tumour growth in vivo and cell proliferation in vitro, the latter being associated with a strong impairment in ERK activation and cell cycle arrest.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour growth', 'Disease', 'MESH:D006130', (102, 115))	('impairment', 'NegReg', (199, 209))	('activation', 'MPA', (217, 227))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('ERK', 'Pathway', (213, 216))	('melanoma', 'Disease', (15, 23))	('tamoxifen', 'Chemical', 'MESH:D013629', (40, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (232, 249))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('ERK', 'molecular_function', 'GO:0004707', ('213', '216'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('232', '249'))	('cell proliferation', 'CPA', (128, 146))	('deletion', 'Var', (58, 66))	('cell cycle arrest', 'CPA', (232, 249))	('blocked', 'NegReg', (94, 101))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))	('tumour growth', 'Disease', (102, 115))
81427	28497782	NRAS mutant melanomas rarely harbour either mutations in, or silencing of the negative regulator of the PI3K pathway, phosphatase and tensin homologue and exhibit lower levels of constitutive AKT signalling than those with BRAF mutations.	('AKT', 'Gene', (192, 195))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('PI3K', 'molecular_function', 'GO:0016303', ('104', '108'))	('signalling', 'biological_process', 'GO:0023052', ('196', '206'))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('phosphatase', 'molecular_function', 'GO:0016791', ('118', '129'))	('silencing', 'NegReg', (61, 70))	('AKT', 'Gene', '11651', (192, 195))	('mutations', 'Var', (44, 53))	('mutant', 'Var', (5, 11))	('NRAS', 'Gene', (0, 4))	('lower', 'NegReg', (163, 168))	('melanomas', 'Disease', (12, 21))
81428	28497782	Whatever the level of contribution of these signalling pathways in RAS-induced melanoma, our results demonstrate that the RAF/MEK/ERK pathway is absolutely required downstream of NRASQ61K from initiation to tumour maintenance.	('tumour', 'Disease', (207, 213))	('ERK', 'molecular_function', 'GO:0004707', ('130', '133'))	('signalling', 'biological_process', 'GO:0023052', ('44', '54'))	('MEK', 'Gene', (126, 129))	('NRASQ61K', 'Var', (179, 187))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('MEK', 'Gene', '17242', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
81433	28497782	The role of ARAF in NRAS-induced melanoma has not been a matter of intense investigation mainly because of the well-described paradoxical effects of RAF inhibitors in RAS-mutated tumours, which is thought to rely mostly on BRAF and CRAF dimerization.	('inhibitors', 'Var', (153, 163))	('effects', 'Reg', (138, 145))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('tumours', 'Phenotype', 'HP:0002664', (179, 186))	('melanoma', 'Disease', (33, 41))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('RAF', 'Protein', (149, 152))	('CRAF', 'molecular_function', 'GO:0004709', ('232', '236'))	('tumours', 'Disease', 'MESH:D009369', (179, 186))	('tumours', 'Disease', (179, 186))
81436	28497782	The potential role of ARAF in NRAS-induced melanoma is further reinforced by an in silico search in public databases that allowed us to identify patients with metastatic melanomas harbouring an ARAF mutation associated with activating NRAS mutations (Supplementary Fig.	('patients', 'Species', '9606', (145, 153))	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('ARAF', 'Gene', (194, 198))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('NRAS', 'Gene', (235, 239))	('activating', 'PosReg', (224, 234))	('mutation', 'Var', (199, 207))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('melanomas', 'Disease', (170, 179))	('mutations', 'Var', (240, 249))
81437	28497782	This activating ARAFS214F mutation has been very recently identified in lung adenocarcinomas, but to our knowledge, this is the first time that it is detected in melanoma and found specifically associated with an NRAS mutation.	('activating', 'PosReg', (5, 15))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('NRAS', 'Disease', (213, 217))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('mutation', 'Var', (26, 34))	('lung adenocarcinomas', 'Disease', (72, 92))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (72, 92))	('associated', 'Reg', (194, 204))	('ARAFS214F', 'Mutation', 'rs1057519786', (16, 25))	('ARAFS214F', 'Gene', (16, 25))
81447	28497782	Taken together, our results demonstrate that only BRAF is necessary during the early stages of NRAS-induced melanomagenesis, thereby revealing a specific function for BRAF in tumour initiation that cannot be compensated by ARAF and CRAF.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('tumour initiation', 'Disease', (175, 192))	('BRAF', 'Var', (167, 171))	('CRAF', 'molecular_function', 'GO:0004709', ('232', '236'))	('tumour initiation', 'Disease', 'MESH:D009369', (175, 192))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('melanoma', 'Disease', (108, 116))
81449	28497782	CreERT2-induced floxed Braf allele recombination was efficiently achieved in primary tumours grafted in nude mice or cultured in vitro.	('primary tumours', 'Disease', (77, 92))	('Braf', 'Gene', '109880', (23, 27))	('primary tumours', 'Disease', 'MESH:D009369', (77, 92))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('Braf', 'Gene', (23, 27))	('floxed', 'Var', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('nude mice', 'Species', '10090', (104, 113))
81454	28497782	However, the effects of single CRAF deletion were very weak compared to that of the double BRAF/CRAF KO, and far from sufficient to block tumour growth, clearly indicating a compensatory effect implicating BRAF.	('CRAF', 'molecular_function', 'GO:0004709', ('96', '100'))	('CRAF', 'molecular_function', 'GO:0004709', ('31', '35'))	('block tumour growth', 'Disease', (132, 151))	('deletion', 'Var', (36, 44))	('block tumour growth', 'Disease', 'MESH:D006130', (132, 151))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))
81461	28497782	Another mouse model of RAS-driven skin carcinogenesis revealed that BRAF or CRAF ablation in keratinocytes prevented tumoral initiation and maintenance but through different mechanisms, BRAF being necessary for ERK activation and proliferation and CRAF for inhibition of keratinocyte differentiation.	('CRAF', 'molecular_function', 'GO:0004709', ('76', '80'))	('ERK', 'molecular_function', 'GO:0004707', ('211', '214'))	('skin carcinogenesis', 'Disease', (34, 53))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('prevented', 'NegReg', (107, 116))	('ablation', 'Var', (81, 89))	('tumoral initiation', 'Disease', (117, 135))	('keratinocyte differentiation', 'CPA', (271, 299))	('tumoral initiation', 'Disease', 'MESH:D009369', (117, 135))	('inhibition of keratinocyte differentiation', 'biological_process', 'GO:0045617', ('257', '299'))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (34, 53))	('mouse', 'Species', '10090', (8, 13))	('CRAF', 'molecular_function', 'GO:0004709', ('248', '252'))
81490	28497782	Primary tumour tissue was dissected from melanoma-bearing Braf+/+;Craff/f;Tyr::NRASQ61K/o;Ink4a+/-;Tyr::CreERT2/o, Braff/f;Craf+/+;Tyr::NRASQ61K/o;Ink4a+/-;Tyr::CreERT2/o or Braff/f;Craff/f; Tyr::NRASQ61K/o;Ink4a+/-;Tyr::CreERT2/o mice and cut into small pieces.	('Craf', 'Gene', '110157', (66, 70))	('Tyr', 'Chemical', 'MESH:D014443', (156, 159))	('Tyr', 'Chemical', 'MESH:D014443', (99, 102))	('Braf', 'Gene', '109880', (115, 119))	('Primary tumour', 'Disease', (0, 14))	('Craf', 'molecular_function', 'GO:0004709', ('123', '127'))	('Tyr', 'Chemical', 'MESH:D014443', (131, 134))	('Tyr', 'Chemical', 'MESH:D014443', (74, 77))	('Braf', 'Gene', '109880', (58, 62))	('Craf', 'Gene', (182, 186))	('Braf', 'Gene', (174, 178))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('Tyr', 'Chemical', 'MESH:D014443', (216, 219))	('Craf', 'Gene', '110157', (182, 186))	('Craf', 'Gene', (123, 127))	('Craf', 'Gene', '110157', (123, 127))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('Tyr', 'Chemical', 'MESH:D014443', (191, 194))	('Ink4a+/-', 'Var', (207, 215))	('mice', 'Species', '10090', (231, 235))	('Braf', 'Gene', (115, 119))	('Braf', 'Gene', '109880', (174, 178))	('Craf', 'Gene', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('Primary tumour', 'Disease', 'MESH:D009369', (0, 14))	('Braf', 'Gene', (58, 62))
81520	22472884	ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression.	('ASS', 'Gene', (98, 101))	('PEG20', 'Chemical', 'MESH:C000595209', (4, 9))	('ADI-PEG20', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('tumour', 'Disease', (78, 84))	('melanoma', 'Disease', (54, 62))	('patients', 'Species', '9606', (63, 71))	('ASS', 'Gene', '445', (98, 101))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
81531	22472884	Inclusion criteria included: (1) histologically confirmed metastatic melanoma, (2) unresectable and measurable/evaluable disease, (3) progressive disease after chemotherapy, radiotherapy, surgery or immunotherapy, no longer responding to standard therapy or have refused standard therapy, (4) been off previous treatment for at least 4 weeks, (5) fully recovered from prior surgery, (6) age >=18 years old, (7) KPS >=70, (8) expected survival of >=l2 weeks, (9) absolute neutrophil count >1500 per mul, platelets >100 000 per mul, serum bilirubin <=3 mg dl-1, albumin >3 g dl-1, alkaline phosphatase <5 x ULN, glucose >60 mg dl-1, amylase <1.5 x ULN, (10) signed an IRB approved informed consent, and (11) not enroled in other IND studies.	('dl-1', 'Gene', (625, 629))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('>100 000', 'Var', (513, 521))	('dl-1', 'Gene', '28514', (625, 629))	('dl-1', 'Gene', (573, 577))	('dl-1', 'Gene', '28514', (573, 577))	('phosphatase', 'molecular_function', 'GO:0016791', ('588', '599'))	('>1500', 'Var', (488, 493))	('serum bilirubin', 'MPA', (531, 546))	('dl-1', 'Gene', (554, 558))	('dl-1', 'Gene', '28514', (554, 558))	('albumin', 'MPA', (560, 567))	('alkaline phosphatase', 'MPA', (579, 599))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
81579	22472884	Interestingly, two patients who were ASS negative by immunohistochemistry and RT-PCR at the start of therapy had a response to ADI-PEG20.	('response', 'MPA', (115, 123))	('patients', 'Species', '9606', (19, 27))	('ADI-PEG20', 'Var', (127, 136))	('PEG20', 'Chemical', 'MESH:C000595209', (131, 136))	('ASS', 'Gene', (37, 40))	('ASS', 'Gene', '445', (37, 40))
81581	22472884	The first patient had lung metastases and had a PR to ADI-PEG20.	('patient', 'Species', '9606', (10, 17))	('lung metastases', 'Disease', (22, 37))	('PEG20', 'Chemical', 'MESH:C000595209', (58, 63))	('lung metastases', 'Disease', 'MESH:D009362', (22, 37))	('ADI-PEG20', 'Var', (54, 63))
81601	22472884	Taken altogether, the data suggest that a higher dose of ADI-PEG20 may be needed to keep arginine levels down in the long term.	('arginine levels', 'MPA', (89, 104))	('arginine', 'Chemical', 'MESH:D001120', (89, 97))	('PEG20', 'Chemical', 'MESH:C000595209', (61, 66))	('ADI-PEG20', 'Var', (57, 66))
81613	22472884	In this regard, we plan a follow-up study in which only advanced melanoma patients whose tumours are ASS negative will be treated with ADI-PEG20 at 320 IU m-2.	('ASS', 'Gene', '445', (101, 104))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (74, 82))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumours', 'Disease', (89, 96))	('ASS', 'Gene', (101, 104))	('ADI-PEG20 at', 'Var', (135, 147))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('PEG20', 'Chemical', 'MESH:C000595209', (139, 144))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
81615	22472884	Currently, there are clinical trials in progress with ADI-PEG20 in hepatocellular carcinoma, small-cell lung carcinoma and mesothelioma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('PEG20', 'Chemical', 'MESH:C000595209', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('small-cell lung carcinoma and mesothelioma', 'Disease', 'MESH:D055752', (93, 135))	('ADI-PEG20', 'Var', (54, 63))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (93, 118))
81617	22472884	However, given our experience in melanoma patients with ADI-PEG20 and the scientific rationale for depleting arginine with this agent, it seems logical to target only patients with ASS-negative deficiency.	('PEG20', 'Chemical', 'MESH:C000595209', (60, 65))	('ASS', 'Gene', (181, 184))	('ASS', 'Gene', '445', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('patients', 'Species', '9606', (167, 175))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('ADI-PEG20', 'Var', (56, 65))	('depleting', 'NegReg', (99, 108))	('patients', 'Species', '9606', (42, 50))	('arginine', 'Chemical', 'MESH:D001120', (109, 117))
81618	22472884	Another important observation from our trial is that the dose of ADI-PEG20 used to deplete arginine may be important for response.	('ADI-PEG20', 'Var', (65, 74))	('arginine', 'Chemical', 'MESH:D001120', (91, 99))	('deplete arginine', 'MPA', (83, 99))	('PEG20', 'Chemical', 'MESH:C000595209', (69, 74))
81624	22472884	The incidence of ASS expression was similar at both doses of ADI-PEG20.	('ASS', 'Gene', (17, 20))	('ADI-PEG20', 'Var', (61, 70))	('ASS', 'Gene', '445', (17, 20))	('PEG20', 'Chemical', 'MESH:C000595209', (65, 70))
81629	22472884	Taken together, the data suggest that higher doses of ADI-PEG20 than the OBD may be needed in certain ASS-negative patients for response and patients who benefit have tumours which are negative for ASS expression.	('patients', 'Species', '9606', (115, 123))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('PEG20', 'Chemical', 'MESH:C000595209', (58, 63))	('tumours', 'Disease', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('ADI-PEG20', 'Var', (54, 63))	('ASS', 'Gene', (198, 201))	('ASS', 'Gene', '445', (198, 201))	('patients', 'Species', '9606', (141, 149))	('ASS', 'Gene', (102, 105))	('ASS', 'Gene', '445', (102, 105))
81630	22472884	Importantly, serious toxicity from ADI-PEG20 was uncommon.	('toxicity', 'Disease', (21, 29))	('ADI-PEG20', 'Var', (35, 44))	('PEG20', 'Chemical', 'MESH:C000595209', (39, 44))	('toxicity', 'Disease', 'MESH:D064420', (21, 29))
81631	22472884	ADI-PEG20 has been well tolerated in clinical trials with other cancer types.	('PEG20', 'Chemical', 'MESH:C000595209', (4, 9))	('ADI-PEG20', 'Var', (0, 9))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
81639	22472884	Whether higher mRNA copies may be another factor governing the sensitivity to ADI-PEG20 as well as the development of resistance is not clear and requires large number of patients' samples.	('PEG20', 'Chemical', 'MESH:C000595209', (82, 87))	('ADI-PEG20', 'Var', (78, 87))	('mRNA copies', 'MPA', (15, 26))	('patients', 'Species', '9606', (171, 179))
81645	22472884	Overall, resistance to ADI-PEG20 can be due to: (1) autophagy and (2) induction of ASS.	('autophagy', 'biological_process', 'GO:0016236', ('52', '61'))	('autophagy', 'CPA', (52, 61))	('autophagy', 'biological_process', 'GO:0006914', ('52', '61'))	('ASS', 'Gene', (83, 86))	('ASS', 'Gene', '445', (83, 86))	('PEG20', 'Chemical', 'MESH:C000595209', (27, 32))	('ADI-PEG20', 'Var', (23, 32))
81648	22472884	We have shown that combination of cisplatin (via the intrinsic apoptotic pathway) or TRAIL (via extrinsic pathway) with ADI-PEG20 increases cell death in vitro.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('ADI-PEG20', 'Var', (120, 129))	('TRAIL', 'Gene', (85, 90))	('cell death', 'CPA', (140, 150))	('combination', 'Interaction', (19, 30))	('intrinsic apoptotic pathway', 'biological_process', 'GO:0097193', ('53', '80'))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('cisplatin', 'Var', (34, 43))	('PEG20', 'Chemical', 'MESH:C000595209', (124, 129))	('TRAIL', 'Gene', '8743', (85, 90))	('increases', 'PosReg', (130, 139))
81650	22472884	Furthermore, activation of caspase 8 by TRAIL also cleaves Beclin1 and ATG5 resulting in attenuation of autophagy and thus, redirecting cells to apoptosis.	('TRAIL', 'Gene', (40, 45))	('caspase 8', 'Gene', '841', (27, 36))	('caspase 8', 'Gene', (27, 36))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('Beclin1', 'Gene', (59, 66))	('autophagy', 'CPA', (104, 113))	('cleaves', 'Var', (51, 58))	('attenuation', 'NegReg', (89, 100))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('ATG5', 'Gene', '9474', (71, 75))	('activation', 'PosReg', (13, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('Beclin1', 'Gene', '8678', (59, 66))	('redirecting', 'Reg', (124, 135))	('TRAIL', 'Gene', '8743', (40, 45))	('ATG5', 'Gene', (71, 75))
81654	22472884	Further clinical trials in melanoma with ADI-PEG20 should be considered to be conducted only in ASS-negative patients, perhaps in combination therapy with cisplatin or TRAIL to potentiate the response.	('TRAIL', 'Gene', '8743', (168, 173))	('ASS', 'Gene', '445', (96, 99))	('patients', 'Species', '9606', (109, 117))	('TRAIL', 'Gene', (168, 173))	('ASS', 'Gene', (96, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('PEG20', 'Chemical', 'MESH:C000595209', (45, 50))	('ADI-PEG20', 'Var', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
81663	33488678	Passenger mutations can become driver mutations (and vice versa) under changing environmental conditions and selection pressures, increasing the complexity of intratumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Passenger mutations', 'Var', (0, 19))
81683	33488678	The OR2C3 mutation relevance score in TCGA-BC-A10X is evidently high (OR2C3 and k = TCGA-BC-A10X) and is ranked 1st.	('TCGA-BC-A10X', 'Var', (38, 50))	('A10X', 'Mutation', 'p.A10X', (92, 96))	('OR2C3', 'Gene', '81472', (4, 9))	('OR2C3', 'Gene', '81472', (70, 75))	('OR2C3', 'Gene', (4, 9))	('A10X', 'Mutation', 'p.A10X', (46, 50))	('OR2C3', 'Gene', (70, 75))
81696	33488678	In general, considering the weights for the different types of mutations (Weighted_MinNetRank) had a better performance than other six methods (MinNetRank, Mean, Maximum, NetICS, DawnRank, and Freq) in all six cancer datasets (TCGA-LIHC, TCGA-STAD, TCGA-BLCA, TCGA-LUAD, TCGA-SKCM, and LIRI-LIHC).	('mutations', 'Var', (63, 72))	('TCGA-SKCM', 'Disease', (271, 280))	('TCGA-LUAD', 'Disease', (260, 269))	('TCGA-LIHC', 'Disease', (227, 236))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCGA-STAD', 'Disease', (238, 247))	('TCGA-BLCA', 'Disease', (249, 258))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
81719	33488678	TP53 was one of the most frequent alterations and potential prognostic markers in human cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('alterations', 'Var', (34, 45))	('human', 'Species', '9606', (82, 87))
81743	33488678	Besides mutation data, other events, such as miRNA differential expression, epigenetic changes, copy number variation, and structure variation, could also contribute to cancer progression.	('cancer', 'Disease', (169, 175))	('structure', 'MPA', (123, 132))	('copy number variation', 'Var', (96, 117))	('miRNA differential expression', 'MPA', (45, 74))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('epigenetic changes', 'Var', (76, 94))	('contribute', 'Reg', (155, 165))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
81760	33488678	Although synonymous mutations do not alter amino acids, some deleterious synonymous mutations play important roles in cancer.	('cancer', 'Disease', (118, 124))	('roles', 'Reg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('synonymous mutations', 'Var', (73, 93))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('play', 'Reg', (94, 98))
81811	32858528	To validate the 21-gene signature in other populations, we calculated the risk score for melanoma patients in GSE54467 (n = 79) and GSE65904 (n = 210) using the same formula and performed risk stratification in the same way as with the TCGA cohort.	('GSE54467', 'Var', (110, 118))	('patients', 'Species', '9606', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('GSE65904', 'Var', (132, 140))
81818	32858528	Both the risk score and tumor stage were significantly correlated with prognosis in GSE65904; however, only the risk score was significantly associated with OS in the multivariate analysis (Log-rank test, P < 0.01).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('correlated', 'Reg', (55, 65))	('GSE65904', 'Var', (84, 92))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
81821	32858528	Only BRAF showed a significantly high mutation load in the low-risk group (89/215 vs. 114/202, Fisher's exact test, P = 2.389E-3).	('BRAF', 'Gene', (5, 9))	('BRAF', 'Gene', '673', (5, 9))	('mutation', 'Var', (38, 46))
81837	32858528	EPHX1 is also a member of another enriched pathway, the metabolism of DMBA (Figure 6C); DMBA is a widely used chemical compound to induce skin cancer in animal models.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('DMBA', 'Var', (88, 92))	('DMBA', 'Chemical', 'MESH:C082386', (88, 92))	('EPHX1', 'Gene', (0, 5))	('skin cancer', 'Phenotype', 'HP:0008069', (138, 149))	('metabolism', 'biological_process', 'GO:0008152', ('56', '66'))	('EPHX1', 'Gene', '2052', (0, 5))	('skin cancer', 'Disease', (138, 149))	('induce', 'PosReg', (131, 137))	('DMBA', 'Chemical', 'MESH:C082386', (70, 74))	('skin cancer', 'Disease', 'MESH:D012878', (138, 149))
81840	32858528	Moreover, we noticed that three upregulated genes in the high-risk group, ALDH3A1, ALDH3B2, and ADH7, participate in the cytochrome P450-mediated metabolism of trichloroethylene (Figure 6D); trichloroethylene is an organic chemical, exposure to which can cause cancer.	('ALDH3A1', 'Gene', '218', (74, 81))	('ADH', 'molecular_function', 'GO:0047636', ('96', '99'))	('metabolism', 'biological_process', 'GO:0008152', ('146', '156'))	('ALDH', 'molecular_function', 'GO:0004030', ('83', '87'))	('ALDH3A1', 'Gene', (74, 81))	('cause', 'Reg', (255, 260))	('trichloroethylene', 'Var', (191, 208))	('ALDH3B2', 'Gene', (83, 90))	('trichloroethylene', 'Chemical', 'MESH:D014241', (160, 177))	('cytochrome P450', 'Gene', (121, 136))	('cytochrome P450', 'molecular_function', 'GO:0005490', ('121', '136'))	('cancer', 'Disease', (261, 267))	('ALDH3B2', 'Gene', '222', (83, 90))	('trichloroethylene', 'Chemical', 'MESH:D014241', (191, 208))	('cytochrome P450', 'molecular_function', 'GO:0019825', ('121', '136'))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cytochrome P450', 'Gene', '4051', (121, 136))	('ADH', 'molecular_function', 'GO:0004022', ('96', '99'))	('ADH7', 'Gene', (96, 100))	('upregulated', 'PosReg', (32, 43))	('ADH7', 'Gene', '131', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('ALDH', 'molecular_function', 'GO:0004030', ('74', '78'))
81891	32858528	Interestingly, the NAD pathway enzymes are receiving increasing attention due to their roles in several aspects of immune cell fate and function, once again highlighting that the inhibition of NAD synthesis could restore metabolic balance in the tumor microenvironment.	('restore', 'PosReg', (213, 220))	('inhibition', 'Var', (179, 189))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('NAD', 'Chemical', 'MESH:D009243', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('NAD synthesis', 'biological_process', 'GO:0009435', ('193', '206'))	('NAD', 'Chemical', 'MESH:D009243', (19, 22))	('tumor', 'Disease', (246, 251))	('metabolic balance', 'MPA', (221, 238))
81933	31040906	Study of de novo synthesized or translationally suppressed proteins under environmental stress revealed key molecules responsible for metabolic shift, malignant transformation, or epigenetic regulation in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('epigenetic regulation', 'Var', (180, 201))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('regulation', 'biological_process', 'GO:0065007', ('191', '201'))
81934	31040906	More importantly, our approach has discovered a novel pathway of hypoxia-driven cell cycle arrest via epigenetic regulation.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (80, 97))	('epigenetic regulation', 'Var', (102, 123))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))	('hypoxia', 'Disease', (65, 72))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('80', '97'))
81938	31040906	By genetic depletion of PHF14 protein, hypoxic cancer cells increased the expression of CDK inhibitors, p15INK4b and p16INK4a, and p53-dependent cell cycle regulator, p14ARF, and consequently inhibited G1-to-S phase transition.	('CDK', 'Protein', (88, 91))	('p53', 'Gene', (131, 134))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('G1-to-S phase transition', 'CPA', (202, 226))	('PHF14', 'Gene', (24, 29))	('p16INK4a', 'Gene', (117, 125))	('expression', 'MPA', (74, 84))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('145', '165'))	('hypoxic cancer', 'Disease', 'MESH:D009369', (39, 53))	('p14ARF', 'Gene', '1029', (167, 173))	('hypoxic cancer', 'Disease', (39, 53))	('depletion', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('protein', 'Protein', (30, 37))	('increased', 'PosReg', (60, 69))	('p16INK4a', 'Gene', '1029', (117, 125))	('p15INK4b', 'Gene', '1030', (104, 112))	('inhibited', 'NegReg', (192, 201))	('p15INK4b', 'Gene', (104, 112))	('p14ARF', 'Gene', (167, 173))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('S phase', 'biological_process', 'GO:0051320', ('208', '215'))	('p53', 'Gene', '7157', (131, 134))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('145', '165'))
81939	31040906	In addition, PHF14 knockdown was associated with inhibition of AKT-mTOR-4E-BP1/S6K phosphorylation, which implicated that hypoxia-mediated suppression of PHF14 may regulate protein synthesis through AKT-mTOR signaling pathway.	('AKT', 'Gene', (199, 202))	('AKT', 'Gene', (63, 66))	('signaling pathway', 'biological_process', 'GO:0007165', ('208', '225'))	('hypoxia', 'Disease', (122, 129))	('mTOR', 'Gene', (67, 71))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('mTOR', 'Gene', '2475', (203, 207))	('4E-BP1', 'Gene', (72, 78))	('protein synthesis', 'biological_process', 'GO:0006412', ('173', '190'))	('S6K', 'Gene', (79, 82))	('protein synthesis', 'MPA', (173, 190))	('knockdown', 'Var', (19, 28))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('mTOR', 'Gene', '2475', (67, 71))	('regulate', 'Reg', (164, 172))	('AKT', 'Gene', '207', (199, 202))	('AKT', 'Gene', '207', (63, 66))	('PHF14', 'Gene', (13, 18))	('S6K', 'Gene', '6198', (79, 82))	('PHF14', 'Gene', (154, 159))	('4E-BP1', 'Gene', '1978', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('suppression', 'NegReg', (139, 150))	('inhibition', 'NegReg', (49, 59))	('mTOR', 'Gene', (203, 207))
81941	31040906	Briefly, A431 cells grown in "light" medium, containing unlabeled [12C6, 14N2]-Lys and [12C6]-Arg, were switched to "heavy" medium, containing labeled [13C6, 15N2]-Lys and [13C6]-Arg for 24 hr.	('Arg', 'Chemical', 'MESH:D001120', (94, 97))	('[12C6]-Arg', 'Chemical', '-', (87, 97))	('12C6, 14N2]-Lys', 'Chemical', '-', (67, 82))	('13C6]', 'Chemical', '-', (173, 178))	('[13C6]-Arg', 'Var', (172, 182))	('A431', 'CellLine', 'CVCL:0037', (9, 13))	('13C6, 15N2]-Lys', 'Chemical', '-', (152, 167))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))	('13C6', 'Var', (152, 156))
81990	31040906	Collectively, inhibition of NuRD complex under hypoxia can release cancer cells from suppressive effects on oncogenic potentials such as Snail, TGFbeta signaling, focal adhesion process, or MAPK activities (Figure 4E).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('NuRD complex', 'cellular_component', 'GO:0016581', ('28', '40'))	('MAPK', 'molecular_function', 'GO:0004707', ('190', '194'))	('cancer', 'Disease', (67, 73))	('focal', 'MPA', (163, 168))	('TGFbeta signaling', 'MPA', (144, 161))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('163', '177'))	('Snail', 'MPA', (137, 142))	('NuRD complex', 'Gene', (28, 40))	('inhibition', 'Var', (14, 24))
81998	31040906	Interestingly, expression of p14ARF, an alternatively spliced gene of the INK4b-ARF-INK4a locus, was increased in both normoxic and hypoxic PHF14 knockdown A431 cells.	('knockdown', 'Var', (146, 155))	('increased', 'PosReg', (101, 110))	('p14ARF', 'Gene', '1029', (29, 35))	('INK4b', 'Gene', (74, 79))	('expression', 'MPA', (15, 25))	('A431', 'CellLine', 'CVCL:0037', (156, 160))	('INK4b', 'Gene', '1030', (74, 79))	('p14ARF', 'Gene', (29, 35))
82003	31040906	As shown in Figure 6A, depletion of PHF14 reduced the phosphorylation level of AKT S473, mTOR S2448, 4E-BP1 T37/46, and p70S6K T389.	('S473', 'Var', (83, 87))	('mTOR', 'Gene', '2475', (89, 93))	('phosphorylation level', 'MPA', (54, 75))	('reduced', 'NegReg', (42, 49))	('depletion', 'Var', (23, 32))	('AKT', 'Gene', (79, 82))	('p70S6K', 'Gene', '6198', (120, 126))	('p70S6K', 'Gene', (120, 126))	('PHF14', 'Gene', (36, 41))	('4E-BP1', 'Gene', (101, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('AKT', 'Gene', '207', (79, 82))	('mTOR', 'Gene', (89, 93))	('4E-BP1', 'Gene', '1978', (101, 107))
82009	31040906	We observed a significant inhibition in growth of tumors derived from the PHF14 KD cells compared with controls (p = 0.0165; Figure 6C).	('PHF14 KD', 'Var', (74, 82))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('growth', 'MPA', (40, 46))	('inhibition', 'NegReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
82010	31040906	The mean weight of tumors generated by A431 PHF14 KD cells was 63.6% of that generated by A431-con cells assessed at the same time point, indicating that depletion of PHF14 can potently restrict tumor growth in vivo.	('A431', 'CellLine', 'CVCL:0037', (39, 43))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('PHF14', 'Gene', (167, 172))	('depletion', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('restrict', 'NegReg', (186, 194))	('A431', 'CellLine', 'CVCL:0037', (90, 94))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
82024	31040906	Since epigenetic changes are directly linked to various gene expressions, hypoxia-mediated modulation of epigenetic regulators could be an efficient way to induce a phenotypic shift in cancer cells.	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('hypoxia', 'Disease', (74, 81))	('phenotypic shift', 'CPA', (165, 181))	('induce', 'Reg', (156, 162))	('modulation', 'Var', (91, 101))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
82027	31040906	Study for correlation between hypoxia-mediated cellular response and PHF14 expression showed that PHF14 knockdown inhibited G1-to-S phase transition by upregulation of CDK inhibitors, p15INK4b and p16INK4a, and a p53-dependent cell cycle inhibitor, p14ARF.	('G1-to-S phase transition', 'CPA', (124, 148))	('p16INK4a', 'Gene', (197, 205))	('upregulation', 'PosReg', (152, 164))	('p53', 'Gene', '7157', (213, 216))	('CDK inhibitors', 'Protein', (168, 182))	('p16INK4a', 'Gene', '1029', (197, 205))	('CDK', 'molecular_function', 'GO:0004693', ('168', '171'))	('p14ARF', 'Gene', '1029', (249, 255))	('p53', 'Gene', (213, 216))	('inhibited', 'NegReg', (114, 123))	('hypoxia', 'Disease', (30, 37))	('S phase', 'biological_process', 'GO:0051320', ('130', '137'))	('cell cycle', 'biological_process', 'GO:0007049', ('227', '237'))	('p15INK4b', 'Gene', '1030', (184, 192))	('knockdown', 'Var', (104, 113))	('p15INK4b', 'Gene', (184, 192))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('p14ARF', 'Gene', (249, 255))	('PHF14', 'Gene', (98, 103))
82029	31040906	While expression of PHF14 was directly related with mRNA level of CDK inhibitors, AKT-mTOR signaling pathway was regulated by phosphorylation cascade, indicating that PHF14 may contribute to the expression of upstream ligands as an epigenetic regulator.	('mTOR', 'Gene', '2475', (86, 90))	('mTOR', 'Gene', (86, 90))	('PHF14', 'Var', (167, 172))	('CDK', 'molecular_function', 'GO:0004693', ('66', '69'))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('AKT', 'Gene', '207', (82, 85))	('PHF14', 'Gene', (20, 25))	('signaling pathway', 'biological_process', 'GO:0007165', ('91', '108'))	('AKT', 'Gene', (82, 85))
82034	31040906	Generally epigenetic modifiers regulate gene expression by the assembly of relevant interacting partners, thus, contradict outcome of PHF14 depletion in different cancer cells might be associated with its functional binding partners and environmental stress may affect the complex formation.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('binding', 'Interaction', (216, 223))	('complex', 'MPA', (273, 280))	('affect', 'Reg', (262, 268))	('gene expression', 'MPA', (40, 55))	('depletion', 'NegReg', (140, 149))	('gene expression', 'biological_process', 'GO:0010467', ('40', '55'))	('PHF14', 'Gene', (134, 139))	('associated', 'Interaction', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('regulate', 'Reg', (31, 39))	('binding', 'molecular_function', 'GO:0005488', ('216', '223'))	('formation', 'biological_process', 'GO:0009058', ('281', '290'))	('cancer', 'Disease', (163, 169))	('epigenetic modifiers', 'Var', (10, 30))
82053	31040906	The automatic gain control settings of the full MS and MS2 scans were 3E6 and 2E5, respectively.	('MS2', 'Gene', (55, 58))	('MS2', 'Gene', '100271694', (55, 58))	('3E6', 'Var', (70, 73))
82057	31040906	Flow cytometric analysis of PI-stained cells was performed to demonstrate the effects of hypoxia and PHF14 depletion on cell cycle progression.	('PHF14', 'Gene', (101, 106))	('cell cycle', 'biological_process', 'GO:0007049', ('120', '130'))	('hypoxia', 'Disease', 'MESH:D000860', (89, 96))	('hypoxia', 'Disease', (89, 96))	('cell cycle progression', 'CPA', (120, 142))	('depletion', 'Var', (107, 116))
82061	31040906	The mice received subcutaneous injection of 1 x 106 A431-con (n=6) or A431-shPHF14 (n=6) cancer cells into either the left or right flank, and tumor size was monitored with a caliper.	('A431-shPHF14', 'Var', (70, 82))	('tumor', 'Disease', (143, 148))	('mice', 'Species', '10090', (4, 8))	('A431', 'CellLine', 'CVCL:0037', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('A431', 'CellLine', 'CVCL:0037', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
82068	22253555	The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive.	('vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('GSK2118436', 'Chemical', 'MESH:C561627', (106, 116))	('V600 mutation positive', 'Var', (143, 165))	('BRAF', 'Gene', (138, 142))	('patients', 'Species', '9606', (121, 129))	('GSK', 'molecular_function', 'GO:0050321', ('106', '109'))
82069	22253555	In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials.	('patient', 'Species', '9606', (37, 44))	('MEK', 'Gene', '5609', (57, 60))	('BRAF', 'Gene', (25, 29))	('mutant', 'Var', (30, 36))	('MEK', 'Gene', (57, 60))
82077	22253555	While stimulating the immune system via T-cell activation to control tumour growth has demonstrated clinical benefit in an unselected group of melanoma patients, so far the benefit of the BRAF and MEK targeted agents is confined to the BRAF V600 mutant population alone.	('tumour', 'Disease', (69, 75))	('MEK', 'Gene', '5609', (197, 200))	('BRAF', 'Gene', (236, 240))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('melanoma', 'Disease', (143, 151))	('T-cell activation', 'biological_process', 'GO:0042110', ('40', '57'))	('V600 mutant', 'Var', (241, 252))	('MEK', 'Gene', (197, 200))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('patients', 'Species', '9606', (152, 160))
82084	22253555	Pre-clinical studies demonstrated that injection of anti-CTLA-4 antibodies into mouse models could stimulate the rejection of murine tumours in colon, ovarian and fibrosarcoma models.	('Pre', 'molecular_function', 'GO:0003904', ('0', '3'))	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (163, 175))	('stimulate', 'PosReg', (99, 108))	('antibodies', 'Var', (64, 74))	('murine', 'Species', '10090', (126, 132))	('mouse', 'Species', '10090', (80, 85))	('tumours in colon, ovarian and fibrosarcoma', 'Disease', 'MESH:D005354', (133, 175))	('anti-CTLA-4', 'Gene', (52, 63))	('anti-CTLA-4 antibodies', 'Var', (52, 74))
82092	22253555	Importantly the 1- and 2-year survival rates improved to 45.6% and 23.5% respectively with ipilimumab compared to 25.5% and 13.7% with gp100 alone.	('ipilimumab', 'Var', (91, 101))	('improved', 'PosReg', (45, 53))	('gp100', 'Gene', '6490', (135, 140))	('ipilimumab', 'Chemical', 'MESH:D000074324', (91, 101))	('gp100', 'Gene', (135, 140))
82100	22253555	Activation of the Raf Sarcoma (RAS) family of GTPases by growth factors or by RAS mutation then drives activation of the RAF kinase family (ARAF, BRAF, CRAF) with subsequent phosphorylation and activation of MEK kinases (MEK 1 and 2) and extracellular signal- regulated kinases (ERK 1 and 2).	('Sarcoma', 'Disease', 'MESH:D012509', (22, 29))	('activation', 'PosReg', (194, 204))	('RAF', 'Gene', '22882', (121, 124))	('MEK 1 and 2', 'Gene', '5604;5605', (221, 232))	('ARAF', 'Gene', '369', (140, 144))	('ARAF', 'Gene', (140, 144))	('RAF', 'Gene', '22882', (153, 156))	('MEK', 'Gene', (221, 224))	('Raf', 'Gene', (18, 21))	('RAS', 'Gene', (78, 81))	('Sarcoma', 'Disease', (22, 29))	('phosphorylation', 'MPA', (174, 189))	('RAF', 'Gene', '22882', (141, 144))	('mutation', 'Var', (82, 90))	('CRAF', 'molecular_function', 'GO:0004709', ('152', '156'))	('RAF', 'Gene', (121, 124))	('ERK 1 and 2', 'Gene', '5595;5594', (279, 290))	('Sarcoma', 'Phenotype', 'HP:0100242', (22, 29))	('extracellular', 'cellular_component', 'GO:0005576', ('238', '251'))	('RAF', 'Gene', (153, 156))	('activation', 'PosReg', (103, 113))	('Raf', 'Gene', '22882', (18, 21))	('RAF', 'Gene', (141, 144))	('MEK', 'Gene', (208, 211))	('extracellular signal- regulated kinases', 'Pathway', (238, 277))	('ERK 1', 'molecular_function', 'GO:0004707', ('279', '284'))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('CRAF', 'Gene', (152, 156))	('MEK', 'Gene', '5609', (208, 211))	('RAF', 'Gene', '22882', (147, 150))	('MEK 1', 'molecular_function', 'GO:0004708', ('221', '226'))	('CRAF', 'Gene', '5894', (152, 156))	('MEK', 'Gene', '5609', (221, 224))	('RAF', 'Gene', (147, 150))
82101	22253555	MAPK pathway activity is key for normal cell function but abnormal activation, through mutations and other aberrations have been implicated in a number of cancer sub-types, including melanoma, colorectal cancer and borderline ovarian cancer, among others.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('activation', 'PosReg', (67, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (193, 210))	('mutations', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (226, 240))	('colorectal cancer', 'Disease', (193, 210))	('implicated', 'Reg', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (204, 210))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('borderline ovarian cancer', 'Disease', (215, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (193, 210))	('cancer', 'Disease', (155, 161))	('borderline ovarian cancer', 'Disease', 'MESH:D010051', (215, 240))	('abnormal', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('cancer', 'Disease', (234, 240))
82102	22253555	Genetic aberrations in the MAPK pathway are present in over 80% of cutaneous melanomas, involving abnormalities in RAS, RAF, MEK and ERK.	('ERK', 'molecular_function', 'GO:0004707', ('133', '136'))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('ERK', 'Gene', '5594', (133, 136))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('RAF', 'Gene', (120, 123))	('ERK', 'Gene', (133, 136))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (67, 86))	('MEK', 'Gene', (125, 128))	('Genetic aberrations', 'Var', (0, 19))	('abnormalities', 'Var', (98, 111))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (67, 86))	('MEK', 'Gene', '5609', (125, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('RAF', 'Gene', '22882', (120, 123))	('RAS', 'Protein', (115, 118))	('MAPK pathway', 'Pathway', (27, 39))	('cutaneous melanomas', 'Disease', (67, 86))
82103	22253555	The most common mutation appears to be in the activating v-raf murine sarcoma viral oncogene homologue B1 (BRAF), occurring in 36%-59% of primary melanomas and 42%-66% of metastatic melanomas and has been characterised as an oncogenic mutation.	('melanomas', 'Disease', 'MESH:D008545', (182, 191))	('BRAF', 'Gene', (107, 111))	('melanomas', 'Disease', 'MESH:D008545', (146, 155))	('mutation', 'Var', (16, 24))	('v-raf', 'Gene', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanomas', 'Phenotype', 'HP:0002861', (146, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('sarcoma viral', 'Disease', 'MESH:D001102', (70, 83))	('metastatic', 'Disease', (171, 181))	('melanomas', 'Disease', (182, 191))	('v-raf', 'Gene', '110157', (57, 62))	('melanomas', 'Disease', (146, 155))	('sarcoma viral', 'Disease', (70, 83))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanomas', 'Phenotype', 'HP:0002861', (182, 191))	('murine', 'Species', '10090', (63, 69))
82104	22253555	The most common somatic mutation is found at V600E in exon 15 in 66%-90% of BRAF mutant melanomas.	('BRAF', 'Gene', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('V600E', 'Var', (45, 50))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('mutant', 'Var', (81, 87))	('V600E', 'Mutation', 'rs113488022', (45, 50))	('melanomas', 'Disease', (88, 97))
82105	22253555	This is a point mutation in DNA (1799T-> A) resulting in a single amino-acid substitution at Valine 600 to Glutamic acid in the activating segment, which leads to elevated kinase activity compared with BRAF wild type, stimulated phosphorylation of downstream endogenous ERK and subsequent cellular proliferation and survival.	('phosphorylation', 'biological_process', 'GO:0016310', ('229', '244'))	('elevated', 'PosReg', (163, 171))	('cellular proliferation', 'CPA', (289, 311))	('ERK', 'molecular_function', 'GO:0004707', ('270', '273'))	('ERK', 'Gene', '5594', (270, 273))	('stimulated', 'PosReg', (218, 228))	('ERK', 'Gene', (270, 273))	('kinase activity', 'MPA', (172, 187))	('DNA', 'Gene', (28, 31))	('substitution', 'Var', (77, 89))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('Valine 600 to Glutamic acid', 'Mutation', 'rs113488022', (93, 120))	('kinase activity', 'molecular_function', 'GO:0016301', ('172', '187'))	('survival', 'CPA', (316, 324))	('1799T-> A', 'Mutation', 'rs113488022', (33, 42))	('phosphorylation', 'MPA', (229, 244))
82106	22253555	The V600 K mutation has been reported in 7%-28.5% of patients with BRAF mutant metastatic melanoma and involves two point mutations (GTG to AAG) with a lysine for valine substitution.	('melanoma', 'Disease', (90, 98))	('GTG', 'Gene', '2678', (133, 136))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('patients', 'Species', '9606', (53, 61))	('valine', 'Chemical', 'MESH:D014633', (163, 169))	('mutant', 'Var', (72, 78))	('GTG', 'Gene', (133, 136))	('lysine', 'Chemical', 'MESH:D008239', (152, 158))	('BRAF', 'Gene', (67, 71))	('AAG', 'Gene', (140, 143))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('AAG', 'Gene', '4350', (140, 143))	('V600 K', 'Mutation', 'rs121913227', (4, 10))	('V600 K', 'Var', (4, 10))
82111	22253555	The two agents that have demonstrated significant clinical benefit in melanoma are vemurafenib (PLX4032/RG 7204) and GSK2118436.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('GSK2118436', 'Var', (117, 127))	('vemurafenib', 'Chemical', 'MESH:D000077484', (83, 94))	('PLX4032', 'Chemical', 'MESH:D000077484', (96, 103))	('GSK', 'molecular_function', 'GO:0050321', ('117', '120'))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('GSK2118436', 'Chemical', 'MESH:C561627', (117, 127))
82112	22253555	Vemurafenib is an orally available, highly potent, ATP competitive inhibitor of mutant BRAF.	('BRAF', 'Gene', (87, 91))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('mutant', 'Var', (80, 86))
82115	22253555	The BRAF in Melanoma 2 (BRIM-2) phase II study enrolled 132 patients with previously treated BRAF V600E mutant stage IV melanoma and demonstrated a RR of 53%, stable disease in a further 29%, median PFS of 6.7 months and OS at 6 and 12 months of 77% and 58% respectively.	('BRAF', 'Gene', (93, 97))	('V600E mutant', 'Var', (98, 110))	('patients', 'Species', '9606', (60, 68))	('Melanoma 2', 'Disease', 'MESH:D008545', (12, 22))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('OS', 'Chemical', '-', (221, 223))	('melanoma', 'Disease', (120, 128))	('Melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('Melanoma 2', 'Disease', (12, 22))
82116	22253555	Additionally in early 2011, the phase III BRAF Inhibitor in Melanoma 3 (BRIM3) trial included 675 BRAF V600E mutation positive metastatic melanoma patients and reported a significant improvement in OS in patients who were treated with vemurafenib compared to the standard firstline chemotherapy dacarbazine.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('patients', 'Species', '9606', (204, 212))	('Melanoma', 'Disease', (60, 68))	('melanoma', 'Disease', (138, 146))	('V600E', 'Var', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('improvement', 'PosReg', (183, 194))	('BRAF', 'Gene', (98, 102))	('dacarbazine', 'Chemical', 'MESH:D003606', (295, 306))	('Melanoma', 'Disease', 'MESH:D008545', (60, 68))	('patients', 'Species', '9606', (147, 155))	('Melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('OS', 'Chemical', '-', (198, 200))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('vemurafenib', 'Chemical', 'MESH:D000077484', (235, 246))
82117	22253555	The RR was 48% versus 5% with a significant prolonged median PFS of 5.3 months in the vemurafenib arm compared to 1.6 months on dacarbazine [HR 0.26 (95% CI 0.20-0.33) P < 0.0001].	('vemurafenib', 'Var', (86, 97))	('PFS', 'MPA', (61, 64))	('prolonged', 'PosReg', (44, 53))	('vemurafenib', 'Chemical', 'MESH:D000077484', (86, 97))	('dacarbazine', 'Chemical', 'MESH:D003606', (128, 139))
82119	22253555	GSK2118436 is another ATP competitive, reversible inhibitor of mutant BRAF V600E, as well as V600D/K and V600G kinases.	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('BRAF', 'Gene', (70, 74))	('mutant', 'Var', (63, 69))	('GSK2118436', 'Chemical', 'MESH:C561627', (0, 10))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('V600G', 'Mutation', 'rs113488022', (105, 110))	('V600E', 'Var', (75, 80))	('V600G', 'Var', (105, 110))	('V600D', 'SUBSTITUTION', 'None', (93, 98))	('ATP', 'Chemical', 'MESH:D000255', (22, 25))	('V600D', 'Var', (93, 98))
82120	22253555	The phase I/II trial included 61 patients, 52 with BRAF mutant melanoma and V600E/D/K mutations.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('patients', 'Species', '9606', (33, 41))	('V600E', 'Var', (76, 81))	('V600E', 'SUBSTITUTION', 'None', (76, 81))	('BRAF', 'Gene', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
82128	22253555	Ongoing studies are assessing GSK2118436 versus dacarbazine in previously untreated patients with BRAF mutant advanced or metastatic melanoma, as well as a study of GSK2118436 in BRAF mutant metastatic melanoma to the brain.	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('patients', 'Species', '9606', (84, 92))	('mutant', 'Var', (184, 190))	('mutant', 'Var', (103, 109))	('BRAF', 'Gene', (98, 102))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('GSK2118436', 'Chemical', 'MESH:C561627', (30, 40))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanoma', 'Disease', (202, 210))	('GSK', 'molecular_function', 'GO:0050321', ('165', '168'))	('GSK2118436', 'Chemical', 'MESH:C561627', (165, 175))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('dacarbazine', 'Chemical', 'MESH:D003606', (48, 59))
82129	22253555	In addition to inhibiting BRAF signalling with selective BRAF inhibitors, there is good pre-clinical evidence of anti-proliferative activity of MEK inhibitors in melanoma.	('inhibitors', 'Var', (148, 158))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('signalling', 'biological_process', 'GO:0023052', ('31', '41'))	('melanoma', 'Disease', (162, 170))	('pre', 'molecular_function', 'GO:0003904', ('88', '91'))	('MEK', 'Gene', (144, 147))	('MEK', 'Gene', '5609', (144, 147))	('BRAF signalling', 'MPA', (26, 41))	('inhibiting', 'NegReg', (15, 25))	('anti-proliferative activity', 'MPA', (113, 140))
82131	22253555	The earliest MEK inhibitors in preclinical and clinical development demonstrated limited clinical activity and included PD98059, UO126 and CI-1040.	('MEK', 'Gene', '5609', (13, 16))	('PD98059', 'Var', (120, 127))	('CI-1040', 'Chemical', 'MESH:C120227', (139, 146))	('clinical activity', 'MPA', (89, 106))	('PD98059', 'Chemical', 'MESH:C093973', (120, 127))	('MEK', 'Gene', (13, 16))
82132	22253555	PD0325901, a structural analogue of CI-1040, was a second generation MEK inhibitor evaluated in phase I and II trials in metastatic cutaneous melanoma patients with some early evidence of response and disease stabilisation, but its further development was limited by toxicity, particularly ocular toxicity.	('toxicity', 'Disease', (297, 305))	('ocular toxicity', 'Disease', 'MESH:D005128', (290, 305))	('ocular toxicity', 'Disease', (290, 305))	('PD0325901', 'Var', (0, 9))	('CI-1040', 'Chemical', 'MESH:C120227', (36, 43))	('MEK', 'Gene', (69, 72))	('cutaneous melanoma', 'Disease', (132, 150))	('patients', 'Species', '9606', (151, 159))	('MEK', 'Gene', '5609', (69, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('toxicity', 'Disease', 'MESH:D064420', (297, 305))	('toxicity', 'Disease', 'MESH:D064420', (267, 275))	('toxicity', 'Disease', (267, 275))
82134	22253555	Single-agent clinical trials have not been pursued with this agent but phase 2 combination trials with dacarbazine, docetaxel and temsirolimus are currently underway in BRAF mutant metastatic melanoma in the first-line setting.	('dacarbazine', 'Chemical', 'MESH:D003606', (103, 114))	('BRAF', 'Gene', (169, 173))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('docetaxel', 'Chemical', 'MESH:D000077143', (116, 125))	('temsirolimus', 'Chemical', 'MESH:C401859', (130, 142))	('mutant', 'Var', (174, 180))
82135	22253555	In contrast, the phase I/II study of the MEK inhibitor GSK1120212showed good tolerability in the 162 enrolled patients, predominantly with melanoma and pancreatic cancer.	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('pancreatic cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (152, 169))	('pancreatic cancer', 'Disease', 'MESH:D010190', (152, 169))	('GSK', 'molecular_function', 'GO:0050321', ('55', '58'))	('GSK1120212showed', 'Var', (55, 71))	('GSK1120212showed', 'Chemical', '-', (55, 71))	('patients', 'Species', '9606', (110, 118))
82136	22253555	There were 20 evaluable patients with BRAF mutant melanoma and at the recommended phase-II dose of 2 mg once daily, RRs were 40% (8 from 20 patients) and a further 18% had stable disease (SD).	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('mutant', 'Var', (43, 49))	('BRAF', 'Gene', (38, 42))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (24, 32))	('RRs', 'MPA', (116, 119))	('stable', 'MPA', (172, 178))	('SD', 'Disease', 'MESH:D029461', (188, 190))
82138	22253555	There is also pre-clinical and early clinical evidence that the combination of a BRAF and MEK inhibitor (GSK2118436 and GSK1120212) shows clinical activity in BRAF V600 mutant melanoma not only with a potential reduction in drug resistance but also with decreased toxicity.	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('GSK2118436', 'Chemical', 'MESH:C561627', (105, 115))	('toxicity', 'Disease', (264, 272))	('GSK1120212', 'Chemical', 'MESH:C560077', (120, 130))	('BRAF', 'Gene', (159, 163))	('reduction', 'NegReg', (211, 220))	('MEK', 'Gene', '5609', (90, 93))	('drug resistance', 'MPA', (224, 239))	('GSK2118436', 'Var', (105, 115))	('pre', 'molecular_function', 'GO:0003904', ('14', '17'))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('GSK', 'molecular_function', 'GO:0050321', ('105', '108'))	('drug resistance', 'Phenotype', 'HP:0020174', (224, 239))	('MEK', 'Gene', (90, 93))	('GSK', 'molecular_function', 'GO:0050321', ('120', '123'))	('GSK1120212', 'Var', (120, 130))	('toxicity', 'Disease', 'MESH:D064420', (264, 272))	('V600 mutant', 'Var', (164, 175))	('drug resistance', 'biological_process', 'GO:0042493', ('224', '239'))	('drug resistance', 'biological_process', 'GO:0009315', ('224', '239'))
82141	22253555	Preliminary results at doses of GSK2118436 150 mg twice daily and GSK1120212 2 mg daily in 19 patients have demonstrated a complete response rate of 11%, a total RR (CR + PR) of 74% and clinical benefit rate (CR + PR + SD) of 100%.	('GSK', 'molecular_function', 'GO:0050321', ('32', '35'))	('patients', 'Species', '9606', (94, 102))	('GSK2118436', 'Chemical', 'MESH:C561627', (32, 42))	('GSK', 'molecular_function', 'GO:0050321', ('66', '69'))	('GSK2118436 150', 'Var', (32, 46))	('GSK1120212', 'Var', (66, 76))	('GSK1120212', 'Chemical', 'MESH:C560077', (66, 76))	('SD', 'Disease', 'MESH:D029461', (219, 221))
82156	22253555	Interestingly and taking into account the difficulties with cross trial comparison and the greater experience with management, ipilimumab at 10 mg/kg in combination with dacarbazine in the phase 3 trial compared to monotherapy in phase 2 data seemed to be associated with less grade 3 and 4 diarrhoea and colitis.	('dacarbazine', 'Chemical', 'MESH:D003606', (170, 181))	('ipilimumab', 'Chemical', 'MESH:D000074324', (127, 137))	('diarrhoea and colitis', 'Disease', 'MESH:D003092', (291, 312))	('diarrhoea', 'Phenotype', 'HP:0002014', (291, 300))	('ipilimumab', 'Var', (127, 137))	('man', 'Species', '9606', (115, 118))	('colitis', 'Phenotype', 'HP:0002583', (305, 312))	('less', 'NegReg', (272, 276))
82182	22253555	Investigation of immune and non-immune hepatotoxicity should included hepatitis serology, CMV and EBV serology, anti-nuclear antibodies (ANA), antimitochondrial antibodies, liver-pancreas-specific antigen, liver- kidney microsomes and smooth muscle antigen (SMA) as well as consultation with a hepatologist (Level of Evidence II).	('antimitochondrial', 'Var', (143, 160))	('hepatotoxicity', 'Disease', (39, 53))	('hepatitis', 'Disease', (70, 79))	('hepatitis', 'Phenotype', 'HP:0012115', (70, 79))	('hepatitis', 'Disease', 'MESH:D056486', (70, 79))	('hepatotoxicity', 'Disease', 'MESH:D056486', (39, 53))	('anti-nuclear', 'Var', (112, 124))	('antimitochondrial antibodies', 'Phenotype', 'HP:0030167', (143, 171))
82200	22253555	A recent case report described a case of anti- CTLA-4 antibody-induced lupus nephritis, confirmed on renal biopsy and electron microscopy.	('antibody', 'cellular_component', 'GO:0019815', ('54', '62'))	('nephritis', 'Phenotype', 'HP:0000123', (77, 86))	('antibody', 'cellular_component', 'GO:0019814', ('54', '62'))	('antibody', 'molecular_function', 'GO:0003823', ('54', '62'))	('anti-', 'Var', (41, 46))	('lupus nephritis', 'Disease', (71, 86))	('lupus nephritis', 'Disease', 'MESH:D008181', (71, 86))	('antibody', 'cellular_component', 'GO:0042571', ('54', '62'))
82201	22253555	Antibodies to double-stranded DNA were also detected and regressed after ipilimumab was withdrawn and the patient was treated with predisone (1 mg/kg daily).	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('ipilimumab', 'Chemical', 'MESH:D000074324', (73, 83))	('patient', 'Species', '9606', (106, 113))	('predisone', 'Chemical', '-', (131, 140))	('detected', 'Reg', (44, 52))	('double-stranded', 'Var', (14, 29))
82208	22253555	GSK2118436 is also very well tolerated with similar side effects reported in the phase I/II trial including skin changes (all grades 37%; grade 3 (G3):1 patient), low grade cutaneous SCC (2 pts/3%), headache (all grades 19%, G3:1 pt), nausea (18% G1), fatigue (15% G1) and vomiting (all grades 13%, G2:4).	('fatigue', 'Disease', (252, 259))	('fatigue', 'Phenotype', 'HP:0012378', (252, 259))	('nausea', 'Disease', 'MESH:D009325', (235, 241))	('GSK', 'molecular_function', 'GO:0050321', ('0', '3'))	('headache', 'Phenotype', 'HP:0002315', (199, 207))	('GSK2118436', 'Chemical', 'MESH:C561627', (0, 10))	('SCC', 'Gene', '6317', (183, 186))	('skin', 'Disease', (108, 112))	('headache', 'Disease', (199, 207))	('vomiting', 'Disease', 'MESH:D014839', (273, 281))	('fatigue', 'Disease', 'MESH:D005221', (252, 259))	('SCC', 'Gene', (183, 186))	('skin changes', 'Phenotype', 'HP:0000951', (108, 120))	('patient', 'Species', '9606', (153, 160))	('nausea', 'Phenotype', 'HP:0002018', (235, 241))	('vomiting', 'Phenotype', 'HP:0002013', (273, 281))	('vomiting', 'Disease', (273, 281))	('GSK2118436', 'Var', (0, 10))	('headache', 'Disease', 'MESH:D006261', (199, 207))	('nausea', 'Disease', (235, 241))
82210	22253555	Interestingly, the BRAF and MEK inhibitor combination (GSK2118436 and GSK1120212) not only demonstrated a potential reduction in drug resistance but also a lower incidence of rash, BRAF-induced hyperproliferative skin lesions and SCC.	('hyperproliferative skin lesions', 'Disease', (194, 225))	('reduction', 'NegReg', (116, 125))	('GSK1120212', 'Var', (70, 80))	('lower', 'NegReg', (156, 161))	('drug resistance', 'MPA', (129, 144))	('drug resistance', 'biological_process', 'GO:0009315', ('129', '144'))	('MEK', 'Gene', '5609', (28, 31))	('rash', 'Phenotype', 'HP:0000988', (175, 179))	('drug resistance', 'biological_process', 'GO:0042493', ('129', '144'))	('GSK1120212', 'Chemical', 'MESH:C560077', (70, 80))	('drug resistance', 'Phenotype', 'HP:0020174', (129, 144))	('GSK2118436', 'Chemical', 'MESH:C561627', (55, 65))	('SCC', 'Gene', '6317', (230, 233))	('MEK', 'Gene', (28, 31))	('rash', 'Disease', (175, 179))	('GSK', 'molecular_function', 'GO:0050321', ('55', '58'))	('GSK', 'molecular_function', 'GO:0050321', ('70', '73'))	('hyperproliferative skin lesions', 'Disease', 'MESH:D012871', (194, 225))	('SCC', 'Gene', (230, 233))	('rash', 'Disease', 'MESH:D005076', (175, 179))	('GSK2118436', 'Var', (55, 65))
82214	22253555	Fever secondary to the BRAF inhibitors, primarily GSK2118436, can usually be managed with supportive care but thorough assessment is recommended to exclude a source of sepsis.	('GSK', 'molecular_function', 'GO:0050321', ('50', '53'))	('Fever', 'Phenotype', 'HP:0001945', (0, 5))	('man', 'Species', '9606', (77, 80))	('Fever', 'Disease', (0, 5))	('sepsis', 'Phenotype', 'HP:0100806', (168, 174))	('BRAF', 'Gene', (23, 27))	('sepsis', 'Disease', (168, 174))	('GSK2118436', 'Chemical', 'MESH:C561627', (50, 60))	('sepsis', 'Disease', 'MESH:D018805', (168, 174))	('GSK2118436', 'Var', (50, 60))	('Fever', 'Disease', 'MESH:D005334', (0, 5))
82218	22253555	As evidenced with both selective BRAF inhibitors though less commonly with GSK2118436, there is an increased incidence of cutaneous SCC.	('GSK', 'molecular_function', 'GO:0050321', ('75', '78'))	('GSK2118436', 'Chemical', 'MESH:C561627', (75, 85))	('SCC', 'Gene', (132, 135))	('SCC', 'Gene', '6317', (132, 135))	('GSK2118436', 'Var', (75, 85))
82219	22253555	This usually develops between weeks 2 to 14 and is hypothesised to be due to upstream RAS mutations in pre-existing SCC skin lesions, which may occur in approximately 15% of patients.	('SCC', 'Gene', (116, 119))	('mutations', 'Var', (90, 99))	('SCC', 'Gene', '6317', (116, 119))	('pre', 'molecular_function', 'GO:0003904', ('103', '106'))	('patients', 'Species', '9606', (174, 182))	('skin lesions', 'Disease', 'MESH:D012871', (120, 132))	('skin lesions', 'Disease', (120, 132))	('upstream RAS', 'Gene', (77, 89))
82220	22253555	Selective inhibition of downstream BRAF can lead to CRAF signalling by this mutant RAS with subsequent development of SCCs.	('BRAF', 'Gene', (35, 39))	('lead to', 'Reg', (44, 51))	('inhibition', 'NegReg', (10, 20))	('mutant', 'Var', (76, 82))	('CRAF', 'Gene', (52, 56))	('SCC', 'Gene', (118, 121))	('CRAF', 'Gene', '5894', (52, 56))	('CRAF', 'molecular_function', 'GO:0004709', ('52', '56'))	('SCC', 'Gene', '6317', (118, 121))	('signalling', 'biological_process', 'GO:0023052', ('57', '67'))
82226	22253555	Among the cases of left ventricular systolic dysfunction, few were considered related to GSK1120212 and it was rarely symptomatic.	('left ventricular systolic dysfunction', 'Disease', (19, 56))	('GSK1120212', 'Var', (89, 99))	('GSK1120212', 'Chemical', 'MESH:C560077', (89, 99))	('left ventricular systolic dysfunction', 'Phenotype', 'HP:0025169', (19, 56))	('GSK', 'molecular_function', 'GO:0050321', ('89', '92'))	('left ventricular systolic dysfunction', 'Disease', 'MESH:D018487', (19, 56))	('systolic dysfunction', 'Phenotype', 'HP:0006673', (36, 56))
82247	22253555	The phase I study with PD0325901 demonstrated RVO in 3 from 66 patients, particularly with the continuous schedule, and this limited further trials beyond phase II.	('RVO', 'MPA', (46, 49))	('PD0325901', 'Var', (23, 32))	('RVO', 'Phenotype', 'HP:0012636', (46, 49))	('PD0325901', 'Chemical', 'MESH:C506614', (23, 32))	('patients', 'Species', '9606', (63, 71))
82253	22253555	AZD6244 is tenfold less potent than PD0325901 and it was hypothesised that the ocular side-effects may correlate with the extent of MEK inhibition.	('PD0325901', 'Chemical', 'MESH:C506614', (36, 45))	('MEK', 'Gene', (132, 135))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('MEK', 'Gene', '5609', (132, 135))
82254	22253555	In the pre-clinical and phase I/II studies with GSK1120212, there have also been reports of RVO and CSR.	('CSR', 'Phenotype', 'HP:0025567', (100, 103))	('GSK', 'molecular_function', 'GO:0050321', ('48', '51'))	('pre', 'molecular_function', 'GO:0003904', ('7', '10'))	('RVO', 'Disease', (92, 95))	('RVO', 'Phenotype', 'HP:0012636', (92, 95))	('GSK1120212', 'Var', (48, 58))	('GSK1120212', 'Chemical', 'MESH:C560077', (48, 58))	('CSR', 'Disease', (100, 103))
82256	22253555	CSR has been reported in 3 cases from 162 patients treated with GSK1120212 and changes were reversible on drug cessation in all cases.	('GSK', 'molecular_function', 'GO:0050321', ('64', '67'))	('GSK1120212', 'Var', (64, 74))	('GSK1120212', 'Chemical', 'MESH:C560077', (64, 74))	('patients', 'Species', '9606', (42, 50))	('CSR', 'Disease', (0, 3))	('CSR', 'Phenotype', 'HP:0025567', (0, 3))
82257	22253555	The phase III study comparing GSK1120212 to chemotherapy in subjects with advanced or metastatic BRAF mutant melanoma excludes patients with a history of RVO or CSR and patients with predisposing factors such as uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes.	('hypercoagulability', 'Phenotype', 'HP:0100724', (349, 367))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (298, 315))	('hypertension', 'Phenotype', 'HP:0000822', (244, 256))	('ocular hypertension', 'Disease', (237, 256))	('ocular hypertension', 'Phenotype', 'HP:0007906', (237, 256))	('hypertension', 'Disease', 'MESH:D006973', (271, 283))	('glaucoma', 'Phenotype', 'HP:0000501', (225, 233))	('GSK1120212', 'Var', (30, 40))	('glaucoma', 'Disease', (225, 233))	('melanoma', 'Disease', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('hypertension', 'Disease', (271, 283))	('glaucoma', 'Disease', 'MESH:D005901', (225, 233))	('GSK1120212', 'Chemical', 'MESH:C560077', (30, 40))	('ocular hypertension', 'Disease', 'MESH:D009798', (237, 256))	('RVO', 'Phenotype', 'HP:0012636', (154, 157))	('diabetes mellitus', 'Disease', (298, 315))	('hypertension', 'Phenotype', 'HP:0000822', (271, 283))	('GSK', 'molecular_function', 'GO:0050321', ('30', '33'))	('CSR', 'Phenotype', 'HP:0025567', (161, 164))	('patients', 'Species', '9606', (169, 177))	('hypertension', 'Disease', 'MESH:D006973', (244, 256))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('hyperviscosity or hypercoagulability syndromes', 'Disease', 'MESH:D019851', (331, 377))	('patients', 'Species', '9606', (127, 135))	('hypertension', 'Disease', (244, 256))	('diabetes mellitus', 'Disease', 'MESH:D003920', (298, 315))	('excludes', 'NegReg', (118, 126))	('hyperviscosity or hypercoagulability syndromes', 'Disease', (331, 377))
82269	22253555	BRAF inhibition has been shown to improve recognition by antigen-specific T cells and increase intratumoural and peritumoural lymphocytes shortly after drug initiation.	('increase', 'PosReg', (86, 94))	('inhibition', 'Var', (5, 15))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('improve', 'PosReg', (34, 41))	('recognition', 'CPA', (42, 53))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('BRAF', 'Gene', (0, 4))	('tumour', 'Disease', (100, 106))	('tumour', 'Disease', (117, 123))
82270	22253555	Interestingly, patients who develop resistance to BRAF inhibition demonstrate a decrease in intratumoural and peritumoural lymphocytes.	('tumour', 'Disease', (97, 103))	('tumour', 'Disease', (114, 120))	('patients', 'Species', '9606', (15, 23))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('resistance', 'Var', (36, 46))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('decrease', 'NegReg', (80, 88))
82274	22253555	Thus, there remain many challenges in the treatment of patients with metastatic melanoma - how to best treat patients without a BRAF mutation, how to overcome resistance mechanisms that develop to BRAF and MEK inhibition and how to best combine immune and targeted therapy to optimise patient outcome.	('mutation', 'Var', (133, 141))	('man', 'Species', '9606', (19, 22))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (109, 117))	('MEK', 'Gene', (206, 209))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('MEK', 'Gene', '5609', (206, 209))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('patient', 'Species', '9606', (285, 292))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (55, 63))
82275	22253555	The availability of novel agents targeting immune system modulation and specific genetic aberrations in metastatic melanoma has given hope to those patients, who up to recent times, had limited treatment options.	('patients', 'Species', '9606', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('genetic aberrations', 'Var', (81, 100))
82429	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'))
82436	26631117	miR-409-3p and miR-605were down-regulated exclusively in G361 cells.	('miR-409-3p', 'Var', (0, 10))	('miR-605', 'Gene', '693190', (15, 22))	('miR-605', 'Gene', (15, 22))	('down-regulated', 'NegReg', (27, 41))
82441	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'))
82456	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))
82484	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))
82485	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))	('miR-211', 'Gene', (254, 261))	('upregulated', 'PosReg', (29, 40))	('miR-15a', 'Gene', (159, 166))	('bind', 'Interaction', (125, 129))	('IL-10Ralpha', 'Gene', (146, 157))	('G361', 'Var', (44, 48))	('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))
82514	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))
82515	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))	('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))	('expression', 'MPA', (37, 47))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('DcR2', 'Gene', (68, 72))	('DcR1', 'Gene', (59, 63))
82544	31063355	Our previous study found that C116S mutations in both JNK1 and JNK2 rendered them insensitive to the covalent pan-JNK inhibitor JNK-IN-8 while retaining kinase activity.	('C116S', 'Mutation', 'p.C116S', (30, 35))	('JNK2', 'Gene', (63, 67))	('C116S', 'Var', (30, 35))	('JNK', 'molecular_function', 'GO:0004705', ('63', '66'))	('kinase activity', 'MPA', (153, 168))	('kinase activity', 'molecular_function', 'GO:0016301', ('153', '168'))	('JNK1', 'Gene', (54, 58))	('JNK', 'molecular_function', 'GO:0004705', ('54', '57'))	('JNK', 'molecular_function', 'GO:0004705', ('114', '117'))	('insensitive to', 'MPA', (82, 96))	('JNK', 'molecular_function', 'GO:0004705', ('128', '131'))
82545	31063355	To delineate the specific roles of JNK1 and JNK2 in melanoma cell proliferation and invasiveness, we expressed the wild type (WT) and C116S mutants in melanoma cell lines and used JNK-IN-8 to enable chemical-genetic dissection of JNK1 and JNK2 activity.	('C116S', 'Mutation', 'p.C116S', (134, 139))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('C116S', 'Var', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('JNK', 'molecular_function', 'GO:0004705', ('180', '183'))	('JNK', 'molecular_function', 'GO:0004705', ('44', '47'))	('JNK', 'molecular_function', 'GO:0004705', ('230', '233'))	('JNK', 'molecular_function', 'GO:0004705', ('239', '242'))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('JNK', 'molecular_function', 'GO:0004705', ('35', '38'))
82546	31063355	When cells individually expressing WT or C116S JNK1/2 were subcutaneously implanted into immunodeficient mice, we again found that bypass of JNK-IN-8-mediated inhibition of JNK signaling by expression of JNK2C116S specifically resulted in enhanced tumor growth in vivo.	('JNK2C116S', 'Var', (204, 213))	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('tumor growth', 'Disease', (248, 260))	('tumor growth', 'Disease', 'MESH:D006130', (248, 260))	('JNK', 'molecular_function', 'GO:0004705', ('173', '176'))	('immunodeficient', 'Disease', 'MESH:D007153', (89, 104))	('immunodeficient', 'Disease', (89, 104))	('C116S', 'Mutation', 'p.C116S', (41, 46))	('C116S', 'Var', (41, 46))	('JNK', 'molecular_function', 'GO:0004705', ('47', '50'))	('JNK', 'molecular_function', 'GO:0004705', ('141', '144'))	('JNK signaling', 'MPA', (173, 186))	('JNK', 'molecular_function', 'GO:0004705', ('204', '207'))	('C116S', 'Mutation', 'p.C116S', (208, 213))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('enhanced', 'PosReg', (239, 247))	('inhibition', 'NegReg', (159, 169))
82548	31063355	JNK-IN-8 significantly enhanced the response to dabrafenib in resistant cells overexpressing JNK1WT, JNK2WT, and JNK1C116S but had no effect on cells expressing JNK2C116S, suggesting that JNK2 signaling is also crucial for BRAFi resistance in a subset of melanomas.	('JNK', 'molecular_function', 'GO:0004705', ('93', '96'))	('BRAF', 'Gene', '673', (223, 227))	('JNK1WT', 'Var', (93, 99))	('signaling', 'biological_process', 'GO:0023052', ('193', '202'))	('dabrafenib', 'Chemical', 'MESH:C561627', (48, 58))	('BRAF', 'Gene', (223, 227))	('JNK2WT', 'Var', (101, 107))	('JNK', 'molecular_function', 'GO:0004705', ('113', '116'))	('JNK', 'molecular_function', 'GO:0004705', ('188', '191'))	('JNK', 'molecular_function', 'GO:0004705', ('161', '164'))	('enhanced', 'PosReg', (23, 31))	('melanomas', 'Disease', 'MESH:D008545', (255, 264))	('melanomas', 'Disease', (255, 264))	('JNK1C116S', 'Var', (113, 122))	('response to dabrafenib', 'MPA', (36, 58))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('JNK', 'molecular_function', 'GO:0004705', ('0', '3'))	('JNK', 'molecular_function', 'GO:0004705', ('101', '104'))	('melanomas', 'Phenotype', 'HP:0002861', (255, 264))
82559	31063355	Although distinct drivers such as mutant BRAF and NRAS have now been established for melanoma, one unifying theme is that melanomas typically exhibit high ERK activity.	('ERK', 'molecular_function', 'GO:0004707', ('155', '158'))	('ERK', 'Gene', (155, 158))	('melanomas', 'Disease', (122, 131))	('NRAS', 'Gene', (50, 54))	('NRAS', 'Gene', '4893', (50, 54))	('BRAF', 'Gene', '673', (41, 45))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('BRAF', 'Gene', (41, 45))	('melanoma', 'Disease', (122, 130))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('ERK', 'Gene', '5594', (155, 158))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('mutant', 'Var', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
82569	31063355	RNA sequencing data derived from cutaneous melanoma clinical data sets (PanCancer Atlas; n = 448) and deposited in cBioPortal demonstrate that both JNK1 (MAPK8) and JNK2 (MAPK9) are expressed in melanomas.	('JNK2', 'Var', (165, 169))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('melanomas', 'Disease', (195, 204))	('JNK1', 'Gene', (148, 152))	('Cancer', 'Disease', (75, 81))	('melanomas', 'Phenotype', 'HP:0002861', (195, 204))	('JNK', 'molecular_function', 'GO:0004705', ('148', '151'))	('MAPK8', 'Gene', (154, 159))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('MAPK9', 'Gene', '5601', (171, 176))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('MAPK', 'molecular_function', 'GO:0004707', ('154', '158'))	('MAPK', 'molecular_function', 'GO:0004707', ('171', '175'))	('JNK', 'molecular_function', 'GO:0004705', ('165', '168'))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('MAPK8', 'Gene', '5599', (154, 159))	('melanomas', 'Disease', 'MESH:D008545', (195, 204))	('MAPK9', 'Gene', (171, 176))
82572	31063355	We used C116S mutant alleles of JNK1 (JNK1C116S) and JNK2 (JNK2C116S), which confer resistance to JNK-IN-8 without affecting the kinase activity of JNKs, to dissect the individual contribution of each kinase.	('resistance', 'MPA', (84, 94))	('JNK1', 'Gene', (32, 36))	('JNK', 'molecular_function', 'GO:0004705', ('98', '101'))	('C116S', 'Mutation', 'p.C116S', (63, 68))	('JNK', 'molecular_function', 'GO:0004705', ('38', '41'))	('JNK', 'molecular_function', 'GO:0004705', ('53', '56'))	('C116S', 'Mutation', 'p.C116S', (42, 47))	('kinase activity', 'molecular_function', 'GO:0016301', ('129', '144'))	('JNK', 'molecular_function', 'GO:0004705', ('59', '62'))	('JNK2C116S', 'Var', (59, 68))	('JNK2', 'Gene', (53, 57))	('C116S', 'Mutation', 'p.C116S', (8, 13))	('JNK', 'molecular_function', 'GO:0004705', ('32', '35'))	('C116S', 'Var', (8, 13))
82573	31063355	For our experiments, we expressed WT and mutant JNK1C116S and JNK2C116S alleles using lentiviral transduction in 501MEL, WM239A, and HMEL-T1 cell lines and used JNK-IN-8 to enable chemical-genetic dissection of JNK1 and JNK2 activity (Figure 2A,B).	('JNK', 'molecular_function', 'GO:0004705', ('161', '164'))	('-IN-', 'Chemical', 'MESH:D007204', (164, 168))	('mutant', 'Var', (41, 47))	('transduction', 'biological_process', 'GO:0009293', ('97', '109'))	('JNK', 'molecular_function', 'GO:0004705', ('220', '223'))	('JNK', 'molecular_function', 'GO:0004705', ('62', '65'))	('HMEL-T1', 'CellLine', 'CVCL:M858', (133, 140))	('JNK', 'molecular_function', 'GO:0004705', ('211', '214'))	('JNK2C116S', 'Gene', (62, 71))	('JNK', 'molecular_function', 'GO:0004705', ('48', '51'))	('JNK1C116S', 'Gene', (48, 57))
82574	31063355	Importantly, we confirmed that these mutant alleles retain signaling to c-Jun by exposing the lines to an established activator of JNKs, ultraviolet radiation (Newport, SOL-UV), and showing that c-JUN is still phosphorylated in cells expressing the C116S mutant alleles even in the presence of JNK-IN-8 (Supplementary Figure 1).	('JNK', 'molecular_function', 'GO:0004705', ('294', '297'))	('c-JUN', 'Gene', '3725', (195, 200))	('c-Jun', 'Gene', (72, 77))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('signaling', 'MPA', (59, 68))	('C116S', 'Mutation', 'p.C116S', (249, 254))	('c-JUN', 'Gene', (195, 200))	('c-Jun', 'Gene', '3725', (72, 77))	('C116S', 'Var', (249, 254))
82576	31063355	Indeed, by then using the ratio of responses of inhibitor-treated cells over control-treated cells, we found that JNK-IN-8 inhibited individual colony expansion by approximately 40% in 501MEL cells over-expressing GFP, JNK1WT, JNK2WT, or JNK1C116S compared to vehicle control but did so by only 19% in cells overexpressing JNK2C116S.	('JNK1WT', 'Var', (219, 225))	('individual colony expansion', 'CPA', (133, 160))	('JNK2WT', 'Var', (227, 233))	('over-expressing', 'PosReg', (198, 213))	('-IN-', 'Chemical', 'MESH:D007204', (117, 121))	('JNK', 'molecular_function', 'GO:0004705', ('114', '117'))	('JNK1C116S', 'Var', (238, 247))	('JNK', 'molecular_function', 'GO:0004705', ('219', '222'))	('JNK', 'molecular_function', 'GO:0004705', ('238', '241'))	('JNK', 'molecular_function', 'GO:0004705', ('323', '326'))	('JNK', 'molecular_function', 'GO:0004705', ('227', '230'))	('inhibited', 'NegReg', (123, 132))	('GFP', 'Var', (214, 217))
82577	31063355	Similarly, we observed 35% and 99% increased levels of colony formation in WM239A and HMEL-T1 cells, respectively, that overexpressed JNK2C116S and 12-28% growth inhibition in JNK-IN-8-treated cells overexpressing JNK1WT, JNK2WT, or JNK1C116S.	('increased', 'PosReg', (35, 44))	('HMEL-T1', 'CellLine', 'CVCL:M858', (86, 93))	('JNK', 'molecular_function', 'GO:0004705', ('176', '179'))	('formation', 'biological_process', 'GO:0009058', ('62', '71'))	('JNK2C116S', 'Var', (134, 143))	('JNK', 'molecular_function', 'GO:0004705', ('134', '137'))	('JNK', 'molecular_function', 'GO:0004705', ('214', '217'))	('JNK', 'molecular_function', 'GO:0004705', ('233', '236'))	('growth inhibition', 'CPA', (155, 172))	('colony formation', 'CPA', (55, 71))	('JNK', 'molecular_function', 'GO:0004705', ('222', '225'))
82582	31063355	Indeed, by then using the ratio of responses of inhibitor-treated cells to control-treated cells, we found that 501MEL and HMEL-T1 cells expressing JNK2C116S were alone able to significantly augment cell invasion by 84% and 416%, respectively, as compared to GFP control cells [n = 10 (Figure 3A,B)].	('JNK2C116S', 'Var', (148, 157))	('cell invasion', 'CPA', (199, 212))	('JNK', 'molecular_function', 'GO:0004705', ('148', '151'))	('augment', 'PosReg', (191, 198))	('HMEL-T1', 'CellLine', 'CVCL:M858', (123, 130))
82583	31063355	We also observed a 67 +- 3.1% reduction in 501MEL cells overexpressing the C116S JNK1 mutant but not in HMEL-T1 cells.	('C116S', 'Mutation', 'p.C116S', (75, 80))	('HMEL-T1', 'CellLine', 'CVCL:M858', (104, 111))	('JNK1', 'Gene', (81, 85))	('reduction', 'NegReg', (30, 39))	('JNK', 'molecular_function', 'GO:0004705', ('81', '84'))	('C116S', 'Var', (75, 80))
82584	31063355	However, there was no significant difference in cell migration among cells overexpressing JNK1/2WT or JNK1/2C116S.	('cell migration', 'CPA', (48, 62))	('cell migration', 'biological_process', 'GO:0016477', ('48', '62'))	('JNK', 'molecular_function', 'GO:0004705', ('102', '105'))	('C116S', 'Mutation', 'p.C116S', (108, 113))	('JNK', 'molecular_function', 'GO:0004705', ('90', '93'))	('JNK1/2WT', 'Var', (90, 98))	('JNK1/2C116S', 'Var', (102, 113))
82587	31063355	When cells stably expressing JNK1/2WT or JNK1/2C116S were subcutaneously implanted into opposite flanks of immunodeficient NCr nude mice, we again found that only JNK2C116S-mediated bypass of JNK inhibition by JNK-IN-8 resulted in the most robust tumor growth (Figure 4A-E).	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('C116S', 'Mutation', 'p.C116S', (47, 52))	('C116S', 'Mutation', 'p.C116S', (167, 172))	('JNK', 'molecular_function', 'GO:0004705', ('41', '44'))	('JNK1/2C116S', 'Var', (41, 52))	('JNK', 'molecular_function', 'GO:0004705', ('163', '166'))	('JNK2C116S-mediated', 'Var', (163, 181))	('immunodeficient NCr', 'Disease', (107, 126))	('JNK', 'molecular_function', 'GO:0004705', ('192', '195'))	('JNK', 'Gene', (192, 195))	('nude mice', 'Species', '10090', (127, 136))	('immunodeficient NCr', 'Disease', 'MESH:D007153', (107, 126))	('JNK', 'molecular_function', 'GO:0004705', ('29', '32'))	('JNK', 'molecular_function', 'GO:0004705', ('210', '213'))	('tumor growth', 'Disease', (247, 259))	('tumor growth', 'Disease', 'MESH:D006130', (247, 259))
82588	31063355	Interestingly JNK1C116S-expressing tumors exhibited a slight decrement in tumor growth following treatment with JNK-IN-8 (Figure 4C), also consistent with the notion that JNK2 is the more important driver of tumorigenesis relative to JNK1.	('JNK', 'molecular_function', 'GO:0004705', ('171', '174'))	('JNK', 'molecular_function', 'GO:0004705', ('112', '115'))	('decrement', 'NegReg', (61, 70))	('tumor growth', 'Disease', (74, 86))	('tumor', 'Disease', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('JNK', 'molecular_function', 'GO:0004705', ('14', '17'))	('tumor', 'Disease', (35, 40))	('-IN-', 'Chemical', 'MESH:D007204', (115, 119))	('tumor', 'Disease', (208, 213))	('JNK', 'molecular_function', 'GO:0004705', ('234', '237'))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor growth', 'Disease', 'MESH:D006130', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (35, 41))	('JNK1C116S-expressing', 'Var', (14, 34))
82592	31063355	Notably, in the tumors expressing JNK2C116S, COX-2 levels were higher following JNK-IN-8 treatment than those of tumor samples overexpressing JNK1WT, JNK2WT, and JNK1C116S.	('tumor', 'Disease', (113, 118))	('JNK', 'molecular_function', 'GO:0004705', ('150', '153'))	('JNK', 'molecular_function', 'GO:0004705', ('34', '37'))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('JNK', 'molecular_function', 'GO:0004705', ('142', '145'))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('JNK2C116S', 'Var', (34, 43))	('tumor', 'Disease', (16, 21))	('JNK', 'molecular_function', 'GO:0004705', ('162', '165'))	('JNK', 'molecular_function', 'GO:0004705', ('80', '83'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (16, 22))	('higher', 'PosReg', (63, 69))	('COX-2', 'Gene', '4513', (45, 50))	('COX-2', 'Gene', (45, 50))
82595	31063355	For this analysis, we identified proteins that were up- or downregulated in both WT and C116S mutants of JNK1/2 in the absence of JNK-IN-8.	('JNK1/2', 'Gene', (105, 111))	('JNK', 'molecular_function', 'GO:0004705', ('105', '108'))	('downregulated', 'NegReg', (59, 72))	('up-', 'PosReg', (52, 55))	('JNK', 'molecular_function', 'GO:0004705', ('130', '133'))	('C116S', 'Var', (88, 93))	('-IN-', 'Chemical', 'MESH:D007204', (133, 137))	('C116S', 'Mutation', 'p.C116S', (88, 93))
82599	31063355	Given the ability of JNK2 to drive tumorigenic properties of melanoma cells, including the apparent activation of RAS signaling in the proteomic pathway analysis described above, we then asked whether JNK2 could impact resistance to targeted therapies.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('drive', 'PosReg', (29, 34))	('JNK2', 'Gene', (21, 25))	('resistance to', 'CPA', (219, 232))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('RAS signaling', 'MPA', (114, 127))	('JNK2', 'Var', (201, 205))	('tumor', 'Disease', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('impact', 'Reg', (212, 218))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('JNK', 'molecular_function', 'GO:0004705', ('201', '204'))	('activation', 'PosReg', (100, 110))	('signaling', 'biological_process', 'GO:0023052', ('118', '127'))	('JNK', 'molecular_function', 'GO:0004705', ('21', '24'))
82600	31063355	Using phospho-c-Jun as a reporter of JNK pathway activity, we observed a high level of expression of phosphorylated JNK, phosphorylated c-Jun, and total c-Jun in m229R and SK-MEL28R human melanoma cells resistant to the BRAF inhibitor (BRAFi) compared to paired isogenic m229S and SK-MEL28S sensitive cells (Figure 5A).	('SK-MEL28S', 'CellLine', 'CVCL:0526', (281, 290))	('c-Jun', 'Gene', '3725', (136, 141))	('c-Jun', 'Gene', (153, 158))	('m229S', 'Chemical', '-', (271, 276))	('c-Jun', 'Gene', (136, 141))	('m229R', 'Var', (162, 167))	('JNK', 'molecular_function', 'GO:0004705', ('37', '40'))	('BRAF', 'Gene', '673', (220, 224))	('c-Jun', 'Gene', '3725', (14, 19))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('BRAF', 'Gene', (220, 224))	('c-Jun', 'Gene', (14, 19))	('SK-MEL28R', 'Chemical', '-', (172, 181))	('m229R', 'Chemical', '-', (162, 167))	('BRAF', 'Gene', '673', (236, 240))	('human', 'Species', '9606', (182, 187))	('BRAF', 'Gene', (236, 240))	('JNK', 'molecular_function', 'GO:0004705', ('116', '119'))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('c-Jun', 'Gene', '3725', (153, 158))
82604	31063355	In addition, to confirm the effect of JNK2 in the adaptive BRAFi resistance, we compared the dose-response curve upon administration of the pan-JNK inhibitor among cells over-expressing WT and mutated JNK1 and JNK2.	('JNK2', 'Gene', (210, 214))	('JNK', 'molecular_function', 'GO:0004705', ('38', '41'))	('JNK', 'molecular_function', 'GO:0004705', ('144', '147'))	('mutated', 'Var', (193, 200))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('JNK', 'molecular_function', 'GO:0004705', ('210', '213'))	('JNK', 'molecular_function', 'GO:0004705', ('201', '204'))	('JNK1', 'Gene', (201, 205))
82605	31063355	We found that JNK-IN-8 significantly enhanced the effect of dabrafenib on resistant cells expressing JNK1WT, JNK1C116S, and JNK2WT but had no such effect on cells expressing JNK2C116S (Figure 5C-G).	('JNK', 'molecular_function', 'GO:0004705', ('174', '177'))	('JNK', 'molecular_function', 'GO:0004705', ('14', '17'))	('effect', 'MPA', (50, 56))	('JNK', 'molecular_function', 'GO:0004705', ('101', '104'))	('dabrafenib', 'Chemical', 'MESH:C561627', (60, 70))	('JNK1WT', 'Var', (101, 107))	('JNK1C116S', 'Var', (109, 118))	('JNK', 'molecular_function', 'GO:0004705', ('109', '112'))	('enhanced', 'PosReg', (37, 45))	('JNK', 'molecular_function', 'GO:0004705', ('124', '127'))	('-IN-', 'Chemical', 'MESH:D007204', (17, 21))
82608	31063355	These data suggest that activation of JNK2 is sufficient for inducing the BRAFi resistance in this subset of melanoma cell lines.	('JNK2', 'Gene', (38, 42))	('activation', 'Var', (24, 34))	('JNK', 'molecular_function', 'GO:0004705', ('38', '41'))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('inducing', 'PosReg', (61, 69))
82615	31063355	Importantly, our data strongly suggest that concomitant inhibition of JNK1 by JNK-IN-8 in the context of JNK2C116S expression (and intact JNK2 signaling) contributes to tumor progression.	('inhibition', 'NegReg', (56, 66))	('JNK', 'molecular_function', 'GO:0004705', ('105', '108'))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('JNK-IN-8', 'Gene', (78, 86))	('JNK', 'molecular_function', 'GO:0004705', ('78', '81'))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('JNK', 'molecular_function', 'GO:0004705', ('70', '73'))	('JNK2C116S', 'Var', (105, 114))	('tumor', 'Disease', (169, 174))	('JNK', 'molecular_function', 'GO:0004705', ('138', '141'))	('JNK1', 'Gene', (70, 74))	('signaling', 'biological_process', 'GO:0023052', ('143', '152'))
82616	31063355	If this were the case, one would expect that JNK1C116S-expressing cells and tumors might suffer a decrement in invasiveness or progression.	('invasiveness', 'CPA', (111, 123))	('progression', 'CPA', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('decrement', 'NegReg', (98, 107))	('JNK1C116S-expressing', 'Var', (45, 65))	('JNK', 'molecular_function', 'GO:0004705', ('45', '48'))
82617	31063355	This is observed in the invasiveness of 501MEL (Figure 3A) and to a less significant degree in JNK1C116S-expressing HMEL-T1 tumors (Figure 4C).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('HMEL-T1 tumors', 'Disease', 'MESH:C538397', (116, 130))	('JNK1C116S-expressing', 'Var', (95, 115))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('HMEL-T1 tumors', 'Disease', (116, 130))	('501MEL', 'Disease', (40, 46))	('JNK', 'molecular_function', 'GO:0004705', ('95', '98'))
82618	31063355	Inhibitors of JNK2, by preventing both its activation and cellular activity, could potentially be effective inhibitors of BRAF mutant melanoma.	('JNK2', 'Gene', (14, 18))	('JNK', 'molecular_function', 'GO:0004705', ('14', '17'))	('BRAF', 'Gene', '673', (122, 126))	('Inhibitors', 'Var', (0, 10))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('cellular activity', 'MPA', (58, 75))	('preventing', 'NegReg', (23, 33))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('activation', 'MPA', (43, 53))
82629	31063355	In brief, 10 mug of lentiviral plasmids (pLenti6/GFP, pLenti6/V5-JNK1WT, pLenti6/V5-JNK1C116S, pLenti6/V5-JNK2WT, and pLenti6/V5-JNK2C116S) and 0.3 mug of VSVG/2.7 mug of Delta8.9 Packaging Mix were mixed in 1.5 mL of Opti-MEM medium.	('Delta8', 'Mutation', 'c.del8', (171, 177))	('mug', 'molecular_function', 'GO:0043739', ('148', '151'))	('mug', 'molecular_function', 'GO:0043739', ('164', '167'))	('Opti-MEM medium', 'Chemical', '-', (218, 233))	('pLenti6/V5-JNK1WT', 'Var', (54, 71))	('JNK', 'molecular_function', 'GO:0004705', ('106', '109'))	('JNK', 'molecular_function', 'GO:0004705', ('84', '87'))	('pLenti6/V5-JNK1C116S', 'Var', (73, 93))	('mug', 'molecular_function', 'GO:0043739', ('13', '16'))	('JNK', 'molecular_function', 'GO:0004705', ('129', '132'))	('JNK', 'molecular_function', 'GO:0004705', ('65', '68'))
82642	31063355	Dynabeads protein A (50 muL) was coated with 10 mug of targeted antibody p-JNK (Cell Signaling) overnight at 4  C according to the manufacturer's instructions (Life Technology).	('p-JNK', 'Var', (73, 78))	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('mug', 'molecular_function', 'GO:0043739', ('48', '51'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('muL', 'Gene', '4591', (24, 27))	('Signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('muL', 'Gene', (24, 27))	('JNK', 'molecular_function', 'GO:0004705', ('75', '78'))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))
82649	31063355	Eight mice were used per condition: JNK1WT/JNK1C116S vehicle, JNK1WT/JNK1C116S JNK-IN-8, JNK2WT/JNK2C116S vehicle, and JNK2WT/JNK2C116S JNK-IN-8 (for a total of 32 mice).	('JNK', 'molecular_function', 'GO:0004705', ('96', '99'))	('JNK', 'molecular_function', 'GO:0004705', ('43', '46'))	('JNK', 'molecular_function', 'GO:0004705', ('36', '39'))	('JNK1WT/JNK1C116S', 'Var', (62, 78))	('JNK', 'molecular_function', 'GO:0004705', ('89', '92'))	('mice', 'Species', '10090', (164, 168))	('JNK', 'molecular_function', 'GO:0004705', ('136', '139'))	('mice', 'Species', '10090', (6, 10))	('JNK', 'molecular_function', 'GO:0004705', ('119', '122'))	('JNK', 'molecular_function', 'GO:0004705', ('79', '82'))	('JNK', 'molecular_function', 'GO:0004705', ('69', '72'))	('JNK2WT/JNK2C116S', 'Var', (119, 135))	('JNK1WT/JNK1C116S', 'Var', (36, 52))	('JNK2WT/JNK2C116S', 'Var', (89, 105))	('-IN-', 'Chemical', 'MESH:D007204', (139, 143))	('JNK', 'molecular_function', 'GO:0004705', ('62', '65'))	('-IN-', 'Chemical', 'MESH:D007204', (82, 86))	('JNK', 'molecular_function', 'GO:0004705', ('126', '129'))
82659	33619278	Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis Melanoma is the most lethal skin malignancy, driven by genetic and epigenetic alterations in the complex tumour microenvironment.	('skin malignancy', 'Disease', (135, 150))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('skin malignancy', 'Disease', 'MESH:D012878', (135, 150))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('Melanoma', 'Disease', 'MESH:D008545', (107, 115))	('Melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('skin malignancy', 'Phenotype', 'HP:0008069', (135, 150))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('Melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', (26, 34))	('tumour', 'Disease', (212, 218))	('epigenetic alterations', 'Var', (174, 196))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
82665	33619278	The anti-tumor effect of silencing ZNF180 is further validated using in vivo xenografts.	('silencing', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('ZNF180', 'Gene', '7733', (35, 41))	('ZNF180', 'Gene', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))
82672	33619278	Mutations in BRAF, NRAS, NF1, and KIT have been all implicated as melanoma drivers.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('NRAS', 'Gene', (19, 23))	('BRAF', 'Gene', '673', (13, 17))	('NRAS', 'Gene', '4893', (19, 23))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('KIT', 'Gene', '3815', (34, 37))	('NF1', 'Gene', (25, 28))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('NF1', 'Gene', '4763', (25, 28))	('KIT', 'Gene', (34, 37))
82685	33619278	This integrative approach has proven effective in identifying causal molecular alterations in complex diseases such as Alzheimer's disease, asthma, breast cancer, and gastric cancer.	("Alzheimer's disease", 'Disease', (119, 138))	('alterations', 'Var', (79, 90))	('asthma', 'Phenotype', 'HP:0002099', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('gastric cancer', 'Disease', (167, 181))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (119, 138))	('asthma', 'Disease', (140, 146))	('asthma', 'Disease', 'MESH:D001249', (140, 146))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (119, 138))
82691	33619278	We identified PTPN6 and PTPRCAP as potential modulators of epigenetic regulation of the leukocyte activation pathway in M7 (see Epigenetic silencing of T-cell activation leads to poor prognosis in Supplementary Methods; epigenetic regulatory network in Supplementary Data 6).	('regulation', 'biological_process', 'GO:0065007', ('70', '80'))	('PTPRCAP', 'Gene', '5790', (24, 31))	('leukocyte activation pathway', 'Pathway', (88, 116))	('T-cell activation', 'biological_process', 'GO:0042110', ('152', '169'))	('leukocyte activation', 'biological_process', 'GO:0045321', ('88', '108'))	('leads to', 'Reg', (170, 178))	('PTPRCAP', 'Gene', (24, 31))	('Epigenetic silencing', 'Var', (128, 148))	('PTPN6', 'Gene', (14, 19))	('poor prognosis', 'CPA', (179, 193))	('PTPN6', 'Gene', '5777', (14, 19))
82692	33619278	M112 captured the PD1/PD-L1 signaling pathway, including PD-L1 and several key regulators of the PD-L1 transcription pathway as its hubs, such as STAT1 and IRF1.	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('IRF1', 'Gene', '3659', (156, 160))	('PD-L1', 'Gene', '29126', (97, 102))	('signaling pathway', 'biological_process', 'GO:0007165', ('28', '45'))	('PD-L1', 'Gene', (22, 27))	('PD-L1', 'Gene', (57, 62))	('PD-L1', 'Gene', '29126', (57, 62))	('M112', 'Var', (0, 4))	('PD-L1', 'Gene', '29126', (22, 27))	('IRF1', 'Gene', (156, 160))	('PD-L1', 'Gene', (97, 102))
82696	33619278	Genes in M7 sub-modules were expressed in distinct cell types, predominantly melanoma cells (expressed in M401, M402, M110, M639, and M642), M1-macrophages (expressed in M400, M401, and M642), B-cells (expressed in M111), CD8+ T cells (expressed in M399, M401, M402, and M403) and CD4+ T cells (expressed in M399, M401, and M402, Supplementary Fig.	('M401', 'Var', (314, 318))	('CD4', 'Gene', '920', (281, 284))	('CD8', 'Gene', (222, 225))	('M403', 'Var', (271, 275))	('CD4', 'Gene', (281, 284))	('CD8', 'Gene', '925', (222, 225))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('M402', 'Var', (261, 265))	('melanoma', 'Disease', (77, 85))	('M401', 'Var', (255, 259))	('M402', 'Var', (324, 328))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('M399', 'Var', (249, 253))	('M399', 'Var', (308, 312))	('M402', 'Var', (112, 116))
82698	33619278	For example, the interferon-gamma (IFN-gamma) response modules M401 and M402 significantly overlap the macrophage-enriched modules in the CLS3 sc-network (cFET p = 9.48E - 20).	('interferon-gamma', 'Gene', '3458', (17, 33))	('M402', 'Var', (72, 76))	('M401', 'Var', (63, 67))	('interferon-gamma', 'molecular_function', 'GO:0005133', ('17', '33'))	('interferon-gamma', 'Gene', (17, 33))
82716	33619278	M205 includes a nuclear pore component (NUP205) and a splicing factor (TNPO3).	('NUP205', 'Gene', '23165', (40, 46))	('M205', 'Var', (0, 4))	('TNPO3', 'Gene', '23534', (71, 76))	('splicing', 'biological_process', 'GO:0045292', ('54', '62'))	('TNPO3', 'Gene', (71, 76))	('NUP205', 'Gene', (40, 46))	('nuclear pore', 'cellular_component', 'GO:0005643', ('16', '28'))
82727	33619278	To validate the 18 candidate regulators of the molecular networks underlying primary melanoma prognosis, we performed siRNA knockdown experiments in SKmel147 (NRAS mutant) and A375 (BRAF mutant) cell lines (see siRNA screening of candidate targets in Supplementary Methods).	('NRAS', 'Gene', (159, 163))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('SKmel147', 'Chemical', '-', (149, 157))	('mutant', 'Var', (187, 193))	('NRAS', 'Gene', '4893', (159, 163))	('A375', 'CellLine', 'CVCL:0132', (176, 180))	('BRAF', 'Gene', '673', (182, 186))	('SKmel147', 'Gene', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('BRAF', 'Gene', (182, 186))
82734	33619278	Of these candidates, only the knock-down of ZNF180 showed significant anti-proliferative effects in SKmel147.	('SKmel147', 'Chemical', '-', (100, 108))	('ZNF180', 'Gene', '7733', (44, 50))	('ZNF180', 'Gene', (44, 50))	('anti-proliferative effects', 'CPA', (70, 96))	('knock-down', 'Var', (30, 40))
82735	33619278	Therefore, we further investigated the anti-proliferative effect of ZNF180 silencing in vivo.	('ZNF180', 'Gene', (68, 74))	('silencing', 'Var', (75, 84))	('ZNF180', 'Gene', '7733', (68, 74))
82738	33619278	Mice injected with shZNF180 transduced cells showed significantly reduced tumor growth (p < 0.0001) and weight at termination (p < 0.0001) compared to mice injected with cells carrying a non-targeting shRNA (Fig.	('ZNF180', 'Gene', (21, 27))	('ZNF180', 'Gene', '7733', (21, 27))	('reduced tumor', 'Disease', (66, 79))	('weight at termination', 'CPA', (104, 125))	('mice', 'Species', '10090', (151, 155))	('reduced tumor', 'Disease', 'MESH:C536418', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('transduced', 'Var', (28, 38))	('Mice', 'Species', '10090', (0, 4))
82742	33619278	Genes differentially expressed in response to silencing ZNF180 (termed siZNF180-DEGs; Supplementary Data 8) were significantly enriched in the subnetwork of ZNF180 in the pSKCM network using threshold-free rank-rank hypergeometric overlap test (see Analysis of RNA-sequencing data of siRNA knock-down SKmel147 cells in Supplementary Methods; Supplementary Fig.	('ZNF180', 'Gene', (56, 62))	('ZNF180', 'Gene', '7733', (56, 62))	('silencing', 'Var', (46, 55))	('ZNF180', 'Gene', (73, 79))	('ZNF180', 'Gene', (157, 163))	('ZNF180', 'Gene', '7733', (73, 79))	('SKmel147', 'Chemical', '-', (301, 309))	('RNA', 'cellular_component', 'GO:0005562', ('261', '264'))	('ZNF180', 'Gene', '7733', (157, 163))
82753	33619278	In contrast, those enriched for the genes downregulated by siZNF180 were associated with DNA repair, epithelial-mesenchymal transition (M25), oncogenesis (M24, M25, and M257), pre-mRNA splicing (M25 and M30), protein modification/degradation and chromatin modification/remodeling (Fig.	('M25', 'Var', (160, 163))	('oncogenesis', 'biological_process', 'GO:0007048', ('142', '153'))	('downregulated', 'NegReg', (42, 55))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('protein', 'cellular_component', 'GO:0003675', ('209', '216'))	('pre', 'molecular_function', 'GO:0003904', ('176', '179'))	('chromatin modification', 'biological_process', 'GO:0016569', ('246', '268'))	('protein modification/degradation', 'CPA', (209, 241))	('chromatin modification/remodeling', 'CPA', (246, 279))	('chromatin', 'cellular_component', 'GO:0000785', ('246', '255'))	('DNA repair', 'biological_process', 'GO:0006281', ('89', '99'))	('protein modification', 'biological_process', 'GO:0036211', ('209', '229'))	('pre-mRNA splicing', 'CPA', (176, 193))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('101', '134'))	('M30', 'Var', (203, 206))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('176', '193'))	('M25', 'Var', (195, 198))	('ZNF180', 'Gene', (61, 67))	('ZNF180', 'Gene', '7733', (61, 67))	('chromatin modification', 'biological_process', 'GO:0006325', ('246', '268'))	('degradation', 'biological_process', 'GO:0009056', ('230', '241'))	('M257', 'Var', (169, 173))	('DNA repair', 'CPA', (89, 99))	('epithelial-mesenchymal transition', 'CPA', (101, 134))	('M24', 'Var', (155, 158))	('oncogenesis', 'CPA', (142, 153))
82776	33619278	As there is only one tumor with somatic STAT1 mutation in pSKCM, we do not have the power to determine the relationship between STAT1 mutation and M1 macrophage abundance.	('tumor', 'Disease', (21, 26))	('mutation', 'Var', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('STAT1', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
82783	33619278	High expression of a co-inhibitory T-cell checkpoint, PD-L1, was also found to be associated with a good prognosis in pSKCM (log-rank p = 1.32E - 2).	('pSKCM', 'Disease', (118, 123))	('High expression', 'Var', (0, 15))	('PD-L1', 'Gene', (54, 59))	('PD-L1', 'Gene', '29126', (54, 59))
82789	33619278	2D) also suggests high PD-L1 as a marker for the INF-gamma dominant microenvironment.	('PD-L1', 'Gene', '29126', (23, 28))	('high', 'Var', (18, 22))	('PD-L1', 'Gene', (23, 28))
82792	33619278	Consistent with the suppression of DNA repair pathways in melanoma cells by the knockdown of ZNF180, the module primarily regulated by siZNF180, M25, harbors interactions between DNA repair pathways involving MSH2, and oncogenic pathways involving PIK3CA, Rho kinases, and GTPases.	('MSH2', 'Gene', '4436', (209, 213))	('oncogenic pathways', 'Pathway', (219, 237))	('PIK3CA', 'Gene', '5290', (248, 254))	('ZNF180', 'Gene', '7733', (137, 143))	('ZNF180', 'Gene', (137, 143))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))	('DNA repair pathways', 'Pathway', (179, 198))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('DNA repair', 'biological_process', 'GO:0006281', ('179', '189'))	('PIK3CA', 'Gene', (248, 254))	('suppression', 'NegReg', (20, 31))	('knockdown', 'Var', (80, 89))	('MSH2', 'Gene', (209, 213))	('interactions', 'Interaction', (158, 170))	('DNA repair', 'biological_process', 'GO:0006281', ('35', '45'))	('ZNF180', 'Gene', (93, 99))	('ZNF180', 'Gene', '7733', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
82794	33619278	In contrast, several modules upregulated by silencing of ZNF180 include tumor suppressors such as BRMS1 (Breast cancer metastasis suppressor 1; within M170) and negative regulator of cell cycle GADD45GIP1 as hub genes.	('Breast cancer metastasis suppressor 1', 'Gene', (105, 142))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('upregulated', 'PosReg', (29, 40))	('Breast cancer metastasis suppressor 1', 'Gene', '25855', (105, 142))	('tumor', 'Disease', (72, 77))	('BRMS1', 'Gene', (98, 103))	('GIP', 'molecular_function', 'GO:0005095', ('200', '203'))	('GADD45GIP1', 'Gene', '90480', (194, 204))	('ZNF180', 'Gene', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('BRMS1', 'Gene', '25855', (98, 103))	('ZNF180', 'Gene', '7733', (57, 63))	('Breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('silencing', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GADD45GIP1', 'Gene', (194, 204))	('cell cycle', 'biological_process', 'GO:0007049', ('183', '193'))
82796	33619278	PAI-1 has been shown to promote macrophage infiltration in melanoma via phosphorylation of FAK-Tyr925  (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('PAI-1', 'Gene', (0, 5))	('Tyr925', 'Chemical', '-', (95, 101))	('FAK', 'molecular_function', 'GO:0004717', ('91', '94'))	('phosphorylation', 'MPA', (72, 87))	('FAK-Tyr925', 'Var', (91, 101))	('PAI-1', 'Gene', '5054', (0, 5))	('promote', 'PosReg', (24, 31))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('macrophage infiltration', 'CPA', (32, 55))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
82865	27831464	We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.	('presence', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNAs', 'Disease', (114, 118))	('cancer', 'Disease', (137, 143))	('heterochromatin', 'cellular_component', 'GO:0000792', ('30', '45'))	('heterochromatin', 'Var', (30, 45))
82867	27831464	There are several different types of DNA alterations and one that is frequently seen in cancer cells is known as a "copy number alteration" (or CNA for short).	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('alterations', 'Var', (41, 52))
82871	27831464	Analysing datasets from almost 6000 patients with 20 different types of cancer showed that mutations in several genes are linked to a higher or lower number of CNAs in patients.	('patients', 'Species', '9606', (36, 44))	('lower', 'NegReg', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (168, 176))	('CNAs', 'Disease', (160, 164))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
82879	27831464	It has also been observed that DNA contact points in genome-wide chromosome conformation capture (HiC) proximity maps are more likely to become CNA breakpoints.	('HiC', 'Gene', '29969', (98, 101))	('HiC', 'Gene', (98, 101))	('DNA contact points', 'Var', (31, 49))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
82880	27831464	The observation that certain genes tend to be mutated in CNA-rich (TP53 and SPOP) or CNA-poor (CTCF and ARID1A) cancers implies that, besides epigenetic factors, the genetic background of the cell influences CNA variation.	('SPOP', 'Gene', '8405', (76, 80))	('CTCF', 'Gene', '10664', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('mutated', 'Var', (46, 53))	('CNA-rich', 'Disease', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('SPOP', 'Gene', (76, 80))	('ARID1A', 'Gene', '8289', (104, 110))	('ARID1A', 'Gene', (104, 110))	('cancers', 'Disease', (112, 119))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('influences', 'Reg', (197, 207))	('CTCF', 'Gene', (95, 99))
82882	27831464	We identify mutations in genes that are statistically linked to the number of CNAs in cancer patients.	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CNAs', 'Disease', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('linked', 'Reg', (54, 60))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', (86, 92))
82893	27831464	Mutations in 62 of these genes are associated with significantly fewer CNAs, whereas one gene (TP53) is associated with a significantly higher number of CNAs (see Supplementary file 1 for the full gene list and Figure 2A for two examples).	('Mutations', 'Var', (0, 9))	('fewer', 'NegReg', (65, 70))	('CNAs', 'Disease', (71, 75))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
82896	27831464	We contemplated whether mutations in the remaining 48 genes contribute to the progression of the cancer or are just a by-product of the increased mutation rates found in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (170, 176))	('contribute', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
82897	27831464	Accordingly, we used functional impact scores to estimate the pathogenicity of the mutations found in CONIM genes that had not been previously implicated in cancer progression.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('CONIM genes', 'Gene', (102, 113))	('cancer', 'Disease', (157, 163))
82898	27831464	To estimate the temporal order of somatic events, we compared the variant allele fractions (VAFs) of mutations in non-cancer CONIM genes to the VAFs of mutations from equally often mutated genes.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('non-cancer', 'Disease', (114, 124))	('mutations', 'Var', (101, 110))	('non-cancer', 'Disease', 'MESH:D009369', (114, 124))
82899	27831464	We found that in two out of five cancer types tested, mutations in CONIM genes were associated with a lower VAF (Figure 2:figure supplement 1).	('lower', 'NegReg', (102, 107))	('cancer', 'Disease', (33, 39))	('CONIM genes', 'Gene', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (54, 63))	('VAF', 'CPA', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
82900	27831464	To investigate the potential mechanisms through which mutations in genes encoding CONIM proteins affect the amount of CNAs in a tumor, we explored the functions of the CONIM gene set.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('affect', 'Reg', (97, 103))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CONIM', 'Gene', (82, 87))	('tumor', 'Disease', (128, 133))	('amount of CNAs in a', 'MPA', (108, 127))
82909	27831464	The overlap between the mutated genes found in samples with a differential CNA length and those found in samples with a differential CNA number was larger than expected by chance (p < e-16; chi-square test).	('e-16', 'Gene', (184, 188))	('e-16', 'Gene', '26766', (184, 188))	('differential', 'Var', (62, 74))
82911	27831464	Mutations in components of the SWI/SNF complex have been observed in different tumor types, but their contribution to carcinogenesis is only poorly understood.	('carcinogenesis', 'Disease', (118, 132))	('tumor', 'Disease', (79, 84))	('SWI/SNF', 'Gene', (31, 38))	('observed', 'Reg', (57, 65))	('Mutations', 'Var', (0, 9))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('31', '46'))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
82914	27831464	Instead, we explicitly tested whether epigenetic marks around breakpoints are enriched in those tissues where the breakpoint frequently occurs during cancer development versus those tissues where the breakpoint does not occur.	('tested', 'Reg', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('epigenetic marks', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
82918	27831464	We found that non-silent mutations in these genes affect a greater proportion of samples in cancer types (luad, lusc, lihc and skcm) that show a strong H3K9me3 enrichment (> 2-fold change in 10 kb windows around breakpoints; p < 0.05; Mann-Whitney-Wilcoxon test) in their tissue-of-origin (p < e-6; chi-square test).	('mutations', 'Var', (25, 34))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('affect', 'Reg', (50, 56))	('H3K9me3', 'Protein', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('non-silent mutations', 'Var', (14, 34))
82924	27831464	Mutations in NIPBL have been associated with chromatin decompaction and, indeed, mutations that are predicted to have a more severe effect on NIPBL exhibit a stronger effect on chromatin.	('NIPBL', 'Gene', '25836', (13, 18))	('NIPBL', 'Gene', (13, 18))	('NIPBL', 'Gene', '25836', (142, 147))	('stronger effect', 'PosReg', (158, 173))	('NIPBL', 'Gene', (142, 147))	('Mutations', 'Var', (0, 9))	('chromatin decompaction', 'MPA', (45, 67))	('chromatin', 'cellular_component', 'GO:0000785', ('45', '54'))	('chromatin', 'cellular_component', 'GO:0000785', ('177', '186'))	('mutations', 'Var', (81, 90))	('associated', 'Reg', (29, 39))	('chromatin', 'MPA', (177, 186))
82925	27831464	We therefore tested whether mutations in the HEAT domain, which is necessary to target NIPBL to sites of DNA damage, have a stronger effect on CNA number in cancers than do other missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CNA number', 'MPA', (143, 153))	('NIPBL', 'Gene', '25836', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('NIPBL', 'Gene', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('cancers', 'Disease', (157, 164))	('effect', 'Reg', (133, 139))	('mutations', 'Var', (28, 37))
82926	27831464	We also checked whether cancers with truncating mutations in the N-terminus of NIPBL are associated with a significantly lower CNA number as compared to those with truncating mutations in the C-terminus (Figure 5B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NIPBL', 'Gene', '25836', (79, 84))	('CNA number', 'CPA', (127, 137))	('NIPBL', 'Gene', (79, 84))	('lower', 'NegReg', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('truncating mutations in', 'Var', (37, 60))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
82927	27831464	In both cases, we observed a significant difference, with mutations that have an anticipated stronger functional or structural impact on NIPBL being associated with fewer CNAs.	('CNAs', 'Disease', (171, 175))	('mutations', 'Var', (58, 67))	('NIPBL', 'Gene', '25836', (137, 142))	('NIPBL', 'Gene', (137, 142))	('fewer', 'NegReg', (165, 170))
82937	27831464	One explanation for this observation could be that mutations in CONIM genes tend to occur late during cancer development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (51, 60))	('CONIM genes', 'Gene', (64, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
82941	27831464	Inactivation of TP53 decreases sensitivity to apoptosis, and therefore more DNA damage (including CNAs) is tolerated.	('decreases', 'NegReg', (21, 30))	('sensitivity to apoptosis', 'MPA', (31, 55))	('TP53', 'Gene', '7157', (16, 20))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('TP53', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
82943	27831464	The CNA-rich group has been associated with recurrent mutations in TP53 and the mutation-rich (and CNA-depleted) group with mutations in ARID1A and CTCF.	('ARID1A', 'Gene', '8289', (137, 143))	('mutations', 'Var', (124, 133))	('ARID1A', 'Gene', (137, 143))	('associated', 'Reg', (28, 38))	('mutations', 'Var', (54, 63))	('CTCF', 'Gene', (148, 152))	('TP53', 'Gene', '7157', (67, 71))	('CTCF', 'Gene', '10664', (148, 152))	('TP53', 'Gene', (67, 71))
82950	27831464	ATM is required for the repair of DNA double-strand breaks in heterochromatic regions, a process which is characterised by slow repair kinetics.	('ATM', 'Gene', (0, 3))	('DNA double-strand breaks', 'Var', (34, 58))	('DNA', 'cellular_component', 'GO:0005574', ('34', '37'))	('ATM', 'Gene', '472', (0, 3))
82951	27831464	ATM-mediated phosphorylation of KAP1 (KRAB-associated protein 1) triggers local decondensation of heterochromatin and thereby facilitates efficient repair.	('facilitates', 'PosReg', (126, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('13', '28'))	('heterochromatin', 'Protein', (98, 113))	('KAP1', 'Gene', (32, 36))	('KRAB-associated protein 1', 'Gene', (38, 63))	('repair', 'MPA', (148, 154))	('local decondensation', 'MPA', (74, 94))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('KAP1', 'Gene', '10155', (32, 36))	('phosphorylation', 'Var', (13, 28))	('ATM', 'Gene', (0, 3))	('KRAB-associated protein 1', 'Gene', '10155', (38, 63))	('heterochromatin', 'cellular_component', 'GO:0000792', ('98', '113'))	('ATM', 'Gene', '472', (0, 3))
82954	27831464	These factors are governed by the properties of the tissue-of-origin (which contribute to the variability in the number, length and distribution of CNAs over cancer types) and could be influenced by abnormal activity of epigenetic modifiers through mutation or differential expression (contributing to the variation on the patient-level).	('influenced by', 'Reg', (185, 198))	('mutation', 'Var', (249, 257))	('differential expression', 'Var', (261, 284))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('patient', 'Species', '9606', (323, 330))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
82956	27831464	In accordance with previous studies, we show that TP53 deficiency is strongly associated with high CNA numbers.	('associated', 'Reg', (78, 88))	('TP53', 'Gene', '7157', (50, 54))	('high CNA numbers', 'CPA', (94, 110))	('deficiency', 'Var', (55, 65))	('TP53', 'Gene', (50, 54))
82957	27831464	In summary, our observations suggest that the epigenome impacts CNA occurrence in a tissue- and patient-specific manner.	('epigenome', 'Var', (46, 55))	('CNA', 'Disease', (64, 67))	('patient', 'Species', '9606', (96, 103))	('impacts', 'Reg', (56, 63))
82973	27831464	We computed VAFs as the read count supporting mutation divided by the total read count for each mutation in ucec, hnsc, luad, brca and skcm, as these cancer types had at least 100 mutations in non-cancer CONIM genes (considering genes with at least 15 non-silent mutations), read count information and cancer gene classification available.	('brca', 'Gene', '672', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (180, 189))	('brca', 'Gene', (126, 130))	('non-cancer', 'Disease', 'MESH:D009369', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', (197, 203))	('non-cancer', 'Disease', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
82995	27831464	We repeated the analysis for all possible combinations of healthy tissues as well as for 1,000 random associations between heterochromatin proportions and cancer-type-specific CNA numbers and lengths.	('heterochromatin', 'Var', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('heterochromatin', 'cellular_component', 'GO:0000792', ('123', '138'))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
83013	27831464	Since ovarian cancer has frequent TP53 mutations, the question was raised as to whether TP53-mutatant cancers exhibit the same relations between heterochromatin and CNA burden.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('heterochromatin', 'cellular_component', 'GO:0000792', ('145', '160'))	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (6, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (6, 20))	('mutations', 'Var', (39, 48))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('TP53', 'Gene', '7157', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TP53', 'Gene', (88, 92))	('ovarian cancer', 'Disease', (6, 20))	('TP53', 'Gene', '7157', (34, 38))
83016	27831464	"The manuscript is improved but the primary result-that 62 genes are associated with decreased CNA rates and only one (TP53) was associated with increased rates-raises the concern that a confounder continues to drive much of the association between mutation rates in specific genes and lack of CNAs.	('mutation', 'Var', (249, 257))	('decreased', 'NegReg', (85, 94))	('CNA rates', 'CPA', (95, 104))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
83028	27831464	We see that in the previous version of the manuscript 1) the motivation was not very well explained, 2) presenting the two pipelines at different positions of the manuscript was confusing and 3) combining the single cancer p-values with the Fisher Method also suppresses cancer type-specific effects.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('suppresses', 'NegReg', (260, 270))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (216, 222))	('p-values', 'Var', (223, 231))	('cancer', 'Disease', (271, 277))
83038	27831464	We agree with the reviewers that ovarian cancer may not show the same behavior like other cancer types due to frequent TP53 mutations and we include a corresponding paragraph in the Discussion section.	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (124, 133))	('ovarian cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('TP53', 'Gene', '7157', (119, 123))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', (119, 123))
83043	27831464	This suggests that even though we have a variation in dependence of the specific algorithmic details or the underlying data, we observe a robust functional enrichment towards epigenetic modifiers and a higher number of genes associated with lower CNA number (with exception of the cancer type-specific pipeline where the second effect is less pronounced).	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('CNA', 'MPA', (247, 250))	('cancer', 'Disease', (281, 287))	('lower', 'NegReg', (241, 246))	('epigenetic', 'Var', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
83047	27831464	We again observed elevated mutation frequencies in cancer types that correspond to H3K9me3-enriched tissues.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('elevated', 'PosReg', (18, 26))
83048	27831464	Also, we do not filter genes that do not give a signal in single cancer types or those that are also associated with silent mutations.	('cancer', 'Disease', (65, 71))	('silent mutations', 'Var', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
83050	31048499	The small GTPase ARF6 activates PI3K in melanoma to induce a pro-metastatic state Melanoma has an unusual capacity to spread in early stage disease, prompting aggressive clinical intervention in very thin primary tumors.	('Melanoma', 'Disease', 'MESH:D008545', (82, 90))	('Melanoma', 'Disease', (82, 90))	('primary tumors', 'Disease', 'MESH:D001932', (205, 219))	('PI3K', 'molecular_function', 'GO:0016303', ('32', '36'))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('ARF6', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('induce', 'PosReg', (52, 58))	('melanoma', 'Disease', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('primary tumors', 'Disease', (205, 219))	('pro-metastatic state', 'MPA', (61, 81))	('Melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('small', 'Var', (4, 9))	('ARF6', 'Gene', '11845', (17, 21))
83053	31048499	ARF6Q67L promoted spontaneous metastasis from significantly smaller primary tumors than PTENNULL, implying an enhanced ability of ARF6-GTP to drive distant spread.	('primary tumors', 'Disease', (68, 82))	('ability', 'MPA', (119, 126))	('PTEN', 'Gene', '19211', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('primary tumors', 'Disease', 'MESH:D001932', (68, 82))	('spontaneous metastasis', 'CPA', (18, 40))	('enhanced', 'PosReg', (110, 118))	('PTEN', 'Gene', (88, 92))	('ARF6Q67L', 'Chemical', '-', (0, 8))	('promoted', 'PosReg', (9, 17))	('ARF6-GTP', 'Chemical', '-', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('distant spread', 'CPA', (148, 162))	('ARF6Q67L', 'Var', (0, 8))
83055	31048499	Unexpectedly, ARF6Q67L tumors showed upregulation of Pik3r1 expression, which encodes the p85 regulatory subunit of PI3 kinase (PI3K).	('expression', 'MPA', (60, 70))	('PI3 kinase', 'Gene', (116, 126))	('Pik3r1', 'Gene', '18708', (53, 59))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('ARF6Q67L', 'Var', (14, 22))	('Pik3r1', 'Gene', (53, 59))	('upregulation', 'PosReg', (37, 49))	('p85', 'Gene', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('PI3 kinase', 'Gene', '18708', (116, 126))	('ARF6Q67L', 'Chemical', '-', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('p85', 'Gene', '21981', (90, 93))
83056	31048499	Tumor cells expressing ARF6Q67L displayed increased PI3K protein levels and activity, enhanced PI3K distribution to cellular protrusions, and increased AKT activation in invadopodia.	('increased', 'PosReg', (42, 51))	('AKT', 'Pathway', (152, 155))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PI3K', 'Protein', (95, 99))	('PI3K', 'molecular_function', 'GO:0016303', ('52', '56'))	('increased', 'PosReg', (142, 151))	('activity', 'MPA', (76, 84))	('activation', 'PosReg', (156, 166))	('ARF6Q67L', 'Chemical', '-', (23, 31))	('PI3K', 'Protein', (52, 56))	('enhanced', 'PosReg', (86, 94))	('ARF6Q67L', 'Var', (23, 31))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))
83057	31048499	We provide evidence for aberrant ARF6 activation in human melanoma samples, which is associated with reduced survival.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('aberrant', 'Var', (24, 32))	('ARF6', 'Protein', (33, 37))	('human', 'Species', '9606', (52, 57))	('reduced', 'NegReg', (101, 108))	('activation', 'PosReg', (38, 48))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
83062	31048499	The critical role for ARF6 in cutaneous melanoma appears to be common, as knockdown of ARF6 uniformly inhibits invasion in a broad panel of human melanoma cell lines.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('human', 'Species', '9606', (140, 145))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('knockdown', 'Var', (74, 83))	('melanoma', 'Disease', (40, 48))	('cutaneous melanoma', 'Disease', (30, 48))	('ARF6', 'Gene', (87, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('invasion', 'CPA', (111, 119))	('inhibits', 'NegReg', (102, 110))
83065	31048499	In uveal melanoma, ARF6 is activated by mutant GNAQ to control tumor growth.	('tumor', 'Disease', (63, 68))	('ARF6', 'Gene', (19, 23))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('GNAQ', 'Gene', '14682', (47, 51))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('GNAQ', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutant', 'Var', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('activated', 'PosReg', (27, 36))
83067	31048499	In addition, ARF6 has a critical role in the functional output of mutant p53 and RAS.	('RAS', 'Gene', (81, 84))	('p53', 'Gene', '22060', (73, 76))	('p53', 'Gene', (73, 76))	('mutant', 'Var', (66, 72))
83068	31048499	Aberrant PI3K pathway activation is a known driver of melanoma disease progression, with up to 70% of melanomas showing reduced PTEN expression or activation of the kinase AKT.	('expression', 'MPA', (133, 143))	('melanomas', 'Disease', (102, 111))	('melanoma disease', 'Disease', 'MESH:D008545', (54, 70))	('Aberrant', 'Var', (0, 8))	('melanoma disease', 'Disease', (54, 70))	('PTEN', 'Gene', (128, 132))	('PI3K pathway', 'Pathway', (9, 21))	('activation', 'PosReg', (22, 32))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('PI3K', 'molecular_function', 'GO:0016303', ('9', '13'))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('activation', 'PosReg', (147, 157))	('reduced', 'NegReg', (120, 127))	('PTEN', 'Gene', '19211', (128, 132))
83071	31048499	PTEN deletion or activation of PI3K or AKT1 accelerates metastasis in genetically engineered mouse models (GEMMs) of BRAF-mutant melanoma.	('AKT1', 'Gene', (39, 43))	('metastasis', 'CPA', (56, 66))	('deletion', 'Var', (5, 13))	('accelerates', 'PosReg', (44, 55))	('mouse', 'Species', '10090', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('activation', 'PosReg', (17, 27))	('AKT1', 'Gene', '11651', (39, 43))	('PI3K', 'Gene', (31, 35))	('PTEN', 'Gene', '19211', (0, 4))	('PTEN', 'Gene', (0, 4))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))
83072	31048499	Approximately 20% of BRAF mutant melanomas show genetic loss of PTEN or rare gain-of-function mutations in PIK3CA or AKT.	('loss', 'NegReg', (56, 60))	('mutations', 'Var', (94, 103))	('PIK3CA', 'Gene', '18706', (107, 113))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('gain-of-function', 'PosReg', (77, 93))	('PTEN', 'Gene', '19211', (64, 68))	('AKT', 'Gene', (117, 120))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('PIK3CA', 'Gene', (107, 113))	('PTEN', 'Gene', (64, 68))	('BRAF', 'Gene', (21, 25))	('mutant', 'Var', (26, 32))	('melanomas', 'Disease', (33, 42))
83079	31048499	Further, we provide evidence for aberrant ARF6 activation in patient samples.	('ARF6', 'Protein', (42, 46))	('aberrant', 'Var', (33, 41))	('patient', 'Species', '9606', (61, 68))	('activation', 'PosReg', (47, 57))
83120	31048499	Two BRAFV600E/Cdkn2ANULL control tumor samples were outliers in principle component analysis and were excluded from further analysis.	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BRAFV600E/Cdkn2ANULL', 'Var', (4, 24))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
83145	31048499	Matrigels were permeablized for 40 minutes in PBSA+ 0.02%TritonX-100 at room temperature, followed by a blocking in PBSA + 3% v/v bovine serum albumin (BSA) for 60 minutes.	('PBSA', 'Chemical', 'MESH:C437084', (46, 50))	('serum albumin', 'Gene', '11657', (137, 150))	('PBSA+ 0.02%', 'Var', (46, 57))	('PBSA', 'Chemical', 'MESH:C437084', (116, 120))	('serum albumin', 'Gene', (137, 150))	('TritonX-100', 'Chemical', 'MESH:D017830', (57, 68))
83190	31048499	To test our hypothesis, we utilized RCAS-mediated delivery of Cre recombinase specifically in the melanocytic lineage to induce constitutive activation of BRAFV600E (BrafCA) and deletion of Cdkn2a (Cdkn2af/f).	('Cdkn2a', 'Gene', '12578', (190, 196))	('Cdkn2a', 'Gene', (190, 196))	('BRAFV600E', 'Var', (155, 164))	('Cdkn2a', 'Gene', (198, 204))	('BRAFV600E', 'Mutation', 'rs113488022', (155, 164))	('deletion', 'Var', (178, 186))	('RCAS', 'Chemical', '-', (36, 40))	('BrafCA', 'Chemical', '-', (166, 172))	('activation', 'PosReg', (141, 151))	('Cdkn2a', 'Gene', '12578', (198, 204))
83197	31048499	In mice with metastases, there was a dramatic increase in metastatic volume in the ARF6Q67L cohort (Figure 1a-c).	('ARF6Q67L', 'Var', (83, 91))	('increase', 'PosReg', (46, 54))	('metastatic volume', 'CPA', (58, 75))	('mice', 'Species', '10090', (3, 7))	('metastases', 'Disease', (13, 23))	('ARF6Q67L', 'Chemical', '-', (83, 91))	('metastases', 'Disease', 'MESH:D009362', (13, 23))
83198	31048499	Control mice showed negligible metastatic disease with infrequent and very early microscopic foci of tumor in the lungs (Figure 1a and c), whereas mice with ARF6Q67L demonstrated bulky metastatic disease (Figure 1b and c).	('mice', 'Species', '10090', (147, 151))	('tumor in the lungs', 'Phenotype', 'HP:0100526', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('metastatic disease', 'CPA', (31, 49))	('ARF6Q67L', 'Chemical', '-', (157, 165))	('ARF6Q67L', 'Var', (157, 165))	('mice', 'Species', '10090', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
83199	31048499	Thus, ARF6-GTP was sufficient to expedite the metastatic process, leading to accelerated disease progression.	('expedite', 'PosReg', (33, 41))	('accelerated', 'PosReg', (77, 88))	('metastatic process', 'CPA', (46, 64))	('ARF6-GTP', 'Chemical', '-', (6, 14))	('disease progression', 'CPA', (89, 108))	('ARF6-GTP', 'Var', (6, 14))
83202	31048499	Although ARF6Q67L primary tumors did not show a growth advantage over controls, ARF6Q67L primary tumor cells showed increased proliferation and decreased apoptosis in vitro (Figure S2e and f), demonstrating context-dependent functions of activated ARF6.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('pen', 'Chemical', 'MESH:C058388', (217, 220))	('decreased', 'NegReg', (144, 153))	('ARF6Q67L', 'Chemical', '-', (80, 88))	('ARF6Q67L', 'Chemical', '-', (9, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('154', '163'))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('apoptosis', 'biological_process', 'GO:0006915', ('154', '163'))	('ARF6Q67L', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('apoptosis', 'CPA', (154, 163))	('primary tumors', 'Disease', (18, 32))	('tumor', 'Disease', (97, 102))	('increased', 'PosReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('primary tumors', 'Disease', 'MESH:D001932', (18, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
83204	31048499	Together these data suggest that ARF6-GTP might convey a proliferative or survival advantage specifically to tumor cells en route to or colonizing distant organs.	('ARF6-GTP', 'Chemical', '-', (33, 41))	('ARF6-GTP', 'Var', (33, 41))	('proliferative', 'CPA', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('survival advantage', 'CPA', (74, 92))	('tumor', 'Disease', (109, 114))
83208	31048499	We found that ARF6-GTP dramatically enhanced metastatic lung colony formation in this model (Figure 1d-f).	('metastatic lung colony formation', 'CPA', (45, 77))	('formation', 'biological_process', 'GO:0009058', ('68', '77'))	('ARF6-GTP', 'Chemical', '-', (14, 22))	('enhanced', 'PosReg', (36, 44))	('ARF6-GTP', 'Var', (14, 22))
83209	31048499	Specifically, circulating tumor cells expressing ARF6Q67L colonized the lungs in 100% of mice, whereas controls colonized the lungs in 33% of mice (Figure 1f).	('ARF6Q67L', 'Var', (49, 57))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mice', 'Species', '10090', (142, 146))	('ARF6Q67L', 'Chemical', '-', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
83211	31048499	Thus, ARF6 activation provides a selective advantage for survival of circulating tumor cells, extravasation, end-organ invasion and/or establishment of metastatic colonies while inactivation of ARF6 curbs this pro-metastatic phenotype.	('inactivation', 'Var', (178, 190))	('ARF6', 'Gene', (194, 198))	('curbs', 'NegReg', (199, 204))	('advantage', 'PosReg', (43, 52))	('establishment of metastatic colonies', 'CPA', (135, 171))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ARF6', 'Gene', (6, 10))	('extravasation', 'CPA', (94, 107))	('end-organ invasion', 'CPA', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('activation', 'PosReg', (11, 21))	('tumor', 'Disease', (81, 86))	('survival', 'CPA', (57, 65))
83213	31048499	All mice engineered to express HA-tagged ARF6Q67L in tumors were confirmed by anti-HA immunostaining (see Figure S1a for examples) and/or by qRT-PCR (Figure S3).	('mice', 'Species', '10090', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('ARF6Q67L', 'Chemical', '-', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('ARF6Q67L', 'Var', (41, 49))	('tumors', 'Disease', (53, 59))
83220	31048499	Despite lagging behind in tumor incidence, disease latency and tumor growth, the Arf6Q67L mice demonstrated a metastatic incidence that is equivalent to the Ptenf/f mice (Figure 1g).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Arf6Q67L', 'Var', (81, 89))	('Pten', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (90, 94))	('Pten', 'Gene', '19211', (157, 161))	('metastatic incidence', 'CPA', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
83223	31048499	These phenotypes indicate that while PTEN loss incites aggressive primary tumor growth as well as progression to metastasis, ARF6-GTP function in this model specifically promotes metastasis.	('ARF6-GTP', 'Chemical', '-', (125, 133))	('PTEN loss incites aggressive primary tumor', 'Disease', 'MESH:D006223', (37, 79))	('ARF6-GTP', 'Var', (125, 133))	('PTEN loss incites aggressive primary tumor', 'Disease', (37, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('metastasis', 'CPA', (179, 189))	('promotes', 'PosReg', (170, 178))
83224	31048499	This is an important distinction, because it demonstrates that activation of ARF6 can promote a pro-metastatic state that is independent of tumor growth, possibly increasing the risk of distant spread in smaller tumors, a notorious clinical feature of melanoma.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('ARF6', 'Gene', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('promote', 'PosReg', (86, 93))	('distant spread', 'CPA', (186, 200))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('increasing', 'PosReg', (163, 173))	('pro-metastatic state', 'MPA', (96, 116))	('tumors', 'Disease', (212, 218))	('activation', 'Var', (63, 73))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('tumor', 'Disease', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('pen', 'Chemical', 'MESH:C058388', (129, 132))	('tumor', 'Disease', (140, 145))
83229	31048499	To identify novel ARF6-regulated target genes and pathways, we analyzed transcriptomes from our BRAFV600E/CDKN2ANull +- ARF6Q67L mouse melanoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('BRAFV600E', 'Mutation', 'rs113488022', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('BRAFV600E/CDKN2ANull', 'Var', (96, 116))	('melanoma tumors', 'Disease', (135, 150))	('ARF6Q67L', 'Chemical', '-', (120, 128))	('melanoma tumors', 'Disease', 'MESH:D008545', (135, 150))	('mouse', 'Species', '10090', (129, 134))
83232	31048499	Interestingly, mTOR signaling components were upregulated in ARF6Q67L tumors (Figure 2a), including Pik3r1, which encodes the p85 regulatory subunit of PI3 kinase (PI3K).	('Pik3r1', 'Gene', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('p85', 'Gene', (126, 129))	('mTOR', 'Gene', (15, 19))	('PI3K', 'molecular_function', 'GO:0016303', ('164', '168'))	('PI3 kinase', 'Gene', '18708', (152, 162))	('tumors', 'Disease', (70, 76))	('ARF6Q67L', 'Chemical', '-', (61, 69))	('p85', 'Gene', '21981', (126, 129))	('mTOR', 'Gene', '56717', (15, 19))	('Pik3r1', 'Gene', '18708', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ARF6Q67L', 'Var', (61, 69))	('PI3 kinase', 'Gene', (152, 162))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))	('upregulated', 'PosReg', (46, 57))
83233	31048499	This finding is provocative because the PI3K pathway is strongly linked to melanoma disease progression and because our ARF6Q67L mice showed a comparable metastatic phenotype to mice with PTEN loss.	('linked', 'Reg', (65, 71))	('mice', 'Species', '10090', (178, 182))	('PI3K pathway', 'Pathway', (40, 52))	('melanoma disease', 'Disease', 'MESH:D008545', (75, 91))	('PTEN', 'Gene', '19211', (188, 192))	('PTEN', 'Gene', (188, 192))	('melanoma disease', 'Disease', (75, 91))	('ARF6Q67L', 'Chemical', '-', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('mice', 'Species', '10090', (129, 133))	('ARF6Q67L', 'Var', (120, 128))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))
83235	31048499	Likewise, p85 protein levels were significantly increased in primary tumor cell lines derived from ARF6Q67L mouse melanomas (Figure 2c).	('increased', 'PosReg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('p85', 'Gene', (10, 13))	('tumor', 'Disease', (69, 74))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('mouse', 'Species', '10090', (108, 113))	('ARF6Q67L', 'Chemical', '-', (99, 107))	('p85', 'Gene', '21981', (10, 13))	('melanomas', 'Disease', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ARF6Q67L', 'Var', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
83240	31048499	Compared to BRAFV600E/Cdkn2aNULL controls, ARF6Q67L tumors showed the most dramatic increase in phosphorylated AKT (pAKT) levels (Figure 2d).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Cdkn2a', 'Gene', '12578', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('Cdkn2a', 'Gene', (22, 28))	('ARF6Q67L', 'Chemical', '-', (43, 51))	('increase', 'PosReg', (84, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (12, 21))	('ARF6Q67L', 'Var', (43, 51))
83242	31048499	Interestingly, myosin IIa upregulation distinguishes ARF6Q67L tumors from PTENNULL tumors (Figure 2d).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('PTENNULL tumors', 'Disease', 'MESH:D009369', (74, 89))	('PTENNULL tumors', 'Disease', (74, 89))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('ARF6Q67L', 'Chemical', '-', (53, 61))	('tumors', 'Disease', (83, 89))	('myosin IIa', 'Gene', '17886', (15, 25))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('ARF6Q67L', 'Var', (53, 61))	('upregulation', 'PosReg', (26, 38))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('myosin IIa', 'Gene', (15, 25))
83243	31048499	ARF6Q67L tumors also show a stronger signal for tuberin T1462 phosphorylation than PTENNULL tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tuberin', 'Gene', '22084', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tuberin', 'Gene', (48, 55))	('stronger', 'PosReg', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('ARF6Q67L', 'Chemical', '-', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('PTENNULL tumors', 'Disease', 'MESH:D009369', (83, 98))	('tumors', 'Disease', (92, 98))	('PTENNULL tumors', 'Disease', (83, 98))	('ARF6Q67L', 'Var', (0, 8))
83244	31048499	As Tuberin T1462 is a PI3K-regulated AKT substrate and constitutively phosphorylated in PTENNULL cells, these data suggest that ARF6-GTP is a potent activator of PI3K and/or AKT.	('PI3K', 'Pathway', (162, 166))	('ARF6-GTP', 'Var', (128, 136))	('Tuberin', 'Gene', '22084', (3, 10))	('Tuberin', 'Gene', (3, 10))	('PTEN', 'Gene', '19211', (88, 92))	('AKT', 'Pathway', (174, 177))	('PTEN', 'Gene', (88, 92))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('PI3K', 'molecular_function', 'GO:0016303', ('162', '166'))	('ARF6-GTP', 'Chemical', '-', (128, 136))	('activator', 'PosReg', (149, 158))
83246	31048499	Together, these findings help explain the overlapping but distinct phenotypes between PTENNULL and ARF6Q67L.	('PTEN', 'Gene', '19211', (86, 90))	('ARF6Q67L', 'Var', (99, 107))	('ARF6Q67L', 'Chemical', '-', (99, 107))	('PTEN', 'Gene', (86, 90))
83250	31048499	Immunoflourescent staining confirmed that p85 and p110alpha levels increased in the presence of ARF6Q67L (Figure 3), consistent with transcriptome and Western blot analysis (Figure 2c and d).	('ARF6Q67L', 'Var', (96, 104))	('p110alpha', 'Gene', (50, 59))	('p85', 'Gene', (42, 45))	('increased', 'PosReg', (67, 76))	('p110alpha', 'Gene', '18706', (50, 59))	('ARF6Q67L', 'Chemical', '-', (96, 104))	('p85', 'Gene', '21981', (42, 45))
83257	31048499	We found that the catalytic activity of endogenous PI3K increased in the presence of ARF6Q67L (Figure 4a).	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('18', '36'))	('increased', 'PosReg', (56, 65))	('ARF6Q67L', 'Chemical', '-', (85, 93))	('ARF6Q67L', 'Var', (85, 93))	('catalytic activity', 'MPA', (18, 36))
83258	31048499	Further, we observed higher levels of activated AKT (pAKT) in ARF6Q67L mouse melanoma cells relative to controls (Figure 4b).	('ARF6Q67L', 'Var', (62, 70))	('activated', 'MPA', (38, 47))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('higher', 'PosReg', (21, 27))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('ARF6Q67L', 'Chemical', '-', (62, 70))	('mouse', 'Species', '10090', (71, 76))
83259	31048499	Ectopic expression of ARF6Q67L was also sufficient to activate AKT in NIH3T3 cells (Figure 4c), suggesting a broader phenomenon.	('ARF6Q67L', 'Chemical', '-', (22, 30))	('NIH3T3', 'CellLine', 'CVCL:0594', (70, 76))	('AKT', 'Pathway', (63, 66))	('ARF6Q67L', 'Var', (22, 30))	('activate', 'PosReg', (54, 62))
83261	31048499	Immunohistochemical staining revealed that pAKT is detectable in more than half of primary tumors from ARF6Q67L mice whereas pAKT was not detected in primary tumors from control mice (Figure 4d).	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('primary tumors', 'Disease', (83, 97))	('ARF6Q67L', 'Var', (103, 111))	('primary tumors', 'Disease', (150, 164))	('mice', 'Species', '10090', (178, 182))	('primary tumors', 'Disease', 'MESH:D001932', (150, 164))	('primary tumors', 'Disease', 'MESH:D001932', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('ARF6Q67L', 'Chemical', '-', (103, 111))
83265	31048499	Together these results demonstrate that ARF6-GTP is sufficient for activation of the PI3K pathway and suggest that ARF6-GTP may engage PI3K signaling in specific cell populations within a tumor.	('tumor', 'Disease', (188, 193))	('engage', 'Reg', (128, 134))	('ARF6-GTP', 'Var', (115, 123))	('ARF6-GTP', 'Chemical', '-', (115, 123))	('activation', 'PosReg', (67, 77))	('PI3K signaling', 'biological_process', 'GO:0014065', ('135', '149'))	('ARF6-GTP', 'Chemical', '-', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('PI3K signaling', 'Pathway', (135, 149))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('PI3K pathway', 'Pathway', (85, 97))	('PI3K', 'molecular_function', 'GO:0016303', ('85', '89'))
83268	31048499	Further, ectopic expression of ARF6T27N reduced pAKT levels in 10 of 15 melanoma cell lines, independent of the primary driver gene mutation status (Figure 5b, c and S6a).	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('pen', 'Chemical', 'MESH:C058388', (97, 100))	('ARF6T27N', 'Var', (31, 39))	('reduced', 'NegReg', (40, 47))	('pAKT levels', 'MPA', (48, 59))
83269	31048499	ARF6T27N also reduced pAKT levels in a KRAS-mutant carcinoma cell line (HEY-T30), suggesting that ARF6 also regulates PI3K signaling in non-melanoma cancer cells (Figure 5b and S6a).	('melanoma cancer', 'Disease', 'MESH:D009369', (140, 155))	('PI3K signaling', 'biological_process', 'GO:0014065', ('118', '132'))	('reduced', 'NegReg', (14, 21))	('pAKT levels', 'MPA', (22, 33))	('ARF6T27N', 'Var', (0, 8))	('melanoma cancer', 'Disease', (140, 155))	('carcinoma', 'Disease', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('PI3K signaling', 'Pathway', (118, 132))	('HEY-T30', 'CellLine', 'CVCL:2Z96', (72, 79))	('regulates', 'Reg', (108, 117))	('carcinoma', 'Disease', 'MESH:D009369', (51, 60))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
83270	31048499	In a proteomic phosphokinase array, ARF6T27N incited the greatest impact on AKT and its substrate PRAS40, reducing phosphorylation of both (Figure S6c).	('AKT', 'Pathway', (76, 79))	('reducing', 'NegReg', (106, 114))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('PRAS40', 'Gene', (98, 104))	('PRAS40', 'Gene', '67605', (98, 104))	('ARF6T27N', 'Var', (36, 44))	('phosphorylation', 'MPA', (115, 130))
83271	31048499	Importantly, this proteomic survey corroborates our findings in mouse melanoma cells whereby AKT phosphorylation is one of the strongest signals in ARF6Q67L tumors (Figure 2e).	('melanoma', 'Disease', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('ARF6Q67L', 'Var', (148, 156))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', (157, 163))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ARF6Q67L', 'Chemical', '-', (148, 156))	('mouse', 'Species', '10090', (64, 69))	('AKT phosphorylation', 'MPA', (93, 112))
83274	31048499	We previously reported that knockdown of ARF6 or pharmacologic inhibition of ARF6 universally reduces invasion of human cutaneous melanoma cell lines in vitro.	('ARF6', 'Gene', (77, 81))	('reduces', 'NegReg', (94, 101))	('ARF6', 'Gene', (41, 45))	('human', 'Species', '9606', (114, 119))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('knockdown', 'Var', (28, 37))	('cutaneous melanoma', 'Disease', (120, 138))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))
83275	31048499	showed that ectopic ARF6T27N inhibits invasion, whereas ARF6Q67L increases invasion of LOX melanoma cells.	('ARF6Q67L', 'Var', (56, 64))	('increases', 'PosReg', (65, 74))	('ectopic ARF6T27N', 'Var', (12, 28))	('invasion', 'CPA', (75, 83))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('ARF6T27N', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('invasion', 'CPA', (38, 46))	('inhibits', 'NegReg', (29, 37))	('ARF6Q67L', 'Chemical', '-', (56, 64))
83276	31048499	Consistent with these findings, ectopic ARF6Q67L increased Matrigel invasion of A2058 melanoma cells in vitro (Figure 6).	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('ectopic ARF6Q67L', 'Var', (32, 48))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('ARF6Q67L', 'Chemical', '-', (40, 48))	('increased', 'PosReg', (49, 58))	('ARF6Q67L', 'Var', (40, 48))	('A2058', 'CellLine', 'CVCL:1059', (80, 85))
83277	31048499	Indeed, the pan-AKT inhibitor MK2206 (Figure 6a and b) and the pan-Class I PI3K inhibitor GSK-0941 (Figure 6c and d) both abrogated ARF6Q67L-dependent Matrigel invasion, demonstrating that PI3K signaling is necessary for ARF6-mediated invasion.	('GSK', 'molecular_function', 'GO:0050321', ('90', '93'))	('ARF6Q67L', 'Chemical', '-', (132, 140))	('PI3K signaling', 'biological_process', 'GO:0014065', ('189', '203'))	('PI3K', 'molecular_function', 'GO:0016303', ('189', '193'))	('GSK-0941', 'Chemical', '-', (90, 98))	('MK2206', 'Var', (30, 36))	('ARF6Q67L-dependent', 'Var', (132, 150))	('abrogated', 'NegReg', (122, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('75', '79'))	('pen', 'Chemical', 'MESH:C058388', (143, 146))	('MK2206', 'Chemical', 'MESH:C548887', (30, 36))
83280	31048499	The untreated and vector control cells showed a rounded morphology on undigested Matrigel whereas ARF6Q67L incited cell spreading into plump, polygonal shapes with extended cell processes (top row, Figure 6e).	('cell spreading', 'CPA', (115, 129))	('ARF6Q67L', 'Var', (98, 106))	('ARF6Q67L', 'Chemical', '-', (98, 106))	('incited', 'Reg', (107, 114))
83281	31048499	Treatment with the pan-AKT inhibitor MK2206 reduced pAKT staining and restored the rounded cell shape.	('MK2206', 'Var', (37, 43))	('rounded cell shape', 'CPA', (83, 101))	('restored', 'PosReg', (70, 78))	('MK2206', 'Chemical', 'MESH:C548887', (37, 43))	('reduced', 'NegReg', (44, 51))	('pAKT staining', 'MPA', (52, 65))
83282	31048499	ARF6Q67L expression led to an increase in these pAKT-rich invadopodia.	('ARF6Q67L', 'Chemical', '-', (0, 8))	('ARF6Q67L expression', 'Var', (0, 19))	('increase', 'PosReg', (30, 38))
83283	31048499	ARF6-GTP induced condensation and colocalization of pAKT and cortactin in invadopodia and was also seen in melanoma cells invading and digesting gelatin matrix (Figure 6f).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('condensation', 'MPA', (17, 29))	('colocalization', 'MPA', (34, 48))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('cortactin', 'Gene', (61, 70))	('ARF6-GTP', 'Var', (0, 8))	('digesting', 'Var', (135, 144))	('ARF6-GTP', 'Chemical', '-', (0, 8))
83284	31048499	Our data are consistent with findings in breast cancer cells in which PI3K and AKT mediate invadopodia formation and function.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('mediate', 'Reg', (83, 90))	('PI3K', 'Var', (70, 74))	('AKT', 'Pathway', (79, 82))	('invadopodia formation', 'CPA', (91, 112))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))
83286	31048499	Activation of ARF6 induces 1) transcriptional upregulation of the p85 regulatory subunit of PI3K, causing stabilization of the p110 catalytic subunit, leading to 2) p110 transport to invadopodia, where AKT is activated.	('p110', 'Gene', (165, 169))	('p110', 'Gene', '18706', (127, 131))	('upregulation', 'PosReg', (46, 58))	('p85', 'Gene', (66, 69))	('p110', 'Gene', '18706', (165, 169))	('stabilization', 'MPA', (106, 119))	('transport', 'biological_process', 'GO:0006810', ('170', '179'))	('ARF6', 'Gene', (14, 18))	('p85', 'Gene', '21981', (66, 69))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('Activation', 'Var', (0, 10))	('p110', 'Gene', (127, 131))
83288	31048499	Our current data reveal that ARF6-GTP is sufficient for metastasis and provide mechanistic insight.	('metastasis', 'CPA', (56, 66))	('ARF6-GTP', 'Var', (29, 37))	('ARF6-GTP', 'Chemical', '-', (29, 37))
83302	31048499	ARF6 is expressed in a wide variety of cancer types, including melanoma, and high ARF6 expression correlates with reduced survival in pancreatic cancer.	('cancer', 'Disease', (145, 151))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (134, 151))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('high', 'Var', (77, 81))	('reduced', 'NegReg', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (134, 151))	('ARF6', 'Gene', (82, 86))	('expression', 'MPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('survival', 'MPA', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('pancreatic cancer', 'Disease', (134, 151))
83308	31048499	In squamous cell carcinoma of the head and neck, high expression of AMAP1 correlates with reduced survival.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('AMAP1', 'Gene', (68, 73))	('AMAP1', 'Gene', '104601', (68, 73))	('reduced', 'NegReg', (90, 97))	('neck', 'cellular_component', 'GO:0044326', ('43', '47'))	('survival', 'MPA', (98, 106))	('high', 'Var', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (17, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
83309	31048499	To investigate ARF6 pathway expression in a large melanoma cohort, we queried The Cancer Genome Atlas (TCGA) cutaneous melanoma RNAseq data for alterations in the ARF6 pathway that correlate with overall survival from the time of diagnosis.	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Disease', (119, 127))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('ARF6 pathway', 'Pathway', (163, 175))	('alterations', 'Var', (144, 155))	('cutaneous melanoma', 'Disease', (109, 127))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (109, 127))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (109, 127))
83313	31048499	Specifically, low ARF GAP expression significantly correlated with reduced overall survival compared to high ARF GAP expression (Figures 7b and S7).	('ARF', 'Disease', 'MESH:D058186', (109, 112))	('reduced', 'NegReg', (67, 74))	('ARF', 'Disease', (109, 112))	('overall survival', 'MPA', (75, 91))	('ARF', 'Disease', 'MESH:D058186', (18, 21))	('low', 'Var', (14, 17))	('ARF', 'Disease', (18, 21))
83316	31048499	To a lesser extent, loss of ADAP1 and AGAP2 were associated with worse prognosis, although the association was not statistically significant (Figure S7b).	('AGAP2', 'Gene', (38, 43))	('loss', 'Var', (20, 24))	('AGAP2', 'Gene', '216439', (38, 43))	('ADAP1', 'Gene', '231821', (28, 33))	('ADAP1', 'Gene', (28, 33))
83321	31048499	In the active, GTP-bound state, ARF6 is not only sufficient to accelerate metastases, it confers equal metastatic capacity, from smaller tumors, compared to deletion of the tumor suppressor Pten.	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('accelerate', 'PosReg', (63, 73))	('metastases', 'Disease', (74, 84))	('tumor', 'Disease', (137, 142))	('ARF6', 'Var', (32, 36))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('GTP', 'Chemical', 'MESH:D006160', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('Pten', 'Gene', (190, 194))	('Pten', 'Gene', '19211', (190, 194))	('tumor suppressor', 'biological_process', 'GO:0051726', ('173', '189'))	('tumor', 'Disease', (173, 178))	('metastatic capacity', 'CPA', (103, 122))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
83329	31048499	This mechanism helps explain how ARF6 activation can synergize with Pten deletion in vivo to exacerbate metastasis.	('metastasis', 'CPA', (104, 114))	('Pten', 'Gene', (68, 72))	('ARF6', 'Protein', (33, 37))	('exacerbate', 'PosReg', (93, 103))	('Pten', 'Gene', '19211', (68, 72))	('activation', 'PosReg', (38, 48))	('deletion', 'Var', (73, 81))
83330	31048499	ARF6-induced PI3K expression and redistribution leads to increased pools of activated PI3K, while loss of PTEN eliminates the metabolism of its product PIP3, thus leading to increased PIP3 and activated AKT.	('PIP3', 'MPA', (184, 188))	('activated', 'PosReg', (193, 202))	('increased', 'PosReg', (174, 183))	('PIP3', 'Chemical', '-', (152, 156))	('pools', 'MPA', (67, 72))	('eliminates', 'NegReg', (111, 121))	('PI3K', 'Enzyme', (13, 17))	('PTEN', 'Gene', (106, 110))	('increased', 'PosReg', (57, 66))	('loss', 'Var', (98, 102))	('PTEN', 'Gene', '19211', (106, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('PI3K', 'molecular_function', 'GO:0016303', ('13', '17'))	('metabolism of its product PIP3', 'MPA', (126, 156))	('metabolism', 'biological_process', 'GO:0008152', ('126', '136'))	('PIP3', 'Chemical', '-', (184, 188))
83345	31048499	In the future, it will be important to determine if targeting ARF6 can inhibit the PI3K pathway in metastatic progression, particularly in the presence of PTEN loss.	('PI3K pathway', 'Pathway', (83, 95))	('PTEN', 'Gene', '19211', (155, 159))	('PTEN', 'Gene', (155, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('inhibit', 'NegReg', (71, 78))	('loss', 'NegReg', (160, 164))	('targeting', 'Var', (52, 61))	('ARF6', 'Gene', (62, 66))	('metastatic progression', 'CPA', (99, 121))
83360	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))
83372	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))	('tumour', 'Disease', (101, 107))	('mitosis', 'Disease', (194, 201))	('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))
83385	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))
83415	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))	('epithelioid subtype', 'Disease', (60, 79))	('associated', 'Reg', (40, 50))
83420	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))
83422	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))
83423	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'))
83424	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'))
83425	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))
83426	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))	('metastasis', 'CPA', (152, 162))	('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))	('tumours', 'Phenotype', 'HP:0002664', (183, 190))	('SF3B1', 'Gene', '23451', (210, 215))	('tumours', 'Disease', 'MESH:D009369', (183, 190))	('mutation', 'Var', (198, 206))
83427	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))
83428	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))	('SF3B1', 'Gene', (31, 36))	('EIF1AX', 'Gene', (23, 29))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', '1964', (23, 29))	('behaviour', 'biological_process', 'GO:0007610', ('128', '137'))	('SF3B1', 'Gene', '23451', (31, 36))	('BAP1', 'Gene', '8314', (41, 45))
83429	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))
83434	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))
83435	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))
83436	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))
83438	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))
83439	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))
83441	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))	('alterations', 'Var', (39, 50))	('tumour', 'Disease', (58, 64))
83442	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))
83444	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))
83447	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))
83464	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))
83466	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))
83467	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))
83470	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))
83471	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))	('mutated', 'Var', (46, 53))	('BAP1', 'Gene', '8314', (0, 4))	('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))	('metastasized uveal melanoma', 'Disease', 'MESH:D009362', (79, 106))
83473	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))
83476	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))
83478	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))
83480	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))
83482	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'))
83483	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))	('tumours', 'Disease', (214, 221))	('metastasis', 'CPA', (246, 256))	('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))
83484	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))
83485	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))
83486	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))	('ZRSR2', 'Gene', (43, 48))	('mutations', 'Var', (13, 22))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (96, 110))
83487	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.	('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))	('retinoic acid signalling', 'MPA', (128, 152))
83488	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'))
83489	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', (16, 25))	('Ras', 'Gene', (64, 67))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('thyroid', 'Disease', (125, 132))	('ovary', 'Disease', (115, 120))	('ovary', 'Disease', 'MESH:D010051', (115, 120))	('mutations', 'Var', (68, 77))
83495	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))	('EDNRB', 'Gene', (48, 53))	('GNAQ', 'Gene', (134, 138))	('expression', 'MPA', (63, 73))	('signalling dysregulation', 'MPA', (81, 105))	('signalling', 'biological_process', 'GO:0023052', ('81', '91'))	('reduced', 'NegReg', (40, 47))	('GNAQ', 'Gene', '2776', (134, 138))	('EDNRB', 'Gene', '1910', (48, 53))
83496	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))
83497	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))
83518	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))
83521	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))
83533	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))
83542	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', 'Phenotype', 'HP:0002664', (65, 71))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('numerous cancers', 'Disease', (116, 132))	('hypermethylation', 'Var', (4, 20))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('tumour', 'Disease', (65, 71))	('inactivation', 'Var', (88, 100))	('uveal melanoma', 'Disease', (143, 157))
83543	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))
83544	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))
83545	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))
83547	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'))
83549	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))
83550	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))
83551	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))
83552	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))
83556	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))
83572	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))
83573	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))
83592	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-363-3p', 'Var', (98, 108))	('miR-146a', 'Gene', (67, 75))	('miR-204', 'Gene', (77, 84))	('miR-211', 'Gene', (86, 93))	('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))
83615	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))
83621	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))
83624	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'))
83627	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))
83647	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))
83654	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))
83661	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))
83666	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'))	('expression', 'MPA', (97, 107))	('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))	('promote', 'PosReg', (83, 90))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('BAP1', 'Gene', (54, 58))	('c-Myc', 'Gene', (91, 96))
83668	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))
83672	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))
83683	32549336	Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('Excess body', 'Var', (0, 11))	('cancers', 'Disease', (74, 81))	('Excess body weight', 'Phenotype', 'HP:0004324', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
83693	32549336	Increased number of melanocytic nevi (moles) and fairness of skin are important host risk factors, and although there is not a strong genetic link, polymorphisms of the melanocortin 1 receptor gene, that are responsible for the different human skin-color phenotypes leads to heightened sensitivity to UV and thus increased susceptibility to cutaneous melanoma.	('fairness', 'Disease', (49, 57))	('sensitivity to UV', 'MPA', (286, 303))	('cutaneous melanoma', 'Disease', (341, 359))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (341, 359))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (341, 359))	('moles', 'Phenotype', 'HP:0003764', (38, 43))	('heightened', 'PosReg', (275, 285))	('melanocortin 1 receptor', 'Gene', (169, 192))	('nevi', 'Phenotype', 'HP:0003764', (32, 36))	('polymorphisms', 'Var', (148, 161))	('fairness', 'Disease', 'MESH:C567300', (49, 57))	('melanocortin 1 receptor', 'Gene', '4157', (169, 192))	('fairness of skin', 'Phenotype', 'HP:0007513', (49, 65))	('human', 'Species', '9606', (238, 243))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (20, 36))	('melanoma', 'Phenotype', 'HP:0002861', (351, 359))
83694	32549336	Excess body weight has been identified as a risk factor for many types of cancers, however the association with cutaneous melanoma incidence is not as strong.	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('Excess body weight', 'Phenotype', 'HP:0004324', (0, 18))	('cutaneous melanoma', 'Disease', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('Excess', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
83713	32549336	FASN expression correlates with poor prognosis in cutaneous melanoma, and inhibition of FASN reduces proliferation of B16-F10 melanoma cells in vitro and reduces incidence of metastasis in vivo.	('inhibition', 'Var', (74, 84))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))	('reduces', 'NegReg', (93, 100))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('proliferation', 'CPA', (101, 114))	('melanoma', 'Disease', (60, 68))	('cutaneous melanoma', 'Disease', (50, 68))	('incidence of metastasis', 'CPA', (162, 185))	('B16-F10', 'CellLine', 'CVCL:0159', (118, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('FASN', 'Gene', (88, 92))	('reduces', 'NegReg', (154, 161))
83729	32549336	Mechanistically, increased serum levels of acetoacetate are observed in mice on a high fat ketogenic diet, and this metabolite can selectively enhance BRAFV600E mutant-dependent mitogen activated protein kinase kinase (MAP2K; MEK1) activation (Figure 2).	('increased', 'PosReg', (17, 26))	('enhance', 'PosReg', (143, 150))	('acetoacetate', 'MPA', (43, 55))	('BRAFV600E', 'Mutation', 'rs113488022', (151, 160))	('activation', 'PosReg', (232, 242))	('mutant-dependent', 'Var', (161, 177))	('acetoacetate', 'Chemical', 'MESH:C016635', (43, 55))	('MEK1', 'Gene', (226, 230))	('BRAFV600E mutant-dependent', 'Var', (151, 177))	('high fat ketogenic diet', 'Phenotype', 'HP:0001946', (82, 105))	('MEK1', 'molecular_function', 'GO:0004708', ('226', '230'))	('mice', 'Species', '10090', (72, 76))	('MAP2K', 'molecular_function', 'GO:0004708', ('219', '224'))	('MEK1', 'Gene', '26395', (226, 230))	('MAP2K', 'Gene', (219, 224))	('serum levels', 'MPA', (27, 39))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
83759	32549336	Interestingly, modulation of fatty acid metabolism has been shown to enhance CD8+ memory T cell function, however paradoxically, the fatty acid oxidation gene CPT1A has also been linked with T cell dysfunction, whereby CPT1A is upregulated in early stage exhausted T cells following viral infection.	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('29', '50'))	('linked', 'Reg', (179, 185))	('CPT1A', 'Gene', (159, 164))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (191, 209))	('infection', 'Disease', (289, 298))	('infection', 'Disease', 'MESH:D007239', (289, 298))	('memory', 'biological_process', 'GO:0007613', ('82', '88'))	('CD8', 'Gene', '925', (77, 80))	('CPT', 'molecular_function', 'GO:0004142', ('219', '222'))	('memory T', 'Disease', (82, 90))	('enhance', 'PosReg', (69, 76))	('CPT', 'molecular_function', 'GO:0004142', ('159', '162'))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('133', '153'))	('CPT1A', 'Gene', (219, 224))	('modulation', 'Var', (15, 25))	('T cell dysfunction', 'Disease', (191, 209))	('CD8', 'Gene', (77, 80))	('T cell dysfunction', 'Disease', 'MESH:C536780', (191, 209))	('CPT', 'molecular_function', 'GO:0004095', ('219', '222'))	('fatty acid', 'Chemical', 'MESH:D005227', (29, 39))	('viral infection', 'biological_process', 'GO:0016032', ('283', '298'))	('fatty acid', 'Chemical', 'MESH:D005227', (133, 143))	('CPT', 'molecular_function', 'GO:0004095', ('159', '162'))	('upregulated', 'PosReg', (228, 239))	('memory T', 'Disease', 'MESH:D008569', (82, 90))
83761	32549336	Demonstrating causality, ectopic expression of PGC1A was sufficient to partially reverse the observed metabolic alterations and enhanced function of exhausted CD8+ T cells, whilst T cell reinvigoration via anti-PDL1 reprogrammed metabolism in subsets of the exhausted T cells.	('PDL1', 'Gene', (211, 215))	('PGC1A', 'Gene', (47, 52))	('metabolic alterations', 'MPA', (102, 123))	('CD8', 'Gene', (159, 162))	('enhanced', 'PosReg', (128, 136))	('reverse', 'NegReg', (81, 88))	('PGC1A', 'Gene', '10891', (47, 52))	('metabolism', 'biological_process', 'GO:0008152', ('229', '239'))	('PDL1', 'Gene', '29126', (211, 215))	('CD8', 'Gene', '925', (159, 162))	('ectopic expression', 'Var', (25, 43))	('function', 'MPA', (137, 145))
83764	32549336	Conversely, modulation of this axis may also represent an opportunity to enhance response to immunotherapies that exploit the PD-1/PDL-1 immune checkpoint.	('enhance', 'PosReg', (73, 80))	('modulation', 'Var', (12, 22))	('PDL-1', 'Gene', '29126', (131, 136))	('PDL-1', 'Gene', (131, 136))
83778	32549336	The 5-year overall survival rates for the dabrafenib plus trametinib combination in BRAF mutant melanoma patients is 34%.	('patients', 'Species', '9606', (105, 113))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('trametinib', 'Chemical', 'MESH:C560077', (58, 68))	('mutant', 'Var', (89, 95))	('dabrafenib', 'Chemical', 'MESH:C561627', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
83779	32549336	The mutation in BRAF locks the kinase into an active conformation leading to constitutive activation of the MAPK pathway and as consequence increased cell growth, proliferation and survival (Figure 1).	('activation', 'PosReg', (90, 100))	('MAPK pathway', 'Pathway', (108, 120))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutation', 'Var', (4, 12))	('survival', 'CPA', (181, 189))	('cell growth', 'biological_process', 'GO:0016049', ('150', '161'))	('cell growth', 'CPA', (150, 161))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('increased', 'PosReg', (140, 149))
83800	32549336	Induction of oxidative phosphorylation and mitochondrial biogenesis biomarkers has been identified in 30-50% of BRAFV600E melanomas with both de novo and acquired resistance to MAPK pathway inhibitors, and inhibition of mitochondrial biogenesis eradicated intrinsically resistant cells and improved efficacy of MAPK pathway inhibitors.	('intrinsically resistant cells', 'CPA', (256, 285))	('mitochondrial biogenesis', 'MPA', (43, 67))	('melanomas', 'Disease', (122, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('177', '181'))	('mitochondrial', 'CPA', (220, 233))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('13', '38'))	('eradicated', 'NegReg', (245, 255))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('MAPK', 'molecular_function', 'GO:0004707', ('311', '315'))	('inhibition', 'Var', (206, 216))	('improved', 'PosReg', (290, 298))	('oxidative phosphorylation', 'MPA', (13, 38))	('efficacy', 'MPA', (299, 307))	('melanomas', 'Disease', 'MESH:D008545', (122, 131))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('BRAFV600E', 'Mutation', 'rs113488022', (112, 121))	('MAPK pathway', 'Pathway', (311, 323))	('BRAFV600E', 'Gene', (112, 121))
83803	32549336	Moreover, preclinical analysis of adipocyte crosstalk with BRAFV600E signaling via the FATP/ SLC27A fatty acid transporters would be predicted to abrogate response of obese patients to MAPK pathway targeted therapies based on potentiation of BRAFV600E driven melanoma progression by adipocyte-melanoma cell crosstalk.	('melanoma', 'Disease', 'MESH:D008545', (259, 267))	('fatty acid transporter', 'Gene', (100, 122))	('BRAFV600E', 'Var', (242, 251))	('obese', 'Disease', (167, 172))	('MAPK pathway', 'Pathway', (185, 197))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))	('melanoma', 'Disease', (293, 301))	('obese', 'Disease', 'MESH:D009765', (167, 172))	('patients', 'Species', '9606', (173, 181))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('fatty acid transporter', 'Gene', '376497', (100, 122))	('FATP', 'Gene', '376497', (87, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('melanoma', 'Disease', (259, 267))	('BRAFV600E', 'Mutation', 'rs113488022', (242, 251))	('MAPK', 'molecular_function', 'GO:0004707', ('185', '189'))	('FATP', 'Gene', (87, 91))	('abrogate', 'NegReg', (146, 154))	('melanoma', 'Disease', 'MESH:D008545', (293, 301))
83804	32549336	Similarly, increased dietary fat has a pathogenic role in BRAFV600E-expressing melanoma which would be predicted to blunt MAPK pathway targeted therapies.	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('MAPK', 'molecular_function', 'GO:0004707', ('122', '126'))	('BRAFV600E-expressing', 'Var', (58, 78))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
83831	32549336	The improved response was associated with increased number and function of tumor infiltrating CD8+ T cells together with a decrease in PD-1 expressing T cells; indicating that anti-PD1 therapy overcame obesity-driven T-cell exhaustion.	('increased', 'PosReg', (42, 51))	('PD-1', 'MPA', (135, 139))	('decrease', 'NegReg', (123, 131))	('obesity', 'Phenotype', 'HP:0001513', (202, 209))	('function', 'MPA', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('obesity', 'Disease', 'MESH:D009765', (202, 209))	('CD8', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('obesity', 'Disease', (202, 209))	('CD8', 'Gene', '925', (94, 97))	('anti-PD1', 'Var', (176, 184))	('T-cell exhaustion', 'Phenotype', 'HP:0005435', (217, 234))	('tumor', 'Disease', (75, 80))
83833	32549336	In contrast, treatment response to CTLA-4 blockade was not improved in diet-induced obese mice, however when leptin was neutralized in this model an increase in the co-stimulatory molecule CD86 was observed as was the response to anti-CTLA therapy.	('increase', 'PosReg', (149, 157))	('obese', 'Disease', (84, 89))	('CD86', 'Gene', (189, 193))	('mice', 'Species', '10090', (90, 94))	('CD86', 'Gene', '12524', (189, 193))	('neutralized', 'Var', (120, 131))	('obese', 'Disease', 'MESH:D009765', (84, 89))
83839	32549336	Excess body fat is a complex metabolic disorder that can potentially impact on melanoma growth and immune surveillance at many levels.	('metabolic disorder', 'Disease', (29, 47))	('melanoma growth', 'Disease', (79, 94))	('melanoma growth', 'Disease', 'MESH:D008545', (79, 94))	('metabolic disorder', 'Phenotype', 'HP:0001939', (29, 47))	('metabolic disorder', 'Disease', 'MESH:D008659', (29, 47))	('impact', 'Reg', (69, 75))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('immune surveillance', 'CPA', (99, 118))	('Excess', 'Var', (0, 6))
83909	29776954	PHIP copy number was enriched in metastatic melanomas harboring mutant NRAS or expressing PTEN protein (cohort #2).	('melanomas', 'Disease', (44, 53))	('PTEN', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('NRAS', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (90, 94))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('NRAS', 'Gene', '4893', (71, 75))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))	('mutant', 'Var', (64, 70))
83911	29776954	These results underscore the important role of PHIP copy number elevation in melanoma progression, and identify molecular subtypes of melanoma in which PHIP is enriched.	('copy number elevation', 'Var', (52, 73))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('PHIP', 'Gene', (47, 51))
83929	29776954	FISH for PHIP copy number was performed as previously described using bacterial artificial chromosome (BAC) clones RP11-767O1and CTD-2297E14 to detect the PHIP locus and clones RP11-26M18 and RP11-136K2 to detect 6q11.1 and 6p11.1, respectively (interpreted as chromosome 6 centromere).	('6p11.1', 'Var', (224, 230))	('RP11', 'Gene', '26121', (192, 196))	('chromosome', 'cellular_component', 'GO:0005694', ('261', '271'))	('PHIP', 'Gene', (155, 159))	('RP11', 'Gene', (115, 119))	('centromere', 'cellular_component', 'GO:0000775', ('274', '284'))	('RP11', 'Gene', '26121', (115, 119))	('centromere', 'cellular_component', 'GO:0005698', ('274', '284'))	('RP11', 'Gene', (177, 181))	('chromosome', 'cellular_component', 'GO:0005694', ('91', '101'))	('RP11', 'Gene', (192, 196))	('RP11', 'Gene', '26121', (177, 181))	('6q11.1', 'Var', (213, 219))
83932	29776954	The impact of elevated PHIP copy number on melanoma progression was analyzed in several ways.	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('copy number', 'Var', (28, 39))	('PHIP', 'Gene', (23, 27))
83933	29776954	The cut-point utilized to define high PHIP copy number was that which maximized the average of sensitivity and specificity for predicting DSS (determined to be greater than or equal to 19%).	('DSS', 'Disease', (138, 141))	('high', 'Var', (33, 37))	('DSS', 'Chemical', '-', (138, 141))
83938	29776954	In cohort #3, for the analysis of 7 triple-matched tissue specimens, the significance of monotonically increasing PHIP copy number in melanoma progression was assessed using the Friedman two-way analysis of variance by ranks test.	('copy number', 'Var', (119, 130))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('PHIP', 'Gene', (114, 118))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
83945	29776954	By Kaplan-Meier analysis, high PHIP scores (assessed as a dichotomous variable) were also significantly predictive of DMFS (P=0.0017, Fig.	('high', 'Var', (26, 30))	('PHIP scores', 'MPA', (31, 42))	('predictive', 'Reg', (104, 114))	('DMFS', 'Disease', (118, 122))	('DMFS', 'Chemical', '-', (118, 122))
83958	29776954	Our analysis identified a significant association between elevated PHIP copy number and NRAS mutation status in melanoma.	('mutation status', 'Var', (93, 108))	('NRAS', 'Gene', (88, 92))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('NRAS', 'Gene', '4893', (88, 92))	('melanoma', 'Disease', (112, 120))	('elevated', 'PosReg', (58, 66))	('PHIP', 'Protein', (67, 71))
83975	29776954	By comparison, the mean percentage of cells with elevated PTEN copy number was 9.1% in the primary tumor, 12.7% in the lymph node metastases, and 11.8% in the distant metastases (P=0.19, Friedman test applied to the same 7 matched triplets).	('primary tumor', 'Disease', 'MESH:D009369', (91, 104))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('PTEN', 'Gene', '5728', (58, 62))	('metastases', 'Disease', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('metastases', 'Disease', (130, 140))	('copy number', 'Var', (63, 74))	('elevated', 'PosReg', (49, 57))	('primary tumor', 'Disease', (91, 104))	('metastases', 'Disease', 'MESH:D009362', (167, 177))	('PTEN', 'Gene', (58, 62))
83991	29776954	Our previous studies showed that PHIP mediates some of its effects on melanoma metastasis by virtue of activation of the IGF1R-PI3K pathway.	('melanoma metastasis', 'Disease', (70, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('127', '131'))	('IGF1R-PI3K', 'Gene', (121, 131))	('IGF1R-PI3K', 'Gene', '3480;5293', (121, 131))	('PHIP', 'Var', (33, 37))	('melanoma metastasis', 'Disease', 'MESH:D009362', (70, 89))	('activation', 'PosReg', (103, 113))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
83993	29776954	Our studies in melanoma cell lines showed that PHIP gene silencing results in decreased glycolysis (including reduced LDH expression) in vitro and decreased angiogenesis in vivo.	('glycolysis', 'biological_process', 'GO:0006096', ('88', '98'))	('glycolysis', 'MPA', (88, 98))	('reduced', 'NegReg', (110, 117))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('decreased glycolysis', 'Phenotype', 'HP:0012270', (78, 98))	('decreased', 'NegReg', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('angiogenesis', 'biological_process', 'GO:0001525', ('157', '169'))	('angiogenesis', 'CPA', (157, 169))	('gene silencing', 'Var', (52, 66))	('PHIP', 'Gene', (47, 51))	('decreased', 'NegReg', (78, 87))	('gene silencing', 'biological_process', 'GO:0016458', ('52', '66'))
83995	29776954	In addition, our analyses of cohort #2 identified the molecular subtypes of melanoma in which PHIP copy number elevations are present, and in which they are specifically enriched.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('PHIP', 'Gene', (94, 98))	('copy number elevations', 'Var', (99, 121))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
83996	29776954	Elevated PHIP copy number was present in each molecular subtype of melanoma examined, including melanomas with BRAF mutation, NRAS mutation, as well as in melanomas without any alterations in these markers.	('melanomas', 'Disease', 'MESH:D008545', (155, 164))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('mutation', 'Var', (116, 124))	('Elevated', 'PosReg', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanomas', 'Disease', (155, 164))	('BRAF', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (111, 115))	('NRAS', 'Gene', '4893', (126, 130))	('mutation', 'Var', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('melanomas', 'Disease', (96, 105))	('NRAS', 'Gene', (126, 130))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('PHIP', 'Protein', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanoma', 'Disease', (96, 104))
83997	29776954	Moreover, we found that PHIP copy number was significantly higher in melanomas with NRAS mutation or with intact PTEN expression.	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('NRAS', 'Gene', (84, 88))	('mutation', 'Var', (89, 97))	('PHIP', 'Protein', (24, 28))	('NRAS', 'Gene', '4893', (84, 88))	('PTEN', 'Gene', (113, 117))	('melanomas', 'Disease', (69, 78))	('PTEN', 'Gene', '5728', (113, 117))	('higher', 'PosReg', (59, 65))	('melanomas', 'Disease', 'MESH:D008545', (69, 78))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))
84000	29776954	An intriguing and unexpected finding was the enrichment of PHIP copy number in NRAS-mutant melanoma.	('PHIP', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('copy number', 'Var', (64, 75))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('NRAS', 'Gene', (79, 83))
84001	29776954	Given that NRAS mutations are thought to activate both the MAPK and PI3K pathways, our results suggest the intriguing possibility of novel biochemical functions of PHIP beyond its participation in the IGF1R-PI3K axis.	('PHIP', 'Gene', (164, 168))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('activate', 'PosReg', (41, 49))	('NRAS', 'Gene', '4893', (11, 15))	('PI3K pathways', 'Pathway', (68, 81))	('mutations', 'Var', (16, 25))	('IGF1R-PI3K', 'Gene', '3480;5293', (201, 211))	('MAPK', 'molecular_function', 'GO:0004707', ('59', '63'))	('PI3K', 'molecular_function', 'GO:0016303', ('207', '211'))	('IGF1R-PI3K', 'Gene', (201, 211))	('NRAS', 'Gene', (11, 15))	('MAPK', 'Pathway', (59, 63))
84002	29776954	However, our results are consistent with the observation that PTEN loss is essentially mutually exclusive with NRAS mutation.	('NRAS', 'Gene', (111, 115))	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('NRAS', 'Gene', '4893', (111, 115))	('mutation', 'Var', (116, 124))	('loss', 'NegReg', (67, 71))
84004	29776954	Our studies of cohort #3 analyzed the role of PHIP in the progression cascade of melanoma by comparing copy number changes in matched primary versus metastatic tumors from the same patient.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('patient', 'Species', '9606', (181, 188))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('tumors', 'Disease', (160, 166))	('copy number', 'Var', (103, 114))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
84007	29776954	In addition, in the majority of cases where we had access to the primary tumor, and both lymph node and distant metastases, there was a monotonic increase in PHIP copy number elevation in the transition from primary melanoma to lymph node metastasis, and then to distant metastasis.	('primary tumor', 'Disease', (65, 78))	('increase', 'PosReg', (146, 154))	('melanoma to lymph node metastasis', 'Disease', (216, 249))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('primary melanoma', 'Disease', (208, 224))	('primary tumor', 'Disease', 'MESH:D009369', (65, 78))	('primary melanoma', 'Disease', 'MESH:D008545', (208, 224))	('melanoma to lymph node metastasis', 'Disease', 'MESH:D009362', (216, 249))	('elevation', 'PosReg', (175, 184))	('metastases', 'Disease', (112, 122))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('copy number', 'Var', (163, 174))	('PHIP', 'Gene', (158, 162))
84010	29776954	Similarly, a recent analysis of colon cancer assessed the somatic variants in hypermutable DNA regions in a cohort of 19 patients with primary colon cancer and matched lymph node and distant metastasis, enabling a conclusion that two-thirds of distant metastases have a profile distinct from that of the lymph node metastasis.	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colon cancer', 'Disease', (32, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('metastases', 'Disease', (252, 262))	('variants', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('primary colon cancer', 'Disease', 'MESH:D015179', (135, 155))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('metastases', 'Disease', 'MESH:D009362', (252, 262))	('primary colon cancer', 'Disease', (135, 155))	('patients', 'Species', '9606', (121, 129))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))
84020	33550279	Suppression of p16 alleviates the senescence-associated secretory phenotype Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest.	('p16', 'Gene', (15, 18))	('arrest', 'Disease', (217, 223))	('expression', 'MPA', (140, 150))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (206, 223))	('Suppression', 'Var', (0, 11))	('p16', 'Gene', (179, 182))	('cell cycle', 'biological_process', 'GO:0007049', ('158', '168'))	('alleviates', 'NegReg', (19, 29))	('p16', 'Gene', '1029', (15, 18))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('206', '223'))	('senescence', 'biological_process', 'GO:0010149', ('34', '44'))	('Oncogene-induced senescence', 'Disease', (76, 103))	('senescence', 'biological_process', 'GO:0010149', ('93', '103'))	('senescence-associated secretory', 'MPA', (34, 65))	('increased', 'PosReg', (130, 139))	('p16', 'Gene', '1029', (179, 182))	('OIS', 'biological_process', 'GO:0090402', ('105', '108'))	('arrest', 'Disease', 'MESH:D006323', (217, 223))
84022	33550279	Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence.	('expression', 'MPA', (46, 56))	('OIS', 'biological_process', 'GO:0090402', ('152', '155'))	('knockdown', 'Var', (19, 28))	('IL6', 'molecular_function', 'GO:0005138', ('108', '111'))	('IL6', 'Gene', '3569', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('IL6', 'Gene', (108, 111))	('senescence', 'biological_process', 'GO:0010149', ('179', '189'))	('p16', 'Gene', (32, 35))	('CXCL8', 'Gene', '3576', (116, 121))	('decreases', 'NegReg', (36, 45))	('CXCL8', 'Gene', (116, 121))	('SASP factors', 'Protein', (64, 76))
84030	33550279	Loss of p16 is a common event in human cancer that has been linked to senescence bypass, increased proliferation, and malignant transformation though both canonical and non-canonical (RB-independent) pathways.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('malignant transformation', 'CPA', (118, 142))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('human', 'Species', '9606', (33, 38))	('p16', 'Gene', (8, 11))	('senescence', 'biological_process', 'GO:0010149', ('70', '80'))	('senescence bypass', 'CPA', (70, 87))	('increased', 'PosReg', (89, 98))	('Loss', 'Var', (0, 4))	('proliferation', 'CPA', (99, 112))
84034	33550279	Therefore, changes in LMNB1 expression are tightly linked to SASP gene transcription.	('SASP gene', 'Gene', (61, 70))	('LMNB1', 'Gene', (22, 27))	('linked', 'Reg', (51, 57))	('expression', 'MPA', (28, 38))	('LMNB1', 'Gene', '4001', (22, 27))	('changes', 'Var', (11, 18))	('transcription', 'biological_process', 'GO:0006351', ('71', '84'))	('transcription', 'MPA', (71, 84))
84040	33550279	We found that knockdown of p16 leads to decreased IL6 and CXCL8 (encoding IL8) SASP gene expression in both HRASG12V and BRAFV600E models of OIS.	('IL6', 'Gene', (50, 53))	('CXCL8', 'Gene', '3576', (58, 63))	('expression', 'MPA', (89, 99))	('IL8', 'molecular_function', 'GO:0005153', ('74', '77'))	('HRAS', 'Gene', '3265', (108, 112))	('BRAFV600E', 'Mutation', 'rs113488022', (121, 130))	('CXCL8', 'Gene', (58, 63))	('IL6', 'molecular_function', 'GO:0005138', ('50', '53'))	('IL8', 'Gene', (74, 77))	('p16', 'Gene', (27, 30))	('HRAS', 'Gene', (108, 112))	('IL6', 'Gene', '3569', (50, 53))	('IL8', 'Gene', '3576', (74, 77))	('gene expression', 'biological_process', 'GO:0010467', ('84', '99'))	('OIS', 'biological_process', 'GO:0090402', ('141', '144'))	('knockdown', 'Var', (14, 23))	('decreased', 'NegReg', (40, 49))
84042	33550279	We confirmed these results in p16-wildtype melanoma cells upon knockdown of p16 and in DNA damage-induced senescence.	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('senescence', 'biological_process', 'GO:0010149', ('106', '116'))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('p16', 'Gene', (76, 79))	('knockdown', 'Var', (63, 72))
84044	33550279	Together, our results suggest that p16 may have a role in transcriptionally regulating SASP factors, which has implications for understanding how loss of p16 affects the senescent and tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('p16', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('transcriptionally regulating', 'MPA', (58, 86))	('loss', 'Var', (146, 150))	('affects', 'Reg', (158, 165))	('tumor', 'Disease', (184, 189))	('SASP', 'Protein', (87, 91))	('senescent', 'CPA', (170, 179))
84046	33550279	Knockdown of p16 with BRAFV600E or HRASG12V overexpression (Supplementary Figure 1A) decreased IL6 and CXCL8 expression and suppressed senescence-associated beta-galactosidase (SA-beta-gal) activity and the cell cycle arrest in IMR90 fibroblasts (Figure 1A-1J), a classical model of OIS.	('CXCL8', 'Gene', '3576', (103, 108))	('CXCL8', 'Gene', (103, 108))	('IL6', 'Gene', '3569', (95, 98))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (207, 224))	('OIS', 'biological_process', 'GO:0090402', ('283', '286'))	('activity', 'MPA', (190, 198))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('207', '224'))	('senescence', 'biological_process', 'GO:0010149', ('135', '145'))	('BRAFV600E', 'Mutation', 'rs113488022', (22, 31))	('arrest', 'Disease', (218, 224))	('IMR90', 'CellLine', 'CVCL:0347', (228, 233))	('IL6', 'Gene', (95, 98))	('HRAS', 'Gene', '3265', (35, 39))	('IL6', 'molecular_function', 'GO:0005138', ('95', '98'))	('HRAS', 'Gene', (35, 39))	('beta-galactosidase', 'Gene', '2720', (157, 175))	('beta-galactosidase', 'Gene', (157, 175))	('suppressed', 'NegReg', (124, 134))	('decreased', 'NegReg', (85, 94))	('arrest', 'Disease', 'MESH:D006323', (218, 224))	('BRAFV600E', 'Var', (22, 31))
84048	33550279	Additionally, knockdown of p16 in the BRAFV600E-induced senescence model decreased the expression of other SASP factors including growth factors, proteases, and ligands (Supplementary Figure 1I), suggesting that this is a broader phenomenon not limited to IL6 and CXCL8.	('IL6', 'Gene', (256, 259))	('CXCL8', 'Gene', '3576', (264, 269))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('decreased', 'NegReg', (73, 82))	('IL6', 'Gene', '3569', (256, 259))	('CXCL8', 'Gene', (264, 269))	('BRAFV600E-induced', 'Var', (38, 55))	('p16', 'Gene', (27, 30))	('IL6', 'molecular_function', 'GO:0005138', ('256', '259'))	('expression', 'MPA', (87, 97))	('knockdown', 'Var', (14, 23))	('senescence', 'biological_process', 'GO:0010149', ('56', '66'))
84050	33550279	To investigate whether the observed decrease in IL6 and CXCL8 is a direct effect of p16 suppression and not simply a consequence of senescence bypass, we knocked down p16 at two time points after oncogene expression (Figure 2A and Supplementary Figure 2A-2C).	('senescence', 'biological_process', 'GO:0010149', ('132', '142'))	('p16', 'Gene', (167, 170))	('knocked', 'Var', (154, 161))	('IL6', 'Gene', '3569', (48, 51))	('CXCL8', 'Gene', (56, 61))	('CXCL8', 'Gene', '3576', (56, 61))	('IL6', 'molecular_function', 'GO:0005138', ('48', '51'))	('IL6', 'Gene', (48, 51))	('suppression', 'NegReg', (88, 99))	('p16', 'Protein', (84, 87))	('decrease', 'NegReg', (36, 44))
84051	33550279	Consistent with observations using knockdown of p16 prior to senescence induction (Figure 1), IL6 and CXCL8 expression were both decreased when p16 was knocked down at later time points (Figure 2E and Supplementary Figure 2H).	('CXCL8', 'Gene', (102, 107))	('CXCL8', 'Gene', '3576', (102, 107))	('senescence', 'biological_process', 'GO:0010149', ('61', '71'))	('IL6', 'molecular_function', 'GO:0005138', ('94', '97'))	('p16', 'Gene', (144, 147))	('IL6', 'Gene', '3569', (94, 97))	('IL6', 'Gene', (94, 97))	('knocked down', 'Var', (152, 164))	('decreased', 'NegReg', (129, 138))
84055	33550279	Consistent with our data in fibroblasts (Figures 1, 2), knockdown of p16 in the melanoma cells also decreased IL6 and CXCL8 (Figure 3B-3D).	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('IL6', 'Gene', '3569', (110, 113))	('p16', 'Gene', (69, 72))	('decreased', 'NegReg', (100, 109))	('CXCL8', 'Gene', '3576', (118, 123))	('CXCL8', 'Gene', (118, 123))	('IL6', 'Gene', (110, 113))	('knockdown', 'Var', (56, 65))	('IL6', 'molecular_function', 'GO:0005138', ('110', '113'))
84056	33550279	Finally, expression of IL6 and CXCL8 was also significantly reduced by stable knockdown of p16 in melanoma cells induced to senesce using etoposide (Figure 3E-3H).	('p16', 'Gene', (91, 94))	('IL6', 'Gene', (23, 26))	('etoposide', 'Chemical', 'MESH:D005047', (138, 147))	('IL6', 'molecular_function', 'GO:0005138', ('23', '26'))	('knockdown', 'Var', (78, 87))	('CXCL8', 'Gene', '3576', (31, 36))	('CXCL8', 'Gene', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('expression', 'MPA', (9, 19))	('reduced', 'NegReg', (60, 67))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('IL6', 'Gene', '3569', (23, 26))
84061	33550279	Patients were classified according to their CDKN2A status (p16-low or p16-high, see Methods for details) (Table 1), and differential expression analysis was performed independently for each tumor type.	('p16-low', 'Var', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('p16-high', 'Var', (70, 78))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('CDKN2A', 'Gene', '1029', (44, 50))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', (190, 195))
84062	33550279	Note that there were no significant differences in the number of normal and tumor cells between p16-high and p16-low tumors (Supplementary Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumors', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('p16-low', 'Var', (109, 116))	('p16-high', 'Var', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
84063	33550279	Most of the SASP factors profiled in a published database of RAS-induced senescence (including soluble factors and exosomes, 232 total unique genes) (Supplementary Table 1), were significantly downregulated in p16-low tumors (Supplementary Figure 4A and Supplementary Table 2).	('downregulated', 'NegReg', (193, 206))	('p16-low', 'Var', (210, 217))	('soluble', 'cellular_component', 'GO:0005625', ('95', '102'))	('senescence', 'biological_process', 'GO:0010149', ('73', '83'))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
84064	33550279	Gene Set Enrichment Analysis (GSEA) also showed a decrease in 'Senescence Associated Secretory Phenotype, SASP' (Figure 4B) in p16-low tumors.	("SASP'", 'MPA', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	("'Senescence Associated Secretory Phenotype", 'MPA', (62, 104))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('Senescence', 'biological_process', 'GO:0010149', ('63', '73'))	('GSEA', 'Chemical', '-', (30, 34))	('p16-low', 'Var', (127, 134))	('decrease', 'NegReg', (50, 58))
84065	33550279	Interestingly, 4 out of 6 tumors (PAAD, COADREAD, MESO, and BLCA) showed a decrease in pathways related to inflammation and the immune system such as 'Antigen Processing and Presentation' and 'Cytosolic DNA Sensing Pathway' in p16-low tumors (Supplementary Figure 4B).	('p16-low', 'Var', (227, 234))	('inflammation', 'Disease', (107, 119))	('DNA', 'cellular_component', 'GO:0005574', ('203', '206'))	('decrease', 'NegReg', (75, 83))	('tumors', 'Disease', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('pathways', 'Pathway', (87, 95))	('inflammation', 'biological_process', 'GO:0006954', ('107', '119'))	('Antigen Processing and Presentation', 'biological_process', 'GO:0019882', ('151', '186'))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('tumors', 'Disease', (235, 241))	("'Cytosolic DNA Sensing Pathway", 'Pathway', (192, 222))
84066	33550279	These data demonstrate that p16 status correlates with expression of SASP factors in human tumor samples.	('p16', 'Var', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('expression', 'MPA', (55, 65))	('SASP factors', 'Protein', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('human', 'Species', '9606', (85, 90))
84067	33550279	Importantly, to rule out the possibility of less senescent tumor cells in the p16-low patient samples, we used GSEA to cross-compare p16-low vs. p16-high expression profiles with a previously published senescence expression signature.	('senescence', 'biological_process', 'GO:0010149', ('202', '212'))	('tumor', 'Disease', (59, 64))	('GSEA', 'Chemical', '-', (111, 115))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('p16-low', 'Var', (133, 140))
84071	33550279	To unravel whether this observation is due to a decrease of immune cell infiltration in p16-low vs. p16-high tumors, we compared the number of infiltrating lymphocytes, monocytes, and neutrophils seen on OCT-embedded tissue slides reported by TCGA in 5 out of 6 tumors (note that there is no available data for GBM).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('immune cell infiltration', 'CPA', (60, 84))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('OCT', 'Chemical', 'MESH:C051883', (204, 207))	('decrease', 'NegReg', (48, 56))	('decrease of immune cell', 'Phenotype', 'HP:0002721', (48, 71))	('p16-low', 'Var', (88, 95))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
84072	33550279	No significant differences were observed between p16-low and p16-high tumors (Supplementary Figure 4C).	('p16-low', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('p16-high', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (70, 76))
84075	33550279	We did not observe a strong correlation between CDKN2A and LMNB1 expression (Figure 4C), suggesting that p16 regulation of this pathway and the SASP in tumors may not be directly through modulation of LMNB1.	('LMNB1', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('regulation', 'biological_process', 'GO:0065007', ('109', '119'))	('LMNB1', 'Gene', (59, 64))	('LMNB1', 'Gene', '4001', (201, 206))	('CDKN2A', 'Gene', '1029', (48, 54))	('CDKN2A', 'Gene', (48, 54))	('p16', 'Var', (105, 108))	('tumors', 'Disease', (152, 158))	('LMNB1', 'Gene', '4001', (59, 64))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
84078	33550279	Here we found that knockdown p16 decreases gene expression of two of the most well characterized SASP factors IL6 and CXCL8, in a manner that is uncoupled from senescence bypass (Figures 1, 2).	('p16', 'Gene', (29, 32))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('gene expression', 'MPA', (43, 58))	('knockdown', 'Var', (19, 28))	('IL6', 'Gene', '3569', (110, 113))	('senescence', 'biological_process', 'GO:0010149', ('160', '170'))	('CXCL8', 'Gene', '3576', (118, 123))	('decreases', 'NegReg', (33, 42))	('CXCL8', 'Gene', (118, 123))	('IL6', 'Gene', (110, 113))	('IL6', 'molecular_function', 'GO:0005138', ('110', '113'))
84079	33550279	Knockdown of p16 or low expression of CDKN2A in patient tumors was also associated with lower expression of additional SASP factors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('low', 'NegReg', (20, 23))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('patient', 'Species', '9606', (48, 55))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('CDKN2A', 'Gene', (38, 44))	('lower', 'NegReg', (88, 93))	('expression of', 'MPA', (94, 107))	('p16', 'Var', (13, 16))	('CDKN2A', 'Gene', '1029', (38, 44))
84082	33550279	Importantly, we found that knockdown of p16 decreased SASP gene expression, which was not a consequence of increased LMNB1 expression (Figure 2).	('p16', 'Gene', (40, 43))	('LMNB1', 'Gene', '4001', (117, 122))	('knockdown', 'Var', (27, 36))	('expression', 'MPA', (64, 74))	('LMNB1', 'Gene', (117, 122))	('gene expression', 'biological_process', 'GO:0010467', ('59', '74'))	('SASP gene', 'Gene', (54, 63))	('decreased', 'NegReg', (44, 53))
84084	33550279	Notably, we found that four out of the six tumor types analyzed here have decreased cytosolic DNA sensing pathway signaling in p16-low vs. p16-high tumors (Supplementary Figure 4B); however, no correlation was found between CDKN2A and LMNB1 mRNA expression (Figure 4C), suggesting that additional mechanisms are at play in tumors with low p16 expression.	('LMNB1', 'Gene', '4001', (235, 240))	('tumor', 'Disease', (43, 48))	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cytosolic DNA sensing', 'MPA', (84, 105))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CDKN2A', 'Gene', (224, 230))	('LMNB1', 'Gene', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (323, 329))	('tumors', 'Disease', (148, 154))	('p16-low', 'Var', (127, 134))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('CDKN2A', 'Gene', '1029', (224, 230))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (323, 329))	('decreased', 'NegReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
84086	33550279	Loss of CDKN2A is often due to deletion or hypermethylation of the locus.	('CDKN2A', 'Gene', (8, 14))	('CDKN2A', 'Gene', '1029', (8, 14))	('Loss', 'NegReg', (0, 4))	('deletion', 'Var', (31, 39))	('hypermethylation', 'Var', (43, 59))
84087	33550279	Interestingly, previous work has suggested that melanomas with low MTAP have decreased cGAS-STING signaling, and MTAP is often co-deleted/silenced with CDKN2A.	('CDKN2A', 'Gene', (152, 158))	('cGAS', 'Gene', '115004', (87, 91))	('CDKN2A', 'Gene', '1029', (152, 158))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('MTAP', 'Gene', (113, 117))	('melanomas', 'Disease', (48, 57))	('MTAP', 'Gene', (67, 71))	('cGAS', 'Gene', (87, 91))	('MTAP', 'Gene', '4507', (113, 117))	('MTAP', 'Gene', '4507', (67, 71))	('low', 'Var', (63, 66))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('decreased', 'NegReg', (77, 86))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
84089	33550279	Additionally, p16 can negatively regulate TP53 (encoding for p53) at the transcriptional level and also at the protein level by increasing Mdm2-dependent degradation of p53.	('TP53', 'Gene', '7157', (42, 46))	('Mdm2', 'Gene', (139, 143))	('Mdm2', 'Gene', '4193', (139, 143))	('p53', 'Gene', (169, 172))	('p16', 'Var', (14, 17))	('TP53', 'Gene', (42, 46))	('p53', 'Gene', '7157', (169, 172))	('negatively', 'NegReg', (22, 32))	('degradation', 'biological_process', 'GO:0009056', ('154', '165'))	('p53', 'Gene', '7157', (61, 64))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('increasing', 'PosReg', (128, 138))	('p53', 'Gene', (61, 64))
84092	33550279	In this regard, some studies have found that pharmacological inhibition of canonical downstream targets of p16, namely CDK4/6, leads to an induction of SASP factors, recruitment of antitumor immune cells, and senescence, suggesting that p16-loss-mediated regulation of SASP expression and the tumor immune microenvironment may be due to non-canonical (RB-independent) mechanisms.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('recruitment', 'MPA', (166, 177))	('CDK4/6', 'Gene', (119, 125))	('p16', 'Gene', (107, 110))	('p16-loss-mediated', 'NegReg', (237, 254))	('tumor', 'Disease', (185, 190))	('CDK', 'molecular_function', 'GO:0004693', ('119', '122'))	('regulation', 'biological_process', 'GO:0065007', ('255', '265'))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CDK4/6', 'Gene', '1019;1021', (119, 125))	('p16-loss-mediated', 'Gene', (237, 254))	('senescence', 'CPA', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('inhibition', 'Var', (61, 71))	('SASP factors', 'Protein', (152, 164))	('tumor', 'Disease', (293, 298))	('induction', 'Reg', (139, 148))	('senescence', 'biological_process', 'GO:0010149', ('209', '219'))
84093	33550279	On the contrary, other authors suggest that inhibition of CDK4/6 alone does not induce a SASP and immunologic responses.	('SASP', 'CPA', (89, 93))	('inhibition', 'Var', (44, 54))	('CDK4/6', 'Gene', '1019;1021', (58, 64))	('induce', 'Reg', (80, 86))	('CDK', 'molecular_function', 'GO:0004693', ('58', '61'))	('CDK4/6', 'Gene', (58, 64))
84095	33550279	Additionally, we demonstrated that knockdown of p16 in BRAFV600E-induced senescence in vitro corresponds with a decrease in different SASP factors including inflammatory factors, growth factors, metalloproteinases, and ligands (Figure 1I, 1J and Supplementary Figure 1I).	('senescence', 'CPA', (73, 83))	('decrease', 'NegReg', (112, 120))	('BRAFV600E', 'Mutation', 'rs113488022', (55, 64))	('SASP factors', 'MPA', (134, 146))	('inflammatory factors', 'MPA', (157, 177))	('senescence', 'biological_process', 'GO:0010149', ('73', '83'))	('p16', 'Gene', (48, 51))	('metalloproteinases', 'MPA', (195, 213))	('growth factors', 'MPA', (179, 193))	('BRAFV600E-induced', 'Var', (55, 72))
84097	33550279	Moreover, it will be important to determine whether these tumor-specific SASP signatures alter the clinical course of each tumor type or response to therapy.	('signatures', 'Var', (78, 88))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (123, 128))	('alter', 'Reg', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
84106	33550279	Thus, it is possible that in the context of certain tumor types such as those studied here, the decreased expression of SASP factors observed upon p16 knockdown or in CDKN2A-low patients may contribute to abrogation of senescence surveillance by immune cells, thereby promoting tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('promoting', 'PosReg', (268, 277))	('decreased', 'NegReg', (96, 105))	('p16', 'Gene', (147, 150))	('senescence surveillance', 'MPA', (219, 242))	('expression', 'MPA', (106, 116))	('SASP', 'Protein', (120, 124))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (278, 283))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('patients', 'Species', '9606', (178, 186))	('abrogation', 'NegReg', (205, 215))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('senescence', 'biological_process', 'GO:0010149', ('219', '229'))	('knockdown', 'Var', (151, 160))
84107	33550279	Interestingly, a recent publication shows that depletion of p16 in tumor cells abrogates the cancer immune response and promotes immune checkpoint blockade resistance.	('p16', 'Gene', (60, 63))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promotes', 'PosReg', (120, 128))	('depletion', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('immune response', 'biological_process', 'GO:0006955', ('100', '115'))	('abrogates', 'NegReg', (79, 88))	('immune', 'CPA', (129, 135))
84109	33550279	Although loss of p16 is one of the most common events in cancer (~50% of all human cancers), there are currently no approved targeted therapies.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Disease', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('p16', 'Gene', (17, 20))	('loss', 'Var', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
84112	33550279	For instance, we previously showed that inhibition of nucleotide metabolism through suppression of mTORC1 or the pentose phosphate pathway enzyme Ribose 5-Phosphate Isomerase A (RPIA) induces senescence specifically in p16-low cancers.	('nucleotide metabolism', 'MPA', (54, 75))	('senescence', 'biological_process', 'GO:0010149', ('192', '202'))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('54', '75'))	('mTORC1', 'Gene', (99, 105))	('mTORC1', 'Gene', '382056', (99, 105))	('senescence', 'MPA', (192, 202))	('Ribose 5-Phosphate Isomerase A', 'Gene', '22934', (146, 176))	('pentose phosphate', 'Chemical', 'MESH:D010428', (113, 130))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('mTORC1', 'cellular_component', 'GO:0031931', ('99', '105'))	('inhibition', 'Var', (40, 50))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('113', '138'))	('RPIA', 'Gene', '22934', (178, 182))	('suppression', 'NegReg', (84, 95))	('RPIA', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Ribose 5-Phosphate Isomerase A', 'Gene', (146, 176))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('induces', 'Reg', (184, 191))	('cancers', 'Disease', (227, 234))
84113	33550279	Therefore, induction of senescence in p16-low cancers may be a valuable strategy to inhibit the cell cycle while not activating the potential deleterious effects of the SASP.	('cell cycle', 'biological_process', 'GO:0007049', ('96', '106'))	('p16-low', 'Var', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cell cycle', 'CPA', (96, 106))	('cancers', 'Disease', (46, 53))	('induction', 'Reg', (11, 20))	('inhibit', 'NegReg', (84, 91))	('senescence', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('senescence', 'biological_process', 'GO:0010149', ('24', '34'))
84114	33550279	We found that this phenomenon also occurs in p16-wildtype tumor cells upon p16 knockdown, and there is a decrease in the SASP gene signature in multiple tumor types that are associated with low p16 expression.	('p16 knockdown', 'Var', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('SASP gene', 'Gene', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('knockdown', 'Var', (79, 88))	('decrease', 'NegReg', (105, 113))
84116	33550279	Normal diploid IMR90 human fibroblasts were obtained from ATCC (CCL-186) and cultured according to the ATCC protocol in DMEM (Corning, cat#10-017-CV) supplemented with 5% FBS (VWR, cat#97068-085), L-glutamine (Corning, cat#25-015-CI), non-essential amino acids (Corning, cat#25-025-CI), sodium pyruvate (Corning, cat#25-000-CI), and sodium bicarbonate (Corning, cat#25-035-CI).	('sodium pyruvate', 'MPA', (287, 302))	('CCL', 'molecular_function', 'GO:0044101', ('64', '67'))	('cat', 'molecular_function', 'GO:0004096', ('313', '316'))	('DMEM', 'Chemical', '-', (120, 124))	('cat#25-025-CI', 'Var', (271, 284))	('sodium bicarbonate', 'MPA', (333, 351))	('cat', 'molecular_function', 'GO:0004096', ('219', '222'))	('human', 'Species', '9606', (21, 26))	('cat', 'molecular_function', 'GO:0004096', ('362', '365'))	('cat', 'molecular_function', 'GO:0004096', ('271', '274'))	('cat', 'molecular_function', 'GO:0004096', ('181', '184'))	('cat', 'molecular_function', 'GO:0004096', ('135', '138'))	('non-essential amino acids', 'MPA', (235, 260))	('IMR90', 'CellLine', 'CVCL:0347', (15, 20))
84126	33550279	Briefly, cells were infected with pBabe empty vector control, pBabe BRAFV600E, or pBabe HRASG12V retroviral particles, and 24 hours later cells were infected with a second round of corresponding retroviral particles.	('BRAFV600E', 'Var', (68, 77))	('infected', 'Disease', 'MESH:D007239', (20, 28))	('infected', 'Disease', (20, 28))	('HRAS', 'Gene', '3265', (88, 92))	('infected', 'Disease', 'MESH:D007239', (149, 157))	('HRAS', 'Gene', (88, 92))	('BRAFV600E', 'Mutation', 'rs113488022', (68, 77))	('infected', 'Disease', (149, 157))
84127	33550279	Cells were infected with pLKO.1-shp16 or pLKO.1-shGFP when indicated in Supplementary Figure 1A and Supplementary Figure 2A.	('infected', 'Disease', (11, 19))	('pLKO.1-shGFP', 'Var', (41, 53))	('pLKO.1-shp16', 'Var', (25, 37))	('infected', 'Disease', 'MESH:D007239', (11, 19))
84129	33550279	SKMel28 melanoma cells (p16-wildtype) with stable p16 knockdown (using shp16 hairpin #1) or control (shGFP) were treated with either DMSO or 1muM etoposide (Cayman Chemical, cat#12092) for 6 days (drug replacement every 2 days).	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('etoposide', 'Chemical', 'MESH:D005047', (146, 155))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('knockdown', 'Var', (54, 63))	('DMSO', 'Chemical', 'MESH:D004121', (133, 137))	('SKMel28', 'Chemical', '-', (0, 7))	('cat', 'molecular_function', 'GO:0004096', ('174', '177'))	('p16', 'Gene', (50, 53))
84135	33550279	Antibodies used include: anti-BRAF (Santa Cruz Biotechnology, cat#sc-5284, 1:1000), anti-RAS (BD Sciences, cat#610001, 1:1000), anti-p16 (Abcam, cat#ab108349, 1:1000), anti-p21 (Abcam cat#ab109199, 1:1000), anti-cyclin A2 (Abcam cat#ab181591, 1:2000), anti-vinculin (Sigma-Aldrich cat#V9131, 1:1000), beta-Actin (Sigma-Aldrich, cat#A1978, 1:10000), anti-mouse HRP (Cell Signaling Technology, cat#cst7076, 1:10,000), and anti-rabbit HRP (Cell Signaling Technology, cat#cst7074, 1:5000).	('cat', 'molecular_function', 'GO:0004096', ('184', '187'))	('Signaling', 'biological_process', 'GO:0023052', ('370', '379'))	('cat', 'molecular_function', 'GO:0004096', ('229', '232'))	('anti-rabbit', 'Var', (420, 431))	('cat', 'molecular_function', 'GO:0004096', ('392', '395'))	('cyclin A2', 'Gene', '12428', (212, 221))	('beta-Actin', 'Gene', '11461', (301, 311))	('cyclin', 'molecular_function', 'GO:0016538', ('212', '218'))	('vinculin', 'Gene', '22330', (257, 265))	('p21', 'Gene', (173, 176))	('cat', 'molecular_function', 'GO:0004096', ('145', '148'))	('cat', 'molecular_function', 'GO:0004096', ('281', '284'))	('vinculin', 'Gene', (257, 265))	('mouse', 'Species', '10090', (354, 359))	('beta-Actin', 'Gene', (301, 311))	('cat', 'molecular_function', 'GO:0004096', ('107', '110'))	('cat', 'molecular_function', 'GO:0004096', ('328', '331'))	('cat', 'molecular_function', 'GO:0004096', ('62', '65'))	('cat', 'molecular_function', 'GO:0004096', ('464', '467'))	('cyclin A2', 'Gene', (212, 221))	('p21', 'Gene', '12575', (173, 176))	('anti-mouse HRP', 'Protein', (349, 363))	('Signaling', 'biological_process', 'GO:0023052', ('442', '451'))
84150	33410475	Germline variants are associated with increased primary melanoma tumor thickness at diagnosis Germline genetic variants have been identified, which predispose individuals and families to develop melanoma.	('melanoma tumor', 'Disease', (56, 70))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('predispose', 'Reg', (148, 158))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('variants', 'Var', (111, 119))	('develop', 'PosReg', (187, 194))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('variants', 'Var', (9, 17))	('melanoma', 'Disease', (195, 203))	('melanoma tumor', 'Disease', 'MESH:D008545', (56, 70))	('increased', 'PosReg', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
84154	33410475	To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness.	('variation', 'Var', (113, 122))	('cutaneous melanoma thickness', 'Disease', (199, 227))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (199, 217))	('genetic variation', 'Var', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('patients', 'Species', '9606', (168, 176))	('cutaneous melanoma thickness', 'Disease', 'MESH:C562393', (199, 227))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
84161	33410475	Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.	('variants', 'Var', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('associated', 'Reg', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('melanoma growth', 'Disease', (221, 236))	('tumor', 'Disease', (122, 127))	('lead to', 'Reg', (153, 160))	('melanoma growth', 'Disease', 'MESH:D008545', (221, 236))
84173	33410475	Identifying these genetic variants, and the genes they influence, will lead to a better understanding of the host biological processes that are important for the growth and invasion of melanoma.	('lead to', 'Reg', (71, 78))	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('variants', 'Var', (26, 34))
84183	33410475	rs183471242 is in an intron of the gene low-density lipoprotein receptor class A domain containing 3 (LDLRAD3; Fig.	('rs183471242', 'DBSNP_MENTION', 'None', (0, 11))	('low-density lipoprotein receptor class A domain containing 3', 'Gene', '143458', (40, 100))	('LDLRAD3', 'Gene', (102, 109))	('rs183471242', 'Var', (0, 11))	('LDLRAD3', 'Gene', '143458', (102, 109))	('low-density lipoprotein', 'molecular_function', 'GO:0005322', ('40', '63'))
84185	33410475	Both rs183471242 (G/A) and rs566382949 (C/A) are rare (HRC v1.1 minor A allele 0.0098 and 0.0082, respectively), with the minor allele associated with thicker tumors (Table 2,  Fig.	('rs183471242', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('rs566382949', 'Var', (27, 38))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('associated', 'Reg', (135, 145))	('rs566382949', 'Mutation', 'rs566382949', (27, 38))	('thicker', 'PosReg', (151, 158))	('rs183471242', 'DBSNP_MENTION', 'None', (5, 16))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
84186	33410475	Each minor allele of rs183471242 translates to a 1.423-fold increase on the transformed residuals of tumor thickness.	('rs183471242', 'DBSNP_MENTION', 'None', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('increase', 'PosReg', (60, 68))	('rs183471242', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
84187	33410475	As a sensitivity analysis, we performed the regression of residual and rank normalized residual tumor thickness on rs183471242 and rs566382949 in the same combined dataset used for the GREML analysis (N = 8125), fitting the first six PCs and study covariates in the model.	('rs183471242', 'Var', (115, 126))	('rs566382949', 'Mutation', 'rs566382949', (131, 142))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('rs183471242', 'DBSNP_MENTION', 'None', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('rs566382949', 'Var', (131, 142))
84189	33410475	While none of the previously reported genetic variants associated with primary tumor thickness reached genome-wide significance in this study, the IRF4 functional genetic variant rs12203592 was the most strongly associated (fixed P = 6.50 x 10-4; Supplementary Material, Table S1).	('IRF4', 'Gene', (147, 151))	('tumor', 'Disease', (79, 84))	('rs12203592', 'Var', (179, 189))	('rs12203592', 'Mutation', 'rs12203592', (179, 189))	('associated', 'Interaction', (212, 222))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('IRF4', 'Gene', '3662', (147, 151))
84190	33410475	Given inconsistency in identifying specific germline variants associated with primary melanoma tumor thickness, we first determined whether tumor thickness is heritable (that is, a proportion of phenotypic variance can be explained by additive genetic variants).	('melanoma tumor', 'Disease', 'MESH:D008545', (86, 100))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('variants', 'Var', (53, 61))	('melanoma tumor', 'Disease', (86, 100))	('tumor', 'Disease', (140, 145))
84198	33410475	As this result indicates that primary melanoma tumor thickness is heritable, it shows that with sufficiently well-powered cohorts, it will be possible to identify specific genetic variants associated with tumor thickness.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('melanoma tumor', 'Disease', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('variants', 'Var', (180, 188))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('melanoma tumor', 'Disease', 'MESH:D008545', (38, 52))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('tumor', 'Disease', (47, 52))
84199	33410475	Following confirmation that tumor thickness is heritable, we used the complete dataset to perform a GWAS meta-analysis, identifying two genetic variants in a locus on chromosome 11 at genome-wide significance (P < 5 x 10-8).	('variants', 'Var', (144, 152))	('tumor', 'Disease', (28, 33))	('chromosome', 'cellular_component', 'GO:0005694', ('167', '177'))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
84200	33410475	As tumor thickness values were natural log transformed prior to analysis, the effect size for each minor allele of rs183471242 is associated with a 1.42-fold higher tumor thickness.	('rs183471242', 'Var', (115, 126))	('tumor', 'Disease', (3, 8))	('higher', 'PosReg', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('rs183471242', 'DBSNP_MENTION', 'None', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (165, 170))
84202	33410475	While these genetic variants are in an intron of LDLRAD3, the closest gene is not always the target of associated genetic variants.	('LDLRAD3', 'Gene', (49, 56))	('LDLRAD3', 'Gene', '143458', (49, 56))	('variants', 'Var', (20, 28))
84204	33410475	Neither of these two genetic variants were associated (P > 0.05) with ease of tanning, childhood sunburns or skin and hair color in the UK Biobank (data not shown), melanoma risk, nor nevus count.	('nevus', 'Phenotype', 'HP:0003764', (184, 189))	('childhood sunburns', 'Disease', (87, 105))	('skin', 'Disease', (109, 113))	('variants', 'Var', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
84205	33410475	While none of the previously reported genetic variants associated with tumor thickness reached a P-value<5 x 10-8, the IRF4 functional genetic variant rs12203592 was the most strongly associated (P = 6.51 x 10-4, I2 = 36.4%, Supplementary Table 1).	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('IRF4', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('IRF4', 'Gene', '3662', (119, 123))	('associated', 'Interaction', (184, 194))	('tumor', 'Disease', (71, 76))	('rs12203592', 'Var', (151, 161))	('rs12203592', 'Mutation', 'rs12203592', (151, 161))
84207	33410475	The IRF4 SNP rs12203592 has been associated with risk of melanoma.	('IRF4', 'Gene', '3662', (4, 8))	('IRF4', 'Gene', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('rs12203592', 'Var', (13, 23))	('associated', 'Reg', (33, 43))	('rs12203592', 'Mutation', 'rs12203592', (13, 23))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))
84209	33410475	there is no overlap between genetic variants associated with risk or survival for lung cancer or breast cancer), and as such, it is unclear if we would expect the other known melanoma risk variants (e.g.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('variants', 'Var', (189, 197))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('variants', 'Var', (36, 44))	('breast cancer', 'Disease', (97, 110))	('melanoma', 'Disease', (175, 183))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))
84215	33410475	While both our heritability estimate and the genetic variants associated with tumor thickness following correction for multiple testing require replication in a sufficiently large dataset, these findings indicate germline variants impact tumor development, a strong predictor of melanoma outcome.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('impact', 'Reg', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', (78, 83))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))	('variants', 'Var', (222, 230))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))
84216	33410475	Discovery of specific genetic variants will enable identification of host biological processes influencing melanoma growth and invasion.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma growth', 'Disease', 'MESH:D008545', (107, 122))	('variants', 'Var', (30, 38))	('melanoma growth', 'Disease', (107, 122))
84217	33410475	Genotyped variants were filtered out if they had a minor allele frequency < 0.01, Hardy-Weinberg equilibrium P-value<5 x 10-4 in cancer-free individuals (where melanoma cases were genotyped/cleaned in concert with healthy individuals) or < 5 x 10-10 in those with melanoma.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('variants', 'Var', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma', 'Disease', (264, 272))
84218	33410475	sample contamination or inbreeding), individuals were excluded if they had missingness >0.03, heterozygosity more than three standard deviations (SDs) from the rest of the population, a mismatch between recorded sex and X chromosome determined sex or were considered non-European.	('SDs', 'Chemical', '-', (146, 149))	('heterozygosity', 'Var', (94, 108))	('mismatch', 'Var', (186, 194))	('X chromosome', 'cellular_component', 'GO:0000805', ('220', '232'))
84235	33410475	Imputed dosage data from the Michigan Imputation Server in variant-call format were converted to best guess format (genotype dosage <=0.5 as 0, 0.5-1.5 as 1 and >1.5 as 2) and merged into a single combined dataset using PLINK v1.91.4 beta3.	('variant-call', 'Var', (59, 71))	('beta3', 'Gene', (234, 239))	('beta3', 'Gene', '28883', (234, 239))
84241	33410475	To identify specific genetic variants associated with tumor thickness, within each individual dataset, residual tumor thickness was regressed on imputed genome-wide genotype dosages with the first six ancestry principal components included as covariates.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('variants', 'Var', (29, 37))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (54, 59))
84245	33410475	was supported by Cancer Research UK (c588/a19167) and the NIH (ca083115).	('Cancer', 'Disease', (17, 23))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('c588/a19167', 'Var', (37, 48))	('ca083115', 'Var', (63, 71))
84251	33410475	The AMFS was funded by the NHMRC (APP566946, APP107359, APP211172, APP402761).	('AMFS', 'Disease', (4, 8))	('APP402761', 'Var', (67, 76))	('APP566946', 'Var', (34, 43))	('APP107359', 'Var', (45, 54))	('AMFS', 'Disease', 'None', (4, 8))	('APP211172', 'Var', (56, 65))
84252	33410475	We also recognize the funding from Cancer Councils of Victoria, Queensland and New South Wales (project grants 77/00, 06/10, 371) and by US NIH RO1 grants (CA-83115-01A2 and 2R01CA083115-11A1).	('CA-83115-01A2', 'Var', (156, 169))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', (35, 41))
84258	33410475	Funding from Cancer Research UK (UK C490/A16561, C8216/A6129, C588/A4994) and by the NIH (R01 CA83115) is gratefully recognized.	('Cancer', 'Disease', (13, 19))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('C8216/A6129', 'Var', (49, 60))	('C588/A4994', 'Var', (62, 72))	('C8216/A6129', 'Mutation', 'c.8216,6129C>A', (49, 60))	('R01 CA83115', 'Var', (90, 101))
84359	28389511	Epigenetic Regulation of KPC1 Ubiquitin Ligase Effects the NF-kappaB Pathway in Melanoma Abnormal activation of the NF-kappaB pathway induces a more aggressive phenotype of cutaneous melanoma.	('KPC1', 'Gene', '63891', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('NF-kappaB', 'Gene', '4790', (116, 125))	('NF-kappaB', 'Gene', '4790', (59, 68))	('activation', 'PosReg', (98, 108))	('NF-kappaB', 'Gene', (116, 125))	('Melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Epigenetic', 'Var', (0, 10))	('cutaneous melanoma', 'Disease', (173, 191))	('NF-kappaB', 'Gene', (59, 68))	('Melanoma', 'Disease', 'MESH:D008545', (80, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (173, 191))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (173, 191))	('KPC1', 'Gene', (25, 29))	('Ubiquitin', 'molecular_function', 'GO:0031386', ('30', '39'))	('Melanoma', 'Disease', (80, 88))	('induces', 'Reg', (134, 141))
84366	28389511	Concordantly, KPC1 expression was down-regulated in AJCC stage IV melanoma compared to early stages (stage I/II p=0.013, stage III p=0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n=137, Hazard Ratio 1.810, p=0.006).	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('expression', 'MPA', (19, 29))	('stage IV melanoma', 'Disease', (57, 74))	('KPC1', 'Gene', (149, 153))	('AJCC', 'Disease', (52, 56))	('KPC1', 'Gene', '63891', (14, 18))	('overall survival', 'MPA', (204, 220))	('down-regulated', 'NegReg', (34, 48))	('stage IV melanoma', 'Disease', 'MESH:D008545', (57, 74))	('expression', 'MPA', (154, 164))	('KPC1', 'Gene', '63891', (149, 153))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('stage IV melanoma', 'Disease', (224, 241))	('poor', 'NegReg', (199, 203))	('stage IV melanoma', 'Disease', 'MESH:D008545', (224, 241))	('low', 'Var', (145, 148))	('KPC1', 'Gene', (14, 18))
84368	28389511	This study revealed novel epigenetic regulation of KPC1 associated with NF-kappaB pathway activation, promoting metastatic melanoma progression.	('regulation', 'biological_process', 'GO:0065007', ('37', '47'))	('KPC1', 'Gene', '63891', (51, 55))	('epigenetic regulation', 'Var', (26, 47))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('NF-kappaB', 'Gene', '4790', (72, 81))	('melanoma', 'Disease', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('promoting', 'PosReg', (102, 111))	('NF-kappaB', 'Gene', (72, 81))	('KPC1', 'Gene', (51, 55))
84369	28389511	These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.	('KPC1', 'Gene', (48, 52))	('KPC1', 'Gene', '63891', (48, 52))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))	('epigenetic regulation', 'Var', (61, 82))
84372	28389511	One of the mechanisms that switch non-aggressive melanoma to an aggressive phenotype is dysregulation in the nuclear factor-kappaB (NF-kappaB) pathway.	('NF-kappaB', 'Gene', (132, 141))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('nuclear factor-kappaB', 'Gene', '4790', (109, 130))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('NF-kappaB', 'Gene', '4790', (132, 141))	('melanoma', 'Disease', (49, 57))	('dysregulation', 'Var', (88, 101))	('nuclear factor-kappaB', 'Gene', (109, 130))
84386	28389511	Overall, this study revealed epigenetic regulation of KPC1 associated with abnormal NF-kappaB pathway activation, suggesting KPC1 and its epigenetic regulation's potential as theranostic targets in cutaneous melanoma.	('KPC1', 'Gene', (125, 129))	('NF-kappaB', 'Gene', (84, 93))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('epigenetic regulation', 'Var', (29, 50))	('cutaneous melanoma', 'Disease', (198, 216))	('KPC1', 'Gene', (54, 58))	('associated', 'Reg', (59, 69))	('KPC1', 'Gene', '63891', (125, 129))	('activation', 'PosReg', (102, 112))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (198, 216))	('regulation', 'biological_process', 'GO:0065007', ('149', '159'))	('KPC1', 'Gene', '63891', (54, 58))	('NF-kappaB', 'Gene', '4790', (84, 93))
84391	28389511	Stage I/II melanoma lines (WC00060, WC00080, WC00081 and WC00062) were obtained from Coriell Institute (Camden, NJ) and have been tested by short tandem repeat DNA profiles.	('WC00062', 'Var', (57, 64))	('DNA', 'cellular_component', 'GO:0005574', ('160', '163'))	('II melanoma lines', 'Disease', (8, 25))	('WC00060', 'Var', (27, 34))	('II melanoma lines', 'Disease', 'MESH:D008545', (8, 25))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))
84397	28389511	To establish stable KPC1-overexpressing clones, cells (5 x 105 in 60 mm dishes (Corning)) with low KPC1 expression (IM-0223 and MH-0331) were transfected with Myc-tagged KPC1 vector (KPC1; OriGene, Rockville, MD) using jetPRIME (Polyplus transfection, New York, NY) and were selected using Geneticin (500 mug/ml, Life Technologies).	('KPC1', 'Gene', (183, 187))	('low', 'NegReg', (95, 98))	('KPC1', 'Gene', (170, 174))	('KPC1', 'Gene', '63891', (20, 24))	('KPC1', 'Gene', '63891', (183, 187))	('Myc', 'Gene', '4609', (159, 162))	('Myc', 'Gene', (159, 162))	('mug', 'molecular_function', 'GO:0043739', ('305', '308'))	('KPC1', 'Gene', (99, 103))	('MH-0331', 'Var', (128, 135))	('KPC1', 'Gene', '63891', (170, 174))	('KPC1', 'Gene', (20, 24))	('IM-0223', 'Var', (116, 123))	('KPC1', 'Gene', '63891', (99, 103))
84457	28389511	KPC1 overexpression induced significantly higher levels of p50 produced from exogenous Flag-p105 (p=0.005), but not in control cells (V0), demonstrating that KPC1 is involved in processing into p50.	('p50', 'Gene', (194, 197))	('levels', 'MPA', (49, 55))	('p50', 'Gene', '4790', (59, 62))	('KPC1', 'Gene', '63891', (158, 162))	('p50', 'Gene', '4790', (194, 197))	('KPC1', 'Gene', '63891', (0, 4))	('KPC1', 'Gene', (0, 4))	('higher', 'PosReg', (42, 48))	('p50', 'Gene', (59, 62))	('p105', 'Gene', '4790', (92, 96))	('overexpression', 'Var', (5, 19))	('p105', 'Gene', (92, 96))	('KPC1', 'Gene', (158, 162))
84458	28389511	Despite lower accumulation of p50 observed in IM-0223 V0, p105 diminished strongly, presumably due to other factors such as proteasomal degradation of p105 through ubiquitination by betaTrCP ubiquitin ligase.	('p105', 'Gene', '4790', (151, 155))	('IM-0223 V0', 'Var', (46, 56))	('betaTrCP', 'Gene', (182, 190))	('ubiquitination', 'MPA', (164, 178))	('p105', 'Gene', (151, 155))	('p50', 'Gene', (30, 33))	('proteasomal', 'MPA', (124, 135))	('p105', 'Gene', '4790', (58, 62))	('p50', 'Gene', '4790', (30, 33))	('betaTrCP', 'Gene', '8945', (182, 190))	('ubiquitin', 'molecular_function', 'GO:0031386', ('191', '200'))	('p105', 'Gene', (58, 62))	('diminished', 'NegReg', (63, 73))	('degradation', 'biological_process', 'GO:0009056', ('136', '147'))
84464	28389511	NF-kappaB1 p105 knock-down abrogated the suppressive effect of KPC1 overexpression on melanoma cell proliferation (IM-0223, p=0.011, Fig.	('abrogated', 'NegReg', (27, 36))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('95', '113'))	('melanoma', 'Disease', (86, 94))	('KPC1', 'Gene', '63891', (63, 67))	('NF-kappaB', 'Gene', '4790', (0, 9))	('NF-kappaB', 'Gene', (0, 9))	('p105', 'Gene', '4790', (11, 15))	('p105', 'Gene', (11, 15))	('overexpression', 'PosReg', (68, 82))	('KPC1', 'Gene', (63, 67))	('knock-down', 'Var', (16, 26))
84472	28389511	S2D (i)), known tumor promoters, and significant down-regulation of Cox-2 and c-Myc was also validated in MH-0331 from RPPA analysis (p<0.05, Supplementary Fig.	('regulation', 'biological_process', 'GO:0065007', ('54', '64'))	('S2D', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('c-Myc', 'Gene', '4609', (78, 83))	('Cox-2', 'Gene', '4513', (68, 73))	('tumor', 'Disease', (16, 21))	('Cox-2', 'Gene', (68, 73))	('c-Myc', 'Gene', (78, 83))	('down-regulation', 'NegReg', (49, 64))
84474	28389511	Analysis of amplification or deletion in the genomic region 3p21, where the RNF123 gene is located, showed no significant changes in the TCGA melanoma cohort (data not shown).	('deletion', 'Var', (29, 37))	('melanoma cohort', 'Disease', (142, 157))	('amplification', 'Var', (12, 25))	('RNF123', 'Gene', (76, 82))	('RNF123', 'Gene', '63891', (76, 82))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma cohort', 'Disease', 'MESH:D008545', (142, 157))
84475	28389511	After stratification of cutaneous melanoma into four subtypes characterized by genomic mutation pattern (mutation in BRAF, RAS (N/H/KRAS), NF1 and Triple-wild-type), mutation status was not associated with KPC1 mRNA expression in the TCGA cohort (n=272, Supplementary Fig.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (24, 42))	('mutation', 'Var', (105, 113))	('KRAS', 'Gene', (132, 136))	('KRAS', 'Gene', '3845', (132, 136))	('NF1', 'Gene', (139, 142))	('KPC1', 'Gene', '63891', (206, 210))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (24, 42))	('NF1', 'Gene', '4763', (139, 142))	('BRAF', 'Gene', '673', (117, 121))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('cutaneous melanoma', 'Disease', (24, 42))	('BRAF', 'Gene', (117, 121))	('KPC1', 'Gene', (206, 210))
84520	28389511	We demonstrate, for the first time, the detailed mechanisms regulating KPC1 expression in tumor; methylation regulates miR-155-5p expression, and miR-155-5p controls KPC1 expression.	('expression', 'MPA', (171, 181))	('miR-155', 'Gene', (119, 126))	('controls', 'Reg', (157, 165))	('regulates', 'Reg', (109, 118))	('KPC1', 'Gene', (166, 170))	('miR-155', 'Gene', '406947', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('KPC1', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('KPC1', 'Gene', '63891', (166, 170))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('miR-155', 'Gene', (146, 153))	('miR-155', 'Gene', '406947', (119, 126))	('methylation', 'Var', (97, 108))	('KPC1', 'Gene', '63891', (71, 75))
84525	28389511	We also demonstrated that low KPC1 expression is an independent variable that predicts poor prognosis in melanoma TMA.	('melanoma TMA', 'Disease', 'MESH:D008545', (105, 117))	('KPC1', 'Gene', '63891', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('low', 'Var', (26, 29))	('melanoma TMA', 'Disease', (105, 117))	('expression', 'MPA', (35, 45))	('KPC1', 'Gene', (30, 34))
84529	28389511	Interestingly, higher miR-155-5p expression was associated with mutation in BRAF (p=0.014, TCGA cohort, n=272, data not shown), one of the major driver gene mutations involved in melanoma progression.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (64, 72))	('higher', 'PosReg', (15, 21))	('miR-155', 'Gene', '406947', (22, 29))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))	('miR-155', 'Gene', (22, 29))
84530	28389511	Although the regulatory mechanisms of miR-155-5p expression with BRAF mutation remains unknown, gene-mutation status is another potential mechanism leading to high miR-155-5p expression and advanced metastatic melanoma.	('high', 'PosReg', (159, 163))	('expression', 'MPA', (175, 185))	('miR-155', 'Gene', (164, 171))	('miR-155', 'Gene', '406947', (38, 45))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('miR-155', 'Gene', (38, 45))	('miR-155', 'Gene', '406947', (164, 171))	('BRAF', 'Gene', '673', (65, 69))	('gene-mutation', 'Var', (96, 109))	('mutation', 'Var', (70, 78))	('BRAF', 'Gene', (65, 69))	('melanoma', 'Disease', (210, 218))
84544	32664549	The purpose of this study was to determine whether the detection of ctDNA, based on the identification of BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma.	('men', 'Species', '9606', (151, 154))	('NRAS', 'Gene', (115, 119))	('BRAF', 'Gene', '673', (106, 110))	('NRAS', 'Gene', '4893', (115, 119))	('associated', 'Reg', (172, 182))	('BRAF', 'Gene', (106, 110))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('mutations', 'Var', (120, 129))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))
84545	32664549	In total, 68 BRAF or NRAS-mutated stage IV or unresectable stage III metastatic cutaneous melanoma patients were included and tested for the presence of BRAF and NRAS mutations in circulating DNA before treatment initiation, using the Cobas BRAF/NRAS Mutation Test (Roche).	('BRAF', 'Gene', (153, 157))	('cutaneous melanoma', 'Disease', (80, 98))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (80, 98))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (80, 98))	('mutations', 'Var', (167, 176))	('tested', 'Reg', (126, 132))	('NRAS', 'Gene', '4893', (246, 250))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))	('NRAS', 'Gene', '4893', (21, 25))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('men', 'Species', '9606', (208, 211))	('BRAF', 'Gene', (241, 245))	('NRAS', 'Gene', '4893', (162, 166))	('patients', 'Species', '9606', (99, 107))	('NRAS', 'Gene', (246, 250))	('NRAS', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (241, 245))	('NRAS', 'Gene', (162, 166))	('BRAF', 'Gene', '673', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
84560	32664549	ctDNA is commonly used to identify mutations in the EGFR gene in non-small cell lung cancer (NSCLC), when tumour tissue cannot be sampled or when its analysis is not contributive.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('NSCLC', 'Disease', (93, 98))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('EGFR', 'Gene', '1956', (52, 56))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('EGFR', 'Gene', (52, 56))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (65, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('tumour', 'Disease', (106, 112))	('non-small cell lung cancer', 'Disease', (65, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('52', '56'))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (35, 44))
84561	32664549	Although melanoma tumour tissue is more often accessible, ctDNA can be used to quickly identify theranostic BRAF mutations, without going through the various preanalytical steps commonly performed on tumour tissue (formalin fixation, paraffin embedding, preparation of thick sections).	('tumour', 'Disease', (200, 206))	('melanoma tumour', 'Disease', 'MESH:D008545', (9, 24))	('paraffin', 'Chemical', 'MESH:D010232', (234, 242))	('formalin', 'Chemical', 'MESH:D005557', (215, 223))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma tumour', 'Disease', (9, 24))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('mutations', 'Var', (113, 122))	('tumour', 'Disease', 'MESH:D009369', (200, 206))	('BRAF', 'Gene', '673', (108, 112))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('BRAF', 'Gene', (108, 112))	('tumour', 'Disease', (18, 24))
84562	32664549	Several studies have suggested that the detection of ctDNA, i.e., the identification of genetic alterations in circulating cell-free DNA, may be a prognostic factor for metastatic melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('genetic alterations', 'Var', (88, 107))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))
84563	32664549	In a previous study carried out on baseline detection of BRAF codon 600 mutations by Amplification-Refractory Mutation System (ARMS) qPCR in patients with metastatic melanoma harbouring a BRAF mutation in tumour tissue, we identified the mutation in 29 out of the 38 patients tested.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('tumour', 'Disease', (205, 211))	('patients', 'Species', '9606', (267, 275))	('BRAF', 'Gene', '673', (188, 192))	('BRAF', 'Gene', '673', (57, 61))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('patients', 'Species', '9606', (141, 149))	('BRAF', 'Gene', (188, 192))	('BRAF', 'Gene', (57, 61))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('codon', 'Var', (62, 67))
84564	32664549	Mutations in the BRAF and NRAS genes are the most frequent alterations described in cutaneous melanomas, with a prevalence of ~50% and ~25%, respectively.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('BRAF', 'Gene', '673', (17, 21))	('NRAS', 'Gene', (26, 30))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (84, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (84, 102))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (84, 103))	('NRAS', 'Gene', '4893', (26, 30))	('cutaneous melanomas', 'Disease', (84, 103))
84566	32664549	This study aimed to determine whether the detection of ctDNA, based on the rapid identification of common BRAF and NRAS mutations before systemic treatment initiation, was associated with the prognosis of metastatic melanoma, in an intention-to-treat setting.	('men', 'Species', '9606', (151, 154))	('NRAS', 'Gene', (115, 119))	('BRAF', 'Gene', '673', (106, 110))	('NRAS', 'Gene', '4893', (115, 119))	('associated', 'Reg', (172, 182))	('BRAF', 'Gene', (106, 110))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('mutations', 'Var', (120, 129))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))
84573	32664549	Most patient characteristics did not differ significantly between BRAF and NRAS-mutated patients, with the exception of gender: NRAS mutations were more frequent in women (BRAF-mutated: 8/31 (26%); NRAS-mutated: 23/31 (74%)), while men were mostly BRAF-mutated (BRAF-mutated: 24/37 (65%); NRAS-mutated: 13/37 (35%); p = 0.002).	('men', 'Species', '9606', (232, 235))	('NRAS', 'Gene', (75, 79))	('NRAS', 'Gene', '4893', (198, 202))	('BRAF', 'Gene', '673', (262, 266))	('BRAF', 'Gene', (262, 266))	('patient', 'Species', '9606', (88, 95))	('NRAS', 'Gene', (128, 132))	('women', 'Species', '9606', (165, 170))	('mutations', 'Var', (133, 142))	('men', 'Species', '9606', (167, 170))	('NRAS', 'Gene', '4893', (289, 293))	('NRAS', 'Gene', (198, 202))	('BRAF', 'Gene', '673', (172, 176))	('NRAS', 'Gene', '4893', (75, 79))	('BRAF', 'Gene', (172, 176))	('patient', 'Species', '9606', (5, 12))	('NRAS', 'Gene', '4893', (128, 132))	('patients', 'Species', '9606', (88, 96))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', '673', (248, 252))	('NRAS', 'Gene', (289, 293))	('BRAF', 'Gene', (66, 70))	('BRAF', 'Gene', (248, 252))
84575	32664549	BRAF or NRAS mutations previously identified in tumour tissues were found in 34 out of 68 patients, representing an overall 50% sensitivity between tissue analyses and circulating DNA analysis on the Cobas system.	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('NRAS', 'Gene', (8, 12))	('NRAS', 'Gene', '4893', (8, 12))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('BRAF', 'Gene', '673', (0, 4))	('DNA', 'cellular_component', 'GO:0005574', ('180', '183'))	('tumour', 'Disease', (48, 54))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('patients', 'Species', '9606', (90, 98))
84579	32664549	The lower detectability of ctDNA in women was not linked to the higher representation of NRAS mutations in this subgroup, in multivariate analysis (logit: p = 0.013).	('women', 'Species', '9606', (36, 41))	('NRAS', 'Gene', '4893', (89, 93))	('NRAS', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
84580	32664549	In this study, NRAS mutations were less frequently detected in circulating DNA by the Cobas system than BRAF mutations.	('NRAS', 'Gene', (15, 19))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', '673', (104, 108))	('BRAF', 'Gene', (104, 108))	('mutations', 'Var', (20, 29))
84583	32664549	Mutations identified in tumour tissue were found in circulating DNA with both techniques for 18 patients, while ctDNA was undetectable with both techniques for nine patients.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('DNA', 'cellular_component', 'GO:0005574', ('64', '67'))	('tumour', 'Disease', (24, 30))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (96, 104))
84584	32664549	For two patients, a BRAF mutation identified in the tumour tissue was found in circulating DNA by dPCR, but was not identified by the Cobas analysis.	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (25, 33))	('BRAF', 'Gene', (20, 24))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('BRAF', 'Gene', '673', (20, 24))	('tumour', 'Disease', (52, 58))	('patients', 'Species', '9606', (8, 16))
84585	32664549	In both cases, these BRAF V600E mutations were very poorly represented in the sample (8 copies/mL of plasma, allelic frequency < 0.002%).	('V600E', 'Var', (26, 31))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))
84615	32664549	ctDNA detectability was also correlated with the nature of the mutated gene; NRAS mutations were less frequently identified than BRAF mutations in circulating DNA (13/36 patients (36%) vs. 21/32 patients (66%), respectively).	('patients', 'Species', '9606', (170, 178))	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('NRAS', 'Gene', (77, 81))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', '4893', (77, 81))	('patients', 'Species', '9606', (195, 203))
84616	32664549	reported sensitivities of 40% and 67% for NRAS and BRAF mutations, respectively, with an NGS analysis, while Seremet et al.	('NRAS', 'Gene', '4893', (42, 46))	('mutations', 'Var', (56, 65))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))	('NRAS', 'Gene', (42, 46))
84619	32664549	NRAS mutations were more frequent in women than in men, which is consistent with data from our own daily diagnostic activity on tissue DNA.	('women', 'Species', '9606', (37, 42))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('men', 'Species', '9606', (51, 54))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (0, 4))	('men', 'Species', '9606', (39, 42))	('NRAS', 'Gene', '4893', (0, 4))
84620	32664549	Indeed, out of 3263 samples analysed since 2012 in our routine practice, 822 carried an NRAS mutation (25.2%), among which 447/1528 NRAS-mutated samples were from women (29.3%) vs. 375/1735 NRAS-mutated samples from men (21.6%).	('men', 'Species', '9606', (165, 168))	('men', 'Species', '9606', (216, 219))	('NRAS', 'Gene', (190, 194))	('NRAS', 'Gene', '4893', (132, 136))	('women', 'Species', '9606', (163, 168))	('NRAS', 'Gene', '4893', (190, 194))	('NRAS', 'Gene', (88, 92))	('NRAS', 'Gene', '4893', (88, 92))	('mutation', 'Var', (93, 101))	('NRAS', 'Gene', (132, 136))
84622	32664549	Routine circulating DNA testing is easy and is currently being performed in our hospital for some patients with newly diagnosed metastatic melanoma, to allow a rapid initiation of targeted therapy if a BRAF mutation is identified.	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('patients', 'Species', '9606', (98, 106))	('BRAF', 'Gene', '673', (202, 206))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('DNA', 'cellular_component', 'GO:0005574', ('20', '23'))	('BRAF', 'Gene', (202, 206))	('mutation', 'Var', (207, 215))
84636	32664549	During this time frame, detection of BRAF and NRAS mutation in the patient's tumour was performed using a combination of allele-specific amplification and Sanger sequencing.	('NRAS', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (37, 41))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('BRAF', 'Gene', (37, 41))	('NRAS', 'Gene', '4893', (46, 50))	('mutation', 'Var', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('patient', 'Species', '9606', (67, 74))
84640	32664549	BRAF or NRAS mutations were screened for with the Cobas BRAF/NRAS Mutation Test LSR kit (Roche), an allele-specific real-time PCR test for the qualitative detection and identification of 36 BRAF and NRAS mutations.	('BRAF', 'Gene', (190, 194))	('NRAS', 'Gene', (8, 12))	('BRAF', 'Gene', '673', (56, 60))	('mutations', 'Var', (204, 213))	('BRAF', 'Gene', '673', (190, 194))	('NRAS', 'Gene', '4893', (8, 12))	('BRAF', 'Gene', '673', (0, 4))	('NRAS', 'Gene', (61, 65))	('BRAF', 'Gene', (0, 4))	('NRAS', 'Gene', (199, 203))	('NRAS', 'Gene', '4893', (199, 203))	('NRAS', 'Gene', '4893', (61, 65))	('BRAF', 'Gene', (56, 60))
84673	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('transcription', 'biological_process', 'GO:0006351', ('21', '34'))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
84674	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
84680	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('HNF1B', 'Gene', (93, 98))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (9, 15))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
84694	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
84696	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('PCLO', 'Gene', (165, 169))	('HYDIN', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('mutations', 'Var', (41, 50))	('HMCN1', 'Gene', (211, 216))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('KMT2D', 'Gene', '8085', (240, 245))	('CSMD3', 'Gene', '114788', (130, 135))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('FAT3', 'Gene', '120114', (231, 235))	('FLG', 'Gene', '2312', (171, 174))	('LRP1B', 'Gene', '53353', (151, 156))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('RYR', 'cellular_component', 'GO:1990425', ('218', '221'))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
84714	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('negatively', 'NegReg', (47, 57))	('overall', 'MPA', (74, 81))
84716	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('HNF1B', 'Gene', (11, 16))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('overall', 'MPA', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('liver hepatocellular carcinoma', 'Disease', (37, 67))
84728	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
84729	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
84732	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
84734	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('splicing', 'biological_process', 'GO:0045292', ('170', '178'))	('missense mutation', 'Var', (68, 85))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('gene deletion', 'Var', (47, 60))
84735	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
84736	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('TP53', 'Gene', (96, 100))	('MUC16', 'Gene', (110, 115))	('mutations', 'Var', (62, 71))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
84748	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
84751	28849221	TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear In contrast to TP53, cancer development is rarely associated with mutations in the TP63 and TP73 genes.	('cancer', 'Disease', (138, 144))	('TP63', 'Gene', (200, 204))	('cutaneous melanoma', 'Disease', (31, 49))	('frequent', 'Reg', (19, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (31, 49))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (31, 49))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('TP63', 'Gene', '8626', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('TP63', 'Gene', (0, 4))	('TP73', 'Gene', (209, 213))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('TP63', 'Gene', '8626', (200, 204))
84752	28849221	Recently, next generation sequencing analysis revealed that TP63 mutations are frequent, specifically in cutaneous melanomas.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('TP63', 'Gene', (60, 64))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (105, 124))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (105, 124))	('cutaneous melanomas', 'Disease', (105, 124))	('mutations', 'Var', (65, 74))
84754	28849221	In the present study, we first determined whether all three members of the P53 family of transcription factors were found mutated in cutaneous melanomas by retrieving all TP53, TP63 and TP73 mutations from cBioPortal .	('TP53', 'Gene', (171, 175))	('cutaneous melanomas', 'Disease', (133, 152))	('TP63', 'Gene', (177, 181))	('mutations', 'Var', (191, 200))	('TP73', 'Gene', (186, 190))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (133, 152))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (133, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))
84755	28849221	Then, we tried to evaluate the potential role of TP63 mutations as drivers or passengers in the tumorigenic process.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TP63', 'Gene', (49, 53))
84756	28849221	Using a yeast-based functional assay, the observed hotspot mutant R379CP63 protein exhibited a substantial residual activity compared to the wild-type (>70%).	('yeast', 'Species', '4932', (8, 13))	('R379CP63', 'Var', (66, 74))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('protein', 'Protein', (75, 82))	('activity', 'MPA', (116, 124))
84757	28849221	This result does not support a major role of the mutant P63 protein in melanomagenesis while it is still consistent with the TP63 gene being a recorder of UV exposure.	('mutant', 'Var', (49, 55))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('protein', 'Protein', (60, 67))	('P63', 'Gene', (56, 59))
84759	28849221	The TP63 mutations were more frequent at CpGs sites (p<0.0001) in EDs and at PyPy sites (p<0.0001) in cutaneous melanomas.	('frequent', 'Reg', (29, 37))	('cutaneous melanomas', 'Disease', (102, 121))	('mutations', 'Var', (9, 18))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('EDs', 'Disease', (66, 69))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('TP63', 'Gene', (4, 8))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (102, 121))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (102, 121))
84760	28849221	We conclude that TP63 mutations are frequent in cutaneous melanoma, support UV etiology, but their role in melanomagenesis is unclear.	('cutaneous melanoma', 'Disease', (48, 66))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('frequent', 'Reg', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('TP63', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
84761	28849221	Despite protein and gene structure similarities, the overlap in cellular functions between P53, P63 and P73 is limited as highlighted by comparing their role in human physiology.	('human', 'Species', '9606', (161, 166))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('P63', 'Var', (96, 99))	('P73', 'Var', (104, 107))	('P53', 'Var', (91, 94))
84763	28849221	Furthermore, TP53 germline mutations are associated with the development of the cancer prone Li-Fraumeni and Li-Fraumeni like syndromes.	('germline mutations', 'Var', (18, 36))	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('associated with', 'Reg', (41, 56))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Li-Fraumeni and Li-Fraumeni', 'Disease', 'MESH:D016864', (93, 120))	('cancer', 'Disease', (80, 86))
84764	28849221	No genetic disorder has been linked to TP73 germinal mutations, whereas heterozygous mutations in the TP63 gene underlie a subset of human ectodermal dysplasia syndromes (EDs).	('ectodermal dysplasia syndromes', 'Disease', (139, 169))	('heterozygous mutations', 'Var', (72, 94))	('genetic disorder', 'Disease', (3, 19))	('TP63', 'Gene', (102, 106))	('TP73', 'Gene', (39, 43))	('underlie', 'Reg', (112, 120))	('genetic disorder', 'Disease', 'MESH:D030342', (3, 19))	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (139, 159))	('human', 'Species', '9606', (133, 138))	('ectodermal dysplasia syndromes', 'Disease', 'MESH:D004476', (139, 169))
84765	28849221	Despite the fact that cancer development is rarely associated with TP63 and TP73 mutations, both genes play an active role in carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('TP73', 'Gene', (76, 80))	('cancer', 'Disease', (22, 28))	('TP63', 'Gene', (67, 71))	('carcinogenesis', 'Disease', (126, 140))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
84766	28849221	Flores et al demonstrated the contribution of P63 and P73 in tumor development by revealing that TP63+/- and TP73+/- mice develop malignant tumors at a higher frequency with respect to the wild-type counterparts.	('higher', 'PosReg', (152, 158))	('develop', 'PosReg', (122, 129))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('TP73+/-', 'Var', (109, 116))	('malignant tumors', 'Disease', (130, 146))	('TP63+/-', 'Var', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mice', 'Species', '10090', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('malignant tumors', 'Disease', 'MESH:D018198', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (140, 145))
84767	28849221	In addition, TP53+/-TP63+/- and TP53+/-TP73+/- compound mutant mice developed a more severe phenotype (e.g., more metastases) compared to the TP53+/- mice, indicating that P63 and P73 have functions independent of P53.	('metastases', 'Disease', (114, 124))	('mice', 'Species', '10090', (150, 154))	('TP53+/-TP73+/-', 'Var', (32, 46))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('TP53+/-TP63+/-', 'Var', (13, 27))	('mice', 'Species', '10090', (63, 67))	('more', 'PosReg', (109, 113))
84768	28849221	The tumor-suppressive activities of P63 and P73 appear to be tissue-specific.	('tumor', 'Disease', (4, 9))	('P73', 'Var', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('P63', 'Var', (36, 39))
84769	28849221	In fact, the tumor spectrum detected in mice defective for TP63 and TP73 is quite different from that of TP53-deficient mice.	('tumor', 'Disease', (13, 18))	('mice', 'Species', '10090', (120, 124))	('TP73', 'Var', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('mice', 'Species', '10090', (40, 44))	('TP63', 'Var', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
84770	28849221	TP63+/- and TP73+/- mice develop primarily lung adenomas (TP63+/-, 25%; TP73+/-, 40%) squamous cell hyperplasia (TP63+/-, 50%; TP73+/-, 30%), while TP53+/- mice primarily develop thymic lymphomas and osteosarcomas.	('squamous cell hyperplasia', 'Disease', 'MESH:D002294', (86, 111))	('lymphomas', 'Disease', (186, 195))	('mice', 'Species', '10090', (20, 24))	('lung adenomas', 'Disease', 'MESH:D000236', (43, 56))	('osteosarcomas', 'Disease', (200, 213))	('TP73+/-', 'Var', (72, 79))	('squamous cell hyperplasia', 'Disease', (86, 111))	('lymphomas', 'Disease', 'MESH:D008223', (186, 195))	('TP63+/-', 'Var', (113, 120))	('TP63+/-', 'Var', (58, 65))	('lymphomas', 'Phenotype', 'HP:0002665', (186, 195))	('osteosarcomas', 'Phenotype', 'HP:0002669', (200, 213))	('mice', 'Species', '10090', (156, 160))	('lung adenomas', 'Disease', (43, 56))	('osteosarcomas', 'Disease', 'MESH:D012516', (200, 213))	('squamous cell hyperplasia', 'Phenotype', 'HP:0002860', (86, 111))	('TP63+/-', 'Var', (0, 7))
84771	28849221	These differences are probably due to the different patterns of expression of the P53 family members, while P53 is ubiquitous, the P63 and P73 proteins are highly expressed in epithelial tissues.	('P73 proteins', 'Var', (139, 151))	('expression', 'Species', '29278', (64, 74))	('P63', 'Var', (131, 134))
84774	28849221	This was due to the fact that the TP53 gene: i) is very sensitive to point mutations; ii) alterations in its coding sequence occur in >50% of all human types of cancer; and iii) ~80% of these alterations are missense mutations leading to proteins with a single amino acid substitution.	('alterations', 'Var', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP53', 'Gene', (34, 38))	('proteins', 'Protein', (238, 246))	('human', 'Species', '9606', (146, 151))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('alterations', 'Var', (192, 203))
84775	28849221	The relationship between the exposure to a carcinogen and the presence of specific TP53 mutations in specific tumors has been extensively studied and described.	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
84776	28849221	TP53 mutations identified in tumors and cell lines have been collected in a database that contains more than 30,000 entries .	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))
84780	28849221	About 50% of skin cancers exhibit the signature of UV-induced mutagenesis on TP53.	('mutagenesis', 'Var', (62, 73))	('skin cancer', 'Phenotype', 'HP:0008069', (13, 24))	('skin cancers', 'Phenotype', 'HP:0008069', (13, 25))	('skin cancers', 'Disease', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('skin cancers', 'Disease', 'MESH:D012878', (13, 25))	('mutagenesis', 'biological_process', 'GO:0006280', ('62', '73'))	('TP53', 'Gene', (77, 81))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
84781	28849221	TP53 mutations are frequent in both normal-appearing sun-exposed skin and premalignant actinic keratosis lesions, which are considered precursors of squamous cell carcinoma.	('TP53', 'Gene', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 172))	('keratosis lesions', 'Disease', (95, 112))	('keratosis lesions', 'Disease', 'MESH:D007642', (95, 112))	('mutations', 'Var', (5, 14))	('squamous cell carcinoma', 'Disease', (149, 172))	('actinic keratosis', 'Phenotype', 'HP:0025127', (87, 104))
84783	28849221	The identification of gene mutations that directly or indirectly confer a selective growth advantage to the cell in which they occur ('driver mutations') among a plethora of other mutations devoid of a role in the cancer process ('passenger mutations') is a formidable challenge.	('mutations', 'Var', (27, 36))	('plethora', 'Phenotype', 'HP:0001050', (162, 170))	('cancer', 'Disease', (214, 220))	('growth advantage', 'CPA', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
84785	28849221	Furthermore, the number of driver mutations sufficient for a cell to evolve into an advanced cancer is thought to be extremely low.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
84786	28849221	In solid tumors of adults, including melanoma, alterations in as few as three driver genes are sufficient.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('solid tumors', 'Disease', (3, 15))	('melanoma', 'Disease', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('alterations', 'Var', (47, 58))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))
84796	28849221	TERT promoter mutations were observed at a high incidence in intermediate lesions and melanomas in situ.	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('TERT promoter', 'Gene', (0, 13))	('TERT', 'CellLine', 'CVCL:C452', (0, 4))	('melanomas', 'Disease', (86, 95))	('intermediate lesions', 'Disease', (61, 81))	('mutations', 'Var', (14, 23))
84797	28849221	Biallelic CDKN2A inactivation emerged exclusively in invasive melanomas, while PTEN and TP53 mutations were found only in advanced primary melanomas and their presence appears to represent the transition to metastatic tumors.	('inactivation', 'Var', (17, 29))	('melanomas', 'Phenotype', 'HP:0002861', (139, 148))	('invasive melanomas', 'Disease', (53, 71))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('melanomas', 'Disease', 'MESH:D008545', (139, 148))	('invasive melanomas', 'Disease', 'MESH:D008545', (53, 71))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanomas', 'Disease', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('PTEN', 'Disease', 'MESH:D006223', (79, 83))	('PTEN', 'Disease', (79, 83))	('melanomas', 'Disease', (139, 148))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('CDKN2A', 'Gene', (10, 16))	('tumors', 'Disease', (218, 224))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
84798	28849221	Recently, using NGS, missense mutations in the TP63 gene were frequently and specifically found in cutaneous melanomas (~15%).	('cutaneous melanomas', 'Disease', (99, 118))	('found', 'Reg', (90, 95))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('TP63', 'Gene', (47, 51))	('missense mutations', 'Var', (21, 39))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (99, 118))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (99, 118))
84799	28849221	This observation prompted us to study the features of TP63 mutations from the molecular epidemiology point of view and to ascertain whether all three members of the P53 family were mutated in melanomas with equal frequency.	('TP63', 'Gene', (54, 58))	('melanomas', 'Disease', (192, 201))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('mutations', 'Var', (59, 68))	('melanomas', 'Phenotype', 'HP:0002861', (192, 201))	('melanomas', 'Disease', 'MESH:D008545', (192, 201))
84807	28849221	Yeast vectors expressing mutant isoforms (DeltaN-P63alpha R379C and TA-P63alpha R379C) were constructed using the experimental strategy as previously described.	('R379C', 'Mutation', 'rs761885185', (80, 85))	('Yeast', 'Species', '4932', (0, 5))	('TA-P63alpha R379C', 'Var', (68, 85))	('DeltaN-P63alpha R379C', 'Var', (42, 63))	('R379C', 'Mutation', 'rs761885185', (58, 63))
84808	28849221	Briefly, for R379C mutation, a pair of complementary oligonucleotides (which served as forward and reverse primers) was synthesized, with the mutated nucleotide (underlined the corresponding codon) adjacent to the central position (R379C forward, 5'-aagcgcccgt tttgtcagaacacacatggt-3' and reverse, 5'-accatgtgtgttctgacaaaacgggcgctt-3').	('R379C', 'Var', (13, 18))	('oligonucleotides', 'Chemical', 'MESH:D009841', (53, 69))	('R379C', 'Mutation', 'rs761885185', (232, 237))	('R379C', 'Mutation', 'rs761885185', (13, 18))	('R379C', 'Var', (232, 237))
84812	28849221	Yeast vectors expressing R379C mutant protein (DeltaN-P63alpha and TA-P63alpha isoforms) under the inducible GAL1-GAL10 promoter (pTSG-based), were constructed by double-digesting the pTS-based expression vectors with the XhoI and NotI restriction enzymes.	('expression vectors', 'Species', '29278', (194, 212))	('GAL1', 'Gene', '852308', (114, 118))	('R379C', 'Mutation', 'rs761885185', (25, 30))	('GAL1', 'Gene', (114, 118))	('GAL1', 'Gene', (109, 113))	('GAL1', 'Gene', '852308', (109, 113))	('Yeast', 'Species', '4932', (0, 5))	('R379C', 'Var', (25, 30))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))
84826	28849221	Clearly, for all three genes the majority (>83%) of mutations were single base pair substitutions (TP53, 88/105=83.8%; TP63, 101/111=91%; TP73, 10/10=100%), at least 80% of which were localized at adjacent pyrimidines (PyPy).	('mutations', 'Var', (52, 61))	('TP63', 'Var', (119, 123))	('pyrimidines', 'Chemical', 'MESH:D011743', (206, 217))	('TP73', 'Var', (138, 142))
84827	28849221	Thus, TP53 and TP63, but not TP73, mutations are frequently found in cutaneous melanomas and their molecular features are reminiscent of a UV-exposure, suggesting that TP53 and TP63 genes behave like two 'recorders of UV-exposure'.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (69, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (69, 88))	('cutaneous melanomas', 'Disease', (69, 88))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('mutations', 'Var', (35, 44))
84829	28849221	To verify the assumption of molecular epidemiology, namely that carcinogens leave distinguishable fingerprints, 101 germinal TP63 mutations found in patients affected by a specific subset of EDs were retrieved from the literature.	('mutations', 'Var', (130, 139))	('patients', 'Species', '9606', (149, 157))	('TP63', 'Gene', (125, 129))
84830	28849221	Excluding a tandem mutation (1 CGC>CAA, R318Q) with no feature of UV-induced tandem mutation, a total of 100 TP63 base pair substitutions were analyzed and compared with the TP63 mutations found in cutaneous melanomas (Table II).	('R318Q', 'Var', (40, 45))	('cutaneous melanomas', 'Disease', (198, 217))	('TP63', 'Gene', (109, 113))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanomas', 'Phenotype', 'HP:0002861', (208, 217))	('1 CGC>CAA', 'Mutation', 'c.1CGC>CAA', (29, 38))	('R318Q', 'Mutation', 'p.R318Q', (40, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (198, 217))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (198, 217))
84832	28849221	Indeed, significantly more TP63 mutations were located at CpGs in EDs than in melanomas (74 vs. 37%; p<0.0001), and vice versa, significantly more TP63 mutations were located at PyPy in melanomas than in EDs (97 vs. 70%; p<0.0001).	('melanomas', 'Disease', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanomas', 'Phenotype', 'HP:0002861', (186, 195))	('mutations', 'Var', (152, 161))	('melanomas', 'Disease', 'MESH:D008545', (186, 195))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('mutations', 'Var', (32, 41))	('TP63', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('TP63', 'Gene', (27, 31))	('melanomas', 'Disease', (186, 195))
84833	28849221	In conclusion, using a mutational spectrometry approach we demonstrated that a UV fingerprint could be recognized in the TP63 mutations found in cutaneous melanomas and that such a mutation spectrum is distinguishable from the one observed in EDs.	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('TP63', 'Gene', (121, 125))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (145, 164))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (145, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (145, 163))	('cutaneous melanomas', 'Disease', (145, 164))	('mutations', 'Var', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
84834	28849221	Since TP53 and TP63 mutations are relatively frequent in cutaneous melanomas a question arises.	('TP53', 'Gene', (6, 10))	('TP63', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (57, 76))	('frequent', 'Reg', (45, 53))	('cutaneous melanomas', 'Disease', (57, 76))	('mutations', 'Var', (20, 29))
84835	28849221	Do these mutations play a role as potential drivers or passengers in the tumorigenic process?	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutations', 'Var', (9, 18))
84837	28849221	However, the abundance of TP63 mutations (similar to the one of TP53) along with the FATHMM-MKL prediction reveal that TP63 mutations may play some role in cutaneous melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanomas', 'Phenotype', 'HP:0002861', (166, 175))	('mutations', 'Var', (31, 40))	('role', 'Reg', (148, 152))	('mutations', 'Var', (124, 133))	('TP63', 'Gene', (26, 30))	('TP63', 'Gene', (119, 123))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (156, 175))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (156, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (156, 174))	('play', 'Reg', (138, 142))	('cutaneous melanomas', 'Disease', (156, 175))
84838	28849221	In order to shed more light on the functional effects of amino acid substitutions, we experimentally determined the outcome of the substitution of the arginine at codon 379 with a cysteine (R379C) on the transactivation ability of the P63 protein.	('transactivation', 'MPA', (204, 219))	('transactivation', 'biological_process', 'GO:2000144', ('204', '219'))	('R379C', 'Mutation', 'rs761885185', (190, 195))	('R379C', 'Var', (190, 195))	('arginine at codon 379 with a cysteine', 'Mutation', 'rs761885185', (151, 188))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('substitution', 'Var', (131, 143))
84841	28849221	The results revealed that the R379C amino acid substitution did not markedly affect the transactivation ability of DeltaN-P63alpha and TA-P63alpha proteins with respect to the wild-type (Fig.	('R379C', 'Mutation', 'rs761885185', (30, 35))	('R379C', 'Var', (30, 35))	('transactivation', 'biological_process', 'GO:2000144', ('88', '103'))	('transactivation', 'MPA', (88, 103))
84842	28849221	Specifically, when expressed as the DeltaN-P63alpha isoform the R379C protein exhibited a transactivation activity comparable to that of the wild-type P63.	('protein', 'Protein', (70, 77))	('R379C', 'Var', (64, 69))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('transactivation activity', 'MPA', (90, 114))	('R379C', 'Mutation', 'rs761885185', (64, 69))	('transactivation', 'biological_process', 'GO:2000144', ('90', '105'))
84844	28849221	These results suggest that, according to our yeast-based P63 functional assay, the R379C mutant P63 cannot be immediately classified as a potential pathogenic.	('P63', 'Gene', (96, 99))	('yeast', 'Species', '4932', (45, 50))	('R379C', 'Mutation', 'rs761885185', (83, 88))	('R379C', 'Var', (83, 88))
84847	28849221	Two years later, Hodis et al discovered novel melanoma genes and revealed that the spectrum of mutations provided evidence for a direct mutagenic role of UV light in melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('mutations', 'Var', (95, 104))
84850	28849221	Biallelic CDKN2A inactivation emerged exclusively in invasive melanomas, while the presence of PTEN and TP53 mutations appears to represent the transition to metastatic tumors.	('inactivation', 'Var', (17, 29))	('invasive melanomas', 'Disease', (53, 71))	('TP53', 'Gene', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('invasive melanomas', 'Disease', 'MESH:D008545', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PTEN', 'Disease', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('PTEN', 'Disease', 'MESH:D006223', (95, 99))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('tumors', 'Disease', (169, 175))	('CDKN2A', 'Gene', (10, 16))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
84851	28849221	Only recently missense mutations in the TP63 gene were noted to be frequently and specifically found in cutaneous melanoma (~15%) in contrast to the previous prevailing notion that TP63 mutations are seldom found in cancer.	('cutaneous melanoma', 'Disease', (104, 122))	('TP63', 'Gene', (40, 44))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (104, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('found', 'Reg', (95, 100))	('missense mutations', 'Var', (14, 32))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
84852	28849221	This observation prompted us to ascertain whether all three members of the P53 family of transcription factors were found mutated in cutaneous melanomas .	('cutaneous melanomas', 'Disease', (133, 152))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (133, 152))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (133, 152))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('mutated', 'Var', (122, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (133, 151))
84854	28849221	The TP63 and TP53 mutations found in cutaneous melanomas revealed a UV-recognizable mutation fingerprint, high percentage of GC>AT transitions at PyPy sites, along with a few tandem mutations (Table I).	('cutaneous melanomas', 'Disease', (37, 56))	('TP53', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (37, 56))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (37, 56))	('TP63', 'Gene', (4, 8))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (37, 55))	('mutations', 'Var', (18, 27))
84855	28849221	These observations strongly suggest that TP63 and TP53 mutations in cutaneous melanomas are UV-induced.	('mutations', 'Var', (55, 64))	('cutaneous melanomas', 'Disease', (68, 87))	('UV-induced', 'Disease', (92, 102))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (68, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('TP53', 'Gene', (50, 54))	('TP63', 'Gene', (41, 45))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (68, 87))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (68, 87))
84856	28849221	To reinforce this suggestion the TP63 mutations found in cutaneous melanomas were compared with those observed at the germinal level in patients affected by a specific subset of P63-associated disorders (EDs).	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('TP63', 'Gene', (33, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('patients', 'Species', '9606', (136, 144))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (57, 76))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 76))	('mutations', 'Var', (38, 47))	('cutaneous melanomas', 'Disease', (57, 76))
84857	28849221	The TP63 mutations in EDs were significantly more frequent at CpGs sites (p<0.0001; Table II), while those in skin melanomas were significantly more frequent at PyPy sites (p<0.0001; Table II).	('TP63 mutations', 'Var', (4, 18))	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('CpGs', 'Disease', (62, 66))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('frequent', 'Reg', (50, 58))	('skin melanomas', 'Disease', (110, 124))	('skin melanomas', 'Disease', 'MESH:D008545', (110, 124))
84858	28849221	Altogether these results demonstrated that the TP63 mutations observed in cutaneous melanomas are UV-specific, while those observed in EDs are likely of spontaneous origin, with deamination of 5'-mC at CpG sites being a likely candidate responsible of such events.	('mutations', 'Var', (52, 61))	('cutaneous melanomas', 'Disease', (74, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('TP63', 'Gene', (47, 51))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	("5'-mC", 'Chemical', '-', (193, 198))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (74, 93))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (74, 93))
84860	28849221	Therefore, we experimentally determined the functional consequences of the TP63 R379C mutation on the transactivation ability with respect to the wild-type counterpart, since this mutant P63 protein was the most frequent amino acid substitution observed in cutaneous melanomas and the two bioinformatics tools reported different prediction for the same mutation.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (257, 276))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (257, 276))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (257, 275))	('R379C', 'Mutation', 'rs761885185', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('cutaneous melanomas', 'Disease', (257, 276))	('P63', 'Var', (187, 190))	('melanomas', 'Phenotype', 'HP:0002861', (267, 276))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('TP63', 'Gene', (75, 79))	('R379C', 'Var', (80, 85))	('transactivation', 'biological_process', 'GO:2000144', ('102', '117'))	('transactivation', 'MPA', (102, 117))
84861	28849221	Using our yeast-based P63 functional assay the R379C protein exhibited a substantial residual activity compared to the wild-type (70-100%, depending on the yeast reporter strain) (Fig.	('R379C', 'Var', (47, 52))	('yeast', 'Species', '4932', (156, 161))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('activity', 'MPA', (94, 102))	('yeast', 'Species', '4932', (10, 15))	('R379C', 'Mutation', 'rs761885185', (47, 52))
84862	28849221	This result is in keeping with the prediction of the Mutation Assessor and appears to not support a major role of this mutant P63 protein in melanomagenesis, while it is still compatible with the TP63 gene being a recorder of UV exposure.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('P63', 'Gene', (126, 129))	('mutant', 'Var', (119, 125))
84863	28849221	With regard to the TP53 hot spot mutation in melanomas, i.e., R213Stop, it is obligatorily classified as a loss-of-function mutant because the mutation results in a truncated P53 protein that is not able to oligomerize.	('protein', 'Protein', (179, 186))	('P53 protein', 'Protein', (175, 186))	('results in', 'Reg', (152, 162))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))	('truncated', 'MPA', (165, 174))	('mutation', 'Var', (143, 151))	('R213Stop', 'Var', (62, 70))	('melanomas', 'Disease', (45, 54))	('R213Stop', 'Mutation', 'rs397516436', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
84864	28849221	This observation is in agreement with the predictions of the bioinformatics tools suggesting that TP53 mutations may play a role in melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('play', 'Reg', (117, 121))	('role', 'Reg', (124, 128))	('mutations', 'Var', (103, 112))	('melanoma', 'Disease', (132, 140))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('TP53', 'Gene', (98, 102))
84865	28849221	While TP53 mutations have been recognized to play a role in the transition to metastatic tumors, the indications for the role of TP63 mutations have yet to be elucidated.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (11, 20))	('TP53', 'Gene', (6, 10))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
84866	28849221	The fact that TP63+/- mice developed malignant tumors at a higher frequency with respect to the wild-type counterpart, and that the TP53+/-TP63+/- compound mutant mice developed a more severe phenotype (i.e., higher tumor burden and more metastases) compared to the TP53+/- mice, reveals that TP63 is a tumor/metastasis suppressor gene independent of P53.	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('malignant tumors', 'Disease', 'MESH:D018198', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mice', 'Species', '10090', (274, 278))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Disease', (216, 221))	('malignant tumors', 'Disease', (37, 53))	('metastases', 'Disease', 'MESH:D009362', (238, 248))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('mice', 'Species', '10090', (163, 167))	('metastases', 'Disease', (238, 248))	('tumor', 'Disease', (303, 308))	('higher', 'PosReg', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutant', 'Var', (156, 162))	('TP53+/-TP63+/- compound mutant', 'Var', (132, 162))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
84867	28849221	Thus, TP63 mutations that inactivate the protein function likely contribute to a carcinogenic process.	('carcinogenic process', 'Disease', (81, 101))	('mutations', 'Var', (11, 20))	('TP63', 'Gene', (6, 10))	('protein', 'Protein', (41, 48))	('carcinogenic process', 'Disease', 'MESH:D009385', (81, 101))	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('inactivate', 'NegReg', (26, 36))	('contribute', 'Reg', (65, 75))
84868	28849221	However, besides their relative frequency, TP63 mutations in cutaneous melanomas possibly represent a record of exposure (passenger mutations) rather than driver mutations.	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('TP63', 'Gene', (43, 47))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (61, 80))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (61, 80))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('mutations', 'Var', (48, 57))	('cutaneous melanomas', 'Disease', (61, 80))
84869	28849221	Firstly, through an extensive study that considers all type of tumors TP53 is present among the 125 drivers genes recognized, while TP63 is not.	('TP53', 'Var', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
84870	28849221	Secondly, TP63 and TP53 mutations have a significant tendency towards co-occurrence (p<0.001)  in melanomas, a situation that does not support the hypothesis that both mutations may play a major role during melanomagenesis.	('melanomas', 'Disease', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('TP53', 'Gene', (19, 23))	('TP63', 'Gene', (10, 14))	('mutations', 'Var', (24, 33))	('co-occurrence', 'Interaction', (70, 83))
84871	28849221	Thirdly, a possible mechanism through which the mutant P53 protein may facilitate the transition towards metastatic melanomas may be via interference with the antimetastatic function of the wild-type P63.	('mutant', 'Var', (48, 54))	('melanomas', 'Disease', (116, 125))	('protein', 'Protein', (59, 66))	('interference', 'NegReg', (137, 149))	('antimetastatic function', 'CPA', (159, 182))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('facilitate', 'PosReg', (71, 81))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('P53', 'Gene', (55, 58))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
84872	28849221	Adorno et al proposed such a mechanism in breast cancer cells, revealing that TGF-beta-dependent cell migration, invasion and metastasis were empowered by the mutant P53 protein and opposed by P63: a mutant P53/P63 protein complex appeared assembled with SMAD proteins which served as an essential platform.	('invasion', 'CPA', (113, 121))	('mutant', 'Var', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('protein', 'cellular_component', 'GO:0003675', ('170', '177'))	('breast cancer', 'Disease', (42, 55))	('metastasis', 'CPA', (126, 136))	('protein', 'Protein', (170, 177))	('cell migration', 'CPA', (97, 111))	('protein complex', 'cellular_component', 'GO:0032991', ('215', '230'))	('P53', 'Gene', (166, 169))	('cell migration', 'biological_process', 'GO:0016477', ('97', '111'))
84874	28849221	It should also be considered that TP53/TP63 mutations may also play different roles according to the phase of cancer development in which they occur.	('cancer', 'Disease', (110, 116))	('TP53/TP63', 'Gene', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (44, 53))	('play', 'Reg', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
84875	28849221	UV-induced TP53/TP63 mutations at PyPy sites are an early event in UV-exposed skin that it is still devoid of any cancer-like phenotype.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TP53/TP63', 'Gene', (11, 20))	('cancer', 'Disease', (114, 120))
84876	28849221	However, the presence of these mutations with their effects may allow mutated cells to escape apoptosis, thus progressing towards more advanced stages of the carcinogenesis process.	('progressing', 'PosReg', (110, 121))	('mutations', 'Var', (31, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('carcinogenesis', 'Disease', (158, 172))	('escape apoptosis', 'CPA', (87, 103))	('apoptosis', 'biological_process', 'GO:0097194', ('94', '103'))	('apoptosis', 'biological_process', 'GO:0006915', ('94', '103'))
84877	28849221	In this view, TP53/TP63 may be considered driver mutations of the early carcinogenesis steps.	('carcinogenesis steps', 'Disease', (72, 92))	('carcinogenesis steps', 'Disease', 'MESH:D063646', (72, 92))	('TP53/TP63', 'Var', (14, 23))
84878	28849221	In more advanced cancer stages or in full blown cancer the burden of other mutations prevails, thus giving cancer an aggressive behavior resulting in chemoresistance, metastatisation and decreased survival.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('chemoresistance', 'CPA', (150, 165))	('aggressive behavior', 'Phenotype', 'HP:0000718', (117, 136))	('aggressive behavior', 'CPA', (117, 136))	('metastatisation', 'CPA', (167, 182))	('giving', 'Reg', (100, 106))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('decreased', 'NegReg', (187, 196))	('survival', 'CPA', (197, 205))	('cancer', 'Disease', (107, 113))	('aggressive behavior', 'biological_process', 'GO:0002118', ('117', '136'))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
84879	28849221	Accordingly, TP53/TP63 behave as passenger mutations in these advanced cancer stages.	('cancer', 'Disease', (71, 77))	('TP53/TP63', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
84880	28849221	Two other aspects contribute to maintain the role of TP63 mutations in cutaneous melanomas uncertain.	('mutations', 'Var', (58, 67))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (71, 90))	('TP63', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (71, 90))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('cutaneous melanomas', 'Disease', (71, 90))
84881	28849221	The first is related to a recent study by Matin et al who demonstrated that the two wild-type isoforms of P63, namely TA-P63 and DeltaN-P63, play an anti-apoptotic role in melanoma and confer chemoresistance, even in the absence of TP53 mutations.	('anti-apoptotic', 'CPA', (149, 163))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('confer', 'Reg', (185, 191))	('P63', 'Gene', (106, 109))	('chemoresistance', 'CPA', (192, 207))	('DeltaN-P63', 'Var', (129, 139))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
84882	28849221	In this scenario, the selection of TP63 mutations during melanomagenesis appears to be unnecessary or even deleterious for tumor growth, once again pointing toward a passenger role rather than a driver role for such mutations.	('TP63', 'Gene', (35, 39))	('tumor', 'Disease', (123, 128))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('mutations', 'Var', (40, 49))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
84883	28849221	However, the biological impact of a mutation that is 1 or 20% abundant may be different on tumor behavior.	('is 1', 'Species', '1433131', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('mutation', 'Var', (36, 44))
84886	28849221	We conclude that TP63 mutations are frequent in cutaneous melanoma and support UV etiology, however they do not have a clear role in melanomagenesis.	('cutaneous melanoma', 'Disease', (48, 66))	('frequent', 'Reg', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('TP63', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
84887	28849221	The role of TP63 mutations changes according to the stage of melanoma carcinogenesis when they occur being drivers in early stages and passengers in late stages.	('melanoma carcinogenesis', 'Disease', 'MESH:D063646', (61, 84))	('melanoma carcinogenesis', 'Disease', (61, 84))	('TP63', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('mutations', 'Var', (17, 26))
84894	31659259	Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHigh BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms.	('MRTF', 'Gene', (49, 53))	('RhoHigh', 'Var', (85, 92))	('YAP1', 'Gene', '10413', (58, 62))	('YAP1', 'Gene', (58, 62))	('activated', 'PosReg', (68, 77))
84896	31659259	Most cutaneous melanomas have point mutations in V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF), a serine/threonine kinase with the V600E/K point mutations being the most common.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (5, 23))	('point mutations', 'Var', (30, 45))	('Sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('cutaneous melanomas', 'Disease', (5, 24))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B', 'Gene', (49, 94))	('V600E', 'Var', (138, 143))	('V600E', 'SUBSTITUTION', 'None', (138, 143))	('common', 'Reg', (177, 183))	('BRAF', 'Gene', (96, 100))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))	('V-Raf Murine Sarcoma Viral Oncogene Homolog B', 'Gene', '673', (49, 94))	('serine', 'Chemical', 'MESH:D012694', (105, 111))
84897	31659259	Given the prevalence of these mutations in human melanoma tumors, several drugs have been developed which target mutant BRAF, including vemurafenib and dabrafenib.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('melanoma tumors', 'Disease', (49, 64))	('dabrafenib', 'Chemical', 'MESH:C561627', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('melanoma tumors', 'Disease', 'MESH:D008545', (49, 64))	('BRAF', 'Gene', (120, 124))	('mutations', 'Var', (30, 39))	('vemurafenib', 'Chemical', 'MESH:D000077484', (136, 147))	('mutant', 'Var', (113, 119))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('human', 'Species', '9606', (43, 48))
84898	31659259	Alterations in other genes in the MAPK pathway such as Mitogen-Activated Protein Kinase Kinase (MEK), Neuroblastoma RAS Viral Oncogene Homolog (NRAS), Neurofibromin 1 (NF1), and others also promote resistance to BRAF inhibitors.	('promote', 'PosReg', (190, 197))	('MAPK pathway', 'Pathway', (34, 46))	('NRAS', 'Gene', '4893', (144, 148))	('MAPK', 'molecular_function', 'GO:0004707', ('34', '38'))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (102, 115))	('Mitogen-Activated Protein Kinase Kinase', 'Gene', (55, 94))	('Neuroblastoma RAS Viral Oncogene Homolog', 'Gene', '4893', (102, 142))	('Alterations', 'Var', (0, 11))	('MEK', 'Gene', (96, 99))	('Neurofibromin 1', 'Gene', '4763', (151, 166))	('MEK', 'Gene', '5609', (96, 99))	('resistance to BRAF inhibitors', 'MPA', (198, 227))	('Neurofibromin 1', 'Gene', (151, 166))	('NF1', 'Gene', (168, 171))	('NRAS', 'Gene', (144, 148))	('Mitogen-Activated Protein Kinase Kinase', 'Gene', '5609', (55, 94))	('NF1', 'Gene', '4763', (168, 171))	('Neuroblastoma RAS Viral Oncogene Homolog', 'Gene', (102, 142))
84900	31659259	The combination of BRAF inhibitors with Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) inhibitors was proposed as an approach to overcome BRAF inhibitor resistance  and it is clinically superior to BRAF inhibitor monotherapy against BRAFV600-mutant tumors .	('MEK1', 'molecular_function', 'GO:0004708', ('85', '89'))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Mitogen-Activated Protein Kinase Kinase 1/2', 'Gene', '5604;5605', (40, 83))	('tumors', 'Disease', (255, 261))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('MEK1/2', 'Gene', '5604;5605', (85, 91))	('Mitogen-Activated Protein Kinase Kinase 1/2', 'Gene', (40, 83))	('BRAFV600-mutant', 'Var', (239, 254))	('MEK1/2', 'Gene', (85, 91))
84905	31659259	These data are further supported by the observation that BRAFi/MEKi-resistant cells and tumors can be re-sensitized to treatment with BRAF or MEK inhibitors after a "drug holiday" .	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('inhibitors', 'Var', (146, 156))	('MEK', 'Gene', (63, 66))	('MEK', 'Gene', (142, 145))	('MEK', 'Gene', '5609', (63, 66))	('MEK', 'Gene', '5609', (142, 145))	('BRAF', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
84907	31659259	In melanoma the RhoA subfamily, especially RhoC, promotes invasion and metastasis , and inhibition of the RhoA isoform suppresses tumor growth .	('promotes', 'PosReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('metastasis', 'CPA', (71, 81))	('suppresses', 'NegReg', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('invasion', 'CPA', (58, 66))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('tumor', 'Disease', (130, 135))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('inhibition', 'Var', (88, 98))
84909	31659259	Actin stress fibers have been shown to be increased in melanoma cells with acquired BRAFi resistance  and we confirm and extend that finding here.	('increased', 'PosReg', (42, 51))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('Actin', 'MPA', (0, 5))	('acquired', 'Var', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
84912	31659259	Silencing of MRTF or Serum Response Factor (SRF), a transcription factor by which MRTF modulates gene expression, prevents melanoma metastasis .	('melanoma metastasis', 'Disease', (123, 142))	('gene expression', 'biological_process', 'GO:0010467', ('97', '112'))	('SRF', 'Gene', (44, 47))	('melanoma metastasis', 'Disease', 'MESH:D009362', (123, 142))	('Serum Response Factor', 'Gene', (21, 42))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('Serum Response Factor', 'Gene', '6722', (21, 42))	('prevents', 'NegReg', (114, 122))	('SRF', 'Gene', '6722', (44, 47))	('Silencing', 'Var', (0, 9))	('MRTF', 'Gene', (13, 17))	('transcription factor', 'molecular_function', 'GO:0000981', ('52', '72'))
84913	31659259	Previously, we have developed a series of MRTF-pathway inhibitors including CCG-203971 and CCG-222740  and demonstrated that CCG-203971 prevents melanoma metastasis, induces G1 cell cycle arrest, and reduces growth of melanoma cells .	('arrest', 'Disease', 'MESH:D006323', (188, 194))	('arrest', 'Disease', (188, 194))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma metastasis', 'Disease', (145, 164))	('melanoma', 'Disease', (145, 153))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('177', '194'))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (177, 194))	('melanoma', 'Disease', (218, 226))	('prevents', 'NegReg', (136, 144))	('melanoma metastasis', 'Disease', 'MESH:D009362', (145, 164))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('reduces', 'NegReg', (200, 207))	('induces', 'Reg', (166, 173))	('CCG-203971', 'Var', (125, 135))	('CCG-222740', 'Chemical', '-', (91, 101))
84926	31659259	Three additional pairs of parental (P) and vemurafenib-resistant (R) melanoma lines, M229P/R, M238P/R, and M249P/R cells, were generously provided by Dr. Roger Lo at UCLA .	('vemurafenib', 'Chemical', 'MESH:D000077484', (43, 54))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('M238P', 'Var', (94, 99))	('M229P', 'SUBSTITUTION', 'None', (85, 90))	('M238P', 'SUBSTITUTION', 'None', (94, 99))	('M249P', 'Var', (107, 112))	('M229P', 'Var', (85, 90))	('M249P', 'SUBSTITUTION', 'None', (107, 112))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
84942	31659259	Latrunculin B (#10010631), cytochalasin D (#11330), and erlotinib (#10483) were purchased from Cayman Chemical, Ann Arbor, MI, USA.	('#10010631', 'Var', (15, 24))	('#10483', 'Var', (67, 73))	('cytochalasin D', 'Chemical', 'MESH:D015638', (27, 41))	('Latrunculin B', 'Chemical', 'MESH:C037068', (0, 13))	('#11330', 'Var', (43, 49))	('erlotinib', 'Chemical', 'MESH:D000069347', (56, 65))
84945	31659259	Compound stock solutions were frozen at -20  C. Antibodies against YAP1 (#14074), MLC2 (#3672), pMLC2 (#3674), Sox10 (#89356), and pEGFR (#3777) were purchased from Cell Signaling, Danvers, MA, USA.	('EGFR', 'Gene', '1956', (132, 136))	('Sox10', 'Gene', (111, 116))	('#14074', 'Var', (73, 79))	('EGFR', 'Gene', (132, 136))	('#89356', 'Var', (118, 124))	('MLC2', 'Gene', (97, 101))	('MLC2', 'Gene', '4633', (82, 86))	('#3674', 'Var', (103, 108))	('Signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('Sox10', 'Gene', '6663', (111, 116))	('YAP1', 'Gene', (67, 71))	('MLC2', 'Gene', (82, 86))	('#3672', 'Var', (88, 93))	('YAP1', 'Gene', '10413', (67, 71))	('MLC2', 'Gene', '4633', (97, 101))
84946	31659259	Antibodies against MRTF-A (#sc21558), MRTF-B (#sc98989), and Actin (#sc1616) were purchased from Santa Cruz, Dallas, TX, USA.	('MRTF-B', 'Gene', '57496', (38, 44))	('MRTF-B', 'Gene', (38, 44))	('MRTF-A', 'Gene', (19, 25))	('MRTF-A', 'Gene', '57591', (19, 25))	('#sc21558', 'Var', (27, 35))	('#sc98989', 'Var', (46, 54))
84968	31659259	RNA-Seq data for in vitro generated vemurafenib-resistant M229P/R and M238P/R cells was downloaded from GSE75313.	('M238P', 'Var', (70, 75))	('M238P', 'SUBSTITUTION', 'None', (70, 75))	('M229P', 'Var', (58, 63))	('M229P', 'SUBSTITUTION', 'None', (58, 63))	('vemurafenib', 'Chemical', 'MESH:D000077484', (36, 47))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
84977	31659259	The MRTF signature is comprised of all genes downregulated > 2-fold upon MRTF knockdown in B16F2 melanoma cells  (Table S1).	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('MRTF', 'Gene', (73, 77))	('B16F2', 'CellLine', 'CVCL:0159', (91, 96))	('knockdown', 'Var', (78, 87))	('downregulated', 'NegReg', (45, 58))
84984	31659259	We analyzed a panel of matched parental (denoted by a P at the end of the cell line name) and BRAFi-resistant (denoted by an R at the end of the cell line name) melanoma cell lines and found that three of the resistant cell lines (UACC62R, M229R, and M238R) assumed a fibroblast-like morphology, while there was no overt change in the other two resistant cell lines (SK-Mel-19R and M249R).	('M229R', 'Var', (240, 245))	('SK-Mel-19R', 'Chemical', '-', (367, 377))	('M238R', 'Mutation', 'p.M238R', (251, 256))	('fibroblast-like morphology', 'CPA', (268, 294))	('M249R', 'Mutation', 'p.M249R', (382, 387))	('assumed', 'Reg', (258, 265))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('UACC62R', 'Var', (231, 238))	('melanoma', 'Disease', (161, 169))	('M229R', 'Mutation', 'p.M229R', (240, 245))	('M238R', 'Var', (251, 256))
84986	31659259	There was an increase in the number of actin stress fiber-positive UACC62R, M229R, and M238R cells compared to matched parental control cell lines; there was no overt change in stress fiber levels in the SK-Mel-19R and M249R cells (Fig.	('stress fiber', 'cellular_component', 'GO:0001725', ('177', '189'))	('M249R', 'Mutation', 'p.M249R', (219, 224))	('M229R', 'Mutation', 'p.M229R', (76, 81))	('M238R', 'Mutation', 'p.M238R', (87, 92))	('stress fiber', 'cellular_component', 'GO:0001725', ('45', '57'))	('stress fiber levels', 'MPA', (177, 196))	('SK-Mel-19R', 'Chemical', '-', (204, 214))	('M249R', 'Var', (219, 224))
84990	31659259	MLC2 phosphorylation is increased in the stress fiber-positive UACC62R and M238R cell lines, but not in stress fiber-negative SK-Mel-19R or M249R cells (Fig.	('SK-Mel-19R', 'Chemical', '-', (126, 136))	('phosphorylation', 'MPA', (5, 20))	('stress fiber', 'cellular_component', 'GO:0001725', ('41', '53'))	('MLC2', 'Gene', (0, 4))	('UACC62R', 'Var', (63, 70))	('phosphorylation', 'biological_process', 'GO:0016310', ('5', '20'))	('stress fiber', 'cellular_component', 'GO:0001725', ('104', '116'))	('M238R', 'Var', (75, 80))	('M238R', 'Mutation', 'p.M238R', (75, 80))	('MLC2', 'Gene', '4633', (0, 4))	('increased', 'PosReg', (24, 33))	('M249R', 'Mutation', 'p.M249R', (140, 145))
84996	31659259	M229R cells did not have increased sensitivity to single agent treatment with Rho Inhibitor I, rather Rho Inhibitor I treatment increases vemurafenib sensitivity.	('Rho', 'Var', (102, 105))	('vemurafenib', 'Chemical', 'MESH:D000077484', (138, 149))	('vemurafenib sensitivity', 'MPA', (138, 161))	('increases', 'PosReg', (128, 137))	('M229R', 'Mutation', 'p.M229R', (0, 5))
84999	31659259	Similar to the findings with Rho Inhibitor I, cytochalasin D was more active against all three of the RhoAHigh cell lines as a single agent treatment and it partially re-sensitized M229R cells to vemurafenib (Fig.	('vemurafenib', 'Chemical', 'MESH:D000077484', (196, 207))	('active', 'MPA', (70, 76))	('cytochalasin', 'Var', (46, 58))	('M229R', 'Mutation', 'p.M229R', (181, 186))	('cytochalasin D', 'Chemical', 'MESH:D015638', (46, 60))
85008	31659259	Vemurafenib fails to inhibit ERK phosphorylation in the two RhoALow resistant lines (SK-Mel-19R and M249R), which in the case of M249R is expected since these cells developed resistance by acquiring an NRASQ61K mutation.	('M249R', 'Mutation', 'p.M249R', (129, 134))	('ERK', 'Gene', '5594', (29, 32))	('M249R', 'Mutation', 'p.M249R', (100, 105))	('M249R', 'Var', (129, 134))	('resistance', 'MPA', (175, 185))	('ERK', 'Gene', (29, 32))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('NRAS', 'Gene', (202, 206))	('ERK', 'molecular_function', 'GO:0004707', ('29', '32'))	('inhibit', 'NegReg', (21, 28))	('phosphorylation', 'biological_process', 'GO:0016310', ('33', '48'))	('NRAS', 'Gene', '4893', (202, 206))	('SK-Mel-19R', 'Chemical', '-', (85, 95))
85009	31659259	In the three RhoAHigh resistant cell lines, vemurafenib partially inhibited ERK phosphorylation in two (M229R and UACC62R) but failed to suppress ERK phosphorylation in the other (M238R) (Fig.	('ERK', 'Gene', '5594', (146, 149))	('ERK', 'molecular_function', 'GO:0004707', ('146', '149'))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('ERK', 'Gene', (76, 79))	('ERK', 'Gene', (146, 149))	('M229R', 'Mutation', 'p.M229R', (104, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('80', '95'))	('M238R', 'Mutation', 'p.M238R', (180, 185))	('M229R', 'Var', (104, 109))	('inhibited', 'NegReg', (66, 75))	('vemurafenib', 'Chemical', 'MESH:D000077484', (44, 55))	('M238R', 'Var', (180, 185))	('ERK', 'Gene', '5594', (76, 79))
85011	31659259	2A), and also analyzed published RNA-Seq data for the M229P/R and M238P/R cells.	('M238P', 'SUBSTITUTION', 'None', (66, 71))	('M229P', 'SUBSTITUTION', 'None', (54, 59))	('M229P', 'Var', (54, 59))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))	('M238P', 'Var', (66, 71))
85014	31659259	Interestingly, there was no change in Sox10 protein expression in the M249P/R cells which did not have increased stress fibers (Fig.	('M249P', 'Var', (70, 75))	('Sox10', 'Gene', '6663', (38, 43))	('expression', 'MPA', (52, 62))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('M249P', 'SUBSTITUTION', 'None', (70, 75))	('Sox10', 'Gene', (38, 43))
85031	31659259	As expected, the de-differentiated tumors are predicted to be less sensitive to multiple BRAF and MEK inhibitors, including PLX4720 (a structurally similar vemurafenib analog).	('de-differentiated', 'CPA', (17, 34))	('MEK', 'Gene', (98, 101))	('MEK', 'Gene', '5609', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('vemurafenib', 'Chemical', 'MESH:D000077484', (156, 167))	('less', 'NegReg', (62, 66))	('PLX4720', 'Var', (124, 131))
85043	31659259	We also confirmed that both Y-27632 and fasudil reduce actin stress fiber formation in M229R cells (Fig.	('M229R', 'Mutation', 'p.M229R', (87, 92))	('Y-27632', 'Var', (28, 35))	('stress fiber', 'cellular_component', 'GO:0001725', ('61', '73'))	('fasudil', 'Chemical', 'MESH:C049347', (40, 47))	('Y-27632', 'Chemical', 'MESH:C108830', (28, 35))	('reduce', 'NegReg', (48, 54))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('actin stress fiber formation', 'MPA', (55, 83))
85054	31659259	YAP1 nuclear localization is elevated in M229R and M238R cells compared to matched parental cell lines and is elevated to a lesser extent in UACC62R cells.	('M238R', 'Var', (51, 56))	('elevated', 'PosReg', (29, 37))	('M229R', 'Mutation', 'p.M229R', (41, 46))	('YAP1', 'Gene', (0, 4))	('YAP1', 'Gene', '10413', (0, 4))	('M229R', 'Var', (41, 46))	('nuclear localization', 'MPA', (5, 25))	('M238R', 'Mutation', 'p.M238R', (51, 56))	('localization', 'biological_process', 'GO:0051179', ('13', '25'))
85055	31659259	The converse is true with respect to MRTF-A localization since nuclear MRTF-A is increased in UACC62R cells but not M229R or M238R cells (Fig.	('UACC62R', 'Var', (94, 101))	('nuclear', 'MPA', (63, 70))	('MRTF-A', 'Gene', (37, 43))	('MRTF-A', 'Gene', (71, 77))	('M238R', 'Mutation', 'p.M238R', (125, 130))	('localization', 'biological_process', 'GO:0051179', ('44', '56'))	('M229R', 'Mutation', 'p.M229R', (116, 121))	('MRTF-A', 'Gene', '57591', (71, 77))	('MRTF-A', 'Gene', '57591', (37, 43))	('increased', 'PosReg', (81, 90))
85058	31659259	Several YAP1- and MRTF-related genes are highly expressed in BRAF-mutant cell lines with intrinsic BRAFi resistance (Fig.	('highly', 'PosReg', (41, 47))	('MRTF-related genes', 'Gene', (18, 36))	('YAP1', 'Gene', '10413', (8, 12))	('BRAF-mutant', 'Var', (61, 72))	('YAP1', 'Gene', (8, 12))	('BRAF-mutant', 'Gene', (61, 72))	('expressed', 'MPA', (48, 57))
85084	31659259	While UACC62R does not have as robust YAP1 activation as M229R and M238R, the minor increase in YAP1 nuclear localization could explain why these cells also respond to dasatinib.	('YAP1', 'Gene', (38, 42))	('YAP1', 'Gene', '10413', (38, 42))	('UACC62R', 'Var', (6, 13))	('YAP1', 'Gene', (96, 100))	('YAP1', 'Gene', '10413', (96, 100))	('nuclear localization', 'MPA', (101, 121))	('M238R', 'Var', (67, 72))	('M229R', 'Mutation', 'p.M229R', (57, 62))	('dasatinib', 'Chemical', 'MESH:D000069439', (168, 177))	('localization', 'biological_process', 'GO:0051179', ('109', '121'))	('increase', 'PosReg', (84, 92))	('M229R', 'Var', (57, 62))	('M238R', 'Mutation', 'p.M238R', (67, 72))	('respond', 'MPA', (157, 164))
85087	31659259	Interestingly, in contrast with other similar experiments, we did not observe any change in vemurafenib sensitivity upon deletion of YAP1 with CRISPR (Fig.	('vemurafenib', 'Chemical', 'MESH:D000077484', (92, 103))	('deletion', 'Var', (121, 129))	('YAP1', 'Gene', (133, 137))	('YAP1', 'Gene', '10413', (133, 137))
85088	31659259	S18C/D) Our lab has developed a series of MRTF pathway inhibitors, including CCG-222740 .	('S18C', 'Var', (0, 4))	('S18C', 'SUBSTITUTION', 'None', (0, 4))	('CCG-222740', 'Chemical', '-', (77, 87))	('MRTF pathway', 'Pathway', (42, 54))
85092	31659259	Also, UACC62R cells are more sensitive to CCG-222740 as a single agent (Fig.	('CCG-222740', 'Var', (42, 52))	('sensitive', 'MPA', (29, 38))	('CCG-222740', 'Chemical', '-', (42, 52))
85093	31659259	Interestingly, despite the effect of CCG-222740 on viability and vemurafenib re-sensitization, CCG-222740 (10 muM, 24 h) does not alter expression of several MRTF target genes at the mRNA level (Fig.	('expression', 'MPA', (136, 146))	('muM', 'Gene', '56925', (110, 113))	('CCG-222740', 'Var', (95, 105))	('vemurafenib', 'Chemical', 'MESH:D000077484', (65, 76))	('sensitization', 'biological_process', 'GO:0046960', ('80', '93'))	('muM', 'Gene', (110, 113))	('CCG-222740', 'Chemical', '-', (37, 47))	('CCG-222740', 'Chemical', '-', (95, 105))
85096	31659259	Interestingly when we performed the inverse experiment, deletion of MRTF-A with CRISPR in resistant cells did not alter vemurafenib sensitivity (Fig.	('deletion', 'Var', (56, 64))	('MRTF-A', 'Gene', '57591', (68, 74))	('MRTF-A', 'Gene', (68, 74))	('vemurafenib sensitivity', 'MPA', (120, 143))	('vemurafenib', 'Chemical', 'MESH:D000077484', (120, 131))
85099	31659259	S19), it is possible that MRTF-A depletion may induce MRTF-B activation.	('depletion', 'Var', (33, 42))	('activation', 'PosReg', (61, 71))	('MRTF-A', 'Gene', (26, 32))	('MRTF-A', 'Gene', '57591', (26, 32))	('MRTF-B', 'Gene', '57496', (54, 60))	('MRTF-B', 'Gene', (54, 60))
85110	31659259	In another study silencing of SOX10, which was one of the most downregulated genes in our analysis, promotes BRAFi resistance .	('SOX10', 'Gene', '6663', (30, 35))	('BRAFi resistance', 'MPA', (109, 125))	('SOX10', 'Gene', (30, 35))	('promotes', 'PosReg', (100, 108))	('silencing', 'Var', (17, 26))
85116	31659259	Conversely, our data demonstrates that an MRTF pathway inhibitor increases vemurafenib sensitivity.	('increases', 'PosReg', (65, 74))	('MRTF pathway', 'Pathway', (42, 54))	('inhibitor', 'Var', (55, 64))	('vemurafenib', 'Chemical', 'MESH:D000077484', (75, 86))	('vemurafenib sensitivity', 'MPA', (75, 98))
85121	31659259	In this study deletion of YAP1 in M229R cells did not alter vemurafenib response, where other studies found that YAP1 silencing either partially reverses vemurafenib resistance or increases vemurafenib sensitivity.	('vemurafenib', 'Chemical', 'MESH:D000077484', (154, 165))	('silencing', 'NegReg', (118, 127))	('vemurafenib resistance', 'MPA', (154, 176))	('vemurafenib', 'Chemical', 'MESH:D000077484', (60, 71))	('YAP1', 'Gene', '10413', (26, 30))	('increases', 'PosReg', (180, 189))	('reverses', 'NegReg', (145, 153))	('vemurafenib', 'Chemical', 'MESH:D000077484', (190, 201))	('vemurafenib sensitivity', 'MPA', (190, 213))	('YAP1', 'Gene', (113, 117))	('YAP1', 'Gene', '10413', (113, 117))	('deletion', 'Var', (14, 22))	('M229R', 'Mutation', 'p.M229R', (34, 39))	('YAP1', 'Gene', (26, 30))
85123	31659259	However, it is also possible that YAP1 may promote drug resistance via altering chromatin remodeling, in which case short-term deletion of YAP1 may not provide sufficient time for this process to take place.	('drug resistance', 'biological_process', 'GO:0009315', ('51', '66'))	('YAP1', 'Gene', (34, 38))	('promote', 'PosReg', (43, 50))	('YAP1', 'Gene', '10413', (34, 38))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('drug resistance', 'biological_process', 'GO:0042493', ('51', '66'))	('drug resistance', 'Phenotype', 'HP:0020174', (51, 66))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('80', '100'))	('deletion', 'Var', (127, 135))	('YAP1', 'Gene', (139, 143))	('YAP1', 'Gene', '10413', (139, 143))	('drug resistance', 'MPA', (51, 66))	('chromatin remodeling', 'MPA', (80, 100))	('altering', 'Reg', (71, 79))
85125	31659259	This could be because MRTF-A may promote drug resistance via altering chromatin remodeling, or it could be because MRTF-A deletion induces compensatory activation of other transcriptional mechanisms.	('altering', 'Reg', (61, 69))	('drug resistance', 'Phenotype', 'HP:0020174', (41, 56))	('promote', 'PosReg', (33, 40))	('activation', 'PosReg', (152, 162))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('70', '90'))	('chromatin', 'cellular_component', 'GO:0000785', ('70', '79'))	('MRTF-A', 'Gene', (115, 121))	('drug resistance', 'biological_process', 'GO:0009315', ('41', '56'))	('MRTF-A', 'Gene', (22, 28))	('drug resistance', 'biological_process', 'GO:0042493', ('41', '56'))	('deletion', 'Var', (122, 130))	('drug resistance', 'MPA', (41, 56))	('chromatin remodeling', 'MPA', (70, 90))	('MRTF-A', 'Gene', '57591', (115, 121))	('MRTF-A', 'Gene', '57591', (22, 28))
85130	31659259	For example RhoA increases ERK nuclear localization and RhoA silencing reduces ERK phosphorylation.	('ERK', 'Gene', (79, 82))	('increases', 'PosReg', (17, 26))	('localization', 'biological_process', 'GO:0051179', ('39', '51'))	('ERK', 'molecular_function', 'GO:0004707', ('27', '30'))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('silencing', 'Var', (61, 70))	('ERK', 'Gene', '5594', (79, 82))	('ERK', 'Gene', '5594', (27, 30))	('ERK', 'molecular_function', 'GO:0004707', ('79', '82'))	('reduces', 'NegReg', (71, 78))	('ERK', 'Gene', (27, 30))
85131	31659259	Other studies in different model systems observe the opposite effect since treatment with the ROCKi Y-27632 increases ERK phosphorylation and expression of constitutively active RhoA decreases ERK phosphorylation.	('ERK', 'Gene', '5594', (118, 121))	('ERK', 'Gene', (193, 196))	('increases', 'PosReg', (108, 117))	('ERK', 'Gene', (118, 121))	('decreases ERK', 'Phenotype', 'HP:0000654', (183, 196))	('Y-27632', 'Chemical', 'MESH:C108830', (100, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('197', '212'))	('phosphorylation', 'MPA', (122, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('ERK', 'molecular_function', 'GO:0004707', ('118', '121'))	('decreases', 'NegReg', (183, 192))	('ERK', 'molecular_function', 'GO:0004707', ('193', '196'))	('ROCKi Y-27632', 'Var', (94, 107))	('ERK', 'Gene', '5594', (193, 196))
85149	15381927	Among these is the recent detection of mutations in the BRAF gene (Davies et al, 2002).	('BRAF', 'Gene', '673', (56, 60))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', (56, 60))
85208	31173492	Cutaneous melanoma cell line A2058 were cultured and divided into four groups: (a) A2058-only (Control); (b) A2058 and ESCs continuously co-cultured (Group One); (c) A2058 co-cultured with daily refreshed ESCs (Group two); (d) Group one with VO-Ohpic, inhibitor of PTEN (VO-Ohpic Group).	('VO-Ohpic', 'Chemical', 'MESH:C000600334', (242, 250))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('PTEN', 'Gene', (265, 269))	('PTEN', 'Gene', '5728', (265, 269))	('A2058', 'Var', (166, 171))	('VO-Ohpic', 'Chemical', 'MESH:C000600334', (271, 279))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('A2058', 'Var', (109, 114))	('Cutaneous melanoma', 'Disease', (0, 18))
85209	31173492	The results showed that, compared to control group, A2058 cells in group one exhibited decreased cellular proliferation, migration, invasiveness and vasculogenic mimicry concomitant with an increase in cell apoptosis, accompanied by down-regulation of PI3K/AKT pathway.	('apoptosis', 'biological_process', 'GO:0097194', ('207', '216'))	('migration', 'CPA', (121, 130))	('AKT', 'Gene', (257, 260))	('invasiveness', 'CPA', (132, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('207', '216'))	('decreased', 'NegReg', (87, 96))	('increase', 'PosReg', (190, 198))	('A2058', 'Var', (52, 57))	('regulation', 'biological_process', 'GO:0065007', ('238', '248'))	('vasculogenic mimicry', 'CPA', (149, 169))	('cell apoptosis', 'CPA', (202, 216))	('down-regulation', 'NegReg', (233, 248))	('AKT', 'Gene', '207', (257, 260))	('PI3K', 'molecular_function', 'GO:0016303', ('252', '256'))	('cellular proliferation', 'CPA', (97, 119))
85211	31173492	We demonstrate that ESC microenvironment reduces the malignancy of A2058 by down-regulating PI3K/AKT pathway.	('down-regulating', 'NegReg', (76, 91))	('AKT', 'Gene', '207', (97, 100))	('reduces', 'NegReg', (41, 48))	('AKT', 'Gene', (97, 100))	('malignancy', 'Disease', 'MESH:D009369', (53, 63))	('PI3K', 'molecular_function', 'GO:0016303', ('92', '96'))	('malignancy', 'Disease', (53, 63))	('A2058', 'Var', (67, 72))
85220	31173492	Unlike tumor cells, the critical components that comprise the TME and their roles in tumor progression are common between different cancers.2 Hence, a comprehensive understanding the mechanism of ESC microenvironment on A2058 represent a promising approach to inhibit the development of diverse tumors in clinical management.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('tumor', 'Disease', (85, 90))	('tumors', 'Disease', (295, 301))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('tumor', 'Disease', (7, 12))	('A2058', 'Var', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
85249	31173492	Meanwhile, the MMP1 and MMP9 expression of A2058 in group two were decreased more than that of in group one.	('MMP9', 'molecular_function', 'GO:0004229', ('24', '28'))	('MMP9', 'Gene', '4318', (24, 28))	('MMP1', 'molecular_function', 'GO:0004232', ('15', '19'))	('MMP1', 'Gene', (15, 19))	('MMP1', 'Gene', '4312', (15, 19))	('A2058', 'Var', (43, 48))	('decreased', 'NegReg', (67, 76))	('MMP9', 'Gene', (24, 28))
85252	31173492	Vasculogenic mimicry is uniquely patterned vasculogenic-like networks mediated by highly aggressive tumor cells and predict stronger invasiveness in cutaneous melanoma cells.19, 20 As displayed in Figure 4A, after co-culture with ESCs, A2058 formed less tubular structures than control, more remarkable, A2058 in group two failed to form patterned networks.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('less', 'NegReg', (249, 253))	('tumor', 'Disease', (100, 105))	('cutaneous melanoma', 'Disease', (149, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (149, 167))	('A2058', 'Var', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
85253	31173492	Vascular endothelial-cadherin (Ve-cad) has a strong contributory role in melanoma VM.21 Consistent with VM, both mRNA and protein levels of Ve-cad of A2058 were significantly restrained after co-culture compared to the control as shown in Figure 4B-D.	('A2058', 'Var', (150, 155))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('Vascular endothelial-cadherin', 'Gene', '1003', (0, 29))	('Ve-cad', 'Gene', (31, 37))	('Ve-cad', 'Gene', '1003', (140, 146))	('melanoma VM', 'Disease', (73, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))	('Ve-cad', 'Gene', '1003', (31, 37))	('restrained', 'NegReg', (175, 185))	('Vascular endothelial-cadherin', 'Gene', (0, 29))	('Ve-cad', 'Gene', (140, 146))	('melanoma VM', 'Disease', 'MESH:D008545', (73, 84))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
85257	31173492	The mRNA and protein levels of CD44, PI3K, AKT1, AKT3, and mTOR in A2058 in Figure 5A-F were notably down-regulated after co-culture with ESCs.	('AKT3', 'Gene', (49, 53))	('AKT1', 'Gene', (43, 47))	('AKT3', 'Gene', '10000', (49, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('37', '41'))	('mTOR', 'Gene', (59, 63))	('CD44', 'Gene', '960', (31, 35))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('down-regulated', 'NegReg', (101, 115))	('mTOR', 'Gene', '2475', (59, 63))	('CD44', 'Gene', (31, 35))	('AKT1', 'Gene', '207', (43, 47))	('PI3K', 'Var', (37, 41))
85309	22800556	Among patients in group 1, a large proportion of patients harbored advanced tumors (61% with >=T2, 27% with T4, by current American Joint Committee on Cancer staging criteria), and 2 (2.5%) experienced any dermal recurrence.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('>=T2', 'Var', (93, 97))	('tumors', 'Disease', (76, 82))	('Cancer', 'Disease', (151, 157))	('Cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('patients', 'Species', '9606', (49, 57))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))
85366	22800556	A randomized multicenter trial conducted in France showed that patients with at least one unresectable brain metastasis from melanoma treated with WBRT and fotemustine demonstrated statistically significantly longer time to cerebral progression than patients treated with fotemustine alone (49 versus 56 days), although the clinical significance of this is unclear.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('cerebral progression', 'CPA', (224, 244))	('melanoma', 'Disease', (125, 133))	('fotemustine', 'Chemical', 'MESH:C054368', (272, 283))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('longer', 'PosReg', (209, 215))	('patients', 'Species', '9606', (250, 258))	('fotemustine', 'Chemical', 'MESH:C054368', (156, 167))	('fotemustine', 'Var', (156, 167))	('patients', 'Species', '9606', (63, 71))
85395	33031392	The prognostic efficacy of the signature remained unaffected regardless of whether BRAF or NRAS was mutated.	('mutated', 'Var', (100, 107))	('NRAS', 'Gene', (91, 95))	('BRAF', 'Gene', '673', (83, 87))	('NRAS', 'Gene', '4893', (91, 95))	('BRAF', 'Gene', (83, 87))
85409	33031392	BRAF mutations are found in the genes of about half of melanoma patients, with younger patients making up the majority.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (87, 95))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))
85410	33031392	And targeted BRAF inhibitors have been shown to significantly improve patients' physical condition and survival expectations.	('patients', 'Species', '9606', (70, 78))	('BRAF', 'Gene', '673', (13, 17))	('improve', 'PosReg', (62, 69))	('BRAF', 'Gene', (13, 17))	('survival expectations', 'CPA', (103, 124))	('inhibitors', 'Var', (18, 28))
85435	33031392	We queried the cBioPortal website(https://www.cbioportal.org/) for mutations in multiple related genes in the TCGA dataset, with the highest number of patients with mutations in BRAF and NRAS.	('BRAF', 'Gene', (178, 182))	('NRAS', 'Gene', (187, 191))	('NRAS', 'Gene', '4893', (187, 191))	('patients', 'Species', '9606', (151, 159))	('mutations', 'Var', (67, 76))	('mutations', 'Var', (165, 174))	('BRAF', 'Gene', '673', (178, 182))
85436	33031392	Of the 378 patients included in the analysis, the BRAF gene experienced mutations in 156 patients, and the NRAS gene experienced mutations in 87 patients.	('patients', 'Species', '9606', (145, 153))	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', (50, 54))	('NRAS', 'Gene', '4893', (107, 111))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (11, 19))	('BRAF', 'Gene', '673', (50, 54))	('NRAS', 'Gene', (107, 111))
85437	33031392	Of these 156 patients who experienced BRAF mutations, all mutation types were missense mutations, including 134 patients with BRAF V600E mutations, five patients with BRAF K601E mutations, three patients with BRAF G466E mutations, and 14 patients with other uncommon mutations.	('BRAF', 'Gene', (167, 171))	('patients', 'Species', '9606', (13, 21))	('BRAF', 'Gene', '673', (167, 171))	('K601E', 'Mutation', 'rs121913364', (172, 177))	('V600E', 'Mutation', 'rs113488022', (131, 136))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (126, 130))	('patients', 'Species', '9606', (195, 203))	('BRAF', 'Gene', (38, 42))	('BRAF', 'Gene', '673', (126, 130))	('G466E', 'Mutation', 'rs121913351', (214, 219))	('K601E', 'Var', (172, 177))	('patients', 'Species', '9606', (238, 246))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (112, 120))	('BRAF', 'Gene', (209, 213))	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', '673', (209, 213))	('V600E mutations', 'Var', (131, 146))
85438	33031392	Of the 87 patients who experienced NRAS mutations, all mutation types were missense mutations except for one case with an X37 splice site mutation, of which 39 were NRAS Q61R mutations, 25 were Q61K mutations, 9 were Q61L mutations, 5 were Q61H mutations, and eight other rare mutations.	('Q61R', 'Var', (170, 174))	('Q61L', 'Var', (217, 221))	('Q61K', 'Mutation', 'rs121913254', (194, 198))	('Q61H', 'Mutation', 'rs121913255', (240, 244))	('NRAS', 'Gene', (35, 39))	('Q61K', 'Var', (194, 198))	('Q61R', 'Mutation', 'rs11554290', (170, 174))	('NRAS', 'Gene', '4893', (35, 39))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (10, 18))	('NRAS', 'Gene', (165, 169))	('Q61L', 'Mutation', 'rs11554290', (217, 221))	('NRAS', 'Gene', '4893', (165, 169))
85439	33031392	And we then stratified the dataset into different sub-datasets based on BRAF and NRAS mutation, to verify whether these factors affect the test efficacy of the prognostic signature.	('BRAF', 'Gene', (72, 76))	('affect', 'Reg', (128, 134))	('NRAS', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))	('NRAS', 'Gene', '4893', (81, 85))	('BRAF', 'Gene', '673', (72, 76))
85440	33031392	Besides, to explore the relationship between BRAF or NRAS mutation status and the risk scores we obtained, we then divided patients into two groups based on whether they had BRAF or NRAS mutations and compared the difference in risk scores between the two groups.	('NRAS', 'Gene', '4893', (182, 186))	('BRAF', 'Gene', '673', (174, 178))	('patients', 'Species', '9606', (123, 131))	('NRAS', 'Gene', (53, 57))	('mutations', 'Var', (187, 196))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (174, 178))	('NRAS', 'Gene', '4893', (53, 57))	('NRAS', 'Gene', (182, 186))
85452	33031392	Besides, to analyze whether frequent genetic mutations affect the efficacy of the prognostic signature, we grouped the TCGA-SKCM dataset according to whether BRAFor NRAS was mutated, respectively.	('BRAF', 'Gene', '673', (158, 162))	('BRAF', 'Gene', (158, 162))	('NRAS', 'Gene', (165, 169))	('mutated', 'Var', (174, 181))	('NRAS', 'Gene', '4893', (165, 169))
85453	33031392	The superiority of the signature over other clinical factors as independent prognostic factors was also not affected by BRAF or NRAS mutation in both univariate and multivariate analyses (see in S1 Fig).	('NRAS', 'Gene', (128, 132))	('mutation', 'Var', (133, 141))	('NRAS', 'Gene', '4893', (128, 132))	('BRAF', 'Gene', '673', (120, 124))	('BRAF', 'Gene', (120, 124))
85454	33031392	Besides, we divided patients into two groups based on whether they had BRAF or NRAS mutations and compared the difference in risk scores between the two groups.	('NRAS', 'Gene', '4893', (79, 83))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (20, 28))	('NRAS', 'Gene', (79, 83))
85455	33031392	Interestingly, we found a lower risk score in the BRAF mutation group (P = 0.03947), suggesting that patients may have a better prognosis than those in the non-mutation group.	('patients', 'Species', '9606', (101, 109))	('BRAF', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('BRAF', 'Gene', '673', (50, 54))	('lower', 'NegReg', (26, 31))
85456	33031392	However, when analyzing the NRAS mutations, we did not find any difference in risk scores between the two groups (P = 0.1897).	('NRAS', 'Gene', '4893', (28, 32))	('NRAS', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
85466	33031392	As a result, we found the enrichment of four cancer hallmark gene sets in the high-risk group, including "OXIDATIVE_PHOSPHORYLATION", "ADIPOGENESIS", "MYC_TARGETS_V1", and "MYC_TARGETS_V2" (see in Fig 7), which suggests a crucial role in melanoma progression and prognosis of these significantly enriched gene sets.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('MYC_TARGETS_V1', 'Var', (151, 165))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MYC_TARGETS_V2', 'Var', (173, 187))	('ADIPOGENESIS', 'biological_process', 'GO:0045444', ('132', '144'))	('ADIPOGENESIS', 'biological_process', 'GO:0060612', ('132', '144'))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('OXIDATIVE_PHOSPHORYLATION', 'biological_process', 'GO:0006119', ('105', '130'))	('cancer', 'Disease', (45, 51))
85550	27871313	Eight of them were extracted from GEO (accessions: GSE10072, GSE10245, GSE10445, GSE19188, GSE31210, GSE3141, GSE31908, and GSE4573).	('GSE10072', 'Var', (51, 59))	('GSE4573', 'Var', (124, 131))	('GSE10445', 'Var', (71, 79))	('GSE3141', 'Var', (101, 108))	('GSE3141', 'Chemical', '-', (101, 108))	('GSE4573', 'Chemical', '-', (124, 131))	('GSE19188', 'Var', (81, 89))	('GSE31908', 'Var', (110, 118))	('GSE31210', 'Var', (91, 99))
85553	27871313	Raw data was downloaded from GEO database (accessions: GSE18520, GSE26193, GSE26712, GSE27943, GSE6008, and GSE9899).	('GSE26712', 'Var', (75, 83))	('GSE26193', 'Var', (65, 73))	('GSE18520', 'Var', (55, 63))	('GSE6008', 'Chemical', '-', (95, 102))	('GSE27943', 'Var', (85, 93))	('GSE9899', 'Chemical', '-', (108, 115))	('GSE6008', 'Var', (95, 102))	('GSE9899', 'Var', (108, 115))
85602	27871313	This poor-outcome association was most apparent for metagenes enriched in myeloid cells and occurred most notably in the contexts of GBM and colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colon cancer', 'Disease', (141, 153))	('metagenes', 'Var', (52, 61))	('GBM', 'Disease', (133, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (141, 153))	('colon cancer', 'Disease', 'MESH:D015179', (141, 153))
85614	27871313	That these rare, cell type-specific genes were not major components of our gene signatures could owe to their admixed expression in tumors, where both immune and malignant cells (and/or other stromal cell populations) may co-express the genes thereby abrogating their cellular specificity that otherwise exists among peripheral blood-purified immune cells.	('cellular specificity', 'MPA', (268, 288))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('abrogating', 'NegReg', (251, 261))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('genes', 'Var', (237, 242))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
85722	32489431	Patients with tumor PD-L1 expression >=5% had a higher ORR than patients with PD-L1 expression <5% (60% versus 33%).	('tumor', 'Disease', (14, 19))	('patients', 'Species', '9606', (64, 72))	('PD-L1', 'Gene', (78, 83))	('>=5%', 'Var', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PD-L1', 'Gene', (20, 25))	('ORR', 'MPA', (55, 58))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', '29126', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PD-L1', 'Gene', '29126', (20, 25))
85751	32489431	These results suggested that anti-PD-1 antibodies could prolong survival with acceptable toxicity in patients with advanced or metastatic MM.	('patients', 'Species', '9606', (101, 109))	('PD-1', 'Gene', (34, 38))	('prolong', 'PosReg', (56, 63))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('PD-1', 'Gene', '5133', (34, 38))	('survival', 'MPA', (64, 72))	('MM', 'Phenotype', 'HP:0002861', (138, 140))	('MM', 'Chemical', '-', (138, 140))	('antibodies', 'Var', (39, 49))	('metastatic', 'CPA', (127, 137))
85771	32489431	In contrast, SF3B1 and KIT mutations occur more commonly in MM than in cutaneous melanoma.	('mutations', 'Var', (27, 36))	('KIT', 'molecular_function', 'GO:0005020', ('23', '26'))	('KIT', 'Gene', '3815', (23, 26))	('SF3B1', 'Gene', (13, 18))	('MM', 'Chemical', '-', (60, 62))	('KIT', 'Gene', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('SF3B1', 'Gene', '23451', (13, 18))	('cutaneous melanoma', 'Disease', (71, 89))	('occur', 'Reg', (37, 42))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (71, 89))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('MM', 'Phenotype', 'HP:0002861', (60, 62))
85773	32489431	In cutaneous melanoma, most mutations are ultraviolet radiation-induced C > T transitions at pyrimidine dimers, but MM lacks such a specific mutation pattern.	('MM', 'Phenotype', 'HP:0002861', (116, 118))	('MM', 'Chemical', '-', (116, 118))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', (3, 21))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('pyrimidine', 'Chemical', 'MESH:C030986', (93, 103))	('C > T', 'Var', (72, 77))	('mutations', 'Var', (28, 37))
85775	32489431	found cutaneous melanoma has one of the highest single-nucleotide variants and indel frequencies of any cancer with an average of 49.17 mutations per megabase, while MM only has an average of 1.95 mutations per megabase, a more than 25-fold lower TMB.	('cutaneous melanoma', 'Disease', (6, 24))	('MM', 'Chemical', '-', (166, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (6, 24))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 24))	('TMB', 'Chemical', '-', (247, 250))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lower', 'NegReg', (241, 246))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('mutations', 'Var', (136, 145))	('TMB', 'MPA', (247, 250))	('MM', 'Phenotype', 'HP:0002861', (166, 168))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('single-nucleotide variants', 'Var', (48, 74))
85783	32489431	Conversely, MM patients with tumor PD-L1 expression <5% exhibited a much poorer response than patients with cutaneous disease.	('cutaneous disease', 'Disease', (108, 125))	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cutaneous disease', 'Disease', 'MESH:D034701', (108, 125))	('PD-L1', 'Gene', '29126', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MM', 'Chemical', '-', (12, 14))	('poorer', 'NegReg', (73, 79))	('tumor', 'Disease', (29, 34))	('MM', 'Phenotype', 'HP:0002861', (12, 14))	('PD-L1', 'Gene', (35, 40))	('<5%', 'Var', (52, 55))
85792	30294322	Genetic Alterations of TRAF Proteins in Human Cancers The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors.	('TNF', 'Gene', (90, 93))	('TNF', 'Gene', '7124', (244, 247))	('necrosis', 'biological_process', 'GO:0008219', ('64', '72'))	('signal transduction', 'MPA', (174, 193))	('Cancers', 'Disease', (46, 53))	('Cancers', 'Phenotype', 'HP:0002664', (46, 53))	('Human', 'Species', '9606', (40, 45))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('58', '79'))	('TNF', 'Gene', '7124', (90, 93))	('necrosis', 'biological_process', 'GO:0008220', ('64', '72'))	('tumor necrosis', 'Disease', 'MESH:D009336', (58, 72))	('tumor necrosis', 'Disease', (58, 72))	('necrosis', 'biological_process', 'GO:0070265', ('64', '72'))	('regulate', 'Reg', (161, 169))	('necrosis', 'biological_process', 'GO:0019835', ('64', '72'))	('necrosis', 'biological_process', 'GO:0001906', ('64', '72'))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Cancers', 'Disease', 'MESH:D009369', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('signal transduction', 'biological_process', 'GO:0007165', ('174', '193'))	('TNF', 'Gene', (244, 247))	('Alterations', 'Var', (8, 19))
85795	30294322	Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('loss-of-function', 'NegReg', (41, 57))	('gain-', 'PosReg', (31, 36))	('TRAF', 'Gene', (91, 95))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('genetic alterations', 'Var', (58, 77))
85797	30294322	Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('genetic alterations', 'Var', (102, 121))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TRAF proteins', 'Gene', (125, 138))
85801	30294322	With the rapid progress made in next-generation deep sequencing technology and the tremendous efforts put forth on whole genome/exome/transcriptome sequencing and copy number variation (CNV) analyses of cancers at the post-genome era, it has become increasingly clear that genetic alterations of TRAF proteins are commonly present in various human cancers.	('TRAF', 'Gene', (296, 300))	('cancers', 'Disease', 'MESH:D009369', (348, 355))	('cancers', 'Phenotype', 'HP:0002664', (348, 355))	('cancers', 'Disease', (348, 355))	('present', 'Reg', (323, 330))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('genetic alterations', 'Var', (273, 292))	('human', 'Species', '9606', (342, 347))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
85803	30294322	Moreover, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TRAF proteins', 'Gene', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('genetic alterations', 'Var', (99, 118))
85805	30294322	According to the TCGA and COSMIC datasets of sample size n > 100, the frequency of genetic alterations of TRAF1 is generally <4% in human cancers (Figure 1A).	('genetic alterations', 'Var', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('TRAF1', 'Gene', (106, 111))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
85806	30294322	The eight human cancers with relatively higher genetic alterations of TRAF1 are pancreatic cancer (3.7%), skin cutaneous melanoma (2.9%) (TCGA, PanCancer Atlas), esophageal cancer (2.8%) (TCGA, PanCancer Atlas), stomach cancer (2.7%), sarcoma (2.4%), ovarian cancer (2.3%) (TCGA, Provisional), lung cancer (2.3%), and prostate cancer (2%) (TCGA, Provisional).	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (106, 129))	('lung cancer', 'Disease', (294, 305))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (111, 129))	('stomach cancer', 'Disease', (212, 226))	('skin cutaneous melanoma', 'Disease', (106, 129))	('pancreatic cancer', 'Disease', (80, 97))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (162, 179))	('ovarian cancer', 'Disease', (251, 265))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (251, 265))	('esophageal cancer', 'Disease', (162, 179))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('lung cancer', 'Disease', 'MESH:D008175', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('stomach cancer', 'Disease', 'MESH:D013274', (212, 226))	('prostate cancer', 'Disease', 'MESH:D011471', (318, 333))	('prostate cancer', 'Phenotype', 'HP:0012125', (318, 333))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('stomach cancer', 'Phenotype', 'HP:0012126', (212, 226))	('prostate cancer', 'Disease', (318, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (294, 305))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('genetic alterations', 'Var', (47, 66))	('TRAF1', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (251, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
85807	30294322	Deep deletion (copy loss) is less common but also detected in several types of human cancers (Figure 1).	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('detected', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Deep deletion', 'Var', (0, 13))
85809	30294322	To date, there are 139 different mutations of the TRAF1 gene detected in human cancers, comprising 80% (111/139) mutations that alter the protein sequence of TRAF1 and 20% (28/139) coding silent mutations (Table 1).	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('cancers', 'Disease', (79, 86))	('alter', 'Reg', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TRAF1', 'Gene', (50, 55))	('human', 'Species', '9606', (73, 78))	('mutations', 'Var', (113, 122))	('silent', 'NegReg', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('TRAF1', 'Gene', (158, 163))	('protein sequence', 'MPA', (138, 154))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
85810	30294322	Only 29% (32/111) of the coding-altering mutations of TRAF1 are recurrent and have been detected in at least two patients with various cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('TRAF1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('coding-altering', 'Reg', (25, 40))
85811	30294322	Interestingly, missense mutations of two specific amino acids are detected in more than three patients: R70C or H in the linker between the Zinc finger and the coiled-coil domain, and M182I of the coiled-coil (also known as TRAF-N) domain of the TRAF1 protein (Figure 3).	('patients', 'Species', '9606', (94, 102))	('TRAF1', 'Gene', (246, 251))	('coiled-coil', 'MPA', (197, 208))	('M182I', 'Mutation', 'p.M182I', (184, 189))	('protein', 'cellular_component', 'GO:0003675', ('252', '259'))	('missense', 'Var', (15, 23))	('R70C', 'Var', (104, 108))	('R70C', 'Mutation', 'p.R70C', (104, 108))	('M182I', 'Var', (184, 189))
85812	30294322	The R70 mutations are detected in 4 patients with stomach, colon, and colorectal cancers (TCGA).	('patients', 'Species', '9606', (36, 44))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colon', 'Disease', (59, 64))	('R70 mutations', 'Var', (4, 17))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('stomach', 'Disease', (50, 57))	('colorectal cancers', 'Disease', (70, 88))	('detected', 'Reg', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
85813	30294322	M182I is documented in 4 patients with melanoma and chronic lymphocytic leukemia (CLL).	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (52, 80))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (52, 80))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('M182I', 'Var', (0, 5))	('patients', 'Species', '9606', (25, 33))	('leukemia', 'Phenotype', 'HP:0001909', (72, 80))	('CLL', 'Phenotype', 'HP:0005550', (82, 85))	('chronic lymphocytic leukemia', 'Disease', (52, 80))	('M182I', 'Mutation', 'p.M182I', (0, 5))
85814	30294322	The functional significance of R70C/H and M182I mutations of TRAF1 remains to be determined.	('R70C', 'Mutation', 'p.R70C', (31, 35))	('R70C/H', 'Var', (31, 37))	('TRAF1', 'Gene', (61, 66))	('M182I', 'Var', (42, 47))	('M182I', 'Mutation', 'p.M182I', (42, 47))
85819	30294322	Gene amplification is the most common TRAF1 genetic alteration in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('Gene amplification', 'Var', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF1', 'Gene', (38, 43))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
85822	30294322	In this case, TRAF1 upregulation might be the result of epigenetic alterations and/or aberrant activation of NF-kappaB1/2, as TRAF1 is a direct target gene of NF-kappaB.	('NF-kappaB1', 'Gene', '18033', (109, 119))	('activation', 'PosReg', (95, 105))	('NF-kappaB1', 'Gene', (109, 119))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('95', '118'))	('upregulation', 'PosReg', (20, 32))	('TRAF1', 'Gene', (14, 19))	('epigenetic alterations', 'Var', (56, 78))
85832	30294322	In line with the evidence of TRAF1 overexpression in HLs and NHLs, TRAF1 deficiency inhibits the spontaneous development of small B cell lymphoma in a transgenic mouse model that expresses the human lymphoma-associated NF-kappaB2 mutant p80HT specifically in lymphocytes (p80HT tg mice) (Table 2).	('B cell lymphoma', 'Phenotype', 'HP:0012191', (130, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('p80HT', 'Var', (237, 242))	('spontaneous development', 'CPA', (97, 120))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (124, 145))	('mutant p80HT', 'Var', (230, 242))	('NHLs, TRAF1 deficiency inhibits', 'Disease', 'MESH:C565433', (61, 92))	('HL', 'CellLine', 'CVCL:2492', (62, 64))	('human', 'Species', '9606', (193, 198))	('NHLs', 'Phenotype', 'HP:0012539', (61, 65))	('HL', 'CellLine', 'CVCL:2492', (53, 55))	('cell lymphoma', 'Phenotype', 'HP:0012191', (132, 145))	('HLs', 'Phenotype', 'HP:0012189', (62, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (199, 207))	('lymphoma', 'Disease', (137, 145))	('small B cell lymphoma', 'Disease', (124, 145))	('mice', 'Species', '10090', (281, 285))	('lymphoma', 'Disease', 'MESH:D008223', (137, 145))	('mouse', 'Species', '10090', (162, 167))	('NF-kappaB2', 'Gene', '18034', (219, 229))	('transgenic', 'Species', '10090', (151, 161))	('NF-kappaB2', 'Gene', (219, 229))	('lymphoma', 'Disease', (199, 207))	('HLs', 'Phenotype', 'HP:0012189', (53, 56))	('lymphoma', 'Disease', 'MESH:D008223', (199, 207))	('small B cell', 'Phenotype', 'HP:0010976', (124, 136))
85837	30294322	The frequency of genetic alterations of TRAF2 is generally <6% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 180.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF2', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
85838	30294322	The eight human cancers with relatively higher genetic alterations of TRAF2 are prostate cancer (5.5%), ovarian cancer (5.1%) (TCGA, Provisional), uterine cancer (4.4%) (TCGA, PanCancer Atlas), esophageal cancer (3.9%) (TCGA, PanCancer Atlas), skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas), head and neck squamous cell carcinoma (HNSCC, 3.2%) (TCGA, Provisional), bladder cancer (3.2%) (TCGA, PanCancer Atlas), and stomach cancer (3.1%).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (89, 95))	('stomach cancer', 'Disease', (424, 438))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('Cancer', 'Phenotype', 'HP:0002664', (405, 411))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (309, 337))	('neck squamous cell carcinoma', 'Disease', (309, 337))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('cancer', 'Disease', (16, 22))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('esophageal cancer', 'Disease', (194, 211))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('bladder cancer', 'Disease', 'MESH:D001749', (373, 387))	('bladder cancer', 'Disease', (373, 387))	('cancer', 'Disease', (381, 387))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TRAF2', 'Gene', (70, 75))	('prostate cancer', 'Disease', (80, 95))	('bladder cancer', 'Phenotype', 'HP:0009725', (373, 387))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (244, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (314, 337))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (205, 211))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('stomach cancer', 'Disease', 'MESH:D013274', (424, 438))	('stomach cancer', 'Phenotype', 'HP:0012126', (424, 438))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (249, 267))	('skin cutaneous melanoma', 'Disease', (244, 267))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (155, 161))	('ovarian cancer', 'Disease', (104, 118))	('alterations', 'Var', (55, 66))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('neck', 'cellular_component', 'GO:0044326', ('309', '313'))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', (432, 438))	('uterine cancer', 'Phenotype', 'HP:0010784', (147, 161))
85839	30294322	Notably, although not cataloged in TCGA, mutations of TRAF2 are recognized as one of the most frequent somatic mutations in mantle cell lymphoma (MCL, 6.1%, 10/165) and diffuse large B-cell lymphoma (DLBCL, 6%, 6/101) (Figure 1B).	('mutations', 'Var', (41, 50))	('MCL', 'Disease', (146, 149))	('cell lymphoma', 'Phenotype', 'HP:0012191', (185, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('cell lymphoma', 'Phenotype', 'HP:0012191', (131, 144))	('cell lymphoma', 'Disease', 'MESH:D016399', (185, 198))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (124, 144))	('TRAF2', 'Gene', (54, 59))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (183, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('mantle cell lymphoma', 'Disease', (124, 144))	('MCL', 'Disease', 'OMIM:150800', (146, 149))	('cell lymphoma', 'Disease', (185, 198))	('cell lymphoma', 'Disease', 'MESH:D016399', (131, 144))
85841	30294322	Truncation and fusion of TRAF2 are relatively rare but also detected in human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('TRAF2', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('detected', 'Reg', (60, 68))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
85842	30294322	There are 237 different mutations of TRAF2 detected in human cancers, comprising 86% (205/237) mutations that change the protein sequence of TRAF2 and 14% (32/237) coding silent mutations (Table 1).	('TRAF2', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF2', 'Gene', (141, 146))
85843	30294322	Notably, 45% (92/205) of the coding-altering mutations of TRAF2 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('coding-altering', 'Reg', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TRAF2', 'Gene', (58, 63))
85844	30294322	Interestingly, four mutation hotspots of TRAF2 are detected in more than 5 cancer patients, specifically P9, G10, R372, and Q457 (Figure 3).	('TRAF2', 'Gene', (41, 46))	('detected', 'Reg', (51, 59))	('Q457', 'Var', (124, 128))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('G10', 'Var', (109, 112))	('P9', 'Gene', '11340', (105, 107))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('R372', 'Var', (114, 118))
85845	30294322	In particular, the frameshift deletion occurred at P9 (P9fs*77) is found in 16 patients with colon cancer, colorectal cancer (CRC), uterine cancer, stomach cancer, and sarcoma, and an additional missense mutation at P9 (P9S) is also detected in a CRC patient (TCGA).	('sarcoma', 'Phenotype', 'HP:0100242', (168, 175))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('found', 'Reg', (67, 72))	('frameshift deletion', 'Var', (19, 38))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('P9', 'Gene', '11340', (51, 53))	('P9 (P9S', 'Gene', '11340', (216, 223))	('stomach cancer', 'Disease', (148, 162))	('colon cancer', 'Disease', (93, 105))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('P9', 'Gene', '11340', (216, 218))	('patient', 'Species', '9606', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CRC', 'Disease', (247, 250))	('CRC', 'Phenotype', 'HP:0003003', (247, 250))	('cancer', 'Disease', (118, 124))	('stomach cancer', 'Disease', 'MESH:D013274', (148, 162))	('patient', 'Species', '9606', (251, 258))	('stomach cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('sarcoma', 'Disease', 'MESH:D012509', (168, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('P9', 'Gene', '11340', (55, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))	('sarcoma', 'Disease', (168, 175))	('cancer', 'Disease', (156, 162))	('uterine cancer', 'Phenotype', 'HP:0010784', (132, 146))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', (107, 124))	('patients', 'Species', '9606', (79, 87))	('P9', 'Gene', '11340', (220, 222))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))
85846	30294322	The amino acid right next to P9, G10, also exhibits similar frameshift deletion (G10fs*76) or insertion (G10fs*70) or missense mutation (G10D) in five patients with colon cancer, CRC, gallbladder cancer, and glioblastoma (TCGA).	('G10fs*76', 'Var', (81, 89))	('G10fs*70', 'Mutation', 'p.G10fsX70', (105, 113))	('G10D', 'Var', (137, 141))	('G10D', 'Mutation', 'p.G10D', (137, 141))	('CRC', 'Disease', (179, 182))	('colon cancer', 'Disease', (165, 177))	('frameshift', 'Reg', (60, 70))	('gallbladder cancer', 'Disease', (184, 202))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('G10fs*70', 'Var', (105, 113))	('G10fs*76', 'Mutation', 'p.G10fsX76', (81, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (208, 220))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('P9', 'Gene', '11340', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('glioblastoma', 'Disease', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('gallbladder cancer', 'Disease', 'MESH:D005706', (184, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (208, 220))	('patients', 'Species', '9606', (151, 159))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))
85848	30294322	Another amino acid of the TRAF-C domain, Q457, shows complex mutations, including a truncation (Q457*), a frameshift insertion (Q457fs*277), and missense mutations (Q457K or L) in six patients of HNSCC, oral squamous cell carcinoma (OSCC), stomach cancer, melanoma, and breast cancer (TCGA; COSMIC).	('Q457*', 'SUBSTITUTION', 'None', (96, 101))	('Q457fs*277', 'Var', (128, 138))	('stomach cancer', 'Phenotype', 'HP:0012126', (240, 254))	('breast cancer', 'Phenotype', 'HP:0003002', (270, 283))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('Q457K', 'Var', (165, 170))	('melanoma', 'Disease', (256, 264))	('Q457K', 'Mutation', 'p.Q457K', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (270, 283))	('breast cancer', 'Disease', (270, 283))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('Q457*', 'Var', (96, 101))	('missense', 'Var', (145, 153))	('truncation', 'MPA', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('Q457fs*277', 'Mutation', 'p.Q457fsX277', (128, 138))	('stomach cancer', 'Disease', (240, 254))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('HNSCC', 'Disease', (196, 201))	('patients', 'Species', '9606', (184, 192))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('oral squamous cell carcinoma', 'Disease', (203, 231))	('stomach cancer', 'Disease', 'MESH:D013274', (240, 254))
85849	30294322	Frameshift mutations occurring at P9 and G10 are functionally equivalent to deletion of TRAF2.	('deletion', 'Var', (76, 84))	('P9', 'Gene', '11340', (34, 36))	('TRAF2', 'Gene', (88, 93))	('G10', 'Var', (41, 44))	('Frameshift mutations', 'Var', (0, 20))
85852	30294322	Functional contribution of these TRAF2 fusions to cancer pathogenesis is currently unclear.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('TRAF2', 'Gene', (33, 38))	('pathogenesis', 'biological_process', 'GO:0009405', ('57', '69'))	('fusions', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
85853	30294322	Inactivating mutations of TRAF2 are frequently detected in human MCL and DLBCL, resulting in elevated activation of NF-kappaB1 and NF-kappaB2 in malignant B cells.	('elevated activation', 'PosReg', (93, 112))	('human', 'Species', '9606', (59, 64))	('NF-kappaB1', 'Gene', '18033', (116, 126))	('NF-kappaB1', 'Gene', (116, 126))	('Inactivating mutations', 'Var', (0, 22))	('MCL', 'Disease', 'OMIM:150800', (65, 68))	('TRAF2', 'Gene', (26, 31))	('NF-kappaB2', 'Gene', (131, 141))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('102', '125'))	('MCL', 'Disease', (65, 68))	('NF-kappaB2', 'Gene', '18034', (131, 141))
85856	30294322	Similarly in TRAF2DN-tg mice that express a dominant negative form of TRAF2 specifically in lymphocytes (Igh-TRAF2DN), inhibition of TRAF2 also leads to splenomegaly and lymphadenopathy due to constitutive NF-kappaB2 activation and increased numbers of B cells.	('splenomegaly and lymphadenopathy', 'Disease', 'MESH:C536897', (153, 185))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (170, 185))	('leads to', 'Reg', (144, 152))	('mice', 'Species', '10090', (24, 28))	('NF-kappaB2', 'Gene', (206, 216))	('inhibition', 'Var', (119, 129))	('TRAF2', 'Gene', (133, 138))	('Igh', 'Gene', (105, 108))	('increased', 'PosReg', (232, 241))	('NF-kappaB2', 'Gene', '18034', (206, 216))	('Igh', 'Gene', '111507', (105, 108))	('splenomegaly', 'Phenotype', 'HP:0001744', (153, 165))	('activation', 'PosReg', (217, 227))	('negative', 'NegReg', (53, 61))	('TRAF2', 'Gene', (70, 75))
85857	30294322	Remarkably, TRAF2DN/Bcl-2 double-transgenic mice spontaneously develop small B cell lymphoma progressing to leukemia with many similarities to human CLL (Table 2).	('human', 'Species', '9606', (143, 148))	('small B cell', 'Phenotype', 'HP:0010976', (71, 83))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (77, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('cell lymphoma', 'Phenotype', 'HP:0012191', (79, 92))	('CLL', 'Phenotype', 'HP:0005550', (149, 152))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('develop', 'PosReg', (63, 70))	('leukemia', 'Disease', 'MESH:D007938', (108, 116))	('transgenic mice', 'Species', '10090', (33, 48))	('leukemia', 'Disease', (108, 116))	('TRAF2DN/Bcl-2', 'Var', (12, 25))	('small B cell lymphoma', 'Disease', (71, 92))	('small B cell lymphoma', 'Disease', 'MESH:D016393', (71, 92))	('Bcl-2', 'molecular_function', 'GO:0015283', ('20', '25'))
85859	30294322	Genetic alterations of TRAF2 are detected in 1-2% of human liver cancers, including deletion, mutation and amplification (TCGA, PanCancer Atlas).	('liver cancer', 'Phenotype', 'HP:0002896', (59, 71))	('liver cancers', 'Phenotype', 'HP:0002896', (59, 72))	('deletion', 'Var', (84, 92))	('TRAF2', 'Gene', (23, 28))	('liver cancers', 'Disease', (59, 72))	('liver cancers', 'Disease', 'MESH:D006528', (59, 72))	('amplification', 'MPA', (107, 120))	('detected', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (53, 58))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (94, 102))
85861	30294322	In line with human evidence, deletion of both TRAF2 and RIP1 in liver parenchymal cells (LPC) leads to spontaneous development of hepatocellular carcinoma, which results from extensive hepatocyte apoptosis due to hyperactivation of caspase-8 but impaired NF-kappaB activation induced by TNFalpha (Table 2).	('RIP1', 'Gene', (56, 60))	('deletion', 'Var', (29, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('TRAF2', 'Gene', (46, 51))	('human', 'Species', '9606', (13, 18))	('RIP1', 'Gene', '8737', (56, 60))	('impaired', 'NegReg', (246, 254))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('255', '275'))	('caspase-8', 'Gene', '841', (232, 241))	('hyperactivation', 'PosReg', (213, 228))	('hepatocyte apoptosis', 'biological_process', 'GO:0097284', ('185', '205'))	('caspase-8', 'Gene', (232, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('activation', 'PosReg', (265, 275))	('hepatocyte apoptosis', 'CPA', (185, 205))	('NF-kappaB', 'Protein', (255, 264))	('hepatocellular carcinoma', 'Disease', (130, 154))
85863	30294322	Induced TRAF2 deletion in adult mice results in rapid lethality, in conjunction with increased hepatic necroptosome assembly (Table 2).	('TRAF2', 'Gene', (8, 13))	('rapid lethality', 'MPA', (48, 63))	('mice', 'Species', '10090', (32, 36))	('increased', 'PosReg', (85, 94))	('deletion', 'Var', (14, 22))	('hepatic necroptosome assembly', 'MPA', (95, 124))
85865	30294322	Genetic alterations of TRAF2 are detected in 3-4% of human HNSCC and melanoma (Figure 1A).	('Genetic alterations', 'Var', (0, 19))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('TRAF2', 'Gene', (23, 28))	('human HNSCC', 'Disease', (53, 64))	('detected', 'Reg', (33, 41))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
85869	30294322	Further in support of a role for TRAF2 in skin tumorigenesis, mutations of the TRAF2-deubiquitinating enzyme CYLD are identified in patients with familial cylindromatosis, a condition that results in benign tumors of skin appendages, and CYLD-/- mice are highly susceptible to chemically induced skin tumors.	('TRAF2-deubiquitinating', 'Gene', (79, 101))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('85', '108'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', (207, 213))	('tumors', 'Disease', (301, 307))	('patients', 'Species', '9606', (132, 140))	('familial cylindromatosis', 'Disease', (146, 170))	('skin tumor', 'Phenotype', 'HP:0008069', (42, 52))	('skin tumor', 'Phenotype', 'HP:0008069', (296, 306))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('mutations', 'Var', (62, 71))	('CYLD', 'Gene', (109, 113))	('CYLD', 'Gene', (238, 242))	('skin tumors', 'Disease', (296, 307))	('tumors of skin', 'Phenotype', 'HP:0008069', (207, 221))	('tumors of skin appendages', 'Phenotype', 'HP:0012842', (207, 232))	('familial cylindromatosis', 'Disease', 'MESH:C536611', (146, 170))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (47, 52))	('CYLD', 'Gene', '1540', (109, 113))	('CYLD', 'Gene', '1540', (238, 242))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('skin tumors', 'Disease', 'MESH:D012878', (296, 307))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('skin tumors', 'Phenotype', 'HP:0008069', (296, 307))	('mice', 'Species', '10090', (246, 250))
85870	30294322	Similarly, genetic alterations of TRAF2 are also identified in 2.7% (12/439) of human colon cancers (TCGA, PanCancer Atlas).	('colon cancers', 'Disease', (86, 99))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('colon cancers', 'Phenotype', 'HP:0003003', (86, 99))	('identified', 'Reg', (49, 59))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancers', 'Disease', 'MESH:D015179', (86, 99))	('human', 'Species', '9606', (80, 85))	('TRAF2', 'Gene', (34, 39))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('genetic alterations', 'Var', (11, 30))
85873	30294322	Interestingly, myeloid cell-specific ablation of TRAF2 markedly exacerbates DSS-induced colitis in mice due to enhanced TLR-induced proinflammatory cytokine expression in macrophages.	('mice', 'Species', '10090', (99, 103))	('colitis', 'Phenotype', 'HP:0002583', (88, 95))	('ablation', 'Var', (37, 45))	('enhanced', 'PosReg', (111, 119))	('colitis', 'Disease', 'MESH:D003092', (88, 95))	('exacerbates', 'PosReg', (64, 75))	('colitis', 'Disease', (88, 95))	('TLR-induced proinflammatory cytokine expression', 'MPA', (120, 167))	('TRAF2', 'Gene', (49, 54))
85876	30294322	It is also noteworthy that genetic alterations of TRAF2 are detected in 2.6% (7/265) of human sarcomas (TCGA) and TRAF2-/- mice display decreased viability of skeletal muscle tissue because of defective TNFalpha-induced NF-kappaB activation in myotubes (Table 2).	('sarcomas', 'Disease', (94, 102))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('220', '240'))	('alterations', 'Var', (35, 46))	('defective', 'NegReg', (193, 202))	('TRAF2-/', 'Gene', '7186', (114, 121))	('sarcomas', 'Disease', 'MESH:D012509', (94, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('viability', 'CPA', (146, 155))	('TRAF2', 'Gene', (50, 55))	('TNFalpha-induced NF-kappaB', 'Protein', (203, 229))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('activation', 'PosReg', (230, 240))	('human', 'Species', '9606', (88, 93))	('genetic alterations', 'Var', (27, 46))	('TRAF2-/', 'Gene', (114, 121))	('decreased', 'NegReg', (136, 145))	('mice', 'Species', '10090', (123, 127))
85877	30294322	Additionally, specific deletion of TRAF2 in T cells results in decreased numbers of CD8 naive and memory T cells as well as NKT cells, due to impaired IL-15-induced signaling in these cells (Table 2).	('memory T', 'Disease', 'MESH:D008569', (98, 106))	('CD8', 'Gene', '925', (84, 87))	('deletion', 'Var', (23, 31))	('decreased', 'NegReg', (63, 72))	('IL-15-induced signaling', 'MPA', (151, 174))	('memory T', 'Disease', (98, 106))	('memory', 'biological_process', 'GO:0007613', ('98', '104'))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('IL-15', 'molecular_function', 'GO:0016170', ('151', '156'))	('CD8', 'Gene', (84, 87))	('impaired', 'NegReg', (142, 150))	('TRAF2', 'Gene', (35, 40))
85879	30294322	Potential causal roles of TRAF2 dysregulation in muscle or T cell tumorigenesis remain to be elucidated.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dysregulation', 'Var', (32, 45))	('tumor', 'Disease', (66, 71))	('muscle', 'CPA', (49, 55))	('TRAF2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
85886	30294322	Importantly, suppression of TRAF2 in cancer cells harboring a TRAF2 copy number gain inhibits proliferation, NF-kappaB activation, anchorage-independent growth, and tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('inhibits', 'NegReg', (85, 93))	('copy number', 'Var', (68, 79))	('cancer', 'Disease', (37, 43))	('anchorage-independent growth', 'CPA', (131, 159))	('gain', 'PosReg', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('activation', 'PosReg', (119, 129))	('proliferation', 'CPA', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('NF-kappaB', 'Protein', (109, 118))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('109', '129'))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('TRAF2', 'Gene', (28, 33))	('TRAF2', 'Gene', (62, 67))	('suppression', 'NegReg', (13, 24))	('tumor', 'Disease', (165, 170))
85888	30294322	Thus, TRAF2 is required for the maintenance of the malignant state in certain cancer cells containing TRAF2 amplification or overexpression, and TRAF2 protein levels also regulate the sensitivity of cancer cells to chemotherapy and radiotherapy.	('amplification', 'Var', (108, 121))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (78, 84))	('regulate', 'Reg', (171, 179))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('TRAF2', 'Gene', (102, 107))	('sensitivity', 'MPA', (184, 195))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
85893	30294322	The frequency of genetic alterations of TRAF3 is generally <6% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 250.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF3', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
85894	30294322	The eight human cancers with relatively higher genetic alterations of TRAF3 are HNSCC (5.4%), lung cancer (5.3%) (TCGA, PanCancer Atlas), cervical cancer (4.7%) (TCGA, PanCancer Atlas), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%) (TCGA, PanCancer Atlas), bladder cancer (3.6%), ovarian cancer (3.4%) (TCGA, PanCancer Atlas), and skin cutaneous melanoma (3.4%) (TCGA, PanCancer Atlas).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('bladder cancer', 'Disease', 'MESH:D001749', (280, 294))	('bladder cancer', 'Disease', (280, 294))	('cancer', 'Disease', (288, 294))	('lung cancer', 'Disease', (94, 105))	('Cancer', 'Phenotype', 'HP:0002664', (265, 271))	('bladder cancer', 'Phenotype', 'HP:0009725', (280, 294))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('stomach cancer', 'Disease', (233, 247))	('HNSCC', 'Disease', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (303, 317))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (354, 377))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('genetic alterations', 'Var', (47, 66))	('skin cutaneous melanoma', 'Disease', (354, 377))	('stomach cancer', 'Disease', 'MESH:D013274', (233, 247))	('stomach cancer', 'Phenotype', 'HP:0012126', (233, 247))	('TRAF3', 'Gene', (70, 75))	('ovarian cancer', 'Disease', (303, 317))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('melanoma', 'Phenotype', 'HP:0002861', (369, 377))	('uterine cancer', 'Phenotype', 'HP:0010784', (186, 200))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (359, 377))	('cancer', 'Disease', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
85895	30294322	Interestingly however, a subgroup among the 279 cases of HNSCC cataloged in TCGA, the human papilloma virus-positive (HPV+) HNSCC tumors, has much higher frequency (22%, 8/36) of deep deletions and truncations of TRAF3 than the HPV- HNSCC tumors (Figure 1B).	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('papilloma', 'Phenotype', 'HP:0012740', (92, 101))	('HPV', 'Species', '10566', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('HPV', 'Species', '10566', (228, 231))	('HNSCC tumors', 'Disease', (233, 245))	('HNSCC tumors', 'Disease', 'MESH:C535575', (233, 245))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('deep deletions', 'Var', (179, 193))	('HNSCC tumors', 'Disease', (124, 136))	('HNSCC tumors', 'Disease', 'MESH:C535575', (124, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('human papilloma virus', 'Species', '10566', (86, 107))	('truncations', 'MPA', (198, 209))
85896	30294322	Notably, although not cataloged in TCGA, deletions and mutations of TRAF3 are recognized as one of the most frequent genetic alterations in a variety of B cell malignancies, including gastric marginal zone lymphoma (MZL, 21%), multiple myeloma (MM, 17%), HL (15%), DLBCL (14.3%), splenic MZL (10%), and Waldenstrom's macroglobulinemia (WM, 5.3%) (Figure 1B).	('B cell malignancies', 'Disease', (153, 172))	('gastric marginal zone lymphoma', 'Disease', (184, 214))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (303, 334))	('TRAF3', 'Gene', (68, 73))	("Waldenstrom's macroglobulinemia", 'Disease', (303, 334))	('gastric marginal zone lymphoma', 'Phenotype', 'HP:0045038', (184, 214))	('multiple myeloma', 'Phenotype', 'HP:0006775', (227, 243))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('splenic MZL', 'Disease', (280, 291))	('mutations', 'Var', (55, 64))	('multiple myeloma', 'Disease', 'MESH:D009101', (227, 243))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (303, 334))	('gastric marginal zone lymphoma', 'Disease', 'MESH:D018442', (184, 214))	('deletions', 'Var', (41, 50))	('B cell malignancies', 'Disease', 'MESH:D015448', (153, 172))	('multiple myeloma', 'Disease', (227, 243))	('HL', 'CellLine', 'CVCL:2492', (255, 257))	('DLBCL', 'Disease', (265, 270))	('MM', 'Disease', 'MESH:D009101', (245, 247))
85898	30294322	Truncation and fusion of TRAF3 are less common but also detected in several different types of human cancers (Figure 1).	('fusion', 'Var', (15, 21))	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('detected', 'Reg', (56, 64))	('cancers', 'Disease', (101, 108))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('TRAF3', 'Gene', (25, 30))
85899	30294322	There are 280 different mutations of TRAF3 detected in human cancers, comprising 90% (253/280) mutations that change the protein sequence of TRAF3 and 10% (27/280) coding silent mutations (Table 1).	('TRAF3', 'Gene', (37, 42))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('protein sequence', 'MPA', (121, 137))	('TRAF3', 'Gene', (141, 146))
85900	30294322	Approximately 43% (108/253) of the coding-altering mutations of TRAF3 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (51, 60))	('coding-altering', 'Reg', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF3', 'Gene', (64, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('patients', 'Species', '9606', (118, 126))
85901	30294322	Five mutation hotspots of TRAF3 are identified in more than 5 cancer patients, specifically N16, N285, K286, R310, and R376 (Figure 3).	('K286', 'Chemical', '-', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('K286', 'Var', (103, 107))	('TRAF3', 'Gene', (26, 31))	('N285', 'Var', (97, 101))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patients', 'Species', '9606', (69, 77))	('R310', 'Var', (109, 113))	('R376', 'Var', (119, 123))	('N16', 'Var', (92, 95))
85902	30294322	TRAF3 mutations at N16 have the highest patient count, including the missense mutation (N16T) identified in 10 patients with HNSCC (COSMIC) and the frameshift deletion (N16fs*3) detected in a patient with splenic MZL.	('mutations at N16', 'Var', (6, 22))	('patient', 'Species', '9606', (40, 47))	('patient', 'Species', '9606', (192, 199))	('frameshift deletion', 'Var', (148, 167))	('TRAF3', 'Gene', (0, 5))	('N16T', 'SUBSTITUTION', 'None', (88, 92))	('N16fs*3', 'Var', (169, 176))	('patient', 'Species', '9606', (111, 118))	('N16T', 'Var', (88, 92))	('patients', 'Species', '9606', (111, 119))
85903	30294322	Mutations at the two consecutive amino acids N285 and K286 of the coiled-coil domain of TRAF3 exhibit the most complex pattern.	('TRAF3', 'Gene', (88, 93))	('coiled-coil domain', 'MPA', (66, 84))	('K286', 'Var', (54, 58))	('K286', 'Chemical', '-', (54, 58))
85904	30294322	N285 contains frameshift deletion (N285fs*38), frameshift insertion (N285fs*13) and missense mutation (N285S) identified in 8 patients with HNSCC, MZL, NPC, CRC, stomach cancer and uterine cancer (TCGA; COSMIC).	('N285fs*38', 'Var', (35, 44))	('cancer', 'Disease', (170, 176))	('stomach cancer', 'Disease', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patients', 'Species', '9606', (126, 134))	('N285S', 'Mutation', 'p.N285S', (103, 108))	('N285fs*38', 'Mutation', 'p.N285fsX38', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('N285fs', 'Mutation', 'p.N285fsX', (69, 75))	('frameshift deletion (N285fs*38', 'Var', (14, 44))	('uterine cancer', 'Phenotype', 'HP:0010784', (181, 195))	('MZL', 'Disease', (147, 150))	('stomach cancer', 'Disease', 'MESH:D013274', (162, 176))	('N285fs', 'Mutation', 'p.N285fsX', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('stomach cancer', 'Phenotype', 'HP:0012126', (162, 176))	('N285S', 'Var', (103, 108))	('NPC', 'Disease', (152, 155))	('HNSCC', 'Disease', (140, 145))	('cancer', 'Disease', (189, 195))	('NPC', 'cellular_component', 'GO:0005643', ('152', '155'))	('N285fs*13', 'Var', (69, 78))	('frameshift insertion (N285fs*13', 'Var', (47, 78))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CRC', 'Disease', (157, 160))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
85905	30294322	Similarly, K286 exhibits frameshift deletion (K286fs*7 or fs*11) and truncation (K286*) detected in six patients with B cell malignancies, including MM, CLL and WM.	('K286', 'Chemical', '-', (81, 85))	('K286*', 'Var', (81, 86))	('B cell malignancies', 'Disease', (118, 137))	('K286', 'Var', (11, 15))	('B cell malignancies', 'Disease', 'MESH:D015448', (118, 137))	('K286', 'Chemical', '-', (11, 15))	('detected', 'Reg', (88, 96))	('K286', 'Chemical', '-', (46, 50))	('K286fs', 'Mutation', 'p.K286fsX', (46, 52))	('CLL', 'Phenotype', 'HP:0005550', (153, 156))	('K286fs*7', 'Var', (46, 54))	('MM', 'Disease', 'MESH:D009101', (149, 151))	('CLL', 'Disease', (153, 156))	('fs*11', 'Gene', (58, 63))	('truncation', 'MPA', (69, 79))	('K286*', 'SUBSTITUTION', 'None', (81, 86))	('patients', 'Species', '9606', (104, 112))
85906	30294322	A third amino acid of the coiled-coil domain, R310, is consistently targeted by truncation (R310*) as detected in 8 patients with DLBCL, MM, HNSCC, cervical cancer and uterine cancer (TCGA).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MM', 'Disease', 'MESH:D009101', (137, 139))	('R310*', 'SUBSTITUTION', 'None', (92, 97))	('HNSCC', 'Disease', (141, 146))	('DLBCL', 'Disease', (130, 135))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('R310*', 'Var', (92, 97))	('cancer', 'Disease', (157, 163))	('detected', 'Reg', (102, 110))	('R310', 'Var', (46, 50))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))
85908	30294322	Many of these truncations, frameshifts and missense mutations have been shown to result in inactivation of TRAF3 by disrupting its interaction with NIK, thereby inducing constitutive NF-kappaB2 activation.	('missense mutations', 'Var', (43, 61))	('inducing', 'Reg', (161, 169))	('NIK', 'Gene', (148, 151))	('NF-kappaB2', 'Gene', '18034', (183, 193))	('activation', 'PosReg', (194, 204))	('frameshifts', 'Var', (27, 38))	('disrupting', 'NegReg', (116, 126))	('inactivation', 'MPA', (91, 103))	('NIK', 'Gene', '9020', (148, 151))	('NIK', 'molecular_function', 'GO:0004704', ('148', '151'))	('NF-kappaB2', 'Gene', (183, 193))	('interaction', 'Interaction', (131, 142))	('TRAF3', 'Gene', (107, 112))
85909	30294322	Thus, most of the recurrent genetic alterations of TRAF3 identified in human cancers cause complete loss or inactivation of the TRAF3 protein.	('TRAF3', 'Gene', (51, 56))	('TRAF3', 'Gene', (128, 133))	('genetic alterations', 'Var', (28, 47))	('complete loss', 'Disease', 'MESH:D003638', (91, 104))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('inactivation', 'NegReg', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('protein', 'Protein', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('complete loss', 'Disease', (91, 104))	('human', 'Species', '9606', (71, 76))
85912	30294322	Similar to TRAF2 and also consistent with the frequent deletions and inactivating mutations of TRAF3 identified in human B cell malignancies (Figure 1B), a tumor suppressive role for TRAF3 in B lymphocytes has been demonstrated by in vivo evidence obtained from mouse models.	('B cell malignancies', 'Disease', (121, 140))	('B cell malignancies', 'Disease', 'MESH:D015448', (121, 140))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('mouse', 'Species', '10090', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('human', 'Species', '9606', (115, 120))	('TRAF3', 'Gene', (95, 100))	('tumor', 'Disease', (156, 161))	('deletions', 'Var', (55, 64))
85918	30294322	Intriguingly, lymphocyte-specific TRAF3 transgenic mice also develop plasmacytosis, autoimmunity, inflammation, and cancers, which are likely caused by hyper-responsiveness of B cells to antigens and TLR agonists.	('autoimmunity', 'Phenotype', 'HP:0002960', (84, 96))	('autoimmunity', 'Disease', (84, 96))	('transgenic mice', 'Species', '10090', (40, 55))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('plasmacytosis', 'Disease', (69, 82))	('plasmacytosis', 'Phenotype', 'HP:0030150', (69, 82))	('TRAF3', 'Gene', (34, 39))	('transgenic', 'Var', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('inflammation', 'Disease', (98, 110))	('autoimmunity', 'Disease', 'MESH:D001327', (84, 96))	('cancers', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('develop', 'PosReg', (61, 68))	('inflammation', 'biological_process', 'GO:0006954', ('98', '110'))
85920	30294322	Interestingly, specific deletion of TRAF3 from myeloid cells (granulocytes, monocytes, and macrophages) leads to spontaneous development of histiocytic sarcomas derived from TRAF3-/- tissue-resident macrophages in aging mice.	('TRAF3-/-', 'Gene', '22031', (174, 182))	('TRAF3-/-', 'Gene', (174, 182))	('TRAF3', 'Gene', (36, 41))	('leads to', 'Reg', (104, 112))	('mice', 'Species', '10090', (220, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (152, 160))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('aging', 'biological_process', 'GO:0007568', ('214', '219'))	('histiocytic sarcomas', 'Disease', (140, 160))	('deletion', 'Var', (24, 32))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (140, 160))
85926	30294322	Transgenic expression of human TLR7/TLR8 in mice deficient for endogenous TLR7/TLR8 drives inflammation and proliferative histiocytosis, which can be reversed by compound deletion of MyD88.	('Transgenic', 'Species', '10090', (0, 10))	('inflammation', 'Disease', 'MESH:D007249', (91, 103))	('compound deletion', 'Var', (162, 179))	('inflammation', 'Disease', (91, 103))	('inflammation', 'biological_process', 'GO:0006954', ('91', '103'))	('human', 'Species', '9606', (25, 30))	('MyD88', 'Gene', (183, 188))	('MyD88', 'Gene', '17874', (183, 188))	('histiocytosis', 'Phenotype', 'HP:0100727', (122, 135))	('TLR7/TLR8', 'Gene', (31, 40))	('proliferative histiocytosis', 'MPA', (108, 135))	('mice', 'Species', '10090', (44, 48))	('drives', 'PosReg', (84, 90))
85927	30294322	Collectively, the above in vivo evidence indicates that TRAF3 is a tumor suppressor in macrophages and that dysregulation of the TLR-MyD88-TRAF3-Dok3 axis in macrophages plays causal roles in the pathogenesis of histiocytic sarcoma.	('tumor', 'Disease', (67, 72))	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('histiocytic sarcoma', 'Disease', (212, 231))	('Dok3', 'Gene', '27261', (145, 149))	('pathogenesis', 'biological_process', 'GO:0009405', ('196', '208'))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('Dok3', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('MyD88', 'Gene', (133, 138))	('dysregulation', 'Var', (108, 121))	('MyD88', 'Gene', '17874', (133, 138))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (212, 231))	('TRAF3', 'Gene', (56, 61))
85928	30294322	However, because histiocytic sarcoma in humans is a rare malignancy with sparse pathologic and cytogenetic data, potential TRAF3 genetic alterations in human histiocytic sarcomas require future investigation.	('malignancy', 'Disease', (57, 67))	('histiocytic sarcoma', 'Disease', (17, 36))	('histiocytic sarcomas', 'Disease', (158, 178))	('sarcomas', 'Phenotype', 'HP:0100242', (170, 178))	('humans', 'Species', '9606', (40, 46))	('TRAF3', 'Gene', (123, 128))	('genetic alterations', 'Var', (129, 148))	('human', 'Species', '9606', (152, 157))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (158, 177))	('histiocytic sarcomas', 'Disease', 'MESH:D054747', (158, 178))	('histiocytic sarcoma', 'Disease', 'MESH:D054747', (17, 36))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma', 'Phenotype', 'HP:0100242', (29, 36))	('human', 'Species', '9606', (40, 45))
85934	30294322	In line with the in vivo data, mutations and deletions of TRAF3 are detected in 2.3% (10/439) of human colon cancers (TCGA, PanCancer Atlas).	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colon cancers', 'Phenotype', 'HP:0003003', (103, 116))	('colon cancers', 'Disease', 'MESH:D015179', (103, 116))	('human', 'Species', '9606', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (45, 54))	('detected', 'Reg', (68, 76))	('TRAF3', 'Gene', (58, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('colon cancers', 'Disease', (103, 116))
85941	30294322	Silencing of TRAF3 in ALCL cells not only results in aberrant activation of the NIK-NF-kappaB2 pathway, but also affects the continued PI3K-AKT and JAK-STAT signaling.	('AKT', 'Gene', (140, 143))	('NF-kappaB2', 'Gene', '18034', (84, 94))	('ALCL', 'Phenotype', 'HP:0012193', (22, 26))	('NIK', 'molecular_function', 'GO:0004704', ('80', '83'))	('NIK', 'Gene', (80, 83))	('affects', 'Reg', (113, 120))	('signaling', 'biological_process', 'GO:0023052', ('157', '166'))	('JAK', 'molecular_function', 'GO:0004713', ('148', '151'))	('TRAF3', 'Gene', (13, 18))	('AKT', 'Gene', '207', (140, 143))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('NF-kappaB2', 'Gene', (84, 94))	('Silencing', 'Var', (0, 9))	('activation', 'PosReg', (62, 72))	('JAK-STAT', 'MPA', (148, 156))	('NIK', 'Gene', '9020', (80, 83))
85946	30294322	The frequency of genetic alterations of TRAF4 is generally <11% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 100.	('cancers', 'Disease', (73, 80))	('TRAF4', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
85947	30294322	The eight human cancers with relatively higher genetic alterations of TRAF4 are pancreatic cancer (10.1%), bladder cancer (7.3%), breast cancer (5.5%), uterine cancer (5.1%) (TCGA, PanCancer Atlas), esophageal cancer (3.2%) (TCGA, Provisional), lung cancer (2.6%), melanoma (2.5%), and ovarian cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('pancreatic cancer', 'Disease', (80, 97))	('TRAF4', 'Gene', (70, 75))	('cancer', 'Disease', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Cancer', 'Phenotype', 'HP:0002664', (318, 324))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('lung cancer', 'Disease', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('uterine cancer', 'Phenotype', 'HP:0010784', (152, 166))	('cancer', 'Disease', (294, 300))	('ovarian cancer', 'Disease', 'MESH:D010051', (286, 300))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (199, 216))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('genetic alterations', 'Var', (47, 66))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('ovarian cancer', 'Disease', (286, 300))	('bladder cancer', 'Disease', (107, 121))	('breast cancer', 'Disease', (130, 143))	('cancer', 'Disease', (115, 121))	('esophageal cancer', 'Disease', (199, 216))	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (286, 300))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))
85948	30294322	Deep deletion, truncation and fusion of TRAF4 are relatively rare in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF4', 'Gene', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Deep deletion', 'Var', (0, 13))
85949	30294322	There are 123 different mutations of TRAF4 detected in human cancers, comprising 85% (105/123) mutations that cause changes in the amino acid sequence of TRAF4 and 15% (18/123) coding silent mutations (Table 1).	('TRAF4', 'Gene', (154, 159))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('changes', 'Reg', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('amino acid sequence', 'MPA', (131, 150))	('silent', 'NegReg', (184, 190))	('TRAF4', 'Gene', (37, 42))
85950	30294322	About 42% (44/105) of the coding-altering mutations of the TRAF4 gene are recurrent and detected in at least two cancer patients, including mostly missense mutations (89%, 39/44), 3 truncations, 1 frameshift deletion, and 1 in frame deletion (Table 1 and Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('frameshift deletion', 'Var', (197, 216))	('TRAF4', 'Gene', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('truncations', 'MPA', (182, 193))	('detected', 'Reg', (88, 96))	('coding-altering', 'Reg', (26, 41))	('cancer', 'Disease', (113, 119))	('missense mutations', 'Var', (147, 165))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (42, 51))
85951	30294322	Only two specific amino acids, R448 and R452 located at the C-terminal TRAF-C domain, are mutated in more than 3 patients (Figure 3).	('R452', 'Var', (40, 44))	('patients', 'Species', '9606', (113, 121))	('R448', 'Var', (31, 35))
85952	30294322	For R448, mixed missense mutations (R448Q or L) and a truncation (R448*) are identified in 4 patients with prostate cancer, uterine cancer, HNSCC, and OSCC.	('prostate cancer', 'Disease', (107, 122))	('cancer', 'Disease', (132, 138))	('R448Q', 'Mutation', 'p.R448Q', (36, 41))	('R448*', 'SUBSTITUTION', 'None', (66, 71))	('patients', 'Species', '9606', (93, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (124, 138))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('R448Q or L', 'Var', (36, 46))	('OSCC', 'Disease', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HNSCC', 'Disease', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('R448*', 'Var', (66, 71))
85953	30294322	For R452, missense mutations (R452W or Q or L) are detected in four patients with uterine, colorectal and lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('detected', 'Reg', (51, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('uterine', 'Disease', (82, 89))	('R452W', 'Var', (30, 35))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (91, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (68, 76))	('lung cancers', 'Phenotype', 'HP:0100526', (106, 118))	('R452', 'Var', (4, 8))	('R452W', 'Mutation', 'p.R452W', (30, 35))
85955	30294322	Available human evidence indicates that gene amplification is the most common TRAF4 genetic alteration in cancers and that TRAF4 expression is ubiquitously elevated in many human cancers.	('TRAF4', 'Gene', (78, 83))	('human', 'Species', '9606', (10, 15))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('gene amplification', 'Var', (40, 58))	('cancers', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
85958	30294322	Interestingly, TRAF4-/- dendritic cells (DCs) derived from the null mice exhibit reduced in vivo and in vitro migration.	('mice', 'Species', '10090', (68, 72))	('TRAF4-/-', 'Var', (15, 23))	('reduced', 'NegReg', (81, 88))
85960	30294322	TRAF4 deficiency substantially diminishes IL-17A-induced ERK5 activation and epidermal hyperplasia in mice.	('TRAF4 deficiency', 'Phenotype', 'HP:0040209', (0, 16))	('mice', 'Species', '10090', (102, 106))	('epidermal hyperplasia', 'Disease', (77, 98))	('TRAF4', 'Gene', (0, 5))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('diminishes', 'NegReg', (31, 41))	('deficiency', 'Var', (6, 16))	('ERK5', 'Protein', (57, 61))	('IL-17', 'molecular_function', 'GO:0030367', ('42', '47'))	('IL-17A-induced', 'MPA', (42, 56))	('epidermal hyperplasia', 'Disease', 'MESH:D006965', (77, 98))
85961	30294322	In the DMBA/TPA-induced skin cancer model, TRAF4-/- mice exhibit remarkably reduced tumor incidence and tumor numbers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('skin cancer', 'Phenotype', 'HP:0008069', (24, 35))	('tumor', 'Disease', (104, 109))	('mice', 'Species', '10090', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('skin cancer', 'Disease', (24, 35))	('tumor', 'Disease', (84, 89))	('reduced', 'NegReg', (76, 83))	('DMBA', 'Chemical', 'MESH:C082386', (7, 11))	('TPA', 'molecular_function', 'GO:0031299', ('12', '15'))	('TPA', 'Chemical', '-', (12, 15))	('skin cancer', 'Disease', 'MESH:D012878', (24, 35))	('TRAF4-/-', 'Var', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
85968	30294322	The frequency of genetic alterations of TRAF5 is generally <13% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 140.	('cancers', 'Disease', (73, 80))	('TRAF5', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('genetic alterations', 'Var', (17, 36))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
85969	30294322	The eight human cancers with relatively higher genetic alterations of TRAF5 are breast cancer (12.2%), liver cancer (8.4%) (TCGA, Provisional), uterine cancer (6.4%) (TCGA, PanCancer Atlas), lung cancer (5.3%) (TCGA, Provisional), ovarian cancer (5.1%) (TCGA, Provisional), melanoma (4.0%) (TCGA, Provisional), esophageal cancer (3.8%) (TCGA, Provisional), and prostate cancer (3.3%).	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('TRAF5', 'Gene', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('uterine cancer', 'Phenotype', 'HP:0010784', (144, 158))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (152, 158))	('cancers', 'Disease', (16, 23))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Disease', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (311, 328))	('ovarian cancer', 'Disease', 'MESH:D010051', (231, 245))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', (109, 115))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', (274, 282))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (370, 376))	('cancer', 'Disease', (196, 202))	('genetic alterations', 'Var', (47, 66))	('esophageal cancer', 'Disease', (311, 328))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (361, 376))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (361, 376))	('ovarian cancer', 'Disease', (231, 245))	('liver cancer', 'Disease', (103, 115))	('lung cancer', 'Disease', (191, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('prostate cancer', 'Disease', (361, 376))	('ovarian cancer', 'Phenotype', 'HP:0100615', (231, 245))
85970	30294322	Deep deletion, truncation and fusion of TRAF5 are rare events in human cancers.	('truncation', 'Var', (15, 25))	('fusion', 'Var', (30, 36))	('TRAF5', 'Gene', (40, 45))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Deep deletion', 'Var', (0, 13))
85971	30294322	There are 188 different mutations of TRAF5 detected in human cancers, comprising 85% (160/188) mutations that alter the amino acid sequence of TRAF5 and 15% (28/188) coding silent mutations (Table 1).	('silent', 'NegReg', (173, 179))	('TRAF5', 'Gene', (143, 148))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('amino acid sequence', 'MPA', (120, 139))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF5', 'Gene', (37, 42))
85972	30294322	Approximately 36% (57/160) of the coding-altering mutations of TRAF5 are recurrent in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (50, 59))	('TRAF5', 'Gene', (63, 68))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('coding-altering', 'Reg', (34, 49))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('recurrent', 'Reg', (73, 82))
85973	30294322	Mutations of three specific amino acids, R164, T232, and A548, are detected in more than three patients (Figure 3).	('A548', 'Var', (57, 61))	('R164', 'Var', (41, 45))	('T232', 'Var', (47, 51))	('patients', 'Species', '9606', (95, 103))
85974	30294322	Complex alterations of R164 of the zinc finger motif, including truncation (R164*) and missense mutations (R164Q or L), are detected in six patients with uterine, colon and bile duct cancers and DLBCL (TCGA).	('R164*', 'Var', (76, 81))	('R164', 'Var', (23, 27))	('detected', 'Reg', (124, 132))	('colon and bile duct cancers', 'Disease', 'MESH:D001650', (163, 190))	('DLBCL', 'Disease', (195, 200))	('truncation', 'MPA', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('uterine', 'Disease', (154, 161))	('missense mutations (R164Q or L', 'Var', (87, 117))	('R164Q', 'Mutation', 'p.R164Q', (107, 112))	('patients', 'Species', '9606', (140, 148))	('R164*', 'SUBSTITUTION', 'None', (76, 81))	('bile duct cancers', 'Phenotype', 'HP:0030153', (173, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
85975	30294322	Another missense mutation of the zinc finger motif, T232M, is detected in four patients with colon, breast, and prostate cancers (TCGA; COSMIC).	('detected', 'Reg', (62, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('breast', 'Disease', (100, 106))	('T232M', 'Var', (52, 57))	('T232M', 'Mutation', 'p.T232M', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancers', 'Phenotype', 'HP:0012125', (112, 128))	('prostate cancers', 'Disease', (112, 128))	('colon', 'Disease', (93, 98))	('patients', 'Species', '9606', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('prostate cancers', 'Disease', 'MESH:D011471', (112, 128))
85976	30294322	Missense mutation A548V of the TRAF-C domain is identified in four patients with uterine, cervical, stomach, and breast cancers (TCGA).	('Missense mutation A548V', 'Var', (0, 23))	('identified', 'Reg', (48, 58))	('breast cancers', 'Disease', (113, 127))	('breast cancers', 'Disease', 'MESH:D001943', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('stomach', 'Disease', (100, 107))	('A548V', 'Var', (18, 23))	('patients', 'Species', '9606', (67, 75))	('uterine', 'Disease', (81, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cervical', 'Disease', (90, 98))	('A548V', 'Mutation', 'p.A548V', (18, 23))	('TRAF-C domain', 'Gene', (31, 44))	('breast cancers', 'Phenotype', 'HP:0003002', (113, 127))
85977	30294322	Although not cataloged in TCGA, TRAF5 mutations are detected in 5% (5/101) of human DLBCL.	('detected', 'Reg', (52, 60))	('mutations', 'Var', (38, 47))	('human', 'Species', '9606', (78, 83))	('TRAF5', 'Gene', (32, 37))	('DLBCL', 'Disease', (84, 89))
85980	30294322	Consistent with human evidence, B cells of TRAF5-/- mice show defects in CD40-induced proliferation and up-regulation of surface molecules and activation markers as well as CD40 plus IL-4-induced Ig production (Table 2).	('up-regulation', 'PosReg', (104, 117))	('CD40', 'Var', (173, 177))	('activation', 'MPA', (143, 153))	('human', 'Species', '9606', (16, 21))	('mice', 'Species', '10090', (52, 56))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('surface molecules', 'MPA', (121, 138))	('CD40-induced', 'Gene', (73, 85))	('IL-4', 'molecular_function', 'GO:0005136', ('183', '187'))	('IL-4', 'Gene', (183, 187))	('defects', 'NegReg', (62, 69))	('IL-4', 'Gene', '16189', (183, 187))
85983	30294322	TRAF5 deficiency reverses the CD40-LMP1-induced enlargement of the spleen and lymph nodes, decreases the serum levels of IL-6 and autoantibodies that are elevated by CD40-LMP1-tg expression, and also inhibits LMP1-mediated JNK activation in B lymphocytes (Table 2).	('LMP1', 'Gene', '17494204', (171, 175))	('enlargement of the spleen', 'Disease', 'MESH:D013163', (48, 73))	('JNK', 'Gene', (223, 226))	('enlargement of the spleen', 'Disease', (48, 73))	('JNK', 'Gene', '5599', (223, 226))	('deficiency', 'Var', (6, 16))	('LMP1', 'Gene', (171, 175))	('elevated', 'PosReg', (154, 162))	('serum levels of IL-6', 'MPA', (105, 125))	('LMP1', 'Gene', '17494204', (209, 213))	('decreases', 'NegReg', (91, 100))	('JNK', 'molecular_function', 'GO:0004705', ('223', '226'))	('LMP1', 'Gene', '17494204', (35, 39))	('LMP1', 'Gene', (209, 213))	('enlargement of the spleen', 'Phenotype', 'HP:0001744', (48, 73))	('IL-6', 'molecular_function', 'GO:0005138', ('121', '125'))	('TRAF5', 'Gene', (0, 5))	('LMP1', 'Gene', (35, 39))	('inhibits', 'NegReg', (200, 208))	('reverses', 'NegReg', (17, 25))
85985	30294322	Additionally, available in vivo evidence indicates the importance of TRAF5 in the survival, proliferation and differentiation of different T cell subsets as detailed in Table 2, suggesting that TRAF5 malfunction may contribute to T cell malignancies.	('malfunction', 'Var', (200, 211))	('T cell malignancies', 'Phenotype', 'HP:0005517', (230, 249))	('T cell malignancies', 'Disease', 'MESH:D018273', (230, 249))	('T cell malignancies', 'Disease', (230, 249))	('contribute', 'Reg', (216, 226))	('TRAF5', 'Gene', (194, 199))
85986	30294322	However, the evidence of TRAF5 alterations in human T cell lymphomas/leukemias is still lacking.	('leukemias', 'Disease', (69, 78))	('alterations', 'Var', (31, 42))	('lymphomas', 'Phenotype', 'HP:0002665', (59, 68))	('T cell lymphomas', 'Disease', 'MESH:D016399', (52, 68))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('T cell lymphomas', 'Disease', (52, 68))	('leukemias', 'Disease', 'MESH:D007938', (69, 78))	('human', 'Species', '9606', (46, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (52, 67))	('TRAF5', 'Gene', (25, 30))	('cell lymphoma', 'Phenotype', 'HP:0012191', (54, 67))	('T cell lymphomas', 'Phenotype', 'HP:0012190', (52, 68))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))
85990	30294322	The frequency of genetic alterations of TRAF6 is generally <7% in human cancers (Figure 1A) based on the TCGA and COSMIC datasets of sample size n > 120.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TRAF6', 'Gene', (40, 45))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
85991	30294322	The eight human cancers with relatively higher genetic alterations of TRAF6 are breast cancer (6.9%), uterine cancer (4.5%) (TCGA, PanCancer Atlas), stomach cancer (4.1%), HNSCC (3.6%), lung cancer (3.4%), bladder cancer (3.1%), sarcoma (3%) (TCGA, Provisional), and ovarian cancer (2.8%) (TCGA, Provisional).	('human', 'Species', '9606', (10, 15))	('TRAF6', 'Gene', (70, 75))	('higher', 'PosReg', (40, 46))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('sarcoma', 'Disease', 'MESH:D012509', (229, 236))	('ovarian cancer', 'Disease', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('sarcoma', 'Disease', (229, 236))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancer', 'Disease', (191, 197))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (214, 220))	('stomach cancer', 'Disease', 'MESH:D013274', (149, 163))	('stomach cancer', 'Phenotype', 'HP:0012126', (149, 163))	('cancer', 'Disease', (16, 22))	('uterine cancer', 'Phenotype', 'HP:0010784', (102, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Disease', (206, 220))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (157, 163))	('genetic alterations', 'Var', (47, 66))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('ovarian cancer', 'Disease', 'MESH:D010051', (267, 281))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HNSCC', 'Disease', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('stomach cancer', 'Disease', (149, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
85992	30294322	Although not listed in TCGA, TRAF6 amplification is recognized as one of the most frequent genomic alterations in human lung cancer (9.2%, 24/261) and OSCC (10%, 2/20).	('amplification', 'Var', (35, 48))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TRAF6', 'Gene', (29, 34))	('human', 'Species', '9606', (114, 119))	('OSCC', 'Disease', (151, 155))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
85994	30294322	TRAF6 overexpression is also identified as a prognostic factor for breast and esophageal cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('overexpression', 'Var', (6, 20))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (67, 96))	('TRAF6', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
85995	30294322	Deep deletion of TRAF6 is less common but also detected in several different types of human cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('detected', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Deep deletion', 'Var', (0, 13))	('TRAF6', 'Gene', (17, 22))
85996	30294322	Truncation and fusion of TRAF6 are rare in human cancers.	('fusion', 'Var', (15, 21))	('TRAF6', 'Gene', (25, 30))	('Truncation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('human', 'Species', '9606', (43, 48))
85997	30294322	There are 178 different mutations of TRAF6 detected in human cancers, comprising 85% (152/178) mutations that alter the protein sequence of TRAF6 and 15% (26/178) coding silent mutations (Table 1).	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('protein sequence', 'MPA', (120, 136))	('human', 'Species', '9606', (55, 60))	('TRAF6', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRAF6', 'Gene', (140, 145))
85998	30294322	Only 27% (41/152) of the coding-altering mutations of TRAF6 are recurrently detected in at least two cancer patients.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('TRAF6', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('coding-altering', 'Reg', (25, 40))
85999	30294322	Mutations of only two specific amino acids, R335 and P398, are detected in more than three patients (Figure 3).	('P398', 'Var', (53, 57))	('patients', 'Species', '9606', (91, 99))	('R335', 'Var', (44, 48))
86000	30294322	A truncation (R335*) and missense mutation (R335Q) at R335 within the coiled-coil domain of TRAF6 are detected in five patients with colon and uterine cancers (TCGA).	('uterine cancers', 'Phenotype', 'HP:0010784', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('R335*', 'SUBSTITUTION', 'None', (14, 19))	('patients', 'Species', '9606', (119, 127))	('TRAF6', 'Gene', (92, 97))	('colon and uterine cancers', 'Disease', 'MESH:D015179', (133, 158))	('detected', 'Reg', (102, 110))	('R335Q', 'Mutation', 'p.R335Q', (44, 49))	('uterine cancer', 'Phenotype', 'HP:0010784', (143, 157))	('R335Q', 'Var', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('R335*', 'Var', (14, 19))
86002	30294322	Functional significance of these TRAF6 recurrent mutations in cancer pathogenesis remains to be elucidated.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TRAF6', 'Gene', (33, 38))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('pathogenesis', 'biological_process', 'GO:0009405', ('69', '81'))
86004	30294322	However, available in vivo evidence supports potential contributions of TRAF6 dysregulation in tumorigenesis.	('dysregulation', 'Var', (78, 91))	('TRAF6', 'Gene', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
86005	30294322	Consistent with the genetic alterations (mainly amplification and mutation) and frequent overexpression of TRAF6 detected in human epithelial cancers such as breast cancer and uterine cancer (Figure 1A), deletion of TRAF6 in mice results in loss of NF-kappaB activity in epithelia and vasculature during mouse development (Table 2).	('cancer', 'Disease', (184, 190))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('uterine cancer', 'Phenotype', 'HP:0010784', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('breast cancer', 'Disease', (158, 171))	('NF-kappaB', 'Protein', (249, 258))	('mice', 'Species', '10090', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('TRAF6', 'Gene', (216, 221))	('cancer', 'Disease', (142, 148))	('loss', 'NegReg', (241, 245))	('cancers', 'Disease', (142, 149))	('deletion', 'Var', (204, 212))	('activity', 'MPA', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (125, 130))	('cancer', 'Disease', (165, 171))	('mouse', 'Species', '10090', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
86007	30294322	In line with the in vivo data, knockdown of TRAF6 or inhibition of TRAF6 E3 ligase activity suppresses the survival, proliferation, migration, and metastasis of many human epithelial cancers, including breast, lung, liver, and colon cancers as well as HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colon cancers', 'Disease', 'MESH:D015179', (227, 240))	('colon cancers', 'Disease', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('inhibition', 'NegReg', (53, 63))	('proliferation', 'CPA', (117, 130))	('human', 'Species', '9606', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('TRAF6', 'Gene', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('ligase activity', 'molecular_function', 'GO:0016874', ('76', '91'))	('breast', 'Disease', (202, 208))	('liver', 'Disease', (216, 221))	('migration', 'CPA', (132, 141))	('survival', 'CPA', (107, 115))	('HNSCC', 'Disease', (252, 257))	('metastasis', 'CPA', (147, 157))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('activity', 'MPA', (83, 91))	('suppresses', 'NegReg', (92, 102))	('lung', 'Disease', (210, 214))	('colon cancers', 'Phenotype', 'HP:0003003', (227, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('cancers', 'Disease', (233, 240))	('knockdown', 'Var', (31, 40))
86009	30294322	Hematopoietic-specific deletion of TRAF6 in mice leads to decreased tonic IKKbeta-NF-kappaB activation, impaired hematopoietic stem cell (HSC) self-renewal and loss of hematopoietic stem/progenitor cells (HSPCs) in the bone marrow (BM) (Table 2).	('impaired hematopoietic', 'Disease', (104, 126))	('tonic', 'MPA', (68, 73))	('IKKbeta-NF-kappaB', 'Protein', (74, 91))	('loss', 'NegReg', (160, 164))	('TRAF6', 'Gene', (35, 40))	('deletion', 'Var', (23, 31))	('decreased', 'NegReg', (58, 67))	('impaired hematopoietic', 'Disease', 'MESH:D019337', (104, 126))	('HSC', 'cellular_component', 'GO:0035301', ('138', '141'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('82', '102'))	('activation', 'MPA', (92, 102))	('mice', 'Species', '10090', (44, 48))
86011	30294322	In the lymphoid lineage, TRAF6 mutations have been detected in 2.1% human DLBCL (TCGA) and 2.4% human cutaneous T cell lymphoma (CTCL).	('detected', 'Reg', (51, 59))	('mutations', 'Var', (31, 40))	('human', 'Species', '9606', (68, 73))	('TRAF6', 'Gene', (25, 30))	('human', 'Species', '9606', (96, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (119, 127))	('cutaneous T cell lymphoma', 'Disease', 'MESH:D016410', (102, 127))	('cutaneous T cell lymphoma', 'Disease', (102, 127))	('cell lymphoma', 'Phenotype', 'HP:0012191', (114, 127))	('cutaneous T cell lymphoma', 'Phenotype', 'HP:0012192', (102, 127))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (112, 127))	('CTCL', 'Phenotype', 'HP:0012192', (129, 133))
86016	30294322	T-TRAF6-/- mice also exhibit increased Th17 differentiation due to enhanced sensitivity of CD4 T cells to TGFbeta signaling, but have defects in generating CD8 memory T cells caused by defective AMPK activation in activated CD8 T cells.	('defects', 'NegReg', (134, 141))	('defective', 'NegReg', (185, 194))	('increased', 'PosReg', (29, 38))	('memory T', 'Disease', 'MESH:D008569', (160, 168))	('CD4', 'Gene', '920', (91, 94))	('AMPK', 'molecular_function', 'GO:0004691', ('195', '199'))	('AMPK activation', 'MPA', (195, 210))	('CD8', 'Gene', (224, 227))	('CD4', 'Gene', (91, 94))	('Th17 differentiation', 'CPA', (39, 59))	('CD8', 'Gene', '925', (156, 159))	('memory T', 'Disease', (160, 168))	('AMPK', 'molecular_function', 'GO:0047322', ('195', '199'))	('mice', 'Species', '10090', (11, 15))	('memory', 'biological_process', 'GO:0007613', ('160', '166'))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('T-TRAF6-/-', 'Var', (0, 10))	('sensitivity', 'MPA', (76, 87))	('CD8', 'Gene', '925', (224, 227))	('CD8', 'Gene', (156, 159))	('AMPK', 'molecular_function', 'GO:0050405', ('195', '199'))	('enhanced', 'PosReg', (67, 75))
86019	30294322	Furthermore, inhibition of the IRAK1/4-TRAF6 axis sensitizes human T cell ALL (T-ALL) to chemotherapies.	('IRAK1', 'Gene', '3654', (31, 36))	('IRAK1', 'Gene', (31, 36))	('inhibition', 'Var', (13, 23))	('sensitizes', 'Reg', (50, 60))	('T cell ALL (T-ALL)', 'Disease', 'MESH:D054218', (67, 85))	('human', 'Species', '9606', (61, 66))
86023	30294322	In skeletal muscle, TRAF6 deficiency prevents muscle loss and cancer cachexia in response to transplanted tumor growth, improves regeneration of myofibers upon injury and reduces skeletal muscle atrophy upon starvation through regulating NF-kappaB activation/ubiquitin-proteasome/autophagy-lysosomal systems, Akt/FoxO3a/AMPK activation and Notch signaling, respectively.	('Akt', 'Gene', (309, 312))	('muscle loss', 'Disease', 'MESH:D009133', (46, 57))	('AMPK', 'molecular_function', 'GO:0050405', ('320', '324'))	('regeneration of myofibers', 'CPA', (129, 154))	('muscle atrophy', 'Disease', 'MESH:D009133', (188, 202))	('skeletal muscle atrophy', 'Phenotype', 'HP:0003202', (179, 202))	('injury', 'Disease', 'MESH:D014947', (160, 166))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('238', '258'))	('Akt', 'Gene', '207', (309, 312))	('TRAF6', 'Gene', (20, 25))	('tumor', 'Disease', (106, 111))	('FoxO3a', 'Gene', (313, 319))	('proteasome', 'molecular_function', 'GO:0004299', ('269', '279'))	('AMPK', 'molecular_function', 'GO:0004691', ('320', '324'))	('muscle loss', 'Disease', (46, 57))	('autophagy', 'biological_process', 'GO:0016236', ('280', '289'))	('regeneration', 'biological_process', 'GO:0031099', ('129', '141'))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('regulating', 'Reg', (227, 237))	('signaling', 'biological_process', 'GO:0023052', ('346', '355'))	('proteasome', 'cellular_component', 'GO:0000502', ('269', '279'))	('FoxO3a', 'Gene', '2309', (313, 319))	('muscle atrophy', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cachexia', 'Phenotype', 'HP:0004326', (69, 77))	('cancer cachexia', 'Disease', (62, 77))	('AMPK', 'molecular_function', 'GO:0047322', ('320', '324'))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('autophagy', 'biological_process', 'GO:0006914', ('280', '289'))	('deficiency', 'Var', (26, 36))	('ubiquitin', 'molecular_function', 'GO:0031386', ('259', '268'))	('skeletal muscle atrophy', 'biological_process', 'GO:0014732', ('179', '202'))	('cancer cachexia', 'Disease', 'MESH:D002100', (62, 77))	('NF-kappaB', 'Protein', (238, 247))	('improves', 'PosReg', (120, 128))	('injury', 'Disease', (160, 166))	('muscle loss', 'Phenotype', 'HP:0003202', (46, 57))	('reduces', 'NegReg', (171, 178))
86024	30294322	In line with the mouse data, genetic alterations of TRAF6, including amplification, mutation and deletion, are detected in 1% of human glioblastoma and 3% of human sarcoma (TCGA).	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('TRAF6', 'Gene', (52, 57))	('detected', 'Reg', (111, 119))	('mouse', 'Species', '10090', (17, 22))	('human', 'Species', '9606', (158, 163))	('amplification', 'MPA', (69, 82))	('sarcoma', 'Disease', 'MESH:D012509', (164, 171))	('human', 'Species', '9606', (129, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('glioblastoma', 'Disease', (135, 147))	('sarcoma', 'Disease', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (164, 171))	('deletion', 'Var', (97, 105))	('mutation', 'Var', (84, 92))
86028	30294322	Interestingly, the importance of TRAF6-dependent oncogenic pathways in human cancers is also underscored by the findings that TRAF6 mRNA is the direct target of tumor suppressive mi-RNAs, including miR-146a, and miR-141-3p.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miR-146a', 'Var', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mi-RNAs', 'Var', (179, 186))	('miR-141-3p', 'Var', (212, 222))	('TRAF6', 'Gene', (126, 131))	('tumor', 'Disease', (161, 166))	('human', 'Species', '9606', (71, 76))
86035	30294322	The frequency of genetic alterations of TRAF7 is generally <7% in human cancers (Figure 1A) according to the TCGA and COSMIC datasets of sample size n > 150.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('TRAF7', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('genetic alterations', 'Var', (17, 36))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
86036	30294322	The eight human cancers with relatively higher genetic alterations of TRAF7 are breast cancer (6%), prostate cancer (5.1%), stomach cancer (4.8%) (8), sarcoma (3.8%) (TCGA, Provisional), esophageal cancer (3.3%) (TCGA, PanCancer Atlas), uterine cancer (3.2%) (TCGA, PanCancer Atlas), melanoma (3.1%) (TCGA, PanCancer Atlas), and liver cancer (2.4%) (TCGA, PanCancer Atlas).	('human', 'Species', '9606', (10, 15))	('higher', 'PosReg', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (335, 341))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('stomach cancer', 'Disease', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (359, 365))	('breast cancer', 'Disease', (80, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (329, 341))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('TRAF7', 'Gene', (70, 75))	('sarcoma', 'Phenotype', 'HP:0100242', (151, 158))	('liver cancer', 'Disease', (329, 341))	('cancers', 'Disease', (16, 23))	('cancer', 'Disease', (198, 204))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('cancer', 'Disease', (16, 22))	('melanoma', 'Disease', (284, 292))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophageal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Phenotype', 'HP:0002664', (310, 316))	('uterine cancer', 'Phenotype', 'HP:0010784', (237, 251))	('cancer', 'Disease', (87, 93))	('stomach cancer', 'Disease', 'MESH:D013274', (124, 138))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('stomach cancer', 'Phenotype', 'HP:0012126', (124, 138))	('sarcoma', 'Disease', (151, 158))	('cancer', 'Disease', (245, 251))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('genetic alterations', 'Var', (47, 66))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (132, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('prostate cancer', 'Disease', (100, 115))	('sarcoma', 'Disease', 'MESH:D012509', (151, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('liver cancer', 'Disease', 'MESH:D006528', (329, 341))
86037	30294322	However, it should be noted that although not yet cataloged in TCGA, the rate of TRAF7 mutation is overwhelmingly high in patients with adenomatoid tumors of the male and female genital tracts (100%, 31/31), secretory meningiomas (97%, 29/30), intraneural perineuriomas (62.5%, 10/16), and meningiomas 23% (182/775) (Figure 1B).	('meningiomas', 'Disease', 'MESH:D008579', (290, 301))	('meningiomas', 'Disease', 'MESH:D008579', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('meningiomas', 'Phenotype', 'HP:0002858', (290, 301))	('meningioma', 'Phenotype', 'HP:0002858', (218, 228))	('intraneural perineuriomas', 'Disease', (244, 269))	('meningiomas', 'Phenotype', 'HP:0002858', (218, 229))	('meningioma', 'Phenotype', 'HP:0002858', (290, 300))	('TRAF7', 'Gene', (81, 86))	('high', 'Reg', (114, 118))	('meningiomas', 'Disease', (290, 301))	('patients', 'Species', '9606', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('meningiomas', 'Disease', (218, 229))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (136, 154))	('mutation', 'Var', (87, 95))	('adenomatoid tumors', 'Disease', (136, 154))	('intraneural perineuriomas', 'Disease', 'MESH:D018317', (244, 269))
86038	30294322	In particular, high frequencies (15-26%) of TRAF7 mutations has been reproducibly detected in multiple studies, and knowledge of TRAF7 mutations has contributed significantly to improving the diagnosis, classification, prognosis, and treatment of patients with meningiomas.	('meningiomas', 'Disease', (261, 272))	('TRAF7', 'Gene', (129, 134))	('mutations', 'Var', (50, 59))	('meningiomas', 'Disease', 'MESH:D008579', (261, 272))	('meningiomas', 'Phenotype', 'HP:0002858', (261, 272))	('TRAF7', 'Gene', (44, 49))	('improving', 'PosReg', (178, 187))	('patients', 'Species', '9606', (247, 255))	('meningioma', 'Phenotype', 'HP:0002858', (261, 271))
86039	30294322	Additionally, deletion of TRAF7 is detected in 67% (18/27) of malignant mesothelioma patients' malignant cells in pleural fluids.	('detected', 'Reg', (35, 43))	('TRAF7', 'Gene', (26, 31))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (62, 84))	('patients', 'Species', '9606', (85, 93))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (62, 84))	('deletion', 'Var', (14, 22))	('malignant mesothelioma', 'Disease', (62, 84))
86040	30294322	Truncation and fusion of TRAF7 are rarely detected in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('Truncation', 'Var', (0, 10))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('TRAF7', 'Gene', (25, 30))
86042	30294322	Over half (53%, 174/326) of the TRAF7 coding-altering mutations are recurrently detected in at least two cancer patients.	('TRAF7', 'Gene', (32, 37))	('cancer', 'Disease', (105, 111))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('coding-altering', 'Reg', (38, 53))
86043	30294322	Of particular interest, missense mutations of six specific amino acids located within the C-terminal WD40 repeats, N520, H521, G536, S561, K615, and R641, are identified as mutation hotspots of TRAF7 detected in more than 15 cancer patients (Figure 3).	('H521', 'Var', (121, 125))	('R641', 'Var', (149, 153))	('TRAF7', 'Gene', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('missense', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('G536', 'Var', (127, 131))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Disease', (225, 231))	('N520', 'Var', (115, 119))	('S561', 'Var', (133, 137))	('K615', 'Var', (139, 143))
86044	30294322	N520 mutations (N520S, H, Y, or T) are found in 31 patients with meningioma, mesothelioma, sarcoma and colon cancer.	('meningioma', 'Disease', 'MESH:D008579', (65, 75))	('mesothelioma', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('N520', 'Gene', (0, 4))	('mesothelioma', 'Disease', 'MESH:D008654', (77, 89))	('found', 'Reg', (39, 44))	('sarcoma and colon cancer', 'Disease', 'MESH:D015179', (91, 115))	('N520S', 'Mutation', 'p.N520S', (16, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('meningioma', 'Phenotype', 'HP:0002858', (65, 75))	('patients', 'Species', '9606', (51, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('meningioma', 'Disease', (65, 75))	('N520S', 'Var', (16, 21))
86045	30294322	Mutations of the next amino acid H521 (H521R or N) are identified in 15 patients with adenomatoid tumor, perineurioma, and meningioma.	('H521', 'Gene', (33, 37))	('perineurioma', 'Disease', 'MESH:D018317', (105, 117))	('meningioma', 'Disease', (123, 133))	('H521R', 'Mutation', 'p.H521R', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Mutations', 'Var', (0, 9))	('meningioma', 'Disease', 'MESH:D008579', (123, 133))	('meningioma', 'Phenotype', 'HP:0002858', (123, 133))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (86, 103))	('adenomatoid tumor', 'Disease', (86, 103))	('perineurioma', 'Disease', (105, 117))	('patients', 'Species', '9606', (72, 80))
86046	30294322	G536 mutations (G536S or V) are detected in 16 patients with meningioma, pancreatic cancer, mesothelioma and stomach cancer.	('meningioma', 'Disease', (61, 71))	('pancreatic cancer', 'Disease', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pancreatic cancer', 'Disease', 'MESH:D010190', (73, 90))	('G536', 'Var', (0, 4))	('stomach cancer', 'Phenotype', 'HP:0012126', (109, 123))	('patients', 'Species', '9606', (47, 55))	('meningioma', 'Phenotype', 'HP:0002858', (61, 71))	('detected', 'Reg', (32, 40))	('meningioma', 'Disease', 'MESH:D008579', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('G536S', 'Mutation', 'p.G536S', (16, 21))	('mesothelioma and stomach cancer', 'Disease', 'MESH:D013274', (92, 123))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (73, 90))
86047	30294322	S561 mutations (S561R, N or T) are identified in 19 patients with adenomatoid tumor, perineurioma and meningioma.	('S561R', 'Mutation', 'p.S561R', (16, 21))	('perineurioma and meningioma', 'Disease', 'MESH:D018317', (85, 112))	('S561', 'Gene', (0, 4))	('meningioma', 'Phenotype', 'HP:0002858', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('adenomatoid tumor', 'Disease', 'MESH:D018254', (66, 83))	('adenomatoid tumor', 'Disease', (66, 83))	('S561R', 'Var', (16, 21))	('patients', 'Species', '9606', (52, 60))
86048	30294322	K615E mutations are detected in 15 patients with meningioma and OSCC.	('detected', 'Reg', (20, 28))	('meningioma', 'Disease', 'MESH:D008579', (49, 59))	('K615E', 'Mutation', 'p.K615E', (0, 5))	('OSCC', 'Disease', (64, 68))	('meningioma', 'Disease', (49, 59))	('patients', 'Species', '9606', (35, 43))	('meningioma', 'Phenotype', 'HP:0002858', (49, 59))	('K615E', 'Var', (0, 5))
86049	30294322	R641 mutations (R641H, C, P, or L) are detected in 24 patients with uterine, bile duct, colon, stomach and lung cancers and meningioma (TCGA, PanCancer Atlas).	('colon', 'Disease', (88, 93))	('meningioma', 'Disease', 'MESH:D008579', (124, 134))	('meningioma', 'Phenotype', 'HP:0002858', (124, 134))	('bile duct', 'Disease', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('patients', 'Species', '9606', (54, 62))	('lung cancers', 'Disease', (107, 119))	('R641H', 'Mutation', 'p.R641H', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('R641H', 'Var', (16, 21))	('detected', 'Reg', (39, 47))	('stomach', 'Disease', (95, 102))	('uterine', 'Disease', (68, 75))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('meningioma', 'Disease', (124, 134))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))
86050	30294322	Although the functional significance of most TRAF7 mutations is currently unclear, the exceptionally high recurrence and clustering of missense mutations implicate TRAF7 malfunction as a critical pathogenic event in relevant human cancers.	('TRAF7', 'Gene', (45, 50))	('mutations', 'Var', (51, 60))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Disease', (231, 238))	('human', 'Species', '9606', (225, 230))	('TRAF7', 'Gene', (164, 169))	('missense mutations', 'Var', (135, 153))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
86054	30294322	recently reported that de novo missense mutations in TRAF7 cause developmental abnormalities and other clinical symptoms in seven unrelated patients, including developmental delay (5/5), congenital heart defects (6/7), limb and digital anomalies (7/7), and dysmorphic facial features (7/7).	('developmental abnormalities', 'Disease', 'MESH:D006130', (65, 92))	('developmental delay', 'Phenotype', 'HP:0001263', (160, 179))	('developmental delay', 'Disease', (160, 179))	('dysmorphic facial features', 'Phenotype', 'HP:0001999', (257, 283))	('TRAF7', 'Gene', (53, 58))	('congenital heart defects', 'Disease', 'MESH:D006330', (187, 211))	('dysmorphic facial', 'Disease', 'None', (257, 274))	('cause', 'Reg', (59, 64))	('heart defects', 'Phenotype', 'HP:0030680', (198, 211))	('missense mutations', 'Var', (31, 49))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (65, 92))	('patients', 'Species', '9606', (140, 148))	('developmental abnormalities', 'Disease', (65, 92))	('congenital heart defects', 'Disease', (187, 211))	('dysmorphic facial', 'Disease', (257, 274))	('congenital heart defects', 'Phenotype', 'HP:0001627', (187, 211))	('digital anomalies', 'Phenotype', 'HP:0011297', (228, 245))
86055	30294322	TRAF7 mutations identified in this study include a recurrent R655Q mutation found in four patients, and another 3 single mutations each identified in one patient, including K346E, R371G, and T601A.	('R371G', 'Var', (180, 185))	('R655Q', 'Mutation', 'p.R655Q', (61, 66))	('R371G', 'Mutation', 'p.R371G', (180, 185))	('patient', 'Species', '9606', (154, 161))	('T601A', 'Var', (191, 196))	('K346E', 'Mutation', 'p.K346E', (173, 178))	('T601A', 'Mutation', 'c.601T>A', (191, 196))	('K346E', 'Var', (173, 178))	('TRAF7', 'Gene', (0, 5))	('patient', 'Species', '9606', (90, 97))	('patients', 'Species', '9606', (90, 98))	('R655Q', 'Var', (61, 66))
86056	30294322	Interestingly, R371 recurrent mutations are also detected in human cancers (Figure 3).	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('detected', 'Reg', (49, 57))	('cancers', 'Disease', (67, 74))	('R371 recurrent', 'Var', (15, 29))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))
86057	30294322	K346 is a ubiquitination site of TRAF7.	('K346', 'Chemical', '-', (0, 4))	('TRAF7', 'Gene', (33, 38))	('K346', 'Var', (0, 4))
86058	30294322	Both K346 and R371 are located in the coiled-coil domain of TRAF7 that is important for TRAF7 homodimerization.	('K346', 'Chemical', '-', (5, 9))	('R371', 'Var', (14, 18))	('K346', 'Var', (5, 9))	('TRAF7', 'Gene', (60, 65))
86059	30294322	The recurrent R655Q mutation has also been previously identified as a de novo event in an autism patient.	('autism', 'Phenotype', 'HP:0000717', (90, 96))	('autism', 'Disease', 'MESH:D001321', (90, 96))	('R655Q', 'Var', (14, 19))	('autism', 'Disease', (90, 96))	('R655Q', 'Mutation', 'p.R655Q', (14, 19))	('patient', 'Species', '9606', (97, 104))
86060	30294322	Both T601 and R665 are located in the C-terminal WD40 repeats of TRAF7, which contain most mutation hotspots of TRAF7 detected in human cancers (Figure 3) and are known to mediate the interaction of TRAF7 with MEKK3 or c-Myb.	('c-Myb', 'Gene', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('MEKK3', 'Protein', (210, 215))	('MEKK3', 'molecular_function', 'GO:0004709', ('210', '215'))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('TRAF7', 'Gene', (112, 117))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('T601', 'Var', (5, 9))	('TRAF7', 'Gene', (65, 70))	('interaction', 'Interaction', (184, 195))	('R665', 'Var', (14, 18))	('c-Myb', 'Gene', '4602', (219, 224))	('human', 'Species', '9606', (130, 135))
86061	30294322	further revealed that transfection of the R665Q, T601A, or R371G mutants of TRAF7 into HEK293T cells results in significantly reduced levels of ERK1/2 phosphorylation, both basal and in response to TNFalpha signaling.	('TRAF7', 'Gene', (76, 81))	('HEK293T', 'CellLine', 'CVCL:0063', (87, 94))	('ERK1/2', 'Gene', (144, 150))	('T601A', 'Mutation', 'c.601T>A', (49, 54))	('ERK1/2', 'Gene', '5595;5594', (144, 150))	('R665Q', 'Var', (42, 47))	('phosphorylation', 'MPA', (151, 166))	('signaling', 'biological_process', 'GO:0023052', ('207', '216'))	('ERK1', 'molecular_function', 'GO:0004707', ('144', '148'))	('R665Q', 'Mutation', 'p.R665Q', (42, 47))	('R371G', 'Var', (59, 64))	('T601A', 'Var', (49, 54))	('R371G', 'Mutation', 'p.R371G', (59, 64))	('reduced', 'NegReg', (126, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('151', '166'))
86062	30294322	Consistent with this biochemical evidence, conditional ERK2-/- mice show a phenotype mirroring that observed in the seven patients with TRAF7 mutations, including craniofacial abnormalities, cardiovascular malformations and limb defects.	('mutations', 'Var', (142, 151))	('ERK2', 'molecular_function', 'GO:0004707', ('55', '59'))	('mice', 'Species', '10090', (63, 67))	('ERK2', 'Gene', '26413', (55, 59))	('TRAF7', 'Gene', (136, 141))	('patients', 'Species', '9606', (122, 130))	('ERK2', 'Gene', (55, 59))	('cardiovascular malformations', 'Phenotype', 'HP:0030680', (191, 219))	('craniofacial abnormalities', 'Disease', (163, 189))	('craniofacial abnormalities', 'Disease', 'MESH:D019465', (163, 189))	('cardiovascular malformations and limb defects', 'Disease', 'MESH:D018376', (191, 236))
86063	30294322	These highly interesting findings warrant further investigation of the in vivo functions of TRAF7 mutations in cancer pathogenesis using animal models.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TRAF7', 'Gene', (92, 97))	('mutations', 'Var', (98, 107))	('pathogenesis', 'biological_process', 'GO:0009405', ('118', '130'))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
86064	30294322	In addition to the above TRAF7-ERK1/2 pathway revealed by studying TRAF7 mutants of patients with developmental defects, the following TRAF7 signaling pathways have been proposed based on in vitro studies.	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('ERK1/2', 'Gene', (31, 37))	('patients', 'Species', '9606', (84, 92))	('mutants', 'Var', (73, 80))	('TRAF7', 'Gene', (67, 72))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('developmental defects', 'Disease', 'MESH:D009436', (98, 119))	('ERK1', 'molecular_function', 'GO:0004707', ('31', '35'))	('developmental defects', 'Disease', (98, 119))
86065	30294322	(1) Transfection of tumor-derived TRAF7 mutants (H521R, Y538S, or S561R) but not WT TRAF7 in 293T cells causes increased phosphorylation of RelA and expression of the NF-kappaB target gene L1CAM, which is also elevated in adenomatoid tumors.	('tumor', 'Disease', (234, 239))	('293T', 'CellLine', 'CVCL:0063', (93, 97))	('RelA', 'Gene', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('H521R', 'Mutation', 'p.H521R', (49, 54))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('L1CAM', 'Gene', '3897', (189, 194))	('H521R', 'Var', (49, 54))	('S561R', 'Mutation', 'p.S561R', (66, 71))	('RelA', 'Gene', '5970', (140, 144))	('Y538S', 'Mutation', 'p.Y538S', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (222, 240))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('expression', 'MPA', (149, 159))	('Y538S', 'Var', (56, 61))	('L1CAM', 'Gene', (189, 194))	('TRAF7', 'Gene', (34, 39))	('increased', 'PosReg', (111, 120))	('phosphorylation', 'MPA', (121, 136))	('adenomatoid tumors', 'Disease', (222, 240))	('tumor', 'Disease', (20, 25))
86066	30294322	(2) Overexpression of TRAF7 or TNFalpha induces caspase-dependent apoptosis in HEK293 and HeLa cells via the TRAF7-MEKK3-NF-kappaB/p38/JNK-AP1/CHOP pathway, in which TRAF7 interacts with MEKK3 and potentiates the kinase activity of MEKK3.	('induces', 'Reg', (40, 47))	('CHOP', 'Gene', '1649', (143, 147))	('JNK', 'molecular_function', 'GO:0004705', ('135', '138'))	('MEKK3', 'molecular_function', 'GO:0004709', ('187', '192'))	('kinase activity', 'molecular_function', 'GO:0016301', ('213', '228'))	('TNFalpha', 'Gene', (31, 39))	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('MEKK3', 'Protein', (187, 192))	('JNK', 'Gene', (135, 138))	('TRAF7', 'Var', (22, 27))	('potentiates', 'PosReg', (197, 208))	('p38', 'Gene', (131, 134))	('CHOP', 'Gene', (143, 147))	('JNK', 'Gene', '5599', (135, 138))	('HEK293', 'CellLine', 'CVCL:0045', (79, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('AP1', 'cellular_component', 'GO:0005907', ('139', '142'))	('MEKK3', 'molecular_function', 'GO:0004709', ('115', '120'))	('MEKK3', 'molecular_function', 'GO:0004709', ('232', '237'))	('p38', 'Gene', '5594', (131, 134))	('AP1', 'Gene', (139, 142))	('MEKK3', 'Enzyme', (232, 237))	('AP1', 'Gene', '2353', (139, 142))	('caspase-dependent apoptosis', 'CPA', (48, 75))	('kinase activity', 'MPA', (213, 228))	('interacts', 'Interaction', (172, 181))
86075	30294322	TRAF7 mutations or downregulated protein levels may lead to aberrant NF-kappaB activation or altered signaling of ERK1/2, p38, JNK, c-FLIP, c-Myb, or p53 to drive tumorigenesis.	('NF-kappaB', 'Protein', (69, 78))	('ERK1', 'molecular_function', 'GO:0004707', ('114', '118'))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('c-FLIP', 'Gene', '8837', (132, 138))	('ERK1/2', 'Gene', (114, 120))	('p53', 'Gene', '7157', (150, 153))	('ERK1/2', 'Gene', '5595;5594', (114, 120))	('tumor', 'Disease', (163, 168))	('c-Myb', 'Gene', '4602', (140, 145))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('69', '89'))	('c-Myb', 'Gene', (140, 145))	('JNK', 'Gene', (127, 130))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('JNK', 'Gene', '5599', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('p53', 'Gene', (150, 153))	('activation', 'PosReg', (79, 89))	('p38', 'Gene', (122, 125))	('lead', 'Reg', (52, 56))	('mutations', 'Var', (6, 15))	('drive', 'PosReg', (157, 162))	('altered', 'Reg', (93, 100))	('c-FLIP', 'Gene', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('JNK', 'molecular_function', 'GO:0004705', ('127', '130'))	('signaling', 'MPA', (101, 110))	('p38', 'Gene', '5594', (122, 125))	('TRAF7', 'Gene', (0, 5))	('downregulated', 'NegReg', (19, 32))
86076	30294322	Further studies are required to clarify the roles and mechanisms of TRAF7 alterations in cancer pathogenesis.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('TRAF7', 'Gene', (68, 73))	('alterations', 'Var', (74, 85))	('pathogenesis', 'biological_process', 'GO:0009405', ('96', '108'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
86078	30294322	Although the frequency of the genetic alterations of each TRAF is generally low (usually <5%), their combined rate is substantially increased to 10-35% in many types of human cancers (Figure 4) (TCGA).	('genetic alterations', 'Var', (30, 49))	('increased', 'PosReg', (132, 141))	('human', 'Species', '9606', (169, 174))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
86079	30294322	For example, the combined frequency of gene amplification of all seven TRAFs is 35% (709/2015) in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('gene amplification', 'Var', (39, 57))
86080	30294322	The combined frequency of genetic alterations of all seven TRAFs is 23% (71/311) in ovarian cancer (TCGA, Provisional), 19% (77/408) in bladder cancer, 19% (45/240) in uterine cancer, 17% (81/469) in lung cancer (TCGA, PanCancer Atlas), 15% (41/265) in oesophageal cancer, 14% (48/353) in liver cancer (TCGA, PanCancer Atlas), 13% (35/279) in HNSCC, 13% (36/278) in cervical cancer (TCGA, PanCancer Atlas), 13% (58/438) in melanoma (TCGA, PanCancer Atlas), 12% (46/389) in colon cancer (TCGA, PanCancer Atlas), and 10% (106/1013) in prostate cancer.	('ovarian cancer', 'Disease', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (496, 502))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (295, 301))	('cancer', 'Disease', (479, 485))	('colon cancer', 'Disease', 'MESH:D015179', (473, 485))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (542, 548))	('liver cancer', 'Disease', 'MESH:D006528', (289, 301))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('HNSCC', 'Disease', (343, 348))	('alterations', 'Var', (34, 45))	('oesophageal cancer', 'Disease', (253, 271))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('uterine cancer', 'Phenotype', 'HP:0010784', (168, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('Cancer', 'Phenotype', 'HP:0002664', (392, 398))	('Cancer', 'Phenotype', 'HP:0002664', (312, 318))	('prostate cancer', 'Disease', 'MESH:D011471', (533, 548))	('melanoma', 'Phenotype', 'HP:0002861', (423, 431))	('liver cancer', 'Phenotype', 'HP:0002896', (289, 301))	('colon cancer', 'Disease', (473, 485))	('prostate cancer', 'Phenotype', 'HP:0012125', (533, 548))	('liver cancer', 'Disease', (289, 301))	('cancer', 'Disease', (176, 182))	('prostate cancer', 'Disease', (533, 548))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('oesophageal cancer', 'Disease', 'MESH:D009369', (253, 271))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('melanoma', 'Disease', 'MESH:D008545', (423, 431))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('cancer', 'Disease', 'MESH:D009369', (542, 548))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('Cancer', 'Phenotype', 'HP:0002664', (442, 448))	('colon cancer', 'Phenotype', 'HP:0003003', (473, 485))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', (375, 381))	('melanoma', 'Disease', (423, 431))
86083	30294322	Given the often mutually exclusive genetic alterations of different TRAFs in the same cancer, it is very likely that all seven TRAFs may have non-overlapping and distinct contributions to different aspects or at different stages of the initiation, progression and metastasis of the same cancer.	('genetic alterations', 'Var', (35, 54))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
86097	30294322	In particular, consistent with the high frequency of TRAF3 deletions and mutations in HPV+ HNSCC, overexpression of TRAF3 inhibits the growth, migration and chemoresistance of HPV+ HNSCC by decreasing HPV E6 oncoprotein and increasing p53 and RB tumor suppressors.	('deletions', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('chemoresistance', 'CPA', (157, 172))	('RB tumor', 'Disease', (243, 251))	('growth', 'CPA', (135, 141))	('HPV', 'Species', '10566', (201, 204))	('HPV E6 oncoprotein', 'Protein', (201, 219))	('HPV', 'Species', '10566', (176, 179))	('p53', 'Gene', '7157', (235, 238))	('decreasing', 'NegReg', (190, 200))	('HPV', 'Species', '10566', (86, 89))	('HPV+ HNSCC', 'Gene', (86, 96))	('TRAF3', 'Gene', (53, 58))	('inhibits', 'NegReg', (122, 130))	('RB tumor', 'Disease', 'MESH:D012175', (243, 251))	('TRAF3', 'Gene', (116, 121))	('increasing', 'PosReg', (224, 234))	('p53', 'Gene', (235, 238))	('mutations', 'Var', (73, 82))
86101	30294322	Specific deletion of TRAF3 from myeloid cells leads to development of B lymphomas and liver cancer in mice.	('mice', 'Species', '10090', (102, 106))	('B lymphoma', 'Phenotype', 'HP:0012191', (70, 80))	('deletion', 'Var', (9, 17))	('B lymphomas', 'Phenotype', 'HP:0012191', (70, 81))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('lymphomas', 'Phenotype', 'HP:0002665', (72, 81))	('TRAF3', 'Gene', (21, 26))	('B lymphomas and liver cancer', 'Disease', 'MESH:D006528', (70, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))
86102	30294322	Similarly, lymphocyte-specific TRAF3 transgenic mice develop autoimmunity, inflammation and cancers (such as squamous cell carcinomas of the tongue, salivary gland tumors, and hepatoma).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('salivary gland tumors', 'Disease', (149, 170))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (109, 133))	('inflammation', 'biological_process', 'GO:0006954', ('75', '87'))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('hepatoma', 'Disease', 'MESH:D006528', (176, 184))	('squamous cell carcinomas of the tongue', 'Phenotype', 'HP:0030413', (109, 147))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('autoimmunity', 'Disease', (61, 73))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('develop', 'PosReg', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('squamous cell carcinomas', 'Disease', (109, 133))	('transgenic', 'Var', (37, 47))	('inflammation', 'Disease', (75, 87))	('transgenic mice', 'Species', '10090', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('salivary gland tumors', 'Disease', 'MESH:D008949', (149, 170))	('autoimmunity', 'Disease', 'MESH:D001327', (61, 73))	('TRAF3', 'Gene', (31, 36))	('autoimmunity', 'Phenotype', 'HP:0002960', (61, 73))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('hepatoma', 'Disease', (176, 184))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (149, 170))	('cancers', 'Disease', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))
86109	30294322	In this article, we have analyzed the current evidence of genetic alterations of the TRAF family in human cancers.	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('genetic alterations', 'Var', (58, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
86110	30294322	The results revealed that genetic alterations of all seven TRAF genes are present in various human cancers and that recurrent mutations of each TRAF gene have been detected in cancer patients.	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('genetic alterations', 'Var', (26, 45))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (183, 191))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TRAF genes', 'Gene', (59, 69))	('detected', 'Reg', (164, 172))	('present', 'Reg', (74, 81))
86111	30294322	In particular, loss-of-function genetic alterations of TRAF2 and TRAF3 are frequently detected in B cell malignancies, and the rates of missense mutations of TRAF7 are overwhelmingly high in adenomatoid tumors, secretory meningiomas and perineuriomas.	('TRAF2', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('missense mutations', 'Var', (136, 154))	('meningiomas and perineuriomas', 'Disease', 'MESH:D018317', (221, 250))	('meningioma', 'Phenotype', 'HP:0002858', (221, 231))	('B cell malignancies', 'Disease', 'MESH:D015448', (98, 117))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('genetic alterations', 'Var', (32, 51))	('B cell malignancies', 'Disease', (98, 117))	('adenomatoid tumors', 'Disease', 'MESH:D018254', (191, 209))	('adenomatoid tumors', 'Disease', (191, 209))	('TRAF3', 'Gene', (65, 70))	('TRAF7', 'Gene', (158, 163))	('meningiomas', 'Phenotype', 'HP:0002858', (221, 232))	('loss-of-function', 'NegReg', (15, 31))
86112	30294322	Gain-of-function alterations (gene amplification and overexpression) are common for TRAF1, TRAF4, TRAF5, and TRAF6 in human cancers, and are also identified for TRAF2 in epithelial cancers.	('TRAF4', 'Gene', (91, 96))	('TRAF5', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TRAF1', 'Gene', (84, 89))	('overexpression', 'PosReg', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Gain-of-function', 'PosReg', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('TRAF6', 'Gene', (109, 114))	('human', 'Species', '9606', (118, 123))	('cancers', 'Disease', (181, 188))	('alterations', 'Var', (17, 28))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
86113	30294322	Corroborating human evidence, direct causal roles of TRAF genetic alterations (except TRAF7) in tumorigenesis have been demonstrated in vivo with genetically engineered mouse models that have each TRAF gene deleted or overexpressed in specific cell types.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('human', 'Species', '9606', (14, 19))	('TRAF', 'Gene', (53, 57))	('tumor', 'Disease', (96, 101))	('mouse', 'Species', '10090', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('genetic alterations', 'Var', (58, 77))
86114	30294322	Importantly, however, the functional significance of most TRAF point mutations identified in human cancers remains to be assessed in future studies.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('point mutations', 'Var', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TRAF', 'Gene', (58, 62))
86119	31530827	Estimating the Frequency of Single Point Driver Mutations across Common Solid Tumours For cancers, such as common solid tumours, variants in the genome give a selective growth advantage to certain cells.	('solid tumours', 'Disease', 'MESH:D009369', (114, 127))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Disease', (90, 97))	('selective growth advantage', 'CPA', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Tumours', 'Disease', 'MESH:D009369', (78, 85))	('solid tumours', 'Disease', (114, 127))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('Tumours', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('Mutations', 'Var', (48, 57))	('Tumours', 'Disease', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('variants', 'Var', (129, 137))
86120	31530827	It has recently been argued that the mean count of coding single nucleotide variants acting as disease-drivers in common solid tumours is frequently small in size, but significantly variable by cancer type (hypermutation is excluded from this study).	('cancer', 'Disease', (194, 200))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('solid tumours', 'Disease', (121, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('single nucleotide variants', 'Var', (58, 84))	('solid tumours', 'Disease', 'MESH:D009369', (121, 134))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
86121	31530827	In this paper we investigate this proposal through the use of integrative machine-learning-based classifiers we have proposed recently for predicting the disease-driver status of single nucleotide variants (SNVs) in the human cancer genome.	('human', 'Species', '9606', (220, 225))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('single nucleotide variants', 'Var', (179, 205))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
86124	31530827	For common solid tumours, a number of variants in the coding regions of the human cancer genome can act as disease-drivers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('solid tumours', 'Disease', (11, 24))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('variants', 'Var', (38, 46))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('human', 'Species', '9606', (76, 81))	('solid tumours', 'Disease', 'MESH:D009369', (11, 24))
86127	31530827	argued for only a few sequential mutations in a study of lung and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('lung', 'Disease', (57, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
86130	31530827	An exception to this picture is the high mutation count which can stem from alterations to the proofreading domains of DNA polymerases POLE and POLD1, leading to hypermutation.	('alterations', 'Var', (76, 87))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('POLD1', 'Gene', '5424', (144, 149))	('POLD1', 'Gene', (144, 149))	('hypermutation', 'MPA', (162, 175))
86133	31530827	Catalogues covering documented instances of disease-traits associated with single nucleotide variants, across non-cancer diseases, indicate that approximately 90% of these are located in non-coding regions of the human genome and our previous tools predict a large proportion of disease-driver variants in non-coding regions in consequence.	('non-cancer diseases', 'Disease', (110, 129))	('human', 'Species', '9606', (213, 218))	('non-cancer diseases', 'Disease', 'MESH:D009369', (110, 129))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('single nucleotide variants', 'Var', (75, 101))
86134	31530827	we proposed CScape, a method for predicting the disease-driver status of single nucleotide variants in the coding and non-coding regions of the human cancer genome (the method is more fully described in Supplementary Section 1).	('human', 'Species', '9606', (144, 149))	('single nucleotide variants', 'Var', (73, 99))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
86148	31530827	Whereas CS-coding could be viewed as reasonably successful overall and apparently accurate with high confidence prediction, CS-noncoding is weak overall because of our current lack of understanding of the pathogenic impact of variants within non-coding regions of the cancer genome.	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('variants', 'Var', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))
86153	31530827	Mutations driving cancer are typically random in occurrence and the mode of the distribution could be expected to lie at a lower SNV count than the median, as would be the case for a Poissonian distribution (excepting hypermutation, relatively fewer numbers of examples are observed with relatively larger mutation counts).	('driving', 'Reg', (10, 17))	('SNV count', 'MPA', (129, 138))	('lower', 'NegReg', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
86168	31530827	The prospective accumulation of SNV-driver mutations with stage of disease has been argued by many authors, though frequently via observation of tumour mutational burden (TMB), the number of non-synonymous mutations in coding regions of the cancer genome.	('tumour', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('mutations', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (241, 247))
86170	31530827	Since many non-synonymous mutations are not disease-drivers, the TDB is obviously more insightful, but requires a method to separate passengers and drivers.	('TDB', 'Disease', (65, 68))	('non-synonymous mutations', 'Var', (11, 35))	('TDB', 'Disease', 'MESH:D009369', (65, 68))
86189	31530827	Thus somatically acquired mutations have been implicated in gliomas and chondrosarcomas.	('implicated', 'Reg', (46, 56))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('chondrosarcomas', 'Disease', 'MESH:D002813', (72, 87))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('mutations', 'Var', (26, 35))	('chondrosarcomas', 'Disease', (72, 87))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (72, 87))
86190	31530827	Excepting TP53, CScape predicts that all these single point mutations are disease drivers with confidence levels equal to, or exceeding, 0.829.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', '7157', (10, 14))
86191	31530827	TP53 is different in that any alteration at some locations will act as a disease-driver (e.g.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('alteration', 'Var', (30, 40))
86195	31530827	A recurrent point mutation at chromosome 17, position 64738741 G   C, introduces a D463H amino acid substitution and this has been described as a hallmark of chordoid glioma.	('hallmark of chordoid glioma', 'Disease', 'MESH:D005910', (146, 173))	('D463H', 'Mutation', 'p.D463H', (83, 88))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))	('hallmark of chordoid glioma', 'Disease', (146, 173))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('D463H', 'Var', (83, 88))	('chordoid glioma', 'Phenotype', 'HP:0010762', (158, 173))
86207	31530827	Mutations in BRAF are well known and studied in the context of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
86214	31530827	TTN mutations have been reported as highly predictive of patient survival with some cancers and TTN-AS1 has been recently argued as an oncogene across several cancers.	('cancers', 'Disease', (159, 166))	('TTN-AS1', 'Gene', '100506866', (96, 103))	('patient', 'Species', '9606', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('TTN', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TTN', 'Gene', (96, 99))	('cancers', 'Disease', (84, 91))	('TTN', 'Gene', '7273', (0, 3))	('TTN', 'Gene', '7273', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TTN-AS1', 'Gene', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('mutations', 'Var', (4, 13))	('predictive', 'Reg', (43, 53))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('patient survival', 'CPA', (57, 73))
86223	31530827	As we have previously discussed, three mutations in the TERT promoter region have been characterised as disruptive to putative ETS (E26 transformation specific) family transcription factor binding sites and are verified drivers.	('binding sites', 'Interaction', (189, 202))	('ETS', 'Protein', (127, 130))	('mutations', 'Var', (39, 48))	('transcription', 'biological_process', 'GO:0006351', ('168', '181'))	('disruptive', 'NegReg', (104, 114))	('TERT', 'Gene', (56, 60))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('168', '196'))	('TERT', 'Gene', '7015', (56, 60))
86224	31530827	Five additional recurrent driver mutations in regulatory elements upstream of SDHD and PLEKHS1 have been documented.	('SDHD', 'Gene', '6392', (78, 82))	('SDHD', 'Gene', (78, 82))	('mutations', 'Var', (33, 42))	('PLEKHS1', 'Gene', (87, 94))	('PLEKHS1', 'Gene', '79949', (87, 94))
86225	31530827	The exception is one mutation for SDHD which is outside the core response element.	('SDHD', 'Gene', (34, 38))	('SDHD', 'Gene', '6392', (34, 38))	('core', 'cellular_component', 'GO:0019013', ('60', '64'))	('mutation', 'Var', (21, 29))
86229	31530827	This threshold could be cancer-type specific but would provide predictions of actual driver mutations in concordance with such an alternative model.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer-type', 'Disease', (24, 35))	('cancer-type', 'Disease', 'MESH:D009369', (24, 35))	('mutations', 'Var', (92, 101))
86244	31530827	Secondly, the above analysis supports the general message proposed by other groups, that the mean number of coding SNV-drivers for most cancers is typically very small in size, either single digits or low double digits.	('single digits', 'Var', (184, 197))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
86246	31530827	The indicated low driver set sizes, and the ability to partially identify members of these small sets, suggests an ability to identify many of the core variants in the cancer genome which drive the development of a particular tumour.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('core', 'cellular_component', 'GO:0019013', ('147', '151'))	('drive', 'Reg', (188, 193))	('particular tumour', 'Disease', (215, 232))	('particular tumour', 'Disease', 'MESH:D009369', (215, 232))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('variants', 'Var', (152, 160))	('cancer', 'Disease', (168, 174))
86253	22293026	Aberrant Hypermethylation in Primary and Sentinel Lymph Node Metastases in Pediatric Cutaneous Melanoma Patients Debate on how to manage pediatric cutaneous melanoma patients continues; particularly in those with sentinel lymph node(SLN) metastases who are at higher risk of poor outcomes.	('pediatric cutaneous melanoma', 'Disease', (137, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (147, 165))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('pediatric cutaneous melanoma', 'Disease', 'MESH:C562393', (137, 165))	('Melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('Aberrant Hypermethylation', 'Var', (0, 25))	('Metastases in Pediatric Cutaneous Melanoma', 'Disease', (61, 103))	('sentinel lymph node(SLN) metastases', 'Disease', 'MESH:D009362', (213, 248))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('Metastases in Pediatric Cutaneous Melanoma', 'Disease', 'MESH:D009362', (61, 103))	('patients', 'Species', '9606', (166, 174))
86259	22293026	When matched to adult cutaneous melanomas by Breslow thickness and ulceration, hypermethylation of all four TRGs in SLN(+) pediatric melanoma patients was equivalent to or less than in adults.	('SLN(+', 'Var', (116, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (22, 40))	('TRGs', 'Chemical', '-', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('cutaneous melanomas', 'Disease', (22, 41))	('pediatric melanoma', 'Disease', 'MESH:D008545', (123, 141))	('TRGs', 'Gene', (108, 112))	('melanomas', 'Phenotype', 'HP:0002861', (32, 41))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('pediatric melanoma', 'Disease', (123, 141))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (22, 41))	('patients', 'Species', '9606', (142, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (22, 41))	('hypermethylation', 'MPA', (79, 95))	('less', 'NegReg', (172, 176))
86260	22293026	With a median follow-up of 55 months, SLN(+) pediatric melanoma patients with hypermethylation of >1 TRGs versus <=1 TRG had worse disease-free(p=0.02) and overall survival(p=0.02).	('pediatric melanoma', 'Disease', (45, 63))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('patients', 'Species', '9606', (64, 72))	('TRG', 'Gene', (101, 104))	('worse', 'PosReg', (125, 130))	('TRGs', 'Chemical', '-', (101, 105))	('overall survival', 'CPA', (156, 172))	('TRG', 'Gene', '6965', (117, 120))	('TRG', 'Gene', '6965', (101, 104))	('pediatric melanoma', 'Disease', 'MESH:D008545', (45, 63))	('SLN', 'Var', (38, 41))	('TRG', 'Gene', (117, 120))
86262	22293026	SLN biopsy should continue to be performed; within SLN(+) pediatric melanoma patients, hypermethylation of TRGs can be used to identify a subpopulation at highest risk for poor outcomes who warrant vigilant clinical follow-up.	('hypermethylation', 'Var', (87, 103))	('TRGs', 'Chemical', '-', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('pediatric melanoma', 'Disease', 'MESH:D008545', (58, 76))	('SLN', 'Gene', (51, 54))	('TRGs', 'Gene', (107, 111))	('patients', 'Species', '9606', (77, 85))	('pediatric melanoma', 'Disease', (58, 76))
86270	22293026	Epigenetic inactivation of tumor suppressor genes has been implicated in tumorigenesis of various malignancies, including cutaneous melanoma.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('27', '43'))	('malignancies', 'Disease', (98, 110))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (122, 140))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('27', '43'))	('tumor', 'Disease', (73, 78))	('cutaneous melanoma', 'Disease', (122, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (122, 140))	('implicated', 'Reg', (59, 69))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('Epigenetic inactivation', 'Var', (0, 23))
86271	22293026	Our group has shown that epigenetic aberrations, such as hypermethylation of CpG islands in the promoter region of tumor-related genes (TRGs), can significantly silence gene function and promote tumor progression in adult cutaneous melanoma.	('promote', 'PosReg', (187, 194))	('TRGs', 'Gene', (136, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (222, 240))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (222, 240))	('silence', 'NegReg', (161, 168))	('tumor', 'Disease', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('epigenetic aberrations', 'Var', (25, 47))	('cutaneous melanoma', 'Disease', (222, 240))	('TRGs', 'Chemical', '-', (136, 140))	('hypermethylation', 'Var', (57, 73))	('gene function', 'MPA', (169, 182))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
86297	22293026	The frequency of hypermethylation of RASSF1A, RARbeta2, WIF1, and APC from pediatric cutaneous melanoma primary tumors was 35%, 45%, 20%, and 25%, respectively; and 29.4%, 25%, 25%, and 18.8%, respectively in histopathology(+) SLNs (Table 3).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('pediatric cutaneous melanoma', 'Disease', (75, 103))	('RARbeta2', 'Gene', (46, 54))	('RASSF1A', 'Gene', '11186', (37, 44))	('WIF1', 'Gene', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('APC', 'cellular_component', 'GO:0005680', ('66', '69'))	('APC', 'Disease', 'MESH:D011125', (66, 69))	('pediatric cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 103))	('APC', 'Disease', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('melanoma primary tumors', 'Disease', 'MESH:D008545', (95, 118))	('WIF1', 'Gene', '11197', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('melanoma primary tumors', 'Disease', (95, 118))	('hypermethylation', 'Var', (17, 33))	('RASSF1A', 'Gene', (37, 44))
86298	22293026	Of all the TRGs analyzed, only WIF1 hypermethylation in the SLN(+) metastases was slightly higher than in the primary tumor (25% vs. 20%; Table 3), but this was not statistically significant.	('TRGs', 'Chemical', '-', (11, 15))	('metastases', 'Disease', (67, 77))	('higher', 'PosReg', (91, 97))	('WIF1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('WIF1', 'Gene', '11197', (31, 35))	('hypermethylation', 'Var', (36, 52))	('primary tumor', 'Disease', (110, 123))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('primary tumor', 'Disease', 'MESH:D009369', (110, 123))
86299	22293026	In the primary tumors and histopathology(+) SLNs, 60% (12/20) and 64.7% (11/17) were hypermethylated for >= 1 TRG, 45% (9/20) and 23.5% (4/17) for >= 2 TRGs, and 20% (4/20) and 5.9% (1/17) for >= 3 TRGs, respectively.	('TRG', 'Gene', (152, 155))	('primary tumors', 'Disease', (7, 21))	('TRG', 'Gene', '6965', (110, 113))	('primary tumors', 'Disease', 'MESH:D009369', (7, 21))	('TRGs', 'Chemical', '-', (152, 156))	('TRG', 'Gene', (198, 201))	('hypermethylated', 'Var', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('TRG', 'Gene', '6965', (152, 155))	('TRGs', 'Chemical', '-', (198, 202))	('TRG', 'Gene', '6965', (198, 201))	('TRG', 'Gene', (110, 113))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
86300	22293026	None of the patients demonstrated hypermethylation of >= 4 TRGs.	('patients', 'Species', '9606', (12, 20))	('TRGs', 'Chemical', '-', (59, 63))	('TRGs', 'Protein', (59, 63))	('hypermethylation', 'Var', (34, 50))
86301	22293026	Patient clinicopathological parameters were compared with the frequency of hypermethylation of the TRGs in primary tumors and histopathology(+) SLNs.	('TRGs', 'Chemical', '-', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TRGs', 'Gene', (99, 103))	('primary tumors', 'Disease', (107, 121))	('primary tumors', 'Disease', 'MESH:D009369', (107, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('hypermethylation', 'Var', (75, 91))	('Patient', 'Species', '9606', (0, 7))
86302	22293026	As a single TRG, only hypermethylation of RASSF1A was significantly associated with primary tumors located in the head and neck (61.5% (8/13), p=0.018; Table 4).	('associated', 'Reg', (68, 78))	('TRG', 'Gene', (12, 15))	('RASSF1A', 'Gene', (42, 49))	('TRG', 'Gene', '6965', (12, 15))	('hypermethylation', 'Var', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RASSF1A', 'Gene', '11186', (42, 49))	('neck', 'cellular_component', 'GO:0044326', ('123', '127'))	('primary tumors', 'Disease', (84, 98))	('primary tumors', 'Disease', 'MESH:D009369', (84, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors located in the head and neck', 'Phenotype', 'HP:0012288', (92, 127))
86305	22293026	In the SLN(+) metastases group, hypermethylation of the RASSF1A in the pediatric melanoma patients was the same as in adults, however, lower for RARbeta2 (17% vs. 36%), WIF1 (18% vs. 42%), and APC (17% vs. 60%), although none were statistically significant (Fig.	('pediatric melanoma', 'Disease', 'MESH:D008545', (71, 89))	('metastases', 'Disease', (14, 24))	('hypermethylation', 'MPA', (32, 48))	('pediatric melanoma', 'Disease', (71, 89))	('APC', 'cellular_component', 'GO:0005680', ('193', '196'))	('WIF1', 'Gene', (169, 173))	('metastases', 'Disease', 'MESH:D009362', (14, 24))	('RASSF1A', 'Gene', (56, 63))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('lower', 'NegReg', (135, 140))	('RARbeta2', 'Var', (145, 153))	('WIF1', 'Gene', '11197', (169, 173))	('RASSF1A', 'Gene', '11186', (56, 63))	('APC', 'Disease', 'MESH:D011125', (193, 196))	('APC', 'Disease', (193, 196))	('patients', 'Species', '9606', (90, 98))
86306	22293026	Hypermethylation of TRGs in the primary tumor of the pediatric melanoma patients did not correlate to disease outcome.	('TRGs', 'Chemical', '-', (20, 24))	('primary tumor', 'Disease', 'MESH:D009369', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('pediatric melanoma', 'Disease', (53, 71))	('Hypermethylation', 'Var', (0, 16))	('TRGs', 'Gene', (20, 24))	('primary tumor', 'Disease', (32, 45))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('pediatric melanoma', 'Disease', 'MESH:D008545', (53, 71))	('patients', 'Species', '9606', (72, 80))
86307	22293026	However, hypermethylation of TRGs in patients with histopathology(+) SLNs demonstrated an inverse relationship to survival.	('patients', 'Species', '9606', (37, 45))	('TRGs', 'Chemical', '-', (29, 33))	('hypermethylation', 'Var', (9, 25))	('inverse', 'NegReg', (90, 97))	('TRGs', 'Gene', (29, 33))
86309	22293026	Of these SLN(+) patients, those demonstrating >1(+) hypermethylated TRG in the SLN (n=4) versus those with <=1 hypermethylated TRG (n=13) had a poorer OS and DFS (p=0.02; p=0.02, respectively, log-rank test).	('hypermethylated', 'Var', (52, 67))	('poorer', 'NegReg', (144, 150))	('DFS', 'Chemical', 'MESH:C045207', (158, 161))	('patients', 'Species', '9606', (16, 24))	('TRG', 'Gene', (68, 71))	('TRG', 'Gene', (127, 130))	('DFS', 'CPA', (158, 161))	('TRG', 'Gene', '6965', (68, 71))	('TRG', 'Gene', '6965', (127, 130))
86313	22293026	Our group and others have shown that epigenetic inactivation of TRGs via hypermethylation of CpG island promoter regions is significant in adult melanoma progression.	('hypermethylation of CpG island', 'biological_process', 'GO:0044027', ('73', '103'))	('hypermethylation', 'Var', (73, 89))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('adult melanoma', 'Disease', 'MESH:D008545', (139, 153))	('adult melanoma', 'Disease', (139, 153))	('TRGs', 'Chemical', '-', (64, 68))	('epigenetic inactivation', 'Var', (37, 60))	('TRGs', 'Gene', (64, 68))	('significant', 'Reg', (124, 135))
86314	22293026	To our knowledge, this is the first study to evaluate the epigenetic changes of these TRGs in pediatric cutaneous melanoma patients.	('pediatric cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 122))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (104, 122))	('TRGs', 'Chemical', '-', (86, 90))	('patients', 'Species', '9606', (123, 131))	('epigenetic changes', 'Var', (58, 76))	('TRGs', 'Gene', (86, 90))	('pediatric cutaneous melanoma', 'Disease', (94, 122))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
86325	22293026	In comparing the methylation status of the TRGs to clinicopathological parameters, hypermethylation of RASSF1A was found to be significantly associated with primary melanomas of the head and neck.	('melanomas', 'Disease', (165, 174))	('hypermethylation', 'Var', (83, 99))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('RASSF1A', 'Gene', (103, 110))	('neck', 'cellular_component', 'GO:0044326', ('191', '195'))	('associated with', 'Reg', (141, 156))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('TRGs', 'Chemical', '-', (43, 47))	('RASSF1A', 'Gene', '11186', (103, 110))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))
86338	22293026	Changes associated with aging such as damage to elastic tissues, fatty replacement of LNs and a reduction in skin blood and lymphatic flow can impact detection of metastases in the SLN.	('detection', 'MPA', (150, 159))	('fatty replacement', 'Var', (65, 82))	('metastases', 'Disease', (163, 173))	('impact', 'NegReg', (143, 149))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('reduction', 'NegReg', (96, 105))	('aging', 'biological_process', 'GO:0007568', ('24', '29'))
86346	22293026	The caveat however is that these SLN(+) pediatric cutaneous melanoma patients will still need to be closely followed for regional recurrence.	('pediatric cutaneous melanoma', 'Disease', 'MESH:C562393', (40, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('SLN(+', 'Var', (33, 38))	('patients', 'Species', '9606', (69, 77))	('pediatric cutaneous melanoma', 'Disease', (40, 68))
86351	22293026	We demonstrate that epigenetic regulation of tumor-related genes(TRGs) in histopathology(+) SLNs of pediatric melanoma patients has clinical relevance.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('TRGs', 'Chemical', '-', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TRGs', 'Gene', (65, 69))	('tumor', 'Disease', (45, 50))	('patients', 'Species', '9606', (119, 127))	('pediatric melanoma', 'Disease', 'MESH:D008545', (100, 118))	('epigenetic regulation', 'Var', (20, 41))	('pediatric melanoma', 'Disease', (100, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
86352	22293026	Differences in the methylation status of these TRGs in SLN(+) pediatric and adult melanoma patients may account for the clinical differences between the two types of patients.	('adult melanoma', 'Disease', 'MESH:D008545', (76, 90))	('SLN', 'Var', (55, 58))	('patients', 'Species', '9606', (91, 99))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('adult melanoma', 'Disease', (76, 90))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('TRGs', 'Chemical', '-', (47, 51))	('methylation', 'MPA', (19, 30))	('patients', 'Species', '9606', (166, 174))
86353	22293026	Particularly, pediatric melanoma patients that are SLN(+) and demonstrate hypermethylation of >1 TRG have the worst outcomes and warrant close clinical follow-up.	('TRG', 'Gene', (97, 100))	('patients', 'Species', '9606', (33, 41))	('TRG', 'Gene', '6965', (97, 100))	('pediatric melanoma', 'Disease', 'MESH:D008545', (14, 32))	('SLN(+', 'Var', (51, 56))	('hypermethylation', 'Var', (74, 90))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('pediatric melanoma', 'Disease', (14, 32))
86364	27650277	Dysregulation or hyperactivation of this cascade is common in many human cancers.	('cancers', 'Disease', (73, 80))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('hyperactivation', 'PosReg', (17, 32))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
86366	27650277	RAS activating mutations occur in 30 % of all cancers, including a high prevalence in melanoma (15-25 %), with KRAS mutations more common in adenocarcinomas and solid tumors and NRAS mutations more common in leukemia, thyroid carcinoma, and malignant melanoma.	('RAS', 'Gene', (0, 3))	('malignant melanoma', 'Phenotype', 'HP:0002861', (241, 259))	('malignant melanoma', 'Disease', 'MESH:D008545', (241, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('leukemia', 'Disease', 'MESH:D007938', (208, 216))	('NRAS', 'Gene', (178, 182))	('leukemia', 'Disease', (208, 216))	('mutations', 'Var', (183, 192))	('common', 'Reg', (131, 137))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (218, 235))	('mutations', 'Var', (15, 24))	('thyroid carcinoma', 'Disease', (218, 235))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('solid tumors', 'Disease', (161, 173))	('melanoma', 'Disease', (86, 94))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (218, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('mutations', 'Var', (116, 125))	('malignant melanoma', 'Disease', (241, 259))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('KRAS', 'Gene', (111, 115))	('adenocarcinomas', 'Disease', 'MESH:D000230', (141, 156))	('common', 'Reg', (198, 204))	('adenocarcinomas', 'Disease', (141, 156))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('leukemia', 'Phenotype', 'HP:0001909', (208, 216))
86368	27650277	Furthermore, approximately 8 % of human tumors have mutations in BRAF (a member of the RAF family) : melanoma, thyroid cancer, and CRC have been associated with a high frequency of BRAF mutations.	('mutations', 'Var', (52, 61))	('thyroid cancer', 'Phenotype', 'HP:0002890', (111, 125))	('thyroid cancer', 'Disease', (111, 125))	('CRC', 'Disease', (131, 134))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('mutations', 'Var', (186, 195))	('melanoma', 'Disease', (101, 109))	('associated', 'Reg', (145, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (111, 125))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('BRAF', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
86369	27650277	Specifically, the V600E point mutation accounts for more than 80 % of BRAF activating mutations.	('V600E', 'Var', (18, 23))	('activating', 'PosReg', (75, 85))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('BRAF', 'Gene', (70, 74))
86370	27650277	A number of MEK1/2 inhibitors are currently being investigated in the clinic across a range of cancers including gynecologic malignancies, melanoma, colorectal cancer, and acute myelogenous leukemia, with trametinib approved alone and in combination with the BRAF inhibitor dabrafenib for advanced metastatic melanoma with BRAF V600 mutations.	('acute myelogenous leukemia', 'Disease', (172, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('leukemia', 'Phenotype', 'HP:0001909', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (309, 317))	('trametinib', 'Chemical', 'MESH:C560077', (205, 215))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (172, 198))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (178, 198))	('BRAF', 'Gene', (323, 327))	('MEK1', 'molecular_function', 'GO:0004708', ('12', '16'))	('V600 mutations', 'Var', (328, 342))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('colorectal cancer', 'Disease', (149, 166))	('malignancies', 'Disease', (125, 137))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('dabrafenib', 'Chemical', 'MESH:C561627', (274, 284))	('melanoma', 'Disease', (139, 147))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (172, 198))
86372	27650277	For example, TAK-733 has demonstrated activity against multiple cutaneous melanoma cell lines, with a high proportion of BRAF V600E-mutant cell lines showing high sensitivity (IC50 < 0.1 muM) and with no statistically significant association between BRAF status and response, and against uveal melanoma cell lines.	('V600E', 'Var', (126, 131))	('BRAF', 'Gene', (121, 125))	('V600E', 'SUBSTITUTION', 'None', (126, 131))	('melanoma cell lines', 'Disease', 'MESH:D008545', (294, 313))	('melanoma cell lines', 'Disease', 'MESH:D008545', (74, 93))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (294, 302))	('uveal melanoma', 'Phenotype', 'HP:0007716', (288, 302))	('melanoma cell lines', 'Disease', (74, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (64, 82))	('melanoma cell lines', 'Disease', (294, 313))
86400	27650277	One patient (male, age 68 years) with BRAF L597R cutaneous melanoma, who received TAK-733 at 16 mg, had a partial response that was reported at cycle 4 and maintained until cycle 8 (approximate duration of 4 months).	('L597R', 'Var', (43, 48))	('cutaneous melanoma', 'Disease', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('L597R', 'SUBSTITUTION', 'None', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
86403	27650277	Also of note, we showed that two patients with cutaneous melanoma, including one with a BRAF L597R mutation, achieved partial responses that lasted approximately 4 months, suggesting evidence of preliminary antitumor activity with TAK-733.	('BRAF', 'Gene', (88, 92))	('L597R', 'SUBSTITUTION', 'None', (93, 98))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('antitumor', 'MPA', (207, 216))	('cutaneous melanoma', 'Disease', (47, 65))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('L597R', 'Var', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))
86404	27650277	Like the approved agent trametinib, as well as selumetinib and other investigational MEK1/2 inhibitors, TAK-733 is a non-ATP competitive allosteric inhibitor of the MEK1 and MEK2 BRAF substrates.	('MEK1', 'molecular_function', 'GO:0004708', ('85', '89'))	('MEK2', 'Gene', '5605', (174, 178))	('MEK1', 'molecular_function', 'GO:0004708', ('165', '169'))	('MEK2', 'Gene', (174, 178))	('TAK-733', 'Var', (104, 111))	('selumetinib', 'Chemical', 'MESH:C517975', (47, 58))	('MEK2', 'molecular_function', 'GO:0004708', ('174', '178'))
86405	27650277	These are similar to the common toxicities reported with other MEK1/2 inhibitors including trametinib, selumetinib, RO4987655, and PD-0325901; trametinib has been reported to be specifically associated with acneiform eruptions.	('PD-0325901', 'Chemical', 'MESH:C506614', (131, 141))	('acneiform eruptions', 'Disease', 'MESH:D017486', (207, 226))	('RO4987655', 'Chemical', 'MESH:C559138', (116, 125))	('trametinib', 'Var', (143, 153))	('MEK1', 'molecular_function', 'GO:0004708', ('63', '67'))	('associated', 'Reg', (191, 201))	('acneiform eruptions', 'Disease', (207, 226))
86406	27650277	Similarly, DLTs in other phase I studies of MEK1/2 inhibitors have included rash, diarrhea, increased blood CPK, and ocular toxicities with ARRY-424704, refametinib, cobimetinib, ARRY-438162, and pimasertib.	('rash', 'Disease', (76, 80))	('blood CPK', 'MPA', (102, 111))	('pimasertib', 'Chemical', 'MESH:C550600', (196, 206))	('diarrhea', 'Disease', (82, 90))	('rash', 'Phenotype', 'HP:0000988', (76, 80))	('ocular toxicities', 'Disease', (117, 134))	('cobimetinib', 'Chemical', 'MESH:C574276', (166, 177))	('MEK1', 'molecular_function', 'GO:0004708', ('44', '48'))	('refametinib', 'Chemical', 'MESH:C544830', (153, 164))	('ARRY-424704', 'Var', (140, 151))	('ocular toxicities', 'Disease', 'MESH:D005128', (117, 134))	('increased', 'PosReg', (92, 101))	('cobimetinib', 'Gene', (166, 177))	('MEK1/2', 'Gene', (44, 50))	('ARRY-438162', 'Var', (179, 190))	('diarrhea', 'Phenotype', 'HP:0002014', (82, 90))
86409	27650277	a decrease in pERK levels in peripheral blood mononuclear cells, malignant cells, and/or paired tumor biopsies, have been reported with other MEK1/2 inhibitors, including trametinib, selumetinib (79 % geometric mean pERK reduction in paired tumor biopsies), ARRY-424704, and RO4987655, and with the dual Raf/MEK inhibitor RO5126766, although no correlations with response have been reported.	('ARRY-424704', 'Var', (258, 269))	('reduction', 'NegReg', (221, 230))	('decrease', 'NegReg', (2, 10))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('pERK levels', 'MPA', (14, 25))	('MEK1', 'molecular_function', 'GO:0004708', ('142', '146'))	('MEK1/2', 'Gene', (142, 148))	('selumetinib', 'Var', (183, 194))	('RO4987655', 'Var', (275, 284))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('RO5126766', 'Chemical', 'MESH:C577924', (322, 331))
86410	27650277	Notably, the response in a patient with BRAF L597R mutant melanoma is consistent with observations with other MEK1/2 inhibitors, including trametinib, which have shown activity in BRAF-mutant melanoma.	('L597R', 'SUBSTITUTION', 'None', (45, 50))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('MEK1', 'molecular_function', 'GO:0004708', ('110', '114'))	('L597R', 'Var', (45, 50))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
86411	27650277	Specifically, trametinib has been approved by the US FDA for the treatment of BRAF V600E/K-mutant melanoma, having demonstrated substantial response rates of approximately 20 % and improved progression-free survival and overall survival compared to chemotherapy with dacarbazine or paclitaxel in this patient population.	('V600E', 'Var', (83, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (282, 292))	('improved', 'PosReg', (181, 189))	('BRAF', 'Gene', (78, 82))	('V600E', 'SUBSTITUTION', 'None', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('progression-free survival', 'CPA', (190, 215))	('melanoma', 'Disease', (98, 106))	('overall survival', 'CPA', (220, 236))
86425	31179139	According to the TNM staging of metastatic disease in uveal melanoma (MUM), M0 is defined as the absence of distant metastasis, while M1a is a disease with distant metastasis with the largest diameter of 3 cm or less, M1b is metastatic disease with the largest diameter of 3.1 to 8 cm, and M1c is metastatic disease with the largest diameter of 8 cm or more.	('TNM', 'Gene', '10178', (17, 20))	('M1a', 'Var', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('UM', 'Phenotype', 'HP:0007716', (71, 73))	('TNM', 'Gene', (17, 20))	('uveal melanoma', 'Phenotype', 'HP:0007716', (54, 68))
86428	31179139	Oncogenic mutations in G-protein subunits a (GNAQ) and 11 (GNA11) have been described in 80% of uveal melanomas.	('described', 'Reg', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('uveal melanomas', 'Disease', (96, 111))	('GNA11', 'Gene', '2767', (59, 64))	('GNA11', 'Gene', (59, 64))	('GNAQ', 'Gene', (45, 49))	('uveal melanomas', 'Phenotype', 'HP:0007716', (96, 111))	('mutations', 'Var', (10, 19))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('uveal melanomas', 'Disease', 'MESH:C536494', (96, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (96, 110))	('GNAQ', 'Gene', '2776', (45, 49))
86460	31179139	Another large multicenter case series including 56 patients who received anti-PD1 (nivolumab, pembrolizumab) or anti-PDL1 (atezolizumab) agents showed median OS and PFS of 7.6 months and 2.6 months, respectively.	('anti-PD1', 'Var', (73, 81))	('PDL1', 'Gene', '29126', (117, 121))	('atezolizumab', 'Chemical', 'MESH:C000594389', (123, 135))	('PDL1', 'Gene', (117, 121))
86496	30809309	The aberration of glucose metabolism is one of the hall markers of human cancers.	('cancers', 'Disease', (73, 80))	('glucose', 'Chemical', 'MESH:D005947', (18, 25))	('glucose metabolism', 'MPA', (18, 36))	('aberration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('glucose metabolism', 'biological_process', 'GO:0006006', ('18', '36'))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
86500	30809309	Among them, the aberrant expression PKM2 is most common pathogenic subtype in cancers.	('common', 'Reg', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('PKM2', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PKM2', 'Gene', '5315', (36, 40))	('aberrant expression', 'Var', (16, 35))
86515	30809309	The human immortalized liver cell line MIHA and HCC cell lines BEL7402, QGY7701, QGY7703, SMMC7721, PLC8024, HepG2, Huh7 and Hep3B were employed in this study and their background information has been reported previously.	('HCC', 'Phenotype', 'HP:0001402', (48, 51))	('Huh7', 'Gene', '284424', (116, 120))	('human', 'Species', '9606', (4, 9))	('QGY7701', 'CellLine', 'CVCL:6859', (72, 79))	('QGY7703', 'Var', (81, 88))	('SMMC7721', 'CellLine', 'CVCL:0534', (90, 98))	('PLC', 'cellular_component', 'GO:0042824', ('100', '103'))	('HCC', 'Gene', (48, 51))	('Hep3B', 'CellLine', 'CVCL:0326', (125, 130))	('HepG2', 'CellLine', 'CVCL:0027', (109, 114))	('MIHA', 'Gene', '331', (39, 43))	('BEL7402', 'CellLine', 'CVCL:5492', (63, 70))	('HCC', 'Gene', '619501', (48, 51))	('MIHA', 'Gene', (39, 43))	('Huh7', 'Gene', (116, 120))
86550	30809309	MK2206 was dissolved in 30% (w/v) Captisol (Selleck Chemicals, Houston, TX) solution to optimize the solubility and stability.	('Captisol', 'Chemical', 'MESH:C093196', (34, 42))	('MK2206', 'Var', (0, 6))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('solubility', 'MPA', (101, 111))
86582	30809309	To further verify whether LINC01554 is a direct target of miR-365a-3p, we established two constructs, wt-LINC01554 3'-UTR and mutant LINC01554 3'-UTR.	('miR-365a', 'Gene', '100126355', (58, 66))	('LINC01554', 'Gene', (26, 35))	('miR-365a', 'Gene', (58, 66))	('LINC01554', 'Gene', (105, 114))	('LINC01554', 'Gene', (133, 142))	('LINC01554', 'Gene', '202299', (105, 114))	('LINC01554', 'Gene', '202299', (133, 142))	('LINC01554', 'Gene', '202299', (26, 35))	('mutant', 'Var', (126, 132))
86585	30809309	For instance, lncRNAs in the cytoplasm may affect protein translational modifications or gene regulation by behaving as decoys for miRNAs and proteins.	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('protein translational modifications', 'MPA', (50, 85))	('protein', 'cellular_component', 'GO:0003675', ('50', '57'))	('affect', 'Reg', (43, 49))	('gene regulation', 'MPA', (89, 104))	('cytoplasm', 'cellular_component', 'GO:0005737', ('29', '38'))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (131, 134))	('lncRNAs', 'Var', (14, 21))
86614	30809309	The inhibitory effect of LINC01554 on aerobic glycolysis could be reversed when LINC01554 was knocked out (Figure 3A-D).	('LINC01554', 'Gene', '202299', (25, 34))	('LINC01554', 'Gene', (80, 89))	('knocked out', 'Var', (94, 105))	('LINC01554', 'Gene', '202299', (80, 89))	('aerobic glycolysis', 'MPA', (38, 56))	('glycolysis', 'biological_process', 'GO:0006096', ('46', '56'))	('LINC01554', 'Gene', (25, 34))
86625	30809309	Moreover, proliferation marker Ki67 and expression of PKM2 by IHC staining was much lower in xenograft with LINC01554-transfected cells than that with empty-vector transfected cells, but higher in xenograft tumors developed from LIN01554-KO cells compared with xenograft tumors derived from LINC01554-WT cells (Figure 3I, Figure S5E).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('LINC01554', 'Gene', (291, 300))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('LIN01554-KO', 'Var', (229, 240))	('PKM2', 'Gene', (54, 58))	('LINC01554', 'Gene', (108, 117))	('PKM2', 'Gene', '5315', (54, 58))	('higher', 'PosReg', (187, 193))	('expression', 'MPA', (40, 50))	('xenograft tumors', 'Disease', (261, 277))	('LINC01554', 'Gene', '202299', (291, 300))	('xenograft tumors', 'Disease', (197, 213))	('xenograft tumors', 'Disease', 'MESH:D009369', (261, 277))	('proliferation', 'CPA', (10, 23))	('LINC01554', 'Gene', '202299', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('xenograft tumors', 'Disease', 'MESH:D009369', (197, 213))	('lower', 'NegReg', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))
86633	30809309	In line with our hypothesis, p-mTOR and p-p70 S6K were all reduced in LINC01554-tranfected cells compared with vectors (Figure 4A, left).	('reduced', 'NegReg', (59, 66))	('mTOR', 'Gene', (31, 35))	('mTOR', 'Gene', '2475', (31, 35))	('LINC01554', 'Gene', '202299', (70, 79))	('p-p70 S6K', 'Var', (40, 49))	('LINC01554', 'Gene', (70, 79))
86638	30809309	MK2206 is a small molecular inhibitor of Akt and has been currently tested in the clinical trials of cancers treatment.	('Akt', 'Pathway', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('clinical', 'Species', '191496', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('MK2206', 'Var', (0, 6))
86639	30809309	In our study, both cell growth assay and foci formation assay were dramatically inhibited by MK2206 with the increasing concentrations in LINC01554-transfected cells compared to LINC01554- KO cells (Figure 4B-C).	('cell growth', 'biological_process', 'GO:0016049', ('19', '30'))	('MK2206', 'Var', (93, 99))	('LINC01554', 'Gene', (138, 147))	('LINC01554', 'Gene', '202299', (138, 147))	('cell growth assay', 'CPA', (19, 36))	('MK2206', 'Chemical', 'MESH:C548887', (93, 99))	('LINC01554', 'Gene', (178, 187))	('LINC01554', 'Gene', '202299', (178, 187))	('formation', 'biological_process', 'GO:0009058', ('46', '55'))	('inhibited', 'NegReg', (80, 89))	('foci formation assay', 'CPA', (41, 61))
86641	30809309	However, in LINC01554-KO cells, the suppressive impact of MK2206 on Akt and mTOR phosphorylation was attenuated (Figure 4D, the most right).	('MK2206', 'Chemical', 'MESH:C548887', (58, 64))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('suppressive', 'NegReg', (36, 47))	('LINC01554', 'Gene', (12, 21))	('LINC01554', 'Gene', '202299', (12, 21))	('attenuated', 'NegReg', (101, 111))	('MK2206', 'Var', (58, 64))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('Akt', 'Pathway', (68, 71))
86643	30809309	Both glucose consumption and lactate production were decreased after introduction of MK2206 (Figure S6A-B).	('lactate', 'Chemical', 'MESH:D019344', (29, 36))	('MK2206', 'Var', (85, 91))	('lactate production', 'MPA', (29, 47))	('glucose consumption', 'Disease', 'MESH:D014397', (5, 24))	('decreased', 'NegReg', (53, 62))	('MK2206', 'Chemical', 'MESH:C548887', (85, 91))	('glucose consumption', 'Disease', (5, 24))
86647	30809309	Notably, 2 weeks later, the MK2206 groups presented slower growth rate compared to vehicle groups in both BEL7402 and QGY7701 cells (Figure 4E).	('MK2206', 'Chemical', 'MESH:C548887', (28, 34))	('growth rate', 'CPA', (59, 70))	('BEL7402', 'CellLine', 'CVCL:5492', (106, 113))	('slower', 'NegReg', (52, 58))	('QGY7701', 'CellLine', 'CVCL:6859', (118, 125))	('MK2206', 'Var', (28, 34))
86648	30809309	Proteins of xenograft tumors in different groups were extracted to validate the effect of MK2206 on AKT/mTOR pathway.	('mTOR', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mTOR', 'Gene', '2475', (104, 108))	('AKT', 'Gene', (100, 103))	('xenograft tumors', 'Disease', 'MESH:D009369', (12, 28))	('MK2206', 'Chemical', 'MESH:C548887', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('xenograft tumors', 'Disease', (12, 28))	('AKT', 'Gene', '207', (100, 103))	('MK2206', 'Var', (90, 96))
86652	30809309	Recently, extensive studies have revealed that molecular aberration in metabolic events is strongly relevant to initiation and progression of cancers.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('molecular aberration', 'Var', (47, 67))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('relevant', 'Reg', (100, 108))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
86654	30809309	As liver is an organ with high glucose metabolic activity, the dysfunction of sustaining glucose metabolism homeostasis may contribute to the pathogenesis of HCC.	('high glucose', 'Phenotype', 'HP:0003074', (26, 38))	('glucose metabolism', 'biological_process', 'GO:0006006', ('89', '107'))	('pathogenesis', 'biological_process', 'GO:0009405', ('142', '154'))	('HCC', 'Gene', (158, 161))	('glucose metabolism homeostasis', 'Disease', 'MESH:D044882', (89, 119))	('dysfunction', 'Var', (63, 74))	('HCC', 'Gene', '619501', (158, 161))	('glucose', 'Chemical', 'MESH:D005947', (89, 96))	('homeostasis', 'biological_process', 'GO:0042592', ('108', '119'))	('HCC', 'Phenotype', 'HP:0001402', (158, 161))	('contribute', 'Reg', (124, 134))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))	('glucose metabolism homeostasis', 'Disease', (89, 119))
86678	30809309	MK2206 is an oral allosteric inhibitor of pan-Akt, which is able to block the autophosphorylation of threonine 308 and serine 473 domains of target proteins.	('serine', 'Chemical', 'MESH:D012694', (119, 125))	('threonine', 'Chemical', 'MESH:D013912', (101, 110))	('MK2206', 'Chemical', 'MESH:C548887', (0, 6))	('serine 473 domains', 'MPA', (119, 137))	('MK2206', 'Var', (0, 6))	('block', 'NegReg', (68, 73))
86679	30809309	Currently, it has been reported to be in the phase II clinical trials of many solid tumors, including non-small-cell and small cell lung carcinoma (NCT01306045), colon and rectal cancer (NCT01802320), breast carcinoma (NCT01776008) and hepatocellular carcinoma (NCT01239355).	('solid tumors', 'Disease', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (121, 146))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (236, 260))	('breast carcinoma', 'Phenotype', 'HP:0003002', (201, 217))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('solid tumors', 'Disease', 'MESH:D009369', (78, 90))	('NCT01802320', 'Var', (187, 198))	('clinical', 'Species', '191496', (54, 62))	('breast carcinoma', 'Disease', (201, 217))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (236, 260))	('NCT01776008', 'Var', (219, 230))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (121, 146))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('hepatocellular carcinoma', 'Disease', (236, 260))	('NCT01239355', 'Var', (262, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('breast carcinoma', 'Disease', 'MESH:D001943', (201, 217))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (162, 185))	('small cell lung carcinoma', 'Disease', (121, 146))	('NCT01306045', 'Var', (148, 159))
86680	30809309	In line with our hypothesis, the inhibitory effect of MK2206 on cell growth, and phosphorylation of Akt and mTOR were attenuated in LINC01554-KO cells.	('mTOR', 'Gene', (108, 112))	('Akt', 'Pathway', (100, 103))	('phosphorylation', 'MPA', (81, 96))	('mTOR', 'Gene', '2475', (108, 112))	('LINC01554', 'Gene', (132, 141))	('LINC01554', 'Gene', '202299', (132, 141))	('inhibitory effect', 'MPA', (33, 50))	('MK2206', 'Var', (54, 60))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('cell growth', 'CPA', (64, 75))	('attenuated', 'NegReg', (118, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('81', '96'))	('MK2206', 'Chemical', 'MESH:C548887', (54, 60))
86681	30809309	Conversely, the cell proliferation, and phosphorylation of Akt and mTOR were significantly suppressed by MK2206 in LINC01554-transfected cells.	('suppressed', 'NegReg', (91, 101))	('LINC01554', 'Gene', (115, 124))	('LINC01554', 'Gene', '202299', (115, 124))	('Akt', 'Pathway', (59, 62))	('cell proliferation', 'biological_process', 'GO:0008283', ('16', '34'))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('MK2206', 'Var', (105, 111))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('MK2206', 'Chemical', 'MESH:C548887', (105, 111))	('cell proliferation', 'CPA', (16, 34))	('phosphorylation', 'MPA', (40, 55))
86682	30809309	Most importantly, in vivo functional assay suggests that patients with high expression of LINC01554 might achieve better therapeutic effects from the Akt inhibitor MK2206.	('LINC01554', 'Gene', (90, 99))	('high expression', 'Var', (71, 86))	('MK2206', 'Chemical', 'MESH:C548887', (164, 170))	('LINC01554', 'Gene', '202299', (90, 99))	('patients', 'Species', '9606', (57, 65))	('therapeutic effects', 'CPA', (121, 140))	('better', 'PosReg', (114, 120))
86702	27411958	Clonal expansion of IgG-expressing clones against tumor-associated antigens has been reported to correspond to clinical tumor regression.	('IgG-expressing', 'Gene', (20, 34))	('Clonal', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (120, 125))
86734	27411958	High densities of mutations from both cohorts cluster in areas bordering FWR1/CDR1, FWR2/CDR2, CDR2/FWR3 and in FR3 (red boxes).	('CDR1', 'Gene', (78, 82))	('mutations', 'Var', (18, 27))	('CDR2', 'Gene', '1039', (95, 99))	('CDR2', 'Gene', '1039', (89, 93))	('CDR2', 'Gene', (95, 99))	('CDR1', 'Gene', '1038', (78, 82))	('CDR2', 'Gene', (89, 93))
86735	27411958	This signifies somatic hypermutation, supported by clonally-expanded sequences in melanoma and normal skin samples, featuring point mutation divergence from the germline (red) (Figure S6).	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('point mutation divergence', 'Var', (126, 151))	('melanoma', 'Disease', (82, 90))
86744	27411958	B cell clonal family trees from 3 melanoma samples confirmed melanoma-resident clonal expansion and clonally-related sequences with point mutations at more than one residue (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('point mutations', 'Var', (132, 147))	('melanoma', 'Disease', (34, 42))
86761	27411958	Therefore, the combination of affinity maturation, class switch recombination and clonal expansion might be a feature of melanoma-associated antibodies, consistent with active and heightened humoral responses to a specific antigen repertoire.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('clonal expansion', 'Var', (82, 98))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('class switch recombination', 'biological_process', 'GO:0045190', ('51', '77'))	('heightened', 'PosReg', (180, 190))
86773	27411958	Cells were incubated with antibodies for the following surface markers (BD Biosciences): CD45(V500), CD22 (APC), CD19 (BV605), CD3 (APC-Cy7), CD14 (Alexa Fluor 700) and CLA (FITC).	('CD19', 'Gene', (113, 117))	('CD45', 'Gene', '5788', (89, 93))	('APC', 'cellular_component', 'GO:0005680', ('132', '135'))	('APC', 'Disease', (132, 135))	('CD14', 'Gene', (142, 146))	('CD19', 'Gene', '930', (113, 117))	('CLA', 'Gene', '6404', (169, 172))	('APC', 'cellular_component', 'GO:0005680', ('107', '110'))	('APC', 'Disease', 'MESH:D011125', (107, 110))	('CLA', 'Gene', (169, 172))	('CD22', 'Gene', (101, 105))	('CD14', 'Gene', '929', (142, 146))	('FITC', 'Chemical', 'MESH:D016650', (174, 178))	('APC', 'Disease', 'MESH:D011125', (132, 135))	('CD3', 'Var', (127, 130))	('APC', 'Disease', (107, 110))	('CD22', 'Gene', '933', (101, 105))	('CD45', 'Gene', (89, 93))
86788	27411958	Publicly-available data from n = 234 human skin and melanoma samples were extracted from the Gene Expression Omnibus (GEO) database (GSE7553, n = 58); (GSE46517, n = 93); (GSE8401, n = 83).	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('Gene Expression', 'biological_process', 'GO:0010467', ('93', '108'))	('GSE8401', 'Var', (172, 179))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('GSE7553', 'Chemical', '-', (133, 140))	('GSE7553', 'Var', (133, 140))	('human', 'Species', '9606', (37, 42))	('GSE8401', 'Chemical', '-', (172, 179))	('GSE46517', 'Var', (152, 160))
86807	25847062	Those and many other studies have identified driver mutations and molecular pathways and provided insights into the molecular mechanisms and etiology of cancers (reviewed in).	('mutations', 'Var', (52, 61))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
86834	25847062	The predicted metastatic progression scores in primary tumors based on RNA-seq and miRNA-seq showed positive associations with two of five clinical prognostic factors (Table 1, Supplementary Fig.	('primary tumors', 'Disease', 'MESH:D009369', (47, 61))	('metastatic progression', 'CPA', (14, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('RNA', 'cellular_component', 'GO:0005562', ('71', '74'))	('primary tumors', 'Disease', (47, 61))	('miRNA-seq', 'Var', (83, 92))
86839	25847062	Those genes include C7, members of the KRT family, S100A family, MMP family, SERPINB family, IGFL family, F2RL2, LCE3D, MASP1, PAX1, and WNT2.	('LCE3D', 'Gene', (113, 118))	('LCE3D', 'Gene', '84648', (113, 118))	('SERPINB', 'Gene', (77, 84))	('F2RL2', 'Gene', '2151', (106, 111))	('WNT2', 'Gene', '7472', (137, 141))	('PAX1', 'Gene', (127, 131))	('KRT', 'Gene', '643865', (39, 42))	('MASP1', 'Gene', (120, 125))	('WNT2', 'Gene', (137, 141))	('KRT', 'Gene', (39, 42))	('MMP', 'Gene', '4313;4318;4322;4323', (65, 68))	('MMP', 'Gene', (65, 68))	('MASP1', 'Gene', '5648', (120, 125))	('S100A', 'Var', (51, 56))	('MMP', 'molecular_function', 'GO:0004235', ('65', '68'))	('PAX1', 'Gene', '5075', (127, 131))	('S100A', 'SUBSTITUTION', 'None', (51, 56))	('F2RL2', 'Gene', (106, 111))	('SERPINB', 'Gene', '6317;6318', (77, 84))
86927	21571184	Monosomy 3 and gain of chromosome 8q within the tumor associate with a metastatic phenotype whereas gain of chromosome 6p occurs in tumors with low metastatic risk.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('metastatic', 'Disease', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('Monosomy 3', 'Var', (0, 10))
86930	21571184	Gain-of-function mutations in BRAF (40-50%) or NRAS (15-25%) are common among cutaneous melanomas of the trunk and extremities.	('trunk', 'cellular_component', 'GO:0043198', ('105', '110'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (78, 96))	('NRAS', 'Gene', (47, 51))	('BRAF', 'Gene', (30, 34))	('Gain-of-function', 'PosReg', (0, 16))	('BRAF', 'Gene', '673', (30, 34))	('cutaneous melanomas of the trunk', 'Disease', (78, 110))	('NRAS', 'Gene', '4893', (47, 51))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (78, 97))	('cutaneous melanomas of the trunk', 'Disease', 'MESH:C562393', (78, 110))	('mutations', 'Var', (17, 26))
86931	21571184	Increase gene dosage or mutations of KIT (39%) are observed among acral melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('KIT', 'molecular_function', 'GO:0005020', ('37', '40'))	('acral melanomas', 'Phenotype', 'HP:0012060', (66, 81))	('acral melanomas', 'Disease', 'MESH:D008545', (66, 81))	('KIT', 'Gene', (37, 40))	('mutations', 'Var', (24, 33))	('gene dosage', 'Var', (9, 20))	('melanomas', 'Phenotype', 'HP:0002861', (72, 81))	('acral melanomas', 'Disease', (66, 81))
86933	21571184	These genetic alterations lead to activation of the RAS-ERK pathway that is critical for proliferation, survival, migration, and differentiation signals and is virtually activated in the majority of melanomas.	('melanomas', 'Disease', (199, 208))	('RAS-ERK pathway', 'Pathway', (52, 67))	('activation', 'PosReg', (34, 44))	('ERK', 'molecular_function', 'GO:0004707', ('56', '59'))	('melanomas', 'Disease', 'MESH:D008545', (199, 208))	('melanomas', 'Phenotype', 'HP:0002861', (199, 208))	('genetic alterations', 'Var', (6, 25))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))
86934	21571184	Recently, gain-of-function mutations in the GNAQ gene that leads to RAS-ERK activation have been reported in uveal melanoma (83%) as well as in other melanocytic tumors (summarized in Table 1).	('mutations', 'Var', (27, 36))	('melanocytic tumors', 'Disease', (150, 168))	('melanocytic tumors', 'Disease', 'MESH:D009508', (150, 168))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('GNAQ', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('GNAQ', 'Gene', '2776', (44, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (109, 123))	('gain-of-function', 'PosReg', (10, 26))	('ERK', 'molecular_function', 'GO:0004707', ('72', '75'))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('uveal melanoma', 'Disease', (109, 123))	('RAS-ERK', 'Protein', (68, 75))	('uveal melanoma', 'Phenotype', 'HP:0007716', (109, 123))	('activation', 'PosReg', (76, 86))
86937	21571184	Due to sequence homology to GNAQ, mutations in GNA11 gene were also tested.	('GNAQ', 'Gene', '2776', (28, 32))	('GNA11', 'Gene', '2767', (47, 52))	('GNA11', 'Gene', (47, 52))	('GNAQ', 'Gene', (28, 32))	('mutations', 'Var', (34, 43))
86938	21571184	BRAF mutations were found in 53 (44%) and NRAS in 23 cases (19%), however no mutations in GNAQ or GNA11 were identified.	('NRAS', 'Gene', '4893', (42, 46))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '2767', (98, 103))	('GNAQ', 'Gene', '2776', (90, 94))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('found', 'Reg', (20, 25))	('BRAF', 'Gene', (0, 4))	('GNAQ', 'Gene', (90, 94))	('NRAS', 'Gene', (42, 46))
86940	21571184	Benign melanocytic proliferations have also been associated with somatic mutations of the oncogenes associated with melanoma suggesting that these events occur early during development of melanocytic tumors.	('oncogenes', 'Gene', (90, 99))	('melanocytic tumors', 'Disease', (188, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('associated', 'Reg', (49, 59))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Benign melanocytic proliferations', 'Disease', (0, 33))	('Benign melanocytic proliferations', 'Disease', 'MESH:D059545', (0, 33))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('mutations', 'Var', (73, 82))	('melanocytic tumors', 'Disease', 'MESH:D009508', (188, 206))
86941	21571184	Large number of nevi is a risk factor for cutaneous melanoma; BRAF mutations are common in these nevi.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (42, 60))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (42, 60))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('Large number of nevi', 'Phenotype', 'HP:0001054', (0, 20))	('nevi', 'Phenotype', 'HP:0003764', (97, 101))	('mutations', 'Var', (67, 76))	('nevi', 'Phenotype', 'HP:0003764', (16, 20))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('cutaneous melanoma', 'Disease', (42, 60))
86942	21571184	Giant congenital melanocytic nevus is a risk factor for cutanenous melanoma; NRAS mutations are common in this nevus subset.	('nevus', 'Phenotype', 'HP:0003764', (111, 116))	('congenital melanocytic nevus', 'Phenotype', 'HP:0100814', (6, 34))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('nevus', 'Phenotype', 'HP:0003764', (29, 34))	('melanoma', 'Disease', (67, 75))	('NRAS', 'Gene', (77, 81))	('congenital melanocytic nevus', 'Disease', (6, 34))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('mutations', 'Var', (82, 91))	('NRAS', 'Gene', '4893', (77, 81))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (17, 34))	('Giant congenital melanocytic nevus', 'Phenotype', 'HP:0005600', (0, 34))	('congenital melanocytic nevus', 'Disease', 'MESH:C536819', (6, 34))
86943	21571184	GNAQ mutations are found in blue nevus and nevus of Ota.	('blue nevus', 'Disease', (28, 38))	('nevus of Ota', 'Phenotype', 'HP:0009920', (43, 55))	('GNAQ', 'Gene', '2776', (0, 4))	('found', 'Reg', (19, 24))	('nevus', 'Phenotype', 'HP:0003764', (33, 38))	('nevus of Ota', 'Disease', (43, 55))	('mutations', 'Var', (5, 14))	('nevus', 'Phenotype', 'HP:0003764', (43, 48))	('GNAQ', 'Gene', (0, 4))	('blue nevus', 'Phenotype', 'HP:0100814', (28, 38))
86945	21571184	In conclusion, mutations in GNAQ are unique to uveal melanoma subtype and are rare, if any, in cutaneous melanoma.	('uveal melanoma subtype', 'Disease', 'MESH:C536494', (47, 69))	('GNAQ', 'Gene', '2776', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mutations', 'Var', (15, 24))	('uveal melanoma subtype', 'Disease', (47, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (47, 61))	('cutaneous melanoma', 'Disease', (95, 113))	('GNAQ', 'Gene', (28, 32))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
87077	30262507	Therefore, we chose to test the MAGE-A in a similar autochthonous tumor model in which Braf V600E expression and PTEN loss are driven by Cre activation in melanocytes of the skin by tamoxifen induction (Tyr::CreER; BrafCA/+;Ptenlox/lox mice).	('lox', 'Gene', '16948', (228, 231))	('Braf', 'Gene', (215, 219))	('loss', 'NegReg', (118, 122))	('melanocytes of the skin', 'Phenotype', 'HP:0002861', (155, 178))	('lox', 'Gene', (228, 231))	('Braf', 'Gene', (87, 91))	('mice', 'Species', '10090', (236, 240))	('tumor', 'Disease', (66, 71))	('PTEN', 'Gene', (113, 117))	('tamoxifen', 'Chemical', 'MESH:D013629', (182, 191))	('V600E', 'Var', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Cre', 'CPA', (137, 140))	('lox', 'Gene', '16948', (232, 235))	('Braf', 'Gene', '109880', (215, 219))	('Braf', 'Gene', '109880', (87, 91))	('V600E', 'SUBSTITUTION', 'None', (92, 97))	('lox', 'Gene', (232, 235))	('activation', 'PosReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PTEN', 'Gene', '19211', (113, 117))	('Tyr', 'Chemical', 'MESH:C042696', (203, 206))
87096	30262507	The MAGE-A Consensus #1 vaccine generates cross-reactive immune responses against MAGE-A2, MAGE-A3, MAGE-A6 and MAGE-A12.	('A12', 'Gene', '28887', (117, 120))	('rat', 'Species', '10116', (36, 39))	('MAGE-A2', 'Gene', (82, 89))	('A12', 'Gene', (117, 120))	('MAGE-A6', 'Var', (100, 107))
87102	30262507	The reason for this independent regulation is not clear, nor is our understanding of the individual regulation; however, this family of antigens is thought to be silenced by promoter methylation in normal human tissues.	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('silenced', 'NegReg', (162, 170))	('promoter methylation', 'Var', (174, 194))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('human', 'Species', '9606', (205, 210))	('regulation', 'biological_process', 'GO:0065007', ('32', '42'))
87103	30262507	This methylation is removed in tumor cells due to epigenetic re-programming.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('epigenetic re-programming', 'Var', (50, 75))
87219	29641692	In 2008, Viros et al.demonstrated a high frequency of BRAF mutations (68.8%) and a low frequency of NRAS mutations (12.5%) in 16 patients with nodular melanoma.	('NRAS', 'Gene', '4893', (100, 104))	('BRAF', 'Gene', (54, 58))	('patients', 'Species', '9606', (129, 137))	('BRAF', 'Gene', '673', (54, 58))	('nodular melanoma', 'Disease', 'MESH:D020518', (143, 159))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('mutations', 'Var', (59, 68))	('nodular melanoma', 'Disease', (143, 159))	('NRAS', 'Gene', (100, 104))	('nodular melanoma', 'Phenotype', 'HP:0012058', (143, 159))
87243	29641692	According to Murali et al.,the presence of mitosis correlated with the reduction in the time for disease recurrence.	('time for disease recurrence', 'MPA', (88, 115))	('reduction', 'NegReg', (71, 80))	('mitosis', 'Disease', (43, 50))	('mitosis', 'biological_process', 'GO:0000278', ('43', '50'))	('mitosis', 'Disease', 'None', (43, 50))	('presence', 'Var', (31, 39))
87247	29641692	demonstrated that the presence of mitosis in the histopathology was associated to the reduction in disease-free survival (RR=1.911).	('reduction', 'NegReg', (86, 95))	('disease-free survival', 'CPA', (99, 120))	('presence', 'Var', (22, 30))	('mitosis', 'Disease', (34, 41))	('mitosis', 'Disease', 'None', (34, 41))	('mitosis', 'biological_process', 'GO:0000278', ('34', '41'))
87282	29858490	However, it remains largely unknown if and how miRNAs-365 plays a role in melanoma development.	('melanoma', 'Disease', (74, 82))	('miRNAs-365', 'Var', (47, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))
87290	29858490	We also found that the phenotypic alterations by miR-365 were partially due to downregulation of CCND1 and BCL2 oncogenes.	('CCND1', 'Gene', (97, 102))	('BCL2', 'Gene', '596', (107, 111))	('miR-365', 'Chemical', '-', (49, 56))	('CCND1', 'Gene', '595', (97, 102))	('BCL2', 'molecular_function', 'GO:0015283', ('107', '111'))	('miR-365', 'Var', (49, 56))	('downregulation', 'NegReg', (79, 93))	('BCL2', 'Gene', (107, 111))
87298	29858490	Deregulated miRNA expression has been shown to contribute to the development of cancers, including breast cancer, digestive tract cancers, melanoma, and so forth.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('tract cancers', 'Disease', 'MESH:D014571', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tract cancers', 'Disease', (124, 137))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', (80, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('contribute', 'Reg', (47, 57))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('breast cancer', 'Disease', (99, 112))	('cancers', 'Disease', (130, 137))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('miRNA expression', 'Protein', (12, 28))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
87302	29858490	MiR-365 may display either a pro-proliferative or pro-apoptotic role in a specific cancer type.	('MiR-365', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MiR-365', 'Chemical', '-', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
87362	29858490	In addition, we also found that miR-365 led to a substantial increase in cell apoptosis (Figure 1F).	('cell apoptosis', 'CPA', (73, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('miR-365', 'Chemical', '-', (32, 39))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('increase', 'PosReg', (61, 69))	('miR-365', 'Var', (32, 39))
87363	29858490	Together, these results indicated that miR-365 played a tumor suppressive role in melanoma likely through inhibiting cell proliferation, blocking cell cycle progression and enhancing cell apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('cell cycle', 'biological_process', 'GO:0007049', ('146', '156'))	('miR-365', 'Var', (39, 46))	('inhibiting', 'NegReg', (106, 116))	('tumor', 'Disease', (56, 61))	('cell proliferation', 'CPA', (117, 135))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('cell cycle progression', 'CPA', (146, 168))	('melanoma', 'Disease', (82, 90))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('blocking', 'NegReg', (137, 145))	('enhancing', 'PosReg', (173, 182))	('cell apoptosis', 'CPA', (183, 197))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('miR-365', 'Chemical', '-', (39, 46))
87370	29858490	As expected, mRNA (Figure 3A) and protein levels (Figure 3B) of BCL2 and CCND1 were significantly downregulated in cells overexpressing miR-365 compared to control cells.	('downregulated', 'NegReg', (98, 111))	('CCND1', 'Gene', (73, 78))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('BCL2', 'molecular_function', 'GO:0015283', ('64', '68'))	('miR-365', 'Var', (136, 143))	('mRNA', 'MPA', (13, 17))	('BCL2', 'Gene', '596', (64, 68))	('CCND1', 'Gene', '595', (73, 78))	('miR-365', 'Chemical', '-', (136, 143))	('BCL2', 'Gene', (64, 68))
87391	29858490	For example, miR-365 was reported to suppress cell cycle progression and promote apoptosis of colon cancer cells by probably targeting Cyclin D1 and Bcl-2; miR-365 expression levels were reduced in lung cancer tissues and ectopic miR-365 expression could inhibit cell proliferation of lung cancer cell lines by targeting thyroid transcription factor 1 (TTF-1), which is an essential factor in lung developmental and a prognostic marker for non-small cell lung cancer.	('apoptosis', 'biological_process', 'GO:0006915', ('81', '90'))	('miR-365', 'Chemical', '-', (230, 237))	('Bcl-2', 'Gene', (149, 154))	('Cyclin', 'molecular_function', 'GO:0016538', ('135', '141'))	('lung cancer', 'Disease', 'MESH:D008175', (455, 466))	('cell cycle progression', 'CPA', (46, 68))	('lung cancer', 'Disease', (285, 296))	('cell proliferation', 'biological_process', 'GO:0008283', ('263', '281'))	('promote', 'PosReg', (73, 80))	('cell proliferation', 'CPA', (263, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (455, 466))	('lung cancer', 'Disease', (198, 209))	('miR-365', 'Gene', (156, 163))	('non-small cell lung cancer', 'Disease', (440, 466))	('Cyclin D1', 'Gene', '595', (135, 144))	('miR-365', 'Chemical', '-', (13, 20))	('transcription', 'biological_process', 'GO:0006351', ('329', '342'))	('Cyclin D1', 'Gene', (135, 144))	('colon cancer', 'Disease', (94, 106))	('Bcl-2', 'Gene', '596', (149, 154))	('cell cycle', 'biological_process', 'GO:0007049', ('46', '56'))	('transcription factor', 'molecular_function', 'GO:0000981', ('329', '349'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('149', '154'))	('miR-365', 'Chemical', '-', (156, 163))	('lung cancer', 'Disease', 'MESH:D008175', (285, 296))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('targeting', 'Reg', (311, 320))	('ectopic', 'Var', (222, 229))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (440, 466))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (444, 466))	('thyroid transcription factor 1', 'Gene', (321, 351))	('lung cancer', 'Phenotype', 'HP:0100526', (285, 296))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('TTF-1', 'Gene', '7080', (353, 358))	('TTF-1', 'Gene', (353, 358))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('expression', 'MPA', (164, 174))	('apoptosis', 'CPA', (81, 90))	('thyroid transcription factor 1', 'Gene', '7080', (321, 351))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('suppress', 'NegReg', (37, 45))	('reduced', 'NegReg', (187, 194))	('miR-365', 'Gene', (230, 237))	('apoptosis', 'biological_process', 'GO:0097194', ('81', '90'))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (440, 466))	('inhibit', 'NegReg', (255, 262))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
87397	29858490	And the levels of miR-365 was not relevant to the status of BRAF mutation, as it was significantly decreased in both BRAF wildtype cell lines, A375, A2058, and SK-MEL-28, and in BRAF mutant cell lines, SK-MEL-2.	('SK-MEL-2', 'CellLine', 'CVCL:0069', (202, 210))	('A375', 'CellLine', 'CVCL:0132', (143, 147))	('decreased', 'NegReg', (99, 108))	('A2058', 'CellLine', 'CVCL:1059', (149, 154))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (183, 189))	('miR-365', 'Chemical', '-', (18, 25))	('BRAF', 'Gene', '673', (117, 121))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (160, 168))	('mutation', 'Var', (65, 73))	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (178, 182))	('BRAF', 'Gene', (117, 121))
87398	29858490	Next, we found that overexpression of miR-365 led to significant decrease in cell viability (Figure 1C).	('miR-365', 'Chemical', '-', (38, 45))	('overexpression', 'PosReg', (20, 34))	('miR-365', 'Var', (38, 45))	('decrease', 'NegReg', (65, 73))	('cell viability', 'CPA', (77, 91))
87400	29858490	In addition, miR-365 significantly compromised the migration and invasion capacities of melanoma cell in vitro (Figure 2A, 2B).	('miR-365', 'Chemical', '-', (13, 20))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('compromised', 'NegReg', (35, 46))	('miR-365', 'Var', (13, 20))	('melanoma cell', 'Disease', (88, 101))	('melanoma cell', 'Disease', 'MESH:D008545', (88, 101))
87401	29858490	study in melanoma and suggested that miR-365 functioned as a tumor suppressor in melanoma.	('miR-365', 'Chemical', '-', (37, 44))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('miR-365', 'Var', (37, 44))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('tumor suppressor', 'biological_process', 'GO:0051726', ('61', '77'))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('61', '77'))	('tumor', 'Disease', (61, 66))
87409	29858490	study which has shown that BCL2 and CCND1 are direct targets of miR-365 in colon cancer and that knockdown of the endogenous CCND1 or BCL2 was able to mimic the effect of miR-365.	('CCND1', 'Gene', (125, 130))	('miR-365', 'Chemical', '-', (171, 178))	('knockdown', 'Var', (97, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('BCL2', 'Gene', (134, 138))	('BCL2', 'molecular_function', 'GO:0015283', ('27', '31'))	('miR-365', 'Gene', (64, 71))	('BCL2', 'Gene', (27, 31))	('CCND1', 'Gene', '595', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CCND1', 'Gene', (36, 41))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('colon cancer', 'Disease', (75, 87))	('CCND1', 'Gene', '595', (36, 41))	('BCL2', 'Gene', '596', (134, 138))	('BCL2', 'molecular_function', 'GO:0015283', ('134', '138'))	('BCL2', 'Gene', '596', (27, 31))	('miR-365', 'Chemical', '-', (64, 71))
87410	29858490	Together, these results suggested that miR-365 probably is a novel tumor suppresser in melanoma through targeting CCND1 and BCL2, as well as other potential targets.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('BCL2', 'molecular_function', 'GO:0015283', ('124', '128'))	('CCND1', 'Gene', (114, 119))	('miR-365', 'Var', (39, 46))	('BCL2', 'Gene', '596', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BCL2', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CCND1', 'Gene', '595', (114, 119))	('tumor', 'Disease', (67, 72))	('targeting', 'Reg', (104, 113))	('miR-365', 'Chemical', '-', (39, 46))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
87419	29858490	Furthermore, Kaplan-Meier analysis failed to discover significant difference in OS and DFS between patients with high and low miR-365 levels (both P>0.05, Figure 5B, 5C).	('patients', 'Species', '9606', (99, 107))	('miR-365', 'Var', (126, 133))	('DFS', 'MPA', (87, 90))	('miR-365', 'Chemical', '-', (126, 133))
87430	29136453	High-dose or pegylated interferon (IFN) alfa has been shown to improve relapse-free survival (RFS) in patients with surgically resected cutaneous melanoma; however, its efficacy in terms of overall survival (OS) is marginal, and the incidence of severe adverse events (AEs) is relatively high.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('cutaneous melanoma', 'Disease', (136, 154))	('patients', 'Species', '9606', (102, 110))	('interferon', 'Gene', '3439', (23, 33))	('IFN', 'Gene', '3439', (35, 38))	('OS', 'Chemical', '-', (208, 210))	('improve', 'PosReg', (63, 70))	('interferon', 'Gene', (23, 33))	('pegylated', 'Var', (13, 22))	('IFN', 'Gene', (35, 38))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('relapse-free', 'Disease', (71, 83))
87439	29136453	However, these agents have some disadvantages; the costs of these emerging therapies are extremely high, immune-related AEs can occasionally be serious, some endocrine-related AEs can last for long periods of time during which hormone replacement therapy must be continued, and the incidence of BRAF mutation in Asian populations is relatively low.	('BRAF', 'Gene', (295, 299))	('immune-related AEs', 'Disease', (105, 123))	('mutation', 'Var', (300, 308))	('BRAF', 'Gene', '673', (295, 299))
87440	29136453	Recently, the EORTC18071 trial, in which patients with postoperative stage III cutaneous melanoma were randomly assigned to receive ipilimumab at a dose of 10 mg/kg or placebo, showed that ipilimumab resulted in a significantly longer OS than placebo.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('ipilimumab', 'Chemical', 'MESH:D000074324', (189, 199))	('patients', 'Species', '9606', (41, 49))	('ipilimumab', 'Chemical', 'MESH:D000074324', (132, 142))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('ipilimumab', 'Var', (189, 199))	('III cutaneous melanoma', 'Disease', (75, 97))	('III cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 97))	('OS', 'Chemical', '-', (235, 237))	('longer', 'PosReg', (228, 234))
87442	29136453	Since ipilimumab was efficacious in the adjuvant setting, anti-PD-1 antibody might also be capable of activating T cells effectively in the absence of measurable metastatic disease.	('antibody', 'molecular_function', 'GO:0003823', ('68', '76'))	('activating', 'MPA', (102, 112))	('ipilimumab', 'Chemical', 'MESH:D000074324', (6, 16))	('T cells', 'CPA', (113, 120))	('anti-PD-1', 'Var', (58, 67))	('antibody', 'cellular_component', 'GO:0042571', ('68', '76'))	('antibody', 'cellular_component', 'GO:0019815', ('68', '76'))	('antibody', 'cellular_component', 'GO:0019814', ('68', '76'))
87443	29136453	Even if the presently ongoing phase III trials of adjuvant therapy with anti-PD-1 antibodies or ipilimumab (3 mg/kg) show that it is associated with a significantly improved OS with tolerable toxicity, the JCOG1309 study will be continued by revising the protocol to limit the enrolled subjects to patients with stage II or IIIA disease, in whom immunity is less likely to be activated against clinically occult melanoma cells than in patients with more advanced stage disease.	('toxicity', 'Disease', 'MESH:D064420', (192, 200))	('toxicity', 'Disease', (192, 200))	('ipilimumab', 'Chemical', 'MESH:D000074324', (96, 106))	('IIIA disease', 'Disease', (324, 336))	('stage II', 'Disease', (312, 320))	('anti-PD-1', 'Var', (72, 81))	('patients', 'Species', '9606', (298, 306))	('patients', 'Species', '9606', (435, 443))	('IIIA disease', 'Disease', 'MESH:C566889', (324, 336))	('OS', 'Chemical', '-', (174, 176))	('melanoma', 'Disease', 'MESH:D008545', (412, 420))	('melanoma', 'Phenotype', 'HP:0002861', (412, 420))	('melanoma', 'Disease', (412, 420))
87498	33546587	In the liver cancer subtyping and survival analysis, the auto-encoder model was first employed to reduce the dimensions of the feature space given the large-number of genomics features (e.g., gene expression, miRNA, methylation).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('miRNA', 'MPA', (209, 214))	('gene expression', 'biological_process', 'GO:0010467', ('192', '207'))	('liver cancer', 'Phenotype', 'HP:0002896', (7, 19))	('liver cancer', 'Disease', 'MESH:D006528', (7, 19))	('methylation', 'Var', (216, 227))	('liver cancer', 'Disease', (7, 19))	('methylation', 'biological_process', 'GO:0032259', ('216', '227'))
87515	33546587	In summary, there are gene expression (TPM) and copy number variation data of 1967 genes in 46 signaling pathways of 45 cancer cell lines, which was used as the input for the deep learning model.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('copy number variation', 'Var', (48, 69))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('gene expression', 'biological_process', 'GO:0010467', ('22', '37'))
87600	27689028	Individuals with a tendency to become sunburned, who have Fitzpatrick skin phototype I-III, blond or red hair, blue or green eyes, and skin that is resistant to pigmentation and prominently freckled have an increased risk of melanoma.	('pigmentation', 'Disease', (161, 173))	('freckled', 'Phenotype', 'HP:0001480', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('blond', 'Var', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('melanoma', 'Disease', (225, 233))	('red hair', 'Phenotype', 'HP:0002297', (101, 109))	('green eyes', 'Phenotype', 'HP:0000635', (119, 129))	('pigmentation', 'biological_process', 'GO:0043473', ('161', '173'))	('pigmentation', 'Disease', 'MESH:D010859', (161, 173))
87606	27689028	GCMN are well-known risk factors for melanoma development, especially in children.	('children', 'Species', '9606', (73, 81))	('GCMN', 'Var', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))
87618	27689028	In Asians, KIT aberrations, such as mutations and increased copy numbers, are the most frequent changes in cutaneous melanoma of Chinese and Japanese populations.	('cutaneous melanoma', 'Disease', (107, 125))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (107, 125))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (107, 125))	('increased', 'PosReg', (50, 59))	('mutations', 'Var', (36, 45))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('copy', 'MPA', (60, 64))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))
87645	27689028	Moreover, the 5-year survival was significantly different between patient groups with immediate lymphadenectomy based on a positive SLNB versus those who underwent lymphadenectomy after the metastatic lymph nodes became palpable (72% vs. 52%).	('positive', 'Var', (123, 131))	('different', 'Reg', (48, 57))	('patient', 'Species', '9606', (66, 73))	('SLN', 'Gene', (132, 135))	('SLN', 'Gene', '6588', (132, 135))
87660	27689028	The above-mentioned KIT inhibitor imatinib has been used effectively in patients with melanomas harboring KIT mutations.	('KIT', 'molecular_function', 'GO:0005020', ('20', '23'))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('mutations', 'Var', (110, 119))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('melanomas', 'Disease', (86, 95))	('imatinib', 'Chemical', 'MESH:D000068877', (34, 42))	('KIT', 'Gene', (106, 109))	('patients', 'Species', '9606', (72, 80))
87661	27689028	Vemurafenib and dabrafenib have also produced significant responses in melanomas with BRAF mutations.	('melanomas', 'Disease', (71, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('melanomas', 'Disease', 'MESH:D008545', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '673', (86, 90))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('mutations', 'Var', (91, 100))	('BRAF', 'Gene', (86, 90))
87672	20701774	The differential protein profiles of two kinds of subcutaneous transplanted tumor tissues, which was parental B16F10 (B16 group) and corresponding lung metastases (B16M group) were detected by two-dimensional differential in-gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS).	('flight', 'biological_process', 'GO:0060361', ('321', '327'))	('B16F10', 'CellLine', 'CVCL:0159', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('B16M', 'SUBSTITUTION', 'None', (164, 168))	('lung metastases', 'Disease', (147, 162))	('B16M', 'Var', (164, 168))	('lung metastases', 'Disease', 'MESH:D009362', (147, 162))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
87674	20701774	Highly expressed proteins in B16M group included cytoskeleton/structure proteins (vimentin, gamma-actin, beta-actin, laminin binding protein), the chaperone family of proteins (heavy-chain binding protein, Bip), immunoproteasome assembly (proteasome activator REG alpha) and others involved in glycolysis activity (PGK1, enolase, TPI, human skeletal muscle GAPDH) and protein transport (myoglobin).	('protein', 'cellular_component', 'GO:0003675', ('368', '375'))	('beta-actin', 'Gene', '728378', (105, 115))	('B16M', 'Var', (29, 33))	('vimentin', 'Gene', '7431', (82, 90))	('Bip', 'Gene', (206, 209))	('REG alpha', 'Gene', (260, 269))	('vimentin', 'Gene', (82, 90))	('vimentin', 'cellular_component', 'GO:0045098', ('82', '90'))	('human', 'Species', '9606', (335, 340))	('binding', 'molecular_function', 'GO:0005488', ('189', '196'))	('REG alpha', 'Gene', '5720', (260, 269))	('laminin binding', 'molecular_function', 'GO:0043236', ('117', '132'))	('protein transport', 'biological_process', 'GO:0015031', ('368', '385'))	('beta-actin', 'Gene', (105, 115))	('vimentin', 'cellular_component', 'GO:0045099', ('82', '90'))	('glycolysis', 'biological_process', 'GO:0006096', ('294', '304'))	('TPI', 'Gene', '7167', (330, 333))	('laminin binding protein', 'Gene', '3958', (117, 140))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('PGK1', 'Gene', '5230', (315, 319))	('proteasome', 'molecular_function', 'GO:0004299', ('239', '249'))	('laminin binding protein', 'Gene', (117, 140))	('PGK', 'molecular_function', 'GO:0004618', ('315', '318'))	('B16M', 'SUBSTITUTION', 'None', (29, 33))	('cytoskeleton', 'cellular_component', 'GO:0005856', ('49', '61'))	('PGK1', 'Gene', (315, 319))	('Bip', 'Gene', '3309', (206, 209))	('proteasome', 'cellular_component', 'GO:0000502', ('239', '249'))	('protein', 'cellular_component', 'GO:0003675', ('197', '204'))	('TPI', 'Gene', (330, 333))
87675	20701774	Vimentin was significantly up-regulated in B16M group compared with B16 group which was validated by western blotting.	('up-regulated', 'PosReg', (27, 39))	('Vimentin', 'Gene', '7431', (0, 8))	('Vimentin', 'cellular_component', 'GO:0045098', ('0', '8'))	('Vimentin', 'cellular_component', 'GO:0045099', ('0', '8'))	('B16M', 'Var', (43, 47))	('B16M', 'SUBSTITUTION', 'None', (43, 47))	('Vimentin', 'Gene', (0, 8))
87678	20701774	The aberrant immunohistochemical expression of vimentin in primary melanoma tissues may help to call attention for patients with high risk of hematogenous metastasis.	('patients', 'Species', '9606', (115, 123))	('vimentin', 'cellular_component', 'GO:0045098', ('47', '55'))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('aberrant', 'Var', (4, 12))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('vimentin', 'Gene', '7431', (47, 55))	('vimentin', 'Gene', (47, 55))	('vimentin', 'cellular_component', 'GO:0045099', ('47', '55'))
87688	20701774	It is a method of prelabeling fluorescent cyanine dyes (Cy2, Cy3, Cy5) to different samples prior to 2-DE.	('Cy3', 'Var', (61, 64))	('cyanine', 'Chemical', 'MESH:C009469', (42, 49))	('Cy3', 'Chemical', '-', (61, 64))	('Cy2', 'Var', (56, 59))	('Cy5', 'Chemical', 'MESH:C085321', (66, 69))	('Cy2', 'Chemical', '-', (56, 59))
87692	20701774	Therefore, using the subcutaneous transplanted tumor tissues from parental B16-F10 (B16 group) and corresponding lung metastases (B16M group) as proteomic objectives may be the most directly and persuasively way to discover metastatic biomarkers for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('lung metastases', 'Disease', (113, 128))	('B16M', 'Var', (130, 134))	('B16M', 'SUBSTITUTION', 'None', (130, 134))	('lung metastases', 'Disease', 'MESH:D009362', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
87698	20701774	Till the commence of our study, eight spontaneous metastatic models (B16M group) have been created, and the lungs with metastases have been inoculated into the mice groin to be passaged subsequently.	('B16M', 'SUBSTITUTION', 'None', (69, 73))	('metastases', 'Disease', (119, 129))	('mice', 'Species', '10090', (160, 164))	('B16M', 'Var', (69, 73))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
87704	20701774	Fifty ug of individual sample lysates were labeled with Cy3 or Cy5 (200 pmol), and equal quantities samples mixed was labeled with Cy2 as the internal pool standard on all gels to aid protein-spot matching cross-gel.	('Cy3', 'Chemical', '-', (56, 59))	('Cy2', 'Chemical', '-', (131, 134))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('Cy3', 'Var', (56, 59))	('Cy5', 'Var', (63, 66))	('Cy5', 'Chemical', 'MESH:C085321', (63, 66))
87709	20701774	Differential in-gel analysis (DIA) module was used to detect the merged images of Cy2, Cy3 and Cy5 for each gel, while biological variation analysis (BVA) module was used to automatic match all protein-spot maps.	('Cy5', 'Var', (95, 98))	('Cy3', 'Var', (87, 90))	('Cy5', 'Chemical', 'MESH:C085321', (95, 98))	('Cy2', 'Chemical', '-', (82, 85))	('protein', 'cellular_component', 'GO:0003675', ('194', '201'))	('Cy2', 'Var', (82, 85))	('Cy3', 'Chemical', '-', (87, 90))
87733	20701774	MALDI-TOF/TOF-MS analysis and database matching identified spot 625 was vimentin with high sequence coverage and mass accuracy (Figure 1A-C).	('vimentin', 'cellular_component', 'GO:0045099', ('72', '80'))	('vimentin', 'Gene', '7431', (72, 80))	('spot 625', 'Var', (59, 67))	('vimentin', 'cellular_component', 'GO:0045098', ('72', '80'))	('vimentin', 'Gene', (72, 80))
87734	20701774	Western blotting was performed to verify the differential expression of vimentin in eight pairs of B16M group and B16 group.	('vimentin', 'cellular_component', 'GO:0045099', ('72', '80'))	('vimentin', 'Gene', '7431', (72, 80))	('vimentin', 'cellular_component', 'GO:0045098', ('72', '80'))	('vimentin', 'Gene', (72, 80))	('B16M', 'Var', (99, 103))	('B16M', 'SUBSTITUTION', 'None', (99, 103))
87736	20701774	As shown in Figure 1D-E, vimentin was significantly up-regulated in B16M group compared to B16 group (P < 0.05), which was consistent with the 2D-DIGE results.	('vimentin', 'Gene', (25, 33))	('up-regulated', 'PosReg', (52, 64))	('vimentin', 'cellular_component', 'GO:0045098', ('25', '33'))	('B16M', 'Var', (68, 72))	('B16M', 'SUBSTITUTION', 'None', (68, 72))	('vimentin', 'Gene', '7431', (25, 33))	('vimentin', 'cellular_component', 'GO:0045099', ('25', '33'))
87759	20701774	Vimentin was up-regulated 2.06 folds in the B16M group compared with the B16 group in 2D-DIGE and the result was confirmed by western blotting subsequently.	('Vimentin', 'Gene', '7431', (0, 8))	('Vimentin', 'cellular_component', 'GO:0045098', ('0', '8'))	('B16M', 'Var', (44, 48))	('B16M', 'SUBSTITUTION', 'None', (44, 48))	('Vimentin', 'cellular_component', 'GO:0045099', ('0', '8'))	('up-regulated', 'PosReg', (13, 25))	('Vimentin', 'Gene', (0, 8))
87761	20701774	The data showed that high expression of vimentin was significantly associated with melanoma hematogenous metastasis.	('melanoma hematogenous metastasis', 'Disease', (83, 115))	('vimentin', 'cellular_component', 'GO:0045099', ('40', '48'))	('vimentin', 'cellular_component', 'GO:0045098', ('40', '48'))	('high', 'Var', (21, 25))	('vimentin', 'Gene', '7431', (40, 48))	('associated', 'Reg', (67, 77))	('melanoma hematogenous metastasis', 'Disease', 'MESH:D009362', (83, 115))	('vimentin', 'Gene', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
87790	20701774	The aberrant immunohistochemistry expression of vimentin in primary melanoma tissues may help to call attention for patients with high risk of hematogenous metastasis.	('vimentin', 'Gene', '7431', (48, 56))	('vimentin', 'Gene', (48, 56))	('patients', 'Species', '9606', (116, 124))	('aberrant', 'Var', (4, 12))	('vimentin', 'cellular_component', 'GO:0045099', ('48', '56'))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('vimentin', 'cellular_component', 'GO:0045098', ('48', '56'))
87804	31391007	In particular, these effects may compromise the reliability and the potency to detect new cancer predisposition genes.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('effects', 'Var', (21, 28))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('compromise', 'NegReg', (33, 43))
87807	31391007	Identifying predisposition variants underlying cancer heritability is of utmost importance and a critical milestone for personalized medicine.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('variants', 'Var', (27, 35))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
87808	31391007	Strong evidence for variant contribution to cancer development is evident in tens of genes, many of them are rare.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('contribution', 'Reg', (28, 40))	('variant', 'Var', (20, 27))	('men', 'Species', '9606', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
87809	31391007	For example, inherited mutations in BRCA1 and BRCA2 carry high risk for breast and ovarian in women, prostate in men and pancreatic cancer in both gender.	('women', 'Species', '9606', (94, 99))	('men', 'Species', '9606', (96, 99))	('BRCA1', 'Gene', (36, 41))	('BRCA2', 'Gene', (46, 51))	('pancreatic cancer', 'Disease', (121, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('risk', 'Reg', (63, 67))	('BRCA2', 'Gene', '675', (46, 51))	('mutations', 'Var', (23, 32))	('men', 'Species', '9606', (113, 116))	('breast and ovarian', 'Disease', 'MESH:D010051', (72, 90))	('BRCA1', 'Gene', '672', (36, 41))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('prostate', 'Disease', (101, 109))
87810	31391007	The risk and prevalence of specific germline variants in cancer predisposition genes greatly vary across ethnicities and cancer types, as illustrated by the high prevalence of BRCA1 and BRCA2 variants in Ashkenazi Jews.	('variants', 'Var', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('BRCA2', 'Gene', (186, 191))	('BRCA1', 'Gene', '672', (176, 181))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('BRCA1', 'Gene', (176, 181))	('BRCA2', 'Gene', '675', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
87821	31391007	Within each gene, we collected all the called variants (from all samples), and partitioned them into six groups according to the cancer types they had originated from.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('variants', 'Var', (46, 54))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
87833	31391007	The most prominent characteristic shared by cancer types with similar numbers of called variants is the sequencing center contributing to the collection in TCGA (Fig.	('variants', 'Var', (88, 96))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
87840	31391007	Additional file 1: Table S2 provides estimated values for the average number of variants per sample across all 33 cancer types in TCGA.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('variants', 'Var', (80, 88))	('cancer', 'Disease', (114, 120))
87842	31391007	For the six shared cancer types, we report an almost perfect correlation (r = 0.91) between the average number of variants per sample calculated in our analysis to these numbers extracted from Huang, 2018 #242} (Additional file 1: Figure S3B).	('variants', 'Var', (114, 122))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
87847	31391007	We conclude that there are consistent variations among samples from different sequencing centers that are more substantial than naive scaling, leading to enrichment or depletion of called variants in specific genes.	('variants', 'Var', (188, 196))	('men', 'Species', '9606', (160, 163))	('depletion', 'NegReg', (168, 177))
87850	31391007	We noted marked differences associated with the sequencing centers in the distribution of variants along three of these cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (90, 98))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
87858	31391007	We assume that if the identity and distribution of called variants along genes have no impact on pan-cancer downstream clinical interpretation, there will be no difference between genes that are prone to such batch effect and those that are unaffected by it.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('variants', 'Var', (58, 66))
87863	31391007	We expanded the KS paired statistics analysis to include all genes with variants in all six cancer types (overall, 18,421 genes).	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('KS', 'Chemical', '-', (16, 18))	('variants', 'Var', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
87921	30694001	Combining the prognostic outcomes of both GEP and SLN status increased the accuracy of identifying high-risk cases, with sensitivities for recurrence, distant metastasis, all-cause death, and death due to melanoma of 81%, 80%, 82%, and 88%, respectively, and negative predictive values of 81%, 82%, 88%, and 96%, respectively.	('GEP', 'Var', (42, 45))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('death', 'Disease', 'MESH:D003643', (192, 197))	('distant metastasis', 'CPA', (151, 169))	('death', 'Disease', (192, 197))	('death', 'Disease', (181, 186))	('death', 'Disease', 'MESH:D003643', (181, 186))	('increased', 'PosReg', (61, 70))	('SLN', 'Gene', (50, 53))
87963	27321895	C-MIN 6 or greater corresponds to conjunctival melanoma in situ.	('conjunctival melanoma', 'Disease', (34, 55))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (34, 55))	('C-MIN 6', 'Var', (0, 7))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (34, 55))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))
87969	27321895	The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) is an oncogenic mutation in one of the RAF genes and a known contributor to the formation of cutaneous melanoma.	('cutaneous melanoma', 'Disease', (151, 169))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('mutation', 'Var', (74, 82))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (151, 169))	('RAF', 'Gene', (97, 100))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (151, 169))	('RAF', 'Gene', '673;109880', (97, 100))	('RAF', 'Gene', '673;109880', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('formation', 'biological_process', 'GO:0009058', ('138', '147'))	('RAF', 'Gene', (53, 56))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', '673', (4, 50))	('v-raf murine sarcoma viral oncogene homolog B1', 'Gene', (4, 50))
87972	27321895	conducted a large genetic analysis of 78 conjunctival melanoma samples using oncogene hotspot array to screen for known cancer-relevant mutations and found BRAF (of which 91% were V600E) mutations in 29% of the tumors and NRAS in 18% of the tumors, similar to cutaneous melanomas.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (120, 126))	('melanomas', 'Phenotype', 'HP:0002861', (270, 279))	('NRAS', 'Gene', '4893', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('V600E', 'Var', (180, 185))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (41, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (41, 62))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (260, 279))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (260, 279))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (260, 278))	('BRAF', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('NRAS', 'Gene', (222, 226))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cutaneous melanomas', 'Disease', (260, 279))	('tumors', 'Disease', (241, 247))	('conjunctival melanoma', 'Disease', (41, 62))	('V600E', 'Mutation', 'rs113488022', (180, 185))
87973	27321895	GNAQ and GNA11 mutations, often found in uveal melanomas, were not detected in the conjunctival melanomas.	('GNA11', 'Gene', (9, 14))	('uveal melanoma', 'Phenotype', 'HP:0007716', (41, 55))	('GNAQ', 'Gene', '2776', (0, 4))	('mutations', 'Var', (15, 24))	('uveal melanomas', 'Disease', (41, 56))	('uveal melanomas', 'Phenotype', 'HP:0007716', (41, 56))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanomas', 'Phenotype', 'HP:0002861', (47, 56))	('conjunctival melanomas', 'Disease', 'MESH:D003229', (83, 105))	('GNAQ', 'Gene', (0, 4))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (83, 104))	('conjunctival melanomas', 'Disease', (83, 105))	('uveal melanomas', 'Disease', 'MESH:C536494', (41, 56))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('GNA11', 'Gene', '2767', (9, 14))
87974	27321895	also detected the BRAF V600E mutation in 50% of primary tumor samples and 67% in the metastatic samples.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('V600E', 'Mutation', 'rs113488022', (23, 28))	('tumor', 'Disease', (56, 61))	('detected', 'Reg', (5, 13))	('V600E', 'Var', (23, 28))	('BRAF', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
87977	27321895	used CGH in two conjunctival melanoma samples and found multiple chromosomal changes, most notably 10q and 16q loss that is also found in cutaneous melanomas.	('loss', 'NegReg', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (16, 37))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('conjunctival melanoma', 'Phenotype', 'HP:0007716', (16, 37))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (138, 157))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (138, 157))	('10q', 'Var', (99, 102))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (138, 156))	('melanomas', 'Phenotype', 'HP:0002861', (148, 157))	('cutaneous melanomas', 'Disease', (138, 157))	('multiple chromosomal changes', 'Phenotype', 'HP:0040012', (56, 84))	('16q', 'Var', (107, 110))	('conjunctival melanoma', 'Disease', (16, 37))
87978	27321895	reported frequent copy number amplifications of CDKN1A and RUNX2 in primary tumors (6p21.2), both of which have been implicated in cutaneous melanoma tumorigenesis.	('primary tumors', 'Disease', (68, 82))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('primary tumors', 'Disease', 'MESH:D009369', (68, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CDKN1A', 'Gene', (48, 54))	('CDKN1A', 'Gene', '1026', (48, 54))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cutaneous melanoma', 'Disease', (131, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('implicated', 'Reg', (117, 127))	('tumor', 'Disease', (150, 155))	('copy number amplifications', 'Var', (18, 44))	('RUNX2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('RUNX2', 'Gene', '860', (59, 64))
87985	27321895	Mutation of the CDKN2A gene, resulting in decreased p16 protein production, leads to increase mitotic activity and replication and hence melanoma genesis.	('p16', 'Gene', '1029', (52, 55))	('decreased', 'NegReg', (42, 51))	('hence melanoma genesis', 'Disease', 'MESH:D008545', (131, 153))	('hence melanoma genesis', 'Disease', (131, 153))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('Mutation', 'Var', (0, 8))	('mitotic activity', 'CPA', (94, 110))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('p16', 'Gene', (52, 55))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('replication', 'CPA', (115, 126))	('increase', 'PosReg', (85, 93))
87991	27321895	It has been suggested that PLX4023 (vemurafenib), a BRAF inhibitor specific for the V600E mutation, could be used for treatment of metastases.	('metastases', 'Disease', (131, 141))	('V600E', 'Mutation', 'rs113488022', (84, 89))	('PLX4023', 'Chemical', '-', (27, 34))	('metastases', 'Disease', 'MESH:D009362', (131, 141))	('V600E', 'Var', (84, 89))	('vemurafenib', 'Chemical', 'MESH:D000077484', (36, 47))	('men', 'Species', '9606', (123, 126))
88193	26346576	Mutations in the BRAF gene have been reported in 66% of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('BRAF', 'Gene', '673', (17, 21))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (17, 21))	('melanomas', 'Disease', (56, 65))	('reported', 'Reg', (37, 45))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
88194	26346576	Interestingly, genetic mutations tend to favor certain locations for melanoma.	('genetic mutations', 'Var', (15, 32))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
88195	26346576	BRAF-mutated tumors tend to occur on skin subject to high intermittent sun exposure, whereas mutations in the tyrosine kinase receptor KIT are associated with melanomas from acral and mucosal sites.	('associated', 'Reg', (143, 153))	('melanomas', 'Disease', 'MESH:D008545', (159, 168))	('mutations', 'Var', (93, 102))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('KIT', 'molecular_function', 'GO:0005020', ('135', '138'))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('melanomas', 'Disease', (159, 168))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
88242	26346576	Furthermore, as certain genetic mutations favor acral sites for melanoma growth, minorities may have a genetic predisposition for these tumors.	('favor', 'PosReg', (42, 47))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
88276	31296860	We identified promoters that are specifically targeted by DNA methylation in somatic and germline tissues during vertebrate embryogenesis and that are frequently misregulated in human cancers.	('human cancers', 'Disease', (178, 191))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('embryogenesis', 'biological_process', 'GO:0009793', ('124', '137'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('DNA methylation', 'biological_process', 'GO:0006306', ('58', '73'))	('promoters', 'MPA', (14, 23))	('embryogenesis', 'biological_process', 'GO:0009792', ('124', '137'))	('human cancers', 'Disease', 'MESH:D009369', (178, 191))	('DNA methylation', 'Var', (58, 73))	('embryogenesis', 'biological_process', 'GO:0009790', ('124', '137'))
88285	31296860	In mammalian zygotes, the paternal genome is rapidly demethylated shortly after fertilisation, followed by a progressive drop in 5mC of both paternal and maternal genomic contributions.	('drop', 'NegReg', (121, 125))	('5mC', 'Chemical', 'MESH:D044503', (129, 132))	('5mC', 'MPA', (129, 132))	('demethylated', 'Var', (53, 65))	('mammalian', 'Species', '9606', (3, 12))
88291	31296860	Placeholders are hypomethylated domains in the genome, which are enriched in the histone modification H3K4me1 and the histone variant H2AZ.	('H2AZ', 'Var', (134, 138))	('histone modification', 'biological_process', 'GO:0016570', ('81', '101'))	('H2AZ', 'Chemical', '-', (134, 138))	('H3K4me1', 'Protein', (102, 109))
88306	31296860	Specifically, we wanted to capture the developmental period, which in mouse would correspond to the initial specification of PGCs and early demethylation (E6.25-E8.5/E9.5), migration and colonisation of the genital ridge (E8.5/E9.5-E10.5), and global DNA demethylation (E10.5-E12.5/E13.5).	('E8.5/E9.5-E10.5', 'Var', (222, 237))	('DNA demethylation', 'biological_process', 'GO:0080111', ('251', '268'))	('colonisation', 'CPA', (187, 199))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))	('PGCs', 'Protein', (125, 129))	('mouse', 'Species', '10090', (70, 75))	('demethylation', 'biological_process', 'GO:0070988', ('140', '153'))	('E10.5-E12.5/E13.5', 'Var', (270, 287))	('E6.25-E8.5/E9.5', 'Var', (155, 170))
88329	31296860	The majority of these regions were either hypomethylated in 4 hpf PGCs (4 hpf-hypo DMRs, n = 43) or hypermethylated in 24 hpf PGCs (24hpf-hyper DMRs, n = 56) as compared to their methylation state in somatic cells (Fig.	('DMRs', 'Chemical', '-', (144, 148))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))	('DMRs', 'Chemical', '-', (83, 87))	('hypomethylated', 'Var', (42, 56))	('hypermethylated', 'Var', (100, 115))
88332	31296860	These DMRs displayed significant enrichment (p < 0.001, Student's t test) in H3K27ac and H3K4me1 histone marks that are associated with active enhancer and promoter chromatin (Fig.	('H3K27ac', 'Var', (77, 84))	('H3K4me1', 'Var', (89, 96))	('chromatin', 'cellular_component', 'GO:0000785', ('165', '174'))	('DMRs', 'Chemical', '-', (6, 10))
88367	31296860	However, we also identified previously uncharacterised targets of embryonic 5mC promoter remodelling such as seven members of the Pim proto-oncogene, serine/threonine kinase-related family (pimr): pimr57, pimr130, pimr109, pimr137, pimr128, pimr49 and pimr51, among others.	('pimr128', 'Var', (232, 239))	('5mC', 'Chemical', 'MESH:D044503', (76, 79))	('pimr51', 'Var', (252, 258))	('pimr130', 'Var', (205, 212))	('pimr57', 'Var', (197, 203))	('pimr109', 'Var', (214, 221))	('pimr137', 'Var', (223, 230))	('pimr49', 'Var', (241, 247))
88374	31296860	We identified orthologues of these putative 5mC-regulated promoters and plotted their 5mC levels in murine intracellular cell mass (ICM) sample, epiblasts (E6.5, E7.5) and male and female PGCs (E13.5) (Fig.	('intracellular', 'cellular_component', 'GO:0005622', ('107', '120'))	('5mC', 'Chemical', 'MESH:D044503', (44, 47))	('E6.5', 'Var', (156, 160))	('E7.5', 'Var', (162, 166))	('murine', 'Species', '10090', (100, 106))	('E13.5', 'Var', (194, 199))	('5mC', 'Chemical', 'MESH:D044503', (86, 89))
88400	31296860	This is in agreement with previous work that demonstrated how 5-aza-dC, a 5mC inhibitor, can induce long-term changes in the gonads and feminise zebrafish.	('5-aza-dC', 'Var', (62, 70))	('5mC', 'Chemical', 'MESH:D044503', (74, 77))	('induce', 'Reg', (93, 99))	('zebrafish', 'Species', '7955', (145, 154))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (62, 70))	('changes', 'Reg', (110, 117))
88446	31296860	To determine whether 5mC dynamics of putative CTA promoters is conserved in mammalian embryos, we utilised public bisulfite sequencing data from mouse sperm, oocyte, early embryo (ICM, E6.5, E7.5) and PGCs (E13.5 female and E13.5 male) (GSE56697).	('bisulfite', 'Chemical', 'MESH:C042345', (114, 123))	('E13.5 male', 'Var', (224, 234))	('5mC', 'Chemical', 'MESH:D044503', (21, 24))	('mammalian', 'Species', '9606', (76, 85))	('E6.5', 'Var', (185, 189))	('mouse', 'Species', '10090', (145, 150))	('E13.5 female', 'Var', (207, 219))	('E7.5', 'Var', (191, 195))
88462	31296860	Mouse single-cell RNA-seq data for E11.5, E13.5 female, E16.5 female and E16.5 male PGCs and corresponding soma samples were downloaded from GSE79552.	('E13.5', 'Var', (42, 47))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('E16.5', 'Var', (56, 61))	('Mouse', 'Species', '10090', (0, 5))	('E16.5', 'Var', (73, 78))	('E11.5', 'Var', (35, 40))
88481	27087480	Melanoma arises through progressive accumulation of genetic and (epi)genetic alterations that disrupt homeostatic pathways, resulting in uncontrolled tumor cell proliferation followed by invasion and lymphatic or hematogenous dissemination of the tumor cells to distant sites.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('lymphatic or hematogenous dissemination', 'CPA', (200, 239))	('tumor', 'Disease', (247, 252))	('Melanoma', 'Disease', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('alterations', 'Var', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('156', '174'))	('homeostatic pathways', 'Pathway', (102, 122))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (150, 155))	('invasion', 'CPA', (187, 195))
88482	27087480	In cutaneous melanocytic neoplasms, UV radiation is the primary cause of mutations on sun-exposed skin.	('cutaneous melanocytic neoplasms', 'Disease', 'MESH:D009508', (3, 34))	('cause', 'Reg', (64, 69))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (13, 34))	('neoplasms', 'Phenotype', 'HP:0002664', (25, 34))	('mutations', 'Var', (73, 82))	('cutaneous melanocytic neoplasms', 'Disease', (3, 34))
88485	27087480	There is strong evidence for UV-independent mutagenesis in melanoma, a possibility suggested by the occurrence of melanomas at cutaneous locations that are not sun exposed, as well as in the eye and in mucous membranes.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanomas', 'Phenotype', 'HP:0002861', (114, 123))	('melanomas', 'Disease', (114, 123))	('mutagenesis', 'biological_process', 'GO:0006280', ('44', '55'))	('melanomas', 'Disease', 'MESH:D008545', (114, 123))	('mucous', 'cellular_component', 'GO:0070701', ('202', '208'))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('mutagenesis', 'Var', (44, 55))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Disease', (114, 122))
88493	27087480	They also have a high mutation burden and often harbor mutations in NF1, NRAS, BRAFnon-V600E, or KIT.	('KIT', 'molecular_function', 'GO:0005020', ('97', '100'))	('NRAS', 'Gene', '4893', (73, 77))	('KIT', 'Gene', (97, 100))	('mutations', 'Var', (55, 64))	('V600E', 'Mutation', 'p.V600E', (87, 92))	('NF1', 'Gene', (68, 71))	('mutation burden', 'MPA', (22, 37))	('NF1', 'Gene', '4763', (68, 71))	('BRAF', 'Gene', '673', (79, 83))	('harbor', 'Reg', (48, 54))	('BRAF', 'Gene', (79, 83))	('NRAS', 'Gene', (73, 77))
88496	27087480	Both types are associated with distinct precursor lesions, 'non-CSD' with acquired nevi that already exhibit BRAFV600E mutations and 'CSD' with atypical melanocytic neoplasms and melanoma in situ.	('BRAFV600E', 'Gene', (109, 118))	('CSD', 'Gene', (134, 137))	('atypical melanocytic neoplasms', 'Disease', (144, 174))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('nevi', 'Phenotype', 'HP:0003764', (83, 87))	('CSD', 'Gene', '7045', (64, 67))	('acquired nevi', 'Disease', (74, 87))	('atypical melanocytic neoplasms', 'Disease', 'MESH:D009508', (144, 174))	('CSD', 'Gene', '7045', (134, 137))	('neoplasms', 'Phenotype', 'HP:0002664', (165, 174))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (153, 174))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('BRAFV600E', 'Mutation', 'rs113488022', (109, 118))	('mutations', 'Var', (119, 128))	('melanoma', 'Disease', (179, 187))	('CSD', 'Gene', (64, 67))
88510	27087480	In addition, informing individuals without a personal history of disease that they are carriers of a CDKN2A/p16 mutation leads to improvement of photoprotection, self-skin examination and professional examination behaviors, in the absence of melanoma diagnosis.	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('mutation', 'Var', (112, 120))	('CDKN2A', 'Gene', (101, 107))	('p16', 'Gene', '1029', (108, 111))	('photoprotection', 'CPA', (145, 160))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('CDKN2A', 'Gene', '1029', (101, 107))	('self-skin examination', 'CPA', (162, 183))	('improvement', 'PosReg', (130, 141))	('p16', 'Gene', (108, 111))	('men', 'Species', '9606', (137, 140))	('photoprotection', 'biological_process', 'GO:0010117', ('145', '160'))	('professional examination behaviors', 'CPA', (188, 222))
88522	27087480	(iii) Sulforaphane: Experimental studies indicate that sulforaphane upregulates antioxidant genes and may affect immune pathways.	('sulforaphane', 'Var', (55, 67))	('antioxidant genes', 'Gene', (80, 97))	('sulforaphane', 'Chemical', 'MESH:C016766', (55, 67))	('upregulates', 'PosReg', (68, 79))	('Sulforaphane', 'Chemical', 'MESH:C016766', (6, 18))	('men', 'Species', '9606', (26, 29))	('immune pathways', 'Pathway', (113, 128))	('affect', 'Reg', (106, 112))
88529	27087480	Interestingly, both mouse models of melanoma and xenografts of human melanoma in mice show that relief from oxidative stress by treatment with the antioxidant N-acetyl cysteine leads to disease progression, suggesting that these approaches be reassessed in carefully crafted human and animal-model based studies.	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mice', 'Species', '10090', (81, 85))	('oxidative stress', 'MPA', (108, 124))	('melanoma', 'Disease', (36, 44))	('human', 'Species', '9606', (63, 68))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (159, 176))	('human', 'Species', '9606', (275, 280))	('disease progression', 'CPA', (186, 205))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('men', 'Species', '9606', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('relief', 'Var', (96, 102))	('melanoma', 'Disease', (69, 77))	('mouse', 'Species', '10090', (20, 25))
88532	27087480	The approach was found to offer mutant mice significant protection against UV-induced mutagenesis and skin carcinogenesis, although it was tested in a squamous cell carcinoma model.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 174))	('skin carcinogenesis', 'Disease', (102, 121))	('squamous cell carcinoma', 'Disease', (151, 174))	('UV-induced mutagenesis', 'MPA', (75, 97))	('mutant', 'Var', (32, 38))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('mice', 'Species', '10090', (39, 43))	('mutagenesis', 'biological_process', 'GO:0006280', ('86', '97'))
88550	27087480	Current work that addresses discrimination of melanoma from benign or low-grade dyplastic nevi is based on gene expression or DNA copy number changes by comprehensive genomic hybridization (CGH) or fluorescence in situ hybridization (FISH), while gene expression profiling (GEP) based analyses is gaining traction.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('nevi', 'Phenotype', 'HP:0003764', (90, 94))	('melanoma', 'Disease', (46, 54))	('gene expression', 'biological_process', 'GO:0010467', ('247', '262'))	('DNA', 'cellular_component', 'GO:0005574', ('126', '129'))	('gene expression', 'biological_process', 'GO:0010467', ('107', '122'))	('changes', 'Var', (142, 149))	('dyplastic nevi', 'Phenotype', 'HP:0001062', (80, 94))
88552	27087480	For example, high mole density is positively associated with non-CSD melanoma, whereas actinic keratosis and solar lentigines are positively associated with CSD melanoma.	('CSD melanoma', 'Disease', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('high', 'Var', (13, 17))	('keratosis', 'Disease', 'MESH:D007642', (95, 104))	('actinic keratosis', 'Phenotype', 'HP:0025127', (87, 104))	('keratosis', 'Disease', (95, 104))	('associated', 'Reg', (45, 55))	('CSD melanoma', 'Disease', 'MESH:C562576', (157, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('CSD melanoma', 'Disease', 'MESH:C562576', (65, 77))	('mole', 'Phenotype', 'HP:0003764', (18, 22))	('CSD melanoma', 'Disease', (157, 169))
88557	27087480	(ii) Development of refined risk phenotypes could be improved by increasing the sensitivity and specificity of markers tailored to melanoma subtypes (iii) Additional standards useful to identify individuals with increased risk could include clinical or molecular markers indicating mutation load in skin as well as biomarkers for immune-competence and the state of the tumor stroma.	('tumor stroma', 'Disease', (369, 381))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('clinical', 'Species', '191496', (241, 249))	('mole', 'Phenotype', 'HP:0003764', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('men', 'Species', '9606', (12, 15))	('melanoma subtypes', 'Disease', (131, 148))	('mutation load', 'Var', (282, 295))	('tumor stroma', 'Disease', 'MESH:D009369', (369, 381))	('melanoma subtypes', 'Disease', 'MESH:D008545', (131, 148))
88558	27087480	(iv) Improved understanding of how melanomas evolve from precursor lesions will allow development of objective criteria for diagnosis based on the number and type of pathogenic mutations or perturbations in critical signaling pathways.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('men', 'Species', '9606', (93, 96))	('mutations', 'Var', (177, 186))	('melanomas', 'Disease', (35, 44))	('signaling', 'biological_process', 'GO:0023052', ('216', '225'))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))
88606	27087480	Tumor dormancy is thought to depend on at least three elements: (1) cellular dormancy, in which tumor cells survive in a quiescent, slowly dividing state; (2) angiogenic dormancy, in which lack of vascularization holds growth of micrometastases in check and promotes programmed cell death, known as apoptosis; and/or (3) immune-mediated dormancy, where the immune system continues to limit the tumor population.	('tumor', 'Disease', (394, 399))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('metastases', 'Disease', 'MESH:D009362', (234, 244))	('tumor', 'Disease', 'MESH:D009369', (394, 399))	('angiogenic dormancy', 'CPA', (159, 178))	('metastases', 'Disease', (234, 244))	('dormancy', 'biological_process', 'GO:0030431', ('77', '85'))	('man', 'Species', '9606', (9, 12))	('dormancy', 'biological_process', 'GO:0030431', ('6', '14'))	('lack', 'Var', (189, 193))	('promotes', 'PosReg', (258, 266))	('man', 'Species', '9606', (173, 176))	('men', 'Species', '9606', (57, 60))	('man', 'Species', '9606', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (394, 399))	('apoptosis', 'biological_process', 'GO:0097194', ('299', '308'))	('dormancy', 'biological_process', 'GO:0030431', ('337', '345'))	('apoptosis', 'biological_process', 'GO:0006915', ('299', '308'))	('man', 'Species', '9606', (340, 343))	('tumor', 'Disease', (96, 101))	('programmed cell death', 'biological_process', 'GO:0012501', ('267', '288'))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('immune-mediated dormancy', 'CPA', (321, 345))	('programmed cell death', 'CPA', (267, 288))	('dormancy', 'biological_process', 'GO:0030431', ('170', '178'))
88607	27087480	Disruption of these processes can awaken dormant micrometastases and stimulate their expansion into overt metastases, leading to patient morbidity and mortality.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('man', 'Species', '9606', (44, 47))	('patient', 'Species', '9606', (129, 136))	('metastases', 'Disease', (54, 64))	('stimulate', 'PosReg', (69, 78))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('expansion', 'MPA', (85, 94))	('metastases', 'Disease', (106, 116))	('Disruption', 'Var', (0, 10))
88647	27087480	by exploiting VEGFR3-driven luciferase knock-in models); (xi) Methodology to image metastatic and premetastatic niches; (xii) Ability to test how mutational burden affects dormancy; (xiii) Ability to detect conversion from dormant to growing cells in live animals.	('VEGFR3', 'Gene', '2324', (14, 20))	('man', 'Species', '9606', (175, 178))	('dormancy', 'CPA', (172, 180))	('man', 'Species', '9606', (226, 229))	('affects', 'Reg', (164, 171))	('VEGFR3', 'Gene', (14, 20))	('mutational burden', 'Var', (146, 163))	('dormancy', 'biological_process', 'GO:0030431', ('172', '180'))
88686	27087480	Among those, tumors harboring BRAF or NRAS mutations are most prevalent.	('NRAS', 'Gene', '4893', (38, 42))	('prevalent', 'Reg', (62, 71))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutations', 'Var', (43, 52))	('NRAS', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
88687	27087480	Other groups include melanomas with genetic changes in the NF1, KIT or RAC1 genes.	('RAC1', 'Gene', '5879', (71, 75))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('RAC1', 'Gene', (71, 75))	('melanomas', 'Disease', (21, 30))	('genetic changes', 'Var', (36, 51))	('KIT', 'Gene', (64, 67))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('NF1', 'Gene', (59, 62))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('NF1', 'Gene', '4763', (59, 62))
88688	27087480	The genomic landscape of melanoma is also defined by epigenetic changes in complexes of proteins that interact with DNA to regulate gene expression.	('epigenetic changes', 'Var', (53, 71))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('complexes', 'Protein', (75, 84))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))
88699	27087480	In particular, availability of therapies for patients with BRAFV600 mutations, which occur in ~45% of non-acral cutaneous melanomas, has been promising but also identified key challenges that must be overcome to maximize long-term clinical benefits of this strategy.	('cutaneous melanomas', 'Disease', (112, 131))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (106, 130))	('acral cutaneous melanomas', 'Phenotype', 'HP:0012060', (106, 131))	('clinical', 'Species', '191496', (231, 239))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('patients', 'Species', '9606', (45, 53))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('mutations', 'Var', (68, 77))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))
88702	27087480	To date, no targeted therapies have demonstrated significant clinical efficacy in patients whose disease progresses following BRAF/MEK inhibition, thus driving an active area of research.	('patients', 'Species', '9606', (82, 90))	('inhibition', 'Var', (135, 145))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', (126, 130))	('MEK', 'Gene', (131, 134))	('clinical', 'Species', '191496', (61, 69))	('MEK', 'Gene', '5609', (131, 134))
88703	27087480	In addition to new mutations, epigenetic factors and tumor interaction with the microenvironment likely play roles in drug resistance, activities that present diagnostic challenges but also new therapeutic avenues.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('drug resistance', 'biological_process', 'GO:0009315', ('118', '133'))	('mutations', 'Var', (19, 28))	('drug resistance', 'Phenotype', 'HP:0020174', (118, 133))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('epigenetic factors', 'Var', (30, 48))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (92, 95))	('play roles', 'Reg', (104, 114))	('drug resistance', 'MPA', (118, 133))	('drug resistance', 'biological_process', 'GO:0042493', ('118', '133'))
88708	27087480	Finally, it is also critical to identify effective strategies to treat metastatic melanoma in patients lacking BRAFV600 mutations.	('patients', 'Species', '9606', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('BRAF', 'Gene', (111, 115))	('mutations', 'Var', (120, 129))	('BRAF', 'Gene', '673', (111, 115))
88710	27087480	The lessons learned from the still-evolving treatment of patients with BRAFV600 mutations should facilitate progress in developing therapies aimed at patients who lack them, most of whose melanomas harbor activating NRAS or inactivating NF1 mutations.	('men', 'Species', '9606', (49, 52))	('mutations', 'Var', (80, 89))	('BRAF', 'Gene', '673', (71, 75))	('melanomas', 'Disease', (188, 197))	('patients', 'Species', '9606', (57, 65))	('BRAF', 'Gene', (71, 75))	('NRAS', 'Gene', (216, 220))	('patients', 'Species', '9606', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('NF1', 'Gene', '4763', (237, 240))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('NF1', 'Gene', (237, 240))	('NRAS', 'Gene', '4893', (216, 220))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))	('activating', 'PosReg', (205, 215))	('inactivating', 'Var', (224, 236))	('mutations', 'Var', (241, 250))
88711	27087480	Both alterations perturb RAS signaling; thus a key question, which is also relevant to multiple other cancers, is whether to directly target RAS or consider targeting of effectors of RAS signaling, such as RAF protein kinases or phosphatidylinositide (PI)-3' kinases.	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('perturb', 'Reg', (17, 24))	('phosphatidylinositide', 'Chemical', '-', (229, 250))	('alterations', 'Var', (5, 16))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('RAS signaling', 'MPA', (25, 38))
88810	30066755	The Breslow index, which assesses tumor thickness in millimeters, was categorized as T1 (<=1.0mm), T2 (1.01 - 2.0mm), T3 (2.01 - 4.0mm), T4 (>4.0mm), and not recorded or compromised.	('tumor', 'Disease', (34, 39))	('2.01 - 4.0mm', 'Var', (122, 134))	('1.01 - 2.0mm', 'Var', (103, 115))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
88823	30066755	In patients with thicker tumors (Breslow T3 and T4), the odds of coming from the public system were more than double (3.79 and 3.80 times, respectively) when compared to in situ patients.	('Breslow T3', 'Var', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('T4', 'Var', (48, 50))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('patients', 'Species', '9606', (178, 186))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('patients', 'Species', '9606', (3, 11))
88839	30066755	A study in the United States also found an association between low socioeconomic status and nodular melanoma subtype and Breslow T4.	('Breslow T4', 'Disease', (121, 131))	('nodular melanoma subtype', 'Disease', 'MESH:D020518', (92, 116))	('nodular melanoma subtype', 'Disease', (92, 116))	('low socioeconomic status', 'Var', (63, 87))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('nodular melanoma', 'Phenotype', 'HP:0012058', (92, 108))
88868	26927636	Additionally, we found that SOX5 knockdown led to MITF up-regulation in melanoma cells, while double knockdown with SOX10 showed a rescue effect; both effects were validated by reporter assays.	('melanoma cells', 'Disease', (72, 86))	('MITF', 'Gene', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('up-regulation', 'PosReg', (55, 68))	('knockdown', 'Var', (33, 42))	('SOX5', 'Gene', (28, 32))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))	('melanoma cells', 'Disease', 'MESH:D008545', (72, 86))
88890	26927636	The mutation results in a constantly activated kinase that permanently stimulates extracellular-signal regulated protein kinase 2 (ERK2), which in turn phosphorylates and targets MITF proteins for ubiquitin-dependent degradation via the proteasomal pathway and thereby decreases the activity of MITF.	('degradation', 'biological_process', 'GO:0009056', ('217', '228'))	('activated', 'PosReg', (37, 46))	('ERK2', 'Gene', '5594', (131, 135))	('ubiquitin', 'molecular_function', 'GO:0031386', ('197', '206'))	('decreases', 'NegReg', (269, 278))	('mutation', 'Var', (4, 12))	('MITF', 'MPA', (295, 299))	('ERK2', 'Gene', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('proteasomal pathway', 'biological_process', 'GO:0043161', ('237', '256'))	('targets', 'MPA', (171, 178))	('man', 'Species', '9606', (62, 65))	('extracellular-signal regulated protein kinase 2', 'Gene', (82, 129))	('stimulates', 'PosReg', (71, 81))	('phosphorylates', 'MPA', (152, 166))	('ubiquitin-dependent degradation', 'MPA', (197, 228))	('proteins', 'Protein', (184, 192))	('activity', 'MPA', (283, 291))	('ERK2', 'molecular_function', 'GO:0004707', ('131', '135'))	('extracellular-signal regulated protein kinase 2', 'Gene', '5594', (82, 129))	('extracellular', 'cellular_component', 'GO:0005576', ('82', '95'))
88913	26927636	Five melanoma cell lines used in the Hoek and coworkers analysis MaMel-122, MaMel-86b, MaMel-61e and MaMel-79b (own laboratory) as well as A375 purchased from ATCC were cultured at 37  C and 5 % CO2 in RPMI 1640 medium (Gibco, Carlsbad, CA, USA) + 10 % FCS in general without antibiotics.	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('melanoma', 'Disease', (5, 13))	('MaMel-122', 'Gene', (65, 74))	('RPMI', 'Chemical', '-', (202, 206))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('MaMel-61e', 'Var', (87, 96))	('rat', 'Species', '10116', (120, 123))	('A375', 'CellLine', 'CVCL:0132', (139, 143))	('CO2', 'Chemical', '-', (195, 198))
88922	26927636	The qRT-PCR was performed for MITF, SOX5 or SOX10 as the gene of interest (GOI) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the housekeeping gene (HK) using the TaqMan probes HS01117294_m1 MITF, HS00753050_s1 SOX5, HS00366918_m1 SOX10 (Life Technologies, Carlsbad, CA, USA) and HuGAPDH (Applied Biosystems, Foster City, CA, USA), respectively.	('GAPDH', 'Gene', (126, 131))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (84, 124))	('HS00366918_m1', 'Var', (227, 240))	('GAPDH', 'Gene', '2597', (292, 297))	('GAPDH', 'Gene', (292, 297))	('HS01117294_m1', 'Var', (187, 200))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (84, 124))	('HS00753050_s1', 'Var', (207, 220))	('GAPDH', 'Gene', '2597', (126, 131))
88956	26927636	In all three tested melanoma cell lines (MaMel-61e, MaMel-122 and MaMel-86b) the knockdown of SOX5 resulted in significantly increased MITF levels compared to cells transfected with control siRNA.	('increased', 'PosReg', (125, 134))	('MITF levels', 'MPA', (135, 146))	('knockdown', 'Var', (81, 90))	('SOX5', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
88978	26927636	High percentages of melanoma tumor cells show mutations in the BRAF locus Due to the fact, that in melanoma hyper-activated BRAF often suppresses MITF, we compared the BRAF mutation status with the expression of MITF, SOX10 and SOX5.	('suppresses', 'NegReg', (135, 145))	('MITF', 'MPA', (146, 150))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('melanoma hyper', 'Disease', 'MESH:D008545', (99, 113))	('BRAF', 'Gene', '673', (124, 128))	('melanoma hyper', 'Disease', (99, 113))	('melanoma tumor', 'Disease', (20, 34))	('BRAF', 'Gene', '673', (168, 172))	('melanoma tumor', 'Disease', 'MESH:D008545', (20, 34))	('BRAF', 'Gene', '673', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('BRAF', 'Gene', (168, 172))	('BRAF', 'Gene', (124, 128))	('BRAF', 'Gene', (63, 67))
88980	26927636	Strikingly, SOX5 was significantly overexpressed in samples with mutated BRAF (p = 0.006).	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('overexpressed', 'PosReg', (35, 48))	('mutated', 'Var', (65, 72))
88981	26927636	We observed a weakly positive correlation of SOX5 and MITF expression in the BRAF wildtype subgroup (Pearson's correlation r = 0.18), and weakly negative correlation in the BRAF mutated subgroup (PCC r = -0.13) hinting for a stronger regulatory involvement of SOX5 on MITF expression in the tumor cells with BRAF mutation.	('MITF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (308, 312))	('BRAF', 'Gene', '673', (77, 81))	('BRAF', 'Gene', '673', (308, 312))	('PCC', 'cellular_component', 'GO:0120205', ('196', '199'))	('BRAF', 'Gene', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('BRAF', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('mutation', 'Var', (313, 321))	('stronger', 'PosReg', (225, 233))	('tumor', 'Disease', (291, 296))
88982	26927636	Comparing tumor subgroups of NRAS mutated with NRAS wildtype, no significant expression differences were found except for SOX5 which was significantly overexpressed in NRAS mutated samples (p = 0.05).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('NRAS', 'Gene', '4893', (168, 172))	('overexpressed', 'PosReg', (151, 164))	('SOX5', 'Gene', (122, 126))	('tumor', 'Disease', (10, 15))	('mutated', 'Var', (173, 180))	('NRAS', 'Gene', (29, 33))	('NRAS', 'Gene', (47, 51))	('NRAS', 'Gene', '4893', (29, 33))	('NRAS', 'Gene', '4893', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('NRAS', 'Gene', (168, 172))
89004	26927636	We speculate that SOX5 could be an important factor during the transition from primary to metastatic melanoma, as SOX5 knockdown resulted in reduced invasion (Table 2).	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('reduced', 'NegReg', (141, 148))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('knockdown', 'Var', (119, 128))	('SOX5', 'Gene', (114, 118))	('invasion', 'CPA', (149, 157))
89007	26927636	In contrast, our survival analysis revealed a worse prognosis for patients with tumors expressing low-level of SOX5.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('low-level', 'Var', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('patients', 'Species', '9606', (66, 74))
89014	26927636	We found that up-regulation of SOX5 expression co-occurs with BRAF mutations.	('up-regulation', 'PosReg', (14, 27))	('mutations', 'Var', (67, 76))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (62, 66))	('regulation', 'biological_process', 'GO:0065007', ('17', '27'))	('SOX5', 'Protein', (31, 35))
89016	26927636	In future studies, it would be interesting to investigate whether increased SOX5 expression is a downstream effect of BRAF mutation or whether it is rather an independent control mechanism for MITF regulation.	('rat', 'Species', '10116', (149, 152))	('BRAF', 'Gene', '673', (118, 122))	('increased', 'PosReg', (66, 75))	('mutation', 'Var', (123, 131))	('BRAF', 'Gene', (118, 122))	('SOX5 expression', 'MPA', (76, 91))	('regulation', 'biological_process', 'GO:0065007', ('198', '208'))
89023	26927636	Besides SOX10, we identified SOX5 regulating MITF in human melanoma cells and validated its inhibitory effect experimentally by functional and reporter assays.	('melanoma cells', 'Disease', (59, 73))	('MITF', 'Gene', (45, 49))	('SOX5', 'Var', (29, 33))	('human', 'Species', '9606', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma cells', 'Disease', 'MESH:D008545', (59, 73))
89064	33649798	Furthermore, using the cBioportal pan-cancer panel, the present study identified specific cancer types with a number of TMPRSS4 amplifications in LGG, LUAD, STAD, deep deletions in BRCA, HNSC, and shallow deletions in BLCA, BRCA, CESC, ESCA, LUAD, LUSC, OV and TGCT.	('ESCA', 'Disease', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('deep deletions', 'Var', (163, 177))	('LGG', 'Gene', (146, 149))	('BRCA', 'Gene', (181, 185))	('TMPRSS4', 'Gene', (120, 127))	('BRCA', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BLCA', 'Gene', (218, 222))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TMPRSS4', 'Gene', '56649', (120, 127))	('cancer', 'Disease', (38, 44))	('CESC', 'Disease', (230, 234))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('shallow deletions', 'Var', (197, 214))
89065	33649798	Furthermore, there were two datasets for thyroid cancers with a number of patients presenting diploid and not mutated versions of the gene, namely for THYM and THCA.	('THCA', 'Disease', (160, 164))	('diploid', 'Var', (94, 101))	('thyroid cancers', 'Disease', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (74, 82))	('thyroid cancers', 'Disease', 'MESH:D013964', (41, 56))	('THYM', 'Disease', (151, 155))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))
89066	33649798	Of note, in the majority of the studied cancers, the majority of the patients had deletions and partly some gains and amplifications (Fig.	('deletions', 'Var', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('gains', 'PosReg', (108, 113))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
89103	31900433	Spitz tumors, the spectrum of melanocytic neoplasms extending from Spitz nevi to their malignant counterpart Spitz melanoma, are defined in the 2018 WHO classification of skin tumors by the presence of specific genetic alterations such a kinase fusions or HRAS mutations.	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Spitz tumors', 'Disease', 'MESH:D018332', (0, 12))	('Spitz melanoma', 'Disease', (109, 123))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('neoplasms', 'Phenotype', 'HP:0002664', (42, 51))	('skin tumors', 'Disease', (171, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HRAS', 'Gene', '3265', (256, 260))	('melanocytic neoplasms', 'Disease', 'MESH:D009508', (30, 51))	('HRAS', 'Gene', (256, 260))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (30, 51))	('Spitz melanoma', 'Disease', 'MESH:D018332', (109, 123))	('nevi', 'Phenotype', 'HP:0003764', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('kinase fusions', 'Var', (238, 252))	('skin tumors', 'Disease', 'MESH:D012878', (171, 182))	('melanocytic neoplasms', 'Disease', (30, 51))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('Spitz tumors', 'Disease', (0, 12))	('skin tumors', 'Phenotype', 'HP:0008069', (171, 182))
89106	31900433	Only 9 cases (36%) had genetic alterations characteristic of Spitz melanoma, including HRAS mutation or fusion involving BRAF, ALK, NTRK1, or MAP3K8.	('BRAF', 'Gene', (121, 125))	('HRAS', 'Gene', '3265', (87, 91))	('NTRK1', 'Gene', '4914', (132, 137))	('mutation', 'Var', (92, 100))	('Spitz melanoma', 'Disease', (61, 75))	('MAP3K8', 'Gene', '1326', (142, 148))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('HRAS', 'Gene', (87, 91))	('MAP3K', 'molecular_function', 'GO:0004709', ('142', '147'))	('NTRK1', 'Gene', (132, 137))	('ALK', 'Gene', (127, 130))	('MAP3K8', 'Gene', (142, 148))	('fusion', 'Var', (104, 110))	('BRAF', 'Gene', '673', (121, 125))	('ALK', 'Gene', '238', (127, 130))	('Spitz melanoma', 'Disease', 'MESH:D018332', (61, 75))
89107	31900433	Both Spitz melanoma and spitzoid melanomas in which a MAPK activating mutation could not be identified tended to occur in younger patients on skin with little solar elastosis, infrequently harbored TERT promoter mutations, and had a lower burden of pathogenic mutations than spitzoid melanomas with non-Spitz MAPK activating mutations.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (24, 42))	('TERT', 'Gene', '7015', (198, 202))	('spitzoid melanomas', 'Disease', (24, 42))	('MAPK', 'molecular_function', 'GO:0004707', ('309', '313'))	('elastosis', 'Disease', (165, 174))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (275, 293))	('melanomas', 'Phenotype', 'HP:0002861', (284, 293))	('spitzoid melanomas', 'Disease', (275, 293))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (212, 221))	('TERT', 'Gene', (198, 202))	('Spitz melanoma and spitzoid melanomas', 'Disease', 'MESH:D008545', (5, 42))	('elastosis', 'Disease', 'MESH:D005148', (165, 174))
89108	31900433	The MAPK activating mutations identified affected non-V600 residues of BRAF as well as NRAS, MAP2K1/2, NF1 and KIT while BRAF V600 mutations, the most common mutations in melanomas of the WHO low-CSD category, were entirely absent.	('BRAF', 'Gene', (121, 125))	('NF1', 'Gene', '4763', (103, 106))	('MAP2K1/2', 'Gene', (93, 101))	('NRAS', 'Gene', '4893', (87, 91))	('melanomas', 'Disease', (171, 180))	('WHO low-CSD', 'Disease', (188, 199))	('MAPK', 'Gene', (4, 8))	('MAP2K1/2', 'Gene', '5604;5605', (93, 101))	('V600 mutations', 'Var', (126, 140))	('NF1', 'Gene', (103, 106))	('KIT', 'Gene', '3815', (111, 114))	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (171, 180))	('NRAS', 'Gene', (87, 91))	('KIT', 'molecular_function', 'GO:0005020', ('111', '114'))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('MAPK', 'molecular_function', 'GO:0004707', ('4', '8'))	('mutations', 'Var', (20, 29))	('KIT', 'Gene', (111, 114))	('MAP2K', 'molecular_function', 'GO:0004708', ('93', '98'))	('affected', 'Reg', (41, 49))	('activating', 'PosReg', (9, 19))	('melanomas', 'Disease', 'MESH:D008545', (171, 180))	('BRAF', 'Gene', '673', (121, 125))
89115	31900433	These include activating point mutations in HRAS (often with copy number gain of mutant HRAS) and rearrangements involving the serine/threonine kinases BRAF and MAP3K8 or the receptor tyrosine kinases (RTKs) ROS1, ALK, NTRK1, NTRK3, RET, MET, and MERTK and occur in a mutually exclusive fashion with only one mutation in a given Spitz nevus.	('BRAF', 'Gene', (152, 156))	('NTRK1', 'Gene', (219, 224))	('ALK', 'Gene', (214, 217))	('RET', 'Gene', (233, 236))	('HRAS', 'Gene', '3265', (44, 48))	('MET', 'Gene', (238, 241))	('mutant', 'Var', (81, 87))	('nevus', 'Phenotype', 'HP:0003764', (335, 340))	('HRAS', 'Gene', (44, 48))	('MAP3K8', 'Gene', (161, 167))	('gain', 'PosReg', (73, 77))	('ALK', 'Gene', '238', (214, 217))	('NTRK3', 'Gene', '4916', (226, 231))	('NTRK3', 'Gene', (226, 231))	('ROS1', 'Gene', '6098', (208, 212))	('point mutations', 'Var', (25, 40))	('activating', 'PosReg', (14, 24))	('HRAS', 'Gene', '3265', (88, 92))	('MAP3K8', 'Gene', '1326', (161, 167))	('MERTK', 'Gene', '10461', (247, 252))	('HRAS', 'Gene', (88, 92))	('MERTK', 'Gene', (247, 252))	('RET', 'Gene', '5979', (233, 236))	('serine', 'Chemical', 'MESH:D012694', (127, 133))	('NTRK1', 'Gene', '4914', (219, 224))	('MAP3K', 'molecular_function', 'GO:0004709', ('161', '166'))	('BRAF', 'Gene', '673', (152, 156))	('ROS1', 'Gene', (208, 212))
89116	31900433	Despite comprehensive genetic profiling of many Spitz nevi for other oncogenes and tumor suppressors, additional concomitant oncogenic drivers have not been identified, suggesting that these mutations alone are capable of initiating the clonal expansion that results in a Spitz nevus.	('nevus', 'Phenotype', 'HP:0003764', (278, 283))	('results in', 'Reg', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('mutations', 'Var', (191, 200))	('nevi', 'Phenotype', 'HP:0003764', (54, 58))	('Spitz nevus', 'Disease', (272, 283))	('many Spitz nevi', 'Phenotype', 'HP:0001054', (43, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('initiating', 'Reg', (222, 232))
89117	31900433	Thus, the diverse spectrum of initiating mutations in Spitz tumors and the resulting variation in the clinical phenotype likely contributes to the diagnostic difficulty of Spitz tumors.	('mutations', 'Var', (41, 50))	('Spitz tumors', 'Disease', (54, 66))	('Spitz tumors', 'Disease', 'MESH:D018332', (172, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Spitz tumors', 'Disease', (172, 184))	('Spitz tumors', 'Disease', 'MESH:D018332', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
89121	31900433	Spitzoid melanoma is thus a purely morphology-based diagnosis, and prior studies have shown that many tumors classified as such have genetic hallmarks of melanomas of skin with low-cumulative sun-induced damage (low-CSD melanomas), such as BRAF and NRAS mutations and a high mutation burden with a UV signature.	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('NRAS', 'Gene', (249, 253))	('melanomas', 'Phenotype', 'HP:0002861', (220, 229))	('melanomas', 'Disease', 'MESH:D008545', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mutations', 'Var', (254, 263))	('Spitzoid melanoma', 'Disease', 'MESH:D008545', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('melanomas', 'Disease', (154, 163))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('tumors', 'Disease', (102, 108))	('low-CSD melanomas', 'Disease', 'MESH:C562576', (212, 229))	('NRAS', 'Gene', '4893', (249, 253))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanomas', 'Disease', 'MESH:D008545', (220, 229))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Spitzoid melanoma', 'Disease', (0, 17))	('low-CSD melanomas', 'Disease', (212, 229))	('melanomas', 'Disease', (220, 229))	('BRAF', 'Gene', '673', (240, 244))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('BRAF', 'Gene', (240, 244))
89122	31900433	As Spitz nevi do not show activating BRAF or NRAS point mutations, spitzoid melanomas with these mutations are not genetically related to Spitz nevi.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('mutations', 'Var', (97, 106))	('mutations', 'Var', (56, 65))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('nevi', 'Phenotype', 'HP:0003764', (9, 13))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (67, 85))	('NRAS', 'Gene', (45, 49))	('spitzoid melanomas', 'Disease', (67, 85))	('NRAS', 'Gene', '4893', (45, 49))	('nevi', 'Phenotype', 'HP:0003764', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
89125	31900433	Activating BRAF or NRAS mutations, which are typical of other melanomas were identified in 20-86% of spitzoid melanomas across various studies.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('Activating', 'PosReg', (0, 10))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('NRAS', 'Gene', (19, 23))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('melanomas', 'Disease', (62, 71))	('NRAS', 'Gene', '4893', (19, 23))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (101, 119))	('melanomas', 'Disease', (110, 119))	('spitzoid melanomas', 'Disease', (101, 119))	('mutations', 'Var', (24, 33))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
89127	31900433	performed exome sequencing of 27 spitzoid melanomas and BRAF V600 mutations were found in 37% and NRAS mutations in 15% of cases.	('mutations', 'Var', (103, 112))	('BRAF', 'Gene', '673', (56, 60))	('found', 'Reg', (81, 86))	('NRAS', 'Gene', (98, 102))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (33, 51))	('NRAS', 'Gene', '4893', (98, 102))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('spitzoid melanomas', 'Disease', (33, 51))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('BRAF', 'Gene', (56, 60))
89128	31900433	Only one case (4%) had an HRAS mutation indicative of a Spitz lineage.	('HRAS', 'Gene', '3265', (26, 30))	('mutation', 'Var', (31, 39))	('Spitz lineage', 'Disease', (56, 69))	('HRAS', 'Gene', (26, 30))
89147	31900433	We classified truncating mutations in known tumor suppressors as pathogenic.	('truncating mutations', 'Var', (14, 34))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
89148	31900433	For genes in which a cancer related pathogenic alteration was identified, we manually annotated all remaining variants of that gene as pathogenic, likely pathogenic, uncertain significance, and likely benign by literature review, using various databases as annotation resources (OMIM, MyCancerGenome).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('pathogenic', 'Reg', (135, 145))	('Cancer', 'Disease', 'MESH:D009369', (287, 293))	('Cancer', 'Phenotype', 'HP:0002664', (287, 293))	('variants', 'Var', (110, 118))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Disease', (287, 293))
89149	31900433	Shallow deletions of a tumor suppressor accompanied by pathogenic alteration of that tumor suppressor was considered a pathogenic copy number alteration.	('tumor', 'Disease', (85, 90))	('alteration', 'Reg', (66, 76))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('Shallow deletions', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
89150	31900433	Deep deletions of tumor suppressors were counted as two pathogenic alterations.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('Deep deletions', 'Var', (0, 14))	('tumor', 'Disease', (18, 23))
89155	31900433	Pearson correlation was calculated between age, number of pathogenic mutations, and extent of solar elastosis (converting the scale from Landi et al.	('elastosis', 'Disease', 'MESH:D005148', (100, 109))	('mutations', 'Var', (69, 78))	('elastosis', 'Disease', (100, 109))
89164	31900433	Two spitzoid melanomas contained HRAS hotspot mutations with gain of the mutant allele (8%).	('spitzoid melanomas', 'Disease', 'MESH:D008545', (4, 22))	('spitzoid melanomas', 'Disease', (4, 22))	('mutations', 'Var', (46, 55))	('HRAS', 'Gene', '3265', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mutant', 'Var', (73, 79))	('HRAS', 'Gene', (33, 37))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('gain', 'PosReg', (61, 65))
89167	31900433	The other melanoma occurred on the arm of a 75 year-old-woman, and in addition to the HRAS mutation there was a three-codon deletion in MAP2K1 (p.102_104del), a known gain-of-function mutation with a copy number gain of the mutant allele, a hemizygous truncating mutation in ARID1A, an amplification of NOTCH2, and homozygous deletion of CDKN2A (case 23).	('CDKN2A', 'Gene', (338, 344))	('MAP2K', 'molecular_function', 'GO:0004708', ('136', '141'))	('HRAS', 'Gene', '3265', (86, 90))	('ARID1A', 'Gene', '8289', (275, 281))	('HRAS', 'Gene', (86, 90))	('CDKN2A', 'Gene', '1029', (338, 344))	('MAP2K1', 'Gene', (136, 142))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('NOTCH2', 'Gene', '4853', (303, 309))	('gain', 'PosReg', (212, 216))	('amplification', 'Var', (286, 299))	('gain-of-function', 'PosReg', (167, 183))	('MAP2K1', 'Gene', '5604', (136, 142))	('ARID1A', 'Gene', (275, 281))	('NOTCH2', 'Gene', (303, 309))	('p.102_104del', 'Mutation', 'p.102_104del', (144, 156))	('woman', 'Species', '9606', (56, 61))	('p.102_104del', 'Var', (144, 156))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))
89172	31900433	Rearrangements affected the receptor tyrosine kinases (RTKs) ALK in two cases (8%) and NTRK1 in one case (4%).	('affected', 'Reg', (15, 23))	('Rearrangements', 'Var', (0, 14))	('NTRK1', 'Gene', (87, 92))	('ALK', 'Gene', (61, 64))	('ALK', 'Gene', '238', (61, 64))	('NTRK1', 'Gene', '4914', (87, 92))
89174	31900433	Case 10 occurred on the leg of a 34 year-old-man and harbored a fusion of the 3' portion of ALK to an intergenic region of chromosome 11q, with a gain of the distal portion of ALK encoding the kinase domain, suggesting that a complex rearrangement resulted in an ALK kinase fusion as the oncogene in this case.	('ALK', 'Gene', (263, 266))	('fusion', 'Var', (64, 70))	('ALK', 'Gene', (92, 95))	('ALK', 'Gene', '238', (176, 179))	('gain', 'PosReg', (146, 150))	('ALK', 'Gene', '238', (92, 95))	('ALK', 'Gene', '238', (263, 266))	('ALK', 'Gene', (176, 179))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))
89178	31900433	Rearrangements of MAP3K8 were identified in 2 cases by RNA sequencing (8%).	('MAP3K8', 'Gene', '1326', (18, 24))	('Rearrangements', 'Var', (0, 14))	('MAP3K', 'molecular_function', 'GO:0004709', ('18', '23'))	('MAP3K8', 'Gene', (18, 24))	('RNA', 'cellular_component', 'GO:0005562', ('55', '58'))
89179	31900433	Case 2 demonstrated a ZFP36L1-MAP3K8 fusion and occurred on the right arm of an 11-year-old girl and was notable for pigment rich epithelioid and spindled cells with some adnexal extension.	('ZFP36L1', 'Gene', (22, 29))	('MAP3K', 'molecular_function', 'GO:0004709', ('30', '35'))	('ZFP36L1', 'Gene', '677', (22, 29))	('girl', 'Species', '9606', (92, 96))	('MAP3K8', 'Gene', '1326', (30, 36))	('fusion', 'Var', (37, 43))	('MAP3K8', 'Gene', (30, 36))
89182	31900433	While HRAS mutations and BRAF or RTK fusions were identified in the Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) cohort, these alterations occurred at greater prevalence in our cohort (P=0.0479 for HRAS mutation, P=0.00041 for fusions of BRAF, NTRK1, or ALK).	('HRAS', 'Gene', (6, 10))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('HRAS', 'Gene', '3265', (211, 215))	('ALK', 'Gene', '238', (267, 270))	('HRAS', 'Gene', (211, 215))	('NTRK1', 'Gene', '4914', (257, 262))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 118))	('skin cutaneous melanoma', 'Disease', (95, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('ALK', 'Gene', (267, 270))	('NTRK1', 'Gene', (257, 262))	('Cancer', 'Disease', (68, 74))	('mutation', 'Var', (216, 224))	('BRAF', 'Gene', (251, 255))	('BRAF', 'Gene', '673', (251, 255))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('fusions', 'Var', (240, 247))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('HRAS', 'Gene', '3265', (6, 10))
89185	31900433	Other MAP-kinase pathway activating alterations not associated with Spitz nevi were identified in another nine (36%) spitzoid melanomas.	('spitzoid melanomas', 'Disease', 'MESH:D008545', (117, 135))	('activating', 'PosReg', (25, 35))	('alterations', 'Var', (36, 47))	('spitzoid melanomas', 'Disease', (117, 135))	('nevi', 'Phenotype', 'HP:0003764', (74, 78))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('MAP-kinase pathway', 'Pathway', (6, 24))	('MAP', 'molecular_function', 'GO:0004239', ('6', '9'))
89187	31900433	BRAFV600E is common in melanomas without chronic sun-induced damage (non-CSD) and was significantly underrepresented in our spitzoid melanomas as compared to the TCGA SKCM cohort (P=1.3*10^-6).	('melanomas', 'Disease', (23, 32))	('melanomas', 'Disease', (133, 142))	('underrepresented', 'NegReg', (100, 116))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (124, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('spitzoid melanomas', 'Disease', (124, 142))	('melanomas', 'Disease', 'MESH:D008545', (23, 32))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E', 'Var', (0, 9))
89189	31900433	We identified a BRAF D594G mutation in a single case (case 19), which is a class 3 BRAF mutation that is considered weakly activating.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('D594G', 'Var', (21, 26))	('BRAF', 'Gene', '673', (83, 87))	('D594G', 'Mutation', 'rs121913338', (21, 26))	('BRAF', 'Gene', (83, 87))
89191	31900433	MAP2K2, also known as MEK2, acts directly downstream of BRAF in the MAPK pathway, and the MAP2K2 mutation likely cooperates with the class 3 BRAF mutation.	('MAP2K2', 'Gene', (0, 6))	('BRAF', 'Gene', (141, 145))	('MEK2', 'Gene', (22, 26))	('MAP2K2', 'Gene', '5605', (90, 96))	('MEK2', 'Gene', '5605', (22, 26))	('BRAF', 'Gene', '673', (56, 60))	('MAP2K2', 'Gene', (90, 96))	('MEK2', 'molecular_function', 'GO:0004708', ('22', '26'))	('MAP2K', 'molecular_function', 'GO:0004708', ('90', '95'))	('MAP2K', 'molecular_function', 'GO:0004708', ('0', '5'))	('MAPK pathway', 'Pathway', (68, 80))	('mutation', 'Var', (97, 105))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('BRAF', 'Gene', '673', (141, 145))	('MAP2K2', 'Gene', '5605', (0, 6))	('BRAF', 'Gene', (56, 60))
89194	31900433	NRAS hotspot mutations were identified in five of cases (20%), at a similar prevalence as in the SKCM cohort of TCGA.	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))
89196	31900433	In case 25, the NRASQ61H mutation occurred in combination with an activating CTNNB1G34I mutation, a TERT promoter mutation, and IDH1R132C and NFKBIEG41E mutations.	('mutation', 'Var', (88, 96))	('IDH1', 'Gene', '3417', (128, 132))	('CTNNB1', 'Gene', (77, 83))	('NRAS', 'Gene', (16, 20))	('TERT', 'Gene', (100, 104))	('activating', 'PosReg', (66, 76))	('CTNNB1', 'Gene', '1499', (77, 83))	('NRAS', 'Gene', '4893', (16, 20))	('TERT', 'Gene', '7015', (100, 104))	('IDH1', 'Gene', (128, 132))
89197	31900433	This spitzoid melanoma also demonstrated a minor small cell component, which did not demonstrate the strong and uniform beta-catenin staining indicative of CTNNB1 mutation observed in the majority of the melanoma.	('melanoma', 'Disease', (14, 22))	('beta-catenin', 'Gene', '1499', (120, 132))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (5, 22))	('melanoma', 'Disease', (204, 212))	('spitzoid melanoma', 'Disease', (5, 22))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('CTNNB1', 'Gene', '1499', (156, 162))	('mutation', 'Var', (163, 171))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('CTNNB1', 'Gene', (156, 162))	('beta-catenin', 'Gene', (120, 132))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
89198	31900433	This finding suggests that the CTNNB1 mutation arose later in melanoma progression resulting in the epithelioid cytomorphology present in the majority of the melanoma (Supplementary Figure 1).	('melanoma', 'Disease', (62, 70))	('CTNNB1', 'Gene', '1499', (31, 37))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('CTNNB1', 'Gene', (31, 37))	('mutation', 'Var', (38, 46))	('epithelioid cytomorphology', 'CPA', (100, 126))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
89199	31900433	Bi-allelic loss of NF1 occurred in two (8%) cases, in combination with NRASG12D in one case (case 17).	('Bi-allelic loss', 'Var', (0, 15))	('NF1', 'Gene', (19, 22))	('NRAS', 'Gene', (71, 75))	('NF1', 'Gene', '4763', (19, 22))	('NRAS', 'Gene', '4893', (71, 75))
89204	31900433	Mutations in the promoter of TERT are present in ~70% of cutaneous melanomas and are associated with worse prognosis in both conventional and spitzoid melanoma.	('TERT', 'Gene', '7015', (29, 33))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (142, 159))	('spitzoid melanoma', 'Disease', (142, 159))	('TERT', 'Gene', (29, 33))	('conventional', 'Disease', (125, 137))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (57, 76))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (57, 76))	('cutaneous melanomas', 'Disease', (57, 76))	('associated', 'Reg', (85, 95))
89205	31900433	Hotspot TERT promoter alterations were identified in 8 spitzoid melanomas (32%) and were more common in spitzoid melanomas with a non-Spitz nevus MAPK activating mutation (Figure 7C).	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (104, 122))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (55, 73))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('nevus', 'Phenotype', 'HP:0003764', (140, 145))	('spitzoid melanomas', 'Disease', (104, 122))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('alterations', 'Var', (22, 33))	('spitzoid melanomas', 'Disease', (55, 73))	('MAPK', 'molecular_function', 'GO:0004707', ('146', '150'))
89206	31900433	Inactivation of the tumor suppressor CDKN2A is a major driver in melanoma, and homozygous deletion of CDKN2A may be associated with poor outcome in atypical Spitz tumors.	('Spitz tumors', 'Disease', (157, 169))	('CDKN2A', 'Gene', '1029', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (163, 168))	('homozygous deletion', 'Var', (79, 98))	('CDKN2A', 'Gene', '1029', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('Inactivation', 'Var', (0, 12))	('Spitz tumors', 'Disease', 'MESH:D018332', (157, 169))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('associated', 'Reg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('CDKN2A', 'Gene', (37, 43))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('CDKN2A', 'Gene', (102, 108))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('tumor', 'Disease', (20, 25))
89208	31900433	In four cases, bi-allelic loss occurred by homozygous deletion of CDKN2A, and in the remaining case, there was a truncating mutation of CDKN2A with loss of the wild-type allele.	('CDKN2A', 'Gene', '1029', (66, 72))	('truncating mutation', 'Var', (113, 132))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('loss', 'NegReg', (26, 30))	('CDKN2A', 'Gene', (66, 72))
89209	31900433	Four of nine (44%) Spitz melanomas demonstrated bi-allelic inactivation of CDKN2A.	('bi-allelic inactivation', 'Var', (48, 71))	('Spitz melanomas', 'Disease', (19, 34))	('CDKN2A', 'Gene', (75, 81))	('CDKN2A', 'Gene', '1029', (75, 81))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('Spitz melanomas', 'Disease', 'MESH:D018332', (19, 34))	('melanomas', 'Phenotype', 'HP:0002861', (25, 34))
89216	31900433	BRAF V600 mutations found in the majority of low-CSD cutaneous melanomas were completely absent, indicating that spitzoid melanomas do not typically arise from common acquired nevi.	('low-CSD cutaneous melanomas', 'Disease', (45, 72))	('absent', 'NegReg', (89, 95))	('spitzoid melanomas', 'Disease', (113, 131))	('nevi', 'Phenotype', 'HP:0003764', (176, 180))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (53, 72))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('BRAF', 'Gene', '673', (0, 4))	('low-CSD cutaneous melanomas', 'Disease', 'MESH:C562576', (45, 72))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (113, 131))
89217	31900433	Instead we found an increased incidence (30%) of oncogenic alterations typical for Spitz tumors such as HRAS mutation and activating fusions BRAF, MAP3K8, ALK, and NTRK1.	('BRAF', 'Gene', (141, 145))	('MAP3K8', 'Gene', (147, 153))	('ALK', 'Gene', '238', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('MAP3K', 'molecular_function', 'GO:0004709', ('147', '152'))	('NTRK1', 'Gene', (164, 169))	('Spitz tumors', 'Disease', 'MESH:D018332', (83, 95))	('HRAS', 'Gene', (104, 108))	('NTRK1', 'Gene', '4914', (164, 169))	('ALK', 'Gene', (155, 158))	('MAP3K8', 'Gene', '1326', (147, 153))	('Spitz tumors', 'Disease', (83, 95))	('BRAF', 'Gene', '673', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('HRAS', 'Gene', '3265', (104, 108))	('mutation', 'Var', (109, 117))
89218	31900433	The Spitz melanomas with HRAS mutation or ALK or NTRK1 kinase fusion retained the some of the distinct histopathologic features associated with Spitz nevi with these mutations.	('Spitz melanomas', 'Disease', 'MESH:D018332', (4, 19))	('HRAS', 'Gene', (25, 29))	('Spitz nevi', 'Disease', (144, 154))	('ALK', 'Gene', '238', (42, 45))	('NTRK1', 'Gene', (49, 54))	('mutation', 'Var', (30, 38))	('fusion', 'Var', (62, 68))	('ALK', 'Gene', (42, 45))	('Spitz melanomas', 'Disease', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('nevi', 'Phenotype', 'HP:0003764', (150, 154))	('HRAS', 'Gene', '3265', (25, 29))	('NTRK1', 'Gene', '4914', (49, 54))
89220	31900433	Two additional Spitz melanomas had bi-allelic inactivation of CDKN2A.	('bi-allelic inactivation', 'Var', (35, 58))	('Spitz melanomas', 'Disease', (15, 30))	('CDKN2A', 'Gene', (62, 68))	('Spitz melanomas', 'Disease', 'MESH:D018332', (15, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('CDKN2A', 'Gene', '1029', (62, 68))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))
89221	31900433	Case 3 with an NTRK1 fusion, but without other definitely pathogenic mutations demonstrated copy number loss upstream of TERT, suggesting a structural rearrangement.	('loss', 'NegReg', (104, 108))	('NTRK1', 'Gene', '4914', (15, 20))	('copy number', 'MPA', (92, 103))	('fusion', 'Var', (21, 27))	('NTRK1', 'Gene', (15, 20))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))
89222	31900433	Similar rearrangements reactivate TERT in neuroblastoma and have been reported in lethal Spitz melanoma in the absence of a TERT promoter mutation.	('Spitz melanoma', 'Disease', 'MESH:D018332', (89, 103))	('Spitz melanoma', 'Disease', (89, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (42, 55))	('TERT', 'Gene', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('reactivate', 'Reg', (23, 33))	('TERT', 'Gene', (124, 128))	('TERT', 'Gene', '7015', (34, 38))	('neuroblastoma', 'Disease', 'MESH:D009447', (42, 55))	('rearrangements', 'Var', (8, 22))	('TERT', 'Gene', '7015', (124, 128))	('neuroblastoma', 'Disease', (42, 55))
89225	31900433	We further subdivided these 'non-Spitz' spitzoid melanomas into those without any identifiable MAP-kinase pathway mutations and those with MAPK pathway mutation(s) not associated with Spitz nevi such as in NRAS, BRAF, KIT, NF1, and or MAP2K1/2.	('NF1', 'Gene', '4763', (223, 226))	('NRAS', 'Gene', '4893', (206, 210))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('MAP2K1/2', 'Gene', (235, 243))	('nevi', 'Phenotype', 'HP:0003764', (190, 194))	('NF1', 'Gene', (223, 226))	('MAP2K1/2', 'Gene', '5604;5605', (235, 243))	('BRAF', 'Gene', '673', (212, 216))	('BRAF', 'Gene', (212, 216))	('NRAS', 'Gene', (206, 210))	('KIT', 'Gene', (218, 221))	('mutation', 'Var', (152, 160))	('spitzoid melanomas', 'Disease', (40, 58))	('KIT', 'molecular_function', 'GO:0005020', ('218', '221'))	('MAP2K', 'molecular_function', 'GO:0004708', ('235', '240'))	('MAP', 'molecular_function', 'GO:0004239', ('95', '98'))	('MAPK', 'molecular_function', 'GO:0004707', ('139', '143'))	('KIT', 'Gene', '3815', (218, 221))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (40, 58))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
89226	31900433	The melanomas in the latter of these two groups occurred in older patients, with more solar elastosis in the adjacent dermis and had a higher number of pathogenic mutations than the rest of our spitzoid melanomas, suggesting that they have a higher somatic mutation burden due to UV exposure.	('elastosis', 'Disease', (92, 101))	('melanomas', 'Phenotype', 'HP:0002861', (203, 212))	('mutations', 'Var', (163, 172))	('melanomas', 'Disease', (4, 13))	('melanomas', 'Disease', 'MESH:D008545', (4, 13))	('melanomas', 'Disease', (203, 212))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (194, 212))	('melanomas', 'Phenotype', 'HP:0002861', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('elastosis', 'Disease', 'MESH:D005148', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('spitzoid melanomas', 'Disease', (194, 212))	('melanomas', 'Disease', 'MESH:D008545', (203, 212))	('patients', 'Species', '9606', (66, 74))
89227	31900433	One notable exception was a spitzoid melanoma with focused high-level amplification of mutant NRAS that occurred on the ear of a teenager and demonstrated minimal solar elastosis and no additional pathogenic alterations.	('NRAS', 'Gene', (94, 98))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('NRAS', 'Gene', '4893', (94, 98))	('mutant', 'Var', (87, 93))	('elastosis', 'Disease', 'MESH:D005148', (169, 178))	('elastosis', 'Disease', (169, 178))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (28, 45))	('spitzoid melanoma', 'Disease', (28, 45))
89228	31900433	Focused high-level amplification of mutant NRAS has been described in spitzoid tumors on the ear of children.	('children', 'Species', '9606', (100, 108))	('tumors on the ear', 'Phenotype', 'HP:0012780', (79, 96))	('NRAS', 'Gene', (43, 47))	('spitzoid tumors', 'Disease', 'MESH:D009369', (70, 85))	('spitzoid tumors', 'Disease', (70, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('described', 'Reg', (57, 66))	('mutant', 'Var', (36, 42))	('NRAS', 'Gene', '4893', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
89229	31900433	Perhaps secondary amplification of mutant NRAS leads to spitzoid cytomorphologic features by a mechanism similar to HRAS mutation.	('leads to', 'Reg', (47, 55))	('HRAS', 'Gene', (116, 120))	('NRAS', 'Gene', '4893', (42, 46))	('spitzoid cytomorphologic', 'Disease', (56, 80))	('mutant', 'Var', (35, 41))	('HRAS', 'Gene', '3265', (116, 120))	('NRAS', 'Gene', (42, 46))
89230	31900433	For example, when a melanocyte of a conventional nevus, which was initiated by a BRAF (or rarely RAS) mutation, acquires an activating CTNNB1 mutation in addition to the mutation which initiated the nevus, a secondary clonal expansion of melanocytes characterized by increased cell size and pigmentation results in a component of deep penetrating nevus (melanocytoma).	('nevus', 'Phenotype', 'HP:0003764', (347, 352))	('mutation', 'Var', (142, 150))	('CTNNB1', 'Gene', '1499', (135, 141))	('nevus', 'Phenotype', 'HP:0003764', (199, 204))	('nevus', 'Phenotype', 'HP:0003764', (49, 54))	('mutation', 'Var', (102, 110))	('BRAF', 'Gene', '673', (81, 85))	('melanocytoma', 'Disease', (354, 366))	('pigmentation', 'biological_process', 'GO:0043473', ('291', '303'))	('deep penetrating nevus', 'Disease', (330, 352))	('BRAF', 'Gene', (81, 85))	('activating', 'PosReg', (124, 134))	('melanocytoma', 'Disease', 'None', (354, 366))	('CTNNB1', 'Gene', (135, 141))	('pigmentation', 'Disease', 'MESH:D010859', (291, 303))	('pigmentation', 'Disease', (291, 303))
89231	31900433	Bi-allelic loss of BAP1 in a melanocyte of a conventional nevus results in a secondary proliferation of epithelioid melanocytes with distinctive spitzoid cytomorphology.	('loss', 'NegReg', (11, 15))	('BAP1', 'Gene', '8314', (19, 23))	('results in', 'Reg', (64, 74))	('secondary proliferation', 'CPA', (77, 100))	('BAP1', 'Gene', (19, 23))	('nevus', 'Phenotype', 'HP:0003764', (58, 63))	('Bi-allelic', 'Var', (0, 10))
89233	31900433	While we identified a CTNNB1 mutation in one spitzoid melanoma, we did not identify any pathogenic BAP1 mutations in our series.	('CTNNB1', 'Gene', (22, 28))	('BAP1', 'Gene', (99, 103))	('mutation', 'Var', (29, 37))	('CTNNB1', 'Gene', '1499', (22, 28))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (45, 62))	('spitzoid melanoma', 'Disease', (45, 62))	('BAP1', 'Gene', '8314', (99, 103))
89235	31900433	Intriguingly, two spitzoid melanomas harbored activating EZH2 mutations.	('EZH2', 'Gene', (57, 61))	('EZH2', 'Gene', '2146', (57, 61))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (18, 36))	('spitzoid melanomas', 'Disease', (18, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('activating', 'PosReg', (46, 56))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('mutations', 'Var', (62, 71))
89236	31900433	Loss of BAP1 has been shown to lead to increased EZH2 activity and EZH2-dependent transformation.	('EZH2', 'Gene', '2146', (49, 53))	('BAP1', 'Gene', '8314', (8, 12))	('EZH2', 'Gene', (49, 53))	('increased', 'PosReg', (39, 48))	('BAP1', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))	('EZH2', 'Gene', (67, 71))	('EZH2', 'Gene', '2146', (67, 71))
89237	31900433	Perhaps mutational activation of EZH2 is functionally similar to loss of BAP1 and also results in a spitzoid phenotype.	('BAP1', 'Gene', '8314', (73, 77))	('results in', 'Reg', (87, 97))	('mutational', 'Var', (8, 18))	('BAP1', 'Gene', (73, 77))	('spitzoid', 'Disease', (100, 108))	('EZH2', 'Gene', '2146', (33, 37))	('EZH2', 'Gene', (33, 37))
89238	31900433	Most spitzoid melanomas without identified MAP-kinase pathway mutations occurred in young patients with little solar elastosis, similar to Spitz melanomas.	('spitzoid melanomas', 'Disease', (5, 23))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('occurred', 'Reg', (72, 80))	('MAP', 'molecular_function', 'GO:0004239', ('43', '46'))	('Spitz melanomas', 'Disease', (139, 154))	('elastosis', 'Disease', 'MESH:D005148', (117, 126))	('spitzoid melanomas', 'Disease', 'MESH:D008545', (5, 23))	('elastosis', 'Disease', (117, 126))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('Spitz melanomas', 'Disease', 'MESH:D018332', (139, 154))	('patients', 'Species', '9606', (90, 98))	('mutations', 'Var', (62, 71))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
89240	31900433	In one case we identified a CRTC1-TRIM11 fusion which is not predicted to affect MAPK pathway signaling and has been recently described in dermal melanocytic tumors composed of epithelioid and spindled cells with minimal pigmentation that resemble clear cell sarcoma.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('pigmentation', 'biological_process', 'GO:0043473', ('221', '233'))	('sarcoma', 'Disease', 'MESH:D012509', (259, 266))	('CRTC1', 'Gene', (28, 33))	('dermal melanocytic tumors', 'Disease', (139, 164))	('TRIM11', 'Gene', (34, 40))	('dermal melanocytic tumors', 'Disease', 'MESH:D057091', (139, 164))	('pigmentation', 'Disease', 'MESH:D010859', (221, 233))	('fusion', 'Var', (41, 47))	('signaling', 'biological_process', 'GO:0023052', ('94', '103'))	('pigmentation', 'Disease', (221, 233))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('CRTC1', 'Gene', '23373', (28, 33))	('sarcoma', 'Disease', (259, 266))	('TRIM11', 'Gene', '81559', (34, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (259, 266))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('described', 'Reg', (126, 135))
89313	26354726	Disruptive mutations of MC1R are associated with red hair, freckling, and sun sensitivity due to a failure in the processing of red/yellow pheomelanin to brown/black eumelanin.	('mutations', 'Var', (11, 20))	('MC1R', 'Gene', '4157', (24, 28))	('red hair', 'Disease', 'MESH:C567091', (49, 57))	('MC1R', 'Gene', (24, 28))	('freckling', 'Phenotype', 'HP:0001480', (59, 68))	('failure', 'NegReg', (99, 106))	('sun sensitivity', 'Disease', (74, 89))	('associated', 'Reg', (33, 43))	('freckling', 'Disease', (59, 68))	('pheomelanin', 'Chemical', 'MESH:C018362', (139, 150))	('eumelanin', 'Chemical', 'MESH:C041877', (166, 175))	('sun sensitivity', 'Phenotype', 'HP:0000992', (74, 89))	('red hair', 'Disease', (49, 57))	('red hair', 'Phenotype', 'HP:0002297', (49, 57))
89317	26354726	Mutations in tyrosinase result in a rare disorder called oculocutaneous albinism 4, 5, which is associated with ultraviolet (UV) sensitivity, while common variants associated with blue eyes have been linked to melanoma predisposition by GWAS 2.	('albinism', 'Phenotype', 'HP:0001022', (72, 80))	('linked', 'Reg', (200, 206))	('oculocutaneous albinism 4', 'Disease', (57, 82))	('blue eyes', 'Phenotype', 'HP:0000635', (180, 189))	('tyrosinase', 'Gene', (13, 23))	('Mutations', 'Var', (0, 9))	('result in', 'Reg', (24, 33))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))
89320	26354726	Likewise, melanoma GWAS have identified variants linked to the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene 1, 2.	('melanoma GWAS', 'Disease', (10, 23))	('CDKN2A', 'Gene', (101, 107))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('80', '96'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (63, 99))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('63', '96'))	('CDKN2A', 'Gene', '1029', (101, 107))	('melanoma GWAS', 'Disease', 'MESH:D008545', (10, 23))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (63, 99))	('variants', 'Var', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))
89321	26354726	Importantly, loss-of-function mutations in CDKN2A, and its binding partner, the product of the cyclin-dependent kinase 4 (CDK4) gene, have been identified in highly melanoma-prone families 8, 9, 10, firmly linking disruption of cell cycle control and melanoma risk.	('cyclin-dependent kinase 4', 'Gene', (95, 120))	('loss-of-function', 'NegReg', (13, 29))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('CDKN2A', 'Gene', (43, 49))	('cell cycle control', 'biological_process', 'GO:1901987', ('228', '246'))	('CDKN2A', 'Gene', '1029', (43, 49))	('CDK4', 'Gene', '1019', (122, 126))	('CDK4', 'Gene', (122, 126))	('mutations', 'Var', (30, 39))	('cyclin-dependent kinase 4', 'Gene', '1019', (95, 120))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (251, 259))	('melanoma', 'Disease', (165, 173))	('CDK', 'molecular_function', 'GO:0004693', ('122', '125'))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
89323	26354726	First, the telomerase reverse transcriptase gene (TERT) was identified in GWAS studies, and by the analysis of a familial melanoma pedigree, a -57 bp mutation creating an ETS transcription factor binding site that activates the TERT promoter was identified 11.	('TERT', 'Gene', (228, 232))	('binding', 'Interaction', (196, 203))	('TERT', 'Gene', '7015', (228, 232))	('TERT', 'Gene', '7015', (50, 54))	('transcriptase', 'molecular_function', 'GO:0003968', ('30', '43'))	('transcriptase', 'molecular_function', 'GO:0003899', ('30', '43'))	('mutation', 'Var', (150, 158))	('activates', 'PosReg', (214, 223))	('familial melanoma', 'Disease', (113, 130))	('transcriptase', 'molecular_function', 'GO:0034062', ('30', '43'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('175', '203'))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('transcription', 'biological_process', 'GO:0006351', ('175', '188'))	('familial melanoma', 'Disease', 'OMIM:155600', (113, 130))	('TERT', 'Gene', (50, 54))
89324	26354726	More recently, melanoma family studies have identified the protection of telomeres 1 gene (POT1), with mutations in the DNA binding domain of POT1 dramatically increasing telomere length and promoting telomere fragility 12, 13.	('telomere', 'cellular_component', 'GO:0005696', ('171', '179'))	('mutations in', 'Var', (103, 115))	('increasing', 'PosReg', (160, 170))	('telomere', 'cellular_component', 'GO:0005696', ('201', '209'))	('telomere length', 'CPA', (171, 186))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('POT1', 'Gene', '25913', (91, 95))	('telomere', 'cellular_component', 'GO:0000781', ('171', '179'))	('telomere fragility', 'CPA', (201, 219))	('POT1', 'Gene', (91, 95))	('promoting', 'PosReg', (191, 200))	('POT1', 'Gene', '25913', (142, 146))	('DNA binding', 'molecular_function', 'GO:0003677', ('120', '131'))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('POT1', 'Gene', (142, 146))	('telomere', 'cellular_component', 'GO:0000781', ('201', '209'))
89328	26354726	At present, we know that rare loss-of-function variants in the BAP1 gene, encoding the BRCA1-associated protein-1 (ubiquitin carboxy-terminal hydrolase), a deubiquitinating enzyme, predispose to ocular melanoma, with some patients also developing cutaneous melanomas and tumours of other sites 15, 16, yet these mutations account for less than 10% of uveal melanoma families.	('ocular melanoma', 'Disease', (195, 210))	('loss-of-function', 'NegReg', (30, 46))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('156', '179'))	('patients', 'Species', '9606', (222, 230))	('ubiquitin', 'molecular_function', 'GO:0031386', ('115', '124'))	('melanoma', 'Phenotype', 'HP:0002861', (357, 365))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('cutaneous melanomas and tumours', 'Disease', 'MESH:C562393', (247, 278))	('uveal melanoma', 'Disease', (351, 365))	('uveal melanoma', 'Disease', 'MESH:C536494', (351, 365))	('BRCA1-associated protein-1', 'Gene', '8314', (87, 113))	('BAP1', 'Gene', (63, 67))	('BAP1', 'Gene', '8314', (63, 67))	('ocular melanoma', 'Phenotype', 'HP:0007716', (195, 210))	('tumours', 'Phenotype', 'HP:0002664', (271, 278))	('BRCA1-associated protein-1', 'Gene', (87, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (351, 365))	('developing', 'Reg', (236, 246))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('ocular melanoma', 'Disease', 'MESH:D008545', (195, 210))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (257, 265))	('melanomas', 'Phenotype', 'HP:0002861', (257, 266))	('variants', 'Var', (47, 55))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (247, 266))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (247, 265))
89331	26354726	With the exception of mutations in MC1R, few studies have addressed the genetics of predisposition to melanoma development in animal models.	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('MC1R', 'Gene', '4157', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('mutations', 'Var', (22, 31))	('MC1R', 'Gene', (35, 39))
89332	26354726	The studies that have been performed have again revealing an important role for genes that influence pigmentation in the cutaneous disease.	('cutaneous disease', 'Disease', 'MESH:D018366', (121, 138))	('pigmentation', 'Disease', 'MESH:D010859', (101, 113))	('pigmentation', 'Disease', (101, 113))	('cutaneous disease', 'Disease', (121, 138))	('pigmentation', 'biological_process', 'GO:0043473', ('101', '113'))	('genes', 'Var', (80, 85))
89338	26354726	The family studies that identified germline mutations in CDKN2A led to the identification of somatic mutation in this gene, and also deletions of the entire gene locus 9, 20.	('deletions', 'Var', (133, 142))	('mutations', 'Var', (44, 53))	('CDKN2A', 'Gene', '1029', (57, 63))	('CDKN2A', 'Gene', (57, 63))
89339	26354726	Likewise, studies that identified the phosphatase and tensin homolog (PTEN) gene as being mutated in glioma led to the identification of mutations and deletions of this locus in melanoma 21.	('PTEN', 'Gene', (70, 74))	('glioma', 'Disease', (101, 107))	('mutations', 'Var', (137, 146))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('deletions', 'Var', (151, 160))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('38', '68'))	('phosphatase', 'molecular_function', 'GO:0016791', ('38', '49'))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('glioma', 'Disease', 'MESH:D005910', (101, 107))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))
89342	26354726	Several years later, activating mutations of the neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) gene were identified in human melanomas at a frequency of 20% 23, 24, 25, and in 2002, amplicon sequencing studies of melanoma cell lines resulted in the identification of activating BRAF mutations, most converting a valine at position 600 to a glutamic acid (BRAFV600E), generating a constitutively active kinase in around 50% of cases 26.	('melanoma', 'Disease', (223, 231))	('activating', 'PosReg', (277, 287))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('constitutively active kinase', 'MPA', (390, 418))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('BRAF', 'Gene', (288, 292))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('melanoma', 'Disease', (135, 143))	('mutations', 'Var', (293, 302))	('valine at position 600 to a glutamic acid', 'Mutation', 'rs113488022', (322, 363))	('BRAFV600E', 'Mutation', 'rs113488022', (365, 374))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('neuroblastoma', 'Phenotype', 'HP:0003006', (49, 62))	('human', 'Species', '9606', (129, 134))	('neuroblastoma RAS viral (v-ras) oncogene homolog', 'Gene', '4893', (49, 97))	('melanomas', 'Disease', (135, 144))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
89343	26354726	The discovery of this somatic mutation resulting in constitutive activation of the MAPK pathway has revolutionized the field of melanoma genetics and has recently facilitated a revolution in new therapeutics, with clinically approved agents targeting mutant BRAF, and MEK and ERK now in use 27.	('mutant', 'Var', (251, 257))	('ERK', 'Gene', '5594', (276, 279))	('MAPK pathway', 'Pathway', (83, 95))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('ERK', 'molecular_function', 'GO:0004707', ('276', '279'))	('mutation', 'Var', (30, 38))	('ERK', 'Gene', (276, 279))	('MEK', 'Gene', (268, 271))	('MEK', 'Gene', '5609', (268, 271))	('MAPK', 'molecular_function', 'GO:0004707', ('83', '87'))	('BRAF', 'Gene', (258, 262))	('activation', 'PosReg', (65, 75))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
89344	26354726	More recently, next-generation sequencing of melanomas and matched germline DNA has identified as many as 20 genes as being statistically significantly mutated in human melanoma 28, 29, 30.	('mutated', 'Var', (152, 159))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('human', 'Species', '9606', (163, 168))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Disease', (45, 54))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
89347	26354726	Less is known about the genetics of the non-cutaneous forms of melanoma but acral, uveal, and mucosal melanomas tend to harbour mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), the guanine nucleotide binding protein (G protein), alpha 11 (Gq class) (GNA11), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-KIT) genes 17.	('uvea', 'Disease', (83, 87))	('guanine nucleotide-binding protein G(q) subunit alpha', 'Gene', '2776', (145, 198))	('c-KIT', 'Gene', (355, 360))	('nucleotide-binding', 'molecular_function', 'GO:0000166', ('153', '171'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('219', '237'))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('c-KIT', 'Gene', '3815', (355, 360))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('uvea', 'Disease', 'MESH:C536494', (83, 87))	('mutations', 'Var', (128, 137))	('GNA11', 'Gene', '2767', (280, 285))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('mucosal melanomas tend', 'Disease', 'MESH:D008545', (94, 116))	('protein', 'cellular_component', 'GO:0003675', ('238', '245'))	('sarcoma', 'Phenotype', 'HP:0100242', (323, 330))	('GNAQ', 'Gene', '2776', (200, 204))	('mucosal melanomas tend', 'Disease', (94, 116))	('GNAQ', 'Gene', (200, 204))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('KIT', 'molecular_function', 'GO:0005020', ('357', '360'))	('GNA11', 'Gene', (280, 285))	('sarcoma viral', 'Disease', 'MESH:D001102', (323, 336))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (211, 229))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('sarcoma viral', 'Disease', (323, 336))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (145, 163))
89351	26354726	Prior to these studies, we knew, for example, that BRAF and NRAS mutations occurred but tumour sequencing studies have helped us to resolve their absolute prevalence, particularly at positions outside of the canonical BRAFV600 and NRASQ61 residues.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Disease', (88, 94))	('NRAS', 'Gene', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (65, 74))
89352	26354726	For example, hotspot mutations in PPP6C and RAC1 have been identified, and represent potential sites for therapeutic targeting.	('hotspot', 'PosReg', (13, 20))	('RAC1', 'Gene', '5879', (44, 48))	('RAC1', 'Gene', (44, 48))	('PPP6C', 'Gene', (34, 39))	('PPP6C', 'Gene', '5537', (34, 39))	('mutations', 'Var', (21, 30))
89355	26354726	We know now, for example, that the RAC1 P29S hotspot mutation is mutually exclusive from mutations in other components of the Rho family, a result that would be predicted, but is clarifying nonetheless 30.	('P29S', 'Mutation', 'rs1057519874', (40, 44))	('RAC1', 'Gene', (35, 39))	('P29S', 'Var', (40, 44))	('RAC1', 'Gene', '5879', (35, 39))
89356	26354726	We have also learnt that there is a third subtype of cutaneous disease called NRAS/BRAF wild-type melanoma, which is characterized by a high C > T mutation burden, amplifications and mutation of c-KIT, and alterations of NF1 28, 30.	('c-KIT', 'Gene', (195, 200))	('alterations', 'Var', (206, 217))	('NF1', 'Gene', (221, 224))	('cutaneous disease', 'Disease', (53, 70))	('amplifications', 'Var', (164, 178))	('NF1', 'Gene', '4763', (221, 224))	('c-KIT', 'Gene', '3815', (195, 200))	('KIT', 'molecular_function', 'GO:0005020', ('197', '200'))	('NRAS/BRAF', 'Disease', (78, 87))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('cutaneous disease', 'Disease', 'MESH:D018366', (53, 70))	('mutation', 'Var', (183, 191))	('C > T mutation', 'Var', (141, 155))
89359	26354726	Sequencing of human tumours has also informed us that the major mutagen in cutaneous melanoma is UV light which drives a C > T mutation pattern.	('tumours', 'Disease', 'MESH:D009369', (20, 27))	('human', 'Species', '9606', (14, 19))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('C > T mutation', 'Var', (121, 135))	('cutaneous melanoma', 'Disease', (75, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('tumours', 'Disease', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
89372	26354726	Although mice rarely develop melanoma spontaneously, they can do so when genetically engineered to carry defined mutations that mimic the genetic lesions (or their consequences) found in human melanomas.	('genetic lesions', 'Disease', (138, 153))	('melanomas', 'Disease', (193, 202))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('genetic lesions', 'Disease', 'MESH:D020022', (138, 153))	('melanomas', 'Disease', 'MESH:D008545', (193, 202))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('mutations', 'Var', (113, 122))	('human', 'Species', '9606', (187, 192))	('mice', 'Species', '10090', (9, 13))
89373	26354726	These engineered mutations can result in activation of oncogenes (such as mutant BrafV600E or NrasQ61R) and/or inactivation of key tumour suppressor genes (such as Cdkn2a or Pten).	('tumour', 'Disease', (131, 137))	('oncogenes', 'Gene', (55, 64))	('inactivation', 'NegReg', (111, 123))	('BrafV600E', 'Mutation', 'rs113488022', (81, 90))	('Pten', 'Gene', '5728', (174, 178))	('Pten', 'Gene', (174, 178))	('activation', 'PosReg', (41, 51))	('Cdkn2a', 'Gene', (164, 170))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('NrasQ61R', 'Gene', (94, 102))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('BrafV600E', 'Gene', (81, 90))	('mutant', 'Var', (74, 80))
89374	26354726	In mice, genetic modification of the germline melanoma susceptibility gene Cdkn2a (p16Ink4a null mice) does not result in melanoma, with these mice typically developing soft-tissue sarcomas and lymphomas 45.	('sarcomas', 'Disease', 'MESH:D012509', (181, 189))	('sarcomas', 'Phenotype', 'HP:0100242', (181, 189))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('sarcomas', 'Disease', (181, 189))	('melanoma', 'Disease', (46, 54))	('developing', 'Reg', (158, 168))	('lymphomas', 'Disease', 'MESH:D008223', (194, 203))	('genetic modification', 'Var', (9, 29))	('lymphomas', 'Phenotype', 'HP:0002665', (194, 203))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('mice', 'Species', '10090', (3, 7))	('Cdkn2a', 'Gene', (75, 81))	('mice', 'Species', '10090', (97, 101))	('p16Ink4a', 'Gene', (83, 91))	('mice', 'Species', '10090', (143, 147))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (169, 189))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('lymphomas', 'Disease', (194, 203))	('p16Ink4a', 'Gene', '12578', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))
89375	26354726	For example, mice carrying melanocyte-specific (tyrosinase promoter-controlled) expression of activated HRASG12V on an Ink4a-deficient background develop spontaneous cutaneous melanomas after a short latency and with a high penetrance 22.	('mice', 'Species', '10090', (13, 17))	('Ink4a', 'Gene', '12578', (119, 124))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('HRASG12V', 'Gene', '15461', (104, 112))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('Ink4a', 'Gene', (119, 124))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (166, 185))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (166, 185))	('HRASG12V', 'Gene', (104, 112))	('develop', 'PosReg', (146, 153))	('cutaneous melanomas', 'Disease', (166, 185))	('expression', 'Var', (80, 90))
89377	26354726	Mutational activation of BRAF in mice carrying conditional melanocyte-specific expression of BrafV600E (or the mouse equivalent, BrafV618E) has also been used to model melanoma development, tumour progression, and drug resistance 47, 48, 49.	('tumour', 'Disease', (190, 196))	('drug resistance', 'biological_process', 'GO:0042493', ('214', '229'))	('mouse', 'Species', '10090', (111, 116))	('activation', 'PosReg', (11, 21))	('BrafV600E', 'Mutation', 'rs113488022', (93, 102))	('drug resistance', 'CPA', (214, 229))	('drug resistance', 'Phenotype', 'HP:0020174', (214, 229))	('drug resistance', 'biological_process', 'GO:0009315', ('214', '229'))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('mice', 'Species', '10090', (33, 37))	('BRAF', 'Gene', (25, 29))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('BrafV600E', 'Var', (93, 102))	('melanoma', 'Disease', (168, 176))	('tumour', 'Disease', 'MESH:D009369', (190, 196))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
89398	26354726	As described in more detail below, there are a number of receptor tyrosine kinase genes that are mutated in canine melanomas and tyrosine kinase inhibitor drugs are already commercially available and used clinically in canine cancer patients 64, but to date no trials have been published using these compounds in canine melanoma.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('canine', 'Species', '9615', (313, 319))	('melanoma', 'Disease', 'MESH:D008545', (320, 328))	('melanoma', 'Phenotype', 'HP:0002861', (320, 328))	('melanoma', 'Disease', (320, 328))	('canine', 'Species', '9615', (108, 114))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('melanoma', 'Disease', (115, 123))	('mutated', 'Var', (97, 104))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('melanomas', 'Disease', (115, 124))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('138', '154'))	('patients', 'Species', '9606', (233, 241))	('canine', 'Species', '9615', (219, 225))
89403	26354726	The BRAFV600E mutation is found in about 6% of canine oral melanomas 66, as are non-canonical BRAF mutations.	('oral melanoma', 'Disease', 'MESH:D008545', (54, 67))	('BRAFV600E', 'Var', (4, 13))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('melanomas', 'Disease', (59, 68))	('oral melanoma', 'Disease', (54, 67))	('canine', 'Species', '9615', (47, 53))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
89404	26354726	NRAS mutations have also been found at the same location as those in human melanoma (the residue corresponding to Q61), and loss-of-function mutations in PTEN have been reported 56.	('mutations', 'Var', (141, 150))	('human', 'Species', '9606', (69, 74))	('mutations', 'Var', (5, 14))	('loss-of-function', 'NegReg', (124, 140))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('PTEN', 'Gene', (154, 158))
89405	26354726	Also similar to humans, loss of PTEN expression, and c-KIT mutation, and/or overexpression of c-KIT are common in the canine disease.	('c-KIT', 'Gene', '3815', (53, 58))	('PTEN', 'Protein', (32, 36))	('KIT', 'molecular_function', 'GO:0005020', ('55', '58'))	('canine', 'Species', '9615', (118, 124))	('humans', 'Species', '9606', (16, 22))	('c-KIT', 'Gene', (94, 99))	('mutation', 'Var', (59, 67))	('c-KIT', 'Gene', (53, 58))	('KIT', 'molecular_function', 'GO:0005020', ('96', '99'))	('c-KIT', 'Gene', '3815', (94, 99))	('expression', 'MPA', (37, 47))	('loss', 'NegReg', (24, 28))	('overexpression', 'PosReg', (76, 90))
89437	26354726	The causative mutation for this phenotype is a 4.6-kb intronic duplication in the STX17 (syntaxin 17) gene, which constitutes a cis-acting regulatory mutation.	('STX17', 'Gene', (82, 87))	('syntaxin 17', 'Gene', '55014', (89, 100))	('syntaxin 17', 'Gene', (89, 100))	('intronic duplication', 'Var', (54, 74))
89439	26354726	It is known that the duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells from grey horses, highlighting the universal importance of the MAPK/ERK pathway in melanomagenesis 87.	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('STX17', 'Gene', (36, 41))	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('activation', 'PosReg', (83, 93))	('duplication', 'Var', (21, 32))	('horses', 'Species', '9796', (144, 150))	('ERK', 'Gene', '5594', (202, 205))	('associated', 'Reg', (54, 64))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('ERK', 'molecular_function', 'GO:0004707', ('202', '205'))	('MAPK', 'molecular_function', 'GO:0004707', ('197', '201'))	('ERK', 'molecular_function', 'GO:0004707', ('101', '104'))	('ERK', 'Gene', (202, 205))	('melanoma', 'Disease', (217, 225))
89443	26354726	Indeed, grey horses that possess a loss-of-function mutation in the ASIP (agouti signalling protein) gene have a higher incidence of melanoma, implicating melanocortin-1 receptor signalling in melanoma development in these animals 18.	('agouti signalling protein', 'Gene', (74, 99))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('ASIP', 'Gene', '100054335', (68, 72))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('loss-of-function', 'NegReg', (35, 51))	('melanocortin-1 receptor', 'Gene', '100136907', (155, 178))	('melanocortin-1 receptor', 'Gene', (155, 178))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('agouti signalling protein', 'Gene', '100054335', (74, 99))	('melanoma', 'Disease', (133, 141))	('signalling', 'biological_process', 'GO:0023052', ('81', '91'))	('horses', 'Species', '9796', (13, 19))	('ASIP', 'Gene', (68, 72))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('mutation', 'Var', (52, 60))	('signalling', 'biological_process', 'GO:0023052', ('179', '189'))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))
89453	26354726	Zebrafish cancer models have primarily depended on transgenic expression of oncogenes and N-ethyl-N-nitrosourea (ENU)-induced genetic mutations in tumour suppressor genes.	('transgenic', 'Species', '10090', (51, 61))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (90, 111))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('Zebrafish cancer', 'Disease', 'MESH:D009369', (0, 16))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('Zebrafish cancer', 'Disease', (0, 16))	('genetic mutations', 'Var', (126, 143))	('mutations', 'Var', (134, 143))	('tumour', 'Disease', (147, 153))
89455	26354726	In the first zebrafish melanoma model, human BRAFV600E protein expressed from the melanocyte mitfa promoter led to the generation of naevi, and a mutation in p53 (p53-/-) was required for progression to melanoma 100.	('melanoma 100', 'Disease', 'MESH:D008545', (203, 215))	('mitf', 'Gene', (93, 97))	('BRAFV600E', 'Var', (45, 54))	('BRAFV600E', 'Mutation', 'rs113488022', (45, 54))	('zebrafish melanoma', 'Disease', 'MESH:D008545', (13, 31))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma 100', 'Disease', (203, 215))	('protein', 'Protein', (55, 62))	('mitf', 'Gene', '4286', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('naevi', 'CPA', (133, 138))	('naevi', 'Phenotype', 'HP:0003764', (133, 138))	('zebrafish melanoma', 'Disease', (13, 31))	('human', 'Species', '9606', (39, 44))
89456	26354726	This was the first animal model of the BRAFV600E mutation and was consistent with genetics in human patients whereby expression of BRAFV600E is sufficient to drive naevi, but requires additional mutations for progression of melanoma from naevi 26.	('naevi', 'Phenotype', 'HP:0003764', (164, 169))	('BRAFV600E', 'Var', (131, 140))	('BRAFV600E', 'Mutation', 'rs113488022', (131, 140))	('drive', 'PosReg', (158, 163))	('naevi', 'Disease', (164, 169))	('BRAFV600E', 'Mutation', 'rs113488022', (39, 48))	('human', 'Species', '9606', (94, 99))	('patients', 'Species', '9606', (100, 108))	('naevi', 'Phenotype', 'HP:0003764', (238, 243))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))
89457	26354726	Building on the BRAFV600E;p53-/- model, Zon and colleagues generated a modified zebrafish whereby the BRAFV600E transgene was co-expressed with one of 17 candidate genes from a recurrently amplified region in human melanoma on chromosome 1q21 101.	('human', 'Species', '9606', (209, 214))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('chromosome', 'cellular_component', 'GO:0005694', ('227', '237'))	('melanoma', 'Disease', (215, 223))	('melanoma', 'Disease', 'MESH:D008545', (215, 223))	('zebrafish', 'Species', '7955', (80, 89))	('BRAFV600E', 'Mutation', 'rs113488022', (102, 111))	('BRAFV600E', 'Mutation', 'rs113488022', (16, 25))	('BRAFV600E', 'Var', (102, 111))
89462	26354726	A unique temperature-sensitive mitf mutation in zebrafish (mitfavc7) has recently been used to study MITF activity in the control of melanocyte proliferation and differentiation in embryogenesis, and as a cancer gene in the development and survival of melanoma 103, 104, 105.	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('133', '157'))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('zebrafish', 'Species', '7955', (48, 57))	('cancer', 'Disease', (205, 211))	('mitf', 'Gene', '4286', (31, 35))	('embryogenesis', 'biological_process', 'GO:0009792', ('181', '194'))	('melanoma', 'Phenotype', 'HP:0002861', (252, 260))	('melanoma', 'Disease', (252, 260))	('mitf', 'Gene', (59, 63))	('melanoma', 'Disease', 'MESH:D008545', (252, 260))	('embryogenesis', 'biological_process', 'GO:0009790', ('181', '194'))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mitf', 'Gene', '4286', (59, 63))	('embryogenesis', 'biological_process', 'GO:0009793', ('181', '194'))	('MITF', 'Gene', '4286', (101, 105))	('MITF', 'Gene', (101, 105))	('mutation', 'Var', (36, 44))	('mitf', 'Gene', (31, 35))
89466	26354726	While HRASV12 melanoma studies have helped to establish melanoma models important for drug screens and cell biology studies 108, NRAS mutations are the common RAS family melanoma mutation, and genetic models in zebrafish indicate that NRASQ61K mutations in melanocytes require co-operation with loss of p53 to promote melanoma 109.	('melanoma', 'Disease', (14, 22))	('promote', 'PosReg', (310, 317))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('NRAS', 'Gene', (129, 133))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('NRASQ61K mutations', 'Var', (235, 253))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('mutations', 'Var', (134, 143))	('zebrafish', 'Species', '7955', (211, 220))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
89468	26354726	Accelerating tumour formation with HRASV12 mutations enables melanoma to be visualized at the earliest stages in the zebrafish 106, 108.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('HRASV12', 'Gene', (35, 42))	('zebrafish', 'Species', '7955', (117, 126))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('mutations', 'Var', (43, 52))	('tumour', 'Disease', (13, 19))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('formation', 'biological_process', 'GO:0009058', ('20', '29'))
89491	26354726	They also establish naevi as neoplasms that have mutations in oncogenes and tumour suppressor genes, as opposed to the previously held pathological view of naevi as non-neoplastic hamartomas.	('neoplasms', 'Phenotype', 'HP:0002664', (29, 38))	('non-neoplastic hamartomas', 'Phenotype', 'HP:0004390', (165, 190))	('non-neoplastic hamartomas', 'Disease', (165, 190))	('naevi', 'Phenotype', 'HP:0003764', (20, 25))	('mutations', 'Var', (49, 58))	('hamartomas', 'Phenotype', 'HP:0010566', (180, 190))	('naevi', 'Disease', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('neoplasms', 'Disease', (29, 38))	('non-neoplastic hamartomas', 'Disease', 'MESH:D006222', (165, 190))	('neoplasms', 'Disease', 'MESH:D009369', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('oncogenes', 'Gene', (62, 71))	('naevi', 'Phenotype', 'HP:0003764', (156, 161))	('tumour', 'Disease', (76, 82))
89507	27579737	Mutations in genes, such as CDKN2a, CDK4, and BRAF, and low penetrance genes, such as MC1R, have also been associated with melanoma development.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('CDK4', 'Gene', '1019', (36, 40))	('CDK4', 'Gene', (36, 40))	('CDKN2a', 'Gene', (28, 34))	('MC1R', 'Gene', '4157', (86, 90))	('CDK', 'molecular_function', 'GO:0004693', ('36', '39'))	('MC1R', 'Gene', (86, 90))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('CDKN2a', 'Gene', '1029', (28, 34))	('associated with', 'Reg', (107, 122))	('melanoma development', 'CPA', (123, 143))
89529	31212986	More recently, molecular and cytological factors such as monosomy of chromosome 3, additional copies of chromosome 8, and BRCA1 associated protein (BAP1) mutations, have been related to decreased survival.	('monosomy', 'Var', (57, 65))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('BAP1', 'Gene', '8314', (148, 152))	('BRCA1 associated protein', 'Gene', (122, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('69', '79'))	('decreased', 'NegReg', (186, 195))	('BAP1', 'Gene', (148, 152))	('mutations', 'Var', (154, 163))	('BRCA1 associated protein', 'Gene', '8315', (122, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))
89530	31212986	On the other hand, Splicing factor 3B subunit 1 (SF3B1) and Eukaryotic translation initiation factor 1A (EIF1AX) mutations seem to confer improved survival.	('SF3B1', 'Gene', '23451', (49, 54))	('survival', 'CPA', (147, 155))	('Splicing factor 3B subunit 1', 'Gene', '23451', (19, 47))	('improved', 'PosReg', (138, 146))	('EIF1AX', 'Gene', '1964', (105, 111))	('EIF1AX', 'Gene', (105, 111))	('mutations', 'Var', (113, 122))	('translation initiation', 'biological_process', 'GO:0006413', ('71', '93'))	('SF3B1', 'Gene', (49, 54))	('Splicing', 'biological_process', 'GO:0045292', ('19', '27'))	('Splicing factor 3B subunit 1', 'Gene', (19, 47))
89559	31212986	Moreover, inhibition of the HIF pathway with arylsulfonamide 64B in animal UM models results in tumour regression and improved survival, and inhibition of VEGF-A with bevacizumab in both mouse and human uveal melanoma inhibits the establishment of micrometastasis, further reflecting its importance.	('establishment of micrometastasis', 'CPA', (231, 263))	('survival', 'CPA', (127, 135))	('UM', 'Phenotype', 'HP:0007716', (75, 77))	('uveal melanoma', 'Phenotype', 'HP:0007716', (203, 217))	('tumour regression', 'Disease', (96, 113))	('improved', 'PosReg', (118, 126))	('arylsulfonamide 64B', 'Chemical', '-', (45, 64))	('inhibition', 'Var', (10, 20))	('uveal melanoma', 'Disease', (203, 217))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('mouse', 'Species', '10090', (187, 192))	('inhibition', 'Var', (141, 151))	('human', 'Species', '9606', (197, 202))	('inhibits', 'NegReg', (218, 226))	('tumour regression', 'Disease', 'MESH:D009365', (96, 113))	('HIF pathway', 'Pathway', (28, 39))	('bevacizumab', 'Chemical', 'MESH:D000068258', (167, 178))	('VEGF-A', 'Gene', (155, 161))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('uveal melanoma', 'Disease', 'MESH:C536494', (203, 217))
89573	31212986	Despite this relationship not being directly established in UM, the expression of EMT-associated factors does promote invasion and growth, which we believe could be partly explained by their role in vasculogenic mimicry, as has been demonstrated in other tumours.	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumours', 'Phenotype', 'HP:0002664', (255, 262))	('growth', 'CPA', (131, 137))	('EMT', 'biological_process', 'GO:0001837', ('82', '85'))	('expression', 'Var', (68, 78))	('promote', 'PosReg', (110, 117))	('UM', 'Phenotype', 'HP:0007716', (60, 62))	('tumours', 'Disease', 'MESH:D009369', (255, 262))	('invasion', 'CPA', (118, 126))	('tumours', 'Disease', (255, 262))
89579	31212986	The overexpression of MT1-MMP and MMP-2 is regulated by phosphoinositide 3-kinase (PI3K), and specific inhibitors of PI3K are able to abrogate vasculogenic mimicry in both uveal and cutaneous melanoma cells by decreasing the levels of MT1-MMP and MMP-2.	('MT1', 'molecular_function', 'GO:0043834', ('22', '25'))	('MT1-MMP', 'Gene', (235, 242))	('MMP', 'molecular_function', 'GO:0004235', ('239', '242'))	('inhibitors', 'Var', (103, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('MMP', 'molecular_function', 'GO:0004235', ('26', '29'))	('melanoma cells', 'Disease', 'MESH:D008545', (192, 206))	('MMP-2', 'molecular_function', 'GO:0004228', ('247', '252'))	('MT1-MMP', 'Gene', '4323', (235, 242))	('cutaneous melanoma', 'Disease', (182, 200))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (182, 200))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (182, 200))	('abrogate', 'NegReg', (134, 142))	('decreasing', 'NegReg', (210, 220))	('MT1', 'molecular_function', 'GO:0043791', ('235', '238'))	('vasculogenic mimicry', 'CPA', (143, 163))	('phosphoinositide 3-kinase', 'Gene', '5295', (56, 81))	('MT1', 'molecular_function', 'GO:0043791', ('22', '25'))	('melanoma cells', 'Disease', (192, 206))	('MT1-MMP', 'Gene', (22, 29))	('MT1', 'molecular_function', 'GO:0047152', ('235', '238'))	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('PI3K', 'Var', (117, 121))	('levels', 'MPA', (225, 231))	('MMP-2', 'MPA', (247, 252))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('MT1', 'molecular_function', 'GO:0043834', ('235', '238'))	('phosphoinositide 3-kinase', 'Gene', (56, 81))	('MT1-MMP', 'Gene', '4323', (22, 29))	('MT1', 'molecular_function', 'GO:0047152', ('22', '25'))	('MMP-2', 'molecular_function', 'GO:0004228', ('34', '39'))
89602	31212986	Pevonedistat, a selective and potent inhibitor of NEDD8-activating enzyme E1 subunit 1 (NAE1), an enzyme involved in neddylation, is able to repress the cancer stemness properties of UM cell lines, and could therefore potentially interfere with vasculogenic mimicry.	('UM', 'Phenotype', 'HP:0007716', (183, 185))	('NEDD8-activating enzyme E1 subunit 1', 'Gene', (50, 86))	('interfere', 'NegReg', (230, 239))	('repress the cancer stemness', 'Disease', 'MESH:D009369', (141, 168))	('NAE1', 'Gene', '8883', (88, 92))	('Pevonedistat', 'Chemical', 'MESH:C539933', (0, 12))	('NAE1', 'Gene', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('repress the cancer stemness', 'Disease', (141, 168))	('vasculogenic mimicry', 'CPA', (245, 265))	('NEDD8-activating enzyme E1 subunit 1', 'Gene', '8883', (50, 86))	('Pevonedistat', 'Var', (0, 12))
89609	31212986	PARP inhibitors suppress the metastatic potential of some human and murine melanoma cells, due in part to the inhibition of vasculogenic mimicry mediated by the downregulation of VE-cadherin and the inhibition of the EMT pathway.	('inhibition', 'NegReg', (110, 120))	('human', 'Species', '9606', (58, 63))	('PARP', 'Gene', '142', (0, 4))	('PARP', 'Gene', (0, 4))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('melanoma cells', 'Disease', 'MESH:D008545', (75, 89))	('inhibitors', 'Var', (5, 15))	('melanoma cells', 'Disease', (75, 89))	('vasculogenic mimicry', 'CPA', (124, 144))	('downregulation', 'NegReg', (161, 175))	('suppress', 'NegReg', (16, 24))	('metastatic potential', 'CPA', (29, 49))	('murine', 'Species', '10090', (68, 74))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('inhibition', 'NegReg', (199, 209))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('EMT pathway', 'Pathway', (217, 228))	('VE-cadherin', 'Protein', (179, 190))
89627	31212986	The immune infiltrate in UM seems to be related to genetic alterations, with the lack of BAP1 mutations showing a richer T-cell infiltration.	('BAP1', 'Gene', '8314', (89, 93))	('BAP1', 'Gene', (89, 93))	('UM', 'Phenotype', 'HP:0007716', (25, 27))	('mutations', 'Var', (94, 103))
89632	31212986	Indeed, the co-expression of both molecules leads to a high CD8+ T-cell infiltration in cutaneous melanoma, and upregulation of both CCR5/CXCR3 is associated to greater response to different immunotherapies, including checkpoint inhibitors and adoptive cell therapy.	('CCR5', 'Gene', (133, 137))	('CD8', 'Gene', '925', (60, 63))	('cutaneous melanoma', 'Disease', (88, 106))	('CCR', 'molecular_function', 'GO:0043880', ('133', '136'))	('CXCR3', 'Gene', (138, 143))	('upregulation', 'PosReg', (112, 124))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (88, 106))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('CCR5', 'Gene', '1234', (133, 137))	('co-expression', 'Var', (12, 25))	('CXCR3', 'Gene', '2833', (138, 143))	('CD8', 'Gene', (60, 63))
89653	29554022	Clinical Implications of Real-Time Integrative Sequencing in Management of Patients with Suspected Germline BAP1 Mutations The BAP (BRCA associated protein) gene encodes the BAP-1 enzyme that catalyzes de-ubiquitination of protein substrates involved in cell cycle regulation, cell differentiation and cell death.	('BAP1', 'Gene', '8314', (108, 112))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('254', '275'))	('cell death', 'biological_process', 'GO:0008219', ('302', '312'))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('protein', 'cellular_component', 'GO:0003675', ('223', '230'))	('BAP-1', 'Gene', '8314', (174, 179))	('BAP (BRCA associated protein', 'Gene', '11331', (127, 155))	('Mutations', 'Var', (113, 122))	('Patients', 'Species', '9606', (75, 83))	('BAP1', 'Gene', (108, 112))	('de-ubiquitination', 'MPA', (202, 219))	('BAP-1', 'Gene', (174, 179))	('cell differentiation', 'biological_process', 'GO:0030154', ('277', '297'))
89656	29554022	In this report, we present the case of a patient with recurrent metastatic melanoma who was subsequently found to have a pathogenic germline BAP1 and somatic BRAF mutation by clinical genomic sequencing.	('BAP1', 'Gene', '8314', (141, 145))	('BAP1', 'Gene', (141, 145))	('BRAF', 'Gene', '673', (158, 162))	('patient', 'Species', '9606', (41, 48))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('BRAF', 'Gene', (158, 162))	('mutation', 'Var', (163, 171))
89670	29554022	Sequencing revealed a somatic BRAF (V600E) point mutation, as well as a BAP1 (p. D567X) germline pathogenic variant.	('D567X', 'SUBSTITUTION', 'None', (81, 86))	('BAP1', 'Gene', '8314', (72, 76))	('D567X', 'Var', (81, 86))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('BRAF', 'Gene', (30, 34))	('BAP1', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (30, 34))	('V600E', 'Var', (36, 41))
89675	29554022	This damage results in somatic mutations to genes, one of the most common being BRAF V600E, which is involved in 40-60% of melanomas.	('mutations', 'Var', (31, 40))	('results in', 'Reg', (12, 22))	('BRAF', 'Gene', (80, 84))	('melanomas', 'Disease', (123, 132))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('BRAF', 'Gene', '673', (80, 84))
89676	29554022	In addition to spontaneous somatic mutations, heterozygous germline mutations to a tumor suppressor gene such as BAP1 and the subsequent development of TPDS can also be involved in development of melanoma.	('involved', 'Reg', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('men', 'Species', '9606', (144, 147))	('tumor suppressor', 'biological_process', 'GO:0051726', ('83', '99'))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('83', '99'))	('BAP1', 'Gene', '8314', (113, 117))	('heterozygous', 'Var', (46, 58))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('TPDS', 'Disease', (152, 156))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('TPDS', 'Disease', 'OMIM:614327', (152, 156))	('men', 'Species', '9606', (188, 191))	('BAP1', 'Gene', (113, 117))	('germline mutations', 'Var', (59, 77))
89679	29554022	However, this gene has high penetrance, with malignancy developing in 69.74% of carriers and nearly all individuals with germline BAP1 mutations develop malignancies by age 55.	('BAP1', 'Gene', (130, 134))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('malignancies', 'Disease', (153, 165))	('develop', 'PosReg', (145, 152))	('mutations', 'Var', (135, 144))	('malignancy', 'Disease', (45, 55))	('BAP1', 'Gene', '8314', (130, 134))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))
89682	29554022	The earliest reported case of cutaneous melanoma related to BAP1 mutations prior to this case was at the age of 25.	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('BAP1', 'Gene', '8314', (60, 64))	('related', 'Reg', (49, 56))	('cutaneous melanoma', 'Disease', (30, 48))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (30, 48))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (30, 48))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
89684	29554022	This sequencing revealed a somatic BRAF mutation that could be exploited with targeted therapy if needed in the future.	('mutation', 'Var', (40, 48))	('BRAF', 'Gene', (35, 39))	('BRAF', 'Gene', '673', (35, 39))
89685	29554022	Further, a germline BAP1 mutation (p. D567X) was identified.	('BAP1', 'Gene', '8314', (20, 24))	('D567X', 'Var', (38, 43))	('D567X', 'SUBSTITUTION', 'None', (38, 43))	('BAP1', 'Gene', (20, 24))
89686	29554022	The presence of both a somatic BRAF mutation and germline BAP1 mutation have been implicated in cutaneous melanoma.	('cutaneous melanoma', 'Disease', (96, 114))	('BAP1', 'Gene', (58, 62))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (96, 114))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (96, 114))	('mutation', 'Var', (63, 71))	('implicated', 'Reg', (82, 92))	('BRAF', 'Gene', '673', (31, 35))	('BAP1', 'Gene', '8314', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('mutation', 'Var', (36, 44))	('BRAF', 'Gene', (31, 35))
89687	29554022	Identification of specific, previously identified mutations allows for early screening of related malignancies, screening for family members and genetic counseling.	('mutations', 'Var', (50, 59))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('malignancies', 'Disease', (98, 110))
89689	29554022	2016 proposed recommendations for families with germline BAP1 mutations.	('BAP1', 'Gene', '8314', (57, 61))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('men', 'Species', '9606', (19, 22))
89693	29554022	In our case, evidence of confirmed germline BAP1 mutation led to screening for uveal melanoma by ophthalmology and close monitoring for cutaneous melanoma for the patient as well genetic screening for other family members.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('mutation', 'Var', (49, 57))	('BAP1', 'Gene', '8314', (44, 48))	('patient', 'Species', '9606', (163, 170))	('uveal melanoma', 'Disease', (79, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('cutaneous melanoma', 'Disease', (136, 154))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (136, 154))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 154))	('BAP1', 'Gene', (44, 48))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))
89714	29346178	Sequencing of NRAS exon 3 showed a heterozygous point mutation (c.A182G; p.Q61R) (Fig.	('NRAS', 'Gene', '4893', (14, 18))	('c.A182G; p.Q61R', 'Var', (64, 79))	('c.A182G', 'Mutation', 'rs11554290', (64, 71))	('p.Q61R', 'Mutation', 'rs11554290', (73, 79))	('NRAS', 'Gene', (14, 18))	('p.Q61R', 'Var', (73, 79))
89717	29346178	Genomic DNA extracted from peripheral blood under standard conditions was analysed by next-generation sequencing [Hereditary Cancer Syndromes, Comprehensive Diagnostics (ID 93.00); MGZ, Munich, Germany] - this being a multigene diagnostic panel testing for mutations in 94 genes that have been associated with familial-cancer or multiple-cancer syndromes.	('mutations', 'Var', (257, 266))	('associated', 'Reg', (294, 304))	('multiple-cancer syndromes', 'Disease', 'MESH:D009369', (329, 354))	('multiple-cancer syndromes', 'Disease', (329, 354))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('Cancer', 'Disease', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('8', '11'))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('familial-cancer', 'Disease', (310, 325))	('familial-cancer', 'Disease', 'MESH:D009369', (310, 325))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
89732	29346178	NRAS mutations occur in 13-25% of cutaneous melanoma, the p.Q61R change accounting for ~35% of NRAS-mutated tumours.	('tumours', 'Disease', (108, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (34, 52))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mutations', 'Var', (5, 14))	('NRAS', 'Gene', (95, 99))	('p.Q61R', 'Mutation', 'rs11554290', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('p.Q61R', 'Var', (58, 64))	('NRAS', 'Gene', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('cutaneous melanoma', 'Disease', (34, 52))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', '4893', (95, 99))
89733	29346178	Advanced cutaneous melanoma containing NRAS mutations have a worse prognosis, with shorter median survival and more aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (116, 134))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('shorter', 'NegReg', (83, 90))	('NRAS', 'Gene', (39, 43))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('aggressive disease', 'Disease', (116, 134))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', '4893', (39, 43))
89736	29346178	It is, therefore, plausible that our patient's tumour has a currently unidentified protective mutation and next-generation sequencing of the tumour DNA might be valuable here.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('patient', 'Species', '9606', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour', 'Disease', (141, 147))	('mutation', 'Var', (94, 102))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
89738	29346178	Aberrations of chromosome 6 are the most common cytogenetic change in melanomas, with 6p gain in up to 85% of uveal melanomas, and more than 90% of sinonasal and cutaneous melanomas.	('melanomas', 'Disease', (116, 125))	('uveal melanoma', 'Phenotype', 'HP:0007716', (110, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('melanomas', 'Disease', (172, 181))	('uveal melanomas', 'Disease', (110, 125))	('cutaneous melanomas', 'Disease', (162, 181))	('uveal melanomas', 'Phenotype', 'HP:0007716', (110, 125))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('Aberrations', 'Var', (0, 11))	('melanomas', 'Phenotype', 'HP:0002861', (172, 181))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('gain', 'PosReg', (89, 93))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (162, 180))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('uveal melanomas', 'Disease', 'MESH:C536494', (110, 125))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (162, 181))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (162, 181))	('melanomas', 'Disease', (70, 79))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('melanomas', 'Disease', 'MESH:D008545', (172, 181))
89785	33614938	Patients appropriate for the study were identified by the Academic Health Center Information Exchange using a list of current procedural terminology codes (11640, 11640P, AS11640, 11640T, 11621, 11621P, 11621T, AS11621, 11642, 11642P, 11642T, AS11642, 11622, 11622P, 11622T, AS11622, 11641, 11641P, 11641T, AS11641, 11623, 11623T, 11623P, AS11623, 11643, AS11643, 11643T, 11643P, 11626, AS11626, 11626P, 11626T, 11624, 11624T, AS11624, 11624P, 11620, 11620T, AS11620, 11620P, 11646, AS11646, 11646P, 11646T, 11644, 11644P, 11644T, AS11644, 21012, 21012P, AS21012, 21012T, 21011, 21011P, AS21011, 21011T, 21555, 21555T, AS21555, 21555P, 21556, AS21556, 21556T, 21552, 21552P, 21552T, AS21552), and a set of patient medical record numbers was provided by the University of Minnesota integrated informatics core (Best Practices Integrated Informatics Core [BPIC]).	('11644T', 'Var', (523, 529))	('patient', 'Species', '9606', (706, 713))	('21552', 'Var', (660, 665))	('AS21556', 'Var', (643, 650))	('Patients', 'Species', '9606', (0, 8))	('11644', 'Var', (508, 513))	('21555T', 'Var', (611, 617))	('21556', 'Var', (636, 641))	('21011T', 'Var', (596, 602))	('AS11646', 'Var', (483, 490))	('21555', 'Var', (604, 609))	('21556T', 'Var', (652, 658))	('11646T', 'Var', (500, 506))	('21012T', 'Var', (564, 570))	('21552T', 'Var', (675, 681))	('21011', 'Var', (572, 577))	('AS21555', 'Var', (619, 626))	('AS21012', 'Var', (555, 562))	('AS11644', 'Var', (531, 538))	('AS21011', 'Var', (587, 594))	('core', 'cellular_component', 'GO:0019013', ('804', '808'))
89809	33614938	Still, confidence intervals trended toward higher risk: patients with Breslow depth > 1 mm had 2.17 times the odds of recurrence (OR = 2.17, 95% CI = 0.84-5.55) and patients with nodular melanoma had 1.89 times the odds of recurrence (95% CI = 0.74-4.89).	('patients', 'Species', '9606', (56, 64))	('nodular melanoma', 'Phenotype', 'HP:0012058', (179, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('nodular melanoma', 'Disease', 'MESH:D008545', (179, 195))	('> 1 mm', 'Var', (84, 90))	('patients', 'Species', '9606', (165, 173))	('nodular melanoma', 'Disease', (179, 195))
89813	33614938	Although mitotic rate was removed from the most recent AJCC melanoma staging system, mitotic rate >=1 has been associated with increased incidence of positive SLNB and decreased survival.	('mitotic', 'Var', (85, 92))	('decreased', 'NegReg', (168, 177))	('survival', 'CPA', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('AJCC melanoma', 'Disease', (55, 68))	('increased', 'PosReg', (127, 136))	('AJCC melanoma', 'Disease', 'MESH:D008545', (55, 68))
89814	33614938	2 ,  4 ,  24 ,  25 ,  26  Babajanian et al report similar findings in a cohort of patients with melanomas of the head and neck; mitotic rate >=1 was associated with an increased incidence of positive SLNB, higher incidence of recurrence, and negative impact on overall and disease-free survival.	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('patients', 'Species', '9606', (82, 90))	('neck', 'cellular_component', 'GO:0044326', ('122', '126'))	('melanomas', 'Disease', (96, 105))	('positive', 'Var', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('mitotic rate', 'CPA', (128, 140))
89844	29657129	The discovery that approximately half of all melanomas are driven by BRAFV600 mutations as well as advances in tumor immunology have translated to targeted and immune therapies with impressive response rates and significantly improved survival.	('improved', 'PosReg', (226, 234))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('driven by', 'Reg', (59, 68))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (111, 116))	('melanomas', 'Disease', (45, 54))	('BRAF', 'Gene', '673', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('BRAF', 'Gene', (69, 73))	('melanomas', 'Disease', 'MESH:D008545', (45, 54))	('melanomas', 'Phenotype', 'HP:0002861', (45, 54))
89853	29657129	While dedifferentiation could promote resistance to current therapies, we reasoned it might also render cells more susceptible to new vulnerabilities.	('promote', 'PosReg', (30, 37))	('mi', 'Chemical', 'MESH:C011506', (86, 88))	('dedifferentiation', 'biological_process', 'GO:0043696', ('6', '23'))	('resistance', 'MPA', (38, 48))	('render', 'Reg', (97, 103))	('dedifferentiation', 'Var', (6, 23))
89877	29657129	In the BRAF mutant cell lines M229P and M238P, we observed that cell lines begin with different initial differentiation stages as defined by their subtype signatures, but shift notably towards the undifferentiated signature upon acquired resistance to vemurafenib (M229R, M238R) (Figure 2A).	('M229R', 'Mutation', 'p.M229R', (265, 270))	('M238R', 'Mutation', 'p.M238R', (272, 277))	('M229P', 'Var', (30, 35))	('M238P', 'Var', (40, 45))	('M229R', 'Var', (265, 270))	('mutant', 'Var', (12, 18))	('BRAF', 'Gene', '673', (7, 11))	('vemurafenib', 'Chemical', 'MESH:D000077484', (252, 263))	('M229P', 'Mutation', 'p.M229P', (30, 35))	('M238R', 'Var', (272, 277))	('M238P', 'Mutation', 'p.M238P', (40, 45))	('BRAF', 'Gene', (7, 11))
89879	29657129	As a negative control, resistance mediated by genomic alterations that directly reactivate the MAPK pathway, such as through NRAS mutation (M249R) or BRAF alternative splicing (M395R, M397R) do not show differentiation changes (Figure 2A).	('NRAS', 'Gene', (125, 129))	('M397R', 'Var', (184, 189))	('M249R', 'Mutation', 'p.M249R', (140, 145))	('M395R', 'Var', (177, 182))	('NRAS', 'Gene', '4893', (125, 129))	('MAPK', 'molecular_function', 'GO:0004707', ('95', '99'))	('M397R', 'Mutation', 'p.M397R', (184, 189))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('splicing', 'biological_process', 'GO:0045292', ('167', '175'))	('mi', 'Chemical', 'MESH:C011506', (50, 52))	('MAPK pathway', 'Pathway', (95, 107))	('M249R', 'Var', (140, 145))	('M395R', 'Mutation', 'p.M395R', (177, 182))	('reactivate', 'Reg', (80, 90))
89883	29657129	This line was tested because reported resistant sublines of M397 (M397R) occurred through BRAF alternative splicing, a resistance mechanism that re-activates the MAPK pathway and have the same differentiation state as their parental line (Figure 2A).	('BRAF', 'Gene', (90, 94))	('MAPK', 'molecular_function', 'GO:0004707', ('162', '166'))	('splicing', 'biological_process', 'GO:0045292', ('107', '115'))	('MAPK pathway', 'Pathway', (162, 174))	('BRAF', 'Gene', '673', (90, 94))	('M397R', 'Mutation', 'p.M397R', (66, 71))	('M397 (M397R', 'Var', (60, 71))
89885	29657129	In alternate cases, the dedifferentiation state can be stabilized, such as through loss of SOX10 by epigenetic reprogramming.	('dedifferentiation', 'biological_process', 'GO:0043696', ('24', '41'))	('SOX10', 'Gene', (91, 96))	('SOX10', 'Gene', '6663', (91, 96))	('mi', 'Chemical', 'MESH:C011506', (120, 122))	('epigenetic', 'Var', (100, 110))	('loss', 'NegReg', (83, 87))
89889	29657129	In this model, dedifferentiation decreased tumor antigen presentation, as scored by loss of melanocytic biomarkers (gp100, TRP2), and resulted in tumor progression.	('tumor antigen', 'molecular_function', 'GO:0008222', ('43', '56'))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TRP2', 'Gene', '7218', (123, 127))	('dedifferentiation', 'Var', (15, 32))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('TRP2', 'molecular_function', 'GO:0004167', ('123', '127'))	('dedifferentiation', 'biological_process', 'GO:0043696', ('15', '32'))	('loss of melanocytic', 'Disease', 'MESH:D009508', (84, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gp100', 'Protein', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('decreased', 'NegReg', (33, 42))	('TRP2', 'Gene', (123, 127))	('tumor', 'Disease', (43, 48))	('antigen presentation', 'biological_process', 'GO:0019882', ('49', '69'))	('loss of melanocytic', 'Disease', (84, 103))
89907	29657129	The ferroptosis inducing compounds include erastin, (1S, 3R)-RSL3, ML162, and ML210.	('ferroptosis', 'biological_process', 'GO:0097707', ('4', '15'))	('ML210', 'Var', (78, 83))	('ferroptosis', 'Disease', (4, 15))	('ML162', 'Var', (67, 72))	('(1S, 3R)-RSL3', 'Chemical', '-', (52, 65))	('erastin', 'Chemical', 'MESH:C477224', (43, 50))
89909	29657129	Compounds (1S, 3R)-RSL3 (hereafter referred to as RSL3), ML162, ML210 induce ferroptosis by direct inhibition of GPX4, while erastin indirectly inhibits GPX4 further upstream through depletion of glutathione by targeting the System Xc- transporter.	('GPX4', 'Gene', '2879', (113, 117))	('glutathione', 'Chemical', 'MESH:D005978', (196, 207))	('inhibits', 'NegReg', (144, 152))	('ferroptosis', 'Disease', (77, 88))	('depletion', 'MPA', (183, 192))	('erastin', 'Chemical', 'MESH:C477224', (125, 132))	('RSL3', 'Chemical', '-', (19, 23))	('RSL3', 'Chemical', '-', (50, 54))	('inhibition', 'NegReg', (99, 109))	('ferroptosis', 'biological_process', 'GO:0097707', ('77', '88'))	('induce', 'PosReg', (70, 76))	('(1S, 3R)-RSL3', 'Chemical', '-', (10, 23))	('ML162', 'Var', (57, 62))	('ML210', 'Var', (64, 69))	('GPX4', 'Gene', (153, 157))	('GPX4', 'Gene', '2879', (153, 157))	('GPX4', 'Gene', (113, 117))
89919	29657129	As a negative control, M249R, which achieves resistance through acquisition of an NRAS mutation with no change in differentiation status (Figure 2A), was equally insensitive to ferroptosis induction as its parental line (Figures 4E and 4F).	('M249R', 'Mutation', 'p.M249R', (23, 28))	('ferroptosis', 'biological_process', 'GO:0097707', ('177', '188'))	('NRAS', 'Gene', (82, 86))	('NRAS', 'Gene', '4893', (82, 86))	('mutation', 'Var', (87, 95))
89930	29657129	To test if the differences in ROS levels in the less sensitive cells were due to the inability of erastin to deplete glutathione, we measured glutathione by mass spectrometry in isogenic sub-lines M229P and M229R, and M238P and M238R (Figure S6E and Table S5).	('M229P', 'Var', (197, 202))	('M238R', 'Var', (228, 233))	('glutathione', 'Chemical', 'MESH:D005978', (117, 128))	('M238P', 'Var', (218, 223))	('M229R', 'Mutation', 'p.M229R', (207, 212))	('glutathione', 'Chemical', 'MESH:D005978', (142, 153))	('M229R', 'Var', (207, 212))	('M229P', 'Mutation', 'p.M229P', (197, 202))	('erastin', 'Chemical', 'MESH:C477224', (98, 105))	('M238P', 'Mutation', 'p.M238P', (218, 223))	('M238R', 'Mutation', 'p.M238R', (228, 233))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
89932	29657129	However, the erastin-sensitive M229R and M238R sub-lines had lower basal levels of GSH and GSSG, and also exhibited a greater fold-change decrease with treatment compared to their respective parental lines.	('lower', 'NegReg', (61, 66))	('fold-change', 'MPA', (126, 137))	('M229R', 'Mutation', 'p.M229R', (31, 36))	('GSH', 'Chemical', '-', (83, 86))	('M229R', 'Var', (31, 36))	('M238R', 'Mutation', 'p.M238R', (41, 46))	('decrease', 'NegReg', (138, 146))	('erastin', 'Chemical', 'MESH:C477224', (13, 20))	('GSSG', 'Chemical', 'MESH:D019803', (91, 95))	('M238R', 'Var', (41, 46))
89937	29657129	To evaluate the feasibility of combination treatment to overcome BRAF inhibitor resistance, we confirmed that the presence of vemurafenib does not reduce the high lethality from ferroptosis induction in dedifferentiated, vemurafenib-resistant cell lines.	('presence', 'Var', (114, 122))	('vemurafenib', 'Chemical', 'MESH:D000077484', (126, 137))	('ferroptosis', 'biological_process', 'GO:0097707', ('178', '189'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (221, 232))	('BRAF', 'Gene', '673', (65, 69))	('BRAF', 'Gene', (65, 69))
89938	29657129	As expected, vemurafenib treatment alone was effective in reducing the viability of parental cell lines M229P and M238P, but had little effect on vemurafenib-resistant lines M229R and M238R.	('vemurafenib', 'Chemical', 'MESH:D000077484', (13, 24))	('M238P', 'Var', (114, 119))	('M229P', 'Mutation', 'p.M229P', (104, 109))	('reducing', 'NegReg', (58, 66))	('vemurafenib', 'Chemical', 'MESH:D000077484', (146, 157))	('M238P', 'Mutation', 'p.M238P', (114, 119))	('M238R', 'Mutation', 'p.M238R', (184, 189))	('viability', 'CPA', (71, 80))	('M229R', 'Mutation', 'p.M229R', (174, 179))
89942	29657129	Since dedifferentiation is an adaptive response to BRAF inhibition, we sought to directly test the efficacy of combining ferroptosis inducing drugs with BRAFi against a cohort of BRAF mutant melanomas.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('mutant', 'Var', (184, 190))	('melanomas', 'Phenotype', 'HP:0002861', (191, 200))	('BRAF', 'Gene', '673', (179, 183))	('dedifferentiation', 'biological_process', 'GO:0043696', ('6', '23'))	('melanomas', 'Disease', 'MESH:D008545', (191, 200))	('ferroptosis', 'biological_process', 'GO:0097707', ('121', '132'))	('BRAF', 'Gene', (179, 183))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (51, 55))	('melanomas', 'Disease', (191, 200))
90051	29657129	Melanoma dedifferentiation increases sensitivity to ferroptosis.	('ferroptosis', 'biological_process', 'GO:0097707', ('52', '63'))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('increases', 'PosReg', (27, 36))	('Melanoma', 'Disease', (0, 8))	('dedifferentiation', 'Var', (9, 26))	('dedifferentiation', 'biological_process', 'GO:0043696', ('9', '26'))	('sensitivity to ferroptosis', 'MPA', (37, 63))
90062	31387639	Clinical studies have noted the association of high TMB with improved patient responses and survival benefit after ICI treatment either in a single cancer type (eg.	('improved', 'PosReg', (61, 69))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('TMB', 'Gene', (52, 55))	('high', 'Var', (47, 51))	('patient', 'Species', '9606', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TMB', 'Chemical', '-', (52, 55))	('survival benefit', 'CPA', (92, 108))	('patient responses', 'CPA', (70, 87))
90075	31387639	The TMB was calculated as the number of non-synonymous somatic, coding, base substitution, and indel mutations per megabase (Mb) of genome examined, and 38 Mb was used as the estimate of the whole exome size.	('base substitution', 'Var', (72, 89))	('indel mutations', 'Var', (95, 110))	('TMB', 'Chemical', '-', (4, 7))
90078	31387639	Notably, for F1CDx and TSO500, synonymous mutations were also included in order to reduce sampling noise as the developers proposed.	('TSO500', 'Gene', (23, 29))	('F1CDx', 'Var', (13, 18))	('F1CDx', 'Chemical', '-', (13, 18))
90079	31387639	Previous studies have suggested that the inclusion of synonymous mutations could enhance the precision of panel-based TMB estimation.	('precision', 'MPA', (93, 102))	('synonymous mutations', 'Var', (54, 74))	('enhance', 'PosReg', (81, 88))	('TMB', 'Chemical', '-', (118, 121))
90279	30402447	On that basis, they designed a randomized controlled trial (the International Multicenter Selective Lymphadenectomy Trial - MSLT-I), in patients with clinically localized primary cutaneous melanoma, to determine the long-term survival impact of SLNB followed by immediate radical lymphadenectomy (for SLN metastases) compared to observation and delayed lymphadenectomy when nodal metastases become clinically apparent .	('delayed lymphadenectomy', 'Phenotype', 'HP:0002732', (345, 368))	('SLN metastases', 'Disease', 'MESH:D009362', (301, 315))	('metastases', 'Disease', (305, 315))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (179, 197))	('metastases', 'Disease', (380, 390))	('SLN metastases', 'Disease', (301, 315))	('patients', 'Species', '9606', (136, 144))	('SLNB', 'Var', (245, 249))	('metastases', 'Disease', 'MESH:D009362', (305, 315))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('cutaneous melanoma', 'Disease', (179, 197))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (179, 197))	('metastases', 'Disease', 'MESH:D009362', (380, 390))
90286	30402447	During the enrollment phase of the study (2000-2007), immediate radical regional lymphadenectomy was performed for nodal metastatic tumor deposit >0.2 mm in diameter identified on pathological evaluation of the SLN(s), while it was not performed in patients with tumor deposits <=0.2 mm and in patients who refused the procedure.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('patients', 'Species', '9606', (249, 257))	('patients', 'Species', '9606', (294, 302))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', (263, 268))	('>0.2', 'Var', (146, 150))
90299	30402447	Table 1 summarizes patient and tumor characteristics according to SLN status and suggests that lymph node metastases were more common in patients with ages >60 years, Breslow thickness >2 mm, Clark level IV-V, and ulcerated melanoma.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('ulcerated melanoma', 'Disease', 'MESH:D014456', (214, 232))	('patient', 'Species', '9606', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patient', 'Species', '9606', (137, 144))	('tumor', 'Disease', (31, 36))	('>2 mm', 'Var', (185, 190))	('patients', 'Species', '9606', (137, 145))	('ulcerated melanoma', 'Disease', (214, 232))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('metastases', 'Disease', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('common', 'Reg', (127, 133))
90314	30402447	Full-adjusted Cox regression analysis showed that: (1) only Breslow thickness >2 mm was significantly associated to relapse; (2) male sex and Breslow thickness >2 mm were significantly associated to MSM; (3) SLN metastasis was not significantly associated either to relapse or to MSM (Table 5).	('associated', 'Reg', (185, 195))	('MSM', 'Disease', (199, 202))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('Breslow', 'Var', (142, 149))
90333	30402447	By contrast, in older patients (>60 years old) positive SLN was associated with a higher occurrence of thick, ulcerated melanomas; and the tendency for more aggressive disease in the elderly population has been hypothesized to be related to a lack of self-examination, and a tendency to mistake early melanoma for other age-related skin changes, such as seborrheic keratosis.	('seborrheic keratosis', 'Disease', (354, 374))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('aggressive disease', 'Disease', 'MESH:D001523', (157, 175))	('thick', 'Disease', (103, 108))	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (354, 374))	('ulcerated melanomas', 'Disease', (110, 129))	('patients', 'Species', '9606', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('melanoma', 'Disease', (301, 309))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (354, 374))	('ulcerated melanomas', 'Disease', 'MESH:D014456', (110, 129))	('positive', 'Var', (47, 55))	('skin changes', 'Phenotype', 'HP:0000951', (332, 344))	('SLN', 'Gene', (56, 59))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (301, 309))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('aggressive disease', 'Disease', (157, 175))
90340	30402447	in a prospective study showed that the proportion of patients with both a progressive disease and a tumor-related death was not significantly higher in patients with positive SLN than in those with negative SLN.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (53, 61))	('positive SLN', 'Var', (166, 178))	('tumor', 'Disease', (100, 105))	('progressive disease', 'Disease', 'MESH:D018450', (74, 93))	('progressive disease', 'Disease', (74, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('patients', 'Species', '9606', (152, 160))
90348	30402447	In conclusion, this study confirmed the validity of SLNB for better tumor staging, and as a warning to identify which patients will experience a worse prognosis due to the positivity of SLN.	('tumor', 'Disease', (68, 73))	('positivity', 'Var', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('SLN', 'Gene', (186, 189))	('patients', 'Species', '9606', (118, 126))
90358	31655118	Mutations identified in mucosal melanoma should be incorporated into routine clinical testing, as there are targeted therapies already developed for treating patients with these mutations in the precision medicine era.	('mucosal melanoma', 'Disease', (24, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('mucosal melanoma', 'Disease', 'MESH:D008545', (24, 40))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (158, 166))
90385	31655118	Recently, several studies have been conducted using targeted sequencing, whole-exome sequencing (WES) or whole-genome sequencing (WGS) approaches to characterize and identify somatic mutations in mucosal melanoma.	('mutations', 'Var', (183, 192))	('mucosal melanoma', 'Disease', 'MESH:D008545', (196, 212))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('mucosal melanoma', 'Disease', (196, 212))
90395	31655118	In cutaneous melanoma, the MAPK pathway is commonly activated by mutations in the key signaling components, BRAF, NRAS and NF1.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('NRAS', 'Gene', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('NRAS', 'Gene', '4893', (114, 118))	('NF1', 'Gene', '4763', (123, 126))	('NF1', 'Gene', (123, 126))	('MAPK', 'molecular_function', 'GO:0004707', ('27', '31'))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('BRAF', 'Gene', '673', (108, 112))	('activated', 'PosReg', (52, 61))	('MAPK pathway', 'Pathway', (27, 39))	('BRAF', 'Gene', (108, 112))	('mutations', 'Var', (65, 74))	('cutaneous melanoma', 'Disease', (3, 21))
90396	31655118	Recently, the Cancer Genome Atlas Network (TCGA) proposed a genomic classification for cutaneous melanoma defined by four subgroups, each harboring mutations in BRAF, NRAS, NF1, or "triple wildtype", corresponding to tumors lacking these mutations.	('NF1', 'Gene', '4763', (173, 176))	('mutations', 'Var', (148, 157))	('NF1', 'Gene', (173, 176))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('cutaneous melanoma', 'Disease', (87, 105))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (87, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (87, 105))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('NRAS', 'Gene', (167, 171))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('NRAS', 'Gene', '4893', (167, 171))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer', 'Disease', (14, 20))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))
90398	31655118	A vast majority of cutaneous melanomas (94%) contain MAPK pathway activating mutations (BRAF, NRAS, NF1), whereas only a 28% of mucosal melanomas harbor these mutations (Figure 1 A-B).	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('MAPK', 'molecular_function', 'GO:0004707', ('53', '57'))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('NF1', 'Gene', '4763', (100, 103))	('cutaneous melanomas', 'Disease', (19, 38))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('NRAS', 'Gene', '4893', (94, 98))	('NF1', 'Gene', (100, 103))	('mucosal melanomas', 'Disease', 'MESH:D008545', (128, 145))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('mucosal melanomas', 'Disease', (128, 145))	('mutations', 'Var', (77, 86))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (19, 37))	('NRAS', 'Gene', (94, 98))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('MAPK pathway', 'Pathway', (53, 65))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (19, 38))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (19, 38))
90399	31655118	Although found at a lower rate, MAPK activating pathway mutations can be therapeutically targeted, thus it remains important to understand the role that mutations in the MAPK pathway may be playing in mucosal melanoma tumorigenesis.	('mutations', 'Var', (153, 162))	('MAPK', 'molecular_function', 'GO:0004707', ('170', '174'))	('mucosal melanoma tumorigenesis', 'Disease', 'MESH:D063646', (201, 231))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('MAPK', 'molecular_function', 'GO:0004707', ('32', '36'))	('MAPK', 'Gene', (170, 174))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('mucosal melanoma tumorigenesis', 'Disease', (201, 231))
90401	31655118	The BRAF oncogene is found to be highly mutated at codon V600 in multiple cancers and known to occur in approximately 35-50% of cutaneous melanomas (Figure 1B).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('occur', 'Reg', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (128, 147))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (128, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('BRAF', 'Gene', (4, 8))	('codon V600', 'Var', (51, 61))	('BRAF', 'Gene', '673', (4, 8))	('cutaneous melanomas', 'Disease', (128, 147))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
90406	31655118	We observed that only approximately 6% of mucosal melanomas harbor BRAF-V600 mutations (Figure 1A), which was seen at similar mutational rates in both the upper and lower mucosal melanoma regions (Figure 1C-D).	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('mucosal melanoma', 'Disease', (171, 187))	('mucosal melanoma', 'Disease', 'MESH:D008545', (171, 187))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('mutations', 'Var', (77, 86))	('mucosal melanoma', 'Disease', 'MESH:D008545', (42, 58))	('mucosal melanomas harbor BRAF-V600', 'Disease', 'MESH:C537062', (42, 76))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('mucosal melanomas harbor BRAF-V600', 'Disease', (42, 76))
90407	31655118	Interestingly, in mucosal melanoma, there is an increased number of non-canonical BRAF mutations (L505H, G469A, L597R, and T599I), which are known to lead to weaker MAPK activation as compared to BRAF-V600.	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('G469A', 'Mutation', 'rs121913355', (105, 110))	('mucosal melanoma', 'Disease', 'MESH:D008545', (18, 34))	('T599I', 'Var', (123, 128))	('MAPK activation', 'biological_process', 'GO:0000187', ('165', '180'))	('activation', 'PosReg', (170, 180))	('G469A', 'Var', (105, 110))	('L505H', 'Mutation', 'p.L505H', (98, 103))	('mucosal melanoma', 'Disease', (18, 34))	('MAPK', 'Protein', (165, 169))	('BRAF', 'Gene', '673', (196, 200))	('MAPK', 'molecular_function', 'GO:0004707', ('165', '169'))	('BRAF', 'Gene', (196, 200))	('T599I', 'Mutation', 'rs121913375', (123, 128))	('weaker', 'NegReg', (158, 164))	('L505H', 'Var', (98, 103))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('L597R', 'Mutation', 'rs121913366', (112, 117))	('L597R', 'Var', (112, 117))
90408	31655118	However, it remains unclear if these non-canonical BRAF mutations will be clinically responsive to MAPK pathway inhibition, indicating the importance of understanding the effects of non-canonical BRAF mutations.	('mutations', 'Var', (56, 65))	('BRAF', 'Gene', '673', (196, 200))	('MAPK pathway', 'Pathway', (99, 111))	('BRAF', 'Gene', '673', (51, 55))	('BRAF', 'Gene', (196, 200))	('MAPK', 'molecular_function', 'GO:0004707', ('99', '103'))	('BRAF', 'Gene', (51, 55))
90410	31655118	Activating point mutations in NRAS are commonly found at the G12, G13 and Q61 sites, which are the somatic mutations that we report for NRAS in our meta-analysis.	('Activating', 'PosReg', (0, 10))	('NRAS', 'Gene', '4893', (30, 34))	('point mutations', 'Var', (11, 26))	('NRAS', 'Gene', (30, 34))	('NRAS', 'Gene', (136, 140))	('NRAS', 'Gene', '4893', (136, 140))
90411	31655118	Mucosal melanomas harbor NRAS mutations at a rate of 8%, which is lower than the rate seen in cutaneous melanoma (28%) (Figure 1A-B).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('Mucosal melanomas harbor NRAS', 'Disease', 'MESH:C537062', (0, 29))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('cutaneous melanoma', 'Disease', (94, 112))	('melanomas', 'Phenotype', 'HP:0002861', (8, 17))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('Mucosal melanomas harbor NRAS', 'Disease', (0, 29))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('mutations', 'Var', (30, 39))
90412	31655118	Previous studies have reported conflicting observations regarding the enrichment of NRAS mutations in mucosal melanomas arising from upper or lower regions.	('mucosal melanomas', 'Disease', (102, 119))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('NRAS', 'Gene', (84, 88))	('mucosal melanomas', 'Disease', 'MESH:D008545', (102, 119))	('NRAS', 'Gene', '4893', (84, 88))	('mutations', 'Var', (89, 98))
90414	31655118	Interestingly, they noticed that vaginal melanomas have a significantly higher proportion of NRAS mutations (43%) as compared to other mucosal melanoma subtypes, and were associated with a significantly worse overall survival.	('vaginal melanomas', 'Phenotype', 'HP:0030418', (33, 50))	('NRAS', 'Gene', '4893', (93, 97))	('mucosal melanoma sub', 'Disease', 'MESH:D008545', (135, 155))	('vaginal melanomas', 'Disease', 'MESH:D008545', (33, 50))	('mutations', 'Var', (98, 107))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('vaginal melanomas', 'Disease', (33, 50))	('overall survival', 'MPA', (209, 225))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('NRAS', 'Gene', (93, 97))	('mucosal melanoma sub', 'Disease', (135, 155))
90415	31655118	However, a study of 16 esophageal melanomas identified NRAS (Q61, G12/13) mutations in 37.5% of cases (6/16), which the authors conclude that this data suggests that esophageal mucosal melanomas may display an enrichment of NRAS mutations.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mucosal melanomas', 'Disease', (177, 194))	('NRAS', 'Gene', '4893', (224, 228))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('NRAS', 'Gene', '4893', (55, 59))	('melanomas', 'Disease', (185, 194))	('mutations', 'Var', (229, 238))	('mutations', 'Var', (74, 83))	('mucosal melanomas', 'Disease', 'MESH:D008545', (177, 194))	('melanomas', 'Disease', (34, 43))	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('NRAS', 'Gene', (224, 228))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('NRAS', 'Gene', (55, 59))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))
90417	31655118	NF1, Neurofibromin 1, is a negative regulator of Ras, and is commonly lost or harbors loss of function mutations in cancers, and thus is considered to be a tumor suppressor.	('mutations', 'Var', (103, 112))	('Neurofibromin 1', 'Gene', '4763', (5, 20))	('Neurofibromin 1', 'Gene', (5, 20))	('negative', 'NegReg', (27, 35))	('lost', 'NegReg', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('loss of function', 'NegReg', (86, 102))	('Ras', 'Protein', (49, 52))	('NF1', 'Gene', '4763', (0, 3))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('NF1', 'Gene', (0, 3))	('tumor', 'Disease', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
90418	31655118	Loss of NF1 is associated with increased MAPK pathway activity, and has been shown to be significantly enriched in cutaneous melanoma tumors lacking either BRAF or NRAS mutations.	('NF1', 'Gene', (8, 11))	('NRAS', 'Gene', '4893', (164, 168))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('BRAF', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('increased', 'PosReg', (31, 40))	('BRAF', 'Gene', '673', (156, 160))	('NF1', 'Gene', '4763', (8, 11))	('cutaneous melanoma tumors', 'Disease', (115, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('cutaneous melanoma tumors', 'Disease', 'MESH:C562393', (115, 140))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('NRAS', 'Gene', (164, 168))	('activity', 'MPA', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Loss', 'Var', (0, 4))	('MAPK pathway', 'Pathway', (41, 53))
90419	31655118	In our current meta-analysis, we observed that NF1 is mutated at a rate of 14% in mucosal melanoma, which is also found at the same rate observed in the TCGA cohort of cutaneous melanoma (14%) (Figure 1 A-B).	('cutaneous melanoma', 'Disease', (168, 186))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (168, 186))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (168, 186))	('mucosal melanoma', 'Disease', 'MESH:D008545', (82, 98))	('NF1', 'Gene', (47, 50))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('mutated', 'Var', (54, 61))	('NF1', 'Gene', '4763', (47, 50))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('mucosal melanoma', 'Disease', (82, 98))
90420	31655118	Of interest, one study found that NF1 was significantly co-mutated with KIT in 32% of mucosal melanomas, which is a significantly higher rate than in cutaneous melanoma (4%).	('cutaneous melanoma', 'Disease', 'MESH:C562393', (150, 168))	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('KIT', 'molecular_function', 'GO:0005020', ('72', '75'))	('KIT', 'Gene', (72, 75))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('co-mutated', 'Var', (56, 66))	('cutaneous melanoma', 'Disease', (150, 168))	('mucosal melanomas', 'Disease', (86, 103))	('NF1', 'Gene', (34, 37))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('mucosal melanomas', 'Disease', 'MESH:D008545', (86, 103))	('NF1', 'Gene', '4763', (34, 37))	('KIT', 'Gene', '3815', (72, 75))
90423	31655118	SPRED1 loss was found in 26% (11/43) of mucosal melanomas, which included bi-allelic inactivation through either deep deletion or by truncating mutation combined with loss of the wild type SPRED1 allele.	('loss', 'NegReg', (7, 11))	('mucosal melanomas', 'Disease', (40, 57))	('mucosal melanomas', 'Disease', 'MESH:D008545', (40, 57))	('truncating mutation', 'Var', (133, 152))	('SPRED1', 'Gene', '161742', (189, 195))	('SPRED1', 'Gene', (189, 195))	('SPRED1', 'Gene', (0, 6))	('SPRED1', 'Gene', '161742', (0, 6))	('deep deletion', 'Var', (113, 126))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
90424	31655118	identified SPRED1 aberrations in 5 of 67 mucosal melanomas through whole genome sequencing.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('aberrations', 'Var', (18, 29))	('mucosal melanomas', 'Disease', (41, 58))	('SPRED1', 'Gene', '161742', (11, 17))	('SPRED1', 'Gene', (11, 17))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
90425	31655118	observed a trend towards a pattern of mutual exclusivity with SPRED1 loss and NF1 loss of function mutations, suggesting that SPRED1 loss and NF1 loss may play similar roles in tumor progression in mucosal melanoma.	('NF1', 'Gene', '4763', (142, 145))	('loss', 'NegReg', (69, 73))	('NF1', 'Gene', '4763', (78, 81))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('NF1', 'Gene', (142, 145))	('loss', 'NegReg', (146, 150))	('loss of function', 'NegReg', (82, 98))	('NF1', 'Gene', (78, 81))	('tumor', 'Disease', (177, 182))	('mucosal melanoma', 'Disease', 'MESH:D008545', (198, 214))	('SPRED1', 'Gene', '161742', (126, 132))	('SPRED1', 'Gene', '161742', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mucosal melanoma', 'Disease', (198, 214))	('SPRED1', 'Gene', (126, 132))	('SPRED1', 'Gene', (62, 68))	('loss', 'NegReg', (133, 137))	('mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))
90427	31655118	In vitro and in vivo models demonstrated that in the context of KIT mutations, SPRED1 loss resulted in increased MAPK pathway activity and conferred resistance to the KIT tyrosine kinase inhibitor dasatinib.	('loss', 'NegReg', (86, 90))	('KIT', 'Gene', '3815', (64, 67))	('MAPK pathway', 'Pathway', (113, 125))	('KIT', 'Gene', '3815', (167, 170))	('conferred', 'Reg', (139, 148))	('MAPK', 'molecular_function', 'GO:0004707', ('113', '117'))	('tyrosine kinase', 'Gene', (171, 186))	('activity', 'MPA', (126, 134))	('dasatinib', 'Chemical', 'MESH:D000069439', (197, 206))	('tyrosine kinase', 'Gene', '7294', (171, 186))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('SPRED1', 'Gene', '161742', (79, 85))	('KIT', 'Gene', (64, 67))	('KIT', 'Gene', (167, 170))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('180', '196'))	('increased', 'PosReg', (103, 112))	('KIT', 'molecular_function', 'GO:0005020', ('167', '170'))	('SPRED1', 'Gene', (79, 85))	('mutations', 'Var', (68, 77))
90428	31655118	These results lay the groundwork to establish SPRED1 as a tumor suppressor gene that cooperates with activating KIT mutations to sustain MAPK signaling and may confer resistance to KIT inhibition.	('KIT', 'Gene', (181, 184))	('KIT', 'Gene', '3815', (112, 115))	('MAPK', 'molecular_function', 'GO:0004707', ('137', '141'))	('MAPK signaling', 'MPA', (137, 151))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('tumor', 'Disease', (58, 63))	('KIT', 'Gene', '3815', (181, 184))	('sustain', 'PosReg', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('KIT', 'molecular_function', 'GO:0005020', ('112', '115'))	('KIT', 'molecular_function', 'GO:0005020', ('181', '184'))	('resistance', 'MPA', (167, 177))	('MAPK signaling', 'biological_process', 'GO:0000165', ('137', '151'))	('mutations', 'Var', (116, 125))	('KIT', 'Gene', (112, 115))	('SPRED1', 'Gene', '161742', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('SPRED1', 'Gene', (46, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
90431	31655118	Once it is activated through dimerization, it regulates the activation of several oncogenic downstream signaling pathways such as MAPK and AKT pathways.	('oncogenic downstream signaling pathways', 'Pathway', (82, 121))	('AKT', 'Gene', '207', (139, 142))	('dimerization', 'Var', (29, 41))	('MAPK', 'molecular_function', 'GO:0004707', ('130', '134'))	('activation', 'PosReg', (60, 70))	('MAPK', 'Pathway', (130, 134))	('AKT', 'Gene', (139, 142))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('activated', 'PosReg', (11, 20))	('regulates', 'Reg', (46, 55))
90432	31655118	The common KIT alterations observed in melanomas are amplifications and missense mutations, which occur throughout the coding region at a high frequency in the juxta-membrane autoinhibitory domain (encoded by exon 11) and the tyrosine kinase domains (encoded by exons 12-21).	('melanomas', 'Disease', (39, 48))	('tyrosine kinase', 'Gene', '7294', (226, 241))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('membrane', 'cellular_component', 'GO:0016020', ('166', '174'))	('melanomas', 'Disease', 'MESH:D008545', (39, 48))	('KIT', 'Gene', '3815', (11, 14))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('tyrosine kinase', 'Gene', (226, 241))	('missense mutations', 'Var', (72, 90))	('KIT', 'Gene', (11, 14))	('amplifications', 'Var', (53, 67))
90433	31655118	In the current meta-analysis, we reported all non-synonymous KIT mutations in mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (78, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('KIT', 'Gene', '3815', (61, 64))	('KIT', 'molecular_function', 'GO:0005020', ('61', '64'))	('KIT', 'Gene', (61, 64))	('mucosal melanoma', 'Disease', (78, 94))	('mutations', 'Var', (65, 74))
90434	31655118	We found KIT mutations at a rate of 13% in all mucosal melanomas, and we observed a similar frequency in both upper (15%) and lower (13%) regions (Figure 1C-D).	('KIT', 'Gene', '3815', (9, 12))	('mucosal melanomas', 'Disease', (47, 64))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('KIT', 'Gene', (9, 12))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (47, 64))	('mutations', 'Var', (13, 22))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))
90435	31655118	While KIT mutations are found at a lower rate in cutaneous melanoma, previous reports identify that cutaneous melanomas lacking recurrent mutations in BRAF or NRAS have a significant enrichment of alterations in KIT.	('cutaneous melanoma', 'Disease', (49, 67))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (49, 67))	('alterations', 'Reg', (197, 208))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (49, 67))	('BRAF', 'Gene', '673', (151, 155))	('NRAS', 'Gene', '4893', (159, 163))	('BRAF', 'Gene', (151, 155))	('KIT', 'Gene', (6, 9))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('KIT', 'Gene', '3815', (212, 215))	('KIT', 'Gene', '3815', (6, 9))	('NRAS', 'Gene', (159, 163))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (100, 119))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (100, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('mutations', 'Var', (138, 147))	('KIT', 'molecular_function', 'GO:0005020', ('212', '215'))	('cutaneous melanomas', 'Disease', (100, 119))	('KIT', 'molecular_function', 'GO:0005020', ('6', '9'))	('KIT', 'Gene', (212, 215))
90436	31655118	Given that KIT mutations are enriched in mucosal melanomas, it is important to understand the clinical implications of KIT mutations as a prognostic factor, as there are conflicting reports on the prognostic impact.	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('mucosal melanomas', 'Disease', (41, 58))	('KIT', 'molecular_function', 'GO:0005020', ('119', '122'))	('KIT', 'Gene', '3815', (119, 122))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('KIT', 'Gene', '3815', (11, 14))	('KIT', 'Gene', (119, 122))	('mucosal melanomas', 'Disease', 'MESH:D008545', (41, 58))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('KIT', 'Gene', (11, 14))
90437	31655118	In a cohort of 86 French patients, of various mucosal melanomas, 11.6% (5/96) harbored KIT mutations, however there was no prognostic impact of KIT mutant patients compared to KIT wild type patients.	('KIT', 'Gene', '3815', (176, 179))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('patients', 'Species', '9606', (190, 198))	('patients', 'Species', '9606', (155, 163))	('KIT', 'Gene', '3815', (144, 147))	('KIT', 'Gene', '3815', (87, 90))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('KIT', 'molecular_function', 'GO:0005020', ('176', '179'))	('harbored', 'Reg', (78, 86))	('KIT', 'Gene', (176, 179))	('patients', 'Species', '9606', (25, 33))	('KIT', 'molecular_function', 'GO:0005020', ('144', '147'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (46, 63))	('KIT', 'Gene', (144, 147))	('KIT', 'Gene', (87, 90))	('KIT', 'molecular_function', 'GO:0005020', ('87', '90'))	('mutant', 'Var', (148, 154))	('mutations', 'Var', (91, 100))	('mucosal melanomas', 'Disease', (46, 63))
90438	31655118	Further, in a pan mucosal melanoma study, KIT mutations were most frequently found in 35% (8/23) mucosal melanomas of the vulva as compared to all other sites.	('mucosal melanomas', 'Disease', 'MESH:D008545', (97, 114))	('KIT', 'Gene', (42, 45))	('mucosal melanoma', 'Disease', 'MESH:D008545', (97, 113))	('mutations', 'Var', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('found', 'Reg', (77, 82))	('mucosal melanoma', 'Disease', (18, 34))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('mucosal melanomas', 'Disease', (97, 114))	('mucosal melanoma', 'Disease', 'MESH:D008545', (18, 34))	('KIT', 'Gene', '3815', (42, 45))
90439	31655118	Additionally, when KIT protein levels were analyzed by immunohistochemistry, there was a significant increase in KIT protein expression in KIT mutant tumors as compared to KIT wildtype tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('tumors', 'Disease', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('KIT', 'molecular_function', 'GO:0005020', ('139', '142'))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('tumors', 'Disease', (150, 156))	('increase', 'PosReg', (101, 109))	('KIT', 'Gene', (139, 142))	('KIT', 'Gene', '3815', (172, 175))	('KIT', 'Gene', (113, 116))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('KIT', 'Gene', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('mutant', 'Var', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('KIT', 'molecular_function', 'GO:0005020', ('172', '175'))	('KIT', 'Gene', '3815', (139, 142))	('KIT', 'Gene', '3815', (113, 116))	('KIT', 'molecular_function', 'GO:0005020', ('113', '116'))	('KIT', 'Gene', '3815', (19, 22))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('KIT', 'Gene', (172, 175))
90442	31655118	Again, there was no prognostic impact of KIT mutations as compared to KIT wildtype patients in this cohort.	('KIT', 'Gene', '3815', (70, 73))	('mutations', 'Var', (45, 54))	('KIT', 'molecular_function', 'GO:0005020', ('41', '44'))	('KIT', 'Gene', (70, 73))	('KIT', 'molecular_function', 'GO:0005020', ('70', '73'))	('KIT', 'Gene', '3815', (41, 44))	('patients', 'Species', '9606', (83, 91))	('KIT', 'Gene', (41, 44))
90443	31655118	In contrast to the previously mentioned studies, KIT mutational analysis from a large cohort of 755 mucosal melanoma Asian patients found that KIT mutant positive patients (8.7%, 66/755) had worse overall survival in mucosal melanomas, as compared to NRAS and BRAF mutations, which did not have any effect on prognosis.	('KIT', 'Gene', '3815', (143, 146))	('mucosal melanoma', 'Disease', 'MESH:D008545', (217, 233))	('NRAS', 'Gene', '4893', (251, 255))	('KIT', 'molecular_function', 'GO:0005020', ('143', '146'))	('overall survival', 'MPA', (197, 213))	('patients', 'Species', '9606', (123, 131))	('KIT', 'molecular_function', 'GO:0005020', ('49', '52'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (217, 234))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('KIT', 'Gene', (49, 52))	('patients', 'Species', '9606', (163, 171))	('melanomas', 'Phenotype', 'HP:0002861', (225, 234))	('BRAF', 'Gene', '673', (260, 264))	('mucosal melanomas', 'Disease', (217, 234))	('mucosal melanoma', 'Disease', 'MESH:D008545', (100, 116))	('BRAF', 'Gene', (260, 264))	('NRAS', 'Gene', (251, 255))	('KIT', 'Gene', (143, 146))	('mutant positive', 'Var', (147, 162))	('mucosal melanoma', 'Disease', (100, 116))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('KIT', 'Gene', '3815', (49, 52))	('worse', 'NegReg', (191, 196))
90444	31655118	However, it is important to note that none of these previously mentioned studies of the prognostic factor of KIT mutations was done in the context of KIT targeted therapy, which is discussed in section 4.2.	('KIT', 'Gene', '3815', (150, 153))	('KIT', 'molecular_function', 'GO:0005020', ('109', '112'))	('KIT', 'Gene', '3815', (109, 112))	('mutations', 'Var', (113, 122))	('KIT', 'Gene', (150, 153))	('KIT', 'Gene', (109, 112))	('KIT', 'molecular_function', 'GO:0005020', ('150', '153'))
90448	31655118	Mutations in SF3B1 are considered to be neomorphic resulting in alternative splicing that promotes global transcriptomic dysregulation.	('global transcriptomic dysregulation', 'MPA', (99, 134))	('splicing', 'biological_process', 'GO:0045292', ('76', '84'))	('SF3B1', 'Gene', (13, 18))	('alternative splicing', 'MPA', (64, 84))	('Mutations', 'Var', (0, 9))	('SF3B1', 'Gene', '23451', (13, 18))	('promotes', 'PosReg', (90, 98))
90449	31655118	SF3B1 mutations have been identified in myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), prostate cancer, breast cancer, and uveal melanomas (Figure 2B).	('MDS', 'Disease', 'MESH:D009190', (66, 69))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('myelodysplastic syndrome', 'Disease', (40, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('identified', 'Reg', (26, 36))	('MDS', 'Disease', (66, 69))	('SF3B1', 'Gene', (0, 5))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (72, 100))	('uveal melanomas', 'Disease', 'MESH:C536494', (144, 159))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('breast cancer', 'Disease', (125, 138))	('chronic lymphocytic leukemia', 'Disease', (72, 100))	('mutations', 'Var', (6, 15))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (72, 100))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (40, 64))	('SF3B1', 'Gene', '23451', (0, 5))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (40, 64))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('MDS', 'Phenotype', 'HP:0002863', (66, 69))	('uveal melanomas', 'Disease', (144, 159))	('uveal melanomas', 'Phenotype', 'HP:0007716', (144, 159))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CLL', 'Phenotype', 'HP:0005550', (102, 105))	('prostate cancer', 'Disease', (108, 123))
90451	31655118	Across cancer types, SF3B1 mutations are heterozygous and enriched for the R625, K666 and K700 residues, here defined as "canonical hotspot mutations".	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('SF3B1', 'Gene', (21, 26))	('K700', 'Var', (90, 94))	('R625', 'Var', (75, 79))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('SF3B1', 'Gene', '23451', (21, 26))	('K666', 'Var', (81, 85))
90452	31655118	Interestingly, SF3B1 mutations in mucosal and uveal melanoma are almost exclusively enriched for the R625 residue, which is found at a lower frequency in hematologic malignancies and breast cancer, where the K666 and K700 residues predominate (Figure 2B).	('K700', 'Var', (217, 221))	('R625', 'Var', (101, 105))	('mucosal', 'Disease', (34, 41))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('SF3B1', 'Gene', '23451', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('uveal melanoma', 'Disease', 'MESH:C536494', (46, 60))	('uveal melanoma', 'Phenotype', 'HP:0007716', (46, 60))	('uveal melanoma', 'Disease', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SF3B1', 'Gene', (15, 20))	('hematologic malignancies and breast cancer', 'Disease', 'MESH:D001943', (154, 196))	('mutations', 'Var', (21, 30))
90454	31655118	Thus, for our current meta-analysis we reported all non-synonymous SF3B1 mutations in mucosal melanoma.	('mucosal melanoma', 'Disease', (86, 102))	('SF3B1', 'Gene', '23451', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('mucosal melanoma', 'Disease', 'MESH:D008545', (86, 102))	('mutations', 'Var', (73, 82))	('SF3B1', 'Gene', (67, 72))
90455	31655118	Interestingly, we observed that SF3B1 mutations may be enriched in lower regions of mucosal melanomas (27%) as compared to the mucosal melanomas in the upper regions (7%) (Figure 1 C-D).	('mucosal melanomas', 'Disease', 'MESH:D008545', (84, 101))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('mucosal melanomas', 'Disease', 'MESH:D008545', (127, 144))	('melanomas', 'Phenotype', 'HP:0002861', (92, 101))	('SF3B1', 'Gene', '23451', (32, 37))	('mucosal melanomas', 'Disease', (127, 144))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('mutations', 'Var', (38, 47))	('SF3B1', 'Gene', (32, 37))	('mucosal melanomas', 'Disease', (84, 101))
90457	31655118	observed that SF3B1 mutations were present in 7/19 (35%) of mucosal melanomas, the most common sites being anorectal (3/5,60%) and vulvovaginal (4/9, 44.4%), as compared to nasopharyngeal (1/5, 20%).	('mucosal melanomas', 'Disease', 'MESH:D008545', (60, 77))	('anorectal', 'Disease', (107, 116))	('SF3B1', 'Gene', (14, 19))	('present', 'Reg', (35, 42))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('vulvovaginal', 'Disease', (131, 143))	('melanomas', 'Phenotype', 'HP:0002861', (68, 77))	('SF3B1', 'Gene', '23451', (14, 19))	('mucosal melanomas', 'Disease', (60, 77))	('mutations', 'Var', (20, 29))
90458	31655118	It is important to note that only the lower regions of mucosal melanomas (anorectal and vulvovaginal) harbored SF3B1-R635 hotspot mutations, whereas the upper regions (nasal) harbored a non-canonical SF3B1-E1105G mutation located in the HEAT domain of SF3B1.	('mucosal melanomas', 'Disease', 'MESH:D008545', (55, 72))	('SF3B1', 'Gene', (252, 257))	('SF3B1', 'Gene', '23451', (200, 205))	('SF3B1', 'Gene', '23451', (111, 116))	('SF3B1', 'Gene', '23451', (252, 257))	('mutations', 'Var', (130, 139))	('mucosal melanomas', 'Disease', (55, 72))	('SF3B1', 'Gene', (200, 205))	('SF3B1', 'Gene', (111, 116))	('E1105G', 'Mutation', 'p.E1105G', (206, 212))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
90459	31655118	observed that SF3B1 mutations were the most common mutation (6/27, 22%), where SF3B1-R625 hotspot mutations were enriched (5/6, 83%) and were exclusively found in vulvovaginal (5/19, 26%) and anorectal (3/5, 60%) sites, as compared to oral and nasal locations.	('SF3B1', 'Gene', (14, 19))	('SF3B1', 'Gene', (79, 84))	('SF3B1', 'Gene', '23451', (14, 19))	('SF3B1', 'Gene', '23451', (79, 84))	('mutations', 'Var', (20, 29))
90460	31655118	Furthermore, SF3B1 mutations were associated with shorter overall and progression free survival (34.9 and 16.9 months, respectively) compared to SF3B1 wild type mucosal melanomas (79.9 and 35.7 months, respectively).	('overall', 'MPA', (58, 65))	('SF3B1', 'Gene', '23451', (145, 150))	('type mucosal melanomas', 'Disease', 'MESH:D008545', (156, 178))	('type mucosal melanomas', 'Disease', (156, 178))	('SF3B1', 'Gene', (13, 18))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanomas', 'Phenotype', 'HP:0002861', (169, 178))	('mutations', 'Var', (19, 28))	('SF3B1', 'Gene', (145, 150))	('SF3B1', 'Gene', '23451', (13, 18))	('progression free survival', 'CPA', (70, 95))	('shorter', 'NegReg', (50, 57))
90461	31655118	We performed meta-analysis of SF3B1 mutations on overall survival from three mucosal melanoma studies (total patients, n=53) and found that SF3B1 mutations trend towards an increase in overall survival (Figure 2C).	('SF3B1', 'Gene', (30, 35))	('mucosal melanoma', 'Disease', 'MESH:D008545', (77, 93))	('mutations', 'Var', (146, 155))	('SF3B1', 'Gene', (140, 145))	('overall survival', 'MPA', (185, 201))	('patients', 'Species', '9606', (109, 117))	('mutations', 'Var', (36, 45))	('SF3B1', 'Gene', '23451', (30, 35))	('SF3B1', 'Gene', '23451', (140, 145))	('increase', 'PosReg', (173, 181))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mucosal melanoma', 'Disease', (77, 93))
90462	31655118	The differential effect of clinical outcomes associated with SF3B1 mutations indicates that the prognostic value of SF3B1 mutations still needs to be explored in a larger patient cohort.	('SF3B1', 'Gene', (116, 121))	('SF3B1', 'Gene', (61, 66))	('patient', 'Species', '9606', (171, 178))	('SF3B1', 'Gene', '23451', (116, 121))	('SF3B1', 'Gene', '23451', (61, 66))	('mutations', 'Var', (67, 76))
90463	31655118	WGS has been performed in an oral mucosal melanoma cohort, and the authors identified specific structural variants were associated with worse prognosis.	('associated', 'Reg', (120, 130))	('variants', 'Var', (106, 114))	('oral mucosal melanoma', 'Disease', 'MESH:D008545', (29, 50))	('oral mucosal melanoma', 'Disease', (29, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
90465	31655118	BRAF fusion genes represent an alternate mechanism of MAPK pathway activation and are commonly identified in identified in a small percentage of "Triple-Wild Type" tumors, lacking BRAF, NRAS or NF1 mutations, in cutaneous melanoma.	('activation', 'PosReg', (67, 77))	('NRAS', 'Gene', (186, 190))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('mutations', 'Var', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('BRAF', 'Gene', '673', (180, 184))	('cutaneous melanoma', 'Disease', (212, 230))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (212, 230))	('BRAF', 'Gene', (180, 184))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (212, 230))	('tumors', 'Disease', (164, 170))	('NF1', 'Gene', '4763', (194, 197))	('NRAS', 'Gene', '4893', (186, 190))	('MAPK pathway', 'Pathway', (54, 66))	('NF1', 'Gene', (194, 197))	('tumors', 'Disease', 'MESH:D009369', (164, 170))
90466	31655118	The frequency of BRAF fusions in mucosal melanoma is comparable to the frequency of BRAF fusions found in triple wild type cutaneous melanomas.	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (123, 142))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (123, 142))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('BRAF', 'Gene', '673', (84, 88))	('cutaneous melanomas', 'Disease', (123, 142))	('BRAF', 'Gene', '673', (17, 21))	('BRAF', 'Gene', (84, 88))	('fusions', 'Var', (22, 29))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('BRAF', 'Gene', (17, 21))	('mucosal melanoma', 'Disease', (33, 49))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('mucosal melanoma', 'Disease', 'MESH:D008545', (33, 49))
90470	31655118	Melanoma cells harboring the ZNF767-BRAF fusion displayed resistance to the BRAF inhibitor vemurafenib in vitro, which recapitulated the clinical response seen in the mucosal melanoma patient harboring the BRAF fusion, but demonstrated sensitivity to the MEK inhibitor trametinib in vitro.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('BRAF', 'Gene', '673', (206, 210))	('trametinib', 'Chemical', 'MESH:C560077', (269, 279))	('ZNF767', 'Gene', '79970', (29, 35))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('BRAF', 'Gene', (206, 210))	('patient', 'Species', '9606', (184, 191))	('mucosal melanoma', 'Disease', 'MESH:D008545', (167, 183))	('Melanoma', 'Disease', (0, 8))	('resistance', 'MPA', (58, 68))	('mucosal melanoma', 'Disease', (167, 183))	('BRAF', 'Gene', '673', (36, 40))	('BRAF', 'Gene', (36, 40))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('MEK', 'Gene', '5609', (255, 258))	('ZNF767', 'Gene', (29, 35))	('fusion', 'Var', (41, 47))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('MEK', 'Gene', (255, 258))	('vemurafenib', 'Chemical', 'MESH:D000077484', (91, 102))
90471	31655118	Mechanistically, the ZNF767-BRAF fusion activates the MAPK pathway through the formation of RAF homo- and hetero-dimers.	('MAPK', 'molecular_function', 'GO:0004707', ('54', '58'))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('hetero-dimers', 'MPA', (106, 119))	('ZNF767', 'Gene', '79970', (21, 27))	('MAPK pathway', 'Pathway', (54, 66))	('activates', 'PosReg', (40, 49))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('RAF', 'Gene', (29, 32))	('RAF', 'Gene', '22882', (29, 32))	('RAF', 'Gene', (92, 95))	('RAF', 'Gene', '22882', (92, 95))	('ZNF767', 'Gene', (21, 27))	('fusion', 'Var', (33, 39))
90473	31655118	Anaplastic lymphoma kinase (ALK) fusions are oncogenic and occur in 3-7% of NSCLC, and clinically are sensitive to small molecule inhibitors targeting ALK.	('occur', 'Reg', (59, 64))	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('NSCLC', 'Disease', (76, 81))	('fusions', 'Var', (33, 40))	('ALK', 'Gene', (151, 154))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('ALK', 'Gene', (28, 31))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('ALK', 'Gene', '238', (151, 154))
90475	31655118	identified a mucosal melanoma that contained several novel EML4-ALK fusion variants, and was sensitive to ALK inhibition in vitro and in vivo.	('mucosal melanoma', 'Disease', (13, 29))	('fusion variants', 'Var', (68, 83))	('ALK', 'Gene', '238', (106, 109))	('mucosal melanoma', 'Disease', 'MESH:D008545', (13, 29))	('EML4', 'Gene', (59, 63))	('ALK', 'Gene', (106, 109))	('ALK', 'Gene', (64, 67))	('EML4', 'Gene', '27436', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('ALK', 'Gene', '238', (64, 67))	('variants', 'Var', (75, 83))
90480	31655118	One of the benefits of WGS is the ability to assess genome-wide copy number variations (CNV) in mucosal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('copy number variations', 'Var', (64, 86))	('mucosal melanoma', 'Disease', (96, 112))	('mucosal melanoma', 'Disease', 'MESH:D008545', (96, 112))
90482	31655118	Amplifications in the 12q13-15, containing CDK4 and TERT, in >50% of oral mucosal melanomas (33/65 samples), representing the most commonly altered genomic region.	('CDK4', 'Gene', (43, 47))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('CDK4', 'Gene', '1019', (43, 47))	('TERT', 'Gene', (52, 56))	('Amplifications', 'Var', (0, 14))	('oral mucosal melanomas', 'Disease', (69, 91))	('TERT', 'Gene', '7015', (52, 56))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('oral mucosal melanomas', 'Disease', 'MESH:D008545', (69, 91))
90483	31655118	In addition, chromosome 5p15, containing TERT, was also significantly co-associated with CDK4 amplifications, suggesting a potential functional relevance of TERT and CDK4 as co-amplified genes.	('co-associated', 'Reg', (70, 83))	('CDK4', 'Gene', '1019', (166, 170))	('CDK4', 'Gene', (166, 170))	('TERT', 'Gene', (157, 161))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (157, 161))	('TERT', 'Gene', '7015', (41, 45))	('CDK4', 'Gene', (89, 93))	('amplifications', 'Var', (94, 108))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('CDK', 'molecular_function', 'GO:0004693', ('89', '92'))	('CDK4', 'Gene', '1019', (89, 93))	('CDK', 'molecular_function', 'GO:0004693', ('166', '169'))
90484	31655118	A small whole exome sequencing study of 19 oral mucosal melanomas identified that 11/19 (57.9%) harbored amplifications of chromosome 12q14, which contains CDK4.	('amplifications', 'Var', (105, 119))	('CDK4', 'Gene', (156, 160))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('CDK4', 'Gene', '1019', (156, 160))	('oral mucosal melanomas', 'Disease', 'MESH:D008545', (43, 65))	('CDK', 'molecular_function', 'GO:0004693', ('156', '159'))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('oral mucosal melanomas', 'Disease', (43, 65))
90485	31655118	However, whole exome and whole genome studies of other subtypes of mucosal melanoma, such as head and heck, vulvovaginal and anorectal, did not describe the presence of chromosome 12q14 or CDK4 amplifications.	('anorectal', 'Disease', (125, 134))	('mucosal melanoma', 'Disease', 'MESH:D008545', (67, 83))	('CDK4', 'Gene', (189, 193))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('CDK', 'molecular_function', 'GO:0004693', ('189', '192'))	('chromosome', 'cellular_component', 'GO:0005694', ('169', '179'))	('vulvovaginal', 'Disease', (108, 120))	('mucosal melanoma', 'Disease', (67, 83))	('CDK4', 'Gene', '1019', (189, 193))	('amplifications', 'Var', (194, 208))
90488	31655118	Leveraging the success from the development of targeted therapies, many of the identified mutations in mucosal melanoma have drugs or clinical investigated compounds available to treat these patients (Figure 3).	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (191, 199))	('mucosal melanoma', 'Disease', (103, 119))	('mucosal melanoma', 'Disease', 'MESH:D008545', (103, 119))
90489	31655118	BRAF mutations result in hyperactivation of MAPK pathway signaling and represent a promising therapeutic target in mucosal melanoma.	('hyperactivation', 'PosReg', (25, 40))	('signaling', 'biological_process', 'GO:0023052', ('57', '66'))	('mutations', 'Var', (5, 14))	('MAPK pathway signaling', 'Pathway', (44, 66))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('mucosal melanoma', 'Disease', (115, 131))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('mucosal melanoma', 'Disease', 'MESH:D008545', (115, 131))	('BRAF', 'Gene', (0, 4))
90490	31655118	The ATP-competitive small molecule inhibitors (vemurafenib, dabrafenib and encorafinib) specifically targeting mutant BRAF have resulted in remarkable responses in cutaneous melanoma patients harboring BRAF-V600 mutations, increasing progression free survival and overall survival when compared to chemotherapy.	('BRAF', 'Gene', '673', (118, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 182))	('responses', 'MPA', (151, 160))	('overall survival', 'CPA', (264, 280))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (164, 182))	('progression free survival', 'CPA', (234, 259))	('BRAF', 'Gene', (118, 122))	('mutant', 'Var', (111, 117))	('dabrafenib', 'Chemical', 'MESH:C561627', (60, 70))	('BRAF', 'Gene', '673', (202, 206))	('ATP', 'Chemical', 'MESH:D000255', (4, 7))	('increasing', 'PosReg', (223, 233))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('BRAF', 'Gene', (202, 206))	('patients', 'Species', '9606', (183, 191))	('vemurafenib', 'Chemical', 'MESH:D000077484', (47, 58))	('cutaneous melanoma', 'Disease', (164, 182))	('encorafinib', 'Chemical', '-', (75, 86))
90493	31655118	Dual inhibition of BRAF and MEK with the combination of the following BRAF/MEK inhibitors vemurafenib/cobimetinib, dabrafenib/trametinib and encorafinib/bimimetinib are FDA approved for the treatment of BRAF mutant metastatic melanoma.	('trametinib', 'Chemical', 'MESH:C560077', (126, 136))	('mutant', 'Var', (208, 214))	('vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('encorafinib', 'Chemical', '-', (141, 152))	('melanoma', 'Disease', 'MESH:D008545', (226, 234))	('MEK', 'Gene', '5609', (75, 78))	('MEK', 'Gene', '5609', (28, 31))	('BRAF', 'Gene', '673', (70, 74))	('MEK', 'Gene', (75, 78))	('BRAF', 'Gene', (70, 74))	('MEK', 'Gene', (28, 31))	('BRAF', 'Gene', '673', (203, 207))	('BRAF', 'Gene', (203, 207))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('melanoma', 'Disease', (226, 234))	('dabrafenib', 'Chemical', 'MESH:C561627', (115, 125))	('BRAF', 'Gene', '673', (19, 23))	('bimimetinib', 'Chemical', '-', (153, 164))	('BRAF', 'Gene', (19, 23))	('cobimetinib', 'Chemical', 'MESH:C574276', (102, 113))
90494	31655118	Based on promising results of the combination of BRAF and MEK inhibition in cutaneous melanoma, these BRAF/MEK inhibitors represent an attractive treatment option for BRAFV600 mutant mucosal melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('BRAF', 'Gene', (167, 171))	('mutant', 'Var', (176, 182))	('BRAF', 'Gene', '673', (167, 171))	('mucosal melanoma', 'Disease', 'MESH:D008545', (183, 199))	('BRAF', 'Gene', '673', (102, 106))	('MEK', 'Gene', '5609', (58, 61))	('mucosal melanoma', 'Disease', (183, 199))	('BRAF', 'Gene', (102, 106))	('MEK', 'Gene', '5609', (107, 110))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cutaneous melanoma', 'Disease', (76, 94))	('MEK', 'Gene', (58, 61))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (76, 94))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (76, 94))	('MEK', 'Gene', (107, 110))	('patients', 'Species', '9606', (200, 208))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
90495	31655118	Although mucosal melanomas do not harbor a high rate of BRAF mutations, they do have a high rate of NF1 alterations.	('alterations', 'Var', (104, 115))	('mucosal melanomas', 'Disease', 'MESH:D008545', (9, 26))	('BRAF', 'Gene', '673', (56, 60))	('melanomas', 'Phenotype', 'HP:0002861', (17, 26))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('NF1', 'Gene', (100, 103))	('mucosal melanomas', 'Disease', (9, 26))	('NF1', 'Gene', '4763', (100, 103))	('BRAF', 'Gene', (56, 60))
90496	31655118	Preclinical studies have demonstrated that tumors with alterations in NF1, either loss of function mutations or deletions, are more resistant to BRAF inhibitors.	('loss of function', 'NegReg', (82, 98))	('NF1', 'Gene', '4763', (70, 73))	('alterations', 'Var', (55, 66))	('BRAF', 'Gene', (145, 149))	('deletions', 'Var', (112, 121))	('resistant', 'MPA', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('NF1', 'Gene', (70, 73))	('BRAF', 'Gene', '673', (145, 149))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
90497	31655118	Thus, it remains important to understand how NF1 mutations, RAS mutations and other mutations that activated the MAPK pathway may be targeted by MEK inhibition.	('mutations', 'Var', (49, 58))	('MAPK', 'molecular_function', 'GO:0004707', ('113', '117'))	('MEK', 'Gene', (145, 148))	('MAPK pathway', 'Pathway', (113, 125))	('MEK', 'Gene', '5609', (145, 148))	('NF1', 'Gene', (45, 48))	('RAS', 'Gene', (60, 63))	('NF1', 'Gene', '4763', (45, 48))
90498	31655118	Recent reports in cutaneous melanoma suggest that BRAF fusions may function as a novel resistance mechanism to vemurafenib through promoting reactivation of the MAPK pathway.	('BRAF', 'Gene', (50, 54))	('reactivation', 'MPA', (141, 153))	('cutaneous melanoma', 'Disease', (18, 36))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (18, 36))	('promoting', 'PosReg', (131, 140))	('vemurafenib', 'Chemical', 'MESH:D000077484', (111, 122))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (18, 36))	('MAPK', 'molecular_function', 'GO:0004707', ('161', '165'))	('MAPK pathway', 'Pathway', (161, 173))	('BRAF', 'Gene', '673', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('fusions', 'Var', (55, 62))
90499	31655118	Further preclinical and clinical research needs to be conducted to identify the best targeted therapy for such BRAF fusions, and mucosal melanomas should be screened for such fusions as they may represent sensitivity to MEK inhibition.	('MEK', 'Gene', (220, 223))	('mucosal melanomas', 'Disease', 'MESH:D008545', (129, 146))	('MEK', 'Gene', '5609', (220, 223))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('fusions', 'Var', (116, 123))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('mucosal melanomas', 'Disease', (129, 146))
90500	31655118	Clinical trials in KIT mutant tumors, such as gastrointestinal stromal tumors (GISTs) and cutaneous melanoma, have observed that patients with KIT exon 11 or exon 13 mutations are shown to have a better response to KIT targeted therapy, suggesting that certain KIT alterations may be more sensitive to KIT inhibition.	('GISTs', 'Phenotype', 'HP:0100723', (79, 84))	('KIT', 'Gene', '3815', (215, 218))	('better', 'PosReg', (196, 202))	('KIT', 'Gene', '3815', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('KIT', 'Gene', '3815', (261, 264))	('tumors', 'Disease', (71, 77))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('KIT', 'Gene', '3815', (302, 305))	('mutations', 'Var', (166, 175))	('KIT', 'molecular_function', 'GO:0005020', ('143', '146'))	('KIT', 'molecular_function', 'GO:0005020', ('261', '264'))	('KIT', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (46, 77))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (46, 77))	('tumors', 'Disease', (30, 36))	('KIT', 'molecular_function', 'GO:0005020', ('302', '305'))	('patients', 'Species', '9606', (129, 137))	('KIT', 'Gene', (215, 218))	('KIT', 'Gene', (143, 146))	('mutant', 'Var', (23, 29))	('KIT', 'Gene', (261, 264))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('KIT', 'Gene', (302, 305))	('cutaneous melanoma', 'Disease', (90, 108))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (90, 108))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (90, 108))	('KIT', 'Gene', '3815', (19, 22))	('gastrointestinal stromal tumors', 'Disease', (46, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('response', 'MPA', (203, 211))	('KIT', 'molecular_function', 'GO:0005020', ('215', '218'))
90503	31655118	A seminal study demonstrated that certain KIT alterations may render the tumor more or less sensitive to KIT targeted therapy with imatinib in metastatic melanoma.	('KIT', 'Gene', (42, 45))	('KIT', 'Gene', '3815', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('sensitive', 'MPA', (92, 101))	('imatinib', 'Chemical', 'MESH:D000068877', (131, 139))	('KIT', 'molecular_function', 'GO:0005020', ('42', '45'))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KIT', 'Gene', (105, 108))	('alterations', 'Var', (46, 57))	('tumor', 'Disease', (73, 78))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('KIT', 'Gene', '3815', (42, 45))	('less', 'NegReg', (87, 91))
90504	31655118	This open arm phase II trial with imatinib in 25 patients with KIT mutant metastatic melanoma, consisting of mucosal (n=13), acral (n=10) and chronically sun-damaged (CSD) (n=5) subtypes, displaying a range of mutations in exons 9, 11, 13, 17 and 18 of KIT (21/25).	('CSD', 'Disease', 'MESH:C562576', (167, 170))	('KIT', 'Gene', '3815', (253, 256))	('KIT', 'molecular_function', 'GO:0005020', ('253', '256'))	('CSD', 'Disease', (167, 170))	('KIT', 'Gene', (253, 256))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('mutant', 'Var', (67, 73))	('melanoma', 'Disease', (85, 93))	('KIT', 'Gene', '3815', (63, 66))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('imatinib', 'Chemical', 'MESH:D000068877', (34, 42))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('KIT', 'Gene', (63, 66))
90508	31655118	Patients harboring recurrent KIT mutations previously identified in GIST and melanoma (V559C, L576P, V642E and N822J), had a higher proportion of response (46%) compared to other KIT mutations.	('response', 'MPA', (146, 154))	('V642E', 'Mutation', 'p.V642E', (101, 106))	('V559C', 'Var', (87, 92))	('N822J', 'Var', (111, 116))	('KIT', 'Gene', (29, 32))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('KIT', 'Gene', (179, 182))	('KIT', 'molecular_function', 'GO:0005020', ('29', '32'))	('V642E', 'Var', (101, 106))	('Patients', 'Species', '9606', (0, 8))	('KIT', 'molecular_function', 'GO:0005020', ('179', '182'))	('KIT', 'Gene', '3815', (29, 32))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('KIT', 'Gene', '3815', (179, 182))	('V559C', 'Mutation', 'p.V559C', (87, 92))	('L576P', 'Mutation', 'rs121913513', (94, 99))	('L576P', 'Var', (94, 99))	('N822J', 'SUBSTITUTION', 'None', (111, 116))
90509	31655118	Furthermore, all patients with a partial, durable or complete response (n=6) harbored either L576P or K642E KIT mutations.	('KIT', 'Gene', (108, 111))	('K642E', 'Mutation', 'rs121913512', (102, 107))	('L576P', 'Mutation', 'rs121913513', (93, 98))	('KIT', 'molecular_function', 'GO:0005020', ('108', '111'))	('L576P', 'Var', (93, 98))	('patients', 'Species', '9606', (17, 25))	('KIT', 'Gene', '3815', (108, 111))
90510	31655118	In addition, tumors with a mutant KIT allele in greater abundance that the wild type KIT allele demonstrated a better response rate, time to progression and overall survival as compared to other cases.	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('tumors', 'Disease', (13, 19))	('mutant', 'Var', (27, 33))	('response rate', 'CPA', (118, 131))	('time', 'CPA', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('KIT', 'Gene', '3815', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('better', 'PosReg', (111, 117))	('KIT', 'Gene', (85, 88))	('KIT', 'Gene', '3815', (34, 37))	('KIT', 'molecular_function', 'GO:0005020', ('34', '37'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('KIT', 'Gene', (34, 37))
90511	31655118	This study suggests that some KIT mutations, such as L576P and K642E, may possess a greater oncogenic driver capacity, and thus increased sensitivity to KIT inhibition.	('oncogenic driver capacity', 'CPA', (92, 117))	('KIT', 'molecular_function', 'GO:0005020', ('153', '156'))	('KIT', 'Gene', '3815', (153, 156))	('KIT', 'molecular_function', 'GO:0005020', ('30', '33'))	('K642E', 'Var', (63, 68))	('increased', 'PosReg', (128, 137))	('KIT', 'Gene', '3815', (30, 33))	('KIT', 'Gene', (153, 156))	('K642E', 'Mutation', 'rs121913512', (63, 68))	('sensitivity', 'MPA', (138, 149))	('KIT', 'Gene', (30, 33))	('L576P', 'Mutation', 'rs121913513', (53, 58))	('greater', 'PosReg', (84, 91))	('L576P', 'Var', (53, 58))
90514	31655118	Overall, KIT-mutated patients, as compared to patients with KIT amplifications, have better clinical responses to imatinib and the mutations in exons 11 and 13 were more predictive of imatinib response as compared to other KIT mutations.	('better', 'PosReg', (85, 91))	('KIT', 'Gene', '3815', (9, 12))	('KIT', 'Gene', (223, 226))	('predictive', 'Reg', (170, 180))	('patients', 'Species', '9606', (46, 54))	('imatinib', 'Chemical', 'MESH:D000068877', (114, 122))	('mutations in exons', 'Var', (131, 149))	('KIT', 'Gene', (9, 12))	('KIT', 'Gene', '3815', (60, 63))	('imatinib response', 'MPA', (184, 201))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('imatinib', 'Chemical', 'MESH:D000068877', (184, 192))	('patients', 'Species', '9606', (21, 29))	('KIT', 'molecular_function', 'GO:0005020', ('223', '226'))	('KIT', 'Gene', (60, 63))	('KIT', 'Gene', '3815', (223, 226))	('KIT', 'molecular_function', 'GO:0005020', ('60', '63'))	('clinical responses to imatinib', 'MPA', (92, 122))
90517	31655118	Nilotinib binds to and inhibits KIT, DDR, ABL/BCR-ABL, PDGF and several EPH RTKs, and maintains activity against a variety of KIT mutations in exons 9, 11 and 13.	('activity', 'MPA', (96, 104))	('KIT', 'Gene', '3815', (32, 35))	('ABL', 'Gene', (42, 45))	('inhibits', 'NegReg', (23, 31))	('binds', 'Interaction', (10, 15))	('PDGF', 'molecular_function', 'GO:0005161', ('55', '59'))	('BCR-ABL', 'Gene', '25', (46, 53))	('PDGF', 'Gene', (55, 59))	('KIT', 'molecular_function', 'GO:0005020', ('126', '129'))	('KIT', 'Gene', '3815', (126, 129))	('KIT', 'Gene', (32, 35))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('ABL', 'Gene', '25', (50, 53))	('ABL', 'Gene', '25', (42, 45))	('DDR', 'Gene', (37, 40))	('BCR-ABL', 'Gene', (46, 53))	('Nilotinib', 'Chemical', 'MESH:C498826', (0, 9))	('ABL', 'Gene', (50, 53))	('PDGF', 'Gene', '5156', (55, 59))	('mutations', 'Var', (130, 139))	('KIT', 'Gene', (126, 129))
90520	31655118	The cohort included 19 patients, with 90% (17/19) patients harbored KIT mutations, consisted of acral, CSD and mucosal melanoma, with mucosal consisting of 63% (12/19) patients, 5 of which harbored CNS brain metastases.	('mutations', 'Var', (72, 81))	('metastases', 'Disease', (208, 218))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (23, 31))	('harbored', 'Reg', (59, 67))	('mucosal melanoma', 'Disease', (111, 127))	('KIT', 'Gene', '3815', (68, 71))	('CSD', 'Disease', 'MESH:C562576', (103, 106))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('patients', 'Species', '9606', (168, 176))	('KIT', 'Gene', (68, 71))	('mucosal melanoma', 'Disease', 'MESH:D008545', (111, 127))	('CSD', 'Disease', (103, 106))
90525	31655118	Both of the responding patients had mucosal melanoma harboring either L576P or K642E KIT mutations.	('mucosal melanoma', 'Disease', 'MESH:D008545', (36, 52))	('KIT', 'molecular_function', 'GO:0005020', ('85', '88'))	('patients', 'Species', '9606', (23, 31))	('KIT', 'Gene', '3815', (85, 88))	('L576P', 'Mutation', 'rs121913513', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('KIT', 'Gene', (85, 88))	('L576P', 'Var', (70, 75))	('K642E', 'Mutation', 'rs121913512', (79, 84))	('mucosal melanoma', 'Disease', (36, 52))
90529	31655118	For example, the French Skin Cancer network conducted a phase II study using nilotinib in 25 patients with metastatic melanoma having KIT mutations or amplifications, where mucosal melanoma accounted for 40% of the patients (n=10).	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('patients', 'Species', '9606', (215, 223))	('Skin Cancer', 'Disease', 'MESH:D012878', (24, 35))	('nilotinib', 'Chemical', 'MESH:C498826', (77, 86))	('melanoma having KIT', 'Disease', (118, 137))	('amplifications', 'Var', (151, 165))	('Skin Cancer', 'Disease', (24, 35))	('mucosal melanoma', 'Disease', (173, 189))	('Skin Cancer', 'Phenotype', 'HP:0008069', (24, 35))	('melanoma having KIT', 'Disease', 'MESH:D008545', (118, 137))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mucosal melanoma', 'Disease', 'MESH:D008545', (173, 189))	('patients', 'Species', '9606', (93, 101))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))	('mutations', 'Var', (138, 147))
90531	31655118	In this cohort, KIT mutations in exon 11 and 13 were the most common and found in 44% and 32% of patients, respectively.	('found', 'Reg', (73, 78))	('KIT', 'Gene', '3815', (16, 19))	('KIT', 'molecular_function', 'GO:0005020', ('16', '19'))	('KIT', 'Gene', (16, 19))	('mutations in', 'Var', (20, 32))	('patients', 'Species', '9606', (97, 105))
90540	31655118	Stage one consisted of 51 total patients, where 3 patients harbored KIT mutations, and 6 patients were not tested (n=51 total patients).	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (50, 58))	('harbored', 'Reg', (59, 67))	('KIT', 'molecular_function', 'GO:0005020', ('68', '71'))	('KIT', 'Gene', '3815', (68, 71))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (126, 134))	('KIT', 'Gene', (68, 71))
90541	31655118	However, the patients that achieved a partial response (n=3) did not harbor KIT mutations.	('KIT', 'Gene', '3815', (76, 79))	('mutations', 'Var', (80, 89))	('KIT', 'Gene', (76, 79))	('patients', 'Species', '9606', (13, 21))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))
90542	31655118	In stage two of the study, only KIT mutant positive melanomas were tested (n=22), and 7/22 patients had a partial response, all containing either exon 11 or exon 13 mutations, but did not include L576P mutations.	('exon 13 mutations', 'Var', (157, 174))	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('KIT', 'Gene', '3815', (32, 35))	('patients', 'Species', '9606', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('L576P', 'Mutation', 'rs121913513', (196, 201))	('KIT', 'Gene', (32, 35))	('KIT', 'molecular_function', 'GO:0005020', ('32', '35'))	('melanomas', 'Disease', (52, 61))	('exon 11', 'Var', (146, 153))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))
90543	31655118	Patients harboring KIT mutations in exon 11 or 13 demonstrated a median progression free survival of 4.7 months and a median overall survival of 12.3 months.	('mutations in', 'Var', (23, 35))	('KIT', 'Gene', '3815', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('KIT', 'Gene', (19, 22))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))
90546	31655118	From the published studies, a small subset of mucosal melanoma patients may harbor gene fusions and could be exploited as therapeutic targets.	('harbor', 'Reg', (76, 82))	('gene fusions', 'Var', (83, 95))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('mucosal melanoma', 'Disease', (46, 62))	('patients', 'Species', '9606', (63, 71))	('mucosal melanoma', 'Disease', 'MESH:D008545', (46, 62))
90550	31655118	From the recent WES/WGS studies, SF3B1 was found to be commonly mutated in ~15% in mucosal melanoma.	('mucosal melanoma', 'Disease', (83, 99))	('SF3B1', 'Gene', '23451', (33, 38))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('mucosal melanoma', 'Disease', 'MESH:D008545', (83, 99))	('mutated', 'Var', (64, 71))	('SF3B1', 'Gene', (33, 38))
90551	31655118	In vitro analysis of a subset of alternatively spliced genes identified in SF3B1 mutant breast cancer and uveal melanoma was validated in a cohort of SF3B1-R625 mutant mucosal melanomas.	('SF3B1', 'Gene', (150, 155))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('mucosal melanomas', 'Disease', (168, 185))	('SF3B1', 'Gene', '23451', (150, 155))	('SF3B1', 'Gene', '23451', (75, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutant', 'Var', (81, 87))	('uveal melanoma', 'Disease', (106, 120))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mucosal melanomas', 'Disease', 'MESH:D008545', (168, 185))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('SF3B1', 'Gene', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
90552	31655118	This demonstrates that SF3B1-R625 mutations are functionally involved in alternative splicing in mucosal melanoma.	('alternative splicing', 'MPA', (73, 93))	('mucosal melanoma', 'Disease', 'MESH:D008545', (97, 113))	('splicing', 'biological_process', 'GO:0045292', ('85', '93'))	('involved', 'Reg', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('SF3B1', 'Gene', '23451', (23, 28))	('mucosal melanoma', 'Disease', (97, 113))	('SF3B1', 'Gene', (23, 28))	('mutations', 'Var', (34, 43))
90555	31655118	In the future, this compound could be investigated in mucosal melanoma patients harboring mutations in SF3B1.	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (71, 79))	('SF3B1', 'Gene', (103, 108))	('SF3B1', 'Gene', '23451', (103, 108))	('mucosal melanoma', 'Disease', (54, 70))	('mucosal melanoma', 'Disease', 'MESH:D008545', (54, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
90559	31655118	The anti-tumor effect of palbociclib, was used in an in vivo study with oral mucosal melanoma patient derived xenograft (PDX) harboring CDK4 amplification and resulted in sustained tumor suppression for 8 weeks, which was not observed in a CDK4 wildtype PDX model.	('amplification', 'Var', (141, 154))	('CDK', 'molecular_function', 'GO:0004693', ('136', '139'))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('oral mucosal melanoma', 'Disease', (72, 93))	('tumor', 'Disease', (9, 14))	('CDK4', 'Gene', (240, 244))	('patient', 'Species', '9606', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('palbociclib', 'Chemical', 'MESH:C500026', (25, 36))	('CDK4', 'Gene', (136, 140))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('CDK4', 'Gene', '1019', (240, 244))	('CDK', 'molecular_function', 'GO:0004693', ('240', '243'))	('tumor', 'Disease', (181, 186))	('oral mucosal melanoma', 'Disease', 'MESH:D008545', (72, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('sustained tumor suppression', 'Disease', (171, 198))	('CDK4', 'Gene', '1019', (136, 140))	('sustained tumor suppression', 'Disease', 'MESH:D009369', (171, 198))	('tumor', 'Disease', 'MESH:D009369', (181, 186))
90560	31655118	Suggesting that oral mucosal melanomas harboring CDK4 amplifications may be more likely to benefit from palbociclib treatment.	('oral mucosal melanomas', 'Disease', (16, 38))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('palbociclib', 'Chemical', 'MESH:C500026', (104, 115))	('CDK4', 'Gene', '1019', (49, 53))	('oral mucosal melanomas', 'Disease', 'MESH:D008545', (16, 38))	('CDK', 'molecular_function', 'GO:0004693', ('49', '52'))	('benefit', 'PosReg', (91, 98))	('CDK4', 'Gene', (49, 53))	('amplifications', 'Var', (54, 68))
90561	31655118	Given that there is a subset of mucosal melanomas that harbor CDK4 amplifications, and CDKN2A gene deletions, these patients may be candidates for CDK4/6 inhibition.	('mucosal melanomas', 'Disease', (32, 49))	('CDK4', 'Gene', (62, 66))	('CDK4', 'Gene', '1019', (62, 66))	('CDK', 'molecular_function', 'GO:0004693', ('62', '65'))	('CDKN2A', 'Gene', '1029', (87, 93))	('CDK', 'molecular_function', 'GO:0004693', ('147', '150'))	('patients', 'Species', '9606', (116, 124))	('mucosal melanomas', 'Disease', 'MESH:D008545', (32, 49))	('CDK4/6', 'Gene', '1019;1021', (147, 153))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('CDK4', 'Gene', (147, 151))	('CDK4/6', 'Gene', (147, 153))	('CDK4', 'Gene', '1019', (147, 151))	('amplifications', 'Var', (67, 81))	('CDKN2A', 'Gene', (87, 93))
90570	31655118	analyzed the response to immunotherapy (n=151) compared to chemotherapy (n=78) in mucosal melanoma, and observed that the median overall survival of patients treated with immunotherapy (OS: 15.97 months) was significantly longer than treatment with chemotherapy (OS: 8.82 months).	('longer', 'PosReg', (222, 228))	('patients', 'Species', '9606', (149, 157))	('mucosal melanoma', 'Disease', 'MESH:D008545', (82, 98))	('overall survival', 'MPA', (129, 145))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('immunotherapy', 'Var', (171, 184))	('mucosal melanoma', 'Disease', (82, 98))
90588	30646599	Results: Patients with high-SMS1 plus low-SMS2 expression had a 5-year survival ~10-fold higher than patients with low-SMS1 plus high-SMS2 expression.	('patients', 'Species', '9606', (101, 109))	('SMS2', 'Gene', (42, 46))	('SMS2', 'Gene', '166929', (134, 138))	('Patients', 'Species', '9606', (9, 17))	('SMS2', 'Gene', '166929', (42, 46))	('SMS1', 'molecular_function', 'GO:0033188', ('28', '32'))	('higher', 'PosReg', (89, 95))	('SMS2', 'molecular_function', 'GO:0033188', ('134', '138'))	('SMS1', 'molecular_function', 'GO:0033188', ('119', '123'))	('high-SMS1', 'Var', (23, 32))	('SMS2', 'molecular_function', 'GO:0033188', ('42', '46'))	('SMS2', 'Gene', (134, 138))
90592	30646599	SMSs signature could constitute a valuable prognostic biomarker, with high SMS1 and low SMS2 being a better disease prognosis.	('high SMS1', 'Var', (70, 79))	('SMS1', 'molecular_function', 'GO:0033188', ('75', '79'))	('SMSs', 'Chemical', '-', (0, 4))	('SMS2', 'molecular_function', 'GO:0033188', ('88', '92'))	('SMS2', 'Gene', (88, 92))	('SMS2', 'Gene', '166929', (88, 92))
90596	30646599	In a xenograft model of human GBM, 2OHOA provided a greater anti-tumor effect than temozolomide (TMZ), which is the current standard-of-care first-line chemotherapy against GBM and increases patient's survival by ca.	('human', 'Species', '9606', (24, 29))	('tumor', 'Disease', (65, 70))	('2OHOA', 'Chemical', 'MESH:C483229', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TMZ', 'Chemical', 'MESH:D000077204', (97, 100))	('greater', 'PosReg', (52, 59))	('temozolomide', 'Chemical', 'MESH:D000077204', (83, 95))	('survival', 'CPA', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('2OHOA', 'Var', (35, 40))	('patient', 'Species', '9606', (191, 198))	('increases', 'PosReg', (181, 190))
90597	30646599	In mice, tumors relapsed when treated with TMZ, but not in mice treated with 2OHOA.	('mice', 'Species', '10090', (59, 63))	('TMZ', 'Var', (43, 46))	('mice', 'Species', '10090', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('2OHOA', 'Chemical', 'MESH:C483229', (77, 82))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
90609	30646599	Because 2OHOA has relevant antitumor activity against glioma, and given that its mechanism of action involves SMS activation and altered SMS1 expression is associated with glioma patient survival, we studied the role of these enzymes in glioma tumorigenesis, prognosis and response to 2OHOA.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('SMS', 'Gene', '6611', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (237, 243))	('glioma', 'Disease', 'MESH:D005910', (172, 178))	('2OHOA', 'Chemical', 'MESH:C483229', (8, 13))	('SMS1', 'molecular_function', 'GO:0033188', ('137', '141'))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('activation', 'PosReg', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('2OHOA', 'Chemical', 'MESH:C483229', (285, 290))	('glioma', 'Phenotype', 'HP:0009733', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('SMS', 'Gene', (137, 140))	('associated', 'Reg', (156, 166))	('SMS', 'Gene', '6611', (137, 140))	('expression', 'MPA', (142, 152))	('altered', 'Var', (129, 136))	('glioma', 'Disease', (237, 243))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', (31, 36))	('patient', 'Species', '9606', (179, 186))	('glioma', 'Disease', 'MESH:D005910', (237, 243))	('glioma', 'Disease', (54, 60))	('SMS', 'Gene', (110, 113))	('glioma', 'Disease', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
90615	30646599	Kaplan-Meier plots were used to assess the median survival for patient groups with differential SMS1 or SMS2 gene expression and significant differences in survival (p < 0.05) were determined using the log-rank test.	('SMS2', 'Gene', (104, 108))	('gene expression', 'biological_process', 'GO:0010467', ('109', '124'))	('SMS2', 'molecular_function', 'GO:0033188', ('104', '108'))	('SMS1', 'molecular_function', 'GO:0033188', ('96', '100'))	('SMS2', 'Gene', '166929', (104, 108))	('SMS1', 'Gene', (96, 100))	('differential', 'Var', (83, 95))	('patient', 'Species', '9606', (63, 70))
90617	30646599	Patients with high SMS1 expression (SMS1-high) had longer median survival than patients with low SMS1 expression (SMS1-low; Figure 1A,C).	('SMS1', 'molecular_function', 'GO:0033188', ('19', '23'))	('SMS1', 'molecular_function', 'GO:0033188', ('36', '40'))	('median survival', 'MPA', (58, 73))	('SMS1', 'molecular_function', 'GO:0033188', ('114', '118'))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (51, 57))	('patients', 'Species', '9606', (79, 87))	('SMS1', 'molecular_function', 'GO:0033188', ('97', '101'))	('SMS1', 'Gene', (19, 23))
90619	30646599	Conversely, patients with low SMS2 expression had longer median survival than patients with high SMS2 expression (Figure 1B,C).	('patients', 'Species', '9606', (12, 20))	('SMS2', 'Gene', '166929', (30, 34))	('SMS2', 'molecular_function', 'GO:0033188', ('97', '101'))	('low', 'Var', (26, 29))	('SMS2', 'Gene', (97, 101))	('patients', 'Species', '9606', (78, 86))	('SMS2', 'Gene', '166929', (97, 101))	('SMS2', 'molecular_function', 'GO:0033188', ('30', '34'))	('SMS2', 'Gene', (30, 34))	('longer', 'PosReg', (50, 56))	('median survival', 'MPA', (57, 72))
90620	30646599	Consistent with the median survival, the two-year and five-year survival rates were higher for SMS1-high or SMS2-low groups, whereas patients in SMS1-low or SMS2-high groups had a worse prognosis (Figure 1 C,E,F).	('SMS2', 'Gene', '166929', (157, 161))	('SMS1', 'molecular_function', 'GO:0033188', ('145', '149'))	('SMS2', 'molecular_function', 'GO:0033188', ('108', '112'))	('SMS1', 'molecular_function', 'GO:0033188', ('95', '99'))	('SMS2', 'Gene', (108, 112))	('patients', 'Species', '9606', (133, 141))	('SMS2', 'Gene', '166929', (108, 112))	('SMS2', 'molecular_function', 'GO:0033188', ('157', '161'))	('SMS1-high', 'Var', (95, 104))	('SMS2', 'Gene', (157, 161))	('higher', 'PosReg', (84, 90))
90623	30646599	To evaluate the combined influence of SMS1 plus SMS2 gene expression in glioma patients, 4 groups were evaluated (SMS1-high plus SMS2-low, SMS1-low plus SMS2-low, SMS1-high plus SMS2-high and SMS1-low plus SMS2-high), and significant differences were observed (Figure 3A).	('SMS2', 'Gene', (48, 52))	('SMS1-high', 'Var', (114, 123))	('SMS1-low', 'Var', (139, 147))	('SMS2', 'Gene', '166929', (129, 133))	('gene expression', 'biological_process', 'GO:0010467', ('53', '68'))	('SMS2', 'Gene', '166929', (178, 182))	('SMS2', 'molecular_function', 'GO:0033188', ('206', '210'))	('SMS2', 'molecular_function', 'GO:0033188', ('178', '182'))	('SMS1', 'molecular_function', 'GO:0033188', ('114', '118'))	('SMS2', 'Gene', '166929', (153, 157))	('SMS1', 'molecular_function', 'GO:0033188', ('192', '196'))	('glioma', 'Disease', (72, 78))	('SMS2', 'Gene', '166929', (206, 210))	('SMS2', 'Gene', '166929', (48, 52))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('SMS2', 'Gene', (129, 133))	('SMS2', 'molecular_function', 'GO:0033188', ('153', '157'))	('SMS1', 'molecular_function', 'GO:0033188', ('139', '143'))	('SMS2', 'Gene', (178, 182))	('SMS1-high', 'Var', (163, 172))	('SMS2', 'molecular_function', 'GO:0033188', ('129', '133'))	('SMS2', 'molecular_function', 'GO:0033188', ('48', '52'))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('SMS1', 'molecular_function', 'GO:0033188', ('163', '167'))	('SMS2', 'Gene', (153, 157))	('patients', 'Species', '9606', (79, 87))	('SMS1', 'molecular_function', 'GO:0033188', ('38', '42'))	('SMS2', 'Gene', (206, 210))
90644	30646599	In these cell lines, the mRNA levels of SMS1 but not of SMS2 strongly correlated with the IC50 values for 2OHOA (Figure 4D left panel) and similar results were observed in other cancer cell lines (Figure 4D right panel).	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('SMS1', 'molecular_function', 'GO:0033188', ('40', '44'))	('SMS2', 'Gene', (56, 60))	('IC50 values', 'MPA', (90, 101))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('SMS2', 'Gene', '166929', (56, 60))	('2OHOA', 'Chemical', 'MESH:C483229', (106, 111))	('SMS2', 'molecular_function', 'GO:0033188', ('56', '60'))	('SMS1', 'Var', (40, 44))	('correlated', 'Reg', (70, 80))	('mRNA levels', 'MPA', (25, 36))
90656	30646599	In line with these results, SMS1 silencing prevented 2OHOA-induced DHFR reduction, while SMS2 silencing had no effect on 2OHOA-induced decrease of DHFR levels.	('reduction', 'NegReg', (72, 81))	('SMS2', 'Gene', '166929', (89, 93))	('2OHOA', 'Chemical', 'MESH:C483229', (121, 126))	('DHFR', 'molecular_function', 'GO:0004146', ('147', '151'))	('DHFR', 'Gene', (67, 71))	('SMS1', 'molecular_function', 'GO:0033188', ('28', '32'))	('silencing', 'Var', (33, 42))	('DHFR', 'Gene', '1719', (67, 71))	('DHFR', 'Gene', (147, 151))	('2OHOA', 'Chemical', 'MESH:C483229', (53, 58))	('DHFR', 'molecular_function', 'GO:0004146', ('67', '71'))	('SMS1', 'Gene', (28, 32))	('DHFR', 'Gene', '1719', (147, 151))	('prevented', 'NegReg', (43, 52))	('SMS2', 'molecular_function', 'GO:0033188', ('89', '93'))	('SMS2', 'Gene', (89, 93))
90659	30646599	In this context, N-Cadherin levels increased 65% and 30% upon SMS1 or SMS2 overexpression respectively, although a distinct N-Cadherin cellular distribution pattern was observed by confocal microscopy depending on the isoform overexpressed (Figure 5C,E).	('Cadherin', 'molecular_function', 'GO:0008014', ('19', '27'))	('increased', 'PosReg', (35, 44))	('Cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('SMS1', 'molecular_function', 'GO:0033188', ('62', '66'))	('SMS2', 'Gene', (70, 74))	('N-Cadherin', 'Gene', (17, 27))	('N-Cadherin', 'Gene', '1000', (17, 27))	('SMS2', 'Gene', '166929', (70, 74))	('overexpression', 'Var', (75, 89))	('SMS1', 'Gene', (62, 66))	('N-Cadherin', 'Gene', (124, 134))	('SMS2', 'molecular_function', 'GO:0033188', ('70', '74'))	('N-Cadherin', 'Gene', '1000', (124, 134))
90660	30646599	A 2-fold increase in N-Cadherin was observed after 2OHOA treatment, an effect that was maintained when SMS1 was overexpressed but was abolished when SMS2 was overexpressed (Figure 5C).	('2OHOA treatment', 'Var', (51, 66))	('2OHOA', 'Chemical', 'MESH:C483229', (51, 56))	('SMS1', 'molecular_function', 'GO:0033188', ('103', '107'))	('N-Cadherin', 'Gene', (21, 31))	('Cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('increase', 'PosReg', (9, 17))	('SMS2', 'Gene', (149, 153))	('N-Cadherin', 'Gene', '1000', (21, 31))	('SMS2', 'Gene', '166929', (149, 153))	('SMS2', 'molecular_function', 'GO:0033188', ('149', '153'))
90661	30646599	Accordingly, following siRNA-mediated SMS1 silencing there was a 45% decrease in N-Cadherin, whereas SMS2 downregulation caused a 30% increase in the levels of this protein (Figure 5D).	('N-Cadherin', 'Gene', (81, 91))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('N-Cadherin', 'Gene', '1000', (81, 91))	('downregulation', 'NegReg', (106, 120))	('SMS2', 'Gene', (101, 105))	('SMS2', 'molecular_function', 'GO:0033188', ('101', '105'))	('silencing', 'Var', (43, 52))	('decrease', 'NegReg', (69, 77))	('SMS1', 'Gene', (38, 42))	('levels', 'MPA', (150, 156))	('SMS2', 'Gene', '166929', (101, 105))	('Cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('increase', 'PosReg', (134, 142))	('SMS1', 'molecular_function', 'GO:0033188', ('38', '42'))
90662	30646599	Moreover, silencing of SMS1, but not SMS2, abolished 2OHOA's effect on N-Cadherin expression.	('SMS1', 'Gene', (23, 27))	('N-Cadherin', 'Gene', (71, 81))	('SMS1', 'molecular_function', 'GO:0033188', ('23', '27'))	('N-Cadherin', 'Gene', '1000', (71, 81))	('SMS2', 'molecular_function', 'GO:0033188', ('37', '41'))	('2OHOA', 'Chemical', 'MESH:C483229', (53, 58))	('SMS2', 'Gene', (37, 41))	('Cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('SMS2', 'Gene', '166929', (37, 41))	('abolished', 'NegReg', (43, 52))	('silencing', 'Var', (10, 19))
90670	30646599	Upregulation of N-Cadherin is associated with inhibition of the beta-catenin pathway, and when N-Cadherin/beta-catenin complexes are cleaved at the plasma membrane, beta-catenin is intensely phosphorylated at Thr41 and subsequently degraded.	('N-Cadherin', 'Gene', (95, 105))	('Upregulation', 'PosReg', (0, 12))	('degraded', 'NegReg', (232, 240))	('N-Cadherin', 'Gene', '1000', (95, 105))	('beta-catenin', 'Gene', '1499', (106, 118))	('N-Cadherin', 'Gene', '1000', (16, 26))	('inhibition', 'NegReg', (46, 56))	('beta-catenin', 'Gene', (165, 177))	('beta-catenin', 'Gene', '1499', (165, 177))	('plasma membrane', 'cellular_component', 'GO:0005886', ('148', '163'))	('Thr41', 'Chemical', '-', (209, 214))	('beta-catenin', 'Gene', (64, 76))	('Cadherin', 'molecular_function', 'GO:0008014', ('18', '26'))	('Thr41', 'Var', (209, 214))	('beta-catenin', 'Gene', '1499', (64, 76))	('beta-catenin', 'Gene', (106, 118))	('N-Cadherin', 'Gene', (16, 26))	('Cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))
90675	30646599	Conversely, SMS2 silencing or overexpression did not alter the activation of the beta-catenin pathway (Figure 5H).	('beta-catenin', 'Gene', '1499', (81, 93))	('SMS2', 'molecular_function', 'GO:0033188', ('12', '16'))	('SMS2', 'Gene', (12, 16))	('beta-catenin', 'Gene', (81, 93))	('SMS2', 'Gene', '166929', (12, 16))	('silencing', 'Var', (17, 26))
90694	30646599	We showed that either high SMS1 or low SMS2 mRNA levels represented a good prognostic factor in glioma.	('glioma', 'Disease', (96, 102))	('SMS1', 'molecular_function', 'GO:0033188', ('27', '31'))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('high SMS1', 'Var', (22, 31))	('SMS2', 'Gene', (39, 43))	('SMS2', 'molecular_function', 'GO:0033188', ('39', '43'))	('SMS2', 'Gene', '166929', (39, 43))
90695	30646599	Moreover, the combination of SMS1-high plus SMS2-low expression resulted in a significant and marked increase in median survival compared to the other expression profiles.	('median survival', 'MPA', (113, 128))	('SMS1-high', 'Var', (29, 38))	('increase', 'PosReg', (101, 109))	('SMS1', 'molecular_function', 'GO:0033188', ('29', '33'))	('SMS2', 'Gene', (44, 48))	('SMS2', 'molecular_function', 'GO:0033188', ('44', '48'))	('SMS2', 'Gene', '166929', (44, 48))
90696	30646599	By contrast, SMS1-low and SMS2-high expression, independently or combined, was associated with poor prognosis and significantly worse survival parameters.	('SMS2', 'Gene', '166929', (26, 30))	('SMS1', 'molecular_function', 'GO:0033188', ('13', '17'))	('SMS2', 'molecular_function', 'GO:0033188', ('26', '30'))	('SMS1-low', 'Var', (13, 21))	('SMS2', 'Gene', (26, 30))
90700	30646599	For example, a reduced proliferation capacity in glioma cells overexpressing SMS1 would agree with longer survival in glioma patients with high SMS1 expression.	('patients', 'Species', '9606', (125, 133))	('proliferation capacity', 'CPA', (23, 45))	('longer', 'PosReg', (99, 105))	('glioma', 'Disease', (118, 124))	('SMS1', 'Gene', (77, 81))	('SMS1', 'molecular_function', 'GO:0033188', ('77', '81'))	('SMS1', 'Gene', (144, 148))	('glioma', 'Disease', 'MESH:D005910', (49, 55))	('glioma', 'Phenotype', 'HP:0009733', (49, 55))	('reduced', 'NegReg', (15, 22))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('SMS1', 'molecular_function', 'GO:0033188', ('144', '148'))	('high', 'Var', (139, 143))	('glioma', 'Disease', (49, 55))
90701	30646599	However, when SMS1 and SMS2 were silenced using specific siRNAs, cell viability decreased in both cases, and this is consistent with the clinical response to low SMS2 levels, but not with the response to low SMS1 levels of expression.	('SMS2', 'Gene', '166929', (23, 27))	('SMS2', 'Gene', (162, 166))	('SMS1', 'molecular_function', 'GO:0033188', ('208', '212'))	('SMS2', 'molecular_function', 'GO:0033188', ('162', '166'))	('cell viability', 'CPA', (65, 79))	('SMS1', 'Gene', (14, 18))	('decreased', 'NegReg', (80, 89))	('SMS2', 'Gene', '166929', (162, 166))	('low', 'Var', (158, 161))	('SMS2', 'Gene', (23, 27))	('SMS2', 'molecular_function', 'GO:0033188', ('23', '27'))	('SMS1', 'molecular_function', 'GO:0033188', ('14', '18'))
90703	30646599	Thus, although the lowest SMS1 expression was about 57%, the highest expression measured in glioma patients (Figure S8), siSMS1 caused a reduction to 10% of the control SMS1 expression in vitro, potentially compromising GBM cell survival.	('compromising', 'NegReg', (207, 219))	('SMS1', 'molecular_function', 'GO:0033188', ('169', '173'))	('expression', 'MPA', (174, 184))	('expression', 'MPA', (69, 79))	('reduction', 'NegReg', (137, 146))	('GBM cell survival', 'CPA', (220, 237))	('expression', 'MPA', (31, 41))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('SMS1', 'molecular_function', 'GO:0033188', ('26', '30'))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('siSMS1', 'Var', (121, 127))	('SMS1', 'Gene', (169, 173))
90712	30646599	In this work, 2OHOA treatments, performed between 5 min and 24 h, indeed increased SMS activity, and now we provide further detail on this effect showing that SMS activity increase is exclusively due to the activation of SMS1 and that this effect fades away for longer incubation times.	('increased', 'PosReg', (73, 82))	('2OHOA', 'Chemical', 'MESH:C483229', (14, 19))	('increase', 'PosReg', (172, 180))	('SMS', 'Gene', '6611', (159, 162))	('SMS1', 'molecular_function', 'GO:0033188', ('221', '225'))	('SMS', 'Gene', '6611', (83, 86))	('activation', 'PosReg', (207, 217))	('SMS', 'Gene', '6611', (221, 224))	('treatments', 'Var', (20, 30))	('SMS', 'Gene', (83, 86))	('SMS', 'Gene', (159, 162))	('SMS', 'Gene', (221, 224))
90715	30646599	Not only were the levels of N-Cadherin induced by 2OHOA relevant to cell differentiation, but its distribution was also relevant to the membrane recruitment of beta-Catenin, thus driving its exclusion from the nucleus and its ensuing degradation.	('degradation', 'MPA', (234, 245))	('cell differentiation', 'biological_process', 'GO:0030154', ('68', '88'))	('membrane', 'cellular_component', 'GO:0016020', ('136', '144'))	('beta-Catenin', 'Gene', (160, 172))	('2OHOA', 'Var', (50, 55))	('beta-Catenin', 'Gene', '1499', (160, 172))	('Cadherin', 'molecular_function', 'GO:0008014', ('30', '38'))	('N-Cadherin', 'Gene', (28, 38))	('nucleus', 'cellular_component', 'GO:0005634', ('210', '217'))	('N-Cadherin', 'Gene', '1000', (28, 38))	('degradation', 'biological_process', 'GO:0009056', ('234', '245'))	('2OHOA', 'Chemical', 'MESH:C483229', (50, 55))	('exclusion', 'MPA', (191, 200))
90721	30646599	In fact, the activation of apoptosis and autophagy following knockdown of beta-catenin was recently reported in head and neck squamous cancer cells.	('squamous cancer', 'Disease', (126, 141))	('autophagy', 'CPA', (41, 50))	('autophagy', 'biological_process', 'GO:0016236', ('41', '50'))	('activation of apoptosis', 'biological_process', 'GO:0006915', ('13', '36'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('knockdown', 'Var', (61, 70))	('activation', 'PosReg', (13, 23))	('beta-catenin', 'Gene', (74, 86))	('autophagy', 'biological_process', 'GO:0006914', ('41', '50'))	('apoptosis', 'CPA', (27, 36))	('squamous cancer', 'Phenotype', 'HP:0002860', (126, 141))	('neck', 'cellular_component', 'GO:0044326', ('121', '125'))	('squamous cancer', 'Disease', 'MESH:D002294', (126, 141))	('activation of apoptosis', 'biological_process', 'GO:0043065', ('13', '36'))	('beta-catenin', 'Gene', '1499', (74, 86))
90727	30646599	In general, GBM cells in which the expression of SMS1 increased showed lower proliferative capacity (accompanied by reduced levels of DHFR), increased differentiation and induction of autophagic cell death.	('differentiation', 'CPA', (151, 166))	('DHFR', 'molecular_function', 'GO:0004146', ('134', '138'))	('increased', 'PosReg', (141, 150))	('proliferative capacity', 'CPA', (77, 99))	('autophagic cell death', 'CPA', (184, 205))	('increased', 'PosReg', (54, 63))	('DHFR', 'Gene', (134, 138))	('SMS1', 'Gene', (49, 53))	('DHFR', 'Gene', '1719', (134, 138))	('autophagic cell death', 'biological_process', 'GO:0048102', ('184', '205'))	('reduced', 'NegReg', (116, 123))	('SMS1', 'molecular_function', 'GO:0033188', ('49', '53'))	('expression', 'Var', (35, 45))	('lower', 'NegReg', (71, 76))
90737	30646599	Nevertheless, SMS1 increase due to SMS2 silencing did not significantly increase the expression of the corresponding protein.	('expression', 'MPA', (85, 95))	('SMS1', 'Gene', (14, 18))	('SMS2', 'Gene', (35, 39))	('increase', 'PosReg', (19, 27))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('SMS2', 'Gene', '166929', (35, 39))	('silencing', 'Var', (40, 49))	('SMS2', 'molecular_function', 'GO:0033188', ('35', '39'))	('SMS1', 'molecular_function', 'GO:0033188', ('14', '18'))
90738	30646599	Although neither SMS1 protein nor mRNA levels increased when SMS2 was silenced, its enzymatic activity was boosted, which suggests functional regulatory post-translational processes of this key enzyme.	('SMS1', 'molecular_function', 'GO:0033188', ('17', '21'))	('SMS2', 'Gene', '166929', (61, 65))	('SMS1', 'Gene', (17, 21))	('enzymatic activity', 'MPA', (84, 102))	('silenced', 'Var', (70, 78))	('protein', 'Protein', (22, 29))	('boosted', 'PosReg', (107, 114))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('SMS2', 'Gene', (61, 65))	('mRNA levels', 'MPA', (34, 45))	('SMS2', 'molecular_function', 'GO:0033188', ('61', '65'))
90739	30646599	The fact that only SMS1 silencing induced SMS2 mRNA increase, while SMS2 silencing did not affect SMS1 mRNA levels, reflected that most SM is synthesized by SMS1, so that its lack would induce a compensatory increase of SMS2 expression, whereas lack of SMS2 would not have a high impact in the cell.	('SMS2', 'molecular_function', 'GO:0033188', ('253', '257'))	('SMS2', 'molecular_function', 'GO:0033188', ('220', '224'))	('SMS2', 'Gene', (253, 257))	('SMS2', 'molecular_function', 'GO:0033188', ('42', '46'))	('expression', 'MPA', (225, 235))	('SMS2', 'Gene', (220, 224))	('SMS2', 'molecular_function', 'GO:0033188', ('68', '72'))	('SMS2', 'Gene', '166929', (42, 46))	('SM', 'Chemical', 'MESH:D013109', (253, 255))	('SMS2', 'Gene', (68, 72))	('SM', 'Chemical', 'MESH:D013109', (157, 159))	('SM', 'Chemical', 'MESH:D013109', (220, 222))	('SMS1', 'molecular_function', 'GO:0033188', ('19', '23'))	('SMS1', 'molecular_function', 'GO:0033188', ('157', '161'))	('lack', 'NegReg', (175, 179))	('increase', 'PosReg', (52, 60))	('SM', 'Chemical', 'MESH:D013109', (68, 70))	('SMS1', 'molecular_function', 'GO:0033188', ('98', '102'))	('SM', 'Chemical', 'MESH:D013109', (42, 44))	('SMS2', 'Gene', '166929', (253, 257))	('SMS1', 'Gene', (19, 23))	('SMS2', 'Gene', '166929', (220, 224))	('SMS2', 'Gene', (42, 46))	('SM', 'Chemical', 'MESH:D013109', (19, 21))	('SM', 'Chemical', 'MESH:D013109', (136, 138))	('SM', 'Chemical', 'MESH:D013109', (98, 100))	('increase', 'PosReg', (208, 216))	('SMS2', 'Gene', '166929', (68, 72))	('silencing', 'Var', (24, 33))
90748	30646599	It also sheds light on the mechanism of action of 2OHOA and, opens new avenues for the rational design of specific SMS2 inhibitors to treat GBM and potentially other cancers.	('GBM', 'Disease', (140, 143))	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('inhibitors', 'Var', (120, 130))	('SMS2', 'Gene', (115, 119))	('SMS2', 'Gene', '166929', (115, 119))	('2OHOA', 'Chemical', 'MESH:C483229', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('SMS2', 'molecular_function', 'GO:0033188', ('115', '119'))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
90753	30646599	The databases used to study this relationship were: GSE4412 for patients with grade III and IV glioma; TCGA-GBM for glioblastoma; GSE12417 for cytogenetically normal acute myeloid leukemia (CN-AML); GSE62254 for gastric cancer; TCGA-KIRK for kidney renal clear cell carcinoma (KIRC); GSE30219 for lung cancer; GSE4475 for lymphoma; GSE21501 for pancreatic ductal adenocarcinoma (PDAC); TCGA-SARC for sarcoma; and TCGA-SKCM for skin cutaneous melanoma (SKCM).	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (345, 377))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('GSE62254', 'Var', (199, 207))	('lymphoma', 'Disease', (322, 330))	('PDAC', 'Phenotype', 'HP:0006725', (379, 383))	('pancreatic ductal adenocarcinoma', 'Disease', (345, 377))	('lymphoma', 'Disease', 'MESH:D008223', (322, 330))	('glioblastoma', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (166, 188))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (427, 450))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (166, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('gastric cancer', 'Disease', (212, 226))	('skin cutaneous melanoma', 'Disease', (427, 450))	('CN-AML', 'Disease', 'MESH:D015470', (190, 196))	('lung cancer', 'Disease', (297, 308))	('CN-AML', 'Disease', (190, 196))	('GSE21501', 'Var', (332, 340))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (345, 377))	('sarcoma', 'Disease', 'MESH:D012509', (400, 407))	('sarcoma', 'Disease', (400, 407))	('glioma', 'Disease', (95, 101))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (242, 275))	('melanoma', 'Phenotype', 'HP:0002861', (442, 450))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (172, 188))	('gastric cancer', 'Disease', 'MESH:D013274', (212, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('glioma', 'Disease', 'MESH:D005910', (95, 101))	('GSE30219', 'Var', (284, 292))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (432, 450))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('GSE4475', 'Var', (310, 317))	('patients', 'Species', '9606', (64, 72))	('lung cancer', 'Disease', 'MESH:D008175', (297, 308))	('lymphoma', 'Phenotype', 'HP:0002665', (322, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('kidney renal clear cell carcinoma', 'Disease', (242, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (400, 407))	('lung cancer', 'Phenotype', 'HP:0100526', (297, 308))	('acute myeloid leukemia', 'Disease', (166, 188))
90772	30646599	Cells were incubated overnight at 4  C with antibodies against LC3 (Cell Signalling, Leiden, The Netherlands), N-Cadherin or beta-Catenin (BD-Bioscience, then washed 5 times with TBS and then incubated for 1 h at room temperature with the appropriate Alexa Fluor  488- or Alexa Fluor  598-conjugated IgGs (Invitrogen, Carlsbad, CA, USA).	('beta-Catenin', 'Gene', (125, 137))	('LC3', 'Gene', '84557', (63, 66))	('Alexa Fluor  598', 'Chemical', '-', (272, 288))	('antibodies', 'Var', (44, 54))	('Signalling', 'biological_process', 'GO:0023052', ('73', '83'))	('LC3', 'Gene', (63, 66))	('Cadherin', 'molecular_function', 'GO:0008014', ('113', '121'))	('N-Cadherin', 'Gene', (111, 121))	('N-Cadherin', 'Gene', '1000', (111, 121))	('Alexa Fluor  488', 'Chemical', '-', (251, 267))	('beta-Catenin', 'Gene', '1499', (125, 137))
90786	30646599	SMSs signature could constitute a valuable prognostic biomarker, high SMS1 and low SMS2 indicating a better disease prognosis.	('high SMS1', 'Var', (65, 74))	('SMS2', 'molecular_function', 'GO:0033188', ('83', '87'))	('SMS2', 'Gene', (83, 87))	('SMS1', 'molecular_function', 'GO:0033188', ('70', '74'))	('SMS2', 'Gene', '166929', (83, 87))	('SMSs', 'Chemical', '-', (0, 4))	('low', 'NegReg', (79, 82))
90796	32232919	Genetic variants in PDSS1 and SLC16A6 in the ketone body metabolic pathway predict cutaneous melanoma-specific survival A few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival though genome-wide association studies, but stringent multiple testing corrections required for the hypothesis-free testing may have masked some true associations.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('single-nucleotide', 'Chemical', '-', (126, 143))	('associated with', 'Reg', (192, 207))	('SLC16A6', 'Gene', '9120', (30, 37))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (83, 101))	('single-nucleotide', 'Var', (126, 143))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('variants', 'Var', (8, 16))	('PDSS1', 'Gene', '23590', (20, 25))	('SLC16A6', 'Gene', (30, 37))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (208, 226))	('PDSS1', 'Gene', (20, 25))	('ketone body', 'Phenotype', 'HP:0001946', (45, 56))
90797	32232919	Using a hypothesis-driven analysis approach, we sought to evaluate associations between SNPs in ketone body metabolic pathway genes and CM survival.	('SNPs', 'Var', (88, 92))	('ketone', 'Chemical', 'MESH:D007659', (96, 102))	('associations', 'Interaction', (67, 79))	('ketone body', 'Phenotype', 'HP:0001946', (96, 107))	('ketone body metabolic pathway genes', 'Gene', (96, 131))
90798	32232919	We comprehensively assessed associations between 4,196 (538 genotyped and 3,658 imputed) common SNPs in ketone body metabolic pathway genes and CM survival, using a dataset of 858 patients of a case-control study from The University of Texas M.D.	('associations', 'Interaction', (28, 40))	('ketone', 'Chemical', 'MESH:D007659', (104, 110))	('SNPs', 'Var', (96, 100))	('patients', 'Species', '9606', (180, 188))	('ketone body', 'Phenotype', 'HP:0001946', (104, 115))	('ketone body metabolic pathway genes', 'Gene', (104, 139))
90801	32232919	We identified two independent SNPs (i.e., PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A) that were associated with CM survival, with allelic hazards ratios of 0.58 (95% confidence interval [CI]=0.44-0.76, P=9.00x10-5) and 1.98 (95% CI=1.34-2.94, P=6.30x10-4), respectively.	('SLC16A6', 'Gene', '9120', (67, 74))	('rs12254548', 'Mutation', 'rs12254548', (48, 58))	('PDSS1', 'Gene', (42, 47))	('rs71387392', 'Mutation', 'rs71387392', (75, 85))	('rs71387392 G>A', 'Var', (75, 89))	('rs12254548 G>C', 'Var', (48, 62))	('SLC16A6', 'Gene', (67, 74))	('CM survival', 'CPA', (117, 128))	('PDSS1', 'Gene', '23590', (42, 47))	('associated with', 'Reg', (101, 116))
90803	32232919	Once validated by larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be biomarker for CM survival.	('rs12254548', 'Var', (40, 50))	('SLC16A6', 'Gene', (55, 62))	('rs12254548', 'Mutation', 'rs12254548', (40, 50))	('PDSS1', 'Gene', '23590', (34, 39))	('PDSS1', 'Gene', (34, 39))	('SLC16A6', 'Gene', '9120', (55, 62))	('rs71387392', 'Mutation', 'rs71387392', (63, 73))	('rs71387392', 'Var', (63, 73))
90811	32232919	Recently, the aberrant expression of ketogenic enzymes have been reported in cancer cells of neuroectodermal origin, including melanoma .	('ketogenic enzymes', 'Enzyme', (37, 54))	('reported', 'Reg', (65, 73))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('aberrant', 'Var', (14, 22))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('melanoma', 'Disease', (127, 135))
90817	32232919	Studies have shown that germline single-nucleotide polymorphisms (SNPs) are associated with cancer risk and survival , suggesting the importance of a genetic basis as a molecular mechanism underlying tumor progression.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('associated', 'Reg', (76, 86))	('germline', 'Var', (24, 32))	('survival', 'CPA', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('single-nucleotide', 'Chemical', '-', (33, 50))
90818	32232919	Considering the role of ketogenesis in melanoma growth, it is likely that genetic variants in the ketone body metabolic pathway genes could also serve as novel biomarkers of prognostic significance for CM patients.	('ketone', 'Chemical', 'MESH:D007659', (98, 104))	('genetic variants', 'Var', (74, 90))	('melanoma growth', 'Disease', (39, 54))	('patients', 'Species', '9606', (205, 213))	('melanoma growth', 'Disease', 'MESH:D008545', (39, 54))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('ketone body', 'Phenotype', 'HP:0001946', (98, 109))	('ketone body metabolic pathway', 'Gene', (98, 127))
90819	32232919	To test such a hypothesis, we performed a pathway-based multigene approach to identify SNPs in genes in the ketone body metabolic pathway and examined their associations with survival in CM patients using two published available GWAS datasets.	('ketone body', 'Phenotype', 'HP:0001946', (108, 119))	('patients', 'Species', '9606', (190, 198))	('ketone', 'Chemical', 'MESH:D007659', (108, 114))	('SNPs', 'Var', (87, 91))	('ketone body metabolic pathway', 'Pathway', (108, 137))	('associations', 'Interaction', (157, 169))
90839	32232919	After Cox regression analysis with adjustment for age and sex, 14 SNPs (all imputed) of two genes were validated and considered significantly associated with CMSS at P < 0.05, including ten SNPs in PDSS1 (decaprenyl diphosphate synthase subunit 1) and four SNPs in SLC16A6 (solute carrier family 16 member 6) (Table 1).	('SLC16A6', 'Gene', (265, 272))	('PDSS1', 'Gene', '23590', (198, 203))	('carrier', 'molecular_function', 'GO:0005215', ('281', '288'))	('PDSS1', 'Gene', (198, 203))	('solute carrier family 16 member 6', 'Gene', (274, 307))	('associated', 'Reg', (142, 152))	('solute carrier family 16 member 6', 'Gene', '9120', (274, 307))	('SLC16A6', 'Gene', '9120', (265, 272))	('decaprenyl diphosphate synthase subunit 1', 'Gene', (205, 246))	('decaprenyl diphosphate synthase subunit 1', 'Gene', '23590', (205, 246))	('CMSS', 'Disease', (158, 162))	('SNPs', 'Var', (190, 194))
90841	32232919	We further performed LD analysis of the 14 SNPs in PDSS1 and SLC16A6 and found that except for rs2368182, nine other SNPs (i.e., rs12254548, rs1809359, rs3808914, rs7896301, rs68159164, rs71483808, rs11015232, rs7904343 and rs1960383) in PDSS1 were in high LD (Figure S2a).	('rs7896301', 'Var', (163, 172))	('rs12254548', 'Var', (129, 139))	('PDSS1', 'Gene', '23590', (238, 243))	('rs11015232', 'Mutation', 'rs11015232', (198, 208))	('rs1960383', 'Mutation', 'rs1960383', (224, 233))	('SLC16A6', 'Gene', '9120', (61, 68))	('rs68159164', 'Mutation', 'rs68159164', (174, 184))	('rs7904343', 'Var', (210, 219))	('rs3808914', 'Var', (152, 161))	('SLC16A6', 'Gene', (61, 68))	('rs11015232', 'Var', (198, 208))	('rs12254548', 'Mutation', 'rs12254548', (129, 139))	('PDSS1', 'Gene', (51, 56))	('rs71483808', 'Var', (186, 196))	('rs2368182', 'Mutation', 'rs2368182', (95, 104))	('rs71483808', 'Mutation', 'rs71483808', (186, 196))	('PDSS1', 'Gene', '23590', (51, 56))	('rs3808914', 'Mutation', 'rs3808914', (152, 161))	('rs1960383', 'Var', (224, 233))	('PDSS1', 'Gene', (238, 243))	('rs1809359', 'Var', (141, 150))	('rs68159164', 'Var', (174, 184))	('rs1809359', 'Mutation', 'rs1809359', (141, 150))	('rs7904343', 'Mutation', 'rs7904343', (210, 219))	('rs7896301', 'Mutation', 'rs7896301', (163, 172))
90842	32232919	For SLC16A6, four SNPs were in high LD with each other (i.e., rs71387392, rs35924680, rs34080227 and rs12945324) (Figure S2b).	('rs35924680', 'Var', (74, 84))	('SLC16A6', 'Gene', (4, 11))	('rs12945324', 'Mutation', 'rs12945324', (101, 111))	('rs35924680', 'Mutation', 'rs35924680', (74, 84))	('rs34080227', 'Mutation', 'rs34080227', (86, 96))	('rs12945324', 'Var', (101, 111))	('SLC16A6', 'Gene', '9120', (4, 11))	('rs34080227', 'Var', (86, 96))	('rs71387392', 'Mutation', 'rs71387392', (62, 72))	('rs71387392', 'Var', (62, 72))
90843	32232919	Functional prediction indicated that five SNPs (i.e., rs1960383, rs12254548, rs3808914, rs7896301 and rs11015232) in PDSS1 had a RegulomeDB scores   4 and two SNPs in SLC16A6 were suggested to be located in the 3'-UTR (Table S4).	('RegulomeDB scores', 'MPA', (129, 146))	('rs3808914', 'Var', (77, 86))	('rs7896301', 'Mutation', 'rs7896301', (88, 97))	('rs11015232', 'Var', (102, 112))	('rs7896301', 'Var', (88, 97))	('rs11015232', 'Mutation', 'rs11015232', (102, 112))	('rs12254548', 'Mutation', 'rs12254548', (65, 75))	('SLC16A6', 'Gene', '9120', (167, 174))	('rs12254548', 'Var', (65, 75))	('rs3808914', 'Mutation', 'rs3808914', (77, 86))	('rs1960383', 'Mutation', 'rs1960383', (54, 63))	('rs1960383', 'Var', (54, 63))	('PDSS1', 'Gene', '23590', (117, 122))	('SLC16A6', 'Gene', (167, 174))	('PDSS1', 'Gene', (117, 122))
90844	32232919	In consideration of P values, LD, and predicted functions, we selected rs2368182 and rs12254548 in PDSS1 and rs71387392 in SLC16A6 as the independent tagSNPs for further analysis.	('rs2368182', 'Var', (71, 80))	('rs2368182', 'Mutation', 'rs2368182', (71, 80))	('rs12254548', 'Var', (85, 95))	('rs71387392', 'Mutation', 'rs71387392', (109, 119))	('rs71387392', 'Var', (109, 119))	('PDSS1', 'Gene', '23590', (99, 104))	('SLC16A6', 'Gene', '9120', (123, 130))	('PDSS1', 'Gene', (99, 104))	('SLC16A6', 'Gene', (123, 130))	('rs12254548', 'Mutation', 'rs12254548', (85, 95))
90846	32232919	As a result, PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A remained in the model as independent predictors of CMSS (Table S5).	('SLC16A6', 'Gene', (38, 45))	('rs71387392', 'Mutation', 'rs71387392', (46, 56))	('rs71387392 G>A', 'Var', (46, 60))	('CMSS', 'Disease', (112, 116))	('PDSS1', 'Gene', '23590', (13, 18))	('rs12254548 G>C', 'Var', (19, 33))	('PDSS1', 'Gene', (13, 18))	('rs12254548', 'Mutation', 'rs12254548', (19, 29))	('SLC16A6', 'Gene', '9120', (38, 45))
90847	32232919	In the MDACC study (with adjustment for covariates where appropriate), a protective effect of the PDSS1 rs12254548 C allele (Ptrend = 0.005) but a risk effect of the SLC16A6 rs71387392 A allele (Ptrend = 0.006) on CM survival were statistically significant in the trend test.	('MDACC', 'Chemical', '-', (7, 12))	('SLC16A6', 'Gene', (166, 173))	('PDSS1', 'Gene', '23590', (98, 103))	('rs12254548', 'Mutation', 'rs12254548', (104, 114))	('PDSS1', 'Gene', (98, 103))	('rs71387392 A', 'Var', (174, 186))	('rs71387392', 'Mutation', 'rs71387392', (174, 184))	('rs12254548 C', 'Var', (104, 116))	('SLC16A6', 'Gene', '9120', (166, 173))
90848	32232919	We also observed similar results for the PDSS1 rs12254548 C allele in the NHS/HPFS dataset (Ptrend = 0.004), and the combined dataset of MDACC and NHS/HPFS (Ptrend < 0.0001) and for the SLC16A6 rs71387392 A allele in the NHS/HPFS dataset (Ptrend = 0.038) and the combined dataset of MDACC and NHS/HPFS (Ptrend < 0.0001) (Table 2).	('PDSS1', 'Gene', (41, 46))	('rs71387392', 'Var', (194, 204))	('MDACC', 'Chemical', '-', (137, 142))	('rs71387392', 'Mutation', 'rs71387392', (194, 204))	('rs12254548 C', 'Var', (47, 59))	('SLC16A6', 'Gene', '9120', (186, 193))	('MDACC', 'Chemical', '-', (283, 288))	('SLC16A6', 'Gene', (186, 193))	('rs12254548', 'Mutation', 'rs12254548', (47, 57))	('PDSS1', 'Gene', '23590', (41, 46))
90849	32232919	We also present Kaplan-Meier survival curves of the associations with CMSS for risk genotypes of PDSS1 rs12254548 and SLC16A6 rs71387392 in Figure 2a-2f.	('PDSS1', 'Gene', (97, 102))	('CMSS', 'Disease', (70, 74))	('rs12254548', 'Mutation', 'rs12254548', (103, 113))	('rs71387392', 'Var', (126, 136))	('rs71387392', 'Mutation', 'rs71387392', (126, 136))	('associations', 'Interaction', (52, 64))	('rs12254548', 'Var', (103, 113))	('SLC16A6', 'Gene', (118, 125))	('PDSS1', 'Gene', '23590', (97, 102))	('SLC16A6', 'Gene', '9120', (118, 125))
90850	32232919	We combined the risk genotypes of PDSS1 rs12254548 GG and SLC16A6 rs71387392 GA+AA into one variable as a genetic score to estimate the joint effect of the two SNPs.	('rs12254548', 'Var', (40, 50))	('SLC16A6', 'Gene', '9120', (58, 65))	('PDSS1', 'Gene', '23590', (34, 39))	('rs71387392', 'Mutation', 'rs71387392', (66, 76))	('rs71387392', 'Var', (66, 76))	('PDSS1', 'Gene', (34, 39))	('rs12254548', 'Mutation', 'rs12254548', (40, 50))	('SLC16A6', 'Gene', (58, 65))
90851	32232919	As shown in Table 2, we observed a risk-genotype dose-response effect on CMSS associated with the genetic score in the MDACC dataset (Ptrend = 0.0001), the NHS/HPFS dataset (Ptrend = 0.001), and the combined dataset of MDACC and NHS/HPFS (Ptrend < 0.0001).	('genetic score', 'Var', (98, 111))	('MDACC', 'Chemical', '-', (219, 224))	('CMSS', 'Disease', (73, 77))	('MDACC', 'Chemical', '-', (119, 124))
90857	32232919	Only the rs12254548 C allele demonstrated a significant association with an increased mRNA expression level of PDSS1 in the additive model and the dominant model (P = 0.0006 and P = 0.0004, respectively, Figure 3a-3b), while this was not the case for the SLC16A6 rs71387392 A allele (data not shown).	('PDSS1', 'Gene', (111, 116))	('SLC16A6', 'Gene', (255, 262))	('increased', 'PosReg', (76, 85))	('rs12254548', 'Mutation', 'rs12254548', (9, 19))	('SLC16A6', 'Gene', '9120', (255, 262))	('mRNA expression level', 'MPA', (86, 107))	('PDSS1', 'Gene', '23590', (111, 116))	('rs12254548 C', 'Var', (9, 21))	('rs71387392', 'Mutation', 'rs71387392', (263, 273))
90858	32232919	However, in the TCGA data based on 59 samples of primary cutaneous melanoma tissue, the SLC16A6 rs71387392 A allele was associated with an increased mRNA expression level of SLC16A6 in a dominant model (P = 0.039, Figure S5).	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('SLC16A6', 'Gene', '9120', (174, 181))	('increased', 'PosReg', (139, 148))	('melanoma', 'Disease', (67, 75))	('rs71387392 A', 'Var', (96, 108))	('SLC16A6', 'Gene', '9120', (88, 95))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('SLC16A6', 'Gene', (88, 95))	('rs71387392', 'Mutation', 'rs71387392', (96, 106))	('mRNA expression level', 'MPA', (149, 170))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (57, 75))	('SLC16A6', 'Gene', (174, 181))
90859	32232919	We also found the two SNPs (i.e., rs12254548 and rs71387392) to be located in a DNase I hypersensitive site, where CpG islands, and histone modification H3K27 acetylation may regulate activities of enhancer or promoter functions by using experimental data from the in ENCODE project.	('DNase I', 'molecular_function', 'GO:0004530', ('80', '87'))	('rs12254548', 'Var', (34, 44))	('activities', 'MPA', (184, 194))	('regulate', 'Reg', (175, 183))	('histone modification', 'biological_process', 'GO:0016570', ('132', '152'))	('promoter functions', 'MPA', (210, 228))	('rs71387392', 'Mutation', 'rs71387392', (49, 59))	('enhancer', 'MPA', (198, 206))	('rs71387392', 'Var', (49, 59))	('rs12254548', 'Mutation', 'rs12254548', (34, 44))
90860	32232919	It has also been suggested that rs71387392 is located on the Hoxd8 motif by the DNase cluster and transcription factor CHIP-seq data (Figure S6).	('rs71387392', 'Mutation', 'rs71387392', (32, 42))	('rs71387392', 'Var', (32, 42))	('Hoxd8', 'Gene', '3234', (61, 66))	('transcription factor', 'molecular_function', 'GO:0000981', ('98', '118'))	('transcription', 'biological_process', 'GO:0006351', ('98', '111'))	('Hoxd8', 'Gene', (61, 66))
90861	32232919	In the present study, we analyzed associations between SNPs in genes of the ketone body metabolism pathway and CMSS using two previously published datasets.	('CMSS', 'Disease', (111, 115))	('associations', 'Interaction', (34, 46))	('ketone body metabolism pathway', 'Pathway', (76, 106))	('ketone', 'Chemical', 'MESH:D007659', (76, 82))	('SNPs', 'Var', (55, 59))	('ketone body metabolism', 'biological_process', 'GO:1902224', ('76', '98'))	('ketone body', 'Phenotype', 'HP:0001946', (76, 87))
90862	32232919	We identified two SNPs (i.e., PDSS1 rs12254548 and SLC16A6 rs71387392) that were significantly associated with CMSS.	('CMSS', 'Disease', (111, 115))	('SLC16A6', 'Gene', (51, 58))	('rs12254548', 'Var', (36, 46))	('PDSS1', 'Gene', '23590', (30, 35))	('PDSS1', 'Gene', (30, 35))	('SLC16A6', 'Gene', '9120', (51, 58))	('rs12254548', 'Mutation', 'rs12254548', (36, 46))	('rs71387392', 'Var', (59, 69))	('rs71387392', 'Mutation', 'rs71387392', (59, 69))	('associated', 'Reg', (95, 105))
90863	32232919	In subsequent functional prediction analysis, we found that the PDSS1 rs12254548 C allele was associated with increased mRNA expression levels of in the 373 established blood cell lines and that the SLC16A6 rs71387392 A allele was associated with increased mRNA expression levels in primary cutaneous melanoma tissues of 59 samples from the TCGA dataset.	('SLC16A6', 'Gene', (199, 206))	('rs71387392 A', 'Var', (207, 219))	('rs71387392', 'Mutation', 'rs71387392', (207, 217))	('increased', 'PosReg', (110, 119))	('rs12254548', 'Mutation', 'rs12254548', (70, 80))	('mRNA expression levels', 'MPA', (120, 142))	('PDSS1', 'Gene', '23590', (64, 69))	('melanoma', 'Disease', 'MESH:D008545', (301, 309))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('melanoma', 'Disease', (301, 309))	('mRNA expression levels', 'MPA', (257, 279))	('rs12254548 C', 'Var', (70, 82))	('PDSS1', 'Gene', (64, 69))	('SLC16A6', 'Gene', '9120', (199, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (291, 309))	('increased', 'PosReg', (247, 256))
90865	32232919	Derangements of the ketone body metabolism can affect pathophysiological processes in cancer.	('ketone', 'Chemical', 'MESH:D007659', (20, 26))	('ketone body metabolism', 'biological_process', 'GO:1902224', ('20', '42'))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ketone body metabolism', 'MPA', (20, 42))	('Derangements', 'Var', (0, 12))	('affect', 'Reg', (47, 53))	('ketone body', 'Phenotype', 'HP:0001946', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
90874	32232919	Genetic variants in PDSS1 have also been identified in patients with mitochondrial disorders, suggesting its potential role in mitochondrial function .	('identified', 'Reg', (41, 51))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (69, 92))	('PDSS1', 'Gene', '23590', (20, 25))	('mitochondrial disorders', 'Disease', (69, 92))	('PDSS1', 'Gene', (20, 25))	('patients', 'Species', '9606', (55, 63))	('Genetic variants', 'Var', (0, 16))
90875	32232919	Because ketone bodies are involved in biological functions, the C allele of PDSS1 rs12254548 is associated with increased mRNA expression levels but a better survival, suggesting that PDSS1 is likely to be a tumor suppressor in CM progression and prognosis.	('rs12254548', 'Mutation', 'rs12254548', (82, 92))	('PDSS1', 'Gene', '23590', (184, 189))	('PDSS1', 'Gene', (76, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('208', '224'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('PDSS1', 'Gene', (184, 189))	('ketone bodies', 'Phenotype', 'HP:0001946', (8, 21))	('rs12254548', 'Var', (82, 92))	('mRNA expression levels', 'MPA', (122, 144))	('better', 'PosReg', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('ketone', 'Chemical', 'MESH:D007659', (8, 14))	('increased', 'PosReg', (112, 121))	('tumor', 'Disease', (208, 213))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('208', '224'))	('PDSS1', 'Gene', '23590', (76, 81))	('survival', 'MPA', (158, 166))
90879	32232919	In addition, SLC16A6 variants have been significantly associated with risk of breast cancer .	('variants', 'Var', (21, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('SLC16A6', 'Gene', '9120', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('associated with', 'Reg', (54, 69))	('SLC16A6', 'Gene', (13, 20))	('breast cancer', 'Disease', (78, 91))
90883	32232919	In conclusion, we report some significant associations between CMSS and genetic variants in PDSS1 and SLC16A6.	('associations', 'Interaction', (42, 54))	('PDSS1', 'Gene', '23590', (92, 97))	('PDSS1', 'Gene', (92, 97))	('SLC16A6', 'Gene', '9120', (102, 109))	('genetic variants', 'Var', (72, 88))	('CMSS', 'Disease', (63, 67))	('SLC16A6', 'Gene', (102, 109))
90885	32232919	We believe that these results are likely biologically plausible, since the genotype-phenotype correlation demonstrates that PDSS1 expression levels may be modulated by rs12254548, although additional investigation is needed to unravel the underlying molecular mechanisms.	('PDSS1', 'Gene', (124, 129))	('rs12254548', 'Var', (168, 178))	('modulated', 'Reg', (155, 164))	('expression levels', 'MPA', (130, 147))	('PDSS1', 'Gene', '23590', (124, 129))	('rs12254548', 'Mutation', 'rs12254548', (168, 178))
91022	29058705	The MSS was associated with prolonged overall survival in a large cohort of melanoma patients in The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (101, 120))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('MSS', 'Var', (4, 7))	('prolonged', 'PosReg', (28, 37))	('patients', 'Species', '9606', (85, 93))	('overall survival', 'MPA', (38, 54))	('Cancer Genome Atlas', 'Disease', (101, 120))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
91026	29058705	While recently-developed inhibitors of MAPK pathway components and immune checkpoint mediators represent the first meaningful progress in the treatment of advanced forms of melanoma, most patients still develop resistance to these agents and succumb to metastatic disease.	('MAPK', 'Gene', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('patients', 'Species', '9606', (188, 196))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('MAPK', 'molecular_function', 'GO:0004707', ('39', '43'))	('develop', 'Reg', (203, 210))	('inhibitors', 'Var', (25, 35))	('resistance', 'CPA', (211, 221))	('metastatic disease', 'CPA', (253, 271))
91032	29058705	We recently showed that concomitant ablation of the NME1 and NME2 genes greatly enhances metastatic potential in a mouse model of ultraviolet light-induced melanoma, providing strong in vivo evidence of its metastasis suppressor function.	('NME1', 'Gene', (52, 56))	('ablation', 'Var', (36, 44))	('enhances', 'PosReg', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('light-induced melanoma', 'Phenotype', 'HP:0031420', (142, 164))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('mouse', 'Species', '10090', (115, 120))	('metastatic potential', 'CPA', (89, 109))	('NME2', 'Gene', '18103', (61, 65))	('NME2', 'Gene', (61, 65))
91041	29058705	Moreover, disruption of the NDPK active site by a site-directed point mutation of the catalytic histidine-118 residue (H118F) modestly impaired metastasis suppressor function of NME1 in the human melanoma cell line 1205Lu.	('metastasis suppressor function', 'CPA', (144, 174))	('point mutation', 'Var', (64, 78))	('H118F', 'SUBSTITUTION', 'None', (119, 124))	('impaired', 'NegReg', (135, 143))	('H118F', 'Var', (119, 124))	('NDPK', 'Gene', '129607', (28, 32))	('NDPK', 'Gene', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('human', 'Species', '9606', (190, 195))	('disruption', 'Var', (10, 20))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('histidine', 'Chemical', 'MESH:D006639', (96, 105))
91043	29058705	Site-directed mutagenesis of NME1 and NME2 has identified a number of amino acid residues critical for enzymatic and metastasis suppressor functions.	('mutagenesis', 'biological_process', 'GO:0006280', ('14', '25'))	('mutagenesis', 'Var', (14, 25))	('NME2', 'Gene', (38, 42))	('NME1', 'Gene', (29, 33))	('NME2', 'Gene', '18103', (38, 42))
91046	29058705	We posited that genes which were regulated by wild-type NME1, but not the suppressor-deficient mutants E5A and K12Q, would yield a signature enriched with genes that mediate metastasis suppressor activity.	('metastasis suppressor activity', 'CPA', (174, 204))	('NME1', 'Gene', (56, 60))	('K12Q', 'SUBSTITUTION', 'None', (111, 115))	('K12Q', 'Var', (111, 115))	('E5A', 'Chemical', '-', (103, 106))
91047	29058705	The approach involved forced expression of wild-type NME1 or one of the metastasis suppressor-deficient mutants in the human melanoma cell line, WM793, followed by assessment of their impacts on gene expression by microarray analysis.	('gene expression', 'biological_process', 'GO:0010467', ('195', '210'))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('impacts', 'Reg', (184, 191))	('mutants', 'Var', (104, 111))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('WM793', 'CellLine', 'CVCL:8787', (145, 150))	('gene expression', 'MPA', (195, 210))	('NME1', 'Gene', (53, 57))	('expression', 'Species', '29278', (200, 210))	('expression', 'Species', '29278', (29, 39))	('human', 'Species', '9606', (119, 124))
91055	29058705	Briefly, cDNA of wild-type or mutant variants of NME1 was cloned into mammalian expression vector pCI-EGFP (provided by S. Kraner, University of Kentucky), followed by transfection into WM793 or M14 cells.	('NME1', 'Gene', (49, 53))	('mammalian', 'Species', '9606', (70, 79))	('expression', 'Species', '29278', (80, 90))	('WM793', 'CellLine', 'CVCL:8787', (186, 191))	('mutant variants', 'Var', (30, 45))	('variants', 'Var', (37, 45))
91057	29058705	Stable knockdown of NME1 expression in WM278 cells was achieved by lentiviral delivery of Mission shRNA (Sigma-Aldrich, St. Louis, MO, USA) TRCN0000010062 (shNME1#1) or Non-target shRNA pLK0.1 (SHC002, Sigma-Aldrich) as a negative control.	('knockdown', 'Var', (7, 16))	('WM278', 'CellLine', 'CVCL:6473', (39, 44))	('expression', 'Species', '29278', (25, 35))	('NME1', 'Gene', (20, 24))
91060	29058705	Parental WM793 cells or WM793 stably expressing wild-type or mutant NME1 were seeded at a density of 1.5 x 105 per 100-mm plastic dish and grown for 3 days to 75-80% confluence in Tu2%.	('WM793', 'CellLine', 'CVCL:8787', (24, 29))	('WM793', 'CellLine', 'CVCL:8787', (9, 14))	('NME1', 'Gene', (68, 72))	('mutant', 'Var', (61, 67))	('Tu2', 'Chemical', '-', (180, 183))
91083	29058705	For the current study, a panel of WM793-derived cell lines was used that had been created by stable transfection to provide forced expression of wild-type NME1 and the NME1 point mutants glutamate-5 to alanine (E5A), lysine-12 to glutamine (K12Q), and histidine-118 to phenylalanine (H118F).	('NME1', 'Gene', (168, 172))	('NME1', 'Gene', (155, 159))	('H118F', 'SUBSTITUTION', 'None', (284, 289))	('WM793', 'CellLine', 'CVCL:8787', (34, 39))	('H118F', 'Var', (284, 289))	('glutamate-5 to alanine', 'Mutation', 'p.E5A', (187, 209))	('K12Q', 'SUBSTITUTION', 'None', (241, 245))	('glutamate-5', 'Var', (187, 198))	('lysine-12 to', 'Var', (217, 229))	('K12Q', 'Var', (241, 245))	('histidine-118 to phenylalanine', 'Mutation', 'p.H118F', (252, 282))	('lysine-12 to glutamine', 'Mutation', 'p.K12Q', (217, 239))	('expression', 'Species', '29278', (131, 141))	('E5A', 'Chemical', '-', (211, 214))	('histidine-118 to', 'Var', (252, 268))
91084	29058705	The E5A variant is deficient in 3'-5' exonuclease activity, variant K12Q is deficient in both the 3'-5' exonuclease and NDPK activities, and H118F is deficient only in the NDPK activity.	('H118F', 'SUBSTITUTION', 'None', (141, 146))	("3'-5' exonuclease", 'MPA', (98, 115))	('deficient', 'NegReg', (19, 28))	('E5A', 'Chemical', '-', (4, 7))	('NDPK', 'Gene', '129607', (172, 176))	("3'-5' exonuclease activity", 'molecular_function', 'GO:0008408', ('32', '58'))	('NDPK', 'Gene', (120, 124))	("3'-5' exonuclease activity", 'MPA', (32, 58))	('K12Q', 'SUBSTITUTION', 'None', (68, 72))	('H118F', 'Var', (141, 146))	('NDPK', 'Gene', (172, 176))	('deficient', 'NegReg', (76, 85))	('E5A', 'Var', (4, 7))	('K12Q', 'Var', (68, 72))	('NDPK', 'Gene', '129607', (120, 124))
91085	29058705	Of these point mutants, E5A and K12Q are deficient in metastasis suppressor activity in context of the human melanoma cell line 1205Lu.	('metastasis suppressor activity', 'CPA', (54, 84))	('human', 'Species', '9606', (103, 108))	('E5A', 'Chemical', '-', (24, 27))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('K12Q', 'SUBSTITUTION', 'None', (32, 36))	('melanoma', 'Disease', (109, 117))	('K12Q', 'Var', (32, 36))	('deficient', 'NegReg', (41, 50))	('E5A', 'Var', (24, 27))
91086	29058705	NME1 is rarely mutated in cancers, however, the use of point-mutations that fail to suppress metastasis allows for more streamlined examination of the metastasis suppressor functions of NME1 in experimental settings.	('metastasis', 'CPA', (151, 161))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('point-mutations', 'Var', (55, 70))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
91087	29058705	The WM793 panel was considered for the current study in light of its higher levels of forced NME1 expression than obtained in the 1205Lu panel, with each NME1 mutant variant expressed at approximately 4-fold over endogenous NME1 levels (Fig.	('WM793', 'CellLine', 'CVCL:8787', (4, 9))	('over', 'PosReg', (208, 212))	('NME1', 'Gene', (154, 158))	('expression', 'Species', '29278', (98, 108))	('mutant variant', 'Var', (159, 173))	('variant', 'Var', (166, 173))
91090	29058705	In contrast, expression of the E5A or K12Q variants had no significant suppressor effect on lung colonizing activity (50% lung colony-positive for both), consistent with loss of metastasis suppressor activity, as previously described in 1205Lu cells.	('E5A', 'Var', (31, 34))	('expression', 'Species', '29278', (13, 23))	('K12Q', 'Var', (38, 42))	('loss of metastasis', 'Disease', 'MESH:D009362', (170, 188))	('E5A', 'Chemical', '-', (31, 34))	('loss of metastasis', 'Disease', (170, 188))	('lung colonizing activity', 'CPA', (92, 116))	('K12Q', 'SUBSTITUTION', 'None', (38, 42))
91091	29058705	Also consistent with prior results in 1205Lu cells, expression of the NDPK-deficient variant H118F had no statistically significant effect on lung colonization in the WM793 line.	('expression', 'Species', '29278', (52, 62))	('H118F', 'SUBSTITUTION', 'None', (93, 98))	('NDPK', 'Gene', '129607', (70, 74))	('H118F', 'Var', (93, 98))	('WM793', 'CellLine', 'CVCL:8787', (167, 172))	('NDPK', 'Gene', (70, 74))	('lung colonization', 'CPA', (142, 159))
91092	29058705	Taken together, these analyses showed the WM793-derived cell lines expressing wildtype NME1 and the E5A and K12Q variants would provide a robust system for identifying genes whose expression tracks with the metastasis suppressor function of NME1.	('K12Q', 'SUBSTITUTION', 'None', (108, 112))	('WM793', 'CellLine', 'CVCL:8787', (42, 47))	('expression', 'Species', '29278', (180, 190))	('E5A', 'Chemical', '-', (100, 103))	('K12Q', 'Var', (108, 112))	('metastasis', 'CPA', (207, 217))	('variants', 'Var', (113, 121))	('E5A', 'Var', (100, 103))	('NME1', 'Gene', (87, 91))
91093	29058705	To better identify which of the 153 genes regulated by wild-type (WT) NME1 were associated with its metastasis suppressor activity, microarray analyses were also conducted in WM793 cells expressing the metastasis suppressor-deficient mutants of NME1 (E5A and K12Q).	('metastasis', 'Disease', (202, 212))	('NME1', 'Gene', (70, 74))	('E5A', 'Chemical', '-', (251, 254))	('NME1', 'Gene', (245, 249))	('K12Q', 'SUBSTITUTION', 'None', (259, 263))	('metastasis suppressor activity', 'CPA', (100, 130))	('K12Q', 'Var', (259, 263))	('E5A', 'Var', (251, 254))	('WM793', 'CellLine', 'CVCL:8787', (175, 180))
91094	29058705	The marked loss of metastasis suppressor activity for the E5A and K12Q mutants made them ideal tools for identifying NME1-regulated genes mediating the suppressor function.	('K12Q', 'SUBSTITUTION', 'None', (66, 70))	('loss of metastasis', 'Disease', 'MESH:D009362', (11, 29))	('E5A', 'Chemical', '-', (58, 61))	('K12Q', 'Var', (66, 70))	('loss of metastasis', 'Disease', (11, 29))	('E5A', 'Var', (58, 61))
91096	29058705	The H118F-dependent gene expression profile was not included in our filtering approach for the MSS, as the H118F mutation did not significantly alter the metastasis suppressor activity of NME1 in vivo (Table 1).	('metastasis suppressor activity', 'CPA', (154, 184))	('gene expression', 'biological_process', 'GO:0010467', ('20', '35'))	('expression', 'Species', '29278', (25, 35))	('H118F', 'Var', (4, 9))	('H118F', 'SUBSTITUTION', 'None', (4, 9))	('H118F', 'Var', (107, 112))	('H118F', 'SUBSTITUTION', 'None', (107, 112))
91097	29058705	After three separate comparisons, (WT vs Parent, WT vs E5A, and WT vs K12Q) were compiled, six genes were consistently regulated by wild-type NME1 but not a metastasis suppressor-deficient mutant (Fig.	('K12Q', 'SUBSTITUTION', 'None', (70, 74))	('NME1', 'Gene', (142, 146))	('E5A', 'Chemical', '-', (55, 58))	('K12Q', 'Var', (70, 74))	('regulated', 'Reg', (119, 128))
91100	29058705	In addition, we measured expression of MSS genes in H118F-expressing WM793 cells to identify any potential contributions of the NDPK function to their regulation.	('expression', 'Species', '29278', (25, 35))	('WM793', 'CellLine', 'CVCL:8787', (69, 74))	('MSS genes', 'Gene', (39, 48))	('expression', 'MPA', (25, 35))	('H118F', 'Var', (52, 57))	('NDPK', 'Gene', '129607', (128, 132))	('H118F', 'SUBSTITUTION', 'None', (52, 57))	('regulation', 'biological_process', 'GO:0065007', ('151', '161'))	('NDPK', 'Gene', (128, 132))
91101	29058705	In agreement with microarray and immunoblot analyses, the Nanostring approach demonstrated a 3-to-4-fold induction of NME1 RNA in WM793 cell lines expressing wild-type NME1 and the variants E5A, K12Q and H118F (Fig.	('K12Q', 'Var', (195, 199))	('H118F', 'SUBSTITUTION', 'None', (204, 209))	('induction', 'PosReg', (105, 114))	('E5A', 'Var', (190, 193))	('RNA', 'cellular_component', 'GO:0005562', ('123', '126'))	('NME1 RNA', 'Gene', (118, 126))	('H118F', 'Var', (204, 209))	('E5A', 'Chemical', '-', (190, 193))	('K12Q', 'SUBSTITUTION', 'None', (195, 199))	('WM793', 'CellLine', 'CVCL:8787', (130, 135))
91102	29058705	Consistent with the microarray analysis, Nanostring validated the induction of EREG, LRP1b and TRIML2 transcripts by wild-type NME1, and not the metastasis suppressor-deficient variants E5A and K12Q.	('TRIML2', 'Gene', (95, 101))	('LRP1b', 'Gene', (85, 90))	('K12Q', 'SUBSTITUTION', 'None', (194, 198))	('TRIML2', 'Gene', '205860', (95, 101))	('E5A', 'Chemical', '-', (186, 189))	('K12Q', 'Var', (194, 198))	('EREG', 'Gene', (79, 83))	('LRP1b', 'Gene', '53353', (85, 90))
91104	29058705	Wild-type and E5A forms of NME1, which both retain full NDPK activity, induced ALDOC mRNA but the K12Q and H118F mutants did not.	('induced', 'Reg', (71, 78))	('ALDOC', 'Gene', (79, 84))	('E5A', 'Chemical', '-', (14, 17))	('H118F', 'Var', (107, 112))	('H118F', 'SUBSTITUTION', 'None', (107, 112))	('NDPK', 'Gene', '129607', (56, 60))	('ALDOC', 'Gene', '230', (79, 84))	('K12Q', 'SUBSTITUTION', 'None', (98, 102))	('NDPK', 'Gene', (56, 60))	('K12Q', 'Var', (98, 102))	('NME1', 'Gene', (27, 31))
91105	29058705	The Nanostring analysis yielded considerable variability with impacts of the K12Q mutant on expression of the CXCL11 and NETO2 transcripts limiting the ability to interpret if one or more enzymatic function of NME1 were critical for their expression.	('NETO2', 'Gene', (121, 126))	('NETO', 'biological_process', 'GO:0051523', ('121', '125'))	('limiting', 'NegReg', (139, 147))	('NETO2', 'Gene', '81831', (121, 126))	('K12Q', 'SUBSTITUTION', 'None', (77, 81))	('expression', 'Species', '29278', (92, 102))	('CXCL11', 'Gene', (110, 116))	('CXCL11', 'Gene', '6373', (110, 116))	('expression', 'Species', '29278', (239, 249))	('expression', 'MPA', (92, 102))	('K12Q', 'Var', (77, 81))
91113	29058705	As predicted, loss of endogenous NME1 induced the expression of NME1-suppressed genes CTAGE4, MACF1 and MMP3 (Fig.	('MMP3', 'molecular_function', 'GO:0004248', ('104', '108'))	('MACF1', 'Gene', (94, 99))	('NME1-suppressed', 'Gene', (64, 79))	('induced', 'PosReg', (38, 45))	('loss', 'Var', (14, 18))	('NME1', 'Gene', (33, 37))	('MMP3', 'Gene', (104, 108))	('expression', 'Species', '29278', (50, 60))	('CTAGE4', 'Gene', (86, 92))	('expression', 'MPA', (50, 60))
91171	29058705	GPCRs are frequently mutated in melanoma and other cancers, exemplified by the identification of GRIN2A mutations in over 33% of human melanomas.	('mutations', 'Var', (104, 113))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('GRIN2A', 'Gene', (97, 103))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('melanoma', 'Disease', (32, 40))	('melanoma', 'Disease', (135, 143))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('GRIN2A', 'Gene', '2903', (97, 103))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (129, 134))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('melanomas', 'Disease', (135, 144))
91174	29058705	Our study utilized NME1 variants that we showed previously to be deficient not only in metastasis suppressor activity, but also in NDPK and 3'-5' exonuclease activities of the NME1 protein.	('NDPK', 'Gene', (131, 135))	("3'-5' exonuclease activities", 'MPA', (140, 168))	('variants', 'Var', (24, 32))	('deficient', 'NegReg', (65, 74))	('metastasis suppressor activity', 'CPA', (87, 117))	('NME1', 'Gene', (19, 23))	('NDPK', 'Gene', '129607', (131, 135))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))
91175	29058705	While NME1 is rarely mutated in cancers, these variants represent powerful experimental tools to help differentiate the metastasis suppressor functions of NME1 from other potential housekeeping functions.	('variants', 'Var', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Disease', (32, 39))	('metastasis suppressor', 'CPA', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
91176	29058705	In the current study as well as our prior one, metastasis suppressor function was disrupted significantly only in those variants lacking 3'-5' exonuclease activity (E5A and K12Q), suggesting the possibility that this enzymatic function contributes in some way to regulation of the MSS genes.	("3'-5' exonuclease", 'MPA', (137, 154))	('disrupted', 'NegReg', (82, 91))	('K12Q', 'Var', (173, 177))	('E5A', 'Chemical', '-', (165, 168))	('K12Q', 'SUBSTITUTION', 'None', (173, 177))	('MSS', 'Gene', (281, 284))	("3'-5' exonuclease activity", 'molecular_function', 'GO:0008408', ('137', '163'))	('metastasis suppressor function', 'CPA', (47, 77))	('regulation', 'biological_process', 'GO:0065007', ('263', '273'))	('lacking', 'NegReg', (129, 136))
91183	29058705	Of particular interest were a number of RNA processing factors, such as GEMIN5, BOP1, ACIN1, PABP and HNRNPA2B, suggesting NME1 may regulate gene expression via impacts on RNA splicing, stability and other post-transcriptional events.	('RNA', 'cellular_component', 'GO:0005562', ('172', '175'))	('RNA', 'cellular_component', 'GO:0005562', ('40', '43'))	('RNA splicing', 'MPA', (172, 184))	('NME1', 'Var', (123, 127))	('RNA processing', 'biological_process', 'GO:0006396', ('40', '54'))	('gene expression', 'biological_process', 'GO:0010467', ('141', '156'))	('stability', 'MPA', (186, 195))	('RNA splicing', 'biological_process', 'GO:0008380', ('172', '184'))	('gene expression', 'MPA', (141, 156))	('expression', 'Species', '29278', (146, 156))	('impacts', 'Reg', (161, 168))	('regulate', 'Reg', (132, 140))
91195	27762323	It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME).	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutation load', 'Var', (34, 47))	('paucity of T cells', 'Phenotype', 'HP:0005403', (62, 80))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('paucity', 'MPA', (62, 69))	('tumor', 'Disease', (92, 97))	('T cells', 'CPA', (73, 80))
91197	27762323	Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells.	('PDAC', 'Chemical', '-', (41, 45))	('reduced', 'NegReg', (244, 251))	('reduced', 'NegReg', (142, 149))	('neoantigens', 'MPA', (84, 95))	('efficient', 'PosReg', (191, 200))	('PDAC', 'Disease', (41, 45))	('markers', 'Var', (180, 187))	('PDAC', 'Phenotype', 'HP:0006725', (41, 45))	('antigen presentation', 'MPA', (201, 221))	('activation signature', 'MPA', (150, 170))	('signature of markers', 'MPA', (252, 272))	('antigen presentation', 'biological_process', 'GO:0019882', ('201', '221'))
91206	27762323	TAAs can be neoantigens, arising as a result of processed cancer-specific mutant peptides, or aberrant self-antigens like mesothelin or epidermal growth factor receptor (EGFR), due to overexpression of oncogenic proteins.	('mesothelin', 'Gene', '10232', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('TAAs', 'Disease', (0, 4))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('136', '159'))	('EGFR', 'Gene', '1956', (170, 174))	('epidermal growth factor receptor', 'Gene', '1956', (136, 168))	('EGFR', 'molecular_function', 'GO:0005006', ('170', '174'))	('mesothelin', 'Gene', (122, 132))	('EGFR', 'Gene', (170, 174))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('mutant', 'Var', (74, 80))	('epidermal growth factor receptor', 'Gene', (136, 168))
91207	27762323	Not surprisingly, cancers with higher mutation loads also harbor higher numbers of neontigens presented on HLA molecules, thereby leading to an influx of greater numbers of TAA-reactive T cells.	('HLA', 'Gene', '3113', (107, 110))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('mutation loads', 'Var', (38, 52))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('influx', 'PosReg', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('neontigens', 'Protein', (83, 93))	('HLA', 'Gene', (107, 110))	('higher', 'PosReg', (65, 71))	('TAA-reactive T cells', 'MPA', (173, 193))	('greater', 'PosReg', (154, 161))
91209	27762323	Another example of this correlation between mutational load and TILs is observed in cancers with microsatellite instability (e.g., Lynch syndrome), where large numbers of TILs are observed in cases that bear thousands of neoantigens.	('microsatellite instability', 'MPA', (97, 123))	('Lynch syndrome', 'Disease', (131, 145))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('Lynch syndrome', 'Disease', 'MESH:D003123', (131, 145))	('mutational', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
91216	27762323	In line with this, it has recently been shown that T cells engineered against Mesothelin, a surface antigen present on mesothelial cells, can cause tumor lysis and increased survival in PDAC patients.	('Mesothelin', 'Gene', (78, 88))	('PDAC', 'Phenotype', 'HP:0006725', (186, 190))	('PDAC', 'Disease', (186, 190))	('T cells engineered', 'Var', (51, 69))	('patients', 'Species', '9606', (191, 199))	('survival', 'CPA', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('lysis', 'biological_process', 'GO:0019835', ('154', '159'))	('PDAC', 'Chemical', '-', (186, 190))	('cause', 'Reg', (142, 147))	('Mesothelin', 'Gene', '10232', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('increased', 'PosReg', (164, 173))
91227	27762323	Notably, KRAS codon 12 mutations are the most common genetic alteration in this cancer, and indeed, the corresponding mutant peptide was predicted to generate likely immunogenic neoantigens for most of the TCGA and ICGC patients bearing this mutation (Supplementary Fig.	('KRAS', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (23, 32))	('mutant', 'Var', (118, 124))	('patients', 'Species', '9606', (220, 228))	('KRAS', 'Gene', '3845', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
91228	27762323	Other examples of mutations that we found to generate potential neoantigens for multiple patients were KRAS Q61H, TP53 R273N, TP53 R282W, MT-ND4 A318T, FCGBP A2493V, RBM12 P693S, and RET A1019V.	('TP53', 'Gene', (126, 130))	('MT-ND4', 'Gene', (138, 144))	('R282W', 'Mutation', 'rs28934574', (131, 136))	('TP53', 'Gene', '7157', (114, 118))	('FCGBP', 'Gene', '8857', (152, 157))	('RBM12 P693S', 'Var', (166, 177))	('R273N', 'Mutation', 'p.R273N', (119, 124))	('MT-ND4', 'Gene', '4538', (138, 144))	('A318T', 'Mutation', 'c.318A>T', (145, 150))	('TP53', 'Gene', '7157', (126, 130))	('A2493V', 'Mutation', 'p.A2493V', (158, 164))	('KRAS', 'Gene', '3845', (103, 107))	('neoantigens', 'MPA', (64, 75))	('TP53', 'Gene', (114, 118))	('R282W', 'Var', (131, 136))	('KRAS', 'Gene', (103, 107))	('P693S', 'Mutation', 'rs1352970439', (172, 177))	('Q61H', 'Mutation', 'rs17851045', (108, 112))	('A1019V', 'Mutation', 'p.A1019V', (187, 193))	('patients', 'Species', '9606', (89, 97))	('FCGBP', 'Gene', (152, 157))
91243	27762323	Similarly to how antigen presentation-related gene expressions inversely correlated with immune cytotoxicity, mutation load also showed a negative correlation with cytotoxic immune markers (Fig.	('cytotoxic', 'MPA', (164, 173))	('correlated', 'Reg', (73, 83))	('antigen presentation', 'biological_process', 'GO:0019882', ('17', '37'))	('cytotoxicity', 'Disease', (96, 108))	('negative', 'NegReg', (138, 146))	('mutation load', 'Var', (110, 123))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))
91244	27762323	Notably, CD8A expression exhibited a negative correlation with mutation load in the TCGA (p < 0.01) and in the ICGC (p = 0.0817) PDAC data sets.	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('CD8A', 'Gene', '925', (9, 13))	('mutation load', 'Var', (63, 76))	('expression', 'MPA', (14, 24))	('CD8A', 'Gene', (9, 13))	('PDAC', 'Chemical', '-', (129, 133))	('negative', 'NegReg', (37, 45))
91245	27762323	Most of the class II (but not class I) antigen presentation and effector T-cell markers correlated negatively with mutation load in the TCGA pancreatic data set, and a few of them in the ICGC cohort as well.	('pancreatic', 'Disease', (141, 151))	('antigen presentation', 'biological_process', 'GO:0019882', ('39', '59'))	('mutation load', 'Var', (115, 128))	('negatively', 'NegReg', (99, 109))	('pancreatic', 'Disease', 'MESH:D010195', (141, 151))
91251	27762323	GP6, GP7 and GP8 scores (which represent immune programs) negatively correlated with mutation load (Fig.	('GP7', 'Gene', (5, 8))	('GP6', 'Gene', (0, 3))	('mutation load', 'Var', (85, 98))	('GP8 scores', 'Gene', (13, 23))	('GP6', 'Gene', '51206', (0, 3))	('negatively', 'NegReg', (58, 68))
91252	27762323	Interestingly, we found positive correlations between mutation and neoantigen load with GP4 (proliferation) and GP5 (activated MYC pathways, autophagy, and RNA processing) programs.	('mutation', 'Var', (54, 62))	('RNA processing', 'biological_process', 'GO:0006396', ('156', '170'))	('autophagy', 'CPA', (141, 150))	('RNA', 'cellular_component', 'GO:0005562', ('156', '159'))	('autophagy', 'biological_process', 'GO:0016236', ('141', '150'))	('GP5', 'Gene', (112, 115))	('GP4', 'Gene', '948', (88, 91))	('autophagy', 'biological_process', 'GO:0006914', ('141', '150'))	('GP5', 'Gene', '2814', (112, 115))	('GP4', 'Gene', (88, 91))	('MYC pathways', 'CPA', (127, 139))
91263	27762323	It was recently shown that T-cell receptors (TCRs) that are reactive to KRAS G12V and G12D neoantigens can be isolated.	('G12D', 'Mutation', 'rs121913529', (86, 90))	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (72, 76))	('G12V', 'Mutation', 'rs121913529', (77, 81))	('G12D', 'Var', (86, 90))
91268	27762323	This is surprising because high HLA and neoantigen expression is associated with better prognosis in other cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('HLA', 'Gene', (32, 35))	('HLA', 'Gene', '3113', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high', 'Var', (27, 31))	('neoantigen', 'Protein', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
91286	27762323	Lastly, we identified high levels of immune-suppressive iNOS (NOS2) as a potential mediator of immune suppression, and targeting iNOS could help to augment immune response in PDAC.	('NOS2', 'Gene', (62, 66))	('PDAC', 'Chemical', '-', (175, 179))	('iNOS', 'Gene', '4843', (56, 60))	('immune response', 'biological_process', 'GO:0006955', ('156', '171'))	('targeting', 'Var', (119, 128))	('NOS2', 'Gene', '4843', (62, 66))	('PDAC', 'Disease', (175, 179))	('iNOS', 'Gene', (56, 60))	('PDAC', 'Phenotype', 'HP:0006725', (175, 179))	('augment', 'PosReg', (148, 155))	('iNOS', 'Gene', '4843', (129, 133))	('iNOS', 'Gene', (129, 133))	('immune response', 'CPA', (156, 171))
91289	27762323	We predicted all possible 8-12-mer mutated neo-peptides and their respective HLA-binding affinities (HLA-A, -B, -C) as described earlier.	('mutated', 'Var', (35, 42))	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('HLA', 'Gene', (101, 104))	('HLA', 'Gene', (77, 80))	('HLA', 'Gene', '3113', (101, 104))	('HLA-A, -B, -C', 'Gene', '3105;3106;3107', (101, 114))	('HLA', 'Gene', '3113', (77, 80))
91414	22674455	Additional factors associated with a decreased likelihood of receiving a SLNB included head and neck primary tumor site, high or unknown serum LDH, Asian, Hispanic, Native American or unknown race, and increasing age.	('Asian', 'Disease', (148, 153))	('Hispanic', 'Disease', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('head and neck primary tumor', 'Phenotype', 'HP:0012288', (87, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('neck', 'cellular_component', 'GO:0044326', ('96', '100'))	('high', 'Var', (121, 125))	('decreased', 'NegReg', (37, 46))	('tumor', 'Disease', (109, 114))
91419	22674455	Developed and popularized by Morton in 1992, SLNB represents the current standard for evaluation of the draining lymphatic basin for intermediate thickness (>= 1 mm but <= 4 mm) melanoma, supplanting the technique of elective lymph node dissection.	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('>= 1 mm', 'Var', (157, 164))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))
91420	22674455	In a multicenter randomized clinical trial, patients who received a SLNB did not have significantly improved melanoma-specific survival relative to those who received wide excision of their melanoma and observation of the lymph node basin.	('SLNB', 'Var', (68, 72))	('patients', 'Species', '9606', (44, 52))	('improved', 'PosReg', (100, 108))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))
91421	22674455	Patients who received a completion lymphadenectomy due to a positive SLNB had superior melanoma-specific survival compared to those patients whose lymphadenectomy was delayed until the onset of clinically palpable disease, however.	('melanoma', 'Disease', (87, 95))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('SLNB', 'Gene', (69, 73))	('Patients', 'Species', '9606', (0, 8))	('superior', 'PosReg', (78, 86))	('positive', 'Var', (60, 68))	('patients', 'Species', '9606', (132, 140))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
91561	32431053	The same trend was seen for the Hallmark myogenesis pathway, the Hallmark angiogenesis pathway, and the Hallmark complement pathway with upregulation in the group of SN vs. AST and downregulation in the group of AST vs. MST.	('myogenesis', 'biological_process', 'GO:0042692', ('41', '51'))	('AST', 'Chemical', '-', (212, 215))	('angiogenesis pathway', 'Pathway', (74, 94))	('downregulation', 'NegReg', (181, 195))	('myogenesis', 'biological_process', 'GO:0048740', ('41', '51'))	('angiogenesis', 'biological_process', 'GO:0001525', ('74', '86'))	('myogenesis', 'biological_process', 'GO:0007519', ('41', '51'))	('upregulation', 'PosReg', (137, 149))	('AST', 'Chemical', '-', (173, 176))	('SN vs.', 'Var', (166, 172))	('SN', 'Chemical', '-', (166, 168))
91602	32431053	NF1 alterations are found in approximately 10 % of cutaneous melanomas [19] and have also been reported in subgroups of Spitzoid melanocytic neoplasms [25, 34.	('alterations', 'Var', (4, 15))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))	('Spitzoid melanocytic neoplasms', 'Disease', 'MESH:D009508', (120, 150))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (51, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (51, 70))	('melanomas', 'Phenotype', 'HP:0002861', (61, 70))	('Spitzoid melanocytic neoplasms', 'Disease', (120, 150))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanocytic neoplasms', 'Phenotype', 'HP:0002861', (129, 150))	('cutaneous melanomas', 'Disease', (51, 70))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', '4763', (0, 3))
91639	32431053	In our series, the majority of MST represented lower stage melanomas (86%, n = 14, Breslow thickness between =/< 1.0 mm (T1) or 1.0-2.0 mm (T2); Table S1).	('MST', 'Disease', (31, 34))	('1.0-2.0 mm', 'Var', (128, 138))	('stage melanomas', 'Disease', (53, 68))	('stage melanomas', 'Disease', 'MESH:D008545', (53, 68))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
91650	32431053	These included IL11RA, IL10, IL12RB2, IL11RB, IL13RA2, CD40, IL20RRB, IL7, IL20RA, LEF1, and IL1R2 (Table S2).	('IL7', 'molecular_function', 'GO:0005139', ('70', '73'))	('IL11RB', 'Var', (38, 44))	('IL10', 'Gene', (23, 27))	('IL20RA', 'Gene', (75, 81))	('IL1R2', 'Gene', (93, 98))	('LEF1', 'Gene', (83, 87))	('IL20', 'molecular_function', 'GO:0045517', ('61', '65'))	('IL13', 'molecular_function', 'GO:0005144', ('46', '50'))	('IL12RB2', 'Gene', '3595', (29, 36))	('IL10', 'molecular_function', 'GO:0005141', ('23', '27'))	('IL11RA', 'Gene', '3590', (15, 21))	('IL10', 'Gene', '3586', (23, 27))	('IL7', 'Gene', '3574', (70, 73))	('IL12RB2', 'Gene', (29, 36))	('IL11', 'molecular_function', 'GO:0005142', ('15', '19'))	('IL20', 'molecular_function', 'GO:0045517', ('75', '79'))	('CD40', 'Gene', (55, 59))	('IL11RA', 'Gene', (15, 21))	('IL11', 'molecular_function', 'GO:0005142', ('38', '42'))	('IL7', 'Gene', (70, 73))	('LEF1', 'Gene', '51176', (83, 87))	('IL13RA2', 'Gene', (46, 53))	('CD40', 'Gene', '958', (55, 59))	('IL1R2', 'Gene', '7850', (93, 98))	('IL20RA', 'Gene', '53832', (75, 81))	('IL12', 'molecular_function', 'GO:0005143', ('29', '33'))	('IL13RA2', 'Gene', '3598', (46, 53))	('IL1R', 'molecular_function', 'GO:0004908', ('93', '97'))	('IL20RRB', 'Var', (61, 68))
91666	31848373	COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair.	('mismatch repair', 'biological_process', 'GO:0006298', ('176', '191'))	('associated', 'Reg', (103, 113))	('patients', 'Species', '9606', (82, 90))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (146, 162))	('spontaneous deamination of 5-methylcytosine', 'MPA', (119, 162))	('UVM', 'Phenotype', 'HP:0007716', (78, 81))	('defective', 'NegReg', (166, 175))	('mutations', 'Var', (65, 74))
91675	31848373	The GNAQ/GNA11 mutations frequently observed in UVM patients have also been reported to activate the MAPK pathway, but clinical trials with the MEK1/2 inhibitor, selumetinib, have failed to improve survival.	('GNA11', 'Gene', (9, 14))	('MEK1/2', 'Gene', (144, 150))	('GNAQ', 'Gene', '2776', (4, 8))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('MAPK pathway', 'Pathway', (101, 113))	('mutations', 'Var', (15, 24))	('selumetinib', 'Chemical', 'MESH:C517975', (162, 173))	('GNAQ', 'Gene', (4, 8))	('UVM', 'Phenotype', 'HP:0007716', (48, 51))	('MEK1', 'molecular_function', 'GO:0004708', ('144', '148'))	('activate', 'PosReg', (88, 96))	('MEK1/2', 'Gene', '5604;5605', (144, 150))	('patients', 'Species', '9606', (52, 60))	('GNA11', 'Gene', '2767', (9, 14))
91686	31848373	A total of 1,994 and 32,508 single nucleotide variants (SNVs) and DNVs were identified in 80 UVM and 67 SKCM patients, respectively, and were included in the COSMIC mutational signature analyses.	('DNV', 'Chemical', '-', (66, 69))	('UVM', 'Phenotype', 'HP:0007716', (93, 96))	('patients', 'Species', '9606', (109, 117))	('UVM', 'Disease', (93, 96))	('SNV', 'Chemical', '-', (56, 59))	('single nucleotide variants', 'Var', (28, 54))
91702	31848373	The MYC copy number gain was associated with UVM-specific survival (P = 0.028; Fig.	('MYC', 'Gene', (4, 7))	('copy number gain', 'Var', (8, 24))	('UVM-specific survival', 'Disease', (45, 66))	('MYC', 'Gene', '4609', (4, 7))	('UVM', 'Phenotype', 'HP:0007716', (45, 48))
91706	31848373	Notably, significantly more BAP1 mutations were observed in patients with high MYC copy number (P < 0.002).	('BAP1', 'Gene', '8314', (28, 32))	('MYC', 'Gene', (79, 82))	('more', 'PosReg', (23, 27))	('patients', 'Species', '9606', (60, 68))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('MYC', 'Gene', '4609', (79, 82))
91707	31848373	In multivariate cox proportional hazards model, hazard ratios were 2.27 (P = 0.201) and 5.45 (P = 0.001) for MYC copy number gain and BAP1 mutation, respectively.	('mutation', 'Var', (139, 147))	('BAP1', 'Gene', (134, 138))	('copy number', 'Var', (113, 124))	('gain', 'PosReg', (125, 129))	('MYC', 'Gene', '4609', (109, 112))	('BAP1', 'Gene', '8314', (134, 138))	('MYC', 'Gene', (109, 112))
91708	31848373	Harrell's C indices were 0.623 and 0.687 for for MYC copy number gain and BAP1 mutation, respectively.	('MYC', 'Gene', (49, 52))	('copy number gain', 'Var', (53, 69))	('BAP1', 'Gene', '8314', (74, 78))	('mutation', 'Var', (79, 87))	('MYC', 'Gene', '4609', (49, 52))	('BAP1', 'Gene', (74, 78))
91714	31848373	SNVs, small insertions/deletions, and copy number variations of the genome alter the function of oncogenes and tumor suppressor genes, and can cause cancer.	('SNV', 'Chemical', '-', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Disease', (149, 155))	('oncogenes', 'Protein', (97, 106))	('function', 'MPA', (85, 93))	('alter', 'Reg', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (111, 116))	('cause', 'Reg', (143, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('111', '127'))	('copy number variations', 'Var', (38, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('111', '127'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
91715	31848373	Intense research efforts regarding cancer genomes have identified several oncogenic pathways important in human cancers, and have led to improved therapeutic outcomes for tumors with EGFR, ALK, and BRAF mutations.	('human', 'Species', '9606', (106, 111))	('ALK', 'Gene', '238', (189, 192))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ALK', 'Gene', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('BRAF', 'Gene', '673', (198, 202))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('EGFR', 'Gene', (183, 187))	('BRAF', 'Gene', (198, 202))	('cancers', 'Disease', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('183', '187'))	('tumors', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('oncogenic pathways', 'Pathway', (74, 92))	('mutations', 'Var', (203, 212))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('EGFR', 'Gene', '1956', (183, 187))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('improved', 'PosReg', (137, 145))	('cancer', 'Disease', (35, 41))
91716	31848373	Cancer genome sequencing studies using UVM have identified frequent mutations in GNAQ/GNA11.	('GNAQ', 'Gene', (81, 85))	('UVM', 'Phenotype', 'HP:0007716', (39, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('GNA11', 'Gene', (86, 91))	('mutations', 'Var', (68, 77))	('GNA11', 'Gene', '2767', (86, 91))	('GNAQ', 'Gene', '2776', (81, 85))
91717	31848373	Mutant GNAQ/GNA11-induced activation of the MAPK and Hippo-YAP pathways has been reported in many basic and translational studies, and has suggested as essential for tumorigenesis of UVM.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('YAP', 'Gene', (59, 62))	('GNA11', 'Gene', '2767', (12, 17))	('GNA11', 'Gene', (12, 17))	('GNAQ', 'Gene', '2776', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MAPK', 'Pathway', (44, 48))	('tumor', 'Disease', (166, 171))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('UVM', 'Disease', (183, 186))	('activation', 'PosReg', (26, 36))	('GNAQ', 'Gene', (7, 11))	('Mutant', 'Var', (0, 6))	('YAP', 'Gene', '10413', (59, 62))	('UVM', 'Phenotype', 'HP:0007716', (183, 186))
91727	31848373	In MYC-driven cancers, MYC deregulation affects gene expression, DNA replication, or repair processes, leading to oncogenic proliferation.	('cancers', 'Disease', (14, 21))	('oncogenic proliferation', 'CPA', (114, 137))	('MYC', 'Gene', (3, 6))	('deregulation', 'Var', (27, 39))	('repair processes', 'CPA', (85, 101))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('affects', 'Reg', (40, 47))	('gene expression', 'biological_process', 'GO:0010467', ('48', '63'))	('DNA replication', 'CPA', (65, 80))	('MYC', 'Gene', '4609', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('MYC', 'Gene', '4609', (3, 6))	('MYC', 'Gene', (23, 26))	('gene expression', 'MPA', (48, 63))	('leading to', 'Reg', (103, 113))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('DNA replication', 'biological_process', 'GO:0006260', ('65', '80'))
91731	31848373	Importantly, MYC copy number gain was associated with aggressive pathological features and poor survival outcomes in UVM patients.	('UVM', 'Phenotype', 'HP:0007716', (117, 120))	('aggressive pathological features', 'CPA', (54, 86))	('UVM', 'Disease', (117, 120))	('MYC', 'Gene', '4609', (13, 16))	('copy number gain', 'Var', (17, 33))	('patients', 'Species', '9606', (121, 129))	('MYC', 'Gene', (13, 16))
91732	31848373	Because MYC deregulation is observed in multiple human cancers and associated with poor prognoses, there have been intense research efforts to develop treatments that target MYC.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('MYC', 'Gene', '4609', (174, 177))	('deregulation', 'Var', (12, 24))	('MYC', 'Gene', (8, 11))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('MYC', 'Gene', '4609', (8, 11))	('MYC', 'Gene', (174, 177))	('cancers', 'Disease', (55, 62))
91741	31848373	Considering the Harrell's C indices for MYC copy number gain and BAP1 mutation, we think that both factors affect survival outcomes of uveal melanoma patients independently.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('affect', 'Reg', (107, 113))	('BAP1', 'Gene', '8314', (65, 69))	('MYC', 'Gene', '4609', (40, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (135, 149))	('copy number', 'Var', (44, 55))	('gain', 'PosReg', (56, 60))	('uveal melanoma', 'Disease', (135, 149))	('BAP1', 'Gene', (65, 69))	('uveal melanoma', 'Phenotype', 'HP:0007716', (135, 149))	('patients', 'Species', '9606', (150, 158))	('MYC', 'Gene', (40, 43))	('mutation', 'Var', (70, 78))
91742	31848373	Interestingly, some cases showed BAP1 mutation in primary tumors, but not in metastases, while high 8q copy number was detected in these metastases.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('metastases', 'Disease', (77, 87))	('BAP1', 'Gene', '8314', (33, 37))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutation', 'Var', (38, 46))	('BAP1', 'Gene', (33, 37))	('metastases', 'Disease', (137, 147))
91743	31848373	Considering that MYC is located at the 8q24 locus, it is possible that the MYC copy number gain is associated with 8q gains in metastatic UVM.	('MYC', 'Gene', (17, 20))	('MYC', 'Gene', '4609', (75, 78))	('gains', 'PosReg', (118, 123))	('MYC', 'Gene', '4609', (17, 20))	('metastatic UVM', 'Disease', (127, 141))	('MYC', 'Gene', (75, 78))	('copy number', 'Var', (79, 90))	('gain', 'PosReg', (91, 95))	('UVM', 'Phenotype', 'HP:0007716', (138, 141))
91747	31848373	Based on the present study, we expect that WEE1 inhibition will ameliorate intrinsic chemoresistance and increase the survival of metastatic UVM patients.	('patients', 'Species', '9606', (145, 153))	('WEE1', 'Gene', '7465', (43, 47))	('increase', 'PosReg', (105, 113))	('ameliorate', 'PosReg', (64, 74))	('inhibition', 'Var', (48, 58))	('survival', 'CPA', (118, 126))	('WEE1', 'Gene', (43, 47))	('metastatic UVM', 'Disease', (130, 144))	('intrinsic chemoresistance', 'CPA', (75, 100))	('UVM', 'Phenotype', 'HP:0007716', (141, 144))
91751	31848373	Whole exome sequencing data (Mutation Packager Oncotated Calls; downloaded from https://gdac.broadinstitute.org) were used for identification of SNVs, DNVs, insertions, and deletions.	('insertions', 'Var', (157, 167))	('SNV', 'Chemical', '-', (145, 148))	('DNVs', 'Var', (151, 155))	('DNV', 'Chemical', '-', (151, 154))	('SNVs', 'Disease', (145, 149))	('deletions', 'Var', (173, 182))
91767	31848373	performed the cell viability tests using multiple cancer cells; Y.J.K., S.C.L.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Y.J.K.', 'Var', (64, 70))
91775	23078649	With regard to the effect of concentration on SBR a trend (P = 0.066) was found favouring the 600, 800 and 1000 muM groups over the 1200 muM group.	('muM', 'Gene', '56925', (137, 140))	('muM', 'Gene', (112, 115))	('muM', 'Gene', (137, 140))	('600', 'Var', (94, 97))	('muM', 'Gene', '56925', (112, 115))
91843	23418523	Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (223, 241))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (223, 241))	('N-RAS', 'Gene', (289, 294))	('phosphorylation', 'biological_process', 'GO:0016310', ('170', '185'))	('Akt', 'Gene', '207', (112, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('decrease', 'NegReg', (158, 166))	('downregulated', 'NegReg', (11, 24))	('mutations', 'Var', (295, 304))	('c-Met', 'Gene', '4233', (105, 110))	('Akt', 'Gene', (189, 192))	('C-RAF', 'Gene', '5894', (127, 132))	('EGFR', 'Gene', (91, 95))	('IGF-1R', 'Gene', '3480', (97, 103))	('IGF-1R', 'Gene', (97, 103))	('Erk1/2', 'Enzyme', (197, 203))	('B-RAF', 'Gene', '673', (279, 284))	('Akt', 'Gene', '207', (189, 192))	('Erk1', 'molecular_function', 'GO:0004707', ('197', '201'))	('N-RAS', 'Gene', '4893', (289, 294))	('B-RAF', 'Gene', '673', (117, 122))	('C-RAF', 'Gene', (127, 132))	('c-Met', 'Gene', (105, 110))	('expression', 'MPA', (29, 39))	('B-RAF', 'Gene', (279, 284))	('EGFR', 'Gene', '1956', (91, 95))	('Akt', 'Gene', (112, 115))	('B-RAF', 'Gene', (117, 122))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('phosphorylation', 'MPA', (170, 185))	('Ganetespib', 'Chemical', 'MESH:C533237', (0, 10))	('cutaneous melanoma', 'Disease', (223, 241))
91845	23418523	Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition.	('Ganetespib', 'Chemical', 'MESH:C533237', (13, 23))	('B-RAF', 'Gene', '673', (99, 104))	('B-RAF', 'Gene', (37, 42))	('B-RAF', 'Gene', (99, 104))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('mutated', 'Var', (43, 50))	('melanoma', 'Disease', (51, 59))	('B-RAF', 'Gene', '673', (37, 42))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
91851	23418523	Inhibition of HSP90 results in increased degradation of client proteins via the ubiquitin proteasome pathway.	('proteasome pathway', 'biological_process', 'GO:0043161', ('90', '108'))	('proteasome', 'molecular_function', 'GO:0004299', ('90', '100'))	('increased', 'PosReg', (31, 40))	('ubiquitin proteasome pathway', 'Pathway', (80, 108))	('degradation', 'biological_process', 'GO:0009056', ('41', '52'))	('HSP90', 'Gene', (14, 19))	('HSP90', 'Gene', '3320', (14, 19))	('Inhibition', 'Var', (0, 10))	('ubiquitin', 'molecular_function', 'GO:0031386', ('80', '89'))	('degradation of client proteins', 'MPA', (41, 71))	('proteasome', 'cellular_component', 'GO:0000502', ('90', '100'))
91854	23418523	HSP90 has recently been recognized as a potential therapeutic target for cancer, as accumulation of over-expressed and mutated client proteins has been shown to promote a shift to the active and super-chaperone complex form of HSP90 in cancer cells, conferring a greater sensitivity of malignant cells to the loss of HSP90 function.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('cancer', 'Disease', (236, 242))	('active', 'MPA', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('HSP90', 'Gene', (227, 232))	('promote', 'PosReg', (161, 168))	('HSP90', 'Gene', (317, 322))	('HSP90', 'Gene', '3320', (317, 322))	('HSP90', 'Gene', '3320', (227, 232))	('mutated', 'Var', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('accumulation', 'PosReg', (84, 96))	('chaperone complex', 'cellular_component', 'GO:0101031', ('201', '218'))	('shift', 'MPA', (171, 176))
91866	23418523	These alterations ultimately result in cell cycle arrest and apoptosis in melanoma cells.	('alterations', 'Var', (6, 17))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('apoptosis', 'CPA', (61, 70))	('result in', 'Reg', (29, 38))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('39', '56'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('cell cycle arrest', 'CPA', (39, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))
91868	23418523	Cell lines K028 and K029 harbor B-RAF V600E mutation while K033 and M23 carry N-RAS Q61R mutation.	('V600E', 'Var', (38, 43))	('Q61R', 'Mutation', 'rs11554290', (84, 88))	('B-RAF', 'Gene', (32, 37))	('N-RAS', 'Gene', (78, 83))	('N-RAS', 'Gene', '4893', (78, 83))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('B-RAF', 'Gene', '673', (32, 37))
91893	23418523	Cyclin B1 was increased in K008 cells and in M23 cells treated with 250 and 500 nM ganetespib while it was reduced in K029 and K033 cells and in K028 and M23 cells treated with 100 nM ganetespib.	('increased', 'PosReg', (14, 23))	('Cyclin B1', 'Gene', (0, 9))	('ganetespib', 'Var', (83, 93))	('reduced', 'NegReg', (107, 114))	('Cyclin', 'molecular_function', 'GO:0016538', ('0', '6'))	('Cyclin B1', 'Gene', '891', (0, 9))	('ganetespib', 'Chemical', 'MESH:C533237', (83, 93))	('ganetespib', 'Chemical', 'MESH:C533237', (184, 194))
91894	23418523	The expression of CDK1 was significantly reduced in K008, K028, M23 and K033 cells and to a lesser extent in K029 cells.	('reduced', 'NegReg', (41, 48))	('K033', 'Var', (72, 76))	('expression', 'MPA', (4, 14))	('CDK', 'molecular_function', 'GO:0004693', ('18', '21'))	('CDK1', 'Gene', '983', (18, 22))	('K028', 'Var', (58, 62))	('CDK1', 'Gene', (18, 22))
91900	23418523	As ganetespib significantly induced apoptosis in melanoma cells, we next investigated the response of antiapoptotic proteins to ganetespib.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('ganetespib', 'Chemical', 'MESH:C533237', (128, 138))	('apoptosis', 'CPA', (36, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('ganetespib', 'Chemical', 'MESH:C533237', (3, 13))	('induced', 'Reg', (28, 35))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('ganetespib', 'Var', (3, 13))
91901	23418523	Bcl-2 was decreased in K033 cells while it was increased in the rest of cell lines.	('decreased', 'NegReg', (10, 19))	('Bcl-2', 'molecular_function', 'GO:0015283', ('0', '5'))	('K033', 'Var', (23, 27))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))
91903	23418523	Mcl-1 was decreased in K008 cells, increased in M23 and K033 cells, and unaltered in K028 and K029 cells.	('decreased', 'NegReg', (10, 19))	('increased', 'PosReg', (35, 44))	('Mcl-1', 'Gene', (0, 5))	('Mcl-1', 'Gene', '4170', (0, 5))	('K008', 'Var', (23, 27))
91904	23418523	Oncogenic B-RAF and N-RAS mutations have been detected in approximately 60% and 20% of cutaneous melanoma respectively.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('cutaneous melanoma', 'Disease', (87, 105))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (87, 105))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (87, 105))	('B-RAF', 'Gene', '673', (10, 15))	('detected', 'Reg', (46, 54))	('mutations', 'Var', (26, 35))	('N-RAS', 'Gene', (20, 25))	('B-RAF', 'Gene', (10, 15))	('N-RAS', 'Gene', '4893', (20, 25))
91905	23418523	While B-RAF inhibition is initially effective for melanoma carrying a B-RAF mutation, resistance to B-RAF inhibition develops within months after start of treatment.	('B-RAF', 'Gene', '673', (6, 11))	('B-RAF', 'Gene', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('B-RAF', 'Gene', (6, 11))	('B-RAF', 'Gene', '673', (100, 105))	('B-RAF', 'Gene', '673', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('men', 'Species', '9606', (160, 163))	('B-RAF', 'Gene', (100, 105))	('mutation', 'Var', (76, 84))
91908	23418523	Treatment with 100 and 250 nM ganetespib resulted in marked downregulation of wild type and mutant B-RAF and C-RAF expression in all 5 melanoma cells lines tested (Figure 5).	('B-RAF', 'Gene', '673', (99, 104))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('downregulation', 'NegReg', (60, 74))	('melanoma', 'Disease', (135, 143))	('ganetespib', 'Chemical', 'MESH:C533237', (30, 40))	('C-RAF', 'Gene', (109, 114))	('B-RAF', 'Gene', (99, 104))	('expression', 'MPA', (115, 125))	('mutant', 'Var', (92, 98))	('men', 'Species', '9606', (5, 8))	('C-RAF', 'Gene', '5894', (109, 114))
91912	23418523	GDC-0879 is a B-RAF mutant specific inhibitor and has been shown to inhibit the growth of melanoma cells harboring B-RAF mutations.	('melanoma', 'Disease', (90, 98))	('mutations', 'Var', (121, 130))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('growth', 'CPA', (80, 86))	('inhibit', 'NegReg', (68, 75))	('B-RAF', 'Gene', '673', (14, 19))	('B-RAF', 'Gene', (14, 19))	('B-RAF', 'Gene', '673', (115, 120))	('B-RAF', 'Gene', (115, 120))	('GDC-0879', 'Chemical', 'MESH:C540167', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
91916	23418523	Resistance to GDC-0879 was associated with increased expression of B-RAF, C-RAF, and Erk1/2 activity (Figure 6C) in agreement with previous findings.	('B-RAF', 'Gene', '673', (67, 72))	('C-RAF', 'Gene', (74, 79))	('GDC-0879', 'Chemical', 'MESH:C540167', (14, 22))	('B-RAF', 'Gene', (67, 72))	('men', 'Species', '9606', (121, 124))	('GDC-0879', 'Var', (14, 22))	('C-RAF', 'Gene', '5894', (74, 79))	('Erk1', 'molecular_function', 'GO:0004707', ('85', '89'))	('increased', 'PosReg', (43, 52))	('expression', 'MPA', (53, 63))	('activity', 'MPA', (92, 100))	('Erk1/2', 'Protein', (85, 91))
91918	23418523	The HSP90 inhibitor ganetespib, with IC50 values <100 nM, exhibited profound antiproliferative activity against a panel of cutaneous melanoma cells including those that carry B-RAF and N-RAS mutations, as well as those with acquired resistance to B-RAF inhibition.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (123, 141))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 141))	('B-RAF', 'Gene', '673', (175, 180))	('HSP90', 'Gene', (4, 9))	('HSP90', 'Gene', '3320', (4, 9))	('B-RAF', 'Gene', '673', (247, 252))	('mutations', 'Var', (191, 200))	('ganetespib', 'Chemical', 'MESH:C533237', (20, 30))	('antiproliferative activity', 'CPA', (77, 103))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('B-RAF', 'Gene', (175, 180))	('N-RAS', 'Gene', (185, 190))	('B-RAF', 'Gene', (247, 252))	('cutaneous melanoma', 'Disease', (123, 141))	('N-RAS', 'Gene', '4893', (185, 190))
91922	23418523	Inhibition of these pathways may contribute to ganetespib induced growth inhibition and apoptosis as inhibition of these pathways, alone or in combination, reduced viability of K008 and K028 cells (data not shown) and induced apoptosis in melanoma cells.	('apoptosis', 'CPA', (88, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('88', '97'))	('inhibition', 'Var', (101, 111))	('viability', 'CPA', (164, 173))	('induced', 'Reg', (218, 225))	('apoptosis', 'CPA', (226, 235))	('ganetespib', 'Chemical', 'MESH:C533237', (47, 57))	('melanoma', 'Disease', 'MESH:D008545', (239, 247))	('reduced', 'NegReg', (156, 163))	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('melanoma', 'Disease', (239, 247))	('apoptosis', 'biological_process', 'GO:0097194', ('226', '235'))	('apoptosis', 'biological_process', 'GO:0006915', ('226', '235'))	('apoptosis', 'biological_process', 'GO:0097194', ('88', '97'))	('growth inhibition', 'CPA', (66, 83))
91926	23418523	In agreement with being client proteins of HSP90, the expression of these receptors was decreased by ganetespib.	('expression', 'MPA', (54, 64))	('HSP90', 'Gene', (43, 48))	('HSP90', 'Gene', '3320', (43, 48))	('men', 'Species', '9606', (8, 11))	('ganetespib', 'Var', (101, 111))	('decreased', 'NegReg', (88, 97))	('ganetespib', 'Chemical', 'MESH:C533237', (101, 111))
91929	23418523	Small molecule inhibitors of c-Met, EGFR or IGF-1R reduced viability of K008 and K028 cells that express all these receptors (unpublished data), suggesting that these receptor tyrosine kinases may play a role in survival and growth of these cell lines and their inhibition may be relevant to the anti-melanoma activity of ganetespib.	('ganetespib', 'Chemical', 'MESH:C533237', (322, 332))	('viability', 'CPA', (59, 68))	('reduced', 'NegReg', (51, 58))	('EGFR', 'molecular_function', 'GO:0005006', ('36', '40'))	('play', 'Reg', (197, 201))	('c-Met', 'Gene', (29, 34))	('IGF-1R', 'Gene', '3480', (44, 50))	('EGFR', 'Gene', '1956', (36, 40))	('melanoma', 'Disease', 'MESH:D008545', (301, 309))	('melanoma', 'Phenotype', 'HP:0002861', (301, 309))	('melanoma', 'Disease', (301, 309))	('IGF-1R', 'Gene', (44, 50))	('c-Met', 'Gene', '4233', (29, 34))	('EGFR', 'Gene', (36, 40))	('inhibitors', 'Var', (15, 25))
91950	23418523	It is widely believed that inhibition of Hsp90 with small molecule inhibitors can disrupt the physical binding of survivin to Hsp90, leading to survivin downregulation.	('Hsp90', 'Gene', '3320', (126, 131))	('survivin', 'Protein', (114, 122))	('Hsp90', 'Gene', (41, 46))	('physical binding', 'Interaction', (94, 110))	('Hsp90', 'Gene', '3320', (41, 46))	('binding', 'molecular_function', 'GO:0005488', ('103', '110'))	('inhibition', 'Var', (27, 37))	('downregulation', 'NegReg', (153, 167))	('disrupt', 'NegReg', (82, 89))	('survivin', 'Protein', (144, 152))	('Hsp90', 'Gene', (126, 131))
91952	23418523	Although the molecular events for this increase is not clear, it has been reported that survivin expression was induced by HSP90 inhibitors in some cancer cell lines via cell context dependent transcriptional, translational and/or post-translational (such as 26S proteasome-mediated protein degradation) mechanisms.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('protein degradation', 'biological_process', 'GO:0030163', ('283', '302'))	('26S proteasome', 'cellular_component', 'GO:0000504', ('259', '273'))	('HSP90', 'Gene', (123, 128))	('inhibitors', 'Var', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('26S proteasome', 'cellular_component', 'GO:0005837', ('259', '273'))	('protein', 'cellular_component', 'GO:0003675', ('283', '290'))	('HSP90', 'Gene', '3320', (123, 128))	('proteasome', 'molecular_function', 'GO:0004299', ('263', '273'))	('26S proteasome-mediated protein degradation', 'MPA', (259, 302))	('survivin', 'Gene', (88, 96))	('26S proteasome', 'cellular_component', 'GO:0000502', ('259', '273'))	('induced', 'PosReg', (112, 119))	('expression', 'MPA', (97, 107))
91955	23418523	The proapoptotic BIM proteins have also been recently shown to be induced by XL888 and play a role in XL888 induced apoptosis in melanoma cells.	('induced', 'PosReg', (66, 73))	('XL888', 'Chemical', 'MESH:C559121', (77, 82))	('apoptosis', 'CPA', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('XL888', 'Chemical', 'MESH:C559121', (102, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('BIM proteins', 'Protein', (17, 29))	('XL888', 'Gene', (77, 82))	('XL888', 'Var', (102, 107))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))
91956	23418523	Ganetespib profoundly inhibited the growth of melanoma cells harboring wild type and mutated B-RAF or N-RAS.	('inhibited', 'NegReg', (22, 31))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('N-RAS', 'Gene', (102, 107))	('B-RAF', 'Gene', '673', (93, 98))	('growth', 'CPA', (36, 42))	('mutated', 'Var', (85, 92))	('N-RAS', 'Gene', '4893', (102, 107))	('B-RAF', 'Gene', (93, 98))	('Ganetespib', 'Chemical', 'MESH:C533237', (0, 10))
91957	23418523	B-RAF and N-RAS mutations play a key role in the development of human melanomas.	('human', 'Species', '9606', (64, 69))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('B-RAF', 'Gene', '673', (0, 5))	('B-RAF', 'Gene', (0, 5))	('mutations', 'Var', (16, 25))	('men', 'Species', '9606', (56, 59))	('melanomas', 'Disease', (70, 79))	('N-RAS', 'Gene', (10, 15))	('N-RAS', 'Gene', '4893', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))
91958	23418523	B-RAF mutations have been found in approximately 50% of human melanomas with V600E being the most common mutation.	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('B-RAF', 'Gene', '673', (0, 5))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('B-RAF', 'Gene', (0, 5))	('melanomas', 'Disease', (62, 71))	('human', 'Species', '9606', (56, 61))	('found', 'Reg', (26, 31))	('V600E', 'Var', (77, 82))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
91959	23418523	B-RAF V600E stimulates constitutive activation of MEK/Erk/12 pathway, resulting in growth factor independent proliferation.	('growth factor independent proliferation', 'CPA', (83, 122))	('Erk', 'molecular_function', 'GO:0004707', ('54', '57'))	('B-RAF', 'Gene', '673', (0, 5))	('B-RAF', 'Gene', (0, 5))	('activation', 'PosReg', (36, 46))	('Erk', 'Gene', (54, 57))	('Erk', 'Gene', '5594', (54, 57))	('V600E', 'Mutation', 'rs113488022', (6, 11))	('MEK', 'Gene', (50, 53))	('MEK', 'Gene', '5609', (50, 53))	('V600E', 'Var', (6, 11))
91960	23418523	In agreement with being clients of HSP90, the expression of both wild-type and mutant B-RAF was decreased by ganetespib in all melanoma cell lines including those cells with acquired resistance to B-RAF inhibition.	('decreased', 'NegReg', (96, 105))	('men', 'Species', '9606', (8, 11))	('mutant', 'Var', (79, 85))	('B-RAF', 'Gene', (197, 202))	('ganetespib', 'Chemical', 'MESH:C533237', (109, 119))	('HSP90', 'Gene', (35, 40))	('B-RAF', 'Gene', '673', (86, 91))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('B-RAF', 'Gene', (86, 91))	('HSP90', 'Gene', '3320', (35, 40))	('expression', 'MPA', (46, 56))	('B-RAF', 'Gene', '673', (197, 202))
91963	23418523	Interestingly, although ganetespib exerted antiproliferative activity towards melanoma cells harboring mutated N-RAS, N-RAS was induced by ganetespib in most of the cell lines tested.	('mutated', 'Var', (103, 110))	('N-RAS', 'Gene', '4893', (111, 116))	('N-RAS', 'Gene', (118, 123))	('ganetespib', 'Chemical', 'MESH:C533237', (24, 34))	('N-RAS', 'Gene', '4893', (118, 123))	('antiproliferative activity', 'MPA', (43, 69))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('ganetespib', 'Chemical', 'MESH:C533237', (139, 149))	('N-RAS', 'Gene', (111, 116))
91965	23418523	In melanoma cells carrying the B-RAF mutations, activation through B-RAF and subsequent downstream signaling is the major driving force for tumor progression, making B-RAF an attractive target for anti-melanoma therapy.	('B-RAF', 'Gene', '673', (67, 72))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('B-RAF', 'Gene', (67, 72))	('signaling', 'biological_process', 'GO:0023052', ('99', '108'))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('B-RAF', 'Gene', '673', (31, 36))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('B-RAF', 'Gene', '673', (166, 171))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('activation', 'PosReg', (48, 58))	('melanoma', 'Disease', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('melanoma', 'Disease', (3, 11))	('B-RAF', 'Gene', (31, 36))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('B-RAF', 'Gene', (166, 171))	('tumor', 'Disease', (140, 145))
91966	23418523	Clinical data has shown that treatment with B-RAF inhibitor vemurafenib resulted in tumor shrinkage and median progression-free survival for greater than six months in patients with B-RAF V600E mutated melanoma.	('B-RAF', 'Gene', '673', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('V600E mutated', 'Var', (188, 201))	('B-RAF', 'Gene', '673', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('progression-free survival', 'CPA', (111, 136))	('B-RAF', 'Gene', (44, 49))	('tumor', 'Disease', (84, 89))	('shrinkage', 'NegReg', (90, 99))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('B-RAF', 'Gene', (182, 187))	('melanoma', 'Disease', (202, 210))	('patients', 'Species', '9606', (168, 176))	('V600E', 'Mutation', 'rs113488022', (188, 193))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('vemurafenib', 'Chemical', 'MESH:D000077484', (60, 71))	('men', 'Species', '9606', (34, 37))
92013	33976978	Excessive ROS can lead to double-stranded DNA breaks and genotoxicity, eventually leading to genomic mutations and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ROS', 'Var', (10, 13))	('genotoxicity', 'Disease', (57, 69))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('tumor', 'Disease', (115, 120))	('double-stranded DNA breaks', 'MPA', (26, 52))	('leading to', 'Reg', (82, 92))	('genotoxicity', 'Disease', 'None', (57, 69))	('OS', 'Phenotype', 'HP:0025464', (11, 13))	('lead to', 'Reg', (18, 25))	('genomic mutations', 'CPA', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
92062	33976978	Interestingly, these genes were found to have several cancer-related roles: CXCR3 can interact with LRP1 leading to ligand-induced conformational changes on the cell membrane, which results in increased tumor cell migration; ISG15 is highly expressed in hepatocellular carcinoma tissues and interacts with XIAP to drive proliferation and metastasis; CCR5 is positively associated with the size of the primary tumor, whereas its overexpression significantly promotes leukocyte accumulation, angiogenesis, and tumor progression in oral squamous cell carcinoma; NDUFA9 is related to colitis-associated cancer and may be connected with the activation of the LKB1/AMPK pathway in colorectal epithelial cells; PIK3R2 is closely related to liver cancer prognosis, since its overexpression significantly increases the probability of liver cancer metastasis and angiogenesis; and SLPI provides a local immune response to human papillomavirus infection in the cervical mucosa, while its modulation significantly inhibits the expression of apoptosis-associated genes, promoting the proliferation and metastasis of gastric cancer.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (254, 278))	('CXCR3', 'Gene', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (548, 557))	('cancer', 'Disease', (1111, 1117))	('colitis-associated cancer', 'Disease', 'MESH:D009369', (580, 605))	('angiogenesis', 'biological_process', 'GO:0001525', ('490', '502'))	('AMPK', 'molecular_function', 'GO:0050405', ('659', '663'))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (529, 557))	('liver cancer metastasis', 'Disease', 'MESH:D006528', (825, 848))	('cell membrane', 'cellular_component', 'GO:0005886', ('161', '174'))	('cancer', 'Phenotype', 'HP:0002664', (831, 837))	('LRP1', 'Gene', '4035', (100, 104))	('apoptosis-associated genes', 'Gene', (1029, 1055))	('liver cancer metastasis', 'Disease', (825, 848))	('tumor', 'Disease', (409, 414))	('tumor', 'Phenotype', 'HP:0002664', (508, 513))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('AMPK', 'Gene', '5562', (659, 663))	('AMPK', 'molecular_function', 'GO:0047322', ('659', '663'))	('gastric cancer', 'Disease', 'MESH:D013274', (1103, 1117))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('liver cancer', 'Disease', 'MESH:D006528', (733, 745))	('cancer', 'Disease', 'MESH:D009369', (599, 605))	('apoptosis', 'biological_process', 'GO:0097194', ('1029', '1038'))	('CXCR3', 'Gene', '2833', (76, 81))	('SLPI', 'Gene', '6590', (871, 875))	('proliferation', 'CPA', (1071, 1084))	('apoptosis', 'biological_process', 'GO:0006915', ('1029', '1038'))	('CCR', 'molecular_function', 'GO:0043880', ('350', '353'))	('gastric cancer', 'Phenotype', 'HP:0012126', (1103, 1117))	('expression', 'MPA', (1015, 1025))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (508, 513))	('tumor', 'Disease', 'MESH:D009369', (508, 513))	('cancer', 'Disease', 'MESH:D009369', (739, 745))	('LRP1', 'Gene', (100, 104))	('NDUFA9', 'Gene', (559, 565))	('colitis', 'Phenotype', 'HP:0002583', (580, 587))	('PIK3R2', 'Gene', '5296', (704, 710))	('CCR5', 'Gene', '1234', (350, 354))	('tumor', 'Disease', (203, 208))	('angiogenesis', 'CPA', (853, 865))	('cancer', 'Disease', 'MESH:D009369', (831, 837))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (739, 745))	('increases', 'PosReg', (796, 805))	('SLPI', 'Gene', (871, 875))	('overexpression', 'PosReg', (767, 781))	('CCR5', 'Gene', (350, 354))	('hepatocellular carcinoma', 'Disease', (254, 278))	('XIAP', 'Gene', (306, 310))	('modulation', 'Var', (977, 987))	('promoting', 'PosReg', (1057, 1066))	('cancer', 'Phenotype', 'HP:0002664', (1111, 1117))	('liver cancer', 'Phenotype', 'HP:0002896', (733, 745))	('liver cancer', 'Disease', (733, 745))	('immune response', 'biological_process', 'GO:0006955', ('893', '908'))	('PIK3R2', 'Gene', (704, 710))	('cancer', 'Disease', (54, 60))	('AMPK', 'Gene', (659, 663))	('liver cancer', 'Disease', 'MESH:D006528', (825, 837))	('inhibits', 'NegReg', (1002, 1010))	('papillomavirus infection', 'Disease', 'MESH:D030361', (918, 942))	('cancer', 'Disease', (599, 605))	('cell migration', 'biological_process', 'GO:0016477', ('209', '223'))	('XIAP', 'Gene', '331', (306, 310))	('gastric cancer', 'Disease', (1103, 1117))	('ISG15', 'Gene', (225, 230))	('LKB1', 'Gene', '6794', (654, 658))	('angiogenesis', 'biological_process', 'GO:0001525', ('853', '865'))	('ligand', 'molecular_function', 'GO:0005488', ('116', '122'))	('cancer', 'Phenotype', 'HP:0002664', (739, 745))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (918, 942))	('LKB1', 'Gene', (654, 658))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('NDUFA9', 'Gene', '4704', (559, 565))	('human', 'Species', '9606', (912, 917))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('ISG15', 'Gene', '9636', (225, 230))	('papillomavirus infection', 'Disease', (918, 942))	('cancer', 'Disease', (831, 837))	('oral squamous cell carcinoma', 'Disease', (529, 557))	('colitis-associated cancer', 'Disease', (580, 605))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (254, 278))	('cancer', 'Disease', 'MESH:D009369', (1111, 1117))	('AMPK', 'molecular_function', 'GO:0004691', ('659', '663'))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (534, 557))	('cancer', 'Phenotype', 'HP:0002664', (599, 605))	('liver cancer', 'Phenotype', 'HP:0002896', (825, 837))	('metastasis', 'CPA', (1089, 1099))
92076	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))
92078	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))
92079	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))	('cancer', 'Disease', (394, 400))	('cancers', 'Disease', (394, 401))	('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))
92084	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))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
92090	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))
92091	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))	('PGC', 'Gene', (0, 3))	('upregulated', 'PosReg', (19, 30))	('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))
92095	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))
92097	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))	('cancers', 'Disease', (375, 382))	('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))	('cancer', 'Disease', (375, 381))
92117	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))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('CCLE', 'Chemical', '-', (122, 126))	('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))
92118	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))
92123	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))
92136	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))
92148	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))
92159	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))
92183	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))
92186	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))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA4', 'Gene', (6, 10))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
92187	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))
92188	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))
92189	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))
92192	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))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('CCLE', 'Chemical', '-', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('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))
92193	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))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('affect', 'Reg', (338, 344))	('associated', 'Reg', (211, 221))	('cancer', 'Disease', (245, 251))	('activation', 'PosReg', (231, 241))	('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))	('PGC', 'Gene', (328, 331))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
92212	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))
92214	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))
92235	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))
92236	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))
92237	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))
92238	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))
92240	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))
92241	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))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (175, 178))
92243	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))
92285	20737564	Specified rare histologies (8722-8741,8745-8790) were grouped with malignant melanomas of unspecified histology (MM, NOS): 8720; 99.97% of cases were confirmed microscopically.	('melanomas', 'Disease', (77, 86))	('unspecified', 'Species', '32644', (90, 101))	('malignant melanomas', 'Phenotype', 'HP:0002861', (67, 86))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('8722-8741,8745-8790', 'Var', (28, 47))	('malignant melanoma', 'Phenotype', 'HP:0002861', (67, 85))	('malignant melanoma', 'Disease', (67, 85))	('malignant melanoma', 'Disease', 'MESH:D008545', (67, 85))
92303	20737564	These findings held among women as well: Low-SES NHW women had a RR of 1.63 (95% CI 1.46, 1.83) for thicker tumors compared to High-SES NHW women; the RR increased to 1.98 (95% CI: 1.55, 2.51) for Low-SES versus High-SES Hispanic women.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('women', 'Species', '9606', (53, 58))	('women', 'Species', '9606', (26, 31))	('women', 'Species', '9606', (140, 145))	('women', 'Species', '9606', (230, 235))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('Low-SES', 'Var', (41, 48))
92307	20737564	Conversely, only 8% of thicker tumors occurred in Low-SES NHWs, while 30% and 26% of thicker tumors occurred in Low-SES Hispanic men and women, respectively (P <.0001 for both sexes).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('Low-SES', 'Var', (50, 57))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('men', 'Species', '9606', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('men', 'Species', '9606', (129, 132))	('women', 'Species', '9606', (137, 142))	('tumors', 'Disease', (93, 99))
92310	20737564	High-SES NHW males had more lower limb/hip melanomas than low SES-NHW males (10% vs. 7%, P <.0001: Table 4).	('hip melanomas', 'Disease', (39, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('High-SES NHW', 'Var', (0, 12))	('hip melanomas', 'Disease', 'MESH:D008545', (39, 52))	('lower limb', 'Phenotype', 'HP:0006385', (28, 38))
92311	20737564	Conversely, High-SES Hispanic males had significantly lower proportions of these melanomas than Low-SES Hispanic males (19% vs. 27%, P for trend= .0002).	('High-SES', 'Var', (12, 20))	('melanomas', 'Disease', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('lower', 'NegReg', (54, 59))
92312	20737564	While the percent of melanomas on the trunk was stable across SES categories for NHW males, it was significantly higher among High-SES versus Low-SES Hispanic males (34% versus 23%, P for trend=.0003).	('higher', 'PosReg', (113, 119))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('High-SES', 'Var', (126, 134))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('trunk', 'cellular_component', 'GO:0043198', ('38', '43'))
92326	20737564	The association between lower SES and thicker melanoma was also stronger among Hispanics, to the extent that melanomas in Low-SES Hispanics were more than twice as likely to be >2mm thick than those in High-SES Hispanics.	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanomas', 'Disease', (109, 118))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('melanomas', 'Disease', 'MESH:D008545', (109, 118))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('Low-SES', 'Var', (122, 129))
92363	30675668	In patients with melanoma harboring KIT mutation in exon 11 or 13, KIT inhibitors can be a treatment option; however, none of them have been approved in Japan.	('KIT', 'molecular_function', 'GO:0005020', ('67', '70'))	('mutation in', 'Var', (40, 51))	('KIT', 'Gene', (36, 39))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('KIT', 'molecular_function', 'GO:0005020', ('36', '39'))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))
92372	30675668	Systemic therapies for advanced melanoma have been dramatically revolutionized by the development of targeted therapies, such as BRAF and MEK inhibitors, and immunotherapies, such as anti-PD-1 antibodies alone or in combination with anti-CTLA-4 antibody.	('antibody', 'cellular_component', 'GO:0042571', ('245', '253'))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('antibody', 'cellular_component', 'GO:0019815', ('245', '253'))	('melanoma', 'Disease', (32, 40))	('antibody', 'cellular_component', 'GO:0019814', ('245', '253'))	('anti-PD-1', 'Var', (183, 192))	('MEK', 'Gene', (138, 141))	('antibody', 'molecular_function', 'GO:0003823', ('245', '253'))
92390	30675668	KIT mutations were found in approximately 15% of acral and mucosal melanomas, and BRAF or NRAS mutation was found in approximately 10-15% of acral melanoma, but was less frequent in mucosal melanoma .	('acral melanoma', 'Disease', (141, 155))	('NRAS', 'Gene', (90, 94))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('found', 'Reg', (19, 24))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (182, 198))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('mucosal melanomas', 'Disease', (59, 76))	('melanomas', 'Phenotype', 'HP:0002861', (67, 76))	('BRAF', 'Gene', (82, 86))	('acral melanoma', 'Disease', 'MESH:D008545', (141, 155))	('mucosal melanoma', 'Disease', 'MESH:D008545', (59, 75))	('mucosal melanomas', 'Disease', 'MESH:D008545', (59, 76))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('acral melanoma', 'Phenotype', 'HP:0012060', (141, 155))	('mucosal melanoma', 'Disease', (182, 198))
92391	30675668	Acral and mucosal subtypes of melanoma are predominant in the Japanese population, and the overall detection rates of BRAF, NRAS, and KIT mutations are approximately 30%, 12%, and 13%, respectively.	('BRAF', 'Gene', (118, 122))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('NRAS', 'Gene', (124, 128))	('KIT', 'Gene', (134, 137))	('KIT', 'molecular_function', 'GO:0005020', ('134', '137'))	('mutations', 'Var', (138, 147))
92392	30675668	Since subungual melanoma specimens obtained from patients undergoing digital amputation are unlikely to have been included in the aforementioned studies due to the decalcification procedures in the bone, the actual detection rate of BRAF mutations in Japanese patients with melanoma may be lower than that reported in those studies.	('mutations', 'Var', (238, 247))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Disease', (274, 282))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('BRAF', 'Gene', (233, 237))
92394	30675668	A KIT inhibitor, imatinib, demonstrated its clinical efficacy in phase II studies involving patients with KIT mutations, although it was not effective in another clinical trials that did not include KIT mutation or amplification in the eligibility criteria.	('mutations', 'Var', (110, 119))	('KIT', 'molecular_function', 'GO:0005020', ('106', '109'))	('KIT', 'molecular_function', 'GO:0005020', ('199', '202'))	('KIT', 'molecular_function', 'GO:0005020', ('2', '5'))	('imatinib', 'Chemical', 'MESH:D000068877', (17, 25))	('KIT', 'Gene', (106, 109))
92395	30675668	In another phase II study of 43 patients, ten (23%) patients responded to imatinib, of these, nine had KIT gene mutations (exon 11 in six and exon 13 in three patients) and the other one had KIT gene amplification.	('exon 13', 'Var', (142, 149))	('KIT gene', 'Gene', (103, 111))	('exon 11', 'Var', (123, 130))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('imatinib', 'Chemical', 'MESH:D000068877', (74, 82))	('KIT', 'molecular_function', 'GO:0005020', ('103', '106'))	('responded to imatinib', 'MPA', (61, 82))
92396	30675668	In a phase II study in which seven (29%) of 24 patients responded to imatinib, seven of 13 patients with KIT mutations responded, whereas none of 11 patients with KIT amplification responded.	('responded to imatinib', 'MPA', (56, 77))	('KIT', 'molecular_function', 'GO:0005020', ('105', '108'))	('mutations', 'Var', (109, 118))	('KIT', 'molecular_function', 'GO:0005020', ('163', '166'))	('imatinib', 'Chemical', 'MESH:D000068877', (69, 77))
92397	30675668	At present, imatinib is likely most effective in patients with melanoma harboring KIT mutations (exon 11 or 13); however, the response rate is not that high, and a durable response seems not to be expected.	('mutations', 'Var', (86, 95))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('imatinib', 'Chemical', 'MESH:D000068877', (12, 20))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('KIT', 'Gene', (82, 85))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
92410	30675668	NRAS mutation is found in approximately 15% of acral melanoma, but it is rarely seen in mucosal melanoma .	('mucosal melanoma', 'Disease', 'MESH:D008545', (88, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('acral melanoma', 'Phenotype', 'HP:0012060', (47, 61))	('acral melanoma', 'Disease', (47, 61))	('acral melanoma', 'Disease', 'MESH:D008545', (47, 61))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (17, 22))	('mucosal melanoma', 'Disease', (88, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('mutation', 'Var', (5, 13))
92411	30675668	In patients with NRAS-mutant melanoma, a phase III randomized controlled trial assigned either MEK inhibitor, binimetinib, or dacarbazine (DTIC) at a ratio of 2:1 (NEMO).	('MEK', 'Enzyme', (95, 98))	('NRAS-mutant', 'Var', (17, 28))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('DTIC', 'Chemical', 'MESH:D003606', (139, 143))	('dacarbazine', 'Chemical', 'MESH:D003606', (126, 137))	('binimetinib', 'Chemical', 'MESH:C581313', (110, 121))
92418	30675668	Melanomas occurring in sun-exposed skin tend to have higher numbers of mutations, whereas those occurring in sun-protected areas, such as mucosal or acral melanomas, have significantly lower total numbers of single-nucleotide variants .	('melanomas', 'Phenotype', 'HP:0002861', (155, 164))	('acral melanoma', 'Phenotype', 'HP:0012060', (149, 163))	('acral melanomas', 'Disease', (149, 164))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('acral melanomas', 'Phenotype', 'HP:0012060', (149, 164))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('Melanomas', 'Disease', (0, 9))	('mutations', 'Var', (71, 80))	('acral melanomas', 'Disease', 'MESH:D008545', (149, 164))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))
92420	30675668	A multi-institutional retrospective study evaluated the clinical efficacy of anti-PD-1 antibody in 25 and 35 patients with acral and mucosal melanoma, respectively.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mucosal melanoma', 'Disease', 'MESH:D008545', (133, 149))	('antibody', 'cellular_component', 'GO:0019814', ('87', '95'))	('antibody', 'cellular_component', 'GO:0019815', ('87', '95'))	('acral', 'Disease', (123, 128))	('antibody', 'molecular_function', 'GO:0003823', ('87', '95'))	('mucosal melanoma', 'Disease', (133, 149))	('antibody', 'cellular_component', 'GO:0042571', ('87', '95'))	('anti-PD-1', 'Var', (77, 86))
92440	30675668	The EORTC18071 trial, a randomized phase III trial of adjuvant therapy with ipilimumab administered at the dose of 10 mg/kg in patients with postoperative stage III cutaneous melanoma, showed a significantly longer OS in the ipilimumab arm than in the placebo arm.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (165, 183))	('ipilimumab', 'Chemical', 'MESH:D000074324', (76, 86))	('ipilimumab', 'Var', (225, 235))	('ipilimumab', 'Chemical', 'MESH:D000074324', (225, 235))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('longer', 'PosReg', (208, 214))	('III cutaneous melanoma', 'Disease', (161, 183))	('III cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 183))
92463	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'))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('SF3B1', 'Gene', (5, 10))
92464	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))
92465	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))
92467	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))	('cutaneous melanoma', 'Disease', (13, 31))	('R625', 'Var', (65, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (13, 31))
92468	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))
92469	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))
92471	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))
92472	24709888	In uveal melanoma, recurrent mutations at codon 625 of SF3B1 have been identified .	('SF3B1', 'Gene', '23451', (55, 60))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('mutations at codon 625', 'Var', (29, 51))	('SF3B1', 'Gene', (55, 60))	('identified', 'Reg', (71, 81))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', (3, 17))
92474	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))
92475	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))	('mutation', 'Var', (27, 35))	('MDS', 'Disease', (109, 112))	('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))
92476	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))	('R625 mutations', 'Var', (39, 53))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('SF3B1', 'Gene', (33, 38))
92478	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))
92480	24709888	The whole-exome sequencing of 295 melanoma samples identified 5 with mutations in SF3B1 R625 (Table 2).	('SF3B1', 'Gene', (82, 87))	('mutations', 'Var', (69, 78))	('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))
92481	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', 'MESH:C536494', (54, 68))	('uveal melanoma', 'Disease', (54, 68))	('cutaneous melanoma', 'Disease', (98, 116))	('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))
92482	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))
92484	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))
92486	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))
92488	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))
92491	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))
92492	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))
92493	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))
92496	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))
92497	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))
92498	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))
92499	24709888	Different cancers also have different predominate mutations in SF3B1.	('mutations', 'Var', (50, 59))	('SF3B1', 'Gene', (63, 68))	('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))
92500	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))	('hematological', 'Disease', (3, 16))	('R625', 'Var', (112, 116))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (29, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('codon K700', 'Var', (48, 58))
92503	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))
92504	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))
92505	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))
92506	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))
92507	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))	('uveal melanomas', 'Disease', (154, 169))	('mutations', 'Var', (70, 79))	('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))
92509	32733040	Escape from nonsense-mediated decay associates with anti-tumor immunogenicity Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Frameshift insertion/deletions', 'Var', (78, 108))	('nonsense-mediated decay', 'MPA', (12, 35))	('tumor', 'Disease', (57, 62))	('Escape', 'Var', (0, 6))
92510	32733040	Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('degradation', 'biological_process', 'GO:0009056', ('125', '136'))	('degradation', 'MPA', (125, 136))	('fs-indels', 'Var', (108, 117))	('escape', 'NegReg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('elicit', 'Reg', (141, 147))
92511	32733040	Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (Pmeta = 0.0039).	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('mutations', 'Var', (53, 62))	('NMD-escape', 'Gene', (42, 52))	('CPI', 'Chemical', '-', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))
92512	32733040	NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting.	('TMB', 'Chemical', '-', (90, 93))	('mutations', 'Var', (11, 20))	('NMD-escape', 'Gene', (0, 10))
92513	32733040	Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('mutation', 'Var', (77, 85))	('NMD-escape', 'Gene', (66, 76))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
92514	32733040	The transcripts generated by frameshifts and indels in cancer are frequently degraded by nonsense mediated decay.	('nonsense mediated decay', 'MPA', (89, 112))	('transcripts', 'MPA', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('frameshifts', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('indels', 'Var', (45, 51))	('cancer', 'Disease', (55, 61))	('degraded', 'NegReg', (77, 85))
92518	32733040	In particular, the primary hypothesis that derives from TMB as an immunotherapy biomarker relates to the fact that somatic variants are able to generate tumor specific neoantigens.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('TMB', 'Chemical', '-', (56, 59))	('variants', 'Var', (123, 131))
92522	32733040	Detailed analysis of TMB to identify the true underlying subsets of mutations driving immunogenicity may substantially optimise biomarker accuracy and improve therapeutic targeting of neoantigens.	('TMB', 'Chemical', '-', (21, 24))	('therapeutic targeting', 'MPA', (159, 180))	('optimise', 'PosReg', (119, 127))	('biomarker accuracy', 'MPA', (128, 146))	('improve', 'PosReg', (151, 158))	('mutations', 'Var', (68, 77))
92523	32733040	We have previously shown that frameshift insertion/deletions (fs-indels) are an infrequent (pan-cancer median = 4 per tumor) but highly immunogenic subset of somatic variants.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('frameshift insertion/deletions', 'Var', (30, 60))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
92524	32733040	Fs-indels can produce an increased abundance of tumor specific neoantigens with greater mutant-binding specificity.	('tumor', 'Disease', (48, 53))	('mutant-binding', 'Interaction', (88, 102))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Fs-indels', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
92525	32733040	We found that fs-indels are associated with improved response to CPI therapy and may be attractive candidates for therapeutic personalised tumor vaccines.	('fs-indels', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('CPI', 'Chemical', '-', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('response to CPI therapy', 'MPA', (53, 76))	('improved', 'PosReg', (44, 52))
92526	32733040	We hypothesized that a subset of fs-indels may escape NMD degradation, and which when translated contribute substantially to directing anti-tumor immunity.	('fs-indels', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('degradation', 'biological_process', 'GO:0009056', ('58', '69'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('escape', 'NegReg', (47, 53))	('directing', 'Reg', (125, 134))	('NMD degradation', 'MPA', (54, 69))	('tumor', 'Disease', (140, 145))
92527	32733040	Based on these rules, ~30% of fs-indels across cancers are predicted to escape NMD.	('escape', 'NegReg', (72, 78))	('NMD', 'Disease', (79, 82))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('fs-indels', 'Var', (30, 39))
92528	32733040	Fs-indel mutations escaping NMD have been shown to be an abundant source of expressed neoantigen protein in microsatellite instable (MSI) tumors and to correlate with high levels of CD8 infiltration.	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('CD8', 'Gene', (182, 185))	('CD8', 'Gene', '925', (182, 185))	('microsatellite', 'MPA', (108, 122))	('NMD', 'Gene', (28, 31))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Fs-indel mutations', 'Var', (0, 18))
92529	32733040	In addition, targeted inhibition of NMD has been shown to strongly suppress tumor growth.	('targeted inhibition', 'Var', (13, 32))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('suppress', 'NegReg', (67, 75))	('tumor', 'Disease', (76, 81))	('NMD', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
92530	32733040	has demonstrated that NMD-escaping fs-indels strongly associate with improved response to CPI therapy.	('response', 'MPA', (78, 86))	('fs-indels', 'Var', (35, 44))	('CPI', 'Chemical', '-', (90, 93))	('improved', 'PosReg', (69, 77))
92533	32733040	Collectively these results highlight a subset of fs-indels which escape NMD, and associate with anti-tumor immune response.	('escape', 'NegReg', (65, 71))	('fs-indels', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('immune response', 'biological_process', 'GO:0006955', ('107', '122'))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('associate with', 'Reg', (81, 95))	('NMD', 'CPA', (72, 75))
92541	32733040	For each sample, mutation burden was quantified based on the following classifications: (i) TMB: all non-synonymous SNVs (nsSNVs), (ii) expressed nsSNVs, (iii) fs-indels, and (iv) NMD-escape expressed fs-indels.	('expressed nsSNVs', 'Var', (136, 152))	('fs-indels', 'Var', (160, 169))	('TMB', 'Chemical', '-', (92, 95))
92542	32733040	In meta-analysis of the four melanoma cohorts with both WES and RNAseq (total n = 103), nsSNV, expressed nsSNV and fs-indel counts were higher in patients experiencing clinical benefit, but with non-significant p-value (meta-analysis across all cohorts, Pmeta = 0.073, Pmeta = 0.19 and Pmeta = 0.064, respectively, Fisher's combined probability test) (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('higher', 'PosReg', (136, 142))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('RNAseq', 'Var', (64, 70))	('nsSNV', 'Var', (88, 93))	('patients', 'Species', '9606', (146, 154))
92543	32733040	Patients with one or more NMD-escape mutations had higher rates of clinical benefit to immune checkpoint blockade compared to patients with no NMD-escape mutations: 56% versus 12% (Van Allen et al.	('clinical benefit', 'MPA', (67, 83))	('NMD-escape', 'Gene', (26, 36))	('mutations', 'Var', (37, 46))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (126, 134))	('immune checkpoint blockade', 'MPA', (87, 113))
92551	32733040	Patients with one or more NMD-escape mutation retained a relatively high rate of clinical benefit from CPI at 53%, compared to 15% for patients with zero NMD-escape events (Odds Ratio  = 6.0, 95% confidence interval [1.4-28.9], P = 0.0094, Fisher's exact test, Fig.	('patients', 'Species', '9606', (135, 143))	('clinical', 'MPA', (81, 89))	('NMD-escape', 'Gene', (26, 36))	('mutation', 'Var', (37, 45))	('CPI', 'Chemical', '-', (103, 106))	('Patients', 'Species', '9606', (0, 8))
92552	32733040	This suggests a potential utility for assessment of NMD-escape mutations in tumors with low overall TMB scores.	('mutations', 'Var', (63, 72))	('TMB', 'Chemical', '-', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('NMD-escape', 'Gene', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
92553	32733040	To further investigate the importance of NMD-escape mutations in directing anti-tumor immune response, we analyzed matched DNA and RNA sequencing data from patients with melanoma (n = 22) treated with adoptive cell therapy (ACT).	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('RNA', 'cellular_component', 'GO:0005562', ('131', '134'))	('melanoma', 'Disease', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('tumor', 'Disease', (80, 85))	('NMD-escape', 'Gene', (41, 51))	('immune response', 'biological_process', 'GO:0006955', ('86', '101'))
92554	32733040	TMB nsSNVs (P = 0.027), fs-indels (P = 0.025) and NMD-escape count (P = 0.021) were all significantly associated with clinical benefit from therapy (Fig.	('TMB', 'Chemical', '-', (0, 3))	('fs-indels', 'Var', (24, 33))	('clinical benefit', 'MPA', (118, 134))	('associated', 'Reg', (102, 112))
92558	32733040	The peptide/spectral match derives from a fs-indel in gene C15orf39 (sample TCGA-AA-3672), located in the penultimate exon 2 of 3, a region with low predicted NMD efficiency.	('fs-indel', 'Var', (42, 50))	('C15orf39', 'Gene', (59, 67))	('C15orf39', 'Gene', '56905', (59, 67))
92559	32733040	While only descriptive in nature, this example fits a model of NMD-escape, and interestingly the neo open reading frame (neoORF) triggered from this mutation is highly elongated in nature, generating a total of 131 amino acids of mutated sequence (Fig.	('fits', 'Disease', (47, 51))	('neoORF', 'Disease', 'None', (121, 127))	('fits', 'Disease', 'MESH:D012640', (47, 51))	('neoORF', 'Disease', (121, 127))	('mutation', 'Var', (149, 157))
92562	32733040	Across these three studies, 15 different fs-indel mutations generated peptides that were functionally validated as eliciting immune reactivity (Table S1); thus at a proof of concept level the ability of fs-indels to elicit anti-tumor immune response has been established.	('immune reactivity', 'MPA', (125, 142))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('eliciting', 'Reg', (115, 124))	('elicit', 'Reg', (216, 222))	('tumor', 'Disease', (228, 233))	('immune response', 'biological_process', 'GO:0006955', ('234', '249'))
92563	32733040	Although limited by a small sample size, we note that immunogenic fs-indel mutations (n = 15) had a significantly longer neoORF length (median = 27 amino acids) than screened, but non-immunogenic, fs-indel mutations (n = 4, median = 5 amino acids, P = 0.0032, Mann-Whitney U test) (Fig.	('longer neoORF', 'Disease', 'None', (114, 127))	('fs-indel mutations', 'Var', (66, 84))	('longer neoORF', 'Disease', (114, 127))
92566	32733040	In the context of SNORF mutations, we next considered redundancy in HLA allele binding, based on the hypothesis that SNORF events (and indeed fs-indels in general) would generate peptides capable of binding to a broader spectrum of patient HLA alleles.	('patient', 'Species', '9606', (232, 239))	('peptides', 'MPA', (179, 187))	('binding', 'Interaction', (199, 206))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('events', 'Var', (123, 129))	('mutations', 'Var', (24, 33))	('SNORF events', 'Var', (117, 129))	('binding', 'molecular_function', 'GO:0005488', ('199', '206'))
92567	32733040	This is likely to be of particular importance in the context loss of heterozygosity at the HLA locus (LOHHLA), a mechanism used by tumor cells to achieve immune evasion.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('immune evasion', 'biological_process', 'GO:0042783', ('154', '168'))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('immune evasion', 'biological_process', 'GO:0051842', ('154', '168'))	('loss', 'NegReg', (61, 65))	('heterozygosity', 'Var', (69, 83))
92569	32733040	Next, we assessed for evidence of selective pressure against NMD-escape mutations, which may reflect the potential to generate native anti-tumor immunogenicity.	('NMD-escape', 'Gene', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))
92570	32733040	Using the skin cutaneous melanoma (SKCM) TCGA cohort, we annotated all fs-indels (n = 1527) and stop-gain SNVs (n = 9439) for exonic position.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (10, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (15, 33))	('skin cutaneous melanoma', 'Disease', (10, 33))	('fs-indels', 'Var', (71, 80))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))
92571	32733040	penultimate and last), leading to cancer cells with middle exon fs-indels being more likely to survive immunoediting.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('middle exon fs-indels', 'Var', (52, 73))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
92578	32733040	NMD-escape mutation count was found to significantly associate with clinical benefit from immunotherapy, across both CPI and ACT modalities, and with a stronger association than either nsSNVs or fs-indels.	('mutation', 'Var', (11, 19))	('CPI', 'Chemical', '-', (117, 120))	('benefit', 'PosReg', (77, 84))	('NMD-escape', 'Gene', (0, 10))
92579	32733040	CPI clinical benefit rates for patients with >=1 NMD-escape mutation were elevated (range across the cohorts analysed = 0.56-0.75) compared to patients with zero such events (range 0.12-0.35).	('mutation', 'Var', (60, 68))	('CPI', 'Chemical', '-', (0, 3))	('elevated', 'PosReg', (74, 82))	('patients', 'Species', '9606', (143, 151))	('NMD-escape', 'Gene', (49, 59))	('patients', 'Species', '9606', (31, 39))
92583	32733040	Experimental evidence, analyzed from anti-tumor vaccine and CPI studies, demonstrates T cell reactivity against frameshifted neoepitopes directly in human patients (n = 15).	('tumor', 'Disease', (42, 47))	('frameshifted', 'Var', (112, 124))	('human', 'Species', '9606', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('patients', 'Species', '9606', (155, 163))	('CPI', 'Chemical', '-', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
92584	32733040	T cell reactive fs-indel neoantigens were also enriched for longer neoORF length (median = 27 amino acids), versus experimentally screened, but T cell non-reactive fs-indels (median = 5 amino acids) (P = 0.0032).	('longer neoORF', 'Disease', (60, 73))	('fs-indel', 'Var', (16, 24))	('longer neoORF', 'Disease', 'None', (60, 73))
92585	32733040	These elongated neoORF mutations create the additional benefit of increased redundancy in HLA allele binding, based on the intuitive result that a greater number of peptides will be capable of binding to a broader spectrum of patient HLA alleles.	('neoORF', 'Disease', (16, 22))	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('patient', 'Species', '9606', (226, 233))	('mutations', 'Var', (23, 32))	('redundancy', 'MPA', (76, 86))	('binding', 'Interaction', (101, 108))	('binding', 'Interaction', (193, 200))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('neoORF', 'Disease', 'None', (16, 22))
92586	32733040	Selection analysis demonstrated a depletion of fs-indels in penultimate and last exon positions, as compared to functionally equivalent stop-gain SNVs, suggesting potential negative immune selection against NMD-escape events during tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', (232, 237))	('fs-indels', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (232, 237))
92589	32733040	Furthermore, we acknowledge that neoantigen presentation is an inefficient process, and that NMD-escape mutations identified by DNA/RNA sequencing are unlikely to be directly causative in all tumors.	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('NMD-escape', 'Gene', (93, 103))	('RNA', 'cellular_component', 'GO:0005562', ('132', '135'))
92602	32733040	MSI tumors were selected on account of the high numbers of fs-indels per sample, and hence greater power to measure NMD-escape.	('MSI tumors', 'Disease', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('NMD-escape', 'MPA', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('fs-indels', 'Var', (59, 68))	('MSI tumors', 'Disease', 'MESH:D009369', (0, 10))
92609	32733040	VarScan2 somatic (version 2.3.6) used output from SAMtools mpileup to identify somatic variants between tumor and matched germline samples.	('variants', 'Var', (87, 95))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
92610	32733040	2a, b, variants were annotated on a tumor specific isoform basis.	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('variants', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
92628	32733040	Data for the pan-cancer CPI analysis came from accession numbers: phs001572.v1.p1, EGAS00001002556, EGAS00001002928 and phs000980.v1.p1.	('EGAS00001002928', 'Var', (100, 115))	('CPI', 'Chemical', '-', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('phs000980.v1.p1', 'Var', (120, 135))	('phs001572.v1.p1', 'Var', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
92644	29713020	This reduces the dimensionality of large genomic datasets involving thousands of altered genes into a sensibly smaller set of altered mechanisms that are more interpretable, possibly actionable in a pharmacological or experimental way, and that can be used as therapeutic markers whose predictive ability is significantly improved when compared to that of genomic lesions in individual genes.	('men', 'Species', '9606', (224, 227))	('genes', 'Gene', (89, 94))	('men', 'Species', '9606', (19, 22))	('altered', 'Var', (81, 88))	('reduces', 'NegReg', (5, 12))
92645	29713020	Additionally, this facilitates the stratification of cancer patients into informative subtypes, the characterisation of rare somatic mutations, and the identification of the spectrum of possible alterations underpinning a common evolutionarily successful trait acquired by a normal cell as it transforms itself into a precancerous cell and ultimately into a cancer.	('cancer', 'Disease', (358, 364))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Disease', (321, 327))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('cancer', 'Disease', 'MESH:D009369', (358, 364))
92649	29713020	Finally, after verifying that the majority of these predominances are led by somatic mutations in established high-confidence cancer genes, we show that they are maintained when excluding these mutations from the analysis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('led by', 'Reg', (70, 76))	('mutations', 'Var', (85, 94))
92659	29713020	The problem we tackle here is rather different: we want to test the hypothesis that, in a given cohort of cancer patients (or any population under evolutionary pressure), the number of samples harbouring a mutation in at least one gene belonging to a given pathway is significantly larger than its expectation (when considering the size of the measured cohort, the background mutation rate and the non-overlapping total exonic block lengths of all the genes).	('patients', 'Species', '9606', (113, 121))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('mutation', 'Var', (206, 214))	('cancer', 'Disease', (106, 112))	('larger', 'PosReg', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
92666	29713020	Based on this, a pathway alteration score can be computed observing the deviance of the number of samples harbouring somatic mutations in P from its expectation, and its statistical significance quantified analytically (Supplementary Figure S1C).	('mutations', 'Var', (125, 134))	('alteration', 'Reg', (25, 35))	('men', 'Species', '9606', (226, 229))
92680	29713020	Subsequently, we reasoned that since the main role of cancer driver alterations is to enable cells to achieve a series of phenotypic traits termed the cancer hallmarks, that can be linked to gene mutations, it would be informative to group the pathways according to the hallmark they are associated to.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer hallmarks', 'Disease', (151, 167))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer hallmarks', 'Disease', 'MESH:D009369', (151, 167))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('alterations', 'Var', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (196, 205))
92701	29713020	The acquisition of the Genome Instability and mutation hallmark seems to be dominated in COREAD by alterations in the HDR Through Single Strand Annealing (SSA), Resolution Of D Loop Structures Through Synthesis Dependent Strand Annealing (SDSA), Homologous DNA Pairing And Strand Exchange and other pathways more specifically linked to a microsatellite instability led hypermutator phenotype, known to be prevalent in this cancer type.	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('HDR', 'biological_process', 'GO:0000724', ('118', '121'))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('alterations', 'Var', (99, 110))	('SDSA', 'biological_process', 'GO:0045003', ('239', '243'))	('DNA', 'cellular_component', 'GO:0005574', ('257', '260'))	('Strand', 'Var', (273, 279))	('cancer', 'Disease', (423, 429))
92702	29713020	This is consistent with the high burden of mutations observed in melanoma being the effect of this hallmark rather than leading its acquisition.	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('mutations', 'Var', (43, 52))	('melanoma', 'Disease', (65, 73))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
92703	29713020	This suggests that mutations in this pathway, involving ATM (as the most recurrently mutated gene, and known to induce miRNA biogenesis following DNA damage), impair the ability of melanocytes to properly respond to insults from UV light and may have a significant role in the tumourigenesis of melanoma.	('role', 'Reg', (265, 269))	('tumour', 'Disease', 'MESH:D009369', (277, 283))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('119', '135'))	('miRNA biogenesis', 'MPA', (119, 135))	('have', 'Reg', (246, 250))	('tumour', 'Disease', (277, 283))	('ATM', 'Gene', '472', (56, 59))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('impair', 'NegReg', (159, 165))	('melanoma', 'Disease', (295, 303))	('respond to insults from UV light', 'MPA', (205, 237))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('tumour', 'Phenotype', 'HP:0002664', (277, 283))	('ATM', 'Gene', (56, 59))
92705	29713020	This could explain why immunotherapies, such as PD-1 inhibition, have a relatively low response rate in COREAD when compared to, for example, non-small cell lung cancer, melanoma or renal-cell carcinoma.	('non-small cell lung cancer', 'Disease', (142, 168))	('inhibition', 'Var', (53, 63))	('COREAD', 'Disease', (104, 110))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('PD', 'Disease', 'MESH:D010300', (48, 50))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal-cell carcinoma', 'Disease', (182, 202))
92706	29713020	In fact, response to PD-1 inhibition in COREAD is limited to tumours with mismatch-repair deficiency, perhaps due to their high rate of neoantigen creation.	('PD', 'Disease', 'MESH:D010300', (21, 23))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('inhibition', 'NegReg', (26, 36))	('mismatch-repair deficiency', 'Var', (74, 100))	('tumours', 'Disease', (61, 68))	('deficiency', 'Var', (90, 100))	('mismatch-repair', 'biological_process', 'GO:0006298', ('74', '89'))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
92714	29713020	Genomic alterations in this pathway have not been linked to cancer so far.	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Genomic alterations', 'Var', (0, 19))
92721	29713020	Results show consistency with the established predominance of certain hallmarks in determined cancer types such as, for example, a high CHS for Genome instability and mutation in BRCA and OV, for Tumour-promoting inflammation and Avoiding immune-destruction in COREAD.	('BRCA', 'Gene', (179, 183))	('BRCA', 'Gene', '672', (179, 183))	('Tumour-promoting', 'CPA', (196, 212))	('mutation', 'Var', (167, 175))	('Genome instability', 'CPA', (144, 162))	('CHS', 'Disease', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Tumour', 'Phenotype', 'HP:0002664', (196, 202))	('inflammation', 'Disease', 'MESH:D007249', (213, 225))	('inflammation', 'biological_process', 'GO:0006954', ('213', '225'))	('CHS', 'Disease', 'MESH:D002609', (136, 139))	('inflammation', 'Disease', (213, 225))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
92726	29713020	To this aim, for each pathway P enriched in a given cancer type T, we computed an HCG-dominance score as the ratio between the number of samples with mutations in HCGs in P and the number of samples with mutations in any gene in P. Results of this analysis are shown in Supplementary Figures S7 and S8.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('Supplementary Figures S7', 'Disease', 'MESH:D017034', (270, 294))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (150, 159))	('cancer', 'Disease', (52, 58))	('HCGs in P', 'Gene', (163, 172))	('Supplementary Figures S7', 'Disease', (270, 294))
92731	29713020	5, Supplementary Table S9 and Supplementary Figure S10), showed that the majority of the enrichments identified in the original analyses (on the unfiltered genomic datasets) were actually led by alterations in the HCGs (consistent with their condition of high reliable cancer genes).	('alterations', 'Var', (195, 206))	('led by', 'Reg', (188, 194))	('HCGs', 'Protein', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('men', 'Species', '9606', (9, 12))	('men', 'Species', '9606', (36, 39))	('men', 'Species', '9606', (95, 98))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
92741	29713020	As a consequence, looking at the somatic mutations of its composing genes (of which only Matrix Metallopeptidase 2 - MMP2 - has been reported as harbouring cancer-driving alterations in LUAD) might reveal novel key components of this pathway leading to metastatic transitions.	('mutations', 'Var', (41, 50))	('MMP2', 'molecular_function', 'GO:0004228', ('117', '121'))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Matrix Metallopeptidase 2', 'Gene', '4313', (89, 114))	('Matrix Metallopeptidase 2', 'Gene', (89, 114))	('leading', 'Reg', (242, 249))	('MMP2', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('MMP2', 'Gene', '4313', (117, 121))	('metastatic transitions', 'CPA', (253, 275))
92743	29713020	Furthermore, blockade of PLG with monoclonal antibodies, DNA-based vaccination or silencing through small interfering RNAs has been recently proposed to counteract cancer invasion and metastasis.	('small interfering RNAs', 'Var', (100, 122))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('PLG', 'Gene', '5340', (25, 28))	('silencing', 'MPA', (82, 91))	('blockade', 'NegReg', (13, 21))	('PLG', 'Gene', (25, 28))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
92748	29713020	Consistent with these findings, OSMR is the member of this pathway with the largest number of mutations in the SKCM cohort (Fig.	('SKCM', 'Gene', (111, 115))	('OSMR', 'Gene', (32, 36))	('OSMR', 'Gene', '9180', (32, 36))	('mutations', 'Var', (94, 103))
92752	29713020	The first of these two pathway enrichments is characterised by patterns of highly mutually exclusive somatic mutations in Platelet-derived growth factor (PDGF) genes, and their corresponding receptors: a network that has been recently proposed as an autocrine endogenous mechanism involved in melanoma proliferation control.	('PDGF', 'molecular_function', 'GO:0005161', ('154', '158'))	('melanoma', 'Disease', (293, 301))	('melanoma', 'Disease', 'MESH:D008545', (293, 301))	('PD', 'Disease', 'MESH:D010300', (154, 156))	('men', 'Species', '9606', (37, 40))	('mutations', 'Var', (109, 118))	('Platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('122', '152'))	('melanoma', 'Phenotype', 'HP:0002861', (293, 301))
92758	29713020	Whereas alterations in some nodes of this network are known to be an alternative to p53 repression, conferring chemoresistance and poor prognosis, dissecting the functional relations between them is still widely considered a formidable challenge.	('chemoresistance', 'CPA', (111, 126))	('alterations', 'Var', (8, 19))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))
92765	29713020	A number of possible limitations could hamper the derivation of definitive conclusions from our study, such as the use of only mutations, the possibility that some of the analysed cohorts of patients are representative only of well-defined disease subtypes, the limitation of our knowledge of pathways, and the possibility that pathways that we were not mapped onto cancer hallmarks in our curation could correspond to specific capabilities of cancer cell in certain tumour types.	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Disease', (444, 450))	('cancer hallmarks', 'Disease', (366, 382))	('cancer', 'Disease', 'MESH:D009369', (444, 450))	('patients', 'Species', '9606', (191, 199))	('cancer hallmarks', 'Disease', 'MESH:D009369', (366, 382))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('tumour', 'Phenotype', 'HP:0002664', (467, 473))	('tumour', 'Disease', 'MESH:D009369', (467, 473))	('cancer', 'Disease', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (444, 450))	('tumour', 'Disease', (467, 473))	('mutations', 'Var', (127, 136))
92767	29713020	Additionally further refinements could account for structural variants such as small indels and copy number alterations, known to play an important role in cancer.	('small indels', 'Var', (79, 91))	('cancer', 'Disease', (156, 162))	('copy number alterations', 'Var', (96, 119))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('account', 'Reg', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('men', 'Species', '9606', (27, 30))
92781	29713020	This resource (available at http://www.cancerrxgene.org/gdsc1000/GDSC1000_WebResources//Data/suppData/TableS2B.xlsx) encompasses variants from sequencing of 6,815 tumor normal sample pairs derived from 48 different sequencing studies and reannotated using a pipeline consistent with the COSMIC database (Vagrent: https://zenodo.org/record/16732#.VbeVY2RViko).	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (163, 168))	('variants', 'Var', (129, 137))
92787	29713020	Particularly, for n   {800, 400, 250} for BRCA and n = 250 for the other cancer types, 50 different SLAPenrich analyses were performed on n samples randomly selected from the genomic dataset of the cancer type under consideration, with the parameter specifications described in the previous section.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('BRCA', 'Gene', '672', (42, 46))	('cancer', 'Disease', (198, 204))	('BRCA', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('n   {800', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('n =', 'Var', (51, 54))
92872	24061524	Accurate assessment of pathologic features of a primary melanoma allows prognosis to be reliably estimated; it also guides selection of appropriate management (width of excision margins, appropriateness of sentinel node biopsy); inaccurate pathologic assessment can lead to inappropriate (usually insufficient) therapy.	('men', 'Species', '9606', (257, 260))	('primary melanoma', 'Disease', (48, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('men', 'Species', '9606', (15, 18))	('men', 'Species', '9606', (154, 157))	('inaccurate', 'Var', (229, 239))	('primary melanoma', 'Disease', 'MESH:D008545', (48, 64))
92958	24061524	Moreover, T1b melanomas may also be defined by a dermal mitotic rate of >=1/mm2 or ulceration, rather than Clark level of invasion (as in the sixth edition).	('ulcer', 'Disease', 'MESH:D014456', (83, 88))	('ulcer', 'Disease', (83, 88))	('T1b', 'Var', (10, 13))	('mm2', 'Gene', '10687', (76, 79))	('melanomas', 'Disease', (14, 23))	('mm2', 'Gene', (76, 79))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanomas', 'Phenotype', 'HP:0002861', (14, 23))	('melanomas', 'Disease', 'MESH:D008545', (14, 23))
92963	24061524	Other criteria for the N category are satellites, in-transit metastases, and microsatellites.	('metastases', 'Disease', 'MESH:D009362', (61, 71))	('microsatellites', 'Var', (77, 92))	('satellites', 'CPA', (38, 48))	('metastases', 'Disease', (61, 71))
92973	24061524	There are associations between the presence of some mutations and the anatomic site of a melanoma and the degree of solar elastosis.	('mutations', 'Var', (52, 61))	('solar elastosis', 'Disease', 'MESH:D005148', (116, 131))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('solar elastosis', 'Disease', (116, 131))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
92975	24061524	For example, melanomas associated with prominent solar damage (lentigo maligna melanomas) commonly have NRAS and sometimes KIT mutations, whereas superficial spreading melanomas that arise in the skin of intermittently sun-exposed areas often have BRAF mutations.	('superficial spreading melanoma', 'Phenotype', 'HP:0012057', (146, 176))	('melanomas', 'Disease', (13, 22))	('superficial spreading melanomas', 'Phenotype', 'HP:0012057', (146, 177))	('KIT', 'Gene', (123, 126))	('NRAS', 'Gene', (104, 108))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('lentigo maligna melanoma', 'Phenotype', 'HP:0012059', (63, 87))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('lentigo maligna melanomas', 'Disease', (63, 88))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('mutations', 'Var', (127, 136))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))	('melanomas', 'Disease', 'MESH:D008545', (168, 177))	('melanomas', 'Disease', 'MESH:D008545', (79, 88))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('lentigo maligna melanomas', 'Phenotype', 'HP:0012059', (63, 88))	('melanomas', 'Disease', (79, 88))	('melanomas', 'Disease', (168, 177))	('NRAS', 'Gene', '4893', (104, 108))	('BRAF', 'Gene', '673', (248, 252))	('lentigo maligna melanomas', 'Disease', 'MESH:D018327', (63, 88))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))	('BRAF', 'Gene', (248, 252))
92976	24061524	KIT-mutated melanomas most often involve acral (acral-lentiginous melanoma) and mucosal sites.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('acral-lentiginous melanoma', 'Disease', (48, 74))	('acral-lentiginous melanoma', 'Disease', 'MESH:D007911', (48, 74))	('KIT-mutated', 'Var', (0, 11))	('-lentiginous melanoma', 'Phenotype', 'HP:0012060', (53, 74))	('melanomas', 'Disease', (12, 21))
93023	24061524	With the recent development and testing of new promising targeted therapies for patients with metastatic melanoma, molecular pathology mutation testing for BRAF, NRAS, KIT, and other mutations has become common in many melanoma treatment centers.	('BRAF', 'Gene', (156, 160))	('patients', 'Species', '9606', (80, 88))	('men', 'Species', '9606', (233, 236))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('NRAS', 'Gene', '4893', (162, 166))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('men', 'Species', '9606', (23, 26))	('KIT', 'molecular_function', 'GO:0005020', ('168', '171'))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('KIT', 'Gene', (168, 171))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('mutation', 'Var', (135, 143))	('NRAS', 'Gene', (162, 166))	('melanoma', 'Disease', (219, 227))	('BRAF', 'Gene', '673', (156, 160))
93033	31329578	Aberrant DNA methylation defines isoform usage in cancer, with functional implications Alternative transcript isoforms are common in tumors and act as potential drivers of cancer.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('cancer', 'Disease', (172, 178))
93038	31329578	Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oncogenes', 'Gene', (59, 68))	('methylation-correlated', 'Var', (9, 31))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
93039	31329578	These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNA', 'Protein', (79, 82))	('dysregulated', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))	('cancer', 'Disease', (98, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('79', '94'))
93041	31329578	Given that dysregulation of DNA methylation is a cancer hallmark, we suspect the same regulation holds in cancer and contributes to cancer progression.	('cancer', 'Disease', (132, 138))	('DNA', 'Protein', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('DNA', 'cellular_component', 'GO:0005574', ('28', '31'))	('cancer', 'Disease', (106, 112))	('dysregulation', 'Var', (11, 24))	('DNA methylation', 'biological_process', 'GO:0006306', ('28', '43'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
93049	31329578	To date, researchers seeking to learn more about the mechanisms underlying aberrant isoform activity in cancer have primarily focused on mutations in splicing regulatory sites or altered/deregulated splicing factors.	('splicing factor', 'Gene', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('splicing', 'biological_process', 'GO:0045292', ('199', '207'))	('splicing', 'biological_process', 'GO:0045292', ('150', '158'))	('mutations', 'Var', (137, 146))	('splicing factor', 'Gene', '10569', (199, 214))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
93050	31329578	For example, we now know that mutations in the tumor suppressor gene BRCA1 cause inappropriate exon skipping and inactivation of BRCA1, whereas upregulation of NUMA1 splice isoforms in breast cancer cause increased cell proliferation.	('inactivation', 'MPA', (113, 125))	('increased', 'PosReg', (205, 214))	('BRCA1', 'Gene', '672', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('upregulation', 'PosReg', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('BRCA1', 'Gene', (129, 134))	('NUMA1', 'Gene', (160, 165))	('NUMA1', 'Gene', '4926', (160, 165))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('47', '63'))	('cell proliferation', 'biological_process', 'GO:0008283', ('215', '233'))	('cell proliferation', 'CPA', (215, 233))	('tumor suppressor', 'biological_process', 'GO:0051726', ('47', '63'))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (47, 52))	('exon', 'MPA', (95, 99))	('BRCA1', 'Gene', '672', (69, 74))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('BRCA1', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
93054	31329578	Moreover, intragenic DNAm within exons or near exon boundaries can regulate alternative splicing outcomes by (1) preventing access of the DNA-binding protein CTCF, whose presence mediates local RNA polymerase II pausing for inclusion of weak exons or (2) facilitating access of the DNA-binding protein MeCP2, involved in inclusion of alternatively spliced exons.	('alternative splicing', 'MPA', (76, 96))	('regulate', 'Reg', (67, 75))	('CTCF', 'Gene', (158, 162))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('facilitating', 'PosReg', (255, 267))	('protein', 'cellular_component', 'GO:0003675', ('294', '301'))	('CTCF', 'Gene', '10664', (158, 162))	('DNA-binding', 'molecular_function', 'GO:0003677', ('138', '149'))	('DNA-binding', 'molecular_function', 'GO:0003677', ('282', '293'))	('DNAm', 'Var', (21, 25))	('MeCP2', 'Gene', '4204', (302, 307))	('splicing', 'biological_process', 'GO:0045292', ('88', '96'))	('preventing', 'NegReg', (113, 123))	('access', 'MPA', (124, 130))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('RNA', 'cellular_component', 'GO:0005562', ('194', '197'))	('MeCP2', 'Gene', (302, 307))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))
93055	31329578	Affecting differential use of transcription termination sites, CGI methylation directs imprinting of murine H13 isoforms between paternal and maternal alleles.	('directs', 'Reg', (79, 86))	('imprinting', 'MPA', (87, 97))	('murine', 'Species', '10090', (101, 107))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('transcription', 'biological_process', 'GO:0006351', ('30', '43'))	('methylation', 'Var', (67, 78))
93057	31329578	In this study, recent advances in transcriptome sequencing and DNAm analysis, coupled with expansive collections of tumor samples, enabled us to test the hypothesis that DNAm dysregulation in cancers can disrupt isoform usage and contribute to tumorigenesis, as a common phenomenon.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('DNAm', 'Gene', (170, 174))	('dysregulation', 'Var', (175, 188))	('tumor', 'Disease', (244, 249))	('isoform usage', 'MPA', (212, 225))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('disrupt', 'NegReg', (204, 211))	('contribute', 'Reg', (230, 240))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
93059	31329578	Based on a comprehensive analysis of data for 18 cancer types from The Cancer Genome Atlas (TCGA), we report that, within 11 cancer types, DNAm in the top 25% of variable methylated sites is associated with isoform switching, and this isoform switching is predicted to have functional consequences for tumorigenesis, involving 10-21% of genes.	('Cancer Genome Atlas', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('isoform switching', 'MPA', (207, 224))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (302, 307))	('methylated sites', 'Var', (171, 187))	('associated', 'Reg', (191, 201))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (49, 55))	('DNAm', 'Var', (139, 143))
93065	31329578	To further investigate the connection between DNAm and isoform usage, for each cancer type we identified methylation probes with the most variable values, which were most likely to behave differently across samples (i.e., those whose standard deviation across tumors fell within the top 25% for all sites).	('methylation', 'Var', (105, 116))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (260, 266))
93074	31329578	We found negative correlations enriched among probes within OSRs, compared to other regions, in 9 out of 11 cancer types (#gene = 232) (Fig 1C) whereas the same enrichment was seen for CGIs in only 6 out of 11 cancer types, suggesting that TSS-correlated DNAm need not be confined to CGIs to impact transcription initiation.	('transcription', 'biological_process', 'GO:0006351', ('299', '312'))	('probes', 'Var', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('transcription initiation', 'MPA', (299, 323))	('impact', 'Reg', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('negative', 'NegReg', (9, 17))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
93076	31329578	These findings suggest that, across most cancer types, DNAm at isoform positions > = exon 4 correlates with inclusion of distal exons in the gene body, indicative of transcriptional elongation.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('DNAm', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
93081	31329578	For example, the very long terminal exon in BHLHE41 contains two internal methylation sites positively correlated with the inclusion of a long terminal exon but negatively correlated with the shorter isoform (Fig 3C).	('BHLHE41', 'Gene', '79365', (44, 51))	('negatively', 'NegReg', (161, 171))	('inclusion', 'Var', (123, 132))	('BHLHE41', 'Gene', (44, 51))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('correlated', 'Reg', (103, 113))
93095	31329578	To determine whether these subtype-discerning, isoform switching-linked DNAm alterations could impact tumorigenesis, we analyzed the functional outcomes of isoform switching among BRCA subtype samples, and also in normal breast tissue samples, using software designed for this purpose, IsoformSwitchAnalyzeR.	('impact', 'Reg', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BRCA', 'Gene', (180, 184))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
93104	31329578	Nevertheless, the overrepresentation remained statistically significant across all n values (hypergeometric test; p < 1E-2) (S1 Table), suggesting DNAm-correlated isoform alterations may be positively selected in cancer-related genes, consistent with our hypothesis.	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (171, 182))	('cancer', 'Disease', (213, 219))
93109	31329578	Thus, alteration of the DNAm of these genes may correspond to alteration of their functional domains and influence pathway functions in many types of cancer.	('influence', 'Reg', (105, 114))	('DNAm', 'MPA', (24, 28))	('pathway functions', 'CPA', (115, 132))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('functional domains', 'MPA', (82, 100))	('cancer', 'Disease', (150, 156))	('alteration', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('alteration', 'Reg', (62, 72))
93113	31329578	Thus, this study shows that DNAm-correlated isoform usage alterations are common, could functionally contribute to cancer processes, and represent a new paradigm in the cancer epigenomic landscape.	('contribute', 'Reg', (101, 111))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (169, 175))	('isoform usage', 'MPA', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('alterations', 'Var', (58, 69))
93115	31329578	These correlations suggest a potential blueprint for DNAm-regulated isoform activities worthy of further experimental elucidation while controlling for other isoform-regulating mechanisms such as aforementioned splicing factor alterations and recently reported regulation via miRNA binding at 3'UTRs.	('miRNA', 'Protein', (276, 281))	('splicing factor', 'Gene', '10569', (211, 226))	('splicing', 'biological_process', 'GO:0045292', ('211', '219'))	('miRNA binding', 'molecular_function', 'GO:0035198', ('276', '289'))	('splicing factor', 'Gene', (211, 226))	('regulation', 'biological_process', 'GO:0065007', ('261', '271'))	('alterations', 'Var', (227, 238))
93117	31329578	First, the main functional role established for cancer-associated DNAm alterations is gene silencing via promoter CGI methylation.	('gene', 'MPA', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gene silencing', 'biological_process', 'GO:0016458', ('86', '100'))	('alterations', 'Var', (71, 82))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('promoter', 'MPA', (105, 113))
93118	31329578	Thus, most cancer studies have focused on causal relationships between aberrant promoter hypermethylation and tumor suppressor gene silencing, paying less attention to the functional consequences of intragenic DNAm alterations.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('110', '126'))	('silencing', 'NegReg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('promoter', 'MPA', (80, 88))	('paying less attention', 'Phenotype', 'HP:0000736', (143, 164))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('tumor suppressor', 'biological_process', 'GO:0051726', ('110', '126'))	('gene silencing', 'biological_process', 'GO:0016458', ('127', '141'))	('aberrant', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
93121	31329578	Integrative analysis of these factors (using ChIP-Seq datasets, for example) coupled with exon-level expression data may provide insights into a mechanistic link between DNAm alterations and deleterious alternative splicing in cancer.	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('splicing', 'biological_process', 'GO:0045292', ('215', '223'))	('DNAm', 'MPA', (170, 174))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('alterations', 'Var', (175, 186))
93131	31329578	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms, and (iv) probes with missing rates >= 90% across all samples for a given cancer type.	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('probes', 'Var', (135, 141))
93146	29767233	Additionally, we analyzed the expression of RRM2 mRNA and discovered that high expression of RRM2 is associated with worse overall survival.	('high', 'Var', (74, 78))	('RRM2', 'Gene', '6241', (93, 97))	('RRM2', 'Gene', (93, 97))	('overall survival', 'MPA', (123, 139))	('associated', 'Reg', (101, 111))	('RRM2', 'Gene', '6241', (44, 48))	('RRM2', 'Gene', (44, 48))
93164	29767233	It is clearly visible that changes in the expression of cyclin F negatively correlates with the RRM2 level, which may suggest their cooperation in the axis, important for genome stability and DNA repair.	('RRM2', 'Gene', (96, 100))	('cyclin', 'molecular_function', 'GO:0016538', ('56', '62'))	('negatively', 'NegReg', (65, 75))	('RRM2', 'Gene', '6241', (96, 100))	('expression', 'MPA', (42, 52))	('cyclin F', 'Gene', (56, 64))	('changes', 'Var', (27, 34))	('DNA repair', 'biological_process', 'GO:0006281', ('192', '202'))	('cyclin F', 'Gene', '899', (56, 64))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))
93166	29767233	Furthermore, cells with high content of RRM2 are characterized by much more effective DNA repair systems which impair the effectiveness of therapy.	('more', 'PosReg', (71, 75))	('DNA repair', 'biological_process', 'GO:0006281', ('86', '96'))	('RRM2', 'Gene', '6241', (40, 44))	('RRM2', 'Gene', (40, 44))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('high content', 'Var', (24, 36))	('DNA repair systems', 'CPA', (86, 104))
93168	29767233	In the present study, using the data available in the cBioPortal database, we showed for first time that high expression of cyclin F mRNA is associated with poorer prognosis in patients with skin cutaneous melanoma.	('high', 'Var', (105, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (196, 214))	('cyclin', 'molecular_function', 'GO:0016538', ('124', '130'))	('patients', 'Species', '9606', (177, 185))	('cyclin F', 'Gene', (124, 132))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (191, 214))	('cyclin F', 'Gene', '899', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('skin cutaneous melanoma', 'Disease', (191, 214))
93177	29767233	Furthermore, expression of RRM2 mRNA had a significant influence on median survival (102.04 vs. 61.47; P=0.034), but no effect on DSF was noted (Fig.	('RRM2', 'Gene', '6241', (27, 31))	('RRM2', 'Gene', (27, 31))	('median survival', 'MPA', (68, 83))	('expression', 'Var', (13, 23))	('influence', 'Reg', (55, 64))
93185	29767233	The list of biological processes altered by cyclin F dysregulation are presented in Tables IV and VI.	('dysregulation', 'Var', (53, 66))	('cyclin F', 'Gene', (44, 52))	('cyclin F', 'Gene', '899', (44, 52))	('cyclin', 'molecular_function', 'GO:0016538', ('44', '50'))
93186	29767233	Furthermore, data presenting biological processes influenced by changes in RRM2 expression are presented in Tables VIII and X.	('changes', 'Var', (64, 71))	('VIII', 'Gene', (115, 119))	('VIII', 'Gene', '1351', (115, 119))	('RRM2', 'Gene', '6241', (75, 79))	('RRM2', 'Gene', (75, 79))
93189	29767233	Nuclear accumulation of RRM2, which allows efficient DNA repair, is preceded by downregulation of cyclin F. As it has been shown by D'Angiolella et al the insertion of wild-type cyclin F into hTERT RPE-1 cells prevents transposition of RRM2 from the cytoplasm to the nucleus.	('cyclin F', 'Gene', (178, 186))	('RRM2', 'Gene', '6241', (24, 28))	('nucleus', 'cellular_component', 'GO:0005634', ('267', '274'))	('cyclin F', 'Gene', '899', (178, 186))	('DNA repair', 'biological_process', 'GO:0006281', ('53', '63'))	('cyclin F', 'Gene', (98, 106))	('RRM2', 'Gene', (24, 28))	('cyclin F', 'Gene', '899', (98, 106))	('cyclin', 'molecular_function', 'GO:0016538', ('178', '184'))	('prevents', 'NegReg', (210, 218))	('RRM2', 'Gene', '6241', (236, 240))	('DNA', 'cellular_component', 'GO:0005574', ('53', '56'))	('insertion', 'Var', (155, 164))	('transposition', 'MPA', (219, 232))	('cyclin', 'molecular_function', 'GO:0016538', ('98', '104'))	('hTERT RPE-1', 'CellLine', 'CVCL:4388', (192, 203))	('RRM2', 'Gene', (236, 240))	('cytoplasm', 'cellular_component', 'GO:0005737', ('250', '259'))	('transposition', 'biological_process', 'GO:0032196', ('219', '232'))
93190	29767233	It has also been shown that overexpression of RRM2 may affect the proliferation of melanoma cells, their response to treatment in vivo, and is associated with worse overall survival in melanoma patients bearing mutations in the BRAF oncogene.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('associated', 'Reg', (143, 153))	('affect', 'Reg', (55, 61))	('BRAF', 'Gene', '673', (228, 232))	('patients', 'Species', '9606', (194, 202))	('BRAF', 'Gene', (228, 232))	('proliferation', 'CPA', (66, 79))	('mutations', 'Var', (211, 220))	('RRM2', 'Gene', (46, 50))	('worse', 'NegReg', (159, 164))	('RRM2', 'Gene', '6241', (46, 50))	('overexpression', 'PosReg', (28, 42))	('response to treatment in vivo', 'MPA', (105, 134))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('melanoma', 'Disease', (83, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
93194	29767233	Interestingly our analysis revealed that high expression of cyclin F mRNA is associated with poorer prognosis in skin cutaneous melanoma.	('cyclin F', 'Gene', '899', (60, 68))	('skin cutaneous melanoma', 'Disease', (113, 136))	('cyclin', 'molecular_function', 'GO:0016538', ('60', '66'))	('high', 'Var', (41, 45))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (113, 136))	('cyclin F', 'Gene', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
93198	29767233	On the other hand, high cyclin B1 expression was found to reduce lymph node metastasis and distant metastasis stage, and was also associated with higher survival rates in colorectal cancer.	('higher', 'PosReg', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cyclin B1', 'Gene', '891', (24, 33))	('cyclin B1', 'Gene', (24, 33))	('high', 'Var', (19, 23))	('expression', 'MPA', (34, 44))	('colorectal cancer', 'Disease', (171, 188))	('lymph node metastasis', 'Disease', (65, 86))	('survival rates', 'CPA', (153, 167))	('distant metastasis stage', 'CPA', (91, 115))	('lymph node metastasis', 'Disease', 'MESH:D009362', (65, 86))	('reduce lymph node', 'Phenotype', 'HP:0002732', (58, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('rectal cancer', 'Phenotype', 'HP:0100743', (175, 188))	('reduce', 'NegReg', (58, 64))	('cyclin', 'molecular_function', 'GO:0016538', ('24', '30'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))
93199	29767233	High expression of cyclin D1 is a poor prognostic factor in gastric, oropharyngeal and breast cancer.	('cyclin D1', 'Gene', '595', (19, 28))	('High', 'Var', (0, 4))	('cyclin D1', 'Gene', (19, 28))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('gastric', 'Disease', (60, 67))	('oropharyngeal', 'Disease', (69, 82))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))
93201	29767233	Some evidence has shown that low expression of cyclin F may be tumorigenic.	('tumor', 'Disease', (63, 68))	('cyclin F', 'Gene', (47, 55))	('cyclin F', 'Gene', '899', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('low expression', 'Var', (29, 43))	('cyclin', 'molecular_function', 'GO:0016538', ('47', '53'))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
93208	29767233	Inactivation of Rb1 via CCNF/PP1 is also associated with enhanced ovarian cancer aggressiveness.	('CCNF', 'Gene', '899', (24, 28))	('Rb1', 'Gene', (16, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (66, 80))	('CCNF', 'Gene', (24, 28))	('ovarian cancer aggressiveness', 'Disease', 'MESH:D010051', (66, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (81, 95))	('PP1', 'Gene', (29, 32))	('ovarian cancer aggressiveness', 'Disease', (66, 95))	('Rb1', 'Gene', '5925', (16, 19))	('PP1', 'Gene', '5540', (29, 32))	('enhanced', 'PosReg', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Inactivation', 'Var', (0, 12))
93212	29767233	Degradation of Cdh1 is essential for S phase entry and loss of cyclin F impairs cell cycle progression.	('loss', 'Var', (55, 59))	('cyclin', 'molecular_function', 'GO:0016538', ('63', '69'))	('cell cycle progression', 'CPA', (80, 102))	('S phase', 'biological_process', 'GO:0051320', ('37', '44'))	('cyclin F', 'Gene', (63, 71))	('cyclin F', 'Gene', '899', (63, 71))	('impairs', 'NegReg', (72, 79))	('cell cycle', 'biological_process', 'GO:0007049', ('80', '90'))	('Cdh1', 'Gene', (15, 19))	('Cdh1', 'Gene', '999', (15, 19))
93215	29767233	Loss of INPP4B was found to increase AKT activation and drive higher proliferation rate and metastasis.	('AKT', 'Gene', '207', (37, 40))	('metastasis', 'CPA', (92, 102))	('INPP4B', 'Gene', '8821', (8, 14))	('higher', 'PosReg', (62, 68))	('AKT', 'Gene', (37, 40))	('INPP4B', 'Gene', (8, 14))	('activation', 'PosReg', (41, 51))	('Loss', 'Var', (0, 4))	('increase', 'PosReg', (28, 36))
93229	29767233	Noteworthy, transfection of a primary cutaneous melanoma cell line with low tumorigenic and metastatic potential with low-molecular cyclin E forms resulted in the development of angiogenic tumors with prominent perineural invasion.	('cyclin', 'Gene', (132, 138))	('tumor', 'Disease', (189, 194))	('angiogenic tumors', 'Disease', 'MESH:D009369', (178, 195))	('angiogenic tumors', 'Disease', (178, 195))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('cyclin', 'molecular_function', 'GO:0016538', ('132', '138'))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('resulted in', 'Reg', (147, 158))	('low-molecular', 'Var', (118, 131))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cyclin', 'Gene', '5111', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cutaneous melanoma', 'Disease', (38, 56))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (38, 56))
93230	29767233	Additionally, truncated forms of cyclin E triggered a dramatic increase in a number of metastasis events.	('cyclin', 'Gene', '5111', (33, 39))	('increase', 'PosReg', (63, 71))	('cyclin', 'Gene', (33, 39))	('truncated forms', 'Var', (14, 29))	('cyclin', 'molecular_function', 'GO:0016538', ('33', '39'))	('metastasis events', 'CPA', (87, 104))
93232	29767233	Silencing of cyclin B exerts an antitumor effect on melanoma cells and lung metastases, both in vitro and in vivo.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('cyclin', 'molecular_function', 'GO:0016538', ('13', '19'))	('cyclin', 'Gene', '5111', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('lung metastases', 'Disease', (71, 86))	('lung metastases', 'Disease', 'MESH:D009362', (71, 86))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cyclin', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (36, 41))
93238	29767233	The abrogation of FOXO3a function was found to lead to increased tumor aggressiveness in melanoma and renal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('function', 'MPA', (25, 33))	('aggressiveness', 'Phenotype', 'HP:0000718', (71, 85))	('increased', 'PosReg', (55, 64))	('FOXO3a', 'Gene', '2309', (18, 24))	('renal carcinoma', 'Phenotype', 'HP:0005584', (102, 117))	('FOXO3a', 'Gene', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('tumor aggressiveness in melanoma and renal carcinoma', 'Disease', 'OMIM:614456', (65, 117))	('abrogation', 'Var', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
93244	29767233	Increased levels of phosphorylated 4E-BP1 are also associated with poor overall survival and significant difference in post-recurrence survival.	('4E-BP1', 'Gene', (35, 41))	('overall survival', 'CPA', (72, 88))	('phosphorylated', 'Var', (20, 34))	('poor', 'NegReg', (67, 71))	('4E-BP1', 'Gene', '1978', (35, 41))
93249	29767233	Aird et al showed that high RRM2 expression is correlated with worse outcome in melanoma patients.	('high', 'Var', (23, 27))	('RRM2', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('RRM2', 'Gene', '6241', (28, 32))	('patients', 'Species', '9606', (89, 97))	('expression', 'MPA', (33, 43))
93250	29767233	Silencing of RRM2 inhibited melanoma growth which suggests the involvement of RRM2 in melanoma progression.	('melanoma', 'Disease', (28, 36))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('melanoma growth', 'Disease', (28, 43))	('RRM2', 'Gene', '6241', (78, 82))	('inhibited', 'NegReg', (18, 27))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma growth', 'Disease', 'MESH:D008545', (28, 43))	('RRM2', 'Gene', (78, 82))	('Silencing', 'Var', (0, 9))	('RRM2', 'Gene', '6241', (13, 17))	('RRM2', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
93251	29767233	Silencing of RRM2 and treatment with mutant BRAF inhibitor PLX4720 simultaneously and synergistically inhibited melanoma growth.	('BRAF', 'Gene', '673', (44, 48))	('melanoma growth', 'Disease', (112, 127))	('inhibited', 'NegReg', (102, 111))	('BRAF', 'Gene', (44, 48))	('melanoma growth', 'Disease', 'MESH:D008545', (112, 127))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('Silencing', 'Var', (0, 9))	('RRM2', 'Gene', '6241', (13, 17))	('RRM2', 'Gene', (13, 17))
93261	29767233	Loss of XRCC1 confers a more aggressive phenotype in melanoma.	('XRCC1', 'Gene', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('XRCC1', 'Gene', '7515', (8, 13))	('Loss', 'Var', (0, 4))
93266	29767233	High expression of TFRC is associated with unfavorable prognosis in breast and pancreatic cancer.	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (27, 37))	('TFRC', 'Gene', '7037', (19, 23))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (68, 96))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('TFRC', 'Gene', (19, 23))
93281	27779995	SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months.	('PMs', 'Chemical', 'MESH:D011399', (1, 4))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('primary melanomas', 'Disease', 'MESH:D008545', (48, 65))	('better', 'PosReg', (103, 109))	('thinner', 'NegReg', (24, 31))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('melanoma', 'Disease', (122, 130))	('patients', 'Species', '9606', (189, 197))	('overall', 'CPA', (110, 117))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('SPM', 'Var', (86, 89))	('patients', 'Species', '9606', (90, 98))	('primary melanomas', 'Disease', (48, 65))
93313	27779995	When single and SPM patients were matched, patients with a SPM had significantly better overall survival (OS; P < 0.0001) and melanoma specific survival (MSS; P < 0.0001).	('better', 'PosReg', (81, 87))	('patients', 'Species', '9606', (43, 51))	('MSS', 'Chemical', '-', (154, 157))	('patients', 'Species', '9606', (20, 28))	('overall survival', 'CPA', (88, 104))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanoma', 'Disease', (126, 134))	('OS', 'Chemical', '-', (106, 108))	('SPM', 'Var', (59, 62))
93361	33409455	We restricted survival analysis to malignant melanoma (ICD-O-3 behavior code 3) arising in the skin (ICD-O-3 topography codes C44.0-C44.9), including the skin of the labia majora (C51.0), vulva (C51.9), penis (C60.9), and scrotum (C63.2).	('C51.0', 'Var', (180, 185))	('malignant melanoma', 'Phenotype', 'HP:0002861', (35, 53))	('malignant melanoma', 'Disease', 'MESH:D008545', (35, 53))	('including the skin of the labia', 'Phenotype', 'HP:0000065', (140, 171))	('C60.9', 'Var', (210, 215))	('malignant melanoma', 'Disease', (35, 53))	('C51.9', 'Var', (195, 200))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))
93373	33409455	We selected melanomas of the skin on the basis of topographic codes C44.0-C44.9 (skin), C51.0 (including the skin of the labia majora), C51.9 (vulva), C60.9 (penis), or C63.2 (scrotum).	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('C44.0-C44.9', 'Var', (68, 79))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('C63.2', 'Var', (169, 174))	('C51.0', 'Var', (88, 93))	('C60.9', 'Var', (151, 156))	('C51.9', 'Var', (136, 141))	('melanomas', 'Disease', (12, 21))	('including the skin of the labia', 'Phenotype', 'HP:0000065', (95, 126))
93374	33409455	Melanomas were further categorized by anatomic subsite as arising in the skin of the head and neck (C44.0-C44.4), the trunk (C44.5), the limbs (C44.6-C44.7), or the genital organs (C51.0, C51.9, C60.9, C63.2), as lesions overlapping 2 of those categories, or of the skin with anatomic location not otherwise specified (C44.8-C44.9).	('C51.0', 'Var', (181, 186))	('C63.2', 'Var', (202, 207))	('Melanomas', 'Disease', 'MESH:D008545', (0, 9))	('neck', 'cellular_component', 'GO:0044326', ('94', '98'))	('Melanomas', 'Disease', (0, 9))	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('trunk', 'cellular_component', 'GO:0043198', ('118', '123'))	('C51.9', 'Var', (188, 193))
93375	33409455	Histological subtypes were grouped according to the first revision of ICD-O-3 as malignant melanoma, not otherwise specified (NOS, 8720), superficial spreading (8743), lentigo maligna (8742), nodular (8721), acral (8744), and all other morphologies (8722-8723, 8726-8727, 8730, 8740-8741, 8743, 8745-8746, 8750, 8760-8761, 8770-8774, 8780, 8790).	('8744', 'Var', (215, 219))	('superficial spreading', 'Disease', (138, 159))	('malignant melanoma', 'Phenotype', 'HP:0002861', (81, 99))	('8726-8727', 'Var', (261, 270))	('malignant melanoma', 'Disease', 'MESH:D008545', (81, 99))	('lentigo maligna', 'Phenotype', 'HP:0012059', (168, 183))	('8760-8761', 'Var', (312, 321))	('8743', 'Var', (289, 293))	('8742', 'Var', (185, 189))	('8730', 'Var', (272, 276))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('8745-8746', 'Var', (295, 304))	('lentigo maligna', 'Disease', (168, 183))	('8743', 'Var', (161, 165))	('8722-8723', 'Var', (250, 259))	('8740-8741', 'Var', (278, 287))	('acral', 'Disease', (208, 213))	('nodular', 'Disease', (192, 199))	('malignant melanoma', 'Disease', (81, 99))	('8750', 'Var', (306, 310))	('8722-8723, 8726-8727, 8730, 8740-8741, 8743, 8745-8746, 8750, 8760-8761, 8770-8774, 8780', 'Mutation', 'c.8722-8723,8726dup', (250, 338))	('lentigo maligna', 'Disease', 'MESH:D018327', (168, 183))	('8721', 'Var', (201, 205))
93423	33409455	Vemurafenib, the first licensed targeted treatment for patients with metastatic disease and the BRAF V600E mutation, was also shown to increase short-term survival.	('V600E', 'Mutation', 'rs113488022', (101, 106))	('increase', 'PosReg', (135, 143))	('V600E', 'Var', (101, 106))	('men', 'Species', '9606', (46, 49))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('short-term survival', 'CPA', (144, 163))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('patients', 'Species', '9606', (55, 63))
93424	33409455	A phase III randomized trial of 675 patients diagnosed with metastatic melanoma showed an overall 6-month survival of 84% (95% CI = 78% to 89%) in those treated with vemurafenib compared with 64% (95% CI = 56% to 73%) in those treated with dacarbazine.	('patients', 'Species', '9606', (36, 44))	('vemurafenib', 'Var', (166, 177))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('dacarbazine', 'Chemical', 'MESH:D003606', (240, 251))	('vemurafenib', 'Chemical', 'MESH:D000077484', (166, 177))
93434	33409455	A recent study designed to identify factors associated with the treatment of metastatic melanoma in the United States found that older patients were less likely to receive ipilimumab or to be tested for the BRAF mutation.	('BRAF', 'Gene', (207, 211))	('ipilimumab', 'Chemical', 'MESH:D000074324', (172, 182))	('less', 'NegReg', (149, 153))	('men', 'Species', '9606', (69, 72))	('BRAF', 'Gene', '673', (207, 211))	('patients', 'Species', '9606', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('mutation', 'Var', (212, 220))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('tested', 'Reg', (192, 198))	('ipilimumab', 'MPA', (172, 182))
93458	29532857	Cutaneous melanoma: From pathogenesis to therapy (Review) In less than 10 years, melanoma treatment has been revolutionized with the approval of tyrosine kinase inhibitors and immune checkpoint inhibitors, which have been shown to have a significant impact on the prognosis of patients with melanoma.	('pathogenesis', 'biological_process', 'GO:0009405', ('25', '37'))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('patients', 'Species', '9606', (277, 285))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('tyrosine', 'Var', (145, 153))	('melanoma', 'Disease', (291, 299))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
93481	29532857	As regards genetic susceptibility, the polymorphisms of the melanocortin 1 receptor (MC1R) gene, are responsible for the different human skin-color phenotypes.	('melanocortin 1 receptor', 'Gene', '4157', (60, 83))	('polymorphisms', 'Var', (39, 52))	('MC1R', 'Gene', (85, 89))	('human', 'Species', '9606', (131, 136))	('melanocortin 1 receptor', 'Gene', (60, 83))	('MC1R', 'Gene', '4157', (85, 89))	('responsible', 'Reg', (101, 112))
93486	29532857	Germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) and, less common, mutations in cyclin-dependent kinase 4 (CDK4) are the most frequent genetic abnormalities identified in these families.	('cyclin-dependent kinase 4', 'Gene', (106, 131))	('frequent', 'Reg', (152, 160))	('genetic abnormalities', 'Disease', 'MESH:D030342', (161, 182))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('39', '55'))	('mutations', 'Var', (93, 102))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (22, 58))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (22, 58))	('p16', 'Gene', '1029', (70, 73))	('CDK4', 'Gene', (133, 137))	('genetic abnormalities', 'Disease', (161, 182))	('CDKN2A', 'Gene', (60, 66))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('22', '55'))	('CDK4', 'Gene', '1019', (133, 137))	('CDKN2A', 'Gene', '1029', (60, 66))	('cyclin-dependent kinase 4', 'Gene', '1019', (106, 131))	('p16', 'Gene', (70, 73))	('CDK', 'molecular_function', 'GO:0004693', ('133', '136'))	('cyclin', 'molecular_function', 'GO:0016538', ('106', '112'))
93492	29532857	The main genetic drivers are B-Raf proto-oncogene (BRAF), neurofibromin 1 (NF1) and NRAS mutations, and usually melanomas associated with chronically sun-exposed skin have a high mutational load related to UV exposure.	('melanomas', 'Disease', (112, 121))	('B-Raf proto-oncogene', 'Gene', '673', (29, 49))	('B-Raf proto-oncogene', 'Gene', (29, 49))	('neurofibromin 1', 'Gene', (58, 73))	('NRAS', 'Gene', (84, 88))	('NF1', 'Gene', (75, 78))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('mutational load', 'MPA', (179, 194))	('NF1', 'Gene', '4763', (75, 78))	('NRAS', 'Gene', '4893', (84, 88))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('neurofibromin 1', 'Gene', '4763', (58, 73))	('BRAF', 'Gene', '673', (51, 55))	('mutations', 'Var', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('BRAF', 'Gene', (51, 55))
93493	29532857	On the other hand, melanoma associated with intermittent sun-exposed skin cases arise in younger-aged individuals (<55 years), on less sun-exposed areas, such as the trunk and proximal extremities, and are usually associated with BRAFV600E and a lower mutational load.	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanoma', 'Disease', (19, 27))	('trunk', 'cellular_component', 'GO:0043198', ('166', '171'))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('BRAFV600E', 'Var', (230, 239))	('BRAFV600E', 'Mutation', 'rs113488022', (230, 239))
93499	29532857	When this usually occurs, it is associated with the acquisition of subsequent mutations in key genes, such as TERT or CDKN2A.	('CDKN2A', 'Gene', (118, 124))	('CDKN2A', 'Gene', '1029', (118, 124))	('mutations', 'Var', (78, 87))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('associated', 'Reg', (32, 42))
93504	29532857	Several studies have demonstrated that melanoma spreading is the result of genetic mutations and tumor microenvironmental alterations, characterized by the overexpression of proteins able to favor tumor invasion and surrounding infiltration.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('overexpression', 'PosReg', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('tumor', 'Disease', (97, 102))	('favor', 'PosReg', (191, 196))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('proteins', 'Protein', (174, 182))	('tumor', 'Disease', (197, 202))
93507	29532857	It has been demonstrated that MMP-9 overexpression observed in melanoma is caused by intragenic methylation phenomena that lead to protein overexpression.	('overexpression', 'PosReg', (139, 153))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('overexpression', 'PosReg', (36, 50))	('MMP-9', 'molecular_function', 'GO:0004229', ('30', '35'))	('lead to', 'Reg', (123, 130))	('caused by', 'Reg', (75, 84))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('methylation', 'Var', (96, 107))	('MMP-9', 'Gene', '4318', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('protein', 'MPA', (131, 138))	('MMP-9', 'Gene', (30, 35))
93510	29532857	The most frequent somatic mutations in chronically or intermittent sun-exposed skin melanomas affect genes that control central cellular process, such us proliferation (BRAF, NRAS and NF1), growth and metabolism [phosphatase and tensin homolog (PTEN) and KIT proto-oncogene receptor tyrosine kinase (KIT)], resistance to apoptosis [tumor protein p53 (TP53)], cell cycle control [cyclin-dependent kinase inhibitor 2A (CDKN2A)] and replicative lifespan [telomerase reverse transcriptase (TERT)].	('BRAF', 'Gene', (169, 173))	('NF1', 'Gene', (184, 187))	('CDKN2A', 'Gene', (417, 423))	('BRAF', 'Gene', '673', (169, 173))	('transcriptase', 'molecular_function', 'GO:0034062', ('471', '484'))	('TP53', 'Gene', '7157', (351, 355))	('affect', 'Reg', (94, 100))	('KIT', 'molecular_function', 'GO:0005020', ('300', '303'))	('skin melanomas', 'Disease', (79, 93))	('replicative lifespan', 'CPA', (430, 450))	('mutations', 'Var', (26, 35))	('PTEN', 'Gene', '5728', (245, 249))	('skin melanomas', 'Disease', 'MESH:D008545', (79, 93))	('KIT', 'molecular_function', 'GO:0005020', ('255', '258'))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('379', '412'))	('cell cycle control', 'biological_process', 'GO:1901987', ('359', '377'))	('CDKN2A', 'Gene', '1029', (417, 423))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('396', '412'))	('transcriptase', 'molecular_function', 'GO:0003899', ('471', '484'))	('NRAS', 'Gene', (175, 179))	('cellular process', 'biological_process', 'GO:0009987', ('128', '144'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (379, 415))	('protein', 'cellular_component', 'GO:0003675', ('338', '345'))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('TP53', 'Gene', (351, 355))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', (255, 298))	('p53', 'Gene', '7157', (346, 349))	('apoptosis', 'biological_process', 'GO:0097194', ('321', '330'))	('metabolism', 'biological_process', 'GO:0008152', ('201', '211'))	('tumor', 'Disease', (332, 337))	('apoptosis', 'biological_process', 'GO:0006915', ('321', '330'))	('phosphatase', 'molecular_function', 'GO:0016791', ('213', '224'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (379, 415))	('NRAS', 'Gene', '4893', (175, 179))	('TERT', 'Gene', (486, 490))	('TERT', 'Gene', '7015', (486, 490))	('NF1', 'Gene', '4763', (184, 187))	('PTEN', 'Gene', (245, 249))	('cellular process', 'cellular_component', 'GO:0042995', ('128', '144'))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('resistance', 'CPA', (307, 317))	('cell cycle control', 'CPA', (359, 377))	('KIT proto-oncogene receptor tyrosine kinase', 'Gene', '3815', (255, 298))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('213', '243'))	('transcriptase', 'molecular_function', 'GO:0003968', ('471', '484'))	('p53', 'Gene', (346, 349))
93511	29532857	These genomic alterations typically lead to the aberrant activation of two main signaling pathways in melanoma: The RAS/RAF/MEK/ERK signaling cascade [also known as the mitogen-activated protein kinase (MAPK) pathway] and the phosphoinositol-3-kinase (PI3K)/AKT pathway.	('alterations', 'Var', (14, 25))	('MAPK', 'Gene', (203, 207))	('signaling cascade', 'biological_process', 'GO:0007165', ('132', '149'))	('phosphoinositol-3-kinase', 'Gene', (226, 250))	('MEK', 'Gene', '5609', (124, 127))	('RAF', 'Gene', '22882', (120, 123))	('ERK', 'Gene', '5594', (128, 131))	('phosphoinositol-3-kinase', 'Gene', '5294', (226, 250))	('MAPK', 'Gene', '5594', (203, 207))	('activation', 'PosReg', (57, 67))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('MEK', 'Gene', (124, 127))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('RAF', 'Gene', (120, 123))	('AKT', 'Gene', (258, 261))	('ERK', 'Gene', (128, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('252', '256'))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('MAPK', 'molecular_function', 'GO:0004707', ('203', '207'))	('RAS', 'Chemical', 'MESH:D011883', (116, 119))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('AKT', 'Gene', '207', (258, 261))	('ERK', 'molecular_function', 'GO:0004707', ('128', '131'))
93516	29532857	Among the different mechanisms responsible for abnormal MAPK pathway signaling in melanoma, the most frequent genetic abnormalities are, by far, BRAF mutations.	('frequent', 'Reg', (101, 109))	('BRAF', 'Gene', (145, 149))	('MAPK', 'Gene', '5594', (56, 60))	('MAPK', 'molecular_function', 'GO:0004707', ('56', '60'))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('signaling', 'biological_process', 'GO:0023052', ('69', '78'))	('melanoma', 'Disease', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('mutations', 'Var', (150, 159))	('genetic abnormalities', 'Disease', 'MESH:D030342', (110, 131))	('MAPK', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (145, 149))	('genetic abnormalities', 'Disease', (110, 131))
93517	29532857	Indeed, 37 to 50% of melanomas carry a somatic mutation in the BRAF gene with the highest frequency in cutaneous melanomas derived from intermittent sun exposure damage (approximately 60% carry a BRAF mutation).	('melanomas', 'Disease', (113, 122))	('sun exposure damage', 'Phenotype', 'HP:0000992', (149, 168))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('mutation', 'Var', (47, 55))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (103, 122))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (103, 122))	('BRAF', 'Gene', '673', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanomas', 'Disease', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (113, 122))	('BRAF', 'Gene', (196, 200))	('BRAF', 'Gene', '673', (63, 67))	('melanomas', 'Disease', 'MESH:D008545', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cutaneous melanomas', 'Disease', (103, 122))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('BRAF', 'Gene', (63, 67))
93518	29532857	Usually, BRAF mutations detected in cutaneous melanoma are missense mutations that determine amino acid substitution at valine 600.	('BRAF', 'Gene', (9, 13))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('amino acid substitution', 'Var', (93, 116))	('valine', 'Chemical', 'MESH:D014633', (120, 126))	('cutaneous melanoma', 'Disease', (36, 54))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (36, 54))	('valine 600', 'Var', (120, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (36, 54))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
93519	29532857	Approximately 80-90% of BRAF mutations are V600E (valine to glutamic acid), while 5-12% are valine to lysine substitution (V600K) and <=5% are V600D (valine to aspartic acid) or V600R (valine to arginine).	('V600R', 'Var', (178, 183))	('V600D', 'Mutation', 'rs121913377', (143, 148))	('V600K', 'Mutation', 'rs121913227', (123, 128))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('mutations', 'Var', (29, 38))	('glutamic acid', 'Chemical', 'MESH:D018698', (60, 73))	('valine', 'Chemical', 'MESH:D014633', (50, 56))	('valine', 'Chemical', 'MESH:D014633', (92, 98))	('arginine', 'Chemical', 'MESH:D001120', (195, 203))	('valine', 'Chemical', 'MESH:D014633', (150, 156))	('BRAF', 'Gene', (24, 28))	('lysine', 'Chemical', 'MESH:D008239', (102, 108))	('BRAF', 'Gene', '673', (24, 28))	('V600R', 'Mutation', 'rs121913227', (178, 183))	('V600E', 'Var', (43, 48))	('aspartic acid', 'Chemical', 'MESH:D001224', (160, 173))	('valine', 'Chemical', 'MESH:D014633', (185, 191))
93523	29532857	Most of the non-V600E BRAF mutations act similarly through the alteration of glycine-rich loop and activation segment interaction, thus increasing BRAF kinase activity.	('alteration', 'Reg', (63, 73))	('kinase activity', 'molecular_function', 'GO:0016301', ('152', '167'))	('glycine-rich loop', 'MPA', (77, 94))	('kinase activity', 'MPA', (152, 167))	('BRAF', 'Gene', '673', (22, 26))	('increasing', 'PosReg', (136, 146))	('V600E', 'Mutation', 'rs113488022', (16, 21))	('activation segment interaction', 'MPA', (99, 129))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (147, 151))	('glycine', 'Chemical', 'MESH:D005998', (77, 84))	('non-V600E', 'Var', (12, 21))
93525	29532857	NRAS is mutated in 15-30% of melanomas and in the majority of cases, these mutations are missense mutations of codon 12, 13 or 61 (the latter account for 80% of all NRAS mutations in melanoma).	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (29, 38))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('NRAS', 'Gene', '4893', (0, 4))	('missense mutations', 'Var', (89, 107))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Disease', 'MESH:D008545', (29, 38))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', (165, 169))	('melanomas', 'Disease', (29, 38))	('NRAS', 'Gene', '4893', (165, 169))
93526	29532857	Mutations of these codons lead to the prolongation of the NRAS-active GTP-bound state, thus abnormally maintaining NRAS signaling through both the MAPK and the PI3K pathways.	('MAPK', 'Gene', '5594', (147, 151))	('NRAS', 'Gene', '4893', (58, 62))	('NRAS', 'Gene', (115, 119))	('MAPK', 'molecular_function', 'GO:0004707', ('147', '151'))	('maintaining', 'PosReg', (103, 114))	('MAPK', 'Gene', (147, 151))	('NRAS', 'Gene', '4893', (115, 119))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('Mutations', 'Var', (0, 9))	('PI3K pathways', 'Pathway', (160, 173))	('PI3K', 'molecular_function', 'GO:0016303', ('160', '164'))	('NRAS', 'Gene', (58, 62))	('prolongation', 'PosReg', (38, 50))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))
93535	29532857	TERT promoter mutations confer proliferative advantage to melanoma cells and along with heterozygous CDKN2A alterations, have been frequently detected in in situ melanoma.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('detected', 'Reg', (142, 150))	('CDKN2A', 'Gene', (101, 107))	('melanoma', 'Disease', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('situ melanoma', 'Disease', (157, 170))	('CDKN2A', 'Gene', '1029', (101, 107))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('situ melanoma', 'Disease', 'MESH:D008545', (157, 170))	('proliferative advantage', 'CPA', (31, 54))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', (58, 66))
93537	29532857	The further bi-allelic inactivation of CDKN2A is a subsequent step to the melanoma invasive phenotype, rarely observed in precursor lesions.	('melanoma invasive', 'Disease', (74, 91))	('CDKN2A', 'Gene', (39, 45))	('CDKN2A', 'Gene', '1029', (39, 45))	('melanoma invasive', 'Disease', 'MESH:D008545', (74, 91))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('bi-allelic inactivation', 'Var', (12, 35))
93539	29532857	PTEN dysregulation is usually detected in vertical growth phase melanoma and metastases with a frequency of 10-30% of cutaneous melanoma.	('dysregulation', 'Var', (5, 18))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('metastases', 'Disease', (77, 87))	('melanoma', 'Disease', (64, 72))	('cutaneous melanoma', 'Disease', (118, 136))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('detected', 'Reg', (30, 38))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('melanoma', 'Disease', (128, 136))
93540	29532857	Missense and frameshift mutations or chromosomal deletions are the most frequent alteration detected in PTEN but also epigenetic mechanisms and microRNAs post transcriptional regulation of PTEN expression have been found.	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('chromosomal deletions', 'Var', (37, 58))	('regulation', 'biological_process', 'GO:0065007', ('175', '185'))	('frameshift mutations', 'Var', (13, 33))	('PTEN', 'Gene', (104, 108))	('Missense', 'Var', (0, 8))	('PTEN', 'Gene', '5728', (104, 108))
93541	29532857	The genomic alteration involving PTEN are usually mutually exclusive with NRAS mutations, but frequently co-occur with BRAF gain-of-function.	('BRAF', 'Gene', '673', (119, 123))	('PTEN', 'Gene', (33, 37))	('NRAS', 'Gene', (74, 78))	('PTEN', 'Gene', '5728', (33, 37))	('BRAF', 'Gene', (119, 123))	('NRAS', 'Gene', '4893', (74, 78))	('gain-of-function', 'PosReg', (124, 140))	('mutations', 'Var', (79, 88))
93543	29532857	Indeed, BRAF mutations and PTEN loss-of-function together activate both the MAPK pathway and the PI3K pathway, thus being potentially equivalent to NRAS-only activation.	('NRAS', 'Gene', (148, 152))	('BRAF', 'Gene', '673', (8, 12))	('PI3K pathway', 'Pathway', (97, 109))	('MAPK', 'Gene', '5594', (76, 80))	('BRAF', 'Gene', (8, 12))	('NRAS', 'Gene', '4893', (148, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('97', '101'))	('MAPK', 'molecular_function', 'GO:0004707', ('76', '80'))	('MAPK', 'Gene', (76, 80))	('PTEN', 'Gene', (27, 31))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (27, 31))	('loss-of-function', 'NegReg', (32, 48))
93544	29532857	In the clinical setting, PTEN loss-of-function represents one of the mechanism responsible for the acquired resistance of BRAF mutant melanoma treated with BRAF inhibitors.	('mutant', 'Var', (127, 133))	('loss-of-function', 'NegReg', (30, 46))	('BRAF', 'Gene', (156, 160))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))	('BRAF', 'Gene', '673', (156, 160))
93545	29532857	Even though a conclusive model of recurrent alterations leading to metastatic progression has yet to be elucidated, beta-catenin-mediated WNT signaling activation has been shown to be associated with metastatic dissemination, as well as melanoma formation.	('melanoma', 'Disease', (237, 245))	('activation', 'PosReg', (152, 162))	('melanoma', 'Disease', 'MESH:D008545', (237, 245))	('signaling', 'biological_process', 'GO:0023052', ('142', '151'))	('alterations', 'Var', (44, 55))	('formation', 'biological_process', 'GO:0009058', ('246', '255'))	('associated', 'Reg', (184, 194))	('metastatic dissemination', 'CPA', (200, 224))	('beta-catenin', 'Gene', (116, 128))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('beta-catenin', 'Gene', '1499', (116, 128))
93546	29532857	CTNNB1 (beta-catenin) gene mutations are detected in 2-4% of malignant melanomas and act through the stabilization of beta-catenin and increased transcription of TCF/LEF-responsive target genes.	('stabilization', 'MPA', (101, 114))	('mutations', 'Var', (27, 36))	('CTNNB1', 'Gene', '1499', (0, 6))	('transcription', 'biological_process', 'GO:0006351', ('145', '158'))	('beta-catenin', 'Gene', (8, 20))	('beta-catenin', 'Gene', (118, 130))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('CTNNB1', 'Gene', (0, 6))	('melanomas', 'Phenotype', 'HP:0002861', (71, 80))	('increased', 'PosReg', (135, 144))	('transcription', 'MPA', (145, 158))	('malignant melanomas', 'Disease', 'MESH:D008545', (61, 80))	('beta-catenin', 'Gene', '1499', (118, 130))	('beta-catenin', 'Gene', '1499', (8, 20))	('malignant melanomas', 'Phenotype', 'HP:0002861', (61, 80))	('malignant melanomas', 'Disease', (61, 80))
93557	29532857	Anti-PD1 antibodies and, with lower magnitude anti-CTLA4 therapeutic agents, offer lower response rates, but potentially long durable responses.	('CTLA4', 'Gene', '1493', (51, 56))	('antibodies', 'Var', (9, 19))	('lower', 'NegReg', (83, 88))	('response', 'MPA', (89, 97))	('PD1', 'Gene', '5133', (5, 8))	('CTLA4', 'Gene', (51, 56))	('PD1', 'Gene', (5, 8))
93559	29532857	Nivolumab and pembrolizumab have shown to be effective on BRAF mutant melanoma after BRAF inhibitor resistance has risen, but there are no similar data for ipilimumab or for BRAF-inhibitor therapy in those with primary or secondary resistance to anti-PD-1 therapy.	('melanoma', 'Disease', (70, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (14, 27))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('mutant', 'Var', (63, 69))	('Nivolumab', 'Chemical', 'MESH:D000077594', (0, 9))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('ipilimumab', 'Chemical', 'MESH:D000074324', (156, 166))	('BRAF', 'Gene', (174, 178))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
93567	29532857	Several studies have described the central role of acquired genetic mutations affecting the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways in inducing resistance to both chemotherapy and targeted therapy in melanoma and other tumor types.	('PTEN', 'Gene', (117, 121))	('genetic mutations', 'Var', (60, 77))	('MEK', 'Gene', '5609', (100, 103))	('Raf', 'Gene', (96, 99))	('inducing', 'Reg', (153, 161))	('ERK', 'Gene', '5594', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('MEK', 'Gene', (100, 103))	('ERK', 'molecular_function', 'GO:0004707', ('104', '107'))	('resistance to', 'MPA', (162, 175))	('PTEN', 'Gene', '5728', (117, 121))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('ERK', 'Gene', (104, 107))	('Raf', 'Gene', '22882', (96, 99))	('mTOR', 'Gene', (126, 130))	('Akt', 'Gene', (122, 125))	('signaling', 'biological_process', 'GO:0023052', ('131', '140'))	('tumor', 'Disease', (237, 242))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('PI3K', 'molecular_function', 'GO:0016303', ('112', '116'))	('Akt', 'Gene', '207', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('mTOR', 'Gene', '2475', (126, 130))
93573	29532857	Notably, ctDNA can be used also for the detection of mutations responsible for resistance to BRAF targeted therapies and in the future, this can be used to guide subsequent treatment strategies.	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (93, 97))	('responsible', 'Reg', (63, 74))	('mutations', 'Var', (53, 62))
93577	29532857	Moreover, several studies have demonstrated the mechanisms through which specific genomic alterations can drive immune checkpoint resistance through the alteration of antigen-presenting mechanisms and IFN-gamma production.	('immune checkpoint resistance', 'CPA', (112, 140))	('drive', 'Reg', (106, 111))	('antigen-presenting mechanisms', 'MPA', (167, 196))	('alteration', 'Reg', (153, 163))	('IFN-gamma', 'Gene', (201, 210))	('IFN-gamma', 'Gene', '3458', (201, 210))	('genomic alterations', 'Var', (82, 101))
93586	31747929	This study aimed to investigate the association of TIM-3 and LGALS9 DNA methylation with gene expression, patients' survival, as well as molecular and immune correlates in malignant melanoma.	('gene expression', 'biological_process', 'GO:0010467', ('89', '104'))	('LGALS9', 'Gene', '3965', (61, 67))	('DNA methylation', 'biological_process', 'GO:0006306', ('68', '83'))	('LGALS9', 'Gene', (61, 67))	('malignant melanoma', 'Phenotype', 'HP:0002861', (172, 190))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('malignant melanoma', 'Disease', 'MESH:D008545', (172, 190))	('TIM-3', 'Gene', '84868', (51, 56))	('TIM-3', 'Gene', (51, 56))	('malignant melanoma', 'Disease', (172, 190))	('methylation', 'Var', (72, 83))	('patients', 'Species', '9606', (106, 114))	('association', 'Interaction', (36, 47))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))
93589	31747929	High TIM-3 mRNA expression (hazard ratio (HR) = 0.88, 95% confidence interval (CI) [0.81-0.97], P = 0.007) was significantly associated with better overall survival.	('High', 'Var', (0, 4))	('better', 'PosReg', (141, 147))	('overall', 'MPA', (148, 155))	('mRNA expression', 'MPA', (11, 26))	('TIM-3', 'Gene', '84868', (5, 10))	('TIM-3', 'Gene', (5, 10))
93591	31747929	High LGALS9 mRNA expression was significantly associated with increased overall survival (HR = 0.83, 95%CI [0.75-0.93], P = 0.001).	('increased', 'PosReg', (62, 71))	('High', 'Var', (0, 4))	('LGALS9', 'Gene', (5, 11))	('overall survival', 'MPA', (72, 88))	('LGALS9', 'Gene', '3965', (5, 11))	('mRNA expression', 'MPA', (12, 27))
93592	31747929	In addition, we found significant correlations between TIM-3 and LGALS9 methylation and mRNA expression with immune cell infiltrates and significant differences among distinct immune cell subsets.	('mRNA expression', 'MPA', (88, 103))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('TIM-3', 'Gene', (55, 60))	('LGALS9', 'Gene', '3965', (65, 71))	('TIM-3', 'Gene', '84868', (55, 60))	('methylation', 'Var', (72, 83))	('differences', 'Reg', (149, 160))	('LGALS9', 'Gene', (65, 71))	('correlations', 'Interaction', (34, 46))
93593	31747929	Our study points toward an epigenetic regulation of TIM-3 and LGALS9 via DNA methylation and might provide an avenue for the development of a predictive biomarker for response to immune checkpoint blockade.	('methylation', 'Var', (77, 88))	('LGALS9', 'Gene', '3965', (62, 68))	('TIM-3', 'Gene', (52, 57))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('regulation', 'biological_process', 'GO:0065007', ('38', '48'))	('LGALS9', 'Gene', (62, 68))	('TIM-3', 'Gene', '84868', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('DNA', 'MPA', (73, 76))	('epigenetic', 'Var', (27, 37))
93601	31747929	Food and Drug Administration (FDA)-approved inhibitors target the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1).	('programmed cell death protein 1', 'Gene', (139, 170))	('programmed cell death protein 1', 'Gene', '100533201', (139, 170))	('inhibitors', 'Var', (44, 54))	('ligand', 'molecular_function', 'GO:0005488', ('205', '211'))	('programmed cell death', 'biological_process', 'GO:0012501', ('139', '160'))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (85, 128))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '397286', (85, 128))	('programmed cell death', 'biological_process', 'GO:0012501', ('183', '204'))	('protein', 'cellular_component', 'GO:0003675', ('119', '126'))	('programmed cell death ligand 1', 'Gene', '574058', (183, 213))	('programmed cell death ligand 1', 'Gene', (183, 213))
93612	31747929	Among epigenetic mechanisms, DNA methylation is of fundamental importance in multiple biological processes, including embryogenesis, imprinting, X chromosome inactivation, T cell differentiation (including T cell exhaustion), and tumorigenesis.	('tumor', 'Disease', (230, 235))	('T cell differentiation', 'CPA', (172, 194))	('embryogenesis', 'biological_process', 'GO:0009793', ('118', '131'))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('X chromosome', 'cellular_component', 'GO:0000805', ('145', '157'))	('DNA methylation', 'biological_process', 'GO:0006306', ('29', '44'))	('X chromosome inactivation', 'biological_process', 'GO:0009048', ('145', '170'))	('X chromosome inactivation', 'Var', (145, 170))	('T cell differentiation', 'biological_process', 'GO:0030217', ('172', '194'))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (206, 223))	('embryogenesis', 'biological_process', 'GO:0009792', ('118', '131'))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('embryogenesis', 'biological_process', 'GO:0009790', ('118', '131'))
93613	31747929	In melanoma, DNA methylation has already been shown to have an important impact on gene transcription, and is believed to play a central role in pathogenesis and disease progression (reviewed in).	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('impact', 'Reg', (73, 79))	('pathogenesis', 'biological_process', 'GO:0009405', ('145', '157'))	('gene transcription', 'MPA', (83, 101))	('methylation', 'Var', (17, 28))	('role', 'Reg', (137, 141))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('DNA methylation', 'biological_process', 'GO:0006306', ('13', '28'))	('melanoma', 'Disease', (3, 11))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
93615	31747929	Two recent studies identified TIM-3 hypomethylation in colorectal and breast cancer tissues compared to normal tissues.	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (55, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypomethylation', 'Var', (36, 51))	('TIM-3', 'Gene', '84868', (30, 35))	('TIM-3', 'Gene', (30, 35))
93618	31747929	Of those, CpGs targeted by beads cg19110684 (1), cg19646897 (2), cg15371617 (3), cg17484237 (4), cg19063654 (5), and cg18374914 (6) were used to assess methylation at the HAVCR2 gene locus and beads cg19654781 (7), cg10699049 (8), cg27625456 (9), cg21157094 (10), cg23290146 (11), cg05105919 (12), cg03909504 (13), and cg06852032 (14) allowed for methylation analysis of the LGALS9 gene (Fig.	('cg03909504', 'Var', (298, 308))	('HAVCR2', 'Gene', (171, 177))	('cg21157094', 'Var', (247, 257))	('cg05105919', 'Var', (281, 291))	('methylation', 'biological_process', 'GO:0032259', ('152', '163'))	('methylation', 'biological_process', 'GO:0032259', ('347', '358'))	('cg27625456', 'Var', (231, 241))	('LGALS9', 'Gene', '3965', (375, 381))	('HAVCR2', 'Gene', '84868', (171, 177))	('cg06852032', 'Var', (319, 329))	('LGALS9', 'Gene', (375, 381))	('cg23290146', 'Var', (264, 274))
93627	31747929	Based on genomic analyses of the most prevalent mutations in the tumors (significantly mutated genes), the TCGA Research Network classified four molecular subtypes for melanoma patients: mutant BRAF, mutant RAS, mutant NF1, and Triple-Wildtype.	('mutant RAS', 'Var', (200, 210))	('mutant', 'Var', (212, 218))	('BRAF', 'Gene', (194, 198))	('patients', 'Species', '9606', (177, 185))	('mutant', 'Var', (187, 193))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('NF1', 'Gene', '4763', (219, 222))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('NF1', 'Gene', (219, 222))	('melanoma', 'Disease', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
93628	31747929	Indeed, we found HAVCR2 methylation correlating positively with mutational subtype (beads 2-5) and in particular with BRAF mutation (beads 1-5), with lower methylation levels present in BRAF-mutated compared to -wildtype tumors (see Additional file 1).	('lower', 'NegReg', (150, 155))	('mutation', 'Var', (123, 131))	('methylation', 'MPA', (24, 35))	('BRAF-mutated', 'Var', (186, 198))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('methylation', 'biological_process', 'GO:0032259', ('156', '167'))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('HAVCR2', 'Gene', (17, 23))	('HAVCR2', 'Gene', '84868', (17, 23))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumors', 'Disease', (221, 227))	('BRAF', 'Disease', (118, 122))	('methylation levels', 'MPA', (156, 174))
93633	31747929	Hence, we tested the leukocyte fraction and tumor purity in BRAF-mutated and BRAF-wildtype melanoma.	('BRAF-wildtype melanoma', 'Disease', (77, 99))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('BRAF-mutated', 'Var', (60, 72))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('BRAF-wildtype melanoma', 'Disease', 'MESH:D008545', (77, 99))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tested', 'Reg', (10, 16))	('tumor', 'Disease', (44, 49))
93634	31747929	We observed statistically significant differences between BRAF-mutated and -wildtype tumors and tumor purity (P = 0.036), but no statistically significant results for the leukocyte fraction (P = 0.057).	('tumors and tumor', 'Disease', 'MESH:D009369', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('differences', 'Reg', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('BRAF-mutated', 'Var', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
93639	31747929	DNA methylation analysis of HAVCR2 and LGALS9 showed the same correlation pattern as observed with mRNA expression and lymphocyte score; methylation status in the promoter regions correlated inversely with the INF-gamma signature while methylation in the gene body showed a positive correlation.	('LGALS9', 'Gene', (39, 45))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('methylation', 'Var', (137, 148))	('inversely', 'NegReg', (191, 200))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('INF-gamma signature', 'MPA', (210, 229))	('HAVCR2', 'Gene', (28, 34))	('methylation', 'biological_process', 'GO:0032259', ('236', '247'))	('LGALS9', 'Gene', '3965', (39, 45))	('HAVCR2', 'Gene', '84868', (28, 34))
93654	31747929	Furthermore, HAVCR2/TIM-3 gene body methylation correlated positively and promoter methylation inversely with total lymphocytes (bead 6: rho = 0.438, bead 2: rho = - 0.408, both P < 0.001), Th1 cells (bead 6: rho = 0.233, bead 2: rho = - 0.380, both P < 0.001;), activated CD4+ memory T cells (bead 6: rho = 0.220; bead 2: rho = - 0.225, P < 0.001), and M1 macrophages (bead 6: rho = 0.211, bead 2: rho = - 0.277, both P < 0.001).	('CD4', 'Gene', '920', (273, 276))	('TIM-3', 'Gene', '84868', (20, 25))	('HAVCR2', 'Gene', (13, 19))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('promoter', 'MPA', (74, 82))	('HAVCR2', 'Gene', '84868', (13, 19))	('CD4', 'Gene', (273, 276))	('memory', 'biological_process', 'GO:0007613', ('278', '284'))	('methylation', 'Var', (36, 47))	('TIM-3', 'Gene', (20, 25))
93665	31747929	The optimal cut-off for mRNA expression was 513.484 n.c. for TIM-3 and 1450 n.c. for LGALS9.	('LGALS9', 'Gene', (85, 91))	('mRNA expression', 'MPA', (24, 39))	('TIM-3', 'Gene', (61, 66))	('LGALS9', 'Gene', '3965', (85, 91))	('TIM-3', 'Gene', '84868', (61, 66))	('513.484 n.c.', 'Var', (44, 56))
93666	31747929	Patients with high expression of TIM-3 and LGAL9S had significantly better overall survival compared to patients with low expressing tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('better', 'PosReg', (68, 74))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('TIM-3', 'Gene', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('overall survival', 'MPA', (75, 91))	('TIM-3', 'Gene', '84868', (33, 38))	('LGAL9S', 'Gene', (43, 49))	('patients', 'Species', '9606', (104, 112))
93670	31747929	Firstly, for both TIM-3 and LGALS9, we detected significant positive correlations between mRNA expression and gene body methylation and inverse correlations between mRNA expression with promoter methylation, suggesting that DNA methylation could epigenetically regulate both genes.	('TIM-3', 'Gene', (18, 23))	('positive', 'PosReg', (60, 68))	('DNA', 'Var', (224, 227))	('inverse', 'NegReg', (136, 143))	('LGALS9', 'Gene', '3965', (28, 34))	('TIM-3', 'Gene', '84868', (18, 23))	('DNA methylation', 'biological_process', 'GO:0006306', ('224', '239'))	('LGALS9', 'Gene', (28, 34))	('DNA', 'cellular_component', 'GO:0005574', ('224', '227'))	('mRNA expression', 'MPA', (165, 180))	('regulate', 'Reg', (261, 269))	('mRNA expression', 'MPA', (90, 105))	('methylation', 'biological_process', 'GO:0032259', ('195', '206'))	('methylation', 'biological_process', 'GO:0032259', ('120', '131'))
93675	31747929	Finally, we found high TIM-3 and LGALS9 mRNA expression to be associated with a significant better overall survival.	('LGALS9', 'Gene', (33, 39))	('mRNA expression', 'MPA', (40, 55))	('TIM-3', 'Gene', (23, 28))	('high', 'Var', (18, 22))	('LGALS9', 'Gene', '3965', (33, 39))	('overall', 'MPA', (99, 106))	('TIM-3', 'Gene', '84868', (23, 28))	('better', 'PosReg', (92, 98))
93678	31747929	As expected, we observed a correlation between methylation and the IFN-gamma signature consistent with the methylation pattern that correlates positively with mRNA expression.	('methylation', 'Var', (47, 58))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('IFN-gamma', 'Gene', '3458', (67, 76))	('IFN-gamma', 'Gene', (67, 76))	('mRNA expression', 'MPA', (159, 174))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))
93680	31747929	DNA methylation of those genes could thus serve as a surrogate biomarker for tumor infiltration by TIM-3- and LGALS9-expressing immune cells.	('TIM-3', 'Gene', '84868', (99, 104))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('methylation', 'Var', (4, 15))	('LGALS9', 'Gene', '3965', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TIM-3', 'Gene', (99, 104))	('LGALS9', 'Gene', (110, 116))
93683	31747929	Multiple clinical trials with various anti-TIM-3 antibodies (BMS-986258 (Bristol-Myers Squibb, New York City, New York, United States), TSR-022 (Tesaro, Waltham, Massachusetts, United States), LY3321367, and LY3415244 (Eli Lilly and Company, Indianapolis, Indiana, United States); INCAGN02390 (Incyte, Wilmington, Delaware, United States), MGB453 (Novartis, Basel, Switzerland), Sym023 (Symphogen A/S, Copenhagen, Denmark), RO7121661 (Hoffmann-La Roche, Basel, Switzerland), BGB-A425 (BeiGene, Peking, China)) are currently ongoing (ClinicalTrials.gov Identifiers: NCT03489343, NCT03680508, NCT02817633, NCT03099109, NCT02608268, NCT03652077, NCT03066648, NCT03446040, NCT03708328, NCT03311412, NCT03744468, NCT03752177, NCT03940352, NCT03307785).	('NCT02608268', 'Var', (617, 628))	('NCT03752177', 'Var', (708, 719))	('NCT03099109', 'Var', (604, 615))	('NCT03940352', 'Var', (721, 732))	('NCT03446040', 'Var', (656, 667))	('NCT03311412', 'Var', (682, 693))	('NCT03066648', 'Var', (643, 654))	('NCT03680508', 'Var', (578, 589))	('TSR', 'molecular_function', 'GO:0047362', ('136', '139'))	('NCT03307785', 'Var', (734, 745))	('NCT03652077', 'Var', (630, 641))	('TIM-3', 'Gene', '84868', (43, 48))	('NCT03744468', 'Var', (695, 706))	('NCT03708328', 'Var', (669, 680))	('TIM-3', 'Gene', (43, 48))	('NCT02817633', 'Var', (591, 602))
93688	31747929	provided data suggesting that DNA methylation of the immune checkpoint gene CTLA4 predicts response to CTLA-4- and PD-1-targeted ICB.	('response', 'MPA', (91, 99))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('methylation', 'Var', (34, 45))	('CTLA4', 'Gene', '1493', (76, 81))	('predicts', 'Reg', (82, 90))	('ICB', 'Chemical', '-', (129, 132))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('CTLA4', 'Gene', (76, 81))
93689	31747929	Our results suggest that methylation testing of TIM-3 could be a promising predictive biomarker to select the subset of melanoma patients who would benefit from TIM-3-targeted ICB.	('TIM-3', 'Gene', '84868', (48, 53))	('TIM-3', 'Gene', (48, 53))	('ICB', 'Chemical', '-', (176, 179))	('patients', 'Species', '9606', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('methylation', 'Var', (25, 36))	('melanoma', 'Disease', (120, 128))	('methylation', 'biological_process', 'GO:0032259', ('25', '36'))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('TIM-3', 'Gene', '84868', (161, 166))	('TIM-3', 'Gene', (161, 166))
93690	31747929	Accordingly, future studies should address the value of TIM-3 methylation testing as companion biomarker for TIM-3 ICB.	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('ICB', 'Chemical', '-', (115, 118))	('TIM-3', 'Gene', '84868', (56, 61))	('TIM-3', 'Gene', (56, 61))	('methylation', 'Var', (62, 73))	('TIM-3', 'Gene', '84868', (109, 114))	('TIM-3', 'Gene', (109, 114))
93693	31747929	Prior studies described hypomethylation of TIM-3 being associated with T cell exhaustion.	('T cell exhaustion', 'Phenotype', 'HP:0005435', (71, 88))	('T cell exhaustion', 'Disease', (71, 88))	('associated', 'Reg', (55, 65))	('hypomethylation', 'Var', (24, 39))	('TIM-3', 'Gene', '84868', (43, 48))	('TIM-3', 'Gene', (43, 48))
93694	31747929	Our study showed that TIM-3 promoter methylation correlated inversely with mRNA expression.	('mRNA expression', 'MPA', (75, 90))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('inversely', 'NegReg', (60, 69))	('TIM-3', 'Gene', (22, 27))	('TIM-3', 'Gene', '84868', (22, 27))
93702	31747929	In the context of immunotherapy, aberrant DNA methylation in melanoma has been described in multiple studies.	('DNA methylation', 'biological_process', 'GO:0006306', ('42', '57'))	('DNA', 'Protein', (42, 45))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('aberrant', 'Var', (33, 41))
93703	31747929	showed that DNA methylation influences PD-L1 expression in melanoma cells, with hypomethylation being accompanied by PD-L1 upregulation.	('PD-L1', 'Gene', (39, 44))	('influences', 'Reg', (28, 38))	('hypomethylation', 'Var', (80, 95))	('DNA methylation', 'biological_process', 'GO:0006306', ('12', '27'))	('upregulation', 'PosReg', (123, 135))	('expression', 'MPA', (45, 55))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('DNA', 'cellular_component', 'GO:0005574', ('12', '15'))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))
93709	31747929	have already shown that epigenetic modification of TIM-3 in human colorectal and breast cancer could be a useful biomarker in these diseases.	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('TIM-3', 'Gene', '84868', (51, 56))	('TIM-3', 'Gene', (51, 56))	('epigenetic modification', 'Var', (24, 47))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (60, 65))
93710	31747929	In the future, methylation testing of TIM-3 might serve as a predictive biomarker for melanoma patients.	('TIM-3', 'Gene', (38, 43))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('methylation testing', 'Var', (15, 34))	('patients', 'Species', '9606', (95, 103))	('TIM-3', 'Gene', '84868', (38, 43))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))
93716	31747929	In accordance with this hypothesis, multiple recent studies found that high levels of TIM-3 expression in tumors were associated with worse overall survival (reviewed in).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('TIM-3', 'Gene', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('TIM-3', 'Gene', '84868', (86, 91))	('high levels', 'Var', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('overall survival', 'MPA', (140, 156))	('worse', 'NegReg', (134, 139))	('expression', 'MPA', (92, 102))
93720	31747929	Therefore, the better survival of patients with high TIM-3 and LGALS9 expression observed in our study might be due to a better immune response in the tumor, regardless of the high expression of TIM-3.	('survival', 'CPA', (22, 30))	('TIM-3', 'Gene', '84868', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('immune response', 'CPA', (128, 143))	('LGALS9', 'Gene', '3965', (63, 69))	('tumor', 'Disease', (151, 156))	('better', 'PosReg', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('TIM-3', 'Gene', (53, 58))	('patients', 'Species', '9606', (34, 42))	('immune response', 'biological_process', 'GO:0006955', ('128', '143'))	('TIM-3', 'Gene', '84868', (53, 58))	('LGALS9', 'Gene', (63, 69))	('high', 'Var', (48, 52))	('TIM-3', 'Gene', (195, 200))	('better', 'PosReg', (15, 21))
93726	31747929	previously showed that promoter methylation of CTLA4 correlates with BRAF mutational status in melanoma.	('CTLA4', 'Gene', (47, 52))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('promoter methylation', 'MPA', (23, 43))	('mutational status', 'Var', (74, 91))	('correlates', 'Reg', (53, 63))	('CTLA4', 'Gene', '1493', (47, 52))	('BRAF', 'Gene', (69, 73))
93727	31747929	detected changes in the tumor microenvironment under BRAF inhibition with an increase of cytotoxic CD8+ T infiltrates and enhanced cytotoxic markers.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('enhanced', 'PosReg', (122, 130))	('cytotoxic markers', 'MPA', (131, 148))	('CD8', 'Gene', (99, 102))	('tumor', 'Disease', (24, 29))	('CD8', 'Gene', '925', (99, 102))	('inhibition', 'Var', (58, 68))	('increase', 'PosReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('changes', 'Reg', (9, 16))
93729	31747929	Several other studies using melanoma cell lines found augmented anti-tumor immune responses under BRAF inhibition.	('melanoma', 'Disease', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('augmented', 'PosReg', (54, 63))	('inhibition', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
93730	31747929	Murine models have already shown the potential of the combination of ICB and BRAF inhibition for an enhanced therapy response.	('inhibition', 'Var', (82, 92))	('enhanced', 'PosReg', (100, 108))	('combination', 'Interaction', (54, 65))	('BRAF', 'Gene', (77, 81))	('therapy response', 'CPA', (109, 125))	('Murine', 'Species', '10090', (0, 6))	('ICB', 'Chemical', '-', (69, 72))	('ICB', 'Gene', (69, 72))
93732	31747929	Altogether, this might provide rationale for future studies investigating potential pathophysiologic connections between immune checkpoint expression, among them TIM-3, and BRAF mutations, or BRAF inhibition in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('BRAF', 'Gene', (173, 177))	('TIM-3', 'Gene', (162, 167))	('TIM-3', 'Gene', '84868', (162, 167))	('mutations', 'Var', (178, 187))
93778	25155861	Following the miRNA qPCR, two miRNAs, miR-30c-5p and miR-181a-5p, were selected as the most stable miRNA using NormFinder.	('miR-30c', 'Gene', '407031', (38, 45))	('miR-181a-5p', 'Var', (53, 64))	('miR-30c', 'Gene', (38, 45))
93843	25155861	Bioinformatics analysis revealed that the miRNAs predictive of recurrence may regulate several key aspects of melanoma biology, including immune signaling pathways, melanogenesis, and the cell cycle.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cell cycle', 'CPA', (188, 198))	('melanoma', 'Disease', (110, 118))	('cell cycle', 'biological_process', 'GO:0007049', ('188', '198'))	('immune signaling pathways', 'Pathway', (138, 163))	('regulate', 'Reg', (78, 86))	('melanogenesis', 'CPA', (165, 178))	('miRNAs', 'Var', (42, 48))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
93844	27914105	Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D.	('investigated', 'Reg', (175, 187))	('cutaneous melanoma', 'Disease', (147, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (147, 165))	('cutaneous melanoma', 'Disease', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (147, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('signaling pathway', 'biological_process', 'GO:0007165', ('268', '285'))	('signaling pathway', 'biological_process', 'GO:0007165', ('33', '50'))	('single nucleotide', 'Var', (204, 221))	('variants', 'Var', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))
93846	27914105	Among these, three independent SNPs (i.e., DOCK1 rs11018104 T>A, rs35748949 C>T and PAK2 rs1718404 C>T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, P = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively].	('DOCK1', 'Gene', '1793', (43, 48))	('rs11018104 T>A', 'Var', (49, 63))	('rs35748949 C>T', 'Var', (65, 79))	('rs1718404', 'Mutation', 'rs1718404', (89, 98))	('rs35748949', 'Mutation', 'rs35748949', (65, 75))	('PAK2', 'Gene', '5062', (84, 88))	('rs1718404 C>T', 'Var', (89, 102))	('DOCK1', 'Gene', (43, 48))	('rs11018104', 'Mutation', 'rs11018104', (49, 59))	('CMSS', 'Disease', (132, 136))	('PAK2', 'Gene', (84, 88))
93849	27914105	Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients.	('modulate', 'Reg', (80, 88))	('signaling pathway', 'biological_process', 'GO:0007165', ('33', '50'))	('patients', 'Species', '9606', (108, 116))	('integrin signaling pathway', 'Pathway', (24, 50))	('Genetic variants', 'Var', (0, 16))
93853	27914105	Recently, several studies have reported that some putatively functional single nucleotide polymorphisms (SNPs) in genes involved in crucial biological pathways are indeed potentially predicting survival of CM patients by using the available genotyping data from published genome-wide association studies (GWASs).	('patients', 'Species', '9606', (209, 217))	('predicting', 'Reg', (183, 193))	('single nucleotide polymorphisms', 'Var', (72, 103))
93879	27914105	Among these SNPs, nine were validated and remained statistically significantly associated with melanoma survival at P <= 0.05 in the Harvard study, including three SNPs in DOCK1 (dedicator of cytokinesis 1) and six SNPs in PAK2 (p21 activated kinase 2) (Table 1).	('PAK2', 'Gene', '5062', (223, 227))	('dedicator of cytokinesis 1', 'Gene', '1793', (179, 205))	('DOCK1', 'Gene', (172, 177))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('dedicator of cytokinesis 1', 'Gene', (179, 205))	('melanoma', 'Disease', (95, 103))	('associated with', 'Reg', (79, 94))	('DOCK1', 'Gene', '1793', (172, 177))	('p21 activated kinase 2', 'Gene', (229, 251))	('PAK2', 'Gene', (223, 227))	('p21 activated kinase 2', 'Gene', '5062', (229, 251))	('cytokinesis', 'biological_process', 'GO:0000910', ('192', '203'))	('SNPs', 'Var', (164, 168))
93881	27914105	We further performed LD analysis of SNPs in DOCK1 and PAK2, and the LD values were obtained from Europeans of the 1000 Genomes Project.	('PAK2', 'Gene', (54, 58))	('SNPs', 'Var', (36, 40))	('DOCK1', 'Gene', '1793', (44, 49))	('PAK2', 'Gene', '5062', (54, 58))	('DOCK1', 'Gene', (44, 49))
93882	27914105	Except for rs11018104, two other SNPs (rs7099958 and rs35748949) in DOCK1 were in high LD (Fig.	('DOCK1', 'Gene', (68, 73))	('DOCK1', 'Gene', '1793', (68, 73))	('rs35748949', 'Var', (53, 63))	('rs35748949', 'Mutation', 'rs35748949', (53, 63))	('rs7099958', 'Mutation', 'rs7099958', (39, 48))	('rs7099958', 'Var', (39, 48))	('rs11018104', 'Mutation', 'rs11018104', (11, 21))
93883	27914105	For PAK2, four SNPs showed high LD with each other (rs843527, rs843533, rs35604781 and rs1718404), except for rs2461514 and rs7648479 that had low LD with the other four SNPs (Fig.	('rs7648479', 'Mutation', 'rs7648479', (124, 133))	('rs2461514', 'Mutation', 'rs2461514', (110, 119))	('PAK2', 'Gene', '5062', (4, 8))	('rs843527', 'Mutation', 'rs843527', (52, 60))	('rs7648479', 'Var', (124, 133))	('PAK2', 'Gene', (4, 8))	('rs843533', 'Var', (62, 70))	('rs35604781', 'Mutation', 'rs35604781', (72, 82))	('rs1718404', 'Mutation', 'rs1718404', (87, 96))	('rs843533', 'Mutation', 'rs843533', (62, 70))	('rs35604781', 'Var', (72, 82))	('rs843527', 'Var', (52, 60))	('rs1718404', 'Var', (87, 96))
93884	27914105	In SNPinfo and RegulomeDB for functional relevance, one SNP in DOCK1 (rs35748949) and three SNPs in PAK2 (rs843527, rs1718404 and rs35604781) were predicted to be putatively functional.	('PAK2', 'Gene', '5062', (100, 104))	('rs1718404', 'Mutation', 'rs1718404', (116, 125))	('rs35604781', 'Mutation', 'rs35604781', (130, 140))	('rs35748949', 'Var', (70, 80))	('rs843527', 'Mutation', 'rs843527', (106, 114))	('DOCK1', 'Gene', (63, 68))	('DOCK1', 'Gene', '1793', (63, 68))	('rs35604781', 'Var', (130, 140))	('rs1718404', 'Var', (116, 125))	('PAK2', 'Gene', (100, 104))	('rs843527', 'Var', (106, 114))	('rs35748949', 'Mutation', 'rs35748949', (70, 80))
93885	27914105	Taken the overall consideration of P value, LD and predicted functions, we chose rs11018104 and rs35748949 in DOCK1 and rs1718404, rs2461514 and rs7648479 in PAK2 as the independent SNPs (Supporting Information Table 2).	('rs2461514', 'Mutation', 'rs2461514', (131, 140))	('rs1718404', 'Mutation', 'rs1718404', (120, 129))	('rs7648479', 'Mutation', 'rs7648479', (145, 154))	('PAK2', 'Gene', (158, 162))	('rs11018104', 'Var', (81, 91))	('rs11018104', 'Mutation', 'rs11018104', (81, 91))	('rs2461514', 'Var', (131, 140))	('rs1718404', 'Var', (120, 129))	('DOCK1', 'Gene', (110, 115))	('rs7648479', 'Var', (145, 154))	('DOCK1', 'Gene', '1793', (110, 115))	('rs35748949', 'Mutation', 'rs35748949', (96, 106))	('rs35748949', 'Var', (96, 106))	('PAK2', 'Gene', '5062', (158, 162))
93886	27914105	As a result, three independent SNPs (rs11018104, rs35748949 and rs1718404) remained significantly associated with CMSS at P <= 0.05 (Fig.	('rs11018104', 'Var', (37, 47))	('CMSS', 'Disease', (114, 118))	('rs11018104', 'Mutation', 'rs11018104', (37, 47))	('rs1718404', 'Mutation', 'rs1718404', (64, 73))	('rs1718404', 'Var', (64, 73))	('rs35748949', 'Mutation', 'rs35748949', (49, 59))	('associated', 'Reg', (98, 108))	('rs35748949', 'Var', (49, 59))
93887	27914105	In multivariate analyses for the three independent SNPs in the MDACC study, the risk effects of the DOCK1 rs11018104 A allele, rs35748949 T allele and protective effect of rs1718404 T allele on CM survival were statistically significant in the trend test (P = 0.013, 0.012, and 0.0004, respectively, Table 2).	('CM survival', 'CPA', (194, 205))	('rs1718404 T', 'Var', (172, 183))	('DOCK1', 'Gene', (100, 105))	('rs1718404', 'Mutation', 'rs1718404', (172, 181))	('DOCK1', 'Gene', '1793', (100, 105))	('rs35748949', 'Mutation', 'rs35748949', (127, 137))	('rs11018104', 'Mutation', 'rs11018104', (106, 116))	('rs11018104 A', 'Var', (106, 118))	('rs35748949 T', 'Var', (127, 139))
93889	27914105	Four different haplotypes [ht1 (T-C), ht2 (T-T), ht3 (A-C), and ht4 (A-T)] at rs11018104 and rs35748949 positions were identified, and ht4 carrying two risk alleles A and T was associated with the poorest clinical outcome in the MDACC study (adjHR = 1.73, 95% CI = 1.19-2.50, P = 0.004) and the Harvard study (adjHR = 2.02, 95% CI = 1.19-3.44, P = 0.010) (Table 2).	('ht4', 'Gene', (135, 138))	('T-T', 'Disease', 'MESH:D001260', (43, 46))	('rs35748949', 'Var', (93, 103))	('rs35748949', 'Mutation', 'rs35748949', (93, 103))	('T-T', 'Disease', (43, 46))	('rs11018104', 'Var', (78, 88))	('rs11018104', 'Mutation', 'rs11018104', (78, 88))
93890	27914105	To better estimate the joint effect of all the three SNPs, we combined their risk genotypes of rs11018104 TA + AA, rs35748949 CT + TT and rs1718404 CC into one variable as a genetic score for the number of unfavorable genotypes (NUGs) (Table 3).	('rs35748949 CT + TT', 'Var', (115, 133))	('rs11018104', 'Mutation', 'rs11018104', (95, 105))	('rs1718404 CC', 'Var', (138, 150))	('rs1718404', 'Mutation', 'rs1718404', (138, 147))	('rs11018104 TA + AA', 'Var', (95, 113))	('rs35748949', 'Mutation', 'rs35748949', (115, 125))
93895	27914105	We found that rs1718404 genotype demonstrated a significant association with a decreased mRNA expression of PAK2 in both additive and dominant models (P = 0.045 and P = 0.029, respectively, Fig.	('PAK2', 'Gene', '5062', (108, 112))	('decreased', 'NegReg', (79, 88))	('rs1718404', 'Mutation', 'rs1718404', (14, 23))	('mRNA expression', 'MPA', (89, 104))	('PAK2', 'Gene', (108, 112))	('rs1718404', 'Var', (14, 23))
93896	27914105	However, there were no significant associations between rs11018104 and rs35748949 genotypes with DOCK1 mRNA expression.	('rs35748949', 'Mutation', 'rs35748949', (71, 81))	('DOCK1', 'Gene', (97, 102))	('rs35748949', 'Var', (71, 81))	('rs11018104', 'Mutation', 'rs11018104', (56, 66))	('DOCK1', 'Gene', '1793', (97, 102))	('rs11018104', 'Var', (56, 66))
93897	27914105	In the present study, we found that the three novel loci, DOCK1 rs11018104 T>A, DOCK1 rs35748949 C>T and PAK2 rs1718404 C>T, independently or jointly modulated survival of CM patients.	('rs35748949', 'Mutation', 'rs35748949', (86, 96))	('DOCK1', 'Gene', (58, 63))	('DOCK1', 'Gene', '1793', (58, 63))	('rs11018104', 'Mutation', 'rs11018104', (64, 74))	('PAK2', 'Gene', '5062', (105, 109))	('DOCK1', 'Gene', (80, 85))	('modulated', 'Reg', (150, 159))	('patients', 'Species', '9606', (175, 183))	('DOCK1', 'Gene', '1793', (80, 85))	('rs11018104 T>A', 'Var', (64, 78))	('rs1718404', 'Mutation', 'rs1718404', (110, 119))	('rs35748949 C>T', 'Var', (86, 100))	('PAK2', 'Gene', (105, 109))
93905	27914105	In the present study, we found two SNPs, rs11018104 and rs35748949, in the intron region of DOCK1 to be associated with CM survival.	('rs35748949', 'Var', (56, 66))	('associated with', 'Reg', (104, 119))	('DOCK1', 'Gene', '1793', (92, 97))	('rs11018104', 'Var', (41, 51))	('rs11018104', 'Mutation', 'rs11018104', (41, 51))	('DOCK1', 'Gene', (92, 97))	('rs35748949', 'Mutation', 'rs35748949', (56, 66))
93906	27914105	According to the ENCODE project data from University of California Santa Cruz (UCSC), rs35748949 is located in a DNase I hypersensitive site, which represents open and active chromatins.	('rs35748949', 'Var', (86, 96))	('hypersensitive', 'Disease', (121, 135))	('California Santa Cruz', 'Disease', (56, 77))	('DNase I', 'molecular_function', 'GO:0004530', ('113', '120'))	('California Santa Cruz', 'Disease', 'MESH:D004670', (56, 77))	('rs35748949', 'Mutation', 'rs35748949', (86, 96))	('hypersensitive', 'Disease', 'MESH:D004342', (121, 135))
93912	27914105	Consistent with this, in the present study, the risk genotype of rs1718404 CC was associated with an increasing PAK2 mRNA expression.	('rs1718404', 'Mutation', 'rs1718404', (65, 74))	('PAK2', 'Gene', '5062', (112, 116))	('PAK2', 'Gene', (112, 116))	('rs1718404 CC', 'Var', (65, 77))
93913	27914105	The annotation of the ENCODE project showed that rs1718404 is also located in the DNase I hypersensitive site, a region of certain level of H3K4Me1 enrichments, which suggests that rs1718404 may be involved in transcriptional activity.	('DNase I', 'molecular_function', 'GO:0004530', ('82', '89'))	('hypersensitive', 'Disease', 'MESH:D004342', (90, 104))	('rs1718404', 'Mutation', 'rs1718404', (181, 190))	('hypersensitive', 'Disease', (90, 104))	('men', 'Species', '9606', (154, 157))	('rs1718404', 'Mutation', 'rs1718404', (49, 58))	('rs1718404', 'Var', (181, 190))	('involved', 'Reg', (198, 206))	('rs1718404', 'Var', (49, 58))
93918	27914105	The current findings suggest that genetic variants in DOCK1 (rs11018104 and rs35748949) and PAK2 (rs1718404) genes of the integrin signaling pathway may be prognostic biomarkers for CM patients, once further validated in future large, prospective studies.	('DOCK1', 'Gene', '1793', (54, 59))	('rs35748949', 'Var', (76, 86))	('rs1718404', 'Mutation', 'rs1718404', (98, 107))	('prognostic', 'Reg', (156, 166))	('rs1718404', 'Var', (98, 107))	('rs11018104', 'Var', (61, 71))	('rs11018104', 'Mutation', 'rs11018104', (61, 71))	('PAK2', 'Gene', '5062', (92, 96))	('patients', 'Species', '9606', (185, 193))	('signaling pathway', 'biological_process', 'GO:0007165', ('131', '148'))	('DOCK1', 'Gene', (54, 59))	('PAK2', 'Gene', (92, 96))	('rs35748949', 'Mutation', 'rs35748949', (76, 86))
93921	27914105	In the present study, we analyzed associations between genetic variants in these genes and cutaneous melanoma survival by using datasets from two published genome-wide association studies.	('associations', 'Interaction', (34, 46))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('variants', 'Var', (63, 71))	('cutaneous melanoma', 'Disease', (91, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))
93922	27914105	Three single nucleotide polymorphisms in two genes, DOCK1 and PAK2, showed predictive effects on survival, suggesting a potential role as prognostic factors for melanoma patients.	('patients', 'Species', '9606', (170, 178))	('PAK2', 'Gene', '5062', (62, 66))	('single nucleotide polymorphisms', 'Var', (6, 37))	('DOCK1', 'Gene', (52, 57))	('DOCK1', 'Gene', '1793', (52, 57))	('PAK2', 'Gene', (62, 66))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))
93954	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))
94006	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))
94007	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))
94008	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))
94009	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))
94010	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))
94012	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))	('canine', 'Species', '9615', (16, 22))	('oral melanomas', 'Disease', 'MESH:D008545', (23, 37))	('SF3B1', 'Gene', '23451', (102, 107))	('SPRED1', 'Gene', '161742', (119, 125))	('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))
94015	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))
94037	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'))
94042	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.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (44, 62))	('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))	('cutaneous melanoma', 'Disease', (44, 62))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('melanomas', 'Disease', (170, 179))	('dog', 'Species', '9615', (14, 17))
94051	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))
94052	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))	('harboured', 'Reg', (62, 71))	('RAS', 'Gene', (72, 75))	('KRAS', 'Gene', '403871', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('acral tumors', 'Disease', (23, 35))	('KRAS', 'Gene', (89, 93))
94075	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))	('activating', 'PosReg', (37, 47))	('humans', 'Species', '9606', (12, 18))	('PIK3', 'Gene', '5294', (136, 140))	('AKT', 'Gene', (141, 144))	('GNAQ', 'Gene', (61, 65))	('GNA11', 'Gene', '2767', (69, 74))	('MAPK', 'Pathway', (127, 131))	('GNA11', 'Gene', (69, 74))	('AKT', 'Gene', '207', (141, 144))	('stimulation', 'PosReg', (107, 118))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('mutations', 'Var', (48, 57))
94078	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))
94090	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))
94096	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))
94097	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))
94164	32405608	Patients were eligible for this study if they met one of three conditions, which included Breslow thickness of 1.0-4.0 mm; Breslow thickness of 0.75-0.99 mm and presence of ulceration, mitoses, and/or age < 40 years; or Breslow thickness of 0.50-0.74 mm and presence of at least two of the following: ulceration, mitoses, and age < 40 years.	('mitoses', 'Disease', (313, 320))	('ulceration', 'Disease', (301, 311))	('Breslow thickness of 0.75-0.99 mm', 'Var', (123, 156))	('Patients', 'Species', '9606', (0, 8))	('mitoses', 'CPA', (185, 192))	('Breslow thickness of 0.50-0.74 mm', 'Var', (220, 253))	('ulceration', 'Disease', (173, 183))
94191	32405608	The high SLNb reduction rate for T1b melanoma is particularly meaningful in light of the increasing incidence of thinner melanoma, for which CP variables are less predictive.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('SLNb', 'MPA', (9, 13))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('CP', 'Gene', '1356', (141, 143))	('reduction', 'NegReg', (14, 23))	('T1b', 'Var', (33, 36))
94256	26308244	Due to a 10% risk of sentinel lymph node (SLN) positivity for primary tumor thickness of 0.76-1 mm with mitoses, surgeons might now be prompted to offer SLN biopsy to patients with thinner melanomas if mitoses are present.	('melanomas', 'Disease', 'MESH:D008545', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mitoses', 'Var', (104, 111))	('tumor', 'Disease', (70, 75))	('melanomas', 'Disease', (189, 198))	('patients', 'Species', '9606', (167, 175))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanomas', 'Phenotype', 'HP:0002861', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('sentinel', 'Disease', (21, 29))
94274	26308244	Moreover, among the genes nominated from melanoma NGS studies, few reports have associated individual mutations with clinical outcomes or studied their use as prognostic biomarkers in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('cutaneous melanoma', 'Disease', (184, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (184, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (184, 202))	('mutations', 'Var', (102, 111))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
94276	26308244	Activating BRAF mutations are present in 50%-60% of melanoma, the majority of which are V600E (~90%) or V600K (~10%).	('Activating', 'PosReg', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('V600K', 'Var', (104, 109))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('V600K', 'Mutation', 'rs121913227', (104, 109))	('V600E', 'Var', (88, 93))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
94277	26308244	BRAF mutations have been described in high frequencies in benign nevi, although occurring less frequently in radial growth phase (RGP) compared to vertical growth phase (VGP) melanomas, suggesting that oncogenic BRAF mutations associate with melanoma progression more strongly than with melanomagenesis [20].	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('melanoma', 'Disease', (287, 295))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Disease', (175, 183))	('BRAF', 'Gene', '673', (212, 216))	('BRAF', 'Gene', (212, 216))	('melanomas', 'Disease', 'MESH:D008545', (175, 184))	('melanomagenesis', 'Disease', (287, 302))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('melanomas', 'Disease', (175, 184))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('melanoma', 'Disease', 'MESH:D008545', (287, 295))	('melanomagenesis', 'Disease', 'None', (287, 302))	('nevi', 'Phenotype', 'HP:0003764', (65, 69))	('associate with', 'Reg', (227, 241))	('melanomas', 'Phenotype', 'HP:0002861', (175, 184))	('mutations', 'Var', (217, 226))
94278	26308244	There are conflicting data on BRAF mutation status as an independent prognostic marker in melanoma.	('melanoma', 'Disease', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutation', 'Var', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
94279	26308244	A meta-analysis found that patients with BRAF mutant tumors have a 1.7 fold increased risk of death compared to BRAF wild-type (WT) tumors.	('death', 'Disease', 'MESH:D003643', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('BRAF', 'Gene', '673', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('patients', 'Species', '9606', (27, 35))	('mutant', 'Var', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('BRAF', 'Gene', (41, 45))	('tumors', 'Disease', (132, 138))	('death', 'Disease', (94, 99))	('tumors', 'Disease', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
94280	26308244	In contrast, many small studies of primary melanomas cite no independent association between BRAF mutation and survival (Table 1), though Ellerhorst et al.	('BRAF', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('primary melanomas', 'Disease', (35, 52))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('primary melanomas', 'Disease', 'MESH:D008545', (35, 52))	('BRAF', 'Gene', '673', (93, 97))
94281	26308244	did find that BRAF mutant primary melanomas may have more adverse pathological characteristics (increased thickness and ulceration) compared to WT tumors, and tend to present clinically with a higher disease stage.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('present', 'Reg', (167, 174))	('increased', 'PosReg', (96, 105))	('primary melanomas', 'Disease', 'MESH:D008545', (26, 43))	('WT tumors', 'Disease', 'MESH:C536751', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('thickness', 'CPA', (106, 115))	('WT tumors', 'Disease', (144, 153))	('BRAF', 'Gene', '673', (14, 18))	('primary melanomas', 'Disease', (26, 43))	('mutant', 'Var', (19, 25))	('BRAF', 'Gene', (14, 18))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))
94282	26308244	NRAS mutations, which occur in about 15% of cutaneous melanomas, most commonly at codon 61 (Q61K or Q61R), also lead to constitutive activation of the MAPK pathway.	('cutaneous melanomas', 'Disease', (44, 63))	('Q61R', 'Mutation', 'rs11554290', (100, 104))	('Q61K', 'Mutation', 'rs121913254', (92, 96))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('Q61K', 'Var', (92, 96))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (44, 63))	('Q61R', 'Var', (100, 104))	('activation', 'PosReg', (133, 143))	('NRAS', 'Gene', (0, 4))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (44, 62))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (44, 63))	('MAPK pathway', 'Pathway', (151, 163))	('NRAS', 'Gene', '4893', (0, 4))
94283	26308244	Similar to BRAF mutations, prognostic implications of NRAS mutations have varied in the literature (Table 1).	('NRAS', 'Gene', (54, 58))	('NRAS', 'Gene', '4893', (54, 58))	('mutations', 'Var', (59, 68))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
94284	26308244	prospectively studied 249 primary melanomas and found that patients with NRAS mutant melanoma (codon 61) had shorter melanoma-specific survival (MSS) (HR=2.51, p=0.05), and trended towards worse recurrence-free survival (RFS) in multivariate analysis (HR 2.2, p=0.09), but NRAS mutation had no impact on OS (HR 1.37, p=0.37).	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('NRAS', 'Gene', (273, 277))	('OS', 'Chemical', '-', (304, 306))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('NRAS', 'Gene', (73, 77))	('primary melanomas', 'Disease', 'MESH:D008545', (26, 43))	('recurrence-free survival', 'CPA', (195, 219))	('patients', 'Species', '9606', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('NRAS', 'Gene', '4893', (273, 277))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('mutant', 'Var', (78, 84))	('worse', 'PosReg', (189, 194))	('NRAS', 'Gene', '4893', (73, 77))	('primary melanomas', 'Disease', (26, 43))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('shorter', 'NegReg', (109, 116))
94285	26308244	NRAS mutated primary melanomas tended to be thicker, have more mitoses, and more frequently be of nodular subtype when compared to BRAF mutant or NRAS/BRAF WT tumors.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRAF', 'Gene', '673', (151, 155))	('BRAF', 'Gene', (151, 155))	('more', 'PosReg', (58, 62))	('mitoses', 'CPA', (63, 70))	('thicker', 'PosReg', (44, 51))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('NRAS', 'Gene', (0, 4))	('mutated', 'Var', (5, 12))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))	('primary melanomas', 'Disease', (13, 30))	('NRAS', 'Gene', '4893', (146, 150))	('BRAF WT tumors', 'Disease', (151, 165))	('BRAF WT tumors', 'Disease', 'MESH:C536751', (151, 165))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('primary melanomas', 'Disease', 'MESH:D008545', (13, 30))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (146, 150))
94286	26308244	Multiple other studies of primary melanomas have shown no association of NRAS mutation status with RFS, MSS, or OS.	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('RFS', 'Disease', (99, 102))	('primary melanomas', 'Disease', 'MESH:D008545', (26, 43))	('association', 'Interaction', (58, 69))	('mutation', 'Var', (78, 86))	('NRAS', 'Gene', '4893', (73, 77))	('primary melanomas', 'Disease', (26, 43))	('OS', 'Chemical', '-', (112, 114))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('MSS', 'Disease', (104, 107))	('NRAS', 'Gene', (73, 77))
94289	26308244	While there were no differences in 5 year OS between patients with BRAF mutant, NRAS mutant or WT tumors, there was a 3-fold increase in melanoma-related death in BRAF and NRAS mutated patients specifically in the high-risk category (T stage T2b or above) compared to patients with WT tumors.	('OS', 'Chemical', '-', (42, 44))	('WT tumors', 'Disease', 'MESH:C536751', (282, 291))	('NRAS', 'Gene', '4893', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('patients', 'Species', '9606', (268, 276))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('patients', 'Species', '9606', (53, 61))	('mutant', 'Var', (72, 78))	('death', 'Disease', 'MESH:D003643', (154, 159))	('increase', 'PosReg', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (137, 145))	('NRAS', 'Gene', (80, 84))	('NRAS', 'Gene', '4893', (172, 176))	('WT tumors', 'Disease', (95, 104))	('mutated', 'Var', (177, 184))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('patients', 'Species', '9606', (185, 193))	('mutant', 'Var', (85, 91))	('WT tumors', 'Disease', 'MESH:C536751', (95, 104))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('BRAF', 'Gene', '673', (67, 71))	('death', 'Disease', (154, 159))	('BRAF', 'Gene', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('melanoma', 'Disease', (137, 145))	('WT tumors', 'Disease', (282, 291))	('NRAS', 'Gene', (172, 176))
94291	26308244	KIT mutations or gene amplifications occur in 10-25% of melanomas arising from areas of acral, mucosal, or sun-damaged skin, are rare (0-2%) in cutaneous melanomas without chronic sun-damage, and can rarely co-exist with BRAF mutations.	('BRAF', 'Gene', '673', (221, 225))	('melanomas', 'Disease', 'MESH:D008545', (154, 163))	('BRAF', 'Gene', (221, 225))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (144, 163))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanomas', 'Disease', (154, 163))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('cutaneous melanomas', 'Disease', (144, 163))	('sun-damage', 'Phenotype', 'HP:0000992', (180, 190))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('sun-damage', 'Phenotype', 'HP:0000992', (107, 117))	('melanomas', 'Phenotype', 'HP:0002861', (154, 163))	('melanomas', 'Disease', (56, 65))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('sun-damaged', 'Phenotype', 'HP:0000992', (107, 118))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (144, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (144, 162))
94292	26308244	There is limited information on the prognostic significance of KIT in melanoma, although melanoma subtypes associated with KIT mutation have a worse overall prognosis compared to more common cutaneous melanomas.	('melanoma', 'Disease', (201, 209))	('melanoma', 'Disease', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('KIT', 'molecular_function', 'GO:0005020', ('123', '126'))	('mutation', 'Var', (127, 135))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (191, 210))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (191, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (191, 209))	('KIT', 'Gene', (123, 126))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('cutaneous melanomas', 'Disease', (191, 210))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanomas', 'Phenotype', 'HP:0002861', (201, 210))
94294	26308244	Up to 10% of cutaneous melanomas harbor loss-of-function alterations in PTEN, which include mutations, deletions, and promoter methylation.	('PTEN', 'Gene', (72, 76))	('promoter methylation', 'Var', (118, 138))	('cutaneous melanomas', 'Disease', (13, 32))	('PTEN', 'Gene', '5728', (72, 76))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanomas', 'Phenotype', 'HP:0002861', (23, 32))	('mutations', 'Var', (92, 101))	('alterations', 'Var', (57, 68))	('deletions', 'Var', (103, 112))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (13, 31))	('loss-of-function', 'NegReg', (40, 56))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (13, 32))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (13, 32))
94296	26308244	In contrast, a recent study reported that tumors with PTEN methylation have worse OS compared to unmethylated PTEN tumors.	('PTEN', 'Gene', '5728', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('PTEN tumors', 'Disease', (110, 121))	('PTEN', 'Gene', (54, 58))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('methylation', 'Var', (59, 70))	('PTEN', 'Gene', '5728', (54, 58))	('PTEN tumors', 'Disease', 'MESH:D006223', (110, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('OS', 'Chemical', '-', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('PTEN', 'Gene', (110, 114))
94298	26308244	NGS studies have expanded the known mutational landscape of melanoma and nominated novel mutations as drivers of melanoma tumorigenesis.	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma tumor', 'Disease', (113, 127))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Disease', (113, 121))	('melanoma tumor', 'Disease', 'MESH:D008545', (113, 127))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
94299	26308244	A mix of recurrent and non-recurrent mutations in the protein phosphatase PPP6C were recently identified in 9-12% of melanomas.	('phosphatase', 'molecular_function', 'GO:0016791', ('62', '73'))	('melanomas', 'Disease', 'MESH:D008545', (117, 126))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('PPP6C', 'Gene', (74, 79))	('identified', 'Reg', (94, 104))	('mutations', 'Var', (37, 46))	('melanomas', 'Disease', (117, 126))	('PPP6C', 'Gene', '5537', (74, 79))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanomas', 'Phenotype', 'HP:0002861', (117, 126))
94300	26308244	Consistent with previous reports, our group recently reported PPP6C mutations in 10.7% (25/233) and 10.4% (8/77) of primary and metastatic melanoma samples, respectively.	('PPP6C', 'Gene', '5537', (62, 67))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('reported', 'Reg', (53, 61))	('mutations', 'Var', (68, 77))	('PPP6C', 'Gene', (62, 67))
94302	26308244	Though present in only 5-9% of melanomas, mutations in RAC1 are predominantly P29S missense mutations that yield aberrant RAC activity, which drives melanoma proliferation and tumorigenesis.	('mutations', 'Var', (42, 51))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanomas', 'Phenotype', 'HP:0002861', (31, 40))	('RAC', 'Gene', (55, 58))	('tumor', 'Disease', (176, 181))	('drives', 'PosReg', (142, 148))	('activity', 'MPA', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('RAC1', 'Gene', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('melanoma proliferation', 'Disease', 'MESH:D008545', (149, 171))	('melanoma proliferation', 'Disease', (149, 171))	('RAC', 'Gene', '5879;8202', (122, 125))	('RAC1', 'Gene', '5879', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('melanomas', 'Disease', 'MESH:D008545', (31, 40))	('melanomas', 'Disease', (31, 40))	('RAC', 'Gene', '5879;8202', (55, 58))	('RAC', 'Gene', (122, 125))	('P29S', 'Mutation', 'rs1057519874', (78, 82))
94303	26308244	A recent study found that only 3.3% (27/814) of primary cutaneous melanomas harbor RAC1 P29S mutations, suggesting that these mutations occur as later events in the natural history of melanoma and may be key drivers of metastatic spread.	('P29S', 'Mutation', 'rs1057519874', (88, 92))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (56, 74))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (56, 75))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (56, 75))	('RAC1', 'Gene', '5879', (83, 87))	('P29S', 'Var', (88, 92))	('cutaneous melanomas', 'Disease', (56, 75))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('RAC1', 'Gene', (83, 87))
94304	26308244	Consistent with this notion, RAC1 mutations were associated with nodal spread at diagnosis, in addition to other negative prognostic indicators.	('nodal spread', 'CPA', (65, 77))	('RAC1', 'Gene', '5879', (29, 33))	('associated', 'Reg', (49, 59))	('RAC1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
94306	26308244	Of these, recurrent mutations in the promoter of TERT, which create novel ETS family transcription factor binding sites, have been documented in up to 70% of melanoma patient samples.	('documented', 'Reg', (131, 141))	('binding', 'Interaction', (106, 113))	('patient', 'Species', '9606', (167, 174))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('85', '113'))	('TERT', 'Gene', (49, 53))	('TERT', 'Gene', '7015', (49, 53))	('transcription', 'biological_process', 'GO:0006351', ('85', '98'))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('mutations', 'Var', (20, 29))	('melanoma', 'Disease', (158, 166))
94307	26308244	TERT promoter mutations result in increased telomerase expression, thus favoring chromosomal stability through maintenance of telomere length, which may improve the fitness of cancer cells harboring such mutations.	('telomere', 'cellular_component', 'GO:0000781', ('126', '134'))	('favoring', 'PosReg', (72, 80))	('telomere', 'cellular_component', 'GO:0005696', ('126', '134'))	('fitness of cancer', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('expression', 'MPA', (55, 65))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('telomere', 'MPA', (126, 134))	('improve', 'PosReg', (153, 160))	('fitness of cancer', 'Disease', 'MESH:D009369', (165, 182))	('increased', 'PosReg', (34, 43))	('chromosomal stability', 'CPA', (81, 102))	('mutations', 'Var', (14, 23))	('telomerase', 'Protein', (44, 54))
94308	26308244	Two recent studies found that TERT promoter mutations (43% and 22% of patients) in primary melanomas associated with key prognostic parameters (tumor thickness, ulceration, and mitotic rates), and poor disease free survival (DFS) and OS.	('ulceration', 'CPA', (161, 171))	('tumor', 'Disease', (144, 149))	('primary melanomas', 'Disease', (83, 100))	('OS', 'Chemical', '-', (234, 236))	('patients', 'Species', '9606', (70, 78))	('TERT', 'Gene', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('poor', 'NegReg', (197, 201))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('TERT', 'Gene', '7015', (30, 34))	('primary melanomas', 'Disease', 'MESH:D008545', (83, 100))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('associated', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('disease free survival', 'CPA', (202, 223))
94314	26308244	built a 5-protein signature (high non-nuclear/nuclear ATF2, high nuclear p21, high total beta-catenin, low non-nuclear/nuclear p16, and low total fibronectin; from 20 candidates evaluated) indicative of favorable prognosis (OS) using immunofluorescence-based automated quantitative analysis (AQUA) histochemistry in 192 AJCC stage II FFPE specimens.	('OS', 'Chemical', '-', (224, 226))	('fibronectin', 'Gene', (146, 157))	('high', 'PosReg', (78, 82))	('p16', 'Gene', (127, 130))	('high', 'Var', (60, 64))	('p21', 'Gene', (73, 76))	('beta-catenin', 'Gene', '1499', (89, 101))	('ATF2', 'Gene', (54, 58))	('low', 'NegReg', (136, 139))	('p21', 'Gene', '644914', (73, 76))	('low total fibronectin', 'Phenotype', 'HP:0032463', (136, 157))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('low', 'NegReg', (103, 106))	('p16', 'Gene', '1029', (127, 130))	('ATF2', 'Gene', '1386', (54, 58))	('fibronectin', 'Gene', '2335', (146, 157))	('beta-catenin', 'Gene', (89, 101))
94331	26308244	performed DASL (cDNA-mediated annealing, selection, extension, and ligation) expression profiling of 502 cancer genes for >350 FFPE cutaneous primary melanomas from two patient cohorts, identifying high osteopontin (SPP1) expression associated with reduced RFS, which confirmed previous findings.	('osteopontin', 'Gene', (203, 214))	('primary melanomas', 'Disease', (142, 159))	('high', 'Var', (198, 202))	('SPP1', 'Gene', '6696', (216, 220))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('RFS', 'Disease', (257, 260))	('SPP1', 'Gene', (216, 220))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('reduced', 'NegReg', (249, 256))	('primary melanomas', 'Disease', 'MESH:D008545', (142, 159))	('patient', 'Species', '9606', (169, 176))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SPP', 'molecular_function', 'GO:0042499', ('216', '219'))	('expression', 'MPA', (222, 232))	('osteopontin', 'Gene', '6696', (203, 214))
94344	26308244	Our group reported 18 miRNA associated with post-recurrence survival, with a subset of 6 of these microRNA (mir-150, mir-342-3p, mir-455-3p, mir-145, mir-155, and mir-497) defined as a post-recurrence survival signature.	('mir-145', 'Gene', '406937', (141, 148))	('associated', 'Reg', (28, 38))	('mir-145', 'Gene', (141, 148))	('mir-455-3p', 'Var', (129, 139))	('mir-342', 'Gene', '442909', (117, 124))	('microRNA (mir-150', 'Gene', '406942', (98, 115))	('mir-155', 'Gene', '406947', (150, 157))	('mir-497', 'Gene', (163, 170))	('mir-497', 'Gene', '574456', (163, 170))	('mir-342', 'Gene', (117, 124))	('mir-155', 'Gene', (150, 157))
94348	26308244	From this data, we defined a 4-miRNA signature (miR-150, miR-15b, miR-16-5p, and miR-374b-3p) that, in combination with AJCC stage, was predictive of development of brain metastasis.	('miR-15b', 'Gene', '406949', (57, 64))	('brain metastasis', 'Disease', (165, 181))	('miR-374b-3p', 'Var', (81, 92))	('brain metastasis', 'Disease', 'MESH:D009362', (165, 181))	('miR-15b', 'Gene', (57, 64))	('miR-150', 'Gene', (48, 55))	('miR-16-5p', 'Var', (66, 75))	('miR-150', 'Gene', '406942', (48, 55))
94358	26308244	MiR-1908, miR-199a-3p, and miR-199a-5p, which were highly up-regulated in these metastatic variants and critical drivers of melanoma progression, were inversely associated with metastasis-free survival in a cohort of 71 primary melanoma samples, though multivariate analyses were not performed and patient characteristics were not reported.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('MiR-1908', 'Gene', (0, 8))	('melanoma', 'Disease', 'MESH:D008545', (228, 236))	('miR-199a-3p', 'Gene', (10, 21))	('associated with', 'Reg', (161, 176))	('miR-199a-3p', 'Gene', '406977', (10, 21))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('MiR-1908', 'Gene', '100302263', (0, 8))	('melanoma', 'Phenotype', 'HP:0002861', (228, 236))	('melanoma', 'Disease', (228, 236))	('primary melanoma', 'Disease', (220, 236))	('primary melanoma', 'Disease', 'MESH:D008545', (220, 236))	('up-regulated', 'PosReg', (58, 70))	('patient', 'Species', '9606', (298, 305))	('miR-199a-5p', 'Var', (27, 38))	('variants', 'Var', (91, 99))	('inversely', 'NegReg', (151, 160))	('metastasis-free survival', 'CPA', (177, 201))
94367	26308244	High immunoscores in colon cancer are associated with improved RFS and OS.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('RFS', 'MPA', (63, 66))	('High', 'Var', (0, 4))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('OS', 'Chemical', '-', (71, 73))	('improved', 'PosReg', (54, 62))	('colon cancer', 'Disease', (21, 33))
94378	26308244	found that absent TIL was predictive of SLN positivity in both univariate and multivariate analysis; however, in contrast to the results of Azimi et al., there was no difference in DFS or OS.	('TIL', 'Gene', '7096', (18, 21))	('OS', 'Chemical', '-', (188, 190))	('absent', 'Var', (11, 17))	('TIL', 'Gene', (18, 21))
94404	26308244	In a cohort of 84 patients prospectively followed with stage I and II cutaneous melanoma, high vs. low serum MIA concentrations were associated with increased recurrence (66% vs. 5%) and reduced DFS at 4 years (30.3% vs. 94.5%).	('low', 'NegReg', (99, 102))	('II cutaneous melanoma', 'Disease', 'MESH:C562393', (67, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('MIA', 'Gene', (109, 112))	('II cutaneous melanoma', 'Disease', (67, 88))	('reduced', 'NegReg', (187, 194))	('DFS', 'MPA', (195, 198))	('MIA', 'Gene', '8190', (109, 112))	('patients', 'Species', '9606', (18, 26))	('recurrence', 'CPA', (159, 169))	('high', 'Var', (90, 94))
94419	26308244	Immunostaining-based molecular markers are routinely assessed for certain cancers, such as HER2 amplification in breast cancer; however, none of the protein-based studies in primary melanoma have advanced into clinical practice.	('amplification', 'Var', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('breast cancer', 'Disease', (113, 126))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('primary melanoma', 'Disease', (174, 190))	('HER2', 'Gene', (91, 95))	('primary melanoma', 'Disease', 'MESH:D008545', (174, 190))	('HER2', 'Gene', '2064', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
94420	26308244	Cancer centers are rapidly incorporating genetic sequencing platforms into routine clinical practice to identify somatic variants in patient tumors, however, primary melanoma patients are unlikely to receive such testing until there is clarity of the mutations that clearly associate with patient outcome or until additional adjuvant therapies become available.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patient', 'Species', '9606', (133, 140))	('patient', 'Species', '9606', (175, 182))	('variants', 'Var', (121, 129))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (175, 183))	('associate', 'Reg', (274, 283))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('primary melanoma', 'Disease', (158, 174))	('patient', 'Species', '9606', (289, 296))	('primary melanoma', 'Disease', 'MESH:D008545', (158, 174))
94421	26308244	Examples of prognostic gene expression signatures already in practice include Mammaprint and OncotypeDX in early stage breast cancers and OncotypeDX in stage II colon cancer.	('breast cancers', 'Disease', 'MESH:D001943', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancers', 'Disease', (119, 133))	('II colon cancer', 'Disease', 'MESH:D015179', (158, 173))	('II colon cancer', 'Disease', (158, 173))	('gene expression', 'biological_process', 'GO:0010467', ('23', '38'))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('OncotypeDX', 'Var', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast cancers', 'Phenotype', 'HP:0003002', (119, 133))
94467	26073980	While many biases hampered an accurate comparison between these two groups, overall survival was higher in patients undergoing resection, when compared to a non-operative group.	('higher', 'PosReg', (97, 103))	('patients', 'Species', '9606', (107, 115))	('resection', 'Var', (127, 136))	('overall survival', 'MPA', (76, 92))
94566	30925758	An association between polymorphisms in the NKC region, including the NKG2D gene and NKG2A promoter, and the risk of cancer has been previously described.	('polymorphisms', 'Var', (23, 36))	('NKG2A', 'Gene', (85, 90))	('NKG2D', 'Gene', '22914', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('NKG2D', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('NKG2A', 'Gene', '3821', (85, 90))
94567	30925758	The aim of this study was to analyze the association of polymorphisms in the NKC region with cutaneous melanoma in patients from southeastern Spain.	('patients', 'Species', '9606', (115, 123))	('cutaneous melanoma', 'Disease', (93, 111))	('association', 'Interaction', (41, 52))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (93, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (93, 111))	('polymorphisms', 'Var', (56, 69))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
94568	30925758	Methods: Seven single-nucleotide polymorphisms (SNPs) in the NKG2D gene (NKC3,4,7,9,10,11,12), and one SNP in the NKG2A promoter (NKC17) were genotyped by a TaqMan 5' Nuclease Assay in 233 melanoma patients and 200 matched healthy controls.	('NKG2D', 'Gene', (61, 66))	('patients', 'Species', '9606', (198, 206))	('NKG2A', 'Gene', '3821', (114, 119))	('single-nucleotide polymorphisms', 'Var', (15, 46))	('NKG2A', 'Gene', (114, 119))	('NKC3,4,7,9,10,11,12', 'Gene', (73, 92))	('NKG2D', 'Gene', '22914', (61, 66))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
94571	30925758	Conclusions: Our results suggest an association between NKG2D polymorphisms and the risk of cutaneous malignant melanoma.	('NKG2D', 'Gene', '22914', (56, 61))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (92, 120))	('NKG2D', 'Gene', (56, 61))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (92, 120))	('cutaneous malignant melanoma', 'Disease', (92, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('polymorphisms', 'Var', (62, 75))	('association', 'Interaction', (36, 47))	('malignant melanoma', 'Phenotype', 'HP:0002861', (102, 120))
94587	30925758	NKG2D polymorphism has been previously associated with a variety of pathologies, including viral and autoimmune diseases, as well as with immune surveillance against cancer.	('polymorphism', 'Var', (6, 18))	('cancer', 'Disease', (166, 172))	('NKG2D', 'Gene', '22914', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('NKG2D', 'Gene', (0, 5))	('viral', 'Disease', (91, 96))	('autoimmune diseases', 'Disease', 'MESH:D001327', (101, 120))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (101, 120))	('autoimmune diseases', 'Disease', (101, 120))
94588	30925758	Even though NKG2D is one of the best characterized primary activating receptors on NK cells, several factors, including tumor microenvironment and genetic variation, impact the efficacy of the NKG2D-mediated antitumor response and, consequently, on the patient s clinical outcome.	('patient', 'Species', '9606', (253, 260))	('impact', 'Reg', (166, 172))	('men', 'Species', '9606', (138, 141))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('NKG2D', 'Gene', '22914', (193, 198))	('NKG2D', 'Gene', '22914', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('genetic variation', 'Var', (147, 164))	('NKG2D', 'Gene', (193, 198))	('tumor', 'Disease', (212, 217))	('NKG2D', 'Gene', (12, 17))
94589	30925758	In fact, specific haplotypes in the NKC region, defined by several single-nucleotide polymorphisms (SNPs) located in the NKG2D and NKG2A genes, have been associated with variations in NK cell cytotoxic activity as well as with the overall cancer risk in a 2006 study of a Japanese population.	('variations', 'Var', (170, 180))	('NKG2D', 'Gene', '22914', (121, 126))	('NKG2A', 'Gene', '3821', (131, 136))	('NK cell cytotoxic activity', 'CPA', (184, 210))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('single-nucleotide polymorphisms', 'Var', (67, 98))	('NKG2D', 'Gene', (121, 126))	('NKG2A', 'Gene', (131, 136))	('cancer', 'Disease', (239, 245))	('associated', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
94591	30925758	A higher risk of cutaneous malignant melanoma in individuals bearing the NK-3 Hb-2 haplotype was found.	('Hb-2', 'Gene', (78, 82))	('NK-3', 'Gene', '4824', (73, 77))	('Hb-2', 'Gene', '3888', (78, 82))	('malignant melanoma', 'Phenotype', 'HP:0002861', (27, 45))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (17, 45))	('NK-3', 'Gene', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('haplotype', 'Var', (83, 92))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (17, 45))	('cutaneous malignant melanoma', 'Disease', (17, 45))
94604	30925758	By contrast, a decreased frequency of the G allele in NKC9 was observed in melanoma patients with SLN metastasis when compared to the control group (77% vs. 92%; p = 0.042, Pc = 0.34, OR = 0.3).	('NKC9', 'Gene', (54, 58))	('patients', 'Species', '9606', (84, 92))	('G allele', 'Var', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('decreased', 'NegReg', (15, 24))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))
94606	30925758	The frequency of the AA genotype in NKC10 was increased in patients with SLN metastasis compared to the control group (23% vs. 8%; p = 0.042, Pc = 1.01, OR = 3.4).	('NKC10', 'Gene', (36, 41))	('increased', 'PosReg', (46, 55))	('AA genotype', 'Var', (21, 32))	('patients', 'Species', '9606', (59, 67))	('SLN metastasis', 'Disease', (73, 87))
94616	30925758	Interestingly, melanoma patients showed a higher frequency of the NK-3 haplotype from the Hb-2 block when compared to the control group (0.039 vs. 0.0, p = 0.00009, Pc = 0.0006).	('haplotype', 'Var', (71, 80))	('NK-3', 'Gene', '4824', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('NK-3', 'Gene', (66, 70))	('Hb-2', 'Gene', (90, 94))	('patients', 'Species', '9606', (24, 32))	('Hb-2', 'Gene', '3888', (90, 94))
94622	30925758	Some of these SNPs have been previously associated with susceptibility to infectious diseases, autoimmunity, or cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('autoimmunity', 'Phenotype', 'HP:0002960', (95, 107))	('autoimmunity', 'Disease', (95, 107))	('infectious diseases', 'Disease', (74, 93))	('autoimmunity', 'Disease', 'MESH:D001327', (95, 107))	('SNPs', 'Var', (14, 18))	('infectious diseases', 'Disease', 'MESH:D003141', (74, 93))	('susceptibility to infectious diseases', 'Phenotype', 'HP:0002718', (56, 93))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (40, 50))
94624	30925758	However, a higher frequency of the NK-3 haplotype from Hb-2 block was observed in melanoma patients compared to the control group, suggesting that NKG2D polymorphisms may influence the onset of cutaneous melanoma.	('NKG2D', 'Gene', '22914', (147, 152))	('patients', 'Species', '9606', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', (204, 212))	('NK-3', 'Gene', '4824', (35, 39))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('NKG2D', 'Gene', (147, 152))	('influence', 'Reg', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('cutaneous melanoma', 'Disease', (194, 212))	('Hb-2', 'Gene', '3888', (55, 59))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (194, 212))	('Hb-2', 'Gene', (55, 59))	('NK-3', 'Gene', (35, 39))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (194, 212))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('polymorphisms', 'Var', (153, 166))
94626	30925758	The 72Thr variant of NKC4 SNP (rs2255336) showed a protective effect against cervical cancer in Polish patients, and the rs11053781 and rs2617167 SNPs of NKG2D increased the risk of developing cholangiocarcinoma in a cohort of European patients with primary sclerosing cholangitis.	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (258, 280))	('rs11053781', 'Var', (121, 131))	('patients', 'Species', '9606', (103, 111))	('rs2255336', 'Mutation', 'rs2255336', (31, 40))	('rs2255336', 'Var', (31, 40))	('cholangitis', 'Disease', 'MESH:D002761', (269, 280))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('rs2617167', 'Mutation', 'rs2617167', (136, 145))	('patients', 'Species', '9606', (236, 244))	('cholangitis', 'Disease', (269, 280))	('cholangiocarcinoma', 'Disease', (193, 211))	('The 72Thr', 'Mutation', 'p.THE72T', (0, 9))	('cancer', 'Disease', (86, 92))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 211))	('increased', 'PosReg', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cholangitis', 'Phenotype', 'HP:0030151', (269, 280))	('NKC4', 'Gene', (21, 25))	('NKG2D', 'Gene', (154, 159))	('rs2617167 SNPs', 'Var', (136, 150))	('rs11053781', 'Mutation', 'rs11053781', (121, 131))	('NKG2D', 'Gene', '22914', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
94627	30925758	However, no association was observed between NKC polymorphisms and cholangiocarcinoma in patients from the USA.	('NKC', 'Gene', (45, 48))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('patients', 'Species', '9606', (89, 97))	('polymorphisms', 'Var', (49, 62))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
94628	30925758	All these results together suggest that the polymorphism of the NKC region, especially in the NKG2D gene, would be related to the susceptibility to different types of cancer.	('susceptibility', 'Reg', (130, 144))	('related to', 'Reg', (115, 125))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('NKG2D', 'Gene', '22914', (94, 99))	('cancer', 'Disease', (167, 173))	('NKG2D', 'Gene', (94, 99))	('polymorphism', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
94633	30925758	Nevertheless, the most frequent haplotypes of the Hb-2 block in our population correspond with those described in the Japanese population.	('Hb-2', 'Gene', (50, 54))	('haplotypes', 'Var', (32, 42))	('Hb-2', 'Gene', '3888', (50, 54))
94635	30925758	These results suggest that the presence of the NK-2 Hb-2 haplotype, previously related to a high cytotoxic activity of NK and CD8+ T cells, could be associated with a protective effect against the development of cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (212, 230))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (212, 230))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', '925', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('Hb-2', 'Gene', (52, 56))	('men', 'Species', '9606', (204, 207))	('Hb-2', 'Gene', '3888', (52, 56))	('NK-2', 'Gene', (47, 51))	('NK-2', 'Gene', '7080', (47, 51))	('presence', 'Var', (31, 39))	('cutaneous melanoma', 'Disease', (212, 230))
94636	30925758	However, studies in larger series and functional assays would be necessary to demonstrate higher NK cell cytotoxic activity in our population associated with the NK-2 Hb-2 haplotype block.	('Hb-2', 'Gene', '3888', (167, 171))	('Hb-2', 'Gene', (167, 171))	('NK cell cytotoxic activity', 'CPA', (97, 123))	('NK-2', 'Gene', (162, 166))	('haplotype block', 'Var', (172, 187))	('NK-2', 'Gene', '7080', (162, 166))	('higher', 'PosReg', (90, 96))
94637	30925758	In the same way, other studies have described an association between the higher cytotoxicity of HNK1 haplotype (equivalent to NK-2 Hb-1 haplotype in this study) and a better clinical outcome in standard risk hematologic malignancies after bone marrow transplant of unrelated HLA compatible donors, as well as a reduced risk of developing colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('colorectal cancer', 'Disease', 'MESH:D015179', (338, 355))	('NK-2', 'Gene', '7080', (126, 130))	('better', 'PosReg', (167, 173))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('HNK1', 'Gene', '27087', (96, 100))	('hematologic malignancies', 'Disease', 'MESH:D019337', (208, 232))	('colorectal cancer', 'Phenotype', 'HP:0003003', (338, 355))	('higher', 'PosReg', (73, 79))	('hematologic malignancies', 'Disease', (208, 232))	('Hb-1', 'Gene', '57824', (131, 135))	('Hb-1', 'Gene', (131, 135))	('colorectal cancer', 'Disease', (338, 355))	('haplotype', 'Var', (101, 110))	('HNK1', 'Gene', (96, 100))	('cytotoxicity', 'Disease', (80, 92))	('NK-2', 'Gene', (126, 130))
94639	30925758	Conversely, an association between the NK-3 Hb-2 haplotype and an increased risk of developing cutaneous melanoma was found in our population.	('Hb-2', 'Gene', (44, 48))	('Hb-2', 'Gene', '3888', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('NK-3', 'Gene', '4824', (39, 43))	('cutaneous melanoma', 'Disease', (95, 113))	('association', 'Interaction', (15, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))	('NK-3', 'Gene', (39, 43))	('haplotype', 'Var', (49, 58))
94653	30925758	Although our results show no significant association between individual NKC SNPs and cutaneous melanoma in a Mediterranean population from the southeast of Spain, a higher risk in individuals bearing the NK-3 Hb-2 haplotype was found.	('Hb-2', 'Gene', (209, 213))	('Hb-2', 'Gene', '3888', (209, 213))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('NK-3', 'Gene', '4824', (204, 208))	('cutaneous melanoma', 'Disease', (85, 103))	('haplotype', 'Var', (214, 223))	('NK-3', 'Gene', (204, 208))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (85, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (85, 103))
94657	30925758	Lourdes Gimeno (CA09/00099) and Ruth Lopez-Hernandez (CA11/00034) are postdoctoral researchers supported by ISCIII, and Fundacion para la Formacion e Investigacion Sanitaria de la Region de Murcia (FFIS), Instituto Murciano de Investigacion Sanitaria de la Region de Murcia (IMIB).	('Murcia', 'Disease', 'None', (267, 273))	('CA11/00034', 'Var', (54, 64))	('Murcia', 'Disease', 'None', (215, 221))	('men', 'Species', '9606', (10, 13))	('Sanitaria de la Region de Murcia', 'Disease', (164, 196))	('Sanitaria de la Region de Murcia', 'Disease', (241, 273))	('CA09/00099', 'Var', (16, 26))	('Murcia', 'Disease', (190, 196))	('Sanitaria de la Region de Murcia', 'Disease', 'MESH:C535395', (164, 196))	('Sanitaria de la Region de Murcia', 'Disease', 'MESH:C535395', (241, 273))	('Murcia', 'Disease', (267, 273))	('Murcia', 'Disease', (215, 221))	('Murcia', 'Disease', 'None', (190, 196))
94682	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))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('BAP1', 'Gene', (127, 131))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('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))
94711	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))	('uveal melanoma', 'Disease', 'MESH:C536494', (97, 111))	('KIT', 'Gene', (71, 74))	('B-RAF', 'Gene', '109880', (56, 61))	('conjunctival melanoma', 'Disease', 'MESH:D003229', (20, 41))	('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))
94712	27366747	Characteristic mutations differ between uveal and cutaneous melanoma and even among tumors itself, accounting for different progression and metastatic behavior.	('uveal', 'Disease', (40, 45))	('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', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))
94721	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))
94740	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))
94756	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))
94757	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))	('uveal melanomas', 'Disease', (45, 60))	('G-protein', 'Protein', (95, 104))	('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))
94760	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))
94774	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))
94782	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))
94785	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))
94813	26218530	First, we show that NKp46+ NK cells infiltrate primary cutaneous melanoma.	('NKp46+ NK', 'Var', (20, 29))	('infiltrate', 'Reg', (36, 46))	('cutaneous melanoma', 'Disease', (55, 73))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (55, 73))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (55, 73))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))
94840	26218530	We used anti-NKp46 mAb (Natural Cytotoxicity Receptor, NCR1), a marker of the NK cell lineage, to stain NK cells in situ.	('NCR1', 'Gene', '9437', (55, 59))	('Cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('anti-NKp46', 'Var', (8, 18))	('NCR1', 'Gene', (55, 59))	('Cytotoxicity', 'Disease', (32, 44))
94857	26218530	Serial slides were stained with monoclonal antibodies against NKp46 (R&D systems), Granzyme B (GrzB+) (AbCAM), CD8 (SpringBioscience), CD34 (Immunotech), and CD68 (Dako).	('CD68', 'Gene', '968', (158, 162))	('Granzyme B', 'Gene', (83, 93))	('CD34', 'Gene', (135, 139))	('and', 'Var', (154, 157))	('NKp46', 'Gene', (62, 67))	('Granzyme B', 'Gene', '3002', (83, 93))	('CD68', 'Gene', (158, 162))	('CD8', 'Gene', (111, 114))	('CD8', 'Gene', '925', (111, 114))	('CD34', 'Gene', '947', (135, 139))
94864	26218530	Macrophages (CD68+) and endothelial cells (CD34+) were too abundant in SLN to be counted as single cells, the staining sections were scored on a scale representing the estimated proportion of positive cells noted (+: moderate, ++: high and +++: intense density).	('SLN', 'Gene', '6588', (71, 74))	('CD34', 'Gene', (43, 47))	('CD34', 'Gene', '947', (43, 47))	('+++', 'Var', (240, 243))	('CD68', 'Gene', (13, 17))	('SLN', 'Gene', (71, 74))	('CD68', 'Gene', '968', (13, 17))
94872	26218530	Numerous NK cells infiltrated primary cutaneous melanomas and corresponded to large granular cells displaying bright red staining with anti-NKp46 mAb (Fig 1A).	('primary cutaneous melanomas', 'Disease', (30, 57))	('anti-NKp46', 'Var', (135, 145))	('primary cutaneous melanomas', 'Disease', 'MESH:C562393', (30, 57))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (38, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (38, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
94896	26218530	The staining with anti-NKp46 was bright red, detected on the membrane and in the cytoplasm in large granular NK cells that were present in low numbers as compared to primary cutaneous melanoma.	('membrane', 'cellular_component', 'GO:0016020', ('61', '69'))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('anti-NKp46', 'Var', (18, 28))	('cytoplasm', 'cellular_component', 'GO:0005737', ('81', '90'))	('cutaneous melanoma', 'Disease', (174, 192))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (174, 192))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (174, 192))
94899	26218530	The intensity of the staining of the SLN slides with the anti-GrzB mAb appeared light red (Fig 3B).	('anti-GrzB', 'Var', (57, 66))	('SLN', 'Gene', (37, 40))	('SLN', 'Gene', '6588', (37, 40))
94906	26218530	A correlation was found between intratumoral and peritumoral NKp46+, GrzB+ and CD8+ T cell numbers (Fig 3D).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NKp46+', 'Var', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CD8', 'Gene', (79, 82))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('CD8', 'Gene', '925', (79, 82))	('tumor', 'Disease', (53, 58))
94907	26218530	When SLN- and SLN+ were analyzed independently, no correlation was found between the number of NKp46+, GrzB+ and CD8+ T cells in the SLN+ (Fig 3E).	('SLN+', 'Gene', '6588', (14, 18))	('SLN+', 'Gene', (133, 137))	('CD8', 'Gene', (113, 116))	('CD8', 'Gene', '925', (113, 116))	('NKp46+', 'Var', (95, 101))	('SLN+', 'Gene', (14, 18))	('SLN- and SLN', 'Gene', '6588', (5, 17))	('SLN+', 'Gene', '6588', (133, 137))
94908	26218530	However, a correlation between NKp46+ and CD8+ T cells as well as between GrzB+ cells and CD8+ T cells was found in the SLN- (Fig 3F).	('SLN-', 'Gene', '6588', (120, 124))	('SLN-', 'Gene', (120, 124))	('CD8', 'Gene', (42, 45))	('CD8', 'Gene', (90, 93))	('NKp46+', 'Var', (31, 37))	('CD8', 'Gene', '925', (42, 45))	('CD8', 'Gene', '925', (90, 93))
94928	26218530	Gene variability of Killer Ig like receptors (KIR) may also influence the disease susceptibility and prognosis of cutaneous malignant melanoma.	('disease susceptibility', 'CPA', (74, 96))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (114, 142))	('KIR', 'Gene', (46, 49))	('cutaneous malignant melanoma', 'Disease', (114, 142))	('influence', 'Reg', (60, 69))	('Killer Ig like receptors', 'Gene', (20, 44))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('malignant melanoma', 'Phenotype', 'HP:0002861', (124, 142))	('Gene variability', 'Var', (0, 16))	('Killer Ig like receptors', 'Gene', '3805', (20, 44))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (114, 142))	('KIR', 'Gene', '3805', (46, 49))
94936	26218530	Compared to NKp46, anti-GrzB mAb stained higher numbers of cells, and both NKp46+ cells and GrzB+ cells are distributed in the medulla surrounding the B follicles of the SLN.	('NKp46+', 'Var', (75, 81))	('SLN', 'Gene', (170, 173))	('SLN', 'Gene', '6588', (170, 173))
94973	27852308	The specific role for miR-29b-3p in melanoma has not been well studied.	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('miR-29b-3p', 'Var', (22, 32))
94974	27852308	We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro.	('miR-29b-3p', 'Var', (42, 52))	('miR-29b-3p', 'Var', (124, 134))	('cellular invasiveness in vitro', 'CPA', (171, 201))	('influence', 'Reg', (161, 170))	('LAMC1', 'Gene', '3915', (67, 72))	('LASP1', 'Gene', '3927', (86, 91))	('LASP1', 'Gene', (86, 91))	('regulation', 'biological_process', 'GO:0065007', ('53', '63'))	('PPIC', 'Gene', (77, 81))	('dysregulation', 'Var', (107, 120))	('LAMC1', 'Gene', (67, 72))
94986	27852308	ArrayCGH studies suggest miR-29b copy number increases in melanoma and a number of miRs have been implicated in melanocyte transformation, melanoma progression, modulating the extent and mode of melanoma cell invasiveness, and switching of cellular phenotype (i.e.	('melanoma cell invasiveness', 'Disease', 'MESH:D008545', (195, 221))	('increases', 'PosReg', (45, 54))	('implicated', 'Reg', (98, 108))	('miR', 'Gene', '220972', (83, 86))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('copy number', 'Var', (33, 44))	('modulating', 'Reg', (161, 171))	('miR', 'Gene', '220972', (25, 28))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('miR', 'Gene', (83, 86))	('melanoma cell invasiveness', 'Disease', (195, 221))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('miR', 'Gene', (25, 28))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
95015	27852308	SOX10 suppression contributes to BRAF- and/or MEK-inhibitor resistance in BRAF mutated melanoma, by activating TGFbeta signalling to upregulate EGFR and PDGFRB, whilst increasing SOX9 transcript abundance has been observed in breast cancer EMT.	('BRAF', 'Gene', '673', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutated', 'Var', (79, 86))	('BRAF', 'Gene', (33, 37))	('MEK', 'Gene', (46, 49))	('EMT', 'biological_process', 'GO:0001837', ('240', '243'))	('TGFbeta', 'Gene', (111, 118))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('melanoma', 'Disease', (87, 95))	('SOX9', 'Gene', (179, 183))	('signalling', 'biological_process', 'GO:0023052', ('119', '129'))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('TGFbeta', 'Gene', '7040', (111, 118))	('upregulate', 'PosReg', (133, 143))	('SOX10', 'Gene', '6663', (0, 5))	('EGFR', 'Gene', '1956', (144, 148))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('suppression', 'NegReg', (6, 17))	('EGFR', 'Gene', (144, 148))	('breast cancer', 'Disease', (226, 239))	('SOX9', 'Gene', '6662', (179, 183))	('activating', 'PosReg', (100, 110))	('PDGFRB', 'Gene', '5159', (153, 159))	('SOX10', 'Gene', (0, 5))	('PDGFRB', 'Gene', (153, 159))	('EGFR', 'molecular_function', 'GO:0005006', ('144', '148'))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('MEK', 'Gene', '5609', (46, 49))
95028	27852308	The role of the fifth ranked micro-RNA, miR-29b-3p, in melanoma has not yet been explored.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('miR-29b-3p', 'Var', (40, 50))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('RNA', 'cellular_component', 'GO:0005562', ('35', '38'))
95033	27852308	Consistent with its role in melanoma progression, miR-340-5p had a particularly strong loading for both "pigmentation" and "EMP" categories, whilst miR-29b-3p was also enriched around 10-fold (~5.5%), providing further support that miR-29b-3p may be regulating melanoma cell invasiveness through a diverse repertoire of regulatory interactions.	('melanoma', 'Disease', (28, 36))	('melanoma cell invasiveness', 'Disease', (261, 287))	('regulating', 'Reg', (250, 260))	('melanoma cell invasiveness', 'Disease', 'MESH:D008545', (261, 287))	('pigmentation', 'Disease', 'MESH:D010859', (105, 117))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('miR-29b-3p', 'Var', (232, 242))	('pigmentation', 'Disease', (105, 117))	('miR-340', 'Gene', (50, 57))	('pigmentation', 'biological_process', 'GO:0043473', ('104', '116'))	('miR-340', 'Gene', '442908', (50, 57))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Disease', (261, 269))
95037	27852308	To elucidate the role of miR-29b in melanoma invasiveness, we examined the effect of miR-29b perturbation on the transcript abundance of several putative targets in a subset of LM-MEL cell lines.	('perturbation', 'Var', (93, 105))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma invasiveness', 'Disease', (36, 57))	('miR-29b', 'Gene', (85, 92))	('transcript', 'MPA', (113, 123))	('melanoma invasiveness', 'Disease', 'MESH:D008545', (36, 57))
95041	27852308	All three genes selected for further investigation (LAMC1, LASP1 and PPIC) exhibited a dose-dependent reduction in transcript level following miR-29b mimic transfection, although this effect was near-maximal at 1nM.	('LASP1', 'Gene', '3927', (59, 64))	('LAMC1', 'Gene', (52, 57))	('transcript level', 'MPA', (115, 131))	('LASP1', 'Gene', (59, 64))	('reduction', 'NegReg', (102, 111))	('miR-29b', 'Gene', (142, 149))	('transfection', 'Var', (156, 168))	('LAMC1', 'Gene', '3915', (52, 57))
95048	27852308	Mild effects were observed for miR-29b-3p mimic in reducing LM-MEL-45 outgrowth survival at 21 days, with little change in cellular proliferation observed at 72 h (Figure AF5.4 & AF5.5 within Additional file 5).	('reducing', 'NegReg', (51, 59))	('LM-MEL-45 outgrowth survival', 'CPA', (60, 88))	('miR-29b-3p mimic', 'Var', (31, 47))	('LM-MEL-45', 'CellLine', 'CVCL:U928', (60, 69))
95049	27852308	To better assess the effect of miR-29b on melanoma cell motility, cultured LM-MEL-45 cells were allowed to migrate into a central detection zone of the Oris plate assay system (without a chemotactic gradient) following treatment with miR-29b mimic or specific siRNA for either LAMC1 or PPIC.	('melanoma cell motility', 'Disease', (42, 64))	('miR-29b mimic', 'Var', (234, 247))	('cell motility', 'biological_process', 'GO:0048870', ('51', '64'))	('LAMC1', 'Gene', '3915', (277, 282))	('LM-MEL-45', 'CellLine', 'CVCL:U928', (75, 84))	('melanoma cell motility', 'Disease', 'MESH:D008545', (42, 64))	('LAMC1', 'Gene', (277, 282))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
95054	27852308	5d) confirmed sharp transitions between relatively acellular surrounding collagen matrix and cell spheroid following miR-29b mimic and LAMC1 transfection (Fig.	('LAMC1', 'Gene', '3915', (135, 140))	('cell spheroid', 'CPA', (93, 106))	('LAMC1', 'Gene', (135, 140))	('collagen', 'molecular_function', 'GO:0005202', ('73', '81'))	('miR-29b', 'Gene', (117, 124))	('transfection', 'Var', (141, 153))
95055	27852308	Unexpectedly, siRNA-mediated knockdown of PPIC dramatically increased LM-MEL-45 cell invasiveness, and on cross-sectional spheroid cell density analysis, no clear transition point was observed in spheroids treated with PPIC siRNA (Fig.	('PPIC', 'Gene', (42, 46))	('LM-MEL-45', 'CellLine', 'CVCL:U928', (70, 79))	('knockdown', 'Var', (29, 38))	('LM-MEL-45 cell invasiveness', 'CPA', (70, 97))	('increased', 'PosReg', (60, 69))
95056	27852308	This finding demonstrates that the effects of miR-29b-3p on melanoma cell migration are not accurately replicated by perturbation of any single mRNA target in isolation.	('melanoma cell migration', 'Disease', 'MESH:D008545', (60, 83))	('cell migration', 'biological_process', 'GO:0016477', ('69', '83'))	('melanoma cell migration', 'Disease', (60, 83))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('miR-29b-3p', 'Var', (46, 56))
95058	27852308	We demonstrate a novel modulatory effect for miR-29b-3p activity on melanoma cell invasiveness, most likely mediated by the combined effects on multiple gene targets.	('miR-29b-3p', 'Var', (45, 55))	('activity', 'MPA', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma cell invasiveness', 'Disease', (68, 94))	('melanoma cell invasiveness', 'Disease', 'MESH:D008545', (68, 94))	('modulatory', 'Reg', (23, 33))
95063	27852308	In a small panel of melanoma cell lines an inverse relationship between miR-29b level and melanoma cell line proliferation was observed, seemingly at odds with the higher miR-29a ~ b1 cluster abundance in some primary melanomas, and our finding that high miR-29b levels are associated with a more proliferative, epithelial-like phenotype.	('melanoma', 'Disease', (90, 98))	('miR-29a', 'Gene', (171, 178))	('miR-29a', 'Gene', '407021', (171, 178))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('primary melanomas', 'Disease', (210, 227))	('inverse', 'NegReg', (43, 50))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanomas', 'Phenotype', 'HP:0002861', (218, 227))	('melanoma', 'Disease', (218, 226))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('miR-29b', 'Var', (72, 79))	('primary melanomas', 'Disease', 'MESH:D008545', (210, 227))	('miR-29b', 'Var', (255, 262))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
95065	27852308	We examined LAMC1 and PPIC in detail as potential mediators of miR-29b-3p effects across our melanoma cell models.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('miR-29b-3p', 'Var', (63, 73))	('LAMC1', 'Gene', '3915', (12, 17))	('LAMC1', 'Gene', (12, 17))
95069	27852308	PPIases are substrates for cyclosporin A and may be secreted in response to cyclosporin exposure; PPIC plays a key role in endoplasmic reticulum redox homeostasis, together with PPIB.	('cyclosporin', 'Chemical', 'MESH:D016572', (76, 87))	('PPIB', 'Gene', (178, 182))	('cyclosporin A', 'Chemical', 'MESH:D016572', (27, 40))	('homeostasis', 'biological_process', 'GO:0042592', ('151', '162'))	('PPIB', 'Gene', '5479', (178, 182))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('123', '144'))	('PPIC', 'Var', (98, 102))	('cyclosporin', 'Chemical', 'MESH:D016572', (27, 38))	('endoplasmic reticulum redox homeostasis', 'MPA', (123, 162))
95082	27852308	This apparently independent regulation of expression of miRs from distinct genomic locations suggests that coordination of miR function may be intricately linked to the expression of other genomic features, possibly linked by transcription factor binding sites, co-location, and local epigenetic chromatin modification, all of which may combine with other regional genomic effects to produce distinct biological consequences.	('linked', 'Reg', (155, 161))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('regulation', 'biological_process', 'GO:0065007', ('28', '38'))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('chromatin modification', 'biological_process', 'GO:0006325', ('296', '318'))	('chromatin', 'cellular_component', 'GO:0000785', ('296', '305'))	('transcription', 'biological_process', 'GO:0006351', ('226', '239'))	('epigenetic chromatin modification', 'Var', (285, 318))	('chromatin modification', 'biological_process', 'GO:0016569', ('296', '318'))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('226', '254'))
95094	27852308	Evidence suggested that miR-29b-3p influences melanoma invasiveness through regulating several mRNA transcripts (Fig.	('miR-29b-3p', 'Var', (24, 34))	('melanoma invasiveness', 'Disease', (46, 67))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('mRNA transcripts', 'MPA', (95, 111))	('melanoma invasiveness', 'Disease', 'MESH:D008545', (46, 67))	('influences', 'Reg', (35, 45))	('regulating', 'Reg', (76, 86))
95108	27852308	This pre-processing retained 198/2592 miRs (note that 916 of the miRs had no reads across any cell line) and 16482/47231 mRNA probes within the LM-MEL data.	('mRNA probes', 'MPA', (121, 132))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('16482/47231', 'Var', (109, 120))	('pre', 'molecular_function', 'GO:0003904', ('5', '8'))
95127	27852308	SR30004, SR302649, SR302655, SR303664; Rockville, MD, USA), at doses indicated in results.	('SR303664', 'Chemical', '-', (29, 37))	('SR302655', 'Var', (19, 27))	('SR302649', 'Chemical', '-', (9, 17))	('SR302655', 'Chemical', '-', (19, 27))	('SR303664', 'Var', (29, 37))	('SR30004', 'Chemical', '-', (0, 7))	('SR30004', 'Var', (0, 7))	('SR302649', 'Var', (9, 17))
95130	27852308	4427975) specific for hsa-miR-211 (ID 000514), hsa-miR-125b-1* (ID 002378), hsa-miR-221* (ID 002096), hsa-miR-9 (ID 000583), hsa-miR-23b (ID 000400), hsa-miR-29b (ID 000413), hsa-miR-222 (ID 002276), hsa-let-7a (ID 000377), or controls RNU44 (ID 001094) and RNU24 (ID 001001).	('ID 002276', 'Var', (188, 197))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '220972', (154, 157))	('hsa-miR-211', 'Gene', '406993', (22, 33))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', '220972', (51, 54))	('ID 000413', 'Var', (163, 172))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', '220972', (26, 29))	('miR', 'Gene', (154, 157))	('miR-222', 'Gene', '407007', (179, 186))	('ID 000377', 'Var', (212, 221))	('miR-221', 'Gene', (80, 87))	('ID 000400', 'Var', (138, 147))	('ID 000514', 'Var', (35, 44))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', (179, 182))	('miR', 'Gene', (51, 54))	('miR-125b-1', 'Gene', (51, 61))	('miR-221', 'Gene', '407006', (80, 87))	('RNU44', 'Gene', (236, 241))	('RNU24', 'Gene', '26820', (258, 263))	('miR', 'Gene', (129, 132))	('miR', 'Gene', (26, 29))	('miR', 'Gene', (106, 109))	('hsa-miR-23b', 'Gene', (125, 136))	('hsa-miR-23b', 'Gene', '407011', (125, 136))	('RNU44', 'Gene', '26806', (236, 241))	('miR-125b-1', 'Gene', '406911', (51, 61))	('miR', 'Gene', '220972', (80, 83))	('ID 000583', 'Var', (113, 122))	('RNU24', 'Gene', (258, 263))	('hsa-miR-211', 'Gene', (22, 33))	('miR-222', 'Gene', (179, 186))	('ID 001094', 'Var', (243, 252))
95180	32869947	5 ,  6 ,  7  A recent study confirmed that disruption of cell adhesion might induce uncontrolled cell proliferation and played a crucial role in epithelial to mesenchymal transition (EMT), cancer formation, progression and tumour propagation.	('disruption', 'Var', (43, 53))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('cell adhesion', 'biological_process', 'GO:0007155', ('57', '70'))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('formation', 'biological_process', 'GO:0009058', ('196', '205'))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('145', '181'))	('tumour', 'Disease', (223, 229))	('uncontrolled', 'MPA', (84, 96))	('epithelial to mesenchymal transition', 'CPA', (145, 181))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cell adhesion', 'Protein', (57, 70))	('progression', 'CPA', (207, 218))	('EMT', 'biological_process', 'GO:0001837', ('183', '186'))	('induce', 'Reg', (77, 83))	('cancer', 'Disease', (189, 195))
95195	32869947	Decreased variation in FLG was a significant risk factor for atopic dermatitis.	('atopic dermatitis', 'Disease', 'MESH:D003876', (61, 78))	('FLG', 'Gene', (23, 26))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (61, 78))	('dermatitis', 'Phenotype', 'HP:0011123', (68, 78))	('variation', 'Var', (10, 19))	('Decreased', 'NegReg', (0, 9))	('atopic dermatitis', 'Disease', (61, 78))	('FLG', 'Gene', '2312', (23, 26))
95204	29438700	In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis.	('Braf-V600E-driven', 'Var', (75, 92))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('zebrafish', 'Species', '7955', (13, 22))	('mouse', 'Species', '10090', (3, 8))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('JMJD2C', 'Gene', (48, 54))	('promoted', 'PosReg', (66, 74))	('V600E', 'Mutation', 'rs113488022', (80, 85))
95207	29438700	Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('restores', 'PosReg', (36, 44))	('tumor', 'Disease', (69, 74))	('demethylase', 'Gene', (23, 34))	('senescence', 'MPA', (45, 55))	('demethylase', 'Gene', '8932', (23, 34))	('Inhibition', 'Var', (0, 10))	('H3K9', 'Gene', '109741', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('H3K9', 'Gene', (18, 22))	('senescence', 'biological_process', 'GO:0010149', ('45', '55'))
95216	29438700	Moreover, given additional non-H3K9 histone and non-histone targets of LSD1 and JMJD2C, including components of the p53 pathway, it is conceivable that functions not related to H3K9 methylation might contribute to their oncogenic potential as well.	('H3K9', 'Gene', '109741', (177, 181))	('his', 'Chemical', 'MESH:D006639', (36, 39))	('H3K9', 'Gene', (177, 181))	('oncogenic potential', 'CPA', (220, 239))	('LSD1', 'Gene', (71, 75))	('JMJD2C', 'Var', (80, 86))	('H3K9', 'Gene', '109741', (31, 35))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('H3K9', 'Gene', (31, 35))	('contribute', 'Reg', (200, 210))	('his', 'Chemical', 'MESH:D006639', (52, 55))
95219	29438700	While Ras-expressing cells expectedly entered full-featured senescence, LSD1-or JMJD2C (as well as JMJD2A or JMJD2B)-co-expressing MEFs kept proliferating, shown by exponentially increasing cell numbers, significant colony formation, and fewer SA-beta-gal-positive cells (Figures 1A-1C, S1A, and S1B).	('SA-beta', 'Gene', '24056', (244, 251))	('formation', 'biological_process', 'GO:0009058', ('223', '232'))	('beta-gal', 'Chemical', '-', (247, 255))	('SA-beta', 'Gene', (244, 251))	('proliferating', 'CPA', (141, 154))	('increasing', 'PosReg', (179, 189))	('fewer', 'NegReg', (238, 243))	('cell numbers', 'CPA', (190, 202))	('JMJD2C', 'Var', (80, 86))	('colony formation', 'CPA', (216, 232))	('MEFs', 'CellLine', 'CVCL:9115', (131, 135))	('LSD1-or', 'Var', (72, 79))	('senescence', 'biological_process', 'GO:0010149', ('60', '70'))
95221	29438700	In contrast, Ras induction in MEFs overexpressing LSD1 or JMJD2C produced no significant changes in cyclin A and p16INK4a, and resulted rather in slightly elevated amounts of PCNA (Figure 1D).	('cyclin A', 'Gene', '12428', (100, 108))	('PCNA', 'Gene', (175, 179))	('p16INK4a', 'Gene', (113, 121))	('MEFs', 'CellLine', 'CVCL:9115', (30, 34))	('JMJD2C', 'Var', (58, 64))	('cyclin A', 'Gene', (100, 108))	('amounts', 'MPA', (164, 171))	('LSD1', 'Var', (50, 54))	('cyclin', 'molecular_function', 'GO:0016538', ('100', '106'))	('p16INK4a', 'Gene', '12578', (113, 121))	('elevated', 'PosReg', (155, 163))	('PCNA', 'Gene', '18538', (175, 179))	('PCNA', 'molecular_function', 'GO:0003892', ('175', '179'))
95223	29438700	Consistent with their known specificities for mono-, di-, and trimethylated H3K9, no Ras-related changes in H3K9me1 and H3K9me2 levels became detectable in LSD1-overexpressing cells, while JMJD2C had little effect here, but, like LSD1, completely prevented an increase of H3K9me3 levels in response to Ras (Figure 1D).	('H3K9', 'Gene', (76, 80))	('H3K9', 'Gene', '109741', (120, 124))	('prevented', 'NegReg', (247, 256))	('H3K9', 'Gene', (120, 124))	('H3K9', 'Gene', '109741', (272, 276))	('JMJD2C', 'Var', (189, 195))	('H3K9me1', 'Gene', '109741', (108, 115))	('H3K9', 'Gene', (272, 276))	('H3K9', 'Gene', '109741', (108, 112))	('H3K9', 'Gene', '109741', (76, 80))	('H3K9me1', 'Gene', (108, 115))	('H3K9', 'Gene', (108, 112))
95226	29438700	Overexpression of either LSD1 or JMJD2C also abrogated the Ras-dependent formation of senescence-associated heterochromatin foci and H3K9me3-positive chromatin blobs in particular in HDF (Figure 1E).	('abrogated', 'NegReg', (45, 54))	('HDF', 'Disease', (183, 186))	('H3K9', 'Gene', '109741', (133, 137))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('H3K9', 'Gene', (133, 137))	('chromatin', 'cellular_component', 'GO:0000785', ('150', '159'))	('senescence-associated heterochromatin foci', 'cellular_component', 'GO:0035985', ('86', '128'))	('Ras-dependent', 'MPA', (59, 72))	('JMJD2C', 'Var', (33, 39))	('LSD1', 'Var', (25, 29))	('senescence', 'biological_process', 'GO:0010149', ('86', '96'))
95227	29438700	Taken together, LSD1 and JMJD2C effectively prevent focal H3K9me3-based heterochromatinization and counter Ras-induced senescence.	('prevent', 'NegReg', (44, 51))	('JMJD2C', 'Var', (25, 31))	('senescence', 'biological_process', 'GO:0010149', ('119', '129'))	('H3K9', 'Gene', '109741', (58, 62))	('LSD1', 'Var', (16, 20))	('H3K9', 'Gene', (58, 62))
95231	29438700	Moreover, additional genetic analyses ruled out that LSD1 and JMJD2C disable OIS independent of their catalytic function or via non-histone targets, specifically within the p53 pathway (Figure S2).	('his', 'Chemical', 'MESH:D006639', (132, 135))	('disable', 'NegReg', (69, 76))	('p53 pathway', 'Pathway', (173, 184))	('OIS', 'biological_process', 'GO:0090402', ('77', '80'))	('JMJD2C', 'Var', (62, 68))	('OIS', 'MPA', (77, 80))	('LSD1', 'Var', (53, 57))
95232	29438700	To further substantiate that H3K9 methylation operates as an essential component in the OIS process, we generated a histone H3 mutant with an arginine substitution of the lysine 9 residue (termed H3R9), which can no longer be methylated at this position .	('mutant', 'Var', (127, 133))	('H3K9', 'Gene', (29, 33))	('H3K9', 'Gene', '109741', (29, 33))	('arginine substitution of the lysine 9', 'Mutation', 'p.K9R', (142, 179))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('arginine substitution', 'Var', (142, 163))	('his', 'Chemical', 'MESH:D006639', (241, 244))	('his', 'Chemical', 'MESH:D006639', (116, 119))	('H3', 'Gene', '109741', (196, 198))	('H3', 'Gene', '109741', (124, 126))	('OIS', 'biological_process', 'GO:0090402', ('88', '91'))	('H3', 'Gene', '109741', (29, 31))
95233	29438700	Since it is difficult to efficiently reduce endogenous H3 expression by RNA interference due to numerous H3 genes and variants, the H3R9 cDNA was stably transferred into MEFs retaining wild-type H3, and a retrovirus encoding wild-type H3 (H3K9) was used as a control.	('RNA interference', 'MPA', (72, 88))	('H3K9', 'Gene', '109741', (239, 243))	('H3', 'Gene', '109741', (105, 107))	('H3', 'Gene', '109741', (239, 241))	('H3', 'Gene', '109741', (235, 237))	('variants', 'Var', (118, 126))	('H3K9', 'Gene', (239, 243))	('H3', 'Gene', '109741', (195, 197))	('RNA', 'cellular_component', 'GO:0005562', ('72', '75'))	('RNA interference', 'biological_process', 'GO:0016246', ('72', '88'))	('MEFs', 'CellLine', 'CVCL:9115', (170, 174))	('H3', 'Gene', '109741', (55, 57))	('H3', 'Gene', '109741', (132, 134))
95239	29438700	If preceding expression of H3K9-active demethylases or the H3R9 mutant enables oncogenic Ras to bypass a senescence response, we hypothesized that these moieties might permit cell-cycle re-entry even after OIS has been already established.	('demethylase', 'Gene', (39, 50))	('bypass a senescence response', 'MPA', (96, 124))	('demethylase', 'Gene', '8932', (39, 50))	('senescence', 'biological_process', 'GO:0010149', ('105', '115'))	('H3K9', 'Gene', (27, 31))	('H3K9', 'Gene', '109741', (27, 31))	('H3', 'Gene', '109741', (27, 29))	('OIS', 'biological_process', 'GO:0090402', ('206', '209'))	('cell-cycle', 'biological_process', 'GO:0007049', ('175', '185'))	('cell-cycle re-entry', 'CPA', (175, 194))	('H3', 'Gene', '109741', (59, 61))	('mutant', 'Var', (64, 70))	('permit', 'Reg', (168, 174))
95244	29438700	Interestingly, overexpression of JMJD2C, but not LSD1, immortalized primary MEFs (Figure S4A).	('JMJD2C', 'Var', (33, 39))	('MEFs', 'CellLine', 'CVCL:9115', (76, 80))	('overexpression', 'PosReg', (15, 29))
95245	29438700	However, expression of either one, or the H3R9 mutant, directly permitted transformation in concert with Ras, to form anchorage-independent colonies, albeit with lower efficacy when compared with Ras;Trp53-/- cells (Figure 3A; see Figure S4B for HDF), and to grow as malignant tumors in nude mice (Figure 3B).	('malignant tumors', 'Disease', (267, 283))	('nude mice', 'Species', '10090', (287, 296))	('anchorage-independent colonies', 'CPA', (118, 148))	('permitted', 'Reg', (64, 73))	('malignant tumors', 'Disease', 'MESH:D018198', (267, 283))	('Trp53', 'Gene', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('H3', 'Gene', '109741', (42, 44))	('transformation', 'CPA', (74, 88))	('Trp53', 'Gene', '22059', (200, 205))	('mutant', 'Var', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
95249	29438700	To experimentally explore the possibilities that H3K9-active demethylases might promote bypass of or enforce escape from OIS, we stably expressed primary human melanocytes with Braf-V600E (hereafter referred to as Braf) either after (i.e., probing "senescence bypass") or prior to (i.e., probing "senescence escape") lentiviral transduction with JMJD2C or LSD1.	('human', 'Species', '9606', (154, 159))	('Braf-V600E', 'Var', (177, 187))	('demethylase', 'Gene', (61, 72))	('demethylase', 'Gene', '8932', (61, 72))	('senescence', 'biological_process', 'GO:0010149', ('248', '258'))	('H3K9', 'Gene', '109741', (49, 53))	('OIS', 'biological_process', 'GO:0090402', ('121', '124'))	('H3K9', 'Gene', (49, 53))	('V600E', 'Mutation', 'rs113488022', (182, 187))	('promote', 'PosReg', (80, 87))
95250	29438700	Recapitulating our findings in Ras-exposed fibroblast models (Figure S5A), primary human melanocytes collectively entered senescence in response to Braf, in agreement with previous observations, but virtually no induction of senescence became detectable in melanocytes that were engineered to overexpress LSD1 or JMJD2C prior to or after Braf activation (Figures 4A and 4B).	('human', 'Species', '9606', (83, 88))	('JMJD2C', 'Var', (313, 319))	('overexpress', 'PosReg', (293, 304))	('senescence', 'biological_process', 'GO:0010149', ('122', '132'))	('LSD1', 'Var', (305, 309))	('senescence', 'biological_process', 'GO:0010149', ('225', '235'))
95253	29438700	First, an avian virus/receptor system was used to subcutaneously deliver Cre recombinase with or without LSD1 into mice harboring conditionally active Braf-V600E and floxed Cdkn2a alleles.	('lox', 'Gene', (167, 170))	('Cdkn2a', 'Gene', (173, 179))	('V600E', 'Mutation', 'rs113488022', (156, 161))	('lox', 'Gene', '16948', (167, 170))	('Braf-V600E', 'Var', (151, 161))	('mice', 'Species', '10090', (115, 119))	('Cdkn2a', 'Gene', '12578', (173, 179))
95254	29438700	While after 150 days not even half of the mice succumbed to melanoma development in the absence of LSD1 (due to the limited penetrance of the system), about 90% of the mice had already died from melanoma development prior to day 100 in the LSD1 group, typically without having deleted Cdkn2a (5 of the 6 tested remained p19ARF-positive; Figure 4C).	('LSD1', 'Var', (240, 244))	('p19ARF', 'Gene', (320, 326))	('p19', 'cellular_component', 'GO:0070743', ('320', '323'))	('mice', 'Species', '10090', (42, 46))	('mice', 'Species', '10090', (168, 172))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma', 'Disease', (60, 68))	('p19ARF', 'Gene', '12578', (320, 326))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('Cdkn2a', 'Gene', '12578', (285, 291))	('Cdkn2a', 'Gene', (285, 291))
95258	29438700	To further interrogate the role of LSD1, we used a Braf-V600E-driven, in combination with p53-deficiency, zebrafish melanoma model, and again found LSD1 to profoundly accelerate melanoma development (Figure 4F).	('accelerate', 'PosReg', (167, 177))	('p53-deficiency, zebrafish melanoma', 'Disease', 'MESH:D008545', (90, 124))	('LSD1', 'Gene', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('Braf-V600E-driven', 'Var', (51, 68))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('V600E', 'Mutation', 'rs113488022', (56, 61))
95262	29438700	First, we scanned a panel of seven human melanoma cell lines:with primary as well as Braf-senescent human melanocytes for comparison:regarding their expression levels of the H3K9me3-relevant demethylases LSD1, JMJD1A, JMJD2A, JMJD2B, and JMJD2C.	('JMJD2A', 'Var', (218, 224))	('JMJD2B', 'Var', (226, 232))	('demethylase', 'Gene', '8932', (191, 202))	('human', 'Species', '9606', (35, 40))	('human', 'Species', '9606', (100, 105))	('LSD1', 'Gene', (204, 208))	('H3K9', 'Gene', '109741', (174, 178))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('H3K9', 'Gene', (174, 178))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('JMJD2C', 'Var', (238, 244))	('JMJD1A', 'Var', (210, 216))	('demethylase', 'Gene', (191, 202))
95267	29438700	These findings further imply that other cell lines may have never experienced senescence, require lower demethylase activities to reverse OIS, or overcome this barrier primarily by a H3K9 demethylase-independent mechanism, for example by inactivating CDKN2A mutations as a more frequent or inactivating TP53 mutations as a less frequent, senescence-disabling event.	('demethylase', 'Gene', (188, 199))	('demethylase', 'Gene', '8932', (188, 199))	('senescence', 'biological_process', 'GO:0010149', ('338', '348'))	('inactivating', 'Var', (238, 250))	('mutations', 'Var', (308, 317))	('OIS', 'biological_process', 'GO:0090402', ('138', '141'))	('activities', 'MPA', (116, 126))	('TP53', 'Gene', (303, 307))	('senescence', 'biological_process', 'GO:0010149', ('78', '88'))	('demethylase', 'Gene', '8932', (104, 115))	('H3K9', 'Gene', '109741', (183, 187))	('demethylase', 'Gene', (104, 115))	('mutations', 'Var', (258, 267))	('his', 'Chemical', 'MESH:D006639', (156, 159))	('TP53', 'Gene', '22059', (303, 307))	('inactivating', 'Var', (290, 302))	('CDKN2A', 'Gene', '12578', (251, 257))	('CDKN2A', 'Gene', (251, 257))	('H3K9', 'Gene', (183, 187))
95283	29438700	First, large proportions of murine B16F10 melanoma cells entered senescence when LSD1 or JMJD2C were knocked down, similar to their response to 2-PCPA-1a or IOX1 (Figure S6E).	('melanoma', 'Disease', (42, 50))	('senescence', 'CPA', (65, 75))	('senescence', 'biological_process', 'GO:0010149', ('65', '75'))	('2-PCPA-1a', 'Chemical', '-', (144, 153))	('B16F10', 'CellLine', 'CVCL:0159', (35, 41))	('murine', 'Species', '10090', (28, 34))	('JMJD2C', 'Gene', (89, 95))	('knocked down', 'Var', (101, 113))	('entered', 'Reg', (57, 64))	('LSD1', 'Gene', (81, 85))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
95285	29438700	Figure 5A), and found the demethylase-high group to be particularly susceptible to senescence re-induction by pharmacological or genetic targeting of individual demethylases (Figures 6C, S6F-S6H, and Table S2).	('demethylase', 'Gene', (26, 37))	('demethylase', 'Gene', '8932', (26, 37))	('demethylase', 'Gene', (161, 172))	('susceptible', 'Reg', (68, 79))	('senescence re-induction', 'MPA', (83, 106))	('demethylase', 'Gene', '8932', (161, 172))	('genetic targeting', 'Var', (129, 146))	('senescence', 'biological_process', 'GO:0010149', ('83', '93'))
95286	29438700	As seen before in fibroblasts, LSD1 inhibition only restored senescence if a lowered E2F target-repressive H3K9me3 mark was re-established (Figure S6I).	('inhibition', 'Var', (36, 46))	('senescence', 'biological_process', 'GO:0010149', ('61', '71'))	('LSD1', 'Gene', (31, 35))	('H3K9', 'Gene', '109741', (107, 111))	('H3K9', 'Gene', (107, 111))	('senescence', 'MPA', (61, 71))
95288	29438700	The senescent phenotype in three knocked down LSD1 and JMJD2C melanoma cell lines was further characterized by RNA-seq analysis (Figure 6E).	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('melanoma', 'Disease', (62, 70))	('LSD1', 'Gene', (46, 50))	('knocked down', 'Var', (33, 45))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
95293	29438700	Both agents effectively controlled A375 and WM266.4, but not SK-MEL-28 tumor growth in vivo.	('WM266.4', 'CellLine', 'CVCL:2765', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('A375', 'CellLine', 'CVCL:0132', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('A375', 'Var', (35, 39))
95302	29438700	Reflecting the pivotal role of OIS as a barrier to tumor formation in many pre-malignant tissues, senescence-disabling activities, for example inactivating alterations at the TP53 or CDKN2A loci, are a common hallmark of cancer.	('CDKN2A', 'Gene', (183, 189))	('TP53', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('senescence-disabling activities', 'MPA', (98, 129))	('pre', 'molecular_function', 'GO:0003904', ('75', '78'))	('hallmark of cancer', 'Disease', 'MESH:D009369', (209, 227))	('OIS', 'biological_process', 'GO:0090402', ('31', '34'))	('tumor', 'Disease', (51, 56))	('senescence', 'biological_process', 'GO:0010149', ('98', '108'))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('inactivating alterations', 'Var', (143, 167))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('CDKN2A', 'Gene', '12578', (183, 189))	('TP53', 'Gene', '22059', (175, 179))	('hallmark of cancer', 'Disease', (209, 227))
95313	29438700	Given the enhanced immune cell invasion and tumor-immune interaction observed here and in various settings after senescence induction in vivo, the ability of vemurafenib to induce senescence in Braf-mutant melanomas, and our approach presented here to inhibit H3K9-active demethylases irrespective of acquired insensitivity to vemurafenib, we would like to envision a chemo-free triple-targeting strategy for melanoma (and possibly other cancer entities) that integrates effective suppression of Braf/MEK oncogenic signaling, immune therapy via checkpoint blockade, and, in a presumably synergistic fashion, senescence restoration via demethylase inhibition.	('cancer', 'Disease', (438, 444))	('enhanced', 'PosReg', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (438, 444))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('melanoma', 'Disease', (206, 214))	('melanoma', 'Disease', 'MESH:D008545', (409, 417))	('tumor', 'Disease', (44, 49))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('inhibit', 'NegReg', (252, 259))	('H3K9', 'Gene', '109741', (260, 264))	('senescence', 'biological_process', 'GO:0010149', ('608', '618'))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('vemurafenib', 'Chemical', 'MESH:D000077484', (327, 338))	('senescence', 'biological_process', 'GO:0010149', ('180', '190'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (158, 169))	('MEK', 'Gene', '17242', (501, 504))	('cancer', 'Disease', 'MESH:D009369', (438, 444))	('senescence', 'biological_process', 'GO:0010149', ('113', '123'))	('H3K9', 'Gene', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (409, 417))	('melanoma', 'Disease', (409, 417))	('demethylase', 'Gene', (272, 283))	('demethylase', 'Gene', '8932', (272, 283))	('melanoma', 'Disease', 'MESH:D008545', (206, 214))	('Braf-mutant', 'Var', (194, 205))	('melanomas', 'Disease', 'MESH:D008545', (206, 215))	('senescence', 'MPA', (608, 618))	('MEK', 'Gene', (501, 504))	('demethylase', 'Gene', (635, 646))	('melanomas', 'Disease', (206, 215))	('demethylase', 'Gene', '8932', (635, 646))	('signaling', 'biological_process', 'GO:0023052', ('515', '524'))
95318	29438700	After the observation of Braf-induced pigmented regions, mice received total body gamma-irradiation at a sublethal dose (5 Gy), 3 days prior to the subcutaneous injection of lentivirus co-encoding murine LSD1, JMJD2C, or empty vector with GFP.	('mice', 'Species', '10090', (57, 61))	('murine', 'Species', '10090', (197, 203))	('LSD1', 'Gene', (204, 208))	('JMJD2C', 'Var', (210, 216))	('murine', 'Var', (197, 203))
95328	29438700	Zebrafish develop melanoma when melanocytes express human oncogenic Braf-V600E in a tp53-deficient background.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('V600E', 'Mutation', 'rs113488022', (73, 78))	('human', 'Species', '9606', (52, 57))	('Braf-V600E', 'Var', (68, 78))	('develop', 'Reg', (10, 17))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))	('Zebrafish', 'Species', '7955', (0, 9))
95329	29438700	When crossed to a mitfa loss-of-function mutant, melanocyte development is impaired and melanoma no longer form.	('mutant', 'Var', (41, 47))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('loss-of-function', 'NegReg', (24, 40))	('melanocyte development', 'CPA', (49, 71))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('impaired', 'NegReg', (75, 83))	('mitfa', 'Gene', (18, 23))
95330	29438700	Injection of the transposon-based expression vector MiniCoopR (MCR) into Tg(mitfa:BRAFV600E);tp53-/-;mitfa-/- one-cell stage zebrafish embryos rescues melanocytes by restoring mitfa, and simultaneously allows the expression of a candidate gene in the rescued pigment lineages.	('mitfa', 'MPA', (176, 181))	('restoring', 'PosReg', (166, 175))	('rescues', 'PosReg', (143, 150))	('expression', 'MPA', (213, 223))	('zebrafish', 'Species', '7955', (125, 134))	('tp53-/-;mitfa-/-', 'Var', (93, 109))	('BRAFV600E', 'Mutation', 'rs113488022', (82, 91))	('mitfa-/-', 'Var', (101, 109))	('melanocytes', 'CPA', (151, 162))
95336	29438700	Retroviral plasmids encoding JMJD2A (pLPC-flag-JMJD2A) or a small-hairpin against p53 (shp53), and infections of IMR90 cells were previously described.	('pLPC-flag-JMJD2A', 'Gene', '9682', (37, 53))	('JMJD2A', 'Var', (29, 35))	('IMR90', 'CellLine', 'CVCL:0347', (113, 118))	('pLPC-flag-JMJD2A', 'Gene', (37, 53))
95340	29438700	shRNA sequences to knock-down LSD1, JMJD2C, and MDM2 are listed in the Key Resources Table.	('LSD1', 'Gene', (30, 34))	('MDM2', 'Gene', '17246', (48, 52))	('MDM2', 'Gene', (48, 52))	('knock-down', 'Var', (19, 29))
95358	29438700	Isolation, retroviral infection, and transplantation of Emu-N-Ras transgenic fetal liver cells infected with LSD1 or JMJD2C constructs were performed as previously described .	('transgenic', 'Species', '10090', (66, 76))	('retroviral infection', 'Disease', (11, 31))	('JMJD2C', 'Var', (117, 123))	('retroviral infection', 'Disease', 'MESH:D000071297', (11, 31))
95369	29438700	DMCs used in this study harbor either a Braf exon 15 mutation (c1799T>A) or an N-Ras exon 3 mutation (c181C>A), as determined by Sanger sequencing (Sequiserve, Vaterstetten, Germany).	('c181C>A', 'Mutation', 'c.181C>A', (102, 109))	('c181C>A', 'Var', (102, 109))	('DMCs', 'Chemical', '-', (0, 4))	('c1799T>A', 'Mutation', 'rs113488022', (63, 71))	('c1799T>A', 'Var', (63, 71))	('his', 'Chemical', 'MESH:D006639', (14, 17))
95384	29438700	The accession number for RNA sequencing data reported in this study is GEO: GSE105137 and GSE105138.	('GSE105138', 'Var', (90, 99))	('GSE105137', 'Var', (76, 85))	('his', 'Chemical', 'MESH:D006639', (58, 61))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))
95392	27798773	Furthermore, the results of published studies and case reports demonstrated that CS-PHP with melphalan resulted in favorable tumor response rates in a range of tumor histologies (ocular or cutaneous melanoma, colorectal cancer, and hepatobiliary tumors).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CS-PHP', 'Var', (81, 87))	('colorectal cancer', 'Disease', (209, 226))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('melphalan', 'Chemical', 'MESH:D008558', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cutaneous melanoma', 'Disease', (189, 207))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (189, 207))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (189, 207))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CS-PHP', 'Chemical', '-', (81, 87))	('hepatobiliary tumors', 'Disease', (232, 252))	('colorectal cancer', 'Phenotype', 'HP:0003003', (209, 226))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (125, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (209, 226))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('hepatobiliary tumors', 'Disease', 'MESH:D004066', (232, 252))
95394	27798773	Taken together, these findings indicate that CS-PHP is a promising locoregional therapy for patients with primary and secondary liver tumors and has a acceptable safety profile.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('liver tumor', 'Phenotype', 'HP:0002896', (128, 139))	('patients', 'Species', '9606', (92, 100))	('primary', 'Disease', (106, 113))	('liver tumors', 'Disease', 'MESH:D008113', (128, 140))	('CS-PHP', 'Var', (45, 51))	('liver tumors', 'Phenotype', 'HP:0002896', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('liver tumors', 'Disease', (128, 140))	('CS-PHP', 'Chemical', '-', (45, 51))
95449	27798773	Intravenous (IV) hydration is started to ensure an adequate fluid preload before the procedure; however, this is not consistently done at all institutions, as some centers believe that a fluid preload increases the risk of edema, particularly of the neck, airways, and pulmonary interstitium.	('fluid preload', 'Phenotype', 'HP:0011105', (187, 200))	('pulmonary interstitium', 'Phenotype', 'HP:0006530', (269, 291))	('edema', 'Disease', (223, 228))	('edema', 'Phenotype', 'HP:0000969', (223, 228))	('neck', 'cellular_component', 'GO:0044326', ('250', '254'))	('fluid preload', 'Var', (187, 200))	('edema', 'Disease', 'MESH:D004487', (223, 228))	('fluid preload', 'Phenotype', 'HP:0011105', (60, 73))
95486	27798773	A clinically meaningful and statistically significant improvement in hPFS was observed in the CS-PHP group compared to the BAC group.	('BAC', 'Chemical', '-', (123, 126))	('improvement', 'PosReg', (54, 65))	('hPFS', 'CPA', (69, 73))	('CS-PHP', 'Var', (94, 100))	('CS-PHP', 'Chemical', '-', (94, 100))
95488	27798773	Additionally, there was a statistically significant (P < 0.0001) improvement in the hOR rate with PHP (36.4%) compared to BAC (2.0%).	('PHP', 'Var', (98, 101))	('BAC', 'Chemical', '-', (122, 125))	('improvement', 'PosReg', (65, 76))	('hOR rate', 'CPA', (84, 92))
95515	27798773	The ECOG score trended lower in the CS-PHP group (P = 0.051) compared with the yttrium and chemoembolization groups.	('CS-PHP', 'Var', (36, 42))	('CS-PHP', 'Chemical', '-', (36, 42))	('ECOG score', 'MPA', (4, 14))	('yttrium', 'Chemical', 'MESH:D015019', (79, 86))	('lower', 'NegReg', (23, 28))
95516	27798773	Median hPFS was significantly (P = 0.002) longer with CS-PHP (310 days) than with yttrium (54 days) and chemoembolization (80 days).	('CS-PHP', 'Var', (54, 60))	('CS-PHP', 'Chemical', '-', (54, 60))	('longer', 'PosReg', (42, 48))	('hPFS', 'MPA', (7, 11))	('yttrium', 'Chemical', 'MESH:D015019', (82, 89))
95517	27798773	Median hPFS was also significantly longer with CS-PHP versus yttrium (P < 0.001) and CS-PHP versus chemoembolization (P = 0.008), but not yttrium versus chemoembolization (P = 0.44).	('yttrium', 'Chemical', 'MESH:D015019', (61, 68))	('CS-PHP', 'Var', (47, 53))	('CS-PHP', 'Var', (85, 91))	('CS-PHP', 'Chemical', '-', (85, 91))	('yttrium', 'Chemical', 'MESH:D015019', (138, 145))	('CS-PHP', 'Chemical', '-', (47, 53))	('hPFS', 'MPA', (7, 11))	('longer', 'PosReg', (35, 41))
95543	27798773	In the clinical trial program (specifically, the randomized, controlled phase 3 study), CS-PHP with melphalan resulted in a clinically meaningful and statistically significant improvement in hPFS in patients with unresectable hepatic metastases from ocular or cutaneous melanoma.	('CS-PHP', 'Chemical', '-', (88, 94))	('hepatic metastases', 'Disease', (226, 244))	('ocular', 'Disease', (250, 256))	('improvement', 'PosReg', (176, 187))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('hepatic metastases', 'Disease', 'MESH:D009362', (226, 244))	('melphalan', 'Chemical', 'MESH:D008558', (100, 109))	('patients', 'Species', '9606', (199, 207))	('hPFS', 'MPA', (191, 195))	('cutaneous melanoma', 'Disease', (260, 278))	('CS-PHP', 'Var', (88, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (260, 278))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (260, 278))
95553	30993736	For patients in different clinical stages, genes can have different effects on the Breslow thickness, which is a continuous variable and has been extensively used as a prognostic indicator for melanoma.	('Breslow thickness', 'CPA', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('genes', 'Var', (43, 48))	('patients', 'Species', '9606', (4, 12))	('effects', 'Reg', (68, 75))
95585	30993736	Moreover, it has been demonstrated that SEMA3A suppresses tumor growth and metastasis using multiple in vitro and in vivo approaches in mice melanoma models.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mice', 'Species', '10090', (136, 140))	('melanoma', 'Disease', (141, 149))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('suppresses', 'NegReg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('SEMA3A', 'Var', (40, 46))
95602	30993736	It has been suggested that APOBEC-mediated mutagenesis is universal throughout cancer genomes, and a significant presence of the APOBEC mutation pattern has been found in breast, cervical, bladder, head, neck, and lung cancers.	('cervical', 'Disease', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('breast', 'Disease', (171, 177))	('bladder', 'Disease', (189, 196))	('APOBEC', 'cellular_component', 'GO:0030895', ('27', '33'))	('APOBEC', 'Gene', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (214, 226))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'Var', (136, 144))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('mutagenesis', 'biological_process', 'GO:0006280', ('43', '54'))	('cancer', 'Disease', (219, 225))	('lung cancers', 'Disease', (214, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('head', 'Disease', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lung cancers', 'Phenotype', 'HP:0100526', (214, 226))	('neck', 'cellular_component', 'GO:0044326', ('204', '208'))	('found', 'Reg', (162, 167))	('presence', 'Reg', (113, 121))	('APOBEC', 'cellular_component', 'GO:0030895', ('129', '135'))
95635	32817058	The genetic alterations in acral melanoma are distinct from those in cutaneous melanoma, with KIT mutations more common (15%-20% vs 1%-2%) and BRAF mutations less common (15% vs 45%).	('KIT', 'molecular_function', 'GO:0005020', ('94', '97'))	('KIT', 'Gene', (94, 97))	('rat', 'Species', '10116', (16, 19))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('cutaneous melanoma', 'Disease', (69, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (69, 87))	('BRAF', 'Gene', (143, 147))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 87))	('acral melanoma', 'Disease', 'MESH:D008545', (27, 41))	('mutations', 'Var', (98, 107))	('BRAF', 'Gene', '673', (143, 147))	('common', 'Reg', (113, 119))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('acral melanoma', 'Disease', (27, 41))	('acral melanoma', 'Phenotype', 'HP:0012060', (27, 41))	('KIT', 'Gene', '3815', (94, 97))
95662	32817058	Following heat-induced epitope retrieval using cell conditioning two (32 mins at 95o) omnimap antimouse horseradish peroxidase (HRP) (760-4310) or omnimap antirabbit HRP (760-4311) were used to detect the primaries.	('760-4310', 'Var', (134, 142))	('760-4311', 'Var', (171, 179))	('horseradish peroxidase (HRP', 'molecular_function', 'GO:0004601', ('104', '131'))	('mouse', 'Species', '10090', (98, 103))	('horseradish', 'Species', '3704', (104, 115))
95705	32817058	As the patient's tumour harboured a p.V600E BRAF mutation, dabrafenib was administered and the patient achieved resolution of the lymph node lesion and a partial response in the brain (50% decrease).	('BRAF', 'Gene', '673', (44, 48))	('p.V600E', 'Mutation', 'rs113488022', (36, 43))	('patient', 'Species', '9606', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('patient', 'Species', '9606', (7, 14))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('BRAF', 'Gene', (44, 48))	('p.V600E', 'Var', (36, 43))	('decrease', 'NegReg', (189, 197))	('tumour', 'Disease', (17, 23))	('dabrafenib', 'Chemical', 'MESH:C561627', (59, 69))
95720	32817058	We confirmed increased PI3K/AKT signalling in the presence of CSF in the cell line from the subcutaneous metastasis (online supplementary fig 3A-F), supporting an extrinsic cause for PI3K/AKT activation rather than an intrinsic cause such as a newly acquired mutation in the brain lesion cells.	('signalling', 'biological_process', 'GO:0023052', ('32', '42'))	('CSF', 'Var', (62, 65))	('AKT', 'Gene', (28, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('183', '187'))	('increased', 'PosReg', (13, 22))	('AKT', 'Gene', '207', (188, 191))	('activation', 'PosReg', (192, 202))	('PI3K', 'molecular_function', 'GO:0016303', ('23', '27'))	('AKT', 'Gene', '207', (28, 31))	('rat', 'Species', '10116', (203, 206))	('AKT', 'Gene', (188, 191))
95745	32817058	Unfortunately, due to the limited tissue available we were unable to confirm increased phosphorylation of protein kinase B (AKT) in the brain lesion by IHC.	('protein kinase B', 'Gene', '2185', (106, 122))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('AKT', 'Gene', (124, 127))	('IHC', 'Var', (152, 155))	('protein kinase B', 'Gene', (106, 122))	('phosphorylation', 'MPA', (87, 102))	('AKT', 'Gene', '207', (124, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('87', '102'))
95747	32817058	This is consistent with findings from a study, which showed that a pan-PI3K inhibitor suppressed the growth of melanoma cells both in astrocyte-conditioned media and in the brains of nude mice.	('growth', 'MPA', (101, 107))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('nude mice', 'Species', '10090', (183, 192))	('pan-PI3K', 'Gene', (67, 75))	('inhibitor', 'Var', (76, 85))	('suppressed', 'NegReg', (86, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
95756	33613027	In this context, long noncoding RNAs (lncRNAs) are a new type of noncoding transcripts that their dysregulations are associated with almost all cancers including melanoma.	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('associated', 'Reg', (117, 127))	('dysregulations', 'Var', (98, 112))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
95767	33613027	Although sun exposure is the major risk factor for cutaneous melanoma, specific genetic alterations are also associated with melanoma risk.	('genetic alterations', 'Var', (80, 99))	('associated', 'Reg', (109, 119))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('cutaneous melanoma', 'Disease', (51, 69))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
95771	33613027	In fact, they involve in the epigenetic regulation of other macromolecules through chromatin remodeling, as well as transcriptional and post-transcriptional regulation, and, consequently, their dysregulations lead to different diseases such as cancer.	('involve', 'Reg', (14, 21))	('dysregulations', 'Var', (194, 208))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('lead to', 'Reg', (209, 216))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('83', '103'))	('regulation', 'biological_process', 'GO:0065007', ('157', '167'))	('epigenetic regulation', 'MPA', (29, 50))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('chromatin', 'cellular_component', 'GO:0000785', ('83', '92'))
95773	33613027	Frequent studies are reporting that a significant proportion of the genomic mutations in cancer occur within nonprotein coding regions, usually inside the lncRNA loci.	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('genomic mutations', 'Var', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
95774	33613027	Also, the association between aberrant expression of thousands of lncRNAs with different cancers has been demonstrated.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('association', 'Interaction', (10, 21))	('aberrant expression', 'Var', (30, 49))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
95798	33613027	Accordingly, the CMK-lncRNAs include 2 groups of lncRNAs: (1) those lncRNAs that are both significantly differentially expressed in cutaneous melanoma samples compared with normal ones and have genomic alterations in over 10% of cutaneous melanoma samples; (2) those lncRNAs that are both hubs of the cutaneous melanoma co-alteration/expression networks and have mutations/CNAs (genomic alterations) in over 10% of cutaneous melanoma samples.	('melanoma', 'Phenotype', 'HP:0002861', (239, 247))	('cutaneous melanoma', 'Disease', (301, 319))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (301, 319))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (301, 319))	('melanoma', 'Phenotype', 'HP:0002861', (311, 319))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('CMK', 'Gene', (17, 20))	('cutaneous melanoma', 'Disease', (229, 247))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (229, 247))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (229, 247))	('CMK', 'Gene', '4283', (17, 20))	('mutations/CNAs', 'Var', (363, 377))	('cutaneous melanoma', 'Disease', (132, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('melanoma', 'Phenotype', 'HP:0002861', (425, 433))	('cutaneous melanoma', 'Disease', (415, 433))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (415, 433))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (415, 433))
95804	33613027	To this purpose, the list of all differentially expressed genes in cutaneous melanoma TCGA study was retrieved from the GEPIA web server (Supplementary file 6) and subjected to the expression data; if the CMK-lncRNA was dysregulated, the coexpressed genes that were dysregulated were retained, and if the CMK-lncRNA was normally expressed, the coexpressed genes with normal expression were selected.	('CMK', 'Gene', '4283', (205, 208))	('CMK', 'Gene', '4283', (305, 308))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cutaneous melanoma', 'Disease', (67, 85))	('CMK', 'Gene', (205, 208))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (67, 85))	('CMK', 'Gene', (305, 308))	('dysregulated', 'Var', (220, 232))
95817	33613027	amplification and over-expression) alterations, while CDKN2A-AS1 lncRNA was mostly deleted in cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('cutaneous melanoma', 'Disease', (94, 112))	('over-expression', 'PosReg', (18, 33))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (94, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (94, 112))	('CDKN2A-AS1', 'Gene', '51198', (54, 64))	('amplification', 'Var', (0, 13))	('CDKN2A-AS1', 'Gene', (54, 64))
95830	33613027	Also, it has been demonstrated that targeting of NGLY1, a protein deglycosylation (GO:0006517; associated with LINC00265) enzyme, could promote the efficiency of melanoma targeted therapy and chemotherapy by inducing stress signaling-associated apoptosis, pleiotropic responses, and cytokine surges.	('promote', 'PosReg', (136, 143))	('targeting', 'Var', (36, 45))	('NGLY1', 'Gene', (49, 54))	('stress', 'CPA', (217, 223))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('245', '254'))	('apoptosis', 'biological_process', 'GO:0006915', ('245', '254'))	('inducing', 'PosReg', (208, 216))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('LINC00265', 'Gene', (111, 120))	('protein deglycosylation', 'biological_process', 'GO:0006517', ('58', '81'))	('pleiotropic responses', 'CPA', (256, 277))	('chemotherapy', 'CPA', (192, 204))	('NGLY1', 'Gene', '55768', (49, 54))	('cytokine', 'CPA', (283, 291))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('LINC00265', 'Gene', '349114', (111, 120))
95862	33613027	Among all, 3 biological processes including regulation of keratinocyte proliferation (GO:0010837), keratinocyte differentiation (GO:0030216), and epidermis development (GO:0008544) as well as immune-related biological pathways are the most remarkable ones in the context of cutaneous melanoma.	('regulation of keratinocyte proliferation', 'biological_process', 'GO:0010837', ('44', '84'))	('keratinocyte differentiation', 'biological_process', 'GO:0030216', ('99', '127'))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('keratinocyte differentiation', 'CPA', (99, 127))	('cutaneous melanoma', 'Disease', (274, 292))	('keratinocyte proliferation', 'CPA', (58, 84))	('GO:0030216', 'Var', (129, 139))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (274, 292))	('epidermis development', 'biological_process', 'GO:0008544', ('146', '167'))	('epidermis development', 'CPA', (146, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (274, 292))	('GO:0010837', 'Var', (86, 96))	('GO:0008544', 'Var', (169, 179))
95874	33613027	Furthermore, based on our results, most of the cutaneous melanoma samples with dysregulation in any of the differentially expressed CMK-lncRNAs belong to the stage III or IV melanoma patients with less than 5 years OS/DFS.	('CMK', 'Gene', '4283', (132, 135))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('dysregulation', 'Var', (79, 92))	('cutaneous melanoma', 'Disease', (47, 65))	('CMK', 'Gene', (132, 135))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (47, 65))	('melanoma', 'Disease', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (47, 65))	('patients', 'Species', '9606', (183, 191))
95882	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))
95883	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'))
95884	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'))	('ETS/TCF', 'Gene', (134, 141))	('C250T', 'Var', (62, 67))	('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))
95887	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'))
95889	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))
95893	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))	('MYC', 'Gene', (10, 13))	('TERT', 'Gene', (141, 145))	('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))	('histone', 'Protein', (203, 210))	('activate', 'PosReg', (54, 62))	('TERT', 'Gene', '7015', (141, 145))	('TERT', 'Gene', (156, 160))	('TERT', 'Gene', '7015', (156, 160))
95894	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))
95895	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))
95896	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))
95897	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))
95899	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))
95900	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))
95901	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))
95906	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))
95913	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'))
95914	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))
95918	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))
95919	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))
95923	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))
95924	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))	('518A2', 'Var', (213, 218))	('TERT', 'Gene', (83, 87))	('C228T', 'Var', (98, 103))	('TERT', 'Gene', '7015', (83, 87))	('C250T', 'Mutation', 'rs1184821004', (88, 93))	('A375', 'Var', (229, 233))
95925	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))
95927	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))
95928	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))
95929	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))
95930	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))
95935	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))
95940	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))
95947	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).	('TERTp', 'Gene', (87, 92))	('methylation', 'MPA', (24, 35))	('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))
95949	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))
95950	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'))
95953	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))
95956	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))
95957	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.	('C228T', 'Var', (52, 57))	('TERTp', 'Gene', (58, 63))	('TERTp', 'Gene', '7015', (58, 63))	('hypomethylated', 'MPA', (186, 200))	('C228T', 'Mutation', 'rs763756456', (52, 57))
95964	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))
95972	32267900	WM1361A, WM3506, WM1960 cell lines were a kind gift from Dr. KL Scott (Baylor College of Medicine, Houston, USA).	('WM1361A', 'Var', (0, 7))	('WM3506', 'CellLine', 'CVCL:AP93', (9, 15))	('WM1960', 'CellLine', 'CVCL:AP76', (17, 23))	('WM1960', 'Var', (17, 23))
95988	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))
95989	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))
95990	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))
96000	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))	('Kit', 'Gene', (79, 82))	('A375', 'Var', (194, 198))	('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'))
96001	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'))
96011	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))
96016	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))
96018	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))
96024	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))	('chromatin accessibility', 'MPA', (184, 207))	('TERT', 'Gene', (138, 142))	('association', 'Interaction', (118, 129))	('DNA methylation', 'biological_process', 'GO:0006306', ('163', '178'))	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('DNA', 'MPA', (163, 166))
96036	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))
96037	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))
96041	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))	('TERTp', 'Gene', '7015', (101, 106))	('human', 'Species', '9606', (56, 61))	('TERT', 'Gene', (101, 105))	('mutation', 'Var', (107, 115))
96045	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))
96046	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))
96047	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))	('WT melanoma', 'Disease', 'MESH:D008545', (127, 138))	('TERT', 'Gene', '7015', (54, 58))	('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))
96051	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))
96052	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))
96053	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))	('TERT', 'Gene', (251, 255))	('TERTp', 'Gene', (261, 266))	('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))
96055	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'))
96056	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))
96058	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))	('TERTp', 'Gene', (93, 98))	('positive regulation', 'PosReg', (66, 85))	('TERTp', 'Gene', '7015', (93, 98))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('regulation', 'biological_process', 'GO:0065007', ('75', '85'))
96059	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'))	('TERTp', 'Gene', (224, 229))	('TERT', 'Gene', (250, 254))	('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))
96060	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))
96065	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))
96066	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))
96069	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))
96071	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))
96084	32267900	DNA hypermethylation within TERT promoter upregulates TERT expression in cancer.	('upregulates', 'PosReg', (42, 53))	('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'))	('TERT', 'Gene', '7015', (28, 32))	('TERT', 'Gene', (54, 58))	('hypermethylation', 'Var', (4, 20))
96086	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))
96088	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))
96091	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))
96093	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'))
96104	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))
96112	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))
96123	32188929	Cancers can be caused by an accumulation of genetic mutations in oncogenes or tumor suppressors.	('caused by', 'Reg', (15, 24))	('Cancers', 'Disease', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('genetic mutations', 'Var', (44, 61))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (78, 83))	('oncogenes', 'Protein', (65, 74))
96124	32188929	These mutations are known as "driver" mutations and they are under positive selection; however, only a very small fraction of somatic mutations in a tumor sample are expected to be drivers.	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (149, 154))
96128	32188929	For example, deleterious mutations in POLE, POLD1, and the MMR system defects may lead to a hypermutated phenotype.	('mutations', 'Var', (25, 34))	('POLE', 'Gene', (38, 42))	('lead to', 'Reg', (82, 89))	('hypermutated phenotype', 'MPA', (92, 114))	('system defects', 'Disease', 'MESH:D009421', (63, 77))	('system defects', 'Disease', (63, 77))	('POLD1', 'Gene', '5424', (44, 49))	('MMR', 'biological_process', 'GO:0006298', ('59', '62'))	('POLD1', 'Gene', (44, 49))
96133	32188929	Microsatellite instability (MSI) is a phenotype of an accumulation of deletions/insertions in repetitive DNA tracts, called microsatellites.	('Microsatellite instability', 'Disease', (0, 26))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('deletions/insertions', 'Var', (70, 90))
96137	32188929	The major challenge is that even though the current well-accepted TMB measurement requires counting the non-synonymous somatic mutations in a paired tumor-normal sample using whole-exome sequencing (WES), current diagnostics based on sequencing technologies still rely heavily on targeted panel sequencing.	('TMB', 'Chemical', '-', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (127, 136))
96141	32188929	For example, Foundation Medicine used COSMIC to filter out driver mutations and added synonymous mutations to reach an agreement with WES-based TMB.	('mutations', 'Var', (66, 75))	('synonymous mutations', 'Var', (86, 106))	('TMB', 'Chemical', '-', (144, 147))
96153	32188929	The mutation predictions for MUC16 and TTN then became much closer to the observed values (Supplementary Fig.	('TTN', 'Gene', '7273', (39, 42))	('mutation', 'Var', (4, 12))	('MUC16', 'Gene', (29, 34))	('MUC16', 'Gene', '94025', (29, 34))	('TTN', 'Gene', (39, 42))
96154	32188929	In addition, the observed number of non-synonymous mutations in well-known cancer-specific driver genes, such as TP53, KRAS, and PIK3CA, were much higher than the predicted background ones due to positive selection (Supplementary Fig.	('PIK3CA', 'Gene', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('PIK3CA', 'Gene', '5290', (129, 135))	('TP53', 'Gene', '7157', (113, 117))	('KRAS', 'Gene', (119, 123))	('non-synonymous mutations', 'Var', (36, 60))	('higher', 'PosReg', (147, 153))	('KRAS', 'Gene', '3845', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (113, 117))
96169	32188929	In contrast, ecTMB predictions, using both synonymous and non-synonymous mutations, not only improved correlation coefficients with WES-based TMB, but also reduced MSE, RMSE, sigma, and biases while keeping the slope close to 1.	('correlation coefficients', 'MPA', (102, 126))	('improved', 'PosReg', (93, 101))	('sigma', 'MPA', (175, 180))	('TMB', 'Chemical', '-', (142, 145))	('reduced', 'NegReg', (156, 163))	('RMSE', 'MPA', (169, 173))	('biases', 'MPA', (186, 192))	('TMB', 'Chemical', '-', (15, 18))	('mutations', 'Var', (73, 82))	('MSE', 'MPA', (164, 167))
96170	32188929	As an example, for the predictions of the TST170 panel, ecTMB improved R from 0.71 to 0.77, reduced MAE from 7.05 to 3.21, and decreased sigma from 6.04 to 4.13 if compared with the counting method without filtering (Fig.	('TMB', 'Chemical', '-', (58, 61))	('decreased', 'NegReg', (127, 136))	('improved', 'PosReg', (62, 70))	('sigma', 'MPA', (137, 142))	('ecTMB', 'Var', (56, 61))	('reduced', 'NegReg', (92, 99))	('MAE', 'MPA', (100, 103))
96172	32188929	These performance metrics demonstrated that TMB prediction by ecTMB has a higher agreement with WES-based TMB.	('tri', 'Chemical', '-', (20, 23))	('TMB', 'Chemical', '-', (106, 109))	('TMB', 'Chemical', '-', (64, 67))	('TMB', 'Disease', (44, 47))	('ecTMB', 'Var', (62, 67))	('TMB', 'Chemical', '-', (44, 47))
96177	32188929	ecTMB prediction had pretty good sensitivity and also high precision, leading to higher overall accuracy when comparing to the other 2 methods (Fig.	('higher', 'PosReg', (81, 87))	('accuracy', 'MPA', (96, 104))	('TMB', 'Chemical', '-', (2, 5))	('ecTMB', 'Var', (0, 5))
96185	32188929	We found that a large fraction (92%) of TMB-extreme samples possessed at least one non-synonymous mutation in POLE in aggregated colorectal, endometrial, and stomach cancer samples, among which we detected a high recurrence of 2 known POLE driver mutations (P286R and V411L) (Supplementary Fig.	('stomach cancer', 'Disease', (158, 172))	('P286R', 'Var', (258, 263))	('V411L', 'Mutation', 'rs1196350669', (268, 273))	('TMB-extreme', 'Gene', (40, 51))	('stomach cancer', 'Disease', 'MESH:D013274', (158, 172))	('TMB', 'Chemical', '-', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('V411L', 'Var', (268, 273))	('stomach cancer', 'Phenotype', 'HP:0012126', (158, 172))	('P286R', 'Mutation', 'p.P286R', (258, 263))	('tri', 'Chemical', '-', (147, 150))
96187	32188929	The comparison of non-synonymous mutations in seven MMR genes between TMB-high samples against the rest revealed 2 highly recurred mutations: N674lfs*6 in MLH3 and K383Rfs*32 in MSH3, which have not been reported as driver mutation before (Supplementary Fig.	('K383Rfs*32', 'Mutation', 'rs587776701', (164, 174))	('MMR', 'biological_process', 'GO:0006298', ('52', '55'))	('N674lfs*6', 'Var', (142, 151))	('MLH3', 'Gene', '27030', (155, 159))	('TMB', 'Chemical', '-', (70, 73))	('MSH3', 'Gene', (178, 182))	('K383Rfs*32', 'Var', (164, 174))	('MLH3', 'Gene', (155, 159))	('MSH3', 'Gene', '4437', (178, 182))
96188	32188929	We also found that TMB-high samples generally had a significantly higher fraction (~17%) of INDEL mutations than what was observed in both TMB-low (~5%) and TMB-extreme (~1%) samples (Fig.	('TMB', 'Chemical', '-', (157, 160))	('INDEL mutations', 'Var', (92, 107))	('higher', 'PosReg', (66, 72))	('TMB', 'Chemical', '-', (19, 22))	('TMB', 'Chemical', '-', (139, 142))
96189	32188929	These distinct mutation profiles suggest that defective MMR system could be the likely cause for TMB-high whereas mutated POLE system for TMB-extreme.	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (97, 100))	('TMB-high', 'Disease', (97, 105))	('MMR', 'Protein', (56, 59))	('defective', 'Var', (46, 55))	('MMR', 'biological_process', 'GO:0006298', ('56', '59'))
96200	32188929	First, ecTMB improves the consistency of TMB prediction among assays through systematic correction of panel design biases.	('consistency', 'MPA', (26, 37))	('TMB', 'Chemical', '-', (41, 44))	('improves', 'PosReg', (13, 21))	('ecTMB', 'Var', (7, 12))	('TMB', 'Chemical', '-', (9, 12))	('TMB', 'MPA', (41, 44))
96203	32188929	Although there are other factors influencing the consistency of TMB among assays, such as sequencing depth and choice of somatic mutation caller, we have demonstrated that ecTMB can help to improve the stability of TMB measurement when those factors are fixed.	('TMB', 'Chemical', '-', (64, 67))	('stability', 'MPA', (202, 211))	('TMB', 'MPA', (215, 218))	('ecTMB', 'Var', (172, 177))	('TMB', 'Chemical', '-', (215, 218))	('improve', 'PosReg', (190, 197))	('TMB', 'Chemical', '-', (174, 177))
96208	32188929	Although multiple studies have observed a better prognosis in MSI-H patients, we showed that TMB-extreme caused by dysfunctional POLE showed even better overall survival outcomes compared to TMB-high (MSI-H).	('patients', 'Species', '9606', (68, 76))	('dysfunctional POLE', 'Var', (115, 133))	('TMB', 'Chemical', '-', (191, 194))	('TMB-extreme', 'Disease', (93, 104))	('TMB', 'Chemical', '-', (93, 96))	('better', 'PosReg', (146, 152))
96209	32188929	Similar to our result, studies have reported that mutations in POLE proofreading domain are associated with improved prognosis in several cancer types, including high-grade glioma, lung adenocarcinoma, endometrial cancer, and colorectal cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))	('cancer', 'Disease', (214, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (181, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (181, 200))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('endometrial cancer', 'Phenotype', 'HP:0012114', (202, 220))	('improved', 'PosReg', (108, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('endometrial cancer', 'Disease', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('colorectal cancer', 'Disease', (226, 243))	('mutations', 'Var', (50, 59))	('glioma', 'Disease', (173, 179))	('endometrial cancer', 'Disease', 'MESH:D016889', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('lung adenocarcinoma', 'Disease', (181, 200))
96211	32188929	The TMB-extreme subtype can also be potentially detected with an assay targeting only mutations in the POLE's proofreading domain.	('mutations', 'Var', (86, 95))	('TMB', 'Chemical', '-', (4, 7))	('TMB-extreme', 'Disease', (4, 15))	('detected', 'Reg', (48, 56))
96223	32188929	Different proportions of non-synonymous mutations can be used for TMB prediction.	('non-synonymous mutations', 'Var', (25, 49))	('TMB', 'Chemical', '-', (66, 69))	('TMB', 'Disease', (66, 69))
96224	32188929	In BLCA, SKCM, LUSC, and LUAD, which are known to harbor somatic mutations caused by environmental factors, the prediction accuracy increased as a higher proportion of non-synonymous mutations were included (Supplementary Fig.	('LUAD', 'Disease', (25, 29))	('SKCM', 'Disease', (9, 13))	('BLCA', 'Disease', 'MESH:D001749', (3, 7))	('LUSC', 'Disease', 'MESH:D002294', (15, 19))	('increased', 'PosReg', (132, 141))	('LUAD', 'Disease', 'MESH:D000077192', (25, 29))	('LUSC', 'Disease', (15, 19))	('BLCA', 'Disease', (3, 7))	('SKCM', 'Disease', 'MESH:C562393', (9, 13))	('non-synonymous mutations', 'Var', (168, 192))	('LUAD', 'Phenotype', 'HP:0030078', (25, 29))
96252	30538110	In a syngeneic melanoma mouse model, mPGES1 knockout increased melanoma expression of PD-L1, increased infiltration of CD8a+ T cells and CD8a+ dendritic cells into tumors and suppressed tumor growth.	('mouse', 'Species', '10090', (24, 29))	('tumor', 'Disease', (164, 169))	('knockout', 'Var', (44, 52))	('suppressed', 'NegReg', (175, 185))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (186, 191))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mPGES1', 'Gene', (37, 43))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('expression', 'MPA', (72, 82))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('PD-L1', 'Gene', (86, 91))	('infiltration', 'CPA', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (164, 170))	('mPGES1', 'Gene', '64292', (37, 43))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))
96254	30538110	Analysis of a stage III melanoma tissue microarray revealed significant associations between high mPGES1 expression and low CD8+ infiltration, which correlated with a shorter patient survival.	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('shorter', 'NegReg', (167, 174))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('rat', 'Species', '10116', (135, 138))	('patient', 'Species', '9606', (175, 182))	('mPGES1', 'Gene', (98, 104))	('low', 'NegReg', (120, 123))	('CD8', 'Gene', (124, 127))	('mPGES1', 'Gene', '64292', (98, 104))	('CD8', 'Gene', '925', (124, 127))	('high', 'Var', (93, 97))	('expression', 'MPA', (105, 115))	('melanoma', 'Disease', (24, 32))
96281	30538110	A CRISPR/CAS9 knockout kit for mouse mPGES1 (KN314172) was purchased from Origene Technologies Inc. (Rockville, MD, USA) and used according to the manufacturer's specifications.	('mPGES1', 'Gene', (37, 43))	('KN314172', 'Var', (45, 53))	('mouse', 'Species', '10090', (31, 36))	('mPGES1', 'Gene', '64292', (37, 43))	('CAS', 'cellular_component', 'GO:0005650', ('9', '12'))
96282	30538110	Finally, the success/efficiency of mPGES1 knockout were confirmed by Western blot analysis, and PGE2 level in the cells was measured.	('PGE2', 'Chemical', 'MESH:D015232', (96, 100))	('mPGES1', 'Gene', '64292', (35, 41))	('knockout', 'Var', (42, 50))	('mPGES1', 'Gene', (35, 41))
96293	30538110	After 8 days, the mice began intraperitoneally receiving anti-PD-1 monoclonal antibody (200 mug per mouse, BE0416, Bio X Cell, NH) or IgG (control, BE0086, Bio X Cell, NH) every 3 days for 2 weeks.	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('mouse', 'Species', '10090', (100, 105))	('mice', 'Species', '10090', (18, 22))	('mug', 'molecular_function', 'GO:0043739', ('92', '95'))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('anti-PD-1', 'Gene', (57, 66))	('200 mug', 'Var', (88, 95))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))
96323	30538110	To test whether the link between COX2 and mPGES1 is important for PGE2 production, mPGES1 was knocked down or inhibited in WM793 human melanoma cells, which express high levels of COX2 and mPGES1 and produce high levels of PGE2.	('mPGES1', 'Gene', (83, 89))	('mPGES1', 'Gene', '64292', (42, 48))	('WM793', 'CellLine', 'CVCL:8787', (123, 128))	('mPGES1', 'Gene', '64292', (83, 89))	('mPGES1', 'Gene', '64292', (189, 195))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('PGE2', 'Chemical', 'MESH:D015232', (223, 227))	('inhibited', 'NegReg', (110, 119))	('PGE2', 'Chemical', 'MESH:D015232', (66, 70))	('mPGES1', 'Gene', (42, 48))	('human', 'Species', '9606', (129, 134))	('mPGES1', 'Gene', (189, 195))	('knocked', 'Var', (94, 101))	('COX2', 'Gene', (180, 184))
96324	30538110	The selective COX2 inhibitor celecoxib and selective mPGES1 inhibitor PF9184 significantly suppressed PGE2 production (Figure 1D, left), as did knockout of mPGES1 (Figure 1D, right).	('suppressed', 'NegReg', (91, 101))	('PGE2', 'Chemical', 'MESH:D015232', (102, 106))	('PF9184', 'Chemical', 'MESH:C548452', (70, 76))	('mPGES1', 'Gene', (53, 59))	('mPGES1', 'Gene', (156, 162))	('PGE2 production', 'MPA', (102, 117))	('knockout', 'Var', (144, 152))	('PF9184', 'Var', (70, 76))	('mPGES1', 'Gene', '64292', (53, 59))	('mPGES1', 'Gene', '64292', (156, 162))	('celecoxib', 'Chemical', 'MESH:D000068579', (29, 38))
96331	30538110	As shown in Figure 3A, treatment of melanoma cells with the inhibitor, PF9184, reduced or eliminated expression of several pro-inflammatory cytokines and chemokines, including CCL, CXCL5, ANG1, and ANG2, suggesting that mPGES1 regulates and promotes features of inflammation.	('inflammation', 'Disease', (262, 274))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('PF9184', 'Var', (71, 77))	('ANG2', 'Gene', '285', (198, 202))	('ANG2', 'Gene', (198, 202))	('eliminated', 'NegReg', (90, 100))	('CCL', 'Gene', '200575', (176, 179))	('mPGES1', 'Gene', (220, 226))	('ANG1', 'Gene', '284', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('reduced', 'NegReg', (79, 86))	('melanoma', 'Disease', (36, 44))	('CXCL5', 'Gene', (181, 186))	('PF9184', 'Chemical', 'MESH:C548452', (71, 77))	('CXCL5', 'Gene', '6374', (181, 186))	('CCL', 'Gene', (176, 179))	('pro-inflammatory cytokines', 'MPA', (123, 149))	('promotes', 'PosReg', (241, 249))	('inflammation', 'biological_process', 'GO:0006954', ('262', '274'))	('inflammation', 'Disease', 'MESH:D007249', (262, 274))	('mPGES1', 'Gene', '64292', (220, 226))	('ANG1', 'Gene', (188, 192))	('CCL', 'molecular_function', 'GO:0044101', ('176', '179'))	('expression', 'MPA', (101, 111))
96334	30538110	Despite the significant associations in the large dataset, treatment with celecoxib or PF9184 did not affect IFNgamma-induced PD-L1 expression in A375 and SB2 melanoma cells or the constitutive PD-L1 levels expressed in LOXIMVI cells (Figure 3C and supplementary Figure 4), suggesting that the COX2/mPGES1 pathway does not directly regulate PD-L1 expression.	('melanoma', 'Disease', (159, 167))	('SB2', 'CellLine', 'CVCL:0516', (155, 158))	('associations', 'Interaction', (24, 36))	('IFNgamma', 'Gene', (109, 117))	('PF9184', 'Chemical', 'MESH:C548452', (87, 93))	('mPGES1', 'Gene', '64292', (299, 305))	('IFNgamma', 'Gene', '3458', (109, 117))	('A375', 'CellLine', 'CVCL:0132', (146, 150))	('PD-L1', 'Gene', (126, 131))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('celecoxib', 'Chemical', 'MESH:D000068579', (74, 83))	('PF9184', 'Var', (87, 93))	('mPGES1', 'Gene', (299, 305))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
96346	30538110	Since the basic leucine zipper ATF-like transcription factor 3 (Batf3)-dependent subfamily of dendritic cells characterized by CD8a expression are important for anticancer responses, we assessed the effect of mPGES1 deletion on these cells and found that they were expressed at significantly greater levels in the PTGES-KO tumors (Figure 4E, a-c).	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('greater', 'PosReg', (292, 299))	('mPGES1', 'Gene', (209, 215))	('transcription', 'biological_process', 'GO:0006351', ('40', '53'))	('transcription factor', 'molecular_function', 'GO:0000981', ('40', '60'))	('cancer', 'Disease', (165, 171))	('tumors', 'Disease', (323, 329))	('deletion', 'Var', (216, 224))	('Batf3', 'Gene', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (323, 329))	('mPGES1', 'Gene', '64292', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('Batf3', 'Gene', '55509', (64, 69))
96348	30538110	To explain how mPGES1 deletion led to the tumor infiltration with CD8a+ DC and T cells, we performed the mouse cancer inflammation and immunity PCR array which includes 84 key genes involved in mediating communication between tumor cells and the cellular mediators of inflammation and immunity.	('inflammation', 'Disease', 'MESH:D007249', (268, 280))	('inflammation', 'Disease', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', (42, 47))	('inflammation', 'Disease', (268, 280))	('mPGES1', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rat', 'Species', '10116', (54, 57))	('inflammation', 'biological_process', 'GO:0006954', ('118', '130'))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancer inflammation', 'Disease', 'MESH:D009369', (111, 130))	('led to', 'Reg', (31, 37))	('deletion', 'Var', (22, 30))	('mPGES1', 'Gene', '64292', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('inflammation', 'Disease', 'MESH:D007249', (118, 130))	('inflammation', 'biological_process', 'GO:0006954', ('268', '280'))	('cancer inflammation', 'Disease', (111, 130))	('mouse', 'Species', '10090', (105, 110))	('tumor', 'Disease', (226, 231))
96349	30538110	mPGES1 knockout induced the expression of STAT1, CCL2, CCL4, and CCL5 which are products of type I IFN pathway activation and the expression of CXCL9 and CXCL10 which are T cell attracting chemokines secreted by CD8a+ DCs.	('CCL4', 'Gene', (55, 59))	('CCL5', 'Gene', (65, 69))	('expression', 'MPA', (130, 140))	('CXCL10', 'Gene', '15945', (154, 160))	('CCL', 'molecular_function', 'GO:0044101', ('65', '68'))	('STAT1', 'Gene', (42, 47))	('CCL2', 'Gene', (49, 53))	('CCL', 'molecular_function', 'GO:0044101', ('49', '52'))	('expression', 'MPA', (28, 38))	('CXCL10', 'Gene', (154, 160))	('CCL', 'molecular_function', 'GO:0044101', ('55', '58'))	('knockout', 'Var', (7, 15))	('STAT1', 'Gene', '20846', (42, 47))	('mPGES1', 'Gene', (0, 6))	('mPGES1', 'Gene', '64292', (0, 6))
96351	30538110	In contrast, PTGES deletion decreased the expression of several tumor promoting factors including CXCL1, CXCL5 and SPP1 (Figure 4F, Right).	('CXCL1', 'Gene', '2919', (98, 103))	('tumor', 'Disease', (64, 69))	('decreased', 'NegReg', (28, 37))	('CXCL1', 'Gene', (98, 103))	('PTGES', 'Gene', (13, 18))	('CXCL5', 'Gene', (105, 110))	('CXCL5', 'Gene', '6374', (105, 110))	('expression', 'MPA', (42, 52))	('deletion', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('SPP', 'molecular_function', 'GO:0042499', ('115', '118'))	('SPP1', 'Gene', '6696', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('SPP1', 'Gene', (115, 119))
96352	30538110	Collectively, these results suggest that the loss of mPGES1 leads to the CD8a+ DC infiltration in tumor via the activation of type I IFN pathway and CD8a+ DCs attract effector CD8+T cells by secreting T cell-attracting chemokines.	('CD8', 'Gene', '925', (176, 179))	('tumor', 'Disease', (98, 103))	('mPGES1', 'Gene', (53, 59))	('activation', 'PosReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('rat', 'Species', '10116', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD8', 'Gene', (73, 76))	('CD8', 'Gene', (149, 152))	('mPGES1', 'Gene', '64292', (53, 59))	('CD8', 'Gene', '925', (149, 152))	('type I IFN pathway', 'Pathway', (126, 144))	('CD8', 'Gene', (176, 179))	('attract', 'PosReg', (159, 166))	('CD8', 'Gene', '925', (73, 76))	('loss', 'Var', (45, 49))
96356	30538110	Since, in a published study, combination of a COX inhibitor with an anti-PD-1 antibody promoted regression of melanoma cells to a greater extent than anti-PD-1 alone, we tested whether deletion of mPGES1 also enhances the anti-PD-1 effect on tumor regression.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('tested', 'Reg', (170, 176))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('regression', 'CPA', (96, 106))	('mPGES1', 'Gene', (197, 203))	('COX', 'Gene', '1351', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('mPGES1', 'Gene', '64292', (197, 203))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('deletion', 'Var', (185, 193))	('tumor', 'Disease', (242, 247))	('enhances', 'PosReg', (209, 217))	('COX', 'Gene', (46, 49))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))
96393	30538110	DCs play a significant role in the control of cancer by adaptive immunity, which is influenced by PGE2 and our finding that deletion of mPGES1 enhanced the accumulation of tumor-infiltrating conventional, lymphoid and CD8+ DCs supports dendritic cell-mediated immune suppression.	('PGE2', 'Chemical', 'MESH:D015232', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CD8', 'Gene', (218, 221))	('CD8', 'Gene', '925', (218, 221))	('dendritic cell-mediated immune suppression', 'CPA', (236, 278))	('cancer', 'Disease', (46, 52))	('enhanced', 'PosReg', (143, 151))	('tumor', 'Disease', (172, 177))	('rat', 'Species', '10116', (184, 187))	('mPGES1', 'Gene', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mPGES1', 'Gene', '64292', (136, 142))	('accumulation', 'PosReg', (156, 168))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('deletion', 'Var', (124, 132))
96396	30538110	PGE2 inhibits type I IFN production and suppresses PGE2 synthesis while mPGES1 inhibitor treatment increased type I IFN Our genetic deletion of mPGES1 increased these chemokines that appears to enable CD8a+ DC infiltration in tumor via the activation of type I IFN pathway.	('increased', 'PosReg', (151, 160))	('PGE2', 'Chemical', 'MESH:D015232', (51, 55))	('type I IFN production', 'MPA', (14, 35))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('mPGES1', 'Gene', '64292', (144, 150))	('type', 'MPA', (109, 113))	('mPGES1', 'Gene', '64292', (72, 78))	('mPGES1', 'Gene', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('inhibits', 'NegReg', (5, 13))	('deletion', 'Var', (132, 140))	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('synthesis', 'biological_process', 'GO:0009058', ('56', '65'))	('suppresses', 'NegReg', (40, 50))	('type I IFN production', 'biological_process', 'GO:0032606', ('14', '35'))	('PGE2 synthesis', 'MPA', (51, 65))	('mPGES1', 'Gene', (144, 150))	('rat', 'Species', '10116', (216, 219))	('tumor', 'Disease', (226, 231))
96405	30538110	The blockade of the PD-1 pathway reinvigorates exhausted T cells and our results demonstrated that about 30% of CD8+ T cells showed the exhaustion phenotype.	('CD8', 'Gene', (112, 115))	('PD-1 pathway', 'Pathway', (20, 32))	('CD8', 'Gene', '925', (112, 115))	('blockade', 'Var', (4, 12))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (41, 44))
96411	30538110	Knockout of mPGES1, as shown in Figure 5 of the present study, more dramatically enhanced the antitumor effect of anti-PD1 therapy than either of these agents.	('enhanced', 'PosReg', (81, 89))	('mPGES1', 'Gene', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mPGES1', 'Gene', '64292', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Knockout', 'Var', (0, 8))	('tumor', 'Disease', (98, 103))
96419	30538110	The first clinical trial with the mPGES1 inhibitor LY3023703 showed more potent inhibition of inducible PGE2 synthesis than celecoxib, without PGI2 or thromboxane A2 suppression.	('PGI2', 'Chemical', 'MESH:D011464', (143, 147))	('inhibition', 'NegReg', (80, 90))	('inducible PGE2 synthesis', 'MPA', (94, 118))	('synthesis', 'biological_process', 'GO:0009058', ('109', '118'))	('LY3023703', 'Var', (51, 60))	('PGE2', 'Chemical', 'MESH:D015232', (104, 108))	('mPGES1', 'Gene', (34, 40))	('celecoxib', 'Chemical', 'MESH:D000068579', (124, 133))	('LY3023703', 'Chemical', '-', (51, 60))	('mPGES1', 'Gene', '64292', (34, 40))
96421	30538110	More preclinical and clinical studies on mPGES1 inhibitors are needed if they are to serve as novel treatments for inflammation and cancer and as more effective adjuvants for immunotherapy.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('cancer', 'Disease', (132, 138))	('inflammation', 'biological_process', 'GO:0006954', ('115', '127'))	('mPGES1', 'Gene', '64292', (41, 47))	('inflammation', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('inhibitors', 'Var', (48, 58))	('mPGES1', 'Gene', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
96426	30538110	Therefore, these results support development of a rational therapeutic strategy targeting specific PGE2 inflammatory mediators, and identify the mPGES1 inhibition as a useful approach for improving clinical responses to check point inhibition, and possibly later to other types of immune based therapy.	('mPGES1', 'Gene', (145, 151))	('PGE2', 'Chemical', 'MESH:D015232', (99, 103))	('mPGES1', 'Gene', '64292', (145, 151))	('rat', 'Species', '10116', (50, 53))	('rat', 'Species', '10116', (73, 76))	('clinical responses to check point inhibition', 'MPA', (198, 242))	('improving', 'PosReg', (188, 197))	('inhibition', 'Var', (152, 162))
96551	28654463	Loss of p16 is associated with tumor progression of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('melanoma', 'Disease', (52, 60))	('p16', 'Gene', '1029', (8, 11))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('tumor', 'Disease', (31, 36))	('associated', 'Reg', (15, 25))	('p16', 'Gene', (8, 11))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
96554	28654463	studied the staining patterns of S100, NK1/C3, HMB45, and MART-1 in nodal metastatic melanoma and found a heterogenous pattern of staining with S100, NK1/C3, MART-1 and HMB45 staining 98%, 93%, 82% and 76% of cases, respectively.	('NK1', 'Gene', (150, 153))	('NK1', 'Gene', '6869', (150, 153))	('NK1', 'Gene', '6869', (39, 42))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('MART-1', 'Gene', (158, 164))	('MART-1', 'Gene', '2315', (158, 164))	('NK1', 'Gene', (39, 42))	('MART-1', 'Gene', '2315', (58, 64))	('MART-1', 'Gene', (58, 64))	('S100', 'Var', (144, 148))
96562	28654463	Nevus cells stained with S100 and MART-1 but did not label with HMB45; less than 1% of nevus cells labeled with Ki-67.	('nevus', 'Phenotype', 'HP:0003764', (87, 92))	('Nevus', 'Phenotype', 'HP:0003764', (0, 5))	('MART-1', 'Gene', '2315', (34, 40))	('MART-1', 'Gene', (34, 40))	('Ki-67', 'Var', (112, 117))
96572	31186280	Identification of targetable recurrent MAP3K8 rearrangements in melanomas lacking known driver mutations Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling.	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('MAPK) signaling', 'biological_process', 'GO:0000165', ('221', '236'))	('melanomas', 'Disease', (64, 73))	('Melanomas', 'Disease', 'MESH:D008545', (105, 114))	('Melanomas', 'Disease', (105, 114))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('loss-of-function', 'NegReg', (147, 163))	('MAP3K8', 'Gene', '1326', (39, 45))	('promote', 'PosReg', (179, 186))	('MAPK', 'molecular_function', 'GO:0004707', ('221', '225'))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('MAP3K', 'molecular_function', 'GO:0004709', ('39', '44'))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('MAP3K8', 'Gene', (39, 45))	('Melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('mutations', 'Var', (164, 173))	('rearrangements', 'Var', (46, 60))
96575	31186280	We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in over 15% of tumors without known driver mutations (BRAF, NRAS, KIT, GNAQ, GNA11 and NF1).	('GNA11', 'Gene', '2767', (163, 168))	('NF1', 'Gene', '4763', (173, 176))	('KIT', 'Gene', '3815', (152, 155))	('GNAQ', 'Gene', '2776', (157, 161))	('MAP3K', 'molecular_function', 'GO:0004709', ('24', '29'))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('GNAQ', 'Gene', (157, 161))	('MAP3K8', 'Gene', (24, 30))	('NF1', 'Gene', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('rearrangements', 'Var', (31, 45))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NRAS', 'Gene', (146, 150))	('GNA11', 'Gene', (163, 168))	('melanomas', 'Disease', (57, 66))	('NRAS', 'Gene', '4893', (146, 150))	('KIT', 'Gene', (152, 155))	('BRAF', 'Gene', '673', (140, 144))	('BRAF', 'Gene', (140, 144))	('KIT', 'molecular_function', 'GO:0005020', ('152', '155'))	('tumors', 'Disease', (101, 107))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
96578	31186280	We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('MAP3K', 'molecular_function', 'GO:0004709', ('72', '77'))	('rearrangements', 'Var', (79, 93))	('MAP3K8', 'Gene', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
96579	31186280	Rearrangement and amplification of the MAP3K8 locus in melanoma cells results in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and, a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition.	('BRAF', 'Gene', (215, 219))	('MAP3K8', 'Gene', (121, 127))	('protein', 'Protein', (128, 135))	('resistance', 'CPA', (201, 211))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('MEK', 'Gene', '5609', (250, 253))	('melanoma', 'Disease', (55, 63))	('levels of a truncated', 'MPA', (91, 112))	('oncogenic dependency', 'CPA', (137, 157))	('MAP3K8', 'Gene', (39, 45))	('MEK', 'Gene', (250, 253))	('amplification', 'Var', (18, 31))	('Rearrangement', 'Var', (0, 13))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('aberrant', 'Var', (165, 173))	('MAP3K', 'molecular_function', 'GO:0004709', ('39', '44'))	('ERK1', 'molecular_function', 'GO:0004707', ('257', '261'))	('increased', 'PosReg', (81, 90))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('MAP3K', 'molecular_function', 'GO:0004709', ('174', '179'))	('MAP3K', 'molecular_function', 'GO:0004709', ('121', '126'))	('BRAF', 'Gene', '673', (215, 219))
96580	31186280	Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma; and provide insight to therapeutic approaches for patients with these tumors.	('MAP3K', 'molecular_function', 'GO:0004709', ('72', '77'))	('patients', 'Species', '9606', (193, 201))	('truncating rearrangements', 'Var', (79, 104))	('tumors', 'Disease', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('MAP3K8', 'Gene', (72, 78))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
96581	31186280	These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements.	('ERK', 'Gene', '5594', (46, 49))	('melanomas', 'Disease', (112, 121))	('MAP3K8', 'Gene', (143, 149))	('ERK', 'molecular_function', 'GO:0004707', ('98', '101'))	('ERK', 'Gene', (46, 49))	('ERK', 'Gene', '5594', (98, 101))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('MAP3K', 'molecular_function', 'GO:0004709', ('143', '148'))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('ERK', 'Gene', (98, 101))	('ERK', 'molecular_function', 'GO:0004707', ('46', '49'))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))	('rearrangements', 'Var', (150, 164))
96582	31186280	This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.	('truncating', 'Var', (68, 78))	('rearrangements', 'Var', (86, 100))	('MAP3K8', 'Gene', (79, 85))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('MAP3K', 'molecular_function', 'GO:0004709', ('79', '84'))
96584	31186280	In melanoma, recurrent "driver" mutations have been identified in BRAF, NRAS, KIT, NF1, GNAQ, and GNA11; these clinically actionable alterations now define molecular subsets of the disease that oncologists use to properly align patients with effective targeted therapy.	('NF1', 'Gene', '4763', (83, 86))	('NRAS', 'Gene', (72, 76))	('GNAQ', 'Gene', (88, 92))	('GNA11', 'Gene', (98, 103))	('KIT', 'molecular_function', 'GO:0005020', ('76', '79'))	('NRAS', 'Gene', '4893', (72, 76))	('KIT', 'Gene', '3815', (78, 81))	('patients', 'Species', '9606', (228, 236))	('GNA11', 'Gene', '2767', (98, 103))	('mutations', 'Var', (32, 41))	('KIT', 'Gene', (78, 81))	('BRAF', 'Gene', '673', (66, 70))	('GNAQ', 'Gene', '2776', (88, 92))	('melanoma', 'Disease', (3, 11))	('NF1', 'Gene', (83, 86))	('BRAF', 'Gene', (66, 70))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
96588	31186280	These findings suggest that additional alterations may activate the MAPK/ERK pathway in melanomas lacking currently catalogued driver mutations.	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('ERK', 'Gene', (73, 76))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('activate', 'PosReg', (55, 63))	('alterations', 'Var', (39, 50))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))	('melanomas', 'Disease', (88, 97))	('ERK', 'Gene', '5594', (73, 76))
96589	31186280	We recently identified BRAF kinase gene fusions occurring exclusively in driver-negative melanomas, further emphasizing the dependency of melanomas on MAPK signaling.	('melanomas', 'Disease', 'MESH:D008545', (138, 147))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('MAPK signaling', 'biological_process', 'GO:0000165', ('151', '165'))	('melanomas', 'Disease', (89, 98))	('BRAF', 'Gene', '673', (23, 27))	('fusions', 'Var', (40, 47))	('BRAF', 'Gene', (23, 27))	('melanomas', 'Disease', (138, 147))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))
96590	31186280	Using a focused approach for known MAPK regulators, we examined RNA-Seq data from TCGA for evidence of structural gene alterations and identified recurrent MAP3K8 rearrangements in six melanoma tumors (1.7% overall).	('melanoma tumors', 'Disease', (185, 200))	('melanoma tumors', 'Disease', 'MESH:D008545', (185, 200))	('MAP3K', 'molecular_function', 'GO:0004709', ('156', '161'))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('rearrangements', 'Var', (163, 177))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('MAP3K8', 'Gene', (156, 162))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
96591	31186280	The rearrangements were exclusive to driver-negative melanomas (6 of 38, 15.8%) and result in a truncated, active MAP3K8.	('melanomas', 'Disease', (53, 62))	('rearrangements', 'Var', (4, 18))	('result in', 'Reg', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('MAP3K8', 'Gene', (114, 120))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('truncated', 'MPA', (96, 105))	('MAP3K', 'molecular_function', 'GO:0004709', ('114', '119'))
96599	31186280	Expression values from probes hybridizing to intron 1 (235421_at) or the 3'UTR (205027_s_at) of MAP3K8 were extracted and expression discordance evaluated by scatterplot and expression ratios.	('expression', 'Species', '29278', (174, 184))	('MAP3K', 'molecular_function', 'GO:0004709', ('96', '101'))	('MAP3K8', 'Gene', (96, 102))	('Expression', 'Species', '29278', (0, 10))	('235421_at', 'Var', (55, 64))	('205027_s_at', 'Var', (80, 91))	('expression', 'Species', '29278', (122, 132))
96609	31186280	Immunoblotting was performed using HA 6E2 (1:1000, Cell Signaling #2367S), MEK (1:500, Cell Signaling #4694S), phospho-MEK1/2 Ser17/Thr221 (1:500, Cell Signaling #9121S), GAPDH (1:1000, Millipore, MAB374), phospho-Erk1/2 Thr202/204 (1:1000, Cell Signaling, #4370), total Erk1/2 (1:1000, Cell Signaling, #9107) and MAP3K8 (R&D Systems, MAB4586).	('MEK', 'Gene', (119, 122))	('1:500', 'Var', (140, 145))	('Signaling', 'biological_process', 'GO:0023052', ('246', '255'))	('Erk1/2', 'Gene', (271, 277))	('Erk1/2', 'Gene', (214, 220))	('MEK (1', 'molecular_function', 'GO:0004708', ('75', '81'))	('Signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('Erk1', 'molecular_function', 'GO:0004707', ('214', '218'))	('MEK', 'Gene', '5609', (75, 78))	('Ser', 'cellular_component', 'GO:0005790', ('126', '129'))	('MAP3K', 'molecular_function', 'GO:0004709', ('314', '319'))	('Signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('MEK', 'Gene', (75, 78))	('Signaling', 'biological_process', 'GO:0023052', ('152', '161'))	('Erk1/2', 'Gene', '5595;5594', (271, 277))	('Erk1', 'molecular_function', 'GO:0004707', ('271', '275'))	('Erk1/2', 'Gene', '5595;5594', (214, 220))	('MEK1', 'molecular_function', 'GO:0004708', ('119', '123'))	('GAPDH', 'Gene', '2597', (171, 176))	('Signaling', 'biological_process', 'GO:0023052', ('292', '301'))	('MEK', 'Gene', '5609', (119, 122))	('GAPDH', 'Gene', (171, 176))
96614	31186280	After overnight attachment, growth medium was replaced with either medium (control) or medium containing half-log serial dilutions of vemurafenib (Selleckchem), MEK inhibitor trametinib (Selleckchem) or SCH772984 (Selleckchem).	('trametinib', 'Chemical', 'MESH:C560077', (175, 185))	('SCH772984', 'Var', (203, 212))	('MEK', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (161, 164))	('SCH772984', 'Chemical', 'MESH:C587178', (203, 212))	('vemurafenib', 'Chemical', 'MESH:D000077484', (134, 145))
96615	31186280	WM3311 and D35 cells (5000 cells/well) were reverse-transfected with 0.2 muL/well RNAimax lipid (Invitrogen) and 25nM of non-targeting control (Qiagen), cell death control (Qiagen) or four siRNAs targeting MAP3K8 (D-003511-07, D-003511-08, D-003511-09, D-003511-10, Dharmacon/GE Life Sciences) siRNA in 96-well culture dishes.	('D-003511-07', 'Var', (214, 225))	('D-003511-09', 'Var', (240, 251))	('lipid', 'Chemical', 'MESH:D008055', (90, 95))	('D-003511-08', 'Var', (227, 238))	('WM3311', 'CellLine', 'CVCL:0B72', (0, 6))	('MAP3K', 'molecular_function', 'GO:0004709', ('206', '211'))	('D-003511-10', 'Var', (253, 264))	('cell death', 'biological_process', 'GO:0008219', ('153', '163'))
96621	31186280	For fluorescence in situ hybridization (FISH) analysis, tissue sections were hybridized overnight with the probes (Empire Genomics): RPCI-11#257J14 (Orange, 5-TAMRA-dUTP) and RPCI-11#122B23 (Green, 5-Fluorescein-dUTP).	('RPCI-11#257J14', 'Var', (133, 147))	('5-Fluorescein-dUTP', 'Chemical', '-', (198, 216))	('RPCI-11#122B23', 'Var', (175, 189))	('5-TAMRA-dUTP', 'Chemical', '-', (157, 169))
96631	31186280	We additionally found DNA-level evidence of a rearrangement within the intron between exons seven and eight in one tumor for which whole-genome sequencing was available (TCGA-ER-A196) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('rearrangement', 'Var', (46, 59))	('DNA', 'cellular_component', 'GO:0005574', ('22', '25'))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
96633	31186280	Of the 343 tumor samples evaluated, 305 (88.9%) had mutations in known driver genes (BRAF, NRAS, NF1, KIT, GNAQ and GNA11), with 38 samples lacking driver mutations (Supplemental Table 2).	('mutations', 'Var', (52, 61))	('NF1', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('NF1', 'Gene', '4763', (97, 100))	('GNA11', 'Gene', (116, 121))	('tumor', 'Disease', (11, 16))	('BRAF', 'Gene', (85, 89))	('GNAQ', 'Gene', '2776', (107, 111))	('KIT', 'Gene', '3815', (102, 105))	('BRAF', 'Gene', '673', (85, 89))	('GNA11', 'Gene', '2767', (116, 121))	('NRAS', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('KIT', 'Gene', (102, 105))	('NRAS', 'Gene', '4893', (91, 95))	('GNAQ', 'Gene', (107, 111))	('KIT', 'molecular_function', 'GO:0005020', ('102', '105'))
96635	31186280	Cutaneous melanomas typically exhibit elevated mutation rates compared to other tumors, with a high frequency of cytosine to thymine (C > T) transitions generated from misrepair of UV-induced pyrimidine dimers.	('Cutaneous melanomas', 'Disease', 'MESH:C562393', (0, 19))	('Cutaneous melanomas', 'Phenotype', 'HP:0012056', (0, 19))	('cytosine', 'Chemical', 'MESH:D003596', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('pyrimidine', 'Chemical', 'MESH:C030986', (192, 202))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Cutaneous melanomas', 'Disease', (0, 19))	('tumors', 'Disease', (80, 86))	('mutation rates', 'MPA', (47, 61))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('misrepair', 'Var', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('thymine', 'Chemical', 'MESH:D013941', (125, 132))	('cytosine to thymine', 'MPA', (113, 132))
96636	31186280	Tumors with MAP3K8 alterations had significantly fewer mutations in coding regions compared with other melanomas (average 53 vs. 857 mutations/tumor, p=1.66e-16; Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fewer', 'NegReg', (49, 54))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('Tumors', 'Disease', (0, 6))	('alterations', 'Var', (19, 30))	('MAP3K8', 'Gene', (12, 18))	('melanomas', 'Disease', (103, 112))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('MAP3K', 'molecular_function', 'GO:0004709', ('12', '17'))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))	('mutations', 'MPA', (55, 64))
96637	31186280	The frequency of UV-associated mutations (C>T and G>A) was also significantly lower in MAP3K8-rearranged samples (40% vs. 74%, p=0.0023) and together with the decreased mutational burden, suggest that these tumors are likely not associated with sun exposure (Fig.	('tumors', 'Disease', (207, 213))	('G>A', 'Var', (50, 53))	('C>T', 'Var', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('MAP3K8-rearranged', 'Gene', (87, 104))	('lower', 'NegReg', (78, 83))	('UV-associated', 'Disease', (17, 30))	('MAP3K', 'molecular_function', 'GO:0004709', ('87', '92'))
96638	31186280	Patients with MAP3K8 rearrangements were clinically similar to melanoma as a whole, displaying similar distribution between males and females, primary and metastatic disease, and across ages (Fig.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('rearrangements', 'Var', (21, 35))	('MAP3K8', 'Gene', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('MAP3K', 'molecular_function', 'GO:0004709', ('14', '19'))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
96639	31186280	Overall survival was significantly reduced for patients harboring MAP3K8 rearrangements compared to all other melanomas (median survival 20.5 vs. 80.6 months, p=0.0046), however given the small sample size (n=6) these data should be interpreted with caution and require further validation, as differing treatments could have also impacted the interpretation of these results (Supplemental Fig 1).	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanomas', 'Phenotype', 'HP:0002861', (110, 119))	('impacted', 'Reg', (330, 338))	('reduced', 'NegReg', (35, 42))	('melanomas', 'Disease', 'MESH:D008545', (110, 119))	('MAP3K8', 'Gene', (66, 72))	('patients', 'Species', '9606', (47, 55))	('rearrangements', 'Var', (73, 87))	('MAP3K', 'molecular_function', 'GO:0004709', ('66', '71'))	('melanomas', 'Disease', (110, 119))	('Overall survival', 'MPA', (0, 16))
96642	31186280	MAP3K8 expression resulted in detection of a single 53 kD or 49 kD protein band for full-length and truncated MAP3K8, respectively; these Western signals represent the long (aa 1-467) isoform, as the shorter isoform generated from an alternative start codon (aa 30-467) is not detectable by the addition of an N-terminal HA tag (Fig.	('MAP3K8', 'Gene', (0, 6))	('MAP3K', 'molecular_function', 'GO:0004709', ('110', '115'))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('expression', 'Species', '29278', (7, 17))	('truncated', 'Var', (100, 109))	('MAP3K8', 'Gene', (110, 116))	('MAP3K', 'molecular_function', 'GO:0004709', ('0', '5'))
96643	31186280	Over expression of full-length and to a greater degree truncated MAP3K8 increased both phosphorylated forms of MEK1/2 and ERK1/2 (Fig.	('phosphorylated', 'MPA', (87, 101))	('increased', 'PosReg', (72, 81))	('MAP3K', 'molecular_function', 'GO:0004709', ('65', '70'))	('MAP3K8', 'Gene', (65, 71))	('ERK1', 'molecular_function', 'GO:0004707', ('122', '126'))	('truncated', 'Var', (55, 64))	('MEK1', 'molecular_function', 'GO:0004708', ('111', '115'))	('expression', 'Species', '29278', (5, 15))
96644	31186280	To define the functional role of MAP3K8 truncations in melanoma cells, we generated stable cell lines expressing exogenous HA-tagged MAP3K8 using SK-MEL-28 cells, a well-characterized melanoma cell line harboring a BRAF V600E mutation that is sensitive to BRAF and MEK inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (146, 155))	('V600E', 'Var', (220, 225))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (184, 192))	('BRAF', 'Gene', (215, 219))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('MEK', 'Gene', (265, 268))	('BRAF', 'Gene', '673', (256, 260))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('MAP3K', 'molecular_function', 'GO:0004709', ('33', '38'))	('BRAF', 'Gene', (256, 260))	('MEK', 'Gene', '5609', (265, 268))	('MAP3K', 'molecular_function', 'GO:0004709', ('133', '138'))	('V600E', 'Mutation', 'rs113488022', (220, 225))	('MAP3K8', 'Gene', (133, 139))	('melanoma', 'Disease', (55, 63))	('BRAF', 'Gene', '673', (215, 219))
96645	31186280	At baseline, expression of full-length and truncated MAP3K8 did not alter phosho-ERK1/2 levels; however, both displayed elevated phospho-MEK levels dependent on MAP3K8 kinase activity (Fig.	('expression', 'Species', '29278', (13, 23))	('MEK', 'Gene', (137, 140))	('kinase activity', 'molecular_function', 'GO:0016301', ('168', '183'))	('MEK', 'Gene', '5609', (137, 140))	('MAP3K', 'molecular_function', 'GO:0004709', ('53', '58'))	('elevated', 'PosReg', (120, 128))	('truncated', 'Var', (43, 52))	('MAP3K8', 'Gene', (53, 59))	('MAP3K', 'molecular_function', 'GO:0004709', ('161', '166'))	('ERK1', 'molecular_function', 'GO:0004707', ('81', '85'))
96647	31186280	However, expression of MAP3K8DeltaC and to a lesser extent full-length MAP3K8 activated MAPK signaling (p-MEK and p-ERK1/2) in the presence of vemurafenib, demonstrating that MAP3K8 activates ERK signaling downstream of BRAF (Fig.	('MAPK signaling', 'MPA', (88, 102))	('MAPK signaling', 'biological_process', 'GO:0000165', ('88', '102'))	('MAP3K8DeltaC', 'Gene', (23, 35))	('ERK', 'Gene', '5594', (192, 195))	('MAP3K', 'molecular_function', 'GO:0004709', ('71', '76'))	('MAP3K', 'molecular_function', 'GO:0004709', ('175', '180'))	('ERK', 'Gene', (116, 119))	('activates', 'PosReg', (182, 191))	('MAP3K8', 'Var', (175, 181))	('BRAF', 'Gene', '673', (220, 224))	('MAP3K8', 'Gene', (71, 77))	('ERK', 'molecular_function', 'GO:0004707', ('192', '195'))	('BRAF', 'Gene', (220, 224))	('ERK', 'Gene', (192, 195))	('vemurafenib', 'Chemical', 'MESH:D000077484', (143, 154))	('MAPK', 'molecular_function', 'GO:0004707', ('88', '92'))	('MEK', 'Gene', '5609', (106, 109))	('expression', 'Species', '29278', (9, 19))	('activated', 'PosReg', (78, 87))	('MAP3K8DeltaC', 'Gene', '1326', (23, 35))	('MEK', 'Gene', (106, 109))	('signaling', 'biological_process', 'GO:0023052', ('196', '205'))	('ERK', 'Gene', '5594', (116, 119))	('MAP3K', 'molecular_function', 'GO:0004709', ('23', '28'))	('ERK1', 'molecular_function', 'GO:0004707', ('116', '120'))
96648	31186280	To determine if sustained ERK signaling from MAP3K8 and MAP3K8DeltaC can confer resistance to BRAF inhibition, we analyzed cell viability after treatment of the panel of SK-MEL-28 cells with vemurafenib.	('MAP3K8DeltaC', 'Gene', (56, 68))	('MAP3K', 'molecular_function', 'GO:0004709', ('56', '61'))	('MAP3K8DeltaC', 'Gene', '1326', (56, 68))	('BRAF', 'Gene', (94, 98))	('ERK', 'Gene', '5594', (26, 29))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (170, 179))	('MAP3K', 'molecular_function', 'GO:0004709', ('45', '50'))	('signaling', 'biological_process', 'GO:0023052', ('30', '39'))	('ERK', 'Gene', (26, 29))	('vemurafenib', 'Chemical', 'MESH:D000077484', (191, 202))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('BRAF', 'Gene', '673', (94, 98))	('MAP3K8', 'Var', (45, 51))
96649	31186280	Cells expressing the empty vector control and kinase-inactive MAP3K8 proteins displayed similar sensitivity to vemurafenib, while cells expressing either full-length MAP3K8 or MAP3K8DeltaC were significantly less sensitive to BRAF inhibition (Fig.	('MAP3K8DeltaC', 'Gene', (176, 188))	('sensitivity', 'MPA', (96, 107))	('less', 'NegReg', (208, 212))	('BRAF', 'Gene', '673', (226, 230))	('vemurafenib', 'MPA', (111, 122))	('vemurafenib', 'Chemical', 'MESH:D000077484', (111, 122))	('BRAF', 'Gene', (226, 230))	('MAP3K', 'molecular_function', 'GO:0004709', ('176', '181'))	('MAP3K', 'molecular_function', 'GO:0004709', ('62', '67'))	('MAP3K8', 'Var', (62, 68))	('MAP3K', 'molecular_function', 'GO:0004709', ('166', '171'))	('MAP3K8DeltaC', 'Gene', '1326', (176, 188))
96650	31186280	To determine if MAP3K8 activates the MAPK pathway downstream of BRAF, we treated cells with increasing doses of MEK (trametinib) and ERK (SCH772984) inhibitors.	('MAPK', 'molecular_function', 'GO:0004707', ('37', '41'))	('MEK', 'Gene', (112, 115))	('BRAF', 'Gene', '673', (64, 68))	('MEK', 'Gene', '5609', (112, 115))	('MAP3K8', 'Var', (16, 22))	('BRAF', 'Gene', (64, 68))	('MAP3K', 'molecular_function', 'GO:0004709', ('16', '21'))	('MAPK pathway', 'Pathway', (37, 49))	('ERK', 'Gene', '5594', (133, 136))	('activates', 'PosReg', (23, 32))	('ERK', 'Gene', (133, 136))	('trametinib', 'Chemical', 'MESH:C560077', (117, 127))	('ERK', 'molecular_function', 'GO:0004707', ('133', '136'))	('SCH772984', 'Chemical', 'MESH:C587178', (138, 147))
96652	31186280	Inhibition of ERK with SCH72984 was confirmed by decreased phosphorylation of the substrate RSK1 (Fig.	('ERK', 'Gene', (14, 17))	('SCH72984', 'Chemical', '-', (23, 31))	('SCH72984', 'Var', (23, 31))	('ERK', 'molecular_function', 'GO:0004707', ('14', '17'))	('RSK1', 'Gene', (92, 96))	('RSK1', 'Gene', '6195', (92, 96))	('decreased', 'NegReg', (49, 58))	('phosphorylation', 'biological_process', 'GO:0016310', ('59', '74'))	('ERK', 'Gene', '5594', (14, 17))	('phosphorylation of the substrate', 'MPA', (59, 91))
96653	31186280	The uniformly decreased p-ERK levels were paralleled by similar sensitivities to trametinib and SCH772984 among all engineered SK-MEL-28 cells, demonstrating that MAP3K8 activates MAPK upstream of ERK and MEK, and that tumors with MAP3K8DeltaC rearrangements may retain sensitivity to MEK and ERK but not BRAF inhibition (Fig.	('MAP3K8', 'Var', (163, 169))	('ERK', 'Gene', '5594', (26, 29))	('MEK', 'Gene', (285, 288))	('ERK', 'molecular_function', 'GO:0004707', ('293', '296'))	('MEK', 'Gene', (205, 208))	('ERK', 'molecular_function', 'GO:0004707', ('26', '29'))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('ERK', 'Gene', (26, 29))	('MAP3K', 'molecular_function', 'GO:0004709', ('163', '168'))	('ERK', 'molecular_function', 'GO:0004707', ('197', '200'))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (127, 136))	('ERK', 'Gene', '5594', (293, 296))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('MAP3K', 'molecular_function', 'GO:0004709', ('231', '236'))	('ERK', 'Gene', '5594', (197, 200))	('MAP3K8DeltaC', 'Gene', '1326', (231, 243))	('tumors', 'Disease', (219, 225))	('activates', 'PosReg', (170, 179))	('MAPK', 'Enzyme', (180, 184))	('trametinib', 'Chemical', 'MESH:C560077', (81, 91))	('MAP3K8DeltaC', 'Gene', (231, 243))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('BRAF', 'Gene', '673', (305, 309))	('ERK', 'Gene', (293, 296))	('ERK', 'Gene', (197, 200))	('MEK', 'Gene', '5609', (285, 288))	('BRAF', 'Gene', (305, 309))	('MAPK', 'molecular_function', 'GO:0004707', ('180', '184'))	('MEK', 'Gene', '5609', (205, 208))	('SCH772984', 'Chemical', 'MESH:C587178', (96, 105))
96654	31186280	Since MAP3K8DeltaC rearrangements result in a 44 amino acid truncation, including part of the PEST protein degradation domain, we evaluated the protein half-life of full-length and truncated MAP3K8 protein expressed in 293T cells by immunoblot at serial time points after cyclohexamide treatment (Fig.	('MAP3K', 'molecular_function', 'GO:0004709', ('191', '196'))	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('293T', 'CellLine', 'CVCL:0063', (219, 223))	('truncation', 'MPA', (60, 70))	('cyclohexamide', 'Chemical', '-', (272, 285))	('MAP3K', 'molecular_function', 'GO:0004709', ('6', '11'))	('MAP3K8DeltaC', 'Gene', '1326', (6, 18))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('protein degradation', 'biological_process', 'GO:0030163', ('99', '118'))	('MAP3K8', 'Gene', (191, 197))	('result in', 'Reg', (34, 43))	('rearrangements', 'Var', (19, 33))	('MAP3K8DeltaC', 'Gene', (6, 18))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
96660	31186280	Given the DNA copy number and RNA positional qPCR imbalance evidence for a MAP3K8 rearrangement in WM3311 cells, we performed RNA-seq.	('rearrangement', 'Var', (82, 95))	('RNA', 'cellular_component', 'GO:0005562', ('126', '129'))	('MAP3K', 'molecular_function', 'GO:0004709', ('75', '80'))	('WM3311', 'CellLine', 'CVCL:0B72', (99, 105))	('imbalance', 'Phenotype', 'HP:0002172', (50, 59))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('RNA', 'cellular_component', 'GO:0005562', ('30', '33'))	('MAP3K8', 'Gene', (75, 81))
96665	31186280	3F); variable knockdown efficiency between the individual siRNAs correlated with reductions in phosphorylated and total MEK and ERK1/2 (Fig.	('MEK', 'Gene', (120, 123))	('ERK1/2', 'Protein', (128, 134))	('reductions', 'NegReg', (81, 91))	('MEK', 'Gene', '5609', (120, 123))	('ERK1', 'molecular_function', 'GO:0004707', ('128', '132'))	('knockdown', 'Var', (14, 23))	('phosphorylated', 'MPA', (95, 109))
96668	31186280	To determine if pharmaceutical agents are effective in targeting cells dependent on truncated MAP3K8, we treated WM3311 cells with several inhibitors of the MAPK/ERK pathway (Fig.	('MAPK', 'molecular_function', 'GO:0004707', ('157', '161'))	('ERK', 'Gene', (162, 165))	('MAP3K', 'molecular_function', 'GO:0004709', ('94', '99'))	('WM3311', 'CellLine', 'CVCL:0B72', (113, 119))	('MAP3K8', 'Gene', (94, 100))	('truncated', 'Var', (84, 93))	('ERK', 'Gene', '5594', (162, 165))	('ERK', 'molecular_function', 'GO:0004707', ('162', '165'))
96682	31186280	Further analysis identified definitive evidence (30 discordant read pairs and 30 breakpoint-spanning reads) for an interchromosomal MAP3K8 rearrangement (chr10:30748415-chr6:10543467) generating a hybrid transcript between exon 7 of MAP3K8 and the intronic region (I3-I4) of GCNT2 (Fig.	('MAP3K8', 'Gene', (233, 239))	('MAP3K', 'molecular_function', 'GO:0004709', ('233', '238'))	('generating', 'Reg', (184, 194))	('MAP3K8', 'Gene', (132, 138))	('MAP3K', 'molecular_function', 'GO:0004709', ('132', '137'))	('rearrangement', 'Var', (139, 152))	('GCNT2', 'Gene', '2651', (275, 280))	('GCNT2', 'Gene', (275, 280))
96686	31186280	4H), similar to WM3311 cells harboring an endogenous MAP3K8 rearrangement (Fig.	('MAP3K8', 'Gene', (53, 59))	('rearrangement', 'Var', (60, 73))	('MAP3K', 'molecular_function', 'GO:0004709', ('53', '58'))	('WM3311', 'CellLine', 'CVCL:0B72', (16, 22))
96687	31186280	3I) and SK-MEL28 cells overexpressing truncated MAP3K8 (Figs.	('SK-MEL28', 'CellLine', 'CVCL:0526', (8, 16))	('MAP3K', 'molecular_function', 'GO:0004709', ('48', '53'))	('truncated', 'Var', (38, 47))	('MAP3K8', 'Gene', (48, 54))
96688	31186280	Immunoblot analysis of MAPK/ERK pathway supported the viability data, with trametinib and SCH772984 decreasing and vemurafenib not effecting p-ERK levels (Fig.	('ERK', 'Gene', (28, 31))	('trametinib', 'Chemical', 'MESH:C560077', (75, 85))	('MAPK', 'molecular_function', 'GO:0004707', ('23', '27'))	('ERK', 'Gene', (143, 146))	('SCH772984', 'Var', (90, 99))	('ERK', 'Gene', '5594', (143, 146))	('vemurafenib', 'Chemical', 'MESH:D000077484', (115, 126))	('ERK', 'molecular_function', 'GO:0004707', ('143', '146'))	('ERK', 'Gene', '5594', (28, 31))	('decreasing', 'NegReg', (100, 110))	('ERK', 'molecular_function', 'GO:0004707', ('28', '31'))	('SCH772984', 'Chemical', 'MESH:C587178', (90, 99))
96690	31186280	Viability was was not significantly affected in melanoma cell lines lacking the rearrangement and only cell lines harboring truncated MAP3K8 (WM3311 and D35) were sensitive to siRNAs targeting MAP3K8 (Supplemental Fig.	('melanoma', 'Disease', (48, 56))	('MAP3K', 'molecular_function', 'GO:0004709', ('193', '198'))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('MAP3K', 'molecular_function', 'GO:0004709', ('134', '139'))	('truncated', 'Var', (124, 133))	('WM3311', 'CellLine', 'CVCL:0B72', (142, 148))	('MAP3K8', 'Gene', (134, 140))
96692	31186280	Tumors with truncated MAP3K8 were significantly enriched genes in pathways relating to the unfolded protein response, MYC targets, E2F targets and G2M checkpoint.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('G2M checkpoint', 'biological_process', 'GO:0000075', ('147', '161'))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MAP3K', 'molecular_function', 'GO:0004709', ('22', '27'))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('truncated', 'Var', (12, 21))	('MAP3K8', 'Gene', (22, 28))
96695	31186280	WM3311 cells harboring a known rearrangement displayed a single yellow signal with several individual red signals, indicating a breakpoint and amplification of MAP3K8 proximal to the breakpoint, consistent with CGH data (Fig.	('amplification', 'PosReg', (143, 156))	('MAP3K', 'molecular_function', 'GO:0004709', ('160', '165'))	('MAP3K8', 'Gene', (160, 166))	('WM3311', 'CellLine', 'CVCL:0B72', (0, 6))	('breakpoint', 'Var', (128, 138))
96696	31186280	D35 cells displayed split green and red signals indicting a single breakpoint without amplification and validating the discordant mRNA expression and truncated MAP3K8 protein (Fig.	('truncated', 'Var', (150, 159))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('expression', 'Species', '29278', (135, 145))	('MAP3K', 'molecular_function', 'GO:0004709', ('160', '165'))	('MAP3K8', 'Gene', (160, 166))
96698	31186280	We identified seven tumors positive for MAP3K8 rearrangements by FISH, with either individual split green and red signals (Fig.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('MAP3K', 'molecular_function', 'GO:0004709', ('40', '45'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('rearrangements', 'Var', (47, 61))	('MAP3K8', 'Gene', (40, 46))
96700	31186280	All seven breakpoint-positive specimens were identified in tumors lacking BRAF or NRAS mutations (Supplemental Fig.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('NRAS', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('NRAS', 'Gene', '4893', (82, 86))	('mutations', 'Var', (87, 96))
96704	31186280	Importantly, the N-terminal truncated portion of the gene was shown to rapidly induce T-cell lymphoblastic lymphomas when expressed under a T cell-specific promoter in transgenic mice.	('T-cell lymphoblastic lymphomas', 'Disease', (86, 116))	('T-cell lymphoblastic lymphomas', 'Disease', 'MESH:D054218', (86, 116))	('N-terminal truncated', 'Var', (17, 37))	('induce', 'PosReg', (79, 85))	('lymphomas', 'Phenotype', 'HP:0002665', (107, 116))	('transgenic mice', 'Species', '10090', (168, 183))
96705	31186280	However, to date, with the exception of rare activating MAP3K8 mutations in lung cancer, MAP3K8 alterations have largely been undescribed in human cancers.	('mutations', 'Var', (63, 72))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MAP3K', 'molecular_function', 'GO:0004709', ('89', '94'))	('MAP3K8', 'Gene', (56, 62))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('activating', 'PosReg', (45, 55))	('human', 'Species', '9606', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MAP3K', 'molecular_function', 'GO:0004709', ('56', '61'))
96706	31186280	With this study, we offer the first description and biochemical characterization of oncogenic MAP3K8 alterations in human cancer, occurring exclusively in driver mutation-negative melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('alterations', 'Var', (101, 112))	('MAP3K', 'molecular_function', 'GO:0004709', ('94', '99'))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('MAP3K8', 'Gene', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('human', 'Species', '9606', (116, 121))
96707	31186280	We identified six carboxy-terminal truncating MAP3K8 rearrangements in both primary and metastatic melanomas that were associated with decreased overall survival.	('MAP3K', 'molecular_function', 'GO:0004709', ('46', '51'))	('melanomas', 'Disease', (99, 108))	('overall survival', 'MPA', (145, 161))	('MAP3K8', 'Gene', (46, 52))	('melanomas', 'Disease', 'MESH:D008545', (99, 108))	('decreased', 'NegReg', (135, 144))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanomas', 'Phenotype', 'HP:0002861', (99, 108))	('rearrangements', 'Var', (53, 67))
96708	31186280	Using a break-apart FISH strategy, we identified seven additional MAP3K8 rearrangements in an independent collection of human melanomas; as observed in the TCGA tumors, these rearrangements were found exclusively in driver mutation-negative melanomas with a similar frequency (17.9% vs. 15.8%).	('melanomas', 'Disease', 'MESH:D008545', (241, 250))	('human', 'Species', '9606', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('tumors', 'Disease', (161, 167))	('melanomas', 'Disease', (126, 135))	('MAP3K8', 'Gene', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('rearrangements', 'Var', (73, 87))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('melanomas', 'Disease', (241, 250))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MAP3K', 'molecular_function', 'GO:0004709', ('66', '71'))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('melanomas', 'Phenotype', 'HP:0002861', (241, 250))
96709	31186280	The break-apart FISH strategy and sequencing-based approaches have the potential to identify patients with MAP3K8 truncating rearrangements.	('patients', 'Species', '9606', (93, 101))	('MAP3K8', 'Gene', (107, 113))	('MAP3K', 'molecular_function', 'GO:0004709', ('107', '112'))	('truncating rearrangements', 'Var', (114, 139))
96712	31186280	Importantly, melanomas with MAP3K8 rearrangements have on average 16-fold fewer nonsynonymous mutations than melanoma as a whole.	('MAP3K8', 'Gene', (28, 34))	('MAP3K', 'molecular_function', 'GO:0004709', ('28', '33'))	('rearrangements', 'Var', (35, 49))	('melanomas', 'Disease', (13, 22))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('melanoma', 'Disease', (13, 21))	('fewer', 'NegReg', (74, 79))	('nonsynonymous mutations', 'MPA', (80, 103))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
96713	31186280	MAP3K8 rearranged melanomas also lack the hallmark UV mutation pattern (C>T and G>A) caused by misrepair of thymidine dimers from UV exposure.	('melanomas', 'Disease', 'MESH:D008545', (18, 27))	('MAP3K8', 'Gene', (0, 6))	('misrepair of thymidine dimers', 'MPA', (95, 124))	('thymidine', 'Chemical', 'MESH:D013936', (108, 117))	('melanomas', 'Disease', (18, 27))	('MAP3K', 'molecular_function', 'GO:0004709', ('0', '5'))	('rearranged', 'Var', (7, 17))	('lack', 'NegReg', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanomas', 'Phenotype', 'HP:0002861', (18, 27))	('UV mutation', 'Disease', (51, 62))
96714	31186280	These findings are consistent with a previous publication in which triple wild-type (BRAF, NRAS and NF1) status was associated with a lower rate of UV-associated mutations.	('lower', 'NegReg', (134, 139))	('UV-associated', 'Disease', (148, 161))	('triple wild-type', 'Var', (67, 83))	('NF1', 'Gene', '4763', (100, 103))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('NRAS', 'Gene', (91, 95))	('NF1', 'Gene', (100, 103))	('NRAS', 'Gene', '4893', (91, 95))
96715	31186280	Therefore, immune checkpoint therapy combinations are unlikely to benefit patients with melanomas carrying MAP3K8 truncations.	('truncations', 'Var', (114, 125))	('MAP3K8', 'Gene', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('patients', 'Species', '9606', (74, 82))	('melanomas', 'Disease', 'MESH:D008545', (88, 97))	('MAP3K', 'molecular_function', 'GO:0004709', ('107', '112'))	('melanomas', 'Disease', (88, 97))
96717	31186280	Cell lines with MAP3K8 truncations displayed sensitivity to both MEK and ERK inhibitors, providing rationale for a dual combination approach.	('ERK', 'molecular_function', 'GO:0004707', ('73', '76'))	('sensitivity', 'MPA', (45, 56))	('ERK', 'Gene', (73, 76))	('MEK', 'Gene', (65, 68))	('MEK', 'Gene', '5609', (65, 68))	('MAP3K', 'molecular_function', 'GO:0004709', ('16', '21'))	('truncations', 'Var', (23, 34))	('MAP3K8', 'Gene', (16, 22))	('ERK', 'Gene', '5594', (73, 76))
96718	31186280	Both MAP3K8 and MAP3K8DeltaC expression caused and increased phosphorylated MEK and resistance to vemurafenib in a BRAF-mutated cell line, validating a recent kinome screen in which full-length MAP3K8 expression conferred vemurafenib resistance in BRAF mutated cells.	('MAP3K8', 'Var', (5, 11))	('expression', 'Species', '29278', (29, 39))	('MAP3K', 'molecular_function', 'GO:0004709', ('194', '199'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (98, 109))	('vemurafenib resistance', 'MPA', (222, 244))	('caused', 'Reg', (40, 46))	('MEK', 'Gene', '5609', (76, 79))	('MAP3K8DeltaC', 'Gene', '1326', (16, 28))	('increased', 'PosReg', (51, 60))	('MAP3K', 'molecular_function', 'GO:0004709', ('16', '21'))	('MEK', 'Gene', (76, 79))	('conferred', 'Reg', (212, 221))	('expression', 'Species', '29278', (201, 211))	('phosphorylated', 'MPA', (61, 75))	('vemurafenib', 'Chemical', 'MESH:D000077484', (222, 233))	('BRAF', 'Gene', '673', (115, 119))	('MAP3K8DeltaC', 'Gene', (16, 28))	('BRAF', 'Gene', (115, 119))	('resistance to vemurafenib', 'MPA', (84, 109))	('MAP3K8', 'Gene', (194, 200))	('BRAF', 'Gene', '673', (248, 252))	('MAP3K', 'molecular_function', 'GO:0004709', ('5', '10'))	('BRAF', 'Gene', (248, 252))
96721	31186280	Truncating MAP3K8 rearrangements appear to be unique to primary melanoma tumors lacking known drivers, while MAP3K8 amplification occurs as a mechanism of resistance to RAF inhibitors in treatment-resistant disease.	('MAP3K8', 'Gene', (11, 17))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('RAF', 'Gene', '22882', (169, 172))	('rearrangements', 'Var', (18, 32))	('RAF', 'Gene', (169, 172))	('melanoma tumors', 'Disease', (64, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('Truncating', 'Var', (0, 10))	('MAP3K', 'molecular_function', 'GO:0004709', ('109', '114'))	('MAP3K8', 'Gene', (109, 115))	('MAP3K', 'molecular_function', 'GO:0004709', ('11', '16'))	('melanoma tumors', 'Disease', 'MESH:D008545', (64, 79))
96723	31186280	There is already precedence for MEK inhibitor activity in BRAF wild-type patients (10% response rate) with trametinib and unidentified MAP3K8 rearrangements may have contributed to these responses.	('MAP3K', 'molecular_function', 'GO:0004709', ('135', '140'))	('MAP3K8', 'Gene', (135, 141))	('activity', 'MPA', (46, 54))	('rearrangements', 'Var', (142, 156))	('trametinib', 'Chemical', 'MESH:C560077', (107, 117))	('BRAF', 'Gene', '673', (58, 62))	('MEK', 'Gene', (32, 35))	('MEK', 'Gene', '5609', (32, 35))	('patients', 'Species', '9606', (73, 81))	('BRAF', 'Gene', (58, 62))
96724	31186280	Using a variety of genomic approaches, we identified endogenous MAP3K8 rearrangements in two cell lines lacking known driver mutations that displayed exquisite dependency on MAP3K8 and sensitivity to MEK inhibition.	('MAP3K', 'molecular_function', 'GO:0004709', ('174', '179'))	('MEK', 'Gene', '5609', (200, 203))	('MEK', 'Gene', (200, 203))	('rearrangements', 'Var', (71, 85))	('MAP3K8', 'Gene', (64, 70))	('MAP3K', 'molecular_function', 'GO:0004709', ('64', '69'))
96725	31186280	A recent study has identified truncating MAP3K8 alterations in a spitzoid melanoma lacking known driver mutations responding to the ERK in inhibitor LTT462 in a clinical trial, validating the preclinical sensitivity of cell lines with truncating MAP3K8 alterations to MEK and ERK inhibitors in the current study.	('ERK', 'Gene', '5594', (132, 135))	('MAP3K', 'molecular_function', 'GO:0004709', ('246', '251'))	('ERK', 'molecular_function', 'GO:0004707', ('132', '135'))	('ERK', 'Gene', '5594', (276, 279))	('MAP3K', 'molecular_function', 'GO:0004709', ('41', '46'))	('ERK', 'molecular_function', 'GO:0004707', ('276', '279'))	('alterations', 'Var', (48, 59))	('MAP3K8', 'Gene', (41, 47))	('ERK', 'Gene', (132, 135))	('ERK', 'Gene', (276, 279))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('MEK', 'Gene', (268, 271))	('MEK', 'Gene', '5609', (268, 271))	('MAP3K8', 'Gene', (246, 252))	('spitzoid melanoma', 'Disease', 'MESH:D008545', (65, 82))	('spitzoid melanoma', 'Disease', (65, 82))
96726	31186280	These truncating MAP3K8 rearrangements highlight the diverse mechanisms of MAPK/ERK pathway activation in melanomas and provide a tractable biomarker to identify additional patients that may benefit from targeted inhibition of MEK and ERK.	('ERK', 'Gene', '5594', (80, 83))	('rearrangements', 'Var', (24, 38))	('MAP3K', 'molecular_function', 'GO:0004709', ('17', '22'))	('activation', 'PosReg', (92, 102))	('melanomas', 'Disease', (106, 115))	('patients', 'Species', '9606', (173, 181))	('ERK', 'Gene', (80, 83))	('ERK', 'Gene', '5594', (235, 238))	('ERK', 'molecular_function', 'GO:0004707', ('235', '238'))	('ERK', 'Gene', (235, 238))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('MEK', 'Gene', (227, 230))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('MEK', 'Gene', '5609', (227, 230))	('melanomas', 'Disease', 'MESH:D008545', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('MAP3K8', 'Gene', (17, 23))	('ERK', 'molecular_function', 'GO:0004707', ('80', '83'))
96730	29051489	The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mutator', 'Var', (63, 70))	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
96738	29051489	As seen in earlier studies demonstrating that therapeutic targets were reliable predictive biomarkers, recent studies reported that tumor PD-L1 expression or its amplification was significantly associated with better response in patients undergoing anti-PD-1/PD-L1 therapies, although not all responders had high PD-L1 expression.	('patients', 'Species', '9606', (229, 237))	('PD-L1', 'Gene', (259, 264))	('PD-L1', 'Gene', '29126', (313, 318))	('amplification', 'Var', (162, 175))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-1', 'Gene', (254, 258))	('PD-1', 'Gene', '5133', (254, 258))	('better', 'PosReg', (210, 216))	('PD-L1', 'Gene', '29126', (138, 143))	('PD-L1', 'Gene', '29126', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('PD-L1', 'Gene', (313, 318))	('PD-L1', 'Gene', (138, 143))	('response', 'MPA', (217, 225))
96785	29051489	Interestingly, a global analysis of all tumors showed a significant positive correlation between the non-synonymous mutation rate and the IS score (R 2 = 0.017, P < 0.001, Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('positive', 'PosReg', (68, 76))	('IS score', 'MPA', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('non-synonymous mutation', 'Var', (101, 124))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
96793	29051489	When two data sets were integrated, tumors were clearly separated into three major groups: tumors with high mutational burden and low CIN (mutator or M type), those with low mutational burden but high CIN (chromosome-instable or C type), and those not otherwise specified (NOS) (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('206', '216'))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('CIN', 'Disease', (134, 137))	('CIN', 'Phenotype', 'HP:0040012', (201, 204))	('CIN', 'Phenotype', 'HP:0040012', (134, 137))	('CIN', 'Disease', 'MESH:D007674', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CIN', 'Disease', (201, 204))	('low CIN', 'Disease', (130, 137))	('low CIN', 'Disease', 'MESH:D009800', (130, 137))	('tumors', 'Disease', (36, 42))	('CIN', 'Disease', 'MESH:D007674', (201, 204))	('high mutational burden', 'Var', (103, 125))
96803	29051489	Interestingly, non-synonymous mutation rates were also modestly correlated with tumor purity, suggesting that the correlation was not specific to CIN scores.	('non-synonymous mutation', 'Var', (15, 38))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CIN', 'Phenotype', 'HP:0040012', (146, 149))	('tumor', 'Disease', (80, 85))	('CIN', 'Disease', (146, 149))	('CIN', 'Disease', 'MESH:D007674', (146, 149))
96809	29051489	Not surprisingly, IS scores are positively correlated with high stromal fraction in tumor mass (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('correlated', 'Reg', (43, 53))	('tumor', 'Disease', (84, 89))	('high', 'Var', (59, 63))
96811	29051489	In contrast to tumor antigens, some of the positively correlated mutations might be selected under host immunogenic pressure as part of cancer cells' mechanisms to evade immune surveillance.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', (15, 20))	('mutations', 'Var', (65, 74))
96812	29051489	Mutations in HLA-A, -B, and -C, B2M, and CASP8 might fall into this category since CASP8 is an executor of ligand-mediated apoptosis and HLA-A, -B, and -C and B2M encode major antigen presenting machinery to immune cells.	('fall', 'Phenotype', 'HP:0002527', (53, 57))	('ligand', 'molecular_function', 'GO:0005488', ('107', '113'))	('HLA-A, -B, and -C and B2M', 'Gene', '3105;3106;3107', (137, 162))	('CASP8', 'Gene', (41, 46))	('CASP8', 'Gene', (83, 88))	('CASP8', 'Gene', '841', (41, 46))	('Mutations', 'Var', (0, 9))	('CASP8', 'Gene', '841', (83, 88))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('HLA-A, -B, and -C, B2M', 'Gene', '3105;3106;3107', (13, 35))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))
96813	29051489	Any loss-of-function mutations would give a significant advantage to cancer cells to evade immune surveillance.	('loss-of-function', 'NegReg', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('evade', 'CPA', (85, 90))	('cancer', 'Disease', (69, 75))	('mutations', 'Var', (21, 30))
96814	29051489	In good agreement, tumors with mutations in these genes represent typical M type characteristics (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
96816	29051489	3d), the amplification of ERBB2 (HER2) was significantly associated with low IS scores.	('amplification', 'Var', (9, 22))	('HER2', 'Gene', (33, 37))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('HER2', 'Gene', '2064', (33, 37))	('low', 'NegReg', (73, 76))	('associated', 'Reg', (57, 67))
96818	29051489	Importantly, recent study demonstrated that loss of PTEN is indeed significantly associated with resistant to immunotherapy with anti-PD-1 antibodies in melanoma, strongly suggesting that many of identified candidates might play key roles in host immunity to cancer cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('PTEN', 'Gene', (52, 56))	('PD-1', 'Gene', (134, 138))	('PTEN', 'Gene', '5728', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('PD-1', 'Gene', '5133', (134, 138))	('melanoma', 'Disease', (153, 161))	('resistant to immunotherapy', 'CPA', (97, 123))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('loss', 'Var', (44, 48))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', (259, 265))
96819	29051489	Interestingly, expression of HLA-A, HLA-B, and HLA-C had a significant negative correlation with CIN scores in tumors with amplified genes or deleted genes (Fig.	('HLA-C', 'Gene', (47, 52))	('HLA-A', 'Gene', (29, 34))	('CIN', 'Disease', 'MESH:D007674', (97, 100))	('deleted genes', 'Var', (142, 155))	('HLA-C', 'Gene', '3107', (47, 52))	('CIN', 'Phenotype', 'HP:0040012', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('amplified genes', 'Var', (123, 138))	('CIN', 'Disease', (97, 100))	('expression', 'MPA', (15, 25))	('HLA-B', 'Gene', (36, 41))	('HLA-A', 'Gene', '3105', (29, 34))	('HLA-B', 'Gene', '3106', (36, 41))	('negative', 'NegReg', (71, 79))
96820	29051489	7c), suggesting that some of the copy number-altered genes might be involved in the suppression of antigen presentation in cancer cells either alone or in combination with other genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('antigen presentation', 'MPA', (99, 119))	('copy number-altered genes', 'Var', (33, 58))	('genes', 'Var', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('suppression', 'NegReg', (84, 95))	('antigen presentation', 'biological_process', 'GO:0019882', ('99', '119'))
96827	29051489	First, IS scores reliably identified responders to immunotherapy in a mouse model treated with anti-CTLA-4 antibodies.	('mouse', 'Species', '10090', (70, 75))	('anti-CTLA-4', 'Gene', (95, 106))	('anti-CTLA-4', 'Var', (95, 106))
96841	29051489	In another study analyzing of samples from clinical trials with CTLA-4 and PD-1 blockade treatments, copy number loss is associated with resistance to immunotherapy.	('copy number loss', 'Var', (101, 117))	('PD-1', 'Gene', (75, 79))	('associated', 'Reg', (121, 131))	('PD-1', 'Gene', '5133', (75, 79))	('resistance to immunotherapy', 'CPA', (137, 164))
96842	29051489	A lack of neoantigen production due to low mutation rates may account for the insensitivity of C-type tumors to immunotherapy, however loss of key immune mediators is also likely to contribute.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mutation', 'Var', (43, 51))	('neoantigen production', 'MPA', (10, 31))	('loss', 'NegReg', (135, 139))	('C-type tumors', 'Disease', 'MESH:D019698', (95, 108))	('C-type tumors', 'Disease', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lack', 'NegReg', (2, 6))
96845	29051489	M-type tumors have frequent mutations in genes involved in antigen presentation.	('M-type tumors', 'Disease', 'MESH:C566367', (0, 13))	('antigen presentation', 'biological_process', 'GO:0019882', ('59', '79'))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('M-type tumors', 'Disease', (0, 13))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
96847	29051489	Likewise, mutations in CASP8, which is a key mediator of apoptosis, give an advantage to cancer cells to become insensitive to T-cell-mediated cell death.	('CASP8', 'Gene', (23, 28))	('T-cell-mediated cell death', 'biological_process', 'GO:0001913', ('127', '153'))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('mutations', 'Var', (10, 19))	('advantage', 'PosReg', (76, 85))	('CASP8', 'Gene', '841', (23, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
96850	29051489	In good agreement with our analysis that identified PTEN as a key modulator of tumor immunity, recent study showed that PTEN play roles in T-cell activation and loss of PTEN is significantly associated with resistance of melanoma to immunotherapy.	('PTEN', 'Gene', (52, 56))	('tumor', 'Disease', (79, 84))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Disease', (221, 229))	('PTEN', 'Gene', '5728', (52, 56))	('PTEN', 'Gene', (169, 173))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('PTEN', 'Gene', '5728', (169, 173))	('PTEN', 'Gene', '5728', (120, 124))	('T-cell activation', 'biological_process', 'GO:0042110', ('139', '156'))	('PTEN', 'Gene', (120, 124))	('associated with', 'Reg', (191, 206))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('loss', 'Var', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
96868	29051489	In the current study, we showed that the potential benefit of immunotherapy highly varies across cancer lineages and revealed global subtypes of tumors and genomic alterations significantly associated with the potential benefit of immunotherapy.	('cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('associated', 'Reg', (190, 200))	('alterations', 'Var', (164, 175))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
96887	29051489	For each cancer type, we performed logistic analysis with IS score as the independent variable, and dichotomized status in genomic data such as higher or lower than median mutation number or CIN scores as the dependent variables.	('cancer', 'Disease', (9, 15))	('lower', 'NegReg', (154, 159))	('mutation number', 'Var', (172, 187))	('CIN', 'Disease', 'MESH:D007674', (191, 194))	('CIN', 'Phenotype', 'HP:0040012', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CIN', 'Disease', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
96889	29051489	To estimate the significance of correlation in each cancer type, subgroup analysis of logistic regression was carried out to compute odds ratio (OR) of mutation rate or CIN score.	('CIN', 'Disease', 'MESH:D007674', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CIN', 'Phenotype', 'HP:0040012', (169, 172))	('CIN', 'Disease', (169, 172))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutation', 'Var', (152, 160))
96891	30670742	A CATH domain functional family based approach to identify putative cancer driver genes and driver mutations Tumour sequencing identifies highly recurrent point mutations in cancer driver genes, but rare functional mutations are hard to distinguish from large numbers of passengers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Tumour', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('point mutations', 'Var', (155, 170))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
96892	30670742	The primary filter identifies enrichment of cancer mutations in CATH functional families (CATH-FunFams) - structurally and functionally coherent sets of evolutionary related domains.	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (44, 50))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
96894	30670742	Using a set of mutations from 22 cancers we detect 151 putative cancer drivers, of which 79 are not listed in cancer resources and include recently validated cancer associated genes EPHA7, DCC netrin-1 receptor and zinc-finger protein ZNF479.	('cancer', 'Disease', (33, 39))	('EPHA7', 'Gene', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ZNF479', 'Gene', (235, 241))	('protein', 'cellular_component', 'GO:0003675', ('227', '234'))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('DCC netrin-1 receptor', 'Gene', (189, 210))	('cancer', 'Disease', (64, 70))	('cancers', 'Disease', (33, 40))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (158, 164))	('EPHA7', 'Gene', '2045', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('DCC netrin-1 receptor', 'Gene', '1630', (189, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('DCC', 'cellular_component', 'GO:0120206', ('189', '192'))	('ZNF479', 'Gene', '90827', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
96897	30670742	Mutations observed in tumours may be drivers, positively influencing tumour progression, or passengers, which are incidental and have no net effect.	('tumour', 'Disease', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('tumour', 'Disease', (22, 28))	('tumours', 'Disease', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('influencing', 'Reg', (57, 68))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
96900	30670742	Multiple recent methods aid driver gene identification using structure-based algorithms: by calculating frequencies of distances between mutated residue pairs; calculating a clustering coefficient using weighted sums of mutated pairs; using permutation testing of mutation distance distributions; finding mutational hotspots within spherical regions and testing protein complexes.	('complexes', 'Interaction', (370, 379))	('protein', 'Protein', (362, 369))	('protein', 'cellular_component', 'GO:0003675', ('362', '369'))	('mutational', 'Var', (305, 315))	('aid', 'Gene', (24, 27))	('aid', 'Gene', '57379', (24, 27))	('testing', 'Reg', (354, 361))
96903	30670742	In particular, multiple genes containing mutations in a tumour sample may belong to different components of the same biological pathway, and databases such as PathwayCommons can help predict functional consequences of such mutated gene sets.	('mutations', 'Var', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('belong', 'Reg', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))
96905	30670742	We present a novel study that detects enrichment of cancer mutations in our CATH Functional Families (CATH-FunFams).	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (52, 58))
96909	30670742	Finally, we performed 3D clustering of all available mutations mapped to representative domain structures of the MutFams, followed by detailed proximity analysis of clusters to various functional sites, on the premise that mutations from different cancers that cluster near the same sites are likely to be having similar functional impacts.	('cancers', 'Disease', (248, 255))	('MutFam', 'Chemical', '-', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('mutations', 'Var', (53, 62))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('mutations', 'Var', (223, 232))
96910	30670742	We find that, in general, our 3D clustered mutations are closer to functional sites than unfiltered cancer mutations.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
96913	30670742	The score reflects other evidence supporting a gene's involvement in cancer: the predicted functional effects; the identification of cancer-enriched modules on a functional interaction network; significant clustering of mutations on protein structures near functional sites and/or agreement with the Cancer Genome Census (CGC) or Pfam based gene sets.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('cancer', 'Disease', (133, 139))	('Cancer', 'Phenotype', 'HP:0002664', (300, 306))	('Cancer Genome Census', 'Disease', 'MESH:D009369', (300, 320))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Cancer Genome Census', 'Disease', (300, 320))	('mutations', 'Var', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (69, 75))	('protein', 'Protein', (233, 240))
96915	30670742	The value of our approach is that by filtering mutations to enrich for those with functional effects it could help with identification and prioritisation of driver genes from large-scale cancer genomics studies.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('help', 'Reg', (110, 114))
96916	30670742	We analysed somatic, missense mutations from exome/genome-wide studies from 22 cancer types to identify mutationally enriched CATH-FunFam domain families, which we term MutFams (Fig.	('missense', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MutFam', 'Chemical', '-', (169, 175))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
96918	30670742	We grouped somatic missense mutations from 9,950 whole exome (or genome) samples in COSMIC v71 into 22 cancer types (based on tumour site, histology and respective subtypes) from which we identified a total of 259 MutFams (p < 0.05, permutation test with Benjami-Hochberg correction).	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('MutFam', 'Chemical', '-', (214, 220))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('missense mutations', 'Var', (19, 37))
96925	30670742	We used neutral mutations (polymorphisms) from UniProt as a non-cancer control, resulting in 8 MutFams, with half of these belonging to Class II Major Histo-compatibility Antigens, for which a pool of variant alleles is likely to be advantageous.	('variant', 'Var', (201, 208))	('non-cancer', 'Disease', (60, 70))	('non-cancer', 'Disease', 'MESH:D009369', (60, 70))	('MutFam', 'Chemical', '-', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
96928	30670742	In agreement with other domain based methods mutations in the tumour suppressor p53 are commonly observed.	('observed', 'Reg', (97, 105))	('mutations', 'Var', (45, 54))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('p53', 'Gene', (80, 83))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('p53', 'Gene', '7157', (80, 83))	('tumour', 'Disease', (62, 68))
96930	30670742	p53 point mutations are observed in many cancers and may be found at multiple sequence positions, but the positions are not generally specific to the cancer type.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('point mutations', 'Var', (4, 19))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
96932	30670742	Inhibition of PTEN has been shown to suppress regulation of the PIP3 secondary messenger, leading to increased growth factor signalling.	('PTEN', 'Gene', (14, 18))	('regulation of the PIP3 secondary messenger', 'MPA', (46, 88))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('PTEN', 'Gene', '5728', (14, 18))	('signalling', 'biological_process', 'GO:0023052', ('125', '135'))	('increased', 'PosReg', (101, 110))	('suppress', 'NegReg', (37, 45))	('growth factor signalling', 'MPA', (111, 135))	('Inhibition', 'Var', (0, 10))
96935	30670742	The large number of skin cutaneous melanoma (SKCM) MutFams (87) may be due to skin exposure to external carcinogens and is consistent with the highest mutation burden being observed in melanomas in general.	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('due', 'Reg', (71, 74))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (25, 43))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (20, 43))	('melanomas', 'Disease', (185, 194))	('skin cutaneous melanoma', 'Disease', (20, 43))	('MutFam', 'Chemical', '-', (51, 57))	('melanomas', 'Phenotype', 'HP:0002861', (185, 194))	('melanomas', 'Disease', 'MESH:D008545', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('MutFams', 'Var', (51, 58))
96941	30670742	We compared genes from MutFams with a subset of cancer implicated genes from the Wellcome-Sanger Cancer Gene Census (CGC) containing somatic missense mutations known to be associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('MutFam', 'Chemical', '-', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('associated', 'Reg', (172, 182))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (48, 54))	('missense mutations', 'Var', (141, 159))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Wellcome-Sanger Cancer', 'Disease', 'MESH:D009369', (81, 103))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Wellcome-Sanger Cancer', 'Disease', (81, 103))
96946	30670742	MutFam genes were significantly closer (less dispersed) on the network compared to randomly selected sets of genes (DS-Score 1.212, , Mann-Whitney test).	('MutFam', 'Chemical', '-', (0, 6))	('MutFam genes', 'Var', (0, 12))	('closer', 'PosReg', (32, 38))
96956	30670742	The genes commonly identified by MutFam, Miller and CGC were enriched in receptor signalling processes and downstream kinase signalling pathways (see Supplementary Section 1.1).	('signalling', 'biological_process', 'GO:0023052', ('125', '135'))	('signalling', 'biological_process', 'GO:0023052', ('82', '92'))	('receptor signalling processes', 'Pathway', (73, 102))	('MutFam', 'Var', (33, 39))	('MutFam', 'Chemical', '-', (33, 39))
96957	30670742	Such convergence may be very specific; a functional module identified from MutFam genes was associated with NOTCH signalling via NOTCH genes, whereas a module in Miller identified upstream and downstream regulators of the same pathway.	('NOTCH signalling', 'MPA', (108, 124))	('signalling', 'biological_process', 'GO:0023052', ('114', '124'))	('MutFam genes', 'Var', (75, 87))	('NOTCH genes', 'Gene', (129, 140))	('associated', 'Reg', (92, 102))	('MutFam', 'Chemical', '-', (75, 81))
96969	30670742	We used functionally pure CATH-FunFams to detect domain families (MutFams) enriched in cancer disease mutations.	('pure', 'molecular_function', 'GO:0034023', ('21', '25'))	('cancer disease', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MutFam', 'Chemical', '-', (66, 72))	('mutations', 'Var', (102, 111))	('cancer disease', 'Disease', 'MESH:D009369', (87, 101))
96971	30670742	Therefore, by seeking evidence of 3D clustering of mutations from MutFam genes we are able to filter out passenger mutations and identify a subset of putative driver genes and driver mutations with higher confidence to be associated with one or more cancers.	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('mutations', 'Var', (183, 192))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('cancers', 'Disease', (250, 257))	('MutFam', 'Chemical', '-', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('associated', 'Reg', (222, 232))
96973	30670742	CHEK2 is an essential regulator of genome integrity and becomes activated in response to double-stranded DNA damage.	('CHEK2', 'Gene', (0, 5))	('double-stranded', 'Var', (89, 104))	('response to double-stranded DNA', 'biological_process', 'GO:1990784', ('77', '108'))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('activated', 'PosReg', (64, 73))	('CHEK2', 'Gene', '11200', (0, 5))
96974	30670742	We observe mutations in CHEK2 clustering near the ATP binding pocket (centred on residue 355) and in the activation loop (centred around residues 392, 394 and 396), functional sites critical for CHEK2 kinase activity.	('CHEK2', 'Gene', '11200', (195, 200))	('mutations', 'Var', (11, 20))	('CHEK2', 'Gene', '11200', (24, 29))	('CHEK2', 'Gene', (24, 29))	('CHEK2', 'Gene', (195, 200))	('ATP binding', 'molecular_function', 'GO:0005524', ('50', '61'))	('kinase activity', 'molecular_function', 'GO:0016301', ('201', '216'))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
96975	30670742	Mutations affecting CHEK2 kinase activity could drive tumourigenesis by preventing inhibition of cell-cycle progression in response to DNA damage thus leading to genome instability.	('cell-cycle', 'CPA', (97, 107))	('CHEK2', 'Gene', (20, 25))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('genome instability', 'MPA', (162, 180))	('tumour', 'Disease', (54, 60))	('inhibition', 'MPA', (83, 93))	('Mutations', 'Var', (0, 9))	('drive', 'PosReg', (48, 53))	('cell-cycle', 'biological_process', 'GO:0007049', ('97', '107'))	('CHEK2', 'Gene', '11200', (20, 25))	('leading to', 'Reg', (151, 161))	('kinase activity', 'molecular_function', 'GO:0016301', ('26', '41'))	('preventing', 'NegReg', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
96978	30670742	CHEK2 is identified in the CGC from frameshift germline mutations (i.e.	('CHEK2', 'Gene', (0, 5))	('CHEK2', 'Gene', '11200', (0, 5))	('frameshift germline mutations', 'Var', (36, 65))
96979	30670742	not somatic missense mutations) and annotated as a tumour suppressor whereby frameshifts variants lead to increased risk of familial breast cancer.	('familial breast cancer', 'Disease', 'MESH:D001943', (124, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('familial breast cancer', 'Disease', (124, 146))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('frameshifts variants', 'Var', (77, 97))	('tumour', 'Disease', (51, 57))
96980	30670742	Clustering of cancer mutations near key functional sites is further illustrated for the extra-cellular dimerization interface of EGFR and for the BRAF kinase domain in Supplementary Fig.	('cancer', 'Disease', (14, 20))	('BRAF', 'Gene', (146, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('129', '133'))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('BRAF', 'Gene', '673', (146, 150))	('extra-cellular dimerization interface', 'MPA', (88, 125))	('EGFR', 'Gene', '1956', (129, 133))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('EGFR', 'Gene', (129, 133))	('mutations', 'Var', (21, 30))
96982	30670742	The mutations in oncogenes from the unfiltered pan-cancer set tend to be closer to catalytic residues than neutral mutations, though not significantly (, Fisher's exact test), while TSGs show an equivalent but significant tendency .	('catalytic residues', 'MPA', (83, 101))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('closer', 'PosReg', (73, 79))	('pan-cancer', 'Disease', 'MESH:C537931', (47, 57))	('mutations', 'Var', (4, 13))	('oncogenes', 'Gene', (17, 26))	('pan-cancer', 'Disease', (47, 57))
96984	30670742	Protein interfaces can cover large areas on the surface of the protein, thus substantial proportions of both cancer and neutral mutations are close to interfaces (Fig.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
96985	30670742	Unfiltered cancer mutations in both oncogenes and TSGs show significantly higher propensities to lie close to interfaces (as defined by IBIS) than neutral mutations (oncogenes ; TSGs , Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('oncogenes', 'Gene', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('IBIS', 'Chemical', '-', (136, 140))	('cancer', 'Disease', (11, 17))	('TSGs', 'Gene', (50, 54))	('mutations', 'Var', (18, 27))
96987	30670742	However, MutFam clustered mutations are significantly closer to ligand-binding sites than neutral ) (Fig.	('ligand-binding sites', 'MPA', (64, 84))	('mutations', 'Var', (26, 35))	('MutFam', 'Chemical', '-', (9, 15))	('ligand', 'molecular_function', 'GO:0005488', ('64', '70'))	('closer', 'PosReg', (54, 60))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
96995	30670742	Since comparing the number of putative driver genes in MutFams with the list of CGC genes containing missense mutations (downloaded September 2016), additional cancer driver genes have been added to CGC.	('missense mutations', 'Var', (101, 119))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('MutFam', 'Chemical', '-', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
97000	30670742	Although having only 2 mutations within the FunFam boundaries of the gene EPHA7 itself, the MutFam (Ephrin type-B receptor 2) was found to be enriched based on 12 mutations found in Ovarian cancer across 8 genes within the FunFam.	('mutations', 'Var', (163, 172))	('Ovarian cancer', 'Disease', (182, 196))	('Ephrin type-B receptor 2', 'Gene', '2048', (100, 124))	('EPHA7', 'Gene', '2045', (74, 79))	('Ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('Ephrin', 'molecular_function', 'GO:0005106', ('100', '106'))	('Ephrin', 'molecular_function', 'GO:0046875', ('100', '106'))	('EPHA7', 'Gene', (74, 79))	('Ephrin type-B receptor 2', 'Gene', (100, 124))	('MutFam', 'Chemical', '-', (92, 98))
97003	30670742	By using the total set of pan-cancer mutations, a total of 46 mutations in this FunFam gave a significant cluster in 3D that was near a predicted functional site.	('pan-cancer', 'Disease', (26, 36))	('FunFam', 'Gene', (80, 86))	('pan-cancer', 'Disease', 'MESH:C537931', (26, 36))	('mutations', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
97006	30670742	The genes PLXNA1, PLXNA2 and PLXNA4 are enriched in cellular development - axon guidance processes and 68 pan-cancer mutations show a significant clustering of mutations, near a predicted functional site (i.e.	('PLXNA4', 'Gene', (29, 35))	('mutations', 'Var', (117, 126))	('mutations', 'Var', (160, 169))	('axon guidance', 'biological_process', 'GO:0007411', ('75', '88'))	('pan-cancer', 'Disease', (106, 116))	('PLXNA2', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cellular development - axon guidance processes', 'CPA', (52, 98))	('PLXNA1', 'Gene', (10, 16))	('axon', 'cellular_component', 'GO:0030424', ('75', '79'))	('PLXNA2', 'Gene', '5362', (18, 24))	('PLXNA4', 'Gene', '91584', (29, 35))	('pan-cancer', 'Disease', 'MESH:C537931', (106, 116))	('PLXNA1', 'Gene', '5361', (10, 16))
97010	30670742	Previous studies demonstrated the value of looking for mutationally enriched regions within proteins on the premise that mutations in these regions could convey functional effects driving cancer.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', (188, 194))
97014	30670742	There is a correlation with the number of mutations per cancer type and the number of MutFams, suggesting that cancers with high mutational burden, due to exposure to external mutagens (such as skin, lung and colorectal cancers), have a larger pool of mutations from which tumour evolution can select a more diverse range of functional mutations than cancers having a lower mutational burden.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('colorectal cancers', 'Disease', 'MESH:D015179', (209, 227))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('lung', 'Disease', (200, 204))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Disease', (56, 62))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancers', 'Phenotype', 'HP:0002664', (351, 358))	('tumour', 'Disease', 'MESH:D009369', (273, 279))	('cancers', 'Disease', (351, 358))	('tumour', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MutFam', 'Chemical', '-', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (351, 357))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('colorectal cancers', 'Disease', (209, 227))	('mutations', 'Var', (252, 261))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancer', 'Disease', (220, 226))	('cancers', 'Disease', (220, 227))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancers', 'Disease', 'MESH:D009369', (351, 358))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('skin', 'Disease', (194, 198))	('mutations', 'Var', (336, 345))	('cancer', 'Disease', (351, 357))
97017	30670742	The lower overall dispersion of MutFam genes on a PPI network compared to random implied that the genes were closer together on the network and therefore likely to be in related processes.	('MutFam', 'Chemical', '-', (32, 38))	('dispersion', 'MPA', (18, 28))	('MutFam', 'Var', (32, 38))	('PPI', 'biological_process', 'GO:0060134', ('50', '53'))
97019	30670742	Furthermore, the cancer sets identified by the MutFam and Miller methods were found to be biased towards different tissues, and the genes therefore operating in different cellular contexts, which may partly explain this low overlap.	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('MutFam', 'Chemical', '-', (47, 53))	('MutFam', 'Var', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
97025	30670742	Other non-structural regions, such as protein N and C termini, may have cancer-associated mutations but are not included in our analyses if they lie outside the domain.	('mutations', 'Var', (90, 99))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('protein N', 'Disease', 'MESH:C536108', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('protein N', 'Disease', (38, 47))	('cancer', 'Disease', (72, 78))
97036	30670742	Cancer datasets: 22 cancer-specific datasets were generated comprising somatic, non-synonymous missense exonic mutations from COSMIC v71, using variants from whole exome/genome studies, then filtering for each cancer type using tumour site and histology data with TCGA-style classes to define cancer types (summarised in Supplementary Table 1).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (293, 299))	('variants', 'Var', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('tumour', 'Disease', (228, 234))	('missense exonic mutations', 'Var', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('COSMIC v71', 'Gene', (126, 136))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Disease', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))
97039	30670742	Pan-cancer dataset: 800,704 somatic, non-synonymous missense exonic variants from whole genome/exome studies from COSMIC v71 with no filtering by tumour site or histology.	('tumour', 'Disease', (146, 152))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('missense exonic variants', 'Var', (52, 76))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
97041	30670742	This set is used to give as large and comprehensive cancer mutation dataset to use for 3D clustering as possible, based on the hypothesis that mutations from different cancers that cluster near the same functional site are likely to act via similar functional impacts.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Disease', (168, 174))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (143, 152))
97045	30670742	For each of the cancer datasets (pan-cancer plus 22 cancer-specific) and UniProt neutral, we identified 'MutFams' as CATH FunFam domains significantly enriched in mutations.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('MutFam', 'Chemical', '-', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (163, 172))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (16, 22))	('pan-cancer', 'Disease', 'MESH:C537931', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('pan-cancer', 'Disease', (33, 43))
97046	30670742	Enrichment score significance was assessed using a permutation test as follows: For each FunFam f: Get the set of human genes containing the FunFam domain For each permutation i (1 to 10000): For each gene, g, count the number of mutations ng; randomly distribute the ng mutations across gene g, allowing multiple mutations per amino acid.	('mutations', 'Var', (230, 239))	('human', 'Species', '9606', (114, 119))	('mutations', 'Var', (271, 280))
97054	30670742	CGC: We used a subset of the full cancer driver gene list from Wellcome-Sanger Cancer Gene Census comprising those annotated as having missense mutations, resulting in 232 known driver genes; other mutation types may also have been annotated in these genes, e.g.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Wellcome-Sanger Cancer', 'Disease', 'MESH:D009369', (63, 85))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Wellcome-Sanger Cancer', 'Disease', (63, 85))	('cancer', 'Disease', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('missense mutations', 'Var', (135, 153))
97062	30670742	We also separately calculated a set of pan-cancer MutFams using 800,704 somatic missense mutations from any whole exome or genome tumour sample, without any grouping by cancer type, to give 541 MutFams (p < 0.05, permutation test with Benjami-Hochberg correction).	('pan-cancer', 'Disease', (39, 49))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (43, 49))	('tumour', 'Disease', (130, 136))	('pan-cancer', 'Disease', 'MESH:C537931', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('MutFam', 'Chemical', '-', (194, 200))	('missense mutations', 'Var', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('MutFam', 'Chemical', '-', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
97064	30670742	We use this pan-cancer set to provide the largest possible dataset for 3D clustering, as mutations from different cancers clustering near a given functional site are likely to have similar functional impact.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('pan-cancer', 'Disease', 'MESH:C537931', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pan-cancer', 'Disease', (12, 22))
97065	30670742	Mutations in the pan-cancer MutFams were mapped to their CATH representative domain PDB structures, where available.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('MutFam', 'Chemical', '-', (28, 34))	('pan-cancer', 'Disease', (17, 27))	('Mutations', 'Var', (0, 9))	('pan-cancer', 'Disease', 'MESH:C537931', (17, 27))
97068	30670742	For each MutFam, we assigned all of the observed mutations to residues in the PDB structure at random and with equal probability, and then calculated the observed mutation counts near each residue as above.	('MutFam', 'Chemical', '-', (9, 15))	('PDB', 'Gene', (78, 81))	('mutations', 'Var', (49, 58))
97070	30670742	Odds ratios were calculated for the distance distributions of cancer mutations to functional sites by comparison with neutral mutations using Fisher's exact test with 8A as the upper bound for proximity; test based on Gao et al..	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
97085	33105692	Indeed, most metastatic cutaneous melanoma patients with mutated BRAF-V600 (around 40-50%) exhibit a spectacular and rapid initial response to the BRAF inhibitor treatments, which significantly enhances their overall survival (OS) and progression-free survival (PFS) compared to conventional chemotherapy, without resulting in a higher level of toxicity.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (24, 42))	('enhances', 'PosReg', (194, 202))	('patients', 'Species', '9606', (43, 51))	('BRAF', 'Gene', (65, 69))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('BRAF', 'Gene', '673', (65, 69))	('progression-free survival', 'CPA', (235, 260))	('toxicity', 'Disease', 'MESH:D064420', (345, 353))	('toxicity', 'Disease', (345, 353))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('mutated', 'Var', (57, 64))	('cutaneous melanoma', 'Disease', (24, 42))	('overall survival', 'CPA', (209, 225))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (24, 42))
97089	33105692	Several clinical trials in innate BRAF-m metastatic cutaneous melanoma demonstrated that the combination of either BRAF inhibitors with MEK inhibitors (MEK: Mitogen-activated protein kinase kinase) or of anti-PD1 with anti-CTLA-4 improve PFS compared to BRAF inhibitors or anti-CTLA-4 alone.	('MEK', 'Gene', (136, 139))	('inhibitors', 'Var', (120, 130))	('improve', 'PosReg', (230, 237))	('BRAF', 'Gene', '673', (254, 258))	('BRAF', 'Gene', (254, 258))	('combination', 'Interaction', (93, 104))	('CTLA-4', 'Gene', '1493', (278, 284))	('CTLA-4', 'Gene', '1493', (223, 229))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('anti-PD1', 'Gene', (204, 212))	('CTLA-4', 'Gene', (278, 284))	('CTLA-4', 'Gene', (223, 229))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('MEK', 'Gene', '5609', (152, 155))	('BRAF', 'Gene', '673', (115, 119))	('PFS', 'Disease', (238, 241))	('BRAF', 'Gene', (115, 119))	('MEK', 'Gene', '5609', (136, 139))	('MEK', 'Gene', (152, 155))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
97108	33105692	This panel encompassed two mutually exclusive genetic subsets of cutaneous melanoma, since MeWo and HMCB are BRAF-wt and NRAS mutated (NRAS-m), A375 and SK-MEL-28 are BRAF-m and NRAS wildtype (NRAS-wt).	('NRAS', 'Gene', (193, 197))	('cutaneous melanoma', 'Disease', (65, 83))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (65, 83))	('BRAF', 'Gene', (167, 171))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (65, 83))	('BRAF', 'Gene', '673', (167, 171))	('NRAS', 'Gene', '4893', (135, 139))	('NRAS', 'Gene', (178, 182))	('NRAS', 'Gene', (121, 125))	('mutated', 'Var', (126, 133))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('A375', 'CellLine', 'CVCL:0132', (144, 148))	('NRAS', 'Gene', (135, 139))	('NRAS', 'Gene', '4893', (193, 197))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('NRAS', 'Gene', '4893', (178, 182))	('NRAS', 'Gene', '4893', (121, 125))	('SK-MEL-28', 'Chemical', '-', (153, 162))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))
97129	33105692	With NHC-Pt-I2, the mean intracellular Pt concentration at 24 h (9.35 x 10-5 +- 8.54 x 10-5 micromol/106 cells) was not significantly different to the initial amount loaded (p = 0.162), and remained significantly higher (p = 0.0008) than with cisplatin, but not significantly different to that of NHC-Pt-Br2 (p = 0.0551).	('NHC-Pt-I2', 'Chemical', '-', (5, 14))	('NHC-Pt-Br2', 'Chemical', '-', (297, 307))	('higher', 'PosReg', (213, 219))	('intracellular', 'cellular_component', 'GO:0005622', ('25', '38'))	('cisplatin', 'Chemical', 'MESH:D002945', (243, 252))	('NHC-Pt-I2', 'Var', (5, 14))	('Pt', 'Chemical', 'MESH:D010984', (39, 41))	('Pt', 'Chemical', 'MESH:D010984', (301, 303))	('Pt', 'Chemical', 'MESH:D010984', (9, 11))
97140	33105692	After 48 h post-treatment, the compound NHC-Pt-I2 induced a high level of DSB, followed by NHC-Pt-Br2.	('NHC-Pt-I2', 'Var', (40, 49))	('induced', 'Reg', (50, 57))	('NHC-Pt-I2', 'Chemical', '-', (40, 49))	('NHC-Pt-Br2', 'Chemical', '-', (91, 101))	('DSB', 'Chemical', '-', (74, 77))	('DSB', 'MPA', (74, 77))
97141	33105692	At 72 h post-treatment, NHC-Pt-I2 induced the most important level of DSB whereas the cisplatin impact was negligible compared to the untreated control cells.	('NHC-Pt-I2', 'Var', (24, 33))	('DSB', 'MPA', (70, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('DSB', 'Chemical', '-', (70, 73))	('NHC-Pt-I2', 'Chemical', '-', (24, 33))
97144	33105692	Caspase-dependent death Apoptosis results either directly from a transduction of DNA adduct signals via various pathways such as MAPK, or indirectly following mismatch repair processes via the activation of several cell-cycle regulators, such as P53.	('P53', 'Gene', (246, 249))	('mismatch repair', 'biological_process', 'GO:0006298', ('159', '174'))	('DNA adduct signals', 'MPA', (81, 99))	('P53', 'Gene', '7157', (246, 249))	('mismatch repair', 'Var', (159, 174))	('transduction', 'biological_process', 'GO:0009293', ('65', '77'))	('cell-cycle', 'biological_process', 'GO:0007049', ('215', '225'))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('transduction', 'Reg', (65, 77))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('MAPK', 'molecular_function', 'GO:0004707', ('129', '133'))
97149	33105692	In the absence of Q-VD-OPh, the uptake of SYTOX Green  began at 40 h and reached 25% at 70 h. For NHC-Pt-I2 and NHC-Pt-Br2 (Figure 5A,B) the presence of the pan-caspase inhibitor protected the cells from cell death, whereas its absence led to the linear uptake of SYTOX GreenTM from 10 h (NHC-Pt-I2) and 35 h (NHC-Pt-Br2) onwards for up to 55-60 h. These results demonstrate that the death of cells treated for 1 h with NHC-Pt-I2 or NHC-Pt-Br2 was caspase-dependent, suggesting a major role of apoptosis in the cytotoxicity of these compounds.	('NHC-Pt-Br2', 'Chemical', '-', (433, 443))	('NHC-Pt-I2', 'Chemical', '-', (289, 298))	('SYTOX Green', 'Chemical', 'MESH:C402795', (264, 275))	('uptake', 'biological_process', 'GO:0098657', ('32', '38'))	('cytotoxicity', 'Disease', (511, 523))	('uptake', 'biological_process', 'GO:0098657', ('254', '260'))	('cytotoxicity', 'Disease', 'MESH:D064420', (511, 523))	('NHC-Pt-I2', 'Chemical', '-', (420, 429))	('uptake', 'biological_process', 'GO:0098739', ('32', '38'))	('NHC-Pt-Br2', 'Chemical', '-', (112, 122))	('SYTOX GreenTM', 'Chemical', '-', (264, 277))	('OPh', 'molecular_function', 'GO:0004063', ('23', '26'))	('NHC-Pt-Br2', 'Var', (433, 443))	('NHC-Pt-I2', 'Var', (420, 429))	('uptake', 'biological_process', 'GO:0098739', ('254', '260'))	('cell death', 'biological_process', 'GO:0008219', ('204', '214'))	('NHC-Pt-Br2', 'Chemical', '-', (310, 320))	('apoptosis', 'biological_process', 'GO:0097194', ('494', '503'))	('apoptosis', 'biological_process', 'GO:0006915', ('494', '503'))	('NHC-Pt-I2', 'Chemical', '-', (98, 107))	('Q-VD-OPh', 'Chemical', 'MESH:C468548', (18, 26))	('SYTOX Green', 'Chemical', 'MESH:C402795', (42, 53))
97161	33105692	Here, we unveiled the drastic effect of NHC-Pt-I2, an NHC-containing platinum complex, in strongly inhibiting the proliferation of a large panel of human melanoma cell lines.	('NHC-Pt-I2', 'Var', (40, 49))	('inhibiting', 'NegReg', (99, 109))	('NHC-Pt-I2', 'Chemical', '-', (40, 49))	('human', 'Species', '9606', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('proliferation', 'CPA', (114, 127))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('NHC', 'Chemical', '-', (54, 57))	('platinum', 'Chemical', 'MESH:D010984', (69, 77))	('NHC', 'Chemical', '-', (40, 43))
97163	33105692	Although its cytotoxicity was lower towards the cell line derived from a metastatic site (MeWo) compared to the three cell lines derived from primary tumors, NHC-Pt-I2 displayed significant cytotoxicity compared to other tested compounds.	('cytotoxicity', 'Disease', (190, 202))	('lower', 'NegReg', (30, 35))	('NHC-Pt-I2', 'Var', (158, 167))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cytotoxicity', 'Disease', (13, 25))	('cytotoxicity', 'Disease', 'MESH:D064420', (190, 202))	('primary tumors', 'Disease', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('NHC-Pt-I2', 'Chemical', '-', (158, 167))	('cytotoxicity', 'Disease', 'MESH:D064420', (13, 25))	('primary tumors', 'Disease', 'MESH:D001932', (142, 156))
97166	33105692	Indeed, cisplatin which is delivered at a two-fold lower dose than dacarbazine due to its higher toxicity, provides a similar objective rate of remission (<=10%) as dacarbazine, hence confirming the potential of Pt based chemotherapeutics in the management of metastatic cutaneous melanoma.	('cutaneous melanoma', 'Disease', (271, 289))	('dacarbazine', 'Chemical', 'MESH:D003606', (67, 78))	('cisplatin', 'Var', (8, 17))	('Pt', 'Chemical', 'MESH:D010984', (212, 214))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (271, 289))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (271, 289))	('melanoma', 'Phenotype', 'HP:0002861', (281, 289))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('toxicity', 'Disease', 'MESH:D064420', (97, 105))	('dacarbazine', 'Chemical', 'MESH:D003606', (165, 176))	('toxicity', 'Disease', (97, 105))
97168	33105692	Interestingly, A375 cells overexpressing the anti-apoptotic protein Bcl-xL were also affected by NHC-Pt-I2, although they displayed a lower rate of apoptosis.	('Bcl-xL', 'Gene', '598', (68, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('148', '157'))	('apoptosis', 'biological_process', 'GO:0006915', ('148', '157'))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('Bcl-xL', 'Gene', (68, 74))	('affected', 'Reg', (85, 93))	('NHC-Pt-I2', 'Var', (97, 106))	('A375', 'CellLine', 'CVCL:0132', (15, 19))	('NHC-Pt-I2', 'Chemical', '-', (97, 106))
97169	33105692	Further mechanistic studies are required to determine the other pathway of cell death induced by NHC-Pt compounds and investigate the impact of mutated p53, the role of which has been established in the resistance to chemotherapy, particularly to cisplatin.	('NHC-Pt compounds', 'Chemical', '-', (97, 113))	('mutated', 'Var', (144, 151))	('p53', 'Gene', (152, 155))	('p53', 'Gene', '7157', (152, 155))	('cell death', 'biological_process', 'GO:0008219', ('75', '85'))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))
97170	33105692	Additionally, the higher cellular uptake of NHC-Pt-I2 suggests the participation of a passive cell entrance flux in contrast with cisplatin which mainly enters cells via the copper-transporting P-type adenosine triphosphate.	('uptake', 'biological_process', 'GO:0098739', ('34', '40'))	('NHC-Pt-I2', 'Var', (44, 53))	('passive cell entrance flux', 'MPA', (86, 112))	('adenosine', 'Chemical', 'MESH:D000241', (201, 210))	('copper', 'Chemical', 'MESH:D003300', (174, 180))	('NHC-Pt-I2', 'Chemical', '-', (44, 53))	('cellular uptake', 'MPA', (25, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('higher', 'PosReg', (18, 24))	('uptake', 'biological_process', 'GO:0098657', ('34', '40'))
97171	33105692	Therefore, NHC-Pt-I2 uptake may not be affected by the mutation of the CTR1 copper transporters associated with resistance to cisplatin in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('CTR1', 'Gene', '799', (71, 75))	('cancers', 'Disease', (153, 160))	('CTR1', 'Gene', (71, 75))	('copper', 'Chemical', 'MESH:D003300', (76, 82))	('resistance', 'MPA', (112, 122))	('associated', 'Reg', (96, 106))	('uptake', 'biological_process', 'GO:0098739', ('21', '27'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('uptake', 'biological_process', 'GO:0098657', ('21', '27'))	('mutation', 'Var', (55, 63))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('NHC-Pt-I2', 'Chemical', '-', (11, 20))
97172	33105692	Aberrant activation of Raf/Mek/ERK MAPK is known to be strongly implicated in the proliferation and survival of cutaneous melanoma cells, by increasing the phosphorylation of downstream targets which results in excessive cell survival and proliferation, independently of growth factors.	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('Mek', 'Gene', '5609', (27, 30))	('Mek', 'Gene', (27, 30))	('excessive', 'PosReg', (211, 220))	('increasing', 'PosReg', (141, 151))	('Raf', 'Gene', '673', (23, 26))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('ERK', 'Gene', '5594', (31, 34))	('Raf', 'Gene', (23, 26))	('ERK', 'molecular_function', 'GO:0004707', ('31', '34'))	('MAPK', 'molecular_function', 'GO:0004707', ('35', '39'))	('cell survival', 'CPA', (221, 234))	('implicated', 'Reg', (64, 74))	('phosphorylation', 'MPA', (156, 171))	('ERK', 'Gene', (31, 34))	('cutaneous melanoma', 'Disease', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('proliferation', 'CPA', (239, 252))
97175	33105692	Future studies could also take into consideration NF-1 mutations, which are identified in roughly 10% of metastatic cutaneous melanoma or other genomic markers, the predictive role of which, in the management of stage IV melanoma, may arise in the future.	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('mutations', 'Var', (55, 64))	('melanoma', 'Disease', (221, 229))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('NF-1', 'Gene', '4763', (50, 54))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', (116, 134))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('NF-1', 'Gene', (50, 54))	('melanoma', 'Disease', (126, 134))
97215	33105692	To investigate the impact of an overexpression of the Bcl-xL protein, implicated in cell resistance to chemotherapy, the importance and the speed of the cell death process was similarly studied using Bcl-xL mutant A375 cells; the overexpression of the anti-apoptotic protein was validated by immunoblot.	('Bcl-xL', 'Gene', (54, 60))	('protein', 'cellular_component', 'GO:0003675', ('267', '274'))	('Bcl-xL', 'Gene', '598', (54, 60))	('Bcl-xL', 'Gene', '598', (200, 206))	('mutant', 'Var', (207, 213))	('A375', 'CellLine', 'CVCL:0132', (214, 218))	('Bcl-xL', 'Gene', (200, 206))	('cell death', 'biological_process', 'GO:0008219', ('153', '163'))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
97223	33105692	; Investigation, E.C., M.B., C.C.-D. and G.D.; Methodology, G.I., A.C., H.C.M., P.T., J.C. and C.B.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('H.C.M.', 'Var', (72, 78))	('P.T.', 'Var', (80, 84))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('C', 'Chemical', 'MESH:D002244', (68, 69))
97232	33974041	The authors show that LILRB4 is expressed largely on TAMs and suppresses antitumor immunity.	('LILRB4', 'Var', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('suppresses', 'NegReg', (62, 72))	('tumor', 'Disease', (77, 82))	('TAMs', 'Chemical', '-', (53, 57))
97233	33974041	Genetic deletion of LILRB4 or anti-LILRB4 antibody treatment modulates T cells to an effector phenotype and TAMs to a less immunosuppressive phenotype and increases survival against tumor challenge.	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('T cells', 'CPA', (71, 78))	('tumor', 'Disease', (182, 187))	('TAMs', 'Reg', (108, 112))	('increases', 'PosReg', (155, 164))	('Genetic deletion', 'Var', (0, 16))	('TAMs', 'Chemical', '-', (108, 112))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('less immunosuppressive phenotype', 'MPA', (118, 150))	('LILRB4', 'Gene', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('modulates', 'Reg', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
97238	33974041	After tumor challenge, LILRB4-/- mice and mice treated with anti-LILRB4 antibody showed reduced tumor burden and increased survival.	('survival', 'CPA', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('antibody', 'cellular_component', 'GO:0042571', ('72', '80'))	('antibody', 'molecular_function', 'GO:0003823', ('72', '80'))	('antibody', 'cellular_component', 'GO:0019815', ('72', '80'))	('mice', 'Species', '10090', (42, 46))	('tumor', 'Disease', (96, 101))	('antibody', 'cellular_component', 'GO:0019814', ('72', '80'))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('anti-LILRB4', 'Gene', (60, 71))	('anti-LILRB4', 'Var', (60, 71))	('mice', 'Species', '10090', (33, 37))	('increased', 'PosReg', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('reduced', 'NegReg', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
97239	33974041	LILRB4-/- genotype or LILRB4 blockade increased tumor immune infiltrates and the effector (Teff) to regulatory (Treg) T cell ratio and modulated phenotypes of TAMs toward less suppressive, CD4+ T cells to Th1 effector, and CD8+ T cells to less exhausted.	('blockade', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('rat', 'Species', '10116', (125, 128))	('rat', 'Species', '10116', (67, 70))	('tumor', 'Disease', (48, 53))	('LILRB4', 'Gene', (22, 28))	('CD8', 'Gene', (223, 226))	('TAMs', 'Chemical', '-', (159, 163))	('CD8', 'Gene', '925', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('increased', 'PosReg', (38, 47))
97242	33974041	One arm of cancer immunotherapy involves administration of antibodies against these receptors to block their interactions with their ligands and prevent this suppression.	('interactions', 'Interaction', (109, 121))	('ligands', 'Protein', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('block', 'NegReg', (97, 102))	('prevent', 'NegReg', (145, 152))	('antibodies', 'Var', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('rat', 'Species', '10116', (49, 52))
97255	33974041	Soluble LILRB4 has been found in the serum of pancreatic carcinoma, colorectal carcinoma, and melanoma patients, and T cell responses are increased in vitro upon treatment with anti-LILRB4 antibody.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (46, 66))	('T cell responses', 'CPA', (117, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('antibody', 'molecular_function', 'GO:0003823', ('189', '197'))	('increased', 'PosReg', (138, 147))	('antibody', 'cellular_component', 'GO:0042571', ('189', '197'))	('anti-LILRB4', 'Var', (177, 188))	('colorectal carcinoma', 'Disease', (68, 88))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (68, 88))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('pancreatic carcinoma', 'Disease', (46, 66))	('melanoma', 'Disease', (94, 102))	('Soluble', 'cellular_component', 'GO:0005625', ('0', '7'))	('antibody', 'cellular_component', 'GO:0019815', ('189', '197'))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('antibody', 'cellular_component', 'GO:0019814', ('189', '197'))	('patients', 'Species', '9606', (103, 111))
97275	33974041	Within CD11b+ cells, LILRB4 was expressed on both F4/80+ macrophages and CD11b+ GR-1+ neutrophils.	('GR-1', 'Gene', '546644', (80, 84))	('CD11b+', 'Var', (73, 79))	('GR-1', 'Gene', (80, 84))	('F4/80', 'Gene', (50, 55))	('F4/80', 'Gene', '13733', (50, 55))	('LILRB4', 'Gene', (21, 27))
97278	33974041	Within CD3+ T cells, the expression of LILRB4 was higher on CD4+ T cells than CD8+ T cells (Fig.	('CD8', 'Gene', (78, 81))	('CD4+ T', 'Var', (60, 66))	('higher', 'PosReg', (50, 56))	('CD3', 'Gene', (7, 10))	('expression', 'MPA', (25, 35))	('CD8', 'Gene', '925', (78, 81))	('LILRB4', 'Gene', (39, 45))	('CD3', 'Gene', '12501', (7, 10))
97281	33974041	Similarly, we found the expression of LILRB4 was higher on CD4+ T cells than on CD8+ T cells within tumor-infiltrating CD3+ T cells in the mouse renal carcinoma model RENCA.	('renal carcinoma', 'Phenotype', 'HP:0005584', (145, 160))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('CD3', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CD8', 'Gene', '925', (80, 83))	('CD3', 'Gene', '12501', (119, 122))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('renal carcinoma', 'Disease', 'MESH:C538614', (145, 160))	('rat', 'Species', '10116', (112, 115))	('mouse', 'Species', '10090', (139, 144))	('CD4+ T', 'Var', (59, 65))	('LILRB4', 'Gene', (38, 44))	('CD8', 'Gene', (80, 83))	('higher', 'PosReg', (49, 55))	('renal carcinoma', 'Disease', (145, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
97284	33974041	We found a similar pattern of expression of LILRB4 in the TRAMP-C2 prostate cancer model, where the expression of LILRB4 was higher on CD4+ T cells than on CD8+ T cells (Fig.	('LILRB4', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('expression', 'MPA', (100, 110))	('TRAMP-C2 prostate cancer', 'Disease', (58, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('CD4+ T', 'Var', (135, 141))	('higher', 'PosReg', (125, 131))	('TRAMP-C2 prostate cancer', 'Disease', 'MESH:D011471', (58, 82))	('CD8', 'Gene', (156, 159))	('CD8', 'Gene', '925', (156, 159))
97294	33974041	To comprehensively profile the intratumoral T cell populations expressing LILRB4, we used mass cytometry and a well-validated, data-driven unsupervised clustering approach on cells from MC38 and B16/F10 tumors.	('MC38', 'Var', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('cluster', 'Species', '100569', (152, 159))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('LILRB4', 'Gene', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Disease', (36, 41))
97319	33974041	The highest expression of LILRB4 was on cluster 6 (CD11b+ F4/80low Arg-1+ IDO+ CCR2high CX3CR1+ cluster), cluster 10 (CD11b+ F4/80+ CD68high Arg1+ Ly6C+ cluster), and cluster 18 (CD11b+ F4/80+ CD68+ iNOS2high CD204high Arg1+ Tim3high PD-L1high Ly6C+ cluster; Fig.	('F4/80', 'Gene', (125, 130))	('cluster', 'Species', '100569', (250, 257))	('F4/80', 'Gene', '13733', (186, 191))	('CCR', 'molecular_function', 'GO:0043880', ('79', '82'))	('PD-L1', 'Gene', '60533', (234, 239))	('cluster; Fig', 'Species', '100569', (250, 262))	('F4/80', 'Gene', '13733', (58, 63))	('IDO', 'molecular_function', 'GO:0047719', ('74', '77'))	('cluster', 'Species', '100569', (153, 160))	('CX3CR1', 'Gene', '13051', (88, 94))	('F4/80', 'Gene', (186, 191))	('CD11b+', 'Var', (118, 124))	('LILRB4', 'Gene', (26, 32))	('CX3CR1', 'Gene', (88, 94))	('Arg-1', 'Gene', (67, 72))	('Tim3', 'Gene', '171285', (225, 229))	('F4/80', 'Gene', (58, 63))	('cluster', 'Species', '100569', (96, 103))	('S', 'Chemical', 'MESH:D013455', (202, 203))	('cluster', 'Species', '100569', (106, 113))	('cluster', 'Species', '100569', (40, 47))	('PD-L1', 'Gene', (234, 239))	('CCR2', 'Gene', (79, 83))	('Arg-1', 'Gene', '11846', (67, 72))	('Tim3', 'Gene', (225, 229))	('cluster', 'Species', '100569', (167, 174))	('F4/80', 'Gene', '13733', (125, 130))	('CCR2', 'Gene', '12772', (79, 83))	('IDO', 'molecular_function', 'GO:0033754', ('74', '77'))	('expression', 'MPA', (12, 22))
97346	33974041	Cluster 9 had high expression of Arg1,along with expression of Msr1(Cd204) and Ms4a4c.	('expression', 'MPA', (19, 29))	('Msr1', 'Gene', (63, 67))	('Arg1', 'Protein', (33, 37))	('Ms4a4c', 'Var', (79, 85))	('Cluster', 'Species', '100569', (0, 7))
97352	33974041	Almost 30% of mice that received anti-LILRB4 completely rejected tumors, and mice that did show tumor burden had delayed tumor growth.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (121, 126))	('anti-LILRB4', 'Var', (33, 44))	('tumors', 'Disease', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('rejected', 'NegReg', (56, 64))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
97358	33974041	Similar to the B16F/10 tumor model, we observed a significant decrease in tumor burden and increase in survival in LILRB4-/- mice compared with WT control (Fig.	('LILRB4-/-', 'Gene', (115, 124))	('B16F', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('increase', 'PosReg', (91, 99))	('mice', 'Species', '10090', (125, 129))	('B16F', 'SUBSTITUTION', 'None', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (74, 79))	('decrease', 'NegReg', (62, 70))	('survival', 'CPA', (103, 111))	('tumor', 'Disease', (23, 28))	('S', 'Chemical', 'MESH:D013455', (0, 1))
97362	33974041	We found prolonged survival in mice injected with anti-LILRB4 antibody compared with isotype control antibody (Fig.	('antibody', 'cellular_component', 'GO:0019814', ('62', '70'))	('survival', 'CPA', (19, 27))	('antibody', 'molecular_function', 'GO:0003823', ('101', '109'))	('antibody', 'molecular_function', 'GO:0003823', ('62', '70'))	('mice', 'Species', '10090', (31, 35))	('antibody', 'cellular_component', 'GO:0042571', ('101', '109'))	('antibody', 'cellular_component', 'GO:0042571', ('62', '70'))	('anti-LILRB4 antibody', 'Var', (50, 70))	('prolonged', 'PosReg', (9, 18))	('antibody', 'cellular_component', 'GO:0019815', ('62', '70'))	('antibody', 'cellular_component', 'GO:0019814', ('101', '109'))	('antibody', 'cellular_component', 'GO:0019815', ('101', '109'))
97364	33974041	We sought to determine whether the anti-LILRB4 antibody produces immunological memory in treated mice.	('antibody', 'cellular_component', 'GO:0042571', ('47', '55'))	('immunological memory', 'Disease', (65, 85))	('anti-LILRB4', 'Var', (35, 46))	('immunological memory', 'Disease', 'MESH:D007153', (65, 85))	('antibody', 'cellular_component', 'GO:0019814', ('47', '55'))	('antibody', 'cellular_component', 'GO:0019815', ('47', '55'))	('mice', 'Species', '10090', (97, 101))	('antibody', 'molecular_function', 'GO:0003823', ('47', '55'))	('memory', 'biological_process', 'GO:0007613', ('79', '85'))
97369	33974041	These data indicate that anti-LILRB4 antibody induces tumor antigen-specific immunity in treated mice.	('antibody', 'cellular_component', 'GO:0019815', ('37', '45'))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mice', 'Species', '10090', (97, 101))	('antibody', 'cellular_component', 'GO:0019814', ('37', '45'))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor antigen', 'molecular_function', 'GO:0008222', ('54', '67'))	('antibody', 'molecular_function', 'GO:0003823', ('37', '45'))	('induces', 'PosReg', (46, 53))	('tumor', 'Disease', (54, 59))	('anti-LILRB4', 'Var', (25, 36))	('antibody', 'cellular_component', 'GO:0042571', ('37', '45'))
97379	33974041	Anti-LILRB4 antibody significantly decreased tumor weight compared with isotype control antibody (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('antibody', 'cellular_component', 'GO:0042571', ('12', '20'))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('Anti-LILRB4', 'Var', (0, 11))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('decreased tumor weight', 'Disease', (35, 57))	('antibody', 'cellular_component', 'GO:0019814', ('12', '20'))	('antibody', 'cellular_component', 'GO:0019815', ('12', '20'))	('antibody', 'molecular_function', 'GO:0003823', ('12', '20'))	('decreased tumor weight', 'Disease', 'MESH:D015431', (35, 57))
97383	33974041	There was a significant increase in percentages and population of CD3+ T cell population within tumors in the anti-LILRB4-treated animal group compared with isotype control (Fig.	('increase', 'PosReg', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CD3', 'Gene', (66, 69))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('CD3', 'Gene', '12501', (66, 69))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('anti-LILRB4-treated', 'Var', (110, 129))
97385	33974041	CD8+ T cell percentages and numbers were also elevated within tumors injected with anti-LILRB4 antibody (Fig.	('elevated', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('antibody', 'cellular_component', 'GO:0042571', ('95', '103'))	('tumors', 'Disease', (62, 68))	('anti-LILRB4 antibody', 'Var', (83, 103))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('antibody', 'cellular_component', 'GO:0019815', ('95', '103'))	('CD8', 'Gene', (0, 3))	('antibody', 'cellular_component', 'GO:0019814', ('95', '103'))	('CD8', 'Gene', '925', (0, 3))	('antibody', 'molecular_function', 'GO:0003823', ('95', '103'))
97387	33974041	We found a significant increase in both CD8+ T cell and CD4+ Teff cell to Treg cell ratios within tumor in anti-LILRB4-treated mice (Fig.	('mice', 'Species', '10090', (127, 131))	('CD8', 'Gene', '925', (40, 43))	('rat', 'Species', '10116', (84, 87))	('CD4+ Teff cell to Treg cell ratios', 'CPA', (56, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('increase', 'PosReg', (23, 31))	('tumor', 'Disease', (98, 103))	('anti-LILRB4-treated', 'Var', (107, 126))	('CD8', 'Gene', (40, 43))
97393	33974041	We observed less secretion of IFN-gamma from CD8+ T cells and CD4+ T cells in the presence of WT Treg cells than LILRB4-/- Treg cells, suggesting that LILRB4-/- Treg cells were less suppressive than WT Treg cells (Fig.	('less', 'NegReg', (12, 16))	('IFN-gamma', 'Gene', '15978', (30, 39))	('CD8', 'Gene', (45, 48))	('secretion', 'MPA', (17, 26))	('secretion', 'biological_process', 'GO:0046903', ('17', '26'))	('CD8', 'Gene', '925', (45, 48))	('LILRB4-/-', 'Var', (151, 160))	('IFN-gamma', 'Gene', (30, 39))
97395	33974041	Phenotypic analysis by flow cytometry of TILs from B16/F10-challenged tumor suggests that LILRB4+CD4+ T cells expressed higher surface LAP/TGFbeta compared with LILRB4-CD4+ T cells.	('LAP', 'Gene', '13708', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TGFbeta', 'Gene', (139, 146))	('LAP', 'Gene', (135, 138))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('P', 'Chemical', 'MESH:D010758', (137, 138))	('tumor', 'Disease', (70, 75))	('LILRB4+CD4+ T', 'Var', (90, 103))	('higher', 'PosReg', (120, 126))	('TGFbeta', 'Gene', '21802', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
97397	33974041	We found decreased surface LAP/TGFbeta on LILRB4-/- Treg cells compared with WT Treg cells, and this could be one of the mechanisms of reduced suppressive capability of LILRB4-/- Treg cells compared with WT Treg cells.	('LAP', 'Gene', '13708', (27, 30))	('TGFbeta', 'Gene', '21802', (31, 38))	('reduced', 'NegReg', (135, 142))	('decreased', 'NegReg', (9, 18))	('TGFbeta', 'Gene', (31, 38))	('LILRB4-/-', 'Var', (42, 51))	('LAP', 'Gene', (27, 30))	('suppressive capability', 'CPA', (143, 165))
97400	33974041	We found that WT conventional naive T cells (Tconv cells) secrete more IFN-gamma in the presence of LILRB4-/- macrophages compared with WT macrophages, suggesting that LILRB4-/- bone marrow-derived (BMD) M2-type macrophages are less suppressive than WT BMD M2-type macrophages (Fig.	('secrete', 'MPA', (58, 65))	('IFN-gamma', 'Gene', (71, 80))	('IFN-gamma', 'Gene', '15978', (71, 80))	('LILRB4-/-', 'Var', (168, 177))
97401	33974041	Our RT-PCR analysis of expression of cytokine genes in WT and LILRB4-/- BMD M2-type macrophages suggest an increased expression of IL1b (IL-1beta) and Nos2 (iNOS2) cytokines transcripts in LILRB4-/- M2-type macrophages compared with WT control M2-type macrophages (Fig.	('IL1b', 'Gene', (131, 135))	('IL-1beta', 'Gene', (137, 145))	('Nos2', 'Gene', '18126', (151, 155))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('P', 'Chemical', 'MESH:D010758', (7, 8))	('IL-1beta', 'Gene', '16175', (137, 145))	('IL1b', 'Gene', '16176', (131, 135))	('S', 'Chemical', 'MESH:D013455', (160, 161))	('IL1', 'molecular_function', 'GO:0005149', ('131', '134'))	('LILRB4-/- M2-type', 'Var', (189, 206))	('IL-1', 'molecular_function', 'GO:0005149', ('137', '141'))	('Nos2', 'Gene', (151, 155))
97402	33974041	To understand the mechanisms underlying the anti-LILRB4 antibody-mediated decrease in tumor growth and increase in survival, we analyzed the effects of anti-LILRB4 monoclonal antibody treatment on both intratumoral myeloid and lymphoid cell populations.	('increase', 'PosReg', (103, 111))	('antibody', 'molecular_function', 'GO:0003823', ('175', '183'))	('antibody', 'molecular_function', 'GO:0003823', ('56', '64'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('antibody', 'cellular_component', 'GO:0042571', ('175', '183'))	('antibody', 'cellular_component', 'GO:0042571', ('56', '64'))	('anti-LILRB4', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('rat', 'Species', '10116', (205, 208))	('antibody', 'cellular_component', 'GO:0019815', ('175', '183'))	('antibody', 'cellular_component', 'GO:0019815', ('56', '64'))	('decrease', 'NegReg', (74, 82))	('survival', 'CPA', (115, 123))	('tumor', 'Disease', (207, 212))	('antibody', 'cellular_component', 'GO:0019814', ('175', '183'))	('antibody', 'cellular_component', 'GO:0019814', ('56', '64'))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
97407	33974041	Among monocyte/macrophage clusters, clusters 1, 5, 6, and 12 decreased in frequency after the treatment with anti-LILRB4 monoclonal antibody.	('frequency', 'MPA', (74, 83))	('antibody', 'cellular_component', 'GO:0042571', ('132', '140'))	('antibody', 'cellular_component', 'GO:0019815', ('132', '140'))	('cluster', 'Species', '100569', (36, 43))	('anti-LILRB4', 'Var', (109, 120))	('cluster', 'Species', '100569', (26, 33))	('antibody', 'cellular_component', 'GO:0019814', ('132', '140'))	('antibody', 'molecular_function', 'GO:0003823', ('132', '140'))	('decreased', 'NegReg', (61, 70))
97409	33974041	The expression of Arg-1, CX3CR1, or IDO suggests that macrophage clusters that decrease in frequency with anti-LILRB4 have suppressive phenotypes.	('suppressive phenotypes', 'CPA', (123, 145))	('Arg-1', 'Gene', '11846', (18, 23))	('CX3CR1', 'Gene', (25, 31))	('macrophage clusters', 'CPA', (54, 73))	('Arg-1', 'Gene', (18, 23))	('decrease', 'NegReg', (79, 87))	('IDO', 'molecular_function', 'GO:0033754', ('36', '39'))	('cluster', 'Species', '100569', (65, 72))	('IDO', 'molecular_function', 'GO:0047719', ('36', '39'))	('anti-LILRB4', 'Var', (106, 117))	('CX3CR1', 'Gene', '13051', (25, 31))
97410	33974041	Also, the clusters that were decreased in frequency after anti-LILRB4 antibody had high surface expression of CCR2 and CX3CR1, which are associated with poor prognosis in tumors.	('cluster', 'Species', '100569', (10, 17))	('antibody', 'cellular_component', 'GO:0042571', ('70', '78'))	('CX3CR1', 'Gene', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('antibody', 'Var', (70, 78))	('anti-LILRB4 antibody', 'Var', (58, 78))	('CCR', 'molecular_function', 'GO:0043880', ('110', '113'))	('CCR2', 'Gene', '12772', (110, 114))	('antibody', 'cellular_component', 'GO:0019815', ('70', '78'))	('surface expression', 'MPA', (88, 106))	('antibody', 'cellular_component', 'GO:0019814', ('70', '78'))	('antibody', 'molecular_function', 'GO:0003823', ('70', '78'))	('CX3CR1', 'Gene', '13051', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('CCR2', 'Gene', (110, 114))	('anti-LILRB4', 'Gene', (58, 69))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
97412	33974041	The monocyte/macrophage clusters that were increased after the anti-LILRB4 monoclonal antibody include clusters 7, 8, 10, and 14.	('cluster', 'Species', '100569', (24, 31))	('anti-LILRB4', 'Gene', (63, 74))	('antibody', 'cellular_component', 'GO:0042571', ('86', '94'))	('anti-LILRB4', 'Var', (63, 74))	('cluster', 'Species', '100569', (103, 110))	('antibody', 'cellular_component', 'GO:0019815', ('86', '94'))	('antibody', 'cellular_component', 'GO:0019814', ('86', '94'))	('increased', 'PosReg', (43, 52))	('antibody', 'molecular_function', 'GO:0003823', ('86', '94'))
97414	33974041	Cluster 14 is CD11blow CD11c- CD54+CD103+ CCR2+ Ly6G+ MHCII+ VISTA+ LILRB4low CD14+ CD40+ and expresses very low levels of CD11b in control, and this low CD11b expression goes away after anti-LILRB4 antibody treatment (data not shown).	('antibody', 'cellular_component', 'GO:0019815', ('199', '207'))	('VISTA', 'Gene', (61, 66))	('antibody', 'cellular_component', 'GO:0019814', ('199', '207'))	('antibody', 'molecular_function', 'GO:0003823', ('199', '207'))	('CD11blow', 'Var', (14, 22))	('CCR2', 'Gene', '12772', (42, 46))	('VISTA', 'Gene', '74048', (61, 66))	('antibody', 'cellular_component', 'GO:0042571', ('199', '207'))	('CCR2', 'Gene', (42, 46))	('CCR', 'molecular_function', 'GO:0043880', ('42', '45'))	('Cluster', 'Species', '100569', (0, 7))
97420	33974041	All CD4+ Teff cell clusters increased in frequency after anti-LILRB4 treatment, but only cluster 3 showed statistically significant increase.	('increased', 'PosReg', (28, 37))	('anti-LILRB4', 'Var', (57, 68))	('cluster', 'Species', '100569', (19, 26))	('cluster', 'Species', '100569', (89, 96))	('CD4+ Teff cell clusters', 'CPA', (4, 27))
97424	33974041	Cluster 2 is identified as a PD1+ LAG3+ Tim3+ exhausted CD8+ T cell cluster, and this cluster significantly decreased after anti-LILRB4 treatment.	('cluster', 'Species', '100569', (86, 93))	('cluster', 'Species', '100569', (68, 75))	('anti-LILRB4', 'Var', (124, 135))	('LAG3', 'Gene', '100125962', (34, 38))	('LAG3', 'Gene', (34, 38))	('decreased', 'NegReg', (108, 117))	('P', 'Chemical', 'MESH:D010758', (29, 30))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))	('Cluster', 'Species', '100569', (0, 7))	('Tim3', 'Gene', '171285', (40, 44))	('Tim3', 'Gene', (40, 44))
97429	33974041	These results suggest that treatment of tumors with anti-LILRB4 antibody modulates CD4+ T cells toward a more Th1 effector phenotype.	('antibody', 'cellular_component', 'GO:0019814', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('64', '72'))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('anti-LILRB4', 'Gene', (52, 63))	('anti-LILRB4', 'Var', (52, 63))	('modulates', 'Reg', (73, 82))	('antibody', 'cellular_component', 'GO:0042571', ('64', '72'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('antibody', 'cellular_component', 'GO:0019815', ('64', '72'))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
97435	33974041	Our results, which showed reduced suppressive efficacy of LILRB4-/- M2-type macrophages and increased T cell infiltration in LILRB4-/- tumors, suggest that LILRB4 could be a potential target in cold tumors.	('tumors', 'Disease', (199, 205))	('T cell infiltration', 'CPA', (102, 121))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('cold tumors', 'Disease', 'MESH:D000067390', (194, 205))	('rat', 'Species', '10116', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('reduced', 'NegReg', (26, 33))	('increased', 'PosReg', (92, 101))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('increased T cell', 'Phenotype', 'HP:0100828', (92, 108))	('cold tumors', 'Disease', (194, 205))	('LILRB4-/-', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('suppressive efficacy', 'CPA', (34, 54))
97438	33974041	Combining a checkpoint blockade antibody such as anti-CTLA4 or anti-PD1 with anti-LILRB4, which can have an impact on TAMs, could improve the clinical outcome of such patients.	('improve', 'PosReg', (130, 137))	('antibody', 'cellular_component', 'GO:0042571', ('32', '40'))	('CTLA4', 'Gene', (54, 59))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('anti-PD1', 'Gene', (63, 71))	('patients', 'Species', '9606', (167, 175))	('antibody', 'cellular_component', 'GO:0019815', ('32', '40'))	('TAMs', 'Disease', (118, 122))	('antibody', 'cellular_component', 'GO:0019814', ('32', '40'))	('antibody', 'molecular_function', 'GO:0003823', ('32', '40'))	('clinical outcome', 'CPA', (142, 158))	('anti-LILRB4', 'Var', (77, 88))	('TAMs', 'Chemical', '-', (118, 122))	('CTLA4', 'Gene', '1493', (54, 59))	('impact', 'Reg', (108, 114))
97441	33974041	showed that LILRB4 is expressed on myeloid suppressor cells, and non-small cell lung cancer patients with a higher fraction of LILRB4high subsets in myeloid cells had a shorter median survival compared with the patients with a lower fraction of LILRB4high cells.	('LILRB4high', 'Var', (127, 137))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('patients', 'Species', '9606', (211, 219))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('median', 'MPA', (177, 183))	('patients', 'Species', '9606', (92, 100))	('lung cancer', 'Disease', (80, 91))	('shorter', 'NegReg', (169, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
97493	33974041	These patients were treated at The University of Texas MDACC and had tumor samples collected and analyzed under Institutional Review Board-approved protocols (IRB 2012-0846; 2015-0041; PA13-0291; LAB00-063) and in accordance with the Declaration of Helsinki.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('P', 'Chemical', 'MESH:D010758', (185, 186))	('rat', 'Species', '10116', (239, 242))	('patients', 'Species', '9606', (6, 14))	('PA13-0291', 'Var', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
97545	33974041	S2 shows that LILRB4 is expressed largely on Treg cells, exhausted CD8+ T cells, and CD11b+ TAMs in the B16/F10 tumor model.	('LILRB4', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('CD11b+', 'Var', (85, 91))	('CD8', 'Gene', (67, 70))	('TAMs', 'Chemical', '-', (92, 96))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('CD8', 'Gene', '925', (67, 70))
97547	33974041	S4 shows that tumor-challenged LILRB4-/- mice or WT mice given anti-LILRB4 treatment have reduced tumor burden compared with controls during primary challenge and rechallenge.	('anti-LILRB4', 'Gene', (63, 74))	('tumor', 'Disease', (14, 19))	('reduced', 'NegReg', (90, 97))	('anti-LILRB4', 'Var', (63, 74))	('mice', 'Species', '10090', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('S', 'Chemical', 'MESH:D013455', (0, 1))
97655	31901239	Another explanation was that acral melanoma was reported to have a significantly lower proportion of BRAF mutations than non-acral cutaneous melanoma, and BRAF mutation in melanoma was associated with poor prognosis, which may lead to a better prognosis for acral melanoma in this study.	('acral melanoma', 'Phenotype', 'HP:0012060', (29, 43))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('acral melanoma', 'Disease', 'MESH:D008545', (258, 272))	('acral melanoma', 'Phenotype', 'HP:0012060', (258, 272))	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('BRAF', 'Gene', '673', (101, 105))	('BRAF', 'Gene', (101, 105))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('mutation', 'Var', (160, 168))	('lower', 'NegReg', (81, 86))	('melanoma', 'Disease', (141, 149))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('acral melanoma', 'Disease', (29, 43))	('cutaneous melanoma', 'Disease', (131, 149))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (131, 149))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (131, 149))	('acral cutaneous melanoma', 'Phenotype', 'HP:0012060', (125, 149))	('BRAF', 'Gene', '673', (155, 159))	('acral melanoma', 'Disease', (258, 272))	('melanoma', 'Disease', (35, 43))	('melanoma', 'Disease', (172, 180))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('BRAF', 'Gene', (155, 159))	('acral melanoma', 'Disease', 'MESH:D008545', (29, 43))	('mutations', 'Var', (106, 115))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma', 'Disease', (264, 272))
97666	31235855	However, aberrant migration can also promote diseases such as cancer and metastatic spread.	('promote', 'PosReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('aberrant', 'Var', (9, 17))	('metastatic spread', 'CPA', (73, 90))
97677	31235855	Furthermore, a recent study shows that Ruta graveolens 30CH is able to decrease cell viability and cell migration, by increasing apoptosis of the human colon cancer.	('apoptosis', 'biological_process', 'GO:0097194', ('129', '138'))	('increasing', 'PosReg', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('apoptosis', 'CPA', (129, 138))	('decrease', 'NegReg', (71, 79))	('colon cancer', 'Disease', (152, 164))	('Ruta graveolens', 'Species', '37565', (39, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('129', '138'))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('cell viability', 'CPA', (80, 94))	('human', 'Species', '9606', (146, 151))	('cell migration', 'biological_process', 'GO:0016477', ('99', '113'))	('cell migration', 'CPA', (99, 113))	('Ruta graveolens', 'Var', (39, 54))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))
97687	31235855	Then, the diminution between the control cells and the treated cells outside circles was at 28 and 27.5% for B16F1 and B16F10 cells respectively.	('B16F10', 'Var', (119, 125))	('B16F1', 'CellLine', 'CVCL:0158', (109, 114))	('B16F1', 'CellLine', 'CVCL:0158', (119, 124))	('B16F10', 'CellLine', 'CVCL:0159', (119, 125))	('B16F1', 'Var', (109, 114))
97689	31235855	Under Phenacetinum 4CH treatment, the migratory capacities of B16 cells were significantly reduced by 27% at 510 +- 9 mum for B16F1 cells, and by 31% at 670 +- 18 mum for B16F10 cells.	('Phenacetinum 4CH', 'Chemical', '-', (6, 22))	('B16F1', 'CellLine', 'CVCL:0158', (126, 131))	('migratory capacities of B16 cells', 'CPA', (38, 71))	('reduced', 'NegReg', (91, 98))	('B16F10', 'CellLine', 'CVCL:0159', (171, 177))	('B16', 'CellLine', 'CVCL:N540', (62, 65))	('B16F1', 'CellLine', 'CVCL:0158', (171, 176))	('B16', 'CellLine', 'CVCL:N540', (126, 129))	('B16', 'CellLine', 'CVCL:N540', (171, 174))	('B16F1', 'Var', (126, 131))
97692	31235855	These results confirm that Phenacetinum 4CH decreased the distances of the cell migration by a decrease of the B16 cell migration speeds in a fibronectin context.	('decrease', 'NegReg', (95, 103))	('fibronectin', 'Gene', '14268', (142, 153))	('cell migration', 'biological_process', 'GO:0016477', ('115', '129'))	('cell migration', 'biological_process', 'GO:0016477', ('75', '89'))	('distances of the cell migration', 'CPA', (58, 89))	('fibronectin', 'Gene', (142, 153))	('B16', 'CellLine', 'CVCL:N540', (111, 114))	('B16 cell migration speeds', 'CPA', (111, 136))	('Phenacetinum 4CH', 'Chemical', '-', (27, 43))	('Phenacetinum 4CH', 'Var', (27, 43))	('decreased', 'NegReg', (44, 53))
97693	31235855	Furthermore, we confirmed that the effect of Phenacetinum 4CH specifically acts on cell migration mechanism since we did not find any significant alteration in the cellular viability after 24 h of treatment compared to control cells (Supplementary Fig.	('cell migration', 'CPA', (83, 97))	('cell migration', 'biological_process', 'GO:0016477', ('83', '97'))	('Phenacetinum 4CH', 'Chemical', '-', (45, 61))	('Phenacetinum 4CH', 'Var', (45, 61))
97706	31235855	Phenacetinum 4CH caused a decrease of cell stiffness by factor 9.5 (3.8 +- 1.9 kPa to 0.4 +- 0.2 kPa) for B16F1 cells, and by factor 5.8 (5.9 +- 3.7 kPa to 1.0 +- 0.6 kPa) for B16F10 cells (Fig.	('B16F10', 'CellLine', 'CVCL:0159', (176, 182))	('decrease', 'NegReg', (26, 34))	('cell stiffness', 'CPA', (38, 52))	('Phenacetinum 4CH', 'Chemical', '-', (0, 16))	('B16F1', 'CellLine', 'CVCL:0158', (106, 111))	('Phenacetinum 4CH', 'Var', (0, 16))	('B16F1', 'CellLine', 'CVCL:0158', (176, 181))
97708	31235855	As a conclusion, these results indicate that Phenacetinum 4CH is able to specifically decrease B16 cell stiffness, disturbs the cell polarity, and quickly influences the persistence of the trajectories followed by cells.	('B16 cell stiffness', 'CPA', (95, 113))	('Phenacetinum 4CH', 'Chemical', '-', (45, 61))	('disturbs', 'Reg', (115, 123))	('influences', 'Reg', (155, 165))	('cell polarity', 'CPA', (128, 141))	('B16', 'CellLine', 'CVCL:N540', (95, 98))	('persistence of the trajectories followed by cells', 'CPA', (170, 219))	('Phenacetinum 4CH', 'Var', (45, 61))	('cell polarity', 'biological_process', 'GO:0007163', ('128', '141'))	('decrease', 'NegReg', (86, 94))
97712	31235855	Finally, the control cells exhibited mainly an actin cytoskeleton network with stress fibers highly organized (white arrows) and on the contrary, treated cells with Phenacetinum 4CH induced an important disintegration of actin cytoskeleton network.	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('47', '65'))	('disintegration', 'MPA', (203, 217))	('actin cytoskeleton network', 'MPA', (221, 247))	('Phenacetinum 4CH', 'Chemical', '-', (165, 181))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('221', '239'))	('Phenacetinum 4CH', 'Var', (165, 181))
97718	31235855	These results demonstrate that Phenacetinum 4CH causes an increase of the actin network destruction and disorganization of B16 cells on fibronectin, while this being known to play a crucial role in cell migration.	('actin', 'MPA', (74, 79))	('increase', 'PosReg', (58, 66))	('fibronectin', 'Gene', '14268', (136, 147))	('cell migration', 'biological_process', 'GO:0016477', ('198', '212'))	('Phenacetinum 4CH', 'Chemical', '-', (31, 47))	('Phenacetinum 4CH', 'Var', (31, 47))	('fibronectin', 'Gene', (136, 147))	('disorganization', 'CPA', (104, 119))	('B16', 'CellLine', 'CVCL:N540', (123, 126))
97730	31235855	Phenacetin formed hydrogen bonds with lipid head groups, mainly glycerol, and was also able to form hydrogen bonds with itself (Table 1).	('glycerol', 'Chemical', 'MESH:D005990', (64, 72))	('glycerol', 'MPA', (64, 72))	('hydrogen bonds', 'Interaction', (18, 32))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('Phenacetin', 'Var', (0, 10))	('hydrogen', 'Chemical', 'MESH:D006859', (100, 108))	('hydrogen', 'Chemical', 'MESH:D006859', (18, 26))	('Phenacetin', 'Chemical', 'MESH:D010615', (0, 10))
97732	31235855	In order to investigate the benefits gained from the Phenacetinum 4CH mechanistic effect on B16 cells and on basis previous MD information, we studied its action on the phospholipid organization contained in the plasma membrane of cells plated on fibronectin.	('Phenacetinum 4CH', 'Chemical', '-', (53, 69))	('Phenacetinum', 'Var', (53, 65))	('fibronectin', 'Gene', '14268', (247, 258))	('B16', 'CellLine', 'CVCL:N540', (92, 95))	('fibronectin', 'Gene', (247, 258))	('phospholipid', 'Chemical', 'MESH:D010743', (169, 181))	('plasma membrane', 'cellular_component', 'GO:0005886', ('212', '227'))
97736	31235855	Homeopathic drug treatment causes an increase of GP values of 0.01 +- 0.03 and -0.37 +- 0.02 for B16F1 and B16F10 respectively.	('B16F1', 'CellLine', 'CVCL:0158', (107, 112))	('B16F10', 'CellLine', 'CVCL:0159', (107, 113))	('B16F1', 'CellLine', 'CVCL:0158', (97, 102))	('B16F1', 'Var', (97, 102))	('GP values', 'MPA', (49, 58))	('increase', 'PosReg', (37, 45))	('B16F10', 'Var', (107, 113))
97737	31235855	To conclude, Phenacetinum 4CH induces a 27% shift in B16F10 cells and 18% in B16F1 cells to increase their membrane stiffness on fibronectin and after 1 h of treatment (Fig.	('membrane', 'cellular_component', 'GO:0016020', ('107', '115'))	('Phenacetinum 4CH', 'Chemical', '-', (13, 29))	('B16F1', 'CellLine', 'CVCL:0158', (53, 58))	('B16F1', 'CellLine', 'CVCL:0158', (77, 82))	('fibronectin', 'Gene', '14268', (129, 140))	('B16F10', 'CellLine', 'CVCL:0159', (53, 59))	('increase', 'PosReg', (92, 100))	('Phenacetinum 4CH', 'Var', (13, 29))	('fibronectin', 'Gene', (129, 140))
97750	31235855	Interestingly the lack of effect of Phenacetinum 4CH on key parameters of MEFs cells, such as cell migration and cell stiffness, strongly confirms its specific action on cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('MEFs', 'CellLine', 'CVCL:9115', (74, 78))	('cancer', 'Disease', (170, 176))	('Phenacetinum 4CH', 'Var', (36, 52))	('cell migration', 'CPA', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cell migration', 'biological_process', 'GO:0016477', ('94', '108'))	('Phenacetinum 4CH', 'Chemical', '-', (36, 52))
97751	31235855	Our data showed that under Phenacetinum 4CH treatment, the development of membrane protrusions was anarchic, which reduced quickly and sustainably the dispersed cell migration.	('dispersed cell migration', 'CPA', (151, 175))	('membrane', 'cellular_component', 'GO:0016020', ('74', '82'))	('reduced', 'NegReg', (115, 122))	('Phenacetinum 4CH', 'Chemical', '-', (27, 43))	('Phenacetinum', 'Var', (27, 39))	('cell migration', 'biological_process', 'GO:0016477', ('161', '175'))
97752	31235855	Finally, we considered that reinforced by MD simulations, Phenacetinum 4CH upset the lipid membrane organization in increasing Lo domains.	('lipid membrane organization', 'MPA', (85, 112))	('upset', 'Reg', (75, 80))	('membrane', 'cellular_component', 'GO:0016020', ('91', '99'))	('lipid', 'Chemical', 'MESH:D008055', (85, 90))	('increasing', 'PosReg', (116, 126))	('membrane organization', 'biological_process', 'GO:0061024', ('91', '112'))	('Phenacetinum 4CH', 'Chemical', '-', (58, 74))	('Phenacetinum 4CH', 'Var', (58, 74))	('Lo domains', 'MPA', (127, 137))
97758	31235855	Based on this knowledge, we suggest that Phenacetinum 4CH may increase the rigidity of the plasma membrane, involving probably an elevation of cholesterol level.	('rigidity', 'Disease', 'MESH:D009127', (75, 83))	('elevation', 'PosReg', (130, 139))	('elevation of cholesterol', 'Phenotype', 'HP:0003124', (130, 154))	('cholesterol', 'Chemical', 'MESH:D002784', (143, 154))	('plasma membrane', 'cellular_component', 'GO:0005886', ('91', '106'))	('Phenacetinum 4CH', 'Chemical', '-', (41, 57))	('Phenacetinum 4CH', 'Var', (41, 57))	('cholesterol level', 'MPA', (143, 160))	('rigidity', 'Disease', (75, 83))	('rigidity', 'Phenotype', 'HP:0002063', (75, 83))	('increase', 'PosReg', (62, 70))
97767	31235855	Also, thanks to the greatly reduced complexity of the lipid membrane structure construction, these MD simulations data allowed us to consolidate the previous results indicating that Phenacetinum 4CH could get into biological membranes and increase the membrane rigidity through the accumulation of Lo phases.	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('rigidity', 'Disease', (261, 269))	('rigidity', 'Phenotype', 'HP:0002063', (261, 269))	('Phenacetinum 4CH', 'Chemical', '-', (182, 198))	('Lo phases', 'CPA', (298, 307))	('membrane', 'cellular_component', 'GO:0016020', ('60', '68'))	('rigidity', 'Disease', 'MESH:D009127', (261, 269))	('increase', 'PosReg', (239, 247))	('Phenacetinum 4CH', 'Var', (182, 198))	('membrane', 'cellular_component', 'GO:0016020', ('252', '260'))
97775	31235855	Using the highly sensitive and spatial resolution of AFM approach, our results on cell mechanical properties reveal that after 1 h, Phenacetinum 4CH induces a strong reduction of B16 cell stiffness.	('B16', 'CellLine', 'CVCL:N540', (179, 182))	('reduction', 'NegReg', (166, 175))	('B16 cell stiffness', 'CPA', (179, 197))	('Phenacetinum 4CH', 'Chemical', '-', (132, 148))	('Phenacetinum 4CH', 'Var', (132, 148))
97777	31235855	In that way, the rapid increase of cell fluidity induced by Phenacetinum 4CH directly reflects a perturbation of the structure and/or function of the underlying actin cytoskeleton that may result in a reduction of membrane-cytoskeleton adhesion.	('cytoskeleton', 'cellular_component', 'GO:0005856', ('223', '235'))	('reduction', 'NegReg', (201, 210))	('Phenacetinum 4CH', 'Chemical', '-', (60, 76))	('Phenacetinum 4CH', 'Var', (60, 76))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('161', '179'))	('increase', 'PosReg', (23, 31))	('membrane', 'cellular_component', 'GO:0016020', ('214', '222'))	('cell', 'MPA', (35, 39))	('membrane-cytoskeleton adhesion', 'MPA', (214, 244))
97779	31235855	On the contrary, our present results demonstrated that Phenacetinum 4CH was able to impede the polarity of B16 cells by the development of many peripheral lamellae, which increase the cell circularity.	('increase', 'PosReg', (171, 179))	('B16', 'CellLine', 'CVCL:N540', (107, 110))	('impede', 'NegReg', (84, 90))	('polarity of B16 cells', 'CPA', (95, 116))	('Phenacetinum 4CH', 'Chemical', '-', (55, 71))	('Phenacetinum 4CH', 'Var', (55, 71))	('cell circularity', 'CPA', (184, 200))
97783	31235855	Similarly, another study also demonstrated the importance of cholesterol in membrane-cytoskeletal dynamic, since cholesterol depletion results in Src kinase-mediated Rho activation and stress fibers formation.	('activation', 'PosReg', (170, 180))	('cholesterol', 'Chemical', 'MESH:D002784', (61, 72))	('membrane', 'cellular_component', 'GO:0016020', ('76', '84'))	('cholesterol', 'Chemical', 'MESH:D002784', (113, 124))	('stress fibers formation', 'CPA', (185, 208))	('cholesterol depletion', 'Var', (113, 134))	('formation', 'biological_process', 'GO:0009058', ('199', '208'))	('Src kinase-mediated Rho', 'Pathway', (146, 169))
97786	31235855	In conclusion, our results propose that Phenacetinum 4CH influences protrusion and retraction processes, limiting the capacity of single cell to cover local distance.	('Phenacetinum 4CH', 'Chemical', '-', (40, 56))	('Phenacetinum 4CH', 'Var', (40, 56))	('retraction processes', 'CPA', (83, 103))	('limiting', 'NegReg', (105, 113))	('influences', 'Reg', (57, 67))	('protrusion', 'CPA', (68, 78))
97788	31235855	Indeed, the likely insertion of Phenacetinum 4CH into the plasma membrane of B16 cells, strongly comforted by MD simulations, appears to disturb their organization as evidenced by an increase of Lo phases.	('organization', 'MPA', (151, 163))	('Phenacetinum 4CH', 'Var', (32, 48))	('increase', 'PosReg', (183, 191))	('Lo phases', 'CPA', (195, 204))	('disturb', 'NegReg', (137, 144))	('B16', 'CellLine', 'CVCL:N540', (77, 80))	('plasma membrane', 'cellular_component', 'GO:0005886', ('58', '73'))	('Phenacetinum 4CH', 'Chemical', '-', (32, 48))	('insertion', 'Var', (19, 28))
97813	31235855	B16F1 and B16F10 were plated at low density onto plastic LabTek (Nunc, Dutscher, France) previously coated with 7 mug/mL of fibronectin for 12 h at 4  C and blocked with 1% BSA.	('B16F10', 'CellLine', 'CVCL:0159', (10, 16))	('fibronectin', 'Gene', (124, 135))	('B16F10', 'Var', (10, 16))	('mug', 'molecular_function', 'GO:0043739', ('114', '117'))	('B16F1', 'CellLine', 'CVCL:0158', (0, 5))	('B16F1', 'CellLine', 'CVCL:0158', (10, 15))	('fibronectin', 'Gene', '14268', (124, 135))
97822	31235855	B16F1 and B16F10 were plated at low density onto a cell culture dish (35 mm diameter, FluoroDish WPI), previously coated with 7 mug/mL fibronectin for 12 h at 4  C and blocked with 1% BSA.	('B16F10', 'CellLine', 'CVCL:0159', (10, 16))	('fibronectin', 'Gene', '14268', (135, 146))	('fibronectin', 'Gene', (135, 146))	('B16F10', 'Var', (10, 16))	('B16F1', 'CellLine', 'CVCL:0158', (0, 5))	('B16F1', 'CellLine', 'CVCL:0158', (10, 15))	('mug', 'molecular_function', 'GO:0043739', ('128', '131'))
97843	32054078	During the past decade, systemic treatment for melanoma has enormously changed as knowledge of the key driver mutations and pathways of tumor cells have led to the development of new therapeutic options.	('mutations', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('tumor', 'Disease', (136, 141))
97853	32054078	BRAF mutations are more frequent in melanomas that develop in sun-exposed skin.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('mutations', 'Var', (5, 14))	('melanomas', 'Disease', 'MESH:D008545', (36, 45))	('melanomas', 'Phenotype', 'HP:0002861', (36, 45))	('BRAF', 'Gene', (0, 4))	('frequent', 'Reg', (24, 32))	('melanomas', 'Disease', (36, 45))
97854	32054078	About 50% of CMM harbor an activating mutation of the BRAF gene that consists in the substitution of a single nucleotide in codon 600.	('BRAF', 'Gene', (54, 58))	('CMM', 'Disease', (13, 16))	('CMM', 'Disease', 'MESH:C562393', (13, 16))	('activating', 'PosReg', (27, 37))	('CMM', 'Phenotype', 'HP:0012056', (13, 16))	('substitution', 'Var', (85, 97))
97855	32054078	The most common mutation is the result of a substitution of glutamic acid for valine in codon 600 (BRAFV600E), which occurs in approximately 90% of BRAF-mutant melanomas.	('melanomas', 'Disease', 'MESH:D008545', (160, 169))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('substitution', 'Var', (44, 56))	('melanomas', 'Phenotype', 'HP:0002861', (160, 169))	('melanomas', 'Disease', (160, 169))	('glutamic acid for valine in codon 600', 'Mutation', 'rs113488022', (60, 97))	('BRAFV600E', 'Mutation', 'rs113488022', (99, 108))
97856	32054078	The second most common mutation is BRAFV600K (substituting valine for lysine), which accounts for 5%-6% of BRAF-mutant melanomas.	('BRAFV600K', 'Var', (35, 44))	('valine', 'Chemical', 'MESH:D014633', (59, 65))	('melanomas', 'Disease', (119, 128))	('lysine', 'Chemical', 'MESH:D008239', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('BRAF-mutant', 'Gene', (107, 118))	('melanomas', 'Phenotype', 'HP:0002861', (119, 128))	('melanomas', 'Disease', 'MESH:D008545', (119, 128))	('BRAFV600K', 'Mutation', 'rs121913227', (35, 44))
97857	32054078	Different clinical characteristics (i.e., gender, age) have been reported between patients with BRAF p.V600E and p.V600K mutation.	('clinical', 'Species', '191496', (10, 18))	('patients', 'Species', '9606', (82, 90))	('p.V600E', 'Var', (101, 108))	('BRAF', 'Gene', (96, 100))	('p.V600K', 'Var', (113, 120))	('p.V600K', 'Mutation', 'rs121913227', (113, 120))	('p.V600E', 'Mutation', 'rs113488022', (101, 108))
97865	32054078	NRAS and BRAF mutations are usually mutually exclusive in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('BRAF', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (0, 4))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('mutations', 'Var', (14, 23))	('melanoma', 'Disease', (58, 66))
97868	32054078	Mutations in NRAS favor the formation of GTP-bound, activating RAS proteins.	('GTP-bound', 'MPA', (41, 50))	('GTP', 'Chemical', 'MESH:D006160', (41, 44))	('activating', 'MPA', (52, 62))	('RAS proteins', 'Protein', (63, 75))	('formation', 'MPA', (28, 37))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('formation', 'biological_process', 'GO:0009058', ('28', '37'))	('NRAS', 'Gene', '4893', (13, 17))	('favor', 'PosReg', (18, 23))
97870	32054078	However, to date, direct pharmacological inhibition of mutant RAS proteins is difficult because of their very tight binding to GDP/GTP.	('GDP', 'Chemical', 'MESH:D006153', (127, 130))	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('binding', 'Interaction', (116, 123))	('mutant', 'Var', (55, 61))	('RAS proteins', 'Protein', (62, 74))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))
97878	32054078	The most common c-KIT mutations in melanoma are L676P and K642E.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('K642E', 'Var', (58, 63))	('K642E', 'Mutation', 'rs121913512', (58, 63))	('L676P', 'Var', (48, 53))	('c-KIT', 'Gene', (16, 21))	('L676P', 'Mutation', 'p.L676P', (48, 53))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('KIT', 'molecular_function', 'GO:0005020', ('18', '21'))	('melanoma', 'Disease', (35, 43))	('c-KIT', 'Gene', '3815', (16, 21))
97883	32054078	NF1 mutations are present in <15% of melanoma cases and may be present together with NRAS/BRAF mutations.	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('NRAS', 'Gene', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('NRAS', 'Gene', '4893', (85, 89))	('NF1', 'Gene', '4763', (0, 3))
97890	32054078	Inhibition of MCL-1 through miR-32 may be an effective anti-melanoma strategy, regardless of the status of NRAS, BRAF or PTEN, as MCL-1 inhibition exhibits synergistic effects with Vemurafenib.	('MCL-1', 'Gene', '4170', (14, 19))	('MCL-1', 'Gene', (14, 19))	('PTEN', 'Gene', (121, 125))	('rat', 'Species', '10116', (71, 74))	('PTEN', 'Gene', '5728', (121, 125))	('miR-32', 'Gene', '407036', (28, 34))	('NRAS', 'Gene', '4893', (107, 111))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (181, 192))	('melanoma', 'Disease', (60, 68))	('miR-32', 'Gene', (28, 34))	('Inhibition', 'Var', (0, 10))	('MCL-1', 'Gene', '4170', (130, 135))	('MCL-1', 'Gene', (130, 135))	('NRAS', 'Gene', (107, 111))
97903	32054078	Reduction of miR-200c increases Bmi-1 expression, which in turn leads to the activation of the PI3K/AKT and MAPK pathways and the acquisition of features seen in EMT, such as downregulation of E-cadherin and upregulation of N-cadherin, ABCG5, and MDR1.	('Bmi-1', 'Gene', '648', (32, 37))	('MAPK', 'Gene', '5594', (108, 112))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('EMT', 'biological_process', 'GO:0001837', ('162', '165'))	('upregulation', 'PosReg', (208, 220))	('miR-200c', 'Gene', (13, 21))	('increases Bmi', 'Phenotype', 'HP:0031418', (22, 35))	('AKT', 'Gene', (100, 103))	('MDR1', 'Gene', (247, 251))	('Bmi-1', 'Gene', (32, 37))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('expression', 'MPA', (38, 48))	('E-cadherin', 'Gene', (193, 203))	('E-cadherin', 'Gene', '999', (193, 203))	('N-cadherin', 'Gene', (224, 234))	('AKT', 'Gene', '207', (100, 103))	('N-cadherin', 'Gene', '1000', (224, 234))	('downregulation', 'NegReg', (175, 189))	('activation', 'PosReg', (77, 87))	('ABCG5', 'Gene', (236, 241))	('cadherin', 'molecular_function', 'GO:0008014', ('226', '234'))	('MAPK', 'Gene', (108, 112))	('ABCG5', 'Gene', '64240', (236, 241))	('MDR', 'molecular_function', 'GO:0004745', ('247', '250'))	('MDR1', 'Gene', '5243', (247, 251))	('miR-200c', 'Gene', '406985', (13, 21))	('increases', 'PosReg', (22, 31))	('Reduction', 'Var', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))
97905	32054078	Restoration of miR-200c expression or knockdown of Bmi-1 in resistant melanoma cells potentiates the effect of MAPK pathway inhibitory drugs and impairs the establishment of resistance, thus suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance.	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('effect of', 'MPA', (101, 110))	('Restoration', 'Var', (0, 11))	('miR-200c', 'Gene', (15, 23))	('BRAFi', 'Chemical', '-', (269, 274))	('MAPK', 'molecular_function', 'GO:0004707', ('111', '115'))	('knockdown', 'Var', (38, 47))	('miR-200c', 'Gene', '406985', (202, 210))	('potentiates', 'PosReg', (85, 96))	('impairs', 'NegReg', (145, 152))	('miR-200c', 'Gene', (202, 210))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('establishment of resistance', 'MPA', (157, 184))	('rat', 'Species', '10116', (5, 8))	('MAPK', 'Gene', (111, 115))	('Bmi-1', 'Gene', '648', (51, 56))	('miR-200c', 'Gene', '406985', (15, 23))	('MAPK', 'Gene', '5594', (111, 115))	('Bmi-1', 'Gene', (51, 56))
97915	32054078	Antisense-mediated knockdown of miR-21 has been shown to suppress growth, increase apoptosis, and enhance the chemo- or radio-sensitivity of cutaneous melanoma cells.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('enhance', 'PosReg', (98, 105))	('growth', 'CPA', (66, 72))	('cutaneous melanoma', 'Disease', (141, 159))	('knockdown', 'Var', (19, 28))	('miR-21', 'Gene', '406991', (32, 38))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (141, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('increase', 'PosReg', (74, 82))	('suppress', 'NegReg', (57, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('Antisense-mediated', 'Var', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('miR-21', 'Gene', (32, 38))	('apoptosis', 'CPA', (83, 92))
97924	32054078	In particular, the adaptative cell response to BRAF inhibitors increases expression of RTK and RTK ligands such as the chemokine monocyte chemoattractant protein-1 (CCL-2), which in turn activates the expression of miR-34a, miR-100, and miR-125b.	('increases', 'PosReg', (63, 72))	('CCL-2', 'Gene', '6347', (165, 170))	('expression', 'MPA', (201, 211))	('miR-100', 'Gene', (224, 231))	('CCL-2', 'Gene', (165, 170))	('miR-34a', 'Gene', '407040', (215, 222))	('activates', 'PosReg', (187, 196))	('miR-125b', 'Gene', (237, 245))	('miR-34a', 'Gene', (215, 222))	('expression', 'MPA', (73, 83))	('CCL', 'molecular_function', 'GO:0044101', ('165', '168'))	('miR-100', 'Gene', '406892', (224, 231))	('protein', 'cellular_component', 'GO:0003675', ('154', '161'))	('inhibitors', 'Var', (52, 62))	('miR-125b', 'Chemical', '-', (237, 245))
97926	32054078	Inhibition of CCL2 and of these miRNAs restores both cell apoptosis and drug efficacy in resistant melanoma cells.	('drug efficacy', 'CPA', (72, 85))	('miR', 'Gene', (32, 35))	('restores', 'PosReg', (39, 47))	('cell apoptosis', 'CPA', (53, 67))	('CCL2', 'Gene', (14, 18))	('CCL', 'molecular_function', 'GO:0044101', ('14', '17'))	('apoptosis', 'biological_process', 'GO:0097194', ('58', '67'))	('apoptosis', 'biological_process', 'GO:0006915', ('58', '67'))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('Inhibition', 'Var', (0, 10))	('melanoma', 'Disease', (99, 107))	('CCL2', 'Gene', '6347', (14, 18))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('miR', 'Gene', '220972', (32, 35))
97928	32054078	mir-514a has been reported to be involved in the modulation of BRAFi sensitivity in melanoma cells.	('BRAFi sensitivity', 'Gene', (63, 80))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('mir-514a', 'Var', (0, 8))	('BRAFi', 'Chemical', '-', (63, 68))
97931	32054078	Both NF1 direct silencing with siRNA and miR-514a upregulation lead to decreased NF1 levels and thus considerably reduce drug sensitivity in the short term in vitro cell proliferation assays.	('drug sensitivity', 'Phenotype', 'HP:0020174', (121, 137))	('drug sensitivity', 'MPA', (121, 137))	('rat', 'Species', '10116', (177, 180))	('NF1', 'Gene', (5, 8))	('cell proliferation', 'biological_process', 'GO:0008283', ('165', '183'))	('NF1', 'Gene', (81, 84))	('upregulation', 'PosReg', (50, 62))	('miR', 'Gene', '220972', (41, 44))	('NF1', 'Gene', '4763', (5, 8))	('miR', 'Gene', (41, 44))	('NF1', 'Gene', '4763', (81, 84))	('direct', 'Var', (9, 15))	('reduce', 'NegReg', (114, 120))	('decreased', 'NegReg', (71, 80))
97941	32054078	Antibodies against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed cell Death 1 (PD-1) (Ipilimumab and Nivolumab/Pembrolizumab, respectively) were the first agents to be approved by the FDA.	('Programmed cell Death 1 (PD-1', 'Gene', '5133', (65, 94))	('Lymphocyte Antigen', 'molecular_function', 'GO:0005557', ('31', '49'))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (97, 107))	('Cytotoxic T-Lymphocyte Antigen 4', 'Gene', '1493', (19, 51))	('Antibodies', 'Var', (0, 10))	('Nivolumab', 'Chemical', 'MESH:D000077594', (112, 121))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (122, 135))	('CTLA-4', 'Gene', (53, 59))	('Cytotoxic T-Lymphocyte Antigen 4', 'Gene', (19, 51))	('Programmed cell Death', 'biological_process', 'GO:0012501', ('65', '86'))
97944	32054078	Based on the results of clinical trials, anti-PD1 antibodies have shown the highest efficacy in melanoma.	('clinical', 'Species', '191496', (24, 32))	('anti-PD1', 'Var', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
97993	32054078	miR-155 is able to induce MDSCs recruitment in TME, inhibiting SOCS1.	('SOCS1', 'Gene', (63, 68))	('inhibiting', 'NegReg', (52, 62))	('SOCS1', 'Gene', '8651', (63, 68))	('MDSCs recruitment', 'MPA', (26, 43))	('miR-155', 'Var', (0, 7))
98051	23303902	When NRASG12D was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi, but did not induce cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (192, 210))	('blue nevi', 'Phenotype', 'HP:0100814', (162, 171))	('congenital melanocytic lesions', 'Disease', (110, 140))	('congenital melanocytic lesions', 'Disease', 'MESH:C536819', (110, 140))	('melanocyte proliferation', 'CPA', (81, 105))	('G12D', 'Mutation', 'rs121913529', (9, 13))	('congenital melanocytic lesions', 'Phenotype', 'HP:0100814', (110, 140))	('induced', 'PosReg', (73, 80))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('81', '105'))	('nevi', 'Phenotype', 'HP:0003764', (167, 171))	('NRASG12D', 'Var', (5, 13))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('human', 'Species', '9606', (156, 161))	('cutaneous melanoma', 'Disease', (192, 210))
98054	23303902	NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS.	('melanoma of the CNS', 'Disease', 'MESH:D008545', (48, 67))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (48, 67))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (114, 133))	('primary', 'Disease', (106, 113))	('NRAS', 'Gene', (192, 196))	('mutations', 'Var', (179, 188))	('melanoma of the CNS', 'Disease', (48, 67))	('children', 'Species', '9606', (137, 145))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (114, 133))	('melanoma of the CNS', 'Disease', (114, 133))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
98055	23303902	We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor to primary melanoma of the CNS in children and present a mouse model of this disease.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('mouse', 'Species', '10090', (164, 169))	('children', 'Species', '9606', (141, 149))	('NRAS', 'Gene', (53, 57))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (118, 137))	('risk factor', 'Reg', (95, 106))	('mutations', 'Var', (40, 49))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (118, 137))	('melanoma of the CNS', 'Disease', (118, 137))
98061	23303902	BRAF and NRAS are mutated in ~45% and ~20% respectively of cutaneous melanomas.	('mutated', 'Var', (18, 25))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (59, 78))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('NRAS', 'Gene', (9, 13))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (59, 78))	('cutaneous melanomas', 'Disease', (59, 78))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanomas', 'Phenotype', 'HP:0002861', (69, 78))
98062	23303902	By contrast, in acral melanoma, BRAF mutations occur in only ~16% of cases, NRAS mutations are absent or very rare, and KIT mutations occur in ~20% of patients.	('acral melanoma', 'Phenotype', 'HP:0012060', (16, 30))	('NRAS', 'Gene', (76, 80))	('acral melanoma', 'Disease', (16, 30))	('BRAF', 'Gene', (32, 36))	('patients', 'Species', '9606', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('mutations', 'Var', (37, 46))	('KIT', 'molecular_function', 'GO:0005020', ('120', '123'))	('acral melanoma', 'Disease', 'MESH:D008545', (16, 30))
98063	23303902	Furthermore, in uveal melanomas BRAF, NRAS and KIT mutations appear to be extremely rare and instead this disease is driven by mutations in GNAQ, GNA11 and BAP1.	('mutations', 'Var', (51, 60))	('uveal melanomas BRAF', 'Disease', (16, 36))	('BAP1', 'Gene', (156, 160))	('BAP1', 'Gene', '104416', (156, 160))	('KIT', 'molecular_function', 'GO:0005020', ('47', '50'))	('NRAS', 'Gene', (38, 42))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('GNAQ', 'Gene', (140, 144))	('driven by', 'Reg', (117, 126))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('GNAQ', 'Gene', '14682', (140, 144))	('melanomas', 'Phenotype', 'HP:0002861', (22, 31))	('KIT', 'Gene', (47, 50))	('uveal melanomas BRAF', 'Disease', 'MESH:C536494', (16, 36))	('mutations', 'Var', (127, 136))	('uveal melanomas', 'Phenotype', 'HP:0007716', (16, 31))	('GNA11', 'Gene', (146, 151))	('GNA11', 'Gene', '14672', (146, 151))
98068	23303902	However, it was recently reported that the adult disease is associated with mutations in GNAQ and GNA11, and in one case, NRAS.	('adult disease', 'Disease', (43, 56))	('mutations', 'Var', (76, 85))	('GNA11', 'Gene', (98, 103))	('GNA11', 'Gene', '14672', (98, 103))	('GNAQ', 'Gene', '14682', (89, 93))	('GNAQ', 'Gene', (89, 93))	('NRAS', 'Disease', (122, 126))	('associated', 'Reg', (60, 70))
98071	23303902	In adult mice, BRAFV600E induced skin darkening at 2 months, blue nevus-like lesions at 4 months, and melanoma in ~80% of the animals within 2 years.	('nevus', 'Phenotype', 'HP:0003764', (66, 71))	('blue nevus-like lesions', 'CPA', (61, 84))	('BRAFV600E', 'Var', (15, 24))	('BRAFV600E', 'Mutation', 'rs113488022', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('skin darkening', 'CPA', (33, 47))	('blue nevus', 'Phenotype', 'HP:0100814', (61, 71))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('mice', 'Species', '10090', (9, 13))	('skin darkening', 'Phenotype', 'HP:0000953', (33, 47))
98072	23303902	In contrast, when BRAFV600E was expressed in the melanocytes of developing embryos (congenital expression), it induced developmental abnormalities and embryonic lethality.	('induced', 'Reg', (111, 118))	('BRAFV600E', 'Var', (18, 27))	('BRAFV600E', 'Mutation', 'rs113488022', (18, 27))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (119, 146))	('embryonic lethality', 'Disease', 'MESH:D020964', (151, 170))	('embryonic lethality', 'Disease', (151, 170))	('developmental abnormalities', 'Disease', (119, 146))	('developmental abnormalities', 'Disease', 'MESH:D006130', (119, 146))
98074	23303902	We found that expression of NRASG12D in the melanocytes of adult mice induced skin darkening and blue nevus-like lesions, but not cutaneous melanoma.	('expression', 'Var', (14, 24))	('blue nevus-like lesions', 'CPA', (97, 120))	('skin darkening', 'Phenotype', 'HP:0000953', (78, 92))	('induced', 'Reg', (70, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (130, 148))	('G12D', 'Mutation', 'rs121913529', (32, 36))	('blue nevus', 'Phenotype', 'HP:0100814', (97, 107))	('mice', 'Species', '10090', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('nevus', 'Phenotype', 'HP:0003764', (102, 107))	('cutaneous melanoma', 'Disease', (130, 148))	('skin darkening', 'CPA', (78, 92))	('NRASG12D', 'Gene', (28, 36))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (130, 148))
98075	23303902	Expression of NRASG12D in the melanocytes of embryonic mice also induced skin darkening and congenital blue nevus-like lesions, but again, it did not induce cutaneous melanoma.	('cutaneous melanoma', 'Disease', (157, 175))	('G12D', 'Mutation', 'rs121913529', (18, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (157, 175))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (157, 175))	('nevus', 'Phenotype', 'HP:0003764', (108, 113))	('NRASG12D', 'Var', (14, 22))	('skin darkening', 'CPA', (73, 87))	('mice', 'Species', '10090', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('skin darkening', 'Phenotype', 'HP:0000953', (73, 87))	('induced', 'Reg', (65, 72))	('congenital blue nevus-like', 'Disease', (92, 118))	('blue nevus', 'Phenotype', 'HP:0100814', (103, 113))
98076	23303902	However, when it was expressed in congenital nevi, NRASG12D induced melanoma of the CNS and critically, the course of the disease in these mice closely resembled the course of disease in two children who developed melanoma of the CNS driven by oncogenic NRAS.	('melanoma of the CNS', 'Disease', (214, 233))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (214, 233))	('induced', 'Reg', (60, 67))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (68, 87))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('NRASG12D', 'Var', (51, 59))	('melanoma of the CNS', 'Disease', (68, 87))	('children', 'Species', '9606', (191, 199))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (214, 233))	('mice', 'Species', '10090', (139, 143))	('nevi', 'Phenotype', 'HP:0003764', (45, 49))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (68, 87))	('G12D', 'Mutation', 'rs121913529', (55, 59))
98078	23303902	To develop NRAS-driven melanoma models, we expressed NRASG12D at physiological levels in mouse melanocytes.	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('melanoma', 'Disease', (23, 31))	('G12D', 'Mutation', 'rs121913529', (57, 61))	('melanoma', 'Disease', 'MESH:D008545', (23, 31))	('NRASG12D', 'Var', (53, 61))	('mouse', 'Species', '10090', (89, 94))
98086	23303902	However, despite this clear evidence that NRASG12D drives melanocyte proliferation, none of the mice developed tumors even after 24-months of expression (Supplementary Fig.	('mice', 'Species', '10090', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('G12D', 'Mutation', 'rs121913529', (46, 50))	('NRASG12D', 'Var', (42, 50))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('58', '82'))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('melanocyte proliferation', 'CPA', (58, 82))
98089	23303902	We previously reported that expression of BRAFV600E in embryonic melanocytes caused hydrocephaly, disruption to the development of the eyes and hearts, and embryonic lethality.	('embryonic lethality', 'Disease', (156, 175))	('BRAFV600E', 'Var', (42, 51))	('BRAFV600E', 'Mutation', 'rs113488022', (42, 51))	('hydrocephaly', 'Phenotype', 'HP:0000238', (84, 96))	('disruption', 'CPA', (98, 108))	('hydrocephaly', 'Disease', 'MESH:D006849', (84, 96))	('caused', 'Reg', (77, 83))	('hydrocephaly', 'Disease', (84, 96))	('embryonic lethality', 'Disease', 'MESH:D020964', (156, 175))
98090	23303902	We were therefore intrigued that live-born Nras+/LSL-G12D;Tyr::CreA/  and NrasLSL-G12D/LSL-G12D;Tyr::CreA/  offspring were obtained at the expected ratio and did not present any signs of hydrocephaly (Fig 1B), or developmental abnormalities of the eyes or hearts (Supplementary Fig.	('developmental abnormalities of the eyes', 'Disease', 'MESH:D005124', (213, 252))	('hydrocephaly', 'Phenotype', 'HP:0000238', (187, 199))	('Tyr', 'Chemical', 'MESH:D014443', (96, 99))	('NrasLSL-G12D/LSL-G12D;Tyr::CreA/', 'Var', (74, 106))	('hydrocephaly', 'Disease', 'MESH:D006849', (187, 199))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (213, 240))	('hydrocephaly', 'Disease', (187, 199))	('Nras+/LSL-G12D', 'Var', (43, 57))	('Tyr::CreA/', 'Var', (96, 106))	('G12D', 'Mutation', 'rs121913529', (53, 57))	('G12D', 'Mutation', 'rs121913529', (82, 86))	('G12D', 'Mutation', 'rs121913529', (91, 95))	('developmental abnormalities of the eyes', 'Disease', (213, 252))	('Tyr', 'Chemical', 'MESH:D014443', (58, 61))	('abnormalities of the eyes', 'Phenotype', 'HP:0000478', (227, 252))
98095	23303902	1D, 1E) confirming that expression of NRASG12D in embryonic melanocytes induced congenital nevi.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('NRASG12D', 'Var', (38, 46))	('congenital nevi', 'Disease', (80, 95))	('induced', 'Reg', (72, 79))	('nevi', 'Phenotype', 'HP:0003764', (91, 95))
98096	23303902	Despite clearly driving melanocyte proliferation in the congenital setting, NRASG12D did not induce cutaneous melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('cutaneous melanoma', 'Disease', (100, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (100, 118))	('melanocyte proliferation', 'biological_process', 'GO:0097325', ('24', '48'))	('G12D', 'Mutation', 'rs121913529', (80, 84))	('driving', 'Reg', (16, 23))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (100, 118))	('NRASG12D', 'Var', (76, 84))	('melanocyte proliferation', 'CPA', (24, 48))
98106	23303902	Sequencing of this fragment revealed that NrasG12D was expressed in the tumors, but not the normal brains of the Tyr::CreA/  littermate controls (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('G12D', 'Mutation', 'rs121913529', (46, 50))	('NrasG12D', 'Var', (42, 50))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Tyr', 'Chemical', 'MESH:D014443', (113, 116))
98109	23303902	We therefore diagnosed primary melanoma of the CNS and cells derived from these tumors displayed constitutive ERK activity that was sensitive to the MEK inhibitors PD184352, U0126 and AZD6244 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ERK', 'Gene', '26413', (110, 113))	('MEK', 'Gene', (149, 152))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('U0126', 'Var', (174, 179))	('tumors', 'Disease', (80, 86))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('AZD6244', 'Var', (184, 191))	('AZD6244', 'Chemical', 'MESH:C517975', (184, 191))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (31, 50))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('melanoma of the CNS', 'Disease', (31, 50))	('PD184352', 'Var', (164, 172))	('MEK', 'Gene', '17242', (149, 152))	('ERK', 'Gene', (110, 113))	('activity', 'MPA', (114, 122))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (31, 50))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('PD184352', 'Chemical', 'MESH:C120227', (164, 172))	('U0126', 'Chemical', 'MESH:C113580', (174, 179))
98110	23303902	Importantly, PD184352 also delayed the growth of tumor allografts formed by these cells in syngeneic immuno-competent mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('delayed', 'NegReg', (27, 34))	('tumor', 'Disease', (49, 54))	('PD184352', 'Var', (13, 21))	('PD184352', 'Chemical', 'MESH:C120227', (13, 21))	('growth', 'CPA', (39, 45))	('mice', 'Species', '10090', (118, 122))
98125	23303902	These features are consistent with a diagnosis of leptomeningeal melanomatosis and DNA sequencing did not uncover mutations in BRAF, HRAS, GNAQ, GNA11, CDKN2A or TP53 (data not shown), but did reveal a c.182A>G, p.(Q61R) mutation in NRAS (Fig.	('GNA11', 'Gene', '14672', (145, 150))	('c.182A>G', 'Var', (202, 210))	('p.(Q61R)', 'Mutation', 'rs121913233', (212, 220))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('c.182A>G', 'Mutation', 'rs121912666', (202, 210))	('HRAS', 'Gene', '15461', (133, 137))	('NRAS', 'Gene', (233, 237))	('TP53', 'Gene', (162, 166))	('CDKN2A', 'Gene', '12578', (152, 158))	('GNAQ', 'Gene', (139, 143))	('CDKN2A', 'Gene', (152, 158))	('TP53', 'Gene', '22059', (162, 166))	('GNA11', 'Gene', (145, 150))	('GNAQ', 'Gene', '14682', (139, 143))	('leptomeningeal melanomatosis', 'Disease', (50, 78))	('leptomeningeal melanomatosis', 'Disease', 'MESH:D008577', (50, 78))	('p.(Q61R', 'Var', (212, 219))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('HRAS', 'Gene', (133, 137))
98135	23303902	DNA sequencing did not reveal mutations in BRAF, HRAS, GNAQ, GNA11, CDKN2A or TP53 (data now shown), but did reveal a c.181C>A, p.(Q61K) mutation in NRAS in the tumor (Fig.	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('CDKN2A', 'Gene', '12578', (68, 74))	('CDKN2A', 'Gene', (68, 74))	('GNAQ', 'Gene', '14682', (55, 59))	('TP53', 'Gene', '22059', (78, 82))	('tumor', 'Disease', (161, 166))	('GNA11', 'Gene', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('p.(Q61K)', 'Mutation', 'rs28933406', (128, 136))	('HRAS', 'Gene', (49, 53))	('c.181C>A', 'Var', (118, 126))	('GNA11', 'Gene', '14672', (61, 66))	('c.181C>A', 'Mutation', 'rs876658468', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('p.(Q61K', 'Var', (128, 135))	('HRAS', 'Gene', '15461', (49, 53))	('NRAS', 'Gene', (149, 153))	('TP53', 'Gene', (78, 82))	('GNAQ', 'Gene', (55, 59))
98136	23303902	Here we show that oncogenic NRAS induced dose-dependent hyperpigmentation of the skin when expressed in the mature melanocytes of adult mice, or the developing melanocytes of embryonic mice.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (185, 189))	('oncogenic', 'Var', (18, 27))	('hyperpigmentation of the skin', 'Phenotype', 'HP:0000953', (56, 85))	('hyperpigmentation of the skin', 'CPA', (56, 85))	('NRAS', 'Gene', (28, 32))
98137	23303902	This is consistent with previous data showing that NRASQ61K also increased skin pigmentation when expressed in embryonic mouse melanocytes using the tyrosinase promoter, and that oncogenic KRAS induced skin hyperpigmentation when expressed in mature melanocytes from the endogenous Kras gene or from an Actb (beta-Actin) promoter fragment.	('KRAS', 'Gene', (189, 193))	('Actb', 'Gene', (303, 307))	('beta-Actin', 'Gene', '11461', (309, 319))	('Kras', 'Gene', '16653', (282, 286))	('skin pigmentation', 'Disease', (75, 92))	('KRAS', 'Gene', '16653', (189, 193))	('skin hyperpigmentation', 'Disease', (202, 224))	('Actb', 'Gene', '11461', (303, 307))	('beta-Actin', 'Gene', (309, 319))	('skin hyperpigmentation', 'Phenotype', 'HP:0000953', (202, 224))	('increased', 'PosReg', (65, 74))	('skin pigmentation', 'Disease', 'MESH:D010859', (75, 92))	('NRASQ61K', 'Var', (51, 59))	('skin hyperpigmentation', 'Disease', 'MESH:D017495', (202, 224))	('tyrosinase', 'Gene', (149, 159))	('tyrosinase', 'Gene', '22173', (149, 159))	('pigmentation', 'biological_process', 'GO:0043473', ('80', '92'))	('mouse', 'Species', '10090', (121, 126))	('increased skin pigmentation', 'Phenotype', 'HP:0000953', (65, 92))	('Kras', 'Gene', (282, 286))
98138	23303902	We also show that like KRASG12V, when NRASG12D was expressed in mature melanocytes, it induced paucicellular nevi in the deep dermal layers of the skin that resembled human blue nevi.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('NRASG12D', 'Var', (38, 46))	('paucicellular nevi in the', 'CPA', (95, 120))	('nevi', 'Phenotype', 'HP:0003764', (109, 113))	('KRAS', 'Gene', (23, 27))	('KRAS', 'Gene', '16653', (23, 27))	('blue nevi', 'Phenotype', 'HP:0100814', (173, 182))	('induced', 'Reg', (87, 94))	('human', 'Species', '9606', (167, 172))	('nevi', 'Phenotype', 'HP:0003764', (178, 182))
98139	23303902	We also show that when NRASG12D was expressed in developing melanocytes it induced congenital blue nevus-like lesions, complementing a recent report showing that NRASQ61K also induced congenital nevi when expressed using a tyrosinase promoter fragment.	('congenital blue nevus-like lesions', 'Disease', (83, 117))	('induced', 'Reg', (75, 82))	('blue nevus', 'Phenotype', 'HP:0100814', (94, 104))	('G12D', 'Mutation', 'rs121913529', (27, 31))	('tyrosinase', 'Gene', (223, 233))	('nevus', 'Phenotype', 'HP:0003764', (99, 104))	('congenital nevi', 'Disease', (184, 199))	('tyrosinase', 'Gene', '22173', (223, 233))	('nevi', 'Phenotype', 'HP:0003764', (195, 199))	('induced', 'Reg', (176, 183))	('NRASG12D', 'Var', (23, 31))
98140	23303902	We previously reported that when BRAFV600E was expressed in embryonic melanocytes, it disrupted heart and eye development, and caused embryonic lethality, but show here that NRASG12D did not induce these effects.	('embryonic lethality', 'Disease', (134, 153))	('eye development', 'biological_process', 'GO:0001654', ('106', '121'))	('BRAFV600E', 'Var', (33, 42))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))	('G12D', 'Mutation', 'rs121913529', (178, 182))	('disrupted', 'NegReg', (86, 95))	('embryonic lethality', 'Disease', 'MESH:D020964', (134, 153))	('caused', 'Reg', (127, 133))
98141	23303902	The basis of this difference is unclear, but a possible explanation is that BRAFV600E transforms developing melanocytes more readily than NRASG12D, causing them to disrupt the development of the organs that they colonize.	('disrupt', 'NegReg', (164, 171))	('G12D', 'Mutation', 'rs121913529', (142, 146))	('BRAFV600E', 'Var', (76, 85))	('BRAFV600E', 'Mutation', 'rs113488022', (76, 85))	('development of the organs', 'CPA', (176, 201))
98142	23303902	Alternatively, perhaps oncogenic NRAS induces melanocyte senescence or apoptosis, so that unlike the BRAFV600E melanocytes, the NRASG12D melanocytes are unable to disrupt the development of their host organs.	('NRAS', 'Var', (33, 37))	('G12D', 'Mutation', 'rs121913529', (132, 136))	('apoptosis', 'CPA', (71, 80))	('BRAFV600E', 'Mutation', 'rs113488022', (101, 110))	('NRASG12D', 'Var', (128, 136))	('development of', 'CPA', (175, 189))	('induces', 'Reg', (38, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('melanocyte senescence', 'CPA', (46, 67))	('senescence', 'biological_process', 'GO:0010149', ('57', '67'))
98143	23303902	Critically, although none of the mice developed cutaneous melanoma when NRASG12D was expressed in the melanocytes of embryonic or mature mice, when NRASG12D was expressed in the melanocytes of the embryos, the mice developed leptomeningeal melanoma that presented as neuronal symptoms at a median of 4 months for the homozygous animals and 12.5 months for the heterozygous animals.	('cutaneous melanoma', 'Disease', (48, 66))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (48, 66))	('mice', 'Species', '10090', (210, 214))	('G12D', 'Mutation', 'rs121913529', (76, 80))	('G12D', 'Mutation', 'rs121913529', (152, 156))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 66))	('leptomeningeal melanoma', 'Disease', (225, 248))	('NRASG12D', 'Var', (148, 156))	('mice', 'Species', '10090', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (225, 248))	('mice', 'Species', '10090', (137, 141))
98150	23303902	We were intrigued that although we observed melanoma of the CNS when we expressed NRASG12D off the endogenous Nras gene, when NRASQ61K was expressed using the tyrosinase promoter it did not induce leptomeningeal melanoma.	('tyrosinase', 'Gene', '22173', (159, 169))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (44, 63))	('G12D', 'Mutation', 'rs121913529', (86, 90))	('melanoma of the CNS', 'Disease', (44, 63))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('leptomeningeal melanoma', 'Disease', (197, 220))	('NRASQ61K', 'Var', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('induce', 'Reg', (190, 196))	('tyrosinase', 'Gene', (159, 169))	('leptomeningeal melanoma', 'Disease', 'MESH:D008545', (197, 220))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (44, 63))	('NRASG12D', 'Var', (82, 90))
98151	23303902	However, as discussed below, the disease in our mice, which was driven by NRASG12D, mimicked the cardinal features of the disease in the children, which was driven by NRASQ61K/R.	('NRASQ61K/R', 'Var', (167, 177))	('mice', 'Species', '10090', (48, 52))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('children', 'Species', '9606', (137, 145))	('NRASG12D', 'Var', (74, 82))
98156	23303902	Similarly, deletion of p16INK4A cooperated with HRASG12V and NRASQ61K to induce melanoma, and KRAS driven melanomagenesis was inefficient unless BRAFD594A was also expressed, or KRASG12V was strongly over-expressed using the Actb promoter.	('KRAS', 'Gene', (178, 182))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('p16INK4A', 'Gene', (23, 31))	('deletion', 'Var', (11, 19))	('p16INK4A', 'Gene', '12578', (23, 31))	('KRAS', 'Gene', (94, 98))	('Actb', 'Gene', '11461', (225, 229))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('KRAS', 'Gene', '16653', (94, 98))	('HRAS', 'Gene', '15461', (48, 52))	('HRAS', 'Gene', (48, 52))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('Actb', 'Gene', (225, 229))	('induce', 'PosReg', (73, 79))	('melanoma', 'Disease', (106, 114))	('KRAS', 'Gene', '16653', (178, 182))
98157	23303902	Note however that we do not interpret this to mean that NRASG12D alone was sufficient to induce leptomeningeal melanomagenesis and we are currently working to identify the cooperating events using insertional mutagenesis and genomics.	('induce', 'Reg', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('leptomeningeal melanomagenesis', 'Disease', 'MESH:D008577', (96, 126))	('mutagenesis', 'biological_process', 'GO:0006280', ('209', '220'))	('NRASG12D', 'Var', (56, 64))	('G12D', 'Mutation', 'rs121913529', (60, 64))	('leptomeningeal melanomagenesis', 'Disease', (96, 126))
98164	23303902	Thus, despite the evidence that NRASG12D induced proliferation of both cutaneous and leptomeningeal melanocytes none of the animals developed cutaneous melanoma, whereas 75% of the heterozygous mice and all of the homozygous mice developed melanoma of the CNS.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (240, 259))	('cutaneous melanoma', 'Disease', (142, 160))	('G12D', 'Mutation', 'rs121913529', (36, 40))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (142, 160))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (142, 160))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (240, 259))	('NRASG12D', 'Var', (32, 40))	('mice', 'Species', '10090', (225, 229))	('melanoma of the CNS', 'Disease', (240, 259))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('mice', 'Species', '10090', (194, 198))
98165	23303902	This is supported by the observation that one of the children's tumors shared the same NRAS mutation as his giant congenital melanocytic nevus, suggesting a common ancestry, but nevertheless a more susceptible population in the leptomeninges.	('giant congenital melanocytic nevus', 'Disease', 'MESH:C536819', (108, 142))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutation', 'Var', (92, 100))	('giant congenital melanocytic nevus', 'Disease', (108, 142))	('congenital melanocytic nevus', 'Phenotype', 'HP:0100814', (114, 142))	('children', 'Species', '9606', (53, 61))	('nevus', 'Phenotype', 'HP:0003764', (137, 142))	('melanocytic nevus', 'Phenotype', 'HP:0000995', (125, 142))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('NRAS', 'Gene', (87, 91))
98166	23303902	Although we have reported two cases of childhood melanoma of the CNS that carry NRAS mutations, we note that in adults, melanoma of the CNS is associated with mutations in GNAQ and GNA11, whereas NRAS mutations are rare.	('NRAS', 'Gene', (80, 84))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (120, 139))	('associated', 'Reg', (143, 153))	('mutations', 'Var', (159, 168))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (49, 68))	('child', 'Species', '9606', (39, 44))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (120, 139))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (49, 68))	('melanoma of the CNS', 'Disease', (120, 139))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('mutations', 'Var', (85, 94))	('GNA11', 'Gene', (181, 186))	('GNAQ', 'Gene', '14682', (172, 176))	('GNA11', 'Gene', '14672', (181, 186))	('GNAQ', 'Gene', (172, 176))	('melanoma of the CNS', 'Disease', (49, 68))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))
98167	23303902	Previous studies have shown that truly congenital cutaneous melanocytic nevi harbor NRAS mutations and patients with these lesions may also present congenital deposits of leptomeningeal melanocytes.	('NRAS', 'Gene', (84, 88))	('nevi', 'Phenotype', 'HP:0003764', (72, 76))	('congenital cutaneous melanocytic nevi', 'Disease', (39, 76))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (60, 76))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (103, 111))
98169	23303902	We posit that there is a link between prenatal proliferation of melanocytes and early onset melanoma of the CNS and that acquisition of somatic oncogenic mutations in NRAS in the melanocytes of the CNS is a predisposing risk factor to melanoma of the CNS.	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (92, 111))	('risk factor', 'Reg', (220, 231))	('melanoma of the CNS', 'Disease', (235, 254))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('NRAS', 'Gene', (167, 171))	('melanoma of the CNS', 'Disease', (92, 111))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('mutations', 'Var', (154, 163))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (92, 111))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (235, 254))	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (235, 254))
98170	23303902	We present a mouse model that can be used to study this rare and devastating disease and note that the tumor cells from our mice are susceptible to MEK inhibitors, suggesting a potential therapeutic approach for these patients.	('mouse', 'Species', '10090', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibitors', 'Var', (152, 162))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Disease', (103, 108))	('MEK', 'Gene', '17242', (148, 151))	('mice', 'Species', '10090', (124, 128))	('MEK', 'Gene', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
98193	23303902	We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early onset melanoma of the CNS.	('melanoma of the CNS', 'Phenotype', 'HP:0100836', (116, 135))	('embryogenesis', 'biological_process', 'GO:0009790', ('69', '82'))	('NRAS', 'Gene', (32, 36))	('melanoma of the CNS', 'Disease', (116, 135))	('embryogenesis', 'biological_process', 'GO:0009793', ('69', '82'))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('mutations', 'Var', (37, 46))	('risk factor', 'Reg', (88, 99))	('melanoma of the CNS', 'Disease', 'MESH:D008545', (116, 135))	('embryogenesis', 'biological_process', 'GO:0009792', ('69', '82'))
98197	32046729	While PD-1/PD-L1 blockade therapy can be effective as cancer immunotherapy, interruption of PD-1/PD-L1 interactions alone does not completely restore T cell function in some patients indicating the involvement of additional negative regulatory pathways, such as Tim-3/Gal-9, in T cell exhaustion.	('Tim-3', 'Gene', (262, 267))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Tim-3', 'Gene', '84868', (262, 267))	('cancer', 'Disease', (54, 60))	('patients', 'Species', '9606', (174, 182))	('interruption', 'Var', (76, 88))	('men', 'Species', '9606', (205, 208))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (278, 295))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Gal-9', 'Gene', '3965', (268, 273))	('Gal-9', 'Gene', (268, 273))
98206	32046729	Conclusions: This study provides preliminary evidence to support a rationale for incorporating antibodies against the Gal9/TIM3 pathway during and/or following remission induction therapy for AML.	('Gal9', 'Gene', (118, 122))	('antibodies', 'Var', (95, 105))	('AML', 'Disease', 'MESH:D015470', (192, 195))	('TIM3', 'Gene', (123, 127))	('AML', 'Disease', (192, 195))	('TIM3', 'Gene', '84868', (123, 127))	('Gal9', 'Gene', '3965', (118, 122))
98207	32046729	Zhang L, Gajewski TF, Kline J, PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model.	('PD-1/PD-L1', 'Gene', (31, 41))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (102, 124))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Kline J', 'Chemical', 'MESH:C077098', (22, 29))	('acute myeloid leukemia', 'Disease', (102, 124))	('interactions', 'Var', (42, 54))	('murine', 'Species', '10090', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (102, 124))	('tumor', 'Disease', (67, 72))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (108, 124))	('inhibit', 'NegReg', (55, 62))	('leukemia', 'Phenotype', 'HP:0001909', (116, 124))
98227	32046729	The aim of our study is to investigate the role of EVs in the mechanisms of drug resistance and phenotypic alteration in primary melanoma cell lines MEL50 BRAF-V600mut and M257 BRAF-Wild Type.	('BRAF', 'Gene', (155, 159))	('BRAF', 'Gene', (177, 181))	('BRAF', 'Gene', '673', (177, 181))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('drug resistance', 'biological_process', 'GO:0009315', ('76', '91'))	('melanoma', 'Disease', (129, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (76, 91))	('drug resistance', 'biological_process', 'GO:0042493', ('76', '91'))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('BRAF', 'Gene', '673', (155, 159))	('M257', 'Var', (172, 176))
98232	32046729	While the expression of classic EVs markers was similar for EVs produced by either cell line, the extension of EVs marker characterization to the whole surfaceome of the parental cell line, may reveal the same heterogeneity, which could be used as biomarkers to identify BRAF mutated or wild type melanomas in liquid biopsies, and opens the door to investigating the role of specific EVs in drug resistance and phenotypic transformation.	('drug resistance', 'Phenotype', 'HP:0020174', (391, 406))	('mark', 'Gene', '4139', (251, 255))	('melanomas', 'Phenotype', 'HP:0002861', (297, 306))	('drug resistance', 'biological_process', 'GO:0009315', ('391', '406'))	('mark', 'Gene', (36, 40))	('melanomas', 'Disease', 'MESH:D008545', (297, 306))	('mark', 'Gene', (115, 119))	('mark', 'Gene', '4139', (115, 119))	('mutated', 'Var', (276, 283))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('BRAF', 'Gene', (271, 275))	('mark', 'Gene', '4139', (36, 40))	('BRAF', 'Gene', '673', (271, 275))	('drug resistance', 'biological_process', 'GO:0042493', ('391', '406'))	('mark', 'Gene', (251, 255))	('melanomas', 'Disease', (297, 306))
98255	32046729	The 1-year LC (in SRS field) was 53% for all lesions, 59% in IPI + RT and 8% in NO IPI (p = 0.001) (Fig.	('IPI + RT', 'Var', (61, 69))	('IPI', 'Chemical', 'MESH:C078466', (61, 64))	('SRS', 'Disease', 'MESH:C536678', (18, 21))	('SRS', 'Disease', (18, 21))	('NO IPI', 'Chemical', 'MESH:C078466', (80, 86))	('IPI', 'Chemical', 'MESH:C078466', (83, 86))
98257	32046729	The 1-year IC (out SRS field) was 45% for all pts, 44% for IPI + RT and 51% for NO IPI (p = 0.73).	('pts', 'Species', '9606', (46, 49))	('IPI + RT', 'Var', (59, 67))	('IPI', 'Chemical', 'MESH:C078466', (59, 62))	('NO IPI', 'Chemical', 'MESH:C078466', (80, 86))	('IPI', 'Chemical', 'MESH:C078466', (83, 86))	('SRS', 'Disease', 'MESH:C536678', (19, 22))	('SRS', 'Disease', (19, 22))
98277	32046729	In the BALB/c-derived 4T1 mouse model of ICB-refractory metastatic breast cancer, we have previously shown that tumor-targeted radiation therapy (RT) combined with CTLA4 blockade induces CD8+ T cell-mediated regression of irradiated tumors and inhibits lung metastases [2].	('lung metastases', 'Disease', (253, 268))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('blockade', 'Var', (170, 178))	('tumor', 'Disease', (233, 238))	('inhibits', 'NegReg', (244, 252))	('tumor', 'Disease', (112, 117))	('CD8', 'Gene', '925', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CTLA4', 'Gene', (164, 169))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('irradiated tumors', 'Disease', (222, 239))	('breast cancer', 'Disease', (67, 80))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('induces', 'PosReg', (179, 186))	('irradiated tumors', 'Disease', 'MESH:D012793', (222, 239))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD8', 'Gene', (187, 190))	('lung metastases', 'Disease', 'MESH:D009362', (253, 268))	('mouse', 'Species', '10090', (26, 31))
98283	32046729	Results: Out of 309 total mutations initially identified in 4T1 cancer cells, two MHC-I and one MHC-II neoepitopes were immunogenic in vaccination experiments as assessed by IFNgamma/TNFalpha response after T cell re-stimulation.	('MHC-II', 'Gene', '111364', (96, 102))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MHC-II', 'Gene', (96, 102))	('mutations', 'Var', (26, 35))	('men', 'Species', '9606', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
98288	32046729	Conclusions: Overall, our data demonstrate the potential of RT to modulate the expression of antigenic mutations in tumors which could enhance responses to immunotherapy.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (103, 112))	('antigenic', 'Gene', (93, 102))	('expression', 'MPA', (79, 89))	('responses', 'CPA', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('enhance', 'PosReg', (135, 142))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('modulate', 'Reg', (66, 74))
98329	32046729	Conclusions: SNS-301 is a novel immunotherapy that may overcome prior challenges of cancer vaccines and cell therapies.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('SNS-301', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
98342	32046729	The median TMB was slightly higher in the whole collective (median TMB = 14 mut/Mb) when compared to the subgroup of patients with BRAFV600E/K mutation (median TMB = 11 mut/Mb).	('TMB', 'Chemical', 'MESH:D014289', (160, 163))	('TMB', 'Chemical', 'MESH:D014289', (11, 14))	('BRAFV600E', 'Mutation', 'rs113488022', (131, 140))	('higher', 'PosReg', (28, 34))	('TMB', 'Chemical', 'MESH:D014289', (67, 70))	('BRAFV600E/K', 'Var', (131, 142))	('TMB', 'MPA', (11, 14))	('patients', 'Species', '9606', (117, 125))
98343	32046729	The highest TMB was observed in patients with other BRAF mutations (median TMB = 55 mut/Mb).	('patients', 'Species', '9606', (32, 40))	('TMB', 'MPA', (12, 15))	('TMB', 'Chemical', 'MESH:D014289', (75, 78))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', '673', (52, 56))	('TMB', 'Chemical', 'MESH:D014289', (12, 15))	('BRAF', 'Gene', (52, 56))
98344	32046729	When analyzing the whole collective, we found no difference in terms of median relapse-free survival (mRFS; p = 0.4689) and median overall survival (mOS; p = 0.5534) for patients with high and low-TMB.	('patients', 'Species', '9606', (170, 178))	('low-TMB', 'Var', (193, 200))	('mOS', 'Gene', (149, 152))	('mOS', 'Gene', '17451', (149, 152))	('relapse-free survival', 'CPA', (79, 100))	('TMB', 'Chemical', 'MESH:D014289', (197, 200))	('high', 'Var', (184, 188))
98345	32046729	In patients harboring a BRAFV600E/K mutation the same results were observed, when the median TMB for this cohort was used as cut-off (mRFS; p = 0.3235 and mOS; p = 0.7547).	('BRAFV600E', 'Mutation', 'rs113488022', (24, 33))	('mOS', 'Gene', (155, 158))	('BRAFV600E/K', 'Var', (24, 35))	('mOS', 'Gene', '17451', (155, 158))	('TMB', 'Chemical', 'MESH:D014289', (93, 96))	('patients', 'Species', '9606', (3, 11))
98352	32046729	Methods: This is a multicenter retrospective study of advanced cancer patients (any histology, regardless of treatment line) treated with anti-PD-1/PD-L1 (mono)immunotherapy, with a minimum time to treatment failure (TTF) of 12 months.	('patients', 'Species', '9606', (70, 78))	('men', 'Species', '9606', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('anti-PD-1/PD-L1', 'Var', (138, 153))	('men', 'Species', '9606', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
98392	32046729	By defining SPADE trees clustered on cell surface markers, we traced multiple phosphorylation events monitored with ERK1,2 (pT202/pY204), p38MAPK (pT180/pY182), STAT1 (pY701), STAT3 (pY705) and STAT5 (pY694) in HD and B-ALL sample at basal levels and after stimulation.	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('HD', 'Disease', 'MESH:D006816', (211, 213))	('STAT1', 'Gene', '6772', (161, 166))	('cell surface', 'cellular_component', 'GO:0009986', ('37', '49'))	('pY701', 'Var', (168, 173))	('ERK1,2', 'Gene', '5595;5594', (116, 122))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('pY705', 'Var', (183, 188))	('STAT1', 'Gene', (161, 166))	('mark', 'Gene', '4139', (50, 54))	('STAT3', 'Gene', (176, 181))	('STAT5', 'Gene', '6776', (194, 199))	('pT202/pY204', 'Var', (124, 135))	('mark', 'Gene', (50, 54))	('STAT5', 'Gene', (194, 199))	('pY694', 'Var', (201, 206))	('pT180/pY182', 'Var', (147, 158))	('ERK1', 'molecular_function', 'GO:0004707', ('116', '120'))	('STAT3', 'Gene', '6774', (176, 181))
98426	32046729	The antitumor immune response in peripheral blood lymphocytes has been monitored, in order to evaluate whether the combination of antiCTLA4 and anti-PD1 is able to increase the number and/or the repertoire of melanoma-specific T-cells after treatments.	('antiCTLA4', 'Var', (130, 139))	('PD1', 'Gene', '5133', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('repertoire', 'CPA', (195, 205))	('PD1', 'Gene', (149, 152))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('men', 'Species', '9606', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('immune response', 'biological_process', 'GO:0006955', ('14', '29'))	('tumor', 'Disease', (8, 13))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('increase', 'PosReg', (164, 172))
98487	32046729	A Phase II trial in CM (NCT02535078), a Phase I/II trial in UM (NCT02570308), and a Pivotal RCT in UM (NCT03070392) are ongoing.	('NCT03070392', 'Var', (103, 114))	('NCT03070392', 'Chemical', 'MESH:C079985', (103, 114))	('NCT02570308', 'Var', (64, 75))	('NCT02535078', 'Var', (24, 35))
98490	32046729	In pts we found increased T cell infiltration upon D + T after short-term MAPKi, while this was frequently below baseline levels after > 2 weeks (W) MAPKi.	('pts', 'Species', '9606', (3, 6))	('increased', 'PosReg', (16, 25))	('MAPKi', 'Var', (74, 79))	('T cell infiltration', 'CPA', (26, 45))
98491	32046729	Methods: Treatment-naive BRAFV600E/K mutant advanced melanoma pts (n = 32) started PEM 200 mg Q3W and were randomized in W6 to continue PEM only (cohort 1), or to receive in addition intermittent D 150 mg BID + T 2 mg QD for 2x 1 W (cohort 2), 2x 2 W (cohort 3), or continuous for 6 W (cohort 4).	('BID', 'Gene', '637', (205, 208))	('BRAFV600E', 'Mutation', 'rs113488022', (25, 34))	('men', 'Species', '9606', (14, 17))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('BID', 'Gene', (205, 208))	('pts', 'Species', '9606', (62, 65))	('BRAFV600E/K mutant', 'Var', (25, 43))	('advanced melanoma', 'Disease', 'MESH:D008545', (44, 61))	('advanced melanoma', 'Disease', (44, 61))
98502	32046729	Methods: 41 patients with previously untreated stage IV metastatic melanoma received >= 1 dose of BEMPEG (0.006 mg/kg) + NIVO (360 mg) q3w.	('patients', 'Species', '9606', (12, 20))	('0.006 mg/kg', 'Var', (106, 117))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('BEMPEG', 'Chemical', 'None', (98, 104))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('NIVO', 'Chemical', 'None', (121, 125))
98517	32046729	Epigenetic modulation, and Histone Deacetylase (HDAC) inhibition in particular is intended to enhance the immunogenicity of the tumor, alter the tumor microenvironment and thus increase the chance of clinical activity to such immunotherapy, having the potential of a new clinical approach to overcome tumor escape mechanisms.	('Histone Deacetylase', 'Gene', (27, 46))	('enhance', 'PosReg', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('HDAC', 'Gene', '9734', (48, 52))	('clinical activity', 'CPA', (200, 217))	('tumor', 'Disease', (145, 150))	('alter', 'Reg', (135, 140))	('HDAC', 'Gene', (48, 52))	('Histone Deacetylase', 'Gene', '9734', (27, 46))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Epigenetic modulation', 'Var', (0, 21))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('inhibition', 'Var', (54, 64))	('men', 'Species', '9606', (163, 166))	('immunogenicity', 'MPA', (106, 120))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('increase', 'PosReg', (177, 185))
98552	32046729	Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH > ULN; 25% received prior anti-PD(L)1.	('PD(L)1', 'Gene', '29126', (108, 114))	('LDH > ULN', 'Var', (73, 82))	('uveal', 'CPA', (47, 52))	('PD(L)1', 'Gene', (108, 114))
98564	32046729	Nevertheless, no data are reported on the role of miR-193a on the control of melanoma cell proliferation and metastasis.	('melanoma cell proliferation', 'Disease', (77, 104))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('miR-193a', 'Var', (50, 58))	('melanoma cell proliferation', 'Disease', 'MESH:D008545', (77, 104))
98567	32046729	Materials and methods: In order to evaluate the tumour suppressor role of miR-193a in melanoma cells, we studied its influence on intracellular pathways regulating survival, proliferation, apoptosis and migration, such as MAPK/ERK, and PI3K/Akt, and on markers involved in epithelial-mesenchymal transition (EMT).	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('273', '306'))	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('apoptosis', 'CPA', (189, 198))	('mark', 'Gene', '4139', (253, 257))	('ERK', 'Gene', (227, 230))	('mark', 'Gene', (253, 257))	('ERK', 'molecular_function', 'GO:0004707', ('227', '230'))	('intracellular', 'cellular_component', 'GO:0005622', ('130', '143'))	('migration', 'CPA', (203, 212))	('Akt', 'Gene', (241, 244))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('MAPK', 'molecular_function', 'GO:0004707', ('222', '226'))	('Akt', 'Gene', '207', (241, 244))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('EMT', 'biological_process', 'GO:0001837', ('308', '311'))	('miR-193a', 'Var', (74, 82))	('ERK', 'Gene', '5594', (227, 230))	('PI3K', 'molecular_function', 'GO:0016303', ('236', '240'))
98591	32046729	These patients were characterised by < 3 metastatic sites (6/6), good PS (6/6), normal LDH values (5/6), no brain metastases and prevalence of M1a/b score (4/6).	('brain metastases', 'Disease', 'MESH:D009362', (108, 124))	('brain metastases', 'Disease', (108, 124))	('LDH values', 'MPA', (87, 97))	('patients', 'Species', '9606', (6, 14))	('M1a/b', 'Var', (143, 148))
98612	32467670	Mutant BRAF has been shown to be significantly associated with worsen overall survival and metastasis free survival of melanoma, meanwhile mutant BRAF has been also proven to be a good therapeutic target for melanoma, but the resistance of small molecule drugs against mutant BRAF for melanoma is invariably observed.	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Phenotype', 'HP:0002861', (285, 293))	('melanoma', 'Disease', (285, 293))	('worsen', 'NegReg', (63, 69))	('BRAF', 'Gene', '673', (276, 280))	('BRAF', 'Gene', (276, 280))	('overall survival', 'CPA', (70, 86))	('BRAF', 'Gene', '673', (7, 11))	('BRAF', 'Gene', (7, 11))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('Mutant', 'Var', (0, 6))	('BRAF', 'Gene', '673', (146, 150))	('melanoma', 'Disease', 'MESH:D008545', (285, 293))	('BRAF', 'Gene', (146, 150))	('metastasis free survival', 'CPA', (91, 115))
98614	32467670	BRAF and NRAS mutations have been used as molecular biomarkers in evaluating the clinical course of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('NRAS', 'Gene', (9, 13))	('NRAS', 'Gene', '4893', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('mutations', 'Var', (14, 23))
98630	32467670	By OSskcm, we found that high expression of SAE1 gene is associated with poor prognosis of cutaneous melanoma (Fig.	('SAE1', 'Gene', (44, 48))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('SAE', 'cellular_component', 'GO:0031510', ('44', '47'))	('SAE1', 'Gene', '10055', (44, 48))	('high', 'Var', (25, 29))	('cutaneous melanoma', 'Disease', (91, 109))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))
98644	32467670	Breast cancer patients with lower SAE1 expression have been reported to have significantly lower instances of metastatic cancer and increased survival compared to those that express a higher level of SAE1.	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lower', 'NegReg', (28, 33))	('survival', 'CPA', (142, 150))	('patients', 'Species', '9606', (14, 22))	('SAE', 'cellular_component', 'GO:0031510', ('34', '37'))	('lower', 'NegReg', (91, 96))	('increased', 'PosReg', (132, 141))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('SAE', 'cellular_component', 'GO:0031510', ('200', '203'))	('SAE1', 'Gene', (34, 38))	('SAE1', 'Gene', '10055', (34, 38))	('SAE1', 'Gene', (200, 204))	('expression', 'Var', (39, 49))	('SAE1', 'Gene', '10055', (200, 204))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('cancer', 'Disease', (121, 127))
98714	19223509	CpG Island Methylator Phenotype Predicts Progression of Malignant Melanoma The CpG island methylator phenotype (CIMP) may be associated with development of malignancy through coordinated inactivation of tumor suppressor and tumor-related genes (TRG) and methylation of multiple noncoding, methylated-in-tumor (MINT) loci.	('tumor suppressor', 'biological_process', 'GO:0051726', ('203', '219'))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('methylation', 'Var', (254, 265))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('TRG', 'Chemical', '-', (245, 248))	('associated', 'Reg', (125, 135))	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('methylation', 'biological_process', 'GO:0032259', ('254', '265'))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('TRG', 'Gene', (245, 248))	('Malignant Melanoma', 'Phenotype', 'HP:0002861', (56, 74))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (303, 308))	('malignancy', 'Disease', (156, 166))	('CpG', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('203', '219'))	('inactivation', 'NegReg', (187, 199))	('Malignant Melanoma', 'Disease', (56, 74))	('CIMP', 'Chemical', '-', (112, 116))	('Malignant Melanoma', 'Disease', 'MESH:D008545', (56, 74))
98715	19223509	These epigenetic changes create a distinct CIMP pattern that has been linked to recurrence and survival in gastrointestinal cancers.	('gastrointestinal cancers', 'Disease', (107, 131))	('linked', 'Reg', (70, 76))	('CIMP', 'Chemical', '-', (43, 47))	('epigenetic changes', 'Var', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (107, 131))
98716	19223509	Because epigenetic inactivation of TRGs also has been shown in malignant melanoma, we hypothesized the existence of a clinically significant CIMP in cutaneous melanoma progression.	('CIMP', 'Chemical', '-', (141, 145))	('TRG', 'Chemical', '-', (35, 38))	('cutaneous melanoma', 'Disease', (149, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('malignant melanoma', 'Phenotype', 'HP:0002861', (63, 81))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (149, 167))	('TRGs', 'Gene', (35, 39))	('malignant melanoma', 'Disease', (63, 81))	('malignant melanoma', 'Disease', 'MESH:D008545', (63, 81))	('shown', 'Reg', (54, 59))	('epigenetic inactivation', 'Var', (8, 31))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
98719	19223509	Furthermore, we find a significant positive association between the methylation status of MINT17, MINT31, and TRGs.	('TRG', 'Chemical', '-', (110, 113))	('MINT1', 'Gene', '320', (90, 95))	('MINT3', 'Gene', '9546', (98, 103))	('TRGs', 'Gene', (110, 114))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('positive', 'PosReg', (35, 43))	('MINT3', 'Gene', (98, 103))	('MINT1', 'Gene', (90, 95))	('methylation status', 'Var', (68, 86))
98720	19223509	The methylation status of MINT31is associated with disease outcome in stage III melanoma.	('MINT3', 'Gene', '9546', (26, 31))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('stage III melanoma', 'Disease', 'MESH:D008545', (70, 88))	('associated with', 'Reg', (35, 50))	('MINT3', 'Gene', (26, 31))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('methylation status', 'Var', (4, 22))	('stage III melanoma', 'Disease', (70, 88))
98722	19223509	Future prospective large-scale studies may determine if CIMP-positive primary melanomas are at high risk of metastasis or recurrence.	('melanomas', 'Disease', (78, 87))	('CIMP-positive', 'Var', (56, 69))	('primary melanoma', 'Disease', 'MESH:D008545', (70, 86))	('CIMP', 'Chemical', '-', (56, 60))	('metastasis', 'CPA', (108, 118))	('primary melanoma', 'Disease', (70, 86))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanomas', 'Disease', 'MESH:D008545', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))
98724	19223509	To date, there have been limited studies addressing the role of epigenetic changes during early melanoma progression, or evaluating differences in the epigenetic patterns of primary versus metastatic tumors.	('epigenetic changes', 'Var', (64, 82))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('melanoma', 'Disease', 'MESH:D008545', (96, 104))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma', 'Disease', (96, 104))
98725	19223509	However, epigenetic inactivation of tumor suppressor genes has been implicated in tumorigenesis and progression of a variety of different malignancies, and recent studies are beginning to show the role of epigenetic events in cutaneous melanoma.	('tumor suppressor', 'biological_process', 'GO:0051726', ('36', '52'))	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('36', '52'))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('epigenetic inactivation', 'Var', (9, 32))	('implicated', 'Reg', (68, 78))	('malignancies', 'Disease', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cutaneous melanoma', 'Disease', (226, 244))	('tumor', 'Disease', (82, 87))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('tumor', 'Disease', (36, 41))
98728	19223509	Although the observation of methylation changes in CpG island promoter regions in a few tumor-related genes and tumor suppressor genes has been reported in the case of malignant cutaneous melanoma, the clinical significance of these molecular aberrations is still being defined.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (178, 196))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('reported', 'Reg', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('malignant cutaneous melanoma', 'Disease', 'MESH:C562393', (168, 196))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('tumor', 'Disease', (112, 117))	('methylation', 'Var', (28, 39))	('malignant cutaneous melanoma', 'Disease', (168, 196))	('tumor', 'Disease', (88, 93))
98730	19223509	noted that TFPI2 was methylated in 5 of 17 (29%) metastatic melanoma lesions but none of the primary tumors examined, suggesting that methylation-induced inactivation of this gene is involved in melanoma metastasis.	('melanoma metastasis', 'Disease', 'MESH:D009362', (195, 214))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('melanoma lesions', 'Disease', 'MESH:D008545', (60, 76))	('inactivation', 'Var', (154, 166))	('methylated', 'Var', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('melanoma lesions', 'Disease', (60, 76))	('primary tumors', 'Disease', (93, 107))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('TFPI2', 'Gene', (11, 16))	('involved', 'Reg', (183, 191))	('TFPI2', 'Gene', '7980', (11, 16))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('primary tumors', 'Disease', 'MESH:D009369', (93, 107))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma metastasis', 'Disease', (195, 214))	('methylation-induced', 'Var', (134, 153))
98731	19223509	Silencing of WIF1, a Wnt pathway antagonist, has been implicated in cellular proliferation of a variety of tumor types including non-small cell lung cancer, bladder and renal cell cancers, and gastrointestinal cancers, and restoration of WIF1 expression has been shown to inhibit growth of melanoma in vitro and in vivo.	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (193, 217))	('tumor', 'Disease', (107, 112))	('expression', 'MPA', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('melanoma', 'Disease', 'MESH:D008545', (290, 298))	('WIF1', 'Gene', (238, 242))	('growth', 'CPA', (280, 286))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('WIF1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('cell lung cancer', 'Disease', 'MESH:D008175', (139, 155))	('gastrointestinal cancers', 'Disease', (193, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cell lung cancer', 'Disease', (139, 155))	('restoration', 'Var', (223, 234))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('melanoma', 'Phenotype', 'HP:0002861', (290, 298))	('melanoma', 'Disease', (290, 298))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cellular proliferation', 'CPA', (68, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (129, 155))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('bladder and renal cell cancers', 'Disease', 'MESH:C538614', (157, 187))	('implicated', 'Reg', (54, 64))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (133, 155))	('WIF1', 'Gene', '11197', (238, 242))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('inhibit', 'NegReg', (272, 279))	('WIF1', 'Gene', '11197', (13, 17))
98733	19223509	Expression of GATA4, a gene encoding a transcription factor thought to act like a tumor suppressor gene through its activation of several other genes with antitumor effects, has been found to be epigenetically silenced in gastrointestinal cancers and lung cancer, although there are no reports to date of its role in melanoma development.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('transcription', 'biological_process', 'GO:0006351', ('39', '52'))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', (82, 87))	('melanoma', 'Phenotype', 'HP:0002861', (317, 325))	('GATA4', 'Gene', '2626', (14, 19))	('melanoma', 'Disease', (317, 325))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('transcription factor', 'molecular_function', 'GO:0000981', ('39', '59'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('lung cancer', 'Disease', (251, 262))	('silenced', 'NegReg', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('epigenetically', 'Var', (195, 209))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (222, 246))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('GATA4', 'Gene', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (317, 325))	('gastrointestinal cancers', 'Disease', (222, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('activation', 'PosReg', (116, 126))
98734	19223509	RARbeta2 methylation has been shown previously by our laboratory to be present in a high percentage of clinical melanoma specimens and to be associated with increased Breslow depth of primary melanomas, implicating its role in tumori-genesis.	('methylation', 'Var', (9, 20))	('tumor', 'Disease', (227, 232))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('primary melanoma', 'Disease', 'MESH:D008545', (184, 200))	('primary melanoma', 'Disease', (184, 200))	('associated', 'Reg', (141, 151))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('melanomas', 'Disease', 'MESH:D008545', (192, 201))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('melanomas', 'Disease', (192, 201))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('RARbeta2', 'Gene', (0, 8))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('Breslow', 'Disease', (167, 174))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('increased', 'PosReg', (157, 166))	('melanomas', 'Phenotype', 'HP:0002861', (192, 201))
98735	19223509	Our laboratory and others have shown the significance of RASSF1A and RARbeta2 hypermethylation in predicting nonresponsiveness to biochemotherapy in American Joint Committee on Cancer (AJCC) stage IV melanoma patients.	('Cancer', 'Disease', 'MESH:D009369', (177, 183))	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('RASSF1A', 'Gene', '11186', (57, 64))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('nonresponsiveness', 'MPA', (109, 126))	('melanoma', 'Disease', (200, 208))	('patients', 'Species', '9606', (209, 217))	('hypermethylation', 'Var', (78, 94))	('RARbeta2', 'Gene', (69, 77))	('Cancer', 'Disease', (177, 183))	('RASSF1A', 'Gene', (57, 64))
98742	19223509	In gastric and colorectal cancer, the existence of a CpG island methylator phenotype (CIMP) has been described and found to be associated with tumor development through coordinated inactivation of multiple tumor suppressor and mismatch repair genes.	('gastric', 'Disease', (3, 10))	('CIMP', 'Chemical', '-', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('associated', 'Reg', (127, 137))	('tumor', 'Disease', (143, 148))	('inactivation', 'Var', (181, 193))	('tumor', 'Disease', (206, 211))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('mismatch repair', 'biological_process', 'GO:0006298', ('227', '242'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('206', '222'))	('colorectal cancer', 'Disease', (15, 32))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('206', '222'))
98743	19223509	The CIMP is marked by methylation of multiple noncoding, methylated-in-tumor (MINT) loci, which have been shown to underlie epigenetic changes in gastrointestinal tumors.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (163, 168))	('gastrointestinal tumors', 'Disease', (146, 169))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (146, 169))	('tumor', 'Disease', (71, 76))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (146, 169))	('methylation', 'Var', (22, 33))	('CIMP', 'Chemical', '-', (4, 8))
98744	19223509	Methylation of MINT loci is thought to be associated with a high degree of hypermethylation of tumor-related genes (TRG) as observed, for example, with the high prevalence of p16 and THBS1 hypermethylation in CIMP-positive colorectal tumors.	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('colorectal tumors', 'Disease', 'MESH:D015179', (223, 240))	('Methylation', 'Var', (0, 11))	('THBS1', 'Gene', (183, 188))	('CIMP-positive', 'Gene', (209, 222))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('THBS1', 'Gene', '7057', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('hypermethylation', 'Var', (189, 205))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('p16', 'Gene', (175, 178))	('CIMP', 'Chemical', '-', (209, 213))	('p16', 'Gene', '1029', (175, 178))	('TRG', 'Chemical', '-', (116, 119))	('tumor', 'Disease', (95, 100))	('colorectal tumors', 'Disease', (223, 240))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('TRG', 'Gene', (116, 119))
98782	19223509	Methylation-specific PCR and absolute quantitative analysis of methylated allele primers and probes were initially screened using eight melanoma tumor specimens to detect promoter methylation of six TRGs and methylation of seven MINT loci, respectively.	('TRG', 'Chemical', '-', (199, 202))	('methylation', 'Var', (208, 219))	('methylation', 'biological_process', 'GO:0032259', ('208', '219'))	('methylation', 'biological_process', 'GO:0032259', ('180', '191'))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('melanoma tumor', 'Disease', (136, 150))	('TRGs', 'Gene', (199, 203))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('melanoma tumor', 'Disease', 'MESH:D008545', (136, 150))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('promoter methylation', 'MPA', (171, 191))
98787	19223509	WIF1, TFPI2, RASSF1A, RARbeta2, SOCS1, GATA4, MINT17, and MINT31 were each methylated in at least 50% of the 12 melanoma cell lines tested (Table 2).	('MINT3', 'Gene', (58, 63))	('methylated', 'Var', (75, 85))	('RASSF1A', 'Gene', (13, 20))	('WIF1', 'Gene', (0, 4))	('WIF1', 'Gene', '11197', (0, 4))	('GATA4', 'Gene', '2626', (39, 44))	('MINT1', 'Gene', '320', (46, 51))	('SOCS1', 'Gene', '8651', (32, 37))	('TFPI2', 'Gene', (6, 11))	('GATA4', 'Gene', (39, 44))	('TFPI2', 'Gene', '7980', (6, 11))	('MINT3', 'Gene', '9546', (58, 63))	('RASSF1A', 'Gene', '11186', (13, 20))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('SOCS1', 'Gene', (32, 37))	('MINT1', 'Gene', (46, 51))
98799	19223509	MINT31 methylation was positively associated with methylation of all six TRGs.	('TRG', 'Chemical', '-', (73, 76))	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('MINT3', 'Gene', '9546', (0, 5))	('associated', 'Interaction', (34, 44))	('methylation', 'Var', (7, 18))	('TRGs', 'Protein', (73, 77))	('methylation', 'MPA', (50, 61))	('MINT3', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
98801	19223509	There was no statistically significant relationship between methylation of MINT17 compared with GATA4, RASSF1A, or RARbeta2; methylation of GATA4 was associated with RASSF1A and RARbeta2 methylation, however.	('associated', 'Reg', (150, 160))	('methylation', 'biological_process', 'GO:0032259', ('125', '136'))	('GATA4', 'Gene', (96, 101))	('MINT1', 'Gene', (75, 80))	('MINT1', 'Gene', '320', (75, 80))	('RASSF1A', 'Gene', (103, 110))	('methylation', 'MPA', (187, 198))	('GATA4', 'Gene', '2626', (140, 145))	('methylation', 'biological_process', 'GO:0032259', ('187', '198'))	('RASSF1A', 'Gene', (166, 173))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('GATA4', 'Gene', (140, 145))	('RASSF1A', 'Gene', '11186', (103, 110))	('RASSF1A', 'Gene', '11186', (166, 173))	('methylation', 'Var', (125, 136))	('GATA4', 'Gene', '2626', (96, 101))
98809	19223509	MINT31 methylation was found to be a significant predictor of improved overall survival (Cox proportional hazards regression model; hazard ratio = 0.237; P = 0.024) for all 25 patients in our study with AJCC stage III disease.	('patients', 'Species', '9606', (176, 184))	('improved', 'PosReg', (62, 70))	('MINT3', 'Gene', '9546', (0, 5))	('methylation', 'Var', (7, 18))	('overall survival', 'MPA', (71, 87))	('MINT3', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
98814	19223509	Methylation of MINT17, MINT31, TFPI2, WIF1, RASSF1A, and SOCS1 increased significantly with advancing clinical stage, strongly suggesting that inactivation of these genes and loci is associated with tumor progression.	('RASSF1A', 'Gene', '11186', (44, 51))	('WIF1', 'Gene', '11197', (38, 42))	('SOCS1', 'Gene', '8651', (57, 62))	('associated', 'Reg', (183, 193))	('RASSF1A', 'Gene', (44, 51))	('WIF1', 'Gene', (38, 42))	('MINT1', 'Gene', (15, 20))	('MINT1', 'Gene', '320', (15, 20))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('TFPI2', 'Gene', '7980', (31, 36))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('SOCS1', 'Gene', (57, 62))	('MINT3', 'Gene', '9546', (23, 28))	('inactivation', 'Var', (143, 155))	('increased', 'PosReg', (63, 72))	('Methylation', 'MPA', (0, 11))	('MINT3', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('TFPI2', 'Gene', (31, 36))
98815	19223509	These findings in melanoma are consistent with previous reports of MINT methylation as a determinant of a cancer-specific CIMP in gastric and colorectal cancers and of the association of TRG hypermethylation with melanoma and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (232, 238))	('cancers', 'Disease', (232, 239))	('hypermethylation', 'Var', (191, 207))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('colorectal cancers', 'Disease', (142, 160))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('association', 'Interaction', (172, 183))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('gastric', 'Disease', (130, 137))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('TRG', 'Chemical', '-', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('CIMP', 'Chemical', '-', (122, 126))	('colorectal cancers', 'Disease', 'MESH:D015179', (142, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('methylation', 'Var', (72, 83))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Disease', (18, 26))
98817	19223509	One plausible explanation could be that hyper-methylation of MINT17 and WIF1 is involved with the initiation of the metastatic process, such that tumor clones with a higher degree of hypermethylation are more likely to migrate to and establish metastases in regional lymph nodes, whereas those tumor cells with a lower degree of hyper-methylation are more suited to formation of distant metastases.	('hypermethylation', 'Var', (183, 199))	('tumor', 'Disease', (146, 151))	('WIF1', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('formation', 'biological_process', 'GO:0009058', ('366', '375'))	('MINT1', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('MINT1', 'Gene', '320', (61, 66))	('methylation', 'biological_process', 'GO:0032259', ('335', '346'))	('metastases', 'Disease', 'MESH:D009362', (387, 397))	('tumor', 'Disease', (294, 299))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('metastases', 'Disease', 'MESH:D009362', (244, 254))	('migrate to', 'CPA', (219, 229))	('WIF1', 'Gene', '11197', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('metastases', 'Disease', (387, 397))	('metastases', 'Disease', (244, 254))
98820	19223509	To our knowledge, this is the first clinical evidence of the role of WIF1 methylation in melanoma progression.	('methylation', 'Var', (74, 85))	('WIF1', 'Gene', (69, 73))	('WIF1', 'Gene', '11197', (69, 73))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
98821	19223509	These data strongly support the results of earlier in vitro and animal studies of the involvement of Wnt signaling in melanoma tumor growth, the ability to inhibit tumor growth with the restoration of WIF1 expression, and the potential use of Wnt pathway inhibition as a targeted therapy for high-risk or metastatic melanoma.	('melanoma tumor', 'Disease', (118, 132))	('tumor', 'Disease', (164, 169))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('melanoma', 'Disease', (118, 126))	('restoration', 'Var', (186, 197))	('WIF1', 'Gene', '11197', (201, 205))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('inhibit', 'NegReg', (156, 163))	('expression', 'MPA', (206, 216))	('WIF1', 'Gene', (201, 205))	('melanoma tumor', 'Disease', 'MESH:D008545', (118, 132))	('involvement', 'Reg', (86, 97))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
98822	19223509	In contrast, RARbeta2 methylation was seen in 58% of all tumor specimens tested without a detectable association with AJCC stage, implying that epigenetic inactivation of this particular gene may be a very early event in tumorigenesis.	('epigenetic inactivation', 'Var', (144, 167))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (221, 226))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
98823	19223509	Although there was considerable variability in GATA4 methylation status across tumor stage groupings, GATA4 methylation was identified in a significant percentage of stage I tumors (Table 3A) but not in the melanocyte or dermal fibroblast cell lines (Table 2) or normal skin specimens (data not shown).	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('stage I tumors', 'Disease', (166, 180))	('stage I tumors', 'Disease', 'MESH:D062706', (166, 180))	('tumor', 'Disease', (79, 84))	('methylation', 'biological_process', 'GO:0032259', ('108', '119'))	('GATA4', 'Gene', '2626', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('GATA4', 'Gene', (47, 52))	('GATA4', 'Gene', '2626', (102, 107))	('methylation', 'Var', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('GATA4', 'Gene', (102, 107))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
98826	19223509	Methylation of MINT31 was positively associated with methylation of all six TRGs, as was methylation of TFPI2 and WIF1.	('associated', 'Interaction', (37, 47))	('MINT3', 'Gene', '9546', (15, 20))	('TRG', 'Chemical', '-', (76, 79))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('Methylation', 'Var', (0, 11))	('methylation', 'biological_process', 'GO:0032259', ('53', '64'))	('WIF1', 'Gene', (114, 118))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('MINT3', 'Gene', (15, 20))	('TFPI2', 'Gene', '7980', (104, 109))	('methylation', 'MPA', (53, 64))	('WIF1', 'Gene', '11197', (114, 118))	('TFPI2', 'Gene', (104, 109))	('methylation', 'MPA', (89, 100))
98828	19223509	A pattern emerging from these data suggests that MINT17 methylation is a particularly sensitive marker for disease progression because it is present in conjunction with methylation of the TRGs that are strongly associated with advancing clinical stage.	('methylation', 'Var', (56, 67))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('TRG', 'Chemical', '-', (188, 191))	('methylation', 'biological_process', 'GO:0032259', ('169', '180'))	('MINT1', 'Gene', (49, 54))	('associated', 'Reg', (211, 221))	('MINT1', 'Gene', '320', (49, 54))
98829	19223509	Because MINT31 methylation is associated with methylation of all of the TRGs, it is perhaps more suitable as a biomarker of disease presence or absence.	('associated', 'Reg', (30, 40))	('methylation', 'Var', (15, 26))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('TRG', 'Chemical', '-', (72, 75))	('methylation', 'MPA', (46, 57))	('MINT3', 'Gene', (8, 13))	('MINT3', 'Gene', '9546', (8, 13))	('TRGs', 'Protein', (72, 76))
98830	19223509	MINT17 and MINT31 methylation may therefore be representative of a CIMP for malignant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('MINT3', 'Gene', (11, 16))	('CIMP', 'Chemical', '-', (67, 71))	('malignant melanoma', 'Phenotype', 'HP:0002861', (76, 94))	('MINT1', 'Gene', (0, 5))	('MINT1', 'Gene', '320', (0, 5))	('MINT3', 'Gene', '9546', (11, 16))	('malignant melanoma', 'Disease', 'MESH:D008545', (76, 94))	('methylation', 'Var', (18, 29))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('malignant melanoma', 'Disease', (76, 94))
98831	19223509	Potential clinical applications of this knowledge include the testing of primary melanomas for MINT17 hypermethylation and, used in conjunction with clinicopathologic factors such as Breslow depth, Clark level, ulceration, and mitotic rate to, offer further treatment such as lymph node biopsy based on the result.	('primary melanoma', 'Disease', (73, 89))	('melanomas', 'Disease', (81, 90))	('MINT1', 'Gene', (95, 100))	('MINT1', 'Gene', '320', (95, 100))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('hypermethylation', 'Var', (102, 118))	('primary melanoma', 'Disease', 'MESH:D008545', (73, 89))
98833	19223509	Survival plots stratified by methylation status were notable for improved disease-free and overall survival associated with methylation of MINT31 but not of any other biomarkers.	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('improved', 'PosReg', (65, 73))	('MINT3', 'Gene', (139, 144))	('overall survival', 'CPA', (91, 107))	('disease-free', 'CPA', (74, 86))	('methylation', 'Var', (124, 135))	('MINT3', 'Gene', '9546', (139, 144))
98834	19223509	It is conceivable that alterations in the activation status of additional genes or gene products other than those examined here may result in phenotypic changes leading to slower disease progression and/or tumor cell doubling times, or perhaps improved recognition of tumor cells by the immune system.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (206, 211))	('improved', 'PosReg', (244, 252))	('tumor', 'Disease', (268, 273))	('alterations', 'Var', (23, 34))	('slower disease progression', 'CPA', (172, 198))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
98889	31611978	Overexpression of PPIA was associated with poor relapse free survival of lung adenocarcinoma in datasets GSE32210 and GSE8894 using various primers, and poor OS in datasets GSE32210, GSE13213, jacob-00182-UM and GSE13213.	('PPIA', 'Gene', '5478', (18, 22))	('lung adenocarcinoma', 'Disease', (73, 92))	('PPIA', 'Gene', (18, 22))	('poor', 'NegReg', (43, 47))	('Overexpression', 'Var', (0, 14))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('relapse free survival', 'CPA', (48, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
98891	31611978	In breast cancer, there was a certain level of contradiction, although the OS was revealed to be positively correlated with PPIA expression level (HR, 0.83) in dataset GSE9893, the other survival values of breast cancer were negatively correlated with PPIA expression, such as disease free survival in GSE4922-GPL96 (HR, 6.99 and 6.07 with different primers), relapse free survival in GSE1456-GPL96 (HR, 7.41 and 7.12 with different primers), distant metastasis free survival in GSE11121, GSE9195 and GSE2990, and disease specific survival in GSE3494-GPL96 and GSE1456-GPL96.	('GSE2990', 'Var', (501, 508))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('distant metastasis free survival', 'CPA', (443, 475))	('PPIA', 'Gene', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('disease specific survival', 'CPA', (514, 539))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('PPIA', 'Gene', '5478', (252, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('negatively', 'NegReg', (225, 235))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('relapse free survival', 'CPA', (360, 381))	('PPIA', 'Gene', (252, 256))	('PPIA', 'Gene', '5478', (124, 128))	('GSE9195', 'Var', (489, 496))
98892	31611978	These results indicated that overexpression of PPIA was a risk factor for breast cancer progression and metastasis, and may be harnessed as a therapeutic target.	('breast cancer', 'Disease', (74, 87))	('PPIA', 'Gene', (47, 51))	('metastasis', 'CPA', (104, 114))	('PPIA', 'Gene', '5478', (47, 51))	('overexpression', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
98902	31611978	The prognoses of tumor grade 1, 2, 3 and 4 in those with high PPIA expression levels were all poorer than the prognoses of respective tumor grades with low or median PPIA expression levels in LIHC.	('PPIA', 'Gene', '5478', (166, 170))	('PPIA', 'Gene', (62, 66))	('tumor', 'Disease', (17, 22))	('high', 'Var', (57, 61))	('PPIA', 'Gene', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('LIHC', 'Disease', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PPIA', 'Gene', '5478', (62, 66))	('LIHC', 'Disease', 'MESH:D006528', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (134, 139))
98903	31611978	The prognosis of low or median PPIA expression in every tumor grade was better than the prognosis of high PPIA expression in every tumor grade, as presented in Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PPIA', 'Gene', (31, 35))	('tumor', 'Disease', (56, 61))	('PPIA', 'Gene', '5478', (106, 110))	('tumor', 'Disease', (131, 136))	('low', 'Var', (17, 20))	('PPIA', 'Gene', (106, 110))	('PPIA', 'Gene', '5478', (31, 35))	('expression', 'MPA', (36, 46))
98923	31611978	The OS of patients with high PPIA expression levels was significantly decreased compared with patients with low PPIA expression levels in the sorafenib-administered group.	('patients', 'Species', '9606', (94, 102))	('PPIA', 'Gene', '5478', (29, 33))	('sorafenib', 'Chemical', 'MESH:C471405', (142, 151))	('PPIA', 'Gene', '5478', (112, 116))	('decreased', 'NegReg', (70, 79))	('PPIA', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('PPIA', 'Gene', (112, 116))
98924	31611978	This indicated that PPIA played a specific role in the progression of LIHC in the poorer OS subgroup of the sorafenib-administered group and that inhibition of PPIA expression or PPIA inhibitor ciclosporin A may be beneficial for sorafenib-administered patients.	('PPIA', 'Gene', '5478', (160, 164))	('PPIA', 'Gene', (20, 24))	('LIHC', 'Disease', (70, 74))	('LIHC', 'Disease', 'MESH:D006528', (70, 74))	('patients', 'Species', '9606', (253, 261))	('sorafenib', 'Chemical', 'MESH:C471405', (108, 117))	('PPIA', 'Gene', '5478', (20, 24))	('PPIA', 'Gene', (160, 164))	('PPIA', 'Gene', '5478', (179, 183))	('ciclosporin A', 'Chemical', 'MESH:D016572', (194, 207))	('inhibition', 'Var', (146, 156))	('PPIA', 'Gene', (179, 183))	('sorafenib', 'Chemical', 'MESH:C471405', (230, 239))
98933	31611978	Lu et al revealed that basolateral CD147 induced hepatocyte polarity loss by E-cadherin ubiquitination and degradation in the progression of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('cadherin', 'molecular_function', 'GO:0008014', ('79', '87'))	('loss', 'NegReg', (69, 73))	('hepatocellular carcinoma', 'Disease', (141, 165))	('hepatocyte polarity', 'MPA', (49, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('degradation', 'MPA', (107, 118))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('basolateral', 'Var', (23, 34))	('degradation', 'biological_process', 'GO:0009056', ('107', '118'))	('ubiquitination', 'MPA', (88, 102))	('CD147', 'Gene', (35, 40))
98945	31611978	CD4+ T cells expressing more CD147 migrated more readily to PPIA.	('migrated', 'CPA', (35, 43))	('CD147', 'Var', (29, 34))	('CD4', 'Gene', '920', (0, 3))	('PPIA', 'Gene', '5478', (60, 64))	('PPIA', 'Gene', (60, 64))	('CD4', 'Gene', (0, 3))
98968	32085461	Among the main mechanisms used by mitochondria for the malignant transformation of cells, first, there is the production of ROS, which favors the accumulation of potential oncogenic defects in DNA, and the activation of probable oncogenic signaling pathways.	('mitochondria', 'cellular_component', 'GO:0005739', ('34', '46'))	('favors', 'PosReg', (135, 141))	('DNA', 'cellular_component', 'GO:0005574', ('193', '196'))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('oncogenic signaling pathways', 'Pathway', (229, 257))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('accumulation', 'PosReg', (146, 158))	('ROS', 'Gene', (124, 127))	('activation', 'PosReg', (206, 216))	('defects', 'Var', (182, 189))
98975	32085461	HIG2A has a role in the respiratory supercomplexes assembly, a function that has been evidenced in the C2C12 mouse cell line, where the knockdown of Higd2a (nomenclature of mice gene) impaired supercomplex formation by the release of CIV.	('formation', 'biological_process', 'GO:0009058', ('206', '215'))	('supercomplex formation', 'MPA', (193, 215))	('impaired', 'NegReg', (184, 192))	('Higd2a', 'Gene', (149, 155))	('rat', 'Species', '10116', (29, 32))	('knockdown', 'Var', (136, 145))	('mice', 'Species', '10090', (173, 177))	('release', 'MPA', (223, 230))	('CIV', 'MPA', (234, 237))	('respiratory supercomplexes assembly', 'MPA', (24, 59))	('mouse', 'Species', '10090', (109, 114))
98976	32085461	Recently, we showed that the knockdown of HIGD2A (nomenclature of a human gene) decreases the activity of Complex I in the supercomplexes of HEK293 cells.	('human', 'Species', '9606', (68, 73))	('knockdown', 'Var', (29, 38))	('decreases', 'NegReg', (80, 89))	('activity', 'MPA', (94, 102))	('HIGD2A', 'Gene', (42, 48))	('Complex I', 'Enzyme', (106, 115))	('decreases the activity of Complex I', 'Phenotype', 'HP:0011923', (80, 115))	('Complex I', 'cellular_component', 'GO:0030964', ('106', '115'))
98981	32085461	These studies evidenced several probable binding sites for different transcription factors related to cell cycle control, including E2F-1, E2F-2, E2F-3a, E2F-4, and E2F-5.	('E2F-4', 'Gene', '1874', (154, 159))	('binding', 'molecular_function', 'GO:0005488', ('41', '48'))	('E2F-4', 'Gene', (154, 159))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('E2F-5', 'Gene', (165, 170))	('E2F-3a', 'Var', (146, 152))	('binding', 'Interaction', (41, 48))	('cell cycle control', 'biological_process', 'GO:1901987', ('102', '120'))	('E2F-5', 'Gene', '1875', (165, 170))	('E2F-1, E2F-2', 'Gene', '1869;1870', (132, 144))
98989	32085461	Depletion of HIGD2A selectively impairs the viability of colon adenocarcinoma cells (DLD1), which are Ras mutant cells, suggesting a role of HIG2A in cell cycle regulation and a potential target in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutant', 'Var', (106, 112))	('viability', 'CPA', (44, 53))	('cancer', 'Disease', (198, 204))	('colon adenocarcinoma', 'Disease', (57, 77))	('HIGD2A', 'Gene', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Depletion', 'MPA', (0, 9))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (57, 77))	('impairs', 'NegReg', (32, 39))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('150', '171'))
98994	32085461	The microarray Illumina Human HT-12 V4.0 expression bead chips were used in the study; "Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL".	('facilitates', 'PosReg', (192, 203))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (121, 136))	('Lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('B-cell Lymphoma', 'Disease', (121, 136))	('Human', 'Species', '9606', (24, 29))	('selective translation', 'Var', (163, 184))	('HK2', 'Gene', (188, 191))	('HK2', 'Gene', '3099', (188, 191))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('DLBCL', 'Disease', (219, 224))	('development', 'CPA', (204, 215))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (121, 136))
99024	32085461	The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) database indicates that the HIGD2A gene (COSG58129) has been reported as having mutations in 29 unique samples out of a total of 35183 samples; therefore, HIGD2A is not a known cancer-driving gene.	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('mutations', 'Var', (159, 168))	('cancer', 'Disease', (256, 262))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('Cancer', 'Disease', (38, 44))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('HIGD2A', 'Gene', (107, 113))
99026	32085461	On the other hand, DNA methylation is a vital epigenetic mechanism that stabilizes gene expression and cellular states; their alteration has a role in tumor initiation and evolution.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor initiation', 'Disease', (151, 167))	('methylation', 'Var', (23, 34))	('alteration', 'Var', (126, 136))	('stabilizes', 'MPA', (72, 82))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('role', 'Reg', (143, 147))	('rat', 'Species', '10116', (130, 133))	('gene expression', 'MPA', (83, 98))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('tumor initiation', 'Disease', 'MESH:D009369', (151, 167))	('cellular states', 'MPA', (103, 118))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
99051	32085461	The effect of HIGD2A high expression level on DLBCL patient survival illustrates a downward trend of survival probability in patients (n = 11) with high expression in relation with patients (n = 36) with low expression, p = 0.85 (Figure 8).	('HIGD2A', 'Gene', (14, 20))	('survival', 'MPA', (101, 109))	('rat', 'Species', '10116', (75, 78))	('patient', 'Species', '9606', (181, 188))	('downward', 'NegReg', (83, 91))	('patients', 'Species', '9606', (181, 189))	('patient', 'Species', '9606', (52, 59))	('patient', 'Species', '9606', (125, 132))	('high expression', 'Var', (148, 163))	('patients', 'Species', '9606', (125, 133))
99099	32085461	Roscovitine is an inhibitor of CDK that suppresses the proliferation of mammalian cells lines, and roscovitine induced a significant increase in HIGD2A gene expression in the human embryonic kidney HEK293 cell line.	('human', 'Species', '9606', (175, 180))	('embryonic kidney', 'Disease', (181, 197))	('mammalian', 'Species', '9606', (72, 81))	('expression', 'MPA', (157, 167))	('rat', 'Species', '10116', (62, 65))	('roscovitine', 'Var', (99, 110))	('suppresses', 'NegReg', (40, 50))	('embryonic kidney', 'Disease', 'MESH:D007674', (181, 197))	('CDK', 'molecular_function', 'GO:0004693', ('31', '34'))	('increase', 'PosReg', (133, 141))	('HIGD2A gene', 'Gene', (145, 156))	('Roscovitine', 'Chemical', 'MESH:D000077546', (0, 11))	('roscovitine', 'Chemical', 'MESH:D000077546', (99, 110))	('gene expression', 'biological_process', 'GO:0010467', ('152', '167'))
99119	25120707	Molecular analysis of BRAF, using a pyrosequencing approach, revealed the presence of BRAF V600E mutation.	('V600E', 'Var', (91, 96))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('BRAF', 'Gene', (86, 90))
99144	25120707	The molecular analysis revealed no evidence of a BRAF V600E mutation (Fig.	('V600E', 'Var', (54, 59))	('BRAF', 'Gene', (49, 53))	('V600E', 'Mutation', 'rs113488022', (54, 59))
99164	25120707	In addition, the BRAF inhibitor, vemurafenib, has not been considered as a common treatment option for patients with mucosal melanoma, as BRAF mutations have been identified much less frequently in patients with mucosal melanoma compared with those arising from cutaneous surfaces.	('mucosal melanoma', 'Disease', (212, 228))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('patients', 'Species', '9606', (198, 206))	('mucosal melanoma', 'Disease', 'MESH:D008545', (212, 228))	('mucosal melanoma', 'Disease', (117, 133))	('mucosal melanoma', 'Disease', 'MESH:D008545', (117, 133))	('vemurafenib', 'Chemical', 'MESH:D000077484', (33, 44))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('patients', 'Species', '9606', (103, 111))	('BRAF', 'Gene', (138, 142))	('mutations', 'Var', (143, 152))
99165	25120707	However, recent molecular advances have led to the identification of c-KIT as a promising target in OMM, as c-KIT gene alterations have been associated with a frequency of 10-40% in patients with mucosal melanoma, with clinical trials demonstrating the activity of c-KIT inhibitors in the subgroup harboring KIT mutations.	('c-KIT', 'Gene', (69, 74))	('c-KIT', 'Gene', '3815', (69, 74))	('patients', 'Species', '9606', (182, 190))	('as c', 'Gene', '29108', (105, 109))	('KIT', 'molecular_function', 'GO:0005020', ('110', '113'))	('associated', 'Reg', (141, 151))	('c-KIT', 'Gene', (108, 113))	('as c', 'Gene', (105, 109))	('c-KIT', 'Gene', '3815', (108, 113))	('rat', 'Species', '10116', (242, 245))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('KIT', 'molecular_function', 'GO:0005020', ('267', '270'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (196, 212))	('c-KIT', 'Gene', (265, 270))	('OMM', 'Disease', (100, 103))	('rat', 'Species', '10116', (123, 126))	('c-KIT', 'Gene', '3815', (265, 270))	('KIT', 'molecular_function', 'GO:0005020', ('308', '311'))	('alterations', 'Var', (119, 130))	('mucosal melanoma', 'Disease', (196, 212))	('KIT', 'molecular_function', 'GO:0005020', ('71', '74'))	('OMM', 'Chemical', '-', (100, 103))
99166	25120707	While mucosal and acral melanomas account for ~65% of all melanomas in Chinese and other Asian populations, in Caucasian populations the predominant location is the trunk and legs, with detection of KIT mutations identified in <=11% of all melanomas in China.	('acral melanomas', 'Disease', 'MESH:D008545', (18, 33))	('melanomas', 'Disease', 'MESH:D008545', (240, 249))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('trunk', 'cellular_component', 'GO:0043198', ('165', '170'))	('acral melanomas', 'Phenotype', 'HP:0012060', (18, 33))	('melanomas', 'Disease', (240, 249))	('melanomas', 'Disease', (58, 67))	('China', 'Species', '998089', (253, 258))	('KIT', 'molecular_function', 'GO:0005020', ('199', '202'))	('melanomas', 'Disease', 'MESH:D008545', (24, 33))	('acral melanomas', 'Disease', (18, 33))	('melanomas', 'Disease', (24, 33))	('melanomas', 'Phenotype', 'HP:0002861', (240, 249))	('mutations', 'Var', (203, 212))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('KIT', 'Gene', (199, 202))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
99167	25120707	By contrast, a high prevalence of BRAF mutations (36%) and a lack of KIT mutations were previously found in a study of 11 patients with sinonasal melanoma in Italy.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('KIT', 'molecular_function', 'GO:0005020', ('69', '72'))	('sinonasal melanoma', 'Disease', 'MESH:D008545', (136, 154))	('mutations', 'Var', (39, 48))	('sinonasal melanoma', 'Disease', (136, 154))	('patients', 'Species', '9606', (122, 130))	('BRAF', 'Gene', (34, 38))
99171	25120707	A novel therapeutic approach has been suggested for advanced-stage cutaneous melanoma, whereby a BRAF mutation at codon 600 has been identified, leading to a novel approach for drug development in the advanced setting.	('mutation', 'Var', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('cutaneous melanoma', 'Disease', (67, 85))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (67, 85))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (67, 85))	('BRAF', 'Gene', (97, 101))
99172	25120707	V600E, a protein substitution of valine for glutamic acid at position 600 (Val600Glu), is the most common BRAF mutation observed in cutaneous melanoma, which consists of a T1799A transversion mutation in exon 15 of this gene.	('T1799A', 'Mutation', 'rs113488022', (172, 178))	('cutaneous melanoma', 'Disease', (132, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (132, 150))	('BRAF', 'Gene', (106, 110))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('valine for glutamic acid at position 600', 'Mutation', 'rs113488022', (33, 73))	('Val600Glu', 'SUBSTITUTION', 'None', (75, 84))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('V600E', 'Var', (0, 5))	('Val600Glu', 'Var', (75, 84))
99173	25120707	This mutation accounts for >90% of all BRAF mutations detected thus far in cutaneous melanoma, leading to ERK activation and a subsequent proliferation and survival advantage in melanoma cells.	('ERK', 'Protein', (106, 109))	('activation', 'PosReg', (110, 120))	('proliferation', 'CPA', (138, 151))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('mutations', 'Var', (44, 53))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('survival advantage', 'CPA', (156, 174))	('cutaneous melanoma', 'Disease', (75, 93))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (75, 93))	('ERK', 'molecular_function', 'GO:0004707', ('106', '109'))	('rat', 'Species', '10116', (145, 148))
99175	25120707	Frequently, NRAS and BRAF mutations have been observed in cutaneous melanoma and in subsets of mucosal melanoma.	('mucosal melanoma', 'Disease', 'MESH:D008545', (95, 111))	('cutaneous melanoma', 'Disease', (58, 76))	('observed', 'Reg', (46, 54))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('NRAS', 'Gene', (12, 16))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('mutations', 'Var', (26, 35))	('NRAS', 'Gene', '4893', (12, 16))	('BRAF', 'Gene', (21, 25))	('mucosal melanoma', 'Disease', (95, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))
99177	25120707	Mutations in the c-KIT gene, along with BRAF mutations, in part, considered to be involved in the mechanism of development and progression of melanoma, have been identified in mucosal melanoma, which not only implicates BRAF, but also c-KIT, as a promising molecular target.	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('mutations', 'Var', (45, 54))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('melanoma', 'Disease', (184, 192))	('c-KIT', 'Gene', (17, 22))	('identified', 'Reg', (162, 172))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('c-KIT', 'Gene', '3815', (17, 22))	('mucosal melanoma', 'Disease', (176, 192))	('Mutations', 'Var', (0, 9))	('mucosal melanoma', 'Disease', 'MESH:D008545', (176, 192))	('KIT', 'molecular_function', 'GO:0005020', ('237', '240'))	('c-KIT', 'Gene', (235, 240))	('c-KIT', 'Gene', '3815', (235, 240))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
99179	25120707	One targeted therapy is vemurafenib, which was approved by the US Food and Drug Administration in August 2011 for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E.	('patients', 'Species', '9606', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('vemurafenib', 'Chemical', 'MESH:D000077484', (24, 35))	('V600E', 'Mutation', 'rs113488022', (191, 196))	('rat', 'Species', '10116', (88, 91))	('BRAF V600E', 'Var', (186, 196))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
99183	25120707	These types are all characterized by unique combinations of genome-wide aberrations in DNA copy number and oncogenic alterations.	('rat', 'Species', '10116', (76, 79))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('aberrations', 'Var', (72, 83))	('DNA copy', 'Gene', (87, 95))	('rat', 'Species', '10116', (121, 124))
99184	25120707	The current study presents a case of OMM harboring the BRAF V600E mutation, and highlights the importance of testing patients with oral melanoma for the presence of BRAF mutations.	('oral melanoma', 'Disease', (131, 144))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('OMM', 'Chemical', '-', (37, 40))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('oral melanoma', 'Disease', 'MESH:D008545', (131, 144))	('patients', 'Species', '9606', (117, 125))	('V600E', 'Var', (60, 65))	('BRAF', 'Gene', (55, 59))
99187	25120707	Despite BRAF mutations appearing to be frequently involved in the pathogenesis and progression of cutaneous malignant melanoma, recently, several studies have demonstrated a low incidence of BRAF mutations in melanoma arising from non-hair-bearing skin that is relatively protected from ultraviolet light damage, in melanoma arising from mucosa that is completely sun protected and in oral malignant melanoma.	('BRAF', 'Gene', (191, 195))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (98, 126))	('oral malignant melanoma', 'Disease', 'MESH:D008545', (385, 408))	('pathogenesis', 'biological_process', 'GO:0009405', ('66', '78'))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (98, 126))	('rat', 'Species', '10116', (166, 169))	('melanoma', 'Disease', 'MESH:D008545', (400, 408))	('oral malignant melanoma', 'Disease', (385, 408))	('malignant melanoma', 'Phenotype', 'HP:0002861', (390, 408))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('melanoma', 'Disease', (316, 324))	('cutaneous malignant melanoma', 'Disease', (98, 126))	('mutations', 'Var', (196, 205))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('melanoma', 'Phenotype', 'HP:0002861', (400, 408))	('melanoma', 'Disease', (400, 408))	('malignant melanoma', 'Phenotype', 'HP:0002861', (108, 126))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))
99346	19223760	Figure 2E demonstrates that after 16 days in soft agar, both the C8161 and C8161-Neo cells were able to form numerous large colonies, whereas all four EphA2 AS clones formed only a few small colonies under the same culture conditions.	('colon', 'Disease', (191, 196))	('colon', 'Disease', 'MESH:D015179', (124, 129))	('agar', 'Chemical', 'MESH:D000362', (50, 54))	('C8161', 'Var', (65, 70))	('colon', 'Disease', 'MESH:D015179', (191, 196))	('C8161-Neo', 'Var', (75, 84))	('colon', 'Disease', (124, 129))
99347	19223760	Based on our in vitro observations, we challenged the C8161, C8161-Neo, EphA2 AS 0.2-1, EphA2 0.2-2, EphA2 0.2-3 and EphA2 0.35-1 to form tumors in vivo using an orthotopic mouse model for cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (189, 207))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (189, 207))	('C8161', 'Var', (54, 59))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('mouse', 'Species', '10090', (173, 178))	('C8161-Neo', 'Var', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('cutaneous melanoma', 'Disease', (189, 207))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
99353	19223760	Immunohistochemical analysis of EphA2 in tumor xenografts from mice injected with C8161, C8161-Neo, EphA2 AS 0.2-2-1 or EphA2 AS 0.4-8-2, revealed a decrease in the level of EphA2 expression in both EphA2 AS clones, as demonstrated in Figure 3B.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EphA2', 'Protein', (174, 179))	('C8161', 'Var', (82, 87))	('tumor', 'Disease', (41, 46))	('expression', 'MPA', (180, 190))	('mice', 'Species', '10090', (63, 67))	('C8161-Neo', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('decrease', 'NegReg', (149, 157))
99354	19223760	Next, we assessed in vivo tumor cell proliferation by measuring tumor size over the course of three weeks after injection of C8161, C8161-Neo, EphA2 AS 0.2-2-1 or EphA2 AS 0.4-8-2.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('tumor', 'Disease', (64, 69))	('C8161-Neo', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('C8161', 'Var', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
99359	19223760	3E) have evidence of metastatic lesions in a pattern that has previously been reported for this cell line; however we were unable to detect this pattern of metastasis in mice injected with EphA2 AS clones as shown in Figure 3E (C8161 LN vs. EphA2 AS 0.2-2 LN and C8161-Neo lung vs. EphA2 AS 0.2-2 lung).	('C8161 LN', 'Var', (228, 236))	('C8161-Neo lung', 'Disease', (263, 277))	('mice', 'Species', '10090', (170, 174))	('C8161-Neo lung', 'Disease', 'MESH:D008171', (263, 277))
99379	19223760	Activation of Chk2 through phosphorylation on T68 in response to DNA damage associated with cellular stress, results in the phosphorylation of p53 thus promoting growth arrest at the G1 checkpoint.	('growth arrest', 'Disease', 'MESH:D006323', (162, 175))	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('p53', 'Gene', '7157', (143, 146))	('growth arrest', 'Phenotype', 'HP:0001510', (162, 175))	('promoting', 'PosReg', (152, 161))	('Chk2', 'Gene', (14, 18))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('DNA', 'cellular_component', 'GO:0005574', ('65', '68'))	('T68', 'Var', (46, 49))	('Activation', 'PosReg', (0, 10))	('phosphorylation', 'MPA', (124, 139))	('Chk2', 'Gene', '11200', (14, 18))	('phosphorylation', 'Var', (27, 42))	('growth arrest', 'Disease', (162, 175))	('p53', 'Gene', (143, 146))
99381	19223760	However, it has been reported that the C8161 cells contain a mutation for p53 in one allele, essentially rendering the G1 checkpoint ineffective in this particular cell line.	('mutation', 'Var', (61, 69))	('p53', 'Gene', (74, 77))	('G1 checkpoint ineffective', 'MPA', (119, 144))	('p53', 'Gene', '7157', (74, 77))
99384	19223760	C8161 is reported to contain WT B-Raf, and so it is plausible that EphA2 promotes melanoma proliferation principally by regulating the activity of kinases responsible for mediating the G2 checkpoint, in cases where p53 is mutated or absent.	('melanoma proliferation', 'Disease', (82, 104))	('regulating', 'Reg', (120, 130))	('B-Raf', 'Gene', (32, 37))	('B-Raf', 'Gene', '673', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('p53', 'Gene', (215, 218))	('C8161', 'Var', (0, 5))	('activity', 'MPA', (135, 143))	('EphA2', 'Gene', (67, 72))	('p53', 'Gene', '7157', (215, 218))	('promotes', 'PosReg', (73, 81))	('melanoma proliferation', 'Disease', 'MESH:D008545', (82, 104))
99385	19223760	Further experiments are needed to rigorously address this issue and to determine how EphA2 results in increased phosphorylation of Chk2.	('Chk2', 'Gene', '11200', (131, 135))	('phosphorylation', 'MPA', (112, 127))	('Chk2', 'Gene', (131, 135))	('increased', 'PosReg', (102, 111))	('EphA2', 'Var', (85, 90))	('phosphorylation', 'biological_process', 'GO:0016310', ('112', '127'))
99386	19223760	Although we propose that proliferation is the underlying mechanism for the inability of the metastatic melanoma tumor cells having decreased levels of EphA2 to form tumors in an orthotopic mouse model, the means by which proliferation is affected could be two fold: (1) If EphA2 serves as a growth factor receptor for melanoma, then downregulation of this receptor would result in a decrease in the proliferative capacity of these cells; and/or (2) if EphA2 plays a role in tumor neovascularization either by promoting angiogenesis and/or vasculogenic mimicry, tumor growth would be inhibited due to an inadequate blood supply.	('proliferative capacity', 'CPA', (399, 421))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('downregulation', 'NegReg', (333, 347))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('melanoma tumor', 'Disease', 'MESH:D008545', (103, 117))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (474, 479))	('melanoma', 'Disease', (103, 111))	('mouse', 'Species', '10090', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (561, 566))	('growth factor receptor', 'Gene', '20187', (291, 313))	('tumor', 'Disease', 'MESH:D009369', (561, 566))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('inhibited', 'NegReg', (583, 592))	('EphA2', 'Var', (273, 278))	('angiogenesis', 'biological_process', 'GO:0001525', ('519', '531'))	('tumor', 'Disease', (112, 117))	('growth factor receptor', 'Gene', (291, 313))	('tumors', 'Disease', (165, 171))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('melanoma tumor', 'Disease', (103, 117))	('tumor', 'Disease', (165, 170))	('vasculogenic mimicry', 'CPA', (539, 559))	('decrease', 'NegReg', (383, 391))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('tumor', 'Disease', (474, 479))	('promoting', 'PosReg', (509, 518))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', (561, 566))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('EphA2', 'Var', (452, 457))	('tumor', 'Disease', 'MESH:D009369', (474, 479))	('angiogenesis', 'CPA', (519, 531))
99389	19223760	Furthermore, there have been several reports for both ovarian and colon carcinoma linking EphA2 to increased microvessel density.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('EphA2', 'Var', (90, 95))	('ovarian and colon carcinoma', 'Disease', 'MESH:D010051', (54, 81))	('increased', 'PosReg', (99, 108))	('microvessel density', 'CPA', (109, 128))
99397	19223760	Additionally, our in vivo observations demonstrating C8161 cells but not EphA2 AS cells injected orthotopically into nu/nu mice form metastatic lesions in a pattern that has been described previously, despite having injected only one-quarter of the cells typically used for this particular model, suggest that EphA2 may serve as a promoter of melanoma metastasis.	('C8161', 'Var', (53, 58))	('melanoma metastasis', 'Disease', 'MESH:D009362', (343, 362))	('melanoma', 'Phenotype', 'HP:0002861', (343, 351))	('melanoma metastasis', 'Disease', (343, 362))	('metastatic lesions', 'CPA', (133, 151))	('mice', 'Species', '10090', (123, 127))
99398	19223760	It may be that EphA2 simply offers a selective growth advantage for melanoma cells that is coincidental with an invasive phenotype, thereby concomitantly selecting for both highly proliferative and invasive melanoma tumor cells.	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('EphA2', 'Var', (15, 20))	('invasive melanoma tumor', 'Disease', 'MESH:D008545', (198, 221))	('melanoma', 'Disease', (68, 76))	('growth advantage', 'CPA', (47, 63))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('highly proliferative', 'CPA', (173, 193))	('invasive melanoma tumor', 'Disease', (198, 221))
99407	19223760	The human cutaneous melanoma cell lines, C8161, A375P and A375M have been described previously and were maintained in RPMI 1640 (Invitrogen Corporation, Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS) and 0.1% gentamicin sulfate (Gemini Bioproducts, Calabasas CA).	('A375M', 'Var', (58, 63))	('bovine', 'Species', '9913', (195, 201))	('A375P', 'Var', (48, 53))	('RPMI', 'Chemical', '-', (118, 122))	('human', 'Species', '9606', (4, 9))	('gentamicin sulfate', 'Chemical', 'MESH:D005839', (223, 241))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('C8161', 'Var', (41, 46))	('cutaneous melanoma', 'Disease', (10, 28))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (10, 28))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (10, 28))
99448	33490091	Further in vitro biochemical experiments, including CCK8 assays, wound-healing assays and transwell assays, have verified that IL10RA can significantly inhibit the proliferation, migration and invasion of melanoma cells.	('inhibit', 'NegReg', (152, 159))	('wound-healing', 'biological_process', 'GO:0042060', ('65', '78'))	('si', 'Chemical', 'MESH:D012825', (138, 140))	('IL10', 'molecular_function', 'GO:0005141', ('127', '131'))	('proliferation', 'CPA', (164, 177))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('melanoma', 'Disease', (205, 213))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('IL10RA', 'Var', (127, 133))
99470	33490091	We have conducted further in-vitro biochemical experiments, including CCK8 assays, wound-healing assays and transwell assays, and verified that IL10RA can significantly inhibit the proliferation, migration and invasion of melanoma cells.	('proliferation', 'CPA', (181, 194))	('inhibit', 'NegReg', (169, 176))	('IL10', 'molecular_function', 'GO:0005141', ('144', '148'))	('si', 'Chemical', 'MESH:D012825', (214, 216))	('IL10RA', 'Var', (144, 150))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('melanoma', 'Disease', (222, 230))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('wound-healing', 'biological_process', 'GO:0042060', ('83', '96'))	('si', 'Chemical', 'MESH:D012825', (155, 157))
99477	33490091	Second, an adjacency matrix is constructed using a power function as below 1: in which Aij is the adjacency element between gene i and gene j, pij represents the PCC between gene i and gene j, and beta is a soft thresholding parameter that could stress strong correlations between genes and penalize weak correlations.	('stress', 'PosReg', (246, 252))	('pij', 'Var', (143, 146))	('correlations', 'Interaction', (260, 272))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('PCC', 'cellular_component', 'GO:0120205', ('162', '165'))
99523	33490091	The malfunction of these genes may result in melanoma metastasis, as reported that Rho guanine-nucleotide exchange factor is necessary for effective melanoma metastasis (Lindsay et al.,).	('result in', 'Reg', (35, 44))	('melanoma metastasis', 'Disease', (45, 64))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('guanine', 'Chemical', 'MESH:D006147', (87, 94))	('melanoma metastasis', 'Disease', (149, 168))	('melanoma metastasis', 'Disease', 'MESH:D009362', (45, 64))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('melanoma metastasis', 'Disease', 'MESH:D009362', (149, 168))	('Rho guanine-nucleotide exchange factor', 'molecular_function', 'GO:0005089', ('83', '121'))	('malfunction', 'Var', (4, 15))
99534	33490091	found that in papillary thyroid carcinoma frequent deletion variants were detected in the 6q25.2 region containing the OPMR1 and IPCEF1 genes, and the 7q14.2 region containing the AOAH and ELMO1 genes.	('ELMO1', 'Gene', (189, 194))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (24, 41))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (14, 41))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (14, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('IPCEF1', 'Gene', (129, 135))	('OPMR1', 'Gene', (119, 124))	('ELMO1', 'Gene', '9844', (189, 194))	('IPCEF1', 'Gene', '26034', (129, 135))	('deletion variants', 'Var', (51, 68))	('papillary thyroid carcinoma', 'Disease', (14, 41))
99535	33490091	Besides, according to the risk classification of the American Joint Committee on Cancer stage and American Thyroid Association (ATA), deletion variants are more frequent in lower risk sample (Passon et al.,).	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('Cancer', 'Disease', (81, 87))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('deletion variants', 'Var', (134, 151))	('si', 'Chemical', 'MESH:D012825', (35, 37))
99543	33490091	For example, IL10 deficient patients develop severe infantile-onset inflammatory bowel disease (IBD) (Shouval et al.,).	('IBD', 'Disease', (96, 99))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (68, 94))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (68, 94))	('IBD', 'Disease', 'MESH:D015212', (96, 99))	('inflammatory bowel disease', 'Disease', (68, 94))	('IL10', 'Gene', '3586', (13, 17))	('IL10', 'molecular_function', 'GO:0005141', ('13', '17'))	('IL10', 'Gene', (13, 17))	('deficient', 'Var', (18, 27))	('patients', 'Species', '9606', (28, 36))	('IBD', 'Phenotype', 'HP:0002037', (96, 99))
99550	33490091	Moreover, it has been reported that the IL10RA Ser138Gly variant showed a weak association with the risk of all lymphoma combined (odds ratio [OR], 0.81; 95% CI, 0.65-1.02), mainly driven by the 50% risk reduction for Hodgkin's lymphoma (HL) (Nieters et al.,).	('lymphoma', 'Disease', (112, 120))	('reduction', 'NegReg', (204, 213))	('IL10RA', 'Gene', (40, 46))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (218, 236))	("Hodgkin's lymphoma", 'Disease', (218, 236))	('HL', 'Gene', '3990', (238, 240))	('lymphoma', 'Disease', 'MESH:D008223', (228, 236))	('lymphoma', 'Disease', 'MESH:D008223', (112, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (228, 236))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (218, 236))	('IL10', 'molecular_function', 'GO:0005141', ('40', '44'))	('HL', 'Phenotype', 'HP:0012189', (238, 240))	('Ser', 'cellular_component', 'GO:0005790', ('47', '50'))	('Ser138Gly', 'Var', (47, 56))	('Ser138Gly', 'SUBSTITUTION', 'None', (47, 56))	('lymphoma', 'Disease', (228, 236))
99556	33490091	We next tested whether IL10RA can affect the migration of melanoma cells.	('tested', 'Reg', (8, 14))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('IL10RA', 'Var', (23, 29))	('IL10', 'molecular_function', 'GO:0005141', ('23', '27'))	('affect', 'Reg', (34, 40))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
99557	33490091	After 24 h, A375 and B16-F10 cells transfected with si-IL10RA migrated to the middle were much larger than the control group, as shown in Figure 8 (p < 0.001).	('IL10', 'molecular_function', 'GO:0005141', ('55', '59'))	('si-IL10RA', 'Var', (52, 61))	('larger', 'PosReg', (95, 101))	('B16-F10', 'CellLine', 'CVCL:0159', (21, 28))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('A375', 'CellLine', 'CVCL:0132', (12, 16))
99558	33490091	Therefore, wound healing assays demonstrated that knockdown of IL10RA can promote the migration of melanoma cells compared to control groups.	('wound healing', 'biological_process', 'GO:0042060', ('11', '24'))	('promote', 'PosReg', (74, 81))	('knockdown', 'Var', (50, 59))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('IL10RA', 'Gene', (63, 69))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('IL10', 'molecular_function', 'GO:0005141', ('63', '67'))
99560	33490091	After incubated at 37 C for 24 h, the number of A375 and B16-F10 cells transfected with si-IL10RA from the upper chamber to the lower chamber was larger that of the control group, which indicates that invasion of melanoma cells are promoted by IL10RA downregulation, as shown in Figure 9 (p < 0.001).	('promoted', 'PosReg', (232, 240))	('B16-F10', 'CellLine', 'CVCL:0159', (57, 64))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('A375', 'CellLine', 'CVCL:0132', (48, 52))	('IL10', 'molecular_function', 'GO:0005141', ('91', '95'))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('downregulation', 'NegReg', (251, 265))	('si-IL10RA', 'Var', (88, 97))	('IL10', 'molecular_function', 'GO:0005141', ('244', '248'))	('IL10RA', 'Gene', (244, 250))	('melanoma', 'Disease', 'MESH:D008545', (213, 221))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('melanoma', 'Disease', (213, 221))
99567	33490091	Importantly, they also found that HI-511, a dual-target inhibitor against both AURKB and BRAF V600E, suppresses both drug-sensitive and -resistant melanoma development by inducing apoptosis and mediating the inhibition of the BRAF/MEK/ERKs and PI3K-AKT signaling pathways.	('HI-511', 'Chemical', '-', (34, 40))	('suppresses', 'NegReg', (101, 111))	('AKT', 'Gene', '207', (249, 252))	('HI-511', 'Var', (34, 40))	('BRAF', 'Gene', '673', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('BRAF', 'Gene', (89, 93))	('apoptosis', 'CPA', (180, 189))	('apoptosis', 'biological_process', 'GO:0097194', ('180', '189'))	('AURKB', 'Gene', (79, 84))	('AKT signaling', 'biological_process', 'GO:0043491', ('249', '262'))	('apoptosis', 'biological_process', 'GO:0006915', ('180', '189'))	('si', 'Chemical', 'MESH:D012825', (125, 127))	('BRAF', 'Gene', '673', (226, 230))	('BRAF', 'Gene', (226, 230))	('si', 'Chemical', 'MESH:D012825', (253, 255))	('AKT', 'Gene', (249, 252))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('si', 'Chemical', 'MESH:D012825', (186, 188))	('inhibition', 'NegReg', (208, 218))	('AURKB', 'Gene', '9212', (79, 84))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('PI3K', 'molecular_function', 'GO:0016303', ('244', '248'))	('inducing', 'PosReg', (171, 179))	('V600E', 'Mutation', 'rs113488022', (94, 99))
99572	33490091	PI3K/AKT signaling activation and EBV lytic induction responded to IL-10 knockdown (Gao et al.,).	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('AKT signaling', 'biological_process', 'GO:0043491', ('5', '18'))	('IL-10', 'Gene', (67, 72))	('activation', 'PosReg', (19, 29))	('AKT', 'Gene', '207', (5, 8))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('IL-10', 'Gene', '3586', (67, 72))	('AKT', 'Gene', (5, 8))	('IL-10', 'molecular_function', 'GO:0005141', ('67', '72'))	('EBV lytic induction', 'CPA', (34, 53))	('knockdown', 'Var', (73, 82))
99573	33490091	found that the PI3K agonist impaired the tolerance of Kupffer cells (KCs) to endotoxin and increased the phosphorylation levels of NF-kappaB in KCs, while the secretion of IL10 was significantly decreased.	('PI3K', 'molecular_function', 'GO:0016303', ('15', '19'))	('IL10', 'Gene', (172, 176))	('IL10', 'Gene', '3586', (172, 176))	('phosphorylation levels', 'MPA', (105, 127))	('decreased', 'NegReg', (195, 204))	('IL10', 'molecular_function', 'GO:0005141', ('172', '176'))	('secretion', 'biological_process', 'GO:0046903', ('159', '168'))	('NF-kappaB', 'Gene', '4790', (131, 140))	('increased', 'PosReg', (91, 100))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('secretion', 'MPA', (159, 168))	('PI3K', 'Var', (15, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('105', '120'))	('tolerance', 'MPA', (41, 50))	('NF-kappaB', 'Gene', (131, 140))	('impaired', 'NegReg', (28, 36))
99576	33490091	Therefore, we speculate that IL10RA may inhibit the metastasis of melanoma by regulating the PI3K-AKT signaling pathway, which we plan to do further exploration to verify the mediation of IL10RA in PI3K-AKT pathway.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('inhibit', 'NegReg', (40, 47))	('signaling pathway', 'biological_process', 'GO:0007165', ('102', '119'))	('metastasis of', 'CPA', (52, 65))	('AKT', 'Gene', '207', (98, 101))	('PI3K', 'molecular_function', 'GO:0016303', ('198', '202'))	('IL10RA', 'Var', (29, 35))	('regulating', 'Reg', (78, 88))	('IL10', 'molecular_function', 'GO:0005141', ('188', '192'))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('AKT', 'Gene', (203, 206))	('PI3K', 'molecular_function', 'GO:0016303', ('93', '97'))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('IL10', 'molecular_function', 'GO:0005141', ('29', '33'))	('AKT', 'Gene', (98, 101))	('AKT signaling', 'biological_process', 'GO:0043491', ('98', '111'))	('AKT', 'Gene', '207', (203, 206))
99584	33490091	Aberrant IL10RA expression in melanoma creates autocrine circuitry involving endogenous IL10, which disrupts basal STAT3 phosphorylation and dampens the induction of anti-inflammatory signals, such as IL6, and slightly increases the resistance of A375 cells to apoptosis, thus showing that receptor absence is a critical mechanism for preventing this autocrine loop, enabling effective paracrine communication and controlling the cellular response (Kang et al.,).	('si', 'Chemical', 'MESH:D012825', (184, 186))	('increases', 'PosReg', (219, 228))	('autocrine', 'MPA', (47, 56))	('IL10', 'Gene', '3586', (9, 13))	('IL6', 'Gene', (201, 204))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('IL10', 'Gene', '3586', (88, 92))	('IL10', 'molecular_function', 'GO:0005141', ('9', '13'))	('phosphorylation', 'biological_process', 'GO:0016310', ('121', '136'))	('apoptosis', 'biological_process', 'GO:0097194', ('261', '270'))	('A375', 'CellLine', 'CVCL:0132', (247, 251))	('apoptosis', 'biological_process', 'GO:0006915', ('261', '270'))	('Aberrant', 'Var', (0, 8))	('IL6', 'molecular_function', 'GO:0005138', ('201', '204'))	('IL10', 'molecular_function', 'GO:0005141', ('88', '92'))	('disrupts', 'NegReg', (100, 108))	('resistance', 'MPA', (233, 243))	('induction of anti-inflammatory signals', 'MPA', (153, 191))	('enabling', 'PosReg', (367, 375))	('cellular response', 'CPA', (430, 447))	('STAT3', 'Gene', (115, 120))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('si', 'Chemical', 'MESH:D012825', (267, 269))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('STAT3', 'Gene', '6774', (115, 120))	('dampens', 'NegReg', (141, 148))	('IL10', 'Gene', (9, 13))	('IL10', 'Gene', (88, 92))	('si', 'Chemical', 'MESH:D012825', (235, 237))	('IL6', 'Gene', '3569', (201, 204))	('paracrine communication', 'MPA', (386, 409))
99585	33490091	also found that gene expression of IL10, IL10RA, and IL10RB were remarkably overexpressed in diffuse large B-cell lymphomas (DLBCLs) which were dependent on IL10-STAT3 signaling and blocking the IL10R killed DLBCL cell lines through cell cycle arrest and induction of apoptosis due to the interruption of IL10-JAK-STAT signaling.	('B-cell lymphomas', 'Disease', (107, 123))	('STAT', 'Gene', '6774', (314, 318))	('IL10R', 'molecular_function', 'GO:0004920', ('195', '200'))	('STAT', 'Gene', (314, 318))	('IL10', 'Gene', '3586', (35, 39))	('overexpressed', 'PosReg', (76, 89))	('si', 'Chemical', 'MESH:D012825', (319, 321))	('IL10RB', 'Gene', '3588', (53, 59))	('gene expression', 'biological_process', 'GO:0010467', ('16', '31'))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('apoptosis', 'CPA', (268, 277))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (233, 250))	('IL10', 'Gene', (157, 161))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('IL10R', 'Gene', (41, 46))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (107, 123))	('signaling', 'biological_process', 'GO:0023052', ('319', '328'))	('IL10R', 'Gene', '3587', (53, 58))	('IL10', 'molecular_function', 'GO:0005141', ('157', '161'))	('blocking', 'Var', (182, 190))	('arrest', 'Disease', (244, 250))	('IL10', 'Gene', (53, 57))	('IL10R', 'Gene', '3587', (195, 200))	('JAK', 'molecular_function', 'GO:0004713', ('310', '313'))	('IL10', 'molecular_function', 'GO:0005141', ('35', '39'))	('IL10', 'molecular_function', 'GO:0005141', ('305', '309'))	('IL10', 'Gene', '3586', (157, 161))	('IL10', 'Gene', (195, 199))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('255', '277'))	('IL10R', 'Gene', (53, 58))	('STAT3', 'Gene', (162, 167))	('IL10', 'Gene', '3586', (41, 45))	('IL10R', 'Gene', (195, 200))	('IL10', 'Gene', '3586', (53, 57))	('IL10', 'Gene', (305, 309))	('lymphomas', 'Phenotype', 'HP:0002665', (114, 123))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('233', '250'))	('IL10', 'Gene', (41, 45))	('STAT3', 'Gene', '6774', (162, 167))	('IL10', 'Gene', '3586', (195, 199))	('arrest', 'Disease', 'MESH:D006323', (244, 250))	('IL10', 'Gene', (35, 39))	('interruption', 'NegReg', (289, 301))	('si', 'Chemical', 'MESH:D012825', (274, 276))	('IL10', 'molecular_function', 'GO:0005141', ('53', '57'))	('IL10RB', 'Gene', (53, 59))	('IL10R', 'Gene', '3587', (41, 46))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (107, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('STAT', 'Gene', '6774', (162, 166))	('IL10', 'molecular_function', 'GO:0005141', ('41', '45'))	('IL10', 'Gene', '3586', (305, 309))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('STAT', 'Gene', (162, 166))
99587	33490091	found higher levels of IL10RA is accompanied by a corresponding decrease in miR-15a, miR-185, and miR-211 in melanoma samples.	('miR-185', 'Gene', (85, 92))	('miR-211', 'Gene', (98, 105))	('decrease', 'NegReg', (64, 72))	('IL10RA', 'Var', (23, 29))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('miR-15a', 'Gene', '406948', (76, 83))	('melanoma', 'Disease', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('miR-15a', 'Gene', (76, 83))	('IL10', 'molecular_function', 'GO:0005141', ('23', '27'))	('miR-211', 'Gene', '406993', (98, 105))	('higher', 'PosReg', (6, 12))	('miR-185', 'Gene', '406961', (85, 92))
99588	33490091	IL10RA was a target of these miRNAs, and inhibition of them obviously promotes the proliferation in the melanoma cell lines, and this effect will be suppressed by specific knockdown of IL10RA (Venza et al.,).	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('IL10RA', 'Gene', (185, 191))	('proliferation', 'CPA', (83, 96))	('IL10', 'molecular_function', 'GO:0005141', ('0', '4'))	('inhibition', 'Var', (41, 51))	('IL10', 'molecular_function', 'GO:0005141', ('185', '189'))	('promotes', 'PosReg', (70, 78))	('suppressed', 'NegReg', (149, 159))	('knockdown', 'Var', (172, 181))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
99589	33490091	In this study, we demonstrated that high IL10RA expression is correlated with positive prognosis of metastatic malignant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('malignant melanoma', 'Phenotype', 'HP:0002861', (111, 129))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('expression', 'MPA', (48, 58))	('malignant melanoma', 'Disease', 'MESH:D008545', (111, 129))	('IL10RA', 'Gene', (41, 47))	('malignant melanoma', 'Disease', (111, 129))	('IL10', 'molecular_function', 'GO:0005141', ('41', '45'))	('high', 'Var', (36, 40))	('si', 'Chemical', 'MESH:D012825', (80, 82))
99590	33490091	In addition, our in vitro experiments proved that knockdown of IL10RA promotes the proliferation, migration and invasion of melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('proliferation', 'CPA', (83, 96))	('knockdown', 'Var', (50, 59))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('migration', 'CPA', (98, 107))	('promotes', 'PosReg', (70, 78))	('IL10RA', 'Gene', (63, 69))	('IL10', 'molecular_function', 'GO:0005141', ('63', '67'))
99647	28653984	Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing The long non-coding RNA ANRIL, antisense to the CDKN2B locus, is transcribed from a gene that encompasses multiple disease-associated polymorphisms.	('Melanoma Cells', 'Disease', 'MESH:D008545', (30, 44))	('Melanoma Cells', 'Disease', (30, 44))	('Variations', 'Var', (77, 87))	('ANRIL', 'Gene', '100048912', (21, 26))	('CDKN2B', 'Gene', '1030', (150, 156))	('RNA', 'cellular_component', 'GO:0005562', ('122', '125'))	('CDKN2B', 'Gene', (150, 156))	('ANRIL', 'Gene', (126, 131))	('ANRIL', 'Gene', (21, 26))	('Melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('ANRIL', 'Gene', '100048912', (126, 131))
99667	28653984	ANRIL transcripts containing the Alu repeats were predicted to form a stem-loop structure, suggesting RNA-chromatin interactions as potential effector mechanisms.	('ANRIL', 'Gene', '100048912', (0, 5))	('Alu repeats', 'Var', (33, 44))	('chromatin', 'cellular_component', 'GO:0000785', ('106', '115'))	('RNA', 'cellular_component', 'GO:0005562', ('102', '105'))	('ANRIL', 'Gene', (0, 5))
99700	28653984	Multiple isoforms of circANRIL were observed (Table 1) with various exon combinations and multiple junction variants in these two cell lines.	('circANRIL', 'Chemical', '-', (21, 30))	('circANRIL', 'Gene', (21, 30))	('variants', 'Var', (108, 116))
99704	28653984	Of all the isoforms detected in both cell lines, exons 4, 5 and 6 were most abundantly found in almost all the circANRIL variants.	('circANRIL', 'Disease', (111, 120))	('circANRIL', 'Chemical', '-', (111, 120))	('variants', 'Var', (121, 129))
99716	28653984	However, none of these completely matched circANRIL variants found in this study (Table 1), therefore we excluded the involvement of an exon skipping mechanism in circANRIL formation.	('circANRIL', 'Chemical', '-', (42, 51))	('variants', 'Var', (52, 60))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('circANRIL', 'Chemical', '-', (163, 172))	('circANRIL', 'Gene', (42, 51))
99719	28653984	We performed quantitative RT-PCR for different exons of ANRIL (exon 1, exons 5-6, exons 6-7 and the last exons of both the short and long isoforms) in seven cell lines (NZM6, NZM7, NZM37, NZM40, NZM48, NZM 55 and NZM87) (Figure 4B,C and Figure S6B-F).	('ANRIL', 'Gene', '100048912', (56, 61))	('NZM40', 'Var', (188, 193))	('NZM37', 'Var', (181, 186))	('ANRIL', 'Gene', (56, 61))
99732	28653984	Genomic deletions leading to fusion of 5'-MTAP and 3'-ANRIL sequences have been described in melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('MTAP', 'Gene', '4507', (42, 46))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('described', 'Reg', (80, 89))	('ANRIL', 'Gene', (54, 59))	('melanomas', 'Disease', (93, 102))	('MTAP', 'Gene', (42, 46))	('deletions', 'Var', (8, 17))	('ANRIL', 'Gene', '100048912', (54, 59))
99752	28653984	Diverse populations of circANRIL could also arise due to the presence of SNPs in the melanoma cell lines investigated, as SNPs associated with diseases including coronary artery disease (CAD), diabetes, and cancers are highly associated with ANRIL expression and splicing.	('coronary artery disease', 'Disease', (162, 185))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('associated', 'Reg', (127, 137))	('cancers', 'Disease', (207, 214))	('expression', 'MPA', (248, 258))	('CAD', 'Disease', 'None', (187, 190))	('diabetes', 'Disease', 'MESH:D003920', (193, 201))	('ANRIL', 'Gene', '100048912', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('CAD', 'Disease', (187, 190))	('splicing', 'MPA', (263, 271))	('ANRIL', 'Gene', '100048912', (27, 32))	('SNPs', 'Var', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('circANRIL', 'Chemical', '-', (23, 32))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('ANRIL', 'Gene', (242, 247))	('splicing', 'biological_process', 'GO:0045292', ('263', '271'))	('associated', 'Reg', (226, 236))	('diabetes', 'Disease', (193, 201))	('coronary artery disease', 'Disease', 'MESH:D003324', (162, 185))	('ANRIL', 'Gene', (27, 32))
99754	28653984	Identification of isoforms is critical as the function of ANRIL may vary with the type of transcript variant expressed in each cell or tissue type, and hence secondary structure.	('ANRIL', 'Gene', '100048912', (58, 63))	('ANRIL', 'Gene', (58, 63))	('vary', 'Reg', (68, 72))	('variant', 'Var', (101, 108))
99758	28653984	Therefore, further analysis for the presence of Alu repeat elements was done using published databases and circANRIL variants to investigate a possible role of these features in the circANRIL species identified in our melanoma cells.	('circANRIL', 'Chemical', '-', (182, 191))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('variants', 'Var', (117, 125))	('circANRIL', 'Chemical', '-', (107, 116))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))
99760	28653984	Exon skipping has also been considered as a plausible mechanism of circular RNA formation, but was not the case for circANRIL.	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('RNA formation', 'biological_process', 'GO:0032774', ('76', '89'))	('circular RNA formation', 'Disease', (67, 89))	('Exon skipping', 'Var', (0, 13))	('circANRIL', 'Chemical', '-', (116, 125))
99762	28653984	However, no association was found between PRC2 complexes and full length or truncated ANRIL in urothelial carcinoma, and also possibly in melanoma.	('ANRIL', 'Gene', (86, 91))	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('urothelial carcinoma', 'Disease', (95, 115))	('ANRIL', 'Gene', '100048912', (86, 91))	('truncated', 'Var', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (95, 115))
99768	28653984	In uveal and blue-nevus melanomas, mutations in the SF3B1 splicing factor arise recurrently; in carcinomas and gliomas, the regulator SRPK1 is overexpressed.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('SRPK1', 'Gene', (134, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('blue-nevus', 'Phenotype', 'HP:0100814', (13, 23))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('blue-nevus melanomas', 'Disease', (13, 33))	('splicing', 'biological_process', 'GO:0045292', ('58', '66'))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('SF3B1', 'Gene', (52, 57))	('nevus', 'Phenotype', 'HP:0003764', (18, 23))	('SRPK1', 'Gene', '6732', (134, 139))	('melanomas', 'Phenotype', 'HP:0002861', (24, 33))	('carcinomas and gliomas', 'Disease', 'MESH:D005910', (96, 118))	('blue-nevus melanomas', 'Disease', 'MESH:D018329', (13, 33))	('SF3B1', 'Gene', '23451', (52, 57))	('mutations', 'Var', (35, 44))
99873	21479687	Blacks who underwent biopsy, wide excision or surgery NOS were at significantly higher risk of overall mortality when compared to whites with these same treatments, whereas risk of overall mortality was similar between patients who were white and other race with these same treatments.	('overall mortality', 'MPA', (95, 112))	('wide excision', 'Var', (29, 42))	('biopsy', 'Var', (21, 27))	('patients', 'Species', '9606', (219, 227))
99909	26093898	In this study, we employed multiple integrated bioinformatic approaches to identify the probable epigenetic factors, molecular pathways, and functionalities associated with mda-9 dysregulation during cancer progression.	('dysregulation', 'Var', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('mda-9', 'Gene', '6386', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('mda-9', 'Gene', (173, 178))	('cancer', 'Disease', (200, 206))
99927	26093898	One area that has not yet been investigated is how genetic and epigenetic factors contribute to its elevated expression during cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('expression', 'MPA', (109, 119))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('elevated', 'PosReg', (100, 108))	('epigenetic factors', 'Var', (63, 81))
99973	26093898	Except for two ( and cg10129404), the CpG sites were mostly unmethylated across all the cancer datasets.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cg10129404', 'Chemical', '-', (21, 31))	('cg10129404', 'Var', (21, 31))
99975	26093898	The CpG site is exactly 1105 bases from the 3' edge of the CpG island, while cg10129404 is part of the 3' UTR, making it less likely for the latter to be a factor in transcription of mda-9 (this will be clarified in the next subsection).	('cg10129404', 'Chemical', '-', (77, 87))	('mda-9', 'Gene', '6386', (183, 188))	('cg10129404', 'Var', (77, 87))	('mda-9', 'Gene', (183, 188))	('transcription', 'biological_process', 'GO:0006351', ('166', '179'))
99979	26093898	As mentioned above, it is unlikely that the 3' UTR CpG site cg10129404 influences mda-9 transcript levels.	('transcript levels', 'MPA', (88, 105))	('cg10129404', 'Chemical', '-', (60, 70))	('cg10129404', 'Var', (60, 70))	('mda-9', 'Gene', '6386', (82, 87))	('mda-9', 'Gene', (82, 87))
99980	26093898	A simple analysis was conducted by plotting mda-9 expression vs the beta value for or cg10129404 for two select TCGA datasets (glioma and KIRP) (Figure 7).	('cg10129404', 'Var', (86, 96))	('mda-9', 'Gene', (44, 49))	('glioma', 'Disease', 'MESH:D005910', (127, 133))	('glioma', 'Phenotype', 'HP:0009733', (127, 133))	('glioma', 'Disease', (127, 133))	('cg10129404', 'Chemical', '-', (86, 96))	('mda-9', 'Gene', '6386', (44, 49))
99981	26093898	In glioma, it is clear that the methylation at may influence mda-9 expression (R2 = 0.38; linear regression).	('mda-9', 'Gene', (61, 66))	('methylation', 'Var', (32, 43))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('glioma', 'Disease', (3, 9))	('mda-9', 'Gene', '6386', (61, 66))	('expression', 'MPA', (67, 77))	('influence', 'Reg', (51, 60))
99982	26093898	In contrast, cg10129404 appears to have a negligible effect on mda-9 expression (R2 = 0.051).	('mda-9', 'Gene', '6386', (63, 68))	('mda-9', 'Gene', (63, 68))	('expression', 'MPA', (69, 79))	('cg10129404', 'Chemical', '-', (13, 23))	('cg10129404', 'Var', (13, 23))
99984	26093898	Overall, these analyses indicate that cg10129404's influence on mda-9 expression is unlikely.	('cg10129404', 'Var', (38, 48))	('mda-9', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('cg10129404', 'Chemical', '-', (38, 48))	('mda-9', 'Gene', '6386', (64, 69))
99988	26093898	However, it is also clear that among the samples with only two copies of mda-9, those with low degree of methylation at the cg17197774 tend to have a higher mda-9 expression level (R = -0.61; expression vs. cg17197774 beta value).	('mda-9', 'Gene', (157, 162))	('cg17197774', 'Var', (124, 134))	('expression level', 'MPA', (163, 179))	('cg17197774', 'Chemical', '-', (124, 134))	('higher', 'PosReg', (150, 156))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('mda-9', 'Gene', '6386', (73, 78))	('cg17197774', 'Chemical', '-', (207, 217))	('mda-9', 'Gene', (73, 78))	('mda-9', 'Gene', '6386', (157, 162))
99989	26093898	By itself, it appears that cg17197774 methylation status may be a reliable marker of survival in glioma (Figure 9).	('cg17197774', 'Var', (27, 37))	('cg17197774', 'Chemical', '-', (27, 37))	('glioma', 'Disease', (97, 103))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
99990	26093898	On average, SKCM samples have the lowest beta values for cg17197774, at -0.295 (Table 3).	('cg17197774', 'Var', (57, 67))	('cg17197774', 'Chemical', '-', (57, 67))	('lowest', 'NegReg', (34, 40))
99993	26093898	For the TCGA COAD dataset, both copy number and cg17197774 methylation appear to factor in mda-9 expression, with the former (R = 0.47) having greater influence than the latter (-0.22).	('copy number', 'Var', (32, 43))	('factor', 'Reg', (81, 87))	('cg17197774 methylation', 'Var', (48, 70))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))	('mda-9', 'Gene', '6386', (91, 96))	('expression', 'MPA', (97, 107))	('mda-9', 'Gene', (91, 96))	('cg17197774', 'Chemical', '-', (48, 58))
99994	26093898	A great majority of KIRP samples have a neutral copy number (CN =2) at the mda-9 locus.	('mda-9', 'Gene', (75, 80))	('neutral copy number', 'Var', (40, 59))	('mda-9', 'Gene', '6386', (75, 80))
99995	26093898	Not surprisingly, the elevated mda-9 expression is primarily due to hypomethylation at cg17197774 (mda-9 expression vs. cg17197774 methylation correlation coefficient = -0.5).	('hypomethylation', 'Var', (68, 83))	('mda-9', 'Gene', (99, 104))	('cg17197774', 'Var', (87, 97))	('cg17197774', 'Chemical', '-', (87, 97))	('elevated', 'PosReg', (22, 30))	('mda-9', 'Gene', '6386', (31, 36))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('mda-9', 'Gene', (31, 36))	('cg17197774', 'Chemical', '-', (120, 130))	('expression', 'MPA', (37, 47))	('mda-9', 'Gene', '6386', (99, 104))
99996	26093898	In contrast to KIRP, the mode of mda-9 dysregulation in prostate cancer samples is primarily through copy number gain (R= 0.67), with cg17197774 methylation apparently lacking any effect on the gene's expression level.	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('cg17197774 methylation', 'Var', (134, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('copy', 'MPA', (101, 105))	('gain', 'PosReg', (113, 117))	('mda-9', 'Gene', '6386', (33, 38))	('methylation', 'Var', (145, 156))	('mda-9', 'Gene', (33, 38))	('cg17197774', 'Chemical', '-', (134, 144))	('dysregulation', 'NegReg', (39, 52))	('prostate cancer', 'Disease', (56, 71))
99997	26093898	Among LIHC primary tumors, it is clear that both copy number (R = 0.55) and cg17197774 methylation (R = -0.45) are factors influencing mda-9 RNA levels.	('LIHC primary tumors', 'Disease', (6, 25))	('influencing', 'Reg', (123, 134))	('cg17197774', 'Chemical', '-', (76, 86))	('mda-9', 'Gene', '6386', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('RNA', 'cellular_component', 'GO:0005562', ('141', '144'))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('LIHC primary tumors', 'Disease', 'MESH:D009369', (6, 25))	('mda-9', 'Gene', (135, 140))	('cg17197774 methylation', 'Var', (76, 98))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('methylation', 'Var', (87, 98))
99998	26093898	For a unified view on the effects of both copy number and cg17197774 methylation on mda-9 expression, we used the PANCAN-normalized expression value for mda-9.	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('mda-9', 'Gene', '6386', (153, 158))	('mda-9', 'Gene', '6386', (84, 89))	('cg17197774', 'Var', (58, 68))	('mda-9', 'Gene', (153, 158))	('mda-9', 'Gene', (84, 89))	('cg17197774', 'Chemical', '-', (58, 68))
99999	26093898	Figures 10 A-B show the same Cartesian plot (i.e., PANCAN-normalized mda-9 expression value vs. methylation at cg17197774) with varying information for each data point.	('cg17197774', 'Var', (111, 121))	('mda-9', 'Gene', '6386', (69, 74))	('cg17197774', 'Chemical', '-', (111, 121))	('mda-9', 'Gene', (69, 74))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('expression', 'MPA', (75, 85))
100000	26093898	As discussed previously, the highest mda-9 expression levels were those of SKCM samples, owing to the low beta values for cg17197774.	('mda-9', 'Gene', '6386', (37, 42))	('cg17197774', 'Var', (122, 132))	('cg17197774', 'Chemical', '-', (122, 132))	('expression levels', 'MPA', (43, 60))	('mda-9', 'Gene', (37, 42))
100002	26093898	This indicates that copy number can elevate mda-9 expression levels irrespective of the methylation status of cg17197774.	('mda-9', 'Gene', (44, 49))	('cg17197774', 'Chemical', '-', (110, 120))	('expression levels', 'MPA', (50, 67))	('copy number', 'Var', (20, 31))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('elevate', 'PosReg', (36, 43))	('mda-9', 'Gene', '6386', (44, 49))
100003	26093898	This shows that the methylation status of cg17197774 has greater influence (compared to mda-9 copy number) towards the gene's expression level.	('methylation', 'MPA', (20, 31))	('influence', 'Reg', (65, 74))	('cg17197774', 'Chemical', '-', (42, 52))	('mda-9', 'Gene', '6386', (88, 93))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('cg17197774', 'Var', (42, 52))	('mda-9', 'Gene', (88, 93))	('expression level', 'MPA', (126, 142))
100004	26093898	Figure 10C shows a superimposed exponential regression model (JMP Pro 10) relating mda-9 expression and cg17197774.	('expression', 'MPA', (89, 99))	('cg17197774', 'Var', (104, 114))	('cg17197774', 'Chemical', '-', (104, 114))	('mda-9', 'Gene', '6386', (83, 88))	('mda-9', 'Gene', (83, 88))
100006	26093898	At this point, we already know that tumor samples with neutral copy number for mda-9 can have an elevated expression of the gene if it is hypomethylated at cg17197774.	('elevated', 'PosReg', (97, 105))	('mda-9', 'Gene', (79, 84))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cg17197774', 'Var', (156, 166))	('neutral copy number', 'Var', (55, 74))	('cg17197774', 'Chemical', '-', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('mda-9', 'Gene', '6386', (79, 84))
100014	26093898	For MDA-9, two different antibodies were used: HPA023840 from Sigma-Aldrich and CAB012245 from Abcam.	('HPA023840', 'Var', (47, 56))	('CAB012245', 'Var', (80, 89))	('MDA-9', 'Gene', '6386', (4, 9))	('MDA-9', 'Gene', (4, 9))
100016	26093898	As shown in the figure (bottom right), the HPA023840 signal was much stronger in melanoma compared to glioma.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('stronger', 'PosReg', (69, 77))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('glioma', 'Disease', (102, 108))	('HPA023840', 'Var', (43, 52))
100020	26093898	Since we have already established (from TCGA analysis) that the methylation at the CpG site cg17197774 correlates with decreased mda-9 expression, it would be of interest to investigate how this CpG site may also affect the constitution of chromatin covering the mda-9 locus.	('decreased', 'NegReg', (119, 128))	('methylation', 'Var', (64, 75))	('cg17197774', 'Var', (92, 102))	('affect', 'Reg', (213, 219))	('mda-9', 'Gene', '6386', (129, 134))	('cg17197774', 'Chemical', '-', (92, 102))	('expression', 'MPA', (135, 145))	('mda-9', 'Gene', '6386', (263, 268))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('chromatin', 'cellular_component', 'GO:0000785', ('240', '249'))	('mda-9', 'Gene', (129, 134))	('mda-9', 'Gene', (263, 268))
100022	26093898	As indicated in Figure 13A, the MDA-9 promoter region of HUVEC (hypomethylated at cg17197774; beta value = -0.353) exhibits greater affinity (darker bands) for Histone H3 mono-, di-, or tri-methylated at K4 (H3K4me1, H3K4me2, H3K4me3), and acetylated at K9 (H3K9ac), compared to that of H1-hESC (highly methylated at cg17197774; beta value = 0.230).	('ES', 'Chemical', '-', (291, 293))	('H3', 'Chemical', 'MESH:C012616', (208, 210))	('tri-methylated', 'Var', (186, 200))	('Histone H3', 'Protein', (160, 170))	('cg17197774', 'Chemical', '-', (317, 327))	('greater', 'PosReg', (124, 131))	('H3', 'Chemical', 'MESH:C012616', (258, 260))	('di-', 'Var', (178, 181))	('H3', 'Chemical', 'MESH:C012616', (217, 219))	('H3', 'Chemical', 'MESH:C012616', (226, 228))	('H3', 'Chemical', 'MESH:C012616', (168, 170))	('MDA-9', 'Gene', (32, 37))	('cg17197774', 'Var', (82, 92))	('cg17197774', 'Chemical', '-', (82, 92))	('MDA-9', 'Gene', '6386', (32, 37))	('affinity', 'MPA', (132, 140))
100023	26093898	Those histone modifications, just like hypomethylation at cg17197774, are associated with more active transcription.	('modifications', 'Var', (14, 27))	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('more', 'PosReg', (90, 94))	('cg17197774', 'Chemical', '-', (58, 68))	('active transcription', 'MPA', (95, 115))	('associated', 'Reg', (74, 84))
100024	26093898	Four other markers (H4K20me1 which is associated with transcriptional activity; H3K36me3 which is associated with RNAPII elongation; H3K27me3 which is associated with promoter silencing; and the transcriptional repressor CTCF) were not significantly different between the two cell lines.	('H3K27me3', 'Var', (133, 141))	('CTCF', 'Gene', (221, 225))	('K20', 'Gene', (22, 25))	('H3K36me3', 'Var', (80, 88))	('CTCF', 'Gene', '10664', (221, 225))	('K20', 'Gene', '54474', (22, 25))
100028	26093898	As shown in Figure 13B, H1-hESC, HepG2 and HMEC, which are all highly methylated at cg17197774, are predicted to exhibit less active MDA-9 promoter and transcriptional activity (interpretations for segmental colors are listed in Figure 13C).	('less', 'NegReg', (121, 125))	('HepG2', 'CellLine', 'CVCL:0027', (33, 38))	('cg17197774', 'Var', (84, 94))	('cg17197774', 'Chemical', '-', (84, 94))	('HMEC', 'CellLine', 'CVCL:0307', (43, 47))	('ES', 'Chemical', '-', (28, 30))	('transcriptional activity', 'MPA', (152, 176))	('active', 'MPA', (126, 132))	('MDA-9', 'Gene', '6386', (133, 138))	('MDA-9', 'Gene', (133, 138))
100029	26093898	In contrast, MDA-9 expression is expected to be higher for cell lines GM12878, K562 and HUVEC, which are all weakly methylated at cg17197774.	('MDA-9', 'Gene', '6386', (13, 18))	('expression', 'MPA', (19, 29))	('K562', 'CellLine', 'CVCL:0004', (79, 83))	('higher', 'PosReg', (48, 54))	('cg17197774', 'Var', (130, 140))	('cg17197774', 'Chemical', '-', (130, 140))	('MDA-9', 'Gene', (13, 18))
100066	26093898	Its down-regulation among mda-9 high glioma is consistent with recent observations that relatively low expression of the gene correlates with the absence of 1p/19q co-deletion (which are established markers of good prognosis).	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('mda-9', 'Gene', (26, 31))	('low', 'NegReg', (99, 102))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('expression', 'MPA', (103, 113))	('1p/19q co-deletion', 'Var', (157, 175))	('high glioma', 'Disease', 'MESH:D005910', (32, 43))	('high glioma', 'Disease', (32, 43))	('mda-9', 'Gene', '6386', (26, 31))	('absence', 'NegReg', (146, 153))	('down-regulation', 'NegReg', (4, 19))
100158	26093898	In glioma, both mda-9 expression level and methylation at cg17197774 can provide prognostic markers, with elevated expression and hypomethylation, respectively, correlating with poor survival.	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('cg17197774', 'Gene', (58, 68))	('expression', 'MPA', (115, 125))	('elevated', 'PosReg', (106, 114))	('glioma', 'Disease', (3, 9))	('mda-9', 'Gene', '6386', (16, 21))	('hypomethylation', 'Var', (130, 145))	('cg17197774', 'Chemical', '-', (58, 68))	('expression', 'MPA', (22, 32))	('mda-9', 'Gene', (16, 21))
100159	26093898	Among the cancer types included in the TCGA Pan Cancer (PANCAN) dataset, melanoma exhibits the highest level of mda-9 (which is consistent with information downloaded from the Human Protein Atlas), which may be explained by its generally low methylation level at the cg17197774 CpG site (which has the lowest among the 6 TCGA datasets analyzed for CpG methylation).	('methylation', 'biological_process', 'GO:0032259', ('242', '253'))	('melanoma', 'Disease', (73, 81))	('mda-9', 'Gene', (112, 117))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cg17197774', 'Var', (267, 277))	('cg17197774', 'Chemical', '-', (267, 277))	('Human', 'Species', '9606', (176, 181))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('methylation', 'biological_process', 'GO:0032259', ('352', '363'))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('methylation level', 'MPA', (242, 259))	('low', 'NegReg', (238, 241))	('mda-9', 'Gene', '6386', (112, 117))	('cancer', 'Disease', (10, 16))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
100160	26093898	Hypomethylation at cg17197774 is associated with higher intensity of modified histones such as H3K4 di- and tri-methylation and H3K9 acetylation in the promoter area.	('H3', 'Chemical', 'MESH:C012616', (128, 130))	('tri-methylation', 'MPA', (108, 123))	('H3K4', 'Protein', (95, 99))	('Hypomethylation', 'Var', (0, 15))	('acetylation', 'MPA', (133, 144))	('H3', 'Chemical', 'MESH:C012616', (95, 97))	('intensity', 'MPA', (56, 65))	('cg17197774', 'Var', (19, 29))	('cg17197774', 'Chemical', '-', (19, 29))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('H3K9', 'Protein', (128, 132))	('di-', 'MPA', (100, 103))
100161	26093898	H3K4 methylations are characteristics of active (or poised to be activated) promoters, while H3K9 acetylation describes a likely active transcription.	('H3', 'Chemical', 'MESH:C012616', (93, 95))	('methylations', 'Var', (5, 17))	('H3K4', 'Protein', (0, 4))	('transcription', 'biological_process', 'GO:0006351', ('136', '149'))	('H3', 'Chemical', 'MESH:C012616', (0, 2))
100165	26093898	Among the top gene groups and molecular pathways identified using the scheme described above are those previously linked with both mda-9 dysregulation and glioma progression (e.g., matrix metalloproteinases, interleukins, IGFBP2 signaling, NF-kappaB activation).	('dysregulation', 'Var', (137, 150))	('NF-kappaB', 'Gene', '4790', (240, 249))	('IGFBP2', 'Gene', '3485', (222, 228))	('mda-9', 'Gene', '6386', (131, 136))	('activation', 'PosReg', (250, 260))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('IGFBP2', 'Gene', (222, 228))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('NF-kappaB', 'Gene', (240, 249))	('mda-9', 'Gene', (131, 136))	('signaling', 'biological_process', 'GO:0023052', ('229', '238'))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('240', '260'))	('glioma', 'Disease', (155, 161))
100167	26093898	Through the integrated bioinformatic analyses of publicly available cancer genomic datasets, we were able to comprehensively analyze the various epigenetic and molecular factors associated with the dysregulation of mda-9 in various types of cancer.	('mda-9', 'Gene', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (241, 247))	('mda-9', 'Gene', '6386', (215, 220))	('dysregulation', 'Var', (198, 211))
100168	26093898	The following is a list of the most important conclusions obtained from this exercise:  The driving forces behind a gene's dysregulated expression in cancer (either upregulation or downregulation) involve a multitude of factors including gene copy number variations, epigenetic regulation and transcription factors.	('expression', 'MPA', (136, 146))	('transcription', 'biological_process', 'GO:0006351', ('293', '306'))	('regulation', 'biological_process', 'GO:0065007', ('278', '288'))	('downregulation', 'NegReg', (181, 195))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('epigenetic regulation', 'Var', (267, 288))	('gene copy number variations', 'Var', (238, 265))	('cancer', 'Disease', (150, 156))	('upregulation', 'PosReg', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('dysregulated', 'PosReg', (123, 135))
100174	26093898	In contrast, the copy number influence is most pronounced in PRAD samples, which are mostly highly methylated at cg17197774.	('cg17197774', 'Var', (113, 123))	('cg17197774', 'Chemical', '-', (113, 123))	('PRAD', 'Disease', (61, 65))
100175	26093898	The influence of cg17197774 methylation towards mda-9 levels is readily observed in the 5 other tumor types.	('mda-9', 'Gene', '6386', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('mda-9', 'Gene', (48, 53))	('cg17197774 methylation', 'Var', (17, 39))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('cg17197774', 'Chemical', '-', (17, 27))
100176	26093898	Our identification of cg17197774 as the most differentially methylated (and most highly associated with mda-9 transcript levels) is consistent with recent observations by Irizarry and colleagues.	('mda-9', 'Gene', '6386', (104, 109))	('cg17197774', 'Var', (22, 32))	('cg17197774', 'Chemical', '-', (22, 32))	('mda-9', 'Gene', (104, 109))	('associated', 'Reg', (88, 98))
100180	26093898	For example, an H3 histone di- or tri-methylated at K4 is indicative of a poised or active promoter.	('H3 histone', 'Protein', (16, 26))	('H3', 'Chemical', 'MESH:C012616', (16, 18))	('tri-methylated', 'Var', (34, 48))	('di-', 'Var', (27, 30))
100181	26093898	A mono-methylated H3 histone is often associated with enhancer downstream of a start site.	('enhancer', 'PosReg', (54, 62))	('H3 histone', 'Protein', (18, 28))	('mono-methylated', 'Var', (2, 17))	('H3', 'Chemical', 'MESH:C012616', (18, 20))
100183	26093898	Active transcription may also be characterized by an H4 histone methylated at K20.	('K20', 'Gene', '54474', (78, 81))	('K20', 'Gene', (78, 81))	('Active', 'MPA', (0, 6))	('methylated', 'Var', (64, 74))	('transcription', 'biological_process', 'GO:0006351', ('7', '20'))	('H4 histone', 'Protein', (53, 63))
100185	26093898	What we observed is that cell lines weakly methylated at cg17197774 (such as GM12878, K562 and HUVEC) tend to have more intense binding by H3 methylated at K4 or acetylated at K9, and H4 methylated at K20.	('intense', 'PosReg', (120, 127))	('H3', 'Chemical', 'MESH:C012616', (139, 141))	('K20', 'Gene', '54474', (201, 204))	('binding', 'molecular_function', 'GO:0005488', ('128', '135'))	('K562', 'CellLine', 'CVCL:0004', (86, 90))	('binding', 'Interaction', (128, 135))	('cg17197774', 'Var', (57, 67))	('K20', 'Gene', (201, 204))	('cg17197774', 'Chemical', '-', (57, 67))	('acetylated', 'MPA', (162, 172))
100187	26093898	For now, we can just assume that the methylation at cg17197774 may be detrimental to the binding affinity of these modified histones.	('cg17197774', 'Var', (52, 62))	('cg17197774', 'Chemical', '-', (52, 62))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('binding affinity', 'Interaction', (89, 105))	('methylation', 'MPA', (37, 48))
100202	26093898	CTLA4 (expressed in Helper T cells and a negative regulator of T lymphocytes) increased ~ 3-fold in mda-9 High relative to mda-9 Low glioma.	('High', 'Var', (106, 110))	('CTLA4', 'Gene', '1493', (0, 5))	('Low glioma', 'Disease', (129, 139))	('mda-9', 'Gene', '6386', (123, 128))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('CTLA4', 'Gene', (0, 5))	('mda-9', 'Gene', (123, 128))	('mda-9', 'Gene', '6386', (100, 105))	('Helper T', 'CellLine', 'CVCL:3174', (20, 28))	('increased', 'PosReg', (78, 87))	('mda-9', 'Gene', (100, 105))	('Low glioma', 'Disease', 'MESH:D005910', (129, 139))
100239	26986135	Furthermore, another group demonstrated that a low dose administration of neutralizing nanobody targeting leptin receptor led to the tumor size shrinkage in the mouse model.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('shrinkage', 'NegReg', (144, 153))	('leptin receptor', 'Gene', '16847', (106, 121))	('neutralizing nanobody', 'Var', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('leptin receptor', 'Gene', (106, 121))	('mouse', 'Species', '10090', (161, 166))
100260	26986135	As shown in Table 2 and Figure 1, both raw and adjusted leptin levels were significantly higher in the patients with positive SN.	('higher', 'PosReg', (89, 95))	('leptin levels', 'MPA', (56, 69))	('positive SN', 'Var', (117, 128))	('patients', 'Species', '9606', (103, 111))
100299	33076560	TRIM28 emerged as a regulator Interferon Regulatory Factor family of transcription factors' expression, mediating epigenetic repression of IRF family members in "stemness high/immune low" melanomas.	('epigenetic repression', 'Var', (114, 135))	('TRIM28', 'Gene', (0, 6))	('transcription', 'biological_process', 'GO:0006351', ('69', '82'))	('melanomas', 'Disease', (188, 197))	('TRIM28', 'Gene', '10155', (0, 6))	('IRF', 'Gene', (139, 142))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanomas', 'Phenotype', 'HP:0002861', (188, 197))	('melanomas', 'Disease', 'MESH:D008545', (188, 197))
100302	33076560	TRIM28 high expression is associated with worse melanoma patient outcomes.	('melanoma', 'Disease', (48, 56))	('TRIM28', 'Gene', (0, 6))	('patient', 'Species', '9606', (57, 64))	('TRIM28', 'Gene', '10155', (0, 6))	('high expression', 'Var', (7, 22))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
100309	33076560	Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells.	('melanoma tumors', 'Disease', 'MESH:D008545', (21, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('melanoma tumors', 'Disease', (21, 36))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('depleted', 'NegReg', (56, 64))	('TRIM28HIGH', 'Var', (10, 20))
100336	33076560	Specifically, TRIM28 high expression correlated with significant depletion of interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) response in melanomas, which resulted from significant downregulation of IRF (Interferon Regulatory Factor) transcription factor family members.	('interferon alpha', 'MPA', (78, 94))	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('interferon gamma (IFN-gamma', 'Gene', '3458', (111, 138))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('transcription factor', 'molecular_function', 'GO:0000981', ('248', '268'))	('TRIM28', 'Gene', (14, 20))	('transcription', 'biological_process', 'GO:0006351', ('248', '261'))	('downregulation', 'NegReg', (195, 209))	('high expression', 'Var', (21, 36))	('IFN-alpha', 'Gene', '3439', (96, 105))	('TRIM28', 'Gene', '10155', (14, 20))	('interferon gamma', 'molecular_function', 'GO:0005133', ('111', '127'))	('melanomas', 'Disease', (152, 161))	('IFN-alpha', 'Gene', (96, 105))	('depletion', 'MPA', (65, 74))
100337	33076560	TRIM28 emerged as a regulator of IRF expression, mediating epigenetic repression of IRF family members in stemness-high melanomas.	('stemness-high melanomas', 'Disease', (106, 129))	('TRIM28', 'Gene', (0, 6))	('TRIM28', 'Gene', '10155', (0, 6))	('epigenetic repression', 'Var', (59, 80))	('IRF', 'Gene', (84, 87))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('stemness-high melanomas', 'Disease', 'MESH:D008545', (106, 129))
100345	33076560	We identified more than 9000 differentially expressed genes (DEGs) at either higher (n = 3301) or lower (n = 5864) levels in the TRIM28HIGH patients (p < 0.05; FDR < 0.05); (Figure 1C).	('TRIM28HIGH', 'Var', (129, 139))	('patients', 'Species', '9606', (140, 148))	('lower', 'NegReg', (98, 103))	('differentially expressed genes', 'MPA', (29, 59))
100348	33076560	On the other hand, the transcription profile of the TRIM28HIGH SKCM patients was highly depleted with genes that are associated with Interferon gamma response (NES = -3.09, p < 0.0001, FDR < 0.0001), Interferon alpha response (NES = -2.72, p < 0.0001, FDR < 0.0001), Inflammatory response (NES = -2.86, p < 0.0001, FDR < 0.0001), and other immune-related terms (Figure 1D).	('depleted', 'NegReg', (88, 96))	('TRIM28HIGH', 'Var', (52, 62))	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('transcription profile', 'MPA', (23, 44))	('Interferon gamma', 'molecular_function', 'GO:0005133', ('133', '149'))	('patients', 'Species', '9606', (68, 76))	('Inflammatory response', 'biological_process', 'GO:0006954', ('267', '288'))	('Interferon gamma', 'Gene', '3458', (133, 149))	('Interferon gamma', 'Gene', (133, 149))	('Interferon alpha response', 'MPA', (200, 225))	('Inflammatory response', 'CPA', (267, 288))
100352	33076560	The SKCM cohort expressing high levels of TRIM33 tend to have a lower survival rate, although the differences are not statistically significant (p = 0.0644), (Figure S1B).	('TRIM33', 'Gene', '51592', (42, 48))	('high levels', 'Var', (27, 38))	('lower', 'NegReg', (64, 69))	('TRIM33', 'Gene', (42, 48))	('survival rate', 'CPA', (70, 83))
100357	33076560	Using the GSEA, we demonstrated that significant enrichment of stemness-associated terms accompanied with substantial depletion of immune-related terms was present only in the TRIM28HIGH melanoma phenotype (Figure 1F).	('GSEA', 'Chemical', '-', (10, 14))	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('TRIM28HIGH', 'Var', (176, 186))
100359	33076560	dataset (GSE65904), the survival of the TRIM28HIGH expressing melanomas tend to be worse, although we did not observe statistical significance (p = 0.1373); (Figure S2A).	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('worse', 'NegReg', (83, 88))	('TRIM28HIGH expressing', 'Var', (40, 61))	('survival', 'CPA', (24, 32))	('melanomas', 'Disease', (62, 71))	('melanomas', 'Phenotype', 'HP:0002861', (62, 71))	('melanomas', 'Disease', 'MESH:D008545', (62, 71))
100366	33076560	Moreover, using GSEA and all significantly differentially expressed genes in the TRIM28HIGH samples as an input, we demonstrated that the TRIM28HIGH phenotype is significantly enriched with markers of Wong_ESC_core stemness gene signature (NES = 3.340, p < 0.0001, FDR < 0.0001) (Figure 2D) as well as other stemness-associated gene signature (NES = 2.076, p < 0.0001, FDR < 0.0001) (Figure 2E).	('core', 'cellular_component', 'GO:0019013', ('210', '214'))	('Wong_ESC_core', 'Gene', (201, 214))	('TRIM28HIGH', 'Var', (138, 148))	('GSEA', 'Chemical', '-', (16, 20))
100370	33076560	Furthermore, the GSEA analysis of genes that highly correlate (r < -0.4 and r > 0.4) with TRIM28 expression in each of the datasets revealed significant enrichment with the mRNA Stemness Index signature in the TRIM28HIGH phenotype (GSE65904: NES = 3.114, p < 0.0001, FDR < 0.0001; GSE19234: NES = 3.336, p < 0.0001, FDR < 0.0001) (Figure S3C,D).	('TRIM28', 'Gene', (90, 96))	('TRIM28', 'Gene', (210, 216))	('GSE65904:', 'Var', (232, 241))	('TRIM28', 'Gene', '10155', (90, 96))	('GSE19234', 'Var', (281, 289))	('TRIM28', 'Gene', '10155', (210, 216))	('GSEA', 'Chemical', '-', (17, 21))
100380	33076560	As expected, cells with downregulated TRIM28 expression formed significantly smaller colonies in all tested cell lines (Figure 3G and Figure S4A).	('TRIM28', 'Gene', (38, 44))	('colonies', 'CPA', (85, 93))	('downregulated', 'NegReg', (24, 37))	('TRIM28', 'Gene', '10155', (38, 44))	('expression', 'Var', (45, 55))	('smaller', 'NegReg', (77, 84))
100388	33076560	Moreover, using previously reported transcriptome signatures of specific leukocyte subpopulations, we detected significant depletion of cytotoxic T cells; helper T cells; B cells; as well as macrophages, dendritic cells, eosinophils, and neutrophils in the TRIM28HIGH expressing melanomas (Figure 4E).	('melanomas', 'Disease', 'MESH:D008545', (279, 288))	('melanomas', 'Disease', (279, 288))	('B cells', 'CPA', (171, 178))	('cytotoxic T cells', 'CPA', (136, 153))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('TRIM28HIGH expressing', 'Var', (257, 278))	('depletion', 'MPA', (123, 132))	('melanomas', 'Phenotype', 'HP:0002861', (279, 288))
100390	33076560	Lower lymphocyte infiltration in the TRIM28HIGH melanomas might result in significant depletion of IFN-alpha and IFN-gamma signaling (Figure 1D).	('signaling', 'biological_process', 'GO:0023052', ('123', '132'))	('TRIM28HIGH', 'Var', (37, 47))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('IFN-alpha', 'Gene', (99, 108))	('melanomas', 'Disease', (48, 57))	('IFN-alpha', 'Gene', '3439', (99, 108))	('Lower lymphocyte', 'Phenotype', 'HP:0001888', (0, 16))	('IFN-gamma', 'Gene', '3458', (113, 122))	('IFN-gamma', 'Gene', (113, 122))	('Lower lymphocyte infiltration', 'CPA', (0, 29))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
100403	33076560	The methylation of IRF1, IRF2, IRF5, and IRF8 transcription factor promoters was significantly higher in the StemnessHIGH/ImmuneLOW melanoma patients (p < 0.0001) (Figure 6E), suggesting that epigenetic silencing of interferon-inducible signaling ultimately results in the acquisition of melanoma stem cell-like phenotype.	('IRF1', 'Gene', (19, 23))	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('melanoma', 'Disease', 'MESH:D008545', (132, 140))	('acquisition', 'PosReg', (273, 284))	('higher', 'PosReg', (95, 101))	('IRF1', 'Gene', '3659', (19, 23))	('StemnessHIGH/ImmuneLOW melanoma', 'Disease', (109, 140))	('patients', 'Species', '9606', (141, 149))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('methylation', 'MPA', (4, 15))	('IRF5', 'Gene', (31, 35))	('melanoma', 'Disease', 'MESH:D008545', (288, 296))	('StemnessHIGH/ImmuneLOW melanoma', 'Disease', 'MESH:D008545', (109, 140))	('IRF2', 'Gene', '3660', (25, 29))	('transcription factor', 'molecular_function', 'GO:0000981', ('46', '66'))	('IRF8', 'Gene', '3394', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('signaling', 'biological_process', 'GO:0023052', ('237', '246'))	('melanoma', 'Disease', (132, 140))	('epigenetic silencing', 'Var', (192, 212))	('IRF2', 'Gene', (25, 29))	('IRF5', 'Gene', '3663', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('melanoma', 'Disease', (288, 296))	('results in', 'Reg', (258, 268))	('IRF8', 'Gene', (41, 45))
100405	33076560	As presented in Figure 6F, we observed significant upregulation of IRF1 and IRF2 expression in SK-MEL28 cells upon shRNA-mediated TRIM28 depletion which is consistent with previously reported data.	('upregulation', 'PosReg', (51, 63))	('IRF1', 'Gene', (67, 71))	('IRF1', 'Gene', '3659', (67, 71))	('depletion', 'Var', (137, 146))	('IRF2', 'Gene', '3660', (76, 80))	('IRF2', 'Gene', (76, 80))	('SK-MEL28', 'Chemical', '-', (95, 103))	('TRIM28', 'Gene', (130, 136))	('TRIM28', 'Gene', '10155', (130, 136))	('expression', 'MPA', (81, 91))
100411	33076560	Furthermore, using transcriptomic data from melanoma samples, we revealed distinct gene expression profiles of the TRIM28HIGH melanomas robustly enriched with genes involved in stemness-facilitating biological processes and significantly depleted with markers associated with immune cell infiltration.	('melanomas', 'Disease', (126, 135))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('gene expression', 'biological_process', 'GO:0010467', ('83', '98'))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('melanomas', 'Phenotype', 'HP:0002861', (126, 135))	('depleted', 'NegReg', (238, 246))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanomas', 'Disease', 'MESH:D008545', (126, 135))	('melanoma', 'Disease', (126, 134))	('enriched', 'Reg', (145, 153))	('TRIM28HIGH', 'Var', (115, 125))
100424	33076560	The TRIM28HIGH-expressing melanomas were significantly enriched with c-Myc associated gene signature.	('melanomas', 'Disease', (26, 35))	('c-Myc', 'Gene', (69, 74))	('melanomas', 'Phenotype', 'HP:0002861', (26, 35))	('TRIM28HIGH-expressing', 'Var', (4, 25))	('melanomas', 'Disease', 'MESH:D008545', (26, 35))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('c-Myc', 'Gene', '4609', (69, 74))
100425	33076560	As c-Myc is sufficient to induce cancer stem cell phenotype in epithelial cancers, it is possible that (at least partially) melanoma stem cell-like phenotype of the TRIM28HIGH melanomas results from significant c-Myc activation.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('cancer', 'Disease', (33, 39))	('c-Myc', 'Gene', (3, 8))	('melanoma', 'Disease', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('As c', 'Gene', '29108', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Disease', (74, 80))	('c-Myc', 'Gene', '4609', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('activation', 'PosReg', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('c-Myc', 'Gene', '4609', (3, 8))	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('epithelial cancers', 'Disease', 'MESH:D009369', (63, 81))	('melanomas', 'Disease', (176, 185))	('epithelial cancers', 'Disease', (63, 81))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))	('TRIM28HIGH', 'Var', (165, 175))	('c-Myc', 'Gene', (211, 216))	('As c', 'Gene', (0, 4))
100426	33076560	We further suggest that TRIM28 high expression facilitates the acquisition of a stem cell-like phenotype.	('TRIM28', 'Gene', (24, 30))	('facilitates', 'PosReg', (47, 58))	('TRIM28', 'Gene', '10155', (24, 30))	('acquisition of a stem cell-like phenotype', 'CPA', (63, 104))	('high expression', 'Var', (31, 46))
100430	33076560	As TRIM28 depletion did not affect cell proliferation or cell death directly (preliminary data for SK-MEL28, not shown), we suggest that it might attenuate the maintenance of stem cell-like population, therefore resulting in smaller sizes of melanospheres.	('cell death', 'biological_process', 'GO:0008219', ('57', '67'))	('TRIM28', 'Gene', '10155', (3, 9))	('death', 'Disease', (62, 67))	('attenuate', 'NegReg', (146, 155))	('depletion', 'Var', (10, 19))	('death', 'Disease', 'MESH:D003643', (62, 67))	('cell proliferation', 'biological_process', 'GO:0008283', ('35', '53'))	('smaller', 'NegReg', (225, 232))	('smaller sizes of melanospheres', 'Phenotype', 'HP:0005592', (225, 255))	('SK-MEL28', 'Chemical', '-', (99, 107))	('TRIM28', 'Gene', (3, 9))	('maintenance', 'CPA', (160, 171))
100447	33076560	Interestingly, we observed significant downregulation of the IRF transcription factor family members (IRF1, IRF2, IRF5, IRF8) corresponding to attenuated interferon signaling in TRIM28HIGH melanomas, probably as a consequence of low immune cell infiltration.	('IRF8', 'Gene', (120, 124))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('TRIM28HIGH', 'Var', (178, 188))	('melanomas', 'Phenotype', 'HP:0002861', (189, 198))	('IRF2', 'Gene', (108, 112))	('IRF transcription', 'Gene', (61, 78))	('interferon signaling', 'MPA', (154, 174))	('IRF5', 'Gene', '3663', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('attenuated', 'NegReg', (143, 153))	('IRF1', 'Gene', (102, 106))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('transcription factor', 'molecular_function', 'GO:0000981', ('65', '85'))	('IRF8', 'Gene', '3394', (120, 124))	('melanomas', 'Disease', 'MESH:D008545', (189, 198))	('low immune cell', 'Phenotype', 'HP:0002721', (229, 244))	('IRF1', 'Gene', '3659', (102, 106))	('melanomas', 'Disease', (189, 198))	('IRF5', 'Gene', (114, 118))	('IRF2', 'Gene', '3660', (108, 112))	('downregulation', 'NegReg', (39, 53))
100449	33076560	As TRIM28 is a well-known transcriptional co-repressor, we suggest that low IRF1, IRF2, IRF5, and IRF8 expression (in the absence of stimulating signaling) result from TRIM28-mediated epigenetic modifications within the IRF promoters.	('TRIM28', 'Gene', '10155', (3, 9))	('TRIM28', 'Gene', (3, 9))	('TRIM28', 'Gene', '10155', (168, 174))	('expression', 'MPA', (103, 113))	('IRF2', 'Gene', '3660', (82, 86))	('epigenetic modifications', 'Var', (184, 208))	('IRF8', 'Gene', (98, 102))	('IRF5', 'Gene', '3663', (88, 92))	('IRF1', 'Gene', (76, 80))	('IRF1', 'Gene', '3659', (76, 80))	('IRF8', 'Gene', '3394', (98, 102))	('IRF5', 'Gene', (88, 92))	('IRF2', 'Gene', (82, 86))	('low', 'NegReg', (72, 75))	('TRIM28', 'Gene', (168, 174))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
100460	33076560	Additional datasets used in this study (GSE65904, melanoma, n = 214 samples; GSE19234, metastatic melanoma, n = 44 samples) were obtained from the R2: Genomics Analysis and Visualization Platform .	('GSE65904', 'Var', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('GSE19234', 'Var', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))
100467	33076560	To produce lentiviral vectors (LV-shTRIM28, LV-puro-ctrl, LV-shTRIM28-TRIM28 (rescue)), HEK-293T cells were co-transfected with psPAX2, pMD2.G and lentiviral plasmid pWPTS-shTRIM28, pWPTS-puro-ctrl, or pWPTS-shTRIM28-TRIM28.	('TRIM28', 'Gene', '10155', (174, 180))	('TRIM28', 'Gene', (70, 76))	('pWPTS-puro-ctrl', 'Var', (182, 197))	('TRIM28', 'Gene', (210, 216))	('TRIM28', 'Gene', (63, 69))	('HEK-293T', 'CellLine', 'CVCL:0063', (88, 96))	('TRIM28', 'Gene', '10155', (217, 223))	('TRIM28', 'Gene', '10155', (70, 76))	('TRIM28', 'Gene', '10155', (210, 216))	('TRIM28', 'Gene', '10155', (63, 69))	('TRIM28', 'Gene', (36, 42))	('TRIM28', 'Gene', (174, 180))	('TRIM28', 'Gene', (217, 223))	('TRIM28', 'Gene', '10155', (36, 42))
100473	33076560	Protein concentration was measured with PierceTM BCA Protein Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA), and then samples were subjected to SDS-PAGE (using Mini-PROTEAN  Tetra Cell System, Bio-Rad) followed by immunoblotting with antibodies for TRIM28 (ab10483 or ab10484, Abcam, Cambridge, UK) and GAPDH (ab9485, Abcam).	('SDS', 'Chemical', 'MESH:D012967', (152, 155))	('ab10484', 'Var', (276, 283))	('TRIM28', 'Gene', (257, 263))	('Kit', 'Gene', (67, 70))	('Rad', 'Gene', '6236', (205, 208))	('TRIM28', 'Gene', '10155', (257, 263))	('Rad', 'Gene', (205, 208))	('Kit', 'Gene', '3815', (67, 70))	('ab10483', 'Var', (265, 272))	('Rad', 'biological_process', 'GO:1990116', ('205', '208'))	('GAPDH', 'Gene', '2597', (311, 316))	('GAPDH', 'Gene', (311, 316))
100475	33076560	A 20 muL aliquot of full medium containing 1 muCi of 3H-thymidine (specific activity 70-90 Ci/mmol, 2590-3330 GBq/mmol, Perkin Elmer, Waltham, MA, USA) was added to each well 16-18 h before the termination of culture by freezing.	('A 20', 'Gene', (0, 4))	('3H-thymidine', 'Chemical', '-', (53, 65))	('A 20', 'Gene', '28935', (0, 4))	('2590-3330 GBq/mmol', 'Var', (100, 118))
100481	33076560	To conclude, our data indicate that TRIM28 high expression might facilitate "stemness high/immune low" melanoma phenotype by the attenuation of interferon signaling (leading to a worse prognosis for melanoma patients).	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('high expression', 'Var', (43, 58))	('patients', 'Species', '9606', (208, 216))	('facilitate', 'PosReg', (65, 75))	('attenuation', 'NegReg', (129, 140))	('TRIM28', 'Gene', (36, 42))	('interferon signaling', 'MPA', (144, 164))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('TRIM28', 'Gene', '10155', (36, 42))	('melanoma', 'Disease', (199, 207))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
100488	30415923	Here, we examine the role of AMPK in murine KrasG12D mediated non-small cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor - the predominant upstream activating kinase of AMPK and twelve related kinases.	('Kras', 'Gene', '16653', (44, 48))	('LKB1', 'Gene', (174, 178))	('AMPK', 'Gene', (29, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('murine', 'Species', '10090', (37, 43))	('AMPK', 'molecular_function', 'GO:0050405', ('244', '248'))	('AMPK', 'molecular_function', 'GO:0050405', ('29', '33'))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('inactivating mutations', 'Var', (144, 166))	('humans', 'Species', '9606', (115, 121))	('AMPK', 'Gene', '5563', (244, 248))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('AMPK', 'molecular_function', 'GO:0004691', ('244', '248'))	('AMPK', 'molecular_function', 'GO:0004691', ('29', '33'))	('AMPK', 'Gene', '5563', (29, 33))	('non-small cell lung cancer', 'Disease', (62, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('179', '195'))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('Kras', 'Gene', (44, 48))	('cancer type', 'Disease', (100, 111))	('NSCLC', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('AMPK', 'Gene', (244, 248))	('cancer type', 'Disease', 'MESH:D009369', (100, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('179', '195'))	('AMPK', 'molecular_function', 'GO:0047322', ('244', '248'))	('AMPK', 'molecular_function', 'GO:0047322', ('29', '33'))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('tumor', 'Disease', (179, 184))
100490	30415923	Moreover, deletion of AMPK in KrasG12D p53f/f tumors reduced lung tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('f tumors reduced lung tumor', 'Disease', (44, 71))	('AMPK', 'Gene', (22, 26))	('Kras', 'Gene', (30, 34))	('AMPK', 'molecular_function', 'GO:0047322', ('22', '26'))	('AMPK', 'molecular_function', 'GO:0050405', ('22', '26'))	('Kras', 'Gene', '16653', (30, 34))	('f tumors reduced lung tumor', 'Disease', 'MESH:D009369', (44, 71))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '22059', (39, 42))	('deletion', 'Var', (10, 18))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('lung tumor', 'Phenotype', 'HP:0100526', (61, 71))	('AMPK', 'Gene', '5563', (22, 26))	('AMPK', 'molecular_function', 'GO:0004691', ('22', '26'))
100498	30415923	LKB1 was originally identified as the causal tumor suppressor gene on human chromosome 19p3 mutated in the inherited autosomal dominant cancer disorder Peutz Jeghers Syndrome (Hemminki et al., 1998).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('inherited autosomal dominant cancer disorder Peutz Jeghers Syndrome', 'Disease', 'MESH:D009386', (107, 174))	('tumor suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('LKB1', 'Gene', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumor', 'Disease', (45, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('human', 'Species', '9606', (70, 75))	('mutated', 'Var', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
100499	30415923	Subsequent studies identified LKB1 mutations in sporadic cancers, particularly in non-small cell lung cancers (NSCLC), where LKB1 mutations are the third most frequent genetic alteration (~20%) and are often concurrent with Kras mutations (; Sanchez-Cespedes et al., 2002).	('NSCLC', 'Disease', (111, 116))	('Kras', 'Gene', (224, 228))	('LKB1', 'Gene', (125, 129))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (82, 109))	('LKB1', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('Kras', 'Gene', '16653', (224, 228))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (82, 108))	('lung cancers', 'Phenotype', 'HP:0100526', (97, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('non-small cell lung cancers', 'Disease', (82, 109))	('cancers', 'Disease', (102, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (82, 109))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (130, 139))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (86, 109))	('mutations', 'Var', (35, 44))
100502	30415923	However, soon after LKB1 was also found to directly phosphorylate and activate a family of 12 additional kinases in the AMPK superfamily, hence loss of LKB1 in tumors is accompanied by loss of the activity of AMPK as well as the other 12 AMPK-related kinases.	('loss', 'Var', (144, 148))	('AMPK', 'Gene', '5563', (209, 213))	('AMPK', 'molecular_function', 'GO:0047322', ('209', '213'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('AMPK', 'molecular_function', 'GO:0050405', ('120', '124'))	('tumors', 'Disease', (160, 166))	('AMPK', 'Gene', '5563', (120, 124))	('AMPK', 'Gene', (209, 213))	('activity', 'MPA', (197, 205))	('AMPK', 'molecular_function', 'GO:0050405', ('238', '242'))	('AMPK', 'Gene', '5563', (238, 242))	('loss', 'NegReg', (185, 189))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('AMPK', 'molecular_function', 'GO:0050405', ('209', '213'))	('AMPK', 'molecular_function', 'GO:0004691', ('120', '124'))	('AMPK', 'Gene', (120, 124))	('LKB1', 'Gene', (152, 156))	('AMPK', 'molecular_function', 'GO:0004691', ('238', '242'))	('AMPK', 'molecular_function', 'GO:0004691', ('209', '213'))	('AMPK', 'molecular_function', 'GO:0047322', ('120', '124'))	('AMPK', 'Gene', (238, 242))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('AMPK', 'molecular_function', 'GO:0047322', ('238', '242'))
100504	30415923	Though genetic studies in mice found that LKB1 deletion triggered loss of most AMPK activity, CAMKK2 was found to provide some basal level of AMPK activation in the absence of LKB1, meaning such tumors were not abolished of AMPK activity.	('AMPK', 'Gene', '5563', (224, 228))	('AMPK activity', 'molecular_function', 'GO:0004679', ('224', '237'))	('AMPK', 'molecular_function', 'GO:0004691', ('142', '146'))	('AMPK activity', 'molecular_function', 'GO:0004679', ('79', '92'))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('CAMKK2', 'Gene', '207565', (94, 100))	('AMPK', 'Gene', '5563', (79, 83))	('AMPK', 'Gene', '5563', (142, 146))	('deletion', 'Var', (47, 55))	('AMPK', 'Gene', (224, 228))	('AMPK', 'molecular_function', 'GO:0047322', ('142', '146'))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('loss', 'NegReg', (66, 70))	('LKB1', 'Gene', (42, 46))	('AMPK', 'Gene', (79, 83))	('AMPK', 'Gene', (142, 146))	('mice', 'Species', '10090', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('CAMKK2', 'Gene', (94, 100))	('AMPK', 'molecular_function', 'GO:0050405', ('142', '146'))
100506	30415923	Supporting this, direct activation of AMPK by small molecules has been shown to suppress tumor growth in several experimental tumor models (Huang et al., 2008; Lee et al., 2011).	('AMPK', 'molecular_function', 'GO:0004691', ('38', '42'))	('AMPK', 'Gene', '5563', (38, 42))	('AMPK', 'molecular_function', 'GO:0047322', ('38', '42'))	('suppress', 'NegReg', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('AMPK', 'molecular_function', 'GO:0050405', ('38', '42'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('AMPK', 'Gene', (38, 42))	('small molecules', 'Var', (46, 61))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('activation', 'PosReg', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (126, 131))
100507	30415923	Furthermore, suppression of AMPK activity in tumors outside of LKB1 mutation has been suggested to promote tumor growth, including via inhibitory phosphorylation of AMPKalpha1 at Ser487 by AKT or degradation of AMPK by E3 ligases such as TRIM28 or UBE20 (; Vila et al., 2017).	('AMPK', 'Gene', (211, 215))	('tumor', 'Disease', (107, 112))	('mutation', 'Var', (68, 76))	('TRIM28', 'Gene', (238, 244))	('tumor', 'Disease', (45, 50))	('phosphorylation', 'biological_process', 'GO:0016310', ('146', '161'))	('AMPK', 'molecular_function', 'GO:0004691', ('211', '215'))	('AMPK', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('degradation', 'MPA', (196, 207))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('AKT', 'Gene', (189, 192))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('degradation', 'biological_process', 'GO:0009056', ('196', '207'))	('E3 ligases', 'Protein', (219, 229))	('Ser', 'cellular_component', 'GO:0005790', ('179', '182'))	('AMPK', 'molecular_function', 'GO:0047322', ('211', '215'))	('inhibitory phosphorylation', 'MPA', (135, 161))	('suppression', 'NegReg', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('AMPK', 'Gene', '5563', (165, 169))	('tumors', 'Disease', (45, 51))	('AMPK', 'Gene', '5563', (211, 215))	('AKT', 'Gene', '11651', (189, 192))	('TRIM28', 'Gene', '21849', (238, 244))	('promote', 'PosReg', (99, 106))	('Ser', 'Chemical', 'MESH:C530429', (179, 182))	('AMPK', 'Gene', '5563', (28, 32))	('AMPK', 'molecular_function', 'GO:0050405', ('211', '215'))	('LKB1', 'Gene', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('AMPK', 'Gene', (165, 169))	('AMPK activity', 'molecular_function', 'GO:0004679', ('28', '41'))
100508	30415923	Consistent with the idea that AMPK itself may behave as a tumor suppressor, one of the first genetic studies of AMPK function in mouse models of cancer revealed that whole-body AMPKalpha1 knockout mice increase tumor burden in the Eu-Myc model of Burkitt's lymphoma.	('cancer', 'Disease', (145, 151))	('AMPK', 'molecular_function', 'GO:0047322', ('112', '116'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('AMPK', 'Gene', (30, 34))	('AMPK', 'molecular_function', 'GO:0047322', ('30', '34'))	('tumor', 'Disease', (211, 216))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('mice', 'Species', '10090', (197, 201))	('AMPK', 'Gene', '5563', (177, 181))	('AMPK', 'Gene', '5563', (112, 116))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('increase', 'PosReg', (202, 210))	('AMPK', 'molecular_function', 'GO:0050405', ('112', '116'))	('AMPK', 'molecular_function', 'GO:0050405', ('30', '34'))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (247, 265))	('AMPK', 'Gene', (177, 181))	('Myc', 'Gene', (234, 237))	('AMPK', 'Gene', (112, 116))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (247, 265))	("Burkitt's lymphoma", 'Disease', (247, 265))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mouse', 'Species', '10090', (129, 134))	('AMPK', 'molecular_function', 'GO:0004691', ('112', '116'))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('AMPK', 'Gene', '5563', (30, 34))	('AMPK', 'molecular_function', 'GO:0004691', ('30', '34'))	('knockout', 'Var', (188, 196))	('Eu', 'Chemical', 'MESH:D005063', (231, 233))	('Myc', 'Gene', '17869', (234, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (257, 265))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
100513	30415923	In one model, deletion of AMPKalpha1 and alpha2 rendered the leukemic cells sensitive to cell death induced by dietary restriction through redox imbalance.	('death', 'Disease', 'MESH:D003643', (94, 99))	('imbalance', 'Phenotype', 'HP:0002172', (145, 154))	('redox imbalance', 'Phenotype', 'HP:0025463', (139, 154))	('cell death', 'biological_process', 'GO:0008219', ('89', '99'))	('leukemic', 'Disease', (61, 69))	('AMPKalpha1', 'Gene', (26, 36))	('alpha2', 'Gene', '20454', (41, 47))	('redox imbalance', 'MPA', (139, 154))	('deletion', 'Var', (14, 22))	('death', 'Disease', (94, 99))	('leukemic', 'Disease', 'MESH:D007938', (61, 69))	('alpha2', 'Gene', (41, 47))
100515	30415923	Notably, all of the aforementioned studies of AMPK deletion have been exclusively performed in blood borne cancer models, and while AMPK function in xenograft tumor models has been studied via shRNA, the conditional genetic deletion of AMPK in genetically engineered autochthonous solid tumor models has not been described to date.	('AMPK', 'Gene', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('AMPK', 'Gene', (236, 240))	('AMPK', 'molecular_function', 'GO:0050405', ('46', '50'))	('AMPK', 'molecular_function', 'GO:0004691', ('132', '136'))	('AMPK', 'molecular_function', 'GO:0047322', ('236', '240'))	('blood borne cancer', 'Disease', (95, 113))	('AMPK', 'Gene', '5563', (46, 50))	('AMPK', 'molecular_function', 'GO:0004691', ('46', '50'))	('tumor', 'Disease', (287, 292))	('AMPK', 'molecular_function', 'GO:0047322', ('132', '136'))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('AMPK', 'molecular_function', 'GO:0050405', ('236', '240'))	('AMPK', 'Gene', '5563', (132, 136))	('tumor', 'Disease', (159, 164))	('AMPK', 'molecular_function', 'GO:0047322', ('46', '50'))	('deletion', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('AMPK', 'Gene', '5563', (236, 240))	('AMPK', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('AMPK', 'molecular_function', 'GO:0050405', ('132', '136'))	('AMPK', 'molecular_function', 'GO:0004691', ('236', '240'))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('blood borne cancer', 'Disease', 'MESH:D009369', (95, 113))
100518	30415923	We examined the expression of AMPKalpha1 and AMPKalpha2 in human NSCLC cell lines and in a murine KrasG12D model of NSCLC and found that proteins for each appear well-expressed (Figure S1A), suggesting that genetic depletion of both Prkaa1 and Prkaa2 would be needed to functionally remove all AMPK activity, as has been reported previously.	('Kras', 'Gene', (98, 102))	('AMPK', 'Gene', (30, 34))	('AMPK', 'Gene', '5563', (294, 298))	('Prkaa2', 'Gene', (244, 250))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('Kras', 'Gene', '16653', (98, 102))	('NSCLC', 'Disease', (116, 121))	('remove', 'NegReg', (283, 289))	('depletion', 'NegReg', (215, 224))	('AMPK', 'Gene', '5563', (45, 49))	('AMPK', 'Gene', (294, 298))	('Prkaa1', 'Gene', (233, 239))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('murine', 'Species', '10090', (91, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('AMPK activity', 'molecular_function', 'GO:0004679', ('294', '307'))	('Prkaa2', 'Gene', '108079', (244, 250))	('NSCLC', 'Disease', (65, 70))	('human', 'Species', '9606', (59, 64))	('AMPK', 'Gene', '5563', (30, 34))	('AMPK', 'Gene', (45, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('genetic', 'Var', (207, 214))	('Prkaa1', 'Gene', '105787', (233, 239))
100520	30415923	In tissue-specific KO studies, depletion of both AMPKalpha1 and AMPKalpha2 results in complete loss of phosphorylated-ACC at serine 79 (P-ACCS79).	('phosphorylated-ACC at serine 79', 'MPA', (103, 134))	('depletion', 'MPA', (31, 40))	('AMPKalpha1', 'Var', (49, 59))	('serine', 'Chemical', 'MESH:C047902', (125, 131))	('AMPKalpha2', 'Var', (64, 74))	('loss', 'NegReg', (95, 99))
100522	30415923	AMPK deletion lead to complete loss of P-ACCS79 detection in AMPKalpha1/alpha2 null livers (Figure S1B).	('alpha2', 'Gene', (72, 78))	('P-ACCS79', 'Gene', (39, 47))	('loss', 'NegReg', (31, 35))	('deletion', 'Var', (5, 13))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'Gene', '5563', (61, 65))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('detection', 'MPA', (48, 57))	('alpha2', 'Gene', '20454', (72, 78))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('AMPK', 'Gene', (61, 65))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('AMPK', 'Gene', (0, 4))
100524	30415923	We confirmed that loss of both AMPKalpha1 and AMPKalpha2 was required in KrasG12D lung tumors to fully genetically deplete AMPK activity (Figure S1C).	('AMPK', 'Gene', (46, 50))	('lung tumors', 'Disease', 'MESH:D008175', (82, 93))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('loss', 'Var', (18, 22))	('deplete', 'NegReg', (115, 122))	('AMPK', 'Gene', (123, 127))	('lung tumors', 'Disease', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('lung tumors', 'Phenotype', 'HP:0100526', (82, 93))	('AMPK', 'Gene', '5563', (31, 35))	('Kras', 'Gene', (73, 77))	('AMPK', 'Gene', '5563', (46, 50))	('Kras', 'Gene', '16653', (73, 77))	('AMPK activity', 'molecular_function', 'GO:0004679', ('123', '136'))	('lung tumor', 'Phenotype', 'HP:0100526', (82, 92))	('AMPK', 'Gene', (31, 35))	('AMPK', 'Gene', '5563', (123, 127))
100526	30415923	In these mice, activation of KrasG12D in the lung epithelium via intranasal instillation of adenovirus expressing Cre-recombinase (Ad-Cre) is coupled to simultaneous deletion of Prkaa1 and Prkaa2 and activation of firefly luciferase to allow for non-invasive bioluminescence imaging (BLI) of NSCLC development.	('Prkaa1', 'Gene', '105787', (178, 184))	('Kras', 'Gene', (29, 33))	('Kras', 'Gene', '16653', (29, 33))	('deletion', 'Var', (166, 174))	('bioluminescence', 'biological_process', 'GO:0008218', ('259', '274'))	('NSCLC', 'Disease', (292, 297))	('Prkaa1', 'Gene', (178, 184))	('NSCLC', 'Disease', 'MESH:D002289', (292, 297))	('Prkaa2', 'Gene', '108079', (189, 195))	('Prkaa2', 'Gene', (189, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (292, 297))	('mice', 'Species', '10090', (9, 13))
100529	30415923	Using a combination of western blotting on tumors (Figure S1D), laser-capture microdissection (Figure S1E), and P-ACCS79 immunohistochemistry (Figure S1J-K), it became clear that we were getting very inefficient deletion of AMPKalpha1 and AMPKalpha2 in the tumors.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('deletion', 'Var', (212, 220))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('AMPKalpha1', 'Gene', (224, 234))	('AMPKalpha2', 'Gene', (239, 249))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
100535	30415923	KL tumors initiated by Lenti-Cre displayed enhanced growth in a manner identical to that observed in Ad-Cre cohorts (Figure 1B, S1H).	('enhanced', 'PosReg', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('S1H', 'Chemical', 'MESH:C042345', (128, 131))	('KL tumors', 'Disease', (0, 9))	('Lenti-Cre', 'Var', (23, 32))	('growth', 'MPA', (52, 58))	('KL tumors', 'Disease', 'MESH:D009369', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
100539	30415923	Given that KA lung tumor growth does not phenocopy LKB1 loss using either system, these data demonstrate that AMPK deficiency is not sufficient to mimic the tumor suppressor effects of LKB1 in KrasG12D NSCLC.	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('Kras', 'Gene', '16653', (193, 197))	('lung tumor', 'Disease', 'MESH:D008175', (14, 24))	('AMPK', 'molecular_function', 'GO:0047322', ('110', '114'))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AMPK', 'Gene', '5563', (110, 114))	('AMPK', 'molecular_function', 'GO:0050405', ('110', '114'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('157', '173'))	('deficiency', 'Var', (115, 125))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor suppressor', 'biological_process', 'GO:0051726', ('157', '173'))	('AMPK', 'molecular_function', 'GO:0004691', ('110', '114'))	('AMPK', 'Gene', (110, 114))	('lung tumor', 'Disease', (14, 24))	('tumor', 'Disease', (157, 162))	('NSCLC', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('lung tumor', 'Phenotype', 'HP:0100526', (14, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('Kras', 'Gene', (193, 197))
100542	30415923	These data suggest that the discrepancy between KA phenotypes in Ad-Cre versus Lenti-Cre cohorts may be a function of the deletion efficiency of AMPK.	('AMPK', 'Gene', (145, 149))	('AMPK', 'molecular_function', 'GO:0050405', ('145', '149'))	('AMPK', 'molecular_function', 'GO:0004691', ('145', '149'))	('AMPK', 'molecular_function', 'GO:0047322', ('145', '149'))	('deletion', 'Var', (122, 130))	('AMPK', 'Gene', '5563', (145, 149))
100551	30415923	When we calculated tumor number we found a reduction in the number of tumors in KA mice compared to K mice (Figure 1H), however, we did not find any differences in the average size of the tumors (Figure 1I) suggesting that the reduction in total lung tumor burden that occurs when AMPK is deleted is mostly due to reduction in the number of tumors and not tumor size.	('tumor', 'Disease', (188, 193))	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', (251, 256))	('AMPK', 'Gene', '5563', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumors', 'Disease', (341, 347))	('deleted', 'Var', (289, 296))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('reduction', 'NegReg', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('lung tumor', 'Disease', (246, 256))	('reduction', 'NegReg', (314, 323))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AMPK', 'molecular_function', 'GO:0050405', ('281', '285'))	('mice', 'Species', '10090', (83, 87))	('tumors', 'Disease', (70, 76))	('AMPK', 'Gene', (281, 285))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('lung tumor', 'Phenotype', 'HP:0100526', (246, 256))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumors', 'Disease', (188, 194))	('tumor', 'Disease', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('AMPK', 'molecular_function', 'GO:0004691', ('281', '285'))	('tumor', 'Disease', (356, 361))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('lung tumor', 'Disease', 'MESH:D008175', (246, 256))	('tumor', 'Disease', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('AMPK', 'molecular_function', 'GO:0047322', ('281', '285'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
100553	30415923	Finally, to corroborate our BLI results from KA1 and KA2 mice we performed post-hoc analyses and detected no significant changes in tumor burden or tumor number upon Lenti-Cre induced single deletion of either AMPKalpha1 or AMPKalpha2, consistent with the redundancy observed between both catalytic subunits of AMPK (Figure S1O, P).	('AMPK', 'Gene', '5563', (224, 228))	('tumor', 'Disease', (132, 137))	('AMPK', 'Gene', (210, 214))	('KA1', 'Gene', (45, 48))	('AMPK', 'Gene', '5563', (311, 315))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('KA2', 'Gene', (53, 56))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('AMPK', 'molecular_function', 'GO:0050405', ('311', '315'))	('AMPK', 'Gene', (224, 228))	('KA2', 'Gene', '14809', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('AMPK', 'Gene', (311, 315))	('KA1', 'Gene', '21423', (45, 48))	('AMPK', 'molecular_function', 'GO:0004691', ('311', '315'))	('mice', 'Species', '10090', (57, 61))	('AMPK', 'Gene', '5563', (210, 214))	('single deletion', 'Var', (184, 199))	('tumor', 'Disease', (148, 153))	('AMPK', 'molecular_function', 'GO:0047322', ('311', '315'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
100555	30415923	Given that LKB1 is the major activating kinase of AMPK and its deletion should result in near complete loss of AMPK activity (which spurred the hypothesis that AMPK loss should mimic LKB1 loss), we directly compared AMPK signaling in lysates from individual tumors isolated from K, KA and KL mice to determine whether KL tumors had in fact completely lost AMPK activity comparable to KA (Figure 1J).	('AMPK', 'Gene', '5563', (216, 220))	('signaling', 'biological_process', 'GO:0023052', ('221', '230'))	('AMPK', 'molecular_function', 'GO:0004691', ('160', '164'))	('mice', 'Species', '10090', (292, 296))	('AMPK', 'Gene', '5563', (160, 164))	('deletion', 'Var', (63, 71))	('AMPK', 'molecular_function', 'GO:0050405', ('50', '54'))	('KL tumors', 'Disease', (318, 327))	('AMPK', 'molecular_function', 'GO:0047322', ('216', '220'))	('AMPK', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('AMPK activity', 'molecular_function', 'GO:0004679', ('111', '124'))	('AMPK', 'Gene', '5563', (111, 115))	('AMPK', 'molecular_function', 'GO:0047322', ('160', '164'))	('AMPK activity', 'molecular_function', 'GO:0004679', ('356', '369'))	('AMPK', 'Gene', (216, 220))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('AMPK', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('AMPK', 'molecular_function', 'GO:0004691', ('50', '54'))	('AMPK', 'Gene', '5563', (356, 360))	('tumors', 'Disease', (258, 264))	('LKB1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('AMPK', 'molecular_function', 'GO:0050405', ('216', '220'))	('KL tumors', 'Disease', 'MESH:D009369', (318, 327))	('AMPK', 'Gene', '5563', (50, 54))	('AMPK', 'Gene', (111, 115))	('tumors', 'Disease', (321, 327))	('loss', 'NegReg', (103, 107))	('AMPK', 'molecular_function', 'GO:0047322', ('50', '54'))	('AMPK', 'molecular_function', 'GO:0050405', ('160', '164'))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('AMPK', 'Gene', (356, 360))	('lost', 'NegReg', (351, 355))	('AMPK', 'molecular_function', 'GO:0004691', ('216', '220'))	('tumors', 'Disease', 'MESH:D009369', (321, 327))
100558	30415923	Thus KL tumors still retain residual AMPK activity compared to KA tumors, which are completely nullified for AMPK and thus helps explains why LKB1 deletion would not have the same inability to restore energetic balance in the face of metabolic stress as AMPK deletion does.	('AMPK', 'Gene', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('KL tumors', 'Disease', 'MESH:D009369', (5, 14))	('tumors', 'Disease', (8, 14))	('AMPK', 'molecular_function', 'GO:0004691', ('254', '258'))	('AMPK', 'molecular_function', 'GO:0047322', ('109', '113'))	('AMPK', 'Gene', '5563', (254, 258))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('AMPK', 'Gene', '5563', (109, 113))	('AMPK', 'molecular_function', 'GO:0047322', ('254', '258'))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('deletion', 'Var', (147, 155))	('AMPK', 'molecular_function', 'GO:0050405', ('109', '113'))	('AMPK', 'Gene', (254, 258))	('KL tumors', 'Disease', (5, 14))	('AMPK', 'Gene', '5563', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('AMPK activity', 'molecular_function', 'GO:0004679', ('37', '50'))	('AMPK', 'Gene', (109, 113))	('tumors', 'Disease', (66, 72))	('LKB1', 'Gene', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('energetic balance', 'MPA', (201, 218))	('AMPK', 'molecular_function', 'GO:0050405', ('254', '258'))	('AMPK', 'molecular_function', 'GO:0004691', ('109', '113'))
100559	30415923	Given that AMPK is required for optimal growth of KrasG12D NSCLC, we reasoned that AMPK deletion may impose a metabolic liability during NSCLC development.	('AMPK', 'molecular_function', 'GO:0050405', ('11', '15'))	('NSCLC', 'Disease', (137, 142))	('deletion', 'Var', (88, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('AMPK', 'Gene', '5563', (11, 15))	('AMPK', 'Gene', (83, 87))	('Kras', 'Gene', '16653', (50, 54))	('AMPK', 'molecular_function', 'GO:0004691', ('11', '15'))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('AMPK', 'molecular_function', 'GO:0050405', ('83', '87'))	('impose', 'Reg', (101, 107))	('NSCLC', 'Disease', (59, 64))	('AMPK', 'Gene', (11, 15))	('AMPK', 'molecular_function', 'GO:0047322', ('83', '87'))	('AMPK', 'molecular_function', 'GO:0047322', ('11', '15'))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('AMPK', 'molecular_function', 'GO:0004691', ('83', '87'))	('AMPK', 'Gene', '5563', (83, 87))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('metabolic liability', 'MPA', (110, 129))	('Kras', 'Gene', (50, 54))
100565	30415923	KPL mice also developed a large number of local and distant metastases (Figure S2A), demonstrating that simultaneous deletion of p53 and LKB1 leads to enhanced lung tumor growth and more aggressive metastatic NSCLC compared to single deletion of either tumor suppressor alone.	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('metastases', 'Disease', (60, 70))	('p53', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('mice', 'Species', '10090', (4, 8))	('enhanced', 'PosReg', (151, 159))	('lung tumor', 'Disease', (160, 170))	('lung tumor', 'Phenotype', 'HP:0100526', (160, 170))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('253', '269'))	('LKB1', 'Gene', (137, 141))	('deletion', 'Var', (117, 125))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('more', 'PosReg', (182, 186))	('p53', 'Gene', '22059', (129, 132))	('tumor', 'Disease', (253, 258))	('tumor suppressor', 'biological_process', 'GO:0051726', ('253', '269'))	('NSCLC', 'Disease', (209, 214))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('lung tumor', 'Disease', 'MESH:D008175', (160, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('aggressive metastatic', 'CPA', (187, 208))	('metastases', 'Disease', 'MESH:D009362', (60, 70))
100572	30415923	Quantitation of total lung tumor burden in KP and KPA mice revealed that AMPK deletion resulted in a significant decrease in lung tumor burden (Figures 2G and S2E), and when escaper tumors were excluded, AMPK deletion reduced lung tumor burden by 85% compared to KP mice.	('lung tumor', 'Disease', 'MESH:D008175', (125, 135))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('AMPK', 'Gene', (204, 208))	('lung tumor', 'Phenotype', 'HP:0100526', (226, 236))	('AMPK', 'Gene', '5563', (73, 77))	('lung tumor', 'Disease', 'MESH:D008175', (22, 32))	('AMPK', 'molecular_function', 'GO:0004691', ('73', '77'))	('reduced', 'NegReg', (218, 225))	('mice', 'Species', '10090', (266, 270))	('AMPK', 'molecular_function', 'GO:0004691', ('204', '208'))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumors', 'Disease', (182, 188))	('deletion', 'Var', (78, 86))	('AMPK', 'Gene', (73, 77))	('AMPK', 'molecular_function', 'GO:0047322', ('73', '77'))	('lung tumor', 'Disease', 'MESH:D008175', (226, 236))	('lung tumor', 'Disease', (125, 135))	('decrease', 'NegReg', (113, 121))	('AMPK', 'molecular_function', 'GO:0047322', ('204', '208'))	('lung tumor', 'Disease', (22, 32))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('lung tumor', 'Phenotype', 'HP:0100526', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('lung tumor', 'Phenotype', 'HP:0100526', (22, 32))	('AMPK', 'Gene', '5563', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('AMPK', 'molecular_function', 'GO:0050405', ('73', '77'))	('lung tumor', 'Disease', (226, 236))	('mice', 'Species', '10090', (54, 58))	('AMPK', 'molecular_function', 'GO:0050405', ('204', '208'))
100573	30415923	AMPK deletion also led to a 40% decrease in total tumor number (Figures 2H and S2F).	('deletion', 'Var', (5, 13))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('S2F', 'Chemical', 'MESH:D013455', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('AMPK', 'Gene', (0, 4))	('decrease', 'NegReg', (32, 40))	('tumor', 'Disease', (50, 55))
100586	30415923	To further dissect how AMPK activation may be impacting control of growth and metabolism in Kras mutant lung tumors, we performed CRISPR/Cas9 deletion of AMPKalpha1 and alpha2 in murine KP lung adenocarcinoma cells in vitro.	('Kras', 'Gene', '16653', (92, 96))	('AMPK', 'Gene', '5563', (154, 158))	('lung tumors', 'Disease', 'MESH:D008175', (104, 115))	('AMPK', 'molecular_function', 'GO:0050405', ('23', '27'))	('alpha2', 'Gene', (169, 175))	('metabolism', 'biological_process', 'GO:0008152', ('78', '88'))	('KP lung adenocarcinoma', 'Disease', 'MESH:C538231', (186, 208))	('deletion', 'Var', (142, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('lung tumors', 'Phenotype', 'HP:0100526', (104, 115))	('lung tumor', 'Phenotype', 'HP:0100526', (104, 114))	('AMPK', 'molecular_function', 'GO:0004691', ('23', '27'))	('AMPK', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lung tumors', 'Disease', (104, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (189, 208))	('AMPK', 'Gene', '5563', (23, 27))	('Cas', 'cellular_component', 'GO:0005650', ('137', '140'))	('KP lung adenocarcinoma', 'Disease', (186, 208))	('AMPK', 'molecular_function', 'GO:0047322', ('23', '27'))	('alpha2', 'Gene', '20454', (169, 175))	('murine', 'Species', '10090', (179, 185))	('Kras', 'Gene', (92, 96))	('AMPK', 'Gene', (23, 27))
100587	30415923	We transfected guide RNAs (gRNAs) designed to delete AMPKalpha1 and alpha2 into two luciferase-expressing mouse NSCLC cell lines derived from KP lung tumors, 634T and 368T1 (Winslow et al., 2011), and screened clones for AMPKalpha1 and alpha2 deletion (designated as double knockout, DKO) by immunoblotting.	('AMPKalpha1', 'Var', (221, 231))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('368T1', 'CellLine', 'CVCL:0I01', (167, 172))	('lung tumor', 'Phenotype', 'HP:0100526', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('alpha2', 'Gene', (68, 74))	('alpha2', 'Gene', '20454', (236, 242))	('KP lung tumors', 'Disease', (142, 156))	('alpha2', 'Gene', '20454', (68, 74))	('deletion', 'Var', (243, 251))	('alpha2', 'Gene', (236, 242))	('KP lung tumors', 'Disease', 'MESH:D008175', (142, 156))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('mouse', 'Species', '10090', (106, 111))	('AMPKalpha1', 'Gene', (53, 63))	('delete', 'Var', (46, 52))	('NSCLC', 'Disease', (112, 117))	('lung tumors', 'Phenotype', 'HP:0100526', (145, 156))
100589	30415923	AMPK deletion led to a complete loss in AMPK signaling that was fully restored with stable re-expression of AMPKalpha1 but not kinase dead AMPKalpha1 (Figures 3A and S3A).	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('AMPK', 'Gene', (139, 143))	('deletion', 'Var', (5, 13))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'Gene', (40, 44))	('AMPK', 'Gene', '5563', (139, 143))	('loss', 'NegReg', (32, 36))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('AMPK', 'molecular_function', 'GO:0050405', ('40', '44'))	('AMPK', 'molecular_function', 'GO:0004691', ('40', '44'))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('AMPK', 'Gene', '5563', (108, 112))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('AMPK', 'molecular_function', 'GO:0047322', ('40', '44'))	('AMPK', 'Gene', (0, 4))	('AMPK', 'Gene', '5563', (40, 44))	('AMPK', 'Gene', (108, 112))
100591	30415923	To determine if the residual AMPK activity left in KP tumor cells lacking LKB1 was sufficient to mediate growth and survival, we used CRISPR/Cas9 to delete AMPKalpha1 and alpha2 in two mouse lung adenocarcinoma cell lines derived from KPL lung tumors harboring LKB1 inactivation, 821T4 and 807LN (Figure S3C).	('KP tumor', 'Disease', 'MESH:D009369', (51, 59))	('AMPK', 'Gene', (156, 160))	('AMPK', 'Gene', (29, 33))	('LKB1', 'Gene', (261, 265))	('AMPK activity', 'molecular_function', 'GO:0004679', ('29', '42'))	('inactivation', 'Var', (266, 278))	('lung tumors', 'Disease', 'MESH:D008175', (239, 250))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('alpha2', 'Gene', '20454', (171, 177))	('lung tumors', 'Phenotype', 'HP:0100526', (239, 250))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('LKB1', 'Gene', (74, 78))	('Cas', 'cellular_component', 'GO:0005650', ('141', '144'))	('lung tumor', 'Phenotype', 'HP:0100526', (239, 249))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (191, 210))	('lung adenocarcinoma', 'Disease', (191, 210))	('lung tumors', 'Disease', (239, 250))	('alpha2', 'Gene', (171, 177))	('AMPK', 'Gene', '5563', (156, 160))	('AMPK', 'Gene', '5563', (29, 33))	('mouse', 'Species', '10090', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('delete', 'Var', (149, 155))	('KP tumor', 'Disease', (51, 59))	('807LN', 'Var', (290, 295))	('821T4', 'Var', (280, 285))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
100593	30415923	Moreover, when KPL cells with or without AMPK deletion were placed into soft agar, tumor cells retaining AMPK showed greater survival and growth (Figure S3E), indicating that even the low level of AMPK activity left in LKB1-deficient KP lung tumor cells is sufficient to support survival.	('AMPK', 'Gene', (197, 201))	('tumor', 'Disease', (83, 88))	('growth', 'CPA', (138, 144))	('AMPK', 'Gene', '5563', (41, 45))	('AMPK', 'molecular_function', 'GO:0004691', ('105', '109'))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('AMPK', 'molecular_function', 'GO:0047322', ('41', '45'))	('deletion', 'Var', (46, 54))	('LKB1-deficient KP lung tumor', 'Disease', 'MESH:D008175', (219, 247))	('AMPK', 'Gene', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('greater', 'PosReg', (117, 124))	('AMPK', 'molecular_function', 'GO:0047322', ('105', '109'))	('AMPK', 'Gene', (41, 45))	('LKB1-deficient KP lung tumor', 'Disease', (219, 247))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lung tumor', 'Phenotype', 'HP:0100526', (237, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('AMPK', 'molecular_function', 'GO:0050405', ('41', '45'))	('AMPK', 'Gene', '5563', (197, 201))	('AMPK activity', 'molecular_function', 'GO:0004679', ('197', '210'))	('AMPK', 'molecular_function', 'GO:0050405', ('105', '109'))	('AMPK', 'molecular_function', 'GO:0004691', ('41', '45'))	('AMPK', 'Gene', '5563', (105, 109))
100604	30415923	Gene Set Enrichment Analysis (GSEA) considering both biological replicates revealed that KEGG Lysosome was the only significant term associated with the RNA-seq dataset after 12 hours of glucose deprivation, and that the KEGG Lysosome gene set positively correlates with genes upregulated in AMPKalpha1 expressing cells compared to DKO (Figure 3J).	('glucose deprivation', 'Disease', 'MESH:D018149', (187, 206))	('upregulated', 'PosReg', (277, 288))	('glucose deprivation', 'Disease', (187, 206))	('RNA', 'cellular_component', 'GO:0005562', ('153', '156'))	('AMPKalpha1', 'Var', (292, 302))	('Lysosome', 'cellular_component', 'GO:0005764', ('226', '234'))	('Lysosome', 'cellular_component', 'GO:0005764', ('94', '102'))
100608	30415923	not in isogenic AMPK add-back cells, we performed RNA-seq analysis of 634T cells that were deleted for AMPKalpha1/alpha2 in polyclonal pools and compared them to the WT polyclonal controls under conditions of glucose deprivation (Figure S3J).	('alpha2', 'Gene', (114, 120))	('AMPK', 'Gene', (16, 20))	('AMPK', 'Gene', '5563', (103, 107))	('AMPK', 'molecular_function', 'GO:0050405', ('16', '20'))	('glucose deprivation', 'Disease', 'MESH:D018149', (209, 228))	('AMPK', 'molecular_function', 'GO:0004691', ('16', '20'))	('deleted', 'Var', (91, 98))	('AMPK', 'Gene', (103, 107))	('glucose deprivation', 'Disease', (209, 228))	('alpha2', 'Gene', '20454', (114, 120))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))	('AMPK', 'molecular_function', 'GO:0047322', ('16', '20'))	('AMPK', 'Gene', '5563', (16, 20))
100636	30415923	We found that the induction of Hexa, Cd63 and Neu1 during AMPK activation under no glucose was minimally impacted by Tfeb knockdown, despite efficient Tfeb depletion (Figures 4F and S4H-K).	('Hexa', 'Gene', (31, 35))	('AMPK', 'Gene', '5563', (58, 62))	('Cd63', 'Gene', (37, 41))	('AMPK', 'molecular_function', 'GO:0047322', ('58', '62'))	('Tfeb', 'Gene', (117, 121))	('Tfeb', 'Gene', '21425', (117, 121))	('S4H-K', 'Chemical', 'MESH:C024755', (182, 187))	('knockdown', 'Var', (122, 131))	('AMPK', 'Gene', (58, 62))	('glucose', 'Chemical', 'MESH:D005947', (83, 90))	('AMPK', 'molecular_function', 'GO:0050405', ('58', '62'))	('Neu1', 'Gene', (46, 50))	('Neu1', 'Gene', '18010', (46, 50))	('depletion', 'MPA', (156, 165))	('AMPK', 'molecular_function', 'GO:0004691', ('58', '62'))	('Tfeb', 'Gene', (151, 155))	('Tfeb', 'Gene', '21425', (151, 155))	('Cd63', 'Gene', '12512', (37, 41))	('Hexa', 'Gene', '15211', (31, 35))
100637	30415923	However, Tfe3 knockdown significantly reduced the induction of these genes in AMPKalpha1 restored cells during glucose starvation, down to basal expression levels measured under high glucose and equivalent to simultaneous knockdown of Tfeb and Tfe3 (Figures 4F and S4I-K).	('Tfeb', 'Gene', (235, 239))	('Tfeb', 'Gene', '21425', (235, 239))	('reduced', 'NegReg', (38, 45))	('glucose', 'Chemical', 'MESH:D005947', (183, 190))	('glucose', 'Chemical', 'MESH:D005947', (111, 118))	('knockdown', 'Var', (14, 23))	('high glucose', 'Phenotype', 'HP:0003074', (178, 190))	('induction', 'MPA', (50, 59))
100638	30415923	Importantly, Tfe3 knockdown had no effect on the expression of Hexa, Cd63 and Neu1 under high glucose culture conditions, consistent with its hyper-phosphorylation and cytoplasmic retention.	('high glucose', 'Phenotype', 'HP:0003074', (89, 101))	('knockdown', 'Var', (18, 27))	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('Hexa', 'Gene', (63, 67))	('Cd63', 'Gene', '12512', (69, 73))	('Neu1', 'Gene', '18010', (78, 82))	('Hexa', 'Gene', '15211', (63, 67))	('Neu1', 'Gene', (78, 82))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('retention', 'biological_process', 'GO:0051235', ('180', '189'))	('Tfe3', 'Gene', (13, 17))	('Cd63', 'Gene', (69, 73))
100640	30415923	Oncogenic Tfeb and Tfe3 gene fusions have been described in renal cell carcinoma and Tfeb and Tfe3 were shown to play a crucial role in autophagy-lysosome function to promote the growth of pancreatic ductal adenocarcinoma (PDAC).	('renal cell carcinoma', 'Disease', (60, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('Tfe3', 'Gene', (94, 98))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (189, 221))	('Tfeb', 'Gene', (85, 89))	('fusions', 'Var', (29, 36))	('promote', 'PosReg', (167, 174))	('Tfeb', 'Gene', '21425', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('growth', 'MPA', (179, 185))	('Tfe3', 'Gene', (19, 23))	('autophagy', 'biological_process', 'GO:0016236', ('136', '145'))	('Tfeb', 'Gene', (10, 14))	('Tfeb', 'Gene', '21425', (10, 14))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (189, 221))	('autophagy', 'biological_process', 'GO:0006914', ('136', '145'))	('lysosome', 'cellular_component', 'GO:0005764', ('146', '154'))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (60, 80))	('pancreatic ductal adenocarcinoma', 'Disease', (189, 221))
100644	30415923	To dissect the function of Tfeb and Tfe3 in lung tumorigenesis, we performed CRISPR/Cas9 deletion of each in polyclonal pools of luciferase expressing 634T cells using two different gRNAs (designated as KO#1 and KO#2) (Figure 5C).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('lung tumor', 'Disease', 'MESH:D008175', (44, 54))	('lung tumor', 'Disease', (44, 54))	('Tfeb', 'Gene', (27, 31))	('deletion', 'Var', (89, 97))	('Tfeb', 'Gene', '21425', (27, 31))	('lung tumor', 'Phenotype', 'HP:0100526', (44, 54))	('Cas', 'cellular_component', 'GO:0005650', ('84', '87'))
100645	30415923	Deletion of Tfeb and Tfe3 led to significant loss of protein expression in polyclonal pools of cells (Figure 5D) and, consistent with Figure 4F, Tfe3 deletion but not Tfeb deletion led to a loss of Hexa induction upon 991 treatment (Figure S4D).	('Tfe3', 'Gene', (21, 25))	('Tfeb', 'Gene', (12, 16))	('Hexa', 'Gene', '15211', (198, 202))	('Tfeb', 'Gene', (167, 171))	('Tfeb', 'Gene', '21425', (12, 16))	('Tfeb', 'Gene', '21425', (167, 171))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('loss', 'NegReg', (190, 194))	('Tfe3', 'Gene', (145, 149))	('deletion', 'Var', (150, 158))	('Hexa', 'Gene', (198, 202))	('loss', 'NegReg', (45, 49))	('protein expression', 'MPA', (53, 71))	('Deletion', 'Var', (0, 8))
100646	30415923	Neither Tfeb nor Tfe3 inactivation resulted in basal proliferation rate changes (Figure S5E), but both were required for maximal protection against glucose deprivation (Figure S5F), mirroring our observations in AMPK KO lung cancer cells (Figure 3B-C).	('inactivation', 'Var', (22, 34))	('AMPK', 'molecular_function', 'GO:0004691', ('212', '216'))	('glucose deprivation', 'Disease', (148, 167))	('Tfeb', 'Gene', (8, 12))	('glucose deprivation', 'Disease', 'MESH:D018149', (148, 167))	('AMPK', 'Gene', '5563', (212, 216))	('Tfeb', 'Gene', '21425', (8, 12))	('AMPK', 'molecular_function', 'GO:0047322', ('212', '216'))	('KO lung cancer', 'Disease', (217, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('AMPK', 'Gene', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('AMPK', 'molecular_function', 'GO:0050405', ('212', '216'))	('KO lung cancer', 'Disease', 'MESH:D008175', (217, 231))	('3B-C', 'Chemical', 'MESH:C014396', (246, 250))	('Tfe3', 'Gene', (17, 21))
100649	30415923	However, Tfe3 deletion led to a significant reduction in lung tumor growth in both KO cell lines (Figures 5E-G).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('lung tumor', 'Disease', (57, 67))	('Tfe3', 'Gene', (9, 13))	('reduction', 'NegReg', (44, 53))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))	('deletion', 'Var', (14, 22))
100650	30415923	This was further supported by quantitative analysis of lung tumor burden from H&E stained sections where Tfe3 deletion led to significant reduction in lung tumor burden (Figure 5H-I), attributable to reduced tumor number (Figure 5J) but not tumor size (Figure S5G).	('reduced tumor number', 'Disease', (200, 220))	('significant', 'NegReg', (126, 137))	('reduced tumor number', 'Disease', 'MESH:D006987', (200, 220))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (208, 213))	('lung tumor', 'Disease', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('lung tumor', 'Disease', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('Tfe3', 'Var', (105, 109))	('lung tumor', 'Phenotype', 'HP:0100526', (151, 161))	('lung tumor', 'Phenotype', 'HP:0100526', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('where', 'Gene', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('lung tumor', 'Disease', 'MESH:D008175', (151, 161))	('lung tumor', 'Disease', 'MESH:D008175', (55, 65))
100651	30415923	Notably, Tfeb deletion led to modest reduction in lung tumor burden that did not reach statistical significance.	('Tfeb', 'Gene', (9, 13))	('Tfeb', 'Gene', '21425', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lung tumor', 'Disease', (50, 60))	('reduction', 'NegReg', (37, 46))	('lung tumor', 'Disease', 'MESH:D008175', (50, 60))	('deletion', 'Var', (14, 22))	('lung tumor', 'Phenotype', 'HP:0100526', (50, 60))
100653	30415923	To further delineate the role of AMPK and to determine whether the CLEAR network is also deregulated in KPA lung tumors we analyzed the impact of AMPK deletion in vivo using several methodologies.	('AMPK', 'Gene', (146, 150))	('lung tumors', 'Phenotype', 'HP:0100526', (108, 119))	('AMPK', 'Gene', (33, 37))	('AMPK', 'molecular_function', 'GO:0050405', ('33', '37'))	('lung tumor', 'Phenotype', 'HP:0100526', (108, 118))	('AMPK', 'molecular_function', 'GO:0004691', ('33', '37'))	('AMPK', 'Gene', '5563', (146, 150))	('AMPK', 'molecular_function', 'GO:0004691', ('146', '150'))	('AMPK', 'molecular_function', 'GO:0050405', ('146', '150'))	('lung tumors', 'Disease', 'MESH:D008175', (108, 119))	('AMPK', 'molecular_function', 'GO:0047322', ('33', '37'))	('deletion', 'Var', (151, 159))	('AMPK', 'Gene', '5563', (33, 37))	('AMPK', 'molecular_function', 'GO:0047322', ('146', '150'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lung tumors', 'Disease', (108, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
100654	30415923	Given that AMPK deletion led to a dramatic reduction in KP tumor size (Figure 2) we wondered if AMPK activity might be higher in small tumors to support their outgrowth.	('AMPK', 'molecular_function', 'GO:0050405', ('11', '15'))	('AMPK', 'molecular_function', 'GO:0004691', ('11', '15'))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('AMPK', 'Gene', '5563', (96, 100))	('deletion', 'Var', (16, 24))	('reduction', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('AMPK', 'molecular_function', 'GO:0047322', ('11', '15'))	('KP tumor', 'Disease', 'MESH:D009369', (56, 64))	('AMPK', 'Gene', '5563', (11, 15))	('KP tumor', 'Disease', (56, 64))	('AMPK', 'Gene', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('small tumors', 'Disease', 'MESH:D058405', (129, 141))	('AMPK', 'Gene', (11, 15))	('AMPK activity', 'molecular_function', 'GO:0004679', ('96', '109'))	('small tumors', 'Disease', (129, 141))
100659	30415923	As expected, AMPK deletion led to loss of phosphorylation of the well-documented AMPK sites in the direct AMPK substrates ACC, Raptor and ULK1 (Figure S6B).	('AMPK', 'Gene', '5563', (106, 110))	('Raptor', 'Gene', '74370', (127, 133))	('AMPK', 'molecular_function', 'GO:0047322', ('13', '17'))	('AMPK', 'molecular_function', 'GO:0050405', ('106', '110'))	('AMPK', 'Gene', '5563', (81, 85))	('AMPK', 'molecular_function', 'GO:0050405', ('81', '85'))	('AMPK', 'Gene', (106, 110))	('loss', 'NegReg', (34, 38))	('ULK1', 'Gene', (138, 142))	('AMPK', 'Gene', '5563', (13, 17))	('AMPK', 'molecular_function', 'GO:0004691', ('106', '110'))	('AMPK', 'molecular_function', 'GO:0050405', ('13', '17'))	('AMPK', 'molecular_function', 'GO:0004691', ('81', '85'))	('AMPK', 'Gene', (81, 85))	('AMPK', 'molecular_function', 'GO:0047322', ('106', '110'))	('phosphorylation', 'MPA', (42, 57))	('ULK1', 'Gene', '22241', (138, 142))	('AMPK', 'Gene', (13, 17))	('AMPK', 'molecular_function', 'GO:0004691', ('13', '17'))	('Raptor', 'Gene', (127, 133))	('AMPK', 'molecular_function', 'GO:0047322', ('81', '85'))	('phosphorylation', 'biological_process', 'GO:0016310', ('42', '57'))	('deletion', 'Var', (18, 26))
100663	30415923	Loss of GLUT1 was shown to contribute to elevated ROS and cell death from metabolic dysfunction in those models.	('metabolic dysfunction', 'Disease', (74, 95))	('metabolic dysfunction', 'Disease', 'MESH:D008659', (74, 95))	('death', 'Disease', 'MESH:D003643', (63, 68))	('GLUT1', 'Gene', '20525', (8, 13))	('death', 'Disease', (63, 68))	('ROS', 'MPA', (50, 53))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('elevated', 'PosReg', (41, 49))	('Loss', 'Var', (0, 4))	('GLUT1', 'Gene', (8, 13))
100665	30415923	Next, to determine if the lysosome is affected by AMPK in vivo, we investigated the impact of AMPK deletion in KPA tumors on the expression of lysosomal associated membrane protein-2, LAMP2, a well-established lysosomal marker, by IHC.	('lysosomal associated membrane protein-2', 'Gene', (143, 182))	('AMPK', 'Gene', (94, 98))	('KPA tumors', 'Disease', (111, 121))	('protein', 'cellular_component', 'GO:0003675', ('173', '180'))	('lysosome', 'cellular_component', 'GO:0005764', ('26', '34'))	('AMPK', 'molecular_function', 'GO:0050405', ('50', '54'))	('AMPK', 'molecular_function', 'GO:0004691', ('94', '98'))	('AMPK', 'Gene', (50, 54))	('lysosomal associated membrane protein-2', 'Gene', '16784', (143, 182))	('LAMP2', 'Gene', '16784', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('membrane', 'cellular_component', 'GO:0016020', ('164', '172'))	('AMPK', 'molecular_function', 'GO:0004691', ('50', '54'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('AMPK', 'molecular_function', 'GO:0047322', ('94', '98'))	('AMPK', 'Gene', '5563', (94, 98))	('KPA tumors', 'Disease', 'MESH:D009369', (111, 121))	('LAMP2', 'Gene', (184, 189))	('AMPK', 'molecular_function', 'GO:0047322', ('50', '54'))	('deletion', 'Var', (99, 107))	('AMPK', 'Gene', '5563', (50, 54))	('AMPK', 'molecular_function', 'GO:0050405', ('94', '98'))
100687	30415923	We then queried the Lung Adenocarcinoma dataset for LKB1 mutant tumors, breaking the dataset into an Altered group with mutation in LKB1 (STK11) or an Unaltered group with functional LKB1.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('Lung Adenocarcinoma', 'Disease', 'MESH:C538231', (20, 39))	('Lung Adenocarcinoma', 'Disease', (20, 39))	('STK11', 'molecular_function', 'GO:0033868', ('138', '143'))	('mutation', 'Var', (120, 128))	('LKB1', 'Gene', (52, 56))	('STK11', 'Gene', (138, 143))	('STK11', 'Gene', '20869', (138, 143))	('mutant', 'Var', (57, 63))	('LKB1', 'Gene', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('Adenocarcinoma dataset', 'Disease', (25, 47))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('Adenocarcinoma dataset', 'Disease', 'MESH:D000230', (25, 47))
100688	30415923	As expected, the LKB1-dependent phosphorylation of AMPK at T172 was significantly reduced in LKB1 mutant tumors, while total AMPK protein level was up regulated (Figure 7F).	('tumors', 'Disease', (105, 111))	('AMPK', 'Gene', (51, 55))	('LKB1', 'Gene', (93, 97))	('reduced', 'NegReg', (82, 89))	('up regulated', 'PosReg', (148, 160))	('mutant', 'Var', (98, 104))	('AMPK', 'molecular_function', 'GO:0047322', ('125', '129'))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('AMPK', 'molecular_function', 'GO:0050405', ('51', '55'))	('AMPK', 'molecular_function', 'GO:0004691', ('51', '55'))	('AMPK', 'Gene', '5563', (125, 129))	('AMPK', 'molecular_function', 'GO:0050405', ('125', '129'))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('phosphorylation', 'biological_process', 'GO:0016310', ('32', '47'))	('AMPK', 'Gene', '5563', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('AMPK', 'molecular_function', 'GO:0004691', ('125', '129'))	('AMPK', 'molecular_function', 'GO:0047322', ('51', '55'))	('AMPK', 'Gene', (125, 129))
100694	30415923	Indeed some genetic studies, crossing germline whole-body knockouts of AMPKalpha1 or AMPKbeta1 to the Emu-Myc B-cell lymphoma model or the p53-null T-cell lymphoma model each revealed an acceleration of tumor burden, suggesting AMPK may be functioning as a tumor suppressor in some regard.	('tumor', 'Disease', (203, 208))	('AMPK', 'Gene', (228, 232))	('AMPK', 'Gene', (85, 89))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (110, 125))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('257', '273'))	('p53', 'Gene', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('knockouts', 'Var', (58, 67))	('Myc B', 'Gene', (106, 111))	('AMPK', 'molecular_function', 'GO:0047322', ('228', '232'))	('tumor', 'Disease', (257, 262))	('tumor suppressor', 'biological_process', 'GO:0051726', ('257', '273'))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('AMPK', 'Gene', '5563', (71, 75))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (148, 163))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('acceleration', 'PosReg', (187, 199))	('p53', 'Gene', '22059', (139, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('AMPK', 'molecular_function', 'GO:0050405', ('228', '232'))	('lymphoma', 'Phenotype', 'HP:0002665', (117, 125))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (148, 163))	('Myc B', 'Gene', '107771', (106, 111))	('AMPK', 'Gene', '5563', (228, 232))	('cell lymphoma', 'Phenotype', 'HP:0012191', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('AMPK', 'Gene', '5563', (85, 89))	('T-cell lymphoma', 'Disease', (148, 163))	('AMPK', 'Gene', (71, 75))	('AMPK', 'molecular_function', 'GO:0004691', ('228', '232'))	('cell lymphoma', 'Phenotype', 'HP:0012191', (150, 163))
100695	30415923	In contrast, our discovery that deletion of both AMPKalpha1 and AMPKalpha2 suppresses rather than promotes growth of KrasG12D and KrasG12D p53-/- lung tumors adds to the growing list of evidence of a requirement for AMPK activation to support tumorigenesis.	('AMPK', 'Gene', '5563', (216, 220))	('deletion', 'Var', (32, 40))	('AMPK', 'Gene', '5563', (49, 53))	('Kras', 'Gene', (130, 134))	('suppresses', 'NegReg', (75, 85))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('lung tumor', 'Phenotype', 'HP:0100526', (146, 156))	('p53', 'Gene', (139, 142))	('growth', 'MPA', (107, 113))	('lung tumors', 'Disease', (146, 157))	('tumor', 'Disease', (243, 248))	('AMPK', 'Gene', '5563', (64, 68))	('AMPK', 'molecular_function', 'GO:0047322', ('216', '220'))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Kras', 'Gene', '16653', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('AMPK', 'Gene', (216, 220))	('AMPK', 'Gene', (49, 53))	('promotes', 'PosReg', (98, 106))	('AMPK', 'Gene', (64, 68))	('p53', 'Gene', '22059', (139, 142))	('AMPK', 'molecular_function', 'GO:0050405', ('216', '220'))	('Kras', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (151, 156))	('lung tumors', 'Disease', 'MESH:D008175', (146, 157))	('Kras', 'Gene', '16653', (117, 121))	('AMPK', 'molecular_function', 'GO:0004691', ('216', '220'))	('lung tumors', 'Phenotype', 'HP:0100526', (146, 157))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
100701	30415923	AMPK deletion or pharmacologic inhibition in B-ALL led to leukemic cell death and improved survival from ALL.	('survival', 'CPA', (91, 99))	('leukemic cell death', 'Disease', (58, 77))	('deletion', 'Var', (5, 13))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('leukemic cell death', 'Disease', 'MESH:D003643', (58, 77))	('pharmacologic inhibition', 'Var', (17, 41))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('B-ALL', 'Gene', (45, 50))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))	('cell death', 'biological_process', 'GO:0008219', ('67', '77'))	('AMPK', 'Gene', (0, 4))	('improved', 'PosReg', (82, 90))
100707	30415923	Consistent with this, we show that CRISPR mediated deletion of AMPK in LKB1 null tumor cell lines reduces proliferation under glucose deprivation conditions and is essential for growth in soft agar (Figure S3D-E).	('glucose deprivation conditions', 'Disease', 'MESH:D018149', (126, 156))	('AMPK', 'Gene', '5563', (63, 67))	('AMPK', 'molecular_function', 'GO:0047322', ('63', '67'))	('AMPK', 'Gene', (63, 67))	('reduces', 'NegReg', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('AMPK', 'molecular_function', 'GO:0050405', ('63', '67'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('AMPK', 'molecular_function', 'GO:0004691', ('63', '67'))	('deletion', 'Var', (51, 59))	('proliferation', 'MPA', (106, 119))	('glucose deprivation conditions', 'Disease', (126, 156))	('tumor', 'Disease', (81, 86))	('LKB1', 'Gene', (71, 75))
100732	30415923	AMPKalpha1fl/fl and AMPKalpha2fl/fl mice were a kind gift from Benoit Violet and were backcrossed into FVB/n mice for 10 generations before the generation of KrasLSLG12D/+; AMPKalpha1fl/fl, KrasLSLG12D/+; AMPKalpha2fl/fl, KrasLSLG12D/+; AMPKalpha1fl/fl AMPKalpha2fl/fl or KrasLSLG12D/+; p53fl/fl AMPKalpha1fl/fl AMPKalpha2fl/fl mice.	('Kras', 'Gene', (190, 194))	('Kras', 'Gene', '16653', (190, 194))	('mice', 'Species', '10090', (328, 332))	('Kras', 'Gene', (222, 226))	('Kras', 'Gene', '16653', (222, 226))	('AMPKalpha1fl/fl', 'Var', (237, 252))	('Kras', 'Gene', (158, 162))	('Kras', 'Gene', '16653', (158, 162))	('Kras', 'Gene', (272, 276))	('p53', 'Gene', '22059', (287, 290))	('mice', 'Species', '10090', (36, 40))	('Kras', 'Gene', '16653', (272, 276))	('p53', 'Gene', (287, 290))	('mice', 'Species', '10090', (109, 113))
100762	30415923	634T and 368T1 cells were transfected with gRNAs and clones were screened for deletion of AMPKalpha1 and AMPKalpha2 by western blot.	('AMPKalpha1', 'Gene', (90, 100))	('368T1', 'CellLine', 'CVCL:0I01', (9, 14))	('deletion', 'Var', (78, 86))	('AMPKalpha2', 'Gene', (105, 115))
100764	30415923	634T cells were transfected with gRNAs for 24hrs and selected with 2ug/ml puromycin for 48hrs before being expanded and subjected to western blot to assess deletion of Tfeb and Tfe3 at the first passage.	('puromycin', 'Chemical', 'MESH:D011691', (74, 83))	('Tfeb', 'Gene', (168, 172))	('Tfeb', 'Gene', '21425', (168, 172))	('Tfe3', 'Gene', (177, 181))	('deletion', 'Var', (156, 164))
100766	30415923	For western blotting, antibodies from Cell Signaling Technologies (Denvers, MA USA) were diluted 1:1,000 and include P-ACCS79 (#3661), P-AMPKT172 (#2535), P-Raptor (#2083), ACC (#3662), AMPKalpha (#2532), for human cells AMPKalpha1 (#2795), for human cells AMPKalpha2 (#2757), LKB1 (#3047), Raptor (#2280), cleaved Caspase 3 (#9661), ULK (#8054), P-ULK1S555 (#5869), P-S6S235/236 (#2211), TXNIP (VDUP-1 #K0205-3), Tfe3 (#14779), 4EBP1 (#9452), P-S6K (#9205), S6 (#2217), and HDAC3 (#3949).	('human', 'Species', '9606', (209, 214))	('Raptor', 'Gene', (291, 297))	('P-S6K', 'Gene', '6198', (444, 449))	('Raptor', 'Gene', (157, 163))	('HDAC3', 'Gene', (475, 480))	('AMPK', 'Gene', (257, 261))	('#9205', 'Var', (451, 456))	('#14779', 'Var', (420, 426))	('VDUP-1', 'Gene', (396, 402))	('4EBP1', 'Gene', '1978', (429, 434))	('#2211', 'Var', (381, 386))	('ULK1', 'Gene', '22241', (349, 353))	('AMPK', 'Gene', (186, 190))	('TXNIP', 'Gene', (389, 394))	('Raptor', 'Gene', '74370', (291, 297))	('VDUP-1', 'Gene', '10628', (396, 402))	('AMPK', 'Gene', (137, 141))	('#8054', 'Var', (339, 344))	('#9452', 'Var', (436, 441))	('human', 'Species', '9606', (245, 250))	('AMPK', 'Gene', '5563', (221, 225))	('Raptor', 'Gene', '74370', (157, 163))	('#2217', 'Var', (463, 468))	('P-S6S235', 'Chemical', 'MESH:C056056', (367, 375))	('#3949', 'Var', (482, 487))	('TXNIP', 'Gene', '10628', (389, 394))	('HDAC3', 'Gene', '8841', (475, 480))	('P-Raptor', 'Species', '126213', (155, 163))	('P-S6S235/236 (#2211', 'Var', (367, 386))	('#9661', 'Var', (326, 331))	('4EBP1', 'Gene', (429, 434))	('P-S6K', 'Gene', (444, 449))	('AMPK', 'Gene', (221, 225))	('AMPK', 'Gene', '5563', (257, 261))	('Signaling', 'biological_process', 'GO:0023052', ('43', '52'))	('ULK1', 'Gene', (349, 353))	('AMPK', 'Gene', '5563', (186, 190))	('AMPK', 'Gene', '5563', (137, 141))
100768	30415923	For mouse cells, EMD Millipore (#07-350) was used to detect AMPKalpha1, and (#07-363) was used to detect AMPKalpha2.	('EMD Millipore', 'Disease', (17, 30))	('AMPKalpha1', 'Var', (60, 70))	('EMD Millipore', 'Disease', 'None', (17, 30))	('mouse', 'Species', '10090', (4, 9))
100772	30415923	siRNAs targeting mouse Tfeb (#L-050607-02-0010) and mouse Tfe3 (#L-054750-00-0010) were purchased from Dharmacon.	('L-050607-02-0010', 'Chemical', 'MESH:C479460', (30, 46))	('Tfeb', 'Gene', (23, 27))	('mouse', 'Species', '10090', (17, 22))	('mouse', 'Species', '10090', (52, 57))	('Tfeb', 'Gene', '21425', (23, 27))	('#L-050607-02-0010', 'Var', (29, 46))	('#L-054750-00-0010', 'Var', (64, 81))	('L-054750-00-0010', 'Chemical', 'MESH:D014800', (65, 81))
100785	30415923	Cells were then stained with 5 muL of phycoerythrin (PE)-conjugated AnnexinV antibody (Cat #556422 BD Pharmingen) and 5 muL of 7AAD (Cat# 51-2359KC BD Pharmingen) and incubated at room temperature for 15 minutes.	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('Cat# 51-2359KC', 'Var', (133, 147))	('Cat', 'molecular_function', 'GO:0004096', ('133', '136'))	('Cat #556422 BD', 'Var', (87, 101))	('2359KC BD Pharmingen', 'Chemical', 'MESH:C577569', (141, 161))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('Cat', 'molecular_function', 'GO:0004096', ('87', '90'))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))
100799	30415923	DOI for 634T cell data, "RNA-seq profiling of 634T murine KP NSCLC cells deleted for AMPK subjected to no glucose conditions": 10.17632/3cy28w7v9k.1.	('AMPK', 'Gene', '5563', (85, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('deleted', 'Var', (73, 80))	('AMPK', 'Gene', (85, 89))	('NSCLC', 'Disease', (61, 66))	('glucose', 'Chemical', 'MESH:D005947', (106, 113))	('RNA', 'cellular_component', 'GO:0005562', ('24', '27'))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('murine', 'Species', '10090', (51, 57))
100800	30415923	AMPK does not phenocopy the lung tumor suppressor role of its activator LKB1 AMPK deletion reduces tumor burden in Krasg12d and Kras p53-/- lung cancer models AMPK is required during glucose deprivation to induce Tfeb and Tfe3 activation Tfe3 activity is required for growth of mouse lung tumors	('Kras', 'Gene', (115, 119))	('mouse', 'Species', '10090', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung tumor', 'Disease', 'MESH:D008175', (284, 294))	('AMPK', 'Gene', (77, 81))	('Tfeb', 'Gene', (213, 217))	('Tfeb', 'Gene', '21425', (213, 217))	('lung tumor', 'Disease', 'MESH:D008175', (28, 38))	('AMPK', 'molecular_function', 'GO:0004691', ('77', '81'))	('AMPK', 'molecular_function', 'GO:0047322', ('159', '163'))	('Kras', 'Gene', (128, 132))	('p53', 'Gene', '22059', (133, 136))	('tumor', 'Disease', (99, 104))	('lung cancer', 'Disease', (140, 151))	('Kras', 'Gene', '16653', (115, 119))	('AMPK', 'Gene', '5563', (0, 4))	('AMPK', 'molecular_function', 'GO:0050405', ('0', '4'))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (33, 38))	('lung tumors', 'Disease', 'MESH:D008175', (284, 295))	('AMPK', 'Gene', '5563', (159, 163))	('Kras', 'Gene', '16653', (128, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('AMPK', 'molecular_function', 'GO:0047322', ('77', '81'))	('glucose deprivation', 'Disease', 'MESH:D018149', (183, 202))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('glucose deprivation', 'Disease', (183, 202))	('lung tumors', 'Phenotype', 'HP:0100526', (284, 295))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('AMPK', 'molecular_function', 'GO:0050405', ('159', '163'))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('AMPK', 'molecular_function', 'GO:0004691', ('0', '4'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('AMPK', 'Gene', (0, 4))	('p53', 'Gene', (133, 136))	('lung tumor', 'Disease', (28, 38))	('lung tumor', 'Phenotype', 'HP:0100526', (284, 294))	('AMPK', 'Gene', '5563', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('AMPK', 'Gene', (159, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('lung tumor', 'Phenotype', 'HP:0100526', (28, 38))	('lung tumors', 'Disease', (284, 295))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('deletion', 'Var', (82, 90))	('AMPK', 'molecular_function', 'GO:0004691', ('159', '163'))	('AMPK', 'molecular_function', 'GO:0050405', ('77', '81'))	('reduces', 'NegReg', (91, 98))	('AMPK', 'molecular_function', 'GO:0047322', ('0', '4'))
100804	31888467	The results were validated by using the well-known TERT regulation by the ETS1 transcription factor in a subset of melanomas with mutations in the TERT promoter.	('melanomas', 'Phenotype', 'HP:0002861', (115, 124))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('melanomas', 'Disease', 'MESH:D008545', (115, 124))	('TERT', 'Gene', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('transcription factor', 'molecular_function', 'GO:0000981', ('79', '99'))	('TERT', 'Gene', (51, 55))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('TERT', 'Gene', '7015', (147, 151))	('mutations', 'Var', (130, 139))	('TERT', 'Gene', '7015', (51, 55))	('melanomas', 'Disease', (115, 124))	('ETS1', 'Gene', '2113', (74, 78))	('ETS1', 'Gene', (74, 78))
100814	31888467	Previous studies showed that TERT promoter mutations can induce its expression in cancer cells.	('TERT', 'Gene', '7015', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (43, 52))	('induce', 'Reg', (57, 63))	('TERT', 'Gene', (29, 33))
100816	31888467	Here, we performed an in silico pan-cancer analysis of TERT regulation by using an evolved version of the "Mixed Integer linear Programming based Regulatory Interaction Predictor" (MIPRIP, version 2.0) to predict TFs regulating the gene expression of TERT.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TERT', 'Gene', (251, 255))	('cancer', 'Disease', (36, 42))	('MIPRIP', 'Chemical', '-', (181, 187))	('regulation', 'biological_process', 'GO:0065007', ('60', '70'))	('TERT', 'Gene', '7015', (251, 255))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TFs', 'Var', (213, 216))	('gene expression', 'MPA', (232, 247))
100817	31888467	The new version bases on MIPRIP (https://github.com/KoenigLabNM/MIPRIP) which was previously developed to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in Saccharomyces cerevisiae between yeast deletion strains with shorter telomeres and strains with wild-type telomere length.	('MIPRIP', 'Chemical', '-', (64, 70))	('telomere', 'cellular_component', 'GO:0000781', ('314', '322'))	('MIPRIP', 'Chemical', '-', (25, 31))	('deletion', 'Var', (247, 255))	('yeast', 'Species', '4932', (241, 246))	('telomere', 'cellular_component', 'GO:0005696', ('314', '322'))	('Saccharomyces cerevisiae', 'Species', '4932', (208, 232))	('telomerase', 'MPA', (176, 186))
100840	31888467	To show that the prediction of TERT expression from our models is better than expected by a set of TFs selected by random chance, we randomly selected non-TERT TFs used by our model to predict the expression of TERT in the melanoma samples with a TERT promoter mutation.	('melanoma', 'Disease', (223, 231))	('TERT', 'Gene', '7015', (211, 215))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('TERT', 'Gene', (247, 251))	('TERT', 'Gene', '7015', (247, 251))	('mutation', 'Var', (261, 269))	('TERT', 'Gene', (31, 35))	('TERT', 'Gene', '7015', (31, 35))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', (211, 215))	('TERT', 'Gene', '7015', (155, 159))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
100843	31888467	Melanoma skin cancer was the first cancer type for which a high frequency of TERT promoter mutations was discovered, mainly in two hotspot C > T mutations at position 124 bp and 146 bp upstream of the translational start codon.	('cancer', 'Disease', (14, 20))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('C > T', 'Var', (139, 144))	('skin cancer', 'Phenotype', 'HP:0008069', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (35, 41))	('Melanoma skin cancer', 'Disease', 'MESH:D012878', (0, 20))	('Melanoma skin cancer', 'Disease', (0, 20))
100846	31888467	Considering this and the high rate of TERT promoter mutations we divided the dataset into samples with and without TERT promoter mutation objecting to improve our predictions.	('mutations', 'Var', (52, 61))	('TERT', 'Gene', '7015', (115, 119))	('TERT', 'Gene', (38, 42))	('TERT', 'Gene', '7015', (38, 42))	('TERT', 'Gene', (115, 119))
100851	31888467	Indeed, TERT expression was lower in the ETS1 knockdown sample compared to controls (fold change: 0.82).	('TERT', 'Gene', (8, 12))	('TERT', 'Gene', '7015', (8, 12))	('knockdown', 'Var', (46, 55))	('ETS1', 'Gene', '2113', (41, 45))	('lower', 'NegReg', (28, 33))	('ETS1', 'Gene', (41, 45))
100856	31888467	In summary, splitting up the melanoma dataset into two pre-defined cancer subgroups with and without the TERT promoter mutations led to more reliable modelling results (r = 0.29).	('TERT', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('TERT', 'Gene', '7015', (105, 109))	('cancer', 'Disease', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pre', 'molecular_function', 'GO:0003904', ('55', '58'))	('mutations', 'Var', (119, 128))
100863	31888467	It is known that a TERT promoter mutation leads to a further binding site of TFs of the ETS family.	('TERT', 'Gene', (19, 23))	('TERT', 'Gene', '7015', (19, 23))	('mutation', 'Var', (33, 41))	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))	('binding', 'Interaction', (61, 68))
100880	31888467	In their model, loss of MYC led to suppression of TERT, which was substantially rescued only by a co-suppression of AR.	('suppression', 'NegReg', (35, 46))	('MYC', 'Gene', (24, 27))	('TERT', 'Gene', '7015', (50, 54))	('AR', 'Gene', '367', (116, 118))	('loss', 'Var', (16, 20))	('MYC', 'Gene', '4609', (24, 27))	('TERT', 'Gene', (50, 54))
100888	31888467	As described in the literature, cutaneous melanoma skin cancer patients have a high rate of TERT promoter mutations, being responsible for an upregulation of TERT by enabling a further binding site of TFs from the ETS family.	('TERT', 'Gene', (92, 96))	('upregulation', 'PosReg', (142, 154))	('TERT', 'Gene', '7015', (92, 96))	('TFs', 'Protein', (201, 204))	('binding', 'molecular_function', 'GO:0005488', ('185', '192'))	('TERT', 'Gene', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('TERT', 'Gene', '7015', (158, 162))	('enabling', 'PosReg', (166, 174))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('cutaneous melanoma skin cancer', 'Disease', 'MESH:D012878', (32, 62))	('binding site', 'Interaction', (185, 197))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (32, 50))	('mutations', 'Var', (106, 115))	('patients', 'Species', '9606', (63, 71))	('cutaneous melanoma skin cancer', 'Disease', (32, 62))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
100890	31888467	We identified ETS1 as a highly significant regulator for TERT in tumors with TERT promoter mutation.	('mutation', 'Var', (91, 99))	('TERT', 'Gene', (57, 61))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (57, 61))	('TERT', 'Gene', '7015', (77, 81))	('ETS1', 'Gene', '2113', (14, 18))	('ETS1', 'Gene', (14, 18))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
100891	31888467	To further validate this finding we analyzed publicly available expression data of an ETS1 siRNA knockdown experiment in a melanoma cell line with TERT promoter mutation and found a downregulation of TERT compared to controls.	('TERT', 'Gene', (147, 151))	('mutation', 'Var', (161, 169))	('TERT', 'Gene', '7015', (147, 151))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('downregulation', 'NegReg', (182, 196))	('ETS1', 'Gene', '2113', (86, 90))	('ETS1', 'Gene', (86, 90))	('TERT', 'Gene', (200, 204))	('TERT', 'Gene', '7015', (200, 204))
100893	31888467	Furthermore, it was shown elsewhere that TERT promoter mutations can lead to a two- to four-fold higher TERT promoter activity in melanoma cells.	('higher', 'PosReg', (97, 103))	('mutations', 'Var', (55, 64))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('TERT', 'Gene', (104, 108))	('TERT', 'Gene', '7015', (104, 108))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))
100896	31888467	AR and E2F were also predicted as common TERT regulators in our multi-mode MIPRIP analysis.	('MIPRIP', 'Chemical', '-', (75, 81))	('E2F', 'Var', (7, 10))	('E2', 'Chemical', 'MESH:D004958', (7, 9))	('TERT', 'Gene', (41, 45))	('TERT', 'Gene', '7015', (41, 45))	('AR', 'Gene', '367', (0, 2))
100904	31888467	While only a few samples showed a TERT promoter mutation, it is still unclear if there is an association between HMGA2 expression and TERT promoter mutations.	('HMGA2', 'Gene', '8091', (113, 118))	('TERT', 'Gene', (34, 38))	('TERT', 'Gene', (134, 138))	('HMGA2', 'Gene', (113, 118))	('TERT', 'Gene', '7015', (34, 38))	('mutation', 'Var', (48, 56))	('TERT', 'Gene', '7015', (134, 138))
100905	31888467	According to our predictions, we suggest that TERT regulation by HMGA2 and TERT promoter mutations are mutually exclusive, which has to be validated in future experiments.	('TERT', 'Gene', '7015', (46, 50))	('regulation', 'biological_process', 'GO:0065007', ('51', '61'))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('HMGA2', 'Gene', '8091', (65, 70))	('HMGA2', 'Gene', (65, 70))	('mutations', 'Var', (89, 98))	('TERT', 'Gene', (46, 50))
100907	31888467	Using the specific application of known ETS binding site in the TERT promoter of melanoma samples with a TERT promoter mutation as a case study, we compared the results from MIPRIP 2.0 with ISMARA.	('TERT', 'Gene', (105, 109))	('TERT', 'Gene', (64, 68))	('mutation', 'Var', (119, 127))	('TERT', 'Gene', '7015', (105, 109))	('TERT', 'Gene', '7015', (64, 68))	('MIPRIP', 'Chemical', '-', (174, 180))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('ISMARA', 'Chemical', '-', (190, 196))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))
100909	31888467	Particularly, ISMARA did not identify ETS1 as a regulator for TERT in samples with a TERT promoter mutation.	('TERT', 'Gene', (85, 89))	('ETS1', 'Gene', '2113', (38, 42))	('ETS1', 'Gene', (38, 42))	('ISMARA', 'Chemical', '-', (14, 20))	('TERT', 'Gene', '7015', (85, 89))	('mutation', 'Var', (99, 107))	('TERT', 'Gene', (62, 66))	('TERT', 'Gene', '7015', (62, 66))
100911	31888467	It was shown elsewhere that GABPA can bind only to the TERT promoter mutation at site C228T, but not at C250T.	('C228T', 'Mutation', 'rs533877788', (86, 91))	('C228T', 'Var', (86, 91))	('GABPA', 'Gene', (28, 33))	('C250T', 'Mutation', 'rs770668556', (104, 109))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('bind', 'Interaction', (38, 42))	('GABPA', 'Gene', '2551', (28, 33))
100912	31888467	However, only one third of the mutated samples had the mutation at C228T, while two-third showed a C250T mutation.	('C228T', 'Mutation', 'rs533877788', (67, 72))	('C228T', 'Var', (67, 72))	('C250T', 'Mutation', 'rs770668556', (99, 104))	('C250T', 'Var', (99, 104))
100920	31888467	Furthermore, the predicted TERT regulators were compared in melanoma samples with wildtype versus mutated TERT promoters.	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('TERT', 'Gene', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('TERT', 'Gene', '7015', (27, 31))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('mutated', 'Var', (98, 105))
100958	31888467	performed siRNA mediated knockdowns of 45 TFs and signaling molecules in the melanoma cell line A375.	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('A375', 'CellLine', 'CVCL:0132', (96, 100))	('TFs', 'Gene', (42, 45))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('knockdowns', 'Var', (25, 35))
100960	31888467	A fold change was calculated for TERT upon ETS1 knockdown compared to the controls.	('ETS1', 'Gene', '2113', (43, 47))	('ETS1', 'Gene', (43, 47))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('knockdown', 'Var', (48, 57))
100966	31888467	For both datasets, the regulators AR, JUND, E2F1, E2F2 and ETS1 were selected most often (Additional file 1: Table S6, column "FPKM").	('E2F1', 'Var', (44, 48))	('E2F2', 'Gene', (50, 54))	('ETS1', 'Gene', '2113', (59, 63))	('ETS1', 'Gene', (59, 63))	('E2F2', 'Gene', '1870', (50, 54))	('AR', 'Gene', '367', (34, 36))	('JUND', 'Gene', '3727', (38, 42))	('JUND', 'Gene', (38, 42))
100971	31888467	This work was supported by the project CancerTelSys (01ZX1302B, 01ZX1602B) in the e:Med program and the project CSCC (01EO1002, 01EO1502) of the German Federal Ministry of Education and Research (BMBF), and the Deutsche Forschungsgemeinschaft (KO 3678/5-1).	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('01ZX1302B', 'Var', (53, 62))	('Cancer', 'Disease', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))
100979	19843243	Both types of melanoma have activating oncogene mutations that provide autonomous pro-proliferative signals, yet the consensus is that those are not sufficient for tumor progression.	('melanoma', 'Disease', (14, 22))	('tumor', 'Disease', (164, 169))	('oncogene', 'Gene', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('rat', 'Species', '10116', (93, 96))
100981	19843243	To stimulate further debate and inquiry we describe here a few examples of potential signals that might modify the fate of disseminated cell and provide brief description of the current knowledge on dormancy in other cancers.	('fate of disseminated cell', 'CPA', (115, 140))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('dormancy', 'biological_process', 'GO:0030431', ('199', '207'))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancers', 'Disease', (217, 224))	('modify', 'Reg', (104, 110))	('signals', 'Var', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
100984	19843243	Until recently, the prevailing theory was that metastases arise from a late-forming small sub-population of cancer cells which, through mutation and selections, become highly adapted to processes of dissemination and growth in secondary sites.	('mutation', 'Var', (136, 144))	('metastases', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
101018	19843243	Also, blockade of signaling through the protease receptor uPAR leads to alpha5beta1 integrin inactivation, decrease in the EGFR signaling and induction of dormancy.	('EGFR', 'Gene', (123, 127))	('beta1 integrin', 'Gene', (78, 92))	('signaling', 'biological_process', 'GO:0023052', ('128', '137'))	('uPAR', 'Gene', '5329', (58, 62))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('inactivation', 'NegReg', (93, 105))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('induction', 'Reg', (142, 151))	('induction of dormancy', 'biological_process', 'GO:0097436', ('142', '163'))	('blockade', 'Var', (6, 14))	('beta1 integrin', 'Gene', '3688', (78, 92))	('decrease', 'NegReg', (107, 115))	('uPAR', 'Gene', (58, 62))	('EGFR', 'Gene', '1956', (123, 127))	('uPAR', 'molecular_function', 'GO:0030377', ('58', '62'))
101033	19843243	As Notch-1 has been implicated in melanoma progression, and melanoma appears to evade senescence, it is tempting to speculate that, during expansion and/or quiescent phases, Notch and HES-1 may protect melanoma from entering senescence.	('HES-1', 'Gene', (184, 189))	('Notch-1', 'Gene', (3, 10))	('Notch-1', 'Gene', '4851', (3, 10))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HES-1', 'Gene', '3280', (184, 189))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Disease', (34, 42))	('implicated', 'Reg', (20, 30))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('Notch', 'Var', (174, 179))	('senescence', 'biological_process', 'GO:0010149', ('225', '235'))	('senescence', 'biological_process', 'GO:0010149', ('86', '96'))
101055	19843243	Inhibition of the ABCB5 pump significantly reversed resistance to doxorubicin.	('ABCB5', 'Gene', (18, 23))	('ABCB5', 'Gene', '340273', (18, 23))	('reversed', 'Reg', (43, 51))	('resistance to doxorubicin', 'MPA', (52, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('Inhibition', 'Var', (0, 10))
101069	19843243	To accept TICs quiescence one would have to accept the possibility that therapy, microenvironment or the stem cell-dependent reprogramming into dormancy might neutralize the action of mutant B-Raf once senescence is bypassed or more importantly antagonize mutant N-Ras signals or restore PTEN pathway function.	('antagonize', 'NegReg', (245, 255))	('mutant', 'Var', (184, 190))	('B-Raf', 'Gene', '673', (191, 196))	('TIC', 'Disease', 'None', (10, 13))	('mutant', 'Var', (256, 262))	('senescence', 'biological_process', 'GO:0010149', ('202', '212'))	('action', 'MPA', (174, 180))	('neutralize', 'NegReg', (159, 169))	('PTEN', 'Gene', (288, 292))	('N-Ras', 'Gene', (263, 268))	('TIC', 'Disease', (10, 13))	('N-Ras', 'Gene', '4893', (263, 268))	('restore', 'Reg', (280, 287))	('B-Raf', 'Gene', (191, 196))	('function', 'MPA', (301, 309))	('TICs', 'Phenotype', 'HP:0100033', (10, 14))	('PTEN', 'Gene', '5728', (288, 292))	('TIC', 'Phenotype', 'HP:0100033', (10, 13))	('quiescence', 'biological_process', 'GO:0044838', ('15', '25'))	('dormancy', 'biological_process', 'GO:0030431', ('144', '152'))
101089	19843243	It is also possible that in spite of carrying genetic alterations that favor growth, the DTCs are forced into quiescence by the micro-environment, or epigenetic or therapy-derived mechanisms.	('growth', 'MPA', (77, 83))	('favor', 'PosReg', (71, 76))	('quiescence', 'biological_process', 'GO:0044838', ('110', '120'))	('rat', 'Species', '10116', (58, 61))	('alterations', 'Var', (54, 65))
101092	19843243	This suggests that the bone microenvironment may delay cancer progression and thus prolong patient survival but also, that perturbations of this microenvironment might trigger growth.	('prolong', 'PosReg', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient survival', 'CPA', (91, 107))	('perturbations', 'Var', (123, 136))	('delay', 'NegReg', (49, 54))	('trigger', 'Reg', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('growth', 'MPA', (176, 182))	('patient', 'Species', '9606', (91, 98))	('cancer', 'Disease', (55, 61))
101094	19843243	In melanoma cell lines, targeting of specific integrins can curtail growth, while interaction of melanoma cells with fibrillar collagen induces cell cycle inhibitor p15INK4b expression and growth arrest.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('p15INK4b', 'Gene', '1030', (165, 173))	('cell cycle', 'biological_process', 'GO:0007049', ('144', '154'))	('p15INK4b', 'Gene', (165, 173))	('curtail', 'NegReg', (60, 67))	('cell', 'MPA', (144, 148))	('targeting', 'Var', (24, 33))	('growth', 'MPA', (68, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('growth arrest', 'Phenotype', 'HP:0001510', (189, 202))	('growth arrest', 'CPA', (189, 202))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('expression', 'MPA', (174, 184))	('integrins', 'Protein', (46, 55))	('induces', 'Reg', (136, 143))	('interaction', 'Interaction', (82, 93))	('collagen', 'molecular_function', 'GO:0005202', ('127', '135'))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
101098	19843243	On the other hand, others have shown that adhesion regulated ERK1/2 activation in melanocytes is by-passed by mutation of B-Raf in malignant melanoma cells, although melanoma cells may still be dependent on integrin activated PI3K and Akt signaling for survival.	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('B-Raf', 'Gene', (122, 127))	('PI3K', 'molecular_function', 'GO:0016303', ('226', '230'))	('activation', 'PosReg', (68, 78))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('Akt', 'Gene', (235, 238))	('malignant melanoma', 'Disease', (131, 149))	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('melanoma', 'Disease', (141, 149))	('Akt', 'Gene', '207', (235, 238))	('Akt signaling', 'biological_process', 'GO:0043491', ('235', '248'))	('B-Raf', 'Gene', '673', (122, 127))	('mutation', 'Var', (110, 118))	('ERK1/2', 'Gene', '5595;5594', (61, 67))	('ERK1/2', 'Gene', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('malignant melanoma', 'Phenotype', 'HP:0002861', (131, 149))	('malignant melanoma', 'Disease', 'MESH:D008545', (131, 149))	('ERK1', 'molecular_function', 'GO:0004707', ('61', '65'))
101100	19843243	Several interesting transgenic melanoma mouse models have been developed, including two very recent ones, in which conditionally activated B-rafV600E alone, or in combination with PTEN-tumor suppressor gene silencing led to melanoma generation.	('B-rafV600E', 'Var', (139, 149))	('rat', 'Species', '10116', (237, 240))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('gene silencing', 'biological_process', 'GO:0016458', ('202', '216'))	('mouse', 'Species', '10090', (40, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('transgenic', 'Species', '10090', (20, 30))	('PTEN-tumor', 'Disease', (180, 190))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Disease', (224, 232))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Disease', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('led to', 'Reg', (217, 223))	('PTEN-tumor', 'Disease', 'MESH:D006223', (180, 190))
101104	19843243	At day 12-14 only ~3.5% of the inoculated cells remained as solitary cells, of this only 3% was stained with Ki-67, a marker of proliferation, while ~40% of cells in small, medium or large metastases stained positively for this marker.	('rat', 'Species', '10116', (135, 138))	('metastases', 'Disease', (189, 199))	('Ki-67', 'Var', (109, 114))	('metastases', 'Disease', 'MESH:D009362', (189, 199))
101148	19843243	Uveal melanomas develop characteristic chromosomal abnormalities, such as loss of chromosome 3, abnormalities in chromosome 6 and, less frequently, gains in chromosome 8q.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (39, 64))	('abnormalities', 'Var', (96, 109))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('loss', 'NegReg', (74, 78))	('gains', 'Var', (148, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('chromosomal abnormalities', 'Disease', (39, 64))	('Uveal melanomas', 'Phenotype', 'HP:0007716', (0, 15))	('chromosome', 'cellular_component', 'GO:0005694', ('157', '167'))
101159	19843243	While B-Raf and N-Ras mutations, which are mutually exclusive, are predominant in cutaneous melanoma, they are almost completely absent in uveal melanoma.	('N-Ras', 'Gene', '4893', (16, 21))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('uveal melanoma', 'Phenotype', 'HP:0007716', (139, 153))	('uveal melanoma', 'Disease', 'MESH:C536494', (139, 153))	('B-Raf', 'Gene', (6, 11))	('predominant', 'Reg', (67, 78))	('uveal melanoma', 'Disease', (139, 153))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('B-Raf', 'Gene', '673', (6, 11))	('mutations', 'Var', (22, 31))	('N-Ras', 'Gene', (16, 21))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))
101160	19843243	Instead, 46% of uveal melanoma and 83% of blue nevi carry mutations in the GNAQ gene, a Gq protein a-subunit that when mutated in the 209 position has transforming capacity.	('mutations', 'Var', (58, 67))	('blue nevi', 'Phenotype', 'HP:0100814', (42, 51))	('GNAQ', 'Gene', (75, 79))	('transforming capacity', 'CPA', (151, 172))	('uveal melanoma', 'Disease', (16, 30))	('blue nevi', 'Disease', (42, 51))	('uveal melanoma', 'Disease', 'MESH:C536494', (16, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('nevi', 'Phenotype', 'HP:0003764', (47, 51))	('uveal melanoma', 'Phenotype', 'HP:0007716', (16, 30))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('GNAQ', 'Gene', '2776', (75, 79))
101162	19843243	It is possible that progression driven by this genetic variation follows different kinetics from that of B-Raf or N-ras mutation and that it maintains responsiveness to yet unidentified growth suppressive microenvironmental cues.	('responsiveness', 'MPA', (151, 165))	('B-Raf', 'Gene', '673', (105, 110))	('B-Raf', 'Gene', (105, 110))	('genetic variation', 'Var', (47, 64))	('N-ras', 'Gene', '4893', (114, 119))	('N-ras', 'Gene', (114, 119))
101163	19843243	The direct link between the different genetic and epigenetic alterations in melanoma and tumor progression remains elusive.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('epigenetic alterations', 'Var', (50, 72))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('rat', 'Species', '10116', (65, 68))
101166	19843243	A small study showed an association between the disease-free survival periods with the presence of B-Raf and N-Ras mutations.	('mutations', 'Var', (115, 124))	('association', 'Interaction', (24, 35))	('N-Ras', 'Gene', '4893', (109, 114))	('B-Raf', 'Gene', '673', (99, 104))	('B-Raf', 'Gene', (99, 104))	('N-Ras', 'Gene', (109, 114))
101167	19843243	In this study of around 40 patients, 21% had disease free periods longer than 5 yr and median DFS was 10 yr. Of the patients that showed long disease free periods an impressive 75% had B-Raf mutations (V600E or K601E); none had N-Ras mutations.	('N-Ras', 'Gene', '4893', (228, 233))	('V600E', 'Var', (202, 207))	('long disease', 'Disease', (137, 149))	('patients', 'Species', '9606', (116, 124))	('long disease', 'Disease', 'MESH:D008133', (137, 149))	('N-Ras', 'Gene', (228, 233))	('B-Raf', 'Gene', (185, 190))	('K601E)', 'Var', (211, 217))	('K601E', 'Mutation', 'rs121913364', (211, 216))	('patients', 'Species', '9606', (27, 35))	('B-Raf', 'Gene', '673', (185, 190))	('V600E', 'Mutation', 'rs113488022', (202, 207))
101168	19843243	Three patients (7.9%) bearing V-600E B-raf mutations were free of disease for 13-16.7 yr. Other authors have noticed no effect on DFI in patients with B-Raf mutations.	('B-raf', 'Gene', (37, 42))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (157, 166))	('patients', 'Species', '9606', (6, 14))	('B-Raf', 'Gene', '673', (151, 156))	('B-Raf', 'Gene', (151, 156))	('B-raf', 'Gene', '673', (37, 42))
101169	19843243	Although very limited, this study suggests that even activating mutations, considered to be responsible for cancer progression in oncogene 'addicted' tumors appear to, at least temporarily respond to host-imposed controls.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	("'addicted' tumors", 'Disease', (139, 156))	("'addicted' tumors", 'Disease', 'MESH:D019966', (139, 156))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutations', 'Var', (64, 73))	('activating', 'PosReg', (53, 63))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
101170	19843243	Is it possible, as evidenced in patients, that these controls can silence tumor cells with activating mutations for a decade or longer?	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('silence', 'NegReg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (74, 79))
101171	19843243	In conditional transgenic models, oncogene inactivation can induce tumor cell elimination, or terminal differentiation/senescence and, as in case of Myc inactivation in hepatocellular carcinoma, induction of cancer cell dormancy (for review see), suggesting that the outcome might be specific to cellular and genetic context.	('induce', 'PosReg', (60, 66))	('cancer', 'Disease', (208, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('senescence', 'biological_process', 'GO:0010149', ('119', '129'))	('Myc', 'Gene', (149, 152))	('tumor', 'Disease', (67, 72))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (169, 193))	('terminal differentiation/senescence', 'CPA', (94, 129))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('dormancy', 'biological_process', 'GO:0030431', ('220', '228'))	('Myc', 'Gene', '17869', (149, 152))	('terminal differentiation', 'biological_process', 'GO:0048468', ('94', '118'))	('inactivation', 'Var', (43, 55))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('transgenic', 'Species', '10090', (15, 25))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (169, 193))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('oncogene', 'Gene', (34, 42))	('induction', 'Reg', (195, 204))	('hepatocellular carcinoma', 'Disease', (169, 193))
101174	19843243	For example, as already mentioned, in melanoma with mutated B-Raf the activation of ERK was shown to be independent of integrin/matrix engagement.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('ERK', 'Gene', '5594', (84, 87))	('mutated', 'Var', (52, 59))	('B-Raf', 'Gene', (60, 65))	('ERK', 'Gene', (84, 87))	('B-Raf', 'Gene', '673', (60, 65))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('melanoma', 'Disease', (38, 46))
101176	19843243	Does it mean that once ERK pathway is activated through B-Raf or N-Ras mutation, its activity, and thus melanoma cell proliferation, must continue unabated?	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('rat', 'Species', '10116', (125, 128))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('mutation', 'Var', (71, 79))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('ERK', 'Gene', '5594', (23, 26))	('ERK', 'molecular_function', 'GO:0004707', ('23', '26'))	('ERK', 'Gene', (23, 26))	('N-Ras', 'Gene', '4893', (65, 70))	('activated', 'PosReg', (38, 47))	('B-Raf', 'Gene', '673', (56, 61))	('B-Raf', 'Gene', (56, 61))	('N-Ras', 'Gene', (65, 70))
101178	19843243	It is possible then that, although the mutant B-Raf stimulus to ERK activation is autonomous, the downstream effectors of the pathway might be dependent on the microenvironment and/or epigenetic mechanisms.	('B-Raf', 'Gene', '673', (46, 51))	('ERK', 'Gene', '5594', (64, 67))	('ERK', 'Gene', (64, 67))	('mutant', 'Var', (39, 45))	('B-Raf', 'Gene', (46, 51))	('ERK', 'molecular_function', 'GO:0004707', ('64', '67'))
101179	19843243	For example have shown that expression of B-RafV600E mutant in primary cells leads to synthesis and secretion of IGFBP7, which through autocrine/paracrine pathways inhibits BRAF-MEK-ERK signaling and, by inducing a pro-apoptotic protein BNIP3L, leads to senescence and apoptosis.	('IGFBP7', 'Gene', '3490', (113, 119))	('ERK', 'molecular_function', 'GO:0004707', ('182', '185'))	('IGFBP7', 'Gene', (113, 119))	('apoptosis', 'CPA', (269, 278))	('MEK', 'Gene', '5609', (178, 181))	('synthesis', 'MPA', (86, 95))	('BNIP3L', 'Gene', (237, 243))	('ERK', 'Gene', '5594', (182, 185))	('leads to', 'Reg', (245, 253))	('secretion', 'biological_process', 'GO:0046903', ('100', '109'))	('apoptosis', 'biological_process', 'GO:0097194', ('269', '278'))	('apoptosis', 'biological_process', 'GO:0006915', ('269', '278'))	('B-RafV600E', 'Var', (42, 52))	('MEK', 'Gene', (178, 181))	('inhibits', 'NegReg', (164, 172))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (173, 177))	('ERK', 'Gene', (182, 185))	('secretion', 'MPA', (100, 109))	('senescence', 'biological_process', 'GO:0010149', ('254', '264'))	('synthesis', 'biological_process', 'GO:0009058', ('86', '95'))	('signaling', 'biological_process', 'GO:0023052', ('186', '195'))	('inducing', 'PosReg', (204, 212))	('BNIP3L', 'Gene', '665', (237, 243))	('protein', 'cellular_component', 'GO:0003675', ('229', '236'))	('senescence', 'CPA', (254, 264))
101182	19843243	B-Raf and GNAQ, in addition to being mutated in melanoma, are also mutated in benign nevi.	('melanoma', 'Disease', (48, 56))	('GNAQ', 'Gene', '2776', (10, 14))	('benign nevi', 'Disease', (78, 89))	('B-Raf', 'Gene', (0, 5))	('GNAQ', 'Gene', (10, 14))	('mutated', 'Var', (67, 74))	('B-Raf', 'Gene', '673', (0, 5))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
101184	19843243	In a recently developed mouse model of melanoma conditional activation of mutant B-RafV600E was sufficient to yield melanomas but those formed only after very long latency.	('mouse', 'Species', '10090', (24, 29))	('melanomas', 'Disease', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('melanoma', 'Disease', (116, 124))	('activation', 'PosReg', (60, 70))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('B-RafV600E', 'Gene', (81, 91))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))	('mutant', 'Var', (74, 80))
101186	19843243	PTEN, tumor suppressor, which resides on human chromosome 10q23.3, has been shown to be deleted in a proportion of melanoma cell lines and in a small number of primary melanomas.	('primary melanomas', 'Disease', 'MESH:D008545', (160, 177))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('human', 'Species', '9606', (41, 46))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('deleted', 'Var', (88, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('PTEN', 'Gene', (0, 4))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('6', '22'))	('tumor', 'Disease', (6, 11))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('melanoma', 'Disease', (115, 123))	('primary melanomas', 'Disease', (160, 177))	('tumor suppressor', 'biological_process', 'GO:0051726', ('6', '22'))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('melanomas', 'Phenotype', 'HP:0002861', (168, 177))	('PTEN', 'Gene', '5728', (0, 4))
101187	19843243	Importantly, it was found to be epigenetically silenced by several mechanisms, including by promoter methylation, in nearly 40% of melanoma samples, an event linked to activation of the PI3K/Akt pathway.	('Akt', 'Gene', '207', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('Akt', 'Gene', (191, 194))	('promoter', 'MPA', (92, 100))	('PI3K', 'molecular_function', 'GO:0016303', ('186', '190'))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('epigenetically', 'Var', (32, 46))
101188	19843243	In melanoma, expression of some 50 genes has been shown to be deregulated through aberrant DNA methylation, and/or inappropriate targeting of histone modifications and chromatin remodeling.	('histone', 'Protein', (142, 149))	('DNA methylation', 'biological_process', 'GO:0006306', ('91', '106'))	('expression', 'MPA', (13, 23))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('168', '188'))	('chromatin', 'cellular_component', 'GO:0000785', ('168', '177'))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('deregulated', 'PosReg', (62, 73))	('DNA', 'Protein', (91, 94))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('aberrant', 'Var', (82, 90))
101190	19843243	The silencing of PTEN in melanoma allows for activation of Akt/PKB which in turn, activates the transcription of genes involved in immune activation, cell proliferation, apoptosis and cell survival.	('cell proliferation', 'biological_process', 'GO:0008283', ('150', '168'))	('transcription of genes', 'MPA', (96, 118))	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('PTEN', 'Gene', (17, 21))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('170', '179'))	('apoptosis', 'biological_process', 'GO:0006915', ('170', '179'))	('silencing', 'Var', (4, 13))	('Akt', 'Gene', (59, 62))	('PKB', 'Gene', '207', (63, 66))	('cell proliferation', 'CPA', (150, 168))	('PKB', 'Gene', (63, 66))	('activates', 'PosReg', (82, 91))	('Akt', 'Gene', '207', (59, 62))	('PTEN', 'Gene', '5728', (17, 21))	('rat', 'Species', '10116', (162, 165))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('activation', 'PosReg', (45, 55))
101197	19843243	Although, in growing melanomas the mutated B-Raf overrides this pathway, its complexity suggests possibilities for control by the microenvironment.	('mutated', 'Var', (35, 42))	('B-Raf', 'Gene', '673', (43, 48))	('B-Raf', 'Gene', (43, 48))	('melanomas', 'Disease', (21, 30))	('overrides', 'PosReg', (49, 58))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))
101202	19843243	It is also conceivable that signals from the microenvironment restore expression of the epigenetically silenced PTEN.	('restore', 'PosReg', (62, 69))	('epigenetically silenced', 'Var', (88, 111))	('expression', 'MPA', (70, 80))	('PTEN', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (112, 116))
101218	19843243	One exception is the study which found no gene expression patterns that correlate with activating mutations in B-Raf or N-Ras, but instead identified transcriptional signatures specific to 'proliferative' melanoma sensitive, and invasive melanoma resistant to TGFbeta inhibition.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('melanoma', 'Disease', (238, 246))	('invasive melanoma', 'Disease', (229, 246))	('melanoma', 'Disease', 'MESH:D008545', (238, 246))	('rat', 'Species', '10116', (197, 200))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('melanoma', 'Disease', (205, 213))	('N-Ras', 'Gene', '4893', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('mutations', 'Var', (98, 107))	('invasive melanoma', 'Disease', 'MESH:D008545', (229, 246))	('transcriptional', 'MPA', (150, 165))	('N-Ras', 'Gene', (120, 125))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	("'proliferative", 'PosReg', (189, 203))	('B-Raf', 'Gene', '673', (111, 116))	('B-Raf', 'Gene', (111, 116))
101219	19843243	The proliferative cohort had highly activated Wnt signaling pathway with high SOX10, MITF1 and TFAP.	('SOX10', 'Gene', (78, 83))	('SOX10', 'Gene', '6663', (78, 83))	('TFAP', 'Gene', (95, 99))	('activated', 'PosReg', (36, 45))	('rat', 'Species', '10116', (11, 14))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('46', '67'))	('high', 'Var', (73, 77))	('MITF1', 'Gene', (85, 90))	('Wnt signaling pathway', 'Pathway', (46, 67))
101239	19843243	Other lines of research might need to explore whether there is a difference in the way the microenvironment cross-talks with melanoma cells bearing B-Raf versus N-Ras mutations.	('B-Raf', 'Gene', '673', (148, 153))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('N-Ras', 'Gene', '4893', (161, 166))	('mutations', 'Var', (167, 176))	('N-Ras', 'Gene', (161, 166))	('B-Raf', 'Gene', (148, 153))
101247	31814762	This benefit of clinical outcomes persisted in patients with ALM, Breslow thickness <=2 mm, or no ulceration, but not in patients with non-ALM, Breslow thickness >2 mm, or ulceration.	('ALM', 'Disease', 'MESH:D007911', (61, 64))	('Breslow thickness <=2 mm', 'Var', (66, 90))	('ALM', 'Phenotype', 'HP:0012060', (139, 142))	('patients', 'Species', '9606', (47, 55))	('ALM', 'Phenotype', 'HP:0012060', (61, 64))	('ALM', 'Disease', (139, 142))	('ALM', 'Disease', (61, 64))	('ALM', 'Disease', 'MESH:D007911', (139, 142))	('patients', 'Species', '9606', (121, 129))
101293	31814762	This benefit of clinical outcomes persisted in patients with ALM, Breslow thickness <=2 mm, or no ulceration but not in patients with non-ALM, Breslow thickness >2 mm, or ulceration.	('ALM', 'Disease', 'MESH:D007911', (61, 64))	('ALM', 'Disease', (138, 141))	('Breslow thickness <=2 mm', 'Var', (66, 90))	('patients', 'Species', '9606', (47, 55))	('ALM', 'Phenotype', 'HP:0012060', (61, 64))	('ALM', 'Disease', 'MESH:D007911', (138, 141))	('patients', 'Species', '9606', (120, 128))	('ALM', 'Phenotype', 'HP:0012060', (138, 141))	('ALM', 'Disease', (61, 64))
101298	31814762	These results were consistent with our findings that SLNB benefitted patients with Breslow thickness <=2 mm, nonulcerated melanoma, and ALM.	('<=2', 'Var', (101, 104))	('ALM', 'Disease', (136, 139))	('SLN', 'Gene', (53, 56))	('SLN', 'Gene', '6588', (53, 56))	('ALM', 'Disease', 'MESH:D007911', (136, 139))	('nonulcerated melanoma', 'Disease', (109, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('ALM', 'Phenotype', 'HP:0012060', (136, 139))	('patients', 'Species', '9606', (69, 77))	('nonulcerated melanoma', 'Disease', 'MESH:D008545', (109, 130))
101406	30499222	Moreover, specific dysregulated ncRNAs were shown to have a diagnostic or prognostic role in melanoma and to drive the establishment of drug resistance.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('drive', 'Reg', (109, 114))	('ncRNA', 'Gene', (32, 37))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('drug resistance', 'biological_process', 'GO:0042493', ('136', '151'))	('ncRNA', 'Gene', '220202', (32, 37))	('dysregulated', 'Var', (19, 31))	('drug resistance', 'biological_process', 'GO:0009315', ('136', '151'))	('drug resistance', 'Phenotype', 'HP:0020174', (136, 151))
101414	30499222	Studies on germline mutations focusing on the cyclin-dependent kinase inhibitor 2A (CDKN2A), have shown mutations in 5-15% of familial cases affected by CM.	('cyclin-dependent kinase inhibitor 2A', 'Gene', (46, 82))	('mutations', 'Var', (104, 113))	('CDKN2A', 'Gene', (84, 90))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (46, 82))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('63', '79'))	('familial cases', 'Disease', (126, 140))	('CM', 'Phenotype', 'HP:0012056', (153, 155))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('46', '79'))
101418	30499222	Indeed, the knowledge of genetic alterations in primary and metastatic tumors has offered clinically actionable targets.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('genetic alterations', 'Var', (25, 44))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
101421	30499222	In the context of this project, 333 samples of primary and metastatic cutaneous melanoma (SKCM) were analyzed by Whole Exome Sequencing and classified into four main genomic subtypes: mutant BRAF, mutant NRAS, mutant neurofibromatosis type 1 (NF1) and triple-wild-type (Cancer Genome Atlas, 2015).	('BRAF', 'Gene', (191, 195))	('mutant', 'Var', (184, 190))	('Cancer', 'Disease', 'MESH:D009369', (270, 276))	('neurofibromatosis type 1', 'Gene', '4763', (217, 241))	('cutaneous melanoma', 'Disease', (70, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('NF1', 'Gene', '4763', (243, 246))	('NRAS', 'Gene', '4893', (204, 208))	('Cancer', 'Phenotype', 'HP:0002664', (270, 276))	('NF1', 'Gene', (243, 246))	('neurofibromatosis type 1', 'Gene', (217, 241))	('mutant', 'Var', (197, 203))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (217, 234))	('CM', 'Phenotype', 'HP:0012056', (92, 94))	('Cancer', 'Disease', (270, 276))	('NRAS', 'Gene', (204, 208))	('BRAF', 'Gene', '673', (191, 195))
101423	30499222	When copy number variations were included in this classification, CM was characterized by dysregulation in the following signaling pathways: MAPK in 92% of the samples, PI3K in 56%, RTKs in 48%, Histone modification in 48%, Cell cycle in 40%, SWI/SNF in 38%, TP53 in 37% and WNT in 29%.	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('Histone modification', 'MPA', (195, 215))	('TP53', 'Gene', (259, 263))	('MAPK', 'molecular_function', 'GO:0004707', ('141', '145'))	('Cell cycle', 'biological_process', 'GO:0007049', ('224', '234'))	('CM', 'Phenotype', 'HP:0012056', (66, 68))	('TP53', 'Gene', '7157', (259, 263))	('RTKs', 'Var', (182, 186))	('signaling pathways', 'Pathway', (121, 139))	('Histone modification', 'biological_process', 'GO:0016570', ('195', '215'))	('MAPK', 'Gene', (141, 145))	('PI3K', 'Var', (169, 173))	('copy number variations', 'Var', (5, 27))	('dysregulation', 'Reg', (90, 103))	('Cell cycle', 'CPA', (224, 234))	('PI3K', 'molecular_function', 'GO:0016303', ('169', '173'))
101424	30499222	1, we present a picture of the most significantly mutated genes in melanoma, obtained using TCGA SKCM samples.	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('mutated', 'Var', (50, 57))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('CM', 'Phenotype', 'HP:0012056', (99, 101))
101428	30499222	BRAF gene mutations are found in 52% of melanomas (Cancer Genome Atlas Network, 2015), and 90% of those mutations are a single nucleotide alteration (nucleotide 1799 T>A), resulting in substitution of glutamic acid for valine (BRAFV600E) (Ascierto et al., 2012).	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanomas', 'Phenotype', 'HP:0002861', (40, 49))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (104, 113))	('glutamic acid', 'Chemical', 'MESH:D018698', (201, 214))	('1799 T>A', 'Mutation', 'rs113488022', (161, 169))	('Cancer', 'Disease', (51, 57))	('valine', 'Chemical', 'MESH:D014633', (219, 225))	('glutamic acid', 'MPA', (201, 214))	('BRAFV600E', 'Mutation', 'rs113488022', (227, 236))	('substitution', 'Var', (185, 197))	('melanomas', 'Disease', 'MESH:D008545', (40, 49))	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('BRAF', 'Gene', '673', (227, 231))	('BRAF', 'Gene', (227, 231))	('melanomas', 'Disease', (40, 49))	('mutations', 'Var', (10, 19))
101429	30499222	This mutation causes the constitutive activation of the kinase and also insensitivity to negative feedback mechanisms, finally promoting angiogenesis (via HIFalpha and VEGF activation), apoptosis evasion, invasion and metastasis (Maurer et al., 2011).	('invasion', 'CPA', (205, 213))	('promoting', 'PosReg', (127, 136))	('apoptosis', 'biological_process', 'GO:0097194', ('186', '195'))	('VEGF', 'Gene', '7422', (168, 172))	('metastasis', 'CPA', (218, 228))	('angiogenesis', 'CPA', (137, 149))	('angiogenesis', 'biological_process', 'GO:0001525', ('137', '149'))	('activation', 'PosReg', (38, 48))	('apoptosis', 'CPA', (186, 195))	('mutation', 'Var', (5, 13))	('VEGF', 'Gene', (168, 172))	('apoptosis', 'biological_process', 'GO:0006915', ('186', '195'))
101430	30499222	BRAFV600E also regulates interleukin (IL)-8, which promotes the adhesion of melanocytes to the vasculature, thereby helping to promote metastases (Singh et al., 1994).	('metastases', 'Disease', (135, 145))	('promote', 'PosReg', (127, 134))	('metastases', 'Disease', 'MESH:D009362', (135, 145))	('IL)-8', 'molecular_function', 'GO:0005153', ('38', '43'))	('interleukin (IL)-8', 'Gene', (25, 43))	('promotes', 'PosReg', (51, 59))	('adhesion', 'MPA', (64, 72))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('regulates', 'Reg', (15, 24))	('BRAFV600E', 'Var', (0, 9))	('interleukin (IL)-8', 'Gene', '3576', (25, 43))
101431	30499222	In addition, BRAF mutations have been also detected in typical and atypical melanocytic nevi.	('BRAF', 'Gene', '673', (13, 17))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (76, 92))	('BRAF', 'Gene', (13, 17))	('typical', 'Disease', (55, 62))	('nevi', 'Phenotype', 'HP:0003764', (88, 92))	('detected', 'Reg', (43, 51))	('mutations', 'Var', (18, 27))
101432	30499222	In nevi, BRAF mutations initially trigger growth in lesions that will eventually stop proliferating and remain benign (Michaloglou et al., 2005).	('nevi', 'Phenotype', 'HP:0003764', (3, 7))	('BRAF', 'Gene', (9, 13))	('growth', 'MPA', (42, 48))	('trigger', 'Reg', (34, 41))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
101433	30499222	This oncogene-induced senescence is theorized to occur in the 82% of melanocytic nevi with BRAF mutations (Wajapeyee et al., 2008).	('melanocytic nevi', 'Phenotype', 'HP:0000995', (69, 85))	('BRAF', 'Gene', '673', (91, 95))	('senescence', 'biological_process', 'GO:0010149', ('22', '32'))	('BRAF', 'Gene', (91, 95))	('nevi', 'Phenotype', 'HP:0003764', (81, 85))	('melanocytic nevi', 'Disease', (69, 85))	('mutations', 'Var', (96, 105))
101434	30499222	A second mutation causing the loss of a tumor-suppressor gene or causing a second mutation could cause a transition from 'benign' BRAF-mutated nevi to malignant melanoma (Arkenau et al., 2011; Jovanovic et al., 2010; McKenzie et al., 2010; Michaloglou et al., 2005).	('mutation', 'Var', (9, 17))	('malignant melanoma', 'Phenotype', 'HP:0002861', (151, 169))	('BRAF-', 'Gene', (130, 135))	('mutation', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('malignant melanoma', 'Disease', 'MESH:D008545', (151, 169))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('40', '56'))	('malignant melanoma', 'Disease', (151, 169))	('nevi', 'Phenotype', 'HP:0003764', (143, 147))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('loss', 'NegReg', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cause', 'Reg', (97, 102))	('BRAF-', 'Gene', '673', (130, 135))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))
101436	30499222	NRAS mutations have been found in 28% of melanomas (Cancer Genome Atlas Network, 2015), mostly occurring on chronically sun-exposed skin (van Dijk et al., 2005; Dong et al., 2003; Jovanovic et al., 2010).	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('melanomas', 'Disease', 'MESH:D008545', (41, 50))	('mutations', 'Var', (5, 14))	('Cancer', 'Disease', (52, 58))	('melanomas', 'Disease', (41, 50))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('found', 'Reg', (25, 30))	('NRAS', 'Gene', '4893', (0, 4))
101437	30499222	Most mutations in NRAS occur at codon 61 and make the protein constitutively active.	('NRAS', 'Gene', '4893', (18, 22))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('mutations', 'Var', (5, 14))	('constitutively active', 'MPA', (62, 83))	('protein', 'Protein', (54, 61))	('NRAS', 'Gene', (18, 22))
101439	30499222	NRAS mutations are mutually exclusive with BRAF mutations with very rare exceptions (van Dijk et al., 2005).	('BRAF', 'Gene', '673', (43, 47))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', (43, 47))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))
101440	30499222	KRAS and HRAS mutations have been found respectively in 2% and 1% of CM.	('HRAS', 'Gene', '3265', (9, 13))	('CM', 'Phenotype', 'HP:0012056', (69, 71))	('found', 'Reg', (34, 39))	('HRAS', 'Gene', (9, 13))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('KRAS', 'Gene', '3845', (0, 4))
101447	30499222	In the last few years, the detection of somatic mutations, the development of target therapies, and the introduction of immune checkpoint inhibitors have led to important therapeutic advances for melanoma patients (Kirchberger et al., 2018).	('patients', 'Species', '9606', (205, 213))	('melanoma', 'Phenotype', 'HP:0002861', (196, 204))	('melanoma', 'Disease', (196, 204))	('melanoma', 'Disease', 'MESH:D008545', (196, 204))	('mutations', 'Var', (48, 57))
101454	30499222	In the past two decades, dysregulated expression of small ncRNAs, including microRNAs (miRNAs), and lncRNAs has been reported in many, if not all, tumor types.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('ncRNA', 'Gene', '220202', (101, 106))	('expression', 'MPA', (38, 48))	('reported', 'Reg', (117, 125))	('ncRNA', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('ncRNA', 'Gene', (101, 106))	('ncRNA', 'Gene', '220202', (58, 63))	('dysregulated', 'Var', (25, 37))
101455	30499222	The relevance of ncRNA in cancer development is becoming clearer with every passing day: ncRNAs constitute an additional layer of complexity in the cellular regulatory machinery and their alteration is a well-established driver of cancer in addition to genetic, epigenetic and protein-coding gene expression dysregulation.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('alteration', 'Var', (188, 198))	('gene expression', 'biological_process', 'GO:0010467', ('292', '307'))	('cancer', 'Disease', (231, 237))	('ncRNA', 'Gene', (89, 94))	('protein', 'cellular_component', 'GO:0003675', ('277', '284'))	('ncRNA', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ncRNA', 'Gene', '220202', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('ncRNA', 'Gene', '220202', (17, 22))
101480	30499222	TRPM1/miR-211 levels are frequently downregulated or lost during the transition from nevi to primary melanoma, and high TRPM1 levels correlate with longer disease-free survival in primary melanoma patients (Hammock et al., 2006).	('patients', 'Species', '9606', (197, 205))	('longer', 'PosReg', (148, 154))	('miR-211', 'Gene', '406993', (6, 13))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('nevi', 'Phenotype', 'HP:0003764', (85, 89))	('lost', 'NegReg', (53, 57))	('levels', 'MPA', (14, 20))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('TRPM1', 'Gene', (0, 5))	('TRPM1', 'Gene', (120, 125))	('disease-free survival', 'CPA', (155, 176))	('miR-211', 'Gene', (6, 13))	('TRPM1', 'Gene', '4308', (120, 125))	('high', 'Var', (115, 119))	('primary melanoma', 'Disease', (93, 109))	('primary melanoma', 'Disease', (180, 196))	('primary melanoma', 'Disease', 'MESH:D008545', (93, 109))	('primary melanoma', 'Disease', 'MESH:D008545', (180, 196))	('TRPM1', 'Gene', '4308', (0, 5))	('downregulated', 'NegReg', (36, 49))
101483	30499222	The role of miR-211 in melanotic melanoma cells is to contribute to a 'normalization program' activated by the inhibition of the ERK pathway: the resulting de-repression of MITF promotes a switch from glycolysis to oxidative phosphorylation involving PGC1alpha and mitochondrial biogenesis.	('melanoma cells', 'Disease', 'MESH:D008545', (33, 47))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('ERK', 'Gene', '5594', (129, 132))	('melanotic melanoma', 'Disease', 'MESH:D008545', (23, 41))	('glycolysis', 'biological_process', 'GO:0006096', ('201', '211'))	('melanotic melanoma', 'Disease', (23, 41))	('promotes', 'PosReg', (178, 186))	('PGC1alpha', 'Gene', '10891', (251, 260))	('miR-211', 'Gene', '406993', (12, 19))	('oxidative phosphorylation', 'MPA', (215, 240))	('mitochondrial biogenesis', 'MPA', (265, 289))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('215', '240'))	('ERK', 'Gene', (129, 132))	('de-repression', 'Var', (156, 169))	('switch', 'MPA', (189, 195))	('melanoma cells', 'Disease', (33, 47))	('MITF', 'Gene', '4286', (173, 177))	('PGC1alpha', 'Gene', (251, 260))	('glycolysis', 'MPA', (201, 211))	('ERK', 'molecular_function', 'GO:0004707', ('129', '132'))	('MITF', 'Gene', (173, 177))	('miR-211', 'Gene', (12, 19))
101486	30499222	Melanoma cell proliferation can be influenced by miRNAs; in fact the dysregulation of some miRNAs can sustain and induce proliferative signals or repress growth-suppressive pathways, thereby promoting melanoma carcinogenesis.	('miR', 'Gene', (91, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('9', '27'))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('growth-suppressive pathways', 'Pathway', (154, 181))	('proliferative signals', 'MPA', (121, 142))	('Melanoma', 'Disease', (0, 8))	('repress', 'NegReg', (146, 153))	('miR', 'Gene', '220972', (49, 52))	('dysregulation', 'Var', (69, 82))	('miR', 'Gene', (49, 52))	('promoting', 'PosReg', (191, 200))	('induce', 'PosReg', (114, 120))	('melanoma carcinogenesis', 'Disease', 'MESH:D063646', (201, 224))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))	('melanoma carcinogenesis', 'Disease', (201, 224))	('miR', 'Gene', '220972', (91, 94))
101505	30499222	This miRNA targets cyclin-dependent kinase 4 (CDK4), cyclin D1 (CCND1) and cyclin C, and transfection of miR-206 induces G1 arrest in multiple melanoma cell lines (Georgantas et al., 2014).	('miR', 'Gene', '220972', (5, 8))	('CDK', 'molecular_function', 'GO:0004693', ('46', '49'))	('transfection', 'Var', (89, 101))	('CDK4', 'Gene', '1019', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('miR', 'Gene', '220972', (105, 108))	('cyclin', 'molecular_function', 'GO:0016538', ('19', '25'))	('miR', 'Gene', (5, 8))	('multiple melanoma', 'Disease', 'MESH:D008545', (134, 151))	('multiple melanoma', 'Disease', (134, 151))	('cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('CCND1', 'Gene', '595', (64, 69))	('miR', 'Gene', (105, 108))	('cyclin D1', 'Gene', (53, 62))	('CCND1', 'Gene', (64, 69))	('cyclin-dependent kinase 4', 'Gene', (19, 44))	('cyclin C', 'Gene', '892', (75, 83))	('cyclin', 'molecular_function', 'GO:0016538', ('53', '59'))	('miR-206', 'Gene', (105, 112))	('induces', 'Reg', (113, 120))	('CDK4', 'Gene', (46, 50))	('miR-206', 'Gene', '406989', (105, 112))	('cyclin C', 'Gene', (75, 83))	('cyclin-dependent kinase 4', 'Gene', '1019', (19, 44))	('cyclin D1', 'Gene', '595', (53, 62))
101512	30499222	It was suggested that dysregulation of this miRNA may contribute to melanoma progression.	('dysregulation', 'Var', (22, 35))	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('contribute', 'Reg', (54, 64))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))
101525	30499222	Both miR-203 and 126/126* were found to be downregulated in melanoma, in particular in metastatic melanoma.	('downregulated', 'NegReg', (43, 56))	('miR-203', 'Gene', (5, 12))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('126/126*', 'Var', (17, 25))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('miR-203', 'Gene', '406986', (5, 12))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))
101528	30499222	In addition, it was observed that ectopic expression of miR-203 in melanoma cells reduced the expression of E2F3a and E2F3b, leading to the inhibition of cell growth and induction of cell cycle arrest and senescence (Noguchi et al., 2012b).	('miR-203', 'Gene', (56, 63))	('miR-203', 'Gene', '406986', (56, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (183, 200))	('senescence', 'CPA', (205, 215))	('E2F3a', 'Gene', (108, 113))	('melanoma cells', 'Disease', 'MESH:D008545', (67, 81))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma cells', 'Disease', (67, 81))	('induction', 'Reg', (170, 179))	('cell growth', 'CPA', (154, 165))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('140', '165'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('183', '200'))	('inhibition', 'NegReg', (140, 150))	('cell cycle arrest', 'CPA', (183, 200))	('expression', 'MPA', (94, 104))	('reduced', 'NegReg', (82, 89))	('senescence', 'biological_process', 'GO:0010149', ('205', '215'))	('E2F3b', 'Var', (118, 123))
101568	30499222	In addition, the replacement of miR-26a promoted cell death by targeting directly the anti-apoptotic protein silencer of death domains (SODD) (Reuland et al., 2013).	('replacement', 'Var', (17, 28))	('promoted', 'PosReg', (40, 48))	('silencer of death', 'Disease', (109, 126))	('miR-26a', 'Gene', '407015', (32, 39))	('cell death', 'CPA', (49, 59))	('silencer of death', 'Disease', 'MESH:D003643', (109, 126))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('cell death', 'biological_process', 'GO:0008219', ('49', '59'))	('miR-26a', 'Gene', (32, 39))
101578	30499222	In particular, the transfection of miR-200c in melanoma cells induces an ameboid-like invasion mode, with the cells assuming a round cell-body phenotype.	('ameboid-like invasion mode', 'CPA', (73, 99))	('transfection', 'Var', (19, 31))	('melanoma cells', 'Disease', 'MESH:D008545', (47, 61))	('induces', 'Reg', (62, 69))	('melanoma cells', 'Disease', (47, 61))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('cell-body', 'cellular_component', 'GO:0044297', ('133', '142'))	('miR-200c', 'Gene', (35, 43))	('miR-200c', 'Gene', '406985', (35, 43))
101588	30499222	In this study, mice treated with anti-miR-21 molecules showed a significant reduction of TIMP3 expression and tumor growth and invasiveness.	('reduction', 'NegReg', (76, 85))	('TIMP3', 'Protein', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mice', 'Species', '10090', (15, 19))	('invasiveness', 'CPA', (127, 139))	('anti-miR-21 molecules', 'Var', (33, 54))	('expression', 'MPA', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
101607	30499222	MicroR-625 was found downregulated in malignant melanoma and it was shown that its ectopic expression inhibits proliferation and migration in malignant melanoma.	('MicroR-625', 'Gene', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('malignant melanoma', 'Disease', 'MESH:D008545', (142, 160))	('malignant melanoma', 'Disease', 'MESH:D008545', (38, 56))	('malignant melanoma', 'Disease', (38, 56))	('malignant melanoma', 'Phenotype', 'HP:0002861', (142, 160))	('downregulated', 'NegReg', (21, 34))	('malignant melanoma', 'Phenotype', 'HP:0002861', (38, 56))	('ectopic', 'Var', (83, 90))	('malignant melanoma', 'Disease', (142, 160))	('inhibits', 'NegReg', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
101617	30499222	In addition, they blocked miR-339-3p using an antagomir and found an increase of melanoma cell invasion, an effect that could be phenocopied by RNAi-mediated silencing of MCL1, which is a target of miR-339-3p.	('blocked', 'NegReg', (18, 25))	('mir', 'Gene', (52, 55))	('increase', 'PosReg', (69, 77))	('miR', 'Gene', (198, 201))	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', (26, 29))	('MCL1', 'Gene', '4170', (171, 175))	('3p', 'Chemical', '-', (206, 208))	('miR', 'Gene', '220972', (26, 29))	('RNAi', 'biological_process', 'GO:0016246', ('144', '148'))	('MCL1', 'Gene', (171, 175))	('mir', 'Gene', '220972', (52, 55))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('silencing', 'Var', (158, 167))	('3p', 'Chemical', '-', (34, 36))
101618	30499222	Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma, an effect that could be accentuated by their dual alteration (Orso et al., 2016).	('elevating', 'PosReg', (21, 30))	('dissemination of melanoma', 'Disease', (52, 77))	('dissemination of melanoma', 'Disease', 'MESH:D008545', (52, 77))	('miR-148b', 'Gene', (31, 39))	('Depleting', 'Var', (0, 9))	('blocked', 'NegReg', (40, 47))	('miR-214', 'Protein', (10, 17))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
101619	30499222	In fact, they demonstrated that the dual alteration suppresses the passage of malignant cells through the blood vessel endothelium by reducing the expression of the cell adhesion molecules ITGA5 and ALCAM; furthermore, single or combined miR-214 downregulation and miR-148b upregulation in tumor cells inhibits metastasis formation in mice.	('downregulation', 'NegReg', (246, 260))	('expression', 'MPA', (147, 157))	('formation', 'biological_process', 'GO:0009058', ('322', '331'))	('inhibits', 'NegReg', (302, 310))	('ITGA5', 'Gene', (189, 194))	('tumor', 'Disease', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('reducing', 'NegReg', (134, 142))	('ITGA5', 'Gene', '16402', (189, 194))	('metastasis formation', 'CPA', (311, 331))	('upregulation', 'PosReg', (274, 286))	('alteration', 'Var', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('miR-214', 'Gene', (238, 245))	('mice', 'Species', '10090', (335, 339))	('ALCAM', 'Gene', (199, 204))	('miR-148b', 'Var', (265, 273))	('cell adhesion', 'biological_process', 'GO:0007155', ('165', '178'))	('suppresses', 'NegReg', (52, 62))	('ALCAM', 'Gene', '11658', (199, 204))
101684	30499222	They demonstrated that miR-17, miR-19a, miR-21, miR-126 and miR-149 are expressed at higher levels in plasma-derived exosomes from patients with metastatic melanoma.	('patients', 'Species', '9606', (131, 139))	('miR-149', 'Gene', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('melanoma', 'Disease', (156, 164))	('higher', 'PosReg', (85, 91))	('miR-19a', 'Gene', (31, 38))	('miR-149', 'Gene', '406941', (60, 67))	('melanoma', 'Disease', 'MESH:D008545', (156, 164))	('miR-17', 'Gene', (23, 29))	('miR-126', 'Gene', '406913', (48, 55))	('miR-126', 'Gene', (48, 55))	('miR-19a', 'Gene', '406979', (31, 38))	('miR-21', 'Var', (40, 46))	('miR-17', 'Gene', '406952', (23, 29))
101686	30499222	found that inhibition of BRAFV600E with vemurafenib and dabrafenib was associated with increased secretion of EVs from melanoma cells.	('increased', 'PosReg', (87, 96))	('BRAFV600E', 'Mutation', 'rs113488022', (25, 34))	('secretion of EVs', 'MPA', (97, 113))	('melanoma cells', 'Disease', 'MESH:D008545', (119, 133))	('BRAFV600E', 'Gene', (25, 34))	('melanoma cells', 'Disease', (119, 133))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('inhibition', 'Var', (11, 21))	('secretion', 'biological_process', 'GO:0046903', ('97', '106'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (40, 51))	('dabrafenib', 'Chemical', 'MESH:C561627', (56, 66))
101694	30499222	The dysregulated expression of specific miRNAs in melanoma cells could serve as a prognostic biomarker for the patients or interfere with their response to treatments (Table 3).	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('expression', 'MPA', (17, 27))	('melanoma cells', 'Disease', 'MESH:D008545', (50, 64))	('melanoma cells', 'Disease', (50, 64))	('interfere', 'NegReg', (123, 132))	('response', 'MPA', (144, 152))	('dysregulated', 'Var', (4, 16))	('patients', 'Species', '9606', (111, 119))
101696	30499222	(2018) demonstrated that the loss of miR-204 is common in melanomas with NRAS sole mutation but is less frequent in those harboring CDKN2A mutations.	('NRAS', 'Gene', '4893', (73, 77))	('melanomas', 'Phenotype', 'HP:0002861', (58, 67))	('miR-204', 'Gene', (37, 44))	('melanomas', 'Disease', 'MESH:D008545', (58, 67))	('loss', 'NegReg', (29, 33))	('mutation', 'Var', (83, 91))	('melanomas', 'Disease', (58, 67))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('miR-204', 'Gene', '406987', (37, 44))	('NRAS', 'Gene', (73, 77))
101713	30499222	(2016) found that the expression of miR-579-3p is a prognostic factor; in particular, low levels of miR-579-3p are associated with a poor prognosis.	('miR-579', 'Gene', (100, 107))	('miR-579', 'Gene', '693164', (100, 107))	('3p', 'Chemical', '-', (108, 110))	('low levels', 'Var', (86, 96))	('miR-579', 'Gene', (36, 43))	('miR-579', 'Gene', '693164', (36, 43))	('3p', 'Chemical', '-', (44, 46))
101719	30499222	The changes in miR-455-5p editing sites modified its activity on the target genes and conferred completely different biological functions on this miRNA.	('biological functions', 'MPA', (117, 137))	('different', 'Reg', (107, 116))	('modified', 'Reg', (40, 48))	('activity on', 'MPA', (53, 64))	('miR', 'Gene', (146, 149))	('miR', 'Gene', '220972', (146, 149))	('changes', 'Var', (4, 11))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
101721	30499222	Micro (mi)R-378a-3p undergoes A-to-I modification only in the non-metastatic melanoma cells.	('melanoma cells', 'Disease', 'MESH:D008545', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma cells', 'Disease', (77, 91))	('Micro (mi)R-378a-3p', 'Var', (0, 19))	('3p', 'Chemical', '-', (17, 19))
101729	30499222	In addition, the overexpression of miR-432 in melanoma can be attributed to frequent genomic amplification and aberrant hypomethylation patterns of the DLK1-DIO3 locus on chromosome 14.	('chromosome', 'cellular_component', 'GO:0005694', ('171', '181'))	('DIO3', 'Gene', '1735', (157, 161))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('DIO3', 'Gene', (157, 161))	('melanoma', 'Disease', (46, 54))	('miR-432', 'Gene', '574451', (35, 42))	('hypomethylation', 'MPA', (120, 135))	('DLK1', 'Gene', '8788', (152, 156))	('aberrant', 'Var', (111, 119))	('miR-432', 'Gene', (35, 42))	('overexpression', 'PosReg', (17, 31))	('DLK1', 'Gene', (152, 156))
101741	30499222	Moreover, LLME23 silencing reduced tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('reduced', 'NegReg', (27, 34))	('LLME23', 'Gene', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('silencing', 'Var', (17, 26))
101746	30499222	The same authors also demonstrated a negative correlation between UCA1 and miR-507, and that UCA1 silencing decreases the levels of FOXM1 by releasing miR-507.	('UCA1', 'Gene', '652995', (66, 70))	('UCA1', 'Gene', (93, 97))	('UCA1', 'Gene', (66, 70))	('miR-507', 'Gene', '574512', (151, 158))	('FOXM1', 'Gene', (132, 137))	('FOXM1', 'Gene', '2305', (132, 137))	('releasing', 'PosReg', (141, 150))	('silencing', 'Var', (98, 107))	('decreases', 'NegReg', (108, 117))	('miR-507', 'Gene', (75, 82))	('levels', 'MPA', (122, 128))	('miR-507', 'Gene', '574512', (75, 82))	('miR-507', 'Gene', (151, 158))	('UCA1', 'Gene', '652995', (93, 97))
101749	30499222	(2012) the authors described a panel of 39 lncRNAs regulated by BRAFV600E in melanoma; the most significant was BRAF-activated non-coding RNA (BANCR).	('BRAF-', 'Gene', (112, 117))	('BANCR', 'Gene', (143, 148))	('ncRNA', 'Gene', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('BANCR', 'Gene', '100885775', (143, 148))	('RNA', 'cellular_component', 'GO:0005562', ('138', '141'))	('ncRNA', 'Gene', '220202', (44, 49))	('BRAF-', 'Gene', '673', (112, 117))	('regulated', 'Reg', (51, 60))	('BRAFV600E', 'Var', (64, 73))	('BRAFV600E', 'Mutation', 'rs113488022', (64, 73))
101752	30499222	ANRIL is located in chromosome 9p21, nearby CDKN2A/B genes, and SNPs in this region have been associated with human diseases, e.g.	('ANRIL', 'Gene', '100048912', (0, 5))	('CDKN2A/B', 'Gene', '1029;1030', (44, 52))	('SNPs', 'Var', (64, 68))	('p21', 'Gene', '1026', (32, 35))	('human', 'Species', '9606', (110, 115))	('associated', 'Reg', (94, 104))	('ANRIL', 'Gene', (0, 5))	('p21', 'Gene', (32, 35))	('CDKN2A/B', 'Gene', (44, 52))	('chromosome', 'cellular_component', 'GO:0005694', ('20', '30'))
101756	30499222	ANRIL silencing was able to restore the proper expression of CDKN2A and B in a melanoma xenograft model (Xu et al., 2016).	('ANRIL', 'Gene', '100048912', (0, 5))	('CDKN2A', 'Gene', (61, 67))	('restore', 'PosReg', (28, 35))	('melanoma xenograft', 'Disease', 'MESH:D008545', (79, 97))	('ANRIL', 'Gene', (0, 5))	('melanoma xenograft', 'Disease', (79, 97))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('silencing', 'Var', (6, 15))	('expression', 'MPA', (47, 57))
101776	30510916	Serum Level of Soluble CD163 May Be a Predictive Marker of the Effectiveness of Nivolumab in Patients With Advanced Cutaneous Melanoma Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma.	('CD163', 'Gene', (23, 28))	('Advanced Cutaneous Melanoma', 'Disease', 'MESH:C562393', (107, 134))	('protein', 'cellular_component', 'GO:0003675', ('176', '183'))	('melanoma', 'Disease', 'MESH:D008545', (289, 297))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('programmed cell death', 'biological_process', 'GO:0012501', ('154', '175'))	('programmed cell death protein 1', 'Gene', (154, 185))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancers', 'Disease', (261, 268))	('Advanced Cutaneous Melanoma', 'Disease', (107, 134))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('nivolumab', 'Chemical', 'MESH:D000077594', (195, 204))	('CD163', 'Gene', '9332', (23, 28))	('Melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('programmed cell death protein 1', 'Gene', '5133', (154, 185))	('Patients', 'Species', '9606', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (289, 297))	('melanoma', 'Disease', (289, 297))	('Antibodies', 'Var', (135, 145))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('pembrolizumab', 'Chemical', 'MESH:C582435', (209, 222))	('Nivolumab', 'Chemical', 'MESH:D000077594', (80, 89))	('Soluble', 'cellular_component', 'GO:0005625', ('15', '22'))
101818	30510916	The sensitivity and specificity of serum sCD163 in cutaneous melanoma were 84.6 and 87.0%, respectively (p = 0.0030; Figure 1B), whereas the sensitivity and specificity of serum sCD163 in non-cutaneous melanoma were 100 and 66.7%, respectively (p = 0.3154; Figure 2B).	('non-cutaneous melanoma', 'Disease', 'MESH:C562393', (188, 210))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (192, 210))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('cutaneous melanoma', 'Disease', (51, 69))	('serum sCD163', 'Var', (35, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (51, 69))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (51, 69))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('non-cutaneous melanoma', 'Disease', (188, 210))
101823	30510916	previously reported sCD163 and CD163+ TAMs as a prognostic marker for early-stage cutaneous melanoma.	('sCD163', 'Var', (20, 26))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('TAMs', 'Chemical', '-', (38, 42))	('CD163+ TAMs', 'Var', (31, 42))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))
101824	30510916	reported, PD-1 expression is a key factor in maintaining TAMs as M2-polarized, and blockade of PD-1/PD-L1 leads to conversion of TAMs into M1-polarized activated macrophages.	('TAMs', 'Chemical', '-', (57, 61))	('PD-1', 'Gene', '5133', (95, 99))	('PD-1', 'Gene', (95, 99))	('PD-1', 'Gene', (10, 14))	('PD-1', 'Gene', '5133', (10, 14))	('blockade', 'Var', (83, 91))	('TAMs', 'Chemical', '-', (129, 133))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (95, 105))	('PD-1/PD-L1', 'Disease', (95, 105))	('conversion', 'MPA', (115, 125))
101825	30510916	Because TAMs in melanoma comprise a heterogeneous, mainly immunosuppressive population, and because repolarization of TAMs into the activated subtype by immunomodulatory drugs has been reported to significantly suppress melanoma growth in a spontaneous mouse melanoma model, we hypothesized that one of the targets for nivolumab in melanoma is activated CD163+ TAMs.	('melanoma', 'Disease', 'MESH:D008545', (259, 267))	('melanoma growth', 'Disease', (220, 235))	('nivolumab', 'Chemical', 'MESH:D000077594', (319, 328))	('TAMs', 'Chemical', '-', (8, 12))	('mouse', 'Species', '10090', (253, 258))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (332, 340))	('melanoma', 'Disease', (332, 340))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('TAMs', 'Chemical', '-', (118, 122))	('melanoma', 'Disease', (220, 228))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('melanoma', 'Disease', (259, 267))	('melanoma growth', 'Disease', 'MESH:D008545', (220, 235))	('TAMs', 'Chemical', '-', (361, 365))	('suppress', 'NegReg', (211, 219))	('repolarization', 'Var', (100, 114))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Disease', 'MESH:D008545', (332, 340))	('melanoma', 'Disease', 'MESH:D008545', (220, 228))
101845	23785608	Intrinsic factors include the inherited degree of skin pigmentation (skin type I-V) or mutations of tumor-suppressor genes (e.g., CDKN2A, encoding for Cyclin-dependent kinase inhibitor 2A), which might be reflected by a positive family history of melanoma.	('CDKN2A', 'Gene', (130, 136))	('skin pigmentation', 'Phenotype', 'HP:0000953', (50, 67))	('skin pigmentation', 'Disease', (50, 67))	('mutations', 'Var', (87, 96))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (151, 187))	('CDKN2A', 'Gene', '1029', (130, 136))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('tumor-suppressor', 'Gene', '7248', (100, 116))	('melanoma', 'Disease', 'MESH:D008545', (247, 255))	('pigmentation', 'biological_process', 'GO:0043473', ('55', '67'))	('skin pigmentation', 'Disease', 'MESH:D010859', (50, 67))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('168', '184'))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', (151, 187))	('tumor-suppressor', 'Gene', (100, 116))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('151', '184'))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanoma', 'Disease', (247, 255))
101905	23785608	The relative simple two-step method developed by Segura et al uses protective, as well as risk factors, whereby the presence of two risk factors results in a sensitivity of 86.1% and a specificity of 95.3% for the diagnosis of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('presence', 'Var', (116, 124))
101940	33095773	The presence of BRAF V600K mutation is associated with higher age, higher degrees of chronic sun damage and lower disease-free interval.	('V600K', 'Var', (21, 26))	('BRAF', 'Gene', (16, 20))	('age', 'Gene', (62, 65))	('BRAF', 'Gene', '673', (16, 20))	('V600K', 'Mutation', 'rs121913227', (21, 26))	('age', 'Gene', (100, 103))	('chronic sun damage and lower disease-free', 'Disease', 'MESH:D008569', (85, 126))	('sun damage', 'Phenotype', 'HP:0000992', (93, 103))	('age', 'Gene', '5973', (62, 65))	('age', 'Gene', '5973', (100, 103))
101941	33095773	The possibly higher prevalence of V600K in scalp melanoma can be another explanation for its worst prognosis, but there is a lack of studies proving this association.	('scalp melanoma', 'Disease', 'MESH:C538225', (43, 57))	('V600K', 'Mutation', 'rs121913227', (34, 39))	('V600K', 'Var', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('scalp melanoma', 'Disease', (43, 57))
101976	33095773	Additionally, desmoplastic melanoma has a high frequency of NF1 mutations, distinct from conventional melanoma.	('NF1', 'Gene', '4763', (60, 63))	('NF1', 'Gene', (60, 63))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('mutations', 'Var', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (14, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('desmoplastic melanoma', 'Disease', (14, 35))
102080	20629968	We show that absence of keratinocytic RXRalpha in combination with mutant Cdk4 generated cutaneous melanoma that metastasized to lymph nodes in a bigenic mouse model.	('mouse', 'Species', '10090', (154, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('Cdk', 'molecular_function', 'GO:0004693', ('74', '77'))	('Cdk4', 'Gene', (74, 78))	('metastasized', 'CPA', (113, 125))	('absence', 'NegReg', (13, 20))	('Cdk4', 'Gene', '12567', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('mutant', 'Var', (67, 73))	('cutaneous melanoma', 'Disease', (89, 107))
102086	20629968	The present work highlights cooperative effects of aberrant keratinocytic signaling and activated Cdk4 in melanoma metastasis.	('melanoma metastasis', 'Disease', (106, 125))	('Cdk', 'molecular_function', 'GO:0004693', ('98', '101'))	('activated', 'PosReg', (88, 97))	('aberrant', 'Var', (51, 59))	('Cdk4', 'Gene', (98, 102))	('melanoma metastasis', 'Disease', 'MESH:D009362', (106, 125))	('keratinocytic signaling', 'MPA', (60, 83))	('Cdk4', 'Gene', '12567', (98, 102))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))
102092	20629968	The transfer of melanin from melanocytes to keratinocytes aids in the prevention of UV-induced genetic mutations and requires interaction between these two cell types.	('melanin', 'Chemical', 'MESH:D008543', (16, 23))	('interaction', 'Interaction', (126, 137))	('UV-induced', 'Disease', (84, 94))	('genetic mutations', 'Var', (95, 112))
102096	20629968	The RXRalpha-null mutation is embryonic lethal in mice, thereby preventing analysis of in vivo function of this protein in skin homeostasis and diseases.	('RXRalpha-null', 'Gene', (4, 17))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('mutation', 'Var', (18, 26))	('mice', 'Species', '10090', (50, 54))	('skin homeostasis and diseases', 'Disease', 'MESH:D012871', (123, 152))	('homeostasis', 'biological_process', 'GO:0042592', ('128', '139'))
102098	20629968	In a two-step chemical carcinogen model using topical applications of the tumor initiator 7, 12-dimethyl-benz[a]antracene (DMBA) and tumor promoter 12-0-tetradecanoylphorbol-13 acetate (TPA), RXRalphaep-/- mice developed a higher number of dermal melanocytic growths (nevi) compared to control mice.	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (74, 79))	('nevi', 'Phenotype', 'HP:0003764', (268, 272))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('DMBA', 'Chemical', '-', (123, 127))	('dermal melanocytic growths', 'Disease', 'MESH:D006130', (240, 266))	('-13 acetate', 'Chemical', '-', (173, 184))	('TPA', 'Chemical', '-', (186, 189))	('antracene', 'Chemical', '-', (112, 121))	('7, 12-dimethyl-benz[a', 'Chemical', '-', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('dermal melanocytic growths', 'Disease', (240, 266))	('topical', 'molecular_function', 'GO:0003809', ('46', '53'))	('tumor', 'Disease', (133, 138))	('mice', 'Species', '10090', (294, 298))	('TPA', 'molecular_function', 'GO:0031299', ('186', '189'))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('mice', 'Species', '10090', (206, 210))	('RXRalphaep-/-', 'Var', (192, 205))	('higher', 'PosReg', (223, 229))
102099	20629968	Only nevi from RXRalpha mutant mice progressed to human-melanoma-like tumors, suggesting that RXRalpha-mediated distinct non-cell autonomous molecular events appear to regulate suppression of nevi formation and melanoma progression.	('mutant', 'Var', (24, 30))	('nevi', 'Phenotype', 'HP:0003764', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('formation', 'biological_process', 'GO:0009058', ('197', '206'))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (31, 35))	('nevi', 'Phenotype', 'HP:0003764', (5, 9))	('melanoma-like tumors', 'Disease', (56, 76))	('nevi formation', 'CPA', (192, 206))	('human', 'Species', '9606', (50, 55))	('melanoma-like tumors', 'Disease', 'MESH:D008545', (56, 76))
102104	20629968	Mice containing the Cdk4R24C/R24C mutation in cooperation with deregulated receptor tyrosine kinase signaling, or activated Ras, has been shown to promote development of spontaneous and carcinogen-induced metastatic melanoma.	('R24C', 'Mutation', 'rs11547328', (24, 28))	('promote', 'PosReg', (147, 154))	('Cdk4R24C/R24C', 'Var', (20, 33))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('Mice', 'Species', '10090', (0, 4))	('R24C', 'Mutation', 'rs11547328', (29, 33))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('signaling', 'biological_process', 'GO:0023052', ('100', '109'))	('Cdk', 'molecular_function', 'GO:0004693', ('20', '23'))
102106	20629968	We investigated the contributions of Cdk4R24C/R24C and keratinocytic RXRalpha to influence metastatic progression in a mouse model.	('mouse', 'Species', '10090', (119, 124))	('Cdk', 'molecular_function', 'GO:0004693', ('37', '40'))	('R24C', 'Mutation', 'rs11547328', (41, 45))	('influence', 'Reg', (81, 90))	('R24C', 'Mutation', 'rs11547328', (46, 50))	('metastatic progression', 'CPA', (91, 113))	('Cdk4R24C/R24C', 'Var', (37, 50))
102119	20629968	RXRalphaL2/L2 (floxed RXRalpha mice containing LoxP sequences flanking exon 3) mice were used as wild-type controls, and those with single mutation (RXRalphaep-/- and Cdk4R24C/R24C) served as additional controls.	('Cdk4R24C/R24C', 'Var', (167, 180))	('R24C', 'Mutation', 'rs11547328', (171, 175))	('mice', 'Species', '10090', (79, 83))	('Cdk', 'molecular_function', 'GO:0004693', ('167', '170'))	('mice', 'Species', '10090', (31, 35))	('R24C', 'Mutation', 'rs11547328', (176, 180))	('RXRalphaep-/-', 'Var', (149, 162))
102120	20629968	Although all mice in each cohort developed melanocytic tumors (MT) within the timecourse of the study, a greater number of MTs grew to sizes larger than 2mm in diameter in both the RXRalphaep-/- and RXRalphaep-/-/Cdk4R24C/R24C mice compared to the RXRalphaL2/L2 or Cdk4R24C/R24C mice.	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (199, 226))	('R24C', 'Mutation', 'rs11547328', (222, 226))	('mice', 'Species', '10090', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('R24C', 'Mutation', 'rs11547328', (217, 221))	('mice', 'Species', '10090', (279, 283))	('RXRalphaep-/-', 'Var', (181, 194))	('mice', 'Species', '10090', (227, 231))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('R24C', 'Mutation', 'rs11547328', (269, 273))	('melanocytic tumors', 'Disease', 'MESH:D009508', (43, 61))	('Cdk', 'molecular_function', 'GO:0004693', ('213', '216'))	('R24C', 'Mutation', 'rs11547328', (274, 278))	('Cdk', 'molecular_function', 'GO:0004693', ('265', '268'))	('melanocytic tumors', 'Disease', (43, 61))
102123	20629968	All subsequent comparative studies were performed on RXRalphaep-/-/Cdk4R24C/R24C and Cdk4R24C/R24C mice to determine the contribution of keratinocytic RXRalpha signaling on melanomagenesis.	('mice', 'Species', '10090', (99, 103))	('Cdk', 'molecular_function', 'GO:0004693', ('85', '88'))	('Cdk4R24C/R24C', 'Var', (85, 98))	('R24C', 'Mutation', 'rs11547328', (89, 93))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('R24C', 'Mutation', 'rs11547328', (76, 80))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('signaling', 'biological_process', 'GO:0023052', ('160', '169'))	('R24C', 'Mutation', 'rs11547328', (94, 98))	('Cdk', 'molecular_function', 'GO:0004693', ('67', '70'))	('R24C', 'Mutation', 'rs11547328', (71, 75))
102124	20629968	To further characterize the MTs formed in the dorsal skin of the Cdk4R24C/R24C and RXRalphaep-/-/Cdk4R24C/R24C mice, we performed hematoxylin and eosin (H&E) staining of 5mum thick paraffin sections of melanocytic tumors from both genotypes (Figure 2B).	('paraffin', 'Chemical', 'MESH:D010232', (181, 189))	('R24C', 'Mutation', 'rs11547328', (106, 110))	('melanocytic tumors', 'Disease', 'MESH:D009508', (202, 220))	('eosin', 'Chemical', 'MESH:D004801', (146, 151))	('Cdk', 'molecular_function', 'GO:0004693', ('97', '100'))	('melanocytic tumors', 'Disease', (202, 220))	('Cdk4R24C/R24C', 'Var', (65, 78))	('R24C', 'Mutation', 'rs11547328', (69, 73))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('R24C', 'Mutation', 'rs11547328', (101, 105))	('hematoxylin', 'Chemical', 'MESH:D006416', (130, 141))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('Cdk', 'molecular_function', 'GO:0004693', ('65', '68'))	('R24C', 'Mutation', 'rs11547328', (74, 78))	('H&E', 'Chemical', '-', (153, 156))
102125	20629968	A significant increase in epidermal thickness was observed in the skin from RXRalphaep-/-/Cdk4R24C/R24C skin compared to Cdk4R24C/R24C alone (Figure 2C).	('R24C', 'Mutation', 'rs11547328', (130, 134))	('Cdk', 'molecular_function', 'GO:0004693', ('90', '93'))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (76, 103))	('R24C', 'Mutation', 'rs11547328', (99, 103))	('Cdk', 'molecular_function', 'GO:0004693', ('121', '124'))	('R24C', 'Mutation', 'rs11547328', (94, 98))	('R24C', 'Mutation', 'rs11547328', (125, 129))	('epidermal thickness', 'CPA', (26, 45))	('increase', 'PosReg', (14, 22))
102126	20629968	This phenotype is a hallmark of mice bearing an epidermal ablation of RXRalpha, as the basal layer keratinocytes maintain a hyperproliferative state.	('mice', 'Species', '10090', (32, 36))	('RXRalpha', 'Gene', (70, 78))	('ablation', 'Var', (58, 66))	('hyperproliferative state', 'CPA', (124, 148))
102129	20629968	Altogether the above results suggest a synergistic effect of RXRalpha ablation and activated Cdk4 in the development of cutaneous melanoma.	('Cdk4', 'Gene', '12567', (93, 97))	('Cdk', 'molecular_function', 'GO:0004693', ('93', '96'))	('cutaneous melanoma', 'Disease', (120, 138))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('Cdk4', 'Gene', (93, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (120, 138))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (120, 138))	('ablation', 'Var', (70, 78))
102131	20629968	Immunohistochemical staining was performed on paraffin sections of tumors taken from Cdk4R24C/R24C and RXRalphaep-/-/Cdk4R24C/R24C mice after DMBA/TPA treatment.	('Cdk', 'molecular_function', 'GO:0004693', ('85', '88'))	('R24C', 'Mutation', 'rs11547328', (126, 130))	('TPA', 'molecular_function', 'GO:0031299', ('147', '150'))	('Cdk', 'molecular_function', 'GO:0004693', ('117', '120'))	('Cdk4R24C/R24C', 'Var', (85, 98))	('TPA', 'Chemical', '-', (147, 150))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('R24C', 'Mutation', 'rs11547328', (89, 93))	('paraffin', 'Chemical', 'MESH:D010232', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('R24C', 'Mutation', 'rs11547328', (121, 125))	('DMBA', 'Chemical', '-', (142, 146))	('R24C', 'Mutation', 'rs11547328', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mice', 'Species', '10090', (131, 135))	('tumors', 'Disease', (67, 73))
102133	20629968	A significantly higher percentage (67% vs 21%) of Trp1+ cells were co-labeled with Pcna (Trp1+/Pcna+) in the RXRalphaep-/-/Cdk4R24C/R24C skin compared to the Cdk4R24C/R24C skin [(p < 0.01), Figures 3A and 3B].	('R24C', 'Mutation', 'rs11547328', (127, 131))	('higher', 'PosReg', (16, 22))	('R24C', 'Mutation', 'rs11547328', (167, 171))	('Cdk', 'molecular_function', 'GO:0004693', ('123', '126'))	('Trp1', 'Gene', (89, 93))	('Pcna', 'Gene', '18538', (83, 87))	('Trp1+/Pcna+', 'Gene', (89, 100))	('Pcna', 'Gene', (95, 99))	('Trp1', 'Gene', '22178', (89, 93))	('Trp1+/Pcna+', 'Gene', '18538;22178', (89, 100))	('R24C', 'Mutation', 'rs11547328', (132, 136))	('Trp1', 'molecular_function', 'GO:0004167', ('50', '54'))	('R24C', 'Mutation', 'rs11547328', (162, 166))	('Pcna', 'Gene', (83, 87))	('Pcna', 'molecular_function', 'GO:0003892', ('95', '99'))	('Trp1', 'molecular_function', 'GO:0004167', ('89', '93'))	('Trp1', 'Gene', (50, 54))	('Cdk', 'molecular_function', 'GO:0004693', ('158', '161'))	('Pcna', 'Gene', '18538', (95, 99))	('Pcna', 'molecular_function', 'GO:0003892', ('83', '87'))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (109, 136))	('Trp1', 'Gene', '22178', (50, 54))
102135	20629968	That combination showed increased staining in all of the MTs from the RXRalphaep-/-/Cdk4R24C/R24C compared to the Cdk4R24C/R24C mice, suggesting a larger population of malignant cells in these tumors (Figures 3C and 3D).	('Cdk', 'molecular_function', 'GO:0004693', ('114', '117'))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (70, 97))	('R24C', 'Mutation', 'rs11547328', (123, 127))	('R24C', 'Mutation', 'rs11547328', (118, 122))	('Cdk', 'molecular_function', 'GO:0004693', ('84', '87'))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('staining', 'MPA', (34, 42))	('mice', 'Species', '10090', (128, 132))	('R24C', 'Mutation', 'rs11547328', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('R24C', 'Mutation', 'rs11547328', (88, 92))	('larger', 'PosReg', (147, 153))	('increased', 'PosReg', (24, 33))
102136	20629968	Similarly, an increased immunoreactivity for the endothelial cell-specific marker CD31 was also detected in the bigenic mice (17% of DAPI positive cells) compared to Cdk4R24C/R24C mice (5% of DAPI stained cells), suggesting enhanced vascularization in the MTs from those mice (Figures 3E and 3F).	('increased', 'PosReg', (14, 23))	('immunoreactivity', 'MPA', (24, 40))	('DAPI', 'Chemical', 'MESH:C007293', (192, 196))	('DAPI', 'Chemical', 'MESH:C007293', (133, 137))	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (271, 275))	('enhanced', 'PosReg', (224, 232))	('CD31', 'Gene', '18613', (82, 86))	('R24C', 'Mutation', 'rs11547328', (175, 179))	('CD31', 'Gene', (82, 86))	('Cdk', 'molecular_function', 'GO:0004693', ('166', '169'))	('Cdk4R24C/R24C', 'Var', (166, 179))	('mice', 'Species', '10090', (180, 184))	('R24C', 'Mutation', 'rs11547328', (170, 174))	('vascularization', 'CPA', (233, 248))
102138	20629968	In order to determine if combinatorial alterations of multiple molecular pathways could activate a malignant neoplastic process, we analyzed draining lymph nodes and internal organs from RXRalphaep-/-/Cdk4R24C/R24C mice for the presence of metastatic melanocytes and compared them with lymph nodes from Cdk4R24C/R24C and RXRalphaep-/- mice.	('malignant neoplastic process', 'CPA', (99, 127))	('R24C', 'Mutation', 'rs11547328', (312, 316))	('mice', 'Species', '10090', (335, 339))	('Cdk', 'molecular_function', 'GO:0004693', ('201', '204'))	('Cdk', 'molecular_function', 'GO:0004693', ('303', '306'))	('R24C', 'Mutation', 'rs11547328', (210, 214))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (187, 214))	('R24C', 'Mutation', 'rs11547328', (307, 311))	('alterations', 'Var', (39, 50))	('R24C', 'Mutation', 'rs11547328', (205, 209))	('neoplastic process', 'Phenotype', 'HP:0002664', (109, 127))	('mice', 'Species', '10090', (215, 219))	('activate', 'PosReg', (88, 96))
102144	20629968	These results demonstrate that the RXRalphaep-/-/Cdk4R24C/R24C line represents a melanoma mouse model with a tendency for metastatic progression.	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (35, 62))	('mouse', 'Species', '10090', (90, 95))	('R24C', 'Mutation', 'rs11547328', (58, 62))	('Cdk', 'molecular_function', 'GO:0004693', ('49', '52'))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('R24C', 'Mutation', 'rs11547328', (53, 57))
102147	20629968	We also examined activation of regulatory proteins that lie downstream of those signaling pathways in both Cdk4R24C/R24C and RXRalphaep-/-/Cdk4R24C/R24C skin.	('R24C', 'Mutation', 'rs11547328', (116, 120))	('Cdk', 'molecular_function', 'GO:0004693', ('107', '110'))	('R24C', 'Mutation', 'rs11547328', (143, 147))	('regulatory proteins', 'Protein', (31, 50))	('R24C', 'Mutation', 'rs11547328', (148, 152))	('Cdk4R24C/R24C', 'Var', (107, 120))	('activation', 'PosReg', (17, 27))	('R24C', 'Mutation', 'rs11547328', (111, 115))	('signaling', 'biological_process', 'GO:0023052', ('80', '89'))	('Cdk', 'molecular_function', 'GO:0004693', ('139', '142'))
102148	20629968	To determine if expression of genes encoding soluble growth factors are altered at the transcriptional level, we utilized quantitative RT-PCR (qRT-PCR) to examine the relative mRNA levels in skin of RXRalphaep-/-/Cdk4R24C/R24C mice compared to the Cdk4R24C/R24C mice.	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (199, 226))	('R24C', 'Mutation', 'rs11547328', (222, 226))	('R24C', 'Mutation', 'rs11547328', (217, 221))	('mice', 'Species', '10090', (262, 266))	('R24C', 'Mutation', 'rs11547328', (257, 261))	('soluble', 'cellular_component', 'GO:0005625', ('45', '52'))	('mRNA levels', 'MPA', (176, 187))	('mice', 'Species', '10090', (227, 231))	('Cdk', 'molecular_function', 'GO:0004693', ('248', '251'))	('Cdk', 'molecular_function', 'GO:0004693', ('213', '216'))	('R24C', 'Mutation', 'rs11547328', (252, 256))
102150	20629968	Similarly, expression of other factors such as Hgf (~1.5 fold), Fgf2 (~1.5 fold), Pomc (the precursor peptide of alpha-MSH, ~2 fold) and Scf (~2 fold) were also upregulated in RXRalphaep-/-/Cdk4R24C/R24C mice.	('mice', 'Species', '10090', (204, 208))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (176, 203))	('Fgf2', 'Gene', '14173', (64, 68))	('Hgf', 'Gene', '15234', (47, 50))	('Fgf2', 'Gene', (64, 68))	('expression', 'MPA', (11, 21))	('Scf', 'Gene', (137, 140))	('R24C', 'Mutation', 'rs11547328', (199, 203))	('upregulated', 'PosReg', (161, 172))	('Scf', 'Gene', '17311', (137, 140))	('Scf', 'molecular_function', 'GO:0005173', ('137', '140'))	('alpha-MSH', 'Gene', (113, 122))	('Pomc', 'Gene', '18976', (82, 86))	('R24C', 'Mutation', 'rs11547328', (194, 198))	('Cdk', 'molecular_function', 'GO:0004693', ('190', '193'))	('Hgf', 'Gene', (47, 50))	('alpha-MSH', 'Gene', '18976', (113, 122))	('Pomc', 'Gene', (82, 86))
102151	20629968	We then evaluated the transcription factor Mitf that regulates expression of several genes implicated in proliferation, survival and apoptosis of melanocytes, since amplification of Mitf has been linked to malignant conversion of MTs.	('Mitf', 'Gene', '17342', (43, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('133', '142'))	('apoptosis', 'biological_process', 'GO:0006915', ('133', '142'))	('transcription factor', 'molecular_function', 'GO:0000981', ('22', '42'))	('Mitf', 'Gene', (43, 47))	('Mitf', 'Gene', '17342', (182, 186))	('amplification', 'Var', (165, 178))	('transcription', 'biological_process', 'GO:0006351', ('22', '35'))	('Mitf', 'Gene', (182, 186))	('linked to', 'Reg', (196, 205))
102152	20629968	Interestingly, relative mRNA levels of Mitf-M, a melanocyte specific isoform, were also found to be increased (~1.5 fold) in the skin of RXRalphaep-/-/Cdk4R24C/R24C mice compared to the control group (Figure 5A).	('Cdk', 'molecular_function', 'GO:0004693', ('151', '154'))	('increased', 'PosReg', (100, 109))	('mice', 'Species', '10090', (165, 169))	('Mitf', 'Gene', '17342', (39, 43))	('Mitf', 'Gene', (39, 43))	('R24C', 'Mutation', 'rs11547328', (155, 159))	('R24C', 'Mutation', 'rs11547328', (160, 164))	('mRNA levels', 'MPA', (24, 35))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (137, 164))
102155	20629968	A modest increase in expression level of p38, Erk and Jnk proteins, and an increased phosphorylation of p38 and Jnk, was seen in the skin of RXRalphaep-/-/Cdk4R24C/R24C compared to Cdk4R24C/R24C mice (Figure 5C, and data not shown).	('Jnk', 'Gene', (112, 115))	('R24C', 'Mutation', 'rs11547328', (159, 163))	('R24C', 'Mutation', 'rs11547328', (190, 194))	('Jnk', 'Gene', '26419', (54, 57))	('Erk', 'Gene', '26413', (46, 49))	('Jnk', 'molecular_function', 'GO:0004705', ('112', '115'))	('mice', 'Species', '10090', (195, 199))	('Jnk', 'Gene', (54, 57))	('Cdk', 'molecular_function', 'GO:0004693', ('155', '158'))	('increased', 'PosReg', (75, 84))	('expression level', 'MPA', (21, 37))	('p38', 'Gene', (41, 44))	('p38', 'Gene', (104, 107))	('phosphorylation', 'MPA', (85, 100))	('R24C', 'Mutation', 'rs11547328', (164, 168))	('Erk', 'Gene', (46, 49))	('Cdk', 'molecular_function', 'GO:0004693', ('181', '184'))	('p38', 'Gene', '26416', (41, 44))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (141, 168))	('Erk', 'molecular_function', 'GO:0004707', ('46', '49'))	('increase', 'PosReg', (9, 17))	('p38', 'Gene', '26416', (104, 107))	('R24C', 'Mutation', 'rs11547328', (185, 189))	('Jnk', 'molecular_function', 'GO:0004705', ('54', '57'))	('Jnk', 'Gene', '26419', (112, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('85', '100'))
102156	20629968	It is possible that absence of RXRalpha in keratinocytes is increasing the basal rate of transcription for specific soluble communication factors in the skin of RXRalphaep-/-/Cdk4R24C/R24C mice through a derepression mechanism.	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (161, 188))	('R24C', 'Mutation', 'rs11547328', (179, 183))	('increasing', 'PosReg', (60, 70))	('mice', 'Species', '10090', (189, 193))	('absence', 'Var', (20, 27))	('R24C', 'Mutation', 'rs11547328', (184, 188))	('transcription', 'biological_process', 'GO:0006351', ('89', '102'))	('Cdk', 'molecular_function', 'GO:0004693', ('175', '178'))	('soluble', 'cellular_component', 'GO:0005625', ('116', '123'))
102159	20629968	Amplification of isolated chromatin using specific primers was performed on wild-type primary keratinocytes, as well as on those collected from mutant RXRalphaep-/- mice.	('RXRalphaep-/-', 'Gene', (151, 164))	('mutant', 'Var', (144, 150))	('mice', 'Species', '10090', (165, 169))	('chromatin', 'cellular_component', 'GO:0000785', ('26', '35'))
102162	20629968	Laser-capture microdissection (LCM) was performed on frozen sections of melanocytic tumors from Cdk4R24C/R24C and RXRalphaep-/-/Cdk4R24C/R24C mice to investigate the influence of RXRalpha epidermal ablation on melanoma progression.	('R24C', 'Mutation', 'rs11547328', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Cdk', 'molecular_function', 'GO:0004693', ('128', '131'))	('melanocytic tumors', 'Disease', (72, 90))	('melanocytic tumors', 'Disease', 'MESH:D009508', (72, 90))	('mice', 'Species', '10090', (142, 146))	('R24C', 'Mutation', 'rs11547328', (132, 136))	('Cdk4R24C/R24C', 'Var', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('Cdk', 'molecular_function', 'GO:0004693', ('96', '99'))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('R24C', 'Mutation', 'rs11547328', (105, 109))	('melanoma', 'Disease', (210, 218))	('R24C', 'Mutation', 'rs11547328', (137, 141))
102166	20629968	Other genes involved in apoptosis inhibition and downregulated in the mutant melanocytic tumors were caspase 8 (~5 fold), Apaf1 (~3 fold), Bcl2l1 (~4 fold), Tnfrsf10b (~2 fold), Tnfrsf1 (~2 fold), E2F1 (~3 fold), Chek2 (~3 fold), CDKN1a (~2 fold), while Birc5/survivin was upregulated (~3 fold).	('Tnfrsf10b', 'Gene', '21933', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('CDKN1a', 'Gene', (230, 236))	('caspase 8', 'Gene', (101, 110))	('Birc5', 'Gene', '11799', (254, 259))	('Tnfrsf1', 'Gene', (178, 185))	('E2F1', 'Gene', '13555', (197, 201))	('caspase 8', 'Gene', '12370', (101, 110))	('Apaf1', 'Gene', (122, 127))	('CDKN1a', 'Gene', '12575', (230, 236))	('downregulated', 'NegReg', (49, 62))	('melanocytic tumors', 'Disease', (77, 95))	('melanocytic tumors', 'Disease', 'MESH:D009508', (77, 95))	('Chek2', 'Gene', '50883', (213, 218))	('mutant', 'Var', (70, 76))	('Birc5', 'Gene', (254, 259))	('Chek2', 'Gene', (213, 218))	('E2F1', 'Gene', (197, 201))	('apoptosis', 'biological_process', 'GO:0097194', ('24', '33'))	('apoptosis', 'biological_process', 'GO:0006915', ('24', '33'))	('Apaf1', 'Gene', '11783', (122, 127))	('Bcl2', 'molecular_function', 'GO:0015283', ('139', '143'))	('survivin', 'Gene', (260, 268))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('survivin', 'Gene', '11799', (260, 268))	('Tnfrsf10b', 'Gene', (157, 166))	('Bcl2l1', 'Gene', (139, 145))	('Bcl2l1', 'Gene', '12048', (139, 145))
102167	20629968	Elements of the plasminogen activation pathway, Plaur and Serpinb2, were up- and down-regulated (~2 and ~3 fold, respectively) in the RXRalphaep-/-/Cdk4R24C/R24C melanomas compared to those in Cdk4R24C/R24C tumors.	('down-regulated', 'NegReg', (81, 95))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('plasminogen activation', 'biological_process', 'GO:0031639', ('16', '38'))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('melanomas', 'Disease', (162, 171))	('tumors', 'Disease', (207, 213))	('Cdk', 'molecular_function', 'GO:0004693', ('193', '196'))	('R24C', 'Mutation', 'rs11547328', (157, 161))	('Cdk', 'molecular_function', 'GO:0004693', ('148', '151'))	('Serpinb2', 'Gene', (58, 66))	('up-', 'PosReg', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('R24C', 'Mutation', 'rs11547328', (197, 201))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('R24C', 'Mutation', 'rs11547328', (202, 206))	('plasminogen activation pathway', 'Pathway', (16, 46))	('Plaur', 'Gene', (48, 53))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (134, 161))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('Serpinb2', 'Gene', '18788', (58, 66))	('R24C', 'Mutation', 'rs11547328', (152, 156))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('Plaur', 'Gene', '18793', (48, 53))
102172	20629968	We have shown that deletion of RXRalpha in keratinocytes contributes to the development of cutaneous melanoma after carcinogen treatment.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('deletion', 'Var', (19, 27))	('contributes to', 'Reg', (57, 71))	('cutaneous melanoma', 'Disease', (91, 109))	('RXRalpha', 'Gene', (31, 39))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))
102177	20629968	Our results suggest a protective role of keratinocytic RXRalpha against aggressive tumor formation, the lack of which resulted in a significantly increased RGP and VGP in the bigenic RXRalphaep-/-/Cdk4R24C/R24C tumors.	('VGP', 'MPA', (164, 167))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('increased', 'PosReg', (146, 155))	('R24C', 'Mutation', 'rs11547328', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('Cdk', 'molecular_function', 'GO:0004693', ('197', '200'))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (183, 210))	('aggressive tumor', 'Disease', 'MESH:D001523', (72, 88))	('R24C', 'Mutation', 'rs11547328', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('aggressive tumor', 'Disease', (72, 88))	('RGP', 'MPA', (156, 159))	('formation', 'biological_process', 'GO:0009058', ('89', '98'))
102180	20629968	Increased staining against melanoma antibody cocktail HMB45 and MART-1 detected in the RXRalphaep-/-/Cdk4R24C/R24C tumors correlated well with the higher VGP in those mice.	('R24C', 'Mutation', 'rs11547328', (110, 114))	('MART-1', 'Gene', '77836', (64, 70))	('antibody', 'molecular_function', 'GO:0003823', ('36', '44'))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('antibody', 'cellular_component', 'GO:0042571', ('36', '44'))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('antibody', 'cellular_component', 'GO:0019815', ('36', '44'))	('tumors', 'Disease', (115, 121))	('Increased', 'PosReg', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('R24C', 'Mutation', 'rs11547328', (105, 109))	('mice', 'Species', '10090', (167, 171))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (87, 114))	('antibody', 'cellular_component', 'GO:0019814', ('36', '44'))	('Cdk', 'molecular_function', 'GO:0004693', ('101', '104'))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('MART-1', 'Gene', (64, 70))	('staining', 'MPA', (10, 18))
102183	20629968	It has been previously shown that the loss of the transcriptional regulator Taf4 in epidermal keratinocytes can lead to melanocytic tumors with invasion of lymph nodes after carcinogen treatment.	('loss', 'Var', (38, 42))	('melanocytic tumors', 'Disease', (120, 138))	('melanocytic tumors', 'Disease', 'MESH:D009508', (120, 138))	('lead to', 'Reg', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Taf4', 'Gene', (76, 80))	('invasion of lymph nodes', 'CPA', (144, 167))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('Taf4', 'Gene', '228980', (76, 80))
102185	20629968	Activating mutations in N-Ras and its downstream effector B-Raf are frequent events in human nevi and melanomas.	('melanomas', 'Disease', (102, 111))	('Activating mutations', 'Var', (0, 20))	('human', 'Species', '9606', (87, 92))	('nevi', 'Phenotype', 'HP:0003764', (93, 97))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('N-Ras', 'Protein', (24, 29))
102186	20629968	Importantly, N-Ras and B-Raf mutations are mutually exclusive, strongly suggesting that both oncogenic activities are in the same linear pathway deregulating the mitogen activated protein kinase (MAPK) pathway.	('MAPK', 'Gene', (196, 200))	('MAPK', 'Gene', '26413', (196, 200))	('mutations', 'Var', (29, 38))	('deregulating', 'NegReg', (145, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('196', '200'))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))
102187	20629968	Mice bearing oncogenic N-RasQ16K or a B-RafV600E have been shown to develop melanomas mimicking the genetics and pathology of the human disease.	('B-RafV600E', 'Var', (38, 48))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('N-RasQ16K', 'Var', (23, 32))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('human', 'Species', '9606', (130, 135))	('melanomas', 'Disease', (76, 85))	('Mice', 'Species', '10090', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('develop', 'PosReg', (68, 75))
102194	20629968	It is noteworthy that the stress activated kinases p38 and Jnk, both of whose expression and subsequent phosphorylation were enhanced in the skin of RXRalphaep-/-/Cdk4R24C/R24C mice, have been shown to lie downstream of Hgf/Met signaling pathways and activate proliferation of melanoma cells.	('R24C', 'Mutation', 'rs11547328', (167, 171))	('activate', 'PosReg', (251, 259))	('Hgf', 'Gene', '15234', (220, 223))	('phosphorylation', 'MPA', (104, 119))	('signaling', 'biological_process', 'GO:0023052', ('228', '237'))	('p38', 'Gene', (51, 54))	('Hgf', 'Gene', (220, 223))	('Jnk', 'molecular_function', 'GO:0004705', ('59', '62'))	('phosphorylation', 'biological_process', 'GO:0016310', ('104', '119'))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('kinases', 'Enzyme', (43, 50))	('melanoma', 'Disease', (277, 285))	('proliferation', 'CPA', (260, 273))	('p38', 'Gene', '26416', (51, 54))	('Jnk', 'Gene', '26419', (59, 62))	('R24C', 'Mutation', 'rs11547328', (172, 176))	('enhanced', 'PosReg', (125, 133))	('Jnk', 'Gene', (59, 62))	('mice', 'Species', '10090', (177, 181))	('expression', 'MPA', (78, 88))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (149, 176))	('melanoma', 'Disease', 'MESH:D008545', (277, 285))	('Cdk', 'molecular_function', 'GO:0004693', ('163', '166'))
102195	20629968	We showed an enhanced expression of the melanocyte master regulator Mitf in the mutant skin, whose expression is shown to be regulated by both MAPK and p38 signaling ( and references therein).	('Mitf', 'Gene', '17342', (68, 72))	('enhanced', 'PosReg', (13, 21))	('MAPK', 'Gene', (143, 147))	('MAPK', 'Gene', '26413', (143, 147))	('mutant', 'Var', (80, 86))	('p38', 'Gene', (152, 155))	('Mitf', 'Gene', (68, 72))	('p38', 'Gene', '26416', (152, 155))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('MAPK', 'molecular_function', 'GO:0004707', ('143', '147'))	('expression', 'MPA', (22, 32))
102199	20629968	We propose a similar model of derepression on the promoters of specific soluble growth factors such as Et-1 and Hgf in our RXRalphaep-/- mice that increases the basal transcriptional activity due to loss of RXRalpha/NR.	('Et-1 and Hgf', 'Gene', '13614;15234', (103, 115))	('increases', 'PosReg', (147, 156))	('loss', 'Var', (199, 203))	('basal transcriptional activity', 'MPA', (161, 191))	('soluble', 'cellular_component', 'GO:0005625', ('72', '79'))	('RXRalpha/NR', 'Protein', (207, 218))	('mice', 'Species', '10090', (137, 141))
102202	20629968	We used LCM technology to show the inherent functional differences between the melanocytic tumors from Cdk4R24C/R24C and RXRalphaep-/-/Cdk4R24C/R24C mice.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Cdk', 'molecular_function', 'GO:0004693', ('135', '138'))	('melanocytic tumors', 'Disease', 'MESH:D009508', (79, 97))	('R24C', 'Mutation', 'rs11547328', (112, 116))	('R24C', 'Mutation', 'rs11547328', (144, 148))	('melanocytic tumors', 'Disease', (79, 97))	('Cdk4R24C/R24C', 'Var', (103, 116))	('R24C', 'Mutation', 'rs11547328', (107, 111))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('R24C', 'Mutation', 'rs11547328', (139, 143))	('Cdk', 'molecular_function', 'GO:0004693', ('103', '106'))
102204	20629968	There was also an upregulation of the caspase activation inhibitor Birc5/Survivin, which is shown to be highly expressed in malignant melanoma but absent in normal melanocytes, suggesting that melanomas from RXRalphaep-/-/Cdk4R24C/R24C mice might utilize multiple pathways to attenuate apoptotic signals.	('upregulation', 'PosReg', (18, 30))	('apoptotic signals', 'CPA', (286, 303))	('mice', 'Species', '10090', (236, 240))	('Birc5', 'Gene', (67, 72))	('melanomas', 'Disease', 'MESH:D008545', (193, 202))	('Cdk', 'molecular_function', 'GO:0004693', ('222', '225'))	('RXRalphaep-/-/Cdk4R24C/R24C', 'Var', (208, 235))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('malignant melanoma', 'Disease', (124, 142))	('melanomas', 'Disease', (193, 202))	('R24C', 'Mutation', 'rs11547328', (226, 230))	('caspase activation', 'biological_process', 'GO:0006919', ('38', '56'))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanomas', 'Phenotype', 'HP:0002861', (193, 202))	('Survivin', 'Gene', '11799', (73, 81))	('caspase', 'Gene', '12370', (38, 45))	('Birc5', 'Gene', '11799', (67, 72))	('malignant melanoma', 'Phenotype', 'HP:0002861', (124, 142))	('caspase', 'Gene', (38, 45))	('Survivin', 'Gene', (73, 81))	('attenuate', 'NegReg', (276, 285))	('malignant melanoma', 'Disease', 'MESH:D008545', (124, 142))	('R24C', 'Mutation', 'rs11547328', (231, 235))
102211	20629968	Loss of Pten favors melanoma formation by reducing apoptosis and promoting cell survival.	('promoting', 'PosReg', (65, 74))	('Pten', 'Gene', (8, 12))	('Pten', 'Gene', '19211', (8, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('reducing', 'NegReg', (42, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('melanoma', 'Disease', (20, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('apoptosis', 'CPA', (51, 60))	('cell survival', 'CPA', (75, 88))	('Loss', 'Var', (0, 4))	('formation', 'biological_process', 'GO:0009058', ('29', '38'))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))
102216	20629968	Screening for genetic polymorphisms for RXRalpha in keratinocytes, in addition to melanocytes, is warranted in human melanoma patients, as we demonstrate keratinocytic contributions to both melanomagenesis and metastatic spread.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('metastatic spread', 'CPA', (210, 227))	('polymorphisms', 'Var', (22, 35))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('RXRalpha', 'Gene', (40, 48))	('human', 'Species', '9606', (111, 116))	('patients', 'Species', '9606', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))
102217	20629968	Generation of RXRalphaep-/- and Cdk4R24C/R24C mice have previously been described.	('Cdk4R24C/R24C', 'Var', (32, 45))	('R24C', 'Mutation', 'rs11547328', (41, 45))	('Cdk', 'molecular_function', 'GO:0004693', ('32', '35'))	('RXRalphaep-/-', 'Var', (14, 27))	('mice', 'Species', '10090', (46, 50))	('R24C', 'Mutation', 'rs11547328', (36, 40))
102222	31146393	False Discovery Rate Control in Cancer Biomarker Selection Using Knockoffs The discovery of biomarkers that are informative for cancer risk assessment, diagnosis, prognosis and treatment predictions is crucial.	('Cancer', 'Disease', (32, 38))	('Knockoffs', 'Var', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
102237	31146393	The FDR for the knockoff + LCD method is slightly higher.	('knockoff', 'Var', (16, 24))	('LCD', 'Disease', (27, 30))	('FDR', 'MPA', (4, 7))	('LCD', 'Disease', 'MESH:C537881', (27, 30))
102245	31146393	In the literature, the CLDN (Claudin) gene family is known to be associated with tumor suppressor genes; for example, hypermethylation of the CLDN11 promoter occurs frequently in malignant melanoma of the skin, which may encode a novel melanoma-specific tumor suppressor gene.	('tumor suppressor', 'biological_process', 'GO:0051726', ('254', '270'))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('malignant melanoma', 'Disease', (179, 197))	('hypermethylation', 'Var', (118, 134))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', (254, 259))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('melanoma', 'Disease', (236, 244))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('malignant melanoma', 'Phenotype', 'HP:0002861', (179, 197))	('CLDN11', 'Gene', (142, 148))	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('malignant melanoma', 'Disease', 'MESH:D008545', (179, 197))	('CLDN11', 'Gene', '5010', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('254', '270'))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
102273	31138334	For example, patients with metastatic SKCM can develop antibodies against cancer testis antigens, and the presence of these antibodies has been associated with clinical benefit from CTLA-4 inhibition.	('CTLA-4', 'Gene', (182, 188))	('metastatic SKCM', 'Disease', (27, 42))	('cancer testis', 'Phenotype', 'HP:0010788', (74, 87))	('patients', 'Species', '9606', (13, 21))	('cancer testis', 'Disease', 'MESH:D013736', (74, 87))	('CTLA-4', 'Gene', '1493', (182, 188))	('antibodies', 'Var', (55, 65))	('develop', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer testis', 'Disease', (74, 87))
102275	31138334	Depletion of B cells was associated with impaired T cell tumor infiltration and cytotoxicity in the murine B16 melanoma model.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('Depletion', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('murine', 'Species', '10090', (100, 106))	('impaired T cell tumor infiltration', 'Disease', (41, 75))	('impaired T cell tumor infiltration', 'Disease', 'MESH:D017254', (41, 75))	('cytotoxicity', 'Disease', (80, 92))
102316	31138334	We next investigated whether any of the subgroups derived from the proposed TCGA classifications on the basis of the most abundant somatic mutations (i.e., mutations in BRAF codons V600 and K601, RAS codons G12, G13, and Q61, and NF1 stop codon mutations) or gene expression profiling (melanogenesis associated transcription factor low (MITF-low), immune-high, and keratin-high) was associated with various BCR measures or other B cell subsets.	('Q61', 'Var', (221, 224))	('BRAF', 'Gene', (169, 173))	('BRAF', 'Gene', '673', (169, 173))	('K601', 'Var', (190, 194))	('BCR measures', 'Disease', (407, 419))	('mutations', 'Var', (156, 165))	('transcription', 'biological_process', 'GO:0006351', ('311', '324'))	('associated', 'Reg', (383, 393))	('NF1', 'Gene', (230, 233))	('V600', 'Var', (181, 185))	('NF1', 'Gene', '4763', (230, 233))	('gene expression', 'biological_process', 'GO:0010467', ('259', '274'))	('MITF', 'Gene', '4286', (337, 341))	('MITF', 'Gene', (337, 341))	('transcription factor', 'molecular_function', 'GO:0000981', ('311', '331'))
102319	31138334	The TCGA molecular subtypes had the most variation across the different subtypes for the BCR diversity measurements (IGHG Shannon entropy, q = 1 x 10- 14, IGHG Gini-Simpson, q = 4 x 10- 9 by ANOVA after Benjamini-Hochberg multiple testing correction), indicating that tumor gene expression differences were associated with variation in B cell diversity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('men', 'Species', '9606', (110, 113))	('gene expression', 'biological_process', 'GO:0010467', ('274', '289'))	('tumor', 'Disease', (268, 273))	('variation', 'Var', (323, 332))	('B cell diversity', 'CPA', (336, 352))	('associated', 'Reg', (307, 317))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
102347	31138334	This idea is further supported by the previous finding that women with SKCM have significantly lower somatic mutation burden than men and our finding in this study that SKCM in women, who are known to have relatively decreased global central immune (i.e., thymic) tolerance and therefore more prone to autoimmune diseases, had a more diverse B cell infiltrate.	('global central immune', 'CPA', (227, 248))	('men', 'Species', '9606', (179, 182))	('men', 'Species', '9606', (62, 65))	('lower', 'NegReg', (95, 100))	('decreased', 'NegReg', (217, 226))	('women', 'Species', '9606', (177, 182))	('autoimmune diseases', 'Disease', 'MESH:D001327', (302, 321))	('prone', 'Reg', (293, 298))	('more', 'PosReg', (329, 333))	('women', 'Species', '9606', (60, 65))	('autoimmune diseases', 'Disease', (302, 321))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (302, 321))	('somatic mutation burden', 'MPA', (101, 124))	('SKCM', 'Var', (169, 173))	('men', 'Species', '9606', (130, 133))
102350	31138334	Since B cells also express immune checkpoint molecules such as CTLA-4, PD-1, and PD-L1 that may negatively regulate BCR signaling, and since treatment with CTLA-4 or PD-1 inhibitors has been associated with increase in certain autoimmune antibodies, it is possible that immune checkpoint inhibitors may enhance activation of B cells and overall contribute to either anti-tumor response (memory B cells) and/or development of autoimmunity.	('tumor', 'Disease', (371, 376))	('CTLA-4', 'Gene', '1493', (156, 162))	('PD-L1', 'Gene', (81, 86))	('men', 'Species', '9606', (146, 149))	('CTLA-4', 'Gene', (156, 162))	('PD-L1', 'Gene', '29126', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('contribute', 'Reg', (345, 355))	('enhance activation', 'PosReg', (303, 321))	('autoimmune antibodies', 'Phenotype', 'HP:0002960', (227, 248))	('memory', 'biological_process', 'GO:0007613', ('387', '393'))	('autoimmunity', 'Disease', (425, 437))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('inhibitors', 'Var', (171, 181))	('CTLA-4', 'Gene', '1493', (63, 69))	('PD-1', 'Gene', (166, 170))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('PD-1', 'Gene', '5133', (166, 170))	('PD-1', 'Gene', (71, 75))	('autoimmunity', 'Disease', 'MESH:D001327', (425, 437))	('PD-1', 'Gene', '5133', (71, 75))	('increase', 'PosReg', (207, 215))	('CTLA-4', 'Gene', (63, 69))	('BCR signaling', 'MPA', (116, 129))	('men', 'Species', '9606', (417, 420))	('autoimmunity', 'Phenotype', 'HP:0002960', (425, 437))	('B cells', 'CPA', (325, 332))
102351	31138334	In support of the former, our analysis of publicly available RNA-seq data corresponding to pre-treatment tumor tissues collected from patients who received CTLA-4 inhibitor suggests that lack of a B cell response is a predictor of poor response to immune checkpoint inhibitors.	('men', 'Species', '9606', (100, 103))	('CTLA-4', 'Gene', '1493', (156, 162))	('pre', 'molecular_function', 'GO:0003904', ('91', '94'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('patients', 'Species', '9606', (134, 142))	('CTLA-4', 'Gene', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))	('lack', 'Var', (187, 191))
102352	31138334	In fact, targeted therapies that can potentially inhibit B cell function if given at high doses, such as ibrutinib, which are currently in clinical development across various malignancies (NCT03021460, NCT02581930), may have undesirable clinical effects based on B cell inhibition.	('men', 'Species', '9606', (155, 158))	('NCT02581930', 'Var', (202, 213))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('B cell function', 'CPA', (57, 72))	('malignancies', 'Disease', (175, 187))	('ibrutinib', 'Chemical', 'MESH:C551803', (105, 114))	('NCT03021460', 'Var', (189, 200))	('inhibit', 'NegReg', (49, 56))	('B cell', 'CPA', (263, 269))
102362	31138334	The BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex and increased clonality of the BCR repertoire was favorably prognostic in SKCM.	('BCR', 'Gene', (132, 135))	('clonality', 'Var', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('prognostic', 'Reg', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SKCM', 'Disease', (175, 179))	('tumor', 'Disease', (75, 80))
102449	20164001	Additional evidence has shown that pesticides, carbon tetrachloride, and formaldehyde are related to increased risk of intraocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('intraocular melanoma', 'Phenotype', 'HP:0007716', (119, 139))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (47, 67))	('formaldehyde', 'Chemical', 'MESH:D005557', (73, 85))	('intraocular melanoma', 'Disease', (119, 139))	('intraocular melanoma', 'Disease', 'MESH:C563596', (119, 139))	('pesticides', 'Var', (35, 45))
102479	30890735	Burden of unique and low prevalence somatic mutations correlates with cancer survival Tumor mutational burden correlates with improved survival and immunotherapy response in some malignancies, and with tumor aggressiveness in others.	('improved', 'PosReg', (126, 134))	('tumor aggressiveness', 'Disease', (202, 222))	('aggressiveness', 'Phenotype', 'HP:0000718', (208, 222))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('malignancies', 'Disease', (179, 191))	('Tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (202, 222))	('mutations', 'Var', (44, 53))	('survival', 'CPA', (135, 143))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
102482	30890735	High TEMMB was associated with improved survival in cutaneous melanoma: hazard ratio (HR) = 0.71 [0.60-0.85], p = 0.0002, urothelial bladder carcinoma: HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma: HR = 0.80 [0.70-0.93], p = 0.003.	('improved', 'PosReg', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('TEMMB', 'Chemical', '-', (5, 10))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('urothelial bladder carcinoma', 'Disease', (122, 150))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (133, 150))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
102483	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma: HR = 1.32 [1.00-1.74], p < 0.05.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('survival', 'MPA', (41, 49))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
102485	30890735	In cancers with a low RS, high TEMMB was correlated with better survival outcomes (r = 0.49, p = 0.02).	('high TEMMB', 'Var', (26, 36))	('survival outcomes', 'CPA', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('better', 'PosReg', (57, 63))	('TEMMB', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
102486	30890735	In conclusion, TEMMB effects on survival depend on recurrent mutation enrichment; tumor types that are highly enriched in passenger mutations show a survival benefit in the setting of high tumor mutational burden.	('tumor', 'Disease', (189, 194))	('TEMMB', 'Chemical', '-', (15, 20))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('survival', 'CPA', (149, 157))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('benefit', 'PosReg', (158, 165))
102489	30890735	Alternatively, highly mutated tumors may develop many novel peptides and thus display more neoantigens, rendering them more susceptible T-cell targets.	('tumors', 'Disease', (30, 36))	('peptides', 'MPA', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('develop', 'PosReg', (41, 48))	('neoantigens', 'MPA', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('more', 'PosReg', (86, 90))	('highly mutated', 'Var', (15, 29))
102490	30890735	For example, patients with melanomas with a high mutational load showed improved survival with ipilimumab and improved overall survival; patients with highly mutated ovarian cancer had improved postoperative chemotherapy response and higher overall survival.	('melanomas', 'Disease', 'MESH:D008545', (27, 36))	('improved', 'PosReg', (185, 193))	('overall', 'MPA', (241, 248))	('improved', 'PosReg', (110, 118))	('highly mutated', 'Var', (151, 165))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('melanomas', 'Disease', (27, 36))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('ipilimumab', 'Chemical', 'MESH:D000074324', (95, 105))	('higher', 'PosReg', (234, 240))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('overall', 'MPA', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('melanomas', 'Phenotype', 'HP:0002861', (27, 36))	('ovarian cancer', 'Disease', (166, 180))
102495	30890735	Furthermore, missense variants specifically have been suggested to be the most frequent class of alterations to carry the potential for neoepitope generation in chronic lymphocytic leukemia malignancy (as compared to frameshift or splice-site variants).	('neoepitope generation', 'MPA', (136, 157))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (161, 189))	('leukemia', 'Phenotype', 'HP:0001909', (181, 189))	('chronic lymphocytic leukemia malignancy', 'Disease', (161, 200))	('chronic lymphocytic leukemia malignancy', 'Disease', 'MESH:D015451', (161, 200))	('missense variants', 'Var', (13, 30))	('lymphocytic leukemia malignancy', 'Phenotype', 'HP:0005526', (169, 200))
102496	30890735	In multiple myeloma, missense mutational load was found to be highly correlated with predicted neoantigen loads.	('multiple myeloma', 'Disease', (3, 19))	('correlated', 'Reg', (69, 79))	('neoantigen loads', 'MPA', (95, 111))	('missense mutational load', 'Var', (21, 45))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
102497	30890735	Total missense mutational burden across all cohorts ranged from a low of 8 (median) missense mutations among acute myeloid leukemia (LAML) and thymoma (THYM), to 256 median mutations among the skin cutaneous melanoma (SKCM) cohort (Fig.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (109, 131))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('thymoma', 'Disease', 'MESH:D013945', (143, 150))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('thymoma', 'Disease', (143, 150))	('acute myeloid leukemia', 'Disease', (109, 131))	('mutations', 'Var', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 216))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (115, 131))	('thymoma', 'Phenotype', 'HP:0100522', (143, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (198, 216))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (109, 131))	('skin cutaneous melanoma', 'Disease', (193, 216))	('missense mutations', 'Var', (84, 102))
102499	30890735	Total (TEMB) and missense (TEMMB) tumor exonic mutational burden were found to be closely correlated among all cohorts: Pearson's r ranged from 0.95-1.00 for all cohorts other than uveal melanoma (UVM) which also revealed a strong positive correlation with r = 0.88 likely due to a small (N = 79) sample size (p < 2.2 x 10-16 for all cohorts) (Fig.	('missense', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('UVM', 'Phenotype', 'HP:0007716', (197, 200))	('uveal melanoma', 'Phenotype', 'HP:0007716', (181, 195))	('uveal melanoma', 'Disease', 'MESH:C536494', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('TEMMB', 'Chemical', '-', (27, 32))	('uveal melanoma', 'Disease', (181, 195))
102501	30890735	Male sex was significantly associated with high TEMMB in renal papillary cell carcinoma (KIRP), sarcoma (SARC), and cutaneous melanoma (SKCM).	('high TEMMB', 'Var', (43, 53))	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('SARC', 'Phenotype', 'HP:0100242', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('associated', 'Reg', (27, 37))	('sarcoma', 'Disease', 'MESH:D012509', (96, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (57, 87))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('cutaneous melanoma', 'Disease', (116, 134))	('TEMMB', 'Chemical', '-', (48, 53))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('renal papillary cell carcinoma', 'Disease', (57, 87))	('sarcoma', 'Disease', (96, 103))
102502	30890735	Female sex was significantly associated with high TEMMB in colorectal adenocarcinoma (COAD) and glioblastoma multiforme (GBM).	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('colorectal adenocarcinoma', 'Disease', (59, 84))	('TEMMB', 'Chemical', '-', (50, 55))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (59, 84))	('COAD', 'Disease', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('glioblastoma multiforme', 'Disease', (96, 119))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('high TEMMB', 'Var', (45, 55))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (96, 119))
102505	30890735	High TEMMB correlated with improved survival in skin cutaneous melanoma (SKCM): HR = 0.71 [0.60-0.85], p = 0.0002, bladder urothelial carcinoma (BLCA): HR = 0.74 [0.59-0.93], p = 0.01, and ovarian carcinoma (OV): HR = 0.80 [0.70-0.93], p = 0.003.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (48, 71))	('improved', 'PosReg', (27, 35))	('OV', 'Phenotype', 'HP:0025318', (208, 210))	('TEMMB', 'Chemical', '-', (5, 10))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('survival', 'MPA', (36, 44))	('skin cutaneous melanoma', 'Disease', (48, 71))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (189, 206))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (53, 71))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (189, 206))	('High TEMMB', 'Var', (0, 10))	('ovarian carcinoma', 'Disease', (189, 206))
102506	30890735	High TEMMB was associated with decreased survival in colorectal adenocarcinoma (COAD): HR = 1.32 [1.00-1.74], p < 0.05 (p = 0.0497).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (53, 78))	('TEMMB', 'Chemical', '-', (5, 10))	('decreased', 'NegReg', (31, 40))	('COAD', 'Disease', (80, 84))	('colorectal adenocarcinoma', 'Disease', (53, 78))	('High TEMMB', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('COAD', 'Disease', 'MESH:D029424', (80, 84))
102508	30890735	To characterize the somatic mutational profile of each cancer, we determined the relative burden of recurrent mutations to total mutations within each cohort, expressed as a recurrence score (RS).	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (110, 119))	('cancer', 'Disease', (55, 61))
102510	30890735	Several cohorts, notably adrenocortical carcinoma (ACC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), pheochromocytoma and paraganglioma (PCPG), thyroid carcinoma (THCA), thymoma (THYM), and uveal melanoma (UVM), revealed mutations occurring at high prevalence among the sequenced population.	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('UVM', 'Phenotype', 'HP:0007716', (225, 228))	('glioma', 'Disease', (148, 154))	('THCA', 'Phenotype', 'HP:0002890', (182, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (63, 79))	('glioma', 'Disease', 'MESH:D005910', (148, 154))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (57, 79))	('uveal melanoma', 'Disease', 'MESH:C536494', (209, 223))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (57, 79))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (163, 180))	('uveal melanoma', 'Disease', (209, 223))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (25, 49))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('mutations', 'Var', (240, 249))	('thyroid carcinoma', 'Disease', (163, 180))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (120, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('glioma', 'Phenotype', 'HP:0009733', (148, 154))	('glioma', 'Disease', (106, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('uveal melanoma', 'Phenotype', 'HP:0007716', (209, 223))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (25, 49))	('glioma', 'Disease', 'MESH:D005910', (106, 112))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (163, 180))	('thymoma', 'Disease', 'MESH:D013945', (189, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adrenocortical carcinoma', 'Disease', (25, 49))	('THYM', 'Phenotype', 'HP:0100522', (198, 202))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('acute myeloid leukemia', 'Disease', (57, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('thymoma', 'Disease', (189, 196))	('ACC', 'Phenotype', 'HP:0006744', (51, 54))	('thymoma', 'Phenotype', 'HP:0100522', (189, 196))
102511	30890735	The recurrent mutations can be readily visualized as sharp peaks in the cancers' mutational profiles.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('mutations', 'Var', (14, 23))
102514	30890735	In the adrenocortical carcinoma (ACC) cohort, 0.29% of all pooled missense mutations were in the ZNF517 gene (p.V349A), and 0.29% of missense mutations were recurrent GARS (p.P42A) mutations.	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (7, 31))	('ZNF517', 'Gene', '340385', (97, 103))	('ZNF517', 'Gene', (97, 103))	('missense mutations', 'Var', (133, 151))	('ACC', 'Phenotype', 'HP:0006744', (33, 36))	('missense mutations', 'Var', (66, 84))	('p.V349A', 'Mutation', 'rs2976653', (110, 117))	('p.P42A', 'Mutation', 'rs1049402', (173, 179))	('adrenocortical carcinoma', 'Disease', (7, 31))	('GARS', 'Gene', '2617', (167, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('GARS', 'Gene', (167, 171))	('p.P42A', 'Var', (173, 179))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (7, 31))
102515	30890735	In uveal melanoma (UVM) cohort, 2.54% were recurrent GNA11 (p.Q209P) mutations, 2.01% were recurrent GNAQ p.Q209P, and 0.75% GNAQ p.Q1209L.	('uveal melanoma', 'Disease', (3, 17))	('p.Q1209L', 'Var', (130, 138))	('GNA11', 'Gene', (53, 58))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('GNA11', 'Gene', '2767', (53, 58))	('p.Q209P', 'Mutation', 'rs1057519742', (106, 113))	('p.Q209P', 'Mutation', 'rs1057519742', (60, 67))	('UVM', 'Phenotype', 'HP:0007716', (19, 22))	('p.Q1209L', 'Mutation', 'p.Q1209L', (130, 138))	('p.Q209P', 'Var', (106, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))	('uveal melanoma', 'Disease', 'MESH:C536494', (3, 17))
102516	30890735	In thyroid carcinoma (THCA), 5.23% were BRAF p.V600E, 0.65% were NRAS p.Q61R, and 0.25% HRAS p.Q61R.	('p.Q61R', 'Mutation', 'rs755829919', (70, 76))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('thyroid carcinoma', 'Disease', (3, 20))	('THCA', 'Phenotype', 'HP:0002890', (22, 26))	('p.Q61R', 'Mutation', 'rs755829919', (93, 99))	('p.V600E', 'Mutation', 'p.V600E', (45, 52))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (3, 20))	('p.V600E', 'Var', (45, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
102517	30890735	In the acute myeloid leukemia (LAML) cohort, 1.38% of missense mutations were in DNMT3A gene (p.R882H), 1.05% were IDH2 p.R140Q, and 0.79% were IDH1 p.R132C.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (7, 29))	('p.R882H', 'Mutation', 'rs147001633', (94, 101))	('leukemia', 'Phenotype', 'HP:0001909', (21, 29))	('missense mutations', 'Var', (54, 72))	('DNMT3A', 'Gene', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (7, 29))	('DNMT3A', 'Gene', '1788', (81, 87))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (13, 29))	('p.R140Q', 'Var', (120, 127))	('p.R132C', 'Mutation', 'rs121913499', (149, 156))	('p.R140Q', 'Mutation', 'rs121913502', (120, 127))	('acute myeloid leukemia', 'Disease', (7, 29))
102518	30890735	In pheochromocytoma and paraganglioma (PCPG), 0.64% of mutations were recurrent HRAS p.Q61R, and 0.36% were CHEK2 p.K152E.	('p.Q61R', 'Var', (85, 91))	('mutations', 'Var', (55, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('CHEK2', 'Gene', '11200', (108, 113))	('p.K152E', 'Mutation', 'rs74751600', (114, 121))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('p.Q61R', 'Mutation', 'rs755829919', (85, 91))	('CHEK2', 'Gene', (108, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (3, 19))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (3, 37))
102520	30890735	Cancers with low RS tended to exhibit survival benefit (HR < 1) with increased adjusted-TEMMB.	('adjusted-TEMMB', 'Var', (79, 93))	('increased', 'PosReg', (69, 78))	('TEMMB', 'Chemical', '-', (88, 93))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival benefit', 'CPA', (38, 54))
102521	30890735	Conversely, cancers with high RS were observed to have a decrease in survival (HR > 1) with increased adjusted-TEMMB.	('decrease', 'NegReg', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('high RS', 'Var', (25, 32))	('cancers', 'Disease', (12, 19))	('increased', 'PosReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('adjusted-TEMMB', 'Var', (102, 116))	('TEMMB', 'Chemical', '-', (111, 116))	('survival', 'MPA', (69, 77))
102522	30890735	Exonic missense mutation distribution displays considerable variability among cancers studied in TCGA.	('Exonic missense mutation', 'Var', (0, 24))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
102524	30890735	Somatic missense mutations strongly contribute to the generation of novel tumor epitopes.	('tumor epitopes', 'Disease', (74, 88))	('tumor epitopes', 'Disease', 'MESH:D009369', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('missense mutations', 'Var', (8, 26))
102529	30890735	Interestingly, low tumor stage was correlated (after Bonferroni adjustment) with high TEMMB in breast carcinoma, colon and rectal adenocarcinoma, and uveal melanoma.	('breast carcinoma', 'Disease', 'MESH:D001943', (95, 111))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('high TEMMB', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('low tumor', 'Disease', 'MESH:D009800', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('low tumor', 'Disease', (15, 24))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (150, 164))	('uveal melanoma', 'Disease', (150, 164))	('uveal melanoma', 'Disease', 'MESH:C536494', (150, 164))	('colon and rectal adenocarcinoma', 'Disease', 'MESH:D012004', (113, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('TEMMB', 'Chemical', '-', (86, 91))	('breast carcinoma', 'Disease', (95, 111))
102536	30890735	Given the high propensity for rapid metastasis in uveal melanoma, it is possible that intercepting such tumors at an early stage may partially be explained by a higher mutational load and thus more favorable immune response.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutational load', 'Var', (168, 183))	('immune response', 'biological_process', 'GO:0006955', ('208', '223'))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('uveal melanoma', 'Phenotype', 'HP:0007716', (50, 64))	('uveal melanoma', 'Disease', 'MESH:C536494', (50, 64))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('uveal melanoma', 'Disease', (50, 64))	('higher', 'PosReg', (161, 167))
102537	30890735	Driver mutations impart tumor growth advantage and are positively selected in cancer evolution, while biologically inert passengers accumulate without directional selection over the tumor growth timespan.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (24, 29))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (7, 16))
102538	30890735	Many established bioinformatics methods to study drivers rely on techniques that identify recurrent mutations, and thus we quantified recurrent and non-recurrent mutations to serve as proxy for relative amounts of drivers and passengers within a cancer type.	('cancer', 'Disease', (246, 252))	('mutations', 'Var', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))
102539	30890735	Our results suggest high TEMMB tends to confer survival benefit in cancers with more non-recurrent (likely passenger) mutations, and decreased survival in cancers with high recurrent (likely driver) fractions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (118, 127))	('benefit', 'PosReg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('survival', 'MPA', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('TEMMB', 'Chemical', '-', (25, 30))	('cancers', 'Disease', (155, 162))	('decreased', 'NegReg', (133, 142))
102540	30890735	We propose that in malignancies with large enrichments of non-recurrent mutations, high TEMMB marks a high passenger count, and increasing passenger mutation load increases neoantigen presentation without imparting additional growth advantage or aggressiveness.	('aggressiveness', 'Disease', (246, 260))	('malignancies', 'Disease', (19, 31))	('TEMMB', 'Chemical', '-', (88, 93))	('passenger mutation load', 'Var', (139, 162))	('aggressiveness', 'Phenotype', 'HP:0000718', (246, 260))	('increases', 'PosReg', (163, 172))	('aggressiveness', 'Disease', 'MESH:D001523', (246, 260))	('increasing', 'PosReg', (128, 138))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('neoantigen presentation', 'MPA', (173, 196))
102541	30890735	Our observed benefit with high TEMMB supports literature findings for melanoma and ovarian carcinoma.	('melanoma', 'Disease', (70, 78))	('ovarian carcinoma', 'Disease', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('high TEMMB', 'Var', (26, 36))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (83, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (83, 100))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('TEMMB', 'Chemical', '-', (31, 36))	('benefit', 'PosReg', (13, 20))
102544	30890735	Recent work has suggested a "double-edged" effect of increased DNA variants, noting that on the one hand, high DNA variation increases accumulation of drivers which are beneficial to tumor adaptation; conversely, high concurrent passenger loads may outweigh the driver effects.	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('high', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('tumor', 'Disease', (183, 188))	('accumulation', 'MPA', (135, 147))
102557	30890735	Cancers with higher proportions of non-recurrent and thus likely passenger mutations showed survival benefit with high TEMMB, while cancers with higher recurrent mutation fractions (likely drivers) revealed a decrease in survival.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('decrease', 'NegReg', (209, 217))	('TEMMB', 'Chemical', '-', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('benefit', 'PosReg', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('survival', 'MPA', (92, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('high TEMMB', 'Var', (114, 124))
102558	30890735	Mutational signatures for some cancers might contribute significantly to overall TEMMB (e.g.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TEMMB', 'Disease', (81, 86))	('TEMMB', 'Chemical', '-', (81, 86))	('contribute', 'Reg', (45, 55))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('Mutational signatures', 'Var', (0, 21))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
102577	30890735	We aggregated all nonsynonymous missense mutations among all individuals in each cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('nonsynonymous missense mutations', 'Var', (18, 50))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
102578	30890735	A somatic recurrence score (RS) was calculated as the fraction of total mutations in the cohort's pool comprised by recurrent mutations as defined above: A RS was assigned to each cancer type, and the correlation between log10-adjusted survival HR and log10-adjusted RS was computed with Pearson's correlation.	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('mutations', 'Var', (126, 135))
102669	28487750	Depth of invasion seems to be the most important risk factor in determining risk of metastasis, as shown by van Geel in the study that proved that patients with a Breslow < 3.5 mm presented better survival and it was Sanchez-Ortiz in the 2005 study that reported that patients with a Breslow <= 1.5 mm did not present pathological lymph node disease regardless of the initial clinical adenopathies.	('patients', 'Species', '9606', (268, 276))	('adenopathies', 'Disease', 'MESH:D000072281', (385, 397))	('lymph node disease', 'Phenotype', 'HP:0002733', (331, 349))	('adenopathies', 'Disease', (385, 397))	('patients', 'Species', '9606', (147, 155))	('lymph node disease', 'Disease', 'MESH:D000072717', (331, 349))	('Breslow', 'Var', (163, 170))	('better', 'PosReg', (190, 196))	('lymph node disease', 'Disease', (331, 349))	('survival', 'CPA', (197, 205))
102674	28487750	It is the case of a patient (case 1) who underwent wide local resection at another institution for infiltrating melanoma with a Breslow of 3.2 mm, positive lymphovascular invasion, the presence of ulceration and mitosis index 2 and a month later had broadening of margins with results for melanosis and a bilateral inguinocrural dissection (BICD) with a result of 16/40 positive lymph nodes, none with macro metastasis.	('presence', 'Var', (185, 193))	('melanosis', 'Disease', (289, 298))	('mitosis', 'biological_process', 'GO:0000278', ('212', '219'))	('BICD', 'Chemical', '-', (341, 345))	('bilateral inguinocrural', 'Disease', 'MESH:D006312', (305, 328))	('ulceration', 'Gene', (197, 207))	('bilateral inguinocrural', 'Disease', (305, 328))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('patient', 'Species', '9606', (20, 27))	('mitosis', 'Disease', (212, 219))	('melanoma', 'Disease', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanosis', 'Disease', 'MESH:D008548', (289, 298))	('mitosis', 'Disease', 'None', (212, 219))
102698	28487750	Since 20% of mucosal melanoma display c-Kit mutations, c-Kit tyrosine kinase inhibitors could be of some use, although the molecular data gathered do not specify this information, since this is a retrospective study.	('mucosal melanoma', 'Disease', (13, 29))	('mucosal melanoma', 'Disease', 'MESH:D008545', (13, 29))	('c-Kit', 'Gene', (38, 43))	('mutations', 'Var', (44, 53))	('c-Kit', 'Gene', '3815', (38, 43))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('c-Kit', 'Gene', (55, 60))	('c-Kit', 'Gene', '3815', (55, 60))
102705	33898322	GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells We defined the lethal interaction between the novel therapeutic GZ17-6.02 and the standard of care combination of the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib in PDX isolates of cutaneous melanoma expressing a mutant B-RAF V600E protein.	('cutaneous melanoma', 'Disease', (278, 296))	('trametinib', 'Chemical', 'MESH:C560077', (213, 223))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (278, 296))	('B-RAF', 'Gene', (37, 42))	('Melanoma', 'Disease', 'MESH:D008545', (63, 71))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (278, 296))	('dabrafenib', 'Chemical', 'MESH:C561627', (248, 258))	('B-RAF', 'Gene', '673', (232, 237))	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('MEK1/2', 'Gene', (196, 202))	('V600E', 'Var', (323, 328))	('GZ17-6', 'Chemical', '-', (0, 6))	('mutant', 'Var', (310, 316))	('B-RAF', 'Gene', '673', (317, 322))	('Melanoma', 'Disease', (63, 71))	('GZ17-6', 'Chemical', '-', (142, 148))	('MEK1', 'molecular_function', 'GO:0004708', ('26', '30'))	('protein', 'cellular_component', 'GO:0003675', ('329', '336'))	('B-RAF', 'Gene', (232, 237))	('Melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('MEK1/2', 'Gene', '5604;5605', (26, 32))	('MEK1/2', 'Gene', (26, 32))	('B-RAF', 'Gene', (317, 322))	('protein', 'Protein', (329, 336))	('B-RAF', 'Gene', '673', (37, 42))	('GZ17-6.02', 'Chemical', '-', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('GZ17-6.02', 'Chemical', '-', (142, 151))	('V600E', 'Mutation', 'rs113488022', (323, 328))	('MEK1', 'molecular_function', 'GO:0004708', ('196', '200'))
102707	33898322	Regardless of prior vemurafenib resistance, the drugs when combined interacted to prolong ATM S1981/AMPK T172 and eIF2alpha S51 phosphorylation and prolong the reduced phosphorylation of JAK2 Y1007, STAT3 Y705 and STAT5 Y694.	('vemurafenib', 'Chemical', 'MESH:D000077484', (20, 31))	('AMPK', 'molecular_function', 'GO:0004691', ('100', '104'))	('phosphorylation', 'MPA', (168, 183))	('STAT3', 'Gene', '6774', (199, 204))	('JAK', 'molecular_function', 'GO:0004713', ('187', '190'))	('phosphorylation', 'MPA', (128, 143))	('prolong', 'PosReg', (82, 89))	('AMPK', 'molecular_function', 'GO:0047322', ('100', '104'))	('reduced', 'NegReg', (160, 167))	('JAK2', 'Gene', '3717', (187, 191))	('eIF2', 'cellular_component', 'GO:0005850', ('114', '118'))	('STAT5 Y694', 'Var', (214, 224))	('ATM', 'Gene', '472', (90, 93))	('AMPK', 'Gene', '5563', (100, 104))	('phosphorylation', 'biological_process', 'GO:0016310', ('168', '183'))	('JAK2', 'Gene', (187, 191))	('phosphorylation', 'biological_process', 'GO:0016310', ('128', '143'))	('AMPK', 'molecular_function', 'GO:0050405', ('100', '104'))	('eIF2alpha', 'Gene', (114, 123))	('AMPK', 'Gene', (100, 104))	('eIF2alpha', 'Gene', '83939', (114, 123))	('ATM', 'Gene', (90, 93))	('STAT3', 'Gene', (199, 204))
102708	33898322	In vemurafenib-resistant cells GZ17-6.02 caused a prolonged reduction in mTORC1 S2448, mTORC2 S2481 and ULK1 S757 phosphorylation; regardless of vemurafenib resistance, GZ17-6.02 caused a prolonged elevation in CD95 and FAS-L expression.	('vemurafenib', 'Chemical', 'MESH:D000077484', (145, 156))	('GZ17-6.02', 'Chemical', '-', (31, 40))	('CD95', 'Gene', '355', (211, 215))	('GZ17-6.02', 'Var', (31, 40))	('reduction', 'NegReg', (60, 69))	('mTORC1', 'cellular_component', 'GO:0031931', ('73', '79'))	('mTORC2', 'Gene', (87, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('mTORC1', 'Gene', (73, 79))	('CD95', 'Gene', (211, 215))	('ULK1', 'Gene', '8408', (104, 108))	('mTORC1', 'Gene', '382056', (73, 79))	('FAS-L', 'Gene', (220, 225))	('mTORC2', 'cellular_component', 'GO:0031932', ('87', '93'))	('GZ17-6.02', 'Chemical', '-', (169, 178))	('ULK1', 'Gene', (104, 108))	('mTORC2', 'Gene', '74343', (87, 93))	('elevation', 'PosReg', (198, 207))	('FAS-L', 'Gene', '356', (220, 225))	('GZ17-6.02', 'Var', (169, 178))	('phosphorylation', 'MPA', (114, 129))	('vemurafenib', 'Chemical', 'MESH:D000077484', (3, 14))
102709	33898322	Knock down of eIF2alpha, Beclin1, ATG5, ATM, AMPKalpha, CD95 or FADD significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with the kinase inhibitors.	('reduced', 'NegReg', (83, 90))	('CD95', 'Gene', (56, 60))	('eIF2alpha', 'Gene', (14, 23))	('ATM', 'Gene', (40, 43))	('Beclin1', 'Gene', (25, 32))	('ATG5', 'Gene', (34, 38))	('eIF2alpha', 'Gene', '83939', (14, 23))	('eIF2', 'cellular_component', 'GO:0005850', ('14', '18'))	('Knock down', 'Var', (0, 10))	('FADD', 'Gene', '8772', (64, 68))	('GZ17-6.02', 'Chemical', '-', (106, 115))	('AMPK', 'Gene', '5563', (45, 49))	('ability', 'MPA', (95, 102))	('CD95', 'Gene', '355', (56, 60))	('AMPK', 'Gene', (45, 49))	('ATM', 'Gene', '472', (40, 43))	('Beclin1', 'Gene', '8678', (25, 32))	('ATG5', 'Gene', '9474', (34, 38))	('FADD', 'Gene', (64, 68))
102712	33898322	Our findings support the use of GZ17-6.02 in combination with trametinib/dabrafenib in the treatment of melanomas expressing mutant B-RAF V600E proteins.	('melanomas', 'Phenotype', 'HP:0002861', (104, 113))	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('B-RAF', 'Gene', (132, 137))	('dabrafenib', 'Chemical', 'MESH:C561627', (73, 83))	('melanomas', 'Disease', 'MESH:D008545', (104, 113))	('V600E', 'Var', (138, 143))	('trametinib', 'Chemical', 'MESH:C560077', (62, 72))	('melanomas', 'Disease', (104, 113))	('B-RAF', 'Gene', '673', (132, 137))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('proteins', 'Protein', (144, 152))	('GZ17-6.02', 'Chemical', '-', (32, 41))
102713	33898322	Great strides have been made over the past 10 years in the treatment of cutaneous melanoma particularly in the use of checkpoint inhibitory immunotherapy and in tumors expressing mutant B-RAF V600E, the combined use of B-RAF and MEK1/2 inhibitors.	('cutaneous melanoma', 'Disease', (72, 90))	('mutant', 'Var', (179, 185))	('MEK1', 'molecular_function', 'GO:0004708', ('229', '233'))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('B-RAF', 'Gene', '673', (219, 224))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (72, 90))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (72, 90))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('MEK1/2', 'Gene', '5604;5605', (229, 235))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MEK1/2', 'Gene', (229, 235))	('B-RAF', 'Gene', (219, 224))	('B-RAF', 'Gene', '673', (186, 191))	('V600E', 'Var', (192, 197))	('B-RAF', 'Gene', (186, 191))
102716	33898322	To combat mutant B-RAF, specific inhibitors of the mutated B-RAF V600E protein were developed, e.g.	('V600E', 'Var', (65, 70))	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('B-RAF', 'Gene', '673', (59, 64))	('B-RAF', 'Gene', '673', (17, 22))	('B-RAF', 'Gene', (17, 22))	('B-RAF', 'Gene', (59, 64))	('V600E', 'Mutation', 'rs113488022', (65, 70))
102718	33898322	Subsequently, it was discovered that the use of the specific mutant B-RAF inhibitors caused activation of RAF-1 and reactivation of the ERK1/2 pathway.	('B-RAF', 'Gene', '673', (68, 73))	('activation', 'PosReg', (92, 102))	('ERK1', 'molecular_function', 'GO:0004707', ('136', '140'))	('RAF-1', 'Gene', (106, 111))	('B-RAF', 'Gene', (68, 73))	('mutant', 'Var', (61, 67))	('RAF-1', 'Gene', '5894', (106, 111))	('ERK1/2', 'Gene', (136, 142))	('ERK1/2', 'Gene', '5595;5594', (136, 142))
102719	33898322	Hence, the therapeutic modality of combined mutant B-RAF inhibition with MEK1/2 inhibition was developed, e.g.	('MEK1/2', 'Gene', '5604;5605', (73, 79))	('inhibition', 'NegReg', (57, 67))	('MEK1/2', 'Gene', (73, 79))	('B-RAF', 'Gene', '673', (51, 56))	('MEK1', 'molecular_function', 'GO:0004708', ('73', '77'))	('mutant', 'Var', (44, 50))	('B-RAF', 'Gene', (51, 56))
102721	33898322	However, despite an initial response of mutant B-RAF V600E cutaneous melanoma cells to the kinase inhibitory drug combination, tumor cells within 12-18 months eventually become drug-resistant and clinical progression occurs.	('B-RAF', 'Gene', '673', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cutaneous melanoma', 'Disease', (59, 77))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('tumor', 'Disease', (127, 132))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (59, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (59, 77))	('B-RAF', 'Gene', (47, 52))	('drug-resistant', 'MPA', (177, 191))	('mutant', 'Var', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
102722	33898322	Thus, novel alternative approaches are still required to attack drug-resistant mutant B-RAF V600E melanoma, and to increase its sensitivity to immunotherapy.	('V600E', 'Mutation', 'rs113488022', (92, 97))	('increase', 'PosReg', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('V600E', 'Var', (92, 97))	('B-RAF', 'Gene', '673', (86, 91))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('B-RAF', 'Gene', (86, 91))
102737	33898322	Mutants defective in nucleotide excision repair, in error-prone repair and in recombinational repair had enhanced sensitivity to harmine, with Rad1/Rad6 double mutants demonstrating that both NER and error-prone repair are independently involved in repair of harmine-induced DNA lesions.	('Rad', 'biological_process', 'GO:1990116', ('148', '151'))	('error-prone', 'MPA', (52, 63))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('21', '47'))	('Rad', 'biological_process', 'GO:1990116', ('143', '146'))	('defective', 'NegReg', (8, 17))	('harmine', 'Chemical', 'MESH:D006247', (259, 266))	('recombinational repair', 'biological_process', 'GO:0000725', ('78', '100'))	('harmine', 'Chemical', 'MESH:D006247', (129, 136))	('Rad1', 'Gene', '5810', (143, 147))	('nucleotide excision repair', 'MPA', (21, 47))	('NER', 'biological_process', 'GO:0006289', ('192', '195'))	('DNA', 'cellular_component', 'GO:0005574', ('275', '278'))	('rat', 'Species', '10116', (175, 178))	('sensitivity to harmine', 'MPA', (114, 136))	('Rad1', 'Gene', (143, 147))	('enhanced', 'PosReg', (105, 113))	('Mutants', 'Var', (0, 7))
102738	33898322	In general agreement with these findings, harmine has also been shown to increase the numbers of micronuclei in eukaryotic cells and in the traditional Ames test, harmine-induced frameshift mutations in S. typhimurium strains TA97 and TA98.	('frameshift mutations', 'Var', (179, 199))	('harmine', 'Chemical', 'MESH:D006247', (42, 49))	('harmine', 'Chemical', 'MESH:D006247', (163, 170))	('S. typhimurium', 'Species', '90371', (203, 217))	('micronuclei in eukaryotic cells', 'CPA', (97, 128))
102739	33898322	We have published that GZ17-6.02 killed GI tumor cells and interacted with 5-fluorouracil (5FU) to further enhance tumor cell death in vitro and in vivo.	('GI tumor', 'Phenotype', 'HP:0007378', (40, 48))	('interacted', 'Interaction', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('GI tumor', 'Disease', (40, 48))	('cell death', 'biological_process', 'GO:0008219', ('121', '131'))	('tumor', 'Disease', (115, 120))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (75, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('5FU', 'Chemical', 'MESH:D005472', (91, 94))	('enhance', 'PosReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Disease', (43, 48))	('GI tumor', 'Disease', 'MESH:D009369', (40, 48))	('GZ17-6.02', 'Chemical', '-', (23, 32))	('GZ17-6.02', 'Var', (23, 32))
102740	33898322	In GI tumor cells GZ17-6.02 activated an ATM-AMPK signaling module which was responsible for inactivation of mTORC1 and mTORC2, dephosphorylation of ULK1 S757, and increased phosphorylation of ULK1 S317 and of ATG13 S318.	('ATG13', 'Gene', (210, 215))	('ULK1', 'Gene', '8408', (149, 153))	('mTORC2', 'Gene', (120, 126))	('mTORC1', 'cellular_component', 'GO:0031931', ('109', '115'))	('ATM', 'Gene', (41, 44))	('AMPK', 'molecular_function', 'GO:0004691', ('45', '49'))	('S318', 'Var', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('increased', 'PosReg', (164, 173))	('GI tumor', 'Disease', 'MESH:D009369', (3, 11))	('ULK1', 'Gene', (149, 153))	('phosphorylation', 'MPA', (174, 189))	('ULK1', 'Gene', '8408', (193, 197))	('GI tumor', 'Phenotype', 'HP:0007378', (3, 11))	('dephosphorylation', 'MPA', (128, 145))	('mTORC2', 'Gene', '74343', (120, 126))	('S757', 'Var', (154, 158))	('S317', 'Var', (198, 202))	('AMPK', 'molecular_function', 'GO:0047322', ('45', '49'))	('ULK1', 'Gene', (193, 197))	('AMPK', 'Gene', '5563', (45, 49))	('ATG13', 'Gene', '9776', (210, 215))	('mTORC2', 'cellular_component', 'GO:0031932', ('120', '126'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('128', '145'))	('phosphorylation', 'biological_process', 'GO:0016310', ('174', '189'))	('GZ17-6.02', 'Chemical', '-', (18, 27))	('GI tumor', 'Disease', (3, 11))	('ATM', 'Gene', '472', (41, 44))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('inactivation', 'NegReg', (93, 105))	('mTORC1', 'Gene', (109, 115))	('AMPK', 'Gene', (45, 49))	('AMPK', 'molecular_function', 'GO:0050405', ('45', '49'))	('mTORC1', 'Gene', '382056', (109, 115))
102741	33898322	GZ17-6.02 and 5FU caused greater ATM activation, more autophagosome formation and more killing; knock down of ULK1, Beclin1 or ATG5 suppressed the lethality of GZ17-6.02.	('ATG5', 'Gene', (127, 131))	('ULK1', 'Gene', (110, 114))	('knock down', 'Var', (96, 106))	('ULK1', 'Gene', '8408', (110, 114))	('Beclin1', 'Gene', (116, 123))	('5FU', 'Chemical', 'MESH:D005472', (14, 17))	('GZ17-6.02', 'Chemical', '-', (0, 9))	('autophagosome', 'cellular_component', 'GO:0005776', ('54', '67'))	('ATM', 'Gene', (33, 36))	('ATM', 'Gene', '472', (33, 36))	('autophagosome formation', 'biological_process', 'GO:0000045', ('54', '77'))	('ATG5', 'Gene', '9474', (127, 131))	('autophagosome formation', 'CPA', (54, 77))	('Beclin1', 'Gene', '8678', (116, 123))	('GZ17-6.02', 'Chemical', '-', (160, 169))	('killing', 'CPA', (87, 94))	('suppressed', 'NegReg', (132, 142))
102742	33898322	The present studies were performed to determine whether GZ17-6.02 alone or combined with the standard of care drugs [trametinib + dabrafenib] killed cutaneous melanoma cells expressing mutant B-RAF V600E and then to define the multiple mechanisms by which cell death occurred.	('mutant', 'Var', (185, 191))	('B-RAF', 'Gene', '673', (192, 197))	('V600E', 'Mutation', 'rs113488022', (198, 203))	('cutaneous melanoma', 'Disease', (149, 167))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('dabrafenib', 'Chemical', 'MESH:C561627', (130, 140))	('GZ17-6.02', 'Chemical', '-', (56, 65))	('trametinib', 'Chemical', 'MESH:C560077', (117, 127))	('B-RAF', 'Gene', (192, 197))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (149, 167))	('cell death', 'biological_process', 'GO:0008219', ('256', '266'))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
102743	33898322	PDX (patient derived xenograft) cutaneous B-RAF V600E melanoma isolates were sub-cultured from the patient into the flanks of NRG mice; they were supplied by Dr. Kirkwood from the University of Pittsburgh cell bank: TPF-8-196 (MEL1), TPF-12-293 (MEL2), TPF-12-510 (MEL3), TPF-12-198 (MEL4), TPF-12-542 (MEL5), TPF-11-1081 (MEL6).	('patient', 'Species', '9606', (99, 106))	('mice', 'Species', '10090', (130, 134))	('patient', 'Species', '9606', (5, 12))	('B-RAF', 'Gene', '673', (42, 47))	('TPF-12-542', 'Var', (291, 301))	('TPF-12-510', 'Var', (253, 263))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('MEL4', 'CellLine', 'CVCL:B866', (284, 288))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('B-RAF', 'Gene', (42, 47))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('TPF-12-198', 'Var', (272, 282))	('TPF-11-1081', 'Var', (310, 321))	('TPF-12-293', 'CellLine', 'CVCL:0045', (234, 244))
102746	33898322	Antibodies used: AIF (5318), BAX (5023), BAK (12105), BAD (9239), BIM (2933), BAK1 (12105), Beclin1 (3495), cathepsin B (31718), CD95 (8023), FADD (2782), eIF2alpha (5324), P-eIF2alpha S51 (3398), ULK-1 (8054), P-ULK-1 S757 (14202), P-AMPK S51 (2535), AMPKalpha (2532), P-ATM S1981 (13050), ATM (2873), ATG5 (12994), mTOR (2983), P-mTOR S2448 (5536), P-mTOR S2481 (2974), ATG13 (13468), MCL-1 (94296), BCL-XL (2764), P-AKT T308 (13038), P-ERK1/2 (5726), P-STAT3 Y705 (9145), P-p65 S536 (3033), p62 (23214), LAMP2 (49067) all from Cell Signaling Technology (Danvers, MA); P-ULK-1 S317 (3803a) was from Abgent; P-ATG13 S318 (19127) from Novus Biologicals.	('ULK-1', 'Gene', (573, 578))	('BAK', 'Gene', (41, 44))	('Beclin1', 'Gene', (92, 99))	('eIF2alpha', 'Gene', '83939', (175, 184))	('AMPK', 'Gene', (235, 239))	('ATG13', 'Gene', '9776', (611, 616))	('cathepsin B', 'Gene', (108, 119))	('AMPK', 'Gene', (252, 256))	('BAK', 'Gene', '578', (41, 44))	('LAMP2', 'Gene', (507, 512))	('FADD', 'Gene', (142, 146))	('ULK-1', 'Gene', '8408', (213, 218))	('eIF2', 'cellular_component', 'GO:0005850', ('175', '179'))	('AMPK', 'molecular_function', 'GO:0047322', ('235', '239'))	('ATM', 'Gene', (272, 275))	('ATG5', 'Gene', '9474', (303, 307))	('mTOR', 'Gene', '2475', (353, 357))	('cathepsin B', 'Gene', '1508', (108, 119))	('BIM', 'Gene', '10018', (66, 69))	('ATG13', 'Gene', (372, 377))	('ULK-1', 'Gene', (213, 218))	('AKT', 'Gene', (419, 422))	('ULK-1', 'Gene', '8408', (197, 202))	('ERK1/2', 'Gene', (439, 445))	('ATG5', 'Gene', (303, 307))	('AMPK', 'molecular_function', 'GO:0050405', ('235', '239'))	('CD95', 'Gene', '355', (129, 133))	('ULK-1', 'Gene', (197, 202))	('BAK', 'Gene', (78, 81))	('ATM', 'Gene', '472', (291, 294))	('ATG13', 'Gene', (611, 616))	('eIF2', 'cellular_component', 'GO:0005850', ('155', '159'))	('BAK', 'Gene', '578', (78, 81))	('mTOR', 'Gene', (317, 321))	('ERK1', 'molecular_function', 'GO:0004707', ('439', '443'))	('BCL-XL', 'Gene', (402, 408))	('eIF2alpha', 'Gene', (155, 164))	('ERK1/2', 'Gene', '5595;5594', (439, 445))	('FADD', 'Gene', '8772', (142, 146))	('Beclin1', 'Gene', '8678', (92, 99))	('P-p65', 'Var', (475, 480))	('Signaling', 'biological_process', 'GO:0023052', ('535', '544'))	('eIF2alpha', 'Gene', '83939', (155, 164))	('AKT', 'Gene', '207', (419, 422))	('LAMP2', 'Gene', '3920', (507, 512))	('mTOR', 'Gene', (332, 336))	('AMPK', 'Gene', '5563', (235, 239))	('BAK1', 'Gene', '578', (78, 82))	('p62', 'Gene', '23636', (494, 497))	('AMPK', 'molecular_function', 'GO:0004691', ('235', '239'))	('BAX', 'Gene', (29, 32))	('p62', 'Gene', (494, 497))	('BAX', 'Gene', '581', (29, 32))	('AMPK', 'Gene', '5563', (252, 256))	('STAT3', 'Gene', (456, 461))	('mTOR', 'Gene', '2475', (317, 321))	('CD95', 'Gene', (129, 133))	('ATM', 'Gene', '472', (272, 275))	('BAK1', 'Gene', (78, 82))	('ATG13', 'Gene', '9776', (372, 377))	('ATM', 'Gene', (291, 294))	('ULK-1', 'Gene', '8408', (573, 578))	('mTOR', 'Gene', '2475', (332, 336))	('mTOR', 'Gene', (353, 357))	('BCL-XL', 'Gene', '598', (402, 408))	('STAT3', 'Gene', '6774', (456, 461))	('eIF2alpha', 'Gene', (175, 184))	('BIM', 'Gene', (66, 69))
102749	33898322	Specific multiple independent siRNAs to knock down the expression of CD95, FADD, Beclin1, ATG5 and eIF2alpha, and scramble control, were purchased from Qiagen (Hilden Germany).	('FADD', 'Gene', (75, 79))	('CD95', 'Gene', '355', (69, 73))	('FADD', 'Gene', '8772', (75, 79))	('eIF2alpha', 'Gene', '83939', (99, 108))	('knock', 'Var', (40, 45))	('ATG5', 'Gene', '9474', (90, 94))	('Beclin1', 'Gene', '8678', (81, 88))	('ATG5', 'Gene', (90, 94))	('eIF2alpha', 'Gene', (99, 108))	('CD95', 'Gene', (69, 73))	('Beclin1', 'Gene', (81, 88))	('eIF2', 'cellular_component', 'GO:0005850', ('99', '103'))
102760	33898322	Plasmids to express FLIP-s (16016), BCL-XL (46972), dominant negative caspase 9 (11819), activated AKT (11547), activated mTOR (19994) and activated MEK1 EE (31880) were used throughout the study (Addgene, Waltham, MA).	('11547', 'Var', (104, 109))	('MEK1', 'Gene', (149, 153))	('11819', 'Var', (81, 86))	('MEK1', 'molecular_function', 'GO:0004708', ('149', '153'))	('AKT', 'Gene', '207', (99, 102))	('BCL-XL', 'Gene', '598', (36, 42))	('caspase 9', 'Gene', (70, 79))	('mTOR', 'Gene', (122, 126))	('AKT', 'Gene', (99, 102))	('mTOR', 'Gene', '2475', (122, 126))	('MEK1', 'Gene', '5604', (149, 153))	('caspase 9', 'Gene', '842', (70, 79))	('BCL-XL', 'Gene', (36, 42))
102770	33898322	GZ17-6.02, however, caused significantly more killing than curcumin alone or the additive lethal effects of harmine and curcumin.	('GZ17-6.02', 'Var', (0, 9))	('GZ17-6.02', 'Chemical', '-', (0, 9))	('curcumin', 'Chemical', 'MESH:D003474', (120, 128))	('more', 'PosReg', (41, 45))	('killing', 'MPA', (46, 53))	('curcumin', 'Chemical', 'MESH:D003474', (59, 67))	('harmine', 'Chemical', 'MESH:D006247', (108, 115))
102773	33898322	Surprisingly, using supra-physiologic concentrations of [trametinib + dabrafenib], low concentrations of GZ17-6.02 were more efficacious at killing melanoma cells ( Figure 1C ).	('GZ17-6.02', 'Var', (105, 114))	('trametinib', 'Chemical', 'MESH:C560077', (57, 67))	('rat', 'Species', '10116', (94, 97))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('GZ17-6.02', 'Chemical', '-', (105, 114))	('melanoma', 'Disease', (148, 156))	('dabrafenib', 'Chemical', 'MESH:C561627', (70, 80))	('rat', 'Species', '10116', (45, 48))
102775	33898322	We next defined over a time course the impact of GZ17-6.02, the kinase inhibitors, and the combination on cell signaling parameters in the MEL4 isolate and in the MEL2 isolate that is vemurafenib resistant.	('cell signaling', 'MPA', (106, 120))	('MEL4', 'CellLine', 'CVCL:B866', (139, 143))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('vemurafenib', 'Chemical', 'MESH:D000077484', (184, 195))	('GZ17-6.02', 'Var', (49, 58))	('GZ17-6.02', 'Chemical', '-', (49, 58))
102777	33898322	In the MEL4 isolate, after 4h, the kinase inhibitors and GZ17-6.02 interacted to reduce the phosphorylation of ULK1 S757, STAT3 Y705, STAT5 Y694 and to increase the phosphorylation of PERK T980 and eIF2alpha S51 ( Figure 2 ).	('eIF2alpha', 'Gene', '83939', (198, 207))	('ULK1', 'Gene', (111, 115))	('phosphorylation', 'MPA', (92, 107))	('STAT5 Y694', 'Var', (134, 144))	('reduce', 'NegReg', (81, 87))	('increase', 'PosReg', (152, 160))	('ULK1', 'Gene', '8408', (111, 115))	('eIF2', 'cellular_component', 'GO:0005850', ('198', '202'))	('phosphorylation', 'biological_process', 'GO:0016310', ('92', '107'))	('PERK', 'Gene', (184, 188))	('STAT3', 'Gene', '6774', (122, 127))	('phosphorylation', 'MPA', (165, 180))	('eIF2alpha', 'Gene', (198, 207))	('PERK', 'Gene', '9451', (184, 188))	('STAT3', 'Gene', (122, 127))	('MEL4', 'CellLine', 'CVCL:B866', (7, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('165', '180'))	('GZ17-6.02', 'Chemical', '-', (57, 66))
102778	33898322	In the MEL2 isolate, the combination interacted to reduce STAT3 Y705, but not STAT5 Y694, and to increase ULK1 S317 phosphorylation, but generally the effects of the individual treatments on signaling were of a lower amplitude than observed in MEL4 cells.	('ULK1', 'Gene', '8408', (106, 110))	('increase', 'PosReg', (97, 105))	('phosphorylation', 'biological_process', 'GO:0016310', ('116', '131'))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('reduce', 'NegReg', (51, 57))	('STAT3', 'Gene', '6774', (58, 63))	('ULK1', 'Gene', (106, 110))	('MEL4', 'CellLine', 'CVCL:B866', (244, 248))	('S317', 'Var', (111, 115))	('STAT3', 'Gene', (58, 63))
102780	33898322	In both isolates combination of the agents lead to a greater dephosphorylation of p70 S6K T389 and of ERK1/2 T185/Y187, and reduced HSP70 expression.	('p70 S6K', 'Gene', '6198', (82, 89))	('HSP70', 'Gene', '3308', (132, 137))	('reduced', 'NegReg', (124, 131))	('ERK1/2', 'Gene', '5595;5594', (102, 108))	('dephosphorylation', 'biological_process', 'GO:0016311', ('61', '78'))	('T185/Y187', 'Var', (109, 118))	('HSP70', 'Gene', (132, 137))	('expression', 'MPA', (138, 148))	('p70 S6K', 'Gene', (82, 89))	('dephosphorylation', 'MPA', (61, 78))	('T389', 'Var', (90, 94))	('ERK1/2', 'Gene', (102, 108))	('ERK1', 'molecular_function', 'GO:0004707', ('102', '106'))
102781	33898322	As a single agent in both isolates, GZ17-6.02 reduced the expression of FLIP-s, MCL1 and BCL-XL and increased the levels of BAX, BAD, BIM, Noxa, Puma, CHOP, CD95, FAS-L, GRP78, HSP90, Beclin1 and ATG5.	('BCL-XL', 'Gene', (89, 95))	('Beclin1', 'Gene', '8678', (184, 191))	('expression', 'MPA', (58, 68))	('CHOP', 'Gene', '1649', (151, 155))	('Puma', 'Gene', '27113', (145, 149))	('Puma', 'Gene', (145, 149))	('increased', 'PosReg', (100, 109))	('HSP90', 'Gene', '3320', (177, 182))	('GRP78', 'Gene', '3309', (170, 175))	('CD95', 'Gene', (157, 161))	('FLIP-s', 'Gene', (72, 78))	('GRP78', 'Gene', (170, 175))	('BCL-XL', 'Gene', '598', (89, 95))	('ATG5', 'Gene', '9474', (196, 200))	('CHOP', 'Gene', (151, 155))	('Beclin1', 'Gene', (184, 191))	('Noxa', 'Gene', '5366', (139, 143))	('GZ17-6.02', 'Chemical', '-', (36, 45))	('BAX', 'Gene', (124, 127))	('reduced', 'NegReg', (46, 53))	('BAX', 'Gene', '581', (124, 127))	('BIM', 'Gene', (134, 137))	('GZ17-6.02', 'Var', (36, 45))	('MCL1', 'Gene', (80, 84))	('FAS-L', 'Gene', (163, 168))	('Noxa', 'Gene', (139, 143))	('ATG5', 'Gene', (196, 200))	('levels', 'MPA', (114, 120))	('FAS-L', 'Gene', '356', (163, 168))	('BAD', 'MPA', (129, 132))	('BIM', 'Gene', '10018', (134, 137))	('CD95', 'Gene', '355', (157, 161))	('HSP90', 'Gene', (177, 182))
102783	33898322	In MEL2 cells as a single agent, and unaltered by the kinase inhibitors, GZ17-6.02 enhanced PP1 levels and decreased JAK2 phosphorylation.	('JAK2', 'Gene', (117, 121))	('GZ17-6.02', 'Var', (73, 82))	('enhanced', 'PosReg', (83, 91))	('JAK', 'molecular_function', 'GO:0004713', ('117', '120'))	('decreased', 'NegReg', (107, 116))	('GZ17-6.02', 'Chemical', '-', (73, 82))	('JAK2', 'Gene', '3717', (117, 121))	('phosphorylation', 'biological_process', 'GO:0016310', ('122', '137'))	('PP1', 'Gene', (92, 95))	('PP1', 'Gene', '5540', (92, 95))
102784	33898322	GZ17-6.02 decreased c-SRC Y416 and increased c-SRC Y527 phosphorylation, which is indicative that c-SRC was being inactivated ( Figure 4C ).	('c-SRC', 'Gene', '6714', (20, 25))	('c-SRC', 'Gene', (98, 103))	('GZ17-6.02', 'Var', (0, 9))	('decreased', 'NegReg', (10, 19))	('increased', 'PosReg', (35, 44))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('c-SRC', 'Gene', (20, 25))	('GZ17-6.02', 'Chemical', '-', (0, 9))	('c-SRC', 'Gene', '6714', (45, 50))	('Y416', 'Chemical', '-', (26, 30))	('c-SRC', 'Gene', (45, 50))	('Y527', 'Chemical', '-', (51, 55))	('Y416', 'Var', (26, 30))	('c-SRC', 'Gene', '6714', (98, 103))
102785	33898322	In both MEL2 and MEL4 cells, the drug combination maintained the phosphorylation of AMPKalpha T172 and eIF2alpha S51 and the dephosphorylation of STAT3 Y705 ( Figure 5 ).	('eIF2alpha', 'Gene', (103, 112))	('STAT3', 'Gene', (146, 151))	('S51', 'Var', (113, 116))	('AMPK', 'Gene', (84, 88))	('dephosphorylation', 'MPA', (125, 142))	('phosphorylation', 'biological_process', 'GO:0016310', ('65', '80'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('125', '142'))	('phosphorylation', 'MPA', (65, 80))	('eIF2alpha', 'Gene', '83939', (103, 112))	('MEL4', 'CellLine', 'CVCL:B866', (17, 21))	('eIF2', 'cellular_component', 'GO:0005850', ('103', '107'))	('AMPK', 'Gene', '5563', (84, 88))	('STAT3', 'Gene', '6774', (146, 151))
102790	33898322	Prior studies in other cell types have shown GZ17-6.02 killing through mechanisms using the death receptor CD95 and autophagosome formation.	('autophagosome', 'cellular_component', 'GO:0005776', ('116', '129'))	('CD95', 'Gene', '355', (107, 111))	('GZ17-6.02', 'Chemical', '-', (45, 54))	('GZ17-6.02', 'Var', (45, 54))	('autophagosome formation', 'CPA', (116, 139))	('autophagosome formation', 'biological_process', 'GO:0000045', ('116', '139'))	('CD95', 'Gene', (107, 111))
102793	33898322	Similar data were obtained knocking down ATM or AMPKalpha or knocking down CD95 or FADD.	('knocking down', 'Var', (27, 40))	('CD95', 'Gene', (75, 79))	('CD95', 'Gene', '355', (75, 79))	('AMPK', 'Gene', '5563', (48, 52))	('FADD', 'Gene', (83, 87))	('FADD', 'Gene', '8772', (83, 87))	('ATM', 'Gene', (41, 44))	('knocking down', 'Var', (61, 74))	('AMPK', 'Gene', (48, 52))	('ATM', 'Gene', '472', (41, 44))
102794	33898322	In further agreement with the CD95/FADD knock down data, over-expression of the caspase 8/10 inhibitor FLIP-s also suppressed cell death ( Figure 8 ).	('FLIP-s', 'Var', (103, 109))	('cell death', 'CPA', (126, 136))	('cell death', 'biological_process', 'GO:0008219', ('126', '136'))	('CD95', 'Gene', (30, 34))	('over-expression', 'PosReg', (57, 72))	('FADD', 'Gene', (35, 39))	('FADD', 'Gene', '8772', (35, 39))	('suppressed', 'NegReg', (115, 125))	('caspase 8/10', 'Gene', '841;843', (80, 92))	('caspase 8/10', 'Gene', (80, 92))	('CD95', 'Gene', '355', (30, 34))
102796	33898322	Expression of mutant active forms of mTOR, AKT or MEK1 significantly reduced drug combination lethality.	('MEK1', 'Gene', (50, 54))	('reduced', 'NegReg', (69, 76))	('mutant', 'Var', (14, 20))	('AKT', 'Gene', '207', (43, 46))	('reduced drug combination', 'Phenotype', 'HP:0020173', (69, 93))	('mTOR', 'Gene', (37, 41))	('mTOR', 'Gene', '2475', (37, 41))	('AKT', 'Gene', (43, 46))	('drug', 'CPA', (77, 81))	('MEK1', 'molecular_function', 'GO:0004708', ('50', '54'))	('MEK1', 'Gene', '5604', (50, 54))
102798	33898322	Endoplasmic reticulum stress, as manifested by eIF2alpha S51 phosphorylation, was maintained for at least 8h after drug exposure.	('phosphorylation', 'MPA', (61, 76))	('eIF2alpha', 'Gene', '83939', (47, 56))	('S51', 'Var', (57, 60))	('eIF2', 'cellular_component', 'GO:0005850', ('47', '51'))	('eIF2alpha', 'Gene', (47, 56))	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))
102799	33898322	Over-expression of GRP78, which inhibits PERK signaling to eIF2alpha, HSP90 or HSP70 significantly reduced the lethality of the agents individually and combined ( Figures 9A, B ).	('PERK', 'Gene', (41, 45))	('signaling', 'biological_process', 'GO:0023052', ('46', '55'))	('PERK', 'Gene', '9451', (41, 45))	('eIF2alpha', 'Gene', '83939', (59, 68))	('GRP78', 'Gene', '3309', (19, 24))	('HSP70', 'Gene', '3308', (79, 84))	('lethality', 'MPA', (111, 120))	('GRP78', 'Gene', (19, 24))	('inhibits', 'NegReg', (32, 40))	('Over-expression', 'Var', (0, 15))	('HSP90', 'Gene', (70, 75))	('HSP90', 'Gene', '3320', (70, 75))	('reduced', 'NegReg', (99, 106))	('eIF2', 'cellular_component', 'GO:0005850', ('59', '63'))	('HSP70', 'Gene', (79, 84))	('eIF2alpha', 'Gene', (59, 68))
102802	33898322	Collectively the data in  Figures 7 - 9  indicates that GZ17-6.02 and [trametinib + dabrafenib] interact to kill PDX isolates of cutaneous mutant B-RAF V600E expressing cells via activation of death receptor signaling and autophagy resulting in mitochondrial dysfunction leading to apoptotic and non-apoptotic forms of cell killing.	('trametinib', 'Chemical', 'MESH:C560077', (71, 81))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('leading to', 'Reg', (271, 281))	('autophagy', 'CPA', (222, 231))	('B-RAF', 'Gene', (146, 151))	('autophagy', 'biological_process', 'GO:0016236', ('222', '231'))	('cell killing', 'biological_process', 'GO:0001906', ('319', '331'))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (245, 270))	('apoptotic', 'CPA', (282, 291))	('V600E', 'Mutation', 'rs113488022', (152, 157))	('non-apoptotic forms of cell killing', 'CPA', (296, 331))	('dabrafenib', 'Chemical', 'MESH:C561627', (84, 94))	('autophagy', 'biological_process', 'GO:0006914', ('222', '231'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (245, 270))	('mitochondrial dysfunction', 'Disease', (245, 270))	('V600E', 'Var', (152, 157))	('mutant', 'Var', (139, 145))	('GZ17-6.02', 'Chemical', '-', (56, 65))	('B-RAF', 'Gene', '673', (146, 151))	('activation', 'PosReg', (179, 189))
102806	33898322	Melanoma cells expressing mutant B-RAF V600E can be efficaciously treated with checkpoint inhibitory antibodies.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('B-RAF', 'Gene', (33, 38))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('Melanoma', 'Disease', (0, 8))	('V600E', 'Var', (39, 44))	('B-RAF', 'Gene', '673', (33, 38))
102807	33898322	Treatment of cells with GZ17-6.02, [trametinib + dabrafenib] or the agents in combination enhanced the expression of MHCA and decreased the levels of PD-L1, which would predict for a greater anti-tumor immunotherapy response in vivo ( Figure 11A ).	('dabrafenib', 'Chemical', 'MESH:C561627', (49, 59))	('decreased', 'NegReg', (126, 135))	('trametinib', 'Chemical', 'MESH:C560077', (36, 46))	('tumor', 'Disease', (196, 201))	('GZ17-6.02', 'Var', (24, 33))	('expression', 'MPA', (103, 113))	('GZ17-6.02', 'Chemical', '-', (24, 33))	('PD-L1', 'Gene', (150, 155))	('enhanced', 'PosReg', (90, 98))	('MHCA', 'Gene', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('PD-L1', 'Gene', '29126', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
102809	33898322	Knock down of all HDACs tested to varying extents reduced the expression of PD-L1 with knock down of [HDAC2 + HDAC3] in all isolates and of [HDAC1 and HDAC2] in two isolates being most efficacious ( Figure 11B ,  ).	('HDAC2', 'Gene', '3066', (102, 107))	('HDAC', 'Gene', '9734', (18, 22))	('HDAC2', 'Gene', (102, 107))	('HDAC3', 'Gene', (110, 115))	('HDAC2', 'Gene', (151, 156))	('reduced', 'NegReg', (50, 57))	('HDAC2', 'Gene', '3066', (151, 156))	('HDAC1', 'Gene', (141, 146))	('HDAC', 'Gene', '9734', (151, 155))	('HDAC', 'Gene', (18, 22))	('HDAC', 'Gene', '9734', (110, 114))	('knock down', 'Var', (87, 97))	('HDAC', 'Gene', (151, 155))	('HDAC', 'Gene', '9734', (102, 106))	('HDAC', 'Gene', (110, 114))	('HDAC1', 'Gene', '3065', (141, 146))	('HDAC3', 'Gene', '8841', (110, 115))	('expression', 'MPA', (62, 72))	('HDAC', 'Gene', '9734', (141, 145))	('HDAC', 'Gene', (102, 106))	('PD-L1', 'Gene', (76, 81))	('HDAC', 'Gene', (141, 145))	('PD-L1', 'Gene', '29126', (76, 81))
102810	33898322	Knock down of HDACs almost uniformly increased MHCA levels.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('MHCA levels', 'MPA', (47, 58))	('increased MHCA', 'Phenotype', 'HP:0025548', (37, 51))	('increased', 'PosReg', (37, 46))	('Knock down', 'Var', (0, 10))
102811	33898322	The ability of HDAC knock down to alter ODC expression was variable based on the isolate tested; in MEL1 knock down of [HDAC1 + HDAC3]; in MEL2 HDAC8; in MEL4 [HDAC1 + HDAC3], [HDAC2 + HDAC3], HDAC6, HDAC8 or HDAC10.	('HDAC6', 'Gene', (193, 198))	('HDAC1', 'Gene', (160, 165))	('HDAC', 'Gene', (193, 197))	('HDAC', 'Gene', '9734', (185, 189))	('HDAC', 'Gene', '9734', (128, 132))	('HDAC', 'Gene', '9734', (160, 164))	('HDAC', 'Gene', '9734', (200, 204))	('HDAC', 'Gene', '9734', (177, 181))	('MEL4', 'CellLine', 'CVCL:B866', (154, 158))	('HDAC1', 'Gene', '3065', (120, 125))	('HDAC', 'Gene', (209, 213))	('HDAC', 'Gene', '9734', (120, 124))	('HDAC3', 'Gene', '8841', (168, 173))	('HDAC', 'Gene', '9734', (144, 148))	('HDAC', 'Gene', (185, 189))	('HDAC', 'Gene', (128, 132))	('HDAC', 'Gene', '9734', (168, 172))	('HDAC', 'Gene', (160, 164))	('HDAC', 'Gene', (200, 204))	('HDAC3', 'Gene', '8841', (128, 133))	('HDAC', 'Gene', (177, 181))	('HDAC1', 'Gene', '3065', (209, 214))	('HDAC10', 'Gene', (209, 215))	('MEL1', 'Gene', (100, 104))	('HDAC1', 'Gene', '3065', (160, 165))	('ODC', 'Gene', '4953', (40, 43))	('HDAC', 'Gene', '9734', (15, 19))	('HDAC', 'Gene', (120, 124))	('HDAC8', 'Gene', '55869', (200, 205))	('HDAC', 'Gene', (144, 148))	('HDAC6', 'Gene', '10013', (193, 198))	('HDAC3', 'Gene', (185, 190))	('HDAC', 'Gene', (168, 172))	('HDAC8', 'Gene', (200, 205))	('HDAC1', 'Gene', (209, 214))	('ODC', 'Gene', (40, 43))	('HDAC', 'Gene', (15, 19))	('HDAC8', 'Gene', '55869', (144, 149))	('HDAC8', 'Gene', (144, 149))	('HDAC2', 'Gene', (177, 182))	('HDAC2', 'Gene', '3066', (177, 182))	('HDAC3', 'Gene', (168, 173))	('HDAC1', 'Gene', (120, 125))	('HDAC', 'Gene', '9734', (193, 197))	('knock down', 'Var', (105, 115))	('HDAC10', 'Gene', '83933', (209, 215))	('HDAC3', 'Gene', (128, 133))	('HDAC3', 'Gene', '8841', (185, 190))	('HDAC', 'Gene', '9734', (209, 213))
102812	33898322	In all isolates, knock down of either [HDAC1 + HDAC2] or [HDAC2 + HDAC3] was most efficacious at reducing IDO1 expression.	('HDAC3', 'Gene', '8841', (66, 71))	('HDAC1', 'Gene', (39, 44))	('IDO', 'molecular_function', 'GO:0033754', ('106', '109'))	('HDAC2', 'Gene', (47, 52))	('HDAC2', 'Gene', '3066', (47, 52))	('HDAC3', 'Gene', (66, 71))	('IDO', 'molecular_function', 'GO:0047719', ('106', '109'))	('HDAC1', 'Gene', '3065', (39, 44))	('HDAC2', 'Gene', '3066', (58, 63))	('IDO1', 'Gene', '3620', (106, 110))	('expression', 'MPA', (111, 121))	('HDAC2', 'Gene', (58, 63))	('reducing', 'NegReg', (97, 105))	('knock down', 'Var', (17, 27))	('IDO1', 'Gene', (106, 110))
102813	33898322	The present studies were performed to determine whether GZ17-6.02 at low concentrations could kill cutaneous melanoma cells that express the B-RAF V600E mutation and whether it interacted with the standard of care therapy, [trametinib + dabrafenib], to cause higher levels of tumor cell killing.	('cell killing', 'biological_process', 'GO:0001906', ('282', '294'))	('V600E', 'Var', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('rat', 'Species', '10116', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('GZ17-6.02', 'Chemical', '-', (56, 65))	('tumor', 'Disease', (276, 281))	('B-RAF', 'Gene', '673', (141, 146))	('trametinib', 'Chemical', 'MESH:C560077', (224, 234))	('cutaneous melanoma', 'Disease', (99, 117))	('dabrafenib', 'Chemical', 'MESH:C561627', (237, 247))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (99, 117))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('B-RAF', 'Gene', (141, 146))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (99, 117))
102814	33898322	In an additive fashion, regardless of vemurafenib resistance in MEL2 cells, GZ17-6.02 and [trametinib + dabrafenib] interacted to kill B-RAF V600E mutated melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('vemurafenib', 'Chemical', 'MESH:D000077484', (38, 49))	('trametinib', 'Chemical', 'MESH:C560077', (91, 101))	('B-RAF', 'Gene', '673', (135, 140))	('B-RAF', 'Gene', (135, 140))	('V600E', 'Mutation', 'rs113488022', (141, 146))	('GZ17-6.02', 'Chemical', '-', (76, 85))	('V600E mutated', 'Var', (141, 154))	('interacted', 'Interaction', (116, 126))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('mutated', 'Var', (147, 154))	('melanoma', 'Disease', (155, 163))	('dabrafenib', 'Chemical', 'MESH:C561627', (104, 114))
102820	33898322	The expression of CHOP was enhanced by GZ17-6.02 as a single agent in both MEL2 and MEL4 cells after 4h of exposure, and in both isolates had returned to baseline by 8h.	('GZ17-6.02', 'Chemical', '-', (39, 48))	('MEL4', 'CellLine', 'CVCL:B866', (84, 88))	('enhanced', 'PosReg', (27, 35))	('expression', 'MPA', (4, 14))	('CHOP', 'Gene', '1649', (18, 22))	('GZ17-6.02', 'Var', (39, 48))	('CHOP', 'Gene', (18, 22))
102822	33898322	In other tumor cell types, we have shown that drug combinations that elevate Beclin1 and ATG5 expression and enhance autophagosome formation can reduce the levels of multiple HDAC proteins.	('HDAC', 'Gene', (175, 179))	('ATG5', 'Gene', '9474', (89, 93))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('autophagosome formation', 'CPA', (117, 140))	('ATG5', 'Gene', (89, 93))	('combinations', 'Var', (51, 63))	('Beclin1', 'Gene', '8678', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('elevate', 'PosReg', (69, 76))	('autophagosome formation', 'biological_process', 'GO:0000045', ('117', '140'))	('tumor', 'Disease', (9, 14))	('autophagosome', 'cellular_component', 'GO:0005776', ('117', '130'))	('HDAC', 'Gene', '9734', (175, 179))	('expression', 'MPA', (94, 104))	('Beclin1', 'Gene', (77, 84))	('reduce', 'NegReg', (145, 151))	('enhance', 'PosReg', (109, 116))
102833	33898322	Molecular manipulation of HDAC expression revealed that knock down of [HDAC2 + HDAC3] was particularly efficacious at reducing PD-L1 and IDO1 levels.	('knock down', 'Var', (56, 66))	('HDAC', 'Gene', (79, 83))	('HDAC2', 'Gene', (71, 76))	('HDAC3', 'Gene', '8841', (79, 84))	('HDAC2', 'Gene', '3066', (71, 76))	('HDAC3', 'Gene', (79, 84))	('HDAC', 'Gene', '9734', (79, 83))	('reducing', 'NegReg', (118, 126))	('IDO1', 'Gene', '3620', (137, 141))	('IDO', 'molecular_function', 'GO:0033754', ('137', '140'))	('PD-L1', 'Gene', (127, 132))	('HDAC', 'Gene', (26, 30))	('HDAC', 'Gene', (71, 75))	('HDAC', 'Gene', '9734', (26, 30))	('PD-L1', 'Gene', '29126', (127, 132))	('HDAC', 'Gene', '9734', (71, 75))	('IDO', 'molecular_function', 'GO:0047719', ('137', '140'))	('IDO1', 'Gene', (137, 141))
102835	33898322	Recent studies have linked curcumin-induced dephosphorylation of STAT3 Y705 to increased expression of PD-L1 and an enhanced in vivo efficacy of an anti-PD1 antibody.	('PD-L1', 'Gene', '29126', (103, 108))	('increased', 'PosReg', (79, 88))	('enhanced', 'PosReg', (116, 124))	('expression', 'MPA', (89, 99))	('antibody', 'cellular_component', 'GO:0019814', ('157', '165'))	('antibody', 'cellular_component', 'GO:0019815', ('157', '165'))	('dephosphorylation', 'biological_process', 'GO:0016311', ('44', '61'))	('PD1', 'Gene', '5133', (153, 156))	('antibody', 'molecular_function', 'GO:0003823', ('157', '165'))	('Y705', 'Var', (71, 75))	('PD1', 'Gene', (153, 156))	('STAT3', 'Gene', '6774', (65, 70))	('curcumin', 'Chemical', 'MESH:D003474', (27, 35))	('PD-L1', 'Gene', (103, 108))	('antibody', 'cellular_component', 'GO:0042571', ('157', '165'))	('STAT3', 'Gene', (65, 70))	('dephosphorylation', 'MPA', (44, 61))
102837	33898322	Many studies over the past 5 years have linked resistance to B-RAF/MEK inhibitors in B-RAF V600E mutated melanoma to correlate with evolutionary survival-induced activation of ERBB family receptors, including ERBB1 and ERBB3.	('B-RAF', 'Gene', (61, 66))	('ERBB1', 'Gene', (209, 214))	('B-RAF', 'Gene', (85, 90))	('MEK', 'Gene', '5609', (67, 70))	('ERBB', 'Gene', (219, 223))	('V600E mutated', 'Var', (91, 104))	('ERBB1', 'Gene', '1956', (209, 214))	('ERBB3', 'Gene', '2065', (219, 224))	('V600E', 'Mutation', 'rs113488022', (91, 96))	('ERBB', 'Gene', (209, 213))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('MEK', 'Gene', (67, 70))	('ERBB', 'Gene', (176, 180))	('ERBB', 'Gene', '1956;2064;2065', (219, 223))	('ERBB', 'Gene', '1956;2064;2065', (209, 213))	('B-RAF', 'Gene', '673', (61, 66))	('B-RAF', 'Gene', '673', (85, 90))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('mutated', 'Var', (97, 104))	('melanoma', 'Disease', (105, 113))	('ERBB', 'Gene', '1956;2064;2065', (176, 180))	('ERBB3', 'Gene', (219, 224))	('activation', 'PosReg', (162, 172))
102841	33898322	MCL1, but also, as noted above, can result in elevated PD-L1 expression and an enhanced immunotherapy response in vivo.	('MCL1', 'Var', (0, 4))	('elevated', 'PosReg', (46, 54))	('PD-L1', 'Gene', '29126', (55, 60))	('enhanced', 'PosReg', (79, 87))	('immunotherapy response', 'CPA', (88, 110))	('PD-L1', 'Gene', (55, 60))	('expression', 'MPA', (61, 71))
102842	33898322	Future studies will be needed to determine whether GZ17-6.02 has anti-melanoma properties in vivo.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('GZ17-6.02', 'Chemical', '-', (51, 60))	('GZ17-6.02', 'Var', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
102850	27167340	RMEL3 knockdown led to downregulation of activators or effectors of these pathways, including FGF2, FGF3, DUSP6, ITGB3 and GNG2.	('downregulation', 'NegReg', (23, 37))	('FGF3', 'Gene', '2248', (100, 104))	('ITGB3', 'Gene', '3690', (113, 118))	('RMEL3', 'Gene', (0, 5))	('FGF2', 'Gene', '2247', (94, 98))	('activators', 'MPA', (41, 51))	('ITGB3', 'Gene', (113, 118))	('GNG2', 'Gene', (123, 127))	('GNG2', 'Gene', '54331', (123, 127))	('DUSP6', 'Gene', (106, 111))	('FGF3', 'Gene', (100, 104))	('FGF2', 'Gene', (94, 98))	('knockdown', 'Var', (6, 15))	('DUSP6', 'Gene', '1848', (106, 111))
102851	27167340	RMEL3 knockdown induces gain of protein levels of tumor suppressor PTEN and the G1/S cyclin-Cdk inhibitors p21 and p27, as well as a decrease of pAKT (T308), BRAF, pRB (S807, S811) and cyclin B1.	('decrease', 'NegReg', (133, 141))	('cyclin', 'molecular_function', 'GO:0016538', ('85', '91'))	('protein levels', 'MPA', (32, 46))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('pRB', 'Gene', '5925', (164, 167))	('pRB', 'Gene', (164, 167))	('p27', 'Gene', '10671', (115, 118))	('BRAF', 'Gene', '673', (158, 162))	('PTEN', 'Gene', (67, 71))	('BRAF', 'Gene', (158, 162))	('tumor', 'Disease', (50, 55))	('cyclin B1', 'Gene', '891', (185, 194))	('gain', 'PosReg', (24, 28))	('cyclin B1', 'Gene', (185, 194))	('cyclin', 'molecular_function', 'GO:0016538', ('185', '191'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('PTEN', 'Gene', '5728', (67, 71))	('p27', 'Gene', (115, 118))	('RMEL3', 'Gene', (0, 5))	('Cdk', 'molecular_function', 'GO:0004693', ('92', '95'))	('p21', 'Gene', (107, 110))	('p21', 'Gene', '644914', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))	('knockdown', 'Var', (6, 15))
102852	27167340	Thus, TCGA data and functional experiments demonstrate that RMEL3 is required for MAPK and PI3K signaling, and its knockdown decrease BRAFV600E melanoma cell survival and proliferation.	('BRAFV600E', 'Gene', (134, 143))	('BRAFV600E', 'Gene', '673', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('melanoma', 'Disease', (144, 152))	('decrease', 'NegReg', (125, 133))	('PI3K signaling', 'biological_process', 'GO:0014065', ('91', '105'))	('MAPK', 'molecular_function', 'GO:0004707', ('82', '86'))	('melanoma', 'Disease', 'MESH:D008545', (144, 152))	('proliferation', 'CPA', (171, 184))	('knockdown', 'Var', (115, 124))
102854	27167340	Targeted therapies against BRAFV600 mutations, which are present in ~50% of metastatic melanomas, achieve impressive initial clinical responses and benefit, but the development of acquired resistance to these agents is almost universal.	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))	('clinical', 'Species', '191496', (125, 133))	('mutations', 'Var', (36, 45))	('BRAF', 'Gene', '673', (27, 31))	('melanomas', 'Disease', (87, 96))	('BRAF', 'Gene', (27, 31))	('melanomas', 'Phenotype', 'HP:0002861', (87, 96))	('melanomas', 'Disease', 'MESH:D008545', (87, 96))
102855	27167340	The identification of additional melanoma oncogenic mechanisms initiated by oncogenic BRAF will facilitate the development of more long-term effective therapeutic approaches.	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('BRAF', 'Gene', (86, 90))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('oncogenic', 'Var', (76, 85))	('BRAF', 'Gene', '673', (86, 90))
102859	27167340	This study supports that RMEL3 knockdown inhibits MAPK and PI3K pathways in melanoma.	('melanoma', 'Disease', (76, 84))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))	('inhibits', 'NegReg', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('RMEL3', 'Gene', (25, 30))	('MAPK', 'molecular_function', 'GO:0004707', ('50', '54'))	('knockdown', 'Var', (31, 40))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
102865	27167340	RMEL3 knockdown in BRAFV600E melanoma cells, such as the A375-SM cell line, which has high RMEL3 expression (Figure 2A), markedly reduced colony formation (Figure 2B and 2C).	('colony formation', 'CPA', (138, 154))	('RMEL3', 'Gene', (91, 96))	('RMEL3', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('BRAFV600E', 'Gene', '673', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('A375-SM', 'CellLine', 'CVCL:5649', (57, 64))	('reduced', 'NegReg', (130, 137))	('formation', 'biological_process', 'GO:0009058', ('145', '154'))	('knockdown', 'Var', (6, 15))	('BRAFV600E', 'Gene', (19, 28))
102867	27167340	RMEL3 knockdown in a BRAF wild type cell line also reduced colony count, however less dramatically.	('reduced', 'NegReg', (51, 58))	('RMEL3', 'Gene', (0, 5))	('colony count', 'CPA', (59, 71))	('BRAF', 'Gene', '673', (21, 25))	('BRAF', 'Gene', (21, 25))	('knockdown', 'Var', (6, 15))
102871	27167340	RMEL3-regulated genes identified by gene knockdown (log2 fold change <-0.5 or >0.5, p-value <0.01, n=2942; d-content>Supplementary Table S2) were compared to the melanoma TCGA data (log2 fold change <-0.5 or >0.5, adj.	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('RMEL3-regulated genes', 'Gene', (0, 21))	('melanoma', 'Disease', (162, 170))	('knockdown', 'Var', (41, 50))
102875	27167340	RMEL3 knockdown in A375-SM melanoma cells altered a total of 91 proteins (p<0.05; Supplementary Table S6).	('RMEL3', 'Gene', (0, 5))	('altered', 'Reg', (42, 49))	('A375-SM', 'CellLine', 'CVCL:5649', (19, 26))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('knockdown', 'Var', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
102877	27167340	RMEL3 knockdown reduced cell cycle regulators just as pRB (S807, S811) and Cyclin-B1, and increased p27 (Figure 4B).	('Cyclin-B1', 'Gene', (75, 84))	('pRB', 'Gene', (54, 57))	('Cyclin-B1', 'Gene', '891', (75, 84))	('p27', 'Gene', '10671', (100, 103))	('S811', 'Var', (65, 69))	('RMEL3', 'Gene', (0, 5))	('increased', 'PosReg', (90, 99))	('p27', 'Gene', (100, 103))	('reduced', 'NegReg', (16, 23))	('pRB', 'Gene', '5925', (54, 57))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('knockdown', 'Var', (6, 15))	('Cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('cell cycle regulators', 'MPA', (24, 45))
102879	27167340	Consistent with the impact of RMEL3 knockdown in the clonogenic ability, we showed by western blot an increase of the p21 and p27 G1/S cyclin-Cdk inhibitors, and a decrease of cyclin B1 (Figure 4D).	('p27', 'Gene', '10671', (126, 129))	('RMEL3', 'Gene', (30, 35))	('cyclin B1', 'Gene', (176, 185))	('cyclin B1', 'Gene', '891', (176, 185))	('p27', 'Gene', (126, 129))	('p21', 'Gene', (118, 121))	('cyclin', 'molecular_function', 'GO:0016538', ('135', '141'))	('knockdown', 'Var', (36, 45))	('decrease', 'NegReg', (164, 172))	('increase', 'PosReg', (102, 110))	('p21', 'Gene', '644914', (118, 121))	('cyclin', 'molecular_function', 'GO:0016538', ('176', '182'))	('Cdk', 'molecular_function', 'GO:0004693', ('142', '145'))
102882	27167340	Consistently RMEL3 knockdown induced a potent blockage over BRAFV600E melanoma cell growth and survival (Figure 2A-2C).	('melanoma', 'Disease', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('blockage', 'NegReg', (46, 54))	('BRAFV600E', 'Gene', (60, 69))	('knockdown', 'Var', (19, 28))	('RMEL3', 'Gene', (13, 18))	('cell growth', 'biological_process', 'GO:0016049', ('79', '90'))	('BRAFV600E', 'Gene', '673', (60, 69))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
102886	27167340	Shared molecular signatures between RMEL3 knockdown and BRAF suppression also highlights the association of RMEL3 with BRAF.	('RMEL3', 'Gene', (36, 41))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('association', 'Interaction', (93, 104))	('RMEL3', 'Gene', (108, 113))	('knockdown', 'Var', (42, 51))	('BRAF', 'Gene', (56, 60))
102888	27167340	We also demonstrated, at the proteins levels, that RMEL3 knockdown decreased BRAF levels and increased the tumor suppressor PTEN concentration (Figure 4A), which commonly blocks BRAFV600E-induced malignancy.	('PTEN', 'Gene', (124, 128))	('tumor', 'Disease', (107, 112))	('increased', 'PosReg', (93, 102))	('BRAFV600E', 'Gene', (178, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('BRAF', 'Gene', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('malignancy', 'Disease', 'MESH:D009369', (196, 206))	('PTEN', 'Gene', '5728', (124, 128))	('BRAFV600E', 'Gene', '673', (178, 187))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('BRAF', 'Gene', '673', (77, 81))	('malignancy', 'Disease', (196, 206))	('knockdown', 'Var', (57, 66))	('BRAF', 'Gene', (77, 81))	('RMEL3', 'Gene', (51, 56))	('BRAF', 'Gene', '673', (178, 182))	('decreased', 'NegReg', (67, 76))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
102889	27167340	As expected, we detected reduced levels of pAkt (T308) and Akt (Figure 4A).	('T308', 'Var', (49, 53))	('Akt', 'Gene', (59, 62))	('reduced', 'NegReg', (25, 32))	('Akt', 'Gene', '207', (44, 47))	('Akt', 'Gene', '207', (59, 62))	('Akt', 'Gene', (44, 47))
102892	27167340	These results are consistent with the drastic reduction of clonogenic ability (Figure 2B-2C), G1 arrest and an increase in cell death rates (subG0/G1) (Figure 4E) caused by RMEL3 knockdown.	('cell death rates', 'CPA', (123, 139))	('increase', 'PosReg', (111, 119))	('reduction', 'NegReg', (46, 55))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('cell death', 'biological_process', 'GO:0008219', ('123', '133'))	('knockdown', 'Var', (179, 188))	('clonogenic ability', 'CPA', (59, 77))	('arrest', 'Disease', (97, 103))	('RMEL3', 'Gene', (173, 178))
102895	27167340	Interestingly, several changes tend to shift the balance towards apoptosis, including decrease of anti-apoptotic Bcl2 mRNA expression (Supplementary Table S2) and protein levels (Figure 4C); an intense downregulation of transglutaminase protein that can inhibit bax-induced apoptosis; increased pro-apoptotic p38 and caspase-8 protein levels; and decrease of YAP (pS127), which is phosphorylated by Akt to reduce p73-mediated induction of Bax expression.	('increased', 'PosReg', (285, 294))	('changes', 'Var', (23, 30))	('caspase-8', 'Gene', '841', (317, 326))	('p38', 'Gene', '1432', (309, 312))	('decrease', 'NegReg', (347, 355))	('inhibit', 'NegReg', (254, 261))	('decrease', 'NegReg', (86, 94))	('shift', 'Reg', (39, 44))	('Bcl2', 'molecular_function', 'GO:0015283', ('113', '117'))	('YAP', 'Gene', '10413', (359, 362))	('anti-apoptotic', 'MPA', (98, 112))	('Bcl2', 'Gene', (113, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('protein levels', 'MPA', (163, 177))	('Bcl2', 'Gene', '596', (113, 117))	('p73', 'Gene', '7161', (413, 416))	('caspase-8', 'Gene', (317, 326))	('p73', 'Gene', (413, 416))	('Akt', 'Gene', (399, 402))	('bax', 'Gene', (262, 265))	('protein', 'cellular_component', 'GO:0003675', ('163', '170'))	('protein', 'cellular_component', 'GO:0003675', ('327', '334'))	('apoptosis', 'biological_process', 'GO:0097194', ('274', '283'))	('downregulation', 'NegReg', (202, 216))	('apoptosis', 'biological_process', 'GO:0006915', ('274', '283'))	('Akt', 'Gene', '207', (399, 402))	('p38', 'Gene', (309, 312))	('transglutaminase protein', 'Protein', (220, 244))	('YAP', 'Gene', (359, 362))	('Bax', 'Gene', (439, 442))	('bax', 'Gene', '581', (262, 265))	('Bax', 'Gene', '581', (439, 442))
102896	27167340	In conclusion, this work provides strong evidence that RMEL3, initially implicated by its specificity to melanoma, can affect malignancy through MAPK and PI3K stimulation.	('malignancy', 'Disease', (126, 136))	('MAPK', 'molecular_function', 'GO:0004707', ('145', '149'))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('MAPK', 'Var', (145, 149))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('PI3K', 'molecular_function', 'GO:0016303', ('154', '158'))	('affect', 'Reg', (119, 125))	('RMEL3', 'Gene', (55, 60))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('PI3K stimulation', 'Var', (154, 170))
102914	27336610	In addition, we draw attention to low-frequency actionable mutations and highlight frequent non-coding mutations in melanoma where little is known about their biological function that may provide novel avenues for the development of treatment strategies for melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (258, 266))	('patients', 'Species', '9606', (267, 275))	('non-coding mutations', 'Var', (92, 112))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('mutations', 'Var', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('melanoma', 'Disease', (258, 266))
102920	27336610	Hotspot mutations in the V600 codon of BRAF in ~50% of melanomas and the G12, G13 and Q61 codons of NRAS in ~25% of cases were identified before the era of next-generation sequencing.	('NRAS', 'Gene', '4893', (100, 104))	('melanomas', 'Phenotype', 'HP:0002861', (55, 64))	('melanomas', 'Disease', 'MESH:D008545', (55, 64))	('BRAF', 'Gene', (39, 43))	('Q61', 'Var', (86, 89))	('V600', 'Var', (25, 29))	('melanomas', 'Disease', (55, 64))	('NRAS', 'Gene', (100, 104))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('G12', 'Var', (73, 76))
102926	27336610	In addition, we draw attention to low-frequency actionable mutations that could inform on potential rare combination strategies to further personalise treatment options for patients.	('inform', 'Reg', (80, 86))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (173, 181))
102927	27336610	Finally, we examine the discoveries of non-coding mutations that occur in a large fraction of patients where little is known about their biology that provide new avenues of investigation in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('patients', 'Species', '9606', (94, 102))	('non-coding mutations', 'Var', (39, 59))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))
102929	27336610	Over 75% of the cutaneous melanoma samples sequenced in the TCGA cohort possessed a UV signature, defined by having C>T transitions at dipyrimidine sites accounting for >60%, or CC>TT mutations in >5%, of the total mutation burden.	('CC>TT mutations', 'Var', (178, 193))	('cutaneous melanoma', 'Disease', (16, 34))	('C>T transitions', 'Var', (116, 131))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('dipyrimidine', 'Chemical', '-', (135, 147))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (16, 34))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (16, 34))
102937	27336610	For example, more than 500 genes were mutated in at least 10% of the 121 melanomas sequenced - many of which were not expressed in melanocytes and melanoma cell lines.	('mutated', 'Var', (38, 45))	('melanoma', 'Disease', (73, 81))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanomas', 'Disease', (73, 82))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('genes', 'Gene', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))
102938	27336610	Using this tool, genes that were found to be significantly mutated included well-established melanoma oncogenes and tumour suppressors, BRAF, NRAS, MAP2K1, PTEN and CDKN2A, as well as novel significantly mutated genes (SMGs) containing hotspot and loss-of-function mutations that were expressed in melanoma cell lines.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (265, 274))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('PTEN', 'Gene', (156, 160))	('NRAS', 'Gene', '4893', (142, 146))	('tumour', 'Disease', (116, 122))	('melanoma', 'Disease', 'MESH:D008545', (298, 306))	('CDKN2A', 'Gene', '1029', (165, 171))	('PTEN', 'Gene', '5728', (156, 160))	('loss-of-function', 'NegReg', (248, 264))	('MAP2K1', 'Gene', '5604', (148, 154))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('NRAS', 'Gene', (142, 146))	('MAP2K', 'molecular_function', 'GO:0004708', ('148', '153'))	('MAP2K1', 'Gene', (148, 154))	('melanoma', 'Phenotype', 'HP:0002861', (298, 306))	('melanoma', 'Disease', (298, 306))	('CDKN2A', 'Gene', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
102939	27336610	These novel SMGs that possessed hotspot mutations caused by C>T transitions were the Rho GTPase, RAC1 (p. P29S), the catalytic subunit of the heterotrimeric PP6 protein phosphatase complex, PPP6C (p. R301C), and the serine threonine kinase, STK19 (p. D89N).	('PPP6C', 'Gene', (190, 195))	('RAC1', 'Gene', (97, 101))	('R301C', 'SUBSTITUTION', 'None', (200, 205))	('STK19', 'molecular_function', 'GO:0004686', ('241', '246'))	('phosphatase complex', 'cellular_component', 'GO:1903293', ('169', '188'))	('R301C', 'Var', (200, 205))	('STK19', 'Gene', '8859', (241, 246))	('D89N', 'SUBSTITUTION', 'None', (251, 255))	('PPP6C', 'Gene', '5537', (190, 195))	('phosphatase', 'molecular_function', 'GO:0016791', ('169', '180'))	('D89N', 'Var', (251, 255))	('STK19', 'Gene', (241, 246))	('RAC1', 'Gene', '5879', (97, 101))	('protein', 'cellular_component', 'GO:0003675', ('161', '168'))	('P29S', 'SUBSTITUTION', 'None', (106, 110))	('P29S', 'Var', (106, 110))
102940	27336610	Novel SMGs possessing loss-of-function mutations included ARID2, which encodes a component of the SWI/SNF chromatin-remodeling complex.	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('106', '126'))	('mutations', 'Var', (39, 48))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('106', '134'))	('ARID2', 'Gene', '196528', (58, 63))	('loss-of-function', 'NegReg', (22, 38))	('ARID2', 'Gene', (58, 63))
102945	27336610	Almost all IDH1 mutations encoded the p.R132C amino-acid substitution with an incidence of ~5% and ~2% in samples of the TCGA and Yale cohorts, respectively.	('p.R132C amino-acid', 'Var', (38, 56))	('IDH1', 'Gene', '3417', (11, 15))	('p.R132C', 'Mutation', 'rs121913499', (38, 45))	('mutations', 'Var', (16, 25))	('encoded', 'Reg', (26, 33))	('IDH1', 'Gene', (11, 15))
102948	27336610	Germline mutations in NF1 are known to cause an inherited multisystem genetic disorder, neurofibromatosis type 1, which is characterised by changes in skin colouring pigmentation (e.g., cafe-au-lait spots) and the growth of both benign and malignant tumours.	('Germline mutations', 'Var', (0, 18))	('cause', 'Reg', (39, 44))	('inherited multisystem genetic disorder', 'Disease', (48, 86))	('neurofibromatosis type 1', 'Gene', (88, 112))	('NF1', 'Gene', (22, 25))	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('pigmentation', 'biological_process', 'GO:0043473', ('166', '178'))	('NF1', 'Gene', '4763', (22, 25))	('inherited multisystem genetic disorder', 'Disease', 'MESH:D030342', (48, 86))	('neurofibromatosis type 1', 'Gene', '4763', (88, 112))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (88, 105))	('changes', 'Reg', (140, 147))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('malignant tumours', 'Disease', 'MESH:D009369', (240, 257))	('malignant tumours', 'Disease', (240, 257))	('cafe-au-lait spots', 'Phenotype', 'HP:0000957', (186, 204))
102950	27336610	Both the and observed that close to 40-50% of melanomas that lacked a hotspot mutation in BRAF (p.V600 or K601E) or NRAS (p. G12, G13 or Q61) possessed loss-of-function mutations in NF1.	('BRAF', 'Gene', (90, 94))	('NF1', 'Gene', '4763', (182, 185))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('Q61', 'Var', (137, 140))	('p. G12', 'Var', (122, 128))	('p.V600', 'Var', (96, 102))	('NF1', 'Gene', (182, 185))	('NRAS', 'Gene', (116, 120))	('K601E', 'Mutation', 'rs121913364', (106, 111))	('loss-of-function', 'NegReg', (152, 168))	('melanomas', 'Disease', (46, 55))	('NRAS', 'Gene', '4893', (116, 120))	('G13 or Q61', 'Var', (130, 140))	('K601E', 'Var', (106, 111))
102951	27336610	Previous studies have clearly demonstrated the mutual exclusivity of hotspot BRAF and NRAS mutations in melanoma; however, NF1 mutations were also significantly anticorrelated with hotspot BRAF, but not NRAS, mutations.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('NRAS', 'Gene', (86, 90))	('melanoma', 'Disease', (104, 112))	('NRAS', 'Gene', '4893', (203, 207))	('NRAS', 'Gene', '4893', (86, 90))	('NF1', 'Gene', '4763', (123, 126))	('NF1', 'Gene', (123, 126))	('mutations', 'Var', (127, 136))	('NRAS', 'Gene', (203, 207))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
102952	27336610	Altogether, these results supported the categorisation of cutaneous melanoma into four genetic subgroups by MAPK driver mutations: BRAF, RAS (N-H-K), NF1 (lacking a BRAF p.V600 or RAS p.G12, G13 and Q61 hotspot mutation) and Triple wild-type (WT) melanomas (Table 1).	('cutaneous melanoma', 'Disease', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('p.G12', 'Var', (184, 189))	('NF1', 'Gene', (150, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('melanomas', 'Disease', (247, 256))	('NF1', 'Gene', '4763', (150, 153))	('MAPK', 'Gene', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('mutations', 'Var', (120, 129))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('BRAF', 'Disease', (131, 135))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('melanomas', 'Disease', 'MESH:D008545', (247, 256))	('RAS', 'Gene', (137, 140))
102953	27336610	NF1 subtype patients were older, had a higher mutation burden and were reported to possess significant co-occurring mutations in additional RASopathy genes (e.g., RASA1, RASA2, PTPN11 and SOS1).	('patients', 'Species', '9606', (12, 20))	('higher', 'PosReg', (39, 45))	('RASA1', 'Gene', '5921', (163, 168))	('RASopathy', 'Disease', 'None', (140, 149))	('mutation burden', 'MPA', (46, 61))	('SOS1', 'Gene', (188, 192))	('RASA1', 'Gene', (163, 168))	('RASA2', 'Gene', (170, 175))	('mutations', 'Var', (116, 125))	('RASopathy', 'Disease', (140, 149))	('NF1', 'Gene', (0, 3))	('SOS1', 'Gene', '6654', (188, 192))	('PTPN11', 'Gene', '5781', (177, 183))	('NF1', 'Gene', '4763', (0, 3))	('RASA2', 'Gene', '5922', (170, 175))	('PTPN11', 'Gene', (177, 183))
102954	27336610	Furthermore, WES analysis of desmoplastic melanoma, a rare form of melanoma with sarcomatous histology that occur in chronically sun-exposed skin, revealed significant loss-of-function mutations in NF1 in over 50% of samples.	('melanoma', 'Disease', (42, 50))	('sarcomatous', 'Disease', 'MESH:D018316', (81, 92))	('desmoplastic melanoma', 'Disease', 'MESH:D008545', (29, 50))	('NF1', 'Gene', (198, 201))	('desmoplastic melanoma', 'Disease', (29, 50))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('loss-of-function', 'NegReg', (168, 184))	('NF1', 'Gene', '4763', (198, 201))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('sarcomatous histology', 'Phenotype', 'HP:0100242', (81, 102))	('sarcomatous', 'Disease', (81, 92))	('mutations', 'Var', (185, 194))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
102955	27336610	Notably, BRAF p.V600E and NRAS p.Q61L/R mutations were not found, providing strong genetic evidence of a role for NF1 in melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('p.V600E', 'Var', (14, 21))	('melanoma', 'Disease', (121, 129))	('NF1', 'Gene', '4763', (114, 117))	('p.Q61L', 'Var', (31, 37))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('NRAS', 'Gene', (26, 30))	('p.Q61L', 'SUBSTITUTION', 'None', (31, 37))	('p.V600E', 'Mutation', 'rs113488022', (14, 21))	('NRAS', 'Gene', '4893', (26, 30))	('NF1', 'Gene', (114, 117))
102956	27336610	Somatic copy number analysis revealed Triple WT melanomas had a higher fraction of samples possessing significant copy number amplifications consistent with other studies (e.g.,).	('copy number amplifications', 'Var', (114, 140))	('Triple WT melanomas', 'Disease', 'MESH:D008545', (38, 57))	('Triple WT melanomas', 'Disease', (38, 57))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
102960	27336610	We suspect that the established genomic framework based on somatic alterations including MAPK mutations can aid in personalised therapeutic decision-making in melanoma (Table 1).	('melanoma', 'Disease', (159, 167))	('mutations', 'Var', (94, 103))	('MAPK', 'Gene', (89, 93))	('aid', 'Reg', (108, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('89', '93'))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))
102965	27336610	Intermediate lesions harboured BRAF (p.V600K/K601E) and NRAS mutations, as well as additional driver events that included TERT promoter mutations, which were commonly found in both intermediate lesions and melanomas in situ.	('NRAS', 'Gene', (56, 60))	('melanomas', 'Disease', 'MESH:D008545', (206, 215))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('TERT', 'Gene', (122, 126))	('TERT', 'Gene', '7015', (122, 126))	('NRAS', 'Gene', '4893', (56, 60))	('melanomas', 'Disease', (206, 215))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('p.V600K', 'SUBSTITUTION', 'None', (37, 44))	('p.V600K', 'Var', (37, 44))	('K601E', 'Mutation', 'rs121913364', (45, 50))	('BRAF', 'Gene', (31, 35))
102966	27336610	Biallelic inactivation of CDKN2A and mutations in chromatin remodellers (e.g., ARID2) were found in invasive melanomas.	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('CDKN2A', 'Gene', (26, 32))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('found', 'Reg', (91, 96))	('CDKN2A', 'Gene', '1029', (26, 32))	('Biallelic inactivation', 'Var', (0, 22))	('mutations', 'Var', (37, 46))	('melanomas', 'Phenotype', 'HP:0002861', (109, 118))	('invasive melanomas', 'Disease', (100, 118))	('ARID2', 'Gene', '196528', (79, 84))	('ARID2', 'Gene', (79, 84))	('invasive melanomas', 'Disease', 'MESH:D008545', (100, 118))
102967	27336610	In addition, PTEN and TP53 mutations were found in advanced tumours.	('mutations', 'Var', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('TP53', 'Gene', '7157', (22, 26))	('found', 'Reg', (42, 47))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('TP53', 'Gene', (22, 26))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
102976	27336610	Subsequent combined BRAF and MEK inhibitor phase III clinical trials for patients with a BRAF (p.V600E or p.V600K) mutation were shown to increase PFS and/or OS compared with BRAF inhibitor monotherapy.	('p.V600K', 'Var', (106, 113))	('increase', 'PosReg', (138, 146))	('p.V600K', 'Mutation', 'rs121913227', (106, 113))	('p.V600E', 'Mutation', 'rs113488022', (95, 102))	('PFS', 'CPA', (147, 150))	('p.V600E', 'Var', (95, 102))	('BRAF', 'Gene', (89, 93))	('patients', 'Species', '9606', (73, 81))
102977	27336610	Inhibition of the MAPK pathway targeting two nodes resulted in a reduction in BRAF inhibitor resistance in ~25% of patients and a decrease in secondary SCCs and keratoacanthomas, presumably by preventing paradoxical MAPK activation.	('patients', 'Species', '9606', (115, 123))	('MAPK pathway', 'Pathway', (18, 30))	('BRAF inhibitor resistance', 'MPA', (78, 103))	('keratoacanthomas', 'Disease', 'MESH:D007636', (161, 177))	('decrease', 'NegReg', (130, 138))	('MAPK activation', 'biological_process', 'GO:0000187', ('216', '231'))	('keratoacanthomas', 'Phenotype', 'HP:0031525', (161, 177))	('secondary SCCs', 'Disease', (142, 156))	('Inhibition', 'Var', (0, 10))	('SCCs', 'Phenotype', 'HP:0002860', (152, 156))	('keratoacanthomas', 'Disease', (161, 177))	('MAPK', 'molecular_function', 'GO:0004707', ('216', '220'))	('reduction', 'NegReg', (65, 74))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
102978	27336610	However, resistance is still a problem, and combination immune and targeted therapy strategies are next steps in treating BRAF mutant melanoma patients (reviewed in).	('mutant', 'Var', (127, 133))	('patients', 'Species', '9606', (143, 151))	('BRAF', 'Gene', (122, 126))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
102981	27336610	Furthermore, combination therapies with anti-PD-1 and anti-PD-L1 appear to be more promising given their reduced toxicity.	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('PD-1', 'Gene', '18566', (45, 49))	('PD-1', 'Gene', (45, 49))	('combination', 'Interaction', (13, 24))	('anti-PD-L1', 'Var', (54, 64))
102986	27336610	However, the majority of these mechanisms involve reactivation of the MAPK pathway, including mutations of NRAS, promotion of the splice variant, p61 BRAF p.V600, and BRAF p.V600E amplification, which all lead to increased BRAF dimerisation and constitutive signalling.	('mutations', 'Var', (94, 103))	('MAPK pathway', 'Pathway', (70, 82))	('constitutive signalling', 'MPA', (245, 268))	('NRAS', 'Gene', '4893', (107, 111))	('MAPK', 'molecular_function', 'GO:0004707', ('70', '74'))	('p61', 'Var', (146, 149))	('p.V600E', 'Mutation', 'rs113488022', (172, 179))	('p.V600', 'Var', (155, 161))	('signalling', 'biological_process', 'GO:0023052', ('258', '268'))	('amplification', 'MPA', (180, 193))	('p.V600E', 'Var', (172, 179))	('promotion', 'PosReg', (113, 122))	('BRAF dimerisation', 'MPA', (223, 240))	('increased', 'PosReg', (213, 222))	('NRAS', 'Gene', (107, 111))	('BRAF p.V600E', 'Var', (167, 179))
102987	27336610	Recent studies of RAF inhibitors able to inhibit both BRAF V600E and BRAF mutant dimers may have more clinical promise and may reduce incidence of resistance.	('RAF', 'Gene', '22882', (18, 21))	('RAF', 'Gene', '22882', (55, 58))	('RAF', 'Gene', (18, 21))	('RAF', 'Gene', '22882', (70, 73))	('RAF', 'Gene', (55, 58))	('RAF', 'Gene', (70, 73))	('reduce', 'NegReg', (127, 133))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('inhibit', 'NegReg', (41, 48))	('incidence', 'MPA', (134, 143))	('mutant', 'Var', (74, 80))	('resistance', 'MPA', (147, 157))	('V600E', 'Var', (59, 64))
102988	27336610	Given the clinical utility of MAPK targeted therapy and the anticorrelative relationship of hotspot BRAF, RAS and loss-of-function NF1 mutations, we suspect that the framework generated by the TCGA study will be useful to guide personalised therapeutic decisions for cutaneous melanoma (Table 1).	('NF1', 'Gene', (131, 134))	('MAPK', 'molecular_function', 'GO:0004707', ('30', '34'))	('NF1', 'Gene', '4763', (131, 134))	('mutations', 'Var', (135, 144))	('cutaneous melanoma', 'Disease', (267, 285))	('loss-of-function', 'NegReg', (114, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (267, 285))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (267, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))
102989	27336610	Currently, ongoing clinical trials of MEK and CDK4 inhibitors have shown clinical promise in treating patients with NRAS mutant melanomas, which were based on preclinical studies that demonstrated MEK inhibitors induce low-level apoptosis in melanoma, but not cell cycle arrest in a NRAS-driven mouse model.	('CDK', 'molecular_function', 'GO:0004693', ('46', '49'))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('mutant', 'Var', (121, 127))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('patients', 'Species', '9606', (102, 110))	('CDK4', 'Gene', '1019', (46, 50))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('260', '277'))	('NRAS', 'Gene', '4893', (283, 287))	('NRAS', 'Gene', '4893', (116, 120))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('melanoma', 'Disease', (242, 250))	('melanomas', 'Disease', 'MESH:D008545', (128, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('229', '238'))	('apoptosis', 'biological_process', 'GO:0006915', ('229', '238'))	('melanomas', 'Disease', (128, 137))	('low-level', 'MPA', (219, 228))	('CDK4', 'Gene', (46, 50))	('NRAS', 'Gene', (283, 287))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (260, 277))	('NRAS', 'Gene', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('mouse', 'Species', '10090', (295, 300))	('melanoma', 'Disease', (128, 136))
102992	27336610	Other studies have shown not all NF1 mutant melanomas respond to MEK inhibitors.	('melanomas', 'Disease', (44, 53))	('NF1', 'Gene', (33, 36))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('NF1', 'Gene', '4763', (33, 36))	('melanomas', 'Phenotype', 'HP:0002861', (44, 53))	('mutant', 'Var', (37, 43))	('melanomas', 'Disease', 'MESH:D008545', (44, 53))
102993	27336610	Further investigation is required to determine the mechanisms that mediate MEK inhibitor response in NF1 mutant melanomas, which may aid in further stratifying patients who could benefit from such therapies in combination with immune checkpoint inhibitors given the co-occurring high mutation burden of this subtype (see below and Table 1).	('melanomas', 'Disease', (112, 121))	('patients', 'Species', '9606', (160, 168))	('NF1', 'Gene', (101, 104))	('NF1', 'Gene', '4763', (101, 104))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('mutant', 'Var', (105, 111))
102994	27336610	In addition, other studies have suggested that pan-RAF and MEK inhibitor combinations may be a useful strategy to target NF1 mutant cancers.	('cancers', 'Disease', (132, 139))	('RAF', 'Gene', '22882', (51, 54))	('NF1', 'Gene', '4763', (121, 124))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('RAF', 'Gene', (51, 54))	('mutant', 'Var', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('NF1', 'Gene', (121, 124))
102996	27336610	Finally, Triple WT melanomas were found to possess more frequent KIT recurrent mutations as well as amplification of the 4q12 amplicon containing KIT, PDGFRA and KDR.	('Triple WT melanomas', 'Disease', 'MESH:D008545', (9, 28))	('KDR', 'Gene', '3791', (162, 165))	('PDGFRA', 'Gene', '5156', (151, 157))	('Triple WT melanomas', 'Disease', (9, 28))	('PDGFRA', 'Gene', (151, 157))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('melanomas', 'Phenotype', 'HP:0002861', (19, 28))	('KIT', 'Gene', (146, 149))	('KIT', 'MPA', (65, 68))	('KDR', 'Gene', (162, 165))	('KIT', 'molecular_function', 'GO:0005020', ('146', '149'))	('KIT', 'molecular_function', 'GO:0005020', ('65', '68'))	('mutations', 'Var', (79, 88))
103004	27336610	Immune therapies to treat melanoma can be broadly characterised into categories that include cytokines/chemokines (e.g., HD IL-2), cancer vaccine therapies, oncolytic virus therapies (e.g., T-VEC), immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1) and adoptive cell transfer (ACT).	('cancer', 'Disease', (131, 137))	('IL-2', 'molecular_function', 'GO:0005134', ('124', '128'))	('PD-1', 'Gene', '18566', (255, 259))	('IL-2', 'Gene', '3558', (124, 128))	('anti-CTLA-4', 'Var', (234, 245))	('PD-1', 'Gene', (255, 259))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('IL-2', 'Gene', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('adoptive cell transfer', 'CPA', (265, 287))	('HD', 'Disease', 'MESH:D006816', (121, 123))
103007	27336610	Anti-PD-1 (e.g., nivolumab and pembrolizumab), anti-PD-L1 and anti-CTLA-4 (e.g., ipilimumab) antibodies can reverse immune suppression and activate T cells, triggering an antitumour response.	('pembrolizumab', 'Chemical', 'MESH:C582435', (31, 44))	('T cells', 'CPA', (148, 155))	('antibodies', 'Var', (93, 103))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('anti-PD-L1', 'Gene', (47, 57))	('tumour', 'Disease', (175, 181))	('triggering', 'Reg', (157, 167))	('anti-CTLA-4', 'Gene', (62, 73))	('nivolumab', 'Chemical', 'MESH:D000077594', (17, 26))	('ipilimumab', 'Chemical', 'MESH:D000074324', (81, 91))	('PD-1', 'Gene', (5, 9))	('immune suppression', 'CPA', (116, 134))	('PD-1', 'Gene', '18566', (5, 9))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('activate', 'PosReg', (139, 147))
103011	27336610	In the phase III Checkmate 067 study that evaluated monotherapies of either nivolumab or ipilimumab compared with combination therapy (nivolumab and ipilimumab), stratifying patients by BRAF mutation, disease stage and PD-L1 expression (PD-L1 positivity cutoff >=5% on tumour cells with any staining of any intensity on the cell surface), revealed an overall response rate (ORR) of 57.6% for the combination group vs 43.7% and 19% for monotherapies nivolumab and ipilimumab, respectively.	('BRAF', 'Gene', (186, 190))	('ipilimumab', 'Chemical', 'MESH:D000074324', (463, 473))	('ipilimumab', 'Chemical', 'MESH:D000074324', (89, 99))	('nivolumab', 'Chemical', 'MESH:D000077594', (449, 458))	('ipilimumab', 'Chemical', 'MESH:D000074324', (149, 159))	('nivolumab', 'Chemical', 'MESH:D000077594', (135, 144))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('patients', 'Species', '9606', (174, 182))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('cell surface', 'cellular_component', 'GO:0009986', ('324', '336'))	('nivolumab', 'Chemical', 'MESH:D000077594', (76, 85))	('mutation', 'Var', (191, 199))	('tumour', 'Disease', (269, 275))
103013	27336610	One could interpret these results that given the increased toxicity of dual checkpoint inhibitor treatment, combination anti-PD-1 and anti-CTLA-4 could be reserved for PD-L1-negative patients who have shown improved ORR and PFS compared with monotherapy.	('anti-CTLA-4', 'Var', (134, 145))	('ORR', 'CPA', (216, 219))	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('toxicity', 'Disease', (59, 67))	('improved', 'PosReg', (207, 215))	('PD-1', 'Gene', '18566', (125, 129))	('PD-1', 'Gene', (125, 129))	('PFS', 'CPA', (224, 227))	('patients', 'Species', '9606', (183, 191))
103015	27336610	In contrast, it should be noted that the Checkmate 069 study demonstrated the superiority of combination therapy (ipilimumab and nivolumab) over ipilimumab monotherapy with an ORR of 61% compared with 11% in BRAF wild-type patients (similar results found in BRAF mutant patients), and also that the ORR was independent of PD-L1 status with similar response rates in PD-L1-positive and -negative tumours.	('nivolumab', 'Chemical', 'MESH:D000077594', (129, 138))	('patients', 'Species', '9606', (270, 278))	('ipilimumab', 'Chemical', 'MESH:D000074324', (114, 124))	('ipilimumab', 'Chemical', 'MESH:D000074324', (145, 155))	('tumour', 'Phenotype', 'HP:0002664', (395, 401))	('tumours', 'Phenotype', 'HP:0002664', (395, 402))	('mutant', 'Var', (263, 269))	('tumours', 'Disease', 'MESH:D009369', (395, 402))	('patients', 'Species', '9606', (223, 231))	('tumours', 'Disease', (395, 402))
103018	27336610	To date, a number of studies have revealed molecular features of melanoma that modulate response to immune therapy, which include: mutational load, intrinsic transcriptomic states and intestinal microbiome, as well as the composition of peripheral immune cells in patients and melanoma immune infiltrates.	('mutational', 'Var', (131, 141))	('melanoma', 'Disease', 'MESH:D008545', (277, 285))	('melanoma', 'Phenotype', 'HP:0002861', (277, 285))	('melanoma', 'Disease', (277, 285))	('patients', 'Species', '9606', (264, 272))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('modulate', 'Reg', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
103020	27336610	The earliest multipatient melanoma exome sequencing study with anti-CTLA-4 blockade response data revealed that a high mutational burden was associated with increased survival.	('survival', 'MPA', (167, 175))	('patient', 'Species', '9606', (18, 25))	('increased', 'PosReg', (157, 166))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('mutational', 'Var', (119, 129))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
103023	27336610	A study of 110 patients with complete WES and a subset of RNA-seq data determined mutational and neoantigen load, as well as expression of cytolytic markers in the microenvironment were associated with clinical benefit to anti-CTLA4 treatment.	('RNA', 'cellular_component', 'GO:0005562', ('58', '61'))	('patients', 'Species', '9606', (15, 23))	('CTLA4', 'Gene', '1493', (227, 232))	('CTLA4', 'Gene', (227, 232))	('mutational', 'Var', (82, 92))	('neoantigen load', 'MPA', (97, 112))
103028	27336610	Although few specific gene mutations have been found to modulate response to immune therapy, mutations in BRCA2 have been linked to improved response and PTEN mutations/deletions in resistance to anti-PD-1 checkpoint inhibitors.	('response', 'MPA', (141, 149))	('mutations', 'Var', (93, 102))	('improved', 'PosReg', (132, 140))	('PD-1', 'Gene', '18566', (201, 205))	('PD-1', 'Gene', (201, 205))	('BRCA2', 'Gene', (106, 111))	('mutations/deletions', 'Var', (159, 178))	('BRCA2', 'Gene', '675', (106, 111))	('PTEN', 'Gene', (154, 158))	('PTEN', 'Gene', '5728', (154, 158))
103039	27336610	Such analyses has revealed low frequency actionable mutations in EZH2, AKT3 and PIK3CA, as well as driver mutations frequently found in other types of melanoma, such as GNAQ and GNA11.	('mutations', 'Var', (52, 61))	('GNAQ', 'Gene', (169, 173))	('EZH2', 'Gene', (65, 69))	('EZH2', 'Gene', '2146', (65, 69))	('GNAQ', 'Gene', '2776', (169, 173))	('GNA11', 'Gene', (178, 183))	('AKT3', 'Gene', '10000', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('PIK3CA', 'Gene', (80, 86))	('melanoma', 'Disease', (151, 159))	('AKT3', 'Gene', (71, 75))	('GNA11', 'Gene', '2767', (178, 183))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('PIK3CA', 'Gene', '5290', (80, 86))
103040	27336610	Therapeutic strategies to target these frequently mutated G proteins in uveal melanomas include combination MAPK- (e.g., PD0325901 or MEK162) and PKC- (e.g., AEB071) targeted therapies.	('G proteins', 'Protein', (58, 68))	('PKC', 'molecular_function', 'GO:0004697', ('146', '149'))	('PKC', 'Disease', 'MESH:C537180', (146, 149))	('melanomas', 'Phenotype', 'HP:0002861', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('PD0325901', 'Var', (121, 130))	('uveal melanomas', 'Disease', (72, 87))	('uveal melanomas', 'Phenotype', 'HP:0007716', (72, 87))	('PKC', 'Disease', (146, 149))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('uveal melanomas', 'Disease', 'MESH:C536494', (72, 87))
103041	27336610	In addition, hotspot mutations in epigenetic regulators, such as IDH1 (p. R132), and less the frequently mutated EZH2 (p.Y641), indicate another potential mode of action for targeted therapy in melanoma.	('IDH1', 'Gene', '3417', (65, 69))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('p. R132', 'Var', (71, 78))	('p.Y641', 'Var', (119, 125))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('IDH1', 'Gene', (65, 69))	('EZH2', 'Gene', '2146', (113, 117))	('EZH2', 'Gene', (113, 117))
103043	27336610	Furthermore, AKT1/3 and PIK3CA mutations observed in BRAF and RAS mutant melanomas may be useful biomarkers for possible combination therapy utilising MAPK and PI(3)K/AKT/mTOR inhibitors.	('AKT', 'Gene', (167, 170))	('mutant', 'Var', (66, 72))	('PIK3CA', 'Gene', '5290', (24, 30))	('mTOR', 'Gene', '2475', (171, 175))	('AKT', 'Gene', (13, 16))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))	('AKT1', 'Gene', (13, 17))	('melanomas', 'Disease', (73, 82))	('RAS', 'Gene', (62, 65))	('AKT', 'Gene', '207', (167, 170))	('MAPK', 'molecular_function', 'GO:0004707', ('151', '155'))	('PI(3)K', 'molecular_function', 'GO:0016303', ('160', '166'))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('BRAF', 'Gene', (53, 57))	('AKT', 'Gene', '207', (13, 16))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('AKT1', 'Gene', '207', (13, 17))	('mTOR', 'Gene', (171, 175))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
103046	27336610	In 2013, two concurrent studies identified two mutually exclusive recurrent TERT promoter mutations found in ~70% of cutaneous melanoma.	('TERT', 'Gene', '7015', (76, 80))	('mutations', 'Var', (90, 99))	('cutaneous melanoma', 'Disease', (117, 135))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('TERT', 'Gene', (76, 80))
103047	27336610	These hotspot mutations were discovered through interrogation of familial melanomas and the analysis of WGS data.	('familial melanomas', 'Disease', (65, 83))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('familial melanomas', 'Disease', 'OMIM:155600', (65, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mutations', 'Var', (14, 23))
103048	27336610	In the familial study, linkage analysis and high-throughput sequencing of a melanoma prone family revealed a disease-segregating germline mutation in the TERT promoter.	('melanoma', 'Disease', (76, 84))	('germline mutation in', 'Var', (129, 149))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('TERT', 'Gene', (154, 158))	('TERT', 'Gene', '7015', (154, 158))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
103049	27336610	Subsequent sequencing of sporadic melanomas did not identify the same TERT promoter mutation, but instead identified 74% of metastatic melanoma cell lines, 85% of metastatic tissue and 33% of primary melanomas that possessed TERT promoter mutations predominantly at two positions, chr 5: 1 295 228 C>T (C228T) and chr 5: 1 295 250 C>T (C250T), in a mutually exclusive manner (Table 2).	('250 C>T', 'Var', (327, 334))	('C250T', 'Mutation', 'c.250C>T', (336, 341))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('melanoma', 'Disease', (200, 208))	('TERT', 'Gene', (70, 74))	('melanomas', 'Disease', 'MESH:D008545', (34, 43))	('TERT', 'Gene', '7015', (70, 74))	('sporadic melanomas', 'Disease', 'MESH:D008545', (25, 43))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('melanomas', 'Disease', 'MESH:D008545', (200, 209))	('melanomas', 'Disease', (34, 43))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanomas', 'Disease', (200, 209))	('TERT', 'Gene', (225, 229))	('TERT', 'Gene', '7015', (225, 229))	('250 C>T', 'SUBSTITUTION', 'None', (327, 334))	('melanoma', 'Disease', 'MESH:D008545', (200, 208))	('228 C>T', 'SUBSTITUTION', 'None', (294, 301))	('228 C>T', 'Var', (294, 301))	('melanomas', 'Phenotype', 'HP:0002861', (34, 43))	('C228T', 'Mutation', 'c.228C>T', (303, 308))	('melanomas', 'Phenotype', 'HP:0002861', (200, 209))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('sporadic melanomas', 'Disease', (25, 43))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
103050	27336610	These mutants produce a new ETS/TCF binding motif that led to increased transcriptional activity and TERT expression.	('TERT', 'Gene', '7015', (101, 105))	('increased', 'PosReg', (62, 71))	('transcriptional', 'MPA', (72, 87))	('mutants', 'Var', (6, 13))	('binding', 'molecular_function', 'GO:0005488', ('36', '43'))	('TERT', 'Gene', (101, 105))
103053	27336610	Sequencing analyses of 20 desmoplastic melanomas identified hotspot promoter mutations in NFKBIE in ~15% of cases (Table 2), altering the binding motifs for several transcription factors (e.g., ELF1).	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (26, 48))	('ELF1', 'Gene', '1997', (194, 198))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('melanomas', 'Phenotype', 'HP:0002861', (39, 48))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('binding', 'Interaction', (138, 145))	('ELF1', 'Gene', (194, 198))	('mutations', 'Var', (77, 86))	('NFKBIE', 'Gene', '4794', (90, 96))	('altering', 'Reg', (125, 133))	('transcription', 'biological_process', 'GO:0006351', ('165', '178'))	('NFKBIE', 'Gene', (90, 96))	('desmoplastic melanomas', 'Disease', (26, 48))
103056	27336610	In addition, a number of frequent non-coding mutations causing C>T transitions have been found in cutaneous melanoma, including the mutation in the 5'-UTR of RPS27 identified in ~10% of samples by combining data sets generated from four NGS studies with unpublished data (Table 2).	('RPS27', 'Gene', (158, 163))	('RPS27', 'Gene', '6232', (158, 163))	('mutation in', 'Var', (132, 143))	('cutaneous melanoma', 'Disease', (98, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('C>T transitions', 'Var', (63, 78))
103057	27336610	RPS27 is a component of the 40S subunit of ribosomes whose aberrant expression has been linked to a number of cancers, including melanoma.	('number of cancers', 'Disease', (100, 117))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('linked', 'Reg', (88, 94))	('melanoma', 'Disease', (129, 137))	('aberrant expression', 'Var', (59, 78))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('number of cancers', 'Disease', 'MESH:D009369', (100, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('RPS27', 'Gene', (0, 5))	('RPS27', 'Gene', '6232', (0, 5))
103058	27336610	The RPS27 mutation is thought to increase its expression by expanding the 5'TOP element, a motif known to control mRNA translation regulated through the PI(3)K/AKT and mTOR pathways.	('mTOR', 'Gene', (168, 172))	('mTOR', 'Gene', '2475', (168, 172))	('AKT', 'Gene', '207', (160, 163))	('expanding', 'PosReg', (60, 69))	('mutation', 'Var', (10, 18))	('increase', 'PosReg', (33, 41))	('translation', 'biological_process', 'GO:0006412', ('119', '130'))	('AKT', 'Gene', (160, 163))	('PI(3)K', 'molecular_function', 'GO:0016303', ('153', '159'))	('expression', 'MPA', (46, 56))	("5'TOP element", 'MPA', (74, 87))	('RPS27', 'Gene', (4, 9))	('RPS27', 'Gene', '6232', (4, 9))
103059	27336610	Additional genes whose expression is positively regulated by non-coding mutations include a bi-directional promoter mutation in ~10% of melanomas in two genes, diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes (Table 2).	('mutations', 'Var', (72, 81))	('melanomas', 'Disease', (136, 145))	('diphthamide', 'Chemical', 'MESH:C027527', (160, 171))	('mutation', 'Var', (116, 124))	('OXNAD1', 'Gene', '92106', (246, 252))	('DPH3', 'Gene', '285381', (188, 192))	('NAD-binding', 'molecular_function', 'GO:0070403', ('213', '224'))	('NAD-binding', 'molecular_function', 'GO:0051287', ('213', '224'))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('biosynthesis', 'biological_process', 'GO:0009058', ('172', '184'))	('DPH3', 'Gene', (188, 192))	('melanomas', 'Disease', 'MESH:D008545', (136, 145))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('OXNAD1', 'Gene', (246, 252))	('expression', 'MPA', (23, 33))
103061	27336610	Although reporter assays have suggested that the recurrent mutations in DPH3 and OXNAD1 results in a significant increase in promoter activity, increased mRNA expression of these genes in tumours was not observed.	('promoter activity', 'MPA', (125, 142))	('DPH3', 'Gene', '285381', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('OXNAD1', 'Gene', '92106', (81, 87))	('tumours', 'Disease', 'MESH:D009369', (188, 195))	('tumours', 'Disease', (188, 195))	('DPH3', 'Gene', (72, 76))	('increase', 'PosReg', (113, 121))	('mutations', 'Var', (59, 68))	('OXNAD1', 'Gene', (81, 87))
103062	27336610	In contrast, WGS studies revealed promoter mutations that reduce expression in two genes, which included the succinate dehydrogenase complex, subunit D (SDHD) and the NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9 (NUDFB9) (Table 2).	('succinate dehydrogenase', 'Gene', (109, 132))	('SDHD', 'Gene', (153, 157))	('SDHD', 'Gene', '6392', (153, 157))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('109', '140'))	('mutations', 'Var', (43, 52))	('expression', 'MPA', (65, 75))	('reduce', 'NegReg', (58, 64))	('succinate dehydrogenase', 'Gene', '6390', (109, 132))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('109', '140'))
103063	27336610	A pancancer WGS analysis first revealed the SDHD promoter mutations, which disrupt ETS binding sites, resulting in decreased expression.	('mutations', 'Var', (58, 67))	('binding', 'molecular_function', 'GO:0005488', ('87', '94'))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('binding sites', 'Interaction', (87, 100))	('cancer', 'Disease', (5, 11))	('SDHD', 'Gene', (44, 48))	('SDHD', 'Gene', '6392', (44, 48))	('decreased', 'NegReg', (115, 124))	('expression', 'MPA', (125, 135))	('disrupt', 'NegReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('ETS', 'Protein', (83, 86))
103065	27336610	Decreased SDHD expression caused by the promoter mutations is consistent with its tumour suppressor function.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('mutations', 'Var', (49, 58))	('Decreased', 'NegReg', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('expression', 'MPA', (15, 25))	('SDHD', 'Gene', (10, 14))	('SDHD', 'Gene', '6392', (10, 14))
103066	27336610	The recurrent NDUFB9 promoter mutation was discovered from the first sequencing of a melanoma cell line, COLO-829, and was subsequently validated with TCGA data and functional studies, which determined that ~5% of melanomas possess this mutation.	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('mutation', 'Var', (30, 38))	('melanoma', 'Disease', (214, 222))	('melanomas', 'Phenotype', 'HP:0002861', (214, 223))	('NDUFB9', 'Gene', '4715', (14, 20))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('melanomas', 'Disease', 'MESH:D008545', (214, 223))	('COLO-829', 'CellLine', 'CVCL:1137', (105, 113))	('NDUFB9', 'Gene', (14, 20))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanomas', 'Disease', (214, 223))
103067	27336610	Luciferase assays demonstrated modest effects on the promoter activity, and the expression of the corresponding gene in tumour data is not significant between mutant and wild-type samples.	('promoter activity', 'MPA', (53, 70))	('mutant', 'Var', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
103074	27336610	Furthermore, genomic studies to date have revealed actionable, low-frequency driver mutations in melanoma.	('mutations', 'Var', (84, 93))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))
103076	27336610	It is clear that preclinical studies are needed to determine efficacy of such treatment strategies to target less well-understood mutations in melanoma, including NF1 mutant melanomas.	('NF1', 'Gene', (163, 166))	('NF1', 'Gene', '4763', (163, 166))	('melanomas', 'Disease', (174, 183))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('mutant', 'Var', (167, 173))	('melanoma', 'Disease', (143, 151))	('melanoma', 'Disease', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('melanomas', 'Disease', 'MESH:D008545', (174, 183))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))
103077	27336610	Finally, understanding the biological significance of novel recurrent non-coding mutations in genes with poorly understood function that occur in a relatively large fraction of patients may provide new therapeutic strategies to treat melanoma.	('patients', 'Species', '9606', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('melanoma', 'Disease', (234, 242))	('non-coding mutations', 'Var', (70, 90))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))
103078	23947671	A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma Many people frequently tan indoors despite being aware of the increased risk of melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('genetic variants', 'Var', (17, 33))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('people', 'Species', '9606', (95, 101))	('dopamine', 'Chemical', 'MESH:D004298', (37, 45))
103080	23947671	In this pilot study, we relied on questionnaire and DNA data from a recently completed case-control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls.	('dopamine', 'Chemical', 'MESH:D004298', (190, 198))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('single-nucleotide polymorphisms', 'Var', (120, 151))	('dopamine', 'Gene', (190, 198))	('drug metabolism', 'biological_process', 'GO:0017144', ('212', '227'))
103082	23947671	In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment.	('ANKK1', 'Gene', '255239', (202, 207))	('associated', 'Reg', (129, 139))	('indoor tanning use', 'Disease', (145, 163))	('ANKK1', 'Gene', '255239', (90, 95))	('variants', 'Var', (42, 50))	('ANKK1', 'Gene', (202, 207))	('DRD2', 'Gene', (63, 67))	('ANKK1', 'Gene', (90, 95))	('DRD2', 'Gene', '1813', (63, 67))	('dopamine', 'Chemical', 'MESH:D004298', (68, 76))	('signalling', 'biological_process', 'GO:0023052', ('96', '106'))
103083	23947671	Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma.	('DRD2', 'Gene', (26, 30))	('SNPs', 'Var', (8, 12))	('DRD2', 'Gene', '1813', (26, 30))	('associated', 'Reg', (31, 41))	('ANKK1', 'Gene', '255239', (16, 21))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('ANKK1', 'Gene', (16, 21))	('associated', 'Reg', (99, 109))	('indoor tanning', 'Disease', (47, 61))
103095	23947671	One hypothesis about a relationship between indoor tanning and substance use is that UVR exposure modifies biological reward pathways in the brain, such as through the dopamine system, similar to the effects of nicotine, alcohol or other chemical substances.	('UVR', 'Var', (85, 88))	('alcohol', 'Chemical', 'MESH:D000438', (221, 228))	('dopamine', 'Chemical', 'MESH:D004298', (168, 176))	('biological reward pathways', 'Pathway', (107, 133))	('nicotine', 'Chemical', 'MESH:D009538', (211, 219))	('modifies', 'Reg', (98, 106))
103096	23947671	There is now a growing body of work to support associations of genetic variants from genes involved with dopamine regulation and drug metabolism with addiction.	('drug metabolism', 'biological_process', 'GO:0017144', ('129', '144'))	('addiction', 'Disease', (150, 159))	('genetic variants', 'Var', (63, 79))	('dopamine', 'Chemical', 'MESH:D004298', (105, 113))	('associations', 'Interaction', (47, 59))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))
103097	23947671	Associations of variants in DRD2 with dependency for alcohol, cocaine, heroin and nicotine have been verified by meta-analysis.	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('heroin', 'Chemical', 'MESH:D003932', (71, 77))	('Associations', 'Interaction', (0, 12))	('DRD2', 'Gene', (28, 32))	('dependency for alcohol', 'Phenotype', 'HP:0030955', (38, 60))	('nicotine', 'Chemical', 'MESH:D009538', (82, 90))	('DRD2', 'Gene', '1813', (28, 32))	('cocaine', 'Chemical', 'MESH:D003042', (62, 69))	('variants', 'Var', (16, 24))
103098	23947671	The purpose of this study was to explore the association of single-nucleotide polymorphisms (SNPs) in candidate genes involved in dopamine regulation and drug metabolism (ANKK1, CYP2A6, CYP2A7, DRD2 and SLCA3) with indoor tanning behaviour for participants in the Skin Health Study.	('dopamine', 'Chemical', 'MESH:D004298', (130, 138))	('ANKK1', 'Gene', (171, 176))	('DRD2', 'Gene', '1813', (194, 198))	('association', 'Interaction', (45, 56))	('drug metabolism', 'biological_process', 'GO:0017144', ('154', '169'))	('indoor tanning behaviour', 'Disease', (215, 239))	('regulation', 'biological_process', 'GO:0065007', ('139', '149'))	('single-nucleotide polymorphisms', 'Var', (60, 91))	('CYP2A6', 'Gene', '1548', (178, 184))	('participants', 'Species', '9606', (244, 256))	('behaviour', 'biological_process', 'GO:0007610', ('230', '239'))	('ANKK1', 'Gene', '255239', (171, 176))	('CYP2A7', 'Gene', (186, 192))	('CYP2A7', 'Gene', '1549', (186, 192))	('SLCA3', 'Gene', (203, 208))	('CYP2A6', 'Gene', (178, 184))	('DRD2', 'Gene', (194, 198))
103105	23947671	Hair colour, eye colour and inability to tan were assigned a numerical value, and the sum of these phenotypes, ranging from 1 to 5, represents the phenotypic index score: hair colour (1 = black/dark brown; 2 = light brown/blond; 3 = red), eye colour (0 = black/brown; 1 = hazel/green/grey/blue) and inability to tan (0 = easily tan; 1 = poorly tan).	('0 =', 'Var', (251, 254))	('inability', 'Disease', 'MESH:D016388', (28, 37))	('inability', 'Disease', 'MESH:D016388', (299, 308))	('inability', 'Disease', (28, 37))	('inability', 'Disease', (299, 308))
103117	23947671	Participants with BMIs 30 and above were less likely to have ever tanned indoors compared with participants with BMIs between 18.5 and 24.9 (OR = 0.42; CI: 0.29, 0.62).	('participants', 'Species', '9606', (95, 107))	('Participants', 'Species', '9606', (0, 12))	('BMIs 30', 'Var', (18, 25))	('less', 'NegReg', (41, 45))
103119	23947671	Of the 67 SNPs investigated, three SNPs in ANKK1 and one SNP in DRD2 were each positively associated with having ever tanned indoors among controls (unadjusted P-value < 0.05; Tables 1 and S2).	('SNPs', 'Var', (35, 39))	('DRD2', 'Gene', '1813', (64, 68))	('ANKK1', 'Gene', (43, 48))	('associated with', 'Reg', (90, 105))	('ANKK1', 'Gene', '255239', (43, 48))	('DRD2', 'Gene', (64, 68))
103120	23947671	The association between individuals with variants in the three ANKK1 SNPs, rs2734848, rs1003641, rs12422191, with indoor tanning remained significant after adjustment for age and sex.	('rs12422191', 'Var', (97, 107))	('ANKK1', 'Gene', (63, 68))	('rs12422191', 'Mutation', 'rs12422191', (97, 107))	('indoor tanning', 'CPA', (114, 128))	('rs1003641', 'Var', (86, 95))	('rs2734848', 'Var', (75, 84))	('rs2734848', 'Mutation', 'rs2734848', (75, 84))	('ANKK1', 'Gene', '255239', (63, 68))	('rs1003641', 'Mutation', 'rs1003641', (86, 95))
103121	23947671	However, with adjustment, the association between individuals with variants in DRD2 SNP rs2440390 and indoor tanning observed in the crude analysis was attenuated and no longer statistically significant.	('rs2440390', 'Mutation', 'rs2440390', (88, 97))	('DRD2', 'Gene', (79, 83))	('variants', 'Var', (67, 75))	('indoor tanning', 'CPA', (102, 116))	('attenuated', 'NegReg', (152, 162))	('DRD2', 'Gene', '1813', (79, 83))	('rs2440390', 'Var', (88, 97))
103122	23947671	No SNPs in the SLC6A3 and CYP6A or CYP7A genes were associated with tanning behaviour among controls (Table S3).	('tanning', 'Disease', (68, 75))	('CYP7A', 'Var', (35, 40))	('associated', 'Reg', (52, 62))	('SLC6A3', 'Gene', (15, 21))	('CYP6A', 'Gene', (26, 31))	('behaviour', 'biological_process', 'GO:0007610', ('76', '85'))	('SLC6A3', 'Gene', '6531', (15, 21))
103123	23947671	Similar to the individual SNP analysis, haplotypes within ANKK1 and DRD2 were also positively associated with having ever tanned indoors among controls (Table 2).	('DRD2', 'Gene', (68, 72))	('ANKK1', 'Gene', (58, 63))	('DRD2', 'Gene', '1813', (68, 72))	('haplotypes', 'Var', (40, 50))	('associated', 'Reg', (94, 104))	('ANKK1', 'Gene', '255239', (58, 63))
103124	23947671	The age- and sex-adjusted OR for the ANKK1 haplotype, which included the three SNPs found to be associated with indoor tanning in the first analysis, and two new SNPs (rs1800497, rs1279490), was 1.68 (95% CI: 1.31, 2.50, P-value = 0.01) for having ever versus never tanned indoors.	('indoor tanning', 'Disease', (112, 126))	('rs1279490', 'Var', (179, 188))	('rs1279490', 'Mutation', 'rs1279490', (179, 188))	('associated', 'Reg', (96, 106))	('ANKK1', 'Gene', '255239', (37, 42))	('rs1800497', 'Mutation', 'rs1800497', (168, 177))	('rs1800497', 'Var', (168, 177))	('ANKK1', 'Gene', (37, 42))
103125	23947671	A DRD2 haplotype, comprised of nine SNPs (including rs2440390 from the first analysis), was also positively associated with having ever tanned indoors among controls, but the association was only marginally significant after adjustment for age and sex (P-value = 0.06).	('rs2440390', 'Var', (52, 61))	('DRD2', 'Gene', (2, 6))	('DRD2', 'Gene', '1813', (2, 6))	('rs2440390', 'Mutation', 'rs2440390', (52, 61))
103126	23947671	As was observed for the individual SNPs, no haplotypes in the SLC6A3 and CYP6A or CYP7A genes were associated with tanning behaviour (Table S3) among controls.	('SLC6A3', 'Gene', (62, 68))	('SLC6A3', 'Gene', '6531', (62, 68))	('CYP6A', 'Gene', (73, 78))	('haplotypes', 'Var', (44, 54))	('tanning', 'Disease', (115, 122))	('CYP7A', 'Gene', (82, 87))	('behaviour', 'biological_process', 'GO:0007610', ('123', '132'))	('associated', 'Reg', (99, 109))
103127	23947671	In the analysis comparing cases and controls, two SNPs in ANKK1 (including rs1003641 from the individual and haplotype analyses) and three SNPs in DRD2 (all part of the DRD2 haplotype) were positively associated with increased risk of melanoma after adjustment for age, sex and phenotypic index (Table 3).	('DRD2', 'Gene', (147, 151))	('SNPs', 'Var', (139, 143))	('SNPs', 'Var', (50, 54))	('ANKK1', 'Gene', (58, 63))	('rs1003641', 'Var', (75, 84))	('DRD2', 'Gene', '1813', (147, 151))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('ANKK1', 'Gene', '255239', (58, 63))	('melanoma', 'Disease', (235, 243))	('rs1003641', 'Mutation', 'rs1003641', (75, 84))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('associated', 'Reg', (201, 211))	('DRD2', 'Gene', (169, 173))	('DRD2', 'Gene', '1813', (169, 173))
103131	23947671	Two DRD2 SNPS, rs12805897 and rs12364283, were associated with increased risk of melanoma in participants who had ever tanned indoors, but only weakly associated with decreased risk of melanoma in participants who had never tanned indoors.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('DRD2', 'Gene', (4, 8))	('rs12805897', 'Mutation', 'rs12805897', (15, 25))	('rs12805897', 'Var', (15, 25))	('rs12364283', 'Var', (30, 40))	('rs12364283', 'Mutation', 'rs12364283', (30, 40))	('DRD2', 'Gene', '1813', (4, 8))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('participants', 'Species', '9606', (93, 105))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))	('participants', 'Species', '9606', (197, 209))
103133	23947671	Conversely, ANKK1 SNP rs12422191 and DRD2 SNP rs2440390 were associated with increased risk of melanoma in those that had never tanned indoors while being only weakly associated with a decreased risk of melanoma in those that had ever tanned indoors.	('DRD2', 'Gene', (37, 41))	('SNP', 'Var', (42, 45))	('rs12422191', 'Var', (22, 32))	('DRD2', 'Gene', '1813', (37, 41))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('rs2440390', 'Mutation', 'rs2440390', (46, 55))	('ANKK1', 'Gene', '255239', (12, 17))	('rs12422191', 'Mutation', 'rs12422191', (22, 32))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('rs2440390', 'Var', (46, 55))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('ANKK1', 'Gene', (12, 17))
103134	23947671	This is the first study to examine the relationship of variants in genes involved in dopamine regulation and drug metabolism with tanning behaviour in a highly exposed population.	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('variants', 'Var', (55, 63))	('drug metabolism', 'biological_process', 'GO:0017144', ('109', '124'))	('behaviour', 'biological_process', 'GO:0007610', ('138', '147'))	('tanning', 'Disease', (130, 137))	('dopamine', 'Chemical', 'MESH:D004298', (85, 93))
103135	23947671	However, consistent associations of SNPs in the ANKK1 and DRD2 genes with indoor tanning persisted across single SNP and haplotype analysis.	('ANKK1', 'Gene', '255239', (48, 53))	('SNPs', 'Var', (36, 40))	('indoor tanning', 'Disease', (74, 88))	('ANKK1', 'Gene', (48, 53))	('DRD2', 'Gene', (58, 62))	('DRD2', 'Gene', '1813', (58, 62))
103136	23947671	A SNP in ANKK1 was also associated with risk of melanoma and could be important to the relationship between other addictive exposures and melanoma risk.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Disease', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('associated', 'Reg', (24, 34))	('ANKK1', 'Gene', '255239', (9, 14))	('SNP', 'Var', (2, 5))	('ANKK1', 'Gene', (9, 14))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
103137	23947671	No consistent associations were found for SNPs in the SLC6A3 dopamine receptor gene or the CYP2A6 and CYP2A7 drug metabolism genes.	('CYP2A7', 'Gene', (102, 108))	('CYP2A6', 'Gene', '1548', (91, 97))	('CYP2A7', 'Gene', '1549', (102, 108))	('CYP2A6', 'Gene', (91, 97))	('drug metabolism', 'biological_process', 'GO:0017144', ('109', '124'))	('SLC6A3', 'Gene', (54, 60))	('SNPs', 'Var', (42, 46))	('dopamine', 'Chemical', 'MESH:D004298', (61, 69))	('SLC6A3', 'Gene', '6531', (54, 60))
103142	23947671	Theoretically, dysregulation of dopamine receptor function could modify the reward response from UV exposure and increase the desire to tan.	('reward response', 'MPA', (76, 91))	('dopamine receptor', 'Protein', (32, 49))	('dopamine', 'Chemical', 'MESH:D004298', (32, 40))	('increase', 'PosReg', (113, 121))	('modify', 'Reg', (65, 71))	('dysregulation', 'Var', (15, 28))	('desire to tan', 'MPA', (126, 139))
103152	23947671	The SNP rs1003641 was consistently associated with increased likelihood to have ever tanned indoors in single SNP analyses and in haplotype analyses and with increased risk of melanoma.	('rs1003641', 'Var', (8, 17))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('rs1003641', 'Mutation', 'rs1003641', (8, 17))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))
103153	23947671	Other SNPs in ANNK1 and DRD2 were also associated with increased risk of melanoma.	('melanoma', 'Disease', (73, 81))	('ANNK1', 'Gene', (14, 19))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('DRD2', 'Gene', (24, 28))	('DRD2', 'Gene', '1813', (24, 28))	('SNPs', 'Var', (6, 10))	('associated', 'Reg', (39, 49))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
103157	23947671	Other factors related to addictive behaviour such as frequent sun exposure, and alcohol, smoking or other substance use should be considered in the development of melanoma in never tanners with ANKK1 and DRD2 variants.	('DRD2', 'Gene', '1813', (204, 208))	('addictive behaviour', 'Phenotype', 'HP:0030858', (25, 44))	('variants', 'Var', (209, 217))	('behaviour', 'biological_process', 'GO:0007610', ('35', '44'))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('ANKK1', 'Gene', '255239', (194, 199))	('ANKK1', 'Gene', (194, 199))	('DRD2', 'Gene', (204, 208))	('alcohol', 'Chemical', 'MESH:D000438', (80, 87))
103159	23947671	Interestingly, when we queried the TCGA skin cutaneous melanoma data set for mutations and copy number variations (CNVs) in DRD2 and ANKK1 using the cBio Cancer Genomics portal, we found that nearly 12% of the skin cutaneous melanomas contained DRD2/ANKK1 mutations or CNVs, the highest prevalence compared with other cancers studied thus far, including lung cancer for which there are published studies suggesting an association of DRD2 SNPs with smoking status and lung cancer risk.	('lung cancer', 'Disease', (467, 478))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DRD2', 'Gene', '1813', (433, 437))	('ANKK1', 'Gene', '255239', (250, 255))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (215, 234))	('mutations', 'Var', (256, 265))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (215, 233))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (40, 63))	('ANKK1', 'Gene', (133, 138))	('skin cutaneous melanomas', 'Disease', 'MESH:C562393', (210, 234))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('skin cutaneous melanoma', 'Disease', (40, 63))	('association', 'Interaction', (418, 429))	('cancers', 'Phenotype', 'HP:0002664', (318, 325))	('cancers', 'Disease', (318, 325))	('lung cancer', 'Disease', (354, 365))	('DRD2', 'Gene', (245, 249))	('lung cancer', 'Disease', 'MESH:D008175', (467, 478))	('melanomas', 'Phenotype', 'HP:0002861', (225, 234))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (45, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (467, 478))	('DRD2', 'Gene', (124, 128))	('ANKK1', 'Gene', '255239', (133, 138))	('contained', 'Reg', (235, 244))	('ANKK1', 'Gene', (250, 255))	('DRD2', 'Gene', '1813', (245, 249))	('lung cancer', 'Disease', 'MESH:D008175', (354, 365))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('CNVs', 'Var', (269, 273))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (210, 233))	('DRD2', 'Gene', (433, 437))	('skin cutaneous melanomas', 'Disease', (210, 234))	('cancers', 'Disease', 'MESH:D009369', (318, 325))	('cancer', 'Phenotype', 'HP:0002664', (472, 478))	('DRD2', 'Gene', '1813', (124, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (354, 365))
103160	23947671	There was a strong tendency for mutations and CNVs in DRD2 and ANKK1 to occur together (i.e.	('DRD2', 'Gene', '1813', (54, 58))	('ANKK1', 'Gene', (63, 68))	('CNVs', 'Var', (46, 50))	('mutations', 'Var', (32, 41))	('DRD2', 'Gene', (54, 58))	('ANKK1', 'Gene', '255239', (63, 68))
103161	23947671	Although it is unclear how DRD2 somatic genetic variants might influence tanning behaviour, these results suggest that the DRD2 dopamine receptor gene and ANKK1 signalling genes are intriguing candidates for association with tanning behaviour.	('behaviour', 'biological_process', 'GO:0007610', ('81', '90'))	('ANKK1', 'Gene', '255239', (155, 160))	('tanning behaviour', 'Disease', (225, 242))	('DRD2', 'Gene', '1813', (123, 127))	('DRD2', 'Gene', (27, 31))	('dopamine', 'Chemical', 'MESH:D004298', (128, 136))	('variants', 'Var', (48, 56))	('DRD2', 'Gene', '1813', (27, 31))	('ANKK1', 'Gene', (155, 160))	('influence', 'Reg', (63, 72))	('behaviour', 'biological_process', 'GO:0007610', ('233', '242'))	('signalling', 'biological_process', 'GO:0023052', ('161', '171'))	('association', 'Interaction', (208, 219))	('DRD2', 'Gene', (123, 127))
103174	31880399	In the past decade, the collective work from several groups has led to the identification of important recurrent mutations and overactive signaling pathways in this cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('signaling', 'biological_process', 'GO:0023052', ('138', '147'))	('overactive', 'PosReg', (127, 137))
103175	31880399	This includes constitutively active variants of GNAQ and GNA11, which are found in over 90% of cases (Van Raamsdonk et al., 2009, 2010).	('GNA11', 'Gene', (57, 62))	('GNAQ', 'Gene', (48, 52))	('GNA11', 'Gene', '14672', (57, 62))	('variants', 'Var', (36, 44))
103176	31880399	A smaller subset of tumors harbor activating mutations in the G protein-coupled receptor cysteinyl leukotriene receptor 2 (CYSLTR2) or phospholipase C beta 4 (PLCB4) (Johansson et al., 2016; Moore et al., 2016).	('PLCB4', 'Gene', (159, 164))	('activating', 'Reg', (34, 44))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', (20, 26))	('cysteinyl leukotriene receptor 2', 'Gene', '70086', (89, 121))	('CYSLTR2', 'Gene', '70086', (123, 130))	('cysteinyl leukotriene receptor 2', 'Gene', (89, 121))	('CYSLTR2', 'Gene', (123, 130))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('protein', 'cellular_component', 'GO:0003675', ('64', '71'))	('PLCB4', 'Gene', '18798', (159, 164))	('phospholipase C beta 4', 'Gene', '18798', (135, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('phospholipase C beta 4', 'Gene', (135, 157))
103177	31880399	There is a second node of nearly mutually exclusive mutations that classifies uveal melanomas and affects prognosis.	('mutations', 'Var', (52, 61))	('melanomas', 'Disease', (84, 93))	('uveal melanomas', 'Phenotype', 'HP:0007716', (78, 93))	('affects', 'Reg', (98, 105))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('uveal melanoma', 'Phenotype', 'HP:0007716', (78, 92))	('uveal melanoma', 'Disease', 'MESH:C536494', (78, 92))	('uveal melanoma', 'Disease', (78, 92))
103180	31880399	Most importantly, tumors with loss-of-function BAP1 mutations carry the worst prognosis, as approximately 84% of metastatic uveal melanomas are of this subtype (Harbour et al., 2010; Shain et al., 2019).	('mutations', 'Var', (52, 61))	('melanomas', 'Disease', (130, 139))	('loss-of-function', 'NegReg', (30, 46))	('uveal melanoma', 'Disease', (124, 138))	('uveal melanoma', 'Disease', 'MESH:C536494', (124, 138))	('uveal melanoma', 'Phenotype', 'HP:0007716', (124, 138))	('melanomas', 'Phenotype', 'HP:0002861', (130, 139))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('melanomas', 'Disease', 'MESH:D008545', (130, 139))	('BAP1', 'Gene', '104416', (47, 51))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('uveal melanomas', 'Phenotype', 'HP:0007716', (124, 139))	('BAP1', 'Gene', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
103182	31880399	Monosomy 3 co-occurs with BAP1 mutation, thereby eliminating both functional alleles (Field et al., 2018; Robertson et al., 2017).	('BAP1', 'Gene', (26, 30))	('eliminating', 'NegReg', (49, 60))	('mutation', 'Var', (31, 39))	('BAP1', 'Gene', '104416', (26, 30))	('Monosomy 3', 'Var', (0, 10))	('functional alleles', 'MPA', (66, 84))
103194	31880399	However, tumorigenesis in these models required mutation of p53, and metastasis was difficult to assess because of the induction of multiple primary tumors (Mouti et al., 2016; Perez et al., 2018).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('primary tumors', 'Disease', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53', 'Gene', (60, 63))	('tumor', 'Disease', (9, 14))	('mutation', 'Var', (48, 56))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('primary tumors', 'Disease', 'MESH:D001932', (141, 155))	('p53', 'Gene', '22060', (60, 63))
103226	31880399	Interestingly, there are a few syngeneic models that do carry canonical uveal melanoma mutations.	('uveal melanoma', 'Phenotype', 'HP:0007716', (72, 86))	('uveal melanoma', 'Disease', 'MESH:C536494', (72, 86))	('uveal melanoma', 'Disease', (72, 86))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('mutations', 'Var', (87, 96))
103227	31880399	Immortalized mouse melanocytes transduced with driver mutations found in patients undergo oncogenic transformation and are capable of producing tumors and even metastases (Moore et al., 2016; Van Raamsdonk et al., 2010).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mouse', 'Species', '10090', (13, 18))	('undergo', 'Reg', (82, 89))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('metastases', 'Disease', (160, 170))	('mutations', 'Var', (54, 63))	('oncogenic transformation', 'CPA', (90, 114))	('metastases', 'Disease', 'MESH:D009362', (160, 170))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patients', 'Species', '9606', (73, 81))	('producing', 'PosReg', (134, 143))
103229	31880399	Further details on other mutations in this cell line would allow for a more complete assessment of its suitability as a model for uveal melanoma.	('mutations', 'Var', (25, 34))	('uveal melanoma', 'Phenotype', 'HP:0007716', (130, 144))	('uveal melanoma', 'Disease', 'MESH:C536494', (130, 144))	('uveal melanoma', 'Disease', (130, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))
103240	31880399	Frequently used cell lines with validated uveal melanoma mutations are included in Table 2a,b.	('mutations', 'Var', (57, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (42, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (42, 56))	('uveal melanoma', 'Disease', (42, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
103245	31880399	Some lines historically thought to be uveal melanoma have been found to harbor BRAFV600E mutations and are now recognized as being of cutaneous origin (Griewank et al., 2012; Yu et al., 2015).	('uveal melanoma', 'Disease', (38, 52))	('BRAFV600E', 'Mutation', 'rs113488022', (79, 88))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('BRAFV600E', 'Gene', (79, 88))	('mutations', 'Var', (89, 98))	('uveal melanoma', 'Phenotype', 'HP:0007716', (38, 52))	('uveal melanoma', 'Disease', 'MESH:C536494', (38, 52))
103282	31880399	In the first, a Tet-on system was used to induce GNAQQ209L expression in mice deficient for p16Ink4a and p19Ink4b (Feng et al., 2014).	('GNAQQ209L', 'Gene', (49, 58))	('p16Ink4a', 'Gene', '12578', (92, 100))	('induce', 'PosReg', (42, 48))	('mice', 'Species', '10090', (73, 77))	('p19Ink4b', 'Var', (105, 113))	('Tet', 'Chemical', 'MESH:C010349', (16, 19))	('p16Ink4a', 'Gene', (92, 100))	('p19', 'cellular_component', 'GO:0070743', ('105', '108'))
103286	31880399	In a different model, the expression of GNAQQ209L in a lox-stop-lox conditional knock-in allele inserted at the Rosa26 locus produced uveal melanoma in 3 months with 100% penetrance (Huang, Urtatiz, & Van Raamsdonk, 2015).	('lox', 'Gene', (64, 67))	('Rosa26', 'Gene', '14910', (112, 118))	('GNAQQ209L', 'Var', (40, 49))	('lox', 'Gene', '16948', (64, 67))	('uveal melanoma', 'Disease', 'MESH:C536494', (134, 148))	('produced', 'Reg', (125, 133))	('Rosa26', 'Gene', (112, 118))	('lox', 'Gene', (55, 58))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('lox', 'Gene', '16948', (55, 58))	('uveal melanoma', 'Disease', (134, 148))	('uveal melanoma', 'Phenotype', 'HP:0007716', (134, 148))
103291	31880399	When Bap1 deletion was combined with GNA11Q209L expression, uveal melanomas were unexpectedly smaller.	('melanomas', 'Disease', 'MESH:D008545', (66, 75))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('uveal melanomas', 'Phenotype', 'HP:0007716', (60, 75))	('GNA11', 'Gene', (37, 42))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('GNA11', 'Gene', '14672', (37, 42))	('smaller', 'NegReg', (94, 101))	('melanomas', 'Disease', (66, 75))	('uveal melanoma', 'Disease', 'MESH:C536494', (60, 74))	('Bap1', 'Gene', '104416', (5, 9))	('deletion', 'Var', (10, 18))	('uveal melanoma', 'Phenotype', 'HP:0007716', (60, 74))	('uveal melanoma', 'Disease', (60, 74))	('Bap1', 'Gene', (5, 9))
103298	31880399	Interestingly, induction of Tyr-creER in 8-week-old mice in the GNAQQ209L model did not produce overt uveal melanoma.	('Tyr-creER', 'Var', (28, 37))	('Tyr', 'Chemical', 'MESH:D014443', (28, 31))	('mice', 'Species', '10090', (52, 56))	('uveal melanoma', 'Phenotype', 'HP:0007716', (102, 116))	('uveal melanoma', 'Disease', (102, 116))	('uveal melanoma', 'Disease', 'MESH:C536494', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))
103309	31880399	In this model, the suprachoroidal injection of an AAV5-CMV-Cre vector produced ocular melanocytic tumors in adult mice carrying conditional null alleles of the Hippo kinases Lats1 and Lats2, which normally function to suppress YAP/TAZ signaling.	('AAV5-CMV-Cre', 'Var', (50, 62))	('TAZ', 'Gene', (231, 234))	('melanocytic tumors in adult', 'Phenotype', 'HP:0002861', (86, 113))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('Lats1', 'Gene', '16798', (174, 179))	('YAP', 'Gene', (227, 230))	('Lats2', 'Gene', '50523', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ocular melanocytic tumors', 'Disease', 'MESH:D009508', (79, 104))	('Lats2', 'Gene', (184, 189))	('YAP', 'Gene', '22601', (227, 230))	('TAZ', 'Gene', '66826', (231, 234))	('mice', 'Species', '10090', (114, 118))	('Lats1', 'Gene', (174, 179))	('signaling', 'biological_process', 'GO:0023052', ('235', '244'))	('ocular melanocytic tumors', 'Disease', (79, 104))
103324	31880399	Additionally, the loss of Bap1 did not enhance the aggressiveness of uveal melanomas; in fact, the ocular phenotype was weaker, and there was no increase in size or incidence of lung lesions compared with mice expressing GNA11Q209L alone (Moore et al., 2018).	('GNA11', 'Gene', (221, 226))	('GNA11', 'Gene', '14672', (221, 226))	('loss', 'Var', (18, 22))	('weaker', 'NegReg', (120, 126))	('lung lesions', 'Disease', 'MESH:D008171', (178, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (69, 83))	('Bap1', 'Gene', (26, 30))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanomas', 'Phenotype', 'HP:0002861', (75, 84))	('mice', 'Species', '10090', (205, 209))	('uveal melanomas', 'Phenotype', 'HP:0007716', (69, 84))	('Bap1', 'Gene', '104416', (26, 30))	('aggressiveness of uveal melanomas', 'Disease', 'MESH:C536494', (51, 84))	('aggressiveness of uveal melanomas', 'Disease', (51, 84))	('aggressiveness', 'Phenotype', 'HP:0000718', (51, 65))	('lung lesions', 'Disease', (178, 190))
103446	23015891	Ultraviolet light also causes sunburn and photoaging damage to the skin.	('photoaging damage', 'CPA', (42, 59))	('sunburn', 'Disease', 'MESH:D013471', (30, 37))	('causes', 'Reg', (23, 29))	('Ultraviolet', 'Var', (0, 11))	('sunburn', 'Disease', (30, 37))
103543	23015891	Although studies are limited, vitamin D deficiency may affect an athlete's performance.	('deficiency', 'Var', (40, 50))	('affect', 'Reg', (55, 61))	('performance', 'CPA', (75, 86))	('vitamin D', 'Chemical', 'MESH:D014807', (30, 39))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (30, 50))	('vitamin D', 'Gene', (30, 39))
103621	31871622	Among patients who were treated with adjuvant therapy (IFNalpha2b or other), 37% had a treatment modification during treatment (most commonly dose reduction), and 56% discontinued adjuvant treatment (as reported by the physician).	('IFNalpha2b', 'Gene', '3440', (55, 65))	('discontinued', 'NegReg', (167, 179))	('dose reduction', 'Var', (142, 156))	('IFNalpha2b', 'Gene', (55, 65))	('patients', 'Species', '9606', (6, 14))	('treatment', 'MPA', (87, 96))
103648	31871622	In addition to inconsistencies in survival benefits, high-dose IFNalpha2b is associated with substantial toxicities.	('high-dose', 'Var', (53, 62))	('toxicities', 'Disease', 'MESH:D064420', (105, 115))	('IFNalpha2b', 'Gene', (63, 73))	('IFNalpha2b', 'Gene', '3440', (63, 73))	('toxicities', 'Disease', (105, 115))
103690	32043781	Prevalence of NRAS Mutation, PD-L1 Expression and Amplification, and Overall Survival Analysis in 36 Primary Vaginal Melanomas Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential.	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('Vaginal Melanomas', 'Phenotype', 'HP:0030418', (109, 126))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (135, 151))	('melanomas', 'Phenotype', 'HP:0002861', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (135, 152))	('NRAS', 'Gene', '4893', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('aggressive tumors', 'Disease', (170, 187))	('Primary Vaginal Melanomas', 'Disease', 'MESH:D008545', (101, 126))	('aggressive tumors', 'Disease', 'MESH:D001523', (170, 187))	('Mutation', 'Var', (19, 27))	('Primary vaginal melanomas', 'Disease', (127, 152))	('PD-L1', 'Gene', (29, 34))	('PD-L1', 'Gene', '29126', (29, 34))	('NRAS', 'Gene', (14, 18))	('Primary vaginal melanomas', 'Disease', 'MESH:D008545', (127, 152))	('Primary Vaginal Melanomas', 'Disease', (101, 126))	('Melanomas', 'Phenotype', 'HP:0002861', (117, 126))
103695	32043781	Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively.	('primary vaginal melanomas', 'Disease', 'MESH:D008545', (111, 136))	('KIT', 'molecular_function', 'GO:0005020', ('19', '22'))	('primary vaginal melanomas', 'Disease', (111, 136))	('KIT', 'Gene', '3815', (19, 22))	('TERT', 'Gene', (28, 32))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (119, 136))	('Mutations', 'Var', (0, 9))	('NRAS', 'Gene', (13, 17))	('KIT', 'Gene', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('TERT', 'Gene', '7015', (28, 32))	('identified', 'Reg', (47, 57))	('NRAS', 'Gene', '4893', (13, 17))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (119, 135))
103698	32043781	Patients who had NRAS mutations had a poorer overall survival compared with those with a wild-type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08-8.83).	('poorer', 'NegReg', (38, 44))	('NRAS', 'Gene', (17, 21))	('Patients', 'Species', '9606', (0, 8))	('NRAS', 'Gene', (99, 103))	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('NRAS', 'Gene', '4893', (99, 103))	('overall survival', 'MPA', (45, 61))
103701	32043781	NRAS mutations and PD-L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets.	('vaginal melanoma', 'Phenotype', 'HP:0030418', (81, 97))	('PD-L1', 'Gene', (19, 24))	('NRAS', 'Gene', '4893', (0, 4))	('expression', 'MPA', (25, 35))	('prevalent', 'Reg', (46, 55))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (81, 98))	('PD-L1', 'Gene', '29126', (19, 24))	('mutations', 'Var', (5, 14))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('NRAS', 'Gene', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('primary vaginal melanomas', 'Disease', 'MESH:D008545', (73, 98))	('primary vaginal melanomas', 'Disease', (73, 98))
103702	32043781	This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD-L1 expression and copy number in 36 primary vaginal melanomas.	('PD-L1', 'Gene', '29126', (147, 152))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (194, 211))	('primary vaginal melanomas', 'Disease', 'MESH:D008545', (186, 211))	('primary vaginal melanomas', 'Disease', (186, 211))	('copy number', 'Var', (168, 179))	('mutations', 'Var', (133, 142))	('PD-L1', 'Gene', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (194, 210))	('melanomas', 'Phenotype', 'HP:0002861', (202, 211))
103713	32043781	Several studies have focused on identifying the molecular alterations of melanomas composed of specific mutations in NRAS, BRAF, KIT, TERT, and GNAQ/GNA11, observed in distinct subtypes of melanomas.	('TERT', 'Gene', (134, 138))	('TERT', 'Gene', '7015', (134, 138))	('melanomas', 'Phenotype', 'HP:0002861', (189, 198))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))	('GNA11', 'Gene', (149, 154))	('mutations', 'Var', (104, 113))	('NRAS', 'Gene', '4893', (117, 121))	('melanomas', 'Disease', (73, 82))	('KIT', 'Gene', (129, 132))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas', 'Disease', 'MESH:D008545', (189, 198))	('GNA11', 'Gene', '2767', (149, 154))	('NRAS', 'Gene', (117, 121))	('GNAQ', 'Gene', '2776', (144, 148))	('melanomas', 'Disease', (189, 198))	('KIT', 'molecular_function', 'GO:0005020', ('129', '132'))	('KIT', 'Gene', '3815', (129, 132))	('GNAQ', 'Gene', (144, 148))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
103714	32043781	The overall rate of BRAF mutation in melanoma has been found to be up to 67% 14, 15, and the mutation frequently occurs in non-chronically sun-damaged (CSD) skin.	('sun-damaged', 'Phenotype', 'HP:0000992', (139, 150))	('mutation', 'Var', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('BRAF', 'Gene', '673', (20, 24))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('BRAF', 'Gene', (20, 24))
103716	32043781	An increase in copy number (up to 25%) and mutations (10%-20%) of KIT in mucosal, acral, and CSD melanomas were identified 19.	('KIT', 'Gene', (66, 69))	('melanomas', 'Disease', 'MESH:D008545', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanomas', 'Phenotype', 'HP:0002861', (97, 106))	('copy number', 'MPA', (15, 26))	('mutations', 'Var', (43, 52))	('melanomas', 'Disease', (97, 106))	('KIT', 'molecular_function', 'GO:0005020', ('66', '69'))	('KIT', 'Gene', '3815', (66, 69))	('increase', 'PosReg', (3, 11))
103717	32043781	Mutations in GNAQ/GNA11, a gene encoding an alpha subunit of heterotrimeric G proteins, are found in up to 83% of uveal melanomas 20, 21, 22.	('uveal melanomas', 'Disease', 'MESH:C536494', (114, 129))	('found', 'Reg', (92, 97))	('uveal melanoma', 'Phenotype', 'HP:0007716', (114, 128))	('GNAQ', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('Mutations', 'Var', (0, 9))	('melanomas', 'Phenotype', 'HP:0002861', (120, 129))	('uveal melanomas', 'Disease', (114, 129))	('GNA11', 'Gene', (18, 23))	('uveal melanomas', 'Phenotype', 'HP:0007716', (114, 129))	('GNA11', 'Gene', '2767', (18, 23))	('GNAQ', 'Gene', '2776', (13, 17))
103718	32043781	GNAQ and GNA11 mutations in melanomas affect codons 209 or 183 and result in consistent activation of the protein kinase C and MAPK pathways 21, 23.	('GNA11', 'Gene', (9, 14))	('MAPK pathways 21', 'Pathway', (127, 143))	('activation', 'PosReg', (88, 98))	('GNAQ', 'Gene', '2776', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('mutations', 'Var', (15, 24))	('melanomas', 'Disease', (28, 37))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('GNAQ', 'Gene', (0, 4))	('codons 209', 'MPA', (45, 55))	('melanomas', 'Phenotype', 'HP:0002861', (28, 37))	('MAPK', 'molecular_function', 'GO:0004707', ('127', '131'))	('affect', 'Reg', (38, 44))	('melanomas', 'Disease', 'MESH:D008545', (28, 37))	('GNA11', 'Gene', '2767', (9, 14))
103719	32043781	TERT, which encodes the catalytic subunit of telomerase, is mutated in cutaneous melanoma 24, 25, 26 and has been found to be associated with aggressive behavior of the melanoma and a poorer prognosis 25, 27.	('aggressive behavior', 'Phenotype', 'HP:0000718', (142, 161))	('associated with', 'Reg', (126, 141))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('aggressive behavior of the melanoma', 'Disease', 'MESH:D001523', (142, 177))	('mutated', 'Var', (60, 67))	('cutaneous melanoma', 'Disease', (71, 89))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (71, 89))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (71, 89))	('aggressive behavior of the melanoma', 'Disease', (142, 177))	('aggressive behavior', 'biological_process', 'GO:0002118', ('142', '161'))
103720	32043781	In recent years, mutant-selective BRAF 28, MEK 29, 30, 31, and KIT inhibitors 32 have demonstrated impressive clinical results in molecularly selected patients.	('MEK', 'Gene', '5609', (43, 46))	('mutant-selective', 'Var', (17, 33))	('patients', 'Species', '9606', (151, 159))	('BRAF', 'Gene', '673', (34, 38))	('KIT', 'Gene', '3815', (63, 66))	('BRAF', 'Gene', (34, 38))	('KIT', 'molecular_function', 'GO:0005020', ('63', '66'))	('MEK', 'Gene', (43, 46))	('KIT', 'Gene', (63, 66))
103736	32043781	Mutations in BRAF exon 15 V600E were identified by the 7500 real-time quantitative PCR system (Applied Biosystems) using the minor groove binder (MGB) probes.	('groove', 'cellular_component', 'GO:0097610', ('131', '137'))	('BRAF', 'Gene', '673', (13, 17))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', (13, 17))	('V600E', 'Var', (26, 31))
103752	32043781	NRAS mutations were found in 5 of the 36 (13.9%) primary melanomas, of which 4 had Q61R mutation, and one had Q61P mutation.	('Q61R', 'Mutation', 'rs11554290', (83, 87))	('melanomas', 'Disease', (57, 66))	('Q61R mutation', 'Var', (83, 96))	('melanomas', 'Disease', 'MESH:D008545', (57, 66))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanomas', 'Phenotype', 'HP:0002861', (57, 66))	('NRAS', 'Gene', (0, 4))	('found', 'Reg', (20, 25))	('Q61P', 'Var', (110, 114))	('Q61P', 'Mutation', 'rs11554290', (110, 114))	('NRAS', 'Gene', '4893', (0, 4))
103754	32043781	KIT sequence analysis was performed in 34 cases, of which a missense and V559D mutation in KIT exon 11 was detected in one patient (2.9%, 1/34).	('KIT', 'Gene', '3815', (91, 94))	('V559D', 'Mutation', 'rs121913517', (73, 78))	('patient', 'Species', '9606', (123, 130))	('KIT', 'molecular_function', 'GO:0005020', ('0', '3'))	('KIT', 'Gene', (91, 94))	('KIT', 'molecular_function', 'GO:0005020', ('91', '94'))	('KIT', 'Gene', '3815', (0, 3))	('V559D', 'Var', (73, 78))	('KIT', 'Gene', (0, 3))
103764	32043781	Furthermore, Kaplan-Meier survival analyses showed that patients with mutated NRAS had a worse OS compared with those with a wild-type NRAS (33.5 vs. 14.0 months; HR, 3.09; 95% CI, 1.08-8.83; p = .035; Fig.	('patients', 'Species', '9606', (56, 64))	('NRAS', 'Gene', (135, 139))	('NRAS', 'Gene', '4893', (135, 139))	('NRAS', 'Gene', (78, 82))	('NRAS', 'Gene', '4893', (78, 82))	('OS', 'Chemical', '-', (95, 97))	('mutated', 'Var', (70, 77))
103778	32043781	We also reported the patients with or without PD-L1 expression may benefit from immune checkpoint inhibitors.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', '29126', (46, 51))	('patients', 'Species', '9606', (21, 29))	('benefit', 'PosReg', (67, 74))	('expression', 'Var', (52, 62))
103780	32043781	In contrast to existing literature, NRAS mutations were frequently found in melanomas of the skin with CSD and had mutation rates of up to 24% 42.	('mutations', 'Var', (41, 50))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('NRAS', 'Gene', (36, 40))	('NRAS', 'Gene', '4893', (36, 40))	('found', 'Reg', (67, 72))	('melanomas', 'Disease', (76, 85))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
103781	32043781	The frequency of NRAS mutations varied among mucosal melanomas, with a wide range of 0%-43% mutation rates reported in previous studies 10, 43, 44, 45, 46.	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mucosal melanomas', 'Disease', (45, 62))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('NRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('NRAS', 'Gene', '4893', (17, 21))	('mucosal melanomas', 'Disease', 'MESH:D008545', (45, 62))
103782	32043781	It was found that NRAS mutations were present in 37.5% (6/16) of esophageal mucosal melanomas 47 and 7.1%-30% of sinonasal melanomas 48, 49, 50, and none were detected until now in oral mucosal melanomas 50, 51.	('melanomas', 'Disease', (84, 93))	('melanomas', 'Disease', 'MESH:D008545', (194, 203))	('melanomas', 'Disease', 'MESH:D008545', (123, 132))	('melanomas', 'Disease', (194, 203))	('NRAS', 'Gene', (18, 22))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('melanomas', 'Disease', (123, 132))	('esophageal mucosal melanomas', 'Disease', 'MESH:D008545', (65, 93))	('mutations', 'Var', (23, 32))	('esophageal mucosal melanomas', 'Disease', (65, 93))	('oral mucosal melanomas', 'Disease', (181, 203))	('melanomas', 'Phenotype', 'HP:0002861', (194, 203))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('present', 'Reg', (38, 45))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('oral mucosal melanomas', 'Disease', 'MESH:D008545', (181, 203))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('NRAS', 'Gene', '4893', (18, 22))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))
103784	32043781	In our series, NRAS mutations were detected in 13.9% of vaginal melanomas.	('detected', 'Reg', (35, 43))	('vaginal melanomas', 'Disease', (56, 73))	('NRAS', 'Gene', (15, 19))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (56, 72))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('NRAS', 'Gene', '4893', (15, 19))	('vaginal melanomas', 'Disease', 'MESH:D008545', (56, 73))	('mutations', 'Var', (20, 29))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (56, 73))
103785	32043781	Previously, NRAS mutations have been observed to be associated with some features predictive of aggressive behavior in cutaneous melanomas, such as the Clark level of invasion, Breslow thickness, ulceration rate, and adverse outcome 15, 16.	('ulceration rate', 'CPA', (196, 211))	('Breslow thickness', 'Disease', (177, 194))	('cutaneous melanomas', 'Disease', (119, 138))	('aggressive behavior', 'biological_process', 'GO:0002118', ('96', '115'))	('NRAS', 'Gene', (12, 16))	('associated', 'Reg', (52, 62))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanomas', 'Phenotype', 'HP:0002861', (129, 138))	('NRAS', 'Gene', '4893', (12, 16))	('aggressive behavior', 'Disease', (96, 115))	('aggressive behavior', 'Disease', 'MESH:D001523', (96, 115))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (119, 138))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (119, 138))	('mutations', 'Var', (17, 26))	('aggressive behavior', 'Phenotype', 'HP:0000718', (96, 115))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (119, 137))
103787	32043781	Several studies have been carried out to examine the effect of NRAS mutations on clinical outcomes and none of them found any impact on OS 52, 53, 54.	('mutations', 'Var', (68, 77))	('NRAS', 'Gene', (63, 67))	('NRAS', 'Gene', '4893', (63, 67))	('OS', 'Chemical', '-', (136, 138))
103788	32043781	reported that NRAS mutations were an adverse prognostic factor in multivariate analysis in a prospective cohort of 249 patients with melanoma 55.	('NRAS', 'Gene', '4893', (14, 18))	('patients', 'Species', '9606', (119, 127))	('mutations', 'Var', (19, 28))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('NRAS', 'Gene', (14, 18))
103789	32043781	In the present study, it was found that patients with mutated NRAS had inferior OS compared with those with wild-type NRAS, although NRAS mutation status but had no significant correlation with any of the investigated clinicopathological features.	('NRAS', 'Gene', '4893', (62, 66))	('OS', 'Chemical', '-', (80, 82))	('inferior OS', 'CPA', (71, 82))	('patients', 'Species', '9606', (40, 48))	('NRAS', 'Gene', (118, 122))	('NRAS', 'Gene', (133, 137))	('NRAS', 'Gene', '4893', (118, 122))	('mutated', 'Var', (54, 61))	('NRAS', 'Gene', '4893', (133, 137))	('NRAS', 'Gene', (62, 66))
103790	32043781	56 found KIT mutations in 15.6% of mucosal melanomas, and Curtin et al.	('KIT', 'Gene', '3815', (9, 12))	('KIT', 'Gene', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanomas', 'Phenotype', 'HP:0002861', (43, 52))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('mucosal melanomas', 'Disease', (35, 52))	('mutations', 'Var', (13, 22))	('mucosal melanomas', 'Disease', 'MESH:D008545', (35, 52))
103791	32043781	19 found KIT mutations and/or an increase in the copy number of KIT in 39.0% of mucosal melanomas.	('mucosal melanomas', 'Disease', 'MESH:D008545', (80, 97))	('KIT', 'Gene', '3815', (9, 12))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanomas', 'Phenotype', 'HP:0002861', (88, 97))	('KIT', 'Gene', (9, 12))	('KIT', 'Gene', '3815', (64, 67))	('KIT', 'molecular_function', 'GO:0005020', ('9', '12'))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('increase', 'PosReg', (33, 41))	('mucosal melanomas', 'Disease', (80, 97))	('KIT', 'Gene', (64, 67))	('mutations', 'Var', (13, 22))	('copy number', 'MPA', (49, 60))
103792	32043781	In contrast to our present study, only one patient (2.9%) was found to harbor the KIT V559D mutation, which was located in the juxtamembrane domain of the KIT receptor.	('KIT', 'molecular_function', 'GO:0005020', ('155', '158'))	('patient', 'Species', '9606', (43, 50))	('KIT', 'Gene', '3815', (82, 85))	('juxtamembrane', 'cellular_component', 'GO:0005886', ('127', '140'))	('V559D', 'Var', (86, 91))	('KIT', 'molecular_function', 'GO:0005020', ('82', '85'))	('KIT', 'Gene', '3815', (155, 158))	('juxtamembrane', 'cellular_component', 'GO:0009898', ('127', '140'))	('KIT', 'Gene', (82, 85))	('V559D', 'Mutation', 'rs121913517', (86, 91))	('juxtamembrane', 'cellular_component', 'GO:0009897', ('127', '140'))	('juxtamembrane', 'cellular_component', 'GO:0019897', ('127', '140'))	('KIT', 'Gene', (155, 158))
103793	32043781	Our finding is in line with previous studies that have also reported a low frequency (0%-8.3%) of KIT mutations, with only one case reported in vaginal melanomas (supplemental online Table 4).	('vaginal melanomas', 'Disease', (144, 161))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (144, 160))	('vaginal melanomas', 'Disease', 'MESH:D008545', (144, 161))	('KIT', 'Gene', '3815', (98, 101))	('mutations', 'Var', (102, 111))	('KIT', 'Gene', (98, 101))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (144, 161))	('KIT', 'molecular_function', 'GO:0005020', ('98', '101'))
103794	32043781	Patients with melanoma with this type of mutation were reported to benefit from imatinib 57, whereas a recent ECOG phase II trial investigating the use of dasatinib in mucosal melanomas with KIT alterations revealed low response rate 58, demonstrating that molecularly targeted therapy may not always be effective.	('melanoma', 'Disease', (14, 22))	('KIT', 'Gene', '3815', (191, 194))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('KIT', 'molecular_function', 'GO:0005020', ('191', '194'))	('melanoma', 'Disease', (176, 184))	('KIT', 'Gene', (191, 194))	('mucosal melanomas', 'Disease', (168, 185))	('imatinib', 'Chemical', 'MESH:D000068877', (80, 88))	('mutation', 'Var', (41, 49))	('dasatinib', 'Chemical', 'MESH:D000069439', (155, 164))	('Patients', 'Species', '9606', (0, 8))	('benefit', 'PosReg', (67, 74))	('mucosal melanomas', 'Disease', 'MESH:D008545', (168, 185))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
103796	32043781	No patients were found with mutations in BRAF exon 15 in the present study, which was similar with other published data on vaginal melanoma 10, 43, 44, 46.	('vaginal melanoma', 'Phenotype', 'HP:0030418', (123, 139))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('vaginal melanoma', 'Disease', (123, 139))	('BRAF', 'Gene', '673', (41, 45))	('patients', 'Species', '9606', (3, 11))	('BRAF', 'Gene', (41, 45))	('vaginal melanoma', 'Disease', 'MESH:D008545', (123, 139))	('mutations', 'Var', (28, 37))
103798	32043781	However, in mucosal melanoma, BRAF mutations occur at a lower frequency (3.0%-15.5% in unspecialized mucosal melanoma) 15, 19.	('unspecialized mucosal melanoma', 'Disease', (87, 117))	('unspecialized mucosal melanoma', 'Disease', 'MESH:D008545', (87, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('BRAF', 'Gene', (30, 34))	('mucosal melanoma', 'Disease', (12, 28))	('BRAF', 'Gene', '673', (30, 34))	('mucosal melanoma', 'Disease', 'MESH:D008545', (12, 28))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('mucosal melanoma', 'Disease', 'MESH:D008545', (101, 117))	('mutations', 'Var', (35, 44))
103799	32043781	This is similar for vaginal melanoma, in which only four cases of BRAF mutations have been reported to date; one case was found in Aulmann et al.	('vaginal melanoma', 'Phenotype', 'HP:0030418', (20, 36))	('mutations', 'Var', (71, 80))	('vaginal melanoma', 'Disease', (20, 36))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('vaginal melanoma', 'Disease', 'MESH:D008545', (20, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
103800	32043781	Mutation in GNAQ/GNA11 exhibits tissue specificity in melanomas.	('GNAQ', 'Gene', (12, 16))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('Mutation', 'Var', (0, 8))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('GNA11', 'Gene', (17, 22))	('GNAQ', 'Gene', '2776', (12, 16))	('GNA11', 'Gene', '2767', (17, 22))	('melanomas', 'Disease', (54, 63))
103804	32043781	To our knowledge, this present study is the first investigate the TERT promoter mutations in vaginal melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('vaginal melanomas', 'Disease', (93, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('mutations', 'Var', (80, 89))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (93, 109))	('TERT', 'Gene', (66, 70))	('TERT', 'Gene', '7015', (66, 70))	('vaginal melanomas', 'Disease', 'MESH:D008545', (93, 110))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (93, 110))
103805	32043781	Two patients (7.7%) with primary tumors were diagnosed as stage IIIC vaginal melanomas with TERT promoter mutations in C228T and had an overall survival of less than 12 months.	('vaginal melanomas', 'Disease', (69, 86))	('TERT', 'Gene', (92, 96))	('TERT', 'Gene', '7015', (92, 96))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (69, 85))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('C228T', 'Mutation', 'c.228C>T', (119, 124))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('vaginal melanomas', 'Disease', 'MESH:D008545', (69, 86))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (4, 12))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (69, 86))	('tumors', 'Disease', (33, 39))	('C228T', 'Var', (119, 124))
103806	32043781	Moreover, TERT promoter mutations have been reported to be associated with older patients, increased Breslow thickness, and worse prognosis 25, 26.	('Breslow thickness', 'CPA', (101, 118))	('TERT', 'Gene', (10, 14))	('patients', 'Species', '9606', (81, 89))	('associated', 'Reg', (59, 69))	('TERT', 'Gene', '7015', (10, 14))	('increased', 'PosReg', (91, 100))	('mutations', 'Var', (24, 33))
103807	32043781	By contrast, an investigation from Asia demonstrated that the TERT promoter mutations were not correlated with OS 61.	('mutations', 'Var', (76, 85))	('OS 61', 'Disease', (111, 116))	('OS', 'Chemical', '-', (111, 113))	('TERT', 'Gene', (62, 66))	('TERT', 'Gene', '7015', (62, 66))
103808	32043781	The difference in frequencies and relationship with clinicopathological features reveal that the TERT promoter mutations may vary depending on the melanoma subtypes and locations.	('mutations', 'Var', (111, 120))	('TERT', 'Gene', (97, 101))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('TERT', 'Gene', '7015', (97, 101))
103812	32043781	The genes most commonly mutated in vulvar melanomas were KIT (26.5%, 9/34) and BRAF (27%, 9/33), whereas NRAS mutations were more prevalent than KIT and BRAF mutations in vaginal melanomas 45.	('mutated', 'Var', (24, 31))	('BRAF', 'Gene', (153, 157))	('NRAS', 'Gene', (105, 109))	('KIT', 'Gene', '3815', (57, 60))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))	('KIT', 'molecular_function', 'GO:0005020', ('57', '60'))	('KIT', 'Gene', (145, 148))	('vulvar melanomas', 'Disease', (35, 51))	('melanomas', 'Phenotype', 'HP:0002861', (179, 188))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (35, 50))	('vulvar melanomas', 'Disease', 'MESH:D008545', (35, 51))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (171, 187))	('vaginal melanomas', 'Disease', 'MESH:D008545', (171, 188))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (171, 188))	('NRAS', 'Gene', '4893', (105, 109))	('KIT', 'Gene', (57, 60))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('vaginal melanomas', 'Disease', (171, 188))	('KIT', 'Gene', '3815', (145, 148))	('melanomas', 'Phenotype', 'HP:0002861', (42, 51))	('vulvar melanomas', 'Phenotype', 'HP:0030418', (35, 51))	('KIT', 'molecular_function', 'GO:0005020', ('145', '148'))	('BRAF', 'Gene', '673', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
103814	32043781	This finding is essential for patients with vaginal melanomas who harbor frequent NRAS mutations because they might benefit from MEK inhibition 30.	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('vaginal melanomas', 'Disease', 'MESH:D008545', (44, 61))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (44, 60))	('mutations', 'Var', (87, 96))	('vaginal melanomas', 'Phenotype', 'HP:0030418', (44, 61))	('NRAS', 'Gene', (82, 86))	('patients', 'Species', '9606', (30, 38))	('NRAS', 'Gene', '4893', (82, 86))	('vaginal melanomas', 'Disease', (44, 61))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (129, 132))
103825	32043781	Nevertheless, this observation could act as a hint that patients with vaginal melanoma with PD-L1 expression could benefit from immune checkpoint inhibitors even for those without PD-L1 expression, which is in line with the report of a previous study 65.	('patients', 'Species', '9606', (56, 64))	('PD-L1', 'Gene', '29126', (180, 185))	('expression', 'Var', (98, 108))	('PD-L1', 'Gene', (92, 97))	('vaginal melanoma', 'Disease', 'MESH:D008545', (70, 86))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (70, 86))	('benefit', 'PosReg', (115, 122))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('PD-L1', 'Gene', '29126', (92, 97))	('vaginal melanoma', 'Disease', (70, 86))	('PD-L1', 'Gene', (180, 185))
103837	32043781	In this cohort of patients with primary vaginal melanoma, we observed that NRAS mutations and PD-L1 expression were most prevalent, whereas the detection rate of KIT and TERT mutations was low.	('primary vaginal melanoma', 'Disease', 'MESH:D008545', (32, 56))	('KIT', 'Gene', '3815', (162, 165))	('PD-L1', 'Gene', (94, 99))	('prevalent', 'Reg', (121, 130))	('NRAS', 'Gene', '4893', (75, 79))	('mutations', 'Var', (80, 89))	('KIT', 'Gene', (162, 165))	('PD-L1', 'Gene', '29126', (94, 99))	('NRAS', 'Gene', (75, 79))	('expression', 'MPA', (100, 110))	('KIT', 'molecular_function', 'GO:0005020', ('162', '165'))	('primary vaginal melanoma', 'Disease', (32, 56))	('patients', 'Species', '9606', (18, 26))	('vaginal melanoma', 'Phenotype', 'HP:0030418', (40, 56))	('TERT', 'Gene', (170, 174))	('TERT', 'Gene', '7015', (170, 174))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
103838	32043781	Patients with NRAS mutations had a poorer survival outcome as compared with those with wild-type NRAS.	('NRAS', 'Gene', (97, 101))	('NRAS', 'Gene', '4893', (14, 18))	('NRAS', 'Gene', '4893', (97, 101))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('NRAS', 'Gene', (14, 18))
103856	29318162	Furthermore, inflammatory conditions can preclude a malignant transformation and/or an oncogene alteration sustains the inflammatory microenvironment favorable for tumor development.	('oncogene', 'Gene', (87, 95))	('tumor', 'Disease', (164, 169))	('men', 'Species', '9606', (145, 148))	('malignant transformation', 'CPA', (52, 76))	('men', 'Species', '9606', (177, 180))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('alteration', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
103859	29318162	One of the first reported studies on melanoma mouse models has shown that DTIC proved in mouse the highest sensitivity.	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanoma', 'Disease', (37, 45))	('mouse', 'Species', '10090', (46, 51))	('DTIC', 'Chemical', 'MESH:D003606', (74, 78))	('DTIC', 'Var', (74, 78))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('mouse', 'Species', '10090', (89, 94))
103876	29318162	At day 7, the tumor volume of low concentration of DTIC group was lower than the untreated group (Figure 1).	('tumor', 'Disease', (14, 19))	('lower', 'NegReg', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('low concentration', 'Var', (30, 47))	('DTIC', 'Chemical', 'MESH:D003606', (51, 55))
103994	21081840	We hypothesized that the expression level of miR-29 is associated to TRG methylation status and may have prognostic utility in melanoma.	('TRG', 'Gene', '6965', (69, 72))	('TRG', 'Gene', (69, 72))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('associated', 'Reg', (55, 65))	('miR-29', 'Gene', (45, 51))	('methylation', 'Var', (73, 84))	('melanoma', 'Disease', 'MESH:D008545', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanoma', 'Disease', (127, 135))	('expression level', 'MPA', (25, 41))	('miR-29', 'Gene', '407021', (45, 51))
104001	21081840	Hypermethylation status of TRGs and non-coding MINT loci in different stages of melanoma showed an inverse association with miR-29c expression.	('miR-29c', 'Gene', (124, 131))	('TRG', 'Gene', '6965', (27, 30))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('inverse', 'NegReg', (99, 106))	('melanoma', 'Disease', (80, 88))	('TRG', 'Gene', (27, 30))	('expression', 'MPA', (132, 142))	('miR-29c', 'Gene', '407026', (124, 131))	('Hypermethylation status', 'Var', (0, 23))
104011	21081840	Cutaneous melanoma is the sixth most common cancer in the US with increasing incidence worldwide and methylation of gene promoter region has been found to epigenetically regulate cell functions in melanoma.	('regulate', 'Reg', (170, 178))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('cancer', 'Disease', (44, 50))	('melanoma', 'Disease', (197, 205))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('epigenetically', 'Var', (155, 169))	('cell functions', 'CPA', (179, 193))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('methylation', 'Var', (101, 112))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('methylation', 'biological_process', 'GO:0032259', ('101', '112'))	('melanoma', 'Disease', (10, 18))	('Cutaneous melanoma', 'Disease', (0, 18))
104013	21081840	Tumor-related genes (TRGs) and other noncoding methylated-in-tumor (MINT) loci were found inactivated in a coordinated fashion through methylation of promoter CpG islands in melanoma.	('TRG', 'Gene', '6965', (21, 24))	('methylation', 'Var', (135, 146))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('TRG', 'Gene', (21, 24))	('melanoma', 'Disease', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('methylation', 'biological_process', 'GO:0032259', ('135', '146'))
104030	21081840	Of all of the biomarkers assessed, only RASSF1A hypomethylation was significantly correlated to miR29c expression (p = 0.045).	('miR29c', 'Gene', '407026', (96, 102))	('RASSF1A', 'Gene', '11186', (40, 47))	('hypomethylation', 'Var', (48, 63))	('correlated', 'Reg', (82, 92))	('RASSF1A', 'Gene', (40, 47))	('miR29c', 'Gene', (96, 102))
104037	21081840	When analyzed in a multivariate Cox Regression model, greater than or equal to median miR-29c expression level is significantly correlated to improved OS (HR 0.324, 95% CI: 0.156-0.670, p = 0.002), but not DFS.	('greater', 'Var', (54, 61))	('OS', 'Chemical', '-', (151, 153))	('improved', 'PosReg', (142, 150))	('miR-29c', 'Gene', (86, 93))	('expression', 'MPA', (94, 104))	('miR-29c', 'Gene', '407026', (86, 93))	('Cox', 'Gene', '1351', (32, 35))	('Cox', 'Gene', (32, 35))
104051	21081840	Past studies have shown that both methyltransferases, DNMT3A and DNMT3B, are involved in de novo methylation, and silencing these enzymes by knockdown or deletion leads to hypomethylation of TRGs.	('DNMT3B', 'Gene', (65, 71))	('involved', 'Reg', (77, 85))	('TRG', 'Gene', (191, 194))	('DNMT3A', 'Gene', (54, 60))	('DNMT3A', 'Gene', '1788', (54, 60))	('silencing', 'Var', (114, 123))	('methylation', 'MPA', (97, 108))	('TRG', 'Gene', '6965', (191, 194))	('hypomethylation', 'MPA', (172, 187))	('deletion', 'Var', (154, 162))	('methylation', 'biological_process', 'GO:0032259', ('97', '108'))	('DNMT3B', 'Gene', '1789', (65, 71))
104055	21081840	We did, however, find an inverse correlation between RASSF1A hypermethylation and miR-29c expression in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('miR-29c', 'Gene', (82, 89))	('miR-29c', 'Gene', '407026', (82, 89))	('expression', 'MPA', (90, 100))	('hypermethylation', 'Var', (61, 77))	('RASSF1A', 'Gene', (53, 60))	('RASSF1A', 'Gene', '11186', (53, 60))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
104056	21081840	RASSF1A has been considered to have a role in cell growth and metastasis in various cancers including melanoma; RASSF1A hypermethylation has been reported as a mechanism by which the suppressor is negatively regulated in cancer and contributes to melanoma progression.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('hypermethylation', 'Var', (120, 136))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('negatively regulated', 'NegReg', (197, 217))	('melanoma', 'Disease', (102, 110))	('contributes to', 'Reg', (232, 246))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('melanoma', 'Disease', 'MESH:D008545', (247, 255))	('RASSF1A', 'Gene', '11186', (112, 119))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (221, 227))	('RASSF1A', 'Gene', '11186', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('RASSF1A', 'Gene', (112, 119))	('metastasis', 'Disease', (62, 72))	('RASSF1A', 'Gene', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanoma', 'Disease', (247, 255))	('metastasis', 'Disease', 'MESH:D009362', (62, 72))
104058	21081840	The detection of hypermethylated melanoma-related TRGs has been correlated to poor OS and DFS, and we demonstrated in this study that miR-29c and DNMT3B can also independently predict disease outcome.	('DNMT3B', 'Gene', (146, 152))	('predict', 'Reg', (176, 183))	('miR-29c', 'Gene', (134, 141))	('disease', 'Disease', (184, 191))	('TRG', 'Gene', (50, 53))	('melanoma', 'Disease', (33, 41))	('DNMT3B', 'Gene', '1789', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('OS', 'Chemical', '-', (83, 85))	('TRG', 'Gene', '6965', (50, 53))	('miR-29c', 'Gene', '407026', (134, 141))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('hypermethylated', 'Var', (17, 32))	('DFS', 'Disease', (90, 93))	('poor OS', 'Disease', (78, 85))
104063	21081840	Another study demonstrated that the expression of DNMT3A to be significantly associated with only OS, while no significant correlation was observed for DNMT3B in the same lung cancer patient group.	('DNMT3A', 'Gene', (50, 56))	('DNMT3A', 'Gene', '1788', (50, 56))	('only OS', 'Disease', (93, 100))	('lung cancer', 'Disease', (171, 182))	('DNMT3B', 'Gene', (152, 158))	('DNMT3B', 'Gene', '1789', (152, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('expression', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patient', 'Species', '9606', (183, 190))	('OS', 'Chemical', '-', (98, 100))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('associated', 'Reg', (77, 87))
104114	33219855	Risk for metastases strongly depends on monosomy 3 (Shields et al.).	('metastases', 'Disease', (9, 19))	('monosomy 3', 'Var', (40, 50))	('metastases', 'Disease', 'MESH:D009362', (9, 19))
104189	25885043	At the molecular level, several signaling pathways have been implicated in the control of melanoma tumor formation, including the Ras-Raf-Mek-Erk cascade, which often exhibits activating mutations in cutaneous malignant melanoma.	('melanoma tumor', 'Disease', 'MESH:D008545', (90, 104))	('malignant melanoma', 'Phenotype', 'HP:0002861', (210, 228))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('Mek', 'Gene', (138, 141))	('Erk cascade', 'biological_process', 'GO:0070371', ('142', '153'))	('Mek', 'Gene', '5609', (138, 141))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (200, 228))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('melanoma tumor', 'Disease', (90, 104))	('Erk', 'Gene', (142, 145))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (200, 228))	('Erk', 'Gene', '5594', (142, 145))	('Raf', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Erk', 'molecular_function', 'GO:0004707', ('142', '145'))	('cutaneous malignant melanoma', 'Disease', (200, 228))	('mutations', 'Var', (187, 196))	('activating', 'PosReg', (176, 186))	('Raf', 'Gene', '22882', (134, 137))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
104210	25885043	Several studies have reported that p21 was detected in primary melanomas and metastatic lesions, while p21 levels were low or undetectable in melanocytic nevi.	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('p21', 'Var', (35, 38))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (142, 158))	('melanomas', 'Disease', (63, 72))	('detected', 'Reg', (43, 51))	('melanomas', 'Disease', 'MESH:D008545', (63, 72))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanomas', 'Phenotype', 'HP:0002861', (63, 72))
104211	25885043	p21 might play an important role in melanoma progression, but the mechanisms are unknown.	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('p21', 'Var', (0, 3))	('play', 'Reg', (10, 14))
104216	25885043	Antibodies against LIF, p15, p21, c-myc, p-Stat3 (Tyr705), Stat3 and beta-tubulin were from Santa Cruz Biotechnologies (Santa Cruz, CA, USA).	('c-myc', 'Gene', '4609', (34, 39))	('c-myc', 'Gene', (34, 39))	('Stat3', 'Gene', '6774', (43, 48))	('p21', 'Var', (29, 32))	('p15', 'Gene', (24, 27))	('p15', 'Gene', '1030', (24, 27))	('Stat3', 'Gene', (43, 48))	('LIF', 'Gene', '3976', (19, 22))	('Stat3', 'Gene', '6774', (59, 64))	('Tyr705', 'Chemical', '-', (50, 56))	('LIF', 'Gene', (19, 22))	('Stat3', 'Gene', (59, 64))
104217	25885043	Scrambled, p21 and LIF siRNAs were from Sigma (Oakville, ON, Canada).	('LIF', 'Gene', (19, 22))	('LIF', 'Gene', '3976', (19, 22))	('p21', 'Var', (11, 14))
104221	25885043	The WM278 cell line harbors a V600E mutation in the BRAF gene, and a hemizygous deletion of PTEN.	('V600E', 'Mutation', 'rs113488022', (30, 35))	('PTEN', 'Gene', (92, 96))	('PTEN', 'Gene', '5728', (92, 96))	('WM278', 'CellLine', 'CVCL:6473', (4, 9))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('V600E', 'Var', (30, 35))
104223	25885043	WM793B cells are positive for a V600E BRAF mutation and carry a W274X mutation as well as a hemizygous deletion of PTEN.	('WM793B', 'CellLine', 'CVCL:8787', (0, 6))	('PTEN', 'Gene', (115, 119))	('V600E', 'Mutation', 'rs113488022', (32, 37))	('W274X', 'Mutation', 'rs587782607', (64, 69))	('PTEN', 'Gene', '5728', (115, 119))	('BRAF', 'Gene', '673', (38, 42))	('V600E', 'Var', (32, 37))	('BRAF', 'Gene', (38, 42))	('W274X', 'Var', (64, 69))
104224	25885043	This cell line also has a mutation K22Q of CDK4.	('CDK4', 'Gene', (43, 47))	('CDK4', 'Gene', '1019', (43, 47))	('K22Q', 'Var', (35, 39))	('CDK', 'molecular_function', 'GO:0004693', ('43', '46'))	('K22Q', 'Mutation', 'p.K22Q', (35, 39))
104239	25885043	For transient transfection, WM278 or WM793B cells were plated in 6-well dishes in RPMI1640, 10% FBS (1-4 x 105 cells per well), and incubated overnight.	('FBS', 'Disease', (96, 99))	('FBS', 'Disease', 'MESH:D005198', (96, 99))	('WM793B', 'CellLine', 'CVCL:8787', (37, 43))	('WM278', 'CellLine', 'CVCL:6473', (28, 33))	('WM793B', 'Var', (37, 43))	('RPMI1640', 'Chemical', '-', (82, 90))
104253	25885043	As shown in Figure 1A, WM793B and WM278 responded well to TGFbeta showing a significant induction of G1 arrest.	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('WM278', 'Var', (34, 39))	('WM793B', 'Var', (23, 29))	('TGFbeta', 'Gene', (58, 65))	('arrest', 'Disease', (104, 110))	('TGFbeta', 'Gene', '7040', (58, 65))	('WM278', 'CellLine', 'CVCL:6473', (34, 39))	('WM793B', 'CellLine', 'CVCL:8787', (23, 29))	('induction', 'PosReg', (88, 97))
104261	25885043	As shown in Figure 2C, while a control scrambled siRNA showed no effect, blocking LIF expression was able to almost completely block the TGFbeta effect on the induction of G1 arrest, indicating that LIF plays a major role in the TGFbeta-induced cell cycle arrest.	('TGFbeta', 'Gene', (229, 236))	('LIF', 'Gene', '3976', (82, 85))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('245', '262'))	('block', 'NegReg', (127, 132))	('LIF', 'Gene', '3976', (199, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (245, 262))	('LIF', 'Gene', (199, 202))	('TGFbeta', 'Gene', (137, 144))	('TGFbeta', 'Gene', '7040', (229, 236))	('arrest', 'Disease', 'MESH:D006323', (256, 262))	('LIF', 'Gene', (82, 85))	('blocking', 'Var', (73, 81))	('arrest', 'Disease', 'MESH:D006323', (175, 181))	('arrest', 'Disease', (256, 262))	('TGFbeta', 'Gene', '7040', (137, 144))	('arrest', 'Disease', (175, 181))
104262	25885043	We then tested the effect of silencing LIF gene expression on the induction of caspase-mediated apoptosis by TGFbeta in WM278 cells.	('tested', 'Reg', (8, 14))	('caspase-mediated', 'CPA', (79, 95))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('TGFbeta', 'Gene', (109, 116))	('silencing', 'Var', (29, 38))	('WM278', 'CellLine', 'CVCL:6473', (120, 125))	('TGFbeta', 'Gene', '7040', (109, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('LIF', 'Gene', (39, 42))	('LIF', 'Gene', '3976', (39, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
104264	25885043	Efficiency of the LIF siRNA knockdown was assessed by qPCR (Figure 2E).	('LIF', 'Gene', (18, 21))	('LIF', 'Gene', '3976', (18, 21))	('knockdown', 'Var', (28, 37))
104267	25885043	These include p15 and p21 that were shown to be induced by TGFbeta and the oncogene c-MYC that was found to be downregulated by TGFbeta in keratinocytes.	('c-MYC', 'Gene', '4609', (84, 89))	('TGFbeta', 'Gene', '7040', (59, 66))	('TGFbeta', 'Gene', '7040', (128, 135))	('p21', 'Var', (22, 25))	('c-MYC', 'Gene', (84, 89))	('p15', 'Gene', (14, 17))	('downregulated', 'NegReg', (111, 124))	('p15', 'Gene', '1030', (14, 17))	('TGFbeta', 'Gene', (59, 66))	('TGFbeta', 'Gene', (128, 135))	('induced', 'Reg', (48, 55))
104272	25885043	However, when p21 expression was silenced, the TGFbeta effect was completely abolished, suggesting that p21 not only is required downstream of TGFbeta to mediate cell cycle arrest in melanoma cells but also plays a central role in the regulation of these events.	('p21', 'Var', (104, 107))	('regulation', 'biological_process', 'GO:0065007', ('235', '245'))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (162, 179))	('melanoma', 'Disease', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('TGFbeta', 'Gene', (47, 54))	('arrest', 'Disease', 'MESH:D006323', (173, 179))	('TGFbeta', 'Gene', (143, 150))	('arrest', 'Disease', (173, 179))	('plays', 'Reg', (207, 212))	('TGFbeta', 'Gene', '7040', (47, 54))	('TGFbeta', 'Gene', '7040', (143, 150))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('162', '179'))
104273	25885043	p21 has also been linked to the apoptotic process, however its exact function remains unclear and controversial, as it was shown to inhibit apoptosis in lymphoma cells, primary fibroblasts, and hepatoma cells, while it promotes apoptosis in ovarian cancer cells, hepatocytes and hepatocarcinoma cells, and thymocytes.	('hepatocarcinoma', 'Disease', (279, 294))	('apoptosis', 'biological_process', 'GO:0097194', ('228', '237'))	('ovarian cancer', 'Disease', 'MESH:D010051', (241, 255))	('hepatoma', 'Disease', 'MESH:D006528', (194, 202))	('apoptosis', 'biological_process', 'GO:0006915', ('228', '237'))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('apoptotic process', 'biological_process', 'GO:0006915', ('32', '49'))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('apoptosis', 'CPA', (140, 149))	('promotes', 'PosReg', (219, 227))	('p21', 'Var', (0, 3))	('ovarian cancer', 'Disease', (241, 255))	('inhibit', 'NegReg', (132, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (241, 255))	('hepatoma', 'Disease', (194, 202))	('apoptosis', 'biological_process', 'GO:0097194', ('140', '149'))	('lymphoma', 'Disease', (153, 161))	('apoptosis', 'biological_process', 'GO:0006915', ('140', '149'))	('hepatocarcinoma', 'Disease', 'None', (279, 294))	('lymphoma', 'Disease', 'MESH:D008223', (153, 161))
104275	25885043	As shown in Figure 3D, silencing p21 expression with a specific siRNA almost completely blocked TGFbeta-mediated caspase-mediated cell death, defining a new role for p21 in melanoma as a pro-apoptotic factor.	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('silencing', 'Var', (23, 32))	('TGFbeta', 'Gene', (96, 103))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('cell death', 'biological_process', 'GO:0008219', ('130', '140'))	('p21', 'Gene', (33, 36))	('TGFbeta', 'Gene', '7040', (96, 103))
104279	25885043	This indicates that p21 mediates some of the pro-apoptotic effects of TGFbeta by inducing the expression of specific pro-apoptotic genes in melanoma.	('TGFbeta', 'Gene', '7040', (70, 77))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('TGFbeta', 'Gene', (70, 77))	('melanoma', 'Disease', (140, 148))	('expression', 'MPA', (94, 104))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('p21', 'Var', (20, 23))	('inducing', 'PosReg', (81, 89))
104287	25885043	Furthermore, we found this effect to take place at the transcriptional level, as LIF gene expression knockdown using a specific LIF siRNA completely blocked TGFbeta-induced p21 gene promoter activity.	('blocked', 'NegReg', (149, 156))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('p21 gene', 'Gene', (173, 181))	('LIF', 'Gene', (128, 131))	('TGFbeta', 'Gene', (157, 164))	('LIF', 'Gene', '3976', (128, 131))	('LIF', 'Gene', '3976', (81, 84))	('TGFbeta', 'Gene', '7040', (157, 164))	('LIF', 'Gene', (81, 84))	('knockdown', 'Var', (101, 110))
104297	25885043	As shown in Figure 4G, knocking down LIF blocked the phosphorylation of STAT3 by TFGbeta, further demonstrating that LIF is required for this regulation.	('STAT3', 'Gene', (72, 77))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('LIF', 'Gene', (117, 120))	('LIF', 'Gene', '3976', (117, 120))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))	('knocking down', 'Var', (23, 36))	('blocked', 'NegReg', (41, 48))	('LIF', 'Gene', '3976', (37, 40))	('STAT3', 'Gene', '6774', (72, 77))	('LIF', 'Gene', (37, 40))	('TFGbeta', 'Gene', (81, 88))
104304	25885043	This was confirmed using a specific LIF siRNA: while a scrambled siRNA showed no effect, blocking LIF expression significantly inhibit the TGFbeta effect on melanoma cell migration by about 60% (Figure 5B).	('LIF', 'Gene', (98, 101))	('TGFbeta', 'Gene', (139, 146))	('LIF', 'Gene', '3976', (36, 39))	('blocking', 'Var', (89, 97))	('cell migration', 'biological_process', 'GO:0016477', ('166', '180'))	('TGFbeta', 'Gene', '7040', (139, 146))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('melanoma', 'Disease', (157, 165))	('LIF', 'Gene', (36, 39))	('inhibit', 'NegReg', (127, 134))	('expression', 'Protein', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('LIF', 'Gene', '3976', (98, 101))
104321	25885043	Through its amino-terminal CDK-cyclin inhibitory domain, p21 binds to both the cyclin subunit and the CDK subunit of CDK-cyclin complexes, preventing them from binding to p107, p130, and Rb, which are involved in cell cycle progression.	('cyclin', 'molecular_function', 'GO:0016538', ('79', '85'))	('cyclin', 'molecular_function', 'GO:0016538', ('31', '37'))	('cyclin', 'Gene', '5111', (31, 37))	('cyclin', 'Gene', '5111', (79, 85))	('CDK', 'molecular_function', 'GO:0004693', ('102', '105'))	('preventing', 'NegReg', (139, 149))	('p21', 'Var', (57, 60))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('cyclin', 'Gene', (31, 37))	('cyclin', 'Gene', (79, 85))	('binding', 'molecular_function', 'GO:0005488', ('160', '167'))	('cyclin', 'Gene', '5111', (121, 127))	('binding', 'Interaction', (160, 167))	('p130', 'Gene', '9221', (177, 181))	('cell cycle', 'biological_process', 'GO:0007049', ('213', '223'))	('p107', 'Gene', (171, 175))	('CDK', 'molecular_function', 'GO:0004693', ('117', '120'))	('cyclin', 'molecular_function', 'GO:0016538', ('121', '127'))	('p107', 'Gene', '5933', (171, 175))	('p130', 'Gene', (177, 181))	('cyclin', 'Gene', (121, 127))
104323	25885043	Similarly, p21 depletion in human embryonic fibroblasts was reported to induce cell death in these cells.	('depletion', 'Var', (15, 24))	('p21', 'Gene', (11, 14))	('human', 'Species', '9606', (28, 33))	('cell death', 'CPA', (79, 89))	('cell death', 'biological_process', 'GO:0008219', ('79', '89'))
104324	25885043	In hepatoma cells, p21 was found to bind caspase 3, thereby preventing caspase activation and Fas-induced apoptosis.	('hepatoma', 'Disease', 'MESH:D006528', (3, 11))	('caspase 3', 'Gene', (41, 50))	('Fas-induced apoptosis', 'CPA', (94, 115))	('activation', 'MPA', (79, 89))	('caspase 3', 'Gene', '836', (41, 50))	('caspase activation', 'biological_process', 'GO:0006919', ('71', '89'))	('p21', 'Var', (19, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('caspase', 'Protein', (71, 78))	('preventing', 'NegReg', (60, 70))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('hepatoma', 'Disease', (3, 11))	('Fas', 'Chemical', 'MESH:C038178', (94, 97))
104325	25885043	Indeed, p21 prevents stress-induced apoptosis mediated by the JNK and p38 signaling pathways by binding to and inhibiting the activity of the MAP3K5 (ASK1; MEKK5) in human rhabdomyosarcoma cells and by binding to JNK kinases, further preventing their activation by upstream kinases.	('p38', 'Gene', (70, 73))	('MEKK', 'molecular_function', 'GO:0004709', ('156', '160'))	('JNK', 'Gene', (213, 216))	('JNK', 'Gene', (62, 65))	('binding', 'molecular_function', 'GO:0005488', ('202', '209'))	('JNK', 'Gene', '5599', (213, 216))	('JNK', 'Gene', '5599', (62, 65))	('MAP3K5', 'Gene', '4217', (142, 148))	('MAP3K5', 'Gene', (142, 148))	('p21', 'Var', (8, 11))	('JNK', 'molecular_function', 'GO:0004705', ('213', '216'))	('activation', 'MPA', (251, 261))	('binding', 'molecular_function', 'GO:0005488', ('96', '103'))	('MEKK5', 'Gene', '4217', (156, 161))	('binding', 'Interaction', (202, 209))	('human', 'Species', '9606', (166, 171))	('MEKK5', 'Gene', (156, 161))	('rhabdomyosarcoma cells', 'Disease', 'MESH:D012208', (172, 194))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (172, 188))	('activity', 'MPA', (126, 134))	('p38', 'Gene', '1432', (70, 73))	('ASK1', 'Gene', '4217', (150, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('36', '45'))	('binding', 'Interaction', (96, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('36', '45'))	('inhibiting', 'NegReg', (111, 121))	('JNK', 'molecular_function', 'GO:0004705', ('62', '65'))	('signaling', 'biological_process', 'GO:0023052', ('74', '83'))	('ASK1', 'Gene', (150, 154))	('MAP3K', 'molecular_function', 'GO:0004709', ('142', '147'))	('rhabdomyosarcoma cells', 'Disease', (172, 194))
104327	25885043	Reports showed that p21 could also facilitate deoxycholic acid-induced apoptosis in primary mouse hepatocytes and ceramide-induced apoptosis in human hepatoma cells.	('deoxycholic acid', 'Chemical', 'MESH:D003840', (46, 62))	('deoxycholic acid-induced apoptosis', 'MPA', (46, 80))	('human', 'Species', '9606', (144, 149))	('facilitate', 'PosReg', (35, 45))	('ceramide', 'Chemical', 'MESH:D002518', (114, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('131', '140'))	('mouse', 'Species', '10090', (92, 97))	('hepatoma', 'Disease', 'MESH:D006528', (150, 158))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('apoptosis', 'biological_process', 'GO:0006915', ('131', '140'))	('p21', 'Var', (20, 23))	('hepatoma', 'Disease', (150, 158))	('ceramide-induced apoptosis', 'MPA', (114, 140))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))
104329	25885043	Our study indicates that, in the context of human cutaneous melanoma, p21 acts as a potent pro-apoptotic factor.	('human', 'Species', '9606', (44, 49))	('p21', 'Var', (70, 73))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('cutaneous melanoma', 'Disease', (50, 68))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (50, 68))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (50, 68))
104330	25885043	We also showed that p21 acts downstream of the TGFbeta/LIF signaling cascade and that it promotes caspase-dependent cell death though induced-expression of pro-apoptotic molecules, such as Bax and Bim.	('Bim', 'Gene', '10018', (197, 200))	('cell death', 'biological_process', 'GO:0008219', ('116', '126'))	('Bax', 'Gene', '581', (189, 192))	('promotes', 'PosReg', (89, 97))	('LIF', 'Gene', '3976', (55, 58))	('TGFbeta', 'Gene', (47, 54))	('LIF', 'Gene', (55, 58))	('caspase-dependent cell death', 'CPA', (98, 126))	('Bax', 'Gene', (189, 192))	('p21', 'Var', (20, 23))	('TGFbeta', 'Gene', '7040', (47, 54))	('induced-expression', 'PosReg', (134, 152))	('signaling cascade', 'biological_process', 'GO:0007165', ('59', '76'))	('Bim', 'Gene', (197, 200))
104347	25885043	The authors further found that loss of LIF-R expression in non-metastatic breast cancer cells induced a metastatic behavior.	('breast cancer', 'Disease', (74, 87))	('metastatic behavior', 'CPA', (104, 123))	('LIF-R', 'Gene', (39, 44))	('loss', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('LIF-R', 'Gene', '3977', (39, 44))	('induced', 'Reg', (94, 101))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
104351	25885043	Moreover, melanoma patients with high levels of serum TGFbeta also showed favorable overall survival compared to patients with lower levels.	('TGFbeta', 'Gene', (54, 61))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (113, 121))	('TGFbeta', 'Gene', '7040', (54, 61))	('overall survival', 'CPA', (84, 100))	('high levels', 'Var', (33, 44))	('melanoma', 'Disease', 'MESH:D008545', (10, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma', 'Disease', (10, 18))
104433	31708274	90% (9 of 10) of patients continued on systemic treatment, predominantly consisting molecularly targeted therapy or checkpoint inhibition (as shown in Table 2).	('patients', 'Species', '9606', (17, 25))	('checkpoint inhibition', 'CPA', (116, 137))	('molecularly targeted therapy', 'Var', (84, 112))
104569	30651148	In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('expression', 'MPA', (119, 129))	('patients', 'Species', '9606', (44, 52))	('MIR-199A2', 'Gene', (109, 118))	('MIR-199A2', 'Gene', '406977', (109, 118))	('DNA methylation', 'biological_process', 'GO:0006306', ('133', '148'))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('DNA methylation', 'Var', (133, 148))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
104570	30651148	Thus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('dissemination of melanoma', 'Disease', 'MESH:D008545', (116, 141))	('dissemination of melanoma', 'Disease', (116, 141))	('epigenetic-', 'Var', (28, 39))
104573	30651148	Since 2011, new targeted therapies against mutated BRAF (vemurafenib) and immunotherapies such as anti-CTLA4 (ipilimumab) and anti-PD1/PD-L1 antibodies emerged, giving very promising long-term responses.	('PD-L1', 'Gene', (135, 140))	('CTLA4', 'Gene', '1493', (103, 108))	('PD-L1', 'Gene', '29126', (135, 140))	('ipilimumab', 'Chemical', 'MESH:D000074324', (110, 120))	('PD1', 'Gene', (131, 134))	('CTLA4', 'Gene', (103, 108))	('BRAF', 'Gene', (51, 55))	('PD1', 'Gene', '6622', (131, 134))	('BRAF', 'Gene', '673', (51, 55))	('vemurafenib', 'Chemical', 'MESH:D000077484', (57, 68))	('mutated', 'Var', (43, 50))
104576	30651148	Interestingly, targeting of the epigenetic regulation is promising for the development of new anticancer treatments in solid tumours.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('epigenetic regulation', 'Var', (32, 53))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('solid tumours', 'Disease', 'MESH:D009369', (119, 132))	('cancer', 'Disease', (98, 104))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('solid tumours', 'Disease', (119, 132))
104577	30651148	In the past few years, various studies reported on epigenetic alterations in metastatic melanoma, more specifically DNA methylation, and associated them with disease progression.	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('DNA', 'MPA', (116, 119))	('DNA methylation', 'biological_process', 'GO:0006306', ('116', '131'))	('epigenetic alterations', 'Var', (51, 73))
104581	30651148	Hypomethylation of repetitive DNA elements and hypermethylation of CpG islands located in promoter regions of specific genes are hallmarks of melanoma malignancy.	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('Hypomethylation', 'Var', (0, 15))	('melanoma malignancy', 'Disease', 'MESH:D008545', (142, 161))	('CpG islands', 'Gene', (67, 78))	('repetitive DNA elements', 'Protein', (19, 42))	('hypermethylation', 'Var', (47, 63))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma malignancy', 'Disease', (142, 161))
104582	30651148	Specific methylation signatures were also found for melanoma tumours harbouring BRAF mutations.	('melanoma tumours', 'Disease', 'MESH:D008545', (52, 68))	('BRAF', 'Gene', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma tumours', 'Disease', (52, 68))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('mutations', 'Var', (85, 94))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('BRAF', 'Gene', '673', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
104584	30651148	In this context, we investigated the implication of DNA methylation in the aggressiveness of metastatic melanoma and whether the use of demethylating agents can reverse its invasive phenotype.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('aggressiveness of metastatic melanoma', 'Disease', (75, 112))	('aggressiveness', 'Phenotype', 'HP:0000718', (75, 89))	('aggressiveness of metastatic melanoma', 'Disease', 'MESH:D008545', (75, 112))	('DNA methylation', 'biological_process', 'GO:0006306', ('52', '67'))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('methylation', 'Var', (56, 67))
104586	30651148	Furthermore, some miRs are described to be epigenetically regulated and to participate in the acquisition of invasive capabilities of cancer cells, including melanoma.	('epigenetically', 'Var', (43, 57))	('cancer', 'Disease', (134, 140))	('participate', 'Reg', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('acquisition', 'PosReg', (94, 105))	('melanoma', 'Disease', (158, 166))
104587	30651148	Here, we identified one specific hypermethylated miR gene, MIR199A2, whose expression restoration by low doses of 5-aza-2'-deoxycytidine or miR transfection impacts on in vitro cell invasiveness and in vivo metastatic formation.	('MIR199A2', 'Gene', (59, 67))	('formation', 'biological_process', 'GO:0009058', ('218', '227'))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (114, 136))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('impacts', 'Reg', (157, 164))	('transfection', 'Var', (144, 156))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('MIR199A2', 'Gene', '406977', (59, 67))	('expression', 'MPA', (75, 85))
104595	30651148	Hence, low concentrations of 5azadC, inducing little cell death and inhibition of cell proliferation (EC50 = 100 nM), were chosen for the 3D invasion assay to limit non-specific cytotoxic effects and favour an epigenetic effect.	('5azadC', 'Chemical', 'MESH:D000077209', (29, 35))	('cell proliferation', 'CPA', (82, 100))	('cell death', 'biological_process', 'GO:0008219', ('53', '63'))	('epigenetic', 'MPA', (210, 220))	('inhibition', 'NegReg', (68, 78))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('68', '100'))	('5azadC', 'Var', (29, 35))
104600	30651148	Altogether, our data revealed that 5azadC displays an anti-invasive effect in a 3D metastatic melanoma model at low concentrations.	('5azadC', 'Chemical', 'MESH:D000077209', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('5azadC', 'Var', (35, 41))	('anti-invasive effect', 'CPA', (54, 74))
104603	30651148	Using data from a genome-wide DNA methylation analysis (BeadChip Illumina 450 K, data not shown), we compared the methylation profile of WM-266-4 (metastatic cells) and its non-invasive counterpart WM-115 cell lines (derived from the primary tumour of the same patient).	('WM-266-4', 'Var', (137, 145))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('WM-266-4', 'CellLine', 'CVCL:2765', (137, 145))	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('tumour', 'Disease', (242, 248))	('compared', 'Reg', (101, 109))	('patient', 'Species', '9606', (261, 268))	('methylation', 'MPA', (114, 125))	('DNA methylation', 'biological_process', 'GO:0006306', ('30', '45'))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('methylation', 'biological_process', 'GO:0032259', ('114', '125'))
104614	30651148	A significant RNA re-expression of nearly threefold was found with 100 nM of 5azadC for miR-199a-3p, while no significant difference was observed for miR-199a-5p (Fig.	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (150, 153))	('5azadC', 'Var', (77, 83))	('RNA', 'MPA', (14, 17))	('miR-199a-3p', 'Gene', '406977', (88, 99))	('RNA', 'cellular_component', 'GO:0005562', ('14', '17'))	('5azadC', 'Chemical', 'MESH:D000077209', (77, 83))	('miR-199a-3p', 'Gene', (88, 99))	('miR', 'Gene', '220972', (88, 91))
104616	30651148	More specifically, MIR-199A2 promoter demethylation was correlated with the re-expression of its mature form miR-199a-3p.	('miR-199a-3p', 'Gene', '406977', (109, 120))	('MIR-199A2', 'Gene', (19, 28))	('MIR-199A2', 'Gene', '406977', (19, 28))	('demethylation', 'biological_process', 'GO:0070988', ('38', '51'))	('demethylation', 'Var', (38, 51))	('re-expression', 'MPA', (76, 89))	('miR-199a-3p', 'Gene', (109, 120))	('correlated', 'Reg', (56, 66))
104622	30651148	These observations demonstrated that miR-199a-3p alone was able to suppress the 3D invasion ability of WM-266-4 GFP cells, suggesting that its re-expression induced by DNA demethylation can contribute to the anti-invasive effect of 5azadC.	('3D invasion ability', 'CPA', (80, 99))	('miR-199a-3p', 'Gene', '406977', (37, 48))	('suppress', 'NegReg', (67, 75))	('5azadC', 'Chemical', 'MESH:D000077209', (232, 238))	('anti-invasive effect', 'CPA', (208, 228))	('re-expression', 'PosReg', (143, 156))	('demethylation', 'Var', (172, 185))	('WM-266-4', 'CellLine', 'CVCL:2765', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('168', '171'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('168', '185'))	('miR-199a-3p', 'Gene', (37, 48))
104624	30651148	The 3D anti-invasive ability of 5azadC was significantly reduced, and the invasion index was partially restored (Fig.	('5azadC', 'Chemical', 'MESH:D000077209', (32, 38))	('reduced', 'NegReg', (57, 64))	('5azadC', 'Var', (32, 38))	('invasion index', 'CPA', (74, 88))
104632	30651148	In our model, miR-199a-3p ectopic expression, at concentrations inducing an anti-invasive effect (Fig.	('anti-invasive effect', 'CPA', (76, 96))	('ectopic expression', 'Var', (26, 44))	('miR-199a-3p', 'Gene', '406977', (14, 25))	('miR-199a-3p', 'Gene', (14, 25))
104637	30651148	Nevertheless, MET knock down was not sufficient to inhibit 3D invasiveness of metastatic melanoma as shown in Fig.	('knock down', 'Var', (18, 28))	('melanoma', 'Disease', (89, 97))	('3D invasiveness of metastatic', 'CPA', (59, 88))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('inhibit', 'NegReg', (51, 58))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
104643	30651148	Noteworthy, five out of these genes were also downregulated upon 5azadC treatment (Fig.	('5azadC', 'Chemical', 'MESH:D000077209', (65, 71))	('5azadC', 'Var', (65, 71))	('downregulated', 'NegReg', (46, 59))
104646	30651148	SERPINE2, a member of the serine protease inhibitor nexin superfamily, contributes to the invasion in solid tumours and more specifically in colorectal cancers bearing KRAS or BRAF mutations.	('colorectal cancers bearing KRAS', 'Disease', (141, 172))	('serine protease', 'Gene', '2147', (26, 41))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('colorectal cancers bearing KRAS', 'Disease', 'MESH:D015179', (141, 172))	('solid tumours', 'Disease', 'MESH:D009369', (102, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('SERPINE2', 'Gene', '5270', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('serine protease', 'Gene', (26, 41))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('solid tumours', 'Disease', (102, 115))	('mutations', 'Var', (181, 190))	('SERPINE2', 'Gene', (0, 8))	('BRAF', 'Gene', '673', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('invasion', 'CPA', (90, 98))	('BRAF', 'Gene', (176, 180))
104654	30651148	A significant reduction of both parameters was observed upon 5azadC treatment (Fig.	('5azadC', 'Chemical', 'MESH:D000077209', (61, 67))	('reduction', 'NegReg', (14, 23))	('5azadC', 'Var', (61, 67))
104656	30651148	These in vivo experiments validate miR-199a-3p as an anti-tumour effector and the potential interest of re-expressing this miR or using the demethylating drug 5azadC to limit metastasis formation in melanoma cells presenting a hypermethylated MIR-199A2.	('miR', 'Gene', '220972', (123, 126))	('miR-199a-3p', 'Gene', (35, 46))	('MIR-199A2', 'Gene', (243, 252))	('miR', 'Gene', '220972', (35, 38))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('miR-199a-3p', 'Gene', '406977', (35, 46))	('melanoma', 'Disease', (199, 207))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('miR', 'Gene', (123, 126))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('miR', 'Gene', (35, 38))	('limit', 'NegReg', (169, 174))	('5azadC', 'Chemical', 'MESH:D000077209', (159, 165))	('metastasis formation', 'CPA', (175, 195))	('melanoma', 'Disease', 'MESH:D008545', (199, 207))	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('MIR-199A2', 'Gene', '406977', (243, 252))	('hypermethylated', 'Var', (227, 242))
104666	30651148	Taken together, these data support our hypothesis that MIR-199A2 hypermethylation can be important at an early stage for the acquisition of an invasive phenotype by the melanoma tumour cells.	('MIR-199A2', 'Gene', (55, 64))	('hypermethylation', 'Var', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('melanoma tumour', 'Disease', (169, 184))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('MIR-199A2', 'Gene', '406977', (55, 64))	('melanoma tumour', 'Disease', 'MESH:D008545', (169, 184))
104667	30651148	Epigenetic therapies are very promising strategies to fight cancer, since epigenetic modifications are reversible and can be chemically modulated.	('cancer', 'Disease', (60, 66))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
104668	30651148	In particular, promoters' demethylation by 5-azaC or 5-azadC induces the re-expression of several genes or miRs in cancer cells inducing an anti-cancer effect.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', (115, 121))	('induces', 'Reg', (61, 68))	('5-azadC', 'Chemical', 'MESH:D000077209', (53, 60))	('demethylation', 'Var', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('demethylation', 'biological_process', 'GO:0070988', ('26', '39'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('re-expression', 'MPA', (73, 86))	('5-azadC', 'Var', (53, 60))	('miR', 'Gene', '220972', (107, 110))	('5-azaC', 'Chemical', 'MESH:D001374', (43, 49))	('miR', 'Gene', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
104670	30651148	Yet, epigenetic modifications and, in particular, genomic hypermethylation of CpG islands and miR modulation were shown to sign metastatic melanoma progression.	('epigenetic modifications', 'Var', (5, 29))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('genomic hypermethylation', 'Var', (50, 74))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('sign', 'Reg', (123, 127))
104671	30651148	To the best of our knowledge, few reports explored the impact of 5azadC on the cellular mechanism involved in metastatic melanoma, particularly on cell invasiveness, and its potential use as an anti-metastatic drug.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('5azadC', 'Chemical', 'MESH:D000077209', (65, 71))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('5azadC', 'Var', (65, 71))
104674	30651148	Using the metastatic melanoma WM-266-4 GFP cell line, we showed for the first time that low-cytotoxic concentrations of 5azadC inhibit 3D cell invasion in vitro.	('WM-266-4', 'CellLine', 'CVCL:2765', (30, 38))	('5azadC', 'Var', (120, 126))	('5azadC', 'Chemical', 'MESH:D000077209', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('inhibit', 'NegReg', (127, 134))	('melanoma', 'Disease', (21, 29))	('3D cell invasion', 'CPA', (135, 151))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))
104675	30651148	's results on uveal melanoma cells, describing that low concentrations of 5azadC reduced both 2D invasion and clonogenicity.	('uveal melanoma', 'Phenotype', 'HP:0007716', (14, 28))	('uveal melanoma', 'Disease', 'MESH:C536494', (14, 28))	('5azadC', 'Var', (74, 80))	('uveal melanoma', 'Disease', (14, 28))	('5azadC', 'Chemical', 'MESH:D000077209', (74, 80))	('clonogenicity', 'CPA', (110, 123))	('reduced', 'NegReg', (81, 88))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('2D invasion', 'CPA', (94, 105))
104677	30651148	To further elucidate the mechanisms underlying the phenotypical changes induced by 5azadC, we specifically investigated the modifications on miR methylation and expression.	('expression', 'MPA', (161, 171))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('5azadC', 'Var', (83, 89))	('methylation', 'biological_process', 'GO:0032259', ('145', '156'))	('5azadC', 'Chemical', 'MESH:D000077209', (83, 89))
104680	30651148	Here, two miRs, MIR-155HG and MIR-199A2, implicated in migration and invasion processes, were found hypermethylated in the metastatic melanoma cell line (WM-266-4) compared to its primary counterpart (WM-115).	('MIR-199A2', 'Gene', '406977', (30, 39))	('WM-266-4', 'CellLine', 'CVCL:2765', (154, 162))	('MIR-155HG', 'Gene', (16, 25))	('MIR-199A2', 'Gene', (30, 39))	('miR', 'Gene', '220972', (10, 13))	('melanoma', 'Disease', (134, 142))	('miR', 'Gene', (10, 13))	('MIR-155HG', 'Gene', '114614', (16, 25))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('hypermethylated', 'Var', (100, 115))
104683	30651148	Moreover, its ectopic re-expression in the WM-266-4 cells induced a cytotoxic effect rather than an anti-invasive effect.	('WM-266-4', 'CellLine', 'CVCL:2765', (43, 51))	('cytotoxic effect', 'CPA', (68, 84))	('ectopic re-expression', 'Var', (14, 35))
104693	30651148	The A375 subclones, bearing a mutated BRAF, as it is the case of the WM266-4 cell line, overexpressed much higher levels of miR-199a-5p (x 10,000) than of miR-199a-3p (x 10), strongly suggesting that mainly the miR-199a-5p supported the pro-metastatic effect that was observed by the authors in these subclones.	('miR', 'Gene', '220972', (211, 214))	('miR', 'Gene', (211, 214))	('miR-199a-3p', 'Gene', (155, 166))	('pro-metastatic effect', 'CPA', (237, 258))	('BRAF', 'Gene', '673', (38, 42))	('mutated', 'Var', (30, 37))	('higher', 'PosReg', (107, 113))	('miR', 'Gene', '220972', (155, 158))	('miR-199a-3p', 'Gene', '406977', (155, 166))	('miR', 'Gene', (155, 158))	('BRAF', 'Gene', (38, 42))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))	('WM266-4', 'CellLine', 'CVCL:2765', (69, 76))
104701	30651148	In testicular tumour, MIR-199A2 hypermethylation was linked to malignancy progression.	('MIR-199A2', 'Gene', '406977', (22, 31))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('MIR-199A2', 'Gene', (22, 31))	('malignancy', 'Disease', (63, 73))	('linked', 'Reg', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('hypermethylation', 'Var', (32, 48))	('testicular tumour', 'Disease', (3, 20))	('testicular tumour', 'Disease', 'MESH:D013736', (3, 20))	('testicular tumour', 'Phenotype', 'HP:0010788', (3, 20))
104702	30651148	In this model, miR-199a re-expression led to the suppression of cell growth, cancer migration, invasion and metastasis in vitro and in vivo.	('suppression', 'NegReg', (49, 60))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cell growth', 'biological_process', 'GO:0016049', ('64', '75'))	('cell growth', 'CPA', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('re-expression', 'Var', (24, 37))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', (15, 18))
104710	30651148	Interestingly, 5azadC also downregulated common effectors of this multistep biological process (Fig.	('downregulated', 'NegReg', (27, 40))	('biological process', 'biological_process', 'GO:0008150', ('76', '94'))	('5azadC', 'Chemical', 'MESH:D000077209', (15, 21))	('5azadC', 'Var', (15, 21))
104714	30651148	In conclusion, we proved that slightly cytotoxic doses of 5azadC are translated into an anti-invasive effect in a BRAF-mutated metastatic melanoma model.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('5azadC', 'Var', (58, 64))	('5azadC', 'Chemical', 'MESH:D000077209', (58, 64))	('anti-invasive effect', 'CPA', (88, 108))
104715	30651148	This effect is in part associated with MIR-199A2 promoter demethylation and re-expression of its specific mature form miR-199a-3p.	('MIR-199A2', 'Gene', '406977', (39, 48))	('demethylation', 'biological_process', 'GO:0070988', ('58', '71'))	('MIR-199A2', 'Gene', (39, 48))	('miR-199a-3p', 'Gene', (118, 129))	('demethylation', 'Var', (58, 71))	('miR-199a-3p', 'Gene', '406977', (118, 129))
104719	30651148	Taken together, our findings support the use of epigenetic drugs or miR mimetic-based therapeutic strategies, either alone or in combination, for limiting metastatic dissemination of melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('limiting', 'NegReg', (146, 154))	('dissemination of melanoma', 'Disease', (166, 191))	('dissemination of melanoma', 'Disease', 'MESH:D008545', (166, 191))	('melanomas', 'Disease', (183, 192))	('epigenetic drugs', 'Var', (48, 64))
104723	30651148	Additionally, four primary melanoma cell lines (WC00060, WC00062, WC0008 and WC00081) were purchased from the Coriell Cell Repository (Coriell Institute for Medical Research, Camden, NJ, USA).	('WC00081', 'Var', (77, 84))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('WC00060', 'Var', (48, 55))
104778	29795011	Moreover, it was demonstrated that in invasive melanoma the number of UV-induced mutations is higher than the number of nevi (being included here also the matched precursor nevi), and the consequences are increased somatic mutation burdens.	('invasive melanoma', 'Disease', 'MESH:D008545', (38, 55))	('increased', 'PosReg', (205, 214))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('nevi', 'Phenotype', 'HP:0003764', (173, 177))	('invasive melanoma', 'Disease', (38, 55))	('mutations', 'Var', (81, 90))	('nevi', 'Phenotype', 'HP:0003764', (120, 124))	('higher', 'PosReg', (94, 100))
104781	29795011	Cutaneous melanoma was described as one of the most immunogenic cancers with heterogeneous histological and clinical features, and a significant number of mutations, which explains the low rate of tumor regression, multi-drug resistance to targeted therapies, and reduced survival rate.	('drug resistance', 'biological_process', 'GO:0042493', ('221', '236'))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('reduced', 'NegReg', (264, 271))	('immunogenic cancers', 'Disease', 'MESH:D009369', (52, 71))	('Cutaneous melanoma', 'Phenotype', 'HP:0012056', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (221, 236))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('drug resistance', 'biological_process', 'GO:0009315', ('221', '236'))	('Cutaneous melanoma', 'Disease', 'MESH:C562393', (0, 18))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('tumor', 'Disease', (197, 202))	('immunogenic cancers', 'Disease', (52, 71))	('Cutaneous melanoma', 'Disease', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
104799	29795011	According to Grzywa et al, the intratumor heterogeneity is characterized by genomic instability (having as result the acquisition of common mutations:which occur early in tumor evolution and are found in all regions, of shared/branch mutations:that occur later and were detected only in some regions, and of private mutations:that occur in tumor progression phase, present in a single compartment), genomic and epigenomic alterations (having as consequence heterogeneous genes expression), and epigenetic dysregulation.	('men', 'Species', '9606', (392, 395))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('epigenomic alterations', 'CPA', (411, 433))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', (340, 345))
104801	29795011	A considerable progress was registered in the genomic field of melanoma in recent years, a major role being played by the novel techniques like: next-generation sequencing and large-scale expression analyses of tumors which offer a landscape of the mutations existent in melanoma, the mutation rate in melanoma exceeding all the other cancers rates (the number of mutations per Mb ranged from 0.1 to 100 with an average value of 16.8 mutations/Mb according to The Cancer Genome Atlas (TCGA) data).	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Phenotype', 'HP:0002664', (335, 342))	('cancers', 'Disease', (335, 342))	('Cancer', 'Phenotype', 'HP:0002664', (464, 470))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('melanoma', 'Disease', (302, 310))	('melanoma', 'Disease', 'MESH:D008545', (271, 279))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (335, 342))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (464, 483))	('tumors', 'Disease', (211, 217))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('mutations', 'Var', (249, 258))	('Cancer Genome Atlas', 'Disease', (464, 483))	('melanoma', 'Phenotype', 'HP:0002861', (271, 279))	('melanoma', 'Disease', (271, 279))
104803	29795011	The multitude mutations discovered to be engaged in melanoma increases the difficulty in identifying which are the "driver" (causative) mutations and the "passenger" (bystander) mutations.	('melanoma increases', 'Disease', 'MESH:D008545', (52, 70))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('mutations', 'Var', (14, 23))	('melanoma increases', 'Disease', (52, 70))
104805	29795011	Based on the results of a whole-genome sequencing analysis, the genes susceptible to mutations in cutaneous melanoma are: BRAF, cyclin-dependent kinase N2A (CDKN2A), NRAS, and TP53.	('NRAS', 'Gene', '18176', (166, 170))	('NRAS', 'Gene', (166, 170))	('TP53', 'Gene', '22059', (176, 180))	('CDKN2A', 'Gene', '12578', (157, 163))	('BRAF', 'Gene', (122, 126))	('mutations', 'Var', (85, 94))	('cutaneous melanoma', 'Disease', (98, 116))	('CDKN2A', 'Gene', (157, 163))	('TP53', 'Gene', (176, 180))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (98, 116))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (98, 116))	('cyclin', 'molecular_function', 'GO:0016538', ('128', '134'))
104806	29795011	MAPK pathway controls important cellular processes, as: cell cycle progression, differentiation, and upregulation of transcription, and the existence of BRAF mutations will determine impairment of these processes, the end-point being oncogenesis.	('BRAF', 'Gene', (153, 157))	('men', 'Species', '9606', (189, 192))	('cell cycle progression', 'CPA', (56, 78))	('upregulation', 'PosReg', (101, 113))	('MAPK', 'Gene', (0, 4))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('differentiation', 'CPA', (80, 95))	('transcription', 'MPA', (117, 130))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('MAPK', 'molecular_function', 'GO:0004707', ('0', '4'))	('oncogenesis', 'biological_process', 'GO:0007048', ('234', '245'))	('mutations', 'Var', (158, 167))
104807	29795011	BRAF mutations are very common in cutaneous melanoma and trigger MAPK pathway activation (60% of the cutaneous melanomas exhibit MAPK activating mutations), whereas in other types of melanoma, such as acral, mucosal, conjunctival, and uveal, its incidence is quite low.	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('mutations', 'Var', (145, 154))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('BRAF', 'Gene', (0, 4))	('activating', 'PosReg', (134, 144))	('MAPK', 'Gene', (129, 133))	('MAPK', 'molecular_function', 'GO:0004707', ('129', '133'))	('MAPK pathway', 'Pathway', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('mutations', 'Var', (5, 14))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (101, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (101, 119))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (101, 119))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (101, 120))	('cutaneous melanoma', 'Disease', (34, 52))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (34, 52))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (34, 52))	('activation', 'PosReg', (78, 88))	('MAPK', 'molecular_function', 'GO:0004707', ('65', '69'))	('cutaneous melanomas', 'Disease', (101, 120))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
104808	29795011	Valine-to-glutamic acid substitution at codon 600 (BRAF (V600E)) is the most prevalent mutation in melanoma (detected in approximately 50% of melanomas) and might be the repercussion of a secondary effect of UV damage, like a nonclassic DNA mutation induced by UV radiation or the synthesis of reactive oxygen species.	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('melanomas', 'Disease', 'MESH:D008545', (142, 151))	('synthesis', 'biological_process', 'GO:0009058', ('281', '290'))	('UV damage', 'Disease', 'MESH:C563466', (208, 217))	('V600E', 'Mutation', 'rs113488022', (57, 62))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (294, 317))	('prevalent', 'Reg', (77, 86))	('melanomas', 'Disease', (142, 151))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('Valine-to-glutamic acid substitution at codon 600', 'Mutation', 'rs113488022', (0, 49))	('melanoma', 'Disease', (99, 107))	('UV damage', 'Disease', (208, 217))	('DNA', 'cellular_component', 'GO:0005574', ('237', '240'))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('Valine-to-glutamic', 'Var', (0, 18))	('melanomas', 'Phenotype', 'HP:0002861', (142, 151))	('melanoma', 'Disease', (142, 150))
104811	29795011	NRAS mutations represent the second most frequent cause of altered signaling via MAPK pathway.	('mutations', 'Var', (5, 14))	('MAPK', 'molecular_function', 'GO:0004707', ('81', '85'))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '18176', (0, 4))	('MAPK pathway', 'Pathway', (81, 93))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('altered signaling', 'MPA', (59, 76))
104812	29795011	This type of mutations was identified in 15-30% of melanomas and were found at codon 12, 13, or 61.	('melanomas', 'Phenotype', 'HP:0002861', (51, 60))	('melanomas', 'Disease', 'MESH:D008545', (51, 60))	('mutations', 'Var', (13, 22))	('melanomas', 'Disease', (51, 60))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))
104813	29795011	Of note, NRAS and BRAF mutations are mutually exclusive, the presence of co-mutations was rarely observed, and in order to trigger malignant transformation, additional mutations are required, such as loss of tumor suppressors p16INK4A (Cyclin-dependent kinase inhibitor 2A) or PTEN (phosphatase and tensin homolog protein).	('kinase inhibitor', 'biological_process', 'GO:0033673', ('253', '269'))	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('236', '269'))	('NRAS', 'Gene', '18176', (9, 13))	('loss of tumor', 'Disease', (200, 213))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', (236, 272))	('NRAS', 'Gene', (9, 13))	('phosphatase', 'molecular_function', 'GO:0016791', ('283', '294'))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('p16INK4A', 'Gene', (226, 234))	('PTEN', 'Gene', (277, 281))	('mutations', 'Var', (23, 32))	('p16INK4A', 'Gene', '12578', (226, 234))	('PTEN', 'Gene', '19211', (277, 281))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (236, 272))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('283', '313'))	('protein', 'cellular_component', 'GO:0003675', ('314', '321'))	('loss of tumor', 'Disease', 'MESH:D009369', (200, 213))
104814	29795011	The consequences of activated BRAF or NRAS mutations consist of aberrant cell growth, followed by premature growth arrest via oncogene-induced senescence, the resulted lesions remain benign and do not switch to malignancy in the absence of other mutations.	('cell growth', 'CPA', (73, 84))	('premature growth arrest', 'Disease', (98, 121))	('premature growth arrest', 'Disease', 'MESH:D006323', (98, 121))	('BRAF', 'Gene', (30, 34))	('mutations', 'Var', (43, 52))	('NRAS', 'Gene', '18176', (38, 42))	('malignancy', 'Disease', 'MESH:D009369', (211, 221))	('premature growth', 'Phenotype', 'HP:0001510', (98, 114))	('senescence', 'biological_process', 'GO:0010149', ('143', '153'))	('NRAS', 'Gene', (38, 42))	('malignancy', 'Disease', (211, 221))	('cell growth', 'biological_process', 'GO:0016049', ('73', '84'))
104816	29795011	NF1 mutations were associated with initiation of melanoma and are prevalent in chronically sun-exposed skin.	('associated', 'Reg', (19, 29))	('NF1', 'Gene', '18015', (0, 3))	('initiation of melanoma', 'Disease', (35, 57))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('initiation of melanoma', 'Disease', 'MESH:D008545', (35, 57))
104818	29795011	To note, NF1 mutations or suppression might appear in parallel to BRAF mutations.	('mutations', 'Var', (13, 22))	('NF1', 'Gene', (9, 12))	('NF1', 'Gene', '18015', (9, 12))	('suppression', 'NegReg', (26, 37))
104819	29795011	The cyclin-dependent kinase inhibitor 2A gene (CDKN2A) is the familial melanoma locus (located on the short arm of chromosome 9) that controls two tumor suppressor proteins (p14-ARF and p16-INK4A) with major roles in cell proliferation and senescence.	('p14-ARF', 'Gene', (174, 181))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (4, 40))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('21', '37'))	('tumor', 'Disease', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('147', '163'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('4', '37'))	('senescence', 'biological_process', 'GO:0010149', ('240', '250'))	('familial melanoma', 'Disease', (62, 79))	('CDKN2A', 'Gene', '12578', (47, 53))	('CDKN2A', 'Gene', (47, 53))	('p14-ARF', 'Gene', '20202', (174, 181))	('familial melanoma', 'Disease', 'OMIM:155600', (62, 79))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '12578', (4, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('147', '163'))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('p16-INK4A', 'Var', (186, 195))	('short arm', 'Phenotype', 'HP:0009824', (102, 111))	('cell proliferation', 'biological_process', 'GO:0008283', ('217', '235'))
104820	29795011	CDKN2A mutations were reported in approximatively 15% of familial melanomas, the somatic defects happened as a result of an impaired or loss of function (mutations, homozygous deletions or DNA methylation-induced epigenetic silencing) and are correlated with an invasive potential.	('impaired', 'NegReg', (124, 132))	('loss of function', 'Disease', (136, 152))	('loss of function', 'Disease', 'MESH:D060825', (136, 152))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('familial melanomas', 'Disease', (57, 75))	('DNA methylation', 'biological_process', 'GO:0006306', ('189', '204'))	('familial melanomas', 'Disease', 'OMIM:155600', (57, 75))	('CDKN2A', 'Gene', '12578', (0, 6))	('homozygous deletions', 'Var', (165, 185))	('mutations', 'Var', (154, 163))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('CDKN2A', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
104821	29795011	These mutations are prevalent in melanomas (in 90%) and in dysplastic nevi (10%), and are not expressed in common melanocytic nevi.	('dysplastic nevi', 'Disease', 'MESH:D004416', (59, 74))	('dysplastic nevi', 'Phenotype', 'HP:0001062', (59, 74))	('nevi', 'Phenotype', 'HP:0003764', (70, 74))	('nevi', 'Phenotype', 'HP:0003764', (126, 130))	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (114, 130))	('dysplastic nevi', 'Disease', (59, 74))	('prevalent', 'Reg', (20, 29))	('mutations', 'Var', (6, 15))	('melanomas', 'Disease', (33, 42))
104842	29795011	The B16 sublines remained the most common used cell lines for syngeneic transplantation, two of them, B16F1 (low metastatic potential:used for primary tumors development) and B16F10 (high metastatic potential:lung metastases) being well-established sub-clones and reliable platforms of data about melanoma immunology and immunotherapy strategies.	('men', 'Species', '9606', (165, 168))	('primary tumors', 'Disease', (143, 157))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('B16F10', 'Var', (175, 181))	('primary tumors', 'Disease', 'MESH:D009369', (143, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('melanoma immunology', 'Disease', (297, 316))	('melanoma immunology', 'Disease', 'MESH:D007154', (297, 316))	('melanoma', 'Phenotype', 'HP:0002861', (297, 305))	('lung metastases', 'Disease', (209, 224))	('lung metastases', 'Disease', 'MESH:D009362', (209, 224))
104851	29795011	It is well-known that the transformation of a normal cell into a cancerous one involves a series of genetic and epigenetic changes, changes that were also described in melanoma.	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('epigenetic', 'Var', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancerous', 'Disease', (65, 74))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
104853	29795011	The genetic engineered models (GEMs) were performed using different approaches, such as: genetic manipulation of the ectopic expression of oncogenes, inactivation of tumor suppressor genes, and introduction of different mutations.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('oncogenes', 'Gene', (139, 148))	('inactivation', 'Var', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('GEMs', 'cellular_component', 'GO:0015030', ('31', '35'))	('tumor', 'Disease', (166, 171))	('genetic manipulation', 'Var', (89, 109))	('tumor suppressor', 'biological_process', 'GO:0051726', ('166', '182'))	('ectopic expression', 'MPA', (117, 135))	('GEMs', 'cellular_component', 'GO:0097504', ('31', '35'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('166', '182'))	('mutations', 'Var', (220, 229))
104856	29795011	Other important features of GEMs consist of: the capacity to develop spontaneous melanoma tumors at their inherent site (spontaneous melanoma rarely occurs in adult mice), the ability to generate other mutations in order to verify their potential susceptibility or resistance to therapy, and the presence of a fully functional immune system that influences the tumor growth.	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (361, 366))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma tumors', 'Disease', (81, 96))	('melanoma', 'Disease', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('tumor', 'Disease', (90, 95))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('GEMs', 'cellular_component', 'GO:0097504', ('28', '32'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('GEMs', 'cellular_component', 'GO:0015030', ('28', '32'))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('develop', 'PosReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('melanoma tumors', 'Disease', 'MESH:D008545', (81, 96))	('mutations', 'Var', (202, 211))
104859	29795011	The first genetic engineered melanoma mouse model was the transgenic mouse model:Tyr-SV40, that exhibited overexpression of SV40 T antigen (Tag) under the control of melanocyte-specific tyrosinase (Tyr) gene promoter and developed melanoma spontaneously or after UV irradiation.	('mouse', 'Species', '10090', (38, 43))	('SV40', 'Var', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma', 'Disease', (29, 37))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('mouse', 'Species', '10090', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('developed', 'PosReg', (221, 230))	('overexpression', 'PosReg', (106, 120))	('transgenic', 'Species', '10090', (58, 68))	('SV40 T antigen', 'molecular_function', 'GO:0016887', ('124', '138'))	('genetic engineered melanoma', 'Disease', (10, 37))	('genetic engineered melanoma', 'Disease', 'MESH:D030342', (10, 37))
104860	29795011	Linda Chin and her collaborators established the first mouse model:Tyr-HRAS by knocking out melanoma specific genes, Cdkn2a-/-, and developed spontaneous melanoma that do not metastasize.	('Cdkn2a', 'Gene', '12578', (117, 123))	('knocking', 'Var', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('mouse', 'Species', '10090', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (92, 100))	('melanoma', 'Disease', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('Cdkn2a', 'Gene', (117, 123))
104862	29795011	Subsequent studies showed that silencing PTEN gene in BRAFV600E melanoma model led to the development of metastatic melanoma.	('silencing', 'Var', (31, 40))	('men', 'Species', '9606', (97, 100))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('BRAFV600E', 'Mutation', 'rs113488022', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('PTEN', 'Gene', '19211', (41, 45))	('PTEN', 'Gene', (41, 45))
104870	29795011	Still, there were developed melanoma models using hairless mice subjected to DMBA (7,12-dimethylbenzanthracene):as initiator agent and UV irradiation promoter, and transgenic mice carrying BRAF mutations (increased risk to develop melanoma when UV irradiation was added).	('melanoma', 'Disease', (28, 36))	('7,12-dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (83, 110))	('mice', 'Species', '10090', (175, 179))	('mice', 'Species', '10090', (59, 63))	('DMBA', 'Chemical', 'MESH:D015127', (77, 81))	('develop', 'PosReg', (223, 230))	('transgenic mice', 'Species', '10090', (164, 179))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Disease', (231, 239))	('mutations', 'Var', (194, 203))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('BRAF', 'Gene', (189, 193))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
104873	29795011	The most successful protocols to develop melanoma in mice after UV exposure consisted of: exposure of genetic engineered mice overexpressing SV40 Tag and HGF/SF starting with day 4 after birth; these data being somehow in accordance with the results of multiple human epidemiological studies which assert that an increased exposure to sun in the childhood augments the risk for melanoma.	('melanoma', 'Disease', 'MESH:D008545', (378, 386))	('SV40 Tag', 'Var', (141, 149))	('HGF/SF', 'Gene', (154, 160))	('human', 'Species', '9606', (262, 267))	('men', 'Species', '9606', (359, 362))	('augments', 'NegReg', (356, 364))	('mice', 'Species', '10090', (121, 125))	('HGF/SF', 'Gene', '15234', (154, 160))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('melanoma', 'Phenotype', 'HP:0002861', (378, 386))	('mice', 'Species', '10090', (53, 57))	('melanoma', 'Disease', (378, 386))
104891	33937330	The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('HNSC', 'Phenotype', 'HP:0012288', (128, 132))	('BRCA', 'Gene', '672', (79, 83))	('BRCA', 'Gene', (79, 83))	('THCA', 'Phenotype', 'HP:0002890', (89, 93))	('KIRP', 'Disease', (68, 72))	('high', 'Var', (4, 8))	('THCA', 'Disease', (89, 93))	('PERK', 'Gene', (23, 27))	('LGG', 'Disease', (74, 77))	('PERK', 'Gene', '9451', (23, 27))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))
104894	33937330	Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('infiltration', 'CPA', (58, 70))	('deteriorate', 'NegReg', (136, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (189, 203))	('PERK', 'Gene', '9451', (222, 226))	('patients', 'Species', '9606', (164, 172))	('outcomes', 'CPA', (152, 160))	('high expression', 'Var', (16, 31))	('promote', 'PosReg', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('tumor', 'Disease', (103, 108))	('PERK', 'Gene', (35, 39))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (178, 204))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PERK', 'Gene', '9451', (35, 39))	('PERK', 'Gene', (222, 226))
104923	33937330	Inhibitors augment T-cell activity by blocking programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) and show remarkable clinical effects (Topalian et al.,; Gordon et al.,).	('PD-L1', 'Gene', '29126', (103, 108))	('blocking', 'NegReg', (38, 46))	('programmed cell death protein 1', 'Gene', (47, 78))	('augment', 'PosReg', (11, 18))	('programmed cell death protein 1', 'Gene', '5133', (47, 78))	('Inhibitors', 'Var', (0, 10))	('ligand', 'molecular_function', 'GO:0005488', ('95', '101'))	('PD-1', 'Gene', '5133', (90, 94))	('programmed cell death', 'biological_process', 'GO:0012501', ('47', '68'))	('PD-1', 'Gene', (90, 94))	('PD-L1', 'Gene', (103, 108))	('PD-1', 'Gene', (80, 84))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('T-cell activity', 'CPA', (19, 34))	('PD-1', 'Gene', '5133', (80, 84))
104954	33937330	A previous study has shown that PERK inhibition by siRNA or GSK2656157 (a small molecule inhibitor against the PERK/elF2alpha/ATF4 pathway) might improve clinical prognosis and enhance the treatment of esophageal squamous cell carcinoma (ESCC) patients (Wang et al.,), but little research is reported in other types of cancers.	('ATF4', 'Gene', '468', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancers', 'Disease', (319, 326))	('PERK', 'Gene', '9451', (111, 115))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('patients', 'Species', '9606', (244, 252))	('GSK2656157', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('inhibition', 'NegReg', (37, 47))	('GSK', 'molecular_function', 'GO:0050321', ('60', '63'))	('clinical prognosis', 'CPA', (154, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('PERK', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('treatment', 'CPA', (189, 198))	('GSK2656157', 'Chemical', 'MESH:C000597302', (60, 70))	('improve', 'PosReg', (146, 153))	('enhance', 'PosReg', (177, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('PERK', 'Gene', (111, 115))	('ATF4', 'Gene', (126, 130))	('PERK', 'Gene', '9451', (32, 36))
104956	33937330	According to the PrognoScan database, the high expression of PERK was associated with a poor prognosis in brain cancer (shorter OS, p = 0.003) and soft tissue cancer (shorter DRFS, p = 0.008) and related to a favorable prognosis in lung cancer (longer OS and RFS, p < 0.05, Figure 3).	('soft tissue cancer', 'Phenotype', 'HP:0031459', (147, 165))	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('high expression', 'Var', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PERK', 'Gene', (61, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('brain cancer', 'Phenotype', 'HP:0030692', (106, 118))	('cancer', 'Disease', (237, 243))	('PERK', 'Gene', '9451', (61, 65))	('brain cancer', 'Disease', 'MESH:D001932', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lung cancer', 'Disease', (232, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('brain cancer', 'Disease', (106, 118))
104960	33937330	The high expression of PERK was associated with a favorable prognosis in bladder carcinoma (p = 0.006), esophageal squamous cell carcinoma (p = 0.0022), lung adenocarcinoma (p = 0.0054), rectum adenocarcinoma (p = 0.026), and thymoma (p = 0.039, Figure 4) and related to a poor prognosis in kidney renal papillary cell carcinoma (p = 0.014), liver hepatocellular carcinoma (p = 0.023), and thyroid carcinoma (p = 0.0036, Figure 4).	('bladder carcinoma', 'Phenotype', 'HP:0002862', (73, 90))	('thymoma', 'Disease', (226, 233))	('bladder carcinoma', 'Disease', 'MESH:D001749', (73, 90))	('high expression', 'Var', (4, 19))	('thymoma', 'Phenotype', 'HP:0100522', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('kidney renal papillary cell carcinoma', 'Disease', (291, 328))	('rectum adenocarcinoma', 'Disease', (187, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('PERK', 'Gene', '9451', (23, 27))	('lung adenocarcinoma', 'Disease', (153, 172))	('bladder carcinoma', 'Disease', (73, 90))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('liver hepatocellular carcinoma', 'Disease', (342, 372))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (390, 407))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('thyroid carcinoma', 'Disease', (390, 407))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (291, 328))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (187, 208))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (390, 407))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (298, 328))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (348, 372))	('thymoma', 'Disease', 'MESH:D013945', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('PERK', 'Gene', (23, 27))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (342, 372))
104964	33937330	According to the UALCAN database, the high expression of PERK was associated with a poor prognosis in kidney renal papillary cell carcinoma (KIRP) (p = 0.01), brain lower grade glioma (LGG) (p = 0.00016), and THCA (p = 0.017, Figure 5).	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (109, 139))	('THCA', 'Phenotype', 'HP:0002890', (209, 213))	('glioma', 'Disease', (177, 183))	('high expression', 'Var', (38, 53))	('THCA', 'Disease', (209, 213))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('PERK', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (102, 139))	('PERK', 'Gene', '9451', (57, 61))
104965	33937330	Consistent with the results of the Kaplan:Meier plotter database, PERK expression in BRCA had a poor prognosis (OS < 4,000 days, ~130 months, p = 0.025, Figure 5).	('BRCA', 'Gene', (85, 89))	('PERK', 'Gene', (66, 70))	('expression', 'Var', (71, 81))	('PERK', 'Gene', '9451', (66, 70))	('BRCA', 'Phenotype', 'HP:0003002', (85, 89))	('BRCA', 'Gene', '672', (85, 89))
104967	33937330	Together, the high expression of PERK is associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('THCA', 'Phenotype', 'HP:0002890', (98, 102))	('THCA', 'Disease', (98, 102))	('PERK', 'Gene', (33, 37))	('HNSC', 'Disease', (137, 141))	('LGG', 'Disease', (83, 86))	('KIRP', 'Disease', (77, 81))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (137, 141))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('BRCA', 'Gene', '672', (88, 92))	('PERK', 'Gene', '9451', (33, 37))	('BRCA', 'Gene', (88, 92))
105000	33937330	Lung cancer was an exception where high levels of PERK expression showed a better prognosis.	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('PERK', 'Gene', (50, 54))	('high levels', 'Var', (35, 46))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('PERK', 'Gene', '9451', (50, 54))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
105002	33937330	The UALCAN database analysis demonstrated that the high expression of PERK was associated with a poor prognosis in KIRP, LGG, THCA, and BRCA (Figure 5).	('KIRP', 'Disease', (115, 119))	('PERK', 'Gene', (70, 74))	('LGG', 'Disease', (121, 124))	('THCA', 'Phenotype', 'HP:0002890', (126, 130))	('THCA', 'Disease', (126, 130))	('BRCA', 'Gene', '672', (136, 140))	('PERK', 'Gene', '9451', (70, 74))	('high expression', 'Var', (51, 66))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
105005	33937330	Inhibition of CREB3L1 by genetic or pharmacological methods suppresses cancer cell invasion and metastasis (Feng et al.,).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CREB3L1', 'Gene', '90993', (14, 21))	('cancer', 'Disease', (71, 77))	('suppresses', 'NegReg', (60, 70))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CREB3L1', 'Gene', (14, 21))
105006	33937330	Another report showed that inhibition of the PERK-eIF2alpha-GRP94 signaling pathway silenced the epidermal growth factor receptor (EGFR) and then increased the radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells (Zhang et al.,).	('radiosensitivity', 'CPA', (160, 176))	('EGFR', 'Gene', (131, 135))	('inhibition', 'Var', (27, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('squamous cell carcinoma', 'Disease', (233, 256))	('PERK', 'Gene', '9451', (45, 49))	('increased', 'PosReg', (146, 155))	('silenced', 'NegReg', (84, 92))	('OSCC', 'Phenotype', 'HP:0012182', (258, 262))	('GRP94', 'Gene', '7184', (60, 65))	('EGFR', 'Gene', '1956', (131, 135))	('eIF2alpha', 'Gene', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('eIF2alpha', 'Gene', '83939', (50, 59))	('GRP94', 'Gene', (60, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('66', '83'))	('eIF2', 'cellular_component', 'GO:0005850', ('50', '54'))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (219, 256))	('epidermal growth factor receptor', 'Gene', (97, 129))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('97', '120'))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('PERK', 'Gene', (45, 49))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
105025	33937330	Expansion of myeloid-derived suppressor cells (MDSCs) has emerged as a key mechanism of antitumor immune evasion and correlates with a poor clinical outcome and resistance to cancer immunotherapy (Lu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('immune evasion', 'biological_process', 'GO:0042783', ('98', '112'))	('tumor', 'Disease', (92, 97))	('immune evasion', 'biological_process', 'GO:0051842', ('98', '112'))	('Expansion', 'Var', (0, 9))
105027	33937330	PERK deletion transformed MDSCs into myeloid cells that activated CD8+ T-cell-mediated immunity against cancer (Mohamed et al.,).	('PERK', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('T-cell-mediated immunity', 'biological_process', 'GO:0002456', ('71', '95'))	('PERK', 'Gene', '9451', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('activated', 'PosReg', (56, 65))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
105028	33937330	Another study showed that inhibition of PERK in CD8+ T cells abrogates mitochondrial ROS generation in PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs), which boosts CD8+ TIL viability and enhances antitumor immunity (Hurst et al.,).	('abrogates', 'NegReg', (61, 70))	('boosts', 'PosReg', (159, 165))	('CD8', 'Gene', '925', (48, 51))	('ROS', 'Chemical', '-', (85, 88))	('CD8', 'Gene', '925', (166, 169))	('CD8', 'Gene', '925', (109, 112))	('tumor', 'Disease', (202, 207))	('inhibition', 'Var', (26, 36))	('ROS generation', 'biological_process', 'GO:1903409', ('85', '99'))	('tumor', 'Disease', (114, 119))	('mitochondrial ROS generation', 'MPA', (71, 99))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PD-1', 'Gene', (103, 107))	('CD8', 'Gene', (48, 51))	('PERK', 'Gene', (40, 44))	('PD-1', 'Gene', '5133', (103, 107))	('enhances', 'PosReg', (189, 197))	('CD8', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CD8', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PERK', 'Gene', '9451', (40, 44))
105114	27255356	In the metastatic sub-group the presence of nested CD147 positive cells was correlated with ciliary body involvement (p = 0.042).	('presence', 'Var', (32, 40))	('CD147', 'Gene', '682', (51, 56))	('ciliary body involvement', 'Disease', (92, 116))	('correlated', 'Reg', (76, 86))	('CD147', 'Gene', (51, 56))
105158	27255356	HCC cells with silenced MMP-2 and MMP-9 genes were less invasive compared to MMP-2 and MMP-9 silenced fibroblasts or CD147-silenced HCC cells when co-cultured with fibroblasts.	('MMP-2', 'Gene', (24, 29))	('MMP-2', 'Gene', '4313', (77, 82))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('MMP-2', 'molecular_function', 'GO:0004228', ('77', '82'))	('MMP-9', 'molecular_function', 'GO:0004229', ('87', '92'))	('invasive', 'CPA', (56, 64))	('MMP-9', 'Gene', '4318', (34, 39))	('MMP-2', 'Gene', (77, 82))	('MMP-9', 'Gene', (34, 39))	('HCC', 'Phenotype', 'HP:0001402', (132, 135))	('CD147', 'Gene', '682', (117, 122))	('silenced', 'Var', (15, 23))	('MMP-2', 'Gene', '4313', (24, 29))	('MMP-2', 'molecular_function', 'GO:0004228', ('24', '29'))	('MMP-9', 'Gene', '4318', (87, 92))	('MMP-9', 'Gene', (87, 92))	('less', 'NegReg', (51, 55))	('MMP-9', 'molecular_function', 'GO:0004229', ('34', '39'))	('CD147', 'Gene', (117, 122))
105181	27255356	The presence of clustered CD147 in uveal melanomas was significantly associated with tumor stage in the non-metastatic subgroup.	('melanomas', 'Phenotype', 'HP:0002861', (41, 50))	('tumor', 'Disease', (85, 90))	('CD147', 'Gene', '682', (26, 31))	('clustered', 'Var', (16, 25))	('associated', 'Reg', (69, 79))	('CD147', 'Gene', (26, 31))	('uveal melanomas', 'Disease', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('uveal melanomas', 'Phenotype', 'HP:0007716', (35, 50))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('presence', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('uveal melanomas', 'Disease', 'MESH:C536494', (35, 50))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
105206	21188111	In contrast, a British trial examining excision margins in melanomas greater than 2 mm thick demonstrated an increased rate of locoregional recurrence after excision with 1 cm margins in comparison with 3 cm margins.	('melanomas', 'Disease', (59, 68))	('locoregional recurrence', 'CPA', (127, 150))	('1 cm margins', 'Var', (171, 183))	('melanomas', 'Disease', 'MESH:D008545', (59, 68))	('melanomas', 'Phenotype', 'HP:0002861', (59, 68))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))
105208	21188111	Based on these data, at our institution, we recommend 1 cm surgical margins for invasive melanomas <=1.0 mm thick, 1 to 2 cm margins for melanomas between 1.01 and 2.0 mm in thickness, and 2 cm margins for melanomas thicker than 2.0 mm.	('melanomas', 'Disease', (137, 146))	('invasive melanomas', 'Disease', 'MESH:D008545', (80, 98))	('melanomas', 'Disease', 'MESH:D008545', (206, 215))	('melanomas', 'Disease', (89, 98))	('melanomas', 'Phenotype', 'HP:0002861', (137, 146))	('melanomas', 'Phenotype', 'HP:0002861', (89, 98))	('melanomas', 'Disease', 'MESH:D008545', (137, 146))	('melanomas', 'Disease', (206, 215))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('invasive melanomas', 'Disease', (80, 98))	('melanomas', 'Disease', 'MESH:D008545', (89, 98))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('<=1.0', 'Var', (99, 104))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))
105213	21188111	For example, primary tumor thickness was a strong predictor of survival, and 92% of patients with node negative, T1 (<1 mm thick) melanoma primary tumors survived 10 years compared with only 50% of patients with node negative T4 (>4 mm thick) tumors.	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumor', 'Disease', (21, 26))	('patients', 'Species', '9606', (198, 206))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (243, 248))	('tumor', 'Disease', (147, 152))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('T1 (<1 mm thick', 'Var', (113, 128))	('melanoma primary tumors', 'Disease', (130, 153))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', (147, 153))	('melanoma primary tumors', 'Disease', 'MESH:D008545', (130, 153))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))
105214	21188111	The new staging guidelines from the American Joint Committee on Cancer (AJCC) also identify primary tumor ulceration as an independent prognosticator of survival, and in a pooled meta-analysis of three large adjuvant interferon trials E1684, E1690, and E1694, primary tumor ulceration was associated with worse relapse-free survival (RFS, HR = 1.54) and overall survival (OS, HR = 1.73).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Cancer', 'Disease', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('overall survival', 'CPA', (354, 370))	('tumor', 'Disease', (100, 105))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('E1690', 'Var', (242, 247))	('tumor', 'Disease', (268, 273))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('E1684', 'Var', (235, 240))	('E1694', 'Var', (253, 258))	('relapse-free survival', 'CPA', (311, 332))	('worse', 'NegReg', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
105225	21188111	Furthermore, patients undergoing sentinel lymph node biopsy only have a much lower incidence of surgical complications, including lymphedema, wound infection, and hematoma/seroma formation, than patients undergoing complete regional lymph node dissections.	('lower', 'NegReg', (77, 82))	('formation', 'biological_process', 'GO:0009058', ('179', '188'))	('surgical complications', 'CPA', (96, 118))	('edema', 'Phenotype', 'HP:0000969', (135, 140))	('sentinel', 'Var', (33, 41))	('hematoma/seroma', 'Disease', (163, 178))	('patients', 'Species', '9606', (13, 21))	('lymphedema', 'Disease', (130, 140))	('infection', 'Disease', (148, 157))	('patients', 'Species', '9606', (195, 203))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('lymphedema', 'Disease', 'MESH:D008209', (130, 140))	('hematoma/seroma', 'Disease', 'MESH:D049291', (163, 178))	('lymphedema', 'Phenotype', 'HP:0001004', (130, 140))
105237	21188111	CT imaging detects occult disease in 0.5%-3.7% of patients with microscopic nodal metastases on sentinel lymph node biopsy and in 4%-16% of patients with clinically palpable nodal disease.	('occult disease', 'Disease', (19, 33))	('microscopic', 'Var', (64, 75))	('patients', 'Species', '9606', (50, 58))	('nodal metastases', 'Disease', (76, 92))	('nodal disease', 'Disease', 'MESH:D013611', (174, 187))	('patients', 'Species', '9606', (140, 148))	('nodal metastases', 'Disease', 'MESH:D009362', (76, 92))	('nodal disease', 'Disease', (174, 187))
105280	21188111	These results suggest that intratumoral electroporation of plasmid DNA encoding IL-12 could lead to systemic antitumor immune responses with minimal systemic toxicity.	('tumor', 'Disease', (113, 118))	('toxicity', 'Disease', 'MESH:D064420', (158, 166))	('lead to', 'Reg', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('toxicity', 'Disease', (158, 166))	('IL-12', 'Gene', (80, 85))	('electroporation', 'Var', (40, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (32, 37))	('IL-12', 'molecular_function', 'GO:0005143', ('80', '85'))
105300	21188111	High-dose interleukin-2 therapy is associated with substantial toxicity including hypotension, oliguria, renal insufficiency, hepatocellular damage, edema, respiratory compromise, fevers, chills, pruritis, diarrhea, myocardial infarction, sepsis, and death.	('myocardial infarction', 'Disease', (216, 237))	('edema', 'Phenotype', 'HP:0000969', (149, 154))	('diarrhea', 'Disease', 'MESH:D003967', (206, 214))	('death', 'Disease', 'MESH:D003643', (251, 256))	('respiratory compromise', 'Disease', (156, 178))	('chills', 'Disease', (188, 194))	('toxicity', 'Disease', 'MESH:D064420', (63, 71))	('myocardial infarction', 'Phenotype', 'HP:0001658', (216, 237))	('hepatocellular damage', 'Disease', 'MESH:D056486', (126, 147))	('hypotension', 'Disease', (82, 93))	('fever', 'Disease', 'MESH:D005334', (180, 185))	('fever', 'Disease', (180, 185))	('pruritis', 'Disease', 'MESH:D011537', (196, 204))	('oliguria', 'Disease', 'MESH:D009846', (95, 103))	('myocardial infarction', 'Disease', 'MESH:D009203', (216, 237))	('edema', 'Disease', 'MESH:D004487', (149, 154))	('renal insufficiency', 'Disease', 'MESH:D051437', (105, 124))	('sepsis', 'Phenotype', 'HP:0100806', (239, 245))	('renal insufficiency', 'Phenotype', 'HP:0000083', (105, 124))	('sepsis', 'Disease', 'MESH:D018805', (239, 245))	('hypotension', 'Disease', 'MESH:D007022', (82, 93))	('chills', 'Phenotype', 'HP:0025143', (188, 194))	('toxicity', 'Disease', (63, 71))	('High-dose', 'Var', (0, 9))	('edema', 'Disease', (149, 154))	('oliguria', 'Disease', (95, 103))	('fever', 'Phenotype', 'HP:0001945', (180, 185))	('hypotension', 'Phenotype', 'HP:0002615', (82, 93))	('sepsis', 'Disease', (239, 245))	('oliguria', 'Phenotype', 'HP:0100520', (95, 103))	('diarrhea', 'Phenotype', 'HP:0002014', (206, 214))	('death', 'Disease', (251, 256))	('hepatocellular damage', 'Disease', (126, 147))	('interleukin-2', 'Gene', '3558', (10, 23))	('pruritis', 'Phenotype', 'HP:0000989', (196, 204))	('fevers', 'Phenotype', 'HP:0001945', (180, 186))	('interleukin-2', 'Gene', (10, 23))	('pruritis', 'Disease', (196, 204))	('diarrhea', 'Disease', (206, 214))	('renal insufficiency', 'Disease', (105, 124))
105307	21188111	Thus anti-CTLA4 antibodies have been developed to abrogate these inhibitory interactions, favoring immune stimulation and in principle, breaking immune tolerance to melanoma.	('breaking', 'NegReg', (136, 144))	('antibodies', 'Var', (16, 26))	('CTLA4', 'Gene', '1493', (10, 15))	('abrogate', 'NegReg', (50, 58))	('favoring', 'PosReg', (90, 98))	('CTLA4', 'Gene', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('immune', 'MPA', (145, 151))	('immune stimulation', 'MPA', (99, 117))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
105312	21188111	A recent meta-analysis of 3 phase II studies of ipilimumab, CA184-008, CA184-022, and CA184-007, examined overall survival in a pretreated population.	('CA184-022', 'Var', (71, 80))	('ipilimumab', 'Chemical', 'MESH:D000074324', (48, 58))	('CA184', 'Chemical', '-', (60, 65))	('examined', 'Reg', (97, 105))	('CA184', 'Chemical', '-', (86, 91))	('overall survival', 'MPA', (106, 122))	('CA184-008', 'Var', (60, 69))	('CA184', 'Chemical', '-', (71, 76))	('CA184-007', 'Var', (86, 95))
105351	21188111	Several oncogenic mutations have been identified in cutaneous melanoma that may drive the malignant phenotype by altering downstream signaling through the PI3K/AKT/mTOR and MAP kinase pathways to decrease apoptosis and increase cell cycling.	('decrease', 'NegReg', (196, 204))	('mTOR', 'Gene', '2475', (164, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('205', '214'))	('apoptosis', 'CPA', (205, 214))	('downstream signaling', 'MPA', (122, 142))	('apoptosis', 'biological_process', 'GO:0006915', ('205', '214'))	('AKT', 'Gene', '207', (160, 163))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('PI3K', 'molecular_function', 'GO:0016303', ('155', '159'))	('increase', 'PosReg', (219, 227))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('altering', 'Reg', (113, 121))	('cutaneous melanoma', 'Disease', (52, 70))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (52, 70))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (52, 70))	('MAP', 'molecular_function', 'GO:0004239', ('173', '176'))	('cell cycling', 'CPA', (228, 240))	('MAP kinase pathways', 'Pathway', (173, 192))	('AKT', 'Gene', (160, 163))	('mTOR', 'Gene', (164, 168))	('mutations', 'Var', (18, 27))
105352	21188111	Known oncogenic mutations in melanoma include NRAS mutations, found in 10%-15% of melanomas, loss of PTEN, observed in 10%-30%, c-KIT mutations seen in 23% of acral melanomas, and activating BRAF mutations, seen in 60%-80% of cutaneous melanoma tumors (see Figure 2).	('c-KIT', 'Gene', '3815', (128, 133))	('BRAF', 'Gene', (191, 195))	('mutations', 'Var', (51, 60))	('loss', 'NegReg', (93, 97))	('PTEN', 'Gene', (101, 105))	('NRAS', 'Gene', '4893', (46, 50))	('melanoma', 'Disease', 'MESH:D008545', (29, 37))	('melanomas', 'Disease', 'MESH:D008545', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('melanoma', 'Disease', 'MESH:D008545', (236, 244))	('acral melanomas', 'Disease', 'MESH:D008545', (159, 174))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('melanomas', 'Disease', (82, 91))	('acral melanomas', 'Phenotype', 'HP:0012060', (159, 174))	('PTEN', 'Gene', '5728', (101, 105))	('activating', 'PosReg', (180, 190))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('mutations', 'Var', (134, 143))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Disease', (165, 173))	('cutaneous melanoma tumors', 'Disease', 'MESH:C562393', (226, 251))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('acral melanomas', 'Disease', (159, 174))	('NRAS', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('KIT', 'molecular_function', 'GO:0005020', ('130', '133'))	('melanoma', 'Disease', (29, 37))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('melanoma', 'Disease', (236, 244))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('cutaneous melanoma tumors', 'Disease', (226, 251))	('mutations', 'Var', (196, 205))	('acral melanoma', 'Phenotype', 'HP:0012060', (159, 173))	('melanomas', 'Disease', (165, 174))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('c-KIT', 'Gene', (128, 133))	('BRAF', 'Gene', '673', (191, 195))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
105357	21188111	PLX4032 is a novel tyrosine kinase inhibitor engineered to have a high degree of specificity for mutant BRAFV600E.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('28', '44'))	('BRAFV600E', 'Mutation', 'rs113488022', (104, 113))	('PLX4032', 'Chemical', 'MESH:D000077484', (0, 7))	('mutant', 'Var', (97, 103))	('BRAFV600E', 'Gene', (104, 113))
105361	21188111	In a retrospective analysis of biopsy specimens from 189 melanoma lesions, mutations of c-KIT exons 11, 13, and 17 were observed in 1.7% of cutaneous melanomas, 23% of acral melanomas, and 15.6% of mucosal melanomas.	('acral melanomas', 'Disease', 'MESH:D008545', (168, 183))	('melanoma lesions', 'Disease', 'MESH:D008545', (57, 73))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('observed', 'Reg', (120, 128))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanomas', 'Phenotype', 'HP:0002861', (174, 183))	('melanoma', 'Phenotype', 'HP:0002861', (206, 214))	('acral melanomas', 'Phenotype', 'HP:0012060', (168, 183))	('melanomas', 'Phenotype', 'HP:0002861', (206, 215))	('melanoma lesions', 'Disease', (57, 73))	('acral melanomas', 'Disease', (168, 183))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (140, 159))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (140, 158))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (140, 159))	('acral melanoma', 'Phenotype', 'HP:0012060', (168, 182))	('c-KIT', 'Gene', (88, 93))	('cutaneous melanomas', 'Disease', (140, 159))	('c-KIT', 'Gene', '3815', (88, 93))	('KIT', 'molecular_function', 'GO:0005020', ('90', '93'))	('mucosal melanomas', 'Disease', 'MESH:D008545', (198, 215))	('mutations', 'Var', (75, 84))	('mucosal melanomas', 'Disease', (198, 215))
105364	21188111	However, in preliminary results from an ongoing phase II trial restricted to patients with tumors harboring somatic c-KIT mutations, imatinib dosed at 400 mg twice daily induced partial tumor responses in three of five patients and the remaining two patients achieved prolonged stabilization of disease.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('c-KIT', 'Gene', '3815', (116, 121))	('KIT', 'molecular_function', 'GO:0005020', ('118', '121'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (250, 258))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (186, 191))	('patients', 'Species', '9606', (77, 85))	('imatinib', 'Chemical', 'MESH:D000068877', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', (91, 96))	('c-KIT', 'Gene', (116, 121))
105366	21188111	In addition to the phase II imatinib trial, a case report describes 70% tumor shrinkage after treatment with sunitinib in a patient with metastatic mucosal melanoma bearing a mutation in KIT exon 11.	('imatinib', 'Chemical', 'MESH:D000068877', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('tumor', 'Disease', (72, 77))	('mucosal melanoma', 'Disease', (148, 164))	('KIT', 'molecular_function', 'GO:0005020', ('187', '190'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (148, 164))	('patient', 'Species', '9606', (124, 131))	('mutation in', 'Var', (175, 186))	('sunitinib', 'Chemical', 'MESH:D000077210', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
105367	21188111	In a recent report, the c-KIT mutation L576P was associated with resistance to multiple KIT inhibitors including imatinib, nilotinib, and sorafenib, but objective tumor responses could be induced in 2 patients bearing the KIT L576P mutation after treatment with dasatinib.	('L576P', 'Mutation', 'rs121913513', (226, 231))	('L576P', 'Var', (226, 231))	('associated', 'Reg', (49, 59))	('dasatinib', 'Chemical', 'MESH:D000069439', (262, 271))	('KIT', 'molecular_function', 'GO:0005020', ('88', '91'))	('tumor', 'Disease', (163, 168))	('sorafenib', 'Chemical', 'MESH:D000077157', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('mutation L576P', 'Var', (30, 44))	('KIT', 'molecular_function', 'GO:0005020', ('26', '29'))	('patients', 'Species', '9606', (201, 209))	('nilotinib', 'Chemical', 'MESH:C498826', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('imatinib', 'Chemical', 'MESH:D000068877', (113, 121))	('L576P', 'Mutation', 'rs121913513', (39, 44))	('resistance', 'MPA', (65, 75))	('L576P', 'Var', (39, 44))	('c-KIT', 'Gene', (24, 29))	('KIT', 'molecular_function', 'GO:0005020', ('222', '225'))	('c-KIT', 'Gene', '3815', (24, 29))
105368	21188111	Currently, 6 separate trials are testing c-KIT inhibitors in patients with melanoma arising from chronically sun-damaged skin, acral melanoma, mucosal melanoma, or documented c-KIT mutant melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('KIT', 'molecular_function', 'GO:0005020', ('177', '180'))	('mucosal melanoma', 'Disease', 'MESH:D008545', (143, 159))	('patients', 'Species', '9606', (61, 69))	('sun-damaged', 'Phenotype', 'HP:0000992', (109, 120))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('acral melanoma', 'Disease', (127, 141))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('mucosal melanoma', 'Disease', (143, 159))	('KIT', 'molecular_function', 'GO:0005020', ('43', '46'))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('c-KIT', 'Gene', (175, 180))	('mutant', 'Var', (181, 187))	('acral melanoma', 'Disease', 'MESH:D008545', (127, 141))	('c-KIT', 'Gene', (41, 46))	('c-KIT', 'Gene', '3815', (175, 180))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('c-KIT', 'Gene', '3815', (41, 46))	('melanoma', 'Disease', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('acral melanoma', 'Phenotype', 'HP:0012060', (127, 141))
105375	21188111	One retrospective study that stratified for differences in age, number of brain lesions, and the presence of symptoms prior to treatment found a survival benefit of 7.3 months (P = 0.05) associated with gamma knife radiosurgery or surgical excision when combined with whole brain irradiation in comparison to whole brain irradiation alone.	('brain lesions', 'Disease', (74, 87))	('gamma knife radiosurgery', 'Var', (203, 227))	('brain lesions', 'Disease', 'MESH:D001927', (74, 87))	('surgical', 'Disease', (231, 239))